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ACETYL 2-HYDROXY-l, 3-DIAMINOALKANES
BACKGROUND OF THE INVEEETION
Field of the Invention
The invention relates to acetyl 2-hydroxy-l,3-
diaminoalkanes and to such compounds that are useful in the
treatment of Alzheimer's disease and related diseases. More
specifically, it relates to such compounds that are capable of
inhibiting beta-secretase, an enzyme that cleaves amyloid
precursor protein to produce amyloid beta peptide (A beta), a
major component of the amyloid plaques found in the brains of
Alzheimer's sufferers.
Background of the Invention
Alzheimer's disease (AD) is a progressive degenerative
diseast of the brain primarily associated with aging.
Cliniqpal presentation of AD is characterized by loss of.
memory., cognition, reasoning, judgment, and orientation. As
the Msease progresses, motor, sensory, and linguistic
abilities are also affected until there is global impairment
of multiple cognitive functions. These cognitive losses occur
gradually, but typically lead to severs impairment and
eventual death in the range of four to twelve years.
Alzheimer's disease is characterized by two major
pathologic observations in the brain: neurofihrillary tangles
and beta amyloid (or neuritic) plaques, comprised
predominantly of an aggregate of a peptide fragment know as A
beta. Individuals with AD exhibit characteristic beta-amyloid
deposits in the brain (beta amyloid plaques) and in cerebral
blood vessels (beta amyloid angiopathy) as well as
neurofibrillary tangles. Neurofibrillary tangles occur not
only in Alzheimer's disease but also in other dementia-
inducing disorders. On autopsy, large numbers of these
lesions are generally found in areas of the human brain
important for memory and cognition.
Smaller numbers of these lesions in a more restricted
anatomical distribution are found in the brains of most aged
humans who do not have clinical AD. Amyloidogenic plaques and
amyloid angiopathy also characterize the brains of
individuals with Trisomy 21 (Down's Syndrome), Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-
D), and other neurodegenerative disorders. Beta-amyloid is a
defining feature of AD, now believed to be a causative
precursor or factor in the development of disease. Deposition
of A beta in areas of the brain responsible for cognitive
activities is a major factor in the development of AD. Beta-
amyloid plaques are predominantly composed of amyloid beta
peptide (A beta, also sometimes designated betaA4). A beta
peptide is derived by proteolysis of the amyloid precursor
protein (APP) and is comprised of 3 9-42 amino acids. Several
proteases called secretases are involved in the processing of
APP.
Cleavage of APP at the N-terminus of the A beta peptide
by beta-secretase and at the C-terminus by one or more gamma-
secretases constitutes the beta-amyloidogenic pathway, i.e.
the pathway by which A beta is formed. Cleavage of APP by
alpha-secretase produces alpha-sAPP, a secreted form of APP
that does not result in beta-amyloid plaque formation. This
alternate pathway precludes the formation of A beta peptide.
A description of the proteolytic processing fragments of APP
is found, for example, in U.S. Patent Nos. 5,441,870;
5,721,130; and 5,942,400.
An aspartyl protease has been identified as the enzyme
responsible for processing of APP at the beta-secretase
cleavage site. The beta-secretase enzyme has been disclosed
using varied nomenclature, including BACE, Asp, and Memapsin.
See, for example, Sinha et al., 1999, Nature 402:537-554
(p501) and published PCT application WO00/17369.
Several lines of evidence indicate that progressive
cerebral deposition of beta-amyloid peptide (A beta) plays a
seminal role in the pathogenesis of AD and can precede
cognitive symptoms by years or decades. See, for example,
Selkoe, 1991, Neuron 6:487. Release of A beta from neuronal
cells grown in culture and the presence of A beta in
cerebrospinal fluid (CSF) of both normal individuals and AD
patients has been demonstrated. See, for example, Seubert et
al., 1992, Nature 359:325-327.
It has been proposed that A beta peptide accumulates as a
result of APP processing by beta-secretase, thus inhibition of
this enzyme's activity is desirable for the treatment of AD.
In vivo processing of APP at the beta-secretase cleavage site
is thought to be a rate-limiting step in A beta production,
and is thus a therapeutic target for the treatment of AD. See
for example, Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-
19.
BACE1 knockout mice fail to produce A beta, and present a
normal phenotype. When crossed with transgenic mice that over
express APP, the progeny show reduced amounts of A beta in
brain extracts as compared with control animals (Luo et al.,
2001 Nature Neuroscience 4:231-232). This evidence further
supports the proposal that inhibition of beta-secretase
activity and reduction of A beta in the brain provides a
therapeutic method for the treatment of AD and other beta
amyloid disorders.
At present there are no effective treatments for halting,
preventing, or reversing the progression of Alzheimer's
disease. Therefore, there is an urgent need for
pharmaceutical agents capable of slowing the progression of
Alzheimer's disease and/or preventing it in the first place.
Compounds that are effective inhibitors of beta-
secretase, that inhibit beta-secretase-mediated cleavage of
APP, that are effective inhibitors of A beta production,
and/or are effective to reduce amyloid beta deposits or
plaques, are needed for the treatment and prevention of
disease characterised by amyloid beta deposits or plaques,
such as AD.
SUMMARY OF THE INVENTION
The invention encompasses the compounds of formula (I)
shown below, pharmaceutical compositions containing the
compounds and methods employing such compounds or compositions
in the treatment of Alzheimer's disease and more specifically
compounds that are capable of inhibiting beta-secretase, an
enzyme that cleaves amyloid precursor protein to produce A-
beta peptide, a major component of the amyloid plaques found
in the brains of Alzheimer's sufferers.
In a broad aspect, the invention provides compounds of
formula I
and pharmaceutically acceptable salts thereof, wherein
Z is hydrogen, or
Z is (C3-C7 cycloalkyL)0-1(C1-C6 alkyl)-, (C3-C7 cycloalkyl)0-1(C2-
C6 alkenyl)-, (C3-C7 cycloalkyl) 0-1(C2-C6 alkynyl)- or (C3-C7
cycloalkyl)-, wherein each of said groups is optionally
substituted with 1, 2, or 3 Rz groups, wherein 1 or 2
methylene groups within said (C3-C7 cycloalkyl)0-1 (C1-C6
alkyl)-, (C3-C7 cycloalkyl)0-1(C2-C6 alkenyl)-, (C3-C7
cycloalkyl)0-1(C2-C6 alkynyl)- or (C3-C7 cycloalkyl)- groups
are optionally replaced with -(C=O)-;
Rz at each occurrence is independently halogen (in one
aspect, F or Cl), -OH, -SH, -CN, -CF3, -OCF3, C1-C6
alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy or
NR100R101;
Rloo and R101 at each occurrence are independently H,
C1-C6 alkyl, phenyl, CO(C1-C6 alkyl) or SO2C1-C6
alkyl;
X is -(C=0)- or -(SO2) -;
R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, =O, -SH, -CN,
-CF3, -OCF3, -C3.7 cycloalkyl, -C1-C4 alkoxy, amino, mono-
or dialkylamino, aryl, heteroaryl, and heterocycloalkyl,
wherein each aryl group is optionally substituted with 1,
2 or 3 R50 groups; each heteroaryl is optionally
substituted with 1 or 2 R50 groups; and each
heterocycloalkyl group is optionally substituted
with 1 or 2 groups that are independently R50 or =0;
Rso is selected from halogen, OH, SH, CN, -CO-(C1-C4
alkyl), -NR7R8, -S{O)0-2-(C1-C4 alkyl), C1-C6 alkyl, C2-
C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and C3-C8
cycloalkyl; wherein
the alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl
groups are optionally substituted with 1 or 2
substituents independently selected from C1-C4
alkyl, halogen, OH, -NRSRS, CN, C1-C4 haloalkoxy,
NR7R8, and C1-C4 alkoxy; wherein
Rs and R6 are independently H or C1-C6 alkyl; or
Rs and R6 and the nitrogen to which they are
attached form a 5 or S membered
heterocycloalkyl ring;
R7 and R8 are independently selected from H; -C1-C4
alkyl optionally substituted with 1, 2, or 3
groups independently selected from -OH, -NH2,
and halogen; -C3-C6 cycloalkyl; -(C1-C4 alkyl)-O-
(C1-C4 alkyl); -C2-C4 alkenyl; and -C2-C4
alkynyl;
R2 and R3 are independently selected from H; F; -C1-C6 alkyl
optionally substituted with -F, -OH, -C=N, -CF3, C1-C3
alkoxy, or -NRSR6; -(CH2)0-2-R17; -(CH2) 0-2-Ris; -C2-C6 alkenyl
or C2-C6 alkynyl, wherein the alkenyl and alkynyl groups
are optionally substituted with 1 or 2 groups that are
independently -F, -OH, -C=N, -CF3 or C1-C3 alkoxy; -(CH2)0-
2-C3-C7 cycloalkyl, which is optionally substituted with 1
or 2 groups that are independently -F, -OH, -C=N, -CF3,
C1-C3 alkoxy and -NR5R6;
R17 at each occurrence is an aryl group (preferably
selected from phenyl, 1-naphthyl, 2-naphthyl
indanyl, indenyl, dihydronaphthyl and tetralinyl,)
wherein said aryl group is optionally substituted
with one or two groups that are independently -C1-C3
alkyl; -C1-C4 alkoxy; CF3; -C2-C6 alkenyl or -C2-C6
alkynyl each of which is optionally substituted with
one substituent selected from F, OH, C1-C3 alkoxy;
halogen; OH; -C=N; -C3-C7 cycloalkyl; -CO-(C1-C4
alkyl); or -SO2-(C1-C4 alkyl);
R18 is a heteroaryl group (preferably selected from
pyridinyl, pyrimidinyl, quinolinyl, indolyl,
pryidazinyl, pyrazinyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,
oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl or thiadiazolyl,) wherein said
heteroaryl groups are optionally substituted with
one or two groups that are independently -C1-C6 alkyl
optionally substituted with one substituent selected
from OH, C=N, CF3, C1-C3 alkoxy, and -NRSR6;
R15 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6
alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, halo C1-C6 alkyl,
each of which is unsubstituted or substituted with 1, 2,
3, or 4 groups independently selected from halogen, C1-C6
alkyl, hydroxy, C1-C6 alkoxy, and NH2, and -R26-R27; wherein
R26 is selected from a bond, -C(O)-, -SO2-, -CO2-,
-C(O)NR5-, and -NR5C(O)-,
R27 is selected from C1-C6 alkyl, C1-C6 alkoxy, aryl C2-C6
alkyl, heterocycloalkyl, and heteroaryl, wherein
each of the above is unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that are independently
C1-C4 alkyl, C1-C4 alkoxy, halogen, haloalkyl,
hydroxyalkyl, -NR5R6-, or -C(O)NR5R6; or
R2, R3 and the carbon to which they are attached form a C3-C7
carbocycle, wherein 1, 2, or 3 carbon atoms are
optionally replaced by groups that are independently
selected from -O-, -S-, -SO2-, -C(0)-, or -NR7-;
Rc is selected from - (CH2)0-3-(C3-C8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3
groups independently selected from -R205; and -CO2- (C3-C4
alkyl) ; - (CR245R250)0-4-aryl; - (CR245R250)0-4-heteroaryl; -
(CR245R250)0-4-heterocycloalkyl;- (CR245R250) 0-4-aryl -
heteroaryl; - (CR245R2S0) 0-4-aryl-heterocycloalkyl;
- (CR245R250)0-4-aryl-aryl; - (CR245R250)0-4-heteroaryl-aryl;
(CR245R250)0-4-heteroaryl-heterocycloalkyl; - (CR245R250)0-4-
heteroaryl-heteroaryl; -CHR245-CHR2S0-aryl; - (CR245R2S0)0-4-
heterocycloalkyl-heteroaryl; - (CR245R250)0-4-
heterocycloalkyl-heterocycloalkyl;- (CR24SR250)0-4-
heterocycloalkyl-aryl; a monocyclic or bicyclic ring of
5, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl
(preferably phenyl), heteroaryl (preferably pyridyl,
imidazolyl, thienyl, thiazolyl, or pyrirnidyl), or
heterocycloalkyl (preferably piperidinyl or piperazinyl)
groups;
wherein 1, 2 or 3 carbons of the monocyclic or bicyclic
ring are optionally replaced with -NH-, -N(CO) 0-1R-215-
, -N(CO) 0-1R220-, -O-, or -S(=0)0-2-, and wherein the
monocyclic or bicyclic ring is optionally
substituted with 1, 2 or 3 groups that are
independently -R205, -R245, -R250 or =O;
and -C2-C6 alkenyl optionally substituted with 1, 2, or 3
R205 groups;
wherein each aryl or heteroaryl group attached directly
or indirectly to the - (CR245R250) 0-1 group is
optionally substituted with 1, 2, 3 or 4 R2O0 groups;
wherein each heterocycloalkyl attached directly or
indirectly to the - (CR245R250) 0-4 group is optionally
substituted with 1, 2, 3, or 4 R210;
R200 at each occurrence is independently selected from
C1-C6 alkyl optionally substituted with 1, 2, or 3
R205 groups,- -OH; -N02; -halogen; -CsN; - (CH2)0-4-CO-
NR220R225; - (CH2)0-4-CO-(C1-C8 alkyl); - (CH2)0-4-CO-(C2-Ca
alkenyl) ; - (CH2)0-4-CO- (C2-C8 alkynyl); - (CH2)0-4-CO-
(C3-C7 cycloalkyl); -(CH2)0-4-(CO)0-1-aryl (preferably
phenyl); -(CH2)0-4-(CO)0-1-heteroaryl (preferably
pyridyl, pyrimidyl, furanyl, imidazolyl, thienyl,
oxazolyl, thiazolyl, or pyrazinyl); -(CH2)0-4-(CO)0-1
heterocycloalkyl (preferably imidazolidinyl,
piperazinyl, pyrrolidinyl, piperidinyl, or
tetrahydropyranyl) ; - (CH2) o-4-C02R2iS; - (CH2) 0-4-SO2-
NR220R225; -(CH2)0-4-S(O)0-2-(C1-C6 alkyl);-(CH2)Q-4-
S(O)0-2-(C3-C7 cycloalkyl); - (CH2)0-4-N(H or R215)-
CO2R215; -{CH2)0-4-N(H or R215)-SO2-R220; -(CH2)0-4-N(H or
R215)-CO-N(R215)2; -(CH2)0-4-N(-H or R21S) -CO-R220;
- (CH2)0-4-NR220R225; -(CH2)Q-4-O-CO-(C1-C6 alkyl); -(CH2)0-
4-O-(R215); -(CH2)0-4-S-(R215) ; -(CH2)0-4-O-(C1-C6 alkyl
optionally substituted with 1, 2, 3, or 5 -F); -C2-C6
alkenyl optionally substituted with i or 2 R205
groups; -C2-C6 alkynyl optionally substituted with 1
or 2 R205 groups; adamantly, and -(CH2)0-4-C3-C7
cycloalkyl;
each aryl and heteroaryl group included within R200
is optionally substituted with 1, 2, or 3
groups that are independently -R205, -R210 or -C1-
C6 alkyl substituted with 1, 2, or 3 groups that
are independently R205 or R2i0;
each heterocycloalkyl group included within R200 is
optionally substituted with 1, 2, or 3 groups
that are independently R210;
R2O5 at each occurrence is independently selected
from -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6
alkynyl, -C1-C6 haloalkoxy, - (CH2) 0-3 (C3-C7
cycloalkyl), -halogen, -(CH2)0-6-OH, -O-phenyl,
OH, SH, -(CH2)0-6-CsN, - (CH2)0-6-C (=0) NR235R240,
CF3, -C1-C6 alkoxy, C1-C6 alkoxycarbonyl, and
-NR235R240;
R210 at each occurrence is independently selected
from -Ci-C6 alkyl optionally substituted with
1, 2, or 3 R205 groups; -C2-C6 alkenyl optionally
substituted with 1, 2, or 3 R205 groups; C1-C6
alkanoyl; -SO2- (C1-C6 alkyl); -C2-C6 alkynyl
optionally substituted with 1, 2, or 3 R205
groups; -halogen; -C1-C6 alkoxy; -C1-C6
haloalkoxy; -NR220R225; -OH; -C=N; -C3-C7
cycloalkyl optionally substituted with 1, 2, or
3 R205 groups; -CO-(C1-C4 alkyl);.SO2-NR235R240; -
CO-NR235R240; -SO2-(C1-C4 alkyl); and =O;
R215 at each occurrence is independently selected
from -C1-C6 alkyl, - (CH2)0-2-(aryl), -C2-C6
alkenyl, -C2-C6 alkynyl, -C3-C7 cycloalkyl,
(CH2)0-2-(heteroaryl), and - (CH2)0-2-
(heterocycloalkyl); wherein the aryl group
included within R215 is optionally substituted
with 1, 2, or 3 groups that are independently -
R205 or -R210; wherein the heterocycloalkyl and
heteroaryl groups included within R215 are
optionally substituted with 1, 2, or 3 R210;
R220 and R225 at each occurrence are independently H,
-C1-C6 alkyl, -CHO, hydroxy C1-C6 alkyl, C1-C6
alkoxycarbonyl, -amino C1-C6 alkyl, -SO2-C1-C6
alkyl, C1-C6 alkanoyl optionally substituted
with up to three halogens, -C(0)NH2, -C(O)NH(C1-
C6 alkyl), -C(O)N(C1-C6 alkyl) (C1-C6 alkyl),
-halo C1-C6 alkyl, -(CH2)0-2-(C3-C7 cycloalkyl),
- (C1-C6 alkyl)-O-(C1-C3 alkyl), -C2-C6 alkenyl, -
C2-C6 alkynyl, -aryl (preferably phenyl),
-heteroaryl, or -heterocycloalkyl; wherein the
aryl, heteroaryl and heterocycloalkyl groups
included within R220 and R225 is optionally
substituted with 1, 2, or 3 R270 groups,
R270 at each occurrence is independently -R205, -
C1-C6 alkyl optionally substituted with 1,
2, or 3 R205 groups; -C2-C6 alkenyl
optionally substituted with 1, 2, or 3 R205
groups; -C2-C6 alkynyl optionally
substituted with 1, 2, or 3 R205 groups; -
phenyl; -halogen; -C1-C6 alkoxy; -C1-C6
haloalkoxy; -NR235R240; -OH; -C=N; -C3-C7
cycloalkyl optionally substituted with 1,
2, or 3 R205 groups; -CO-{C1-C4 alkyl);
-SO2-NR235R240; -CO-NR235R240; -SO2-(C1-C4
alkyl); and =O;
R235 and RZ40 at each occurrence are
independently -H, -C1-C6 alkyl, C2-C6
alkanoyl, -SO2- (C1-C6 alkyl), or -phenyl;
R245 and R250 at each occurrence are independently selected
from H, -(CH2)0-4CO2C1-C4 alkyl, - (CH2)0-4C (=O) C1-C4
alkyl, -C1-C4 alkyl, -C1-C4 hydroxyalkyl, -C1-C4
alkoxy, -C1-C4 haloalkoxy, - (CH2)Q-4-C3-C7 cycloalkyl,
-C2-C6 alkenyl, -C2-C6 alkynyl,. (CH2)0-4 aryl, -(CH2)0-4
heteroaryl, and -(CH2)0-4 heterocycloalkyl, or
R245 and R250 are taken together with the carbon to which
they are attached to form a monocycle or bicycle of
3 f 4, 5, 6, 7 or 8 carbon atoms, where 1, 2, or 3
carbon atoms are optionally replaced by 1, 2, or 3
gropus that are independently -0-, -S-, -S02-, -0(0)-
. -NR920-, or -NR220R220- wherein both R220 groups are
alkyl; and wherein the ring is optionally
substituted with 1, 2, 3, 4, 5, or 6 groups that are
independently C!-C4 alkyl, Ci-C4 alkoxy, hydroxyl,
NH2, NH(Ci-C6 alkyl), N(C!-C6 alkyl) (CX~C& alkyl), -NH-
C(O)Ci-C5 alkyl, -NH-S02- (Ci.-Cs alkyl), or halogen;
wherein the aryl, heteroaryl or heterocycloalkyl
groups included within R245 and R250 are
optionally substituted with 1, 2, or 3 groups
that are independenly halogen, C1-6 alkyl, CN or
OH.
The invention also provides methods for the ireatment or
prevention of Alzheimer's disease, mild cognitive impairment
Down's syndrome, Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy,
other degenerative dementias, dementias of mixed vascular and
degenerative origin, dementia associated with Parkinson's
disease, dementia associated with progressive supranuclear
palsy, dementia associated with cortical basal degeneration,
diffuse Lewy body type of Alzheimer's disease comprising
administration of a therapeutically effective amount of a
compound or salt of formula I, to a patient in need thex-eof.
Preferably, the patient is a human.
More preferably, the disease is Alzheimer's disease.
More preferably, the disease is dementia.
The invention also provides pharmaceutical compositions
comprising a compound or salt of formula I and at least one
pharmaceutically acceptable carrier, solvent, adjuvant or
diluent.
The invention also provides the use of a compound or salt
according to formula I for the manufacture of a medicament.
The invention also provides the use of a compound or salt
of formula I for the treatment or prevention of Alzheimer's
disease, mild cognitive impairment Down's syndrome, Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,
cerebral amyloid angiopathy, other degenerative dementias,
dementias of mixed vascular and degenerative origin, dementia
associated with Parkinson's disease, dementia associated with
progressive supranuclear palsy, dementia associated with
cortical basal degeneration, or diffuse Lewy body type of
Alzheimer's disease.
The invention also provides compounds, pharmaceutical
positions, kits, and methods for inhibiting beta-secretase-
mediated cleavage of amyloid precursor protein (APP). More
particularly, the compounds, compositions, and methods of the
invention are effective to inhibit the production of A-beta
peptide and to treat or prevent any human or veterinary
disease or condition associated with a pathological form of A-
beta peptide.
The compounds, compositions, and methods of the invention
are useful for treating humans who have Alzheimer's Disease
(AD), for helping prevent or delay the onset of AD, for
treating patients with mild cognitive impairment (MCI), and
preventing or delaying the onset of AD in those patients who
would otherwise be expected to progress from MCI to AD, for
treating Down's syndrome, for treating Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch Type, for treating
cerebral beta-amyloid angiopathy and preventing its potential
consequences such as single and recurrent lobar hemorrhages,
for treating other degenerative dementias, including dementias
of mixed -vascular and degenerative origin, for treating
dementia associated with Parkinson's disease, dementia
associated with progressive supranuclear palsy, dementia
associated with cortical basal degeneration, and diffuse Lewy
body type AD, and for treating frontotemporal dementias with
parkinsonism (FTDP).
The compounds of the invention possess beta-secretase
inhibitory activity. The inhibitory activities of the
compounds of the invention is readily demonstrated, for
example, using one or more of the assays described herein or
known in the art.
Unless the substituents for a particular formula are
expressly defined for that formula, they are understood to
carry the definitions set forth in connection with the
preceding formula to which the particular formula makes
reference.
The invention also provides methods of preparing the
compounds of the invention and the intermediates used in those
methods.
The invention also provides the use of compounds and
pharmaceutically acceptable salts of formula I for the
manufacture of a medicament for use in: treating a subject who
has, or in preventing a subject from developing Alzheimer's
disease (AD); preventing or delaying the onset of Alzheimer's
disease; treating subjects with mild cognitive impairment
(MCI); preventing or delaying the onset of Alzheimer's disease
in subjects who would progress from MCI to AD; treating Down's
syndrome; treating subjects who have Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type; treating
cerebral amyloid angiopathy and preventing its potential
consequences; treating other degenerative dementias; treating
dementia associated with Parkinson's disease, progressive
supranuclear palsy, or cortical basal degeneration; treating
diffuse Lewy body type AD; and treating frontotemporal
dementias with parkinsonism (FTDP).
DETAILED DESCRIPTION OF THE INVENTION
As noted above, the invention provides compounds of
formula I. In accordance with compounds of formula I and
other applicable formulas below, when Z is (C3-C7 cycloalkyl) 0.
1(C1-C6 alkyl)-, (C3-C7 cycloalkyl)0-1 (C2-C6 alkenyl)-, (C3-C7
cycloalkyl)0-1 (C2-C6 alkynyl) - or (C3-C7 cycloalkyl)-, 1 or 2
methylene groups within said (C3-C7 cycloalkyl)0-1 (C1-C6 alkyl)-,
(C3-C7 cycloalkyl)0-1 (C2-C6 alkenyl)-, (C3-C7 cycloalkyl)0-1 (C2-C6
alkynyl)- or (C3-C7 cycloalkyl)- groups are optionally replaced
with - (C=0)-. This optionally substitution may be alpha to X,
e.g., a,b-diketo compounds are contemplated by the invention
Further such carbonyl substitution contemplates compounds, for
example, in which a methylene group is replaced in the cyclic
portion the cycloalkyl group (to form a cyclic ketone moiety)
and/or in which a methylene group is replaced in the alkyl,
alkenyl or alkynyl portion of such groups.
Preferred compounds of formula I include those wherein Z
1 (C3-C7 cycloalkyl)0-1(C1-C6 alkyl)-, (C3-C7 cycloalkyl)0-1 (C2-C6
alkenyl)-, (C3-C7 cycloalkyl)0-1 (C2-C6 alkynyl)- or (C3-C7
cycloalkyl)-, wherein each of said groups is optionally
substituted with 1, 2, or 3 Rz groups;
Rz at each occurrence is independently halogen, -OH, -CN,
C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy, or
-NR100R101;
R100 and R101 are independently H, C1-C6 alkyl,, phenyl,
CO(C1-C6 alkyl) or SO2C1-C6 alkyl.
In another preferred embodiment, the invention
encompasses compounds of formula I wherein Z is as defined
above and X is -(C=0)-. In an alternative embodiment, X is -
(C=0)-, and Z is H. In another preferred embodiment, X is -
(C=0)-, and Z is C1-C4 alkyl, more preferably C1-C3 alkyl, even
more preferably methyl.
Preferred compounds of formula I further include those
wherein R1 is C1-C10 alkyl optionally substituted with 1 or 2
groups independently selected from halogen, -OH, =0, -CF3,
OCF3, -C3-7 cycloalkyl,. -C1-C4 alkoxy, amino and aryl, wherein
the aryl (preferably phenyl) group is optionally substituted
with 1 or 2 R50 groups;
R50 is selected from halogen, OH, -CO- (Ci-C4 alkyl),
-NR7R8, C1-C6 alkyl, C1-C6 alkoxy and C3-C8 cycloalkyl;
wherein the alkyl, alkoxy and cycloalkyl groups are
optionally substituted with 1 or 2 substituents
independently selected from C1-C4 alkyl, halogen, OH,
-NR5R6, NR7R8, and C3.-C4 alkoxy;
R5 and R6 at are independently H or C1-C6 alkyl; or
Rs and Rs and the nitrogen to which they are attached
form a 5 or 6 membered heterocycloalkyl ring;
and
R7 and R8 are independently selected from -H; -C1-C4
alkyl optionally substituted with 1, 2, or 3
groups independently selected from -OH, -NH2,
and halogen; -C3-C6 cycloalkyl; and - (C1-C4
alkyl)-O- (C1-C4 alkyl).
Preferred compounds of formula I also include those
wherein
R1 is -CH2-phenyl where the phenyl ring is optionally
substituted with 1 or 2 groups independently selected
from halogen, C1-C2 alkyl, C1-C2 alkoxy and hydroxy. More
preferably, R1 is benzyl, 3-fluorobenzyl or 3,5-
difluorobenzyl.
Preferred compounds of formula I include those wherein R2
and R3 are independently -H or -C1-C6 alkyl.
Equally preferred compounds of formula I include those
wherein R15 is H.
In another aspect, the invention provides compounds of
the formula II:
and pharmaceutically acceptable salts thereof, wherein
Z is hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -
C3-C7 cycloalkyl, where each of said groups is optionally
substituted with 1 or 2 Rz groups, wherein 1 or 2
methylene groups within said -C1-C6 alkyl, -C2-C6 alkenyl,
-C2-C6 alkynyl or -C3-C7 cycloalkyl groups are optionally
replaced with -(C=0)-;
Rz at each occurrence is independently halogen, -OH, -CN,
-CF3, Ci-Cg alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy
or -NRlooR101;
R100 and R1O1 are independently H, C1-C6 alkyl,
phenyl, CO (C1-C6 alkyl) or SO2C1-C6 alkyl;
X is -C(=O)-;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 groups
independently selected from halogen, -OH, =0, -CN, -CF3,
-OCF3, -C3-C7 cycloalkyl, -C1-C4 alkoxy, arnino, mono-
dialkylamino, aryl, heteroaryl or heterocycloalkyl,
wherein the aryl group is optionally substituted with 1
or 2 R50 groups;
R50 is halogen, OH, CN, -CO- (C1-C4 alkyl), -NR7R8, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, and
C3-C8 cycloalkyl;
R7 and R8 are selected from H; -C1-C4 alkyl
optionally substituted with 1, 2, or 3 groups
selected from -OH, -NH2 and halogen; -C3-C6
cycloalkyl; - (C1-C4 alkyl)-O- (C1-C4 alkyl); -C2-
C4 alkenyl; and -C2-C4 alkynyl;
Rc is selected from - (CR245R250)0-4-aryl; - (CR245R250)0-4-heteroaryl;
- (CR24SR250)0-4-heterocycloalkyl; where the aryl and
heteroaryl groups attached to the - (CR245R250)0-4- group are
optionally substituted with 1, 2, 3 or 4 R200 groups;
where the heterocycloalkyl group attached to the
- (CR245R250)0-4- group is optionally substituted with 1, 2,
3, or 4 R210 groups; and
R245 R250, R200, and R210 are as defined above.
In another aspect, the invention provides compounds
wherein
Rc is - (CR245R250)0-4-heterocycloalkyl (preferably piperidinyl,
piperazinyl, pyrrolidinyl, 2-oxo-tetrahydroquinolinyl, 2-
oxo-dihydro-lH-indolyl, or imidazolidinyl); v/here the
heterocycloalkyl group attached to the - (CR245R250) 0-4-
group is optionally substituted with 1, 2, 3, or 4 R210
groups.
In a further preferred embodiment for compounds of
formula II, Z is -C1-C6 alkyl;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 aryl
groups, which are optionally substituted with 1 or 2 R50
groups,
each R50 is independently halogen, OH, CN, -NR7R8 or C1-C6
alkyl,
R7 and R8 are independently -H; -C1-C4 alkyl
optionally substituted with 1 or 2 groups
independently selected from -OH, -NH2, and
halogen; or -C3-C6 cycloalkyl; and
Rc is - (CR245R250) o-4-aryl or - (CR245R250)0-4-heteroaryl (preferably
the heteroaryl is pyridyl, pyrimidyl, guinolinyl,
isoquinolinyl, more preferably pyridyl), where the aryl
and heteroaryl groups are optionally substituted with 1
or 2 R200 groups, where R200 is as defined above.
Still more preferred compounds of formula II, include
those wherein
R1 is C1-C10 alkyl substituted with one aryl group, where the
aryl (preferably phenyl or naphthyl, still more
preferably phenyl) group is optionally substituted with 1
or 2 R50 groups ;
Rc is - (CR245R250)1-4-aryl or - (CR245R250)1-4-heteroaryl,
R245 and R250 are independently selected from H, -(CH2)0-
4CO2C1-C4 alkyl, - (CH2)0-4CO2H, -C1-C4 alkyl, - (C1-C4
alkyl)OH, or
R245; R250 and the carbon to which they are attached form a
monocycle or bicycle of 3, 4, 5, 6, 7 or 8 carbon
atoms, where 1 or 2 carbon atoms are optionally
replaced by -O-, -S-, -SO2-, or -NR220- where R220 is
as defined above; and
wherein the aryl and heteroaryl groups attached to the
- (CR245R250)1-4- groups are optionally substituted with
1 or 2 R200 groups.
In another preferred embodiment of compounds of formula
II,
R1 is C1-C10 alkyl substituted with one aryl group (preferably
phenyl or naphthyl), which is optionally substituted with
1 or 2 R50 groups,
R50 is independently halogen, OH, or Cx-C6 alkyl;
Rc is - (CR245R2so)-aryl or - (CR24SR25o) -heteroaryl, wherein the
aryl and heteroaryl groups attached to the - (CR245R250) 1-4-
groups are optionally substituted with 1 or 2
substitutents selected from -Cl, -Br, -I, -C1-C3 alkyl, -
(C1-C3 alkyl)OH, -CN, -C=CH, -C=C-CH2-OH, -CF3, -thienyl
optionally substituted with a -C(=O)H group, -phenyl
optionally substituted with 1 or 2 C1-C3 alkyl groups, -
(C1-C3 alkyl)OH group or -CO(C1-C3 alkyl) group,
isoxazolyl optionally substituted with a C1-C4 alkyl
group, or - (C1-C2 alkyl)oxazolyl where the oxazole ring is
optionally substituted with -Ci-C2 alkyl group;
R245 and R250 at each occurance are independently -H, -C1-C3
alkyl, - (C1-C3 alkyl)CO2H, -(C1-C3 alkyl)C02 (C1-C3
alkyl), or - (C1-C3 alkyl) OH, or
R245 and R2S0 are taken together with the carbon to which
they are attached to form a monocycle or bicycle of
3, 4, 5, 6, 7 or 8 carbon atoms, where 1 or 2 carbon
atoms is optionally replaced by -0-, -S-, -S02-, or -
NR220-, and
R220 is as defined above.
In another aspect, the invention provides compounds of
the formula III:
and pharmaceutically acceptable salts thereof; where
Z, X, R1, R2, R3 and R15 are as definded above;
X1 is CH2, CHR200, C(R2O0)2, or - (C=0) - ;
X2; and X3 are independently CH2, CHR2O0, C(R200)2, O, C=0, S,
SO2, NH, or NR7;
X4 is a bond, CH2, CHR200, C(R200)2 0, C=0, S, SO2, NH, or NR7;
provided that when Xx is -(C=O)-, X2 is CH2, CHR200, C(R200)2 O,
NH or NR7 and the X3 group attached to X2 is CH2, CHR200,
C(R200)2, or SO2 when X2 is NH or NR7 and X4 is CH2, CHR200,
or C(R200)2 or a bond; or
-X2-X3- is -(C=0)0-, -O(C=O)-, -(C=O)NH-, -NH(C=O)-, -
(C=O)NR7-, or -NR7(C=O.)-, with the proviso that X1 is not
- (C=O) - and with the proviso that X4 is CH2, CHR200, or
C(R200)2 or a bond; or
-X3-X4- is -(C=O)O-, -O(C=O)-, -(C=O)NH-, -NH(C=O)-, -(C=O)NR7-
, or -NR7(C=O)-, with the proviso that X2 is CH2, CHR2O0,
or C(R200)2; or
-X2-X3-X4- is - (C=O)NH-SO2- or -SO2-NH (C=O) -, - (C=O) NR7-SO2- or
-SO2-NR7 (C=0) -, with the proviso that X1 is not -(C=O)-;
and
X5, X6, X7 and X8 are CH or CR200, where 1 or 2 of X5, X6, X7 and
XB is optionally replaced with N, and where R200 and R7 are
as defined above.
In a preferred embodiment of compounds of formula III,
the invention further provides compounds of the formula IV:
wherein
Z is hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -
C3-C7 cycloalkyl, where each is optionally substituted
with 1 or 2 Rz groups, and wherein 1 or 2 methylene groups
within said -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or
-C3-C7 cycloalkyl groups are optionally replaced with -
(C=0)-;
Rz at each occurrence is independently halogen, -OH, -CN,
-CF3, C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy
or -NR100R101 ;
Rl00 and R101 are independently H, C1-C6 alkyl, phenyl,
CO(C1-C6 alkyl) or SO2(C1-C6 alkyl;
X is -C(=0)-;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 groups
independently selected from halogen, -OH, =O, -CN, -CF3,
-OCF3, -C3-C7 cycloalkyl, -C1-C4 alkoxy, amino, mono-
dialkylamino, aryl optionally substituted with 1 or 2 R50
groups, heteroaryl or heterocycloalkyl;
R50 is halogen, OH, CN, -CO-(C1-C4 alkyl), -NR7R8, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or
C3-C8 cycloalkyl; and
R7 and R8 are selected from H; -C1-C4 alkyl
optionally substituted with 1, 2, or 3 groups
selected from -OH, -NH2 and halogen; -C3-C6
cycloalkyl; - (C1-C4 alkyl)-0-(C1-C4 alkyl); -C2-
C4 alkenyl; and -C2-C4 alkynyl.
In other preferred compounds of formula IV,
Z is -C1-C6 alkyl,-
R1 is C1-C10 alkyl optionally substituted with 1 or 2 aryl
(preferably phenyl or naphthyl) groups, which are
optionally substituted with 1 or 2 R50 groups,
R50 is independently halogen, OH, CN, -NR7R8 or C1-C6
alkyl, R7 and R8 are independently H; -C1-C4 alkyl
optionally substituted with 1 or 2 groups independently
selected from -OH, -NH2, and halogen; or -C3-C6
cycloalkyl; and
X1, X2 or X3 are CH2 or CHR2O0, where one of X2 or X3 is
optionally replaced with 0, C=0, SO2, NH, NR7,
X4 is a bond; and
X5, X6, X7 and X8 are CH or CR200, where one of Xs, Xe, X7 or X8
is optionally replaced with N, and
R2O0 is as defined above.
In yet another preferred aspect of the invention for
compounds of formula VI, R1 is C1-C10 alkyl substituted with one
aryl group, where the aryl group is optionally substituted
with 1 or 2 R50 groups;
X1# X2 and X3 are CH2, CHR2oo, or C(R2Oo)2, where one of X2 or X3
is optionally replaced with 0, NH or NR7, and where X4 is a
bond; and
Xs, X6, X7 and XB are CH or CR2Oo, where one of X5, X6, X7 or X8
is optionally replaced with N, where R50, R2oo and R7 are as
defined above.
In a futher preferred embodiment of compound of formula
IV,
R1 is C1-C10 alkyl substituted with one aryl group (preferably
phenyl or naphthyl, more preferably phenyl), where the
aryl group is optionally substituted with 1 or 2 R50
groups,
R50 is independently halogen,. OH, or C1-C6 alkyl;
Xl, X2 and X3 are CH2 or CHR200, where one of X2 or X3 is
optionally replaced with 0, NH or NR7;
X4 is a bond;
X5, X6, X7 and X8 are CH or CR200, where one of X5, X6, X7 and Xe
is optionally replaced with N; and
R2O0 is -C1-4 alkyl, -halogen; -O-C1-3 alkyl; -pyrrolyl or -
(CH2) 1-3-N (R7)2, where R7 is as defined above.
In another aspect, the invention provides compounds of V-.
and a pharmaceutically acceptable salt thereof, wherein
Z is hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -
C3-C7 cycloalkyl, where each of said groups is optionally
substituted with 1 or 2 Rz groups, wherein 1 or 2
methylene groups within said -C1-C6 alkyl, -C2-C6 alkenyl,
-C2-C6 alkynyl or -C3-C7 cycloalkyl groups are optionally
replaced with -(C=O)-;
Rz at each occurrence is independently halogen, -OH, -CM,
-CF3, Ci-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy
or -NR100R101;
R100 and R1Oi are independently H, Ci-C6 alkyl, phenyl,
COlCi-Cg alkyl) or SO2Ci-Cs alkyl;
X is -C(=0)-;
Ri is Ci-Cio alkyl optionally substituted with 1 or 2 groups
independently selected from halogen, -OH, =0, -CN, -CF3,
-OCF3, -C3-C7 cycloalkyl, -C1-C4 alkoxy, amino, mono-
dialkylamino, aryl optionally substituted with 1 or 2 R50
groups, heteroaryl or heterocycloalkyl;
R50 is halogen, OH, CN, -CO-(C1-C4 alkyl), -NR7R8, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and
C3-C8 cycloalkyl;
R7 and R8 are selected from H; -C1-C4 alkyl optionally
substituted with 1, 2, or 3 groups selected from -OH, -NH2
and halogen; -C3-C6 cycloalkyl; - (C1-C4 alkyl)-O-(C1-C4
alkyl); -C2-C4 alkenyl; and -C2-C4 alkynyl;
X1-X8 are indepdendently CH or CR2O0, where 1, 2, 3 or 4 of X1 -
X8 are optionally replaced with N (more preferably, 1, 2,
or 3 are replaced with N);
where R200 is as def inded above.
In another preferred embodiment for compounds of forumula
V,
Z is -C1-C6 alkyl;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 aryl
groups, where each aryl group is optionally substituted
with 1 or 2 Rso groups,
R50 is independently halogen, OH, CN, -NR7Ra or C1-C6
alkyl,
R7 and R8 are independently H; -C1-C4 alkyl optionally
substituted with 1 or 2 groups independently
selected from -OH, -NH2, and halogen; or -C3-C6
cycloalkyl; and
X1 - X8 are CH or CR200, where one or two of X1 - X8 is
optionally replaced with N, and R50 and R200 are as defined
above.
In another preferred embodiment for compounds of forumula
V,
R1 is C1-C10 alkyl substituted with one aryl group, where the
aryl group (preferably phenyl) is optionally substituted
with 1 or 2 R50 groups,
R50 is independently selected from halogen, OH, or C1-C6
alkyl;
X1 - X8 are CH or CR200, where one of X1-X8 is optionally
replaced with N.
In another preferred embodiment for compounds of forumula
v,
R2O0 is -C1-C5 alkyl, -C2-C5 alkenyl, -C3-C6 cycloalkyl, halogen,
-CF3, -O-C1-C3 alkyl, - (C1-C3, alkyl)-O-(C3-C3 alkyl),
pyrrolyl, or -(CH2) 1-3-N (R7) 2•
In a further aspect, the invention provides compounds of
the formula VI:
and a pharmaceutically acceptable salt thereof, wherein
Z is hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -
C3-C7 cycloalkyl, where each of said groups is optionally
substituted with 1 or 2 Rz groups, wherein 1 or 2
methylene groups within said -C1-C6 alkyl, -C2-C6 alkenyl,
-C2-C6 alkynyl or -C3-C7 cycloalkyl groups are optionally
replaced with -(C=0)-;
Rz at each occurrence is independently halogen, -OH, -CN,
-CF3, C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy
or -NR100R101;
R100 and R1O1 are independently H, C1-C6 alkyl,
phenyl, CO(C1-C6 alkyl) or SO2C1-C6 alkyl;
X is -C(=0)-;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 groups
independently selected from halogen, -OH, =0, -CN, -CF3,
-OCF3, -C3-C7 cycloalkyl, -C1-C4 alkoxy, amino, mono-
dialkylaraino, aryl, heteroaryl and heterocycloalkyl,
wherein the aryl, heterocycloalkyl and heteroaryl groups
are optionally substituted with 1 or 2 R50 groups, wherein
the heterocycloalkyl group is optionally further
substituted with -=0;
R50 is halogen, OH, CM, -CO-(C1-C4 alkyl), -NR7R8, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy arid
C3-C8 cycloalkyl;
R7 and R8 are selected from H; -C1-C4 alkyl optionally
substituted with 1, 2, or 3 groups selected from -OH, -NI-I2
and halogen; -C3-C6 cycloalkyl; -(C1-C4 alkyl)-O-(C1-C4
alkyl); -C2-C4 alkenyl; and -C2-C4 alkynyl;
R4 is H or -C1-C4 alkyl;
R5 is -C1-C4 alkyl;
X1 - X4 are indepdendently CH or CR200, where 1 or 2 of X1 - X4
are optionally replaced with N; and where
R2O0 is as definded above.
In a preferred embodiment for compounds of formula VI,
Z is -C1-C6 alkyl;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 aryl
groups, where each aryl group is optionally substituted
with 1 or 2 R50 groups,
each R50 is independently halogen, OH, CN, -NR7R8 or C1-C6
alkyl,
R7 and R8 are independently H; -C1-C4 alkyl optionally
substituted with 1 or 2 groups independently
selected from -OH, -NH2, and halogen; or -C3-C6
cycloalkyl; and
X1 - X4 are CH or CR200, where one or two of X1 - X4 is
optionally replaced with N,
R200 is as defined above.
In.a further preferred embodiment for compounds of
formula VI,
R1 is C1-C10 alkyl. substituted with one aryl group (preferably
phenyl), where the aryl group is optionally substituted
with 1 or 2 R50 groups,
R50 is independently selected from halogen, OH, or C1-C6
alkyl;
X1-X4 are CH or CR2O0, where one of X1 - X4 is optionally-
replaced with N, and where R50 and R200 are as defined above.
In yet another preferred embodiment for compounds of
formula VI,
R2O0 is -C1-C6 alkyl, -C1-C6 alkenyl, -C3-C6 cycloalkyl,
halogen, -CF3, -O-C1-C3 alkyl, - (C1-C3 alkyl)-O-(C1-C3 alkyl),
pyrrolyl, or - (CH2)1-3-N(R7) 2.
In another aspect, the invention provides compounds of
the formula VII:
and pharmaceutically acceptable salts thereof, wherein
Z, X, R1, R2 and R3 are as defined above;
m is 0 or an integer of 1-6;
Y is H, CN, OH, C1-C6 alkoxy, CO2H, CO2R215, NH2, aryl or
heteroaryl; and
X1-X5 are indepdendently CH or CR2O0, where 1, or 2 of X1-X5 are
optionally replaced with N, and
R200 is as definded as above.
In a preferred embodiment of compounds of formula VII, R2,
R3 and Ri5 are H;
Z is hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -
C3-C7 cycloalkyl, where each of said groups is optionally
substituted with 1 or 2 Rz groups, wherein 1 or 2
methylene groups within said -C1-C6 alkyl, -C2-Cs alkenyl,
-C2-C6 alkynyl or -C3-C7 cycloalkyl groups are optionally
replaced with -(C=O)-;
Rs at each occurrence is independently halogen, -OH, -CM,
-CF3, C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy
or -NR1O0R101;
R1O0 and R101 are independently H, C1-C6 alkyl, phenyl,
CO(C1-C6 alkyl) or SO2C1-C6 alkyl;
X is -C(=0) -;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 groups
independently selected from halogen, -OH, =0, -CN, -CF3,
-OCF3, -C3-C7 cycloalkyl, -C1-C4 alkoxy, amino, mono-
dialkylamino, aryl, heteroaryl or heterocycloalkyl,
wherein the aryl, heterocycloalkyl and heteroaryl groups
are optionally substituted with 1 or 2 R50 groups, and
wherein the heterocycloalkyl group is optionally further
substituted with =0;
R50 is halogen, OH, CN, -CO-(C1-C4 alkyl), -NR7Ra, C1-C6
alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy or
C3-C8 cycloalkyl;
R7 and R8 are independently H; -C1-C4 alkyl optionally
substituted with 1, 2, or- 3 groups selected
from -OH, -NH2 and halogen; -C3-C6 cycloalkyl; -
(C1-C4 alkyl)-O-(C1-C4 alkyl); -C2-C4 alkenyl; or
-C2-C4 alkynyl,-
Y is as defined above;
X1-X5 are indepdendently CH or CR200, where 1 or 2 of X1-X5 are
optionally replaced with N; and
R200 is as definded above.
In yet another preferred embodiment for compounds of
forumula VII,
Z is -C1-C6 alkyl;
R1 is C1-C10 alkyl optionally substituted with 1 or 2 aryl
groups, where each aryl group is optionally substituted
with 1 or 2 R50 groups,
R50 is independently halogen, OH, CN, -NR7RB or C1-C6
alkyl, R7 and R8 are independently -H; -C1-C4 alkyl
optionally substituted with 1 or 2 groups
independently selected from -OH, -NH2, and halogen;
or -C3-C6 cycloalkyl;
X1-X5 are CH or CR200, where one or two of X1-X5 is optionally
replaced with N.
More preferably for compounds of formula VII,
R1 is C1-C10 alkyl substituted with one aryl group, where the
aryl qroup is optionally substituted with 1 or 2 R50
groups, where R50 is independently selected from halogen,
OH, or C1-C6 alkyl;
wherein X1 - X5 are CH or. CR2O0, where one of X1 - X5 is
optionally replaced with N,
where R50 and R200 are as definded above.
In yet another preferred embodiment for compounds of
formula VII,
R2oo is -C1-C5 alkyl, -C1-C5 alkenyl, -C3-C6 cycloalkyl, halogen,
-CF3, -O-C1-C3 alkyl, -(C1-C3 alkyl)-0- ( C1-C3 alkyl),
pyrrolyl, or - (CH2)1-3-N(R7) 2, where R7 is as defined above.
In another aspect, the invention provides compounds of
formula II, i.e., compounds of formula Il-a, wherein
Rx is C1-C10 alkyl optionally substituted with 1 or 2 groups
independently selected from halogen, -OH, =0, -CF3, -OCF3,
-C3-7 cycloalkyl, -C1-C4 alkoxy, amino and aryl, wherein
the aryl group is optionally substituted with 1 or 2 R50
groups;
wherein
R50 is selected from halogen, OH, -CO-(C1-C4 alkyl),
-NR7R8, C1-C6 alkyl, C1-C6 alkoxy and C3-CB cycloalkyl;
and
R7 and RB are independently -H; -C1-C4 alkyl optionally
substituted with 1, 2, or 3 groups independently
selected from -OH, -NH2, and halogen; -C3-Cs
cycloalkyl; or - (d-C4 alkyl)-O-(d-C4 alkyl).
Preferred compounds of formula Il-a, include those of
formula Il-b, i.e., compounds wherein
Rc is (CR245R250)1-aryl, where the aryl is optionally substituted
with 1, 2, or 3 R2O0 groups; and
R245 is H and R2S0 is H or Cx-C6 alkyl; or
R245 and R250 are independently C1-C3 alkyl (preferably both are
methyl); or
CR245R250 represents a C3-C7 cycloalkyl group.
Preferred compounds of formula II-b, include those of
formula II-c, i.e., compounds wherein
the (CR245R250) 1-aryl is (CR245R250)1-phenyl where the phenyl is
optionally substituted with 1, 2, or 3 R200 groups.
Preferred compounds of formula II-c, include those of
formula Il-d, i.e., compounds wherein the phenyl in (CR245R250) 1-
phenyl is substituted with 1-3 independently selected R2O0
groups, or
1 or 2 independently selected R200 groups, and
1 heteroaryl group optionally substituted with 1 R2O0
group or 1 phenyl group optionally substituted with 1 R200
group.
Other preferred comounds include those wherein the phenyl
is substituted with a heterocycloalkyl group, which is
optionally substituted with 1 -or 2 R2O0 groups and/or =0.
Preferred compounds of formula Il-d, include those of
formula II-e, i.e., compounds wherein R245 is hydrogen and R250
is C1-C3 alkyl.
Preferred compounds of formula Il-d, include those of
formula II-f, i.e., compounds wherein R24S and R250 are both
hydrogen.
Preferred compounds of formula II-f, include those of
formula Il-g, i.e., compounds wherein the phenyl in (CR245R250) 1-
phenyl is substituted with 1 R2Oo group, and 1 heteroaryl group
optionally substituted with 1 R200 group or
1 R200 group, and 1 phenyl group optionally substituted
with 1 R200 group; or
1 R200 group, and 1 heterocycloalkyl, which is optionally
substituted with one R2oo or =0.
Preferred compounds of formula Il-g, include those of
formula Il-h, i.e., compounds wherein
R2oo is Ci-C6 alkyl, C2-C6 alkenyl, C±-C6 alkoxy, hydroxy(Cx-
C6) alkyl,.Ci-C6 alkoxy (Cx-Cg) alkyl, heterocycloalkyl,
heteroaryl, halogen, hydroxy, cyano, or -NR220R22S, where
R22o and R225 are independently hydrogen or alkyl.
Preferred compounds of formulas Il-g and Il-h, include
those of formula Il-i, i.e., compounds wherein
R1 is benzyl where the phenyl portion is optionally substituted
with 1 or 2 groups independently selected from halogen,
C1-C2 alkyl, C1-C2 alkoxy, -O-allyl, and hydroxy.
Preferred compounds of formula II-i, include those of
formula II-j, i.e., compounds wherein
Z is hydrogen or C1-C3 alkyl.
Preferred compounds of formula Il-i, include those of
formula Il-k, i.e., compounds wherein
the phenyl in (CR245R250) i-phenyl is substituted with
1 R2O0 group, and 1 heteroaryl group, wherein
the heteroaryl is a 5-6 membered heteroaromatic ring
containing 0 or 1-3 nitrogen atoms and 0 or 1 oxygen
atoms provided that the ring contains at least one
nitrogen or oxygen atom, and where the ring is
optionally substituted with one or two groups which
are independently C1-C6 alkyl, C1-C6 alkoxy,
hydroxy (C1-C6) alkyl, hydroxy, halogen, cyano, nitro,
trif luoromethyl, amino, mono (C1-C6) alkylamino, or
di (C1-C6) alkylamino.
Other preferred compounds include those of formula Il-i, i.e.,
compounds of formula II-K-1, wherein
the phenyl in (CR245R250)1-phenyl is substituted withl R2O0 group,
and 1 heterocycloalkyl group, which is piperazinyl,
piperidinyl or pyrrolidinyl and where the ring is
optionally substituted with one or two groups which are
independently C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-
C6)alkyl, hydroxy, halogen, cyano, nitro, trifluoromethyl,
-SO2-(C1-C4 alkyl), -C1-C6 alkanoyl, amino, mono(C1-
C6) alkylamino, or di (C1-C6) alkylamino.
Preferred compounds of formula Il-k include those of
formula II-l, i.e., compounds wherein
the heteroaryl is pyridinyl, pyrimidinyl, imidazolyl,
pyrazolyl, furanyl, thiazolyl, or oxazolyl, each of which
is optionally substituted with one or two groups which
are independently C1-C6 alkyl, C1-C6 alkoxy, hydroxy(C1-
C6)alkyl, hydroxy, halogen, cyano, nitro, trifluoromethyl,
amino, mono (C1-C6) alkylaraino, or di(C1-C6) alkylamino.
Preferred compounds of formula II-1 include those of
formula II-m, i.e., compounds wherein R2O0 is C1-C6 alkyl, or C2-
C6 alkenyl.
Preferred compounds of formula II-d include those of
formula II-n, i.e., compounds wherein CR245R250 represents a C3-
C7 cycloalkyl group.
Preferred compounds of formula II-n include those of
formula II-o, i.e., compounds wherein CR245R250 represents a Cs-
C7 cycloalkyl group.
Preferred compounds of formula II-n, include those of
formula II-p, i.e., compounds wherein CR245R250 represents a C3-
C6 cycloalkyl group.
Preferred compounds of formula II-p include those of
formula II-q, i.e., compounds wherein CR245R250 represents a C6
cycloalkyl.
Preferred compounds of formula II-q include those of
formula Il-r, i.e., compounds wherein the phenyl in (CR245R250)1-
phenyl is substituted with
1 R2Q0 group; or
1 R200 group and one heteroaryl group optionally
substituted with one R2Oo group or
1 R200 group and one phenyl group optionally substituted
with one R2oo group.
Preferred compounds of formula II-r include those of
formula II-s, i.e., compounds wherein
the phenyl in (CR245R250) i-phenyl is substituted with 1 R200
group.
Preferred compounds of formula II-s, include those of
formula Il-t, i.e., compounds wherein
R200 is Ci-Cg alkyl, C2-C6 alkenyl, Ci-Cg alkoxy, hydroxy (Ci-
Cs) alkyl, Ca.-C6 alkoxy (Ci-CG) alkyl, halogen, hydroxy,
cyano, or -NR220R225, where
R22o and R225 are independently hydrogen or alkyl.
Preferred compounds of formula Il-t, include those of
formula II-u, i.e., compounds wherein
R1 is benzyl where the phenyl portion of the benzyl group
is optionally substituted with 1 or 2 groups independently
selected from halogen, C1-C2 alkyl, C1-C2 alkoxy, -O-allyl, and
hydroxy.
Preferred compounds of formula II-u, include those of
formula II-v, i.e., compounds wherein Z is H or C1-C3 alkyl.
Preferred compounds of formula II-v, include those of
formula II-w, i.e., compounds wherein
R200 is C1-C6 alkyl or C2-C5 alkenyl.
Preferred compounds of formula II-w, include those of
formula II-x, i.e., compounds wherein
Z is C1-C2 alkyl and
R1 is benzyl, 3-fluorobenzyl or 3,5-difluorobenzyl.
Preferred compounds of formula II-m, include those of
formula Il-y, i.e., compounds wherein
Z is C1-C2 alkyl optionally substituted with one halogen (which
is preferably F or Cl) and R1 is benzyl, 3-fluorobenzyl or
3,5-difluorobenzyl.
Preferred compounds of formula II-w, include those of
formula II-z, i.e., compounds wherein R200 is C3-C5 alkyl.
Preferred compounds of formula II-m, include those of
formula Il-aa, i.e., compounds wherein R200is C3-C5 alkyl.
In another aspect, the invention provides compounds of
formula Il-bb, i.e., compounds of formulas II to Il-aa,
wherein
R2 is H, methyl, or hydroxymethyl and R3 is H.
Other preferred compounds of formula II include those of
formula II-cc, wherein Rc is a monocyclic or bicyclic ring of
5, 6, 7 8, 9, or 10 carbons fused to 1 aryl (preferably
phenyl), heberoaryl (preferably pyridyl, imidazolyl, thienyl,
or pyrimidyl), or heterocycloalkyl (preferably piperidinyl or
piperazinyl) groups;
wherein 1, 2 or 3 carbons of the monocyclic or bicyclic ring
are optionally replaced with -NH-, -N (CO) 0-1R215-, -N(CO)0-
1R220-, -O-, or -S (=O)0-2-, and wherein the monocyclic or
bicyclic ring is optionally substituted with 1, 2 or 3
groups that are independently -R205, -R245, -R250 or =O.
More preferably, Rc is as defined above and Rx is C1-C10
alkyl substituted with one aryl group (preferably
phenyl), where the aryl group is optionally substituted
with 1 or 2 R50 groups. More preferably, Z is also -CH2-
halogen or -CH3.
Other preferred compounds of formula II include those of
formula II-dd, wherein Rc is -CHR245-CHR250-phenyl; wherein the
phenyl is optionally substituted with 1, 2, 3 or 4 R200 groups;
and
R245 and R250 are taken together with the carbon to which they
are attached to form a monocycle or bicycle of 5, 6, 7 or
8 carbon atoms, where 1, or 2 carbon atoms are optionally
replaced by 1 or 2 groups that are independently -0-, -S-
, -SO2-, -C(0)-, or -NR220-, and wherein the ring is
optionally substituted with 1, 2, 3, 4, 5, or 6 groups
that are independently C1-C4 alkyl, C1-C4 alkoxy, hydroxyl,
NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl) (C1-C6 alkyl), -NH-
C(0)C1-C6 alkyl, -NH-SO2-(Cx-C6 alkyl), or halogen; and
R1 is C1-C10 alkyl substituted with one aryl group (preferably
phenyl), where the aryl group is optionally substituted
with 1 or 2 R50 groups. More preferably, Z is also -CH2-
halogen or -CH3.
Preferred compounds of formula II-cc include those of formula
Il-dd, i.e. compounds of formula II-cc, wherein
R245 and R250 are taken together with the carbons to which they
are attached to form a monocycle or bicycle of 5, 6, 7 or
8 carbon atoms, and wherein the ring is optionally
substituted with 1, 2, 3, 4, 5, or 6 groups that are
independently C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, NH2,
NH(C1-C6 alkyl), N(C1-C6 alkyl) {C1-C6 alkyl), -NH-C (0) C1-C5
alkyl, -NH-SO2-(C1-C6 alkyl), or halogen.
Preferred compounds of formula II-dd include those of formula
II-ee, i.e. compounds of formula Il-dd, wherein
R-245 and R250 are taken together with the carbons to which they
are attached to form a monocycle or bicycle of 5, or 6,
carbon atoms, and wherein the ring is optionally
substituted with 1, 2, 3, 4, 5, or 6 groups that are
independently C1-C4 alkyl, C1-C4 alkoxy, hydroxyl, NH2,
NH(C1-C6 alkyl), N(C1-C6 alkyl) (C1-C6 alkyl), -NH-C(0)C1-C6
alkyl, -NH-SO2-(C1-C6 alkyl), or halogen.
Preferred compounds of formula II include those of formula II-
ff, i.e. compounds of formula II wherein
Rc is - (CR245R250) -heteroaryl (preferred heteroaryl groups
include thienyl, pyridyl, pyrimidyl, quinolinyl,
oxazolyl, and thiazolyl), wherein the heteroaryl group
attached to the - (CR245R250)1-4- group is optionally
substituted with 1 or 2 substitutents selected from -Cl,
,-Br, -I, -C1-C6 alkyl, -(C1-C3 alkyl) OH, -CN, -C=CH, -C=C-
CH2-OH, -CF3, or -phenyl optionally substituted with 1 or
2 C1-C3 alkyl groups, - (C1-C3 alkyl)OH group or -CO(C1-C3
alkyl) group, wherein
R245 and R250 at each occurance are independently -H, -C1-C3
alkyl, -(C1-C3 alkyl)CO2H, or - (C1-C3 alkyl) OH, (in
one aspect R245 is H; in another aspect, R245 and R250
are H; in another aspect, R245 and R250 are both
methyl) or
R245 and R250 are taken together with the carbon to which
they are attached to form a monocycle or bicycle of
3, 4, 5, 6, 7 or 8 carbon atoms (preferably 6 carbon
atoms), where 1 or 2 carbon atoms is optionally
replaced by -O-, -C(O)-, -S-, -S02-, or -NR220-, and
R220 is as defined above.
In another aspect, the invention provides compounds of
the formula VIII:
and pharmaceutically acceptable salts thereof, wherein.
R245 and R250 are taken together with the carbon to which they
are attached to form a monocycle or bicycle of 3, 4, 5,
6, 7, or 8 carbon atoms, where 1, 2, or 3 CH2 groups are
optionally replaced by 1, 2, or 3 groups that are
independently -O-, -S-, -SO2-, -C(0)-, or -NR220-; and
wherein the ring is optionally substituted with 1, 2, 3,
4, 5, or 6 groups that are independently C1-C4 alkyl, C3-C4
alkoxy, =0, hydroxyl and halogen;
Z, R2, Rso, R200, and R220 are as defined for formula I.
Preferred compounds of formula VIII include compounds of
formula VHI-a, i.e., compounds of formula VIII, wherein at
least one of the Rso groups is a halogen.
Preferred compounds of formula VUI-a, include compounds
of formula VHI-b, i.e., compounds wherein Z is -CH2-halogen
(preferably the halogen is F or Cl) or CH3.
Preferred compounds of formula VHI-b include compounds
of formula VIII-c, i.e., compounds of formula VHI-b, wherein
at least one R50 group is halogen. More preferably, the other
R50 group is H, OH or -0-allyl.
In another aspect, both Rso groups are halogen and more
preferably, F or Cl. Still more preferably, both R50 groups
are F. Still more preferably, the R50 groups are "meta"
relative to each other, i.e., 1-3 to each other.
Preferred compounds of formula VIII, VI11-a, VHI-b and
VIII-c include compounds of formula VHI-d, wherein
R245 and R25/3 are taken together with the carbon to which they
are attached to form a monocycle of 3, 4, 5, 6, or 7
carbon atoms (preferably 4, 5, or 6 carbon atoms, more
preferably, 5 or 6 carbon atoms), wherein the ring is
optionally substituted with 1, 2, 3, 4, 5, or 6 groups
that are independently C1-C4 alkyl, C1-C4 alkoxy, hydroxyl,
=0, and halogen. More preferably, the ring is optionally
substituted with 1, 2, or 3 groups. Still more
preferably, if the ring is substituted, one of the groups
is =0.
Preferred compounds of formula VIII, VHI-a, VTII-b and
VIII-c include compounds of formula VHI-e, wherein
R245 and R2S0 are taken together with the carbon to which they
are attached to form a bicycle of 5, 6, 7, or 8 carbon
atoms, where 1, carbon atom is optionally replaced by a
group selected from -0-, -S-, -S02-, -C(0)-, and -NR220-;
and wherein the ring is optionally substituted with 1, 2,
3, 4, 5, or 6 groups that are independently C1-C4 alkyl,
C1-C4 alkoxy, hydroxyl and halogen. Preferably the
bicycle is bicyclo[3.1.0]hexyl, 6-aza-
bicyclo[3.1.0]hexane wherein the nitrogen is optionally
substituted with -C(0)CH3 or CH3, octahydro-
cyclopenta[c]pyrrolyl, 5-oxo-octahydro-pentalenyl, or 5-
hydroxy-octahydro-pentalenyl, each of which is optionally
substituted with 1, 2, 3, 4, 5, or 6 groups that are
independently C1-C4. alkyl, C1-C4 alkoxy, hydroxyl and
halogen.
Preferred compounds of formulas VIII-c, VHI-d and VHI-e
include compounds wherein one R200 is imidazolyl, thiazolyl,
oxazolyl, tetrazolyl, thienyl, furanyl, benzyl, piperidinonyl,
or pyridyl, wherein each is optionally substituted with
halogen, or C1-C4 alkyl. Also preferred are compounds wherein
a second R2O0 is C1-C6 alkyl (preferably C2-C6 alkyl, more
preferably tert-butyl, neopentyl or isopropyl.)
Preferred compounds of formula VIII, VHI-a, VHI-b and
VIII-c, and include compounds of formula Vlll-f, i.e.,
compounds wherein
R245 and R2S0 are taken together with the carbon to which they
are attached to form a monocycle of 3, 4, 5, 6, or 7
carbon atoms, where at least 1, but up to 3 carbon atoms
are replaced by groups that are independently -0-, -S-, -
S02-, -C(0)-, or -NR220- (in one aspect, preferably -O-) ;
and wherein the ring is optionally substituted with 1, 2,
3, 4, 5, or 6 groups that are independently C1-C4 alkyl,
C1-C4 alkoxy, hydroxyl and halogen. Preferably the
monocycle is tetrahydropyranyl, 2-oxo-
tetrahydropyrimidinonyl, piperidinyl, 2-
oxo(1,3)oxazinonyl, or cyclohexanonyl. Preferably, R220
is H, -C1-C6 alkyl, -CHO, hydroxy C1-C6 alkyl, C1-C6
alkoxycarbonyl, -amino C1-C6 alkyl, -SO2-C1-C6 alkyl, C1-C6
alkanoyl optionally substituted with up to three
halogens, -C(O)NH2, -C (O)NH (C1-C6 alkyl), -C(O)N(C1-C6
alkyl) (C1-C6 alkyl), -halo C1-C6 alkyl, or -(CH2) 0-2-(C3-C7
cycloalkyl). More preferably, R220 is H, -C1-C6 alkyl, C1-
C6 alkoxycarbonyl, -SO2-C1-C6 alkyl, -C(O)CF3, -C(O)NH2,
-C(O)NH(C1-C6 alkyl), or -C (0) N (C1-C6 alkyl) (C1-C6 alkyl).
Preferred compounds of formulas VHI-d and VHI-e include
compounds of formula VTII-g, i.e., compounds wherein at least
one R200 is C1-C6 alkyl. More preferably, R2O0 is C2-C6 alkyl.
Still more preferably it is C3-C6 alkyl.
Preferred compounds of formula VIIa-VIIIg include
compounds of formula VTII-h, i.e., compounds wherein Rc is of
the formula:
More preferably, Rc is of the formula:
In another aspect, the invention provides compounds of
formulas VIII-VIII-h, wherein R2 is H.
In another aspect, the invention provides compounds of
formulas VIII-VIII-h, wherein R2 is C1-C4 alkyl or hydroxy C1-C4
alkyl.
In another aspect, the invention provides compounds of
formula IX:
wherein
A is -CH2-CR100R101-, -CH2-S-, -CH2-S(O)-, -CH2-S (0) 2-, -CH2-NR100-
, -CH2-C(O)-, -CH2-O-, -0-CR100R101-, -S02-NR10o, or -C(O)-O-
Rl00 and R101 are independently H, C1-C6 alkyl, phenyl, CO(C1-C6
alkyl) or SO2C1-C6 alkyl;
V is CH, CR50, or N;
R300 is H or C1-C4 alkyl (preferably the alkyl is methyl),- and
Z, R50 and R2O0, are as defined for formula I.
Preferred compounds of formula IX include compounds of
formula IX-a, i.e., compounds of formula IX, wherein at least
one of the R50 groups is a halogen. In another aspect, the
other R50 group is H, OH, or -O-allyl. Preferred compounds of
formula IX-a, include compounds of formula IX-b, i.e.,
compounds wherein Z is -CH2-halogen (where the halogen is
preferably P or Cl) or CH3. Preferred compounds of formula IX-
b include compounds of formula IX-c, i.e., compounds of
formula IX-b, wherein both R50 groups are halogen and more
preferably, F or Cl. Still more preferably, both Rso groups
are F. In other preferred compounds, at least one R50 is OH or
-O-benzyl. More preferably, a second R50 is present and it is
a halogen (preferably F or Cl.)
Preferred compounds of formula IX, IX-a, IX-b, and IX-c,
include those of formula IX-d, i.e., compounds wherein at
least one R2O0 is C1-C6 alkyl. In one aspect, R2O0 is C3-C6
alkyl, preferably neopentyl, tert-butyl or isopropyl. In
another aspect, R2O0 is C1-C4 alkyl.
Preferred compounds of formual IX-d include those wherein
A is -CH2-O- or -CH2-CH2-. Also preferred are compounds
wherein A is -C(O)-O-, Also preferred are compounds wherein A
is -CH2-NR1Oo- • Also preferred are compounds wherein A is -CH2-
S-, -CH2-S(O)-, or -CH2-S(O)2-.
Preferred compounds of formula IX include compounds
wherein one R2O0 is C1-C6 alkyl, preferably C2-C6 alkyl, more
preferably C3-C5 alkyl.
Also preferred are compounds wherein a second R200 is
present and it is imidazolyl, thiazolyl, oxazolyl, tetrasolyl,
thienyl, furanyl, benzyl, or pyridyl, wherein each cyclic
group is optionally substituted with -R205, halogen, and/or C1-
C4 alkyl. In another aspect, they are substituted with
halogen, and/or C3-C4 alkyl. Also preferred are compounds
wherein a second R2O0 is C1-C6 alkyl. Also preferred are
compounds wherein R100 and R101 are independently H or C1-C6
alkyl.
In another aspect, preferred compounds of formula IX-d
include those wherein R3O0 is methyl. In another aspect, when
R3O0 is methyl, A is -CH2-O- or -CH2-CH2-.
In one aspect, the invention provides compounds of the
formula A-I:
and a pharmaceutically acceptable salt thereof, wherein
the A ring is a heteroaryl group, selected from pyridinyl,
pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, furanyl,
thienyl, pyrrolyl, wherein said heteroaryl groups are
optionally substituted with one, two, three, or four Rc
and/or Rd groups, wherein
Rc and Rd at each occurrence are independently
C1-C6 alkyl optionally substituted with one, two or three
substituents selected from C1-C3 alkyl, halogen, OH,
SH, C=N, CF3, C1-C3 alkoxy, and -NR5R6; or
OH; N02; halogen; CO2H; C=N; - (CH2)0-4-CO-NR21R22 wherein
R21 and R22 are the same or different and are selected from
H; -Cx-Ce alkyl optionally substituted with one
substituent selected from OH and -NH2; -C1-C6 alkyl
optionally substituted with one to three groups that
are independently -F, -Cl, -Br, or -I; -C3-C7
cycloalkyl; - {C1-22 alkyl) - (C3-C7 cycloalkyl) ; -(C1-C6
alkyl)-O- (C1-C3 alkyl); -C2-C6 alkenyl; -C2-C6
alkynyl; -C1-C6 alkyl chain with one double bond and
one triple bond; R17; and R18; or
- (CH2) o-4-CO- (C1-C12 alkyl) ; - (CH2)0-4-CO- (C2-C12 alkenyl) ;
-(CH2)0-4-CO-(C2-C12 alkynyl); -(CH2)0-4-CO-(C3-C7
cycloalkyl); -(CH2)0-4-CO-R17; -(CH2)0-4-CO-R18; -(CH2)0-
4-CO-R19; or -(CH2)0-4-CO-R11 wherein
Ri7 at each occurrence is an aryl group selected from
phenyl, 1-naphthyl, 2-naphthyl and indanyl, indenyl,
dihydronaphthyl, or tetralinyl, wherein said aryl
groups are optionally substituted with one, two,
three, or four groups that are independently
C1-C6 alkyl optionally substituted with one, two or
three substituents selected from C1-C3 alkyl,
F, Cl, Br, I, OH, SH, and -NR5RS, Cs=N, CF3, and
C1-C3 alkoxy;
or
C2-C6 alkenyl or C2-Cs alkynyl each of which is
optionally substituted with one, two or three
substituents selected from F, Cl, OH, SH, C=N,
CF3, C1-C3 alkoxy, and -NRSR6;
or
halogen; -C1-C6 alkoxy optionally substituted with
one, two, or three F; -NR21R22; OH; CsN; C3-C7
cycloalkyl, optionally substituted with one,
two or three substituents selected from. F, Cl,
OH, SH, C=N, CF3, C1-C3 alkoxy, and -NR5R6; or
-CO-(C1-C4 alkyl) ; -SO2-NR5RS; -CO-NR5R6; or -S02-(C1-C4
alkyl);
R18 at each occurrence is a heteroaryl group selected from
pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,
indolyl, indolinyl, pryidazinyl, pyrazinyl,
isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,
phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl-, indolizinyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzofuranyl,
furanyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl,
oxazolopyridinyl, imidazopyridinyl, isothiazolyl,
naphthyridinyl, cinnolinyl, carbazolyl, beta-
carbolinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl,
isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl,
purinyl, benzodioxolyl, triazinyl, phenoxazinyl,
phenothiazinyl, pteridinyl, benzothiazolyl,
imidasopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl,
benzothiopyranyl, coumarinyl, isocoumarinyl,
chromonyl, chromanonyl, pyridinyl-N-oxide,
tetrahydroquinolinyl, dihydroquinolinyl,
dihydroquinolinonyl, dihydroisoquinolinonyl,
dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl,
pyrrolyl N-oxide, pyrimidinyl N-oxide, pyridazinyl
N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide,
indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-
oxide, quinazolinyl N-oxide, quinoxalinyl N-oxide,
phthalazinyl N-oxide, imidazolyl N-oxide, isoxazolyl
N-oxide, oxazolyl N-oxide, thiazolyl N-oxide,
indolizinyl N-oxide, indazolyl N-oxide,
benzothiazolyl N-oxide, benzimidazolyl N-oxide,
pyrrolyl N-oxide, oxadiazolyl N-oxide, thiadiazolyl
N-oxide, triazolyl N-oxide, tetrazolyl N-oxide,
benzothiopyranyl S-oxide, and benzothiopyranyl S,S-
dioxide, wherein said heteroaryl group is optionally
substituted with one, two, three, or four groups
that are independently
C1-C6 alkyl optionally substituted with one, two or
three substituents selected.from C1-C3 alkyl,
F, Cl, Br, I, OH, SH, C=N, CF3, C3-C3 alkoxy,
and -NR5R6; or
C2-C6 alkenyl or C2-Cs alkynyl each of which is
optionally substituted with one, two or three
substituents selected from -F, -Cl, -OH, -SH,
-C=N, -CF3, C1-C3 alkoxy, and -NR5R6; or
halogen; -C1-C6 alkoxy optionally substituted with
one, two, or three -F; -NR21R22; -OH; -C=N; C3-C7
cycloalkyl optionally substituted with one, two
or three substituents independently selected
from F, Cl, OH, SH, C==N, CF3, C1-C3 alkoxy, and
-NR5R6; -CO-(C1-C4 alkyl); -SO2-NRsRe; -CO-NR5R6;
or -SO2-(C1-C4 alkyl);
Ri9 at each occurrence is independently morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide,
thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl,
tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,
tetrahydrothienyl, homopiperidinyl, homomorpholinyl,
homothiomorpholinyl,, homothiomorpholinyl S,S-
dioxide, oxazolidinonyl, dihydropyrazolyl,
dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl,
dihydropyrimidinyl, dihydrofuryl, dihydropyranyl,
tetrahydrothienyl S-oxide, tetrahydrothienyl S,S-
dioxide, or homothiomorpholinyl S-oxide; wherein said
R19 group is optionally substituted with one, two,
three, or four groups that are independently
C1-C6 alkyl optionally substituted with one, two or
three substituents selected from C1-C3 alkyl,
P, Cl, Br, I, OH, SH, CsN, CF3, C1-C3 alkoxy,
and -NR5R6;
C2-C6 alkenyl or C2-C6 alkynyl, wherein each is
optionally substituted with one, two or three
substituents selected from F, Cl, OH, SH, C=N,
CF3, C1-C3 alkoxy, and -NR5R6;
halogen; C1-C6 alkoxy; C1-C6 alkoxy optionally
substituted with one, two, or three F; OH; C=N;
-NR21R22; C3-C7 cycloalkyl optionally substituted
with one, two, or three substituents
independently selected from F, Cl, OH, SH,
C=N, CF3, C1-C3 alkoxy, and -NR5R6; -CO-(C1-C4
alkyl); -SO2-NR5RS; -CO-NR5R6. -S02-(C1-C4 alkyl);
or =0;
R11 is selected from morpholinyl, thiorrlorpholinyl,
piperazinyl, piperidinyl, homomorpholinyl,
homothiomorpholinyl, homomorpholinyl S-oxide,
homothiomorpholinyl S,S-dioxide, pyrrolinyl and
pyrrolidinyl where each group is optionally
substituted with one, two, three, or four groups
that are independently C1-C6 alkyl, C1-C6 alkoxy, and
halogen;
or
Rc and Rd at each occurrence are independently - (CH2)0-4-C02R20;-
(CH2)0-4-SO2-NR21R22; - (CH2)0-4-SO-(C1-C8 alkyl); - (CH2)0-4-SO2-
(C1-C12 alkyl), - (CH2)0-4-SO2-(C3-C7 cycloalkyl) ; -(CH2)0-4-
N(H or R20 )-CO-O-R20; - (CH2) 0-4-N(H or R20) -CO-N (R20) 2; -
(CH2)0-4-N-CS-N(R20)2; - (CH2) 0-4-N (-H or R20) -CO-R21; - (CH2) 0--
NR21R22; - (CH2)0-4-R11; - (CH2) 0-4-O-CO- (C1-C6 alkyl),- -(CH2)0-4-
0-P(0) - (OR5)2; - (CH2)0-4-O-CO-N(R20)2; - (CH2) 0-4-0-CS-N (R20) 2;
-(CH2)0-4-O-(R20)2; -(CH2)0-4-O-(R20)-CO2H; - (CH2) 0.4-S-(R20) ; -
(CH2)0-4-0-(C1-C6 alkyl optionally substituted with one,
two, three, four, or five halogens); C3-C7 cycloalkyl;
- (CH2)0-4-N(-H or R20) -SO2-R21; or - (CH2)0-4- C3-C7
cycloalkyl; wherein
R20 is selected from C1-C6 alkyl, - (CH2) 0-2- (R17), C2-Cs
alkenyl, C2-Cs alkynyl, C3-C7 cycloalkyl, and - (CH2) 0-
2- (Rib) ;
or
Rc and Rd at each occurrence are independently C2-Cg alkenyl or
C2-C6 alkynyl, each of which is optionally substituted
with C1-C3 alkyl, F, Cl, Br, I, OH, SH, C=N, CF3, C1-C3
alkoxy, or -NR5R6;
or
the A ring is an aromatic hydrocarbon selected from phenyl,
naphthyl, tetralinyl, indanyl, dihydronaphthyl or
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, wherein each
aromatic hydrocarbon is optionally substituted with one,
two, three, or four Rc and/or R
occurrence can be the same or different and are:
C1-C6 alkyl, optionally substituted with one, two or three
substituents selected from C1-C3 alkyl, halogen, OH,
SH, C=N, CF3, C1-C3 alkoxy, and -NR5RS;
-OH; -N02; halogen; -CO2H; -C^N; - (CH2) 0-4-CO-NR21R22;
- (CH2) 0-4-CO- (d~d2 alkyl), - (CH2) 0.4-CO- (C2-C12
alkenyl), - (CH2)0-4-CO- {C2-C12 alkynyl), - (CH2)0-4-CO- (C3-
C7 cycloalkyl), - (CH2) 0-4-CO~Ri7; - (CH2) 0-4-CO-R18;
- (CH2) 0-4-CO-R19; - (CH2) 0.4-CO-Rn; - (CH2) 0-4-C02R20;
(CH2)0-4-SO2-NR21R22; - (CH2) 0.4-SO- (d-C8 alkyl); -(CH2)0-
4-SO2- (C1-C12 alkyl), - (CH2)0-4-SO2- (C3-C7 cycloalkyl) ;
-(CH2)0-4-N(H or R20)-CO2R20; - (CH2) 0-4-N (H or R2O)-CO-
N(R20)2; - (CH2)0-4-N-CS-N(R20)2; - (CH2) 0-4-N (-H or R20) -
CO-R21; -(CH2)0-4-NR21R22; - (CH2)0-4-R11; - (CH2)0-4-O-CO-
(C1-C6 alkyl); -(CH2)0-4-O-P(0)-(OR5)2; - (CH2) 0-4-O-CO-
N(R20)2; - (CH2)0-4-0-CS-N(R2o)2; - (CH2) 0-4-O-(R20) 2;
(CH2)0-4-O- (R20)-CO2H; - (CH2) 0-4-S- (R20) ; - (CH2) 0-4-O- (d~
Ce alkyl optionally substituted with one, two, three,
four, or five -F) ; C3-C7 cycloalkyl; - (CH2)0-4-N (-H or
R20) -SO2-R21; -(CH2)0-4- C3-C7 cycloalkyl;
or
C2-C6 alkenyl or C2-C6 alkynyl each of which is optionally
substituted with C1-C3 alkyl, F, Cl, Br, I, OH, SH,
C=N, CF3, C1-C3 alkoxy, or -NR5R6;
Ra and Rb are independently selected from C1-C3 alkyl, F, OH,
SH, C=N, CF3, C1-C6 alkoxy, =O, and -NR5R6; or
Ra and Rb and the carbon to which they are attached form a C3-C7
spirocycle which is optionally substituted with 1 or 2
groups that are independently Cj^-d alkyl, d~C4 alkoxy,
halogen, CF3, or CN;
Rx is C1-C10 alkyl optionally substituted with 1, 2, 01- 3 groups
independently selected from halogen, -OH, =O, -SH, -CN,
-CF3, -C1-C4 alkoxy, amino, mono- or dialkylamino,
-N(R)C(O)R'r -OC(=O)-amino and -OC(=0)-mono- or
dialkylamino; or
Ri is C2-Cs alkenyl or C2-C6 alkynyl, each of which is
optionally substituted with 1, 2, or- 3 groups
independently selected from halogen, OH, SH, C=N, CF3,
OCF3/ C2.-C4 alkoxy, amino, and mono- or dialkylamino; or
R1 is aryl, heteroaryl, heterocyclyl, aryl C1-C6 alkyl,
heteroaryl C^-Cg alkyl, or heterocycloalkyl C1-C6 alkyl,
wherein
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 Rso groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups that
are independently R50 or =0;
R1 is G-L-A-E-W-, wherein
W is a bond, absent, -S-, -S(O)-, -SO2-, -0-, -NH- or
-N(d-C4 alkyl) ;
E is a bond, absent, or C1-C3 alkylene;
A is absent, alkyl, aryl or cycloalkyl where each aryl or
cycloalkyl is optionally substituted with one, two
or three R100 groups; heteroaryl optionally
substituted with 1 or 2 R100 groups; or
heterocycloalkyl optionally substituted with 1 or 2
R200 groups, wherein
R100 at each occurrence is independently selected
from N02, CsN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl, -N (R) CO (R' ) R, -CO2-R25, -NH-CO2-R25, -0-
(C2-Cs alkyl) -CO2H, -NRR', -SR, CH2OH, -C(0)-(d-
C6) alkyl, -C(O)NRR', -SO2NRR', CO2H, CF3, halogen,
C1-C3 alkoxy, -OCF3, -NH2, OH, CN, halogen, and
- (CH2)0-2-O- (CH2) 0-2-OH;
wherein
R25 is selected from C^-Cg alkyl, -(CH2)o-2-
cycloalkyl, - (CH2)0-2-aryl, where the aryl
is optionally substituted with halogen,
hydroxy, Cx-C6 alkyl, Ci-C6 alkyl, amino,
mono (Ci-C6) alkylamino, or di (Ci-
C6)alkylamino, and hydrogen, and
R and R' at each occurrence are independently
hydrogen, C1-C6 alkyl, - (CH2)0-2-aryl, or
- (CH2)0-2-cycloalkyl, where each aryl or
cycloalkyl is optionally substituted with
halogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl,
amino, mono(C1-C6) alkylamino, or di(C1-
C6)alkylamino;
R2O0 at each occurrence is independently selected
from =O, C1-C3 alkyl, CF3, F, Cl, Br, I, C1-C3
alkoxy, OCF3, NH2, OH, and C=N;
provided that L is a bond or absent when G is absent,
or
L is -G(O)-, -S(O)-, -S02-, -O-, -C(R110) (Rn2)O-,
-OC(R110) (R112)-, -N(R110)-, -CON(R110)-, -N(R110)CO-,
-C(R110) (R')-,-C(OH)R110-, -SO2NR110-, -N (Rllo) S02-,
-N(R110)CON(R112)-, N(Rno)CSN(R112)-, -0C02-, -NCO2-, or
-OCON(R110)-, where in
R110 and R112 are independently hydrogen, C1-C4 alkyl,
C1-C4 hydroxyalkyl, C1-C4 alkoxy C1-C4 alkyl or
C1-C4 fluoroalkyl;
and
G is absent or d~do alkyl optionally substituted with 1,
2, or 3 groups independently selected from -CO2H,
-CO2(d-C4 alkyl), Ci-C6 alkoxy, -OH, -NRR', -Cx-C6
haloalkyl, - (d-do alkyl)-0-(d-C3 alkyl), -C2-do
alkenyl, -C2-do alkynyl, -C4-do alkyl chain with one
double bond and one triple bond, aryl optionally
substituted with 1, 2, or 3 Rioo# heteroaryl
optionally substituted with 1, 2, or 3 R100/ and Cx-C6
alkyl;
or
G is - (CH2) 0-3- (C3-C7) cycloalkyl where the cycloalkyl is
optionally substituted with one, two or three
substituents independently selected from -CO2H,-C02-
(d-C4 alkyl), d-C6 alkoxy, OH, -NH2, -d-C6
haloalkyl, - (C1-C10 alkyl)-O-(C1-C3 alkyl), -C2-C10
alkenyl with. 1 or 2 double bonds, C2-C10 alkynyl with
1 or 2 triple bonds, -C4-C10 alkyl chain with one
double bond and one triple bond, aryl optionally
substituted with R100, heteroaryl optionally
substituted with R100, mono(C1-C6 alkyl) amino, di (C1-C6
alkyl) amino, and C1-C6 alkyl,
or
G is - (CH2)0-4-aryl, - (CH2)0-4-heteroaryl, or -(CH2)0-4-
heterocycle, wherein the aryl, heteroaryl -(CH2)0-4-
heterocycle, groups are optionally substituted with
1, 2, or 3 R100, wherein the heterocycle group is
optionally substituted with 1 or 2 R200 groups; or
G is -C(R10) (R12)-CO-NH-R14 wherein
R10 and R12 are the same or different and are selected, from
H, -C1-C6 alkyl, - (C1-C4 alkyl)-aryl, where the aryl
is optionally substituted with 1, 2, or 3 R1O0
groups; - (C1-C4 alkyl)-heteroaryl where the
heteroaryl is optionally substituted with 1, 2, or 3
R100 groups; - (C1-C4 alkyl)-heterocycle, where the
heterocycle is optionally substituted, with 1 or 2
R200 groups; heteroaryl optionally substituted with
1, 2, 01- 3 R1O0 groups; heterocycle optionally
substituted with 1 or 2 R200 groups; - (CH2)1-4-OH,
- (CH2)1-4-Y-(CH2)1-4-aryl where the aryl is optionally
substituted with 1, 2, or 3 Rj.00 groups; - (CH2) 1-4-Y-
(CHn) 1-4-heteroaryl where the heteroaryl is optionally
substituted with 1, 2, or 3 R100 groups; -aryl
optionally substituted with 1, 2, or 3 R:Loo groups, -
heteroaryl optionally substituted with 1, 2, or 3
R100 groups, and -heterocycle optionally substituted
with 1, 2, or 3 R200 groups, wherein
Y is -0-, -S-, -NH-, or -NH(Ci-C6 alkyl); and
R14 is H, -C1-C6 alkyl, -aryl optionally substituted with 1, 2,
or 3 R100 groups, -heteroaryl optionally substituted with
1, 2, or 3 R100 groups, -heterocycle optionally
substituted with 1 or 2 R2O0 groups, - (C3-C4 alkyl)-aryl,
where the aryl is optionally substituted with 1, 2, or 3
R100 groups- - (C1-C4 alkyl) -heteroaryl where the heteroaryl
is optionally substituted with 1, 2, or 3 R100 groups;
- (C1-C4 alkyl)-heterocycle, where the heterocycle is
optionally substituted with 1 or 2 R200 groups, or
- (CH2)0-2-O-(CH2)1-2-OH;
R2 and R3 are independently selected from -H, C1-C6 alkyl,
optionally substituted with one, two or three
substituents selected from C1-C3 alkyl, -F, -Cl, -Br, -I,
-OH, -SH, -C=N, -CF3, C1-C3 alkoxy, and -NR5RS; -(CH2)0-4-
R17; - (CH2)0-4-R10; C2-C6 alkenyl or C2-C6 alkynyl, wherein
each is optionally substituted with one, two or three
substituents selected from -F, -Cl, -OH, -SH, -CsN, -CF3,
C1-C3 alkoxy, and -NR5R6; - (CH2)0-4-C3-C7 cycloalkyl,
optionally substituted with one, two or three
substituents selected from -F, -Cl, -OH, -SH, -C=N, -CF3,
C1-C3 alkoxy, and -NRSRS; wherein
R5 and Rs at each occurrence are independently H or Ci-C6
alkyl; or
R5 and R6 and the nitrogen to which they are attached, at
each occurrence form a 5 or 6 mernbered
heterocycloalkyl ring; or
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru seven carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -0-, -S-, -SO2-, or -NR7~;
R15 at each occurrence is independently selected from
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6
alkyl, hydroxy C1-C6 alkyl, halo C1-C6 alkyl, C1-C6
alkanoyl, each of which is unsubstituted or substituted
with 1, 2, 3, or 4 groups independently selected from
halogen, alkyl, hydroxy, alkoxy, NH2, and -R26-R27; and
-R26-R27; wherein
R26 is selected from a bond, -C(O)-, -S02-, -CO2-,
-C(O)NR5-, and -NR5C (0) -,
R27 is selected from Ci-C6 alkyl, Ci-C6 alkoxy, aryl Cx-Cs
alkyl, heterocycloalkyl, and heteroaryl, wherein
each of the above is unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that are independently
C1-C4 alkyl, C1-C4 alkoxy, halogen, haloalkyl,
hydroxyalkyl, -NR5R6, -C(O)NR5R6;
Z is selected from H; C1-C6 alkoxy; C1-C6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently
OH, halogen, C1-C4 alkoxy, CF3, OCF3, NO2, CN, and NRSR6;
aryl; heteroaryl; arylalkyl; and heteroarylalkyl; and
wherein each aryl, heteroaryl, arylalkyl, and
heteroarylalkyl group is optionally substituted with 1 or
2 gx-oups that are independently C1-C4 alkyl, halogen,
haloalkyl, and C1-C4 alkoxy.
