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MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS
CROSS REFERNCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application Serial
No.
61/112,152, which was filed November 6, 2008. The entire contents of U.S.
Provisional
Application Serial No. 61/112,152 is incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] The present invention relates to modulators of ATP-Binding Cassette
("ABC")
transporters or fragments thereof, including Cystic Fibrosis Transmembrane
Conductance
Regulator ("CFTC"), compositions thereof and methods therewith. The present
invention
also relates to methods of treating ABC transporter mediated diseases using
such modulators.
BACKGROUND OF THE INVENTION
[0003] ABC transporters are a family of membrane transporter proteins that
regulate the
transport of a wide variety of pharmacological agents, potentially toxic
drugs, and
xenobiotics, as well as anions. ABC transporters are homologous membrane
proteins that
bind and use cellular adenosine triphosphate (ATP) for their specific
activities. Some of
these transporters were discovered as multidrug resistance proteins (like the
MDR1-P
glycoprotein, or the multidrug resistance protein, MRP1), defending malignant
cancer cells
against chemotherapeutic agents. To date, 48 ABC Transporters have been
identified and
grouped into 7 families based on their sequence identity and function.
[0004] ABC transporters regulate a variety of important physiological roles
within the
body and provide defense against harmful environmental compounds. Because of
this, they
represent important potential drug targets for the treatment of diseases
associated with defects
in the transporter, prevention of drug transport out of the target cell, and
intervention in other
diseases in which modulation of ABC transporter activity may be beneficial.
[0005] One member of the ABC transporter family commonly associated with
disease is
the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressed in a variety of
cells
types, including absorptive and secretory epithelia cells, where it regulates
anion flux across
the membrane, as well as the activity of other ion channels and proteins. In
epithelia cells,
normal functioning of CFTR is critical for the maintenance of electrolyte
transport
throughout the body, including respiratory and digestive tissue. CFTR is
composed of
approximately 1480 amino acids that encode a protein made up of a tandem
repeat of
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transmembrane domains, each containing six transmembrane helices and a
nucleotide binding
domain. The two transmembrane domains are linked by a large, polar, regulatory
(R)-domain
with multiple phosphorylation sites that regulate channel activity and
cellular trafficking.
[0006] The gene encoding CFTR has been identified and sequenced (See Gregory,
R. J. et
al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362),
(Riordan, J. R.
et al. (1989) Science 245:1066-1073). A defect in this gene causes mutations
in CFTR
resulting in Cystic Fibrosis ("CF"), the most common fatal genetic disease in
humans. Cystic
Fibrosis affects approximately one in every 2,500 infants in the United
States. Within the
general United States population, up to 10 million people carry a single copy
of the defective
gene without apparent ill effects. In contrast, individuals with two copies of
the CF
associated gene suffer from the debilitating and fatal effects of CF,
including chronic lung
disease.
[0007] In patients with cystic fibrosis, mutations in CFTR endogenously
expressed in
respiratory epithelia leads to reduced apical anion secretion causing an
imbalance in ion and
fluid transport. The resulting decrease in anion transport contributes to
enhanced mucus
accumulation in the lung and the accompanying microbial infections that
ultimately cause
death in CF patients. In addition to respiratory disease, CF patients
typically suffer from
gastrointestinal problems and pancreatic insufficiency that, if left
untreated, results in death.
In addition, the majority of males with cystic fibrosis are infertile and
fertility is decreased
among females with cystic fibrosis. In contrast to the severe effects of two
copies of the CF
associated gene, individuals with a single copy of the CF associated gene
exhibit increased
resistance to cholera and to dehydration resulting from diarrhea - perhaps
explaining the
relatively high frequency of the CF gene within the population.
[0008] Sequence analysis of the CFTR gene of CF chromosomes has revealed a
variety of
disease causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369;
Dean, M. et al.
(1990) Cell 61:863:870; and Kerem, B-S. et al. (1989) Science 245:1073-1080;
Kerem, B-S
et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, > 1000
disease causing
mutations in the CF gene have been identified
(http://www.genet.sickkids.on.ca/cftr/). The
most prevalent mutation is a deletion of phenylalanine at position 508 of the
CFTR amino
acid sequence, and is commonly referred to as AF508-CFTR. This mutation occurs
in
approximately 70% of the cases of cystic fibrosis and is associated with a
severe disease.
[0009] The deletion of residue 508 in AF508-CFTR prevents the nascent protein
from
folding correctly. This results in the inability of the mutant protein to exit
the ER, and traffic
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to the plasma membrane. As a result, the number of channels present in the
membrane is far
less than observed in cells expressing wild-type CFTR. In addition to impaired
trafficking,
the mutation results in defective channel gating. Together, the reduced number
of channels in
the membrane and the defective gating lead to reduced anion transport across
epithelia
leading to defective ion and fluid transport. (Quinton, P. M. (1990), FASEB J.
4: 2709-
2727). Studies have shown, however, that the reduced numbers of AF508-CFTR in
the
membrane are functional, albeit less than wild-type CFTR. (Dalemans et al.
(1991), Nature
Lond. 354: 526-528; Denning et al., supra; Pasyk and Foskett (1995), J. Cell.
Biochem. 270:
12347-50). In addition to AF508-CFTR, other disease causing mutations in CFTR
that result
in defective trafficking, synthesis, and/or channel gating could be up- or
down-regulated to
alter anion secretion and modify disease progression and/or severity.
[0010] Although CFTR transports a variety of molecules in addition to anions,
it is clear
that this role (the transport of anions) represents one element in an
important mechanism of
transporting ions and water across the epithelium. The other elements include
the epithelial
Na' channel, ENaC, Na+/2C1-/K+ co-transporter, Na+-K+-ATPase pump and the
basolateral
membrane K+ channels, that are responsible for the uptake of chloride into the
cell.
[0011] These elements work together to achieve directional transport across
the
epithelium via their selective expression and localization within the cell.
Chloride absorption
takes place by the coordinated activity of ENaC and CFTR present on the apical
membrane
and the Na+-K+-ATPase pump and Cl- channels expressed on the basolateral
surface of the
cell. Secondary active transport of chloride from the luminal side leads to
the accumulation
of intracellular chloride, which can then passively leave the cell via Cl-
channels, resulting in
a vectorial transport. Arrangement of Na+/2C1-/K+ co-transporter, Na+-K+-
ATPase pump and
the basolateral membrane K+ channels on the basolateral surface and CFTR on
the luminal
side coordinate the secretion of chloride via CFTR on the luminal side.
Because water is
probably never actively transported itself, its flow across epithelia depends
on tiny
transepithelial osmotic gradients generated by the bulk flow of sodium and
chloride.
[0012] In addition to Cystic Fibrosis, modulation of CFTR activity may be
beneficial for
other diseases not directly caused by mutations in CFTR, such as secretory
diseases and other
protein folding diseases mediated by CFTR. These include, but are not limited
to, chronic
obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.
[0013] COPD is characterized by airflow limitation that is progressive and not
fully
reversible. The airflow limitation is due to mucus hypersecretion, emphysema,
and
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bronchiolitis. Activators of mutant or wild-type CFTR offer a potential
treatment of mucus
hypersecretion and impaired mucociliary clearance that is common in COPD.
Specifically,
increasing anion secretion across CFTR may facilitate fluid transport into the
airway surface
liquid to hydrate the mucus and optimized periciliary fluid viscosity. This
would lead to
enhanced mucociliary clearance and a reduction in the symptoms associated with
COPD.
Dry eye disease is characterized by a decrease in tear aqueous production and
abnormal tear
film lipid, protein and mucin profiles. There are many causes of dry eye, some
of which
include age, Lasik eye surgery, arthritis, medications, chemical/thermal bums,
allergies, and
diseases, such as Cystic Fibrosis and Sjogrens's syndrome. Increasing anion
secretion via
CFTR would enhance fluid transport from the corneal endothelial cells and
secretory glands
surrounding the eye to increase corneal hydration. This would help to
alleviate the symptoms
associated with dry eye disease. Sjogrens's syndrome is an autoimmune disease
in which the
immune system attacks moisture-producing glands throughout the body, including
the eye,
mouth, skin, respiratory tissue, liver, vagina, and gut. Symptoms, include,
dry eye, mouth,
and vagina, as well as lung disease. The disease is also associated with
rheumatoid arthritis,
systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis.
Defective protein
trafficking is believed to cause the disease, for which treatment options are
limited.
Modulators of CFTR activity may hydrate the various organs afflicted by the
disease and help
to elevate the associated symptoms.
[0014] As discussed above, it is believed that the deletion of residue 508 in
AF508-CFTR
prevents the nascent protein from folding correctly, resulting in the
inability of this mutant
protein to exit the ER, and traffic to the plasma membrane. As a result,
insufficient amounts
of the mature protein are present at the plasma membrane and chloride
transport within
epithelial tissues is significantly reduced. In fact, this cellular phenomenon
of defective ER
processing of ABC transporters by the ER machinery has been shown to be the
underlying
basis not only for CF disease, but for a wide range of other isolated and
inherited diseases.
The two ways that the ER machinery can malfunction is either by loss of
coupling to ER
export of the proteins leading to degradation, or by the ER accumulation of
these
defective/misfolded proteins [Aridor M, et al., Nature Med., 5(7), pp 745- 751
(1999);
Shastry, B.S., et al., Neurochem. International, 43, pp 1-7 (2003);
Rutishauser, J., et al., Swiss
Med Wkly, 132, pp 211-222 (2002); Morello, JP et al., TIPS, 21, pp. 466- 469
(2000); Bross
P., et al., Human Mut., 14, pp. 186-198 (1999)]. The diseases associated with
the first class
of ER malfunction are Cystic fibrosis (due to misfolded AF508-CFTR as
discussed above),
Hereditary emphysema (due to al-antitrypsin; non Piz variants), Hereditary
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hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C
deficiency, Type
1 hereditary angioedema, Lipid processing deficiencies, such as Familial
hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal
storage
diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses (due to
Lysosomal
processing enzymes), Sandhof/Tay-Sachs (due to (3-Hexosaminidase), Crigler-
Najjar type II
(due to UDP-glucuronyl-sialyc-transferase), Polyendocrinopathy/Hyperinsulemia,
Diabetes
mellitus (due to Insulin receptor), Laron dwarfism (due to Growth hormone
receptor),
Myleoperoxidase deficiency, Primary hypoparathyroidism (due to
Preproparathyroid
hormone), Melanoma (due to Tyrosinase). The diseases associated with the
latter class of ER
malfunction are Glycanosis CDG type 1, Hereditary emphysema (due to al-
Antitrypsin (PiZ
variant), Congenital hyperthyroidism, Osteogenesis imperfecta (due to Type I,
II, IV
procollagen), Hereditary hypofibrinogenemia (due to Fibrinogen), ACT
deficiency (due to
al-Antichymotrypsin), Diabetes insipidus (DI), Neurophyseal DI (due to
Vasopvessin
hormone/V2-receptor), Neprogenic DI (due to Aquaporin II), Charcot-Marie Tooth
syndrome
(due to Peripheral myelin protein 22), Perlizaeus-Merzbacher disease,
neurodegenerative
diseases such as Alzheimer's disease ( due to (3APP and presenilins),
Parkinson's disease,
Amyotrophic lateral sclerosis, Progressive supranuclear plasy, Pick's disease,
several
polyglutamine neurological disorders asuch as Huntington, Spinocerebullar
ataxia type I,
Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, and Myotonic
dystrophy, as
well as Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob
disease (due to
Prion protein processing defect), Fabry disease (due to lysosomal (X-
galactosidase A) and
Straussler-Scheinker syndrome (due to Prp processing defect).
[0015] In addition to up-regulation of CFTR activity, reducing anion secretion
by CFTR
modulators may be beneficial for the treatment of secretory diarrheas, in
which epithelial
water transport is dramatically increased as a result of secretagogue
activated chloride
transport. The mechanism involves elevation of cAMP and stimulation of CFTR.
[0016] Although there are numerous causes of diarrhea, the major consequences
of
diarrheal diseases, resulting from excessive chloride transport are common to
all, and include
dehydration, acidosis, impaired growth and death.
[0017] Acute and chronic diarrheas represent a major medical problem in many
areas of
the world. Diarrhea is both a significant factor in malnutrition and the
leading cause of death
(5,000,000 deaths/year) in children less than five years old.
[0018] Secretory diarrheas are also a dangerous condition in patients of
acquired
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immunodeficiency syndrome (AIDS) and chronic inflammatory bowel disease (IBD).
16
million travelers to developing countries from industrialized nations every
year develop
diarrhea, with the severity and number of cases of diarrhea varying depending
on the country
and area of travel.
[0019] Diarrhea in barn animals and pets such as cows, pigs and horses, sheep,
goats, cats
and dogs, also known as scours, is a major cause of death in these animals.
Diarrhea can
result from any major transition, such as weaning or physical movement, as
well as in
response to a variety of bacterial or viral infections and generally occurs
within the first few
hours of the animal's life.
[0020] The most common diarrhea causing bacteria is enterotoxogenic E-coli
(ETEC)
having the K99 pilus antigen. Common viral causes of diarrhea include
rotavirus and
coronavirus. Other infectious agents include cryptosporidium, giardia lamblia,
and
salmonella, among others.
[0021] Symptoms of rotaviral infection include excretion of watery feces,
dehydration and
weakness. Coronavirus causes a more severe illness in the newborn animals, and
has a
higher mortality rate than rotaviral infection. Often, however, a young animal
may be
infected with more than one virus or with a combination of viral and bacterial
microorganisms at one time. This dramatically increases the severity of the
disease.
[0022] Accordingly, there is a need for modulators of an ABC transporter
activity, and
compositions thereof, that can be used to modulate the activity of the ABC
transporter in the
cell membrane of a mammal.
[0023] There is a need for methods of treating ABC transporter mediated
diseases using
such modulators of ABC transporter activity.
[0024] There is a need for methods of modulating an ABC transporter activity
in an ex
vivo cell membrane of a mammal.
[0025] There is a need for modulators of CFTR activity that can be used to
modulate the
activity of CFTR in the cell membrane of a mammal.
[0026] There is a need for methods of treating CFTR-mediated diseases using
such
modulators of CFTR activity.
[0027] There is a need for methods of modulating CFTR activity in an ex vivo
cell
membrane of a mammal.
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[0028] SUMMARY OF THE INVENTION
[0029] It has now been found that compounds of this invention, and
pharmaceutically
acceptable compositions thereof, are useful as modulators of ABC transporter
activity,
particularly CTFR activity. These compounds have the general formula I:
1 ~ O
B
~ N
n(R2~
A R1
I
or a pharmaceutically acceptable salt thereof, wherein R1, R2, ring A, ring B,
and n are
defined below.
It has also now been found that compounds of this invention, and
pharmaceutically
acceptable compositions thereof, are useful as modulators of ABC transporter
activity. These
compounds have the general formula II:
R1 R1 R1
R1 R3
H
R N I ~ \
O
R R2 N R5 %
R4
II
or a pharmaceutically acceptable salt thereof, wherein R, R1, R2, R3, R4, and
R5 are defined
below.
[0030] These compounds and pharmaceutically acceptable compositions are useful
for
treating or lessening the severity of a variety of diseases, disorders, or
conditions, including,
but not limited to, cystic fibrosis, hereditary emphysema, hereditary
hemochromatosis,
coagulation-fibrinolysis deficiencies, such as protein C deficiency, Type 1
hereditary
angioedema, lipid processing deficiencies, such as familial
hypercholesterolemia, Type 1
chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, such as I-
cell
disease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-
Najjar type II,
polyendocrinopathy/hyperinsulemia, diabetes mellitus, laron dwarfism,
myleoperoxidase
deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1,
hereditary
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emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT deficiency, diabetes insipidus, neurophysiol,
nephrogenic,
Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative
diseases
such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis, progressive
supranuclear plasy, Pick's disease, several polyglutamine neurological
disorders asuch as
Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular atrophy,
dentatorubal
pallidoluysian, and myotonic dystrophy, as well as spongiform
encephalopathies, such as
hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker
syndrome, COPD,
dry-eye disease, and Sjogren's disease.
[0031] DETAILED DESCRIPTION OF THE INVENTION
[0032] I. DEFINITIONS
[0033] As used herein, the following definitions shall apply unless otherwise
indicated.
[0034] The term "ABC-transporter" as used herein means an ABC-transporter
protein or a
fragment thereof comprising at least one binding domain, wherein said protein
or fragment
thereof is present in vivo or in vitro. The term "binding domain" as used
herein means a
domain on the ABC-transporter that can bind to a modulator. See, e.g., Hwang,
T. C. et al., J.
Gen. Physiol. (1998): 111(3), 477-90.
[0035] The term "CFTR" as used herein means cystic fibrosis transmembrane
conductance
regulator or a mutation thereof capable of regulator activity, including, but
not limited to,
AF508 CFTR and G551D CFTR (see, e.g., http://www.genet.sickkids.on.ca/cftr/,
for CFTR
mutations).
[0036] The term "modulating" as used herein means increasing or decreasing,
e.g. activity,
by a measurable amount. Compounds that modulate ABC Transporter activity, such
as
CFTR activity, by increasing the activity of the ABC Transporter, e.g., a CFTR
anion
channel, are called agonists. Compounds that modulate ABC Transporter
activity, such as
CFTR activity, by decreasing the activity of the ABC Transporter, e.g., CFTR
anion channel,
are called antagonists. An agonist interacts with an ABC Transporter, such as
CFTR anion
channel, to increase the ability of the receptor to transduce an intracellular
signal in response
to endogenous ligand binding. An antagonist interacts with an ABC Transporter,
such as
CFTR, and competes with the endogenous ligand(s) or substrate(s) for binding
site(s) on the
receptor to decrease the ability of the receptor to transduce an intracellular
signal in response
to endogenous ligand binding.
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[0037] The phrase "treating or reducing the severity of an ABC Transporter
mediated
disease" refers both to treatments for diseases that are directly caused by
ABC Transporter
and/or CFTR activities and alleviation of symptoms of diseases not directly
caused by ABC
Transporter and/or CFTR anion channel activities. Examples of diseases whose
symptoms
may be affected by ABC Transporter and/or CFTR activity include, but are not
limited to,
Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis, Coagulation-
Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary
angioedema, Lipid
processing deficiencies, such as Familial hypercholesterolemia, Type 1
chylomicronemia,
Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell
disease/Pseudo-Hurler,
Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,
Myleoperoxidase
deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1,
Hereditary
emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophysiol DI,
Nephrogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,
neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease,
Amyotrophic
lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine
neurological disorders such as Huntington, Spinocerebullar ataxia type I,
Spinal and bulbar
muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well
as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease,
Fabry disease,
Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease.
[0038] For purposes of this invention, the chemical elements are identified in
accordance
with the Periodic Table of the Elements, CAS version, Handbook of Chemistry
and Physics,
75th Ed. Additionally, general principles of organic chemistry are described
in "Organic
Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999, and
"March's
Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John
Wiley & Sons,
New York: 2001, the entire contents of which are hereby incorporated by
reference.
[0039] As described herein, compounds of the invention may optionally be
substituted
with one or more substituents, such as are illustrated generally above, or as
exemplified by
particular classes, subclasses, and species of the invention.
[0040] As used herein the term "aliphatic" encompasses the terms alkyl,
alkenyl, alkynyl,
each of which being optionally substituted as set forth below.
[0041] As used herein, an "alkyl" group refers to a saturated aliphatic
hydrocarbon group
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containing 1-12 (e.g., 1-8, 1-6, or 1-4) carbon atoms. An alkyl group can be
straight or
branched. Examples of alkyl groups include, but are not limited to, methyl,
ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-
ethylhexyl. An alkyl
group can be substituted (i.e., optionally substituted) with one or more
substituents such as
halo, phospho, cycloaliphatic [e.g., cycloalkyl or cycloalkenyll,
heterocycloaliphatic [e.g.,
heterocycloalkyl or heterocycloalkenyll, aryl, heteroaryl, alkoxy, aroyl,
heteroaroyl, acyl
[e.g., (aliphatic)carbonyl, (cycloaliphatic)carbonyl, or
(heterocycloaliphatic)carbonyl], nitro,
cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino, (heterocycloalkyl)carbonylamino,
(heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino,
heteroaralkylcarbonylamino alkylaminocarbonyl, cycloalkylaminocarbonyl,
heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl],
amino
[e.g., aliphaticamino, cycloaliphaticamino, or heterocycloaliphaticamino],
sulfonyl [e.g.,
aliphatic- SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl,
sulfamide, oxo,
carboxy, carbamoyl, cycloaliphaticoxy, heterocycloaliphaticoxy, aryloxy,
heteroaryloxy,
aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.
Without
limitation, some examples of substituted alkyls include carboxyalkyl (such as
HOOC-alkyl,
alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl,
alkoxyalkyl,
acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (such as (alkyl-
S02-amino)alkyl),
aminoalkyl, amidoalkyl, (cycloaliphatic)alkyl, or haloalkyl.
[0042] As used herein, an "alkenyl" group refers to an aliphatic carbon group
that contains
2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and at least one double bond. Like
an alkyl group,
an alkenyl group can be straight or branched. Examples of an alkenyl group
include, but are
not limited to allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group
can be optionally
substituted with one or more substituents such as halo, phospho,
cycloaliphatic [e.g.,
cycloalkyl or cycloalkenyl], heterocycloaliphatic [e.g., heterocycloalkyl or
heterocycloalkenyll, aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g.,
(aliphatic)carbonyl, (cycloaliphatic)carbonyl, or
(heterocycloaliphatic)carbonyl], nitro, cyano,
amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino,
aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino alkylaminocarbonyl,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or
heteroarylaminocarbonyl], amino [e.g., aliphaticamino, cycloaliphaticamino,
heterocycloaliphaticamino, or aliphatic sulfonylamino], sulfonyl [e.g.,
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alkyl-S02-, cycloaliphatic-S02-, or aryl-S02-], sulfinyl, sulfanyl, sulfoxy,
urea, thiourea,
sulfamoyl, sulfamide, oxo, carboxy, carbamoyl, cycloaliphaticoxy,
heterocycloaliphaticoxy,
aryloxy, heteroaryloxy, aralkyloxy, heteroaralkoxy, alkoxycarbonyl,
alkylcarbonyloxy, or
hydroxy. Without limitation, some examples of substituted alkenyls include
cyanoalkenyl,
alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl,
(sulfonylamino)alkenyl (such as (alkyl-S02-amino)alkenyl), aminoalkenyl,
amidoalkenyl,
(cycloaliphatic)alkenyl, or haloalkenyl.
[0043] As used herein, an "alkynyl" group refers to an aliphatic carbon group
that contains
2-8 (e.g., 2-12, 2-6, or 2-4) carbon atoms and has at least one triple bond.
An alkynyl group
can be straight or branched. Examples of an alkynyl group include, but are not
limited to,
propargyl and butynyl. An alkynyl group can be optionally substituted with one
or more
substituents such as aroyl, heteroaroyl, alkoxy, cycloalkyloxy,
heterocycloalkyloxy, aryloxy,
heteroaryloxy, aralkyloxy, nitro, carboxy, cyano, halo, hydroxy, sulfo,
mercapto, sulfanyl
[e.g., aliphaticsulfanyl or cycloaliphaticsulfanyll, sulfinyl [e.g.,
aliphaticsulfinyl or
cycloaliphaticsulfinyll, sulfonyl [e.g., aliphatic-S02-, aliphaticamino-S02-,
or cycloaliphatic-
S02-1, amido [e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino,
cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl,
cycloalkylcarbonylamino,
arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (cycloalkylalkyl)carbonylamino,
heteroaralkylcarbonylamino, heteroarylcarbonylamino or
heteroarylaminocarbonyl], urea,
thiourea, sulfamoyl, sulfamide, alkoxycarbonyl, alkylcarbonyloxy,
cycloaliphatic,
heterocycloaliphatic, aryl, heteroaryl, acyl [e.g., (cycloaliphatic)carbonyl
or
(heterocycloaliphatic)carbonyl], amino [e.g., aliphaticamino], sulfoxy, oxo,
carboxy,
carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, or
(heteroaryl)alkoxy.
[0044] As used herein, an "amido" encompasses both "aminocarbonyl" and
"carbonylamino". These terms when used alone or in connection with another
group refer to
an amido group such as -N(Rx)-C(O)-RY or -C(O)-N(Rx)2, when used terminally,
and -C(O)-
N(Rx)- or -N(Rx)-C(O)- when used internally, wherein Rx and RY are defined
below.
Examples of amido groups include alkylamido (such as alkylcarbonylamino or
alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido,
(heteroaryl)amido,
(heterocycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido,
or
cycloalkylamido.
[0045] As used herein, an "amino" group refers to -NRxRY wherein each of Rx
and RY is
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independently hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic)aliphatic,
aryl, araliphatic,
heterocycloaliphatic, (heterocycloaliphatic)aliphatic, heteroaryl, carboxy,
sulfanyl, sulfinyl,
sulfonyl, (aliphatic)carbonyl, (cycloaliphatic)carbonyl,
((cycloaliphatic)aliphatic)carbonyl,
arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl, or
(heteroaraliphatic)carbonyl, each of which being defined herein and being
optionally
substituted. Examples of amino groups include alkylamino, dialkylamino, or
arylamino.
When the term "amino" is not the terminal group (e.g., alkylcarbonylamino), it
is represented
by -NRx-. Rx has the same meaning as defined above.
[0046] As used herein, an "aryl" group used alone or as part of a larger
moiety as in
"aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic (e.g., phenyl);
bicyclic (e.g.,
indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic
(e.g., fluorenyl
tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in
which the
monocyclic ring system is aromatic or at least one of the rings in a bicyclic
or tricyclic ring
system is aromatic. The bicyclic and tricyclic groups include benzofused 2-3
membered
carbocyclic rings. For example, a benzofused group includes phenyl fused with
two or more
C4.8 carbocyclic moieties. An aryl is optionally substituted with one or more
substituents
including aliphatic [e.g., alkyl, alkenyl, or alkynyll; cycloaliphatic;
(cycloaliphatic)aliphatic;
heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;
alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;
(araliphatic)oxy;
(heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic
carbocyclic ring of
a benzofused bicyclic or tricyclic aryl); nitro; carboxy; amido; acyl [e.g.,
(aliphatic)carbonyl;
(cycloaliphatic)carbonyl; ((cycloaliphatic)aliphatic)carbonyl;
(araliphatic)carbonyl;
(heterocycloaliphatic)carbonyl; ((heterocycloaliphatic)aliphatic)carbonyl; or
(heteroaraliphatic)carbonyl]; sulfonyl [e.g., aliphatic-S02- or amino-S02-];
sulfinyl [e.g.,
aliphatic-S(O)- or cycloaliphatic-S(O)-]; sulfanyl [e.g., aliphatic-S-1;
cyano; halo; hydroxy;
mercapto; sulfoxy; urea; thiourea; sulfamoyl; sulfamide; or carbamoyl.
Alternatively, an aryl
can be unsubstituted.
[0047] Non-limiting examples of substituted aryls include haloaryl [e.g., mono-
, di (such
as
p,m-dihaloaryl), and (trihalo)aryl]; (carboxy)aryl [e.g.,
(alkoxycarbonyl)aryl,
((aralkyl)carbonyloxy)aryl, and (alkoxycarbonyl)aryl]; (amido)aryl [e.g.,
(aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl,
(alkylcarbonyl)aminoaryl,
(arylaminocarbonyl)aryl, and (((heteroaryl)amino)carbonyl)aryl]; aminoaryl
[e.g.,
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((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl]; (cyanoalkyl)aryl;
(alkoxy)aryl;
(sulfamoyl)aryl [e.g., (aminosulfonyl)aryl]; (alkylsulfonyl)aryl; (cyano)aryl;
(hydroxyalkyl)aryl; ((alkoxy)alkyl)aryl; (hydroxy)aryl, ((carboxy)alkyl)aryl;
(((dialkyl)amino)alkyl)aryl; (nitroalkyl)aryl;
(((alkylsulfonyl)amino)alkyl)aryl;
((heterocycloaliphatic)carbonyl)aryl; ((alkylsulfonyl)alkyl)aryl;
(cyanoalkyl)aryl;
(hydroxyalkyl)aryl; (alkylcarbonyl)aryl; alkylaryl; (trihaloalkyl)aryl; p-
amino-m-
alkoxycarbonylaryl; p-amino-m-cyanoaryl; p-halo-m-aminoaryl; or (m-
(heterocycloaliphatic)-
o-(alkyl))aryl.
[0048] As used herein, an "araliphatic" such as an "aralkyl" group refers to
an aliphatic
group (e.g., a C1.4 alkyl group) that is substituted with an aryl group.
"Aliphatic," "alkyl,"
and "aryl" are defined herein. An example of an araliphatic such as an aralkyl
group is
benzyl.
[0049] As used herein, an "aralkyl" group refers to an alkyl group (e.g., a
C1.4 alkyl group)
that is substituted with an aryl group. Both "alkyl" and "aryl" have been
defined above. An
example of an aralkyl group is benzyl. An aralkyl is optionally substituted
with one or more
substituents such as aliphatic [e.g., alkyl, alkenyl, or alkynyl, including
carboxyalkyl,
hydroxyalkyl, or haloalkyl such as trifluoromethyl], cycloaliphatic [e.g.,
cycloalkyl or
cycloalkenyll, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl,
aryl, heteroaryl,
alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,
aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,
alkylcarbonyloxy,
amido [e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, or heteroaralkylcarbonylaminol, cyano, halo, hydroxy,
acyl,
mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0050] As used herein, a "bicyclic ring system" includes 8-12 (e.g., 9, 10, or
11)
membered structures that form two rings, wherein the two rings have at least
one atom in
common (e.g., 2 atoms in common). Bicyclic ring systems include
bicycloaliphatics (e.g.,
bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and
bicyclic
heteroaryls.
[0051] As used herein, a "carbocycle" or "cycloaliphatic" group encompasses a
"cycloalkyl" group and a "cycloalkenyl" group, each of which being optionally
substituted as
set forth below.
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[0052] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic
mono- or
bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbon atoms. Examples
of cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
adamantyl,
norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl,
bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl,
bicyclo[2.2.2]octyl, adamantyl,
or ((aminocarbonyl)cycloalkyl)cycloalkyl.
[0053] A "cycloalkenyl" group, as used herein, refers to a non-aromatic
carbocyclic ring
of 3-10 (e.g., 4-8) carbon atoms having one or more double bonds. Examples of
cycloalkenyl
groups include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl,
cyclooctenyl,
hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl,
bicyclo[2.2.2]octenyl,
or bicyclo[3.3.1]nonenyl.
[0054] A cycloalkyl or cycloalkenyl group can be optionally substituted with
one or more
substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or alkynyll,
cycloaliphatic,
(cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic)
aliphatic, aryl,
heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy, aryloxy,
heteroaryloxy,
(araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido
[e.g.,
(aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,
((cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino,
(araliphatic)carbonylamino,
(heterocycloaliphatic)carbonylamino,
((heterocycloaliphatic)aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,
carboxy [e.g.,
HOOC-, alkoxycarbonyl, or alkylcarbonyloxyl, acyl [e.g.,
(cycloaliphatic)carbonyl,
((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyll,
cyano, halo,
hydroxy, mercapto, sulfonyl [e.g., alkyl-S02- and aryl-S02-], sulfinyl [e.g.,
alkyl-S(O)-],
sulfanyl [e.g., alkyl-S-1, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,
or carbamoyl.
[0055] As used herein, the term "heterocycle" or "heterocycloaliphatic"
encompasses a
heterocycloalkyl group and a heterocycloalkenyl group, each of which being
optionally
substituted as set forth below.
[0056] As used herein, a "heterocycloalkyl" group refers to a 3-10 membered
mono- or
bicylic (fused or bridged) (e.g., 5- to 10-membered mono- or bicyclic)
saturated ring
structure, in which one or more of the ring atoms is a heteroatom (e.g., N, 0,
S, or
combinations thereof). Examples of a heterocycloalkyl group include piperidyl,
piperazyl,
tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-
dioxolanyl, oxazolidyl,
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isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl,
octahydrochromenyl,
octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl,
decahydroquinolinyl,
octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-
bicyclo[2.2.2]octyl, 3-aza-
bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03'7]nonyl. A monocyclic
heterocycloalkyl
group can be fused with a phenyl moiety to form structures, such as
tetrahydroisoquinoline,
which would be categorized as heteroaryls.
[0057] A "heterocycloalkenyl" group, as used herein, refers to a mono- or
bicylic (e.g., 5-
to 10-membered mono- or bicyclic) non-aromatic ring structure having one or
more double
bonds, and wherein one or more of the ring atoms is a heteroatom (e.g., N, 0,
or S).
Monocyclic and bicyclic heterocycloaliphatics are numbered according to
standard chemical
nomenclature.
[0058] A heterocycloalkyl or heterocycloalkenyl group can be optionally
substituted with
one or more substituents such as phosphor, aliphatic [e.g., alkyl, alkenyl, or
alkynyl],
cycloaliphatic, (cycloaliphatic)aliphatic, heterocycloaliphatic,
(heterocycloaliphatic)aliphatic,
aryl, heteroaryl, alkoxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy,
aryloxy,
heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl,
amino, amido
[e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino,
((cycloaliphatic)
aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino,
(heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)
aliphatic)carbonylamino,
(heteroaryl)carbonylamino, or (heteroaraliphatic)carbonylamino], nitro,
carboxy [e.g.,
HOOC-, alkoxycarbonyl, or alkylcarbonyloxyl, acyl [e.g.,
(cycloaliphatic)carbonyl,
((cycloaliphatic) aliphatic)carbonyl, (araliphatic)carbonyl,
(heterocycloaliphatic)carbonyl,
((heterocycloaliphatic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyll,
nitro, cyano, halo,
hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyll, sulfinyl
[e.g., alkylsulfinyll,
sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamide,
oxo, or
carbamoyl.
[0059] A "heteroaryl" group, as used herein, refers to a monocyclic, bicyclic,
or tricyclic
ring system having 4 to 15 ring atoms wherein one or more of the ring atoms is
a heteroatom
(e.g., N, 0, S, or combinations thereof) and in which the monocyclic ring
system is aromatic
or at least one of the rings in the bicyclic or tricyclic ring systems is
aromatic. A heteroaryl
group includes a benzofused ring system having 2 to 3 rings. For example, a
benzofused
group includes benzo fused with one or two 4 to 8 membered
heterocycloaliphatic moieties
(e.g., indolizyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl,
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quinolinyl, or isoquinolinyl). Some examples of heteroaryl are azetidinyl,
pyridyl, 1H-
indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl,
tetrazolyl, benzofuryl,
isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine,
dihydroindole,
benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl,
benzimidazolyl,
benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl,cinnolyl, phthalazyl,
quinazolyl,
quinoxalyl, isoquinolyl, 4H-quinolizyl, benzo-1,2,5-thiadiazolyl, or 1,8-
naphthyridyl.
[0060] Without limitation, monocyclic heteroaryls include furyl, thiophenyl,
2H-pyrrolyl,
pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
1,3,4-thiadiazolyl,
2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or
1,3,5-triazyl.
Monocyclic heteroaryls are numbered according to standard chemical
nomenclature.
[0061] Without limitation, bicyclic heteroaryls include indolizyl, indolyl,
isoindolyl, 3H-
indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl,
isoquinolinyl, indolizinyl,
isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl,
benzimidazyl, benzthiazolyl,
purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl,
quinazolyl, quinoxalyl,
1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to
standard
chemical nomenclature.
[0062] A heteroaryl is optionally substituted with one or more substituents
such as
aliphatic [e.g., alkyl, alkenyl, or alkynyll; cycloaliphatic;
(cycloaliphatic)aliphatic;
heterocycloaliphatic; (heterocycloaliphatic)aliphatic; aryl; heteroaryl;
alkoxy;
(cycloaliphatic)oxy; (heterocycloaliphatic)oxy; aryloxy; heteroaryloxy;
(araliphatic)oxy;
(heteroaraliphatic)oxy; aroyl; heteroaroyl; amino; oxo (on a non-aromatic
carbocyclic or
heterocyclic ring of a bicyclic or tricyclic heteroaryl); carboxy; amido; acyl
[ e.g.,
aliphaticcarbonyl; (cycloaliphatic)carbonyl;
((cycloaliphatic)aliphatic)carbonyl;
(araliphatic)carbonyl; (heterocycloaliphatic)carbonyl;
((heterocycloaliphatic)aliphatic)carbonyl; or (heteroaraliphatic)carbonyl];
sulfonyl [e.g.,
aliphaticsulfonyl or aminosulfonyl]; sulfinyl [e.g., aliphaticsulfinyl];
sulfanyl [e.g.,
aliphaticsulfanyll; nitro; cyano; halo; hydroxy; mercapto; sulfoxy; urea;
thiourea; sulfamoyl;
sulfamide; or carbamoyl. Alternatively, a heteroaryl can be unsubstituted.
[0063] Non-limiting examples of substituted heteroaryls include
(halo)heteroaryl [e.g.,
mono- and di-(halo)heteroaryl]; (carboxy)heteroaryl [e.g.,
(alkoxycarbonyl)heteroaryl];
cyanoheteroaryl; aminoheteroaryl [e.g., ((alkylsulfonyl)amino)heteroaryl and
((dialkyl)amino)heteroaryl]; (amido)heteroaryl [e.g., aminocarbonylheteroaryl,
((alkylcarbonyl)amino)heteroaryl,
((((alkyl)amino)alkyl)aminocarbonyl)heteroaryl,
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(((heteroaryl)amino)carbonyl)heteroaryl,
((heterocycloaliphatic)carbonyl)heteroaryl, and
((alkylcarbonyl)amino)heteroaryl]; (cyanoalkyl)heteroaryl; (alkoxy)heteroaryl;
(sulfamoyl)heteroaryl [e.g., (aminosulfonyl)heteroaryl]; (sulfonyl)heteroaryl
[e.g.,
(alkylsulfonyl)heteroaryl]; (hydroxyalkyl)heteroaryl; (alkoxyalkyl)heteroaryl;
(hydroxy)heteroaryl; ((carboxy)alkyl)heteroaryl; (((dialkyl) amino)
alkyl]heteroaryl;
(heterocycloaliphatic)heteroaryl; (cycloaliphatic)heteroaryl;
(nitroalkyl)heteroaryl;
(((alkylsulfonyl)amino)alkyl)heteroaryl; ((alkylsulfonyl)alkyl)heteroaryl;
(cyanoalkyl)heteroaryl; (acyl)heteroaryl [e.g., (alkylcarbonyl)heteroaryll;
(alkyl)heteroaryl,
and (haloalkyl)heteroaryl [e.g., trihaloalkylheteroaryl].
[0064] A "heteroaraliphatic" (such as a heteroaralkyl group) as used herein,
refers to an
aliphatic group (e.g., a C14 alkyl group) that is substituted with a
heteroaryl group.
"Aliphatic," "alkyl," and "heteroaryl" have been defined above.
[0065] A "heteroaralkyl" group, as used herein, refers to an alkyl group
(e.g., a C1.4 alkyl
group) that is substituted with a heteroaryl group. Both "alkyl" and
"heteroaryl" have been
defined above. A heteroaralkyl is optionally substituted with one or more
substituents such
as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as
trifluoromethyl),
alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
(heterocycloalkyl)alkyl,
aryl, heteroaryl, alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy,
heteroaryloxy,
aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy,
alkoxycarbonyl,
alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy,
acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or
carbamoyl.
[0066] As used herein, "cyclic moiety" and "cyclic group" refer to mono-, bi-,
and tri-
cyclic ring systems including cycloaliphatic, heterocycloaliphatic, aryl, or
heteroaryl, each of
which has been previously defined.
[0067] As used herein, a "bridged bicyclic ring system" refers to a bicyclic
heterocyclicaliphatic ring system or bicyclic cycloaliphatic ring system in
which the rings are
bridged. Examples of bridged bicyclic ring systems include, but are not
limited to,
adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,
bicyclo[3.3.1]nonyl,
bicyclo[3.2.3]nonyl, 2-oxabicyclo[2.2.2]octyl, 1-azabicyclo[2.2.2]octyl, 3-
azabicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03'7]nonyl. A bridged
bicyclic ring
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system can be optionally substituted with one or more substituents such as
alkyl (including
carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl,
alkynyl,
cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl,
aryl, heteroaryl,
alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,
aralkyloxy,
heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl,
alkylcarbonyloxy,
aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,
(cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino,
(heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino,
heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy,
acyl, mercapto,
alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or
carbamoyl.
[0068] As used herein, an "acyl" group refers to a formyl group or Rx-C(O)-
(such as
alkyl-C(O)-, also referred to as "alkylcarbonyl") where Rx and "alkyl" have
been defined
previously. Acetyl and pivaloyl are examples of acyl groups.
[0069] As used herein, an "aroyl" or "heteroaroyl" refers to an aryl-C(O)- or
a
heteroaryl-C(O)-. The aryl and heteroaryl portion of the aroyl or heteroaroyl
is optionally
substituted as previously defined.
[0070] As used herein, an "alkoxy" group refers to an alkyl-O- group where
"alkyl" has
been defined previously.
[0071] As used herein, a "carbamoyl" group refers to a group having the
structure
-O-CO-NR xRY or -NRx-CO-O-RZ, wherein Rx and RY have been defined above and RZ
can
be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl, or
heteroaraliphatic.
[0072] As used herein, a "carboxy" group refers to -000H, -COORx, -OC(O)H,
-OC(O)Rx, when used as a terminal group; or -OC(O)- or -C(O)O- when used as an
internal
group.
[0073] As used herein, a "haloaliphatic" group refers to an aliphatic group
substituted with
1-3 halogen. For instance, the term haloalkyl includes the group -CF3.
[0074] As used herein, a "mercapto" group refers to -SH.
[0075] As used herein, a "sulfo" group refers to -SO3H or -SO3Rx when used
terminally or
-S(O)3- when used internally.
[0076] As used herein, a "sulfamide" group refers to the structure -NRx-S(0)2-
NRYRZ
when used terminally and -NRx-S(0)2-NRY- when used internally, wherein Rx, RY,
and RZ
have been defined above.
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[0077] As used herein, a "sulfonamide" group refers to the structure -S(0)2-
NRxRY or
-NRx-S(0)2-RZ when used terminally; or -S(0)2-NRx- or -NRx -S(O)2- when used
internally,
wherein Rx, RY, and RZ are defined above.
[0078] As used herein a "sulfanyl" group refers to -S-Rx when used terminally
and -S-
when used internally, wherein Rx has been defined above. Examples of sulfanyls
include
aliphatic-S-, cycloaliphatic-S-, aryl-S-, or the like.
[0079] As used herein a "sulfinyl" group refers to -S(O)-Rx when used
terminally and -
S(O)- when used internally, wherein Rx has been defined above. Exemplary
sulfinyl groups
include aliphatic-S(O)-, aryl-S(O)-, (cycloaliphatic(aliphatic))-S(O)-,
cycloalkyl-S(O)-,
heterocycloaliphatic-S(O)-, heteroaryl-S(O)-, or the like.
[0080] As used herein, a "sulfonyl" group refers to-S(0)2-Rx when used
terminally and
-S(O)2- when used internally, wherein Rx has been defined above. Exemplary
sulfonyl
groups include aliphatic-S(0)2-, aryl-S(O)2-, (cycloaliphatic(aliphatic))-
S(0)2-,
cycloaliphatic-S(0)2-, heterocycloaliphatic-S(0)2-, heteroaryl-S(0)2-,
(cycloaliphatic(amido(aliphatic)))-S(O)2-or the like.
[0081] As used herein, a "sulfoxy" group refers to -0-SO-Rx or -SO-0-Rx, when
used
terminally and -0-S(O)- or -S(O)-O- when used internally, where Rx has been
defined above.
[0082] As used herein, a "halogen" or "halo" group refers to fluorine,
chlorine, bromine or
iodine.
[0083] As used herein, an "alkoxycarbonyl," which is encompassed by the term
carboxy,
used alone or in connection with another group refers to a group such as alkyl-
O-C(O)-.
[0084] As used herein, an "alkoxyalkyl" refers to an alkyl group such as alkyl-
0-alkyl-,
wherein alkyl has been defined above.
[0085] As used herein, a "carbonyl" refer to -C(O)-.
[0086] As used herein, an "oxo" refers to =0.
[0087] As used herein, the term "phospho" refers to phosphinates and
phosphonates.
Examples of phosphinates and phosphonates include -P(O)(RP)2, wherein RP is
aliphatic,
alkoxy, aryloxy, heteroaryloxy, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy
aryl,
heteroaryl, cycloaliphatic or amino.
[0088] As used herein, an "aminoalkyl" refers to the structure (Rx)2N-alkyl-.
[0089] As used herein, a "cyanoalkyl" refers to the structure (NC)-alkyl-.
19
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[0090] As used herein, a "urea" group refers to the structure -NR'-CO-NRYRZ
and a
"thiourea" group refers to the structure -NRx-CS-NRYRZ when used terminally
and -NRx-
CO-NRY- or
-NRx-CS-NRY- when used internally, wherein Rx, RY, and RZ have been defined
above.
[0091] As used herein, a "guanidine" group refers to the structure -
N=C(N(RXRY))N(RXRY) or
-NRx-C(=NRx)NRxRY wherein Rx and RY have been defined above.
[0092] As used herein, the term "amidino" group refers to the structure -
C=(NRX)N(RXRY) wherein Rx and RY have been defined above.
[0093] In general, the term "vicinal" refers to the placement of substituents
on a group that
includes two or more carbon atoms, wherein the substituents are attached to
adjacent carbon
atoms.
[0094] In general, the term "geminal" refers to the placement of substituents
on a group
that includes two or more carbon atoms, wherein the substituents are attached
to the same
carbon atom.
[0095] The terms "terminally" and "internally" refer to the location of a
group within a
substituent. A group is terminal when the group is present at the end of the
substituent not
further bonded to the rest of the chemical structure. Carboxyalkyl, i.e.,
RXO(O)C-alkyl is an
example of a carboxy group used terminally. A group is internal when the group
is present in
the middle of a substituent of the chemical structure. Alkylcarboxy (e.g.,
alkyl-C(O)O- or
alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-
aryl-) are
examples of carboxy groups used internally.
[0096] As used herein, an "aliphatic chain" refers to a branched or straight
aliphatic group
(e.g., alkyl groups, alkenyl groups, or alkynyl groups). A straight aliphatic
chain has the
structure
-[CH2]v-, where v is 1-12. A branched aliphatic chain is a straight aliphatic
chain that is
substituted with one or more aliphatic groups. A branched aliphatic chain has
the structure
-[CQQ]v- where each Q is independently a hydrogen or an aliphatic group;
however, Q shall
be an aliphatic group in at least one instance. The term aliphatic chain
includes alkyl chains,
alkenyl chains, and alkynyl chains, where alkyl, alkenyl, and alkynyl are
defined above.
[0097] The phrase "optionally substituted" is used interchangeably with the
phrase
"substituted or unsubstituted." As described herein, compounds of the
invention can
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optionally be substituted with one or more substituents, such as are
illustrated generally
above, or as exemplified by particular classes, subclasses, and species of the
invention. As
described herein, the variables R1, R2, and R3, and other variables contained
in formulae
described herein encompass specific groups, such as alkyl and aryl. Unless
otherwise noted,
each of the specific groups for the variables R1, R2, and R3, and other
variables contained
therein can be optionally substituted with one or more substituents described
herein. Each
substituent of a specific group is further optionally substituted with one to
three of halo,
cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic,
heterocycloaliphatic,
heteroaryl, haloalkyl, and alkyl. For instance, an alkyl group can be
substituted with
alkylsulfanyl and the alkylsulfanyl can be optionally substituted with one to
three of halo,
cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an
additional
example, the cycloalkyl portion of a (cycloalkyl)carbonylamino can be
optionally substituted
with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and
alkyl. When two
alkoxy groups are bound to the same atom or adjacent atoms, the two alkxoy
groups can form
a ring together with the atom(s) to which they are bound.
[0098] In general, the term "substituted," whether preceded by the term
"optionally" or
not, refers to the replacement of hydrogen radicals in a given structure with
the radical of a
specified substituent. Specific substituents are described above in the
definitions and below
in the description of compounds and examples thereof. Unless otherwise
indicated, an
optionally substituted group can have a substituent at each substitutable
position of the group,
and when more than one position in any given structure can be substituted with
more than
one substituent selected from a specified group, the substituent can be either
the same or
different at every position. A ring substituent, such as a heterocycloalkyl,
can be bound to
another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system,
e.g., both rings share
one common atom. As one of ordinary skill in the art will recognize,
combinations of
substituents envisioned by this invention are those combinations that result
in the formation
of stable or chemically feasible compounds.
[0099] The phrase "stable or chemically feasible," as used herein, refers to
compounds
that are not substantially altered when subjected to conditions to allow for
their production,
detection, and preferably their recovery, purification, and use for one or
more of the purposes
disclosed herein. In some embodiments, a stable compound or chemically
feasible compound
is one that is not substantially altered when kept at a temperature of 40 C
or less, in the
absence of moisture or other chemically reactive conditions, for at least a
week.
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[00100] As used herein, an "effective amount" is defined as the amount
required to confer a
therapeutic effect on the treated patient, and is typically determined based
on age, surface
area, weight, and condition of the patient. The interrelationship of dosages
for animals and
humans (based on milligrams per meter squared of body surface) is described by
Freireich et
al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be
approximately
determined from height and weight of the patient. See, e.g., Scientific
Tables, Geigy
Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient"
refers to a
mammal, including a human.
[00101] Unless otherwise stated, structures depicted herein are also meant to
include all
isomeric (e.g., enantiomeric, diastereomeric, and geometric (or
conformational)) forms of the
structure; for example, the R and S configurations for each asymmetric center,
(Z) and (E)
double bond isomers, and (Z) and (E) conformational isomers. Therefore, single
stereochemical isomers as well as enantiomeric, diastereomeric, and geometric
(or
conformational) mixtures of the present compounds are within the scope of the
invention.
Unless otherwise stated, all tautomeric forms of the compounds of the
invention are within
the scope of the invention. Additionally, unless otherwise stated, structures
depicted herein
are also meant to include compounds that differ only in the presence of one or
more
isotopically enriched atoms. For example, compounds having the present
structures except
for the replacement of hydrogen by deuterium or tritium, or the replacement of
a carbon by a
13C- or 14C-enriched carbon are within the scope of this invention. Such
compounds are
useful, for example, as analytical tools or probes in biological assays, or as
therapeutic
agents.
[00102] Compounds of the present invention are useful modulators of ABC
transporters
and are useful in the treatment of ABC transporter mediated diseases.
[00103] II. COMPOUNDS
[00104] A. Generic Compounds
[00105] The present invention relates to compounds of formula I useful as
modulators of
ABC transporter activity:
1 ~ O
~ N
n(R2~
A Ri
22
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I
or a pharmaceutically acceptable salt thereof.
[00106] R1 is -ZAR4, wherein each ZA is independently a bond or an optionally
substituted
branched or straight C1.6 aliphatic chain wherein up to two carbon units of ZA
are optionally
and independently replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -C02-, -OCO-, -
NRACOZ-,
-0-, -NR ACONRA-, -OCONRA-, -NR ANRA-, -NRACO-, -5-, -SO-, -S02-, -NRA-, -
SO2NRA-,
-NRAS02-, or -NRASOZNRA-. Each R4 is independently RA, halo, -OH, -NH2, -NO2, -
CN, or
-OCF3. Each RA is independently hydrogen, an optionally substituted aliphatic,
an optionally
substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally
substituted aryl, or an optionally substituted heteroaryl.
[00107] R2 is -ZBR5, wherein each ZB is independently a bond or an optionally
substituted
branched or straight C1.6 aliphatic chain wherein up to two carbon units of ZB
are optionally
and independently replaced by -CO-, -CS-, -CONRB-, -CONRBNRB-, -CO2-, -OCO-, -
NR B C02-,
-0-, -NR BCONRB-, -OCONRB-, -NR BNRB-, -NRBCO-, -5-, -SO-, -SO2-, -NRB-, -
SO2NRB-,
-NRBSOZ-, or -NR BS02NRB-. Each R5 is independently RB, halo, -OH, -NH2, -NO2,
-CN, -
CF3, or -OCF3. Each RB is independently hydrogen, an optionally substituted
aliphatic, an
optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an
optionally substituted aryl, or an optionally substituted heteroaryl.
Alternatively, any two
adjacent R2 groups together with the atoms to which they are attached form an
optionally
substituted carbocycle or an optionally substituted heterocycle.
[00108] Ring A is an optionally substituted 3-7 membered monocyclic ring
having 0-3
heteroatoms selected from N, 0, and S.
[00109] Ring B is a group having formula la:
R'3
N
la
or a pharmaceutically acceptable salt thereof, wherein p is 0-3 and each R3
and R'3 is
23
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WO 2010/054138 PCT/US2009/063475
independently -ZcR6, where each Zc is independently a bond or an optionally
substituted
branched or straight C1.6 aliphatic chain wherein up to two carbon units of ZC
are optionally
and independently replaced by -CO-, -CS-, -CONRc-, -CONRcNRc-, -C02-, -OCO-, -
NRcCOz-, -0-,
-NRcCONRc-, -OCONRc-, -NRcNRc-, -NRcCO-, -5-, -SO-, -S02-, -NRc-, -SO2NRc-,
-NRcSO2-, or -NRcS02NRc-. Each R6 is independently Rc, halo, -OH, -NH2, -NO2, -
CN, or
-OCF3. Each Rc is independently hydrogen, an optionally substituted aliphatic,
an optionally
substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally
substituted aryl, or an optionally substituted heteroaryl. Alternatively, any
two adjacent R3
groups together with the atoms to which they are attached form an optionally
substituted
carbocycle or an optionally substituted heterocycle. Furthermore, R'3 and an
adjacent R3
group, together with the atoms to which they are attached, form an optionally
substituted
heterocycle.
[00110] n is 1-3.
[00111] However, in several embodiments, when ring A is unsubstituted
cyclopentyl, n is
1, R2 is 4-chloro, and R1 is hydrogen, then ring B is not 2-(tertbutyl)indol-5-
yl, or (2,6-
dichlorophenyl(carbonyl))-3-methyl-lH-indol-5-yl; and when ring A is
unsubstituted
cyclopentyl, n is 0, and R1 is hydrogen, then ring B is not
O
N O-_
N HN /
N'\ 0
or
O
/ OH
/ ON
[00112] B. Specific Compounds
[00113] 1. R] Group
[00114] R1 is -ZAR4, wherein each ZA is independently a bond or an optionally
substituted
branched or straight C1_6 aliphatic chain wherein up to two carbon units of ZA
are optionally
and independently replaced by -CO-, -CS-, -CONRA-, -CONRANRA-, -C02-, -OCO-, -
NRAC02-,
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-0-, -NRACONRA-, -OCONRA-, -NRANRA-, -NRACO-, -5-, -SO-, -S02-, -NRA , -S02NRA
,
-NRASO2-, or -NRASOZNRA-. Each R4 is independently RA, halo, -OH, -NH2, -NO2, -
CN, or
-OCF3. Each RA is independently hydrogen, an optionally substituted aliphatic,
an optionally
substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally
substituted aryl, or an optionally substituted heteroaryl.
[00115] In several embodiments, R1 is -ZAR4, wherein each ZA is independently
a bond or
an optionally substituted branched or straight C1_6 aliphatic chain and each
R4 is hydrogen.
[00116] In other embodiments, R1 is -ZAR4, wherein each ZA is a bond and each
R4 is
hydrogen.
[00117] 2. R2 Group
[00118] Each R2 is independently -ZBR5, wherein each ZB is independently a
bond or an
optionally substituted branched or straight C1.6 aliphatic chain wherein up to
two carbon units
of ZB are optionally and independently replaced by -CO-, -CS-, -CONRB-, -
CONRBNR]3-, -
C02-9
-OCO-, -NRBC02-, -0-, -NRBCONRB-, -OCONRB-, -NRBNRB-, -NRBCO-, -5-, -SO-9 -SO2-
,
-NRB-, -S02NRB-, -NRBS02-, or -NRBS02NRB-. Each R5 is independently RB, halo, -
OH, -
NH29
-NO2, -CN, -CF3, or -OCF3. Each RB is independently hydrogen, an optionally
substituted
aliphatic, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally
substituted heteroaryl.
Alternatively, any two adjacent R2 groups together with the atoms to which
they are attached
form an optionally substituted carbocycle or an optionally substituted
heterocycle.
[00119] In several embodiments, R2 is an optionally substituted aliphatic. For
example, R2
is an optionally substituted branched or straight C1.6 aliphatic chain. In
other examples, R2 is
an optionally substituted branched or straight C1.6 alkyl chain, an optionally
substituted
branched or straight C2_6 alkenyl chain, or an optionally substituted branched
or straight C2_6
alkynyl chain. In alternative embodiments, R2 is a branched or straight C1.6
aliphatic chain
that is optionally substituted with 1-3 of halo, hydroxy, cyano,
cycloaliphatic,
heterocycloaliphatic, aryl, heteroaryl, or combinations thereof. For example,
R2 is a branched
or straight C1_6 alkyl that is optionally substituted with 1-3 of halo,
hydroxy, cyano,
cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, or combinations
thereof. In still other
examples, R2 is a methyl, ethyl, propyl, butyl, isopropyl, or tert-butyl, each
of which is
optionally substituted with 1-3 of halo, hydroxy, cyano, aryl, heteroaryl,
cycloaliphatic, or
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heterocycloaliphatic. In still other examples, R2 is a methyl, ethyl, propyl,
butyl, isopropyl,
or tert-butyl, each of which is unsubstituted.
[00120] In several other embodiments, R2 is an optionally substituted branched
or straight
C1_5 alkoxy. For example, R2 is a C1_5 alkoxy that is optionally substituted
with 1-3 of
hydroxy, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, or
combinations thereof. In
other examples, R2 is a methoxy, ethoxy, propoxy, butoxy, or pentoxy, each of
which is
optionally substituted with 1-3 of hydroxy, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, or combinations thereof.
[00121] In other embodiments, R2 is hydroxy, halo, or cyano.
[00122] In several embodiments, R2 is -ZBR5, and ZB is independently a bond or
an
optionally substituted branched or straight C14 aliphatic chain wherein up to
two carbon units
of ZB are optionally and independently replaced by -C(O)-, -0-, -5-, -S(O)Z-,
or -NH-, and R5
is RB, halo,
-OH9 -NH2, -NO2, -CN, -CF3, or -OCF3, and RB is hydrogen or aryl.
[00123] In several embodiments, two adjacent R2 groups form an optionally
substituted
carbocycle or an optionally substituted heterocycle. For example, two adjacent
R2 groups
form an optionally substituted carbocycle or an optionally substituted
heterocycle, either of
which is fused to the phenyl of formula I, wherein the carbocycle or
heterocycle has formula
lb:
Z, Z2
Z3NZ
Z45
lb
[00124] Each of Z1, Z2, Z3, Z4, and Z5 is independently a bond, -CR7R'7-, -NR7-
, or -0-;
each R7 is independently -ZDR8, wherein each ZD is independently an optionally
substituted
branched or straight C1.6 aliphatic chain wherein up to two carbon units of ZD
are optionally
and independently replaced by -CO-, -CS-, -CONRD-, -C02-9 -OCO-, -NRDCOZ-, -0-
,
-NR DCONRD-, -OCONRD-, -NR DNRD-, -NRDCO-, -5-, -SO-9 -SO2-, -NRD-, -SOZNRD-,
-NR DSOZ-, or -NR DS02NRD-. Each R8 is independently RD, halo, -OH, -NH2, -
NO2, -CN9 -
CF3, or -OCF3. Each RD is independently hydrogen, an optionally substituted
cycloaliphatic,
an optionally substituted heterocycloaliphatic, an optionally substituted
aryl, or an optionally
26
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WO 2010/054138 PCT/US2009/063475
substituted heteroaryl. Each R'7 is independently hydrogen, optionally
substituted C1.6
aliphatic, hydroxy, halo, cyano, nitro, or combinations thereof.
Alternatively, any two
adjacent R7 groups together with the atoms to which they are attached form an
optionally
substituted 3-7 membered carbocyclic ring, such as an optionally substituted
cyclobutyl ring,
or any two R7 and R'7 groups together with the atom or atoms to which they are
attached form
an optionally substituted 3-7 membered carbocyclic ring or a heterocarbocyclic
ring.
[00125] In several other examples, two adjacent R2 groups form an optionally
substituted
carbocycle. For example, two adjacent R2 groups form an optionally substituted
5-7
membered carbocycle that is optionally substituted with 1-3 of halo, hydroxy,
cyano, oxo,
cyano, alkoxy, alkyl, or combinations thereof. In another example, two
adjacent R2 groups
form a 5-6 membered carbocycle that is optionally substituted with 1-3 of
halo, hydroxy,
cyano, oxo, cyano, alkoxy, alkyl, or combinations thereof. In still another
example, two
adjacent R2 groups form an unsubstituted 5-7 membered carbocycle.
[00126] In alternative examples, two adjacent R2 groups form an optionally
substituted
heterocycle. For instance, two adjacent R2 groups form an optionally
substituted 5-7
membered heterocycle having 1-3 heteroatoms independently selected from N, 0,
and S. In
several examples, two adjacent R2 groups form an optionally substituted 5-6
membered
heterocycle having 1-2 oxygen atoms. In other examples, two adjacent R2 groups
form an
unsubstituted 5-7 membered heterocycle having 1-2 oxygen atoms. In other
embodiments,
two adjacent R2 groups form a heterocyclic ring selected from:
O ,O O `1 O 1% N N
F2C` I N < :NN%
~ 0:a, XA1 XA2 XA3 XA4 XA5 XA6
cu; O= N,,
o<: O
XA7 XA8 XA9 XA10 M1 XA12
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Q
CO
N '0
N s~.. , O 0 OH
XA13 XA14 XA15 XA16 XA17 XA18
)[;
\\ \\ and U I .
N N .
XA19 XA20 XA21
[00127] In alternative examples, two adjacent R2 groups form an optionally
substituted
carbocycle or an optionally substituted heterocycle, and a third R2 group is
attached to any
chemically feasible position on the phenyl of formula I. For instance, an
optionally
substituted carbocycle or an optionally substituted heterocycle, both of which
is formed by
two adjacent R2 groups; a third R2 group; and the phenyl of formula I form a
group having
formula Ic:
Z2 Z1 / R2
Z3
Z4-Zs ~y \
Ic
[00128] Z1, Z2, Z3, Z4, and Z5 has been defined above in formula Ib, and R2
has been
defined above in formula I.
[00129] In several embodiments, each R2 group is independently selected from
hydrogen,
halo,
-OCH3, -OH, -CH2OH, -CH3, and -OCF3, and/or two adjacent R2 groups together
with the
atoms to which they are attached form
0 0 0 `LC N N
O N N
XA1 XA2 XA3 XA4 XA5 XA6
28
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
0=.~ N%%
1xal 00 O H O. N:11;~"
XA7 XA8 XA9 XA10 XA11 XA12
O
(;0:1
N O 0 OH
XA13 XA14 XA15 XA16 XA17 XA18
O N `',z H
'3
N õ
\\ al <\N and <31 . .
XA19 XA20 XA21
[00130] In other embodiments, R2 is at least one selected from hydrogen, halo,
methoxy,
phenylmethoxy, hydroxy, hydroxymethyl, trifluoromethoxy, and methyl.
[00131] In some embodiments, two adjacent R2 groups, together with the atoms
to which
they are attached, form
<O-al F2C
or O
XA1 XA2
[00132] 3. Ring A
[00133] Ring A is an optionally substituted 3-7 membered monocyclic ring
having 0-3
heteroatoms selected from N, 0, and S.
[00134] In several embodiments, ring A is an optionally substituted 3-7
membered
monocyclic cycloaliphatic. For example, ring A is a cyclopropyl, cyclobutyl,
cyclopentyl,
cyclohexyl, or cycloheptyl, each of which is optionally substituted with 1-3
of halo, hydroxy,
C1_5 aliphatic, or combinations thereof.
[00135] In other embodiments, ring A is an optionally substituted 3-7 membered
monocyclic heterocycloaliphatic. For example, ring A is an optionally
substituted 3-7
membered monocyclic heterocycloaliphatic having 1-2 heteroatoms independently
selected
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from N, 0, and S. In other examples, ring A is tetrahydrofuran-yl, tetrahydro-
2H-pyran-yl,
pyrrolidone-yl, or piperidine-yl, each of which is optionally substituted.
[00136] In still other examples, ring A is selected from
,(R8)q /(R8)q (R8)q R8)q g(R8)q
XB1 XB2 XB3 XB4 XB5
NX, (R8)q HN(R8)q HN (R8)q (R8)q
HN
XB6 XB7 XB8 XB9
H
N~~(R8)q HN'~j(R8)q R8)q O (R8)q
HN
XB10 XB11 XB12 XB13
0--\/(R8)q (R8)q (R8)q (R8)q
O
XB14 XB15 XB16 XB17
(R8)q HN_ (R8)q HN (R8)q (R8)q
S HN
s'_ z~ rr's and
XB18 XB19 XB20 XB21
[00137] Each R8 is independently -ZER9, wherein each ZE is independently a
bond or an
optionally substituted branched or straight Ci_s aliphatic chain wherein up to
two carbon units
of ZE are optionally and independently replaced by -CO-, -CS-, -CONRE-, -CO2-,
-OCO-,
-NREC02-, -0-, -NR ECONRE-, -OCONRE-, -NR ENRE-, -NRECO-, -5-, -SO-, -SO2-, -
NRE-,
-S02NRE-, -NRES02-, or -NRESOZNRE-, each R9 is independently RE, -OH9 -NH2, -
NO2, -
CN9
-CF3, oxo, or -OCF3. Each RE is independently hydrogen, an optionally
substituted
cycloaliphatic, an optionally substituted heterocycloaliphatic, an optionally
substituted aryl,
or an optionally substituted heteroaryl.
[00138] q is 0-5.
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[00139] In other embodiments, ring A is one selected from
S"S
XC1 XC2 XC3 XC4 XC5
O
and
XC6 XC4
[00140] In several embodiments, ring A is
[00141] 4. RingBB
[00142] Ring B is a group having formula la:
R'
(R3)p
la
or a pharmaceutically acceptable salt thereof, wherein p is 0-3.
[00143] Each R3 and R'3 is independently -ZCR6, where each Zc is independently
a bond or
an optionally substituted branched or straight C1.6 aliphatic chain wherein up
to two carbon
units of Zc are optionally and independently replaced by -CO-, -CS-, -CONRc-, -
CONRcNRc-, -C02-,
-OCO-, -NRcCO2-, -0-, -NRcCONRc-, -OCONRc-, -NRcNRc-, -NRcCO-, -5-, -SO-, -SO2-
,
-NRc-, -SO2NRc-, -NRcSO2-, or -NRcS02NRc-. Each R6 is independently Rc, halo, -
OH, -
NH2, -NO2, -CN, or -OCF3. Each Rc is independently hydrogen, an optionally
substituted
aliphatic, an optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an optionally substituted aryl, or an optionally
substituted heteroaryl.
Alternatively, any two adjacent R3 groups together with the atoms to which
they are attached
form an optionally substituted carbocycle or an optionally substituted
heterocycle, or R'3 and
an adjacent R3, i.e., attached to the 2 position of the indole of formula Ia,
together with the
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atoms to which they are attached form an optionally substituted heterocycle.
[00144] In several embodiments, ring B is
3 R3
N R'3 N R'3 N
(R2o)q
- N - ~ ~ - N I
(R3)p \J \ / (R3)p I \ / (R3)p-1
X (R )P or
[00145] wherein q is 0-3 and each R20 is -ZGR21, where each ZG is
independently a bond or
an optionally substituted branched or straight C1-5 aliphatic chain wherein up
to two carbon
units of ZG are optionally and independently replaced by -CO-, -CS-, -CONRG-, -
C02-, -
OCO-,
-NRGCO2-, -0-, -OCONRG-, -NR GNRG-, -NRGCO-, -5-, -SO-, -S02-, -NRG-, -SO2NRG-
,
-NRGSO2-, or -NR GS02NRG-. Each R21 is independently RG, halo, -OH, -NH2, -
NO2, -CN, or
-OCF3. Each RG is independently hydrogen, an optionally substituted aliphatic,
an optionally
substituted cycloaliphatic, an optionally substituted heterocycloaliphatic, an
optionally
substituted aryl, or an optionally substituted heteroaryl.
[00146] For example, ring B is
N N N H
H (R2o)q
- \J _ N\I' \J r'- N I
(R3)p \ (R3)p
3)p 3)p or
[00147] In several embodiments, R'3 is hydrogen and R3 is attached to the 2,
3, 4, 6, or 7
position of the indole of formula Ia. In several other examples, R3 is
attached to the 2 or 3
position of the indole of formula Ia, and R3 is independently an optionally
substituted
aliphatic. For instance, R3 is an optionally substituted acyl group. In
several instances, R3 is
an optionally substituted (alkoxy)carbonyl. In other instances, R3 is
(methoxy)carbonyl,
(ethoxy)carbonyl, (propoxy)carbonyl, or (butoxy)carbonyl, each of which is
optionally
substituted with 1-3 of halo, hydroxy, or combinations thereof. In other
instances, R3 is an
optionally substituted (aliphatic)carbonyl. For example, R3 is an optionally
substituted
(alkyl)carbonyl that is optionally substituted with 1-3 of halo, hydroxy, or
combinations
thereof . In other examples, R3 is (methyl)carbonyl, (ethyl)carbonyl,
(propyl)carbonyl, or
(butyl)carbonyl, each of which is optionally substituted with 1-3 of halo,
hydroxy, or
32
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
combinations thereof.
[00148] In several embodiments, R3 is an optionally substituted
(cycloaliphatic)carbonyl or
an optionally substituted (heterocycloaliphatic)carbonyl. In several examples,
R3 is an
optionally substituted (C3_7 cycloaliphatic)carbonyl. For example, R3 is a
(cyclopropyl)carbonyl, (cyclobutyl)carbonyl, (cyclopentyl)carbonyl,
(cyclohexyl)carbonyl, or
(cycloheptyl)carbonyl, each of which is optionally substituted with aliphatic,
halo, hydroxy,
nitro, cyano, or combinations thereof. In several alternative examples, R3 is
an optionally
substituted (heterocycloaliphatic)carbonyl. For example, R3 is an optionally
substituted
(heterocycloaliphatic)carbonyl having 1-3 heteroatoms independently selected
from N, 0,
and S. In other examples, R3 is an optionally substituted
(heterocycloaliphatic)carbonyl
having 1-3 heteroatoms independently selected from N and O. In still other
examples, R3 is
an optionally substituted 4-7 membered monocyclic
(heterocycloaliphatic)carbonyl having 1-
3 heteroatoms independently selected from N and O. Alternatively, R3 is
(piperidine-l-
yl,)carbonyl, (pyrrolidine-1-yl)carbonyl, or (morpholine-4-yl)carbonyl,
(piperazine-l-
yl)carbonyl, each of which is optionally substituted with 1-3 of halo,
hydroxy, cyano, nitro,
or aliphatic.
[00149] In still other instances, R3 is optionally substituted
(aliphatic)amido such as
(aliphatic(amino(carbonyl)) that is attached to the 2 or 3 position on the
indole ring of
formula Ia. In some embodiments, R3 is an optionally substituted
(alkyl(amino))carbonyl that
is attached to the 2 or 3 position on the indole ring of formula Ia. In other
embodiments, R3 is
an optionally substituted straight or branched (aliphatic(amino))carbonyl that
is attached to
the 2 or 3 position on the indole ring of formula Ia. In several examples, R3
is (N,N-
dimethyl(amino))carbonyl, (methyl(amino))carbonyl, (ethyl(amino))carbonyl,
(propyl(amino))carbonyl, (prop-2-yl(amino))carbonyl, (dimethyl(but-2-
yl(amino)))carbonyl,
(tertbutyl(amino))carbonyl, (butyl(amino))carbonyl, each of which is
optionally substituted
with 1-3 of halo, hydroxy, cycloaliphatic, heterocycloaliphatic, aryl,
heteroaryl, or
combinations thereof.
[00150] In other embodiments, R3 is an optionally substituted
(alkoxy)carbonyl. For
example, R3 is (methoxy)carbonyl, (ethoxy)carbonyl, (propoxy)carbonyl, or
(butoxy)carbonyl, each of which is optionally substituted with 1-3 of halo,
hydroxy, or
combinations thereof. In several instances, R3 is an optionally substituted
straight or
branched C1.6 aliphatic. For example, R3 is an optionally substituted straight
or branched C1.6
alkyl. In other examples, R3 is independently an optionally substituted
methyl, ethyl, propyl,
33
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
butyl, isopropyl, or tertbutyl, each of which is optionally substituted with 1-
3 of halo,
hydroxy, cyano, nitro, or combination thereof. In other embodiments, R3 is an
optionally
substituted C3.6 cycloaliphatic. Exemplary embodiments include cyclopropyl, 1-
methyl-
cycloprop-1-yl, etc. In other examples, p is 2 and the two R3 substituents are
attached to the
indole of formula la at the 2,4- or 2,6- or 2,7- positions. Exemplary
embodiments include 6-
F, 3-(optionally substituted C1_6 aliphatic or C3_6 cycloaliphatic); 7-F-2-(-
(optionally
substituted C1_6 aliphatic or C3.6 cycloaliphatic)), 4F-2-(optionally
substituted C1_6 aliphatic or
C3.6 cycloaliphatic); 7-CN-2-(optionally substituted C1_6 aliphatic or C3.6
cycloaliphatic); 7-
Me-2-(optionally substituted C1_6 aliphatic or C3_6 cycloaliphatic) and 7-OMe-
2-(optionally
substituted C1_6 aliphatic or C3.6 cycloaliphatic).
[00151] In several embodiments, R3 is hydrogen.
[00152] In several embodiments, R3 is one selected from:
-H, -CH3, -CH2OH, -CH2CH3, -CH2CH2OH, -CH2CH2CH3, -NH2, halo, -OCH3, -CN, -
CF3,
-C(O)OCH2CH3, -S(O)2CH3, -CH2NH2, -C(O)NH2,
OH
S O O
OH
- - `~ / AKNN
.~~ H H
O OH 0
II ~O O AIN"O
O / \N NN
O H H H
O O O O
O O
~
H H I\ N N
OH
IH
F
O C02CH3 OH
34
CA 02742980 2011-05-06
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N NH O
NH N O H O H N\
CONA-Y
H2 O \ O OH OH 0 0
OH Y-
O OH ~O OH NH NH
z
-0
O 0 '\_~
I~ ~O NH OEt OH
H H/ N OH
\ O O O
H
/N"
N~ N N N~ 1 / O o AON
N N
0
O
N H N 'J~ O \11 O
i I J~OH O OH VC02H
and
[00153] In another embodiment, two adjacent R3 groups form
[00154] In several embodiments, R'3 is independently -ZCR6, where each Zc is
independently a bond or an optionally substituted branched or straight C1.6
aliphatic chain
wherein up to two carbon units of ZC are optionally and independently replaced
by -CO-, -
CS-, -CONRc ,
-CONRCNRC-, -C02-, -OCO-, -NRcCO2-, -0-, -NRcCONRc-, -OCONRc-, -NRcNRc-,
CA 02742980 2011-05-06
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NRcCO-, -5-, -SO-, -S02-, -NRc-, -SO2NRc-, -NRcSO2-, or -NRcSO2NRc-. Each R6
is
independently Rc, halo, -OH, -NH2, -NO2, -CN, or -OCF3. Each Rc is
independently
hydrogen, an optionally substituted aliphatic, an optionally substituted
cycloaliphatic, an
optionally substituted heterocycloaliphatic, or an optionally substituted
heteroaryl. In one
embodiment, each Rc is hydrogen, C1.6 aliphatic, or C3.6 cycloaliphatic,
wherein either of the
aliphatic or cycloaliphatic is optionally substituted with up to 4 -OH
substituents. In another
embodiment, Rc is hydrogen, or C1.6 alkyl optionally substituted with up to 4 -
OH
substituents.
[00155] For example, in many embodiments, R'3 is is independently -ZCR6, where
each Zc
is independently a bond or an optionally substituted branched or straight C1.6
aliphatic chain
wherein up to two carbon units of Zc are optionally and independently replaced
by -C(O)-,
-C(O)NRc-, -C(O)O-, -NRcC(O)O-, -0-, -NRcS(O)2-, or -NRc-. Each R6 is
independently
RC
-OH, or -NH2. Each Rc is independently hydrogen, an optionally substituted
cycloaliphatic,
an optionally substituted heterocycloaliphatic, or an optionally substituted
heteroaryl. In one
embodiment, each Rc is hydrogen, C1.6 aliphatic, or C3.6 cycloaliphatic,
wherein either of the
aliphatic or cycloaliphatic is optionally substituted with up to 4 -OH
substituents. In another
embodiment, Rc is hydrogen, or C1.6 alkyl optionally substituted with up to 4 -
OH
substituents.
[00156] In other embodiments, R'3 is hydrogen or
R31
IZZ R32
OH
[00157] wherein R31 is H or a C1_2 aliphatic that is optionally substituted
with 1-3 of halo, -
OH, or combinations thereof. R32 is -L-R33, wherein L is a bond, -CH2-, -CH2O-
, -
CH2NHS(O)2-,
-CH2C(O)-, -CH2NHC(O)-, or -CH2NH-; and R33 is hydrogen, or C1_2 aliphatic,
cycloaliphatic, heterocycloaliphatic, or heteroaryl, each of which is
optionally subsitututed
with 1 of -OH,
-NH2, or -CN. For example, in one embodiment, R31 is hydrogen and R32 is C1.2
aliphatic
optionally substituted with -OH, -NH2, or -CN.
[00158] In several embodiments, R'3 is independently selected from one of the
following:
36
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
-H, -CH3, -CH2CH3, -C(O)CH3, -CH2CH2OH, -C(O)OCH3,
0 CH
OH 2OH
OH -~CH2OHv~OH .~~
,v-,.,NHCOCH3 '~~~~C02H OHNHMe OMe
, O p
OH "N
NH
OH Nz:N '~'^'~CONHMe
NH2
1O
N,_/ ~0---" H \"/Cp2H NH2
ry"~ NHCOMe ' r--rCN H
' ~CONMe2 OH OH
. NHSO2Me CO2H II N---'--OH 'V' H
OH
NHC02Me 'NH
OH OH _ NHC02Me OH N_N
OH
~O H /~ H
A I I 0H N OH = N OH /NHC02tBu
OH OH O OHO--'
0
0 ~~ ^N -S;O
0
,O Np~ OH N'7
NHSO2Et r~~~ NH NH
OH OH
0
O
H "
' N-S-
OH /
OH N N
N-0 and 0
[00159] In several embodiments, ring B is one selected from:
\ N \ N \ N 0 N 0
OH
H
H
37
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H 0
H
N N N I \ N O \ N H
O
H O-~
H O \ N O \ N O H 0
N H \ I / N I / N I / /
HN--\-OH
O I O O
H H N 0
H N NH No N
N
O
H OH H
N H N H OH N N
OH
I I
F N H N
F _ I _ I I
I \ \ NH2
H
H N N N
N
F \ /
38
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
N
YNNH ~5JXD NH
H
_ \ N N
I
F \ / NH NH NH
\ \ \ F -
F F NH
NH NH NH
HOH HO OH HO
O
N
N N N N H
F F I I F I
0 HO OH HO HO OH
OH
H
N N F N N N
F
-7
I I I I I
F
39
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
0-
0 O p OH
HN OH OH OH
N F ON ON N rN
F O
O
N\ NH NH O NH
O and
[00160] 5. n term
[00161] n is 1-3.
[00162] In several embodiments, n is 1. In other embodiments, n is 2. In still
other
embodiments, n is 3.
In one aspect, the present invention relates to compounds of formula II useful
as
modulators of ABC transporter activity:
R1 R1 R1
R1 R
3
H
R N I ~ \
R O R2 N R5
R4
II
or a pharmaceutically acceptable salt thereof, wherein independently for each
occurrence:
R is H, OH, OCH3 or two R taken together form -OCH2O- or -OCF2O-;
Rl is H or alkyl;
R2 is H or F;
CA 02742980 2011-05-06
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R3 is H or CN;
R4 is H, -CH7OCH7CH(OH)CH7OH, -CH7CH7N(CH3)3, or -CH7CH7OH;
R5 is H, OH, -CH7OCH7CH(OH)CH7OH, -CH7OH, or R4 and R5 taken together form
a five membered ring.
