Note: Descriptions are shown in the official language in which they were submitted.
WO 2011/071570 PCT/US2010/046424
NOVEL OXADIAZOLE COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATION
This application claims priority to U.S. Provisional Application Serial No.
61/267,679
filed on December 8, 2009, the contents of which are incorporated herein.
BACKGROUND OF THE INVENTION
Sphingosine-1-phosphate (SIP) is part of sphingomyelin biosynthetic pathway
and is
known to affect multiple biological processes. SIP is formed through
phosphorylation of
sphingosine by sphingosine kinases (SKI and SK2) and it is degraded through
cleavage by
sphingosine lyase to form palmitaldehyde and phosphoethanolamine or through
dephosphorylation by phospholipid phosphatases. It is present at high levels (-
500 nM) in serum
and it is found in most tissues. It can be synthesized in a wide variety of
cells in response to
several stimuli, which include cytokines, growth factors and G protein-coupled
receptor (GPCR)
ligands. The GPCRs that bind SIP (currently know as the SIP receptors S1P1-5),
couple through
pertusis toxin sensitive (Gi) pathways as well as pertusis toxin insensitive
pathways to stimulate a
variety of processes. The individual receptors of the SIP family are both
tissue and response
specific and so are attractive as therapeutic targets.
SIP evokes many responses from cells and tissues. In particular, SIP has been
shown to
be an agonist at all five GPCRs, S1P1 (Edg-1), S1P2 (Edg-5), S1P3 (Edg-3),
S1P4 (Edg-6) and
S1P5 (Edg-8). The action of S1P at the S1P receptors has been linked to
resistance to apoptosis,
changes in cellular morphology, cell migration, growth, differentiation, cell
division, angiogenesis
and modulation of the immune system via alterations of lymphocyte trafficking.
Therefore, SIP
receptors are targets for therapy of, for example, neoplastic diseases,
autoimmune disorders and
tissue rejection in transplantation. These receptors also share 50-55% amino
acid identity with
three other lysophospholipid receptors, LPA1, LPA2, and LPA3 of the
structurally related
lysophosphatidic acid (LPA).
GPCRs are excellent drug targets with numerous examples of marketed drugs
across
multiple disease areas. GPCRs are cell surface receptors that bind hormones on
the extracellular
surface of the cell and transduce a signal across the cellular membrane to the
inside of the cell.
The internal signal is amplified through interaction with G proteins which in
turn interact with
various second messenger pathways. This transduction pathway is manifested in
downstream
cellular responses that include cytoskeletal changes, cell motility,
proliferation, apoptosis,
secretion and regulation of protein expression to name a few. SIP receptors
make good drug
targets because individual receptors are expressed in different tissues and
signal through different
pathways making the individual receptors both tissue and response specific.
Tissue specificity of
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WO 2011/071570 PCT/US2010/046424
the SIP receptors is desirable because development of an agonist or antagonist
selective for one
receptor localizes the cellular response to tissues containing that receptor,
limiting unwanted side
effects. Response specificity of the SIP receptors is also of importance
because it allows for the
development of agonists or antagonists that initiate or suppress certain
cellular responses without
affecting other responses. For example, the response specificity of the SIP
receptors could allow
for an S1P mimetic that initiates platelet aggregation without affecting cell
morphology.
The physiologic implications of stimulating individual SIP receptors are
largely unknown
due in part to a lack of receptor type selective ligands. Isolation and
characterization of SIP
analogs that have potent agonist or antagonist activity for S1P receptors have
been limited.
S1 P1 for example is widely expressed and the knockout causes embryonic
lethality due to
large vessel rupture. Adoptive cell transfer experiments using lymphocytes
from SIP1 knockout
mice have shown that S1P1 deficient lymphocytes sequester to secondary lymph
organs.
Conversely, T cells overexpressing S1P1 partition preferentially into the
blood compartment
rather than secondary lymph organs. These experiments provide evidence that
S1P1 is the main
sphingosine receptor involved in lymphocyte homing and trafficking to
secondary lymphoid
compartments
Currently, there is a need for novel, potent, and selective agents, which are
agonists or
antagonists of the individual receptors of the SIP receptor family in order to
address unmet
medical needs associated with agonism or antagonism of the individual
receptors of the SIP
receptor family.
SUMMARY OF THE INVENTION
The present invention provides novel compounds described by general Formula
(I), (Ia),
(II), (III), (IV), (Iva), (IVb) or (V) as agonists of the G protein-coupled
receptor S1P1. These
compounds reduce the number of circulating and infiltrating T- and B-
lymphocytes affording a
beneficial immunosuppressive effect. The compounds also exhibit activity
within the SIP
receptor family.
