Note: Descriptions are shown in the official language in which they were submitted.
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BETA-SECRETASE MODULATORS AND METHODS OF USE
FIELD OF THE INVENTION
The invention relates generally to pharmaceutically active compounds,
pharmaceutical compositions and methods of use thereof, to treat Beta-
Secretase
mediated disorders, including Alzheimer's disease, plaque formation on the
brain and
related conditions.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) is a disease that affects greater than 12 million
aging
people worldwide. AD accounts for the majority of dementia clinically
diagnosed after
the age of 60. AD is generally characterized by the progressive decline of
memory,
reasoning, judgement and orientation. As the disease progresses, motor,
sensory, and
vocal abilities are affected until there is global impairment of multiple
cognitive
functions. The loss of cognitive function occurs gradually, typically leading
to a
diminished cognition of self, family and friends. Patients with severe
cognitive
impairment and/or diagnosed as end-stage AD are generally bedridden,
incontinent, and
dependent on custodial care. The AD patient eventually dies in about nine to
ten years, on
average, after initial diagnosis. Due to the incapacitating, generally
humiliating and
ultimately fatal effects of AD, there is a need to effectively treat AD upon
diagnosis.
AD is caused by two major physiological factors in the brain. The first
factor,
beta amyloid plaque formation, supports the "amyloid cascade hyposthesis"
which
alleges that AD is caused by the formation of characteristic beta amyloid
deposits
(commonly referred to as beta amyloid "plaques" or "plaque deposits") in the
brain and in
cerebral blood vessels (beta amyloid angiopathy). The second factor causing AD
is
intraneuronal tangles, consisting of an aggregate form of the protein tau.
Amyloid plaques
are thought to be specific for AD, while intraneuronal tangles are also found
in other
dementia-inducing disorders. Joachim et al., Alz. Dis. Assoc. Dis., 6:7-34
(1992).
Several lines of evidence indicate that progressive cerebral deposition of
beta-
amyloid peptide (A-beta) plays a seminal role in the pathogenisis of AD and
can precede
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cognitive symptoms by years or even decades. Selkoe, Neuron, 6:487 (1991).
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.
Seubert
et al., Nature, 359:325-327 (1992). Autopsies of AD patients have revealed
large numbers
of lesions comprising these 2 factors in areas of the human brain believed to
be 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. Amyloid
containing plaques and vascular amyloid angiopathy were also found in the
brains of
individuals with Down's Syndrome, Herditary Cerebral Hemorrhage with
Amyloidosis of
the Dutch-type (HCHWA-D), and other neurodegenerative disorders.
It has been hypothesized that A-Beta formation is a causative precursor or
factor
in the development of AD. Deposition of A-beta in areas of the brain
responsible for
cognitive factors is a major factor in the development of AD. Beta amyloid
plaques are
primarily composed of amyloid beta peptide (A-beta peptide). A-beta peptide is
derived
from the proteolytic cleavage of a large transmembrane amyloid precursor
protein (APP),
and is a peptide ranging in about 39-42 amino acids. A-beta 42 (42 amino acids
long) is
thought to be the major component of these plaque deposits. Citron, Trends in
Pharmacological Sciences, 25(2):92-97 (2004).
Several aspartyl proteases are thought to be involved in the processing or
cleavage of APP, resulting in the formation of A-beta peptide. Beta secretase
(BACE,
also commonly referred to as memapsin) is thought to first cleave APP to
generate two
fragments of the A-beta peptide: (1) a first N-terminus fragment and (2) a
second C-99
fragment, which is subsequently cleaved by gamma secretase to generate the C-
terminus
fragment of the A-beta peptide. APP has also found to be cleaved by alpha-
secretase to
produce 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
decription of the proteolytic processing fragments of APP is found, for
example, in U.S.
Patent Nos. 5,441,870, 5,712,130 and 5,942,400.
BACE is an aspartyl protease enzyme comprising 501 amino acids and
responsible for processing APP at the beta-secretase specific cleavage site.
BACE is
present in two forms, BACE 1 and BACE 2, designated as such depending upon the
specific cleavage site of APP. Beta secretase is described in Sinha et al.,
Nature, 402:537-
554 (1999) (p5 10) and PCT application WO 2000/17369. It has been proposed
that A-
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beta peptide accumulates as a result of APP processing by BACE. Moreoevr, in
vivo
processing of APP at the beta secretase cleavage site is thought to be a rate-
limiting step
in A-beta production. Sabbagh, M. et al., Alz. Dis. Rev. 3:1-19 (1997). Thus,
inhibition of
the BACE enzyme activity is desirable for the treatment of AD.
Studies have shown that the inhibition of BACE may be linked to the treatment
of AD. BACE 1 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 compares with control animals (Luo et
al., Nature
Neuroscience, 4:231-232 (2001)). This evidence further supports the concept
that
inhibition of beta secretase activity and a corresponding reduction of A-beta
in the brain
should provide a therapeutic method for treating AD and other beta amyloid or
plaque
related disorders.
Several approaches have been taken to treat AD and plaque-related disorders.
One approach has been to reduce the formation of plaque on the brain.
Particularly, a
common approach has been to inhibit the activity of beta secretase. For
example, each of
the following PCT publications:
WO 03/045913, WO 04/043916, WO 03/002122,
WO 03/006021, WO 03/002518, WO 04/024081,
WO 03/040096, WO 04/050619, WO 04/080376,
WO 04/099376, WO 05/004802, WO 04/080459,
WO 04/062625, WO 04/042910, WO 05/004803,
WO 05/005374, WO 03/106405, WO 03/062209,
WO 03/030886, WO 02/002505, WO 01/070671,
WO 03/057721, WO 03/006013, WO 03/037325,
Wo 04/0943 84, Wo 04/094413, WO 03/006423,
WO 03/050073, WO 03/029169 and WO 04/000821, describe inhibitors of beta
secretase, useful for treating AD and other beta-secretase mediated disorders.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a new class of compounds useful for the
modulation of beta secretase and, to that end, useful for the regulation or
reduction of the
formation of A-beta peptide and consequently, the reduction of beta amyloid
plaque
formation on the brain. Accordingly, the compounds of the invention are useful
for the
treatment of Alzheimer's disease and other beta secretase mediated disorders.
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The compounds provided by the invention, including stereoisomers, tautomers,
solvates, pharmaceutically acceptable salts, derivatives or prodrugs thereof,
are defined
by general Formula I
OH i 4
A~ N~ ~R5
W 1" /J
YB R3 R3
I
wherein A, B, W, R3, R4, R5, i and j are as described below. The invention
also provides
procedures for making compounds of Formula I, as well as intermediates useful
in such
procedures.
The compounds provided by the invention are capable of modulating beta
secretase. To this end, the invention further provides for the use of these
compounds for
therapeutic, prophylactic, acute and/or chronic treatment of beta secretase
mediated
diseases, such as those described herein. For example, the compounds are
useful for the
prophylaxis and treatment of AD and other diseases or conditions involving
amyloid
plaque formation on the brain.
The invention also provides pharmaceutical compositions, which comprise one
or more compounds of the invention, methods for the treatment of beta
secretase
mediated diseases, such as AD, using the compounds and compositions of the
invention,
and intermediates and processes useful for the preparation of the compounds of
the
invention. The invention also provides the preparation of a a pharmaceutical
composition
or of a medicament, containing one or more of the compounds, useful to
attenuate,
alleviate, or treat disorders through inhibition of beta secretase. For
example, and in one
embodiment, the invention provides a pharmaceutical composition comprising an
effective dosage amount of a compound of Formula I in association with at
least one
pharmaceutically acceptable carrier.
The foregoing merely summarizes certain aspects of the invention and is not
intended, nor should it be construed, as limiting the invention in any way.
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DETAILED DESCRIPTION OF THE INVENTION
In one embodiment of the invention, the compounds, including stereoisomers,
tautomers, solvates, pharmaceutically acceptable salts, derivatives or
prodrugs thereof, are
defined by
H OH R4
A~ N N R5
W e ~~ 1J
R3 R3
B
wherein A is C1-1o-alkyl, C2_to-alkenyl, C2-1o-alkynyl, R'-CI_1o-alkyl-, R'-
C2.10-
alkenyl- or R'-CZ_lo-alkynyl-, wherein
1, 2 or 3 carbon atoms of (1) said C1-Clo alkyl, C1-CIO alkenyl, C1-Clo
alkynyl or (2) said C1.1o-alkyl, C2-1o-alkenyl, C2-10-alkynyl of R'-C1-1o-
alkyl-, R'-
C2.I0-alkenyl- or R'-C2_1o-alkynyl-, is optionally replaced with a heteroatom
selected from 0, S, S(O), S(O)2 and
N, and optionally substituted independently with one or more substituents of
R9;
and
R' is a fully saturated or a partially or fully unsaturated 3-8 membered
monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system,
said ring system formed of carbon atoms and optionally including 1-3
heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if
tricyclic, said heteroatoms selected from 0, N, or S, wherein said ring system
is
substituted independently with one or more substituents of oxo, R', BY, R9,
NR'R7, NR7R8, OR7, SR7, ORB, SR8, C(O)R7, OC(O)R7, COOR', C(O)R8,
OC(O)R8, COORS, C(O)NR'R7, C(S)NR'R7, NR'C(O)R', NR'C(S)R7,
NR'C(O)NR'R7, NR'C(S)NR'R', NR7(000R7), OC(O)NR7R7, C(O)NR'R8,
C(S)NR'R8, NR7C(O)R8, NR7C(S)R8, NR7C(O)NR7R8, NR7C(S)NR'R8,
NR'(COORB), OC(O)NR7R8, S(O)2NR7R7, NR7S(O)2NR7R7, NR'S(O)2R7,
S(O)2R8, S(O)2NR7R8, NR'S(O)2NR'R8 or NR'S(O)2R8;
W is -C(=O)-, -OC(=O)-, -NHC(=O)-, -S(=O)b- or -NHS(=O)b-, wherein b is 1
or 2;
B is R2-(CR2aR2a)h_, R2-O_(CR2aR2a)h_, R2_S-(CR2aR2a)h_ or R2-N(R2a)-
(CR2aR2a)h_,
wherein
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R2 is C1-C10 alkyl, C1-C10 haloalkyl, CI-C10 alkenyl, C1-Clo alkynyl or a
partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms
selected
from 0, N, or S, wherein said CI-C10 alkyl, CI-C10 alkenyl, CI-C10 alkynyl is
optionally substituted independently with one or more substituents of R9, and
said
ring system is optionally substituted independently with one or more
substituents
of oxo> R'> R >
$ R9> NR7R7, NR7R8, OR'> SR >
S C(O)R'> OC(O)R'
' ORS> SR >
>
COOR', C(O)R8, OC(O)R8, COORS, C(O)NR7R', C(S)NR7R7, NR'C(O)R7,
NR7C(S)R7, NR7C(O)NR7R7, NR'C(S)NR'R', NR'(COOR'), OC(O)NR'R',
C(O)NR'R8, C(S)NR'R8, NR'C(O)R8, NR7C(S)R8, NR'C(O)NR'R8,
NR'C(S)NR'R8, NR7(000RB), OC(O)NR'R8, S(O)2NR7R', NR'S(O)2NR7R7
,
NR7S(O)2R', S(O)2R8, S(O)2NR'R8, NR'S(O)2NR'R8 or NR'S(O)2R8;
each Rea, independently, is H, OH, NO2, CN, NH2, C1-C10 alkyl, C1-C10
alkoxyl or haloalkyl; and
his0, 1,2or3;
i is 1, 2 or 3;
j is 0, 1 or 2;
each R3, independently, is H, haloalkyl, CN, Cl_10-alkyl, C2_10-alkenyl, C2-10-
alkynyl, C3_10-cycloalkyl or C4_I0-cycloalkenyl, each of the CI_lo-alkyl,
C2.10-alkenyl, C2.10-
alkynyl, C3_Io-cycloalkyl and C4_Io-cycloalkenyl optionally comprising 1-4
heteroatoms
selected from N, 0 and S and optionally substituted with 1-5 substituents of
R8 or R9;
R4 is H, haloalkyl, CN, C1_to-alkyl, C2.10-alkenyl, C2_lo-alkynyl, C3_10-
cycloalkyl or
04.10-cycloalkenyl, each of the CI_to-alkyl, C2_lo-alkenyl, C2_to-alkynyl,
C3_10-cycloalkyl
and C4_10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N,
0 and S
and optionally substituted with 1-5 substituents of R8 or R9;
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R5 is
Rio Rio R10
R12 R12 R12 R10
/T11 R11 Rif R12
R11
(X Xi X2 X2) X X
YY Y1\ )): Yõ--'"Y2 M Y~Y2
1
Y2 Y2
Rio Rio Rio Rio
R12
N N,Rt NR11
Ri R72 NR11 R12
1 s' Yt
X2 X1 X2 X2 )m (X2L / xX1
X2 Y2 1 X2 m
Y1 Y 0 Y1 Y O Y 2 Y3)
Y2 2 Rio RIO Rio Rio
R12 R11 Rt R11 R12 N~R1i / R12 N
/1) 1 X r 1 xi m 1 X2
2 Y2 l rm Yz i Y2 X21m
1 v3) ' Y3/ O ~ Y3)0 ~ Y3) O
Rio \ Yi1/R12! %/ S R%X2 4X~ 0 (X 3 0
X1
X2 R12 R12 Xi 1 or IM-r
m
R12
wherein X1 is CR12, C(=O), 0, S, S(O)2 or NR12;
each X2, independently, is CR'2R12;
each of Y1, Y2 and Y3, independently, is CR12R12, 0, S or NR'2;
m is 0, 1 or 2; and
o is 0, 1, 2, 3, 4 or 5;
provided that (a) no more than two of Y', Y2 and Y3 is O, S or NR12 and (b)
when
o is 0, then each of Y' and Y2 is CR12R12;
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R7 is H, C1.10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3.1o-cycloalkyl or C4-10-
cycloalkenyl, each of the C7-10-alkyl, C2_lo-alkenyl, C2.10-alkynyl, C3-1 -
cycloalkyl and C4.
10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S
and
optionally substituted with 1-5 substituents of NR8R9, NR9R9, ORB, SRS, ORS,
SR9,
C(O)R8, OC(O)R8, COORS, C(O)R9, OC(O)R9, COORS, C(O)NR8R9, C(O)NR9R9,
NR9C(O)R8, NR9C(O)R9, NR9C(O)NR8R9, NR9C(O)NR9R9, NR9(000RB), NR9(000R9),
OC(O)NR8R9, OC(O)NR9R9, S(O)2R8, S(0)2NR8R9, S(0)2R9, S(O)2NR9R9,
NR9S(O)2NR8R9, NR9S(O)2NR9R9, NR9S(O)2R8, NR9S(O)2R9, R8 or R9;
R8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-
12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
formed of
carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if
bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0,
N, or S, and
wherein said ring system is optionally substituted independently with 1-5
substituents of
R9, oxo, NR9R9, ORS; SR9, C(O)R9 or a partially or fully saturated or
unsaturated 5-6
membered ring of carbon atoms optionally including 1-3 heteroatoms selected
from 0, N,
or S. and optionally substituted independently with 1-5 substituents of R9;
R9 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1.1o-alkyl, C2.10-
alkenyl, C2.
lo-alkynyl, C3-lo-cycloalkyl, C4_10-cycloalkenyl, C1.lo-alkylamino-, C1-10-
dialkylamino-, C1.
10-alkoxyl, C1_10-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the C1-10-alkyl, C2-10-
alkenyl, C2-10-
alkynyl, C3-10-cycloalkyl, 04.10-cycloalkenyl, Cl-lo-alkylamino-, Cl-lo-
dialkylamino-, C1.10-
alkoxyl, C1_lo-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, Cl_10-alkylamino-,
C1-1o-
dialkylamino-, C1-10-thioalkoxyl, benzyl or phenyl;
R10 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1-10-alkyl, C2_lo-
alkenyl, C2_
lo-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1_lo-alkylamino-, C1.10-
dialkylamino-, C1.
10-alkoxyl, C1-10-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
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heteroatoms selected from 0, N, or S, wherein each of the C1-10-alkyl, C2_10-
alkenyl, C2_10-
alkynyl, C3_1o-cycloalkyl, C4_lo-cycloalkenyl, C1_10-alkylamino-, C1_lo-
dialkylamino-, C1_10-
alkoxyl, Ci_1o-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1 -5 substituents of halo, haloalkyl, CN, NO2, NH2, OH,
oxo, methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1_10-alkylamino-,
Ci.1o-
dialkylamino-, Cl_10-thioalkoxyl, benzyl or phenyl;
R11 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1_10-alkyl, C2.10-
alkenyl, C2-
10-alkynyl, C3_10-cycloalkyl, C4_io-cycloalkenyl, C1_10-alkylamino-, C1-10-
dialkylamino-, Cl_
1o-alkoxyl, C1_io-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the C1_10-alkyl, C2_10-
alkenyl, C2_10-
alkynyl, C3_lo-cycloalkyl, C4_10-cycloalkenyl, C1_10-alkylamino-, C1.10-
dialkylamino-, C1_10-
alkoxyl, Cl_10-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, Cl_10-alkylamino-,
Cl.10-
dialkylamino-, Ci_10-thioalkoxyl, benzyl or phenyl;
alternatively, R10 and R' 1 taken together with the carbon or nitrogen atoms
to
which they are attached form a partially or fully saturated or unsaturated 5-6
membered
second ring of carbon atoms optionally including 1-3 heteroatoms selected from
0, N, or
S, the second ring optionally substituted independently with 1-5 substituents
of R12, R13,
R14 or R15 and optionally fused to a 4-7 membered third ring, the third ring
formed of
carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S,
and
optionally substituted independently with 1-5 substituents of R12, R13, R14 or
R'5;
R12 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, oxo, Ci_lo-alkyl, C2.10-
alkenyl, C2.10-alkynyl, C3.1o-cycloalkyl, C4.lo-cycloalkenyl, C1_1o-alkylamino-
, C1.1o-
dialkylamino-, C1.10-alkoxyl, Ci_lo-thioalkoxyl or a saturated or partially or
fully
unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring
system
formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-
6
heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein
each of the
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C1_lo-alkyl, C2_10-alkenyl, C2_lo-alkynyl, C3-'o-cycloalkyl, C4_lo-
cycloalkenyl, C,.,0-
alkylamino-, Cl_lo-dialkylamino-, CI_10-alkoxyl, Cl.lo-thioalkoxyl and ring of
said ring
system is optionally substituted independently with 1-5 substituents of halo,
haloalkyl,
CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,
isopropyl,
isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyi,
tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,
cyclohexyl, C,_lo-
alkylamino-, Cl_,o-dialkylamino-, Cl_lo-thioalkoxyl, benzyl, phenyl or R14;
R'3 is NR'4R'5, NR'5R'5, OR14, SR14, OR'5, SR15, C(O)R14, OC(O)R14, COOR14,
C(O)R15, OC(O)R'5, COOR15, C(O)NR'4R'5, C(O)NR'5R'5, NR'4C(O)R'4, NR'
IC(O)R!4,
NR'4C(O)R15, NR15C(O)R15, NR15C(O)NR'4R'5, NR15C(O)NR'5R'5, NR' 5(COOR 14),
NR15(COOR's), OC(O)NR'4R15, OC(O)NR'5R'5, S(O)2R'4, S(O)2R'5, S(O)2NR14R'5,
S(o)2NR15R'5, NR14S(O)2NR'4R15, NR15S(O)2NR'sR'5, NR 14 S(0)2R 14 orNW 5S(0)2R
15;
R14 is a saturated or partially or fully unsaturated 3-8 membered monocyclic,
6-12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
formed of
carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if
bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O.
N, or S, and
wherein said ring system is optionally substituted independently with 1-5
substituents of
R15; and
R15 is H, halo, haloalkyl, CN, OH, NO2, NH2, oxo, acetyl, methyl, methoxyl,
ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl,
C,_,o-
alkylamino-, C,_,o-dialkylamino-, CI_10-thioalkoxyl or a partially or fully
saturated or
unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system,
said ring
system formed of carbon atoms optionally including 1-3 heteroatoms if
monocyclic or 1-6
heteroatoms if bicyclic, said heteroatoms selected from O. N, or S, and
optionally
substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO2,
NH2, OH,
oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,
isopropoxyl,
cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl,
isobutyl, sec-
butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl
or phenyl.
In another embodiment, the compounds of Formula I include R'-C(=O)- as A, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include R'-OC(=O)- as A,
in conjunction with any of the above or below embodiments.
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In another embodiment, the compounds of Formula I include R' NHC(=O)- as A,
in conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include R'-S(=O)b- as A
wherein b is 0, 1 or 2, in conjunction with any of the above or below
embodiments.
In another embodiment, the compounds of Formula I include or R'-NHS(=O)b- as
A wherein b is 0, 1 or 2,in conjunction with any of the above or below
embodiments.
In another embodiment, Formula I includes compounds
wherein A is CI.6-alkyl, C2_6alkenyl, C2-6-alkynyl, R'-O-C1_6-alkyl-, R'-S-
CI.6-alkyl-, R'-
S(O)2-C1_6-alkyl-, R'-NH-C1.6-alkyl-, R'-O-C1.-alkenyl-, R'-S-C2-6-alkenyl-,
R'-S(O)2-C2_
6-alkenyl-, R'-NH-C2-6-alkenyl-, R'-O-C1 -alkynyl-, R'-S-C1.6alkynyl-, R'-
S(O)2-C1.5-
alkynyl-, R'-NH-CI-6-alkynyl-, R'-C1-6alkyl-O-C1-6-alkyl-, R'-C1_6-alkyl-S-C1-
6-alkyl-, R'-
C1-6-alkyl-S(O)2-Cl_6-alkyl-, R'-C1.6-alkyl-NH-C1.6-alkyl-, R'-C1.6-alkyl-O-C1-
6-alkenyl-,
R'-C1-6-alkyl-S-C2_6-alkenyl-, R'-C1.6-alkyl-S(O)2-C2-6-alkenyl-, R' -C1.6-
alkyl NH-C2.6-
alkenyl-, R'-CI.6-alkyl-O-C1-6-alkynyl-, R'-C1.6-alkyl-S-C1_6-alkynyl-, R'-
C1_6-alkyl-
S(O)2-C1_6alkynyl- or R'-C1_6-alkyl-NH-C1.6-alkynyl-, in conjunction with any
of the
above or below embodiments.
In another embodiment, Formula I includes compounds
wherein A is CI-6-alkyl, C2_6alkenyl, C2-6-alkynyl, Cl-6alkyl-O-C1-3-alkyl-,
C1-6-alkyl-S-C1_
3-alkyl-, C1-6-alkyl-S(O)2-C1_3-alkyl-, CI{-alkyl-NH-C1_3-alkyl, di-(CI.4-
alkyl)-N-C1.3-
alkyl, C2-6-alkenyl-O-CI.3-alkyl-, C2.6-alkenyl-S-C1_3-alkyl-, C2.6-alkenyl-
S(O)2-Cl_3-alkyl-
, C2-6-alkenyl-NH-CI.3-alkyl- or C2-6-alkynyl-NH-C1.3-alkyl-, wherein the
alkyl, alkenyl or
alkynyl moiety of each is optionally substituted with 1-5 substituents of R9,
in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I
include as R', phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
triazinyl,
quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl,
thiophenyl, furyl,
pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl,
thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,
benzimidazolyl, benzoxazolyl, benzisoxazoly], benzothiazolyl,
benzoisothiazolyl,
benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl,
pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or a ring system of
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R18 Ria 0 0
0 N Rid O NY Ria- Rid R18
(Rib)k
(Rib)k / (Rib)k (Ribk
I SS
R18 0 (Rib)i\, N Rid R1d NRia O (Rib)k /~Rtb)k
N
0 N
\ I O I / I
(R1bk j f Rib \ Rib
R1c tc
/(R1b)k O Ria
0 N) NiRia N O /(Rib)k
N
(Rib)k\ \ (Rib)k\/ N
Rib
R1o
Rib
1b)k
/(Rib)k (Rib)k /(R1b)k q-M
k
0==~ (R1 bA
N~ N
N 0__ _/ N N 0==N
Rib Ri / Ri / S Ria
a Ria
RI, %(R1b)k ~(Rtb)k I (R1b)k (Rib)k
(Rib)% N Rid
R1a 0==~ O
N: N N
or
~ Ri ~ Ri ~ /Ny
O N\~ Ri
wherein R'a is R7, R8, R9, C(O)R7, C(O)R8, C(O)NR7R7, C(S)NR7R7, C(O)NR7R8,
C(S)NR7R8, S(O)2NR7R7, S(O)2R8, or S(O)2NR7R8;
each Rib, R' and Rid, independently, is R7, R8, R9, NR7R7, NR7R8, OR7, SR7,
ORB, SRS, C(O)R7, COOR7, C(O)R8, COOR8, C(O)NR7R7, C(S)NR7R7, NR7C(O)R7,
NR7C(S)R7, NR7C(O)NR7R7, NR7C(S)NR7R7, NR7(000R7), OC(O)NR7R7, C(O)NR7R8,
C(S)NR7R8, NR7C(O)R8, NR7C(S)R8, NR7C(O)NR7R8, NR7C(S)NR7R8, NR7(COOR8),
OC(O)NR7R8, S(O)2NR7R7, NR7S(O)2NR7R7, NR7S(O)2R7, S(O)2R8, S(O)2NR7R8,
NR7S(O)2NR7R8 or NR7S(O)2R8; and
k is 0, 1, 2 or 3, in conjunction with any of the above or below embodiments.
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In the immediately preceeding embodiment, the compounds of Formula I include
R7, R$ or R9, independently, as each ofRla, Rlb, R" and Rid, independently, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include R2-(CR2aR2a)h- as B
wherein each Rea, independently, is H, OH, NO2, CN, NH2, Cl-Clo alkyl, C1-Clo
alkoxyl
or haloalkyl, in conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include R2-O-(CR2aR2a)h- as
B wherein each Rea, independently, is H, OH, NO2, CN, NH2, C1-C10 alkyl, C1-
C10
alkoxyl or haloalkyl, in conjunction with any of the above or below
embodiments.
In another embodiment, the compounds of Formula I include R2-S-(CR2aR2a)h- as
B wherein each Rea, independently, is H, OH, NO2, CN, NH2, C1-Clo alkyl, C1-
Clo
alkoxyl or haloalkyl, in conjunction with any of the above or below
embodiments.
In another embodiment, the compounds of Formula I include R2-NR2a-(CR2aR2a)h-
as B wherein each Rea, independently, is H, OH, NO2, CN, NH2, C1-Clo alkyl, C1-
Cto
alkoxyl or haloalkyl, in conjunction with any of the above or below
embodiments.
In another embodiment, the compounds of Formula I include R2-(CHR2a)h- as B
wherein Rea is OH, NO2, CN, NH2, C1-Clo alkyl, C1-Clo alkoxyl or haloalkyl, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include R2-(CH2)h- as B, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include R2-O-(CH2)h- as B,
in conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include R2-S-(CH2)h- as B,
in conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include RZ NH-(CH2)h- as
B, in conjunction with any of the above or below embodiments.
In another embodiment, Formula I includes compounds wherein R2 is a C1-
C4alkyl, C1-C4alkenyl, C1-C4alkynyl, C1-Clo haloalkyl or an optionally
substituted ring
system selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl,
pyrazinyl,
triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,
phthalazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,
oxazolyl, isoxazolyl,
isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl,
benzothiophenyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,
benzoisothiazolyl,
benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,
thiazolinyl,
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pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, in conjunction with any
of the above
or below embodiments.
In another embodiment, the compounds of Formula I include an optionally
substituted ring system selected from phenyl, naphthyl, pyridyl, pyrimidyl,
triazinyl,
quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, fury],
pyrrolyl,
pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,
isothiazolyl, indolyl,
isoindolyl, benzofuranyl, benzothiophenyl and benzimidazoly as R2, in
conjunction with
any of the above or below embodiments.
In another embodiment, the compounds of Formula I include C1-C10 alkyl, CI-C10
alkenyl or C1-CIO alkynyl as R2, in conjunction with any of the above or below
embodiments.
In another embodiment, the compounds of Formula I include CI-C10 haloalkyl as
R2, in conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include H, haloalkyl, CN,
C1 10-alkyl, C2.1o-alkenyl or C2.10-alkynyl as R3, in conjunction with any of
the above or
below embodiments.
In another embodiment, the compounds of Formula I include H as R3, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include C1.lo-alkyl as R3,
in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include H, haloalkyl, CN,
C1.1o-alkyl, C2.1o-alkenyl or C2.1o-alkynyl as R4, in conjunction with any of
the above or
below embodiments.
In another embodiment, the compounds of Formula I include H as R4, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include haloalkyl or C1.10-
alkyl as R4, in conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include h as 0, 1, 2 or 3,
in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include h as 1 or 2, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include i as 1, 2 or 3, in
conjunction with any of the above or below embodiments.
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In another embodiment, the compounds of Formula I include i as 1, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include j as 0, 1 or 2, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include j as 0, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula I include as R5
R12 ZZ (R12)p R., ZZ (R12)p R12 Z (R12)p R12 ZZ (R12)p
3 3
x X1 X2 x m X 0 X2 " O
mX1 \X m
\~2 Y2
Y1 Y3 1` Y) 3 Y1 (R12)p 1 (R12)p
(R
12)p Y2 (R12)p 2 >
R12 ZZ (R12)p R12 ZZ (R12)p
_') s \ ss \
(R12)p1 ~)(3 (R12)p\ Y
X1
7m
Y2 1 X1 or Y X
Y3/ 0 Zv Y3 0 m
wherein
m, o, R12, X', X2, Y', Y2 and Y3 are as defined hereinabove;
Z2 taken together with the carbon atoms to which it is attached is a partially
or
fully unsaturated 5-8 membered monocyclic ring, said ring formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if
bicyclic, or 1-9
heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S, provided
that (a) no
more than two of Y', Y2 and Y3 is 0, S or NR12 and (b) when o is 0, then each
of Y' and
Y2 is CR12R12; and
p is 0, 1, 2, 3, 4 or 5, in conjunction with any of
the above or below embodiments.
In the immediately preceeding embodiment, the compounds of Formula I include
CR12R12 as X1, in conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include CHR12 as X',
in conjunction with any of the above or below embodiments.
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In the immediately preceeding embodiment, the compounds of Formula I include
C(=O) as X', in conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include CH2 as X1,
in conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include 0 as X', in
conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include S as X1, in
conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include S(O)2 as X1,
in conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include NR12 as X',
in conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include NH as X1, in
conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include CR12R12 as
each X2, independently, in conjunction with any of the above or below
embodiments.
In the preceeding embodiment, the compounds of Formula I include CHR12 as
each X2, independently, in conjunction with any of the above or below
embodiments.
In the preceeding embodiment, the compounds of Formula I include CH2 as each
X2, independently, in conjunction with any of the above or below embodiments.
In the preceeding embodiment, the compounds of Formula I include CR12R12 as
each of Y', Y2 and Y3, independently, in conjunction with any of the above or
below
embodiments.
In the preceeding embodiment, the compounds of Formula I include CHR12 as
each of Y', Y2 and Y3, independently, in conjunction with any of the above or
below
embodiments.
In the preceeding embodiment, the compounds of Formula I include CH2 as each
of Y', Y2 and Y3, independently, in conjunction with any of the above or below
embodiments.
In the preceeding embodiment, the compounds of Formula I include 0 as any one
or two of Y1, Y2 and Y3, independently, in conjunction with any of the above
or below
embodiments.
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In the preceeding embodiment, the compounds of Formula I include S as any one
or two of Y', Y2 and Y3, independently, in conjunction with any of the above
or below
embodiments.
In the preceeding embodiment, the compounds of Formula I include NR12 as any
one or two of Y', Y2 and Y3, independently, in conjunction with any of the
above or
below embodiments.
In the preceeding embodiment, the compounds of Formula I include 0 as Y2 and
CH2 as each of Y' and Y3, in conjunction with any of the above or below
embodiments.
In the preceeding embodiment, the compounds of Formula I include S as Y2 and
CH2 as each of Y' and Y3, in conjunction with any of the above or below
embodiments.
In the preceeding embodiment, the compounds of Formula I include NR12 as Y2
and CH2 as each of Y' and Y3, in conjunction with any of the above or below
embodiments.
In the preceeding embodiment, the compounds of Formula I include an optionally
substituted benzene, pyridine, pyrimidine, triazine, pyridazine, pyrazine,
pyrrole,
imidazole, pyrazole, triazole, thiophene, thiazole, thiadiazole, isothiazole,
furan, oxazole,
oxadiazole or isoxazole ring as Z2, in conjunction with any of the above or
below
embodiments.
In the preceeding embodiment, the compounds of Formula I include compounds
wherein R5 is
R72)p
A3
'r
X(R12 A2
x) Al
Y) o
(R12)
wherein m is 0 or 1;
o is I or 2;
pis0,1,2or3;
A' is CH, C(=O), 0 or NR12;
each of A' and A2, independently, is CR12 or N, provided
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that no more than one of A' and A2 is N;
X2 is CH;
Y3 is CR12 or 0; and
each R12, independently, is H, halo, haloalkyl, CN, OH,
NO2, NH2, acetyl, oxo, C1.lo-alkyl, C2.1o-alkenyl, C2-lo-alkynyl, C3_lo-
cycloalkyl,
C4_lo-cycloalkenyl, C1-10-alkylamino-, C1_lo-dialkylamino-, C1_lo-alkoxyl,
C1_lo-thioalkoxyl
or a ring selected from phenyl, pyridyl, pyrimidinyl, triazinyl, thiophenyl,
furyl,
tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl,
triazolyl, tetrazolyl,
thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl,
oxazolinyl,
isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl,
piperidinyl, piperazinyl,
pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl,
cyclohexyl and
cycloheptyl, wherein each of the.Cl_lo-alkyl, C2_10-alkenyl, C2_1o-alkynyl,
C3_,0-cycloalkyl,
C4_10-cycloalkenyl, C1_10-alkylamino-, Cl_lo-dialkylamino-, C1.10-alkoxyl,
Cl_10-thioalkoxyl
and ring is optionally substituted independently with 1-5 substituents of
halo, haloalkyl,
CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,
isopropyl,
isopropoxyl, cyclopropyl, cyclopropylmethoxyl,.butyl, butoxyl, isobutoxyl,
tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopently, hexyl,
cyclohexyl, C1-,o-
alkylamino-, Cl-lo-dialkylamino-, C,.10-thioalkoxyl, benzyl or phenyl, in
conjunction with
any of the above or below embodiments.
In another embodiment, the compounds of Formula I include as R5
Rio Rio Rio Rio
R12 R12 y~ R12 R12
M
R11 Rtt Rtt Rte
rr RIG ~~~ R16
\X XI X2 X~ M (X X2~X
mX1
R16 R16 R16 R16 R16 R16
Rio Rio Rto R1o R16
R12 12 it Rt2 R16 R12
R11 R11 sS'S
Ric Rib R16 R16
X X1 X2 X m
X1 <X
m I X M R12 R12 X1
R16 RIG ` '
R12 Rio R16
(
lX2~X1 R16
Or
R12
wherein X1 is C(=O), 0, S, S(O)2 or NR12;
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each X2, independently, is CR12R12;
m is 0, l or 2; and
each R16, independently, is haloalkyl, methyl, methoxyl, ethyl, ethoxyl,
alkoxy-
alkyl, alkylamino-alkyl, dialkylamino-alkyl, propyl, propoxyl, isopropyl,
isopropoxyl,
cyclopropyl, butyl, isobutyl, sec-butyl or tert-butyl, in conjunction with any
of the above
or below embodiments.
In another embodiment, the compounds of Formula I include as RS
R10 Rio R10 Rio
R12 R92 /R12
R1R11 R1i R12 Rif
) X {~ Y3} ;)
... - . _ (x. Xi X2 X2 M
zd1jX1 X2~X
Yi\ Y1~ Y~Y2 M Y1
Y2 Y2
Rio Rio R10 Rio
R12 NR11 Ri N R11 R12 R11 Y R12 iR11
N~ N
r 1
(x2 Xi X2 X2) (X2 ;,
m
X2 Y2--- X2 M
Yi Y)o Yt Y)
0 Y~ z Y3)o
Y2 Y2
R1o Rio Rio R10
R12 R1i R1 Rii R12 ~R11 R12 N "R11
YJ \/ SSS i "' Xi /L) , i
/ XJX2
" m m / ~'X2
Y2 Yzm Y2 Xi Y2 X`/ M
~Y3)o Y3)o ~Y3)o Y3)O
Rip Y1` Rip Y1~ Rip Y1
R12 %2 R12 %2 Ri %2
Sd Y3
X2 4X~ X Xi
I X2 R-12 R12 X1 m or 1
M
R12
wherein X' is C(=O), 0, S, S(O)2 or NR'2;
each X2, independently, is CR12R12;
each of Y', Y2 and Y3, independently, is CR12R12,0, S or NR12;
m is 0, 1 or 2; and
ois0, 1,2,3-,4or 5; .
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provided that (a) no more than two of Y', Y2 and Y3 is 0, S or NR12 and (b)
when
o is 0, then each of Y' and Y2 is CR12R12, in conjunction with any of the
above or below
embodiments.
In another embodiment, the invention provides compounds of Formula I, wherein
h is l or 2;
iis1;
j is 0;
A is C1.6-alkyl, C2-6-alkenyl, R'-O-C14-alkyl-, R'-S-C1_6-
alkyl, R1-S(O)2-C1.6-alkyl-, R'-NH-C1-6-alkyl-, R1-0-C1.6-alkenyl-, R'-S-C2_6-
alkenyl-, R'-
S(0)2-C2.6-alkenyl-, R'-NH-C2-6-alkenyl-, R'-C1-6-alkyl-O-C1.6-alkyl-, R1-C1-6-
alkyl-S-C1_
6-alkyl-, R1-C1_6-alkyl-S(O)2-C1_6-alkyl- or R'-C1.6-alkyl-NH-C1.6-alkyl-,
wherein
R' is phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,
phthalazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,
oxazolyl,
isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl,
benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl,
pyrrolidinyl,
oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,
piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl or cycloheptyl, each of which is optionally substituted as defined
in
claim 1;
R2 is an optionally substituted ring system selected from phenyl, naphthyl,
pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,
isoquinazolinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,
oxazolyl, isoxazolyl,
isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,
benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl and
benzimidazolyl;
each R3, independently, is H, haloalkyl, CN, C1_10-alkyl, C2_1o-alkenyl or
C2_10-
alkynyl;
R4 is H, CN or C1_10-alkyl;
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RS is
R12 Z2 (R12)p R12 Z2 (R12)p R12 Z2 (R1 2)p R12 Z2 (R12)p
X X1 X2 X M (Xi ;)o X2 Y3)o
rnx1 I M
\ Y) Y1 \Y2 Y2
Y1/ Y 3 0 1 3 U (R12)p (R12)p
(R 12)p \Y2 (R12)p \ 2 ,
Rig Z2 (R12)p R1P Z2 (R12)p
(R12)p<1 XX3 M (R12)P~ X X1
Y2~ Y3~ 0 1 TT or Y2 Y3` m
0
wherein in, o, R'2, X2, Y', Y2 and Y3 are as defined in claim 1;
X' is C(=O), 0, S, S(0)2 or NR12;
Z2 is an optionally substituted phenyl, pyridine,, pyrimidine, triazine,
pyridazine, pyrazine, pyrrole, imidazole, pyrazole, triazole, thiophene,
thiazole,
thiadiazole, isothiazole, furan, oxazole, oxadiazole or isoxazole ring; and
pis0, 1,2,3,4or5.
R' is H, CI.10-alkyl or C2_10-alkenyl, each of the C,_10-alkyl, or C2_10-
alkenyl
optionally substituted with 1-3 substituents of R9;
R8 is a ring system selected from phenyl, pyridyl, pyrimidinyl, triazinyl,
quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
quinazolinyl,
isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,
thieno-
pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl,
benzothiazolyl,
oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl,
isothiazolyl, indolyl,
azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl,
benzothiophenyl,
benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl,
isoxazolinyl,
thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl,
pyranyl,
dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl,
cyclobutyl,
azetidinyl, cyclopentyl, cyclohexyl and cycloheptyl, said ring system
optionally
substituted independently with 1-3 substituents of R9, oxo, NR9R9, OR9, SR9,
C(O)R9 or a
partially or fully saturated or unsaturated 5-6 membered ring of carbon atoms
optionally
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including 1-3 heteroatoms selected from 0, N, or S, and optionally substituted
independently with 1-5 substituents of R9;
R9 is H, halo, haloalkyl, CN, OH, NO2, NIH2, acetyl, CI.1o-alkyl, C2_10-
alkenyl, C2-
10-alkynyl, C3_7-cycloalkyl, C4-7-cycloalkenyl, C1_10-alkylamino-, C1-lo-
dialkylamino-, Cl_
lo-alkoxyl, C1_lo-thioalkoxyl; and
R12 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, CI_1o-alkyl, C2-10-
alkenyl, C2_
lo-alkynyl, C3_1o-cycloalkyl, C4_to-cycloalkenyl, CI-to-alkylamino-, Cl_lo-
dialkylamino-, C1_
10-alkoxyl, CI-10-thioalkoxyl or a saturated or partially or fully unsaturated
5-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the C1-10-alkyl, C2-lo-
alkenyl, C2-10-
alkynyl, C3.10-cycloalkyl, C4_10-cycloalkenyl, CI_to-alkylamino-, C1_10-
dialkylamino-, CI-10-
alkoxyl, C1_10-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopently, hexyl, cyclohexyl, Cl_lo-alkylamino-,
C1-lo-
dialkylamino-, C1_10-thioalkoxyl, benzyl or phenyl.
In another embodiment, the invention provides compounds of Formula 11,
OH R4
W~.N RS
R3
v
R2
II
or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,
derivative or prodrug
thereof, wherein
A is CI.6-alkyl, C2.6-alkenyl, C2-6alkynyl, R1-C1-6-alkyl-, R'-C2_6-alkenyl-
or R'-C2-
6-alkynyl-, wherein
1, 2 or 3 carbon atoms of (1) said C1-C6 alkyl, CI-C6 alkenyl, CI-C6 alkynyl
or (2)
said C1_6-alkyl, C2-6alkenyl, C2.$-alkynyl of R1-C1-6-alkyl-, R'-C2.6-alkenyl-
or R'-C2.6-
alkynyl-, is optionally replaced with a heteroatom selected from 0, S, S(O),
S(O)2 and
NH, and optionally substituted independently with 1-3 substituents of R9; and
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R' is phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,
triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,
phthalazinyl,
thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl,
oxazolyl,
isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl, isoindolyl,
benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzothiazolyl, benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl,
pyrrolidinyl,
oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,
piperazinyl, pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl or cycloheptyl, each of which is optionally substituted 1-3
substituents
of oxo R8, R9 NR7R7 NR7R8 OR7, SR7 OR$ SR8, C(O)R7, OC(O)R7, COOR7,
C(O)R8, OC(O)R8, COORS, C(O)NR7R7, NR7C(O)R7, NR7C(O)NR7R7,
NR7(0OOR7), OC(O)NR7R7, C(O)NR7R8, NR7C(O)R8, NR7C(O)NR7R8,
NR7(COOR), OC(O)NR7R8, S(O)2NR7R7, NR7S(O)2NR'R7, NR7S(O)2R7,
S(O)2R8, S(O)2NR7R8, NR7S(O)2NR7R8 or NR7S(O)2R8;
W is -C(=O)-, -OC(=O)-, -NHC(=O)-, -S(=O)b- or -NHS(=O)b-, wherein b is 1 or
2;
V is -(CR2aR2a)h-, _0_(CR2aR2a)h-, -S_(CR2aR2a)h- or -NW"_(CR2aR2a)h-, wherein
each Rea, independently, is H, C1-C10 alkyl or haloalkyl, and h is 0, 1 or 2;
R2 is a C1-Cloalkyl, C1-Clohaloalkyl, Cl-Cloalkenyl, C1-Clo alkynyl or a
partially
or fully saturated or unsaturated 3-8 membered monocyclic, 6-12 membered
bicyclic, or
7-14 membered tricyclic ring system, said ring system formed of carbon atoms
optionally
including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9
heteroatoms
if tricyclic, said heteroatoms selected from 0, N, or S, wherein said ring
system is
optionally substituted independently with one or more substituents of oxo, R7,
R8, R9,
NR7R7, NR7R8, OR7, SR7, OR8, SRS, C(O)R7, OC(O)R7, COOR7, C(O)R8, OC(O)R8,
COORS, C(O)NR7R7, C(S)NR7R7, NR7C(O)R7, NR7C(S)R7, NR7C(O)NR7R7,
NR7C(S)NR7R7, NR7(000R), OC(O)NR7R7, C(O)NR7R8, C(S)NR7R8, NR7C(O)R8,
NR7C(S)R8, NR7C(O)NR7R8, NR7C(S)NR7R8, NR7(000R8), OC(O)NR7R8, S(0)2NR7R7,
NR7S(O)2NR7R7, NR7S(O)2R7, S(O)2R8, S(0)2NR7R8, NR7S(O)2NR7R8 or NR7S(O)2R8;
R3 is H, haloalkyl, CN, C1_10-alkyl, C2-10-alkenyl or C2-10-alkynyl;
R4 is H, haloalkyl, CN, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-io-
cycloalkyl or
C4-10-cycloalkenyl, each of the C,-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-
10-cycloalkyl
and C4_10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N,
0 and S
and optionally substituted with 1-5 substituents of R8 or R9;
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RS is
Rio Rio Rio Rio
SS,
R12 Rtz R12 R1z
R11
R11 R11 S R1 i s
X X1 X2 X~ to (Xa Res Xz Res
nX1 ~X M
Rs R16 R16 R16 Ris R16
Rio Rio R RIO
/~-- R12 R12 R~Z 1o R16 / R12 R16
R11 Rit
4
R1s R1s R16 ` R16
1X X1 Xz ~X9m
X1 M ~X M R12 R12 X1
R16 R16 '
R12 R10 R16
( R16
\XzX1
Or M
R12
wherein X1 is C(=O), 0, S, S(O)2 or NR12;
each X2, independently, is CR12R12;and
m is 0, l or 2;
R' is H, C1-10-alkyl, C2-10-alkenyl, C2_10-alkynyl, C3-lo-cycloalkyl or C4-10-
cycloalkenyl, each of the Cl-1o-alkyl, C2-1o-alkenyl, C2_lo-alkynyl, C3_1o-
cycloalkyl and C4_
io-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S
and
optionally substituted with 1-5 substituents of NR8R9, NR9R9, ORB, SRS, ORS,
SR9,
C(O)R8, OC(O)R8, COORS, C(O)R9, OC(O)R9, COORS, C(O)NR8R9, C(O)NR9R9,
NR9C(O)R8, NR9C(O)R9, NR9C(O)NR8R9, NR9C(O)NR9R9, NR9(000RB), NR9(000R),
OC(O)NRBR9, OC(O)NR9R9, S(O)2R8, S(0)2NRBR9, S(O)2R9, S(O)2NR9R9,
NR9S(0)2NR8R9, NR9S(O)2NR9R9, NR9S(O)2R8, NR9S(O)2R9, R8 or R9;
R8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-
12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
formed of
carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if
bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0,
N, or S, and
wherein said ring system is optionally substituted independently with 1-5
substituents of
R9, oxo, NR9R9, ORS; SR9, C(O)R9 or a partially or fully saturated or
unsaturated 5-6
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membered ring of carbon atoms optionally including 1-3 heteroatoms selected
from 0, N,
or S, and optionally substituted independently with 1-5 substituents of R9;
R9 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, Ci_lo-alkyl, C2.10-
alkenyl, C2_
lo-alkynyl, C3_10-cycloalkyl, C4_10-cycloalkenyl, Cl_lo-alkylamino-, Cl_10-
dialkylamino-, C,_
10-alkoxyl, C1_10-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1 -6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the Q-10-alkyl, C2_10-
alkenyl, C2.lo-
alkynyl, C3.10-cycloalkyl, C4_10-cycloalkenyl, Cl_lo-alkylamino-, C1_lo-
dialkylamino-, CI-10-
alkoxyl, Cl_1o-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pently, cyclopently, hexyl, cyclohexyl, Ci_10-alkylamino-,
C1.lo-
dialkylamino-, C,_lo-thioalkoxyl, benzyl or phenyl;
R10 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1_10-alkyl, C2_lo-
alkenyl, C2_
lo-alkynyl, C3_lo-cycloalkyl, C4.10-cycloalkenyl, C1_1o-alkylamino-, Cl_lo-
dialkylamino-, Cl_
lo-alkoxyl, C1-lo-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the C1_10-alkyl, C2.10-
alkenyl, C2.10-
alkynyl, C3_lo-cycloalkyl, C4_lo-cycloalkenyl, C1_lo-alkylamino-, C1_10-
dialkylamino-, C1.1o-
alkoxyl, C1.1o-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pently, cyclopently, hexyl, cyclohexyl, Cl-lo-alkylamino-,
C1.1o-
dialkylamino-, C1-10-thioalkoxyl, benzyl or phenyl;
R" is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1_1o-alkyl, C2_10-
alkenyl, C2_
lo-alkynyl, C3.10-cycloalkyl, C4_10-cycloalkenyl, C1_lo-alkylamino-, Cl_lo-
dialkylamino-, Cl_
lo-alkoxyl, C1_lo-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the C1_10-alkyl, C2-1o-
alkenyl, C2.10-
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alkynyl, C3_10-cycloalkyl, C4_10-cycloalkenyl, C,-,0-alkylamino-, C,_,o-
dialkylamino-, C,_10-
alkoxyl, CI_10-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pently, cyclopently, hexyl, cyclohexyl, C,_10-alkylamino-,
C,_,0-
dialkylamino-, CI_10-thioalkoxyl, benzyl or phenyl;
alternatively, R10 and R" taken together with the carbon atoms to which they
are
attached form a partially or fully saturated or unsaturated 5-6 membered ring
of carbon
atoms optionally including 1-3 heteroatoms selected from 0, N, or S, and the
ring
optionally substituted independently with 1-5 substituents of R12, R13, R14 or
R15;
R12 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, oxo, CI_,o-alkyl, C2_,o-
alkenyl, C2_10-alkynyl, C3-,0-cycloalkyl, C4.10-cycloalkenyl, C,-,o-alkylamino-
, C,_,o-
dialkylamino-, Cl_lo-alkoxyl, C,-,0-thioalkoxyl or a saturated or partially or
fully
unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, said ring
system
formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-
6
heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, wherein
each of the
C'-'o-alkyl, C2_lo-alkenyl, C2_,o-alkynyl, C3_,0-cycloalkyl, C4_,o-
cycloalkenyl, C,-,o-
alkylamino-, C1_lo-dialkylamino-, CI_10-alkoxyl, C1_lo-thioalkoxyl and ring of
said ring
system is optionally substituted independently with 1-5 substituents of halo,
haloalkyl,
CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,
isopropyl,
isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,
tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, cyclobutyl, pently, cyclopently, hexyl,
cyclohexyl, C'-'o-
alkylamino-, C,_,o-dialkylamino-, C1_,o-thioalkoxyl, benzyl or phenyl;
R13 is NR'4R'5, NR'5R15, OR14; SR14, OR15; SR15, C(O)R14, OC(O)R'4, COOR'4,
C(O)R15, OC(O)R15, COOR'5, C(O)NR'4R15, C(O)NR'5R'5, NR'4C(O)R14, NR'5C(O)R'4,
NR'4C(O)R's, NR'5C(O)R'S, NR'5C(O)NR'4R'5, NR15C(O)NR'5R'5, NR15(COOR14),
NR15(000R15), OC(O)NR'4R'5, OC(O)N/R'5R'5, S(O)2R'4S(0)2R", S(O)2NR'4R15,
S(O)2NR'5R'5, NR'4S(O)2NR'4R'5, NR15S(O)2NR'5R'5, NR'4S(O)2R'4 or
NR15S(O)2R15;
R14 is a saturated or partially or fully unsaturated 3-8 membered monocyclic,
6-12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
formed of
carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if
bicyclic,,or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0,
N, or S, and
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wherein said ring system is optionally substituted independently with 1-5
substituents of
R15;
R15 is H, halo, haloalkyl, CN, OH, NO2, NH2, oxo, acetyl, methyl, methoxyl,
ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl,
tert-butyl,
cyclobutyl, C1-10-alkylamino-, C1.10-dialkylamino-, C1-10-thioalkoxyl, benzyl,
phenyl or a
partially or fully saturated or unsaturated 3-8 membered monocyclic or 6-12
membered
bicyclic ring system, said ring system formed of carbon atoms optionally
including 1-3
heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms
selected from
0, N, or S, and optionally substituted independently with 1-5 substituents of
halo,
haloalkyl, CN, NO2, NH2, OH, methyl, methoxyl, ethyl, ethoxyl, propyl,
propoxyl,
isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl,
isobutoxyl,
tert-butoxyl, isobutyl, tert-butyl, cyclobutyl, CI_lo-alkylamino-, 01.10-
dialkylamino-, CI.10-
thioalkoxyl, benzyl or phenyl;
each R16, independently, is haloalkyl, methyl, methoxyl, ethyl, ethoxyl,
alkoxy-
alkyl, alkylamino-alkyl, dialkylamino-alkyl, propyl, propoxyl, isopropyl,
isopropoxyl,
cyclopropyl, butyl, isobutyl, sec-butyl or tert-butyl;
h is 0, 1 or 2; and
iis1,2or3.
In another embodiment, the compounds of Formula II include 0 as X1, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula 11 include S as X1, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula II include NR12 as X1, in
conjunction with any of the above or below embodiments.
In another embodiment, the compounds of Formula II include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl or sec-butyl as R16, independently, in
conjunction with
any of the above or below embodiments.
In another embodiment, the compounds of Formula 11 include each independent
embodiment, as described herein for variables A, B, R', R'a, R'b, R'c, R'd,
R2, R3, R4, R5,
R6, R7, R8, R9, R10, R", R12, Rt3, R14, R15, W, V, X1, X2, Y', Y2, Y3, Z' and
Z2 for
compounds of Formula I, independently, in conjunction with any of the above or
below
embodiments for compounds of Formula II.
In another embodiment, the compounds of Formula I or II include compounds
wherein RS is
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R12)p
_A3
R12 IA2
(k1
R16 R16
wherein m is 0 or 1;
pis0, 1,2or3;
A' is CH, C(=O), 0 or NR12;
each of A' and A2, independently, is CR12 or N, provided
that no more than one of A' and A2 is N;
X2 is CH;
Y3 is CR12 or 0; and
each R12, independently, is H, halo, haloalkyl, CN, OH,
NO2, NH2, acetyl, oxo, Cl_lo-alkyl, C2_lo-alkenyl, CZ_lo-alkynyl, C3_1o-
cycloalkyl,
C4_,0-cycloalkenyl, C1_10-alkylamino-, C1_lo-dialkylamino-, C1_lo-alkoxyl,
Cl_10-thioalkoxyl
or a ring selected from phenyl, pyridyl, pyrimidinyl, triazinyl, thiophenyl,
furyl,
tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl,
triazolyl, tetrazolyl,
thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl,
oxazolinyl,
isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl,
piperidinyl, piperazinyl,
pyranyl, dioxozinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl,
cyclohexyl and
cycloheptyl, wherein each of the C1_10-alkyl, C2_to-alkenyl, C2_lo-alkynyl,
C3_lo-cycloalkyl,
C4-10-cycloalkenyl, C1.10-alkylamino-, C1_1o-dialkylamino-, Cl_10-alkoxyl,
C,_10-thioalkoxyl
and ring is optionally substituted independently with 1-5 substituents of
halo, haloalkyl,
CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,
isopropyl,
isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,
tert-butoxyl,
isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopently, hexyl,
cyclohexyl, C1.10-
alkylamino-, C1_lo-dialkylamino-, C1_lo-thioalkoxyl, benzyl or phenyl, in
conjunction with
any of the above or below embodiments.