Preferred compounds of formula A-1 include those wherein
R2 and R3 are independently selected from H; C1-C6 alkyl
optionally substituted with 1, 2, or 3 substituents that
are independently selected from C1-C4 alkyl, halogen, -
CF3, and C1-C4 alkoxy; and C2-C6 alkenyl or C2-C6 alkynyl
wherein each is optionally substituted with one, two or
three substituents selected from -F, -Cl, -OH, -SH, -
C=N, -CF3; d-C3 alkoxy, and -NR5RS; or
R2r R3 and the carbon to which they are attached form a
carbocycle of three thru seven carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -0-, -S-, -SO2-, or -NR7-; wherein
R7 is selected from H, -Ci-CB alkyl optionally
substituted with 1, 2, or 3 groups independently
selected from -OH, -NH2, phenyl and halogen; C3-C3
cycloalkyl; - (Ci-C2 alkyl)- (C3-C8 cycloalkyl); - (Ci-Cs
alkyl)-0- (C1-C4 alkyl); C2-C6 alkenyl; C2-C6 alkynyl;
Equally preferred compounds of formula A-1 include those
wherein
R15 at each occurrence is independently selected from
hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkanoyl, each
of which is unsubstituted or substituted with 1, 2, 3, or
4 groups independently selected from halogen, alkyl,
hydroxy, C1-C4 alkoxy, and NH2; and -R26-R27; wherein
R26 is selected from a bond, -C(0)-, -S02-, -C02-,
-C(O)NR5-, and -NR5C(O)-; and
R27 is selected from C1-C6 alkyl, C1-C6 alkoxy, and
benzyl, wherein each of the above is unsubstituted
or substituted with 1, 2, 3, 4, or 5 groups that are
independently C3-C4 alkyl, C1-C4 alkoxy, halogen, halo
C1-C4 alkyl, hydroxyalkyl, -C(O)NRSRS, or -NR5R6.
Other equally preferred compounds of formula A-1 include
those wherein
R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, =O, -SH, -CN,
-CF3, -C1-C4 alkoxy, amino, mono- or dialkylamino,
-N(R)C(O)R', -0C (=0)-amino and -OC(=0)-mono- or
dialkylamino; or
Rx is C2-C6 alkenyl or C2-C6 alkynyl, each of which is
optionally substituted with 1, 2, or 3 groups
independently selected from halogen, OH, SH, C=N,
CF3, OCF3, C1-C4 alkoxy, amino, and mono- or
dialkylamino; or
Rx is aryl, heteroaryl, heterocyclyl, aryl C1-C6 alkyl,
heteroaryl C1-C6 alkyl, or heterocycloalkyl C1-C6 alkyl;
wherein
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0; and
R50 at each occurrence is independently selected from halogen,
OH, SH, CN, -CO-(C3.-C4 alkyl), -CO2-(C1-C4
alkyl), -SO2-NR5R6, -NR7R8, -CO-NR5R6, -C0-NR7Re,
-SO2-(C1-C4 alkyl), C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C1-C6 alkoxy, or C3-C8 cycloalkyl;
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently, selected from C1-C4 alkyl,
halogen, OH, SH, -NR5R6, CN, C1-C4
haloalkyl, C1-C4 haloalkoxy, phenyl, NR7RB,
and C1-C4 alkoxy.
Still other equally preferred compounds of formula A-1
include those of formula A-I-l, i.e., compounds of formula A-I
wherein
Rc and Rd are independently selected from C1-C6 alkyl optionally
substituted with one, two or three substituents selected
from C1-C3 alkyl, halogen, OH, SH, C=N, CF3, C1-C3 alkoxy,
and -NR5Rs; hydroxy; nitro; halogen; -CO2H; cyano; and
- (CH2)o-4-CO-NR21R22; wherein
R21 and R22 independently represent hydrogen, C1-C6 alkyl,
hydroxyl (C1-C6) alkyl, amino (C1-C6) alkyl, haloalkyl,
C3-C7 cycloalkyl, - (C1-C2 alkyl)-(C3-C7 cycloalkyl), -
(C1-C6 alkyl)-O-(C1-C3 alkyl), -C2-Cs alkenyl, -C2-C6
alkynyl, -C1-C6 alkyl chain with one double bond and
one triple bond, phenyl, naphthyl, heteroaryl; or
Rc and Rd are independently selected from - (CH2)0-4-CO- (C1-C12
alkyl); - (CH2)0-4-CO-(C2-C1Z alkenyl); CH:2)0-4-CO-(C2-
C12) alkynyl; - (CH2)0-4-CO- (C3-C7 cycloalkyl); - (CH2)0-4-CO-
phenyl; - (CH2)0-4-CO-naphthyl; - (CH2)0-4-CO-heteroaryl ;
- (CH2)0-4-CO-heterocycloalkyl; - (CH2)0-4-CO,R20; wherein
R20 is selected from C1-C6 alkyl, -(CH2)0-2-(phenyl),
(CH2)0-2- (naphthyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C7
cycloalkyl, and - (CH2)0-2-(heteroaryl), or
Rc and Rd are independently selected from - (CH2)0-4-SO2-NR21R22;
-(CH2)0-4-SO-(C1-C6 alkyl); - (CH2)0-4-SO2-(C1-C12 alkyl);
-(CH2)0-4-SO2- (C3-C7 cycloalkyl); - (CH2)0-4-N(H or R20 )-
CO2R20; -(CH2)0-4-N(H or R20 )-CO-N (R20) 2; - (CH2)0-4-N-CS-
N(R20)2; -(CH2)0-4-N(-H or R20)-CO-R21; - (CH2) 0-4-NR21R22; -
(CH2)0-4-heterocycloalkyl; - (CH2) 0-4-O-CO- (C1-C6 alkyl); -
(CH2)0-4-O-P(O) - (0Rs)2; - (CH2)0-4-O-CO-N (R20) 2; - (CH2)0-4-O-CS-
N(R20)2; -(CH2)0-4-O- (R20) ; - (CH2)0-4-O- (R20) -CO2H; -(CH2)0-4-S-
(R20) ; - (CH2)0-4-O-halo (C1-C6) alkyl; - (CH2)0-4-O- (C1-C6) alkyl ;
C3-C8 cycloalkyl; and - (CH2)0-4-N (-H or R20)-SO2-R21; or
Rc and Rd are independently C2-C6 alkenyl or C2-Cs alkynyl, each
of which is optionally substituted with C1-C4 alkyl,
halogen, hydroxy, SH, cyano, CF3, C1-C4 alkoxy, or NR5R6;
wherein
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0;
R50 at each occurrence is independently selected from halogen,
OH, SH, CN, -CO- (C!-C4 alkyl), -C02- (Q1.-C4
alkyl), -SO2-NR5RS, -NR7R8, -CO-NR5RS, -CO-NR7R8,
-SO2-(C1-C4 alkyl), Ci-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, Ci-C6 alkoxy, or C3-C8 cycloalkyl;
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently selected from Cx-C^ alkyl,
halogen, OH, SH, -NR5R6, CN, Ci-C6
haloalkyl, Ci-C6 haloalkoxy, phenyl, NR7R8,
and Ci-Cg alkoxy.
Preferred compounds of formula A-I-l include those of
formula A-II:
Preferred compound of formula A-II include those wherein
R2 and R3 are independently selected from H;- C1-C6 alkyl
optionally substituted with 1, 2, or 3 substituents that
are independently selected from C1-C4 alkyl, halogen, -
CF3, and C1-C4 alkoxy; C2-C6 alkenyl or C2-C& alkynyl,
wherein each is optionally substituted with one, two or
three substituents selected from -F, -Cl, -OH, -SH, -C=N,
-CF3, C1-C3 alkoxy, and -NR5RS;
R5 and R6 at each occurrence are independently H or C1-C6
alkyl; or
Rs and R6 and the nitrogen to which they are attached, at
each occurrence form a 5 or 6 membered
heterocycloalkyl ring;
or
R2, R3 and the carbo'n to which they are attached form a
carbocycle of three thru six carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -0-, -S-, -S02-, or -NR7-; wherein
R7 is selected from H; -C1-C4 alkyl optionally substituted
with 1, 2, or 3 groups independently selected from
-OH, -NH2, and halogen; -C3-C6 cycloalkyl; - (Ci-C4
alkyl)-O-(C1-C4 alkyl); -C2-C4 alkenyl; and -C2-C4
alkynyl.
Even more preferred compounds of formula A-II include
those wherein
Ris at each occurrence is independently selected from hydrogen,
C3.-C4 alkyl, Ci-C6 alkanoyl, benzyl optionally substituted
with OCH3, -C (O)-tertiary butyl, and -CO2-benzyl.
Still even more preferred compounds of formula A-II
lude those wherein
R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, =0, -SH, -CN, -
CF3, -C1-C4 alkoxy, amino, mono- or dialkylamino,
N(R)C(O)R', -OC(=O)-amino 0C(=0)-mono- and dialkylamino;
or
R1 is C2-C6 alkenyl or C2-C6 alkynyl, each of which is
optionally substituted with 1, 2, or 3 groups
independently selected from halogen, OH, SH, C=N,
CF3, OCF3, C1-C4 alkoxy, amino, and mono- or
dialkylamino; or
R1 is aryl, heteroaryl, heterocyclyl, aryl C1-C6 alkyl,
heteroaryl C1-C6 alkyl, or heterocycloalkyl C1-C6 alkyl;
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 Rso groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =O;
Rs0 at each occurrence is independently selected from
halogen, OH, SH, CN, -CO- (C^d alkyl), -C02- (C1-
C4 alkyl), -SO2-NR5R6, -NR7R8, -CO-NRSR6, -C0-
NR7R8, -SO2-(C1-C4 alkyl), C1-C6 alkyl, C2-C6
alkenyl, C2-Cs alkynyl, C1-C6 alkoxy, or C3-CB
cycloalkyl;
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently selected from C1-C4 alkyl,
halogen, OH, SH, -NRSRS, CN,. C1-C4
haloalkyl, C1-C4 haloalkoxy, phenyl, NR7R8,
and C1-C4 alkoxy.
Still more preferred compounds of formula A-II include
those of formula A-II-1, i.e., compound of formula A-II
wherein
R50 at each occurrence is independently selected from halogen,
OH, SH, -NR7R8, -so2-(C1-C4 alkyl), C3-Cs alkyl, C2-Cs
alkenyl, C2-C6 alkynyl, d-Cs alkoxy, or C3-C8 cycloalkyl,-
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally substituted with 1,
2, or 3 substituents independently selected from d~
d alkyl, halogen, OH, SH, -NR5RS, CN, d~d
haloalkyl, C1-C4 haloalkoxy, phenyl, NR7R8, and d-d
alkoxy.
Preferred compounds of formula A-II-1 include those of
formula A-III:
More preferred compounds of formula A-III include those
of formula A-III-1, i.e., compounds of formula A-III wherein
Ri is phenyl, phenyl d-Cg alkyl, naphthyl, or naphthyl d-C6
alkyl, wherein the phenyl or naphthyl group is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups.
Still more preferred compound of formula A-III-1 include
those of formula A-III-2, i.e., compound of formula A-III-1
wherein
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru six carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -0-, -S-, -SO2-, or -NR7-; wherein
R7 is H, -Ci-C8 alkyl optionally substituted with 1, 2, or
3 groups independently selected from -OH, -NH2, and
halogen; -C2-C4 alkenyl; or -C2-d alkynyl.
Preferred compounds of formula A-III-2 include those of
formula A-III-3, i.e., compounds of formula A-III-2 wherein
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru six carbon atoms.
Equally preferred compound of formula A-III-2 include
those of formula A-III-4, i.e., compounds of formula A-III-2
compounds wherein
R2, R3 and the carbon to which they are attached form a
heterocycloalkyl group containing 2 to 5 carbon atoms and
one group selected from -O-, -S-, -SO2-, and -NR7-;
wherein
R7 is H, -C1-C8 alkyl optionally substituted with 1, 2, or
3 groups independently selected from -OH, -NH2, and
halogen; -C2-C4 alkenyl; or -C2-C4 alkynyl.
Other equally preferred compounds of formula A-III-1
include those compounds of formula A-III-5, i.e., compounds of
formula A-III-1 wherein
R2 and R3 are independently selected from H; C1-C6 alkyl
optionally substituted with 1, 2, or 3 substituents that
are independently selected from C1-C4 alkyl, halogen,
CF3, and C3.-C4 alkoxy; C2-C6 alkenyl; and C2-C6 alkynyl.
More preferred compound of formulas A-II1-3, A-III-4, and
A-III-,5 include those of formula A-III-6, i.e., compound of
formulas A-III-3, A-III-4, and A-III-5 wherein
Ra and Rb are independently selected from C1-C6 alkyl, C1-C6
alkoxy, halogen, CN, OH, hydroxyalkyl, C1-C6 haloalkyl,
C1-C6 haloalkoxy, and -C1-C6 alkyl-NRsR6; or
Ra and Rb are attached to the same carbon and form a C3-C7
spirocycle; and
Ris at each occurrence is independently H or Ci-d alkyl.
Preferred compound of formula A-III-6 include those of
formula A-III-6a, i.e., compounds of formula A-III-6 wherein
Rc and Rd are independently selected from Ci-C6 alkyl optionally
substituted with one, two or three substituents selected
from C1-C3 alkyl, halogen, OH, SH, C=N, CF3, d-C3 alkoxy,
and -NR5R6;; hydroxy; halogen; C2-C6 alkenyl or C2-C6
alkynyl, wherein
the alkenyl or alkynyl group is optionally substituted
with C3-C4 alkyl, halogen, hydroxy, SH, cyano, CF3,
C1-C4 alkoxy, or NR5RS.
Other preferred compound of formula A-III-6 include those whe
Rc and Rd are - (CH2)0-4-CO-NR21R22, - (CH2)0-4-SO2-NR21R2:!; -(CH2)0-4-
SO-(C1-C8 alkyl); - (CH2)0-4-SO2-(C1-C12 alkyl); - (CH2)0-4-SO2-
(C3-C7 cycloalkyl) ; - (CH2)0-4-N(H or R20)-CO-O-R20; -(CH2)0-4-
N(H or R20 )-CO-N(R20)2; - (CH2) 0-4-N-CS-N (R20) 2 ; - (CH2)0-4-N (-H
or R20)-CO-R21; or - (CH2)0-4-NR21R22; wherein
R21 and R22 independently represent hydrogen, C1-C6 alkyl,
hydroxyl (C1-C6) alkyl, amino (C1-C6) alkyl, haloalkyl,
C3-C7 cycloalkyl, - (C1-C2 alkyl)- (C3-C7 cycloalkyl), -
(C1-C6 alkyl)-O-(C1-C3 alkyl), -C2-C6 alkenyl, -C2-Cs
alkynyl, phenyl, naphthyl, or heteroaryl;
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0.
Still other preferred compound of formula A-III-6 include
those wherein
Rc and Rd are - (CH2) 0-4-CO- (d-Ci2 alkyl); - (CH2) 0-4-CO- (C2-C12
alkenyl); CH2) 0-4-CO- (C2-Ci2) alkynyl; - (CH2),,-4-CO- (C3-C7
cycloalkyl); - (CH2) o-4-CO-phenyl; - (CH2) 0.4-CO-naphthyl;
- (CH2) 0-4-CO-heteroaryl; - (CH2) 0-4-CO-heterocycloalkyl;
- (CH2)o-4-C02R2o; where
R20 is selected from d-C6 alkyl, - (CH2) 0-2- (phenyl),
(CH2) 0-2- (naphthyl), C2-Cs alkenyl, C2-C6 alkynyl, C3-C7
cycloalkyl, and - (CH2) 0-2- (heteroaryl),-
each aryl group and each heteroaryl group at each
occurrence is optionally substituted with 1, 2, 3,
4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0.
Yet still other preferred compounds of formula A-III-6
include those wherein
Rc and Rd are - (CH2) 0-4-O-CO-(C1-C6 alkyl) ; - (CH2)0-4-O-P (0)-
(0R5)2; -(CH2)0-4-O-CO-N(R20)2; - (CH2)0-4-O-CS-N (R20) 2 ; -(CH2)0-
4-0- (R2o) ; -(CH2)0-4-O- (R20)-CO2H; - (CH2)0-4-S- (R20) ; -(CH2)0-4-
0-halo(C1-C6) alkyl; - (CH2) 0-4-O-(C1-C6) alkyl,- C3-C8
cycloalkyl; or -(CH2)0-4-N (-H or R20)-SO2-R21; wherein
each aryl group and each heteroaryl group at each
occurrence is optionally substituted with 1, 2, 3,
4, or 5 R50 groups ;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently Rso or =0;
R50 at each occurrence is independently selected from halogen,
OH, SH, CN, -CO-(C1-C4 alkyl), -CO2-(C1-C4
alkyl), -SO2-NR5R6, -NR7R8, -CO-NR5R6, -CO-NR7R8,
-SO2- (C1-C4 alkyl), C1-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, C1-C6 alkoxy, or C3-C8 cycloalkyl;
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently selected from C1-C4 alkyl,
halogen, OH, SH, -NR5R6, CN, C1-C6
haloalkyl, C1-C6 haloalkoxy, phenyl, NR7R8,
and C1-C6 alkoxy.
Other preferred compounds of formula A-III include those
of formula A-III-7, i.e., compound of formula A-III wherein
Ri is d-Cio alkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, =0, -SH, -CN,
-CF3, -C1-C4 alkoxy, amino, mono- or dialkylamino,
-N(R)C(0)R', -OC(=O)-amino and -0C(=0)-mono- or
dialkylamino; or
R1 is C2-C6 alkenyl or C2-C6 alkynyl, each of which is
optionally substituted with 1, 2, or 3 groups
independently selected from halogen, OH, SH, C=N, CP3,
OCF3, C1-C4 alkoxy, amino, and mono- or dialkylamino.
More preferred compounds of formula A-III-7 include those
compounds of formula A-III-8, i.e., compounds of formula A-
III-7 wherein
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru six carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -0-, -S-, -SO2-, or -NR7-; wherein
R7 is selected from H or -C3-C4 alkyl optionally
substituted with 1 group selected from -OH, -NH2, and
halogen.
Preferred compounds of formula A-III-8 include those
compounds of formula A-III-9, i.e., compounds of formula A-
III-8 wherein
R2, R3 and the carbon to which they are attached form a
cax"bocycle of three thru six carbon atoms.
Other preferred compounds of formula A-III-8 include
those compounds of formula A-III-10, i.e., compounds of
formula A-III-8 wherein
R2, R3, and the carbon to which they are attached form a
heterocycloalkyl group containing 2 to 5 carbon atoms and
one group selected from -0-, -S-, -S02-, and -NR7-;
wherein
R7 is selected from H or -C1-C4 alkyl optionally
substituted with 1 group selected from -OH, -NH2, and
halogen.
Still other preferred compounds of formula A-III-8
include those compounds of formula A-III-11, i.e., compounds
of formula A-III-8 wherein
R2 and R3 are independently selected from H; C1-C6 alkyl
optionally substituted with 1, or 2 substituents that are
independently selected from C1-C4 alkyl, halogen, -CF3,
and C1-C4 alkoxy; C2-C6 alkenyl; and C2-C6 alkynyl.
More preferred compound of formulas A-III-9, A-III-10,
and A-III-11 include those of formula A-III-12, i.e., compound
of formulas A-III-9, A-III-10, and A-III-11 wherein
Ra and Rb are independently selected from Ci~C3 alkyl, F, OH,
C=N, CF3, C1-C6 alkoxy, and -NRSR6; and
Rl5 at each occurrence is independently H or C1-C4 alkyl.
Preferred compounds of formula A-III-12 include those
compounds wherein
Rc and Rd are independently selected from C1-C6 alkyl optionally
substituted with one, two or three substituents selected
from C1-C3 alkyl, halogen, OH, SH, CsN, CF3, C1-C3 alkoxy,
and -NR5R6; hydroxy; halogen;
C2-C6 alkenyl and C2-Cs alkynyl; wherein
the alkenyl or alkynyl group is optionally substituted
with C1-C4 alkyl, halogen, hydroxy, SH, cyano, CF3,
C1-C4 alkoxy, or NR5R6.
Other preferred compounds of formula A-III-12 include
those compounds wherein
Rc and Rd are - (CH2)0-4-CO-NR21R22; - (CH2)0-4-S02-NR3:lR22; -(CH2)0-4-
SO-(C1-C8 alkyl); - (CH2)0-4-SO2- (C1-C12 alkyl); - (CH2)0-4-SO2-
(C3-C7 cycloalkyl) ; - (CH2)0-4-N(H or R20 ) -CO-O-R20; -(CH2)0-
4-N(H or R20 ) -CO-N(R20)2; - (CH2)0-4-N-CS-N (R20) 2; -(CH2)0-4-
N{-H or R20)-CO-R21; or - (CH2)0-4-NR21R22; wherein
R21 and R22 independently represent hydrogen, C1-C6 alkyl,
hydroxy(C1-C6) alkyl, amino (C1-C6) alkyl, haloalkyl,
C3-C7 cycloalkyl, - (C1-C2 alkyl) - (C3-C7 cycloalkyl), -
(C1-C6 alkyl) -O- (C1-C3 alkyl), -C2-C6 alkenyl, -C2-C6
alkynyl, phenyl, naphthyl, or heteroaryl,-
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 Rso groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =O.
Still other preferred compounds of formula A-III-12
include those compounds wherein
Rc and Rd are - (CH2)0-4-CO-(C1-C12 alkyl) ; - (CH2)0-4-CO- (C2-C12
alkenyl) ; CH2) 0-4-CO- (C2-C12) alkynyl; - (CH2)0-4-CO- (C3-C7
cycloalkyl) ; - (CH2) 0-4-CO-phenyl; - (CH2) 0-4-CO-naphthyl; -
(CH2) 0-4-CO-heteroaryl; - (CH2) o-4-CO-heterocycloalkyl ;
- (CH2) 0-4-CO2R20; where
R20 is selected from Cx-C6 alkyl, - (CH2) 0-2- (phenyl),
- (CH2) 0-2- (naphthyl), C2-C6 alkenyl, C2-Cs
alkynyl, C3-C7 cycloalkyl, -(CH2)0_2-
(heterocycloalkyl) and - (CH2}0.2- (heteroaryl) ;
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 Rso groups;
each heteroaryl at each ' occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0.
Yet still other preferred compounds of formula A-III-12
include those compounds wherein
Rc and Rd are - (CH2) 0-4-0-CO- (Ci-Cg alkyl); - (CH2) 0-4-O-P (0) -
(OR5)2; - (CH2)0-4-O-CO-N(R20)2; - (CH2) 0-4-O-CS-N (R20) 2 ; - (CH2) 0_
4-0- (Rao); - (CH2) 0_4-O- (R20) -CO2H; - (CH2) 0.4-S-(R20) ; - (CH2) 0-4-
O-halo(C1-C6) alkyl; - (CH2) 0-4-O- (Cx-Cg) alkyl; C3-C8
cycloalkyl; or - (CH2) 0-4-N (-H or R20) -SO2-R21; wherein
each aryl group and each heteroaryl group at each
occurrence is optionally substituted with 1, 2, 3,
4, or 5 R50 groups ;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0;
Rso at each occurrence is independently selected from halogen,
OH, SH, CN, -CO-Cd-C* alkyl}, -CO2- (C3.-C4
alkyl), -SO2-NRSR6, -NR7R8/ -CO-NR5R6, -CO-NR7R8/
-SO2-(Ci-C4 alkyl), Ci-C6 alkyl, C2-C6 alkenyl,
C2-C6 alkynyl, d-Cs alkoxy, or C3-C8 cycloalkyl,-
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently selected from Ci-C4 alkyl,
halogen, OH, SH, -KTR5R6, CN, Cx-Cg
haloalkyl, Ci-Cs haloalkoxy, phenyl, NR7R8,
and Ci-C6 alkoxy.
Preferred compounds of formula A-III-6a include those of
formula A-IV
Preferred compounds of formula A-IV include those wherein
R2 and R3 are independently H or Ci-C4 alkyl.
Other preferred compounds of formula A-IV include those
of formula A-IV-1, i.e., compounds of formula A-IV wherein
Ra and Rb are independently H or Ci-C3 alkyl; and
Ri is phenyl, optionally substituted with 1, 2, or 3 Rso
groups; and
Ris at each occurrence is independently H or Ci-C4 alkyl.
Preferred compounds of formula A-IV-1 include those of
formula A-IV-2, i.e., compounds of formula A-IV-1 wherein
Ri is a dihalophenyl; and
R2 and R3 are independently H or Ci-C4 alkyl.
Preferred compounds of formula A-IV-2 include compounds
of formula A-V
wherein
hal at each occurrence is independently selected from F, Cl,
Br, and I.
More preferred compounds of formula A-V include those
compounds wherein
Rc is a C3.-C4 alkyl group.
Other preferred compounds of formula A-IV-2 include
compounds of formula A-VI
wherein
hal at each occurrence is independently selected from F, Cl,
Br, and I.
Preferred compounds of formula A-VI include those
compounds wherein
Rc is a C1-C4 alkyl group.
Other preferred compounds of formula A-IV-2 include
compounds of formula A-VII
R,.
wherein Rb is H.
Still other preferred compounds of formula A-IV-2 include
compounds of formula A-VIII
Other preferred compounds of formula A-I-l include those
compounds of formula A-IX, i.e., compounds of formula A-I-l
wherein
is a 5 or 6 membered heteroaryl group.
Preferred compounds of formula A-IX include compounds of
formula A-IX-1, i.e., compounds of formula A-IX wherein
R2 and R3 are independently selected from H; C1-C6 alkyl
optionally substituted with 1, 2, or 3 substituents that
are independently selected from C1-C4 alkyl, halogen,
CF3, and C1-C4 alkoxy; C2-C6 alkenyl or C2-C6 alkynyl
wherein each is optionally substituted with one, two, or
three substituents selected from -F, -Cl, -OH, -SH, -C=N,
-CF3, C1-C3 alkoxy, and -NR5R6; or
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru six carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -O-, -S-, -S02-, or -NR7-,- wherein
R7 is selected from K; -C1-C4 alkyl optionally substituted
with 1, 2, or 3 groups independently selected from -
OH, -NH2, and halogen; -C3-CB cycloalkyl; - {C1-Ci
alkyl) -0- (d-C4 alkyl); -C2-C4 alkenyl; and -C2-C,i
alkynyl.
Preferred compounds of formula A-IX-1 include those of
formula A-IX-2, i.e., compounds of formula A-IX-1, wherein
R15 at each occurrence is independently selected from hydrogen,
C1-C4 alkyl, C1-C6 alkanoyl, benzyl optionally substituted
with OCH3, -C(0)-tertiary butyl, and -CO2-benzyl.
Preferred compounds of formula A-IX-2 include those of
formula A-IX-3, i.e., compounds of formula A-IX-2, wherein
R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, =O, -SH, -CN, -
CF3, -C1-C4 alkoxy, amino, mono- or dialkylamino,
N(R)C(O)R', -OC(=O)-amino OC(=0)-mono- and dialkylamino;
or
R1 is C2-C6 alkenyl or C2-C6 alkynyl, each of which is
optionally substituted with 1, 2, or 3 groups
independently selected from halogen, OH, SH, C=N,
CF3, OCF3, C1-C4 alkoxy, amino, and mono- or
dialkylamino; or
R1 is aryl, heteroaryl, heterocyclyl, aryl C1-C6 alkyl,
heteroaryl C1-C6 alkyl, or heterocycloalkyl C1-C6 alkyl;
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 Rso groups,-
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0;
R50 at each occurrence is independently selected from halogen,
OH, SH, CN, -CO-(C3.-C4 alkyl), -CO2- (C1-C4
alkyl), -SO2-NR5R6, -NR7R8, -CO-NR5RG, -CO-NR7RB,
-SO2-(C1-C4 alkyl), d-C6 alkyl, C2-Ce alkenyl,
C2-C6 alkynyl, C1-C6 alkoxy, or C3-C8 cycloalkyl;
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently selected from C1-C4 alkyl,
halogen, OH, SH, -NRSR6, CN, C1-C4
haloalkyl, C1-C4 haloalkoxy, phenyl, NR7R8,
and C1-C4 alkoxy.
Preferred compounds of formula A-IX-3 include those of
formula A-IX-4, i.e., compounds of formula A-IX-3, wherein
R50 at each occurrence is independently selected from halogen,
OH, SH, -NR7R8, -SO2-(C1-C4 alkyl), C1-C6 alkyl, C2-Cs
alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C3-C8 cycloalkyl;
wherein the alkyl,. alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally substituted with 1,
2, or 3 substituents independently selected from C:L-
C4 alkyl, halogen, OH, SH, -NRSR6, CN, C1-C4
haloalkyl, C1-C4 haloalkoxy, phenyl, NR7RB, and C1-C4
alkoxy.
Preferred compounds of formula A-IX-4 include those of
formula A-IX-5, i.e., compounds of formula A-X-4, of the
formula
--••.
j.s selected from- pyridinyl, pyrimidinyl, imidazolyl,
oxazolyl, thiazolyl, furanyl, thienyl, pyrazole,
isoxazole, and pyrrolyl.
Preferred compounds of formula A-IX-5 include compounds
of formula A-IX-6, i.e., compounds of formula A-IX-5 wherein
wherein,
R1 is phenyl C1-C6 alkyl or naphthyl C1-C6 alkyl, wherein the
phenyl or naphthyl group is optionally substituted with
1, 2, 3, 4, or 5 Rso groups.
Preferred compounds of formula A-IX-6 include compounds
of formula A-IX-7, i.e., compounds of formula A-IX-6 wherein
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru six carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -0-, -S-, -SO2-, or -NR7-; wherein
R7 is H, -C1-C8 alkyl optionally substituted with 1, 2, or
3 groups independently selected from -OH, -NH2, and
halogen; -C2-C4 alkenyl,- or -C2-C4 alkynyl.
Preferred compounds of formula A-IX-7 include compounds
of formula A-IX-8, i.e., compounds of formula A-IX-7 wherein
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru six carbon atoms.
Other preferred compounds of formula A-IX-7 include
compounds of formula A-IX-9, i.e., compounds of formula A-IX-7
wherein
R2, R3 and the carbon to which they are attached form a
heterocycloalkyl group containing 2 to 5 carbon atoms and
one group selected from -0-, -S-, -S02~, and -NR7-;
wherein
R7 is H, -C1-C6 alkyl optionally substituted with 1, 2, or
3 groups independently selected from -OH, -NH2, and
halogen; -C2-C4 alkenyl; or -C2-C4 alkynyl.
Other preferred compounds of formula A-IX-6 include
compounds of formula A-IX-10, i.e., compounds of formula A-IX-
6 wherein
R2 and R3 are independently selected from H; C1-C4 alkyl
optionally substituted with 1 substituent that is
selected from halogen, -CF3, and C1-C4 alkoxy; C2-C4
alkenyl; C2-C4 alkynyl; and -C02-(C1-C4 alkyl); wherein
Rs and Rs are at each occurrence are independently H or
C1-C6 alkyl; or
R5 and R6 and the nitrogen to which they are attached, at
each occurrence form a 5 or 6 membered
heterocycloalkyl ring.
Preferred compounds of formulas A-IX-8, A-IX-9, or A-IX-
10 include those of formula A-IX-11, i.e., compounds of
formulas A-IX-8, A-IX-9, or A-IX-10 wherein
Ra and Rb are independently selected from C1-C6 alkyl, C1-C6
alkoxy, halogen, CN, OH, hydroxyalkyl, C1-C6 haloalkyl,
C1-C6 haloalkoxy, and -C1-C6 alkyl-NR5Rfa-; or
Ra and Rb are attached to the same carbon and form a C3-C7
spirocycle; and
R15 at each occurrence is independently H or C1-C4 alkyl.
Preferred compounds of formula A-IX-11 include those
wherein
Rc and Rd are independently selected from C1-C6 alkyl optionally
substituted with one, two or three substituents selected
from C1-C3 alkyl, halogen, OH, SH, C=N, CF3, C1-C3 alkoxy,
and -NRSR6; hydroxy; halogen; C2-Cs alkenyl or C2-C6
alkynyl, wherein
the alkenyl or alkynyl group is optionally substituted
with C1-C4 alkyl, halogen, hydroxy, SH, cyano, CF.)#
C1-C4 alkoxy, or NRSR6.
Other preferred compounds of formula A-IX-11 include
those wherein
Rc and Rd are - (CH2)0-4-CO-NR21R22, - (CH2)0-4- SO2-NR21R22 ; - (CH2)0-4-
SO-(C1-C8 alkyl); -(CH2)0-4-SO2-(C1-C12 alkyl); - (CH2)0-4-SO2-
(C3-C7 cycloalkyl), -(CH2)0-4-N(H or R20)-CO-O-R20; - (CH2)0-4-
N(H or R20 )-CO-N(R20)2; - (CB2)0-4-N-CS-N (R20) 2; -(CH2)0-4-N (-H
or R20)-CO-R21; or - (CH2)0-4-NR21R22; wherein
R21 and R22 independently represent hydrogen, C1-C6 alkyl,
hydroxy1 (C1-C6) alkyl, amino (C1-C6). alkyl, haloalkyl,
C3-C7 cycloalkyl, - (C1-C2 alkyl) - (C3-C7 cycloalkyl), -
(C1-C6 alkyl)-0-(C1-C3 alkyl), -C2-CS alkenyl, -C2-C6
alkynyl, phenyl, naphthyl, or heteroaryl
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0.
Still other preferred compounds of formula A-IX-11
include those wherein
Rc and Rd are - (CH2)0-4-CO-(d-C12 alkyl); -(CH2)0-4-CO-(C2-C12
alkenyl) ; CH2)0-4-CO-(C2-C12) alkynyl; -(CH2)0-4-C0- (C3-C7
cycloalkyl) ; - (CH2)0-4-CO-phenyl; -(CH2)0-4-CO-naphthyl; -
(CH2)0-4-CO-heteroaryl; - (CH2)0-4-CO-heterocycloalkyl ;
(CH2)0-4-C02R20; where
R20 is selected from C1-C6 alkyl, -(CH2)0-2- (phenyl),
(CH2)0-2-(naphthyl), C2-C6 alkenyl, C2-C6 alkynyl, C3-C7
cycloalkyl, - (CH2)0-2-(heterocycloalkyl) and -(CH2)0-2-
(heteroaryl);
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0.
Yet still other preferred compounds of formula A-IX-11
include those wherein
Rc and Rd are - (CH2)0-4-O-CO-(C1-C6 alkyl); -(CH2)0-4-O-P (0)-
(OR5)2; -(CH2)0-4-O-CO-N(R20)2; - (CH2)0-4-O-CS-N (R20)2 ; -(CH2)0-
4-O- (R20) ; - (CH2)0-4-O- (R20) -C02H; - (CH2)0-4-S- (R20) ; - (CH2)0-4-
0-halo(C1-C6)alkyl; -(CH2)0-4-O-(C1-C6) alkyl; C3-C8
cycloalkyl; or - (CH2)0-4-N(-H or R20) -SO2-R21; wherein
each aryl group and each heteroaryl group at each
occurrence is optionally substituted with 1, 2, 3.
4, or 5 R50 groups ;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =O;
R50 at each occurrence is independently selected from
halogen, OH, SH, CN, -CO- (C1-C4 alkyl), -CO2-(C1-
C4 alkyl), -SO2-NR5R6, -NR7R8, -CO-NRSR6, -CO-
NR7R8, -SO2-(C1-C4 alkyl), C1-C6 alkyl, C2-C6
alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, or C3-CB
cycloalkyl;
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently selected from C1-C4 alkyl,
halogen, OH, SH, -NR5R6, CN, C1-C6
haloalkyl, C1-C6 haloalkoxy, phenyl, NR7RB,
and C1-C6 alkoxy.
Other preferred compounds of formula A-IX-5 include those
of formula A-IX-12, i.e., compounds of formula A-IX-5, wherein
R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3. groups
independently selected from halogen, -OH, =0, -SH, -CN,
-CF3, -C1-C4 alkoxy, amino, mono- or dialkylamino,
-N(R)C(0)R', -0C(=0)-amino and -0C(=O)-mono- or
dialkylamino,- or
R1 is C2-C6 alkenyl or C2-C6 alkynyl, each of which is
optionally substituted with 1, 2, or 3 groups
independently selected from halogen, OH, SH, CSN, CF3,
OCF3, C1-C4 alkoxy, amino, and mono- or dialkylamino.
Preferred compounds of formula A-IX-12, include those of
formula A-IX-13, i.e., compounds of formula A-IX-12 wherein
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru six carbon atoms, wherein one
carbon atom is optionally replaced by a group selected
from -0-, -S-, -SO2-, or -NR7-; wherein
R7 is selected from H or -C1-C4 alkyl optionally
substituted with 1 group selected from -OH, -NH2, and
halogen.
Preferred compounds of formula A-IX-13, include those of
formula A-IX-14, i.e., compounds of formula A-IX-13 wherein
R2, R3 and the carbon to which they are attached form a
carbocycle of three thru,six carbon atoms.
Other preferred compounds of formula A-IX-13, include
those of formula A-IX-15, i.e., compounds of formula A-IX-13
wherein
R2, R3 and the carbon to which they are attached form a
heterocycloalkyl group containing 2 to 5 carbon atoms and
one group selected from -O-, -S-, -SO2-, and -NR7-;
wherein
R7 is selected from H and -C1-C4 alkyl optionally
substituted with 1 group selected from -OH, -NH2, and
halogen.
Other preferred compounds of formula A-IX-13, include
those of formula A-IX-16, i.e., compounds of formula A-IX-13
wherein
R2 and R3 are independently selected from H; C1-C4 alkyl
optionally substituted with 1 substituent that is
selected from halogen, -CF3, and C1-C4 alkoxy; C2-C4
alkenyl; and C2-C4 alkynyl; wherein
R5 and R6 are at each occurrence are independently -H or
C1-C6 alkyl; or
R5 and R6 and the nitrogen to which they are attached, at
each occurrence form a 5 or 6 membered
heterocycloalkyl ring.
Preferred compounds of formulas A-IX-14, A-XX-15, A-IX-16
include compounds of formula A-IX-17, i.e., compounds of
formulas A-IX-14, A-IX-15, A-IX-16 wherein
Ra and Rb are independently selected from C1-C3 alkyl, F, OH,
SH, C=Nr CF3, Ci.-C6 alkoxy, and -NRSR6; and
Ri5 at each occurrence is independently H or C1-C4 alkyl.
Preferred compounds of formula A-IX-17, include those
compounds wherein
Rc and RA are independently selected from Cx-Ce alkyl optionally
substituted with one, two or three substituents selected
from C!-C3 alkyl, halogen, OH, SH, C=N, CF3, Ql-Cs alkoxy,
and -NRSRS; hydroxy; halogen;
C2-C6 alkenyl or C2~CS alkynyl, wherein
the alkenyl or alkynyl group is optionally substituted
with C1-C4 alkyl, halogen, hydroxy, SH, cyano, CF3,
C1-C4 alkoxy, or NR5R6.
Other preferred compounds of formula A-IX-17, include
those compounds wherein
Rc and Rd are - (CH2)0-4-CO-NR21R22, -(CH2)0-4-SO2-NR21R22; -(CH2)0-4-
SO- (C1-C8 alkyl) ; - (CH2)0-4-SO2- (C1-C12 alkyl) ; - (CH2)0-4-SO2-
(C3-C7 cycloalkyl) ; - (CH2)0-4-N (H or R20 )-CO2R20; -(CH2)0-4-
N(H or R20 )-CO-N(R20)2; -(CH2)0-4-N-CS-N(R20)2; - (CH3)0-4-N (-H
or R20)-CO-R21; or - (CH2)0-4-NR2iR22; wherein
R21 and R22 independently represent hydrogen, C1-C6 alkyl,
hydroxyl (C1-C6) alkyl, amino (C1-C6) alkyl, haloalkyl,
C3-C7 cycloalkyl, - (C1-C2 alkyl)- (C3-C7 cycloalkyl), -
(C1-C6 alkyl)-O-(C1-C3 alkyl), -C2-C6 alkenyl, -C2-C6
alkynyl, phenyl, naphthyl, or heteroaryl;
each aryl group and each heteroaryl group at each
occurrence is optionally substituted with 1, 2, 3,
4, or 5 R50 groups ;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0.
Still other preferred compounds of formula A-IX-17,
include those compounds wherein
Rc and Rd are - (CH2)0-4-CO- (C1-C12 alkyl); -(CH2)0-4-CO- (C2-C12
alkenyl); CH2)0-4-C0-(C2-C12) alkynyl; - (CH2)0-4-CO-(C3-C7
cycloalkyl); - (CH2)0-4-CO-phenyl; - (CH2)0-4-CO-naphthyl;
- (CH2)0-4-CO-heteroaryl; - (CH2)0-4-CO-heterocycloalkyl;
- (CH2)0-4-CO2R20; where
R20 is selected from C1-C6 alkyl, -(CH2)0-2- (phenyl),
(CH2) 0_2-(naphthyl), C2-C6 alkenyl, C2-Cs alkynyl, C3-C7
cycloalkyl, - (CH2) 0-2- (heterocycloalkyl) and - (CH2) 0-2-
(hetei~oaryl) ;
each aryl group at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heteroaryl at each occurrence is optionally
substituted with 1, 2, 3, 4, or 5 R50 groups;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently Rso or =O.
Yet still other preferred compounds of formula A-IX-17,
include those compounds wherein
Rc and Rd are -(CH2)0-4-O-CO- (C1-C6 alkyl) ; - (CH2)0-4-O-P (0) -
(ORs)2; - (CH2)0-4-O-CO-N(R20)2; - (CH2) 0-4-O-CS-N (R20)2; - (CH2) 0-
4-O-(R30); - (CH2)0-4-O-(R20)-CO2H; - (CH2)0-4-S- (R20) ; - (CH2) 0-4-
0-halo(C1-C6) alkyl; - (CH2) 0-4-0-(C1-C6) alkyl; C3-C8
cycloalkyl; or - (CH2) o-4-N (-H or R20) -SO2-R21; wherein
each aryl group and each heteroaryl group at each
occurrence is optionally substituted with 1, 2, 3,
4, or 5 R50 groups ;
each heterocycloalkyl group at each occurrence is
optionally substituted with 1, 2, 3, 4, or 5 groups
that are independently R50 or =0;
R50 at each occurrence is independently selected from
halogen, OH, SH, CN, -CO-(d-C4 alkyl), -C02-(d-
C4 alkyl), -SO3-NR5R6, -NR7R8, -CO-NR5R6, -C0-
NR7R8, -S02-(d-C4 alkyl), d-C6 alkyl, C2-Cs
alkenyl, C2-Cs alkynyl, C±-C6 alkoxy, or C3-C8
cycloalkyl;
wherein the alkyl, alkenyl, alkynyl, alkoxy, or
cycloalkyl groups are optionally
substituted with 1, 2, or 3 substituents
independently selected from Ci-C4 alkyl,
halogen, OH, SH, -NR5R6, CN, d-Cg
haloalkyl, Ci-C6 haloalkoxy, phenyl, NR7R8,
and Ci-C6 alkoxy.
Other preferred compounds of formula A-IX-4 include those
of formula A-X
Preferred compounds of formula A-X include compounds of
formula A-X-l, i.e., compounds of formula A-X wherein
R1 is phenyl C1-C6 alkyl or naphthyl C1-C6 alkyl, wherein the
phenyl or naphthyl group is optionally substituted with
1, 2, 3, 4, or 5 Rso groups; and
R2 and R3 are independently H or C1-C4 alkyl.
Preferred compounds of formula A-X-l include compounds of
formula A-X-2, i.e., compounds of formula A-X-l wherein
Ra and Rb are independently H or C1-C4 alkyl; or
Ra and Rb are attached to the same carbon and form a C3-Cg
carbocycle;
R1 is phenyl, optionally substituted with 1, 2, or 3 R50
groups; and
R15 at each occurrence is independently H or C1-C4 alkyl.
Preferred compounds of formula A-X-2 include compounds of
formula A-X-3, i.e., compounds of formula A-X-2 wherein
R1 is a dihalophenyl.
Preferred compounds of formulas A-IX-5, A-X and A-X-3
include compounds of formula A-X-4, i.e., compounds of
formulas A-IX-5, A-X and A-X-3 having the following structure,
wherein
wherein J at each occurrence is independently selected from N
or CRO, wherein
Rc at each occurrence is independently selected from C1-C6
alkyl, optionally substituted with 1, 2, or 3
substituents independently selected from C1-C3 alkyl,
halogen, OH, SH, CsN, • CF3, C1-C6 alkoxy, C3-C8
cycloalkyl, and NR5RS; hydroxy; halogen; C2-C6 alkenyl
or C2-C6 alkynyl, wherein
the alkenyl or alkynyl group is optionally
substituted with C3-C4 alkyl, halogen, hydroxy,
SH, cyano, CF3, C1-C4 alkoxy, or NR5R6;
provided that at least two Js are CRC.
Other preferred compounds of formulas A-IX-5, A-X and A-
X-3 include compounds of formula A-X-5, i.e., compounds of
formulas A-IX-5, A-X and A-X-3 having the following structure,
wherein
— represents a single or double bond, provided that only one
of the dashed bonds is a double bond;
J is selected from N, S, 0, and CRC, wherein
Rc at each occurrence is independently selected from C1-C6
alkyl, optionally substituted with 1, 2, or 3
substituents independently selected from Cx-C3 alkyl,
halogen, OH, SH, C=N, CF3, C1-C6 alkoxy, C3-C8
cycloalkyl, and NR5R6; hydroxy; halogen; C2-C6 alkenyl
or C2-C6 alkynyl, wherein
the alkenyl or alkynyl group is optionally
substituted with C1-C4 alkyl, halogen, hydroxy,
SH, cyano, CF3, C3.-C4 alkoxy, or NR5R6;
provided that at least one J is CRC.
Other preferred compounds include those compounds
according to any one of embodiments A-I to A-X-5, wherein
Z is Ci-Cs ¦ alkyl, optionally substituted with 1 or 2 groups
that are independently OH, halogen, C1-C4 alkoxy, CF3,
OCF3/ NO,, CN, and NR5R6. More preferably, Z is C1-C4
alkyl. Another preferred embodiment, Z is phenyl,
benzyl, imidazolyl, or -C1-C4-imidazolyl.
Still other preferred compounds include those compounds
according to any one of embodiments A-I to A-X-5, wherein
R5 and Rs at each occurrence are independently H or C1-C4 alkyl.
Preferably, Z is C1-C4 alkyl.
In another aspect, the invention provides a method of
preparing compounds of formula (I)
and a pharmaceutically acceptable salt thereof, wherein Z, X,
R1, R2, R3, R15 and Rc are as defined above.
In another aspect, the invention provides the
intermediates that are useful in the preparation of the
compounds of interest.
The invention also provides methods for treating a
patient who has, or in preventing a patient from getting, a
disease or condition selected from Alzheimer's disease, for
helping prevent or delay the onset of Alzheimer's disease, for
treating patients with mild cognitive impairment (MCI) and
preventing or delaying the onset of Alzheimer's disease in
those who would progress from MCI to AD, for treating Down's
syndrome, for treating humans who have Hereditary Cerebral
Hemorrhage.with Amyloidosis of the Dutch-Type, for treating
cerebral amyloid angiopathy and preventing its potential
consequences, i.e. single and recurrent lobar hemorrhages, for
treating other degenerative dementias, including dementias of
mixed vascular and degenerative origin, dementia associated
with Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, or diffuse Lewy body type of Alzheimer's disease
and who is in need of such treatment which includes
administration of a therapeutically effective amount of a
compound of formula (I) and a pharmaceutically acceptable
salts thereof.
In an embodiment, this method of treatment can be used
where the disease is Alzheimer's disease.
In an embodiment, this method of treatment can help
prevent or delay the onset of Alzheimer's disease.
In an embodiment, this method of treatment can be used
where the disease is mild cognitive impairment.
In an embodiment, this method of treatment can be used
where the disease is Down's syndrome.
In an embodiment, this method of treatment can be used
where the disease is Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type.
In an embodiment, this method of treatment can be used
where the disease is cerebral amyloid angiopathy.
In an embodiment, this method of treatment can be used
where the disease is degenerative dementias.
In an embodiment, this method of treatment can be used
where the disease is diffuse Lewy body type of Alzheimer's
disease.
In an embodiment, this method of treatment can treat an
existing disease.
In an embodiment, this method of treatment can prevent a
disease from developing.
In an embodiment, this method of treatment can employ
therapeutically effective amounts: for oral administration
from about 0.1 mg/day to about 1,000 mg/day; for parenteral,
sublingual, intranasal, intrathecal administration from about
0.5 to about 100 mg/day; for depo administration and implants
from about 0.5 mg/day to about 50 mg/day; for topical
administration from about 0.5 mg/day to about 200 mg/day; for
rectal administration from about 0.5 mg to about 500 mg.
In an embodiment, this method of treatment can employ
therapeutically effective amounts: for oral administration
from about 1 mg/day to about 100 mg/day; and for parenteral
administration from about 5 to about 50 mg daily.
In an embodiment, this method of treatment can employ
therapeutically effective amounts for oral administration from
about 5 mg/day to about 5 0 mg/day.
The invention also includes pharmaceutical compositions
which include a compound of formula (I) and pharmaceutically
acceptable salts thereof.
The invention also includes the use of a compound of
formula (I) or pharmaceutically acceptable salts thereof for
the manufacture of a medicament for use in treating a patient
who has, or in preventing a patient from getting, a disease or
condition selected from Alzheimer's disease, for helping
prevent or delay the onset of Alzheimer's disease, for
treating patients with mild cognitive impairment (MCI) and
preventing or delaying the onset of Alzheimer's disease in
those who would progress from MCI to AD, for treating Down's
syndrome, for treating humans who have Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type, for treating
cerebral amyloid angiopathy and preventing its potential
consequences, i.e. single and recurrent lobar hemorrhages, for
treating other degenerative dementias, including dementias of
mixed vascular and degenerative origin, dementia associated
with Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, diffuse Lewy body type of Alzheimer's disease
and who is in need of such treatment.
In an embodiment, this use of a compound of formula (I)
can be employed where the disease is Alzheimer's disease.
In an embodiment, this use of a compound of formula (I)
can help prevent or delay the onset of Alzheimer's disease.
In an embodiment, this use of a compound of formula (I)
can be employed where the disease is mild cognitive
impairment.
In an embodiment, this use of a compound of formula (I)
can be employed where the disease is Down's syndrome.
In an embodiment, this use of a compound of formula (I)
can be employed where the disease is Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type.
In an embodiment, this use of a compound of formula (I)
can be employed where the disease is cerebral amyloid
angiopathy.
In an embodiment, this use of a compound of formula (I)
can be employed where the disease is degenerative dementias.
In an embodiment, this use of a compound of formula (I)
can be employed where the disease is diffuse Lewy body type of
Alzheimer's disease.
In an embodiment, this use of a compound employs a
pharmaceutically acceptable salt selected from salts of the
following acids hydrochloric, hydrobromic, hydroiodic, nitric,
sulfuric, phosphoric, citric, methanesulfonic, CH3-(CH2)n-COOH
where n is 0 thru 4, HOOC- (CH2) n-COOH where n is as defined
above, HOOC-CH=CH-COOH, and phenyl-COOH.
The invention also includes methods for inhibiting beta-
secretase activity, for inhibiting cleavage of amyloid
precursor protein (APP), in a reaction mixture, at a site
between Met596 and Asp597, numbered for the APP-695 amino acid
isotype, or at a corresponding site of an isotype or mutant
thereof; for inhibiting production of amyloid beta peptide (A
beta) in a cell; for inhibiting the production of beta-amyloid
plaque in an animal; and for treating or preventing a disease
characterized by beta-amyloid deposits in the brain. These
methods each include administration of a therapeutically
effective amount of a compound of formula (I) and
pharmaceutically acceptable salts thereof.
The invention also includes a method for inhibiting beta-
secretase activity, including exposing said beta-secretase to
an effective inhibitory amount of a compound of formula (I),
and pharmaceutically acceptable salt thereof.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of
less than 50 micromolar.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
micromolar or less.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 1
micromolar or less.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
nanomolar or less.
In an embodiment, this method includes exposing said
beta-secretase to said compound in vitro.
In an embodiment, this method includes exposing said
beta-secretase to said compound in a cell.
In an embodiment, this method includes exposing said
beta-secretase to said compound in a cell in an animal.
In an embodiment, this method includes exposing said
beta-secretase to said compound in a human.
The invention also includes a method for inhibiting
cleavage of amyloid precursor protein (APP), in a reaction
mixture, at a site between Met596 and Asp597, numbered for the
APP-695 amino acid isotype; or at a corresponding Kite of an
isotype or mutant thereof, including exposing said reaction
mixture to an effective inhibitory amount of a compound of
formula (I), and a pharmaceutically acceptable salt thereof.
In an embodiment, this method employs a cleavage site:
between Met652 and Asp653, numbered for the APP-751 isotype;
between Met 671 and Asp 672, numbered for the APP-770 isotype;
between Leu596 and Asp597 of the APP-695 Swedish Mutation;
between Leu652 and Asp653 of the APP-751 Swedish Mutation; or
between Leu671 and Asp672 of the APP-770 Swedish Mutation.
In an embodiment, this method exposes said reaction
mixture in vitro.
In an embodiment, this method exposes said reaction
mixture in a cell.
In an embodiment, this method exposes said reaction
mixture in an animal cell.
In an embodiment, this method exposes said reaction
mixture in a human cell.
The invention also includes a method for inhibiting
production of amyloid beta peptide (A beta) in a cell,
including administering to said cell an effective inhibitory
amount of a compound of formula (I), and a pharmaceutically
acceptable salt thereof.
In an embodiment, this method includes administering to
an animal.
In an embodiment, this method includes administering to a
human.
The invention also includes a method for inhibiting the
production of beta-amyloid plaque in an animal, including
administering to said animal an effective inhibitory amount of
a compound of formula (I), and a pharmaceutically acceptable
salt thereof.
In an embodiment, this method includes administering to a
human.
The invention also includes a method for treating or
preventing a disease characterized by beta-amyloid deposits in
the brain including administering to a patient an effective
therapeutic amount of a compound of formula (I), and a
pharmaceutically acceptable salt thereof.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of
less than 50 micromolar.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
micromolar or less.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 1
micromolar or less.
In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
nanomolar or less.
In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 0.1 to about
10 00 mg/day.
In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 15 to about 15 0 0
mg/day.
In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 1 to about 100
mg/day.
In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 5 to about 50
mg/day.
In an embodiment, this method can be used where said
disease is Alzheimer's disease.
In an embodiment, this method can be used where said
disease is Mild Cognitive Impairment, Down's Syndrome, or
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch
Type.
The invention also includes a composition including beta-
secretase complexed with a compound of formula (I), and a
pharmaceutically acceptable salt thereof.
The invention also includes a method for producing a
beta-secretase complex including exposing beta-secretase to a
compound of formula (I), and a pharmaceutically acceptable
salt thereof, in a reaction mixture under conditions suitable
for the production of said complex.
In an embodiment, this method employs exposing in vitro.
In - an embodiment, this method employs a reaction mixture
that is a cell.
The invention also includes a component kit including
component parts capable of being assembled, in which at least
one component part includes a compound of formula I enclosed
in a container.
In an embodiment, this component kit includes lyophilized
compound, and at least one further component part includes a
diluent.
The invention also includes a container kit including a
plurality of containers, each container including one or more
unit dose of a compound of formula (I):, and a
pharmaceutically acceptable salt thereof.
In an embodiment, this container kit includes each
container adapted for oral delivery and includes a tablet,
gel, or capsule.
In an embodiment, this container kit includes each
container adapted for parenteral delivery and includes a depot
product, syringe, ampoule, or vial.
In an embodiment, this container kit includes each
container adapted for topical delivery and includes a patch,
medipad, ointment, or cream.
The invention also includes an agent kit including a
compound of formula (I), and a pharmaceutically acceptable
salt thereof; and one or more therapeutic agent selected from
an antioxidant, an anti-inflammatory, a gamma secretase
inhibitor, a neurotrophic agent, an acetyl cholinesterase
inhibitor, a statin, an A beta peptide, and an anti-A beta
antibody.
The invention also includes a composition including a
compound of formula (I), and a pharmaceutically acceptable
salt thereof; and an inert diluent or edible carrier.
In an embodiment, this composition includes a carrier
that is an oil.
The invention also includes a composition including: a
compound of formula (I), and a pharmaceutically acceptable
salt thereof; and a binder, excipient, disintegrating agent,
lubricant, or gildant.
The invention also includes a composition including a
compound of formula (I), and a pharmaceutically acceptable
salt thereof; disposed in a cream, ointment, or patch.
The invention provides compounds of formula (I), and the
other formulas contained herein, that are useful in treating
and preventing Alzheimer's disease. The compounds of the
invention can be prepared by one skilled in the art based only
on knowledge of the compound's chemical structure. The
chemistry for the preparation of the compounds of this
invention is known to those skilled in the art. In fact, there
is more than one process to prepare the compounds of the
invention. Specific examples of methods of preparation can be
found in the art. For examples, see J. Org. Chem. 1998, 63,
4898-4906; J. Org. Chem. 1991, 62, 9348-9353; J. Org. Chem.
1996, 61, 5528-5531; J. Med. Chem. 1993, 36, 320-330; J. Am.
Chem. Soc. 1999, 121, 1145-1155; and references cited therein.
See also U.S. Patent Nos. 6,150,530, 5,892,052, 5,696,270, and
5,362,912, which are incorporated herein by reference, and
references cited therein.
An example of one of many various processes that can be
used to prepare the compounds of the invention is set forth in
Scheme I.
where Rl X, and Z are as defined above or below.
Scheme I illustrates the preparation of compounds wherein
Rc is an isothiochroman 2,2-dioxide using an optionally
substituted benzoic acid as the starting material. One of
skill in the art will recognize that optionally substituted
benzyl halides or benzyl alcohols may also be used as starting
materials.
In Scheme I, the benzoic acid is reduced to a benzyl
alcohol, which is then converted into a benzyl halide.
Alternatively, the benzyl alcohol may be modified to include a
leaving group such as, for example, a tosylate, brosylate,
nosylate, triflate or raesylate. The benzyl compound is then
reacted with a sulfide to generate the thioether. The
carboxylic ester is then hydrolyzed to form a carboxylic acid,
which is then subjected to annulation reaction conditions to
form the desired bicyclic ring system. The annulation can be
carried out using a Lewis acid, polyphosphoric acid, or P205.
Other suitable reagents that effect cyclization are known in
the art.
The resulting bicyclic sulfide is oxidized to form the
sulfone. The keto group is converted into an amine directly
via reductive amination or indirectly through the generation
of an oxime, which is then reduced to form the amine.
Transition metal catalysts and hydrogen or other reducing
agents, such as NaBH4, LiAlH4 or NaCNBH3, may be used to effect
the reduction.
The resulting amine is used to open the epoxide to form
the resulting coupled product. The coupled product is then
deprotected to form a free amine, which is acylated or
sulfonylated to generate the desired final product. In Scheme
I, the use of a Boc protecting group is illustrated, but one
of skill in the art will appreciate that other protecting
groups, such as CBz, benzyl or others can also be used.
Scheme II illustrates the introduction of a non-hydrogen
R15 group on the 3-position nitrogen atom in the 1,3-
diaminopropane portion of the molecule. The free nitrogen is
reacted with an electrophile, an aldehyde or ketone and a
reducing agent, an acid chloride, an acid anhydride or an acid
with a coupling agent, such as DCC (dicyclohexyl
carbodiimide), DIC (1,3 diisopropyl carbodiimide), EDCI. (1-
ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride),
BBC (1-benzotriazol-l-yloxy-bis(pyrrolidino)uronium
hexafluorophosphate), BDMP (5-(lH-bensotriazol-1-yloxy)-3,4-
dihydro-1-methyl 2F-pyrrolium hexachloroanitimonate), BOMI
(benzotriazol-1-yloxy-N, N-dimethylmethaniminium
hexachloroantimonate), HATU (0-(7-azabenzotriazol-l-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate), HAPyU = 0- (7-
azabenzotriazol-l-yl)- 1,1,3,3-bis(tetramethylene)uronium
hexafluorophosphate, HBTU which is 0-(benzotriazol-1-yl)-
1,1, 3, 3-tetramethyluroniutn hexafluorophosphate, TAPipU which
is 0-(7-azabenzotriazol-l-yl)- 1,1,3,3-
bis(pentamethylene)uronium etrafluoroborate, AOP (0-(7-
azabenzotriazol-1-yl)-tris(dimethylamino)phosphonium
hexafluorophosphate), BDP (benzotriazol-1-yl diethyl
phosphate), BOP (1-
benzotriazolyoxytris(dimethylamino)phosphonium
hexafluorophosphate), PyAOP (7-
azobenzotriazolyoxytris(pyrrolidino)phosphonium
hexafluorophosphate), PyBOP (1-
benzotriazolyoxytris(pyrrolidino)phosphonium
hexafluorophosphate), TDBTU (2-(3, 4-dihydro--4-oxo-l,2,3-
benzotriazin-3-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate), TNTU (2-(5-norbornene-2,3-dicarboximido)-
1,1,3,3-tetramethyluronium tetrafluoroborate), TPTU (2-(2-oxo-
l(2ff) -pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate),
TSTU (2-succinimido-l,1,3,3-tetramethyluronium
tetrafluoroborate), BEMT (2-bromo-3-ethyl-4-methyl thiazolium
tetrafluoroborate), B0P-C1 (bis(2-oxo-3-
oxazolidinyDphosphinic chloride), BroP
(bromotris(dimethylamino)phosphonium hexafluorophosphate),
BTFFH (bis(tetramethylenefluoroformamidinium)
hexafluorophosphate), C1P (2-chloro-l,3-
dimethylimidasolidinium hexafluorophosphate), DEPBT (3-
(diethoxyphosphoryloxy)-1,2,3-benzotriasin-4(3H) -one), Dpp-Cl
(diphenylphosphinic chloride), EEDQ (2-ethoxy-l-
ethoxycarbonyl-l,2-dihydroquinoline), FDPP (pentafluorophenyl
diphenylphosphinate), HOTT (S-(l-oxido-2-pyridinyl)-1,1,3,3-
tetramethylthiouronium ' hexafluorophosphate), PyBroP
(I.vromotris (pyrrolydino)phophonium hexaf luorophosphate), PyCloP
(chlorotris(pyrrolydino)phophonium hexafluorophosphate), TFFH
(tetramethylfluoroformamidinium hexafluorophosphate), and TOTT
{S-(l-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium
tetraf luoroborate) to generate the monosubstituttid product,
which can then be deprotected and coupled to the "X-Z" group.
Conversely, the monosubstituted product can be deprotected,
and the free nitrogen reacted with an electrophile, an
aldehyde or ketone and a reducing agent, an acid chloride, an
acid anhydride or an acid with a coupling agent, such as those
previously exemplified to generate the disubstituted product,
which is then coupled to the "X-Z" group.
c
- Scheme III illustrates the introduction of a. tertiary
amine (R is not hydrogen) or a secondary amine (R is hydrogen)
onto the isothiochroman 2,2-dioxide scaffold. First, the
sulfo-ketone is alkylated using, for example, a Grignard
reagent or other alkylating agent, to generate the tertiary
alcohol, which is then converted into a leaving group. One of
skill in the art will appreciate that many possible leaving
groups may be used. Particular examples include, but are not
limited to triflate, mesylate, paratoluene sulfonate,
nosylate, and brosylate. The leaving group is then displaced
using an azide, such as DPPA or NaN3. Substituted azides may
be used in place of the unsubstituted azide. Alternatively,
the desired compounds can be generated from the alcohol
directly without first converting the alcohol into a leaving
group. Such transformations can be readily accomplished using
conventional SN1 conditions according to procedures available
in the literature.
The resulting azide is then reduced to generate the
desired amine. Many reducing agents that will effect the
desired transformation are known. Examples include H2 and Pd,
H2 and Pt, NaBH4, and NaCNBH3. Stronger reducing agents, such
as LiAlH4 and DIBAL may be used, but the sulfone may also be
reduced. If the sulfone is reduced, it may be reoxidized
using methods known in the art, such as MCPBA.
c
As shown in scheme IV, spirocycles may be- generated by
alkylating a compound in the presence of a strong base.
Examples of strong bases include, LDA, KHMDS, and tertiary-
butyl lithium. One of skill in the art will appreciate that
many other bases are strong enough to deprotonate the starting
material and effect the desired transformation.
The alkylating agent dictates the size the of the
spirocycle that is formed. Dibromo ethane, diiodoethane, or
bromo iodoethane will generate a spirocyclopropyl compound,
wherein n is 1. However, longer alkyl chains generate larger
spirocycloalkyl compounds. For example, a 1,5-dihalopentane
generates a spirocyclohexyl compound, wherein n is 4.
Although dihalo compounds are illustrated, one of skill in the
art will appreciate that other leaving groups, such as, for
example, mesylate, tosylate, triflate, brosylate, and nosylate
may be used. The leaving groups may, but need not, be
identical.
Scheme V illustrates the preparation of fluorene
derivatives using optionally substituted salicylic esters as
starting materials. Non-commercially available substituted
salicylic esters may be obtained by a variety of methods well
known to those skilled in the art of organic synthesis. Such
methods include, but are not limited to, halogenations (Rozen
and Lerman (J. Org. Chem. 1993, 239 - 240)], Suzuki couplings
[Miyaura and Suzuki (Chem. Rev. 1995, 2457 - 2483)],
Sonagashiri couplings [Sonagashira (Metal-Catalyzed Cross-
Coupling Reactions, 1998, Wiley-VCH publishers)], Negishi
couplings [Zhu, et al. (J. Org. Chem. 1991, 1445 - 1453)],
Stille cross-couplings [Littke et al. (Angew. Chem. Int. Ed.
1999, 2411 - 2413)], Heck couplings [Whitcombe et al.
(Tetrahedron 2001, 7449 - 7476)], aminations [Wolfe et al. (J.
Org. Chem. 2000, 1144 - 1157)], oxygenations [Fu and Littke
(Angew. Chem. Int. Ed. 2002, 4177 - 4211)] and carbonylations
[Cai et al. (J Chem Soc, Perkin Trans 1 1997, 2273 - 2274)].
One of skill in the art will recognize that optionally
substituted ortho halo benzoates may also be used as starting
materials.
Phenols of the general formula (1) are readily converted
into triflates employing a triflating source and a base in an
inert solvent. Triflating sources include, but are not
limited to, trifluoromethanesulfonic anhydride,
trifluoromethanesulfonyl chloride and N-
phenyltrifluoromethanesulfonimide. Bases include, but are not
limited to, trialkyl amines (preferably diisopropylethylamine
or triethylamine), aromatic amines (preferably pyridine, 4-
dimethylaminopyridine or 2,6-lutidine) or alkali metal
hydrides (preferably sodium hydride). Inert solvents may
include, but are not limited to, acetonitrile, dialkyl ethers
(preferably diether ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides
(preferably dimethylacetamide), N,N-dialkylforamides
(preferably dimethylformamide), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic, hydrocarbons (preferably benzene
or toluene) or haloalkanes (preferably dichloromethane).
Preferred reaction temperatures range from 0 °C to room
temperature. The progress of this conversion is monitored by
standard chromatographic and spectroscopic methods known to
one skilled in the art of organic synthesis.
Triflates may be treated with an aryl borcnic acid or
aryl boronic acid ester where X is equivalent to B(OH)2 or
B(ORa) (0Rb) (where Ra and Rb are lower alkyl, ie. Ci-Cs, or taken
together Ra and Rb are lower alkylene, ie. C2-C12) in the
presence of a metal catalyst with or without a base in an
inert solvent to give birayls. Metal catalysts include, but
are not limited to, salts or phosphine complexes of Cu, Pd or
Ni (eg. Cu(OAc)2, Pd(PPh3)4, NiCl2 (PPh3)2). Bases include, but
are not limited to, alkaline earth metal carbonates, alkaline
earth metal bicarbonates, alkaline earth metal hydroxides,
alkali metal hydrides (preferably sodium hydride), alkali
metal alkoxides (preferably sodium ethoxide or sodium
methoxide), trialkyl amines (preferably diisopropylethylamine
or triethylamine) or aromatic amines (preferably pyridine).
Inert solvents may include, but are not limited to,
acetonitrile, dialkyl ethers (preferably diether ether),
cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),
N,N-dialkylacetamides (preferably dimethylacetamide), N,N-
alkylforamides (preferably dimethylformamide),
dialkylsulfoxides (preferably dimethylsulfoxide), aromatic
hydrocarbons (preferably benzene or toluene), haloalkanes
(preferably dichloromethane), alkyl alcohols (preferably
methyl alcohol or ethyl alcohol), or water. Preferred
reaction temperatures range from room temperature to the
boiling point of the solvent employed. Non-commercially
available boronic acids or boronic esters may be obtained from
the corresponding optionally substituted aryl halide as
described by Gao, et al. (Tetrahedron 1994, 50, 979 -988).
The progress of the coupling reaction is monitored by standard
chromatographic and spectroscopic methods known to one skilled
in the art of organic synthesis.
Alternately, triflates may be treated with organozinc
reagents as taught by Zhu, et al. (J. Org. Chem. 1991, 1445 -
1453).
One skilled in the art of organic synthesis will
appreciate that the nature of the coupling partners described
above could be reversed and the coupling reaction conducted in
substantially the same manner as described above.
The biaryl ester is hydrolyzed to form a carboxylic acid.
The hydrolysis reaction may be run under a wide variety of
conditions familiar to one skilled in the art of organic
synthesis. The hydrolysis reaction is run in the presence of
a base such as, but not limited to, lithium hydroxide and
sodium hydroxide. Typical solvents include, but are not
limited to, tetrahydrofuran, diethyl ether, dichloromethane,
alkyl alcohols (including methyl alcohol and ethyl alcohol)
and water. The reactions may be successfully run at
temperatures ranging from room temperature to the boiling
point of the solvent employed. The progress of the hydrolysis
reaction is monitored by standard chromatographic and
spectroscopic methods known to one skilled in the art of
organic synthesis.
The carboxylic acid may be subjected to a cyclization
reaction, under a wide variety of conditions known to one
skilled in the art of organic synthesis, to form the desired
tricycle. The cyclization reaction is carried out in the
presence of an acidic reagent. Either Bronsted acids
including, but not limited to, sulfuric acid, hydrochloric
acid, methanesulfonic acid and polyphosphoric acid, or Lewis
acids including, but not limited to, aluminum trichloride,
titanium tetrachloride and tin tetrachloride are useful for
effecting this transformation. The reaction may be performed
neat or with the addition of a co-solvent. Typical co-
solvents include, but are not limited to, acetonitrile,
dialkyl ethers (preferably diether ether), cyclic ethers
(preferably tetrahydrofuran or 1,4-dioxane), N,N-
dialkylacetamides (preferably dimethylacetamide), N,W-
dialkylforamides (preferably dimethylformamide),
dialkylsulfoxides (preferably dimethylsulfoxide), aromatic
hydrocarbons (preferably benzene or toluene), haloalkanes
(preferably dichloromethane) or alkyl alcohols (preferably
methyl alcohol or ethyl alcohol). The reactions may be
successfully run at temperatures ranging from room temperature
to the boiling point of the solvent employed. The progress of
the hydrolysis reaction is monitored by standard
chromatographic and spectroscopic methods known to one skilled
in the art of organic synthesis.
Alternately, the carboxylic acid may be cydized through
the intermediacy of the corresponding activated acid as taught
by Alder,. et al (Justus Liebigs Ann. Chem. 1950; 230 - 238)
Stiles and Libbey (J. Org. Chem 1957, 1243 - 1245) and Ladd,
et al. (J. Med. Chem. 1986 1904 -1912).
The ketone may be converted to the corresponding oxime.
The condensation reaction is carried out in the presence of a
hydroxylamine (of the general formula RONH2; where R = H, C1-
C4) with or without- a base in an inert solvent. Bases
include, but are not limited to, alkaline earth metal
carbonates, alkaline earth metal bicarbonates, alkaline earth
ms hydroxides, alkali metal hydrides (preferably sodium
hydride), alkali metal alkoxides (preferably sodium ethoxide
or sodium methoxide), trialkyl amines (preferably
diisopropylethylamine or triethylamine) or aromatic amines
(preferably pyridine). Inert solvents may include, but are
not limited to, acetonitrile, dialkyl ethers (preferably
diether ether), cyclic ethers (preferably tetrahydrofuran or
1,4-dioxane), N,N-dialkylacetamides (preferably
dimethylacetamide), N,N-dialkylforamides (preferably
dimethylformamide), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic Hydrocarbons (preferably benzene
or toluene), haloalkanes (preferably dichloromethane),. alkyl
alcohols (preferably methyl alcohol or ethyl alcohol), or
water. Preferred reaction temperatures range from room
temperature to the boiling point of the solvent employed. The
progress of the condensation reaction is monitored by standard
chromatographic and spectroscopic methods known to one skilled
in the art of organic synthesis.
Reduction of the corresponding oxime to the desired
amine proceeds in the presence of a reducing agent in an inert
solvent. Suitable reducing agents include, but are not
limited to, transition metals with or without hydrogen and
hydride donating agents. Transition metals that may or may
not be used catalytically with or without the addition of
hydrogen include, but are not limited to, Pd, Pt and Zn.
Hydride donating agents, include but are not limited to BH3,
NaBH4, LiBH4, NaCNBH3 and LiAlH4. Inert solvents may include,
but are not limited to, acetonitrile, dialkyl ethers
(preferably diether ether), cyclic ethers (preferably
tetrahydrofuran or 1,4-dioxane), N,N-dialkylacetamides
(preferably dimethylacetamide), N,N-dialkylforamides
(preferably dimethylformamide), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably benzene
or toluene), haloalkanes (preferably dichloromethane), alkyl
alcohols (preferably methyl alcohol or ethyl alcohol), or
water. Preferred reaction temperatures range from 0 QC to the
boili a point of the solvent employed. The progress of the
condensation reaction is monitored by standard chrocnatographic
and apectroacopic methods known to one skilled in the art of
organic synthesis.
One skilled in the art will appreciate, alternatively to
the indirect procedure described above, that the ketone may be
directly converted to the corresponding atnine directly via a
reductive amination as taught by Dei et al. (Bioorg. Med-
Chem. 2001, 2673-2682).
The resulting amines of general formula (2) may be
treated with a protected epoxide of general formula (3),
including, but not limited to, Boc protected epoxides, with or
without catalysis in an inert solvent. Catalysts include, but
are not limited to, salts or complexes of Yb, Sn, Ti, B and
Cu. Inert solvents may include, but are not limited to,
aeetonitrlle, dialkyl ethers (preferably diether ether),
cyclic ethera (preferably tetrahydrofuran or 1,4-dioxane),
N,N-dialkylacetamides (preferably dimethylacetamide), N,N-
dialkylforamides (preferably dimethylformamide),
dialkylsulfoxides (preferably dimethylsulfoxide), aromatic
hydrocarbons (preferably benzene or toluene), haloalkanes
(preferably dichloromethane), alkyl alcohols (preferably
isopropyl alcohol or tert-butyl alcohol). Preferred reaction
temperatures range from room temperature to the boiling point
of the solvent employed. The progress of the coupling
reaction is monitored by standard chromatographic and
spectroscopic methods known to one skilled in the art of
organic synthesis.
The resulting coupled products of general formula (4) may
be deprotected to yield the amine by treatment with acidic
additives in inert solvents. Acidic additives include, but
are not limited to, TFA., HC1, HBr, AcOH and trichloroacetic
acid- Inert solvents may include, but are not limited to,
acetonitrile, dialkyl ether3 (preferably diether ether),
cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane);
haIoalkanes (preferably dichloromethane), alkyl alcohols
(preferably isopropyl • alcohol or tert-butyl alcohol).
prefered reaction temperatures range from 0 oC to room
temperature. The progress of the deprotection reaction is
monitored by standard chromatographic and spectroscopic
methods known to one skilled in the art of organic synthesis.
The resulting amine may be treated with an acid to give
the final product of general formula (5). The transformation
may be effected utilizing an acid (or equivalent source) and a
coupling reagent with or without a base and in an inert
solvent. Coupling agents include, but are not limited to,
DCC, EDC, HBTU, HATU, CDI, and PyBOP. Bases include, but are
not limited to, alkaline earth metal carbonates, alkaline
earth metal bicarbonates, alkaline earth metal hydroxides,
alkali metal alkoxides (preferably sodium ethoxide or sodium
methoxide), trialkyl amines (preferably diisopropylethylamine
or triethylamine) or aromatic amines (preferably pyridine).
Inert solvents may include, but are not limited to,
acetonitrile, dialkyl ethers (preferably diether ether),
cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane),
N,N-dialkylacetamides (preferably dimethylacetamide), N,N-
dialkylforamides (preferably dimethylformamide),
dialkylsulfoxides (preferably dimethylsulfoxide), aromatic
hydrocarbons (preferably benzene or toluene), haloalkanes
(preferably dichloromethane), alkyl alcohols (preferably
methyl alcohol or ethyl alcohol), or water. Preferred
reaction temperatures range from 0 °C to room temperature. The
progress of the condensation reaction is monitored by standard
chromatographic. and spectroscopic methods known to one skilled
in the art of organic synthesis.
Alternately, the resulting amine may be treated with an
activated acylating agent to give the final product of general
formula (5). The transformation may be effected utilizing an
active acylating agent and with or without a base and in an
inert solvent. Active acylating agents include, but are not
limited to, acyl halides, acyl imidazoles, acyl anhydrides
(symmetrical and unsymmetrical) and acyl oximes. Bases
include, but are not limited to, alkaline earth metal
carbonates', alkaline earth metal bicarbonates, alkaline earth
metal hydroxides, alkali metal hydrides (preferably sodium
hydride), alkali metal alkoxides (preferably sodium ethoxide
or sodium methoxide), trialkyl amines (preferably
diisopropylethylamine or triethylamine) or aromatic amines
(preferably pyridine). Inert solvents may include, but are
not limited to, acetonitrile, dialkyl ethers (preferably
diether ether), cyclic ethers (preferably tetrcihydrofuran or
1,4-dioxane), N,N-dialkylacetamides (preferably
dimethylacetamide), N,N-dialkylforamides (preferably
dimethylformamide), dialkylsulfoxides (preferably
dimethylsulfoxide), aromatic hydrocarbons (preferably benzene
or toluene), haloalkanes (preferably dichloromethane), alkyl
alcohols (preferably methyl alcohol or ethyl alcohol), or
water. Preferred reaction temperatures range from 0 °C to room
temperature. The progress of the condensation reaction is
monitored by standard chromatographic and spectroscopic
methods known to one skilled in the art of organic synthesis.
Scheme VI
As described above and below, one aspect of the invention
provides for compounds of formula (11) as shown above. These
compounds may be made by methods known to those skilled in the
art from starting compounds that are also known to those
skilled in the art. The process chemistry is further well
known to those skilled in the art. A suitable process for the
preparation of compounds of formula (11) is set forth in
Scheme VI above.
Scheme VI illustrates the preparation of the desired
compounds using the readily obtainable 6-iodo-chroman-4-ol (6)
as a starting material (see Synthesis, 1997, 23-25). One
skilled in the art will recognize that there are several
methods for the conversion of the alcohol functionality to the
desired amino compounds of formula (7). In Scheme VI the
alcohol (6) is first activated with methane sulfonyl chloride
and the resulting mesylate displaced with sodium azide NaN3.
Alternative methods for the conversion of an alcohol to an
azide are well known to one skilled in the art. The resulting
azide is subsequently reduced using trimthylphosphine in a
mixture of THF and water. One skilled in the art will
recognize that there are several methods for the reduction of
an azide to the corresponding amine. For examples, see
Larock, R.C. in Comprehensive Organic Transformations, Wiley-
VCH Publishers, 1999. This reduction of the aside produces a
mixture of enantiomers of the amine (7). This enantiomeric
mixture can be separated by means known to those skilled in
the art such as low temperature recrystallization of a chiral
salt or by chiral preparative HPLC, most preferably by HPLC,
employing commercially available chiral columns.
The resulting amine (7) is used to open the epoxide (8)
to afford the protected (6-iodo-3,4-dihydro-2H-chromen-4-
yl)amino propyl carbamate (9). Suitable reaction conditions
for opening the epoxide (8) include running the reaction in a
wide range of common and inert solvents. C1-C6 alcohol solvents
are preferred and isopropyl alcohol most preferred. The
reactions can be run at temperatures ranging from 2 0-25 °C up
to the reflux temperature of the alcohol employed. The
preferred temperature range for conducting the reaction is
between 50°C and the refluxing temperature of the alcohol
employed.
The protected iodo-chromen (9) is deprotected to the
corresponding amine by means known to those skilled in the art
for removal of amine protecting groups. Suitable means for
removal of the amine protecting group depend on the nature of
the protecting group. Those skilled in the art, knowing the
nature of a specific protecting group, know which reagent is
preferable for its removal. For example, it is preferred to
remove the preferred protecting group, BOC, by dissolving the
protected iodo-chroman in a trifluoroacetic acid/
dichloromethane (l/l) mixture. When complete the solvents are
removed under reduced pressure to give the corresponding amine
(as the corresponding salt, i.e. trifluoroacetic acid salt)
which is used without further purification. However, if
desired, the amine can be purified further by means well known
to- those skilled in the art, such as for example
recrystallization. Further, if the non-salt form is desired
that also can be obtained by means known to those skilled in
the art, such as for example, preparing the free base amine
via treatment of the salt with mild basic conditions.
Additional BOC deprotection conditions and deprotection
conditions for other protecting groups can be found in T. W.
Green and P. G. M. Wuts in Protecting Groups in Organic
Chemistry, 3rd edition, John xWiley and Sons, 1999.
The amine is then reacted with an appropriately
substituted amide forming agent Z-(CO)-Y to produce coupled
amides (10) by nitrogen acylation means known to those skilled
in the art. Nitrogen acylation conditions for the reaction of
amine with an amide forming agent Z-(CO)-Y are known to those
skilled in the art and can be found in R.C. Larock in
Comprehensive Organic Transformations, VCH Publishers, 1989,
p. 981, 979, and 972. Y comprises -OH (carboxylic acid) or
halide (acyl halide), preferably chlorine, imidazole (acyl
imidazole), or a suitable group to produce a mixed anhydride.
The acylated iodo-chromen (10) is coupled with an
appropriately functionalzed organometallic R200M to afford
compounds of formula (11) using conditions known to those
skilled in the art. One skilled in the art will recognize
that there are several methods for coupling various alkyl and
aryl groups to an aromatic iodide. For examples, see L. S.
Hegedus Transition Metals in the Synthesis of Complex Organic
Molecules, University Science, 1999.
bcneme VII sees forth alternative routes to to 4
aminochromanes, which are useful for preparing compounds of
formula (11). Amines of formula (16) can be prepared by
coupling the appropriately functionalized organometallic to 6-
iodo-chroman-4-ol (12) or to the appropriately protected iodo-
amino chroman of the formula (14). Further elaboration of the
coupled products using methods known to one of skill in the
art, ultimately yields the desired amines of formula (16).
The chemistry from this point forward follows the
generalizations described in Scheme VIII for converting
compound 9 to 10.
Scheme VIII illustrates another general preparation of
amines of formula (9) that upon following the generalizations
outlined in Schemes VI and VII will result in compounds of the
formula (10). From this point forward, the chemistry is
essentially the same as described for Schemes VI and VII.
Scheme IX
Scheme IX illustrates the synthesis of various 5H-
thiopyranopyrimidinones from a variety of starting materials.
Suitable reaction conditions are described in, for example, J.
Heterocycl. Chem., 21(5), 1437-40; 1984.
One of ordinary skill will appreciate that treating the
sulfide with an oxidizing agent, such as parachlorobenzoic
acid (MCPBA) or oxone, generates the sulfoxide or the sulfone.
The oxidation of the sulfide can be done sequentially, i.e.,
generating and isolating the sulfoxide and then oxidizing it
to the sulfone, or the sulfone can be generated directly from
the sulfide. Further manipulations of the ketone are
described in the application.
It is also understood that the pyrimidyl ring can be
further substituted by means known in the art. For example,
the pyridyl ring can be alkylated, halogenated, acylated,
and/or nitrated. See Organic Transformations by Richard C.
LaRock. All references are herein incorporated by reference
in their entirety, for all purposes.
Scheme X
Scheme X illustrates the synthesis of various 1H-
thiopyranopyridinones. Suitable reaction conditions are
described in, for example, J. Chem. Soc., Perkin Trans. 1,
(7), 1501-5; 1984
One of ordinary skill will appreciate that treating the
sulfide with an oxidizing agent, such as parachlorobenzoic
i
acid (MCPBA) or oxone, generates the sulfoxide or the sulfone.
The oxidation of the sulfide can be done sequentially, i.e.,
generating and isolating the sulfoxide and then oxidizing it
to the sulfone, or the sulfone can be generated directly from
the sulfide. Further manipulations of the ketone are
described in the application.
It is also understood that the pyridyl ring can be
further substituted by means known in the art. For example,
by way of illustration, the pyridyl ring can be alkylated,
halogenated, acylated, and/or nitrated. See Organic
Transformations by Richard C. LaRock.
NOTE: 1) initially stirred with heating and then photochem..
Scheme XI illustrates the synthesis of various
thienothiopyranones from a variety of starting materials.
Suitable reaction conditions are described in, for example,
Journal of the Chemical Society, Perkin Transactions 1:
Organic
and Bio-Organic Chemistry, (18), 2639-2644; 1999.
One of ordinary skill will appreciate that treating the
sulfide with an oxidizing agent, such as parachlorobenzoic
acid (MCPBA) or oxone, generates the sulfoxide or the sulfone.
The oxidation of the sulfide can be done sequentially, i.e.,
generating and isolating the sulfoxide and then oxidizing it
to the sulfone, or the sulfone can be generated directly from
the sulfide. Further manipulations of the ketone are
described in the application.
It is also understood that the thieno ring can be further
substituted by means known in the art. For example, by way of
illustration, the thieno ring can be alkylated, halogenated,
acylated, and/or nitrated. See for example, Organic
Transformations by Richard C. LaRock.
Scheme XII illustrates a method for introducing
functionality into the. sulfur containing ring. Suitable
reaction conditions are described in, for example, U.S. Patent
No. 4734431.
One of ordinary skill will appreciate that treating the
sulfide with an oxidizing agent, such as parachlorobenzoic
acid (MCPBA) or oxone, generates the sulfoxide or the sulfone.
The oxidation of the sulfide can be done sequentially, i.e.,
generating and isolating the sulfoxide and then oxidizing it.
to the sulfone, or the sulfone can be generated directly from
the sulfide. Further manipulations of the ketone are
described in the application.
It is also understood that the pyrazole ring can be
further substituted by means known in the art. For example,
by way of illustration, the pyrazole ring can be alkylated,
halogenated, and/or acylated. See for example, Organic
Transformations by Richard C. LaRock.
Scheme XIII
Scheme XIII illustrates the preparation of isoxazole and
pyrazole containing bicyclic ring systems. Suitable reaction
conditions are described in, for example, J. Heterocycl.
Chenu, 21(5), 1437-40; 1984. One of skill in the art will
recognize that various reagents can be used to introduce
functionality into the above ring systems. For example,
substituted hydrazines are commercially available and can be
used to prepare substituted pyrazoles. Furthermore, standard
reactions such as alkylations and halogenations are known in
the art.
One of ordinary skill will appreciate that treating the
sulfide with an oxidizing agent, such as parachlorobenzoic
acid (MCPBA) or oxone, generates the sulfoxide or the sulfone.
The oxidation of the sulfide can be done sequentially, i.e.,
generating and isolating the sulfoxide and then oxidizing it
to the sulfone, or the sulfone can be generated directly from
the sulfide. Further manipulations of the ketone are
described in the application.
It is also understood that the pyrazole or isoxazole ring
can be further substituted by means known in the art. For
example, by way of illustration, the pyrazole and isoxazole
rings can be alkylated, halogenated, and/or acylated. See for
example, Organic Transformations by Richard C. LaRock.
Scheme XIV illustrates the formation of a furan
containing bicyclic ring system. Suitable reaction conditions
are described in, for example, J. Heterocycl. Chem., 13(2),
365-7; 1976
One of ordinary skill will appreciate that treating the
sulfide with an oxidizing agent, such as parachlorobenzoic
acid (MCPBA) or oxone, generates the sulfoxide or the sulfone.
The oxidation of the sulfide can be done sequentially, i.e.,
generating and isolating the sulfoxide and then oxidizing it
to the sulfone, or the sulfone can be generated directly from
the sulfide. Further manipulations of the ketone are
described in the application.
It is also understood that the furyl ring can be further
substituted by means known in the art. For example, by way of
illustration, the furyl ring can be alkylated, halogenated,
and/or acylated. See for example, Organic Transformations by
Richard C. LaRock.
Scheme XV
The compounds of the invention that comprise
tetrahydroquinoline moieties can be made by methods known in
the art. The following general scheme can also be useful for
tetrahydroquiniline compound synthesis.
Description of general synthetic scheme
Aniline TQ-1 is alkylated with a halide TQ-2B or acrylate
TQ-2A to give TQ-3. TQ-3 is then treated with a strong acid
or with a Lewis acid at temperatures ranging from 0 °C to 140
°C, preferably with phosphorus pentoxide and methanesulfonic
acid at 130 °C, to give ketone TQ-4. The nitrogen of TQ-4 is
then either protected with a protecting group, many of which
are listed in Protective Groups in Organic Synthesis, Greene
and Wuts, 3rd edition, 1999, Wiley-Interscience, or is
substituted with an alkyl group, an acyl group, or a sulfonyl
group, using methods well known to those versed in the art,
using R-Z, to give protected ketone TQ-5. An alternative
preparation of TQ-5 starts with TQ-4 where R' is hydrogen.
Halogenation with halogenating reagents such as N-
bromosuccinimide, N-iodosuccinirnide, dibromatin, and the like
gives TQ-4a where R' is preferably bromine or iodine.
Treatment of TQ-4a under cross coupling conditions such as
those described by Negishi (Tet. Lett. 1983, 3823), Huo (Org.
Lett. 2 003, 423) and reviewed by Knochel (Tetrahedron 1998,
8275) provides TQ-4b where R' is alkyl. Further treatment of
TQ-4b with R-Z as described above gives TQ-5.
Protected ketone TQ-5 is then converted to amine TQ-7 by
several methods, the choice of which may depend on the nature
of the R group. In the first method, TQ-5 is treated with a
hydroxyl amine in the presence of a base and a catalytic
amount of acid in solvents such as methanol, ethanol, butanol,
and the like, at temperatures ranging from room temperature to
the reflux temperature of the solvent, to give oxime TQ-6.