In a first embodiment the invention provides a compound of Formula (I)
N_-O
R1
R2 I
N
R3
O R6
Formula (I)
pharmaceutically acceptable salts, biologically active metabolites, solvates,
hydrates, prodrugs,
racemates, enantiomers or stereoisomers thereof, wherein
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L is a bond or optionally substituted (C1-C3)alkyl;
R1 is -C(O)-NH-phenyl, -NH-C(O)-furanyl, -NH-S(0)2-optionally substituted
phenyl, -0-
optionally substituted (C1-C3)alkyl, -S-optionally substituted (C1-C3)alkyl,
optionally substituted
(C2-C6)alkyl, optionally substituted amino, optionally substituted (C3-
C6)cycloalkyl, -
(CH2)(C3)alkyl, optionally substituted tetrahydrobenzofuranyl, optionally
substituted furanyl,
optionally substituted tetrahydrofuranyl, optionally substituted 2,3-
dihydroisoindolyl, optionally
substituted isoindolinyl, optionally substituted imidazolyl, optionally
substituted 5,6-dihydro
imidazo[1,2-a]pyrazinyl, optionally substituted imidazo[1,2-a]pyrazinyl,
optionally substituted
indolyl, optionally substituted isoxazolyl, optionally substituted
morpholinyl, optionally
substituted naphthyl, optionally substituted phenyl, -0-CH2-optionally
substituted phenyl, -0-
optionally substituted phenyl, -0-optionally substituted phenyl, optionally
substituted piperidinyl,
optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally
substituted
pyrimidinyl, optionally substituted pyrrolidinyl, optionally substituted
1,2,3,4-
tetrahydroisoquinolinyl, optionally substituted quinolinyl, optionally
substituted 3,4-
dihydroquinolinyl, optionally substituted 3,4-dihydroisoquinolinyl, optionally
substituted 5,6,7,8-
tetrahydroimidazo[1,2-a]pyrazinyl, optionally substituted pyrrolyl, optionally
substituted
pyrrolo[2,3-b]pyridinyl, optionally substituted quinolinyl, optionally
substituted thiazolyl or
optionally substituted thienyl;
R2 is Br, Cl, CF3, CN, or -O-(C1-C2)alkyl;
R3 is optionally substituted-(C3-C8)alkyl, deuterated -(C2-C6)alkyl, (C4-
C5)alkenyl, (C4-
C5)alkynyl, optionally substituted-(C3-C6)cycloalkyl, -optionally substituted
(C2-C3)alkyl-0-
optionally substituted (Ci_C3)alkyl, -optionally substituted (C1-C3)alkyl-
imidazolyl, -optionally
substituted (C1-C3)alkyl-morpholinyl, -optionally substituted (C1-C3)alkyl-
optionally substituted
phenyl, -optionally substituted (Ci-C3)alkyl-optionally substituted
piperazinyl, -optionally
substituted (C1-C3)alkyl-pyrrolidinyl, -optionally substituted (C1-C3)alkyl-
piperidinyl, optionally
substituted (C1-C3)alkyl-thienyl, tetrahydrofuranyl or optionally substituted
thiazolyl; and
R6 is H;
provided that
R1 is not substituted by optionally substituted cyclohexyl, -C(O)-cyclohexyl
or -NH-
cyclohexyl;
when L is (C1-C3)alkyl, R1 is not optionally substituted isoxazolyl;
when R3 is optionally substituted (Ci)alkyl, L-R1 is not cyclohexyl or -CH2-
cyclohexyl;
and
provided that the compound is not
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O CH3
CH~ FIZN O / H \ > --(IN / I \ O-C2
N-O CH3 CN O-N CI
In a second embodiment the invention provides the compound according to the
first
embodiment wherein R1 is optionally substituted by one or more substituents
independently
selected from Br, Cl, F, CF3, CN, oxo, -C(=O)H, -N(R9)2, optionally
substituted (C1-C6)alkyl,
optionally substituted (C2-C6)alkenyl, optionally substituted (C2-C6)alkynyl,
optionally substituted
azabicyclo[2.2.1]heptanyl, optionally substituted (C3-C6)cycloalkyl, -C(R9)2-
optionally substituted
(C3-C6)cycloalkyl, -C(R9)2-optionally substituted azetidinyl, -CR92-optionally
substituted
piperidinyl, -C(R9)2-optionally substituted pyrrolidinyl, -C(R9)2-N(R9)2, -
C(O)-optionally
substituted (C1-C6)alkyl, -C(O)-NR9-(C1-C6)alkyl, -C(O)-O-optionally
substituted (C1-C6)alkyl, -
C(R9)2-C(O)-O-optionally substituted (C1-C6)alkyl, -NR9-optionally substituted
(C3-
C6)cycloalkyl, -NR9-optionally substituted azetidinyl, -NR9-furanyl, -NR9-
optionally substituted
pyrrolidinyl, -NR9-C(O)-O-optionally substituted (C1-C3)alkyl, -NR9-optionally
substituted (Ci-
C6)alkyl, -NR9-optionally substituted (C3-C6)cycloalkyl, -NR9-C(O)-azetidinyl,
-NR9-C(O)-
furanyl, -NR9-C(O)-pyridinyl, -NR9-C(O)-optionally substituted pyrrolidinyl, -
NR9-S(0)2-
optionally substituted phenyl, -0-optionally substituted (C1-C6)alkyl, -0-
deuterated -(C2-
C6)alkyl, -0-optionally substituted (C2-C6)alkenyl, -0-optionally substituted
(C3-C6)cycloalkyl, -
O-1H-benzo[d][1,2,3]triazolyl, -S(0)2-N(R9)2, -S(0)2-NR9-optionally
substituted (C1-C4)alkyl,
optionally substituted azetidinyl, optionally substituted piperidinyl,
optionally substituted
pyridinyl, optionally substituted pyrrolidinyl, optionally substituted 1,2,4
oxadizaolyl, optionally
substituted pyrrolidinyl, optionally substituted tetrazolyl,
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-ON N -N -N,.