In yet another embodiment, the invention provides
compounds generally defined by Formula III,
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H
R3 R3 R4
A N N-~!R5
W i \" 1J
R3 R3
B OH
III
or stereoisomer, tautomer, solvate, pharmaceutically acceptable salt,
derivative or prodrug
thereof, wherein
A is Cl_10-alkyl, C2_10-alkenyl, C2_10-alkynyl, R'-CI.10-alkyl-, R'-C2.10-
alkenyl- or
R'-C2.10-alkynyl-, wherein
1, 2 or 3 carbon atoms of (1) said CI-Clo alkyl, C1-C10 alkenyl, CI-Clo
alkynyl or (2) said C1_lo-alkyl, C2-10-alkenyl, CZ_lo-alkynyl of R'-Cl_Io-
alkyl-, R'-
C2_10-alkenyl- or R'-C2_10-alkynyl-, is optionally replaced with a heteroatom
selected from 0, S, S(O), S(O)2 and NH, and optionally substituted
independently
with one or more substituents of R9; and
R' is a fully saturated or a partially or fully unsaturated 3-8 membered
monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system,
said ring system formed of carbon atoms and optionally including 1-3
heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if
tricyclic, said heteroatoms selected from 0, N, or S, wherein said ring system
is
substituted independently with one or more substituents of oxo, R7, R8, R9,
NR7R7, NR'R8, OR7, SR', ORB, SRS, C(O)R7, OC(O)R7, COOR7, C(O)R8,
OC(O)R8, COORS, C(O)NR'R', C(S)NR'R', NR7C(O)R7, NR7C(S)R7,
NR7C(O)NR'R', NR'C(S)NR7R', NR7(COOR'), OC(O)NR'R', C(O)NR7R8,
C(S)NR'R8, NR7C(O)R8, NR'C(S)R8, NR'C(O)NR'R8, NR7C(S)NR7R8,
NR'(COORB), OC(O)NR'R8, S(O)2NR'R', NR7S(O)2NR'R7 , NR'S(O)2R',
S(O)2R8, S(O)2NR'R8, NR7S(O)2NR7R8 or NR7S(0)2R8;
W is -C(=O)-, -OC(=O)-, -NHC(=O)-, -S(=O)b- or -NHS(=O)b-, wherein b is 1
or 2;
B is R2-(CR2aR2a)h-, R2-O-(CR2aR2a)h-, R2-S-(CR2aR2a)h- or R2-NR2a_(CR2aR2a)h
wherein
R2 is CI-Clo alkyl, CI-Clo haloalkyl, CI-C10 alkenyl, C1-C10 alkynyl or a
partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
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formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms
selected
from 0, N, or S, wherein said C1-Clo alkyl, C1-C10 alkenyl, C1-C10 alkynyl is
optionally substituted independently with one or more substituents of R9, and
said
ring system is optionally substituted independently with one or more
substituents
of oxo R' R$ R9 NR7R7 NR7R8 OR7, SR7 OR8 SRS, C(O)R' OC(O)R7,
COOR7, C(O)R8, OC(O)R8, COORS, C(O)NR7R7, C(S)NR7R7, NR7C(O)R7,
NR7C(S)R7, NR7C(O)NR'R7, NR'C(S)NR'R7, NR7(COOR), OC(O)NR7R7,
C(O)NR7R8, C(S)NR7R8, NR7C(O)R8, NR'C(S)R8, NR7C(O)NR7R8,
NR'C(S)NR7R8, NR7(COOR8), OC(O)NR'R8, S(O)2NR'R7, NR7S(O)2NR7R7,
NR'S(O)2R7, S(O)2R8, S(O)2NR7R8, NR 7S(0)2NR7R8 or WS(0)2R!;
each Rea, independently, is H, OH, NO2, CN, NH2, C1-C10 alkyl, Cl-Clo
alkoxyl or haloalkyl; and
his0,1,2or3;
its 1,2or3;
j is 0, 1 or 2;
each R3, independently, is H, haloalkyl, CN, C1_10-alkyl, C2.10-alkenyl, C2.10-
alkynyl, C3_lo-cycloalkyl or C4.1o-cycloalkenyl, each of the Ci_,o-alkyl,
C2_,o-alkenyl, C2_10-
alkynyl, C3_10-cycloalkyl and C4_10-cycloalkenyl optionally comprising 1-4
heteroatoms
selected from N, 0 and S and optionally substituted with 1-5 substituents of
R8 or R9;
R4 is H, haloalkyl, CN, Cl_10-alkyl, C2_10-alkenyl, C2_lo-alkynyl, C3.10-
cycloalkyl or
C4_10-cycloalkenyl, each of the C1_lo-alkyl, C2.10-alkenyl, 02.10-alkynyl,
C3.10-cycloalkyl
and C4_10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N,
0 and S
and optionally substituted with 1-5 substituents of R8 or R9;
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Rs is
Rio Rio R1 Rio
R12I ~S'R12 Rl2 R12
R11 Rtt .S" R11 R11
(X!! X1 XXX~ m (X R16 X2 Ris
mXi
R16 R16 Ris Rio R16 R16
Rio Rio R RIO
R12 R12 R12 10 R16 R12 R16
R11 R11
Ris /XL Ris Xi X21 R16 X R16
~C
X7 Xrm X m R12 Riz X1 m
R16 R76 ' '
R12 Rio R1s
RIG
xlm /X1
m
R12
RIO R10 R10
R12 Riz ~` R12 Rio
c' R11 Ri t ,S R11 Q R12
S R11
X1 X2 X2) (X L Yjy \/
m 2 X1 ) X 2 X
y1y1 \ 'Y o Y2 m y/Y2
y2 Y2
Rio R1o Rio RIO
R12 NrR11 R1 NRii R12 N/R11 R12 N/R11
S I 1 ~'1
(X2 Xi X2 X2)m (X2 '7 {~ ~ l XX
1 X2 Y Y21-- X2 m
Yt y~0 yi Y O \\Y 2 Y31 / 0
Y2 z
Rio RIO
RIO RIO
R12 R11 ,S R1 R11 R12 N, R1, R12
X N~R11
1 xi m / 1 rX1 Yi Xi CX2) m 333'''1 X~ X2
Y2,- Y2m Y2 Y2 2m
1Y3) Y3)o -_~Y3)O t' )O
Rio y1 Rio y1` R1o yt\
R12 % 2 R12 /Y2 " Ri ~ 2
S'e X Y), ~X~ Sc (X y3/)`0
sz Xi
2 ~X2 R12 > R12 X1 m or m
m
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wherein X1 is C(=O), 0, S, S(O)2 or NR 12;
each X2, independently, is CR12R12;
each of Y', Y2 and Y3, independently, is CR12R12, 0, S or NR12;
m is 0, 1 or 2; and
o is 0, 1, 2,3,4 or 5;
provided that (a) no more than two of Y', Y2 and Y3 is 0, S or NR12 and (b)
when
o is 0, then each of Y' and Y2 is CR12R12;
R' is H, CI.10-alkyl, C2-1o-alkenyl, C2-1o-alkynyl, C3-10-cycloalkyl or C4-10-
cycloalkenyl, each of the Q-10-alkyl, C2.19-alkenyl, C2_10-alkynyl, C3.1o-
cycloalkyl and C4-
10-cycloalkenyl optionally comprising 1-4 heteroatoms selected from N, 0 and S
and
optionally substituted with 1-5 substituents ofNR8R9, NR9R9, ORB, SRS, ORS,
SR9,
C(O)R8, OC(O)R8, COORS, C(O)R9, OC(O)R9, COORS, C(O)NR8R9, C(O)NR9R9,
NR9C(O)R8, NR9C(O)R9, NR9C(O)NRBR9, NR9C(O)NR9R9, NR9(000R8), NR9(COOR9),
OC(O)NR8R9, OC(O)NR9R9, S(O)2R8, S(O)2NR8R9, S(O)2R9, S(O)2NR9R9,
NR9S(O)2NRBR9, NR9S(O)2NR9R9, NR9S(O)2R8, NR9S(O)2R9, R8 or R9;
R8 is a partially or fully saturated or unsaturated 3-8 membered monocyclic, 6-
12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
formed of
carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if
bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0,
N, or S, and
wherein said ring system is optionally substituted independently with 1-5
substituents of
R9, oxo, NR9R9, ORS; SRS, C(O)R9 or a partially or fully saturated or
unsaturated 5-6
membered ring of carbon atoms optionally including 1-3 heteroatoms selected
from 0, N,
or S, and optionally substituted independently with 1-5 substituents of R9;
R9 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1_10-alkyl, C2_lo-
alkenyl, C2_
10-alkynyl, C3-lo-cycloalkyl, C4_lo-cycloalkenyl, C1_10-alkylamino-, C1_10-
dialkylamino-, C.
10-alkoxyl, C1_10-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the CI_lo-alkyl, C2_to-
alkenyl, C2-10-
alkynyl, C3_10-cycloalkyl, C4.1o-cycloalkenyl, C1_10-alkylamino-, C1-10-
dialkylamino-, C1.lo-
alkoxyl, CI_10-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
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butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1_lo-alkylamino-,
CI-jo-
dialkylamino-, C1-10-thioalkoxyl, benzyl or phenyl;
R10 is H, halo, haloalkyl, CN, OH, NO2, NH2a acetyl, C1_10-alkyl, C2_70-
alkenyl, C2_
lo-alkynyl, C3.10-cycloalkyl, C4_10-cycloalkenyl, CI_I0-alkylamino-, CI_lo-
dialkylamino-, CI-
10-alkoxyl, CI_lo-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the C1_10-alkyl, C2_10-
alkenyl, C2.10-
alkynyl, C3_10-cycloalkyl, C4_10-cycloalkenyl, C1-10-alkylamino-, Cl_10-
dialkylamino-, C1-10-
1 0 alkoxyl, C1_10-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1_10-alkylamino-,
Cl-I0-
dialkylamino-, Cl_lo-thioalkoxyl, benzyl or phenyl;
R" is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, Cl_10-alkyl, C2_10-
alkenyl, C2_
10-alkynyl, 03.10-cycloalkyl, C4_10-cycloalkenyl, C1_10-alkylamino-, C1-10-
dialkylamino-, Cl_
lo-alkoxyl, C1.1o-thioalkoxyl or a saturated or partially or fully unsaturated
3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from O. N, or S, wherein each of the C1_10-alkyl, C2.10-
alkenyl, C2-IO-
alkynyl, C3_10-cycloalkyl, C4.10-cycloalkenyl, C1_10-alkylamino-, CI.10-
dialkylamino-, CI-1o-
alkoxyl, Cl_lo-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-lo-alkylamino-,
C1-10-
dialkylamino-, CI.10-thioalkoxyl, benzyl or phenyl;
alternatively, R10 and R" taken together with the carbon or nitrogen atoms to
which they are attached form a partially or fully saturated or unsaturated 5-6
membered
second ring of carbon atoms optionally including 1-3 heteroatoms selected from
0, N, or
S, the second ring optionally substituted independently with 1-5 substituents
of R12, R13,
R14 or R15 and optionally fused to a 4-7 membered third ring, the third ring
formed of
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carbon atoms optionally including 1-3 heteroatoms selected from 0, N, or S,
and
optionally substituted independently with 1-5 substituents of R12, R13, R14 or
R15;
R12 is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1_10-alkyl, C2.10-
alkenyl, C2_
lo-alkynyl, C3_lo-cycloalkyl, C4_,o-cycloalkenyl, C1_,0-alkylamino-, C1.1o-
dialkylamino-, CI-
S 10-alkoxyl, CI.10-thioalkoxyl or a saturated or partially or fully
unsaturated 3-8 membered
monocyclic or a 6-12 membered bicyclic, said ring system formed of carbon
atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if
bicyclic, said
heteroatoms selected from 0, N, or S, wherein each of the C1_lo-alkyl, C2_10-
alkenyl, C2.10-
alkynyl, C3_10-cycloalkyl, C4_,0-cycloalkenyl, C1_lo-alkylamino-, C1-lo-
dialkylamino-, C1-10-
alkoxyl, CI_10-thioalkoxyl and ring of said ring system is optionally
substituted
independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo,
methyl,
methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,
cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C1-'o-alkylamino-,
C1-10-
dialkylamino-, Cl_lo-thioalkoxyl, benzyl, phenyl or R14;
R13 is NR'4R15, NR15R15, OR14; SR14, OR15; SR15, C(O)R14, OC(O)R14, COOR14,
C(O)R15, OC(O)R'5, COOR15, C(O)NR14R15, C(O)NR'5R15, NR14C(O)R14, NR15C(O)R14,
NR'4C(O)R15, NR15C(O)R15, NR15C(O)NR'4R'S, NR15C(O)NR'5R'5, NR15(COOR14),
NR15(COOR15), OC(O)NR'4R'5, OC(O)NR15R15, S(O)2R14, S(O)2R15, S(O)2NR14R15,
S(O)2NR15R15, NR'4S(O)2NR14R15, NR15S(O)2NR15R15, 14S(O)2R14 or NR'5S(O)2R'5;
R14 is a saturated or partially or fully unsaturated 3-8 membered monocyclic,
6-12
membered bicyclic, or 7-14 membered tricyclic ring system, said ring system
formed of
carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if
bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from 0,
N, or S, and
wherein said ring system is optionally substituted independently with 1-5
substituents of
R15; and
R15 is H, halo, haloalkyl, CN, OH, NO2, NH2, oxo, acetyl, methyl, methoxyl,
ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,
cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-
butyl, tert-
butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl, phenyl, C,-
10-
alkylamino-, Cl_,o-dialkylamino-, C1_lo-thioalkoxyl or a partially or fully
saturated or
unsaturated 3-8 membered monocyclic or 6-12 membered bicyclic ring system,
said ring
system formed of carbon atoms optionally including 1-3 heteroatoms if
monocyclic or 1-6
heteroatoms if bicyclic, said heteroatoms selected from 0, N, or S, and
optionally
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substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO2,
NH2, OH,
oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl,
isopropoxyl,
cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl,
isobutyl, see-
butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl
or phenyl;
and
each R 16, independently, is haloalkyl, methyl, methoxyl, ethyl, ethoxyl,
alkoxy-
alkyl, alkylamino-alkyl, dialkylamino-alkyl, propyl, propoxyl, isopropyl,
isopropoxyl,
cyclopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
In another embodiment, the compounds of Formula III include each independent
embodiment, as described herein for variables A, B, R', R", R'b, R'O, R'd, R2,
R3, R4, R5,
R6, R', R8, R9, R10, R", R12, R13, R14, R15, W, V, X', X2, Y', Y2, Y3, Z' and
Z2 for
compounds of Formula I, independently, in conjunction with any of the above or
below
embodiments for compounds of Formula III.
In another embodiment, the invention provides each of the Examplary
compounds, and stereoisomers, tautomers, solvates, pharmaceutically acceptable
salts,
derivatives or prodrugs thereof, and related intermediates, described herein.
DEFINITIONS
The following definitions should assist in understanding the invention
described
herein.
The term "comprising" is meant to be open ended, including the indicated
component(s), but not excluding other elements.
The term "H" denotes a single hydrogen atom. This radical may be attached, for
example, to an oxygen atom to form a hydroxyl radical.
The term "Ca,_palkyl", when used either alone or within other terms such as
"haloalkyl" and "alkylamino", embraces linear or branched radicals having a to
13 number
of carbon atoms (such as C1-C10). One or more carbon atoms of the "alkyl"
radical may
be substituted, such as with a cycloalkyl moeity. Examples of "alkyl" radicals
include
methyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl,
cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl, isopropyl, n-
butyl,
cyclopropylbutyl, isobutyl, sec-butyl, tent-butyl, pentyl, isoamyl, hexyl and
the like. The
term "alkylenyl" embraces bridging divalent alkyl radicals such as methylenyl
and
ethylenyl.
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The term "alkenyl", when used alone or in combination, embraces linear or
branched radicals having at least one carbon-carbon double bond in a moiety
having
between two and ten carbon atoms. Included within alkenyl radicals are "lower
alkenyl"
radicals having two to about six carbon atoms and, for example, those radicals
having two
to about four carbon atoms. Examples of alkenyl radicals include, without
limitation,
ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms
"alkenyl" and
"lower alkenyl", embrace radicals having "cis" and "trans" orientations, or
alternatively,
"E" and "Z" orientations, as appreciated by those of ordinary skill in the
art.
The term "alkynyl", when used alone or in combination, denotes linear or
branched radicals having at least one carbon-carbon triple bond and having two
to ten
carbon atoms. Examples of alkynyl radicals include "lower alkynyl" radicals
having two
to about six carbon atoms and, for example, lower alkynyl radicals having two
to about
four carbon atoms. Examples of such radicals include, without limitation,
ethynyl,
propynyl (propargyl), butynyl, and the like.
The term "Ca_palkoxyl" when used alone or in combination, embraces linear or
branched oxygen-containing alkyl radicals each having oc to (3 number of
carbon atoms
(such as C1-C10). The terms "alkoxy" and "alkoxyl", when used alone or in
combination,
embraces linear or branched oxygen-containing radicals each having alkyl and
substituted
alkyl portions of one or more carbon atoms. Examples of such radicals include
methoxy,
ethoxy, propoxy, butoxy and tert-butoxy. Alkoxy radicals may be further
substituted
with one or more halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkoxy"
radicals or with other substitution. Examples of such radicals include
fluoromethoxy,
choromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, fluoropropoxy
and
cyclopropylmethoxy.
The term "aryl", when used alone or in combination, means a carbocyclic
aromatic moiety containing one, two or even three rings wherein such rings may
be
attached together in a fused manner. Every ring of an "aryl" multi-ring system
need not
be aromatic, and the ring(s) fused to the aromatic ring may be partially or
fully
unsaturated and include one or more heteroatoms selected from nitrogen, oxygen
and
sulfur. Thus, the term "aryl" embraces aromatic radicals such as phenyl,
naphthyl,
indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,
benzodioxazinyl,
and the like. The "aryl" group may be substituted, such as with 1 to 5
substituents
including lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and
lower
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37 -
alkylamino, and the like. Phenyl substituted with -O-CH2-O- or -O-CH2-CH2-O-
forms an
aryl benzodioxolyl substituent.
The term "carbocyclic", also referred to herein as "cycloalkyl", when used
alone
or in combination, means a partially or fully saturated ring moiety containing
one
("monocyclic"), two ("bicyclic") or even three ("tricyclic") rings wherein
such rings may
be attached together in a fused manner and formed from carbon atoms. Examples
of
saturated carbocyclic radicals include saturated 3 to 6-membered monocyclic
groups such
as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
The terms "ring" and "ring system" refer to a ring comprising the delineated
number of atoms, the atoms being carbon or, where indicated, a heteroatom such
as
nitrogen, oxygen or sulfur. Where the number of atoms is not delineated, such
as a
"monocyclic ring system" or a "bicyclic ring system", the numbers of atoms are
3-8 for a
monocyclic and 6-12 for a bicyclic ring. The ring itself, as well as any
substitutents
thereon, may be attached at any atom that allows a stable compound to be
formed. The
term "nonaromatic" ring or ring system refers to the fact that at least one,
but not
necessarily all, rings in a bicyclic or tricyclic ring system is nonaromatic.
The term "cycloalkenyl", when used alone or in combination, means a partially
or
fully saturated cycloalkyl containing one, two or even three rings in a
structure having at
least one carbon-carbon double bond in the structure. Examples of cycloalkenyl
groups
include C3-C6 rings, such as compounds including, without limitation,
cyclopropene,
cyclobutene, cyclopentene and cyclohexene. The term also includes carbocyclic
groups
having two or more carbon-carbon double bonds such as "cycloalkyldienyl"
compounds.
Examples of cycloalkyldienyl groups include, without limitation,
cyclopentadiene and
cycloheptadiene.
The term "halo", when used alone or in combination, means halogens such as
fluorine, chlorine, bromine or iodine atoms.
The term "haloalkyl", when used alone or in combination, embraces radicals
wherein any one or more of the alkyl carbon atoms is substituted with halo as
defined
above. For example, this term includes monohaloalkyl, dihaloalkyl and
polyhaloalkyl
radicals such as a perhaloalkyl. A monohaloalkyl radical, for example, may
have either
an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and
polyhaloalkyl
radicals may have two or more of the same halo atoms or a combination of
different halo
radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, tichloromethyl,
pentafluoroethyl,
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heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichioroethyl and dichloropropyl. "Perfluoroalkyl", as used
herein, refers
to alkyl radicals having all hydrogen atoms replaced with fluoro atoms.
Examples include
trifluoromethyl and pentafluoroethyl.
The term "heteroaryl", as used herein, either alone or in combination, means a
fully unsaturated (aromatic) ring moiety formed from carbon atoms and having
one or
more heteroatoms selected from nitrogen, oxygen and sulfur. The ring moiety or
ring
system may contain one ("monocyclic"), two ("bicyclic") or even three
("tricyclic") rings
wherein such rings are attached together in a fused manner. Every ring of a
"heteroaryl"
ring system need not be aromatic, and the ring(s) fused thereto (to the
heteroaromatic
ring) may be partially or fully saturated and optionally include one or more
heteroatoms
selected from nitrogen, oxygen and sulfur. The term "heteroaryl" does not
include rings
having ring members of -O-O-, -O-S- or -S-S-.
Examples of unsaturated heteroaryl radicals, include unsaturated 5- to 6-
membered heteromonocyclyl groups containing I to 4 nitrogen atoms, including
for
example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
pyrimidyl,
pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazoly], IH-1,2,3-
triazolyl, 2H-1,2,3-
triazolyl] and tetrazole; unsaturated 7- to 10- membered heterobicyclyl groups
containing
I to 4 nitrogen atoms, including for example, quinolinyl, isoquinolinyl,
quinazolinyl,
isoquinazolinyl, aza-quinazolinyl, and the like; unsaturated 5- to 6-membered
heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-
furyl, 3-
furyl, benzofuryl, etc.; unsaturated 5 to 6-membered heteromonocyclic group
containing a
sulfur atom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.;
unsaturated 5- to 6-
membered heteromonocyclic group containing I to 2 oxygen atoms and I to 3
nitrogen
atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-
oxadiazolyl, 1,3,4-
oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic
group
containing 1 to 2 sulfur atoms and I to 3 nitrogen atoms, for example,
thiazolyl,
isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazoly], 1,3,4-thiadiazolyl,
1,2,5-thiadiazolyl].
The term "heterocyclic", when used alone or in combination, means a partially
or
fully saturated ring moiety containing one, two or even three rings wherein
such rings
may be attached together in a fused manner, formed from carbon atoms and
including one
or more heteroatoms selected from N, 0 or S. Examples of saturated
heterocyclic radicals
include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4
nitrogen
atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,
piperazinyl]; saturated 3
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to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3
nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic
group
containing I to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl]. Examples of
partially saturated heterocyclyl radicals include dihydrothienyl,
dihydropyranyl,
dihydrofuryl and dihydrothiazolyl.
The term "heterocycle" also embraces radicals where heterocyclic radicals are
fused/condensed with aryl radicals: unsaturated condensed heterocyclic group
containing
1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl,
quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,
tetrazolo [1,5-
b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2
oxygen atoms
and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated
condensed
heterocyclic group containing I to 2 sulfur atoms and 1 to 3 nitrogen atoms
[e.g.,
benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and
unsaturated
condensed heterocyclic group containing I to 2 oxygen or sulfur atoms [e.g.
benzofuryl,
benzothienyl, 2,3-dihydro-benzo[l,4]dioxinyl and dihydrobenzofuryl]. Examples
of
heterocyclic radicals include five to ten membered fused or unfused radicals.
Examples of partially saturated and fully saturated heterocyclyls include,
without
limitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,
pyrazolidinyl, piperazinyl,
morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-
benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl,
dihydrobenzofuryl,
isochromanyl, chromanyl, I,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-
tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-I H-3-aza-fluorenyl, 5,6,7-
trihydro-1,2,4-
triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl,
benzo[1,4]dioxanyl, 2,3-
dihydro-IH-1X'-benzo[d]isothiazol-6-yi, dihydropyranyl, dihydrofuryl and
dihydrothiazolyl, and the like.
The term "alkylamino" includes "N-
alkylamino" where amino radicals are independently substituted with one alkyl
radical.
Preferred alkylamino radicals are "lower alkylamino" radicals having one to
six carbon
atoms. Even more preferred are lower alkylamino radicals having one to three
carbon
atoms. Examples of such lower alkylamino radicals include N-methylamino, and N-
ethylamino, N-propylamino, N-isopropylamino and the like.
The term "dialkylamino" includes "N, N-
dialkylamino" where amino radicals are independently substituted with two
alkyl radicals.
Preferred alkylamino radicals are "lower alkylamino" radicals having one to
six carbon
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atoms. Even more preferred are lower alkylamino radicals having one to three
carbon
atoms. Examples of such lower alkylamino radicals include N,N-dimethylamino,
N,N-
diethylamino, and the like.
The terms "carboxy" or "carboxyl", whether used alone or with other terms,
such
as "carboxyalkyl", denotes -CO2H.
The term "carbonyl", whether used alone or with other terms, such as
"aminocarbonyl", denotes -(C=O)-. "Carbonyl" is also used herein synonymously
with
the term "oxo".
The term "aminocarbonyl" denotes an amide group of the formula -C(=O)NH2.
The term "alkylthio" or "thioalkoxy" embraces radicals containing a linear or
branched alkyl radical, of one to ten carbon atoms, attached to a divalent
sulfur atom. An
example of "alkylthio" or "thioalkoxy" is methylthio,(CH3S-).
The term "haloalkylthio" embraces radicals containing a haloalkyl radical, of
one
to ten carbon atoms, attached to a divalent sulfur atom. An example of
"haloalkylthio" is
trifluoromethylthio.
The term "alkylaminoalkyl" embraces alkyl radicals substituted with alkylamino
radicals. Examples of alkylaminoalkyl radicals include "lower alkylaminoalkyl"
radicals
having alkyl radicals of one to six carbon atoms. Suitable alkylaminoalkyl
radicals may
be mono or dialkyl substituted, such as N-methylaminomethyl, N,N-dimethyl-
aminoethyl,
NN-dethylaminomethyl and the like.
The term "alkylaminoalkoxy" embraces alkoxy radicals substituted with
alkylamino radicals. Examples of alkylaminoalkoxy radicals include "lower
alkylaminoalkoxy" radicals having alkoxy radicals of one to six carbon atoms.
Suitable
alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as N-
methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and the
like.
The term "Formula I" includes any sub formulas, such as Formula I.I.
Similarly,
the term "Formula II" includes any sub formulas and "Formula III', includes
any sub
formulas.
The term "pharmaceutically-acceptable" when used with reference to a
compound of Formulas I-I11 is intended to refer to a form of the compound that
is safe for
administration. For example, a salt form, a solvate, a hydrate or derivative
form of a
compound of Formula I, II or of Formula III, which has been approved for
mammalian
use, via oral ingestion or other routes of administration, by a governing body
or
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regulatory agency, such as the Food and Drug Administration (FDA) of the
United States,
is pharmaceutically acceptable.
Included in the compounds of Formulas I-III are the pharmaceutically
acceptable
salt forms of the free-base compounds. The term "pharmaceutically-acceptable
salts"
embraces salts commonly used to form alkali metal salts and to form addition
salts of free
acids or free bases. As appreciated by those of ordinary skill in the art,
salts may be
formed from ionic associations, charge-charge interactions, covalent bonding,
complexation, coordination, etc. The nature of the salt is not critical,
provided that it is
pharmaceutically acceptable.
Suitable pharmaceutically acceptable acid addition salts of compounds of
Formulas I-III may be prepared from an inorganic acid or from an organic acid.
Examples
of such inorganic acids are hydrochloric, hydrobromic, hydroiodic,
hydrofluoric, nitric,
carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be
selected from
aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic
and sulfonic
classes of organic acids, examples of which include, without limitation,
formic, acetic,
adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic,
tartaric, citric,
ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic,
mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic,
ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-
hydroxyethanesulfonic,
toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric,
camphorsulfonic,
digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,
glycerophosphonic,
heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-
naphthalenesulfonic, oxalic,
palmoic, pectinic, persulfuric, 2-phenyipropionic, picric, pivalic propionic,
succinic,
thiocyanic, undecanoic, stearic, algenic, (3-hydroxybutyric, salicylic,
galactaric and
galacturonic acid. Suitable pharmaceutically-acceptable base addition salts of
compounds
of Formulas I, II and III include metallic salts, such as salts made from
aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from
organic
bases including, without limitation, primary, secondary and tertiary amines,
substituted
amines including cyclic amines, such as caffeine, arginine, diethylamine, N-
ethyl
piperidine, histidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl
morpholine,
piperazine, piperidine, triethylamine, disopropylethylamine and
trimethylamine. All of
these salts may be prepared by conventional means from the corresponding
compound of
the invention by reacting, for example, the appropriate acid or base with the
compound of
Formulas I-III.
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Also, the basic nitrogen-containing groups can be quaternized with such agents
as
lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride,
bromides and
iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl
sulfates, long chain
halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides, aralkyl
halides like benzyl and phenethyl bromides, and others. Water or oil-soluble
or
dispersible products are thereby obtained.
Examples of acids that may be employed to form pharmaceutically acceptable
acid addition salts include such inorganic acids as hydrochloric acid,
hydrobromic acid,
citric acid, sulphuric acid and phosphoric acid and such organic acids as
oxalic acid,
stearic and, salicylic acid, pamoic acid, gluconic acid, ethanesulfonic acid,
methanesulfonic acid, toluenesulfonic acid, tartaric acid, fumaric acid,
medronic acid,
napsylic acid, maleic acid, succinic acid and citric acid. Other examples
include salts
with alkali metals or alkaline earth metals such as sodium, potassium, calcium
or
magnesium, or with organic bases.
Additional examples of such salts can be found in Berge et al., J. Pharm.
Sci.,
66:1 (1977). Conventional methods may be used to form the salts. For example,
a
phosphate salt of a compound of the invention may be made by combining the
desired
compound free base in a desired solvent, or combination of solvents, with
phosphoric acid
in a desired stoichiometric amount, at a desired temperature, typically under
heat
(depending upon the boiling point of the solvent). The salt can be
precipitated upon
cooling (slow or fast) and may crystallize (i.e., if crystalline in nature),
as appreciated by
those of ordinary skill in the art. Further, hemi-, mono-, di, tri- and poly-
salt forms of the
compounds of the present invention are also contemplated herein. Similarly,
hemi-,
mono-, di, tri- and poly-hydrated forms of the compounds, salts and
derivatives thereof,
are also contemplated herein.
The term "derivative" is broadly construed herein, and intended to encompass
any salt of a compound of this invention, any ester of a compound of this
invention, or
any other compound, which upon administration to a patient is capable of
providing
(directly or indirectly) a compound of this invention, or a metabolite or
residue thereof,
characterized by the ability to the ability to modulate an enzyme.
The term "pharmaceutically-acceptable derivative" as used herein, denotes a
derivative which is pharmaceutically acceptable.
The term "prodrug", as used herein, denotes a compound which upon
administration to a subject or patient is capable of providing (directly or
indirectly) a
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compound of this invention. Examples of prodrugs would include esterified or
hydroxylated compounds where the ester or hydroxyl groups would cleave in
vivo, such
as in the gut, to produce a compound according to Formula 1-111. A
"pharmaceutically-
acceptable prodrug" as used herein, denotes a prodrug which is
pharmaceutically
acceptable. Pharmaceutically acceptable modifications to the compounds of
Formula I-III
are readily appreciated by those of ordinary skill in the art.
The compound(s) of Formulas I-III may be used to treat a subject by
administering the compound(s) as a pharmaceutical composition. To this end,
the
compound(s) can be combined with one or more carriers, diluents or adjuvants
to form a
suitable composition, which is described in more detail herein.
The term "carrier", as used herein, denotes any pharmaceutically acceptable
additive, excipient, adjuvant, or other suitable ingredient, other than the
active
pharmaceutical ingredient (API), which is typically included for formulation
and/or
administration purposes. "Diluent" and "adjuvant" are defined hereinafter.
The terms "treat", "treating," "treatment," and "therapy" as used herein refer
to
therapy, including without limitation, curative therapy, prophylactic therapy,
and
preventative therapy. Prophylactic treatment generally constitutes either
preventing the
onset of disorders altogether or delaying the onset of a pre-clinically
evident stage of
disorders in individuals.
The phrase "effective dosage amount" is intended to quantify the amount of
each
agent, which will achieve the goal of improvement in disorder severity and the
frequency
of incidence over treatment of each agent by itself, while avoiding adverse
side effects
typically associated with alternative therapies. Accordingly, this term is not
limited to a
single dose, but may comprise multiple dosages required to bring about a
therapeutic or
prophylactic response in the subject. For example, "effective dosage amount"
is not
limited to a single capsule or tablet, but may include more than one capsule
or tablet,
which is the dose prescribed by a qualified physician or medical care giver to
the subject.
The term "leaving group" (also denoted as "LG") generally refers to groups
that
are displaceable by a nucleophile. Such leaving groups are known in the art.
Examples of
leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl),
sulfonates (e.g.,
mesylate, tosylate), sulfides (e.g., SCH3), N-hydroxsuccinimide, N-
hydroxybenzotriazole,
and the like. Nucleophiles are species that are capable of attacking a
molecule at the point
of attachment of the leaving group causing displacement of the leaving group.
Nucleophiles are known in the art. Examples of nucleophilic groups include,
but are not
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limited to, amines, thiols, alcohols, Grignard reagents, anionic species
(e.g., alkoxides,
amides, carbanions) and the like.
GENERAL SYNTHETIC PROCEDURES
The present invention further comprises procedures for the preparation of
compounds of Formulas I, II and III.
The compounds of Formulas I-III can be synthesized according to the procedures
described in the following Schemes 1-5, wherein the substituents are as
defined for
Formulas 1, II and III above, except where further noted. The synthetic
methods described
below are merely exemplary, and the compounds of the invention may also be
synthesized by alternate routes utilizing alternative synthetic strategies, as
appreciated by
persons of ordinary skill in the art.
The following list of abbreviations used throughout the specification
represent the
following and should assist in understanding the invention:
ACN, McCN - acetonitrile
Aq. - aqueous
BOP - benzotriazol-1-yl-oxy
hexafluorophosphate
Cs2CO3 - cesium carbonate
CHC13 - chloroform
CH2CI2, DCM - dichloromethane, methylene chloride
Cul - copper iodide
DCC - dicyclohexylcarbodiimide
DIC - 1,3-diisopropylcarbodiimide
DIEA, DIPEA - diisopropylethylamine
DME - dimethoxyethane
DMF - dimethylformamide
DMAP - 4-dimethylaminopyridine
DMS - dimethylsulfide
DMSO - dimethylsulfoxide
EDC, EDCI - 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
Et2O - diethyl ether
EtOAc - ethyl acetate
FBS - fetal bovine serum
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G, gm - gram
h, hr - hour
H2 - hydrogen
H2O - water
HATU - 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-
tetramethyluroniumhexafluorophosphate
HBr - hydrobromic acid
HC1 - hydrochloric acid
HOBt - 1-hydroxybenzotriazole hydrate
HOAc - acetic acid
HPLC - high pressure liquid chromatography
IPA, IpOH - isopropyl alcohol
K2C03 - potassium carbonate
KI - potassium iodide
LG - leaving group
LiOH - lithium hydroxide
MgSO4 - magnesium sulfate
MS - mass spectrum
'MeOH - methanol
N2 - nitrogen
NaCNBH3 - sodium cyanoborohydride
Na2CO3 - sodium carbonate
NaHCO3 - sodium bicarbonate
NaH - sodium hydride
NaBH4 - sodium borohydride
NaOH - sodium hydroxide
Na2SO4 - sodium sulfate
NH4Cl - ammonium chloride
NH4OH - ammonium hydroxide
P(t-bu)3 - tri(tert-butyl)phosphine
PBS - phospate buffered saline
Pd/C - palladium on carbon
Pd(PPh3)4 - pall adium(O)triphenylphosphine
tetrakis
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Pd(dppf)C12 - palladium(1,1-
bisdiphenylphosphinoferrocene)
II chloride
Pd(PhCN)2C12 - palladium di-cyanophenyl dichloride
Pd(OAc)2 - palladium acetate
Pd2(dba)3 - tris(dibenzylideneacetone) dipalladium
PyBop - benzotriazol-l-yl-oxy-tripyrrolidino-phosphonium
hexafluorophosphate
RT, rt - room temperature
RBF, rbf - round bottom flask
TLC, tlc - thin layer chromatography
TBTU - O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate
TEA, Et3N - triethylamine
TFA - trifluoroacetic acid
THE - tetrahydrofuran
UV - ultraviolet light
While the synthetic strategy for preparing the compounds of Formulas I, H and
III
may vary, as appreciated by persons skilled in the art, one strategy for
devising a method
of making compounds of these formulas is by retro-synthetic disconnection. For
example,
H OH IR4
H OH R4
A N R AWN N Rs
W i 5 \ !, 5 R3
3 R3
B R2 and
R3 R3 R4
I
I
i
R3 R3
B OH
III
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as shown in Formulas I-I1I above, each squiggly line represents a possible
point of bond-
construction, whose order is generally dependent upon the particular compound
being
synthesized. Such bond construction methods are generally described in
synthetic
Schemes 1 - 5 below.
Scheme 1
O O
A-JO'R hydrolysis ydrolysis
1 2
0 O O, 0
H LG
activation
1 2'
X X R'Ib Rib
L R L~ R L~Q'R R1 L-' -OH
R
e.g., Mitsunob O e.g., Pd assisted hydrolysis
HO-R" coupling, R"M I
H We We We
2 3 4
hydrolysis x
Rt 0 wherein,
R is C1-C4 alkyl, e.g., CH3, C21-15, etc.
L OH and e.g., X = Br, 1, Cl, etc.; Rib = RTbB(OH)2, RTbSnBu3, etc.
H
5
Scheme 1 describes a few methods for preparing A-W acids, useful for preparing
compounds of Formulas I-III (see scheme 2) wherein W is -C(O)- or -S(O)2- and
A is CI_
1o-alkyl, C2_10-alkenyl, 02.10-alkynyl, R'-CI.10-alkyl-, Rl-C2_io-alkenyl- or
R'-C2-10-alkynyl-
("L" in scheme I corresponds to the Cl-1o-alkyl, C2_lo-alkenyl or C2-lo-
alkynyl of A
defined in A-W above). Desired A-W groups may be commercially available and
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purchased, or may be made by known, conventional methods. As shown, esters 1
can be
hydrolyzed to their corresponding acids 2 using known bases, such as NaOH or
LiOH.
Acids 2 can then be coupled to an amine (not shown) to prepare compounds of
Formula I-
III. Similarly, sulfonic acids 1' can be converted to an activated sulfonate
2' by reaction
with oxalyl chloride, for example, to prepare the corresponding sulfonyl
chloride 2'. The
sulfonyl chloride 2' can be reacted with an amine to prepare compounds of
Formula I-III.
In a similar manner, a desired ring R1 of compounds 1", where A is a spacer
"L"
between the R' ring and W, may first be functionalized prior to coupling to
the amino-
backbone, as shown in scheme 2. An ester-halo (X = halogen such as Br or I)
substituted
R' ring acid 4 or 5, both of which include a substitutable nitrogen in the
ring, and which
are generally referred to herein as the left-hand portion of the compounds of
Formulas I,
11 and lit, can be prepared according to the method generally described in the
second half
of Scheme 1. As shown, a methyl ester-halo substituted compound 1" can be
reacted in a
Mitsunobu-type reaction with a desired hydroxyl-substituted R'a compound under
suitable
conditions, such as in the presence of tri-phenyl phosphine and
diethylazodicarboxylate
(commonly referred to as DEAD) for a suitable time period to form the ring N-
Rla
substituted adduct 2". Intermediate 2" may also be formed using a suitable
reductive
amination method as well utilizing an aldehyde, for example (not shown in
scheme 1).
Compound 2" can be reacted in a palladium-catalyzed coupling reaction, such as
a
suzuki-type reaction, in the presence of suitable solvents and accompanying
reagents,
such as a base, to form the R'-Rlb substituted compound 3. Formation of
compound 3
may require heat, up to and including reflux temperatures depending on the
particular
substrate, solvent and reagent(s) concentration, as appreciated by those
skilled in the art.
Compound 3 can then be hydrolyzed in the presence of a suitable base and
solvent to
form the corresponding acid-adduct 4. Acid 4 is then utilized as an
intermediate to couple,
as described in scheme 2 below, with desired intermediates or other building
blocks to
make compounds of Formulas 1-II1.
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Alternatively, compound 1" can be hydrolyzed directly to the corresponding
acid
5. Ester-Halo-substituted compound 5 is a useful intermediate for coupling the
backbone
core compounds with desired B, R3 and R4 substitutions already in place.
Compound 5
can then be modified to include desirable R' substitutions, including Rla, R7,
R$ and R9
groups. In this fashion, analogs of a variety of desired left-hand pieces of
compounds of
Formulas I -III may be readily synthesized (see scheme 3).
By known methods, the acids 1', 2, 4 and 5, may be converted to the
corresponding isocycanates and then reacted with an amine (not shown) to make
a urea
"W" linker or an R'-urea linked A group (where W = -NHC(O)-).
Scheme 2
(R7, 8 or 9)n (R7, 8 or 9)
n
t A + HZN (Pr N(R4)(CH2)jR5 ---- A H (pr N(R4)(CH2)jR5
\(O)MC(O)X B \ (O)mC O)
B
(R7, 8 or 9)n (R7, 8 or 9)
2. + HZN (Pr N(R4)(CH2)jR5 JHN___4125
\COX C
(> B (O) B
(R7, 8 or 9) n (R7,8 or 9)n
3. + HZN (Pr N(Ra)(CHz)1Rs A/ C(O)NH (Pr N(Ra)(CH2)jRs
NHC(O)X \N
B H B
7' 8 or (R7.8 or 9)
~n / H N(R4)(CH2)jR5
4. A + H2 (~' N(R4)(CH2)jRs = Amo N (pr
\S(0)2X B (o) B
Desires A-W groups, which may be substituted with various substitutions
including one or more R7, R8 or R9 groups, can be coupled to the core hydroxyl-
propyl,
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hydroxyl-butyl or hydroxyl-pentyl backbone structure, generally designated in
Scheme 2
as "Pr" group, by various coupling methods as described in Scheme 2. In each
of the 4
sub-schemes, X refers generally to a "LG" or a "leaving group" such as a
halide
(bromine, chlorine, iodine or fluorine), alkylsulfonate and other known groups
(also see
definitions herein) which generally forms an electrophilic species (E) and m
is an integer
from 0-1. The NH2 group (primary amine) is a nucleophilic species (Nu ), as is
secondary
amines, hydroxides, alkoxides, an anionic carbon species and the like, which
should be
sufficiently strong to the attack the E+ species and displace the leaving
group X thereby
effecting a coupling of A-W to the Pr backbone. Examples of suitable
electrophilic
carbonyl species include, without limitation, acid halides, mixed anhydrides,
aldehydes,
carbamoyl-chlorides, sulfonyl chlorides, acids activated by coupling with
activating
reagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP and carbodiimides (DCC,
EDC and the like), and other electrophilic species including halides,
isocyanates,
daizonium ions and the like.
The coupled adduct of A-W and Pr, shown as products in sub-schemes 1-4, can
be brought about using various conventional methods. For example, an amide or
a
sulfonamide linkage, as shown in sub-schemes 2 and 4, can be made utilizing an
amine on
the Pr intermediate and an activated electrophilic species, on the A-W group
such as the
acid chloride or sulfonyl chloride as shown. The reaction proceeds generally
in the
presence of a suitable solvent and/or base. Suitable solvents include, without
limitation,
generally non-nucleophilic, anhydrous solvents such as toluene, CH2C12, THF,
DMF,
DMSO, N,N-dimethylacetamide and the like, including solvent combinations
thereof. The
solvent may range in polarity, as appreciated by those skilled in the art.
Suitable bases
include, for example, tertiary amine bases such as DIEA, TEA, carbonate bases
such as
Na2CO3, K2C03, Cs2CO3, hydrides such as NaH, KH, borohydrides,
cyanoborohydrides
and the like, alkoxides such as NaOCH3, and the like. The base itself may also
serve as a
solvent. The reaction may optionally be run neat, i.e., without any base
and/or solvent.
These coupling reactions are generally fast and conversion occurs typically in
ambient
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conditions. However, depending upon the particular substrate, such reactions
may require
heat, as appreciated by those skilled in the art.
Similarly, carbamates as illustrated in sub-scheme 1 and ureas as illustrated
in
sub-scheme 3 may be made as shown, wherein X has the same definition as above,
using
the same coupling methods described above for sub-schemes 2 and 4. While the
above
methods are so described, they are not exhaustive, and other methods for
linking A-W
groups and desired Pr groups together may be utilized as appreciated by those
skilled in
the art.
The coupling methods described in sub-schemes 1-4 of scheme 2 are also
applicable for coupling desired A-W intermediates to desired Pr intermediates
not
containing desired R5 groups, although sub-schemes 1-4 as illustrated do
contain R5
groups.
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Scheme 3
RIO
H2N (( R11
lX (R5) X1
Y1
Y2
9
reductive
A-i-9,4ration
RIO R10 R10 RIO
O R11 HO R11 N3 R71 H2N-- R11
(R5) R
reduction 5) e.g., OPPA, base (R5) (R )
(X Al (X X1 (X X1 reduction (X X1
Y1\ Y1\ Y1\ Y1~
Y2 Y2 Y2 Y2
7 8 8
mine formation
>~S,O RIO >~S.O RID RIO
Na R11 HN R11 H2N R1,
(X (Rs) X reduction iX (R5) X hydrolysis (Rs)
1 1 (X X1
Y1 Y~ Y1 ~'Y~ Y1 )Y~
Y2 Y2 \Y2
11 9
Amine intermediate 9 (j = 0) can be prepared according to the method generally
5 described in Scheme 3. As shown, spiro-substituted- or gem-dialky-
substituted (not
shown) oxo-R5 ring intermediates 6 can be converted directly to the amino-
intermediate 9
using known reductive amination methods, such as in the presence of sodium
cyanoborohydride and ammonium acetate. Alternatively, the carbonyl of R5 may
be
reduced to the corresponding alcohol using conventional reducing reagents, and
then
10 displaced to form the corresponding azido-intermediate 8 using known
reagents, such as
DPPA, in the presence of a suitable base as shown. Intermediate 8 may be
reduced with a
suitable reducing agent or by known methods, including triphenylphosphene,
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trimethylphosphene or lithium aluminum hydride (LAH), to produce the desired
amino
adduct 9.
Yet another method of forming the amine adduct 9, can be via an imine
formation
to form compound 10. The imine double bond of compound 10 may then be
successively
reduced and hydrolyzed to yield the primary amine product 9. Such steps may be
conducted using known, convention methods, as appreciated by those skilled in
the art.
Scheme 4
Rio
N O (Ra)HN R11 H N OH R4 Rio
/'~~ j 2 N R11
PG- Y v (X (RS) X 1. heat (e9=) \Y 5)
+ (
1. B 2, deprotection B X X1
Y
PG = protecting group 1\Y Y1\
z
12' 9 14' Y2
H RI10 H
I (R4)HNR11 1 OH Ra Rio
2. ) X RW N R11
R'- /N O X (R5
W + 1 (~ X (R5) X
B 1
Yt Y
12 Y Y1\ /,~, o
2 Y
14 2
9
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OsiR3 R10 OH R4 Rio
PG-N (R4)HN R,1 H,N l
p ~(R) 1. e.g., reductive R11
`~ (X X amination
3. tRs)
+ 1 B (X X
B 2. deprotections
PG = protecting group Y1\ Y) Y1 Yo
Y2 \Y
13' 9 14, 2
R1, R4 R
O 10
(R4)HN R11
PG'N H219 OH
p (Rs) 1. e.g., reductive N R11
X X amination t (RS)
\\
4= B 2. deprotections (XL " X1
PG = protecting group Y1\ Y1 )Y)o
Y2 \Y
13 2
9 14'
Scheme 4 describes, generally, multiple different methods for constructing the
bond between the Pr starting material or intermediate 12' (sub-scheme 1) or 12
(sub-
scheme 2) and an R5 ring intermediate 9, thereby synthesizing a desired
intermediate 14'
or a final compound 14 of Formulas I-III. One method to make this bond is to
react an
epoxide intermediate 12 or 12' (Note: the epoxide 12 or 12' may be purchased
commercially or made via known, published methods such as from the olefin
precursor),
with an amino-R5 intermediate 9, as shown. The reaction may proceed in the
presence of
a polar solvent, such as an alcohol or dioxanes, and may require additional
reagents, as
appreciated by those skilled in the art. Additionally, the reaction may
require heat for a
period of time. Note that while the scheme described the addition o heat, this
is by way of
example, and not every reaction would require heat as appreciated by those of
ordinary
skill in the art. The protecting group may be removed using an acid, such as
HCI, such
that the bonded adduct 14' is recovered as an HCI salt.
Alternatively, desired intermediates 14' may be synthesized starting with an
amine-protected aldehyde intermediate 13' (sub-scheme 3) or 13 (sub-scheme 4)
and
condensing the aldehyde with a primary or secondary amine 9 to form an imine
(not
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shown, generally formed in-situ and not isolated). The imine can then be
reduced using a
known reducing agent, such as a hydride or borohydride, the reduced
intermediate may be
deprotected to provide an intermediate 14' having an amine useful to prepare
compounds
14 of Formulas I-III.
Scheme 5
Method A:
PG
PG/
PGA INH R3 1. e.g., HATU, Et3N, HNC R3 N Ra
HO~N-methoxymethylamine
B~\~~1 1. e.g., PhMe2SiH, TFA
- O
O
O R3 R3 2. BMX, e.g., BMgBr O R3 R3 2. e.g., dimethoxypropane B R3
3. e.g., Os04, Na104
16 17
PG = protecting group
R4 Rio
Rio
R3 R3
R HN R11 1. e.g., reductive HZN R
(4) ~~ amination s ~~
(X (n5 X1 H R3 (X (R ) X1
17 + 2. deprotection B OH
Y Y
Y Y1 Y~
2 2
18'
Method B:
R10 R4 Rio
PG Rs Rs
O I R11 1. e.g., reductive HZN N R11
N R3 () Rs amination
03NHR4 CX X1 fR3 R3 X (RS) X1
Y~ 2. deprotection B OH
B R3 R3 \ Y1
Y2 Y
2
19 6 18
Scheme 5 describes, generally, two different methods (Methods A and B) for
constructing intermediates 18' (Method A) or 18 (Method B) which are useful
for making
10 compounds of Formula III. As shown in Method A, the acid group of an
olefinic amino-
acid compound 15 may be modified with a desired B group to form a compound 16,
by
first activating the acid of 15 with a known activating agent, such as HATU in
the
presence of a suitable base, and treating activated 15 with a B-substituted
grignard
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reagent or B-ligand metal reagent, which delivers the desired B group to
displace the
carbonyl activating group and form compound 16. Compound 16 may be oxidized to
the
corresponding ketone 17 by known methods, such as with sodium periodiate and
osmium
tetroxide. Ketone 17 may then be reacted with amine 9, via a reductive
amination step, to
form an amino protected intermediate, which can be deprotected to yield
intermediate
18', as shown.
Alternatively, intermediate 18 may be made using a reductive amination step
with
an amine-protected diamine compound 19 and a ketone 6. Such reductive
amination step
may be employed with conventional conditions using known reducing reagents in
suitable
solvents, at suitable temperatures, as appreciated by one of ordinary skill in
the art.
Amine compounds 18 and 18' can then be coupled to acids and sulfonic acid
compounds 2, 2', 4 and 5, described in scheme 1, to make amides and
sulfonamide
compounds ("W" groups) of Formulas I-III by methods described in scheme 2.
To enhance the understanding and appreciation of the present invention, the
following specific examples (starting reagents, intermediates and compounds of
Formulas
1-111) are set forth. The following analytical methods were used to purify
and/or
characterize the compounds, and intermediates, described in the examples
below.
Analytical HPLC and LC-MS Methods:
Unless otherwise indicated, all analytical HPLC analyses were run on an
AgilentTM Model 1100 series system LC/MSD SL using one of the two following
Columns: (a) Phenomenex SynergiTM (4 micron, C 18, 50x2 mm) or (b) a GeminiTM
column
(5 micron, C 18, 100x2 mm). A typical run through the instrument included:
eluting at I
ml/min with an linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in
water
(0.1 % TFA) over 10 minutes; conditions may be varied to achieve optimal
separation.
Preparative HPLC Method:
Unless otherwise indicated, the compounds described herein were purified via
reverse phase HPLC using one of the following instruments: Shimadzu, varianTM,
GilsonTM;
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utilizing one of the following two HPLC columns: (a) a Phenomenex Luna or (b)
a
Gemini column (5 micron or 10 micron, C18, 150x50 mm)
A typical run through the instrument included: eluting at 45 ml/min with a
linear
gradient of 10%(v/v) to 100% MeCN (0.1 % v/v TFA) in water (0.1 % TFA) over 10
minutes; conditions can be varied to achieve optimal separations.
Proton NMR Spectra:
Unless otherwise indicated, all 'H NMR spectra were run on a Bruker series 300
MHz instrument or a Bruker series 400 MHz instrument. Where so characterized,
all
observed protons are reported as parts-per-million (ppm) downfield from
tetramethylsilane (TMS) or other internal reference in the appropriate solvent
indicated.
Mass Spectra (MS)
Unless otherwise indicated, all mass spectral data for starting materials,
intermediates and/or exemplary compounds are reported as mass/charge (m/z),
having an
(M+H') molecular ion. The molecular ion reported was obtained by electrospray
detection method (commonly referred to as an ESI MS) utilizing a PE SCIEX API
150EX
MS instrument.
Compounds having an isotopic atom, such as bromine and the like, are generally
reported
according to the detected isotopic pattern, as appreciated by those skilled in
the art.
Naming Convention
The compounds disclosed and described herein have been named using the
naming convention provided with Chem-Draw Ultra 8.0 software, available in
Chem
Office. In some instances, compounds were named with the term
"spirocarbocycle"
inserted where appropriate. For example, where the chroman is substituted with
2,2-
spirocyclobutyl, "2,2-spirocyclobutyl" is added to the Chem-Draw nomenclature
in the
appropriate place. Chem-Draw utilizes the ISIS Draw software compound naming
convention, as appreciated by those skilled in the art.
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Examples
The Examples, described herein below, represent various exemplary starting
materials, intermediates and compounds of Formulas 1-III, which should assist
in a better
understanding and appreciation of the scope of the present invention and of
the various
methods which may be used to synthesize compounds of Formulas 1, 11 and III.
It should
be appreciated that the general methods above and specific examples below are
illustrative only, for purpose of assistance, and should not be construed as
limiting the
scope of the present invention in any manner.
Example 1
N-((2S,3R)-4-((S)-2,2-spirocyclobutylchroman-4-ylamino)-3-hyd roxy-l-
phenylbutan-2-yl)acetamide
Step 1. 2,2-spirocyclobutylchroman-4-one
1-(2-hydroxyphenyl)ethanone (3.2 ml, 26.6 mmol), cyclobutanone (4 ml, 53.3
mmol),
pyrrolidine.(2.6 ml, 32 mmol), and diisopropylethyl amine (4.5 ml, 26.6 mmol)
were
dissolved in 30 m] toluene and refluxed under a Dean Stark trap for 3.5 h. The
reaction
was terminated (although a large amount of starting material was still
present). The
cooled reaction mixture was diluted with 100 ml ether, washed with 30 ml HCl
(aq., 5M),
dried over MgSO4 and evaporated. Column chromatography (3% EtOAc in Hexanes)
gave the title compound as a yellow oil 760mg (4.04 mmol, 15%). MS m/z: 189
(M+1).
Step 2. (R)-2,2-spirocyclobutylchroman-4-ol
A solution of (S)-2 Methyl-CBS-oxazaborolidin (1 M, 200 ul, 0.2 mmol) and
borane
DMS complex (0.5 ml, 5.25 mmol) in 10 ml toluene was cooled to -20 C and a
solution
of 2,2-spirocyclobutylchroman-4-one (17 a, 0.76 g, 4.04 mmol) in 5 ml THE was
added
slowly over a period of 2.5 h. The reaction mixture was stirred for 0.5 h at
the same
temperature and was than carefully hydrolyzed with MeOH. The mixture was
washed
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with HCl (1 M, aq.) and NaHCO3 (sat., aq.) and the organic phase was dried
over MgSO4
and evaporated. The crude material was used without further purification in
the next step.
Step 3. (S)-4-azido-2,2-spiroc cly obutylchroman
The crude material from Step 2 was dissolved in 10 ml toluene and dppa (1.17
ml, 5.2
mmol) and dbu (0.776 ml, 5.2 mmol) was added and the mixture was stirred for
12 h.
Two phases were observed and the less heavy layer was diluted with ether and
washed
with HCl (1 M, aq.) and NaHCO3 (sat., aq.), dried over MgSO4 and evaporated.
Column
chromatography (3% EtOAc in hexanes) gave 0.32 g (1.48 mmol, 35% (over 2
steps)) of
the title compound as a yellow oil. MS mnz: 188(40%, M-N2); 173(17%, M-N3).
Step 4.(S)-2,2-spirocyclobutylchroman-4-amine
(S)-4-azido-2,2-spirocyclobutylchroman (0.32 g, 1.48 mmol) was dissolved in 10
ml T14F
and cooled to 3 C. LAH (1M in THF, 4.5 ml, 4.5 mmol) was added and stirring
was
continued for 2.5 h. The reaction mixture was allowed to warm up to room
temperature
during this period of time and 10 ml THE and 10 ml CH2C12 were added. 5 g
NaSO41 OH20 was added carefully, the mixture was stirred 15 min and was
filtered. The
filtrate was dried over MgSO4 and evaporated and the crude product (MS m/z:
173(100%,
M-NH2)) was used without further purification in the next step (240 mg, 1.26
mmol, 86%
crude).
Step 5. tert-Butyl (2S,3R -4-((S)-2,2- irocyclobutylchroman -4-ylamino)-3-
hydroxy-1-
phenylbutan-2-ylcarbamate
(S)-2,2-spirocyclobutylchroman-4-amine (240 mg, 1.26 mmol) was mixed with I ml
of
IPA and tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (396 mg, 1.5
mmol)
and heated in the microwave to 125 C for 15 min. The mixture was diluted wit
2 ml
DMF and purified on the prep HPLC (Gilson) to give the title compound. Yield
(white
TFA salt): 400 mg (0.88 mmol, 70% over 2 steps, MS m/z: 453(100%, M+1)).
Step 6. (2R,3S)-3-amino-1-((S)-2,2-spirocyclobutylchroman-4-ylamino)-4-
phenylbutan-
2-ol
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tert-Butyl (2S,3R)-4-((S)-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-l-
phenylbutan-2-ylcarbamate was dissolved in 2 ml dioxane and 4 ml HCI (4M in
dioxane)
was added and stirring was continued for 2 h. The reaction mixture was
evaporated and
the crude product used without further purification in the next step: white
HCI salt, MS
m/z: 353(100%, M+1).
Step 7. N-((2S,3R)-4-((S) 2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-
phenylbutan-2-yllacetamide
(2R,3S)-3-amino-l-((S)-2,2-spirocyclobutylchroman-4-ylamino)-4-phenylbutan-2-
ol (34
mg, 0.08 mmol) was dissolved in 1 ml DMF and acetic acid (4.5 ul, 0.08 mmol),
hatu (30
mg, 0.08 mmol) and diisopropyl-ethyl amine (40 ul, 0.24 mmol) were added. The
mixture
was stirred for 2 h and 5 drops from a Pasteur pipette of HCI (5 M, aq.) was
added. The
mixture was purified without further work up procedure on the prep HPLC
(Gilson) to
give the title compound as its white TFA salt. MS m/z: 395(100%, M+1).
Example 2
N-((2S,3R)-4((S)-6-ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-l-
phenylbutan-2-yl)acetamide.TFA salt.
To a solution of (2S,3R)-3-amino-l-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-
ylamino)-4-phenylbutan-2-ol (25 mg, 0.06 mmol, synthesized using analogous
procedures as in Example 1), triethylamine (0.02 mL, 0.14 mmol, Aldrich), and
CH2CI2
(1 mL) was added N-acetylimidazole (9 mg, 0.08 mmol, Fluka). Stir at room
temperature. After 2 h, more N-acetylimidazole (5 mg) was added. After 3 days,
the
solution was purified by reverse-phase preparative HPLC on a Phenomenex
Synergi
column (4 micron, MAX-RP, 80 A, 150x30 mm) eluting at 45 ml/min with an linear
gradient of I 0%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 10
minutes to give 3.7 mg of the desired product as a colorless solid. MS m/z:
437.4(M+1).
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Example 3
N-((2S,3R)-4((S)-6-ethyl-2,2-spi rocyclobutylch roman-4-ylamino)-3-hydroxy-l-
phenylbutan-2-yl)-2-(pyridin-4-yl)acetamide.TFA salt
The title compound was synthesized by a method analogous to that described in
Example 1, using(2S,3R)-3-amino-l-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
ylamino)-4-phenylbutan-2-ol dihydrochloride salt and 2-(pyridin-4-yl)acetic
acid
hydrochloride (Aldrich) in the presence of DIPEA to obtain the title compound
as a
colorless solid. MS m/z: 500.3(M+1).
Example 4
N-((1 S,2R)-3-(((4' S)-6'-(2,2-dim ethylpro pyl)-3',4'-di hyd rospiro
[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)-2-(5-
methyl-
1H-pyrazol-1-yl)acetamide
The title compound was prepared via an intermediate obtained by a method
analogous to that described in Example 171 of co-pending patent application
serial No.
60/738,767. The intermediate was finally coupled by a method analogous to that
described in Example 1 above using 2-(5-methyl-lH-pyrazol-l-yl)acetic acid to
provide
the title compound. MS m/z: 546.3 (M+1).
Example 5
Methyl (2S,3R)-3-hydroxy-4-((S)-6-neopentyl-2,2-spirocyclobutyl-3,4-dihydro-2H-
pyrano [2,3-b] pyridin-4-ylamino)-1-phenylbutan-2-ylcarbamate
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The title compound was prepared via an intermediate obtained by a method
analogous to that described in Example 171 of co-pending patent application
serial No.
60/738,767. The intermediate was finally coupled by a method analogous to that
described in Example 3 above using methyl chloroformate to provide the title
compound.
MS m/z: 482.3 (M+1).
Example 6
Ethyl (2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-chroman-4-ylamino)-3-hydroxy-
l-
phenylbutan-2-ylcarbamate
A mixture of di-succinimidyl carbonate (2.56 g, 1.0 eq), DIPEA (1.29 g, 1.0
eq),
and anhydrous EtOH (1.16 mL, 2.0 eq) in dry CH2CI2 and CH3CN was stirred at it
overnight. The solvents were removed and the residue was used directly in the
next step.
TA portion of the crude residue was mixed with (2R,3S)-3-amino-l-((S)-6-ethyl-
2,2-
spirocyclobutyl-chroman-4-ylamino)-4-phenylbutan-2-ol hydrochloric acid salt
in the
presence of 3 drops of DIPEA in anhydrous and the resulting mixture was
stirred at rt
until the complete consumption of the amine. The title product was obtained as
a TFA
salt after purification by BPLC. MS m/z: 453 (M+1).
The following examples were prepared by a method analogous to that described
in Examples 1-6 above.