In one embodiment, the present invention provides compounds of formula II,
wherein
the compounds set forth below are excluded:
H
\ N
~O I/ O F N
H
H
F)O I \ N \
F O / O / N OH
OH
H
F` O N \
F O I/ O F N OH \ N
O N
OH H
H H
\ N \ ~ O \ N
<I/ O I/N <I ON
H
H H
F_oD ~ 7y NI\~ F~( I\ NI\
F O / O / N F O / O F / N
OH
OH , OH 9
H
\ N Do, H \
F -7y p I/ O F I/ N O I/ N
OH OH
OH9 OH9
H H
O \ N Fx I/ oF/N ~XTNtX_f_
N
H ,
H ,
41
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
H
N
< I/ O I/ N F O I\ N \
OH F O / F / N
OH, OH ,
H
\ N
/ O / H
O F N OH ~ N
N
OH, F H
H
~O \ N
O
F O \ N I\ \ O N
OH
F O I / O F H O H O H
H H
/ I\ N I\ N I\ \
O O F N F O N
~OH
OH , OH9
H H
\
i0 N cx
IN O F N O / O N
H , H
H H
~(O \ N \ O \ N \
F' 0) O I/ ~~\N O I/ N OH
H , H
H
N
O O N N
/ O O N OH
OH , H ,
H H
O \ N \ HO \ N \
O O H O I/ O I H
,
H H
\ N N
~O 0 I N O O / N
~OH ~OH
OH9 OH9
42
CA 02742980 2011-05-06
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H
F \ N \
\ N \ F O I/ O I/ N OH
"!0 0 -co OH
oj: 1 ' o+
H OH
H
iO \ N
O I / N HO 1::~ N ~OH
O N
OH9 H
H
\ N
HO N O I/ F N
r~Z H \ \ OH
HO I / O (:: /
N' I
H and OH
In one embodiment of the compounds, two R taken together form -OCFZO-, Rl is
H,
and R2 is F. In another embodiment, two R taken together form -OCF2O-, Ri is
H, R2 is F,
and R3 is H. In another embodiment, two R taken together form -OCF2O-, Ri is
H, R2 is F,
R3 is H, and R4 is H. In another embodiment, two R taken together form -OCFZO-
, Rl is H,
R2 is F, R3 is H, and R4 is -CH2CH2N+(CH3)3. In another embodiment, two R
taken together
form -OCF2O-, Ri is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In
another
embodiment, two R taken together form -OCF2O-, Ri is H, R2 is F, R3 is H, and
R4 and R5
taken together form a five membered ring.
In one embodiment of the compounds, two R taken together form -OCHZO-, Rl is
H,
and R2 is F. In another embodiment, two R taken together form -OCH2O-, Ri is
H, R2 is F,
and R3 is H. In another embodiment, two R taken together form -OCH2O-, Ri is
H, R2 is F,
R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of the compounds, R is OH, Rl is H, R2 is H, R3 is H, and R4
is -
CH2OCH2CH(OH)CH2OH.
In one embodiment of the compounds, at least one R is OCH3, at least two Rl
are
methyl, R2 is H, R3 is H, and R4 is H. In another embodiment, at least one R
is OCH3, at least
two Ri are methyl, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of the compounds, two R taken together form -CH2CH2CH2-, Rl
is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment, the compound is represented by formula IIa:
43
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
>c~i :J~
11 H
F N R5
R4
IIa
or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form
a five membered ring.
[00163] In one embodiment of the compounds, R4 is -CHZOCHZCH(OH)CHZOH, -
CH2CH2N+(CH3)3, or -CH2CH2OH. In another embodiment, R5 is OH, -
CH2OCH2CH(OH)CH2OH, or -CH2OH. In another embodiment, R4 is -
CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and R5 is OH, -
CH2OCH2CH(OH)CH2OH, or -CH2OH.
[00164] C. Exemplary compounds of the present invention
[00165] Exemplary compounds of the present invention include, but are not
limited to,
those illustrated in Table 1 below.
44
CA 02742980 2011-05-06
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Table 1: Exemplary compounds of the present invention.
1 2 3
F
4 5 6
N" ~11 10
r~-'XG/
F
F F
110
O I` N I I F 0 N
N :H
11 12
0
0 f~ f3 = F 0 0
F 0
Ff
CA 02742980 2011-05-06
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13 14 15
S0
0" NH F H
F
~ v ~ I r/ ~~3 #~ I C J /
C, N
H
16 17 18
F
0 HN
0 1 / a 0
1-5
0
1,x-0
19 20 21
G
F#
0 +~ N HO
F 0- t7 N 1 r H
0 Zt4
cH-
23 24
22
H -. tf H
~r o c~ rr "-, 0
o~;: %" I ,mac - 1 g I r I
46
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25 26 27
0
0 ^. 0 N 0
F Ov O
F 0 .~ /
#f
28 29 30
H {3H H 0 O
0 a FI, < 0 r H 0
31 32 33
f--0
{J H
F I3- III ~' "~ N
F I I H 0 N
H
34 35 36
hf.NH
/
N
F C1
+rl ~NH 0 0 I y0 N
J 1
f
0 0 H F I v 11
_C4 2-
47
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WO 2010/054138 PCT/US2009/063475
37 38 39
H
/ + 0 o <~O~N
o~
40 41 42
H0
H H
0 N 0 0 .~ N H
~I
0
F6
F
43 44 45
H
hEF
0 o I I 0 0 JU'
2H
0
0
F
46 47 48
I- 0 I o F O N
I r
of 'IKN
N xH
H
48
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
49 50 51
N
c
C r FE 0 r L FE 0
H
52 53 54
r f
Q~-~ Q .1.~ .~t Y~0tf :oH-
55 56 57
0
F
N F Cj: //+ [? Q C Off. F
H
F
58 59 60
8
N
F,
Ho~
H:N
Q 0 If o r
\_0
49
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61 62 63
F
N
Hc~ `'f
iV r C
H C
N 00 0 H
O I` I~ N ~ ~~ H
}# 'r I H
0y
G.~E3
64 65 6
4-
0H / `#H
.,
00
67 68 69
H
0
H NH
0 `.3 Q N 0
-XANf:+ ) 01,- 0
H / H 7
0
0 ,,.
H
70 71 72
H
0
H H
F 0 :,::-
F F 0 IN I ~ r''
CA 02742980 2011-05-06
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73 74 75
Ho
H<j OH
N
H
O 7w N, \ C3 +
O fl# O :a 0 H
0 /+
H
76 77 78
yN\
79 80 81
H
fl H
e?' ) fl
H N
C3 ~ ~
H
82 83 84
H 0 F F
H f #iC, F
fl H
H f3 F R# r 6d.
H. 0
F 0- 4 fl e ~ f3 ,.'
F
51
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85 86 87
H
88 89 90
H
0 .~ N
Cl H0 7H
0 0 0
91 92 93
H CH
C C
F
Y~H : y a/4
~H
94 95 96
~C
t~
N
N
52
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97 98 99
H H
CI
t] t? 0 ` i 3
jx~ 4D
/N H
100 101 102
k
H 0
0 0
O N H CO I 0 I N
N ~- /
H 0
103 104 105
Cal) H 7Y N
0 I ! 144N
106 107 108
H
0
H
Ho F fd
H
~r'~. 0 I r I 0 HN: I.,t
Cl ICI ~ .N -0
I H
rl
ti
0
F0
F
53
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109 110 111
Hoy
Nab 0
X )-~Zk NH
112 113 114
H
0 O e C `
Ff F .~ 1 F H
H
115 116 117
H f \ ,
Ff
118 119 120
F F
F,~-CA
F
54
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12-1 122 123
Q F HO H :H
o Is lI C 0
o`. I1 r
O`I p I r H H LAN
H
124 125 126
H H
" 0 N F Cj:::Vt4 x",~.~/ 0 o
N X[ F X 0
VH H
127 128 129
`o .~ -'-J < ;Cam; ,e
H H
130 131 132
Ir
H F
4104 H
0 r
N J
H
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133 134 135
H
0
0
H 0 0 0
(j am- 9 H:
0
00 N
136 137 138
0"S--O 0
C3 N H H
F I -- 0 N}~ 0 o r r
139 140 141
O:li
0 N CU I
N :H H N:
Cp p H
H
142 143 144
H
F
N
H hJp
0
F F x 9,D-
F 0 N I `r F C2~ N fi3r,~/+
0 H H
F
o
F
56
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145 146 147
ct
0 H
0 ~. 0 0
N < +
148 '149 150
H H
:cu. Ii r~ 00 I-~ ra
0 H 0 N ~ 1:
0 tN
H
151 '152 '153
f "0
0
H
H 0
0
154 155 156
Y0
H H
N N
0 1/ 0 I
0 0 N.H ~# ! f
H
57
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157 158 159
H
0
FI }
H N H0
0 '~Ao N 0 t
160 36 162
0 Ho
H F N
H
H, N
~ f 0
G E P)_6
F
3 63 164 165
F3
F N
F J /r
H I f ^ Na~ Fj
H N 0 < 00 '()2~N 1:1!r,/*
I-fo
0
-0 \-0
166 167 168
F N 0
H H0
0 N
F O vN o < I. to
~I H
0
!-0
58
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169 170 171
fl'~=
HN H'
H0 1J ZH
I
0 HH
172 173 174
H
N
H H F Co")~' FN
H
175 176 177
0f F H F,
N
0 C a
F 0 0 , =. I N / P''0 IN I fl
H H
0
178 179 180
0
0 1-f~1 H Q
H N F
HF~
59
CA 02742980 2011-05-06
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181 182 183
00
H0 F N
N)ajN 11 H
N (X/+
C- G4
0
184 185 186
N
HN HM
0 rr 0
:r 0 ,D"~o ( I 0
H 0
0 H
F 0
F
187 188 189
0
0
HN
'OH: 0
H H
,y, rf
190 191 192
0 f 0 .~ N 0 0 N
qi0-
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193 194 195
OH 0H
0
H0 = i 0 I ri
0 r 4 0
196 197 198
OH
0l
H t3,
0 14 N4H
)(~o <
0
H ' F I. 0 0
F 0 ~'
199 200 201
H0
F
HN ' 0 N
H
0
0 ~ ~
0 ~-:` 0 N
H
202 203 204
H 0 O:GV
N I !3H F p ` 0 0)(0 0 N
H F x /+
I fI~ C I, N
H r H
61
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205 206 207
F I 13 ~~ ,.- HH I /
J~
F 0 ~ ~ 0 F~
F O~LH
i l H
208 209 210
H. I =`
;:c1L1cI$-1-
FX I
0
211 212 213
H
0
H.
F H \ F
0
H :ccrE-
214 215 216
H
0 I 0 0
H H 0 0
0
62
CA 02742980 2011-05-06
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217 218 219
0 I
Q=5=C
0 aNl Ht
ID2k H ~H
220 221 222
H
HN
Ho 0
C
0 :~/+ x 0:0, '1",
H
f
223 224 225
H
O' ~r 0 P3 a
r }#
H
226 227 228
H F
H
rfr o = r
N
H
C H
r~H
63
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229 230 231
Ho OH H
0
F` 0 0 N N I / 0 I N
232 233 234
H H
H H ZH
H'
235 236 237
HO
H
0:
0
HO
0 h1 _ 0 0 H
00'3- a 5/+ H
238 239 240
0
H
I a H H N 0 0 I [? I H
UN. Ho~ >(O
H
r
F p 1' 0 HI
64
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
241 242 243
Ho
Q NH
Q HH
t3 Q Q" I ' Q I t
JIC m ~
0 ICE ~X+
H
O
IDA
244 245 246
Q QH, H H H
Q H N i O Q N
F p I r f !' H
247 248 249
N-
H
_tN
J:XN~
O Q y Q f
0:[, a 0 OR3
Q
H
250 251 252
Q
H
~ U I -. - f~ ~ Ca Qta Q - N
Q N 144 H F>( I Q I. I H
CA 02742980 2011-05-06
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253 254 255
0# GR
(;[ )+
XG - ZH
256 257 258
0 OH
CH
F 0 :cXrc3
259 260 261
H
I~ o ;' HM I /+
OH f rnt I 0 I 0
0
H
0 `
262 263 264
0
o Ho
0 0_I I 0 N
Q
H~ H p I +
66
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265 266 267
ra 0
0
r
0
I / 1 J~~
0 1
N '(-VN -
0 A H +
268 269 270
~
0 0 c l
-A`f LG_P3 0 0l
F 1 111 1 "
C +
H
271 272
HNC
0- N
< 0-cu I al-~/+
67
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273 274 275
0
z 0.~
H :H 1 0 ~_ s
ÃHra HN
3H H H ~
F 0 " o
F q ~rH I r-! F Q O tE ~1 F 0? l
F I F I~ u Ir
H H
276 277 278
H
B
3r is F B . i s H H
0\ F
[j, :(I(:~-~
,+ \-< F H fV 8 G 0 F 11 H
H I
0
r
279 280 281
H
0 Ho
H
F 0N F C C] F
I r
H F I c I F 0 I F
H
282 283 284
N
oc3 O
H N , H
HOC, HRH
HO N
HoH F ~ ~ 0 v~~~
F 0 F' I r H A
68
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285 286 287
oz/
H H/ HN
0
F :ci- CTE
F 0
C0 N >(
F
C
288 289 290
H
0
H 0 0
H'C)N
H 0 Ho,~ H. 0 r I 0 I F 0 :c1c'i+
F~0
F
291 292 293
N -
0 N
HN 0 0"s-0
HN
F I L] I ti N HC HO
F 0 14 F 0. 0 N
H F 0 I f F H F 01~UN
294 295 296
H0 OC H
HO C H
H y _/
N 0
F r E? ~~ 0
F
e I 0
FA-0 F 0
F F
69
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297 295 299
HO H. N JO
H
c o N F
OH:
300 301 302
H
HO ~ Ho H.
C I Q I
+ F F>I` a' J#~
+ F F>I E3 I
i~A
i H H
303 304 305
H
C CFH"pH
tt4
C3 F C I r' P! I / F F I . t] I yN
306
H
F I jI y,. N
0 /
H
CA 02742980 2011-05-06
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307 M:8 309
f
L=
~ ...:rar..,.
H~+
~`
N
14
F
X1::3 31 315
F '-7
,
~.a
F
316 ~18
H
=4
~ I ~ _~ F 4 II- ~ ~ ~,H
.HN
Z:t 7
71
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319 320 32
F.
y i 1
I;.r I f I V_
3.22
H
Fes: rv?
N
1-- `tali
In another aspect, the present invention relates to a pharmaceutical
composition
comprising (i) a compound of the present invention; and (ii) a
pharmaceutically acceptable
carrier. In another embodiment, the composition further comprises an
additional agent
selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-
infective agent, an
anti-inflammatory agent, CFTR corrector, or a nutritional agent. In another
embodiment, the
composition further comprises an additional agent selected from compounds
disclosed in
U.S. Patent Application Serial No. 11/165,818, published as U.S. Published
Patent
Application No. 2006/0074075, filed June 24, 2005, and hereby incorporated by
reference in
its entirety. In another embodiment, the composition further comprises N-(5-
hydroxy-2,4-
ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide. These compositions are
useful for
treating the diseases described below including cystic fibrosis. These
compositions are also
useful in the kits described below.
In another aspect, the present invention relates to a method of increasing the
number
of functional ABC transporters in a membrane of a cell, comprising the step of
contacting
said cell with a compound of formula II:
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R1 R1 R1
R1 R
3
H
R N I ~ \
R O R2 N R5
R4
II
wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form -CH2CH2CH2-, -OCH2O- or -
OCF2O-;
Rl is H or alkyl;
R2 is H or F;
R3 is H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form
a five membered ring.
In one embodiment of this method, the ABC transporter is CFTR.
In one embodiment of this method, two R taken together form -OCF2O-, Rl is H,
and
R2 is F. In another embodiment, two R taken together form -OCF2O-, Ri is H, R2
is F, and
R3 is H. In another embodiment, two R taken together form -OCF2O-, Rl is H, R2
is F, R3 is
H, and R4 is H. In another embodiment, two R taken together form -OCF2O-, Rl
is H, R2 is
F, R3 is H, and R4 is -CH2CH2N+(CH3)3. In another embodiment, two R taken
together form
-OCF2O-9 Ri is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another
embodiment, two R taken together form -OCF2O-, Ri is H, R2 is F, R3 is H, and
R4 and R5
taken together form a five membered ring.
In one embodiment of this method, two R taken together form -OCH2O-, Rl is H,
and
R2 is F. In another embodiment, two R taken together form -OCH2O-, Ri is H, R2
is F, and
R3 is H. In another embodiment, two R taken together form -OCH2O-, Rl is H, R2
is F, R3 is
H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, R is OH, Ri is H, R2 is H, R3 is H, and R4
is -
CH2OCH2CH(OH)CH2OH.
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In one embodiment of this method, at least one R is OCH3, at least two Rl are
methyl,
R2 is H, R3 is H, and R4 is H. In another embodiment, at least one R is OCH3,
at least two Ri
are methyl, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, two R taken together form -CH2CH2CH2-, Rl is
H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, the compound is represented by formula IIa:
H
>ccr F R5
R4
IIa
or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form
a five membered ring.
In one embodiment of this method, R4 is -CH2OCH2CH(OH)CH2OH, -
CH2CH2N+(CH3)3, or -CH2CH2OH. In another embodiment, R5 is OH9 -
CH2OCH2CH(OH)CH2OH, or -CH2OH. In another embodiment, R4 is -
CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and R5 is OH9 -
CH2OCH2CH(OH)CH2OH, or -CH2OH.
In one embodiment of this method, the compound is selected from Table 1.
In another aspect, the present invention relates to a method of treating a
condition,
disease, or disorder in a patient implicated by ABC transporter activity,
comprising the step
of administering to said patient a compound having formula II:
R1 R1 R1
R1 R3
H
R N I ~ \
O
R R2 N R5 %
R4
II
74
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or a pharmaceutically acceptable salt thereof, wherein independently for each
occurrence:
R is H, OH, OCH3 or two R taken together form -CH2CH2CH2-, -OCH2O- or -
OCF2O-;
Rl is H or alkyl;
R2 is H or F;
R3 is H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form
a five membered ring.
In one embodiment of this method, two R taken together form -OCFZO-, Rl is H,
and
R2 is F. In another embodiment, two R taken together form -OCF2O-, Ri is H, R2
is F, and
R3 is H. In another embodiment, two R taken together form -OCF2O-, Rl is H, R2
is F, R3 is
H, and R4 is H. In another embodiment, two R taken together form -OCFZO-, Rl
is H, R2 is
F, R3 is H, and R4 is -CH2CH2N+(CH3)3. In another embodiment, two R taken
together form
-OCF2O-9 Ri is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another
embodiment, two R taken together form -OCF2O-, Ri is H, R2 is F, R3 is H, and
R4 and R5
taken together form a five membered ring.
In one embodiment of this method, two R taken together form -OCHZO-, Rl is H,
and
R2 is F. In another embodiment, two R taken together form -OCH2O-, Ri is H, R2
is F, and
R3 is H. In another embodiment, two R taken together form -OCH2O-, Rl is H, R2
is F, R3 is
H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, R is OH, Ri is H, R2 is H, R3 is H, and R4
is -
CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, at least one R is OCH3, at least two Rl are
methyl,
R2 is H, R3 is H, and R4 is H. In another embodiment, at least one R is OCH3,
at least two Ri
are methyl, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, two R taken together form -CH2CH2CH2-, Rl is
H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this method, the compound is represented by formula IIa:
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H
>ccr F Re
R4
IIa
or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form
a five membered ring.
In one embodiment of this method, R4 is -CH2OCH2CH(OH)CH2OH, -
CH2CH2N+(CH3)3, or -CH2CH2OH. In another embodiment, R5 is OH, -
CH2OCH2CH(OH)CH2OH, or -CH2OH. In another embodiment, R4 is -
CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and R5 is OH, -
CH2OCH2CH(OH)CH2OH, or -CH2OH.
In one embodiment of this method, the compound is selected from Table 1.
In one embodiment of this method, said condition, disease, or disorder is
selected
from cystic fibrosis, hereditary emphysema, hereditary hemochromatosis,
coagulation-
fibrinolysis deficiencies, such as protein C deficiency, Type 1 hereditary
angioedema, lipid
processing deficiencies, such as familial hypercholesterolemia, Type 1
chylomicronemia,
abetalipoproteinemia, lysosomal storage diseases, such as I-cell
disease/pseudo-Hurler,
mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II,
polyendocrinopathy/hyperinsulemia, diabetes mellitus, laron dwarfism,
myleoperoxidase
deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1,
hereditary
emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary
hypofibrinogenemia, ACT deficiency, diabetes insipidus (di), neurophyseal di,
neprogenic
DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,
neurodegenerative
diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral
sclerosis,
progressive supranuclear plasy, Pick's disease, several polyglutamine
neurological disorders
asuch as Huntington, spinocerebullar ataxia type I, spinal and bulbar muscular
atrophy,
dentatorubal pallidoluysian, and myotonic dystrophy, as well as spongiform
encephalopathies, such as hereditary Creutzfeldt-Jakob disease, Fabry disease,
Straussler-
Scheinker syndrome, COPD, dry-eye disease, and Sjogren's disease.
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In another aspect, the present invention relates to a kit for use in measuring
the
activity of a ABC transporter or a fragment thereof in a biological sample in
vitro or in vivo,
comprising:
(i) a first composition comprising a compound of formula II:
R1 R1 R1
R1 R
3
H
R N I ~ \
R O R2 N R5
R4
II
wherein independently for each occurrence:
R is H, OH, OCH3 or two R taken together form -CH2CH2CH2-, -OCH2O- or -
OCF2O-;
Rl is H or alkyl;
R2 is H or F;
R3 is H or CN;
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form
a five membered ring; and (ii) instructions for: a) contacting the composition
with the
biological sample; and b) measuring activity of said ABC transporter or a
fragment thereof.
In one embodiment, the kit further comprises instructions for a) contacting an
additional composition with the biological sample; b) measuring the activity
of said ABC
transporter or a fragment thereof in the presence of said additional compound,
and c)
comparing the activity of the ABC transporter in the presence of the
additional compound
with the density of the ABC transporter in the presence of said first
composition.
In one embodiment, the kit is used to measure the density of CFTR.
In one embodiment of this kit, two R taken together form -OCF2O-, Rl is H, and
R2 is
F. In another embodiment, two R taken together form -OCF2O-, Ri is H, R2 is F,
and R3 is
H. In another embodiment, two R taken together form -OCF2O-, Ri is H, R2 is F,
R3 is H,
and R4 is H. In another embodiment, two R taken together form -OCF2O-, Rl is
H, R2 is F,
R3 is H, and R4 is -CH2CH2N+(CH3)3. In another embodiment, two R taken
together form -
77
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OCF2O-, Ri is H, R2 is F, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another
embodiment, two R taken together form -OCF2O-, Ri is H, R2 is F, R3 is H, and
R4 and R5
taken together form a five membered ring.
In one embodiment of this kit, two R taken together form -OCH2O-, Rl is H, and
R2
is F. In another embodiment, two R taken together form -OCH2O-, Ri is H, R2 is
F, and R3 is
H. In another embodiment, two R taken together form -OCH2O-, Ri is H, R2 is F,
R3 is H,
and R4 is -CH2OCH2CH(OH)CH2OH. In another embodiment, R is OH, Ri is H, R2 is
H, R3
is H, and R4 is -CH2OCH2CH(OH)CH2OH. In another embodiment, at least one R is
OCH3,
at least two Ri are methyl, R2 is H, R3 is H, and R4 is H. In another
embodiment, at least one
R is OCH3, at least two Ri are methyl, R2 is H, R3 is H, and R4 is -
CH2OCH2CH(OH)CH2OH. In another embodiment, two R taken together form -
CH2CH2CH2-, Ri is H, R2 is H, R3 is H, and R4 is -CH2OCH2CH(OH)CH2OH.
In one embodiment of this kit, the compound is represented by formula IIa:
H
><xfi :J~
F R5
R4
IIa
or a pharmaceutically acceptable salt thereof, wherein:
R4 is H, -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -CH2CH2OH; and
R5 is H, OH, -CH2OCH2CH(OH)CH2OH, -CH2OH, or R4 and R5 taken together form
a five membered ring.
In one embodiment of this kit, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3,
or -CH2CH2OH. In another embodiment, R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH.
In another embodiment, R4 is -CH2OCH2CH(OH)CH2OH, -CH2CH2N+(CH3)3, or -
CH2CH2OH; and R5 is OH, -CH2OCH2CH(OH)CH2OH, or -CH2OH.
In one embodiment of this kit, the compound is selected from Table 1.
[00166] III. SUB GENERIC COMPOUNDS OF THE PRESENT INVENTION
[00167] Another aspect of the present invention provides a compound that is
useful for
modulating ABC transporter activity. The compound has formula Id:
78
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\ O
n(R2 No
A Ri
Ic
or a pharmaceutically acceptable salt thereof.
[00168] R1, R2, and ring A are defined above in formula I, and ring B, R3 and
p are defined
in formula Ia. Furthermore, when ring A is unsubstituted cyclopentyl, n is 1,
R2 is 4-chloro,
and R1 is hydrogen, then ring B is not 2-(tertbutyl)indol-5-yl, or (2,6-
dichlorophenyl(carbonyl))-3-methyl-1H-indol-5-yl; and when ring A is
unsubstituted
cyclopentyl, n is 0, and R1 is hydrogen, then ring B is not
O
N O-_
/ N HN /
N'\ 0
or
O
/ OH
[00169] Another aspect of the present invention provides a compound that is
useful for
modulating ABC transporter activity. The compound has formula Id:
1 ~ O
/ N
n(R2~
A Ri
Id
or a pharmaceutically acceptable salt thereof.
[00170] R1, R2, and ring Aare defined above in formula I, and ring B, R3 and p
are defined
in formula Ia.
[00171] However, when R1 is H, n is 0, ring A is an unsubstituted cyclopentyl,
and ring B
is an indole-5-yl substituted with 1-2 of R3, then each R3 is independently -
ZGR12, where each
79
CA 02742980 2011-05-06
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ZG is independently a bond or an unsubstituted branched or straight C1.6
aliphatic chain
wherein up to two carbon units of ZG are optionally and independently replaced
by -CS-, -
CONRGNRG-, -CO2-, -OCO-, -NRGCO2-, -0-, -NR GCONRG-, -OCONRG-, -NR GNRG-, -5-,
-
SO-, -SO2-, -NRG ,
-SO2NRG-, -NRGSO2-, or -NR GSO2NRc-, each R12 is independently RG, halo, -OH, -
NH29 -
NO2, -CN, or -OCF3, and each RG is independently hydrogen, an unsubstituted
aliphatic, an
optionally substituted cycloaliphatic, an optionally substituted
heterocycloaliphatic, an
unsubstituted aryl, or an optionally substituted heteroaryl; or any two
adjacent R3 groups
together with the atoms to which they are attached form an optionally
substituted heterocycle.
Futhermore, when R1 is H, n is 1, R2 is 4-chloro, ring A is an unsubstituted
cyclopentyl, and
ring B is an indole-5-yl substituted with 1-2 of R3, then each R3 is
independently -Z H R229
where each ZH is independently a bond or an unsubstituted branched or straight
C1.3 aliphatic
chain wherein up to two carbon units of ZH are optionally and independently
replaced by -
CS-, -CONRHNRH, -CO2-, -OCO-9
-NR HCO2-, -0-, -NR HCONRH-, -OCONRH-, -NR HNRH-, -5-, -SO-9 -SO2-, -NRH-, -
SO2NRH-,
-NRHSO2-, or -NR HS02NRH-, each R22 is independently RH, halo, -OH, -NH2, -
NO2, -CN, or
-OCF3, and each RH is independently hydrogen, a substituted C4 alkyl, an
optionally
substitituted C2.6 alkenyl, an optionally substituted C2.6 alkynyl, an
optionally substituted C4
alkenyl, an optionally substituted C4 alkynyl, an optionally substituted
cycloaliphatic, an
optionally substituted heterocycloaliphatic, an optionally substituted
heteroaryl, an
unsubstituted phenyl, or a mono-substituted phenyl, or any two adjacent R3
groups together
with the atoms to which they are attached form an optionally substituted
heterocycle.
[00172] Another aspect of the present invention provides a compound that is
useful for
modulating ABC transporter activity. The compound has formula II:
Z~Z' R2
/ 2 R3
Z3 N
Z4 _Z5
A R, (R3)
II
or a pharmaceutically acceptable salt thereof.
[00173] R1, R2, and ring Aare defined above in formula I; R3, R'3, and pare
defined above
in formula la; and Z1, Z2, Z3, Z4, and Z5 are defined above in formula lb.
[00174] Another aspect of the present invention provides a compound that is
useful for
CA 02742980 2011-05-06
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modulating ABC transporter activity. The compound has formula IIa:
Z 2 Z, R2
Z,
Z4 ZS N11R'3
N \
A R1,
P(R3)
IIa
or a pharmaceutically acceptable salt thereof.
[00175] R1, R2, and ring A are defined above in formula I; R3, R'3, and p are
defined above
in formula Ia; and Z1, Z2, Z3, Z4, and Z5 are defined above in formula lb.
[00176] Another aspect of the present invention provides a compound that is
useful for
modulating ABC transporter activity. The compound has formula IIb:
~ ~z, R2
2
Z3
(R3)p
zq Z5 N \ / I~
A N
R3
IIb
or a pharmaceutically acceptable salt thereof.
[00177] R1, R2, and ring A, are defined above in formula I; R3, R'3, and p are
defined above
in formula Ia; and Z1, Z2, Z3, Z4, and Z5 are defined above in formula lb.
[00178] Another aspect of the present invention provides a compound that is
useful for
modulating ABC transporter activity. The compound has formula IIc:
(R2)n
\/\ o R 3
N
R, P(R3)
He
or a pharmaceutically acceptable salt thereof.
[00179] R1, R2 and n are defined above in formula I; and R3, R'3, and p are
defined in
formula Ia.
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[00180] Another aspect of the present invention provides a compound that is
useful for
modulating ABC transporter activity. The compound has formula IId:
R2 R'
3
O N
R2I \ R3
N
H (R3)0-2
lid
or a pharmaceutically acceptable salt thereof.
[00181] Both R2 groups, together with the atoms to which they are attached
form a group
selected from:
O 11' O O O N N N
I C
~ JL JL ~C <~ ~~
O N N
XA1 XA2 XA3 XA4 XA5 XA6
0=~D N..%
0 N a~, XO I ;' OC 'Nal
XA7 XA8 XA9 XA10 XA11 XA12
i
O
z
N s~.., O O Me0 OH
XA13 XA14 XA15 XA16 XA17 XA18
O N H
N
N ~ and
<\ \\
N
XA19 XA20 XA21
[00182] R'3 is independently selected from one of the following:
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-H, -CH3, -CH2CH3, -C(O)CH3, -CH2CH2OH, -C(O)OCH3,
0 CH
OH 2OH
OH -~CH2OHv~OH .~~
,v-,.,NHCOCH3 '~~~~C02H OHNHMe OMe
, O p
OH "N
NH
OH Nz:N '~'^'~CONHMe
NH2
1O
N~/ ~0---" H \'I C02H IOH NH2
'ry"~ NHCOMe 'r--rCN ~NH
"'~CONMe2 OH OH
H
,,NHS02Me ~CO2H 'N~~OH 'V' ~CO2H p.(
OH
NHC02Me 'NH
OH OH _ NHC02Me OH N_N
OH
~O H /~ H
A I I 0H N OH = N OH /NHC02tBu
OH OH O OHO--'
0
0 ~~ ^N -S;O
0
,O Np~ OH N'7
NHSO2Et r~~, ,~ NH NH
~~~///
OH OH
0
O
H "
' N-S-
OH /
OH N N
N-O and 0 ; and each R3 is independently
selected from -H, -CH3, -CH2OH, -CH2CH3, -CH2CH2OH, -CH2CH2CH3, -NH2, halo, -
OCH3, -CN, -CF3,
-C(O)OCH2CH3, -S(O)2CH3, -CH2NH2, -C(O)NH2,
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OH
O O
OH
H H
0 OH 0
II ~O 0 ~0 /
N
\N N
0 H H H 0 O 0 O O
O O
~
H H I \ N N /
kl-NH
OH
F
O C02CH3 OH
N :NH NE - NH N O H 0 A-Y O
H N\
CONH2 O \ O OH OH 0 0
OH 0 Y-
/ry 0 0 NH
O OH O OH NH z
0 0
NH ~ OEt OH
H~ H N OH
\ 0 O AIL(o -~L
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H N
/N"' N f,'3'1 N N NO O
\ I _~~JC N N H
O
]OH N O O
I J--OH O OH VC02H
and
[00183] IV. GENERIC SYNTHETIC SCHEMES
[00184] The compounds of formulae (I, Ic, Id, II, IIa, IIb, IIc, and IId) may
be readily
synthesized from commercially available or known starting materials by known
methods.
Exemplary synthetic routes to produce compounds of formulae (I, Ic, Id, II,
IIa, Ilb, 11c, and
IId) are provided below in Schemes 1-22 below.
[00185] Preparation of the compounds of the invention is achieved by the
coupling of a
ring B amine with a ring A carboxylic acid as illustrated in Scheme 1.
[00186] Scheme 1:
(R2)n
IV A c (R2)n h~
I / O R
1a
la
(R2)n\
\ I Cl
b
O
A
1b H
a) SOC12, DMF (cat.), DCM; b) R- N-G , pyr.; c) Ri N--@ , HATU, TEA,
DCM/DMF.
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[00187] Referring to Scheme 1, the acid la may be converted to the
corresponding acid
chloride lb using thionyl chloride in the presence of a catalystic amount of
H
dimethylformamide. Reaction of the acid chloride with the amine Ri N B
provides
compounds of the invention I. Alternatively, the acid 1 a may be directly
coupled to the
amine using known coupling reagents such as, for example, HATU in the presence
of
triethylamine.
[00188] Preparation of the acids la may be achieved as illustrated in Scheme
2.
Scheme 2:
A A
CI Br p
N N
a b OH
(R 2)n (R2)n (R2)n
2b la
2a
a) NaOH, BTEAC; b) NaOH, A
[00189] Referring to Scheme 2, the nitrile 2a reacts with a suitable
bromochloroalkane in
the presence of sodium hydroxide and a phase tranfer catalyst such as
butyltriethylammonium
chloride to provide the intermediate 2b. Hydrolysis of the nitrile of 2b
provides the acid la.
In some instances, isolation of the intermediate 2b is unnecessary.
[00190] The phenylacetonitriles 2a are commercially available or may be
prepared as
illustrated in Scheme 3.
Scheme 3
Br a CO2Me b OH
R n~
( 2) (R2)n / (R2)n
3a 3b 3c
C I CI d I CN
(R2)n (R2)n
3d 2a
a) Pd(PPh3)4, CO, MeOH; b) LiA1H4, THF; c) SOC12; d) NaCN
[00191] Referring to Scheme 3, reaction of an aryl bromide 3a with carbon
monoxide in the
presence of methanol and tetrakis(triphenylphosphine)palladium (0) provides
the ester 3b.
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Reduction of 3b with lithium aluminum hydride provides the alcohol 3c which is
converted to
the halide 3d with thionyl chloride. Reaction of 3d with sodium cyanide
provides the nitrile
2a.
[00192] Other methods of producing the nitrile 2a are illustrated in schemes 4
and 5 below.
Scheme 4
H
p a CN
(R2)n 4a (R2) / 2a
b d
OH C _ I \ CI
(R2)n 3c (R2)n 3d
a) TosMIC; b) NaBH4, THF; C) SOC12; d) NaCN
Scheme 5
\ a _ Br I \ b NCI \
(R2)n (R2) n (R2)n
5a 5b 2a
a) NBS, AIBN, CC14; b) NaCN, EtOH
H
[00193] Preparation of Rl N B components is illustrated in the schemes that
follow.
A number of methods for preparing ring B compounds wherein ring B is an indole
have been
reported. See for example Angew. Chem. 2005, 44, 606; J. Am. Chem. Soc. 2005,
127,
5342,); J. Comb. Chem. 2005, 7, 130; Tetrahedron 2006, 62, 3439; J. Chem. Soc.
Perkin
Trans. 1, 2000, 1045.
H
[00194] One method for preparing Rl N B is illustrated in Scheme 6.
Scheme 6
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(R3)p-1 (R3)p-1 (R3)p-1
02N NH2 02N H.NH2 02N H.Ny\R3
'O-
6a 6b 6c
N02 R3 R3
C
N O2N N
(R3)p-1 6d H H
(R3 )p-1 6e
NH2 R3 R3
d
N H2N N
(R3)p-1 H (R3 pp-1 H
6f 6g
a) NaNO2, HCl, SnC12; b) NaOH, R3CH2C(O)R3, EtOH; c) H3PO4, toluene; d) H2, Pd-
C,
EtOH
[00195] Referring to Scheme 6, a nitroaniline 6a is converted to the hydrazine
6b using
nitrous acid in the presence of HCl and stannous chloride. Reaction of 6b with
an aldehyde
or ketone CH3C(O)R3 provides the hydrazone 6c which on treatment with
phophoric acid in
toluene leads to a mixture of nitro indoles 6d and 6e. Catalytic hydrogenation
in the presence
of palladium on carbon provides a mixture of the amino indoles 6f and 6g which
may be
separated using know methods such as, for example, chromatography.
[00196] An alternative method is illustrated in scheme 7.
[00197] Scheme 7
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l i a l i b R3
/ NH2 N R3
(R3)p-1 (R3)p-1 H (R3)p-1 H
7a 7b 7c
(R3)p-1
R3 I R3
H 02N H
(R3)p 1
7d 7e e
(R3)p-1
(R3)p 1\\ I
R3 R3
02N H H2N H
7i ~h 7j
(R3)p-1 f (R3)p-1 (R3)p-1
\, ~ I\ g- J
3
02N NH 'NH2 / .N,YR
2 02N N 02N N \
H H
7f 7g 7h
a) R3a0001, Et3N, CH2C12; b) n-BuLi, THF; c) NaBH4, AcOH; d) KNO3, H2SO4; e)
DDQ,
1,4-dioxane; f) NaNO2, HC1, SnC12.2H20, H20; g) MeCOR3, EtOH; h) PPA; i) Pd/C,
EtOH
or H2, Raney Ni, EtOH or MeOH
[00198]
[00199] Scheme 8
a b
02N NO2
p(R3) p(R3)
\ N~ C
J
02N NO2 H2N
H
P(R3) p(R3)
a) HNO3, H2SO4; b) Me2NCH(OMe)2, DMF; c) H2, Raney Ni, EtOH
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[00200] Scheme 9
a,, a I\ Br b Br c
NH2 / NH2 02N NH2
P(R3) p(R3) p(R3)
TMS
02N / NH2 02N / / H H2N / H
P(R3) p(R3) p(R3)
a) NBS, DMF; b) KNO3, H2SO4; c) HC=C-TMS, Pd(PPh3)2C12, Cul, Et3N, toluene,
H20; d)
Cul, DMF; e) H2, Raney Ni, MeOH
[00201] Scheme 10
NO2 R3
JCO2H / CO2H ,\ C02H
a b
I \I NO2 O2N \ NO2
R3 R3
NO2 R3 NO2
LCO2H iI CO2Et CO2H
separation b
R NO2 02N NO2 I NO2
3
NO2 I NO2 R3
C02Et C ~N / \ I C02Et d
NO2 NO2 H2N H
R3 R3 CO2Et
a) HNO3, H2SO4; b) SOC12; EtOH; c) DMA, DMF; d) Raney Ni, H2, MeOH
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[00202] Scheme 11
(R3)p-1 (R3)p-1
/ C02Et N C02Et
a
O2N \ NO2 02N NO2
(R3)p-\
b Et02C /
HN \ N
2
H
a) DMA, DMF; b) Raney Ni, H2, MeOH
[00203] Scheme 12
R3 R3
a b
N H \
02N H/ 02N H R3
R3
R3 R3 R3 R3
I R3 C R3
O2N H H2N N H
a) R3aCH2COR3b, AcOH, EtOH; b) H3PO4, toluene; c) H2, Pd/C, EtOH
[00204] Scheme 14
(R3)p-1 (R3)p-1 (R3)p 1 -1p(R3)
C VR d
\\ a \\ \\
-
N N N N
H H PG PG
(R3)p-1 (R3)p-1 (R3)p-1 (R
3)p-1
RV \ e R~ I/ I\ f RV 9 RV
/ H O2N H 02N N N
H H2N
H
a) NaBH3CN; b) When PG= S02Ph: PhS02C1, Et3N, DMAP, CH2C12; When PG= Ac: AcC1,
NaHCO3, CH2C12; c) When Rv= RCO: (RCO)20, A1C13, CH2C12; When Rv=Br: Br2,
AcOH;
d) HBr or HC1; e) KNO3, H2SO4; f) Mn02, CH2C12 or DDQ, 1,4-dioxane; g) H2,
Raney Ni,
EtOH.
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[00205] Scheme 14
0
RD a b c
N
N I I/ N / N (R3 p1 SO R
(R3)p1 H (R3)p-1 H (R3)p-1 SO2R 2
RD RD RD
d I e I f
02N
(R p 1
(R3)1 SO2R (R3)1 H H
R RD
g h
02N H H2N H
(R3)p-1 (R3)p-1
a) NaBH3CN; b) RS02C1, DMAP, Et3N, CH2C12; c) R C(O)C1, A1C13, CH2C12; d)
NaBH4,
THF; e) HBr; f) KNO3, H2SO2; g) Mn02; g) Raney Ni, H2, EtOH
[00206] Scheme 15
(R3)p-1 (R3)p_1 R3 (R3)p_1 R3
I\ \ \ a I \ \ b I
~ N N
02N H 02N H H2N H
(R3)p-1 CN (R3)p-1 CN
b
O2N N H2N H
H a) R3X (X=Br, I), zinc triflate, TBAI, DIEA, toluene; b) H2, Raney Ni, EtOH
or H2, Pd/C,
EtOH or SnC12.2H20, EtOH; c) C1SO2NCO, DMF, CH3CN
[00207] Scheme 16
R3 R3 R3
R\ \ a R\ \ b R
02N r \ R3 01 02N R3 O2N R3
/ H N N
R'3 R'3
a) when X=C1, Br, I, or OTs: R'3X, K2CO3, DMF or CH3CN; b) H2, Pd/C, EtOH or
SnC12.2H20, EtOH or SnC12.2H20, DIEA, EtOH.
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[00208] Scheme 17
O2N 02N Br b O2N I Br
all ~ N H 2 NH2 N R
(R3)p-1 (R3)p-1 (R3)p-1 H
02N R3)p-1 R3a O N (R3)p-1 H N (R3) 1
\ d 2 I e 2
R3 R3
JR N
H H H
a) Br2, AcOH; b) RC(O)C1, Et3N, CH2C12; c) HC=CR3a, Pd(PPh3) 2C12, Cul, Et3N;
d) TBAF,
THE or tBuOK, DMF or Pd(PPh3) 2C12, Cul, DMF; e) H2, Pd/C, EtOH or SnC12, MeOH
or
HCO2NH4, Pd/C, EtOH
[00209] Scheme 18
R3
02N all 02N / Br 02N 101, ~O
aI bc
F NH2 F ~I NH2 F NH2
R3 R3 R3
R3 R3
02N O d 02N R3
e H2N / R3
R3 I R3
F NR F N F N
H H H
f
O2N R3 R3
H2N
I e
R
3 R3
I
RDO N RDO N
H H
a) Br2, AcOH, CHC13; b) R3aC=CH, Cul, Et3N, Pd(PPh3) 2C12; c) RCOC1, Et3N,
CH2C12; d)
TBAF, DMF; e) Raney Ni, H2, MeOH; f) ROK, DMF
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[00210] Scheme 19
O N 02N Br (R3)p-1 R
z a I b 02N
NH2 NH2
(R3)p-1 (R3)p-1 \ NH2
02N,111 (R 3)p-1 d H N
C (R3)p-1 R3 3
\ rQ~ N
H H
a) Br2, AcOH; b) HC=CR3a, Pd(PPh3) 2C12, Cul, Et3N; c) Pd(PPh3)2C12, Cul, DMF;
d) H2,
Pd/C, EtOH or SnC12, McOH or HCO2NH4, Pd/C, EtOH
[00211] Scheme 20
02N all O2N O2N X
a b C
F NH NH
(R3)p-1 (R3)p-1 R'3 (R3)p-1 R3
02N R3)p-1 R3 02N /(R3)p-1 H2N (R3)p-1
d e
\ N R3 N R3
NH
I R'3 R'3 R'3
a) H2NR'3; b) X=Br: Br2, HOAc; X=I: NIS; c) HC=CR3, Pd(PPh3)2C12, Cul, Et3N;
d) Cul,
DMF or TBAF, THF; e) H2, Pd/C, EtOH or SnC12, McOH or HCO2NH4, Pd/C, EtOH
[00212] Scheme 21
02N (R3)p 02N / (R3)p O2N VNr
a I b c
F ~ NHR'3 H R'3
p(R3
TMS
02N d 02N H2N
NHR'3 N N
p(R3) p(R3) R 3 p(R3) R 3
a) R'3NH2, DMSO; b) Br2, AcOH; c) TMS-C=CH, Cul, TEA, Pd(PPh3) 2C12; d) Cul,
DMSO;
e) Raney Ni, H2, McOH
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[00213] Scheme 22
R3
02N Br
a 02N b
NHR'3
NHR3
(R3)p-1 (R3)p-1
02N C H2N
R3 R3
N N
(R3)p-1 R13 (R3)p-1 R13
a) R3aC=CH, Cul, TEA, Pd(PPh3) 2C12; b) TBAF, THF; c) Raney Ni, MeOH
[00214] Scheme 23
R3
Br Br Br
~ O c Q~NIR
N02 NH2 I / N~R (R3)1-1 (R3)1-1 (R3)p-1 H (R3)p-1v H
d (T_R3a \ e OZN I \ f H2N
3 3
10~ 10~ 1~~
(I3)p-1 H (I3)p-1 H (R3)p-1 H
a) NaBH4, NiC12, MeOH; b) RC(O)C1; c) Pd(PPh3)C12, HC=C-R3, Cul, Et3N; d)
tBuOK,
DMF; e) KNO3, H2SO4; f) NaBH4, NiC12, MeOH
[00215] Scheme 24
02N \ H2N ~)N
a
(R3)p R-3 (R3)p R-3
a) SnC12, EtOH or Pd/C, HCO2NH4 or H2, Pd/C, EtOH or Raney Ni, H2, EtOH
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[00216] Scheme 25
PPh3Br
OH a I/ PPh3Br b 0-c
NH2 NH2 N OEt
(R3)1-1 (R3)1-1 (R3)p-1 H
c d e N R R
H COZEt N COZEt ~NC02Et
(R3)p-1 (R3)p-1 Boc (R3)p-1 Boc
R 02N R
f R g I R
N C02Et H COZEt
(R3)p-1 (R3)p-1
H
02N R H2N R R
h I R i
I N OH N OH
(R3)p-1 H (R3)p-1 H
a) PPh3, HBr; b) C1(O)CCH2CO2Et; c) tBuOK; d) (Boc) 20, DMAP; e) KHMDS, R-X;
KHMDS, R-X; f) TFA; g) NaNO3, H2SO4; h) LiA1H4, THF; i) SnC12, EtOH
[00217] Scheme 26
OZN III \ RaRb a 02N III \ RaRb b 02N RaRb
H CO2Et R3 H CO2H R H NRyRz
R3 3 3 0
C 02N \ RaRb d 02N \ RaRb
R3 H NRyRz R3 H NRyZ
a) LiOH; b) EDC, HOBt, Et3N, HNRyRz; c) BH3-THF; d) if Rz=H, RC(O)C1(Z=RC(O)-)
or
RS02C1(Z=RSO2-) or RO(CO)C1(Z=RO(CO)-) or (RO(CO)) 20 (Z= Z=RO(CO)-), Et3N,
CH2C12
[00218] Scheme 27
02N 02N H2N
N a I N b I N
R3 H R3 R'3 R3 R'3
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a) R'3-X (X=Br, I, or OTs), base (K2CO3 or Cs2CO3), DMF or CH3CN; b) H2, Pd/C,
EtOH
or Pd/C, HCO2NH4
[00219] Scheme 28
R3a R3a
02N a 02N b H2N
I \ R - R - \ Rib 3b ib
R3 R'3 R3 R'3 R3 R'3
a) R3aX (X=C1, Br, I), A1C13, CH2C12; b) Raney Ni, H2, MeOH
[00220] Scheme 29
H Boc
02N 3N- rN H2N 3N- N H2N N
III III N
R3 H R3 H R3 H
a) HC1/MeOH; Pt02, H2; b) (Boc) 20, Et3N, THE
[00221] Scheme 30
O2N~l3l a OzNYR3l \ b OzN ,3~ \ c O2NY~R3I \
Tlll/~ Tel/~ l/ l
NC R'3 HO2C R'3 RO2C R'3 R'3
3 3
OH
d
R3
OzN, r
9 ~' I N
O R3
NRyRz
le
R3
OzN~
N
R3
NRyRz
a) NaOH or LiOH; b) ROH, HC1; c) NaBH4 or LiA1H4 or DIBAL-H, THF; d) HNRyRz,
HATU, Et3N, EtOH or DMF; e) LiA1H4, THE or BH3=THF; f) H202, H2O (Ry=Rz=H); g)
H2,
Pd/C
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[00222] Scheme 31
O 0 0 0 Ra RbOR RbOH
~J ~J a b c d
/\/\OR FOR O Ra \`O
Ra Rb Cl Cl
OR g
:D~o ~(H e :/-~O RbOR f Ra Rb
02N Br 02N O
/ NH NH2
R3 2 R3
Ra Rb
OR O 0
02N h 02N OR i H2N OR
R/ NH4 R/ N H Ra Rb R H Ra Rb
R3 R 3 3
a) Ra X, NaH; Rb-X, NaH; b) PC15, CH2C12; c) NaOH; d) NaNH2, DMSO; e) CH2N2;
f)
Pd(PPh3)4, Cul, Et3N; g) RC(O)C1, pyr, CH2C12; h) Pd(CH3CN) 2C12, CH3CN; i)
Raney Ni,
H2, MeOH
[00223] Scheme 32
A R3 A R3
0
(R2)n (R2)n
~\ \
0 N r\ I N OR a I\\ N r\ I N OH
/ R1 H / 0 R1 H
A R3
b (R2)n O
~\ / O R \ JII>N_Rz
1 H R y
a) LiOH, THF/H20; b) HNRyRz, HATU, TEA, DMF/CH2C12
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[00224] Scheme 33
A js
(R2),
N UN A R3 a I/ O H OH
(\2)n
N nN O Rl (OR A R
b (R2),
f' / Ra Ra
N
O Rl \ N OH
H
a) LiBH4, THF/H20 or LiAlH4, THF; b) Ra Li, THE
[00225] Scheme 34
A A NO
(R2)n (R2)n b
a / O R` N / O R N
1 / H 1 H
R3 R3
A NH2
(R2)n
/ O R . I N
/ H
R3
a) NaNO2, AcOH/H20; b) Zn, AcOH
[00226] Scheme 35
A A
(R2)n / a (Rz)n / b
\\ O N N\ O N `. I N I / R~ H
I / Ri / H
R3 R3
A A
(R2)n (R2)n
IX X
/ p R N/ p R N
R3 CH2R'3 R3 CH2R'3
a) NaBH3CN; b) R'3CHO, NaHB(OAc) 3, TFA, DCE; c) chloranil or CDC13, light or
DDQ
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[00227] Scheme 36
A A
(R2)n a ~R2\ N /
)l n\
N` I\ I/ 0 R1
` N
/ 0 R1 / H R,
R R3 3 3
3
a) NaH, DMF-THF; R3-X (X=C1, Br, I, or OTs)
[00228] Scheme 37
A A Br
(R2)n / a (R2)n / b
X n\
111 \ 0 N ~. I N _ i\ N `, I N
/ R1 / H / O R1 / H
R3 R3
A Ar
(R2)n
/ 0 R t:) N
1 H
R3
a) NBS; b) Ar-B(OR)2, Pd-FibreCat 1007, K2CO3, EtOH
[00229] Scheme 38
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A SO2R
(R2)n
/ O R . N
1 H
R3
a
A R3
(R2)n
N
An b I/ O R ~. I N
(R2H
N I R3
R `/ H C OH
A
AO
R3 (R2)n
d ~/ 0
R` N
1 / H
R3
A H
(R2)n
1\1 N / O R ~. I N
1 H
R3
e
A CN
(R2)n
/ O R ~. N
1 H
R3
a) RS02C1, NaH, THF-DMF; b) R3-X (X=Br, I, or OTs), NaH, THF-DMF; c) ethylene
dioxide, InC13; d) POC13, DMF; e) H2N-OH, CH2C12; Ac20
[00230] Scheme 39
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A A
(R2)n / a (R2)n ~InN
I N-
/ O Ri `/ N
/ O R, H 40
R3 R3
b / ~c
A A
(R2)n (R2)n
\ O N` I N\ N` I N
/ R, OH / O R / OH
R3 R3
OR NRyRz
a) NaH, THF-DMF; epichlorohydrin; b) ROH; c) HNRyRz
[00231] Scheme 40
A A
(Rz)n (R2)n
O N L/. I N I O N `/. I N
R3 R3
/ R ~H / R ~H
OH OTs
b e ~a
A
(R2)n A
(Rz\ \ / \ (R2An
N ` I / O R
N N f ~~ N~~
R1 / N OH I / O R `/ OH
R3 R3 R3
CN
3 NHR
IC N
A A
(Rz)n (Rz)n (R2An
I N
'
. I\ / O R, N H / O Ri / N OH R OH
R3 R3 N, NH R3
COZH
N=N NR
z
a) TsC1, Et3N, CH2C12; b) NaCN, DMF; c) NaOH, MeOH; d) NaN3, NH4C1; e) NaN3,
DMF;
f) Pd/C, H2, MeOH (R=H); h) R"C(O)C1(Z=R"C(O)-) or R'S02C1(Z=R'SO2-) or
R"O(CO)C1(Z=R" O(CO)-) or (R" O(CO)) 20 (Z=R" O(CO)-), Et3N, CH2C12
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[00232] Scheme 41
A A A
(R2)n (R2)n / (R2)n
~~ N X N \ b ~~ N
/ O R N/ 0 R ~. N 0 `/ N
R3 H R3 R3
CI N3
A A
(R2)n (R2)n
i `/ I N d I/ O Ri `/ I N
N-' N
C I. O R
R3 R3
NH2 NHZ
a) C1CH2CHO, NaHB(OAc)3, CH2C12; CDC13, light; b) NaN3, Nal, DMF; c) H2,
Pd/C, MeOH, AcOH; d) RC(O)CI (Z=RC(O)-) or RS02C1(Z=RSO2-) or
RO(CO)C1(Z=RO(CO)-) or (RO(CO)) 20 (Z= RO(CO)-), Et3N, CH2C12.
Scheme 42
O O O O Ra Rb OR RbOH
d
a 1.1 1.1 b C ::rIO
OR 'FOR O Ra Rb CI
CI
Ra Rb OH R b
Rb O R f R3 Ra OR 9
e Ra
- O ~ p O2 N
O
R3
O2N Br R2 NH2
R 3 O R2 NH2
02N OR
RZ H Ra Rb
b) Ra X, NaH; Rb-X, NaH; b) PC15, CH2C12; c) NaOH; d) NaNH2, DMSO; e)
R-OH, DCC; f) Pd(PPh3)2C12, Cul, Et3N; g) PdC12, CH3CN
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Scheme 43
02N CH2)n-C02R 02N (H2C) CH20H O N
\ a) I \n b 2 n(H2C)-CH
2OP
R / HRa Rb R2 HRa Rb R NRa Rb
2 2 H
c) 02N n(H2C) CH2ORc
\ d H2N I \n(H2C)-CH2ORc
R2 / N Ra Rb /
R4 R2 N Ra Rb
R4
n=0or1
a) DIBAL-H; b) P-LG; P= protecting group like TBDMS and LG= leaving
group like Cl; c) R4-LG, base likeCs2CO3; R4 is alkyl and LG is tosylate, Rc=H
or R4; d)
reducing conditions like Pd/C, H2 or ammonium formate.
Scheme 43
0
02N OR a) 02N I OR b) 02N OH
R2 H Ra Rb R2 / Ra Rb R2 N Ra Rb
R4 R
4
c) H2N OH
R2 N Ra Rb
R4
R4-LG, base likeCs2CO3; R4 is alkyl and LG is tosylate; b) LiA1H4; c) reducing
conditions like Pd/C, H2 or ammonium formate.
[00233] In the schemes above, the radical R employed therein is a substituent,
e.g., RW as
defined hereinabove. One of skill in the art will readily appreciate that
synthetic routes
suitable for various substituents of the present invention are such that the
reaction conditions
and steps employed do not modify the intended substituents.
[00234] V. FORMULATIONS, ADMINISTRATIONS, AND USES
[00235] Accordingly, in another aspect of the present invention,
pharmaceutically
acceptable compositions are provided, wherein these compositions comprise any
of the
compounds as described herein, and optionally comprise a pharmaceutically
acceptable
carrier, adjuvant or vehicle. In certain embodiments, these compositions
optionally further
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comprise one or more additional therapeutic agents.
[00236] It will also be appreciated that certain of the compounds of present
invention can
exist in free form for treatment, or where appropriate, as a pharmaceutically
acceptable
derivative or a prodrug thereof. According to the present invention, a
pharmaceutically
acceptable derivative or a prodrug includes, but is not limited to,
pharmaceutically acceptable
salts, esters, salts of such esters, or any other adduct or derivative which
upon administration
to a patient in need is capable of providing, directly or indirectly, a
compound as otherwise
described herein, or a metabolite or residue thereof.
[00237] As used herein, the term "pharmaceutically acceptable salt" refers to
those salts
which are, within the scope of sound medical judgment, suitable for use in
contact with the
tissues of humans and lower animals without undue toxicity, irritation,
allergic response and
the like, and are commensurate with a reasonable benefit/risk ratio. A
"pharmaceutically
acceptable salt" means any non-toxic salt or salt of an ester of a compound of
this invention
that, upon administration to a recipient, is capable of providing, either
directly or indirectly, a
compound of this invention or an inhibitorily active metabolite or residue
thereof.
[00238] Pharmaceutically acceptable salts are well known in the art. For
example, S. M.
Berge, et al. describes pharmaceutically acceptable salts in detail in J.
Pharmaceutical
Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically
acceptable salts
of the compounds of this invention include those derived from suitable
inorganic and organic
acids and bases. Examples of pharmaceutically acceptable, nontoxic acid
addition salts are
salts of an amino group formed with inorganic acids such as hydrochloric acid,
hydrobromic
acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids
such as acetic
acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or
malonic acid or by
using other methods used in the art such as ion exchange. Other
pharmaceutically acceptable
salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate,
borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate,
gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-
ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate,
sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate
salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline earth
metal, ammonium
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and N+(Ci_4alkyl)4 salts. This invention also envisions the quaternization of
any basic
nitrogen-containing groups of the compounds disclosed herein. Water or oil-
soluble or
dispersible products may be obtained by such quaternization. Representative
alkali or
alkaline earth metal salts include sodium, lithium, potassium, calcium,
magnesium, and the
like. Further pharmaceutically acceptable salts include, when appropriate,
nontoxic
ammonium, quaternary ammonium, and amine cations formed using counterions such
as
halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl
sulfonate and aryl
sulfonate.
[00239] As described above, the pharmaceutically acceptable compositions of
the present
invention additionally comprise a pharmaceutically acceptable carrier,
adjuvant, or vehicle,
which, as used herein, includes any and all solvents, diluents, or other
liquid vehicle,
dispersion or suspension aids, surface active agents, isotonic agents,
thickening or
emulsifying agents, preservatives, solid binders, lubricants and the like, as
suited to the
particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth
Edition, E.
W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers
used in
formulating pharmaceutically acceptable compositions and known techniques for
the
preparation thereof. Except insofar as any conventional carrier medium is
incompatible with
the compounds of the invention, such as by producing any undesirable
biological effect or
otherwise interacting in a deleterious manner with any other component(s) of
the
pharmaceutically acceptable composition, its use is contemplated to be within
the scope of
this invention. Some examples of materials which can serve as pharmaceutically
acceptable
carriers include, but are not limited to, ion exchangers, alumina, aluminum
stearate, lecithin,
serum proteins, such as human serum albumin, buffer substances such as
phosphates, glycine,
sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated
vegetable fatty acids,
water, salts or electrolytes, such as protamine sulfate, disodium hydrogen
phosphate,
potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium
trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-
polyoxypropylene-
block polymers, wool fat, sugars such as lactose, glucose and sucrose;
starches such as corn
starch and potato starch; cellulose and its derivatives such as sodium
carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt;
gelatin; talc;
excipients such as cocoa butter and suppository waxes; oils such as peanut
oil, cottonseed oil;
safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such
a propylene glycol
or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar;
buffering agents
such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free
water;
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isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer
solutions, as well as
other non-toxic compatible lubricants such as sodium lauryl sulfate and
magnesium stearate,
as well as coloring agents, releasing agents, coating agents, sweetening,
flavoring and
perfuming agents, preservatives and antioxidants can also be present in the
composition,
according to the judgment of the formulator.
[00240] In yet another aspect, the present invention provides a method of
treating a
condition, disease, or disorder implicated by ABC transporter activity. In
certain
embodiments, the present invention provides a method of treating a condition,
disease, or
disorder implicated by a deficiency of ABC transporter activity, the method
comprising
administering a composition comprising a compound of formulae (I, Ic, Id, II,
IIa, IIb, IIc,
and IId) to a subject, preferably a mammal, in need thereof.
[00241] In certain preferred embodiments, the present invention provides a
method of
treating Cystic fibrosis, Hereditary emphysema, Hereditary hemochromatosis,
Coagulation-
Fibrinolysis deficiencies, such as Protein C deficiency, Type 1 hereditary
angioedema, Lipid
processing deficiencies, such as Familial hypercholesterolemia, Type 1
chylomicronemia,
Abetalipoproteinemia, Lysosomal storage diseases, such as I-cell
disease/Pseudo-Hurler,
Mucopolysaccharidoses, Sandhof/Tay-Sachs, Crigler-Najjar type II9
Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus, Laron dwarfism,
Myleoperoxidase
deficiency, Primary hypoparathyroidism, Melanoma, Glycanosis CDG type 1,
Hereditary
emphysema, Congenital hyperthyroidism, Osteogenesis imperfecta, Hereditary
hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), Neurophyseal DI,
Neprogenic
DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,
neurodegenerative
diseases such as Alzheimer's disease, Parkinson's disease, Amyotrophic lateral
sclerosis,
Progressive supranuclear plasy, Pick's disease, several polyglutamine
neurological disorders
asuch as Huntington, Spinocerebullar ataxia type I, Spinal and bulbar muscular
atrophy,
Dentatorubal pallidoluysian, and Myotonic dystrophy, as well as Spongiform
encephalopathies, such as Hereditary Creutzfeldt-Jakob disease (due to Prion
protein
processing defect), Fabry disease, Straussler-Scheinker disease, secretory
diarrhea, polycystic
kidney disease, chronic obstructive pulmonary disease (COPD), dry eye disease,
and
Sjogren's Syndrome, comprising the step of administering to said mammal an
effective
amount of a composition comprising a compound of formulae (I, Ic, Id, II, IIa,
Ilb, 11c, and
IId), or a preferred embodiment thereof as set forth above.
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[00242] According to an alternative preferred embodiment, the present
invention provides a
method of treating cystic fibrosis comprising the step of administering to
said mammal a
composition comprising the step of administering to said mammal an effective
amount of a
composition comprising a compound of formulae (I, Ic, Id, II, IIa, IIb, IIc,
and IId), or a
preferred embodiment thereof as set forth above.
[00243] According to the invention an "effective amount" of the compound or
pharmaceutically acceptable composition is that amount effective for treating
or lessening the
severity of one or more of Cystic fibrosis, Hereditary emphysema, Hereditary
hemochromatosis, Coagulation-Fibrinolysis deficiencies, such as Protein C
deficiency, Type
1 hereditary angioedema, Lipid processing deficiencies, such as Familial
hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia, Lysosomal
storage
diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,
Sandhof/Tay-Sachs,
Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes mellitus,
Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,
Glycanosis
CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis
imperfecta,
Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI,
Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,
neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease,
Amyotrophic
lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine
neurological disorders asuch as Huntington, Spinocerebullar ataxia type I,
Spinal and bulbar
muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well
as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease,
Fabry disease,
Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease,
chronic
obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.
[00244] The compounds and compositions, according to the method of the present
invention, may be administered using any amount and any route of
administration effective
for treating or lessening the severity of one or more of Cystic fibrosis,
Hereditary
emphysema, Hereditary hemochromatosis, Coagulation-Fibrinolysis deficiencies,
such as
Protein C deficiency, Type 1 hereditary angioedema, Lipid processing
deficiencies, such as
Familial hypercholesterolemia, Type 1 chylomicronemia, Abetalipoproteinemia,
Lysosomal
storage diseases, such as I-cell disease/Pseudo-Hurler, Mucopolysaccharidoses,
Sandhof/Tay-
Sachs, Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetes
mellitus, Laron
dwarfism, Myleoperoxidase deficiency, Primary hypoparathyroidism, Melanoma,
Glycanosis
CDG type 1, Hereditary emphysema, Congenital hyperthyroidism, Osteogenesis
imperfecta,
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Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),
Neurophyseal DI,
Neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,
neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease,
Amyotrophic
lateral sclerosis, Progressive supranuclear plasy, Pick's disease, several
polyglutamine
neurological disorders asuch as Huntington, Spinocerebullar ataxia type I,
Spinal and bulbar
muscular atrophy, Dentatorubal pallidoluysian, and Myotonic dystrophy, as well
as
Spongiform encephalopathies, such as Hereditary Creutzfeldt-Jakob disease,
Fabry disease,
Straussler-Scheinker disease, secretory diarrhea, polycystic kidney disease,
chronic
obstructive pulmonary disease (COPD), dry eye disease, and Sjogren's Syndrome.
[00245] The exact amount required will vary from subject to subject, depending
on the
species, age, and general condition of the subject, the severity of the
infection, the particular
agent, its mode of administration, and the like. The compounds of the
invention are
preferably formulated in dosage unit form for ease of administration and
uniformity of
dosage. The expression "dosage unit form" as used herein refers to a
physically discrete unit
of agent appropriate for the patient to be treated. It will be understood,
however, that the total
daily usage of the compounds and compositions of the present invention will be
decided by
the attending physician within the scope of sound medical judgment. The
specific effective
dose level for any particular patient or organism will depend upon a variety
of factors
including the disorder being treated and the severity of the disorder; the
activity of the
specific compound employed; the specific composition employed; the age, body
weight,
general health, sex and diet of the patient; the time of administration, route
of administration,
and rate of excretion of the specific compound employed; the duration of the
treatment; drugs
used in combination or coincidental with the specific compound employed, and
like factors
well known in the medical arts. The term "patient", as used herein, means an
animal,
preferably a mammal, and most preferably a human.
[00246] The pharmaceutically acceptable compositions of this invention can be
administered to humans and other animals orally, rectally, parenterally,
intracisternally,
intravaginally, intraperitoneally, topically (as by powders, ointments, or
drops), bucally, as an
oral or nasal spray, or the like, depending on the severity of the infection
being treated. In
certain embodiments, the compounds of the invention may be administered orally
or
parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and
preferably from
about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more
times a day, to
obtain the desired therapeutic effect.
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[00247] Liquid dosage forms for oral administration include, but are not
limited to,
pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions,
syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may
contain inert
diluents commonly used in the art such as, for example, water or other
solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide,
oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils),
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan,
and mixtures thereof. Besides inert diluents, the oral compositions can also
include adjuvants
such as wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and
perfuming agents.
[00248] Injectable preparations, for example, sterile injectable aqueous or
oleaginous
suspensions may be formulated according to the known art using suitable
dispersing or
wetting agents and suspending agents. The sterile injectable preparation may
also be a sterile
injectable solution, suspension or emulsion in a nontoxic parenterally
acceptable diluent or
solvent, for example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P. and
isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally
employed as a solvent or
suspending medium. For this purpose any bland fixed oil can be employed
including
synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid
are used in the
preparation of injectables.
[00249] The injectable formulations can be sterilized, for example, by
filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents in the form
of sterile solid
compositions which can be dissolved or dispersed in sterile water or other
sterile injectable
medium prior to use.
[00250] In order to prolong the effect of a compound of the present invention,
it is often
desirable to slow the absorption of the compound from subcutaneous or
intramuscular
injection. This may be accomplished by the use of a liquid suspension of
crystalline or
amorphous material with poor water solubility. The rate of absorption of the
compound then
depends upon its rate of dissolution that, in turn, may depend upon crystal
size and crystalline
form. Alternatively, delayed absorption of a parenterally administered
compound form is
accomplished by dissolving or suspending the compound in an oil vehicle.
Injectable depot
forms are made by forming microencapsule matrices of the compound in
biodegradable
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polymers such as polylactide-polyglycolide. Depending upon the ratio of
compound to
polymer and the nature of the particular polymer employed, the rate of
compound release can
be controlled. Examples of other biodegradable polymers include
poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared by
entrapping the
compound in liposomes or microemulsions that are compatible with body tissues.
[00251] Compositions for rectal or vaginal administration are preferably
suppositories
which can be prepared by mixing the compounds of this invention with suitable
non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which
are solid at ambient temperature but liquid at body temperature and therefore
melt in the
rectum or vaginal cavity and release the active compound.
[00252] Solid dosage forms for oral administration include capsules, tablets,
pills, powders,
and granules. In such solid dosage forms, the active compound is mixed with at
least one
inert, pharmaceutically acceptable excipient or carrier such as sodium citrate
or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol,
and silicic acid, b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol,
d) disintegrating
agents such as agar--agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such as
paraffin, f) absorption
accelerators such as quaternary ammonium compounds, g) wetting agents such as,
for
example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin
and bentonite
clay, and i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene
glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets and pills,
the dosage form may also comprise buffering agents.
[00253] Solid compositions of a similar type may also be employed as fillers
in soft and
hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high
molecular weight polyethylene glycols and the like. The solid dosage forms of
tablets,
dragees, capsules, pills, and granules can be prepared with coatings and
shells such as enteric
coatings and other coatings well known in the pharmaceutical formulating art.
They may
optionally contain opacifying agents and can also be of a composition that
they release the
active ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally,
in a delayed manner. Examples of embedding compositions that can be used
include
polymeric substances and waxes. Solid compositions of a similar type may also
be employed
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as fillers in soft and hard-filled gelatin capsules using such excipients as
lactose or milk sugar
as well as high molecular weight polethylene glycols and the like.
[00254] The active compounds can also be in microencapsulated form with one or
more
excipients as noted above. The solid dosage forms of tablets, dragees,
capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings,
release controlling
coatings and other coatings well known in the pharmaceutical formulating art.
In such solid
dosage forms the active compound may be admixed with at least one inert
diluent such as
sucrose, lactose or starch. Such dosage forms may also comprise, as is normal
practice,
additional substances other than inert diluents, e.g., tableting lubricants
and other tableting
aids such a magnesium stearate and microcrystalline cellulose. In the case of
capsules,
tablets and pills, the dosage forms may also comprise buffering agents. They
may optionally
contain opacifying agents and can also be of a composition that they release
the active
ingredient(s) only, or preferentially, in a certain part of the intestinal
tract, optionally, in a
delayed manner. Examples of embedding compositions that can be used include
polymeric
substances and waxes.
[00255] Dosage forms for topical or transdermal administration of a compound
of this
invention include ointments, pastes, creams, lotions, gels, powders,
solutions, sprays,
inhalants or patches. The active component is admixed under sterile conditions
with a
pharmaceutically acceptable carrier and any needed preservatives or buffers as
may be
required. Ophthalmic formulation, eardrops, and eye drops are also
contemplated as being
within the scope of this invention. Additionally, the present invention
contemplates the use
of transdermal patches, which have the added advantage of providing controlled
delivery of a
compound to the body. Such dosage forms are prepared by dissolving or
dispensing the
compound in the proper medium. Absorption enhancers can also be used to
increase the flux
of the compound across the skin. The rate can be controlled by either
providing a rate
controlling membrane or by dispersing the compound in a polymer matrix or gel.
[00256] As described generally above, the compounds of the invention are
useful as
modulators of ABC transporters. Thus, without wishing to be bound by any
particular
theory, the compounds and compositions are particularly useful for treating or
lessening the
severity of a disease, condition, or disorder where hyperactivity or
inactivity of ABC
transporters is implicated in the disease, condition, or disorder. When
hyperactivity or
inactivity of an ABC transporter is implicated in a particular disease,
condition, or disorder,
the disease, condition, or disorder may also be referred to as a "ABC
transporter-mediated
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disease, condition or disorder". Accordingly, in another aspect, the present
invention
provides a method for treating or lessening the severity of a disease,
condition, or disorder
where hyperactivity or inactivity of an ABC transporter is implicated in the
disease state.
[00257] The activity of a compound utilized in this invention as a modulator
of an ABC
transporter may be assayed according to methods described generally in the art
and in the
Examples herein.
[00258] It will also be appreciated that the compounds and pharmaceutically
acceptable
compositions of the present invention can be employed in combination
therapies, that is, the
compounds and pharmaceutically acceptable compositions can be administered
concurrently
with, prior to, or subsequent to, one or more other desired therapeutics or
medical procedures.
The particular combination of therapies (therapeutics or procedures) to employ
in a
combination regimen will take into account compatibility of the desired
therapeutics and/or
procedures and the desired therapeutic effect to be achieved. It will also be
appreciated that
the therapies employed may achieve a desired effect for the same disorder (for
example, an
inventive compound may be administered concurrently with another agent used to
treat the
same disorder), or they may achieve different effects (e.g., control of any
adverse effects).
As used herein, additional therapeutic agents that are normally administered
to treat or
prevent a particular disease, or condition, are known as "appropriate for the
disease, or
condition, being treated".
[00259] The amount of additional therapeutic agent present in the compositions
of this
invention will be no more than the amount that would normally be administered
in a
composition comprising that therapeutic agent as the only active agent.
Preferably the
amount of additional therapeutic agent in the presently disclosed compositions
will range
from about 50% to 100% of the amount normally present in a composition
comprising that
agent as the only therapeutically active agent.
[00260] The compounds of this invention or pharmaceutically acceptable
compositions
thereof may also be incorporated into compositions for coating an implantable
medical
device, such as prostheses, artificial valves, vascular grafts, stents and
catheters.
Accordingly, the present invention, in another aspect, includes a composition
for coating an
implantable device comprising a compound of the present invention as described
generally
above, and in classes and subclasses herein, and a carrier suitable for
coating said implantable
device. In still another aspect, the present invention includes an implantable
device coated
with a composition comprising a compound of the present invention as described
generally
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above, and in classes and subclasses herein, and a carrier suitable for
coating said implantable
device. Suitable coatings and the general preparation of coated implantable
devices are
described in US Patents 6,099,562; 5,886,026; and 5,304,121. The coatings are
typically
biocompatible polymeric materials such as a hydrogel polymer,
polymethyldisiloxane,
polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl
acetate, and mixtures
thereof. The coatings may optionally be further covered by a suitable topcoat
of
fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or
combinations thereof to
impart controlled release characteristics in the composition.
[00261] Another aspect of the invention relates to modulating ABC transporter
activity in a
biological sample or a patient (e.g., in vitro or in vivo), which method
comprises
administering to the patient, or contacting said biological sample with a
compound of formula
I or a composition comprising said compound. The term "biological sample", as
used herein,
includes, without limitation, cell cultures or extracts thereof; biopsied
material obtained from
a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears,
or other body
fluids or extracts thereof.
[00262] Modulation of ABC transporter activity in a biological sample is
useful for a
variety of purposes that are known to one of skill in the art. Examples of
such purposes
include, but are not limited to, the study of ABC transporters in biological
and pathological
phenomena; and the comparative evaluation of new modulators of ABC
transporters.
[00263] In yet another embodiment, a method of modulating activity of an anion
channel in
vitro or in vivo, is provided comprising the step of contacting said channel
with a compound
of formulae (I, Ic, Id, II, IIa, IIb, IIc, and IId). In preferred embodiments,
the anion channel is
a chloride channel or a bicarbonate channel. In other preferred embodiments,
the anion
channel is a chloride channel.
[00264] According to an alternative embodiment, the present invention provides
a method
of increasing the number of functional ABC transporters in a membrane of a
cell, comprising
the step of contacting said cell with a compound of formulae (I, Ic, Id, II,
IIa, l1b, 11c, and
IId). The term "functional ABC transporter" as used herein means an ABC
transporter that is
capable of transport activity. In preferred embodiments, said functional ABC
transporter is
CFTR.
[00265] According to another preferred embodiment, the activity of the ABC
transporter is
measured by measuring the transmembrane voltage potential. Means for measuring
the
voltage potential across a membrane in the biological sample may employ any of
the known
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methods in the art, such as optical membrane potential assay or other
electrophysiological
methods.
[00266] The optical membrane potential assay utilizes voltage-sensitive FRET
sensors
described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien (1995)
"Voltage
sensing by fluorescence resonance energy transfer in single cells" Biophys J
69(4): 1272-80,
and Gonzalez, J. E. and R. Y. Tsien (1997) "Improved indicators of cell
membrane potential
that use fluorescence resonance energy transfer" Chem Biol 4(4): 269-77) in
combination
with instrumentation for measuring fluorescence changes such as the
Voltage/Ion Probe
Reader (VIPR) (See, Gonzalez, J. E., K. Oades, et al. (1999) "Cell-based
assays and
instrumentation for screening ion-channel targets" Drug Discov Today 4(9): 431-
439).
[00267] These voltage sensitive assays are based on the change in fluorescence
resonant
energy transfer (FRET) between the membrane-soluble, voltage-sensitive dye,
DiSBAC2(3),
and a fluorescent phospholipid, CC2-DMPE, which is attached to the outer
leaflet of the
plasma membrane and acts as a FRET donor. Changes in membrane potential (V,,,)
cause the
negatively charged DiSBAC2(3) to redistribute across the plasma membrane and
the amount
of energy transfer from CC2-DMPE changes accordingly. The changes in
fluorescence
emission can be monitored using VIPR II, which is an integrated liquid handler
and
fluorescent detector designed to conduct cell-based screens in 96- or 384-well
microtiter
plates.
[00268] In another aspect the present invention provides a kit for use in
measuring the
activity of a ABC transporter or a fragment thereof in a biological sample in
vitro or in vivo
comprising (i) a composition comprising a compound of formulae (I, Ic, Id, II,
Ila, IIb, IIc,
and IId) or any of the above embodiments; and (ii) instructions for a.)
contacting the
composition with the biological sample and b.) measuring activity of said ABC
transporter or
a fragment thereof. In one embodiment, the kit further comprises instructions
for a.)
contacting an additional composition with the biological sample; b.) measuring
the activity of
said ABC transporter or a fragment thereof in the presence of said additional
compound, and
c.) comparing the activity of the ABC transporter in the presence of the
additional compound
with the density of the ABC transporter in the presence of a composition of
formulae (I, Ic,
Id, II, Ila, IIb, IIc, and IId). In preferred embodiments, the kit is used to
measure the density
of CFTR.
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[00269] In order that the invention described herein may be more fully
understood, the
following examples are set forth. It should be understood that these examples
are for
illustrative purposes only and are not to be construed as limiting this
invention in any manner.
[00270] VI. PREPARATIONS AND EXAMPLES
[00271] General Procedure I: Carboxylic Acid Building Block
A
(RxX)x Hal Hal (RXX)x A
I~ \ N I~ \ O
50% NaOH (aq) / OH
Hal = Cl, Br, I
[00272] Benzyltriethylammonium chloride (0.025 equivalents) and the
appropriate dihalo
compound (2.5 equivalents) were added to a substituted phenyl acetonitrile.
The mixture was
heated at 70 C and then 50 % sodium hydroxide (10 equivalents) was slowly
added to the
mixture. The reaction was stirred at 70 C for 12-24 hours to ensure complete
formation of
the cycloalkyl moiety and then heated at 130 C for 24-48 hours to ensure
complete
conversion from the nitrile to the carboxylic acid. The dark brown / black
reaction mixture
was diluted with water and extracted with dichloromethane three times to
remove side
products. The basic aqueous solution was acidified with concentrated
hydrochloric acid to
pH less than one and the precipitate which began to form at pH 4 was filtered
and washed
with 1 M hydrochloric acid two times. The solid material was dissolved in
dichloromethane
and extracted two times with 1 M hydrochloric acid and one time with a
saturated aqueous
solution of sodium chloride. The organic solution was dried over sodium
sulfate and
evaporated to dryness to give the cycloalkylcarboxylic acid. Yields and
purities were
typically greater than 90%.