TQ-6 is then reduced to amine TQ-7 using a suitable catalyst,
preferably palladium, in solvents such as methanol, ethanol,
or ethyl acetate, under a blanket of hydrogen at pressures
ranging from atmospheric to 100 pounds per square inch.
Alternatively, protected ketone TQ-5 is reduced to alcohol TQ-
8 using reducing agents known to those well versed in the art,
preferably and depending on the nature of group R using sodium
borohydride in methanol or ethanol at temperatures ranging
from 0 to 100 °C. Alcohol TQ-8 is then converted to sulfonate
ester TQ-9 with reagents such as methanesulfonyl chloride or
toluenesulfonyl chloride using methods known to those well-
versed in the art. Displacement of the sulfonate ester with
azide using, for example, sodium azide in solvents such as
dichlorome thane and DMF at temperatures ranging from room
temperature to 120 °C, gives azide TQ-10. Azide TQ-10 is then
reduced to amine T-7 using, for example, trimethylphosphine in
solvents such as THF and the like at temperatures between 0 °C
to the reflux temperature of the solvent. Other methods of
reduction of the azide group are known; the choice of reducing
agent will depend on the nature of the R and R' groups and
will be known to those well versed in the art and can be found
in references such as Smith and March, March's Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure, 5th
ed., 2001, Wiley-Interscience. Amine TQ-7 is then stirred in
the presence of epoxide TQ-11 in preferably, but not limited
to, alcoholic solvents such as ethanol, isopropropyl, tert-
butyl, or n-butyl alcohol, at temperatures ranging from 50 °C
to the reflux temperature of the solvent, to give Boc-amine
TQ-12. Boc-amine TQ-12 is then treated with strong acid such
as trifluoroacetic acid in non-reactive solvents such as
dichloromethane or with dry HC1 in solvents such as dialkyl
ethers or alcoholic solvents at temperatures ranging from room
temperature to 8 0 °C to give/ after washing with base, triamine
TQ-13. Triamine TQ-13 is acylated by means well-known to
those versed in the art, for example condensation with a
carboxylic acid using coupling agents such as EDC, DCC, HATU,
or HBTU and the like. Preferred methods are acylation with
acyl imidazole or acetylation with N, N-diacetylmethoxyamine
to give TQ-14.
7-bromo-l-tetralone was prepared according to the
procedure described in Cornelius, L. A.M.; Combs, D. W.
Synthetic Communications 1994, 24, 2777-2788. The above
isomers were separated using silica gel flash chromatography
(Biotage Flash 75, elution solvent 20/1 hexanes:MTBE) to yield
5-bromo-l-tetralone (11.59 g, 51%) and 7-bromo-l-tetralone
(9.45 g, 42%).
Tetralin-1-ol compounds may be prepared as shown in
Example 2 below. Mores specifically, (R)-7-ethyltetralin-l-ol
was prepared in three steps starting from 7-ethyl-l-tetralone.
The first step involves an asymmetric reduction of the ketone
using borane and Corey's oxazaboralidine chiral auxilliary.
This reduction produced a 97:3 mixture of (presumably) R/S
enantiomers. A Mitsunobu-like Sn2 conversion to the azide and
LiAlH4 reduction to the amine produced material 98:2 S/R.
:
See generally: Jones, T. K. ; Mohan, J. J.; Xavier, L.
C; Blacklock, T. J.; Mathre, D. J.; Sohar, P.; Turner-Jones,
E. T.,- Reamer, R. A.; Roberts, F. E.; Grabowski, E. J. J. J.
Org. Chem. 1991, 56, 763-769. More particularly, 7-ethyl-l-
tetralone (2.29 g, 13.1 mmol) was placed in a 100 mL round
bottomed flask and dissolved in anhydrous THF (40 mL).
Activated 4a molecular sieves were added and the mixture was
aged for 2 h before transferring via cannula to a 250 ml
three-necked round bottom flask fitted with a dropping funnel,
thermometer, and a nitrogen inlet. The solution was cooled to
-25 °C and 1M (S)-tetrahydro-1-methyl-3,3-diphenyl-lH,3H-
pyrollo[1,2-c][1,3,2]oxazaborole in toluene (1.3 mL, 1.3 mmol)
was added. The source of the oxazoborole was Aldrich, cat.
no. 45,770-1, n(S)-2-methyl-CBS-oxazaborolidine". Use of the
S-auxilliary will produce R-alcohols. In accordance with the
forging references, the use of 5 mol% oxazaborolidine catalyst
should give comparable results.
The dropping funnel was charged with a solution of
borane-methylsulfide (0.70 g, 0.87 tnL, 9.3 mmol) in anhydrous
THF (15 mL, dried over 4A sieves). The borane solution was
added dropwise over 2 0 min keeping the reaction temperature
less than -20 °C. The mixture was stirred for 1 h at -15 to -
2 0 °C whereupon TLC analysis indicated consumption of the
ketone. The reaction was quenched by careful addition of
methanol (15 mL) at -2 0 °C and allowed to warm to ambient
temperature and stir for 16 h. The volatiles were removed in
vacuo and the residue was purified by silica gel
chromatography (Biotage Flash 65, elution solvent 6/1
hexanes:ethyl acetate) to yield (R)-7-ethyltetralin-l-ol (1.82
g, 79%). Analytical chiral HPLC indicated a 96.6/3.4 mixture
of enantiomers (Chirocel OD-H column, isocratic elution 2:98
IPA/hexane, 0.9 mL/min, RT 15.2 min (minor enantiomer), 17.5
min (major enantiomer).
See generally: Rover, 3.; Adam, G.; Cesura, A. M.;
Galley, G.; Jenck, F.; Monsma Jr., F. J.; Wichmann, J.;
Dautzenberg, F. M. J. Med. Chew. 2000, 43, 1329-1338. The
authors therein report a somewhat diminished yield due to
partial formation of a dihydronapthalene via elimination of
the hydroxyl moiety.
More specifically, a solution of (R)-7-ethyltetralin-l-ol
(1.77 g, 10.1 mmol) in toluene (25 mL) was cooled in an ice
bath and treated with diphenylphosphorylazide (DPPA, 3.3 g,
2.7 mL, 12 mmol). A solution of 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU, 1.8 g, 1.8 mL, 12 mmol) in toluene (8 mL) was
added over 2 0 min and the mixture was allowed to stir at 0 °C
for 2 h and ambient temp for 16 h. The mixture was filtered
through a pad of silica gel (eluted 6:1 hexanes/ethyl acetate)
to remove precipitates and the volatiles were removed in vacuo
to give an oily residue of the crude S-azide. This material
was used directly in the next step without further
characterization.
The azide was dissolved in dry THF (2 0 mL) and added
dropwise at RT to a slurry of lithium aluminum hydride (0.459
g, 12 mmol) in dry THF (2 0 mL). The mixture was stirred at RT
for Ih and then heated to reflux for 1 h. The reaction was
cooled to RT and quenched by successive addition of water
(0.45 mL), 15% aq NaOH (0.45 mL) and water (1.4 mL). The
resulting mixture was stirred for 1 h and then filtered
through a pad of Celite (eluted diethyl ether). The volatiles
were removed in vacuo and the residue taken up into ethyl
acetate (40 mL) and treated with 4N HC1 in dioxane (3 mL).
The resulting precipitate was filtered (wash ethyl acetate),
collected and vacuum dried to give (S)-7-ethyl-l,2,3,4-
tetrahydro-1-napthylamine hydrochloride as a white solid (1.09
g, 51%). Analytical chiral HPLC indicated a 96:4 mixture of
enantiomers (Daicel Crownpak (-) column, isocratic elution 10%
methanol in water (0.1% TFA), 0.8 mL/min, RT 56.2 min (minor
enantiomer), 78.2 min (major enantiomer).
Scheme VIII below depicts formation of a tetralinol,
prepared in three steps starting from 7-bromo-l-tetralone.
The first step involves an asymmetric reduction of the ketone
using borane and Corey's oxazaboralidine chiral auxilliary.
This reduction produced a 98:2 mixture of (presumably) R/S
enantiomers. A Mitsunobu-like Sn2 conversion to the azide and
LiA.u. reduction to the amine produced material 96:4 S/R.
The reduction is performed using the general procedure
described in example 2. Analytical chiral HPLC of the product
indicated a 98:2 mixture of enantiomers (Chirocel OD-H column,
isocratic elution 2:98 IPA/hexane, 0.9 mL/min, RT 18.4 min
(minor enantiomer), 19.5 min (major enantiomer). Proton NMR
was consistent with that previously reported for the
racemate: Saito, M.; Kayama, Y.; Watanabe, T.; Fukushima, H.;
Hara, T. J. Med. Chem. 1980, 23, 1364-1372.
The above compound is prepared essentially according to
the procedure described in Example 3. The final compound is
obtained as a white solid. Analytical chiral HPLC indicated a
96:4 mixture of enantiomers (Daicel Crownpak (-) column,
isocratic elution 10% methanol in water (0.1% TFA), 0.8
mL/min, RT 3 9.4 min (minor enantiomer), 57.6 min (major
enantiomer).
Example 6: Preparation of Precursor Substituted Amines
Precursore amines can generally be prepared as shown
above. Specific examples are described below.
Example 7: Preparation of 3-Ethylbenzaldehyde from 3-
bromobenzaldehyde
3-Bromobenzaldehyde (Aldrich, 1.17 mL, 10.0 mmol) was
dissolved in THF (20 mL) at rt. To it was added
PdCl2 (dppf)•CH2Cl2 complex (Aldrich, 82 mg, 0.10 mmol), 2 M
potassium phosphate (aq, 10 mL, 20 mmol), and triethylborane
(Aldrich, 1.0 M solution in hexanes, 10 mL, 10 mmol). This was
heated to reflux for 4 h, whereupon the mixture was allowed to
cool to rt. The reaction mixture was partitioned between EtOAc
and water. The organic layer was separated, dried (MgSO4), and
concentrated under reduced pressure. The residue was purified
by flash chromatography (2 0% EtOAc/hexanes eluticn) to give a
clear, colorless oil which was used without further
purification: mass spec (CI) 135.1.
Example 8: Preparation of 3-Ethyl-cc-propylbenzyl alcohol from
3-ethylbenzaldehyde
To a solution of 3-ethylbenzaldehyde (641 mg, 4.78 mmol)
in THF (15 mL) cooled to 0 °C was added a solution of
propylmagnesium chloride (Aldrich, 2.0 M in diethyl ether, 7.0
mL, 14.0 mmol) dropwise with stirring. Upon completion of
addition, the reaction mixture was allowed to warm to rt for 2
h. Reaction was then quenched by addition of water (1 mL),
then concentrated under reduced pressure. The residue was
purified by flash chromatography (Rf = 0.71 in 30%
EtOAc/hexanes) to give a colorless oil as product (804 mg,
94%): mass spec (CI) 161.1 (M-OH).
Example 9: Preparatoin of 3-Ethyl-cc-propylbenzyl azide from 3-
ethyl-a-propylbenzyl alcohol
3-Ethyl-a-propylbenzyl alcohol (803 mg, 4.51 mmol) was
dissolved in THF (10 mL), and cooled to 0 °C.
Triphenylphosphine (Aldrich, 1.416 g, 5.40 mmol), diethyl
azodicarboxylate (Aldrich, 0.85 mL, 5.40 mmol), and diphenyl
phosphoryl azide (1.16 mL, 5.38 mmol) was added in succession
by syringe. This was stirred at 0 °C for 1 M h, then at rt for
2 h, whereupon the reaction mixture was concentrated under
reduced pressure. The residue was purified by flash
chromatography (EtOAc/hexanes elution) to give a clear,
colorless oil as product: XH NMR (300 MHz) 5 7.35-7.25 (m, 1H),
7.20-7.05 (m, 2H), 4.39 (t, J = 7.2 Hz, 1H), 2.67 (g, J = 7.6
Hz, 2H), 1.95-1.60 (m, 2H), 1.52-1.25 (m, 2H), 1.25 (t, J" =
7.6 Hz/ 3H), 0.93 (t, J = 7.3 Hz, 3H).
Example 10: Preparation of 3-Ethyl-a-propylbenzyl amine from
3-ethyl-a-propylbenzyl azide
3-Ethyl-a-propylbenzyl azide (724 mg, 3.57 mrnol) in dry
THF (10 mL) was added to a suspension of lithium aluminum
hydride (2 8 0 mg, 7.3 8 mmol) in THF (10 mL) at 0 °C. This was
stirred at 0 °C for 30 min, then at rt for 1 h, whereupon the
reaction was quenched using water (0.2 mL), 15% aq. NaOH (0.2
mL), and water (0.6 mL) in succession. This was stirred at rt
for 1 h. The reaction mixture was then filtered through
diatomaceous earth (CH2C12 elution), and the filtrate
concentrated under reduced pressure. This material was used in
subsequent reactions without further purification: XH NMR (300
MHz) S 7.35-7.20 (m, 1H), 7.20-7.04 (m, 2H), 3.87 (t, J= 6.9
Hz, 1H), 2.65 (q, J = 7.6 Hz, 2H), 1.72-1.57 (m, 2H), 1.50-
1.20 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H), 0.91 (t, J = 7.3 Hz,
3H) ; mass spec (CI) 161.1 (M-NH2).
Magnesium turnings (1.35g, 55.53mmol) were activated via
vigorous stirring overnight under N2 (g) inlet. A few crystals
of iodine were added to the flask, which was then flamed-dried
under vacuum. Anhydrous THF (3 mL) was added to the reaction
flask followed by l-bromo-3-ethylbenzene (Avocado, 2.0mL, 14.59
mmol). The reaction was initiated after briefly heating with a
heat gun. To this was added the remainder of l-bromo-3-
ethylbenzene (1.7mL, 12.43mmol) in a THF solution (15mL). The
reaction mixture was refluxed for 2h. A cyclohexanone (2.2mL,
21.22mmol) in THF (8mL) solution was added once the flask was
cooled to 0°C. After 3. 5h the reaction mixture was quenched
with H2O over an ice bath and partitioned between Et2O and H2O.
The organic layer was removed and acidified with IN HC1. The
organic layer was separated, dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by flash
chromatography (100% CHCl3) to give the desired alcohol
(4.152g, 96%): mass spec (CI) 187.1 (M-16).
Example 12: Preparatoin of 1-(1-Azido-cyclohexyl)-3-ethyl-
benzene from 1-(3-Ethyl-phenyl)-cyclohexanol
1-(3-Ethyl-phenyl)-cyclohexanol (4.02g, 19.68mmol) in
anhydrous chloroform (45mL) was cooled to 0°C under N2 (g) '
inlet. Sodium azide (3.97g, 61.07mmol) was added followed by
dropwise addition of trifluoroacetic acid (7.8mL, 101.25mmol).
The reaction mixture was refluxed for 2h and allowed to stir
at rt o/n. This was then partitioned between H2O and Et2O. The
aqueous layer was removed and the mixture was washed with H20
followed by 1.ON NH4OH. The organic layer was separated, dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was used without further purification (3.30g, 73%):
mass spec (CI) 187.1 (M-42).
The above compound is prepared essentially according to
the procedure described in Example 10. The final compound is
used without further purification: mass spec (CI) 187.1 (M-
16).
Example 14: Preparation of N-{(IS,2R)-1-(3,5-difluorobenzyl)-
3- [ (2-ethyl-7-fluoro-9H-fluoren-9-yl)amino]-2-
hydroxypropyl}acetamide.
Step 1: To 3.0 g (16.6 mmol) of methyl 5-ethyl-2-
hydroxybenzoate in 100 mL of CH2Cl2 at 0 °C was added 5.8 mL
(41.5 mmol, 2.5 eq.) of Et3N. To this stirred solution was
added dropwise 3.6 mL (21.6 mmol, 1.3 eq.) of Tf2O. Following
complete addition 0.2 g (cat.) of 4-dimethylamino pyridine was
added and the reaction mixture was allowed to warm to room
temperature. After 4 h stirring at this temperature the
reaction was judged complete, and quenched by the addition of
a saturated aqueous solution of NaHCO3 (100 mL). The resulting
layers were separated and the aqueous layer extracted twice
with CH2C12 (100 mL). The combined organic layers were dried
over MgSO4, filtered and concencrated under reduced pressure.
The resulting residue was purified by column chromatography to
yield the desired methyl 5-ethyl-2-
{[(trifluoromethyl)sulfonyl]oxy}benzoate. 1H NMR (400 MHz,
CDCl3) : d = 7.94 (d, J = 2.3 Hz, 1H), 7.47 (dd, J =2.3, 8.4
Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 4.00 (s, 3 H), 2.76 (q, J
= 1.6 Hz, 2 H), 1.28 (t, J = 7.6 Hz, 3 H).
Step 2: To 1.5 g (4.8 mmol) of product from Step 1 in
12.5 mL of toluene at room temperature was added 0.2 8 g (0.24
mmol, 0.05 eq.) of Pd(PPh3)4. After stirring for 5 min, 1.1 g
(5.7 mmol, 1.2 eq.) of 4-fluorophenylboronic acid in 5.5 mL of
EtOH followed by 11.5 mL of 2 M aqueous Na2CO3 were added.
After heating at 90 °C for 12 h the reaction was judged
complete, cooled and diluted with Et2O (100 mL) and water (50
mL). The resulting layers were separated and the aqueous
layer extracted twice with Et2O (100 mL). The combined organic
layers are dried over MgSO4, filtered and concentrated under
reduced pressure. The resulting residue was purified by
column chromatography to yield the desired methyl 4-ethyl-4'-
f luoro-1,1'-biphenyl-2-carboxyiate. C16H15O2F+ H+ requires 258
found 2 58..
Step 3: To 1.1 g (4.3 mmol) of the product from Step 2 in
50 mL of 2:2:1 THF:water:MeOH was added 0.9 g (21 mmol) of
LiOH. The mixture was heated to 55 °C for 5 h at which point
the reaction was judged complete. Upon cooling the volatiles
were removed under reduced pressure and the residue portioned
between 10% aqueous HCl (50 mL) and EtOAc (200 mL). The
resulting layers were separated and the aqueous layer
extracted twice with EtOAc (100 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated. The
resulting residue, 4-ethyl-4'-fluoro-1,1'-biphenyl-2-
carboxylic acid, was pure enough to use directly in the next
step. C1SH13F1O2 + H+ requires 244, found 244.
Step 4: To 0.25 g (1 mmol) of product from Step 3 was
added 1 mL of H2SO4 and the resulting mixture was heated to 110
°C for 20 min after which time the reaction was judged
complete. Upon cooling, the mixture was poured onto ice water
(100 mL) and extracted twice with Et2O (200 mL). The combined
organic extracts were washed twice with a saturated aqueous
solution of NaHCO3 (10 0 mL), dried over MgSO4, and concentrated
under reduced pressure. The resulting residue, 2-ethyl-7-
fluoro-9H-fluoren-9-one, was pure enough to use directly in
the next step. C15H11F1O1 + H+ requires 226, found 226.
Step 5: To 0.8 g (3.6 mmol) of the product from Step 4
was added 10 mL of EtOH and 3.2 mL of pyridine. To this
stirred solution was added 1.0 g (14.6 mmol, 4 eq.) of
NH2OH-HC1 and the mixture heated to 65 °C for 6 h sifter which
time the reaction was judged complete. Upon cooling, the
volatiles were removed under reduced pressure and the residue
portioned between 10 % aqueous HC1 (50 mL) and EtOAc (250 mL).
The resulting layers were separated and the organic layers
washed twice more with 10 % aqueous HC1 (50 mL). The organic
layer was dried over MgS04, filtered and concentrated under
reduced pressure. The resulting residue, (9Z)-2-ethyl-7-
fluoro-9H-fluoren-9-one oxime, was pure enough to use directly
in the next step. Cl5H12F1O1N1 + H+ requires 242, found 242.
Step 6: To 0.8 g (3.3 mmol) of the product from Step 5
was added 3 mL of AcOH, 0.1 mL of water and 0.7 g (9.9 mmol, 3
eq.) of Zn. The resulting mixture was vigorously stirred for
2 0 min after which time the reaction was judged complete.
After filtration to remove the solids the volatiles were
removed under reduced pressure. The resulting residue was
portioned between EtOAc (200 mL) and 10% aqueous KOH (100 mL).
The resulting layers were separated and the organic layer
washed once more with 10 % aqueous KOH (50 mL). The organic
layer was dried over Na2S04, filtered and concentrated under
reduced pressure. The resulting residue 2-ethyl-7-fluoro-9H-
fluoren-9-aminewas pure enough to use directly in the next
step. C15H14F1N1 + H+ requires 227, found 211 (-NH3)
Step 7: To 0.45 g. (2.0 mmol) of the product of Step 6 was
added 6 mL of isopropyl alcohol and 0.5 5 g (1.8 mmol, 0.9 eq.)
of Example 134. The mixture was heated at 65 °C for 12 h
after which time the reaction was judged complete. Upon
cooling, the volatiles were removed under reduced pressure.
The resulting residue was purified by column chromatography to
yield the desired tert-butyl (IS,2R)-1-(3,5-difluorobenzyl)-3-
[(2-ethyl-7-fluoro-9H-fluoren-9-yl)amino]-2-
hydroxypropylcarbamate. C30H33F3N2O3 + H+ requires 52 7, found
527.
Steps 8&9: To 0.1 g (0.19 mmol) of product from Step 7
was added 3 mL of CH2C12 and 0.5 mL (excess) of TFA. The
resulting mixture was stirred for 1 h at room temperature
after which time the reaction was judged complete. The
reaction mixture was diluted with toluene (2 mL) and the
volatiles were removed under reduced pressure. After drying
under high vacuum for 1 h, the residue was dissolved in 5 mL
of CH2C12 and 0.061 mL (0.4 mmol, 2.2 eq.) of Et3N followed by
0.02 g (0.2 mmol, 1.05 eq.) of acetyl-imidazole were added.
After stirring for 12 h at room temperature the reaction was
judged complete and poured in a saturated aqueous solution of
NaHCO3 (10 mL). The resulting layers were separated and the
aqueous layer extracted once with EtOAc (50 mL). The combined
organic layers were dried over Na2SO4, filtered and
concentrated under reduced pressure. The resulting residue
was purified by column chromatography to yield the desired N-
{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-7-fluoro-9H-
fluoren-9-yl)amino]-2-hydroxypropyl}acetamide. C27H27F3N2O2 + H+
requires 4 69, found 4 69.
Example 15: Preparation of N-( (IS,2R)-1-(3,5-difluorobenzyl)-
3-{t(4S)-6-ethyl-3,4-dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide
Step 1 Preparation of 6-Iodo-chroman-4-ylamine
To a CH2C12 (80 ml) solution of 6-iodo-4-chromanol (10.0
g, 36 mmol) and diisopropylethyl amine (19 ml, 108 mmol), at
0°C, was added the MsCl (4.2 ml, 54 mmol). After stirring for
1.5 h the solvent was removed in vacuo and the resulting
residue dissolved in 150 ml of DMF followed by the addition of
Na N3 (3.5 g, 54 mmol). The reaction was heated to 70°C for
6.5 h then cooled to rt. followed by the addition of 900 ml Of
1 N HCl and extraction with Et2O (4 x 200 ml). The combined
Et2O layers were dried over MgSO4 and concentrated in vacuo to
yield 9.5 g of the azide as yellow oil. MS (ESI+) for C9H8IN3O
m/z 300.97 (M+H)+. The crude azide (5.0 g, 16.6 mmol) was
dissolved in THF (50 ml) and treated with PPh3 (5.2 g, 20.0
mmol). The mixture stirred at rt. for 3 0 min. followed by the
addition of 4 ml of H2O. The mixture was then heated to 6 0°C
overnight. After cooling the mixture was concentrated in
vacuo and the resulting residue treated with 1 N HCl. The
aqueous layer was washed with CH2C12 and then adjusted to pH =
12 with NaOH pellets. The basic aqueous layer was extracted
with CH2C12 and the combined organic layers dried over Na2S04
and treated with activated carbon. The mixture was filtered
through Celite® and concentrated in vacuo to yield 6-Iodo-
chroman-4-ylamine 3.6 g (79%) as clear oil that solidifies
upon standing. MS (ESI+) for C9H10INO m/z 275.98 (M+H)+.
Step 2 Preparation of tert-butyl (IS,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3- [(6-iodo-3, 4-dihydro-2H-
chromen-4-yl)amino]propylcarbamate
An isopropyl alcohol (25 ml) solution of Example 134 (2.2
g, 7.2 mmol) and 6-Iodo-chroman-4-ylamine (3.0 g, 10.9 mitral)
was stirred at 75°C for 0 h. The IPA was removed in vacuo and
the resulting residue dissolved in EtOAc (200 ml). The
organic layer was washed with 1 N HCl (4 x 50 ml), followed by
NaHCO3 (2 x 50 ml), and brine (1 x 50 ml). The organic layer
was dried over Na2SO4 and concentrated in vacuo to yield 3.5 g
(85%) of the title compound as a mixture of diastereomers as
an off white solid. MS (ESI + ) for C24H29F2IN2O4 m/z 574.8
(M+H)+.
Step 3 Preparation of N-{(IS,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-[(6-iodo-3,4-dihydro-2H-chromen-4-
yl)amino]propyl}acetamide
Tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
[(6-iodo-3,4-dihydro-2H-chromen-4-yl)aminojpropylcarbamate
(3.0 g, 5.2 mmol) was dissolved in 30 mL of 25% TFA/CH2C12 and
stirred at room temperature for 3 0 min. The mixture was
diluted with CH2Cl2 50 mL and washed with NaHCO3 (2 x 30 mL).
The organic layer was washed with brine (1 x 50 mL) and dried
over Na2SO4. The solvent was removed in vacuo and the
resulting residue dissolved in 52 mL of CH2C12. The mixture
was chilled to 0°C followed by the addition of Et3N (1. mL,
11.9 mmol) and acetyl imidazole (0.68 g, 6.2 mmol). The
mixture was warm spontaneously over night. The CH2Cl2 was
removed in vacuo and the residue dissolved in EtOAc (100 mL)
and washed with IN HCl (2 x 30 mL), NaHCO3 (1 x 30 mL), brine,
dried over Na2SO4, and cone, in vacuo to yield 2.5 g (92%) of
the title compound as a light yellow solid. MS (ESI+) for
C21H23F2IN2O3 m/z 517.0 (M+H)+.
Step 4 Preparation N-((IS,2R)-1-(3,5-difluorobenzyl)-3-
{[(4S)-6-ethyl-3,4-dihydro~2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-
3,4-dihydro-2H-chromen-4-yl)aminolpropyl}acetamide (1.0 g, 1.9
mmol) and Pd(dppf)Cl2 (0.078 g, 0.1 mmol) was dissolved in 20
mL of degassed THF. To the mixture was added 10 mL of 2.0 M
K3PO4 followed by the addition of Et3B (3.8 mL, 3.8 mmol, 1.0 M
in THF) via syringe. The reaction mixture was heated to 65°C
under a nitrogen atmosphere. After 2.5 h the reaction was
determined to be complete and diluted with EtOAc (10 0 mL) and
washed with brine (3 x 3 0 mL). The organic layer was dried
over Na2SO4 and conc. in vacuo to yield brown solid. The
diastereomers of the title compound were separated by
preparative chiral HPLC (Chiralpak AD, 20% IPA/8 0%heptane,
0.1% DEA). MS (ESI + ) for C23H26F2N2O3 m/z 419 (M+H)+.
The following compounds are prepared essentially
according to the procedures described in the schemes and
preparations set forth above:
To 0.9 g (4 mmole) of sulfone ketone in 40 ml of THF is
added 2.5. ml (5 mmole, 1.2 5 eq.) of 2 M of Lithium
diisopropylamine(LDA) in heptane/THF/ ethylbenzene at -60 °C.
The mixture is stirred for about 15 minutes, and then 1.24 ml
(20 mmole, 5 eq. ) of methyl iodide is added. The reaction
mixture is stirred f or. 1 hour at -60 °C, and then the cold bath
is removed. After stirring overnight, the reaction mixture is
partitioned between EtOAc and water, washed with 0.5N HCl,
aqueous sodium bicarbonate solution, and brine, dried over
anhydrous sodium sulfate, filtered and concentrated. The
concentrate was purified by column chromatography to afford 0.68
g of the desired product as an oil, which solidified upon
standing. TLC (30%EtOAc/Hexane, Rf=0.39). Mass spec, m/e =
239.1.
The following compounds were prepared essentially
according to the procedures described above:
Step One: Chroman-4-ol.
To a MeOH (250 ml) solution of 4-chromanone (16.6 g, 11
mmol), at 0°C, was added MaBH4 (5.5 g, 145 mmol) in 1 g
portions over a 30 min. period. After complete addition the
mixture was stirred for 1 h with spontaneous warming. The
reaction was quenched with the slow addition of aq. NH4C1 (100
ml). The MeOH was removed in vacuo and the residue extracted
with Et2O (2 x 100 ml). The organic layers were dried over
MgSO4 and treated with activated carbon. After filtration the
Et2O was removed in vacuo to yield 15.8 g of chroman-4-ol as a
clear oil. HRMS (ESI + ) calcd for C9H10O2 m/z 150.0681 (M+H)+.
Found 150.0679.
To a CH2C12 (80 ml) solution of chroman-4-ol (3.1 g,
20.6 mmol) and DIEA (8 ml, 42 mmol), at 0°C/ was added the MsCl
(2.1 ml, 27 mmol) via syringe. After complete addition the
cold bath was removed and stirring continued at room
temperature. After 15 h the CH2Cl2 was removed in vacuo and
the residue dissolved in 8 0 ml of DMF followed by the addition
of NaN3 (1.8 g, 27 mmol). The mixture was heated to 75°C (oil
bath) for 5h then cooled to room temperature. The mixture was
diluted with Et2O (400 ml) and washed with 1 N HCl (2 x 100
ml); NaHCO3 (2 x 100 ml) and brine (100 ml). The organic layer
was dried over Na2SO4 and concentrated in vacuo to yield the
azide as a yellow oil. 1H NMR (400 MHz, CDC13) 5 7.27-7.21 (m,
2 H), 6.97-6.87 (m, 2 H), 4.61 (appt, J = 3.84 Hz, 1 H), 4.31-
4.19 (m, 2 H), 2.18 (m, 1 H), 2.03 (m, 1 H). MS (ESI-) for
C9H10N3O m/z 173.0 (M-H)". The crude azide was dissolved in 60
ml of THF followed by the addition of PPh3 (6.5 g, 25 mmol) and
the mixture stirred at room temperature for 3 0 min. The
mixture was treated with 8 ml of H2O and heated to 60°C (oil
bath) overnight. The mixture was concentrated in vacuo and
the resulting residue treated with 1 N HCl. The aqueous
mixture was extracted with CH2C12 then the pH was adjusted to
12 with NaOH and re-extracted with CH2C12. The second CH2Cl2
layers were combined; dried over Na2SO4 and concentrated in
vacuo to yield 3,4-dihydro-2H-chromen-4-ylamine as a slightly
yellow oil. HRMS (ESI+) calcd for C9H11N0 m/z 150.0919 (M+H)+.
Found 150.0920.
Step Three: tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-3-
(3,4-dihydro-2H-chromen-4-ylamino)-2-
hydroxypropylcarbamate.
An IPA (15 ml) solution of Example 134 (0.54 g, 1.8 mmol)
and 3,4-dihydro-2H-chromen-4-ylamine (0.40 g, 2.6 mmol) was
heated at 60°C (oil bath) with stirring overnight. The IPA was
removed in vacuo and the residue dissolved in EtOAc and washed
with 1 N HCl. The organic layer was dried over MgSO4 and
concentrated in vacuo to yield 0.75 g of the desired product
as a mixture of epimers. HRMS (ESI + ) calcd for C24H30N2O4F2 m/z
449.2252 (M+H)+. Found 449.2258.
Step Four: N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(3,4-
dihydro-2H-chromen-4-ylamino)-2-
hydroxypropyl]acetamide.
The above compound, which is obtained as a clear glass,
is prepared essentially according to the procedure described
in Example 15, step 3. Preparative reverse phase HPLC yields
two fractions:
1H NMR (400 MHz, CDCl3) d 7.29 (m, 1 H), 7.20 (m, 1 H),
6.92 (m, 1 H), 6.85 (dd, J = 6.85, 0.93 Hz, 1 H), 6.79-6.67
(m, 3 H), 5.69 (d, J = 8.91 Hz, 1 H), 4.35-4.23 (m, 2 H), 4.15
(m, 1 H), 3.87 (m, 1 H), 3.58 (m, 1 H), 3.03 (m, 1 H), 2.91-
2.75 (m, 3 H), 2.15-2.08 (m, 1 H), 2.04-1.99 (m, 1H), 1.94 (s,
3 H). MS (ESI + ) for C21H24F2N3O3 m/z 391.3 (M+H) 1H NMR (400 MHz, CDCl3) d 7.31 (m, 1 H), 7.21 (m, 1 H),
6.93 (m, 1 H), 6.86 (dd, J = 8.29, 1.04 Hz, 1 H), 6.79-6.67
(m, 3 H), '5.69 (d, J = 8.91 Hz, 1 H), 4.36-4.24 (m, 2 H), 4.17
(m, 1 H), 3.87 (appt, J = 4.04 Hz, 1 H), 3.54 (m, 1 H), 3.03
(dd, J = 14.31, 4.56 Hz, 1 H), 2.95 (m, 1 H), 2.88-2.79 (m, 2
H), 2.16-2.00 (m, 2 H), 1.92 (s, 3 H). MS (ESI+) for
C21H24F2N3O3 m/z 391.3 (M+H)Example 18: N-((IS,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-
ethyl-3,4-dihydro-2H-chromen-4-yl] amino}-2-
hydroxypropyl)acetamide:
Step One: 6-iodochroman-4-olTo a solution of chroman-4-ol
(19.6g, 131 mmol) in CH2Cl2 (500 mL), at rt., was added HgO
(29.7g, 137 mmol) and I2 (34.8g, 137 mmol) under N2. After
stirring for 48 h. the mixture was filtered through a plug of
silica gel and the plug washed plug with 3 0% EtOAc/Hexanes.
The filtrate was washed with 15% Na2S2O3 and the organic layer
was dried over Na2CO3; filtered and concentrated in vacuo,
yielding 6-iodochroman-4-ol as an off-white solid (32.44g, 90%
crude yield). Recrystallization was performed by dissolving
product in hot dichloromethane (250 mL) and slowly adding
petroleum ether (250 mL). Overall yield 25.9g, 72% yield.
Anal. Calcd for C9H9IO2; C, 39.16, H, 3.29; found C, 39.26, H,
3.27.
Step Two: 6-Iodo-chroman-4-ylamine.
The above compound is prepared essentially according to
the procedure described in Example 17, step 2. The above
compound is obtained as a clear oil that solidifies upon
standing. HRMS (ESI+) calcd for C9H10INO m/z 275.98B7 (M+H)+.
Found 275.9893.
Step Three: tert-butyl (IS,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-t(6-iodo-3,4-dihydro-2H-chromen-4-
yl)amino]propylcarbamate
The above compound is prepared essentially according to
the procedure described in Example 15, step 2; it is obtained
as a mixture of diastereomers, which is used without
purification.. MS (ESI+) for C24H29F2IN2O4 m/z 574.8 (M+H)+.
Step Four: N-{(IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
iodo-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide
The title compound is obtained from the propylcarbamate,
essentially according to the methods described herein, as a
light yellow solid. MS (ESI + ) for C21H23F2IN2O3 m/z 517.0
(M+H)+. Chiral preparative HPLC (20% IPA/Heptane, 0.1% DEA)
yields the two diastereomers.
N- ( (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
iodo-3, 4-dihydro-2H-chromen-4-yl] aminojpropyl) acetaraide 1H NMR
(400 MHz, DMSO-ds) d 7.73 (d, J = 9.12 Hz, 1 H), 7.62 (d, J =
2.07 Hz, 1 H), 7.40 (dd, J = 8.50, 2.28 Hz, 1 H), 7.01 (m, 1
H), 6.89 (m, 2 H), 6.58 (d, J = 8.50 Hz, 1 H), 4.97 (d, J =
6.01 Hz, 1 H), 4.23 (m, 1 H), 4.14 (m, 1 H), 3.93 (m, 1 H),
3.68 (m, 1 H), 3.47 (m, 1 H), 3.01 (dd, J = 13.89, 3.32 Hz, 1
H), 2.61 (m, 2 H), 1.90 (m, 2 H), 1.71 (s, 3 H).
N-((IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4R)-6-
iodo-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide 1H NMR
(400 MHz, DMSO-d6) d 7.75 (d, J = 9.33 Hz, 1 H), 7.64 (d, J =
2.07 Hz, 1 H), 7.41 (dd, J = 8.60, 2.18 Hz, 1 H), 7.02 (m, 1
H), 6.92 (m, 2 H), 6.59 (d, J = 8.50 Hz, i H), 4.96 (d, J =
5.80 Hz, 1 H), 4.22 (m, 1 H), 4.15 (m, 1 H), 3.95 (m, 1 H),
3.68 (m, 1 H), 3.45 (m, 1 H)., 2.98 (dd, J = 13.99, 2.80 Hz, 1
H), 2.73 (m, 1 H), 2.63-2.57 (m, 1 H), 1.87 (m, 2 H), 1.70 (s,
3 H).
Step Five: N-( (IS,2R)-1-(3,5-difluorobenzyl)-3-([6-ethyl-3,4-
dihydro-2H-chromen-4-yl]amino}-2-hydroxypropyl)acetamide
N-{ (1S,2R) -1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-
3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide (1.0 g, 1.9
mmol) and Pd(dppf)Cl2 (0.078 g, 0.1 mmol) was dissolved in 20
mL of degassed THF. To the mixture was added 10 nL of 2.0 M
K3PO4 followed by the addition of Et3B (3.8 mL, 3.8 mmol, 1.0 M
in THF) via syringe. The reaction mixture was heated to 65°C
under a nitrogen atmosphere. After 2.5 h the reaction was
determined to be complete and diluted with EtOAc (100 mL) and
washed with brine (3x 30 mL). The organic layer was dried
over Na2SO4 and cone. in vacuo to yield brown solid. The
diastereomers of N-((IS,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-
ethyl-3,4-dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide were separated by preparative chiral
HPLC (Chiralpak AD, 20% IPA/8 0%heptane, 0.1% DEA). MS (ESI + )
for C23H26F2N2O3 m/z 419 (M+H)+.
To a MTBE (20 ml), CH2Cl2 (5 ml), MeOH (0.5 ml) solution
of N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-ethyl-3,4-
dihydro-2H-chromen-4-yl]amino}-2-hydroxypropyl)acetamide (0.2
g, 0.5 mmol) was added IN HC1 in Et2O (0.38 ml) and the mixture
stirred at room temperature. The final white solid was
isolated by removing the solvent and tritration with Et2O.
HRMS (ESI + ) calcd for C23H2eF2N2O3 m/z 419.2146 (M+H)+. Found
419.2166.
Example 19: N-((IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{[(4S)-6-isobutyl-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide.
Step One: (4R)-6-iodochroman-4-ol
The above compound is prepared essentially according to
the procedure described in Example 18, stepl. Chiral HPLC
separation is performed at this stage. HRMS (El) calcd for
C9H9IO2 275.9649, found 275.9646. (4S) -6-iodochroman-4-ol [a] 20D
= +13 (20 mg-, MeOH) (4R) -6-iodochroman-4-ol [a] 20D = -13 (20
mg, MeOH).
Step Two: (4S)-6-iodochroman-4-amine
To a solution of (4R)-6-iodochroman-4-ol (6.85 g, 24.81
mmol) and toluene (100 mL) under nitrogen at 0°C was added
diphenylphosphoryl azide (6.42 mL, 29.76 mmol). To this
mixture was added a chilled solution of DBU (4.45 mL, 29.76
mmol) as a toluene solution (25 mL) via syringe. Reaction
mixture was allowed to warm to ambient temperature overnight.
Azide solution was filtered through silica gel using 6:1
hexanes :EtOAc as eluant. Filtrate was concentrated in vacuo,
then dissolved in anh. THF (100 mL) to which was added 1. 0M
Me3P in THF (29.76 mL, 29.76 mmol). After lh, deionized H2O (5
mL) was added and reaction mixture was stirred overnight under
nitrogen. Concentrated in vacuo, dissolved in EtOAc, washed
with 10% NaHCO3, brine, then the organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo to give (4S)-6-
iodochroman-4-amine as a white solid. 1H NMR (400 MHz, CDCl3)
d 1.70 (s, 2 H), 1.86 (m, 1 H), 2.13 (m, 1 H), 4.03 (t, J = 5
Hz, 1 H), 4.23 (m, 2 H), 6.60 (d, J = 9 Hz, 1 H), 7.42 (d, J =
9 Hz, 1 H), 7.64 (s, 1 H). MS (ESI + ) for C9H10INO m/z 258.8
(M+H)+.
Step Three: tert-butyl (IS,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-
yl]amino}propylcarbamate.
The above compound was prepared essentially according to
the method of Example 17, step 3. The crude product was
purified via column chromatography using 3% MeOH/DCM as
eluant. The desired compound was obtained as a colorless
solid (6.89 g, 79%). HRMS (ESI); calcd for C24H29N2O4IF2+H1
575.1220, found 575.1194; Specific Rotation (25 C D} =30 (c =
1.04) MeOH.
Step Four: N-((IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{ [ (4S)-6-iodo-3,4-dihydro-2H-chromen-4-
yl]aminojpropyl)acetamide.
The title compound is prepared using procedures described
herein, and isolated as a yellow solid. 1H NMR (400 MHz,
CDCl3) d 1.93 (s, 3 H), 1.97 (m, 1 H), 2.08 (m, 1 H), 2.80 (m,
3 H), 3.09 (dd, J = 4, 14 Hz, 1 H), 3.55 (m, 1 H), 3.84 (m, 1
H), 4.13 (m, 1 H), 4.24 (m, 1 H), 4.31 (m, 1 H), 5.61 (m, 1
H), 6.62 (d, J = 9 Hz, 1 H), 6.70 (m, 1 H), 6.77 (d, J = 6 Hz,
2 H), 7.44 (dd, J = 2, 9 Hz, 1 H), 7.62 (s, 1 H).
Step Five: N-((1S,2R)-1-(3, 5-difluorobenzyl)-2-hydroxy-3-
{[(4S)-6-isobutyl-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide.
To a solution of the product from step 4, (0.300 g, 0.58
mmol) and anh. THF (2.3 mL) was added Pd(dppf)Cl;; (0.024 g,
0.03 mmol) under nitrogen with stirring. To this solution was
added isobutylzinc bromide (9.2 mL of a 0.5M THF solution, 4.6
mmol) and reaction mixture was stirred overnight. Quenched
with methanol, then added Dowex 50WX2-400 resin (used an
excess, 4.6 meq/g). Filtered through a frit, washed resin
with methanol. The alkylated material was released from the
resin using 7N NH3/MeOH. The filtrate was concentrated in
vacuo and then purified via preparative HPLC to yield a
colorless solid fully characterized as the HC1 salt.
To a MeOH (10 ml) solution of N-( (1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-{[(4S)-6-isobutyl-3,4-dihydro-2H-
chromen-4-yl]amino}propyl)acetamide (2.0 g, 4.5 mmol), at 0°C,
was added 3 eguiv. of HCl as a solution in MeOH. Results in
1.97 g of N-((lS,2R)-l-(3,5-difluorobenzyl)-2-hydroxy-3-
{ t (4S) -6-isobutyl-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide -hydrochloride as a white powder
after tritration with CH2C12, HRMS (ESI+) calcd for C25H32F2N2O3
m/z 447.2459 (M+H)+. Found 447.2440. Anal calcd for
C25H32F2N2O3HC1; C, 62.17; H, 6.89; N, 5.80; found C, 62.68; H,
7.05; N, 5.75.
Examples 20-50: General Procedure for Negishi Coupling to 6-
Substituted Chromans:
To a solution of the product of Example 19, step 4 (0.300
g, 0.58 mmol) and anh. THF (2.3 mL) was added Pd(dppf)Cl2
(0.024 g, 0.03 mmol) under nitrogen with stirring. To this
solution was added the zinc bromide reagent (9.2 mL of a 0.5M
THF solution, 4.6 mmol) and reaction mixture was stirred
overnight. Quenched with methanol, then added Dowex 50WX2-400
resin (used an excess, 4.6 meq/g). Filtered through a frit,
washed resin with methanol to remove impurities. Product was
released from resin using 7N NH3/MeOH. Filtrate was
concentrated in vacuo and then purified via preparative HPLC.
Final product was a colorless solid.
To a solution of N-((1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide (0.300 g, 0.58 mmol) and anhydrous
THF (5-mL) -was added Pd(dppf)Cl2 (0.030 g, 0.03 mmol) and K3PO4
(2.9 mL, 5.80 mmol). To this mixture was added boronic acid
(0.310 g, 1.16 mmol) (J. Org. Chem. 1992, 57, 1653) and the
reaction mixture was heated to 65° C overnight under nitrogen
with stirring. Reaction was quenched with deionized water and
then extracted with ethyl acetate. Organic layers were washed
with brine, then dried with MgSO4, filtered, and concentrated
in vacuo. The TIPS-protected compound (0.100 g, 0.16 mmol)
was dissolved in THF (3 mL) and then 0.1M solution of TBAF in
THF (0.32 mL, 0.32 mmol) was added. Reaction mixture was
stirred for 2 h, then concentrated in vacuo. Dissolved in
ethyl acetate, filtered through silica gel plug, then
concentrated in vacuo to give the desired product as an amber
oil (13 0 mg), which is purified by reverse phase prep-HPLC.
HRMS (ESI); calcd for C25H27N3O3F2 + HI 456.2099, found
456.2092.
Example 52: N- ( (IS, 2R) -1-(3,5-d.if luorobenzyl)-2-hydroxy-3-
{[(4S)-6-neopentyl-3,4-dihydro-2H~chromen-4~
yl]amino}propyl)acetamide.
F
Step One: 6-neopentylchroman-4-ol.
To a solution of 6-iodochroman-4-ol (1.0 g, 3.6 mmol) in
18 ml of THF, at 0°C, was added the Pd (dppf)C12•CH2C12 (0.15 g,
0.18 mmol), followed by neopentylmagnesium bromide (10.8 ml,
10.8 mmol, 1.0 M in Et2O). The cold bath was maintained for 10
min., then removed and stirring continued overnight. The
mixture was quenched with NH4C1 (30 ml) and extracted with
EtOAc (3 x 50 ml). The combined organic layers were dried
over MgS04 and concentrated in vacuo to yield a brown oil. The
crude oil was absorbed onto silica gel followed by flash
chromatography (biotage 40S) 10% EtOAc/heptanes ~o yield 0.36
g (46%) of 6-neopentylchroman-4-ol as a white solid. Rf =
0.11. HRMS (ESI + ) calcd for C14H20O2 m/z 220.1463 (M+H)+; found
220.1460.
Step Two: 6-neopentyl-3,4-dihydro-2H-chromen-4-ylamine.
The above compound was prepared essentially according to
the procedure of Example 19, Step 2. First,, the azide was
prepared. 1H NMR (400 MHz, CDC13) d 6.94 (dd, J = 8.40, 2.18
Hz, 1 H), 6.89 (d, J = 2.07 Hz, 1 H), 6.71 (d, J = 8.29 Hz, 1
H), 4.50 (appt, J = 3.73 Hz, 1 H), 4.15 (m, 2 H), 2.36 (s, 2
H), 2.08 (m, 1 H), 1.93 (m, 1 H), 0.83 (s, 9 H). Second, the
azide was reduced to afford the amine as a slightly colored
oil (1.6 g). The amine was taken to the next step without
further purification. HRMS (ESI+) calcd for d4H21NO m/z
219.1623 (M+H)+. Pound 219.1628.
Step Three: tert-butyl (1S, 2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-[(6-neopentyl-3,4-dihydro-2H-chromen-4-
yl)amino]propylcarbamate.
The above compound is prepared essentially according to
the procedure of Example 17, step 3; it is obtained as an off
white solid.1 Flash chromatography (3% MeOH/CHC3, 1 ml of NH40H
per liter) yields the desired px-oduct as a mixture of epimers.
HRMS (ESI + ) calcd for C29H40N2O4F2 m/z 519.3034 (M+H)+. Found
519.3040.
Step Four: N-((IS,2R)-1-(3,5-difluorobenzyl)~2-hydroxy-3-
{ [ (4S).-6-neopentyl-3, 4-dihydro-2H~chromen-4-
yl]amino}propyl)acetamide.
The above compound was prepared essentially according the
method of Example 15, step 3, which resulted in a mixture of
epimers. The epimers were then separated using chiral
preparative HPLC (10% IPA/heptanes, 0.1% DEA) AD column:
N- ( (1S,2R) -1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
neopentyl-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide.
1H NMR (400 MHz, CDCl3) d 7.01 (d, J = 1.87 Hz, 1 H), 6.96 (dd,
J = 8.29, 2.07 Hz, 1 H), 6.79-6.67 (m, 4 H), 5.69 (d, J = 8.50
Hz, 1 H), 4.32-4.15 (m, 3 H), 3.85 (bs, 1 H), 3.60 (bs, 1 H),
3.02 (m, 1 H), 2.88 (m, 2 H), 2.76 (dd, J" = 12.13, 6.74 Hz, 1
H), 2.46 (s, 2 H), 2.15-2.08 (m, 1 H), 2.04-1.98 (m, 1 H),
1.94 (s, 3 H), 0.91 (s, 9 H). HRMS (ESI + ) calcd for C26H34F2N2O3
m/z 461.2615 (M+H)+. Found 461.2621.
N- ( (1S,2R) -1- (3,5-difluorobenzyl)-2-hydroxy-3-{[(4R)-6-
neopentyl-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide.
1H NMR (400 MHz, CDCl3) d 7.04 (d, J = 2.07 Hz, 1 H), 6.96 (dd,
J = 8.29, 1.87 Hz, 1 H), 6.77-6.67 (m, 4 H), 5.69 (d, J = 8.91
Hz, 1 H), 4.'"31-4.16 (m, 3 H), 3.86 (bs, 1 H), 3.57 (bs, 1 H),
3.00 (m, 2 H), 2.82 (m, 2 H), 2.44 (s, 2 H), 2.18-2.00 (m, 3
H), 1.90 (s, 3 H), 0.91 (s, 9 H). HRMS (ESI + ) calcd for
C2SH34F2N2O3 m/z 461.2615 (M+H)+. Found 461.2630. Anal. Calcd
for C26H34F2N2O3; C, 67.81; H, 7.44; N, 6.08. Found C, 67.65; H,
7.51; N, 6.05.
Example 52 A: Chiral Synthesis of Amine.
Step One: (4R)-6-neopentylchroman-4-ol.
(4R)-6-iodochroman-4-ol is converted into (4R)-6-
neopentylchroman-4-ol essentially according to the procedure
of Example 52, step 1. The produce is obtained as a white
solid. Anal. Calcd for C14H2002; C, 76.33; H, 9.15. Found C,
76.31; H, 9.06. [a] D = 22.3, c = 1.14 (CH2Cl2).
To a suspension of amine (S) -mandelic salt (4.55 g, 10.6
mmol) in water (50 mL) was added sodium hydroxide (21 mL, 2 N,
42 mmol) followed by di-tert-butyl dicarbonate (2.58 g, 11.7
mmole) and chloroform (50 mL). The reaction mixture was
stirred at room temperature for 2 h and then diluted with
methylene chloride (100 mL) and water (50 mL). The organic
layer was separated washed with saturated sodium chloride,
dried (sodium sulfate), filtered, and concentrated under
reduced pressure. The residue was triturated with 1:1
hexanes/ethyl ether. The resulting white solid was collected
by filtration and washed with hexanes to provided tert-butyl
(4S)-6-iodo-3,4-dihydro-2H-chromen-4-ylcarbamate (3.30 g,
83%): 1H NMR (300 MHz, CDC13) d 7.55 (d, J = 1.8 Hz, 1H), 7.42
(dd, J = 8.6,2.2 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 4.78 (m,
2H), 4.28-4.20 (m, 1H), 4.18-4.10 (m, 1H), 2.19-2.10 (m, 1H),
2.06-1.96 (m, 1H), 1.49 (s, 9H).
To a suspension of the 0.3 M neopentyl zinc reagent in
THF ( 60 ml, 15 mmol) was added the tert-butyl (4S) -6-iodo-
3,4-dihydro-2H-chromen-4-ylcarbamate (1.8 g, 5.0 mmol) and
Pd(dppf)Cl2 (0.2 g, 0.25 mmol) as solids in one portion. The
mixture was stirred at r.t. under nitrogen for 48 hours
(progress monitored by LC/MS and HPLC). The mixture was
quenched with aqueous NH4C1 (2 0 ml) and extracted with EtOAc (3
x 5 0 ml). • The organic layer was dried over Na2SO4 and
concentrated in vacuo. The crude residue was dissolved in
MeOH(25 ml) and treated with DOWEX® 50WX2-400 ion exchange
resin. The mixture was heated to 50°C for six hours and then
the resing was collected by filtration. The resin was washed
successively with MeOH and CH2C12 these washings were
discarded. The resin was then treated with 7 N NH3/Me0H to
elute the free amine from the resin. The elutions were
concentrated in vacuo to yield a light brown oil (0.63 g, 57%)
of (4S)-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamine. This
material was consistent with previous preparations and was
used as obtained for the subsequent opening of the di-
fluoroPhe epoxide. S)-6-neopentyl-3,4-dihydro-2H-chromen-4-
ylamine was previously characterized as the mono'HCl salt. 1H
NMR (300 MHz, DMSO-dff) 5); 7.25 (s, 1H), 7.02 (rn, 1H,), 6.76
(m, 1H), 4.47 (bs, 1H), 4.21 (m, 2H), 2.38 (s, 2H), 2.24 (m,
1H), 2.10 (m, 1H), 0.87 (s, 9H). HRMS (ESI + ) calculated for
Ci4H2iN1Oi 220.1701; found m/z 220.1698 (M+H)+. Anal. Calcd for
C14H21NOHC1: C, 65.74; H, 8.67; N, 5.48. Found: C, 65.62; H,
8.53; N, 5.42. [a] 2\ = 15.6, c = 1.17 in CH3OH.
]
The above compound was prepared essentially according to
the method of Example 15, step 2; it was obtained as a white
foam. Rf = 0.2 5 (in 3% MeOH in CHC13 with 1 ml of NH4OH per
liter). HRMS (ESI + ) calcd for C29H4oN204F2 m/z 519.3034 (M+H) +.
Found 519.3057.
To neopentyl zinc chloride (prepared as previously-
described) (51 ml, 11 mmol, 0.2 M in THF) under a nitrogen
atmosphere at r.t. was added tert-butyl (1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-
chromen-4-yl]amino}propylcarbamate (1.3 g, 2.2 mmol) and
Pd(dppf)Cl2 (0.09 g, 0.1 mmol) as solids. The reaction mixture
was stirred at r.t. for 12 h and then heated to 50°C for 8h.
The reaction was cooled to r.t. then quenched with 20 ml' of
aqueous NH4Cl and extracted with EtOAc (3x10 0 ml). The
combined organic layers were dried over Na2SO4 and concentrated.
in vacuo to yield a brown oil. The residue was dissolved in
CH2C12 and absorbed onto 6g of silica gel. Flash
chromatography (3-5% MeOH/CHCl3 with 20 drops o£ NH4OH/L,
Biotage 40M) yields the desired product, which is identical to
the material prepared by the previously described methods.
Example 52-E: Alternative preparation of N-((IS,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-3,4-
dihydro-2H-chromen-4-yl]aminojpropyl)acetamide.
The above compound is prepared essentially according to
the method of Example 15, step 3. First, the Boc group is
removed to afford the crude amine as a yellow oil. 1H NMR (400
MHz, CDC13) d 7.00 (d, J = 2.07 Hz, 1 H), 6.95 (dd, J = 8.29,
2.28 Hz, 1 H), 6.78-6.68 (m, 4 H), 4.26 (m, 2 H), 3.82 (appt,
J = 4.15 Hz, 1 H), 3.57 (ddd, J = 8.60, 5.29, 3.52 Hz, 1 H),
3.13 (ddd, J = 9.89, 5.55, 3.73 Hz, 1 H), 3.07 (dd, J = 11.82,
3.52 Hz, 1 H), 2.96 (dd, J= 13.58, 3.42 Hz, 1 H), 2.83 (dd, J
= 11.71, 8.60 Hz, 1 H), 2.53 (dd, J = 13.58, 9.85 Hz, 1 H),
2.44 (s, 2 H), 2.14-1.99 (m, 2 H), 0.91 (s, 9 H).
Second, the crude amine was acylated. The crude acylated
material was purified by flash chromatography (3.5% MeOH/CHC3
with 1 ml of NH4OH per liter), Biotage 40L, affording the
desired product as a white powder. This material was
spectroscopically identical to the N-((1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-3,4-dihydro-2H-
chromen-4-yl]amino}propyl)acetamide prepared by previous
methods.
1
The above compound is prepared essentially according to
the procedure of Example 19, step 5. The resulting residue
was dissolved in CH2C12 and absorbed onto 6g of silica gel.
Flash chromatography (3-5% MeOH/CHCl3 with 2 0 drops of NH4OH/L,
Biotage 40M) yields two fractions. Fraction one yielded 650
mg of the desired product that was 93% pure by analytical
HPLC. The second fraction (430 mg) was a 60:40 mixture of the
desired product and the dehalogenated compound. The first
fraction was re-subjected to preparative reverse phase HPLC
(1% TFA in water/0.6% TFA in CH3CN) to yield 500 mg (38%) of a
white powder after neutralization. This material was
spectroscopically identical to the N-((IS,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-3,4-dihydro-2H-
chemen-4-yl] amino}propyl) acetamide prepared by previous
methods.
Example 52-G: Preparation of the HC1 salt of N-((1S,2R)-
1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-3,4-
dihydro-2H-chromen-4-yl]amino}propyl)acetamide.
The free base (from Ex. 52-F, 0.5 g, 1.08 mmol) was
dissolved in MeOH (10 ml) and treated with HCl/Et2O (2.5 ml,
1.0 M). The solution was stirred at r.t. for 10 mirt. then the
solvent removed in vacuo to yield a clear glass. The glass
was tritrated with Bt2O to yield 536 mg of a white solid that
was dried in vacuo at 4 0°C for 4 8h. Anal Calcd for
C26H34F2N2•VHCl•0.5 H2O, C, 61.71; H, 7.17; N, 5.54. Found C,
61.69; H, 7.31; N, 5.64. HRMS (ESI+) calcd for C26H34N2O3F2 m/z
461.2615 (M+H)+. Found 461.2627.
The above product was prepared essentially according to
the method of Example 17, step 3. The crude product was then
purified by flash chromatography (3% MeOH/CHCl3). HRMS (ESI+)
calcd for C29H41N2O4F m/z 501.3128 (M+H)+. Found 501.3150.
Step two: N-( (1S,2R)-1-(3-fluorobenzyl)-2-hydroxy-3-{ [ (4S)-6-
neopentyl-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide.
The above compound was prepared essentially according to
the method of Example 15, step 3. The crude product was
dissolved in MeOH and purified by reverse phase preparatory
HPLC. HRMS (ESI + ) calcd for C26H35N2O3F m/z 443.2710 (M+H)+.
Found 443.2710.
The above compound was prepared essentially according to
the method of Example 17, step 3. The resulting crude product
was purified by preparative HPLC (1% TFA in water/0.6% TFA in
CB 'N). HRMS (ESI+) calcd for C29H42N2O4 m/z 483.3222 (M+H)+.
Found 483.3219.
The above compound is prepared essentially according to
the method of Example 17, step 3. The resulting crude product
was dissolved in MeOH (5 mL) and purified by reverse phase
preparatory HPLC which gave a white powder. HRMS (ESI+) calcd
for C26H36N2O3 m/z 425.2804 (M+H)+. Found 425.2801.
Step One: 6-isopropyl-2,3-dihydro~4H-chromen-4-one.
A CH2C12 (350 ml) solution of l-isopropyl-4-methoxy
benzene (25 g, 166 mmol) and 3-chloro-propionly chloride (21
ml, 216 mmol), at r.t., was treated withrAlCl3 (33 g, 249 mmol)
in 1-2 g portions over a 1 h period. Stirring was maintain at
r.t. for 24 h at which time the mixture was poured onto
crushed ice followed by the addition of 30 ml of cone. HCl.
washed (avoid emulsion) with 2 N NaOH. The organic layer was
dried over MgSO4 and concentrated in vacuo a pale yellow oil.
Flash chromatography (10% EtOAc/Heptanes) yields 6-isopropyl-
2,3-dihydro-4H-chromen-4-one (7.5 g, 24%). Rf = 0.3. HRMS
(ESI + ) calcd for C12H14O2 m/z 191.1072 (M+H)+. Found 191.1071.
Step Two:. 6-isopropylchroman-4-ol.
The above compound was prepared essentially according to
the method of Example 17, step 1; it was obtained as a white
solid. HRMS (ESI + ) calcd for C12H16O2 m/z 192.1150 (M+H)+.
Found 192.1152.
Step Three: 6-isoproopyl-3,4-dihydro-2H-chromen-4-ylamine.
The above compound was prepared essentially according to
the method of Example 17, step 2. First the azide was
prepared as a yellow oil (7.53 g, 86% crude yield. HRMS calcd
for C12H15N3O + HI 217.1215, found 217.1218. Second, the azide
was reduced with 1.0M Me3P in THF (42.00 mL, 41.59 mmol). The
resulting amine was obtained as a yellow oil (3.5 g, 53% crude
yield). HRMS calcd for C12H17NO + HI 192.1388, found 192.1384.
The crude racemic amine was purified and resolved using chiral
preparative HPLC (5% EtOH/heptanes, 0.1% DEA) using a
Chiralpak AD column. Obtained 1.5 g of (+)-(4R)- 6-isopropyl-
chroman-4-ylamine retention time 15.5 min. [a]D = 4.2 (c = 2.0
in MeOH) and 1.5 g, of (-) -(4S)- 6-isopropyl-chroman-4-ylamin
retention time 18.3 min. [a]D = -3.9 (c = 2.0 in MeOH). 1H NMR
as the HC1 salt (300 MHs, CD3OD) d 1.25 (d, J = 6 Hz, 6 H),
2.15 (m, 1 H), 2.38 (m, 1 H), 2.89 (m, 1 H), 4.27 (m, 2 H),
4.55 (t, J = G Hc, 1 H), 6.83 (d, J = 9 Hz, 1 H), 7.19 (dd, J
=3,9 Hz, 1 H), 7.25 (d, J = 3 Hz, 1 H).
St Four: tert-Butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[(4S)-6-isopropyl-3,4-dihydro-2H-chromen-4-
yl]amino}propylcarbamate.
The above compound was prepared essentially according to
the method of Example 17, step 3. The crude material was used
in the next reaction without purification. 1H NMR (crude-DMSO-
d6) d 7.75 (d, J = 9 Hz, 1 H), 7.14 (br s, 1 H), 7.02 (m, 2 H),
6.9 (m, 1 H), 6.68 (d, J = 9 Hz, 1 H), 5.3 (br s, 2 H), 4.22
(m, 1 H), 4.12 (m, 1 H), 3.9 (m, 1 H), 3.68 (m, 1 H), 3.50 (m,
1 H), 3.02 (dd, J = 11, 3 Hz, 1 H), 2.78 (sept, J = 7 Hz, 1
H), 2.67 (s, 1 H), 2.57 (dd, J = 4, 10 Hz, 1 H), 1.59 (s, 9
H), 1.14 (d, J = 7 Hz, 6 H). LRMS {m/z) M+H: 490.3.
Step Five: N-((IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{[(4S)-6-isopropyl-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide.
The product from step 4 was converted into the above
compound essentially according to the method of Example 15,
step 3. First, the free amine was obtained as a glassy
solid/foam. 1H NMR (crude-CDCl3) d 7.75 (d, J = 9 Hz, 1 H),
7.14 (br s, 1 H), 7.02 (m, 2 H), 6.9 (m/ 1 H), 6.68 (d, J = 9
Hz, 1 H), 4.4 (br s, 2 H), 4.12 (m, 1 H), 3.9 (m, 1 H), 3.68
(m, 1 H), 3.50 (m, 1 H), 3.32 (m, 1 H), 3.02 (dd, J = 11, 3
Hz, 1 H), 2.78 (sept, J = 7 Hz, 1 H), 2.67 (s, 1 H), 2.57 (dd,
J = 4, 10 Hz, 1 H), 1.11 (d, J = 7 Hz, 6 H). LRMS {m/z)
M+H:390.2
Second, the amine was acylated to afford the acetamide as
an oil, which was purified by prep-HPLC. HRMS (ESI + ) calcd
for C24H30F2N2O3 m/z 433.2303 (M+H)+. Found 433.2307.
The same procedure using (+)-(4R)- 6-isopropyl-chroman-4-
ylamine results in the epimer N-( (IS,2R)-1-(3, 5-
difluorobenzyl)-2-hydroxy-3-{[(4R)-6-isopropyl-3,4-dihydro-2H-
chromen-4-yl]aminojpropyl)acetamide. 1H NMR (DMSO-d6) 5 7.76
(d, J = 9 Hz, 1 H), 7.01 (m, 2 H), 7.14 (d, J = 2 Hz, 1 H),
6.99 (dd, J = 8.5, 2 Hz, 1 H), 6.91 (m, 1 H), 6.65 (d, J = 8.5
Hz, 1 H), 4.96 (d, J = 6 Hz, 1 H), 4.2 (dt, J = 10, 3.4 Hz, 1
H), 4.1 (m, 1 H), 3.99 (m, 1 H), 3.64 (br s, 1 H), 3.47 (m, 1
H), 3.0 (dd, J = 14, 3 Hz, 1 H), 2.78 (sept, J = 8 Hz, 1 H),
2.75 (m, 1 H), 2.6 (m, 2 H), 1.86 (m, 3 H), 1.7 (s, 3 H), 1.16
(d, J = 7 Hz, 6 H). HRMS (ESI + ) calcd for C24H30F2N2O3 m/z
433.2303 (M+H)+. Found 433.2301.
(2R,3S) -3-amino-4-(3,5-difluorophenyl)-l-{1 (4S)-6-iodo-
3,4-dihydro-2H-chromen-4-yl]amino}butan-2-ol (1 eguiv) was
combined with 2-methylacetic acid, (1.25equiv), EDC (1.5equiv)
and HOBt (1.5equiv) in DMF/DCM (1:1, lOmL). The reaction
mixture was treated with Et3N and stirred at ambient
temperature for 6h. HPLC determined that the arr.ine had been
consumed by this time, and the reaction mixture was poured
onto EtOAc and washed with 1M HCl, then the organics were
dried over MgSO4 and concentrated to give an oil which was
purified by reverse phase preparative HPLC. HRMS (ESI+) calcd
for C23H27F2IN2O4 m/z 561.1063 (M+H)+. Found 561.1047.
Example 57: N-((IS,2R)-1-(3, 5-difluorobenzyl) -2-hydroxy-3-
{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]aminojpropyl)-1-
hydroxycyclopropanecarboxamide.
The above compound is prepared using the basic
methodology described in Example 56. HRMS (ESI+) calcd for
C23H25F2IN2O4 m/z 559.0907 (M+H)+. Found 559.0903.
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[(4S)-6-iodo-
3,4-dihydro-2H-chromen-4-yl]amino}butan-2-ol (1 equiv) was
dissolved in DCM with TEA (2 equiv) then cooled to 0°C and
treated with MsCl (1.25equiv)while stirring. The reaction
mixture was removed from the cold bath, brought to ambient
temperature, then quenched with MeOH and concentrated. The
residue was dissolved in EtOAc and washed with 1M HC1
(2x1OmL). The organics were dried and concentrated and
chromatographed over silica gel. 1H NMR (CD3OD) d 7.74 (d, J =
2.0 Hz, 1 H), 7.53 (dd, J = 2.0, 8.7 Hz, 1 H), 6.88 (m, 2 H),
6.77 (m, 1 H), 6.67 (d, J = 8.7 Hz, 1 H), 4.23-4.39 (m, 2 H),
4.25 (br m, 1 H), 4.12 (m, 1 H), 3.87 (td, J = 3.1, 7.8 Hz, 1
H), 3.29 (dd, J = 3.5, 13.9 Hz, 1 H), 3.11 (s, 3H), 3.05 (dd,
J = 3.2, 12.7 Hz, 1 H), 2.98 (dd, J = 7.9, 12.6 Hz, 1 H), 2.74
(dd, J = 11.0, 13.9 Hz, 1 H), 2.14 (br m, 2 H). MS (ESI + )
calcd for C20H23F2IN204S m/z 553.38 (M+H)+. Found 553.4:
The Boc protected amine (1 equiv) was dissolved in 10:1
DCM:TFA (to 0. 1M) for 3h at ambient temperature.. The reaction
mixture was concentrated and the residue partitioned between
EtOAc and 1M NaOH. The aqueous layer was removed and the
organics washed with brine (50mL) then dried over MgSO4 and
concentrated to a glassy solid/foam. LRMS (m/z) M+H:418.5.
This was dissolved in CH2Cl2 (to 0.1M), cooled to 0°C and
treated with formyl imidizole (1.25equiv). The reaction was
removed from the cold bath, then stirred for 2h at ambient
temp. When done by HPLC, the reaction mixture was concentrated
and dissolved in MeOH (1.5mL) and purified by reversed phase
preparative HPLC (2 in. column) to give a film which scraped
down to a white powder. 1H NMR (DMSO-d6) d 8.4 6 (br s, 1H),
7.75 (d, J = 9 Hz, 1 H), 7.14 (br s, 1 H), 7.02 (m, 2 H), 6.91
(m, 1 H), 6.69 (d, J= 9 Hz, 1 H), 5.0 (br s, 2 H), 4.21 (m, 1
H), 4.09 (m, 1 H), 3.94 (m, 1 H), 3.72 (m, 1 H), 3.43 (m, 1
H), 3.08 (dd, J = 11, 3 Hz, 1 H), 2.77 (s, 2 H), 2.57 (dd, J =
4, 10 Hz, 1 H), 1.69 (s, 3 H), 1.04 (s, 9 H). MS (ESI + ) for
C25H32F2N2O3 m/z 446.54 (M+H)+. Found 446.3.
Example 60: N-{(IS, 2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
[(4-methyl-6-neopentyl-3,4-dihydro-2H-chromen-4-
yl)amino]propyl}acetamide.
To a CH2C12 ( 300 ml) suspension of 6-iodo-4-chromanol (
15 g, 54.3 mmol) and 30 g of silica gel, at r.t., was added
PCC (15.2 g, 70.6 mmol) as a solid. The mixture was stirred
at r.t. for 3h at which time TLC (20% EtOAc/hexanes) indicated
complete reaction. The reaction mixture was filtered through
a silica gel plug and the filtrate concentrated in vacuo to
yield 14.9 g (95%) of 6-iodo-2,3-dihydro-4H-chromen-4-one as a
white solid consistent with the literature report (Synthesis
1997, 23-25). HRMS (ESI + ) calcd for C9H7IO2 m/z 273.9492;
found 273.9500.
Step Two: 6-iodo-4-methylchroman-4-ol
CeCl3 (4.9 g, 19.8 mmol) was dried in vacuo at 14 0°C for 3h and
then slurried with dry THF (100 ml) for lh. The white
suspension was chilled to -78°C followed by the addition of
MeLi•LiBr (14.2 ml, 21.4 mmol) over 15 minutes. The mixture
was stirred for 30 min followed by the addition of a THF (20
ml) solution of 6-iodo-2,3-dihydro-4H~chromen-4-bne dropwise
via syringe. After 30 min TLC (15% EtOAc/hexanes) indicated
complete reaction. The mixture was treated with NH4C1 (aq.) 30
ml and diluted with water 150 ml. The mixture was extracted
with EtOAc and the organic layer dried over Na2SO4. The
Na2S04 was removed by filtration and the filtrate concentrated
in vacuo to yield 6-iodo-4-methylchroman-4-ol as an off white
solid 4.7 g (95%). HRMS (ESI + ) calcd for C10H11IO2 m/z 289.9806
(M+H)+. Found 289.9803.
Step Three: 6-iodo-4-methylchroman-4-amine
To a mixture of 6-iodo-4-methylchroman-4-ol (1.0 g, 3.4
mmol) and NaN3 (0.7 g, 10.3 mmol) in CHC13 (15 ml), at 0°C, was
added TFA (1.3 ml, 17.2 mmol) as a solution in 10 ml of CHCl3
dropwise via addition funnel. The addition was carried out
over 2 h and stirring continued for an additional 2 h at 0°C.
The mixture was warmed to r.t. and stirred over night. The
mixture was diluted with 3 0 ml of water and extracted with
CH2C12. The organic layer was dried over Na2SO4 and
concentrated in vacuo to yield 4-azido-6-iodo-4-methylchroman
as a yellow oil. 1H NMR (4 00 MHz, CDCl3) d 7.65 (d, J = 2.07
Hz, 1 H), 7.50 (dd, J = 8.71, 2.07 Hz, 1 H), 6.66 (d, J = 8.71
Hz, 1 H), 4.27 (m, 2 H), 2.06 (m, 2 H), 1.68 (s, 3 H). MS
(ESI + ) for C10H10IN3O m/z 273.0 (M+H)+ loss of azide. The crude
azide was dissolved in THF (15 ml) followed by the addition of
trimethylphosphine (4 ml, 1.0 M in THF) at r.t. After 15 min.
3 ml of water was added and stirring continued at r.t. for 2h
until complete as indicated by LC/MS. The solvent was removed
in vacuo and the residue diluted with water (75 ml) and
extracted with CH2Cl2 (3 x 50 ml). The organic layer was dried
over Na2SO4 and concentrated in vacou to yield 6-iodo-4-
methylchroman-4-amine (0.900 g, 91%) as a yellow oil. This
material was used in the next step without purification. 1H
NMR (400 MHz, CDC13) d 7.77 (d, J = 2.07 Hz, 1 H), 7.40 (dd, J
= 8.60, 2.18 Hz, 1 H), 6.59 (d, J = 8.50 Hz, 1 H), 4.25 (m, 2
H), 2.01 (m, 2 H), 1.53 (s, 3 H). MS (ESI + ) for C10H12INO m/z
2 73.2 (M+H)+ loss of NH3.
Step Four: tez-t-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-chromen-4-
yl)amino]propylcarbamate.
The above compound was prepared essentially according to
the method of example 17, step 3. The resulting crude
material was dissolved in CH2Cl2, absorbed onto 7.8 g of silica
gel., and purified by flash chromatography using 50%
EtOAc/Heptanes (Biotage 4 0 M tolumn) as the eluent. Three
fractions were obtained. The final fraction was recovered
amine. Obtained 0.500 g of each of the following
diastereomers overall yield from epoxide 83%.
Diastereomer A: 1H NMR (400 MHz, CDCl3) d 7.67 (bs, 1 H),
7.42 (dd, J = 8.50, 2.07 Hz, 1 H), 6.71 (in, 3 H), 6.59 (d, J =
8.50 Hz, 1 H), 4.52 (d, J = 9.12 Hz, 1 H), 4.35 (m, 1 H), 4.21
(m, 1 H), 3.82 (m, 1 H), 3.42 (m, 1 H), 3.06 (m, 1 H), 2.81
(dd, J" = 14.3, 8.7 Hz, 1 H), 2.62' (m, 2 H), 2.26 (m, 1 H),
1.84 (m, 1 H), 1.40 (m, 2 H), 1.35 (m, 12 H). HRMS (ESI+) for
C25H31N2O4F2I +1H calcd for 589.1376 m/z found 589.1397 (M+H)+
Diastereomer B: 1H NMR (400 MHz, CDCl3) d 7.65 (d, J =
2.07 Hz, 1 H), 7.44 (d; J = 8.50 Hz, 1 H), 6.71 (m, 3 H), 6.67
(d, J = 8.71 Hz, 1 H), 4.54 (bs, 1 H), 4.34 (m, 1 H], 4.16 (m,
1 H), 3.77 (m, 1 H), 3.48 (m, 1 H), 3.10 (m, 1 H), 2.75 (m, 1
H), 2.75 (m, 1 H), 2.62 (m, 2 H), 2.24 (m, 1 H), 1.93 (m, 1
H), 1.60 (m, 2 H), 1.42 (s, 9 H), 1.39 (s, 3 H). HRMS (ESI + )
for C25H31N2O4F2I + 1H calcd for m/z 589.1376; found 589.1375
(M+H)+.
Step Five: N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
iodo-4 -methyl-3,4-dihydro-2H-chromen-4 -
yl)amino]propylJacetamide.
To a CH2C12 (5 ml) solution of tert-butyl (1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-
chromen-4-yl)amino]propylcarbamate (Diastereomer B). (0.47 g,
0.79 mmol), at r.t., was added 25 ml of 20% TFA/CH2C12. The
mixture was stirred at r.t for 3 0 min. The solvent was
removed in vacuo and the residue dissolved in CH2C12 (75 ml)
and washed with aqueous NaHCO3 and brine. The organic layer
was dried over Na2SO4 and concentrated in vacuo to yield a
white foam.. The residue was dissolved in CH2Cl2 (5 ml) and
chilled to 0°C followed by the addition of Et3N (0.24 ml, 1.7
mmol) and acetyl imidazole (0.10 g, 0.90 mmol). The mixture
was then warmed to r.t. and stirred overnight. The reaction
mixture was diluted with CH2C12 (25 ml) and washed with water
and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo to yield a white foam (0.35 g, 84%)
after flash chromatograph 5% MeOH/CHCl3 (Biotage 4 0 S). Rf =
0.29. HRMS (ESI + ) calcd for C22H25N2O3IF2 + 1H calcd m/z
531.0958; found 531.0958 (M+H)+.
Same procedure diastereomer A yields 0.28 g (70%) of the
epimer. 1H NMR (400 MHz, DMSO-d6) d 7.75 (d, J = 2.28 Hz, 1
H), 7.36 (dd, J = 8.71, 2.28 Hz, 1 H), 6.79 (m, 3 H), 6.57 (d,
J = 8.50 Hz, 1 H), 4.31 (m, 1 H), 4.17 (m, 1 H), 4.08 (m, 1
H), 3.51 (m, 1 H), 3.11 (dd, J = 14.1, 3.73 Hz, 1 H), 2.62
(dd, J = 14.1, 10.4 Hz, 1 H), 2.52 (m, 1 H), 2.45 (dd, J =
11.9, 3.63 Hz, 1 H), 2.25 (m, 1 H), 1.79 (s, 3 H), 1.74 (m, 1
H), 1.47 (s, 3 H). Anal. Calcd for C22H25F2IN2O3; C, 49.82; H,
4.75; N, 5.28. Found C, 49.87; H, 4.94; N, 5.05.
To a 20 ml serum capped vial containing N-{(1S,2R)-1-
(3,5-difluorobenzyl)-2-hydroxy-3- [(6-iodo-4-methyl-3,4 -
d.ihydro-2H-chromen-4-yl) amino]propyl]acetamide (0.20 g, 0.37
mmol) and Pd(dppf)Cl2 (0.015 g,.018 mmol) under nitrogen was
added 3.7 ml of a 0.5 M neopentyl zinc chloride (1.85 mmol)
prepared as previously described. The mixture was shaken on
an orbital shaker for 12 h at which time LC/MS indicated only
a trace of the desired compound. An additional 5 eq. of the
zinc reagent and another 5 mol% of catalyst was added and the
reaction mixture was warmed to 4 0 °C. After 6 h LC/MS
indicated complete consumption of SM. The reaction mixture
was quenched with NH4Cl and extracted with EtOAc. The organic
layer was dried over Na2SO4 and concentrated in vacou to yield
a light brown solid (150 mg) after flash chromatography (4%
MeOH/CHCl3 Biotage 40S). This material was subjected to a
final reverse phase preparative column ( 1% TFA in H2O/0.6% TFA
in CH3CN) to yield 50 mg of a light yellow solid. This
material was dissolved in 4 ml of CH2Cl2 and treated with 0.5 g
of 3-mercaptopropyl functionalized silica gel and stirred at
r.t. for 30 min. The mixture was filtered through Celite® to
remove the resin and the filtrate concentrated in vacuo to
yield a white powder (44 mg, 20%). 1H. NMR (400 MHz, DMSO-d6) d
7.08 (d, J= 2.07 Hz, 1 H), 6.87 (dd, J = 8.29, 2.07 Hz, 1 H),
6.78 (m, 3 H), 6066 (d, J = 8.29 Hz, 1 H), 4.27 (m, 1 H), 4.12
(m, 1 H), 4.04 (m, 1 H), 3.54 (m, 1 H), 3.06 (dd, J = 13.99,
3.63 Hz, 1 H), 2.56 (m, 2 H), 2.45 (bs, 2 H), 2.37 (dd, J =
11.82, 7.67 Hz, 1 H), 2.25 (m, 1 H), 1.81 (s, 3 H), 1.78 (m, 1
H); 1.49 (s, 3 H), 0.91 (s, 9 H). MS (ESI + ) for C27H35N2O3F2 rn/z
475.2772 (M+H)+; found, 475.2774.
Same procedure yields 0.049 g (28%) of the epimer 1H NMR
(400 MHz, DMSO-d6) d 7.17 (d, J = 2.07 Hz, 1 H), 6.87 (dd, J =
8.29, 2.07 Hz, 1 H), 6.77 (m, 3 H), 6.66 (d, J = 8.29 Hz, 1
H), 4.27 (m, 1 H), 4.11 (m, 2 H), 3.53 (m, 1 H), 3.06 (dd, J =
14.10, 3.52 Hz, 1 H), 2.53 (m, 3 H), 2.43 (s, 2 H), 2.27 (m, 1
H), 1.78 (m, 4 H), 1.49 (s, 3 H), 0.90 (s, 9 H). MS (ESI + )
calcd for C27H3SN2O3F2 m/z 475.2772 (M+H)+; found, 475.2788.
Example 60 A: An alternative synthesis of 4-methyl-6-
neopentylchroman-4-ol
Step 1': 6-neopentylchroman-4-ol.
To a flame dried round bottom flask containing 6-iodo-
chroman-4-ol (3.0 g, 10.8 mmol) and Pd(dppf)Cl2 (0.44 g, 0.54
mmol) was added 6 ml of anhydrous THF and the mixture chilled
to 0°C. The mixture was treated with neopentyl zinc chloride
(prepared as previously described) (50 ml, 3 0 mmol, 0.6 M in
THF) and stirred under nitrogen at r.t. for 19 h. followed by
5 h at 50°C (oil bath). The reaction was cooled to r.t. and
quenched with NH4C1 and extracted with EtOAc. The organic
layer was dried over Na2SO4 and concentrated in vacuo to 1.9 g
(79%) of a white solid after flash chromatography (10%
EtOAc/heptanes, Biotage 40M) Rf = 0.11. HRMS (ESI+) calcd for
C14H20O2 m/z 220.1463 (M+H)+; found 220.1460.
Step 2: 6-neopentyl-2,3-dihydro-4H-chromen-4-one.
The alcohol was oxidized to the ketone essentially
according to the method of Example 60, step 1; the ketone was
obtained as a clear oil. This material was carried forward
without further purification.. HRMS (ESI + ) calcd for C14H1802
m/z 219.1385 (M+H)+; found 219.1393.
The above compound was prepared essentially according to
the method of Example 60, step 2; the product was obtained as
a clear oil, which was used without further purification. 1H
NMR (300 MHz, CDC13) d 7.23 (d, J = 2.07 Hz, 1 H), 6.95 (dd, J
= 8.29, 2.26 Hz, 1 H), 6.73 (d, J = 8.29 Hz, 1 H), 4.25 (m, 2
H) 2.44 (s, 2 H), 2.09 (m, 2 H), 1.64 (s, 3 H), 0.91 (s, 9
H). MS (ESI + ) calcd for C15H22O2 m/z 234.2 (M+H)+; found 217.3
loss of water.
To a mixture of tert-butyl (4S)-6-iodo-3,4-dihydro-2H-
chromen-4-ylcarbatnate (3.30 g, 8.8 mmol) and
bis(pinacolato)diboron (2.51 g, 9.7 mmol) in methyl sulfoxide
(30 mL) was added potassium acetate (2.60 g, 26.4 mmol)
followed by [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (410 mg, 0.5 mmol). The reaction
mixture was heated under argon at 8 0 °C for 2 h and then
cooled to room temperature. The reaction mixture was diluted
with ethyl ether (100 mL) and washed with water and saturated
sodium chloride, dried (sodium sulfate), filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, 10-20% ethyl
acetate/hexanes) provided the desired product (3.25 g, 98%): 1H
NMR (300 MHz, CDCl3) d 7.72 (s, 1H), 7.62 (dd, J = 8.2,1.5 Hz,
1H), 6.80 (d, J = 8.2 Hz, 1H), 4.79 (m, 2H), 4.31-4.24 (m,
1H), 4.21-4.15 (m, 1H), 2.14-2.11 (m, 2H), 1.48 (s, 9H), 1.34
(s, 6 H), 1.33 (s, 6 H).
Step Two: tert-butyl (4S)-6-hydroxy-3,4-dihydro-2H-chromen-4-
ylcarbamate
To a solution of tert-butyl (4S)-6-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-4-ylcarbamate
(1.09 g, 2.90 mmol) in tetrahydrofuran (10 mL) was added
sodium hydroxide (6 mL, 1 N, 6 mmol) followed by hydrogen
peroxide (10 mL, 30%). The reaction mixture was stirred at
room temperature for 2 h and then quenched with sodium
hydrogen sulfite (5 g in 10 mL of water). The mixture was
adjusted to pH 4 with 2 N sodium hydroxide and then extracted
with ethyl acetate (3 x 50 mL). The combined extracts were
washed with saturated sodium chloride, dried (sodium sulfate),
filtered, and concentrated under reduced pressure. Flash
chromatography (silica gel, 10-25% ethyl acetate/hexanes)
provided (650 mg, 85%) of the•desired product. 1H NMR (300 MHz,
CDC13) d 7.89 (s, 1H), 6.75 (d, J = 2.7 Hz, 1H), 6.72-6.63 (m,
1H), 5.03 (d, J = 7.5 Hz, 1 H), 4.77-4.75 (m, 1H), 4.16-4.08
(m, 2H), 2.30 (s, 1H), 2.16-2.13 (m, 1H), 2.05-1.99 (m, 1H),
1.47 (s, 9H).
Step Three: tert-butyl (4S)-6-isopropoxy-3,4-dihydro-2H-
chromen-4-ylcarbamate
To a solution of the alcohol, from step two, (325 mg,
1.2 2 mmol) in acetone (10 mL) was added cesium carbonate (800
mg, 2.45 mmol) followed by 2-bromopropane (360 mg, 2.93 mmol).
The reaction mixture was stirred at 60 °C for 24 h. The
solvent was removed under reduced pressure. The residue was
diluted with ethyl acetate (100 mL) and water (50 mL). The
organic layer was separated and washed with saturated sodium
chloride, dried (sodium sulfate), filtered, and concentrated
under reduced pressure to provide tert-butyl (4S) -6-
isopropoxy-3,4-dihydro-2H-chromen-4-ylcarbamate (340 mg, 90%):
1H NMR (300 MHz, CDC13) d 6.80 (d, J = 2.1 Hz, 1H), 6.17-6.62
(m, 2H), 4.81 (m, 2 H), 4.45-4.35 (m, 1H), 4.23-4.16 (m, 1H),
4.14-4.06 (m, 1H), 2.22-2.14 (m, 1H), 2.05-1.95 (m, 1H), 1.48
(s, 9H), 1.29 (d, J = 6.2 Hz, 6H). This material was used in
the next step without further purification.
Step Four: (4S)-6-isopropoxychroman-4-amine.
To a solution of tert-butyl (4S)-6-isopropoxy-3,4-
dihydro-2H-chromen-4-ylcarbamate (340 mg, 1.11 mmol) in
methanol (2 mL) was added hydrochloric acid (2 mL, 4 N in 1,4-
dioxane, 8 mmol). The reaction mixture was stirred at room
temperature for 2 h. The solvent was removed under reduced
pressure. The residue was diluted with methylene chloride (50
mL) and water (50 mL). The organic layer was separated and
the aqueous layer was extracted with methylene chloride (2 x
50 mL). The combined extracts were washed with saturated
sodium chloride, dried (sodium sulfate), filtered, and
concentrated under reduced pressure to provide (4S)-6-
isopropoxychroman-4-amine (240 mg, 99% crude yield): 1H NMR
(300 MHz, CDCI3) d 6.96 (d, J = 2.7 Hz, 1H), 6.90-6.86 (m, 1H),
6.80 (d, J = 9.0 Hz, 1H), 4.55-4.46 (m, 2H), 4.24-4.17 (m,
2H), 2.40-2.31 (m, 1H), 2.18-2.08 (m, 1H), 1.28 (d, J = 6.0
Hz, 6H). This material was used in the next step without
further purification.
Step Five: tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[(4S)-6-isopropoxy-3,4-dihydro-2H-chromen-4-
yl] amino}propylcarbamate.
The above compound was prepared essentially according to
the method of Example 17, step 3. Flash chromatography of the
crude product (silica gel, 2 0-50% ethyl acetate/hexanes)
afforded 95 mg of amine and the desired product (330 mg, 93%) :
1H NMR (300 MHz, CDC13) d 6.84 (s, 1H), 6.19-6.12 (m, 4H),
6.70-6.63 (m, 1H), 4.52 (d, J = 9.4 Hz, 1H), 4.45-4.37 (m,
1H), 4.25-4.13 (m, 2H), 3.77-3.69 (m, 2H), 3.45-3.39 (m, 1H),
3.09-3.03 (m, 1H), 2.83-2.75 (m, 3H), 2.05-2.01 (m, 1H), 1.95-
1.87 (m, 1H), 1.37 (s, 9H), 1.30 (d, J= 6.1 Hz, 6H).
Step Six: (2R,3S)-3-amino-4-(3,5-difluorophenyl)-l-{ [ (4S)-6-
isopropoxy-3,4-dihydro-2H-chromen-4-yl]amino}butan-2-ol
hydrochloride.
To a solution of the product from step 6 (330 mg, 0.65
mmol) in 1,4-dioxane (2 mL) was added hydrochloric acid (2 mL,
4 N in 1,4-dioxane, 8 mmol). The reaction mixture was stirred
at room temperature for 4 h. The solvent was removed under
reduced pressure. The residue was triturated with ethyl
ether. The resulting white solid was collected by filtration
and washed with ethyl ether to provide (2R,3S)-3-amino-4-(3,5-
difluorophenyl)-l-{ [(4S)-6-isopropoxy-3,4-dihydro-2H-chromen-
4-yl]amino}butan-2-ol hydrochloride (302 mg, 97%): ESI MS m/z
407 [C22H28F2N2O3 + H]+. This material was used in the next step
without further purification.
Step Seven: N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{ [ (4S)-6-isopropoxy-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide.