Ex. STRUCTURE Mass MW
No. found
7 461 460.614
N-((2S,3 R)-4-((S)-6-ethyl-2,2-sp irocyclobutylchroman-4-
ylamino)-3-hydroxy-l-phenylbutan-2-yl)pent-4-ynamide
8 505 504.711
3 -cyclopentyl-N-((2S,3R)-4-((S)-6-ethyl-2,2-
spirocyclobutylchroman-4-ylamino)-3-hydroxy- l -
phenylbutan-2-yl)propanamide
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9 437 436.592
N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
ylamino)-3-hydroxy- I -phenylbutan-2-yl)propionamide
453 452.591
N-((2 S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
ylamino)-3-hydroxy- l -phenylbutan-2-yl)-2-
methox acetamide
11 531,533 531.487
N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutylchroman-4-
yl amino)-3 -hydroxy- l -phenylbutan-2-y 1)-2-
iso ro oxacetamide
12 503,505 503.434
N-((25,3 R)-4-((S)-6-bromo-2,2-spirocyclobutyl chroman-4-
ylamino)-3-hydroxy- l -phenylbutan-2-yl)-2-
methoxacetamide
13 529,531 529.472
2-(al lyloxy)-N-((2S,3 R)-4-((S)-6-bromo-2,2-
spirocyclobutylchroman-4-ylamino)-3-hydroxy-l -
phenylbutan-2-yl)acetamide
14 517,519 517.461
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)
propyl)-3-(methyloxy)propanamide
517,519 517.461
N.(( 1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro [chromene-
2,1'-cyclobutan]-4-yI)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(ethyloxy)acetamide
16 543,545 543.498
N-((] S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)am ino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((cyclopropylmethyl) oxyacetamide
17 571,573 571.431
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-y1)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((2,2,2-trifluoroethyl)oxy) acetamide
18 493 492.656
2-((cyclopropylmethyl)oxy)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)acetamide
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19 535 534.736
2-((cyclopropylmethyl)oxy)-N-((1 S,2R)-3-(((4S)-6-(2,2-
dimethylpropyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-
4-yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)acetamide
20 397 793.056
N-((] S,2R)-3-(((5 R)-3,3-dimethyl-1,3,4,5-tetrahydro-2-
benzoxepin-5-yl)amino)-2-hydroxy-l -
(phenyl methyl)propyl )ac etam i d e
21 427 853.107
N-((1 S,2R)-3-(((5R)-3,3-dimethyl-1,3,4,5-tetrahydro-2-
benzoxepin-5-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-
2-(methyl oxy) acetamide
22 425 424.581
N-((l S,2R)-3-(((5 S)-7-ethyl-3,3-dimethyl-1,3,4,5-tetrahydro-
2-benzoxepin-5-yl)amino)-2-hydroxy-l-
(phenylmethyl)propy])acetamide
23 455 454.607
N-((1 S,2R)-3-(((5 S)-7-ethyl-3,3-dimethyl-1,3,4,5-tetrahydro-
2-benzoxepin-5-yl)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(methyloxy)acetamide
24 622,624 622.581
2-(1,3-benzothiazol-2-yloxy)-N-((1 S,2R)-3 -(((4 S)-6-bromo-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)acetamide
25 572 571.738
(1,3-benzothiazol-2-yloxy)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro [chromene-2, I'-cyclobutan)-4-yl)amino)-2-
hydroxy-1-(phenylmethyl)propyl)acetamide
26 508 507.627
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cycl obutan]-4-yl)am i no)-2-hydroxy- l -(phenyl methyl)
propyl)-2-(2-oxo-1,3-oxazolidin-
3-yl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-65-
27 558,560 558.47
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-oxo-1,3-oxazolidin-3-yl)acetamide
28 572 571.738
2-(1,3-benzoxazol-2-ylthio)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)acetam ide
29 588 587.805
2-(1,3-benzoth iazol-2-ylthio)-N-((1 S,2R)-3-(((4S)-6-ethyl-
3,4-dihydrospiro [chromene-2, 1'-cyclobutan]-4-yl)amino)-2-
hydroxy-1-(phenylmethyl)propyl)acetamide
30 539 538.688
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(1 H-pyrrolo[2,3-b]pyridin-1-yl)acetamide
31 520 519.638
N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan] -4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-
2-((5-methyl-3-isoxazolyl)oxy)acetamide
32 556 555.671
2-(1,3-benzoxazol-2-yloxy)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy-l-(phenylmethyl)propyl)acetamide
33 489 488.628
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(1 H-pyrazol- l -yl)acetamide
34 586 585.765
2-((1,3-benzothiazol-2-ylmethyi)oxy)-N-((1 S,2R)-3 -(((4S)-6-
ethyl-3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-66-
35 509 508.655
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((3 R)-tetrahydro-3-furanyloxy)acetamide
36 520 .519.63 8
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((1,3-oxazol-2-ylmethyl)oxy) acetamide
37 509 508.655
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-l-(phenylmethyl)
propyl)-2-((3 S)-tetrahydro-3 -furanyloxy)acetamide
38 533 532.6374
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(2-oxo- l ,3-oxazolidin-3-yl)acetamide
39 534 533.6651
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-y1)amino)-2-
hydroxypropyl)-2-((3 S)-tetrahydro-3 -furanyloxy) acetam ide
40 545 544.6484
N-((I S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-((5-methyl-3-isoxazolyl) oxy)acetamide
41 564 563.6983
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(1 H-pyrrolo[2,3 -b]pyridin-l-yl)acetamide
42 551 550.6958
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(2-oxo-1,3-
oxazolidin-3-yl) acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 67-
43 552 551.7235
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((3S)-
tetrahydro-3-furanyloxy) acetamide
44 582 581.7567
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l -(phenylmethyl) propyl)-2-(1 H-
pyrrolo[2,3-b]pyridin-l-yl)acetamide
45 563 562.7068
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-((5-methyl-
3-isoxazolyl)oxy) acetamide
46 533 532.7246
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-3-
(2-(1-methylethyl)-1 H-imidazol-1-yi)propanamide
47 545 544.7356
(2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-
2H-chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)
propyl)-3-(1-(2-methylpropyl)-1 H-imidazol-4-yl)-2-
propenamide
48 502 501.462
N-((1 S,2R)- i -((3-bromophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2, I '-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)acetam i de
49 420 419.522
N-((1 S,2R)-3-(((4S)-6-cyano-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-l -(phenylmethyl)
propyl)acetamide
50 499 498.663
N-((2 S, 3R)-4-((S)-6-ethyl-2,2'-spirocyclobutylchroman-4-
yl am ino)-3 -hydroxy- l -(4-phenyl-phenyl)-butan-2-yl)
acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 68-
51 441 440.556
N-((2S,3R)-4-((S)-6-ethy l-2,2'-spirocyclobutylchroman-4-
ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl) acetamide
52 471 470.582
N-((2S,3R)-4-((S)-6-ethyl-2,2'-spirocyclobutylchroman-4-
ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)-2-
methoxyacetamide
53 439 438.565
N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-l-phenylpropyl)-2-
(methyloxy)acetamide
54 409 408.539
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- I -phenylpropyl)
acetamide
55 532 531.487
N-((1 S,2R)-1-((3-bromophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,I'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(methyloxy)acetamide
56 478 477.602
N-((1 S,2R)-I-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(methyloxy)acetamide
57 575 574.463
N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-((3,5-difluorophenyl)methyl)-2-
hydroxypropyl)-2-(3 -pyri dinyl )acetamide
58 448 447.576
N-((1 S,2R)- I -((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)acetam ide
59 524 523.673
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-phenylacetam ide
1
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 69-
60 540 539.672
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(phenyloxy)acetamide
61 530 529.701
N-((l S,2R)-1-((3-cyanophenyl)methyl)-3 -(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(3-thienyl)acetamide
62 504 503.639
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)tetrahydro-2-furancarboxamide
63 571 570.73
(3S)-N-((IS,2R)-1-((3-cyanophenyl) methyl)-3-(((4S)-6-ethyl-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
ydroxypropyl)-1-cyclobutyl-5-oxo-3-pyrrolidinecarboxamid
64 462 461.603
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)am ino)-2-
hydroxypropyl)propanamide
65 518 517.666
N-((1 S,2R)-I-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-((cyclopropylmethyl)oxy) acetamide
66 542 541.4052
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-((3-
(trifluorom ethyl)phenyl )methyl)propyl)acetamide
67 572 571.431
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2, I'-cyclobutan]-4-yl)amino)-2-hydroxy-l-((3-
(trifluoromethyl)phenyl)methyl)propyl)-2-
(methyloxy)acetamide
68 582.3 581.753
(S)-N-((25,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchrom an-
4-ylamin o)-3-hydroxy- l -phenylbutan-2-yl)-2-(1-
oxo isoindol in-2-yl)propanamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-70-
69 575.3 574.733
N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocycl opentylchroman-4-
ylamino)-3-hydroxy- I -phenylbutan-2-yl)-3-(5-fluoro-2-
methoxyphenyl)propanamide
70 506.3 505.655
(S)-N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-
4-ylamino)-3-hydroxy-l-phenylbutan-2-yl)-5-oxopyrrolidine-
2-carboxamide
71 573.3 572.717
(E)-N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-
4-ylamino)-3-hydroxy- l -phenylbutan-2-yl)-3-(5-fluoro-2-
methoxyphenyl)acrylam ide
72 447.2 446.535
N-((1 S,2R)-1-((3,5-difluorophenyl)rnethyl)-3 -((6-ethyl-2,2-
dimethyl-3, 4-dihydro-2H-chromen-4-yl) am ino)-2-
hydroxypropyl)acetamide
73 459.2 458.546
N-((1S,2R)-1-((3,5-difluorophenyl) methyl)-3-(((4S)-6-ethyl-
3,4-dihydrospiro [chromen a-2, I '-cyclobutan] -4-yl)am ino)-2-
hydroxypropyl) acetamide
74 489.2 488.572
N-((1S,2R)-1-((3,5-difluorophenyl) methyl)-3-(((4S)-6-ethyl-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(methyloxy)acetamide
75 416.2 415.599
N-((I S,2R)-3-(((7S)-2-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-
1,3-benzothiazol-7-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetami de
76 367.2 366.502
N-((1S,2R)-3-(((I S)-3,3-dimethyl-2,3-dihydro-IH-inden-l-
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)acetamide
77 397.2 396.528
N-((1 S,2R)-3-(((I S)-3,3-dimethyl-2,3-dihydro-1 H-inden- l -
yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)-2-
(methyloxy)acetamide
78 494.2 987.201
N-((1 S,2R)- I -((3-cyanophenyl)methyl)-3-(((2S,4S)-6-ethyl-
3,4,4',5'-tetrahydrospiro[chromen e-2,3'-furan]-4-y1)amino)-2-
hydroxypropyl)-2-(methyloxy) acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-71-
79 475.2 949.0896
N-((1 S,2R)-1-((3,5-difluorophenyl) methyl)-3-(((2S,4S)-6-
ethyl-3,4,4',5'-tetrahydrospiro[chromene-2,3'-furan]-4-
yl)amino)-2-hydroxypropyl)acetam ide
80 506.2 1011.231
N-((1 S,2R)-3-(((2R,4S)-6-ethyl-3,4,4',5'-
tetrahydrospiro[chromene-2, 3'-furan]-4-yl)amino)-2-hydroxy-
1-(phenylmethyl) propyl)-2-(1 H-1,2,4-triazol- l -yl) acetamide
81 491.3 490.6442
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-di hydrospiro [cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetam i de
82 542 541.7317
N-((1 S,2 S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-
phenylacetamide
83 551 550.7394
N'-((l S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-I-(phenylmethyl) propyl) N,N-
dimethylbutanediamide
84 560 559.7069
N-((l S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(2-
pyrim i dinyl oxy)acetami de
85 511 510.6312
2-(((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane-
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)amino)-2-oxoethyl dimethylcarbamate
86 548 547.7599
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(2-
thienyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-72-
87 504 503.6829
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-l,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl propyl)-4-pentynamide
88 425 849.0756
N-((I S,2R)-3-(((I R)-3,3-dimethyl-7-(methyloxy)-4-oxo-
1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetamide
89 592 591.7049
2-(((1 S,2R)-1-((3 -cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-
(4-morpholinyl)-3,4-dihydrospiro [chromene-2,1'-cyclobutan]-
4-yl)amino)propyl)amino)-2-oxoethyl dimethylcarbamate
90 587 586.7532
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-
(4-morpholinyl)-3,4-dihydro spiro[chromene-2,1'-cyclobutan]-
4-yl)amino)propyl)-2-(2-thienyl)acetamide
91 576 575.705
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydro-2H-chromen-4-
yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-(9-oxo-
10(9H)-acridinyl)acetamide
92 509 508.655
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydro-2H-chromen-4-
yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2-((2-
fluorophenyl)thio)acetamide
93 616 615.77
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutanj-4-yl)amino)-2-hydroxy-1-(phenylmethyl)
propyl)-2-(9-oxo-10(9H)-acridinyl)acetamide
94 632 630.579
(2Z)-2-(6-bromo-2-oxo- l ,2-dihydro-3H-indol-3 -ylidene)-N-
((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)ethanamide
95 579 579.201
2-((3-chloro-2-methylphenyl)thio)-N-((1 S,2R)-3-(((4S)-6-
ethyl-3,4-dihydrospiro[chromene-2, 1'-cyclobutan]-4-
yI)amino)-2-hydroxy-I -(phenylmethyl) propyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 73-
96 568 567.726
(2S)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylm ethyl)
propyl)-2-(I -oxo-l,3-dihydro-2H-isoindol-2-yl)propanamide
97 557 556.699
2-((2-acetylphenyl)oxy)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)acetamide
98 579 578.7092
N-((1 S,2R)-1-((3-cyanopheny 1)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-
yl)acetamide
99 606 604.5416
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-y1)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)acetamide
100 555 554.6872
N-((2 S, 3 R)-4-((S)-6 -ethyl-2,2-sp iro cyclobutyl-3,4-dihydro-
2H-pyrano [2,3-b]pyridin-4-ylamino)-3-hydroxy-l-
phenylbutan-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide
101 597 596.7676
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(l-oxo-1,3-
dihydro-2H-isoindol-2-yl)acetamide
102 613 612.7666
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-y1)
amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(1-oxo-1,3-
dihydro-2 H-isoindol-2-yl)acetamide
103 482 963.2662
N-((l S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro[furan-3,2'-pyrano[2,3-b] pyridin]-4'-
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 74-
104 512 1023.318
N-((1 S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl)
amino)-2-hydroxy- I -(phenylmethyl)propyl)-2-
(methyloxy)acetamide
105 549 1097.368
N-((1 S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl)
amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(1H-1,2,4-
triazol-1-yl) acetamide
106 549 1097.368
N-((1 S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-yl)
amino)-2-hydroxy-l -(phenylmethyl) propyl)-2-(2H-1,2,3-
triazol-2-yl) acetamide
107 429 428.957
N-((1 S,2R)-3-(((4S)-6-chloro-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-
4-yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)acetamide
108 459 458.983
N-((1 S,2R)-3-(((4S)-6-chloro-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-l-(phenylmethyl)
propyl)-2-(methyloxy)acetamide
109 469 938.833
N-((1 S)-1-((1 R)-2-(((4S)-6-bromo-3,4-
dihydrosp iro[chromene-2,1'-cyclobutan]-4-y1)amino)-l-
hydroxy ethy l) -3 -m ethy lb utyl)-2-(m ethyloxy) acetam i de
110 439 878.782
N-((I S)-1-((1 R)-2-(((4S)-6-bromo-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1-
hydroxyethyl)-3-m ethylbutyl)acetamide
111 473 945.251
N-((1 S,2S)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-
4-yl)amino)-2-hydroxy-1-(1-
naphthal enylmethyl)propyl)acetamide
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-75-
112 503 1005.3
N-((1 S,2S)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-
4-yl)amino)-2-hydroxy-l-(1-naphthalenylmethyl)propyl)-2-
(methyloxy acetamide
113 511 1022.91
N-((1 S,2S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)am ino)-2-hydroxy- l -(1-n aphthal enylmethyl)
propyl) acetamide
114 467 934.889
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-(cyclohexy]methyl)-2-hydroxypropyl)
acetamide
115 467 934.851
N-((1 S,2S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-
2-hydroxy- l -(3-thienylmethyl) propyl) acetamide
116 497 994.902
N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- I -(3-thienylmethyl)propyl)-
2-(methyloxy)acetamide
117 466 465.5658
N-((IS,2R)-1-((3-cyano-5-fluorophenyl) methyl)-3-(((4S)-6-
ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-
yl)amino)-2-hydroxypropyl)acetami de
118 538 538.483
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l-((3-(3-pyridinyl)phenyl)
methyl)propyl)acetamide
119 453 453.2966
N-((3 S,4 S)-5-((S)-6-bromo-2,2-dimethylchroman-4-ylamino)-
1,1,1-trifluoro-4-hydroxypentan-3-yl)acetamide
120 485 485.4191
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-
((3 -ethynylphenyl)methyl)-2-hydroxypropyl)acetam ide
121 488 487.5594
N-((I S)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-1-hydroxyethyl)-3,3,3-trifluoropropyl)-2-
(methyloxy)acetamide
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122 459 458.6196
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl- 1, 1 -dioxido-3,4-
dihydro-2H-1-benzothiopyran-4-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetami de
123 430 429.5819
N-((1 S,2R)-3 -(((4 S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-1-(1,3-thiazol-4-
ylmethyl)propyl)acetamide
124 423 422.566
N-((] S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- l -(phenylmethyl)
propyl)acetamide
125 487 486.652
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
phenylacetamide
126 499 498.663
N-((1 S,2R)-3 -(((4 S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yi)amino)-2-hydroxy-l -(phenylmethyl)propyl)-
2-phenylacetamide
127 529 528.664
(E)-N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
ylamino)-3 -hydroxy- l -phenylbutan-2-yl)-3-(3 -
fluorophenyl)acrylamide
128 385 384.517
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4S)-2,6,6-
trimethyl-4,5,6,7-tetrahydro-l -benzofuran-4-yl)amino)
propyl)acetamide
129 402 400.584
N-((1 S,2R)-2-hydroxy-l -(phenylmethyl)-3-(((4S)-2,6,6-
trimethyl-4,5,6,7-tetrahydro- I -benzothien-4-
yl)am ino)propyl)acetamide
130 432 430.61
N-((I S,2R)-2-hydroxy- l-(phenylmethyl)-3-(((4S)-2,6,6-
imethyl-4,5,6,7-tetrahydro- I -benzothien-4-yl)amino)propyl)-
2-(methyloxy)acetamide
131 445 444.636
N-((1 S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-
1-benzothien-4-yl)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(methyloxy)acetamide
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132 467 466.5898
N-((1 S,2R)-1-((3,5-difluorophenyl) methyl)-2-hydroxy-3-
(((4S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- I -benzothien-4-
yl)amino) propyl)-2-(methyloxy)acetamide
133 437 436.564
N-((1 S,2R)- I -((3,5-difluorophenyl) methyl)-2-hydroxy-3 -
(((4S)-2,6,6-trimethyl-4,5,6,7-tetrahydro- I -benzothien-4-
y l) am ino)propyl)acetam ide
134 426 425.5939
N-((1 S,2R)- 1 -((3 -cyanophenyl)methyl)-2-hydroxy-3 -(((4S)-
2,6,6-trimethyl-4,5,6,7-tetrahydro- l -benzothien-4-yl)amino)
propyl)acetamide
135 456 455.6197
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-
2,6,6-trimethyl-4,5,6,7-tetrahydro- l -benzothien-4-yl)amino)
propyl)-2-(methyloxy)acetamide
136 498 497.7001
N-((1 S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-
1-benzothi en-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-oxo-l -pyrrolidinyl)acetamide
137 547 546.7078
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l -(phenylmethyl) propyl)-2-(3-methyl-
5-isoxazol l) acetamide
138 508 507.6709
N-((1 S,2R)-3-(((4S)-6-((2R,6S)-2,6-dimethyl-4-morpholinyl)-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl )acetamide
139 494 493.6441
N-((1 S,2R)-2-hydroxy-3-(((4 S)-6-((3 S)-3-methyl-4-
morpholinyl)-3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-
yl)amino)-1-(phenylmethyl)propyl)acetamide
140 476 474.3962
N-((1 S,2R)-3-(((4'R)-6'-bromo-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)acetamide
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141 476 474.3962
4-((1 S,2R)-3-(((4'S)-6'-bromo-3',4'-dihydrospiro[cyclobutane-
1,2'-pyrano [2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetamide
142 N-((l S,2R)-I-((3,5-difluorophenyl) methyl)-2-hydroxy-3- 517 516.5856
(((4'S)-6'-(4-morpholinyl)-3',4'-dihydrospiro [cyclobutane-
1,2'-pyrano [2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
143 517 516.5856
N-((1S,2R)-1-((3,5-difluorophenyl) methyl)-2-hydroxy-3-
(((4'R)-6'-(4-morpholinyl)-3',4'-dihydrospiro [cyclobutane-
1,2'-pyrano [2,3-b]pyridin]-4'-yl)amino)propyl)acetam ide
144 509 508.534
N-((1 S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-yl)amino)propyl)-2-
(methyloxy)acetamide
145 493 492.535
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-d ihydrospiro-2,2-spirocycl obutyl
[chromene-2,1'-cyclobutan]-4-yl)amino)propyl)propanamide
146 479 478.508
N-((1 S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-yl)amino)propyl)acetamide
147 561 560.634
N-((1 S,2R)-2-hydroxy-l -(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,I'-cyclobutan]-4-yl) amino)propyl)-2-(3-
thienyl)acetamide
148 555 554.606
N-((1 S,2R)-2-hydroxy- I -(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,]'-cyclobutan]-4-yl) amino)propyl)-2-
phenylacetamide
149 560 559.582
N-((1 S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-yl)amino) propyl)-2-(3-methyl-
5-isoxazolyl) acetamide
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150 441 440.556
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2, I'-cyclobutan]-4-y1)amino)-2-
hydroxy-1 -(phenylmethyl )propyl)acetamide
151 455 454.582
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy-I -(phenylmethyl)propyl) propanamide
152 471 470.582
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy-1-(phenylmethyl)propyl)-2-(methyloxy)acetamide
153 522 521.629
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2, I '-cyclobutan]-4-yl)amino)-2-
hydroxy-l -(ph enylmethyl)propyl)-2-(3-methyl-5-
isoxazolyl)acetami de
154 517 516.653
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)-2-phenylacetamide
155 524 523.645
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy-1-(phenylmethyl)propyl)-2-(2-oxo-1-
pyrrolidinyl)acetamide
156 526 525.617
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)-2-(2-oxo- l,3-oxazol idin-3-
yl)acetamide
157 564 563.57
N-((1 S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,I'-cyclobutan]-4-yl)amino) propyl)-2-(2-oxo- 1,3
oxazolidin-3-yl) acetamide
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158 562 561.598
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-y1)amino) propyl)-2-(2-oxo-1-
pyrrolidinyl)acetamide
159 517 516.6384
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)-2-(2-
pyrazinyloxy)acetamide
160 508 507.6709
N'-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)-N,N-
dimethylbutanediamide
161 505 504.6274
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
(2-pyrimidinyloxy)acetamide
162 496 495.6599
N'-((l S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl) amino)-2-hydroxy-l-(phenylmethyl)propyl)-
N,N-dimethylbutanediamide
163 526 525.661
N'-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)-N,N-
dimethylbutanediamide
164 564 563.6134
N'-((l S,2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-yl) amino)propyl)-N,N-
dimethylbutanediamide
165 437 436.5488
N-((1 S,2R)-3-(((4S)-6-acetyl-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)acetamide
166 517 516.6384
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy-l-(phenylmethyl)propyl)-2-(2-
pyrimi dinyloxy)acetamide
CA 02629402 2008-05-12
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-81-
167 542 541.6485
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro-2,2-spirocyclobutyl [chromene-2,1'-cyclobutan]-
4-yl)amino)-2-hydroxypropyl)-2-(2-
pyrimidinyloxy)acetamide
168 535 534.6285
N-((1 S,2R)-3-(((4S)-6-ethyl-7-fluoro-3,4-dihydrospiro-2,2-
spirocyclobutyl [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(ph enyl methyl)pro pyl)-2-(2-
pyrimidinyloxy)acetamide
169 573 572.5809
N-((1 S,2R)-2-hydroxy- l-(phenylmethyl)-3-(((4S)-6-
((trifluoromethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-y1) amino) propyl)-2-(2-
pyrimidinyloxy) acetamide
170 533 532.681
N'-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro-2,2-spirocycl obutyl [chromene-2,1'-cyclobutan]-
4-yl)am in o)-2-hydroxypropy l)-N,N-dimethylbutan edi am i de
171 542 541.6485
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4 S)-6-
((trifluorom ethyl)oxy)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-yl) amino) propyl)-2-(2-
pyrazinyloxy)acetamide
172 508 1014.844
N-((1 S,2R)-3-(((3R,4S)-6-bromo-3-hydroxy-2,2-dimethyl-
3,4-dihydro-2H-chromen-4-yl) amino)-2-hydroxy-l -
(phenylmethyl)propyl)-2-(methyl oxy)acetamide
173 535 534.6532
N-((1 S,2R)-l -((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-
(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl
[chromene-2,1'-cyclobutan]-4-yl)amino) propyl)-2-
(methyloxy)acetamide
174 505 504.6274
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-
(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocycl obutyi
[chromene-2,1'-cyclobutan]-4-yl)amino) propyl)acetamide
175 652 651.93
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclopentan]-4-y1)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((5R)-2-(3-methylbutyl)-2,3,4,5-tetrahydro-1 H-2-
benzazepin-5-yl) acetamide
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176 467 466.618
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-1-((3-methylphenyl)
methyl)propyl)-2-(methyl oxy) acetamide
177 444 443.491
N-((1 S,2R)-3-(((4S)-6-cyano-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-((3,5-difluorophenyl)methyl)-2-
hydroxypropyl)acetamide
178 525 525.868
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-((2-chlorophenyl)methyl)-2-
hydroxypropyl)-2-(methyloxy)acetamide
179 495 495.842
N-((1 S,2S)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)- i -((2-chlorophenyl)methyl)-2-
hydroxypropyl) acetamide
180 525 525.868
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)- I -((3-chlorophenyl)methyl)-2-
hydroxypropyl)-2-(methyloxy)acetamide
181 495 495.842
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-((2-chlorophenyl)methyl)-2-
hydroxypropyl) acetamide
182 496 495.842
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-((3-chlorophenyl)methyl)-2-
hydroxypropyl) acetamide
183 439 439.347
N-((1 S)-1-((1 R)-2-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-
2H-chromen-4-yl)amino)-1-hydroxyethyl)-3-butyn- l -yl)-2-
(methyloxy)acetamide
184 409 409.322
N-((1 S)-1-((1 R)-2-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-
2H-chromen-4-yl) amino)-1-hydroxyethyl)-3-butyn-l-yl)
acetamide
185 534 533.669
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -((1-(phenylmethyl)-1 H-
1,2,3-triazol-4-yl)methyl)propyl)-2-(methyloxy)acetamide
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186 504 503.643
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -((1-(phenylmethyl)-1 H-
1,2,3-triazol-4-yl)methyl)propyl) acetamide
187 401 400.516
N-((1 S)-1-((1 R)-2-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-
2,1'-cycl obutan]-4-yl)amino)-1-hydroxyethyl)-3 -butyn- l -yl)-
2-(methyloxy)acetamide
188 506 505.45
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy-1-(2-phenylethyl)propyl)-2-
(methyloxy)acetamide
189 475 475.424
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy-1-(2-
phenylethyl)propyl)acetamide
190 491 491.4229
N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -((3-(methyloxy)phenyl)
methyl) propyl)acetamide
191 521 521.4487
N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -((3-
(methyloxy)phenyl)methyl) propyl)-2-(methyloxy)acetamide
192 411 411.3373
N-((1 S)-1-((1 R)-2-(((4 S)-6-bromo-2,2-dimethyl-3,4-dihydro-
2H-chromen-4-yl) amino)-1-hydroxyethyl)-3-buten- l -yl)
acetamide
193 474 473.5171
N-((1 S,2R)-3-(((4S)-6-cyano-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-1-((3,5-difluorophenyl)methyl)-2-
hydroxypropyl)-2-(methyloxy)acetam ide
194 497 497.4301
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-3-butynamide
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195 630 630.5834
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(l -(phenylmethyl)-1 H-1,2,3 -triazol-5-yl)acetamide
196 540 540.459
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-l-(phenylmethyl)
propyl)-2-(1H-1,2,3-triazol-4-yl) acetamide
197 546 545.7237
2-(4-(1, 1-dimethylethyl)- 11H-1 ,2,3-triazol-1-yl)-N-((1 S,2R)-3 -
(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-
yl)am ino)-2-hydroxy-l-(phenylmethyl)propyl)acetamide
198 532 531.6969
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(4-propyl-1 H-1,2,3-triazol- l -yl)acetamide
199 600 599.694
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(3-
(trifluoromethyl)- I H-pyrazol- I -yl)acetamide
200 580 580.1688
2-(4-chloro-3-methyl-1 H-pyrazol- l -yl)-N-((1 S,2R)-3-(((4'S)-
6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutan- 1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- l-
(phenylmethyl) propyl)acetamide
201 594 594.1956
2-(4-chloro-3,5-dimethyl-1 H-pyrazol-1-yl)-N-((I S,2R)-3-
(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro
[cyclobutane-l,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxy- l -(phenylmethyl) propyl)acetam ide
202 614 613.7208
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- l -(phenylmethyl) propyl)-2-(3-methyl-
5-(trifluoromethyl)-1 H-pyrazol-1-yl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-85-
203 519 518.5538
methyl (4S)-4-(((2R,3S)-4-(3,5-difluorophenyl)-2-hydroxy-3-
(((methyloxy) acetyl)amino)butyl)amino)-3,4-
dihydrospiro[chromene-2,1'-cyclobutane]-6-carboxylate
204 561 561.4697
methyl (4S)-4-(((2R,3S)-4-(3-bromophenyl)-2-hydroxy-3-
(((methyloxy) acetyl)amino)butyl)amino)-3,4-
dihydrospiro[chromene-2,1'-cyclobutane]-6-carboxylate
205 505 504.527
(4 S)-4-(((2 R, 3 S)-4-(3, 5-di fl uorophenyl)-2-hydroxy-3 -
(((methyloxy)acetyl)amino) butyl)amino)-3,4-
dihydrospiro[chromene-2,1'-cyclobutane]-6-carboxylic acid
206 601.3 600.771
(E)-N-((2 S,3 R)-4-((S)-6-ethyl-2,2-spirocycloheptylchroman-
4-ylamino)-3-hydroxy- l-phenylbutan-2-yl)-3-(5-fluoro-2-
methoxyphenyl)acrylamide
207 587.3 586.744
(E)-N-((25,3 R)-4-((S)-6-ethyl-2,2-sp irocyclohexylchroman-4-
ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(5-fluoro-2-
methoxyphenyl)acrylamide
208 559.2 558.69
(E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocyclopentylchrom an-
4-ylamino)-3-hydroxy- I -phenylbutan-2-yl)-3-(5-fluoro-2-
methoxyphenyl)acrylami de
209 629.2 628.659
(E)-N-((2 S,3 R)-4-((S)-2,2-spirocyclopentyl-6-
(trifluoromethoxy) chroman-4-ylamino)-3-hydroxy-l-
phenylbutan-2-yl)-3 -(5-fluoro-2-methoxyphenyl)acrylamide
210 587.2 586.744
(E)-3-(5-fluoro-2-methoxyphenyl)-N-((2S,3 R)-3-hydroxy-4-
((S)-6-isopropyl-2,2-spirocyclopentylchroman-4-ylamino)-1-
phenylbutan-2-yl)acrylamide
211 587.3 2346.97
(E)-N-((2 S,3 R)-4-((S)-6-ethyl-2,2-(2-m ethy l)-
spirocyclopentylchroman-4-ylamino)-3-hydroxy- I -
phenylbutan-2-yl)-3-(5-fluoro-2-methoxypheny l)acrylam ide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-86-.
437.2 873.185
N-((1 S,2R)-3-(((4R)-6-ethyl-4-methyl-3,4-
dihydrospiro [chromene-2, I'-cyclobutan]-4-yl)amino)-2-
hydroxy- 1 -(phenylmethyl) propyl)acetamide
213 473.1; 473.408
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene- 475.1
2,1 '-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)acetamide
214 396.2 395.5
N-((1 S,2R)-3-((4'S)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b] pyridin]-4'-ylamino)-2-hydroxy- l -
(phenyl methyl)propyl )acetam i de
215 396.2 395.5
N-((1S,2R)-3-((4'R)-3',4'-dihydrospiro [cyclobutane-1,2'-
pyrano[2,3-c]pyridin]-4'-ylamino)-2-hydroxy- l -
(phenylmethyl) propyl)acetamide
216 396.2 395.5
N-((1S,2R)-3-((4'S)-3',4'-dihydrospiro [cyclobutane-1,2'-
pyrano[2,3-c] pyridin]-4'-ylamino)-2-hydroxy- l -
(phenylmethyl) propyl)acetamide
217 426.2 425.526
N-((1S,2R)-3-((4'S)-3',4'-dihydrospiro [cyclobutane-1,2'-
pyrano[2,3-c]pyridin]-4'-ylamino)-2-hydroxy- l -
(phenylmethyl) propyl)-2-(methyloxy)acetamide
218 464.2 463.497
N-((1 S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4'S)-6'-
(trifluoromethyl)-3',4'-dihydro spiro [cyclobutane-1,2'-
ano[2,3-b] idin]-4'- lamino) ro l)acetamide
219 494.1 493.523
N-((1 S,2R)-2-hydroxy-I-(phenylmethyl)-3-(((4'S)-6'-
(trifluoromethyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)am ino)propyl)-2-
(methyloxy)acetami de
220 430.1 429.945
N-((2 S,3 R)-4-((S)-6-chloro-2,2-spirocyclobutyl-3,4-dihydro-
2H-pyrano [2,3 -b] pyri di n-4-y l amino)-3 -hydroxy- l -
phenylbutan-2-yl)acetamide
221 460.1 459.971
N-((2 S,3 R)-4-((S)-6-chloro-2,2-spirocyclobutyl-3,4-dihydro-
2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxy-l -
phenylbutan-2-yl)-2-methoxyacetamide
CA 02629402 2008-05-12
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-87-
222 430.1 429.945
N-((2S,3R)-4-((R)-6-chloro-2,2-spirocyclobutyl-3,4-dihydro-
2H-pyrano[2,3 -b]pyridin-4-ylamino)-3-hydroxy- l -
phenylbutan-2-yl)acetam i de
223 449.2 448.564
((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-ethyl-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amin o)-2-hydroxypropyl)acetamide
224 454.3 453.579
N-((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane-
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-I. -
(phenylmethyl)propyl)-2-(methyloxy) acetamide
225 NMR only 478.5896
-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-ethyl-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
1)amino)-2-hydrox ro yl)-2-meth lox acetamide
226 496.2 495.6599
N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(3-methylbutyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yI)amino)-1-(phenylmethyl)propyl)-2-(methyloxy)acetamide
227 563.2 562.7748
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(2-methyl-
1,3-thiazol-4- 1) acetamide
228 561.3 560.7346
2-(3,5-dimethyl-4-isoxazolyl)-N-((1 S,2R)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetami de
229 533.3 532.685
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- l -(phenylmethyl) propyl)-2-(1 H- 1,2,4-
triazol- l -yl) acetamide
230 533.3 532.685
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-(2H-1,2,3-
triazol-2-yl) acetamide
CA 02629402 2008-05-12
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- 88-
231 491.2 490.6046
N-((I S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane-
l ,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-l -
hen lmeth 1 ro 1 -2-(2H-1,2,3-triazol-2- l)acetamide
232 491.2 490.6046
N-((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane-
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-I-
(phenylmethyl)propyl)-2-(I H-1,2,4-triazol-1-yl)acetamide
233 606.3 606.2066
2-(4-chloro-3 -cyclopropyl- lH-pyrazol-1 -yl)-N-((1 S,2R)-3-
(((4' S)-6'-(2,2-di methylpropyl)-3',4'-dihydrospiro
[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxy-1-(phenylmethyl) propyl)acetamide
234 560.3 559.7505
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yI)amino)-2-hydroxy-I-(phenylmethyl) propyl)-2-(3,5-
dimethyl-lH-pyrazol-1-yl) acetamide
235 546.3 545.7237
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(3-methyl-
1H-pyrazol-1-yl) acetamide
236 546.3 545.7237
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- 1 -(phenylmethyl) propyl)-2-(4-methyl-
IH-pyrazol-1-yl) acetamide
237 533.2 532.685
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- l-(phenylmethyl) propyl)-2-(4H-1,2,4-
triazol-4-yl) acetamide
238 507.0; 507.8532
N-((1 S,2R)-3-((8-bromo-6-chloro-3,4- 509.0
dihydrospiro[chromene-2, I-cyclobutan]-4-y1)amino)-2-
hydroxy-1-(phenylmethyl) propyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 89-
239 543.0; 543.8334
N-((l S,2R)-3-(((4S)-8-bromo-6-chloro-3,4- 545.0
dihydrospiro[chromene-2, I '-cyclobutan]-4-yl )amino)-1-((3,5-
difluorophenyl)methyl)-2-hydroxypropyl) acetam ide
240 543.0; 543.8334
-((1S,2R)-3-(((4R)-8-bromo-6-chloro-3,4- 545.0
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)- 1 -((3,5-
difluorophenyl)methyl)-2-hydroxypropyl)acetamide
241 532.0; 532.8633
N-((] S,2R)-3-(((4S)-8-bromo-6-chloro-3,4- 534.0
dihydrosp iro[chromene-2,1'-cyclobutan]-4-yl)amino)-1-((3-
cyanophenyl)me thyl)-2-hydroxypropyl)acetamide
242 514.1 514.0624
N-((I S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)acetamide
243 565.1 564.7226
N-((1 S,2R)-3-(((4S)-6,8-di-4-morpholinyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)acetamide
244 550.1 550.0426
N-((1 S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4-
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-1-((3,5-
difluoropheny])methyl)-2-hydroxypropyl) acetamide
245 539.1 539.0725
N-((1 S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4-
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-1-((3-
cyanophenyl)methyl)-2-hydroxypropyl) acetamide
246 566.1 1132.083
N-((1 S,2R)-3-(((2S,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'-
tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-1-((3,5-
difluoropheny l)m ethy l)-2-hydroxypropyl)acetamide
247 523.0; 1047.704
N-((l S,2R)-3-(((2S,4S)-8-bromo-6-chloro-3,4,4',5'- 525.0
tetrahydrospiro [chromen a-2, 3'-furan] -4-yl)am ino)-2-hydroxy-
1-(phenylmethyl)propyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
-90-
248 523.0; 1047.704
N-((1 S,2R)-3-(((2S,4R)-8-bromo-6-chloro-3,4,4',5'- 523.0
tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-2-hydroxy-
1-(phenylmethyl)propyl)acetam ide
249 559.0; 1119.665
N-((1 S,2R)-3-(((2S,4S)-8-bromo-6-chloro-3,4,4',5'- 561.0
tetrahydrospiro[chromene-2,3'-furan]-4-yl)amino)-1-((3,5-
difluorophenyl)methyl)-2-hydroxypropyl) acetamide
250 559.0; 1119.665
N-((1 S,2R)-3-(((2S,4R)-8-bromo-6-chloro-3,4,4',5'- 561.0
tetrahydrospiro [chromene-2,3'-furan]-4-y1)amino)-1-((3,5-
difluorophenyl)methyl)-2-hydroxypropyl) acetamide
251 530.0; 530.0614
N-((1 S,2R)-3-(((2S,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'- 532.0
tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-2-hydroxy-
1-(phenylmethyl)propyl)acetamide
252 530.0; 530.0614
N-((1 S,2R)-3-(((2R,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'- 532;0
tetrahydrospiro [chromene-2,3-furan]-4-y1)amino)-2-hydroxy-
1-(phenylmethyl)propyl)acetamide
253 581 580.643
(E)-N-((25,3 R)-4-((S)-6, 8-difluoro-3 ,4-
dihydrospiro[chromen-2,1'-cyclopentan]-4-ylamino)-3-
hydroxy- l -phenylbutan-2-yl)-3-(5-fluoro-2-
methoxyph enyl)acrylamide
254 563 562.653
(E)-N-((25,3 R)-4-((S)-6-fluoro-3,4-dihydrospiro[chromen-
2,1'-cyclopentan]-4-ylamino)-3-hydroxy- l -phenylbutan-2-yl)-
3-(5-fluoro-2-methoxyphenyl) acrylamide
255 (E)-N-((2S,3R)-4-((S)-6-ethyl-3,4-dihydrospiro[chromen-2,1'- 559 558.69
cyclopentan]-4-ylamino)-3-hydroxy-l-phenylbutan-2-yl)-3-
(5 -fluoro-2-methoxyp h enyl)acryl am ide
256 479 478.673
N-((1 S,2R)-3-(((4S)-6-neopentyl-3,4-dihydrospiro[chromene-
2, l'-cyclopentyl]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl)
propyl)acetamide
257 413 412.502
1-((1 S,2R)-3-(((4S)-6-fluoro-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-
4-yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 91-
258 465 464.646
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro
[chromene-2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -
(phenylm ethyl)propyl)acetamide
259 495 494.672
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro
[chromene-2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)-2-(methyloxy)acetamide
260 463 462.509
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4S)-6-
(trifluoromethyl)-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-4-yl)amino)propyl)acetamide
261 493 492.535
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4S)-6-
(trifluoromethyl)-3,4-dihydrospiro[chromene-2,1'-
cycl obutan]-4-yl)am ino)propyl)-2-(methyloxy)acetamide
262 480 479.617
N-((l S,2R)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1-
(phenylmethyl)propyl)acetami de
263 493 492.66
N-((1 S,2R)-2-hydroxy-3-(((4 S)-6-(4-methyl-l-piperazinyl)-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-1-
(phenylmethyl)propyl)acetamide
264 464 463.618
N-((1 S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4S)-6-(1-
pyrrolidinyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-
y l)amino)propyl)acetamide
265 480 479.661
N-((1 S,2R)-3-(((4S)-6-((2,2-dimethylpropyl)amino)-3,4-
dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)acetamide
266 466 465.634
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)acetamide
CA 02629402 2008-05-12
WO 2007/061670 PCT/US2006/044058
- 92-
267 496 495.66
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-41-
yl)amino)-2-hydroxy-l-(phenylrnethyl) propyl)-2-
(methylo xy)a c etamide
268 N-((IS,2R)-3-(((4S)-6-chloro-7-(4-morpholinylmethyl)-3,4- 559 558.115
dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)-2-(methyloxy)acetamide
269 527 526.6244
2-cyano-N-((l S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-
6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2'-
pyrano[2,3-b] pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetam i de
270 502 501.6143
N-((1 S,2R)-1-((3,5-difluorophenyl) methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetam i de
271 532 531.6401
N-((1 S,2R)-1-((3,5-difluorophenyl) methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2'-
pyrano [2,3-b]pyridin]-4'-yl)amino)-2-hydroxypropyl)-2-
methoxyacetamide
272 534 533.6731
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-l-(phenylrnethyl) propyl)-2-(1H-
tetrazol-5-yl)acetamide
273 545 544.7356
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(1-methyl-
1H-pyrrol-2-yl) acetamide
274 557 556.1428
N-((1 S,2R)-3-(((4S)-6-chloro-7-(1-piperidinylmethyl)-3,4-
dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy-l -(phenylmethyl)propyl)-2-(methyloxy)acetamide
275 521 520.67
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano [2,3-b]pyridin]-4'-yl)am ino)-2-hydroxypropyl)-2-
(methy l oxy)acetamide
CA 02629402 2008-05-12
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- 93-
276 558 557.6951
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxypropyl)-2-(1 H-
1,2,4-triazol- l -yl)acetamide
277 495 494.6758
N-((I S,2R)-3-(((4S)-6-((2-(dimethylamino)
ethyl)(methyl)amino)-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-4-yl)am in(>)-2-hydroxy- l -(phenylmethyl)
propyl)acetamide
278 482 481.6331
N-((1S,2R)-2-hydroxy-3-(((4S)-6-(methyl (2-
(methyloxy)ethyl)amino)-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-1-(phenylmethyl)propyl) acetamide
279 461 460.5748
N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(1H-imidazol- l -yl)-3,4-
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-1-
(phenylmethyl)propyl)acetami de
280 461 460.5748
N-((1 S,2R)-2-hydroxy- I -(phenylmethyl)-3-(((4S)-6-(1 H-
pyrazol-1-yl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-
yl)amino)propyl)acetamide
281 547 546.679
N-((2 S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-4-
ylamino)-3-hydroxy-l-phenylbutan-2-yl)-2-(3-
fluorophenoxy)acetam ide
282 515 514.662
(E)-N-((2 S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-
4-ylamino)-3-hydroxy-l -phenylbutan-2-yl)-3-(furan-2-
yl ac aamide
283 587 586.729
(E)-3-(2,4-dimethoxypyrim idin-5-yl)-N-((2S,3 R)-4-((S)-6-
ethyl-2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-1-
phenylbutan-2-yl)acrylamide
284 515 514.662
(E)-N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-
4-ylamino)-3 -hydroxy- l -pheny lbutan-2-yl)-3 -(furan-3 -
yl)acrylamide
285 569 568.71
(E)-3-(benzo[d] [ 1,3 ] dioxol-5-yl)-N-((2 S,3 R)-4-((S)-6-ethyl-
2,2-spirocyclopentylchroman-4-ylamino)-3-hydroxy-l-
phenylbutan-2-yl)acryl amide
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286 531 530.729
(E)-N-((2 S, 3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-
4-ylamino)-3-hydroxy-l-phenylbutan-2-yl)-3-(thiophen-2-
yl)acrylamide
287 564 563.738
(E)-N-((2 S, 3 R)-4-((S)-6-ethyl-2,2-sp irocyclopentylchroman-
4-ylamino)-3-hydroxy-l -phenylbutan-2-yl)-3-(1H-indol-3-
yl)acrylamide
288 526 525.689
(E)-N-((2S,3R)-4-((S)-6-ethyl-2,2-spirocycl opentylchroman-
4-ylamino)-3-hydroxy-1-phenylbutan-2-yl)-3-(pyridin-4-
yl)acrylamide
289 526 525.689
(E)-N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-
4-ylamino)-3-hydroxy- l -phenylbutan-2-yl)-3-(pyridin-3-
yl)acrylamide
290 526 525.689
(E)-N-((2 S,3 R)-4-((S)-6-ethyl-2,2-spirocyclopentylchroman-
4-ylamino)-3-hydroxy- l-phenylbutan-2-yl)-3-(pyridin-2-
yl)acrylamide
291 411 410.555
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -
(ph enylm ethyl)propyl)ac etam ide
292 503 502.651
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
(phenyloxy)acetamide
293 441 440.58
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylm ethyl)propyl)-2-
(methyloxy)acetamide
294 521 520.641
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
((3 -fl uorophenyl) oxy)acetam i de
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295 535 1069.34
(2S)-N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-
2H-chromen-4-yl) amino)-2-hydroxy- l -
(phenylmethyl)propyI)-2-((3-fluorophenyl)oxy)propanamide
and '(2R)-N-((1 S,2 R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-
dihydro-2H-chrom en-4-yl) amino)-2-hydroxy- l -
(hen lmeth1 ro yl)-2-((3-fluoro hen 1)ox) ro anamide
296 492 491.628
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2 -hydroxy- l -(pheny lm ethyl)propyl)-2-
(3 -methyl-5-isoxazolyl)acetam ide
297 533 532.677
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
((3-(methyl oxy)phenyl)oxy)acetamide
298 501 500.679
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)-3-
phenylpropanamide
299 455 454.607
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yi)amino)-2-hydroxy- l -(phenylmethy l)propyl)-2-
(ethyloxy)acetamide
300 565 564.806
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
(((IR,2S,5R)-5-methyl-2-(1-methylethyl)
c clohex l)ox )acetamide
301 517 516.678
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2-
((2-methylpheny l) oxy)acetam i de
302 533 532.677
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
((2-(methyloxy)phenyl)oxy)acetamide
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303 483 482.661
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
((2-methylpropyl)oxy)acetamide
304 504 503.639
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-
(3-pyridi nyloxy)acetamide
305 425 424.581
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)
propanamide
306 439 438.608
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
methylpropanamide
307 471 941.212
N-((1 S,2R)-3-(((2R,4S)-6-ethyl-2-methyl-2-
((methyloxy)methyl)-3,4-dihydro-2H-chromen-4-yl)amino)-2-
hydroxy-l-(phenylmethyl)propyl)-2-(methyloxy) acetamide
and 'N-((1 S,2R)-3-(((2S,4S)-6-ethyl-2-methyl-2-
((methyloxy)methyl)-3,4-dihydro-2 H-chromen-4-y l)amino)-2-
hydroxy-1-(phenylmethyl)propyl)-2-(methyloxy) acetamide
308 455 909.214
N-((1 S,2R)-3-(((2R,4S)-6-ethyl-2-methyl-2-
((methyloxy)methyl)-3,4-dihydro-2H-chrom en-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)propanamide and 'N-
((1 S,2R)-3-(((2S,4S)-6-ethyl-2-methyl-2-
((methyloxy)methyl)-3,4-dihydro-2H-chrom en-4-yl)am ino)-2-
hydroxy- l -(phenylmethyl)propyl)propanamide
309 424 423.554
N-((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane-
l ,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy- l -
(phenylinethyl)propyl)acetam ide
310 495 494.6718
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)-2-
(tetrahydro-2H-pyran-4-yl)acetamide
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311 481 961.29
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
((2R)-tetrahydro-2-furanyl)acetamide and 'N-((1 S,2R)-3-
(((4 S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-chromen-4-
yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-((2S)-
tetrahydro-2-furanyl)acetamide
312 511 510.6708
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
(tetrahydro-2H-pyran-4-yloxy)acetamide
313 511 1021.342
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)-2-
((3R)-tetrahydro-2H-pyran-3-yloxy)acetamide and 'N-
((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl) amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-
((3S)-tetrahydro-2H-pyran-3-yloxy) acetamide
314 508.3 507.671
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)
propyl)-2-(4-morpholinyl)acetamide
315 531.3 530.748
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- l -((3-(2-propen- l -
yl)phenyl)methyl)propyl)-6-heptenamide
316 N-((IS,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5'- 439.3 877.129
tetrahydrospiro[chromene-2,3'-furan]-4-y1)am ino)-2-hydroxy-
1-(phenylmethyl) propyl)acetamide
317 469.2 937.181
N-((1 S,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5'-
tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-2-hydroxy-
I-(phenylmethyl) propyl)-2-(methyloxy)acetamide
318 412.2 411.543
N-((1 S,2R)-3-(((4S)-2-cyclopropyl-6,6-dimethyl-4,5,6,7-
tetrahydro-1,3-benzoxazol-4-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetamide
319 442.3 441.569
N-((1 S,2R)-3-(((4S)-2-cyclopropyl-6,6-dimethyl-4,5,6,7-
tetrahydro-1,3 -benzoxazol-4-yl)amino)-2-hydroxy-1-
(phenylmethyl)propyl)-2-(methyloxy) acetamide
320 522.3 521.698
N-((1 S,2 R)-3-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-3-(4-morpholinyl)propanamide
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321 396.2 395.544
N-((1 S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((5S)-3,7,7-
trimethyl-5, 6,7,8-tetrahydro-5-quinolinyl)amino)
propyl)acetamide
322 469.2 468.59
N-((1 S,2R)-3-(((2R,4S)-6-ethyl-3,4,4',5'-
tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-2-hydroxy-
1-(phenylmethyl) propyl)-2-(methyloxy)acetamide
323 469.2 468.59
N-((1 S,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5'-
tetrahydrospiro [chromene-2, 3'-furan]-4-yl)amino)-2-hydroxy-
1 -(phenylmethyl) propyl)-2-(methyloxy)acetamide
324 439.2 438.565
N-((1 S,2R)-3-(((2R,4S)-6-ethyl-3,4,4',5'-
tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-2-hydroxy-
1-(phenylmethyl) propyl)acetamide
325 439.2 438.565
N-((l S,2R)-3-(((2S,4S)-6-ethyl-3,4,4',5'-
tetrahydrospiro [chromene-2,3'-furan]-4-yl)amino)-2-hydroxy-
1-(phenylmethyl) propyl)acetamide
326 453.3 452.591
N-((1 S,2R)-3-(((4S)-6-ethyl-2',3,3',4,5',6'-
exahydrospiro [chromene-2,4'-pyran]-4-yl)amino)-2-hydroxy-
1-(phenylmethyl)propyl)acetamide
327 483.3 482.617
N-((1S,2R)-3-(((4S)-6-ethyl-2',3,3', 4,5',6'-
exahydrosp iro [chromen e-2,4'-pyran] -4-yl )amino)-2-hydroxy-
1-(phenylmethyl)propyl)-2-(methyloxy) acetamide
328 438.3 437.5805
N-((1 S,2R)-2-hydroxy-3-(((5'S)-3'-methyl-5,8'-dihydro-6H-
spiro[cyclobutane-1,7'-quinolin]-5'-yl)amino)-1-
(phenylmethyl) propyl)-2-(methyloxy)acetamide
329 474.2 473.5607
N-((1 S,2R)-1-((3,5-difluorophenyl) methyl)-2-hydroxy-3-
(((5'S)-3'-methyl-5',8'-dihydro-6'H-spiro[cyclobutane-1,7'-
qu inol in]-5'-yl)amino)propyl)-2-(methyloxy)acetamide
330 475.2 474.6056
N-((1 S,2R)-2-hydroxy-3-(((5'S)-3'-methyl-5',8'-dihydro-6'H-
spiro[cyclobutane- l ,7'-quinolin]-5'-yl)amino)-1-
(phenylmethyl) propyl)-2-(1H-1,2,4-triazol-1-yl) acetamide
331 511.2 510.5858
N-((l S,2R)-1-((3,5-difluorophenyl) methyl)-2-hydroxy-3-
(((5'S)-3'-methyl-5',8'-dihydro-6'H-spiro [cyclobutane-1,7'-
quinolin]-5'-yl)amino)propyl)-2-(1 H-1,2,4-triazol-l-
yl)acetamide
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332 475.3 474.6412
N-((1 S,2R)-3 -(((4 S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyc]obutan]-4-yl)amino)-2-hydroxy-1-((3-(2-propen- I-
yl)phenyl)methyl)propyl)-2-propenamide
333 489.3 488.668
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- l -((3-(2-propen- l -
yl)phenyl)methyl)propyl)-3 -butenamide
334 503.3 502.6948
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- l -((3 -(2-propen-l-
y1)phenyl)meth yl)propyl)-4-pentenamide
335 517.3 516.7216
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-l -((3-(2-propen- l-
yl)phenyl)methyl)propyl)-5-hexenamide
336 686, 688 686.7268
1,1-dimethylethyl (7-(((1S,2R)-1-((3-bromophenyl)methyl)-3-
(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-
yl)amino)-2-hydroxypropyl)amino)-7-oxoh eptyl)carbamate
337 720, 722 720.744
phenylmethyl (7-(((1 S,2R)-1-((3-bromophenyl)methyl)-3-
(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, l'-cyclobutan]-4-
yl)amino)-2 -hydroxypropyl)amino)-7-oxoheptyl)carbamate
338 465.2 464.646
N-((2 S,3 R)-4-((S)-6-ethyl-2,2-spirocyclobuty lchroman-4-
ylamino)-3-hydroxy- I -phenylbutan-2-yl)pentanamide
339 465.2 464.646
N-((25,3 R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
lamino)-3-hydroxy- l -phenylbutan-2-yl)-3-methylbutanamid
340 465.2 929.292
N-((2S,3 R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
lamino)-3-hydroxy- l -phenylbutan-2-yl)-2-methylbutanami de
341 466.1 465.634
2-(dimethylamino)-N-((2 S,3R)-4-((S)-6-ethyl-2,2-
spirocyclobutylchroman-4-ylamino)-3-hydroxy-l -
phenylbutan-2-yl) acetamide
342 500.2 499.651
N-((2S,3R)-4-((S)-6-ethyl-2,2-sp irocyc lobutylchroman-4-
ylamino)-3-hydroxy- l -phenylbutan-2-yl)-2-(pyridin-2-
yl)acetamide
343 463.1 462.63
2-cyclopropyl-N-((2 S,3 R)-4-((S)-6-ethyl-2,2-
spirocyclobutylchroman-4-ylamino)-3-hydroxy-l -
phenylbutan-2-yl)acetami de
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344 505.1 504.691
N-((2 S, 3 R)-4-((S)-6-ethyl-2,2-spirocycl obutylchroman-4-
ylamino)-3-hydroxy-1-phenylbutan-2-yl)-2-(thiophen-2-
yl)acetamide
345 504.2 503.639
N-((2 S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
yl am ino)-3-hydroxy- l -phenylbutan-2-yl)-2-(3-
methyl i soxazo l-5-yl)acetamide
346 493.2 492.7
N-((25,3 R)-4-((S)-6-ethyl-2,2-spirocyclobutylchroman-4-
ylamino)-3-hydroxy-l-phenylbutan-2-yl)heptanamide
347 491.2 490.684
2-cyclopentyl-N-((2S,3 R)-4-((S)-6-ethyl-2,2-
spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-
phenylbutan-2-yl)acetamide
348 505.1 504.691
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(3-thienyl)acetamide
349 555.1 555.534
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(3-thienyl)acetamide
350 605.1 605.594
2-(1-benzothien-3-yl)-N-((1 S,2R)-3-(((4S)-6-bromo-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)acetamide
351 569.1 569.561
N-((I S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro [chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-methyl-3-thienyl)acetamide
352 584.1 584.576
N-((I S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-y1)amino)-2-hydroxy- 1-(phenylmethyl)
propyl)-2-(2,5-dimethyl-1,3-thiazol-4-yl) acetamide
353 553.2 553.498
N-((1 S,2 R)-3-(((4S)-6-bromo-3,4-dihydrospiro [chromene-
2,1'-cyclobutan]-4-yI)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(1-methyl-]H-imidazol-4-yl) acetamide
354 539.1 539.471
N-((I S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-y1)amino)-2-hydroxy-l -(phenylmethyl)
propyl)-2-(1H-imidazol-I -yl)acetamide
355 503.3 502.655
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(1-methyl-IH-imidazol-4-yl) acetamide
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356 489.3 488.628
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hy droxy- l -(phenylmethyl)
propyl)-2-(1 H-imidazol-1-yl)acetamide
357 472.2 471.638
N-((lS,2R)-1-((1-acetyl-3-piperidinyl) methyl)-3-(((4S)-6-
ethyl-3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-
yl)amino)-2-hydroxypropyl)acetamide
358 506.2 505.655
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro [clu-om ene-2,1'-
cyclobutan}-4-yl)ami no)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-oxo- l -pyrrolidinyl)acetamide
359 556.1 556.498
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-oxo-l-pyrrolidinyl)acetamide
360 554.2 553.699
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(1-oxo-1,3-dihydro-2H-i soindol-2-yl)acetam ide
361 520.3 1039.36
(2R)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-oxo- I -pyrrolidinyl) propanamide
362 520.3 519.682
(2R)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-l -(phenylmethyl)
propyl)-2-(2-oxo- l -pyrrolidinyl) propanamide
363 520.3 519.682
(2S)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-oxo- l -pyrrolidinyl) propanamide
364 480.2 479.617
N--2---acetyl-N--1---((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylm ethyl )propyl)glycinam ide
365 505.3 1009.33
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((1R)-2-oxocyclopentyl) acetamide
366 520.3 1039.36
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-((3 R)-3-methyl-2-oxo-1-pyrrolidinyl)acetamide
367 520.3 519.682
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((3 R)-3-methyl-2-oxo- l -pyrrolidinyl)acetamide
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368 520.3 519.682
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan] -4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-((3 S)-3-methyl-2-oxo- l -pyrrol idinyl)acetamide
369 513.3 512.65
2-(2-cyano-1 H-pyrrol-1-yl)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)acetamide
370 494.2 493.644
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2-
(2-oxo- l -pyrrol idinyl)acetamide
371 436.1 435.565
2-cyano-N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-3,4-
dihydro-2H-chromen-4-y1) amino)-2-hydroxy-1-
(phenylmethyl) propyl) acetamide
372 442.1 883.137
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3 -(((8R)-2,6,6-
trimethyl-3 -oxo-2,3,5,6,7,8-hexahydro-8-
isoquinolinyl)amino)propyl)-2-methoxyacetami de
373 412.1 823.0854
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((8R)-2,6,6-
imethyl-3 -oxo-2, 3, 5,6, 7, 8 -hexah ydro-8-i s oqu ino l inyl) am i no)
propyl) acetamide
374 531.2 530.6652
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4 S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(2-oxo-1-pyrrolidinyl)acetamide
375 545.2 544.692
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(3-methyl-2-oxo- l-pyrrolidinyl)acetamide
376 529.2 528.6494
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4 S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)-2-(3-methyl-5-isoxazolyl) acetamide
377 549.3 548.7236
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-(2-oxo-1-
pyrrolidinyl)acetamide
378 563.3 562.7504
N-((1 S,2 S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- l -(phenylmethyl) propyl)-2-(3-methyl-
2-oxo- I -pyrrolidinyl) acetamide
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379 547.3 546.7078
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(3-methyl-
5-isoxazolyl) acetamide
380 548.3 1095.471
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy- l -(phenylmethyl) propyl)-2-((1 R)-2-
oxocyclopentyl) acetamide
381 559.3 558.7188
N-((1 S,2S)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxy-1-(phenylmethyl) propyl)-2-(2-oxo-
1(2H)-pyridinyl) acetamide
382 577.3 1153.554
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yI)amino)-2-hydroxy-l-(phenylmethyl) propyl)-2-((1 S,2E)-2-
((methyloxy) imino)cyclopentyl)acetamide
383 481.1 480.6054
N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(4-inorpholinyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-1-(phenylmethyl)propyl) acetamide
384 466.1 931.181
N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(tetrahydrofuran-2-yl)-
3',4'-dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-1-(phenylmethyl)propyl) acetamide
385 397.3 793.064
N-((2S,3R)-3-hydroxy- l-phenyl-4-((R)-2,7,7-trimethyl-
5,6,7,8-tetrahydroquinazolin-5-ylamino)butan-
2-yl)acetamide
386 411.3 821.022
N-((1 S,2R)-2-hydroxy-I -(phenylmethyl)-3-((2S,4S)-3,4,4',5'-
tetrahydrospiro [chromene-2,3'-furan]-4-ylamino)propyl)
acetamide
387 489.1 978.8142
N-((1 S,2R)-3-(((2R,4S)-6-bromo-3,4,4',5'-
tetrahydro sp iro [chromene-2, 3'-furan]-
4-yl)amino)-2-hydroxy- l -(phenylmethyl) propyl)acetam ide
388 492.3 491.6283
N-((1 S,2R)-2-hydroxy-3-(((4S)-6-((1 S,4S)-2-oxa-5-
azabicyclo[2.2.1 ]hept-5-yl)-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-
4-yl)amino)-1-(phenylmethyl)propyl) acetamide
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389 507.9 1015.342
N-((1 S,2R)-3-(((4S)-6-((2R,6S)-2,6-dimethyl-4-morpholinyl)-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)acetamide
390 508.3 507.6709
N-((1 S,2R)-3-(((4S)-6-((2S,5S)-2,5-dimethyl-4-morpholinyl)-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)acetamide
391 509 508.655
(3S)-tetrahydro-3-furanyl ((I S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclopentan]-4-yl)amino)-2-
hydroxy-l-(phenylmethyl)propyl)carbamate
392 495 494.628
(3S)-tetrahydro-3-furanyl ((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)carbamate
393 463 462.534
methyl ((1 S,2R)-1-((3,5-difluorophenyl) methyl)-3-(((4S)-6-
ethyl-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl)amino)-2-
hydroxypropyl)carbamate
394 439 438.565
methyl (2S,3R)-4-((S)-6-ethyl-2,2-spirocyclobutyl-chroman-
4-ylamino)-3-hydroxy- l -phenylbutan-2-yl carbamate
395 483 482.617
2-(methyloxy)ethyl((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrosp iro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy-1-(phenylmethyl)propyl)carbamate
396 415 414.611
N-((l S,2R)-3-(((4S)-2-ethyl-6,6-dimethyl-4,5,6,7-tetrahydro-
1-benzothien-4-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetamide
397 512 511.6623
(2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-3 -(3 -pyridinyl)-2-propenamide
398 545 544.6633
(2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-3 -(3-fluoro-4-hydroxyphenyl)-2-propenamide
399 567 566.7418
3-(1 H-benzimi dazol- i -yl)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)-2-methylpropanamide
400 579 579.5315
(2E)-3-(4-bromo-2-furanyl)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-
dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)-2-propenamide
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401 583 582.7652
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-1-(phenylmethyl)
propyl)-2-(4-q uin azolinylthio)acetami de
402 590 590.5584
(2E)-3-(5-bromo-3-pyridinyl)-N-((I S,2R)-3-(((4S)-6-ethyl-
3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenylmethyl)propyl)-2-propenamide
403 597 596.6614
(2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-y1)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-3-(5-fluoro-2-(trifluoromethyl) phenyl)-2-
propenamide
404 514 513.6781
N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-3-(3-pyridinyl)propanamide
405 517 516.682
N-((l S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-3-(1 H-imidazol-l-yl)butanamide
406 519 518.7182
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propy])-3 -(2-thienyl)propanami de
407 532 531.7173
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-y1)amino)-2-hydroxy-1-(phenylmethyl)
propyl)-2-(4-pyridinylthio)acetamide
408 552 551.7723
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l-(phenylmethyl)
propyl)-2-((4-methyl-I,3-thiazol-2-yl) thio)acetamide
409 556 555.6902
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(5-fluoro- I H-indol-3-yl) acetamide
410 562 561.7221
(2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-y1)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-3 -(3-quinolinyl)-2-propenami de
411 565 564.6445
(2E)-N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2, l'-cyclobutan]-4-yl)amino)-2-hydroxy-1 -(phenylmethyl)
propyl)-3-(3,4,5-trifluorophenyl)-2-propenamide
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412 573 572.7169
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)am ino)-2-hydroxy- l -(phenylmethyl)
propyl)-4-(3-fluoro-4-methylphenyl)-4-oxobutanamide
413 576 575.7489
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(2-(3-pyridinyl)phenyl) acetamide
414 583 582.7652
N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy- l -(phenylmethyl)
propyl)-2-(1-phthalazinylthio)acetamide
415 591 590.6634
(2E)-3-(2,2-difluoro-l,3-benzodioxol-4-yl)-N-((I S,2R)-3-
(((4S)-6-ethyl-3,4-dihydrospiro [chromene-2,1'-cyclobutan]-4-
yl)amino)-2-hydroxy- I -(phenylmethyl) propyl)-2-
propenamide
416 610 609.759
N-.1---((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
2,1'-cyclobutan]-4-yl)amino)-2-hydroxy- i -(phenylmethyl)
propyl)-N-2--(2-fluorophenyl)-N-2--
(methylsulfonyl)glycin am ide
417 568 567.7299
(3R)-3-(1 H-1,2,3-benzotriazol-1-yl)-N-((I S,2R)-3-(((4S)-6-
ethyl-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4-
yl)amino)-2-hydroxy-l-(phenylmethyl) propyl)butanamide
418 551 550.7842
N-((I S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2, F-
cyclobutan]-4-yl)amino)-2-hydroxy- I -(phenylmethyl)
propyl)-2-(2-thienylthio)propanamide
The following compounds in Tables 1 and 2 are additional representative
examples of Formulas 1-HI, as provided by the present invention.