[00273] Example 1: 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid
CI Br O
I /O DC)"Of~ld
O 50% NaOH (aq) O [00274] A mixture of 2-(benzo[d][1,3]dioxol-5-
yl)acetonitrile (5.10 g 31.7 mmol), 1-
bromo-2-chloro-ethane (9.00 mL 109 mmol), and benzyltriethylammonium chloride
(0.181 g,
0.795 mmol) was heated at 70 C and then 50% (wt./wt.) aqueous sodium
hydroxide (26 mL)
was slowly added to the mixture. The reaction was stirred at 70 C for 24
hours and then
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heated at 130 C for 48 hours. The dark brown reaction mixture was diluted
with water (400
mL) and extracted once with an equal volume of ethyl acetate and once with an
equal volume
of dichloromethane. The basic aqueous solution was acidified with concentrated
hydrochloric acid to pH less than one and the precipitate filtered and washed
with 1 M
hydrochloric acid. The solid material was dissolved in dichloromethane (400
mL) and
extracted twice with equal volumes of 1 M hydrochloric acid and once with a
saturated
aqueous solution of sodium chloride. The organic solution was dried over
sodium sulfate and
evaporated to dryness to give a white to slightly off-white solid (5.23 g,
80%) ESI-MS m/z
calc. 206.1, found 207.1 (M+1)+. Retention time 2.37 minutes. 1H NMR (400 MHz,
DMSO-
d6) 8 1.07-1.11 (m, 2H), 1.38-1.42 (m, 2H), 5.98 (s, 2H), 6.79 (m, 2H), 6.88
(m, 1H), 12.26
(s, 1H).
[00275] General Procedure II: Carboxylic Acid Building Block
A
(XRX)x Hal Hal (XRX)x A (XRX)x A
N NaOH I / NaOH OH
Hal = Cl, Br, I, all other variables are as defined in the text.
[00276] Sodium hydroxide (50 % aqueous solution, 7.4 equivalents) was slowly
added to a
mixture of the appropriate phenyl acetonitrile, benzyltriethylammonium
chloride (1.1
equivalents), and the appropriate dihalo compound (2.3 equivalents) at 70 T.
The mixture
was stirred overnight at 70 C and the reaction mixture was diluted with water
(30 mL) and
extracted with ethyl acetate. The combined organic layers were dried over
sodium sulfate
and evaporated to dryness to give the crude cyclopropanecarbonitrile, which
was used
directly in the next step.
[00277] The crude cyclopropanecarbonitrile was refluxed in 10% aqueous sodium
hydroxide (7.4 equivalents) for 2.5 hours. The cooled reaction mixture was
washed with
ether (100 mL) and the aqueous phase was acidified to pH 2 with 2M
hydrochloric acid. The
precipitated solid was filtered to give the cyclopropanecarboxylic acid as a
white solid.
[00278] General Procedure III: Carboxylic Acid Building Block
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\ Br Pd(PPh3)4 C02Me LiAIH4
R i / R i R OH
CO/CH3OH
SOC12 \ CI NaCN 1 \ CN
R- /
CICH2CH2Br NaOH
i \ CN R C02H
NaOH R
[00279] Example 2: 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-
cyclopropanecarboxylic
acid
F ` O I Br Pd(PPh3)4 F C02Me LiAIH4 F\ O I \ OH SOCI2
F O / CO/CH30H F O F
F\ O I \ CI Nam F O I \ CN CICH2CH2Br F0 \ CN NaOH
0 / F O / NaOH F 0 I/
F\ O I C02H
F O :e
Fx0 \ Br Pd(PPh3)4 Fx0 \ CO2Me
F p I/ CO/CH3OH F O-
[00280] 2,2-Difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester
[00281] A solution of 5-bromo-2,2-difluoro-benzo[1,3]dioxole (11.8 g, 50.0
mmol) and
tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4, 5.78 g, 5.00 mmol] in
methanol (20
mL) containing acetonitrile (30 mL) and triethylamine (10 mL) was stirred
under a carbon
monoxide atmosphere (55 PSI) at 75 C (oil bath temperature) for 15 hours. The
cooled
reaction mixture was filtered and the filtrate was evaporated to dryness. The
residue was
purified by silica gel column chromatography to give crude 2,2-difluoro-benzo
[1,3] dioxole-
5-carboxylic acid methyl ester (11.5 g), which was used directly in the next
step.
F \ C02Me LiAIH4 F OH
\ )OW FxxO l/ FxxCO l/
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[00282] (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-methanol
[00283] Crude 2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester
(11.5 g)
dissolved in 20 mL of anhydrous tetrahydrofuran (THF) was slowly added to a
suspension of
lithium aluminum hydride (4.10 g, 106 mmol) in anhydrous THF (100 mL) at 0 T.
The
mixture was then warmed to room temperature. After being stirred at room
temperature for 1
hour, the reaction mixture was cooled to 0 C and treated with water (4.1 g),
followed by
sodium hydroxide (10% aqueous solution, 4.1 mL). The resulting slurry was
filtered and
washed with THE The combined filtrate was evaporated to dryness and the
residue was
purified by silica gel column chromatography to give (2,2-difluoro-
benzo[1,3]dioxol-5-yl)-
methanol (7.2 g, 38 mmol, 76 % over two steps) as a colorless oil.
F\ , I \ OH SOCI2 F\ O I \ CI
F O / F O /
[00284] 5-Chloromethyl-2,2-difluoro-benzo[1,3]dioxole
[00285] Thionyl chloride (45 g, 38 mmol) was slowly added to a solution of
(2,2-difluoro-
benzo[1,3]dioxol-5-yl)-methanol (7.2 g, 38 mmol) in dichloromethane (200 mL)
at 0 T. The
resulting mixture was stirred overnight at room temperature and then
evaporated to dryness.
The residue was partitioned between an aqueous solution of saturated sodium
bicarbonate
(100 mL) and dichloromethane (100 mL). The separated aqueous layer was
extracted with
dichloromethane (150 mL) and the organic layer was dried over sodium sulfate,
filtrated, and
evaporated to dryness to give crude 5-chloromethyl-2,2-difluoro-
benzo[1,3]dioxole (4.4 g)
which was used directly in the next step.
F CN
FX I / F\ , I CN
O FxO
[00286] (2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile
[00287] A mixture of crude 5-chloromethyl-2,2-difluoro-benzo[1,3]dioxole (4.4
g) and
sodium cyanide (1.36 g, 27.8 mmol) in dimethylsulfoxide (50 mL) was stirred at
room
temperature overnight. The reaction mixture was poured into ice and extracted
with ethyl
acetate (300 mL). The organic layer was dried over sodium sulfate and
evaporated to dryness
to give crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (3.3 g) which
was used
directly in the next step.
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F\ , I \ CN CICH2CH2Br
x Fx \ CN
F NaOH F p
[00288] 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile
[00289] Sodium hydroxide (50% aqueous solution, 10 mL) was slowly added to a
mixture
of crude (2,2-difluoro-benzo[1,3]dioxol-5-yl)-acetonitrile,
benzyltriethylammonium chloride
(3.00 g, 15.3 mmol), and 1-bromo-2-chloroethane (4.9 g, 38 mmol) at 70 T.
[00290] The mixture was stirred overnight at 70 C before the reaction mixture
was diluted
with water (30 mL) and extracted with ethyl acetate. The combined organic
layers were dried
over sodium sulfate and evaporated to dryness to give crude 1-(2,2-difluoro-
benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile, which was used directly in
the next step.
NaOH
F\ O , I \ CN F\ , I \ CO2H
FxO Xo e
[00291] 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid
[00292] 1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (crude
from the
last step) was refluxed in 10% aqueous sodium hydroxide (50 mL) for 2.5 hours.
The cooled
reaction mixture was washed with ether (100 mL) and the aqueous phase was
acidified to pH
2 with 2M hydrochloric acid. The precipitated solid was filtered to give 1-
(2,2-difluoro-
benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid as a white solid (0.15 g,
1.6% over four
steps). ESI-MS m/z calc. 242.04, found 241.58 (M+1)+; IH NMR (CDC13) 8 7.14-
7.04 (m,
2H), 6.98-6.96 (m, 1H), 1.74-1.64 (m, 2H), 1.26-1.08 (m, 2H).
[00293] Example 3: 2-(2,2-Dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile
NC I :~:CQ> BBr3, DCM NC OH 2,2-d i methoxy- pro
P-TsOH to uenePane NC I ~---
OK
NC I :`~~:O> BBr3, DCMNC OH
O I OH
[00294] (3,4-Dihydroxy-phenyl)-acetonitrile
[00295] To a solution of benzo[1,3]dioxol-5-yl-acetonitrile (0.50 g, 3.1 mmol)
in CH2Cl2
(15 mL) was added dropwise BBr3 (0.78 g, 3.1 mmol) at -78 C under N2. The
mixture was
slowly warmed to room temperature and stirred overnight. H2O (10 mL) was added
to
quench the reaction and the CH2C12 layer was separated. The aqueous phase was
extracted
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with CH2C12 (2 x 7 mL). The combined organics were washed with brine, dried
over Na2SO4
and purified by column chromatography on silica gel (petroleum ether/ethyl
acetate 5:1) to
give (3,4-dihydroxy-phenyl)-acetonitrile (0.25 g, 54%) as a white solid. 1H
NMR (DMSO-d6,
400 MHz) 8 9.07 (s, 1 H), 8.95 (s, 1 H), 6.68-6.70 (m, 2 H), 6.55 (dd, J =
8.0, 2.0 Hz, 1 H),
3.32 (s, 2 H).
OH 2,2-dimethoxy-propane NC O
NC
OH p-TsOH, toluene 0
[00296] 2-(2,2-Dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile
[00297] To a solution of (3,4-dihydroxy-phenyl)-acetonitrile (0.20 g, 1.3
mmol) in toluene
(4 mL) was added 2,2-dimethoxy-propane (0.28 g, 2.6 mmol) and TsOH (0.010 g,
0.065
mmol). The mixture was heated at reflux overnight. The reaction mixture was
evaporated to
remove the solvent and the residue was dissolved in ethyl acetate. The organic
layer was
washed with NaHCO3 solution, H2O, brine, and dried over Na2SO4. The solvent
was
evaporated under reduced pressure to give a residue, which was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give 2-
(2,2-
dimethylbenzo[d][1,3]dioxol-5-yl)acetonitrile (40 mg, 20%). 1H NMR (CDC13, 400
MHz) 8
6.68-6.71 (m, 3 H), 3.64 (s, 2 H), 1.67 (s, 6 H).
[00298] Example 4: 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic acid
OBn BrCH2CH2CI NC aj~ OBn H2 NC aj~ OH NaOH HOOC aj'~" OH
NC
OBn OBn OH OH
OBn BrCH2CH2Cl NC I OBn
NC
a---
OBn OBn
[00299] 1-(3,4-Bis-benzyloxy-phenyl)-cyclopropanecarbonitrile
[00300] To a mixture of (n-C4H9)4NBr (0.50 g, 1.5 mmol), toluene (7 mL) and
(3,4-bis-
benzyloxy-phenyl)-acetonitrile (14 g, 42 mmol) in NaOH (50 g) and H2O (50 mL)
was added
BrCH2CH2C1(30 g, 0.21 mol). The reaction mixture was stirred at 50 C for 5 h
before being
cooled to room temperature. Toluene (30 mL) was added and the organic layer
was separated
and washed with H2O, brine, dried over anhydrous MgSO4, and concentrated. The
residue
was purified by column on silica gel (petroleum ether/ethyl acetate 10:1) to
give 1-(3,4-bis-
benzyloxy-phenyl)-cyclopropanecarbonitrile (10 g, 66%). 1H NMR (DMSO 300 MHz)
8
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7.46-7.30 (m, 10 H), 7.03 (d, J = 8.4 Hz, 1 H), 6.94 (d, J = 2.4 Hz, 1 H),
6.89 (dd, J = 2.4, 8.4
Hz, 1 H), 5.12 (d, J = 7.5 Hz, 4H), 1.66-1.62 (m, 2 H), 1.42-1.37 (m, 2 H).
NC I OBn H2 NC I OH
~ OBn Pd/C ~ OH
[00301] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarbonitrile
[00302] To a solution of 1-(3,4-bis-benzyloxy-phenyl)-cyclopropanecarbonitrile
(10 g, 28
mmol) in MeOH (50 mL) was added Pd/C (0.5 g) under nitrogen atmosphere. The
mixture
was stirred under hydrogen atmosphere (1 atm) at room temperature for 4 h. The
catalyst
was filtered off through a celite pad and the filtrate was evaporated under
vacuum to give 1-
(3,4-dihydroxy-phenyl)-cyclopropanecarbonitrile (4.5 g, 92%). 1H NMR (DMSO 400
MHz)
8 9.06 (br s, 2 H), 6.67-6.71 (m, 2 H), 6.54 (dd, J = 2.4, 8.4 Hz, 1 H), 1.60-
1.57 (m, 2 H),
1.30-1.27 (m, 2 H).
NC I OH NaOH -IBM- ~ HOOC I OH
~ OH OH
[00303] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic acid
[00304] To a solution of NaOH (20 g, 0.50 mol) in H2O (20 mL) was added 1-(3,4-
dihydroxy-phenyl)-cyclopropanecarbonitrile (4.4 g, 25 mmol). The mixture was
heated at
reflux for 3 h before being cooled to room temperature. The mixture was
neutralized with
HCl (0.5 N) to pH 3-4 and extracted with ethyl acetate (20 mL x 3). The
combined organic
layers were washed with water, brine, dried over anhydrous MgSO4, and
concentrated under
vacuum to obtain 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic acid (4.5 g
crude). From
900 mg crude, 500 mg pure 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic acid
was
obtained by preparatory HPLC. 1H NMR (DMSO, 300 MHz) 8 12.09 (br s, 1 H), 8.75
(br s, 2
H), 6.50-6.67 (m, 3 H), 1.35-1.31 (m, 2 H), 1.01-0.97 (m, 2 H).
[00305] Example 5: 1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropane-
carboxylic acid.
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HO I MeOH MeO I HNO3/Ac20 MeO NO2 BBr3
I
O OMe O OMe O OMe
Me0 NO Me0 NH MeO 2 Ni/HZ z triphosgenO I/ OH O I/ OH O I~,,HN~
O ~O
LiOH HO H
N>==O
O / O
H Mew Me0
Oe
0 I - OMe O I - OMe
[00306] 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester
[00307] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50
g, 0.26
mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13
mmol) at
room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH
was
removed by evaporation under vacuum and EtOAc (200 mL) was added. The organic
layer
was washed with sat. aq. NaHCO3 (100 mL) and brine, dried over anhydrous
Na2SO4 and
evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic
acid methyl
ester (53 g, 99%). 'H NMR (CDC13, 400 MHz) 8 7.25-7.27 (m, 2 H), 6.85 (d, J =
8.8 Hz, 2
H), 3.80 (s, 3 H), 3.62 (s, 3 H), 1.58 (q, J = 3.6 Hz, 2 H), 1.15 (q, J = 3.6
Hz, 2 H).
MeO HNO3/Ac20 M e 0 NO2
I OMe~ O I OMe
[00308] 1-(4-Methoxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester
[00309] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid
methyl ester
(30.0 g, 146 mmol) in Ac20 (300 mL) was added a solution of HNO3 (14.1 g, 146
mmol,
65%) in AcOH (75 mL) at 0 C. The reaction mixture was stirred at 0. 5 C for
3 h before
aq. HCl (20%) was added dropwise at 0 C. The resulting mixture was extracted
with EtOAc
(200 mL x 3). The organic layer was washed with sat. aq. NaHCO3 then brine,
dried over
anhydrous Na2SO4 and evaporated under vacuum to give 1-(4-methoxy-3-nitro-
phenyl)-
cyclopropanecarboxylic acid methyl ester (36.0 g, 98%), which was directly
used in the next
step. 'H NMR (CDC13, 300 MHz) 8 7.84 (d, J = 2.1 Hz, 1 H), 7.54 (dd, J = 2.1,
8.7 Hz, 1 H),
7.05 (d, J= 8.7 Hz, 1 H), 3.97 (s, 3 H), 3.65 (s, 3 H), 1.68-1.64 (m, 2 H),
1.22-1.18 (m, 2 H).
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MeO NO2 BBr3 MeO NO2
O OMe O I / OH
[00310] 1-(4-Hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester
[00311] To a solution of 1-(4-methoxy-3-nitro-phenyl)-cyclopropane-carboxylic
acid
methyl ester (10.0 g, 39.8 mmol) in CH2C12 (100 mL) was added BBr3 (12.0 g,
47.8 mmol) at
-70 C. The mixture was stirred at -70 C for 1 hour, then allowed to warm to -
30 C and
stirred at this temperature for 3 hours. Water (50 mL) was added dropwise at -
20 C, and the
resulting mixture was allowed to warm room temperature before it was extracted
with EtOAc
(200 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and
evaporated under vacuum to give the crude product, which was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate 15:1) to afford 1-
(4-hydroxy-3-
nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (8.3 g, 78%). 1H NMR
(CDC13, 400
MHz) 8 10.5 (s, 1 H), 8.05 (d, J = 2.4 Hz, 1 H), 7.59 (dd, J = 2.0, 8.8 Hz, 1
H), 7.11 (d, J =
8.4 Hz, 1 H), 3.64 (s, 3 H), 1.68-1.64 (m, 2 H), 1.20-1.15 (m, 2 H).
'Sl
Me0 N02 Ni/H2 MeO NH2
ii a OH 0 I OH
[00312] 1-(3-Amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester
[00313] To a solution of 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic
acid methyl
ester (8.3 g, 35 mmol) in MeOH (100 mL) was added Raney Nickel (0.8 g) under
nitrogen
atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at 35 C
for 8
hours. The catalyst was filtered off through a Celite pad and the filtrate was
evaporated
under vacuum to give crude product, which was purified by column
chromatography on silica
gel (petroleum ether/ethyl acetate 1:1) to give 1-(3-amino-4-hydroxy-phenyl)-
cyclopropanecarboxylic acid methyl ester (5.3 g, 74%). 1H NMR (CDC13, 400 MHz)
8 6.77
(s, 1 H), 6.64 (d, J= 2.0 Hz, 2 H), 3.64 (s, 3 H), 1.55-1.52 (m, 2 H), 1.15-
1.12 (m, 2 H).
H
MeO NH2 triphosgene MeO
O
I'SIa --VI- >==
O OH O 0
[00314] 1-(2-Oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid
methyl
ester
[00315] To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic
acid
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methyl ester (2.0 g, 9.6 mmol) in THE (40 mL) was added triphosgene (4.2 g, 14
mmol) at
room temperature. The mixture was stirred for 20 minutes at this temperature
before water
(20 mL) was added dropwise at 0 C. The resulting mixture was extracted with
EtOAc (100
mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and
evaporated
under vacuum to give 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-
cyclopropanecarboxylic acid
methyl ester (2.0 g, 91%), which was directly used in the next step. 1H NMR
(CDC13, 300
MHz) 8 8.66 (s, 1 H), 7.13-7.12 (m, 2 H), 7.07 (s, 1 H), 3.66 (s, 3 H), 1.68-
1.65 (m, 2 H),
1.24-1.20 (m, 2 H).
MeO \ Lim H N
O I H O I/ O
[00316] 1-(2-Oxo-2,3-dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid
[00317] To a solution of 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-
cyclopropanecarboxylic
acid methyl ester (1.9 g, 8.1 mmol) in MeOH (20 mL) and water (2 mL) was added
LiOH.H20 (1.7 g, 41 mmol) in portions at room temperature. The reaction
mixture was
stirred for 20 hours at 50 C. MeOH was removed by evaporation under vacuum
before
water (100 mL) and EtOAc (50 mL) were added. The aqueous layer was separated,
acidified
with HCl (3 mol/L) and extracted with EtOAc (100 mL x 3). The combined organic
layers
were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-
2,3-
dihydrobenzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (1.5 g, 84%). 1H NMR
(DMSO,
400 MHz) 8 12.32 (brs, 1 H), 11.59 (brs, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 7.00
(d, J = 8.0 Hz,
1 H), 1.44-1.41 (m, 2 H), 1.13-1.10 (m, 2 H). MS (ESI) m/e (M+H+) 218.1.
[00318] Example 6: 1-(6-Fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic
acid
O O O \
H I \ O~ BBr3 H / I \ OH BrCH2CI/DMF H I \ O NaBH4 HO O>
F p, F OH F O F O
~ > NaCN O O\
SOCIZ CI I \ O NC I \ BrCHZCHZCI NC I \ / Ip- ~ F / F
10% NaOH HOOCO\
//
F0
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O 0
H ao O~BBr3 -10- H I a OH
F 1 F OH
[00319] 2-Fluoro-4,5-dihydroxy-benzaldehyde
[00320] To a stirred suspension of 2-fluoro-4,5-dimethoxy-benzaldehyde (3.00
g, 16.3
mmol) in dichloromethane (100 mL) was added BBr3 (12.2 mL, 130 mmol) dropwise
at -78
C under nitrogen atmosphere. After addition, the mixture was warmed to -30 C
and stirred
at this temperature for 5 h. The reaction mixture was poured into ice water
and the
precipitated solid was collected by filtration and washed with dichloromethane
to afford 2-
fluoro-4,5-dihydroxy-benzaldehyde (8.0 g), which was used directly in the next
step.
O 0
H I \ OH BrCH2CI/DMF H I \ 0>
F / OH FO
[00321] 6-Fluoro-benzo[1,3]dioxole-5-carbaldehyde To a stirred solution of 2-
fluoro-
4,5-dihydroxy-benzaldehyde (8.0 g) and BrC1CH2 (24.8 g, 190 mmol) in dry DMF
(50 mL)
was added Cs2CO3 (62.0 g, 190 mmol) in portions. The resulting mixture was
stirred at 60
C overnight and then poured into water. The mixture was extracted with EtOAc
(200 mL x
3). The combined organic layers were washed with brine (200 mL), dried over
Na2SO4, and
evaporated in vacuo to give crude product, which was purified by column
chromatography on
silica gel (5-20% ethyl acetate/petroleum ether) to afford 6-fluoro-
benzo[1,3]dioxole-5-
carbaldehyde (700 mg, two steps yield: 24%). 1H-NMR (400 MHz, CDC13) 8 10.19
(s, 1 H),
7.23 (d, J = 5.6, 1 H), 6.63 (d, J = 9.6, 1 H), 6.08 (s, 2 H).
O
\ 00 NaBH4 HO I 0>
H
/ O F 0
F
[00322] (6-Fluoro-benzo[1,3]dioxol-5-yl)-methanol
[00323] To a stirred solution of 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde
(700 mg, 4.2
mmol) in MeOH (50 mL) was added NaBH4 (320 mg, 8.4 mmol) in portions at 0 C.
The
mixture was stirred at this temperature for 30 min and was then concentrated
in vacuo to give
a residue. The residue was dissolved in EtOAc and the organic layer was washed
with water,
dried over Na2SO4, and concentrated in vacuo to afford (6-fluoro-
benzo[1,3]dioxol-5-yl)-
methanol (650 mg, 92%), which was directly used in the next step.
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HO F I 00> SOCI2 CI F I 00/
Do.
[00324] 5-Chloromethyl-6-fluoro-benzo[1,3]dioxole
[00325] (6-Eluoro-benzo[1,3]dioxol-5-yl)-methanol (650 mg, 3.8 mmol) was added
to
SOC12 (20 mL) in portions at 0 C. The mixture was warmed to room temperature
for 1 h and
then heated at reflux for 1 h. The excess SOC12 was evaporated under reduced
pressure to
give the crude product, which was basified with sat. NaHCO3 solution to pH -
7. The
aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic
layers were
dried over Na2SO4 and evaporated under reduced pressure to give 5-chloromethyl-
6-fluoro-
benzo[1,3]dioxole (640 mg, 90%), which was directly used in the next step.
O
CI ~I O NaCN NC F
F
[00326] (6-Fluoro-benzo[1,3]dioxol-5-yl)-acetonitrile
[00327] A mixture of 5-chloromethyl-6-fluoro-benzo[1,3]dioxole (640 mg, 3.4
mmol) and
NaCN (340 mg, 6.8 mmol) in DMSO (20 mL) was stirred at 30 C for 1 h and then
poured
into water. The mixture was extracted with EtOAc (50 mL x 3). The combined
organic
layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4,
and
evaporated under reduced pressure to give the crude product, which was
purified by column
chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford
(6-fluoro-
benzo[1,3]dioxol-5-yl)-acetonitrile (530 mg, 70%). 'H-NMR (300 MHz, CDC13) 8
6.82 (d, J
= 4.8, 1 H), 6.62 (d, J= 5.4, 1 H), 5.99 (s, 2 H), 3.65 (s, 2 H).
NC -:::j I \ BrCH2CH2Cl NC F V / /
[00328] 1-(6-Fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile
[00329] A flask was charged with water (10 mL), followed by a rapid addition
of NaOH
(10 g, 0.25 mol) in three portions over a 5 min period. The mixture was
allowed to cool to
room temperature. Subsequently, the flask was charged with toluene (6 mL),
tetrabutyl-
ammonium bromide (50 mg, 0.12 mmol), (6-fluoro-benzo[1,3]dioxol-5-yl)-
acetonitrile (600
mg, 3.4 mmol) and 1-bromo-2-chloroethane (1.7 g, 12 mmol). The mixture stirred
vigorously at 50 C overnight. The cooled flask was charged with additional
toluene (20
mL). The organic layer was separated and washed with water (30 mL) and brine
(30 mL).
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The organic layer was removed in vacuo to give the crude product, which was
purified by
column chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to
give 1-(6-
fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonitrile (400 mg, 60%). 'H NMR
(300 MHz,
CDC13) 8 6.73 (d, J = 3.0 Hz, 1 H), 6.61 (d, J = 9.3 Hz, 1 H), 5.98 (s, 2 H),
1.67-1.62 (m, 2
H), 1.31-1.27 (m, 2 H).
\ O 10% NaOH HOOC I \ O
NC57
/ O, F O,
F
[00330] 1-(6-Fluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarboxylic acid
[00331] A mixture of 1-(6-fluoro-benzo[1,3]dioxol-5-yl)-
cyclopropanecarbonitrile (400
mg, 0.196 mmol) and 10% NaOH (10 mL) was stirred at 100 C overnight. After
the
reaction was cooled, 5% HCl was added until the pH < 5 and then EtOAc (30 mL)
was added
to the reaction mixture. The layers were separated and combined organic layers
were
evaporated in vacuo to afford 1-(6-fluoro-benzo[1,3]dioxol-5-yl)-
cyclopropanecarboxylic
acid (330 mg, 76%). 'H NMR (400 MHz, DMSO) 8 12.2 (s, 1 H), 6.87-6.85 (m, 2
H), 6.00
(s, 1 H), 1.42-1.40 (m, 2 H), 1.14-1.07 (m, 2 H).
[00332] Example 7: 1-(Benzofuran-5-yl)cyclopropanecarboxylic acid
Br(OEt HO \
Me0 \ OB
O I / O^ /OEt
O I / 1
OH NaH, DMF OB
PPA, xylene HO
O O
Me0 Br(OEt HO \
\ OB
I / OB
O I / OH NaH, DMF
OB
[00333] 1-[4-(2,2-Diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid
[00334] To a stirred solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic
acid methyl
ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodium hydride (6.7 g, 170
mmol,
60% in mineral oil) at 0 C. After hydrogen evolution ceased, 2-bromo-1,1-
dethoxy-ethane
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(16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction
was stirred at
160 C for 15 hours. The reaction mixture was poured onto ice (100 g) and was
extracted
with CH2C12. The combined organics were dried over Na2SO4. The solvent was
evaporated
under vacuum to give 1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic
acid (10
g), which was used directly in the next step without purification.
HO
PPA, xylene HO
0
I/ O OD 0 O
Y
OEt
[00335] 1-Benzofuran-5-yl-cyclopropanecarboxylic acid
[00336] To a suspension of 1-[4-(2,2-diethoxy-ethoxy)-phenyl]-
cyclopropanecarboxylic
acid (20 g, -65 mmol) in xylene (100 mL) was added PPA (22.2 g, 64.9 mmol) at
room
temperature. The mixture was heated at reflux (140 C) for 1 hour before it
was cooled to
room temperature and decanted from the PPA. The solvent was evaporated under
vacuum to
obtain the crude product, which was purified by preparative HPLC to provide 1-
(benzofuran-
5-yl)cyclopropanecarboxylic acid (1.5 g, 5%). 1H NMR (400 MHz, DMSO-d6) 8
12.25 (br s,
1 H), 7.95 (d, J = 2.8 Hz, 1 H), 7.56 (d, J = 2.0 Hz, 1 H), 7.47 (d, J = 11.6
Hz, 1 H), 7.25 (dd,
J = 2.4, 11.2 Hz, 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 1.47-1.44 (m, 2 H), 1.17-
1.14 (m, 2 H).
[00337] Example 8: 1-(2,3-Dihydrobenzofuran-6-yl)cyclopropanecarboxylic acid
HO O Pt02, MeOH HO 0
O / 0
[00338] To a solution of 1-(benzofuran-6-yl)cyclopropanecarboxylic acid (370
mg, 1.8
mmol) in MeOH (50 mL) was added Pt02 (75 mg, 20%) at room temperature. The
reaction
mixture was stirred under hydrogen atmosphere (1 atm) at 20 C for 3 d. The
reaction
mixture was filtered and the solvent was evaporated in vacuo to afford the
crude product,
which was purified by prepared HPLC to give 1-(2,3-dihydrobenzofuran-6-
yl)cyclopropanecarboxylic acid (155 mg, 42%). 1H NMR (300 MHz, MeOD) 8 7.13
(d, J =
7.5 Hz, 1 H), 6.83 (d, J = 7.8 Hz, 1 H), 6.74 (s, 1 H), 4.55 (t, J = 8.7 Hz, 2
H), 3.18 (t, J = 8.7
Hz, 2 H), 1.56-1.53 (m, 2 H), 1.19-1.15 (m, 2 H).
[00339] Example 9: 1-(3,3-Dimethyl-2,3-dihydrobenzofuran-5-
yl)cyclopropanecarboxylic acid.
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MeO AICI3/EtSH MeO NIS MeO I
O I/ OM~ O
O I/ OH
OH
MeO
BU3SnH Me0 UGH _ HO
O O 'Y I
AIBN O O O O
MeO AICI3/EtSH Me0
O
Y I / OM~ O I OH
[00340] 1-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester
[00341] To a solution of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate
(10.0 g,
48.5 mmol) in dichloromethane (80 mL) was added EtSH (16 mL) under ice-water
bath. The
mixture was stirred at 0 C for 20 min before A1C13 (19.5 g, 0.15 mmol) was
added slowly at
0 C. The mixture was stirred at 0 C for 30 min. The reaction mixture was
poured into ice-
water, the organic layer was separated, and the aqueous phase was extracted
with
dichloromethane (50 mL x 3). The combined organic layers were washed with H2O,
brine,
dried over Na2SO4 and evaporated under vacuum to give 1-(4-hydroxy-phenyl)-
cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). 1H NMR (400 MHz, CDC13)
8 7.20-
7.17 (m, 2 H), 6.75-6.72 (m, 2 H), 5.56 (s, 1 H), 3.63 (s, 3 H), 1.60-1.57 (m,
2 H), 1.17-1.15
(m, 2 H).
MeO NIS MeO I
l DO-
O I a OH O I/ OH
[00342] 1-(4-Hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic acid methyl
ester
[00343] To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid
methyl ester
(8.9 g, 46 mmol) in CH3CN (80 mL) was added NIS (15.6 g, 69 mmol). The mixture
was
stirred at room temperature for 1 hour. The reaction mixture was concentrated
and the
residue was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate
10:1) to give 1-(4-hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic acid
methyl ester (3.5
g, 18%). 1H NMR (400 MHz, CDC13) 8 7.65 (s, 2 H), 5.71 (s, 1 H), 3.63 (s, 3
H), 1.59-1.56
(m, 2 H), 1.15-1.12 (m, 2 H).
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MeO \ IOH MeO I
O I / O I / O~
I I
[00344] 1-[3,5-Diiodo-4-(2-methyl-allyloxy)-phenyl]-cyclopropanecarboxylic
acid
methyl ester
[00345] A mixture of 1-(4-hydroxy-3,5-diiodo-phenyl)-cyclopropanecarboxylic
acid
methyl ester (3.2 g, 7.2 mmol), 3-chloro-2-methyl-propene (1.0 g, 11 mmol),
K2CO3 (1.2 g,
8.6 mmol), Nal (0.1 g, 0.7 mmol) in acetone (20 mL) was stirred at 20 C
overnight. The
solid was filtered off and the filtrate was concentrated under vacuum to give
1-[3,5-diiodo-4-
(2-methyl-allyloxy)-phenyl]-cyclopropane-carboxylic acid methyl ester (3.5 g,
97%). 1H
NMR (300 MHz, CDC13) 8 7.75 (s, 2 H), 5.26 (s, 1 H), 5.06 (s, 1 H), 4.38 (s, 2
H), 3.65 (s, 3
H), 1.98 (s, 3H), 1.62-1.58 (m, 2 H), 1.18-1.15 (m, 2 H).
Me I
Bu3 Me
30.
O
O 1 AIBN O O
I I
[00346] 1-(3,3-Dimethyl-2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic
acid
methyl ester
[00347] To a solution of 1-[3,5-diiodo-4-(2-methyl-allyloxy)-phenyl]-
cyclopropane-
carboxylic acid methyl ester (3.5 g, 7.0 mmol) in toluene (15 mL) was added
Bu3SnH (2.4 g,
8.4 mmol) and AIBN (0.1 g, 0.7 mmol). The mixture was heated at reflux
overnight. The
reaction mixture was concentrated under vacuum and the residue was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 1-
(3,3 -dimethyl-
2,3-dihydro-benzofuran-5-yl)-cyclopropanecarboxylic acid methyl ester (1.05 g,
62%). 1H
NMR (400 MHz, CDC13) 8 7.10-7.07 (m, 2 H), 6.71 (d, J = 8 Hz, 1 H), 4.23 (s, 2
H), 3.62 (s,
3 H), 1.58-1.54 (m, 2 H), 1.34 (s, 6 H), 1.17-1.12 (m, 2 H).
Me0 LiOH H
O O qol:):-10~
[00348] 1-(3,3-Dimethyl-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid
[00349] To a solution of 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-
cyclopropanecarboxylic acid methyl ester (1.0 g, 4.0 mmol) in MeOH (10 mL) was
added
LiOH (0.40 g, 9.5 mmol). The mixture was stirred at 40 C overnight. HCl (10%)
was added
slowly to adjust the pH to 5. The resulting mixture was extracted with ethyl
acetate (10 mL x
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3). The extracts were washed with brine and dried over Na2SO4. The solvent was
removed
under vaccum and the crude product was purified by preparative HPLC to give 1-
(3,3-
dimethyl-2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxylic acid (0.37 g, 41%).
1H NMR
(400 MHz, CDC13) 8 7.11-7.07 (m, 2 H), 6.71 (d, J = 8 Hz, 1 H), 4.23 (s, 2 H),
1.66-1.63 (m,
2 H), 1.32 (s, 6 H), 1.26-1.23 (m, 2 H).
[00350] Example 10: 2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile.
O O O
MeO I \ OH Me2SO4 MeO I \ OH CH2BrCl MeO 0> LiAIH4
/ OH Na2B4O7 / OH / 0
OH OMe OMe
HO I \ \ SOCIZ _ CI \ NaCN NaCN NC I \ O>
O 1 O / / O
OMe OMe OMe
O 0
MeO OH Me2SO4 Me0 OH
OH OH
OH Na2B407 OMe
[00351] 3,4-Dihydroxy-5-methoxybenzoate
[00352] To a solution of 3,4,5-trihydroxy-benzoic acid methyl ester (50 g,
0.27 mol) and
Na2B4O7 (50 g) in water (1000 mL) was added Me2SO4 (120 mL) and aqueous NaOH
solution (25%, 200 mL) successively at room temperature. The mixture was
stirred at room
temperature for 6 h before it was cooled to 0 C. The mixture was acidified to
pH - 2 by
adding conc. H2SO4 and then filtered. The filtrate was extracted with EtOAc
(500 mL x 3).
The combined organic layers were dried over anhydrous Na2SO4 and evaporated
under
reduced pressure to give methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g 47%),
which was
used in the next step without further purification.
O 0
MeO OH CH2BrCI MeO \ O\
OH NaCN I / O
OMe OMe
[00353] Methyl 7-methoxybenzo[d] [1,3]dioxole-5-carboxylate
[00354] To a solution of methyl 3,4-dihydroxy-5-methoxybenzoate (15.3 g,
0.0780 mol) in
acetone (500 mL) was added CHZBrCI (34.4 g, 0.270 mol) and K2CO3 (75.0 g,
0.540 mol) at
80 C. The resulting mixture was heated at reflux for 4 h. The mixture was
cooled to room
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temperature and solid K2CO3 was filtered off. The filtrate was concentrated
under reduced
pressure, and the residue was dissolved in EtOAc (100 mL). The organic layer
was washed
with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure
to give the
crude product, which was purified by column chromatography on silica gel
(petroleum
ether/ethyl acetate = 10:1) to afford methyl 7-methoxybenzo[d][1,3]dioxole-5-
carboxylate
(12.6 g, 80%). 'H NMR (400 MHz, CDC13) 8 7.32 (s, 1 H), 7.21 (s, 1 H), 6.05
(s, 2 H), 3.93
(s, 3 H), 3.88 (s, 3 H).
O
JL' LiAIH4 HO 0
Me0 O >
O
OMe
OW
[00355] (7-Methoxybenzo[d][1,3]dioxol-5-yl)methanol
[00356] To a solution of methyl 7-methoxybenzo[d][1,3]dioxole-5-carboxylate
(14 g, 0.040
mol) in THE (100 mL) was added LiAlH4 (3.1 g, 0.080 mol) in portions at room
temperature.
The mixture was stirred for 3 h at room temperature. The reaction mixture was
cooled to 0
C and treated with water (3.1 g) and NaOH (10%, 3.1 mL) successively. The
slurry was
filtered off and washed with THE The combined filtrates were evaporated under
reduced
pressure to give (7-methoxy-benzo[d][1,3]dioxol-5-yl)methanol (7.2 g, 52%). 'H
NMR (400
MHz, CDC13) 8 6.55 (s, 1H), 6.54 (s, 1H), 5.96 (s, 2 H), 4.57 (s, 2 H), 3.90
(s, 3 H).
HO I > SOCIZ CI I O
We We
[00357] 6-(Chloromethyl)-4-methoxybenzo[d][1,3]dioxole
[00358] To a solution of SOCl2(150 mL) was added (7-methoxybenzo[d][1,3]dioxol-
5-
yl)methanol (9.0 g, 54 mmol) in portions at 0 C. The mixture was stirred for
0.5 h. The
excess SOC12 was evaporated under reduced pressure to give the crude product,
which was
basified with sat. aq. NaHCO3 to pH - 7. The aqueous phase was extracted with
EtOAc (100
mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and
evaporated to
give 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g 94%), which was used
in the
next step without further purification. 'H NMR (400 MHz, CDC13) 8 6.58 (s, 1
H), 6.57 (s, 1
H), 5.98 (s, 2 H), 4.51 (s, 2 H), 3.90 (s, 3 H).
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CI \ NaCN NC O
OMe OMe
[00359] 2-(7-Methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile
[00360] To a solution of 6-(chloromethyl)-4-methoxybenzo[d][1,3]dioxole (10 g,
40 mmol)
in DMSO (100 mL) was added NaCN (2.4 g, 50 mmol) at room temperature. The
mixture
was stirred for 3 h and poured into water (500 mL). The aqueous phase was
extracted with
EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous
Na2SO4 and
evaporated to give the crude product, which was washed with ether to afford 2-
(7-
methoxybenzo[d][1,3]dioxol-5-yl)acetonitrile (4.6 g, 45%). 1H NMR (400 MHz,
CDC13) 8
6.49 (s, 2 H), 5.98 (s, 2 H), 3.91 (s, 3 H), 3.65 (s, 2 H). 13C NMR (400 MHz,
CDC13) 8 148.9,
143.4, 134.6, 123.4, 117.3, 107.2, 101.8, 101.3, 56.3, 23.1.
[00361] Example 11: 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile.
O QJNC
OBn
Fi O0 NC/~\\r~
a OMe
OMe t-BuOK
[00362] To a suspension of t-BuOK (20.2 g, 0.165 mol) in THE (250 mL) was
added a
solution of TosMIC (16.1 g, 82.6 mmol) in THE (100 mL) at -78 C. The mixture
was
stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-
benzaldehyde (10.0
g, 51.9 mmol) in THE (50 mL) dropwise, and continued to stir for 1.5 hours at -
78 C. To
the cooled reaction mixture was added methanol (50 mL). The mixture was heated
at reflux
for 30 minutes. Solvent was removed to give a crude product, which was
dissolved in water
(300 mL). The aqueous phase was extracted with EtOAc (100 mL x 3). The
combined
organic layers were dried and evaporated under reduced pressure to give crude
product,
which was purified by column chromatography (petroleum ether/ethyl acetate
10:1) to afford
2-(3-(benzyloxy)-4-methoxyphenyl)- acetonitrile (5.0 g, 48%). 1H NMR (300 MHz,
CDC13)
8 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s, 3 H), 3.66
(s, 2 H). 13C NMR
(75 MHz, CDC13) 8 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5, 127.5,
122.1, 120.9,
118.2, 113.8, 112.2, 71.2, 56.2, 23.3.
[00363] Example 12: 2-(3-(Benzyloxy)-4-chlorophenyl)acetonitrile.
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Br
NC We BBr3 NC OH NC OBn
CI al7z~~
CI K2 C03, CH3CN CI
NC OMe BBr3 NC OH
CI
[00364] (4-Chloro-3-hydroxy-phenyl)acetonitrile
[00365] BBr3 (17 g, 66 mmol) was slowly added to a solution of 2-(4-chloro-3-
methoxyphenyl)acetonitrile (12 g, 66 mmol) in dichloromethane (120 mL) at -78
C under
N2. The reaction temperature was slowly increased to room temperature. The
reaction
mixture was stirred overnight and then poured into ice and water. The organic
layer was
separated, and the aqueous layer was extracted with dichloromethane (40 mL x
3). The
combined organic layers were washed with water, brine, dried over Na2SO4, and
concentrated
under vacuum to give (4-chloro-3-hydroxy-phenyl)-acetonitrile (9.3 g, 85%). 1H
NMR (300
MHz, CDC13) 8 7.34 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 2.1 Hz, 1 H), 6.87 (dd,
J = 2.1, 8.4 Hz,
1 H), 5.15 (brs, 1H), 3.72 (s, 2 H).
Br
NC OH I / NC OBn
CI K2CO3, CH3CN I / CI
[00366] 2-(3-(Benzyloxy)-4-chlorophenyl)acetonitrile
[00367] To a solution of (4-chloro-3-hydroxy-phenyl)acetonitrile (6.2 g, 37
mmol) in
CH3CN (80 mL) was added K2CO3 (10 g, 74 mmol) and BnBr (7.6 g, 44 mmol). The
mixture was stirred at room temperature overnight. The solids were filtered
off and the
filtrate was evaporated under vacuum. The residue was purified by column
chromatography
on silica gel (petroleum ether/ethyl acetate 50:1) to give 2-(3-(benzyloxy)-4-
chlorophenyl)-
acetonitrile (5.6 g, 60%). 1H NMR (400 MHz, CDC13) 8 7.48-7.32 (m, 6 H), 6.94
(d, J = 2
Hz, 2 H), 6.86 (dd, J = 2.0, 8.4 Hz,1H),5.18(s,2H),3.71(s,2H).
[00368] Example 13: 2-(3-(Benzyloxy)-4-methoxyphenyl)acetonitrile.
O C
H OBn -0-S112 NC OBn
11
~ aOMe
We t-BuOK
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[00369] To a suspension of t-BuOK (20.2 g, 0.165 mol) in THE (250 mL) was
added a
solution of TosMIC (16.1 g, 82.6 mmol) in THE (100 mL) at -78 C. The mixture
was
stirred for 15 minutes, treated with a solution of 3-benzyloxy-4-methoxy-
benzaldehyde (10.0
g, 51.9 mmol) in THE (50 mL) dropwise, and continued to stir for 1.5 hours at -
78 C. To
the cooled reaction mixture was added methanol (50 mL). The mixture was heated
at reflux
for 30 minutes. Solvent of the reaction mixture was removed to give a crude
product, which
was dissolved in water (300 mL). The aqueous phase was extracted with EtOAc
(100 mL x
3). The combined organic layers were dried and evaporated under reduced
pressure to give
crude product, which was purified by column chromatography (petroleum
ether/ethyl acetate
10:1) to afford 2-(3-(benzyloxy)-4-methoxyphenyl)acetonitril (5.0 g, 48%). 1H
NMR (300
MHz, CDC13) 8 7.48-7.33 (m, 5 H), 6.89-6.86 (m, 3 H), 5.17 (s, 2 H), 3.90 (s,
3 H), 3.66 (s, 2
H). 13C NMR (75 MHz, CDC13) 8 149.6, 148.6, 136.8, 128.8, 128.8, 128.2, 127.5,
127.5,
122.1, 120.9, 118.2, 113.8, 112.2, 71.2, 56.2, 23.3.
[00370] Example 14: 2-(3-Chloro-4-methoxyphenyl)acetonitrile.
0 D~NC
CI
H a CI 0 NC
0 t-BuOK OMe
[00371] To a suspension of t-BuOK (4.8 g, 40 mmol) in THE (30 mL) was added a
solution
of TosMIC (3.9 g, 20 mmol) in THE (10 mL) at -78 C. The mixture was stirred
for 10
minutes, treated with a solution of 3-chloro-4-methoxy-benzaldehyde (1.7 g, 10
mmol) in
THE (10 mL) dropwise, and continued to stir for 1.5 hours at -78 C. To the
cooled reaction
mixture was added methanol (10 mL). The mixture was heated at reflux for 30
minutes.
Solvent of the reaction mixture was removed to give a crude product, which was
dissolved in
water (20 mL). The aqueous phase was extracted with EtOAc (20 mL x 3). The
combined
organic layers were dried and evaporated under reduced pressure to give crude
product,
which was purified by column chromatography (petroleum ether/ethyl acetate
10:1) to afford
2-(3-chloro-4-methoxyphenyl)acetonitrile (1.5 g, 83%). 1H NMR (400 MHz, CDC13)
8 7.33
(d, J = 2.4 Hz, 1 H), 7.20 (dd, J = 2.4, 8.4 Hz, 1 H), 6.92 (d, J = 8.4 Hz, 1
H), 3.91 (s, 3 H),
3.68 (s, 2 H). 13C NMR (100 MHz, CDC13) 8 154.8, 129.8, 127.3, 123.0, 122.7,
117.60,
112.4, 56.2, 22.4.
[00372] Example 15: 2-(3-Fluoro-4-methoxyphenyl)acetonitrile.
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O ~ \N D~NC
F ~ F
H II NC
O
OMe OMe
t-BuOK
[00373] To a suspension of t-BuOK (25.3 g, 0.207 mol) in THE (150 mL) was
added a
solution of TosMIC (20.3 g, 0.104 mol) in THE (50 mL) at -78 C. The mixture
was stirred
for 15 minutes, treated with a solution of 3-fluoro-4-methoxy-benzaldehyde
(8.00 g, 51.9
mmol) in THE (50 mL) dropwise, and continued to stir for 1.5 hours at -78 C.
To the
cooled reaction mixture was added methanol (50 mL). The mixture was heated at
reflux for
30 minutes. Solvent of the reaction mixture was removed to give a crude
product, which was
dissolved in water (200 mL). The aqueous phase was extracted with EtOAc (100
mL x 3).
The combined organic layers were dried and evaporated under reduced pressure
to give crude
product, which was purified by column chromatography (petroleum ether/ethyl
acetate 10:1)
to afford 2-(3-fluoro-4-methoxyphenyl)acetonitrile (5.0 g, 58%). 1H NMR (400
MHz,
CDC13) 8 7.02-7.05 (m, 2 H), 6.94 (t, J = 8.4 Hz, 1 H), 3.88 (s, 3 H), 3.67
(s, 2 H). 13C NMR
(100 MHz, CDC13) 8 152.3, 147.5, 123.7, 122.5, 117.7, 115.8, 113.8, 56.3,
22.6.
[00374] Example 16: 2-(4-Chloro-3-methoxyphenyl)acetonitrile.
OH Mew We NBA Br I We NaCCNN NC We
CI CH3CN ci AIBN, CCI4 ci C2H5OI- CI
OH OMe
Mel, K2CO3
CH3CN
Cl Cl
[00375] Chloro-2-methoxy-4-methyl-benzene
[00376] To a solution of 2-chloro-5-methyl-phenol (93 g, 0.65 mol) in CH3CN
(700 mL)
was added CH3I (110 g, 0.78 mol) and K2C03 (180 g, 1.3 mol). The mixture was
stirred at
25 C overnight. The solid was filtered off and the filtrate was evaporated
under vacuum to
give 1-chloro-2-methoxy-4-methyl-benzene (90 g, 89%). 1H NMR (300 MHz, CDC13)
8 7.22
(d, J = 7.8 Hz, 1 H), 6.74-6.69 (m, 2 H), 3.88 (s, 3 H), 2.33 (s, 3 H).
We NBS Br I We
CI AIBN, CCI4 CI
[00377] 4-Bromomethyl-l-chloro-2-methoxy-benzene
[00378] To a solution of 1-chloro-2-methoxy-4-methyl-benzene (50 g, 0.32 mol)
in CC14
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(350 mL) was added NBS (57 g, 0.32 mol) and AIBN (10 g, 60 mmol). The mixture
was
heated at reflux for 3 hours. The solvent was evaporated under vacuum and the
residue was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate
= 20:1) to
give 4-bromomethyl-l-chloro-2-methoxy-benzene (69 g, 92%). 1H NMR (400 MHz,
CDC13)
8 7.33-7.31 (m, 1 H), 6.95-6.91 (m, 2 H), 4.46 (s, 2 H), 3.92 (s, 3 H).
Br NaCN NC
CI C2H50FI-
CI
[00379] 2-(4-Chloro-3-methoxyphenyl)acetonitrile
[00380] To a solution of 4-bromomethyl-l-chloro-2-methoxy-benzene (68.5 g,
0.290 mol)
in CZH5OH (90%, 500 mL) was added NaCN (28.5 g, 0.580 mol). The mixture was
stirred at
60 C overnight. Ethanol was evaporated and the residue was dissolved in H2O.
The mixture
was extracted with ethyl acetate (300 mL x 3). The combined organic layers
were washed
with brine, dried over Na2SO4 and purified by column chromatography on silica
gel
(petroleum ether/ethyl acetate 30:1) to give 2-(4-chloro-3-
methoxyphenyl)acetonitrile (25 g,
48%). 1H NMR (400 MHz, CDC13) 8 7.36 (d, J = 8 Hz, 1 H), 6.88-6.84 (m, 2 H),
3.92 (s, 3
H), 3.74 (s, 2 H). 13C NMR (100 MHz, CDC13) 8 155.4, 130.8, 129.7, 122.4,
120.7, 117.5,
111.5, 56.2,23.5.
[00381] Example 17: 1-(3-(Hydroxymethyl)-4-
methoxyphenyl)cyclopropanecarboxylic acid.
HO \ MeOH MeO \ MOMCI MeO VO C Na2CO3 IBM- O I We O I We TO, O Me 10
CS2
MeO VOM 0H TBSCI MeO VO OT BS LiOH 40 C HO I \ OH
0 e Oo -Y OMeMeOH/H20 0 OMe
H \ MeOH MeO \
O I OMe O I OMe
[00382] 1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid methyl ester
[00383] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (50
g, 0.26
mol) in MeOH (500 mL) was added toluene-4-sulfonic acid monohydrate (2.5 g, 13
mmol) at
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room temperature. The reaction mixture was heated at reflux for 20 hours. MeOH
was
removed by evaporation under vacuum and EtOAc (200 mL) was added. The organic
layer
was washed with sat. aq. NaHCO3 (100 mL) and brine, dried over anhydrous
Na2SO4 and
evaporated under vacuum to give 1-(4-methoxy-phenyl)-cyclopropanecarboxylic
acid methyl
ester (53 g, 99%). 'H NMR (CDC13, 400 MHz) 8 7.25-7.27 (m, 2 H), 6.85 (d, J =
8.8 Hz, 2
H), 3.80 (s, 3 H), 3.62 (s, 3 H), 1.58 (m, 2 H), 1.15 (m, 2 H).
Me0 MOMCI MeO CI
0 I ~ OMe TiCh 0
I ~ OMe
[00384] 1-(3-Chloromethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid methyl
ester
[00385] To a solution of 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid
methyl ester
(30.0 g, 146 mmol) and MOMC1 (29.1 g, 364 mmol) in CS2 (300 mL) was added
TiC14 (8.30
g, 43.5 mmol) at 5 C. The reaction mixture was heated at 30 C for 1 d and
poured into ice-
water. The mixture was extracted with CH2C12 (150 mL x 3). The combined
organic extracts
were evaporated under vacuum to give 1-(3-chloromethyl-4-methoxy-phenyl)-
cyclopropanecarboxylic acid methyl ester (38.0 g), which was used in the next
step without
further purification.
CI Na2C03 O OH
Me0 OMe Me
O OMe
[00386] 1-(3-Hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid
methyl
ester
[00387] To a suspension of 1-(3-chloromethyl-4-methoxy-phenyl)-
cyclopropanecarboxylic
acid methyl ester (20 g) in water (350 mL) was added Bu4NBr (4.0 g) and Na2CO3
(90 g,
0.85 mol) at room temperature. The reaction mixture was heated at 65 C
overnight. The
resulting solution was acidified with aq. HCl (2 mol/L) and extracted with
EtOAc (200 mL x
3). The organic layer was washed with brine, dried over anhydrous Na2SO4 and
evaporated
under vacuum to give crude product, which was purified by column (petroleum
ether/ethyl
acetate 15:1) to give 1-(3-hydroxymethyl-4-methoxy-phenyl)-
cyclopropanecarboxylic acid
methyl ester (8.0 g, 39%). 'H NMR (CDC13, 400 MHz) 8 7.23-7.26 (m, 2 H), 6.83
(d, J = 8.0
Hz, 1 H), 4.67 (s, 2 H), 3.86 (s, 3 H), 3.62 (s, 3 H), 1.58 (q, J= 3.6 Hz, 2
H), 1.14-1.17 (m, 2
H).
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OH TBSCI MeO O I OTBS
MeO 0
Y
Y
OMe OMe
[00388] 1-[3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-methoxy-
phenyl]cyclopropane
carboxylic acid methyl ester
[00389] To a solution of 1-(3-hydroxymethyl-4-methoxy-phenyl)-
cyclopropanecarboxylic
acid methyl ester (8.0 g, 34 mmol) in CH2C12 (100 mL) were added imidazole
(5.8 g, 85
mmol) and TBSCI (7.6 g, 51 mmol) at room temperature. The mixture was stirred
overnight
at room temperature. The mixture was washed with brine, dried over anhydrous
Na2SO4 and
evaporated under vacuum to give crude product, which was purified by column
(petroleum
ether/ethyl acetate 30:1) to give 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-
4-methoxy-
phenyl]-cyclopropanecarboxylic acid methyl ester (6.7 g, 56%). 1H NMR (CDC13,
400 MHz)
8 7.44-7.45 (m, 1 H), 7.19 (dd, T = 2.0, 8.4 Hz, 1 H), 6.76 (d, T = 8.4 Hz, 1
H), 4.75 (s, 2 H),
3.81 (s, 3 H), 3.62 (s, 3 H), 1.57-1.60 (m, 2 H), 1.15- 1.18 (m, 2 H), 0.96
(s, 9 H), 0.11 (s, 6
H).
MeO I \ OTBS UGH 40 C Do. H I \ OH
O OMe McOH O O OMe
[00390] 1-(3-Hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid
[00391] To a solution of 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-
phenyl]-
cyclopropane carboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) was
added a
solution of LiOH.H20 (1.5 g, 36 mmol) in water (10 mL) at 0 C. The reaction
mixture was
stirred overnight at 40 C. MeOH was removed by evaporation under vacuum. AcOH
(1
mol/L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated,
washed
with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to provide
1-(3-
hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g).
[00392] Example 18: 2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile.
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O O O
H OMe BBr3 H 0H BrCICH2 H NaBH4/THF
OH OH
CI CI CI
O I j OH SOS e I% CI NaCN NC -I j O
CI CI CI
O O
H OMe BBr3 H q OH
I ~ OH I ~ OH
CI CI
[00393] 3-Chloro-4,5-dihydroxybenzaldehyde
[00394] To a suspension of 3-chloro-4-hydroxy-5-methoxy-benzaldehyde (10 g, 54
mmol)
in dichloromethane (300 mL) was added BBr3 (26.7 g, 107 mmol) dropwise at -40
C under
N2. After addition, the mixture was stirred at this temperature for 5 h and
then was poured
into ice water. The precipitated solid was filtered and washed with petroleum
ether. The
filtrate was evaporated under reduced pressure to afford 3-chloro-4,5-
dihydroxybenzaldehyde
(9.8 g, 89%), which was directly used in the next step.
O 0
OH BrCICH2
H I H
OH O
CI CI
[00395] 7-Chlorobenzo[d][1,3]dioxole-5-carbaldehyde
[00396] To a solution of 3-chloro-4,5-dihydroxybenzaldehyde (8.0 g, 46 mmol)
and
BrC1CH2(23.9 g, 185 mmol) in dry DMF (100 mL) was added Cs2CO3 (25 g, 190
mmol).
The mixture was stirred at 60 C overnight and was then poured into water. The
resulting
mixture was extracted with EtOAc (50 mL x 3). The combined extracts were
washed with
brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to
afford 7-
chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g, 70%). 1H NMR (400 MHz,
CDC13) 8
9.74 (s, 1 H), 7.42 (d, J = 0.4 Hz, 1 H), 7.26 (d, J = 3.6 Hz, 1 H), 6.15 (s,
2 H).
0
< I
H NaBH < OH
O
?111
CI CI
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[00397] (7-Chlorobenzo[d][1,3]dioxol-5-yl)methanol
[00398] To a solution of 7-chlorobenzo[d][1,3]dioxole-5-carbaldehyde (6.0 g,
33 mmol) in
THE (50 mL) was added NaBH4 (2.5 g, 64 mmol) ) in portions at 0 C. The
mixture was
stirred at this temperature for 30 min and then poured into aqueous NH4C1
solution. The
organic layer was separated, and the aqueous phase was extracted with EtOAc
(50 mL x 3).
The combined extracts were dried over Na2SO4 and evaporated under reduced
pressure to
afford (7-chlorobenzo[d][1,3]dioxol-5-yl)methanol, which was directly used in
the next step.
OH SOCI2 O CI
IO:(;r 0
CI CI
[00399] 4-Chloro-6-(chloromethyl)benzo[d][1,3]dioxole
[00400] A mixture of (7-chlorobenzo[d][1,3]-dioxol-5-yl)methanol (5.5 g, 30
mmol) and
SOC12 (5.0 mL, 67 mmol) in dichloromethane (20 mL) was stirred at room
temperature for 1
h and was then poured into ice water. The organic layer was separated and the
aqueous phase
was extracted with dichloromethane (50 mL x 3). The combined extracts were
washed with
water and aqueous NaHCO3 solution, dried over Na2SO4 and evaporated under
reduced
pressure to afford 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole, which was
directly used in
the next step.
CI NaCN NC I 0
O O
CI CI
[00401] 2-(7-Chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile
[00402] A mixture of 4-chloro-6-(chloromethyl)benzo[d][1,3]dioxole (6.0 g, 29
mmol) and
NaCN (1.6 g, 32 mmol) in DMSO (20 mL) was stirred at 40 C for 1 h and was
then poured
into water. The mixture was extracted with EtOAc (30 mL x 3). The combined
organic
layers were washed with water and brine, dried over Na2SO4 and evaporated
under reduced
pressure to afford 2-(7-chlorobenzo[d][1,3]dioxol-5-yl)acetonitrile (3.4 g,
58%). 1H NMR 8
6.81 (s, 1 H), 6.71 (s, 1 H), 6.07 (s, 2 H), 3.64 (s, 2 H). 13 C-NMR 8149.2,
144.3, 124.4,
122.0, 117.4, 114.3, 107.0, 102.3, 23.1.
[00403] Example 19: 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid.
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trimethyl
MeO NH2 orthoformate MeO N AICI HO N
OH O O O
trimethyl
MeO I \ NH2 orthoformate Me N
O / OH O O
[00404] 1-Benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester
[00405] To a solution of 1-(3-amino-4-hydroxyphenyl)cyclopropanecarboxylic
acid methyl
ester (3.00 g, 14.5 mmol) in DMF were added trimethyl orthoformate (5.30 g,
14.5 mmol)
and a catalytic amount of p-tolueneslufonic acid monohydrate (0.3 g) at room
temperature.
The mixture was stirred for 3 hours at room temperature. The mixture was
diluted with water
and extracted with EtOAc (100 mL x 3). The combined organic layers were dried
over
anhydrous Na2SO4 and evaporated under vacuum to give 1-benzooxazol-5-yl-
cyclopropanecarboxylic acid methyl ester (3.1 g), which was directly used in
the next step.
IH NMR (CDC13, 400 MHz) 8 8.09 (s, 1), 7.75 (d, J = 1.2 Hz, 1 H), 7.53-7.51
(m, 1 H), 7.42-
7.40 (m, 1 H), 3.66 (s, 3 H), 1.69-1.67 (m, 2 H), 1.27-1.24 (m, 2 H).
Me N AICI3 H
O
O O
O
[00406] 1-(Benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid
[00407] To a solution of 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl
ester (2.9
g) in EtSH (30 mL) was added A1C13 (5.3 g, 40 mmol) in portions at 0 C. The
reaction
mixture was stirred for 18 hours at room temperature. Water (20 mL) was added
dropwise at
0 C. The resulting mixture was extracted with EtOAc (100 mL x 3). The
combined organic
layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give
the crude
product, which was purified by column chromatography on silica gel (petroleum
ether/ethyl
acetate 1:2) to give 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280
mg, 11% over
two steps). 1H NMR (DMSO, 400 MHz) 8 12.25 (brs, 1 H), 8.71 (s, 1 H), 7.70-
7.64 (m, 2 H),
7.40 (dd, J= 1.6, 8.4 Hz, 1 H), 1.49-1.46 (m, 2 H), 1.21-1.18 (m, 2 H). MS
(ESI) m/e
(M+H+) 204.4.
[00408] Example 20: 2-(7-Fluorobenzo[d] [1,3]dioxol-5-yl)acetonitrile
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O O O
H I \ 011 BBr3 H I \ OH BrCH2CI/DMF H O/\ NaBH4 _ HO I \ O
1P .
pH OH G / OJ
F F F F
SOCI2 CI \ O NaCN NC I \ O
F
F
0 O
H I O\ BBr3 --D- H I OH
OH OH
F F
[00409] 3-Fluoro-4,5-dihydroxy-benzaldehyde
[00410] To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.35 g,
7.94
mmol) in dichloromethane (100 mL) was added BBr3 (1.5 mL, 16 mmol) dropwise at
- 78 C
under N2. After addition, the mixture was warmed to - 30 C and it was stirred
at this
temperature for 5 h. The reaction mixture was poured into ice water. The
precipitated solid
was collected by filtration and washed with dichloromethane to afford 3-fluoro-
4,5-
dihydroxy-benzaldehyde (1.1 g, 89%), which was directly used in the next step.
O O
H OH BrCH2CI/DMF H I\ O>
OH O
F F
[00411] 7-Fluoro-benzo[1,3]dioxole-5-carbaldehyde
[00412] To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol)
and
BrC1CH2(4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs2CO3 (12.6 g, 39
mmol). The
mixture was stirred at 60 C overnight and was then poured into water. The
resulting mixture
was extracted with EtOAc (50 mL x 3). The combined organic layers were washed
with
brine (100 mL), dried over Na2SO4 and evaporated under reduced pressure to
give the crude
product, which was purified by column chromatography on silica gel (petroleum
ether/ethyl
acetate = 10/1) to afford 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g,
49%). 1H NMR
(300 MHz, CDC13) 8 9.78 (d, J = 0.9 Hz, 1 H), 7.26 (dd, J = 1.5, 9.3 Hz, 1H),
7.19 (d, J = 1.2
Hz, 1 H), 6.16 (s, 2 H).
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O
O NaBH4 HO I \
H
O O
F F
[00413] (7-Fluoro-benzo[1,3]dioxol-5-yl)-methanol
[00414] To a solution of 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g,
4.7 mmol) in
MeOH (50 mL) was added NaBH4 (0.36 g, 9.4 mmol) in portions at 0 C. The
mixture was
stirred at this temperature for 30 min and was then concentrated to dryness.
The residue was
dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na2SO4
and
concentrated to dryness to afford (7 -fluoro-benzo [ 1, 3 ] dioxol-5 -yl) -
methanol (0.80 g, 98%),
which was directly used in the next step.
O SOCI2 CI O
HO
O
F F
[00415] 6-Chloromethyl-4-fluoro-benzo[1,3]dioxole
[00416] To SOC12 (20 mL) was added (7 -fluoro-benzo [ 1, 3 ] dioxol- 5 -yl) -
methanol (0.80 g,
4.7 mmol) in portions at 0 C. The mixture was warmed to room temperature over
1 h and
then was heated at reflux for 1 h. The excess SOC12 was evaporated under
reduced pressure
to give the crude product, which was basified with saturated aqueous NaHCO3 to
pH - 7.
The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic
layers
were dried over Na2SO4 and evaporated under reduced pressure to give 6-
chloromethyl-4-
fluoro-benzo[1,3]dioxole (0.80 g, 92%), which was directly used in the next
step.
CI > NaCN NC I \ 110- / 0
F F
[00417] 2-(7-Fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile
[00418] A mixture of 6-chloromethyl-4-fluoro-benzo[1,3]dioxole (0.80 g, 4.3
mmol) and
NaCN (417 mg, 8.51 mmol) in DMSO (20 mL) was stirred at 30 C for 1 h and was
then
poured into water. The mixture was extracted with EtOAc (50 mL x 3). The
combined
organic layers were washed with water (50 mL) and brine (50 mL), dried over
Na2SO4 and
evaporated under reduced pressure to give the crude product, which was
purified by column
chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to afford
2-(7-
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fluorobenzo[d][1,3]dioxol-5-yl)acetonitrile (530 mg, 70%). 1H NMR (300 MHz,
CDC13) 8
6.68-6.64 (m, 2 H), 6.05 (s, 2 H), 3.65 (s, 2 H). 13 C-NMR 8151.1, 146.2,
134.1, 124.2,
117.5, 110.4, 104.8, 102.8, 23.3.
[00419] Example 21: 1-(1H-Indol-5-yl)cyclopropanecarboxylic acid
HO TsOH Dj~ MeO 0 KNO3 _ Me Ranney Ni
O / CH3OH O / H2SO4/CH2CI2 O /
NOZ
Me0 ~ ~ SiMe3
Me Br - SiMe3
~/1e0 NBS O
O I /
0 I / NH NH2 Et3N NH2
z
Cui Me0 LiOH H
DMF O N CH3OH O N
H H
HO TsOH Me0
0 I / CH3OH 0 I /
Y
[00420] Methyl 1-phenylcyclopropanecarboxylate
[00421] To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol)
in CH3OH
(200 mL) was added TsOH (3 g, 0.1 mol) at room temperature. The mixture was
refluxed
overnight. The solvent was evaporated under reduced pressure to give crude
product, which
was dissolved into EtOAc. The EtOAc layer was washed with aq. sat. NaHCO3. The
organic
layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to
give
methyl 1-phenylcyclopropanecarboxylate (26 g, 96%), which was used directly in
the next
step. 1H NMR (400 MHz, CDC13) 8 7.37-7.26 (m, 5 H), 3.63 (s, 3 H), 1.63-1.60
(m, 2 H),
1.22-1.19 (m, 2 H).
Me0 KNO3 Me0
I / H2S04/CH2Ci2 0 O I /
N02
[00422] Methyl 1-(4-nitrophenyl)cyclopropanecarboxylate
[00423] To a solution of 1-phenylcyclopropanecarboxylate (20.62 g, 0.14 mol)
in
H2SO4/CH2C12 (40 mL/40 mL) was added KNO3 (12.8 g, 0.13 mol) in portion at 0
C. The
mixture was stirred for 0.5 hr at 0 C. Ice water was added and the mixture
was extracted
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with EtOAc (100 mL x 3). The organic layers were dried with anhydrous Na2SO4
and
evaporated to give methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (21 g,
68%), which was
used directly in the next step. IH NMR (300 MHz, CDC13) 8 8.18 (dd, J = 2.1,
6.9 Hz, 2 H),
7.51 (dd, J= 2.1, 6.9 Hz, 2 H), 3.64 (s, 3 H), 1.72-1.69 (m, 2 H), 1.25-1.22
(m, 2 H).
Me0 Ranney Ni MeO
0 0 NO2 NH2
[00424] Methyl 1-(4-aminophenyl)cyclopropanecarboxylate
[00425] To a solution of methyl 1-(4-nitrophenyl)cyclopropanecarboxylate (20
g, 0.09 mol)
in MeOH (400 mL) was added Ni (2 g) under nitrogen atmosphere. The mixture was
stirred
under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst
was filtered
off through a pad of Celite and the filtrate was evaporated under vacuum to
give crude
product, which was purified by chromatography column on silica gel (petroleum
ether/ethyl
acetate =10:1) to give methyl 1-(4-aminophenyl)cyclopropanecarboxylate (11.38
g, 66%).
1H NMR (300 MHz, CDC13) 8 7.16 (d, J = 8.1 Hz, 2 H), 6.86 (d, J = 7.8 Hz, 2
H), 4.31 (br, 2
H), 3.61 (s, 3 H), 1.55-1.50 (m, 2 H), 1.30-1.12 (m, 2 H).
MeO \ Br
Me0 NBS
0 I / NH Aw- 2 K NH2
2
[00426] Methyl 1-(4-amino-3-bromophenyl)cyclopropanecarboxylate
[00427] To a solution of methyl 1-(4-aminophenyl)cyclopropanecarboxylate
(10.38 g, 0.05
mol) in acetonitrile (200 mL) was added NBS (9.3 g, 0.05 mol) at room
temperature. The
mixture was stirred overnight. Water (200 mL) was added. The organic layer was
separated
and the aqueous phase was extracted with EtOAc (80 mL x3). The organic layers
were dried
with anhydrous Na2SO4 and evaporated to give methyl 1-(4-amino-3-
bromophenyl)cyclopropanecarboxylate (10.6 g, 78%), which was used directly in
the next
step. 1H NMR (400 MHz, CDC13) 8 7.38 (d, J = 2.0 Hz, 1 H), 7.08 (dd, J = 1.6,
8.4 Hz, 1 H),
6.70 (d, J= 8.4 Hz, 1 H), 3.62 (s, 3 H), 1.56-1.54 (m, 2 H), 1.14-1.11(m, 2
H).
\ SiMe3
Me0 ~ Br - SiMe3
MeO NH
O I 10- O I
Y
NH2 Et3N 2
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[00428] Methyl 1-(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropane
carboxylate
[00429] To a degassed solution of methyl 1-(4- amino- 3 -
bromophenyl)cyclopropane
carboxylate (8 g, 0.03 mol) in Et3N (100 mL) was added ethynyl-trimethyl-
silane (30 g, 0.3
mol), DMAP (5% mol) and Pd(PPh3)2C12 (5% mol) under N2. The mixture was
refluxed at
70 C overnight. The insoluble solid was filtered off and washed with EtOAc
(100 mL x 3).
The filtrate was evaporated under reduced pressure to give a residue, which
was purified by
chromatography column on silica gel (petroleum ether/ethyl acetate =20:1) to
give methyl 1-
(4-amino-3-((trimethylsilyl)ethynyl)phenyl)cyclopropanecarboxylate (4.8 g,
56%). 1H NMR
(300 MHz, CDC13) 87.27 (s, 1 H), 7.10 (dd, J = 2.1, 8.4 Hz, 1 H), 6.64 (d, J =
8.4 Hz, 1 H),
3.60 (s, 3 H), 1.55-1.51 (m, 2 H), 1.12-1.09 (m, 2 H), 0.24 (s, 9 H).
Me0
SiMe3 Cul Me0
O
NH2 DMF O I N
H
[00430] Methyl 1-(lH-indol-5-yl)cyclopropanecarboxylate
[00431] To a degassed solution of methyl 1-(4-amino- 3-
((trimethylsilyl)ethynyl)phenyl)
cyclopropanecarboxylate (4.69 g, 0.02 mol) in DMF (20 mL) was added Cul (1.5
g, 0.008
mol) under N2 at room temperature. The mixture was stirred for 3 hr at room
temperature.
The insoluble solid was filtered off and washed with EtOAc (50 mL x 3). The
filtrate was
evaporated under reduced pressure to give a residue, which was purified by
chromatography
column on silica gel (petroleum ether/ethyl acetate =20:1) to give methyl 1-
(1H-indol-5-
yl)cyclopropanecarboxylate (2.2 g, 51%). 1H NMR (400 MHz, CDC13) 8 7.61 (s, 1
H), 7.33
(d, J= 8.4 Hz, 1 H), 7.23-7.18 (m, 2 H), 6.52-6.51 (m, 1 H) 3.62 (s, 3 H),
1.65-1.62 (m, 2 H),
1.29-1.23(m, 2 H).
MeO UGH HO
Y O N CH3OH 0 N
Y
H H
[00432] 1-(1H-Indol-5-yl)cyclopropanecarboxylic acid
[00433] To a solution of methyl 1-(1H-indol-5-yl)cyclopropanecarboxylate (1.74
g, 8
mmol) in CH3OH (50 m L) and water (20 mL) was added LiOH (1.7 g, 0.04 mol).
The
mixture was heated at 45 C for 3 hr. Water was added and the mixture was
acidified with
concentrated HCl to pH -3 before being extracted with EtOAc (20 mL x 3). The
organic
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layers were dried over anhydrous Na2SO4 and evaporated to give 1-(1H-indol-5-
yl)cyclopropanecarboxylic acid (1.4 g, 87%). 1H NMR (300 MHz, DMSO-d6) 7.43
(s, 1 H),
7.30-7.26 (m, 2 H), 7.04 (dd, J= 1.5, 8.4 Hz, 1 H), 6.35 (s, 1 H), 1.45-1.41
(m, 2 H), 1.14-
1.10 (m, 2 H).
[00434] Example 22: 1-(4-Oxochroman-6-yl)cyclopropanecarboxylic acid
O
Me 02C I \ Me02C I \ O 20% HCI
OH Na v O~
O
McO2C I \O 0 OH (COCI)2 HOOC 10 O
McO2C I \ O-\ McO2C I \ 0
OH Na O' -v OJ<
[00435] 1-[4-(2-tert-Butoxycarbonyl-ethoxy)-phenyl]-cyclopropanecarboxylic
methyl
ester
[00436] To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic methyl
ester (7.0 g,
3.6 mmol) in acrylic tert-butyl ester (50 mL) was added Na (42 mg, 1.8 mmol)
at room
temperature. The mixture was heated at 110 C for 1 h. After cooling to room
temperature,
the resulting mixture was quenched with water and extracted with EtOAc (100 mL
x 3). The
combined organic extracts were dried over anhydrous Na2SO4 and evaporated
under vacuum
to give the crude product, which was purified by column chromatography on
silica gel
(petroleum ether/ethyl acetate 20:1) to give 1-[4-(2-tert-butoxycarbonyl-
ethoxy)-phenyl]-
cyclopropanecarboxylic methyl ester (6.3 g, 54%) and unreacted start material
(3.0 g). 1H
NMR (300 MHz, CDC13) 8 7.24 (d, J = 8.7 Hz, 2 H), 6.84 (d, J = 8.7 Hz, 2 H),
4.20 (t, J =
6.6 Hz, 2 H), 3.62 (s, 3 H), 2.69 (t, J= 6.6 Hz, 2 H), 1.59-1.56 (m, 2 H),
1.47 (s, 9 H), 1.17-
1.42 (m, 2 H).
Me0 C 0 20% HCI Me02C 0 2 I O" v O~ I O" v OH
[00437] 1-[4-(2-Carboxy-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester
[00438] A solution of 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl]-
cyclopropanecarboxylic
methyl ester (6.3 g, 20 mmol) in HCl (20%, 200 mL) was heated at 110 C for 1
h. After
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cooling to room temperature, the resulting mixture was filtered. The solid was
washed with
water and dried under vacuum to give 1-[4-(2-carboxy-ethoxy)-phenyl]-
cyclopropanecarboxylic methyl ester (5.0 g, 96%). 1H NMR (300 MHz, DMSO) 8
7.23-7.19
(m, 2 H), 6.85-6.81 (m, 2 H), 4.13 (t, J = 6.0 Hz, 2 H), 3.51 (s, 3 H), 2.66
(t, J= 6.0 Hz, 2 H),
1.43-1.39 (m, 2 H), 1.14-1.10 (m, 2 H).
McOZC I OO (COCI)2 HOOC
V
~ O" v _OH [00439] 1-(4-Oxochroman-6-yl)cyclopropanecarboxylic acid
[00440] To a solution of 1-[4-(2-carboxy-ethoxy)-phenyl]-
cyclopropanecarboxylic methyl
ester (5.0 g, 20 mmol) in CH2C12 (50 mL) were added oxalyl chloride (4.8 g, 38
mmol) and
two drops of DMF at 0 C. The mixture was stirred at 0-5 C for 1 h and then
evaporated
under vacuum. To the resulting mixture was added CH2C12 (50 mL) at 0 C and
stirring was
continued at 0-5 C for 1 h. The reaction was slowly quenched with water and
was extracted
with EtOAc (50 mL x 3). The combined organic extracts were dried over
anhydrous Na2SO4
and evaporated under vacuum to give the crude product, which was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate 20:1-2:1) to give
1-(4-
oxochroman-6-yl)cyclopropanecarboxylic acid (830 mg, 19%) and methyl 1-(4-
oxochroman-
6-yl)cyclopropanecarboxylate (1.8 g, 38%). 1-(4-Oxochroman-6-yl)cyclopropane-
carboxylic
acid: 1H NMR (400 MHz, DMSO) 8 12.33 (br s, 1 H), 7.62 (d, J = 2.0 Hz, 1 H),
7.50 (dd, J =
2.4, 8.4 Hz, 1 H), 6.95 (d, J = 8.4 Hz, 1 H), 4.50 (t, J = 6.4 Hz, 2 H), 2.75
(t, J = 6.4 Hz, 2 H),
1.44-1.38 (m, 2 H), 1.10-1.07 (m, 2H). MS (ESI) m/z (M+H+) 231.4. 1-(4-
Oxochroman-6-
yl)cyclopropanecarboxylate: 1H NMR (400 MHz, CDC13) 8 7.83 (d, J = 2.4 Hz, 1
H), 7.48
(dd, J = 2.4, 8.4 Hz, 1 H), 6.93 (d, J = 8.4 Hz, 1 H), 4.55-4.52 (m, 2 H),
3.62 (s, 3 H), 2.80 (t,
J = 6.4 Hz, 2 H), 1.62-1.56 (m, 2 H), 1.18-1.15 (m, 2H).
[00441] Example 23: 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic
acid
HO Me
O
McO2C \ LOH HOOC I \
O
[00442] 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid
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[00443] To a solution of methyl 1-(4-oxochroman-6-yl)cyclopropanecarboxylate
(1.0 g, 4.1
mmol) in MeOH (20 mL) and water (20 mL) was added LiOH=H20 (0.70 g, 16 mmol)
in
portions at room temperature. The mixture was stirred overnight at room
temperature before
the MeOH was removed by evaporation under vacuum. Water and Et20 were added to
the
residue and the aqueous layer was separated, acidified with HCl and extracted
with EtOAc
(50 mL x 3). The combined organic extracts dried over anhydrous Na2SO4 and
evaporated
under vacuum to give 1-(4-hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic
acid
(480 mg, 44%). 1H NMR (400 MHz, CDC13) 8 12.16 (s, 1 H), 7.73 (d, J = 2.0 Hz,
1 H), 7.47
(dd, J = 2.0, 8.4 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 3.83-3.80 (m, 2 H),
3.39 (s, 3 H), 3.28-
3.25 (m, 2 H), 1.71-1.68 (m, 2 H), 1.25-1.22 (m, 2H). MS (ESI) m/z (M+H+)
263.1.
[00444] Example 24: 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic
acid
VO McOOC NaBH4/TFA McOOC I \ LiOH HOOC I \
McOOC NaBH4/TFA
I \ MeOOC I \
~ O
O
[00445] 1-Chroman-6-yl-cyclopropanecarboxylic methyl ester
[00446] To trifluoroacetic acid (20 mL) was added NaBH4 (0.70 g, 130 mmol) in
portions
at 0 C under N2 atmosphere. After stirring for 5 min, a solution of 1-(4-oxo-
chroman-6-yl)-
cyclopropanecarboxylic methyl ester (1.6 g, 6.5 mmol) was added at 15 C. The
reaction
mixture was stirred for 1 h at room temperature before being slowly quenched
with water.
The resulting mixture was extracted with EtOAc (50 mL x 3). The combined
organic
extracts dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-
chroman-6-yl-
cyclopropanecarboxylic methyl ester (1.4 g, 92%), which was used directly in
the next step.