To a solution of the product from step 7 (302 mg, 0.63
mmol) in methylene chloride (5 mL) was added triethylamine
(322 mg, 3.15 mmol) followed by 1-acetylimidazole (71 mg, 0.63
mmol). The reaction mixture was stirred at room temperature
overnight. The mixture was washed successively with IN
hydrochloric acid, water, saturated sodium bicarbonate and
saturated sodium chloride, and dried (sodium sulfate),
filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel, 0-5%
methanol/methylene chloride provided the desired product (190
mg, 67%) as a white solid: ESI MS m/z 449 [C24H30P2N2O4 + H]+;
HPLC (Method A) 98.7% (AUC), tR = 8.69 min. Anal. Calcd for
C24H30F2N204: C, 64.27; H, 6.74; N, 6.24. Found: C, 64.11; H,
6.65; N, 6.17.
A mixture of (4S)-4-aminochroman-6-ol (165 mg, 1.0 mmol)
and Example 134 (300 mg, 1.0 mmol) in 2-propanol (5 mL) was
stirred at 60 °C for 16 h. The solvent was removed under
reduced pressure. Flash chromatography (silica gel, 0-5%
methanol/methylene chloride) recovered 54 mg of starting amine
and provided the desired product (200 mg, 64%) : 1H NMR (300
MHz, CDC13) d 7.26-6.63 (m, 6H), 4.55 (d, J = 9.0 Hz, 1H),
4.21-4.14 (m, 2H), 3.73-3.71 (m, 2H), 3.47-3.44 (m, 1H), 3.10-
3.02 (m, 1H), 2.84-2.75 (m, 3H), 2.10-2.02 (m; 1H), 1.94-1.90
(m, 1H), 1.37 (sr 9H).
Step Two: (4S)-4-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-
hydroxybutyl]amino}chroman-6~ol hydrochloride.
The above compound was prepared essentially according to
the method of Example 61, step 7. ESI MS m/z 365 [C19H22F2N2O3 +
H]+. This material was used in the next, step without further
purification.
To a solution of the product from step 2 (2 00 mg, 0.43
mmol) in methylene chloride (5 mL) was added triethylamine
(217 mg, 2.15 mmol) followed by 1-acetylimidazole (95 mg, 0.86
mmol). The reaction mixture was stirred at room temperature
for 16 h. The solvent was removed under reduced pressure.
The residue was dissolved in methanol (6 mL) and water (3 mL)
and treated with potassium carbonate (300 mg, 2.17 rrmol). The
reaction mixture was stirred at room temperature for 2 h. The
solvent was removed under reduced pressure. The residue was
acidified with IN hydrochloric acid and extracted with ethyl
acetate (3 x 5 0 mL). The combined extracts were washed with
saturated sodium chloride, and dried (sodium sulfate),
filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel, 0-5%
methanol/methylene chloride provided the desired product (85
mg, 49%) as a white foam. ESI MS mlz 407 [C21H24F2N3O4 + H] + ;
HPaC (Method B) 98.0% (AUC), tR = 7.01 min. Anal. Calcd for
C21H24F2N2O4 • 0.25 H20: C, 61J38; H, 6.01; N, 6.82. Found: C,
61-60; H, 5.68; N, 6.59.
A mixture of (2-cyano-benzyloxy)-acetic acid ethyl ester
(J. Org. Chem. 1985, 50, 2128) (30 g, 136 mmol) and KOH (38 g,
680 mmol) in 1:1 EtOH/H2O (270 ml) was heated to 90°C (oil
bath) for 15 h. After cooling to room temperature the mixture
was treated with cone. HCl until the pH = 1 and extracted with
CH2Cl2. The combined organic layers were dried concentrated in
vacuo to yield an orange oil. The oil was dissolved in aq.
Na2CO3, treated with activated carbon, filtered and the pH
adjusted to 1 with cone. HCl. The resulting solid was
collected by filtration and dried to yield 8.2 g of 2-
[ (carboxymethoxy) methyl]benzoic acid as a tan solid. 1H NMR
(400 MHz, DMSO-d6) d 12.9 (bs, 1 H), 7.87 (dd, J = 7.77, 1.14
Hz, 1 H), 7.66 (m, 1 H), 7.59 (tn, 1 H), 7.39 (n, 1 H), 4.90
(s, 2 H), 4.15 (m, 2 H).
Step Two: lH-isochromen-4(3H)-one.
A mixture of the product of step one (8.2 g, 39.0 mmol),
KOAc (16.5 g, 167.8 mmol) and Ac2O (117 ml) was heated to
reflux for 2 h. The mixture was cooled to room temperature
then poured onto ice. The mixture was extracted with Et2O (3 x
100 ml) and the combined organic layers dried over MgSO4 and
concentrated in vacuo. The resulting residue was dissolved in
4 0 ml of EtOH followed by the addition of 15 ml of 2 N NaOH.
Stirring was continued at room temperature for 2h then the
EtOH was removed in vacuo. The resulting aqueous layer was
extracted with Et2O (3 x 75 ml) and the combined organic layers
dried over MgSO4, concentrated in vacuo to yield 2.7 g of 1H-
isochromen-4(3H)-one as a slight yellow oil after flash
chromatography (10% EtOAc/Hexanes) Rf = 0.25. 1H NMR (400 MHz,.
CDC13) d S.05 (d, J = 7.88 Hz, 1 H), 7.59 (m, 1 H), 7.43 (appt,
J = 7.36 Hz, 1 H), 7.24 (d, J = 7.67 Hz, 1 H), 4.91 (s, 2 H),
4.39 (s, 2 H). Anal calcd for C9H8O2; C, 72.96; H, E.44; found
C, 72.50; H, 5.29. MS (ESI+) for C9H8O2 m/z 14 8.8 (M+H)+.
Alternative Preparation of lH-isochromen-4(3H)-one
To a THF (200 ml) solution of 2-iodo-benzyl alcohol (25
g, 107 mmol), at r.t., was added the NaH (5.12 g, 128 mmol) in
small portions. After complete addition of the NaH the allyl
bromide (11.1 ml, 128 mmol) 'was added via syringe. The
mixture was stirred overnight at room temperature. The
resulting white heterogeneous mixture was quenched with H20
(100 ml) and diluted with 300 ml of Et2O followed by washing
with H2O (2 x 100 ml) and brine (1 x 100 ml). The organic
layer was dried over MgS04 and concentrated in vacuo to yield
31 g of 1-[(allyloxy)methyl]-2-iodobenzene as a faint yellow
oil. HRMS (ESI+) calcd for C10H11IO m/z 273.9857 (M+E)+. Found
273.9855.
(
t.
1-t{allyloxy)methyl]-2-iodobenzene (23 g, 83.9 mmol) was
dissolved in 100 ml of CH3CN and 58 ml of Et3N. The solution
was vacuum degassed ( 3 cycles) followed by the addition of
Pd(OAc)2 (0.9 g, 4.2 mmol) and PPh3 (2.2 g, 8.4 mmol). The
mixture was heated to 80°C until HPLC indicated complete
reaction. The mixture was cooled to room temperature and
diluted with Et2O (200 ml). The mixture was washed with IN HC1
(2x 50 ml); NaHCO3 (2 x 50 ml) ; brine (1 x 50 ml); dried over
Na2SO4 and concentrated in vacuo to yield 4-methylene-3,4-
d.ihydro-lH-isochromene {Heterocycles 1994, 39, 497) as an oil.
HRMS (ESI+) calcd for C10H10O m/z 146.0732 (M+H)+. Found
146.0728. The crude oil was dissolved in 1:1 CH3OH/CH2Cl2 (500
ml) and 5 ml of pyridine added. The mixture was chilled to -
78°C and ozone was bubbled through the mixture for 1 h, at
which time TLC indicated complete reaction. The mixture was
purged with N2 at -78°C and treated with Me2S, then allowed to
warm to room temperature, and stir for 3h. The reaction was
then diluted with CH2Cl2 and washed with H2O and brine. The
organic layer was dried over NaaSO4 and concentrated in vacuo
to yield 5.1 g of lH-isochromen-4(3H)-one as a slight yellow
oil after flash chromatography (10% EtOAc/Hexanes) Rf = 0.25.
1H NMR (400 MHz, CDCl3) 8 8.05 (d, J = 7.88 Hz, 1 H), 7.59 (m,
1 H), 7.43 (appt, J = 7.36 Hz, 1 H), 7.24 (d, J = 7.67 Hz, 1
H), 4.91 (s, 2 H), 4.39 (s, 2 H. Anal calcd for C9H8O2; C,
72.96; H, 5.44; found C, 72.50; H, 5.29. MS (ESI+) for C9H8O2
m/z 14 8.8 (M+H)+.
Step Three: 3,4-dihydro-lH-isochromen-4-ol.
The alcohol was prepared from the ketone essentially
according to the method of Example 17, step 1; it was obtained
as a white solid. 1H NMR (400 MHz, CDC13) d 7.48 (m, 1 H),
7.31 (m, 2 H), 7.04 (m, 1 H), 4.84 (d, J = 15 Hz, 1 H), 4.72
(d, J = 15 Hz, 1 H), 4.58 (appt, J" = 2.38 Hz, 1 H), 4.14 (dd,
J = 12.02, 2.70 Hz, 1 H), 3.91 (dd, J = 12.02, 2.70 Hz, 1 H),
2.24 (bs, 1 H). Anal calcd for C9H10O3; C, 71.98; H, 6.71;
found C, 71.80; H, 6.94.
The above compound was prepared from the alcohol,
essentially according to the method of Example 19, step 2.
First, the alcohol is converted to the azide, which is
obtained as a yellow oil. 1H NMR (300 MHz, CDCl3) d 7.41-7.09
(m, 4 H), 4.90 (d, J = 15.26 Hz, 1 H), 4.75 (d, J = 15.26 Hz,
1 H), 4.23 (m, 2 H), 3.98 (dd, J = 12.43, 3.39 Hz, 1 H). The
crude azide was then reduced using PMe3, affording the amine.
1H NMR (300 MHz, CDC13) d 7.42 (m, 1 H), 7.30-7.22 (m, 2 H),
7.01 (m, 1 H), 4.85 (d, J = 15 Hz, 1 H), 4.75 (d, J = 15 Hz, 1
H), 4.00-3.86 (m, 3 H), 1.80 (bs, 2 H). 13C NMR (100 MHz,
CDC13) 8 138.4, 134.6, 128.6, 127.5, 127.4, 124.5, 12.IS,
68.61, 48.23.MS (ESI+) for C9H11NO m/z 133.2 (M+H)+ (loss of
NH2).
Ste Five: cert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-3-(3, 4-
dihydro-lH-isochromen-4-ylaminQ) -2-
hydroxypropylcarbamate.
)
t
The coupled product was prepared essentially according to
the method of Example 17, step 3; the resulting mixture of
epimers was obtained as an off white solid and was used in the
next step without further purification.. HRMS (ESI+) calcd
for C24 H30F2N2O4 m/z 449.2252 (M+H)+. Found 449.2244.
Step Six: N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(3,4-
dihydro-lH-isochromen-4-ylaraino)-2-
hydroxypropyl]acetamide.
The above compound was prepared essentially according to
the method, of Example 15, step 3; the acetamide was obtained
as a white foam. Small scale reverse phase HPLC of tiie
mixture of epimers results in partial separation.
1H NMR (400 MHz, CDC13) d 7.35 (m, 1 H), 7.28 (m, 2 H),
7.04 (m, 1 H), 6.77 (m, 2 H), 6.68 (m, 1 H), 5.90 (d, J = 8.50
Hz, 1 H), 4.83 (d, J = 15.13 Hz, 1 H), 4.73 (d, J = 15.13 Hz,
1 H), 4.18 (m, 2 H), 3.85 (dd, J = 11.82, 2.90 Hz, 1 H), 3.70
(m, 1 H), 3.62 (m, 1 H), 3.00-2.84 (m, 3 H), 2.71 (dd, J =
12.34, 7.15 Hz, 1 H), 1.93 (s, 3 H). MS (ESI + ) for C21lHZ4F2N2O3
m/z 3 91.5 (M+H)+.
1H NMR (400 MHz, CDC13) d 7.40 (m, 1 H), 7.29 (m, 2 H),
7.05 (m, 1 H), 6.77 (m, 2 H), 6.68 (m, 1 H), 5.88 (d, J = 8.91
Hz, 1 H), 4.87 (d, J = 15.13 H2, 1 H), 4.74 Id, J = 15.13 Hz,
1 H), 4.26-4.16 (m, 2 H), 3.84 (in, 2 H), 3.75 (bs, 1 H), 3.57
(m, 2 H), 3.04-2.85 (m, 3 H), 2.76 (dd, J= 12.34, 6.53 Hz, 1
H), 1.90 (s, 3 H). MS (ESI + ) for C21H24F2:N2O3 m/z 3.91.5 (M+H)+.
Step One: 6-isopropoxy-l,l-dimethyl-3,4-dihydro-lH-
isochromene.
The ether was prepred from the alcohol essentially
according to the method of Example 61, step 3; the ether was
obtained as a pale yellow oil: 1H NMR (300 MHz, CDC13) 8 7.00
(d, J = 8.5 Hz, 1H), 6.71 (dd, J = 8.5, 2.6 Hz, 1H), 6.59 (d,
J = 2.5 Hz, 1H), 4.54-4.46 (m, 1H), 3.92 (t, J = 5.5 Hz, 2H),
2.77 (t, J = 5.5 Hz, 2H), 1.49 (s, 6H), 1.32 (d, J = 6.0 Hz,
6H).
Step Two:- 4-bromo-6-isopropoxy-l,l-dimethyl-3,4-dihydro-lH-
isochromene
A solution of the product from step 1 (0.22 g, 1.0 mmol),
iV-bromosuccinimide (0.19 g, 1.05 mmol), and AIBN (catalytic)
in carbon tetrachloride (3 mL) was degassed with nitrogen for
10 min, and then stirred at 65 °C for 2.5 h. The reaction
mixture was cooled in ' an ice-water bath, diluted with
methylene chloride (150 mL) and washed with water (2 x 50 mL),
saturated sodium chloride (50 mL), dried (sodium sulfate),
filtered, and concentrated. The crude product was purified by
fl chroma tography (silica, 10:1 hexanes/ethyl acetate) to
afford the bromide (1.02 g, 53%) as a pale-yellow oil: 1H NMR
(300 MHz, CDC13) d 6.98 (d, J = 8.5 Hz, 1H), 6.86 (d, J = 2.5
Hz, 1H), 6.80 (dd, J = 8.5, 2.6 Hz, 1H), 5.18 (m, 1H), 4.54-
4.48 (m, 1H), 4.19 (dd, J = 12.8, 3.0 Hz, 1H), 4.11 (dd, J =
12.8, 3.0 Hz, 1H), 1.59 (s, 3H), 1.47 (s, 3H), 1.33 (d, J =
6.0 Hz, 6H).
A solution of 4-bromo-6-isopropoxy--l,l-dimethyl-3,4-
dihydro-lH-isochromene (0.61 g, 2.04 mmol), cesium carbonate
(1.33 g, 4.08 mmol), and tert-butyl (1S,2R)-3-amino-l-(3,5-
difluorobenzyl)-2-hydroxypropylcarbamate (0.64 g, 2.04 mmol)
in N,N-dimethylformamide (10 mL) was stirred at 60 °C, under
nitrogen, for 24 h. The reaction mixture was diluted with
ethyl acetate (100 mL) and washed with 5% lithium chloride (3
x 40 mL), water (2 x 30- mL), saturated sodium chloride (30
mL), dried (sodium sulfate), and concentrated under reduced
pressure. The crude product was purified by flash
chromatography (silica, 95:5 methylene chloride/methanol) to
afford the desired product (0.51 g, 47%) as a pale-yellow
foam: ESI MS m/z 53 5 [C29H40F2N2O5 + H]+.
Step Pour: (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(6-
isopropoxy-1,l-dimethyl-3,4-dihydro-lH~isochromen-4-
yl)amino]butan-2-ol hydrochloride.
The free amine was prepared from the: Boc-amine
essentially according to the method of Example 61, step 7; the
amine was obtained as a yellow solid: ESI MS mlz 43 5
[C24H32F2N2O3 + H] +.
The acetamide was prepared from the free amine
essentially according to the method of Example 61, step 7.
The crude product was purified by flash chromatography
(silica, 95:5 methylene chloride/methanol) to afford the
acetamide as a white foam: 1H NMR (300 MHz, CDCl3) d 7.01 (d,
J = 8.4 Hz, 1H), 6.82-6.74 (m, 4H), 6.69-6.63 (m, 1H), 5.81-
5.78 (m, 1H), 4.56-4.52 (m, 1H), 4.21-4.17 (m, 1H), 3.94 (d, J
= 2.1 Hz, 2H), 3.50-3.48 (m, 2H), 3.00-2.85 (m, 3H), 2.71-2.64
(m, 1H), 1.88 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H), 1.33 (d, J
= 6.0 Hz, 6H) ; ESI MS m/z 477 [C26H34F2N2O4 + H]+; HPLC (Method
A) >99% mixture of diastereomers (AUC), tR = 6.12 and 6.77 min.
Example 65: N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
[(6-nedpentyl-3,4-dihydro-lH-isochromen-4-
yl)amino]propyl}acetamide
Lithium hydroxide monohydrate (11.80 g, 281.6 mmol) was
added at room temperature over several minutes to a solution
of 5-bromophthalide ( 20.0 g, 93.88 mmol) in a 2:1:1 solution
of tetrahydrofuran/methanol/water (570 mL) and the reaction
mixture stirred at room temperature overnight. The reaction
mixture was concentrated under reduced pressure and
azeotropically dried with benzene to give 5-Bromo-2~
hydroxymethyl-benzoic acid as a white solid. The material was
used without further purification: 1H NMR (3 00 MHz, CDC13 +
CD3OD) d 7.89 (d, J = 8.3 Hz, 1H), 7.67 (d, J~ = 1.9 Hz, 1H),
7.50 (dd, J = 8.3, 1.9 Hz, 1H), 3.99 (s, 2H); ESI MS (negative
mode) m/z 229 [C8H7Br03 - H]. Sodium hyride (15.0 g, 375 mmol,
60% dispersion in mineral oil) was added in small portions
over the course of 0.5 h at room temperature to a solution of
5-Bromo-2-hydroxymethyl-benzoic acid in tetrahydrofuran (235
mL) containing bromoacetic acid (14.35 g, 103.2 mmol) and
sodium iodide (1.41 g, 9.4 mmol). The reaction mixture was
heated at reflux overnight. The reaction mixture was cooled
to room temperature and poured into water and then extracted
with diethyl ether. The aqueous phase was acidified with 10%
hydrochloric acid to pH 3-4 and extracted several times with
ethyl acetate. The combined ethyl acetate phases were washed
with water and saturated sodium chloride, dried (sodium
sulfate), filtered, and concentrated to yield -Bromo-2-
carboxymethoxymethyl-benzoic acid as a white solid. The
material was used without further purification: 1H NMR (300
MHz, CD3OD) d 7.93-7.86 (m, 2H), 7.55-7.50 (m, 1H), 4.98 (s,
2H), 4.23 (s, 2H) ; ESI MS (negative mode) m/z 287 [C10H9BrO5 -
H].
A solution of Bromo-2-carboxymethoxymethyl-benzoic acid
in acetic anhydride (350 mL) containing potassium acetate (170
g) was heated at reflux for 2 h. The reaction mixture was
cooled to room temperature and concentrated under reduced
pressure and the residue partitioned between ethyl acetate and
water. The phases were separated and the aqueous phase
extracted with ethyl acetate. The combined ethyl acetate
phase was then washed with saturated sodium chloride, dried
(sodium sulfate), filtered, and concentrated to yield a red
semi-solid. Purification by flash column chromatography over
silica (85:15 hexanes/ethyl acetate) gave; the enol acetate
(7.59 g, 29% for three steps) as a golden syrup: 1H NMR (300
MHz, CDCI3) d 7.37 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (d, J = 1.9
Hz, 1H), 6.82 (d, J= 8.2 Hz, 1H), 5.04 (s, 2H), 2.29 (s, 3H).
Unactivated Dowex 500A OH anion exchange resin (1 g) added in
one portion to a solution of the acetate enol acetate {5.95 g,
22.11 mmol) in methanol (50 mL) and the reaction mixture
stirred at room temperature overnight. The reaction mixture
was gravity filtered and the resin washed with fresh methanol.
The combined ' filtrate was then concentrated under reduced
pressure to yield 6-Bromo-isochroman-4-one (4.32 g, 86%) as a
yellow oil, which solidified on standing: 1H NMR (300 MHz,
CDCl3) d 7.90 (d, J = 8.3 Hz, 1H), 7.56 (dd, J = 8.3, 1.7 Hz,
1H), 7.41 (d, J = 1.7 HZ, 1H), 4.86 (s, 2H), 4.36 (s, 2H).
Step Three: 6-Bromo-isochroman-4-ol
A solution of sodium borohydride (300 mg, 7.93 mmol)
dibsolved in a minimum amount of ice cold water was added
dropwise at 0 °C to a solution of 6-Bromo-isochroman-4-one
(1.49 g, 6.56 mmol) in absolute ethanol (27.0 mL). The
reaction mixture was stirred at room temperature for 2 h. The
reaction mixture was partitioned between ethyl acetate and
saturated sodium bicarbonate solution. The phases were
separated and the organic phase washed with water and
saturated sodium chloride, dried (sodium sulfate), filtered,
and concentrated under reduced pressure to yield 6-Bromo-
isochroman-4-ol (1.44 g, 95%) as a white solid: 1H NMR (300
MHz, CDC13) d 7.40 (dd, J = 8.3, 1.8 Hz, 1H), 7.30 (d, J = 8.3
Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 4.63 (ABq, J = 15.3 Hz,
2H), 4.49 (d, J = 8.6 Hz, 1H), 4.07 (dd, J = 12.0, 2.8 Hz,
1H), 3.83 (dd, J = 12.0, 2.8 Hz, 1H), 2.60 (d, J = 9.2 Hz,
1H).
Diphenyphosphoryl azide (2.11 mL, 9.8 mmol) was added at
0 °C to a solution of 6-Bromo-isochroman-4-ol (1.87 g, 8.16
mmol) in toluene (17 mL). To this was added dropwise over 0.5
h a mixture of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.46 ml,
9.8 mmol) in toluene (5.0 ml). The reaction mixture was then
stirred at room temperature overnight. The reaction mixture
was then passed through a plug of silica and the plug rinsed
with 6:1 hexanes/ethyl acetate. The combined filtrates were
concentrated under reduced pressure to provide the azide as a
yellow oil: 1H NMR (300 MHz, CDC13) d7.46-7.33 (m, 3H), 4.76
(ABq, J = 15.5 Hz, 2H), 4.22-4.16 (m, 3H), 3.93 (dd, J = 11.7,
2.6 Hz, 1H). A solution of lithium aluminum hydride (391 mg,
9.79 mmol) im a minimum amount of tetrahydrofuran (2.0 mL) was
added dropwise at 0 °C to a solution of the azide in
tetrahydrofuran (3 0 mL) and the reaction mixture was heated at
reflux for 1 h. The reaction mixture was cooled to room
temperature and quenched with water (0.5 mL), 15% sodium
hydroxide (1.2 ml), water (0.5 mL) and the reaction mixture
stirred at room temperature for 1 h. The resulting mixture
was then passed through a plug of silica and the plug rinsed
with ether. The combined filtrates were concentrated under
reduced pressure to afford a oil which was dissolved in a
minimum amount of ethyl acetate to which was added hydrogen
chloride (3.0 ml, 4 N in 1,4-dioxane, 12 mmol) and the
reaction mixture stirred at room temperature overnight. The
reaction mixture was vacuum filtered to afford the desired
amine salt (1.54 g, 72 % for two steps) as a white solid: 1H
NMR (300 MHz, CDC13) d 7.54-7.44 (m, 2H), 7.37 (s, 1H), 4.80
(ABq, J = 15.5 Hz, 2H), 4.42 (d, J = 12.8 Hz, 1H), 4.34 (s,
1H), 3.87 (dd, J = 12.8, 2.2 Hz, 1H), 3.66 (s, 3 H) ; ESI MS
m/z 22 8 [C9H10BrNO + H] +.
Di-tert-butyl dicarbonate (1.40 g, 6.40 mmol) was added
in portions to a solution of amine (1.54 g, 5.82 mmol) in
acetonitrile (25 mL) containing N,N-diisopropylethylamine (4.0
mL, 23.28 mmol) and the reaction mixture stirred at room
temperature overnight. The reaction mixture was concentrated
under reduced pressure and partitioned between ethyl acetate
and water. The organic phase was dried (sodium sulfate),
filtered, and concentrated under reduced pressure to afford a
yellow syrup. Purification by flash column chromatography
over silica (80:20 hexanes/ethyl acetate) yielded the desired
product (1.05 g, 55%) as a white solid: 1H NMR (300 MHz, CDC13)
d 7.41-7.23 (m, 2H),7.15 (s, 1H), 5.10-5.07 (m, 1H), 4.69
(ABq, J = 15.5 Hz, 2H), 4.04-4.00 (m, 1H), 3.89-3.81 (m, 1H),
1.45 (s, 9 H).
Neo-pentylmagnesium bromide (10 mL, 9.1 mmol, 1.0 M in
ether) was added dropwise to a solution of 2:inc chloride (18.2
mL, 0.5 M in tetrahydrofuran, 9.1 mmol) over 0.5 h and the
reaction mixture stirred at RT for an additional 0.5 h.
[1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
complex with dichloromethane (1:1) (250 mg, 0.30 mmol) was
added to the reaction mixture followed by (6-Bromo-isochroman-
4-yl)-carbamic acid tert-butyl ester (1.00 g, 3.04 mmol) and
the reaction mixture heated at reflux for 1 h. The reaction
mixture was cooled and then concentrated under reduced
pressure. The residue was re-dissolved in ethyl acetate and
washed with water, sodium chloride, dried (sodium sulfate),
filtered, and concentrated under reduced pressure.
Purification by flash column chromatography over silica (83:17
hexanes/ethyl acetate) yielded the desired protected amine
(303 mg, 31%) as a white solid: 1H NMR (300 MHz, CDCl3) d 7.30-
7.23 (m, 1H), 7.00 (d, J =6.3 Hz, 1H), 6.74 (s, IB), 5.09-
5.06 (m, 1H), 4.79-4.65 (m, 3H), 4.13-3.85 (m, 2H), 2.45 (s,
2H), 1.46 (s, 9 H), 0.89 (s, 9H) ; ESI MS m/z 320 [d19H39NO3 +
H]+. A solution of protected amine (303 mg, 0.95 mmol) in
hydrogen chloride (20 mL, 4 N in 1,4-dioxane, 80 mmol) was
stirred at room temperature overnight. The reaction mixture
was concentrated under reduced pressure to give 6-(2,2-
Dimethyl-propyl)-isochroman-4-ylamine hydrochloride (210 mg,
quantitative) as a white solid: 1H NMR (300 MHz, CDC13) d 7.28
(d, J = 7.6 Hz, 1H), 7.01 (d, J = 7.6, 1.2 Hz, 1H), 6.73 (d, J"
= 1.2 Hz, 1H), 4.75 (ABq, J= 15.0 Hz, 2H), 3.96-3.60 (m, 3H),
2.44 (s, 2H), 1.73 (m, 2H), 0.89 (s, 9H) ; ESI MS m/z 220
[C14H21NO + H]+.
Step Six: text-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-[(6-neopentyl-3,4-dihydro--lH-isochromen-4-
yl)amino]propylcarbamate.
The above compound was prepared essentially according to
the method of Example 17, step 3. The resulting crude
material was purified by flash column chromatography over
silica (94:6 chloroform/methanol) to yield the desired product
as a white foam: ESI MS m/z 519 [C29H40F2N204 + H] +.
The acetamide was prepared from the Boc-protected amine
essentially according to the method of Example 61, steps 7 and
8. First, the Boc-protected amine was deprotected to afford
the free amine as a white solid. Second, the free amine was
acylated to form the acetamide, as a mixture of epimers. 1H
NMR (300 MHz, CDC13) d 7.24-7.16 (m, 2H), 7.01-6.98 (m, 1H),
6.76-6.66 (m, 4H), 5.83 (ABq, J= 15.0 Hz, 2H), 4.10-4.05 (m,
2H), 3.83-3.79 (m, 1H), 3.55-3.51 (m, 2H), 2.93-2.72 (m, 3H),
2.69-2.65 (m, 1H), 2.45 (s, 2H), 1.89 (m, 4H), 0.89 (s, 9H) ;
ESI MS m/z 461 [C26H34F2N2O3 + H]+; HPLC (1-99, 220) 68.1% Major
Epimer (AUC), tR = 10.89 min and 31.8% Minor Epimer (AUC), tR =
11.19 min.
To a solution of tetralone (2.16 g, 10 mmol) in
tetrahydrofuran (50 mL) was added sodium hydride (60%, 1.49 g,
37.1 mmol) followed by dimethyl carbonate (2.73g, 30 mmol).
The reaction mixture was heated at reflux for 3 h and then
allowed to cool to room temperature and quenched with acetic
acid (3.6 mL). The solvent was removed under reduced pressure
and the residue was diluted with ethyl ether (100 mL) and
water (50 mL). The organic layer was separated and the
aqueous layer was extracted with ethyl ether (2 x 50 mL). The
combined extracts were washed with saturated sodium chloride,
dried (sodium sulfate), filtered, and concentrated under
reduced pressure. Flash column chromatography (silica gel,
10-2 0% ethyl acetate/hexanes) provided the desired product
(2.50 g, 91%): 1H NMR (300 MHz, CDCl3) d 12.48 (s, 1H), 7.60
(s, 1H), 7.17-7.08 (m, 2H), 3.85 (s, 3H), 2.84-2.79 (m, 2H),
2.62-2.57 (m, 2H), 2.54 (s, 2H), 0.94 (s, 9H).
Step Two: 2-(tert-Butyl-dimethyl-silanyloxymethyl)-7-(2,2-
dimethyl-propyl)-3,4-dihydro-2H-naphthalen-l-one.
To an ice-cooled solution of 7-(2,2-Dimethyl-propyl)-1-
hydroxy~3,4-dihydro-naphthalene-2-carboxylic acid methyl ester
(2.49 g, 9-07 mmol) in tetrahydrofuran (20 mL) was added
lithium aluminum hydride (l M in tetrahydrofuran, 9 mL, 9
mmol). The reaction mixture was stirred at 0 °C for 2 h and
then quenched with saturated ammonium chloride and ethyl
acetate. The resulting emulsion was filtered through
diatomaceous earth. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate. The combined
extracts were washed with saturated sodium chloride, dried
(sodium sulfate), filtered, and concentrated under reduced
pressure. Flash column chromatography (silica gel, 10-20%
ethyl acetate/hexanes) provided hydroxymethyl tetralone (1.55
g, 70%): 1H NMR (300 MHz, CDCl3) d 7.7B (d, J = 1.4 Hz, 1H),
7.27 (dd, J = 7.8, 1.4 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H),
4.00-3.90 (m, 1H), 3.85-3.75 (m, 1H), 3.20-3.10 (m, 1H), 3.08-
2.90 (m, 2H), 2.75-2.60 (tn, 1H), 2.52 (s, 2H), 2.15-2.05 (m,
1H), 2.00-1.85 (m, 1H), 0.90 (s, 9H).
To a solution of hydroxymethyl tetralone (1.50 g, 6.09
mmol) in N,N-dimethyl formamide (6 mL) was added imidazole
(500 mg, 7.25 mmol) followed by tert-butyldimethylsilyl
chloride (1.03 g, 6.64 mmol). The reaction mixture was
stirred at room temperature for 2 h and then diluted with 1:1
hexanes/ethyl acetate (100 mL). The mixture was washed
successively with IN hydrochloric acid, water, saturated
sodium bicarbonate and saturated sodium chloride, and dried
(sodium sulfate), filtered, and concentrated under reduced
pressure to provide 2-(tert-Butyl-dimethyl-silanyloxymethyl)-
7-(2,2-dimethyl-propyl)-3,4~dihydro-2H-naphthalen-l-one
(2.20g, 99% crude yield): 1H NMR (300 MHz, CDC13) d 7.76 (d, J
= 1.8 Hz, 1H), 7.23 (dd, J= 7.8, 1.8 Hz, 1H), 7.14 (d, J =
7.8 Hz, 1H), 4.16-4.08 (m, 2H), 3.90-3.84 (J, 1H), 3.01-2.95
(m, 2H), 2.68-2.60 (m, 1H), 2.51 (s, 2H), 2.42-2.33 (m, 1H),
2.03-1.95 (m, 1H), 0.89 (s, 9H), 0.87 (s, 9H), 0.07 (s, 3H),
0.06 (s, 3H). This material was used in the next step without
further purification..
To a -30 oC cooled solution of 2-(tert-Butyl-dimethyl-
silanyloxymethyl)-7-(2, 2-dimethyl-propyl)-3,4-dihydro-2H-
naphthalen-1-one (2.20 g, 6.09 mmol) in tetrahydrofuran (20
mL) was added (S)-2-methyl-Cbs-oxazaborolidine (1 M in
toluene, 0.61 mL, 0.61 mmol) and a solution of borane-methyl
sulfide complex (2 M in tetrahydrofuran, 2.15 mL, 4.3 mmol) in
tetrahydrofuran (5 mL). The reaction mixture was heated at -
20 to -5 °C for 5 h. The reaction mixture was quenched with
methanol (8.3 mL) at -5 °C and then allowed to warm to room
temperature and stirred overnight. The solvent was removed
under reduced pressure. Plash column chromatography (silica
gel, 0-5% ethyl acetate/hexanes) recovered 790 mg of ketone
and provided chiral 2-(tert-Butyl-dimethyl-silanyloxymethyl)-
7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naphthalen-l-ol
(980 mg, 70%): 1H NMR (300 MHz, CDCl3) d 7.14 (s, 1H), 7.03-
6.96 (m, 2H), 4.84 (d, J = 2.5 Hz, 1H), 3.92-3.82 (m, 2H),
3.04 (d, J = 3.7 Hz, 1H), 2.92-2.67 (m, 2H), 2.46 (s, 2H),
2.04-1.86 (m, 2H), 1.75-1.63 (m, 1H), 0.91 (s, 9H), 0.90 (s,
9H), 0.10 (s, 3H), 0.09 (s, 3H).
Step Four: [l-Amino-7-(2,2-dimethyl-propyl)-1,2,3,4-
tetrahydro-naphthalen-2-yl]-methanol.
The alcohol was converted into an amine essentially
according to the method of Example 65, step 4. However, the
resulting amine was not protected, as in Example 65, step 4.
First the alcohol was converted to the azide, which was
purified by flash column chromatography (silica gel, 0-5%
ethyl acetate/hexanes). 1H NMR (300 MHz, CDCl3) d 7.15 (s,
1H), 7.03-6.97 (m, 2H), 4.42 (d, J = 2.5 Hz, 1H), 3.75 (dd, J
= 10.1, 5.1 Hz, 1H), 3.67 (dd, J = 10.1, 4.8 Hz, 1H), 2.81-
2.67 (m, 2H), 2.48 (s, 2H), 2.07-1.98 (m, 2H), 1.80-1.67 (m,
1H), 0.91 (s, 9H), 0.89 (s, 9H), 0.08 (s, 3H), 0.07 (s, 3H).
Second, the azide was reduced to the amine. 1H NMR (3 00
MHz, CDC13) 5 7.06 (s, 1H), 7.01-6.92 (m, 2H), 3.83-3.70 (m,
3H), 2.92-2.72 (m, 3H), 2.47 (s, 2H), 1.85-1.69 (m, 2H), 1.48-
1.33 (m, 1H), 0.90 (s, 9H).
The coupling was performed essentially according to the
method of Example 17, step 3. The resulting crude product was
purified by flash chromatography (silica gel, 1-10%
methanol/methylene chloride)-. : 1H NMR (300 MHz, CDC13) d
7.01-6.91 (m, 3H), 6.76-6.60 (m, 5H), 4.62 (d, J = 8.9 Hz,
1H), 4.34-4.30 (m, 1H), 4.07-3.89 (m, 2H), 3.83-3.61 (m,
4H), 3.53-3.47 (m, 2H), 2.95-2.86 (m, 2H), 2.80-2.63 (m, 3H),
2.59-2.57 (m, 2H), 2.45 (s, 2H), 2.15-2.05 (m,, 1H), 1.81-1.77
(m, 1H), 1.36 (s, 9H), 0.89 (s, 9H).
Step Six: N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{[(1S)-2-(hydroxymethyl)-7-neopentyl-l,2,3,4-
tetrahydronaphthalen-1-yl]amino}propyl)acetamide.
The above compound was prepared essentially according to
the method of Example 15, step 3. First the Boc-protected
amine was deprotected. ESI MS m/z 447 [C26H36F2N2O2 + H]+.
Second, the amine was acetylated. Then the residue was
dissolved in methanol (6 mL) and water (3 tnL) and treated with
potassium carbonate (300 mg, 2.17 mmol). The reaction mixture
was stirred at room temperature for 2 h. The isolvent was
removed under reduced pressure. The residue was acidified
with IN hydrochloric acid and extracted with ethyl acetate (3
x 50 mL). The combined extracts were washed with saturated
sodium chloride, and dried (sodium sulfate), filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, 0-5% methanol/methylene
chloride provided the desired product (80 mg, 44%) as a white
foam: IR (ATR) 3265, 3072, 2948, 2864, 1626, 1595, 1550, 1459,
1364, 1315, 1115, 1071, 984, 842 cm"1; 1H NMR (300 MHz, CD3OD) d
7.15 (s, 1H), 7.07-7.00 (m, 2H), 6.83-6.72 (m, 3H), 4.18 (d, J
= 5.9 Hz, 1H), 4,06-3.99 (m, 1H), 3.74-3.64 (m, 2H), 3.57 (t,
J = 8.4 Hz, 1H), 3.34 (s, 2H), 3.13-3.07 (m, 1H), 2.94-2.59
(m, 5H), 2.49 (s, 2H), 2.30-2.20 (m, 1H), 2.04-1.98 (m, 1H),
1.81 (s, 3H), 1.64-1.57 (m, 1H), 0.91 (s, 9H) ; ESI MS m/z 489
[C28H38F2N2O3 + H]+; HPLC (Method C) 98.2% (AUC), tR = 9.41 min.
Anal. Calcd for C21H24F2N2O4 • H2O: C, 66.38; H, 7.96; N, 5.53.
Found: C, 66.18; H, 7.80; N, 5.45.
Example 67: 5-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-
ethyl-1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)amino]-5-oxopentanoic acid.
To a solution of 3-amino-4-(3,5-difluoro-phenyl)-1-(7-
ethyl-1,2,3,4-tetrahydro-naphthalen-l-ylamino)-butan-2-ol
(0.240g, 0.64 mmol), triethylamine (0.268 mL, 1.92 mtnol), and
chloroform (3 mL) was added glutaric anhydride (0.073 g, 0.64
mmol) and reaction was stirred overnight at SO°C. Reaction was
washed with IN HC1, 10% NaHC03, brine, dried, over MgSO4,
filtered, concentrated in vacuo to give 5-[ ((1S,2R)-1-(3,5-
difluorobenzyl)-3-{[(1S)-7-ethyl-l,2,3,4-tetrahydronaphthalen-
l-yl] amino} -2-hydroxypropyl) amino] -5-oxopentanoic acid (100
mg). Purified via prep-HPLC. 1H NMR (400 MHz, CD3OD) d 1.26
(t, J = 8 Hz, 3 H), 1.73 (m, 2 H), 1.39 (m, 1 H), 2.01 (m, 1
H), 2.17 (m, 6 H), 2.68 (d, J = 8 Hz, 2 H), 2.93 (d, J = 6 Hz,
1 H), 3.02 (m, 1 H), 3.30 (m, 2 H), 3.88 (m, 1 H), 4.09 (m, 1
H), 4.57 (m, 1 H), 6.79 (m, 1 H), 6.88 (m, 3 H), 6.93 (d, J =
6 Hz, 1 H), 7.20 (m, 2 H), 7.31 (s, 1 H); OAMS: ES+ 488.9 ES-
486.9
Example 68: 4-[((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-
ethyl-1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)amino]-4-oxobutanoic acid.
The above compound was prepared essentially according to
the method of Example 67. The crude product was purified via
prep-HPLC. 1H NMR (400 MHz, CD3OD) d 1.27 (t, J = 8 Hz, 3 H),
1.88 (m, 1 H), 2.04 (m, 1 H), 2.25 (m, 3 H), 2.48 (m, 2 H),
2.70 (m, 4 H), 2.81 (m, 1 H), 2.93 (m, 1 H), 3.12 (dd, J = 8,
13 Hz, 1 H), 3.32 (m, 2 H), 3.87 (m, 1 H), 4.04 (m, 1 H), 4.51
(s, 1 H), 6.80 (m, 1 H), 6.86 (d, J = 6 Hz, 2 H), 7.18 (dd, J
= 8, 19 Hz, 2 H), 7.32 (s, 1 H); OAMS: ES+ 474.9, ES- 472.9.
EXAMPLE 69: Preparation of l-(3-
isopropylphenyl)cyclohexanamine hydrochloride 3.
Step 1. Preparation of l-(3-isopropylphenyl)cyclohexanol
1.
To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry
THF is added a small crystal of iodine followed by 40 µL of
dibromoethane. This mixture is placed in a water bath at 5 0 °C
and 3-isopropylbromobenzene (5.0 g, 25 mmol) in 15 mL of dry
tetrahydrofuran (THF) is added dropwise over 20 min, while the
bath temperature is raised to 70 °C. The mixture is stirred and
refluxed for 4 0 additional min. The solution is cooled in an
ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of
dry THF is added dropwise over 15 min. The ice bath is removed
and the mixture is allowed to warm to ambient temperature over
lh. The solution is decanted into aqueous saturated NH4Cl, and
combined with an ether wash of the residual magnesium
turnings. The organic phase is washed twice more with aqueous
NH4C1, dried over anhydrous Na2SO4, filtered and concentrated.
Chromatography on silica gel, eluting with 10% ethyl acetate
in heptane, affords 2.7 g (12 mmol, 60%) of compound 1 as an
oil: 1H NMR (CDCI3) d 7.39 (m, 1 H), 7.3 (m, 2 H), 7.12 (m, 1
H), 2.92 (m, 1 H), 1.84-1.54 (m, 10 H), 1.26 (d, J = 7 Hz, 6
H).
Step 2. Preparation of 1- (3-isopropylphenyl)cyclohexylazide
(2).
To 3.20 g (14.7 mmol) of compound 1 in 60 mL of CH2C12
under nitrogen is added 2.10g (32.3 mmol) of sodium azide.
The stirred suspension is cooled to -5°C and a solution of
trif luoroacetic acid (9.0 mL, 120 mmol) in 35 mL of
dichloromethane is added dropwise over 1 h. The resulting
suspension is stirred at 0 °C for an additional hour. To the
cold, vigorously stirred mixture is added, dropwise, 10 mL of
water, followed by dropwise addition of a mixture of 10 mL of
water and 10 mL of concentrated ammonium hydroxide. After 30
min the mixture is poured into a separatory funnel containing
350 mL of a 1:1 mixture of heptane and ethyl acetate, and 100
mL of water. The organic phase is washed with an additional
portion of water, followed successively by 1 N KH2PO4, water,
and brine. It is then dried over anhydrous Na2SO4, filtered and
concentrated to afford 3.6 g (14.7 mmol, 100%) of 2 as a pale
yellow oil: 1H NMR (CDCl3) d 7.3 (m, 2 H), 7.25 (m, 1 H), 7.16
(m, 1 H), 2.92 (m, 1 H), 2.01 (m, 2 H), 1.83 (m, 2 H), 1.73-
1.64 (m, 5 H)-, 1.3 (m, 1 H), 1.26 (d, J = 7 Hz, 6 H).
Step 3. Preparation of l-(3-isopropylphenyl)cyclohexanamine
hydrochloride 3.
To 1-(3-isopropylphenyl)cyclohexylazide 2 (2.7 g, 11
mmol) in 200 mL of ethanol is added 20 mL of glacial acetic
acid and 0.54 g of 10% palladium on carbon. The mixture is
evacuated and placed under 16 psi of hydrogen, with shaking,
for 2.5 h. The reaction mixture is filtered, the catalyst is
washed with ethanol, and the solvents are removed in vacuo.
Residual acetic acid is removed by chasing the residue with
toluene. The acetate salt is dissolved in ethyl acetate and 1
N NaOH is added. The organic phase is washed with more 1 N
NaOH and then with water, dried over Na2SO4, filtered and
concentrated. The residue is dissolved in ether and ethereal
HC1 (concentrated HCl in ether which has been stored over
MgSO4) is added to afford a white solid. This is filtered,
washed with ether, collected as a solution in dichloromethane,
and concentrated to afford 2.1 g (8.3 mmol, 7 5%) of
hydrochloride 3 as a white solid: 1H NMR (CDC13) d 8.42 (br s,
3 H), 7.43 (m, 2 H), 7.25 (m, 1 H), 7.15 (m, 1 H), 2.92 (hept,
J = 7 Hz, 1 H), 2.26 (m, 2 H), 2.00 (m, 2 H), 1.69 (m, 2 H),
1.45-1.3 (m, 4 H), 1.24 (d, J = 7 Hz, 6 H) ; IR (diffuse
reflectance) 2944, 2864, 2766, 2707, 2490, 2447, 2411, 2368,
2052, 1599, 1522, 1455, 1357, 796, 704 cm -I. MS (EI)m/z(rel
intensity) 217 (M+,26), 200 (13), 175 (18), 174 (99), 157
(15), 146 (23), 132 (56), 131 (11), 130 (16), 129 (18). HRMS
(ESI) calcd for C15H23N+H1 218.1909, found 218.1910. Anal. Calcd
for C15H23NHCl: C, 70.98; H, 9.53; N, 5.52; Cl, 13.97. Pound:
C, 70.98; H, 9.38; N, 5.49.
EXAMPLE 70: Preparation of N-((IS,2R)-1-(3,5-difluorobenzyl)-
2-hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
hydrochloride 7
Step 1. Preparation of tert-butyl (1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-{ [1- (3-
isopropylphenyl)cyclohexyl]amino}propylcarbamate
(5).
Compound 3 (2.1 g, 8.3 mmol) is shaken with aqueous 1 N
NaOH and ethyl acetate. The layers are separated and the
organic phase is washed sequentially with aqueous NaOH and
then with 1N NaHCO3. The organic layer is then dried over
Na2SO4, filtered, and concentrated to afford a quantitative
yield (1.8 g) of the free amine as an oil. Example 134 (4, 1.5
g, 5.0 mmol) is combined with the free amine in 3 5 mL of
isopropyl alcohol, and the mixture is heated at reflux for 5.5
h, under nitrogen. The mixture is cooled and concentrated in
vacuo. The resulting residue is dissolved in 250 mL of ethyl
ether, which is washed four times with 30 mL portions of
aqueous 10% HC1 to remove much of the excess amine 3. The
ether phase is then washed twice with 1N NaHCO3, once with
brine, dried over Na2SO4, filtered, and concentrated. The
concentrate is chromatographed over silica gel, eluting with
4% to 6% methanol (containing 2% NH4OH) in CH2C12 to afford
1.98g (3.8 tnmol, 77%) of 5 as a viscous oil: 1H NMR (CDC13) d
7.28-7.21 (m, 3 H), 7.09 (m, 1 H), 6.69 (m, 2 H), 6.62 (m, 1
H), 4.68 (d, J = 10 Hz, 1 H), 3.74 (m, 1 H), 3.47 (m, 1 H),
2.93-2.86 (m, 2 H), 2.67 (dd, J = 8, 14 Hz, 1 H), 2.32 (m, 2
H), 1.88 (m, 4 H), 1.63-1.52 (m, 5 H), 1.36 (s +m, 10 H), 1.24
(d, J = 7 Hz, 6 H); MS (CI) m/z 517.4 (MH+).
Step 2. Preparation of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-
l-{[1-(3-isopropylphenyl)cyclohexyl] amino}butan-2-ol
dihydrochloride 6
To 1.98 g (3.8 mmol) of compound 5 in 15 mL of CH2C12 is
added 6.5 mL of trifluoroacetic acid. The mixture is stirred
under a nitrogen atmosphere for 1 h and then concentrated. The
resulting residue is taken up in ethyl acetate and washed
twice with 10% Na2CO3 and once with 1 N NaHCO3. The organic
layer is dried over anhydrous Na2S04, filtered, and
concentrated to afford 1.6 g (quant.) of a pale yellow oil
(free base of 6), which is generally carried on in the next
step without characterization. The yellow oil may be dissolved
in ether and treated with ethereal HCl to precipitate
(dihydrochloride 6 as a white solid after trituration with
ether: 1H NMR (CDC13 +CD3OD drop) d 7.55 (s, 1 H), 7.45-7.15
(m, 3 H), 6.85 (m, 2 H), 6.75 (m, 1 H), 4.4 (d, J = 9.5 Hz, 1
H), 3.82 (m, 1 H), 2.97 (m, 2 H), 2.81 (dd, J = 8, 14 Hz, 1
H), 2.65 (m, 2 H), 2.5 (obscured by water) 2.26 (m, 1 H), 2.13
(m, 2 H), 1.79 (m, 2 H), 1.59 (m, 1 H), 1.45-1.25 (m, 3 H),
1.28 (d, J = 7 Hz, 6 H); MS (CI) m/z 417.3 (MH+).
Step 3. Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
hydrochloride 7
The free base of compound 6 (1.6 g, 3.8 mmol) is
dissolved in 20 mL of CH2Cl2 under nitrogen, and 0.87 g (7.9
mmol) of acetyl imidazole is added with stirring. After 15
min., 30 mL of methanol is added, followed by 15 mL of 1 N
NaOH to saponify the ester that is formed along with the
amide. The CH2Cl2 is removed in vacuo, and the mixture is
neutralized with 1N KH2PO4. The product is extracted into ethyl
acetate and the organic phase is washed with water, with 1 N
NaHCO3, and with brine. The solution is dried over Na2SO4,
filtered and concentrated to an oil, which is chromatographed
over silica gel, eluting with 5%-7% methanol (containing 1% of
NH4OH) in CH2Cl2- Product-containing fractions are pooled,
concentrated, dissolved in a small volume of ethanol, and
acidified with 0.6 N HCl in dry ether. Concentration from this
solvent mixture affords a gel-like material. This can be
dissolved in ethanol and ethyl acetate, and concentrated to
1.65 g (3.3 mmol, 87%) an off-white solid. This solid is
triturated with ethyl acetate to remove a pale yellow mother
liquor, leaving hydrochloride 7 as a white solid: 1H NMR (CDC13
+CD3OD drop) d 7.44 (s, 1 H), 7.37 (m, 2 H), 7.29 (m, 1 H),
6.70 (m, 2 H), 6.62 (m, 1 H), 3.94 (m, 1 H), 3.87 (m, 1 H),
3.0-2.94 (m, 2 H), 2.64 (m, 4 H), 2.36 (m, 1 H), 2.09 (m, 2
H), 1.84 (s, 3 H), 1.79 (m, 2 H), 1.59 (m, 1 H), 1.5-1.3 (m, 3
H), 1.27 (d, J = 7 Hz, 6 H) ; IR (diffuse reflectance) 3343,
3254, 2958, 2937, 2866, 2497, 2442, 2377, 1660, 1628, 1598,
1553, 1460, 1116, cm -1. MS (EI) m/z (rel intensity) 458 (M+,
7), 415 (20), 230 (35), 202 (18), 201 (99), 200 (26), 159
(35), 157 (32), 133 (41), 129 (28), 117 (17). HRMS (ESI) calcd
for C27H36N2O2F2+H1 459.2823, found 459.2837. Anal. Calcd for
C27H36F2N2O2.HC1: C, 65.51; H, 7.53; N, 5.66; Cl, 7.16; F, 7.68.
Found: C, 65.19; H, 7.70; N, 5.67. Found; Cl, 7.08.
Following essentially the procedure described in Step 1
of EXAMPLE 70, the free base of compound 3 (3.9 mmol) is
reacted with compound 8 (0.80 g, 2 mmol) in 20 mL of isopropyl
alcohol at reflux overnight. After workup and chromatography
over silica gel, eluting with 4% methanol (containing 2% NH4OH)
in CH2C12, compound 9 is obtained as a colorless syrup (0.92 g,
1.5 mmol, 74%): MS (CI) m/z 605.5 (MH+).
Step 2. Preparation of N-((1S,2R)-1-(3-(benzyloxy)-5-
fluorobenzyl)-2-hydroxy-3-{[1- (3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
hydrochloride (10).
Following essentially the procedures of Steps 2 and 3 of
EXAMPLE 70, compound 9 (0.92 g, 1.5 mmol) is converted to
hydrochloride 10, which is a white solid: 1H NMR (CDC13 +CD30D
drop) d 7.46-7.25 (m, 9 H), 6.26 (s, 1 H), 6.53-6.47 (m, 2 H),
5.00 (s, 2 H), 4.01 (m, 1 H), 3.88 (m, 1 H), 2,98-2,89 (m, 2
H), 2.68-2.62 (m, 4 H), 2.3 (m, 1H, obscured by water), 2.14
(m, 2 H), 1.88 (s, 3 H), 1.78 (m, 2 H), 1.58 (m, 1 H), 1.5-1.3
(m, 3 H), 1.26 (d, J = 7 Hz, 6 H); MS (CI) m/z 547.5 (MH+).
Step 3. Preparation of N-((1S,2R)-1-(3-hydroxy-5-
fluorobenzyl)-2-hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]aminojpropyl)acetamide
hydrochloride 11.
To a solution of compound 10 (0.70 g, 1.2 mmol) in 7 0 mL
of ethanol in a Parr bottle is added 0.33 g of 10% palladium
on carbon. The mixture is placed under 20 psi of hydrogen and
shaken for 21 h. The mixture is filtered and the catalyst is
washed with ethanol. Concentration in vacua affords a
colorless oil, which is treated with ethereal HC1 to give a
quantitiative yield of hydrochloride 11 as a white solid: 1H
NMR (CDCl3 +CD3OD drop) d 7.44 (s,.1 H), 7.37 (m, 2 H), 7.28
(V 1 H), 6.59 (s, 1 H), 6.40 (m, 1 H), 6.31 (m, 1 H), 4.0 (m,
1 H), 3.79 (m, 1 H), 2.95 (m, 2 H), 2.63 (m, 4 H), 2.44 (m, 1
H), 2.05 (m; 2 H), 1.90 (s, 3 H), 1.79 (m, 2 H), 1.59 (m, 1
H), 1.5-1.3 (m, 3 H), 1.26 (d, J = 7 Hz, 6 H) ; MS (CI) m/z
457.4 (MH+).
Step 4. Preparation of N-((1S,2R)-1-(3-(hexyloxy)-5-
fluorobenzyl)-2-hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
hydrochloride 12
To 0.40 mmol of hydrochloride 11 in 3 mL of acetone is
added 0.29 mL (2.1 mmol) of 1-bromohexane. The mixture is
heated to reflux, and 0.6 mL of a 1 M solution of potassium t-
butoxide in THF (0.6 mmol) is added. After 1.2 h the mixture
is cooled and aqueous 1 N KH2PO4 and ethyl acetate are added.
The organic phase is washed twice with 1 N NaHCO3 and once with
brine, dried over Na2SO4, and concentrated. Chromatography over
silica gel, eluting with 7%-9& methanol (containing 1% of
NH4OH) in CH2C12, affords a colorless oil. Treatment with
ethereal HC1 produces 147 mg (0.25 mmol, 64%) of hydrochloride
12 as a white solid: 1H NMR (CDCl3 +CD3OD drop) d 7.45 (s, 1
H), 7.37 (m, 2 H), 7.27 (m, 1 H), 6.50 (s, 1 H), 6.43 (m, 2
H), 3.98 (m, 1 H), 3.88 (m + t, J = 6.5 Hz, 3 H), 2.93 (m, 2
H), 2,63 (m, 4 H), 2.38 (m, 1 H), 2.09 (m, 2 H), 1.89 (s, 3
H), 1.75 (m, 4 H), 1.59 (m, 1 H), 1.43-1.32 (m, 10 H), 1.27
(d, J = 7 Hz, 6 H), 0.90 (t, J = 7 Hz, 3 H); MS (CI) m/z 541.5
(MH+).
EXAMPLE 72: Preparation of tert-butyl (IS)-2-[4-(benzyloxy)-3
fluorophenyl]-1-[(2S)-oxiran-2-yl] ethylcarbamate 17
Step 1. Preparation of 1-Benzyloxy-2-fluoro-4-bromobenzene 13.
To a stirred suspension of pulverized K2CO3 (49 g, 350
mmol) in 250 mL of acetone is added 6.5 mL (11.3 g, 59 mmol)
of 2-fluoro-4-bromophenol and 7 mL (10 g, 59 mmol) of benzyl
bromide. The mixture is refluxed under nitrogen 5 h. It is
cooled and filtered, washing the residual K2CO3 with acetone.
Removal of the solvent leaves 17 g of an off-white solid. This
is triturated twice with hexanes, redissolved in 250 mL of
CH2Cl2, and washed successively with 10% Na2CO3, water, and
brine. The organic phase is dried over Na2SO4 and trsated with
decolorizing charcoal. Filtration and evaporation affords
1-benzyloxy-2-fluoro-4-bromobenzene 13 (13.7g, 4 9 mmol,
83%) as a colorless oil which crystallizes to a white solid: 1H
NMR (CDC13) d 7.43-7.33 (m, 5 H), 7.24 (dd, J = 2.3, 10 Hz, 1
H), 7.14 (dt, J = 2, 8.7 Hz, 1 H), 6.86 (t, J = 8.7 Hz, 1 H),
8.12 (s, 2 H).
Step 2. Preparation of tert-butyl (1S)-2-(4-(benzyloxy)-3-
fluorophenyl)-1-[(4S)-2,2-dimethyl-l,3-dioxolan-4-
yl]ethylcarbamate (15).
A solution of l-benzyloxy-2-fluoro-4-bromobenzene 13 (7.0
g, 25 mmol) in 2 0 mL of dry THF is added dropwise over 2 0 min
to 1.22 g (50 mrnol) of magnesium turnings in 10 mL of
refluxing THF under nitrogen and the mixture is refluxed for
an additional 25 min to form the Grignaird reagent. The
Grignard solution is cooled and added by cannula to a
suspension of CuBr-dimethylsulfide complex (0.52 g, 2.5 mmol)
in 15 mL of dry THF at -25 °C. The brown suspension is stirred
at -25 °C for 20 min, and then a solution of tert-butyl (2R)-2-
[ (4S)-2,2-dimethyl-l,3-dioxolan-4-yl]aziridine-1-carboxylate
14 (3.4 g, 14 mmol) in 15 mL of THF is added dropwise over 5
min. The mixture is allowed to gradually warm to ambient
temperature over 3 h. Saturated aqueous NH4C1 and ethyl ether
are added, and the organic phase is washed with two more
portions of saturated NH4Cl and once with brine. The solution
is dried over Na2SO4 and treated with decolorizing carbon.
Filtration and concentration gives a yellow solid, which is
triturated twice with ether/heptane to afford 5.4 g (12 mmol,
86%) of compound 15 as a cream-colored solid: MS (CI) m/z
468.3 (MNa+), 446.3 (MH+).
Step 3. Preparation of tert-butyl (1S, 2S)-1-[4-
(benzyloxy)-3-fluorobenzyl]-2,3-
dihydroxypropylcarbamate 16
To a solution of crude (combined solid and mother liquor)
compound 15 (maximum 14 mmol) in 90 mL of methanol is added 12
g of Dowex 50WX2-400 which has been extensively washed with
water, methanol, and CH2C12, and air-dried. The mixture is
warmed to 50 °C and stirred for 2 h. It is filtered, washing
first with methanol and a 1:1 mixture of methanol and CH2C12.
The receiver is then changed and the product is eluted from
the resin with 1:1 methanol:CH2Cl2 containing 10% of NH4OH. The
filtrate is concentrated to afford 2.7 g of a white solid.
This solid is dissolved in 60 mL of dry THF under nitrogen,
cooled to 0 °C, and 2.0 g (9.2 mmol) of di-tert-
butyldicarbonate is added. The ice bath is removed and the
mixture is stirred at ambient temperature for 18 h. It is
concentrated and chromatographed over silica gel, eluting with
49:49:2 to 58:38:4 ethyl acetate:heptane:methanol, affording
3.0 g (7.4 mmol, 53%, two steps) of compound 16 as a white
solid: 1H NMR (CDC13) d 7.45-7.30 (m, 5 H), 7.01-6.88 (m, 3 H),
5.12 (s, 2 H), 4.52 (d, J = 9 Hz, 1 H), 3.78 (m, 1 H), 3.62
(m, 2 H), 3.32 (m, 2 H), 3.02 (dd, J = 4, 14 Hz, 1 H), 2.82
(m, 2 H), 1.39 (s, 9 H) ; MS (CI) m/z 428.2 (MNa+), 406.3
(MH+).
Step 4. Preparation of tert-butyl (IS)-2-[4-(benzyloxy)-3
fluorophenyl]-1-[(2S)-oxiran-2-yl]ethylcarbamate (17)
Trimethyl orthoacetate (0.94 mL, 7.4 mmol) is added to a
suspension of compound 16 (2.9 g, 7.2 mmol) in 30 mL of CH2Cl2
stirred under nitrogen. Pyridinium p-toluenesulfonate (18 mg,
0.07 mmol) is added and the resulting pale yellow solution is
stirred for 3 0 min and then concentrated to a white solid.
This solid is dissolved in 30 mL of CH2C12, triethylamine (0.10
mL, 0.72 mmol) is added, and the mixture, under nitrogen, is
cooled in an ice bath. Freshly distilled acetyl bromide (0.55
mL, 7.4 mmol) is added dropwise over 3-4 min with stirring.
After 1 h, the ice bath is removed and aqueous 1 N NaHCO3 and
CH2C12 are added. The aqueous phase is extracted with
additional CH2Cl2 and the combined organic phases are dried
over MgS04 and concentrated to a white solid. This solid is
suspended in 25 mL of methanol and 6 mL of THF, and cooled in
at ice bath, under nitrogen. Pulverized KOH (0.60 g, 11 mmol)
in 6 mL of methanol is added all at once. After 15 miri the ice
bath is removed and the mixture is allowed to come to ambient
temperature over 70 min. The mixture is concentrated aind taken
up in ethyl acetate and aqueous IN KH2PO4. The organic phase is
washed with 1N NaHCO3 and then brine, dried over Na2S04, and
concentrated. Chromatography over silica gel, eluting with 20%
ethyl acetate and 5% to 10% CH2C12 in heptane affords 2.0 g
(5.2 mmol, 72%) of compound 17 as a white solid: 1H NMR
(CDC13) d 7.45-7.30 (m, 5 H), 6.99-6.86 (m, 3 H), 5.12 (s, 2
H), 4.43 (br, 1 H), 3.63 (br, 1 H), 2.90 (m, 2 H), 2.79 (m, 2
H), 2.74 (m, 1 H), 1.39 (s, 9 H) ; MS (CI) m/z 410.3 (MNa+),
388.3 (MH+).
EXAMPLE 73: Preparation of N-((1S,2R)-1-(3-fluoro-4-
hydroxybenzyl)-2-hydroxy-3-{[1-(3-isopropylphenyl)cyclohexyl]
amino}propyl)acetamide hydrochloride 20
Step 1. Preparation of tert-butyl (1S,2R)-1-(3-fluoro-4-
(benyloxy)benzyl)-2-hydroxy-3-{ [l-(3-
isopropylphenyl) cyclohexyl] aminojpropylcarbaniiate (18).
The free base (270 mg, 1.24 mmol) of 1-(3-
isopropylphenyl) cyclohexanamine hydrochloride 3 is obtained
as a colorless oil by neutralization of the salt with 1N NaOH,
extraction into ethyl acetate, drying over Na2SO4, and
concentration. This is dissolved in 10 mL of CH2Cl2, and to it
is added compound 17 (280 mg, 0.73 mmol) and 1.25 g of silica
gel. The solvent is removed in vacuo and the reactants on
silica are allowed to stand at ambient temperature for three
days. The product mixture is eluted from the silica with 10%
methanol in CH2C12, concentrated, and chromatographed on silica
gel, eluting with 4% methanol (containing 2% NH4OH) in CH2C12,
to afford compound 18 (238 mg, 0.39 mmol, 54%) as a colorless
oil: 1H NMR (CDCl3) d 7.43-7.26 (m, 8 H), 7.12 (m, 1 H), 6.94-
6.84 (m, 3 H), 5.09 (s, 2 H), 4.64 (d, J = 9 Hz, 1 H), 3.80
(br, 1 H), 3.31 (br, 1 H), 2.92-2.83 (m, 2 H), 2.7 (m, 1 H),
2.3, (m, 2 H), 2.0-1.95 (m, 4 H), 1.67-1.50 (m, 5 H), 1.35
(s+m, 10 H), 1.25 (d, J = 7 Hz, 6 H).
Step 2. Preparation of N-((1S,2R)-1-(3-fluoro-4-
(benzyloxy)benzyl)-2-hydroxy-3-{ [1- (3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
hydrochloride (19).
Following essentially the procedures of Steps 2 and 3 of
EXAMPLE 70, compound 18, (0.238 g, 0.39 mmol) as prepared in
step 1, above, is deprotected with trifluoroacetic acid and
reacted with an excess of acetyl imidazole. This is followed
by alkaline hydrolysis to afford, after workup and
chromatography over silica gel, eluting with 7%-10 % methanol
(containing 1% NH4OH) in CH2Cl2, and conversion to the HC1
salt, 0.19g (0.32 mmol, 75%) hydrochloride 19 as a white
solid: MS (CI) m/z 547.5 (MH+).
Step 3. Preparation of N-((IS,2R)-1-(3-fluoro-4-
hydroxybenzyl)-2-hydroxy-3 -{[1-(3 -
isopropylphenyl)cyclohexyl]aminojpropyl)acetamide
hydrochloride 20
Following essentially the procedure of EXAMPLE 71, Step
3, the product from step 2, compound 19, (0.19 g, 0.32 mmol)
is "deprotected under 20 psi of H2 in the presence of 54 mg of
10% palladium on carbon in 3.5 h, affording, after filtration,
concentration and treatment with ethereal HC1, 20 (0.16 g,
0.32 mmol, quant.) as a cream-white solid: 1H NMR (CDCl3 +
CD3OD drop) d 7.43-7.27 (m, 4 H), 6.86-6.77 fm, 3 H), 3.95 (br,
1 H), 3.8 (br, 1 H), 2.93 (m, 2 H), 2.6 (m, 4 H), 2.4 (m, 1
H), 2.06 (m, 2 H), 1.85 (s, 3 H), 1.8 (m, 2 H), 1.59 (m, 1 H),
1.5-1.3 (m, 3 H), 1.27 (d, J = 7 Hz, 6 H) ; IR (diffuse
reflectance) 3251, 3113, 3087, 3061, 3053, 3028, 2956, 2941,
2865, 2810, 1645, 1596, 1520, 1446, 1294 cm -1. MS (CI) m/z
(rel intensity) 457 (MH+,99), 459 (5), 458 (25), 457 (99), 439
(3), 257 (7), 218 (5), 202 (3), 201 (9), 96 (4), 77 (3). HRMS
(ESI) calcd for C27H37N2O3F+H1 457.2866, found 457.2855. Anal.
Calcd for C27H37FN2O3 HC1.1.5 H2O: C, 62.35; H, 7.95; N, 5.39;
Found: C, 62.63; H, 7.76; N, 5.47.
Step 1. Preparation of 8-(3-isopropylphenyl)-1,4-dioxa-
spiro[4.5]decane-8-alcohol (21)
Following essentially the procedure described in EXAMPLE
72, Step 2, the Grignard reagent formed from 3-
bromoisopropylbenzene (25 mmol) is reacted with 1,4-
cyclohexanedione, monoethylene ketal (3.9 g, 25 mmol) to
afford, after chromatography over silica gel, eluting with 20%
to 30% ethyl acetate in heptane, alcohol 21 (5.6 g, 20 mmol,
80%) as a colorless oil which crystallizes to a white solid on
cooling: 1H NMR (CDCl3) d 7.39 (s, 1 H), 7.33 (m, 1 H), 7.28
(t, J = 7.5 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 1 H), 4.0 (m, 4 H),
2.91 (hept, J = 7 Hz, 1 H), 2.15 (m, 4 H), 1.82 (br d, J =
l115 Hz, 2 H), 1.70 (br d, J = 11.5 Hz, 2 H), 1.25 (d, J = 7
Hz, 6 H);.MS (CI) m/z 259.2 (M-OH).
Step 2. Preparation of 8-(3-isopropylphenyl)-1, 4-dioxa-
spiro[4.5]decane-8-azide (22).
Following essentially the procedure described in EXAMPLE
69, Step 2, alcohol 21 (5.5 g, 20 mmol) is converted to the
azide 22. The resulting crude material is purified by silica
gel chromatography, eluting with 3% acetone in heptane.
Concentration of the product-containing fractions affords 2.2
g (7.3 mmol, 36%) of compound 22 as a colorless oil: 1H NMR
(CDC13) d 7.33-7.26 (m, 3 H), 7.17 (m, 1 H), 3.98 (m, 4 H),
2.92 (hept, J = 1 Hz, 1 H), 2.2-2.12 (m, 2 H), 2.07-1.95 (m, 4
H), 1.72 (m, 2 H), 1.26 (d, J = 7 Hz, 6 H).
Step 3. Preparation of 8-(3-isopropylphenyl)-1,4-dioxa-
spiro[4.5]decane-8-amine acetate 23.
Following essentially the procedure described in EXAMPLE
69, Step 3, 2.2 g (7.3 mmol) of compound 22 in 2 00 mL of
ethanol is reduced under 16 psi of hydrogen in the presence of
0.7 g of 10% palladium on carbon for 4.5 h. Filtration and
removal of solvents with a toluene azeotrope affords a white
solid which is triturated with pentane to yield 2.14 g (6.4
mmol, 87%) of compound 23 as a white solid: 1H NMR (CDCl3) d
7.37-7.33 (m, 2 H), 7.30-7.26 (m, 1 H), 7.13 (d, J= 7.5 Hz, 1
H), 5.91 (br, 3 H), 3.96 (m, 4 H), 2.90 (hept., J = 7 Hz, 1
H), 2.32 (m, 2 H), 2.03 (s, 3 H), 2.0-1.85 (m, 4 H), 1.63 (m,
2 H), 1.25 (d, J = 1 Hz, 6 H) ; MS (CI) m/z 259.2 (M-NH2).
EXAMPLE 75: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
2-hydroxy-3-{[1-(3-isopropylphenyl)cyclohexan-4-
one]amino}propyl) acetamide 26
Step 1. Preparation of tert-butyl (1S,2R)-1-(3,5-
difluorobenzyl)-2-hydroxy-3-{8-(3-isopropylphenyl)-1,4-
dioxa-spiro[4.5]decane-8-amino}propylcarbamate (24)
Following essentially the procedure of EXAMPLE 70,
compound 23 (3.2 mmol) is neutralized and reacted with Example
134 (4, 0.6 g, 2.0 mmol) in refluxing isopropanol (15 mL) for
15.5 h. The reaction mixture is concentrated and
chromatographed over silica gel, eluting with 4% methanol
(containing 2% of NH4OH) in CH2C12 to separate the crude
product from excess 8-(3-isopropylphenyl) -1,4-dioxa-
spiro[4.5]decane-8-amine. The crude product is then re-
chromatographed over silica gel, eluting with 10% to 20%
acetone in CH2Cl2 to afford 0.600 g (1.04 mmol, 52%) of
compound 24 as a colorless oil: 1H NMR (CDC13) 5 7.27-7.20 (m,
3 H), 7.09 (d, J = 7 Hz, 1 H), 6.69 (m, 2 H), 6.63 (m, 1 H),
4.64 (d, J = 9 Hz, 1 H), 3.95 (m, 4 H), 3.72 (m, 1 H), 3.28
(m, 1 H), 2.88 (m, 2 H), 2.69 (dd, J = 8.5, 14 Hz, 1 H), 2.32
(m, 2 H), 2.15 (m, 2 H), 1.99-1.86 (m, 4 H), 1.63 (m, 2 H),
1.35 (s, 9 H), 1.24 (d, J = 7 Hz, 6 H); MS (CI) m/z 575.4
(MH+)
Step 2. Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
2-hydroxy-3-{8-(3-isopropylphenyl)-1,4-dioxa-
spiro [4.5]decane-8-amino}propyl)acetamide (25)
Following essentially the procedures described in EXAMPLE
70, Steps 2 and 3, compound 24 (0.600 g, 1.04 mmol) is
deprotected, acetylated, and saponified to afford, after
chromatography on silica gel, eluting with 32.5% acetone and
2.5% methanol in CH2C12, acetamide 25 (335 mg, 0.65 mmol, 62%)
as a white solid: 1H NMR (CDC13) d 7.31-7.26 (m, 3 H), 7.15 (m,
1 H), 6.69-6.61 (m, 3 H), 5.9 (br, 1 H), 4.13 (m, 1 H), 3.95
(m, 4 H), 3.48 (m, 1 H), 2.92-2.83 (m, 2 H), 2.73 (dd, J =
8.5, 14 Hz, 1 H), 2.45-2.25 (m, 4 H), 2.10 (m, 2 H), 1.88
(s+m, 5 H), 1.62 (m, 2 H), 1.25 (d, J = 7 Hz, 6 H) ; MS (CI)
m/z 517.4 (MH+).
Step 3. Preparation of N-( (1S,2R)-1-(3,5-difluorobenzyl) -
2-hydroxy-3-{[1-(3-isopropylphenyl)cyclohexan-4-
one]amino}propyl)acetamide 26
To acetamide 25 (255 mg, 0.49 mmol) in 5 mL of ethanol
and 5 mL of water is added 6 mL of trifluoroacetic acid, and
the mixture is refluxed for 2 h under nitrogen. It is
concentrated and taken up in aqueous 10% Na2CO3 and ethyl
acetate. The organic phase is washed twice more with 10% Na2CO3
and then with brine. It is dried over Na2SO4, and concentrated
to a colorless oil. Evaporation in vacua from e~hyl ether
affords compound 26 (140 mg, 0.3 0 mmol, 60 %) as a white
solid: 1H NMR (CDC13) d 7.35-7.18 (m, 4 H), 6.71-6.64 (m, 3 H),
5.65 (br, 1 H), 4.12 (m, 1 H), 3.43 (m, 1 H), 2.95-2.90 (m, 2
H), 2.75 (dd, J = 8.5, 14 Hz, 1 H), 2.64 (m, 2 H), 2.4-2.25
(m, 8 H), 1.87 (s, 3 H), 1.25 (d, J = 7 Hz, 6 H) ; MS (CI) m/z
473.4 (MH+). The LC-MS spectrum in methanol solvent shows a
small signal at 505.4 (MH+CH3OH) due to hemiketal formation. IR
(diffuse reflectance) 3311, 2958, 1710, 1646, 1628, 1595,
1550, 1544, 1460, 1372, 1315, 1116, 983, 846, 707 cm"1. MS
(EI)m/z(rel intensity) 472 (M+, 6), 472 (6), 417 (5), 416
(33), 415 (99), 398 (8), 397 (30), 327 (11), 244 (9), 215
(13), 214 (6). HRMS (ESI) calcd for C27H34N2O3F1+Hi 473.2615,
found 473.2627. Anal. Calcd for C27H34F2N2O3+ 0.5 H20: C, 67.34;
H, 7.33; N, 5.82; Found (av): C, 67.89; H, 7.32; N, 5.86.
EXAMPLE 76s Preparation of N-[(1S,2R)-3-{[1-(3-bromophenyl)-1-
methylethyl]amino}-l-(3,5-difluorobenzyl)-2-
hydroxypropyl]acetamide 32
Step 1. Preparation of 2-(3-bromophenyl)-2-propanol 27
To 75 mmol of methylmagnesium bromide in 25 mL of ether
stirring at 6 °C is added, dropwise over 10 min, a solution of
methyl-3-bromobenzoate (4.3 g, 20 mmol) in 25 mL of dry THF.
The mixture is then allowed to warm to ambient temperature and
stirred for 3.5 h, then cooled to 0°C and quenched by dropwise
addition of aqueous 10% HC1. The acidified mixture is
extracted twice with ethyl acetate, and the combined organic
phases are washed with 1 N NaHCO3 and with brine. The solution
is dried over Na2SO4, concentrated, and chromatographed over
silica gel, eluting with 15% ethyl acetate in heptane, to
afford 4.00 g (18.6 mmol, 93%) of 2-(3-bromophenyl)-2-
propanol 27 as a pale yellow oil: 1H NMR (CDC13) d 7.65 (t, J =
2 Hz, 1 H), 7.39 (m, 2 H), 7.20 (t, J = 8 Hz, 1 H), 1.78 (br
s, 1 H), 1.57 (s, 6 H).
Step 2. Preparation of 2-(3-bromophenyl)-2-propylazide
(28).
The above compound was prepared by essentially according
to the method of Example 12. The crude product was purified
by chromatography over silica gel, eluting with heptane, and
thereby affording compound 28 as a colorless oil: 1H NMR (CDCl3)
d 7.58 (t, J = 2 Hz, 1 H), 7.74-7.36 (m, 2 H), 7.24 (t, J = 8
Hz, 1 H), 1.62 (s, 6 H).
Step 3. Preparation of 2-(3-bromophenyl)-2-propylamine
29.
The above compound was prepared essentially according to
the method of Example 10. The crude product was purified by
chromatography over silica gel, eluting with 6% methanol
(containing 1% NH4OH) in CH2C12 to afford compound 29 (7 mmol,
50%) as a pale amber oil: 1H NMR (CDCl3) d 7.67 (t, J = 2 Hz, 1
H), 7.43 (m, 1 H), 7.35 (m, 1 H), 7.20 (t, J = 8 Hz, 1 H),
1.68 (br s, 2 H), 1.48 (s, 6 H).
Step 4. Preparation of 2-(3-bromophenyl)-2-propylamine
hydrochloride
To 2-(3-bromophenyl)-2-propylamine 29 in ether is added
ethereal HC1. Solvent removal affords a tan solid, which is
dissolved in a small volume of ethanol and diluted with ethyl
acetate. The tan crystals which form are filtered to afford 2-
(3-bromophenyl)-2-propylamine hydrochloride 1H NMR (CDC13+
CD3OD drop) d 7.65 (n m, 1 H), 7.51 (app t, 2 H), 7.32 (m, 1
H), 1.77 (s, 6 H); MS (CI) m/z 214.0 (MH+)
Step 5. Preparation of tert-butyl (IS, 2R)-3-{ [1-(3-
bromophenyl) -1-methylethyl] atnino}-l- (3,5-
difluorobenzyl)-2-hydroxypropylcarbamate 30
The above compound was prepared essentially according to
the method of example 17, step 3. Purification of the crude
material over silica gel, eluting with 4% to 6% of methanol
(containing 1% of NH4OH) in CH2C12 affords 365 mg (0.71 mmol,
69%) of compound 30 as a colorless oil: 1H NMR (CDC13) d 7.52
(m, 1 H), 7.35 (m, 2 H), 7.19 (t, J" = 8 Hz, 1 H), 6.73 (m, 2
H), 6.64 (m, 1 H), 4.54 (d, J = 9 Hz, 1 H), 3.73 (m, 1 H),
3.29 (m, 1 H), 2.99 (dd, J = 4, 14 Hz, 1 H), 2.73 (dd, J =
8.5, 14 Hz, 1 H), 2.46-2.35 (m, 2 H), 1.45 (s, 6 H), 1.37 (s,
9 H); MS (CI) m/z 514.2 (MH+).
Step C. Preparation of (1R,2S)-2-(acetylamino)-1-({[1-(3-
bromophenyl)-1-methylethyl]aminojmethyl)-3-(3,5-
difluorophenyl)propyl acetate hydrochloride 31
To 3 65. mg (0.71 mmol) of tert-butyl (IS,2R)-3-{[1-(3-
biomophenyl)-1-methylethyl] amino}-l-(3,5-difluorobenzyl)-2-
hydroxypropylcarbamate 3 0 in 2 mL of CH2C12 is added 1 mL of
trifluoroacetic acid, and the mixture is stirred for 3 0 min.
It is concentrated in vacuo, diluted with ethyl acetate, and
washed with 10% Na2CO3 and then brine. The solution is dried
over Na2SO4, filtered and concentrated to a colorless oil. This
is dissolved in 3 mL of CH2C12 and 172 mg (1.56 mmol) of acetyl
imidazole is added. After 2.5 h the mixture is concentrated
and taken up in ethyl acetate and 1 N KH2P04. The organic phase
is washed with 1N KH2PO4, with brine, dried over Na2SO4,
concentrated, and chromatographed over silica gel. Elution
with 4% methanol (containing 1% of NH4OH) in CH2Cl2 affords a
sticky solid. This is dissolved in ether and treated with
ethereal HCl. Concentration afford 260 mg (0.49 mmol, 68%) of
compound 31 as a white solid: 1H NMR (CDC13 + CD3OD drop) d
7.79 (n m, 1 H), 7.59 (m, 2 H), 7.36 (t, J = 8 Hz, 1 H), 6.69-
6.62 (m, 3 H), 5.15 (m, 1 H), 4.17 (m, 1 H), 3.07 (d, J = 12.5
Hz, 1 H), 2.87-2.75 (m, 2 H), 2.61 (dd, J = 7, 13.5 Hz, 1 H),
2.21 (s, 3 H), 1.95 (s, 3 H), 1.92 (s, 3 H), 1.84 (s, 3 H); IR
(diffuse reflectance) 2985, 2958, 2940, 2755, 2738, 2730,
1749, 1645, 1628, 1596, 1569, 1463, 1372, 1227, 1118 cm -1. MS
(CI)m/z(rel intensity) 497 (MH+, 86), 500 (15), 499 (99), 497
(86), 419 (28), 283 (18), 231 (22), 136 (17), 77 (46), 60
(13), 58- (18). HRMS (ESI) calcd for C23H27N2O3F2Br+H1 497.1252,
found 497.1248. Anal. Calcd for C23H27BrF2N2O3 + HCl + 0. 5H2O: C,
50.89; H, 5.38; N, 5.16; Found: C, 50.95; H, 5.37; N, 5.05.
Step 7. Preparation of N-[(1S,2R)-3-{[1-(3-bromophenyl)-
1-methylethyl]amino}-1-(3,5-difluorobenzylI-2-
hydroxypropy1]acetamide 32
To a solution of 107 mg (0.21 mmol) of hydrochloride 31
in 10 mL of methanol is added 1 mL of 1N NaOH. The mixture is
stirred for 45 min at ambient temperature, then quenched with
1N KH2PO4 and diluted with ethyl acetate. The organic phase is
washed with brine, dried over Na2SO4, filtered and concentrated
to a glassy solid. This is dissolved in methanol and treated
with ethereal HCl to afford 70 mg (0.14 mmol, 68%) of
compound 32 as a white solid: 1H NMR (CDC13+ CD3OD drop) d 7.69
(s, 1 H), 7.56 (m, 2 H), 7.35 (t, J = 8 Hz, 1 H), 6.71 (m, 2
H), 6.63 (m, 1 H), 3.98 (m, 2 H), 2.98 (m, 1 H), 2.8 (m, 1 H),
2.68 (m, 1 H), 2.39 (m, 1 H), 1.92 (s, 3 H), 1.83 (s, 6 H) ; IR
(diffuse reflectance) 3311, 3283, 3257, 3249, 3058, 3007,
2757, 1655, 1646, 1628, 1596, 1551, 1459, 1116, 697 cm'1. MS
(CI)m/z(rel intensity) 457 (15), 455 (MH+,97), 458 (17), 457
(99), 456 (15), 455 (97), 377 (5), 259 (9), 216 (6), 214 (6),
96 (27), 69 (5). HRMS (ESI) calcd for C21H25N2O2F2Br+H1 455.1146,
found 455.1145. Anal. Calcd for C21H25BrF2N2O2. HC1+ H2O: C,
49.47; H, 5.54; N, 5.49; Found: C, 49.45; H, 5.50; N, 5.54.
EXAMPLE 77: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-
hydroxypropyl)acetamide hydrochloride 39
Step 1. Preparation of methyl-3-ethylbenzoate 33.
Compound 33 was prepared essentially according to the
method of Example 7. The crude product was purified by
chromatography over silica gel eluting with 2% to 5% of ethyl
acetate in hexanes, to afford 6.1 g (37 mmol, 93%) of methyl-
3-ethylbenzoate 33 as a colorless oil: 1H NMR (CDCL3) d 7.89-
7.84 (m, 2 H), 7.40-7.33 (m, 2 H), 3.91 (s, 3 H), 2.70 (q, J =
7.6 Hz, 2 H), 1.26 (t, J = 7.6 Hz, 3 H).
Step 2. Preparation of 2-(3-ethylphenyl)-2-propanol 34.
Following essentially the procedure of Example 76, Step
1, methyl-3-ethylbenzoate 33 (6.0 g, 37 mtnol) is converted to
2-(3-ethylphenyl)-2-propanol 34 (6 g, quantitative) which is
obtained as a pale yellow oil, sufficiently pure without
chromatography: 1H NMR (CDC13) d 7.34 (m, 1 H), 7.28 (m, 2 H),
7.09 (m, 1 H), 2.66 (q, J = 7.6 Hz, 2 H), 1.75 (s, 1 H), 1.59
(s, 6 H), 1.25 (t, J = 7.6 Hz, 3 H).
Step 3. Preparation of 2-(3-ethylphenyl)-2-propylazide 35
Following essentially the procedure of EXAMPLE 69, Step
2, but only stirred at ambient temperature for 1 h, alcohol 34
(6.0 g, 37 mmol) is converted to azide 35 (6.6 g, 35 mmol,
94%) which is obtained as a pale yellow oil, and is
sufficiently pure without chromatography: 1H NMR (CDCl3) d 7.25
(m, 3 H), 7.12 (m, 1 H), 2.67 (q, J= 7.. 6 Hz, 2 H), 1.64 (s, 6
H), 1.25 (t, J = 7.6 Hz, 3 H).
Step 4. Preparation of 2-(3-ethylphenyl)-2-propylamine
36.
Following essentially the procedure described in EXAMPLE
76, Step 3, azide 35 (6.6 g, 35 mmol) is converted to amine
36 (3.2 g, 20 mmol, 56%) which is obtained as a pale yellow
oil after chromatography: 1H NMR (CDCl3) d 7.35-7.24 (m, 3 H),
7.07 (d, J = 7.4 Hz, 1 H), 2.66 (q, J = 7.6 Hz, 2 H), 1.55 (s,
2 H), 1.49 (s, 6 H), 1.25 (t, J = 7.6 Hz, 3 H).
Step 5. Preparation of 2-(3-ethylphenyl)-2-propylamine
hydrochloride
To amine 36 in ether is added ethereal HCl. Removal of
the mother liquor affords, 2-(3-ethylphenyl)-2-propyiamine
hydrochloride as a white solid: 1H NMR (CDC13) d 8.93 (s, 3
H), 7.44 (s, 1 H), 7.36 (m, 1 H), 7.26 (t, J = 7.6 Hz, 1 H),
7.13 (d, J = 7.6 Hz, 1 H), 2.63 (q, J = 7.6 Hz, 2 H), 1.81 (s,
C2), 1.22 (t, J = 7.6 Hz, 3 H); MS (CI) m/z 147.0 (MH -NH2)
Step 6. Preparation of tert-butyl (1S,2R)-3-{[1-(3-
ethylphenyl)-1-methylethyl] amino}-1-(3,5-
dif luorobenzyl) -2-hydroxypropylcarbatnate 37.
Following essentially the procedure described in EXAMPLE
76, Step 5, except that t-butanol is used in place of
isopropanol, 2-amine 36 (3.0 g, 18.4 mmol) is reacted with
Example 134 (4, 3.0 g, 10 mmol) to afford, after
chromatography, protected amine 37 (3.8 g, 8.2 mmol, 82%) as a
colorless oil: 1H NMR (CDC13) d 7.27 (m, 3 H), 7.09 (m, 1 H),
6.74 (m, 2 H), 6.65 (m, 1 H), 4.69 (d, J = 9.4 Hz, 1 H), 3.76
(m, 1 H), 3.32 (m, 1 H), 2.97 (dd, J = 4, 14 Hz, 1 H), 2.72
Cm, 1 H), 2.67 (q, J = 7.6 Hz, 2 H), 2.45 (m, 2 H), 1.49 (s, 6
H), 1.40 (s, 9 H), 1.26 (t, J= 7.6 Hz, 3 H).
Step 7. Preparation of (2R,3S)-3-ammo-4-(3,5-
difluorophenyl)-l-{[1-(3-ethylphenyl)-1-
methylethyl]amino}butan-2-ol hydrochloride 38.
Following essentially the procedure described in EXAMPLE
76, Step 6, protected amine 37 (3.5 g, 7.6 mmol) is
deprotected with TFA to afford a quantitative yield of a
slightly yellow oil: 1H NMR (CDC13) 8 7.25 (m, 3 H), 7.08 (m, 1
H), 6.72-6.6 (m, 3 H), 3.39 (m, 1 H), 3.02 (m, 1 H), 2.82 (dd,
J = 3.8, 13.6 Hz, 1 H), 2.67 (q, J = 7.6 Hz, 2 H), 2.59 (dd, J
= 3.6, 11.8 Hz, 1 H), 2.45-2.37 (m, 2 H), 1,48 (s, 6 H), 1.24
(t, J = 7.6 Hz, 3 H). Treatment with ethereal HC1 affords
hydrochloride 38 (86%) as a white solid: MS (CI) m/z 363.3
(MH+).
Step 8. Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-
hydroxypropyl)acetamide hydrochloride 3 9
Following essentially the procedure described for EXAMPLE
76, Step 6, hydrochloride 38 (1.1 mmol) is converted to
acetamide 39, which, following chromatography on silica gel,
eluting with 8% to 10% methanol (containing 1% NH40H) in
CH2C12, is obtained as a colorless oil: 1H NMR (CDC13) d 7.28-
7.20 (m, 3 H), 7.07 (d, J = 1 Hz, 1 H), 6.69-6.61 (m, 3 H),
6.28 (d, J = 9 Hz, 1 H), 4.11 (m, 1 H), 3.40 (m, 1 H), 2.83
(dd, J= 5.2, 14.3 Hz, 1 H), 2.73 (dd, J = 8.4, 14.2 Hz, 1 H),
2.65 (q, J = 7.6 Hz, 2 H), 2.44 (dd, J = 4, 12 Hz, 1 H), 2.34
(dd, J = 5.3, 12 Hz, 1 H), 1.89 (s, 3 H), 1.47 (s, 3 H), 1.46
(s, 3 H), 1.24 (t, J = 7.6 Hz, 3 H). Treatment with ethereal
HCl and concentration affords the hydrochloride 39 (0.22 g,
0.49 mmol, 45%), which is obtained as a white solid: 1H NMR
(CDCl3+ CD3OD drop) d 7.37 (m, 3 H), 7.24 (m, 1 H), 6.71 (m, 2
H), 6.62 (m, 1 H), 3.98 (m, 2 H), 3.0 (dd, J = 4, 14.7 Hz, 1
H), 2.78-2.65 (m+q, J = 7.6 Hz, 4 H), 2.46 (m, 1 H), 1.91 (s,
3 H), 1.84 (s, 3 H), 1.83 (s, 3 H), 1.26 (t, J = 7.6 Hz, 3 H);
IR (diffuse reflectance) 3250, 3229, 3053, 2967, 2933, 2876,
2786, 2764, 1645, 1628, 1595, 1550, 1459, 1377, 1116 cm-1. MS
(CI)m/z(rel intensity) 405 (MH+,99), 407 (6), 406 (41), 405
(99), 387 (7), 259 (23), 176 (8), 164 (18), 148 (7), 147 (19),
77 (15). HRMS (ESI) calcd for C23H30N2O2F2+H1 405.2353, found
405.2369, Anal. Calcd for C23H30F2N202-HC1+ 0.5 H2O: C, 61.39; H,
7.17; N, 6.23; Found: C, 61.27; H, 7.07; N, 6.20..