Table 1
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H OH R4
R~ N N s
0 B R3 R3 Xt
2H5
Ex. Rand
No. R` B R4 Xl S
419 1-mo holin l-CH2- benzyl-O- H NH c clobu l
420 1- i erazinyl-CH2- benzyl-S- H S cyclobutyl
421 1- i eridin l-CH2- ben 1-NH- H 0 c clobu l
422 3-oxo-1- rrolidin l-CH2- ben 1-O- H NH c clo en l
423 1-mo holin l-CH=CH- benzyl-S- H S c clo en l
424 1 - i erazin l-CH=CH- benzyl-NH- H 0 c clo en l
425 oxo- olidin l-CH=CH- Benzyl-CH2- H SO2 c clo ro 1
426 oxazolidinyl-CH=CH- benzyl-O- H NH c clo ro l
427 isoxazolidinyl-CH2- benzyl-S- H S c clo ro l
428 indolinyl-CH2- benzyl-NH- H 0 cyclohexyl
429 1-morpholinyl-CH2- benzyl-CH2- H SO2 cyclohexyl
430 1 -i erazin l-CH2- benzyl-O- H NH c clohex l
431 1- i eridinyl-CH2- benzyl-S- H S c clobu l
432 3-oxo-1- rrolidin l-CH2- benzyl-NH- H 0 c clobu l
433 1-morpholinyl-CH=CH- ben 1-CH2- H SO2 c clobu l
434 1- i erazin l-CH=CH- benzyl-O- H NH c clo en l
435 oxo- olidinyl-CH=CH- benzyl-S- H S cyclo en l
436 oxazolidinyl-CH=CH- benzyl-NH- H 0 c clo pentyl
437 isoxazolidinyl-CH2- benzyl-CH2- H SO2 c clohex l
438 indolinyl-CH2- 4-CH3-phenyl H NH c clohex l
439 CH3-. phenyl H S c clohex l
Table 2
I 4
Rj N N S
p R3 R3 X1
B COH
\C2H5
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le
Ex. and
No. R' B R4 X' S
440 1 -moholin l-CH2- 4-CH3-phenyl H NH cyclobutyl
441 1- i erazinyl-CH2- 4-CH3- hen l H S cyclobutyl
442 1- i eridin l-CH2- 4-CH3- rid l H 0 c clobu l
443 3-oxo-1- rrolidin l-CH2- 4-CH3- hen l H NH cyclo en l
444 1-mo holin l-CH=CH- 3-CH3- hen l H S c clo en l
445 1- i erazin l-CH=CH- 3-CH3- hen l H 0 c clo en l
446 oxo- olidin l-CH=CH- 3-CH3- hen l H SO2 c clo ro 1
447 oxazolidinyl-CH=CH- 3-CH3- hen l H NH c clo ro l
448 isoxazolidinyl-CH2- phenyl H S c clo ro l
449 indolinyl-CH2- phenyl H 0 c clohex l
450 1-morpholinyl-CH2- phenyl H SO2 c clohex l
451 1- i erazin l-CH2- phenyl H NH c clohex l
452 1- i eridin l-CH2- pyridyl H S cyclobutyl
453 3-oxo-1- rrolidin 1-CH2- phenyl H 0 cyclobutyl
454 1-mo holin l-CH=CH- 3-F- hen l H SO2 c clobu l
455 1- i erazin l-CH=CH- 3-CI-phenyl H NH c clo entyl
456 oxo- rrolidin l-CH=CH- 3-CN- hen l H S c clo en l
457 oxazolidin l-CH=CH- 3-NH?-phenyl H 0 c clo en l
458 isoxazolidinyl-CH2- 2-F-hen 1 H SO2 c clohex l
459 indolin l-CH2- 4-CH3-phenyl H NH c clohex I
460 CH3- phenyl H S c clohex l
The following examples provide a further understanding and appreciation of
compounds of the present invention.
Example 461
N-((1 S,2R)-3-(((4S)-6-(2-fluoro-2-methylpropyl)-3,4-dihyd rospiro[chromene-
2,1'-
cyclobutan]-4-yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)acetamide
Step 1: (S)-tert-butyl 6-(2-oxopropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-
chromen-
4-ylcarbamate
Pd2(dba)3 (15 mg, 0.017 mmol), (S)-tert-butyl 6-bromo-2,2-spirocyclobutyl-3,4-
dihydro-2H-chromen-4-ylcarbamate (15 mg, 0.041 mmol), 2-
(dicyclohexylphosphino)-
2'-methylbiphenyl (80 mg, 0.170 mmol), potassium phosphate (179 mg, 0.845
mmol),
and acetone (2.5 ml, 33.8 mmol) were dissolved in 1 ml THE in a sealed tube.
The tube
was sealed and heated to 70 C for 8 hours. The cooled reaction mixture was
diluted with
DCM (10 mL) and poured into saturated sodium bicarbonate (25 mL). The layers
were
separated and the aqueous layer was extracted with DCM 2 x 25 mL_
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The combined organic layers were washed with water and brine, dried over MgSO4
and
evaporated to provide the title compound as a yellow oil (75 mg; 0.166 mmol,
99%). MS
m/z: 368.2 (M+Na).
Step 2: (S)-6-(2-fluoro-2-methypropyi) 2,2-spirocyclobut 3,4-dihydro-2H-
chromen-4-
amine
To pulverized cerium chloride (428 mg, 1.74 mmol) suspended in 10 mL of THE at
0 C
was added methylmagnesium bromide (3.0 M in diethyl ether, 0.60 mL, 1.79
mmol). After
stirring for 20 min a solution of (S)-tert-butyl 6-(2-oxopropyl)-2,2-
spirocyclobutyl-
chroman-4-ylcarbamate (200 mg, 0.579 mmol) in 3 mL of T11F was added and the
resulting
mixture was stirred at 0 C for 30 minutes. The reaction was quenched with
saturated
ammonium chloride (10 mL) and the aqueous layer was extracted with EtOAc 3 x
20 mL.
The combined organic layers were washed with brine, dried over sodium sulfate
and
concentrated to provide the corresponding alcohol (209 mg, 99%) as a yellow
oil. The
derived alcohol (209 mg, 0.578 mmol) was taken up in 1 mL of DCM cooled to -78
C and
treated with DAST (0.153 mL, 1.16 mmol). After stirring for 45 minutes the
reaction was
warmed to 0 C and quenched with saturated potassium carbonate (10 mL). The
layers
were separated and the aqueous layer was extracted with dichloromethane 3 x 10
mL. The
combined organic layers were washed with brine, dried over sodium sulfate,
filtered and
concentrated. The residue was purified by column chromatography (0-25% EtOAc
in
hexanes) to provide the amine as a yellow oil. The derived amine was taken up
in 5 mL of
DCM and treated with 2 mL of TFA. After stirring for 1 hour, the reaction was
diluted with
mL of DCM and poured into 10% aqueous potassium carbonate (50 mL). The layers
were separated and the aqueous layer was extracted with DCM 3 x 20 mL. The
combined
organic layers were washed with water and brine, dried over sodium sulfate and
25 concentrated to provide the title compound as a yellow oil (113 mg, 74%).
MS rn/z: 386.2
(M+Na).
Step 3: N-((1 S,2R)-3-(((4S)-6-(2-fluoro-2-methylpropyl)-3,4-
dihydrospiro[chromene-2,1'-
cvclobutanl-4-yl)amino -2-hydroxy-l-(phenylmethyl)propyl)acetamide
The amine from step 2 was carried on by methods analogous to those described
in Example
464, Steps 8-10 herein to afford the title compound. MS found: m/z: 469 (M+1).
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Example 462
N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-dihydrospiro [cyclo
butane-
1,2'-pyrano [2,3-b] pyridin]-4'-yl)ami n o)-2-hydroxy-l-
(phenyl methyl)propyl)acetamide
Step 1: (S)-tert-butyl 6-(2-oxopropyl)-2 2-spiroc cl~obutyl-3 4-dihvdro-
2H_pyranof2 3-
blpyridi n-4-ylcarbamate
Pd2(dba)3 (409 mg, 0.447 mmol) and 2-(dicyclohexylphosphino)-2'-methylbiphenyl
(391
mg, 1.07 mmol) were combined in a 250 mL sealable tube. THE (15 mL) was added
and
the mixture was purged with nitrogen for 5 minutes before the introduction of
(S)-tert-butyl
6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate
(3.30
mg, 8.94 mmol, potassium phosphate(4.74 g, 22.3 mmol), and acetone (51.9 g,
894 mmol).
The tube was sealed and heated to 70 C for 8 hours. The cooled reaction
mixture was
concentrated and purified by silica gel chromatography (0-100% ethyl acetate
in hexanes)
to provide the title compound as a yellow oil (2.15 g, 69%). MS m/z: 347.2
(M+1).
Step 2: (S)-6-(2-fluoro-2-methylpropyl)-2 2-spirocyclobutyl-3 4-dihvdro-2H-
pyranof2 3-
blpyridin-4-amine
To pulverized cerium chloride (12.0 g, 51 mmol) suspended in 25 mL of THE at 0
C was
added methylmagnesium bromide (3.0 M in diethyl ether, 17.0 mL, 51 mmol).
After
stirring for twenty minutes a solution of (S)-tert-butyl-6-(2-oxopropyl)-2,2-
spirocyclobutyl-
3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (3.50 g, 10 mmol) in 50 mL
of THE
was added over the course of thirty minutes. After stirring at 0 C for 30
minutes the
reaction was quenched with saturated ammonium chloride (100 mL) and the
aqueous layer
was extracted with ethyl acetate 3 x 100 mL. The combined organic layers were
washed
with brine, dried over sodium sulfate and concentrated to provide the
corresponding alcohol
as a yellow oil. The derived alcohol was taken up in 100 mL of DCM and cooled
to -78 C
at which point DAST (7.0 mL, 51 mmol) was added. After stirring for 45 minutes
the
reaction was quenched with saturated sodium bicarbonate (150 mL). The layers
were
separated and the aqueous layer was extracted with DCM 3 x 100 mL. The
combined
organic layers were washed with brine, dried over sodium sulfate, filtered and
concentrated.
The residue was purified by column chromatography (0-35% EtOAc in hexanes) to
provide
the fluoride as a yellow foam. The derived amine was taken up in 50 mL of DCM
and
treated with 20 mL of TFA. After stirring for 1 hour, the reaction was
concentrated, taken
up in 50 mL of DCM and poured into 10% aqueous potassium carbonate (200 mL).
The
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layers were separated and the aqueous layer was extracted with DCM 3 x 100 mL.
The
combined organic layers were washed with water and brine, dried over sodium
sulfate and
concentrated to provide the title compound as a brown oil (1.15 g, 43%). MS
mfh: 365.2
(M+1).
Step 3: N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-
dihydrospiro1cyclobutane-
1,2'-pyrano[2,3-blpyridin]-4'-ylaminn -2-hhydroy-1-(phen
lmethyl)propyl)acetamide
The amine from step 2 was carried on by methods analogous to those described
in Example
464, Steps 8-10 herein to afford the title compound. MS found m/z: 470 (M+1).
Example 463
N-((1 S,2R)-3-(((4' S)-6'-(2,2-dim ethylpropyl)-3',4'-dihydrospiro [cyclopent-
3-ene-1,2'-
pyrano[2,3-b] pyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
Step 1: 4-(2,2-dimethoxvethyl)hepta-1,6-dien-4-ol
In a 2 liter round bottom flask equipped with a stir bar, methyl 3,3-
dimethoxypropanoate
(24 g, 162 mmol) was dissolved in THE (1L). Under nitrogen, the solution was
chilled to -
78 C. Allyl Magnesium bromide, 1.0 M solution in diethyl ether (405 mL, 405
mmol) was
added dropwise in such a way that the internal temperature remained lower than
-75 C.
After addition, the reaction was allowed to stir for 3 hours at -78 C before
being quenched
with saturated ammonium chloride solution (300 mL). The ice bath was removed
and the
reaction allowed to come to RT. Water was added (200 mL) and the reaction was
concentrated on a rotary evaporator to remove as much THE as possible. The
product was
extracted from the resulting aqueous with diethyl ether (3x200 mL). The
organics were
then washed with brine (100 mL), dried over magnesium sulfate, filtered and
concentrated
to afford the product.
Step 2: 1-(2,2-dimethoxyeth ll)cyclopent-3-enol
A solution of 4-(2,2-dimethoxyethyl)hepta-l,6-dien-4-ol (28g, 140mmol) in DCM
(2L) was
charged to a 3 L RB flask. Dry argon was bubbled through the solution for - 30
minutes.
Grubbs second generation catalyst (5.9g, 7.Ommol) was added and the reaction
was allowed
to stir under argon for 15 hours. The reaction was quenched with a solution of
tetrakis -
(hydroxymethyl)phosphonium chloride (27g, 140mmol) in isopropanol (200 mL) and
10 N
NaOH (14 mL), and stirred for 15 hours. The reaction was diluted with water (1
L) and
poured into a seperatory funnel. The DCM layer was separated and the aqueous
was
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extracted with DCM (3x100 mL). The combined organics were concentrated to a
dark oil
which was purified by flash chromatography on a 330g ISCO column eluting by
gradient
hexanes to 20% EtOAc/ hexanes over a 50 minute period. Product fractions were
combined
to afford the title compound.
Step 3: 2-(1-(tert-butyldimethylsilylox~)c c~lopent-3-enyl) acetaldehyde
1-(2,2-dimethoxyethyl)cyclopent-3-enol (13.5g, 78mmol) was dissolved in DCM
(250mL).
This was chilled to 0 C under nitrogen and 2,4,6-trimethylpyridine (42mL,
314mmol) was
added dropwise over 10 minutes. Tert-butyldimethylsilyl
trifluoromethanesulfonate (18
mL, 78mmol) was added dropwise via syringe very slowly over 20 minutes keeping
the
internal temperature below 5 C. The reaction was allowed to come to RT. By TLC
(20%
EtOAc/hexanes; KMnO4 stain), the starting material was completely consumed (-2
hours).
The reaction was then chilled back to 0 C and triethylsilyl
trifluoromethanesulfonate
(35mL, 157mmol) was added in dropwise over a 10 minute period. This was
allowed to stir
at 0 C for 1 hour before adding water (250 mL). The ice bath was removed and
this
mixture was stirred vigorously for -18 hours. The reaction was poured into a
seperatory
funnel and the DCM layer was separated. The organic was washed with dilute
aqueous
HCI, brine, dried over sodium sulfate, filtered and concentrated to afford a
yellow oil which
was flashed on silica by gradient eluting with hexanes to 20% EtOAc/hexanes
over a 40
minute period. Product fractions were combined to afford the title compound.
Step 4: (Z)-N-(2-(1-(tert-butvldimethylsilyloxy)cyclopent-3-enyl ethylidene-2-
methyllpropane-2-sulfinamide
2-(1-(tert-butyldimethylsilyloxy)cyclopent-3-enyl) acetaldehyde (22g, 92mmol)
was
dissolved in DCM (500 mL). To this was added 2(R)-methylpropane-2-sulfinamide
(13g,
110mmol), followed by anhydrous cupric sulfate (128 mmol). This was allowed to
stir at
RT for 72 hours. The reaction was filtered and the resulting mother liquor was
concentrated
to a yellow oil which was purified by flash chromatography eluting with
hexanes to 20%
EtOAc/hexanes over a 40 minute period. Product fractions were combined and
concentrated to afford the product as a colorless oil.
Step 5: (2S)-N-(2-(I-(tertbutvldimethylsilyloxy)cyclopent-3-envl)-1-(2-fluoro-
5-
neopentylp ridi-3-yl)ethyl)-2-methylpropane-2-sulfinamide
In a flame dried flask, 2,2,6,6-tetramethyl piperidine(6.3mL, 37.lmmol) was
added to THE
(20mL). Chilled to -78 C under nitrogen. To this was added dropwise n-
butyllithium
(1.6M in hexanes, 12 mL, 30.3mmol). After stirring an additional 5 minutes at -
78 C, the
reaction was removed from the ice bath and allowed to warm to 0 C and then
recooled to -
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78 C. 2-fluoro-5-neopentyl pyridine (4.5g, 27mmol) was added dropwise over a 5
minute
period. This was allowed to stir for 30 minutes before adding dropwise (Z)-N-
(2-(1-(tert-
butyldimethylsilyloxy) cyclopent-3-enyl)ethylidene-2-methylpropane-2-
sulfinamide (11.6g,
33.7mmol) over a 5 minute period. This was allowed to stir for 3 hours before
being
quenched with saturated bicarbonate solution (100 mL) and the ice bath was
removed.
Product was extracted with EtOAc (3x75 mL), washed with brine, and
concentrated to give
a yellow oil which was purified by column chromatography (20% EtOAc/hexanes).
The
desired compound is the faster running spot at Rf = 0.2, which is UV active.
These product
fractions were combined and concentrated to afford the product.
Step 6: 3',4'-dihydrospiro[cyclopent-3-ene-l,2'-pyrano[2,3-blp, ry idin]-4'-
yl)amine
2(S)-N-(2-(1-(tertbutyldimethylsilyloxy)cyclopent-3-enyl)-1-(2-fluoro-5-
neopentylpyridi-3-
yl)ethyl)-2-methylpropane-2-sulfinamide (600 mg, 1.2mmol) was dissolved in
DMSO (10
mL) under nitrogen. To this was added granulated cesium fluoride (535mg,
3.5mmol). The
mixture was heated at 130 C under nitrogen for 8 hours, then cooled to Rt and
poured onto
200 mL of saturated sodium bicarbonate. The product was extracted with EtOAc
(3x75
mL). Washed with brine, dried over sodium sulfate, filtered and concentrated
to give a
yellow oil which was dissolved in methanol (10 mL). To this was added 4N HCI
in dioxane
(20mL). This was allowed to stir at RT for 1 hour, and concentrated to a
yellowish residue.
The crude salt was free based with 10% sodium carbonate, dried and
concentrated to afford
the free amine product. MS m/z: 273.2 (M+1)
Step 7: N-((I S 2R)-3-(((4'S)-6'-(2 2-dimethylpropyl)-3' 4'-
dihydrospiro[cyclopent-3-ene-
1,2'-p ry anor2,3-b]pyridinl-4'-yl)amino)-I-((4-fluorophenyl)methyl)-2-
h droxypropyl)acetamide
The title compound was obtained using 3',4'-dihydrospiro[cyclopent-3-ene-1,2'-
pyrano[2,3-b]pyridin]-4'-yl)amine in a method analogous to that described in
Example
464 below, Steps 8-10. MS found: m/z: 496 (M+1).
Example 464
N-((1 S,2R)-1-((3-chloro-5-fluorop henyl)methyl)-3-(((4' S)-6'-ethyl-3',4'-
dihyd rospiro[cyclobutane-1,2'-pyrano[2,3-b] pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
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Step 1. (S)-2,3-bis(tent-butyldimethylsilyloxy)propyl 4-methoxybenzoate
To a 1.0 L RB flask containing (R)-2,3-dihydroxypropyl 4-methoxybenzoate
(4.800 g,
21.2 mmol; according to the procedure described in Corey, E.J.; Guzman-Perez,
A.; and
Noe, M.C..J. Am. Chem. Soc. 1995,117,10805-10816) was added DCM (100 mL) and
the mixture was allowed to stir at 0 C for 5 minutes. At this time, TEA (8.87
ml, 63.7
mmol) was added and the reaction was allowed to stir for 5 min before the
dropwise
addition of tert-butyldimethylsilyl triflate (10.2 ml, 44.6 mmol) via syringe.
The reaction
was allowed to stir for 1 h and then quenched by pouring into HCl (0.1 N, 100
mL). The
aqueous layer was extracted with DCM (2 x 75 mL). The combined organics were
washed with HCl (0.1 N, 2 x 150 mL), sodium bicarbonate (1 x 150 mL, sat),
brine, dried
sodium sulfate. The concentrated solution was passed through a plug of silica
gel to and
concentrated to give the title compound as a colorless oil.
Step 2: (S)-2,3-bis(tert-butyldimethylsilyloxy)propan-l-ol To a 1.0 L RB flask
'containing (S)-2,3-bis(tert-butyldimethylsilyloxy)propyl 4-methoxybenzoate
(9.200 g, 20
mmol) was added DCM (100 mL) and the mixture was allowed to stir at -78 C for
5
minutes. At this time, DIBAL-H (1.0 M, hexanes) (61 ml, 61 mmol) was added via
a
syringe. The reaction was allowed to stir for 30 min and then quenched with
MeOH (4.1
ml, 101 mmol). Sodium patassium tartate (sat, 200 mL) and DCM (100 mL) was
added
and the solution was allowed to warm to 23 C and stirred for 3 h. The aq.
layer was
extracted with DCM (3 100 mL). The combined organics were washed with brine
and
dried with sodium sulfate and concentrated to give a residue.
Step 3: (R)-2,3-bis(tart-butyldimeth lsilyyloxy)propanaldehyde
To a 500 mL RB flask containing (S)-2,3-bis(tert-butyldimethylsilyloxy)propan-
l-ol
(4.70 g, 14.7 mmol) was added DCM (100 mL ) and the mixture was allowed to
stir at
23 C for 2 minutes. At this time, SODIUM BICARBONATE (3.69 g, 44.0 mmol) and
Dess-MartinPeriodinane (7.46 g, 17.6 mmol) were added in one portion and the
reaction
was allowed to stir for 1.5 h. The reaction was quenched by the addition of
SODIUM
THIOSULFATE (6.95 g, 44.0 mmol) in one portion followd by sodium bicarbonate
(sat,250 mL) and diethyl ether (250 mL). The quenched reaction was allowed to
stir for
45 min and then the clear layers were separated. The organic layer was washed
with
sodium bicarbonate (2 x 250 mL), water (1 x 250 mL) and brine (1 x 100 mL).
The
organic layer was dried with magnesium sulfate, filtered and concentrated to
give 5.00 g
of a colorless oil. Rf = 0.80 in 20% EtOac in hexanes, not UV, stains
pink/orange to
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anisaldehyde. The aq. layers were back extracted with ether (2 x 125 mL). The
combined back extractions were washed with brine, dried with magnesium
sulfate,
filtered and concentrated to give less than 200 mg of oil.
Step 4: (S,E)-N-((S)-2,3-bis(tert-butyldimethylsilvloxy)propylidene)-2-
methylpro ap ne-2-
sulfinamide
To a 500 mL RB flask containing (R)-2,3-bis(tert-
butyldimethylsilyloxy)propanal (4.670
g, 14.7 mmol) was added DCM (100 mL) and the mixture was allowed to stir at 23
C for
2 minutes. At this time, (S)-2-methylpropane-2-sulfinamide (2.13 g, 17.6 mmol)
and
COPPER(II)SULFATE (5.85 g, 36.6 mmol) (100 g Fluka bottle) were added and the
reaction was allowed to stir for 3 days. At this time tlc showed that all of
the aldehyde
was consumed. The crude reaction mixture was filtered through a plug of
celite7 in order
to remove the solid copper salt. The organic layer was concentrated to give
7.50g of oil,
which was subjected to a 330g Isco column 10-35%EtOAc in hexanes to give the
title
compound as a white solid. rf = 0.50 in 20% EtOAc in hexanes, UV active and
stains
yellow to anisaldehyde.
Step 5: (S)-N-((2S.3 S)-3.4-bis(tert-butyldimethylsilyloxy)-1-(3-chloro-5-
fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide
A 500 mL RB flask containing (3-chloro-5-fluorobenzyl)magnesium chloride, 0.25
M in
diethyl ether (13040 l, 3260 gmol) was allowed to stir at -78 C for 5
minutes. At this
time, TMEDA (492 l, 3260 gmol) was added via a syringe and then THF (10 mL)
was
added via a syringe and the mixture was allowed to stir for 15 min before the
addition of
(S,E)-N-((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-
sulfinamide (550.00 mg, 1304 gmol) (14 mL THF) via a syringe. The reaction was
allowed to stir for 30 min and then quenched with ammonium chloride (sat, 100
mL).
The aq. layer was extracted with EtOAc (3 x 100 mL). The combined organics
were
washed with brine and dried with sodium sulfate. The dried solution was
filtered and
concentrated to give 1.30 g of a crude oil that was purified on a 120g ISCO
column to
give the title compound. Rf = 0.40 in 20 % EtOAc in hexanes.
Step 6: (S)-N-((2S.3S)-3-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-
fluorophenyl)-4-
hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide
To a 50 mL polypropylene bottle containing (S)-N-((2S,3S)-3,4-bis(tert-
butyldimethylsilyloxy)- 1-(3-chloro-5-fluorophenyl)butan-2-yl)-2-methylpropane-
2-
sulfinamide (350.00 mg, 618 gmol) was added THF (10 mL) and the mixture was
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allowed to stir at 0 C for 5 minutes. At this time, PYRIDINE (2699 l, 33371
mol) was
added via syringe before the addition of HF-Pyridine, 70% HF 30% pyr (1782 l,
19775
mol) via a syringe. The reaction was allowed to stir at this temp for 2h and
then
quenched by pouring into sodium bicarbonate (sat 150 ml). The aq. layer was
extracted
with EtOAc 94 x 75 mL). The combined organics were washed with HCl (0.1 N, 3
X. 100
mL), bicarbonate (sat, 100 mL), brine and dried with sodium sulfate. The dried
solution
was filtered and concentrated to give a yellow oil which was purified on a 40
g ISCO
column to give the title compound.
Step 7: (S)-N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-I-(3-chloro-5-
fluorophenyl)-4-
oxobutan-2-vl -2-methylpropane-2-sulfinamide
To a 250 ml rbf was added (S)-N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-
chloro-5-
fluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (160.00 mg)
and
DCM (10 ml) followed by SODIUM BICARBONATE (148.7 mg, 5 eq) and Dess-
MartinPeriod inane (195.1 mg, 1.30 eq). The reaction was allowed to stir for 2
h and then
quenched with sodium bicarbonate (sat, 100 mL) and added SODIUM THIOSULFATE
(391.7 mg, 2477 gmol) along with diethyl ether (100 ml). The quenched reaction
was
allowed to stir for 2 h and then the aq. layer was extracted with ether (3 x
75 mL). The
combined organics were washed with brine and dried with magnesium sulfate,
filtered
and concentrated to give 1280 mg of a solid/oil mixture, which was purified on
a silica
gel column (20% EtOAc in hexanes) to give the title compound as a colorless
oil.
Step 8: (S)-N-((2S,3R)-3-(tert-butyldimethylsilyloxy)-1-(3-chloro-5-
fluorophenyl -4-((S)-
6-ethyl-2,2-spiroc cl~tyl-3,4-dihydro-2H-pyranol2 3-blp idin-4-ylamino)butan-2-
yl)-
2-methylpropane-2-sulfinamide
To a 150 mL rbf containing (S)-N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-
chloro-5-
fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (75.00 mg, 167
mol)
was added DCE (3mL) and the mixture was allowed to stir at 23 C for 2 minutes.
At this
time, 6-ethyl-2,2-spirocyclobutyl-8-azachromanyl-4-amine (36 mg, 167 pmol) was
added
in DCE (5mL) and TRIMETIIYL ORTHOFORMATE (276 jil, 2500 pmol) was added
via a syringe. The reaction was allowed to stir for 20 min when FIA/MS
indicated that
imine had formed. At this time, SODIUM TRIACETOXYBOROHYDRIDE (141 mg,
667 mol) was added in one portion and the reaction was allowed to stir for 12
h. The
reaction was quenched by the addition of sodium carbonate (10%, 30 mL) and
diluted
with DCM (50 mL). The aq. layer was extracted with DCM (3 x 50 mL). The
combined
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organics were washed with brine and dried with sodium sulfate. The dried
solution was
passed through a plug of silica gel and eluted with EtOAc, concentrated and
placed on a
high vacuum to give the title compound as a colorless oil.
Step 9: (2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-1-((S)-6-ethyl-2.2-
spirocyclobut~l-
3,4-dihydro-2H-pyrano(2,3-blpyridin-4-ylamino)butan-2-ol
To a 100 mL rbf was added MeOH (l OmL) and the mixture was allowed to stir at
0 C
for 5 minutes. At this time, ACETYL CHLORIDE (2518 l, 35409 gmol) was added
via
syringe and the reaction was allowed to stir for 20 min before it was added to
a flask
containing Reactant 1 (105.00 mg, 161 mol). The reaction was allowed to stir
at 23 C
for 24 h and checked by LC/MS. The reaction was allowed to stir an additional
2 days
and then the solvents were removed by rotary evaporator. The residue was
placed on a
high vacuum for 3 h. Note that acetyl chloride reacts with anhydrous MeOH,
generating
methylacetate and HCI. In the described procedure above, HC1 is the reactive
reagent for
the removal of sulfinyl or other protecting groups involved in the synthesis
of this
compound or analogs. Alternatively, commercially available reagent HC1(e.g.,
4.0 M in
dioxane) can be used directly.
Step 10: N-((1S,2R)-I-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6'-ethyl-
3',4'-
dihydrospirolcyclobutane-1,2'-p rrano[2,3-blpyridinl-4'-yl)amino)-2-
h ydroxypropyl)acetamide
The title compound was prepared using 1-(1H-imidazol-1-yl)ethanone (18 mg, 159
gmol)
and (2R,3S)-3-amino-4-(3-chloro-5-fluorophenyl)-1-((S)-6-ethyl-2,2-
spirocyclobutyl-3,4-
dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2-ol in DMF. The crude
reaction was
injected into a reverse phase HPLC and the clean fractions were collected and
extracted
after adding sodium carbonate (3 x EtOAc). The combined organics were washed
with
brine, dried with sodium sulfate and concentrated to give the title compound
as a white
solid. MS Found: m/z: 476 (M+1).
Example 465
N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-
1,2'-
pyrano [2,3-b] pyridin]-4'-yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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Step 1: (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxv)-1-(3-
fluorophenyl)butan-2-vl)-
2-methylpropane-2-sulfinamide The title compound was prepared by the method
described in Example 464, Step 5 using 3-fluorobenzyl)magnesium chloride (0.25
M in
diethyl ether) (139 ml, 35 mmol), TMEDA (5.2 ml, 35 mmol) and (S,E)-N-((S)-2,3-
bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide
(4.890 g, 12
mmol).
Step 2: tert-Butyl (2S,3S)-3-(tert-butyldimethvlsilyloxy)-l-(3-fluorophenyl)-4-
hydroxybutan-2-vlcarbamate
To a 500 mL RBF containing (S)-N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-
1-(3-
fluorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (2.600 g, 4.9mmol) was
added
EtOH (25 ml) and the mixture was allowed to stir at 0 C for 15 min. At this
time, HCI
(4N in dioxane) (3.7 ml, 15mmol) was added via syringe. The reaction was
monitored at
lh by LC/MS 76877-2-1 and tic (100% EtOAC amino bis TBS; Rf= 0.80 UV active
stains orange to anisaldehyde amine with primary alcohol deprotected Rf = 0.45
to 0.1
streak, UV active and stains white to anisaldehyde). The reaction was allowed
to stir for
3 h at 0 C and then TEA (4.1 ml, 29 mmol) was added fast dropwise and a white
solid
formed. An LC/Ms was obtained to confirm that the secondary TBS ether was not
removed during the TEA neutralization process. Approximately 15 mL of EtOH
were
removed by rotary evaporator and then DCM (10 mL) was added and the solid went
into
solution. At this time, (BOC)20 (2.3 ml, 9.8 mmol) was added in one portion
and the
reaction was allowed to stir for 1 h and then poured into diethyl ether (300
ml). The
organic layer was washed with ammonium chloride (3 x 150 mL, sat) and brine.
The
organic layer was dried with magnesium sulfate, filtered and concentrated to
give a
colorless crude oil. The desired product has an Rf = 0.40 in 35% EtOAc in
hexanes, UV
active, stains white to anisaldehyde and purple to moly stain. The crude oil
was purified
on a 120g Isco column (10 to 35% EtOAc in hexanes) to give the title compound
as a
colorless oil.
Step 3: Tert-Butyl (2S,3S)-3-(tert-butvldimethylsilyloxy)-1-(3-fluorophenyl)-4-
oxobutan-
2-vlcarbamate
To a 150 mL RBF containing tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-1-
(3-
fluorophenyl)-4-hydroxybutan-2-ylcarbamate (170.00 mg, 411 mol) was added DCM
(10 mL) and the mixture was allowed to stir at 23 C for 2 minutes. At this
time, pyridine
(299 l, 3699 mol) was added via syringe before the addition of Dess-
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MartinPeriodinane (262 mg, 617 .tmol) in one portion. The reaction stayed a
clear
solution and was allowed to stir 1 h before loading directly to a silica gel
column (20%
EtOAc). The purified product was concentrated to give the title compound as a
colorless
oil.
Step 4: N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethyllpropyl)-3',4'-
dihvdrospiro[cyclobutane-1,2'-
pyranof2,3-blpyridinl-4'-yl)amino)-1-((3-fluorophenyl)methyi)-2-
hydroxypropyl lacetamide
The title compound was prepared using the methods described in Example 464,
steps 8-
herein. The final product was purified by reverse phase HPLC and the pure
fraction
10 was lyophilized to give the title compound as a white solid. MS Found m./z:
484(M+1).
Example 466
N-((2S,3R)-4-((S)-2,2-spirocyclop ropyl-6-neopentyl-3,4-dihydro-2H-pyranoj2,3-
b]pyridin-4-ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)acetamide
Step 1: 1-(2,2-dimethoxyethyl)cyclopropanol
To a 1 A L RBF containing methyl 3,3-dimethoxypropanoate (17.6500 g, 119 mmol)
was
added THE (150 ml) and diethyl ether (150 ml), and the mixture was allowed to
stir at
0 C for 15 min. At this time, tetra-isopropoxy titanium (6.98 ml, 23.8 mmol)
was added
in one portion before the dropwise addition of ethylmagnesium bromide (99.3
ml, 298
mmol) via syringe. The reaction was allowed to warm to 23 C and stir for 14
hours
before being re-chilled to 0 C. After 5 min at this temp, water (15 ml) was
added and a
solid formed. Diethyl ether (200 ml) was added and the quenched reaction was
stirred for
10 min before filtering through a plug of magnesium sulfate. The filtrate was
dried with
additional magnesium sulfate, filtered and concentrated to give a colorless
oil. The crude
material was used directly in the next reaction.
Step 2: 2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)acetaidehyde
To a 2.0 L RBF containing 1-(2,2-dimethoxyethyl)cyclopropanol (17.400g, 119
mmol)
was added DCM (550 ml) and the mixture was allowed to stir at 0 C for 15 min.
2,4,6-
Collidine (63.1 ml, 476 mmol) was added and the reaction was allowed to chill
for 5 min
before the addition of tert-butyldimethylsilyl triflate (27.3 ml, 119 mmol)
over 10 min.
The reaction was allowed to stir for 20 min and then analyzed by tic which
showed that
all of the tertiary alcohol had been protected as its TBS ether. So,
triethylsilyl
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trifluoromethanesulfonate (53.8 ml, 238 mmol) was added via syringe over 10
min. After
20 min, tlc showed all of the material was converted to a baseline Rf material
(mixed
acetal) and then water (300 mL) was added and the reaction was allowed to stir
overnight.
The layers were separated. The DCM was washed with dilute HCI to remove the
2,4,6-
collidine. The aq. layer was back extracted with DCM. The combined organics
were
washed with sodium bicarbonate, brine, dried with sodium sulfate and filtered
though a
plug of silica gel. Desired fractions were collected to give the product.
Step 3: (R.E -N-(2-(I-(tert-butyldimeth l~silyloxy)cyclonropyl)ethylidene)-2-
methylpropane-2-sulfin amide
To a 1.0 L round bottom flask containing 2-(1-(tert-
butyldimethylsilyloxy)cyclopropyl)acetaldehyde (5.00 g, 23.3 mmol) (crude 10.5
g with
TESOH, IH NMR showed about 50/50 sin to impurity) was added DCM (200 mL) and
the mixture was allowed to stir at 23 C for 5 min. At this time, (R)-2-
methylpropane-2-
sulfinamide (2.83 g, 23.3 mmol) and cupric sulfate anhydrous (2.58 ml, 58.3
mmol) were
added and the reaction was allowed to stir for 40h. The copper salts were
removed by
celite filtration. The filtrate was concentrated to give a yellow oil that was
purified on a
330g Isco column (5 to 20% EtOAc in hexanes)to afford the title compound as a
colorless
oil.
Step 4: (26R)-N-(2-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-I -(2-fluoro-5-
neopentylpyridin-3-vl)ethyl)-2-methylpropane-2-sulfinamide Prepared following
the
procedure described for Example 272, Step 7 utilizing 2,2,6,6-
tetramethylpiperidine (2.21
ml, 13.0 mmol), butyllithium (4.62 ml, 11.6 mmol), 2-fluoro-5-
neopentylpyridine (1.610
g, 9.63 mmol), and (R,E)-N-(2-(1-(tert-
butyldimethylsilyloxy)cyclopropyl)ethylidene)-2-
methylpropane-2-sulfinamide (3.97 g, 12.5 mmol). The desired product is the
stereoisomer with higher Rf (approx 3:1 ratio) (Rf = 0.45 in 35% EtOAc in
hexanes).
Step 5: (S)-1-(2-amino-2-(2-fluoro-5-neopentylpyridin-3-yl)ethyl)cyclopropanol
To a 500 mL RBF containing (26R)-N-(2-(1-(tert-
butyldimethylsilyloxy)cyclopropyl)-1-
(2-fluoro-5-neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (1.03
g, 2.12
mmol) was added THE (13 ml) and the mixture was allowed to stir at 23 C for 5
min. At
this time, TBAF (1.00 M in THF) (2.12 ml, 2.12 mmol) was added and tic showed
that
the TBS group was removed in the first 5 min. After 30 min, tlc showed that a
rearrangement started to occur at 23 C (higher Rf spot = 0.80 in 35% EtOAc in
hexanes,
UV active, stains pink to anisaldehyse). So, EtOH (5 ml) and HCI (4 N in
dioxane, 5 ml)
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were added and the reaction was allowed to stir for lh. The solution was
poured into
sodium bicarbonate and extracted with EtOAc. The combined organics were washed
with
brine, dried with sodium sulfate, filtered and concentrated to give the title
compound as a
crude, colorless oil.
Step 6: (S)-2,2-spirocyclopropyl-6-neopentyl-3,4-dihvdro-2H-pyrano[2,3-
blpyridin-4-
am ine
To a 500 mL RBF containing 1-(2-amino-2-(2-fluoro-5-neopentylpyridin-3-
yl)ethyl)cyclopropanol (crude) (750.00 mg, 2816 mol) was added THE (200 mL)
and
the mixture was allowed to stir at 23 C for 5 min. At this time, KbLMDS (0.5 M
in
toluene) (5632 Etl, 2816 gmol) was added via syringe over 2 min. TLC at 10 min
showed
all of the starting material was consumed and converted to slightly lower Rf
compound.
The reaction was poured into sodium carbonate (10%, 100 ml) and extracted with
EtOac
(2 x 100 ml). The combined EtOAc were washed with brine, dried with sodium
sulfate,
filtered and concentrated. The aq. layers were combined and then back
extracted with
DCM. The combined organics was concentrated and the resulting residue purified
through a short silica gel column (EtOAc to 10% MeOH (2 M in NH3) in EtOAc to
give
the title compound as a yellow oil.
Step 7: N-((2S.3R)-4-((S -2,2-spirocvclopropyl-6-neopentyl-3.4-dihvdro-2H-
pvrano[2 3-
blpyridin-4-ylamino)-I-(4-fluorophenyl -3=hydroxybutan-2-yl)acetamide
The title compound was prepared by a method analogous to that described in
Example
464, steps 8-10, and the title compound was purified by reverse phase HPLC and
isolated
as a white solid. MS Found: m/z: 470 (M+1).
Example 467
XNC 25
S
ynthesis of (S)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-
pyrano[2,3-c) pyridin-4-amine
Step 1: 2-bromo-5-(methoxymethoxy)p ridine
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To a solution of 6-bromopyridin-3-ol (25 g, 144 mmol) in DMF (300 mL) at 0 C
under
N2 is added portionwise NaH (5.7 g, 144 mmol) over 5 min. The reaction was
stirred I h,
then chloro(methoxy)methane (12 g, 144 mmo]) was added and the reaction
stirred an
additional 1 h at 0 C. Saturated sodium bicarbonate (500 mL) was added slowly
and the
suspension stirred 30 min and warmed to rt. The solution was extracted with
EtOAc (3 x
400 mL), the combined organic layers washed with H2O (500 mL), saturated NaCI
(500
mL), dried (Na2SO4), and concentrated in vacuo to give the title compound as a
brown oil.
Step 2: 5-(methoxymethoxy)-2-neopentylpyridine
To a solution of 2-bromo-5-(methoxymethoxy)pyridine (30.5 g, 140 mmol) in THE
(5
mL) at 0 C under N2 is added dichloro-((bis-diphenylphosphino)ferrocenyl)-
palladium(II)(4.88 g, 5.5 mmol) followed by dropwise addition of
neopentylmagnesium
chloride (155 mL, 155 mmol) over 2 min. After addition, the cooling bath was
removed
and the reaction stirred 3 h at rt. The reaction was cooled to 0 C and
saturated NH4CI
(500 mL) was added, and the aqueous layers extracted with EtOAc (3 x 200 mL).
The
combined organic layers were washed with saturated NaCl, dried (Na2SO4) and
concentrated to give a red oil. Purification by vacuum filtration through a
silica plug (9 x
7 cm, dry load, 10-20%% EtOAc/Hexanes) gives 5-(methoxymethoxy)-2-
neopentylpyridine as a light yellow oil.
Step 3: 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol
To a solution of 5-(methoxymethoxy)-2-neopentylpyridine (16.5 g, 79 mmol) and
in THE
(200 mL) -78 C is added tert-butyllithium (46 ml, 79 mmol) (1.7 M in pentane )
over 2
min via cannula. The reaction was stirred at -78 C 30 min, and acetaldehyde (I
1 ml, 197
mmol) was added. The reaction was stirred at -78 C 10 min, then the reaction
was
warmed to rt and stirred 3 h. The reaction was quenched by addition of
saturated aqueous
N144CI (400 mL), extracted with EtOAc (3 x 200 mL), the combined organic
layers
washed with saturated NaCI (10 mL), dried (Na2SO4), and concentrated to give a
orange
oil, which was purified by chromatography on an ISCO (330 g Si02, 10%-50%
EtOAc/Hexane) gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol as a
clear, light yellow oil.
Step 4: 1-(5-(methoxvmethoxy)-2-neopentylpyridin-4-vl)ethanone
To a solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol (24.4
g, 96.3
mmol) and sodium bicarbonate (32.4 g, 385 mmol) in CHC13 (500 mL) at 0 C was
added
Dess-Martin Periodinane (53.1 g, 125 mmol). The reaction was stirred 5 h,
quenched
with saturated aqueous Na2SO3 (300 mL), extracted with CH2CI2 (3 x 250 mL),
the
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combined organic layers washed with saturated NaCl (300 mL), dried (Na2SO4),
and
concentrated to give a yellow oil. Purification by ISCO (330 g SiO2, 20%
EtOAc/Hexane) gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone as
a
clear, colorless oil.
Step 5: ]-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone
A solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone (21.6 g,
86
mmol) in (2:1:1) 5 M HCI : i-PrOH : TI-IF (800 mL) was stirred 4 h at rt. The
mixture
was concentrated to remove the TIC' and i-PrOH. The resulting solution
consisting of the
product in aqueous HCI was quenched by slow addition to a solution of
saturated aqueous
NaHCO3 (500 mL) containing excess solid NaHCO3 (50 g). The aqueous layer was
extracted with CH2CI2 (3 x 250 mL), the organic layers combined and washed
with
saturated aqueous NaCl (250 mL), dried (MgSO4), and concentrated to give 1-(5-
hydioxy-2-neopentylpyridin-4-yl)ethanone as a brown oil.
Step 6: 2 2-spiroc cly obu 1-6-neopentyi-2 3-dihvdrop rrano[2 3-c]pyridin-4-
one
A mixture of 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone (14.8 g, 71 mmol)
(76894-
11), Hiinig's base (12 ml, 71 mmol) pyrrolidine (8.9 ml, 107 mmol), and
cyclobutanone
(13 ml, 179 mmol) in toluene (300 mL) with a Dean-Stark trap was heated in a
140 C oil
bath for 2 h. The mixture was cooled to rt, then diluted with EtOAc (25 mL),
washed
with H2O, saturated aqueous NH4CI, saturated aqueous NaCI, dried (MgSO4), and
concentrated. Purification by ISCO (120 g Si02, 10-20% EtOAc/Hexane) gives the
title
compound as a yellow solid.
Step 7: 2 2-spirocyclobu l-6-neopentyl-7-oxo-2 3-dihvdrop ry ano [2 3
clpyridin 4 one
2,2-spiroeyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4-one (5.00 g,
19
mmol) was dissolved in 100 ml CHC13 and cooled to 0 C, mCPBA (10.0 g, 58 mmol)
was added portionwise and the reaction was stirred under N2 and allowed to
warm slowly
to rt; stirring was continued for 17 h. The mixture was then cooled to 0 C, IM
NaOH
(100 mL) was added, and stirring was continued vigorously for 10 min. The
mixture was
extracted with CH2C12 (3 x 100 mL), the combined organic layers washed with
saturated
sodium chloride (100 mL), dried (Na2SO4) and evaporated to give the title
compound as a
white solid.
Step 8: 8-chloro-2 2-spiroc lobu l-6-neopentyl-2 3-dih dro pyranof2 3
clpyridin 4 one
2,2-spirocyclobutyl-6-neopentyl-7-oxo-2,3-dihydropyrano[2,3-c]pyridin-4-one.
(5.3 g, 19
mmol) was taken up in phosphoryl trichloride (20 mL, 218 mmol) and the mixture
was
heated to 80 C for 2 h under N2. The reaction mixture was quenched by slow
addition to
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vigorously stirred cold 10% aqueous NaCO3 (300 mL), extracted with EtOAc (3 x
200
mL), the combined organic layers were washed with saturated NaCl (200 mL),
dried
(Na2SO4), and concentrated to give a brown oil. Purification by ISCO (120 g
Si02, 10%
EtOAc/Hexane) gives the title compound as a light yellow solid.
Step 9: (R)-8-chloro-2,2-spiroc cl~ obutyl-6-neopentyl-3,4-dihvdro-2H
pyranof2,3-
c]pyridin-4-ol
To a stirred solution of (s)-2-methyl-cbs-oxazaborolidine (1.7 ml, 1.7 mmol)
in THE (20
mL) at 0 C is added borane-methyl sulfide complex (14 ml, 28 mmol) followed by
a
solution of 8-chloro-2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-
c]pyridin-4-
one (4.90 g, 17 mmol) in THE (40 mL) dropwise via syringe pump over 2.8 h. The
reaction was stirred an additional 30 min, then was quenched by dropwise
addition (1
drop/10 sec) of 5 M HCI (25 mL) at 0 C, after 15 mL HCI was added, bubbling
had
ceased and the addition rate was increased as the ice bath was removed. The
reaction was
stirred an additional 2 h at rt. The reaction was recooled to 0 C and
neutralized with 5 M
NaOH (27 mL). The mixture was then extracted with EtOAc (2 x 150 mL), washed
with
saturated aqueous NaCl (200 mL), dried (MgSO4), and concentrated in vacuo.
Purification by ISCO (120 g SiO2, 20% EtOAc/Hexane) gives the title compound
as a
white foam.
Step 10: (S)-4-azido-8-chloro-2,2-spiroc clobutyl-6-neopentyl-3,4-dihvdro-2H-
pyranof2,3-c]p rim
To a solution of (R)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-
pyrano[2,3-c]pyridin-4-ol (2.33 g, 7.9 mmol) in toluene (43 mL) is added
diphenylphosphoryl azide (2.4 ml, 11 mmol) then 1,8-diazabicyclo(5.4.0)-7-
undecene
(1.6 ml, 11 mmol). The reaction was stirred under N2 at rt 4 days. The clear,
light yellow
solution first turned into a yellow cloudy/opaque solution after 10 min. Water
(100 mL)
was added and the reaction mixture extracted with EtOAc (3 x 100 mL). The
combined
organic layers were washed with saturated NaCl (150 mL), dried (MgSO4), and
concentrated to give the title compound as a brown oil which was used in the
next step
without purification.
Step 11: (S)-8-chioro-2 2-spirocyclobutyl-6-neopentvl-3 4-dihvdro-2H-pyranof2
3-
c]pyridin-4-amine
To a solution of (S)-4-azido-8-chioro-2,2-spirocyclobutyl-6-neopentyl-3,4-
dihydro-2H-
pyrano[2,3-c]pyridine (2.21 g, 6.9 mmol) in 10:1 THF/H20 (44 mL) at 0 C is
added
NaOH (3.0 ml, 15 mmol) (5 N). After 5 min, trimethylphosphine (2.4 ml, 28
mmol) was
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added dropwise over 4 min. The reaction went from brown to pink to purple as
N2
evolution occurred. The ice bath was allowed to melt as the reaction warmed to
rt and
stirred a total of 15 h. The mixture was re-cooled to 0 C and 5 N HCI (25 mL)
was
added. The resulting mixture was extracted with EtOAc (3 x 50 mL), the
combined
organic layers were washed with 2.5 N HCl (2 x 25 mL). The combined aqueous
layers
were cooled to 0 C and basified to pH 14 with 5 N NaOH (100 mL). The aqueous
layer
was extracted with EtOAc (3 x 50 mL) the combined organic layers dried
(Na2SO4), and
concentrated to give the crude product as a viscous yellow oil. The combined
organic
layers were combined with the crude product from above and concentrated to
give a crude
yellow oil. Purification of the crude oil by flash chromatography (5 x 15 cm
Si02, 0-10%
McOH/CH2CI2 gradient elution) gave the title compound as a yellow oil.
Example 468
N-((1S,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4'-
dihyd rospiro [cyclobutane-1,2'-pyrano [2,3-c] pyrid in]-4'-yl)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxy propyl)acetamide
The title compound was synthesized in manner analogous to that of Example 466,
using
(S)-8-chl oro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano [2,3-
c]pyridin-4-
amine and N-((2S,3S)-3-(tert-butyldimethylsilyloxy)-I -(3-fluorophenyl)-4-
oxobutan-2-
yl)acetamide to obtain the title compound as a colorless solid. MS m/z:
518.2(M+1).
Example 469
N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-8-(methylamino)-6-neopentyl-3,4-dihydro-
2H-
pyrano [2,3-c]pyridin-4-ylamino)-1-(3-fluorophenyl)-3-hyd roxybutan-2-
yl)acetamide
To a flame-dried microwave vial under argon is added N-((l S,2R)-3-(((4'S)-8'-
chloro-6'-
(2,2-d imethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-
c]pyridin]-4'-
yl)amino)-I-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide(60 mg, 95
mol),
Pd2dba3 (17 mg, 19 limol), and DavePhos (16 mg, 42 gmol). The vial was purged
with
N2 5 x, then methanamine (949 l, 1898 gmol) and LiHMDS (475 l.el, 475 limol,
1.0 M in
THF) were added. The vial was sealed and heated in a microwave at 110 C for 10
min.
The reaction mixture was directly purified by reverse phase HPLC on a
Phenomenex
Synergi column (5 micron, MAX-RP, 80 A, 150x30 mm) eluting at 45 ml/min with
an
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linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA)
over 30
minutes to give to give the title compound as a white amorphous solid. MS
rn/z:
513.2(M+1).
Example 470
N-((1S,2R)-3-(((4' S)-6'-(2,2-dimethylpropyl)-8'-(methyloxy)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c] pyridin]-4'-yl)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
To a 2 mL microwave vial is added cesium carbonate (283 mg, 869 l.tmol), di-
tert-
butyl(2-(2-isopropylnaphthalen-1-yl)-3,4,5,6-tetramethylphenyl)phosphine (71
mg, 159
mol), palladium(II) acetate (33 mg, 145 mol), and N-((I S,2R)-3-(((4'S)-8'-
chloro-6'-
(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-
4'-
yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide(75 mg, 145
mol)
were added and the vial was flushed with N2 5x, then methanol (160 l, 3619
gmol) and
toluene (1 mL) were added simultaneously. The reaction was heated in the
microwave at
110 C for 30 min. LCMS shows 100% conversion. The reaction mixture was
filtered
through a small plug of silica gel, and the residue purified by reverse phase
HPLC on a
Phenomenex Synergi column (5 micron, MAX-RP, 80 A, I50x30 mm) eluting at 45
ml/min with an linear gradient of 10%(v/v) to 100% MeCN (0.1% v/v TFA) in
water
(0.1% TFA) over 30 minutes to give the title compound as a tan amorphous
solid. MS
m/z: 514.2(M+1).