1H NMR (300 MHz, CDC13) 8 7.07-7.00 (m, 2 H), 6.73 (d, J = 8.4 Hz, 1 H), 4.17
(t, J = 5.1
Hz, 2 H), 3.62 (s, 3 H), 2.79-2.75 (m, 2 H), 2.05-1.96 (m, 2 H), 1.57-1.54 (m,
2 H), 1.16-1.13
(m, 2H).
Me000 MLiOH 10- HOOC I ~
O O
[00447] 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid
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[00448] To a solution of 1-chroman-6-yl-cyclopropanecarboxylic methyl ester
(1.4 g, 60
mmol) in MeOH (20 mL) and water (20 mL) was added LiOH=H20 (1.0 g, 240 mmol)
in
portions at room temperature. The mixture was stirred overnight at room
temperature before
the MeOH was removed by evaporation under vacuum. Water and Et20 were added
and the
aqueous layer was separated, acidified with HCl and extracted with EtOAc (50
mL x 3). The
combined organic extracts dried over anhydrous Na2SO4 and evaporated under
vacuum to
give 1-(4-Hydroxy-4-methoxychroman-6-yl)cyclopropanecarboxylic acid (1.0 g,
76%). 1H
NMR (400 MHz, DMSO) 8 12.10 (br s, 1 H), 6.95 (d, J = 2.4 Hz, 2 H), 6.61-6.59
(m, 1 H),
4.09-4.06 (m, 2 H), 2.70-2.67 (m, 2 H), 1.88-1.86 (m, 2 H), 1.37-1.35 (m, 2
H), 1.04-1.01 (m,
2H). MS (ESI) m/z (M+H+) 217.4.
[00449] Example 25: 1-(3-Methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic
acid
HOOC \ MeOH/TSOH MeOOC AICI3/AcCI MeOOC NHZOH
VOH
OMe OMe N OH N.OAc
LiOH
McOOC N
Me000I \ I Ac20 MeOOC \ I Py/DMF UN. VO
I ON
OH OH HOOC \ N
0
McOOC I AICI3/AcCI McOOC
OMe OH
[00450] 1-(3-Acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester
[00451] To a stirred suspension of A1C13 (58 g, 440 mmol) in CS2 (500 mL) was
added
acetyl chloride (7.4 g, 95 mmol) at room temperature. After stirring for 5
min, methyl 1-(4-
methoxyphenyl)cyclopropanecarboxylate (15 g, 73 mmol) was added. The reaction
mixture
was heated at reflux for 2 h before ice water was added carefully to the
mixture at room
temperature. The resulting mixture was extracted with EtOAc (150 mL x 3). The
combined
organic extracts were dried over anhydrous Na2SO4 and evaporated under reduced
pressure to
give 1-(3-acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (15 g,
81%), which
was used in the next step without further purification. 1H NMR (CDC13, 400
MHz) 8 12.28
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(s, 1 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.47 (dd, J = 2.0, 8.4 Hz, 1 H), 6.94 (d,
J = 8.4 Hz, 1 H),
3.64 (s, 3 H), 2.64 (s, 3 H), 1.65-1.62 (m, 2 H), 1.18-1.16(m, 2 H).
O N OH
McOOC I NH2OH=HCI - McOOC
~ OH ~ OH
[00452] 1-[4-Hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic
methyl ester
[00453] To a stirred solution of 1-(3-acetyl-4-hydroxy-phenyl)-
cyclopropanecarboxylic
methyl ester (14.6 g, 58.8 mmol) in EtOH (500 mL) were added hydroxylamine
hydrochloride (9.00 g, 129 mmol) and sodium acetate (11.6 g, 141 mmol) at room
temperature. The resulting mixture was heated at reflux overnight. After
removal of EtOH
under vacuum, water (200 mL) and EtOAc (200 mL) were added. The organic layer
was
separated and the aqueous layer was extracted with EtOAc (100 mL x 3). The
combined
organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to
give 1-[4-
hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester
(14.5 g,
98%), which was used in the next step without further purification. 1H NMR
(CDC13, 400
MHz) 8 11.09 (s, 1 H), 7.39 (d, J = 2.0 Hz, 1 H), 7.23 (d, J = 2.0 Hz, 1 H),
7.14 (s, 1 H), 6.91
(d, J= 8.4 Hz, 1 H), 3.63 (s, 3 H), 2.36 (s, 3 H), 1.62-1.59 (m, 2 H), 1.18-
1.15 (m, 2 H).
N_OH N_OAc
I I
McOOC
MeOOC I \ OH Ac20 -10- OH
[00454] (E)-Methyl 1-(3-(1-(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropane
carboxylate
[00455] The solution of 1-[4-hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-
cyclopropanecarboxylic methyl ester (10.0 g, 40.1 mmol) in Ac20 (250 mL) was
heated at 45
C for 4 h. The Ac20 was removed by evaporation under vacuum before water (100
mL) and
EtOAc (100 mL) were added. The organic layer was separated and the aqueous
layer was
extracted with EtOAc (100 mL x 2). The combined organic layers were dried over
anhydrous Na2SO4 and evaporated under vacuum to give (E)-methyl 1-(3-(1-
(acetoxyimino)ethyl)-4-hydroxyphenyl)cyclopropanecarboxylate (10.5 g, 99%),
which was
used in the next step without further purification.
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N OAc
MeOOC OH Py/DMF McOOC
~ O N
[00456] Methyl 1-(3-methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylate
[00457] A solution of (E)-methyl 1-(3-(1-(acetoxyimino)ethyl)-4-
hydroxyphenyl)cyclopropane carboxylate (10.5 g, 39.6 mmol) and pyridine (31.3
g, 396
mmol) in DMF (150 mL) was heated at 125 C for 10 h. The cooled reaction
mixture was
poured into water (250 mL) and was extracted with EtOAc (100 mL x 3). The
combined
organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to
give the
crude product, which was purified by column chromatography on silica gel
(petroleum
ether/ethyl acetate 50:1) to give methyl 1-(3-methylbenzo[d]isoxazol-5-
yl)cyclopropanecarboxylate (7.5 g, 82%). 1H NMR (CDC13 300 MHz) 8 7.58-7.54
(m, 2 H),
7.48 (dd, J= 1.5, 8.1 Hz, 1 H), 3.63 (s, 3 H), 2.58 (s, 3 H), 1.71-1.68 (m, 2
H), 1.27-1.23 (m,
2 H).
Me000 VO\I N LiOH HOOC VO\'I N
[00458] 1-(3-Methylbenzo[d]isoxazol-5-yl)cyclopropanecarboxylic acid
[00459] To a solution of methyl 1-(3-methylbenzo[d]isoxazol-5-
yl)cyclopropanecarboxylate (1.5 g, 6.5 mmol) in MeOH (20 mL) and water (2 mL)
was
added LiOH=H20 (0.80 g, 19 mmol) in portions at room temperature. The reaction
mixture
was stirred at room temperature overnight before the MeOH was removed by
evaporation
under vacuum. Water and Et20 were added and the aqueous layer was separated,
acidified
with HCl and extracted with EtOAc (50 mL x 3). The combined organic extracts
were dried
over anhydrous Na2SO4 and evaporated under vacuum to give 1-(3-
methylbenzo[d]isoxazol-
5-yl)cyclopropanecarboxylic acid (455 mg, 32%). 1H NMR (400 MHz, DMSO) 8 12.40
(br
s, 1 H), 7.76 (s, 1 H), 7.60-7.57 (m, 2 H), 2.63 (s, 3 H), 1.52-1.48 (m, 2 H),
1.23-1.19 (m,
2H). MS (ESI) m/z (M+H+) 218.1.
[00460] Example 26: 1-(Spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-
yl)cyclopropane carboxylic acid
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HOOC I a OH Mew McOOC I a OH ff
/ OH / OHS
Me000 I OO* LiO~ HOOC I -o ^
O
HOOC I \ OH Mew McOOC I \ OH
/ OH /
OH
[00461] 1-(3,4-Dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester
[00462] To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid
(4.5 g) in
MeOH (30 mL) was added TsOH (0.25 g, 1.3 mmol). The stirring was continued at
50 C
overnight before the mixture was cooled to room temperature. The mixture was
concentrated
under vacuum and the residue was purified by column chromatography on silica
gel
(petroleum ether/ethyl acetate 3:1) to give 1-(3,4-dihydroxy-phenyl)-
cyclopropanecarboxylic
methyl ester (2.1 g). 1H NMR (DMSO 300 MHz) 8 8.81 (brs, 2 H), 6.66 (d, J =
2.1 Hz, 1 H),
6.61 (d, J = 8.1 Hz, 1 H), 6.53 (dd, J = 2.1, 8.1 Hz, 1 H), 3.51 (s, 3 H),
1.38-1.35 (m, 2 H),
1.07-1.03 (m, 2 H).
O
Me000 \ OH McOOC I \ O
/ OHS
[00463] Methyl 1-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-
yl)cyclopropane
carboxylate
[00464] To a solution of 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic
methyl ester
(1.0 g, 4.8 mmol) in toluene (30 mL) was added TsOH (0.10 g, 0.50 mmol) and
cyclobutanone (0.70 g, 10 mmol). The reaction mixture was heated at reflux for
2 h before
being concentrated under vacuum. The residue was purified by chromatography on
silica gel
(petroleum ether/ethyl acetate 15:1) to give methyl 1-
(spiro[benzo[d][1,3]dioxole-2,1'-
cyclobutane]-5-yl)cyclopropanecarboxylate (0.6 g, 50%). 1H NMR (CDC13 300 MHz)
8
6.78-6.65 (m, 3 H), 3.62 (s, 3 H), 2.64-2.58 (m, 4 H), 1.89-1.78 (m, 2 H),
1.56-1.54 (m, 2 H),
1.53-1.12(m, 2 H).
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McOOC O LiOH HOOC I 3
[00465] 1-(Spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-5-yl)cyclopropane
carboxylic
acid
[00466] To a mixture of methyl 1-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-
5-yl)cycl-
opropanecarboxylate (0.60 g, 2.3 mmol) in THF/H20 (4:1, 10 mL) was added LiOH
(0.30 g,
6.9 mmol). The mixture was stirred at 60 C for 24 h. HCl (0.5 N) was added
slowly to the
mixture at O C until pH 2-3. The mixture was extracted with EtOAc (10 mL x
3). The
combined organic phases were washed with brine, dried over anhydrous MgSO4,
and washed
with petroleum ether to give 1-(spiro[benzo[d][1,3]-dioxole-2,1'-cyclobutane]-
5-
yl)cyclopropane carboxylic acid (330 mg, 59%). 1HNMR (400 MHz, CDC13) 8 6.78-
6.65 (m,
3 H), 2.65-2.58 (m, 4 H), 1.86-1.78 (m, 2 H), 1.63-1.60 (m, 2 H), 1.26-1.19
(m, 2 H).
[00467] Example 27: 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile
H azzz C
O2Et BrH2CCH2Br \ C02Et LAH OH
H CI NaCN C 1C..CN
ABM- c~
0
HO CO2Et BrH2CCH2Br (DID", C02Et
)::~r Am HO O [0
0468] 2,3-Dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester
[00469] To a suspension of Cs2CO3 (270 g, 1.49 mol) in DMF (1000 mL) were
added 3,4-
dihydroxybenzoic acid ethyl ester (54.6 g, 0.3 mol) and 1,2-dibromoethane
(54.3 g, 0.29
mol) at room temperature. The resulting mixture was stirred at 80 C overnight
and then
poured into ice-water. The mixture was extracted with EtOAc (200 mL x 3). The
combined
organic layers were washed with water (200 mL x 3) and brine (100 mL), dried
over Na2SO4
and concentrated to dryness. The residue was purified by column (petroleum
ether/ethyl
acetate 50:1) on silica gel to obtain 2,3-dihydro-benzo[1,4]dioxine-6-
carboxylic acid ethyl
ester (18 g, 29%). 1H NMR (300 MHz, CDC13) 8 7.53 (dd, J = 1.8, 7.2 Hz, 2 H),
6.84-6.87
(m, 1 H), 4.22-4.34 (m, 6 H), 1.35 (t, J = 7.2 Hz, 3 H).
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LAH 0 I \ OH
CO
D~ '*'~
0 0
[00470] (2,3-Dihydro-benzo[1,4]dioxin-6-yl)-methanol
[00471] To a suspension of LiAlH4 (2.8 g, 74 mmol) in THE (20 mL) was added
dropwise
a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15
g, 72 mmol) in
THE (10 mL) at 0 C under N2. The mixture was stirred at room temperature for
1 h and then
quenched carefully with addition of water (2.8 mL) and NaOH (10%, 28 mL) with
cooling.
The precipitated solid was filtered off and the filtrate was evaporated to
dryness to obtain
(2,3 -dihydro-benzo [ 1,4] dioxin-6-yl)-methanol (10.6 g). 'H NMR (300 MHz,
DMSO-d6) 8
6.73-6.78 (m, 3 H), 5.02 (t, J = 5.7 Hz, 1 H), 4.34 (d, J = 6.0 Hz, 2 H), 4.17-
4.20 (m, 4 H).
O SOCI2 (0)
C I \\ SOH
O
[00472] 6-Chloromethyl-2,3-dihydro-benzo[1,4]dioxine
[00473] A mixture of (2,3 -dihydro-benzo [ 1,4] dioxin-6-yl)methanol (10.6 g)
in SOC12 (10
mL) was stirred at room temperature for 10 min and then poured into ice-water.
The organic
layer was separated and the aqueous phase was extracted with dichloromethane
(50 mL x 3).
The combined organic layers were washed with NaHCO3 (sat solution), water and
brine,
dried over Na2SO4 and concentrated to dryness to obtain 6-chloromethyl-2,3-
dihydro-
benzo[1,4]dioxine (12 g, 88% over two steps), which was used directly in next
step.
aCN CO CN
O N
O /
Da"~
[00474] 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)acetonitrile
[00475] A mixture of 6-chloromethyl-2,3-dihydro-benzo[1,4]dioxine (12.5 g,
67.7 mmol)
and NaCN (4.30 g, 87.8 mmol) in DMSO (50 mL) was stirred at rt for 1 h. The
mixture was
poured into water (150 mL) and then extracted with dichloromethane (50 mL x
4). The
combined organic layers were washed with water (50 mL x 2) and brine (50 mL),
dried over
Na2SO4 and concentrated to dryness. The residue was purified by column
(petroleum
ether/ethyl acetate 50:1) on silica gel to obtain 2-(2,3-
dihydrobenzo[b][1,4]dioxin-6-
yl)acetonitrile as a yellow oil (10.2 g, 86%). 'H-NMR (300 MHz, CDC13) 8 6.78-
6.86 (m, 3
H), 4.25 (s, 4 H), 3.63 (s, 2 H).
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[00476] The following Table 2 contains a list of carboxylic acid building
blocks that were
commercially available, or prepared by one of the three methods described
above:
Table 2: Carboxylic acid building blocks.
Name Structure
1-benzo[1,3]dioxol-5-ylcyclopropane-l- H O ~-ao
0)
carboxylic acid 1-(2,2-difluorobenzo[1,3]dioxol-5- H O F
F
yl)cyclopropane-l-carboxylic acid \ / o
1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic OH OH
acid \ / OH
1-(3-methoxyphenyl)cyclopropane-l-carboxylic H O acid HO
1-(2-methoxyphenyl)cyclopropane- l-carboxylic
acid
1-[4-(trifluoromethoxy)phenyl]cyclopropane-l- F O
carboxylic acid HO
1-(2,2-dimethylbenzo[d][1,3]dioxol-5- / \
yl)cyclopropanecarboxylic acid OH
tetrahydro-4-(4-methoxyphenyl)-2H-pyran-4- 0
carboxylic acid
OH
OH
1-phenylcyclopropane-l-carboxylic acid
1-(4-methoxyphenyl)cyclopropane- l -carboxylic
OH
acid " i o
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Name Structure
1-(4-chlorophenyl)cyclopropane- l-carboxylic
OH
acid Cj i o
1-(3-hydroxyphenyl)cyclopropanecarboxylic H 0 OH
acid
O
1-phenylcyclopentanecarboxylic acid OH
1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5- OH _O
yl)cyclopropanecarboxylic acid H ~wo
1-(benzofuran-5-yl)cyclopropanecarboxylic acid 1-(4-
methoxyphenyl)cyclohexanecarboxylic acid \
OH
1-(4-chlorophenyl)cyclohexanecarboxylic acid CI / \
POH
1-(2,3-dihydrobenzofuran-5- H TbDo
yl)cyclopropanecarboxylic acid 1-(3,3-dimethyl-2,3-dihydrobenzofuran-5- / \
yl)cyclopropanecarboxylic acid OH
-O
1-(7-methoxybenzo[d][1,3]dioxol-5- / \
yl)cyclopropanecarboxylic acid L H 0
1-(3-hydroxy-4- OH OH
methoxyphenyl)cyclopropanecarboxylic acid Tdio\
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Name Structure
1-(4-chloro-3- OH OH
hydroxyphenyl)cyclopropanecarboxylic acid Tdi Cl
H
1-(3-(benzyloxy)-4- O
chlorophenyl)cyclopropanecarboxylic acid
Cl
1-(4-chlorophenyl)cyclopentanecarboxylic acid
-C~fOH
1-(3-(benzyloxy)-4-
methoxyphenyl)cyclopropanecarboxylic acid
OH
1-(3-chloro-4- olzzl/ OH Cl
methoxyphenyl)cyclopropanecarboxylic acid _ 1-(3-fluoro-4- OH F
methoxyphenyl)cyclopropanecarboxylic acid Td-O\
1 (4 methoxy 3 OH
methylphenyl)cyclopropanecarboxylic acid \ / 01,
1-(4-(benzyloxy)-3-
methoxyphenyl)cyclopropanecarboxylic acid H
1-(4-chloro-3- OH O-
methoxyphenyl)cyclopropanecarboxylic acid \ 1-(3-chloro-4- OH Cl
hydroxyphenyl)cyclopropanecarboxylic acid _ 1-(3-(hydroxymethyl)-4- OH OH
methoxyphenyl)cyclopropanecarboxylic acid \ /
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Name Structure
1-(4-methoxyphenyl)cyclopentanecarboxylic
acid Z
OH
1-phenylcyclohexanecarboxylic acid C\iOH
1-(3,4-dimethoxyphenyl)cyclopropanecarboxylic OH o-
acid
1-(7-chlorobenzo [d] [ 1,3]dioxol-5 - H to
yl)cyclopropanecarboxylic acid
Cl
1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic H O
~wo
acid 1-(7-fluorobenzo[d][1,3]dioxol-5- H to
yl)cyclopropanecarboxylic acid
F
1-(3,4-difluorophenyl)cyclopropanecarboxylic H o F
acid ~-aF
H
1-(1H-indol-5-yl)cyclopropanecarboxylic acid T-C;NH
1 (1H benzo[d]imidazol 5 H ~WNH
yl)cyclopropanecarboxylic acid 1-(2-methyl-lH-benzo[d]imidazol-5- H O
yl)cyclopropanecarboxylic acid ~-aNH
1-(1-methyl-lH-benzo[d]imidazol-5- H
yl)cyclopropanecarboxylic acid Tc;~k
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Name Structure
1-(3-methylbenzo[d]isoxazol-5- H o -N
yl)cyclopropanecarboxylic acid \ O
1-(spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]- H O
O
5-yl)cyclopropanecarboxylic acid
1-(1H-benzo[d][1,2,3]triazol-5- H O /N--N
yl)cyclopropanecarboxylic acid - 1-(1-methyl-1H-benzo[d][1,2,3]triazol-5- H O
/N--N
yl)cyclopropanecarboxylic acid
1-(1,3-dihydroisobenzofuran-5- H O o
yl)cyclopropanecarboxylic acid
1-(6-fluorobenzo[d][1,3]dioxol-5- H of
yl)cyclopropanecarboxylic acid
F
1-(2,3-dihydrobenzofuran-6- H o
yl)cyclopropanecarboxylic acid \ /
H O
1-(chroman-6-yl)cyclopropanecarboxylic acid
OH
1-(4-hydroxy-4-methoxychroman-6- H Ta yl)cyclopropanecarboxylic acid O
1-(4-oxochroman-6-yl)cyclopropanecarboxylic H
acid o\\// o
1-(3,4-dichlorophenyl)cyclopropanecarboxylic H 0 Cl
ci
acid
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Name Structure
1-(2,3-dihydrobenzo[b] [1,4]dioxin-6- H O
yl)cyclopropanecarboxylic acid T \ / O
HO O O
1-(benzofuran-6-yl)cyclopropanecarboxylic acid
[00477] Specific Procedures: Synthesis of aminoindole building blocks
[00478] Example 28: 3-Methyl-lH-indol-6-amine
\ I NaNO2/HCI 10- O / I -
~N~
OZN NHZ SnCIZ OZN NNHZ.HCI 02N--N
H H
NOZ
H3PO4 / / ffill H2/pd-C
/ ff
6 I N I + OZN \ H HZN \ H
H
NaNO2/HCI
SnCI 02N I N_NH2 HCI
02N NH2 2 H
[00479] (3-Nitro-phenyl)-hydrazine hydrochloride salt
[00480] 3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in the mixture of
H2O (40
mL) and 37% HCl (40 mL). A solution of NaNO2 (13.8 g, 0.2 mol) in H2O (60 mL)
was
added to the mixture at 0 C, and then a solution of SnC12.H20 (135.5 g, 0.6
mol) in 37% HCl
(100 mL) was added at that temperature. After stirring at 0 C for 0.5 h, the
insoluble
material was isolated by filtration and was washed with water to give (3-
nitrophenyl)hydrazine hydrochloride (27.6 g, 73%).
O N I N NH2 HC1 O2N I N' N~/~
2 H H
[00481] N-(3-Nitro-phenyl)-N'-propylidene-hydrazine
[00482] Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred
suspension
of (3-nitrophenyl)hydrazine hydrochloride (1.89 g, 10 mmol) in ethanol (20 mL)
until pH 6.
Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7
g, 12 mmol).
After stirring for 3 h at room temperature, the mixture was poured into ice-
water and the
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resulting precipitate was isolated by filtration, washed with water and dried
in air to obtain
(E)-1-(3-nitrophenyl)-2-propylidenehydrazine, which was used directly in the
next step.
NOZ
/ I ~~~ H3PO4 / I I + OZN ffN
OzN NINA
H & N
H
[00483] 3-Methyl-4-nitro-1H-indole 3 and 3-methyl-6-nitro-lH-indole
[00484] A mixture of (E)-1-(3-nitrophenyl)-2-propylidenehydrazine dissolved in
85 %
H3PO4 (20 mL) and toluene (20 mL) was heated at 90-100 C for 2 h. After
cooling, toluene
was removed under reduced pressure. The resultant oil was basified to pH 8
with 10 %
NaOH. The aqueous layer was extracted with EtOAc (100 mL x 3). The combined
organic
layers were dried, filtered and concentrated under reduced pressure to afford
the mixture of 3-
methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole [1.5 g in total, 86 %,
two steps
from (3-nitrophenyl)hydrazine hydrochloride] which was used to the next step
without
further purification.
N02
/ I I H2/Pd-C
\ I N I + 02N \ H H2N \ H
H
[00485] 3-Methyl-lH-indol-6-amine
[00486] The crude mixture from previous steps (3 g, 17 mmol) and 10% Pd-C (0.5
g) in
ethanol (30 mL) was stirred overnight under H2 (1 atm) at room temperature. Pd-
C was
filtered off and the filtrate was concentrated under reduced pressure. The
solid residue was
purified by column to give 3-methyl-1H-indol-6-amine (0.6 g, 24%). 1H NMR
(CDC13) 8
7.59 (br s. 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 6.64 (s, 1H), 6.57
(m, 1H), 3.57 (brs,
2H), 2.28 (s, 3H); MS (ESI) m/e (M+H+) 147.2.
[00487] Example 29: 3-tert-Butyl-lH-indol-5-amine
H2N I
02N \ OzN Raney Ni/H2
10- N AICI3/CH2CI2 - N N
H H H
02N 02N
N AICI3/~ N
H H
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[00488] 3-tert-Butyl-5-nitro-1H-indole
[00489] To a mixture of 5-nitro-1H-indole (6.0 g, 37 mmol) and A1C13 (24 g,
0.18 mol) in
CH2C12 (100 mL) at 0 C was added 2-bromo-2-methyl-propane (8.1 g, 37 mmol)
dropwise.
After being stirred at 15 C overnight, the mixture was poured into ice (100
mL). The
precipitated salts were removed by filtration and the aqueous layer was
extracted with
CH2C12 (30 mL x 3). The combined organic layers were washed with water, brine,
dried over
Na2SO4 and concentrated under vacuum to obtain the crude product, which was
purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 20:1) to
give 3-tert-
butyl- 5 -nitro- I H-indole (2.5 g, 31%). 1H NMR (CDC13, 400 MHz) 8 8.49 (d, J
= 1.6 Hz, 1
H), 8.31 (brs, 1 H), 8.05 (dd, J = 2.0, 8.8 Hz, 1 H), 7.33 (d, J = 8.8 Hz, 1
H), 6.42 (d, J = 1.6
Hz, 1 H), 1.42 (s, 9 H).
O2N Raney Ni/H2 H2N \
C N N
H H
[00490] 3-tert-Butyl-lH-indol-5-amine
[00491] To a solution of 3 -tert-butyl-5 -nitro- I H-indole (2.5 g, 12 mmol)
in MeOH (30 mL)
was added Raney Nickel (0.2 g) under N2 protection. The mixture was stirred
under
hydrogen atmosphere (1 atm) at 15 C for 1 h. The catalyst was filtered off
and the filtrate
was concentrated to dryness under vacuum. The residue was purified by
preparative HLPC
to afford 3-tert-butyl-1H-indol-5-amine (0.43 g, 19%). 1H NMR (CDC13, 400 MHz)
8 7.72
(br.s, 1 H), 7.11 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 2.0 Hz, 1 H), 6.59 (dd, J
= 2.0, 8.4 Hz, 1 H),
6.09 (d, J = 1.6 Hz, 1 H), 1.37 (s, 9 H); MS (ESI) m/e (M+H+) 189.1.
[00492] Example 30: 2-tert-Butyl-6-fluoro-lH-indol-5-amine and 6-tert-butoxy-2-
tert-
butyl- lH-indol-5-amine
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OZN :)" BrZ 02N \ Br OZN 02N O 10 F NHZ F / NHz F NHZ F H
TBAF O2N H2N
Ni
DMF F N F H
H
BuOK ON Ni HZN I \
D~ N ~p / N
H H
OzN \ Br2 ~ Br
z
F NHz F I a NH
z
[00493] 2-Bromo-5-fluoro-4-nitroaniline
[00494] To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80
mL) and
chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0 C. After
addition,
the resulting mixture was stirred at room temperature for 2 h and then poured
into ice water.
The mixture was basified with aqueous NaOH (10%) to pH - 8.0-9.0 under cooling
and then
extracted with EtOAc (50 mL x 3). The combined organic layers were washed with
water
(80 mL x 2) and brine (100 mL), dried over Na2SO4 and concentrated under
reduced pressure
to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90%). 1H-NMR (400 MHz, DMSO-d6)
8 8.26
(d, J = 8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J = 9.6 Hz, 1H).
02N Br O2N
F NH2 F NH2
[00495] 2-(3,3-Dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline
[00496] A mixture of 2-bromo-5-fluoro-4-nitroaniline (9.0 g, 38.4 mmol), 3,3-
dimethyl-
but-1-yne (9.95 g, 121 mmol), Cul (0.5 g 2.6 mmol), Pd(PPh3)2C12 (3.4 g, 4.86
mmol) and
Et3N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) was heated at 70
C for 4 h.
The aqueous layer was separated and the organic layer was washed with water
(80 mL x 2)
and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure
to dryness.
The residue was recrystallized with ether to afford 2-(3,3-dimethylbut-1-ynyl)-
5-fluoro-4-
nitroaniline (4.2 g, 46%). 1H-NMR (400 MHz, DMSO-d6) 8 7.84 (d, J= 8.4 Hz,
1H), 6.84
(brs, 2H), 6.54 (d, J = 14.4 Hz, 1H), 1.29 (s, 9H).
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~O ^
OZN CI' v \ OZN ~O
F NH2 F H `
[00497] N-(2-(3,3-Dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide
[00498] To a solution of 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline
(4.2 g, 17.8
mmol) in dichloromethane (50 mL) and Et3N (10.3 mL, 71.2 mmol) was added
butyryl
chloride (1.9 g, 17.8 mmol) at 0 C. The mixture was stirred at room
temperature for 1 h and
then poured into water. The aqueous phase was separated and the organic layer
was washed
with water (50 mL x 2) and brine (100 mL), dried over Na2SO4 and concentrated
under
reduced pressure to dryness. The residue was washed with ether to give N-(2-
(3,3-
dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (3.5 g, 67%), which was
used in the
next step without further purification.
OzN TBAF O2N
~-+
)01
O IN- F N v \ F H
H
[00499] 2-tert-Butyl-6-fluoro-5-nitro-1H-indole
[00500] A solution of N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-
nitrophenyl)butyramide
(3.0 g, 9.8 mmol) and TBAF (4.5 g, 17.2 mmol) in DMF (25 mL) was heated at 100
C
overnight. The mixture was poured into water and then extracted with EtOAc (80
mL x 3).
The combined extracts were washed with water (50 mL) and brine (50 mL), dried
over
Na2SO4 and concentrated under reduced pressure to dryness. The residue was
purified by
column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to
give compound
2-tert-butyl- 6-fluoro- 5 -nitro- I H-indole (1.5 g, 65%). 1H-NMR (400 MHz,
CDC13) 8 8.30 (d,
J = 7.2 Hz, 1H), 7.12 (d, J = 11.6 Hz, 1H), 6.35 (d, J = 1.2 Hz, 1H), 1.40 (s,
9H).
OZN HZN
H F N
F H
[00501] 2-tert-Butyl-6-fluoro-lH-indol-5-amine
[00502] A suspension of 2-tert-butyl-6-fluoro-5 -nitro- I H-indole (1.5 g,
6.36 mmol) and Ni
(0.5 g) in MeOH (20 mL) was stirred under H2 atmosphere (1 atm) at the room
temperature
for 3 h. The catalyst was filtered off and the filtrate was concentrated under
reduced pressure
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to dryness. The residue was recrystallized in ether to give 2-tert-butyl-6-
fluoro-lH-indol-5-
amine (520 mg, 38%). 'H-NMR (300 MHz, DMSO-d6) 8 10.46 (brs, 1H), 6.90 (d, J =
8.7
Hz, 1H), 6.75 (d, J= 9.0 Hz, 1H), 5.86 (s, 1H), 4.37 (brs, 2H), 1.29 (s, 9H);
MS (ESI) m/e
206.6.
02N BuOK O?N
o N
F Nu )'\ H
H
[00503] 6-tert-Butoxy-2-tert-butyl-5-nitro-lH-indole
[00504] A solution of N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-
nitrophenyl)butyramide
(500 mg, 1.63 mmol) and t-BuOK (0.37 g, 3.26 mmol) in DMF (10 mL) was heated
at 70 C
for 2 h. The mixture was poured into water and then extracted with EtOAc (50
mL x 3). The
combined extracts were washed with water (50 mL) and brine (50 mL), dried over
Na2SO4
and concentrated under reduced pressure to give 6-tert-butoxy-2-tert-butyl- 5 -
nitro- I H-indole
(100 mg, 21%). 'H-NMR (300 MHz, DMSO-d6) 8 11.35 (brs, 1H), 7.99 (s, 1H), 7.08
(s,
1H), 6.25 (s, 1H), 1.34 (s, 9H), 1.30 (s, 9H).
02N
Raney H2N
O H /O:C H
[00505] 6-tert-Butoxy-2-tert-butyl-lH-indol-5-amine
[00506] A suspension of 6-tert-butoxy-2-tert-butyl-5 -nitro- I H-indole (100
mg, 0.36 mmol)
and Raney Ni (0.5 g) in MeOH (15 mL) was stirred under H2 atmosphere (1 atm)
at the room
temperature for 2.5 h. The catalyst was filtered off and the filtrate was
concentrated under
reduced pressure to dryness. The residue was recrystallized in ether to give 6-
tert-butoxy-2-
tert-butyl-1H-indol-5-amine (30 mg, 32%). 'H-NMR (300 MHz, MeOD) 6.98 (s, 1H),
6.90
(s, 1H), 5.94 (d, J= 0.6 Hz, 1H), 1.42 (s, 9H), 1.36 (s, 9H); MS (ESI) m/e
205Ø
[00507] Example 31: 1-tert-Butyl-lH-indol-5-amine
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I
O2N Sim
02N H2N I \\ Br / AcOH 02N I \ Br = S\ OZN \ / \
v NH 2 /
F NH Pd(PPh3)2Ci2 NH
O2N H2N \
Cul, DMF I / Raney Ni/ H2
N I / N
02N H2N 02NNIZZ
NH
F
[00508] N-tert-Butyl-4-nitroaniline
[00509] A solution of 1-fluoro-4-nitro-benzene (1 g, 7.1 mmol) and tert-
butylamine (1.5 g,
21 mmol) in DMSO (5 mL) was stirred at 75 C overnight. The mixture was poured
into
water (10 mL) and extracted with EtOAc (7 mL x 3). The combined organic layers
were
washed with water, brine, dried over Na2SO4 and concentrated under vacuum to
dryness. The
residue was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate
30:1) to afford N-tert-butyl-4-nitroaniline (1 g, 73%). 1H NMR (CDC13, 400
MHz) 8 8.03-
8.00 (m, 2H), 6.61-6.57 (m, 2H), 4.67 (brs, 1H), 1.42 (s, 9H).
O2N O2N . Br
Br2 / AcOH
NH Do- NH
[00510] (2-Bromo-4-nitro-phenyl)-tert-butyl-amine
[00511] To a solution of N-tert-butyl-4-nitroaniline (1 g, 5.1 mmol) in AcOH
(5 mL) was
added Br2 (0.86 g, 54 mmol) dropwise at 15 C. After addition, the mixture was
stirred at 30
C for 30 min and then filtered. The filter cake was basified to pH 8-9 with
aqueous
NaHCO3. The aqueous layer was extracted with EtOAc (10 mL x 3). The combined
organic
layers were washed with water, brine, dried over Na2SO4 and concentrated under
vacuum to
give (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 43%). 1H-NMR (CDC13,
400 MHz) 8
8.37 (dd, J = 2.4 Hz, 1H), 8.07 (dd, J = 2.4, 9.2 Hz, 1H), 6.86 (d, J = 9.2
Hz, 1H), 5.19 (brs,
1H), 1.48 (s, 9H).
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Si
O2N Br Si, O2N
NH pd(p NH
[00512] tert-Butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine
[00513] To a solution of (2-bromo-4-nitro-phenyl)-tert-butyl-amine (0.6 g, 2.2
mmol) in
Et3N (10 mL) was added Pd(PPh3)2C12 (70 mg, 0.1 mmol), Cul (20.9 mg, 0.1 mmol)
and
ethynyl-trimethyl-silane (0.32 g, 3.3 mmol) successively under N2 protection.
The reaction
mixture was heated at 70 C overnight. The solvent was removed under vacuum
and the
residue was washed with EtOAc (10 mL x 3). The combined organic layers were
washed
with water, brine, dried over Na2SO4 and concentrated under vacuum to dryness.
The residue
was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate 20:1) to
afford tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-amine (100 mg,
16%). 1H-NMR
(CDC13, 400 MHz) 8 8.20 (d, J = 2.4, Hz, 1H), 8.04 (dd, J = 2.4, 9.2 Hz, 1H),
6.79 (d, J = 9.6
Hz, 1H), 5.62 (brs, 1H), 1.41 (s, 9H), 0.28 (s, 9H).
Sim
O N \ O N
2 Cul, DMF_ 2
N
[00514] 1-tert-Butyl-5-nitro-1H-indole
[00515] To a solution of tert-butyl-(4-nitro-2-trimethylsilanylethynyl-phenyl)-
amine (10
mg, 0.035 mmol) in DMF (2 mL), was added Cul (13 mg, 0.07 mmol) under N2
protection.
The reaction mixture was stirred at 100 C overnight. At this time, EtOAc (4
mL) was added
to the mixture. The mixture was filtered and the filtrate was washed with
water, brine, dried
over Na2SO4 and concentrated under vacuum to obtain 1-tert-butyl-5-nitro-1H-
indole (7 mg,
93%). 1H-NMR (CDC13, 300 MHz) 8 8.57 (d, J= 2.1 Hz, 1H), 8.06 (dd, J=2.4,9.3
Hz, 1H),
7.65 (d, J = 9.3 Hz, 1H), 7.43 (d, J = 3.3 Hz, 1H), 6.63 (d, J = 3.3 Hz, 1H),
1.76 (s, 9H).
02N H2N
Raney Ni/ H2
N
[00516] 1-tert-Butyl-lH-indol-5-amine
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[00517] To a solution of 1-tert-butyl-5-nitro-lH-indole (6.5 g, 0.030 mol) in
MeOH (100
mL) was added Raney Nickel (0.65 g, 10%) under N2 protection. The mixture was
stirred
under hydrogen atmosphere (1 atm) at 30 C for 1 h. The catalyst was filtered
off and the
filtrate was concentrated under vacuum to dryness. The residue was purified by
column
chromatography on silica gel (PE/EtOAc 1:2) to give 1-tert-butyl-lH-indol-5-
amine (2.5 g,
45%). 1H-NMR (CDC13, 400 MHz) 8 7.44 (d, J = 8.8 Hz, 1H), 7.19 (dd, J = 3.2
Hz, 1H),
6.96 (d, J = 2.0 Hz, 1H), 6.66 (d, J = 2.0, 8.8 Hz, 1H), 6.26 (d, J = 3.2 Hz,
1H), 1.67 (s, 9H).
MS (ESI) m/e (M+H+) 189.2.
[00518] Example 32: 2-tert-Butyl-l-methyl-lH-indol-5-amine
OZN OZN Br
II I Br2/HOAc _ II I _ OZN
NH NH
NH
TBAF OZN Ni/H2 H2N
N N
Br
Br2/HOAc
02N~ 02N "'a NH
NH /
[00519] (2-Bromo-4-nitro-phenyl)-methyl-amine
[00520] To a solution of methyl-(4-nitro-phenyl)-amine (15.2 g, 0.1 mol) in
AcOH (150
mL) and CHC13 (50 mL) was added Br2 (16.0 g, 0.1 mol) dropwise at 5 C. The
mixture was
stirred at 10 C for lh and then basified with sat. aq. NaHCO3. The resulting
mixture was
extracted with EtOAc (100 mL x 3), and the combined organics were dried over
anhydrous
Na2SO4 and evaporated under vacuum to give (2-bromo-4-nitro-phenyl)-methyl-
amine (2-
bromo-4-nitro-phenyl)-methyl-amine (23.0 g, 99%), which was used in the next
step without
further purification. 1H NMR (300 MHz, CDC13) 8 8.37 (d, J = 2.4 Hz, 1 H),
8.13 (dd, J =
2.4, 9.0 Hz, 1 H), 6.58 (d, J = 9.0 Hz, 1 H), 5.17 (brs, 1 H), 3.01 (d, J =
5.4 Hz, 3 H).
02N Br
02N \
NH
NH
1
[00521] [2-(3,3-Dimethyl-but-1-ynyl)-4-nitro-phenyl]-methyl-amine
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[00522] To a solution of (2-bromo-4-nitro-phenyl)-methyl-amine (22.5 g, 97.4
mmol) in
toluene (200 mL) and water (100 mL) were added Et3N (19.7 g, 195 mmol),
Pd(PPh3)2C12
(6.8 g, 9.7 mmol), Cul (0.7 g, 3.9 mmol) and 3,3-dimethyl-but-1-yne (16.0 g,
195 mmol)
successively under N2 protection. The mixture was heated at 70 C for 3 hours
and then
cooled down to room temperature. The resulting mixture was extracted with
EtOAc (100 mL
x 3). The combined organic extracts were dried over anhydrous Na2SO4 and
evaporated
under vacuum to give [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl]-methyl-amine
(20.1 g,
94%), which was used in the next step without further purification. 1H NMR
(400 MHz,
CDC13) 8 8.15 (d, J = 2.4 Hz, 1H), 8.08 (dd, J = 2.8, 9.2 Hz, 1H), 6.50 (d, J
= 9.2 Hz, 1H),
5.30 (brs, 1H), 3.00 (s, 3H), 1.35 (s, 9H).
02N TBAF I
N
NH
1
[00523] 2-tert-Butyl-l-methyl-5-nitro-1H-indole
[00524] A solution of [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl]-methyl-
amine (5.0 g,
22.9 mmol) and TBAF (23.9 g, 91.6 mmol) in THE (50 mL) was heated at reflux
overnight.
The solvent was removed by evaporation under vacuum and the residue was
dissolved in
brine (100 mL) and EtOAc (100 mL). The organic phase was separated, dried over
Na2SO4
and evaporated under vacuum to give 2-tert-butyl-l-methyl-5-nitro-IH-indole
(5.0 g, 99%),
which was used in the next step without further purification. 1H NMR (CDC13,
400 MHz) 8
8.47 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 2.4, 9.2 Hz, 1H), 7.26-7.28 (m, 1H),
6.47 (s, 1H), 3.94
(s, 3H), 1.50 (s, 9H).
O2N Raney Ni/H2 H2N
[00525] 2-tert-Butyl-l-methyl-lH-indol-5-amine
[00526] To a solution of 2-tert-butyl-1-methyl-5-nitro-IH-indole (3.00 g, 13.7
mmol) in
MeOH (30 mL) was added Raney Ni (0.3 g) under nitrogen atmosphere. The mixture
was
stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The
mixture was
filtered through a Celite pad and the filtrate was evaporated under vacuum.
The crude residue
was purified by column chromatography on silica gel (P.E/EtOAc 20:1) to give 2-
tert-butyl-
1-methyl-1H-indol-5-amine (1.7 g, 66%). 1H NMR (300 MHz, CDC13) 8 7.09 (d, J =
8.4 Hz,
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1H), 6.89-6.9 (m, 1H), 6.66 (dd, J = 2.4, 8.7 Hz, 1H), 6.14 (d, J = 0.6 Hz,
1H), 3.83 (s, 3H),
3.40 (brs, 2H), 1.45 (s, 9H); MS (ESI) m/e (M+H+) 203.1.
[00527] Example 33: 2-Cyclopropyl-lH-indol-5-amine
O2N \ O2N Br Br2, HOAc O2N butyryl chloride
NH2 r.t. NH2 Cul, Et3N NH2
Pd(PPh3)CI2
02N TBAF O2N Raney Ni H2N
0 \N
/ H
H H
02N Br2, HOAc O2N Br
NH2 r.t. NH2
[00528] 2-Bromo-4-nitroaniline
[00529] To a solution of 4-nitro-aniline (25 g, 0.18 mol) in HOAc (150 mL) was
added
liquid Br2 (30 g, 0.19 mol) dropwise at room temperature. The mixture was
stirred for 2
hours. The solid was collected by filtration and poured into water (100 mL),
which was
basified with sat. aq. NaHCO3 to pH 7 and extracted with EtOAc (300 mL x 3).
The
combined organic layers were dried over anhydrous Na2SO4 and evaporated under
reduced
pressure to give 2-bromo-4-nitroaniline (30 g, 80%), which was directly used
in the next step.
02N Br 02N
NH2 Cul, Et3N
NH2
Pd(PPh3)CI2
[00530] 2-(Cyclopropylethynyl)-4-nitroaniline
[00531] To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01
mmol),
ethynyl-cyclopropane (1 g, 15 mmol) and Cul (10 mg, 0.05 mmol) in
triethylamine (20 mL)
was added Pd(PPh3)2C12 (210 mg, 0.3 mmol) under N2. The mixture was heated at
70 C and
stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL
x 3). The
filtrate was evaporated under reduced pressure, and the residue was purified
by column
chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 2-
(cyclopropylethynyl)-4-nitroaniline (470 mg, 23%). 1H NMR (300 MHz, CDC13) 8
8.14 (d,
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J = 2.7 Hz, 1H), 7.97 (dd, J = 2.7, 9.0 Hz, 1H), 6.63 (d, J = 9.0 Hz, 1H),
4.81 (brs, 2H), 1.55-
1.46 (m, 1H), 0.98-0.90 (m, 2H), 0.89-0.84 (m, 2H).
02N I / butyryl chloride 02N 1 O
NH2 N v `
H
[00532] N-(2-(Cyclopropylethynyl)phenyl)-4-nitrobutyramide
[00533] To a solution of 2-(cyclopropylethynyl)-4-nitroaniline (3.2 g, 15.8
mmol) and
pyridine (2.47 g, 31.7 mmol) in CH2C12 (60 mL) was added butyryl chloride
(2.54 g, 23.8
mmol) at 0 C. The mixture was warmed to room temperature and stirred for 3
hours. The
resulting mixture was poured into ice-water. The organic layer was separated.
The aqueous
phase was extracted with CH2C12 (30 m L x 3). The combined organic layers were
dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give the crude
product, which
was purified by column chromatography on silica gel (petroleum ether/ethyl
acetate = 10/1)
to give N-(2-(cyclopropylethynyl)phenyl)-4-nitrobutyramide (3.3 g, 76%). 1H
NMR (400
MHz, CDC13) 8 8.61 (d, J = 9.2 Hz, 1H), 8.22 (d, J = 2.8 Hz, 1H), 8.18 (brs,
1H), 8.13 (dd, J
= 2.4, 9.2 Hz, 1H), 2.46 (t, J = 7.2 Hz, 2H), 1.83-1.76 (m, 2H), 1.59-1.53 (m,
1H), 1.06 (t, J =
7.2 Hz, 3H), 1.03-1.01 (m, 2H), 0.91-0.87 (m, 2H).
02N O TBAF 02N
I_ZZII N" v H
H
[00534] 2-Cyclopropyl-5-nitro-lH-indole
[00535] A mixture of N-(2-(cyclopropylethynyl)phenyl)-4-nitrobutyramide (3.3
g, 0.01
mol) and TBAF (9.5 g, 0.04 mol) in THE (100 mL) was heated at reflux for 24
hours. The
mixture was cooled to the room temperature and poured into ice water. The
mixture was
extracted with CH2C12 (50 m L x 3). The combined organic layers were dried
over
anhydrous Na2SO4 and evaporated under reduced pressure. The residue was
purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to
give 2-
cyclopropyl- 5 -nitro- I H-indole (1.3 g, 64%). 1H NMR (400 MHz, CDC13) 8 8.44
(d, J = 2.0
Hz, 1H), 8.40 (brs, 1H), 8.03 (dd, J = 2.0, 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz,
1H), 6.29 (d, J =
0.8 Hz, 1H), 2.02-1.96 (m, 1H) 1.07-1.02 (m, 2H), 0.85-0.81(m, 2H).
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O2N Raney NI H2N
H
H
[00536] 2-Cyclopropyl-lH-indol-5-amine
[00537] To a solution of 2-cyclopropyl-5 -nitro- I H-indole (1.3 g, 6.4 mmol)
in MeOH (30
mL) was added Raney Nickel (0.3 g) under nitrogen atmosphere. The mixture was
stirred
under hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst
was filtered
through a Celite pad and the filtrate was evaporated under vacuum to give the
crude product,
which was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate =
5/1) to give 2-cyclopropyl-1H-indol-5-amine (510 mg, 56%). 1H NMR (400 MHz,
CDC13) 8
6.89 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 1.6 Hz, 1H), 6.33 (dd, J = 2.0, 8.4 Hz,
1H), 5.76 (s, 1H),
4.33 (brs, 2H), 1.91-1.87 (m, 1H), 0.90-0.85(m, 2H), 0.70-0.66 (m, 2H); MS
(ESI) m/e
(M+H+) 173.2.
[00538] Example 34: 3-tert-Butyl-lH-indol-5-amine
02N
Br O2N Raney Ni/H2 H2N
N A.
N AICL3/ N N
H H H
O2N \N Br* O2N
N AICL3 N
H H
[00539] 3-tert-Butyl-5-nitro-1H-indole
[00540] To a mixture of 5-nitro-1H-indole (6 g, 36.8 mmol) and A1C13 (24 g,
0.18 mol) in
CH2C12 (100 mL) was added 2-bromo-2-methyl-propane (8.1 g, 36.8 mmol) dropwise
at 0
C. After being stirred at 15 C overnight, the reaction mixture was poured
into ice (100 mL).
The precipitated salts were removed by filtration and the aqueous layer was
extracted with
CH2C12 (30 mL x 3). The combined organic layers were washed with water, brine,
dried over
Na2SO4 and concentrated under vacuum to obtain the crude product, which was
purified by
column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to
give 3-tert-butyl-
-nitro-1H-indole (2.5 g, 31%). 1H NMR (CDC13, 400 MHz) 8 8.49 (d, J= 1.6 Hz,
1H), 8.31
(brs, 1H), 8.05 (dd, J = 2.0, 8.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.42 (d,
J = 1.6 Hz, 1H),
1.42 (s, 9H).
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O2N \ Raney Ni/H2 H2N \
N
N
H H
[00541] 3-tert-Butyl-lH-indol-5-amine
[00542] To a solution of 3-tert-butyl-5-nitro-1H-indole (2.5 g, 11.6 mmol) in
MeOH (30
mL) was added Raney Nickel (0.2 g) under N2 protection. The mixture was
stirred under
hydrogen atmosphere (1 atm) at 15 C for 1 hr. The catalyst was filtered off
and the filtrate
was concentrated under vacuum to dryness. The residue was purified by
preparative HLPC
to afford 3-tert-butyl-1H-indol-5-amine (0.43 g, 19%). 1H NMR (CDC13, 400 MHz)
8 7.72
(brs, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.59 (dd, J =
2.0, 8.4 Hz, 1H),
6.09 (d, J = 1.6 Hz, 1H), 1.37 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
[00543] Example 35: 2-Phenyl-lH-indol-5-amine
Ph
O2N 02N Br O N
Ph 2 CI
Br2
NH2 AcOH NH2 Et3N NH2
Ph
O N O2N H2N
2 \ O TBAF I Ph Raney Ni I \ \ Ph
N H
H H
O2N Br2/HOAC O2N Br
NH2 NH2
[00544] 2-Bromo-4-nitroaniline
[00545] To a solution of 4-nitroaniline (50 g, 0.36 mol) in AcOH (500 mL) was
added
liquid Br2 (60 g, 0.38 mol) dropwise at 5 C. The mixture was stirred for 30
min at that
temperature. The insoluble solid was collected by filtration and poured into
EtOAc (200
mL). The mixture was basified with saturated aqueous NaHCO3 to pH 7. The
organic layer
was separated. The aqueous phase was extracted with EtOAc (300 mL x 3). The
combined
organic layers were dried and evaporated under reduced pressure to give 2-
bromo-4-
nitroaniline (56 g, 72%), which was directly used in the next step.
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Ph
02N Br O N
= Ph 2
NH2 Et3N NH2
[00546] 4-Nitro-2-(phenylethynyl)aniline
[00547] To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01
mmol),
ethynyl-benzene (1.53 g, 0.015 mol) and Cul (10 mg, 0.05 mmol) in
triethylamine (20 mL)
was added Pd(PPh3)2C12 (210 mg, 0.2 mmol) under N2. The mixture was heated at
70 C and
stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL
x 3). The
filtrate was evaporated under reduced pressure and the residue was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to give 4-
nitro-2-
(phenylethynyl)aniline (340 mg, 14%). 1H NMR (300 MHz, CDC13) 8 8.37-8.29 (m,
1H),
8.08-8.00 (m, 1H), 7.56-7.51 (m, 2H), 7.41-7.37 (m, 3H), 6.72 (m, 1H), 4.95
(brs, 2H).
Ph O Ph
O2N 02N
CI ` U \
-0
NH2 H
[00548] N-(2-(Phenylethynyl)phenyl)-4-nitrobutyramide
[00549] To a solution of 4-nitro-2-(phenylethynyl)aniline (17 g, 0.07 mmol)
and pyridine
(11.1 g, 0.14 mol) in CH2C12 (100 mL) was added butyryl chloride (11.5 g, 0.1
mol) at 0 C.
The mixture was warmed to room temperature and stirred for 3 hours. The
resulting mixture
was poured into ice-water. The organic layer was separated. The aqueous phase
was
extracted with CH2C12 (30 m L x 3). The combined organic layers were dried
over
anhydrous Na2SO4 and evaporated under reduced pressure. The residue was
purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to
give N-(2-
(phenylethynyl)phenyl)-4-nitrobutyramide (12 g, 55%). 1H NMR (400 MHz, CDC13)
8 8.69
(d, J =9.2 Hz, 1H), 8.39 (d, J =2.8 Hz, 1H), 8.25-8.20 (m, 2H), 7.58-7.55 (m,
2H), 7.45-7.42
(m, 3H), 2.49 (t, J=7.2 Hz, 2H), 1.85-1.79 (m, 2H), 1.06 (t, J= 7.2 Hz, 3H).
Ph
0N % 02N
2 0 TBAF I Ph
H H
[00550] 5-Nitro-2-phenyl-lH-indole
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[00551] A mixture of N-(2-(phenylethynyl)phenyl)-4-nitrobutyramide (5.0 g,
0.020 mol)
and TBAF (12.7 g, 0.050 mol) in THE (30 mL) was heated at reflux for 24 h. The
mixture
was cooled to room temperature and poured into ice water. The mixture was
extracted with
CH2C12 (50 m L x 3). The combined organic layers were dried over anhydrous
Na2SO4 and
evaporated under reduced pressure. The residue was purified by column
chromatography on
silica gel (petroleum ether/ethyl acetate = 10/1) to give 5-nitro-2-phenyl-1H-
indole (3.3 g,
69%). 1H NMR (400 MHz, CDC13) 8 8.67 (s, 1H), 8.06 (dd, J = 2.0, 8.8 Hz, 1H),
7.75 (d, J
=7.6 Hz, 2H), 7.54 (d, J =8.8 Hz, 1H), 7.45 (t, J =7.6 Hz, 2H), 7.36 (t, J =
7.6 Hz, 1H). 6.95
(s, 1H).
Ph Raney Ni Ph
OZN H2N
N
H H
[00552] 2-Phenyl-lH-indol-5-amine
[00553] To a solution of 5-nitro-2-phenyl-1H-indole (2.83 g, 0.01 mol) in MeOH
(30 mL)
was added Raney Ni (510 mg) under nitrogen atmosphere. The mixture was stirred
under
hydrogen atmosphere (1 atm) at room temperature overnight. The catalyst was
filtered
through a Celite pad and the filtrate was evaporated under vacuum to give the
crude product,
which was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate =
5/1) to give 2-phenyl-1H-indol-5-amine (1.6 g, 77%). 1H NMR (400 MHz, CDC13) 8
7.76 (d,
J =7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 7.07 (d, J
= 8.4 Hz, 1H),
6.64 (d, J = 1.6 Hz, 1H), 6.60 (d, J =1.2 Hz, 1H), 6.48 (dd, J = 2.0, 8.4 Hz,
1H), 4.48 (brs,
2H); MS (ESI) m/e (M+H+) 209Ø
[00554] Example 36: 2-tert-Butyl-4-fluoro-lH-indol-5-amine
F F 0 F F
Br NaBH4/NiCl2 Br Br G Pd(PPh3)2CI2 I / pGp
N02 MeOH 6 NH2 6NH4~~ CuI/Et3N NH/~
F F F
t-BuOK I j \ KNO, O2N I % \ NaBH4 H2N I j \
DMF H H2SO4 H McOH H
F F
Br NaBH4/NiC12 Br
N02 MeOH I NH
2
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[00555] 2-Bromo-3-fluoroaniline
[00556] To a solution of 2-bromo-l-fluoro-3-nitrobenzene (1.0 g, 5.0 mmol) in
CH3OH (50
mL) was added NiC12 (2.2 g 10 mmol) and NaBH4 (0.50 g 14 mmol) at 0 C. After
the
addition, the mixture was stirred for 5 min. Water (20 mL) was added and the
mixture was
extracted with EtOAc (20 mL x 3). The organic layers were dried over anhydrous
Na2SO4
and evaporated under vacuum to give 2-bromo-3-fluoroaniline (600 mg, 70%). 1H
NMR
(400 MHz, CDC13) S 7.07-7.02 (m, 1 H), 6.55-6.49(m, 1 H), 4.22 (br s, 2 H).
F 0 F
Br CI~^ I Br 0
NH2 NH
[00557] N-(2-Bromo-3-fluorophenyl)butyramide
[00558] To a solution of 2-bromo-3-fluoroaniline (2.0 g, 11 mmol) in CH2C12
(50 mL) was
added butyryl chloride (1.3 g, 13 mmol) and pyridine (1.7 g, 21 mmol) at 0 C.
The mixture
was stirred at room temperature for 24 h. Water (20 mL) was added and the
mixture was
extracted with CH2C12 (50 mL x 3). The organic layers were dried anhydrous
over Na2SO4
and evaporated under vacuum to give N-(2-bromo-3-fluorophenyl)butyramide (2.0
g, 73%),
which was directly used in the next step.
F F
Br O Pd(PPh3)2CI 0
a NH CuI/Et3N NH
[00559] N-(2-(3,3-Dimethylbut-1-ynyl)-3-fluorophenyl)butyramide
[00560] To a solution of N-(2-bromo-3-fluorophenyl)butyramide (2.0 g, 7.0
mmol) in Et3N
(100 mL) was added 4,4-dimethylpent-2-yne (6.0 g, 60 mmol), Cul (70 mg, 3.8
mmol), and
Pd(PPh3)2C12 (500 mg) successively at room temperature under N2. The mixture
was heated
at 80 C overnight. The cooled mixture was filtered and the filtrate was
extracted with EtOAc
(40 mL x 3). The organic layers were washed with sat. NaCl, dried over
anhydrous Na2SO4,
and evaporated under vacuum. The crude compound was purified by column
chromatography on silica gel (10% EtOAc in petroleum ether) to give N-(2-(3,3-
dimethylbut-
1-ynyl)-3-fluorophenyl)butyramide (1.1 g, 55%). 1H NMR (400 MHz, CDC13) S 8.20
(d, J=
7.6, 1 H), 7.95 (s, 1 H), 7.21 (m, 1 H), 6.77 (t, J = 7.6 Hz, 1 H), 2.39 (t, J
= 7.6 Hz, 2 H),
1.82-1.75 (m, 2 H), 1.40 (s, 9 H), 1.12 (t, J = 7.2 Hz, 3 H).
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F F
O t-BuOK
DMF
NH
H
[00561] 2-tert-Butyl-4-fluoro-1H-indole
[00562] To a solution of N-(2-(3,3-dimethylbut-1-ynyl)-3-
fluorophenyl)butyramide (6.0 g,
20 mmol) in DMF (100 mL) was added t-BuOK (5.0 g, 50 mmol) at room
temperature. The
mixture was heated at 90 C overnight before it was poured into water and
extracted with
EtOAc (100 mL x 3). The organic layers were washed with sat. NaCl and water,
dried over
anhydrous Na2SO4, and evaporated under vacuum to give 2-tert-butyl-4-fluoro-1H-
indole
(5.8 g, 97%). 1H NMR (400 MHz, CDC13) S 8.17 (br s, 1 H), 7.11 (d, J=7.2 Hz, 1
H), 7.05-
6.99 (m, 1 H), 6.76-6.71 (m, 1 H), 6.34 (m, 1 H), 1.41 (s, 9 H).
F F
KNO3 02N I \
H H2SO4 H
[00563] 2-tert-Butyl-4-fluoro-5-nitro-1H-indole
[00564] To a solution of 2-tert-butyl-4-fluoro-1H-indole (2.5 g, 10 mmol) in
H2SO4 (30
mL) was added KNO3 (1.3 g, 10 mmol) at 0 C. The mixture was stirred for 0.5 h
at -10 T.
The mixture was poured into water and extracted with EtOAc (100 mL x 3). The
organic
layers were washed with sat. NaCl and water, dried over anhydrous Na2SO4, and
evaporated
under vacuum. The crude compound was purified by column chromatography on
silica gel
(10% EtOAc in petroleum ether) to give 2-tert-butyl-4-fluoro-5-nitro-1H-indole
(900 mg,
73%). 1H NMR (400 MHz, CDC13) S 8.50 (br s, 1 H), 7.86 (dd, J = 7.6, 8.8 Hz, 1
H), 7.13
(d, J = 8.8 Hz, 1 H), 6.52 (dd, J = 0.4, 2.0 Hz, 1 H), 1.40 (s, 9 H).
F F
O2N I \ NaBH4/NiCI2 H2N
CH McOH N
H
[00565] 2-tert-Butyl-4-fluoro-lH-indol-5-amine
[00566] To a solution of 2-tert-butyl-4-fluoro-5 -nitro- I H-indole (2.1 g,
9.0 mmol) in
methanol (50 mL) was added NiC12 (4.2 g, 18 mmol) and NaBH4 (1.0 g, 27 mmol)
at 0 C.
After the addition, the mixture was stirred for 5 min. Water (20 mL) was added
and the
mixture was extracted with EtOAc (30 mL x 3). The organic layers were washed
with sat.
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NaCl and water, dried over anhydrous Na2SO4, evaporated under vacuum to give 2-
tert-butyl-
4-fluoro-1H-indol-5-amine (900 mg, 50%). 'H NMR (300 MHz, CDC13) S 7.80 (brs,
1 H),
6.91 (d, J = 8.4 Hz, 1 H), 6.64 (dd, J = 0.9, 2.4 Hz, 1 H), 6.23 (s, 1 H),
1.38 (s, 9 H).
[00567] Example 37: 2,3,4,9-Tetrahydro-1H-carbazol-6-amine
02N SnC12 H2N
::C N I / QN
-(Q
H H
[00568] 2,3,4,9-Tetrahydro-1H-carbazol-6-amine
[00569] 6-Nitro-2,3,4,9-tetrahydro-lH-carbazole (0.100 g, 0.462 mmol) was
dissolved in a
40 mL scintillation vial containing a magnetic stir bar and 2 mL of ethanol.
Tin(II) chloride
dihydrate (1.04 g, 4.62 mmol) was added to the reaction mixture and the
resulting suspension
was heated at 70 C for 16 h. The crude reaction mixture was then diluted with
15 mL of a
saturated aqueous solution of sodium bicarbonate and extracted three times
with an
equivalent volume of ethyl acetate. The ethyl acetate extracts were combined,
dried over
sodium sulfate, and evaporated to dryness to yield 2,3,4,9-tetrahydro-1H-
carbazol-6-amine
(82 mg, 95%) which was used without further purification.
[00570] Example 38: 2-tert-Butyl-7-fluoro-lH-indol-5-amine
OzN Br2/HOAc OzN Br 02N CI' v \
NH I / CuI,Pd(PPh3)2Clz, Eta / Py,C
z NHz NHz
F F F
OzN HzN
K, DMF_ I/ N Raney N
OzN eNH~'O~~' tt-BuO
H
H
F H
F
F
OzN
~ Br2/HOAc OzN ~ Br
/ NH r I / NH2
F F
[00571] 2-Bromo-6-fluoro-4-nitro-phenylamine
[00572] To a solution of 2-fluoro-4-nitro-phenylamine (12 g, 77 mmol) in AcOH
(50 mL)
was added Br2 (3.9 mL, 77 mmol) dropwise at 0 C. The mixture was stirred at
20 C for 3 h.
The reaction mixture was basified with sat. aq. NaHCO3, and extracted with
EtOAc (100 mL
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x 3). The combined organics were dried over anhydrous Na2SO4 and evaporated
under
vacuum to give 2-bromo-6-fluoro-4-nitro-phenylamine (18 g, 97%). 1H NMR (400
MHz,
CDC13) 8 8.22 (m, 1 H), 7.90 (dd, J = 2.4, 10.8 Hz, 1 H), 4.88 (brs, 2 H).
02N I \ Br 2N eN NHz C
uI,Pd(PPh3)2C12, Et3N F F
[00573] 2-(3,3-Dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenylamine
[00574] To a solution of 2-bromo-6-fluoro-4-nitro-phenylamine (11 g, 47 mmol)
in dry
Et3N (100 mL) was added Cul (445 mg, 5% mol), Pd(PPh3)2C12 (550 mg, 5% mol)
and 3,3-
dimethyl-but-l-yne (9.6 g, 120 mmol) under N2 protection. The mixture was
stirred at 80 C
for 10 h. The reaction mixture was filtered, poured into ice (100 g), and
extracted with
EtOAc (50 mL x 3). The combined organic extracts were dried over anhydrous
Na2SO4 and
evaporated under vacuum to give the crude product, which was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give 2-
(3,3-dimethyl-
but-1-ynyl)-6-fluoro-4-nitro-phenylamine (4.0 g, 36%). 1H NMR (400 MHz, CDC13)
8 8.02
(d, J = 1.2 Hz, 1 H), 7.84 (dd, J = 2.4, 10.8 Hz, 1 H), 4.85 (brs, 2 H), 1.36
(s, 9 H).
O2N I \ / CI' v \ O2N 1 \O
NH2 Py,C I N
F F H
[00575] N-[2-(3,3-Dimethyl-but-1-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide
[00576] To a solution of 2-(3,3-dimethyl-but-1-ynyl)-6-fluoro-4-nitro-
phenylamine (4.0 g,
17 mmol) and pyridine (2.7 g, 34 mmol) in anhydrous CH2C12 (30 mL) was added
and
butyryl chloride (1.8 g, 17 mmol) dropwise at 0 C. After stirring for 5 h at
0 C, the reaction
mixture was poured into ice (50 g) and extracted with CH2C12 (30 mL x 3). The
combined
organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum
to give N-
[2-(3,3-dimethyl- but-l-ynyl)-6-fluoro-4-nitro-phenyl]-butyramide (3.2 g,
62%), which was
used in the next step without further purification. 1H NMR (300 MHz, DMSO) 8
8.10 (dd, J
= 1.5, 2.7 Hz, 1 H), 7.95 (dd, J = 2.4, 9.6 Hz, 1 H), 7.22 (brs, 1 H), 2.45
(t, J = 7.5 Hz, 2 H),
1.82 (m, 2 H), 1.36 (s, 9 H), 1.06 (t, J = 7.5 Hz, 3 H).
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OzN eNt t-Bum02N I N
H
F F
[00577] 2-tert-Butyl-7-fluoro-5-nitro-1H-indole
[00578] To a solution of N-[2-(3,3-dimethyl-but-1-ynyl)- 6-fluoro-4-nitro-
phenyl]-
butyramide (3.2 g, 10 mmol) in DMF (20 mL) was added t-BuOK (2.3 g, 21 mmol)
at room
temperature. The mixture was heated at 120 C for 2 g before being cooled down
to room
temperature. Water (50 mL) was added to the reaction mixture and the resulting
mixture was
extracted with CH2C12 (30 mL x 3). The combined organic extracts were dried
over
anhydrous Na2SO4 and evaporated under vacuum to give 2-tert-butyl-7-fluoro- 5-
nitro-lH-
indole (2.0 g, 81%), which was used in the next step without further
purification. 1H NMR
(300 MHz, CDC13) 8 9.95 (brs, 1 H), 8.30 (d, J = 2.1 Hz, 1 H), 7.74 (dd, J =
1.8, 11.1 Hz, 1
H), 6.43 (dd, J = 2.4, 3.3 Hz, 1 H), 1.43 (s, 9 H).
o2N H2N
\ Raney Ni/H2
N
H H
F F
[00579] 2-tert-Butyl-7-fluoro-lH-indol-5-amine
[00580] To a solution of 2-tert-butyl-7-fluoro- 5 -nitro- I H-indole (2.0 g,
8.5 mmol) in
MeOH (20 mL) was added Ni (0.3 g) under nitrogen atmosphere. The reaction
mixture was
stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The
catalyst was
filtered off through the celite pad and the filtrate was evaporated under
vacuum. The crude
product was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate
100:1) to give 2-tert-butyl-7-fluoro-1H-indol-5-amine (550 mg, 24%). 1H NMR
(300 MHz,
CDC13) 8 7.87 (brs, 1 H), 6.64 (d, J = 1.5 Hz, 1 H), 6.37 (dd, J = 1.8, 12.3
Hz, 1 H), 6.11 (dd,
J = 2.4, 3.6 Hz, 1 H), 1.39 (s, 9 H). MS (ESI) m/z (M+H+) 207.
[00581] Example 39: 5-Amino-2-tert-butyl-1H-indole-7-carbonitrile
OZN
OZN \ Br OZN eNH
HzN CuI,Pd(PPh3)zClz, Eta B N NiClz/NaBH4 N
NHz H H
CN CN CN CN
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02N I Br O2N
CuI,Pd(PPh3)2C12, Et3N eNH2
NH2 CN CN
[00582] 2-Amino-3-(3,3-dimethylbut-1-ynyl)- 5-nitrobenzonitrile
[00583] To a stirred solution of 2-amino-3-bromo-5-nitrobenzonitrile (2.4 g,
10 mmol) in
dry Et3N (60 mL) was added Cul (380 mg, 5% mol) and Pd(PPh3)2C12 (470 mg, 5%
mol) at
room temperature. 3,3-dimethyl-but-1-yne (2.1 g, 25 mmol) was added dropwise
to the
mixture at room temperature. The reaction mixture was stirred at 80 C for 10
h. The
reaction mixture was filtered and the filtrate was poured into ice (60 g),
extracted with ethyl
acetate. The phases were separated and the organic phase was dried over
Na2SO4. The
solvent was removed under vacuum to obtain the crude product, which was
purified by
column chromatography (2-10% EtOAc in petroleum ether) to obtain 2-amino-3-
(3,3-
dimethylbut-1-ynyl)- 5-nitrobenzonitrile (1.7 g, 71%). 1H NMR (300 MHz, CDC13)
8 8.28
(d, J = 2.7 Hz, 1 H), 8.27 (d, J = 2.7 Hz, 1 H), 5.56 (br s, 2 H), 1.37 (s, 9
H).
O2N eNH2~ TBAF O2N
N
H
CN CN
[00584] 2-tert-Butyl-5-nitro-1H-indole-7-carbonitrile
[00585] To a solution of 2-amino-3-(3,3-dimethylbut-1-ynyl)- 5-
nitrobenzonitrile (1.7 g,
7.0 mmol) in THE (35 mL) was added TBAF (9.5 g, 28 mmol) at room temperature.
The
mixture was heated at reflux overnight. The reaction mixture was cooled and
the THE was
removed under reduced pressure. Water (50m1) was added to the residue and the
mixture was
extracted with EtOAc. The organics were dried over Na2SO4 and the solvent was
evaporated
under vacuum to obtain 0.87 g of crude product 2- te rt-butyl- 5 -nitro- I H-
indole-7 -carbonitrile
which was used directly in the next step without purification.
O2N \ H2N
NiC12/NaBH4 / N
H
CN
CN
[00586] 5-Amino-2-tert-butyl-lH-indol-7-carbonitrile
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[00587] To a solution of crude product 2-tert-butyl-5 -nitro- I H-indole-7-
carbonitrile (0.87
g, 3.6 mmol) in MeOH (10 mL) was added NiC12.6H20 (1.8 g, 7.2 mmol) at -5 C.
The
reaction mixture was stirred for 30 min, then NaBH4 (0.48g, 14.32 mmol) was
added to the
reaction mixture at 0 C. After 5 min, the reaction mixture was quenched with
water, filtered
and extracted with EtOAc. The combined organic layers were dried over Na2SO4
and
concentrated under vacuum to obtain the crude product, which was purified by
column
chromatography (5-20% EtOAc in petroleum ether) to obtain 5-amino-2-tert-butyl-
lH-indol-
7-carbonitrile (470 mg, 32% over two steps). 1H NMR (400 MHz, CDC13) 8 8.25
(s, 1 H),
7.06 (d, J =2.4 Hz, 1 H), 6.84 (d, J = 2.4 Hz, 1 H), 6.14 (d, J = 2.4 Hz, 1
H), 3.57 (br s, 2 H),
1.38 (s, 9 H). MS (ESI) m/z: 214 (M+H+).
[00588] Example 40: Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate
02N KOH, EtOH OZN MeOH
H SOCI2
CN H OH
HZN
OZN Raney-Ni/H2 N
N H
70H O
1
OzN KOH, EtOH OZN /H
CN
H OH
[00589] 2-tert-Butyl-5-nitro-1H-indole-7-carboxylic acid
[00590] 2-tert-Butyl-5-nitro-1H-indole-7-carbonitrile (4.6 g, 19 mmol) was
added to a
solution of KOH in EtOH (10%, 100 mL) and the mixture was heated at reflux
overnight.
The solution was evaporated to remove alcohol, a small amount of water was
added, and then
the mixture was acidified with dilute hydrochloric acid. Upon standing in the
refrigerator, an
orange-yellow solid precipitated, which was purified by chromatography on
silica gel (15%
EtOAc in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-7-
carboxylic acid (4.0 g,
77%). 1H NMR (CDC13, 300 MHz) 8 10.79 (brs, 1 H), 8.66 (s, 1 H), 8.45(s, 1 H),
6.57 (s, 1
H), 1.39 (s, 9 H).
O2N \ \ McOH O2N
/ H SOCI2 H
OH O1'
[00591] Methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate
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[00592] SOC12 (3.6 g, 30mo1) was added dropwise to a solution of 2-tert-butyl-
5-nitro-1H-
indole-7-carboxylic acid (4.0 g, 15 mol) and methanol (30 mL) at 0 C. The
mixture was
stirred at 80 C for 12 h. The solvent was evaporated under vacuum and the
residue was
purified by column chromatography on silica gel (5% EtOAc in petroleum ether)
to afford
methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate (2.95 g, 70%). 1H NMR
(CDC13, 300
MHz) 8 9.99 (brs, 1 H), 8.70 (d, J = 2.1 Hz, 1 H), 8.65 (d, J = 2.1 Hz, 1 H),
6.50 (d, J = 2.4
Hz, 1 H), 4.04 (s, 3H), 1.44(s, 9H).
02N Raney-Ni/H2 H2N
[00593] Methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate
[00594] A solution of 2-tert-butyl-5 -nitro- I H-indole-7-carboxylate (2.0 g,
7.2 mmol) and
Raney Nickel (200 mg) in CH3OH (50 mL) was stirred for 5 h at the room
temperature under
H2 atmosphere. The catalyst was filtered off through a celite pad and the
filtrate was
evaporated under vacuum to give methyl 5-amino-2-tert-butyl-1H-indole-7-
carboxylate (1.2
g, 68%) 1H NMR (CDC13, 400 MHz) 8 9.34 (brs, 1H), 7.24 (d, J= 1.6 Hz, 1H),
7.10 (s, 1H),
6.12 (d, J = 1.6 Hz, 1H), 3.88 (s, 3H), 1.45 (s, 9H).
[00595] Example 41: (5-Amino-2-tert-butyl-lH-indol-7-yl)methanol
02N \ DIBAL-H= 2N Raney H2N I \ \
9-N N N
H H H
O O- OH OH
02N DIBAL-H 02N
low- :N
?NN
H
H
0 0- OH
[00596] (2-tert-Butyl-5-nitro-lH-indol-7-yl) methanol
[00597] To a solution of methyl 2-tert-butyl-5-nitro-1H-indole-7-carboxylate
(6.15 g, 22.3
mmol) and dichloromethane (30m1) was added DIBAL-H (1.0 M, 20 mL, 20 mmol) at
78 C.
The mixture was stirred for 1 h before water (10 mL) was added slowly. The
resulting
mixture was extracted with EtOAc (120 mL x 3). The combined organic extracts
were dried
over anhydrous Na2SO4 and evaporated under vacuum to give (2-tert-butyl-5-
nitro-lH-indol-
7-yl)methanol (4.0 g, 73%), which was used in the next step directly.
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O2N Raney Ni/H2 H2N
H H
OH OH
[00598] (5-Amino-2-tert-butyl-lH-indol-7-yl)methanol
[00599] A mixture of (2-tert-butyl-5-nitro-1H-indol-7-yl)methanol (4.0 g, 16
mmol) and
Raney Nickel (400 mg) in CH3OH (100 mL) was stirred for 5 g at room
temperature under
H2. The catalyst was filtered off through a celite pad and the filtrate was
evaporated under
vacuum to give (5-amino-2-tert-butyl-1H-indol-7-yl)methanol (3.4g, 80%). tH
NMR
(CDC13, 400 MHz) 8 8.53 (br s, 1H), 6.80 (d, J = 2.0 Hz, 1 H), 6.38 (d, J =
1.6 Hz, 1 H), 4.89
(s, 2 H), 1.37 (s, 9H).
[00600] Example 42: 2-(1-Methylcyclopropyl)-1H-indol-5-amine
n-BuLi TBAF
Me2SO4
02N Br2/HOAC 02N Br 02N
NHZ NHz Pd(PPh3)ZCIZ NHz butyryl chloride
02N O2N Raney Ni/H2 H2N
TBAF
O
NH~ N
H H
n-BuLi
Me2SO4
[00601] Trimethyl-(1-methyl-cyclopropylethynyl)-silane
[00602] To a solution of cyclopropylethynyl-trimethyl-silane (3.0 g, 22 mmol)
in ether (20
mL) was added dropwise n-BuLi (8.6 mL, 21.7 mol, 2.5 M solution in hexane) at
0 C. The
reaction mixture was stirred at ambient temperature for 24 h before dimethyl
sulfate (6.85 g,
54.3 mmol) was added dropwise at -10 C. The resulting solution was stirred at
10 C and
then at 20 C for 30 min each. The reaction was quenched by adding a mixture
of sat. aq.
NH4C1 and 25% aq. ammonia (1:3, 100 mL). The mixture was then stirred at
ambient
temperature for 1 h. The aqueous phase was extracted with diethyl ether (3 x
50 mL) and the
combined organic layers were washed successively with 5% aqueous hydrochloric
acid (100
mL), 5% aq. NaHCO3 solution (100 mL), and water (100 mL). The organics were
dried over
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anhydrous NaSO4 and concentrated at ambient pressure. After fractional
distillation under
reduced pressure, trimethyl-(1-methyl-cyclopropylethynyl)-silane (1.7 g, 52%)
was obtained
as a colorless liquid. 1H NMR (400 MHz, CDC13) 8 1.25 (s, 3 H), 0.92-0.86 (m,
2 H), 0.58-
0.56 (m, 2 H), 0.15 (s, 9 H).
TBAF
[00603] 1-Ethynyl-l-methyl-cyclopropane
[00604] To a solution of trimethyl-(1-methyl-cyclopropylethynyl)-silane (20 g,
0.13 mol) in
THE (250 mL) was added TBAF (69 g, 0.26 mol). The mixture was stirred
overnight at 20
C. The mixture was poured into water and the organic layer was separated. The
aqueous
phase was extracted with THE (50 mL). The combined organic layers were dried
over
anhydrous Na2SO4 and distilled under atmospheric pressure to obtain 1-ethynyl-
l-methyl-
cyclopropane (7.0 g, contained 1/2 THF, 34%). 1H NMR (400 MHz, CDC13) 8 1.82
(s, 1 H),
1.26 (s, 3 H), 0.90-0.88 (m, 2 H), 0.57-0.55 (m, 2 H).
O2N Ind Br2/HOAC 02N Br
NH2 NH2
[00605] 2-Bromo-4-nitroaniline
[00606] To a solution of 4-nitro-phenylamine (50 g, 0.36 mol) in AcOH (500 mL)
was
added Br2 (60 g, 0.38 mol) dropwise at 5 C. The mixture was stirred for 30
min at that
temperature. The insoluble solid was collected by filtration and basified with
saturated
aqueous NaHCO3 to pH 7. The aqueous phase was extracted with EtOAc (300 mL x
3). The
combined organic layers were dried and evaporated under reduced pressure to
obtain
compound 2-bromo-4-nitroaniline (56 g, 72%), which was directly used in the
next step.
O2N Br O2N
NH2 Pd(PPh3)2CI2 NH2
[00607] 2-((1-Methylcyclopropyl)ethynyl)-4-nitroaniline
[00608] To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0
mmol) and 1-
ethynyl-1-methyl-cyclopropane (630 mg, 8.0 mmol) in triethylamine (20 mL) was
added Cul
(76 mg, 0.40 mmol) and Pd(PPh3)2C12 (140 mg, 0.20 mmol) under N2. The mixture
was
heated at 70 C and stirred for 24 h. The solid was filtered off and washed
with EtOAc (50
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mL x 3). The filtrate was evaporated under reduced pressure and the residue
was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to
give 2-((1-
methylcyclopropyl)ethynyl)-4-nitroaniline (340 mg, 79%). 1H NMR (300 MHz,
CDC13) 8
8.15-8.14 (m, 1 H), 7.98-7.95 (m, 1 H), 6.63 (d, J = 6.9 Hz, 1 H), 4.80 (brs,
2 H), 1.38 (s, 3
H), 1.04-1.01 (m, 2 H), 0.76-0.73 (m, 2 H).
02N 02N
o
NH2 butyryl chloride IC
C NH
[00609] N-[2-(1-Methyl-cyclopropylethynyl)-4-nitro-phenyl]-butyramide
[00610] To a solution of 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (220
mg, 1.0
mmol) and pyridine (160 mg, 2.0 mol) in CH2C12 (20 mL) was added butyryl
chloride (140
mg, 1.3 mmol) at 0 C. The mixture was warmed to room temperature and stirred
for 3 h.