NN \ E~ L J O O O O
OH OH 'OH IOH
-N \Rr 0 -0 -0 -O
^ O
OHO
O
OH
OH OH
O HO
HO HO HO
O H
-N
~-N \0,0
H -N , -N'O
H OH
H
HO 0 HO HO O
HN
O
H -H /// Or H
HO Q
and
wherein each R9 is independently selected from H or optionally substituted (C1-
C6)alkyl.
In a third embodiment the invention provides a compound according to any of
the
foregoing embodiments wherein the compound is a compound of Formula (Ia)
NCO RI
L
CI JL /
N
O
Formula (la)
wherein L is a bond.
In a fourth embodiment the invention provides a compound according to any of
the
foregoing embodiments wherein R1 is optionally substituted
tetrahydrobenzofuranyl, optionally
substituted furanyl, optionally substituted 2,3-dihydroisoindolyl, optionally
substituted
isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-
dihydro imidazo[1,2-
a]pyrazinyl, optionally substituted imidazo[1,2-a]pyrazinyl, optionally
substituted indolyl,
optionally substituted isoxazolyl, optionally substituted pyrazolyl,
optionally substituted
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WO 2011/071570 PCT/US2010/046424
pyridinyl, optionally substituted pyrimidinyl, optionally substituted
pyrrolidinyl, optionally
substituted 1,2,3,4-tetrahydroisoquinolinyl, optionally substituted
quinolinyl, optionally
substituted 3,4-dihydroquinolinyl, optionally substituted 3,4-
dihydroisoquinolinyl, optionally
substituted 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, optionally substituted
pyrrolyl, optionally
substituted pyrrolo[2,3-b]pyridinyl, optionally substituted quinolinyl,
optionally substituted
thiazolyl or optionally substituted thienyl.
In a fifth embodiment the invention provides a compound according to any of
the
foregoing embodiments wherein R1 is optionally substituted furanyl, optionally
substituted
imidazolyl, optionally substituted isoxazolyl, optionally substituted
pyrazolyl, optionally
substituted pyridinyl, optionally substituted pyrimidinyl, optionally
substituted pyrrolidinyl,
optionally substituted pyrrolyl, optionally substituted thiazolyl or
optionally substituted thienyl.
In a sixth embodiment the invention provides a compound according to any of
the
foregoing embodiments wherein R1 is optionally substituted phenyl or
optionally substituted
indolyl.
In a seventh embodiment the invention provides a compound of according to any
of the
foregoing embodiments wherein
L is optionally substituted (C1-C3)alkyl;
R1 is -C(O)-NH-phenyl, -NH-C(O)-furanyl, -NH-S(O)2-optionally substituted
phenyl,
optionally substituted -0-(C1-C3)alkyl, -S-(C1-C3)alkyl, optionally
substituted benzyloxy,
optionally substituted(C3-C6)cycloalkyl, optionally substituted imidazolyl,
morpholinyl,
optionally substituted naphthyl, optionally substituted phenyl, optionally
substituted phenoxy,
optionally substituted piperazinyl, optionally substituted piperidinyl,
optionally substituted
pyridinyl, optionally substituted pyrrolidinyl or optionally substituted
thienyl;
R2 is Cl;
R3 is isopropyl; and
R6 is H.
In an eighth embodiment the invention provides a compound of according to any
of the
foregoing embodiments wherein L is CH2 and R1 is optionally substituted phenyl
or optionally
substituted (C3-C6)cycloalkyl.
In a ninth embodiment the invention provides a compound of according to any of
the
foregoing embodiments wherein the compound is
4-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4]oxadiazol-5-yl]-3-methyl-pyridine;
3-[3-chloro-4-(1-ethyl-propoxy)-phenyl]-5-o-tolyl-[ 1,2,4]oxadiazole;
3-(3-chloro-4-isopropoxyphenyl)-5-(3-chloropyridin-4-yl)-[1,2,4]-oxadiazole;
3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile;
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WO 2011/071570 PCT/US2010/046424
1-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)-3-
methylazetidine-3-carboxylic acid;
tent-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-
indol-l-
yl)propanoate;
tent-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-
indol-l-
yl)butanoate;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-
yl)propanoic
acid ;
(1R,3S)-3-(4-(3-(3 -chloro-4-isopropoxyphenyl)- 1,2,4-oxadiazol-5 -
yl)phenylamino)cyclopentanecarboxylic acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)propane-1,2-
diol;
(R)-3-{3-chloro-4-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4]oxadiazol-5 -yl]-
phenoxy}-
propane-l,2-diol;
3- {3 -chloro-4- [5-(5 -chloro-6-isopropoxy-pyridin-3 -yl)-[ 1,2,4]oxadiazol-3
-yl] -phenoxy} -
cyclobutanecarboxylic acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)propylphosphonic acid;
ethyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzylidene)cyclobutanecarboxylate;
ethyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)cyclobutanecarboxylate;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)cyclobutanecarboxylic acid;
5 -(3 -(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -yl)-1-methyl-1 H-
pyrazol-3 -amine;
3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-5-yl)-1,2,4-oxadiazole;
1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)pyrrolidine-
3-
carboxylic acid;
3 -amino- l -(4-(3 -(3 -chloro-4-isopropoxyphenyl)- 1,2,4-oxadiazol-5 -
yl)benzyl)pyrrolidine-
3-carboxylic acid;
(S)-1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)pyrrolidine-3-
carboxylic acid;
(R)-1-(4-(3-(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)pyrrolidine-3 -
carboxylic acid;
(S)-1-(4-(3-(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)azetidine-2-
carboxylic acid;
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4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-
yl)butanoic
acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-l-yl)-2-
fluoropropanoic acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-l-yl)-2-
methylpropanoic acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-l-yl)-2,2-
dimethylpropanoic acid;
3-(4-(3-(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrrolo [2,3-
b]pyridin-l-
yl)propanoic acid;
(1R,3S)-3- {4-[3-(5-chloro-6-isopropoxy-pyridin-3-yl)-[ l,2,4]oxadiazol-5-yl]-
3-methyl-
phenylamino}-cyclopentanecarboxylic acid;
4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)-3,3-
dimethylbutanoic acid;
4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)butanoic acid;
1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)pyrrolidine-
3-
carboxylic acid;