Example 471
General procedure for the synthesis of Examples 634-650 and 652, various B and
V-R2
groups of Formulas I and II
Me
MeO
~Oy N,,~OH
O-
1
SAN
(4S,5S)-tert-butyl 5-(hyd roxym ethyl)-2,2-dim ethyl-4-(thiazol-4-ylm
ethyl)oxazolidi ne-
3-carboxylate
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This compound was prepared according to a method described in Example 472,
from (S)-2-
(tert-butoxycarbonyl)-3-(thiazol-4-yl)propanoic acid.
Example 472
Me
MeO
~OUN,j,~OH
O~
SVN
Me
Synthesis of (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-
methylthiazol-
4-yl)methyl)oxazolidine-3-carboxylate
Step 1: (4S,5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-
4-(thiazol-
4- lmethyl)oxazolidine-3-carboxylate
(4S,5S)-Tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-
ylmethyl)oxazolidine-3-
carboxylate (0.096 g, 0.29 mmol) was dissolved in DMF (1 mL) with 1H-imidazole
(0.026 g, 0.38 mmol) and tert-butylchlorodimethylsilane (0.053 g, 0.35 mmol).
The
reaction was stirred 2 hrs, diluted with diethyl ether and washed twice with
water and
once with brine. The organic layer was dried over magnesium sulfate and
concentrated to
furnish the title compound, which was used for the next step without
purification.
Step 2: (4S.5S)-tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2 2-dimethyl-
4-((2-
methylthiazol-4-yl)methyl)oxazol idine-3 -carboxyl ate
(4S,5 S)-Tert-butyl 5-((tent-butyld imethylsilyloxy)methyl)-2,2-dimethyl-4-
(thiazol-4-
ylmethyl)oxazolidine-3-carboxylate (0.100 g, 0.23 mmol) was dissolved in THE
(2.5 mL)
and cooled to -78 C. n-Butyllithium (0.12 ml, 0.29 mmol) was added and the
reaction
was stirred at -50 C for 40 minutes followed by the addition of iodomethane
(0.018 ml,
0.29 mmol). After stirring 40 minutes the reaction was quenched with saturated
ammonium chloride and extracted with ethyl acetate. The combined organic
layers were
washed with water, brine, and dried over sodium sulfate to afford the title
compound. MS
m/z: 457.3 (M+]).
Step 3: (4S,5S)-tert-butyl 5-(hydroxymethyl)-2 2-dimethyl-4-((2-methylthiazol-
4-
yl)methyl)oxazolidine-3-carboxlate (4S,5S)-Tert-butyl 5-((tert-
butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylthiazol-4-yl)m
ethyl)oxazol idine-
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3-carboxylate (0.100 g, 0.219 mmol) was dissolved in THE (4mL) and cooled to 0
C. Next,
TBAF (0.547 ml, 0.547mmo1) was added dropwise and the reaction was stirred 1
hr. and
then quenched with saturated ammonium chloride and diluted with EtOAc. The
layers were
separated and the aqueous layer was extracted with ethyl acetate. The combined
organic
layers were washed with water, brine, dried over sodium sulfate, and
concentrated.
Purification by column chromatography (2.5:1 Hexanes/EtOAc) afforded the title
compound.
Example 473
Me
Me-~- O
OY N,,%-~OH
O~4
S
(4S,5S)-tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-propylthiazol-4-
yl)methyl)oxazolidine-3-carboxylate
The title compound was prepared in a manner analogous to that described in
Example 472.
MS m/z: 371.3 (M+1).
Example 474
Me
Me-- O
+0Y Nom_,;-,~OH
O
SAN
(4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((5-propylthiazol-4-
yl)methyl)oxazoli d ine-3-carboxylate
Step 1: (4S 5S)-tert-butyl 4-((2-(tert-butyldimethylsilyl)thiazol-4-yl)methyl)-
5-((tert-
butvldimethylsilyloxymethyl)-2,2-dimethyloxazolidine-3-carboxylate
(4S,5S)-Tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-
(thiazol-4-
ylmethyl)oxazolidine-3-carboxylate (0.148 g, 0.334mmol) in THE (3mL) was
cooled to -
78 C when n-butyllithium (2.5 M in hexanes)(0.160 ml, 0.401mmol) was added
dropwise. The solution was warmed to -50 C for 40 minutes and then cooled to -
78 C.
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TBS-Cl (0.0605 g, 0.401mmol) in THE (2mL) was added dropwise and the solution
was
allowed to slowly warm to 0 C when it was quenched with saturated ammonium
chloride.
The layers were separated and the aqueous layer was extracted with EtOAc. The
combined organic layers were washed with water, brine and dried over sodium
sulfate to
afford the title compound, which was used without further purification.
Step 2: (4S,5S)-tert-butyl 4-((2-(tert-butyldimethylsi] ll)-5-propylthiazol-4-
vl)methyl)-5-
((tert-butyldimethylsilyloxv methyl)-2,2-dimethyloxazolidine-3-carboxlate
(4S,5S)-Tert-butyl 4-((2-(tert-butyldimethylsilyl)thiazol-4-yl)methyl)-5-
((tert-
butyldimethylsilyloxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.150 g,
0.269
mmol) in THE (3 mL) was cooled to -78 C when N-BUTYLLITHIUM (2.5 M in
hexanes)(0. 119 ml, 0.296 mmol) was added dropwise. The solution was warmed to
-50 C
for 40 minutes and then cooled to -78 C. 1-Iodopropane (0.0549 g, 0.323 mmol)
was
added dropwise and the solution was allowed to slowly warm to -50 C and
stirred for 1
hr. The reaction was quenched with saturated ammonium chloride. The layers
were
separated and the aqueous layer was extracted with ethyl acetate. The combined
organic
layers were washed with water, brine and dried over sodium sulfate to afford
the title
compound, which was used without further purification for the next step.
Step 3: (4S,5 S)-tert-but l 5-(hy rox methyl)-2 2-dimethyl-4-((5-prop
l~thiazol-4-
yl)methyl)oxazolidine-3-carboxylate (4S,5S)-Tert-butyl 4-((2-(tert-
butyldimethylsilyl)-5-
propylthiazol-4-yl)methyl)-5-((tert-butyldimethylsilyloxy)methyl)-2,2-
dimethyloxazolidine-3-carboxylate was dissolved in THE (3mL) and cooled to 0 C
when
TBAF (0.808 ml, 0.808mmoi) was added. The reaction was stirred one hour before
being
quenched with saturated ammonium chloride. The layers were separated and the
aqueous
layer was extracted with EtOAc. The combined organic layers were washed with
water,
brine and dried over sodium sulfate to afford the title compound.
Example 475
0
+OY N O
F3C
Step 1: (S)-methyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl
propanoate
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Iodine (0.0140 g, 0.0553 mmol) was added to zinc (0.542 g, 8.29mmol) and the
solid
mixture was heated under vacuum for 10 minutes. The flask was flushed with
nitrogen three
times and allowed to cool. DMF (0.5mL, degassed with nitrogen) was added and
the
suspension was cooled to 0 C and stirred while (R)-methyl 2-(tert-
butoxycarbonyl)-3-
iodopropanoate (1.82 g, 5.53 mmol) in DMF (2.8 mL) was added dropwise. The
mixture
was stirred for 30 minutes at 0 C and then allowed to come to RT for 30
minutes. 1-Iodo-4-
(trifluoromethyl)benzene (1.50 g, 5.53 mmol),
tris(dibenzylideneacetone)dipalladium
(0.101 g, 0.111 mmol), and dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl
(S-Phos)
(0.182 g, 0.442 mmol) were added. The flask was purged with nitrogen and
heated at 40 C.
After 3 hours the reaction was allowed to cool and partitioned between EtOAc
and an
aqueous solution of -. 9:1 saturated ammonium chloride/ammonium hydroxide. The
aqueous layer was extracted with EtOAc and the combined organic layers were
washed
with water, brine, and dried over sodium sulfate. Concentration and
purification by silica
gel chromatography (6:1 Hexanes/EtOAc) afforded (S)-methyl 2-(tert-
butoxycarbonyl)-3-
(4-(trifluoromethyl)phenyl)propanoate.
Step 2: (S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenvl)propanoic
acid
(S)-Mthyl 2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoate
(6.20 g, 17.9
mmol) was dissolved in THE (180 mL) and cooled to 0 C. A 0.2 M of aq. LiOH
(89.3 ml,
17.9 mmol) was added dropwise and stirred 20 minutes before TLC analysis (2:1
Hexanes/EtOAc) showed no starting material. The PH of the reaction was
carefully
adjusted to PH = 8 with I N HCI. The aqueous layer was washed with diethyl
ether and the
organics were back extracted with 1 % aqueous sodium bicarbonate and the
combined
aqueous layers were carefully brought to a PH = 4 and extracted with EtOAc.
The
combined organic layers were washed with brine, dried over sodium sulfate, and
concentrated to afford (S)-2-(tert-butoxycarbonyl)-3-(4-
(trifluoromethyl)phenyl)propanoic
acid, which was used without further purification.
Example 476
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Me
Me/O
OyN,,,-;,~OH
O
F3C
(4S,5S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-5-(hydroxymethyl)-2,2-
dimethyloxazolidine-3-carboxylate
The title compound was prepared according to the procedures described herein
in Example
472.
Example 477
Me
MefO
Oy N,,,~OH
N
(4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-
ylmethyl)oxazolidine-
3-carboxylate
The title compound was prepared according to the procedures described herein
in Example
472.
Example 478
Me
Me-~- 0
+OyN,_~OH
O
Me
N
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(4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylpyridin-4-
yl)methyl)oxazolidi ne-3-ca rboxylate
Step 1: (4S,5S -tent-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2 2-dimethyl-
4-(pyridin-4-
l~yl)oxazolidine-3-carboxvlate
The title compound was synthesized in manner analogous to that described in
Example 472,
using (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-
ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCI and imidazole, and
was used
without further purification.
Step 2: (4S,5S)-tert-butyl 5-((tert-bu ldimethylsil loxy methyl)-2 2-dimethyl-
4-((2-
methylpyridin-4-yl)methyl)oxazolidine-3-carboxvlate
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-
(pyridin-4-
ylmethyl)oxazolidine-3-carboxylate (0.150 g, 0.344mmol) was dissolved in THE
(3.5mL)
and cooled to 0 C. Acetyl chloride (0.0256 ml, 0.361mmol) was added and the
reaction
was stirred 30 minutes before METHYLMAGNESIUM BROMIDE (0.294 ml, 0.412mmol)
was added. The reaction was stirred 1 hr. at 0 C and then warmed to RT and
quenched with
saturated ammonium chloride and diluted with EtOAc and water. The layers were
separated
and the aqueous layer was extracted with EtOAc. The combined organic layers
were
washed with a 9:1 aqueous solution of saturated ammonium chloride/ammonium
hydroxide,
water, brine, and dried over sodium sulfate. The crude product was dissolved
in
isopropylacetate (4mL) and heated to 50 C before DDQ (0.117 g, 0.515 mmol) was
added.
After 30 minutes the reaction was cooled and diluted with ethyl acetate and
washed twice
with saturated sodium bicarbonate, once with water, brine, and dried over
sodium sulfate.
The mixture was passed through a plug of silica gel with 2:1 Hexanes/EtOAc and
concentrated to afford the title compound, MS m/z: 451.3(100%, M+1)).
Step 3: (4S,5S)-tert-butyl 5-(hydrox methyl)-2 2-dimethyl-4-((2-methyllpyridin-
4-
yl methyl)oxazolidine-3-carboxvlate (4S,5S)-Tert-butyl 5-((tert-
butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylpyridin-4-
yl)methyl)oxazolidine-
3-carboxylate (0.083 g, 0.18mmol) was dissolved in THE (2mL) and cooled to 0
C. Next,
TBAF (0.28 ml, 0.28mmol) was added dropwise and the reaction was stirred 1 hr.
and then
quenched with saturated ammonium chloride and diluted with ethyl acetate. The
layers
were separated and the aqueous layer was extracted with EtOAc. The combined
organic
layers were washed with water, brine, dried over sodium sulfate, and
concentrated.
Purification by column chromatography (19:1 DCM/MeOH) afforded the title
compound,
MS m/z: 337.2 (100%, M+1).
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Example 479
Me
Me-~- 0
OUN.~~OH
IO O
CI d
N
(4S,5S)-tert-butyl 4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-
dim ethyl oxazolidine-3-carboxylate.
The title compound was prepared according to the procedures described herein
in Example
478, from (S)-2-(tert-butoxycarbonyl)-3-(2-chloropyridin-4-yl)propanoic acid.
Example 480
Me
Me-~- 0
OyN-j-~OH
O
CI ~ ~
N
Me
Step 1:(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-
chloropyridin-4-
yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate. The title compound was
synthesized in
a manner analogous to Example 475, step I via (4S,5S)-tert-butyl 4-((2-
chloropyridin-4-
yl)methyl)-5-(hydroxymethyl)-2,2-dimethyl.oxazolidine-3-carboxylate in the
presence of
TBSCI and imidazole and was used without further purification.
Step 2: (4S 5S)-tert-butyl 5-((tert-butyldimethylsilyloxv)methyl)-4-((2-chloro-
6-
methylpy_ridin-4- l)Ymeth,Yl)-2,2-dimethyloxazolidine-3-carbox
Dimethylethanolamine (0.128 ml, 1.27mmol) was added to anhydrous hexanes (1.4
L) and
cooled to 0 C. N-BUTYLLIT14 UM (2.5 M in hexanes)(1.02 ml, 2.55mmol) was added
dropwise and stirred for 30 minutes before being cooled to -78 C. (4S,5S)-Tert-
butyl 5-
((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4-yl)methyl)-2,2-
dimethyloxazolidine-3-carboxylate (0.200 g, 0.425mmo1) in hexanes (lmL) was
added
dropwise and the solution was stirred for 1 hour at -78 C to give a dark
orange solution.
Mel (0.106 ml, 1.70 mmol) in THE (3.2mL) was added dropwise and the reaction
was
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allowed to slowly warm to 0 C and was quenched with saturated aqueous ammonium
chloride. The reaction was diluted with ethyl acetate and water and separated.
The aqueous
layer was extracted with ethyl acetate and the combined organic layers were
washed with
water, brine, dried over sodium sulfate, and concentrated to give the titled
compound which
was used directly for the next step without purification.
Step 3: (4S,5S)-tert-butyl 4-((2-chloro-6-methylpyridin-4-yl)methyl)-5-(h
droxymethyl)-
2,2-dimethyloxazol id ine-3-carboxylate
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloro-6-
methylpyridin-
4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.206 g, 0.425 mmol) was
dissolved
in THE (4mL) and cooled to 0 C. TBAF (0.637 ml, 0.637 mmol) was added to the
mixture dropwise and the reaction was stirred 1 hr and then quenched with
saturated
ammonium chloride and diluted with EtOAc. The layers were separated and the
aqueous
layer was extracted with EtOAc. The combined organic layers were washed with
water,
brine, dried over sodium sulfate, and concentrated. The crude material was
purified by
silica column chromatography (19:1 DCM/MeOH) and then reverse phase HPLC to
give
the title compound. MS rm/z: 371.3 (100%, M+1).
Example 481
Me
MeO
OUN,_j~~OH
'O
MeO
N
(4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-
d im ethyloxazolidine-3-carboxylate
(4S,5S)-Tert-butyl 4-((2-chloropyridin-4-yl)methyl)-S-(hydroxymethyl)-2,2-
dimethyloxazolidine-3-carboxylate (0.200 g, 0.560 mmol) was dissolved in a 25%
solution
of SODIUM METHOXIDE (12.8 ml, 56.0 mmol) in methanol and refluxed for 12 hrs
and
cooled. The reaction was diluted with water and extracted with EtOAc. The
combined
organic layers were washed with water, brine, dried over sodium sulfate and
concentrated to
give (4S,5S)-tert-butyl 5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-
2,2-
dimethyloxazolidine-3-carboxylate, MS m/z: 353.3 (100%, M+l).
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Example 482
Me
Mel- 0
II N~~OH
+OU
O
II
N
Me
(4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((1-methyl-2-oxo-1,2-
dihydropyridin-4-yl)methyl)oxazolidine-3-carboxylate
(4S,5S)-Tert-butyl5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-
dimethyloxazolidine-3-carboxyl ate (0.281 g, 0.797 mmol) was refluxed in
methanol (17
mL) with Mel (0.0798 ml, 1.28 mmol) for 48 hrs. Concentration and purification
by silica
gel chromotography (20:1 DCM/MeOH) afforded the titled compound along with
recovered
starting material.
Example 483
Me
Me 0
OyN~OH
-
F3C----- o
N
(4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-((2-(2,2,2-
trifluoroethoxy) pyridin-4-yl)methyl) oxaazolidin e-3-carboxylate
NaH (60% by weight in mineral oil) (0.672 g, 16.8mmol) was added carefully to
trifluoroethanol (20.0 ml, 276mmol) cooled at 0 C and then stirred at RT for
30 minutes.
The resulting solution is added to (4S,5S)-tert-butyl 4-((2-chloropyridin-4-
yl)methyl)-5-
(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate (0.400 g, 1.12mmol)
dissolved in
10mL of NMP and the resulting solution was microwaved for 30 minutes fixed at
180 C.
The reaction was diluted with EtOAc and washed repeatedly with water. The
combined
aqueous layers were back extracted with EtOAc and the combined organic layers
were
washed with water, brine, dried over sodium sulfate and concentrated. The
product was
purified by silica go] chromatography (2:1 to 1:1 Hexanes/EtOAc) to afford the
title
compound. MS m/z: 421.3 (100%, M+1).
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Example 484
O
EE
>~O&f N O
SOH
S
N-(
CI
(S)-methyl 2-(tert-butoxycarbonyl)-3-(4-chlorothiazol-2-yl)propanoate
The title compound was synthesized in a manner analogous to that described
Example 475,
using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2,4-
dichlorothiazole
(prepared according to Reynaud, Pierre; Robba, Max; Moreau, Robert C; New
synthesis of
the thiazole ring; Bulletin de la Societe Chimique de France (1962), 1735-8).
MS m/z: 321
(23%, M+1), 265.0 (100%, M-55.1).
Example 485
O
cO N 0
&OH
(S)-methyl 3-(benzofuran-2-yl)-2-(tert-butoxycarbonyl)propanoate
The title compound was synthesized in a manner analogous to that described
Example 475,
using(R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 2-
bromobenzofuran. (MS
m/z: 220.1 (100%, M-99).
Example 486
O
NO
OH
NN
CF3
(S)-methyl2-(tert-butoxycarbonyl)-3-(2-(trifluoromethyl)pyrimidin-4-
yl)propanoate
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The title compound was synthesized in a manner analogous to that described
Example 475,
using(R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 4-chloro-2-
(trifluoromethyl)pyrimidine.
Example 487
O
N OSOH
~S
I` TIPS
N
(S)-methyl 2-(te rt-butoxycarbonyl)-3-(2-(triisopropylsilyl)thiazol-5-
yl)propanoate
The title compound was synthesized in a manner analogous to that described
Example 475,
using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 5-bromo-2-
(triisopropylsilyl)thiazole (prepared according to Stangeland, Eric L.;
Sammakia, Tarek,
Use of Thiazoles in the Halogen Dance Reaction: Application to the Total
Synthesis of
WS75624 B, Journal of Organic Chemistry (2004), 69(7), 2381-2385.). MS m/z:
443.3
(100%, M+1).
Example 488
N-((1R,2S)-3-(((4' S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-
1,2'-
pyrano [2,3-b] pyridin]-4'-yl)amino)-2-hydroxy-l-(4-
pyridinylmethyl)propyl)acetamide
This compound was isolated as a minor diastereomer by product following the
final step in
the synthesis of N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane- 1,2'-pyrano[2,3 -b] pyri din] -4'-yl)amino)-2-
hydroxy- 1 -(4-
pyrid inylmethyl )propyl)acetamide.
Example 489
N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-
1,2'-
pyrano[2,3-b] pyridin]-4'-yl)amino)-2-hydroxy-l-((2-oxo-1,2-dihydro-4-
pyridinyl)methyl)propyl)acetamide
N-((I S,2R)-3-(((4'S)-6'-(2,2-Dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-
1,2'-
pyrano [2,3 -b] pyri din]-4'-yl)amino)-2-hydroxy- l -((2-(methyloxy)-4-
pyridinyl)methyl)propyl)acetamide (0.150 g, 0.302mmol) and Nal (0.679 g,
4.53mmol)
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were refluxed in HOAc (3mL). After three hours the reaction was concentrated
and
dissolved in chloroform. The organic layers were washed with IN NaOH, aqueous
sodium
thiolsulfate, and brine. The organic layer was concentrated and purified
directly by reverse-
phase HPLC to afford the title product as a TFA salt. MS m/z: 483.3 (100%,
M+1).
Example 490
N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2-cyano-2-methylpropyl)-
3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano [2,3-bl pyridinl-4'-yl)amino)-2-
hydroxyp ropyl)acetam ide
Step 1: (S)-tert-butyl 6-bromo-2,2-spiroc c butyl-3,4-dihvdro-2H yrano[2 3-
b]pyridin-
4-ylcarbamate
Triethylamine (3.74 ml, 26.8 mmol) and BOC-Anhydride (5.07 g, 23.2 mmol) were
added to (S)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-
amine
(4.81 g, 17.9 mmol) in DCM (50mL) and the reaction was allowed to stir at RT
until TLC
analysis (20:1 DCM/MeOH) demonstrated the reaction to be complete (12 hrs).
The
reaction mixture was concentrated and the crude material was taken up in
EtOAc, washed
twice with saturated ammonium chloride, water, brine, and concentrated. The
product was
purified by a short column of silica gel (10:1 hexanes/EtOAC to 4:1
Hexanes/EtOAC) to
afford the titled product.
Step 2: (S -tert-butyl allyl(6-bromo-2 2-spiroc clobutyl-3 4-dihvdro-2H-
pyrano[2 3-
b]pyridin-4-yl)carbarnate
(S)-Tert-butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3 -
b]pyridin-4-
ylcarbamate was dissolved in DMF (60 mL) and cooled to 0 C. NaH (60% by weight
in
mineral oil)(0.858g, 21.4mmol) was carefully added and the solution was
allowed to stir
for 40 minutes. ALLYL BROMIDE (1.62 ml, 18.8mmol) was added and the reaction
was
stirred 45 minutes and then diluted with saturated ammonium chloride. Water
was added
and the solution was extracted with diethyl ether. The combined organic layers
were
washed with water, brine, dried over magnesium sulfate, and concentrated. The
crude
product was used without further purification. MS m/z: 409.1(100%, M).
Step 3: (S)-tert-butyl allyl(6-(hydroxymethyl)-2 2-spiroc c1Y obutyl-3 4-
dihvdro-2H-
pyrano[2,3 -b]pyridin-4-yl)carbamate
(S)-Tert-butyl ally](6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-
b]pyridin-4-
yl)carbamate (7.02 g, 17.2 mmol) was dissolved in THE (100mL) and cooled to -
78 C. n-
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Butyllithium (2.5 M in hexanes) (8.23 ml, 20.6 mmol) was added dropwise to
give a dark
orange solution. After 30 minutes, DMF (14.5 ml, 189mmol) was added and the
solution
was stirred 45 minutes before being quenched by addition of saturated ammonium
chloride and water. The aqueous solution was extracted with EtOAc and the
combined
organic layers were washed with water, brine, dried over sodium sulfate and
concentrated
to afford (S)-tert-butyl allyl(6-formyl-2,2-spirocyclobutyl-3,4-dihydro-2H-
pyrano[2,3-
b]pyridin-4-yl)carbamate as the product which was used in the next step
without further
purification. MS mhz: 359.2 (100%, M+1).
The crude material was dissolved in 80 mL of methanol and cooled to 0 C when
sodium tetrahydroborate (1.62 g, 42.9 mmol) was added. After stirring 40
minutes the
reaction was quenched by addition of saturated ammonium chloride and water.
The
aqueous solution was extracted with ethyl acetate and the combined organic
layers were
washed with water, brine, dried over sodium sulfate and concentrated. The
product was
purified by column chromatography (1:1 Hex/EtOAc to EtOAc) to give the titled
compound.
Step 4: (S)-tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl-
3,4-dihydro-
2H-p, no[2,3-blpyridin-4-yl)carbamate
(S)-Tert-butyl allyl(6-(hydroxymethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-
pyrano[2,3-
b]pyridin-4-yl)carbamate (1.45 g, 4.02 mmol) in DCM (4OmL) was added to a
solution of
dibromotriphenylphosphorane (1.87g, 4.43 mmol) in DCM (40 mL) at ambient
temperature. After stirring 45 minutes the reaction was concentrated and the
crude
product, (S)-tert-butyl allyl(6-(bromomethyl)-2,2-spirocyclobutyl-3,4-dihydro-
2H-
pyrano[2,3-b]pyridin-4-yl)carbamate taken up in THE (40 mL). In a separate
flask,
diisopropylamine (3.58 ml, 25.3 mmol) was added to THE (100 mL) and the
solution was
cooled to -78 C. n-Butyllithium (2.5 M in hexanes)(9.65 ml, 24.1 mmol) was
added and
the solution was stirred 20 minutes at 0 C. Isobutyronitrile (2.17 ml, 24.1
mmol) was
added and the yellow solution was stirred 30 minutes at 0 C before the
intermediate (S)-
tert-butyl allyl(6-(bromomethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-
b]pyridin-4-yl)carbamate in THE (4OmL) was added dropwise. The reaction was
stirred at
0 C and after 1 hour 30mL of a stock solution of isobutyronitrile enolate
(prepared in the
identical manner from the same amounts of diisopropylamine, n-butyllithium,
isobutyronitrile as above in THE (70mL)) was added to the reaction. After ten
minutes,
the reaction was quenched with saturated ammonium chloride and extracted with
EtOAc.
The combined organic layers were washed with water, brine, and dried over
sodium
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sulfate. Concentration and purification by silica gel column (1.5:1 Hex/EtOAc)
afforded
the titled compound. MS m/z: 412.3 (100%, M+1).
Step 5: (S)-3-(4-amino-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
6-vl)-2,2-
dimethyl ropanenitrile
(S)-Tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl-3,4-
dihydro-2H-
pyrano[2,3-b]pyridin-4-yl)carbamate (0.100g, 0.24 mmol) was stirred in DCM
(2mL) with
TFA (1.0 ml, I3mmol). After 3 hrs the reaction was concentrated. The crude
product was
taken up in DCM and 10% aqueous sodium carbonate and the layers were
separated. The
aqueous layer was extracted with DCM and the combined organic layers were
washed with
brine, dried over sodium sulfate and concentrated to afford (S)-3-(4-
(allylamino)-2,2-
spirocyclobutyl-3,4-dihydro-2.1-1-pyrano [2,3-b]pyridin-6-yl)-2,2-
dimethylpropanenitrile.
The crude product was used without further purification. MS nriz: 312.2 (100%,
M+1).
The crude product was dissolved in degassed (N2) DCM (2 mL) and 1,3-
dimethylbarbituric acid (0.11 g, 0.73 mmol) was added. After two minutes,
tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol) was added and
the
reaction was stirred at 35 C for 3 hours. The reaction was diluted with DCM
and 10%
aqueous sodium carbonate and the layers were separated. The aqueous layer was
extracted with DCM and the combined organic layers were washed with brine,
dried over
sodium sulfate and concentrated. The crude product was purified by silica gel
chromatography (20:1 DCM/MeOH) to afford the titled compound. m/z: 272.2
(M+1).
Step 6: N-((1 S,2R)-l -((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2-cyano-2-
methyllpropyl)-
3',4'-dihydrospiro(cyclobutane-1,2'-p ry ano[2,3-b]pyridin]-4'-yl)amino)-2-
h d~ roxvpropyl)acetamide
The title compound was prepared by a method analogous to that described in
Example
464, steps 8-10. MS Found m/z: 511.2 (M+1)
Example 491
N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(3,3-difluoro-2,2-
dimethylpropyl)-
3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yL)amino)-2-
hyd roxypro pyl)acetamide
Step 1: (S)-tert-butyl allyl(6-(2 2-spirocyclobutyl-3-oxopropyi)-2 2-dimethyl-
3 4-dihydro-
2H-pyrano[2,3-b]pyridin-4-yl)carbamate
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(S)-tert-butyl allyl(6-(2-cyano-2-methylpropyl)-2,2-spirocyclobutyl-3,4-
dihydro-2H-
pyrano[2,3-b]pyridin-4-yl)carbamate (0.708 g, 1.72 mmol) was dissolved in
toluene (12
mL) and cooled to 0 C. DIBAL, 1.0 M solution in hexanes (5.08 ml, 5.08 mmol)
was
added dropwise and the reaction was stirred for 1 hour. The reaction was
quenched with 1
N HCI and diluted with a saturated aqueous sodium potassium tartrate solution
and
vigorously stirred for 3 hours. The layers were separated and the aqueous
layer was
extracted with EtOAc and the combined organic layers were washed with water,
brine,
and dried over sodium sulfate. The crude product was purified by silica gel
chromatography (2:1 Hexanes/EtOAc) to afford the titled compound.
Step 2: (S)-tert-butyl allyl(6-(3,3-difluoro-2,2-dimethylpropyl)-2,2-
spirocyclobu ytl-3,4-
dihydro-2H-pvrano[2,3-b]pyridin-4-yl)carbamate
(S)-Tert-butyl allyl(6-(2,2-spirocyclobutyl-3-oxopropyl)-2,2-dimethyl-3,4-
dihydro-2H-
pyrano[2,3-b]pyridin-4-yl)carbamate (0.196 g, 0.473 mmol) was dissolved in DCM
(1.5mL) and cooled to -78 C. DAST (0.150 ml, 1.13 mmol) was added and the
reaction was
slowly warmed to RT and stirred for 12 hrs. The reaction was carefully
quenched with 10%
aqueous sodium carbonate and diluted with DCM. The aqueous layer was extracted
with
DCM and the combined organic layers were washed with water, brine, and dried
over
sodium sulfate. The crude product was used directly for the next step without
further
purification.
Step 3: N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S -6'- 3,3-difluoro-2.2-
dimethylpropyl)-3',4'-dihydrospirojcyclobutane-1,2'-pyrano[2,3-blpyridinl-4'-
yl)amino)-
2-hydroxypropyl)acetamide
The title compound was prepared in a manner analogous to that described in
Example 490
Step 5 and Step 6. MS Found m/z: 536.2 (M+1).
Example 492
N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2-dimethyl-3-butyn-1-yl)-
3',4'-
dihyd rospiro[cyclobutane-1,2'-pyrano[2,3-b] pyridin]-4'-yl)amino)-2-
hydroxyp ropyl)acetamide
Step 1: (S)-tert-butyl allyl(6-(2.2-dimethylbut-3-yny-1)-2 2-spirocyclobutyl-
3,4-dihydro-
2 H-pvrano [2,3-bl pyridin-4-yl)carbamate
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Potassium carbonate (0.155 g, 1.12 mmol) was added to a solution of (S)-tert-
butyl
al lyl(6-(2,2-spirocycl obutyl-3 -oxopropyl)-2,2-d imethyl-3 ,4-d ihydro-2H-
pyrano[2,3 -
b]pyridin-4-yl)carbamate (0.233 g, 0.562 mmol) and Ohira's Reagent (0.130 g,
0.674
mmol) in MeOH (6 mL). After stirring 1S hrs, the reaction was diluted with 10%
sodium
carbonate and extracted with EtOAc. The combined organic layers were washed
with
water, brine, dried over sodium sulfate, and concentrated. The product
obtained was taken
on without further purification. MS m/z: 411.3 (M+1).
Sten 2: N-((IS,2R) 1-((4-chlorophenyl)methyl -3-(((4'S)-6'-(2,2-dimethyl-3-
butyn-l-yl)-
3' 4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridinl-4'-yI)amino) 2-
hydroxypropyl)acetamide
The title compound was synthesized in analogous manner according to procedures
described for Example 491, Step 3 and purified by column chromatography (20:1
DCM/MeOH). MS Found m/z: 510.2 (M+1).
Example 493
N-((1S,2R)-1-((4-chlorophenyl)methyl)-3-(((4' S)-6'-(2,2-dimethylb utyl)-3',4'-
dihyd rospiro [cyclob u tare-1,2'-pyrano [2,3-b1 pyridin]-4'-yl)amino)-2-
hyd roxypropyl)acetamide
The compound of Example 492 (0.100 g, 0.196 mmol) was dissolved in MeOH (2 mL)
and
diazenedicarboxylic acid, dipotassium salt (0.762 g, 3.92 mmol) was added.
HOAc (0.673
ml, 11.8 mmol) in MeOH (2 mL) was slowly added to the heterogeneous solution
and the
reaction was stirred. After all the acetic acid was added and the solution
went from yellow
to clear and upon complete reduction, the reaction was concentrated and
partitioned
between 1 N NaOH and DCM. The aqueous was layer was extracted with DCM and the
combined organics were washed with brine and concentrated. The crude material
was
dissolved in a minimal amount of MeOH and directly purified by reverse phase
HPLC to
afford the title compound. MS m1z: 514.2 (M+1).
Example 494
N-((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4'-dihydrospiro
[cyclobutane-
1,2'-pyrano[2,3-b] pyridin]-4'-yl)amino)-2-hydroxy-l-
(phenylmethyl)propyl)acetam ide
Step 1: 2,6-difluoro-3-neopentylpyridine
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To a 500 mL RBF was added neopentylmagnesium chloride, l.OM in ether (28.0 ml,
28
mmol) and an ice bath. After cooling, zinc(II) chloride, 0.5M in THE (56.0 ml,
28 mmol)
was added dropwise. The cooling bath was removed and after stirring for 45
minutes,
Reactant 1 (0.26 g, 0.32 mmol) was added followed by 2,6-difluoro-3-
iodopyridine (2.74 g,
8.0 mmol) in TI-1F (10 mL), which was added dropwise. The yellow solution was
then
heated to 60 C. After stirring overnight the reaction was allowed to cool and
sat'd. NH4Cl
was added cautiously. The reaction mixture was partitioned between
EtOAc/Water. The
aqueous layer was extracted with EtOAc (50 mL) and the combined organic layers
washed
with brine and concentrated in vacuo. The crude product was adsorbed onto a
plug of silica
gel and chromatographed through a Redi-Sep pre-packed silica gel column (40
g), eluting
with 1% EtOAc in hexane, to provide 2,6-difluoro-3-neopentylpyridine as a
colorless oil.
MS m/z: 186 (M+l).
Step 2: N-((S)-2-(1-(tert-butyldimethylsilyloxy)cyclobutyl)-l-(2,6-difluoro-5-
neopentylpyridin-3-ylethyll)-2-methylpropane-2-sulfinamide
To a three-necked RBF was added 2,2,6,6-tetramethylpiperidine (0.34 ml, 2
mmol), THE
(1 OmL), and an ethanol/N2 bath. After cooling to -78 C, butyllithium (0.70
ml, 2 mmol)
was added dropwise. After stirring for several minutes, the solution was
cooled to -100 C
of 2,6-difluoro-3-neopentylpyridine (0.230 g, I mmol) in THE (2mL) was added
dropwise.
The solution was then treated with (R,E)-N-(2-(1-(tert-
butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide
(0.71 g, 2
mmol) in THE (3mL). After the addition was complete the reaction was allowed
to warm
to 0 C as the liquid N2 boiled off. The reaction was then quenched with water
(l OmL) and
extracted with EtOAc (3 X 20mL). The combined organic layers were concentrated
in
vacuo and adsorbed onto a plug of silica gel and chromatographed through a
Redi-Sep
pre-packed silica gel column (12 g), eluting with 1% to 20% EtOAc in hexane,
to provide
N-((S)-2-(I -(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2,6-difluoro-5-
neopentylpyridin-3-
yl)ethyl)-2-methylpropane-2-sulfinamide (0.07 g, 11% yield). This material was
used
without further purification in the next step. MS m/z: 517 (M+1).
Step 3: N-((S)-7-fluoro-2,2-dimethyl-6-neopentyl-3,4-dihydro-2H-pyranof2,3-
blpyridin-4-
yl)-2-methypropane-2-sulfinamide To a 150 mL RBF was added N-((S)-2-(l-(tert-
butyldimethylsilyloxy)cyclobutyl)-I-(2,6-difluoro-5-neopentylpyridin-3-
yl)ethyl)-2-
methylpropane-2-sulfinamide (0.070 g, 0.14mmol), THE (3mL), and TBAF, 1M in TI-
fF
(0.14 ml, 0.14mmol). The reaction was stirred at RT. After 20 minutes, the
reaction was
eluted through a plug of silica gel with THE The resulting filtrate was
concentrated in
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vacuo and taken up in THE (2OmL) and treated with NaH (0.035 g, 0.88 mmol, 60%
in
mineral oil). The reaction was stirred at 40 C for 16 hours. The reaction was
allowed to
cool to RT and quenched with sat'd NH4Cl, and extracted with EtOAc (25 mL).
The
combined organic layers were concentrated in vacuo to give N-((S)-7-fluoro-2,2-
dimethyl-
6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-
sulfinamide.
This material was carried forward without further purification. MS m/z: 383
(M+1).
Step 4: (S)-7-fluoro-2 2-spirocyclobutane-6-neopentyl-3 4-dihydro-2H-pyrano[2
3-
blpyridin-4-amine
To a 500 mL RBF was added N-((S)-7-fluoro-2,2-dimethyl-6-neopentyl-3,4-dihydro-
2H-
pyrano[2,3-b]pyridin-4-yl)-2-methylpropane-2-sulfinamide (1.71 g, 4.5mmol),
dichloromethane (20mL), and hydrogen chloride, 4.OM in dioxane (2.00 ml,
8.Ommol).
The reaction was stirred at RT. After 15 hours, the reaction was washed with
sat'd NaHCO3
and the organic layer concentrated in vacuo. The resulting crude product was
adsorbed
onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed
silica gel
column (12g), eluting with 0% to 50% EtOAc in DCM to provide (S)-7-fluoro-2,2-
spirocyclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine as a
light
yellow oil.
Step 5: N-((IS,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3' 4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2 3-blpyridin]-4'-yl)amino)-2-hydroxy-1-
(phen llmethyl)propyl)acetamide
The amine from Step 4 was used in a mthod analogous to that described in
Example 464,
steps 8-10 to give N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-
3',4'-
dihydrospi ro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-hydroxy-l -
(phenylmethyl)propyl)acetamide as a colorless solid. MS m/z: 484 (M+1).
Example 495
N-((1S,2R)-3-(((4' S)-6'-(1-fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro
[cyclobutane-
3 0 1,2'-pyrano[2,3-bjpyridi nj-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetam ide
Step 1: N-al lyl-N-t-butylcarbamate-(4'S -6'-(1-hydroxy-2 2-dimethylpropyl)-3'
4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]p ry idin]-4'-amine
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A solution ofN-allyl-N-t-butylcarbamate-(4'S)-6'-(bromo)-3',4'-
dihydrospiro[cyclobutane-
1,2'-pyrano[2,3-b]pyridin]-4'-amine (4.12 g, 10.1 mmol) in ether (80mL) was
cooled to -
78 C and then t-butyllithium (12.5 ml, 21.3 mmol) was added and stirred for 15
minutes
before the pivalaldehyde (3.80 ml, 35.0 mmol) (Note: freshly distilled) was
added. After 5
minutes, LC-MS shows the starting material has been consumed. The reaction was
quenched with sat'd NH4CI and the organic layer separated. The organic layer
was
combined with previous trial reactions and adsorbed onto a plug of silica gel
and
chromatographed through a Redi-Sepll pre-packed silica gel column (120 g),
eluting with
0% to 30% EtOAc in hexane, to provide N-ally] N-t-butylcarbamate-(4'S)-6'-(1-
hydroxy-
1 0 2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-
b]pyridin]-4'-amine as
a yellow oil. MS m/z: 417 (M+1).
Step 2: N-all ll-(4'S)-6'-(1-fluoro-2,2-dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'
p, r~[2,3-b]pyridinl-4'-amine To a 250mL RBF was added N-allyl-N-t-
butylcarbamate-
(4'S)-6'-(1-hydroxy-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-
b]pyridin]-4'-amine (4.01 g, 9.6mmol), toluene (IOOmL), a dry ice bath, and
after cooling
for 20 minutes DAST (1.81 ml, 14mmol) was added. After 1 hour, LC-MS shows
Reactant
1 consumed. The reaction was quenched with sat'd NH4CI (20mL). The layers were
separated and the aqueous layer extracted with EtOAc (20 mL). The combined
organic
layers were concentrated in vacuo to give a golden oil. The oil was taken up
in MeOH
(50mL) and treated with HCI, 4M in dioxane (5.0 ml, 20mmol). After 1.5 hours,
no
changes were seen by LC-MS. The reaction was treated with an additional HCI (5
mL) and
heated to 60 C. After stirring for 5 hours, the solution was allowed to cool
to RT. After a
further 16 hours, the reaction was concentrated in vacuo to give a brown oil,
which was
taken up in DCM and washed with sat'd NaHCO3, brine and concentrated in vacuo
to give
N-allyl-(4'S)-6'-(1-fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-
1,2'-
pyrano[2,3-b]pyridin]-4'-amine (3.15 g) as a brown oil. MS rWz: 319 (M+1). The
crude
material was used without further purification in the next step.
Step 3: (4'S)-6'-(1-fluoro-2,2-dimethyllprop, ll)-3 ,4'-
dihydrospirolcvclobutane-1,2'-
pyranor2,3-b]pvridin]-4'-amine To a 250 mL RBF was added N-allyl-(4'S)-6'-(1-
fluoro-
3 0 2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-
b]pyridin]-4'-amine
(3.10 g, 9.7 mmol), degassed DCM (80 mL), and 1,3-dimethylbarbituric acid
(4.58 g, 29
mmol). After stirring for 5 minutes, Palladium Tetrakis (0.56 g, 0.48 mmol)
was added and
the solution heated to 40 C. After 4 hours, the solution was poured into a
separator funnel
containing 10% Na2CO3 (50mL) and the layers separated. The organic layer was
again
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extracted with 10% Na2CO3 (5OmL). The combined aqueous layers were back
extracted
with DCM (50 mL). The combined organic layers were concentrated in vacuo and
adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-
packed
silica gel column (80 g), eluting with 50% to 80% EtOAc in hexane, to provide
a mixture of
product and triphenyl-phosphine oxide. The material was taken up in EtOAc and
extracted
with HCl (1N, 2 X 20 mL). The aqueous layer was then neutralized and extracted
with
EtOAc (2 X 20 mL). The combined EtOAc layers were concentrated in vacuo to
give (4'S)-
6'-(l-fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-b]pyridin]-
4'-amine (1.81 g 69% for step 2 and 3) as a colorless oil. MS m/z: 279 (M+]).
Step 4: N-((lS,2R)-3-(((4'S)-6'-(1-fluoro-2,2-dimethylpropyl)-3',4'-
dihydrospirofcyclobutane-1,2'-pyrano(2,3-b]pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydrox ropyl)acetamide
The amine from step 3 was reacted in a manner analogous to that described in
Example
464, steps 8-10, to give the title compound as a white solid. MS m/z: 502
(M+1).
Example 496
N-((1S,2R)-3-(((4' S)-6'-(cyclopropy]methyl)-3',4'-dihydrospiro [cyclobutane-
1,2'-
pyrano [2,3-b] pyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
Step 1: (S -tert-butyl 6-ally]-2,2-s ip rocyclobuty -3,4-dihvdro-2H-p
rrano[2,3-blpvridin-4-
ylcarbamate
A mixture of Pd2(dba)3 (186 mg, 0.203 mmol) tri-t-butylphosphonium
tetrafluoroborate
(354 mg, 1.22 mmol), cesium fluoride (3.08 g, 4.06 mmol) and (S)-tert-butyl 6-
bromo-2,2-
spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate in 12mL of
dioxane
was purged with nitrogen for 30 minutes before being treated with
allyltributylstannane
(6.23mL, 20.3mmol). The mixture was heated to 100 C for 10 hours at which
point the
reaction was allowed to cool to room temperature. The mixture was diluted with
ethyl
acetate (50mL) and successively washed with saturated potassium fluoride
(5OmL), water
and brine. Drying over sodium sulfate and concentration provided a residue
that was
purified by silica gel chromatography (0-25% EtOAc in hexanes) to provide the
title
compound as light yellow solid. MS in/z: 331.2 (M+1).
Step 2: (S)-6-(cyclopropylmethyl)-2,2-spiroc cl~ obutvl-3,4-dihvdro-2H-
pyranof2,3-
blpyridin-4-amine
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A solution of diethylzinc (1.0 M in hexanes, 9.00 mL, 9.00 mmol) was cooled to
-10 C and
treated with TFA (0.70 ml, 9.0 mmol) dropwise over 5 minutes. After an
additional 5
minutes diiodomethane (0.70 ml, 9.0 mmol) was added, and the reaction mixture
was
allowed to stir for 10 minutes. The resulting suspension was treated with a
solution of (S)-
tent-butyl 6-allyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-
ylcarbamate
(0.580 g, 2.00 mmol) in 10 mL dichloromethane. The reaction mixture was
allowed to stir
at -10 C for 30 minutes before being allowed to warm to RT. The suspension was
quenched with MeOH and saturated sodium bicarbonate (5 mL) and was allowed to
stir for
an additional hour. The reaction mixture was then diluted with EtOAc (50 mL)
and filtered
through a short plug of silica. The filtrate was concentrated and the crude
residue was
resubmitted to the reaction conditions and allowed to stir at RT overnight.
The reaction
mixture was quenched with methanol (5 mL) and saturated sodium bicarbonate (5
mL). 6N
NaOH (15 mL) was added and the reaction mixture was allowed to stir for one
hour before
being diluted with DCM (50 mL). The aqueous was extracted with DCM 3 x 50 mL
and the
combined organics were washed with brine, dried over magnesium sulfate and
concentrated. Purification of the crude residue by reverse phase HPLC provided
the title
compound as a yellow oil. MS m/z: 245 (M+1).
Step 3: N-((1 S,2R)-3-(((4'S)-6'-(cyclopropylmethyl)-3',4'-dihydrospirof
cyclobutane-1 2'-
pyranof 2,3-blpyridinl-4'-yl)amino)- I-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
The title compounds made by a method analogous to that described in Example
464, steps
8-10. MS Found m/z: 468 (M+1).
Example 497
N-((1S,2R)-1-((4-Fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((1-
methylcyclopropyl)methyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-
b] pyridin]-4'-yl)amino)propyl)acetamide
Step I= S)-tert-butyl 6-(2-methylallyl)-2 2-spirocyclobutyl-3 4-dihydro-2H-
ayranof2 3-
blp ridin-4-ylcarbamate
A mixture of Pd2(dba)3 (133 mg, 0.145 mmol) tri-t-butylphosphonium
tetrafluoroborate
(252 mg, 0.869 mmol), cesium fluoride (1.32 g, 8.69 mmol) and (S)-tert-butyl 6-
bromo-2,2-
spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate in 3 mL of
dioxane
was purged with nitrogen for 30 minutes before being treated with tributyl(2-
methylallyl)stannane (2.50 g, 7.24 mmol). The mixture was heated to 90 C for
10 hours at
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which point the reaction was allowed to cool to RT and diluted with EtOAc (50
mL) and
successively washed with saturated potassium fluoride (50 mL), water and
brine. Drying
over sodium sulfate and concentration provided a residue that was purified by
silica gel
chromatography (0-25% EtOAc in hexanes) to provide the title compound as light
yellow
solid. MS m/z: 345 (M+1).
Step 2: (S)tertbutyl 6 ((1 methycycloprop 1)) methyl)-2 2-spirocyclobutyl-3 4-
dihydro-
2H-pyranol2 3-blpyrridin-4-ylcarbamate
A solution of diethyl zinc (1.0 M, 35.0 mL, 35 mmol)in 20mL hexanes was cooled
to -10 C
and treated with chloroiodomethane (5.00 mL, 65mmol). After stirring for 30
minutes at
this temperature a solution of (S)-tert-butyl 6-(2-methylallyl)-2,2-
spirocyclobutyl-3,4-
dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate in 20 mL of dichloromethane was
added
and the reaction was allowed to warm to room temperature where it was
maintained for an
additional 10 hours. The reaction was quenched with methanol (10 mL) and
saturated
sodium bicarbonate (3 mL). The slurry was then treated with DIEA (0.80 mL,
4.00 mmol)
and di-tert-butyl dicarbonate (1.0 mL, 4.0 mmol) and allowed to stir for 3
hours. The
reaction was then diluted with EtOAc (25 mL) and washed successively with
saturated
sodium bicarbonate (30 mL), water and brine before being dried over magnesium
sulfate.
Concentration provided a residue that was taken up in 20 mL of DCM and added a
solution
of diethyl zinc (1.0 M, 35.0 mL, 35 mmol) and chloroiodomethane (5.00 mL, 65
mmol) in
20 mL hexanes at -10 C. The reaction was allowed to warm to RT where it was
maintained for an additional 10 hours. The reaction was quenched with methanol
(10 mL)
and saturated sodium bicarbonate (3 mL). The slurry was then treated with DIEA
(0.80
mL, 4.00 mmol) and di-tert-butyl dicarbonate (1.0 mL, 4.0 mmol) and allowed to
stir for 3
hours. The reaction was then diluted with EtOAc (50 mL) and washed
successively with
saturated sodium bicarbonate (50 mL), water and brine before being dried over
magnesium
sulfate. Concentration and purification by silica gel chromatography (0-50%
ethyl acetate
in hexanes) provided the title compound as a yellow oil. MS n1/z: 359 (M+l ).
Step 3: (S) 6 ((1-methvlcyclopropyl)methyl)-2 2-spirocyclobutyl-3 4-dihydro-2H-
pyranol2 3-b]pyridin-4-amine
A solution of (S)-tert-butyl 6-((1-methylcyclopropyl)methyl)-2,2-
spirocyclobutyl-3,4-
dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.860 g, 2.4 mmol) and 2,6-
lutidine (2.80
ml, 24.0 mmol) in 10 mL of DCM was cooled to 0 C and treated with
trimethylsilyl triflate
(2.30 ml, 12.0 mmol). The reaction mixture was allowed to warm to RT and stir
for 10
hours before being diluted with ethyl acetate (50 mL) and washed with
saturated sodium
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bicarbonate (50 mL) and brine. The combined organics were dried over magnesium
sulfate,
concentrated and purified reverse phase HPLC to provide the title compound as
a yellow
oil. MS m/z: 259 (M+I).
Step 4: N-((1 S,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-6'-((1-
methylcyclopropyl)methyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-
blpyridinl-4'-
vl)amino)propyl)acetam ide
The title compound was made by a method analogous to that described in Example
464,
steps 8-10. MS Found m/z: 482 (M+1).
Example 498
N-((1 S,2R)-3-(((4'S)-6'-(3,3-d ifluoro-2-methylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-bj pyridinj-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hyd roxypropyl)acetamide
Step 1: Tert-butyl (S)-6-(2-methyl-3-oxopropyl-2,2-spirocyclobutyl-3,4-dihydro-
2H-
pyran o [2, 3-bl pyri d in-4-vlcarbamate
A solution of (S)-tert-butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-
pyrano[2,3-
b]pyridin-4-ylcarbamate (1.500 g, 4.06 mmol), Pd2(dba)3 (0.186 g, 0.203 mmol),
tri-t-
butylphosphonium tetrafluoroborate (0.3 54 g, 1.22 mmol), 2-methylprop-2-en-l-
ol (1.38
ml, 16.2 mmol), cesium fluoride (0.617 g, 4.06 mmol), and N-cyclohexyl-N-
methylcyclohexanamine (5.17 ml, 24.4 mmol) in 8 mL of dioxane was purged with
nitrogen
for 30 minutes. The reaction vessel was then sealed and heated to 80 C for 10
hours. The
cooled reaction mixture was quenched with saturated sodium bicarbonate (50
mL), and the
aqueous layer was extracted with EtOAc 3 x 50 mL. The combined organics were
washed
with brine, dried over sodium sulfate and concentrated. Purification of the
crude residue by
column chromatography (0-50% EtOAc in hexanes) provided the title compound as
a
colorless oil. MS iilz: 361 (M+1).
Step 2: Tert-butyl (S)-6-(3,3-difluoro-2-methylaropyl)-2,2-spirocyclobutyl-3,4-
dihydro-2H-
pvrano[2,3-b]pyridin-4-vlcarbamate
A solution of tert-butyl (S)-6-(2-methyl-3-oxopropyl)-2,2-spirocyclobutyl-3,4-
dihydro-2H-
pyrano[2,3-b]pyridin-4-ylcarbamate (0.270 g, 0.749 mmol) in 1.5 mL of DCM was
cooled
to -78 C and treated with DAST (0.218 ml, 1.65 mmol). The reaction mixture was
allowed
to warm to RT and stir for 8 hours. An additional equivalent of DAST was
added, and the
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reaction mixture was allowed to stir for 2 hours before being diluted with
EtOAc (25 mL)
and washed with saturated sodium bicarbonate and brine. The organics were
dried over
magnesium sulfate, concentrated and purified by silica gel chromatography (0-
30% EtOAc
in hexanes) to furnish the title compound as a yellow oil. MS m/z: 383 (M+1).
Step 3: (4S)-6-(3,3-difluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihvdro-
2H-
pyrano[2,3-blpyridin-4-amine A solution of tert-butyl (S)-6-(3,3-difluoro-2-
methylpropyl)-
2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.110
g, 0.3
mmol) in 2mL of DCM was treated with HCl (4.0 M in dioxane, 1.50 ml, 6.00
mmol) and
was allowed to stir at RT for 10 hours. The reaction mixture was diluted with
EtOAc (50
mL) and was washed with 2N NaOH (50 mL) and brine. The organics were dried
over
magnesium sulfate and concentrated to provide the title compound as a yellow
solid. MS
m/z: 283 (M+1).
Step 4: N-((IS,2R)-3-(((4'S)-6'-(3.3-difluoro-2-methylpropyl)-3',4'-
dihydrospiro[cyclobutane-1.2'-pyranoi2,3-blpyridin)-4'yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxxpropyl)acetamide
The title compound was made by a method analogous to that described in Example
464,
steps 8-10. MS Found m/z: 506 (M+1).
Example 499
N-((1 S,2R)-3-(((4'S)-6'-((2S)-3-fluoro-2-methylpropyl)-3',4'-
d ihyd rospi ro [cyclobutane-1,2'-pyrano [2,3-b] pyri d in] -4'-yl)amino)-1-
((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide; and N-
((1 S,2R)-3-(((4'S)-6'-((2R)-3-fluoro-2-methylpropyl)-3',4'-dihydrospiro
[cyclobutane-
1,2'-pyrano[2,3-b] pyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-
hyd roxypropyl)acetamide
Step 1: Tert-butyl (S)-6-(3-(tert-butyldimethylsilyloxy)-2-methylpropyl -2 2-
spirocycl obutyl-3,4-dihvdro-2H-pyrano [2,3 -b]pyri d in-4-ylcarbamate
Tert-butyldimethyl(2-methylallyloxy)silane was treated with 9-BBN (0.5 M in
diethyl
ether, 53.0 ml, 26.0 mmol) and the resulting solution was purged with nitrogen
for 15
minutes before being allowed to stir at RT for 10 hours. In a separate flask a
solution of
palladium acetate (100 mg, 0.500 mmol) and SPhos (700 mg, 2.00 mmol) in 2 mL
of
toluene and 2 mL of THE was purged with nitrogen for 30 minutes and allowed to
stir at RT
for one hour. The resulting solution was added to the organoborane, followed
by potassium
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phosphate (4.00 g, 21.0 mmol) and a solution of (S)-tert-butyl 6-bromo-2,2-
spirocyclobutyl-
3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (1.95 g, 5.00 mmol) in 15 mL
of
DMF. The reaction mixture was purged with nitrogen for 15 minutes and heated
to 90 C for
3 hours at which point it was cooled to RT, diluted with EtOAc (50 mL) and
filtered
through a plug of celite. The filtrate was washed with water, brine, and the
organics were
dried over sodium sulfate and concentrated. Purification of the crude residue
by column
chromatography (0-25% EtOAc in hexanes) provided the title compound,
contaminated
with starting olefin, as a colorless oil.
Step 2: Tert-butt'(S)-6-(3-hydroNy-2-methylpropyl)-2,2-spirocyclobutyl-3,4-
dihvdro-2H-
pyrano[2,3-blpyridin-4-ylcarbamate
A solution of tert-butyl (S)-6-(3-(tert-butyldimethylsilyloxy)-2-methylpropyl)-
2,2-
spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (2.80 g, 6
mmol) in 20
mL of DCM was treated with tetrabutyl ammonium fluoride (TBAF; 1.0 M in THF,
29.0
ml, 29.0 mmol) and allowed to stir at RT for 3 hours. The reaction mixture was
concentrated to reduce the volume by half and it was allowed to stir for an
additional hour
at which point it was concentrated and the crude residue was purified by
column
chromatography to furnish the title compound as a white solid. MS m/z: 363
(M+1).
Step 3: 3-((S)-4-(tert-butoxycarbonyl -2,2-spiroc clobutyl-3,4-dihydro-2H-
pyrano[2,3-
blpyridin-6-yl)-2-methylpropyl methanesulfonate
A solution of tert-butyl (S)-6-(3-hydroxy-2-methylpropyl)-2,2-spirocyclobutyl-
3,4-dihydro-
2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.350 g, 0.97 mmol) in 5mL of DCM was
treated
with DIEA (0.340 ml, 1.90 mmol) cooled to 0 C and exposed to methane sulfonyl
chloride
(0.082 ml, 1.10 mmol). The reaction mixture was allowed to warm to RT and was
maintained at this temperature for one hour before being diluted with EtOAc
(50 mL),
washed with water and brine and dried over sodium sulfate. Concentration
provided the title
compound as a white solid. MS m/z: 441 (M+1).
Step 4: (4S)-6-(3-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihvdro-2H-
pyranof2,3-
blpyridin-4-amine
A solution of 3-((S)-4-(tert-butoxycarbonyl)-2,2-spirocyclobutyl-3,4-dihydro-
2H-
pyrano[2,3-b]pyridin-6-yl)-2-methylpropyl methanesulfonate (1.200 g, 3.00
mmol) in THE
(5 mL) was treated with TBAF (1.0 M in THF, 14.0 ml, 14.0 mmol) and heated to
80 C for
10 hours. The cooled reaction mixture was diluted with EtOAc (50 mL) and was
washed
successively with 2N NaOH (25 mL) and brine. The organics were dried over
sodium
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sulfate, filtered and concentrated to provide a residue that was purified by
reverse phase
HPLC to provide the title compound a yellow oil. MS m/z: 265 (M+1).
Step 5: N-((IS,2R -33((4'S)-6'-((2S)-3-fluoro-2-methylpropyl)-3',4'-
dihydrospirofcyclobutane-1,2'-pyrano[2,3-blpyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide; and
N-((1 S,2R)-3-(((4'S)-6'-((2R)-3-fluoro-2-methylpropyl)-3',4'-
dihydrospirofcvclobutane-1,2'-
pyranol2,3-blpyridin]-4'-yl aminoZ 1-((4-fluorophenyl)meth
l~ydroxypropyl)acetamide
The title compounds were made by a method analogous to that described in
Example 464,
steps 8-10. MS Found m/z: 488 (M+1).
Example 500
N-((1 S,2R)-3-(((4 S)-6-(2,2-d imethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahyd ro-
4-
quinolinyl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide
Step 1: 4-bromo-N-(2-methylbut-3-yn-2-yl)benzenamine
To a solution of 4-bromobenzenamine (4.0 g, 23 mmol), TEA (4.3 ml, 31 mmol),
2.0 ml
of water, copper (0.058 g, 0.91 mmol) and copper(I) chloride (0.058 g, 0.59
mmol) in
diethyl ether (9.8 ml, 20 mmol) was added 3-chloro-3-methylbut-l-yne (2.0 g,
20 mmol),
dropwise. After stirring overnight, the reaction mixture was transferred to a
seperatory
funnel containing water and diethyl ether. The aqueous layer was washed 3X
with
EtOAc. The organic layers were combined, dried with MgSO4, filtered and
concentrated.