The mixture was poured into ice-water. The organic layer was separated and the
aqueous
phase was extracted with CH2C12 (30 mL x 3). The combined organic layers were
dried over
anhydrous Na2SO4 and evaporated under reduced pressure to obtain N-[2-(1-
methyl-
cyclopropyl-ethynyl)-4-nitro-phenyl]-butyramide (230 mg, 82%), which was
directly used in
the next step.
02N 02N
O TBAF
NH N
H
[00611] 2-(1-Methylcyclopropyl)-5-nitro-1H-indole
[00612] A mixture of N-[2-(1-methyl-cyclopropylethynyl)-4-nitro-phenyl]-
butyramide (1.3
g, 4.6 mmol) and TBAF (2.4 g, 9.2 mmol) in THE (20 mL) was heated at reflux
for 24 h.
The mixture was cooled to room temperature and poured into ice water. The
mixture was
extracted with CH2C12 (30 mL x 3). The combined organic layers were dried over
anhydrous
Na2SO4 and evaporated under reduced pressure. The residue was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate = 10/1) to afford
2-(1-
methylcyclopropyl)-5 -nitro- I H-indole (0.70 g, 71%). 1H NMR (400 MHz, CDC13)
8 8.56
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(brs, 1 H), 8.44 (d, J = 2.0 Hz, 1 H), 8.01 (dd, J = 2.4, 8.8 Hz, 1 H), 7.30
(d, J = 8.8 Hz, 1 H),
6.34 (d, J = 1.6 Hz, 1 H), 1.52 (s, 3 H), 1.03-0.97 (m, 2 H), 0.89-0.83 (m, 2
H).
02N Raney Ni/H2 H2N
N N
H H
[00613] 2-(1-Methyl-cyclopropyl)-1H-indol-5-ylamine
[00614] To a solution of 2-(1-methylcyclopropyl)-5-nitro-1H-indole (0.70 g,
3.2 mmol) in
EtOH (20 mL) was added Raney Nickel (100 mg) under nitrogen atmosphere. The
mixture
was stirred under hydrogen atmosphere (1 atm) at room temperature overnight.
The catalyst
was filtered off through a celite pad and the filtrate was evaporated under
vacuum. The
residue was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate =
5/1) to afford 2-(1-methyl-cyclopropyl)-1H -indol-5-ylamine (170 mg, 28%). 1H
NMR (400
MHz, CDC13) 8 7.65 (brs, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 6.82 (s, 1 H), 6.57
(d, J = 8.4 Hz, 1
H), 6.14 (s, 1 H), 3.45 (brs, 2 H), 1.47 (s, 3 H), 0.82-0.78 (m, 2 H), 0.68-
0.63 (m, 2 H).
[00615] Example 43: Methyl 2-(5-amino-lH-indol-2-yl)-2-methylpropanoate
OMe
O O
Mel, NaH O O PCIS aq. NaOH
O )W
~ OMe OMe CH Cl
OH
NaNH2 -=\OH CH2N2 -_\~
O
DMSO O
Cl 0-1
0-1
O2N Br \1O/ O2N ON O
NH2 NHZ bLdyryl chloride
Pd(PPh3)4, Cul, B31\1 O
Pd(CH3CN)2CI2 O2N Raney Ni H2N \
H C~~ N
H
O O O O
Mel, NaH
OMe
---0- A
-OMe
[00616] Methyl 2,2-dimethyl-3-oxobutanoate
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[00617] To a suspension of NaH (42 g, 1.1 mol, 60%) in THE (400 mL) was added
dropwise a solution of methyl 3-oxobutanoate (116 g, 1.00 mol) in THE (100 mL)
at 0 C.
The mixture was stirred for 0.5 h at that temperature before Mel (146 g, 1.1
mol) was added
dropwise at 0 C. The resultant mixture was warmed to room temperature and
stirred for 1 h.
NaH (42 g, 1.05 mol, 60%) was added in portions at 0 C and the resulting
mixture was
continued to stir for 0.5 h at this temperature. Mel (146 g, 1.05 mol) was
added dropwise at 0
C. The reaction mixture was warmed to room temperature and stirred overnight.
The
mixture was poured into ice water and the organic layer was separated. The
aqueous phase
was extracted with EtOAc (500 mL x 3). The combined organic layers were dried
and
evaporated under reduced pressure to give methyl 2,2-dimethyl-3-oxobutanoate
(85 g), which
was used directly in the next step.
O O ~+ We
PCI5
We O
CH2CI2 CI
[00618] Methyl 3-chloro-2,2-dimethylbut-3-enoate
[00619] To a suspention of PC15 (270 g, 1.3 mol) in CH2Cl2 (1000 mL) was added
dropwise
methyl 2,2-dimethyl-3-oxobutanoate (85 g) at 0 C, following by addition of
approximately
30 drops of dry DMF. The mixture was heated at reflux overnight. The reaction
mixture was
cooled to ambient temperature and slowly poured into ice water. The organic
layer was
separated and the aqueous phase was extracted with CH2C12 (500 mL x 3). The
combined
organic layers were washed with saturated aqueous NaHCO3 and dried over
anhydrous
Na2SO4. The solvent was evaporated and the residue was distilled under reduced
pressure to
give methyl 3-chloro-2,2-dimethylbut-3-enoate (37 g, 23%). 1H NMR (400 MHz,
CDC13) 8
5.33 (s, 1 H), 3.73 (s, 3 H), 1.44 (s, 6 H).
OMe OH
aq. NaOH
O 0
CI CI
[00620] 3-Chloro-2,2-dimethylbut-3-enoic acid
[00621] A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (33 g, 0.2 mol)
and NaOH
(9.6 g, 0.24 mol) in water (200 mL) was heated at reflux for 5 h. The mixture
was cooled to
ambient temperature and extracted with ether. The organic layer was discarded.
The
aqueous layer was acidified with cold 20% HCl solution and extracted ether
(200 mL x 3).
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The combined organic layers were dried and evaporated under reduced pressure
to give 3-
chloro-2,2-dimethyl-but-3-enoic acid (21 g, 70%), which was used directly in
the next step.
1H NMR (400 MHz, CDC13) 8 7.90 (brs, 1 H), 5.37 (dd, J = 2.4, 6.8 Hz, 2 H),
1.47 (s, 6 H).
q H OH
NaNH2 ==J~~
O DMSO
CI
[00622] 2,2-Dimethyl-but-3-ynoic acid
[00623] Liquid NH3 was condensed in a 3-neck, 250 mL round bottom flask at -78
C. Na
(3.98 g, 0.173 mol) was added to the flask in portions. The mixture was
stirred for 2 h at -78
C before anhydrous DMSO (20 mL) was added dropwise at - 78 C. The mixture was
stirred at room temperature until no more NH3 was given off. A solution of 3-
chloro-2,2-
dimethyl-but-3-enoic acid (6.5 g, 43 mmol) in DMSO (10 mL) was added dropwise
at -40
C. The mixture was warmed and stirred at 50 C for 5 h, then stirred at room
temperature
overnight. The cloudy, olive green solution was poured into cold 20% HCl
solution and then
extracted three times with ether. The ether extracts were dried over anhydrous
Na2SO4 and
concentrated to give crude 2,2-dimethyl-but-3-ynoic acid (2 g), which was used
directly in
the next step. 1H NMR (400 MHz, CDC13) 8 2.30 (s, 1 H), 1.52 (s, 6 H).
OH CH2N2
=Y O
[00624] Methyl 2,2-dimethylbut-3-ynoate
[00625] To a solution of diazomethane (-10 g) in ether (400 mL) was added
dropwise 2,2-
dimethyl-but-3-ynoic acid (10.5 g, 93.7 mmol) at 0 C. The mixture was warmed
to room
temperature and stirred overnight. The mixture was distilled under atmospheric
pressure to
give crude methyl 2,2-dimethylbut-3-ynoate (14 g), which was used directly in
the next step.
1H NMR (400 MHz, CDC13) 8 3.76 (s, 3 H), 2.28 (s, 1 H), 1.50 (s, 6 H).
O
02N Br
\ \\\/~ O2N 0-11
O
NH2 Pd(PPh3)4, Cul, Et3N NH2
[00626] Methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate
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[00627] To a deoxygenated solution of compound 2-bromo-4-nitroaniline (9.43 g,
43.7
mmol), methyl 2,2-dimethylbut-3-ynoate (5.00 g, 39.7 mmol), Cul (754 mg, 3.97
mmol) and
triethylamine (8.03 g, 79.4 mmol) in toluene/H20 (100/30 mL) was added
Pd(PPh3)4 (6.17 g,
3.97 mmol) under N2. The mixture was heated at 70 C and stirred for 24 h.
After cooling,
the solid was filtered off and washed with EtOAc (50 mL x 3). The organic
layer was
separated and the aqueous phase was washed with EtOAc (50 mL x 3). The
combined
organic layers were dried and evaporated under reduced pressure to give a
residue, which was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate
= 10/1) to
obtain methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (900 mg, 9%).
1H NMR
(400 MHz, CDC13) 8 8.17 (d, J = 2.8 Hz, 1 H), 8.01 (dd, J = 2.8, 9.2 Hz, 1 H),
6.65 (d, J = 9.2
Hz, 1 H), 5.10 (brs, 2 H), 3.80 (s, 3 H), 1.60 (s, 6 H).
02N 02N 0
0
NH2 butyryl chloride NH 0
[00628] Methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate
[00629] To a solution of methyl 4-(2-amino-5-nitrophenyl)-2,2-dimethylbut-3-
ynoate (260
mg, 1.0 mmol) and pyridine (160 mg, 2.0 mol) in CH2C12 (20 mL) was added
butyryl
chloride (140 mg, 1.3 mmol) at 0 C. The reaction mixture was warmed to room
temperature
and stirred for 3 h before the mixture was poured into ice-water. The organic
layer was
separated and the aqueous phase was extracted with CH2C12 (30 mL x 3). The
combined
organic layers were dried over anhydrous Na2SO4 and evaporated under reduced
pressure to
obtain methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (150 mg,
45%),
which was used directly in the next step. 1H NMR (400 MHz, CDC13) 8 8.79 (brs,
1 H), 8.71
(d, J = 9.2 Hz, 1 H), 8.24 (d, J = 2.8 Hz, 1 H), 8.17 (dd, J = 2.8, 9.2 Hz, 1
H), 3.82 (s, 3 H),
2.55 (t, J = 7.2 Hz, 2 H), 1.85-1.75 (m, 2 H), 1.63 (s, 6 H), 1.06 (t, J = 6.8
Hz, 3 H).
0-1 02N \ / p Pd(CH3C
O 2N I \
NH N
H
[00630] Methyl2-methyl-2-(5-nitro-lH-indol-2-yl)propanoate
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[00631] To a deoxygenated solution of methyl 4-(2-butyramido-5-nitrophenyl)-
2,2-
dimethylbut-3-ynoate (1.8 g, 5.4 mmol) in acetonitrile (30 mL) was added
Pd(CH3CN)2C12
(0.42 g, 1.6= mmol) under N2. The mixture was heated at reflux for 24 h. After
cooling the
mixture to ambient temperature, the solid was filtered off and washed with
EtOAc (50 mL x
3). The filtrate was evaporated under reduced pressure to give a residue,
which was purified
by column chromatography on silica gel (petroleum ether/ethyl acetate = 30/1)
to give methyl
2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (320 mg, 23%). 1H NMR (400 MHz,
CDC13)
8 9.05 (brs, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 8.09 (dd, J = 2.0, 8.8 Hz, 1 H),
7.37 (d, J = 8.8
Hz, 1 H), 6.54 (d, J = 1.6 Hz, 1 H), 3.78 (d, J = 9.6 Hz, 3 H), 1.70 (s, 6 H).
0
O2N Raney Ni HzN o
H
H
[00632] Methyl2-(5-amino-lH-indol-2-yl)-2-methylpropanoate
[00633] A suspension of methyl 2-methyl-2-(5-nitro-lH-indol-2-yl)propanoate
(60 mg,
0.23 mmol) and Raney Nickel (10 mg) in MeOH (5 mL) was hydrogenated under
hydrogen
(1 atm) at room temperature overnight. The catalyst was filtered off through a
celite pad and
the filtrate was evaporated under vacuum to give a residue, which was purified
by column
chromatography on silica gel (petroleum ether/ethyl acetate = 5/1) to give
methyl 2-(5-amino-
1H-indol-2-yl)-2-methylpropanoate (20 mg, 38%). 1H NMR (400 MHz, CDC13) 8 8.37
(br s,
1 H), 7.13 (d, J = 8.4 Hz, 1 H), 6.87 (d, J = 2.0 Hz, 1 H), 6.63 (dd, J = 2.0,
8.4 Hz, 1 H), 6.20
(d, J = 1.2 Hz, 1 H), 3.72 (d, J = 7.6 Hz, 3 H), 3.43 (br s, 1 H), 1.65 (s, 6
H); MS (ESI) m/e
(M+H+) 233.2.
[00634] Example 44: 2-Isopropyl-lH-indol-5-amine
0-1 OzN O TBAF/DMF O2N I \ Raney Ni HzN
NH~ H H 0-1 O2N O TBAF/DMF O2N
O
NH~
H
[00635] 2-Isopropyl-5-nitro-lH-indole
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[00636] A mixture of methyl 4-(2-butyramido-5-nitrophenyl)-2,2-dimethylbut-3-
ynoate
(0.50 g, 1.5 mmol) and TBAF (790 mg, 3.0 mmol) in DMF (20 mL) was heated at 70
C for
24 h. The reaction mixture was cooled to room temperature and poured into ice
water. The
mixture was extracted with ether (30 mL x 3). The combined organic layers were
dried over
anhydrous Na2SO4 and evaporated under reduced pressure to give a residue,
which was
purified by column chromatography on silica gel (petroleum ether/ethyl acetate
= 20/1) to
give 2-isopropyl-5 -nitro- I H-indole (100 mg, 33%). 1H NMR (400 MHz, CDC13) 8
8.68 (s, 1
H), 8.25 (br s, 1 H), 8.21 (dd, J = 2.4, 10.0 Hz, 1 H), 7.32 (d, J = 8.8 Hz, 1
H), 6.41 (s, 1 H),
3.07-3.14 (m, 1 H), 1.39 (d, J= 6.8 Hz, 6 H).
02N Raney H2N
10~N f~j \
H H
[00637] 2-Isopropyl-lH-indol-5-amine
[00638] A suspension of 2-isopropyl-5 -nitro- I H-indole (100 mg, 0.49 mmol)
and Raney
Nickel (10 mg) in MeOH (10 mL) was hydrogenated under hydrogen (1 atm) at the
room
temperature overnight. The catalyst was filtered off through a celite pad and
the filtrate was
evaporated under vacuum to give a residue, which was purified by column
(petroleum
ether/ethyl acetate = 5/1) to give 2-isopropyl-1H-indol-5-amine (35 mg, 41%).
1H NMR (400
MHz, CDC13) 8 7.69 (br s, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 6.86 (d, J= 2.4Hz,
1 H), 6.58 (dd,
J = 2.4, 8.8 Hz, 1 H), 6.07 (t, J = 1.2 Hz, 1 H), 3.55 (br s, 2 H), 3.06-2.99
(m, 1 H), 1.33 (d, J
= 7.2 Hz, 6 H); MS (ESI) m/e (M+H+) 175.4.
[00639] Example 45: 1-(Benzo[d] [1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-
methylpropan-2-
yl) -1H-indol-5-yl)cyclopropanecarboxamide
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0 0 PPh3Br
OH PPh3 HBr PPh3Br CIOEt 0 0
NH2 NH2OEt
H
(130020 IcCO2E KHMD_S
KOt-Bu N\ DMA P I i N tMel (cO2E,
Et
H
H C02 Et Boc
TFA I I>I2Et conc. H2SO4 H C02Et
OCoH PPh3 HBr
Ph3Br
CN HNH2
C
[00640] Triphenyl(2-aminobenzyl)phosphonium bromide
[00641] 2-Aminobenzyl alcohol (60.0 g, 0.487 mol) was dissolved in
acetonitrile (2.5 L)
and brought to reflux. Triphenylphosphine hydrobromide (167 g, 0.487 mol) was
added and
the mixture was heated at reflux for 3 h. The reaction mixture was
concentrated to
approximately 500 mL and left at room temperature for 1 h. The precipitate was
filtered and
washed with cold acetonitrile followed by hexane. The solid was dried
overnight at 40 C
under vacuum to give triphenyl(2-aminobenzyl)phosphonium bromide (193 g, 88%).
PPh3Br
/ PPh3Br CI OEt I p "'k Et
H OEt
[00642] Triphenyl((ethyl(2-carbamoyl)acetate)-2-benzyl)phosphonium bromide
[00643] To a suspension of triphenyl(2-aminobenzyl)phosphonium bromide (190 g,
0.43
mol) in anhydrous dichloromethane (1 L) was added ethyl malonyl chloride (55
ml, 0.43
mol). The reaction was stirred for 3 h at room temperature. The mixture was
evaporated to
dryness before ethanol (400 mL) was added. The mixture was heated at reflux
until a clear
solution was obtained. The solution was left at room temperature for 3 h. The
precipitate
was filtered, washed with cold ethanol followed by hexane and dried. A second
crop was
obtained from the mother liquor in the same way. In order to remove residual
ethanol both
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crops were combined and dissolved in dichloromethane (approximately 700 mL)
under
heating and evaporated. The solid was dried overnight at 50 C under vacuum to
give
triphenyl((ethyl(2-carbamoyl)acetate)-2-benzyl)-phosphonium bromide (139 g,
58%).
PPh3Br
KOt-Bu
H OEt H C%Et
[00644] Ethyl 2-(1H-indol-2-yl)acetate
[00645] Triphenyl((ethyl(2-carbamoyl)acetate)-2-benzyl)phosphonium bromide
(32.2 g,
57.3 mmol) was added to anhydrous toluene (150 mL) and the mixture was heated
at reflux.
Fresh potassium tert-butoxide (7.08 g, 63.1 mmol) was added in portions over
15 minutes.
Reflux was continued for another 30 minutes. The mixture was filtered hot
through a plug of
celite and evaporated under reduced pressure. The residue was purified by
column
chromatography on silica gel (0-30% ethyl acetate in hexane over 45 min) to
give ethyl 2-
(1H-indol-2-yl)acetate (9.12 g, 78%).
\ V (BOC)20 CC"-NC02Et
/ N CO2Et DMAP H Boc
[00646] tert-Butyl 2-((ethoxycarbonyl)methyl)-1H-indole-l-carboxylate
[00647] To a solution of ethyl 2-(1H-indol-2-yl)acetate (14.7 g, 72.2 mmol) in
dichloromethane (150 mL) was added 4-dimethylaminopyridine (8.83 g, 72.2 mmol)
and di-
tert-butyl carbonate (23.7 g, 108 mmol) in portions. After stirring for 2 h at
room
temperature, the mixture was diluted with dichloromethane, washed with water,
dried over
magnesium sulfate and purified by silica gel chromatography (0 to 20% EtOAc in
hexane) to
give tert-butyl 2-((ethoxycarbonyl)methyl)-1H-indole-l-carboxylate (20.0 g,
91%).
KHMDS
CO2Et Mel CO2Et
Boc Boc
[00648] tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-yl)-1H-indole-l-carboxylate
[00649] tert-Butyl 2-((ethoxycarbonyl)methyl)-1H-indole-l-carboxylate (16.7 g,
54.9
mmol) was added to anhydrous THE (100 mL) and cooled to -78 T. A 0.5M solution
of
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potassium hexamethyldisilazane (165 mL, 82 mmol) was added slowly such that
the internal
temperature stayed below -60 T. Stirring was continued for 30 minutes at
-78 T. To this mixture, methyl iodide (5.64 mL, 91 mmol) was added. The
mixture was
stirred for 30 min at room temperature and then cooled to -78 T. A 0.5M
solution of
potassium hexamethyldisilazane (210 mL, 104 mmol) was added slowly and the
mixture was
stirred for another 30 minutes at -78 T. More methyl iodide (8.6 mL, 137 mmol)
was added
and the mixture was stirred for 1.5 h at room temperature. The reaction was
quenched with
sat. aq. ammonium chloride and partitioned between water and dichloromethane.
The
aqueous phase was extracted with dichloromethane and the combined organic
phases were
dried over magnesium sulfate and evaporated under reduced pressure. The
residue was
purified by column chromatography on silica gel (0 to 20% ethylacetate in
hexane) to give
tert-butyl 2-(2-(ethoxycarbonyl)propan-2-yl)-1H-indole-l-carboxylate (17.1 g,
94%).
TFA
~C02D O:N H C02Et
Boc
[00650] Ethyl 2-(lH-indol-2-yl)-2-methylpropanoate
[00651] tert-Butyl2-(2-(ethoxycarbonyl)propan-2-yl)-1H-indole-l-carboxylate
(22.9 g,
69.1 mmol) was dissolved in dichloromethane (200 mL) before TFA (70 mL) was
added.
The mixture was stirred for 5 h at room temperature. The mixture was
evaporated to dryness,
taken up in dichloromethane and washed with saturated sodium bicarbonate
solution, water,
and brine. The product was purified by column chromatography on silica gel (0-
20% EtOAc
in hexane) to give ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (12.5 g, 78%).
NaN03 02N
--A-
conc. H2SO4 ~NC 0
0:'N~ C02Et 2Et
H H
[00652] Ethyl2-methyl-2-(5-nitro-lH-indol-2-yl)propanoate
[00653] Ethyl2-(1H-indol-2-yl)-2-methylpropanoate (1.0 g, 4.3 mmol) was
dissolved in
concentrated sulfuric acid (6 mL) and cooled to -10 C (salt/ice-mixture). A
solution of
sodium nitrate (370 mg, 4.33 mmol) in concentrated sulfuric acid (3 mL) was
added dropwise
over 30 min. Stirring was continued for another 30 min at -10 T. The mixture
was poured
into ice and the product was extracted with dichloromethane. The combined
organic phases
were washed with a small amount of sat. aq. sodium bicarbonate. The product
was purified
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by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-
methyl-2-
(5 -nitro- 1H-indol-2-yl)propanoate (0.68 g, 57%).
O2N LiA1H4 02N
'::)~~
H C02Et H OH
[00654] 2-Methyl-2-(5-nitro-lH-indol-2-yl)propan-l-ol
[00655] To a cooled solution of LiA1H4 (1.0 M in THF, 1.1 mL, 1.1 mmol) in THE
(5 mL)
at 0 C was added a solution of ethyl 2-methyl-2-(5-nitro-lH-indol-2-
yl)propanoate (0.20 g,
0.72 mmol) in THE (3.4 mL) dropwise. After addition, the mixture was allowed
to warm up
to room temperature and was stirred for 3 h. The mixture was cooled to 0 C
before water (2
mL) was slowly added followed by careful addition of 15% NaOH (2 mL) and water
(4 mL).
The mixture was stirred at room temperature for 0.5 h and was filtered through
a short plug of
celite using ethyl acetate. The organic layer was separated from the aqueous
layer, dried over
Na2SO4, filtered and evaporated under reduced pressure. The residue was
purified by column
chromatography on silica gel (ethyl acetate/hexane = 1/1) to give 2-methyl-2-
(5-nitro-lH-
indol-2-yl)propan-l-ol (0.098 g, 58%).
02N I ~~ SnCI2.2H2O H2N
'N OH N H H
[00656] 2-(5-Amino-lH-indol-2-yl)-2-methylpropan-l-ol
[00657] To a solution of 2-methyl-2-(5-nitro-lH-indol-2-yl)propan-l-ol (0.094
g, 0.40
mmol) in ethanol (4 mL) was added tin chloride dihydrate (0.451 g, 2.0 mmol).
The mixture
was heated in the microwave at 120 C for 1 h. The mixture was diluted with
ethyl acetate
and water before being quenched with saturated aqueous NaHCO3. The reaction
mixture was
filtered through a plug of celite using ethyl acetate. The organic layer was
separated from the
aqueous layer, dried over Na2SO4, filtered and evaporated under reduced
pressure to give 2-
(5-amino- lH-indol-2-yl)-2-methylpropan-l-ol (0.080 g, 98%).
[00658] Example 46: 2-(Pyridin-2-yl)-1H-indol-5-amine
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02N I N
O2N t-BuOK/DMF
/ NH2 N
Pd(PPh3)2CI2/Cul
NH2
02N N- SnC12 H2N N-
N H
H
02N I N
N
02N
):XNH2 Pd(PPh3)2CI2/Cu1 I
NH2
[00659] 4-Nitro-2-(pyridin-2-ylethynyl)aniline
[00660] To the solution of 2-iodo-4-nitroaniline (3.0 g, 11 mmol) in DMF
(60mL) and Et3N
(60 mL) was added 2-ethynylpyridine (3.0 g, 45 mmol), Pd(PPh3)2C12 (600 mg)
and Cul (200
mg) under N2. The reaction mixture was stirred at 60 C for 12 h. The mixture
was diluted
with water and extracted with dichloromethane (3 x 100 mL). The combined
organic layers
were washed with brine, dried over anhydrous Na2SO4 and concentrated in
vacuum. The
residue was purified by chromatography on silica gel (5-10% ethyl
acetate/petroleum ether)
to afford 4-nitro-2-(pyridin-2-ylethynyl)aniline (1.5 g, 60%). 1H NMR (300
MHz, CDC13) 8
8.60 (s, 1 H), 8.13 (d, J = 2.1 Hz, 1 H), 7.98 (d, J = 1.8, 6.9 Hz, 1 H), 7.87-
7.80 (m, 2 H),
7.42-7.39 (m, 1 H), 7.05 (brs, 2 H), 6.80 (d, J = 6.9 Hz, 1 H).
N 02N N-
02N t-BuOWDMFU I / \
N
NH2 H
[00661] 5-Nitro-2-(pyridin-2-yl)-1H-indole
[00662] To the solution of 4-nitro-2-(pyridin- 2-ylethynyl) aniline (1.5 g,
6.3 mmol) in
DMF (50 mL) was added t-BuOK (1.5 g, 13 mmol). The reaction mixture was
stirred at 90
C for 2 h. The mixture was diluted with water and extracted with
dichloromethane (3 x 50
mL). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4
and concentrated in vacuum. The residue was purified by chromatography on
silica gel
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(5-10% ethyl acetate/petroleum ether) to afford 5-nitro-2-(pyridin-2-yl)-1H-
indole (1.0 g,
67%yield). 1H NMR (300 MHz, d-DMSO) 8 12.40 (s, 1H), 8.66 (d, J = 2.1 Hz, 1
H), 8.58 (d,
J = 1.8 Hz, 1 H), 8.07-7.91 (m, 3 H), 7.59 (d, J = 6.6 Hz, 1 H), 7.42-7.37 (m,
2 H).
02N N- SnCl2 Fi2N N-
N Z ICCN>
H H
[00663] 2-(Pyridin-2-yl)-1H-indol-5-amine
[00664] To a solution of 5-nitro-2-(pyridin-2-yl)-1H-indole (700 mg, 2.9 mmol)
in EtOH
(20 mL) was added SnC12 (2.6 g, 12 mmol). The mixture was heated at reflux for
10 h.
Water was added and the mixture was extracted with EtOAc (50 mL x 3). The
combined
organic layers were washed with brine, dried over anhydrous Na2SO4 and
concentrated in
vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl
acetate/petroleum ether) to afford 2-(pyridin-2-yl)-1H-indol-5-amine (120 mg,
20%). 1H
NMR (400 MHz, CDC13) 8 9.33 (brs, 1 H), 8.55 (dd, J = 1.2, 3.6 Hz, 1 H), 7.76-
7.67 (m, 2
H), 7.23 (d, J = 6.4 Hz, 1 H), 7.16-7.12 (m, 1 H), 6.94 (d, J = 2.0 Hz, 1 H),
6.84 (d, J = 2.4
Hz, 1 H), 6.71-6.69 (dd, J = 2.0, 8.4 Hz, 1 H).
[00665] Example 47: 2-(Pyridin-2-yl)-1H-indol-5-amine
O O
O2N I OTBDMS O2N I OzN O----
NH2 ^,OTBDMS I / N,_,OTBDMS
H
H
O
OZN 01"- OzN HzNI~
I \ \
/
PdCIz/CH3CN I / \ DIBAL-H H2/Raney-Ni
- N '
OH OH
OH OH
OH
02N I O- OTBDMS 02N I
/ I / /~/OTBDMS
NH2 H
[00666] [2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-nitro-phenyl)-
amine
[00667] To a solution of 2-iodo-4-nitroaniline (2.0 g, 7.6 mmol) and 2-(tert-
butyldimethylsilyloxy)-acetaldehyde (3.5 g, 75% purity, 15 mmol) in methanol
(30 mL) was
added TFA (1.5 mL) at 0 T. The reaction mixture was stirred at this
temperature for 30 min
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before NaCNBH3 (900 mg, 15 mmol) was added in portions. The mixture was
stirred for 2 h
and was then quenched with water. The resulting mixture was extracted with
EtOAc (30 mL
x 3), the combined organic extracts were dried over anhydrous Na2SO4 and
evaporated under
vacuum, and the residue was purified by chromatography on silica gel (5 %
ethyl
acetate/petroleum) to afford [2-(tert-butyl-dimethyl- silanyloxy) -ethyl] -(2-
iodo-4-nitro-
phenyl)-amine (800 mg, 25 %). 1H NMR (300 MHz, CDC13) 8 8.57 (d, J = 2.7 Hz, 1
H), 8.12
(dd, J = 2.4,9.0 Hz, 1 H), 6.49 (d, J = 9.3 Hz, 1 H), 5.46 (br s, 1 H), 3.89
(t, J = 5.4 Hz, 2 H),
3.3 5 (q, J = 5.4 Hz, 2 H), 0. 93 (s, 9 H), 0. 10 (s, 6 H).
O O
02N I ~O/\ O N O/\
-,_/OTBDMS
,~OTBDMS
H N
H
[00668] 5-{2-[2-(tert-Butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-phenyl}-
3,3-
dimethyl-pent-4-ynoic acid ethyl ester
[00669] To a solution of [2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-(2-iodo-4-
nitro-phenyl)-
amine (800 mg, 1.9 mmol) in Et3N (20 mL) was added Pd(PPh3)2C12 (300 mg, 0.040
mmol),
Cul (76 mg, 0.040 mmol) and 3,3-dimethyl-but-1-yne (880 mg, 5.7 mmol)
successively
under N2 protection. The reaction mixture was heated at 80 C for 6 h and
allowed to cool
down to room temperature. The resulting mixture was extracted with EtOAc (30
mL x 3).
The combined organic extracts were dried over anhydrous Na2SO4 and evaporated
under
vacuum to give 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-nitro-
phenyl}-3,3-
dimethyl-pent-4- ynoic acid ethyl ester (700 mg, 82 %), which was used in the
next step
without further purification. 1H NMR (400 MHz, CDC13) 8 8.09 (s, 1 H), 8.00
(d, J = 9.2 Hz,
1 H), 6.54 (d, J = 9.2 Hz, 1 H), 6.45 (brs, 1 H), 4.17-4.10 (m, 4 H), 3.82 (t,
J = 5.6 Hz, 2 H),
3.43 (q, J = 5.6 Hz, 2 H), 2.49 (s, 2 H), 1.38 (s, 6 H), 1.28 (t, J = 7.2 Hz,
3 H), 0.84 (s, 9 H),
0.00 (s, 6 H).
O O
O2N O2N
N__/OTBDMS PdCI2/CH3CN I / N
H
OH
[00670] 3-[1-(2-Hydroxy-ethyl)-5-nitro-lH-indol-2-yl]-3-methyl-butyric acid
ethyl
ester
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CA 02742980 2011-05-06
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[00671] A solution of 5-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-5-
nitro-
phenyl}-3,3- dimethyl-pent-4- ynoic acid ethyl ester (600 mg, 1.34 mmol) and
PdC12(650
mg) in CH3CN (30 mL) was heated at reflux overnight. The resulting mixture was
extracted
with EtOAc (30 mL x 3). The combined organic extracts were dried over
anhydrous Na2SO4
and evaporated under vacuum. The residue was dissolved in THE (20 mL) and TBAF
(780
mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 1 h,
the solvent
was removed under vaccum, and the residue was purified by chromatography on
silica gel
(10% ethyl acetate/petroleum) to afford 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-
indol-2-yl]-3-
methyl-butyric acid ethyl ester (270 mg, 60 %). 1H NMR (300 MHz, CDC13) 8 8.45
(d, J =
2.1 Hz, 1 H), 8.05 (dd, J = 2.1, 9.0 Hz, 1 H), 6.36 (d, J = 9.0 Hz, 1 H), 6.48
(s, 1 H), 4.46 (t, J
= 6.6 Hz, 2 H), 4.00-3.91 (m, 4 H), 2.76 (s, 2 H), 1.61 (s, 6 H), 0.99 (t, J =
7.2 Hz, 1 H), 0.85
(s, 9 H), 0.03 (s, 6 H).
O
O/\ 02N
O2N
DIBAL-H N
N
OH
OH
OH
[00672] 3-[1-(2-Hydroxy-ethyl)-5-nitro-lH-indol-2-yl]-3-methyl-butan-l-ol
[00673] To a solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-
methyl-butyric
acid ethyl ester (700 mg, 2.1 mmol) in THE (25 mL) was added DIBAL-H (1.0 M,
4.2 mL,
4.2 mmol) at -78 T. The mixture was stirred at room temperature for 1 h. Water
(2 mL)
was added and the resulting mixture was extracted with EtOAc (15 mL x 3). The
combined
organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum.
The residue
was purified by chromatography on silica gel (15 % ethyl acetate/petroleum) to
afford 3-[1-
(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan-1-ol (300 mg, 49%). 1H
NMR (300
MHz, d-DMSO) 8 8.42 (d, J = 1.5 Hz, 1 H), 7.95 (dd, J = 1.2, 8.7 Hz, 1 H),
6.36 (d, J = 9.3
Hz, 1 H), 6.50 (s, 1 H), 5.25 (br s, 1 H), 4.46-4.42 (m, 4 H), 3.69-3.66 (m,2
H), 3.24-3.21 (m,
2 H), 1.42 (s, 6 H).
O2N 1~1 \ H2N lcl~ \
N H2/Raney-Ni N
OH OH
OH OH
[00674] 3-[5-Amino-l-(2-hydroxy-ethyl)-1H-indol-2-yl]-3-methyl-butan-l-ol
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[00675] A solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-
butan-1-ol
(300 mg, 1.03 mmol) and Raney Nickel (200 mg,) in CH3OH (30 mL) was stirred
for 5 h at
room temperature under a H2 atmosphere. The catalyst was filtered through a
celite pad and
the filtrate was evaporated under vacuum to give a residue, which was purified
by preparative
TLC to afford 3-[5-amino-l-(2-hydroxy-ethyl)-1H-indol-2-yl]-3-methyl-butan-1-
ol (70 mg,
26%). 1H NMR (300 MHz, CDC13) 8 7.07 (d, J = 8.7 Hz, 1 H), 6.83 (d, J = 2.1
Hz, 1 H),
6.62 (dd, J = 2.1, 8.4 Hz, 1 H), 6.15 (s, 1 H), 4.47 (t, J = 5.4 Hz, 2 H),
4.07 (t, J = 5.4 Hz, 2
H), 3.68 (t, J = 5.7 Hz, 2 H), 2.16 (t, J = 5.7 Hz, 2 H), 4.00-3.91 (m, 4 H),
2.76 (s, 2 H), 1.61
(s, 6 H), 1.42 (s, 6 H).
[00676] Example 48: tert-Butyl 2-(5-amino-lH-indol-2-yl)piperidine-l-
carboxylate
O2N I \ \ PtO2/H2 FizN I \ HN Boc2O H2N
H H Et3N N
H
02N N- PtO2i/H2 H2N
HN
~C' N
H H
[00677] 2-(Piperidin-2-yl)-1H-indol-5-amine
[00678] 5-Nitro-2-(pyridin-2-yl)-1H-indole (1.0 g, 4.2 mmol) was added to
HCl/MeOH (2
M, 50 mL). The reaction mixture was stirred at room temperature for 1 h and
the solvent was
evaporated under vacuum. Pt02 (200 mg) was added to a solution of the residue
in MeOH
(50 mL) and the reaction mixture was stirred under hydrogen atmosphere (1 atm)
at room
temperature for 2 h. The catalyst was filtered through a celite pad and the
solvent was
evaporated under vacuum to afford 2-(piperidin-2-yl)-1H-indol-5-amine (1.0 g),
which was
directly used in the next step.
HzN \ \ HN Boc20 HzN IN
H Et3N I N
H
[00679] tert-Butyl 2-(5-amino-lH-indol-2-yl)piperidine-l-carboxylate
[00680] To a solution of 2-(piperidin-2-yl)-1H-indol-5-amine (1.0 g) in Et3N
(25 mL) and
THE (25mL) was added Boc2O (640 mg, 2.9 mmol). The reaction mixture was
stirred at
room temperature overnight. The mixture was diluted with water and extracted
with
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dichloromethane (3 x 25 mL). The combined organic layers were washed with
brine, dried
over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by
chromatography on silica gel (5-10% ethyl acetate/petroleum ether) followed by
preparative
HPLC to afford tert-butyl 2-(5-amino- lH-indol-2-yl)piperidine-l-carboxylate
(15 mg, 1%
over 2 steps). 1H NMR (400 MHz, CDC13) 8 8.82 (s, 1 H), 7.58 (s, 1 H), 7.22
(d, J = 8.8 Hz,
1 H), 7.02 (d, J = 1.6, 8.0 Hz, 1 H), 6.42 (s, 1H), 6.25 (s, 1 H), 3.91-3.88
(m, 1 H), 3.12-3.10
(m, 1 H), 2.81-2.76 (m, 1 H), 2.06-1.97 (m, 4 H), 1.70-1.58 (m, 2H), 1.53 (s,
9 H).
[00681] Example 49: 6-amino-lH-indole-2-carbonitrile
O
Na::e' OHCCO Et
INH O N NNH2 HCI O N z z z H `1I
PPA \ I I NaOH C:I I 1, NH3H \
02N H C02Et 02N H C02H 2, NH3.z0 02N H CONH2
(CF3 C7 I Raney \
017 I~
2N H CN H2N H CN
NaNO2/HCI
02N NH SnCl2 02N NNH2HCI
2
[00682] (3-Nitrophenyl)hydrazine hydrochloride
[00683] 3-Nitroaniline (28 g, 0.20 mol) was dissolved in a mixture of H2O (40
mL) and
37% HCl (40 mL). A solution of NaNO2 (14 g, 0.20 mol) in H2O (60 mL) was added
to the
mixture at 0 C, and then a solution of SnC12.H20 (140 g, 0.60 mol) in 37% HCl
(100 mL)
was added. After stirring at 0 C for 0.5 h, the insoluble material was
isolated by filtration
and was washed with water to give (3-nitrophenyl)hydrazine hydrochloride (28
g, 73%).
O
~ I CO2Et O N I NN CO2Et
O2N\/~H =NH2HCI 2 H
[00684] (E)-Ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate
[00685] (3-Nitrophenyl)hydrazine hydrochloride (30 g, 0.16 mol) and 2-oxo-
propionic acid
ethyl ester (22 g, 0.19 mol) were dissolved in ethanol (300 mL). The mixture
was stirred at
room temperature for 4 h before the solvent was evaporated under reduced
pressure to give
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(E)-ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate, which was used directly in
the next
step.
~N CO2Et PPA
OZN H 02N H C02Et
[00686] Ethyl 4-nitro-1H-indole-2-carboxylate and ethyl 6-nitro-1H-indole-2-
carboxylate
[00687] (E)-Ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate was dissolved in
toluene (300
mL) and PPA (30 g) was added. The mixture was heated at reflux overnight and
then was
cooled to room temperature. The solvent was decanted and evaporated to obtain
a crude
mixture that was taken on to the next step without purification (15 g, 40%).
~ I I NaOH
aJ'CO2H
02N H CO2Et 02N H [00688] 4-Nitro-1H-indole-2-carboxylic acid and 6-nitro-1H-
indole-2-carboxylic acid
[00689] A mixture of ethyl 6-nitro-1H-indole-2-carboxylate (0.5 g) and 10 %
NaOH (20
mL) was heated at reflux overnight and then was cooled to room temperature.
The mixture
was extracted with ether and the aqueous phase was acidified with HCl to pH 1 -
2. The
insoluble solid was isolated by filtration to give a crude mixture that was
taken on to the next
step without purification (0.3 g, 68%).
O N I N I CO2H 2. N CONH2
2 H . NH3 H2O H
[00690] 4-Nitro-1H-indole-2-carboxamide and 6-nitro-1H-indole-2-carboxamide
[00691] A mixture of 6-nitro-1H-indole-2-carboxylic acid (12 g, 58 mmol) and
SOC12 (50
mL, 64 mmol) in benzene (150 mL) was heated at reflux for 2 h. The benzene and
excess
SOC12 was removed under reduced pressure. The residue was dissolved in
anhydrous CH2C12
(250 mL) and NH3.H20 (22 g, 0.32 mol) was added dropwise at 0 C. The mixture
was
stirred at room temperature for 1 h. The insoluble solid was isolated by
filtration to obtain
crude mixture (9.0 g, 68%), which was used directly in the next step.
\ I I (CF3CO)20 /
O2N N CONH2 O2N \ I N I CN
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[00692] 4-Nitro-1H-indole-2-carbonitrile and 6-nitro-1H-indole-2-carbonitrile
[00693] 6-Nitro-1H-indole-2-carboxamide (5.0 g, 24 mmol) was dissolved in
CH2C12 (200
mL). Et3N (24 g, 0.24 mol) and (CF3CO)20 (51 g, 0.24 mol) were added dropwise
to the
mixture at room temperature. The mixture was continued to stir for 1 h and was
then poured
into water (100 mL). The organic layer was separated and the aqueous layer was
extracted
with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4,
filtered
and concentrated under reduced pressure to obtain crude product which was
purified by
column chromatography on silica gel to give a impure sample of 4-nitro-1H-
indole-2-
carbonitrile (2.5 g, 55%).
/ I I Raney Ni/H2 /
OZN \ H CN H2N \ N CN
[00694] 6-Amino-1H-indole-2-carbonitrile
[00695] A mixture of 6-nitro-1H-indole-2-carbonitrile (2.5 g, 13 mmol) and
Raney Nickel
(500 mg) in EtOH (50 mL) was stirred at room temperature under H2 (1 atm) for
1 h. Raney
Nickel was removed via filtration and the filtrate was evaporated under
reduced pressure to
give a residue, which was purified by column chromatograpy on silica get to
give 6-amino-
1H-indole-2-carbonitrile (1.0 g, 49 %). 1H NMR (DMSO-d6) 8 12.75 (br s, 1 H),
7.82 (d, J =
8 Hz, 1 H), 7.57 (s, 1H), 7.42 (s, 1 H), 7.15 (d, J = 8 Hz, 1 H); MS (ESI) m/e
(M+H+) 158.2.
[00696] Example 50: 6-Amino-1H-indole-3-carbonitrile
CN
/ N CISO2NCO CN H2/Pd-C /
C)N OzN N HZN \ H
H H
/ CN
CISO2NCO /
J
02N H 02N \ N
H
[00697] 6-Nitro-1H-indole-3-carbonitrile
[00698] To a solution of 6-nitroindole (4.9 g 30 mmol) in DMF (24 mL) and
CH3CN (240
mL) was added dropwise a solution of C1SO2NCO (5.0 mL) in CH3CN (39 mL) at 0
C.
After addition, the reaction was allowed to warm to room temperature and was
stirred for 2 h.
The mixture was then poured into ice-water and basified with sat. NaHCO3
solution to pH
7-8. The mixture was extracted with ethyl acetate. The organics were washed
with brine,
dried over Na2SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile
(4.6 g, 82%).
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CN CN
H2/Pd-C
\ I I H N N
OzN H 2 H
[00699] 6-Amino-1H-indole-3-carbonitrile
[00700] A suspention of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 25 mmol) and
10% Pd-C
(0.46 g) in EtOH (50 mL) was stirred under H2 (1 atm) at room temperature
overnight. After
filtration, the filtrate was concentrated and the residue was purified by
column
chromatography on silica gel (petroleum ether/ethyl acetate = 3/1) to give 6-
amino-lH-
indole-3-carbonitrile (1.0 g, 98%) as a pink solid. 1H NMR (DMSO-d6) 8 11.51
(s, 1 H), 7.84
(d, J = 2.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 6.62 (s, 1H), 6.56 (d, J =
8.4 Hz, 1 H), 5.0 (s,
2H); MS (ESI) m/e (M+H+) 157.1.
[00701] Example 51: 2-tert-Butyl-1H-indol-6-amine
O
CI NH, 6Hrk N n-BuLi NaBH4/AcOH 0:N
Olow N 10 ~ H H
\ DDQ Raney Ni/H2
KNO3/H2SO~ I \ \
OzN / H OzN H HzN I / H
O
~NH2 CI Ip- O
[00702] N-o-Tolylpivalamide
[00703] To a solution of o-tolylamine (21 g, 0.20 mol) and Et3N (22 g, 0.22
mol) in CH2C12
was added 2,2-dimethyl-propionyl chloride (25 g, 0.21 mol) at 10 C. After
addition, the
mixture was stirred overnight at room temperature. The mixture was washed with
aq. HCl
(5%, 80 mL), saturated aq. NaHCO3 and brine. The organic layer was dried over
Na2SO4 and
concentrated under vacuum to give N-o-tolylpivalamide (35 g, 91%). 1H NMR (300
MHz,
CDC13) 8 7.88 (d, J = 7.2 Hz, 1 H), 7.15-7.25 (m, 2 H), 7.05 (t, J = 7.2 Hz, 1
H), 2.26 (s, 3
H), 1.34 (s, 9 H).
n-BuLi
ciiErH
O N
H
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[00704] 2-tert-Butyl-lH-indole
[00705] To a solution of N-o-tolylpivalamide (30.0 g, 159 mmol) in dry THE
(100 mL)
was added dropwise n-BuLi (2.5 M in hexane, 190 mL) at 15 C. After addition,
the mixture
was stirred overnight at 15 C. The mixture was cooled in an ice-water bath
and treated with
saturated NH4C1. The organic layer was separated and the aqueous layer was
extracted with
ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4,
filtered, and
concentrated in vacuum. The residue was purified by column chromatography on
silica gel to
give 2-tert-butyl-1H-indole (24 g, 88%). 1H NMR (300 MHz, CDC13) 8 7.99 (br.
s, 1 H),
7.54 (d, J = 7.2 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 7.06 -7.13 (m, 2 H),
6.26 (s, 1 H), 1.39 (s,
9 H).
NaBH4/AcOH
1OOC O'N N
H H
[00706] 2-tert-Butylindoline
[00707] To a solution of 2-tert-butyl-1H-indole (10 g, 48 mmol) in AcOH (40
mL) was
added NaBH4 at 10 C. The mixture was stirred for 20 minutes at 10 C before
being treated
dropwise with H2O under ice cooling. The mixture was extracted with ethyl
acetate. The
combined organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under
vacuum to give 2-tert-butylindoline (9.8 g), which was used directly in the
next step.
0~~N KNO3/H2SO4 'D::4
02N H
H
[00708] 2-tert-butyl-6-nitroindoline and 2-tert-butyl-5-nitro-1H-indole
[00709] To a solution of 2-tert-butylindoline (9.7 g) in H2SO4 (98%, 80 mL)
was slowly
added KNO3 (5.6 g, 56 mmol) at 0 C. After addition, the reaction mixture was
stirred at
room temperature for 1 h. The mixture was carefully poured into cracked ice,
basified with
Na2CO3 to pH 8 and extracted with ethyl acetate. The combined extracts were
washed with
brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue
was
purified by column chromatography to give 2-tert-butyl-6-nitroindoline (4.0 g,
31 % over two
steps). 1H NMR (300 MHz, CDC13) 8 7.52 (dd, J = 1.8, 8.1 Hz, 1 H), 7.30 (s, 1
H), 7.08 (d, J
=7.8Hz,1H),3.76(t,J=9.6Hz,1H),2.98-3.07 (m,1H),2.82-2.91(m,1H),0.91(s,9
H).
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JO~N~( DDQ \
-AW- Q~
02N H 02N / H
[00710] 2-tert-Butyl-6-nitro-1H-indole
[00711] To a solution of 2-tert-butyl-6-nitroindoline (2.0 g, 9.1 mmol) in 1,4-
dioxane (20
mL) was added DDQ (6.9 g, 30 mmol) at room temperature. The mixture was heated
at
reflux for 2.5 h before being filtered and concentrated under vacuum. The
residue was
purified by column chromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6
g, 80%). 1H
NMR (300 MHz, CDC13) 8 8.30 (br. s, 1 H), 8.29 (s, 1 H), 8.00 (dd, J = 2.1,
8.7 Hz, 1 H),
7.53 (d, J = 9.3 Hz, 1 H), 6.38 (s, 1 H), 1.43 (s, 9 H).
Raney Ni/H2
02N H H2N / H
[00712] 2-tert-Butyl-lH-indol-6-amine
[00713] To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in
MeOH (10
mL) was added Raney Nickel (0.2 g). The mixture was hydrogenated under 1 atm
of
hydrogen at room temperature for 3 h. The reaction mixture was filtered and
the filtrate was
concentrated. The residue was washed with petroleum ether to give 2-tert-butyl-
lH-indol-6-
amine (1.0 g, 89%). 1H NMR (300 MHz, DMSO-d6) 8 10.19 (s, 1 H), 6.99 (d, J=
8.1 Hz, 1
H), 6.46 (s, 1 H), 6.25 (dd, J = 1.8, 8.1 Hz, 1 H), 5.79 (d, J = 1.8 Hz, 1 H),
4.52 (s, 2 H), 1.24
(s, 9 H); MS (ESI) m/e (M+H+) 189.1.
[00714] Example 52: 3-tert-Butyl-lH-indol-6-amine
/ Br Raney Ni-H2
02N H zinc triflate
TBAI, DIEA, 02N N H2N N
/ \ +Br
02N H zinc trif late
TBAI, DIEA, 02N N
H
[00715] 3-tert-Butyl-6-nitro-1H-indole
[00716] To a mixture of 6-nitroindole (1.0 g, 6.2 mmol), zinc triflate (2.1 g,
5.7 mmol), and
TBAI (1.7 g, 5.2 mmol) in anhydrous toluene (11 mL) was added DIEA (1.5 g, 11
mmol) at
room temperature under nitrogen. The reaction mixture was stirred for 10 min
at 120 C,
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followed by the addition of t-butyl bromide (0.71 g, 5.2 mmol). The resulting
mixture was
stirred for 45 min at 120 C. The solid was filtered off and the filtrate was
concentrated to
dryness. The residue was purified by column chromatography on silica gel
(petroleum
ether/ethyl acetate = 20:1) to give 3-tert-butyl-6-nitro-1H-indole (0.25 g,
19%) as a yellow
solid. 1H-NMR (CDC13) 8 8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 2.1, 14.4 Hz,
1H), 7.85 (d, J
= 8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).
Raney Ni-H2
OzN H HzN \ H
[00717] 3-tert-Butyl-1H-indol-6-amine
[00718] A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 14 mmol) and
Raney Nickel
(0.5 g) was hydrogenated under H2 (1 atm) at room temperature for 3 h. The
catalyst was
filtered off and the filtrate was concentrated to dryness. The residue was
purified by column
on silica gel (petroleum ether/ethyl acetate = 4:1) to give 3-tert-butyl-1H-
indol-6-amine (2.0
g, 77%) as a gray solid. 1HNMR (CDC13) b 7.58 (m, 2H), 6.73 (d, J = 1.2 Hz,
1H), 6.66 (s,
1H), 6.57(dd, J = 0.8, 8.6 Hz, 1H), 3.60 (br, 2H), 1.42 (s, 9H).
[00719] Example 53: 5-(Trifluoromethyl)-1H-indol-6-amine
F3C HN03 F3C I \ DMA F3C \ \ N~ Raney Ni/Hz F3C
HzSOa 02N" v NOz pzN'~~~,% NOz HzN I/ H
F3C HNO3 F3C XN02 110- H2SO4 O2NI [00720] 1-Methyl-2,4-dinitro-5-
(trifluoromethyl)benzene
[00721] To a mixture of HNO3 (98%, 30 mL) and H2SO4 (98%, 30 mL) was added
dropwise 1-methyl-3-trifluoromethyl-benzene (10 g, 63 mmol) at 0 C. After
addition, the
mixture was stirred at rt for 30 min and was then poured into ice-water. The
precipitate was
filtered and washed with water to give 1-methyl-2,4-dinitro-5-trifluoromethyl-
benzene (2.0 g,
13%).
F3C I \ \ N~
F3C \ DMA
low
O:N NOz 02NN02
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[00722] (E)-2-(2,4-Dinitro-5-(trifluoromethyl)phenyl)-N,N-dimethylethenamine
[00723] A mixture of 1-methyl-2,4-dinitro-5-trifluoromethyl-benzene (2.0 g,
8.0 mmol)
and DMA (1.0 g, 8.2 mmol) in DMF (20 mL) was stirred at 100 C for 30 min. The
mixture
was poured into ice-water and stirred for 1 h. The precipitate was filtered
and washed with
water to give (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyl)-N,N-
dimethylethenamine (2.1 g,
86%).
F3C \ \ N~ Raney Ni/H2 F3C :c,!::-'C
)W_ 1 7__~
02N NO2 H2N H
[00724] 5-(Trifluoromethyl)-1H-indol-6-amine
[00725] A suspension of (E)-2-(2,4-dinitro-5-(trifluoromethyl)phenyl)-NN-
dimethylethenamine (2.1 g, 6.9 mmol) and Raney Nickel (1 g) in ethanol (80 mL)
was stirred
under H2 (1 atm) at room temperature for 5 h. The catalyst was filtered off
and the filtrate
was concentrated to dryness. The residue was purified by column on silica gel
to give 5-
(trifluoromethyl)-1H-indol-6-amine (200 mg, 14%). 1H NMR (DMSO-d6) S 10.79 (br
s, 1
H), 7.55 (s, 1 H), 7.12 (s, 1 H), 6.78 (s, 1 H), 6.27(s, 1 H), 4.92 (s, 2 H);
MS (ESI) m/e
(M+H+): 200.8.
[00726] Example 54: 5-Ethyl-1H-indol-6-amine
0 16
CON O N AczO/AICI3/CHZCIZ / NaBH4/THF 48%HBr
0.S_0 N N
H Et3N/DMAP/CH2CI2 O=S,O TFA 0.L-0
6
KNOB MnO \ I W__ Raney \ I \
H OzN H azN H HzN H
O
r\ S-CI
/ O N
\ N O M- 0.S; O
H Et3N/DMAP/CH2CI2 6
[00727] 1-(Phenylsulfonyl)indoline
[00728] To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136
mmol) and
indoline (14.7 g, 124 mmol) in CH2C12 (200 mL) was added dropwise Et3N (19.0
g, 186
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mmol) at 0 C. The mixture was stirred at room temperature overnight. The
organic layer
was washed with water (2x), dried over Na2SO4 and concentrated to dryness
under reduced
pressure to obtain 1-(phenylsulfonyl)indoline (30.9 g, 96%).
0
Q N Ac2O/AICI3/CHzClz /
bz~o N
6 O'L-O
6
[00729] 1-(1-(Phenylsulfonyl)indolin-5-yl)ethanone
[00730] To a suspension of A1C13 (144 g, 1.08 mol) in CH2C12 (1070 mL) was
added acetic
anhydride (54 mL). The mixture was stirred for 15 minutes before a solution of
1-
(phenylsulfonyl)indoline (46.9 g, 0.180 mol) in CHzClz (1070 mL) was added
dropwise. The
mixture was stirred for 5 h and was quenched by the slow addition of crushed
ice. The
organic layer was separated and the aqueous layer was extracted with CH2C12.
The combined
organics were washed with saturated aqueous NaHCO3 and brine, dried over
Na2SO4, and
concentrated under vacuum to obtain 1-(1-(phenylsulfonyl)indolin-5-yl)ethanone
(42.6 g).
0
NaBH4/THF \ /
N
N 0-S_
0.O
~ \
o 0 6
[00731] 5-Ethyl-l-(phenylsulfonyl)indoline
[00732] To TFA (1600 mL) at 0 C was added sodium borohydride (64.0 g, 1.69
mol) over
1 h. To this mixture was added dropwise a solution of 1-(1-
(phenylsulfonyl)indolin-5-
yl)ethanone (40.0 g, 0.133 mol) in TFA (700 mL) over 1 h. The mixture was then
stirred
overnight at 25 C. After dilution with H2O (1600 mL), the mixture was made
basic by the
addition of sodium hydroxide pellets at 0 C. The organic layer was separated
and the
aqueous layer was extracted with CH2C12. The combined organic layers were
washed with
brine, dried over Na2SO4 and concentrated under reduced pressure. The residue
was purified
by silica column to give 5-ethyl-l-(phenylsulfonyl)indoline (16.2 g, 47% over
two steps).
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48%HBr
N
O_g=0
H
\ I
[00733] 5-Ethylindoline
[00734] A mixture of 5-ethyl-l-(phenylsulfonyl)indoline (15 g, 0.050 mol) in
HBr (48%,
162 mL) was heated at reflux for 6 h. The mixture was basified with sat. NaOH
to pH 9 and
then it was extracted with ethyl acetate. The organic layer was washed with
brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was purified by
silica column
to give 5-ethylindoline (2.5 g, 32%).
KNO3/H2SO4
\ H OZN a~N
[00735] 5-Ethyl-6-nitroindoline
[00736] To a solution of 5-ethylindoline (2.5 g, 17 mmol) in H2SO4 (98%, 20
mL) was
slowly added KNO3 (1.7 g, 17 mmol) at 0 C. The mixture was stirred at 0 - 10
C for 10
minutes. The mixture was then carefully poured into ice, basified with NaOH
solution to pH
9, and extracted with ethyl acetate. The combined extracts were washed with
brine, dried
over Na2SO4 and concentrated to dryness. The residue was purified by silica
column to give
5-ethyl-6-nitroindoline (1.9 g, 58%).
Mn02
02N \ H 02N H
[00737] 5-Ethyl-6-nitro-1H-indole
[00738] To a solution of 5-ethyl-6-nitroindoline (1.9 g, 9.9 mmol) in CH2C12
(30 mL) was
added Mn02 (4.0 g, 46 mmol). The mixture was stirred at ambient temperature
for 8 h. The
solid was filtered off and the filtrate was concentrated to dryness to give 5-
ethyl-6-nitro-lH-
indole (1.9 g).
Raney Ni/H2`
2N H H2N H
[00739] 5-Ethyl-1H-indol-6-amine
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[00740] A suspension of 5 -ethyl- 6-nitro- I H-indole (1.9 g, 10 mmol) and
Raney Nickel (1
g) was hydrogenated under H2 (1 atm) at room temperature for 2 h. The catalyst
was filtered
off and the filtrate was concentrated to dryness. The residue was purified by
silica gel
column to give 5-ethyl-lH-indol-6-amine (760 mg, 48% over two steps). 1H NMR
(CDC13) 8
7.90 (br s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39
(br s, 2H), 2.63 (q, J
= 7.2 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H); MS (ESI) m/e (M+H+) 161.1.
[00741] Example 55: Ethyl 6-amino-1H-indole-4-carboxylate
02N COOH ON CO2Et
COOH HNO3 I SOCI2;
H2SO4 EtOH
NO2 NO2
NO 2 CO2Et
DMA/DMF N SnCl2
02N low I
H2N /H
C02Et
02N COOH
COON HNO3
H2SO4
NO2
[00742] 2-Methyl-3,5-dinitrobenzoic acid
[00743] To a mixture of HNO3 (95%, 80 mL) and H2SO4 (98%, 80 mL) was slowly
added
2-methylbenzic acid (50 g, 0.37 mol) at 0 C. After addition, the reaction
mixture was stirred
below 30 C for 1.5 h. The mixture then was poured into ice-water and stirred
for 15 min.
The precipitate was filtered and washed with water to give 2-methyl-3,5-
dinitrobenzoic acid
(70 g, 84%).
O2N COOH O2N C02Et
SOCI2;
EtOH
NO2 NO2
[00744] Ethyl 2-methyl-3,5-dinitrobenzoate
[00745] A mixture of 2-methyl-3,5-dinitrobenzoic acid (50 g, 0.22 mol) in
SOC12 (80 mL)
was heated at reflux for 4 h and then was concentrated to dryness. The residue
was dissolved
in CH2C12 (50 mL), to which EtOH (80 mL) was added and the mixture was stirred
at room
temperature for 1 h. The mixture was poured into ice-water and extracted with
EtOAc (3 x
100 mL). The combined extracts were washed sat. Na2CO3 (80 mL), water (2 x 100
mL) and
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brine (100 mL), dried over Na2SO4 and concentrated to dryness to give ethyl 2-
methyl-3,5-
dinitrobenzoate (50 g, 88%)
02N C02Et N02 /
DMNDMF / N Am- 02N -C
N02 CO2Et
[00746] (E)-Ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate
[00747] A mixture of ethyl 2-methyl-3,5-dinitrobenzoate (35 g, 0.14 mol) and
DMA (32 g,
0.27 mol) in DMF (200 mL) was heated at 100 C for 5 h. The mixture was poured
into ice-
water and the precipitated solid was filtered and washed with water to give
(E)-ethyl 2-(2-
(dimethylamino)vinyl)-3,5-dinitrobenzoate (11 g, 48%)
NO 2 CO2Et
N SnCl2
O2N / \ )OW H2N H
CO2Et
[00748] Ethyl 6-amino-lH-indole-4-carboxylate
[00749] A mixture of (E)-ethyl 2-(2-(dimethylamino)vinyl)-3,5-dinitrobenzoate
(11 g,
0.037 mol) and SnC12 (83 g, 0.37 mol) in ethanol was heated at reflux for 4 h.
The mixture
was concentrated to dryness and the residue was poured into water and basified
using sat. aq.
Na2CO3 to pH 8. The precipitated solid was filtered and the filtrate was
extracted with ethyl
acetate (3 x 100 mL). The combined extracts were washed with water (2 x 100
mL) and
brine (150 mL), dried over Na2SO4, and concentrated to dryness. The residue
was purified by
column on silica gel to give ethyl 6-amino-1H-indole-4-carboxylate (3.0 g,
40%). 1HNMR
(DMSO-d6) 8 10.76 (br s, 1 H), 7.11-7.14 (m, 2 H), 6.81-6.82 (m, 1 H), 6.67-
6.68 (m, 1 H),
4.94 (br s, 2 H), 4.32-4.25 (q, J = 7.2 Hz, 2 H), 1.35-1.31 (t, J = 7.2, 3 H);
MS (ESI) m/e
(M+H+) 205Ø
[00750] Example 56: 5-Fluoro-lH-indol-6-amine
o-
/ II HNO3/H2SO4 F / I N-
\/\
F 02N \ NO2
F N H2/Raney-Ni
H2N ~ N
)O' ~
02N NOZ H
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/ I HNO3/H2SO4 F /
F 'a 02N ~ NO2
[00751] 1-Fluoro-5-methyl-2,4-dinitrobenzene
[00752] To a stirred solution of HNO3 (60 mL) and H2SO4 (80 mL) was added
dropwise 1-
fluoro-3-methylbenzene (28 g, 25 mmol) under ice-cooling at such a rate that
the temperature
did not rise above 35 C. The mixture was allowed to stir for 30 min at rt and
was then
poured into ice water (500 mL). The resulting precipitate (a mixture of 1-
fluoro-5-methyl-
2,4-dinitrobenzene and 1-fluoro-3-methyl-2,4-dinitrobenzene, 32 g, ca. 7:3
ratio) was
collected by filtration and purified by recrystallization from 50 mL isopropyl
ether to give
pure 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).
0-
F / I N-
O-
02N NO2 02F
N N02
[00753] (E)-2-(5-Fluoro-2,4-dinitrophenyl)-N,N-dimethylethenamine
[00754] A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol),
DMA (12 g,
100 mmol) and DMF (50 mL) was heated at 100 C for 4h. The solution was cooled
and
poured into water. The precipitated red solid was collected, washed with
water, and dried to
give (E)-2-(5-fluoro-2,4-dinitrophenyl)-N,N-dimethylethenamine (8.0 g, 63%).
F \ N H2/Raney-Ni
/ I l
H2N N
02N NO2 H
[00755] 5-Fluoro-1H-indol-6-amine
[00756] A suspension of (E)-2-(5-fluoro-2,4-dinitrophenyl)-NN-
dimethylethenamine (8.0
g, 31 mmol) and Raney Nickel (8 g) in EtOH (80 mL) was stirred under H2 (40
psi) at room
temperature for 1 h. After filtration, the filtrate was concentrated and the
residue was
purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to
give 5-fluoro-
1H-indol-6-amine (1.0 g, 16%) as a brown solid. 1HNMR (DMSO-d6) 8 10.56 (br s,
1 H),
7.07 (d, J = 12 Hz, 1 H), 7.02 (m, 1H), 6.71 (d, J = 8 Hz, 1H), 6.17 (s, 1H),
3.91 (br s , 2H);
MS (ESI) m/e (M+H+) 150.1.
[00757] Example 57: 5-Chloro-1H-indol-6-amine
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HNO3/H2SO4 CI / p-
CI O2N \ NOz
CI
CI Hz/Raney-Ni
O N NO HzN \ N
z z H
HNO3/H2SO4 CI /
"~/\ O2 2
N \ NO
CI
[00758] 1-Chloro-5-methyl-2,4-dinitrobenzene
[00759] To a stirred solution of HNO3 (55 mL) and H2SO4 (79 mL) was added
dropwise 1-
chloro-3-methylbenzene (25.3 g, 200 mmol) under ice-cooling at such a rate
that the
temperature did not rise above 35 C. The mixture was allowed to stir for 30
min at ambient
temperature and was then poured into ice water (500 mL). The resulting
precipitate was
collected by filtration and purified by recrystallization to give 1-chloro-5-
methyl-2,4-
dinitrobenzene (26 g, 60%).
CI N-\ CI
O2N / NOz O2N NO2
[00760] (E)-2-(5-Chloro-2,4-dinitrophenyl)-N,N-dimethylethenamine
[00761] A mixture of 1-chloro-5-methyl-2,4-dinitro-benzene (11.6 g, 50.0
mmol), DMA
(11.9 g, 100 mmol) in DMF (50 mL) was heated at 100 C for 4 h. The solution
was cooled
and poured into water. The precipitated red solid was collected by filtration,
washed with
water, and dried to give (E)-2-(5-chloro-2,4-dinitrophenyl)-NN-
dimethylethenamine (9.84 g,
72%).
CI I H2/Raney-Ni CI
O N ~NO2 Am ~
H2N \ N
z H
[00762] 5-Chloro-1H-indol-6-amine
[00763] A suspension of (E)-2-(5-chloro-2,4-dinitrophenyl)-NN-
dimethylethenamine (9.8
g, 36 mmol) and Raney Nickel (9.8 g) in EtOH (140 mL) was stirred under H2 (1
atm) at
room temperature for 4 h. After filtration, the filtrate was concentrated and
the residue was
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purified by column chromatograph (petroleum ether/ethyl acetate = 10:1) to
give 5-chloro-
1H-indol-6-amine (0.97 g, 16%) as a gray powder. 1HNMR (CDC13) 8 7.85 (br s, 1
H), 7.52
(s, 1 H), 7.03 (s, 1H), 6.79 (s, 1H), 6.34 (s, 1H), 3.91 (br s, 1H); MS (ESI)
m/e (M+H+) 166Ø
[00764] Example 58: Ethyl6-amino-lH-indole-7-carboxylate
CO2H 1. HNO3/H2SO4 NoeN02 1. SOCI
\ co2H 2
2. SOCI2/EtOH , 2. EtOH
N02 N \
C02Et DMA 02N r \ Ni
H2N H
NO2 EtO2C NO2 C02Et
CO2H 1. HNO3/H2SO4 Noe
\ C02H
2. SOCI2/EtOH I /
NO2
[00765] 3-Methyl-2,6-dinitrobenzoic acid
[00766] To a mixture of HNO3 (95%, 80 mL) and H2SO4 (98%, 80 mL) was slowly
added
3-methylbenzic acid (50 g, 0.37 mol) at 0 C. After addition, the mixture was
stirred below
30 C for 1.5 hours. The mixture was then poured into ice-water and stirred
for 15 min. The
precipitate solid was filtered and washed with water to give a mixture of 3-
methyl-2,6-
dinitro-benzoic acid and 5-methyl-2,4-dinitrobenzoic acid (70 g, 84%). To a
solution of this
mixture (70 g, 0.31 mol) in EtOH (150 mL) was added dropwise SOC12 (54 g, 0.45
mol).
The mixture was heated at reflux for 2 h before being concentrated to dryness
under reduced
pressure. The residue was partitioned between EtOAc (100 mL) and aq. Na2CO3
(10%, 120
mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, and
concentrated to dryness to obtain ethyl 5-methyl-2,4-dinitrobenzoate (20 g),
which was
placed aside. The aqueous layer was acidified by HCl to pH 2 - 3 and the
precipitated solid
was filtered, washed with water, and dried in air to give 3-methyl-2,6-
dinitrobenzoic acid (39
g, 47%).
N02 CO2H 1. SOCI2 N02 C02Et
\ I \
2. EtOH
NO2 ~ N02
[00767] Ethyl 3-methyl-2,6-dinitrobenzoate
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[00768] A mixture of 3-methyl-2,6-dinitrobenzoic acid (39 g, 0.15 mol) and
SOC12(80 mL)
was heated at reflux 4 h. The excess SOC12 was evaporated off under reduced
pressure and
the residue was added dropwise to a solution of EtOH (100 mL) and Et3N (50
mL). The
mixture was stirred at 20 C for 1 h and then concentrated to dryness. The
residue was
dissolved in EtOAc (100 mL), washed with Na2CO3 (10 %, 40 mL x 2), water (50
mL x 2)
and brine (50 mL), dried over Na2SO4 and concentrated to give ethyl 3-methyl-
2,6-
dinitrobenzoate (20 g, 53%).
N02 N
C02Et DMA 02
N02 Et02C NO2
[00769] (E)-Ethyl 3-(2-(dimethylamino)vinyl)-2,6-dinitrobenzoate
[00770] A mixture of ethyl 3-methyl-2,6-dinitrobenzoate (35 g, 0.14 mol) and
DMA (32 g,
0.27 mol) in DMF (200 mL) was heated at 100 C for 5 h. The mixture was poured
into ice
water. The precipitated solid was filtered and washed with water to give (E)-
ethyl 3-(2-
(dimethylamino)vinyl)-2,6-dinitrobenzoate (25 g, 58%).
02N \ Raney Ni/H2
/
H2N N
H
Et02C NO2 C02Et
[00771] Ethyl 6-amino-lH-indole-7-carboxylate
[00772] A mixture of (E)-ethyl 3-(2-(dimethylamino)vinyl)-2,6-dinitrobenzoate
(30 g,
0.097 mol) and Raney Nickel (10 g) in EtOH (1000 mL) was hydrogenated at room
temperature under 50 psi for 2 h. The catalyst was filtered off and the
filtrate was
concentrated to dryness. The residue was purified by column on silica gel to
give ethyl 6-
amino-1H-indole-7-carboxylate as an off-white solid (3.2 g, 16%). 1H NMR (DMSO-
d6) 8
10.38 (s, 1 H), 7.42 (d, J = 8.7 Hz, 1 H), 6.98 (t, J = 3.0 Hz, 1 H), 6.65 (s,
2 H), 6.48 (d, J =
8.7 Hz, 1 H), 6.27-6.26 (m, 1 H), 4.38 (q, J= 7.2 Hz, 2 H), 1.35 (t, J= 7.2
Hz, 3 H).
[00773] Example 59: Ethyl 6-amino-1H-indole-5-carboxylate
COzEt DMA OzN NOz EtO:C
\ I / / Raney N
zC i 2NI H
OzN NOz EtO H
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CO2Et DMA O2N NO2
02N NO EtO2C N
2
[00774] (E)-Ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate
[00775] A mixture of ethyl 5-methyl-2,4-dinitrobenzoate (39 g, 0.15 mol) and
DMA (32 g,
0.27 mol) in DMF (200 mL) was heated at 100 C for 5 h. The mixture was poured
into ice
water and the precipitated solid was filtered and washed with water to afford
(E)-ethyl 5-(2-
(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 28%).
02N / N02 Et02C :
Raney Ni
EtO2C i H2N H
[00776] Ethyl 6-amino-lH-indole-5-carboxylate
[00777] A mixture of (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate
(15 g,
0.050 mol) and Raney Nickel (5 g) in EtOH (500 mL) was hydrogenated at room
temperature
under 50 psi of hydrogen for 2 h. The catalyst was filtered off and the
filtrate was
concentrated to dryness. The residue was purified by column on silica gel to
give ethyl 6-
amino-1H-indole-5-carboxylate (3.0 g, 30%). 'H NMR (DMSO-d6) 8 10.68 (s, 1 H),
7.99 (s,
1 H), 7.01-7.06 (m, 1 H), 6.62 (s, 1 H), 6.27-6.28 (m, 1 H), 6.16 (s, 2 H),
4.22 (q, J = 7.2 Hz,
2 H), 1.32-1.27 (t, J = 7.2 Hz, 3 H).
[00778] Example 60: 5-tert-Butyl-lH-indol-6-amine
t-Bu
t-Bu \ (EtO)2P(O)CI/NaH Li/NH3 t-Buw\ HNO3/H2SO4
O I I`
H EtO-P-OEt
11
O
NO2 0
t-Bu :a I -
t -Bu / /N-< 0- t -Bu SnCI2 t -Bu
+ 02N N02 02 02N N02 H2 H
WN
N tBu` ^ /
t -Bu (EtO)ZP(O)CI/NaH
O
HO EtO-P-OEt
11
O
[00779] 2-tert-Butyl-4-methylphenyl diethyl phosphate
[00780] To a suspension of NaH (60% in mineral oil, 8.4 g, 0.21 mol) in THE
(200 mL)
was added dropwise a solution of 2-tert-butyl-4-methylphenol (33 g, 0.20 mol)
in THE (100
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mL) at 0 C. The mixture was stirred at 0 C for 15 min and then
phosphorochloridic acid
diethyl ester (37 g, 0.21 mol) was added dropwise at 0 C. After addition, the
mixture was
stirred at ambient temperature for 30 min. The reaction was quenched with sat.
NH4C1(300
mL) and then extracted with Et20 (350 mL x 2). The combined organic layers
were washed
with brine, dried over anhydrous Na2SO4, and then evaporated under vacuum to
give 2-tert-
butyl-4-methylphenyl diethyl phosphate (contaminated with mineral oil) as a
colorless oil (60
g, -100%), which was used directly in the next step.
t-Bu
Li/NH3 t-Bu 11:zzz
O II
EtO-P-OEt
n
0
[00781] 1-tert-Butyl-3-methylbenzene
[00782] To NH3 (liquid, 1000 mL) was added a solution of 2-tert-butyl-4-
methylphenyl
diethyl phosphate (60 g, crude from last step, about 0.2 mol) in Et20
(anhydrous, 500 mL) at
-78 C under N2 atmosphere. Lithium metal was added to the solution in small
pieces until
the blue color persisted. The reaction mixture was stirred at -78 C for 15
min and then was
quenched with sat. NH4C1 until the mixture turned colorless. Liquid NH3 was
evaporated and
the residue was dissolved in water. The mixture was extracted with Et20 (400
mL x 2). The
combined organics were dried over Na2SO4 and evaporated to give 1-tert-butyl-3-
methylbenzene (contaminated with mineral oil) as a colorless oil (27 g, 91%),
which was
used directly in next step.
NO2
t-Bu HNO3/H2SO4 t-Bu / I t-Bu
O2N \ NO2 'No,
[00783] 1-tert-Butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl-2,4-
dinitro-benzene
[00784] To HNO3 (95%, 14 mL) was added H2SO4 (98 %, 20 mL) at O C and then 1-
tert-
butyl-3-methylbenzene (7.4 g, --50 mmol, crude from last step) dropwise to the
with the
temperature being kept below 30 C. The mixture was stirred at ambient
temperature for 30
min, poured onto crushed ice (100 g), and extracted with EtOAc (50 mL x 3).
The combined
organic layers were washed with water and brine, before being evaporated to
give a brown
oil, which was purified by column chromatography to give a mixture of 1-tert-
butyl-5-
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methyl-2,4-dinitrobenzene and 1-tert-butyl-3-methyl-2,4-dinitrobenzene (2:1 by
NMR) as a
yellow oil (9.0 g, 61%).
NOz t -Bu
/ t-Bu / N~ - t-Bu
OZN NOz NOz 02N N02
[00785] (E)-2-(5-tert-Butyl-2,4-dinitrophenyl)-N,N-dimethylethenamine
[00786] A mixture of 1-tert-butyl-5-methyl-2,4-dinitrobenzene and 1-tert-butyl-
3-methyl-
2,4-dinitrobenzene (9.0 g, 38 mmol, 2:1 by NMR) and DMA (5.4 g, 45 mmol) in
DMF (50
mL) was heated at reflux for 2 h before being cooled to room temperature. The
reaction
mixture was poured into water-ice and extracted with EtOAc (50 mL x 3). The
combined
organic layers were washed with water and brine, before being evaporated to
give a brown
oil, which was purified by column to give (E)-2-(5-tert-butyl-2,4-
dinitrophenyl)-N,N-
dimethylethen-amine (5.0 g, 68%).
t Bu SnCI t -Bu
02N N02 H2N N
H
[00787] 5-tert-Butyl-1H-indol-6-amine
[00788] A solution of (E)-2-(5-tert-butyl-2,4-dinitrophenyl)-NN-dimethylethen-
amine (5.3
g, 18 mmol) and tin (II) chloride dihydrate (37 g, 0.18 mol) in ethanol (200
mL) was heated
at reflux overnight. The mixture was cooled to room temperature and the
solvent was
removed under vacuum. The residual slurry was diluted with water (500 mL) and
was
basifed with 10 % aq. Na2CO3 to pH 8. The resulting suspension was extracted
with ethyl
acetate (3 x 100 mL). The ethyl acetate extract was washed with water and
brine, dried over
Na2SO4, and concentrated. The residual solid was washed with CH2C12 to afford
a yellow
powder, which was purified by column chromatography to give 5-tert-butyl-lH-
indol-6-
amine (0.40 g, 12%). 1H NMR (DMSO-d6) 8 10.34 (br s, 1 H), 7.23 (s, 1 H), 6.92
(s, 1 H),
6.65 (s, 1H), 6.14 (s, 1 H), 4.43 (br s, 2 H), 2.48 (s, 9 H); MS (ESI) m/e
(M+H+) 189.1.
[00789] General Procedure IV: Synthesis of acylaminoindoles
A RN
( 'XX)X A OH RN HATU (RXX)XOB N`Art
g + HN'Art Et3N, DMF 0
0 DCM
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[00790] One equivalent of the appropriate carboxylic acid and one equivalent
of the
appropriate amine were dissolved in N,N-dimethylformamide (DMF) containing
triethylamine (3 equivalents). O-(7-Azabenzotriazol-1-yl)-N,NN;N'-
tetramethyluronium
hexafluorophosphate (HATU) was added and the solution was allowed to stir. The
crude
product was purified by reverse-phase preparative liquid chromatography to
yield the pure
product.
[00791] Example 61: N-(2-tert-Butyl-lH-indol-5-yl)-1-(4-methoxyphenyl)-
cyclopropanecarboxamide
DMF
U
% I O N E,N N
OH H2N H
[00792] 2-tert-Butyl-1H-indol-5-amine (19 mg, 0.10 mmol) and 1-(4-
methoxyphenyl)-
cyclopropanecarboxylic acid (19 mg, 0.10 mmol) were dissolved in N,N-
dimethylformamide
(1.00 mL) containing triethylamine (28 L, 0.20 mmol). O-(7-Azabenzotriazol-1-
yl)-
NNNN'-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to
the
mixture and the resulting solution was allowed to stir for 3 hours. The crude
reaction mixture
was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 362.2, found
363.3
(M+1)+; Retention time 3.48 minutes.
[00793] General Procedure V: Synthesis of acylaminoindoles
(RXbB A A RN RN
OH SOCI2 (RXX)xDB CI HN pyridine (RXX)x A N'
O DMF O + ~Ari Arl
O
[00794] One equivalent of the appropriate carboxylic acid was placed in an
oven-dried
flask under nitrogen. A minimum (3 equivalents) of thionyl chloride and a
catalytic amount
of and NN-dimethylformamide were added and the solution was allowed to stir
for 20
minutes at 60 T. The excess thionyl chloride was removed under vacuum and the
resulting
solid was suspended in a minimum of anhydrous pyridine. This solution was
slowly added to
a stirred solution of one equivalent the appropriate amine dissolved in a
minimum of
anhydrous pyridine. The resulting mixture was allowed to stir for 15 hours at
110 T. The
mixture was evaporated to dryness, suspended in dichloromethane, and then
extracted three
times with IN HCl. The organic layer was then dried over sodium sulfate,
evaporated to
dryness, and then purified by column chromatography.