EXAMPLE 78: Preparation of (1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{ [1- (3-
isopropylphenyl)cyclohexyl]amino}propylformamide hydrochloride
41
Step 1. Preparation of formyl imidazole 40.
To a solution of formic acid (0.76 mL, 20 mmol, 96%) in
CH2C12 stirring under nitrogen is added, portionwise over 10
min, 3.6 g (22 mmol) of carbonyldiimidazole, and the mixture
is allowed to stir overnight. Anhydrous MgSO4 is added, and
after several hours the mixture is filtered and concentrated
in vacuo (note: formyl imidazole is volatile and this
operation should be carefully monitored for maximum recovery)
to afford 0.7 g of iridescent crystals. The NMR spectrum
showed the presence of formyl imidazole 40: 1H NMR (CDCl3) d
9.15 (s, 1 H), 8.14 (s, 1 H), 7.53 (s, 1 H), 7.20 (s, 1 H).
The crystals also contain imidazole (5 7.71 (s,lH), 7.13 (s,
2H) ) and the relative peak intensity and relative molecular
weights are used to determine the weight % of formyl imidazole
in the product.
Step 2. Preparation of (1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{ [1- (3-isopropylphenyl)
cyclohexyl]amino}propylformamide hydrochloride 41
To a solution of amine 6 (209 mg, 0.43 mmol) in 4 mL of
CH2C12 under nitrogen is added 125]µL (0.9 mmol) of
triethylamine. To this mixture is added 75 mg of the solid
from Step 1, which is determined by NMR to contain 63% by
weight of formyl imidazole (47 mg, 0.49 mmol) and the solution
is stirred for 20 min. Methanol (5 mL is added, followed by 2
mL of 1 N NaOH. The mixture is concentrated in vacuo and
diluted with 1 N KH2PO4 and ethyl acetate. The organic phase is
washed with 1 N NaHCO3 and brine, and dried over Na2SO4.
Concentration and chromatography over silica gel, eluting with
5% to 7.5 % of methanol (containing 1% of NH4OH) in CH2C12
affords a colorless oil. Ether and ethereal HCl are added, and
the gel-like precipitate is concentrated in vacuo from ethanol
and then ethyl acetate to afford 17 6 mg (0.37 mmol, 85%) of
hydrochloride 41 as a white solid: 1H NMR (CDC13+ CD3OD drop) d
7.86 (s, 1 H), 7.39-7.28 (m, 4 H), 6.67 (m, 2 H), 6.60 (m, 1
H), 3.96 (m, 1 H), 3.79 (m, 1 H), 3.08 (dd, 1 H), 2.93 (m, 1
H), 2.7-2.5 (m, 4 H), 2.37 (dd, 1 H), 2.05 (m, 2 H), 1.78 (m,
2 H), 1.6 (m, 1 H), 1.45-1.3 (m, 3 H), 1.25 (dd, J = 1, 7 Hz,
6 H); MS (CI) m/z 445.3 (MH+).
EXAMPLE 79: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
2-hydroxy-3-{[1-(3-isopropylphenyl)cyclohexyl]aminojpropyl)-2-
fluoroacetamide hydrochloride 43
Step 1. Preparation of fluoroacetyl imidazole 42.
To a slurry of 1.2 g (12 mmol) of sodium fluoroacetate in
25 mL of CH2Cl2 is added, with swirling of the flask, 1 mL (12
mmol) of concentrated HCl (note: this operation must be
carried out in an efficient hood; fluoroacetic acid is highly,
toxic!). About 1 teaspoonful of anhydrous MgSO4 is added to the
flask, and the contents are filtered, rinsing the filter paper
with 15 mL of CH2C12. The combined filtrate and wash are placed
under nitrogen, and 1.3 g (8 mmol) of carbonyldiimidazole is
added portionwise to the stirring mixture over 20 min. NMR
analysis of an aliquot removed 40 min later indicates nearly
complete reaction. After 1 h a teaspoonful of MgSO4 is added,
and the mixture is allowed to stir overnight. It is filtered
and concentrated to remove most of the CH2C12, leaving 1.6 g of
a pale yellow oil. The NMR spectrum indicates the presence of
CH2C12, fluoroacetic acid, imidazole, and fluoroacetyl
imidazole 42 : 1H NMR (CDCl3) d 8.26 (s, 1 H), 7.53 (s, 1 H),
7.15 (s, 1 H), 5.40 (d, J = 47 Hz, 2 H). Integration reveals
the oil to be 28% by weight fluoroacetyl imidazole 42 (0.45 g,
3.5 mmol, 44%). The oil is diluted with CH2C12 to make a
solution that is 0.2 M in 42.
Step 2. Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}propyl)-2-
fluoroacetamide hydrochloride 43
To amine 6 (0.64 mmol) is added 1 N NaOH and ethyl
acetate. The organic phase is washed with more 1N NaOH, brine,
and then dried over Na2SO4 and concentrated to 265 mg of a
colorless oil. This free base is dissolved in 3 mL of CH2C12
under nitrogen and 3.2 mL ( 0.64 mmol) of a 0.2 M solution of
fluoroacetyl imidazole 42 in CH2C12 is added. The mixture is
stirred for 5 min, and then aqueous 1N KH2PO4 and ethyl acetate
are added. The organic phase is washed with 1N KH2PO4, IN
NaHC03, and brine, dried over Na2SO4, and concentrated.
Chromatography over silica gel, eluting with 5 % methanol
(containing 2% of NH4OH) in CH2Cl2 affords a colorless oil.
Ether and ethereal HC1 are added, and the solvents are removed
in vacuo to yield 256 mg (0.50 mmol, 78%) of hydrochloride 43
as a white solid: 1H NMR (CDC13) d 9.85 (m, 1 H), 8.0 (m, 1 H),
7.51 (s, 1 H), 7.37 (m, 2 H), 7.27 (m, 1 H), 6.80 (d, J = 7
Hz, 1 H), 6.68 (m, 2 H), 6.63 (m, 1 H), 4.63 (d, J = 47 Hz, 2
H), 4.16 (m, 1 H), 4.10 (m, 1 H), 2.98-2.93 (m, 2 H), 2.77-
2.64 (m, 4 H), 2.35-2.2 (m, 3 H), 1.80 (m, 2 H), 1.59 (m, 1
H), 1.44-1.25 (m, 3 H), 1.28 (d, J = 7 Hz, 6 H) ; MS (CI) m/z
477.4 (MH+).
EXAMPLE 80: Preparation of N-((IS,2R)-1-(3,5-difluorobenzyl)-
3-{ [1-(3-ethylphenyl)-1-methylethyl] amino}-2-hydroxypropyl)-
2,2-difluoroacetamide hydrochloride 44
Following the general procedure of Example 56, compound
38 is converted into hydrochloride 44, which is obtained as a
white solid: 1H NMR (CDCl3) d 9.9 (m, 1 H), 8.1 (m, 1 H), 7.35
(m, 4 H), 7.23 (d, J = 1 Hz, 1 H), 6.66-6.58 (m, 3 H), 5.95
(t, J = 54 Hz, 1 H), 4.6 (v br, 1 H), 4.37 (m, 1 H), 4.10 (m,
1 H), 2.89 (dd, J = 5, 14 Hz, 1 H), 2.80-2.66 (m+q, J = 7.6
Hz, 4 H), 2.34 (m, 1 H), 1.87 (s, 6 H), 1.26 (t, J = 7.6 Hz, 3
H); MS (CI) m/z 441.3 (MH+).
EXAMPLE 81: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
2-hydroxy-3-{[1-(3-isopropylphenyl)
cyclohexyl]amino}propyl)ethanethioamide hydrochloride 46
Thioacetamide (1.9 g, 25 mmol) is suspended in 40 mL of
CH2C12 and cooled in an ice bath under nitrogen.
Phthaloyldichloride (3.6 mL, 25 mmol) is added slowly over 10
min via syringe while the mixture is stirred. The mixture
becomes a clear orange solution transiently, eventually
depositing a precipitate. After stirring for 40 h, the mixture
is concentrated in vacuo (in the hood!). The oily coral solid
is triturated with hexanes. Within minutes the hexanes mother
liquor drops a precipitate, which is filtered off to afford
0.2 g of a light coral solid: 1H NMR (CDC13) d 7.99 (m, 2 H),
7.86 (m, 2 H), 3.08 (s, 3 H). The residual solids remaining
after trituration with hexanes are further triturated with
ether and then with CH2C12. The combined mother liquors are
concentrated to about 3 g of a red oily solid, which is
chromatographed over silica gel, eluting with 10% to 20% ethyl
acetate in heptane. The red fractions contained a product
(concentrated to a coral solid, 0.77 g) with the same TLC
retention (Rf = 0.32, 20% ethyl acetate in heptane) as the
coral solid which had precipitated from hexanes. The total
recovery is 0.97 g, 4.7 mmol, 19%.
Step 2. Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-2-
hydroxy-3-{[1-(3-isopropylphenyl)
cyclohexyl]amino}propyl)ethanethioamide hydrochloride 46.
To 164 mg (0.39mmol) of the free base of compound 6 in 3
mL of approximately 0°C CH2C12 under nitrogen,- is added solid
thioacetyl-N-phthalimide 45 (80 mg, 0.3 9 mmol). The mixture is
stirred for 20 min, and then 3 mL of methanol and 3 mL of IN
NaOH are added. The mixture is taken up in ethyl acetate and
washed twice with 1N NaOH, once with water, and once with
brine. It is dried over Na2S04, concentrated, and
chromatographed over silica gel, eluting with 4% methanol
(containing 2% NH4OH) in CH2Cl2. Product-containing fractions
are concentrated to a colorless oil, which is dissolved in
ether and treated with ethereal HCl. Concentration affords 97
mg (0.19 mmol., 49%) of hydrochloride 46 as a white solid: 1H
NMR {CDC13+ CD3OD drop) d 7.42-7.37 (m, 2 H), 7.29 (tn, 2 H),
6.73 (m, 2 H), 6.62 (m, 2 H), 4.67 (m, 1 H), 4.10 (m, 1 H),
3.11 (dd, J = 5, 14 Hz, 1 H), 2.96 (hept, J = 1 Hz, 1 H), 2.83
(m, 1 H), 2.65-2.4 (m, 4 H, obscured by solvent), 2.38 (s, 3
H), 2.07 (m, 2 H), 1.78 (m, 2 H), 1.59 (m, 1 H), 1.44-1.35 (m,
3 H), 1.28 (d, J = 7 Hz, 6 H) ; MS (CI) m/z 475.3 (MH+).
EXAMPLE 82: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
3-{[1-(3-ethylphenyl)-1-methylethyl]amino}-2-
hydroxypropyl)ethanethioamide hydrochloride 47
Following essentially the procedure described for EXAMPLE
81, compound 38 (220 mg, 0.5 mmol) is converted to the title
compound 47, which is obtained as a white solid (79 mg, 0.17
mmol, 34%): MS (CI) m/z 421.3 (MH+).
EXAMPLE 83: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
3 -{[(IS)-7-ethyl-1,2,3,4-tetrahydronaphthalen-1-y1]amino}-2 -
hydroxypropyl)ethanethioamide hydrochloride 48
Following essentially the procedure described in EXAMPLE
81, (2R,3S)-3-amino-4- (3,5-difluorophenyl)-l-{[(1S)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}butan-2-ol
dihydrochloride (0.71 mmol) is converted to the title compound
48 (158 mg, 0.34 mmol, 47%), which is obtained as a white
solid: 1H NMR (CDC13) d 9.5 (br s, 1 H), 9.1 (d, 1 H), 7.95
(br, 1 H), 7.39 (s, 1 H), 7.15-7.07 (m, 2 H), S.73 (m, 2 H),
6.60 (m, 1 H), 4.77 (m, 1 H), 4.47 (m, 1 H), 4.34 (m, 1 H),
3.0 (d, J = 7 Hz, 2 H), 2.97 (m, 1 H), 2.73 (m, 3 H), 2.61 (q,
J = 7.5 Hz, 2 H), 2.53 (s, 3 H), 2.15 (m, 1 H), 2.02 (m, 1 H),
1.87 (m, 1 H), 1.79 (m, 1 H), 1.23 (t, J = 7.5 Hz, 3 H) ; IR
(diffuse reflectance) 3194.. 3029, 2964, 2932, 2872, 1627,
1597, 1459, 1439, 1420, 1384, 1153, 1119, 982, 847 cm"1. MS
(CI)m/z(rel intensity) 433 (MH+,24), 221 (36), 184 (51), 176
(27), 174 (49), 172 (99), 159 (49), 156 (27), 77 (31), 60
(27), 58 (52). HRMS (ESI) calcd for C24H30N2OSF2+H1 433.2125,
found 433.2114. Anal. Calcd for C24H30F2N2OS.HC1+ H2O: C, 59.19;
H, 6.83; N, 5.75; Cl, 7.28; S, 6.58; Found: C, 59.84; H,
6.70; N, 5.88; Cl, 6.91; S, 6.40.
EXAMPLE 84: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
3-{[(1S)-7-ethyl-l,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)-2,2-difluoroacetamide hydrochloride 49
Using methods analogus to those previously described,
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-l-{[(IS)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}butan-2-ol
dihydrochloride (0.33 mmol) is converted to compound 49 (88
mg, 0.18 mmol, 54%), which is obtained as a white solid: 1H NMR
(CDCl3) d 7.36 (s, 1 H), 7.12 (m, 2 H), 6.71 (m, 2 H), 6.64 (m,
1 H), 5.81 (t, J = 54 Hz, 1 H), 4.46 (m, 1 H), 4.18 (m, 1 H),
4.07 (m, 1 H), 3.12 (m, 2 H), 2.77 (m, 4 H), 2.63 (q, J" = 7.5
Hz, 2 H), 2.2 (m, 1 H), 2.05 (m, 1 H), 1.96 (m, 1 H), 1.86 (m,
1 H), 1.23 (t, J = 7.5 Hz, 3 H); MS (CI) m/z 453.5 (MH+).
EXAMPLE 85: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
3-{[(1S)-7-ethyl-1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl) -2-f luoroacetamide hydrochloride 50
Using methods analogus to those previously described,
(2R,3S)-3-amino-4-(3,5-difluorophenyl)-l-{[(IS)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-ylJ amino}butan-2-ol
dihydrochloride (0.0.71 mmol) is converted to compound 50 (248
mg, 0.53 mmol, 74%)., which is obtained as a white solid: 1H NMR
(CDC13) 5 9.85 (br, 1 H), 8.41 (br, 1 H), 7.45 (s, 1 H), 7.09
(m, 2 H), 6.97 (d, J = 8.6 Hz, 1 H), 6.68 (in, 2 H), 6.62 (m, 1
H), 4.70 (dq, J ~ 50, 11 Hz, 2 H), 4.48 (m, 1 H), 4.29 (m, 1
H), 4.16 (m, 1 H), 3.1-3.0 (m, 2 H), 2..83-2.69 (m, 4 H), 2.59
(q, J" = 7.5 Hz, 2 H), 2.21 (m, 1 H), 2.02 (m, 2 H), 1.78 (m, 1
H), 1.21 (t, J = 7.5 Hz, 3 H); MS (CI) m/z 435.3 (MH+).
Using methods analogus to those previously described, but
without making the HCl • salt, (2R,3S)-3-amino-4-(3,5-
difluorophenyl)-l-{t(1S)-7-ethyl-l,2,3,4-tetrahydronaphthalen-
1-yl]amino}butan-2-ol dihydrochloride (0.0.31 mmol) is
converted to compound 51 (70 mg, 0.17 mmol, 56%), which is
obtained as a white solid. 1H NMR (CDC13) d 8.11 (s, 1 H),
7.16 (s, 1 H), 7.03 (s, 2 H), 6.76 (m, 2 H), 6.67 (m, 1 H),
5.83 (d, J = 9 Hz, 1 H), 4.25 (m, 1 H), 3.74 (m, 1 H), 3.53
(m, 1 H), 3.03 (dd, J = 4.8, 14.4 Hz, 1 H), 2.90-2.69 (m, 5
H), 2.61 (q, J = 7.6 Hz, 2 H), 1.85 (m, 3 H), 1.76 (m, 1 H),
1.23 (t, J = 7.6 Hz, 3 H) ; MS (CI) m/z 403.3 (MH+). A trace
NMR doublet ( J = 11.8 Hz) appears at 8 7.73, tentatively
attributed to an intramolecularly cyclized form of the product
in the deuterochloroform solution.
EXAMPLE 87: Preparation of N-((1S,2R)-1-(3,5-difluorobenzyl)-
3-{[1-(3-ethylphenyl)-1-methylethyl] amino}-2-hydroxypropyl)-
2-fluoroacetamide hydrochloride 52
Using methods analogus to those previously described,
compound 38 (150 mg, 0.34 mmol) is converted to compound 52
(80 mg, 50%), which is obtained as a white solid: 1H NMR
(CDC13) d 9.95 (br, 1 H), 8.37 (br m, 1 H), 7.39-7.34 (m, 3 H),
7.23 (d, J = 7 Hz, 1 H), 6.94 (d, J = 3 Hz, 1 H), 6.67 (m, 2
H), 6.60 (m, 1 H), 4.68 (dq, J = 47, 14 Hz, 2 H), 4.27 (m, 1
H), 4.16 (m, 1 H), 2.97 (dd, 1 H), 2.80 (m, 2 H), 2.70 (q, J =
7.6 Hz, 2 H), 2.38 (m, 1 H), 1.88 (s, 3 H), 1.87 (s, 3 H),
1.27 (t, J= 7.6 Hz, 3 H); MS (CI) m/z 423.3 (MH+).
EXAMPLE 88: Preparation of (1S,2R)-1-(3,5-difluorobenzyl)-3-
{[1-(3-ethylphenyl)-1-methylethyl] amino}-2-
hydroxypropylformamide hydrochloride 53
Using methods analogus to those previously described,
compound 38 (0.60 mmol) is converted to compound 53 (130 mg,
50%), which is obtained as a white solid: 1H NMR (CDC13+ CD3OD
drop) d 7.95 (s, 1 H), 7.39-7.31 (m, 3 H), 7.24 (d, J = 7 Hz,
1 H), 6.71 (m, 2 H), 6.62 (m, 1 H), 4.05 (m, 1 H), 3.95 (m, 1
H), 3.07 (dd, 1 H), 2.80 (m, 1 H), 2.70 (q, J = 7.6 Hz, 2 H),
2.6 (m, obscured, 1 H), 2.47 (m, 1 H), 1.83 (s, 3 H), 1.82 (s,
3 H), 1.26 (t, J = 7.6 Hz, 3 H); MS (CI) m/z 391.3 (MH+). The
NMR spectrum of the free base in pure deuterochloroform shows
a small doublet (J = 11.6 Hz) at d 7.53 which is tentatively
attributed to an intramolecularly cyclized form of the
product.
EXAMPLE 89: Preparation of N-((1S,2R)-2-hydroxy-l-(4-
hydroxybenzyl)-3-{[1-(3-isopropylphenyl)
cyclohexyl]amino}propyl)acetamide hydrochloride 54
Using methods analogus to those previously described,
tert-butyl (1S)-2-(4-hydroxyphenyl)-1-[(2S)-oxiran-2-
yl]ethylcarbamate (0.78 mmol) is converted to compound 54 (70
mg, 0.15 mmol, 19%, 3 steps), which is obtained as a white
solid: 1H NMR (CDC13+ CD3OD drop) d 7.49 (s, 1 H), 7.39 (d, J =
4.6 Hz, 2 H), 7.28 (m, 1 H), 6.91 (d, J = 8 Hz, 2 H), 6.69 (d,
J = 8 Hz, 2 H), 3.97 (m, 1 H), 3.90 (m, 1 H), 2.96 (hept, J =
7 Hz, 1 H), 2.83 (dd, 1 H), 2.62 (m, 4 H), 2.45 (m, 1 H), 2.13
(m, 2 H), 1.89 (s, 3 H), 1.78 (m, 2 H), 1.58 (m, 1 H), 1.45-
1.3 (m, 3 H), 1.27 (d, J = 1 Hz, 6 H),- MS (CI) m/z 439.3
(MH+).
EXAMPLK 90: Preparation of N-((1S,2R)-1-[3-(allyloxy)-5-
fluorobenzyl]-2-hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}propyl) acetamide
hydrochloride 55
Using methods analogus to those previously described,
tert-butyl (1S) -2- [3- (allyloxy) -5-f luorophenyl] -1-[(2S)-
oxiran-2-yl]ethylcarbamate (0.61 mmol) is converted to
compound 55 (0.31 mmol, 51%, 3 steps), which is obtained as a
white solid: 1H NMR (CDC13+ CD3OD drop) d 7.42-7.27 (m, 4 H),
6.54 (m, 1 H), 6.48 (m, 1 H), 6.45 (m, 1 H), 6.05-5.98 (m, 1
H), 5.39 (m, 1 H), 5.28 (m, 1 H), 4.48 (m, 2 H), 3.95 (m, 1
H), 3.77 (m, 1 H), 2.96 (m, 2 H), 2.60 (m, 4 H), 2.4 (m,
obscured, 1 H), 2.1 (m, 2 H), 1.81 (s+m, 5 H), 1.6 (m, 1 H),
1.45-1.3 (m, 3 H), 1.27 (d, J = 7 Hz, 6 H) ; MS (CI) m/z 497.4
(MH+).
EXAMPLE 91: Preparation of- N-[(1S,2R)-2-hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}-1-(thien-2-
ylmethyl)propyl]acetamide hydrochloride 56
Using methods analogus to those previously described,
tert-butyl (1S)-1-[(2S)-oxiran-2-yl]-2-thien-2-
ylethylcarbamate (0.92 mmol) is converted to compound 56 (0.51
mmol, 55%, 3 steps), which is obtained as a white solid: 1H NMR
(CDC13) d 9.8 (br, 1 H), 8.03 (br, 1 H), 7.47 (s, 1 H), 7.37
(tn, 2 H), 7.26 (m, 1 H), 7.21 (m, 1 H), 7.0 (br, 1 H), 6.95
(m, 1 H), 6.90 (d, J = 5 Hz, 1 H), 4.15 (m, 1 H), 3.96 (m, 1
H), 3.9 (v br, 1 H), 2.96 (hept, J = 7 Hz, 1 H), 2.86 (m, 2
H), 2.7-2.55 (m, 3 H), 2.24 (m, 3 H), 2.00 (s, 3 H), 1.8-1.7
(m, 2 H), 1.59 (m, 1 H), 1.45-1.3 (m, 3 H), 1.28 (dd, J = 1.7,
7 Hz, 6 H); MS (CI) m/z 429.3 (MH+).
EXAMPLE 92: Preparation of N-((1S,2R)-2-hydroxy-l-(3-
hydroxybenzyl)-3-{[1-(3-isopropylphenyl)
cyclohexyl]amino}propyl)acetamide hydrochloride 57
Using methods analogus to those previously described,
tert-butyl (1S)-2-[3-(benzyloxy)phenyl]-1-[(2S)-oxiran-2-
yl]ethylcarbamate (1.0 mmol) is converted to compound 57 (0.28
mmol, 28%, 4 steps), obtained as a colorless glass-like solid
which can be pulverized into a beige powder: 1H NMR (CDCl3 +
CD3OD drop) d 7.43 (s, 1 H), 7.37 (m, 2 H), 7.28 (m, 1 H), 7.08
(t, J = 7.7 Hz, 1 H), 6.78 (s, 1 H), 6.69 (d, J = 8 Hz, 1 H),
6.57 (d, J = 7.5 Hz, 1 H), 4.03 (m, 1 H), 3.75 (m, 1 H), 2.97
(m, 2 H), 2.65 (m, 4 H), 2.43 (m, 1 H), 2.12-2 Cm, 2 H), 1.85
(s, 3 H), 1.78 (m, 2 H), 1.59 (m, 1 H), 1.45-1.3 (m, 3 H),
1.27 (d, J= 7 Hz, 6 H); MS (CI) m/z 439.3 (MH+).
EXAMPLE 93: Preparation of N-((1S,2R)-1-(3-fluorobenzyl)-2-
hydroxy-3-{[1-(3-isopropylphenyl)
cyclohexyl]amino}propyl)acetamide hydrochloride 58
Using methods analogus to those previously described,
tert-butyl (1S)-2-(3-fluorophenyl)-1-[(2S)-oxiran-2-
yl]ethylcarbamate (0.82 mmol) is converted to compound 58
(0.37 mmol, 45%, 3 steps), which is obtained as a white solid:
1H NMR (CDC13+ CD3OD drop) d 7.45 (s, 1 H), 7.4-7.35 (m, 2
H), 7.28 (m, 1 H), 7.20 (m, 1 H), 6.93 (m, 1 H), 6.88 (m, 2
H), 4.00 (m, 1 H), 3.87 (m, 1 H), 2.96 (m, 2 H), 2.7-2.6 (m, 4
H), 2.39 (m, 1 H), 2.11 (m, 2 H), 1.88 (s, 3 H), 1.79 (m, 2
H), 1.59 (m, 1 H), 1.45-1.3 (m, 3 H), 1.27 (d, J = 7 Hz, 6 H) ;
MS (CI) m/z 441.5 (MH+).
EXAMPLE 94: Preparation of N- ( (1S,2.R)-1-(3- (heptyloxy)-5-
fluorobenzyl)-2-hydroxy-3-{ [l-(3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
hydrochloride 59.
Using methods analogus to those previously described,
hydrochloride 11 (0.4 mmol) is reacted with 1-bromoheptane to
afford the title compound 59 (0.14 mmol, 34%) as a glass,
which can be pulverized to an off-white solid: 1H NMR (CDC13+
CD3OD drop) d 7.49 (s, 1 H), 7.37 (m, 2 H), 7.27 (m, 1 H), 6.51
(s, 1 H), 6.45 (s, 1 H), 6.43 (s, 1 H), 4.05 (m, 1 H), 3.98
(m, 1 H), 3.88 (t, J = 6.5 Hz, 2 H), 2.96 (hept, J = 7 Hz, 1
H), 2.84 (m, 1 H), 2.6 (3H obscured by solvent), 2.36 (m, 1
H), 2.16 (m, 2 H), 2.01 (s, 3 H), 1.85-1.75 (tn, 4 H), 1.58 (m,
1 H), 1.5-1.26 (m, 18 H), 0.89 (t, J = 6.6 Hz, 3 H) ; MS (CI)
m/z 555.5 (MH+).
EXAMPLE 95: Preparation of N-((1S,2R)-1-(3-(2-(2-
methoxyethoxy)ethoxy)-5-fluorobenzyl)-2-hydroxy-3-{ [1-(3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
hydrochloride 60
Using methods analogus to those previously described,
compound 11 (0.4 mmol) is reacted with l-bromo-2-(2-
methoxyethoxy)ethane to afford the title compound 60 ( 0.21
mmol, 52%) as a hygroscopic white solid: 1H NMR (CDC13) 5 9.4
(br, 1 H), 8.5 (br, 1 H), 8.32 (br, 1 H), 7.54 (s, 1 H), 7.38
(m, 2 H), 7.26 (m, 1 H), 6.56 (s, 1 H), 6.47 (m, 2 H), 4.34 (v
br, water H), 4.1 (m, 4 H), 3.83 (m, 2 H), 3.70 (m, 2 H), 3.58
(m, 2 H), 3.38 (s, 3 H), 2.96 (hept, J = 7 Hz, 1 H), 2.8-2.6
(m, 5 H), 2.4-2.2 (m, 3 H), 2.15 (s, 3 H), 1.80 (m, 2 H), 1.6
(m, 1 H), 1.5-1.3 (m, 3 H), 1.27 (d, J = 7 Hz, 6 H) ; MS (CI)
m/z 559.5 (MH+).
EXAMPLE 96: Preparation of N-((1S,2R)-1-[3-(allyloxy)-5-
fluorobenzyl]-3-{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-lH-
isothiochromen-4-yl]amino}-2-hydroxypropyl)acetamide 61
Using methods analogus to those previously described,
tert-butyl (1S)-2- [3-(allyloxy)-5-fluorophenyl]-1-[(2S)-
oxiran-2-yl]ethylcarbamate (0.37 mmol) and (4R)-6-ethyl-3,4-
dihydro-lH-isothiochromen-4-amine 2,2-dioxide (0.78 mmol) are
reacted together, and the product is further converted, Using
methods analogus to those previously described, (except that
the HCl salt is not formed) to the title compound 61 (0.16
mmol, 43%), which is obtained as a white solid: 1H NMR (CDCl3)
d 7.22-7.19 (m, 2 H), 7.13 (m, 1 H), 6.57 (m, 1 H), 6.51 (m, 2
H), 6.06-5.99 (m, 1 H), 5.75 (br, 1 H), 5.41 (d, J = 17 Hz, 1
H), 5.30 (d, J = 12 Hz, 1 H), 4.67 (d, J = 15 Hz, 1 H), 4.50
(m, 2 H), 4.26 (m, 1 H), 4.17 (d, J = 15 Hz, 1 H), 4.1 (m, 1
H), 3.66 (m, 2 H), 3.48 (m, 1 H), 3.36 (dd, 1 H), 2.90 (m, 2
H), 2.78 (m, 2 H), 2.67 (q, J = 7.6 Hz, 2 H), 1.91 (s, 3 H),
1.25 (t, J = 7.6 Hz, 3 H); MS (CI) m/z 505.4 (MH+).
EXAMPLE 97: Preparation of N-((1S,2R)-1-(cyclohexylmethyl)-3-
{[(4R)-6-ethyl-2, 2-dioxido-3,4-dihydro-lH-isothiochromen-4-
yl]araino)-2-hydroxypropyl)acetamide 62
Using methods analogus to those previously described,
tert-butyl (1S) -2-cyclohexyl-l-[(2S)-oxiran-2-
yl]ethylcarbamate (0.91 mmol) and (4R)-6-ethyl-3,4-dihydro-
lH-isothiochromen-4-amine 2,2-dioxide (1.15 mmol) are coupled.
The resulting product is recovered by chromatography over
silica gel, eluting with 3% methanol (containing 1 % NH40H) in
CH2C12. This material is then converted to compound 62, which
is obtained as a white solid: MS (CI) m/z 437.3 (MH+).
EXAMPLE 98: Preparation of (1S,2R)-1-(cyclohexylmethyl)-3-
{[(4R)-6-ethyl-2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-
yl]amino}-2 -hydroxypropylformamide 6 3.
Using me.thods analogus to those previously described,
tert-butyl (1S) -2-cyclohexyl-l-[(2S)-oxiran-2-
yl]ethylcarbamate (0.91 mmol) and (4R)-S-ethyl-3,4-dihydro-
lH-isothiochromen-4-amine 2,2-dioxide (1.15 mmol) are coupled.
The resulting product (0.63 mmol, 69%) is purified by
chromatography over silica gel, eluting with 3% methanol
(containing 1 % NH4OH) in CH2Cl2. The purified coupled
material is then converted to the title compound 63 (which is
obtained as a white solid), using methods analogous to those
disclosed herein. : MS (CI) m/z 423.3 (MH+).
Example 99: Preparation of N-[ (1S,2R) -1- (3,5-Difluorobenzyl)-
3-((1S)-7-ethyl-1,2,3,4-tetrahydro-naphthalen-l-ylamino)-2-
hydroxy-propyl]-methanesulfonamide (64)
A 30 mg sample of the starting amine in 1 mL of
dichloromethane was treated with 33 uL of triethylamine. A
solution of 6 uL of methanesulfonyl chloride in 0.5 mL of
dichloromethane was added and the solution was stirred
overnight. The solvent was evaporated and the product was
isolated by reverse-phase HPLC. Mass spectroscopy gave m/z =
453.2.
Compounds 65-78 are synthesized in an analogous manner,
substituting methansefulfonyl chloride with various reagents.
EXAMPLE 100:
A. Preparation of 1- tert-Butyl-3-iodo-benzene from 3-(te:rt-
Butyl)aniline
3-(tert-Butyl)aniline (Oakwood, 6.0 g, 4 0.21mmol) was
slowly added to a cold solution of 12 N HC1 (24.5 mL) while
stirring over an ice/acetone bath in a three-neck round bottom
flask equipped with a thermometer. A 2. 9M solution of sodium
nitrite (16 mL) was added via addition funnel to the reaction
flask at a rate so as maintain the temperature below 2°C. The
solution was stirred for 3 0 min. prior to being added to a
reaction flask containing a 4.2M solution of potassium iodide
(100 mL). The reaction mixture was allowed to stir overnight
while warming to RT. The mixture was then extracted with a
hexane/ether solution (1:1) followed by washing with H2O (2X),
0.2N citric acid (2X) and sat. NaCl. The organic phase was
separated, dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by flash chromatography
(100% Hexane) to give the desired iodo intermediate (8.33g,
80%): 1H NMR (CDCl3, 300 MHz) d 1.34 (s, 9H), 7.07 (t, J = 8.0
Hz, 1H), 7.39(d, J = 8.0 Hz, 1H), 7.55(d, J = 8.0 Hz, 1H),
7.77 (t, J = 2.0 Hz, 1H).
B. Preparation of 1-(3-tert-Butyl-phenyl)-cyclohexanol from
1-tert-Butyl-3-iodo-benzene
1-tert-Butyl-3-iodo-benzene(8.19g, 31.49mmol) in anh. THF
(35mL) was cooled to -78°C. A solution of 1. 7M tert-butyl
lithium was added and the reaction mixture was allowed to stir
while under N2 (g) inlet for 2 h. A solution of cyclohexanone
in anh. THF (5mL) was added and the reaction mixture was
stirred for 1 h. before transferring to a 0°C bath for 1 h and
warming to RT for 1 h. The reaction was quenched with H20 and
extracted with ether. The organic layer was separated, dried
(NaSO4) and concentrated under reduce pressure. The residue was
purified by flash chromatography (100% CHC13) to give the
desired alcohol (4.73g, 65%): mass spec (CI) 215.2 (M-OH).
C. Preparation of 1-(1-Azido-cyclohexyl)3-tert-Jbutyl-benzene
from 1- (3-tert-Butyl-phenyl)-cyclohexanol
The above compound was prepared essentially according to
the procedure of Example 12. The crude reaction product was
purified by flash chromatography (100% hexane) to give the
desired azide. mass spec (CI) 215.2 (M-N3).
D. Preparation of 1-(3-tert-Butyl-phenyl)-cyclohexylamine
from 1- (1-Azido-cyclohexyl) 3-tert-butyl-benzene
To a solution of 1-(1-Azido-cyclohexyl)-3-tert-
butylbenzene dissolved in ethanol (5mL) was added acetic acid
(0.5mL) and 10% palladium on carbon (0.l0g, 0.94mmol). The
reaction mixture was placed on the hydrogenator at 19 psi for
3.Shand then filtered through Celite and rinsed with ethanol.
The filtrate. was collected and concentrated under reduce
pressure. This was then partitioned between EtOAc and 1N NaOH.
The aqueous layer was removed and the mixture was washed with
H2O. The organic layer was separated, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was
used without further purification: mass spec (CI) 215.2 (M-
NH2).
E. Preparation of (1S,2R)-N-[3-[1-(3-tert-Butyl-
phenyl)cyclohexylamino]-1-(3,5-Difluorobenzyl)-2-hydroxy-
propyl]acetamide (79)
The product from step D is transformed into the above
product using methods that are analogous to others described
in the application. Mass spec: (CI) 473.2 (M+H).
F. Preparation of 1-(3-Ethynylphenyl)cyclohexylamine from 1-
(3-Bromo-phenyl)-cyclohexylamine
1-(3-Bromo-phenyl)-cyclohexylamine (Pharmacia, 1.04 g,
4.09 mmol) was free based and then dissolved in triethylamine
(20 mL, 143mol) prior to the addition of
dicholorbis(triphenylphosphine) palladium(II) (0.119 g, 0.170
mmol) and copper iodide (0.040 g, 0.211 mmole). The reaction
mixture was heated to reflux at which point
trimethylsilylacetylene (0.85 mL, 6.01 mmole) was added via
syringe. After refluxing for 3h, the reaction mixture was
cooled to RT before partitioning between EtOAc and sat. NaHCO3
(aq). The aqueous phase was collected and extract with EtOAc
(3X). The organic phases were then collect and washed with
sat. NaCl (aq), separated, dried (Na2SO4) and concentrated
under reduced pressure. The crude product was used without
further purification.
The trimethylsilyl intermediate was dissolved in methanol
(5mL) and 1 N KOH (6 mL) and stirred at RT for 5.5 h. The
reaction mixture was then partitioned between EtOAc and sat.
NaHCO3 (ag). The organic layer was separated, dried (Na2SO4),
and concentrated under reduced pressure. The residue was
purified by flash chromatography (5%MeOH, 94.5% CHC12/ 0.5%
NH4OH) to give the desired amine (0.35g, 31%): mass spec (CI)
183.1 (M-16).
G. Preparation of (1S,2R)-N-{l-(3,5-Difluorobenzyl)-3-[1-
(3-(ethynylphenyl)cyclohexylamino] -2-hydroxy-propyl}acetamide
(80)
The. product from step F is transformed into the above
product using methods that are analogous to others described
in the application. Mass spectrometic analysis: (CI) 441.2
(M+H).
H. Preparation of (1S,2R)-N- (1-(3,5-Dif luorobenzyl)-3-{l-[3-
(2,2-dimethylpropyl)phenyl]cyclohexylamino}-2-
hydroxypropyl)acetamide (81)
The desired product is prepared using methods that are
analogous to others described in the application. Mass spec:
(CI) 487.2 (M+H), 509 (M+Na).
EXAMPLE 101:
A. Synthesis of the following inhibitors was performed using
essentially the same coupling conditions described above in
Example 56, except with the variation of carboxylic acid
starting materials as described below.
To dibromobenzylamine (1S,2R) N-[3-(2,5-Dibromo-
benzylamino)-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-
acetamide (0.504 g, 1.0 mM, 1 eq) was added 0.5 M THF solution
of neopentylzinc iodide (20 mL, 10 eq) and 0.082 g, (0.1 mM,
0.1 eq) of [1,1'-bis(diphenylphosphino)ferrocene]
dichloropalladium(II), complex with dichloromethane
(Pd (dppf)Cl2 CH2C12) - A reaction mixture was stirred overnight
at room temperature. The reaction was quenched with a
saturated aqueous solution of NH4Cl (20 mL) and extracted with
ethyl acetate (3 x 30 mL). Combined organic layers were washed
with brine, dried and concentrated.
Compound (90) was purified by HPLC, yielding 0.055 g
(11%). 1H NMR (300 MHz, DMSO-d6) d 8.60-9.00 (m, 1H), 7.88 (d,
J = 8.7 Hz, 1H), 7.61 (s, 1H), 7.39 (s, 1H), 7.08 (s, 1H),
7.05 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 6.9 Hz, 2H), 4.16 (bs,
2H), 3.85 (m,lH), 3.70 (m, 1H), 3.02 (m, 2H), 2.81 (m, 1H),
2.57 (m, 1H), 2.47 (s, 2H), 1.69 (s, 3H), 0.87 (s, 9H) ; 13C NMR
(300 MHz, DMSO-dg) 5 170.0, 164.4, 164.2, 161.1, 160.9, 144.2,
142.9, 134.2, 133.9, 131.8, 131.0, 121.6, 112.9, 112.6, 102.2,
69.3, 53.5, 50.1, 49.1, 35.4, 32.1, 29.6, 23.0; MH+ (CI):
497.2.
Example 10IB
Compound 3 [1S,2R) N-{1-(3,5-Difluorobenzyl)-3-[3-(2,2-
dimethylpropyl)-5-ethyl-benzylamino]-2-hydroxypropyl}-
acetamide] was prepared by reacting Example 101A (compound 2)
with BEt3, a palladium catalyst and potassium phosphate. MH+
(CI): 447.2.
Example 101C
Preparation of [(1S,2R) N-{l-(3,5-Difluorobenzyl)-2-
hydroxy-3-[1-(3-prop-l-ynyl-phenyl)-cyclopropylamino]-propyl}-
acetamide] 5
To a solution of (1S,2R) N-[3-[1-(3-Bromo-phenyl)-
cyclopropylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-
acetamide 4 (0.227 g, 0.5 mM) in Et3N (2 mL) and DMF (0.5 mL)
was added PdCl2 (PPh3)2. A reaction mixture was cooled down to -
3 0°C and propene gas was bubbled through for 1 minute. A
reaction tube was sealed and the mixture was stirred for 2
min. before CuI (O.OOlg) was added. After stirring for
additional 10 min. in a sealed tube at RT color of the
reaction mixture changed from yellow to dark brown. The
reaction was heated at 5 0°C for 48 hrs, cooled down to rt,
filtered and stripped solvent. Purified by HPLC; yield 0.030g
(15%); MH+ (CI): 413.2.
EXAMPLE 102
A. Preparation of N-(15, 2R)-[1-(3,5-Difluoro-benzyl)-2-
hydroxy-3-[(1S)-(7-isobutyl-l,2,3, 4-tetrahydronaphthalen-l-
ylamino)]-propyl]-acetamide
Palladium(II) acetate (0.2 equiv, 0.07 mmol, 15.8 mg) and
2-(di-t-butylphosphino)biphenyl (0.1 equiv, 0.03 5 mmol, 10.5
mg) were dissolved in THF (2 mL) and deoxygenated with a
subsurface N2 (g) purge for 5 minutes. The bromide (1 equiv,
0.352 mmol, 200 mg) was then added to this solution as a
solid, followed by isobutyl zinc bromide (0.5 M solution in
THF, 3 equiv, l.l mmol, 2.1 mL). The reaction was stirred
overnight at ambient temperature under a N2 (g) atmosphere.
After 12 hours, the reaction was partitioned between EtOAc and
H2O, and extracted 3x into EtOAc. The combined organic
extracts were washed with brine and dried over Na2SO4, filtered
and concentrated. Column chromatography on SiO2 with 30 ? 50
% EtOAc in hexanes gave the pure desired Boc protected
product. (148 mg, 77 % yield) M+Na+ (CI) = 567.2
Removal of the Boc group was achieved by dissolving the
above compound in 4N HCl in dioxane (1 mL) and stirring at
ambient temperature for 1 hour under a N2 (g) atmosphere. The
resulting white cloudy mixture was concentrated to give the
final product. (100 mg, 85% yield) 1HNMR (CD3OD): d 7.3 (s,
1H), 7.15 (s, 2H), 6.9 (m, 2H), 6.8 (m, 1H), 4.6 (t, 1H), 4.05
(m, 1H), 3.9 (m, 1H), 3.2 (m, 2H), 3.0 (m, 1H, 2.8 (m, 2H),
2.7 (m, 2H), 2.5 (d, 2H), 2.2 (m, 2H), 2.0 (m, 1H), 1.85 (s,
3H), 1.85, m, 1 H), 0.9 (m, 6H). M+H+ (CI) = 445.2
B. Preparation of N-(1S, 2R) -{l-(3,5-Difluoro-benzyl)-3-
[ (1S)-7-(2,2-dimethylpropyl)-1,2,3,4-tetrahydro-naphthalen-l-
ylamino]-2-hydroxypropyl}-acetamide
The neopentyl zinc was prepared according to the
procedure in Tetrahedron Letters, 1983, volume 24, page 3 823-
3824.
To the bromotetralin amine (1 equiv, 8 mmol, 1.71 g) was
added the crude neopentylsinc chloride suspension (3 equiv, 24
mmol, 48 mL), followed by Pd (dppf) Cl2CH2Cl2 (0.05 equiv, 0.4
mmol, 330 mg). The reaction was stirred at ambient
temperature under N2 (g) overnight. The suspension quickly
turned yellow, and eventually turned purplish overnight.
After 12 h, the reaction was quenched with NH4C1 (aq) and
extracted 3x with EtOAc. The combined organic extracts were
washed with brine and dried over Na2SO4, filtered and
concentrated. Column chromatography on SiO2 with 2 ? 10 %
MeOH in CH2Cl2 gave the desired neopentyl tetralin amine. (1.5
g, 86% yield) 1HNMR (CDC13) : d.7.15 (s,lH), 6.95 (m, 2H),
3.95 (m, 1H), 2.8 (m, 2H), 2.4 (s, 2H), 2.0 (m, 2H), 1.7 (m,
2H), 1.6 (broad s, 2H), 1.0 (s, 9H); M-NH2+ (CI) = 201.2.
The final compound was synthesized via epoxide opening,
protecting group deprotection, and acetylation as previously
described: M+H+ (CI) = 459.2.
C. Preparation of N-(1S, 2R) -{l-(3,5-Difluorobenzyl)-2-
hydroxy-3-[1-(3-isopropenyl-phenyl)-cyclopropylamino]-propyl}-
acetamide
Potassium acetate (5 equiv, 8.8 mmol, 0.864 g),
(dppf)PdCl2-CH2Cl2 (0.04 equiv, 0.0704 mmol, 57.5 mg), and
diboron reagent (1.15 equiv, 2.03 mmol, 0.515g), followed by
the bromide (1 equiv, 1 g, 1.76 mmol) and DMF (7 mL) were
added to a flask. The mixture was deoxygenated via a
subsurface N2 (g) purge, and stirred at 80°C under N2 (g)
overnight. As soon as heating began, the reaction turned
brown. After 18 h, the reaction was partitioned between EtOAc
and H2O, and extracted 3x with EtOAc. The combined organic
extracts were washed with brine, dried over Na2S04, and
filtered before removal of solvent under vacuum. A quick SiO2
column with 20?50% EtOAc in hexanes gave the pure boronic
ester. (0.75 g, 69% yield) 1HNMR (CD3OD) : d 7.6 (t, 1H), 7.25
(m, 1H), 7.1 (m, 1H), 7.8 (dd, 2H), 6.6 (m, 1H), 4.05 (m, 1H),
3.8 (m, 1H), 3.5 (m, 2H), 2.9 (m, 2H), 1.8 (s, 3H), 1.4 (s,
9H), 1.2 (m, 12 H), 1.2 (m, 4 H). M+Na+ (CI) = 623.2
The boron ester (1 eguiv, 0.167 mmol, 100 mg) followed by
Pd(PPh3)2Cl2 (0.1 equiv, 0.017 mmol, 11.7 mg), 2-bromopropene
(1.2 equiv, 0.2 mmol, 24.2 mg, 17.8 uL), 2M Na2CO3 (aq) (1.5
equiv, 0.25 mmol, 0.125 mL), and finally 7:3:2 DME:H20.-EtOH
(0.7 mL) were placed in a reaction vial equipped with a stir
bar. The vial was sealed and the l-eaction was prestirred for
15 s before being microwaved at 160 °C for 7 minutes at Normal
Absportion Level and with Fixed Hold Time on. (A Personal
Chemistry Microwave Reactor was used.) The reaction was
partitioned between EtOAc and H2O, and extracted 3x with EtOAc.
The combined organic extracts were washed with brine, dried
over Na2SO4, and filtered before removal of solvent under
vacuum. Purification via SiO2 column run with 10?35% EtOAc in
hexanes gave the pure Boc protected styrene compound. (45.9
mg, 53% yield) M+Na+ (CI) = 537.2
Boc group removal was achieved by treating the above
protected compound with 1:4 TFA:CH2C13 at 0°C. The reaction
was stirred for 2 h at 0°C, and then concentrated to give the
desired product. HPLC purification gave the pure desired
product (7 mg, 36% yield): M+H+ (CI) = 415.2
D. Preparation of N-(1S, 2R) -(l-(3,5-Difluorobenzyl) -2-
hydroxy-3-[1-(3-isopropylphenyl)-cyclopropylamino]-propyl}-
acetamide
The Boc amine (1 equiv, 0.1 mmol, 55.4 mg) was dissolved
in EtOAc before the addition of 5% Pd-C DeGussa catalyst (an
unmeasured amount). The air was evacuated from the flask
before a balloon of N2 (g) was applied. The; mixture was
stirred for 4 h at ambient temperature, at which point HPLC-MS
determined the reaction was complete. Filtration through
diatomaceous earth followed by removal of solvent by vacuum
resulted in the clean crude reduced material. (56.7 mg,
quantitative) M+H+ (CI) = 517.3.
Removal of the Boc group was achieved by dissolving the
above compound in 50:50 TFA:CH2C12 and stirring at ambient
temperature for 1 hour under a N2 (g) atmosphere. The
resulting solution was concentrated to give the final product.
(41.6 mg, quantitative): 1H NMR (CD3OD) d 7.4 (s, 1H), 7.25
(m, 3H), 6.7 (m, 2H), 6.6 (m, 1H), 4.0 (m, 1H), 3.9 (m, 1H),
2.9 (m, 4H), 2.7 (m, 1H), 1.8 (s, 3H), 1.2 (d, 6 H), 1.2 (m,
4H). M+H+ (CI) = 417.2
EXAMPLE 103
Step 1:
The conversion of compound 1 to compound 2 was performed
essentially according to the method of Example 1. The
resulting crude product was purified by flash column
chromatography to afforded compound 2 as a solid: TLC (10%
EtOAc/Hexane) R£ = 0.48; MH+ (CI) 295.0 (79Br).
Step 2:
Palladium-mediated transfer of the ethyl group onto the
aryl bromide was described previously to give compound 3:
Yield: 84%; MH+ (CI) 245.2.
Step 3:
Formation of the oxime was performed as previously
described to give compound 4. Yield: 97%; MH+ (CI) 260.2.
Step 4:
Reduction of the oxime to the amine was achieved as
previously described to give compound 5: yield: 91%; MH+ (CI)
229.2.
Step 5:
Epoxide opening was performed as previously described:
yield: 79%; MH+ (CI) 545.3.
Step 6:
Boc deprotection and acetylation was performed as
previously described. The resultant diastereomeric mixture was
purified by reverse-phase HPLC to give both isomers of:
N-(1S,2R)-{l-(3,5-Difluorobenzyl)-3- [7- (2,2-
dimethylpropyl)-5-ethyl-l,2,3,4-tetrahydronaphthalen-l-
ylamino]-2-hydroxypropylJacetamide.
Isomer 1: MH+ (CI) 487.3.
Isomer 2: MH+ (CI) 487.3.
EXAMPLE 104: Synthesis Of 3, 5-Disubstituted Benzylamine
Derivatives
A. 3,5-di-tert-butylbenzonitrile from 3,5-di-tert-
butylbromobenzene.
The nitrile is introduced essentially according to the
procedure detailed in Dudley, D. A. et al. J. Med. Chem. 2000,
43, 4063-4070. The crude product was purified by flash
chromatography (Rf = 0.68 in 10% EtOAc/hexanes) to give the
desired product as a white solid: 1H NMR (300 MHz, CDC13) d
7.64 (s, 1H), 7.48 (d, J = 1.8 Hz, 2H), 1.33 (s, 18H); mass
spec (CI): 175.1.
To 3, 5-di-tert-butylbenzonitrile (863 mg, 4.02 mmol) in
dry THF (10 mL) at 0 °C was added lithium aluminum hydride
(304 mg, 8.0 mmol) in one portion. The reaction mixture was
allowed to warm to rt for 2 h, whereupon the reaction was
quenched (0.2 mL water, followed by 0.2 mL 15% potassium
hydroxide solution and 0.6 mL water). The reaction mixture was
stirred at rt for 1 h, then filtered through diatomaceous
earth (CH2Cl2 elution). The filtrate was then concentrated and
used in the next reaction without further purification: 1H NMR
(300 MHz, CDCI3) d 7.33 (s, 1H), 7.16 (d, J = 1.8 Hz, 2H), 3.86
(s, 2H), 1.33 (s, 18H) ; mass spec (CI) : 203.2 (M-NH2).
The free amine was further elaborated, using methods
analogous to those disclosed herein, to form the final
product.
C. N-[(1S, 2R) -3-(3,5-Di-tert-butyl-benzylamino)-1-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide
The above compound was prepared using methods analogous
to those previously described. 1H NMR (300 MHz, CDC13) d 7.36
(s, 1H), 7.16 (d, J = 1.4 Hz, 2H), 6.90 (d, J" = 8.8 Hz, 1H),
6.70 (d, J = 6.2 Hz, 2H), 6.61 (tt, J = 9.0, 2.0 Hz, 1H),
4.22-4.10. (m, 1H), 4.03 (br s, 1H), 3.80 (d, J = 12.9 Hz, 1H),
3.74 (d, J = 12.9 Hz, 1H), 3.72-3.60 (m, 1H), 2.90-2.65 (m,
4H), 1.85 (s, 3H), 1.32 (s, 18H) ; 13C NMR (75 MHz, CDCl3) 5
170.5, 162.8 (dd, J = 248.2, 13.0 Hz, 2C), 151.0, 142.1 (t, J
= 9.1 Hz, 1C), 137.3, 122.6, 121.5, 111.9 (dd, J = 16.9, 7.5
Hz, 2C), 101.8 (t, J = 25.3 Hz, 1C), 70.1, 54.2, 53.6, 50.7,
36.1, 34.7, 31.4, 23.2; MH+ (CI): 461.3.
D. N-[(1S,2R)-3-(3,5-Dibromobenzylamino)-1-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide
The titled compound was prepared using methods analogous
to those previously described. The required dibromo
benzylamine is prepared by treating the commercially available
aldehyde with a nitrogen source and a reducing agent. 1H NMR
(300 MHz, CDC13) d 1.56 (t, J = 1.5 Hz, 1H), 7.40 (d, J = 1.5
Hz, 2H), 6.74 (d, J = 6.2, 1.8 Hz, 2H), 6.68 (tt, J = 9.0, 2.2
Hz, 1H), 5.63 (d, J = 8.9 Hz, 1H), 4.20-4.05 (m, 1H), 3.78 (d,
J = 13.9 Hz, 1H), 3.71 (d, J = 13.9 Hz, 1H), 3.51 (q, J = 5.3
Hz, 1H), 2.99 (dd, J = 14.3, 4.7 Hz, 1H), 2.82 (dd, J = 14.3,
8.7 Hz, 1H), 2.67 (d, J = 3.0 Hz, 2H), 1.93 (s, 3H) ; 13C NMR
(75 MHz, CDCI3) 8 170.4, 163.0 (dd, J = 248.2, 13.0 Hz, 2C),
143.9, 141.7 (t, J = 9.1 Hz, 1C), 132.8, 129.8, 123.0, 112.0
(dd, J = 16.9, 7.5 Hz, 2C), 102.2 (t, J= 25.3 Hz, 1C), 70.7,
52.9, 52.8, 50.5, 36.1, 23.3; MH+ (CI): 505.0 (79Br X 2).
The nitrile was introduced essentially according to the
method of Ornstein, P. L. et al. J. Med. Chem. 1991, 34, 90-
97. The crude product was filtered through silica (CH2C12
elution) to give the product as a white crystalline solid: 1H
NMR (300 MHz, CDCl3) d 8.64 (d, J = 5.3 Hz, 1H), 7.72 (d, J =
1.7 Hz, 1H), 7.56 (dd, J = 5.3, 1.7 Hz, 1H) ; MH+ (CI) : 13 9.0
(35C1).
2-Cyano-4-isopropylpyridine was synthesized according to
the method of Ornstein, P. L. et al. J,. Med. Chem. 1991, 34,
90-97: MH+ (CI): 147.1.
2-Cyano-4-tert-butylpyridine was synthesized according to
the method of Ornstein, P. L. et al. J. Med. Chem. 1991, 34,
90-97: 1H NMR (300 MHz, CDC13) d 8.60 (d, J = 5.3 Hz, 1H), 7.68
(d, J = 1.5 Hz, 1H), 7.49 (dd, J = 5.3, 1.9 Hz, LH), 1.33 (s,
9H); MH+ (CI): 161.1.
2-Cyano-6-neopentylpyridine was synthesized from 2-
neopentylpyridine according to the method of Ornstein, P. L.
et al. J. Med. Chem. 1991, 34, 90-97: Rf = 0.62 in 20%
EtOAc/hexanes; MH+ (CI): 175.1.
A solution of neopentylzinc chloride was prepared
according to the method of Negishi, E.-I. et al. Tetrahedron
Lett. 1983, 24, 3823-3824.
2-Bromopyridine (Aldrich, 0.48 mL, 5.0 mmol) and [1, 1'-
bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex
with dichloromethane (1:1) (Aldrich, 200 mg, 0.25 mmol) were
added to the neopentylzinc chloride suspension. The resulting
suspension was stirred at rt for 21 h, whereupon saturated
ammonium chloride solution (25 mL) was added. The mixture was
extracted with ethyl acetate (3X). The combined organic
extracts were dried (Na2SO4), filtered and concentrated under
reduced pressure. The residue was dissolved in methylene
chloride, and washed with 1 N HCl. The aqueous layer was
separated, basif ied with 10 N NaOH (aq), and extracted with
CH2C12, The organic layer was dried (Na2SO4), filtered and
concentrated under reduced pressure to give 2-
neopentylpyridine as an oil: Rf = 0.33 in 5% MeOH/CH2Cl2.
I
i
This transformation was performed eiccording to the method
of Dai, C. and Fu, G. J. Am. Chem. Soc. 2001, 123, 2719-2724.
The crude residue was purified by filtration through a small
plug of silica (20% ether/hexanes elution) to give the 2-
cyano-4-neopentylpyridine: Rf = 0.25 in 2 0% Et2O/hexanes; MH+
(CI): 175.1.
The method for the synthesis of 2-cyano-4-
neopentylpyridine was used to convert 2-chloro-4-cyanopyridine
(Oakwood) into 4-cyano-2-neopentylpyridine: Rf = 0.47 in 10%
EtOAc/hexanes; 1H NMR (300 MHz, CDC13) d 8.73 (dd, J = 4.9, 0.7
Hz, 1H), 7.55-7.40 (m, 2H), 2.75 (s, 2H), 0.96 (s, 9H) ; MH+
(CI): 175.1.
To a solution of 2-cyano-4-neopentylpyridine (380 mg, 2.2
mmol) in dry THF (6 mL) at rt was added titanium (IV)
isopropoxide (0.7 mL; 2.4 mmol) and ethylmagnesium bromide
(1.0 M in THF, 4.3 mL, 4.3 mmol) in succession with vigorous
stirring. After 30 min, 1 mL water was added. The quenched
reaction mixture was stirred at rt for 3 0 min, then filtered
through diatomaceous earth (10% iPrOH/CHCl3 elution). The
filtrate was concentrated under reduced pressure. The crude
residue was purified by flash chromatography (Rf = 0.2 6 in 10%
MeOH/CH2Cl2) to give 166 mg of the desired product as an oil:
MH+ (CI): 205.1.
H. N-((1S,2R)-l-(3,5-Difluorobenzyl)-3-{[4-(2,2-
dimethylpropyl)pyridin-2-ylmethyl]amino}-2-hydroxypropyl)
acetamide
i
The above compound was prepared from 2-cyano-4-
neopentylpyridine by methods analogous to those disclosed
herein. 1H NMR (300 MHz, CDC13) d 8.39 (d, J = 5.0 Hz, 1H),
7.03-6.92 (m, 2H), 6.72 (appd, J = 6.3 Hz, 2H), 6.63 (tt, J =
9.0, 2.2 Hz, 1H), 6.44 (d, J = 9.0 Hz, 1H), 4.25-4.10 (m, 1H),
3.93 (S, 2H), 3.72-3.62 (m, 1H), 2.94 (dd, J = 14.3, 4.7 Hz,
1H), 2.88-2.70 (m, 3H), 2.48 (s, 2H), 1.87 (s, 3H), 0.91 (s,
9H) ; 13C NMR (75 MHz, CDC13) 5 170.3, 162.8 (dd, J = 248.2,
13.0 Hz, 2C), 157.7, 149.8, 148.3, 142.3 (t, J = 9.1 Hz, 1C),
124.62, 124.56, 112.0 (dd, J = 16.9, 7.4 Hz, 2C), 101.8 (t, J
= 25.1 Hz, 1C), 71.0, 54.1, 52.9, 51.5, 49.5, 35.7, 31.7,
29.3, 23.1; MH+ (CI): 420.2.
I. N-((1S,2R)-1-(3,5-Difluorobenzyl)-3-{l-[4-(2,2-
dimethylpropyl) pyridin-2-yl]cyclopropylaiaino}-2-hydroxypropyl)
acetamide
The above compound was prepared by coupling 2-
Cycloalkylamino-4-neopentylpyridine and example 134 by methods
analogous to those disclosed herein. The coupled product was
then further elaborated using to afford the above compound.
1H NMR (300 MHz, CDC13) d 8.35 (d, J = 5.1 Hz, 1H), 6.89 (dd, J
= 5.1, 1.0 Hz, 1H), 6.80 (s, 1H), 6.73 (dd, J = 6.2, 2.0 Hz,
2H), 6.64 (tt, J = 9.0, 2.0 Hz, 1H), 5.93 (d, J = 9.2 Hz, 1H),
4.22-4.07 (m, 1H), 3.72 (s, 2H), 3.50 (dt, J = 6.6, 3.3 Hz,
1H), 2.96 (dd, J = 14.3, 4.6 Hz, 1H), 2.90-2.70 (m, 3H), 2.46
(s, 2H), 1.88 (s, 3H), 1.16 (d, J = 2.4 Hz, 4H), 0.90 (s, 9H);
13C NMR (75 MHz, CDCl3) d 170.0, 163.3 (dd, J = 248.2, 13.0 Hz,
2C), 162.2, 149.4, 147.5, 142.1 (t, J = 9.1 Hz, 1C), 123.2,
120.9, 112.0 (dd, J = 16.9, 7.4 Hz, 2C), 101.9 (t, J = 25.1
Hz, 1C), 71.1, 63.6, 53.4, 52.6, 49.7, 49.4, 42.7, 35.8, 31.7,
29.3, 23.2, 19.0, 18.5; MH+ (CI): 446.2.
J. N-((lS,2K)-l-(3,5-Difluorobenzyl)-3-{[2-(2,2-
dimethylpropyl) pyridin-4-ylmethyl]-amino)-2-hydroxypropyl)
acetamide
The above compound was prepared essentially according to
the previously described methods. 1H NMR (300 MHz, CDC13) d
8.44 (d, J = 5.0 Hz, 1H), 7.07 (d, J = 5.0 Hz, 1H), 7.06 (s,
1H), 6.72 (d, J = 6.3 Hz, 2H), 6.64 (tt, J = 9.0, 2.2 Hz, 1H),
6.56 (d, J = 8.7 Hz, 1H), 4.25-4.10 (m, 1H), 3.82 (d, J = 14.4
Hz, 1H), 3.76 (d, J = 14.4 Hz, 1H), 3.62 (q, J = 5.0 Hz, 1H),
3.42 (br s, 2H), 2.93 (dd, J = 14.2, 4.9 Hz, 1H), 2.78 (dd, J
= 14.2, 8.9 Hz, 1H), 2.73 (d, J = 4.8 Hz, 2H), 2.66 (s, 2H),
1.88 (s, 3H), 0.94 (s, 9H) ; 13C NMR (75 MHz, CDC13) 8 170.4,
162.7 (dd, J= 248.2, 13.0 Hz, 2C), 160.2, 148.7, 148.0, 142.0
(t, J = 9.1 Hz, 1C), 123.9, 120.3, 111.8 (dd, J = 16.9, 7.5
Hz, 2C), 101.9 (t, J = 25.3 Hz, 1C), 70.5, 53.4, 52.6, 51.7,
50.8, 36.0, 31.9, 29.5, 23.1; MH+ (CI): 420.2.
K. N-{(1S,2R)-1-(3,5-Difluorobenzyl)-2-hydroxy-3-[(4-
isopropylpyridin-2-ylmethyl)-amino]propyl}acetamide
The above compound was prepared essentially according to
the previously described methods. 1H NMR (3 00 MHz, CDC13) d
8.37 (d, J= 4.7 Hz, 1H), 7.10 (s, 1H), 7.06 (d, J = 5.2 Hz,
1H), 6.94 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 6.3 Hz, 2H), 6.61
(tt, J= 9.0, 2.2 Hz, 1H), 4.77 (br s, 2H), 4.25-4.10 (m, 1H),
3.93 (s, 2H), 3.80-3.70 (m, 1H), 3.05-2.70 (m, 5H), 1.86 (s,
3H), 1.23 (d, J = 7.0 Hz, 6H) ; 13C NMR (75 MHz, CDCl3) d 170.4,
162.7 (dd, J = 248.2, 13.0 Hz, 2C), 158.8, 157.4, 148.9, 142.4
(t, J = 9.1 Hz, 1C), 120.9, 112.0 (dd, J = 16.9, 7.5 Hz, 2C),
101.7 (t, J = 25.3 Hz, 1C), 70.8, 54.0, 53.2, 51.6, 35.7,
33.5, 22.9; MH+ (CI): 392.2.
L. N-{1S,2R)-l-(3,5-Difluorobenzyl)-2-hydroxy-3-[1-(4-
isopropylpyridin-2-yl)-cyclopropylamino]propyl}acetamide
The above compound was prepared essentially according to
the previously described methods. MH+ (CI): 418.2.
M. N-[{1S,2R)-3-[(4-tert-Butylpyridin-2-ylmethyl)amino]-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide
The above compound was prepared essentially according to
the previously described methods. 1H NMR (3 00 MHz, CDC13) d
8.40 (d. J= 5.3 Hz. 1H). 7.22 (s. 1H). 7.19 (dd. J= 5.3. 1.7
Hz, 1H), 6.73 (d, J = 6.3 Hz, 2H), 6.65 (tt, J = 9.0, 2.2 Hz,
1H), 4.26 (br s, 2H), 4.25-4.10 (m, 1H), 3.94 (s, 2H), 3.77-
3.67 (m, 1H), 3.05-2.70 (m, 4H), 1.88 (s, 3H), 1.30 (s, 9H) ;
13C NMR (75 MHz, CDCl3) d 170.3, 162.8 (dd, J = 243.2, 13.0 Hz,
2C), 161.2, 157.9, 148.8, 142.4 (t, J = 9.1 Hz, 1C), 119.6,
119.5, 112.1 (dd, J = 16.9, 7.5 Hz, 2C), 101.8 (t, J = 25.3
Hz, 1C), 70.9, 54.3, 53.1, 51.7, 35.8, 34.7, 30.4, 28.7, 23.1;
MH+ (CI): 406.2.
N. N- [(1S,2R) -3- [1-(4-tert-Butylpyridin-2-
yl)cyclopropylamino]-1-(3,5-difluorobenzyl)-2-hydroxypropyl]
acetamide
The above compound was prepared essentially according to
the previously described methods. 1H NMR (300 MHz, CDC13) d
8.38 (d, J= 5.2 Hz, 1H), 7.15-7.05 (m, 2H), 6.73 (d, J= 6.3
Hz, 2H), 6.64 (tt, J = 9.0, 2.2 Hz, 1H), 5.88 (d, J = 9.1 Hz,
1H), 4.22-4.08 (m, 1H), 3.75 (br s, 2H), 3.50 (td, J = 6.5,
3.5 Hz, 1H), 2.99. (dd, J = 14.2, 4.5 Hz, 1H), 2.90-2.70 (m,
3H), 1.89 (s, 3H), 1.30 (s, 9H), 1.25-1.10 (m, 4H) ; 13CNMR (75
MHz, CDC13) d 170.0, 162.9 (dd, J= 248.2,, 13.0 Hz, 2C), 162.5,
160.8, 148.2, 142.1 (t, J = 9.1 Hz, 1C), 118.2, 115.6, 112.0
(dd, J = 16.9, 7.5 Hz, 2C), 101.9 (t, J = 25.3 Hs, 1C), 70.9,
52.6, 49.4, 43.1, 35.9, 34.8, 30.5, 23.2, 18.8, 18.7; MH+
(CI): 432.2.
O. N-{{1S,2R)-1-(3,5-Difluorobenzyl)-3-{[6-(2,2-
dimethylpropyl)pyridin-2-ylmethyl]-amino}-2-hydroxypropyl)
acetamide
The above compound was prepared essentially according to
the previously described methods. 1H NMR (300 MHz, CDCl3) d
7.56 (t, J= 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.02 (d, J
= 7.6 Hz, 1H), 6.74 (dd, J = 6.3, 2.0 Hz, 2H), 6.64 (tt, J =
9.0, 2.2 Hz, 1H), 6.11 (d, J = 9.0 Hz, 1H), 4.25-4.10 (m, 1H),
3.92 (d, J = 1.2 Hz, 2H), 3.70-3.55 (m, 1H), 3.25 (br s, 1H),
2.93 (dd, J = 14.2, 4.9 Hz, 1H), 2.88-2.70 (m, 3H), 2.68 (s,
2H), 1.88 (s, 3H), 0.95 (s, 9H) ; 13C NMR (75 MHz, CDC13)
d 170.0 162.8 (dd, J = 248.2, 13.0 Hz, 2C), 159.8, 157.6,
142.2 (t, J = 9.1 Hz, 1C), 136.3, 123.3, 119.6, 112.0 (dd, J =
16.9, 7.5 Hz, 2C), 101.9 (t, J" = 25.3 Hz, 1C), 70.8, 54.2,
52.8, 51.6, 51.5, 35.7, 32.0, 29.5, 23.2; MH+ (CI): 420.2.
EXAMPLE 106
Step 1. Epoxide opening with 1-(3.-bromophenyl)
cyclopropyl amine.
N-BOC-1-(3-bromophenyl)aminocyclopropane (15.60g, 50.2
mmol) was treated with 4N HCl in dioxane (50 mL) and stirred
for 2 h. The volatiles were evaporated in vacuo and the
residue taken up into 1N NaOH (250 mL). The mixture was
extracted with diethyl ether (2 X 200 mL). The combined ether
extracts were washed with brine (50 mL), dried (sodium
sulfate), then filtered and evaporated in vacuo to provide the
amine free base.
The amine free base was dissolved in 2-propanol (250 mL)
and the epoxide (15.0g, 50.2 mmol) was added. The mixture was
heated to reflux for 22 h and allowed to stand at ambient
temperature for 3 d. Analysis by HPLC indicated that the
desired product predominated, and that some starting
cyclopropylamine remained unreacted. The starting epoxide was
consumed. The volatiles were removed in vacuo and the residue
was purified by silica gel flash chromatography (eluted 2:1
hexane/ethyl acetate) to provide the final product (13.68 g,
53%).
LC-MS: [M+H] = 511, 513, Rt=2.31 min, Phenomenex Luna
C18 (30cm X 4.6 mm), 20-70% CH3CN / water / 0.1%
trifluoroacetic acid in 2.33 min, flow rate 1.5 mL/min.
Step 2. Preparation of S,R 1-(3,5-Difluorobenzyl)-3-[1-
(3-Bromophenyl)Cyclopropylamino)]-2-Hydroxypropyl
Amine.
The Boc-protected amine (13.5 g, 26.7 mrnol) was treated
with 4N HC1 in dioxane (30 mL). Methanol (15 mL) was added
and the mixture became homogeneous before depositing a
precipitate. The mixture was stirred for 3 h before the
volatiles were removed in vacuo. The residue was taken up in
1N NaOH (150 mL) and the mixture was extracted with diethyl
ether (3 X 100 mL). The combined ether extracts were washed
with brine (50 mL), dried (magnesium sulfate), filtered and
evaporated in vacuo to give the desired amine (6.5g), which
was used directly in the next step.
Step 3. Preparation of N-[3-[1-(3-Bromo-phenyl)-
cyclopropylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-
acetamide
The above product was prepared essentially according to
the procedure of Example 56, using acetic acid as the acid.
The desired product was obtained as a white solid (11.75g,
97%). LC-MS analysis indicated a purity of 94%. LC-MS: [M+H]
= 453, 455, Rt=1.86 min, Phenomenex Luna C18 (30cm X 4.6 mm),
20-70% CH3CN / water / 0.1% trifluoroacetic acid in 2.33 min,
flow rate 1.5 mL/min.
LJl
The bromination was performed essentially according to
the procedure of Cornelius, L.A.M. Combs, D.W., Synthetic
Communications 1994, 24, 2777-2788). The product was
separated using silica gel flash chromatography (Biotage Flash
75, 10:1 hexanes:MTBE) to yield the purified product (7.4 g,
75%).
LC-MS analysis indicated the presence of a dibroraoproduct
co-eluting with desired product. This material was taken on
to the next step and separated.
The above product was prepared essentially according to
the method of Example 2. The resulting product was purified
by silica gel chromatography (Biotage Flash 65, 10/1
hexanes/ethyl acetate) to yield (R)-7-ethyl-5-bromotetralin-l-
ol (4.0 g, 53%).
The above compound was prepared essentially according to
the method of Example 3. First the azide was prepared.
Second, the azide was reduced with lithium aluminum hydride to
afford the product as a white solid. LC-MS: [M-NH2] = 237,
239, Rt=6.34 man, Phenomenex Luna C18 (30cm X 4.6 mm), 5-20%
CH3CN/water/0.1% trif luoroacetic acid in 3.33 min, flow rate
1.5 mL/min.
Step 1. Epoxide opening with (S)-7-bromo-l-
aminotetralin.
The above compound was prepared essentially according to
the method of Example 17, step 3. The coupled product -was
crystallized from isopropyl alcohol. LC-MS analysis indicated
about 99% purity. LC-MS: [M+H] = 527, Rt=2.34 min, Phenomenex
Luna C18 (30cm X 4.6 mm), 20-70% CH3CN / water / 0.1%
trifluoroacetic acid in 2.33 min, flow rate 1.5 mL/min.
Step 2. Deprotection Of Boc Group.
The above compound was prepared essentially using the
method of example 106, step 2. The resulting material was
used directly in the next step.
Step 3. Acylation of N-terminal amine
The above compound was prepared essentially using the
method of example 106, step 3. LC-MS analysis indicated a
purity of 99%. LC-MS: [M+H] = 467, 469, Rt=1.94 min,
Phenomenex Luna C18 (30cm X 4.6 mm), 20-70% CH3CN / water /
0.1% trifluoroacetic acid in 2.33 min, flow rate 1.5 mL/min.
The starting compound (7.80g, 16.7 mmol) was dissolved in
dichloromethane (150 mL). Di-tert-butyldicarbonate (3.82g,
17.5 mmol) was added and the mixture was stirred for 3 days.
The mixture was then concentrated in vacuo and the residue
passed through a pad of silica gel (eluted 1L 2:1
hexanes/ethyl acetate, 0.5L 5% MeOH/dichloromethane) to give
the desired product (8.52g, 90%).
LC-MS analysis indicated a purity of 99%. LC-MS: [M+Na]
= 589, 591, Rt=5.12 min, Phenomenex Luna C18 (30cm X 4.6 mm),
20-70% CH3CN / water / 0.1% trifluoroacetic acid in 2.33 min,
flow rate 1.5 mL/min.
Example 109. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-
1,2,3,4-tetrahydroguinolin-4-yl)amino]-2-
hydroxypropyl}acetamide
To a solution of 4-ethyl aniline (10.0 g) in acetic acid
(25 mL) was added ethyl acrylate (10.8 g). The mixture was
heated to 80 °C for 2 hours. Additional ethyl acrylate (1.0
mL) was added, and the mixture was again heated to 80 °C for 1
hour. The mixture was allowed to cool to room temperature and
stir for two days. Sodium hydroxide (8N) was added until the
pH equaled 9. The mixture was partitioned between
dichloromethane and water and the combined organics were
washed once with 1N sodium hydroxide, once with brine, dried
with sodium sulfate, filtered, and concentrated. The mixture
was chromatographed using a 2 0% ethyl acetate in heptane
solvent solution. A mixture of the mono and di ester product
(19.5 g) were obtained (1:1 mixture). MS (ESI + ) for C13H19NO2
m/z 221.99 (M+H)+.
A solution of phosphorus pentoxide (19.53 g) in methane
sulfonic acid (200 mL) was heated to 13 0 °C. The mixture was
stirred at 130 °C for one hour until all the phosphorus
pentoxide had dissolved. The mixuture was allowed to cool for
15 minutes and ethyl N-(4-ethylphenyl)-beta-alaninate (19.53 g
of mono and di-ester mixture) was added. The mixture was
heated to 13 0 °C for one hour and allowed to slowly cool
overnight. The mixture was then cooled in an ice bath and ION
sodium hydroxide was added until the pH reached 9.5. Ethyl
acetate was added to the mixture to help dissolve solids. The
remaining gummy dark solids were dissolved in methanol and
added to the ethyl acetate-aq. sodium hydroxide mixture.
Semi-crystalline solids precipitated and were removed by
filtration through Celite. The filtrate was washed with
water, followed by 1N sodium hydroxide and brine, dried with
magnesium sulfate, filtered, and concentrated.. Silica gel
chromatography using 0.25% ammonium hydroxide in
dichloromethane gave mixed fractions. The mixed fractions
were combined and re-chromatographed using 3 0% esthyl acetate
in heptane. The resulting material was further upgraded by
formation of the hydrochloride salt using 2N HCl in ether.
The salt was collected by filtration and washed with heptane
and dried in an oven under vacuum at 50 °C overnight. The salt
was then partitioned between dichloromethane and 1N sodium
hydroxide. The organic layer was extracted twice with
dichloromethane, washed with IN sodium hydroxide, dried with
sodium sulfate, filtered, and concentrated to give 3.83 g of
the title compound. MS (ESI+) for C11H13NO m/z 175.96 (M+H)+.
A.3. Benzyl 6-ethyl-4-oxo-3,4-dihydroquinoline-l(2H)-
carboxylate
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one
(1.25 g) in THF (15 mL) was added sodium bicarbonate (0.84 g).
Water (5 mL) followed by benzyl chloroformate (1.58 g) were
added to the mixture, and it was stirred at room temperature
overnight. The reaction was not complete as determined by
TLC, so an additional 0.60 g of NaHCO3 were added to the
mixture and it was stirred at room temperature for two
additional hours. The mixture was then concentrated under
reduced pressure and the residue was partitioned between water
and ethyl acetate and the organic layer was washed with brine,
dried with magnesium sulfate, filtered, and concentrated.
Chromotography on silicia gel using 25% ethyl acetate in
heptane solvent solution gave 1.84 g of the title compound.
MS (ESI+) for C19H19NO3 m/z 310.03 (M+H)+.
A.4. Benzyl 6-ethyl-4-hydroxy-3,4-dihydroquinoline-l(2H)-
c arboxylate
The above compound was prepared essentially according to
b-he procedure-of-Example 17, step - 1. The crude -product was
purified by chromatography on silica gel using a 2% MeOH in
dichloromethane solvent solution with 0.5% ammonium hydroxide.
1HNMR (CDC13) d 1.22 (t, J = 8 Hz, 3 H), 1.89 (s, 1 H), 2.04
(m, 2 H), 2.61 (q, J = 8 Hz, 2 H), 3.66 (m, 1 H), 4.11 (m, 1
H), 4.74 (t, J = 4 Hz, 1 H), 5.25 (dd, J = 12, 20 Hz, 2 H),
7.09 (dd, J = 2, 9 Hz, 1 H), 7.21 (d, J = 2 Hz, 1 H), 7.35 (m,
5 H), 7.6 (d, J = 8 Hz, 1 H).
The above compound was prepared essentially according to
the method of Example 17, step 2. First, the alcohol was
converted to the azide. 1H NMR (CDC13) d 1.23 (t, J = 8 Hz, 3
H), 2.09 (m, 2 H), 2.62 (q, J = 8 Hz, 2 H), 3.67 (m, 1 H),
4.12 (m, 1 H), 4.58 (t, J = 4 Hz, 1 H), 5.24 (m, 2 H), 7.09
(d, J = 2 Hz, 1 H), 7.13 (dd, J = 2, 9 Hz, 1 H), 7.35 (m, 5
H), 7.82 (d, J = 8 Hz, 1 H).
Second the azide was reduced using PMe3. MS (ESI+) for
C19H22N2O2 m/z 311.05 (M+H)+.
A. 6. Benzyl 4-{[(2R,3S)-3-[(tert-butoxycarbonyl)amino]
4-(3,5-difluorophenyl)-2-hydroxybutyl]amino}-3,4-
dihydroquinoline-1(2H)-carboxylate
The above compound was prepared essentially according to
the method of Example 17, step 3. The crude product was
purified by silcica gel chromatography using 2% MeOH in
dichloromethane with 0.25% NH4OH as the solvent system. MS
(ESI + ) for C34H41F2N3O5 m/z 510.51 (M+H) +.
A.7. Benzyl 4-{£(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-
hydroxybutyl]amino}-6-ethyl-3,4-dihydroquinoline-l(2H)-
carboxylate
To a solution of the produce from step A. 6 (0.76 g) in
MeOH (10 mL) was added 2N HC1 in Et2O (1.6 mL). The mixture
was stirred at room temperature for two hours and an
additional 1.0 mL of 2N HC1 in Et2O were added. The mixture
was stirred for four more hours. The reaction was still not
complete, so an additional 3. OmL of HC1 in Et2O were added.
The mixture was stirred for two hours and then stripped of
solvent under reduced pressure. The residue was dissolved in
ethyl acetate washed two times with 1N NaOH, dried with
magnesium sulfate, filtered, and concentrated. A silica gel
column was run for purification using 4% MeOH in
dichloromethane with 0.25% NH40H as the solvent solution and
gave 0.44 g of the title compound. MS (ESI+) for C29H33F2N3O3
m/z 510.36 (M+H)+.
A.8. Benzyl 4-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-6-ethyl-3,4-
dihydroquinoline-1(2H)-carboxylate
To a solution of the product from step A.7 (0.43 g) in
dichloromethane (15 mL) was added N,N-diacetyl-O-
methylhydroxylamine (0.11 g). The mixture was stirred
overnight at room temperature. An additional 0.10 g of N,N-
diacetyl-O-methylhydroxylamine were then added and the mixture
was stirred for 6 hours. Another 0.10 g of N,N-diacetyl-O-
methylhydroxylamine were added and the mixture was stirred
overnight and then partitioned between dichloromethane- and -1N—
HC1 and brine. The organic layer was dried with magnesium
sulfate, filtered, and concentrated. A silica gel column was
run for purification using 4% MeOH in dichloromethane with
0.25% NH4OH as the solvent solution and gave 0.35 g of the
title compound. MS (ESI + ) for C31H34F2N3O4 m/z 552.32 (M+H)+.
A. 9. N-{(1S,2R)-l-(3,5-difluorobenzyl)-3- [ (6-ethyl-l,2,3,4-
tetrahydroquinolin-4-yl)amino]-2-hydroxypropyl}acetamide
Nitrogen was bubbled through a solution of the product
from step A. 8 (0.35 g), EtOH (25 mL), and acetic acid (0.75
mL). 10% palladium on carbon (0.29 g) was added to the
mixture and it was shaken on a hydrogenation apparatus under
52 psi of hydrogen for 1.25 h. The catalyst was filtered off
using Celite and the filtrate was concentrated under reduced
pressure. The residue was partitioned between ethyl acetate,
aq. sodium hydroxide (pH 10), and brine, and them dried with
magnesium sulfate, filtered, and concentrated. A silica gel
column was run using 6% MeOH in dichloromethane with 0.25%
NH4OH as the solvent solution and gave 0.04 g of the title
compound. MS (ESI + ) for C23H29F2N3O2 m/z 418.31 (M+H)+.
A.10. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-l-
methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-
hydroxypropyl}acetamide
A.11. Ethyl N-(4-ethylphenyl)-beta-alaninate
To a solution of 4-ethyl aniline (l0.00g) in. acetic acid
(20mL) was added ethyl acrylate (8.26). The mixture was
heated to 70° for 3.5 hours. The mixture was allowed to cool
to room temperature. The mixture was partitioned between
dichloromethane and water, and was extracted three times. The
combined organics were washed once with brine, dried with
sodium sulfate, filtered, and concentrated. The mixture was
taken on to the next step. MS (ESI + ) for C13H19NO2 m/z 223.1
(M+H)+.
A.12. 6-ethyl-2,3-dihydroquinolin-4(1H)-one
A solution of phosphorus pentoxide (11.14g) in methane
sulfonic acid (114mL) was heated to 130°. The: mixture was
stirred at 130° for one hour until all the phosphorus
pentoxide had dissolved. The mixture was allowed to cool for
15 minutes, and ethyl N-(4-ethylphenyl)-beta-alaninate (11.14g
of mono and di-ester mixture) was added. The mixture was
heated to 130° for 1.5 hours, and the mixture was allowed to
cool to room temperature. The mixture was cooled in an ice
bath, and 50% sodium hydroxide was added until the pH reached
8. The gummy dark solids were dissolved in MeOH, and added to
the mixture. Solids began to crash out, so they were filtered
off with celite. The liquids were combined, and were
partitioned between dichloromethane and water, and the
organics were extracted three times with dichloromethane. The
combined organics were washed with brine, dried with sodium
sulfate, filtered, and concentrated. The product was
chromatographed using a 30% ethyl acetate in heptane solvent
solution. 4.10g of the title product were recovered. (28%
yield through first two steps) MS (ESI + ) for C11H13NO m/z
176.00 (M+H)+.
A.13. 6-ethyl-l-methyl-2,3-dihydroquinolin-4(1H)-one
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one
(l.00g) in THF (25mL) was added triethylamine (0.64g) followed
by iodomethane (0.89g). The mixture was refluxed at 70°C
overnight. The solvent was stripped under reduced pressure,
and the residue was partitioned between aqueous sodium
bicarbonate and dichloromethane. The organics were extracted
three times, washed with brine, dried with sodium sulfate,
filtered, and concentrated. Chromatography was used to purify
the title compound using a 40% ethyl acetate in heptane
solvent solution. 0.32g of the title product were recovered.
(30% yield). MS (ESI + ) for C12H15NO m/z 190.10 (M+H)+.
A.14. (4E)-6-ethyl-l-methyl-2,3-dihydroquinolin-4(1H)-one
oxime
To a solution of 6-ethyl-l-methyl-2,3-dihydroquinolin-
4(1H)-one (0.32g) in ethanol (25mL) were added pyridine
(0.53g) and hydroxylamine hydrochloride (0.59g). The mixture
was heated to 90 °C for two hours with a reflux condensor
attatched. The mixture was cooled to room temperature, and
the solvent was stripped under reduced pressure. The residue
was portioned between water and dichloromethane and the
organics were extracted three times. The combined organics
were washed once with brine, dried with sodium sulfate,
filtered, and concentrated. 0.34g of the title product were
recovered. (98% yield). MS (ESI + ) for C12H15N2O m/z 205.02
(M+H)+.
A.15. 6-ethyl-l-methyl-l,2,3,4-tetrahydroquinolin-4-amine
(4E, Z)-6-ethyl-i-methyl-2,3-dihydroquinolin-4(1H)-one
oxime (0.34g), ethanol (2 0mL), and acetic acid (0.27g) were
combined in a hydrogenation flask and degassed with nitrogen.
5% Palladium on carbon was carefully added to the mixture
(0.04g) and the mixture was degassed for several more minutes.
The mixture was set up on the hydrogenation apparatus, and was
put under 50 psi of hydrogen. The mixture was shaken for five
and 1.5 hours, and was taken off the machine, but was not
complete by TLC. The mixture was again degassed, and an
additional 0.l0g of 5% palladium on carbon were added to the
mixture. The mixture was put back on the hydrogenation
apparatus, and was shaken overnight. The palladium on carbon
was filtered off using celite, and the liquids were
concentrated under reduced pressure. The residue was
partitioned between aqueous sodium bicarbonate and
dichloromethane, and the organics were extracted three times.
The combined organics were dried with sodium sulfate,
filtered, and concentrated. 0.26g of the title compound were
recovered. (82% yield).
A.16. tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-
ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-
hydroxypropylcarbamate
The above compound was prepared essentially according to
the method of Example 15, step 2. MS (ESI+) for C27H37F2N3O3 m/z
490.59 (M+H)+.
A. 17. (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(6-ethyl-
1-methyl-l,2,3,4-tetrahydroquinolin-4-yl) amino]butan-2-ol
To a solution of tert-butyl (1S,2R)-1-(3,5-
difluorobenzyl)-3-[(6-ethyl-l-methyl-l,2,3,4-
tetrahydroquinolin-4-yl)amino]-2-hydroxypropylcarbamate
(0.412g) in MeOH (5mL) was added 2N HC1 in Et2O (2.1mL). The
mixture was stirred at room temperature for fifteen minutes.
The mixture was stripped of solvent under reduced pressure.
The residue was partitioned between dichloromethane and
aqueous sodium bicarbonate, and the organic was extracted
three times, washed with brine, dried with sodium sulfate,
filtered, and concentrated. A silica gel column was run for
purification using 5% MeOH in dichloromethane with as the
solvent solution. 0.255g of the title product were recovered.
(78% yield). MS (ESI+) for C22H29F2N3O m/z 390.18 (M+H)+.
A.18. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-l-
methyl-1,2,3, 4-tetrahydroquinolin-4-yl)amino]-2-
hydroxypropyl}acetamide
To a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-
1-[(6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-
yl)amino]butan-2-ol (0.218g) in dichloromethane (15mL) was
added 1-acetylimidazole (0.062g). The mixture was stirred
overnight at room temperature. The mixture was partitioned-
between dichloromethane and brine, and the organic was
extracted three times, dried with sodium sulfate, filtered,
and concentrated. A silica gel column was run for.
purification using 3% MeOH in dichloromethane with 0.5% NH40H
as the solvent solution. HPLC still showed small amounts of
starting material present, so the mixture was waished one time
with 1N HC1, dried with magnesium sulfate, filtered, and
concentrated. 0.115g of the title product were recovered.
(48% yield). MS (ESI + ) for C24H31F2N3O2 m/z 432.18 (M+H)+.
A.19. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-ethyl-
1-methyl-l,2,3,4-tetrahydroquinolin-4-yl]amino}-2-
hydroxypropyDacetamide and N-((1S,2R)-1-(3,5-difluorobenzyl)-
3-{[(4R)-6-ethyl-l-methyl-l,2,3,4-tetrahydroquinolin-4-
yl] amino}-2-hydroxypropyl)acetamide
Silica gel chromatography of approximately 0.1 g of N-
{(1S,2R)-1-(3,5-difluorobenzyl) -3-[(6-ethyl-l-methyl-l,2,3,4-
tetrahydroquinolin-4-yl)amino]-2-hydroxypropyl}acetamide using
methanol/dichloromethane (8/92) with 0.1 % ammonium hydroxide
gave 0.032 g of N-( (1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-
ethyl-l-methyl-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-
hydroxypropyl) acetamide [Rf (MeOH/CH2Cl2/NH4OH) = 0.40; MS
(ESI + ) for C24H31F2N3O2 m/z 432.2 (M+H)+]. Re-chromatography of
mixed fractions gave 0.011 g of a 9:1 mixture of the 4R isomer
[Rf (MeOH/CH2Cl2/NH4OH) = 0.35; MS (ESI + ) for C24H31F2N3O2 m/z
432.2 (M+H)+] and the 4S isomer.
B. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
neopentyl-1,2,3,4-tetrahydroquinolin-4-
yl)amino]propyl}acetamide
The above compound was prepared essentially according to
the method of Example 109, step A.1. The crude product was
purified by chromatography on silica gel using 15% ethyl
acetate in heptane with 0.25% TFA solvent. The purified
mixture comprised the mono and di-ester products (1:1) which
were used in the next step. MS (ESI + ) for C11H15N02 m/z 193.99
(M+H)+.
B.2. 2, 3-dihydroquinolin-4(1H)-one
The above compound was prepared essentially according to
the method of Example 109, step A.2. The crude product was
purified by column chromatography using a 20-30% ethyl acetate
in heptane gradient. MS (ESI+) for C9H9NO m/z 147.96 (M+H)+.
B.3. 6-bromo-2,3-dihydroquinolin-4(1H)-one
To a solution of 2,3-dihydroquinolin-4(1H)- one (2.94 g)
in dichloromethane (25 mL) was added N-bromosuccinimide (3.63
g). The mixture was stirred at room temperature for 1.5 h and
was partitioned between aqueous sodium bicarbonate and
dichloromethane. The organic layer was washed with brine,
dried with sodium sulfate, filtered, and concentrated. The
concentrate was chromatographed on silica gel using a 35%
ethyl acetate in heptane solvent solution and gave 4.14 g of
the title compound. MS (ESI-) for C9H8BrNO m/z 225.77 (M-H)+.
B.4. Benzyl 6-bromo-4-oxo-3,4-dihydroquinoline-l(2H)-
carboxylate
The above compound was prepared essentially according to"
the method of Example 109, step A.3. 1H NMR (CDC13) d 2.78 (t,
J = 7 Hz, 2 H), 4.22 (t, J = 6 Hz, 2 H), 5.28 (s, 2 H) 7.40
(m, 5 H), 7.58 (dd, J = 2, 9 Hz, 1 H), 7.75 (d, J = 9 Hz, 1
H), 8.10 (d, J" = 2 Hz, 1 H).
B.5. Benzyl 6-neopentyl-4-oxo-3,4-dihydroquinoline-l(2H)-
carboxylate
Benzyl 6-bromo-4-oxo-3,4-dihydroquinoline-1(2H)-
carboxylate (3.10 g) and dichloro[1,1'-
bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane
adduct (0.35 g) were combined in a round bottom flask. The
mixture was put under high vacuum and purged with nitrogen. A
0.5 M solution of bromo(neopentyl)zinc (55 mL) prepared using
the procedure of Negishi et al. Tet Lett. 1983, 24, 3823-3824,
was added to the mixture and was stirred at room temperature
for two days. The reaction had not gone to completion, so an
additional 10 mL of bromo(neopentyl)zinc solution was added
and the mixture was stirred for one additional day. The
mixture was then partitioned between ethyl acetate and aqueous
ammonium chloride, dried with magnesium sulfate, filtered, and
concentrated. Silica gel chromatography using a 20% ethyl
acetate in heptane solvent solution gave 2.17g of the title
compound. MS (ESI + ) for C22H25NO3 m/z 353.17 (M+H)+.
B.6. Benzyl 4-hydroxy-6-neopentyl-3,4-dihydroquinoline-
1(2H)-carboxylate
The above compound was prepared essentially according to
the method of Example 17, step 2. The crude product was
purified 1H NMR (CDC13) d 0.90 (s, 9 H), 1.80 (s, 1 H), 2.06
(m, 2 H), 2.45 (s, 2 H), 3.68 (m, 1 H), 4.12 (m, 1 H), 4.75
(t, J = 4 Hz, 1 H), 5.24 (dd, J = 12, 17 Hz, 2 H), 7.02 (dd, J
= 2, 9 Hz, 1 H), 7.12 (d, J = 2 Hz, 1 H), 7.35 (m, 5 H), 7.76
(d, J=8Hz, 1 H).
The above compound was prepared essentially according to
the method of Example 17, step 2. First the azide was
prepared and chromatographed on silica gel using a 15% ethyl
acetate in heptane. 1H NMR (CDC13) d.091 (s, 9 H), 2.09 (m, 2
H), 2.46 (s, 2 H), 3.66 (m, 1 H), 4.14 (m, 1 H), 4.58 (t, J =
4 Hz, 1 H), 4.24 (dd, J = 12, 15 Hz, 2 H), 7.03 (d, J = 2 Hz,
1 H), 7.06 (dd, J = 2, 9 Hz, 1 H), 7.35 (m, 5 H), 7.86 (d, J =
8 Hz, 1 H);
Second, the azide was reduced using PMe3. The resulting
araine was purified by silica gel chromatography using 2.5%
methanol in dichloromethane with 0.5% ammonium hydroxide.MS
(ESI + ) for C22H28N2O2 m/z 353.19 (M+H)+.
B.8. Benzyl 4-{[(2R,3S)-3-amino-4-(3,5-difluorophenyl)-2-
hydroxybutyl]amino}-6-neopentyl-3,4-dihydroquinoline-l(2H)-
carboxylate
To a solution of benzyl 4-amino-6-neopentyl-3,4-
dihydroquinoline-1(2H)-carboxylate (1.31g) in isopropanol (25
mL) was added. Example.134 (0.75 g) and the mixture was heated
at 90 °C for 45 minutes. The temperature was reduced to 60 °C
and the mixture was allowed to stir overnight. An additional
0.36 g of Example 134 were added to the mixture and it was
heated to 80 °C for five hours. The mixture was cooled to
room temperature and the solvent was removed under reduced
pressure. The residue was partitioned between water and ethyl
acetate and the organic layers were dried with magnesium
sulfate, filtered, and concentrated. A silica gel column was
run to attempt to separate the diasteriomers using a gradient
of 2-4% MeOH in dichloromethane with 0.25% NH4OH as the solvent
system. The first fraction contained a 70:30 mixture of the
two diasteriomers and the second fraction was a 50:50 mix of
the diasteriomers. The Boc groups were removed by dissolving
each fraction in a minimal amount of dichloromethane and
adding 15 mL of 2N HCl in ether to each of the two mixtures.
The mixtures were stirred for two hours and concentrated under
reduced pressure. The mixtures were then partitioned between
IN sodium hydroxide and ethyl acetate, dried with magnesium
sulfate, filtered, and concentrated to give 0.. 23 g of the
70:30 title compound mixture and 0.3 0 g of the 50:50 mixture.
MS (ESI + ) for C32H39F2N3O3 m/z 552.32 (M+H)+ for the 70:30
mixture and m/z 552.27 (M+H)+ for the 50:50 mixture. Each of
these mixtures was carried on separately to final product; the
following procedures illustrate that for the 70:30 mixture
only.
B.9. Benzyl 4-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl] amino}-6-neopentyl~3,4-
dihydroquinoline-1(2H)-carboxylate
To a solution of benzyl 4-{[(2R,3S)-3-amino-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-6-neopentyl-3,4-
dihydroquinoline-1(2H)-carboxylate (0.226 g) in
dichloromethane (5 mL) was added N,N-diacetyl-O-
methylhydroxylamine (0.064 g). The mixture was stirred over
the weekend at room temperature. The solvent was then removed
under reduced pressure and the residue was partitioned between
1N HC1 and ethyl acetate, dried with magnesium sulfate,
filtered, and concentrated to give 0.243 g of the title
compound. (99% yield). MS (ESI + ) for C34H41F2N3O4 m/z 594.31
(M+H)+.
B.10. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
neopentyl-1,2,3,4-tetrahydroquinolin-4-
yl)amino]propyl}acetamide
To a solution of benzyl 4-{[(2R,3S)-3-(acetylamino)-4-
(3,5-difluorophenyl)-2-hydroxybutyl]amino}-6-neopentyl-3,4-
dihydroquinoline-1(2H)-carboxylate (0.242 g) in EtOH (30 mL)
was added 1N HCl (1.0 mL) and 10% palladium on carbon (0.030
g). The mixture was degassed with N2 for five minutes. The
mixture was placed on a hydrogenation apparatus under 47 psi
of H2 and was shaken for 4.5 hours. The palladium was filtered
off using Celite and the solvent was concentrated under
reduced pressure. The residue was then partitioned between
water and ethyl acetate and the organic layers were washed
with aqueous sodium bicarbonate, dried with magnesium sulfate,
filtered, and concentrated. A silica gel column using 4% MeOH
in dichloromethane with 0.25% NH4OH as the solvent solution
gave 0.095 g of the title compound. MS (ESI + ) for C26H35F2N3O2
m/z 4 6 0.27 (M+H)+.
The compounds named in Examples 109 (C-TT) can be made
according to the methods analogous to those described above,
as well as those known in the art.
Example 111
Reactions were monitored, and purity evaluated by TLC on
silica gel GF, 250 µ slides obtained from Analtech, Inc.,
Newark, DE. Preparative low pressure (flash) chromatography
was carried out on silica gel 60 (230-400 mesh ASTM) from EM
Science, Gibbstown, NJ. Proton NMR spectra were collected on a
Bruker Avance 400 spectrometer. Chemical shifts (8) are in
ppm, coupling constants (J) are in Hz. 1R absorbances greater
than 1200 cm"1 are reported. All reagents were obtained from
commercial sources and were used without further purification.
Unless otherwise noted, all solvents used in reaction were run
under an inert atmosphere of nitrogen in over-dried glassware.
Preparative flash chromatography was performed on silica gel
60 (230-240 mesh) from EM Science. HPLC analysis were carried
out on a HP1100 system (Agilent) with the following a 1.0
mL/min linear gradient of 0.05% aqueous TFA (A) and 0.05% TFA
in acetonitrile (B): 0% B: 5 min: 60% B, 15 min: 90% B, 2 min:
0% B. All solvents for chromatography were HPLC grade. Where
not commercially available, starting materials and
intermediates, including new. and known compounds, were
prepared by synthetic methods known in the art. HATU, which
stands for N-[(dimethylamino)-1-H-l,2,3-triazolo[4,5-
b]pyrindin-l-ylmethylene]-N- methylmethanaminium
hexafluorophosphate W-oxide, was bought from PE Biosystems.
All hydrochloride salts were formed by addition of ethereal
hydrochloric acid to an ethereal solution of amine, followed
by concentration to dryness.
A. 5-bromo-2-hydroxybenzamide
To a stirred solution of 5-Bromosalicyclic acid (30 g,
135.5 ramol) in n-butylalcohol (60 mL) was added H2SO4 (95.5%,
289 µL, 5.42 mmol) in a 100 ml round bottom flask connected by
a Dean-Stark trap/reflux condenser that, was filled with 12 ml
of n-butylalcohol. After heated to reflux for 2 days, the
reaction was cooled down to R.T. and concentrated to give a
pale yellow oil. The mixture was added 50 mL MeOH, followed by
NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for
another 2 days, monitored by HPLC. After the reaction
complete, it was concentrated to give a white solid. The crude
solid was washed with small amount of EtOAc and hexane to
afford 24 g of the product as a white crystalline solid (82%
yield). 1H NMR (CDCl3) d 12.15 (s, 1 H), 7.54 (m, 2 H), 6.97
(d, J = 12 Hz, 1 H), 6.00 (broad, 2 H).
t
To a stirred solution of the bromobenzamide (8.64 g, 40
mmol) in THF (100 mL) under argon was added [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.96 g,
2.4 mmol) followed by i-BuZnBr (0.5 M, 200 mL). The reaction
mixture was stirred at R.T. for 4 days. The reaction was
quenched with 1N HC1, and then concentrated. The resulting
crude was diluted with ethyl acetate, and washed with water
and brine, dried with sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (5-10% ethyl acetate:
hexane) to afford 4.63 g of the isobutylbenzamide product as
an off-white solid (60% yield). 1H NMR (CDC13) 5 12.02 (s, 1
H), 7.24 (d, J = 8 Hz, 1 H), 7.12 (s, 1 H), 6.93 (d, J = 8 Hz,
1 H), 2.44 (d, J = 8 Hz, 2 H), 1.83 (m, 1 H), 0.93 (d, J = &
Hz, 6 H).
C. 2-cyano-4-isobutylphenyl trifluoromethanesulfonate
At 0 °C, to a stirred solution of the hydroxy-
isobutylbenzamide (3.72 g, 19.3 mmol) in pyridine (15 mL)
under argon, was added trifluoromethanesulfonic anhydride (10.2
ml, 57.8 mmol). The reaction mixture was eventually warmed up
to room temperature and stirred overnight. The reaction was
diluted with ethyl acetate, and washed with 1N HCl (x2), water
(xl) and brine (xl), dried with sodium sulfate, filtered, and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (5% ethyl acetate:
hexane) to afford 2.66 g of the desired product as a clear oil
(50% yield). 1H NMR (CDC13) d 7.56 (s, 1 H), 7.50 (d, J = 8 Hz,
1 H), 7.43 (d, J = 8 Hz, 1 H), 2.57 (d, J = 8 Hz, 2 H), 1.92
(m, 1 H), 0.97 (d, J = 4 Hz, 6 H).
D. 4-isobutyl-l,1'-biphenyl-2-carbonitrile
To a stirred solution of the cyano compound (610 mg, 1.88
mmol), aqueous sodium carbonate (2.0 M, 3.76 mmol) in DME (6
mL) was added tetrakis(triphenylphosphine) palladium(0) (109
mg, 0.094 mmol) followed by phenylboronic acid (230 mg, 2.26
mmol). The reaction mixture was heated to reflux overnight,
and then cooled to R.T. The reaction was diluted with ethyl
acetate, and was washed with water and brine, dried with
sodium sulfate, filtered, and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography (3% ethyl acetate: hexane) to afford 450 mg of
the product as a white solid (90% yield). 1H NMR (CDCl3) d 7.60
(m, 3 H), 7.54 (m, 2 H), 7.48 (m, 3 H), 2.60 (d, J = 8 Hz, 2
H), 1.96 (m, 1 H), 1.00 (d, J" = 6 Hz, 6 H).
E. (4-isobutyl-l,l'-biphenyl-2-yl)methylam±ne
The above compound was prepared essentially according to
the method of Example 10. 1H NMR (CDC13.) d 7.47 (m, 2 H), 7.44
(m, 3 H), 7.30 (s, 1 H), 7.20 (d, J = 8 Hz, 1 H), 7.14 (m, 1
H), 3.84 (s, 2 H), 2.58 (d, J = 8 Hz,. 2 H), 1.93 (m, 1 H),
1.47 (s, 2 H), 1.00 (d, J = 4 Hz, 6 H) ; ESI-MS [M+H+] + =
240.22.
F. tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{[(4-isobutyl-l,1'-biphenyl-2-yl)methyl]amino} propylcarbamate
To a stirred solution of the biphenyl amine (400 mg,
1.67 mmol) in i-propanol (10 mL) was added Example 134 (name
generated using ACD Namepro version 5.09) (336 mg, 1.12 mmol).
The reaction mixture was heated at 80 °C overnight. The
reaction mixture was concentrated, and purified by flash
column chromatography (2-5% MeOH: CH2Cl2) to afford 510 mg of
product as an off-white solid (57% yield). 1H NMR (CDC13) 5
7.45 (m, 2 H), 7.38 (m, 3 H), 7.25 (s, 1 H), 7.21 (m, 1 H),
7.16 (m, 1 H), 6.76 (m, 2 H), 6.70 (m, 1 H), 4.55 (m, 1 H),
3.76 (m, 3 H), 3.34 (m, 1 H), 2.90 (m, 1 H), 2.78 (m, 2 H),
2.64 (m, 2 H), 2.55 (m, 3 H), 1.93 (m, 1 H), 1.40 (s, 9 H),
1.00 (d, 6 H) ; ESI-MS [M+H+]+ = 539.22.
G. N- ((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy--3-{[(4-
isobutyl-1,11-biphenyl-2-yl)methyl] amino}propyl) acetamide
Step 1: To a stirred solution of the starting material
(377 mg, 0.7 mmol) in MeOH (5 mL) was added HCl in 1,4-dioxane
(4.0 M, 2 mL). After stirring at R.T. overnight, the reaction
mixture was concentrated under reduced pressure to provide an
off-white solid, which was used without further purification.
Step 2: To a stirred solution of amine from step 1 in
CH2C12 (8 mL) was added DIPEA (304 uL, 1.75 mtnol), and then 1-
acetylimidazole (86 mg, 0.77 mmol). The reaction mixture was
stirred at R.T. overnight, quenched by addition of 50%
ammonium hydroxide, and diluted with CH2C12. The organic layer
was washed with washed with 1N HC1 (x2), saturated aqueous
sodium bicarbonate (x2) and brine (xl), dried with sodium
sulfate, filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(3-5% MeOH: CH2Cl2) to afford 240 mg of product as an off-white
solid (71% yield, two steps). 2H NMR (CDCl3) d 9.S3 (b, 1 H),
8.48 (b, 1 H), 7.63 (s, 1 H), 7.46 (m, 3 H), 7.28 (m, 4 H),
6.74 (m, 2 H), 6.67 (m, 1 H), 4.24 (m, 1 H), 4.17 (m, 1 H),
4.05 (m, 2 H), 2.80 (m, 4 H), 2.57 (m, 3 H), 1.97 (m, 4 H),
0.97 (d, 6 H) / ESI-MS [M+H+]+ = 481.35.
H. 5-bromo-2-(lH-imidazol-l-yl)benzonitrile
To a stirred solution 5-Bromo-2-fluorobenzonitrile (2.5
g, 12.2 mmol) in DMSO (50 mL) was added K2CO3 (3.337 g, 24.4
mmol), and then lH-imidazole (996 mg, 14.64 mmol). The
reaction mixture was heated to 90°C overnight, and diluted with
water. The reaction mixture was extracted with EtOAC (x2). The
organic layer was washed with washed with water (xl) and brine
(xl), dried with sodium sulfate, filtered, and concentrated
under reduced pressure to afford 2.97 g of the
imidazolylbenzonitrile as an off-white solid (98% yield). 1H
NMR (CDC13) d 7.97 (m, 2 H), 7.90 (m, 1 H), 7.41 (d, J = 8 Hz,
1 H), 7.37 (s, 1 H), 7.32 (s, 1 H).
I. 2-(lH-imidazol-1-yl)-5-isobutylbenzonitrile
The above compound was prepared essentially according to
the method of Example 111, step B, but the reaction mixture
was only stirred overnight. The resulting crude product was
purified by flash column chromatography (50-100% ethyl
acetate: hexane) to afford the product as a dark-brown oil. 1H
NMR (CDC13) d 7.89 (s, 1 H), 7.60 (s, 1 H), 7.53 (d, J = 8 Hz,
1 H), 7.40 (m, 2 H), 7.28 (m, 1 H), 2.60 (d, J = 8 Hz, 2 H),
1.93 (m, 1 H), 0.97 (d, 6 H) ; ESI-MS [M+H+]+ = 226.03.
J. tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{ [2-(lH-imidazol-1-yl)-5-isobutylbenzyl]amino} propylcarbamate
Step 1: At 0 °C, to a stirred solution of BH3 (1.5 M in
THF, 4.9 mL) was added the imidazolyl product from (I) (722
mg, 3.2 mmol) in anhydrous THF (8 mL). The reaction was
eventually warmed up to R.T., and then refluxed for overnight,
and then refluxed for 1 hour. The reaction mixture was cooled
down to R.T, and then quenched with 5N aqueous HCl. The
reaction was poured into CH2C12 (10 mL), washed with saturated
aqueous sodium bicarbonate (x2) and brine (xl), dried with
sodium sulfate, filtered, and concentrated under reduced
pressure without further purification.
Step 2: To a stirred solution of amine from step 1 in i-
propanol (14 mL) was added (1S)-2-(3,5-difluorophenyl)-1-
[(2S)-oxiran-2-yl]ethylcarbamate (509 mg, 1.7 mmol). The
reaction mixture was heated at 65 °C overnight. The reaction
mixture was concentrated, and purified by flash column
chromatography (5-20% MeOH: CH2Cl2) to afford 537 mg of product
as an off-white solid (55% yield, two stops). ESI-MS [M+H+]+ =
529.35.
K. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(1H-
imidazol-1-yl)-5-isobutylbenzyl]amino}propyl)acetamide
e above compound was prepared essentially according to the
method of Example 111, step G. The; crude acetamide was
purified by flash column chromatography (5-20% MeOH: CH2Cl2) to
afford the desired product as an off-white solid (60% yield,
r.wo steps). ESI-MS [M+H+)+ = 471.33.
L. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[5-
isobutyl-2-(1H-1,2,4-triazol-1-yl)benzyl]amino}propyl)
acetamide
Tho above compound is synthesized using procedures
essentially similar to Example 111, step:; J and K. ESI-MS
|M + M+]+ = 472. 0
M. 2-Iodo-5-isobutylbenzamide
Step 1: To a stirred solution of methyl 2-amino-5-
bromobenzoate (5.77 g, 25 mmol) in THF (20 mL) under argon was
added [1,1' -Bis (diphenylphosphi.no) ferrocene]
dichloropalladium(II) (2.04 g, 2.5 mmol} followed by i-BuZnBr
(0.5 M, 200 mL). The reaction mixture was stirred at R.T. for
overnight. The reaction was quenched with 1N HC1, and then
concentrated. The resulting crude was diluted with ethyl
acetate, and washed with water and brine, dried with sodium
sulfate, filtered, and concentrated under reduced pressure
without further purification.
Step 2: At R.T. amine from step 1 was treated with 5%
H2S04 (3.2 mL), and the reaction was heated to 60 °C for 5-10
minutes. The reaction mixture was cooled down to ice-cold, and
then was added drop-wise NaN02 (1.87 g, 27 mmol) in H20 (10
mL). After the addition was complete, the reaction was stirred
at ice-cold temperature for 15 - 20 minutes, and then KI (4.94
g, 2 9.7 mmol) in H20 (20 mL) was added. The reaction was
stirred at R.T. overnight. The next day, the reaction was"'
extracted with EtOAC (x3). The organic layer was washed with
washed with brine (xl), dried (sodium sulfate), filtered, and
concentrated. The crude product was purified by flash column
chromatography (5-10% MeOH: CH2Cl2) to afford 2 g of iodinated
product.
Step 3: To a stirred solution of iodinated product from
step 2 (6.6 g, 2 0.9 mmol) in a mixed solvent of MeOH (3 0 mL),
THF (30 mL), and water (30 mL) was added LiOH•H20 (4.4 mg,
104.5 mmol) at room temperature. After stirred for 12 hour at
room temperature, the reaction mixture was quenched with 1N
HCl, diluted with CH2C12, washed with saturated aqueous sodium
bicarbonate (xl), water (x2), and brine (x2), dried over
sodium sulfate, and concentrated under reduced pressure. The
crude product was used for the next step without further
purification.
Step 4: Was performed essentially according to the
method of Example 56. The resulting crude product was
purified by flash column chromatography (10-50% EtOAC: CH2Cl2)
to afford 900 mg of product as an off-white solid (20% yield,
four steps). 1H NMR (CDCl3) d 7.80 (d, J = 8 Hz, 1 H), 7.30 (s,
1 H), 6.95 (d, J = 8 Hz, H), 5.80 (b, 2 H), 2.47 (d, J = 6
Hz, 2 H), 1.87 (m, 1 H), 0.93 (2, H).
Step 1: At 0 °C, to a stirred solution of BH3 (1.5 M in
THF, 9.3 mL) was added (1.83 8 g, 6.1 mmol) in anhydrous THF
(16 mL). The reaction was eventually warmed up to R.T., and
then refluxed for overnight, and then refluxed for 1 hour. The
reaction mixture was cooled down, to R.T, and then quenched
with 5N aqueous HCl. The reaction was poured into CH2Cl2 (10
mL), washed with saturated aqueous sodium bicarbonate (x2) and
brine (xl), dried with sodium sulfate, filtered, and
concentrated under reduced pressure without further
purification.
Step 2: Was performed essentially according to the method
of Example 15, step 2. The reaction mixture was concentrated
under reduced pressure without further purification.
Step 3: To a. stirred solution of crude form step 2 in
MeOH. (10 mL) was added HC1 in 1,4-dioxane (4.0 M, 5.6 mL).
After stirred at R.T. overnight, the reaction mixture was
concentrated under reduced pressure to provide an off-white
solid. The crude was re-dissolve in CH2C12, washed with
saturated aqueous sodium bicarbonate (x2) and brine (xl),
dried with sodium sulfate, filtered, and concentrated under
reduced pressure without further purification.
Step 4: To a stirred solution of amine from step 3 in
CH2C12 (60 mL) was added DIPEA (3.88 mL, 22.3 mmol), and then
1-acetylimidazole (516 mg, 4.46 mmol). The reaction mixture
was stirred at R.T. overnight, quenched by addition of 50%
ammonium hydroxide, and diluted with CH2Cl2. The organic layer
was washed with washed with 1N HC1 (x2), saturated aqueous
sodium bicarbonate (x2) and brine (xl), dried with sodium
sulfate, filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatography
(3-5% MeOH: CH2C12) to afford 1 mg of product as an off-white
solid (30% yield, four steps). 1H NMR (CDCl3) d 7.76 (d, J = 9
Hz, 1 H), 7.14 (s, 1 H), 6.76 (m, 4 H), 5.97 (d, J = 3 Hz, 1
H), 4.20 (m, 1 H), 3.84 (m, 2 H), 3.63 (m, 1 H), 2.81 (m, 4
H), 2.46 (d, J = 6 Hz, 2 H), 1.88 (m, 4 H), 0.92 (d, 6 H).
O. N-((lS,2R)-l-(3,5-difluorobenzyl)-3-{[(3'-fluoro-4-
isobutyl-1,1'-biphenyl-2-yl)methyl]amino}-2-
hydroxypropyl)acetamide
To a stirred solution of the product of step (N) (97 mg,
0.183 mmol), aqueous sodium carbonate (2.0 M, 0.403 mmol) in
DME (1 mL) was added tetrakis(triphenylphosphine) palladium(O)
(21 mg, 0.0183 mmol) followed by 3-fluoro-phenylboronic acid
(64 mg, 0.458 mmol): The reaction mixture was heated to reflux
overnight, and then cooled to R.T. The reaction was diluted
with CH2Cl2, and was washed with water and brine, dried with
sodium sulfate, filtered, and concentrated under reduced
pressure. The crude, product was purified by flash column
chromatography (3-10% MeOH: CH2Cl2) to afford 36 mg of the
product as a white solid (37% yield). ESI-MS [M+H+]+ = 499.32.
Compounds shown in Examples P-Z are synthesized using
methods that are analogous to those previously described.
Example 112
See Albright, J.D., J. Heterocycl. Chem., 2000, 37, 41-1
for a general reference on preparing pyridyl tetralii
compounds.
STEP 1
To 5.5 g of 3-amino-2-cyclohexan-l-one (49.5 mmole) and 5
g of 2-ethyl acrolein (59.4 mmole, 1.2 eq.) was added 6 ml of
acetic acid and 2 5 ml of toluene. The reaction mixture was
heated to reflux overnight. The reaction was monitored by TLC
to show formation of a new spot with Rf = 0.73 (5 0% MeOH/DCM +
20% EtOH/Hexane.) Solvent was removed and the residue taken
up in toluene, which was removed again. The residue was
extracted with DCM (2x), washed with saturated NaHC03, dried
over anhydrous sodium sulfate, and concentrated to give 9.3 8 g
crude dark tan oil. This crude oil was extracted with hot
hexanes (2x of 125 ml). The extracts were concentrated and
dried in vacuo to give a light tan solid. (4.13 g, 23.6 mmole,
48%). MH+ (ESI) = 17S.1.
Step 2
The oxime was formed using procedures described elsewhere
in the application, yield: 90%; MH+ (ESI) = 191.1.
STEP 3
Reduction of the oxime was performed essentially
according to procedures described elsewhere in the
application, yield: 88%; MH+ (ESI) = 177.1.
STEP 4
The amine hydrochloride salt was free based by
partitioning between 1 N NaOH and EtOAc. The free base
solution was then concentrated and used in the epoxide opening
reaction as previously described: yield: 56%; MH+ (ESI) =
476.2.
STEP 5
Boc deprotection and acetylation was performed as
previously described. Reverse phase HPLC was effective in the
resolution of the two diasteromers:
N- (1S,. 2R)-[1-(3,5-Difluorobenzyl)-3-((55)-3-ethyl-
5,6,7,8-tetrahydroquinolin-5-ylamino)-2-hydroxypropyl] -
acetamide: MH+ (ESI) = 418.2.
N-(1S, 2R)-[1-(3,5-Difluorobenzyl)-3-((5R)-3-ethyl-
5,6,7,8-tetrahydroquinolin-5-ylamino)-2-hydroxypropyl] -
acetamide: MH+ (ESI) = 418.2.
Example 113:
A. Synthesis of Cbiral Amine 2b
The compound (1), which is readily available, was
protected and then underwent palladium-mediated coupling with
neo-pentylzinc chloride (generated in situ) to give neo-pentyl
substituted tetraline 2a. Subsequent deprotection afforded
intermediate amine 2b as its hydrochloride salt, which was
utilized in the construction of additional targets (infra).
7-Bromotetralone (3) was protected as its dioxolane and
then underwent palladium-mediated coupling with neo-pentylzinc
chloride (generated in situ) to afford, after acidic work-up,
neo-pentyl substituted tetralone 4.
Coupling the enantiomerically pure tetralin amine of
amine 2b with (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-
yl]ethylcarbamate followed by Boc-deprotection and HBTU-
mediated acylation afforded the final compound (7), as
predominantly one diastereoisomer.
Claisen condensation of ethyl formate and ethyl
chloroacetate gave ester 11. Treatment of isovaleramide (12)
with phosphorus pentasulfide afforded 3-methyl-thiobutyramide
(13). Cyclization of 11 and 13 afforded 5-carboethoxy-2-iso-
butylthiazole (14).
Reduction of ester 14 followed by treatment of the
resulting alcohol with thionyl chloride followed by
nucleophilic substitution with potassium cyanide gave benzyl
nitrile 15. Cyclopropanation of 15 followed by hydrolysis
afforded amide 16. Hoffman rearrangement, of 16 afforded amine
17. N-Alkylation of 17 followed by de-protection and N-
acetylation provided (18).
Palladium coupling of bromide 44 with neo-pentyl zinc
generated in situ gave alcohol 45). Conversion of alcohol 45
to amine 46 was carried out in two steps. Epoxide opening,
deprotection, and acetylation resulted in (47).
E. Synthesis of Chroman 32
The synthesis of aminochroman (25)) is illustrated in
scheme II. In scheme II, phenol H140 underwent Michael
addition with acrylonitrile to give nitrile H141. Subsequent
acid hydrolysis gave carboxylic acid H142, which was then
converted to the acid chloride and cyclized intramolecularly
to give chromonone. H143..Alpha bromination of ketone H143
gave bromide H144, which was reduced with sodium borohydride
to give bromo alcohol H145. Using Ritters reaction
conditions, H145 was transformed to racemic amino alcohol 29.
More specific experimental procedures follow the scheme.
Step 1: A mixture of 4-etylphenol (H140, 26,69 g, 0.218
mol), acrylonitrile (50 mL, 0.754 mol, 3.5 equiv), and triton
B (40 wt% in methanol, 5 mL, 0.011 mol, 0.05 equiv) was
stirred at 84 °C in a sealed tube overnight. The reaction
mixture was diluted with ether (300 mL) and the brown
precipitate was removed by suction filtration. The ether
solution was washed with 2 M sodium hydroxide aqueous solution
(2 x 100 mL), 1 M hydrochloric acid (100 mL) and saturated
sodium chloride, dried (magnesium sulfate), and concentrated
under reduced pressure. Purification by flash column
chromatography (silica, gradient 10:1, and 6:1 hexanes/ethyl
acetate) provided nitrile H141 (3 0.17 g, 79%) as a white
solid: 1H NMR (300 MHz, CDC13) d 7.17-7.08 (m, 2H), 6.87-6.79
(m, 2H), 4.18 (t, J=6.4 Hz, 2H), 2.80 (t, J=6.4 Hz, 2H), 2.60
(q, J=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H) ; ESI MS m/z 176
[C11H13NO + H]+
Step 2: Nitrile H141 (30.17 g, 0.172 mol) was stirred
with concentrated hydrochloric acid solution (100 mL, 1.20
mol, 7 equiv) at reflux overnight. White precipitate formed
as the reaction proceeded. The reaction mixture was cooled to
room temperature and the solid was collected by suction
filtration. The filter cake was washed several times with
cold water and dried in a vacuum oven at 50 °C for 14 h.
Carboxylic acid H142 was obtained as a white solid (31.79g,
95%): 1H NMR (300 MHz, CDC13) d 7.13-7.08 (m,2H), 6.88-6.80
(m, 2H), 4.20 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H), 2.58
(q, J-7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H) ; ESI MS m/z 193
[C11H14O3 - H].
Step 3: The carboxylic acid H142 (0.800 g, 4.12 mmol)
was stirred with thionyl chloride (6 mL, 82.4 mmol, 20 equiv)
at reflux for 2 h. Excess thionyl chloride was removed under
reduced pressure. The acid chloride thus obtained was used
without further purification in the next reaction.
Aluminum chloride (1.10 g, 8.24 mmol, 2 equiv) was added
in one portion to a solution of acid chloride as above in dry
methylene chloride (50 mL) and the resulting brown mixture was
stirred at reflux for 14 h and cooled to room temperature.
The mixture was poured onto crushed ice in a beaker, followed
by the addition of 6 M hydrochloric acid (2 0 mL) and
extraction with methylene chloride (3 x 40 mL). The combined
organics were washed with saturated sodium chloride, dried
(magnesium sulfate), and concentrated under reduced pressure.
Purification by flash column chromatography (silica, gradient
10:1, and 6:1 hexanes/ethyl acetate) gave chromonone H143 (574
mg, 79%) as a colorless oil: 1H NMR (300 MHz, CDC13) d 7.72
(d, J=2.2 Hz, 1H), 7.32 (dd, J=8.5, 2.2 Hz, 1H), 6.90 (d,
J=8.5 Hz, 1H), 4.52 (t, J=6. 5 Hz, 2H), 2,80 (t, J=6.5 Hz, 2H),
2.60 (q,,7=7.6 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H) ; ESI MS m/z 177
[C11H13O2+H]+.
Step 4: Pyridinium hydrobromide perbromide (743 mg, 2.32
mmol) was added to a solution of chromonone H143 (372 mg, 2.11
mmol) in dry methylene chloride (15 mL) and the reaction
mixture was stirred at room temperature for 2 h. Water (15
mL) was added to the mixture and the layers were separated.
The aqueous layer was further extracted with methylene
chloride (2 x 15 mL). The combined organics were dried
(magnesium sulfate) and concentrated under reduced pressure.
Purification by flash column chromatography (silica, gradient
20:1, and 10:1 hexanes/ethyl acetate) provided brorno ketome
H144 (450 mg, 84%) as a slightly yellow oil: 1H NMR (300 MHz,
CDC13) d 7.77 (d, J=2.2 Hz, 1H), 7.39 (dd, J=8.5, 2.2 Hz, 1H),
6.97 (d, J=8.5 Hz, 1H), 4.68-4.52 (m, 3H), 2.62 (q, J=l. 6 Hz,
2H), 1.22 (t, J=7.6 Hz, 3H) ; ESI MS m/z 255 [C11C11BrO2+H]+.
Step 5: Sodium borohydride (99 mg, 2.61 mmol, equiv) was
added to a solution of bromo ketone H144 (444 mg, 1.74 mmol)
in absolute ethanol (15 mL) and the reaction mixture was
stirred at room temperature for 2 h. the reaction mixture was
quenched with the addition of 1 M hydrochloric acid (4 mL) and
most of ethanol was removed by rotary evaporation. The
residue was partitioned between water and methylene chloride.
The aqueous layer was further extracted with methylene
chloride. The combined organics were dried (sodium sulfate)
and concentrated under reduced pressure. Bromo alcohol H145
was obtained as a white solide (443 mg, 99%) and used in the
next step without further purification: 1H NMR (300 MHz,
CD3OD) d 7.14 (d, J=1.5 Hz, 1H), 7.03 (dd, J=8.3, 1.5 Hz, 1H),
6.69 (d, J=8.3 Hz, 1H), 4.78 (d, J=3.2 Hz, 1H), 4.58-4.49 (m,
1H), 4.35-4.26 (m,2H), 2.56 (q, J=7.6 Hz, 2H), 1.16 (t, J=7.6
Hz, 2H), 1.16 (t, J=7.6 Hz, 3H).
Step 6: The bromo alcohol from step 5 H145 (443 mg, 1.72
mmol) was dissolved in anhydrous acetonitrile (10 mL) and
concentrated sulfuric acid (0.19 mL, 3.47 mmol) was added via
syringe. The reaction mixture was stirred at 40 °C for 5 h
and then reflux for 12 h. Water (10 mL) was added and most of
the acetonitrile was removed under reduced pressure. To the
residue was added 6 M hydrochloric acid (10 mL) and the
resulting mixture was stirred at reflux for 14 h. The
reaction mixture was cooled to room temperature, and placed in
an ice bath. To this was added 6 M sodium hydroxide until pH
12, and the mixture was extracted with methylene chloride ( 3x
50 mL). The combined organics were washed with saturated
sodium chloride, dried (sodium sulfate) and concentrated.
Purification by flash column chromatography (silica, gradient
20:1, 10:1 and 1:1 methylene chloride/methanol) provided amino
alcohol (29, 233 mg, 70%) as a white solid: 1H NMR (300 MHz,
CDC13) d 7.12 (d, J=1.5 Hz, 1H), 7.01 (dd, J=8.3,, 1.5 Hz, 1H)
6.78 (d, J=8.3 Hz, 1H), 4.09 (d, J=11.5 Hz, 1H), 4.00-3.91 (m,
2H), 3.88-3.75 (m, 1H), 2.58 (q, J=7.6 Hz, 2H), 1.60 (br s,
3H) 1.20 (t, J=7.6 Hz, 3H) ; ESI MS m/z 194 [C11H15NO2+H]+; HPLC
(method E) 96.7% (AUC), tR = 9.4 min.
Subsequent coupling of racemic aminochroman 29 with
Example 134, followed by Boc deprotection and HBTU-mediated
acylation afforded (32), as a mixture of diastereoisomers
(Scheme II-a). One possible procedure for preparing compound
32 is described below.
Synthesis of Compound (32)
Step 1: To a solution of 29 (1.00 g, 5.18 mmol) in 2-
propanol (60 mL) was added Example 134 (1.40 g, 4.71 mmol) and
the reaction mixture was heated to 50 °C for 17 h and then to
80 °C for 1 h. The reaction mixture was cooled to room
temperature, and the solvent removed under reduced pressure.
The residue was partitioned between methylene chloride (20 mL)
and water (20 mL). The aqueous phase was extracted with
methylene chloride (10 mL), the combined organic phase washed
successively with 0.5 N hydrochloric acid (10 mL), saturated
sodium bicarbonate (10 mL) and sodium chloride (10 mL), dried
(sodium sulfate), filtered and concentrated under reduced
pressure. The crude product was purified by flash
chromatography (silica, 95:5 methylene chloride/methanol) to
afford amino alcohol 30 (1.30 g, 51%) as a white solid: 1H NMR
(300 MHz, CDC13) d 7.42-7.38 (m, 1H), 7.20-6.96 (m, 1H), 6.78-
6.62 (m, 5H), 4.64-4.58 (m, 1H), 4.56-4.20 (m, 1H), 4.18-4.08
(m, 2H), 3.90-3.48 (m, 4H), 3.16-2.70 (rn, 5H), 2.64-2.50 (m,
2H), 1.50-1.30 (s, 9H), 1.23-1.18 (m, 3H) ; ESI MS m/z 493
[C26H34F2N2OS + H].
Step 2: To a solution of amino alcohol 3 0 (0.4 7 g, 0.95
mmol) in dioxane (20 mL) at room temperature was added
hydrogen chloride (4.77 mL, 4 M solution in dioxane, 19.09
mmol) and the reaction mixture stirred for 17 h. The reaction
mixture was concentrated under reduced pressure and the
residue triturated with diethyl ether to afford amine 31 (0.38
g, 85%) as a white solid: 1H NMR (300 MHz, CD3OD) S 7.40 (s,
1H), 7.19-7.17 (m, 1H), 7.05-6.83 (m, 5H), 4.71-4.69 (m, 1H),
4.44-4.40 (m, 2H), 4.19-4.08 (m, 3H), 3.78 (br s, 1H), 3.78-
3.52 (m,lH), 3.49-3.47 (m, 1H), 3.34-3.30 (m, 1H), 3.12-3.01
(m 2H), 2.98-2.63 (m, 4H), 1.30-1.17 (m, 3H) ; ESI MS m/z 393
[C21H26F2M2O3-+ H].
Step 3: To a suspension of sodium acetate (0.67 g, 0.82
mmol), diisopropylethylamine (0.71 mL, 4.09 mmol) and HBTU
(0.31 g, 0.82 mmol) in methylene chloride (5 mL) was added an
additional solution of amine 31 (0.38 g, 0.82 mmol),
diisopropylethylamine (0.71 mL, 4.09 mmol) in methylene
chloride. (5 mL) and the combined mixture was stirred at room
temperature for 24 h. Water (30 mL) was added and the aqueous
phase was extracted with additional methylene chloride (5 mL).
The combined organic phase was washed successively with 0.5 N
hydrochloric acid (10 mL) and saturated sodium chloride (10
mL), dried (sodium sulfate), filtered and concentrated under
reduced pressure. Purification by preparative HPLC (Method G)
afforded ALB 15297 (32, 55 mg, 4%) as a white foam: IR (ATR)
3254, 2966, 1657, 1627, 1596 cm'1; 1H NMR (3 00 MHz, CD3OD) d
7.34-7.28 (m, 1H), 7.17-7.14 (m, 1H), 6.88-6.75 (m, 5H), 4.56-
4.54 (m, 1H), 4.39-4.34 (m, 1H), 4.16-4.04 (m, 3H), 3.90-3.85
(m, 1H), 3.77-3.62 (m, 1H), 3.54-3.10 (m, 5H), 2.71-2.57 (m,
3H), 1.85-1.82 (m, 3H), 1.28-1.16 (m, 3H) ; ESI MS m/z 435
[C23H28F2N2O4+ H] ; HPLC (Method F) 94.1 (AUC), tR=ll.l, 11.5 min
(3:2 mixture of diastereeoisomers).
F. Synthesis of Acetate 158
Addition of methyl Grignard to ester 155 followed by coupling
with 2-methylpropyl boronic acid gave alcohol 156. Conversion
of the alcohol to the azide and reduction provided amine 157.
Epoxide opening, removal of the protecting group,
acetalization, and formation of the hydrochloric acid salt
gave (158).
General HPLC Methods
Method A: Phenomenex Luna C18 (2) Column, 150 x 4.6 mm, 5jj
A: 0.05% TFA in 95:5 H2O/CH3CN; B: 0.05% TFA in 5:95 H2O/CH3CN
Gradient: 10-90% B over 15 min; flow 1.0 mL/min
Detection: 254 nm
Method B: Phenomenex Luna C18(2) Column, 150 x 4.6 mm, 5µ
A: 0.05% TFA in 95:5 H2O/CH3CN; B: 0.05% TFA in 5:95 H2O/CH3CN
Gradient: 30-100% B over 15 min; flow 1.0 mL/min
Detection: 254 nm
Method C: Phenomenex Synergi Max-RP Column, 150 x 4.6 mm, 4|i
A: H20; B: CH3CN
Gradient: 3 0-100% B over 15 min; flow 1.0 mL/min
Detection: 220 nm
Method D: Phenomenex Luna C18(2) Column, 150 x 4.6 mm, 4µ
A: 95:5 H2O/CH3CN; B: 5:95 H2O/CH3CN
Gradient: 40-100% B over 15 min; flow 1.0 mL/min
Detection: 254 nm
Method E: Phenomenex Luna C18(2) Column, 150 x 4.6 mm, 4µ
A: 95:5 H2O/CH3CN; B: 5:95 H20/CH3CN
Gradient: 1-99% B over 15 min; flow 1.0 mL/min
Detection: 254 nm
Method F: Phenomenex Luna C18 (2) Column, 150 x 4.6 mm, 5µ
A: 0.05% TFA in 95:5 H2O/CH3CN; B: 0.05% TFA in 5:95 H2O/CH3CN
Gradient: 10-90% B over 15 min; flow 1.0 mL/min
Detection: 225 nm
EXAMPLE 114
A. Synthesis of Neo-Pentylmagnesium Bromide
A 3-necked, round-bottom flask fitted with an addition
funnel, water condenser and magnetic stir bar was charged with
magnesium turnings (10.0 g, 413.8 mmol), iodine (100 mg), and
glass shards and then heated vigorously under vacuum with
stirring for 2 0 min. The reaction flask was cooled to room
temperature and then charged with argon and the magnesium
turnings stirred for an additional 0.5 h. The flask was then
charged with diethyl ether (65 mL) and the addition funnel
charged with a solution of neo-pentyl bromide (20.0 g, 132.4
mmol) in diethyl ether (100 mL). Neat rzeo-pentyl bromide
(2.5 g, 16.55 mmol) was added directly to the reaction mixture
and the solution was gently warmed with a heat gun to initiate
the reaction. Once the reaction was initiated, the contents
of the addition funnel were added dropwise over the course of
1 h to maintain, a gentle reflux. Another aliquot of neat neo-
pentyl bromide (2.5 g, 16.55 mmol) was then added to the
reaction mixture in one portion followed by dropwise addition
of 1,2-dibromoethane (14.3 mL, 165.5 mmol) over the course of
1 h. Ethane gas generated was swept from the reaction flask
by a steady stream of nitrogen. The reaction mixture was then
heated at reflux for 24 h and cooled to room temperature to
yield a black solution. The suspended solid was allowed to
settle and the solution above the solid residue was neo-
pentylmagnesium bromide (ca. 1.0 M in ether, 165.5 mmol),
which was used in subsequent coupling reactions.
B. Synthesis of Mine 2b
Step 1: Di-tert-butyl dicarbonate (E5.45 g, 25.0 mmol) was
added in one portion at room temperature to a solution of
compound (1) (5.05 g, 19.23 mmol) and N, N-
diisopropylethylamine (10.0 mL, 57.7 mmol) in acetonitrile (32
mL) and the reaction mixture was stirred at room temperature
for 36 h. The solvent was removed under reduced pressure and
the residue partitioned between ethyl acetate and saturated
sodium bicarbonate. The phases were separated and the organic
phase was washed with water, saturated sodium chloride, dried
(sodium sulfate), filtered, and concentrated under reduced
pressure to yield the desired protected amine (7.38 g,
quantitative) as a waxy solid, which was used in the next step
without further purification: 1H NMR (300 MHz, CDC13) d 7.47
(s, 1H), 7.28-7.24 (m, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.77 (m,
2H), 2.72-2.66 (m, 2H), 2.04-2.00 (m, 1H), 1.83-1.72 (m, 3H),
1.44 (s, 9H).
Step 2: A solution of the neo-pentylmagnesium bromide
prepared above (115.4 mL) was added dropwise at room
temperature to a solution of zinc chloride (115.4 mL, 0.5 M in
tetrahydrofuran, 57.7 mmol) over 40 min. Following Grignard
addition, the reaction mixture was stirred for 0.5 h to yield
a white heterogenous suspension. [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (1.60 g, 1.92 mmol) was added in
one portion followed by dropwise addition over 2 0 min of a
solution of the protected amine prepared in step 1 (7.38 g,
19.23 mmol) in tetrahydrofuran (20 mL) to yield a yellow
reaction mixture. The reaction mixture was stirred at room
temperature for 0.5 h then heated at reflux for 2 h to yield a
brown solution. The reaction mixture was cooled to: room
temperature and carefully quenched with 10% hydrochloric acid
(100 mL) and the reaction mixture was stirred at room
temperature overnight. The reaction mixture was diluted with
diethyl ether and the phases separated. The organic phase was
then washed with water, saturated sodium chloride, dried
(sodium sulfate), filtered, and concentrated under reduced
pressure to yield a brown semisolid. Purification by flash
column chromatography (silica, 19:1 hexanes/ethyl acetate)
afforded protected amine 2a (3.0 g, 49%) as a yellow oil: 1H
NMR (300 MHz, CDCl3) d 7.08 (s, 1H), 6.93-6.90 (m, 2H), 4.82-
4.75 (m, 2H), 2.76-2.69 (m, 2H), 2.43 (s, 2H), 2.04-1.97 (m,
1H), 1.84-1.80 (m, -3H), 1.47 (s, 9H), 0.88 (m, 9H) ; ESI MS m/z
318 [C20H31NO2 + H]+.
Step 3:. To a solution.of amine 2a (3.00 g, 9.45 mmol) in
1,.4-dioxane (25 mL) was added at room temperature a solution
of hydrochloric acid (23.5 mL, 4 N in 1,4-dioxane, 94.5 mmol)
and the reaction mixture stirred at room temperature overnight
to yield a white precipitate. Vacuum filtration yielded amine
2b (2.15 g, 91%) as a white solid: 1H NMR (300 MHz, CDC13 +
CD3OD) d 7.21 (s, 1H), 7.08-7.02 (m, 2H), 4.43 (m, 1H), 3.01-
2.76 (m, 5H), 2.48 (s, 2H), 2.19-2.12 (m, 2H), 1.96-1.87 (m,
2H), 0.90 (m, 9H) ; ESI MS m/z 201 [C15H20]+.
C. Synthesis of Tetralone 4
Step 1: A solution of tetralone 3 (5.0 g, 22.21 mmol) in
benzene (100 mL) containing ethylene glycol (5.0 mL, 88.8
mmol) and p-toluenesulfonic acid monohydrate (420 mg, 2.22
mmol) was heated at reflux in a Dean-Stark apparatus for 24 h.
The reaction mixture was cooled to room temperature,
concentrated under reduced pressure, and the resulting residue
partitioned between ethyl acetate and water. The phases were
separated and the organic phase was washed with saturated
sodium chloride, dried (sodium sulfate), filtered, and
concentrated under reduced pressure to yield the desired
dioxolane (5.97 g, 99%) as a golden oil: 1H NMR (300 MHz,
CDC13) d 7.57 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.2, 2.0 Hz,
1H), 6.96 (d, J = 8.2 Hz, 1H), 4.23-4.07 (m, 4H), 2.73-2.72
(m, 2H), 2.04-1.94 (m, 4H).
Step 2: A solution of the neo-pentylmagnesium bromide
prepared above (60 mL) was added dropwise at room, temperature
over 20 min to a solution of zinc chloride (60 mL, 0.5 M in
tetrahydrofuran, 30.0 mmol). Following Grignard addition, the
reaction mixture was stirred for 0.5 h to yield a white
heterogenous suspension. [1,1'-
Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex
with dichloromethane (1:1) (816 mg, 1.0 mmol) was added in one
portion followed by dropwise addition of a solution of the
dioxolane prepared. in step. 1 (2.69 g, 10.0 mmol) in
tetrahydrofuran (10 mL) to yield a yellow reaction mixture,
which was then heated at reflux for 1 h to yield a brown
solution. The reaction mixture was cooled to room temperature
and carefully quenched with 10% hydrochloric acid (100 mL) and
the reaction mixture was stirred at room temperature
overnight. The reaction mixture was diluted with diethyl
ether and the phases separated. The organic phase was then
washed with water, saturated sodium chloride, dried (sodium
sulfate), filtered, and concentrated under reduced pressure to
yield a black oil. Purification by flash column
chromatography (silica, 19:1 hexanes/ethyl acetate) afforded
compound -(4) (2.17 g, 99%) as a yellow oil: IR (ATR) 3359,
2957, 1762, 1686, 1521, 1236, 1126, 1076, 1053, 1028 cm-1; 1H
NMR (300 MHz, CDC13) d 7.79 (s, 1H), 7.26-7.22 (m, 1H), 7.15
(m, 1H), 2.96-2.92 (m, 2H), 2.67-2.62 (m, 2H), 2.50 (s, 2H),
2.17-2.08 (m, 2H), 0.89 (s, 9H) ; ESI MS m/z 217 [C15H20O + H]+;
HPLC: (Method D) >99% (AUC), tR = 13.30 min.
D. Synthesis of Compound (7)
Step 1: To a solution of 2b (0.22 g, 1.03 mmol) in 2-
propanol (10 mL) was added Example 134 (0.31 g, 1.03 mmol) and
the reaction mixture was heated to 50 °C for 17 h. The
reaction mixture was cooled to room temperature, and the
solvent removed under reduced pressure. The resulting residue
was partitioned between methylene chloride (2 0 mL) and water
(20 mL). The aqueous phase was extracted with methylene
chloride (10 mL), the combined organic phase washed
successively with 0.5 N hydrochloric acid (10 mL), saturated
sodium bicarbonate (10 mL) and sodium chloride (10 mL), dried
(sodium sulfate), filtered and concentrated under reduced
pressure. The crude product was purified by flash
chromatography (silica, 95:5 methylene chloride/methanol) to
afford amino alcohol 5 (0.32 g, 60%) which was carried on
without further characterization: ESI MS m/z 517 [C30H42F2N2O3 +
H].
Step 2: To a solution of amino alcohol 5 (0.32 g, 0.61
mmol) in dioxane (5 mL) at room temperature was added hydrogen
chloride (1.50 mL, 4 M solution in dioxane, 6.18 mmol) and the
reaction mixture stirred for 17 h. The reaction mixture was
concentrated under reduced pressure and the resulting residue
triturated with diethyl ether to afford amine 6 (0.25 g, 85%)
as a white solid, which was carried on without further
purification or characterization: ESI MS m/z 417 [C25H36Cl2F2N2O
+ H].
Step 3: To a suspension of sodium fluoroacetate (0.04 g,
0.82 mmol), N,N-diisopropylethylamine (0.23 mL, 1.41 mmol) and
HBTU (0.17 g, 0.47 mmol) in methylene chloride (2 mL) was
added a solution of amine 6 (0.23 g, 0.47 mmol) and N,N-
diisopropylethylamine (0.15 mL, 0.94 mmol) in methylene
chloride (2 mL) and the combined mixture was stirred at room
temperature for 24 h. Water (2 0 mL) was added and the aqueous
phase was extracted with additional methylene chloride (5 mL).
The combined organic phase was washed successively with 0.5 N
hydrochloric acid (10 mL) and saturated sodium chloride (10
mL), dried (sodium sulfate), filtered and concentrated under
reduced pressure. Purification by preparative HPLC (Method B)
afforded compound (7) (106 mg, 47%) as a white solid: IR
(ATR) 3324, 2957, 1659, 1594 cm-1; 1H NMR (300 MHz, CDCl3) d
7.29 (s, 1H), 7.12-6.95 (m, 2H), 6.82-6.55 (m, 4H), 4.93-4.83
(m, 1H), 4.81-4.67 (m, 1H), 4.27-4.18 (m, 1H), 3.75-3.74 (m,
1H), 3.57-3.52 (m, 1H), 3.10-3.04 (m, 1H), 2.94-2.67 (m, 5H),
2.48 (s, 2H), 1.98-1.75 (m, 4H), 1.60-1.40 (br s, 2H), 0.93
(s, 9H) ; ESI MS m/z 476 [C27H35F3N2O2 + H] ; HPLC (Method C) >99%
(AUC), tR = 8.60 min.
E. Synthesis of 5-Carboethoxy-2-iso-butylthiazole (14)
Step 1: A solution of ethyl formate (38 mL, 470 mmol) and
ethyl chloroacetate (44 mL, 416 mmol) in diethyl ether (200
mL) was added to an ice-cold solution of potassium ethoxide
(33.5 g, 400 mmol) in 1:2 ethyl alcohol/diethyl ether (300
mL). The resulting suspension was stirred overnight at room
temperature. The solid was filtered, washed with diethyl
ether and dissolved in water (200 mL). The solution was
cooled in an ice bath and acidified to pH 4 with concentrated
hydrochloric acid. The solution was extracted with diethyl
ether and the organic layer washed with saturated sodium
chloride, dried (sodium sulfate), filtered, and concentrated
under reduced pressure to give formylchloroacetate (11, 24.2
g, 40%) as a yellow oil: 1H NMR (300 MHz, CDC13) d 4.99-4.19
(m, 2H), 4.08 (s, 1H), 3.64-3.57 (m, 1H), 1.35-1.18 (m, 3H).
Step 2: Phosphorus pentasulfide (3.8 g, 10.9 mmol) was
added in portions to a solution of isovaleramide (12, 10 g, 99
mmol) in diethyl ether (400 mL). The reaction mixture was
stirred at room temperature for 2 h and then filtered. The
filtrate was concentrated under reduced pressure to give
isovalerothioamide (13, 11.60 g, quantitative) as a yellow
oil: 1H NMR (300 MHz, DMSO-d6) d 9.34 (s, 1H), 9.12 (s, 1H),
2.33 (d, J = 7.3 Hz, 2H), 2.17-2.12 (m, 1H), 0.86 (d, J = 8.4
Hz, 6H).
Step 3: A solution of 13 (11.60 g, 98.97 mmol) and 11
(9.98 g, 66.31 mmol) in N, N-dimethylformamide (40 mL) was
heated at 95 °C overnight. The reaction mixture was cooled to
0 °C and cold water (100 mL) added. The reaction mixture was
adjusted to pH 8 by slow addition of solid sodium bicarbonate
and extracted with diethyl ether. The organic layer was
washed with water, saturated sodium chloride, dried (sodium
sulfate), filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (silica, 90:10
hexanes/ethyl acetate) gave 5-carboethoxy-2-iso-butylthiazole
(14, 4.53 g, 32%) as a yellow oil: 1H NMR (300 MHz, CDC13) d
4.36 (q, J = 7.2 Hz, 2H), 2.90 (d, J = 7.2 Hz, 2H), 2.15 (m,
1H), 1.38 (t, J = 7.2 Hz, 3H), 1.06 (d, J= 6.7 Hz, 6H).
F. Synthesis of Compound (18)
Step 1: To an ice-cold solution of lithium aluminum
hydride (18.7 mL, 1.0 -M in tetrahydrofuran, 18.7 mmol) was
added a solution of 14 (2.0 g, 9.37 mmol) in tetrahydrofuran
(3 mL). The reaction mixture was stirred at 0 °C for 0.5 h
and then overnight at room temperature. The reaction mixture
was quenched by sequential addition of water (1 mL), 15%
sodium hydroxide (1 mL) and water (1 mL). The resulting
mixture was dried (sodium sulfate), filtered, and concentrated
under reduced pressure to give the desired alcohol (1.43 g,
89%) as a light yellow oil: 1H NMR (300 MHz, CDC13) d 7.48 (s,
1H), 4.81 (s, 2H), 2.. 83 (d, J = 7.2 Hz, 2H), 2.71 (s, 1H),
2.10 (m, 1H), 0.98 (d, J= 6.7 Hz, 6 Hz).
Step 2: To an ice-cold solution of the alcohol prepared
in step 1 (1.3 g, 7.6 mmol) in methylene chloride (5 mL) was
added thionyl chloride (5.53 mL, 76 mmol). The reaction
mixture was stirred at room temperature for 1 h and evaporated
under reduced pressure. The residue was neutralized by
saturated sodium bicarbonate and then partitioned between
water and methylene chloride. The organic layer was washed
with saturated sodium chloride, triethylamine was added, and
the resulting solution was dried (sodium sulfate), filtered,
and concentrated under reduced pressure to give the desired
chloride (1.15 g, 80%) as a yellow oil: 1H NMR (300 MHz, CDC13)
d 7.59 (s, 1H), 4.78 (s, 2H), 2.85 (d, J = 7.2 Hz, 2H), 2.10
(m, 1H), 0.99 (d, J = 6.7 Hz, 6H).
Step 3: To a solution of the chloride prepared in step 2
(1.15 g, 6.1 mmol) in dimethyl sulfoxide (5 mL) was added
potassium cyanide (475 mg, 7.3 mmol). The reaction mixture
was stirred at room temperature overnight and then partitioned
between water and ethyl acetate. The organic layer was washed
with saturated sodium. chloride, dried (sodium sulfate),
filtered, and concentrated under reduced pressure bo give a
black oil. Purification by flash column chromatography
(silica, 66:34 hexanes/ethyl acetate) gave nitrile 15 (363 mg,
33%) as a yellow oil: 1H NMR (300 MHz, CDCl3) d 7.57 (s, 1H),
3.89 (s, 2H), 2.85 (d, J= 7.2 Hz, 2H), 2.10 (m, 1H), 0.99 (d,
J = 6.6 Hz, 6H).
Step 4: To a mixture of 15 (367 mg, 2.04 mmol), 1-bromo-
2-chloroethane (2.5 mL, 30.5 mmol), and benzyltriethylammonium
chloride (14 mg, 0.06 mmol) at 50 °C was added a solution of
50% sodium hydroxide (3.6 mL). The reaction mixture was
stirred at 50 °C for 1 h, cooled to room temperature and then
partitioned between water and methylene chloride. The organic
layer was washed with saturated sodium chloride, dried (sodium
sulfate), filtered, and concentrated under reduced pressure to
give a black oil. Purification by flash column chromatography
(silica, 66:34 hexanes/ethyl acetate) gave the desired
cyclopropylbenzylnitrile (260 mg, 62%) as a light yellow oil:
1H NMR (300 MHz, CDCl3) d 7.54 (s, 1H), 2.81 (d, J = 7.2 Hz,
2H), 2.05 (m, 1H), 1.77 (m, 2H), 1.43 (m, 2H), 0.98 (d, J =
6.6 Hz, 6H).
Step 5: To a solution of the nitrile prepared in step 4
(250 mg, 1.21 mmol) in 1:1 acetone/water (2 mL) was added
potassium carbonate (17 mg, 0.12 mmol) and urea hydrogen
peroxide (456 mg, 4.85 mmol). The reaction mixture was
stirred at room temperature overnight. Acetone was evaporated
under reduced pressure and the residue diluted with water.
Desired amide 16 (270 mg, quantitative) was collected by
filtration. This compound was used in the next step without
further characterization.
Step 6: To an ice-cold solution of sodium hydroxide (228
mg, 5.7 mmol) in water (2.5 mL) was added bromine (94 µL, 1.84
mmol) dropwise. After stirring for 5 min at 0 °C, amide 16
(336 mg, 1.5 mmol) was added in one portion. The reaction
mixture was -stirred at room temperature for 2 0 min and then
heated at 75 °C for 5 h. The reaction mixture was diluted
with water and extracted with methylene chloride. The organic
layer was washed with saturated sodium chloride, dried (sodium
sulfate), filtered, and concentrated under reduced pressure to
give a yellow solid. Purification by flash column
chromatography (silica, 95:5 methylene chloride/methanol) gave
amine 17 (288 mg, 98%) as a light yellow solid: 1H NMR (300
MHz, CDC13) d 7.35 (s, 1H), 2.79 (d, J = 7.2 Hz, 2H), 2.08 (m,
1H), 1.13 (m, 1H), 1.06-0.97 (m, 8H).
Step 7: A solution of amine 17 (150 mg, 0.76 mmol) and
Example 134 (206 mg, 0.68 mmol) in 2-propanol (5 mL) was
heated at 70 °C overnight. The reaction mixture was cooled to
room temperature and then partitioned between water and
methylene chloride. The organic layer was washed with
saturated sodium chloride, dried (sodium sulfate), filtered,
and concentrated under reduced pressure. Purification by
flash column chromatography (silica, 95:5 methylene
chloride/methanol) gave the N-alkylated amine (108 mg, 32%) as
a yellow solid: ESI MS m/z 496 [C25H35F2N3O3S + H]+.
Step 8: Hydrogen chloride (2.0 mL, 4 N in 1,4-dioxane, 8
mmol) was added at room temperature to a solution of the amine
prepared in step 7 (108 mg, 0.22 mmol) in 1,4-dioxane (1 mL).
The reaction mixture was stirred at room temperature for 3 h
and then concentrated under reduced pressure to give 19 (103
mg, quantitative) as a yellow solid: ESI MS m/z 39S
[C20H27F2N3OS + H]+.
Step 9: To an ice-cold solution of 19 (103 mg, 0.22 mmol)
and triethylamine (129 £iL, 0.92 mmol) in methylene chloride (2
mL) was added 1-acetylimidazole (24 mg, 0.22 mmol). The
reaction mixture was stirred at room temperature overnight and
then partitioned between methylene chloride and water. The
organic layer was washed with saturated sodium chloride, dried
(sodium sulfate), filtered, and concentrated under reduced
pressure.. Purification by flash column chromatography
(silica, 95:5 methylene chloride/methanol) gave compound (18)
(51 mg, 54%) as an off-white solid: IR (ATR) 3330, 2960, 1647,
1595, 1529, 1458, 1112, 980 cm"1; XH NMR (300 MHz, CDCl3) 5 7.34
(s, 1H), 6.74-6.63 (m, 3H), 5.52 (d, J = 9.1 Hz, 1H), 4.08-
4.10 (m, 1H),¦3.43-3.41 (m, 1H), 2.98-2.96 (m, 1H), 2.98-2.70
(m, 5H), 2.10-2.00 (m, 1H), 1.89 (s, 3H), 1.06-0.96 (m, 10H) ;
322
ESI MS m/z 438 [C22H29F2N3O2S + H]+; HPLC (Method E) 98.1% (AUC),
tR = 11.45 min. Anal. Calcd for C22H29F2N3O2S: C, 60.39; H,
6.68; N, 9.60. Found: C, 60.10; H, 6.73; N, 9.57.
G. Synthesis of Compound (47)
Step 1: To a stirred solution of neo-pentyl zinc bromide
(20.93 mL, 0.5 M in diethyl ether, 10.47 mmol), prepared as
describe previously, was added zinc chloride (20.93 mL, 0.5 M
in diethyl ether, 10.47 mmol). The reaction mixture was
stirred for 1 h then Pd(dppf)Cl2 (285 mg, 0.349 mmol) was
added. The reaction mixture was stirred for 5 min then
bromide 44 (750 mg, 3.49 mmol) was added and the reaction
mixture was stirred overnight. The reaction mixture was
partitioned between ethyl acetate and saturated ammonium
chloride. The organic layer was dried (sodium sulfate),
filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (silica, 5:1
hexanes/ethyl acetate) gave alcohol 45 (590 mg, 74%) as a
yellow oil: 1H NMR (300 MHz, CDCl3) d 7.31 (d, J = 7.2 Hz, 1H),
7.25 (obs m, 2H), 6.98 (d, J = 7.2 Hz, 1H), 2.51 (s, 2H), 1.58
(s, 6H), 0.90 (s, 9H).
Step 2: To an ice-cold solution of alcohol 45 (590 mg,
2.60 mmol) and sodium azide (3 3 8 mg, 5.2 0 mmol) in methylene
chloride (12 mL) was added trifluoroacetic acid (2.37 g, 20.80
mmol) in methylene chloride (5 mL) over 1 h. The reaction
mixture was treated with water (3 mL) followed by 1:1
water/concentrated ammonium hydroxide (6 mL) and then diluted
with ethyl acetate. The organic layer was dried (sodium
sulfate), filtered, and concentrated under reduced pressure.
Purification by flash column chrornatography (silica, 9:1
hexanes/ethyl acetate) gave an azide (420 mg, 70%) as a yellow
oil: 1H NMR (300 MHz, CDC13) D 7.27 (obs m, 2H), 7.21-6.98 (m,
2H), 2.53 (s, 2H), 1.63 (s, 6H), 0.91 (s, 9H).
Step 3: A mixture of azide from step 2 (420 mg, 1.82
mmol) and 10% Pd/C was shaken under an atmosphere of hydrogen
for 5 h at 45 psi. The reaction mixture was filtered through
diatomaceous earth and concentrated under reduced pressure to
give amine 46 (340 mg, 91%) as a yellow oil. This amine was
used without any further purification or characterization.
Step 4: A mixture of amine 46 (340 mg, 1.66 mmol) and
Example 134 (496 mg, 1.66mmol) was heated to 60 °C overnight.
The reaction mixture was cooled to room temperature and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, 97:3:1 methylene
chloride/methanol/concentrated ammonium hydroxide) gave an
amine (350 mg, 42%) as a white foam: 1H NMR (300 MHz, CDCl3) d
7.24-7.11 (m, 4H), 6.85-6.79 (m, 3H), 4.52 (m, 1H), 3.74 (m,
1H), 3.36 (m, 1H), 2.84 (m, 1H), 2.48 (m, 3H), 1.82 (m, 1H),
1.53 (s, 5H), 1.36 (s, 9H), 0.91 (d, J = 7.2 Hz, 9H).
Step 5: To a stirred solution of the amine from step 4
(350 mg, 0.694 mmol) in dioxane (3 mL) was added hydrochloric
acid (0.69 mL, 4 N in dioxane, 2.78 mmol). The reaction
mixture was stirred for 72 h and then concentrated under
reduced pressure to give the hydrochloride salt (3 70 mg,
quantitative), which was used without any further purification
or characterization.
Step 6: To a stirred mixture of the salt from step 5 (150
mg, 0.32 mmol) and triethylamine (144 mg, 1.43 mmol) in
methylene chloride (5 mL) was added l-acetylimidazole (35 mg,
0.32 mmol). The reaction mixture was stirred overnight and
then partitioned between methylene chloride and water. The
organic layer was dried (sodium sulfate), filtered, and
concentrated under reduced pressure. Purification by flash
column. chromatography (silica, 9.5:1:1 methylene
chloride/methanol/concentrated ammonium hydroxide) gave a
white solid. The solid was dissolved in methanol (1 mL) and
hydrochloric acid (1 mL, 1 N in diethyl ether, 1 mmol) was
added. The resulting solution was concentrated under reduced
pressure to provide ALB 16810 (47, 80 mg, 52%) as a white
solid: IR (ATR) 3253, 2953, 1725, 1622 cm-1; 1H NMR (300 MHz,
DMS0-d6) d 9.35 (br s, 1H), 9.01 (br s, 1H), 7.92 (d, J = 7.4
Hz, 1H), 7.39-7.29 (m, 3H), 7.17 (d, J = 7.4 Hz, 1H), 7.01-
6.97 (m, 1H), 6.91-6.84 (m, 2H), 5.82 (d, J = 5.9 Hz, 1H),
3.82-3.67 (m, 2H), 2.98 (m, 1H), 2.65 (m, 1H), 2.49 (d, J =
7.2 Hz, 2H), 2.48 (m, 2H), 1.87 (m, 1H), 1.74 (s, 6H), 1.61
(s, 3H), 0.86 (s, 9H) ; ESI MS m/z 447 [C26H36F2N2O2 + H]+; HPLC
(Method B),>99% (AUC), tR = 8.92 min.
H. Synthesis of Compound (158)
Step 1: To an ice-cold, stirred solution of ester 155
(4.64 g, 21. 57 mmol) in tetrahydrofuran (100 mL) was added
methylmagnesium bromide (25.16 mL,. 3.0 M solution in diethyl
ether, 75.48 mmol). The reaction mixture was warmed to room
temperature and stirred overnight. The reaction mixture was
quenched by the addition of saturated ammonium chloride and
diluted with diethyl ether. The organic layer was dried
(sodium sulfate), filtered, and concentrated under reduced
pressure. Purification by flash column chromatography
(silica, 6:1 hexanes/ethyl acetate) gave an alcohol (3.72 g,
90%) as a clear oil: 1H NMR (300 MHz, CDC13) d 7.67 (s, 1H),
7.38 (d, J = 8.7 Hz, 2H), 7.21 (m, 1H), 1.57 (s, 6H).
Step 2: A mixture of the alcohol from step 1 (1.68 g,
7.82 mmol), 2-methylpropylboronic acid (1.19 g, 11.73 mmol),
and sodium carbonate (13.69 mL, 2 M aq, 27.38 mmol) was
degassed- with nitrogen for 2 0 min.
Tetrakis(triphenylphosphine)palladium(O) (450 mg, 0.391 mmol)
was added and the reaction mixture was heated at reflux
overnight. The reaction mixture was cooled to room
temperature, filtered through diatomaceous earth, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, 4:1 hexanes/ethyl acetate) gave
alcohol 156 (1.11 g, 74%) as a clear oil: 1H NMR (300 MHz,
CDCI3) d 7.28-7.24 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 2.48 (d,
JT = 6.1 Hz, 2H), 1.84 (m, 1H), 1.58 (s, 6H), 0.92 (d, J = 7.1
Hz, 3H).
Step 3: To an ice-cold, stirred solution of alcohol 156
(360 mg, 1.87 mol) and sodium azide (244 mg, 3.75 mmol) in
methylene chloride (10 mL) was added trifluoroacetic acid
(1,71 g, 14. 96 mmol) in methylene chloride (3 mL) dropwise
over 1 h. The reaction mixture was treated with water (2 mL)
and 1:1 concentrated ammonium hydroxide/water (4 mL) after 1
h. The reaction mixture was diluted with diethyl ether, the
organic layer was dried (sodium sulfate), filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, hexanes) gave an azide (340 mg,
84%) as a clear oil: 1H NMR (300 MHz, CDC13) d 7.28-7.24 (m,
4H), 2.50 (d, J= 6.1 Hz, 2H), 1.84 (m, 1H), 1.63 (s, 6H),
0.92 (d, J = 7.1 Hz, 3H).
Step 4: A mixture of the azide from step 3 (340 mg, 1.57
mmol) and 10% Pd/C was shaken under an atmosphere of hydrogen
for 2 h at 50 psi. The reaction mixture was filtered through
diatomaceous earth and concentrated under reduced pressure to
give amine 157 (300 mg, quantitative) as a yellow oil: 1H NMR
(300 MHz, CDC13) d 7.28-7.24 (m, 4H), 2.49 (d, J = S.I Hz, 2H),
1.84 (m, 1H), 1.58 (s, 6H), 0.92 (d, J = 7.1 Hz, 3H).
Step 5: A mixture of amine 157 (150 mg, 0.79 mmol) and
Example 134 (215 mg, 0.79 mmol) in 2-propanol (5 mL) was
heated at reflux overnight. The reaction mixture was cooled
to room temperature and concentrated under reduced pressure.
The crude residue was partitioned between methylene chloride
and 1 N hydrochloric acid. The organic layer was dried
(sodium sulfate), filtered, and concentrated under reduced
pressure. Purification by flash column chromatography (8:1
methylene chloride/methanol) gave an alcohol (144 mg, 37%) as
a white foam: 1H NMR (300 MHz, CDC13) d 7.27-7. LI (m, 4H),
6.89-6.77 (m, 3H), 4.55 (m, 1H), 3.78 (m, 1H), 3.36 (m, 1H),
2.84 (m, 1H), 2.48 (m, 3H), 1.82 (m, 1H), 1.53 (s, 5H), 1.36
(s, 9H), 0.91 (d, J = 7.2 Hz, 3H).
Step 6: A mixture of the alcohol from step 5 (144 mg,
0.29- mmol) and hydrochloric acid (2.20 mL, 4 N solution in
dioxane, 8.81 mmol) in dioxane (1 mL) was stirred overnight.
The reaction mixture was concentrated under reduced pressure
to give a dihydrochloride salt (13 6 mg, quantitative) as a
white foam: 1H NMR (300 MHz, DMSO-d6) 5 9.91 (br s, 1H), 9.36
(br s, 1H), 8.11 (br s, 4H), 7.54-6.98 (m, 7H), 6.28 (m, 1H),
4.12 (br s, 1H), 3.10-2.74 (m, 4H), 2.47 (d, J = 6.8 Hz, 2H),
1.91 (m, 1H), 1.72 (s, 6H), 0.87 (d, J = 7.1 Hz, 6H).
Step 7: To a stirred mixture of the salt from step 6 (136
mg, 0.29 mmol) and triethylamine (135 mg, 1.33 mmol) in
methylene chloride (5 mL) was added 1-acetylimidazole (33 mg,
0.29 mmol). The reaction mixture was stirred overnight and
then partitioned between methylene chloride and water. The
organic layer was dried (sodium sulfate), filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (silica, 9.5:1:1 methylene
chloride/methanol/concentrated ammonium hydroxide) gave a
white solid. The solid was dissolved in methanol (1 mL) and
hydrochloric acid (1 mL, 1 N in diethyl ether, 1 mmol). was
added. The resulting solution was concentrated under reduced
pressure to provide compound (158) (85 mg, 61%) as a white
solid: 1H NMR (300 MHz, DMSO-d6) 5 9.45 (br s, 1H), 9.03 (br s,
1H), 7.95 (d, J = 7.4 Hz, 1H), 7.41-7.35 (m, 3H), 7.19 (d, J =
7.4 Hz, 1H), 7.01-6.97 (m, 1H), 6.91-6.84 {m, 2H), 5.82 (d, J
= 5.9 Hz, 1H), 3.82-3.67 (m, 2H), 2.98 (m, 1H), 2.65 (m, 1H),
2.49 (d, J = 7.2 Hz, 2H), 2.48 (m, 2H), 1.87 (m, 1H), 1.74 (s,
6H), 1.61 (s, 3H), 0.86 (d, J = 6.5 Hz, 3H; ; ESI MS m/z 433
[C25H344F2N2O2 + H]+; HPLC (Method A) >99% (AUC), tR = 10.45 min.
Example 115: The invention further comprises indole and
fluorene compounds, such as the compounds contained in Tables
YY and ZZ.
Examples 116-118: The general Scheme below can be used
to synthesize the compounds disclosed and described in
Examples 116-118 and is not limiting to the scope of the
invention.
EXAMPLE 116. Synthesis of N-[(2S, 2R)-3-((1S)-5-Butyl-7-
ethyl-1,2,3,4-tetrahydro-naphthalen-l-ylamino)-1-(3,5-
difluorobenzyl)-2-hydroxy-propyl]-acetamide
A. Preparation of [(1S, 2R)-3-((1S)-5-Bromo-7-ethyl-l,2, 3,4-
tetrahydro-naphthalen-1-ylamino)-1-(3,5-difluoro-benzyl)-2-
hydroxypropyl]-carbamic acid tert-butyl ester 3
A solution of N-BOC-epoxide 1 (869mg, 2.91mmol) and the
bromo-substituted 1-amino-tetrahydronapthalene 2 (783 mg, 2.91
mmol) in 10 mL isopropanol, is heated to 8 0°C for 6 hours.
After completion of the reaction, the mixture is cooled and
product 3 crystallizes from the crude solution, and collected
by filtration. The crystals are washed with cold ethanol.
After vacuum is applied to remove traces of volatiles, the
reaction yields about 995 mg of 3 ([M+H]+ =552.8).
B. Preparation of (3S, 2R)-3-Amino-l-((lS)-5-bromo-7-ethyl-
1,2,3,4-tetrahydro-naphthalen-l-ylamino)-4-(3,5-difluoro-
phenyl)-butan-2-ol 4
Compound 3 (995 mg) is dissolved in 10 mL of anhydrous
CH2C12 followed by the addition of 10 mL of trifluoroacetic
acid (anhydrous). The solution stands for 90 min. then the
volatiles are removed with a stream of nitrogen. The compound
is desalted by extraction between ethyl acetate, l0mL, and
saturated aqueous sodium bicarbonate, 20 mL. The ethyl
acetate phase is washed a second time with saturated sodium
bicarbonate. The organic phase is then dried with MgSO4
(anhydrous), filtered, and.evaporated of volatiles yielding
865 mg of 4 ([M+H]+ =452.8).
C. Preparation of N-[(IS, 2R)-3-((IS)-5-Bromo-7-ethyl-
1,2,3,4-tetrahydro-naphthalen-l-ylamino)-1-(3, 5-
difluorobenzyl)-2-hydroxypropyl]-acetamide 5
To a solution of diamine 4 (350 mg, 0.77 mmol) in 5 mL
anhydrous CH2C12, is added HOBt (125mg, 0.93mmol), N-methyl-
morpholine (0.17mL, 1.55mmol), and glacial acetic acid
(46.4mg, 0.773).
This solution is cooled to 0°C via ice bath and then solid
EDC-HCl (1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride, 163 mg, 0.85 mmol) and a stir bar was added.
The reaction is stirred at 0°C for 12 hours. After the warming
to room temperature, the solvent is removed with a stream of
N2, and the residue washed between ethyl acetate and aqueous
saturated sodium bicarbonate. The ethyl acetate phase is
dried with MgSO4 (anhydrous), filtered then removed of solvent
by rotory evaporation and high vacuum to yield 2 95mg of
compound 5 ([M+H]+ =494.8).
D. Preparation of [(3S, 2R)-3-Acetylamino-4-(3,5-
difluorophenyl)-2-hydroxybutyl]-((1S)-5-bromo-7-ethyl-l,2,3,4-
tetrahydronaphthalen-1-yl)-carbamic acid tert-butyl ester 6
To a solution of amine 5 (295 mg, 0.6 mmol) in 5 mL
anhydrous THF is added N, N'-diisopropylethylamine (0.35 mL,
1.2 mmol) and di-t-butyl dicarbonate (145 mg, 0.66 mmol). The
solution is stirred overnight followed by solvent removal with
stream of nitrogen. The product is isolated by first washing
the residue between ethyl acetate (10 mL) and 1N sodium
bisulfate (20 mL). The ethyl acetate layer was then washed
against aqueous saturated sodium bicarbonate (2 0 mL). The
ethyl acetate layer was dried with MgSO4 (anhydrous), filtered
then removed of solvent by rotory evaporation and high vacuum
to yield 354.4 mg of 6 ( [M+H] + =594.5).
E. Preparation of [(1S, 2R)-3-Acetylamino-2-(tert-butyl-
dimethyl-silanyloxy)-4-(3,5-difluorophenyl)-butyl]-((1S)-5-
bromo-7-ethyl-l,2,3,4-tetrahydro-naphthalen-l-yl)-carbamic
acid tert-butyl ester 7
To a solution of t-butyldimethylsilyl chloride (105 mg,
0.66 mmol) and imidazole (102 mg, 1.5 mmol) in anhydrous
dimethylformamide (3 mL) is added 6 (354 mg, 0.6 mmol) and the
solution allowed to stir at room temperature for 16 hrs. The
DMF is removed via rotory evaporation. The resulting residue
is dissolved in ethyl acetate and washed against 1N soduim
bisulfate and then saturated aqueous sodium bicarbonate. The
ethyl acetate phase is dried with solid MgSO4, filtered, and
evaporated of volatiles via rotory evaporation and high
vacuum. The product 7 gave M+H = 731.2, and was used in
palladium-catalysed couplings without further purification.
F. Preparation of [(1S, 2R)-3-Acetylamino-2-(tert-
butyldimethylsilanyloxy)-4-(3,5-difluorophenyl)-butyl]- ( (1S)-
5-butyl-7-ethyl-l,2,3,4-tetrahydro-naphthalen-l-yl)-carbamic
acid tert-butyl ester 8a
The following process is performed in a nitrogen-filled
glove box. To a solution of 7 (73 mg, 0.1 mmol) in 0.1 mL of
anhydrous THF is added a solution of Pd(0Ac)2 (2.25 mg, 0.01
mmol) and 2-(di-t-butylphosphino)biphenyl (5.9 mg, 0.01 mmol)
in 0.1 mL of anhydrous THF. The reaction is started by
addition of butylzinc bromide (0.5M in THF, 0.5 mL, 0.25
mmol). The reaction is stirred for 16 hrs, after which the
solvent is removed with a stream of nitrogen, and the residue
is redissolved in methanol (lmL) for purification by reversed
phase HPLC. The butylated product 8a ( [M+H]+ = 709.1) is
obtained as an oil after evaporation of solvent (rotory
evaporation and high vacuum).
G. Preparation of N-[(1S, 2R)-3-((IS)-5-Butyl-7-ethyl-
1,2,3,4-tetrahydro-naphthalen-l-ylamino)-1-(3,5-
difluorobenzyl)-2-hydroxypropyl]-acetamide 9a
To a solution of 8a in 1 mL of CH2Cl2 is added imL of
anhydrous trifluoroacetic acid. After 1 hr, the volatiles are
removed with a stream of N2 followed by high vacuum to yield 9a
([M+H]+ = 472.8).
EXAMPLE 117. General procedure for the preparation of
compounds 9
Compounds 8 were prepared from compounds 7 according to
the procedure for preparing 8a (G above), except that the
butylzinc bromide used in the preparation of 8a was replaced
with other zinc reagents as noted in Table 117.A. The
protecting groups were removed from the intermediate compounds
8 as described for the preparation of 9a from 8a.
EXAMPLE 118.
General scheme 118 represents a synthetic route that can
be used to synthesize Compound 15.
Scheme 118
A. Preparation of [(1S, 2R) -3-(3,4-Dibromobenzylamino)-1-
(3,5-difluorobenzyl)-2-hydroxypropyl] carbamic acid tert-butyl
ester 12
Commercially available 3,4-dibromobenzaldehyde (250mg,
0.95 mmol) and N-BOC-diamine 10 (250 mg, 0.79 mmol), are
dissolved together in 10 mL of 10% acetic acid in THF. After
the solution was allowed to stand at room temperature for 3 0
min., 1. 7g (~3.8mmol) of MP-cyanoborohydride (a macroporous
triethylammonium methylpolystyrene cyanoborohydride, Argonaut
Corporation) is added. The suspension is agitated for 3 h.
using an orbit shaker (J-Kem), after which the suspension is
filtered, and the solvent is removed by rotory evaporation.
The residue is dissolved in methanol and divided into 10
aliquots for fractionation by reversed phase HPLC. Fractions
containing pure compound 12 are combined and stripped of
volatiles by rotory evaporation and/or vacuum application.
Mass spectrometry of the final product 12 gave [M+H]+ = 564.7.
B. Preparation of (3S,2R) -3-Amino-l-(3,4-dibromo-
benzylamino)-4-(3,5-difluorophenyl)-butan-2-ol 13
Compound 13 was be prepared from compound 12 using the
procedure described above for the preparation of 4 from 3.
Mass spectral analysis gave m/z = 464.8.
C. Preparation of N-[(1S,2R)-3-(3,4-Dibromobenzylamino)-1-
(3,5-difluorobenzyl)-2-hydroxy-propyl]-acetamide 14
Compound 14 was prepared from compound 13 using the
procedure described above for the preparation of 5 from 4.
Mass spectral analysis gave m/z = 506.8
D. Preparation of N-[(1S,2R)-1-(3,5-Difluorobenzyl)-3-(3,4-
dipropylbenzylamino)-2-hydroxypropyl]-acetamide 15
Preparation of 15 from 14 was performed using the procedure
described above for the preparation of 8a from 7 except that
propylzinc bromide is used instead of the butylzinc bromide.
Mass spectral analysis of the product 13 gave [M+H]+ = 432.9).
EXAMPLE 119
The compounds of the invention that comprise cyclohexyl
moieties can be synthesized according the following general
Scheme 119.
A. N-(1S, 2R)-(1-(3,5-Difluoro-benzyl)-2-hydroxy-3-{l-[3-(4-
methyl-thiophen-2-yl)-phenyl]-cyclohexylamino}-propyl)-
acetamide
Palladium acetate (Pd(OAc)2) (0.82 mgs, 10 mol. Wt. %) and
Biphenyl-2-yl-di-tert-butyl-phosphane (2.16 mgs, 20 mol. Wt.
%) was added to the reaction vessel (Vessel 1). N-(1S, 2R) -
[3-[1-(3-Bromo -phenyl)-cyclohexylamino]-1-(3,5-difluoro-
benzyl)-2-hydroxy-propyl]-acetamide (0.09075 mM) was placed in
a separate reaction vessel (Vessel 2) and dissolved in 200 mL
DME. 4-Methylthiophene-2-boronic acid and Potassium Fluoride
(KF) (3 eq., 6.33 mgs) were added to a separate reaction
vessel and dissolved in 200 µL DME (Vessel 3). Solvents in
Vessels 2 and 3 were added to Vessel 1 under nitrogen. Vessel
1 was stirred over night at room temperature. Reaction was
then concentrated down by vacuum. Crude material purified by
Prep-HPLC. Product fractions collected and concentrated down
by vacuum. MS (ESI + ) for C29H34F2N2O2S m/z 513.0 (M+H) +
B. Additional Compounds.
All compounds in Table 119.A are synthesized according to
the same procedure as that used for synthesizing N-{1S,2R)-(1-
(3,5-Difluoro-benzyl)-2-hydroxy-3-{l-[3-(4-methyl-thiophen-2-
yl)-phenyl]-cyclohexylaminoj-propyl)-acetamide; however in
place of 4-methylthiophene-2-boronic acid, the reagents listed
next to the final products can be used.
Example 12 0.
A. Step 1. 5-Bromo-2-iodobenzamide
To 5-bromo-2-iodobenzoic acid (20g, 61.2 mmol) in 1:1
mixture of dichloromethane and dimethylformamide (200 mL) was
added HATU (25g, 65.8 mmol), and the solution s.tirred 2 min.
Excess ammonium chloride (20 g) was added, and the
heterogeneous mixture was stirred 1 h. Ammonium hydroxide (20
mL) was added causing a white precipitate. The precipitate
was filtered and washed with ethyl acetate. The solution was
diluted with ethyl acetate, washed with water, 1 N
hydrochloric acid, saturated sodium bicarbonate, and saturated
sodium chloride, dried (magnesium sulfate), filtered, and
concentrated under reduced pressure resulting in the formation
of a white precipitate. The solid was filtered to provide the
title compound (14.4 g). ESI MS ml z 327.0 [M + H]+.
Step 2. (4-Bromo-1,1' -biphenyl-2-yl)methylamine
To a stirred solution of 5-bromo-2-iodobenzamide (14.1 g,
43.3 mmol), phenyl boronic acid (5.3 g, 43.3 mmol), and
potassium carbonate (24.4 g, 176.8 mmol) in dimethylformamide
(sparged with nitrogen, 100 mL), was added palladium(0)
tetrakis(triphenylphosphine) (2.6 g, 2.2 mmol). The reaction
was refluxed overnight under N2. The brown solution was cooled
and filtered through Celite. The solution was diluted in
ethyl acetate and water, and then partitioned. The organic
layer was washed with water, 1 N hydrochloric acid, saturated
sodium bicarbonate, and saturated sodium chloride, dried
(magnesium sulfate), filtered, and concentrated under reduced
pressure to a tar. Flash chromatography (silica, 50% ethyl
acetate/hexane) gave a tan solid (2.4 g). The biphenyl amide
was dissolved in tetrahydrofuran (2 0 mL), and BH3-THF (1N, 2 0
mL, 20 mmol) was added slowly. The reaction was refluxed
overnight under N2. The reaction was cooled to 0°C and
quenched with ethyl acetate resulting in gas evolution. After
gas evolution ceased, the. organics were washed with water,
saturated sodium bicarbonate, saturated sodium chloride, dried
(sodium sulfate), filtered, and concentrated to give the title
compound as a gray semi-solid (2.4 g).. ESI MS m/z 262.0/264.0
[M + H]+.