The crude oil was purified with by MPLC (100% DCM to 10% (91/10/1
DCM:MeOH:NH4OH)) to provide the product as an oil. MS n?/z: 240 (M+2).
Step 2: 6-bromo-2,2-dimethvl-1,2-dihydroquinoline
To a solution of 4-bromo-N-(2-methylbut-3-yn-2-yl)benzenamine (3.30 g, 14
mmol) in
toluene (14 ml, 14 mmol) was added copper(I) chloride (0.300 g, 3.0 mmol) in
one
portion. The reaction vessel was sealed and the resulting mixture was heated
to 90 deg C.
After stirring overnight, the mixture was transferred to a separatory funnel
containing
water and EtOAc. The aqueous layer was washed 1X with EtOAc and 3X with DCM.
The organic layers were combined, dried with MgSO4, filtered and concentrated.
The
crude oil was purified with an MPLC (100% DCM to 10% (9 1/10/1
DCM:MeOH:NH4OH)) to provide the product. MS m1z: 238.
Step 3: 6-bromo-2,2-dimethvl-1,2,3,4-tetrahydroauinolin-4-ol
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To a solution of 6-bromo-2,2-dimethyl-1,2-dihydroquinoline (4.50 g, 18.9 mmol)
in
tetrahydrofuran (37.8 ml, 18.9 mmol) was added BH3DMS (3.58 ml, 37.8 mmol)
dropwise at 0 deg C. The resulting solution was allowed to warm to RT and
stirred for 1
hour. The temperature was returned to 0 deg C and sodium hydroxide (6N) (30.0
ml, 18.9
mmol) followed by Hydrogen peroxide (30.0 ml, 18.9 mmol) was slowly added to
the
reaction mixture. The resulting solution was stirred for 45 minutes and then
transferred to
a sep. funnel containing water and EtOAc. The layer were separated and the
aqueous
layer was subsequently washed 3X with DCM. The organic layers were dried with
MgSO4, filtered and concentrated. The crude mixture was then purified with the
MPLC
(100% DCM to 10% 90: 10:1 DCM:MeOH:NH4OH) to provide the desired product. MS
m/z: 257 (M+1).
Step 4 and 5: 6-bromo-2 2-dimethyl-1 2 3 4-tetrahydroquinolin-4-amine
To a solution 6-bromo-2,2-dimethyl- 1,2,3,4-tetrahydroquinolin-4-ol (3.16 g,
12.3 mmol)
and DPPA (1.76 ml, 8.14 mmol) in THE (41.1 ml, 12.3 mmol) at 0 C was added DBU
(1.22 ml, 8.14 mmol) dropwise. The resulting mixture was warmed to RT and
stirred for
18 hours. The crude mixture was poured into a sep. funnel containing water.
The
aqueous layer was washed 3X with EtOAc. The organic layers were combined,
dried
with MgSO4 and concentrated to an oil. The crude product (2.29 g, MS m/z: 240
(M-
N3)) was taken to the next step in the reaction sequence.
To a solution of 4-azido-6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinoline
(2.29g, 8.15mmol), water (6.50m1, 361 mmol), and THE (20.4m1, 8.15mmol) was
added
triphenylphosphine (2.35 g, 8.96mmol) in one portion. The resulting mixture
was heated
to 40 deg C and stirred overnight. The crude mixture was dissolved with EtOAc
and
transferred to a sep. funnel containing 0.5MHCl. The aqueous layer was washed
5X
DCM. The aqueous layer was then neutralized with 6N NaOH and washed 3X with
EtOAc. The organic layers were combined, dried with MgSO4, filtered and
concentrated
to provide the desired product. MS m/z: 239 (M-NH2).
Step 6: 2 2-dimethyl-6-neopentyl-1 2 3 4-tetrahydroquinolin-4-amine
To neopentylmagnesium chloride (1.65 ml, 1.65 mmol) was added zinc(II)
chloride (2.19
ml, 1.10 mmol) dropwise - strong exotherm was observed. The resulting mixture
stirred
for 10 minutes. A solution of 6-bromo-2,2-dimethyl-1,2,3,4-tetrahydroquinolin-
4-amine
(0.0700 g, 0.274 mmol) in tetrahydrofuran (1.37 ml, 0.274 mmol) was then added
followed by palladium tetrakistriphenylphosphine (0.0317 g, 0.0274 mmol). The
reaction
vessel was sealed and heated to 65 deg C. The reaction mixture was stirred for
6 hours.
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The crude mixture was filtered through a plug of celite with EtOAc and
concentrated in
the presence of silica gel. The crude mixture was purified with the MPLC (100%
DCM
to 100% 90:10:1 DCM:MeOH:NH40H) to provide the desired product. MS m/z: 230
(M-NH2).
Step 7: Tert-butyl (2S 3R)-3-(tert-butyldimethylsily)-4-((S)-2,2-dimethyl-6-
neopentyl-1 2 3 4-tetrahydroquinolin-4-ylamino)-1-(3-fluorophenyl)butan-2-
ylcarbamate
To a solution of tert-butyl (2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-
fluorophenyl)-4-
oxobutan-2-ylcarbamate (0.148 g, 0.360 mmol) and (S)-2,2-dimethyl-6-neopentyl-
1,2,3,4-tetrahydroquinolin-4-amine (0.0886 g, 0.360 mmol) in DCM (7.19 ml,
0.360
mmol) was added trimethoxymethane (0.394 ml, 3.60 mmol). The resulting
solution was
stirred for 1 hour at which time, sodium triacetoxyborohydride (0.229 g, 1.08
mmol) was
added. The solution was then stirred for 30 minutes, quenched with saturated
Rochelle's
salt and stirred for an additional 20 minutes. The mixture was transferred to
a sep. funnel
containing DCM and H2O. The aqueous layer was washed 4X with DCM. The organic
layers were combined, washed 1X with brine, dried with MgSO4, filtered and
concentrated to afford the title compound. MS m/z: 642 (M+1).
Step 8: Tert-butyl (2S 3R)-4-((S)-2 2-dimethyl-6-neopentyl-1 2 3 4-
tetrahydroquinolin-4-
ylamino)-1-(3-fluorophenyl)-3-hvdroxybutan-2-ylcarbamate
To a solution of tert-butyl (2S,3R)-3-(tert-butyldimethylsilyloxy)-4-((S)-2,2-
dimethyl-6-
neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-1-(3-fluorophenyl)butan-2-
ylcarbamate
(0.231 g, 0.360 mmol) in DCM (1.20 ml, 0.360 mmol) was added
tetrabutylammonium
fluoride (1.44 ml, 1.44 mmol). The resulting solution was stirred overnight.
The mixture
was transferred to a sep. funnel containing EtOAc and H2O. The aqueous layer
was
washed 4X with EtOAc. The proganic layers were combined, dried over MgSO4,
filtered
and concentrated. The crude mixture was purified by the MPLC. MS m/z: 528
(M+1).
Steps 9 and 10: N-((2S 3R)-4-((S)-2 2-dimethyl-6-neopentyl-1,2,3,4-
tetrahydroquinolin-
4-ylamino)-I -(3-fluorophenyl)-3-hvdroxybutan-2-yl)acetamide
4N HCl in MeOH (15.0 ml, 0.379 mmol) was added to tert-butyl (2S,3R)-4-((S)-
2,2-
dimethyl-6-neopentyl-1,2,3,4-tetrahydroquinolin-4-ylamino)-1-(3-fluorophenyl)-
3-
hydroxybutan-2-ylcarbamate (0.200 g, 0.379 mmol) in a RBF and the resulting
solution
was stirred overnight. The solution was then concentrated and the solid
product was
taken on to the next step.
To a solution of (2R,3S)-3-amino-l-((S)-2,2-dimethyl-6-neopentyl-l,2,3,4-
tetrahydroquinolin-4-ylamino)-4-(3-fluorophenyl)butan-2-ol dihydrochloride
(0.104 g,
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0.379 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.396 ml, 2.27 mmol) in DCM
(1.52 ml, 0.379 mmol) was added 1-(IH-imidazol-1-yl)ethanone (0.0396 g, 0.360
mmol)
in one portion. The resulting solution was stirred over the weekend. The crude
mixture
was concentrated and purified with the HPLC. Due to insufficient purity, the
title
compound was free based and purified with the ISCO MPLC. MS m/z: 470 (M+1).
Example 501
N-((1S,2R)-3-(((4'S)-6'-butyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano [2,3-
b]pyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide
To a solution of N-((2S,3R)-4-((S)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-
pyrano[2,3-b]pyridin-4-ylam ino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)acetam
ide
(0.100 g, 0.203 mmol), tri-t-butylphosphonium tetrafluoroborate (0.0118 g,
0.0406 mmol)
and butylzinc(Il) bromide (2.03 ml, 1.02 mmol) in tetrahydrofuran (2.03 ml,
0.203 mmol)
was added Pd(OAc)2 (0.00456 g, 0.0203 mmol) in one portion at RT. The reaction
mixture was stirred for 2.5 hours. The reaction mixture was then quenched with
water
and the resulting mixture was transferred to a sep. funnel. The aqueous layer
was washed
3X with EtOAc. The organic layer were combined and concentrated. The crude
mixture
was purified with the Gilson HPLC to provide the title compound. MS rn/z: 470
(M+] ).
Example 502
N-((2S,3R)-1-(allyloxy)-3-hydroxy-4-(2,2-spirocyclobutyl-6-neopentyl-3,4-
dihydro-
2H-pyrano [2,3-b] pyridin-5-ylamino)butan-2-yl)acetamide
Step 1: tert-butyl (S)-2-(allyloy)-l-((S)-oxiran-2- 1 ethylcarbamate
To a solution of tert-butyl (S)-2-hydroxy-l-((S)-oxiran-2-yl)ethylcarbamate
(0.125 g, 0.6
mmol; see: Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49, 6195) in toluene (6
mL), was
added allyliodide 0.3 mL, 3 mmol) followed by silver(I) oxide (0.7 g, 3 mmol).
The
solution was stirred at 65 C in a darkened hood for a period of 15 h. The
mixture was then
cooled to ambient temperature, filtered through Celite, washed with CH2CI2,
and conc. in
vacuo. Purification on SiO2 (10-20% EtoAc/Hexanes) gave the title compound as
a yellow
oil.
Step 2: (2S,3S)-4-(allyloxy)-3-(tert-butoxycarbonyl)-2-hydroxybu-tyl acetate
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To a solution of lithium carbonate (0.10 g, 1.4 mmol) in DMF (2.5 mL), was
added AcOH
(0.078 mL, 1.4 mmol) and the solution stirred for a period of 5 min. To this
mixture was
added a solution of tert-butyl (S)-2-(allyloxy)-1-((S)-oxiran-2-
yl)ethylcarbamate (0.11 g,
0.45 mmol) in DMF (2.5 mL). The mixture was heated to 110 C overnight then
cooled to
ambient temperature. The cooled mixture was poured onto H2O and 1 N citric
acid (20
mL). The aqueous phase was extracted with EtOAc (3 x 20 mL) and the organic
extracts
were dried (Na2SO4), filtered, and cone. in vacuo to afford the title compound
as a yellow
oil. The crude material was used without further purification. MS m1z: 326
(M+23)
Step 3: (2S.3S)-4-(allyloxy)-3-(tert-butoxycarbonyl)-2-(tert-
butyldimethylsilyloxy)butyl
acetate
The crude material from Step 2 (0.090 g) was dissolved in CH2C12 (3 mL) and
cooled to 0
C. To the cooled solution, was added 2,6-lutidine (0.10 mL, 0.90 mmol)
followed by
TBSOTf (0.10 mL, 0.4 mmol). The mixture was stirred at 0 C for 2h then
diluted with H2O
and sat'd NaHCO3. The aqueous phase was extracted with CH2C12 (3 x 20 mL) and
the
organic extracts dried (Na2SO4), filtered, and cone in vacuo. Purification on
Si02 (5-20%
EtOAc/Hexanes) gave the title compound as a yellow oil.
Step 4: Tert-butyl (2S,3S)-1-(allyloxy)-3-(tert-butyldirimethylsilyloxy)-4-
hydroxybutan-2-
ylcarbamate
To a solution of (2S,3S)-4-(allyloxy)-3-(tert-butoxycarbonyl)-2-(tert-
butyldimethylsilyloxy)butyl acetate (0.060 g, 0.1 mmol) in MeOH (2 mL), was
added
K2CO3 (0.10 g, 0.7 mmol) and the mixture stirred at ambient temperature
overnight. The
mixture was then cone in vacuo and diluted with EtOAc (25 mL). The organic
layer was
washed with H2O, brine, then dried (Na2SO4), filtered, and cone in vacuo. The
crude
material was used without further purification.
Step 5: Tert-butyl (2S,3S)-1-(allyloxy)-3-(tert-butyldimethylsilyloxy)-4-
oxobutan-2-
ylcarbamate
The crude material from Step 4 (0.040 g) was dissolved in CH2CI2 (3 mL) and
treated with
Dess-Martin periodinane (0.07 g, 0.2 mmol). The mixture was stirred at ambient
temperature for 4 h then diluted with EtOAc (10 mL), sat'd NaHCO3 (5 mL), and
aqueous
Na2S203 (5 mL). The biphasic mixture was stirred until it was colorless. The
organic layer
was washed with brine, dried (Na2SO4), filtered, and cone in vacuo. The crude
aldehyde
was used without further purification.
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Step 6: Tert-butyl (2S,3R)-I-(allyloxy)-3-(tert-butyldimethylsilyloxy)-4-(2,2-
spirocyclobu l-6-neopentyl-3,4-dihvdro-2H-pyrano[2,3-b]pyridin-5-ylamino butan-
2-
ylcarbamate
To a solution of tert-butyl (2S,3S)-1-(allyloxy)-3-(tert-
butyldimethylsilyloxy)-4-oxobutan-
2-ylcarbamate (0.033 g) in 1,2-dichloroethane (1.0 mL), was added 2,2-
spirocyclobutyl-6-
neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-amine (0.03 g, 0.1 mmol)
followed by
sodium triacetoxy(borohydride) (0.03 g, 0.1 mmol). The mixture was stirred
overnight at
ambient temperature then diluted with sat'd NaHCO3 (10 mL). The mixture was
extracted
with EtOAc (3 x 25 ml), and the combined organic layers were dried (Na2SO4),
filtered, and
conc in vacuo. Purification on SiO2 (1.25 to 2.5% MeOH*/CH2CI2;*2.0 M NH3 in
MeOH)
gave the title compound as a light yellow solid. MS m/z: 517 (M-Boc).
Step 7: N-((2S,3R)-I-(allyloxy)-3-h droxy-4-(2,2-spirocyclobutyl-6-neopentyl-3
4-
dihydro-2H-pyranof 2,3-b]pyrridin-5-ylamino)butan-2-yl)acetamide
To a solution of tert-butyl (2S,3R)-1-(allyloxy)-3-(tert-
butyldimethylsilyloxy)-4-(2,2-
spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-
ylamino)butan-2-
ylcarbamate (0.033 g, 0.05 mmol) in 1,4-dioxane (1.0 mL), was added a solution
of HCI
(0.6 mL, 4 M in 1,4-dioxane). The mixture was stirred at ambient temperature
for a period
of 24 h then conc. in vacuo. The crude residue obtained was diluted with EtOAc
(20 mL)
and sat'd NaHCO3 (10 mL). The resulting aqueous layer was extracted with EtOAc
(2 x 25
mL) and the combined organic extracts were washed with brine, dried (Na2SO4),
filtered,
and conc in vacuo. The crude amino alcohol obtained was immediately dissolved
in
CH2CI2 (1.0 mL) and treated with N,N-diisopropylethylamine (0.05 mL, 0.3 mmol)
followed by N-acetyl-imidazole (0.006 g, 0.06 mmol). The mixture was stirred
at ambient
temperature for 15 h then conc in vacuo. Purification on Si02 (2.5%
MeOH*/CH2CI2;*2.0
M NH3 in MeOH) gave the title compound as a white solid. MS m/z: 446 (M+1).
Example 503
N-((1 S,2R)-3-(((1 S)-3,3-dim ethyl-7-((3S)-tetrahydro-3-furanyloxy)-1,2,3,4-
tetrahydro-l-naphthalenyl)amino)-2-hydroxy-l-(phenylmethyl)propyl)acetamide
Step 1. Diethyl 2-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)malonate
Diethylisopropylidenemalonate (6.686 ml, 34.09 mmol) was dissolved in 300 ml
Et2O
and cooled to -78 C. 4-Methoxybenzylmagnesium chloride (150.000 ml, 37.50
mmol)
was added and stirring was continued for 5h. The temperature was warmed up to
0 C.
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The reaction was hydrolyzed with 0.5 M HCl and extracted 3 x EtOAc. Glass col.
Chromatography (10-50 %EtOAc in Hex.) provided diethyl 2-(1-(4-methoxyphenyl)-
2-
methylpropan-2-yl)malonate. MS m/z: 323.1 (M+l ).
Step 2: 7-Methoxv-3 3-dimethyl-3 4-dihydronaphthalen-1(2H)-one contaminated
with 2-
chloro-7-methoxy-3 3-dimethvl-3,4-dih dy ronaphthalen-1(2H)-one
Diethyl 2-(1-(4-methoxyphenyl)-2-methylpropan-2-yl)malonate (6.841 g, 21.22
mmol)
was dissolved in 30 ml MeOH and 100 ml of 50% NaOH (aq.) was added. The
mixture
was refluxed for 4h. The cooled slurry was acidified (cone. HCl) and extracted
4 x EtOAc
(400 ml each). The combined organic extracts were dried over MgSO4 and
evaporated.
The crude oil was next heated to 180 C for lh (decarboxylation). The reaction
mixture
was dissolved in 150 ml benzene and phosphorus pentachloride (6.000 g, 28.81
mmol)
was added. The mixture was refluxed for 45 min and cooled to 0 C. Stannic
chloride
(2.483 ml, 21.22 mmol) was added and the mixture was refluxed for lh. The
mixture was
cooled to 0 C and washed with 2.5M HCl (aq.). The organic phase was
evaporated.
LCMS analysis showed the formation of 2 products approx. 1:1. The products
almost co-
elute on silica. The product mixture was obtained by glass col. chrom. (5-25%
EtOAc in
Hex.): 3g of a yellow oil.
The chlorinated product was characterized by IH NMR of a pure fraction, as was
the
desired title compound (MS m/z: 205.1 (M+1)).
Step 3: 7-Methoxv-3,3-dimethvl-3,4-dih dronaphthalen-1(2H)-one
The product mixture from the previous reaction was dissolved in 30 ml THE and
cooled
to 0 C. 30 ml Rieke Zn (5g in 100 ml THF) was added and the mixture was
stirred for
2.5 h at 0 C. The reaction was hydrolyzed with 20 ml H2O and evaporated. The
mixture
was dissolved in 100 ml DCM and dried over MgSO4, evaporated. Glass col.
Chrom.
afforded 7-methoxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one as a yellow
oil.
Step 4: 7-Hydroxy-3,3-dimethvl-3,4-dihydronaphthalen-1(2H)-one
7-Methoxy-3,3-dimethyl-3,4-dihydronaphthalen- I (2H)-one (2.25 g, 11.0
mmol)was
dissolved in 30 ml CH2Cl2 and cooled to -78 C. Boron tribromide (25.000 ml,
25.0
mmol) was added and the reaction was stirred for 6h. The temperature was
elevated to
0 C during this time. The mixture was pored into ice and extracted 3 x EtOAc
(300 ml
each). The combined organic extracts were dried over MgSO4 and evaporated.
Glass col.
Chrom. gave 7-hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one as a yellow
solid. MS m/z: 191.1 (M+1).
Step 5: (S)-3 3-Dimethyl-7-(tetrahydrofuran-3-yloxy)-3,4-dihydronaphthalen-
1(2H)-one
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7-Hydroxy-3,3-dimethyl-3,4-dihydronaphthalen- I (2H)-one (0.95 g, 4.99 mmol)
was
dissolved in 30 ml DCMand triphenylphosphine (1.96 g, 7.49 mmol) and
diisopropyl
azodicarboxylate (1.23 ml, 6.24 mmol) and (r)-(-)-3-hydroxytetrahydrofuran
(0.600 ml,
7.49 mmol) was added. The mixture was stirred over night. 0.5M HCI (aq.) was
added
and the mixture was extracted 3 times with EtOAc. Glass col. Chrom. (5-30%
EtOAc in
Hex.) provided (S)-3,3-dimethyl-7-(tetrahydrofuran-3-yloxy)-3,4-
dihydronaphthalen-
1(2H)-one as a yellow oil. MS m/z: 261.1 (M+1).
Step 6: N-((1 S,2R)-3-(((1 S)-3,3-dimethyl-7-((3S)-tetrahydro-3-furanyloxy)-
1,2,3,4-
tetrahydro-l-naphthalenyllamino)-2-hydroxy- l-(phenylmethyl)propyl)acetamide
The title compound was made from the product from step 5 by a method analogous
to that
described in Example 464, steps 8-10. MS Found m/z: 467.3 (M+1).
Example 504
N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((5'S)-3'-(2,2-dimethylpropyl)-
5',6'-
dihydrospiro[cyclobutane-1,7'-pyrano[2,3-c] pyridazin]-5'-yl)amino)-2-
hydroxypropyl)acetamide.
Step 1. N-(2-(I-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(3-chloro-6-
neopentylpyridazin-4-yl)ethyl)-2-methylpropane-2-sulfinamide
2,2,6,6-Tetramethylpiperidine (0.68 ml, 4.0 mmol) was dissolved in 120m1 THE
and 1-
butyllithium (1.5 ml, 3.8 mmol) was added at -78 C drop wise. The mixture was
allowed
to warm to 0 C (over a period of 5 min) and kept there for 5 min. The mixture
was cooled
back to -78 C and a solution of 3-chloro-6-neopentylpyridazine (0.45 g, 2.4
mmol) in 10
ml of THE was added drop wise. Stirring was continued for 20 min and a
solution of(E)-
N-(2-(l-(tert-butyldimethylsilyloxy)cyclobutyl)ethylidene)-2-methylpropane-2-
sulfinamide (1.450 g, 4.4 mmol) in 5 ml THE was added drop wise. Stirring was
continued for 10 min and the mixture was hydrolyzed with H2O. The mixture was
extracted with EtOAc (3x 300 ml) dried over MgSO4 and evaporated. The crude
product
was used in the next step without further purification.
Step 2: (S)-7,7-Spirocyclobutyl-3-neopentyl-6,7-dihydro-5H-pyranoj2,3-
clpyridazin-5-
amine
N-(2-(1-(tert-Butyldimethylsilyloxy)cyclobutyl)-1-(3-chloro-6-
neopentylpyridazin-4-
yl)ethyl)-2-methylpropane-2-sulfinamide (0.870 g, 2 mmol) was dissolved in 20
ml of
THE and tetrabutylammonium fluoride, 1.0m in THE (0.5 ml, 2 mmol) was added at
RT.
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The mixture was stirred for 10 min and filtered through a plug of silica (wash
with THF).
The mixture was died over MgSO4 and evaporated and re-dissolved in 200 ml of
THF.
NaH (60%) (0.3 g, 7mmol) was added and the mixture was heated to 66 for 3h.
The
mixture was hydrolyzed with water and extracted 3 times with EtOAc (200 ml
each). The
crude product (MS m/z: 366.2 (M+1)) was re-dissoolved in 5 ml MCOH and 15 ml
4M
HCl in dioxane was added. The mixture was stirred for lh and evaporated and
purified on
the HPLC. The Product was obtained as a brown solid.
Step 3: N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((5'S)-3'-(2,2-
dimethylpropyl)-
5',6'-dihydrospirofcyclobutane-1,7'-pyranor2.3-clpyridazin]-5'-yl)amino)-2-
hydroxypropyl)acetamide
The title compound was made from the product from step 5 by a method analogous
to that
described in Example 464, steps 8-10. MS Found m/z: 503.2 (M+1).
Example 505
N-((1 S,2R)-3-(((4' S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4'-
dihyd rospiro [cyclobutane-1,2'-pyrano [2,3-b] pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide; and
N-((1 S,2R)-3-(((ls,3R,4' S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
Step 1: 1,3-Ditosyloxy-2-methyl-propane
2-Methylpropane-1,3-diol (50 g, 555 mmol) was dissolved in 555 ml pyridine and
cooled
to 0 C. p-Toluenesulfonyl chloride (212 g, 1110 mmol) was added and stirring
was
continued over night. 200 ml H2O was added and the reaction was extracted with
DCM
(2 x 1L). The combined organic extracts were dried over MgSO4 and evaporated.
The
product was recrystallized from EtOH/Hex and the product was obtained as a
white solid.
MS m/z: 399.0 (M+1).
Step 2: 3-Methyl-1SmethylsulfinylL(methylthio)cyclobutane
Methylsulfinyl(methylthio)methane (29.927 g, 240.91 mmol) was dissolved in 500
ml
THE and cooled to -10 C. Butyllithium (96.363 ml, 240.91 mmol) was added
slowly and
stirring was continued for 2h. 1,3-Ditosyloxy-2-methyl-propane (48.000 g,
120.45mmol)
was added at -10 C and the mixture was allowed to warm up to RT. Stirring was
continued over night. 150 ml H2O was added and the mixture was extracted with
DCM,
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dried over MgSO4 and evaporated. The crude material was filtered through a
silica plug
and used without further purification in the next step.
Step 3: 3-Methylcyclobutanone
Crude 3-Methyl-l-(methylsulfinyl)-1-(methylthio)cyclobutane (11.300 g, 63.371
mmol)from the previous step was dissolved in 50 ml Et2O and 20 ml conc. HCI
was
added. The mixture was distilled at 1 atm and 80 C: ether comes over.
Temperature was increased to 110-120 C where the product (along with some
water) was
collected. This fraction was diluted with 100 ml ether, dried over MgSO4 and
evaporated
(carefully) to give 3-methylcyclobutanone.
Step 4: 1-Allyl-3-methylcyclobutanol
Methylcyclobutanone (3.200 g, 38.043 mmol) was dissolved in 200 ml THE and
allylmagnesium bromide (190.21 ml, 190.21 mmol) was added in one portion. The
mixture was stirred for 4h at RT, hydrolyzed with water and extracted. The
combined
organic extracts were dried over MgSO4 and evaporated and purified via glass
col.
Chrom. (25-75% hex. in EtOAc). 1-AllyI-3-methylcyclobutanol (2.250 g, 46.9%
yield)
was obtained as a mixture of cis-trans isomers approx. 4:1 (where the major
compound is
the one Me-cis to OH) based on NMR.
Step 5: (1-Allyl-3-methylcyclobutoxy)(tent-butyl)dimethylsilane
1-Allyl-3-methylcyclobutanol (2.25000 g, 17.8 mmol) (the 4:1 mixture of
cis/trans-
isomers) was dissolved in 50 ml of CH2C12 and DIEA (5.59 ml, 32.1 mmol) and
tert-
butyldimethylsilyl triflate (5.73 ml, 25.0 mmol) were added. The mixture was
stirred for
2h and hydrolyzed with water, extracted with 200 ml Et20 (3x each), dried over
MgSO4
and evaporated. Glass col. chrom. (10-30% EtOAc in Hex.) provided (1-allyl-3-
methylcyclobutoxy)(tert-butyl)dimethylsilane as a yellow oil. Mixture of
cis/trans at the
cyclobutylring (4:1)
Step 6: (E)-N-(2-(1-(tert-butyldimethylsilyloxy) 3-methyIcyclobutyl)eth ly
idene)-2-
methyllpropane-2-su lfi namide
(1-Allyl-3-methylcyclobutoxy)(tert-butyl)dimethylsilane (4.1000 g, 17.05 mmol)
was
dissolved in 150 ml of t-BuOH/H20/THF (2/2/1) and osmium tetroxide (10.84 ml,
0.8525 mmol, 2.5 wt%) and 4-methylmorpholine oxide (2.996 g, 25.58 mmol) were
added. The mixture was stirred for 6h and the mixture was diluted with 250 ml
water and
extracted with EtOAc. The combined organic extracts were evaporated and re-
dissolved
in 150 ml of t-BuOH/H20/THF (2/2/1). Sodium periodate (4.741 g, 22.17 mmol)
was
added and stirring was continued for 6h. The mixture was filtered and diluted
with 250 ml
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of water. The mixture was extracted with Et2O and the combined organic
extracts were
dried over MgSO4, evaporated and re-dissolved in 100 ml CH2CI2. Cupric sulfate
anhydrous (8.164 g, 51.15 mmol), and(r)-( )-2-methyl-2-propanesulfinamide
(4.133 g,
34.10 mmol) were added at RT and stirring was continued over night. The
reaction was
filtered and hydrolyzed with 30 ml water. The mixture was extracted 3 x EtOAc
(3x 150
ml) and the combined organic extracts were dried over MgSO4 and evaporated.
Glass col.
chrom. (20-50% EtOAc in Hex) provided (E)-N-(2-(l -(tert-
butyldimethylsilyloxy)-3-
methylcyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide. Mixture of
cis/trans at the
cyclobutylring (4:1).
Step 7: N-((S)-2-(1-(tert-butyldimethylsilyloxy)-3-methylc clobutyl)-1-(2-
fluoro-5-
neopentylpyridin-3-ylethyl)-2-methylpropane-2-sulfinamide
2,2,6,6-Tetramethylpiperidine (2.47 ml, 14.7 mmol) was dissolved in 100 ml THE
and
cooled to -78 C. 1-Butyllithium (5.23 ml, 13.1 mmol, 2.5M) was added and the
reaction
was allowed to warm up to 0 C for 5 min before it was cooled back to -78 C
again. At
this point, a solution of 2-fluoro-5-neopentylpyridine (1.75000 g, 10.5 mmol)
was added
dropwise and the reaction was stirred for 1h. Next, a solution of (E)-N-(2-(1-
(tert-
butyldimethylsilyloxy)-3-methylcyclobutyl)ethylidene)-2-methylpropane-2-
sulfinamide
(3.98 g, 11.5 mmol) in THE was added dropwise and stirring was continued for
lh. The
mixture was hydrolyzed with NH4CI in the cold, warmed up to RT extracted with
EtOAc
(3x 150 ml), dried over MgSO4 and evaporated. N-((S)-2-(1-(tert-
Butyldimethylsilyloxy)-3-methylcyclobutyl)-1-(2-fluoro-5-neopentylpyridin-3-
yl)ethyl)-
2-methylpropane-2-sulfinamide (3.30 g, 61.5% yield) was obtained after glass
col.
Chrom. (20-70% EtOAc in Hex.). Low yield due to the formation of a minor
diastereomer
at the NH center (approx 30%). Mixture of cis/trans at the cyclobutylring
(4:1).
Step 8: N-((l S,2R)-3-(((4'S)-6'-(2,2-Dimethylpropyl -3-meth lY 3',4'-
dih drospiro[cyclobutane-1,2'-pyrano(2,3-blpyridinl-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide; and
N-((1 S,2R)-3-(({1s,3R,4'S)-6'-(2,2-dimethylpro)yl)-3-methyl-3',4'-
dihydrospirojcyclobutane-1,2'-pyrano12,3-blpyridinl-4'-yl)amino)-1-((4-
fluorophenyl methyl)-2-hydroxypropyl)acetamide
N-((S)-2-(1-(Tert-butyldimethylsilyloxy)-3 -methylcyclobutyl)-1-(2-fluoro-5-
neopentylpyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (3.30 g, 6.435
mmol) was
dissolved in 60 ml THE and tetrabutylammonium fluoride, (1.0 M in THF; 6.435
ml,
6.43 5 mmol) was added. The mixture was stirred for 30 min and filtered
through a plug of
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silica (wash with THF). The solution was evaporated and redissolved in 600 ml
THF.
NaH (0.74 g, 32.17 mmol, 60% in mineral oil) was added and the reaction was
heated up
to 65 C for 3h. The mixture was hydrolyzed carefully with water and extracted
3 times
with EtOAc (3x 200 ml). The combined organic extracts were dried over MgSO4
and
evaporated. The crude product was dissolved in 20 ml McOH and 20 ml 4M HC1 in
dioxane was added. The reaction was stirred for I h, basified with NaOH (5M
aq.) and
extracted 4 times with 200 ml EtOAC (each). Glass col. Chrom. gave the 2
products
which were submitted for separation of the diastereomers. The major isomer was
identified to be the one where the 0 and the Me group are cis to each other
(NOE).
Prior to separation, the title compound, a 4:1 mixture, was made by the method
described in Example 464, steps 8-10. MS Found m/z: 498.2 (M+1).
Example 506
N-((1S,2R)-3-(((1s,3S,4'S)-6'-(2,2-dimethylpropyl)-3-hydroxy-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-1-((4-
fl uorop henyl)methyl)-2-hyd roxyp ropyl)acetamide.
Step 1: 1-((1,3-Dibromopropan-2-yloxv)methyl benzene
2-Benzyloxy-l,3-propanediol (15.000 g, 82.32 mmol) was dissolved in CH2C12
(500m1)
and carbon tetrabromide (81.90 g, 247.0 mmol) and triphenylphosphine (64.77 g,
247.0
mmol) were added. The mixture was stirred overnight and concentrated. The
reaction
was suspended in hexanes and filtered and evaporated to afford the title
compound.
Step 2: 3-(Benzyloxy)cyclobutanone Methylsulfinyl(methylthio)methane (13 ml,
125
mmol) was dissolved in 250 m] THE and cooled to -20 C. n-Butyllithium (50 ml,
125
mmol) was added and the mixture was stirred for 3h at -20 C. The mixture was
cooled
down to -78 C and a solution of 1-((1,3-dibromopropan-2-yloxy)methyl)benzene
(16.000
g, 52 mmol) was added. The reaction was stirred over night and allowed to warm
up to
RT. It was stirred for an additional 6h at RT, hydrolyzed with water and
extracted with
EtOAc. The combined organic extracts were evaporated, dissolved in ether (50
ml) and
treated with conc. HC1(10 ml) for 30 min at reflux. The mixture was
neutralized with
NaOH (I OM) and extracted with EtOAc. The combined organic extracts were dried
over
MgSO4 and evaporated. Glass col. Chrom. (10-50 % EtOAc in Hex) gave 3-
(benzyloxy)cyclobutanone as a yellow oil.
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Step 3: N-((1S,2R)-3-(((1s,3S,4'S)-6'-(2 2-dimethylpropyl)-3-h droxy-3' 4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2 3-blpyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxvpropyl)acetamide
The title compound was prepared in a manner analogous that described in
Example 505.
MS Found m/z: 500 (M+l).
Example 507
N-((1 S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4'S)-6'-((2S)-tetrahydro-2-
furanylmethyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b] pyridin]-4'-
yl)amino)propyl)acetamide; and
N-((1 S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4' S)-6'-((2R)-tetrahyd ro-2-
furanylmethyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b] pyridin]-4'-
yl)amino) propyl)acetam ide
Step 1: (4S 5R)-tert-butyl 4-benzyl-2 2-dimethyl-5-(((S)-6-((tetrahydrofuran-2-
yi)methyl)
2,2-spirocyclobutvl-3 4-dihvdro-2H-pyrano[2 3-blpyridin-4-
ylamino)methyl)oxazolidine 3
carboxylate
A solution of sodium tert-butoxide (74 mg, 769 mol), Pd2(dba)3 (16 mg, 17
gmol) and 1-
(diphenylphosphino)-2-(2-(diphenylphosphino)phenoxy)benzene (19 mg, 35 mol)
in 5mL
of THE was purged with nitrogen for 15 minutes at which point (4S,5R)-tert-
butyl 4-
benzyl-5-(((S)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
4-
ylamino)methyl)-2,2-dimethyloxazolidine-3-carboxylate (200 mg, 349 mol) and
pent-4-
en-1-ol (36 l, 349 gmol) were added. The resulting slurry was then heated at
70 C for 8
hours. The cooled reaction mixture was diluted with EtOAc (15 mL) and poured
into 10%
sodium bicarbonate (25 mL). The layers were separated and the aqueous layer
was
extracted with ethyl acetate 3 x 15 mL. The combined organic layers were
washed with
water then brine and dried over sodium sulfate. After filtration and
concentration the
residue was purified by silica gel chromatography (0-100% ethyl acetate in
hexanes) to
provide the title compound as a yellow oil. MS m/z: 578.2 (M+1).
Step 2: N-((I S,2R)-2-hydroxy-l-(phen llmeth lY)-3-(((4'S)-6'-((2S)-tetrahvdro-
2-
furanylmethyl)-3',4'-dihydrospiro[cyclobutane-1 2'-pyrano[2 3-b]pyridinl-4'-
yl)amino)propylLcetamide: and
N-((1 S,2R)-2-hydroxy-1 -(phenylmethyl)-3-(((4'S)-6'-((2R)-tetrahvdro-2-
furanylmethyl)
3'.4'-dihydrospiro[cyclobutane-1,2'-pyrano[2 3-b]pyridinl-4'-
yl)amino)propyl)acetamide
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The title compounds were prepared in a manner analogous that described in
Example 464,
steps 8-10. MS Found m/z: 480 (M+1).
Example 508
N-((1S,2R)-2-hydroxy-3-(((4' S)-6'-(((2S)-2-methyltetrahydro-2-furanyl)methyl)-
3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano [2,3-b] pyridin]-4'-yl)amino)-1-
(phenylmethyl)propyl)acetamide; and
N-((1 S,2R)-2-hydroxy-3-(((4' S)-6'-(((2R)-2-m ethyltetrahydro-2-fu
ranyl)methyl)-
3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-1-
(phenylmethyl)propyl)acetamide.
Step 1: (4S,5R -tert-butyl 4-benzyl-2,2-dimethyl-5-(((S)-6-((2-methyl-
tetrahydrofuran-2-
yl)methyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-blpyridin-4-
ylamino)methyl)oxazol idine-3-carboxylate
1-(diphenylphosphino)-2-(2-(diphenylphosphino)phenoxy)benzene (29 mg, 0.054
mmol)
and Pd2(dba)3 (25 mg, 0.027 mmol) were combined in a sealed tube and lmL of
THE was
introduced. After stirring for 5 minutes, sodium tert-butoxide (130 mg,
1.35mmol) was
added followed by a solution of (4S,5R)-tert-butyl 4-benzyl-5-(((S)-6-bromo-
2,2-
spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)methyl)-2,2-
dimethyloxazolidine-3-carboxylate (310 mg, 0.541 mmol) and 4-methylpent-4-en-l-
ol (81
mg, 0.812mmol) in 3mL of THF. The tube was sealed and heated at 70 C for 8
hours. The
cooled reaction mixture was diluted with EtOAc (5mL) and poured into 10%
sodium
bicarbonate (25mL). The layers were separated and the aqueous layer was
extracted with
ethyl acetate 3 x 25mL. The combined organic layers were washed with water and
brine
and dried over sodium sulfate. After filtration and concentration the residue
was purified
by silica gel chromatography (0-100% ethyl acetate in hexanes) to provide the
title
compound as a yellow oil. MS m/z: 592.2 (M+l).
Step 2: N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(((2S)-2-meth ltetrahydro-2-
furanyl)methyl)-
3',4'-dihydrospiro[cvclobutane-1.2'-pyrano[2,3-b]pyridinl-4'-yl)amino)-1-
(phen l~yl)propyl)acetamide; and N-((1 S,2R)-2-h droxy-3-(((4'S)-6'-(((2R)-2-
meth lt~ydro-2-furan 1)~ methyl)-3',4'-dihydrospiro[cvclobutane-1,2'-pyrano[2
3-
blpyridinl-4'-yl)amino)-1-(phenylmethyl)propyl)acetamide
The title compounds were prepared in a manner analogous that described in
Example 464,
steps 8-10. MS Found m/z: 494 (M+1).
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Example 509
N-((1 S,2R)-3-(((2R,4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihydro-2H-
chromen-4-yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)acetamide; and
N-((1 S,2R)-3-(((2 S,4S)-6-bromo-2-methyl-2-(trifluoromethyl)-3,4-dihyd ro-2H-
chromen-4-yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)acetamide
Step 1: Z)-2-(1-(benzylimino)ethyl)-4-bromophenol
A mixture of 5"-bromo-2"-hydroxyacetophenone (15.0 g, 69.8 mmol) and
benzylamine
(7.62 ml, 69.8 mmol) in ethanol was stirred at RT for 3 h. The resulting
suspension was
filtered and rinsed with hexane. The crystalline solid was dried in vacuum to
afford (Z)-2-
(1-(benzylimino)ethyl)-4-bromophenol as a bright yellow solid. MS rn/z: 304.
Step 2: (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-1 1 1 -trifluorobut-3-
en-2-one
To a solution of (Z)-2-(1-(benzylimino)ethyl)-4-bromophenol (18.0 g, 59.2
mmol) in
anhydrous THE was added lithium hydride (1.65 g, 207 mmol) portion wise at
room
temperature. The resulting mixture was heated in a oil bath (60 C) to
initialize the reaction
(cool down the mixture with a ice bath). Once the reaction is slowing down,
the mixture
was heated at 70-75 C for 24 h (reaction was monitored by using TLC and LCMS).
At this
point, there was still trace amount of SM left (MS+ = 304). The mixture was
concentrated
to dryness under vacuum. The residue was treated with 120 ml of 7% AcOW H20.
The
precipitate that formed was filtered and rinsed with water. The solid was
dried in vacuum to
give (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-1,1,1-trifluorobut-3-en-2-
one as a
orange color solid. MS m/z: 400. The crude material was used without further
purification
in the next step.
Step 3: (Z)-N-(6-bromo-2-(trifluoromethyl)-4H-chromen-4-
yllidene)(phenyl)methanamine
To a cooled (ice bath) EtOH (96 ml) was bubbled through hydrogen chloride gas
for 30
min. (Z)-4-(benzylamino)-4-(5-bromo-2-hydroxyphenyl)-1,1,1-trifluorobut-3-en-2-
one
(24.0 g, 60 mmol) was then added in one portion to this solution. The reaction
was stirred at
RT for 36 h. The resulted mixture was diluted with 900 ml of cool water, 28%
aq NH3 (96
ml) was then added. The precipitate formed was filtered and washed with water
to give a
brown sticky solid. The solid was dissolved in EtOAc, washed with IN HCl and
brine. The
organic layer was dried over Na2SO4, filtered and concentrated. The residue
was
crystallized from hexane to give the title compound as a brown solid. MS m/z:
382.
Step 4: 6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-one
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A mixture of malonic acid (1.2 ml, 19 mmol) and (Z)-N-(6-bromo-2-
(trifluoromethyl)-4H-
chromen-4-ylidene)(phenyl)methanamine (6.63 g, 17 mmol) in dioxane was heated
to
reflux for 18h until the reaction was completed. The mixture was cooled to RT
and treated
with 50% EtOH/H2O (20 ml) followed by cone. HCI (5.0 m]). The resulted mixture
was left
to stand at RT for 40 min, and then diluted with water (500 ml). The product
was extracted
with hexane (3 x 300 ml). The organic layers were combined, dried over Na2SO4,
filtered
and concentrated. The residue was purified on silica gel column (2-10%
EtOAc/hexane) to
afford the title compound as yellow oil. MS m/z: 310 (M+1).
Step 5: (4R)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-ol
To a cooled (ice bath) solution of (s)-2-methyl-cbs-oxazaborolidine 1.0 M in
toluene (100
l, 100 iimol) was added borane-dimethyl sulfide 2.0 M in THE (500 l, 1000
lcmol). After
stirred 15 min, a solution of 6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-
one (309 mg,
1000 gmol) in toluene was added drop wise. The reaction was completed after
stirring 9h at
0 C. 2N HCI was added slowly to quench the reaction. The resulted mixture was
extracted
with EtOAc. The organic layer was washed with water and brine, dried over
Na2SO4,
filtered and concentrated. The residue was purified on silica gel column to
afford the title
compound.
Step 6:(4S)-4-azido-6-bromo-2-methyl-2-(trifluoromethyl)chroman
To a cooled (ice bath) solution of (4R)-6-bromo-2-methyl-2-
(trifluoromethyl)chroman-4-ol
(277 mg, 890 .tmol) was added drop wise diphenylphosphoryl azide (249 l, 1158
mol).
After stirring 20 min, 1,8-diazabicyclo(5.4.0)undec-7-ene (173 l, 1158 pmol)
was added
drop wise. The reaction was stirred at the same temperature for 2h, then
stirred 15h at
ambient temperature. Water was added to quench the reaction. The resulted
mixture was
extracted with EtOAc. The organics were washed with brine, dried over Na2SO4,
filtered
and concentrated. The residue was purified on a silica gel column (5-20%
EtOAc/hexane)
to afford the title compound. MS m/z: 308(M-N2).
Step 7: (4S)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-amine
To a solution of (4S)-4-azido-6-bromo-2-methyl-2-(trifluoromethyl)chroman (190
mg, 565
p.mol) was added triphenylphosphine (222 mg, 848 p.mol). The mixture was
stirred at RT
for 4h. Water (15 ml) was added and the reaction was heated at refluxing for
24 h. The
resulted mixture was concentrated to dryness and extracted with CHCI3. The
organic layer
was dried over anhydrous Na2SO4, filtered, concentrated and dried in vacuum to
afford the
title compound. MS m/z: 293, 295(M-NH2).
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Step 8: tert-Butyl (2S,3R)-4-((4S)-6-bromo-2-methyl-2-(trifluoromethvl)-3 4-
dihvdro-2H-
chromen-4-ylamino)-3 -hydroxy-l -phenylbutan-2-ylcarbamate
A mixture of (4S)-6-bromo-2-methyl-2-(trifluoromethyl)chroman-4-amine (179 mg,
577
gmol) and tert-butyl (S)-1-((S)-oxiran-2-yl)-2-phenylethylcarbamate (198 mg,
750 gmol) in
ethanol was heated at reflux for 16 h. At this point, there was still the
starting amine left. An
additional 1.3 eq of epoxide was added to the reaction, and continued to
reflux for 6 h. The
resulted mixture was concentrated and purified on Shimadzu HPLC to afford the
title
compound as a TFA salt. MS m/z: 573, 575.
Step 9: N-((I S,2R)-3-(((2R4S)-6-bromo-2-methyl-2-(trifluoromethvl -3 4-
dihvdro-2H-
chromen-4-yl)amino)-2-hvdroxy -l-(phenvlmethyl)propyl)acetamide and
N-((l S,2R)-3-(((2S,4S)-6-bromo-2-methyl-2-(trifluoromethvl)-3 4-dihvdro-2H-
chromen-4-
yl)amino)-2-hvdroxy-l-(phenyl methyl)propyl)acetamide
To a solution of (2R,3S)-3-amino-l-((4S)-6-bromo-2-methyl-2-(trifluoromethyl)-
3,4-
dihydro-2H-chromen-4-ylamino)-4-phenylbutan-2-ol dihydrochloride (160 mg, 338
gmol)
in DMF was added 1-(IH-imidazol-1-yl)ethanone (37.2 mg, 338 gmol) followed by
DIPEA
(177 gl, 1014 gmol). The reaction was stirred at RT for 30 min, then diluted
with MeOH
and purified on Shimadzu HPLC to afford 43.0 mg of the title compounds as a
mixture. MS
m/z: 515, 517.
Example 510
N-((1 S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4S)-6-(2,2,2-trifluoroethyl)-3,4-
dihyd rospiro [chromene-2,1'-cyclobutan]-4-yl)amino)propyl)acetamide
Step 1: 2,2,2-trifluoro-l-(4-hydroxyphenylethanone
To a cooled (-78 C) solution of 2,2,2-trifluoro-4'-methoxyacetophenone (15 ml,
73 mmol)
in DCM was added 1.0 M tribromoborane (73 ml, 73 mmol) drop wise. After the
addition
was completed, the reaction was slowly warmed to RT and stirred for overnight
(15 h). At
this point, reaction was completed by TLC. The product mixture was poured into
ice water.
The organic layer was washed with 10% aq Na2CO3, water and brine, dried over
Na2SO4,
filtered and concentrated. The residue was purified on silica gel column (5-
40%
EtOAc/hexane) to afford the title compound as a white crystalline solid. The
major side
product was a colorless oil with MS+ = 379.
Step 2: 4-(2,2,2-trifluoro- l -hydroxyethyl)phenol
To a solution of 2,2,2-trifluoro- I -(4-hydroxyphenyl)ethanone (5.0 g, 26
mmol) in
dichloroethane was added zinc iodide (2.7 ml, 39 mmol) followed by sodium
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cyanoborohydride (10 ml, 197 mmol). The reaction was stirred at RT for 18 h.
Both TLC
and LCMS showed one product was formed. MS+ = 175 (desired mass 192 - OH). The
mixture was filtered through celite and rinsed with dichloromethane. The
filtrate was
concentrated and dried in vacuum to afford the title compound as colorless
oil. MS m/z:
175(M-H20).
Step 3: 4-(1-chloro-2,2,2-trifluoroethyl)phenol
To a cooled (ice bath) mixture of 4-(2,2,2-trifluoro-l-hydroxyethyl)phenol
(4.3 g, 22 mmol)
and anhydrous pyridine (1.8 ml, 22 mmol) in toluene was added thionyl chloride
(SOC12)
(2.3 ml, 31 mmol) drop wise via a syringe. After stirred for 1 hat 0 C, the
reaction was
heated at 70 C for 2h. At this point, reaction did not go completion,
indicated by LCMS.
Heating was continued for 16 h. Reaction was quenched with ice water. The
resulted
mixture was diluted with EtOAc. The organic layer was washed with saturated
Na2CO3,
water and brine. After dried over Na2SO4, the solution was filtered and
concentrated. The
residue was purified on a silica gel column (5-10% EtOAc/hexane) giving the
title
compound as a light yellow oil. MS nz/z: 211(M 1).
Step 4: 4-(2,2,2-trifluoroethyl)phenol
To a solution of4-(1-chloro-2,2,2-trifluoroethyl)phenol (3.60 g, 17.1 mmol) in
THE was
added sodium borohydride (0.903 ml, 25.6 mmol) in one portion. The reaction
was stirred
at RT for 18 h, and then quenched with MeOH. The resulting mixture was
concentrated and
diluted with EtOAc. After washed with water and brine. The organic layer was
dried over
Na2SO4, filtered and concentrated. The residue was dried in vacuum to afford 4-
(2,2,2-
trifluoroethyl)phenol as a colorless oil. MS m/z: 175(M-1).
Step 5: 1 -(2-hydrox5-(2,2 2-trifluoroethyl)phenyl)ethanone To a solution of 4-
(2,2,2-
trifluoroethyl)phenol (1.00 g, 5.68 mmol) in CH2CI2 (5.0 ml) was added
trifluoromethanesulfonic acid (0.0151 ml, 0.170 mmol) with stirring. A
solution of acetic
chloride (0.444 ml, 6.25 mmol) in CH2Cl2 (5.0 ml) was added drop wise to the
reaction.
After stirred 45 min at RT, all the phenol was consumed. The product mixture
was diluted
with CH2C12, washed with saturated sodium bicarbonate. The organic layer was
dried over
Na2SO4, filtered and concentrated. The residue was dried in vacuum until no
weight loss
was observed. To the above residue was added anhydrous aluminum(111) chloride
(0.757 g,
5.68 mmol). The mixture was heated at 150 C for lh until all the starting
material was
consumed (monitored by TLC). The resulted brown gum was cooled'to 0 C, diluted
with
diethyl ether and IN HCI. Layers'were separated. The aqueous layer was
extracted with
ether. The organic layers were combined, dried over Na2SO4, filtered and
concentrated.
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The residue was purified on silica gel column (2-15% EtOAc/hexane) to afford
the title
compound.
Step 6: 2.2-spirocyclobutyl-6-(2 2 2-trifluoroethyl -2 3-dihydrochromen-4-one
A solution of 1-(2-hydroxy-5-(2,2,2-trifluoroethyl)phenyl)ethanone (320 mg,
1467 mol),
cyclobutanone (617 mg, 8800 mol), N-ethyl-N-isopropylpropan-2-amine (569 mg,
4400
l.tmol) and pyrrolidine (313 mg, 4400 mol) in ACN was heated in microwave at
75 C for
2h. The resulted mixture was diluted with EtOAc, washed with IN HCI, saturated
Na2CO3
and brine. The organics were dried over Na2SO4, filtered and concentrated. The
residue
was purified on silica gel column (2-15% EtOAc/hexane) to afford the title
compound.
Step 7: (R)-2 2-spirocyclobutyl-6-(2 2 2-trifluoroethvl)-3 4-dihvdro-2H-
chromen 4 of
The title compound was prepared according to the methods described in step 5
of
Example 509. MS m/z: 255(M+1-H20).
Step 8: (S-4-azido-2,2-spiroc clobuty1-6-(2 2 2-trifluoroethvl)-3 4-dihvdro-2H-
chromene
The title compound was prepared according to the methods described in step 6
of
Example 509. MS m/z: 270(M+1-N2).
Step 9: (S)-2,2-spirocyclobutyl-6-(2,2 2-trifluoroethvl -3 4-dihvdro-2H-
chromen-4-amine
The title compound was prepared according to the methods described in step 7
of
Example 509. MS rn1z: 255(M-NH2).
Step 10: (4R, 5S)-tert-butyl5-benzyl-4-((6-(2 2 2-trifluoroethvl)-2 2-spiroc
cly obutyl-3 4-
dihvdro-2H-chromen-4-ylamino)methyl)-2 2-dimethylpyrrolidine-I-carboxylate
To a stirred solution of (S)-2,2-spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-
dihydro-2H-
chromen-4-amine (40 mg, 147 gmol) in DCM was added (4S,5S)-tert-butyl 4-benzyl-
5-
formyl-2,2-dimethyloxazolidine-3-carboxylate (71 mg, 221 mol) followed by
tirmethoxymethane (161 l, 1475 gmol). After stirred for 1/2 h, sodium
cyanoborohydride
(46 mg, 737 mol) was added to the reaction. After stirred 3 h at RT, most of
the amine was
consumed. The reaction was quenched by the addition of saturated Na2CO3 and
diluted
with CH2CI2. The resulted mixture was extracted with CH2CI2 (2x). The combined
organics were washed with brine, dried over Na2SO4, filtered and concentrated.
The
residue was purified on silica gel column to afford the title compound. MS
m/z: 575(M+1).
Step 11: N-((1 S 2R)-2-hydroxy-1-(phenylmethyl)-3-(((4S)-6-(2 2 2-
trifluoroethvl)-3 4-
dihydrospiro[chromene-2,1'-cvclobutanl-4-yl)amino)propyl)acetamide TFA salt
The title compound was synthesized in a manner analogous to that described in
Example
509, as a white solid. MS m/z: 477.2(M+1).
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Example 511
N-((1 S,2R)-2-hydroxy-1-(phenylm ethyl)-3-(((4S)-6-(2-pyridinyl)-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)propyl)acetamide. TFA salt
A mixture of (2S,3R)-3-amino-l-(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-
chromen-4-
ylamino)-4-phenylbutan-2-ol dihydrochloride salt (50 mg, 106 umol), 2-tri-n-
butylstannylpyridine (58 l, 158 mol) and
tetrakis(triphenylphosphine)palladium(0) (6
mg, 5 gmol) in dioxane was heated in a sealed tube for 15h. The reaction was
cooled to RT
and filtered. The filtrate was purified on Shimadzu HPLC to afford the title
compound as a
colorless oil. MS m/z: 472.2(M+1).
Example 512
N-((1S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4'S)-6'-(2,2,2-trifuoroethyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
Step 1: 6-bromo-4-(tert-butyldimeth r} lsilyloxy)-2 2-spirolcyclobutyl-3 4-
dihydro-2H-
pyrano(2,3-b)pyri dine
To a cooled (ice bath) solution 6-bromo-2,2-spirolcyclobutyl-3,4-dihydro-2H-
pyrano(2,3-
b)pyridine-4-ol (3.71 g, 13.7 mmol) in DCM was added TEA (3.82 ml, 27.5 mmol)
followed by tert-butyldimethylsilyl trifluoromethanesulfonate (3.47 ml, 15.1
mmol). The
reaction was stirred at RT for 2h until all the alcohol was consumed. 1N HCI
was added to
quench the reaction. The resulted mixture was extracted with CH2CI2. The
organic layers
were combined, washed with water and brine, dried over Na2SO4, filtered and
concentrated. After dried in vacuum, the title compound was obtained as a
yellow solid. It
was carried on to the next step without further purification. MS m/z:
386.1(M+1).
Step 2: 1-(4-(tert-butyldimethylsilyloxy)-2 2-spirolcyclobutyl-3 4-dihydro-2H-
pyrano(2 3-
b)pyridine-6-yl)-2,2,2-trifluoroethanone
To a cooled (-78 C) solution of compound 1 from step 1 (4.20 g, 11 mmol) in
THE was
added slowly butyllithium, 1.6m in hexanes (7.5 ml, 12 mmol) via a syringe.
After stirred
for 15 min, methyl 2,2,2-trifluoroacetate (1.1 ml, 1 I mmol) was added drop
wise. The
reaction was stirred for 15min at the same temperature. At this time, all the
starting
chromen was consumed, determined by LCMS. The reaction was quenched by the
addition
of saturated NH4C1(40 ml0 and EtOAc (50 ml). The mixture was then warmed to
room
temperature. The aqueous layer was extracted with EtOAc (50 ml). The organics
were
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combined, dried over Na2SO4, filtered and concentrated. The residue was
purified on a
silica gel column giving the title compound. MS m/z: 419.8(M+18).
Step 3: 1 (4 (tertbutyldimethylsilyloxy)-2 2-spirolc cly obutyl-3 4-dihydro-2H-
pyrano(2 3-
b)pyridine-6-yl)-2,2,2-trifluoroethanol
To a solution of compound from step 2 (3.30 g, 8.22 mmol) in EtOH was added
sodium
borohydride (0.333 ml, 9.45 mmol). The reaction was stirred 4h at ambient
temperature. At
this point, all the starting material was consumed. Water was added to quench
the reaction.
Solvent was removed under reduced pressure. The aqueous residue was extracted
with
EtOAc (3x). The organic layers were combined, dried over MgSO4, filtered and
concentrated. The residue was purified over silica gel column (2-15%
EtOAc/hexane) to
afford the title compound as a light yellow solid. It contained two fractions.
Each had the
same MS, but had different retention time on TLC. MS rn/z: 404.2(M+1).
Step 4: 4-(tert-butyidimethylsilyloxy)-6-(l-chloro-2,2,2-trifluoroethyl)-2,2-
spiroleyclobutyl-3 4-dihydro-2H-pyrano(2,3-b)pyridine
To a cooled (ice bath) mixture of compound 3 (2.34 g, 5.8 mmol) (from step 3)
and pyridine
(0.47 ml, 5.8 mmol) in toluene was added drop wise thionyl dichloride (0.59
ml, 8.1 mmol)
via a syringe. After the addition was completed, the reaction was stirred at
RT for 30 min,
and heated at 75 C for 16 h. Reaction was cooled to RT and quenched with
water. The
resulted mixture was extracted with EtOAc (2x). The organic layers were
combined, dried
over MgSO4, filtered and concentrated. The residue was dried in vacuum to
afford the title
compound. It was carried to the next step without further purification. MS
m/z: 422.1
(M+1)-
Step 5: 4-(tert-butyldimethylsilyloxy)-6-(2 2 2-trifluoroethyl)-2 2-
spirolcyclobutyl-3,4-
dihydro-2H-Ryrano(2,3-b)p riy dine
To a solution of compound from step 4 (1.78 g, 4.22 mmol) in THE was added
sodium
tetrahydroborate (0.239 g, 6.33 mmol) in one portion. The reaction was heated
under
refluxing for 15 h and all the starting chloride was consumed. After cooled to
room
temperature, water was added to quench the reaction. The mixture was extracted
with
EtOAc (3x). The organic layers were dried over MgSO4, filtered and
concentrated. The
residue was dried in vacuum to afford the title compound. It was carried to
the next step
without further purification. MS m/z: 388.2 (M+l).