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[00795] Example 62: Ethyl5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-
1H-indole-2-carboxylate (Compd. 28)
1) SOCI2 O / O N O
DMF
co
O OH 2) dichloromethane O N OEt
Eta N H
H
N
H2N OEt
[00796] 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.07 g, 10.0
mmol) was
dissolved in thionyl chloride (2.2 mL) under N2. N,N-dimethylformamide (0.3
mL) was
added and the solution was allowed to stir for 30 minutes. The excess thionyl
chloride was
removed under vacuum and the resulting solid was dissolved in anhydrous
dichloromethane
(15 mL) containing triethylamine (2.8 mL, 20.0 mmol). Ethyl 5-amino- IH-indole-
2-
carboxylate (2.04 g, 10.0 mmol) in 15 mL of anhydrous dichloromethane was
slowly added
to the reaction. The resulting solution was allowed to stir for 1 hour. The
reaction mixture
was diluted to 50 mL with dichloromethane and washed three times with 50 mL of
IN HCl,
saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride.
The organic
layer was dried over sodium sulfate and evaporated to dryness to yield ethyl 5-
(1-
(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate as
a gray
solid (3.44 g, 88 %). ESI-MS m/z calc. 392.4; found 393.1 (M+1)+ Retention
time 3.17
minutes. 1H NMR (400 MHz, DMSO-d6) 8 11.80 (s, 1H), 8.64 (s, 1H), 7.83 (m,
1H), 7.33-
7.26 (m, 2H), 7.07 (m, 1H), 7.02 (m, 1H), 6.96-6.89 (m, 2H), 6.02 (s, 2H),
4.33 (q, J = 7.1
Hz, 2H), 1.42-1.39 (m, 2H), 1.33 (t, J= 7.1 Hz, 3H), 1.06-1.03 (m, 2H).
[00797] Example 63: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-lH-indol-5-
yl)cyclopropanecarboxamide
OH H
CI N
0 SOCI2 H2N CH2C12 O I / NH
DMF O + I / N Et3N
OHO O"'O H O"'O
[00798] 1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (1.09 g, 5.30
mmol) was
dissolved in 2 mL of thionyl chloride under nitrogen. A catalytic amount (0.3
mL) of N,N-
dimethylformamide (DMF) was added and the reaction mixture was stirred for 30
minutes.
The excess thionyl chloride was evaporated and the resulting residue was
dissolved in 15 mL
of dichloromethane. This solution was slowly added to a solution of 2-tert-
butyl-lH-indol-5-
amine (1.0 g, 5.3 mmol) in 10 mL of dichloromethane containing triethylamine
(1.69 mL,
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12.1 mmol). The resulting solution was allowed to stir for 10 minutes. The
solvent was
evaporated to dryness and the crude reaction mixture was purified by silica
gel column
chromatography using a gradient of 5-50 % ethyl acetate in hexanes. The pure
fractions were
combined and evaporated to dryness to yield a pale pink powder (1.24 g 62%).
ESI-MS m/z
calc. 376.18, found 377.3 (M+1)+. Retention time of 3.47 minutes. 1H NMR (400
MHz,
DMSO) S 10.77 (s, 1H), 8.39 (s, 1H), 7.56 (d, J = 1.4 Hz, 1H), 7.15 (d, J =
8.6 Hz, 1H), 7.05
- 6.87 (m, 4H), 6.03 (s, 3H), 1.44 - 1.37 (m, 2H), 1.33 (s, 9H), 1.05-1.00 (m,
2H).
[00799] Example 64: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1-
methylcyclopropyl)-1H-indol-5-yl)cyclopropanecarboxamide
HATU H
OH H2N Et3N N
O I/ O 02W\~ O I/ O N
[00800] 1 -Methyl-2-(1-methylcyclopropyl)-1H-indol-5-amine (20.0 mg, 0.100
mmol) and
1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol)
were
dissolved in NN-dimethylformamide (1 mL) containing triethylamine (42.1 L,
0.300 mmol)
and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-
tetramethyluronium
hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the
resulting solution
was allowed to stir for 6 h at 80 C. The crude product was then purified by
preparative
HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic
acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1-methyl-2-(1-methylcyclopropyl)-
1H-indol-5-
yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2, found 389.2 (M+1)+.
Retention time
of 3.05 minutes.
[00801] Example 65: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(1,1-dimethyl-2,3-dihydro-
lH-
pyrrolo [1,2-a]indol-7-yl)cyclopropanecarboxamide
HATU H
C0 OH H2N Et3N N
O I/ O :N 0 O / N
[00802] 1,1-Dimethyl-2,3-dihydro-lH-pyrrolo[1,2-a]indol-7-amine (40.0 mg,
0.200 mmol)
and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (41.2 mg, 0.200
mmol) were
dissolved in NN-dimethylformamide (1 mL) containing triethylamine (84.2 L,
0.600 mmol)
and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-
tetramethyluronium
hexafluorophosphate (84 mg, 0.22 mmol) was added to the mixture and the
resulting solution
was allowed to stir for 5 minutes at room temperature. The crude product was
then purified
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by preparative HPLC utilizing a gradient of 0-99% acetonitrile in water
containing 0.05%
trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(1,1-dimethyl-2,3-
dihydro-1H-
pyrrolo[1,2-a]-indol-7-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 388.2,
found 389.2
(M+1)+. Retention time of 2.02 minutes. 1H NMR (400 MHz, DMSO-d6) 8 8.41 (s,
1H),
7.59 (d, J = 1.8 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.06 - 7.02 (m, 2H), 6.96 -
6.90 (m, 2H),
6.03 (s, 2H), 5.98 (d, J = 0.7 Hz, 1H), 4.06 (t, J = 6.8 Hz, 2H), 2.35 (t, J =
6.8 Hz, 2H), 1.42-
1.38 (m, 2H), 1.34 (s, 6H), 1.05-1.01 (m, 2H).
[00803] Example 66: Methyl 5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-carboxylate
H
CI H2N Et3N l\O N \
O I/ O I/ H O I/ O I/ H
O O O O
[00804] 1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.20
mmol)
and methyl 5-amino-2-tert-butyl-1H-indole-7-carboxylate (49.3 mg, 0.200 mmol)
were
dissolved in N,N-dimethylformamide (2 mL) containing a magnetic stir bar and
triethylamine
(0.084 mL, 0.60 mmol). The resulting solution was allowed to stir for 10
minutes at room
temperature. The crude product was then purified by preparative HPLC using a
gradient of
0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield
methyl 5-(1-
(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarbox-amido)-2-tert-butyl-1H-indole-
7-carboxylate.
ESI-MS m/z calc. 434.2, found 435.5. (M+1)+. Retention time of 2.12 minutes.
[00805] Example 67: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-
methylpropan-2-
yl) -1H-indol-5-yl)cyclopropanecarboxamide
H2N H
\ \ + \ HBTU, I NI \
N OH O OH O / O / N OH
H H
[00806] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic
acid (0.075
g, 0.36 mmol) in acetonitrile (1.5 mL) were added HBTU (0.138 g, 0.36 mmol)
and Et3N
(152 L, 1.09 mmol) at room temperature. The mixture was stirred at room
temperature for
minutes before a solution of 2-(5-amino- lH-indol-2-yl)-2-methylpropan-l-ol
(0.074 g,
0.36 mmol) in acetonitrile (1.94 mL) was added. After addition, the reaction
mixture was
stirred at room temperature for 3 h. The solvent was evaporated under reduced
pressure and
the residue was dissolved in dichloromethane. The organic layer was washed
with 1 N HCl
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(1 x 3 mL) and saturated aqueous NaHCO3 (1 x 3 mL). The organic layer was
dried over
Na2SO4, filtered and evaporated under reduced pressure. The crude material was
purified by
column chromatography on silica gel (ethyl acetate/hexane = 1/1) to give 1-
(benzo [d] [ 1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide (0.11 g, 75%). 1H NMR (400 MHz, DMSO-d6) 8 10.64
(s,
1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04-6.90 (m, 4H),
6.06 (s, 1H), 6.03
(s, 2H), 4.79 (t, J = 2.7 Hz, 1H), 3.46 (d, J = 0.0 Hz, 2H), 1.41-1.39 (m,
2H), 1.26 (s, 6H),
1.05-1.02 (m, 2H).
[00807] Example 67: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2,3,4,9-tetrahydro-lH-
carbazol-
6-yl)cyclopropanecarboxamide
HATU H
(O OH +H2N DIEA (O \ N
O I/ O I/ H O O H
[00808] 2,3,4,9-Tetrahydro-1H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1-
(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol)
were
dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL,
1.32 mmol)
and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N;N'-
tetramethyluronium
hexafluorophosphate (183 mg, 0.482 mmol) was added to the mixture and the
resulting
solution was allowed to stir for 16 h at 70 C. The solvent was evaporated and
the crude
product was then purified on 40 g of silica gel utilizing a gradient of 5-50%
ethyl acetate in
hexanes to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2,3,4,9-tetrahydro-1H-
carbazol-6-
yl)cyclopropanecarboxamide as a beige powder (0.115 g, 70%) after drying. ESI-
MS m/z
calc. 374.2, found 375.3 (M+1)+. Retention time of 3.43 minutes. 1H NMR (400
MHz,
DMSO-d6) S 10.52 (s, 1H), 8.39 (s, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.10 - 6.89
(m, 5H), 6.03
(s, 2H), 2.68 - 2.65 (m, 2H), 2.56 - 2.54 (m, 2H), 1.82 - 1.77 (m, 4H), 1.41 -
1.34 (m, 2H),
1.04 - 0.97 (m, 2H).
[00809] Example 69: tert-Butyl4-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarbox-
amido)-1H-indol-2-yl)piperidine-l-carboxylate
0 CI
HzN
C O O / O O N O
O
\ O
NQ I \ I \ N N~
/H EtaN O
Et, N
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[00810] 1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (43 mg, 0.19
mmol)
and tert-butyl 4-(5-amino- lH-indol-2-yl)piperidine-l-carboxylate (60 mg, 0.19
mmol) were
dissolved in dichloromethane (1 mL) containing a magnetic stir bar and
triethylamine (0.056
mL, 0.40 mmol). The resulting solution was allowed to stir for two days at
room
temperature. The crude product was then evaporated to dryness, dissolved in a
minimum of
N,N-dimethylformamide, and then purified by preparative HPLC using a gradient
of 0-99%
acetonitrile in water containing 0.05% trifluoroacetic acid to yield tert-
butyl 4-(5-(1-
(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)piperidine-
l-
carboxylate. ESI-MS m/z calc. 503.2, found 504.5. (M+1)+. Retention time of
1.99 minutes.
[00811] Example 70: Ethyl2-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-1H-indol-2-yl)propanoate
KHMDS_ TFA_ NaNO3 OzN \ N C02
COZEt Mel COZEt H COZEt conc. HZSO4 / H Et
Boc Boc
SnCIz.2HZO H2N / + /O HBTU, Et3N N
H COzEt O OH O / O H COZEt
KHMDS
~ COzEt Mel f~ COzEt
Boc Boc
[00812] tert-Butyl 2-(1-ethoxy-l-oxopropan-2-yl)-1H-indole-l-carboxylate
[00813] tert-Butyl2-(2-ethoxy-2-oxoethyl)-1H-indole-l-carboxylate (3.0 g, 9.9
mmol) was
added to anhydrous THE (29 mL) and cooled to -78 T. A 0.5M solution of
potassium
hexamethyldisilazane (20 mL, 9.9 mmol) was added slowly such that the internal
temperature
stayed below -60 T. Stirring was continued for 1 h at -78 T. Methyl iodide
(727 L, 11.7
mmol) was added to the mixture. The mixture was stirred for 30 minutes at room
temperature. The mixture was quenched with sat. aq. ammonium chloride and
partitioned
between water and dichloromethane. The aqueous phase was extracted with
dichloromethane
and the combined organic phases were dried over Na2SO4 and evaporated under
reduced
pressure. The residue was purified by column chromatography on silica gel
(ethylacetate/hexane = 1/9) to give tert-butyl 2-(1-ethoxy-l-oxopropan-2-yl)-
1H-indole-l-
carboxylate (2.8 g, 88%).
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NN TFA
C02Et H CO2Et
Boc
[00814] Ethyl 2-(1H-indol-2-yl)propanoate
[00815] tert-Butyl 2-(1-ethoxy-l-oxopropan-2-yl)-1H-indole-l-carboxylate (2.77
g, 8.74
mmol) was dissolved in dichloromethane (25 mL) before TFA (9.8 mL) was added.
The
mixture was stirred for 1.5 h at room temperature. The mixture was evaporated
to dryness,
taken up in dichloromethane and washed with sat. aq. sodium bicarbonate,
water, and brine.
The product was purified by column chromatography on silica gel (0-20% EtOAc
in hexane)
to give ethyl 2-(1H-indol-2-yl)propanoate (0.92 g, 50%).
\
\ N NaNO3 1 11 0 :
N CO2Et conc. H2SO4 N CO2Et
H H
[00816] Ethyl2-(5-nitro-lH-indol-2-yl)propanoate
[00817] Ethyl2-(1H-indol-2-yl)propanoate (0.91 g, 4.2 mmol) was dissolved in
concentrated sulfuric acid (3.9 mL) and cooled to -10 C (salt/ice-mixture). A
solution of
sodium nitrate (0.36 g, 4.2 mmol) in concentrated sulfuric acid (7.8 mL) was
added dropwise
over 35 min. Stirring was continued for another 30 min at -10 T. The mixture
was poured
into ice and the product was extracted with ethyl acetate. The combined
organic phases were
washed with a small amount of sat. aq. sodium bicarbonate. The product was
purified by
column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-(5-
nitro-lH-
indol-2-yl)propanoate (0.34 g, 31%).
02N I \ SnC12.2H20 H2N I \ :~~
H CO2Et H CO2Et
[00818] Ethyl2-(5-amino-lH-indol-2-yl)propanoate
[00819] To a solution of ethyl 2-(5-nitro-lH-indol-2-yl)propanoate (0.10 g,
0.38 mmol) in
ethanol (4 mL) was added tin chloride dihydrate (0.431 g, 1.91 mmol). The
mixture was
heated in the microwave at 120 C for 1 h. The mixture was diluted with ethyl
acetate before
water and saturated aqueous NaHCO3 were added. The reaction mixture was
filtered through
a plug of celite using ethyl acetate. The organic layer was separated from the
aqueous layer.
The organic layer was dried over Na2SO4, filtered and evaporated under reduced
pressure to
give ethyl 2-(5 -amino- 1H-indol-2-yl)propanoate (0.088 g, 99%).
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H
jjo,~, ~ W
H2N
\ + HBTU, Et3N_ N
Of' N H C2Et A OH O O H CO2Et
[00820] Ethyl2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-
indol-
2-yl)propanoate
[00821] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic
acid (0.079
g, 0.384 mmol) in acetonitrile (1.5 mL) were added HBTU (0.146 g, 0.384 mmol)
and Et3N
(160 L, 1.15 mmol) at room temperature. The mixture was allowed to stir at
room
temperature for 10 min before a solution of ethyl 2-(5-amino-lH-indol-2-
yl)propanoate
(0.089 g, 0.384 mmol) in acetonitrile (2.16 mL) was added. After addition, the
reaction
mixture was stirred at room temperature for 2 h. The solvent was evaporated
under reduced
pressure and the residue was dissolved in dichloromethane. The organic layer
was washed
with 1 N HCl (1 x 3 mL) and then saturated aqueous NaHCO3 (1 x 3 mL). The
organic layer
was dried over Na2SO4, filtered and evaporated under reduced pressure. The
crude material
was purified by column chromatography on silica gel (ethyl acetate/hexane =
1/1) to give
ethyl 2-(5-(1-(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-
yl)propanoate (0.081 g, 50%). 1H NMR (400 MHz, CDC13) 8 8.51 (s, 1H), 7.67 (s,
1H),
7.23-7.19 (m, 2H), 7.04-7.01 (m, 3H), 6.89 (d, J = 0.0 Hz, 1H), 6.28 (s, 1H),
6.06 (s, 2H),
4.25-4.17 (m, 2H), 3.91 (q, J = 7.2 Hz, 1H), 1.72-1.70 (m, 2H), 1.61 (s, 2H),
1.29 (t, J = 7.1
Hz, 4H), 1.13-1.11 (m, 2H).
[00822] Example 71: tert-Butyl2-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarbox-
amido)-1H-indol-2-yl)-2-methylpropylcarbamate
O2N O2N O2N
LiOH I \ EDC, HOBt ~NH2
H CO2Et H CO 2H NEt3, NHgCI H O
BH3 THE O2N BOC2O 02N \ Pd/C H2N \
NH2 NEt3 H NHBoc HCO2NH4 H NHBoc
H
H
EDC, HOBt, NEt3 \ N 0~~
o I
a O NHBoc
OH H
0 I / O
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02N \ 02N
UGH
H C02Et H C02H
[00823] 2-Methyl-2-(5-nitro-lH-indol-2-yl)propanoic acid
[00824] Ethyl 2-methyl-2-(5-nitro- 1H-indol-2-yl)propanoate (4.60 g, 16.7
mmol) was
dissolved in THE/water (2:1, 30 mL). LiOH'H20 (1.40 g, 33.3 mmol) was added
and the
mixture was stirred at 50 C for 3 h. The mixture was made acidic by the
careful addition of
3N HCl. The product was extracted with ethylacetate and the combined organic
phases were
washed with brine and dried over magnesium sulfate to give 2-methyl-2-(5-nitro-
lH-indol-2-
yl)propanoic acid (4.15 g, 99%).
02N ~ 02N ~
EDC,HOBt
H C02H Et3N, NH4C1 N NH2
H 0
[00825] 2-Methyl-2-(5-nitro-lH-indol-2-yl)propanamide
[00826] 2-Methyl-2-(5-nitro-lH-indol-2-yl)-propanoic acid (4.12 g, 16.6 mmol)
was
dissolved in acetonitrile (80 mL). EDC (3.80 g, 0.020 mmol), HOBt (2.70 g,
0.020 mmol),
Et3N (6.9 mL, 0.050 mmol) and ammonium chloride (1.34 g, 0.025 mmol) were
added and
the mixture was stirred overnight at room temperature. Water was added and the
mixture was
extracted with ethylacetate. Combined organic phases were washed with brine,
dried over
magnesium sulfate and dried to give 2-methyl-2-(5-nitro-lH-indol-2-
yl)propanamide (4.3 g,
99%).
02N BH3THF 02N I H O NH2
[00827] 2-Methyl-2-(5-nitro-lH-indol-2-yl)propan-l-amine
[00828] 2-Methyl-2-(5-nitro-lH-indol-2-yl)propanamide (200 mg, 0.81 mmol) was
suspended in THE (5 ml) and cooled to 0 T. Borane-THF complex solution (1.0 M,
2.4 mL,
2.4 mmol) was added slowly and the mixture was allowed to stir overnight at
room
temperature. The mixture was cooled to 0 C and carefully acidified with 3 N
HCl. THE was
evaporated off, water was added and the mixture was washed with ethylacetate.
The aqueous
layer was made alkaline with 50% NaOH and the mixture was extracted with
ethylacetate.
The combined organic layers were dried over magnesium sulfate, filtered and
evaporated to
give 2-methyl-2-(5-nitro-1H-indol-2-yl)propan-1-amine (82 mg, 43%).
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02N Boc2O 02N
H NH2 NEt3,THF N NHBoc H
[00829] tert-Butyl 2-methyl-2-(5-nitro-lH-indol-2-yl)propylcarbamate
[00830] 2-Methyl-2-(5-nitro-lH-indol-2-yl)propan-l-amine (137 mg, 0.587 mmol)
was
dissolved in THE (5 mL) and cooled to 0 T. Et3N (82 L, 0.59 mmol) and di-tert-
butyl
dicarbonate (129 mg, 0.587 mmol) were added and the mixture was stirred at
room
temperature overnight. Water was added and the mixture was extracted with
ethylacetate.
The residue was purified by silica gel chromatography (10-40% ethylacetate in
hexane) to
give tert-butyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propylcarbamate (131 mg,
67%).
02N Pd/C H2N I
/ H\ NHBoc HCO2NH4 H\ NHBoc
[00831] tert-Butyl 2-(5-amino-lH-indol-2-yl)-2-methylpropylcarbamate
[00832] To a solution of tert-butyl 2-methyl-2-(5-nitro-lH-indol-2-
yl)propylcarbamate (80
mg, 0.24 mmol) in THE (9 mL) and water (2 mL) was added ammonium formate (60
mg,
0.96 mmol) followed by 10% Pd/C (50 mg). The mixture was stirred at room
temperature for
45 minutes. Pd/C was filtered off and the organic solvent was removed by
evaporation. The
remaining aqueous phase was extracted with dichloromethane. The combined
organic phases
were dried over magnesium sulfate and evaporated to give tert-butyl 2-(5-amino-
lH-indol-2-
yl)-2-methylpropylcarbamate (58 mg, 80%).
H
H2N \ EDC, HOBt, NEt3 / N / H NHBoc OH H NHBoc
CO
[00833] tert-Butyl 2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-
1H-
indol-2-yl)-2-methylpropylcarbamate
[00834] tert-Butyl2-(5-amino- 1H-indol-2-yl)-2-methylpropylcarbamate (58 mg,
0.19
mmol), 1-(benzo[d][1,3]dioxol-6-yl)cyclopropanecarboxylic acid (47 mg, 0.23
mmol), EDC
(45 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol) and Et3N (80 L, 0.57 mmol) were
dissolved
in DMF (4 mL) and stirred overnight at room temperature. The mixture was
diluted with
water and extracted with ethylacetate. The combined organic phases were dried
over
magnesium sulfate and evaporated to dryness. The residue was purified by
silica gel
chromatography (10-30% ethylacetate in hexane) to give tert-butyl 2-(5-(1-
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(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-2-
methylpropyl-
carbamate (88 mg, 94%). 1H NMR (400 MHz, CDC13) S 8.32 (s, 1H), 7.62 (d, J =
1.5 Hz,
1H), 7.18 - 7.16 (m, 2H), 7.02 - 6.94 (m, 3H), 6.85 (d, J = 7.8 Hz, 1H), 6.19
(d, J = 1.5 Hz,
1H), 6.02 (s, 2H), 4.54 (m, 1H), 3.33 (d, J = 6.2 Hz, 2H), 1.68 (dd, J = 3.7,
6.8 Hz, 2H), 1.36
(s, 9H), 1.35 (s, 6H), 1.09 (dd, J = 3.7, 6.8 Hz, 2H).
[00835] Example 72: (R)-N-(2-tert-Butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-yl)-
1-
(2,2-difluorobenzo [d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
OTs
O)< HzN O~,_
OzN O O2 Pd/C
H Cs2CO3 NH4'CO2 N
H O
O O
CI
F>~ H H
F O Fx N PTSA F O
0 Et3N F O O N 'Cr_ O
YO\ / OH
O OH
OTs
O2N \ O O.2N
N Cs2CO3 N
H
/\
O
[00836] (R)-2-tert-Butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitro-lH-
indole
[00837] To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-
methylbenzenesulfonate (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under
nitrogen gas
was added 2-tert-butyl- 5 -nitro- I H-indole (1.00 g, 4.58 mmol) followed by
Cs2CO3 (2.99 g,
9.16 mol). The mixture was stirred and heated at 80 C under nitrogen gas.
After 20 hours,
50% conversion was observed by LCMS. The reaction mixture was re-treated with
Cs2CO3
(2.99 g, 9.16 mol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-
methylbenzenesulfonate
(1.58 g, 5.50 mmol) and heated at 80 C for 24 hours. The reaction mixture was
cooled to
room temperature. The solids were filtered and washed with ethyl acetate and
hexane (1:1).
The layers were separated and the organic layer was washed with water (2 x 10
mL) and
brine (2 x 10 mL). The organic layer was dried over Na2SO4, filtered and
evaporated under
reduced pressure. The residue was purified by column chromatography on silica
gel
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(dichloromethane /hexane = 1.5/1) to give (R)-2-tert-butyl-l-((2,2-dimethyl-
1,3-dioxolan-4-
yl)methyl)-5-nitro-1H-indole (1.0 g, 66%). 1H NMR (400 MHz, CDC13) S 8.48 (d,
J = 2.2
Hz, 1H), 8.08 (dd, J = 2.2, 9.1 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 6.00 (s,
1H), 4.52-4.45 (m,
3H), 4.12 (dd, J = 6.0, 8.6 Hz, 1H), 3.78 (dd, J = 6.0, 8.6 Hz, 1H), 1.53 (s,
3H), 1.51 (s, 9H),
1.33 (s, 3H).
H2N
02 Pd/C
CN NH4*CO2
O\/ OK
/\ O
O
[00838] (R)-2-tert-Butyl-l-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl-lH-indol-5-
amine
[00839] To a stirred solution of (R)-2-tert-butyl-l-((2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)-5-
nitro-IH-indole (1.0 g, 3.0 mmol) in ethanol (20 mL) and water (5 mL) was
added ammonium
formate (0.76 g, 12 mmol) followed by slow addition of 10 % palladium on
carbon (0.4 g). The
mixture was stirred at room temperature for 1 h. The reaction mixture was
filtered through a
plug of celite and rinsed with ethyl acetate. The filtrate was evaporated
under reduced pressure
and the crude product was dissolved in ethyl acetate. The organic layer was
washed with water
(2 x 5 mL) and brine (2 x 5 mL). The organic layer was dried over Na2SO4,
filtered and
evaporated under reduced pressure to give (R)-2-tert-butyl-l-((2,2-dimethyl-
1,3-dioxolan-4-
yl)methyl-lH-indol-5-amine (0.89 g, 98%). 1H NMR (400 MHz, CDC13) S 7.04 (d, J
= 4 Hz,
1H), 6.70 (d, J = 2.2 Hz, 1H), 6.48 (dd, J = 2.2, 8.6 Hz, 1H), 6.05 (s, 1H),
4.38-4.1 (m, 2H), 4.21
(dd, J = 7.5, 16.5 Hz, 1H), 3.87 (dd, J = 6.0, 8.6 Hz, 1H), 3.66 (dd, J = 6.0,
8.6 Hz, 1H), 3.33 (br
s, 2H), 1.40 (s, 3H), 1.34 (s, 9H), 1.25 (s, 3H).
H
H2N / Et3N FxO
N F O
~/ FXO
thcI
K
O O
SOCI2
F O I OH
FAO / O
[00840] N-((R)-2-tert-Butyl-l-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-
indol-5-yl)-1-
(2,2-difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamide
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[00841] To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.73 g,
3.0 mmol) was
added thionyl chloride (660 L, 9.0 mmol) and DMF (20 L) at room temperature.
The mixture
was stirred for 30 minutes before the excess thionyl chloride was evaporated
under reduced
pressure. To the resulting acid chloride, dichloromethane (6.0 mL) and Et3N
(2.1 mL, 15 mmol)
were added. A solution of (R)-2-tert-butyl-l-((2,2-dimethyl-1,3-dioxolan-4-
yl)methyl-lH-indol-
5-amine (3.0 mmol) in dichloromethane (3.0 mL) was added to the cooled acid
chloride solution.
After addition, the reaction mixture was stirred at room temperature for 45
minutes. The reaction
mixture was filtered and the filtrate was evaporated under reduced pressure.
The residue was
purified by column chromatography on silica gel (ethyl acetate/hexane = 3/7)
to give N-((R)-2-
tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-indol-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (1.33 g, 84%). 1H NMR
(400 MHz,
CDC13) S 7.48 (d, J = 2 Hz, 1H,), 7.31 (dd, J = 2, 8 Hz, 1H), 7.27 (dd, J = 2,
8 Hz, 1H), 7.23 (d, J
= 8 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.02 (dd, J = 2, 8 Hz, 1H), 6.92 (br s,
1H), 6.22 (s, 1H),
4.38-4.05 (m, 3H), 3.91 (dd, J = 5, 8 Hz, 1H), 3.75 (dd, J = 5, 8 Hz, 1H),
2.33 (q, J = 8 Hz, 2H),
1.42 (s, 3H), 1.37 (s, 9H), 1.22 (s, 3H), 1.10 (q, J = 8 Hz, 2H).
H H
F~ PTSA F N
F O F ` I/ O
N
OH
O
OH
[00842] N-((R)-2-tert-Butyl-l-((2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2-
difluorobenzo-
[d] [ 1,3 ]dioxol-5-yl)cyclopropanecarboxamide
[00843] To a stirred solution of N-(2-tert-butyl-l-((2,2-dimethyl-1,3-dioxolan-
4-yl)methyl)-
1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide
(1.28 g, 2.43
mmol) in methanol (34 mL) and water (3.7 mL) was added para-toluenesulfonic
acid-hydrate
(1.87 g, 9.83 mmol). The reaction mixture was stirred and heated at 80 C for
25 minutes. The
solvent was evaporated under reduced pressure. The crude product was dissolved
in ethyl
acetate. The organic layer was washed with saturated aqueous NaHCO3 (2 x 10
mL) and brine (2
x 10 mL). The organic layer was dried over Na2SO4, filtered and evaporated
under reduced
pressure. The residue was purified by column chromatography on silica gel
(ethyl acetate/hexane
= 13/7) to give N-((R)-2-tert-butyl-l-((2,3-dihydroxypropyl)-1H-indol-5-yl)-1-
(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.96 g, 81%). 1H NMR
(400 MHz,
CDC13) S 7.50 (d, J = 2 Hz, 1H), 7.31 (dd, J = 2, 8 Hz, 1H), 7.27 (dd, J = 2,
8 Hz, 1H), 7.23 (d, J
= 8 Hz, 1H), 7.14 (d, J = 8 Hz, 1H), 7.02 (br s, 1H,), 6.96 (dd, J = 2, 8 Hz,
1H), 6.23 (s, 1H),
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4.35 (dd, J = 8, 15 Hz, 1H), 4.26 (dd, J = 4, 15 Hz, 1H,), 4.02-3.95 (m, 1H),
3.60 (dd, J = 4, 11
Hz, 1H), 3.50 (dd, J = 5, 11 Hz, 1H), 1.75 (q, J = 8 Hz, 3H), 1.43 (s, 9H),
1.14 (q, J = 8 Hz, 3H).
[00844] Example 73: 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-hydroxypropanoic acid
AcO OAc
SIT OAc
H H
F ~~ N /~ 0 F~% N ~~
F 0 / O \ N F O / O N
DMSO, RT
I-C OH ~OOH
OH O H
NaBH4 F` O N
O R T F O I/ O I N
OH
-OH
AcO OAc
~I~ OAc
O H
H
N O F\//~O N /
F~0 O \ I N F O O I N
DMSO,RT
I-COH O
OH O OH
[00845] 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarbox-
amido)-1H-indol-1-yl)-2-oxopropanoic acid
[00846] To a solution of N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-
yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (97 mg, 0.20 mmol)
in DMSO
(1 mL) was added Dess-Martin periodinane (130 mg, 0.30 mmol). The mixture was
stirred at
room temperature for 3 h. The solid was filtered off and washed with EtOAc.
The filtrate
was partitioned between EtOAc and water. The aqueous layer was extracted with
EtOAc
twice and the combined organic layers were washed with brine and dried over
MgSO4. After
the removal of solvent, the residue was purified by preparative TLC to yield 3-
(2-tert-butyl-
5-(1-(2,2-difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-
l-yl)-2-
oxopropanoic acid that was used without further purification.
N H
F 3I/ 0 \I N NaB FX I~ /I
McOH, RT F0 / O N~
O
OH
O OH
O OH
237
CA 02742980 2011-05-06
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[00847] 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarbox-
amido)-1H-indol-1-yl)-2-hydroxypropanoic acid
[00848] To a solution of 3-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-
5-
yl)cyclopropanecarboxamido)- 1H-indol-1-yl)-2-oxopropanoic acid (50 mg, 0.10
mmol) in
MeOH (1 mL) was added NaBH4 (19 mg, 0.50 mmol) at 0 C. The mixture was
stirred at
room temperature for 15 min. The resulting mixture was partitioned between
EtOAc and
water. The aqueous layer was extracted with EtOAc twice and the combined
organic layers
were washed with brine and dried over anhydrous MgSO4. After the removal of
the solvent,
the residue was taken up in DMSO and purified by preparative LC/MS to give 3-
(2-tert-
butyl-5-(1-(2,2-difluorobenzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-
1H-indol-1-yl)-
2-hydroxypropanoic acid. 1H NMR (400 MHz, CDC13) S 7.36 (s), 7.27-7.23 (m,
2H), 7.15-
7.11 (m, 2H), 6.94 (d, J = 8.5 Hz, 1H), 6.23 (s, 1H), 4.71 (s, 3H), 4.59 (q, J
= 10.3 Hz, 1H),
4.40-4.33 (m, 2H), 1.70 (d, J = 1.9 Hz, 2H), 1.15 (q, J = 4.0 Hz, 2H). 13C NMR
(400 MHz,
CDC13) 8 173.6, 173.1, 150.7, 144.1, 143.6, 136.2, 135.4, 134.3, 131.7, 129.2,
129.0, 127.6,
126.7, 116.6, 114.2, 112.4, 110.4, 110.1, 99.7, 70.3, 48.5, 32.6, 30.9, 30.7,
16.8. MS (ESI)
m/e (M+H+) 501.2.
[00849] Example 74: (R)-N-(2-tert-Butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-yl)-
1-
(2,2-dideuteriumbenzo [d] [ 1,3 ]dioxol-5-yl) cyclopropanecarboxamide
HO :]j OH MeOH ` HO :]j 0,, CD2Br2 D O I \ O NaOH
HO 0 p-Ts0H HO 0
Cs2CO3, DMF, 120 C D O O THE-H
HZN
\ I N
O H
0 OH K D N
O P-Ts
D HATU, NEt3, DMF, RT Me0H-H20, 80 C
O/K
I-C
O
H
D` O I \ N 1 \N
D O OJ7N~
OH
OH
Hp \ O~
HO\ OH MeOH
HO 0 p-TsOH HO 0
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[00850] Methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate
[00851] To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid
(190 mg, 1.0
mmol) in MeOH (3 mL) was added 4-methylbenzenesulfonic acid (19 mg, 0.10
mmol). The
mixture was heated at 80 C overnight. The reaction mixture was concentrated in
vacuo and
partitioned between EtOAc and water. The aqueous layer was extracted with
EtOAc twice
and the combined organic layers were washed with sat. NaHCO3 and brine and
dried over
MgSO4. After the removal of solvent, the residue was dried in vacuo to yield
methyl 1-(3,4-
dihydroxyphenyl)cyclopropanecarboxylate (190 mg, 91%) that was used without
further
purification. 1H NMR (400 MHz, DMSO-d6) 8 6.76-6.71 (m, 2H), 6.66 (d, J = 7.9
Hz, 1H),
3.56 (s, 3H), 1.50 (q, J = 3.6 Hz, 2H), 1.08 (q, J = 3.6 Hz, 2H).
HO O\ CD2Br2 D O \ O\
HO I O Cs2CO3, DMF, 120 C D O I O
[00852] Methyl 1-(2,2-dideuteriumbenzo[d] [1,3]dioxol-5-
yl)cyclopropanecarboxylate
[00853] To a solution of methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate
(21 mg,
0.10 mmol) and CD2Br2 (35 mg, 0.20 mmol) in DMF (0.5 mL) was added Cs2CO3 (19
mg,
0.10 mmol). The mixture was heated at 120 C for 30 min. The reaction mixture
was
partitioned between EtOAc and water. The aqueous layer was extracted with
EtOAc twice
and the combined organic layers were washed with IN NaOH and brine before
being dried
over MgSO4. After the removal of solvent, the residue was dried in vacuo to
yield methyl 1-
(2,2-dideuteriumbenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylate (22 mg) that
was used
without further purification. 1H NMR (400 MHz, CDC13) 8 6.76-6.71 (m, 2H),
6.66 (d, J =
7.9 Hz, 1H), 3.56 (s, 3H), 1.50 (q, J = 3.6 Hz, 2H), 1.08 (q, J = 3.6 Hz, 2H).
D O I O NaOH D O I\ OH
all&~; O THE-H2O 80 C D O O
D O
[00854] 1-(2,2-Dideuteriumbenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid
[00855] To a solution of methyl 1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylate (22 mg, 0.10 mmol) in THE (0.5 mL) was added NaOH
(1N,
0.25 mL, 0.25 mmol). The mixture was heated at 80 C for 2 h. The reaction
mixture was
partitioned between EtOAc and IN NaOH. The aqueous layer was extracted with
EtOAc
twice, neutralized with IN HCl and extracted with EtOAc twice. The combined
organic
layers were washed with brine and dried over MgSO4. After the removal of
solvent, the
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residue was dried in vacuo to yield 1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylic acid (21 mg) that was used without further
purification.
HZN
~ I N
O\ H
D` IOH D O I~ N / DO p 0 / O N
HATU, NEt3, DMF, RT
O~
O
[00856] (R)-N-(2-tert-Butyl-l-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-
indol-5-yl)-
1-(2,2-dideuteriumbenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
[00857] To a solution of 1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylic acid (21 mg, 0.10 mmol), (R)-2-tert-butyl-l-((2,2-
dimethyl-1,3-
dioxolan-4-yl)methyl)-1H-indol-5-amine (30 mg, 0.10 mmol), HATU (42 mg, 0.11
mol) in
DMF (1 mL) was added triethylamine (0.030 mL, 0.22 mmol). The mixture was
heated at
room temperature for 5 min. The reaction mixture was partitioned between EtOAc
and water.
The aqueous layer was extracted with EtOAc twice and the combined organic
layers were
washed with IN NaOH, IN HCl, and brine before being dried over MgSO4. After
the
removal of solvent, the residue was purified by column chromatography (20-40%
ethyl
acetate/hexane) to yield (R)-N-(2-tert-butyl-l-((2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)-1H-
indol-5-yl)-1-(2,2-dideuteriumbenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide
(24 mg,
49% from methyl 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylate). MS (ESI) m/e
(M+H+)
493.5.
H H
N N
Dx O P-TsOH D~
D 0, INl MeO D O D11fo 10::~N~
YO 'X\ / 1-C OH
OH
[00858] (R)-N-(2-tert-Butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,2-
dideuterium-benzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamide
[00859] To a solution of (R)-N-(2-tert-butyl-l-((2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)-
1H-indol-5-yl)-1-(2,2-dideuterium-benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamide (24
mg, 0.050 mmol), in methanol (0.5 mL) and water (0.05 mL) was added 4-
methylbenzenesulfonic acid (2.0 mg, 0.010 mmol). The mixture was heated at 80
C for 30
min. The reaction mixture was partitioned between EtOAc and water. The aqueous
layer was
extracted with EtOAc twice and the combined organic layers were washed with
sat. NaHCO3
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CA 02742980 2011-05-06
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and brine before being dried over MgSO4. After the removal of solvent, the
residue was
purified by preparative HPLC to yield (R)-N-(2-tert-butyl-1-((2,2-dimethyl-1,3-
dioxolan-4-
yl)methyl)-1H-indol-5-yl)-1-(2,2-dideuteriumbenzo [d] [ 1,3]dioxol-5-
yl)cyclopropanecarboxamide (12 mg, 52%). 1H NMR (400 MHz, CDC13) 8 7.44 (d, J
= 2.0
Hz, 1H), 7.14 (dd, J = 22.8, 14.0 Hz, 2H), 6.95-6.89 (m, 2H), 6.78 (d, J = 7.8
Hz, 1H), 6.14
(s, 1H), 4.28 (dd, J = 15.1, 8.3 Hz, 1H), 4.19 (dd, J = 15.1, 4.5 Hz, 1H),
4.05 (q, J = 7.1 Hz,
1H), 3.55 (dd, J = 11.3, 4.0 Hz, 1H), 3.45 (dd, J = 11.3, 5.4 Hz, 1H), 1.60
(q, J = 3.5 Hz, 2H),
1.35 (s, 9H), 1.02 (q, J = 3.5 Hz, 2H). 13C NMR (400 MHz, CDC13) 8 171.4,
149.3, 147.1,
146.5, 134.8, 132.3, 129.2, 126.5, 123.6, 114.3, 111.4, 110.4, 109.0, 107.8,
98.5, 70.4, 63.1,
46.6, 31.6, 30.0, 29.8, 15.3. MS (ESI) m/e (M+H+) 453.5.
[00860] It is further noted that the mono-deuterated analogue for this
compound can be
synthesized by substitution the reagent CHDBR2 for CD2BR2 and following the
procedures
described in example 74. Furthermore, mono-deuterated analogues of other
compounds of
the present invention can be synthesized by substituting the reagent CHDBR2
for CD2BR2
and following the steps described herein.
[00861] Example 75: 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-
1H-
indol-2-yl)-4-methylpentanoic acid
H
\
l OH i) SOCI2,DMF // NI /
\ O ii) HzN \ CN
O
CN H
\ \ I N
/ N
H
H
KOH / I \ N I \
/ O / N
H OH
\7 H
O~ V SOH i) SOCIZ,DMF ~ V V N
ii) / IOI HZN o/ o / N CN
CN H
N
H
[00862] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-
indol-5-
yl)cyclopropanecarboxamide
[00863] To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.068 g,
0.33 mmol)
was added thionyl chloride (72 L, 0.99 mmol) and DMF (20 L) at room
temperature. The
mixture was stirred for 30 minutes before the excess thionyl chloride was
evaporated under
reduced pressure. To the resulting acid chloride, dichloromethane (0.5 mL) and
Et3N (230
241
CA 02742980 2011-05-06
WO 2010/054138 PCT/US2009/063475
L, 1.7 mmol) were added. A solution of 4-(5 -amino- IH-indol-2-yl)-4-
methylpentanenitrile
(0.33 mmol) in dichloromethane (0.5 mL) was added to the acid chloride
solution and the
mixture was stirred at room temperature for 1.5 h. The resulting mixture was
diluted with
dichloromethane and washed with 1 N HCl (2 x 2 mL), saturated aqueous NaHCO3
(2 x 2
mL) and brine (2 x 2 mL). The organic layer was dried over anhydrous Na2SO4
and
evaporated under reduced pressure to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-
cyano-2-
methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide.
N
O N \ KOH lO \ \
C
O I O I/ N CN O O I/ N
H H OH
O
[00864] 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-
yl)-4-
methylpentanoic acid
[00865] A mixture of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-
2-yl)-1H-
indol-5-yl)cyclopropanecarboxamide (0.060 g, 0.15 mmol) and KOH (0.081 g, 1.5
mmol) in
50% EtOH/water (2 mL) was heated in the microwave at 100 C for 1 h. The
solvent was
evaporated under reduced pressure. The crude product was dissolved in DMSO (1
mL),
filtered, and purified by reverse phase preparative HPLC to give 4-(5-(1-
(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-4-
methylpentanoic
acid. 1H NMR (400 MHz, DMSO-d6) 8 11.98 (s, 1H), 10.79 (s, 1H), 8.44 (s, 1H),
7.56 (s,
1H), 7.15 (d, J = 8.6 Hz, 1H), 7.03-6.90 (m, 4H), 6.05 (s, 1H), 6.02 (s, 2H),
1.97-1.87 (m,
4H), 1.41-1.38 (m, 2H), 1.30 (s, 6H), 1.04-1.02 (m, 2H).
[00866] Example 76: 1-(Benzo[d] [1,3]dioxol-5-yl)-N-(2-(1-hydroxypropan-2-yl)-
1H-
indol-5-yl)cyclopropanecarboxamide
02N \ \ LiAIH4 0,N, NN SnC'2.2H20
/ H C02Et H OH
H2N \
/ O HBTU, Et3N \ \ \
H COH \ / OH 0 N OH
H
O2N \ LiAIH4 O2N I \ \
H C02Et / H OH
[00867] 2-(5-Nitro-lH-indol-2-yl)propan-l-ol
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CA 02742980 2011-05-06
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[00868] To a cooled solution of LiAlH4 (1.0 M in THF, 1.2 mL, 1.2 mmol) in THE
(5.3
mL) at 0 C was added a solution of ethyl 2-(5-nitro-lH-indol-2-yl)propanoate
(0.20 g, 0.76
mmol) in THE (3.66 mL) dropwise. After addition, the mixture was allowed to
warm up to
room temperature and was stirred at room temperature for 3 h. The mixture was
cooled to 0
T. Water (2 mL) was slowly added followed by careful addition of 15% NaOH (2
mL) and
water (4 mL). The mixture was stirred at room temperature for 0.5 h and was
then filtered
through a short plug of celite using ethyl acetate. The organic layer was
separated from the
aqueous layer, dried over Na2SO4, filtered and evaporated under reduced
pressure. The
residue was purified by column chromatography on silica gel (ethyl
acetate/hexane = 1/1) to
give 2-(5-nitro-lH-indol-2-yl)propan-l-ol (0.14 g, 81%).
02N N SnC12.2H20 H2N N
H OH H OH
[00869] 2-(5-Amino-lH-indol-2-yl)propan-l-ol
[00870] To a solution of 2-(5-nitro-lH-indol-2-yl)propan-l-ol (0.13 g, 0.60
mmol) in
ethanol (5 mL) was added tin chloride dihydrate (0.67 g, 3.0 mmol). The
mixture was heated
in the microwave at 120 C for 1 h. The mixture was diluted with ethyl acetate
before water
and saturated aqueous NaHCO3 were added. The reaction mixture was filtered
through a
plug of celite using ethyl acetate. The organic layer was separated from the
aqueous layer,
dried over Na2SO4, filtered and evaporated under reduced pressure to give 2-(5-
amino-lH-
indol-2-yl)propan-l-ol (0.093 g, 82%).
HZN H
C + HBTU, Et3N_ ~ N
ji D-- ~
H H O OH O1OC-KOH
H
[00871] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxypropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
[00872] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic
acid (0.10 g,
0.49 mmol) in acetonitrile (2.0 mL) were added HBTU (0.185 g, 0.49 mmol) and
Et3N (205
L, 1.47 mmol) at room temperature. The mixture was allowed to stir at room
temperature
for 10 minutes before a slurry of 2-(5-amino-lH-indol-2-yl)propan-l-ol (0.093
g, 0.49 mmol)
in acetonitrile (2.7 mL) was added. After addition, the reaction mixture was
stirred at room
temperature for 5.5 h. The solvent was evaporated under reduced pressure and
the residue
was dissolved in dichloromethane. The organic layer was washed with 1 N HCl (1
x 3 mL)
and saturated aqueous NaHCO3 (1 x 3 mL). The organic layer was dried over
Na2SO4,
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filtered and evaporated under reduced pressure. The crude material was
purified by column
chromatography on silica gel (ethyl acetate/hexane = 13/7) to give 1-
(benzo[d][1,3]dioxol-5-
yl)-N-(2-(1-hydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.095
g, 51%).
1H NMR (400 MHz, DMSO-d6) 8 10.74 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.14
(d, J = 8.6
Hz, 1H), 7.02-6.90 (m, 4H), 6.06 (s, 1H), , 6.02 (s, 2H), 4.76 (t, J = 5.3 Hz,
1H), 3.68-3.63
(m, 1H), 3.50-3.44 (m, 1H), 2.99-2.90 (m, 1H), 1.41-1.38 (m, 2H), 1.26 (d, J =
7.0 Hz, 3H),
1.05-1.02 (m, 2H).
[00873] Example 77: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-lH-indol-5-
yl)-N-
methylcyclopropanecarboxamide
I HATU
HN Et3N lO \
O OOH + I/ N O I/ O N I/ N
H H
[00874] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-lH-indol-5-yl)-N-
methylcyclopropanecarboxamide
[00875] 2-tert-Butyl-N-methyl-1H-indol-5-amine (20.2 mg, 0.100 mmol) and 1-
(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (20.6 mg, 0.100 mmol)
were
dissolved in NN-dimethylformamide (1 mL) containing triethylamine (42.1 L,
0.300 mmol)
and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N;N'-
tetramethyluronium
hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the
resulting solution
was allowed to stir for 16 h at 80 C. The crude product was then purified by
preparative
HPLC utilizing a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic
acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-yl)-N-
methylcyclopropanecarboxamide. ESI-MS m/z calc. 390.2, found 391.3 (M+1)+.
Retention
time of 3.41 minutes.
[00876] Example 78: N-(2-tert-Butyl-l-methyl-lH-indol-5-yl)-1-
(benzo[d][1,3]dioxol-
6-yl)-N-methylcyclopropanecarboxamide
N / I THF/DMF
-
\ N 1) NaH N
/ O H 2) CH31 O O
O O
[00877] Sodium hydride (0.028 g, 0.70 mmol, 60% by weight dispersion in oil)
was slowly
added to a stirred solution of N-(2-tert-butyl-1H-indol-5-yl)-1-
(benzo[d][1,3]dioxol-6-
yl)cyclopropanecarboxamide (0.250 g, 0.664 mmol) in a mixture of 4.5 mL of
anhydrous
tetrahydrofuran (THF) and 0.5 mL of anhydrous NN-dimethylformamide (DMF). The
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resulting suspension was allowed to stir for 2 minutes and then iodomethane
(0.062 mL, 1.0
mmol) was added to the reaction mixture. Two additional aliquots of sodium
hydride and
iodomethane were required to consume all of the starting material which was
monitored by
LC / MS. The crude reaction product was evaporated to dryness, redissolved in
a minimum
of DMF and purified by preparative LC / MS chromatography to yield the pure
product
(0.0343 g, 13%) ESI-MS m/z calc. 404.2, found 405.3 (M+1)+. Retention time of
3.65
minutes.
[00878] Example 79: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(hydroxymethyl)-1H-indol-
5-
yl)cyclopropanecarboxamide
H H
O/ I O I\ O LiBH4, THE/H2O / I 0 I\
O N OEt 25 C, 16 hrs O \ N OH
H H
[00879] Ethyl5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-
2-
carboxylate (1.18 g, 3.0 mmol) was added to a solution of LiBH4 (132 mg, 6.0
mmol) in THE
(10 mL) and water (0.1 mL). The mixture was allowed to stir for 16h at 25 C
before it was
quenched with water (10 mL) and slowly made acidic by addition of 1 N HCl. The
mixture
was extracted with three 50-mL portions of ethyl acetate. The organic extracts
were dried
over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-
(hydroxymethyl)-
1H-indol-5-yl)cyclopropanecarboxamide (770 mg, 73%). A small amount was
further
purified by reverse phase HPLC. ESI-MS m/z calc. 350.4, found 351.3 (M+1)+;
retention time
2.59 minutes.
[00880] Example 80: 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N-
tert-butyl- lH-indole-2-carboxamide
H H H2Nr N UGH N 0 0 H
0
N OEt H20/ 1,4-dioxane KN OH HATU, Et3N, DMF< N ( / HN~
H H H
H H
0 i \ O UGH O O
O N / OEt H20/ 1,4-dioxane O N OH
H H
[00881] 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-
carboxylic acid
[00882] Ethyl5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-
2-
carboxylate (392 mg, 1.0 mmol) and LiOH (126 mg, 3 mmol) were dissolved in H2O
(5 mL)
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and 1,4-dioxane (3 mL). The mixture was heated in an oil bath at 100 C for 24
hours before
it was cooled to room temperature. The mixture was acidified with IN HCl and
it was
extracted with three 20 mL portions of dichloromethane. The organic extracts
were dried
over Na2SO4 and evaporated to yield 5-(1-(benzo[d][1,3]-dioxol-5-
yl)cyclopropanecarboxamido)-1H-indole-2-carboxylic acid (302 mg, 83%). A small
amount
was further purified by reverse phase HPLC. ESI-MS m/z calc. 364.1, found
365.1 (M+1)+;
retention time 2.70 minutes.
H2N O/ I O I\ N O IT\ /O / I O I\ N O
N / / OH HATU, Et3N, DMF N / / N~
H H
[00883] 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N-tert-butyl-
lH-
indole-2-carboxamide
[00884] 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-1H-indole-2-
carboxylic acid (36 mg, 0.10 mmol) and 2-methylpropan-2-amine (8.8 mg, 0.12
mmol) were
dissolved in NN-dimethylformamide (1.0 mL) containing triethylamine (28 L,
0.20 mmol).
O-(7-Azabenzotriazol-1-yl)-NNN;N'-tetramethyluronium hexafluorophosphate (46
mg, 0.12
mmol) was added to the mixture and the resulting solution was allowed to stir
for 3 hours.
The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-
(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-N-tert-butyl-lH-indole-2-
carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)+; retention time 3.12
minutes.
[00885] Example 81: N-(3-Amino-2-tert-butyl-lH-indol-5-yl)-1-
(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamide
H H
O/ O \ N NaNOZ O
AcOWHZO O N
H H NO
H
Zn \ I O I ~ ~
AcOH O N
H NFiZ
[00886] A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-
yl)cyclopropane carboxamide (50 mg, 0.13 mmol) was dissolved in AcOH (2 mL)
and
warmed to 45 C. To the mixture was added a solution of NaNO2 (9 mg) in H2O
(0.03 mL).
The mixture was allowed to stir for 30 min at 45 C before the precipitate was
collected and
washed with Et20. This material was used in the next step without further
purification. To
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the crude material, 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-nitroso-lH-
indol-5-
yl)cyclopropanecarboxamide, was added AcOH (2 mL) and Zn dust (5 mg). The
mixture
was allowed to stir for lh at ambient temperature. EtOAc and H2O were added to
the
mixture. The layers were separated and the organic layer was washed with sat.
aq. NaHCO3,
dried over MgSO4, and concentrated in vacuo. The residue was taken up in DMF
(1 mL) and
was purified using prep-HPLC. LCMS: m/z 392.3; retention time of 2.18 min.
[00887] Example 82: 1-(Benzo[d] [1,3]dioxol-5-yl)-N-(2-tert-butyl-3-
(methylsulfonyl)-
1H-indol-5-yl)cyclopropanecarboxamide
H 1)NaH H SO2Me
7 N
co"YO DMF-THF I I\
H 2) McSOzCI ` \ O / N
H
[00888] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(methylsulfonyl)-1H-
indol-5-
yl)cyclopropanecarboxamide
[00889] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-lH-indol-
5-
yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL,
1:9)
was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After
30 min
under N2, the suspension was cooled down to -15 C and a solution of
methanesulfonyl
chloride (1.1 eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture
was stirred for
30 min at -15 C then for 6 h at room temperature. Water (0.5 mL) was added at
0 C, solvent
was removed, and the residue was diluted with MeOH, filtrated and purified by
preparative
HPLC to give 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(methylsulfonyl)-
1H-indol-5-
yl)cyclopropanecarboxamide. 1H NMR (400 MHz, DMSO) 8 11.6 (s, 1H), 8.7 (s,
1H), 7.94
(d, J =1.7 Hz, 1H), 7.38 (d, J =8.7 Hz, 1H), 7.33 (dd, JI =1.9 Hz, J2 =8.7 Hz,
1H), 7.03 (d, J
=1.7 Hz, 1H), 6.95 (dd, JI =1.7 Hz, J2 =8.0 Hz, 1H), 6.90 (d, J =8.0 Hz, 1H),
6.02 (s, 2H),
3.07 (s, 3H), 1.56-1.40 (m, 9H), 1.41 (dd, JI =4.0 Hz, J2 =6.7 Hz, 2H), 1.03
(dd, JI =4.0 Hz,
J2 =6.7 Hz, 2H). MS (ESI) m/e (M+H+) 455.5.
[00890] Example 83: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-phenyl-lH-indol-5-
yl)cyclopropane carboxamide
OH
HOB
I, H
\ N \ NBS N Br \ N
I
p l i O I/ H O O I H FibreCat 1001 O / O H
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O N NBS <p I N Br
Nz~ O N p O
H H
[00891] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-lH-indol-5-
yl)cyclopropanecarboxamide
[00892] Freshly recrystallized N-bromosuccinimde (0.278 g, 1.56 mmol) was
added
portionwise to a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(1H-indol-5-
yl)cyclopropanecarboxamide (0.500 g, 1.56 mmol) in N,N-dimethylformamide (2
mL) over 2
minutes. The reaction mixture was protected from light and was stirred bar for
5 minutes.
The resulting green solution was poured into 40 mL of water. The grey
precipitate which
formed was filtered and washed with water to yield 1-(benzo[d][1,3]dioxol-5-
yl)-N-(3-
bromo-lH-indol-5-yl)cyclopropanecarboxamide (0.564 g, 91%). ESI-MS m/z calc.
398.0,
found 399.3 (M+1)+. Retention time of 3.38 minutes. 1H NMR (400 MHz, DMSO-d6)
11.37 (s, 1H), 8.71 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 2.6 Hz,
1H), 7.29 (d, J = 8.8
Hz, 1H), 7.22 (dd, J = 2.0, 8.8 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.96 - 6.88
(m, 2H), 6.03 (s,
2H), 1.43 - 1.40 (m, 2H), 1.09 - 1.04 (m, 2H).
OH
HOB
H
H Br N
O i O I H FibreCat 1001 O O H
[00893] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-phenyl-lH-indol-5-
yl)cyclopropanecarboxamide
[00894] Phenyl boronic acid (24.6 mg, 0.204 mmol) was added to a solution of 1-
(benzo[d][1,3]-dioxol-5-yl)-N-(3-bromo-1H-indol-5-yl)cyclopropanecarboxamide
(39.9 mg,
0.100 mmol) in ethanol (1 mL) containing FibreCat 1001 (6 mg) and 1M aqueous
potassium
carbonate (0.260 mL). The reaction mixture was then heated at 130 C in a
microwave
reactor for 20 minutes. The crude product was then purified by preparative
HPLC utilizing a
gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid
to yield 1-
(benzo[ d][ 1,3]dioxol-5-yl)-N-(3-phenyl-lH-indol-5-yl)cyclopropane
carboxamide. ESI-MS
m/z calc. 396.2, found 397.3 (M+1)+. Retention time of 3.52 minutes. 1H NMR
(400 MHz,
DMSO-d6) S 11.27 (d, J = 1.9 Hz, 1H), 8.66 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H),
7.65-7.61 (m,
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3H), 7.46-7.40 (m, 2H), 7.31 (d, J = 8.7 Hz, 1H), 7.25-7.17 (m, 2H), 7.03 (d,
J = 1.6 Hz, 1H),
6.98-6.87 (m, 2H), 6.02 (s, 2H), 1.43-1.39 (m, 2H), 1.06-1.02 (m, 2H).
[00895] Example 84: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-cyano-lH-
indol-5-
yl)cyclopropanecarboxamide
H
O O POCI3, DMF < O I
H2N-OH, DCM
O H
4
H H
O
H H
O I\ O / I C N AcZO O I\ O / I N
O H O H \ /
HO -N N
H
O POC13, DMF O \ O N
H H H
O
[00896] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-lH-indol-5-
yl)cyclopropane-carboxamide
[00897] POC13 (12 g, 80 mmol) was added dropwise to DMF (40 mL) held at -20
C.
After the addition was complete, the reaction mixture was allowed to warm to 0
C and was
stirred for 1 h. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-
yl)cyclopropanecarboxamide (3.0 g, 8.0 mmol) was added and the mixture was
warmed to 25
C. After stirring for 30 minutes the reaction mixture was poured over ice and
stirred for 2 h.
The mixture was then heated at 100 C for 30 min. The mixture was cooled and
the solid
precipitate was collected and washed with water. The solid was then dissolved
in 200 mL
dichloromethane and washed with 200 mL of a saturated aq. NaHCO3. The organics
were
dried over Na2SO4 and evaporated to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-
tert-butyl-3-
formyl-lH-indol-5-yl)cyclopropane-carboxamide (2.0 g, 61%). ESI-MS m/z calc.
404.5,
found 405.5 (M+1)+; retention time 3.30 minutes. 'H NMR (400 MHz, DMSO-d6) 8
11.48
(s, 1H), 10.39 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 7.35-7.31 (m, 2H), 7.04-
7.03 (m, 1H), 6.97-
6.90 (m, 2H), 6.03 (s, 2H), 1.53 (s, 9H), 1.42-1.39 (m, 2H), 1.05-1.03 (m,
2H).
H H
OJ I N HZN-OH, DCM I\ O I N
~\ \ O~N \
H H H
O HO -N
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[00898] (Z)-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-
((hydroxyimino)methyl)-1H-
indol-5-yl)cyclopropanecarboxamide
[00899] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-formyl-
1H-indol-5-
yl)cyclopropanecarboxamide (100 mg, 0.25 mmol) in dichloromethane (5 mL) was
added
hydroxylamine hydrochloride (21 mg, 0.30 mmol). After stirring for 48 h, the
mixture was
evaporated to dryness and purified by column chromatography (0-100% ethyl
acetate/hexanes) to yield (Z)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-
((hydroxyimino)methyl)-1H-indol-5-yl)cyclopropanecarboxamide (81 mg, 77%). ESI-
MS
m/z calc. 419.5, found 420.5 (M+1)+; retention time 3.42 minutes. 1H NMR (400
MHz,
DMSO-d6) 8 10.86 (s, 0.5H), 10.55 (s, 0.5H), 8.56-8.50 (m, 2H), 8.02 (m, 1H),
7.24-7.22
(m, 1H), 7.12-7.10 (m, 1H), 7.03 (m, 1H), 6.96-6.90 (m, 2H), 6.03 (s, 2H),
1.43 (s, 9H), 1.40-
1.38 (m, 2H), 1.04-1.01 (m, 2H).
H H
O N Ac2O N O / N
H HO
_N H -N
N
[00900] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-cyano-lH-indol-5-
yl)cyclopropane-carboxamide
[00901] (Z)-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)-
methyl)-1H-
indol-5-yl)cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic
anhydride
(1 mL) and heated at reflux for 3 h. The mixture was cooled in an ice bath and
the precipitate
was collected and washed with water. The solid was further dried under high
vacuum to
yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-cyano-1H-indol-5-
yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.5, found 402.5 (M+1)+;
retention time
3.70 minutes. 1H NMR (400 MHz, DMSO-d6) 8 11.72 (s, 1H), 8.79 (s, 1H), 7.79
(s, 1H),
7.32 (m, 2H), 7.03-7.02 (m, 1H), 6.95-6.89 (m, 2H), 6.03 (s, 2H), 1.47 (s,
9H), 1.43-1.41 (m,
2H), 1.06-1.04 (m, 2H).
[00902] Example 85: 1-(Benzo[d] [1,3]dioxol-5-yl)-N-(2-tert-butyl-3-methyl-lH-
indol-5-
yl)cyclopropanecarboxamide
H H
O I O / N Mel, DMF I O / I N
O N O / N
H H
[00903] A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-
yl)cyclopropanecarboxamide (75 mg, 0.20 mmol) and iodomethane (125 L, 2.0
mmol) in
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N,N-dimethylformamide (1 mL) was heated at 120 C in a sealed tube for 24 h.
The reaction
was filtered and purified by reverse phase HPLC. ESI-MS m/z calc. 390.5, found
391.3
(M+1)+; retention time 2.04 minutes. 'H NMR (400 MHz, DMSO-d6) 8 10.30 (s,
1H), 8.39
(s, 1H), 7.51 (m, 1H), 7.13-7.11 (m, 1H), 7.03-6.90 (m, 4H), 6.03 (s, 2H),
2.25 (s, 3H), 1.40-
1.38 (m, 11H), 1.03-1.01 (m, 2H).
[00904] Example 86: 1-(Benzo[d] [1,3]dioxol-5-yl)-N-(2-tert-butyl-3-(2-
hydroxyethyl)-
1H-indol-5-yl)cyclopropanecarboxamide
H O H
\ O / N U <O N
p I N InCl3, DCM p I/ N
H H
OH
[00905] Approximately 100 L of ethylene dioxide was condensed in a reaction
tube at -78
C. A solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-5-
yl)cyclopropanecarboxamide (200 mg, 0.50 mmol) and indium trichloride (20 mg,
0.10
mmol) in dichloromethane (2 mL) was added and the reaction mixture was
irradiated in the
microwave for 20 min at 100 C. The volatiles were removed and the residue was
purified by
column chromatography (0-100 % ethyl acetate/hexanes) to give 1-
(benzo[d][1,3]dioxol-5-
yl)-N-(2-tert-butyl-3-(2-hydroxyethyl)-1H-indol-5-yl)cyclopropanecarboxamide
(5 mg, 3%).
ESI-MS m/z calc. 420.5, found 421.3 (M+1)+; retention time 1.67 minutes. 'H
NMR (400
MHz, CD3CN) S 8.78 (s, 1H), 7.40 (m, 1H), 7.33 (s, 1H), 7.08 (m, 1H), 6.95 -
6.87 (m, 3H),
6.79 (m, 1H), 5.91 (s, 2H), 3.51 (dd, J = 5.9, 7.8 Hz, 2H), 2.92 - 2.88 (m,
2H), 2.64 (t, J = 5.8
Hz, 1H), 1.50 (m, 2H), 1.41 (s, 9H), 1.06 (m, 2H).
[00906] Example 87: 2-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-
1H-
indol-2-yl)acetic acid
H UGH. HZO H
O \ N \ TH F/HZO \O \ N \
"
O I O I H COZEt O O H COZH
[00907] To a solution of ethyl 2-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-1H-indol-2-yl)acetate (0.010 g, 0.025 mmol) in THE
(0.3 mL)
were added LiOH.H20 (0.002 g, 0.05 mmol) and water (0.15 mL) were added. The
mixture
was stirred at room temperature for 2 h. dichloromethane (3 mL) was added to
the reaction
mixture and the organic layer was washed with 1 N HCl (2 x 1.5 mL) and water
(2 x 1.5 mL).
The organic layer was dried over Na2SO4 and filtered. The filtrate was
evaporated under
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reduced pressure to give 2-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-1H-
indol-2-yl)-acetic acid. 1H NMR (400 MHz, DMSO-d6) 8 12.53 (s, 1H), 10.90 (s,
1H), 8.42
(s, 1H), 7.57 (s, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.05-6.90 (m, 4H), 6.17 (s,
1H), 6.02 (s, 2H),
3.69 (s, 2H), 1.41-1.39 (m, 2H), 1.04-1.02 (m, 2H).
[00908] Example 88: 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-
tert-
butyl-1H-indole-7-carboxylic acid
N UGH O N \
O I/ O I /~N O I/ O I/ N
H H
O O O OH
[00909] Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-
butyl-
1H-indole-7-carboxylate (30 mg, 0.069 mmol) was dissolved in a mixture of 1,4-
dioxane
(1.5 mL) and water (2 mL) containing a magnetic star bar and lithium hydroxide
(30 mg, 0.71
mmol). The resulting solution was stirred at 70 C for 45 minutes. The crude
product was
then acidified with 2.6 M hydrochloric acid and extracted three times with an
equivalent
volume of dichloromethane. The dichloromethane extracts were combined, dried
over
sodium sulfate, filtered, and evaporated to dryness. The residue was dissolved
in a minimum
of N,N-dimethylformamide and then purified by preparative HPLC using a
gradient of 0-
99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 5-(1-
(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-1H-indole-7-
carboxylic
acid. ESI-MS m/z calc. 434.2, found 435.5. Retention time of 1.85 minutes. 1H
NMR (400
MHz, DMSO-d6) S 13.05 (s, 1H), 9.96 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 1.9 Hz,
1H), 7.74 (d,
J = 2.0 Hz, 1H), 7.02 (d, J = 1.6 Hz, 1H), 6.96-6.88 (m, 2H), 6.22 (d, J = 2.3
Hz, 1H), 6.02 (s,
2H), 1.43 - 1.40 (m, 2H), 1.37 (s, 9H), 1.06-1.02 (m, 2H).
[00910] Example 89: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(1,3-
dihydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
O H Na(OAc)3B H Chloranil0 \ H
<O O N 01~ O I, N - <OI O I N
H
OHO OHOH OHOH
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N i Na(OAc)3BH N
T7 r D i O N O O N
H
Ox0 OH OH
[00911] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(1,3-dihydroxypropan-2-
yl)indolin-5-yl)cyclopropanecarboxamide
[00912] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-
yl)cyclopropanecarboxamide (50 mg, 0.13 mmol) was dissolved in dichloroethane
(0.20 mL)
and 2,2-dimethyl-1,3-dioxan-5-one (0.20 mL). Trifluoroacetic acid was added
(0.039 mL)
and the resulting solution was allowed to stir for 20 minutes. Sodium
triacetoxyborohydride
was added (55 mg, 0.26 mmol) and the reaction mixture was stirred for 30
minutes. The
crude reaction mixture was then evaporated to dryness, dissolved in NN-
dimethylformamide
and purified by preparative HPLC using a gradient of 0-99% acetonitrile in
water containing
0.05% trifluoroacetic acid.
H Chloranil O N \
I, O I, - eo O I~ N
O N
OH OH OH OH
[00913] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(1,3-dihydroxypropan-2-
yl)-1H-
indol-5-yl)cyclopropanecarboxamide
[00914] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(1,3-dihydroxypropan-2-
yl)indolin-
5-yl)cyclopropanecarboxamide (40.3 mg, 0.0711 mmol as the trifluoracetic acid
salt) was
dissolved in toluene (1 mL). To the resulting solution was added 2,3,5,6-
tetrachlorocyclohexa-2,5-diene-1,4-dione (35 mg, 0.14 mmol). The resulting
suspension was
heated at 100 C in an oil bath for 10 minutes. The crude product was then
evaporated to
dryness, dissolved in a 1 mL of N,N-dimethylformamide and purified by purified
by
preparative HPLC using a gradient of 0-99% acetonitrile in water containing
0.05%
trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-
(1,3-
dihydroxypropan-2-yl)- 1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc.
450.2,
found 451.5 (M+1)+. Retention time of 1.59 minutes.
[00915] Example 90: N-(7-(Aminomethyl)-2-tert-butyl-lH-indol-5-yl)-1-
(benzo [d] [ 1,3 ] -dioxol-5-yl)cyclopropanecarboxamide
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H Pd/C H
CO \ N Hz C \ N
O I/ O N O I/ O N
H H
NI NH2
[00916] N-(7-(Aminomethyl)-2-tert-butyl-lH-indol-5-yl)-1-(benzo[d][1,3]dioxol-
5-
yl)cyclopropanecarboxamide
[00917] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-cyano-1H-indol-5-
yl)cyclopropanecarboxamide (375 mg, 0.934 mmol) was dissolved in 35 mL of
ethyl acetate.
The solution was recirculated through a continuous flow hydrogenation reactor
containing
10% palladium on carbon at 100 C under 100 bar of hydrogen for 8 h. The crude
product
was then evaporated to dryness and purified on 12 g of silica gel utilizing a
gradient of 0-
100% ethyl acetate (containing 0.5% triethylamine) in hexanes to yield N-(7-
(aminomethyl)-
2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]-dioxol-5-yl)-
cyclopropanecarboxamide (121
mg, 32%). ESI-MS m/z calc. 405.2, found 406.5 (M+1)+. Retention time of 1.48
minutes.
[00918] Example 91: 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-
tert-
butyl-1H-indole-7-carboxamide
CO I ~ N I ~ \ H?02 _ O I \ N I \ \~
O / O Nj O Nj
H H
IN O NH2
[00919] 5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-butyl-
lH-
indole-7-carboxamide
[00920] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-cyano-1H-indol-5-yl)-
cyclopropanecarboxamide (45 mg, 0.11 mmol) was suspended in a mixture of
methanol (1.8
mL), 30% aqueous hydrogen peroxide (0.14 mL, 4.4 mmol) and 10% aqueous sodium
hydroxide (0.150 mL). The resulting suspension was stirred for 72 h at room
temperature.
The hydrogen peroxide was then quenched with sodium sulfite. The reaction
mixture was
diluted with 0.5 mL of NN-dimethylformamide, filtered, and purified by
preparative HPLC
using a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic acid to yield
5-(1-(benzo [d] [ 1,3] dioxol-5 -yl)cyclopropane-carboxamido)-2-tert-butyl-1H-
indole-7-
carboxamide. ESI-MS m/z calc. 419.2, found 420.3 (M+1)+. Retention time of
1.74 minutes.
[00921] Example 92: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-
(methylsulfonamido-methyl)-1H-indol-5-yl)cyclopropanecarboxamide
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CH3SO2CI H
C0 \ N Et3N ca-'Y N O I/ O N O N
H H
NHz NH
O S-
O
[00922] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-
(methylsulfonamidomethyl)-1H-
indol-5-yl)cyclopropanecarboxamide
[00923] N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-
5-
yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL)
containing triethylamine (20.6 L, 0.147 mmol) and a magnetic stir bar.
Methanesulfonyl
chloride (4.2 L, 0.054 mmol) was then added to the reaction mixture. The
reaction mixture
was allowed to stir for 12 h at room temperature. The crude product was
purified by
preparative HPLC using a gradient of 0-99% acetonitrile in water containing
0.05%
trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-7-
(methylsulfonamidomethyl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z
calc.
483.2, found 484.3 (M+1)+. Retention time of 1.84 minutes.
[00924] Example 93: N-(7-(Acetamidomethyl)-2-tert-butyl-lH-indol-5-yl)-1-
(benzo [d] [ 1,3 ] -dioxol-5-yl)cyclopropanecarboxamide
CH3000I H
( \ N E13N co--'Y N I
O I/ O IN ~ 0 O N
H H
NH2 NH
0-~-
[00925] N-(7-(Aminomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-
5-
yl)cyclopropanecarboxamide (20 mg, 0.049 mmol) was dissolved in DMF (0.5 mL)
containing triethylamine (20.6 L, 0.147 mmol) and a magnetic stir bar. Acetyl
chloride (4.2
L, 0.054 mmol) was then added to the reaction mixture. The reaction mixture
was allowed
to stir for 16 h at room temperature. The crude product was purified by
preparative HPLC
using a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic acid to yield
N-(7-(acetamidomethyl)-2-tert-butyl-1H-indol-5-yl)-1-(benzo [d] [ 1,3]dioxol-5-
yl)cyclopropanecarboxamide. ESI-MS m/z calc. 447.2, found 448.3 (M+1)+.
Retention time
of 1.76 minutes.
[00926] Example 94: N-(1-Acetyl-2-tert-butyl-lH-indol-5-yl)-1-
(benzo[d][1,3]dioxol-5-
yl)-cyclopropanecarboxamide
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'\7 H
H 1) NaH N
O/ I N I DMF-THF O/ \
N 2) AcCI O\ O I N
H
O
[00927] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-
5-
yl)cyclopropanecarboxamide (120 mg, 0.31 mmol) in anhydrous DMF-THF (3.3 mL,
1:9)
was added NaH (60% in mineral oil, 49 mg, 1.2 mmol) at room temperature. After
30 min
under N2, the suspension was cooled down to -15 C and a solution of acetyl
chloride (1.1
eq.) in DMF (0.5 mL) was added dropwise. The reaction mixture was stirred for
30 min at -
15 C then for 6 h at room temperature. Water (0.5 mL) was added at 0 C,
solvent was
removed, and the residue was diluted with MeOH, filtrated and purified by
preparative HPLC
to give N-(1-acetyl-2-tert-butyl-1H-indol-5-yl)-1-(benzo[d][1,3]dioxol-5-
yl)cyclo-
propanecarboxamide. 1H NMR (400 MHz, DMSO) 8 8.9 (s, 1H), 7.74 (d, J =2.1 Hz,
1H),
7.54 (d, J =9.0 Hz, 1H), 7.28 (dd, JI =2.1 Hz, J2 =9.0 Hz, 1H), 7.01 (d, J
=1.5 Hz, 1H), 6.93
(dd, JI =1.7 Hz, J2 =8.0 Hz, 1H), 6.89 (d, J =8.0 Hz, 1H), 6.54 (bs, 1H), 6.02
(s, 2H), 2.80 (s,
3H), 1.42-1.40 (m, 11H), 1.06-1.05 (m, 2H). MS (ESI) m/e (M+H+) 419.3.
[00928] Example 95: N-(1-(2-Acetamidoethyl)-2-tert-butyl-6-fluoro-lH-indol-5-
yl)-1-
(2,2-difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamide
H H
N
TFA, CH2C12 FXO N
F O / O F / N F / O F N
O
HNNH2
0--~
H
CH30001
N
I \
Ft3N, DMF F O / O F N
H O
HN
H H
N
F,XO TFA, CH2C12 FXO N
N / O N
F F O F O O F
HN-/~ NH2
[00929] N-(1-(2-Aminoethyl)-2-tert-butyl-6-fluoro-lH-indol-5-yl)-1-(2,2-
difluorobenzo-
[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
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[00930] To a solution of tert-butyl 2-(2-tert-butyl-5-(1-(2,2-
difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-6-fluoro-lH-indol-1-yl)ethylcarbamate (620 mg,
1.08 mmol)
in CH2C12 (8 mL) was added TFA (2 mL). The reaction was stirred at room
temperature for
1.5 h before being neutralized with solid NaHCO3. The solution was partitioned
between
H2O and CH2C12. The organic layer was dried over MgSO4, filtered and
concentrated to
yield the product as a cream colored solid (365 mg, 71%). 1H NMR (400 MHz,
DMSO-d6) S
8.38 (s, 1H), 7.87 (br s, 3H, NH3), 7.52 (s, 1H), 7.45-7.38 (m, 3H), 7.32 (dd,
J = 8.3, 1.5 Hz,
1H), 6.21 (s, 1H), 4.46 (m, 2H), 3.02 (m, 2H), 1.46 (m, 2H), 1.41 (s, 9H),
1.14 (m, 2H).
HPLC ret. time 1.66 min, 10-99 % CH3CN, 3 min run; ESI-MS 474.4 m/z (M+H+).
H H
N N
CH30001
O I/ O F N Et3N, DMF O O F I N
H
NH2 HN
[00931] N-(1-(2-Acetamidoethyl)-2-tert-butyl-6-fluoro-lH-indol-5-yl)-1-(2,2-
difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide
[00932] To a solution of N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-
yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamide (47 mg, 0.10 mmol)
and Et3N
(28 L, 0.20 mmol) in DMF (1 mL) was added acetyl chloride (7.1 L, 0.10
mmol). The
mixture was stirred at room temperature for 1 h before being filtered and
purified by reverse
phase HPLC (10 - 99 % CH3CN/ H2O) to yield N-(1-(2-acetamidoethyl)-2-tert-
butyl-6-
fluoro-lH-indol-5-yl)-1-(2,2-difluorobenzo[d] [ 1,3]dioxol-5-
yl)cyclopropanecarboxamide.
1H NMR (400 MHz, DMSO-d6) S 8.35 (s, 1H), 8.15 (t, J = 5.9 Hz, 1H), 7.53 (s,
1H), 7.43-
7.31 (m, 4H), 6.17 (s, 1H), 4.22 (m, 2H), 3.30 (m, 2H), 1.85 (s, 3H), 1.47 (m,
2H), 1.41 (s,
9H), 1.13 (m, 2H). HPLC ret. time 2.06 min, 10-99 % CH3CN, 3 min run; ESI-MS
516.4
m/z (M+H+).
[00933] Example 96: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2-hydroxy-
3-
methoxy-propyl)-1H-indol-5-yl)cyclopropenecarboxamide
1. NaH, DMF-THF
O H
N ~CI O N
O I O I ~N \ 2. MeOH O\ I O I N
H
H
O
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[00934] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-lH-indol-5-
yl)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture
composed of
anhydrous DMF (0.5 mL) and anhydrous THE (5 mL) under N2. NaH (60% in mineral
oil,
120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the
reaction
mixture was cooled to -15 C before a solution of epichlorohydrin (79 L, 1.0
mmol) in
anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for
15 min at
-15 C, then for 8 h at room temperature. MeOH (1 mL) was added and the
mixture was
heated for 10 min at 105 C in the microwave oven. The mixture was cooled,
filtered and
purified by preparative HPLC to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-
butyl-l-(2-
hydroxy-3-methoxy-propyl)-1H-indol-5-yl)cyclopropanecarboxamide. 1H NMR (400
MHz,
DMSO-d6) S 8.44 (s, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H),
7.03 (dd, J =
8.7, 1.9 Hz, 2H), 6.95 (dd, J = 8.0, 1.7 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H),
6.16 (s, 1H), 6.03 (s,
2H), 4.33 (dd, J = 15.0, 4.0 Hz, 1H), 4.19 (dd, J = 15.0, 8.1 Hz, 1H), 4.02
(ddd, J = 8.7, 4.8
Hz, 1H), 3.41-3.32 (m, 2H), 3.30 (s, 3H), 1.41 (s, 9H), 1.41-1.38 (m, 2H),
1.03 (dd, J= 6.7,
4.0 Hz, 2H). MS (ESI) m/e (M+H+) 465Ø
[00935] Example 97: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2-hydroxy-
3-
(methyl-amino)propyl)-1H-indol-5-yl)cyclopropanecarboxamide
1. NaH, DMF-THF
O H
~ ~ O N I\ \
O N O
2.McNH2 N
H
HO
HN
[00936] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-lH-indol-5-
yl)cyclopropanecarboxamide (320 mg, 0.84 mmol) was dissolved in a mixture
composed of
anhydrous DMF (0.5 mL) and anhydrous THE (5 mL) under N2. NaH (60% in mineral
oil,
120 mg, 3.0 mmol) was added at room temperature. After 30 min of stirring, the
reaction
mixture was cooled to -15 C before a solution of epichlorohydrin (79 L, 1.0
mmol) in
anhydrous DMF (1 mL) was added dropwise. The reaction mixture was stirred for
15 min at
-15 C, then for 8 h at room temperature. MeNH2 (2.0 M in MeOH, 1.0 mL) was
added and
the mixture was heated for 10 min at 105 C in the microwave oven. The mixture
was
cooled, filtered and purified by preparative HPLC to give 1-
(benzo[d][1,3]dioxol-5-yl)-N-(2-
tert-butyl- l -(2-hydroxy-3-(methylamino)propyl)-1 H-indol-5-
yl)cyclopropanecarboxamide.