2-(1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)pyrrolidin-3-
yl)acetic acid;
(1R,3S)-3-(4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(R)-1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -
yl)phenyl)pyrrolidin-3-
amine, acetic acid;
(1R,2S)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1 S,2R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
(S)-1-(3 -(4-(3 -(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -
yl)phenylamino)pyrrolidin-1-yl)ethanone;
(1R,2R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
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(1R,2S)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
(1R,2S)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
(1 S,2R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
(1R,2R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
(1 S,2S)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
(1 S,2R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1 S,2S)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclohexanecarboxylic acid;
(S)-N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)-1-
(methylsulfonyl)pyrrolidin-3 -amine;
(S)-2-(3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)pyrrolidin-1-yl)acetic acid;
(1R,3S)-3-(2-bromo-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(2-bromo-3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-
ylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)pyridin-2-
ylamino)cyclopentanecarboxylic acid;
(3S)-3-(4-(3 -(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -yl)phenylamino)-
1-
methylcyclopentanecarboxylic acid;
2-((1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentyl)acetic acid;
(1 S,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)-1-
methylcyclopentanecarboxylic acid;
(1R,3S)-3 -(4-(3-(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)-1-
methylcyclopentanecarboxylic acid;
(35)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)-1-
fluorocyclopentanecarboxylic acid;
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(1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid;
(3S)-3-(4-(3 -(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -yl)phenylamino)-
1-
hydroxycyclopentanecarboxylic acid;
(1R,3S)-3-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
chlorophenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(3-bromo-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
(trifluoromethyl)phenylamino)cyclopentanecarboxylic acid;
(R)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-l-yl)-
2-
methylpropanoic acid;
(S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-l-yl)-
2-
methylpropanoic acid;
(1R,2S)-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylate;
(1S,2R)-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylate;
(1R,2R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1 S,2S)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
3-(3-chloro-4-isopropoxyphenyl)-5-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-
1,2,4-
oxadiazole;
(R)-3-(4-(3-(4-(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)-1H-indol-1-yl)propanoic acid;
(1R,3S)-3-[4-(5-biphenyl-2-yl-[ 1,2,4]oxadiazol-3-yl)-2-methyl-phenylamino]-
cyclopentanecarboxylic acid;
(1R,3S)-3-[4-(5-biphenyl-3-yl-[ 1,2,4]oxadiazol-3-yl)-2-methyl-phenylamino]-
cyclopentanecarboxylic acid;
(1R,3S)-3-[4-(5-biphenyl-4-yl-[ 1,2,4]oxadiazol-3-yl)-2-methyl-phenylamino]-
cyclopentanecarboxylic acid;
(1R,3S)-3-{ 4-[5-(4-cyclohexyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2-methyl-
phenylamino}-
cyclopentanecarboxylic acid;
WO 2011/071570 PCT/US2010/046424
(1R,3S)-3-((4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)(methyl)amino)cyclopentanecarboxylic acid;
methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-l-
yl)cyclopentanecarboxylate;
3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-l-
yl)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
ethynylphenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3 -(5-(3-(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1 H-
indol-l -
yl)cyclopentanecarboxylic acid;
(1 S,4R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
methoxyphenyl)-
2-azabicyclo [2.2.1 ]heptan-3-one;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
methoxyphenylamino)cyclopentanecarboxylic acid;
(R)-3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
methylphenoxy)propane-1,2-diol;
N-(4-(3 -(3-chloro-4-isopropoxyphenyl)- 1,2,4-oxadiazol-5-
yl)phenyl)isonicotinamide;
N-(4-(3 -(3-chloro-4-isopropoxyphenyl)- 1,2,4-oxadiazol-5-
yl)phenyl)isonicotinamide;
(3S)-3-(4-(3 -(3-chloro-4-isopropoxyphenyl)- 1,2,4-oxadiazol-5 -
yl)phenylamino)-1-
hydroxycyclopentanecarboxylic acid;
(1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid;
1-amino-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)cyclopentanecarboxylic acid;
1-amino-3-(3-chloro-4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-
yl)phenoxy)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-
methylphenylamino)cyclopentanecarboxylic acid;
(1 S,4R)-2-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-
methylphenyl)-2-azabicyclo[2.2.1]heptan-3-one;
(1R,3S)-3-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-
methylphenylamino)cyclopentanecarboxylic acid;
methyl 2-(5-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)-
2H-
tetrazol-2-yl)acetate;
3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)-1,2,4-
oxadiazol-
5(2H)-one;
11
WO 2011/071570 PCT/US2010/046424
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
ethylphenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
cyanophenylamino)cyclopentanecarboxylic acid;
(2R,4R)-4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)pyrrolidine-2-carboxylic acid;
2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)propan-1-ol;
(R)-2 -(4-(3 -(4-isopropoxy-3 -(trifluoromethyl)phenyl)- 1,2,4-oxadiazol-5 -
yl)phenoxy)propanoic acid;
(R)-N-(2 -hydroxyethyl)-2-(4-(3 -(4-i sopropoxy-3 -(trifluoromethyl)phenyl)-
1,2,4-
oxadiazol-5 -yl)phenoxy)propanamide;
(R)-2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)propanal;
3-{3-Chloro-4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-3-yl]-
phenoxy}-
cyclobutanecarboxylic acid; or
(1R, 3S)-3-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1, 2, 4-oxadiazol-3-yl)
phenylamino) cyclopentane carboxylic acid.