Step 3. N-[(1S,2R)-3-{[(4-Bromo-l,1'-biphenyl-2-
yDmethyl]amino}-l-(3,5-dif luorobenzyl)-2-
hydroxypropyl] acetamide
To solution of (4-bromc-l,1'-biphenyl-2-yl)methylamine
(2.4 g, 9.2 mmol) in isopropanol (50 mL) was added Example
134 (1.8 g, 6.1 mmol), and the reaction was refluxed 2 h. The
solution was concentrated, and the residue was redissolved in
ethyl acetate, washed with 1 N hydrochloric acid and saturated
sodium chloride, dried (sodium sulfate), filtered, and
concentrated under reduced pressure. The residue (3.3 g) was
redissolved in methanol, and 4 N hydrochloric acid in dioxane
(5 mL) was added. The reaction stirred 30 min, then
concentrated to a tan foam (3.1 g). The salt was dissolved in
dichloromethane (25 mL) and diisopropylethylamine (4 mL, 23
mmol), then acetylimidazole (636 mg, 5.8 mmol) was added. The
reaction stirred overnight at room temperature. The organics
were washed with water, 1N hydrochloric acid, saturated sodium
bicarbonate, and. saturated sodium chloride, dried (sodium
sulfate), filtered, and concentrated under reduced pressure.
Purification by flash chromatography. (silica, 10%
methanol/dichloromethane) provided the title compound (550
mg). ESI MS ml z 504.3 [M + H]+. A small amount of the product
was dissolved in ether, precipitated with excess IN HCl in
ether, and concentrated to provide the mono-HCl salt.
B. Step 1. N-[(1S,2R)-3-{[(4-Acetyl-l,1'-biphenyl-2-
yl)methyl] amino}-l-(3,5-difluorobenzyl)-2-hydroxypropyl]
acetamide hydrochloride
To N-E(1S,2R)-3-{[(4-bromo-l,l'-biphenyl-2-
yl)methyl]amino}-l-(3,5-difluorobenzyl)-2-hydroxypropyl]
acetamide (120 mg, 0.24 mmol) in toluene (1 mL) was added
tributyl(1-ethoxyvinyl) tin (100 µL, 0.28 mmol) and bis-
triphenylphoshine palladium(II) dichloride (10 mg, 0.012
mmol), and the reaction was heated at 100°C 3 h under N2. The
solution was cooled to room temperature, IN hydrochloric acid
(1 mL) was added, and the mixture was stirred 20 min. The
mixture was partitioned, and the organics were washed with
saturated potassium fluoride (aq). The reaction mixture was
dried (sodium sulfate), filtered, and concentrated under
reduced pressure. Purification by flash column chromatography
(silica gel, 8% methanol/methylene chloride) provided an oil.
The residue was dissolved in ether, precipitated with excess
IN HC1 in ether, and concentrated to provide the title
compound (11 mg). ESI MS m/z 467.28 [M + H]+.
C. N-[(1S,2R)-3-{ [(4-sec-Butyl-l,l'-biphenyl-2-
yl)methyl]amino}-l-(3,5-difluorobenzyl)-2-hydroxypropyl]
acetamide
To N-[(1S,2R) -3-{[(4-bromo-l,1'-biphen.yl-2-
yl)methyl] amino}-1-(3, 5-difluorobenzyl) -2-hydroxypropyl]
acetamide (150 mg, 0.3 mmol) in THF (2 mL) was added 2M
potassium phosphate (0.65 mmol), tri-sec butylborane (1M in
THF, 330 µL, 0.33 mmol), and bis-triphenylphoshine
palladium(II) dichloride (3 mg, 0.003 mmol), and the reaction
was heated at reflux for 2 days. Tri-sec butylborane (1M in
THF, 1.2 mL, 1.2 mmol) was added, then bis-triphenylphoshine
palladium(II) dichloride (10 mg, 0.012 mmol), and the reaction
was refluxed 16 h. The solution is diluted in ethyl acetate
and washed with water, 1N hydrochloric acid, saturated sodium
bicarbonate, and saturated sodium chloride. The: organic layer
was dried over sodium sulfate, filtered and concentrated under
reduced pressure. Flash chromatography (7%
methanol/dichloromethane) gave the title compound. MS (ESI)
[M+H+] = 481.34.
D. Step 1. 4-Neopentyl-l, I1 -biphenyl-2-carboxamide
To methyl 5-bromo--2-iodobenzoate (4.41 g, 13 mmol),
phenylboronic acid (1.6 g, 13 mmol), potassium carbonate (3.6
g, 26 mmol), and cesium carbonate (4.2 g, 13 mmol) in DMF (50
mL, sparged with nitrogen) was added palladium(0)
tetrakis(triphenylphosphine) (751 mg, 0.65 mmol). The
reaction was refluxed 16 h, cooled and washed with water, 1N
hydrochloric acid, saturated sodium bicarbonate, and saturated
sodium chloride. The organic layer was dried over sodium
sulfate, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography (5% ethyl
acetate/hexane) to yield methyl 4-bromo-l,1'-biphenyl-2-
carboxylate (1.3 g). To methyl 4-bromo-l,1'-biphenyl-2-
carboxylate (500 mg, 1.72 mmol) and Pd(dppf)Cl2-CH2Cl2 (70 mg,
0.086 mmol) in THF (5 mL) was added 1M neopentyl magnesium
chloride (5 mL, 5 mmol) slowly at room temperature. The
reaction was stirred overnight and then quenched with water.
The reaction was diluted in ethyl acetate, and the resulting
brown solid was filtered away. The organic layer was washed
with water, 1N hydrochloric acid, saturated sodium
bicarbonate, and saturated sodium chloride. The organic layer
was dried over sodium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by flash
chromatography (1% ethyl acetate/hexane) to yield a yellow
solid (200 mg).
The solid was redissolved in 2:1:1 THF/methanol/water (8
mL) and lithium hydroxide monohydrate (60 mg, 1.4 mmol) was
added. The reaction stirred 6 days, and the solution was
concentrated to dryness. (An addition 1.7 g 4-bromo-l,1'-
biphenyl-2-carboxylate was used to prepare a combined total of
1. 8g residue from hydrolysis). The pooled lots were
redissolved in DMF (10 mL), and diisopropylethylamine (3.7 mL,
21 mmol), HATU (4 g, 10.2 mmol), and ammonium chloride (5 g)
were added. The reaction was stirred 1 h. Ammonium hydroxide
was added causing a white precipitate. The liquid was diluted
in ethyl acetate and was washed with water, 1N hydrochloric
acid, saturated sodium bicarbonate, and saturated sodium
chloride. The organic layer was dried over sodium sulfate,
filtered and concentrated under reduced pressure to a black
oil. The residue was purified by flash chromatography (60%
ethyl acetate/hexane) to yield the title compound as a tan
solid (210 mg). ESI MS m/z 268 [M + H]+.
Step 2. (4-Neopentyl-l,1'-biphenyl-2-yl)methylamine
To borane-THF (1M, 1.7 mL, 1.7 mmol) was added 4-
neopentyl-1,1'-biphenyl-2-carboxamide (200 mg, 0.75 mmol), and
the reaction stirred at reflux 16 h. The solution was cooled
and quenched with 1N HC1. The solution was basified with
saturated sodium bicarbonate, and the product was extracted
into ethyl acetate. The organics were washed with saturated
sodium chloride, dried (sodium sulfate), filtered, and
concentrated in vacuo to give the title compound as an oil
(200 mg). ESI MS m/z 254.22 [M + H]+.
Step 3. N-((1S,2R)-1-(3,5-Diflucrobenzyl)-2-hydroxy-3-
{[(4-neopentyl-1,1'-biphenyl-2-
yl) methyl]amino}propyl) acetamide hydrochloride
To solution of (4-Neopentyl-1,1'-biphenyl-2-
yl)methylamine (200 mg, 0.8 mmol) in isopropanol (5 mL) was
added Example 134 (120 mg, 0.4 mmol), and the reaction was
refluxed 2 h. The solution was concentrated, and the residue
was dissolved in ethyl acetate, washed with 1 N hydrochloric
acid and saturated sodium chloride, dried (sodium sulfate),
filtered, and concentrated under reduced pressure. The
residue was dissolved in methanol, and 4 N hydrochloric acid
in dioxane (5 mL) was added. The reaction stirred 30 min,
then concentrated to a white foam (100 mg). The salt was
dissolved in dichloromethane (2 mL) and diisopropylethylamine
(100 µL, 0.5 mmol), then acetylimidazole (30 mg, 0.3 mmol) was
added. The reaction stirred 1 h at room temperature. The
organics were washed with water, 1N hydrochloric acid,
saturated sodium bicarbonate, and saturated sodium chloride.
dried (sodium sulfate), filtered, and concentrated under
reduced pressure. Purification by flash chromatography
(silica, 8% methanol/dichloromethane) provided the title
compound (60 mg) in crude form. The material was purified by
preparative RP-HPLC to give the desired compound. The
product was dissolved in ether, precipitated with excess 1N
HC1 in ether, and concentrated to provide the mono-HCl salt (6
mg). ESI MS m/z 4 95 [M + H]+.
E. Step 1. 2-Fluoro-5-isobutyl-benzonitrile
To 5-bromo-2-fluorobenzonitrile (2.3 g, 11.7 mmol) in THF
(5 mL) was added 0.5 M isobutylzinc bromide (70 mL, 35 mmol),
then Pd(dppf)Cl2 (955 mg, 1.17 mmol), and the reaction was
stirred 16 h at room temperature under N2. The reaction was
quenched with excess aqueous hydrochloric acid (1N). Ethyl
acetate was added, and the solution was partitioned. The
organic layer was washed with saturated sodium chloride.
Plash chromatography (silica, 4% ethyl acetate/ hexane)
yielded a colorless oil (1.3 g).
Step 2
i
To (product from step 1) (230 mg, 1.3 mmol) in THF (2 mL)
was added borane-THF (1M, 3 mL, 3 mmol) slowly at 0°C. The
reaction was stirred 16 h at room temperature. The solution
was cooled and quenched with 1N HC1. The solution was
basified with saturated sodium bicarbonate, and the product
was extracted into ethyl acetate. The organics were washed
with saturated sodium chloride, dried (sodium sulfate),
filtered, and concentrated in vacuo to give an oil. The
residue was dissolved in isopropanol (2 mL), Example 134 (120
mg, 0.4 mmol) was added, and the reaction was refluxed 3 h. 4
N hydrochloric acid in dioxane (5 mL) was added, and the
reaction stirred 1.5 h, then concentrated to a white foam.
The residue was dissolved in dichloromethane (5 mL) and
diisopropylethylamine (678 µL, 3.9 mmol), then acetylimidazole
(66 mg, 0.6 mmol) was added. The reaction stirred 30 min at
room temperature. Additional acetylimidazole (30 mg, 0.3
mmol) was added. The organics were washed with water,
saturated sodium bicarbonate, and saturated sodium chloride,
dried (sodium sulfate), filtered, and concentrated under
reduced pressure. Purification by flash chromatography
(silica, 8% metlianol/dichloromethane) provided the title
compound as a white solid (89 mg). ESI MS m/z 423 [M + H]+.
F. N-[(1S,2R)-1-(3,5-Difluorobenzyl)-2-hydroxy-3-({2-[(2-
hydroxyethyl)amino]-5-isobutylbenzyl}amino)propyl]acetamide
2-Fluoro-5-isobutyl-benzonitrile (533 g, 3 mmol) in
ethanolamine (5 mL) was heated at 100°C 2 h in a sealed tube.
The reaction was diluted in ethyl acetate, and the organic
layer was washed with water and saturated sodium chloride.
The solution was dried (sodium sulfate), filtered, and
concentrated to an oil. The residue was redissolved in THF (3
mL), and this solution was added to borane-THF (9 mL) at 0°C.
The reaction was stirred at room temperature 16 h. The
solution was poured onto ice, and ethyl acetate was added.
The organic was partitioned, washed with saturated sodium
chloride, dried (sodium sulfate), filtered, and concentrated
to an oil (220 mg). The residue was dissolved in isopropanol
(5 mL), 2-Fluoro-5-isobutyl-benzonitrile (160 mg, 0.5 mmol)
was added, and the reaction was refluxed 2 h. The reaction
was cooled and concentrated. Flash chromatography (silica, 8%
methanol/dichloromethane) yielded an oil (108 mg). The
residue was treated with 4 N hydrochloric acid in dioxane (5
mL), and the reaction stirred 1 h, then concentrated to a
white solid. The residue was dissolved in dichloromethane (5
mL) and diisopropylethylamine (108 µL, 0.6 mmol), then
acetyliraidazole (44 mg, 0.4 mmol) was added. The reaction
stirred 30 min at room temperature. The organics were washed
with water, saturated sodium bicarbonate, and saturated sodium
chloride, dried (sodium sulfate), filtered, and concentrated
under reduced pressure. Purification by flash chromatography
(silica, 8% methanol/dichloromethane) provided the title
compound as an oil (18 mg). ESI MS mlz 464.34 [M + H]+.
EXAMPLE 122. Synthesis of N-(1S, 2R)-{1-(3,5-Difluoro-benzyl) -
3-[3-(2,2-dimethyl-propyl)-benzylamino]-2-hydroxy-propyl}-
acetamide
A. 3-Bromo-benzylamine
3-Bromo-benzylamine HC1 salt (0.75 g) was dissolved in 10
mL 15% IPA in CH2C12. 7 drops of 10N Sodium Hydroxide (NaOH)
was added and stirred for 3 minutes. To the reaction mixture,
5 mL of dH2O was added and stirred for 5 minutes. The IPA/
CH2C12 layer was extracted. The aqueous layer was rinsed with
10 mL 15% IPA in CH2C12. All organic layers were added
together and concentrated under vacuum. MS (ESI + ) for C7H8BrN
m/z 186.3 (M+H)+
{1S, 2R)-[2-(3,5-Difluoro-phenyl)-1-oxiranyl-ethyl]-
carbamic acid tert-butyl ester (0.32 g, 1.075 mM) was added to
a sealed tube along with 3-Bromo-benzylamine (0.2 g, 1.0 75
mM). 2 mL of IPA was added to the sealed tube. The reaction
mixture was stirred and heated at 80°C for 2 hours. Once the
reaction was complete, the reaction mixture was concentrated
down by vacuum. The product was then dissolved in 750 µL of
4N HC1 in dioxane. Reaction stood for 1 hour. The reaction
was then concentrated down by vacuum. MS (ESI + ) for
C17H19BrF2N2O m/z 387.1 (M+H)+
C. N-{1S,2R) - [3- (3-bromobenzylamino) -1-(3,5-difluorobenzyl) -
2-hydroxypropyl]acetamide
(1S, 2R) -3-Amino-l-(3-bromo-benzylamino)-4-(3,5-difluoro-
phenyl)-butan-2-ol (0.348 g, 0.9040 mM) was dissolved in 9 mL
of CH2C12. N-Methylmorpholine (NMM)(0.4114 g, 4.0679 mM) was
added to the reaction mixture. The reaction mixture was
cooled to 0°C and stirred for 15 minutes. Acetic acid (0.057
g, 0.9944 mM) was added slowly to reaction mixture and stirred
for 5 minutes. HOBt (0.134 g, 0.9944 mM) was then added, then
EDC (0.190 g, 0.9944 mM). The reaction mixture stirred at
room temperature for two days. Once reaction complete,
solvent was taken off by vacuum. The crude material was
purified on a Silica column using 10% Methanol in CH2C12. MS
(ESI + ) for C19H21BrF2N2O2 m/z 427.2 (M+H)+
D. {1S,2R)-[3-Acetylamino-4-(3,5-difluorophenyl)-2-
hydroxybutyl]-(3-bromobenzyl)-carbamic acid tert-butyl ester
N-(1s, 2r)-[3-(3-bromo-benzylamino)-1-(3,5-difluoro-
benzyl) -2-hydroxy-propyl]-acetamide (0.10 g, 0.234 mm) was
dissolved in ch2cl2 (2.3 ml, 0.1 m). Reaction cooled to 0°c.
Di-tert-butyl dicarbonate (boc2o) (0.051 g, 0.234 mm) was added
slowly to reaction. Allowed reaction to stir at room
temperature over night. The reaction was concentrated down by
vacuum. Ms (esi+) for c24h29brf2n2o4 m/z 529.1 (m+h)+
E. N- (ls,2r)-{l-(3,5-difluoro-benzyl)-3-[3-(2,2-dimethyl-
propyl)-benzylamino]-2-hydroxy-propyl}-acetamide
r
I-Iodo-2,2 dimethyl-propane (1.5 eg., 0.0579 g, 0.2926
mM) and Zinc metal (1.6 eq., 0.0204 g, 0.3122 mM) was added to
an oven dried sealed tube (with rubber septa for the top). 2
raL THF was added to the sealed tube. The reaction stirred for
30 minute's under nitrogen. l-Methyl-2-pyrrolidinone (dried
with Molecular Sieves) (0.43 mL) was added to the reaction
mixture. Bis(Tri-t-butylphosphine) Palladium [0] (0.15 eq.,
0.0149 g, 0.02926 mM) and N-(IS, 2R)-[3-Acetylamino-4-(3,5-
difluoro-phenyl)-2-hydroxy-butyl]-(3-bromo-benzyl)-carbamic
acid tert-butyl ester (0.1029 g, 0.1951 mM) was added to the
reaction mixture. The screw cap was added to the sealed tube.
The reaction was heated to 100°C over night. The reaction
mixture was then cooled to room temperature and transferred to
separatory funnel. The reaction mixture was diluted with 10
mL Ethyl Acetate. Organic layer washed once with 7 mL dH2O and
once with 7 mL Brine. Organic layer dried with Magnesium
Sulfate, filtered, and concentrated under vacuum. Product was
then dissolved in 500 µL 4N HC1 and stood for 1 hour.
Reaction concentrated down by vacuum and purified by Prep-
HPLC. MS (ESI + ) for C24H32F2N2O2 m/z 419.2 (M+H)+
Example 123: General synthesis for N-(1S, 2R)- [1-(3,5-
Difluoro-benzyl)-2-hydroxy-3-(1S)-(1,2,3,4-tetrahydro-
naphthalen-1-ylamino)-propyl]-acetamide
Example 124: General synthesis for N-(1S, 2R)-[l-(3,5-
Difluoro-benzyl)-3-((1S)-7-furan-3-yl-l,2,3,4-tetrahydro-
naphthalen-1-ylamino)-2-hydrcxy-propyl]-acetamide
3-Bromofuran (4.85 mgs, 0.033 mM) and Tetrakis(triphenyl-
phosphine) palladium [0] (3.81 mgs, 10. mol. wt %) was dissolve
in 300 µL 1,2-Dimethoxyethane (glyme) (DME). 99 µL 2M Na2CO3
in dH2O was added to the reaction mixture. N-{18, 2R)-[3-
Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-[7-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-(IS)-1,2,3,4-
tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester
(20.28 mgs, 0.033 mM) was added to the reaction mixture and
stirred at 90°C over night. The reaction mixture was
concentrated down under vacuum then dissolves in 1.5 mL
methanol. The reaction mixture was purified by Prep-HPLC.
The isolate product was concentrated down by vacuum. The
product was dissolved in 500 µL 4N HC1 in Dioxane and stood at
room temperature for 3 0 minutes. The reaction mixture was
then concentrated down by vacuum. MS (ESI + ) for C26H28F2N2O3 m/z
455.2 (M+H)+
All final compounds in Table 124.A can be synthesized
using the same procedure as that for N-(1S, 2R)-[1-(3,5-
Difluoro-benzyl)-3-((1S)-7-furan-3-yl-l,2,3,4-tetrahydro-
naphthalen-1-ylamino)-2-hydroxy-propyl]-acetamide; however in
place of 3-bromofuran, the reagents listed next to the final
products were used.
Example 125: Synthesis of N-(1S, 2R)-[1-(3,5-Difluoro-
benzyl)-2-hydroxy-3-(3-isopropenyl-benzylamino)-propyl]-
acetamide and
N-(1S,2R)-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(3-
isopropyl-benzylamino)-propyl]-acetamide
A. (1S,2R)-3-Amino-4-(3,5-difluoro-phenyl)-1-(3-isopropenyl-
benzylamino)-butan-2-ol
(1S,2R)-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(3-
isopropenyl-benzylamino)-propyl]-carbamic acid tert-butyl
ester was dissolved in 6 mL CH2Cl2 with 600 µL TFA. The
reaction mixture stirred for 4 hours at room temperature. 15
mL of 15% IPA in Chloroform was added to reaction mixture was
washed with 10 mL Saturated Sodium Bicarbonate (Sat. NaHCO3) in
dH2O. The Sat. NaHC03 in dH2O layer was rinsed with 15% IPA in
Chloroform. All organic layers were combined and dried with
Magnesium Carbonate, filtered and concentrated under vacuum.
MS (ESI + ) for C20H24F2N2O m/z 347.4 (M+H)+
B. N-(1S,2R)-[1-(3,5-Difluoro-benzyl)-2~hydroxy-3-(3-
isopropenyl-benzylamino)-propyl]-acetamide
The above compound was prepared essentially according to
the method of Example 56. The crude material was purified on
Silica gel using 5% Methanol in CH2C12. MS (ESI + ) for
C22H26F2N2O2 m/z 3 8 9.5 (M+H)+
C. N-(lS,2R) - [1- (3,5-Difluoro-benzyl) -2-hydroxy-3-(3-
isopropyl-benzylamino)-propyl] -acetamide
The product from step B (0.036 g) was dissolved in 2 mL
Methanol. 5% Pd/C (0.004 g) was added to the vial. The
reaction was hydrogenated at 50 psi for 4 hours. The reaction
mixture was filtered and the filtrate was concentrated. MS
(ESI+) for C22H28F2N2O2 m/z 391.4 (M+H)+
Example 12 6
N-(1S,2R)-(1-(3,5-Difluoro-benzyl)-2-hydroxy-3-{l-[3-(4-
methyl-thiophen-2-yl)-phenyl] -cyclopropylamino}-propyl)-
acetamide
Palladium acetate (Pd(OAc)2) (0.82 mgs, 10 mol. wt. %) and
Biphenyl-2-yl-di-tert-butyl-phosphane (2.16 mgs, 20 mol. wt.
%) was added to the reaction vessel (Vessel 1). N-(2S, 2R)-
[3-Acetylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]- [1-(3-
bromo-phenyl)-cyclopropyl]-carbamic acid tert-butyl ester
(13.88 mgs, 0.09075 mM) was placed in a separate reaction
vessel (Vessel 2) and dissolved in 200 mL DME. 4-
Methylthiophene-2-boronic acid and Potassium Fluoride (KF) (3
eq., 6.33 mgs) were added to a separate reaction vessel and
dissolved in 200 µL DME (Vessel 3). Solvents in Vessels 2 and
3 were added to Vessel 1 under nitrogen. Vessel 1 was stirred
over night at room temperature. Reaction was then
concentrated down by vacuum. Crude material purified by Prep-
HPLC. Product fractions collected and concentrated down by
vacuum. Product then dissolved in 500 µL 4N HC1 in dioxane.
Allowed to stand for 30 minutes at room temperature. Reaction
mixture then concentrated down by vacuum. MS (ESI + ) for
C25H28F2N2O2S m/z All.2 (M+H) +
All compounds in Table 126.A were synthesi2:ed using the
same general procedure as used in the synthesis of Example
126. The table illustrates the boronic acid derivative that
was used, the mass of the product, and the name of the
product.
Table 126.A
3-Bromobenzylnitrile was obtained from Kimera. Powder
KOH was obtained from Oxechem. Other reagents were from
Aldrich.
Step 1: 1- (3-bromoph.enyl) cyclohexanecarbonitrile
To a 5 L 3-neck round bottom flask equipped with N2 inlet,
temperature probe, addition funnel, and mechanical stirrer was
added 3-bromobenzylnitrile (297 g, 1.51 mol, 1.0 eq) and THF
(2.75 L). The clear solution was cooled to 0-5° C via ice
bath. KOtBu (3 74 g, 3.3 3 mol, 2.2 eq) was weighed out inside
the glove box into a 200 mL round bottom flask and added to
the cold clear solution in shots. The first shot (71.1 g) was
added over 30 seconds and an immediate exotherm of 9° C was
observed along with color change from clear to orange/brown
solution. After waiting for 15 min for the solution to cool
back down to 5.1° C, the second shot (96.0 g) was added and an
exotherm of 6.5° C was observed. After another 15 min, the
third shot (100.4 g) was added and an exotherm of 5° C was
observed. After another 15 min, the fourth and final shot
(106.5 g) was added and an exotherm of 3.8° C was observed.
The orange/brown solution was stirred in ice bath for 30 min
upon which the solution thickened. Carefully add 1,5-
dibromopentane (365.5 g, 1.56 mol, 1.05 eq) to orange/brown
mixture at such a rate to maintaining reaction temperature
slurry and the exotherm will continue to climb during
addition. The addition took ca 2 hours. The addition funnel
was rinsed with THF (250 mL) and added to the brown slurry.
The ice bath was then removed and the slurry self-warmed to RT
while maintaining medium agitation. Sample of the slurry was
pulled after 1 hour of stirring. GC indicated completion with
only excess 1,5-dibromopentane and product. The light brown
slurry was then filtered over a pad of celite to remove salts.
The cake was rinsed with THF (ca 2 L) until clear. Ice (ca 1
L in volume) was then added to the burgundy filtrate and
stirred at RT overnight. The mixture was then concentrated to
remove THF and the resultant biphasic brown mixture was
extracted with EtOAc and saturated NaCl solution. The orange
organic layers were dried with anhydrous Na2SO4, filtered and
rinsed with EtOAc. The orange filtrate was then concentrated
to dryness to give red oil. EtOAc (100 mL) was added to
redissolve oil. While stirring at medium speed, heptane (2 L)
was added over 1-2 min upon which burgundy oil sticks to
bottom and sides of flask. The yellow solution was then
carefully decanted away from the sticky oil and concentrated
to dryness to give light orange oil (379.7 g, 95% yield). GC
of light orange oil indicated excess 1,5-dibromopentane (2.8
area%), product (95.3 area%), and 7 other peaks having less
than 0.5 area% (total =1.9 area%).
GC Conditions: 15m DB5 0.25 x 0.25 micron; Init. Temp. =
75° C, Init. Time = 5 min, Rate = 15° C/min, Final Temp. =
275° C, Final Time = 2 min, Inj. Temp. = 275° C, Det. Temp. =
250° C; 1,5-dibromopentane RT = 6.35 min. Prod. RT = 13.47
min.
1H NMR (400 MHz, CDC13) d 7.62 (s, 1H), 7.45 (d, 2H), 7.26
(t, 1H), 2.14 (d, 2H), 1.74-1.88 (m, 6H), 1.26-1.29 (m, 2H).
13C NMR (100.S MHz, CDC13) 5 143.63, 130.98, 130.40, 128.73,
124.41, 122.94, 122.07, 44.14, 37.23, 24.82, 23.46.
Step 2: 1-(3-bromophenyl)cyc1ohexanecarboxamide
With overhead stirrer, a mixture of crude product from
step 1, above, (380 g, 1207 mmol), powdered KOH (720 g) and t-
BuOH (2.5 L) was heated at reflux overnight. See Hall, J. H.;
Gisler, M. A simple method for converting nitriles to amides.
Hydrolysis with potassium hydroxide in tert-butyl alcohol. J.
Org. Chem..1976, 41, 3769-3770. If deemed complete by GC
analysis, it was cooled with ice-water (cool slowly to avoid
shock to the glass), quenched with ice-water (1500 mL). The
quenched mixture was then extracted with MTBE (3.5 L + 1.5 L).
MTBE layers were concentrated to a yellow solid, 3 90 g.
GC Conditions: 15m DB5 0.25 x 0.25 micron; Init. Temp. =
75° C, Init. Time = 5 min, Rate = 15° C/min, Final Temp. =
275° C, Final Time = 2 min, Inj. Temp. = 275° C, Det. Temp. =
250° C; Product RT = 15.3 man.
Step 3: 1-(3-bromophenyl)cyclohexanamine hydrochloride.
The product from step 2, above (189 g, 603 mmol) was
suspended in warmed t-BuOH (1140 mL) at -35°C, 3N NaOH (570 mL,
2.8 equiv) was added. The reaction cooled to 30°C. NaOCl (380
mL, 13.6wt%, 1.4 equiv.) was added in one portion. The
reaction mixture was cooled to 26°C, and then started to warm
up. Ice was directly added to the mixture to controlled the
temperature
generation stopped after 15 min. All solids dissolved at that
point. Assayed organic layer at 30 min, GC indicated
completion. The mixture was extracted with 1100 mL of MTBE.
The organic layer was combined with the organic layer of a
parallel run of the same scale, and filtered to remove some
white ppt (likely urea side product). The aqueous layers were
extracted with 300 mL of MTBE. The combined MTBE layers (ca.
5 L) was treated with 150 mL of cone. HCl (1.8 mol), stirred
for 4h, cooled to 0°C and filtered. The white solid was dried
at 50°C to give 1st crop 180 g (52%) of material. The filtrate
was treated with NaOH and NaHSO3 to pH>12. The organic layer
was concentrated to an oil. This oil was dissolved in 1 L of
MTBE and treated with 75 mL of cone. HCl, cooled, filtered and
dried to give 140 g (40%) of the desired product.Anal. Calcd
for C12HlsBrN. HCl: C, 49.59; H, 5.90; N, 4.82; Br, 27.49; Cl,
12.20; Found: C, 50.34; H, 6.23; N, 4.70; HRMS calcd for
C12H16BrN+ 253.0467, found 253.0470.
GC Conditions: 15m DB5 0.25 x 0.25 micron; Init. Temp. =
75° C, Init. Time = 5 min, Rate = 15° C/min, Final Temp. =
2 75° C, Final Time = 2 min, Inj. Temp. = 2 75° C, Det. Temp. =
250° C; Product RT = 12.9 min.
Step 4: tert-butyl-(1S,2R)-3-{[l-(3-
bromophenyl)cyclohexyl]amino}-l-(3,5-difluorobenzyl)-2-
hydroxypropylcarbamate,
The product from step 3, above (90 g, 310 mmol, 1.5 eq)
was converted into a free base in 1000 mL of MTBE/400 mL of 2N
NaOH. MTBE layer was separated, washed with brine. Aqueous
layers were back extracted with 400 mL of MTBE. Combined MTBE
layer was concentrated (thereotical 78.3 g) to afford the free
base.
61.7 g the epoxide (206 mmol, 1 eq., FW 299.3) and the
above free base were suspended in 320 ml t-BuOH (warm). A
mantle and thermo/probe was used to heat the stirring mixture
to 80°C at 5°C/hour ramp overnight. The mixture was
concentrated on rotovap with 20°C condenser. The resulting oil
was dissolved in MTBE (1L), washed with 1N HC1 (200ml, then
100 mL x 5) (contain the product from step 3, the first wash
was quickly separated to avoid crash out). Aqueous layer was
sequentially back-extracted with MTBE (200 mL). The MTBE
layer was stirred with 1N NaOH (500 mL) for 30 min, then
separated. MTBE layer was washed with brine and then
concentrated to dryness. Recrystallized in MTBE/Heptane
(150/900 mL). Filtered at 0°C and washed with heptane (150 mL
x 2), dried at 45°C, 95.3 g (83.5%).
The HC1 washes (suspension) were basified with 50% NaOH
(ca. 50 g), extracted with MTBE (400 mL + 200 mL). The MTBE
layer was treated with cone. HC1 (15 mL). The resulting
suspension was cooled and filtered to give the unreacted
starting amine, the product from step 3, above, 31.3 g (52%).
HPLC conditions: Luna C18(2), 3 micron, min, 80:20
0.1%TFA in MeOH/0.1%TFA in water; 10 min, Product, RT= 2.0
min.
Example 134
tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-
yl]ethylcarbamate
Step 1: (2S)-2-[(tert-butoxycarbonyl)araino]-3-(3,5-
difluorophenyl)propanoic acid methyl ester
To a 1-L 3-neck round bottom flask equipped with a
magnetic stirrer, nitrogen inlet and thermocouple is added
(2S)-2- [ (tert-butoxycarbonyl)amino]-3-(3,5-
difluorophenyl)propanoic acid (I, 40 g, 0.133 moles, 1
equivalent) followed by THF (240 mL). Lithium hydroxide
monohydrate (5.6 g, 0.133 moles, 1 equivalent) is added in a
single portion and is allowed to stir for 3 0 min at which
time, the contents are cooled to 0°. Once cooled, dimethyl
sulfate (12.6 mL, 0.133 moles, 1 equivalent) is added dropwise
via syringe and then stirred for 3 0 min. The mixture is then
heated to about 50° and monitored (by HPLC) until 90%
conversion had been achieved. At that time, the; mixture is
cooled to below 2 0° (solids form). The mixture is then poured
into sodium bicarbonate (200 mL), stirred for 15 min then
extracted with methyl t-butyl ether (200 mL). The phases are
separated and the aqueous layer is extracted with methyl t-
butyl ether (2 x 200 mL). The combined organic phases are
washed with water (400 mL) dried over sodium sulfate, filtered
and concentrated under reduced pressure to give a solid. This
material is then recrystallized from hexanes to give the title
compound, NMR (DMSO-d6) d 7.51, 7.15-7.25, 4.43, 3.81, 3.00-
3.26 and 1.49; CMR (DMSO-d6) d 172.43, 163.74, 161.20, 155.67,
142.58, 112.70, 120.23, 78.69, 54.71, 52.24, 39.25 and 28.37.
To a 1-L 3-neck round bottom flask equipped with a
magnetic stirrer, nitrogen inlet, thermocouple and additional
funnel is added (2S)-2-[(tert-butoxycarbonyl)amino] -3-(3,5-
difluorophenyDpropanoic acid methyl ester (II, Step 1, 10.0
g, 0.0317 moles, 1 equivalent) followed by THF (175 mL) then
cooled to -78°. Once the mixture is cooled, iodochloromethane
(9.25 mL, 0.127 moles, 4 equivalents) is added in one portion
via syringe. The addition funnel is charged with LDA (79 mL,
0.158 moles, 5 equivalents, 2.0 M in heptane/THF) and is
subsequently added dropwise to the mixture keeping the
internal temperature below -70°. Once the addition is
complete, the contents are stirred for 15 min at which time
acetic acid (47.2 mL, 0.824 moles, 26 equivalents) is added
dropwise via the addition funnel keeping the internal
temperature below -65°. Once this addition is complete, the
mixture is stirred for 15 min then warmed to 0° and. poured into
water (500 mL), saline (500 mL) and methyl t-butyl ether (500
mL) then transferred to a separatory funnel. The phases are
separated and the aqueous phase is extracted with methyl t-
butyl ether (2 x 250 mL). The combined organic phases are
washed with saturated sodium bicarbonate (500 mL), sodium
sulfite (500 mL) and water (500 mL). The organic phase is
then dried over sodium' sulfate, filtered and concentrated
under reduced pressure to give a solid. The solid is
recrystallized from heptane/i-propyl alcohol (10/l)to give the
title compound, NMR (DMSO-d6) 8 7.47, 7.06-7.14, 4.78, 4.49,
3.20, 2.82 and 1.40; CMR (DMSO-d6) 8 200.87, 163.74, 161.20,
142.74, 112.80, 102.13, 79.04, 58.97, 47.72, 34.95 and 28.30.
Step 3: tert-butyl (1S,2S)-3-chloro-l-(3,5-difluorobenzyl)-
2-hydroxypropylcarbamate (IV)
To a 250 mL 3-neck round bottom flask equipped with
magnetic stir bar, nitrogen inlet and thermocouple, is added
tert-butyl (IS)-3-chloro-l-(3,5-difluorobenzyl)-2-
oxopropylcarbamate (III, Step 2, 4.4 g, 0.0132 moles, 1
equivalent) followed by THF (20 mL) and ethanol (30 mL) then
cooled to -78°. Once the mixture is cooled, sodium borohydride
(2.0 g, 0.0527 moles, 4 equivalents) is added as a solid
portion wise over 3 0 min keeping the internal temperature
below -70°. Once this addition is complete, the contents are
stirred for 2 hr at -78° then warmed to 0° and stirred an
additional 1 hr. The mixture is quenched by the addition of
saturated potassium bisulfate (15 mL) and water (15 mL).
This slurry is stirred for 30 min at 20-25° then concentrated
under reduced pressure to half its volume. The mixture is
then cooled to 0° and stirred for 3 0 min. After this time, the
resultant solids are collected by filtration and washed with
water (2 x 50 mL) then dried under reduced pressure at 50° to
give crude product. A syn/anti ratio of 4-9:1 has been
observed. The desired product is recrystallized from
hexanes/ethanol (25/1) to give the title compound, NMR (DMSO-
de) 5 6.89-7.16, 5.61, 3.64-3.83, 3.19, 2.69 and 1.41; CMR
(DMSO-d6) 5 163.67, 161.24, 155.44, 112.70, 101.55, 78.04,
72.99, 54.29, 48.24, 35.97 and 28.37.
Step 4: tert-Butyl (IS)-2-(3,5-difluorophenyl)-1-[(2S)-
oxiran-2-yl]ethylcarbamate
To a 250 mL 3-neck round bottom flask equipped with
magnetic stir bar, nitrogen inlet and thermocouple, is added
tert-butyl (1S,2S)-3-chloro-l-(3,5-difluorobenzyl)-2-
hydroxypropylcarbamate (IV, Step 3, 3.5 g, 0.010 moles, 1
equivalent) followed by absolute ethanol (60 mL) and cooled to
0°. To this mixture is added potassium hydroxide (0.73 g,
0.013 moles, 1.25 equivalents) dissolved in absolute ethanol
(10 mL) over 1 hr and the resulting suspension is warmed to
15-20° and stirred for 1 hr. At this time, water (100 mL) is
added and the reaction contents are cooled to -5° and stirred
for 3 0 min. The solids are collected by filtration and washed
with cold water (2 x 25 mL) then dried under reduced pressure
at 45° to give the title compound; NMR (DMS0-d6) 5 7.03, 3.61,
2.68-2.98 and 1.33; CMR (DMSO-d6) 8 163.72, 161.29, 155.55,
143.35, 112.65, 101.80, 78.17, 53.42, 52.71, 44.90, 36.98 and
28.36.
Example 13 5
The following compounds are prepared essentially
according to the procedures set forth in the above examples
and schemes.
Ex. No. Compound Name
A1. N-[(1S,2R)-3-{ [(1R)-5-(3-aminophenyl)- 7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}-1-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide;
A2. N-((1S,2R)-1-(3, 5-difluorobenzyl)-3-{[(1R)-7-ethyl-
5- (1,3-thiazol-2-yl)-1,2,3,4-tetrahydronaphthalen-l-
yl]amiho}-2-hydroxypropyl)acetamide;
A3. N-((1S,2R)-l-(3,5-difluorobenzyl)-3-{ [ (1R)-7-ethyl-
5-pyridin-2-yl-1,2,3,4 -tetrahydronaphthalen-1-yl]amino}-
2-hydroxypropyl)acetamide;
A4. N-{(1S,2R)-l-(3,5-difluorobenzyl)-3-{ [ (1R)-7-ethyl-
5-(3-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalen-1-
yl]amino}-2-hydroxypropyl)acetamide;
A5. N- ((1S,2R)-1-(3,5-difluorobenzyl)-3-{ [ (1R)- 7-ethyl-
5-(4-methylpyridin-2-yl)-1,2,3,4-tetrahydronaphthalen-1-
yl]amino}-2-hydroxypropyl)acetamide;
A6. N-[(1S,2R)-3-{[l-acetyl-4- (3-
isopropylphenyl)piperidin-4-yl]amino}-1-(3,5-
difluorobenzyl) -2-hydroxypropyl]acetamide;
A7. N- ((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[4-
(3-isopropylphenyl)-1-(methylsulfonyl)piperidin-4-
yl]aminoJpropyl)acetamide;
A8. N- ( (1R,2S)-1-[4-(benzyloxy)-3-fluorobenzyl]-3-
{[(IS)-7-(2,2-dimethylpropyl)-1,2,3,4-
tetrahydronaphthalen-1-yl]amino}-2-
hydroxypropyl) acetamide;
A9. N-[(1R,2S)-3-{[4-(3-tert-butylphenyl)tetrahydro-2H-
pyran-4-yl]amino}-1-(3,5-difluorobenzyl)- 2-
hydroxypropyl]acetamide;
A10. N- [ (1R,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({l-
[3-
(trifluoromethyl)phenyl]cyclohexyl}amino)propyl]acetamid
e;
All. N- ( (1S,2R)-1-(3,5-difluorobenzyl)-3-{ [ (4R)-6-(2,2-
dimethylpropyl)-3,4-dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)-2-fluoroacetamide;
A12. N- ( (1R,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{ [4-
(3-isopropoxyphenyl)tetrahydro-2H-pyran-4-
yl]amino}propyl)-N'-phenylurea;
A13. phenyl { (l.R, 2S)-1-(3, 5-dif luorobenzyl)-2-hydroxy-3-
[(6-isopropoxy-i,1-dimethyl-3,4-dihydro-lH-isochromen-4-
yl)amino]propyl}carbamate;
A14. N-((lR,2S)-l-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-
(2-isobutyl-l,3-thiazol-5-yl)-1-
methylethyl]amino)propyl)acetamide;
A15. N-[(lS,2R)-3-({l-[3-(2-
adamantyl)phenyl]cyclohexyl}amino)-1- (3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide;
A16. N-[(lS,2R)-3-{[l-(3-
cyclopentylphenyl)cyclopropyl]amino}-1-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide;
A17. N- [(lS,2R)-3-{[1-(3-bicyclo[2.2.1]hept-2-
yl phenyl)cyclopropyl]amino}-1-(3,5-difluorobenzyl)-2-
hydroxypropyl]acetamide;
A18. Ethyl 3-[3-(l-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl) -2-
hydroxybutyl]amino}cyclohexyl)phenyl]propanoate;
A19. N-[(lS,2R)-3-{ [1-(3-sec-
butylphenyl)cyclopropyl]amino}-!-(3,5-difluorobenzyl)-2-
hydroxypropyl]acetamide;
A20. N- ((1S,2R) -1-(3,5-difluorobenzyl)-3-{[1-(3',5'-
difluorobiphenyl-3-yl)cyclopropyl]amino}-2-
hydroxypropy 1 ) acetamide;
A21. N- ( (1S,2R) -1-(3,5-difluorobenzyl) -3-{ [5-(2,2-
dimethylpropyl)-2-(2-propyl-1H-imidazol-1-
yl)benzyl]amino}-2-hydroxypropyl)acetamide;
A22. N-[(lS,2R)-3-{ [1- (3-sec-
butylphenyl)cyclohexyl]amino}-1-(3,5-difluorobenzyl)-2-
hydroxypropyl]acetamide;
A23. N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({l-
[3-(3-
methylbutyl)phenyl]cyclohexyl}amino)propyl]acetamide;
A24. N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({l-[3-(1-
ethylpropyl) phenyl].cyclohexyl}amino) -2-
hydroxypropy1]acetamide;
A25. N- [(lS,2R)-3-{ [1-(3-
cyclopentylphenyl)cyclohexyl]amino}-l-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide;
A26. N-((1S,2R)-1~(3,5-difluorobenzyl)-2-hydroxy-3-{ti-
p-pent-4-en-1-
ylphenyl) cyclohexyl] atnino}propyl) acetamide;
Bl. N-((IS,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-
(3-pyridin-2-ylphenyl)cyclohexyl]amino}propyl)acetamide;
B2. N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({l-
[3-(3-methylpyridin-2-
yl)phenyl]cyclohexyl}amino)propyl]acetamide;
B3. N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({l-
[3-(l,3-thiazol-2-
yl)phenyl]cyclohexyl}amino)propyl]acetamide ;
B.4. N- [(1S,2R)-1- (3,5-difluorobenzyl) -2-hydroxy-3- ({l-
[3-(3-methyl-2-
thienyl)phenyl]cyclohexyl}amino)propyl]acetamide;
B5. N-[(1S,2R)-1-(3,5-difluorobenzyl)-3- ({l-[3-(2-
fluorobenzyl)phenyl]cyclohexyl}amino)-2-
hydroxypropyl]acetamide ;
B6. N-[(1S,2R)-1-(3,5-difluorobenzyl)-3- ({l-[3-(4-
fluorobenzyl)phenyl]cyclohexyl}amino)-2-
hydroxypropyl]acetamide;
B7. N-[(lR,2S)-3-{[(IS)-7-(2,2-dimethylpropyl)-1,2,3,4-
tetrahydronaphthalen-1-yl]amino}-1-(3-fluoro-4-
hydroxybenzyl)-2-hydroxypropyl]acetamide; and
B8. N-((1S,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-
(-3 -i.sopropylphenyl) tetrahydro-2H-pyran-3-
yl]amino}propyl)acetamide.
Example 13 6
The following compounds are prepared essentially
according to the procedures set forth in the above examples
and schemes.
Ex. Compound
No.
Al. (1S,2R)-N-[3- [1-(3-tert-Butyl-phenyl)-4-oxo-
cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl]-acetamide;
A2. (1S,2R)-N-[3- [5-(3-tert-Butyl-phenyl)-2-oxo-
[1,3]oxazinan-5-ylamino]-1-(3,5-difluoro-benzyl)-2-
hydroxy-propyl]-acetamide;
A3. (IS, 2R)-N-[3-[5-(3-tert-Butyl-phenyl)-2-oxo-hexahydro-
pyrimidin-5-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl]-acetamide;
A4. (IS,2R)-N-[3-[1-(3-Bromo-5-tert-butyl-phenyl)-
cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl]-acetamide;
A5. (1S,2R)-N- [3-[1-(3-tert-Butyl-5-ethyl-phenyl)-
cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl]-acetamide;
A6. (1S,2R)-N- [3-[4-(3-tert-Butyl-5-ethyl-phenyl)-
tetrahydropyran-4-ylamino]-1-(3, 5-difluoro-benzyl)-2-
hydroxypropyl]-acetamide;
A7. (1S,2R)-N-[3-[4-(3-Bromo-5-tert-butyl-phenyl)-
tetrahydropyran-4-ylamino]-1-(3,5-difluorobenzyl)-2-
hydroxypropyl]-acetamide;
A8. (1S,2R)-N- [3- [1-(3-tert-Butyl-5-
ethylphenyl)cyclopropylamino]-1-(3,5-difluorobenzyl)-2-
hydroxypropyl]-acetamide;
A9. (1S,2R)-N-[3-{l-[3-Bromo-5-(2,2-dimethyl-propyl)-
phenyl]-cyclopropylamino}-1-(3,5-difluoro-benzyl)-2-
hydroxy-propyl]-acetamide;
A10. (1S,2R)-N-(1-(3,5-Difluorobenzyl)-3-{l- [5- (2,2-
dimethylpropyl)-2-imidazol-1-yl-phenyl]-
cyclopropylamino}-2-hydroxy-propyl)-acetamide;
All. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3- [5- (2,2-
dimethylpropyl)-2-(5-ethyl-imidazol-l-yl)-benzylamino]-
2-hydroxypropyl}-acetamide;
A12. (1S,2R)-N-[3- [3-Chloro-5-(2,2-dimethyl-propyl)-2-
imidazol-1-yl-benzylamino]-1-(3,5-difluoro-benzyl)-2-
hydroxy-propyl]-acetamide;
A13. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3-[5-(2,2-dimethyl-
propyl)-2-tetrazol-l-yl-benzylamino]-2-hydroxy-propyl}-
acetamide;
A14. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3-[5-(2,2-
dimethyl-propyl)-2-oxazol-5-yl-benzylamino]-2-hydroxy-
propyl}-acetamide;
A15. (1S,2R)-N-{l-(3,5-Difluoro-benzyl)-3-[5-(2,2-
dimethyl-propyl)-2-oxazol-2-yl-benzylamino]-2-hydroxy-
propyl}-acetamide;
A16. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3-[6-(2,2-
dimethyl-propyl)-1-methyl-l,2,3,4-tetrahydro-quinolin-4-
ylamino]-2-hydroxy-propyl}-acetamide ;
A17. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3-[6-(2,2-
dimethyl-propyl)-thiochroman-4-ylamino]-2-hydroxy-
propyl}-acetamide;
A18. (1S,2R)-N-{l-(3,5-Difluoro-benzyl)-3-[6-(2,2-
dimethyl-propyl)-8-ethyl-chroman-4-ylamino]-2-hydroxy-
propyl }-acetamide;
A19. (1S,2R)-N-[3-[8-Bromo-6-(2,2-dimethylpropyl)-
chroman-4-ylamino]-1-(3,5-difluoro-benzyl)-2-
hydroxypropyl]-acetamide;
A20. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3- [6- (2,2-
dimethyl-propyl)-2-oxo-chroman-4-ylamino]-2-hydroxy-
propyl}-acetamide;
A21. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3-[7-(2,2-
dimethyl-propyl)-4-oxo-l,2,3,4-tetrahydro-naphthalen-l-
ylamino]-2-hydroxy-propyl}-acetamide;
A22. (1S,2R)-N-{1-(3,5-Difluoro-benzyl)-3-[6-(2,2-
dimethyl-propyl)-l-oxo-lX4-thiochroman-4-ylamino]-2-
hydroxypropyl}-acetamide;
A23.. (IS,2R)-N-{1-(3,5-Difluoro-benzyl)-3-[6-(2,2-
dimethyl-propyl)-1,l-dioxo-lX"-thiochroman-4-ylamino]-2-
hydroxy-propyl}-acetamide;
A24. N- ((1S,2R)-1-(3,5-difluorobenzyl)-3-{ [7- (2,2-
dimethylpropyl)-5-ethyl-l,2,3,4-tetrahydronaphthalen-l-
yl]amino}-2-hydroxypropyl)acetamide;
A25. N- ((1S,2R)-1-(3,5-difluorobenzyl)-3-{ [ (4R)-6-(2,2-
dimethylpropyl)-3,4-dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide;
A26. N- ((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(IS)-7-(2,2-
diraethylpropyl)-1,2,3,4-tetrahydronaphthalen-l-
yl]amino}-2-hydroxypropyl)acetamide;
B1. N-[(lS,2R)-3-{[l-(3-tert-
butylphenyl)cyclohexyl]amino}-1-(3,5-difluorobenzyl)-2-
hydroxypropy1]acetamide;
B2. N-[(1S,2R) -3-{ [4- (3-tert-butylphenyl) t.etrahydro-2H-
pyran-4-yl]amino}-1-(3, 5-difluorobenzyl)-2-
hydroxypropy1]acetamide;
B3. N- ((IS,2R)-1-(3,5-difluorobenzyl)-3-{[6-(2,2-
dimethylpropyl)-1,2,3,4-tetrahydroquinolin-4-yl]amino}-
2 -hydroxypropyl) acetamide
B4. N- ( (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-
(3 -isopropylpheny1)-4 -
oxocyclohexyl]amino}propyl)acetamide;
B5. N-[(1S,2R)-3-{ [(4S) -G-(2,2-dimethylpropyl)-3,4-
dihydro-2H-chromen-4-yl]amino}-1-(3-fluorobenzyl)-2-
hydroxypropy1] acetamide;
B6. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{ [5- (2,2-
dimethylpropyl)-2-(lH-imidazol-1-yl)benzyl]amino}-2-
hydroxypropyl)acetamide;
B7. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[7-(2,2-
dimethylpropyl)-1-methyl-1,2,3,4-tetrahydronaphthalen-l-
yl]amino}-2-hydroxypropyl)acetamide;
B8. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[6-(2,2-
dimethylpropyl)-4-methyl-3,4-dihydro-2H-chromen-4-
yl]amino}-2-hydroxypropyl)acetamide;
B9. N-((1S,2R)-1-(3-fluoro-4-hydroxybenzyl)-2-hydroxy-
3-{[l-(3-..
isopropylphenyl)cyclohexyl]aminojpropyl)acetamide;
B10. N- ( (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{ [1-
(3-isopropylphenyl)cyclohexyl]anri.no Jpropyl)-2-
fluoroacetamide;
B11. N-((1S,2R)-1-[3-(allyloxy)-5-fluorobenzyl] -2-
hydroxy-3-{[1- (3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide;
B12. N- [(1S,2R)-1-(3,5-difluorobenzyl)-3-({l-[3-(2,2-
dimethylpropyDphenyl] -1-methylethyl}amino) -2-
hydroxypropyl]-2-fluoroacetamide;
B13. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(IS) -7-(2,2-
dimethylpropyl)-1,2,3,4-tetrahydronaphthalen-l-
yl]amino}-2-hydroxypropyl)-2-fluoroacetamide;
B14. N- [ (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({l-
[3-(3-thienyl)phenyl]cyclohexyl}amino)propyl]acetamide;
B15 N-[(1S,2R) -1-(3,5-difluorobenzyl)-3- ({l- [4-(2,2-
dimethylpropyl)pyridin-2-yl]cyclopropyl}amino)-2 -
hydroxypropyl]acetamide
B16 N-((1R,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-
{ [ (IS)-7-propyl-l,2,3,4-tetrahydronaphthalen-l-
yl]amino}propyl)acetamide
B17 N- ( (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-
(3-isobutylphenyl)cyclohexyl]amino}propyl)acetamide
B18 N-((IS,2R)-2-hydroxy-l-(4-hydroxybenzyl)-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}propyl)acetamide
B19 N-((1R,2S)-1-(3,5-difluorobenzyl)-3-{ [ (IS)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)-2-ethoxyacetamide
B20 N-((1S,2R) -1-(3,5-difluorobenzyl)-3-{[(1R)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropy1)-2,2-difluoroacetamide
Example 137
The following compounds are prepared essentially
according to the procedures set forth in the above examples
and schemes.
Ex. Compound
No.
Al. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[1-(3-isopropyl-
phenyl) -cyclobutylamino] -propyl} -acetamide;
A2. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[1-(3-isopropyl
phenyl)-cyclopentylamino]-propyl}-acetamide;
A3. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[3-(3-isopropyl-
phenyl)-bicyclo[3.1.0]hex-3-ylamino]-propyl}-acetamide,-
A4. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[3-(3-isopropyl-
phenyl)-6-aza-bicyclo[3.1.0]hex-3-ylamino]-propyl}-
acetamide;
A5. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[3-(3-isopropylT
phenyl)-6-methyl-6-aza-bicyclo[3.1.0]hex-3-ylamino]-
propyl}-acetamide;
A6. N-.[3- [6-Acetyl-3- (3-isopropyl-phenyl) -6-aza-
bicyclo [3.1.0]hex-3-ylamino]-1-(3,5-difluoro-benzyl)-2-
hydroxy-propyl]-acetamide;
A7. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[3-(3-isopropyl-
phenyl)-6-methanesulfonyl-6-aza-bicyclo[3.1.0]hex-3-
ylamino]-propyl}-acetamide;
A8. N- {l- (3,5-Difluoro-benzyl)-2-hydroxy-3-[1 -(3-isopropyl-
phenyl)-2,2,4,4-tetramethyl-3-oxo-cyclobutylamino]-
propyl}-acetamide;
A9. N-{l-(3,5-Difluoro-benzyl)-2 -hydroxy-3 -[3-hydroxy-l-(3-
isopropyl-phenyl)-2,2,4,4-tetramethyl-cyclobutylamino]-
propyl}-acetamide;
A10. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[5-(3-isopropyl-
phenyl) -octahydro-cyclopenta [c]pyrrol-5-ylamino] -
propyl}-acetamide;
All. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[5-(3-isopropyl-
phenyl)-2-methyl-octahydro-cyclopenta[c]pyrrol-5-
ylamino]-propyl}-acetamide,-
A12. N- [3- [2-Acetyl-5- (3-isopropyl-pheriyl) -octahydro-
cyclopenta [c]pyrrol-5-ylamino] -1-(3,5-difluoro-benzyl)-
2-hydroxy-propyl]-acetamide;
A13. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[5-(3-isopropyl-
phenyl)-2-methanesulfonyl-octahydro-cyclopenta[c]pyrrol-
5-ylamino]-propyl}-acetamide;
A14. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl)-5-oxo-octahydro-pentalen-2-ylamino]-propyl}-
acetamide;
A15. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3- [5-hydroxy-2- (3-
isopropyl-phenyl)-octahydro-pentalen-2-ylamino]-propyl}-
acetamide;
A16. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl)-3a,6a-dimethyl-5-oxo-octahydro-pentalen-2-
ylamino]-propyl}-acetamide;
A17. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[5-hydroxy-2-(3-
isopropyl-phenyl)-3a,6a-dimethyl-octahydro-pentalen-2-
ylamino]-propyl}-acetamide;
A18. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl)-5-oxo-cyclohexylamino]-propyl}-acetamide;
A19. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[5-hydroxy-2-(3-
isopropyl-phenyl) -5-methyl-cyclohe:xylamino] -propyl}-
acetamide,-" ¦
A20. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl)-5-methanesulfonylamino-cyclohexylamino]-propyl}-
acetamide;
A21. N-[3-[5-Acetylamino-2-(3-isopropyl-phenyl)-
cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl] -acetamide;
A22. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl)-4-oxo-cyclohexylamino]-propyl}-acetamide;
A23. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-hydroxy-2-(3-
isopropyl-phenyl)-4-methyl-cyclohexylamino]-propyl}-
acetamide;
A24. N-[3-[4-Acetylamino-2-(3-isopropyl-phenyl)-
cyclohexylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl]-acetamide;
A25. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl) -4-methanesulfonylamino-cyclohexylamino]-propyl}-
acetamide;
A26. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl) -4-oxo-cyclopentylamino]-propyl}-acetamide;
Bl. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-hydroxy-2-(3-
isopropyl-phenyl)-4-methyl-cyclopentylamino]-propyl}-
acetamide;
B2. N-[3-[4-Acetylamino-2-(3-isopropyl-phenyl)-
cyclopentylamino]-1-(3,5-difluororbenzyl)-2-hydroxy-
propyl] -acetamide;
B3. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[2-(3-isopropyl-
phenyl) -4-methanesulfonylamino-cyclopentylamino]-
propyl}-acetamide;
B4. N-{1-(3,5-Difluoro-benzyl)-3-[4-(2,2-dimethyl-propyl)-
pyridin-3-ylamino]-2-hydroxy-propyl}-acetamide;
B5. N-(1-(3,5-Difluoro-benzyl)-3-{[4-(2,2-dimethyl-propyl)-
pyridin-3-ylmethyl]-amino}-2-hydroxy-propyl)-acetamide;
B6. N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(5-isobutyl-2-
piperazin-1-yl-benzylamino)-propyl]-acetamide;
B7. N-{l- (-3, 5-Difluoro-benzyl) -2 -hydroxy-3 - [5-isobutyl-2 - (4-
methyl-piperazin-1-yl)-benzylamino]-propyl}-acetamide;
B8. N-[3-[2-(4-Acetyl-piperazin-l-yl)-5-isobutyl-
benzylamino] -1- (3,-5-difluoro-benzyl) -2-hydroxy-propyl] -
acetamide;
B9. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[5-isobutyl-2-(4-
methanesulfonyl-piperazin-1-yl)-benzylamino]-propyl}-
acetamide;
B10. N-{1-(3,5-Difluoro-benzyl)-3-[4-(2,2-dimethyl-propyl)-
piperidin-3-ylamino]-2-hydroxy-propyl}-acetamide;
Bll. N-(1-(3,5-Difluoro-benzyl)-3-{[4-(2,2-dimethyl-propyl)-
piperidin-3-ylmethyl]-amino}-2-hydroxy-propyl)-
acetamide;
B12. N-[3-[l-Acetyl-4-(2,2-dimethyl-propyl)-piperidin-3-
ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-
acetamide;
B13. N-[3-{ [l-Acetyl-4-(2,2-dimethyl-propyl)-piperidin-3-
ylmethyl]-amino}-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl] -acetamide;
B14. N-{1-(3,5-Difluoro-benzyl)-3-[4-(2,2-dimethyl-propyl)-1-
methanesulfonyl-piperidin-3-ylamino]-2-hydroxy-propyl}-
acetamide;
B15. N-(1-(3,5-Difluoro-benzyl)-3-{[4-(2,2-dimethyl-propyl)-
1-methanesulfonyl-piperidin-3-ylmethyl]-amino}-2-
hydroxy-propyl)-acetamide;
B16. N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3- (6-isopropyl-2-
oxo-1,2,3,4-tetrahydro-quinolin-4-ylamino)-propyl]-
acetamide;
B17. N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(5-isopropyl-2-
oxor2,3-dihydro-lH-indol-3-ylamino)-propyl]-acetamide;
B18. N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3- (7-isopropyl-3-
oxo-1,2,3,4-tetrahydro-naphthalen-1-ylamino)-propyl]-
acetamide;
B19. N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3 - (3-hydroxy-7-
isopropyl-3-methyl-1,2,3, 4-tetrahydro-naphthalen-l-
ylamino)-propyl]-acetamide;
B2 0. N-[3-(3-Acetylamino-7-isopropyl-l,2,3,4-tetrahydro-
naphthalen-1-ylamino)-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl] -acetamide;
B21. N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3 -(7-isopropyl-3-
methanesulfonylamino-1,2,3,4-tetrahydro-naphthalen-l-
ylamino)-propyl]-acetamide;
B22. N- [1- (3,5-Difluoro-benzyl)-2-hydroxy-3-(6-isopropyl-2-
oxo-indan-1-ylamino)-propyl]-acetamide;
B23. N- [1- (3, 5-Difluoro-benzyl)-2-hydroxy-3- (2-hydroxy-6-
isopropyl-2-methyl-indan-1-ylamino)-propyl]-acetamide;
B24. N-[3-(2-Acetylamino-6-isopropyl-indan-l-ylamino)-1-(3,5-
difluoro-benzyl)-2-hydroxy-propyl]-acetamide;
B25. N- [1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(6-isopropyl-2-
methanesulfonylamino-indan-1-ylamino)-propyl]-acetamide;
B26. N-[1-(3,5-Difluoro-benzyl)-2-hydroxy-3-(5-isobutyl-2-
piperidin-4-yl-benzylamino) -propyl]-acetamide;
C1. N-[3-[2-(l-Acetyl-piperidin-4-yl)-5-isobutyl-
benzylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl]-
acetamide;
C2. N-{l-(3,5-Difluoro-benzyl)-2-hydroxy-3-[5-isobutyl-2-(1-
methanesulfonyl-piperidin-4-yl)-benzylamino]-propyl}-
acetamide;
C3. N-{l- (3,5-Difluoro-benzyl)-3-[5-(2,2-dimethyl-propyl)-2-
piperidin-4-yl-benzylamino] -2-hydroxy-propyl}-acetamide;
C4. N- [3- [2-(l-Acetyl-piperidin-4-yl)-5-(2,2-dimethyl-
propyl)-benzylamino]-1-(3, 5-difluoro-benzyl)-2-hydroxy-
propyl] -acetamide
C5. N-{1-(3,5-Difluoro-benzyl)-3-[5-(2,2-dimethyl-propyl)-2-
(l-methanesulfonyl-piperidin-4-yl)-benzylamino]-2-
hydroxy-propyl}-acetamide;
C6. N-[1-(3,5-Difluoro-benzyl) -2-hydroxy-3-(6-isobutyl-2,2-
dioxo-1,2, 3,.4-tetrahydro-2l6-benzo[c] [1, 2] th:Lazin-4-
ylamino)-propyl] -acetamide;
C7. N-{1-(3,5-Difluoro-benzyl)-3-[6-(2,2-dimethyl-propyl)-1-
methyl-2,2Tdioxo-l,2,3,4-tetrahydro-2Xs-
benzo[c][1,2]thiazin-4-ylamino]-2-hydroxy-propyl}-
acetamide;
C8. N- [3- [6- (2,2-Dimethyl-propyl)-2,2-dioxo-l,2,3,4-
tetrahydro-2As-benzo [c] [1, 2] thiazin-4-ylamino] -1- (3-
fluoro-4-hydroxy-benzyl)-2-hydroxy-propyl]-acetamide;
C9. N-{l- (3,5-Difluoro-benzyl)-3-[5- (2,2-dimethyl-propyl)-2-
methanesulfonylamino-benzylamino]-2-hydroxy-propyl}-
acetamide;
C10. N-[3-[2-Benzenesulfonylamino-5-(2,2-dimethyl-propyl)-
benzylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl] -
acetamide;
Cll. N-{1-(3,5-Difluoro-benzyl)-3- [5- (2,2-dimethyl-propyl) -2-
phenylsulfamoyl-benzylamino]-2-hydroxy-propyl}-
acetamide,-
C12. N-{l-(3,5-Difluoro-benzyl)-3-[5-(2,2-dimethyl-propyl)-2-
methylsulfamoyl -benzylamino]-2-hydroxy-propyl}-
acetamide;
C13. N-{1-(3,5-Difluoro-benzyl)-3-[5-(2,2-dimethyl-propyl)-2-
(2-oxo-piperidin-4-yl)-benzylamino]-2-hydroxy-propyl}-
acetamide;
C14. N-{l-(3,5-Difluoro-benzyl)-3-[5-(2,2-dimethyl-propyl)-2-
(l-methyl-2-oxo-piperidin-4-yl)-benzylamino]-2-hydroxy-
propyl }-acetamide;
C15. N-[3-[6- (2,2-Dimethyl-propyl)-chroman-4-ylamino] -1-
(3-fluoro-4-hydroxy-benzyl)-2-hydroxy-propyl]-acetamide;
C16. N- [3-[7- (2,2-Dimethyl-propyl)-1,2,3,4-tetrahydro-
naphthalen-1-ylamino]-1-(3-fluoro-4-hydroxy-benzyl)-2-
hydroxy-propyl]-acetamide;
C17. N- [3-[7- (2,2-Dimethyl-propyl)-1,2,3,4-tetrahydro-
naphthalen-1-ylamino]-2-hydroxy-l-(5-hydroxy-pyridin-2-
ylmethyl)-propyl]-acetamide;
C18. N-[3-[6-(2,2-Dimethyl-propyl)-chroman-4-ylamino]-2-
hydroxy-1-(5-hydroxy-pyridin-2-ylmethyl)-propyl]-
acetamide;
C19. N-[3-[4- (3-tert-Butyl-phenyl)-tetrahydro-pyran-4-
ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-butyl]-
acetamide;
C20; N-[3-[4-(3-tert-Butyl-phenyl)-tetrahydro-pyran-4-
ylamino]-1-(3,5-difluoro-benzyl)-2,4-dihydroxy-butyl]-
acetamide;
C21. N-[3-(5-tert-Butyl-2-imidazo1-1-yl-benzylamino)-1-(3,5-
difluoro-benzyl)-2-hydroxy-butyl]-acetamide,:
C22. N-[3-(5-tert-Butyl-2-imidazol-l-yl-benzylamino)-1-(3,5-
difluoro-benzyl)-2,4-dihydroxy-butyl]-acetamide;
C23. N-{ (1S,2R)-1-(3,5-Difluoro-benzyl) -2-hydroxy-3- [4- (3-
isopropyl-phenyl)-tetrahydro-thiopyran-4-ylamino]-
propyl}-acetamide;
C24. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-
isopropyl-phenyl)-1,1-dioxo-tetrahydro-thiopyran-4-
ylamino]-propyl}-acetamide;
C25. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-
isopropyl-phenyl)-l-oxo-tetrahydro-thiopyran-4-ylamino]-
propyl}-acetamide;
C26. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-
isopropyl-phenyl)-l-methanesulfonyl-piperidin-4-
ylamino]-propyl}-acetamide;
D1. N-[(1S,2R)-3-[l-Acetyl-4-(3-isopropyl-phenyl)-piperidin-
4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-propyl] -
acetamide;
D2. N-{ (1S,2R)-1-(3,5-Difluoro-benzyl)- 2 -hydroxy-3 -[4-(3-
isopropyl-phenyl)-piperidin-4-ylamino]-propyl}-
acetamide;
D3. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-
isopropyl-phenyl)-1-trifluoroacetyl-piperidin-4 -
ylamino]-propyl}-acetamide;
D4. N-{(1S,2R)-1-(3,5-Difluoro-benzyl) -2-hydroxy-3-[4-(3-
isopropoxy-phenyl)-tetrahydro-pyran-4-ylamino]-propyl}-
acetamide;
D5. N-{(1S,2R)-1-(3,5-Difluoro-benzyl) -2-hydroxy-3-[4-(3-
isopropyl-phenyl)-1,1-dimethyl-piperidin-4-ylamino]-
propyl}-acetamide;
D6. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-[l-formyl-4-(3-
isopropyl-phenyl)-piperidin-4-ylamino]-2-hydroxy-
propyl}-acetamide;
D7. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-[l-ethyl-4-(3-
isopropyl-phenyl)-piperidin-4-ylamino]-2-hydroxy-
propyl}-acetamide;
D8. N- [3-[4-(3-tert-Butyl-phenyl)-tetrahydro-pyran-4-
ylamino]-1- (3,5-difluoro-benzyl)-2-hydroxy-propyl]-
acetamide;
D9. N-{(1S,2R)-1-(3,5-Difluoro-4-hydroxy-benzyl)-2-hydroxy-
3-[1-(3-isopropyl-phenyl)-cyclohexylamino]-propyl}-
acetamide;
D10. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[1-(2-
isobutyl-thiazol-5-yl)-1-methyl-ethylamino]-propyl}-
acetamide;
Dll. N-{ (1S,2R) -1- (3,5-Difluoro-benzyl) --2-hydroxy-3- [3- (3-
isopropoxy-phenyl)-tetrahydro-pyran-3-ylamino]-propyl}-
acetamide;
D12. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)--2-hydroxy-3- [3-(3-
isopropyl-phenyl)-tetrahydro-pyran-3-ylamino]-propyl}-
acetamide;
D13. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-2-hydroxy-3-[4-(3-
isopropoxy-phenyl)-tetrahydro-pyran-4-ylamino]-propyl}-
2-fluoro-acetamide;
D14. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-[6-(2,2-dimethyl-
propyl)-chroman-4-ylamino]-2-hydroxy-propyl}-2-fluoro-
acetamide;
D15. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-{l-[2-(2,2-
dimethyl-propyl)-thiazol-5-yl]-1-methyl-ethylamino}-2-
hydroxy-propyl)-acetamide;
D16. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-{l-[3-(2,2-
dimethyl-propyl)-phenyl]-1-methyl-ethylamino}-2-hydroxy-
propyl)-2-fluoro-acetamide;
D17. N-{ (1S,2R)-1-(3,5-Difluoro-benzyl)-2-hydroxy-3- [4-(3-
isopropyl-phenyl)-tetrahydro-pyran-4-ylamino]-propyl}-
acetamide;
D18. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)- 2 -hydroxy-3 -[4-(3-
isopropyl-phenyl)-l-methyl-piperidin-4-ylamino]-propyl}-
acetamide;
D19. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-[1-ethanesulfonyl-
4-(3-isopropyl-phenyl)-piperidin-4-ylamino]-2-hydroxy-
propyl}-acetamide;
D20. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-[1-propanesulfonyl-
4-(3-isopropyl-phenyl)-piperidin-4-ylamino]-2-hydroxy-
propyl}-acetamide;
D21. N-{(1S,2R)-1-(3,5-Difluoro-benzyl)-3-[2-propanesulfonyl-
4-(3-isopropyl-phenyl)-piperidin-4-ylamino]-2-hydroxy-
propyl}-acetamide;
D22. N-[(1S,2R)-3-[4-(3-tert-Butyl-phenyl)-1-ethanesulfonyl-
piperidin-4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl]-acetamide;
D23. N-[(1S,2R)-3-[4-(3-tert-Butyl-phenyl)-1-methanesulfonyl-
piperidin-4-ylamino]-1-(3,5-difluoro-benzyl)-2-hydroxy-
propyl]-acetamide;
D24. 4-[(2R,3S)-3-Acetylamino-4-(3,5-difluoro-phenyl)-2-
hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-piperidine-
1-carboxylic acid amide;
D25. 4-[(2R,3S)-3-Acetylamino-4-(3,5-difluoro-phenyl) -2-
hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-piperidine-
1-carboxylic acid methylamide;
D26. 4-[(2R,3S)-3-Acetylamino-4-(3,5-difluoro-phenyl) -2-
hydroxy-butylamino]-4-(3-tert-butyl-phenyl)-piperidine-
1-carboxylic acid methyl ester;
El. N-[(1S,2R)-3-[(4s)-4-(3-tert-Butyl-phenyl)-1-
methanesulfonyl-azepan-4-ylamino]-1-(3,5-difluoro-
benzyl) -2-hydroxy-propyl]-acetamide;
E2. N- [ (1S, 2R) -3-.[.(4R) -4- (3-tert-Butyl-phenyl) -1-
methanesulfonyl-azepan-4-ylamino]-1-(3,5-difluoro-
benzyl) -2-hydroxy-propyl]-acetamide;
E3. N- [(1S,2R)-3- [(4R)-4-(3-tert-Butyl-phenyl)-azepan-4-
ylamino]-1-(3,6-difluoro-benzyl)-2-hydroxy-propyl]-
acetamide; and
E4. N- [ (1S,2R) -3- [ (4S) -4- (3-tert-Butyl-phenyl) -arepan-4-
ylamino] -1- (3, 5-dif luoro-benzyl) -2-hydroxy-propyl] -
acetamide.
Example 13 8
The following compounds are prepared essentially
according to the procedures set forth in the above examples
and schemes.
Ex. No. Compound
Al. N- [(1S,2R)-3-[(3-bromobenzyl)amino]-l-(3,5-
difluorobenzyl)-2 -hydroxypropyl]acetamide;
A2. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4R) -6-
isopropyl-2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-
yl]amino}propyl)acetamide;
A3. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
isopropyl-2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-
yl]amino}propyl)acetamide;
A4. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino] -2-
hydroxypropyl}acetamide;
A5. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
A6. N-[(1S,2R)-3-{[1-(3-bromophenyl)cyclopropyl]amino}-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide
hydrochloride;
A7. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
bromophenyl) propanoate;
A8. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-
ethylbenzyl)amino]- 2-hydroxypropyl}acetamide;
A9. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
e thylphenyl)propanoate;
A10. 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-difluorophenyl)-2-
hydroxybutyl]amino}-3-(3-ethylphenyl)propanoic acid;
All. N-((1S,2R)-1-(3, 5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-
3-hydroxypropyl]amino}-2-hydroxypropyl)acetamide;
A12. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1S)-
1,2,3,4-tetrahydronaphthalen-l-ylamino]propyl}acetamide;
A13. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,2-dioxido-3,4-
dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
A14. N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-
methylamino-acetamide;
A15. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-
iodobenzyl)amino]propyl}acetamide;
A16. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
iodophenyl) propanoate,-
A17. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3- [3-(3-
hydroxyprop-1-ynyl)phenyl]propanoate;
A18. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-
hydroxy-1-(3-iodophenyl)propyl]amino}propyl)acetamide;
A19. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
di fluorophenyl)-2-hydroxybutyl]amino}-3-[3 -(3-
hydroxypropyl)phenyl]propanoate;
A20. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-
methoxy-1,2,3,4-tetrahydronaphthalen-l-
yl)amino]propyl}acetamide;
A21. 2-Amino-N- [1-(3,5-difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-
2?6-isothiochroman-4-ylamino)-2-hydroxy-propyl]-
acetamide;
A2 2. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[6-ethyl-2-
(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-4-
yl] amino} -2-hydroxypropyl) acetamide,-
A23. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{ [(IS)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)acetamide;
A24. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]araino}-2-
hydroxypropyl)acetamide;
A25. N-[(1S,2R)-3-{[1-(3-bromophenyl)cyclopropyl]amino}-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
A26. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3- [3- (5-
formylthien-2-yl)phenyl]propanoate;
B1. methyl 3-{[(2.R,3S)-3-(acetylamino)-4-(3,5-
dif luorophenyl)-2-hydroxybutyl]amino}-3-(2'-acetyl-1,1' -
biphenyl-3-yl)propanoate;
B2. N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2, 2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-methyl-
butyramide;
B3. N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({l-[3'-
(hydroxymethyl)-1,1'-biphenyl-3 -
yl]cyclopropyl}amino)propyl]acetamide;
B4. N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({l-[3-(5-
formylthien-2-yl)phenyl]cyclopropyl}amino)-2-
hydroxypropyl]acetamide;
B5. N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(9H-fluoren-9-
ylamino)-2-hydroxypropyl]acetamide;
B6. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-[3-
(trifluoromethyl)phenyl]propanoate;
B7. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
cyanophenyl)propanoate;
B8. N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-hydroxy-
2,2-dimethyl-propionamide;
B9. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclopropyl]amino}-2-
hydroxypropyl)acetamide;
B10. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
bromophenyl)propanoate;
Bll. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1- (3-
ethynylphenyl)cyclopropyl]amino}-2-
hydroxypropyl)acetamide;
B12. N-[(1S,2R)-3-[(2-bromo-9H-fluoren-9-yl)amino]-1-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide;
B13. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-9H-
fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
B14. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,2-dioxido-3,4-
dihydro-1,2-benzoxathiin-4-yl)amino]-2-
hydroxypropyl}acetamide ;
B15. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-
3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide;
B16. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
iodo-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide;
B17. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4R)-6-
iodo-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide;
B18. N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-hydroxy-
propionamide;
B19. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-l,2-benzoxathiin-4-yl)amino]-2-
hydroxypropyl}acetamide;
B20. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-l,2-benzoxathiin-4-yl)amino]-2 -
hydroxypropyl}acetamide;
B21. N-((1S, 2R-)-1-(-3-,-5--difluorobenzyl-)-3-{[4- (-3-=
ethylphenyl)tetrahydro-2H-pyran-4-yl] amino}-2-
hydroxypropyl)acetamide;
B22. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-
ethylphenyl)butyl]amino}-2-hydroxypropyl)acetamide;
B23. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-ethyl-3,4-
dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide;
B24. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-3,4-
dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide;
B25. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(7-ethyl-l,2,3,4-
tetrahydronaphthalen-1-yl)amino]-2-
hydroxypropyl}acetamide,-
B26. N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-hydroxy-
butyramide;
Cl. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclohexyl]amino}-2-hydroxypropyl)acetamide;
C2. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-
ethylphenyl)cyclopentyl]amino}-2-
hydroxypropyl)acetamide;
C3. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3,4-
dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
C4. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-5-fluoro-
9H-fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
C5. methyl (3S)-3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)butanoate;
C6. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
isobutylisoxazol-5-
yl)cyclopropyl]amino}propyl)acetamide;
C7. N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-phenyl-
acetamide;
C8. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-7-fluoro-
9H-fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
C9. methyl (3R)-3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)butanoate;
C10. N-{ (1S,2R) -1-(3,5-difluorobenzyl)-3-[(2,5-
dipropylbenzyl)amino]-2-hydroxypropyl}acetamide;
Cll. {[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propylcarbamoyl]-
methyl}-methyl-carbamic acid tert-butyl ester;
C12. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
isobutyl-9H-fluoren-9-yl)amino]propyl}acetamide;
C13. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-6-ethyl-2,3-
dihydro-lH-inden-1-yl]amino}-2-hydroxypropyl)acetamide;
C14. N-[1-(3,5-Difluoro-benzyl)-3- (6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-methyl-2-
methylamino-propionamide;
C15. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-ethyl-l-(3-
ethylphenyl)propyl]amino}-2-hydroxypropyl)acetamide;
C16. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-2,l-benzothiazin-4-yl)amino]-2-
hydroxypropyl}acetamide;
C17. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-2,l-benzothiazin-4-yl)amino]-2-
hydroxypropyl}acetamide ;
C18. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3-methyl-
2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide ;
C19. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3-methyl-
2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide ;
C20. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-l-methyl-
1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-
hydroxypropyl}acetamide ;
C21. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)propanoate;
C22. N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-(1H-
imidazol-4-yl)-acetamide;
C23. methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)propanoate;
C24. N-[(1S,2R)-3-[(2-bromo-9-methyl-9H-fluoren-9-yl)amino]-
1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
C25. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(1-ethylpropyl)-
9H-fluoren-9-yl]amino}-2-hydroxypropyl)acetamide;
C26. N-[(1S,2R)-3-[(2-cyclopentyl-9H-fluoren-9-yl)amino]-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
Dl. n-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2?6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-
propionamide;
D2. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3- [ (2-ethyl-9-methyl-
9H-fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
D3. N- [ (1S,2R)-3-[(2-cyclohexyl-9H-fluoren-9-yl)amino]-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
D4. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(4-ethylpyridin-
2-yl)cyclopropyl]amino}-2-hydroxypropyl)acetamide;
D5. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
(lH-pyrrol-3-yl)-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide;
D6. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5R)-3-ethyl-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]amino}-2-
hydroxypropyl)acetamide;
D7. N- [ (1S,2R)-3-{[1-(3-bromophenyl)-1-methylethyl]amino}-l-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
D8. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(dimethylamino)-
9H-fluoren-9-yl]amino}-2-hydroxypropyl)acetamide;
D9. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(IS)-7-
propyl-1,2,3,4-tetrahydronaphthalen-l-
yl] amino Jpropyl) acetamide;.
D10. N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({(1S)-7-
[(dimethylamino)methyl]-1, 2,3,4-tetrahydronaphthalen-l-
yl}amino)-2-hydroxypropyl]acetamide,-
Dll. N-[(1S,2R)-3-{[(1S)-7-bromo-l,2,3,4-
tetrahydronaphthalen-1-yl]amino}-1-(3,5-difluorobenzyl)-
2-hydroxypropyl]acetamide;
D12. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
propylphenyl)cyclopropyl]amino}propyl)acetamide;
D13. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-
ethylphenyl)cycloheptyl]amino}-2 -
hydroxypropyl)acetamide;
D14. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
isopropyl-3,4-dihydro-2H-chromen-4-
yl)amino]propyl}acetamide;
D15. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2-hydroxy-
2,3-dihydro-lH-inden-l-yl)amino]-2-
hydroxypropyl}acetamide;
D16. N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-6-fluoro-
9H-fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
D17. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-
(methoxymethyl)-9H-fluoren-9-yl] amino}propyl)acetamide;
D18. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-
2-(5-methyl-l,3-oxazol-2-yl)ethyl]amino}-2-
hydroxypropyl)acetamide hydrochloride;
D19. N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(3,4-dihydro-2H-
chromen-4-ylamino)-2-hydroxypropyl]acetamide;
D20. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-ethyl-5-
(trifluoromethyl)-9H-fluoren-9-yl]amino}-2-
hydroxypropyl)acetamide;
D21. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(3-
methylbutyl)-9H-fluoren-9-yl]amino}propyl)acetamide;
D22. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
isopropyl-9H-fluoren-9-yl)amino]propyl}acetamide;
D23. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
neopentyl-9H-fluoren-9-yl)amino]propyl}acetamide;
D24. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
isopropenyl-9H-fluoren-9-yl)amino]propyl}acetamide;
D25. N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-
1-methylethyl]amino}-2-hydroxypropyl)acetamide
hydrochloride,-
D2 6. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3 -{[(4S)-6-
isobutyl-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide;
El. N-[(1S,2R)-3-{[(4S)-6-cyano-3,4-dihydro-2H-chromen-4-
yl]amino}-1-(3,5-difluorobenzyl)-2-
hydroxypropyl]acetamide;
E2. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
neopentyl-3,4-dihydro-2H-chromen~4-
yl]amino}propyl)acetamide;
E3. N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
neopentyl-3,4-dihydro-2H-chromen-4-
yl)amino]propyl}acetamide;
E4. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-
(isopropylamino)-9H-fluoren-9-yl]amino}propyl)acetamide;
E5. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
isobutylphenyl)cyclopropyl]amino}propyl)acetamide; and
E6. N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-
isobutyl-1,1'-biphenyl-2-
yl)methyl]amino}propyl)acetamide.
Generally, the protection of amines is conducted, where
appropriate, by methods known to those skilled in the art.
Amino protecting groups are known to those skilled in the art.
See for example, "Protecting Groups in Organic Synthesis",
John Wiley and sons, New York, N.Y., 1981, Chapter 7;
"Protecting Groups in Organic Chemistry", Plenum Press, New
York, N.Y., 1973, Chapter 2. When the amino protecting group
is no longer needed, it is removed by methods known to those
skilled in the art. By definition the amino protecting group
must be readily removable. A variety of suitable
methodologies are known to those skilled in the art; see also
T.W. Green and P.G.M. Wuts in "Protective Groups in Organic
Chemistry, John Wiley and Sons, 3rd edition, 1999. Suitable
amino protecting groups include t-butoxycarbonyl, benzyl-
oxycarbonyl, formyl, trityl, phthalimido, trichloro-acetyl,
chloroacetyl, bromoacetyl, iodoacetyl, 4-
phenylbenzyloxycarbonyl, 2-methylberizyloxycarbonyl, 4-
ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-
chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-
chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-
bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-
nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-
xenyl)isopropoxycarbonyl, 1,1-diphenyleth-l-yloxycarbonyl,
1,1-diphenylprop-l-yloxycarbonyl, 2-phenylprop-2-
yloxycarbonyl, 2 -(p-toluyl)prop-2-yloxy-carbonyl,
cyclopentanyloxycarbonyl, 1-methylcyclo-pentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methyl-cyclohexanyloxycabonyl, 2-
methylcyclohexanyloxycarbonyl, 2- (4-
toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)-
ethoxycarbonyl, 2 -(triphenylphosphino)ethoxycarbonyl,
fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxy-carbonyl,
allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-l-
enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-
acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-
ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-
(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, 1-
piperidyloxycarbonyl, 9-fluoroenylmethyl carbonate, -CH-CH=CH2
and phenyl-C(=N-)-H.
It is preferred that the protecting group be t-
butoxycarbonyl (BOC) and/or benzyloxycarbonyl (CBZ), it is
more preferred that the protecting group be t-butoxycarbonyl.
One skilled in the art will recognize suitable methods of
introducing a t-butoxycarbonyl or benzyloxycarbonyl protecting
group and may additionally consult T.W. Green and P.G.M. Wuts
in "Protective Groups in Organic Chemistry, John Wiley and
Sons, 3rd edition, 1999 for guidance.
The compounds of the invention may contain geometric or
optical isomers as tautomers. Thus, the invention includes
all tautomers and pure geometric isomers, such as the E and Z
geometric isomers, as mixtures thereof. Further, the
invention includes pure enantiomers, diastereomers and/or
mixtures thereof, including racemic mixtures. The individual
geometric isomers, enantiomers or diastereomers may be
prepared or isolated by methods known to those in the art,
including but not limited to chiral chromatography; preparing
diastereomers, separating the diastereomers and then
converting the diastereomers into enantiomers.
Compounds of the invention with designated
stereochemistry can be included in mixtures, including racemic
mixtures, with other enantiomers, diastereomers, geometric
isomers or tautomers. In a preferred aspect, compounds of the
invention are typically present in these mixtures in
diastereomeric and/or enantiomeric excess of at least 50
percent. Preferably, compounds of the invention are present
in these mixtures in diastereomeric and/or enantiomeric excess
of at least 80 percent. More preferably, compounds of the
invention with the desired stereochemistry are present in
diastereomeric and/or enantiomeric excess of at least 90
percent. Even more preferably, compounds of the invention
with the desired stereochemistry are present in diastereomeric
and/or enantiomeric excess of at least 99 percent. Preferably
the compounds of the invention have the "S" configuration at
position 1. Also preferred are compounds that have the "R"
configuration at position 2. Most preferred are compounds
that have the "1S,2R" configuration.
All compound names were generated using ACD Namepro
version 5.09, Chemdraw v. 6.02, or were derived therefrom.
Several of the compounds of formula (I) are amines, and
as such form salts when reacted with acids. Pharmaceutically
acceptable salts are preferred over the corresponding amines
since they produce compounds which are more water soluble,
stable and/or more crystalline. Pharmaceutically acceptable
salts are any salt which retains the activity of the parent
compound and does not impart any deleterious or undesirable
effect on the subject to whom it is administered and in the
context in which it. is administered. Pharmaceutically
acceptable salts include salts of both inorganic and organic
acids. The preferred pharmaceutically acceptable salts
include salts of the following acids acetic, aspartic,
benzenesulfonic, benzoic, bicarbonic, bisulfuric, bitartaric,
butyric, calcium edetate, camsylic, carbonic, chlorobenzoic,
citric, edetic, edisylic, estolic, esyl, esylic, formic,
fumaric, gluceptic, gluconic, glutamic, glycollylarsanilic,
hexamic, hexylresorcinoic, hydrabamic, hydrobromic,
hydrochloric, hydroiodic, hydroxynaphthoic, isethionic,
lactic, lactobionic, maleic, malic, malonic, mandelic,
methanesulfonic, methylnitric, methylsulfuric, mucic, muconic,
napsylic, nitric, oxalic, p-nitromethanesulfonic, pamoic,
pantothenic, phosphoric, monohydrogen phosphoric, dihydrogen
phosphoric, phthalic, polygalactouronic, propionic, salicylic,
stearic, succinic, sulfamic, sulfanilic, sulfonic, sulfuric,
tannic, tartaric, teoclic and toluenesulfonic. For other
acceptable salts, see Int. J. Pharm., 33, 201-217 (1986) and
J. Pharm. Sci., 66(1), 1, (1977).
The invention provides compounds, compositions, kits, and
methods for inhibiting beta-secretase enzyme activity and A
beta peptide production. Inhibition of beta-secretase enzyme
activity halts or reduces the production of A beta from APP
and reduces or eliminates the formation of beta-amyloid
deposits in the brain.
Methods of the Invention
The compounds of the invention, and pharmaceutically
acceptable salts thereof, are useful for treating humans or
animals suffering from a condition characterized by a
pathological form of beta-amyloid peptide, such as beta-
amyloid plaques, and for helping to prevent or delay the onset
of such a condition. For example, the compounds are useful
for treating Alzheimer's disease, for helping prevent or delay
the onset of Alzheimer's disease, for treating patients with
MCI (mild cognitive impairment) and preventing or delaying the
onset of Alzheimer's disease in those who would progress from
MCI to AD, for treating Down's syndrome, for treating humans
who have Hereditary Cerebral Hemorrhage with Amyloidosis of
the Dutch-Type, for treating cerebral amyloid angiopathy and
preventing its potential consequences, i.e. single and
recurrent lobal hemorrhages, for treating other degenerative
dementias, including dementias of mixed vascular and
degenerative origin, dementia associated with Parkinson's
disease, dementia associated with progressive supranuclear
palsy, dementia associated with cortical basal degeneration,
and diffuse Lewy body type Alzheimer's disease. The compounds
and compositions of the invention are particularly useful for
treating or preventing Alzheimer's disease. When treating or
preventing these diseases, the compounds of the invention can
either be used individually or in combination, as is best for
the patient.
As used herein, the term "treating" means that the
compounds of the invention can be used in humans with at least
a tentative diagnosis of disease. The compounds of the
invention will delay or slow the progression of the disease
thereby giving the individual a more useful life span.
The term "preventing" means that the compounds of the
invention are useful when administered to a patient who has
not been diagnosed as possibly having the disease at the time
of administration, but who would normally be expected to
develop the disease or be at increased risk for the disease.
The compounds of the invention will slow the development of
disease symptoms, delay the onset of the disease, or prevent
the individual from developing the disease at all. Preventing
also includes administration of the compounds of the invention
to those individuals, thought to be predisposed to the disease
due to age, familial history, genetic or chromosomal
abnormalities, and/or due to the presence of one or more
biological markers for the disease, such as a known genetic
mutation of APP or APP cleavage products in brain tissues or
fluids.