1H NMR (400 MHz, DMSO-d6) 8 8.50 (s, 1H), 7.60-7.59 (m, 1H), 7.35 (dd, J =
14.3, 8.9 Hz,
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1H), 7.10 (d, J = 8.8 Hz, 1H), 1H), 6.94 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (d, J
= 7.9 Hz, 1H),
6.20 (d, J = 2.3 Hz, 1H), 6.03 (s, 2H), 2.82 (d, J = 4.7 Hz, 1H), 2.72 (d, J =
4.7 Hz, 1H), 2.55
(dd, J = 5.2, 5.2 Hz, 1H), 2.50 (s, 3H), 1.43 (s, 9H), 1.39 (dd, J = 6.4, 3.7
Hz, 2H), 1.04 (dd, J
= 6.5, 3.9 Hz, 2H). MS (ESI) m/e (M+H+) 464Ø
[00937] Example 98: (S)-N-(1-(3-Amino-2-hydroxypropyl)-2-tert-butyl-lH-indol-5-
yl)-
1-(2,2-difluorobenzo [d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
O ~ H
F~O / O TsCI, TEA, DCM F> NaNs
F O N
~OH
~OH
OH OTs
F O H
FO / O N Pd/C F'-,x O
:]C "IC) F .O O
~OH OH
N3 NH2
F / O N N TsCI, TEA, DCM F O O N
~C H ~C H
OH OTs
[00938] (R)-3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarbox-amido)-1H-indol-1-yl)-2-hydroxypropyl-4-
methylbenzenesulfonate
[00939] To a stirred solution of (R)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-
1H-indol-5-
yl)-1-(2,2-difluoro-benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (3.0 g,
6.1 mmol) in
dichloromethane (20 mL) was added triethylamine (2 mL) and para-
toluenesulfonylchloride
(1.3 g, 7.0 mmol). After 18 hours, the reaction mixture was partitioned
between 10 mL of
water and 10 mL of ethyl acetate. The organic layer was dried over magnesium
sulfate,
filtered and evaporated. The residue was purified using column chromatography
on silica gel
(0-60% ethyl acetate/hexane) providing (R)-3-(2-tert-butyl-5-(1-(2,2-
difluorobenzo[d][1,3]-
dioxol-5-yl)cyclopropanecarboxamido)-1 H-indol-1-yl)-2-hydroxypropyl-4-methyl-
benzenesulfonate (3.21 g, 86%). LC/MS (M + 1) = 641.2. 1H NMR (400 MHz, CDC13)
8
7.77 (d, 2H, J = 16 Hz), 7.55 (d, 1H, J = 2 Hz), 7.35 (d, 2H, J = 16 Hz), 7.31
(m, 3H), 6.96 (s,
1H), 6.94 (dd, 1H, J = 2, 8 Hz), 6.22 (s, 1H), 4.33 (m, 1H), 4.31 (dd, 1H, J =
6, 15 Hz), 4.28
(dd, 1H, J = 11, 15 Hz), 4.18 (m, 1H), 3.40 (dd, 1H, J = 3, 6 Hz), 3.36 (dd,
1H, J = 3, 6 Hz),
2.46 (s, 3H), 2.40 (br s, 1H), 1.74 (m, 2H), 1.40 (s, 9H), 1.11 (m, 2 H).
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H H F_ N
Fx N~ NaN3
F O / O \N~ F p / O N
OH ~OH
OTs N3
[00940] (R)-N-(1-(3-Azido-2-hydroxypropyl)-2-tert-butyl-lH-indol-5-yl)-1-(2,2-
difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide
[00941] To a stirred solution (R)-3-(2-tert-butyl-5-(1-(2,2-
difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-1H-indol-1-yl)-2-hydroxypropyl-4-
methylbenzenesulfonate
(3.2 g, 5.0 mmol) in DMF (6 mL) was added sodium azide (2.0 g, 30 mmol). The
reaction
was heated at 80 C for 2 h. The mixture was partitioned between 20 mL ethyl
acetate and 20
mL water. The layers were separated and the organic layer was evaporated. The
residue was
purified using column chromatography (0-85% ethyl acetate/hexane) to give (R)-
N-(1-(3-
azido-2-hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluorobenzo[d]
[1,3]dioxol-5-
yl)-cyclopropanecarboxamide (2.48 g). LC/MS (M + 1) = 512.5. 1H NMR (400 MHz,
CDC13) 8 7.55 (d, 1H, J = 2 Hz), 7.31 (m, 3H), 6.96 (s, 1H), 6.94 (dd, 1H, J =
2, 8 Hz), 6.22
(s, 1H), 4.33 (m, 1H), 4.31 (dd, 1H, J = 6, 15 Hz), 4.28 (dd, 1H, J = 11, 15
Hz), 4.18 (m, 1H),
3.40 (dd, 1H, J = 3, 6 Hz), 3.36 (dd, 1H, J = 3, 6 Hz), 2.40 (br s, 1H), 1.74
(m, 2H), 1.40 (s,
9H), 1.11 (m, 2 H).
H
F~ p N Pd/C F F O N
~OH O
Ns
N
H2
[00942] (S)-N-(1-(3-Amino-2-hydroxypropyl)-2-tert-butyl-lH-indol-5-yl)-1-(2,2-
difluoro-benzo [d] [ 1,3 ] dioxol-5-yl)cyclopropanecarboxamide
[00943] To a stirred solution (R)-N-(1-(3-azido-2-hydroxypropyl)-2-tert-butyl-
lH-indol-5-
yl)-1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamide (2.4 g,
4.0 mmol) in
MeOH (25 mL) was added 5 % Pd/C (2.4 g) under a Hydrogen gas filled balloon.
After 18
h, the reaction mixture was filtered through celite and rinsed with 300 mL
ethyl acetate. The
organic layer was washed with 1 N HCl and evaporated to give (S)-N-(1-(3-amino-
2-
hydroxypropyl)-2-tert-butyl-1H-indol-5-yl)-1-(2,2-difluoro-benzo[d] [1,3]-
dioxol-5-
yl)cyclopropane-carboxamide (1.37 g). MS (M + 1) = 486.5.
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[00944] Example 99: (S)-Methyl 3-(2-tert-butyl-5-(1-(2,2-
difluorobenzo[d][1,3]dioxol-
5-yl)cyclopropanecarboxamido)- lH-indol-1-yl)-2-hydroxypropylcarbamate
H
H
F~ \ McOC(O)CI F \
O / O N
F / O N DCM, TEA
H
OH NH
NH 2 z
O O--
[00945] To a stirred solution (R)-N-(1-(3-amino-2-hydroxypropyl)-2-tert-butyl-
lH-indol-5-
yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.10 g,
0.20 mmol) in
methanol (1 mL) was added 2 drops of triethylamine and methylchloroformyl
chloride (0.020
mL, 0.25 mmol). After 30 min, the reaction mixture was filtered and purified
using reverse
phase HPLC providing (S)-methyl 3-(2-tert-butyl-5-(1-(2,2-
difluorobenzo[d][1,3]dioxol-5-
yl)cyclo-propanecarboxamido)-1H-indol-1-yl)-2-hydroxypropylcarbamate. The
retention
time on a three minute run is 1.40 min. LC/MS (M + 1) = 544.3. 1H NMR (400
MHz,
CDC13) 8 7.52 (d, 1H, J = 2Hz), 7.30 (dd, 1H, J = 2, 8 Hz), 7.28(m, 1H), 7.22
(d, 1H, J = 8
Hz), 7.14 (d, 1H, J = 8 Hz), 7.04 (br s, 1H), 6.97 (dd, 1H, J = 2, 8 Hz), 6.24
(s, 1H), 5.19 (1H,
br s), 4.31 (dd, 1H, J = 6, 15 Hz), 4.28 (dd, 1H, J = 11, 15 Hz), 4.18 (m,
1H), 3.70 (s, 3H),
3.40 (dd, 1H, J= 3, 6 Hz), 3.36 (dd, 1H, J= 3, 6 Hz), 3.26 (m, 1H), 1.74 (m,
2H), 1.40 (s, 9
H), 1.11 (m, 2 H).
[00946] Example 100: 4-(5-(1-(Benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-2-
tert-butyl-lH-indol-1-yl)butanoic acid
O
OH
H H _
NI[ NaBH3CN, AcOH / I N I\ O
O N p oC \ O N NaBH3CN,
H H MeOH-AcOH
N CDCI3, light H
open air collfo N I O N N
N
O
OH OH
H H
O / N \ NaBH3CN, AcOH N
O\ 0 N O\ O/
H H
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[00947] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-
yl)cyclopropanecarboxamide
[00948] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1H-indol-
5-yl)cyclo-
propanecarboxamide (851 mg, 2.26 mmol) in acetic acid (60 mL) was added
NaBH3CN (309
mg, 4.91 mmol) at 0 T. The reaction mixture was stirred for 5 min at room
temperature after
which no starting material could be detected by LCMS. The solvent was
evaporated under
reduced pressure and the residue was purified by column chromatography on
silica gel (5-
40% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-
butylindolin-5-
yl)cyclopropanecarboxamide (760 mg, 89%).
O
SOH
H
p, O O/
O I O N NaBH3CN, O O N
H MeOH-AcOH
O
OH
[00949] 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-
butylindolin-1-yl)butanoic acid
[00950] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-
yl)cyclopropanecarboxamide (350 mg, 0.93 mmol, 1 eq) in anhydrous methanol
(6.5 mL) and
AcOH (65 L) was added 4-oxobutanoic acid (15% in water, 710 mg, 1.0 mmol) at
room
temperature. After 20 min of stirring, NaBH3CN (130 mg, 2.0 mmol) was added in
one
portion and the reaction mixture was stirred for another 4 h at room
temperature. The reaction
mixture was quenched by addition of AcOH (0.5 mL) at 0 C and the solvent was
removed
under reduced pressure. The residue was purified by column chromatography on
silica gel
(5-75% ethyl acetate/hexanes) to give 4-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-2-tert-butylindolin-1-yl)butanoic acid (130 mg,
30%).
O N CDCI3, light O N
open air
O / N <\ O I' N
O 0
OH OH
[00951] 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-
butyl-lH-
indol-1-yl)butanoic acid
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[00952] 4-(5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2-tert-
butylindolin-
1-yl)butanoic acid (130 mg, 0.28 mmol) was taken up in a mixture of
acetonitrile-H20-TFA.
The solvent was removed under reduced pressure and the residue obtained was
dissolved in
CDC13. After a brief exposition to daylight (5-10 min), the solution turned
purple. The
mixture was stirred open to the atmosphere at room temperature until complete
disappearance
of the starting material (8 h). Solvent was removed under reduced pressure and
the residue
was purified by reverse pharse HPLC to give 4-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-2-tert-butyl-lH-indol-1-yl)butanoic acid. 1H NMR
(400 MHz,
CDC13) 8 7.52 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 7.16 (s, 1H),
7.03 (dd, J = 9.4, 1.9
Hz, 1H), 7.00-6.98 (m, 2H), 6.85 (d, J = 7.9 Hz, 1H), 6.16 (s, 1H), 6.02 (s,
2H), 4.29-4.24 (m,
2H), 2.48 (dd, J = 6.9, 6.9 Hz, 2H), 2.12-2.04 (m, 2H), 1.69 (dd, J = 6.8, 3.7
Hz, 2H), 1.43 (s,
9H), 1.09 (dd, J = 6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 463Ø
[00953] Example 101: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(4-(2-
hydroxyethyl-amino)-4-oxobutyl)-1H-indol-5-yl)cyclopropanecarboxamide
H H
N DHBTU MF ' Et3N, O\ I O N
O N
N
ethanolamine
O
OH HN-/_OH
[00954] To a solution of 4-(5-(1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-2-
tert-butyl-lH-indol-1-yl)butanoic acid (10 mg) in anhydrous DMF (0.25 mL) were
successively added Et3N (9.5 mL, 0.069 mmol) and HBTU (8.2 mg, 0.022 mmol).
After
stirring for 10 min at 60 C, ethanolamine (1.3 L, 0.022 mmol) was added, and
the mixture
was stirred for another 4 h at 60 T. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-
butyl-l-(4-(2-
hydroxyethyl-amino)-4-oxobutyl)-1H-indol-5-yl)cyclopropanecarboxamide (5.8 mg,
64%)
was obtained after purification by preparative HPLC. MS (ESI) m/e (M+H+)
506Ø
[00955] Example 102: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2-
(dimethylamino)-2-oxoethyl)-1H-indol-5-yl)cyclopropanecarboxamide
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1. NaH, DMF-THF
O
H H
O N ~ O / N < I O
H 2. DMF, Pd-C N
Off/
N-
[00956] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-
yl)cyclopropanecarboxamide (62 mg, 0.16 mmol) in anhydrous DMF (0.11 mL) and
THE (1
mL) was added NaH (60% in mineral oil, 21 mg, 0.51 mmol) at room temperature
under N2.
After 30 min of stirring, the reaction mixture was cooled to 0 C and 2-chloro-
N,N-
dimethylacetamide (11 mL, 0.14 mmol,) was added. The reaction mixture was
stirred for 5
min at 0 C and then for 10 h at room temperature. The mixture was purified by
preparative
HPLC and the resultant solid was dissolved in DMF (0.6 mL) in the presence of
Pd-C (10
mg). The mixture was stirred open to the atmosphere overnight at room
temperature. The
reaction mixture was filtrated and purified by preparative HPLC providing 1-
(benzo [d] [ 1,3]dioxol-5-yl)-N-(2-tert-butyl- l-(2-(dimethylamino)-2-
oxoethyl)-1H-indol-5-
yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 462Ø
[00957] Example 103: 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclo-
propanecarboxamido)-lH-indol-1-yl)propanoic acid
~C~N 1. NaBH(OAc)3 ~CN\r NaCN, DMF,
DCM F KI, EtOH-H20
F O / H O F O O N
~ICI
CI
~( N 1.50 % aq KOH
F" ` O 1,4-dioxane F N
O Fx O N
2. CDCI3, light, air
//
N O OH
77
F-> / I N I\ DCMBH(OAc)3 F N I\
F O O N O F O N\
H QCI /
CI
[00958] N-(2-tert-Butyl-l-(2-chloroethyl)indolin-5-yl)-1-(2,2-
difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
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[00959] To a solution of N-(2-tert-butyl-l-(2-cyanoethyl)indolin-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (71 mg, 0.17 mmol) in
anhydrous dichloromethane (1 mL) was added chloroacetaldehyde (53 L, 0.41
mmol) at
room temperature under N2. After 20 min of stirring, NaBH(OAc)3 (90 mg, 0.42
mmol) was
added in two portions. The reaction mixture was stirred overnight at room
temperature. The
product was purified by column chromatography on silica gel (2-15% ethyl
acetate/hexanes)
providing N-(2-tert-butyl-l-(2-chloroethyl)indolin-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-
5-yl)cyclopropanecarboxamide (51 mg, 63%).
H N DMF, H
F O/ I I\ KI, EtOH-H20 F* / I I\
F 0 O / N F O\ O / N
/
Cl
N
[00960] N-(2-tert-Butyl-l-(2-cyanoethyl)indolin-5-yl)-1-(2,2-
difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
[00961] N-(2-tert-butyl-l-(2-chloroethyl)indolin-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-
5-yl)cyclopropanecarboxamide (51 mg), NaCN (16 mg, 0.32 mmol) and KI (cat) in
EtOH
(0.6 mL) and water (0.3 mL) were combined and heated at 110 C for 30 min in
the
microwave. The solvent was removed under reduced pressure and the residue was
purified
by column chromatography on silica gel (2-15% ethyl acetate/hexanes) providing
N-(2-tert-
butyl- l-(2-cyanoethyl)indolin-5-yl)-1-(2,2-difluorobenzo [d] [ 1,3]dioxol-5-
yl)cyclopropanecarboxamide (24 mg, 48%).
H H
FX :30 N \ 1.50 % aq KOH F~ N I \ F 0 I / N 1,4-dioxane F O / N
2. CDCI3, light, air
OH
N 0
[00962] 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclo-
propanecarbox-amido)-lH-indol-1-yl)propanoic acid
[00963] N-(2-tert-butyl-l-(2-cyanoethyl)indolin-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-
5-yl)cyclopropane-carboxamide (24 mg, 0.050 mmol) was taken up in 50% aq. KOH
(0.5
mL) and 1,4-dioxane (1 mL). The mixture was heated at 125 C for 2 h. The
solvent was
removed and the residue was purified by preparative HPLC. The residue was
dissolved in
CDC13 (1 mL) then briefly exposed to daylight. The purple solution that formed
was stirred
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until complete disappearance of the starting material (1 h). The solvent was
removed under
reduced pressure and the residue was purified by preparative HPLC providing 3-
(2-tert-butyl-
5-(1-(2,2-difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclo-propanecarboxamido)-1H-
indol- l-
yl)propanoic acid. MS (ESI) m/e (M+H+) 485Ø
[00964] Example 104: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-l-
(2-
hydroxy-ethyl)-1H-indol-5-yl)cyclopropenecarboxamide
1. Q, OO
O/ N \ H H I N I\
O\ I O F I/ N NaBH3CN c O F / N
H MeOH-AcOH
2. CDCI3, light,
air OH
[00965] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-
fluoroindolin-5-
yl)cyclopropanecarboxamide (340 mg, 0.86 mmol) in anhydrous MeOH (5.7 mL)
containing
1% of acetic acid was added glyoxal 40% in water (0.60 mL, 5.2 mmol) at room
temperature
under N2. After 20 min of stirring, NaBH3CN (120 mg, 1.9 mmol) was added in
one portion
and the reaction mixture was stirred overnight at room temperature. The
solvent was
removed under reduced pressure and the residue obtained was purified by column
chromatography on silica gel (10-40% ethyl acetate/hexanes) providing a pale
yellow oil
which was treated with 50/50 CH3CN-H20 containing 0.05% TFA and CDC13. Solvent
was
removed under reduced pressure and the residue was purified by column
chromatography on
silica gel (20-35% ethyl acetate/hexanes) to give 1-(benzo[d][1,3]dioxol-5-yl)-
N-(2-tert-
butyl-6-fluoro-l-(2-hydroxyethyl)-1H-indol-5-yl)cyclopropanecarboxamide. 1H
NMR (400
MHz, CDC13) S 8.02 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 6.93 (dd, J
= 1.6, 7.9 Hz,
1H), 6.90 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 7.9 Hz,
1H), 6.08 (s, 1H),
5.92 (s, 2H), 4.21 (dd, J = 6.9, 6.9 Hz, 2H), 3.68 (m, 2H), 2.28 (s, 1H), 1.60
(dd, J = 3.7, 6.7
Hz, 2H), 1.35 - 1.32 (m, 9H), 1.04 (dd, J = 3.7, 6.8 Hz, 2H). MS (ESI) m/e
(M+H+) 439Ø
[00966] Example 105: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-l-
(3-
hydroxy-propyl)-1H-indol-5-yl)cyclopropanecarboxamide
O
I
OBn
H
aH(OAc)3O N O\ F /
p / N \ :::
air O O F N
3. Pd-C, H2, MeOH
HO
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OH PCC, DCM O
~- OBn - _OBn
[00967] 3-(Benzyloxy)propanal
[00968] To a suspension of PCC (606 mg, 2.82 mmol) in anhydrous
dichloromethane (8
mL) at room temperature under N2 was added a solution of 3-benzyloxy-l-
propanol (310 mg,
1.88 mmol) in anhydrous dichloromethane. The reaction mixture was stirred
overnight at
room temperature, filtrated through Celite, and concentrated. The residue was
purified by
column chromatography on silica gel (1-10% ethyl acetate/hexanes) to give 3-
(benzyloxy)propanal (243 mg, 79%).
1 O~ v ^
OBn
p / N I N/ /\ I < I I
O c F O N
3. Pd-C, H2, M--OH
HO
[00969] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-l-(3-
hydroxypropyl)-1H-
indol-5-yl)cyclopropanecarboxamide
[00970] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-
fluoroindolin-5-
yl)cyclopropanecarboxamide (160 mg, 0.50 mmol) in anhydrous dichloromethane
(3.4 mL)
was added 3-(benzyloxy)propanal (160 mg, 0.98 mmol) at room temperature. After
10 min of
stirring, NaBH(OAc)3 (140 mg, 0.65 mmol) was added in one portion and the
reaction
mixture was stirred for 4 h at room temperature. The solvent was removed under
reduced
pressure and the residue was taken-up in a mixture of 50/50 CH3CN-H20
containing 0.05%
TFA. The mixture was concentrated to dryness and the residue was dissolved in
CDC13 (5
mL) and briefly exposed to daylight. The purple solution was stirred open to
the atmosphere
at room temperature for 2 h. The solvent was removed under reduced pressure
and the
residue was treated with Pd-C (10 mg) in MeOH (2 mL) under 1 atm of H2 for 2
h. The
catalyst was filtered through Celite and the solvent was removed under reduced
pressure.
The residue was purified by preparative TLC 30% ethyl acetate/hexanes to
provide 1-
(benzo [d] [ 1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro- l-(3-hydroxypropyl)-1H-
indol-5-
yl)cyclopropanecarboxamide (18 mg, 8% from 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-
tert-butyl-
6-fluoroindolin-5-yl)cyclopropane-carboxamide). 1H NMR (400 MHz, CDC13) 8 8.11
(d, J =
7.8 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 6.94 (dd, J = 7.9, 1.7 Hz, 1H), 6.91
(d, J = 1.6 Hz, 1H),
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6.85 (d, J = 11.7 Hz, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.10 (s, 1H), 5.94 (s,
2H), 4.25-4.21 (m,
2H), 3.70 (dd, J = 5.7, 5.7 Hz, 2H), 1.93-1.86 (m, 2H), 1.61 (dd, J = 6.8, 3.7
Hz, 2H), 1.35 (s,
9H), 1.04 (dd, J = 6.8, 3.7 Hz, 2H). MS (ESI) m/e (M+H+) 453Ø
[00971] Example 106: N-(1-(2-Acetamidoethyl)-2-tert-butyl-lH-indol-5-yl)-1-
(benzo [d] [ 1,3 ]-dioxol-5-yl) cyclopropanecarboxamide
H H 1. Pd-C, H21 atm H
N DCM BH(OAc)3 N McOH-AcOH N \ \
\ I O N O <O O I N\ 2. Et3N, THF, ~O O I/ N
H U ci / AcCI
2. CDCI3, light, (
N3
air
3. NaN3, Nal,
DMF 0
ON DCMBH(OAc)3 / N
O\ O / H O O\ O nl
~ICI (l\
2. CDCI3, light, N3
3
air
3. NaN3, Nal,
DMF
[00972] N-(1-(2-azidoethyl)-2-tert-butyl-lH-indol-5-yl)-1-(benzo[d][1,3]dioxol-
5-yl)-
cyclopropanecarboxamide
[00973] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butylindolin-5-
yl)cyclopropane-carboxamide (73 mg, 0.19 mmol) in anhydrous dichloromethane
(1.2 mL)
was added chloroacetaldehyde (60 L, 0.24 mmol) at room temperature. After 10
min of
stirring, NaBH(OAc)3 (52 mg, 0.24 mmol) was added in one portion and the
reaction mixture
was stirred for another 30 min at room temperature. The solvent was removed
under reduced
pressure and the residue was purified by preparative HPLC to give the
indoline, which
oxidized to the corresponding indole when taken-up in CDC13. The resulting
indole was
treated with NaN3 (58 mg, 0.89 mmol) and Nal (cat) in anhydrous DMF (0.8 mL)
for 2 h at
85 T. The reaction mixture was purified by preparative HPLC providing N-(1-(2-
azidoethyl)-2-tert-butyl-1 H-indol-5-yl)-1-(benzo[d] [ 1,3]dioxol-5-
yl)cyclopropanecarboxamide (15 mg, 18% from 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-
tert-
butylindolin-5-yl)cyclopropane-carboxamide).
H 1. Pd-C, H2 H
00~ly N McOH-ACOH O o~o N \
O I N 2. Et3N, THF, I N
AcCI
N3 NH
O
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[00974] N-(1-(2-Acetamidoethyl)-2-tert-butyl-lH-indol-5-yl)-1-(benzo[d][1,3]-
dioxol-5-
yl)cyclopropanecarboxamide
[00975] A solution of N-(1-(2-azidoethyl)-2-tert-butyl-lH-indol-5-yl)-1-
(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (13 mg, 0.029 mmol) in MeOH-
AcOH
(0.2 mL, 99:1) in the presence of Pd-C (2 mg) was stirred at room temperature
under 1 atm of
H2 for 2 h, filtered through Celite, and concentrated under reduced pressure.
The crude
product was treated with AcCl (0.05 mL) and Et3N (0.05 mL) in anhydrous THE
(0.2 mL) at
0 C for 30 min and then 1 h at room temperature. The mixture was purified by
preparative
HPLC providing N-(1-(2-acetamidoethyl)-2-tert-butyl-lH-indol-5-yl)-1-
(benzo[d][1,3]-
dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 462Ø
[00976] Example 107: N-(2-tert-Butyl-l-(3-cyano-2-hydroxypropyl)-1H-indol-5-
yl)-1-
(2,2-difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamide
Fx N j \ TsCI, Et3N N NaCN F~ P \ O N / \
F N DCM F O O N DMF F O N
HO~ HO~ HO
HO TsO
N
H H
N
FFO \ I O I/ N DCM Et3N ~ I O N I N
HOJ HO
HO TSO
[00977] 3-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarbox-
amido)-1H-indol-1-yl)-2-hydroxypropyl-4-methylbenzenesulfonate
[00978] To a solution of N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-
yl)-1-(2,2-
difluorobenzo[d][ 1,3]-dioxol-5-yl)cyclopropanecarboxamide (172 mg, 0.35 mmol)
in
anhydrous dichloromethane (1.4 mL) at 0 C in the presence of Et3N (56 L,
0.40 mmol) was
added TsCl (71 mg, 0.37 mmol). The reaction mixture was stirred for 2 h at
room
temperature before being cooled to 0 C and another portion of TsCl (71 mg,
0.37 mmol) was
added. After 1 h of stirring at room temperature, the mixture was purified by
column
chromatography on silica gel (10-30% ethyl acetate/hexanes) providing 3-(2-
tert-butyl-5-(1-
(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-1-yl)-
2-
hydroxypropyl-4-methylbenzene-sulfonate (146 mg, 64%).
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H
F~ N I N
NaCN, DMF F
F O N F O / N
H H
Ts0 \
N
[00979] N-(2-tert-Butyl-l-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1-(2,2-
difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
[00980] N-(2-tert-Butyl-l-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)-cyclopropanecarboxamide (145 mg, 0.226 mmol)
was
treated with powdered NaCN (34 mg, 0.69 mmol) in anhydrous DMF (1.5 mL) at 85
C for 2
h. The reaction mixture was cooled down to room temperature before it was
diluted with
dichloromethane (10 mL) and aq. sat. NaHCO3 (10 mL). The organic phase was
separated
and the aqueous phase was extracted with dichloromethane (2 x 10 mL). The
organic phases
were combined, washed with brine, dried with sodium sulfate, filtered then
concentrated. The
residue was purified by column chromatography on silica gel (25-55% ethyl
acetate/hexanes)
providing N-(2-tert-butyl-l-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (89 mg, 79%). 1H NMR
(400
MHz, CDC13) 8 7.43 (d, J = 1.9 Hz, 1H), 7.20-7.16 (m, 2H), 7.08 (d, J = 8.8
Hz, 1H), 7.04 (d,
J = 8.2 Hz, 1H), 6.94 (s, 1H), 6.88 (dd, J = 8.7, 2.0 Hz, 1H), 6.16 (s, 1H),
4.32-4.19 (m, 3H),
2.83 (s, 1H), 2.40 (dd, J = 5.2, 5.2 Hz, 2H), 1.62 (dd, J = 6.6, 3.6 Hz, 2H),
1.35 (s, 9H), 1.04
(dd, J = 6.9, 3.9 Hz, 2H). MS (ESI) m/e (M+H+) 496Ø
[00981] Example 108: N-(2-tert-Butyl-l-(2-hydroxy-3-(2H-tetrazol-5-yl)propyl)-
1H-
indol-5-yl)-1-(2,2-difluorobenzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamide
H H
F N
~/ \ I I N NaN3, NH4CI F O N
F O
N
HO HO
N 14 NI
NN
H
[00982] To a solution of N-(2-tert-butyl-l-(3-cyano-2-hydroxypropyl)-1H-indol-
5-yl)-1-
(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (27 mg, 0.054
mmol) in
anhydrous DMF (1.2 mL) were successively added NH4C1(35 mg, 0.65 mmol) and
NaN3 (43
mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 4 h
at 110 C in
the microwave, at which stage 50% of the starting material was converted to
the desired
product. The reaction mixture was purified by preparative HPLC to provide N-(2-
tert-butyl-
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1- (2-hydroxy-3 -(2H-tetrazol-5 -yl)propyl) -1 H-indol- 5 -yl) -1- (2, 2-
difluorobenzo-
[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 539Ø
[00983] Example 109: 4-(2-tert-Butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclo-
propanecarboxamido)-lH-indol-1-yl)-3-hydroxybutanoic acid
H H
F-> O / I N I \ McOH, NaOH N
F O O / N F O O I/ N
HO HO
HO
N O
[00984] A solution of N-(2-tert-butyl-l-(3-cyano-2-hydroxypropyl)-1H-indol-5-
yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (14 mg, 0.028 mmol)
in
methanol (0.8 mL) and 4 M NaOH (0.8 mL) was stirred at 60 C for 4 h. The
reaction
mixture was neutralized with 4 M HCl and concentrated. The residue was
purified by
preparative HPLC to provide 4-(2-tert-butyl-5-(1-(2,2-
difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)- 1H-indol-1-yl)-3-hydroxybutanoic acid. MS (ESI)
m/e
(M+H+) 515Ø
[00985] Example 110: N-(1-(2-(2H-Tetrazol-5-yl)ethyl)-2-tert-butyl-lH-indol-5-
yl)-1-
(benzo [d] [ 1,3 ] dioxol-5-yl)cyclopropanecarboxamide
H NaCN, KI H 1. NHQCI, NaN3, H
(O / N \ EtOH-H,O C / I N I \ DMF / N \
O O N O\ O / N 2. CDCI3, light, \ I O I/ N
air
N N, ' N
N-NH
H NaCN, KI H
C O/ N I A EtOH-H20 <O \ I O / N ID < \ O ~ N I I/ N
CI
N
[00986] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2-cyanoethyl)indolin-5-
yl)-
cyclopropanecarboxamide
[00987] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2-
chloroethyl)indolin-5-yl)cyclopropanecarboxamide (66 mg, 0.15 mmol) in ethanol
(0.8 mL)
and water (0.4 mL) were added NaCN (22 mg, 0.45 mmol) and KI (cat) at room
temperature.
The reaction mixture was stirred for 30 min at 110 C in the microwave before
being purified
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by column chromatography on silica gel (5-15% ethyl acetate/hexanes) to
provide 1-
(benzo[d] [1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2-cyano-ethyl)indolin-5-
yl)cyclopropanecarboxamide (50 mg, 77%).
H 1. NH4CI, NaN3,
COIIYO N~ DMF / N ~
/ N / \ I O I/
2. CDCI3, light, \ N
air
N %% N~' N
N--NH
[00988] N-(1-(2-(2H-Tetrazol-5-yl)ethyl)-2-tert-butyl-lH-indol-5-yl)-1-
(benzo [d] [ 1,3 ] dioxol-5-yl)cyclopropanecarboxamide
[00989] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2-
cyano-
ethyl)indolin-5-yl)cyclopropanecarboxamide (50 mg, 0.12 mmol) in anhydrous DMF
(2.6
mL) was added NH4C1(230 mg, 4.3 mmol) and NaN3 (280 mg, 4.3 mmol). The
reaction
mixture was stirred for 30 min at 110 C in the microwave, filtrated, and
purified by
preparative HPLC. The solid residue was dissolved in CDC13 (3 mL) and briefly
(2 to 4 min)
exposed to daylight, which initiated a color change (purple). After 2 h of
stirring open to the
atmosphere at room temperature, the solvent was removed and the residue was
purified by
preparative HPLC to give N-(1-(2-(2H-tetrazol-5-yl)ethyl)-2-tert-butyl-lH-
indol-5-yl)-1-
(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 473Ø
[00990] Example 111: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-l-
((tetrahydro-2H-pyran-3-yl)methyl)-1H-indol-5-yl)cyclopropanecarboxamide
N DCM H(OAc)3, H
N
O O F / H ~\+ O CO F N
2. CDCI3
[00991] To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-
fluoroindolin-5-
yl)cyclopropane-carboxamide (150 mg, 0.38 mmol) in anhydrous dichloromethane
(2.3 mL)
at room temperature under N2 was added tetrahydropyran-3-carbaldehyde (54 mg,
0.47
mmol). After 20 min of stirring, NaBH(OAc)3 (110 mg, 0.51 mmol) was added in
one
portion at room temperature. The reaction mixture was stirred for 6 h at room
temperature
before being purified by column chromatography on silica gel (5-20% ethyl
acetate/hexanes)
to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-l-
((tetrahydro-2H-pyran-3-
yl)methyl)indolin-5-yl)cyclopropanecarboxamide (95 mg, 50%). CDC13 was added
to the
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indoline and the solution was allowed to stir overnight at ambient
temperature. The solution
was concentrated to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-6-fluoro-
l-
((tetrahydro-2H-pyran-3-yl)methyl)-1H-indol-5-yl)cyclopropanecarboxamide. MS
(ESI) m/e
(M+H+) 493Ø
[00992] Example 112: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(2-hydroxypropan-2-yl)-
1H-
indol-5-yl)cyclopropanecarboxamide
(O \ N -O CH3Li (O \ N OH
O I/ O I/ H O- O O I N
H
[00993] Methyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-1H-
indole-2-
carboxylate (100 mg, 0.255 mmol) was dissolved in anhydrous tetrahydrofuran (2
mL) under
an argon atmosphere. The solution was cooled to 0 C in an ice water bath
before
methyllithium (0.85 mL, 1.6 M in diethyl ether) was added by syringe. The
mixture was
allowed to warm to room temperature. The crude product was then partitioned
between a
saturated aqueous solution of sodium chloride (5 mL) and dichloromethane (5
mL). The
organic layers were combined, dried over sodium sulfate, filtered, evaporated
to dryness, and
purified on 12 g of silica gel utilizing a gradient of 20-80% ethyl acetate in
hexanes to yield
1-(benzo[d] [1,3]dioxol-5-yl)-N-(2-(2-hydroxypropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide (35 mg, 36%) as a white solid. ESI-MS m/z calc.
378.2, found
379.1 (M+1)+. Retention time of 2.18 minutes. 1H NMR (400 MHz, DMSO-d6) S
10.78 (s,
1H), 8.39 (s, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.03 -
6.90 (m, 4H), 6.12
(d, J= 1.5 Hz, 1H), 6.03 (s, 2H), 5.18 (s, 1H), 1.50 (s, 6H), 1.41 - 1.38 (m,
2H), 1.05-0.97 (m,
2H).
[00994] Example 113: N-(2-(1-Amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-
(benzo [d] [ 1,3 ]-dioxol-5-yl) cyclopropanecarboxamide
N \ TFA N \
O IOI H NHBoc O H NH2
[00995] Trifluoroacetic acid (0.75 mL) was added to a solution of tert-butyl 2-
(5-(1-
(benzo [d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indol-2-yl)-2-
methylpropylcarbamate (77 mg, 0.16 mmol) in dichloromethane (3 mL) and the
mixture was
stirred at room temperature for 1.5 h. The mixture was evaporated, dissolved
in
dichloromethane, washed with saturated sodium bicarbonate solution, dried over
magnesium
sulfate and evaporated to dryness to give N-(2-(1-amino-2-methylpropan-2-yl)-
1H-indol-5-
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yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (53 mg, 86%). 1H NMR
(400
MHz, CDC13) S 9.58 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.18 - 7.15 (m, 2H),
7.02 - 6.94 (m,
3H), 6.85 (d, J = 7.8 Hz, 1H), 6.14 (d, J = 1.2 Hz, 1H), 6.02 (s, 2H), 2.84
(s, 2H), 1.68 (dd, J
= 3.6, 6.7 Hz, 2H), 1.32 (s, 6H), 1.08 (dd, J = 3.7, 6.8 Hz, 2H).
[00996] Example 114: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(1-(dimethylamino)-2-
methyl-
propan-2-yl)-1H-indol-5-yl) cyclopropanecarboxamide
H Mel H
\ \ K2CO3 N \
0 0 H NH2~ O O H NMe2
[00997] To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-
(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (20 mg, 0.051 mmol) in DMF
(1 mL)
was added potassium carbonate (35 mg, 0.26 mmol) and iodomethane (7.0 L, 0.11
mmol).
The mixture was stirred for 2 h. Water was added and the mixture was extracted
with
dichloromethane. Combined organic phases were dried over magnesium sulfate,
evaporated,
coevaporated with toluene (3x) and purified by silica gel chromatography (0-
30% EtOAc in
hexane) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-(dimethylamino)-2-
methylpropan-2-yl)-
1H-indol-5-yl)cyclopropanecarboxamide (7 mg, 33%). 1H NMR (400 MHz, CDC13) S
9.74
(s, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.15 (s, 1H),
7.01 - 6.95 (m, 3H),
6.85 (d, J = 7.9 Hz, 1H), 6.10 (d, J = 0.9 Hz, 1H), 6.02 (s, 2H), 2.43 (s,
2H), 2.24 (s, 6H), 1.68
(dd, J = 3.7, 6.7 Hz, 2H), 1.33 (s, 6H), 1.08 (dd, J = 3.7, 6.8 Hz, 2H).
[00998] Example 115: N-(2-(1-Acetamido-2-methylpropan-2-yl)-1H-indol-5-yl)-1-
(benzo [d] [ 1,3 ]-dioxol-5-yl) cyclopropanecarboxamide
f~ \ N \ Ac20 \ N \
O NH2 PY 0 0 H NHAc
[00999] To a solution of N-(2-(1-amino-2-methylpropan-2-yl)-1H-indol-5-yl)-1-
(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (21 mg, 0.054 mmol) in
dichloromethane (1 mL) was added pyridine (14 L, 0.16 mmol) followed by
acetic
anhydride (6.0 L, 0.059 mmol). The mixture was stirred for 2 h. Water was
added and the
mixture was extracted with dichloromethane, evaporated, coevaporated with
toluene (3x) and
purified by silica gel chromatography (60-100% ethylacetate in hexane) to give
N-(2-(1-
acetamido-2-methylpropan-2-yl)-1H-indol-5-yl)-1-(benzo[d] [ 1,3]-dioxol-5-
yl)cyclopropanecarboxamide (17 mg, 73%). 1H NMR (400 MHz, DMSO) S 10.79 (s,
1H),
8.39 (s, 1H), 7.66 (t, J = 6.2 Hz, 1H), 7.56 (d, J = 1.7 Hz, 1H), 7.18 - 7.14
(m, 1H), 7.02 -
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6.89 (m, 4H), 6.08 (d, J = 1.5 Hz, 1H), 6.03 (s, 2H), 3.31 (d, J = 6.2 Hz,
2H), 1.80 (s, 3H),
1.41 - 1.38 (m, 2H), 1.26 (s, 6H), 1.04 - 1.01 (m, 2H).
[001000] Example 116: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(2-methyl-4-(1H-
tetrazol-5-
yl)butan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
N,11
NH:CI _X, y N
O H NaN 0I/ O H -N
3
HN,N.N
[001001] 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(4-cyano-2-methylbutan-2-yl)-1H-
indol-5-
yl)cyclopropanecarboxamide (83 mg, 0.20 mmol) was dissolved in N,N-
dimethylformamide
(1 mL) containing ammonium chloride (128 mg, 2.41 mmol), sodium azide (156 mg,
2.40
mmol), and a magnetic stir bar. The reaction mixture was heated at 110 C for
40 minutes in
a microwave reactor. The crude product was filtered and then purified by
preparative HPLC
using a gradient of 0-99% acetonitrile in water containing 0.05%
trifluoroacetic acid to yield
1-(benzo [d] [ 1,3]dioxol-5-yl)-N-(2-(2-methyl-4-(1H-tetrazol-5-yl)butan-2-yl)-
1H-indol-5-
yl)cyclopropanecarboxamide. ESI-MS m/z calc. 458.2, found 459.2 (M+1)+.
Retention time
of 1.53 minutes. 1H NMR (400 MHz, CD3CN) 9.23 (s, 1H), 7.51 - 7.48 (m, 2H),
7.19 (d, J =
8.6 Hz, 1H), 7.06 - 7.03 (m, 2H), 6.95 - 6.89 (m, 2H), 6.17 (dd, J = 0.7, 2.2
Hz, 1H), 6.02 (s,
2H), 2.61 - 2.57 (m, 2H), 2.07 - 2.03 (m, 2H), 1.55-1.51 (m, 2H), 1.39 (s,
6H), 1.12-1.09 (m,
2H).
[001002] Example 117: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-1H-
indol-5-
yl)cyclopropanecarboxamide
N WA C N H
cc~o N I/ O I/
H H
[001003] tert-Butyl2-(5-(1-(benzo[d][1,3]dioxol-5-yl)cyclo-propanecarboxamido)-
1H-
indol-2-yl)piperidine-l-carboxylate (55 mg, 0.11 mmol) was dissolved in
dichloromethane
(2.5 mL) containing trifluoroacetic acid (1 mL). The reaction mixture was
stirred for 6 h at
room temperature. The crude product was purified by preparative HPLC using a
gradient of
0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-
(benzo [d] [ 1,3]dioxol-5-yl)-N-(2-(piperidin-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide.
ESI-MS m/z calc. 403.2, found 404.4 (M+1)+. Retention time of 0.95 minutes.
[001004] Example 118: 5-tert-Butyl-lH-indol-6-ylamine
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HCCSiMe3
Br KNO3, HZSOL_ Z/ Br Pd(PPh3)2CIZ
NBS, DMF
NH2 / NH2 ON NHZ Cul, D3N
Tol, H2O
/ I \ Si' Cul, DMF / I \ H2, Raney Ni
OZN NHZ OZN H HZN I H
\ I NBS, \ I Br
NH2 NHz
[001005] 2-Bromo-4-tert-butyl-phenylamine
[001006] To a solution of 4-tert-Butyl-phenylamine (447 g, 3.00 mol) in DMF
(500 mL) was
added dropwise NBS (531 g, 3.00 mol) in DMF (500 mL) at room temperature. Upon
completion, the reaction mixture was diluted with water and extracted with
EtOAc. The
organic layer was washed with water, brine, dried over Na2SO4 and
concentrated. The crude
product was directly used in the next step without further purification.
\ I Br KNO3 H2SO~ \ I Br
NH2 OZN NH2
[001007] 2-Bromo-4-tert-butyl-5-nitro-phenylamine
[001008] 2-Bromo-4-tert-butyl-phenylamine (160 g, 0.71 mol) was added dropwise
to
H2SO4 (410 mL) at room temperature to yield a clear solution. This clear
solution was then
cooled down to -5 to -10 C. A solution of KNO3 (83 g, 0.82 mol) in H2SO4 (410
mL) was
added dropwise while the temperature was maintained between -5 to -10 C. Upon
completion, the reaction mixture was poured into ice / water and extracted
with EtOAc. The
combined organic layers were washed with 5% Na2CO3 and brine, dried over
Na2SO4 and
concentrated. The residue was purified by a column chromatography (ethyl
acetate/petroleum
ether 1:10) to give 2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid
(150 g, 78%).
HCCSiMe3
Br Pd(PPh3)2CI2 Aim- Sim
0N \ NH2 Cul, Et3N
Tol, H2O O2N NH2
[001009] 4-tert-Butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine
[001010] To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100
mmol) in
toluene (200 mL) and water (100 mL) was added Et3N (27.9 mL, 200 mmol),
Pd(PPh3)2C12
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(2.11 g, 3.00 mmol), Cul (950 mg, 0.500 mmol) and trimethylsilyl acetylene
(21.2 mL, 150
mmol) under a nitrogen atmosphere. The reaction mixture was heated at 70 C in
a sealed
pressure flask for 2.5 h., cooled down to room temperature and filtered
through a short plug
of Celite. The filter cake was washed with EtOAc. The combined filtrate was
washed with
5% NH4OH solution and water, dried over Na2SO4 and concentrated. The crude
product was
purified by column chromatography (0 - 10 % ethyl acetate/petroleum ether) to
provide 4-
tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine as a brown viscous
liquid (25 g, 81
Jo).
Sim Cul, DMF 02N NH2 02N H
[001011] 5-tert-Butyl-6-nitro-1H-indole
[001012] To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-
phenylamine (25 g,
86 mmol) in DMF (100 mL) was added Cul (8.2 g, 43 mmol) under a nitrogen
atmosphere.
The mixture was heated at 135 C in a sealed pressure flask overnight, cooled
down to room
temperature and filtered through a short plug of Celite. The filter cake was
washed with
EtOAc. The combined filtrate was washed with water, dried over Na2SO4 and
concentrated.
The crude product was purified by column chromatography (10 - 20 % ethyl
aetate/hexane)
to provide 5-tert-butyl-6-nitro-1H-indole as a yellow solid (13 g, 69 %).
/ \ H2, Raney Ni /
0N I H H2N \ I H
[001013] 5-tert-Butyl-lH-indol-6-ylamine
[001014] Raney Nickel (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (15 g,
67 mmol) in
methanol (100 mL). The mixture was stirred under hydrogen (1 atm) at 30 C for
3 h. The
catalyst was filtered off. The filtrate was dried over Na2SO4 and
concentrated. The crude
dark brown viscous oil was purified by column chromatography (10 - 20 % ethyl
acetate/petroleum ether) to give 5-tert-butyl-1H-indol-6-ylamine as a gray
solid (11 g, 87 %).
'H NMR (300 MHz, DMSO-d6) 8 10.3 (br s, 1H), 7.2 (s, 1H), 6.9 (m, 1H), 6.6 (s,
1H), 6.1
(m, 1H), 4.4 (br s, 2H), 1.3 (s, 9H).
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1-(2,3-Dihydro-1H-inden-5-yl)cyclopropanecarboxylic acid
O O
(:Cr' (::O'
OH C) cfjOH
OH
d) all Ch cl( C I CN g) (Do O , (::' '-- Y
a) Ac20, A1C13, CH2C12; b) NaC1O; c) LiAlH4, THF, -78 C; d) SOC12, CHC13; e)
NaCN, DMSO; f) BrCHZCHZCI, NaOH, Bu4NBr, toluene; g) NaOH
[001] Step a: 1-(2,3-Dihydro-1H-inden-6-yl)ethanone
[002] A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and acetic
anhydride
(104.2 g, 1.35 mol) was added drop-wise to a slurry of A1C13 (272.0 g, 2.04
mol) in CHzClz
(1000 ml) at 0 C over a period of 3h. The reaction mixture was stirred at
room temperature
under a nitrogen atmosphere for 15 h. Then the reaction mixture was poured
into ice water
(500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic
layers were
washed with brine (500 mL), dried over Na2SO4 and evaporated in vacua. The
residue that
was purified by column chromatography (petroleum ether : ethyl acetate = 20 :
1) to give the
product (120.0 g, 88%).'H NMR (400 MHz, CDC13) 8 2.08-2.15 (m, 2H), 2.58 (s,
3H), 2.95
(t, J = 7.2, 4 H), 7.28 (d, J = 8.0, 1H), 7.75 (d, J = 8.0, 1H) 7.82 (s,1H).
[003] Step b: 2,3-dihydro-1H-indene-5-carboxylic acid
[004] To a stirred aqueous sodium hypochlorite solution (2230 ml, 1.80
mmol, 6%) at 55 C was added 1-(2,3-dihydro-1H-inden-6-yl) ethanone (120.0
g,0.75 mol)
and the mixture was stirred at 55 C for 2 h. After cooling to room
temperature, saturated
NaHCO3 solution was added until the solution became clear. The produced
precipitate was
filtered, washed several times with water and dried to afford the desired
product (120.0 g,
99%).'H NMR (CDC13, 300MHz) 8 2.07-2.17 (m, 2H), 2.96 (t, J = 7.5Hz, 4H), 7.30
(d, J
=7.8, 1H,), 7.91 (d, J = 7.8, 1H), 7.96 (s, 1H).
[005] Step c: (2,3-dihydro-1H-inden-5-yl)methanol
[006] To a stirred solution of LAH (72.8 g, 1.92 mol) in THE (2.5 L) at 0 C
was slowly added 2,3-dihydro-1H-indene-5-carboxylic acid (100.0 g, 0.62 mol).
The reaction
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mixture was stirred at 0 C for lh. Then the reaction was quenched with H2O (72
ml) and
NaOH (68 ml, 20%). The mixture was filtered and the organic layer was dried
over Na2SO4,
evaporated in vacuo and the residue was purified by column chromatography
(petroleum
ether : ethyl acetate = 10 : 1) to give the desired product (82.0 g, 90%). 1H
NMR (CDC13,
300MHz); 8 2.03-2.13 (m, 2H), 2.91 (t, J = 7.5Hz, 4H), 4.64 (s, 2H), 7.13 (d,
J = 7.5, 1H),
7.18-7.24 (m, 2H).
[007] Step d: 5-(chloromethyl)-2,3-dihydro-1H-indene
[008] Thionyl chloride (120 ml, 1.65 mol) was added drop-wise to a rapidly
stirred mixture of (2,3-dihydro-1H-inden-5-yl)methanol (81.4 g, 0.55 mol) in
chloroform
(500 ml) at 0 C. After the addition was complete, the resulting mixture was
allowed to warm
to room temperature and the stirring was continued for an additional 12 h. The
chloroform
was evaporated under reduced pressure to give a residue, that was purified by
column
chromatography (petroleum ether : ethyl acetate = 15 : 1) to afford 5-
(chloromethyl)-2,3-
dihydro-1H-indene (90.5 g, 99%). 1H NMR (300 MHz, CDC13) 8 2.06-2.19 (m, 4H),
2.93 (t,
J = 7.5, 4H), 4.54 (s, 2H), 7.15-7.31 (m, 3H).
[009] Step e: 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile
[010] To a stirred solution of 5-(chloromethyl)-2,3-dihydro-1H-indene (90.0
g, 0.54 mol) in DMSO (500 ml) was added sodium cyanide (54.0 g, 1.08mol) at 0
C portion
wise. The reaction mixture was then stirred at room temperature for 3 hours.
The reaction
was quenched with water (1000 ml), extracted with ethyl acetate (3 x 250 mL).
The
combined organic layers were washed with brine, dried over Na2SO4 and
evaporated in vacuo
to afford 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (82.2 g, 97%), that was
used in the next
step without further purification.
[011] Step f: 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile
[012] To a stirred solution of 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (50.0
g, 0.32 mol) in toluene (150 mL) was added sodium hydroxide (300 mL, 50
percent in water
W/W), 1-bromo-2-chloroethane (92.6 ml,1.12 mol) and (n-Bu)4NBr (5 g, 15.51
mmol). The
mixture was heated at 60 C overnight. After cooling to room temperature, the
reaction
mixture was diluted with water (400 mL) and extracted with EtOAc (3 x 200 mL).
The
combined organic extracts were washed with brine, dried over Na2SO4, filtered
and
concentrated under vacuum and purified by column chromatography (petroleum
ether : ethyl
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acetate = 10 : 1) to yield 1-(2,3-dihydro-1H-inden-6-
yl)cyclopropanecarbonitrile (9.3 g,16%).
'H NMR (CDC13,300MHz) 8 1.35-1.38 (m, 2H), 1.66-1.69 (m, 2H), 2.05-2.13 (m,
2H), 2.87-
294 (m, 4H), 7.07-7.22 (m,3H).
[013] Step g: 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarboxylic acid
[014] To a stirred 1-(2,3-dihydro-1H-inden-6-yl)cyclopropanecarbonitrile
(9.3 g,50.8 mmol) in methanol (40 mL) was added a solution of 150 mL of sodium
hydroxide
(25% NaOH w/w in water). The mixture was heated at 100 C for 8 hours. After
cooling to
room temperature, the reaction mixture was poured over ice-water (0 C), the
pH was
adjusted to pH=4 with hydrogen chloride (1 N) and the mixture was extracted
with
dichloromethane (3 x 100 mL). The combined organic layers were dried over
Na2SO4 and
evaporated under vacuum. The residue that was purified by column
chromatography
(petroleum ether : ethyl acetate = 5 : 1) to give 1-(2,3-dihydro-1H-inden-6-
yl)cyclopropanecarboxylic acid (4.8 g,47%). 1H NMR (CDC13, 400 MHz) 8 1.23-
1.26 (m,
2H), 1.62-1.65 (m, 2H), 2.03-210 (m, 2H), 2.81-2.91 (m, 4H), 7.11-7.21 (m,
3H).
5-Amino-2-tert-butyl-1 H-indole-4-carbonitrile
F N
02N a) 02 N H2N
I b)
N N N
H H H
a) KCN, DMSO; b) Pd/C, EtOAc
[015] Step a: 2-tert-butyl- 5 -nitro- I H-indole-4-carbonitrile
[016] To a solution of 2-tert-butyl-4-fluoro-5 -nitro- I H-indole (4.0 g, 17
mmol) in DMSO (30 mL) was added KCN (3.4 g, 51 mmol). The mixture was stirred
at
70 C for 3 hours, and poured into water (80 mL) and extracted with ethyl
acetate (50 mL x
3). The combined organic layers were washed with brine, dried over anhydrous
Na2SO4 and
concentrated under vacuum. The residue was purified by column chromatography
on silica
gel (7% EtOAc in petroleum ether) to afford 2-tert-butyl-5 -nitro- I H-indole-
4-carbonitrile
(2.2 g, 53%). 1H NMR (DMSO, 300 MHz) 8 12.23 (br s, 1 H), 8.09 (d, J = 9.0 Hz,
1 H), 7.75
(d, J= 9.0 Hz, 1 H), 6.50 (s, 1 H), 1.38 (s, 9 H). MS (ESI) m/z: 244.2 [M+H+].
[017] Step b: 5-amino-2-tert-butyl-1H-indole-4-carbonitrile
[018] To a solution of 2-tert-butyl- 5 -nitro- I H-indole-4-c arbonitrile (550
mg,
2.3 mmol) in EtOAc (10 mL) was added Raney Ni (0.1 g) under a nitrogen
atmosphere. The
mixture was stirred under hydrogen atmosphere (1 atm) at room temperature for
1 h. The
catalyst was filtered over Celite and the filtrate was evaporated in vacuo to
afford 5-amino-2-
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tert-butyl-1H-indole-4-carbonitrile (250 mg, 51%). 1H NMR (DMSO, 300 MHz) 8
10.93 (br
s, 1 H), 7.25 (d, J = 8.7 Hz, 1 H), 6.49 (d, J = 8.7 Hz, 1 H), 5.94 (d, J =
2.1 Hz, 1 H), 5.40 (br
s, 2 H), 1.30 (s, 9 H). MS (ESI) m/z: 214.0 [M+H+].
N-(2-tert-butyl-4-cyano-lH-indol-5-yl)-1-(2,2-difluorobenzo[d] [1,3]dioxol-5-
yl)cyclopropanecarboxamide
N H CN
;x:cT HzEt3N, DMF F0 I/ N F" O I/ O I/ N
H H
[019] Step a: N-(2-tert-butyl-4-cyano-lH-indol-5-yl)-1-(2,2-
difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
[020] 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl
chloride (26 mg, 0.1 mmol) was added to a solution of 5-amino-2-tert-butyl-1H-
indole-4-
carbonitrile (21 mg, 0.1 mmol) and triethylamine (41.7 L, 0.3 mmol) in DMF (1
mL). The
reaction was stirred at room temperature overnight, then filtered and purified
by reverse-
phase HPLC to yield the product, N-(2-tert-butyl-4-cyano-lH-indol-5-yl)-1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc.
437.2, found
438.7 (M+1)+. Retention time 2.10 minutes. IH NMR (400 MHz, DMSO-d6) 8 11.48
(s,
1H), 8.88 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H), 7.32
(dd, J = 1.5, 8.3 Hz,
1H), 7.03 (d, J = 8.6 Hz, 1H), 6.21 (d, J = 1.8 Hz, 1H), 1.51 - 1.49 (m, 2H),
1.36 (s, 9H), 1.18
1.16 (m, 2H).
N-(2-tert-butyl-4-cyano-l-(2-hydroxyethyl)-1 H-indol-5-yl)-1-(2,2-
difluorobenzo[d] [1,3]dioxol-5-yl)cyclopropanecarboxamide
CN CN CN
02N 02N H2N
-^0H tc H2, Pd-C
N
H Cs OC 3 DMF N EtOH
~--~
OH OH
H
Fk0 ~~ CI
F 0 0 F"0 N
F 0 0 N
Et3N, CH2CI2
OH
[021] Step a: 2-tert-butyl- 1-(2-hydroxyethyl)-5 -nitro- I H-indole-4-
carbonitrile
[022] A mixture of 2-tert-butyl-5 -nitro- I H-indole-4-carbonitrile (200 mg,
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0.82 mmol), 2-iodoethanol (77 L, 0.98 mmol), cesium carbonate (534 mg, 1.64
mmol) and
DMF (1.3 mL) was heated to 90 C overnight. Then more 2-iodoethanol (77 L,
0.98 mmol)
was added and the reaction was stirred at 90 C for 3 days. The reaction
mixture was
partitioned between ethyl acetate and water. The aqueous layer was washed with
ethyl
acetate and then the combined ethyl acetate layers were washed with water (x3)
and brine,
dried over MgSO4 and concentrated. The residue was purified by column
chromatography
(50 - 100% CH2C12 - Hexanes) to yield the product as a yellow solid (180 mg, -
25% purity
by NMR, product co-elutes with the indole starting material). ESI-MS m/z calc.
287.1, found
288.5 (M+1)+. Retention time 1.59 minutes. 1H NMR (400 MHz, DMSO-d6) 8 12.23
(s, 1H),
8.14 (d, J = 9.1 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 6.60 (s, 1H), 5.10 (t, J =
5.5 Hz, 1H), 4.55
(t, J = 6.3 Hz, 2H), 3.78 - 3.73 (m, 2H) and 1.49 (s, 9H) ppm.
[023] Step b: 5-amino-2-tert-butyl-l-(2-hydroxyethyl)-1H-indole-4-carbonitrile
[024] To a solution of 2-tert-butyl- 1-(2-hydroxyethyl)-5 -nitro- I H-indole-4-
carbonitrile (180 mg, 0.63 mmol) in ethanol (6 mL) under N2 atmosphere was
added Pd-C
(5% wt, 18 mg). The reaction was flushed with N2 (g) and then with H2 (g) and
stirred under
H2 (atm) at room temperature for 1.5 hours. The reaction was filtered over
Celite and
concentrated to yield the product (150 mg, 93 %). ESI-MS m/z calc. 257.2,
found 258.5
(M+1)+. Retention time 1.26 minutes.
[025] Step c: N-(2-tert-butyl-4-cyano-l-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-
difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamide
[026] 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl
chloride (196 mg, 0.75 mmol) was added to a solution of 5-amino-2-tert-butyl-l-
(2-
hydroxyethyl)-1H-indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine
(242 L,
1.74 mmol) in dichloromethane (2 mL). The reaction was stirred at room
temperature
overnight. The reaction mixture was diluted with dichloromethane and extracted
with IN
HCl solution (x2), saturated NaHCO3 solution (x2), brine, dried over Mg504,
filtered and
concentrated. The residue was dissolved in DMSO and purified by reverse-phase
HPLC to
yield the product, N-(2-tert-butyl-4-cyano-l-(2-hydroxyethyl)-1H-indol-5-yl)-1-
(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc.
481.2, found
482.5 (M+1)+. Retention time 1.99 minutes. 1H NMR (400 MHz, DMSO-d6) 8 8.93
(s, 1H),
7.71 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.33 (d, J =
1.6 Hz, 1H), 7.08
(d, J = 8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J = 5.6 Hz, 1H), 4.42 (t, J = 6.8
Hz, 2H), 3.70 - 3.65
(m, 2H), 1.51 - 1.48 (m, 2H), 1.44 (s, 9H), 1.19 - 1.16 (m, 2H).
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2-(2-tert-butyl-5-(1-(2,2-difluorobenzo [d] [1,3] dioxol-5-
yl)cyclopropanecarboxamido)-6-fluoro-1 H-indol-1-yl)-N,N,N-
trimethylethanaminium chloride
F\,O
OH HZN / I \ i) 3, DMF :iii N
) Et Et3N DCM \ N 7Y
+ F\ / O F \ I N
HNO
O HN1j
O-~
H i) Mel, Et3N, DMF
TFNDCM FkkO N ii) HCI/MeOH H
FO O \~ \ FXo \ N /I \
F /\ O F N
NH2 CI-
[027] Step a: tert-Butyl 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-
5-
yl)cyclopropanecarboxamido)-6-fluoro-lH-indol-1-yl)ethylcarbamate
[028] To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic
acid (90.14 mg, 0.3722 mmol) in thionyl chloride (81.28 L, 1.117 mmol) was
added N,N -
dimethyl formamide (8.204 L, 0.1064 mmol). The reaction mixture was stirred
at room
temperature for 30 minutes before excess thionyl chloride and NN -dimethyl
formamide
were removed in vacuo to yield the acid chloride. The acid chloride was then
dissolved in
dichloromethane (1.5 mL) and added slowly to a solution of tert-butyl 2-(5-
amino-2-tert-
butyl-6-fluoro-lH-indol-1-yl)ethylcarbamate (156.1 mg, 0.4467 mmol) and
triethylamine
(155.6 L, 1.117 mmol) in dichloromethane (1.5 mL). The resulting reaction
mixture was
stirred at room temperature for 21 hours. The reaction mixture was diluted
with
dichloromethane (5 mL) and washed with IN aqueous HCl (5 mL) and a saturated
aqueous
NaHCO3 solution (5 mL). The organic layer was dried over Na2SO4, filtered and
evaporated
under reduced pressure. The crude product was purified by column
chromatography on silica
gel (0-30% ethyl acetate in hexane) to yield tert-butyl 2-(2-tert-butyl-5-(1-
(2,2-
difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1 H-indol-
l-
yl)ethylcarbamate as a white solid (140 mg, 66%). ESI-MS m/z calc. 573.2,
found 574.7
(M+1)+. Retention time 2.41 minutes. 1H NMR (400.0 MHz, DMSO) d 8.35 (s, 1H),
7.53
(s, 1H), 7.44 - 7.41 (m, 2H), 7.34 - 7.29 (m, 2H), 7.13 - 7.10 (m, 1H), 6.17
(s, 1H), 4.24 -
4.20 (m, 2H), 3.20 - 3.17 (m, 2H), 1.48-1.45 (m, 2H), 1.41 (s, 18H) and 1.15-
1.12 (m, 2H)
ppm.
[029] Step b: N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-
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difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamide
[030] To a solution of tert-butyl 2-(2-tert-butyl-5-(1-(2,2-
difluorobenzo[d] [ 1,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1 H-indol-
l-
yl)ethylcarbamate (137.5 mg, 0.24 mmol) in dichloromethane (1.8 mL) was added
trifluoroacetic acid (444 L, 5.8 mmol) and the mixture was stirred at room
temperature for 1
hour. The reaction was diluted with dichloromethane and washed with saturated
aqueous
NaHCO3 solution (3 mL) and brine (3 mL). The organic layer was dried over
Na2SO4,
filtered and evaporated under reduced pressure. The crude product was purified
by column
chromatography on silica gel (0-10% methanol in dichloromethane) to yield N-(1-
(2-
aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo [d] [
1,3]dioxol-5-
yl)cyclopropanecarboxamide as a white solid (93.7 mg, 82%). ESI-MS m/z calc.
473.19,
found 474.5 (M+1)+. Retention time 1.61 minutes.
[031] Step c: 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-6-fluoro-lH-indol-1-yl)-N,N,N-
trimethylethanaminium
chloride
[032] To a clear solution of N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-
indol-5-
yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (50 mg,
0.1056 mmol)
in NN -dimethyl formamide (1 mL), methyl iodide (336.8 mg, 147.7 L, 2.37
mmol) and
triethylamine (106.9 mg, 147.2 L, 1.05 mmol) were added and the mixture was
heated at 80
C for 2 hours. The crude product was purified by reverse phase preparative
HPLC. 22 mg of
this product were dissolved in 1.25 M HCl in methanol (112 L, 0.14 mmol) and
heated at 60
C for 1 hour. The reaction was cooled to room temperature. The product was
first dried and
then dissolved in dichloromethane and dried again. This procedure was repeated
four times
to yield 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxamido)-6-fluoro-lH-indol-1-yl)-N,N,N-
trimethylethanaminium
chloride. ESI-MS m/z calc. 516.25, found 516.7 (M+1)+. Retention time 1.69
minutes. 1H
NMR (400.0 MHz, DMSO) d 8.43 (s, 1H), 7.53 (s, 1H), 7.45 - 7.41 (m, 2H), 7.36 -
7.31 (m,
2H), 6.27 (s, 1H), 4.74 - 4.70 (m, 2H), 3.57 - 3.53 (m, 2H), 3.29 (s, 9H),
1.48 - 1.42 (m, 11H),
and 1.15 (dd, J = 3.9, 6.8 Hz, 2H) ppm.
2-(4-(Tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-6-fluoro-5-nitro-1 H-
indole
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O
02N :a OZN OZN" v \ Br ~OEt 02N
IOI~I/ HCI Bra I p
F / H F NHz F NHz Pd(PPh3)zClz/Et3N F I NH EIO
z
PdClz OzN O2N
DID I / N
TBSCITBSCI, imidazole O2N
A
F H O F H OH DCM F H
OEt OTBS
[033] Step a: 3-fluoro-4-nitroaniline
[034] A mixture of N-(3-fluoro-4-nitro-phenyl)-2, 2-dimethyl-propionamide
(87.0 g, 0.36 mol) in CH2C12 (400 mL) and 6N hydrochloric acid (800 mL) was
heated to
reflux for 2 hours. The reaction mixture was cooled to room temperature. The
reaction
mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate
(500.0 g) was
added portion wise. The aqueous solution was separated and the organic layer
was washed
with brine and dried over anhydrous Na2SO4. The solvent was removed by
evaporation
under reduced pressure; the residue was purified by column chromatography on
silica gel
(petroleum ether / ethyl acetate 30: 1) to afford 3-fluoro-4-nitroaniline
(56.0 g, 99 %). 1H
NMR (300 MHz, CDC13) 8 8.07 (t, J = 8.7 Hz, 1 H), 7.86 (dd, J= 2.1, 13.2 Hz 1
H), 7.59
(brs, 2 H), 7.22 (s, 1 H).
[035] Step b: 2-bromo-5-fluoro-4-nitroaniline
To a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500
mL) was added
drop-wise bromine (17.7 mL, 0.36 mol) over 1 hour. The reaction mixture was
stirred for 1
hour at 0-5 C in an ice bath. The reaction mixture was basified with
saturated Na2CO3 and
extracted with ethyl acetate (200 mL x 3). The combined organic layers were
washed with
brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced
pressure to
yield a residue that was purified by column chromatography on silica gel
(petroleum ether /
ethyl acetate 10 : 1) to give the 2-bromo-5-fluoro-4-nitroaniline ( 45.6 g, 84
% ) as a yellow
solid. 1H NMR (400 MHz, CDC13) 8 8.29 (d, J = 7.6 Hz, 1 H), 653 (d, J = 12.4
Hz, 1 H), 4.94
(br s, 2 H).
[036] Step c: ethyl 5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-
ynoate
[037] To a solution of 2-bromo-5-fluoro-4-nitroaniline (45.7 g, 0.19 mol) and
ethyl 3,3-dimethylpent-4-ynoate (88.3 g, 0.57 mol) in Et3N (700 mL) was added
Pd(PPh3)2C12 (13.8 g, 0.02 mol) and Cul (3.6 g, 0.02 mol) under N2. The
reaction mixture
was stirred at 70 C for 8 hours. The reaction mixture was diluted with 500 mL
of ethyl
acetate and 1500 mL of water. The organic layer was separated and the aqueous
phase was
extracted with ethyl acetate (500 mLx3), the combined organic layers were
washed with
brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced
pressure and
the residue was purified by column chromatography on silica gel (petroleum
ether / ethyl
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acetate 10: 1) to give ethyl-5-(2-amino-4-fluoro-5- nitrophenyl)-3,3-
dimethylpent-4-ynoate
(34.5 g, 57 %). 1H NMR (300 MHz, CDC13) 8 8.05 (d, J = 8.1Hz, 1 H), 6.36 (d, J
= 13.2 Hz,
1 H), 5.60 (brs, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 2.51 (s, 2 H), 1.40 (s, 6
H), 1.28 (t, J = 7.2 Hz,
3 H).
[038] Step d: ethyl 3-(6-fluoro-5-nitro-lH-indol-2-yl)-3-methylbutanoate
[039] To a mixture of ethyl 5-(2-amino-4-fluoro-5-nitrophenyl)-3, 3-
dimethylpent-4-ynoate (34.5 g, 0.11 mol) and PdC12 (10.4 g, 58.6 nmol) in
CH3CN (350 mL)
was heated to reflux for 1.5 hours. The reaction mixture was cooled down to
room
temperature. Ethyl acetate (300 mL) was added, the precipitate was filtered
off and washed
with methanol. The filtrate was concentrated under reduced pressure and the
residue was
purified by column chromatography on silica gel (petroleum ether / ethyl
acetate 40: 1) to
give ethyl 3-(6-fluoro-5-nitro-lH-indol-2-yl)-3-methylbutanoate (34.0 g, 98 %)
as a deep
yellow solid. 1H NMR (300 MHz, CDC13) 8 10.11 (brs, 1 H), 8.30 (d, J = 7.2 Hz,
1 H), 7.14
(d,J=11.7Hz,1H),6.35(d,J=1.5Hz,1H),4.17(q,J= 7.2 Hz, 2 H), 2.69 (s, 2 H), 1. 5
1
(s, 6 H), 1.25 (t, J = 7.2 Hz, 3 H).
[040] Step e: 3-(6-fluoro-5-nitro-lH-indol-2-yl)-3-methylbutan-l-ol
[041] To a solution of ethyl 3-(6-fluoro-5-nitro-lH-indol-2-yl)-3-
methylbutanoate (34 g, 0.11 mol) in dry CH2C12 (400 mL) was added drop-wise
DIBAL-H
(283.4 mL, 0.27 mol) over 2 hours at -78 C. The reaction mixture was stirred
for 10 hours at
-78 C and then quenched by adding water (200 mL). The precipitate was filtered
off and
washed with methanol. The filtrate was extracted with CH2C12 (200 mLx3), the
combined
organic layers were washed with brine, dried over anhydrous Na2SO4 and
concentrated under
reduced pressure. The residue was purified by column chromatography on silica
gel
(petroleum ether / ethyl acetate 50: 1) to give 3-(6-fluoro-5-nitro-lH-indol-2-
yl)-3-
methylbutan-1-ol (6.6 g, 22 %). 1H NMR (400 MHz, CDC13) 8 9.35 (brs, 1 H),
8.30 (d, J
7.6 Hz, 1 H), 7.11 (d, J = 12.0 Hz, 1 H), 6.35 (d, J = 1.2 Hz, 1 H), 3.74 (t,
J = 6.4 Hz, 2 H),
1.9(t,J=6.4Hz,2H), 1.4(s,6H).
[042] Step f: 2-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-6-fluoro-5-
nitro-lH-
indole
[043] To a solution of 3-(6-fluoro-5-nitro-lH-indol-2-yl)-3-methylbutan-l-ol
(6.6 g, 25 mmol) in CH2C12 (80 mL) was added TBSC1 (3.7 g, 25 nmol) and
imidazole (4.2 g,
62 nmol) at 0 C. The reaction mixture was stirred at room temperature for 12
hours. The
precipitate was filtered off and washed with the methanol. The filtrate was
concentrated
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under reduced pressure. The residue was purified by column chromatography on
silica gel
(petroleum ether / ethyl acetate 10: 1) to give the desired product as a brown
solid (5.0 g, 53
%). 1H NMR (300 MHz, CDC13) 8 9.80 (brs, 1 H), 8.30 (d, J = 7.2 Hz,1 H), 7.05
(d, J = 11.7
Hz, 1 H), 6.33 (t, J = 1.2 Hz, 1 H), 3.7 (t, J = 6.0 Hz, 2 H), 1.91 (t, J =
6.0 Hz, 2 H), 1.42 (s ,
6 H), 0.94 (s, 9 H), 0.12 (s, 6 H). MS (ESI) m/z (M+H+): 381.1.
Benzyl 2,2-dimethylbut-3-ynoate
O~ JOB NaH, Mel f0~ ~O PCIS, CH2CIz CI O NaOH, H2O
fv o"I A~ `O1-1 : ~0o reflux
CI 0 NaNH2 0 BnOH - 0
- OH DM SO ~OH DCC, CH2CI2 ~OCH2Ph
[044] Step a: methyl 2,2-dimethyl-3-oxobutanoate
[045] To a suspension of NaH (28.5 g, 0.718 mol, 60%) in THE (270 mL) was
added dropwise a solution of 3-oxo-butyric acid methyl ester (78.6 g, 0.677
mol) in THE (70
mL) at 0 C. The mixture was stirred for 0.5 hours at 0 C. Mel (99.0 g, 0.698
mol) was
added dropwise at 0 C. The resultant mixture was warmed to room temperature
and stirred
for 1 hour. NaH (28.5 g, 0.718 mol, 60%) was added in portions at 0 C and the
resulting
mixture was continued to stir for 0.5 h at 0 C. Mel (99.0 g, 0.698 mol) was
then added
dropwise at 0 C. The reaction mixture was warmed to room temperature and
stirred
overnight. The mixture was poured into ice water. The organic layer was
separated. The
aqueous phase was extracted with EtOAc (300 mL x 3). The combined organic
layers were
dried and evaporated under reduced pressure to give methyl 2,2-dimethyl-3-
oxobutanoate (52
g, 53%), which was used directly in the next step.
[046] Step b: methyl 3-chloro-2,2-dimethylbut-3-enoate
[047] To a suspention of PC15 (161 g, 0.772 mol) in dichloromethane (600 mL)
was
added dropwise methyl 2,2-dimethyl-3-oxobutanoate (52 g, 0.361 mol, crude from
last step)
at 0 C, followed by the addition of approximately 20 drops of dry DMF. The
mixture was
heated at reflux overnight. After cooling, the reaction mixture was slowly
poured into ice
water. The organic layer was separated and the aqueous phase was extracted
with
dichloromethane (300 mL x 3). The combined organic layers were washed with
saturated
aqueous NaHCO3 solution and dried over anhydrous Na2SO4. The solvent was
evaporated to
give the product, methyl 3-chloro-2,2-dimethylbut-3-enoate which was used
without further
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purification (47 g, 82%).
[048] Step c: 3-chloro-2,2-dimethylbut-3-enoic acid
[049] A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (42.0 g, 0.26 mol)
and
NaOH (12.4 g, 0.31 mol) in water (300 mL) was heated at reflux overnight.
After cooling,
the reaction mixture was extracted with ether. The organic layer contained 20g
of methyl 3-
chloro-2,2-dimethylbut-3-enoate (48 % recovered). The aqueous layer was
acidified with
cold 20% HCl solution and was extracted with ether (250 mL x 3). The combined
organic
layers were dried and evaporated under reduced pressure to give 3-chloro-2,2-
dimethylbut-3-
enoic acid (17 g, 44 %), which was used directly in the next step.
[050] Step d: 2,2-dimethylbut-3-ynoic acid
[051] To a three-neck flask (500 mL) was added NaNH2 (17.8 g, 0.458 mmol,
pellets) and DMSO (50 mL). The mixture was stirred at room temperature until
no more
NH3 (g) was given off. A solution of 3-chloro-2,2-dimethylbut-3-enoic acid
(17.0 g, 114
mmol) in DMSO (50 mL) was added dropwise at 0 C. The mixture was warmed and
stirred
at 50 C for 5 hours, then stirred at room temperature overnight. The mixture
was poured
into cold 20% HCl solution, and then extracted three times with ether. The
ether extracts
were dried over anhydrous Na2SO4 and concentrated to give a 6:1 ratio of
starting material
and alkyne product. The residue was re-dried using ether and Na2SO4 and re-
subjected to the
reaction conditions above. The reaction mixture was worked up in the same
manner to
provide 2,2-dimethylbut-3-ynoic acid (12.0 g, 94 %).
[052] benzyl 2,2-dimethylbut-3-ynoate
[053] To a stirred solution of 2,2-dimethylbut-3-ynoic acid (87.7 g, 0.782
mmol) and
benzyl alcohol (114.6 g, 0.938 mol) in dichloromethane (800 mL) was added DCC
(193.5 g,
0.938 mmol) at -20 C. The reaction mixture was stirred at room temperature
overnight and
then the solvent was evaporated in vacuo. The residue was purified by
chromatography on
silica gel (2% ethyl acetate in petroleum ether as eluant) to afford benzyl
2,2-dimethylbut-3-
ynoate (100 g, 59 % yield). 1H NMR (CDC13, 400 MHz) 8 7.37-7.36 (m, 5 H), 5.19
(s, 2 H),
2.28 (s, 1 H), 1.52 (s, 6 H).
2-(1-(Tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1 H-
indole
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~OCH2Ph
02N IO 2 N p PdC12 1P
\
F / NH2 Pd(PPh3)2C12/E13N O
F NH2 ph
p2N 02N \ 02N \
\ \ DIBAL-H I \ >_~ T I \
3W )
O / N / N
F N F H HO CH2C12 F H TBSO
H OCH2Ph
[054] Step a: benzyl 4-(2-amino-4-fluoro-5-nitrophenyl)-2,2-dimethylbut-3-
ynoate
[055] To a solution of 2-bromo-5-fluoro-4-nitroaniline (23.0 g, 0.1 mol) in
Et3N
(250 mL) was added benzoic 2,2-dimethylbut-3-ynoic anhydride (59.0 g, 0.29
mol), Cul
(1.85 g) and Pd(PPh3)2C12 (2.3 g) at room temperature. The mixture was stirred
at 80 C
overnight. After cooling to room temperature, the reaction was quenched with
water and the
aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined
organic layer
was dried over anhydrous Na2SO4, the solvent was evaporated in vacua. The
residue was
purified by chromatography on silica gel (10% ethyl acetate in petroleum
ether) to give
benzyl 4-(2-amino-4-fluoro-5-nitrophenyl)-2,2-dimethylbut-3-ynoate (20.0 g,
56%). 1H NMR
(400 MHz, CDC13) 8.05 (d, J = 8.4 Hz, 1 H), 7.39-7.38 (m, 5 H), 6.33 (d, J =
13.2 Hz, 1 H),
5.20 (s, 2 H), 4.89 (br s, 2 H), 1.61 (s, 6 H).
[056] Step b: benzyl 2-(6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate
[057] To a solution of benzyl 4-(2-amino-4-fluoro-5-nitrophenyl)-2,2-
dimethylbut-
3-ynoate (20.0 g, 56 mmol) in acetonitrile (100 mL) was added PdCl2 (5.0 g, 28
mmol) at
room temperature. The mixture was stirred at 80 C overnight. The mixture was
filtered off
and the solvent was evaporated in vacuo, the residue was purified by
chromatography on
silica gel (10% EtOAc in petroleum ether) to give benzyl 2-(6-fluoro-5-nitro-
1H-indol-2-yl)-
2-methylpropanoate (18.0 g, 90%). 1H NMR (300 MHz, CDC13) 8.96 (br s, 1 H),
8.33 (d, J =
7.2 Hz, 1 H) 7.35-7.28 (m, 5 H) 7.08 (d, J = 11.7 Hz, 1 H), 6.47 (s, 1 H),
5.18 (s, 2 H) 1.69 (s,
6 H).
[058] Step c: 2-(6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropan- l-ol
To a solution of benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate
(18.0 g, 0.05
mol) in CH2C12(100 mL) was added DIBAL-H (12 mL) at -78 C. The mixture was
stirred
for 1 h at that temperature and was warmed to room temperature. The reaction
was quenched
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with water and the aqueous layer was extracted with EtOAc (100 mL x 3). The
combined
organic layers were dried over anhydrous Na2SO4, the solvent was evaporated in
vacuo. The
residue was purified by chromatography on silica gel (10% EtOAc in petroleum
ether) to give
2-(6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropan-l-ol (10.0 g, 77%). 1H NMR
(300 MHz,
CDC13) 9.37 (s, 1 H), 8.32 (d, J = 7.2 Hz, 1 H), 7.11 (d, J = 11.7 Hz, 1 H),
6.36 (s, 1 H), 3.73
(d, J = 5.1 Hz 2 H), 1.97 (t, J = 5.1 Hz, 1 H), 1.39 (s, 6 H).