In a tenth embodiment the invention provides a compound of Formula (II)
NCO
R1
R2
N
R3
Y R6
Formula (II)
pharmaceutically acceptable salts, biologically active metabolites, solvates,
hydrates, prodrugs,
enantiomers or stereoisomers thereof, wherein
Y is a bond;
Lisa bond or CH2;
R1 is optionally substituted (C1-C4)alkyl, optionally substituted indolyl or
optionally
substituted phenyl;
R2 is CF3,
R3 is H, morpholinyl, optionally substituted piperidine or (C3-C5)cycloalkyl;
and
R6 is H.
12
WO 2011/071570 PCT/US2010/046424
In an eleventh embodiment the invention provides a compound according to the
tenth
embodiment wherein R1 is optionally substituted by one or more substituents
independently
selected from Cl, F, CN, optionally substituted (C1-C3)alkyl,-CH2-optionally
substituted
azetidinyl, -CH2-optionally substituted pyrrolidinyl, -CH2NR Rd, -NH-
optionally substituted (C3-
C6)cycloalkyl, optionally substituted piperidinyl,
HO
N
O
OH or -N
wherein R and Rd are independently H, optionally substituted (C1-C6)alkyl or
optionally
substituted (C3-C6)cycloalkyl;
In a twelfth embodiment the invention provides a compound according to the
tenth and
eleventh embodiments wherein the compound is
1-((4-(3-(4-(4-fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5 -
yl)benzylamino)methyl)cyclopropanecarboxylic acid;
(R)-1-(4-(3-(4-(4-fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)benzyl)pyrrolidine-3-carboxylic acid;
(S)-1-(4-(3-(4-(4-fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)benzyl)pyrrolidine-3-carboxylic acid;
1-(4-(3 -(4-(4-fluoropip eridin-1-yl)-3 -(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5 -
yl)benzylamino)cyclopropanecarboxylic acid;
1-(4-f 3-[4-(4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl]- [
1,2,4]oxadiazol-5 -yl} -
benzylamino)-cyclopropanecarboxylic acid;
1-(4-f 3-[4-(4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl]- [
1,2,4]oxadiazol-5 -yl} -
benzyl)-pyrrolidine-3-carboxylic acid;
1-(4- {3 -[4-(4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl]- [
1,2,4]oxadiazol-5 -yl} -
benzyl)-4-methyl-pyrrolidine-3-carboxylic acid;
4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl]-[ 1,2,4]oxadiazol-5-yl}-
benzylamino)-
acetic acid;
[(S)- 1-(4- {3 -[4-(4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl]-[
1,2,4] oxadiazol-5-
yl}-benzyl)-pyrrolidin-2-yl]-acetic acid;
[ 1-(4- {3- [4-(4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl] -[
1,2,4]oxadiazol-5 -yl}-
benzylamino)-cyclopropyl]-methanol;
1-(4- {3 -[4-(4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl]- [
1,2,4]oxadiazol-5 -yl} -
benzyl)-4,4-dimethyl-pyrrolidine-3-carboxylic acid;
13
WO 2011/071570 PCT/US2010/046424
1-[(4-f 3-[4-(4-fluoro-piperidin-1-yl)-3-trifluoromethyl-phenyl] -[
1,2,4]oxadiazol-5 -yl}-
benzylamino)-methyl]-cyclopropanol;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
(trifluoromethyl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
methylphenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
methylphenylamino)cyclopentanecarboxylic acid;
4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)-2-
methylbutanoic acid;
tent-butyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)acetate;
tent-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)propanoate;
1-amino-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)cyclopentanecarboxylic acid;
3- {4- [3 -(3 -chloro-4-isopropoxy-phenyl)- [ 1,2,4]oxadiazol-5 -yl] -phenoxy
}-
cyclobutanecarboxylic acid;
2-(6-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-
dihydroquinolin-1(2H)-
yl)acetic acid;
3-(6-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-
dihydroquinolin-1(2H)-
yl)propanoic acid;
(E)-4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
methylphenoxy)but-
2-enoic acid;
4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
methylphenoxy)butanoic
acid;
4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-4-
methylphenoxy)butanoic
acid;
(3- {4-[3 -(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4] oxadiazol-5-yl]-
phenylamino}-propyl)-
phosphonic acid diethyl ester;
(3- {4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-benzylamino}-
propyl)-
phosphonic acid;
(1 S,3R)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonic acid;
(1 R,3R)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonic acid;
(1R,3R)-3-(2-bromo-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonic acid;
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WO 2011/071570 PCT/US2010/046424
(1 R,3 S)-3 -(4-(3-(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -
yl)phenylamino)cyclopentylphosphonic acid;
(1 R,3 S)-3 -(2-bromo-4-(3-(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonic acid;
(1 S,3 S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonic acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)cyclobutanecarboxylic acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)cyclopentanecarboxylic acid;
1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-
carboxylic acid;
2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2-
amine;
methyl 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)propan-2-
ylamino)propanoate;
3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2-
ylamino)propanoic acid;
3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4-oxadiazole;
(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine;
3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)cyclopentylamino)propanoic
acid;
4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)cyclopentylamino)butanoic