In treating or preventing the above diseases, the
compounds of the invention - are administered in a
therapeutically effective amount. The therapeutically
effective amount will vary depending on the particular
compound used and the route of administration, as is known to
those skilled in the art.
In treating a patient displaying any of the diagnosed
above conditions a physician may administer a compound of the
invention immediately and continue administration
indefinitely, as needed. In treating patients who are not
diagnosed as having Alzheimer's disease, but who are believed
to be at substantial risk for Alzheimer's disease, the
physician should preferably start treatment when the patient
first experiences early pre-Alzheimer's symptoms such as,
memory or cognitive problems associated with aging. In
addition, there are some patients who may be determined to be
at risk for developing Alzheimer's through the detection of a
genetic marker such as AP0E4 or other biological indicators
that are predictive for Alzheimer's disease. In these
situations, even though the patient does not have symptoms of
the disease, administration of the compounds of the invention
may be started before symptoms appear, and treatment may be
continued indefinitely to prevent or delay the onset of the
disease.
Dosage Forms and Amounts
The compounds of the invention can be administered
orally, parenterally, (IV, IM, depo-IM, SQ, and depo SQ),
sublingually, intranasally (inhalation), intrathecally,
topically, or rectally. Dosage forms known to those of skill
in the art are suitable for delivery of the compounds of the
invention.
Compositions are provided that contain therapeutically
effective amounts of the compounds of the invention. The
compounds are preferably formulated into suitable
pharmaceutical preparations such as tablets, capsules, or
elixirs for oral administration or in sterile solutions or
suspensions for parenteral administration. Typically the
compounds described above are formulated into pharmaceutical
compositions using techniques and procedures well known in the
art.
About.1 to 500 mg of a compound or mixture of compounds
of the invention or a physiologically acceptable salt is
compounded with a physiologically acceptable vehicle, carrier,
excipient, binder, preservative, stabilizer, flavor, etc., in
a unit dosage form as called for by accepted pharmaceutical
practice. The amount of active substance. in those
compositions or preparations is such that a suitable dosage in
the range indicated is obtained. The compositions are
preferably formulated in a unit dosage form, each dosage
containing from about 2 to about 100 mg, more preferably about
10 to about 30 mg of the active ingredient. The term "unit
dosage from" refers to physically discrete units suitable as
unitary dosages for human subjects and other mammals, each
unit containing a predetermined quantity of active material
calculated to produce the desired therapeutic effect, in
association with a suitable pharmaceutical excipient.
To prepare compositions, one or more compounds of the
invention are mixed with a suitable pharmaceutically
acceptable carrier. Upon mixing or addition of the
compound(s), the resulting mixture may be a solution,
suspension, emulsion, or the like. Liposomal suspensions may
also be suitable as pharmaceutically acceptable carriers.
These may be prepared according to methods known to those
skilled in the art. The form of the resulting mixture depends
upon a number of factors, including the intended mode of
administration and the solubility of the compound in the
selected carrier or vehicle. The effective concentration is
sufficient for lessening or ameliorating at least one symptom
of the disease, disorder., or condition treated and may be
empirically determined.
Pharmaceutical carriers or vehicles suitable for
administration of the compounds provided herein include any-
such carriers known to those skilled in the art to be suitable
for the particular mode of administration. In addition, the
active materials can also be mixed with other active materials
that do not impair the desired action, or with materials that
supplement the desired action, or have another action. The
compounds may be formulated as the sole pharmaceutically-
active ingredient in the composition or may be combined with
other active ingredients.
Where the compounds exhibit insufficient solubility,
methods for solubilizing may be used. Such methods are known
and include, but are not limited to, using cosolvents such as
dimethylsulfoxide (DMSO), using surfactants such as Tween®,
and dissolution in aqueous sodium bicarbonate. Derivatives of
the compounds, such as salts or prodrugs may also be used in
formulating effective pharmaceutical compositions.
The concentration of the compound is effective for
delivery of an amount upon administration that lessens or
ameliorates at least one symptom of the disorder for which the
compound is administered. Typically, the compositions are
formulated for single dosage administration.
The compounds of the invention may be prepared with
carriers that protect them against rapid elimination from the
body, such as time-release formulations or coatings. Such
carriers include controlled release formulations, such as, but
not limited to, microencapsulated delivery systems. The
active compound is included in the pharmaceutically acceptable
carrier in an amount sufficient to exert a therapeutically
useful effect in the absence of undesirable side effects on
the patient treated. The therapeutically effective
concentration may be determined empirically by testing the
compounds in known in vitro and in vivo model systems for the
treated disorder.
The compounds and compositions of the invention can be
enclosed in multiple or single dose containers. The enclosed
compounds and compositions can be provided in kits, for
example, including component parts that can be assembled for
use. For example, a compound inhibitor in lyophilized form
and a suitable diluent may be provided as separated components
for combination prior to use. A kit may include a compound
inhibitor and a second therapeutic agent for co-
administration. The inhibitor and second therapeutic agent
may be provided as separate component parts. A kit may
include a plurality of containers, each container holding one
or more unit dose of the compound of the invention. The
containers are preferably adapted for the desired mode of
administration, including, but not limited to tablets, gel
capsules, sustained-release capsules, and the like for oral
administration; depot products, pre-filled syringes, ampoules,
vials, and the like for parenteral administration; and
patches, medipads, creams, and the like for topical
administration.
The concentration of active compound in. the drug
composition will depend on absorption, inactivation, and
excretion rates of the active compound, the dosage schedule,
and amount administered as well as other factors known to
those of skill in the art.
The active ingredient may be administered at once, or may
be divided into a number of smaller doses to be administered
at intervals of time. It is understood that the precise
dosage and duration of treatment is a function of the disease
being treated and may be determined empirically using known
testing protocols or by extrapolation from in vivo or in vitro
test data. It is to be noted that concentrations and dosage
values may also vary with the severity of the condition to be
alleviated. It is to be further understood that for any
particular subject, specific dosage regimens should be
adjusted over time according to the individual need and the
professional judgment of the person administering or
supervising the administration of the compositions, and that
the concentration ranges set forth herein are exemplary only
and are not intended to limit the scope or practice of the
claimed compositions.
If oral administration is desired, the compound should be
provided in a composition that protects it from the acidic
environment of the stomach. For example, the composition can
be formulated in an enteric coating that maintains its
integrity in the stomach and releases the active compound in
the intestine. The composition may also be formulated in
combination with an antacid or other such ingredient.
Oral compositions will generally include an inert diluent
or an edible carrier and may be compressed into tablets or
enclosed in gelatin capsules. For the purpose of oral
therapeutic administration, the active compound or compounds
can be incorporated with excipients and used in the form of
tablets, capsules, or troches. Pharmaceutically compatible
binding agents and adjuvant materials can be included as part
of the composition.
The tablets, pills, capsules, troches, and the like can
contain any of the following ingredients or compounds of a
similar nature: a binder such as, but not limited to, gum
tragacanth, acacia, corn starch, or gelatin; an excipient such
as microcrystalline cellulose, starch, or lactose; a
disintegrating agent such as, but not limited to, alginic acid
and corn starch; a lubricant such as, but not limited to,
magnesium stearate; a gildant, such as, but not limited to,
colloidal silicon dioxide; a sweetening agent such as sucrose
or saccharin; and a flavoring agent such as peppermint, methyl
salicylate, or fruit flavoring.
When the dosage unit form is a capsule, it can contain,
in addition to material of the above type, a liquid carrier
such as a fatty oil. In addition, dosage unit forms can
contain various other materials, which modify the physical
form of the dosage unit, for example, coatings of sugar and
other enteric agents. The compounds can also be administered
as a component of an elixir, -suspension, syrup, wafer, chewing
gum or the like. A syrup may contain, in addition to the
active compounds, sucrose as a sweetening agent and certain
preservatives, dyes and colorings, and flavors.
The active materials can also be mixed with other active
materials that do not impair the desired action, or with
materials that supplement the desired action.
Solutions or suspensions used for parenteral,
intradermal, subcutaneous, or topical application can include
any of the following components: a sterile diluent such as
water for injection, saline solution, fixed oil, a naturally
occurring vegetable oil such as sesame oil, coconut oil,
peanut oil, cottonseed oil, and the like, or a synthetic fatty
vehicle such as ethyl oleate, and the like, polyethylene
glycol, glycerine, propylene glycol, or other synthetic
solvent; antimicrobial agents such as benzyl alcohol and
methyl parabens; antioxidants such as ascorbic acid and sodium
bisulfite; chelating agents such as ethylenediaminetetraacetic
acid (EDTA); buffers such as acetates, citrates, and
phosphates; and agents for the adjustment of tonicity such as
sodium chloride and dextrose. Parenteral preparations can be
enclosed in ampoules, disposable syringes, or multiple dose
vials made of glass, plastic, or other suitable material.
Buffers, preservatives, antioxidants, and the like can be
incorporated as required.
Where administered intravenously, suitable carriers
include physiological saline, phosphate buffered saline (PBS),
and solutions containing thickening and solubilizing agents
such as glucose, polyethylene glycol, polypropyleneglycol, and
mixtures thereof. Liposomal suspensions including tissue-
targeted liposomes may also be suitable as pharrnaceutically
acceptable carriers. These may be prepared according to
methods known for example, as described in U.S. Patent No.
4, 522,811.
The active compounds may be prepared with carriers that
protect the compound against rapid elimination from the body,
such as time-release formulations or coatings. Such carriers
include controlled release formulations, such as, but not
limited to, implants and microencapsulated delivery systems,
and biodegradable, biocompatible polymeirs such as collagen,
ethylene vinyl acetate, polyanhydrides, polyglycolic acid,
polyorthoesters, polylactic acid, and the like. Methods for
preparation of such formulations are known to those in the
art.
The compounds of the invention can be administered
orally, parenterally (IV, IM, depo-IM, SQ, and depo-SQ),
sublingually, intranasally (inhalation), intrathecally,
topically, or rectally. Dosage forms known to those skilled
in the art are suitable for delivery of the compounds of the
invention.
Compounds of the invention may be administered enterally
or parenterally. When administered orally, compounds of the
invention can be administered in usual dosage forms for oral
administration as is well known to those skilled in the art.
These dosage forms include the usual solid unit dosage forms
of tablets and capsules as well as liquid dosage forms such as
solutions, suspensions, and elixirs. When the solid dosage
forms are used, it is preferred that they be of the sustained
release type so that the compounds of the invention need to be
administered only once or twice daily.
The oral dosage forms are administered to the patient 1,
2, 3, or 4 times daily. It is preferred that the compounds of
the invention be administered either three or fewer times,
more preferably once or twice daily. Hence, it is preferred
that the compounds of the invention be administered in oral
dosage form. It is preferred that whatever oral dosage form
is used, that it be designed so as to protect the compounds of
the invention from the acidic environment of the stomach.
Enteric coated tablets are well known to those skilled in the
art. In addition, capsules filled with small spheres each
coated to protect from the acidic stomach, are also well known
to those- skilled in the art.
When administered orally, an administered amount
therapeutically effective to inhibit beta-secretase activity,
to inhibit A beta production, to inhibit A beta deposition, or
to treat or prevent AD is from about 0.1 mg/day to about 1,000
mg/day. It is preferred that the oral dosage is from about 1
mg/day to about 100 mg/day. It is more preferred that the
oral dosage is from about 5 mg/day to about 50 mcf/day. It is
understood that while a patient may be started at one dose,
that dose may be varied over time as the patient's condition
changes.
Compounds of the invention may also be advantageously
delivered in a nano crystal dispersion formulation.
Preparation of such formulations is described, for example, in
U.S. Patent 5,145,684. Nano crystalline dispersions of HIV
protease inhibitors and their method of use are described in
U.S. Patent No. 6,045,829. The nano crystalline formulations
typically afford greater bioavailability of drug compounds.
The compounds of the invention can be administered
parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC.
When administered parenterally, a therapeutically effective
amount of about 0.5 to about 100 mg/day, preferably from about
5 to about 50 mg daily should be delivered. When a depot
formulation is used for injection once a month or once every
two weeks, the dose should be about 0.5 mg/day to about 50
mg/day, or a monthly dose of from about 15 mg to about 1,500
mg. In part because of the forgetfulness of the patients with
Alzheimer's disease, it is preferred that the parenteral
dosage form be a depo formulation.
The compounds of the invention can be administered
sublingually. When given sublingually, the compounds of the
invention should be given one to four times daily in the
amounts described above for IM administration.
The compounds of the invention can be administered
intranasally. When given by this route, the appropriate
dosage forms are a nasal spray or dry powder, as is known to
those skilled in the art. The dosage of the compounds of the
invention for intranasal administration is the amount
described above for IM administration.
The compounds of the invention can be administered
intrathecally. When given by this route the appropriate
dosage form can be a parenteral dosage form as is known to
those skilled in the art. The dosage of the compounds of the
invention for intrathecal administration is the amount
described above for IM administration.
The compounds of the invention can be administered
topically. When given by this route, the appropriate dosage
form is a cream, ointment, or patch. Because of the amount of
the compounds of the invention to be administered, the patch
is preferred. When administered topically, the dosage is from
about 0.5 mg/day to about 200 mg/day. Because the amount that
can be delivered by a patch is limited,, two or more patches
may be used. The number and size of the patch is not
important, what is important is that a therapeutically
effective amount of the compounds of the invention be
delivered as is known to those skilled in the: art. The
compounds of the invention can be administered rectally by
suppository as is known to those skilled in the art. When
administered by suppository, the therapeutically effective
amount is from about 0.5 mg to about 500 mg.
The compounds of the invention can be administered by
implants as is known to those skilled in the art. When
administering a compound of the invention by implant, the
therapeutically effective amount is the amount described above
for depot administration.
Given a particular compound of the invention and a
desired dosage form, one skilled in the art would know how to
prepare and administer the appropriate dosage form.
The compounds of the invention are used in the same
manner, by the same routes of administration, using the same
pharmaceutical dosage forms, and at the same dosing schedule
as described above, for preventing disease or treating
patients with MCI (mild cognitive impairment) and preventing
or delaying the onset of Alzheimer's disease in those who
would progress from MCI to AD, for treating or preventing
Down's syndrome, for treating humans who have Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for
treating cerebral amyloid angiopathy and preventing its
potential consequences, i.e. single and recurrent lobar
hemorrhages, for treating other degenerative dementias,
including dementias of mixed vascular and degenerative origin,
dementia associated with Parkinson's disease, dementia
associated with progressive supranuclear palsy, dementia
associated with cortical basal degeneration, and diffuse Lewy
body type of Alzheimer's disease.
The compounds of the invention can be used in
combination, with each other or with other therapeutic agents
or approaches used to treat or prevent the conditions listed
above. Such agents or approaches include: acetylcholine
esterase inhibitors such as tacrine (tetrahydroaminoacridine,
marketed as COGNEX®), donepezil hydrochloride, (marketed as
Aricept® and rivastigmine (marketed as Exelon®); gamma-
secretase inhibitors; anti-inflammatory agents such as
cyclooxygenase II inhibitors; anti-oxidants such as Vitamin E
and ginkolides; immunological approaches, such as, for
example, immunization with A beta peptide or administration of
anti-A beta peptide antibodies; statins; and direct or
indirect neurotropic agents such as Cerebrolysin®, AIT-082
(Emilieu, 2000, Arch. Neurol. 57:454), and other neurotropic
agents of the future.
In addition, the compounds of formula (I) can also be
used with inhibitors of P-glycoprotein (P-gp). P-gp
inhibitors and the use of such compounds are known to those
skilled in the art. See for example, Cancer Research, 53,
4595-4602 (1993), Clin. Cancer Res., 2, 7-12 (1996), Cancer
Research, 56, 4171-41.79 (1996), International Publications
WO99/64001 and WO01/10387. The important thing is that the
blood level of the P-gp inhibitor be such that it exerts its
effect in inhibiting P-gp from decreasing brain blood levels
of the compounds of formula (A). To that end the P-gp
inhibitor and the compounds of formula (A) can be administered
at the same time, by the same or different route of
administration, or at different times. The important thing is
not the time of administration but having an effective blood
level of the P-gp inhibitor.
Suitable P-gp inhibitors include cyclosporin A,
verapamil, tamoxifen, quinidine, Vitamin E-TGPS,. ritonavir,
megestrol acetate, progesterone, rapamycin, 10,11-
methanodibenzosuberane, phenothiazines, acridine derivatives
such as GF120918, FK506, VX-710, LY335979, PSC-833, GF-102,918
and other steroids. It is to be understood that additional
agents will be found that have the same function and therefore
achieve the same outcome; such compounds are also considered
to be useful.
The P-gp inhibitors can be administered orally,
parenterally, (IV, IM, IM-depo, SQ, SQ-depo), topically,
sublingually, rectally, intranasally, intrathecally and by
implant.
The therapeutically effective amount of the P-gp
inhibitors is from about 0.1 to about 300 mg/kg/day,
preferably about 0.1 to about 150 mg/kg daily. It is
understood that, while a patient may be started on one dose,
that dose may have to be varied over time as the patient's
condition changes.
When administered orally, the P-gp inhibitors can be
administered in usual dosage forms for oral administration as
is known to those skilled in the art. These dosage forms
include the usual solid unit dosage forms of tablets and
capsules as well as liquid dosage forms such as solutions,
suspensions and elixirs. When the solid dosage forms are
used, it is preferred that they be of the sustained release
type, so that the P-gp inhibitors need to be administered only
once or twice daily. The oral dosage forms are administered
to the patient one thru four times daily. It is preferred
that the P-gp inhibitors be administered either three or fewer
times a day, more preferably once or twice daily. Hence, it
is preferred that the P-gp inhibitors be: administered in solid
dosage form and further it is preferred that the solid dosage
form be a sustained release form which permits once or twice
daily dosing. It is preferred that what ever dosage form is
used, that it be designed so as to protect, the P-gp inhibitors
from the acidic environment of the stomach. Enteric coated
tablets are well known to those skilled in the art. In
addition, capsules filled with small spheres each coated to
protect from the acidic stomach, are also well known to those
skilled in the art.
In addition, the P-gp inhibitors can be administered
parenterally. When administered parenterally they can be
administered IV, IM, depo-IM, SQ or depo-SQ.
The P-gp inhibitors can be given sublingually. When
given sublingually, the P-gp inhibitors should be given one
thru four times daily in the same amount as for IM
administration.
The P-gp inhibitors can be given intranasally. When
given by this route of administration, the appropriate dosage
forms are a nasal spray or dry powder as is known to those
skilled in the art. The dosage of the; P-gp inhibitors for
intranasal administration is the same as for IM
administration.
The P-gp inhibitors can be given intrathecally. When
given by this route of administration the appropriate dosage
form can be a parenteral dosage form as is known to those
skilled in the art.
The P-gp inhibitors can be given topically. when given
by this route of administration, the appropriate dosage form
is a cream, ointment or patch. Because of the amount of the
P-gp inhibitors needed to be administered the patch is
preferred. However, the amount that can be delivered by a
patch is limited. Therefore, two or more patches may be
required. The number and size of the patch is not important,
what is important is that a therapeutically effective amount
of the P-gp inhibitors be delivered as is known to those
skilled in the art.
The P-gp inhibitors can be administered rectally by
suppository or by implants, both of which are known to those
skilled in the art.
There is nothing novel about the route of administration
nor the dosage forms for administering the P-gp inhibitors.
Given a particular P-gp inhibitor, and a desired dosage form,
one skilled in the art would know how to prepare the
appropriate dosage form for the P-gp inhibitor.
It should be apparent to one skilled in the art that the
exact dosage and frequency of administration will depend on
the particular compounds of the invention administered, the
particular condition being treated, the severity of the
condition being treated, the age, weight, general physical
condition of the particular patient, and other medication the
individual may be taking as is well known to administering
physicians who are skilled in this art.
Inhibition of APP Cleavage
The compounds of the invention inhibit cleavage of APP
between Met595 and Asp596 numbered for the APP695 isoform, or
a mutant thereof, or at a corresponding site of a different
isoform, such as APP.751 or APP770, or a mutant thereof
(sometimes referred to as the "beta secretase site"). While
not wishing to be bound by a particular theory, inhibition of
beta-secretase activity is thought to inhibit production of
beta amyloid peptide (A beta). Inhibitory activity is
demonstrated in one of a variety of inhibition assays, whereby
cleavage of an APP substrate in the presence of a beta-
secretase enzyme is analyzed, in the presence of the inhibitory
compound, under conditions normally sufficient to result in
cleavage at the beta-secretase cleavage site. Reduction of
APP cleavage at the beta-secretase cleavage site compared with
an untreated or inactive control is correlated with inhibitory-
activity. Assay systems that can be used to demonstrate
efficacy of the compound inhibitors of the invention are
known. Representative assay systems are described, for
example, in U.S. Patents No. 5,942,400, 5,744,346, as well as
in the Examples below.
The enzymatic activity of beta-secretase and the
production of A beta can be analyzed in vitro or in vivo,
using natural, mutated, and/or synthetic APP substrates,
natural, mutated, and/or synthetic enzyme, and the test
compound. The analysis may involve primary or secondary cells
expressing - native, mutant, and/or synthetic APP and enzyme,
animal models expressing native APP and enzyme, or may utilize
transgenic animal models expressing the substrate; and enzyme.
Detection of enzymatic activity can be by analysis of one or
more of the cleavage products, for example, by immunoassay,
fluorometric or chromogenic assay, HPLC, or other means of
detection. Inhibitory compounds are determined as those
having the ability to decrease the amount of beta-secretase
cleavage product produced in comparison to a control, where
beta-secretase mediated cleavage in the reaction system is
observed and measured in the absence of inhibitory compounds.
Beta-Secretase
Various forms of beta-secretase enzyme are known, and are
available and useful for assay of enzyme activity and
inhibition of enzyme activity. These include native,
recombinant, and synthetic forms of the enzyme. Human beta-
secretase is known as Beta Site APP Cleaving Enzyme (BACE),
Asp2, and memapsin 2, and has been characterized, for example,
in U.S. Patent No. 5,744,346 and published PCT patent
applications WO98/22597, WO00/03819, WO0l/23533, and
WO00/17369, as well as in literature publications (Hussain et
al., 1999, Mol. Cell. Neurosci. 14:419-427; Vassar et al.,
1999, Science 286:735-741; Yan et al., 1999, Nature 402:533-
537; Sinha et al., 1999, Nature 40:537-540; and Lin et al.,
2000, PNAS USA 97:1456-1460). Synthetic forms of the enzyme
have also been described (WO98/22597 and WO00/17369). Beta-
secretase can be extracted and purified from human brain
tissue and can be produced in cells, for example mammalian
cells expressing recombinant enzyme.
Preferred compounds are effective to inhibit 50% of beta-
secretase enzymatic activity at a concentration of less than
50 micromolar, preferably at a concentration of 10 micromolar
or less, more preferably 1 micromolar or less, and most
preferably 10 nanomolar or less.
APP Substrate
Assays that demonstrate inhibition of beta-secretase-
mediated cleavage of APP can utilize any of the known forms of
APP, including the 695 amino acid "normal" isotype described
by Rang. et al., 1987, Nature 325:733-6, the 770 amino acid
isotype described by Kitaguchi et. al., 1981, Nature 331:530-
532, and variants such as the Swedish Mutation (KM670-1NL)
(APP-SW), the London Mutation (V7176F), and others. See, for
example, U.S. Patent No. 5,766,846 and also Hardy, 1992,
Nature Genet. 1:233-234,- for a review of known variant
mutations. Additional useful substrates; include the dibasic
amino acid modification, APP-KK disclosed, for example, in WO
00/17369, fragments of APP, and synthetic peptides containing
the beta-secretase cleavage site, wild type (WT) or mutated
form, e.g., SW, as described, for example, in U.S. Patent No
5,942,400 and WO00/03819.
The APP substrate contains the beta-secretase cleavage
site of APP (KM-DA or NL-DA) for example, a complete APP
peptide or variant, an APP fragment, a recombinant or
synthetic APP, or a fusion peptide. Preferably, the fusion
peptide includes the beta-secretase cleavage site fused to a
peptide having a moiety useful for enzymatic assay, for
example, having isolation and/or detection properties. A
useful moiety may be an antigenic epitope for antibody
binding, a label or other detection moiety, a binding
substrate, and the like.
Antibodies
Products characteristic of APP cleavage can be measured
by immunoassay using various antibodies, as described, for
example, in Pirttila et al., 1999, Neuro. Lett. 249:21-4, and
in U.S. Patent No. 5,612,486. Useful antibodies to detect A
beta include, for example, the monoclonal antibody 6E10
(Senetek, St. Louis, MO) that specifically recognizes an
epitope on amino acids 1-16 of the A beta peptide; antibodies
162 and 164 (New York State Institute for Basic Research,
Staten Island, NY) that are specific for human A beta 1-40 and
1-42, respectively; and antibodies that recognize the junction
region of beta-amyloid peptide, the site between residues 16
and 17, as described in U.S. Patent No. 5,593,846. Antibodies
raised against a synthetic peptide of residues 591 to 596 of
APP and SW192 antibody raised against 590-596 of the Swedish
mutation are also useful in immunoassay of APP and its
cleavage products, as described in U.S. Patent Nos. 5,604,102
and 5,721,13 0.
Assay Systems
Assays for determining APP cleavage at the beta-secretase
cleavage site are well known in the art. Exemplary assays,
are described, for example, in U.S. Patent Nos. 5,744,346 and
5,942,400, and described in the Examples below.
Cell Free Assays
¦ Exemplary assays that can be used to demonstrate the
inhibitory activity of the compounds of the invention are
described, for example, in WO00/17369, WO 00/03819, and U.S.
Patents No. 5,942,400 and 5,744,346. Such assays can be
performed in cell-free incubations or in cellular incubations
using cells expressing a beta-secretase and an APP substrate
having a beta-secretase cleavage site.
An APP substrate containing the beta-secretase cleavage
site of APP, for example, a complete APP or variant, an APP
fragment, or a recombinant or synthetic APP substrate
containing the amino acid sequence: KM-DA or NL-DA, is
incubated in the presence of beta-secretase enzyme, a
fragment thereof, or a synthetic or recombinant polypeptide
variant having beta-secretase activity and effective to cleave
the beta-secretase cleavage site of APP, under incubation
conditions suitable for the cleavage activity of the enzyme.
Suitable substrates optionally include derivatives that may be
fusion proteins or peptides that contain the substrate peptide
and a modification useful to facilitate the purification or
detection of the peptide or its beta-secretase cleavage
products. Useful modifications include the insertion of a
known antigenic epitope for antibody binding; the linking of a
label or detectable moiety, the linking of a binding
substrate, and the like.
Suitable incubation conditions for a cell-free in vitro
assay include, for example: approximately 200 nanomolar to 10
micromolar substrate, approximately 10 to 200 picomolar
enzyme, and approximately 0.1 nanomolar to 10 micromolar
inhibitor compound, in aqueous solution, at an approximate pH
of 4 -7, at approximately 37 degrees C, for a time period of
approximately 10 minutes to 3 hours. These incubation
conditions are exemplary only, and can be varied as required
for the particular assay components and/or desired measurement
system. Optimization of the incubation conditions for the
particular assay components should account for the specific
beta-secretase enzyme used and its pH optimum, any additional
enzymes and/or markers that might be used in the assay, and
the like. Such optimization is routine and will not require
undue experimentation.
One useful assay utilizes a fusion peptide having maltose
binding protein (MBP) fused to the C-terminal 125 amino acids
of APP-SW. The MBP portion is captured on an assay substrate
by anti-MBP capture antibody. Incubation of the captured
fusion protein in the presence of beta-secretase results in
cleavage of the substrate at the beta-secretase cleavage site.
Analysis of the cleavage activity can be, for example, by
immunoassay of cleavage products. One such immunoassay
detects a unique epitope exposed at the carboxy terminus of
the cleaved fusion protein, for example, using the antibody
SW192. This assay is described, for example, in U.S. Patent
No 5,942,400.
Cellular Assay
Numerous cell-based assays can be used to analyze beta-
secretase activity and/or processing of APP to release- A beta.
Contact of an APP substrate with a beta-secretase enzyme
within the cell and in the presence or absence of a compound
inhibitor of the invention can be used to demonstrate beta-
secretase inhibitory activity of the compound. Preferably,
assay in the presence of a useful inhibitory compound provides
at least about 30%, most preferably at least about 50%
inhibition of the enzymatic activity, as compared with a non-
inhibited control.
In one embodiment, cells that naturally express beta-
secretase are used. Alternatively, cells are modified to
express a recombinant beta-secretase or synthetic variant
enzyme as discussed above. The APP substrate may be added to
the culture medium and is preferably expressed in the cells.
Cells that naturally express APP, variant or mutant forms of
APP, or cells transformed to express an isoform of APP, mutant
or variant APP, recombinant or synthetic APP, APP fragment, or
synthetic APP peptide or fusion protein containing the beta-
secretase APP cleavage site can be used, provided that the
expressed APP is permitted to contact the enzyme and enzymatic
cleavage activity can be analyzed.
Human cell lines that normally process A beta from APP
provide a useful means to assay inhibitory activities of the
compounds of the invention. Production and release of A beta
and/or other cleavage products into the culture medium can be
measured, for example by immunoassay, such as Western blot or
enzyme-linked immunoassay (EIA) such as by ELISA.
Cells expressing an APP substrate and an active beta-
secretase can be incubated in the presence of a compound
inhibitor to demonstrate inhibition of enzymatic activity as
compared with a control. Activity of beta-secretase can be
measured by analysis of one or more cleavage products of the
APP substrate. For example, inhibition of beta-secretase
activity against the substrate APP would be expected to
decrease release of specific beta-secretase induced APP
cleavage products such as A beta.
Although both neural and non-neural cells process and
release A beta, levels of endogenous beta-secretase activity
are low and often difficult to detect by EIA. The use of cell
types known to have enhanced beta-secretase activity, enhanced
processing of APP to A beta, and/or enhanced production of A
beta are therefore preferred. For example, transfection of
cells with the Swedish Mutant form of APP (APP-SW) ; with APP-
KK; or with APP-SW-KK provides cells having enhanced beta-
secretase activity and producing amounts of A beta that can be
readily measured.
In such assays, for example, the cells expressing APP and
beta-secretase are incubated in a culture medium under
conditions suitable for beta-secretase enzymatic activity at
its cleavage site on the APP substrate. On exposure of the
cells to the compound inhibitor, the amount of A beta released
into the medium and/or the amount of CTF99 fragments of APP in
the cell lysates is reduced as compared with the control. The
ravage products of APP can be analyzed, for example, by
pune reactions with specific antibodies, as discussed above.
preferred cells for analysis of beta-secretase activity
include primary human neuronal cells, primary transgenic
animal neuronal cells where the transgene is APP, and other
cells such as those of a stable 2 93 cell line expressing APP,
for example, APP-SW.
In vivo Assays: Animal Models
Various animal models can be used to analyze beta-
secretase activity and /or processing of APP to release A
beta, as described above. For example, transgenic animals
expressing APP substrate and beta-secretase enzyme can be used
to demonstrate inhibitory activity of the compounds of the
invention. Certain transgenic animal models have been
described, for example, in U.S. Patent Nos.: 5,877,399;
5,612,486; 5,387,742; 5,720,936; 5,850,003; 5,877,015,, and
5,811,633, and in Ganes et al., 1995, Nature 373:523.
Preferred are animals that exhibit characteristics associated
with the pathophysiology of AD. Administration of the
compound inhibitors of the invention to the transgenic mice
described herein provides an alternative method for
demonstrating the inhibitory activity of the compounds.
Administration of the compounds in a pharmaceutically
effective carrier and via an administrative route that reaches
the target tissue in an appropriate therapeutic amount is also
preferred.
Inhibition of beta-secretase mediated cleavage of APP at
the beta-secretase cleavage site and of A beta release can be
analyzed in these animals by measure of cleavage fragments in
the animal's body fluids such as cerebral fluid or tissues.
Analysis of brain tissues for A beta deposits or plaques is
preferred.
On contacting an APP substrate with a beta-secretase
enzyme in the presence of an inhibitory compound of the
mention and under conditions sufficient to permit enzymatic
me ted cleavage of APP and/or release of A beta from the
substitute, the compounds of the invention are effective to
reduce beta-secretase-mediated cleavage of APP at the beta-
secretase cleavage site and/or effective to reduce released
amounts of A beta. Where such contacting is the
administration of the inhibitory compounds of the invention to
an animal model, for example, as described above, the
compounds are effective to reduce A beta deposition in brain
tissues of the animal, and to reduce the number and/or size of
beta amyloid plaques. Where such administration is to a human
subject, the compounds are effective to inhibit or slow the
progression of disease characterized by enhanced amounts of A
beta, to slow the progression of AD in the, and/or to prevent
onset or development of AD in a patient at risk for the
disease.
Unless defined otherwise, all scientific and technical
terms used herein have the same meaning as commonly understood
by one of skill in the art to which this invention belongs.
All patents and publications, referred to herein are hereby
incorporated by reference for all purposes.
Definitions
The definitions and explanations below are for the terms
as used throughout this, entire document including both the
specification and the claims.
It should be noted that, as used in this specification
and the appended claims, the singular forms "a," "an," and
"the" include plural referents unless the content clearly
dictates otherwise. Thus, for example, reference to a
composition containing "a compound" includes a mixture of two
or more compounds. It should also be noted that the term "or"
is generally employed in its sense including "and/or" unless
the content clearly dictates otherwise.
Where multiple substituents are indicated as being
at ched to a structure, it is to be understood that the
substituents can be the same or different. Thus for example
"Rm optionally substituted with 1, 2 or 3 Rq groups" indicates
that Rm is substituted with 1, 2, or 3 Rq groups where the Rq
groups can be the same or different.
APP, amyloid precursor protein, is defined as any APP
polypeptide, including APP variants, mutations, and isoforms,
for example, as disclosed in U.S. Patent No. 5,766,846.
A beta, amyloid beta peptide, is defined as any peptide
resulting from beta-secretase mediated cleavage of APP,
including peptides of 39, 40, 41, 42, and 43 amino acids, and
extending from the beta-secretase cleavage site to amino acids
39, 40, 41, 42, or 43.
Beta-secretase (BACE1, Asp2, Memapsin 2) is an aspartyl
protease that mediates cleavage of APP at the amino-terminal
edge of A beta. Human beta-secretase is described, for
example, in WO00/173 69.
Pharmaceutically acceptable refers to those; properties
and/or substances that are acceptable to the patient from a
pharmacological/toxicological point of view and to the
manufacturing pharmaceutical chemist from a physical/chemical
point of view regarding composition, formulation, stability,
patient acceptance and bioavailability.
A therapeutically effective amount is defined as an
amount effective to reduce or lessen at least one: symptom of
the disease being treated or to reduce or delay onset of one
or more clinical markers or symptoms of the disease.
By "alkyl" and "C1-C6 alkyl" in the present invention is
meant straight or branched chain alkyl groups having 1-6
carbon atoms, such as, methyl, ethyl, propyl, isopropyl, n-
butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl,
neopentyl, hexyl, 2-hexyl,.3-hexyl, and 3-methylpentyl. It is
understood that in cases where an alkyl chain of a substituent
(e.g. of an alkyl, alkoxy or alkenyl group) is shorter or
Anger than.6 carbons, it will be so indicated in the second
"C" as, for example, "C1-C10" indicates a maximum of 10 carbons.
By "alkoxy" and "C1-C6 alkoxy" in the present invention is
meant straight or branched chain alkyl groups having 1-6
carbon atoms, attached through at least one divalent oxygen
atom, such as, for example, methoxy, ethoxy, propoxy,
isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,
isopentoxy, neopentoxy, hexoxy, and 3-methylpentoxy.
By the term "halogen" in the present invention is meant
fluorine, bromine, chlorine, and iodine.
"Alkenyl" and "C2-C6 alkenyl" means straight and branched
hydrocarbon radicals having from 2 to 6 carbon atoms and from
one to three double bonds and includes, for example, ethenyl,
propenyl, l-but-3-enyl, l-pent-3-enyl, l-hex-5-enyl and the
like.
"Alkynyl" and "C2-C6 alkynyl" means straight and branched
hydrocarbon radicals having from 2 to 6 carbon atoms and one
or two triple bonds and includes ethynyl, propynyl, butynyl,
pentyn-2-yl and the like.
As used herein, the term "cycloalkyl" refers to saturated
carbocyclic radicals having three to twelve carbon atoms. The
cycloalkyl can be monocyclic, a polycyclic fused system, or a
bi or polycyclic bridged system, such as adamantyl or
bicyclo[2.2.1] heptyl. Examples of such radicals include
cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Preferred cycloalkyl groups are cyclopentyl, cyclohexyl, and
cycloheptyl. The cycloalkyl groups herein are unsubstituted
or, as specified, substituted in one or more substitutable
positions with various groups. For example, such cycloalkyl
groups may be optionally substituted with, for example, C1-C6
alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino,
mono (C1-C6)alkylamino, di(C1-C6) alkylamino, C2-C6alkenyl, C2-
C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino (C1-C6) alkyl,
mono (C1-C6) alkylamino (C1-C6) alkyl or di (C1-C6)alkylamino (C1-
C6)alkyl.
By "aryl" is meant an aromatic carbocyclic group having a
single ring (e.g., phenyl) or multiple condensed rings in
which at least one is aromatic, (e.g., 1,2,3,4-
tetrahydronaphthyl, naphthyl), which is optionally mono-, di-,
or trisubstituted. Preferred aryl groups of the present
invention are phenyl, 1-naphthyl, 2-naphthyl, indanyl,
indenyl, dihydronaphthyl, fluorenyl, tetralinyl or 6,7,8,9-
tetrahydro-5H-benzo[a]cycloheptenyl. The aryl groups herein
are unsubstituted or, as specified, substituted in one or more
substitutable positions with various groups. For example,
such aryl groups may be optionally substituted with, for
example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano,
nitro, amino, mono (C1-C6) alkylamino, di (C1-C6) alkylamino, C2-
C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,
amino (C1-C6) alkyl, mono (C1-C6)alkylamino(C1-C6)alkyl or di(C1-
Cs) alkylamino (C1-C6)alkyl.
By "heteroaryl" is mean at least one or more aromatic
ring systems of 5-, 6-, or 7-membered rings which includes
fused ring systems of 9-11 atoms containing at¦least one and
up to four heteroatoms selected from nitrogen, oxygen, or
sulfur. Preferred heteroaryl groups of the present invention
include pyridinyl, pyrimidinyl, quinolinyl, benzothienyl,
indolyl, indolinyl, pryidazinyl, pyrazinyl, isoindolyl,
isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
imidazopyridinyl, isothiazolyl, naphthyridinyl, cinnolinyl,
carbazolyl, beta-carbolinyl, isochromanyl, chromanyl,
tetrahydroisoquinolinyl, isoindolinyl,
isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, phenoxazinyl, phesnothiazinyl,
pteridinyl, benzothiasolyl, imidazopyridinyl,
imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl,
benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl,
benzothiopyranyl, coumarinyl, isocoumarinyl, chromonyl,
chromanonyl, pyridinyl-N-oxide, tetrahydroquinolinyl,
dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl, dihydrocoumarinyl,
dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl,
benzoxazolinonyl, pyrrolyl N-oxide,, pyrimidinyl N-oxide,
pyridazinyl N-oxide, pyrazinyl N-oxide, quinolinyl N-oxide,
indolyl N-oxide, indolinyl N-oxide, isoquinolyl N-oxide,
quinazolinyl N-oxide, quinoxalinyl N-oxide, phthalazinyl N-
oxide, imidazolyl N-oxide, isoxazolyl N-oxide, oxazolyl N-
oxide, thiazolyl N-oxide, indolizinyl N-oxide, indazolyl N-
oxide, benzothiazolyl N-oxide, benzimidazolyl N-oxide, pyrrolyl
N-oxide, oxadiazolyl N-oxide, thiadiazolyl N-oxide, triazolyl
N-oxide, tetrazolyl N-oxide, benzothiopyranyl S-oxide,
benzothiopyranyl S,S-dioxide, tetrahydrocarbazole,
tetrahydrobetacarboline. The heteroaryl groups herein are
unsubstituted or, as specified, substituted in one or more
substitutable positions with various groups. For example,
such heteroaryl groups may be optionally substituted with, for
example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano,
nitro, amino, mono (C1-C6)alkylamino, di C1-C6) alkylamino, C2-
C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy,
amino (C1-C6) alkyl, mono (C1-C6) alkylamino (C1-C6) alkyl or di (C1-
C6) alkylamino (C1-C6) alkyl.
By "heterocycle", "heterocycloalkyl" or "heterocyclyl"
is meant one or more carbocyclic ring systems of 4-, 5-, 6-.
or 7-membered rings which includes fused ring systems of 9-11
atoms containing at least one and up to four heteroatoms
selected from nitrogen, oxygen, or sulfur. Preferred
heterocycles of the present invention include morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-
dioxide, piperazinyl, homopiperazinyl, pyrrolidinyl,
pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl,
tetrahydrothienyl, homopiperidinyl, homomorpholinyl,
homothiomorpholinyl, homothiomorpholinyl S,S-dioxide,
oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyriraidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide and homothiomorpholinyl S-oxide.
The heterocycle groups herein are unsubstituted or, as
specified, substituted in one or more substitutable positions
with various groups. For example, such heterocycle groups may
be optionally substituted with, for example, C1-C6 alkyl, C1-C6
alkoxy, halogen, hydroxy, cyano, nitro, amino, mono(C1-
C6)alkylamino, di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl,
C1-C6 haloalkyl, C1-C6 haloalkoxy, amino (C1-C6) alkyl, mono(C1-
C6) alkylamino (C1-C6) alkyl, di(C1-C6)alkylamino(C1-C6)alkyl or
=O.
All patents and publications referred to herein are
hereby incorporated by reference for all purposes.
Structures were named using Name Pro IUPAC Naming
Software, version 5.09, available from Advanced Chemical
Development, Inc., 90 Adelaide Street West, Toronto, Ontario,
M5H 3V9, Canada.
The present invention may be better understood with
reference to the following examples. These examples are
intended to be representative of specific embodiments of the
invention, and are not intended as limiting the scope of the
invention.
The following abbreviations may be used in the Examples:
EDC stands for 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide or the hydrochloride salt;
DIEA stands for diisopropylethylamine,-
PyBOP stands for benzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate;
HATU stands for 0-(7-azabenzotriazol-l-yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate;
THF stands for tetrahydrofuran;
EtBz stands for ethylbenzene;
DCM stands for dichloromethane.
BIOLOGY EXAMPLES
Example A
Enzyme Inhibition Assay
The compounds of the invention are analyzed for
inhibitory activity by use of the MBP-C125 assay.. This assay
determines the relative inhibition of beta-secretase cleavage
of a model APP substrate, MBP-C125SW, by the compounds assayed
as compared with an untreated control. A detailed description
of the assay parameters can be found, for example, in U.S.
Patent No. 5,942,400. Briefly, the substrate is a fusion
peptide formed of maltose binding protein (MBP) and the
carboxy terminal 125 amino acids of APP-SW, the Swedish
mutation. The beta-secretase enzyme is derived from human
brain tissue as described in Sinha et al, 1999, Nature 40:537-
54 0) or recombinantly produced as the full-length enzyme
(amino acids 1-501), and can be prepared, for example, from
293 cells expressing the recombinant cDNA, as described in
WO00/47618.
Inhibition of the enzyme is analyzed, for example, by
immunoassay of the enzyme's cleavage products. One exemplary
ELISA uses an anti-MBP capture antibody that is deposited on
precoated and blocked 96-well high binding plates, followed by
incubation with diluted enzyme reaction supernatant,
incubation with a specific reporter antibody, for example,
biotinylated anti-SW192 reporter antibody, and further
incubation with streptavidin/alkaline phosphatase. In the
assay, cleavage of the intact MBP-C125SW fusion protein
results in the generation of a truncated amino-terminal
fragment, exposing a new SW-192 antibody-positive epitope at
the carboxy terminus. Detection is effected by a fluorescent
substrate signal on cleavage by the phosphatase. ELISA only
detects cleavage following Leu 596 at the substrate's APP-SW
751 mutation site.
Specific Assay Procedure:
Compounds are diluted in a 1:1 dilution series to a six-
point concentration curve (two wells per concentration) in one
96-plate row per compound tested. Each of the test compounds
is prepared in DMSO to make up a 10 millimolar stock solution.
The stock solution is serially diluted in DMSO to obtain a
final compound concentration of 2 00 micromolar at the high
point of a 6-point dilution curve. Ten (10) microliters of
each dilution is added to each of two wells on row C of a
corresponding V-bottom plate to which 190 microliters of 52
millimolar NaOAc, 7.9% DMSO, pH 4.5 are pre-added. The NaOAc
diluted compound plate is spun down to pellet precipitant and
20 microliters/well is transferred to a corresponding flat-
bottom plate to which 30 microliters of ice-cold enzyme-
substrate mixture (2.5 microliters MBP-C125SW substrate, 0.03
microliters enzyme and 24.5 microliters ice cold 0.09% TX100
per 30 microliters) is added. The final reaction mixture of
200 micromolar compound at the highest curve point is in 5%
DMSO, 20 millimolar NaOAc, 0.06% TX100, at pH 4.5.
Warming the plates to. 37 degrees C starts the enzyme
reaction. After 90 minutes at 37 degrees C, 200
microliters/well cold specimen diluent is added to stop the
reaction and 2 0 microliters/well was transferred to a
corresponding anti-MBP antibody coated ELISA plate for
capture, containing 80 microliters/well specimen diluent.
This reaction is incubated overnight at 4 degrees C and the
ELISA is developed the next day after a 2 hour incubation with
anti-192SW antibody, followed by Streptavidin-AP conjugate and
fluorescent substrate. The signal is read on a fluorescent
plate reader.
Relative compound inhibition potency is determined by
calculating the concentration of compound that showed a fifty
percent reduction in detected signal (IC50) compared to the
enzyme reaction signal in the control wells with no added
compound. In this assay, preferred compounds of- the invention
exhibit an IC50 of'less than 50 micromolar.
Example B
Cell Free Inhibition Assay Utilizing a Synthetic APP
Substrate
A synthetic APP substrate that can be cleaved by beta-
secretase and having N-terminal biotin and made fluorescent by
the covalent attachment of Oregon green at the Cys residue is
used to assay beta-secretase activity in the presence or
absence of the inhibitory compounds of the invention. Useful
substrates include the following:
Biotin-SEVNL-DAEFRC[oregon green]KK [SEQ ID NO:
1]
Biotin-SEVKM-DAEFRC[oregon green]KK [SEQ ID NO:
2]
Biotin-GLNIKTEEISEISY-EVEFRC[oregon green]KK [SEQ ID NO:
3]
Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL-DAEFRC
[oregon green]KK [SEQ ID NO:
4]
Biotin-FVNQHLCoxGSHLVEALY-LVCoxGERGFFYTPKAC
[oregon green]KK [SEQ ID NO:
5]
The enzyme (0.1 nanomolar) and test compounds (0.001-100
micromolar) are incubated in pre-blocked, low affinity, black
plates (384 well) at 37 degrees for 30 minutes. The reaction
is initiated by addition of 150 millimolar substrate to a
final volume of 30 microliter per well. The final assay
conditions are: 0.001-100 micromolar compound inhibitor; 0.1
molar sodium acetate (pH 4.5); 150 nanomolar substrate; 0.1
nanomolar soluble beta-secretase; 0.001% Tween 20, and 2%
DMSO. The assay mixture is incubated for 3 hours at 37
degrees C, and the reaction is terminated by the addition of a
saturating concentration of immunopure streptavidin. After
incubation with streptavidin at room temperature for 15
minutes, fluorescence polarization is measured, for example,
using a LJL Acqurest (Ex4 85 nm/ Em530 nm). The activity of
the beta-secretase enzyme is detected by changes in the
fluorescence polarization that occur when the substrate is
cleaved by the enzyme. Incubation in the presence or absence
of compound inhibitor demonstrates specific inhibition of
beta-secretase enzymatic cleavage of its synthetic APP
substrate. In this assay, preferred compounds of the
invention exhibit an IC50 of less than 50 micromolar. More
preferred compounds of the invention exhibit an IC50 of less
than 10 micromolar. Even more preferred compounds of the
invention exhibit an IC50 of less than 5 micromolar.
Example C
Beta-Secretase Inhibition; P26-P4'SW Assay
Synthetic substrates containing the beta-secretase
cleavage site of APP are used to assay beta-secretase
activity, using the methods described, for example, in
published PCT application WO00/47618. The P26-P4'SW substrate
is a peptide of the sequence:
(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF [SEQ ID NO:
S]
The P26-P1 standard has the sequence:
(biotin)CGGADRGLTTRPGSGLTNIKTEEISEVNL [SEQ ID NO:
7].
Briefly, the biotin-coupled synthetic substrates are
incubated at a concentration of from about 0 to about 200
micromolar in this assay. When testing inhibitory compounds,
a substrate concentration of about 1.0 micromolar is
preferred. Test compounds diluted in DMSO are added to the
reaction mixture, with a final DMSO concentration of 5%.
Controls also contain a final DMSO concentration of 5%. The
concentration of beta secretase enzyme in the reaction is
varied, to give product concentrations with the linear range
of the ELISA assay, about 125 to 2000 picomolar, after
dilution.
The reaction mixture also includes 20 millimolar sodium
acetate, pH 4.5, 0.06% Triton X100, and is incubated at 37
degrees C for about 1 to.3 hours. Samples are then diluted in
assay buffer (for example, 145.4 nanomolar sodium chloride,
9.51 millimolar sodium phosphate, 7.7 millimolar sodium azide,
0.05% Triton X405, 6g/liter bovine serum albumin, pH 7.4) to
quench the reaction, then diluted further for immunoassay of
the cleavage products.
Cleavage products can be assayed by ELISA. Diluted
samples and standards are incubated in assay plates coated
with capture antibody, for example, SW192, for about 24 hours
at 4 degrees C. After washing in TTBS buffer (150 millimolar
sodium chloride, 25 millimolar Tris, 0.05% Tween 20, pH 7.5),
the samples are incubated with streptavidin-AP according to
the manufacturer's instructions. After a one hour incubation
at room temperature, the samples are washed in TTBS and
incubated with fluorescent substrate solution A (31.2 g/liter
2-amino-2-methyl-l-propanol, 30 mg/liter, pH 9.5). Reaction
with streptavidin-alkaline phosphate permits detection by
fluorescence. Compounds that are effective inhibitors of
beta-secretase activity demonstrate reduced cleavage of the
substrate as compared to a control.
Example D
Assays using Synthetic Oligopeptide-Substrates
Synthetic oligopeptides are prepared that incorporate the
known cleavage site of beta-secretase, and optionally
detectable tags, such as fluorescent or chromogenic moieties.
Examples of such peptides, as well as their production and
detection methods are described in U.S. Patent No: 5,942,400,
herein incorporated by reference. Cleavage products can be
detected using high performance liquid chromatography, or
fluorescent or chromogenic detection methods appropriate to
the peptide to be detected, according to methods well known in
the art.
By way of example, one such peptide has the sequence
SEVNL-DAEF [SEQ ID NO: 8], and the cleavage site is between
residues 5 and 6. Another preferred substrate has the
sequence ADRGLTTRPGSGLTNIKTEEISEVNL-BAEF [SEQ ID NO: 9], and
the cleavage site is between residues 26 and 27.
These synthetic APP substrates are incubated in the
presence of beta-secretase under conditions sufficient to
result in beta-secretase mediated cleavage of the substrate.
Comparison of the cleavage results in the presence of the
compound inhibitor to control results provides a measure of
the compound's inhibitory activity.
Example E
Inhibition of Beta-Secretase Activity - Cellular Assay
An exemplary assay for the analysis of inhibition of
beta-secretase activity utilizes the human embryonic kidney
cell line HEKp293 (ATCC Accession No. CRL-1573) transfected
with APP751 containing the naturally occurring double mutation
Lys651Met52 to Asn651Leu652 (numbered for APP751), commonly
called the Swedish mutation and- shown to overproduce A beta
(Citron et al., 1992, Nature 360:672-674), as described in
U.S. Patent No. 5,604,102.
The cells are incubated in the presence/absence of the
inhibitory compound (diluted in DMSO) at the desired
concentration, generally up to 10 micrograms/ml. At the end
of the treatment period, conditioned media is analyzed for
beta-secretase activity, for example, by analysis of cleavage
fragments. A beta can be analyzed by immunoassay, using
specific detection antibodies. The enzymatic activity is
measured in the presence and absence of the compound
inhibitors to demonstrate specific inhibition of beta-
secretase mediated cleavage of APP substrate.
Example F
Inhibition o£ Beta-Secretase in Animal Models of AD
Various animal models can be used to screen for
inhibition of beta-secretase activity. Examples of animal
models useful in the invention include, but are not limited
to, mouse, guinea pig, dog, and the like. The animals used
can be wild type, transgenic, or knockout models. In addition,
mammalian models can express mutations in APP, such as APP695-
SW and the like described herein. Examples of transgenic non-
human mammalian models are described in U.S. Patent Nos.
5,604,102, 5,912,410 and 5,811,633.
PDAPP mice, prepared as described in Games et al., 1995,
Nature 373:523-527 are useful to analyze in vivo suppression
of A beta release in the presence of putative inhibitory
compounds. As described in U.S. Patent No. 6,191,166, 4 month
old PDAPP mice are administered compound formulated in
vehicle, such as corn oil. The mice are dosed with compound
(1-30 mg/ml; preferably 1-10 mg/ml). After time, e.g., 3-10
hours, the animals are sacrificed, and brains removed for
analysis.
Transgenic animals are administered an amount of the
compound inhibitor formulated in a carrier suitable for the
chosen mode of administration. Control animals are untreated,
treated with vehicle, or treated with an inactive compound.
Administration can be acute, i.e., single dose or multiple
doses in one day, or can be chronic, i.e., dosing is repeated
daily for a period of days. Beginning at time 0, brain tissue
or cerebral fluid is obtained from selected animals and
analysed for the presence of APP cleavage peptides, including
A beta, for example, by immunoassay using specific antibodies
for A beta detection. At the end of the test period, animals
are sacrificed and brain tissue or cerebral fluid is analyzed
for the presence of A beta and/or beta-amyloid plaques. The
tissue is also analyzed for necrosis.
Animals administered the compound inhibitors of the
invention are expected to demonstrate reduced A beta in brain
tissues or cerebral fluids and reduced beta amyloid plaques
in brain tissue, as compared with non-treated controls.
Example 6
Inhibition of A Beta Production in Human Patients
Patients suffering from Alzheimer's Disease (AD)
demonstrate an increased amount of A beta in the brain. AD
patients are administered an amount of the compound inhibitor
formulated in a carrier suitable for the chosen mode of
administration. Administration is repeated daily for the
duration of the test period. Beginning on day 0, cognitive
and memory tests are performed, for example, once per month.
Patients administered the compound inhibitors are
expected to demonstrate slowing or stabilization of disease
progression as analyzed by changes in one or more of the
following disease parameters: A beta present in CSF or
plasma; brain or hippocampal volume; A beta deposits in the
brain; amyloid plaque in the brain; and scores for cognitive
and memory function, as compared with control, non-treated
patients.
Example H
Prevention of A Beta Production in Patients at Risk for
AD
Patients predisposed or at risk for developing AD " are
identified either by recognition of a familial inheritance
pattern, for example, presence of the Swedish Mutation, and/or
by monitoring diagnostic parameters. Patients identified as
predisposed or at risk for developing AD are administered an
amount of the compound inhibitor formulated in a carrier
suitable for the chosen mode of administration.
Administration is repeated daily for the duration of the test
period. Beginning on day 0, cognitive and memory tests are
performed, for example, once per month.
Patients administered the compound inhibitors are
expected to demonstrate slowing or stabilization of disease
progression as analyzed by changes in one or more of the
following disease parameters: A beta present in CSF or plasma;
brain or hippocampal volume; amyloid plaque in the brain; and
scores for cognitive and memory function, as compared with
control, non-treated patients.
The invention has been described with reference to
various specific and preferred embodiments and techniques.
However, it should be understood that many variations and
modifications may be made while remaining within the spirit
and scope of the invention.
WE CLAIM :
1. A compound of the formula I:
or pharmaceutically acceptable salts thereof, wherein
Z is hydrogen, or
Z is (C3-C7 cycloalkyl)0-1 (C1-C6 alkyl)-, (C3-C7 cycloalkyl)0-1 (C2-
C6 alkenyl)-, (C3-C7 cycloalkyl) 0-1 (C2-C6 alkynyl) - or (C3-C7
cycloalkyl)-, wherein each of said groups is optionally
substituted with 1, 2, or 3 Rz groups, wherein 1 or 2
methylene groups within said (C3-C7 cycloalkyl)0-1 (C1-C6
alkyl)-, (C3-C7 cycloalkyl) 0-1 (C2-C6 alkenyl)-, (C3-C7
cycloalkyl)0-1 (C2-C6 alkynyl) - or (C3-C7 cycloalkyl)- groups
are optionally replaced with -(C=0)-;
Rz at each occurrence is independently halogen (in one
aspect, F or Cl), -OH, -SH, -CN, -CF3, -OCF3, Ci-Ce
alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkoxy or - NR100R101;
R100 and R101 at each occurrence are independently H,
C1-C6 alkyl, phenyl, CO(C1-C6 alkyl) or SO2C1-C6 alkyl;
X is -(C=0)- or -(SO2)-;
R1 is C1-C10 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from halogen, -OH, =0, -SH, -CN,
-CF3, -OCF3, -C3-7 cycloalkyl, -C1-C4 alkoxy, amino, mono-
or dialkylamino, aryl, heteroaryl, and heterocycloalkyl,
wherein each aryl group is optionally substituted with 1,
2 or 3 R50 groups; each heteroaryl is optionally
substituted with 1 or 2 R50 groups; and each
heterocycloalkyl group is optionally substituted
with 1 or 2 groups that are independently R50 or =0;
R50 is selected from halogen, OH, SH, CN, -CO-(C1-C4
alkyl), -NR7R8, -S(O)0-2- (C1-C4 alkyl), C1-C6 alkyl, C2-
C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and C3-C8
cycloalkyl; wherein
the alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl
groups are optionally substituted with 1 or 2
substituents independently selected from C1-C4
alkyl, halogen, OH, -NR5R6, CN, C1-C4 haloalkoxy,
NR7R8, and C1-C4 alkoxy; wherein
R5 and R6 are independently H or C1-C6 alkyl; or
R5 and R6 and the nitrogen to which they are attached to
form a 5 or 6 membered heterocycloalkyl ring;
R7 and R8 are independently selected from H; -C1-C4
alkyl optionally substituted with 1, 2, or 3
groups independently selected from -OH, -NH2,
and halogen; -C3-C6 cycloalkyl; -(C1-C4 alkyl)-0-
(C1-C4 alkyl); -C2-C4 alkenyl; and -C2-C4 alkynyl;
R2 and R3 are independently selected from H; F; -C1-C6 alkyl
optionally substituted with -F, -OH, -C=N, -CF3, C1-C3
alkoxy, or -NR5R6; -(CH2)0-2-R17; - (CH2)0-2-R18; -C2-C6 alkenyl
or C2-C6 alkynyl, wherein the alkenyl and alkynyl groups
are optionally substituted with 1 or 2 groups that are
independently -F, -OH, -C=N, -CF3 or C1-C3 alkoxy; -(CH2)o-
2-C3-C7 cycloalkyl, which is optionally substituted with 1
or 2 groups that are independently -F, -OH, -C=N, -CF3,
C1-C3 alkoxy and -NR5R6;
R17 at each occurrence is an aryl group (preferably
selected from phenyl, 1-naphthyl, 2-naphthyl,
indanyl, indenyl, dihydronaphthyl and tetralinyl, )
wherein said aryl group is optionally substituted
with one or two groups that are independently -C1-C3
alkyl; -C1-C4 alkoxy; CF3; -C2-C6 alkenyl or -C2-C6
alkynyl each of which is optionally substituted with
one substituent selected from F, OH, C1-C3 alkoxy;
halogen; OH; -C=N; -C3-C7 cycloalkyl; -CO-(C1-C4
alkyl); or -SO2-(C1-C4 alkyl);
R18 is a heteroaryl group (preferably selected from
pyridinyl, pyrimidinyl, quinolinyl, indolyl,
pryidazinyl, pyrazinyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,
oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl or thiadiazolyl,) wherein said
heteroaryl groups are optionally substituted with
one or two groups that are independently -C1-C6 alkyl
optionally substituted with one substituent selected
from OH, C=N, CF3, C1-C3 alkoxy, and -NR5R6;
R15 is selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6
alkoxy C1-C6 alkyl, hydroxy C1-C6 alkyl, halo C1-C6 alkyl,
each of which is unsubstituted or substituted with 1, 2,
3, or 4 groups independently selected from halogen, C1-C6
alkyl, hydroxy, C1-C6 alkoxy, and NH2, and -R26-R27; wherein
R26 is selected from a bond, -C(0)-, -SO2-, -CO2-,
-C(O)NR5-, and -NRsC(O)-,
R27 is selected from C1-C6 alkyl, C1-C6 alkoxy, aryl C1-C6
alkyl, heterocycloalkyl, and heteroaryl, wherein
each of the above is unsubstituted or substituted
with 1, 2, 3, 4, or 5 groups that are independently
C1-C4 alkyl, C1-C4 alkoxy, halogen, haloalkyl,
hydroxyalkyl, -NR5R6, or -C(O)NR5R6; or
R2, R3 and the carbon to which they are attached form a C3-C7
carbocycle, wherein 1, 2, or 3 carbon atoms are
optionally replaced by groups that are independently
selected from -O-, -S-, -SO2-, -C(O)-, or -NR7-;
Rc is selected from - (CH2)0-3-(C3-C8) cycloalkyl wherein the
cycloalkyl is optionally substituted with 1, 2, or 3
groups independently selected from -R205; and -CO2-(C1-C4
alkyl); -(CR245R250)0-4-aryl; -(CR245R250)0-4-heteroaryl; -
(CR245R250)0-4-heterocycloalkyl; -(CR245R250)0-4-aryl-
heteroaryl; -(CR245R250)0-4-aryl-heterocycloalkyl;
- (CR245R250)0-4-aryl-aryl; -(CR245R250)0-4-heteroaryl-aryl; -
(CR245R250) o-4-heteroaryl-heterocycloalkyl; - (CR245R250) 0-4-
heteroaryl-heteroaryl; -CHR245-CHR25o-aryl; - (CR245R250) 0-4-
heterocycloalkyl-heteroaryl; - (CR245R250) 0-4-
heterocycloalkyl-heterocycloalkyl; - (CR245R250) 0-4-
heterocycloalkyl-aryl; a monocyclic or bicyclic ring of
5, 6, 7 8, 9, or 10 carbons fused to 1 or 2 aryl
(preferably phenyl), heteroaryl (preferably pyridyl,
imidazolyl, thienyl, thiazolyl, or pyrimidyl), or
heterocycloalkyl (preferably piperidinyl or piperazinyl)
groups;
wherein 1, 2 or 3 carbons of the monocyclic or bicyclic
ring are optionally replaced with -NH-, -N(CO)0-1R215-
, -N(CO)0-1R220-, -O-, or -S(=0)0-2-, and wherein the
monocyclic or bicyclic ring is optionally
substituted with 1, 2 or 3 groups that are
independently -R205, -R245, -R250 or ==0;
and -C2-C6 alkenyl optionally substituted with 1, 2, or 3
R205 groups;
wherein each aryl or heteroaryl group attached directly
or indirectly to the - (CR245R250) 0-4 group is
optionally substituted with 1, 2, 3 or 4 R200 groups;
wherein each heterocycloalkyl attached directly or
indirectly to the - (CR245R250) 0-4 group is optionally
substituted with 1, 2, 3, or 4 R210;
R200 at each occurrence is independently selected from -
C1-C6 alkyl optionally substituted with 1, 2, or 3
R205 groups; -OH; -NO2; -halogen; -C==N; - (CH2)0-4-CONR220R225;
- (CH2)0-4-CO-(C1-C6 alkyl); -(CH2)0-4-CO- (C2-C8
alkenyl); -(CH2)0-4-CO-(C2-C8 alkynyl) ; -(CH2)0-4-CO-
(C3-C7 cycloalkyl) ; -(CH2)0-4-(CO)0-1-aryl (preferably
phenyl); -(CH2)0-4-(CO)0-1-heteroaryl (preferably
pyridyl, pyrimidyl, furanyl, imidazolyl, thienyl,
oxazolyl, thiazolyl, or pyrazinyl) ; -(CH2)0-4-(CO)0-1-
heterocycloalkyl (preferably imidazolidinyl,
piperazinyl, pyrrolidinyl, piperidinyl, or
tetrahydropyranyl) ; -(CH2)0-4-CO2R215; -(CH2)0-4-SO2-
NR220R225; - (CH2)0-4-S (0)0-2-(C1-C8 alkyl) ; -(CH2)0-4-
S(O)0-2- (C3-C7 cycloalkyl) ; -(CH2)0-4-N (H or R215)-
CO2R215; -(CH2)0-4-N(H or R215)-SO2-R220; - (CH2)0-4-N (H or
R215)-CO-N(R215)2; -(CH2)0-4-N(-H or R215)-CO-R220;
- (CH2)0-4-NR220R225; - (CH2)0-4-O-CO- (C1-C6 alkyl); -(CH2)0-
4-O-(R215); -(CH2)0-4-S-(R215); -(CH2)0-4-O-(C1-C6 alkyl
optionally substituted with 1, 2, 3, or 5 -F); -C2-C6
alkenyl optionally substituted with 1 or 2 R205
groups; -C2-C6 alkynyl optionally substituted with 1
or 2 R205 groups; adamantly, and -(CH2)0-4- C3-C7 cycloalkyl;
each aryl and heteroaryl group included within R200
is optionally substituted with 1, 2, or 3
groups that are independently -R205, -R210 or -C1-
C6 alkyl substituted with 1, 2, or 3 groups that
are independently R205 or R210;
each heterocycloalkyl group included within R200 is
optionally substituted with 1, 2, or 3 groups
that are independently R210;
R205 at each occurrence is independently selected
from -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6
alkynyl, -C1-C6 haloalkoxy, - (CH2)0-3 (C3-C7
cycloalkyl), -halogen, - (CH2)0-6-OH, -O-phenyl,
OH, SH, -(CH2)0-6-C=N, - (CH2)0-6-C(=0)NR235R240, -
CF3, -C1-C6 alkoxy, C1-C6 alkoxycarbonyl, and -NR235R240;
R210 at each occurrence is independently selected
from -C1-C6 alkyl optionally substituted with
1, 2, or 3 R205 groups; -C2-C6 alkenyl optionally
substituted with 1, 2, or 3 R205 groups; C1-C6
alkanoyl; -SO2-(C1-C6 alkyl); -C2-C6 alkynyl
optionally substituted with 1, 2, or 3 R205
groups; -halogen; -C1-C6 alkoxy; -C1-C6
haloalkoxy; -NR220R225; -OH; -C=N; -C3-C7
cycloalkyl optionally substituted with 1, 2, or
3 R205 groups; -CO-(C1-C4 alkyl) ; -SO2-NR235R240; -
CO-NR235R240; -SO2-(C1-C4 alkyl) ; and =O;
R215 at each occurrence is independently selected
from -C1-C6 alkyl, - (CH2)0-2-(aryl), -C2-C6
alkenyl, -C2-C6 alkynyl, -C3-C7 cycloalkyl, -
(CH2)0-2-(heteroaryl), and -(CH2)0-2-
(heterocycloalkyl); wherein the aryl group
included within R215 is optionally substituted
with 1, 2, or 3 groups that are independently -
R205 or -R210; wherein the heterocycloalkyl and
heteroaryl groups included within R215 are
optionally substituted with 1, 2, or 3 R210;
R220 and R225 at each occurrence are independently H,
-C1-C6 alkyl, -CHO, hydroxy C1-C6 alkyl, C1-C6
alkoxycarbonyl, -amino C1-C6 alkyl, -SO2-C1-C6
alkyl, C1-C6 alkanoyl optionally substituted
with up to three halogens, -C(0)NH2, -C(O)NH(C1-
C6 alkyl), -C(O)N (C1-C6 alkyl) (C1-C6 alkyl),
-halo C1-C6 alkyl, - (CH2)0-2-(C3-C7 cycloalkyl),
-(C1-C6 alkyl)-O-(C1-C3 alkyl), -C2-C6 alkenyl, -
C2-C6 alkynyl, -aryl (preferably phenyl),
-heteroaryl, or -heterocycloalkyl; wherein the
aryl, heteroaryl and heterocycloalkyl groups
included within R220 and R225 is optionally
substituted with 1, 2, or 3 R270 groups,
R270 at each occurrence is independently -R205, -
C1-C6 alkyl optionally substituted with 1,
2, or 3 R205 groups; -C2-C6 alkenyl
optionally substituted with 1, 2, or 3 R205
groups; -C2-C6 alkynyl optionally
substituted with 1, 2, or 3 R205 groups; -
phenyl; -halogen; -C1-C6 alkoxy; -C1-C6
haloalkoxy; -NR235R240; -OH; -C=N; -C3-C7
cycloalkyl optionally substituted with 1,
2, or 3 R205 groups; -CO-(C1-C4 alkyl);
-SO2-NR235R240; -CO-NR235R240; -SO2-(C1-C4 alkyl); and =O;
R235 and R240 at each occurrence are
independently -H, -C1-C6 alkyl, C2-C6
alkanoyl, -SO2-(C1-C6 alkyl), or -phenyl;
R245 and R250 at each occurrence are independently selected
from H, - (CH2)0-4CO2C1-C4 alkyl, -(CH2)0-4C(=0)C1-C4
alkyl, -C1-C4 alkyl, -C1-C4 hydroxyalkyl, -C1-C4
alkoxy, -C1-C4 haloalkoxy, - (CH2)0-4-C3-C7 cycloalkyl,
-C2-C6 alkenyl, -C2-C6 alkynyl, - (CH2)0-4 aryl, -(CH2)0-4
heteroaryl, and -(CH2)0-4 heterocycloalkyl, or
R245 and R250 are taken together with the carbon to which
they are attached to form a monocycle or bicycle of
3, 4, 5, 6, 7 or 8 carbon atoms, where 1, 2, or 3
carbon atoms are optionally replaced by 1, 2, or 3
gropus that are independently -0-, -S-, -SO2-, -C(O)-
, -NR220-, or -NR220R220- wherein both R220 groups are
alkyl; and wherein the ring is optionally
substituted with 1, 2, 3, 4, 5, or 6 groups that are
independently C1-C4 alkyl, C1-C4 alkoxy, hydroxyl,
NH2, NH(C1-C6 alkyl), N (C1-C6 alkyl) (C1-C6 alkyl), -NH-C(O)
C1-C5 alkyl, -NH-SO2-(C1-C6 alkyl), or halogen;
wherein the aryl, heteroaryl or heterocycloalkyl
groups included within R245 and R250 are optionally
substituted with 1, 2, or 3 groups that are: independently
halogen, C1-6 alkyl, CN or OH.
2. A compound as claimed in claim 1, wherein Z is (C3-C7
cycloalkyl)0-1 (C1-C6 alkyl)-, (C3-C7 cycloalkyl)0-1 (C2-C6
alkenyl)-, (C3-C7 cycloalkyl)0-1 (C2-C6 alkynyl)- or (C3-C7
cycloalkyl)-, wherein each of said groups is optionally
substituted with 1, 2, or 3 Rz groups;
wherein, Rz at each occurrence is independently halogen, -
OH, -CN, C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7
cycloalkoxy, -NR100R101;
-here R100 and R101 are independently H, C1-C6 alkyl,
phenyl, CO(C1-C6 alkyl) or SO2C1-C6 alkyl.
3. A compound as claimed in claim 1, wherein X is -(C=O)-.
4. A compound as claimed in claim 3, wherein Z is H.
5. A compound as claimed in claim 1, wherein R1 is C1-C10
alkyl optionally substituted with 1 or 2 groups independently
selected from halogen, -OH, =0, -CF3, -OCF3, -C3-7 cycloalkyl, -
C1-C4 alkoxy, amino or aryl, wherein the aryl group is
optionally substituted with 1 or 2 R50 groups;
wherein R50 is selected from halogen, OH, -C0-(C1-C4
alkyl), -NR7R8, C1-C6 alkyl, C1-C6 alkoxy and C3-C8
cycloalkyl;
wherein the alkyl, alkoxy and cycloalkyl groups are
optionally substituted with 1 or 2 substituents
independently selected from C1-C4 alkyl, halogen, OH,
-NR5R6, NR7R8, and C1-C4 alkoxy;
wherein R5 and R6 at are independently H or
C1-C6 alkyl; or
wherein R5 and R6 and the nitrogen to which
they are attached form a 5 or 6 membered
heterocycloalkyl ring; and
wherein R7 and R8 are independently selected
from -H; -C1-C4 alkyl optionally substituted with 1, 2, or 3
groups independently selected from -OH, -NH2, and halogen; -
C3-C6 cycloalkyl; -(C1-C4 alkyl)-O-(C1-C4 alkyl).
6. A compound as claimed in claim 5, wherein R1 is -CH2-
phenyl where the phenyl ring is optionally substituted with 1
or 2 groups independently selected from halogen, C1-C2 alkyl,
C1-C2 alkoxy and hydroxy.
7. A compound as claimed in claim 6, wherein R1 is
benzyl, 3-fluorobenzyl or 3,5-difluorobenzyl.
8. A compound as claimed in claim 1, wherein R15 is H.
9. A compound as claimed in claim 7, wherein R15 is H.
10. A compound according to claim 1 of the formula II:
wherein Z is hydrogen, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6
alkynyl or -C3-C7 cycloalkyl, where each of said groups is
optionally substituted with 1 or 2 Rz groups, wherein 1 or 2
methylene groups within said -C1-C6 alkyl, -C2-C6 alkenyl, -C2-
C6 alkynyl or -C3-C7 cycloalkyl groups are optionally replaced
with -(C=O)-;
wherein Rz at each occurrence is independently halogen, -
OH, -CN, -CF3, C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7
cycloalkoxy or -NR100R101;
where R100 and R101 are independently H, C1-C6 alkyl,
phenyl, CO(C1-C6 alkyl) or SO2C1-C6 alkyl;
wherein X is -C(=O)-;
wherein R1 is C1-C10 alkyl optionally substituted with 1 or 2
groups independently selected from halogen, -OH, =O, -CN, -CF3,
-OCF3, -C3-C7 cycloalkyl, -C1-C4 alkoxy, amino, mono-
dialkylamino, aryl, heteroaryl or heterocycloalkyl, wherein
the aryl group is optionally substituted with 1 or 2 Rso
groups;
where R50 is halogen, OH, CN, -CO-(C1-C4 alkyl), -NR7R8, C1-
C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy and C3-
C6 cycloalkyl;
where R7 and R8 are selected from H; -C1-C4 alkyl
optionally substituted with 1, 2, or 3 groups
selected from -OH, -NH2 and halogen; -C3-C6
cycloalkyl; -(C1-C4 alkyl)-O-(C1-C4 alkyl); -C2-C4
alkenyl; and -C2-C4 alkynyl;
wherein Rc is selected from
- (CR245R250) 0-4-aryl;
- (CR245R250) 0-4-heteroaryl;
- (CR245R250) 0-4-heterocycloalkyl;
where the aryl group attached to the -(CR245R250)0-4- group is
optionally substituted with 1, 2, 3 or 4 R200 groups;
where the heteroaryl group attached to the -(CR245R250)0-4- group
is optionally substituted with 1, 2, 3, or 4 R200 groups;
where the heterocycloalkyl group attached to the -(CR245R250)0-4-
group is optionally substituted with 1, 2, 3, or 4 R210 groups.
11. A compound as claimed in claim 10, wherein
Z is -C1-C6 alkyl;
R1 is C1-C10 alkyl substituted with 1 phenyl group, where the
phenyl group attached to the alkyl is optionally
substituted with 1 or 2 R50 groups, where each R50 is
independently halogen, OH, CN, or C1-C6 alkyl; and
Rc is -(CR245R250)0-4-aryl or - (CR245R250)0-4-heteroaryl, where the
aryl and heteroaryl groups are optionally substituted
with 1 or 2 R200 groups.
12. A compound as claimed in claim 1 which is
N-[(lS,2R)-3-[(3-bromobenzyl)amino]-l-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4R)-6-
isopropyl-2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-
yl]amino}propyl)acetamide;
N-((1S,2R)-l-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
-isopropyl-2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-
yl]amino}propyl)acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-l-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-[(1S,2R)-3-{[1-(3-bromophenyl)cyclopropyl]amino}-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide hydrochloride;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
bromophenyl)propanoate;
N-{ (1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-
ethylbenzyl)amino]-2-hydroxypropyl}acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)propanoate;
3-{[(2R,3S)-3-(acetylamino)-4-(3,5-difluorophenyl)-2-
hydroxybutyl]amino}-3-(3-ethylphenyl)propanoic acid;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-
3-hydroxypropyl]amino}-2-hydroxypropyl)acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1S)-
1,2,3,4-tetrahydronaphthalen-l-ylamino]propyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,2-dioxido-3,4-
dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropy1}acetamide;
N-[l-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2e6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-
methylaminoacetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-
iodobenzyl)amino]propyl}acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
-difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
iodophenyl)propanoate;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-[3-(3-hydroxyprop-l-
ynyl)phenyl]propanoate;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[3-
hydroxy-1-(3-iodophenyl)propyl]amino}propyl)acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-[3-(3-
hydroxypropyl)phenyl]propanoate;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(7-
methoxy-1,2,3,4-tetrahydronaphthalen-l-
yl)amino]propyl}acetamide;
2-Amino-N-[1-(3,5-difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-
2e6-isothiochroman-4-ylamino)-2-hydroxy-propyl]-acetamide;
N-((lS,2R)-l-(3,5-difluorobenzyl)-3-{[6-ethyl-2-
(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-4-yl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)acetamide;
N-[(1S,2R)-3-{[1-(3-bromophenyl)cyclopropyl]amino}-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-[3-(5-formylthien-2-
yl)phenyl]propanoate;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(2'-acetyl-1,1'-
biphenyl-3-yl)propanoate;
N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2e6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-methylbutyramide;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1- [3'-
(hydroxymethyl)-1,1'-biphenyl-3-
yl]cyclopropyl}amino)propyl]acetamide;
N-[(lS,2R)-l-(3,5-difluorobenzyl)-3-({l-[3-(5-
formylthien-2-yl)phenyl]cyclopropyl}amino)-2-
hydroxypropyl]acetamide;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(9H-fluoren-9-
ylamino)-2-hydroxypropyl]acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-[3-
(trifluoromethyl)phenyl]propanoate;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
cyanophenyl)propanoate;
N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2e6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-hydroxy-2,2-
dimethyl-propionamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[l-(3-
ethylphenyl)cyclopropyl]amino}-2-hydroxypropyl)acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
bromophenyl)propanoate;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-
ethynylphenyl)cyclopropyl]amino}-2-hydroxypropyl)acetamide;
N-[(1S,2R)-3-[(2-bromo-9H-fluoren-9-yl)amino]-1-(3,5-
difluorobenzyl)-2-hydroxypropyl]acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-9H-fluoren-
9-yl)amino]-2-hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2,2-dioxido-3,4-
dihydro-1,2-benzoxathiin-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-
3, 4-dihydro-2H-chromen-4-yl) amino]propyl}acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
iodo-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4R)-6-
iodo-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide;
N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2e6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-
hydroxypropionamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-l,2-benzoxathiin-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-l,2-benzoxathiin-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{ [4-(3-
ethylphenyl)tetrahydro-2H-pyran-4-yl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[l-(3-
ethylphenyl)butyl]amino}-2-hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4S)-6-ethyl-3,4-
dihydro-2H-chromen-4-yl]amino}-2-hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(4R)-6-ethyl-3,4-
dihydro-2H-chromen-4-yl]amino}-2-hydroxypropyl)acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(7-ethyl-l,2,3,4-
tetrahydronaphthalen-1-yl)amino]-2-hydroxypropyl)acetamide;
N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2e6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-3-
hydroxybutyramide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[l-(3-
ethylphenyl)cyclohexyl]amino}-2-hydroxypropyl)acetamide;
N-((lS,2R)-l-(3,5-difluorobenzyl)-3-{[l-(3-
ethylphenyl)cyclopentyl]amino}-2-hydroxypropyl)acetamide;
N-{(lS,2R)-l-(3,5-difluorobenzyl)-3-[(6-ethyl-3,4-
dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-5-fluoro-
9H-fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
methyl (3S)-3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)butanoate ;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
isobutylisoxazol-5-yl)cyclopropyl]amino}propyl)acetamide;
N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2ee-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-phenylacetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-7-fluoro-
9H-fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
methyl (3R)-3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)butanoate ;
N-{(lS,2R)-l-(3,5-difluorobenzyl)-3-[(2,5-
dipropylbenzyl)amino]-2-hydroxypropyl}acetamide;
{[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2ë6-
isothiochroman-4-ylamino)-2-hydroxy-propylcarbamoyl]-methyl}-
methyl-carbamic acid tert-butyl ester;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
isobutyl-9H-fluoren-9-yl)amino]propyl}acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-6-ethyl-2,3-
dihydro-lH-inden-1-yl]amino}-2-hydroxypropyl)acetamide;
N-[l-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2ë6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-methyl-2-
methylamino-propionamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-ethyl-l-(3-
ethylphenyl)propyl]amino}-2-hydroxypropyl)acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-2,l-benzothiazin-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2,2-
dioxido-3,4-dihydro-lH-2,l-benzothiazin-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3-methyl-
2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-3-methyl-
2,2-dioxido-3,4-dihydro-lH-isothiochromen-4-yl)amino]-2-
hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-l-methyl-
1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-
hydroxypropyl}acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)propanoate;
N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2ë6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-2-(lH-imidazol-4-
yl)-acetamide;
methyl 3-{[(2R,3S)-3-(acetylamino)-4-(3,5-
difluorophenyl)-2-hydroxybutyl]amino}-3-(3-
ethylphenyl)propanoate;
N-[(1S,2R)-3-[(2-bromo-9-methyl-9H-fluoren-9-yl)amino]-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(1-ethylpropyl)-
9H-fluoren-9-yl]amino}-2-hydroxypropyl)acetamide;
N-[(1S,2R)-3-[(2-cyclopentyl-9H-fluoren-9-yl)amino]-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
N-[1-(3,5-Difluoro-benzyl)-3-(6-ethyl-2,2-dioxo-2ë6-
isothiochroman-4-ylamino)-2-hydroxy-propyl]-propionamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-9-methyl-
9H-fluoren-9-yl)amino]-2-hydroxypropyl} acetamide;
N-[(1S,2R)-3-[(2-cyclohexyl-9H-fluoren-9-yl)amino]-1-
(3,5-difluorobenzyl)-2-hydroxypropyl] acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(4-ethylpyridin-
2-yl)cyclopropyl]amino}-2-hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
(lH-pyrrol-3-yl)-3,4-dihydro-2H-chromen-4-
yl]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(5R)-3-ethyl-
6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl]amino}-2-
hydroxypropyl)acetamide;
N-[(1S,2R)-3-{[1-(3-bromophenyl)-1-methylethyl]amino}-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-(dimethylamino)-
9H-fluoren-9-yl]amino}-2-hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(1S)-7-
propyl-1,2,3,4-tetrahydronaphthalen-l-
yl]amino}propyl)acetamide;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({(1S)-7-
[(dimethylamino)methyl]-1,2,3,4-tetrahydronaphthalen-l-
yl}amino)-2-hydroxypropyl]acetamide;
N-[(1S,2R)-3-{[(1S)-7-bromo-l,2,3,4-tetrahydronaphthalen-
1-yl]amino}-l-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
N-((1S, 2R)-1-(3, 5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
propylphenyl)cyclopropyl]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-
ethylphenyl)cycloheptyl]amino}-2-hydroxypropyl)acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
isopropyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-2-hydroxy-
2,3-dihydro-lH-inden-l-yl)amino]-2-hydroxypropyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(2-ethyl-6-fluoro-
9H-fluoren-9-yl)amino]-2-hydroxypropyl}acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-
(methoxyraethyl)-9H-fluoren-9-yl]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-
2-(5-methyl-l,3-oxazol-2-yl)ethyl]amino}-2-
hydroxypropyl)acetamide hydrochloride;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-(3,4-dihydro-
2Hchromen-4-ylamino)-2-hydroxypropyl]acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[2-ethyl-5-
(trifluoromethyl)-9H-fluoren-9-yl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-(3-
methylbutyl)-9H-fluoren-9-yl]amino}propyl)acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
isopropyl-9H-fluoren-9-yl)amino]propyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
neopentyl-9H-fluoren-9-yl)amino]propyl}acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(2-
isopropenyl-9H-fluoren-9-yl)amino]propyl}acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[1-(3-ethylphenyl)-
1-methylethyl]amino}-2-hydroxypropyl)acetamide hydrochloride;
N-((lS,2R)-l-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
isobutyl-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide;
N-[(1S,2R)-3-{[(4S)-6-cyano-3,4-dihydro-2H-chromen-4-
yl]amino}-l-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-
neopentyl-3,4-dihydro-2H-chromen-4-yl]amino}propyl)acetamide;
N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-
neopentyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[2-
(isopropylamino)-9H-fluoren-9-yl]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[l-(3-
isobutylphenyl)cyclopropyl]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4-
isobutyl-1,1'-biphenyl-2-yl)methyl]amino}propyl)acetamide;
N-((lS,2R)-l-(3,5-difluorobenzyl)-3-{[7-(2,2-
dimethylpropyl)-5-ethyl-l,2,3,4-tetrahydronaphthalen-l-
yl]amino}-2-hydroxypropyl)acetamide;
N-((lS,2R)-l-(3,5-difluorobenzyl)-3-{[(4R)-6-(2,2-
dimethylpropyl)-3,4-dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-(2,2-
dimethylpropyl)-1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)acetamide;
N-[(1S,2R)-3-{[1-(3-tert-butylphenyl)cyclohexyl]amino}-1-
(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
N-[(lS,2R)-3-{[4-(3-tert-butylphenyl)tetrahydro-2H-pyran-
4-yl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[6-(2,2-
dimethylpropyl)-1,2,3,4-tetrahydroquinolin-4-yl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
isopropylphenyl)-4-oxocyclohexyl]amino}propyl)acetamide;
N-[(1S,2R)-3-{[(4S)-6-(2,2-dimethylpropyl)-3,4-dihydro-
2H-chromen-4-yl]aminoj-l-(3-fluorobenzyl)-2-
hydroxypropyl]acetamide;
N-((1S,2R)-l-(3,5-difluorobenzyl)-3-{[5-(2,2-
dimethylpropyl)-2-(lH-imidazol-1-yl)benzyl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[7-(2,2-
dimethylpropyl)-1-methyl-l,2,3,4-tetrahydronaphthalen-l-
yl ]amino}-2-hydroxypropyl)acetamide;
N-((1S,2R)-l-(3,5-difluorobenzyl)-3-{[6-(2,2-
dimethylpropyl)-4-methyl-3,4-dihydro-2H-chromen-4-yl]amino}-2-
hydroxypropyl)acetamide;
N-((1S,2R)-1-(3-fluoro-4-hydroxybenzyl)-2-hydroxy-3-{[1-
(3-isopropylphenyl)cyclohexyl]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
isopropylphenyl)cyclohexyl]amino}propyl)-2-fluoroacetamide;
N-((1S,2R)-1-[3-(allyloxy)-5-fluorobenzyl]-2-hydroxy-3-
{[1-(3-isopropylphenyl)cyclohexyl]amino}propyl)acetamide;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({1-[3-(2,2-
dimethylpropyl)phenyl]-1-methylethyl}amino)-2-hydroxypropyl]-
2-fluoroacetamide;
N-((1S,2R)-l-(3,5-difluorobenzyl)-3-{[ (IS)-7-(2,2-
dimethylpropyl)-1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-
hydroxypropyl)-2-fluoroacetamide;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-({1-[3-(3-
thienyl)phenyl]cyclohexyl}amino)propyl]acetamide;
N-[(1S,2R)-1-(3,5-difluorobenzyl)-3-({1-[4-(2,2-
dimethylpropyl)pyridin-2-yl]cyclopropyl}amino)-2-
hydroxypropyl]acetamide;
N-((1R,2S)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(lS)-7-
propyl-1,2,3,4-tetrahydronaphthalen-l-
yl ]amino}propyl)acetamide;
N-((1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[1-(3-
isobutylphenyl)cyclohexyl]aminojpropyl)acetamide;
N-((1S,2R)-2-hydroxy-l-(4-hydroxybenzyl)-3-{[1-(3-
isopropylphenyl)cyclohexyl]aminojpropyl)acetamide;
N-((1R,2S)-1-(3,5-difluorobenzyl)-3-{[(1S)-7-ethyl-
1,2,3,4-tetrahydronaphthalen-l-yl]amino}-2-hydroxypropyl)-2-
ethoxyacetamide; or
N-((1S,2R)-1-(3,5-difluorobenzyl)-3-{[(1R)-7-ethyl-
1,2,3, 4-tetrahydronaphthalen-l-yl]amino}-2-hydroxypropyl)-2,2-
difluoroacetamide; or a pharmaceutically acceptable salt
thereof.
13. A method for preparing a compound of the formula I:
or a pharmaceutically acceptable salt thereof, wherein Z, X,
R1, R2, R3, R15 and Rc are as claimed in claim 1.
14. A pharmaceutical composition comprising a compound or salt
as claimed in claim 1 and at least one pharmaceutically
acceptable carrier, solvent, adjuvant or diluent.
15. A pharmaceutical composition as claimed in claim 14, for
treating or preventing a subject from developing Alzheimer's
disease (AD); preventing or delaying the onset of Alzheimer's
disease; treating subjects with mild cognitive impairment
(MCI); preventing or delaying the onset of Alzheimer's disease
in subjects who would progress from MCI to AD; treating Down's
syndrome; treating subjects who have Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type; treating
cerebral amyloid angiopathy and preventing its potential
consequences; treating other degenerative dementias; treating
dementia associated with Parkinson's disease, progressive
supranuclear palsy, or cortical basal degeneration; treating
diffuse Lewy body type AD; and treating frontotemporal
dementias with parkinsonism (FTDP), comprising administering a
pharmaceutically acceptable amount of a compound as claimed in
claim 1 to a patient in need of such treatment.
The invention relates to 2-hydroxy-l,3- diaminoalkane
derivatives of formula I:
where variables Z, X, R15, R2, R3, and Rc are defined herein,
and to such compounds that are useful in the treatment of
Alzheimer's disease and other neurodegenerative disorders.
Particularly, the invention relates to compounds that are
capable of inhibiting beta-secretase, an enzyme that cleaves
amyloid precursor protein to produce amyloid beta peptide, a
major component of the amyloid plaques found in the brains of
Alzheimer's sufferers. Pharmaceutical compositions and methods
of preparing the claimed compounds are also disclosed. |