[059] Step d: 2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-fluoro-
5-nitro-
1H-indole
[060] To a stirred solution of 2-(6-fluoro-5-nitro-lH-indol-2-yl)-2-
methylpropan-l-
ol (10.0g) in CH2C12 was added TBSC1 (8.9 g), imidazole (8.1g, 0.12 mol) at
room
temperature. The mixture was stirred overnight. The solvent was evaporated in
vacuo and
the residue was purified by chromatography on silica gel (10% EtOAc in
petroleum ether) to
give 2- (1 -(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl) -6-fluoro- 5 -
nitro- I H-indole (5.3
g, 38 %). 1H NMR (300 MHz, CDC13) 9.51 (s, 1 H), 8.31 (d, J = 7.5 Hz, 1 H),
7.02 (d, J =
11.7 Hz, 1 H), 6.32 (s, 1 H), 3.63 (s, 2 H), 1.35 (s, 6 H), 0.99 (s, 9 H),
0.11 (s, 6 H).
6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole, (R)-3-
(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-
yl)-3-methylbutan-1-ol, 2-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)methoxy)-2-methylbutan-2-yl)-1-(((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)-6-fluoro-5-nitro-1H-indole, 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-
methylbutan-1-ol and (R)-2-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-
2-methylbutan-2-yl)-6-fluoro-5-nitro-1 H-indole
--~-O
0
OTs OH O
OZN I OZN 1I \ OZN I \ OZN \
/ F / N + N
F H CsCO3,DMF F / N + F
OTBDMS
o~ O-
OH Oy
OzN I \ ~ OzN I \
F H F H
[061] Step a: 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-lH-pyrrolo[1,2-
a]indole,
(R)-3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-
yl)-3-
methylbutan-1-ol, 2-(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-
methylbutan-2-yl)-
1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indole, 3-
(6-fluoro-5-
nitro-lH-indol-2-yl)-3-methylbutan-l-ol and (R)-2-(4-((2,2-dimethyl-1,3-
dioxolan-4-
yl)methoxy)-2-methylbutan-2-yl)-6-fluoro-5-nitro-1 H-indole
[062] To a solution of 2-(4-(tert-butyldimethylsilyloxy)-2-methylbutan-2-yl)-6-
fluoro- 5 -nitro- I H-indole (1.9 g, 5.0 mmol) and (S)-(2,2-dimethyl-1,3-
dioxolan-4-yl)methyl
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4-methylbenzenesulfonate (2.86 g, 10.0 mmol) in DMF (10 mL) was added Cs2CO3
(4.88 g,
15.0 mmol). The mixture was heated at 90 C for 24 hours. The reaction was
partitioned
between ethyl acetate and water. The aqueous layer was extracted with ethyl
acetate and the
combined organic layers were washed with brine and dried over MgSO4. After the
removal
of solvent, the residue was purified by column chromatography (10-50% ethyl
acetate -
hexane) to afford 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-lH-pyrrolo[1,2-
a]indole (600
mg, 48%). ESI-MS m/z calc. 248.1, found 249.2 (M+1)+. Retention time 2.00
minutes; 2-
(4-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-yl)-1-(((R)-
2,2-dimethyl-
1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indole (270 mg, containing some
(R)-2-(4-
((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-yl)-6-fluoro-5-nitro-
1H-indole).
ESI-MS m/z calc. 494.2 and 380.2, found 495.4 and 381.4 (M+1)+. Retention time
2.12 and
1.92 minutes; (R)-3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-
nitro-lH-indol-
2-yl)-3-methylbutan-l-ol (1.0 g, containing some 3-(6-fluoro-5-nitro-lH-indol-
2-yl)-3-
methylbutan-1-ol). ESI-MS m/z calc. 380.2 and 266.1, found 381.2 and 267.2
(M+1)+.
Retention time 1.74 and 1.48 minutes.
(R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1 H-indol-
2-yl)-2-methylpropan-1-ol and 3-(6-fluoro-5-nitro-1H-indol-2-yl)-3-
methylbutan-1-ol
`Ts_
OzN I T O _ 02N \
I \ OH OzN OH
\ ` ~ ) \% ` / + ) O
F H OTBDMS CsCO F N F H
O
O~
[063] A mixture containing (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-5-nitro-lH-indol-2-yl)-2-methylpropan-l-ol and 3-(6-fluoro-5-nitro-lH-
indol-2-yl)-3-
methylbutan-1-ol was obtained following the procedure shown above starting
from 2-(1-(tert-
butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole. (R)-2-
(1-((2,2-
dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-
methylpropan- l-ol,
ESI-MS m/z calc. 366.2, found 367.2 (M+1)+. Retention time 1.71 minutes; 3-(6-
fluoro-5-
nitro-lH-indol-2-yl)-3-methylbutan-l-ol, ESI-MS m/z calc. 252.1, found 253.4
(M+1)+.
Retention time 1.42 minutes.
1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-N-(6-fluoro-1,1-dimethyl-2,3-dihydro-
1H-pyrrolo [1,2-a]indol-7-yl)cyclopropanecarboxamide
OZN H2N \ Fxo ~~~7off F O` N
NH4+COZ I ::F F F N
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[064] Step a: 6-fluoro-1,1-dimethyl-2,3-dihydro-lH-pyrrolo[1,2-a]indol-7-amine
[065] To a solution of 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-lH-
pyrrolo[1,2-a]indole (600 mg, 2.4 mmol) in ethanol (15 mL) was added ammonium
formate
(600 mg, 9.5 mmol) and Pd/C (10%, 129 mg, 0.12 mmol). The mixture was refluxed
for 10
min. The Pd catalyst was removed via filtration through Celite and washed with
ethanol.
The filtrate was concentrated and purified by column chromatography (20-40%
ethyl acetate-
hexanes) to provide 6-fluoro-1,1-dimethyl-2,3-dihydro-lH-pyrrolo[1,2-a]indol-7-
amine (260
mg, 49 %). ESI-MS m/z calc. 218.1, found 219.2 (M+1)+. Retention time 1.01
minutes.
[066] Step b: 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-1,1-
dimethyl-
2,3-dihydro-1 H-pyrrolo [ 1,2-a]indol-7-yl)cyclopropanecarboxamide
[067] To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylic acid (346 mg,1.4 mmol), 6-fluoro-1,1-dimethyl-2,3-
dihydro-lH-
pyrrolo[1,2-a]indol-7-amine (260 mg, 1.2 mmol) and HATU (543 mg, 1.4 mmol) in
DMF (5
mL) was added triethylamine (0.40 mL, 2.9 mmol). The reaction was stirred at
room
temperature overnight and then partitioned between ethyl acetate and water.
The aqueous
layer was extracted with ethyl acetate and the combined organic layers were
washed with
brine and dried over MgS04. After the removal of solvent, the residue was
purified by
column chromatography (10-20% ethyl acetate - hexanes) to afford 1-(2,2-
difluorobenzo[d] [ 1,3]dioxol-5-yl)-N-(6-fluoro-1,1-dimethyl-2,3-dihydro-1 H-
pyrrolo [ 1,2-
a]indol-7-yl)cyclopropanecarboxamide (342 mg, 65 %). ESI-MS m/z calc. 442.2,
found
443.5 (M+1)+. Retention time 2.30 minutes. 'H NMR (400 MHz, DMSO-d6) 8 8.20
(d, J =
7.6 Hz, 1H), 7.30 - 7.25 (m, 3H), 7.20 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.84
(d, J = 11.1 Hz,
1H), 6.01 (d, J = 0.5 Hz, 1H), 3.98 (t, J = 6.8 Hz, 2H), 2.37 (t, J = 6.8 Hz,
2H), 1.75 (dd, J =
3.8, 6.9 Hz, 2H), 1.37 (s, 6H) and 1.14 (dd, J = 3.9, 6.9 Hz, 2H) ppm.
(R)-1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-
fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
OH OH H OH
OzN HzN ~ F O OH FO N
NH4*CO2 I Fx0 O
F N Pd-C, EtOH F / N \ / HATU, Et3N, DMF F 0 / ~Y'N
~00/~
H OH
N
F` ,O
pTSA.HzO x
MeOH, H2O F 0 )10 F):) N
~OH
OH
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[068] Step a: (R)-3-(5-amino- l-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-
1 H-indol-2-yl)-3-methylbutan-l-ol
[069] To a solution of (R)-3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-5-nitro-lH-indol-2-yl)-3-methylbutan-l-ol containing some 3-(6-fluoro-5-
nitro-lH-
indol-2-yl)-3-methylbutan-l-ol (500 mg, 1.3 mmol) in ethanol (10 mL) was added
ammonium formate (500 mg, 7.9 mmol) and Pd/C (10%, 139 mg, 0.13 mmol). The
mixture
was refluxed for 5 min. The Pd catalyst was removed via filtration through
Celite and
washed with ethanol. The filtrate was evaporated to dryness and purified by
column
chromatography (30-50% ethyl acetate-hexanes) to provide (R)-3-(5-amino-1-
((2,2-dimethyl-
1,3-dioxolan-4-yl)methyl)-6-fluoro-lH-indol-2-yl)-3-methylbutan-l-ol (220 mg,
48 %,
contains some 3-(5-amino- 6-fluoro-lH-indol-2-yl)-3-methylbutan-l-ol). ESI-MS
m/z calc.
350.2 found 351.4 (M+1)+. Retention time 0.94 minutes.
[070] Step b: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-
1,3-
dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1 H-indol-5 -
yl)cyclopropanecarboxamide
[071] To a mixture of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylic acid (183 mg, 0.75 mmol), (R)-3-(5-amino- l-((2,2-
dimethyl-l,3-
dioxolan-4-yl)methyl)-6-fluoro-lH-indol-2-yl)-3-methylbutan-l-ol containing
some 3-(5-
amino-6-fluoro-lH-indol-2-yl)-3-methylbutan-l-ol (220 mg, 0.63 mmol) and HATU
(287
mg, 0.75 mmol) in DMF (3.0 mL) was added triethylamine (0.21 mL, 1.5 mmol).
The
reaction was stirred at room temperature overnight and then partitioned
between ethyl acetate
and water. The aqueous layer was extracted with ethyl acetate and the combined
organic
layers were washed with brine and dried over MgSO4. After the removal of
solvent, the
residue was purified by column chromatography (20-40% ethyl acetate - hexanes)
to afford
(R)-1-(2,2-difluorobenzo [d] [ 1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)-
6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide (315
mg, 87 %, contains some 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-
(4-hydroxy-
2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide). ESI-MS m/z calc.
574.2
found 575.7 (M+1)+. Retention time 2.08 minutes.
[072] Step c: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-
dihydroxypropyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
[073] To a solution of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-
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((2,2-dimethyl-1, 3-dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-
2-yl)-1 H-
indol-5-yl)cyclopropanecarboxamide containing some 1-(2,2-
difluorobenzo[d][1,3]dioxol-5-
yl)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
(315 mg, 0.55 mmol) in methanol (3 mL) and water (0.3 mL) was added p-TsOH.H20
(21
mg, 0.11 mmol). The mixture was heated at 80 C for 30 minutes. The reaction
was
partitioned between ethyl acetate and water and the aqueous layer was
extracted with ethyl
acetate twice. The combined organic layers were washed with saturated. NaHCO3
solution
and brine and dried over MgSO4. After the removal of solvent, the residue was
purified by
column chromatography (20-80% ethyl acetate - hexanes) to provide (R)-1-(2,2-
difluorobenzo[d] [ 1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(4-
hydroxy-2-
methylbutan-2-yl)- 1H-indol-5-yl)cyclopropanecarboxamide (92 mg, 31%). ESI-MS
m/z calc.
534.2, found 535.5 (M+1)+. Retention time 1.72 minutes. 'H NMR (400 MHz, DMSO-
d6) 8
8.32 (s, 1H), 7.53 (d, J = 1.0 Hz, 1H), 7.43 - 7.31 (m, 4H), 6.17 (s, 1H),
4.97 - 4.92 (m, 2H),
4.41 (dd, J = 2.4, 15.0 Hz, 1H), 4.23 (t, J = 5.0 Hz, 1H), 4.08 (dd, J = 8.6,
15.1 Hz, 1H), 3.87
(s, 1H), 3.48 - 3.44 (m, 1H), 3.41 - 3.33 (m, 1H), 3.20 (dd, J = 7.4, 12.7 Hz,
2H), 1.94 - 1.90
(m, 2H), 1.48 - 1.45 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H) and 1.15 - 1.12 (m,
2H) ppm.
1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-N-(2-(4-((S)-2,3-dihydroxypropoxy)-
2-methylbutan-2-yl)-1-((R)-2,3-dihydroxypropyl)-6-fluoro-1H-indol-5-
yl)cyclopropanecarboxamide and (S)-1-(2,2-difluorobenzo[d] [1,3]dioxol-5-
yl)-N-(2-(4-(2,3-dihydroxypropoxy)-2-methylbutan-2-yl)-6-fluoro-1 H-
indol-5-yl)cyclopropanecarboxamide
HO HO
HOB HOB
H O H O
FXxO N Fx0 lil~t N N
F p l/ O F I/ N F p O F I/
H
OH
OH
[074] 1-(2,2-difluorobenzo[ d][1,3]dioxol-5-yl)-N-(2-(4-((S)-2,3-
dihydroxypropoxy)-
2-methylbutan-2-yl)-1-((R)-2,3-dihydroxypropyl)-6-fluoro-lH-indol-5-
yl)cyclopropanecarboxamide and (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-
(2-(4-(2,3-
dihydroxypropoxy)-2-methylbutan-2-yl)-6-fluoro-1 H-indol-5-
yl)cyclopropanecarboxamide
[075] 1-(2,2-difluorobenzo[ d][1,3]dioxol-5-yl)-N-(2-(4-((S)-2,3-
dihydroxypropoxy)-
2-methylbutan-2-yl)-1-((R)-2,3-dihydroxypropyl)-6-fluoro-lH-indol-5-
yl)cyclopropanecarboxamide and (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-
(2-(4-(2,3-
dihydroxypropoxy)-2-methylbutan-2-yl)-6-fluoro-1 H-indol-5-
yl)cyclopropanecarboxamide
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were made following a scheme similar as shown above starting from 2-(4-(((R)-
2,2-dimethyl-
1,3-dioxolan-4-yl)methoxy)-2-methylbutan-2-yl)-1-(((R)-2,2-dimethyl-1,3-
dioxolan-4-
yl)methyl)-6-fluoro-5-nitro-1H-indole containing some (R)-2-(4-((2,2-dimethyl-
1,3-dioxolan-
4-yl) methoxy)-2-methylbutan-2-yl) -6-fluoro-5 -nitro-1 H-indole). 1-(2,2-
difluorobenzo[d] [ 1,3]dioxol-5-yl)-N-(2-(4-((S)-2,3-dihydroxypropoxy)-2-
methylbutan-2-yl)-
1-((R)-2,3-dihydroxypropyl)-6-fluoro-lH-indol-5-yl)cyclopropanecarboxamide,
ESI-MS m/z
calc. 608.2, found 609.5 (M+1)+. Retention time 1.67 minutes. 1H NMR (400 MHz,
DMSO-
d6) 8 8.32 (s, 1H), 7.53 (s, 1H), 7.43 - 7.31 (m, 4H), 6.19 (s, 1H), 4.95 -
4.93 (m, 2H), 4.51
(d, J = 5.0 Hz, 1H), 4.42 - 4.39 (m, 2H), 4.10 - 4.04 (m, 1H), 3.86 (s, 1H),
3.49 - 3.43 (m,
2H), 3.41 - 3.33 (m, 1H), 3.30 - 3.10 (m, 6H), 2.02 - 1.97 (m, 2H), 1.48 -
1.42 (m, 8H) and
1.13 (dd, J = 4.0, 6.7 Hz, 2H) ppm ; (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-
yl)-N-(2-(4-
(2, 3-dihydroxypropoxy)-2-methylbutan-2-yl)-6-fluoro-1 H-indol-5-
yl)cyclopropanecarboxamide, ESI-MS m/z calc. 534.2, found 535.5 (M+1)+.
Retention time
1.81 minutes. 1H NMR (400 MHz, DMSO-d6) 8 10.91 (d, J = 1.5 Hz, 1H), 8.30 (s,
1H), 7.53
(s, 1H), 7.42 - 7.33 (m, 3H), 7.03 (d, J = 10.9 Hz, 1H), 6.07 (d, J = 1.6 Hz,
1H), 4.56 (d, J =
5.0 Hz, 1H), 4.43 (t, J = 5.7 Hz, 1H), 3.51 - 3.46 (m, 1H), 3.31 - 3.13 (m,
6H), 1.88 (t, J = 7.3
Hz, 2H), 1.48 - 1.45 (m, 2H), 1.31 (s, 6H) and 1.15 - 1.12 (m, 2H) ppm.
1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl)-N-(6-fluoro-2-(1-hydroxy-2-
methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide
H
><: I O ~~~/N
F H
[076] 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(1-hydroxy-2-
methylpropan-2-yl)-1 H-indol-5-yl)cyclopropanecarboxamide
[077] 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(1-hydroxy-2-
methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide was made following
the
scheme shown above starting from a mixture containing (R)-2-(1-((2,2-dimethyl-
l,3-
dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropan-l-ol and
3-(6-fluoro-
5-nitro-lH-indol-2-yl)-3-methylbutan-l-ol. ESI-MS m/z calc. 446.2, found 447.5
(M+1)+.
Retention time 1.88 minutes. 1H NMR (400 MHz, CDC13) 8 8.68 (s, 1H), 8.20 (d,
J = 7.7 Hz,
1H), 7.30 - 7.21 (m, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 11.2 Hz, 1H),
6.18 (s, 1H),
3.64 (s, 2H), 1.75 (dd, J = 3.8, 6.8 Hz, 2H), 1.34 (s, 6H) and 1.14 (dd, J =
3.9, 6.9 Hz, 2H)
ppm.
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(R)-1-(2,2-Difluorobenzo[d] [1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-
fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1 H-indol-5-
yl)cyclopropanecarboxamide
O17
Ts O O~ 1\/
OzN \ ~~ 02N \ O / OzN O 02N \ OH
O \ + \ LIAIHn, THF
F H OCH2Ph CsCO3, DMF F N F N F / N
OH
H2Ni \ OH Fx0 O F~/ON \ OH F~ \ OH
Hy Pd-C \ SOCI DMF /~ ) pTSA.H20
EtOH F / NI\_ F O O F / N McOH, H2O F O O F ' N
`O' 2) Et3N, CH2C12 Ox- OH
OH
[078] Step a: (R)-Benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-5-
nitro-1H-indol-2-yl)-2-methylpropanoate and ((S)-2,2-Dimethyl-1,3-dioxolan-4-
yl)methyl 2-
(1-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1 H-indol-2-
yl) -2-
methylpropanoate
[079] Cesium carbonate (8.23 g, 25.3 mmol) was added to a mixture of
benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (3.0 g, 8.4 mmol)
and (S)-
(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (7.23 g, 25.3
mmol) in
DMF (17 mL). The reaction was stirred at 80 C for 46 hours under nitrogen
atmosphere. The
mixture was then partitioned between ethyl acetate and water. The aqueous
layer was
extracted with ethyl acetate. The combined ethyl acetate layers were washed
with brine, dried
over MgS04, filtered and concentrated. The crude product, a viscous brown oil
which
contains both of the products shown above, was taken directly to the next step
without further
purification. (R)-Benzyl2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-
5-nitro-1H-
indol-2-yl)-2-methylpropanoate, ESI-MS m/z calc. 470.2, found 471.5 (M+1)+.
Retention
time 2.20 minutes. ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((R)-2,2-
dimethyl-1,3-
dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-
MS m/z
calc. 494.5, found 495.7 (M+1)+. Retention time 2.01 minutes.
[080] Step b: (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-
nitro-
1 H-indol-2-yl)-2-methylpropan- l -ol
[081] To the crude reaction mixture obtained in step (a) was dissolved in
THE (42 mL) and cooled in an ice-water bath. LiAlH4 (16.8 mL of 1 M solution,
16.8 mmol)
was added drop-wise. After the addition was complete, the reaction was stirred
for an
additional 5 minutes. The reaction was quenched by adding water (1 mL), 15%
NaOH
solution (1 mL) and then water (3 mL). The mixture was filtered over Celite,
and the solids
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were washed with THE and ethyl acetate. The filtrate was concentrated and
purified by
column chromatography (30-60% ethyl acetate- hexanes) to obtain the product as
a brown oil
(2.68g, 87 % over 2 steps). ESI-MS m/z calc. 366.4, found 367.3 (M+1)+.
Retention time
1.68 minutes. 1H NMR (400 MHz, DMSO-d6) 8 8.34 (d, J = 7.6 Hz, 1H), 7.65 (d, J
= 13.4
Hz, 1H), 6.57 (s, 1H), 4.94 (t, J = 5.4 Hz, 1H), 4.64 - 4.60 (m, 1H), 4.52 -
4.42(m, 2H), 4.16 -
4.14 (m, 1H), 3.76 - 3.74 (m, 1H), 3.63 - 3.53 (m, 2H), 1.42 (s, 3H), 1.38 -
1.36 (m, 6H) and
1.19 (s, 3H) ppm
[082] Step c: (R)-2-(5-amino- 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-
1 H-indol-2-yl)-2-methylpropan- l -ol
[083] (R)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-
1H-indol-2-yl)-2-methylpropan-l-ol (2.5 g, 6.82 mmol) was dissolved ethanol
(70 mL) and
the reaction was flushed with N2. Then Pd-C (250 mg, 5% wt) was added. The
reaction was
flushed with nitrogen again and then stirred under H2 (atm). After 2.5 hours
only partial
conversion to the product was observed by LCMS. The reaction was filtered
through Celite
and concentrated. The residue was re-subjected to the conditions above. After
2 hours LCMS
indicated complete conversion to product. The reaction mixture was filtered
through Celite.
The filtrate was concentrated to yield the product as a black solid (1.82 g,
79 %). ESI-MS
m/z calc. 336.2, found 337.5 (M+1)+. Retention time 0.86 minutes. 1H NMR (400
MHz,
DMSO-d6) 8 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.03 (s, 1H),
4.79 - 4.76 (m,
1H), 4.46 (s, 2H), 4.37 - 4.31 (m, 3H),4.06 (dd, J = 6.1, 8.3 Hz, 1H), 3.70 -
3.67 (m, 1H), 3.55
- 3.52 (m, 2H), 1.41 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
[084] Step d: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-
1,3-
dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
[085] DMF (3 drops) was added to a stirring mixture of 1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (1.87 g, 7.7
mmol) and thionyl
chloride (1.30 mL, 17.9 mmol). After 1 hour a clear solution had formed. The
solution was
concentrated under vacuum and then toluene (3 mL) was added and the mixture
was
concentrated again. The toluene step was repeated once more and the residue
was placed on
high vacuum for 10 minutes. The acid chloride was then dissolved in
dichloromethane (10
mL) and added to a mixture of (R)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)-6-
fluoro-lH-indol-2-yl)-2-methylpropan-l-ol (1.8 g, 5.4 mmol) and triethylamine
(2.24 mL,
16.1 mmol) in dichloromethane (45 mL). The reaction was stirred at room
temperature for 1
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hour. The reaction was washed with IN HCl solution, saturated NaHCO3 solution
and brine,
dried over MgSO4 and concentrated to yield the product as a black foamy solid
(3g, 100%).
ESI-MS m/z calc. 560.6, found 561.7 (M+1)+. Retention time 2.05 minutes. 1H
NMR (400
MHz, DMSO-d6) 8 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34 - 7.30
(m, 3H), 6.24
(s, 1H), 4.51 - 4.48 (m, 1H), 4.39 - 4.34 (m,2H), 4.08 (dd, J = 6.0, 8.3 Hz,
1H), 3.69 (t, J = 7.6
Hz, 1H), 3.58 - 3.51 (m, 2H), 1.48 - 1.45 (m, 2H), 1.39 (s, 3H), 1.34 - 1.33
(m, 6H), 1.18 (s,
3H) and 1.14 - 1.12 (m, 2H) ppm
[086] Step e: (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-
dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
[087] (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide (3.0 g, 5.4 mmol) was dissolved in methanol (52
mL). Water
(5.2 mL) was added followed by p-TsOH.H20 (204 mg, 1.1 mmol). The reaction was
heated
at 80 C for 45 minutes. The solution was concentrated and then partitioned
between ethyl
acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over
MgS04 and
concentrated. The residue was purified by column chromatography (50-100 %
ethyl acetate -
hexanes) to yield the product as a cream colored foamy solid. (1.3 g, 47 %, ee
>98% by
SFC). ESI-MS m/z calc. 520.5, found 521.7 (M+1)+. Retention time 1.69 minutes.
1H NMR
(400 MHz, DMSO-d6) 8 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.38 (m, 2H), 7.33 -
7.30 (m, 2H),
6.22 (s, 1H), 5.01 (d, J = 5.2 Hz, 1H), 4.90 (t, J = 5.5 Hz, 1H), 4.75 (t, J =
5.8 Hz, 1H), 4.40
(dd, J = 2.6, 15.1 Hz, 1H), 4.10 (dd, J = 8.7, 15.1 Hz, 1H), 3.90 (s, 1H),
3.65 - 3.54 (m, 2H),
3.48 - 3.33 (m, 2H), 1.48 - 1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 -
1.11 (m, 2H)
ppm.
(S)-1-(2,2-Difluorobenzo[d] [1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-
fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1 H-indol-5-
yl)cyclopropanecarboxamide
,N o>~ ozN ozN o o ozN OH
LIAIHa THE
F H OCH2Ph CsCO DMF F o + F N F N
O
on
N OH
HEN OH F~ON. SOH F\p? YO
Hz, Pd-C SOCK, DMF //\\PTSAH2O X ::CH
N
EtOH F N F McOH, Hz0 F
p) Et,N, CH2G12 ."'k 'OH
O OH
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[088] Step a: (S)-Benzyl 2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-5-
nitro-1H-indol-2-yl)-2-methylpropanoate and ((R)-2,2-Dimethyl-1,3-dioxolan-4-
yl)methyl 2-
(1-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1 H-indol-2-
yl)-2-
methylpropanoate
[089] Cesium carbonate (2.74 g, 8.4 mmol) was added to a mixture of benzyl
2-(6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate (1.0 g, 2.8 mmol) and
(S)-(2,2-
dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (3.21 g, 11.2 mmol)
in DMF
(5.6 mL). The reaction was stirred at 80 C for 64 hours under nitrogen
atmosphere. The
mixture was then partitioned between ethyl acetate and water. The aqueous
layer was
extracted with ethyl acetate. The combined ethyl acetate layers were washed
with brine, dried
over MgSO4, filtered and concentrated. The crude product, a viscous brown oil
which
contains both of the products shown above, was taken directly to the next step
without further
purification. (S)-Benzyl2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-
5-nitro-1H-
indol-2-yl)-2-methylpropanoate, ESI-MS m/z calc. 470.2, found 471.5 (M+1)+.
Retention
time 2.22 minutes. ((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((S)-2,2-
dimethyl-1,3-
dioxolan-4-yl)methyl)-6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate, ESI-
MS m/z
calc. 494.5, found 495.5 (M+1)+. Retention time 2.03 minutes.
[090] Step b: (S)-2-(1-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-
nitro-
1 H-indol-2-yl)-2-methylpropan- l -ol
[091] The mixture of crude reaction mixture of (S)-benzyl 2-(1-((2,2-
dimethyl- 1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-
methylpropanoate and
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl 2-(1-(((S)-2,2-dimethyl-1,3-
dioxolan-4-
yl)methyl)-6-fluoro-5-nitro-lH-indol-2-yl)-2-methylpropanoate was dissolved in
THE (15
mL) and cooled in an ice-water bath. LiAlH4 (2.8 mL of 1 M solution, 2.8 mmol)
was added
dropwise. After addition was complete the reaction was stirred for 5 minutes.
The reaction
was quenched by adding water (0.5 mL), 15% NaOH solution (0.5 mL) and then
water (1.5
mL). The mixture was filtered over Celite, and the solids were washed with THE
and ethyl
acetate. The filtrate was concentrated and purified by column chromatography
(30-60% ethyl
acetate- hexanes) to obtain the product as a brown oil (505 mg, 49 % over 2
steps). ESI-MS
m/z calc. 366.4, found 367.3 (M+1)+. Retention time 1.68 minutes. 1H NMR (400
MHz,
DMSO-d6) 8 8.34 (d, J = 7.6 Hz, 1H), 7.65(d, J = 13.5 Hz, 1H), 6.57 (s, 1H),
4.94 (t, J = 5.4
Hz, 1H), 4.64 - 4.60 (m, 1H), 4.52 - 4.42 (m, 2H), 4.14 (dd, J = 6.2, 8.4 Hz,
1H), 3.74 (dd, J =
7.0, 8.3 Hz, 1H), 3.63 - 3.53 (m,2H), 1.42 (s, 3H), 1.37 (m, 6H) and 1.19 (s,
3H) ppm.
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[092] Step c: (S)-2-(5-amino-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-
fluoro-
1 H-indol-2-yl)-2-methylpropan- l -ol
[093] (S)-2-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-nitro-
1H-indol-2-yl)-2-methylpropan-l-ol (500 mg, 1.4 mmol) was dissolved ethanol
(15 mL) and
the reaction was flushed with N2. Then Pd-C (50 mg, 5% wt) was added. The
reaction was
flushed with nitrogen again and then stirred under H2 (atm). After 1 hour only
partial
conversion to the product was observed by LCMS. The reaction was filtered
through Celite
and concentrated. The residue was resubjected to the conditions above. After 1
hour LCMS
indicated complete conversion to product. The reaction mixture was filtered
through Celite.
The filtrate was concentrated to yield the product as a black solid (420 mg,
91 %). ESI-MS
m/z calc. 336.2, found 337.5 (M+1)+. Retention time 0.90 minutes. 1H NMR (400
MHz,
DMSO-d6) 8 7.17 (d, J = 12.6 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 6.03 (s, 1H),
4.78 (br s, 1H),
4.46 (s, 2H), 4.41 - 4.27 (m, 3H), 4.06(dd, J = 6.1, 8.3 Hz, 1H), 3.70 - 3.67
(m, 1H), 3.53 (dd,
J = 10.7, 17.2 Hz, 2H), 1.40 (s, 3H), 1.32 (s, 6H) and 1.21 (s, 3H) ppm.
[094] Step d: (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-
1,3-
dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
[095] DMF (3 drops) was added to a stirring mixture of 1-(2,2-
difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (187 mg, 0.8
mmol) and
thionyl chloride (0.13 mL, 1.8 mmol). After 30 minutes a clear solution had
formed. A small
amount was mixed piperidine to test that the acid chloride had been formed.
The solution was
concentrated on the rotovap and then toluene (1 mL) was added and the mixture
was
concentrated again. The toluene step was repeated once more and the residue
was placed on
high vacuum for 10 minutes. The acid chloride was then dissolved in
dichloromethane (2
mL) and added to a mixture of (S)-2-(5-amino-I-((2,2-dimethyl-1,3-dioxolan-4-
yl)methyl)-6-
fluoro-lH-indol-2-yl)-2-methylpropan-l-ol (200 mg, 0.6 mmol) and triethylamine
(0.25 mL,
1.8 mmol) in dichloromethane (4 mL). The reaction was stirred at room
temperature for 45
minutes. The reaction was washed with IN HCl solution, saturated NaHCO3
solution and
brine, dried over Mg504 and concentrated to yield the product as a black foamy
solid (320
mg, 96 %). ESI-MS m/z calc. 560.6, found 561.5 (M+1)+. Retention time 2.05
minutes. IH
NMR (400 MHz, DMSO-d6) 8 8.31 (s, 1H), 7.53 (s, 1H), 7.42 - 7.40 (m, 2H), 7.34
- 7.30 (m,
3H), 6.24 (s, 1H), 4.84 (t, J = 5.5 Hz, 1H), 4.51 - 4.46 (m, 1H), 4.41 - 4.32
(m, 2H), 4.08 (dd,
J = 6.0, 8.3 Hz, 1H), 3.71 - 3.67 (m, 1H), 3.58 - 3.50 (m, 2H), 1.48 - 1.45
(m, 2H), 1.40 (s,
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3H), 1.34 - 1.33 (m, 6H), 1.18 (s, 3H) and 1.14 - 1.12 (m, 2H) ppm.
[096] Step e: (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-
dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide
[097] (S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-
dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-
yl)cyclopropanecarboxamide (290 g, 0.5 mmol) was dissolved in methanol (5 mL).
Water
(0.5 mL) was added followed by p-TsOH.H20 (20 mg, 0.1 mmol). The reaction was
heated
at 80 C for 45 minutes. The solution was then partitioned between ethyl
acetate and
saturated NaHCO3 solution. The ethyl acetate layer was dried over MgS04 and
concentrated.
The residue was purified by column chromatography (50-100 % ethyl acetate -
hexanes) to
yield the product as a cream colored foamy solid. (146 mg, 54 %, ee >97% by
SFC). ESI-MS
m/z calc. 520.5, found 521.5 (M+1)+. Retention time 1.67 minutes. 1H NMR (400
MHz,
DMSO-d6) 8 8.31 (s, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.33 -
7.30 (m, 2H),
6.22 (s, 1H), 5.01 (d, J = 5.0 Hz, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.75 (t, J =
5.8 Hz, 1H), 4.42 -
4.38 (m, 1H), 4.10 (dd, J = 8.8, 15.1 Hz, 1H), 3.90 (s, 1H), 3.64 - 3.54 (m,
2H), 3.48 - 3.33
(m, 2H), 1.48 - 1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 - 1.11 (m,
2H) ppm.
(R)-1-(benzo[d] [1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-6-
fluoro-1 H-indol-5-yl)cyclopropanecarboxamide
H
CO \ N
O O F N
OH
OH
[098] (R)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-
6-
fluoro-lH-indol-5-yl)cyclopropanecarboxamide was prepared using an
experimental
procedure similar to example 72 from 1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylic
acid and 2-tert-butyl-6-fluoro-5-nitro-lH-indole.
(S)-1-(benzo [d] [1,3] dioxol-5-yl)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-6-
fluoro-1 H-indol-5-yl)cyclopropanecarboxamide
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H
CO D0110 N O F N
OH
OH
[099] (S)-1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-
6-
fluoro-lH-indol-5-yl)cyclopropanecarboxamide was prepared using an
experimental
procedure similar to Example 72 from 1-(benzo[d][1,3]dioxol-5-
yl)cyclopropanecarboxylic
acid and 2-tert-butyl-6-fluoro-5 -nitro- I H-indole.
(R)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(3,4-
dihydroxyphenyl)cyclopropanecarboxamide
H
HO ::::f N HO I O I / N
OH
OH
[0100] (R)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(3,4-
dihydroxyphenyl)cyclopropanecarboxamide was prepared using an experimental
procedure
similar to Example 72 from 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid
and 2-tert-
butyl-5-nitro-1 H-indole.
(R)-N-(2-tert-butyl-l -(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,3-dihydro-
1H-inden-5-yl)cyclopropanecarboxamide
H
N
N
OH
OH
[001015] (R)-N-(2-tert-butyl-l-(2,3-dihydroxypropyl)-1H-indol-5-yl)-1-(2,3-
dihydro-lH-
inden-5-yl)cyclopropanecarboxamide was prepared using an experimental
procedure similar
to Example 72 from 1-(2,3-dihydro-1H-inden-5-yl)cyclopropanecarboxylic acid
and 2-tert-
butyl-5-nitro-1 H-indole.
[001016] A person skilled in the chemical arts can use the examples and
schemes along with
known synthetic methodologies to synthesize compounds of the present
invention, including
the compounds in Table 3, below.
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Table 3: Physical data of exemplary compounds.
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d M+1 Min d M+1 Min
No. No.
1 373.3 2.49 11 452.3 2.51
2 469.4 3.99 12 527 2.36
3 381.3 3.69 13 498 1.85
4 448.3 1.75 14 404.5 1.18
389.3 3.3 15 369.2 3.81
6 463 1.87 16 419.2 2.24
7 363.3 3.7 17 389.2 2.02 H NMR (400
8 405.5 3.87 MHz, DMSO)
8.41 (s, 1H), 7.59
9 487.3 2.12 H NMR (400
(d, J = 1.8 Hz,
MHz, DMSO-d6) 1H), 7.15 (d, J =
8.65 (s, 1H), 7.55 8.6 Hz, 1H), 7.06
(d, J = 1.7 Hz, - 7.02 (m, 2H),
1H), 7.49 (d, J = 6.96 - 6.90 (m,
1.4 Hz, 1H), 7.38 2H), 6.03 (s, 2H),
(d, J = 8.3 5.98 (d, J = 0.7
Hz,1H), 7.30-7.25 Hz, 1H), 4.06 (t, J
(m, 2H), 7.08 (dd, = 6.8 Hz, 2H),
J =8.8, 1.9 Hz, 2.35 (t, J = 6.8
1H), 6.11 (s, 1H), Hz, 2H), 1.42-
4.31 (t, J = 7.4 1.38 (m, 2H),
Hz, 2H), 3.64 (t, J 1.34 (s, 6H),
= 7.3 Hz, 2H), 1.05-1.01 (m, 2H)
3.20 (t, J = 7.6
Hz, 2H), 1.92 (t, J
= 7.6 Hz, 2H),
1.45 (m, 2H),
1.39 (s, 6H), 1.10
(m, 2H)
388 3.34
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d M+1 Min d M+1 Min
No. No.
18 395.3 3.6 H NMR (400 22 421.14 1.53
MHz, DMSO) 23 363.3 3.62
10.91 (s, 1H),
7.99 (s, 1H), 7.67 24 378.5 2.66
(d, J = 7.7 Hz, 25 417.5 3.53
1H), 7.08-6.92
26 454.3 3.18
(m, 4H), 6.09 -
6.03 (m, 3H), 27 596.2 2.58
1.47 - 1.42 (m, 28 379.3 2.92
2H), 1.31 (d, J =
7.3 Hz, 9H), 1.09- 29 481 1.69
1.05 (m, 2H) 30 504.2 1.95
19 457.2 1.97 H NMR (400 31 517 1.92
MHz, CD3CN) 32 403.5 3.5 H NMR (400
7.50 (d, J = 1.9 MHz, DMSO)
Hz, 1H), 7.41 (d, 10.76 (s, 1H),
J = 1.6 Hz, 2H), 8.72 (s, 1H), 7.79
7.36 (dd, J = 1.7,
(d, J = 2.3 Hz,
8.3 Hz, 1H), 7.29
1H), 7.62 (dd, J =
- 7.24 (m, 2H), 2.4, 8.6 Hz, 1H),
7.02 (dd, J = 2.1,
7.55 (d, J = 1.5
8.8 Hz, 1H), 6.24
Hz, 1H), 7.14 (d,
(s, 1H), 4.40 (t, J
J = 8.6 Hz, 1H),
= 7.1 Hz, 2H),
7.05 - 7.01 (m,
3.80 (t, J = 7.1 2H), 6.03 (d, J =
Hz, 2H), 1.59
1.6 Hz, 1H), 4.54
1.55 (m, 2H), (t, J = 6.4 Hz,
1.50 (s, 9H), 2H), 2.79 (t, J =
1.15-1.12 (m, 2H) 6.4 Hz, 2H), 1.44
20 375.5 3.71 (m, 2H), 1.32 (s,
9H), 1.03 (m, 2H)
21 496 206
33 321.3 2.98
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d M+1 Min d M+1 Min
No. No.
34 450.2 2.02 41 397.3 3.41 H NMR (400
35 395.1 3.59 MHz, DMSO)
11.44 (s, 1H),
36 509 2.01 8.52 (s, 1H), 7.85
37 447.2 2.02 (d, J = 1.2 Hz,
2H), 7.71 (d, J =
38 379.1 2.16 H NMR (400
1.7 Hz, 1H), 7.47
MHz, DMSO)
- 7.43 (m, 2H),
10.78 (s, 1H),
7.32 - 7.26 (m,
8.39 (s, 1H), 7.57
2H), 7.12 (dd, J =
(d, J = 1.7 Hz,
2.0, 8.7 Hz, 1H),
1H),7.17(d,J=
7.04(d,J=1.6
8.6 Hz, 1H), 7.03
Hz, 1H), 6.97 -
- 6.90 (m, 4H),
6.90 (m, 2H),
6.12 (d, J = 1.5
6.84 (d, J = 1.3
Hz, 1H), 6.03 (s,
Hz, 1H), 6.03 (s,
2H), 5.18 (s, 1H),
2H), 1.43 - 1.40
1.50 (s, 6H), 1.41
(m, 2H), 1.07-
- 1.38 (m, 2H),
1.03 (m, 2H)
1.05-0.97 (m, 2H)
39 373.3 3.74
40 372.8 3.8
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d M+1 Min d M+1 Min
No. No.
42 505.3 2.23 H NMR (400 46 391.3 3.41
MHz, DMSO-d6)
47 377.5 3.48
8.33 (s, 1H), 7.52
(s, 1H), 7.42-7.39 48 427.5 4.09
(m, 2H), 7.33- 49 402.2 3.06
7.25 (m, 2H),
50 421.1 1.81
6.14 (s, 1H), 4.99
(s, 1H), 4.31-4.27 51 407.5 3.34
(m, 3H), 3.64 (t, J 52 464.3 2.87
= 7.0 Hz, 2H),
3.20 (t, J = 7.6 53 405.3 3.65
Hz, 2H), 1.91 (t, J 54 375 1.84
= 7.6 Hz, 2H), 55 505.4 1.96
1.46 (m, 2H),
1.39 (s, 6H), 1.13 56 335.3 3.18
(m, 2H) 57 445.2 3.27
43 505.4 1.97 58 491 1.88
44 407.7 1.76 H NMR (400 59 478 1.98
MHz, DMSO)
60 413.3 3.95
10.31 (s, 1H),
8.34 (s, 1H), 7.53 61 402.5 3.71
(d, J = 1.8 Hz, 62 393.3 1.98
1H), 7.03 (d, J =
1.6 Hz, 1H), 6.97 63 407.2 2.91
- 6.90 (m, 3H), 64 505.4 1.98
6.05 - 6.03 (m,
65 377.5 3.53
3H), 4.72 (s, 2H),
1.40 - 1.38 (m, 66 417.5 4.06
2H), 1.34 (s, 9H), 67 333.3 3.53
1.04-1.00(m, 2H)
68 397.3 3.86
45 497.2 2.26
69 506 1.67
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d M+1 Min d M+1 Min
No. No.
70 501 2.1 94 377.5 3.41
71 335.3 3.22 95 375.3 3.43 H NMR (400
72 487 1.93 MHz, DMSO)
10.52 (s, 1H),
73 417.5 3.88 8.39 (s, 1H), 7.46
74 395 1.95 (d, J = 1.8 Hz,
1H), 7.10 - 6.89
75 548 1.64
(m, 5H), 6.03 (s,
76 418.3 2.9 2H), 2.68 - 2.65
77 377.3 3.87 (m, 2H), 2.56 -
2.54 (m, 2H),
78 363.3 3.48 1.82 - 1.77 (m,
79 476 1.8 4H), 1.41 - 1.34
80 447.3 2.18 (m, 2H), 1.04 -
0.97 (m, 2H)
81 492.4 2
96 346.1 3.1
82 564.3 1.35
97 367.3 3.72
83 467.3 1.72
98 440.3 3.26
84 445.2 3.08
85 389.5 3.86
86 374.3 3.11
87 435 3.87
88 465 1.89
89 411.3 3.89
90 449.3 3.92
91 393.3 3.12
92 469.6 1.75
93 476.5 2.88
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d M+1 Min d M+1 Min
No. No.
99 393.1 3.18 H NMR (400 101 387.5 2.51
MHz, DMSO-d6) 102 479 3.95
11.80 (s, 1H),
8.64 (s, 1H), 7.83 103 420.3 3.12
(m, 1H), 7.33- 104 469.5 3.97
7.26 (m, 2H),
105 391.3 2.04
7.07 (m, 1H),
7.02 (m, 1H), 106 375.2 2.82
6.96-6.89 (m, 107 349.3 3.33
2H), 6.02 (s, 2H),
4.33 (q, J = 7.1 108 503.3 1.88
Hz, 2H), 1.42- 109 451.5 1.59
1.39 (m, 2H), 110 361.5 3.7
1.33 (t, J = 7.1
Hz, 3H), 1.06- 111 391.3 3.65
1.03 (m, 2H) 112 335.3 3.03
100 421.3 1.85 H NMR (400 113 496.5 1.68
MHz, DMSO)
114 381.5 3.72
13.05 (s, 1H),
9.96 (d, J = 1.6 115 390.3 3.22
Hz, 1H), 7.89 (d,
J = 1.9 Hz, 1H),
7.74 (d, J = 2.0
Hz, 1H), 7.02 (d,
J = 1.6 Hz, 1H),
6.96-6.88 (m,
2H), 6.22 (d, J =
2.3 Hz, 1H), 6.02
(s, 2H), 1.43 -
1.40 (m, 2H),
1.37 (s, 9H),
1.06-1.02 (m, 2H)
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d M+1 Min d M+1 Min
No. No.
116 397.3 3.52 H NMR (400 126 459.2 1.53 H NMR (400
MHz, DMSO-d6) MHz, CD3CN)
11.27 (d, J = 1.9 9.23 (s, 1H), 7.51
Hz, 1H), 8.66 (s, - 7.48 (m, 2H),
1H), 8.08 (d, J = 7.19 (d, J = 8.6
1.6 Hz, 1H), 7.65- Hz, 1H), 7.06 -
7.61 (m, 3H), 7.03 (m, 2H),
7.46-7.40 (m, 6.95 - 6.89 (m,
2H), 7.31 (d, J = 2H), 6.17 (dd, J =
8.7 Hz, 1H), 7.25- 0.7, 2.2 Hz, 1H),
7.17 (m, 2H), 6.02 (s, 2H), 2.61
7.03 (d, J = 1.6 - 2.57 (m, 2H),
Hz, 1H), 6.98- 2.07 - 2.03 (m,
6.87 (m, 2H), 2H), 1.55-1.51
6.02 (s, 2H), (m, 2H), 1.39 (s,
1.43-1.39 (m, 6H), 1.12-1.09
2H), 1.06-1.02 (m, 2H)
(m, 2H) 127 408.5 2.48
117 377.5 3.77
128 393 3.26
118 515.3 2.3
129 420.2 2.16
119 381.3 3.8 130 406.3 2.88
120 464.2 2.1
131 473.3 4.22
121 465 1.74
132 417.3 3.8
122 395.2 3.74
133 465 1.74
123 383.3 3.52
134 464.3 2.91
124 388.5 3.56
135 347.3 3.42
125 411.3 3.85
136 511 2.35
137 455.5 3.29
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Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
d M+1 Min d M+1 Min
No. No.
138 393.3 3.54 162 475 2.06
139 335.1 3.08 163 437.2 2.35
140 434.5 2.74 164 379.2 2.76
141 381.3 2.91 165 462 3.44
142 431.5 3.97 166 465.2 2.15
143 539 1.89 167 455.2 2.45
144 515 1.89 168 451 1.65
145 407.5 3.6 169 528 1.71
146 379.5 1.51 170 374.3 3.4
147 409.3 4 171 449.5 1.95
148 392.2 1.22 172 381.3 3.8
149 375.3 3.37 173 346.3 2.93
150 377.3 3.61 174 483.1 2.25
151 377.22 3.96 175 411.2 3.85
152 504.5 1.99 176 431.5 4.02
153 393.1 3.47 177 485.5 4.02
154 363.3 3.52 178 528.5 1.18
155 321.3 3.13 179 473 1.79
156 407.5 3.2 180 479 2.15
157 406.3 1.43 181 387.5 2.56
158 379.3 1.89 182 365.3 3.13
159 451 3.34 183 493 2.3
160 375.3 3.82
161 355.1 3.32
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d M+1 Min d M+1 Min
No. No.
184 461.3 2.4 H NMR (400 190 435.5 3.67 H NMR (400
MHz, DMSO-d6) MHz, DMSO)
10.89 (s, 1H), 11.83 (s, 1H),
8.29 (s, 1H), 7.52 10.76 (s, 1H),
(s, 1H), 7.42-7.37 8.53 (s, 1H), 7.93
(m, 2H), 7.32 (dd, (d, J = 1.8 Hz,
J = 8.3, 1.4 Hz, 1H), 7.60 (dd, J =
1H), 7.01 (d, J = 2.3, 8.5 Hz, 1H),
10.9 Hz, 1H), 7.53 (d, J = 1.4
6.05 (d, J = 1.7 Hz, 1H), 7.14 (d,
Hz, 1H), 4.29 (t, J J = 8.6 Hz, 1H),
= 5.0 Hz, 1H), 7.02 - 6.97 (m,
3.23 (m, 2H), 2H), 6.02 (d, J =
1.81 (t, J = 7.7 1.5 Hz, 1H), 3.71
Hz, 2H), 1.46 (m, (t, J = 6.2 Hz,
2H), 1.29 (s, 6H), 2H), 3.37 (t, J =
1.13 (m, 2H) 6.2 Hz, 2H), 3.25
185 377.5 3.63 (s, 3H), 1.44 (m,
2H), 1.32 (s, 9H),
186 464 1.46 1.08 (m, 2H)
187 339.1 3.2 191 421.3 3.32
188 435.5 1.64 192 404.4 0.95
189 392.3 2.18 193 451 1.71
194 465 1.69
195 434.2 2.29
196 363.3 3.4
197 501 1.91
198 411.2 3.14
199 439 1.89
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No. No.
200 434.4 1.53 211 381.3 3.69
201 462 3.22 212 461 2.04
202 351.3 2.59 213 469 1.72
203 495.2 2.71 214 363.3 3.48
204 435 3.94 215 432.3 3.07
205 397.3 3.69 216 403.5 3.94
206 493 2.26 217 420.4 1.27
207 487 1.87 218 475 2.2
208 391.3 2.94 219 484.3 1.84
209 397.2 3.3 220 419.3 3.87
210 487.2 1.85 H NMR (400 221 486.3 0.91
MHz, CD3CN) 222 391.3 3.01
7.50 (d, J = 2.0
Hz, 1H), 7.41 (d, 223 398.3 1.3
J = 1.6 Hz, 2H), 224 349.2 2.54
7.37-7.32 (m,
225 375.5 3.74
2H), 7.25 (d, J =
8.3 Hz, 1H), 6.98 226 377.5 3.47 H NMR (400
(dd, J = 2.1, 8.8 MHz, DMSO-d6)
Hz, 1H), 6.27 (d, 10.76 (s, 1H),
J = 0.6 Hz, 1H), 8.39 (s, 1H), 7.55
4.40 - 4.28 (m, (s, 1H), 7.15-7.13
2H), 4.12 - 4.06 (m, 1H), 7.03-
(m, 1H), 3.59 - 6.89 (m, 4H),
3.51 (m, 2H), 6.03 (m, 3H),
1.59 - 1.50 (m, 1.41-1.38 (m,
2H), 1.47 (s, 9H), 2H), 1.32 (s, 9H),
1.15 - 1.12 (m, 1.04-1.01 (m, 2H)
2H) 227 393.3 2.03
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No. No.
228 398.3 1.24 248 407.3 1.52 H NMR (400
229 487.2 1.78 MHz, DMSO)
10.74 (d, J = 1.2
230 361.1 3.47 Hz, 1H), 8.40 (s,
231 435.5 2.12 1H), 7.54 (d, J =
1.8 Hz, 1H), 7.15
232 321.3 2.91
(d, J = 8.6 Hz,
233 413.3 3.77 1H), 7.03 - 6.90
234 393.3 1.58 (m, 4H), 6.03-
6.00 (m, 3H),
235 465 1.92
3.26-3.22 (m,
236 361.3 3.18 2H), 1.85-1.80
237 421 1.8 (m, 2H), 1.41 -
1.38 (m, 2H),
238 405.5 3.79 1.31 (s, 6H),
239 544.3 1.4 1.05-1.01 (m, 2H)
240 405.3 3.9 249 393.3 3.32
241 462 1.74 250 406.2 2.08
242 550 1.68 251 511 2.39
243 395.2 1.98 252 379.3 3.3
244 517.3 1.94 253 383 3.46
245 372.2 3.59 254 401.2 3.26
246 361.3 3.58 255 398.3 1.38
247 490 1.95 256 512.5 1.96
257 389.2 3.05
258 321.3 3.02
259 392.1 2.74
260 462 1.81
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No. No.
261 453 1.91 264 421.3 1.66 H NMR (400
262 349.3 3.22 MHz, CD3CN)
8.78 (s, 1H), 7.40
263 391.1 3.67 H NMR (400
(m, 1H), 7.33 (s,
MHz, DMSO) 1H), 7.08 (m,
1.01-1.05 (dd, J = 1H), 6.95 - 6.87
4.0, 6.7 Hz, 2H), (m, 3H), 6.79 (m,
1.41 - 1.39 (m, 1H), 5.91 (s, 2H),
11H), 3.81 (s, 3.51 (dd, J = 5.9,
3H), 6.03 (s, 2H), 7.8 Hz, 2H), 2.92
6.15 (s, 1H), 6.96 - 2.88 (m, 2H),
- 6.90 (m, 2H), 2.64 (t, J = 5.8
7.02 (d, J = 1.6 Hz, 1H), 1.50 (m,
Hz, 1H), 7.09 (dd, 2H), 1.41 (s, 9H),
J = 2.0, 8.8 Hz, 1.06 (m, 2H)
1H), 7.25 (d, J =
8.8 Hz, 1H), 7.60 265 475 2.15
(d, J = 1.9 Hz, 266 347.3 3.32
1H), 8.46 (s, 1H) 267 420.5 1.81
268 416.2 1.76
269 485 2.06
270 395.3 3.89
271 492 1.59
272 405.5 3.96
273 547.2 1.65
274 631.6 1.91
275 590.4 2.02
276 465.7 1.79
277 411.3 2.14
315
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d M+1 Min d M+1 Min
No. No.
278 385.3 1.99 288 512.5 1.89 H NMR (400
279 425.3 2.19 MHz, DMSO)
8.77 (s, 1H), 7.97
280 473.2 1.74
(s, 1H), 7.51 (s,
281 469.4 2.02 H NMR (400 1H), 7.43 - 7.40
MHz, DMSO) (m, 2H), 7.33 (d,
8.82 (s, 1H), 7.84 J = 8.2 Hz, 1H),
(d, J = 1.7 Hz, 6.36 (s, 1H), 4.99
1H), 7.55 - 7.51 - 4.97 (m, 2H),
(m, 2H), 7.40 - 4.52 (d, J = 13.1
7.35 (m, 2H), Hz, 1H), 4.21 (dd,
7.29 (dd, J = 1.7, J = 9.2, 15.2 Hz,
8.3 Hz, 1H), 7.04 1H), 3.86 (m,
(s, 1H), 4.98 (t, J 1H), 3.51 - 3.36
= 5.6 Hz, 1H), (m, 2H), 1.51 -
4.27 (t, J = 6.1 1.48 (m, 2H),
Hz, 2H), 3.67 (q, 1.43 (s, 9H), 1.17
J = 6.0 Hz, 2H), - 1.15 (m, 2H)
1.48 (dd, J = 4.0, 289 437.3 1.6
6.7 Hz, 2H), 1.13
(dd, J = 4.1, 6.8
Hz, 2H)
282 644.4 1.83
283 544.6 1.97
284 465.4 1.56
285 485.2 1.8
286 475.2 1.87
287 564.2 1.95
316
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d M+1 Min d M+1 Min
No. No.
290 499.5 1.81 H NMR (400 291 455.4 2.02 H NMR (400
MHz, DMSO) MHz, DMSO)
8.82 (s, 1H), 7.83 8.62 (s, 1H), 7.56
(d, J = 1.7 Hz, (s, 1H), 7.50 (s,
1H), 7.55 - 7.50 1H), 7.38 (d, J =
(m, 2H), 7.39 - 8.3 Hz, 1H), 7.29
7.28 (m, 3H), (dd, J = 1.5, 8.3
7.03 (s, 1H), 4.97 Hz, 1H), 7.23 (d,
(d, J = 5.6 Hz, J = 8.7 Hz, 1H),
1H), 4.83 (t, J = 7.06 (dd, J = 1.7,
5.6 Hz, 1H), 4.33 8.7 Hz, 1H), 6.19
(dd, J = 3.4, 15.1 (s, 1H), 4.86 (t, J
Hz, 1H), 4.09 (dd, = 5.4 Hz, 1H),
J = 8.7, 15.1 Hz, 4.03 (t, J = 6.1
1H), 3.80 - 3.78 Hz, 2H), 3.73 (qn,
(m, 1H), 3.43 - J = 8.5 Hz, 1H),
3.38 (m, 1H), 3.57 (q, J = 5.9
3.35 - 3.30 (m, Hz, 2H), 2.39 -
1H), 1.49 - 1.46 2.33 (m, 2H),
(m, 2H), 1.14 - 2.18 - 1.98 (m,
1.11 (m, 2H) 3H), 1.88 - 1.81
(m, 1H), 1.47 -
1.44 (m, 2H),
1.11-1.09(m,
2H)
292 578.4 1.99
293 630.4 1.8
317
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d M+1 Min d M+1 Min
No. No.
294 443.4 1.98 H NMR (400 295 482.3 2 H NMR (400
MHz, DMSO) MHz, DMSO)
8.62 (s, 1H), 7.55 8.78 (s, 1H), 7.92
(d, J = 1.8 Hz, (s, 1H), 7.51 (s,
1H), 7.50 (d, J = 1H), 7.45 (s, 1H),
1.5 Hz, 1H), 7.38 7.41 (d, J = 8.3
(d, J = 8.3 Hz, Hz, 1H), 7.33 (d,
1H), 7.30 - 7.24 J = 8.4 Hz, 1H),
(m, 2H), 7.05 (dd, 6.34 (s, 1H), 5.01
J = 2.0, 8.8 Hz, (t, J = 5.7 Hz,
1H), 6.13 (s, 1H), 1H), 4.41 (t, J =
4.88 (t, J = 5.5 6.6 Hz, 2H), 3.68
Hz, 1H), 4.14 (t, J (m, 2H), 1.51 -
= 6.1 Hz, 2H), 1.47 (m, 2H),
3.61 (m, 2H), 1.42 (s, 9H), 1.19
3.21 (septet, J = - 1.15 (m, 2H)
6.8 Hz, 1H), 1.47 296 438.7 2.12 H NMR (400
- 1.44 (m, 2H), MHz, DMSO)
1.26 (d, J = 6.8 11.43 (s, 1H),
Hz, 6H), 1.11
8.74 (s, 1H), 7.63
1.08 (m, 2H) (s, 1H), 7.51 (s,
1H), 7.45 - 7.40
(m, 2H), 7.33 (dd,
J = 1.4, 8.3 Hz,
1H), 6.25 (d, J =
1.5 Hz, 1H), 1.51
- 1.48 (m, 2H),
1.34 (s, 9H), 1.17
- 1.14 (m, 2H)
297 449.3 1.6
298 517.5 1.64
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Compoun LC/MS LC/RT NMR Compoun LC/MS LC/RT NMR
d M+1 Min d M+1 Min
No. No.
299 391.5 2.05 304 425.1 2.04 H NMR (400
300 449.3 1.59 MHz, DMSO)
12.16 (s, 1H),
301 501.2 1.93 8.80 (s, 1H), 7.83
302 503.5 1.63 (s, 1H), 7.51 (d, J
= 1.4 Hz, 1H),
303 437.3 1.6
7.39 - 7.28 (m,
4H), 6.95 (s, 1H),
1.48 (dd, J = 4.0,
6.6 Hz, 2H), 1.13
(dd, J = 4.0, 6.7
Hz, 2H)
305 459.2 1.67
306 558.4 2.05
Cmpd. LC/MS LC/RT NMR
No. M+1 Min
307 447.5 1.93
308 516.7 1.69 H NMR (400 MHz, DMSO-d6) 6 8.32 (s, 1H), 7.53 (s,
1H), 7.43 - 7.31 (m, 4H), 6.19 (s, 1H), 4.95 - 4.93 (m,
2H), 4.51 (d, J = 5.0 Hz, 1H), 4.42 - 4.39 (m, 2H), 4.10
- 4.04 (m, 1H), 3.86 (s, 1H), 3.49 - 3.43 (m, 2H), 3.41 -
3.33 (m, 1H), 3.30 - 3.10 (m, 6H), 2.02 - 1.97 (m, 2H),
1.48 - 1.42 (m, 8H) and 1.13 (dd, J = 4.0, 6.7 Hz, 2H)
ppm
309 535.7 1.79 1H NMR (400.0 MHz, DMSO) d 8.43 (s, 1H), 7.53 (s,
1H), 7.45 - 7.41 (m, 2H), 7.36 - 7.31 (m, 2H), 6.27 (s,
1H), 4.74 - 4.70 (m, 2H), 3.57 - 3.53 (m, 2H), 3.29 (s,
9H), 1.48 - 1.42 (m, 11H), and 1.15 (dd, J = 3.9, 6.8
Hz, 2H) ppm.
310 609.5 1.64
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311 535.7 1.7 H NMR (400 MHz, DMSO-d6) 6 8.32 (s, 1H), 7.53 (d,
J = 1.0 Hz, 1H), 7.43 - 7.31 (m, 4H), 6.17 (s, 1H), 4.97
- 4.92 (m, 2H), 4.41 (dd, J = 2.4, 15.0 Hz, 1H), 4.23 (t,
J = 5.0 Hz, 1H), 4.08 (dd, J = 8.6, 15.1 Hz, 1H), 3.87 (s,
1H), 3.48 - 3.44 (m, 1H), 3.41 - 3.33 (m, 1H), 3.20 (dd,
J = 7.4, 12.7 Hz, 2H), 1.94 - 1.90 (m, 2H), 1.48 - 1.45
(m, 2H), 1.42 (s, 3H), 1.41 (s, 3H) and 1.15 - 1.12 (m,
2H) ppm.
312 443 2.31 H NMR (400 MHz, DMSO-d6) 6 8.93 (s, 1H), 7.71 (d,
J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H),
7.33 (d, J = 1.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.28
(s, 1H), 5.05 (t, J = 5.6 Hz, 1H), 4.42 (t, J = 6.8 Hz,
2H), 3.70 - 3.65 (m, 2H), 1.51 - 1.48 (m, 2H), 1.44 (s,
9H), 1.19 - 1.16 (m, 2H) ppm.
313 521.5 1.69 1H NMR (400.0 MHz, CD3CN) d 7.69 (d, J = 7.7 Hz,
1H), 7.44 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 1.7, 8.3 Hz,
1H), 7.31 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.20 (d, J =
12.0 Hz, 1H), 6.34 (s, 1H), 4.32 (d, J = 6.8 Hz, 2H),
4.15 - 4.09 (m, 1H), 3.89 (dd, J = 6.0, 11.5 Hz, 1H),
3.63 - 3.52 (m, 3H), 3.42 (d, J = 4.6 Hz, 1H), 3.21 (dd,
J = 6.2, 7.2 Hz, 1H), 3.04 (t, J = 5.8 Hz, 1H), 1.59 (dd,
J = 3.8, 6.8 Hz, 2H), 1.44 (s, 3H), 1.33 (s, 3H) and 1.18
(dd, J = 3.7, 6.8 Hz, 2H) ppm
314 447.5 1.86 H NMR (400 MHz, DMSO-d6) 6 8.20 (d, J = 7.6 Hz,
1H), 7.30 - 7.25 (m, 3H), 7.20 (m, 1H), 7.12 (d, J = 8.2
Hz, 1H), 6.84 (d, J = 11.1 Hz, 1H), 6.01 (d, J = 0.5 Hz,
1H), 3.98 (t, J = 6.8 Hz, 2H), 2.37 (t, J = 6.8 Hz, 2H),
1.75 (dd, J = 3.8, 6.9 Hz, 2H), 1.37 (s, 6H) and 1.14
(dd, J = 3.9, 6.9 Hz, 2H) ppm.
315 482.5 1.99 H NMR (400 MHz, DMSO) 8.93 (s, 1H), 7.71 (d, J =
8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.33
(d, J = 1.6 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.28 (s,
1H), 5.05 (t, J = 5.6 Hz, 1H), 4.42 (t, J = 6.8 Hz, 2H),
3.70 - 3.65 (m, 2H), 1.51 - 1.48 (m, 2H), 1.44 (s, 9H),
1.19-1.16 (m, 2H)
316 438.7 2.1 H NMR (400 MHz, DMSO) 11.48 (s, 1H), 8.88 (s,
1H), 7.52 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H),
7.32 (dd, J = 1.5, 8.3 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H),
6.21 (d, J = 1.8 Hz, 1H), 1.51 - 1.49 (m, 2H), 1.36 (s,
9H), 1.18 - 1.16 (m, 2H) ppm.
317 439.4 1.36
318 469.016 1.66
319 469.016 1.66
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320 465.7 1.79 H NMR (400 MHz, DMSO) 9.26 (s, 1H), 7.65 (d, J =
1.9 Hz, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.9
Hz, 1H), 7.11 (dd, J = 1.9, 8.9 Hz, 1H), 6.89 (d, J = 8.8
Hz, 2H), 6.14 (s, 1H), 4.42 - 4.37 (m, 1H), 4.16 - 4.10
(m, 1H), 3.90 - 3.88 (m, 1H), 3.73 (s, 3H), 3.46 - 3.42
(m, 2H), 1.41 (s, 9H), 1.36 (d, J = 5.0 Hz, 1H), 1.21 (s,
3H), 0.99 (d, J = 5.0 Hz, 1H), 0.84 (s, 3H)
321 391.5 2.05 H NMR (400 MHz, DMSO) 10.73 (s, 1H), 9.23 (s,
1H), 7.61 (d, J = 1.5 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H),
7.13 (s, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.88 (d, J = 8.8
Hz, 2H), 6.02 (d, J = 1.8 Hz, 1H), 3.73 (s, 3H), 1.36 (d,
J = 5.0 Hz, 1H), 1.31 (s, 9H), 1.22 (s, 3H), 0.98 (d, J =
5.0 Hz, 1H), 0.84 (s, 3H)
322 521.5 1.67 1H NMR (400.0 MHz, DMSO) d 8.31 (s, 1H), 7.53 (d,
J = 1.1 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.33 - 7.30 (m,
2H), 6.22 (s, 1H), 5.01 (d, J = 5.0 Hz, 1H), 4.91 (t, J =
5.5 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.42 - 4.38 (m,
1H), 4.10 (dd, J = 8.8, 15.1 Hz, 1H), 3.90 (s, 1H), 3.64
- 3.54 (m, 2H), 3.48 - 3.33 (m, 2H), 1.48 - 1.45 (m,
2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14 - 1.11 (m, 2H)
ppm
Assays for Detecting and Measuring AF508-CFTR Correction Properties of
Compounds
Membrane potential optical methods for assaying AF508-CFTR modulation
properties of
compounds.
The assay utilizes fluorescent voltage sensing dyes to measure changes in
membrane
potential using a fluorescent plate reader (e.g., FLIPR III, Molecular
Devices, Inc.) as a readout
for increase in functional AF508-CFTR in NIH 3T3 cells. The driving force for
the response is
the creation of a chloride ion gradient in conjunction with channel activation
by a single liquid
addition step after the cells have previously been treated with compounds and
subsequently
loaded with a voltage sensing dye.
Identification of Correction Compounds
To identify small molecules that correct the trafficking defect associated
with AF508-
CFTR; a single-addition HTS assay format was developed. Assay Plates
containing cells are
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incubated for -2-4 hours in tissue culture incubator at 37oC, 5%CO2, 90%
humidity. Cells are then
ready for compound exposure after adhering to the bottom of the assay plates.
The cells were incubated in serum-free medium for 16-24 hrs in tissue culture
incubator at
37oC, 5%CO2, 90% humidity in the presence or absence (negative control) of
test compound. The
cells were subsequently rinsed 3X with Krebs Ringers solution and loaded with
a voltage sensing
redistribution dye. To activate AF508-CFTR, 10 M forskolin and the CFTR
potentiator,
genistein (20 M), were added along with Cl--free medium to each well. The
addition of Cl--free
medium promoted Cl- efflux in response to AF508-CFTR activation and the
resulting membrane
depolarization was optically monitored using voltage sensor dyes.
Identification of Potentiator Compounds
To identify potentiators of AF508-CFTR, a double-addition HTS assay format was
developed. This HTS assay utilizes fluorescent voltage sensing dyes to measure
changes in
membrane potential on the FLIPR III as a measurement for increase in gating
(conductance) of
AF508 CFTR in temperature-corrected AF508 CFTR NIH 3T3 cells. The driving
force for the
response is a Cl- ion gradient in conjunction with channel activation with
forskolin in a single
liquid addition step using a fluoresecent plate reader such as FLIPR III after
the cells have
previously been treated with potentiator compounds (or DMSO vehicle control)
and
subsequently loaded with a redistribution dye.
Solutions:
Bath Solution #1: (in mM) NaC1 160, KC14.5, CaC12 2, MgC12 1, HEPES 10, pH 7.4
with NaOH.
Chloride-free bath solution: Chloride salts in Bath Solution #1 are
substituted with
gluconate salts.
Cell Culture
NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for optical
measurements of membrane potential. The cells are maintained at 37 C in 5%
CO2 and 90 %
humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM
glutamine, 10 %
fetal bovine serum, 1 X NEAA, R-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2
culture
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flasks. For all optical assays, the cells were seeded at -20,000/well in 384-
well matrigel-coated
plates and cultured for 2 hrs at 37 C before culturing at 27 C for 24 hrs.
for the potentiator
assay. For the correction assays, the cells are cultured at 27 C or 37 C
with and without
compounds for 16 - 24 hours.
Electrophysiological Assays for assaying AF508-CFTR modulation properties of
compounds.
1.Ussing Chamber Assay
Ussing chamber experiments were performed on polarized airway epithelial cells
expressing AF508-CFTR to further characterize the AF508-CFTR modulators
identified in the
optical assays. Non-CF and CF airway epithelia were isolated from bronchial
tissue, cultured as
previously described (Galietta, L.J.V., Lantero, S., Gazzolo, A., Sacco, 0.,
Romano, L., Rossi, G.A., &
Zegarra-Moran, O. (1998) In Vitro Cell. Dev. Biol. 34, 478-481), and plated
onto Costar SnapwellTm
filters that were precoated with NIH3T3-conditioned media. After four days the
apical media
was removed and the cells were grown at an air liquid interface for >14 days
prior to use. This
resulted in a monolayer of fully differentiated columnar cells that were
ciliated, features that are
characteristic of airway epithelia. Non-CF HBE were isolated from non-smokers
that did not
have any known lung disease. CF-HBE were isolated from patients homozygous for
AF508-
CFTR.
HBE grown on Costar SnapwellTM cell culture inserts were mounted in an Ussing
chamber (Physiologic Instruments, Inc., San Diego, CA), and the
transepithelial resistance and
short-circuit current in the presence of a basolateral to apical Cl- gradient
(Isc) were measured
using a voltage-clamp system (Department of Bioengineering, University of
Iowa, IA). Briefly,
HBE were examined under voltage-clamp recording conditions Mold = 0 mV) at 37
C. The
basolateral solution contained (in mM) 145 NaCl, 0.83 K2HPO4, 3.3 KH2PO4, 1.2
MgC12, 1.2
CaC12, 10 Glucose, 10 HEPES (pH adjusted to 7.35 with NaOH) and the apical
solution
contained (in mM) 145 NaGluconate, 1.2 MgC12, 1.2 CaC12, 10 glucose, 10 HEPES
(pH adjusted
to 7.35 with NaOH).
Identification of Correction Compounds
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Typical protocol utilized a basolateral to apical membrane Cl- concentration
gradient. To
set up this gradient, normal ringer was used on the basolateral membrane,
whereas apical NaCl
was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to
give a large Cl-
concentration gradient across the epithelium. All experiments were performed
with intact
monolayers. To fully activate AF508-CFTR, forskolin (10 M), PDE inhibitor,
IBMX (100 M)
and CFTR potentiator, genistein (50 M) were added to the apical side.
As observed in other cell types, incubation at low temperatures of FRT cells
and human
bronchial epithelial cells isolated from diseased CF patients (CF-
HBE)expressing AF508-CFTR
increases the functional density of CFTR in the plasma membrane. To determine
the activity of
correction compounds, the cells were incubated with test compound for 24-48
hours at 37 C and
were subsequently washed 3X prior to recording. The cAMP- and genistein-
mediated Isc in
compound-treated cells was normalized to 37 C controls and expressed as
percentage activity of
CFTR activity in wt-HBE. Preincubation of the cells with the correction
compound significantly
increased the cAMP- and genistein-mediated Isc compared to the 37 C controls.
Identification of Potentiator Compounds
Typical protocol utilized a basolateral to apical membrane Cl- concentration
gradient. To
set up this gradient, normal ringers was used on the basolateral membrane,
whereas apical NaCl
was replaced by equimolar sodium gluconate (titrated to pH 7.4 with NaOH) to
give a large Cl-
concentration gradient across the epithelium. Forskolin (10 M) and all test
compounds were
added to the apical side of the cell culture inserts. The efficacy of the
putative AF508-CFTR
potentiators was compared to that of the known potentiator, genistein.
2. Patch-clamp Recordings
Total Cl- current in AF508-NIH3T3 cells was monitored using the perforated-
patch
recording configuration as previously described (Rae, J., Cooper, K., Gates,
P., & Watsky, M.
(1991) J. Neurosci. Methods 37, 15-26). Voltage-clamp recordings were
performed at 22 C
using an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc., Foster
City, CA). The
pipette solution contained (in mM) 150 N-methyl-D-glucamine (NMDG)-Cl, 2
MgC12, 2 CaC12,
EGTA, 10 HEPES, and 240 pg/ml amphotericin-B (pH adjusted to 7.35 with HC1).
The
extracellular medium contained (in mM) 150 NMDG-Cl, 2 MgC12, 2 CaC12, 10 HEPES
(pH
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adjusted to 7.35 with HC1). Pulse generation, data acquisition, and analysis
were performed
using a PC equipped with a Digidata 1320 A/D interface in conjunction with
Clampex 8 (Axon
Instruments Inc.). To activate AF508-CFTR, 10 M forskolin and 20 M genistein
were added
to the bath and the current-voltage relation was monitored every 30 sec.
Identification of Correction Compounds
To determine the activity of correction compounds for increasing the density
of
functional AF508-CFTR in the plasma membrane, we used the above-described
perforated-
patch-recording techniques to measure the current density following 24-hr
treatment with the
correction compounds. To fully activate AF508-CFTR, 10 M forskolin and 20 M
genistein
were added to the cells. Under our recording conditions, the current density
following 24-hr
incubation at 27 C was higher than that observed following 24-hr incubation at
37 C. These
results are consistent with the known effects of low-temperature incubation on
the density of
AF508-CFTR in the plasma membrane. To determine the effects of correction
compounds on
CFTR current density, the cells were incubated with 10 M of the test compound
for 24 hours at
37 C and the current density was compared to the 27 C and 37 C controls (%
activity). Prior to
recording, the cells were washed 3X with extracellular recording medium to
remove any
remaining test compound. Preincubation with 10 M of correction compounds
significantly
increased the cAMP- and genistein-dependent current compared to the 37 C
controls.
Identification of Potentiator Compounds
The ability of AF508-CFTR potentiators to increase the macroscopic AF508-CFTR
Cl-
current (IAF508) in NIH3T3 cells stably expressing AF508-CFTR was also
investigated using
perforated-patch-recording techniques. The potentiators identified from the
optical assays
evoked a dose-dependent increase in IAF508 with similar potency and efficacy
observed in the
optical assays. In all cells examined, the reversal potential before and
during potentiator
application was around -30 mV, which is the calculated Ec1(-28 mV).
Cell Culture
NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for whole-cell
recordings. The cells are maintained at 37 C in 5% CO2 and 90 % humidity in
Dulbecco's
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modified Eagle's medium supplemented with 2 mM glutamine, 10 % fetal bovine
serum, 1 X
NEAA, R-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2 culture flasks. For
whole-cell
recordings, 2,500 - 5,000 cells were seeded on poly-L-lysine-coated glass
coverslips and cultured
for 24 - 48 hrs at 27 C before use to test the activity of potentiators; and
incubated with or
without the correction compound at 37 C for measuring the activity of
correctors.
3.Single-channel recordings
Gating activity of wt-CFTR and temperature-corrected AF508-CFTR expressed in
NIH3T3 cells was observed using excised inside-out membrane patch recordings
as previously
described (Dalemans, W., Barbry, P., Champigny, G., Jallat, S., Dott, K.,
Dreyer, D., Crystal, R.G.,
Pavirani, A., Lecocq, J-P., Lazdunski, M. (1991) Nature 354, 526 - 528) using
an Axopatch 200B
patch-clamp amplifier (Axon Instruments Inc.). The pipette contained (in mM):
150 NMDG,
150 aspartic acid, 5 CaC12, 2 MgC12, and 10 HEPES (pH adjusted to 7.35 with
Tris base). The
bath contained (in mM): 150 NMDG-Cl, 2 MgC12, 5 EGTA, 10 TES, and 14 Tris base
(pH
adjusted to 7.35 with HC1). After excision, both wt- and AF508-CFTR were
activated by adding
1 mM Mg-ATP, 75 nM of the catalytic subunit of cAMP-dependent protein kinase
(PKA;
Promega Corp. Madison, WI), and 10 mM NaF to inhibit protein phosphatases,
which prevented
current rundown. The pipette potential was maintained at 80 mV. Channel
activity was
analyzed from membrane patches containing <_ 2 active channels. The maximum
number of
simultaneous openings determined the number of active channels during the
course of an
experiment. To determine the single-channel current amplitude, the data
recorded from 120 sec
of AF508-CFTR activity was filtered "off-line" at 100 Hz and then used to
construct all-point
amplitude histograms that were fitted with multigaussian functions using Bio-
Patch Analysis
software (Bio-Logic Comp. France). The total microscopic current and open
probability (Po)
were determined from 120 sec of channel activity. The Po was determined using
the Bio-Patch
software or from the relationship Po = Ui(N), where I = mean current, i =
single-channel current
amplitude, and N = number of active channels in patch.
Cell Culture
NIH3T3 mouse fibroblasts stably expressing AF508-CFTR are used for excised-
membrane patch-clamp recordings. The cells are maintained at 37 C in 5% CO2
and 90 %
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WO 2010/054138 PCT/US2009/063475
humidity in Dulbecco's modified Eagle's medium supplemented with 2 mM
glutamine, 10 %
fetal bovine serum, 1 X NEAA, R-ME, 1 X pen/strep, and 25 mM HEPES in 175 cm2
culture
flasks. For single channel recordings, 2,500 - 5,000 cells were seeded on poly-
L-lysine-coated
glass coverslips and cultured for 24 - 48 hrs at 27 C before use.
[001017] The compounds of Table 1 were found to exhibit Correction activity as
measured in
the assay described above.
[001018] Compounds of the invention are useful as modulators of ATP binding
cassette
transporters. Using the procedures described above, the activities, i.e.,
EC50s, of compounds of
the present invention have been measured to be from about 3.8 nM to about 13.5
[M.
Furthermore, using those methods described above, the efficacies of compounds
of the present
invention have been measured to be from about 35 % to about 110 %.
In Table 4, the following meanings apply:
EC50: "+++" means <2 uM; "++" means between 2 uM to 5 uM; "+" means between 5
uM to 25 uM.
% Efficacy: "+" means < 25%; "++" means between 25% and 100%; "+++" means >
100%.
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WO 2010/054138 PCT/US2009/063475
Table 4.
Cmpd. EC50 Binned Max Binned
No. EC50 Efficacy Max
Efficacy
307 0.981 +++ 160 +++
308 3.095 ++ 100 +++
309 0.0381 +++ 122 +++
310 0.1595 +++ 120.5 +++
311 0.08175 +++ 126 +++
312 0.181 +++ 117.5 +++
313 0.2835 +++ 102 +++
314 0.2285 +++ 124.5 +++
315 0.272 +++ 106 +++
316 0.285 +++ 126.5 +++
317 4.525 ++ 65.5 ++
318 0.06595 +++ 132 +++
319 0.03905 +++ 125.5 +++
320 4.315 ++ 94 ++
321 1.81 +++ 76 ++
322 None
[001019] OTHER EMBODIMENTS
[001020] It is to be understood that while the invention has been described in
conjunction with
the detailed description thereof, the foregoing description is intended to
illustrate and not limit
the scope of the invention, which is defined by the scope of the appended
claims. Other aspects,
advantages, and modifications are within the scope of the following claims.
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