acid;
(S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)propane-
1,2-
diol;
4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide;
tent-butyl3,3'-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylsulfonylazanediyl)dipropanoate;
tent-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylsulfonamido)propanoate;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylsulfonamido)propanoic acid;
2,2'-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylsulfonylazanediyl)diacetic acid;
tent-butyl2,2'-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylsulfonylazanediyl)diacetate;
WO 2011/071570 PCT/US2010/046424
tent-butyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylsulfonamido)acetate;
2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylsulfonamido)acetic
acid;
tent-butyl 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-
dihydroisoquinolin-2(1H)-yl)acetate;
tent-butyl 5 -(3 -(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -yl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate;
3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1,2,4-
oxadiazole;
2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-
dihydroisoquinolin-
2(1H)-yl)acetic acid;
tent-butyl 3 -(5 -(3 -(3 -chloro-4-i sopropoxyphenyl)-1,2,4-oxadiazol-5 -yl)-
3,4-
dihydroisoquinolin-2(1H)-yl)propanoate;
3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-
dihydroisoquinolin-
2(1H)-yl)propanoic acid;
2-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4]oxadiazol-5-yl]-3-methyl-5,6,7,8-
tetrahydro-
imidazo [ 1,2-a]pyrazine;
1- {2-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4]oxadiazol-5-yl]-3-methyl-5,6-
dihydro-8H-
imidazo [ 1,2-a]pyrazin-7-yl} -ethanone;
{2-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-5,6-
dihydro-8H-
imidazo[1,2-a]pyrazin-7-yl}-acetic acid tent-butyl ester;
{2-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-5,6-
dihydro-8H-
imidazo[1,2-a]pyrazin-7-yl}-acetic acid;
3-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4] oxadiazol-5 -yl]-2-methyl-imidazo
[ 1,2-
a]pyrazine;
3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-
yl)methoxy)phenyl)-1,2,4-oxadiazole;
2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)acetic
acid;
1-(4-(3-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-
carboxylic acid;
1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)cyclopropanecarbonitrile;
1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)cyclopropanecarbaldehyde;
3-((1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)cyclopropyl)methylamino)propanoic acid;
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WO 2011/071570 PCT/US2010/046424
N-(4-(3 -(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)-1-(2,2-
dimethyl-
1,3-dioxolan-4-yl)methanamine;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzylamino)propane-
1,2-
diol;
(Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)acrylate;
trans-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)cyclopropanecarboxylate;
trans-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)cyclopropanecarboxylic acid;
tent-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindoline-
2-
carboxylate;
3-(3-chloro-4-isopropoxyphenyl)-5-(isoindolin-5-yl)-1,2,4-oxadiazole;
methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindolin-2-
yl)propanoate;
3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindolin-2-
yl)propanoic
acid;
(Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)acrylate;
(Z)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylic
acid;
3-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclobutanecarboxylic acid;
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclobutanecarboxylic acid;
1-(4-(3 -(4-(4-fluoropip eridin-1-yl)-3 -(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5 -
yl)benzyl)azetidine-3-carboxylic acid;
of 5-((4-(3-(4-(4-fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)benzylamino)methyl)isoxazol-3-ol;
2-((4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)methyl)morpholine;
(1R,3S)-3-(4-(3-(4-((S)-tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)phenyl)-
1,2,4-
oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3 -(4-(3-(4-(4-fluoropiperidin-1-yl)-3 -(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(4-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-
1,2,4-
oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid;
(1 S,3S)-3-(4-(3-(4-(4-fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
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WO 2011/071570 PCT/US2010/046424
(1R,3R)-3-(4-(3-(4-(4-fluoropiperidin-l-yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid;
(1 S,3R)-3-(4-(5-(3-cyano-4-(4-fluoropiperidin-1-yl)phenyl)-1,2,4-oxadiazol-3-
yl)-2-
(trifluoromethyl)phenylamino)cyclopentanecarboxylic acid;
(1 S,3R)-3-(4-(5-(3-cyano-4-(4-fluoropiperidin-1-yl)phenyl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid;
5-[3-(4-Fluoro-phenyl)- [ 1,2,4]oxadiazol-5 -yl]-2-(4-fluoro-piperidin-l-yl)-
benzonitrile;
5-[3-(4-Fluoro-3 -trifluoromethyl-phenyl)-[ 1,2,4]oxadiazol-5-yl]-2-(4-fluoro-
piperidin-l-
yl)-benzonitrile;
(1R,3S)-3-[4-(5-biphenyl-2-yl-[ 1,2,4]oxadiazol-3-yl)-2-methyl-phenylamino]-
cyclopentanecarboxylic acid;
(1R,3S)-3-[4-(5-biphenyl-3-yl-[ l,2,4]oxadiazol-3-yl)-2-methyl-phenylamino]-
cyclopentanecarboxylic acid;
(1R,3S)-3-{ 4-[5-(4-cyclohexyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2-methyl-
phenylamino}-
cyclopentanecarboxylic acid; or
(1R,3S)-3-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid.