Step 6: 6-(2 2 2-trifluoroethyl)-2 2-spirolcyclobutyl-3 4-dihydro-2H-
pyrano(2,3-b)pyridine-
4-ol
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To compound 5 (1.21 g, 3 mmol) (crude from step 5) was added 4 N HCI/dioxane.
The
reaction was stirred at room temperature until all the starting material was
consumed. The
mixture was concentrated and dried in vacuum to give the title compound. It
was carried to
the next step without further purification.
Step 7: 6-(2 2 2-trifluoroethyl)-2 2-spirolcyclobutyl-2 3-dihvdropyrano(2,3-
b)pyridin-4-one
To a stirred solution of compound (0.82 g, 3.0 mmol)(crude from step 6) in DCM
was
added sodium bicarbonate (0.12 ml, 3.0 mmol) in one portion followed by Dess
martin
Reactant 3 (1.3 g, 3.0 mmol) Stirring was continued for 3h at RT and 1.0 ml
MeOH was
added. After Stirring for an additional 30 min, the mixture was filtrated. The
filtrate was
treated with 4 ml of 1M NaOH and stirred for 20 min. The mixture was extracted
with 20
ml DCM (2x) and the combined organic extracts were dried over MgSO4, filtered
and
concentrated under reduced pressure. The residue was purified on silica gel
column to
afford the title compound. MS m/z: 272.0 (M+1).
Step 8: (R)-2 2-spirolcyclobutyl-6-(2 2 2-trifluoroethyl)-3 4-dihvdro-2H-
pyrano(2 3-
b)pyridin-4-ol
The title compound was prepared according to the methods described in step 5
of Example
509. MS m/z: 274.1 (M+1).
Step 9: (S)-4-azido-2 2-spirolcyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihvdro-
2H-
pyran o(2,3-b)pyridi ne
The title compound was prepared according to the methods described in step 6
of Example
509. MS nzlz: 299.1 (M+1).
Step 10: (S)-2 2-spirolcyclobutyl-6-(2 2 2-trifluoroethyl)-3 4-dihvdro-2H-
pyrano(2,3-
b)pyridine-4-amine
To a cooled (ice bath) solution of (S)-4-azido-2,2-spirolcyclobutyl-6-(2,2,2-
trifluoroethyl)-
3,4-dihydro-2H-pyrano(2,3-b)pyridine (196 mg, 657 mol) in THE was added
lithium
aluminum hydride (657 l, 1314 mol) drop wise. After stirred 1 h at room
temperature,
reduction was completed. The reaction mixture was diluted with THE and
quenched by the
slow addition ofNa2S04 12H20 until no bubble producing. The resulted mixture
was
filtered and the filtrate was concentrated, and dried in vacuum to afford the
title compound
as colorless oil. MS m/z: 256 (M-NH2), 273 (M+1).
Step 11: N-((1 S 2R)-2-hydroxy-l-(phenylmethlam)-3-(((4'S)-6'-(2,2.2-
trifluoroethyl)-3',4'-
dihydrospirofcyclobutane-1 2'-pyrano[2,3-b]pyridinl-4'-
yl)amino)propyl)acetamide. TFA
salt
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The title compound was prepared according to the methods described in steps 10
and 11 of
Example 510. MS m/z: 478.1 (M+1).
Example 513
N-((1 S,2R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((2R)-3,3,3-
trifluoro-2-
methylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2'-pyrano [2,3-b] pyridi n]-4'-
yl)amino)propyl)acetamide; and
N-((1 S,2R)-1-((3-fluorophenyl)methyl)-2-hyd roxy-3-(((4'S)-6'-((2S)-3,3,3-
trifluoro-2-
methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino) propyl)acetamide
Step 1: Tert-butyl allyl((S)-2 2-spirolcyclobutyl-6-(3 3 3-trifluoro-l-hydroxy-
2-
methylpropyl)-3 4-dihvdro-2H-pyrano(2 3-b)pyridine-4-yl)carbamate
To a cooled (-78 C) solution of (S)-tert-butyl allyl(6-bromo-2,2-
spirocyclobutyl-3,4-
dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate (8.70 g, 21 mmol) in
diethylether was
added tert-butyllithium (25 ml, 43 mmol) dropwise. After stirred 15 min, the
fresh distilled
3,3,3-trifluoro-2-methylpropanal (5.8 ml, 53 mmol) was added. The reaction was
stirred 30
min, then quenched with sat. NH40. The resulted mixture was warmed to RT and
extracted
with EtOAc (3x). The organic layers were combined, dried over Na2SO4, filtered
and
concentrated. The residue was purified on silica gel column to afford the
title compound as
light yellow oil. MS m/z: 457 (M+1).
Step 2: Tert-butyl allyl((S)-2 2-spirolcvclobutyl-6-(3 3 3-trifluoro-l -chloro-
2-
methylpropyl)-3 4-dihvdro-2H-pyrano(2 3-b)Qyridine-4-yl)carbamate
To a cooled (ice bath) mixture of compound 1 (1.33 g, 2.9 mmol) (from step 1)
and
pyridine, anhydrous (0.24 ml, 2.9 mmol) in toluene was added thionyl chloride
(SOC12)
(0.30 ml, 4.1 mmol) dropwise. After the addition was completed, the mixture
was warmed
to RT and then heated at 45 C for 2 h. At this point, all the Reactant 1 was
consumed and
the desired product was formed, determined by LCMS. The reaction was cooled to
RT and
quenched with water (25 ml). The layers were separated. The aqueous layer was
extracted
with EtOAc (2x). The organic layers were combined, washed with brine and dried
over
Na2SO4. After filtration, the filtrate was concentrated and purified on silica
gel column (5-
15% EtOAc/hexane) to provide the title compound as yellow oil. MS "/z: 475
(M+1).
Step 3: (4S)-6 (3 3 3-trifluoro-l-chloro-2-methylpropyl)-2 2 spirocyclobutyl-3
4-dihydro-
2H-pyrano(2,3-b)pyridine-4-amine To compound (1.06 g, 2 mmol) from step 2 was
added
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hydrogen chloride 4.Om in 1,4-dioxane (2.0 ml, 9 mmol). After stirred 15 h
(over night), the
Boc group was removed. The resulted mixture was diluted with CH2C12 and
neutralized
with saturated Na2HCO3 (25 ml). The aqueous layer was extracted with CH2C12
(2x). The
organic layers were combined, dried over Na2SO4, filtered and concentrated.
The residue
was dried in vacuum to provide a yellow oil product. MS m/z: 475.2 (M+1). The
yellow oil
product from above was dissolved in CH2C12. 1,3-dimethylpyrimidine-2,4,6(1
H,3H,5H)-
trione (1 g, 7 mmol) was then added. After degassed for 10 min,
PalladiumTetrakis (0.1 g,
0.1 mmol) was added and the mixture was heated at 40 C for 1.5 h under N2
atmosphere.
At this point, reaction was completed, determined by LCMS. Reaction was then
warmed to
room temperature and quenched with I N HCI. The organic layer was washed with
1 N HCl
(2x). The aqueous layers were combined, neutralized with sat. Na2CO3 to PH =
6.5, and
then extracted with CH2C12 (3x). The organic layers were combined, dried over
Na2SO4,
filtered and concentrated. The residue was dried in vacuum to provide 845 mg
of the title
compound as off-white foam. MS m/z: 335 (M+1).
Step 4: N-((l S,2R)-1-((3-fluorophenl)methyl)-2-hydroxy-3-(((4'S)-6'-((2R)-3,3
3-trifluoro-
2-methvlpropyi)-3',4'-dihydrospiro[cyclobutane-1 2'_pyrano[2 3-bjpyridinl-4'-
amino)propyl)acetamide; and
N-((I S,2R)-l -((3-fluorophen 1)methyl)-2-hydroxy-3-(((4'S)-6'-((2S)-3 3 3-
trifluoro-2-
methylpropyl -3' 4'-dihydrospiro[eyclobutane-] 2'-pyranof2 3-b]pyridinl-4'-
yl)amino)propyl)acetamide
The title compounds were prepared by the method described in co-pending patent
application serial no. 60/738,767 Example 170. MS m/z: 524.2 (M+1).
Example 514
Ethyl 1-(2-(((1S,2R)-3-(((4S)-6-bromo-3,4-dihyd rospiro[chromene-2,1'-
cyclobutanl-
4-yl)amino)-2-hyd roxy-l-(phenylmethyl)propyl)amino)-2-oxoethyl)-1H-1,2,3-
triazole-4-carboxylate
Step 1: 2-Azido N-((2S.3R)-4-((S)-6-bromo-2 2-spirocyclobuiylchroman-4-
ylamino)-3-
hydroxy-l-phenylbutan-2-yl)acetamide
The (2R,3S)-3-amino-l-((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-4-
phenylbutan-2-ol (0.43 g, 0.99 mmol) and 2-azidoacetic acid (0.100 g, 0.99
mmol) were
dissolved in dmf (6.0 mL). Hunig's Base (0.22 ml, 1.2 mmol) was added. HATU
(0.38 g,
0.99 mmol) was added, and the mixture was stirred at rt for 12 h. The reaction
was
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concentrated to remove most of the DMF. The residue was taken up in EtOAc (100
mL)
and the organic layer was extracted with water (7 mL), half-saturated brine (7
mL), and
saturated brine (7 mL), then was dried over sodium sulfate and concentrated.
The
material was purified through silica gel (70 mL) which had been deactivated
with Et3N
(7.5 mL) eluting with EtOAc, affording the title compound. MS m/z 514/516
(M+1).
Step 2: Ethyl 1-(2-(((1 S 2R)-3-(((4S)-6-bromo-3 4-dihydrospiro[chromene-2 1'-
cyclobutanl-4-yl)amino)-2-hydroxv-l-(phenylmethyl)propyl)amino)-2-oxoeth l
1 2,3-triazole-4-carboxylate
In a sealable vessel, ethyl propiolate (0.0067 ml, 0.066 mmol) and 2-azido-N-
((2S,3R)-4-
((S)-6-bromo-2,2-spirocyclobutylchroman-4-ylamino)-3-hydroxy-l-phenylbutan-2-
yl)acetamide (0.020 g, 0.039 mmol) were dissolved in dioxane (0.3 mL). The
vessel was
sealed and placed in an 80 deg oil bath for 12 h. The reaction was cooled,
taken up in
EtOAc (60 mL) and the organic layer was extracted with dilute NaHCO3 (5 mL),
half-
saturated brine (5 mL) and saturated brine (5 mL), then was dried over sodium
sulfate and
concentrated. The material was purified through silica gel (15 mL) which had
been
deactivated with Et3N (2 mL), eluting with 3% MeOH-EtOAc, yielding the title
compound as a white solid. MS m/z 612/614 (M+1).
Example 515
N-((1 S,2R)-1-((3-Bromo-4-fluorophenyl)methyl)-3-(((4' S)-6'-(2,2-
dimethylpropyl)-
3',4'-dihyd rospiro[cyclobutane-1,2'-pyrano[2,3-b] pyridin]-4'-yl)amino)-2-
hyd roxy p ro py l) a cetam i d e
Step 1: (3-Bromo-4-fluorophenyl)methanol
3-Bromo-4-fluorobenzaldehyde (0.300 g, 1.48 mmol) was dissolved in methanol (3
mL).
Sodium borohydride (0.0671 g, 1.77 mmol) was added. After 3 h, the reaction
was
quenched with methanol (1 mL), and the mixture was concentrated. The residue
was
taken up in 2:1 EtOAc-hexane (60 mL). The organic layer was extracted with
dilute
NaHCO3 (6 mL) then half-saturated brine (6 mL), then was dried over sodium
sulfate and
concentrated. The material was purified through silica gel (45 mL) using 30%
to 40%
EtOAc-hexane to afford the title compound.
Step 2: 2-Bromo-4-(bromomethyl)-1-fluor)benzene
(3-Bromo-4-fluorophenyl)methanol (0.264 g, 1.29 mmol) was dissolved in DCM (3
mL).
The solution was cooled to 0 deg, and tribromoborane (1.0 M in DCM, 0.863 ml,
0.863
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mmol) was added. The mixture was stirred at 0 deg for 1 h, then rt for I h.
The reaction
was quenched with water, and the mixture was transfered to a separatory funnel
with half-
saturated NaHCO3 (15 mL), and the aqueous phase was extracted with DCM (3 x 20
mL).
The organics were combined, washed with half-saturated brine (5 mL), dried
over sodium
sulfate and concentrated. Purification of the residue through silica gel (40
mL) using 5%
EtOAc-hexane afforded the title compound.
Step 3: N-((1S,2R)-1-((3-Bromo-4-fluorophen l)methvl)-3-(((4'S)-6'-(2 2-
dimethylpropyl)-3'.4'-dih drospirofcvclobutane-i 2'_pyrano[2 3-blpvridinl-4'-
yl)amino)-
2-h yd roxyp ro py l )acetam i d e
2-Bromo-4-(bromomethyl)-1-fluorobenzene was converted to the title compound
using a
method analogous to that described in Examples 509 and 510.
Example 516
2-(5-(Aminomethyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R)-3-(((4S)-6-bromo-3,4-
di hydrospiro [chromene-2,1'-cyclobutan]-4-yl)amino)-2-hyd roxy-l-
(phenylmethyl)propyl)acetamide; and
2-(4-(aminomethyl)-1H-1,2,3-triazol-1-yl)-N-((1S,2R)-3-(((4S)- 6-bromo-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4-y1)amino)-2-hydroxy-l-
(phenylmethyl)propyl)acetamide
In a microwave vessel, 2-azido-N-((2S,3R)-4-((S)-6-bromo-2,2-
spirocyclobutylchroman-
4-ylamino)-3-hydroxy-l-phenylbutan-2-yl)acetamide (0.020 g, 0.039 mmol) was
taken up
in prop-2-yn-l-amine (0.49 ml, 7.2 mmol). The vessel was sealed and placed in
a 100
deg oil bath. After 12 h, the reaction was concentrated on the rotovap. The
residue was
purified through silica gel (15 mL) which had been deactivated with Et3N (2.0
mL) using
5% MeOH-dichloromethane to afford the title compounds as an equal mixture of
isomers.
MS m1z 569/571 (M+1)
Example 517
N-((lS,2R)-1-((3-Cyano-4-fluorophenyl)methyl)-3-(((4' S)-6'-(2,2-
dimethylpropyl)-
3',4'-dihydrospiro[cyclobutane-1,2'-pyrano [2,3-b] pyridin]-4'-y1)amino)-2-
hyd roxypropyl)acetamide
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Step 1: (S -(2S,3S)-1-(3-Bromo-4-fluorophenyl)-3,4-bis(tert-
butyldimethylsi lyloxy)butan-2-yl)-2-methyl propane-2-sulfinamide
The title compound was prepared from (S,E)-N-((S)-2,3-bis(tert-
butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide and 2-bromo-4-
(bromomethyl)-1-fluorobenzene using a method analogous to that described in
Examples
509 and 510.
Step 2: (S)-N-((2S,3S)-3,4-Bis(tert-bu ldimethylsilyloxy)-1-(3-cyano-4-
fluorophenyl butan-2-yl -2-methylpropane-2-sulfinamide
The (S)-N-((2S,3S)-1-(3-bromo-4-fluorophenyl)-3,4-bis(tert-
butyldimethylsilyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide (0.247 g,
0.404
mmol), Pd2(dba)3-CHC13 (0.209 g, 0.202 mmol) dppf (0.224 g, 0.404 mmol) and
zinc
cyanide (0.0522 g, 0.445 mmol) were suspended in dmf (10 mL). A condenser was
affixed and the flask was placed in a 120 deg oil bath. After 14 h, flask was
concentrated.
The residue was taken up in EtOAc (100 mL) and water (10 mL), and the mixture
was
filtered through Celite. The aqueous layer was separated and the organic layer
was
extracted with saturated brine (10 mL), dried over sodium sulfate and
concentrated.
Purification of the black residue through silica gel (40 mL) using 10% to 15%
EtOAc-
hexane afforded the title compound. MS m/z 557 (M+1).
Step 3: N-((1 S2R)-1-((3-Cyano-4-fluorophenyl)methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3'.4'-dihydrospiro[cyclobutane-1.2'-p, ry anoj2,3-blpyridinl-
4'-yl)amino)-
2-hydroxypropyl)acetami de
(S)-N-((2S,3 S)-3,4-bis(tent-butyldimethylsilyloxy)-1-(3-cyano-4-
fluorophenyl)butan-2-
yl)-2-methylpropane-2-sulfinamide was converted to the title compound using a
method
analogous to that described in Examples 509 and 5 10. MS m/z 509 (M+1).
Example 518
N-((1 S,2R)-1-((3-Chloro-2,4-difluo rophenyl)methyl)-3-(((4' S)-6'-(2,2-
dimethylpropyl)-3',4'-dihyd rospiro[cyclobutane-1,2'-pyrano[2,3-bl pyridinl-4'-
yl)amino)-2-hydroxypropyl)acetamide
Step l : (3-Chloro-2,4-difluorophenyl)methanol
3-Chloro-2,4-difluorobenzoic acid (5.37 g, 27.9 mmol) was dissolved in THE (20
mL)
and the solution was cooled to 0 deg. Borane methylsulfide (2.0 M in THF, 55.8
ml, 112
mmol) was added. The *resulting solution was warmed to it and stirred for 14
h. The
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solution was cooled in an ice bath, and 10% aqueous Na2CO3 (7 mL) was added
slowly.
The material was concentrated on the rotovap to a white solid. The residue was
acidified
with 3M aqueous HCI (30 mL), diluted with dichloromethane (50 mL), and the
mixture
was filtered through Celite. The layers were separated, and the organic layer
was dried
5- over sodium sulfate and concentrated. The residue was purified through
silica gel (500
mL) using 30% EtOAc-hexane, to afford the title compound.
Step 2: 1-(Bromomethyl)-3-chloro-2.4-difluorobenzene
(3-chloro-2,4-difluorophenyl)methanol was converted to the title compound
using the
procedure described in Example 461, Step 2. 'H NMR in CDCl3 0: 7.29 (m, 1H),
6.98
(td, 1H, J= 8.4, 1.6), 4.48 (s, 2H).
Step 3: N-((1 S 2R)-1-((3-Chloro-2 4-difluorophen 1)y methyl)-3-(((4'S)-6'-(2
2-
dimethylpropyl)-3' 4'-dihydrospiro[cyclobutane-1 2'-p ry anoj2 3-b]pvridin] 4'
yl amino)
2-hydroxypropyl)acetamide
I -(Bromomethyl)-3 -chloro-2,4-difluorobenzene was converted to the title
compound
using a method analogous to that described in Examples 509 and 510. MS m/z 536
(M+1).
Example 519
N-((1S,2R)-1-((4-Chlorophenyl)methyl)-2-hydroxy-3-(((4'S)-6'-((1-
methylethyl)oxy)-
3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
Step 1: (S)-tert-Butyl 6-bromo-2 2-spirocyclobutyl-3 4-dihvdro-2H-pyrano[2 3-
b]pyridin
4-ylcarbamate
(S)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine
(968 mg,
3.6 mmol), Hunig's base (0.94 mL, 5.4 mmol), and Boc anhydride (0.98 g, 4.5
mmol)
were dissolved in dichloromethane (15 mL), and the mixture was stirred at rt
for 14 h.
The reaction was quenched with ethanolamine (0.13 mL, 2.2 mmol), diluted with
10%
aqueous sodium carbonate (9 mL), and the aqueous layerwas extracted with DCM
(3 x
20 mL). The organics were combined, washed with dilute brine, dried over
sodium
sulfate and concentrated. The product was purified through silica gel (200 mL)
using
28% EtOAc-hexane to afford the title compound. MS m/z 369/371 (M+1).
Step 2: (S)-tert-Butyl allyl(6-bromo-2.2-spirocvclobu_tyl-3 4-dihvdro-2H-
pyrano[2 3-
blpyridin-4-yl)carbamate
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(S)-tert-Butyl 6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-
4-
ylcarbamate (1.27 g, 3.45 mmol) was dissolved in DMF (10 mL) and NaH (60%, 165
mg,
4.14 mmol) was added. The suspension was cooled to 0 deg, and allyl bromide
(0.418
mL, 4.83 mmol) was added. The mixture was stirred at 0 deg for 5 h. The
mixture was
concentrated, diluted with 90% ether-hexane (60 mL), and the organic layer was
washed
with water (2 x 5 mL) and saturated brine (5 mL). The organic layer was dried
over
magnesium sulfate, filtered, and concentrated. The residue was purified
through silica gel
(150 mL) using 20% EtOAc-hexane to afford the title compound. MS m/z 409/411
(M+1).
Step 3: (S)-tert-Bu l aliys6-hydroxy-2,2-spirocyclobutyl-3,4-dihydro-2H-
pyrano[2,3-
b l pyri d i n-4-yl )carbam ate
(S)-tert-Butyl allyl(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-
b]pyridin-4-
yl)carbamate (1.16 g, 2.8 mmol) and triisopropylborate (3.3 mL, 14 mmol) were
dissolved in THE (25 mL). The solution was cooled to -78 deg. A solution of n-
butyllithium in hexane (2.5 M, 2.1 mL, 5.2 mmol) was added. The solution was
stirred at
-78 deg for 30 min, then warmed to 0 deg. An aqueous solution of hydrogen
peroxide
(30% w/w, 2.9 mL, 28 mmol) and 2.5 M aqueous NaOH (6.5 mL) was added, and the
mixture were stirred for 30 min. The aqueous layer was extracted with EtOAc (3
x 25
mL). The organics were combined, washed with saturated brine (2 x 5 mL), dried
over
sodium sulfate and concentrated. The material was purified through silica gel
(125 mL)
using 50% EtOAc-hexane to afford the title compound. MS m/z 347 (M+1).
Step 4: (S)-tert-Butyl all l(6-isopropoxL2,2_spiroc cly obutyl-3,4-dihydro-2H-
p, rano[2,3-
blpyridin-4-vl )carbamate
In a sealable vessel, (S)-tert-butyl allyl(6-hydroxy-2,2-spirocyclobutyl-3,4-
dihydro-2H-
pyrano[2,3-b]pyridin-4-yl)carbamate (180 mg, 0.52 mmol) and
cetyltrimethylammonium
bromide (19 mg, 0.052 mmol) were dissolved in dioxane (0.42 mL) and 3.0 M
aqueous
potassium hydroxide (0.866 mL, 2.6 mmol) was added. Isopropyl bromide (0.098
mL,
1.04 mmol) was added. The vessel was sealed and the reaction mixture was
heated at 100
deg for 3 h. The vessel was cooled, to rt, the mixture was diluted with ether
(60 mL), and
the organic layer was washed with water (2 x 6 mL) and saturated brine (6 mL).
The
organic layer was dried over magnesium sulfate, filtered, and concentrated.
The residue
was purified through silica gel (40 mL) using 30% EtOAc-hexane to afford the
title
compound. MS m/z 389 (M+I).
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Step 5: (S)-N-Allyl-6-isopropoxy-2 2-spirocyclobutyl-3 4-dihydro-2H-pyrano[2 3-
blpyridin-4-amine
In a sealable vessel,(S)-tert-butyl allyl(6-isopropoxy-2,2-spirocyclobutyl-3,4-
dihydro-2H-
pyrano[2,3-b]pyridin-4-yl)carbamate (246 mg, 0.63 mmol) was dissolved in
dichloromethane (3.5 mL). TFA (0.488 mL, 6.3 mmol) was added. The vessel was
sealed
and heated at 50 deg for 6 h. The mixture was concentrated, and the residue
was
neutralized with 10% aqueous sodium carbonate (8 mL). The aqueous phase was
extracted with 5% MeOH-dichloromethane (60 mL). The organic layer was dried
over
sodium sulfate and concentrated to afford the title compound. MS m/z 289
(M+1).
Step 6: (S)-6-Isopropoxy-2 2-spirocyclobutyl-3 4-dihydro-2H-pyrano[2 3
b]pyridin 4
amine
(S)-N-Al lyl-6-isopropoxy-2,2-sp irocyclobutyl-3,4-dihydro-2H-pyrano[2,3-
b]pyridin-4-
amine (181 mg, 0.63 mmol), 1,3-dimethylpyrimidine,2,4,6(1H,3H,5H)-trione
(0.294 g,
1.88 mmol), Pd(PPh3)4 (36.3 mg, 0.031 mmol) were dissolved in dichloromethane
(4
mL). The mixture was heated at 35 deg for 1.5 h. The mixture was diluted with
0.5 M
aqueous sodium carbonate (8 mL) and the aqueous phase was extracted with 5%
MeOH-
dichloromethane (3 x 20 mL). The organics were combined, washed with dilute
brine (5
mL), dried over sodium sulfate, and concentrated. The residue was purified
through
silica gel (25 mL) which had been deactivated with triethylamine (2.5 mL),
eluting with
0.5% MeOH-dichloromethane to afford the title compound. MS m/z 249 (M+1).
Step 7: N-((1S,2R)-1-((4-Chlorophenyl)methyl)=2h droxy-3-(((4'S)-6'-((1-
methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1 2'-p rano[2 3-blpyridinl-4'-
yl)amino)propyl)acetamide
(S)-6-Isopropoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-
amine was
converted to the title compound using a method analogous to that described in
Examples
509 and 510. MS m/z 488 (M+1).
The following compounds are further examples of the present invention, and
were made by methods described hereinabove.
Table 4
Ex. Compound Name Mass Found Cell Assay
No.
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N-((1 S,2R)-I-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
520 (((4S)-6-(1-methyl-1H-1,2,3-triazol-4-yl)-3,4- 512 2.158087
dihydrospiro[chromene-2,1'-cyclobutan]-4-
yl)am ino)propyl)acetam i de
N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(1-methyl-1 H-1,2,3-
521 triazol-4-yl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 476 10
yl)amin)-1-(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-6-((2R)-2-fluoropropyl)-3,4-
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2-
522 hydroxy-l-(phenylmethyl)propyl)acetamide 455 0.010493
N-((I S,2R)-3-(((4S)-6-((2S)-2-fluoropropyl)-3,4-
dihydrospiro[chromene-2, I'-cyclobutan]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)acetamide
N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4'-
523 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 452 0.004092
yl)amino)-1-(phenylmethyl)propyl)acetamide
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2-
524 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 495 0.002424
pyrano [2, 3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-31,4'-
525 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 0.003945
yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((l S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
526 chromen-4-yl)amino)-1-((3-cyanophenyl)methyl)-2- 486,488 0.116235
hydroxypropyl)acetamide
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N-((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-2H-
527 chromen-4-yl)amino)-1-((3-cyanophenyl)methyl)-2- 516, 518 0.12029
hydroxypropyl)-2-(methyloxy)acetamide
N-1--((1 S,2R)-3-(((4S)-6-bromo-2,2-dimethyl-3,4-dihydro-
528 2H-chromen-4-yl)amino)-1-((3-cyanophenyl)methyl)-2- 529, 531 1.122924
hydroxypropyl)-N-2-,N-2--dimethyl glycinami de
N-((l S,2R)-3-(((4S)-8-bromo-6-ethyl-2,2-dimethyl-3,4-
529 dihydro-2H-chromen-4-yl)amino)-1-((3- 514, 516 0.033865
cyanophenyl)methyl)-2-hydroxypropyl)ac etam ide
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((1 S)-3,3-
dimethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro-l-
naphthaleny])amino)-2-hydroxypropyl)-2-
530 (methyloxy)acetamide N-((1S,2R)-1-((3- 480 0.220964
cyanophenyl)methyl)-3-(((1 R)-3,3-dimethyl-7-(methyloxy)-
4-oxo-1,2,3,4-tetrahydro- l -naphthalenyl)amino)-2-
hydroxypropyl)-2-(methyloxy)acetamide
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((1 S)-3,3-
d imethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro- l -
531 naphthaleny])amino)-2-hydroxypropyl)acetamide 450 0.135497
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-3-(((1 R)-3,3-
dimethyl-7-(methyloxy)-4-oxo-1,2,3,4-tetrahydro-l-
naphthalenyl)am ino)-2-hydroxypropyl)acetamide
N-((1 S,2R)- 1-((3 -cyanophenyl)methyl)-3-(((4S)-6-ethyl-2,2-
532 dimethyl-8-(4-morpholinyl)-3,4-dihydro-2H-chromen-4- 521 0.011199
y l)am ino)-2-hydroxypropyl)acetamide
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N-((I S,2R)-3-(((4R)-6-ethyl-2,2-dimethyl-8-(l-pyrrolidinyl)-
3,4-dihydro-2H-chromen-4-yl)amino)-2-hydroxy- l -
533 (phenylmethyl)propyl)acetamide N-((1S,2R)-3-
480 0.064408
(((4S)-6-ethyl-2,2-dimethyl-8-(I-pyrrolidinyl)-3,4-dihydro-
2H-chromen-4-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-8-(dimethylamin)-6-ethyl-2,2-
dimethyl-3,4-dihydro-2H-chromen-4-yl)amino)-2-hydroxy-
534 1-(phenylmethyl)propyl)acetamide N-((l S,2R)- 454 0.022928
3-(((4R)-8-(dimethylam ino)-6-ethyl-2,2-dimethyl-3,4-
dihydro-2H-chromen-4-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-6-ethyl-2,2-dimethyl-8-(methylamino)-
535 3,4-dihydro-2H-chromen-4-y1)amino)-2-hydroxy-l- 440 0.923788
(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-8-(4-
536 morpholinyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 568 2.090331
yl)amino)- 1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-8-(4-
537 morpholinyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 550 1.96531
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)acetamide
N-((1 S)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-31,4'-
538 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 432 0.176659
yl)amino)-1-hydroxyethyl)-3-methylbutyl)acetam i de
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N-((1 S)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
539 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 430 0.050267
yl)amino)-1-hydroxyethyl)-3-inethyl-3 -buten- I -yl)acetamide
N-((l S,2R)- 1-((3-cyanophenyl)methyl)-3-(((4'S)-6'-(2,2-
540 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 0.002035
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-2-hydroxy-3-(((5'S)-3'-methyl-5',8'-dihydro-6'H-
541 Spiro[cyclobutane-1,7'-quinolin]-5'-yl)amino)-1- 408 0.650675
(phenyl me thy l)propyl )ac etam i de
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((5'S)-
542 3'-methyl-5',8'-dihydro-6'H-spiro[cyclobutane-1,7'-quinolin]- 433 0.064592
5'-yl)ami no)propyl)acetamide
N-((1 S,2R)-1-((3-cyan ophenyl)methyl)-2-hydroxy-3 -(((5S)-
543. 3,7,7-trimethyl-5,6,7,8-tetrahydro-5- 421 0.123613
qu i no l inyl)amino)propyl)ac etam ide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
544 (((4S)-6-(1,3-oxazol-2-yi)-3,4-dihydrospiro[chromene-2,1'- 498 0.631397
cyc lobutan]-4-yl) am ino)propyl)acetamide
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-
545 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)amino)-2- 454 0.004607
hydroxy- l -(ph enylm ethyl)propyl)acetamide
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186 -
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-
546 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)amino)-1-((3- 472 0.001669
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
547 dihydrospiro[cyclopentane-1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.034798
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3 -(((4'S)-6'-(2,2-
548 dimethylpropyl)-3',4'-dihydrospiro[cyclopentane-1,2'- 516 0.002832
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
549 dihydrospiro[cyclopentane-1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.006927
yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
550 dihydrospiro[cyclopropane-1,2'-pyrano[2,3-b]pyridin]-4'- 442 0.020321
yl)amino)-1-((4-fluoro-3-methylphenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-((I S)- 1-fluoro-2-methylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-1-((4-fluoroph enyl)methyl)-2-
551 hydroxypropyl)acetamide N- 488 1.647171
((1 S, 2R)-3-(((4'S)-6'-((1 R)-1-fluoro-2-methylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin] -4'-
yl)amino)-I-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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N-((1 S,2R)-3-(((4'S)-6'-((1 R)- I -fluoro-2-methylpropyl)-3',4'-
552 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 1.260258
yl)amino)- I -((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-((1 S)-1-fluoro-2-methylpropyl)-3',4'-
553 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 0.271801
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-((1 S)- 1-fluoro-2-methylpropyl)-3',4'-
554 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 2.581944
yl)amino)-2-hydroxy-l-(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-((1 S)-1-fluoro-2-methylpropyl)-3',4'-
555 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
l)amino)-1-((3-fluoroPhenYI)methYl)-2 488 1.429449
Y -
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((1 S)-3,3-dimethyl-7-((2-
(methyloxy)ethyl)amino)-4-ox o-1,2,3,4-tetrahydro- l -
naphthalenyl)amino)-2-hydroxy-l-
556 (phenylmethyl)propyl)acetamide N-((1 S,2R)- 468 10
3-(((1 R)-3,3 -dimethyl-7-((2-(methyloxy)ethyl)amino)-4-oxo-
1,2,3,4-tetrahydro- l -naphthalenyl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetam ide
N-((l S,2R)-3-(((1 R)-7-(cyclopentylamino)-3,3-dimethyl-4-
oxo-1,2,3,4-tetrahydro-1-naphthalenyl)amino)-2-hydroxy- l -
557 (phenylmethyl)propyl)acetamide N-((1S,2R)-3- 478 0.038437
(((I S)-7-(cyclopentylamino)-3,3-dimethyl-4-oxo-1,2,3,4-
tetrahydro-1-naphthalenyl)amino)-2-hydroxy- I -
(phenylmethyl)propyl)acetamide
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- 188 -
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3 -(((1 S)-7-(2,2-
dimethylpropyl)-3,3-dimethyl-4-oxo-1,2,3,4-tetrahydro- l -
naphthalenyl)amino)-2-hydroxypropyl)acetamide 558
501 0.038226
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((1R)-7-(2,2-
dimethylpropyl)-3,3-dimethyl-4-oxo-1,2,3,4-tetrahydro-l -
naphthalenyl)amino)-2-hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydro-
559 1'H-spiro[cyclobutane-1,2'-quinolin]-4'-yl)amino)-1-((4- 482 0.104975
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-
560 dimethylpropyl)-3',4'-dihydro-1'H-spiro[cyclobutane-1,2'- 500 0.011735
quinolin]-4'-yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydro-
561 1'H-spiro[cyclobutane-1,2'-quinolin]-4'-yl)amino)-1-((3- 482 0.029368
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-bromo-4-fluorophenyl)methyl)-3-(((4'S)-
562 6'-(2,2-dimethylpropyl)-3',4'-dihydro-1'H-spiro[cyclobutane- 561 0.14112
1,2'-quinolin]-4'-yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-di methylpropyl)-1'-oxo-3',4'-
563 dihydro-1'H-spiro[cyclopentane-1,2'-naphthalen]-4'- 509 10
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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- 189 -
N-((l S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)- I'-oxo-3',4'-
564 dihydro-I'H-spiro[cyclopentane-1,2'-naphthalen]-4'- 509 0.569059
yl)amino)- I -((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((3 S,4'S)-6'-chloro-3',4,4',5-
tetrahydrospiro [furan-3,2'-pyrano [2,3-b]pyridin]-4'-
565 yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide 446 10
N-((1 S,2R)-3-(((3R,4'S)-6-chloro-3',4,4',5-
tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyrid in]-4'-
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-ethyl-3',4'-dihydrospiro[cyclobutane-
566 1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)- 1 -((3- 442 0.029044
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6'-
567 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 0.003274
pyrano[2,3-b]pyrid in]-4'-yl)amin o)-2-
hydroxypropyl)acetamide
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
568 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 484 0.008126
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
569 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 484 0.005216
yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
570 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 484 0.022073
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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- 190 -
N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-
571 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 0.080924
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-
572 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)amino)-1-((4- 472 0.013847
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4S)-6-(2,2-
573 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 490 0.003117
b]pyridin-4-yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2S)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-
574 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488 0.110607
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
575 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.004641
yl)amino)-1-((4-fluoro-3-methylphenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
576 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.002151
yl)amino)-1-((3-fluoro-4-methylphenyl)methyl)-2-
hydroxypropyl)acetamide
methyl ((1S,2R)-3-(((4S)-6'-(2,2-dimethylpropyl)-3',4'-
577 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 500 0.060048
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)carbamate
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- 191 -
N-((I S,2R)-1-((4-fluoro-3-methylphenyl)methyl)-3-(((4'S)-
578 6'-(2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 502 0.028506
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amin o)-2-
hydroxypropyl)acetam i de
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
579 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 496 0.00461
yl)amino)-2-hydroxy- 1 -((3-
(methyloxy)phenyl)methyl)propyl)acetamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2-
580 dimethylpropyl)-3',4'-dihydrospiro[cyclopropane-I,2'- 486 0.119905
pyrano [2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethyl-3-(methyloxy)propyl)-
581 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514 0.137018
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2-
582 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 509 0.031787
pyrano[2,3-c]pyridin]-4'-yl)amino)-2-hydroxy- I -
(ph enyl methyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4'-
583 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 518 0.112144
yl)amino)-I-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-
584 (ethylamino)-3',4'-dihydrospiro[cyclobutane- 1,2'-pyrano[2,3 - 527
0.005288
c]pyridin]-4'-yl)amino)-I-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetam i de
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N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((I -
585 methylethyl)amino)-3',4'-dihydrospiro[cyclobutane-1,2'- 541 0.022345
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
fl uorophenyl)methy l)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-8'-(cyclopropylamino)-6'-(2,2-
586 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 539 0.014049
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(tetrahydro-
587 2H-pyran-4-ylamino)-3',4'-dihydrospiro[cyclobutane-1,2'- 583 0.008485
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-8'-(dimethyiamino)-6'-(2,2-
588 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 527 0.052264
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((l S,2R)-3-(((4'S)-8'-((l ,1-dimethyl ethyl)amino)-6'-(2,2-
589 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 555 0.615121
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-
590 (methylamino)-3',4'-dihydrospiro[cyclobutane-1,2'- 513 0.001406
pyrano[2,3-c]pyridin]-4'-y1)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-
591 (ethylamino)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3'- 527 0.002976
c]pyridin]-4'-yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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- 193 -
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(tetrahydro-
592 2H-pyran-4-ylamino)-3',4'-dihydrospiro[cyclobutane-1,2'- 583 0.003238
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxypropyl) acetamide
N-((1 S,2R)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2-
593 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3- 527 0.023623
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-oxo-
594 3',4',7',8'-tetrahydrospiro[cyclobutane-1,2'-pyrano[2,3- 500 0.023364
c]pyri din]-4'-yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-((1-
methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
595 fluorophenyl)methyl)-2-hydroxypropyl)acetamide 542 0.607192
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((1-
methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetami de
N-((1 S,2 R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-((1-
methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3-
596 fluorophenyl)methyl)-2-hydroxypropyl)acetamide 542 0.036426
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((1-
methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
CA 02629402 2008-05-12
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- 194 -
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'R)-6'-(2,2-
dimethylpropyl)-8'-((1-methylethyl)oxy)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-
597 yl)amino)-2-hydroxypropyl)acetamide 560 0.050591
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-8'-((1-methylethyl)oxy)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((l S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((4'S)-8'-
598 (dimethylamino)-6'-(2,2-dimethylpropyl)-3',4'- 545 0.026836
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((l S,2R)-3-(((4'S)-8'-(dimethylamino)-6'-(2,2-
599 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 552 0.167357
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((4-
(dimethylamino)phenyl)methyl)-2-hydroxypropyl)acetam ide
N-((1 S,2R)-I-((4-chlorophenyl)methyl)-3-(((4'S)-8'-
600 (dimethylamino)-6'-(2,2-dimethylpropyl)-3',4'- 543 0.633888
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-c] pyridin]-4'-
yl)am ino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((2,3-difluoropheny])methyl)-3-(((4'S)-8'-
601 (dimethylamino)-6'-(2,2-dimethylpropyl)-3',4'- 545 0.226574
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-S'-(cyclopropylamino)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
602 539 0.002887
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
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- 195 -
1,1-dimethylethyl (2-(((4'S)-4'-(((2R,3S)-3-(acetylamino)-4-
603 (3-fluorophenyl)-2-hydroxybutyl)amino)-6'-(2,2- 642 0.012859
dimethy lpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
pyrano [2,3-c]pyridin]-8'-yl)amino)ethyl)carbamate
N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(3-
(methyloxy)-1-azetidinyl)-3',4'-dihydrospiro[cyclobutane-
604 1,2'-pYmnoL2,3-c]pyridin]-4'-yl)amino)-1-((3- 569 0.00579
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((I S,2R)-3-(((4'S)-8'-amino-6'-(2,2-dimethylpropyl)-3',4'-
605 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 499 0.001558
yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetam ide
N-((I S,2R)-3 -(((4'S)-8'-((2-aminoethyl)amino)-6'-(2,2-
606 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 542 0.004432
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-((1-
methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'-
607 ano[2,3-c]pYridin]-4' Y1)amino)- 1 -((4542 0.080297
PYr -
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-((I -
methylethyl)oxy)-3',4'-dihydrospiro[cyclobutan a-1,2'-
608 pyrano[2,3-c]pyridin]-4'-yl)amino)-l-((4- 542 0.064326
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'R)-6'-(2,2-dimethylpropyl)-8'-((1-
609 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'- 542 0.06672
pyrano[2,3-c]pyridin]-4'-yl)amino)-I -((3-
flu orophenyl) methyl)-2-hydroxypropyl)acetam i de
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- 196 -
N-((1 S,2R)-3 -(((4'S)-6'-(2,2-dimethylpropyl)-8'-((1-
610 methylethyl)oxy)-3',4'-dihydrospiro[cyclobutane-1,2'- 542 0.017223
pyrano[2,3-c]pyridin]-4'-yl)amino)-1-((3-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'R)-6'-(2,2-
611 dimethylpropyl)-8'-((1-methylethyl)oxy)-3',4'- 560 0.161326
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-
612 dimethylpropyl)-8'-((1-methylethyl)oxy)-3',4'- 560 0.024218
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-
613 (methyloxy)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 514 0.103038
c]pyridin]-4'-yl)amino)- 1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(3-
(methyloxy)-1-azetidinyl)-3',4'-dihydrospiro[cyclobutane-
569 0.059045
614 1,2'-pyrano[2,3-c]pyridin]-4'-yl)amino)- 1-((4-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3 -
615 (((1 s,3R,4'S)-3-methyl-6'-(2-methylpropyl)-3',4'- 484 0.024809
dihydrospiro[cyclobutane- 1,2-pyrano[2,3-b]pyridin]-4T-
y l)am ino)propyl)ac etam i de
N-((1 S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3 -
616 (((1r,3S,4'S)-3-methyl-6'-(2-methylpropyl)-3',4'- 484 0.062677
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)am ino)propyl )ac etam ide
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- 197 -
N-((1 S,2R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3-
617 (((1s,3R,4'S)-3-methyl-6'-(2-methylpropyl)-3',4'- 484 0.002985
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetam ide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-2-hydroxy-3 -
618 (((1s,3R,4'S)-3-methyl-6'-(2-methylpropyl)-3',4'- 500 0.072183
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
N-((1 S,2R)-3-(((I S,2S,4'S)-6'-(2,2-dimethylpropyl)-2-
methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-
619 ~ 498 0.032589
b]pyr'din]-4-yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((1 S,2S,4'S)-6'-
620 (2,2-dimethylpropyl)-2-methyl-3',4'- 514 0.062047
dihydrospiro[cyclobutane-1,2'-pyrano[2,3 -b]pyri din]-4'-
yl)am ino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((1 R,2R,4'S)-6'-(2,2-dimethylpropyl)-2-
621 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 498 10
b]pyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((1 R,2R,4'S)-6'-
622 (2,2-dimethylpropyl)-2-methyl-3',4'- 514 10
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((1 S,2R,4'S)-6'-(2,2-dimethylpropyl)-2-
623 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 498 0.038235
b]pyridin]-4'-yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetam i de
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- 198 -
N-((1 S,2R)-I-((4-chlorophenyl)methyl)-3-(((1 S,2R,4' S)-6'-
624 (2,2-dimethylpropyl)-2-methyl-3',4'- 514 0.061497
dihydrospiro[cyclobutane-1,2'-pyrano[2,3 -b] pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((1 R,2 S,4'S)-6'-(2,2-dimethylpropyl)-2-
625 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 498 10
b]pyridin]-4'-yl)amino)-I-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((I R,2S,4'S)-6'-
626 (2,2-dimethylpropyl)-2-methyl-3',4'- 514 10
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
methyl ((1S,2R)-1-((4-chorophenyl)methyl)-3-(((4'S)-6'-
627 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 516 0.936069
pyrano [2,3-b] pyridin]-4'-yl)amino)-2-
hydroxypropyl)carbamate
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
628 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514 0.010499
yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2-
(methyloxy)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
629 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502 0.012573
yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2-
fluoroacetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
630 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.036373
yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2,2-
difluoroacetamide
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- 199 -
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
631 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 538 0.05701
yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-
2,2,2-trifluoroacetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'..
632 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 552 0.30775
yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-
3, 3,3 -trifluoropropanamide
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
633 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 528 0.017117
yl)amino)-1-((4-fluoropheny])methyl)-2-hydroxypropyl)-3-
(methyloxy)propanamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
634 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 473.3 0.014226
yl)amino)-2-hydroxy- l -(1 ,3 -thiazol-4-
y lm ethyl)propyl)acetam i de
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
635 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 467.3 0.003044
yl)amino)-2-hydroxy- l -(4-pyridinylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
636 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 515.3 0.01464
yl)amino)-2-hydroxy- l -((2-propyl-1,3-thiazol-4-
yl)methyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
637 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 515.3 0.921516
yl)amino)-2-hydroxy- l -((5-propyl- l ,3-thiazol-4-
yI)methyl)propyl)acetamide
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- 200 -
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
638 dihydrospiro[cyclobutane-I,2'-pyrano[2,3-b]pyridin]-4'- 473.3 0.002316
yl)amino)-2-hydroxy- l -(1,3-thiazol-5-
ylmethyl)propyl)acetamide
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
639 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 487.3 0.023717
yl)amino)-2-hydroxy- l -((2-methyl- l ,3-th i azol-4-
yl)methyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
640 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 481.3 0.009886
yl)amino)-2-hydroxy-1-((2-methyl-4-
pyri dinyl)methyl)propyl)acetam ide
N-((1 S,2R)-1-((4-chloro-1,3-thiazol-2-yl)methyl)-3-(((4'S)-
641 6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 507.3 0.00682
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((l S,2R)-1 -((2-chloro-4-pyridinyl)methyl)-3-(((4'S)-6'-
642 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 501.3 0.003369
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
643 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 497.4 0.006793
yl)amino)-2-hydroxy- l -((2-(methyloxy)-4-
pyridinyl)methyl)propyl)acetamide
N-((1 S,2R)- 1-((2-chloro-6-methyl-4-pyridinyl)methyl)-3-
644 (((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1 2'-pyrano[2,3-b]pyridin] 515.3 0.006321
-4 -
yl)am ino)-2-hydroxypropyl)acetamide
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- 201 -
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro [cyclobutane- I ,2'-pyrano [2,3-b]pyridin]-4'-
645 1)amino)-2-hYdroxY- I -((2-((2,2,2-trifluoroethYl)oxY)-4_ 565.3 0.005164
Y
pyridinyl)methyl)propyl)acetam ide
N-((1 S, 2 R)-1-(1-benzofuran-2-ylmethyl)-3 -(((4'S)-6'-(2,2-
646 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 506.3 0.052887
pyrano[2,3 -b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
647 1 -((2-(trifluoromethY1)-4 536.3 0.152163
yl)amino)-2-hydroxy- -
pyri midinyl)m ethyl)propyl)acetamide
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
648 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 534.3 0.189329
yl)amino)-2-hydroxy- l -((4-
(trifluoromethyl)phenyl)methyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
649 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 497.3 0.030021
yl)amino)-2-hydroxy- l -((1-methyl-2-oxo-1,2-dihydro-4-
pyridinyl)methyl)propyl)acetamide
N-((1 S,2R)-3 -(((4'S)-6'-(2-cyano-2-methylpropyl)-3',4'-
650 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 495.3 0.020206
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2-cyano-2-methylpropyl)-3',4'-
651 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 495.2 0.004239
yl)amino)-I -((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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- 202 -
N-((I S,2R)-3-(((4'S)-6'-(3,3-difluoro-2,2-dimethylpropyl)-
652 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2
0.00784
yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)acetamide
N-((I S,2R)-3-(((4S)-2-ethyl-4,7-dihydro-5H-spiro[ 1-
653 benzothiophene-6,1'-cyclobutan]-4-yl)amino)-2-hydroxy-l- 427.2 0.126989
(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-2-(2,2-dimethylpropyl)-6,6-dimethyl-
654 4,5,6,7-tetrahydro-I-benzothien-4-yl)amino)-2-hydroxy-l- 457.2 0.01385
(phenylmethyl)propyl)acetamide
methyl ((1S,2R)-3-(((4S)-2-(2,2-dimethylpropyl)-6,6-
655 dimethyl-4,5,6,7-tetrahydro- I -benzothien-4-yl)amino)-2- 473.2 0.104522
hydroxy-1-(phenylmethyl)propyl)carbamate
N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-3-(((3 S,4'R)-6'-
(2,2-dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2'-
pyrano [2,3 -b]pyridin]-4'-yl)am ino)-2-
656 hydroxypropyl)acetamide N-((1S,2R)-1-((3,5- 518.2 0.041264
difluorophenyl)methyl)-3-(((3R,4'R)-6'-(2,2-
dimethylpropyl)-3',4,4', 5-tetrahydrospiro [furan-3,2'-
pyrano [2,3-b] pyridin]-4'-yl)amino)-2-
hydroxypropyl)a cetam ide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((3S,4'S)-6'-
(2,2-dimethylpropyl)-3',4,4',5-tetrahydrospiro [furan-3,2'-
pyrano[2,3-b]pyridin]-4'-yl)am ino)-2-
657 hydroxypropyl)acetamide N-((IS,2R)-1-((3,5- 518.2 0.002512
difluorophenyl)methyl)-3-(((3R,4'S)-6'-(2,2-
dimethylpropyl)-3',4,4',5-tetrahydrosp iro [furan-3,2'-
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
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- 203 -
N-((1 S,2R)-3-(((3 S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro [furan-3,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-1-((4-fluorophenyl)methyl)-2-
658 hydroxypropyl)acetamide N-((1S,2R)-3- 500.2 0.020173
(((3 R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4, 5-
tetrahydrospiro [furan-3,2'-pyrano [2,3-b]pyridin]-4'-
yI)amino)-1-((4-fluorophenyl )methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-
659 dimethylpropyl)-7'-fluoro-3',4'-dihydrospiro[cyclobutane- 520.2 0.006422
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro [furan-3 ,2'-pyrano [2, 3 -b] pyridin] -4'-
yl)amino)-1-((3-fluorophenyl)methyl)-2-
660 hydroxypropyl)acetamide N-((lS,2R)-3- 500.2 0.003621
(((3 R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
tetrahydrospiro[furan-3,2'-pyrano [2,3-b]pyridin]-4'-
yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4'-
661 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 0.010152
yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-7'-fluoro-3',4'-
662 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2 0.094665
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetam ide
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- 204 -
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((3 S,4' S)-6'-(2,2-
dimethylpropyl)-3',4,4', 5-tetrahydrospiro [furan-3,2'-
pyrano [2,3 -b] pyridin]-4'-yl)am in o)-2-
663 hydroxypropyl)acetamide N-((1 S,2R)- 1 -((4- 516.2 0.099545
ch lorophenyl)methyl)-3 -(((3R,4' S)-6'-(2,2-dimethylpropyl)-
3',4,4', 5-tetrahydrospiro[furan-3,2'-pyrano [2, 3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((3 S,4'R)-6'-(2,2-
dimethylpropyl)-3',4,4', 5-tetrahydrosp iro[furan-3,2'-
pyrano [2,3-b] pyridin]-4'-yl)am ino)-2-
664 hydroxypropyl)acetamide N-((1 S,2R)-1-((4- 516.2 TBD
chlorophenyl)methyl)-3-(((3 R,4'R)-6'-(2,2-dimethylpropyl)-
3',4,4',5-tetrahydrosp iro [furan-3,2'-pyrano[2,3-b]pyri din]-4'-
yl)amin o)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
665 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514.2 0.00853
yl)amino)-1-((3-fluoro-4-(methyloxy)phenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
666 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 514.2 0.16163
yl)amino)-1-((3-fluoro-4-(methyloxy)phenyl)methyl)-2-
hydroxypropyl)ac etamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2,2-
667 dimethylpropyl)-7'-fluoro-3',41-dihydrospiro[cyclobutane- 518.2 0.384736
1,2'-pyrano[2,3 -b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
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- 205 -
N-((1 R,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrosp iro [cyclobutane- l ,2'-pyrano[2, 3-b]pyridin] -4'-
yl)amino)-1-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-
668 hydroxypropyl)acetamide N-((1 S,2R)- 552.2 0.156196
3-(((4'S)-6'-(2,2-dim ethylpropyl)-3',4'-
dihydrospiro [cyclobutane-1,2'-pyrano[2,3 -b]pyridin] -4'-
yl)amino)-1-((3-fluoro-4-(trifluoromethyl)phenyl)methyl)-2-
hydroxypropyl)acetamide
N-((l S,2R)-1-((4-chlorophenyl)methyl)-3-(((3 S,4'S)-6'-(2,2-
669 dimethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2'- 516.2 10
pyrano[2,3-b]pyridin]-4'-yl)am ino)-2-
hydroxypropyl) acetam i de
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((3R,4'S)-6'-(2,2-
670 dim ethylpropyl)-3',4,4',5-tetrahydrospiro[furan-3,2'- 516.2 0.051785
pyrano [2,3-b] pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((3S,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
671 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'- 500.2 0.020468
yl)amino)-1-((4-fluorophenyl) m ethyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((3R,4'S)-6'-(2,2-dimethylpropyl)-3',4,4',5-
672 tetrahydrospiro[furan-3,2'-pyrano[2,3-b]pyridin]-4'- 500.2 0.023752
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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N-((1 S,2R)-I-((4-chlorophenyl)methyl)-3-(((4'S)-6'-((1 R)-1-
fluoro-2,2-dimethyl propyl)-3',4'-dihydrospiro [cyc] obutane-
1,2'-pyrano [2,3-b]pyridin]-4'-yl)am ino)-2-
673 hydroxypropyl)acetamide N- 518.2 0.05856
((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((4' S)-6'-((1 S)-1-
fl uoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-
1,2'-pyrano[2, 3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-((l S)-1-fluoro-2,2-dimethylpropyl)-
674 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2
1.081474
yl)amino)- I -((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetam i de
N-((1 S,2R)-3-(((4'S)-6'-((1 R)-1-fluoro-2,2-dimethylpropyl)-
675 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2
0.012112
yl)amino)- I -((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
676 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 552.2 0.018142
yl)amino)- 1-((4-fluoro-3-(trifluoromethyl)phenyl)methyl)-2-
hydroxypropyl)acetam id e
N-((1 S,2R)-1-((2,3-difluorophenyl)methyl)-3-(((4'S)-6'-
677 ((1R)-1-fluoro-2,2-dimethylpropyl)-3',4'- 520.2 0.008608
dihydrospiro[cycl obutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-((1 R)-1-fluoro-2,2-dimethylpropyl)-
678 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 502.2
0.002069
yl)amino)-1-((3-fl uorophenyl)methyl)-2-
hydroxypropyl)acetamide
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- 207 -
N-((1 S,2R)-3-(((4'S)-6'-((1R)-1-fluoro-2,2-dimethylpropyl)-
679 3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 484.3
0.006045
yl)amino)-2-hydroxy- l -(phenylm ethyl)propyl)acetami de
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-((1 R)-1-
680 fluoro-2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane- 518.2 0.023122
1,2'-pyrano [2, 3 -b] pyridin] -4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluoropheny])methyl)-3-(((4'S)-6'-
681 ((1R)-1-fluoro-2,2-dimethylpropyl)-3',4'- 520.3 0.003463
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'--
yl)amino)-2-hydroxypropyl)acetamide
N-((l S,2R)-3-(((4'S)-6'-(cyclobutylmethyl)-3',4'-
682 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 482.2 0.066452
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetam ide
N-((l S,2R)-3-(((5R,5aS)-3-(2,2-dimethylpropyl)-5a,6,7,8-
683 tetrahydro-5H-pyrrolo[ 1',2':1,5]pyrrolo[2,3-b]pyridin-5-
1 -((4-fluorophenY1)methY1)-2 469 0.523798
yl)amino)- -
hydroxypropyl)acetamide
N-((1 S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
684 6'-(1-hydroxypentyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 522 2.86427
pyrano [2,3 -b] pyridin]-4'-yl)am ino)propyl) acetam i de
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'..