In a thirteenth embodiment the invention provides a compound of Formula (III)
NCO
R1
R2
N
R3 E
Y
N /
R6 /
Formula (III)
pharmaceutically acceptable salts, biologically active metabolites, solvates,
hydrates, prodrugs,
enantiomers or stereoisomers thereof, wherein
E is CH or N;
Y is a bond;
Lisa bond;
R1 is optionally substituted aryl;
R2 is H;
R3 is H; and
R6 is H or optionally substituted (C1-C3)alkyl.
N a fourteenth embodiment the invention provides a compound of Formula (IV):
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WO 2011/071570 PCT/US2010/046424
N-_O R1
RZ
N
R3
Y X Rs
Formula (IV)
or a pharmaceutically acceptable salt, solvate, hydrate, metabolite, prodrug,
enantiomer or
stereoisomer thereof,
wherein:
X is N or CR4;
L is a bond, -CH2CH2-, (C3-C6)cycloalkyl, or -CHR5;
Y is -0-, -NR'- or -C(R7)(R'')-;
R1 is optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted
heterocyclyl, optionally substituted -(C1-C6)alkyl-O-(C1-C3)alkyl, optionally
substituted -(Ci-
C6)alkyl-O-(C1-C6)alkyl -0-(C1-C3)alkyl, optionally substituted -(C1-C6)alkyl-
O-aryl,
alkylsulfanylalkyl, unsubstituted (C2-C5)alkyl, substituted (C1-C6)alkyl, -
COR", optionally
substituted -O-(C1-C3)alkyl, -N(R7)(R), -N(R7)SO2-R1' or optionally
substituted (C3-
C6)cycloalkyl, and wherein R1 is not substituted cyclopentathiophene,
halothiophene, substituted
indan or substituted chromenone;
R2 and R6 may be the same or different and are independently H, -(C1-C4)alkyl,
-O-(Ci-
C3)alkyl, -CF3, -CN, halo or -COO-(Ci-C4)alkyl;
R3 is optionally substituted aryl, optionally substituted heterocyclyl,
optionally substituted
heteroaryl, optionally substituted (C3-C6)cycloalkyl, -(CH2)ri R11, -CO-OR", -
CO-R1', -
CON(R7)(R11), -N(R7)(R11), -SOR" , -S02R11 and optionally substituted straight
or branched (Ci-
C8)alkyl chain optionally including -CO-, -COO-, -SO-, -SO2-, -CONH-, -NHCO-, -
N- or -0-
groups embedded within the alkyl chain; and when Y is 0, R3 is not
alkyldiazeapane, -
C(CH3)2COOCH2CH3 or -CH2CH2N(CH2CH3)2, and when Y is -CH2-, R3 is not -
CH2COOH;
or Y is a bond and R3 is optionally substituted morpholino;
R4 is H, -(C1-C4)alkyl, -O-(C1-C3)alkyl, -CF3, -CN or halo;
R5 is H, O-(C1-C3)alkyl or (C1-C3)alkyl;
each occurrence of R7 or R7' is independently H or optionally substituted (C1-
C3)alkyl;
R8 is H, optionally substituted CH3, or -COR";
R11 is hydrogen, optionally substituted (C1-C3)alkyl, optionally substituted
alkynyl,
optionally substituted aryl, optionally substituted heteroaryl, optionally
substituted
heterocyclyl or optionally substituted (C3-C6)cycloalkyl; and
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WO 2011/071570 PCT/US2010/046424
nis1,2,3or4;
provided that
R1 is not optionally substituted furanyl or -C(O)-optionally substituted
furanyl;
R3 is not optionally substituted quinolinyl;
R" is not optionally substituted cyclopropyl, optionally substituted
cyclohexyl, optionally
substituted furanyl, optionally substituted imidazolyl, optionally substituted
indolyl, optionally
substituted naphthyl, optionally substituted piperazinyl, optionally
substituted pyrazolyl,
optionally substituted pyridazinyl or optionally substituted quinolinyl;
R1 is not substituted by -C(O)-cyclopentyl, optionally substituted
cyclopentyl, -C(O)-
cyclobutyl, cyclobutyl, -C(O)-cyclohexyl or optionally substituted cyclohexyl;
R3 is not substituted by -C(O)-cyclopropyl;
when R3 is CH3 or 4-chlorophenylmethyl, L-R1 is not cyclopropyl, cyclopentyl,
optionally
substituted cyclohexyl, -CH2-cyclohexyl, -NH-cyclohexyl, -CH2CH2-cyclohexyl or
optionally
substituted pyrazolyl;
when Y is 0, R3 is not -(Co-C4)alkyl-optionally substituted isoxazolyl or
optionally
substituted pyrazolyl;
when L is (C1-C3)alkyl, R1 is not optionally substituted isoxazolyl;
when L is a bond, R1 is not optionally substituted cyclobutyl, optionally
substituted
cyclohexyl, optionally substituted naphthyl, -CH2-optionally substituted
naphthyl, -CH2-0-