685 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.009279
yl)amino)-2-hydroxy- 1 -((2,4,5-
trifluorophenyl)methyl)propyl)acetamide
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- 208 -
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
686 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.007068
yI)amino)-2-hydroxy-1-((3,4,5-
trifluorophenyl)methyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(cyclopropylmethyl)-3',4'-
687 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 486 0.007837
yl)amino)-1-((3,5-difluorophenyl)methyl)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4R)-6-bromo-2,2-dimethyl-1,2,3,4-
tetrahydro-4-quinolinyl)amino)-2-hydroxy-l -
688 (phenylmethyl)propyl)acetamide N-((1S,2R)-3-(((4S)-6- 461 0.230897
b romo-2, 2-di methyl-1,2,3, 4-tetrahydro-4-quin o I inyl)am ino)-
2-hydroxy- l -(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4R)-6-(2,2-dimethylpropyl)-2,2-dimethyl-
1,2,3,4-tetrahydro-4-quinolinyl)amino)-2-hydroxy- l -
689 (phenylmethyl)propyl)acetamide N-((IS,2R)-3-(((4S)-6- 452 0.072801
(2,2-dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4-
quinolinyl)amino)-2-hydroxy-l -
(phenymethyl)propyl)acetamide
N-((1 S,2R)-3-(((4R)-1-acetyl-6-bromo-2,2-dimethyl-1,2,3,4-
tetrahydro-4-quinolinyl)amino)-2-hydroxy-l -
690 (phenylmethyl)propyl)acetamide N-((1S,2R)-3-(((4S)-1- 503 0.873045
acetyl-6-bromo-2,2-dimethyl-1,2,3, 4-tetrahydro-4-
quinolinyl)amino)-2-hydroxy- l -
(phenyl methy l)propyl )ac etam ide
N-(( I S,2R)- 1 -((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2-
691 ethylbutyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 516 0.095804
b]pyridin]-4'-yl)amino)-2-hydroxypropyl)acetamide
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N-((1 S,2R)-3-(((4 S)-6-(2,2-d imethylpropyl)-2,2-dimethyl-
692 1,2,3,4-tetrahydro-4-quinolinyl)amino)-2-hydroxy-l- 452 0.030558
(phenylmethyl)propyl) acetamide
N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-3 -(((4S)-6-(2,2-
693 dimethylpropyl)-2,2-dimethyl-1,2,3,4-tetrahydro-4- 488 0.005491
quinolinyl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
694 6'-propyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 456 0.037222
b]pyridin]-4'-yl)amino)propyl)acetamide
N-((1 S,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
695 '6'-((2S)-2-methylbutyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 484 0.043378
pyrano [2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
N-((I S,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
696 6'-(2-methyl-l-propen-I-yl)-3',4'-dihydrospiro[cyclobutane- 468 0.253945
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropanoyl)-3',4'-
697 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 498 0.276687
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
2-aai do-N-((1 S,2R)-3-(((4S)-6-bromo-3,4-
698 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2- 514.7 2.377589
hydroxy- l -(phenylmethyl)propyl)acetamide
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210 -
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4'S)-
699 6'-(trifluoromethyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 488.8 0.848676
pyrano[2,3-b] pyridin]-4'-yl)amino)propyl)acetami de
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 -
700 (((4'S)-6'-(trifluoromethyl)-3',4'-dihydrospiro[cyclobutane- 499.8
1.199997
I , 2'-pyrano [2,3 -b] pyri d in] -4'-yl)am ino)pro pyl) acetamide
N-((1 S,2R)-1-((3,4-difluorophenyl)methyl)-3 -(((4'S)-6'-(2,2-
701 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 501.9 0.002356
pyrano [2, 3 -b]pyri din] -4'-yl)am i n o)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-chlorophenyl)methyl)-3-(((4' S)-6'-(2,2-
702 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 499.9 0.001238
pyrano [2,3 -b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
703 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 483.9 0.005085
yl)amino)-1-((2-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)- I -((2,4-difluorophenyl)methyl)-3 -(((4'S)-6'-(2,2-
704 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 502.2 0.018443
pyrano[2,3-b] pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
705 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 428.2 0.432865
yl)amino)-I -hydroxyethyl)-3-pentyn- I -yl)acetamide
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- 211 -
N-((1 S,2R)-1-((3-chloro-4-fluorophenyl)methyl)-3-(((4'S)-6'-
(2 2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
706 pyrano[2,3-b]pyridin]-4'-yl)amino)-2- 517.8 0.003113
hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chloropheny])methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
707 pyrano[2,3-b]pyridin]-4'-yl)amino)-2- 499.9 0.012555
hydroxypropyl)acetamide
N-((1 S,2R)- I -((2-chlorophenyl)methyl)-3 -(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
708 pyrano[2,3-b]pyridin]-4'-yl)amino)-2- 499.9 0.023419
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-(dimethylamino)-4-fluorophenyl)methyl)-
709 3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 526.9 0.008013
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
710 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 526.9 0.004251
yl)amino)- I -((3-(ethylamino)-4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2 R)-1-((3,4-dichlorophenyl)methyl)-3-(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
711 533.8 0.029584
pyrano[2,3-b]pyridin]-4 -yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
712 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 549.8 0.064957
yl)amino)-2-hydroxy-l-((4-
((trifluoromethyl)oxy)phenyl)methyl)propyl)acetamide
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- 212 -
N-((1 S,2R)-1-((3-chloro-4-fluorophenyl)methyl)-3-
713 (((1 s,3R,4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4'- 532.2 0.015499
dihydrospiro[cyclobutane-1,2'-pyrano[2, 3-b]pyridin]-4'-
yI)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((1 s, 3 R,4'S)-6'-
714 (2,2-dimethylpropyl)-3-methyl-3',4'- 514.2 0.026711
dihydrospiro[cyclobutane-1,2'-pyrano[2, 3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
715 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 429.9 0.040837
yl)amino)-1-hydroxyethyl)-4-penten- l -yl)acetamide
N-((1 S,2R)- I -((4-chloro-3-(trifluoromethyl)phenyl)methyl)-
716 3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 567.8 0.023342
dihydrospiro[cyclobutane-1,2'-pyrano [2,3 -b]pyridin]-4'-
yl) am in o)-2-hydroxypropyl) acetamide
N-((1 S)-1-((1 R)-2-(((1 s,3R,4'S)-6-(2,2-dimethylpropyl)-3-
717 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 443.9 0.052462
b]pyridin] -4'-yl)amino)-1-hydroxyethyl)-4-penten- l -
yl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
718 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3 -b]pyridin]-4'- 533.9 0.003985
yl)amino)-2-hydroxy-1-((3-
(trifluoromethyl)phenyl)methyl)propyl)acetamide
N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4'-
719 dihydrospiro[cyclobutane-I,2'-pyrano[2,3-b]pyridin]-4'- 519.9 0.009351
yl)amino)- I -((3-
(trifluoromethyl)phenyl)methyl)propyl)acetam ide
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- 213 -
N-((1 S,2R)-1-((4-chloro-3-fluorophenyl)methyl)-3-(((4'S)-6'-
(2,2-dimethylpropyl)-3',4'-dihydrospiro [cyclobutane-1,2'-
517.8 0.00856?
720 pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chloro-3-(methyloxy)phenyl)methyl)-3-
721 (((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 530.2 0.021395
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
y I)am in o)-2-hydroxypropyl)acetami de
N-((1 S,2R)-1-(cycl opropylmethyl)-3 -(((4'S)-6'-(2,2-
dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
722 pyrano[2,3-b]pyridin]-4'-yl)amino)-2- 430.2 0.046453
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
723 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 444.3 0.194643
yl)amino)-2-hydroxy-1-((2-
methylcyclopropyl)methyl)propyl)acetamide
N-((I S,2R)-1-(cyclopropylmethyl)-3-(((4'S)-6'-(4,4-difluoro-
2,2-dimethylbutyl)-3',4'-dihydrospiro[cyclobutane-1,2'-
724 pyrano[2,3-b]pyridin]-4'-yl)amino)-2- 480.2 0.183543
hydroxypropyl)acetamide
N-((1 S,2R)-1-(cyclopropyimethyl)-3-(((I s, 3 R,4'S)-6'-(2,2-
725 dimethylpropyl)-3-methyl-3',4'-dihydrospiro[cyclobutane- 444.2 0.068761
1,2'-pyrano[2,3 -b]pyrid in]-4'-yl)amino)-2-
hydroxypropyl)acetam i de
N-((l S,2R)-1-((2-((difluoromethyl)oxy)-4-
726 pyridinyl)methyl)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 533.2 0.009724
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin] -4'-
yl)am ino)-2-hydroxypropyl)acetamide
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- 214 -
N-I -((1 S,2R)-3-(((4S)-6-bromo-3,4-
727 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1-((3- 541 0.300311
cyanophenyl)methyl)-2-hydroxypropyl)-N-2-,N-2--
dimethylglycinamide
methyl (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-3-((N,N-
728 dimethylglycyl)amino)-2-hydroxybutyl)amino)-3,4- 521 0.043943
dihydrospiro[chromene-2,1'-cyclobutane]-6-carboxylate
methyl (4S)-4-(((2R,3S)-3-(acetylamino)-4-(3-cyanophenyl)-
729 2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2, 1'- 478 1.449592.
cyclobutane]-6-carb oxyl ate
methyl (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-2-hydroxy-3-
730 (((methyloxy)acetyl)amino)butyl)amino)-3,4- 508 1.018648
dihydrospiro[chromene-2,1'-cyclobutane]-6-carboxylate
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
731 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-l- 377 2.52388
((methyloxy)methyl) propyl)acetami de
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
732 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1- 405 3.263952
((propyloxy)m ethyl)propyl)acetam i de
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
733 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-l- 453 10
(((phenylmethyl)oxy)methyl)propyl)acetamide
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- 215 -
N-((1 S,2R)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-
734 2,1'-cyclobutan]-4-yl)amino)-2-hydroxy-1-(1H-pyrazol-l- 413 5.365972
ylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3 -b]pyridin] -4'-
735 yl)amino)-2-hydroxy-l-(1H-pyrazol- l - 478 f 0
yl m ethy l)propy l) acetamide
N-((1 S)-1-((I R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
736 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 416 0.03402
yl)amino)-1-hydroxyethyl)-3-buten- l -yl)acetamide
N-((1 S)-1-((1 S)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
737 dihydrospiro[cyclobutane-i,2'-pyrano[2,3-b]pyridin]-4'- 416 10
yl)amino)-1-hydroxyethyl)-3 -buten- l -y l)acetamide
N-((1 S)-I-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
738 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 472 1.420952
yl)amino)-1-hydroxyethyl)-4,4,4-trifluorobutyl)acetamide
N-((1 S,3E)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
739 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 430 0.298128
yl)amino)-1-hydroxyethyl)-3-penten- I -yl)acetamide
N-((1 S)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
740 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 402 3.33333
yl)amino)- I -hydroxyethyl)-2-propen- l -yl)acetamide
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- 216 -
N-((1 S)-1-((1 R)-2-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-
741 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 420 0.193221
yl)amino)-1-hydroxyethyl)-3-buten-1-yl)acetamide
N-((1 S)-1-((1 R)-2-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
742 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 442 0.285911
yl)amino)-1-hydroxyethyl)-3-hexyn- l -yl)acetamide
N-((1 S,2R)-3-(((2S,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'-
tetrahydrospiro[chromene-2,3'-furan]-4-yl)am ino)-1-((3,5-
743 difluorophenyl)methyl)-2-hydroxypropyl)acetamide 566.1 0.302172
N-(( I S,2R)-3-(((2R,4S)-6-chloro-8-(4-morpholinyl)-3,4,4',5'-
tetrahydrospiro[chromene-2,3'-furan]-4-yl) amino)-1-((3, 5-
difluoropheny l)methyl)-2-hydroxypropyl)acetamide
744 N-((l S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4- 546.3 0.005722
dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2-
hydroxy- I -(phenyl methyl)propyl)-2-(1 H-2-methyl-imidazol-
I- l) acetamide
N-((I S,2R)-3-(((4'S)-6'-bromo-3',4'-
745 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 510.0; 512.0
0.033121
yl)am ino)-I-((3,5-difluorophenyl)methyl)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
746 (((4'S)-6'-(1 H-pyrazol- I -yl)-3',4'-dihydrospiro[cyclobutane- 498.1
0.214725
1,2'-pyrano[2,3-b]pyridin]-4'-yl)am ino)propyl)acetamide
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- 217 -
N-((l S,2 R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 -
747 (((4'S)-6'-(1H-imidazol-1-yl)-3',4'-dihydrospiro[cyclobutane- 498.2
0.497891
1,2'-pyrano[2,3-b]pyri din]-4'-yl)amino)propyl)acetamide
N-((I S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
748 (((4'S)-6'-(1,3-thiazol-2-yl)-3',4'-dihydrospiro[cyclobutane- 515.1
1.051834
1 ,2'-pyrano [2,3-b]pyridin]-4'-yl)am ino)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
749 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 466.2 0.013955
yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide
N-((I S,2R)- 1 -((3 -chloro-5-fluorophenyl)methyl)-3 -(((4'S)-6'-
750 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518.2 0.020286
pyrano [2,3-c]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-2-hydroxy-
751 3-(((4'S)-6'-(2-hydroxy-2-methylpropyl)-3',4'- 520.2 0.038775
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'-
yl)am ino)propyl)acetami de
N-((1 S,2R)-3-(((4' S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4'-
752 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 552.1 0.042155
yl)amino)-1-((3-chloro-5-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((I S,2R)-3-(((4'S)-8'-chloro-6'-(2,2-dimethylpropyl)-3',4'-
753 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 500.2 0.01375
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)acetamide
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N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(4-
754 morpholinyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 551.3
0.052212
c]pyridin]-4'-yl)amino)-2-hydroxy-l -
(phenylmethyl)propyl)acetam ide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-8'-(1-
755 pyrrolidinyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 535.3
0.006495
c]pyridin]-4'-yl)amino)-2-hydroxy- l -
(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-8-(dimethylamino)-6-(2,2-
756 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 558.3 0.199655
c]pyridin-4-yl)amino)-1-((3-(dimethylamino)-5-
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((l S,2R)-1-((3-chloro-5-fluorophenyl)methyi)-3-(((4S)-8-
757 (dimethylamino)-6-(2,2-dimethylpropyl)-2,2-dimethyl-3,4- 549.2 0.068949
dihydro-2H-pyrano [2,3-c]pyridin-4-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,4-difluorophenyl)methyl)-3-(((4S)-6-(2,2-
758 dimethylpropyl)-2,2-dimethyl-8-(1-pyrrolidinyl)-3,4- 559.3 0.040129
dihydro-2H-pyrano [2,3-c]pyri din-4-yl)amino)-2-
hydroxypropyl )acetam i de
N-((1 S,2R)-1-((3-(dimethylamino)-5-fluorophenyl)methyl)-
759 3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'- 527.3 0.017872
dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,4-difluorophenyl)methyl)-3-(((4S)-6-(2,2-
760 dimethylpropyl)-2,2-dimethyl-8-(methylamino)-3,4-dihydro- 519.2 0.011255
2H-pyrano [2,3 -c]pyridin-4-y1)amino)-2-
hydroxypropyl)acetamide
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N-((1 S,2R)-3-(((4S)-8-chloro-6-(2,2-dimethylpropyl)-2,2-
761 dimethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)- 506.2 0.126221
1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4S)-8-(dimethylamino)-6-(2,2-
762 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 515.3 0.165675
c]pyridin-4-yl)amino)- I -((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-I-((3-bromo-5-fluorophenyl)methyl)-3-(((4'S)-
763 6-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 562.1;
0.006487
pyrano[2,3-b]pyridin]-4'-yl)amino)-2- '
hydroxypropyl)acetamide
N-(( I S,2R)-1-((3,5-difluorophenyl)methyl)-3 -(((4'S)-6'-(2,2-
764 dimethylpropyl)-3-methyl-3',4'-dihydrospiro[cyclobutane- 516.2 0.001554
1,2'-pyrano [2,3-b] pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((1s,3R,4'S)-
765 6'-(2,2-dimethylpropyl)-3-methyl-3',4'- 516.2 0.001138
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyrddin]-4'-
yl)amino)-2-hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3-methyl-3',4'-
766 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-blpyridin]-4'- 498.2 0.015805
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((1 s,3 R,4' S)-6'-(2,2-dimethylpropyl)-3-
767 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 498.2 0.005703
b]pyridin]-4'-yl)amino)- I -((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
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- 220 -
N-(( I S,2R)- I -((2,3-difluorophenyl)methyl)-3 -(((1 r,3 S,4'S)-
768 6'-(2,2-dimethylpropyl)-3-methyl-3',4'- 516 0.03889
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((l S,2R)-1-((2,3-difluorophenyl)methyl)-3 -(((1 s, 3R,4'S)-
769 6'-(2,2-dimethylpropyl)-3-methyl-3',4'- 516 0.033758
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((1 s,3R,4'S)-6'-(2,2-dimethylpropyl)-3 -
770 methyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 498 2 0.002464
b]pyridin] -4'-yl)am ino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4S)-6-(cyclopentylamino)-3,4-
771 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-2- 478.3 0.165691
hydroxy- l -(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-6-((1,1-dimethylethyl)amino)-3,4-
772 dihydrospiro[chromene-2, l'-cyclobiutan]-4-yl)amino)-2- 466.3 0.980967
hydroxy- 1-(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4S)-6-chloro-8-(1 H-imidazol- l -yl)-3,4-
773 dihydrospiro[chromene-2,I'-cyclobutan]-4-yl)amino)-1- 532.2 0.021949
((3, 5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-
774 2,1'-cyclobutan]-4-yl)amino)-1-((3,5- 510.2 0.088192
difluorophenyl)methyl)-2-hydroxypropyl)acetamide
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- 221 -
N-((1 S,2R)-3-(((4S)-8-(1 H-benzimidazol- l -yl)-6-chloro-3,4-
775 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1- 582.2 0.212243
((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-(( 1 S,2R)-3-(((4S)-6-chloro-8-(1 H-pyrazol- l -yl)-3,4-
776 dihydrospiro[chromene-2,1'-cyclobutan]-4-y1)amino)-1- 532.2 0.124289
((3,5-difluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
777 (((4S)-6-(IH-pyrazol-l-yl)-3,4-dihydrospiro[chromene-2, 1'- 497.2 0.041157
cyclobutan]-4-yl)amino)propyl)acetamide
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4S)-6-(2-
778 thienyl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 477.2 0.083329
yl)amino)propyl)acetamide
N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(1-(2-methylpropyl)-1 H-
779 pyrazol-3-yl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 517.3 0.190194
yl)amino)-1-(phenylmethyl)propyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
780 (((4S)-6-(1-(2-methylpropyl)-1H-pyrazol-3-yl)-3,4-
dihydrospiro[chromene-2,1'-cyclobutan]-4 553.3 1.652355
yl)amino)propyl)acetam ide
N-((1 S,2S)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
781 (((4S)-6-(1H-pyrazol-l-yl)-3,4-dihydrospiro[chromene-2, 1'- 497.2 1.158731
cyclobutan]-4-yl)amino)propyl)acetamide
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N-((1 S,2R)-1-((3 ,5-difluorophenyl)methyl)-2-hydroxy-3-
782 (((4S)-6-(1H-imidazol-1-y])-3,4-dihydrospiro[chromene-2,1'- 497.2 0.081605
cyclobutan]-4-yl)am ino)propyl)acetam ide
N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(1-methyl-1 H-pyrazol-3-
783 yl)-3,4-dihydrospiro[chromene-2,1'-cyclobutan]-4- 475.3 3.244922
yl)amino)-1-(phenylmethyl)propyl)acetamide
N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
784 (((4S)-6-(1-methyl-1 H-pyrazol-3-yl)-3,4- 511.3 1.654726
dihydrospiro[chromene-2,1'-cyclobutan]-4-
yl)amino)propyl)acetamide
N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3 -
785 (((4S)-6-(2-thienyl)-3,4-dihydrospiro[chromene-2, 1'- 513.3 2.967655
cycl obutan]-4-yl)am i n o)propy l) acetamide
N-((1 S,2S)-3-(((4S)-6-chloro-8-(1 H-pyrazol- l-yl)-3,4-
786 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1- 532.2 1.367329
((3, 5-difluorophenyl)methyl)-2-hydroxypropyl)acetam ide
N-((1 S,2R)-3-(((4S)-7-bromo-3,4-dihydrospiro[chromene-
787 2,1'-cyclobutan]-4-y1)amino)-1-((3,5- 510.1 10
difluorophenyl)methyl)-2-hydroxypropyl)acetam ide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
788 (((4S)-7-(i H-imidazol- I -yl)-3,4-dihydrospiro[chromene-2, 1'- 497.2
cyclobutan]-4-yl)amino)propyl)acetamide
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N-((4S)-4-(((2R,3 S)-3 -(acetylamino)-4-(3,5-difluorophenyl)-
789 2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2, 1'- 488.2 0.017688
cyclobutan]-6-y l)acetami de
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 -
790 (((4S)-6-((3R)-tetrahydro-3-furanylamino)-3,4- 516.3 0.05852
dihydrospiro[chromene-2, I'-cyclobutan]-4-
yl)amino)propyl)acetami de
N-((1 S,2R)- I -((3,5-difluorophenyl)methyl)-2-hydroxy-3-
791 (((4S)-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydrospiro[chromene- 498.3 0.803182
2,1'-cyclobutan]-4-yl)amino)propyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
792 (((4S)-6-(1H-1,2,4-triazol-l-yl)-3,4-dihydrospiro[chromene- 498.3 0.137058
2,1'-cyclobutan]-4-yl)amino)propyl)acetamide
N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-2-hydroxy-3 -
793 (((4S)-6-(2-oxo-l-pyrrolidinyl)-3,4-dihydrospiro[chromene- 514.2 0.358885
2,1'-cyclobutan]-4-yl)amino)propyl)acetamide
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-
794 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-2- 454.3 0.034817
hydroxy- I -(phenylmethyl)propyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
795 (((4S)-6-(2-oxo-l-azetidinyl)-3,4-dihydrospiro[chromene- 500.2 0.255326
2, 1'-cyclobutan]-4-yl)amino)propyl)acetamide
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N-((1 S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-6-
796 (2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H- 507.3 0.008388
pyrano[2,3-c]pyridin-4-yl)amino)-2-
hydroxypropyl)acetamide
N-((I S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4S)-6-
797 (2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H- 521.3 0.01127
pyrano [2,3-c]pyridin-4-yl)amino)-2-
hydroxypropyl)propanamide
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-
798 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-1-((3- 472.3 0.006725
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2-dimethyl-
799 3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)amino)-1-((4- 472.3 0.045368
fluorophenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4S)-6-(2,2-
800 dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3- 490.3 0.003558
c]pyridin-4-yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((48)-6-bromo-7-fluoro-3,4-
801 dihydrospiro[chromene-2,1'-cyclobutan]-4-y1)amino)-1- 528.1 0.570646
((3, 5-difluorophenyl)methyl)-2-hydroxypropyl)acetami de
N-((1 S,2R)-3-(((4S)-6-bromo-7-fluoro-2,2-dimethyl-3,4-
802 dihydro-2H-chromen-4-yl)amino)-l-((3,5- 516.1 0.525381
difluorophenyl)methyl)-2-hydroxypropyl)acetamide
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N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4S)-7-
803 fluoro-6-((3R)-tetrahydro-3-furanylamino)-3,4- 534.3 0.115798
dihydrospiro[chromene-2,1'-cyclobutan]-4-y1)amino)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4S)-7-
804 fluoro-3,4-dihydrospiro[chromene-2, I'-cyclobutan]-4- 449.2 2.952856
yl)amino)-2-hydroxypropyl)acetamide
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
805 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 583.4 0.005137
yl)amino)-1-((3-fluoro-5-(tetrahydro-2H-pyran-4-
ylamino)phenyl)methyl)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4S)-7-
806 fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-3,4- 548.3 0.451865
dihydrospiro[chromene-2, 1'-cyclobutan]-4-yl)amino)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-1-((3-fluorophenyl)methyl)-3-(((4S)-7-fluoro-6-
807 (1H-pyrazol-l-yl)-3,4-dihydrospiro[chromene-2,1'- 497.2 0.48859
cyc lobutan]-4-yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-fluorophenyl)methyl)-3-(((4S)-7-fluoro-6-
808 (1 H-pyrazol- l -yl)-3,4-dihydrospiro[chromene-2, 1'- 497.2 1.94044
cyclobutan]-4-yI)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-1-(cyclobutylmethyl)-3-(((4'S)-6'-(2,2-
809 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 444.3 0.078673
pyrano[2,3-b]pyridin]-4'-yl)am ino)-2-
hydroxypropyl)acetamide
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N-((1 S,2R)-1-((2-bromophenyl)methyl)-3-(((4'S)-6'-(2,2-
810 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 545.2 0.197405
pyrano[2,3-b]pyridin]-4'-yl)ami no)-2-
hydroxypropyl)acetam i de
N-((1 S,2R)-I-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6'-
811 ((1 R)-1-fluoro-2,2-dimethylpropyl)-3',4'- 537.2
dihydrospiro[cyclobutane-1,2'-pyrano [2,3-b]pyridin] -4'-
yl)am ino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((2R,4S)-1'-acetyl-6-ethyl-3,4-
dihydrospiro [chromene-2,3'-pyrrolidin]-4-yl)am ino)-2-
812 hydroxy-l-(phenylmethyl)propyl)acetamide N- 1.948759
((1 S,2R)-3-(((2S,4S)-1'-acetyl-6-ethyl-3,4-
dihydrospiro[chromene-2,3'-pyrrolidin]-4-yl)amino)-2-
hydroxy- l -(phenylmethyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
813 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3 -b]pyridinj-4'- 520 0.100123
yl)amino)-2-hydroxy- 1 -((2,4,6-
trifluorophenyl)methyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
814 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.056329
yl)amino)-2-hydroxy- 1 -((2,3,4-
trifluoroph enyl)methyl)propyl) acetami de
N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4'-
815 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 506 0.224171
yl)amino)-1-((2,4,6-trifluorophenyl)methyl)propyl)acetamide
N-((1 S,2R)-2-hydroxy-3-(((4'S)-6'-(2-methylpropyl)-3',4'-
816 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 506 0.137486
yl)amino)-1-((2,3,4-trifluorophenyl)methyl)propyl)acetamide
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N-((1 S,2R)-1-((4-chloropheny])methyl)-3-(((4'S)-6'-(2,2-
817 dimethylpropyl)-3',4'-dihydrospiro[cyclopentane-1,2'- 515 0.131569
pyrano[2,3-b]pyri din]-4'-yl)amino)-2-
hydroxypropyl)acetam ide
N-((1 S,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
818 6'-(phenylmethyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 504 1.80048
pyrano[2,3 -b]pyridin]-4'-y1)amino)propyl)acetam ide
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3 -(((4S)-6-((2R)-
tetrahydro-2-furanyl)-3,4-dihydrospiro[chromene-2,1'-
819 cyclobutan]-4-yl)amino)propyl)acetamide 465 0.160704
N-((1 S,2R)-2-hydroxy-l -(phenylmethyl)-3-(((4S)-6-((2S)-
tetrahydro-2-furanyl)-3,4-dihydrospiro[chromene-2,1'-
cyclobutan]-4-yl)amino)propyl)acetamide
N-((1 S,2R)-2-hydroxy- l-(phenylmethyl)-3-(((4'S)-6'-((2R)-
tetrahydro-2-furanylm ethyl)-3',4'-dihydrospiro[cyclobutane-
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)-2-
820 (methyloxy)acetamide N-((l S,2R)-2- 510 0.098566
hydroxy- l -(phenylmethyl)-3 -(((4'S)-6'-((2S)-tetrahydro-2-
furanylmethyl)-3',4'-dihydrospiro [cyclobutane- 1,2'-
pyrano[2,3-b]pyridin]-4'-yl)am ino)propyi)-2-
(methyloxy)acetamide
N-((l S,2R)-2-hydroxy-l-(phenylmethyl)-3-(((4S)-6-((2S)-
tetrahydro-2-furanylmethyl)-3,4-dihydrospiro [chromene-
821 2,1'-cyclobutan]-4-yl)amino)propyl)acetamide 479 0.104947
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3 -(((4S)-6-((2R)-
tetrahydro-2-furanyl m ethyl)-3 ,4-di hydro Spiro [chromene-
2,1'-cyclobutan]-4-yl)amino)propyl)acetamide
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N-((1 S,2R)-2-hydroxy-3-(((4S)-6-(5-hydroxypentyl)-3,4-
822 dihydrospiro[chromene-2,1'-cyclobutan]-4-yl)amino)-1- 481 0.066235
(ph enylmethyl)propyl)acetamide
N-((2S,3R)-3-hydroxy-4-((S)-6-isopropoxy-2,2-
823 spirocyclobutyl-chroman-4-ylamino)-1-phenylbutan-2- 453 0.310061
yl)acetamide
N-((I S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
824 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 467 0.002325
yl)amino)-2-hydroxy-I-(3-pyridinylmethyl)propyl)acetamide
N-((1 S,2R)-1-((2,3-difiuorophenyl)methyl)-3-(((4'S)-6'-(2,2-
825 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 502 0.004339
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)- I -((2,6-difluorophenyl)methyl)-3-(((4'S)-6'-(2,2-
826 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 502 0.006934
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((I S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-
827 dihydrospiro[cyclobutane-I,2'-pyrano[2,3-c]pyridin]-4'- 488 0.025843
yl)amino)-1-((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((4-chlorophenyl)methyl)-3-(((4'S)-6'-(2-
828 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 504 0.07843
pyrano [2, 3-b]pyri din ]-4'-yl)amino)-2-
hydroxypropyl)ac etam i de
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N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
829 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 487 2.629707
yl) amino)-2-hydroxy-1-((1-methyl-3-
pip eridinyl)methyl)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin] -4'-
830 1)amino)- 1-((5-fluoro-3-PYridinY1)methYl)-2 485 0.001825
Y -
hydroxypropyl)acetam ide
N-((1 S,2S)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
831 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 485 0.166762
yl)amino)- 1-((5-fluoro-3-pyridinyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3,4-bis(methyloxy)phenyl)methyl)-3-(((4'S)-
832 6'-(2,2-dimethylpropyl)-3',4'-dihydrospro[cyclobutane-1,2'- 526 0.009283
pyrano[2,3 -b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((2,3-difluorophenyl)methyl)-3-(((4'S)-6'-(2-
833 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 506 0.031005
pyrano[2,3 -b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3 -bromo-4-fluorophenyl)methyl)-3-(((4'S)-
834 6'-(2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 566 0.009305
I ,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((l S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-(2-
835 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 506 0.002048
pyrano[2,3 -b] pyridin]-4'-yl)ami no)-2-
hydroxypropyl)acetamide
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N-((1 S,2R)-1-((3-chl oro-4-fluorophenyl)methyl)-3-(((4'S)-6'-
836 (2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 522 0.01471
1,2'-pyrano[2, 3-b] pyridin]-4'-yl)am ino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-chloro-5-fluorophenyl)methyl)-3-(((4'S)-6'-
837 (2-fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 522 0.003578
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2-fluoro-2-methylpropyl)-3',4'-
838 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 538 0.013298
yl)amino)-2-hydroxy-1-((3-
(trifluoromethyl)phenyl)methyl)propyl)acetamide
N-((1 S,2R)-l -(1,3-benzodioxol-5-ylmethyl)-3-(((4'S)-6'-(2,2-
839 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 510 0.005492
pyrano [2,3-b]pyri din]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4'S)-6'-(2-
840 fluoro-2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 514 0.027663
pyrano [2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-2-hydroxy- 1 -(phenylmethyl)-3-(((4'S)-6'-(2,2,2-
841 trifluoroethyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 478.2 0.084821
pyrano[2,3-b]pyridin]-4'-yl)am ino)propyl)acetam ide
N-((1 S,2R)-1-((3,4-difluorophenyl)methyl)-2-hydroxy-3-
842 (((4'S)-6'-(2,2,2-trifluoroethyl)-3',4'- 514.2 0.106066
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
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N-((1 S,2R)-3-(((4'S)-6'-bromo-3',4'-
843 dihydrospiro[cyclobutane- 1,2'-pyrano[2,3-b]pyridin]-4'- 512.2 0.503441
yl)amino)- 1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)- I -((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
844 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 470.2 0.003627
pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetam ide
N-((l S,2R)- I -((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
845 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 470.2 0.011411
pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
N-((1 S,2R)- 1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-
846 (((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 488.2 0.001722
1,2'-pyrano [2,3-b]pyridin]-4'-yI)amino)propyl)acetamide
N-((1 S,2R)-1-((3-chloro-5 -fluorophenyl)methyl)-2-hydroxy-
847 3-(((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 504.2
0.004272
1 ,2'-pyrano[2, 3-b]pyridin]-4'-yl)amino)propyl)acetami de
3-((2 S,3 R)-2-(acetylamino)-3-hydroxy-4-(((4'S)-6'-(2-
848 methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 495.2 0.012834
pyrano [2,3-b]pyridin]-4'-y1)amino)butyl)benzamide
N-((1 S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4'S)-
849 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 477.2 0.001259
pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
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N-((1 S,2R)-1-((2,3-difluorophenyl)methyl)-2-hydroxy-3-
850 (((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 488.2 0.008683
1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
N-((1 S,2R)-1-((3,4-difluorophenyl)methyl)-2-hydroxy-3 -
851 (((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 488.2 0.003236
I ,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
N-((1 S,2R)-3-(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3',4'-
852 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 470.2 0.051988
yl)amino)-2-hydroxy- I -(phenylmethyl)propyl)acetamide
N-((1 S,2R)-1-((3,5-difluoropheny])methyl)-3-(((4'S)-7'-
853 fluoro-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 506.2 0.011208
1,2'-pyrano[2,3 -b] pyridin]-4'-y1)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3',4'-
854 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488.2 0.151206
yl)amino)-1-((4-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-7'-fluoro-6'-(2-methylpropyl)-3',4'-
855 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 488.2 0.025226
yl)amino)- I -((3-fluorophenyl)methyl)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((2,3-difluorophenyl)methyl)-3-(((4'S)-7'-
856 fluoro-61-(2- methylpropyl)-3',4'-dihydrospiro[cyclobutane- 506.2 0.205783
I,2 -pyrano[2,3-b]pyridin]-4 -y1)amino)-2-
hydroxypropyl)acetam i de
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N-((1 S,2R)-1-((4-chloro-3-fluorophenyl)methyl)-2-hydroxy-
857 3-(((4'S)-6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane- 504.2
0.026204
1,2'-pyrano [2,3-b]pyridin]-4'-yl)amino)propyl)acetamide
N-((1 S,2R)- I -((4-chloropheny l)methyl)-2-hydroxy-3-(((4' S)-
858 6'-(2-methylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 486.2 0.052694
pyrano[2,3 -b]pyridin]-4'-yl)amino)propyl)acetamide
N-((1 S,2R)- 1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
859 6'-(1,3,3,3-tetrafluoro-2-methylpropyl)-3',4'- 542.2 0.148464'
dihydrospiro[cyclobutane- I ,2'-pyrano [2,3-b]pyridin]-4'-
y 1)am ino)propyl)acetam ide
N-((1 S,2R)-1-((4-chorophenyl)methyl)-2-hydroxy-3 -(((4'S)-
860 6'-(1,3,3,3-tetrafluoro-2-methylpropyl)-3',4'- 558.2 0.452497
dihydrospiro[cyclobutane-l ,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
N-((1 S,2 R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3 -(((4'S)-
861 6'-(1,3,3,3-tetrafluoro-2-methylpropyl)-3',4'- 542.2 0.026399
dihydrospiro [cyc lobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
N-((1 S,2R)-2-hydroxy- I -(phenylmethyl)-3 -(((4'S)-6'-
862 (1,3,3,3-tetrafluoro-2-methylpropyl)-3',4'- 524.2 0.074055
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
N-((I S,2R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
863 6'-(3,3,3-trifluoro-l-hydroxy-2-methylpropyl)-3',4'- 540.2 1.82816
dihydrospiro [cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
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N-((1 S,2R)-1-((4-chIorophenyl)methyl)-2-hydroxy-3-(((4'S)-
864 6'-(3,3,3-trifluoro-l-hydroxy-2-methylpropyl)-3',4'- 556.2 10
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)amino)propyl)acetamide
N-((1 S,2R)-2-hydroxy- l -(phenylmethyl)-3-(((4'S)-6'-(3,3,3-
865 trifluoro-1-hydroxy-2-methylpropyl)-3',4'- 522.2 1.931998
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)am ino)propyl)ac etamide
N-((1 R,2R)- 1-((3-chloro-2-fluorophenyl)methyl)-3-(((4'S)-
866 6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 10
pyrano[2,3-b]pyridin]-4'-y1)am ino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((5-chloro-2-fluorophenyl)methyl)-3-(((4'S)-6'-
867 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 0.002326
pyrano[2,3 -b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-chloro-2-fluorophenyl)methyl)-3-(((4'S)-6'-
868 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 0.006256
pyrano [2,3 -b]pyridin]-4'-y l)am ino)-2-
hydroxypropyl)acetamide
N-((1 S,2R)-1-((3-chloro-4,5-difluorophenyl)methyl)-3 -
869 (((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 536 0.017919
yl)amino)-2-hydroxypropyl)acetamide
N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
870 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.035578
yl)amino)-2-hydroxy- l -((2, 3,6-
trifluoroph enyl)methyl)propyl)acetamide
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N-((1 S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
871 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 520 0.002026
yl)amino)-2-hydroxy- l -((2,3 ,5-
trifluorophenyl )methyl)propyl)acetamide
N-((l S,2R)-1-((4-bromophenyl)methyl)-3-(((4'S)-6'-(2,2-
872 dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 544/546 0.034468
pyrano [2,3-b]pyridin]-4'-yl)ami no)-2-
hydroxypropyl)acetamide
methyl ((1S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
873 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'- 482 0.020588
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)carbamate
N-((1 S, 2R)-1-((3,5 -difluorophenyl)methyl)-3 -(((4' S)-6'-
874 ethyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 460 0.012128
b]pyridin]-4'-yl)am ino)-2-hydroxypropyl)acetamide
methyl ((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-
875 ethyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3- 476 0.325018
b]pyridin]-4'-yl)amino)-2-hydroxypropyl)c arbamate
methyl ((1 S,2R)-1-((3,5-difluorophenyl)methyl)-3-(((4'S)-6'-
876 (2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'- 518 0.010815
pyrano[2,3-b]pyridin]-4'-yl)amino)-2-
hydroxypropyl)carbamate
N-((l S,2R)-3-(((4'S)-6'-(2,2-dimethylpropyl)-3',4'-
877 dihydrospiro[cyclobutane-1,2'-pyrano[2,3-c]pyridin]-4'- 480 0.064123
yl)amino)-2-hydroxy- l -(phenylmethyl)propyl)propanamide
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N-((1 S,2R)-1-((4-fluorophenyl)methyl)-2-hydroxy-3-(((4'S)-
878 6'-(3-hydroxy-2,2-dimethylpropyl)-3',4'- 500 0.235839
dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-
yl)am ino)propyl)acetamide
The present invention also provides methods for making compounds of Formulas
1-111. In another embodiment of the invention, there is provided a method of
making a
compound of Formula I or II, the method comprising the step of reacting a
compound 20
OH R4
HZN N~~ RS
i l" 1.1
B Ra R3
20 wherein i, j, A, B, R3, R4 and R5 are as defined herein,
with a compound having the structure A-W-X, wherein A and W are as defined
herein
and X is a leaving group, to make a compound of Formulas I or II.
In another embodiment of the invention, there is provided a method of making a
compound of Formula III, the method comprising the step of reacting a compound
30
R3 R3 R4
HZN N R5
`~
R3 R3
B OH
,wherein i, j, B, R3, R4 and R5 are as defined herein, with a compound having
the structure
15 A-W-X, wherein A and W are as defined herein with respect to Formula III
and X is a
leaving group, to make a compound of Formula 111.
As can be appreciated by the skilled artisan, the above synthetic schemes and
representative examples are not intended to comprise a comprehensive list of
all means by
which the compounds described and claimed in this application may be
synthesized.
20 Further methods will be evident to those of ordinary skill in the art.
Additionally, the
various synthetic steps described above may be performed in an alternate
sequence or
order to give the desired compounds.
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For example, in these procedures, the steps may be preceded, or followed, by
additional protection/deprotection steps as necessary. Particularly, if one or
more
functional groups, for example carboxy, hydroxy, amino, or mercapto groups,
are or need
to be protected in preparing the compounds of the invention, because they are
not
intended to take part in a specific reaction or chemical transformation,
various known
conventional protecting groups may be used. For example, protecting groups
typically
utilized in the synthesis of natural and synthetic compounds, including
peptides, nucleic
acids, derivatives thereof and sugars, having multiple reactive centers,
chiral centers and
other sites potentially susceptible to the reaction reagents and/or
conditions, may be used.
The protecting groups may already be present in precursors and should protect
the functional groups concerned against unwanted secondary reactions, such as
acylations, etherifications, etterifications, oxidations, solvolysis, and
similar reactions. It
is a characteristic of protecting groups that they readily lend themselves,
i.e. without
undesired secondary reactions, to removal, typically accomplished by
solvolysis,
reduction, photolysis or other methods of removal such as by enzyme activity,
under
conditions analogous to physiological conditions. It should also be
appreciated that the
protecting groups should not be present in the end-products. The specialist
knows, or can
easily establish, which protecting groups are suitable with the reactions
described herein.
Synthetic chemistry transformations and protecting group methodologies
(protection and
20- deprotection) useful in synthesizing the inhibitor compounds described
herein are known
in the art and include, for example, those such as described in R. Larock,
Comprehensive
Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts,
Protective Groups in Organic Synthesis, 3`d edition, John Wiley and Sons
(1999); L.
Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John
Wiley and
Sons (1994); A. Katritzky and A. Pozharski, Handbook of Heterocyclic
Chemistry, 2nd
edition (2001); M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis,
Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the
Alumino-
and Borohydrides in Organic Synthesis, 2nd edition, Wiley-VCH, (1997); and L.
Paquette,
editor, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons
(1995).
Salts of a compound of the invention having a salt-forming group may be
prepared in a conventional manner or manner known to persons skilled in the
art. For
example, acid addition salts of compounds of the invention may be obtained by
treatment
with an acid or with a suitable anion exchange reagent. A salt with two acid
molecules
(for example a dihalogenide) may also be converted into a salt with one acid
molecule per
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compound (for example a monohalogenide); this may be done by heating to a
melt, or for
example by heating as a solid under a high vacuum at elevated temperature, for
example
from 50 C to 170 C, one molecule of the acid being expelled per molecule of
the
compound.
Acid salts can usually be converted to free-base compounds, e.g. by treating
the
salt with suitable basic agents, for example with alkali metal carbonates,
alkali metal
hydrogen carbonates, or alkali metal hydroxides, typically potassium carbonate
or sodium
hydroxide. Exemplary salt forms and their preparation are described herein in
the
Definition section of the application.
All synthetic procedures described herein can be carried out under known
reaction conditions, advantageously under those described herein, either in
the absence or
in the presence (usually) of solvents or diluents. As appreciated by those of
ordinary skill
in the art, the solvents should be inert with respect to, and should be able
to dissolve, the
starting materials and other reagents used. Solvents should be able to
partially or wholly
solubilize the reactants in the absence or presence of catalysts, condensing
agents or
neutralizing agents, for example ion exchangers, typically cation exchangers
for example
in the H* form. The ability of the solvent to allow and/or influence the
progress or rate of
the reaction is generally dependant on the type and properties of the
solvent(s), the
reaction conditions including temperature, pressure, atmospheric conditions
such as in an
inert atmosphere under argon or nitrogen, and concentration, and of the
reactants
themselves.
Suitable solvents for conducting reactions to synthesize compounds of the
invention include, without limitation, water; esters, including lower alkyl-
lower
alkanoates, e.g., EtOAc; ethers including aliphatic ethers, e.g., Et2O and
ethylene glycol
dimethylether or cyclic ethers, e.g., THF; liquid aromatic hydrocarbons,
including
benzene, toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH,
n- and
t-butanol; nitriles including CH3CN; halogenated hydrocarbons, including
CH2Cl2, CHC13
and CCl4i acid amides including DMF; sulfoxides, including DMSO; bases,
including
heterocyclic nitrogen bases, e.g. pyridine; carboxylic acids, including lower
alkanecarboxylic acids, e.g., AcOH; inorganic acids including HCI, HBr, HF,
H2SO4 and
the like; carboxylic acid anhydrides, including lower alkane acid anhydrides,
e.g., acetic
anhydride; cyclic, linear, or branched hydrocarbons, including cyclohexane,
hexane,
pentane, isopentane and the like, and mixtures of these solvents, such as
purely organic
solvent combinations, or water-containing solvent combinations e.g., aqueous
solutions.
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These solvents and solvent mixtures may also be used in "working-up" the
reaction as
well as in processing the reaction and/or isolating the reaction product(s),
such as in
chromatography.
Purification methods are known in the art and include, for example,
crystallization, chromatography (liquid and gas phase, and the like),
extraction,
distillation, trituration, reverse phase HPLC and the like. Reactions
conditions such as
temperature, duration, pressure, and atmosphere (inert gas, ambient) are known
in the art
and may be adjusted as appropriate for the reaction.
The invention further encompasses "intermediate" compounds, including
structures produced from the synthetic procedures described, whether isolated
or not,
prior to obtaining the finally desired compound. Structures resulting from
carrying out
steps from a transient starting material, structures resulting from divergence
from the
described method(s) at any stage, and structures forming starting materials
under the
reaction conditions are all "intermediates" included in the invention.
Further, structures
produced by using starting materials in the form of a reactive derivative or
salt, or
produced by a compound obtainable by means of the process according to the
invention
and structures resulting from processing the compounds of the invention in
situ are also
within the scope of the invention.
New starting materials and/or intermediates, as well as processes for the
preparation thereof, are likewise the subject of this invention. In select
embodiments,
such starting materials are used and reaction conditions so selected as to
obtain the
desired compound(s).
Starting materials of the invention, are either known, commercially available,
or
can be synthesized in analogy to or according to methods that are known in the
art. Many
starting materials may be prepared according to known processes and, in
particular, can
be prepared using processes described in the examples. In synthesizing
starting materials,
functional groups may be protected with suitable protecting groups when
necessary.
Protecting groups, their introduction and removal are described above.
Compounds of the present invention can possess, in general, one or more
asymmetric carbon atoms and are thus capable of existing in the form of
optical isomers
as well as in the form of racemic or non-racemic mixtures thereof. The optical
isomers
can be obtained by resolution of the racemic mixtures according to
conventional
processes, e.g., by formation of diastereoisomeric salts, by treatment with an
optically
active acid or base. Examples of appropriate acids are tartaric,
diacetyltartaric,
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dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then
separation of the
mixture of diastereoisomers by crystallization followed by liberation of the
optically
active bases from these salts. A different process for separation of optical
isomers
involves the use of a chiral chromatography column optimally chosen to
maximize the
separation of the enantiomers. Still another available method involves
synthesis of
covalent diastereoisomeric molecules by reacting compounds of the invention
with an
optically pure acid in an activated form or an optically pure isocyanate. The
synthesized
diastereoisomers can be separated by conventional means such as
chromatography,
distillation, crystallization or sublimation, and then hydrolyzed to deliver
the
enantiomerically pure compound. The optically active compounds of the
invention can
likewise be obtained by using optically active starting materials. These
isomers may be
in the form of a free acid, a free base, an ester or a salt. All such isomeric
forms of such
compounds are expressly included in the present invention.
The compounds of this invention may also be represented in multiple tautomeric
1.5 forms. The compounds may also occur in cis- or trans- or E- or Z- double
bond isomeric
forms. The invention expressly includes all tautomeric forms of the compounds
described
herein.
All crystal forms of the compounds described herein are expressly included in
the present invention.
Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may be attached to
specific atoms, whereby they are intended to be fixed to that atom, or they
may be drawn
unattached to a specific atom, whereby they are intended to be attached at any
available
atom that is not already substituted by an atom other than H (hydrogen). For
example, the
R12 substituent is drawn unattached to any specific atom of ring Z2, and
therefore each of
the n number of R12 substituents may be attached to any atom of Z2.
The compounds of the invention may be modified by appending appropriate
functionalities to enhance selective biological properties. Such modifications
are known
in the art and include those which increase biological penetration into a
given biological
compartment (e.g., blood, lymphatic system, central nervous system), increase
oral
availability, increase solubility to allow administration by injection, alter
metabolism and
alter rate of excretion. By way of example, a compound of the invention may be
modified
to incorporate a hydrophobic group or "greasy" moiety in an attempt to enhance
the
passage of the compound through a hydrophobic membrane, such as a cell wall.
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Although the pharmacological properties of the compounds of the invention
(Formulas I-III) vary with structural change, in general, activity possessed
by compounds
of Formulas I, II and III may be demonstrated both in vitro as well as in
vivo.
Particularly, the pharmacological properties of the compounds of this
invention may be
confirmed by a number of pharmacological in vitro assays. The following
exemplified
pharmacological assays have been carried out with the compounds according to
the
invention. Compounds of the invention were found to modulate BACE activity.
BIOLOGICAL EVALUATION
The following biological assays were used to characterize the ability of
compounds of the invention to regulate the cleavage of amyloid beta precursor
protein,
thereby reducing or inhibiting the production of amyloid beta.
In vitro enzymatic RACE FRET (fluorescence resonance energy transfer) assay
Assay buffer is 0.05 M acetate, pH 4.2, 10% DMSO final, 100 uM genapol
(which is a nonionic detergent, below it's Critical Micelle Concentration).
Enzyme
(0.2nM) is pre-incubated for one hour with inhibitors added in 1 uL of DMSO.
Then the
assay is started by the addition of FRET substrate (50nM) and incubated for
one hour.
The FRET assay is terminated with by addition of Tris buffer, which raises the
pH to
neutrality, and the fluorescence is determined. The FRET substrate is a
peptide with
commercially available fluorophore and quencher, on opposite sides of the BACE
cleavage site. Proteolytic cleavage of the FRET substrate releases quenching
of
fluorescence (excitation 488 nm and emission 425 nm).
The compounds of Examples 1-19, 24-52, 54-74, 78-91, 93-108, 111-113, 115-
137, 139, 141-142, 144-171, 173-178, 180, 182, 185-187, 190-204,206-213,218-
247,
249-262, 264,266-276, 278-287, 289-314, 320-327, 329-384, 386, 388, 393-418,
461-
466, 468-470, 488-501, 503-510, 512 and 514-520, 522-527, 529-534, 537-562,
564-608,
610, 612-620, 623-624, 627-655, 657-663, 665-689, 691-727, 729-730, 732-734,
736,
738-739, 741-441, 443-448, 781-782, 784-787, 789-828, 830-863 and 865-878
exhibited
IC50 values of 5 p.M or less in the FRET in vitro enzyme assay.
RACE cell-based assay:
The cell-based assay measures inhibition or reduction of A(340in conditioned
medium of test compound treated cells expressing amyloid precursor protein.
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Cells stably expressing Amyloid Precursor Protein (APP) were plated at a
density
of 40K cells/well in 96 well plates (Costar). The cells were cultivated for 24
hours at 37
C and 5% CO2 in DMEM supplemented with 10% FBS. The test compounds were then
added to cells in 10-point dose response concentrations with the starting
concentration
being either 100 M or 10 M. The compounds were diluted from stock solutions
in
DMSO and the final DMSO concentration of the test compounds on cells was 0.l
%.
After 24 h of incubation with the test compounds the supernatant conditioned
media was
collected and the AR 40 levels were determined using a sandwich ELISA. The
IC50 of the
compound was calculated from the percent of control or percent inhibition of
A(3 40 as a
function of the concentration of the test compound.
The sandwich ELISA to detect AR 40 was performed in 96 well microtiter plates,
which were pre-treated with goat anti-rabbit IgG (Pierce). The capture and
detecting
antibody pair that were used to detect A(3 40 from cell supernatants were
affinity purified
pAb40 (Biosource) and biotinylated 6E10 (Signet Labs Inc.), respectively. The
optimal
concentration for the pAb40 antibody was 3 g/ml in Superblock/TBS (Pierce)
that was
supplemented with 0.05%Tween 20 (Sigma). Optimal concentration for the
detection
antibody 6E10-biotinylated was 0.5 g/ml in Superblock/TBS (Pierce) that had
been
supplemented with 2% normal goat serum and 2 % normal mouse serum.
Cellular supernatants were incubated with the capture antibody for 3 h at 4
C,
followed by 3 wash steps in TBS-tween (0.05%). The detecting antibody
incubation was
for 2 h at 4 C, again followed by the wash steps as described previously. The
final
readout of the ELISA is Time-Resolved Fluorescence (counts per minute) using
Delfia
reagents Streptavidin-Europium and Enhancement solutions (Perkin Elmer) and
the
Victor 2 multilabel counter (Perkin Elmer).
Of the compounds tested, Examples 1-3, 5-7, 9-10, 16, 18-19, 24-35, 38-44, 46-
52, 54-68, 70-74, 76-91, 93-108, 111-124, 126-137, 139, 141-142, 144-145, 152-
171,
173-187, 190-204, 207-213, 218-223, 225-247, 249, 251-252, 254-281, 291-294,
296-
299, 301-314, 315-317, 320-335, 337, 341-343, 345-349, 352-382, 384, 386, 388,
393-
418, 461-466, 468-470, 488-501, 503-510, 512 and 514-519 exhibited activities
with IC50
values of 5 M or less in the cell-based assay. In addition, the cell based
assay data for
each of Examples 520-876 is provided in Table 4. The majority of those
Examples
exhibited activities with 1C5o values of 5 9M or less in the cell-based assay.
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INDICATIONS
Accordingly, compounds of the invention are useful for, but not limited to,
the
prevention or treatment of beta-secretase related diseases, including
Alzheimer's disease.
The compounds of the invention have the ability to modulate the formation of
amyloid
beta, and reduce the formation and deposition of plaque on the brain. In one
embodiment
of the invention, there is provided a method of treating a disorder related to
a beta-
secretase enzyme in a subject, the method comprising administering to the
subject an
effective dosage amount of a compound of Formulas I, II or III. In another
embodiment,
there is provided a method of reducing production of amyloid beta, and of
reducing
plaque formation. In yet another embodiment, there is provided a method of
treating
Alzheimer's disease.
Accordingly, the compounds of the invention would be useful in therapy as CNS
agents in treating neurological disorders and related conditions.
Besides being useful for human treatment, these compounds are useful for
veterinary treatment of companion animals, exotic animals and farm animals,
including
mammals, rodents, and the like. For example, animals including horses, dogs,
and cats
may be treated with compounds provided by the invention.
FORMULATIONS AND METHOD OF USE
Treatment of diseases and disorders herein is intended to also include
therapeutic
administration of a compound of the invention, or a pharmaceutical salt
thereof, or a
pharmaceutical composition of either to a subject (i. e., an animal,
preferably a mammal,
most preferably a human) which may be in need of preventative treatment, such
as, for
example, for pain, inflammation and the like. Treatment also encompasses
prophylactic
administration of a compound of the invention, or a pharmaceutical salt
thereof, or a
pharmaceutical composition of either to a subject (i.e., an animal, preferably
a mammal,
most preferably a human). Generally, the subject is initially diagnosed by a
licensed
physician and/or authorized medical practitioner, and a regimen for
prophylactic and/or
therapeutic treatment via administration of the compound(s) or compositions of
the
invention is suggested, recommended or prescribed.
The amount of compound(s) which is/are administered and the dosage regimen
for treating neurological disorders and beta-secretase mediated diseases with
the
compounds and/or compositions of this invention depends on a variety of
factors,
including the age, weight, sex and medical condition of the subject, the type
of disease,
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the severity of the disease, the route and frequency of administration, and
the particular
compound employed. Thus, the dosage regimen may vary widely, but can be
determined
routinely using standard methods. A daily dose of about 0.01 to 500 mg/kg,
advantageously between about 0.01 and about 50 mg/kg, more advantageously
about 0.01
and about 30 mg/kg, and even more advantageously between about 0.1 and about
10
mg/kg body weight may be appropriate, and should be useful for all methods of
use
disclosed herein. The daily dose can be administered in one to four doses per
day.
While it may be possible to administer a compound of the invention alone, in
the
methods described, the compound administered normally will be present as an
active
ingredient in a pharmaceutical composition. Thus, in another embodiment of the
invention, there is provided a pharmaceutical composition comprising a
compound of this
invention in combination with a pharmaceutically acceptable carrier, which
includes
diluents, excipients, adjuvants and the like (collectively referred to herein
as "carrier"
materials) as described herein, and, if desired, other active ingredients. A
pharmaceutical
composition of the invention may comprise an effective amount of a compound of
the
invention or an effective dosage amount of a compound of the invention. An
effective
dosage amount of a compound of the invention includes an amount less than,
equal to or
greater than an effective amount of the compound. For example, a
pharmaceutical
composition in which two or more unit dosages, such as in tablets, capsules
and the like,
are required to administer an effective amount of the compound, or
alternatively, a multi-
dose pharmaceutical composition, such as powders, liquids and the like, in
which an
effective amount of the compound is administered by administering a portion of
the
composition.
The compound(s) of the present invention may be administered by any suitable
route, preferably in the form of a pharmaceutical composition adapted to such
a route,
and in a dose effective for the treatment intended. The compounds and
compositions of
the present invention may, for example, be administered orally, mucosally,
topically,
rectally, pulmonarily such as by inhalation spray, or parentally including
intravascularly,
intravenously, intraperitoneally, subcutaneously, intramuscularly
intrasternally and
infusion techniques, in dosage unit formulations containing conventional
pharmaceutically acceptable carriers, adjuvants, and vehicles.
For oral administration, the pharmaceutical composition may be in the form of,
for example, a tablet, capsule, suspension or liquid. The pharmaceutical
composition is
preferably made in the form of a dosage unit containing a particular amount of
the active
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ingredient. Examples of such dosage units are tablets or capsules. For
example, these
may contain an amount of active ingredient from about 1 to 2000 mg,
advantageously
from about 1 to 500 mg, and typically from about 5 to 150 mg. A suitable daily
dose for
a human or other mammal may vary widely depending on the condition of the
patient and
other factors, but, once again, can be determined using routine methods and
practices.
For therapeutic purposes, the active compounds of this invention are
ordinarily
combined with one or more adjuvants or "excipients" appropriate to the
indicated route of
administration. If orally administered on a per dose basis, the compounds may
be
admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic
acids, cellulose
alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium
and calcium
salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, to form the final formulation.
For
example, the active compound(s) and excipient(s) may be tableted or
encapsulated by
known and accepted methods for convenient administration. Examples of suitable
formulations include, without limitation, pills, tablets, soft and hard-shell
gel capsules,
troches, orally-dissolvable forms and delayed or controlled-release
formulations thereof.
Particularly, capsule or tablet formulations may contain one or more
controlled-release
agents, such as hydroxypropylmethyl cellulose, as a dispersion with the active
compound(s).
Formulations for parenteral administration may be in the form of aqueous or
non-
aqueous isotonic sterile injection solutions or suspensions. These solutions
and
suspensions may be prepared from sterile powders or granules using one or more
of the
carriers or diluents mentioned for use in the formulations for oral
administration or by
using other suitable dispersing or wetting agents and suspending agents. The
compounds
may be dissolved in water, polyethylene glycol, propylene glycol, ethanol,
corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,
tragacanth gum,
and/or various buffers. Other adjuvants and modes of administration are well
and widely
known in the pharmaceutical art. The active ingredient may also be
administered by
injection as a composition with suitable carriers including saline, dextrose,
or water, or
with cyclodextrin (ie. Captisol), cosolvent solubilization (ie. propylene
glycol) or micellar
solubilization (ie. Tween 80).
The sterile injectable preparation may also be a sterile injectable solution
or
suspension in a non-toxic parenterally acceptable diluent or solvent, for
example as a
solution in 1,3-butanediol. Among the acceptable vehicles and solvents that
may be
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employed are water, Ringer's solution, and isotonic sodium chloride solution.
In
addition, sterile, fixed oils are conventionally employed as a solvent or
suspending
medium. For this purpose any bland fixed oil may be employed, including
synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid find use in
the
preparation of injectables.
The active ingredient may also be administered by injection as a composition
with suitable carriers including saline, dextrose, or water. The daily
parenteral dosage
regimen will be from about 0.1 to about 30 mg/kg of total body weight, and
preferably
from about 0.1 to about 10 mg/kg.
For pulmonary administration, the pharmaceutical composition may be
administered in the form of an aerosol or with an inhaler including dry powder
aerosol.
The pharmaceutical compositions may be subjected to conventional
pharmaceutical operations such as sterilization and/or may contain
conventional
adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers,
buffers etc.
Tablets and pills can additionally be prepared with enteric coatings. Such
compositions
may also comprise adjuvants, such as wetting, sweetening, flavoring, and
perfuming
agents.
Accordingly, in yet another embodiment of the present invention, there is
provided a method of manufacturing a medicament, the method comprising
combining an
amount of a compound according to Formulas I, II or III with a
pharmaceutically
acceptable carrier to manufacture the medicament.
In yet another embodiment, there is provided a method of manufacturing a
medicament for the treatment of Alzheimer's disease, the method comprising
combining
an amount of a compound according to Formulas I, II or III with a
pharmaceutically
acceptable carrier to manufacture the medicament.
COMBINATIONS
While the compounds of the invention can be dosed or administered as the sole
active pharmaceutical agent, they can also be used in combination with one or
more
compounds of the invention or in conjunction with other agents. When
administered as a
combination, the therapeutic agents can be formulated as separate compositions
that are
administered simultaneously or sequentially at different times, or the
therapeutic agents
can be given as a single composition.
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The phrase "co-therapy" (or "combination-therapy"), in defining use of a
compound of the present invention and another pharmaceutical agent, is
intended to
embrace administration of each agent in a sequential manner in a regimen that
will
provide beneficial effects of the drug combination, and is intended as well to
embrace co-
administration of these agents in a substantially simultaneous manner, such as
in a single
capsule having a fixed ratio of these active agents or in multiple, separate
capsules for
each agent.
Specifically, the administration of compounds of the present invention may be
in
conjunction with additional therapies known to those skilled in the art in the
prevention or
treatment of beta-secretase, gamma-secretase and/or other reagents known in
influence
the formation and/or deposition of amyloid beta, otherwise responsible for the
formation
of plaque on the brain.
If formulated as a fixed dose, such combination products employ the compounds
of this invention within the accepted dosage ranges. Compounds of Formulas I,
II and III
may also be administered sequentially with known anti-inflammatory agents when
a
combination formulation is inappropriate. The invention is not limited in the
sequence of
administration; compounds of the invention may be administered either prior
to,
simultaneous with or after administration of the known anti-inflammatory
agent.
The foregoing description is merely illustrative of the invention and is not
intended to limit the invention to the disclosed compounds, compositions and
methods.
Variations and changes, which are obvious to one skilled in the art, are
intended to be
within the scope and nature of the invention, as defined in the appended
claims. From the
foregoing description, one skilled in the art can easily ascertain the
essential
characteristics of this invention, and without departing from the spirit and
scope thereof,
can make various changes and modifications of the invention to adapt it to
various usages
and conditions.