optionally substituted naphthyl, optionally substituted pyrazolyl or
tetrahydrobenzofuranyl;
provided the compound is not
'N I N\ I / ~N I \ N~
HOOC HOOC
N-O N-O
provided the compound is not
C- R3
N I H 2 -- 1105~ ~O-N
wherein R3 is optionally substituted piperazinyl or optionally substituted
phenyl;
provided the compound is not
Y- R3
N
R1~
O-N
wherein R1 is optionally substituted pyridine or 3-chlorophenyl and -Y-R3 is
-NH-C(O)-optionally substituted phenyl;
-0-optionally substituted pyridinyl;
WO 2011/071570 PCT/US2010/046424
-NH-C(O)-OCH3i
-CH2-optionally substituted piperazinyl;
-0-optionally substituted (C1-Cg)alkyl;
-CH2-morpholinyl; or
-O-C(O)-optionally substituted pyridinyl;
provided the compound is not
O `zz Y- R3
O-N
R O
wherein
L is CH2, CH(CH3) or CH2CH2;
Y is O or CH2i
R2 is H or OCH3;
R3 is CH3 or OCF3; and
R is H or NO2;
provided the compound is not
% I C-COON
>--~ "-- - CH3
O-N
provided the compound is not
OMe
N Nzzt
~ 14-
R O
N-O
wherein R1 is phenyl, 4-chlorophenyl, piperidinyl or thienyl.
In a fifteenth embodiment the invention provides a compound according t the
fourteenth
embodiment wherein
R1 is optionally substituted phenyl, optionally substituted
tetrahydrobenzofuranyl,
optionally substituted furanyl, optionally substituted 2,3-dihydroisoindolyl,
optionally substituted
isoindolinyl, optionally substituted imidazolyl, optionally substituted 5,6-
dihydro imidazo[1,2-
a]pyrazinyl, optionally substituted imidazo[1,2-a]pyrazinyl, optionally
substituted indolyl,
optionally substituted isoxazolyl, optionally substituted pyrazolyl,
optionally substituted
pyridinyl, optionally substituted pyrimidinyl, optionally substituted
pyrrolidinyl, optionally
substituted 1,2,3,4-tetrahydroisoquinolinyl, optionally substituted
quinolinyl, optionally
substituted 3,4-dihydroquinolinyl, optionally substituted 3,4-
dihydroisoquinolinyl, optionally
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substituted 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, optionally substituted
pyrrolyl, optionally
substituted pyrrolo[2,3-b]pyridinyl, optionally substituted quinolinyl,
optionally substituted
thiazolyl, optionally substituted thienyl, optionally substituted -(C1-
C6)alkyl-O-(C1-C3)alkyl,
optionally substituted -(C1-C6)alkyl-O-(C1-C6)alkyl -0-(C1-C3)alkyl,
optionally substituted -(Ci-
C6)alkyl-O-phenyl, unsubstituted (C2-C5)alkyl, substituted (C1-C6)alkyl, -
COR11, optionally
substituted -O-(C1-C3)alkyl, -N(R7)(R8), -N(R7)SO2-R11 or optionally
substituted (C3-
C6)cycloalkyl;
R2 and R6 may be the same or different and are independently H, -(C1-C4)alkyl,
-O-(Ci-
C3)alkyl, -CF3, -CN, Cl, or F.
In a sixteenth embodiment the invention provides a compound according to the
fourteenth
and fifteenth embodiments wherein
L is a bond, -CH2CH2-, or -CHR5;
Y is -0-, -NR'- or -C(R7)(R'')-;
R1 is optionally substituted phenyl, ; optionally substituted furanyl,
optionally substituted
isoindolinyl, optionally substituted imidazolyl, optionally substituted
imidazo[1,2-a]pyrazinyl,
optionally substituted indolyl, optionally substituted isoxazolyl, optionally
substituted pyrazolyl,
optionally substituted pyridinyl, optionally substituted pyrimidinyl,
optionally substituted
pyrrolidinyl, ; optionally substituted quinolinyl, optionally substituted
pyrrolyl, optionally
substituted pyrrolo[2,3-b]pyridinyl, optionally substituted quinolinyl,
optionally substituted
thiazolyl, optionally substituted thienyl, optionally substituted -(C1-
C6)alkyl-O-(C1-C3)alkyl,
optionally substituted -(C1-C6)alkyl-O-phenyl, unsubstituted (C2-C5)alkyl,
substituted (Ci-
C6)alkyl, -COR11, optionally substituted -O-(C1-C3)alkyl, -N(R7)(R8), -
N(R7)SO2-R" or optionally
substituted (C3-C6)cycloalkyl;
R2 and R6 may be the same or different and are independently H, -(C1-C4)alkyl,
-O-(Ci-
C3)alkyl, -CF3, -CN, Cl or F;
R3 is optionally substituted phenyl, optionally substituted piperidinyl,
optionally
substituted furanyl, optionally substituted pyrimidinyl, optionally
substituted pyridinyl,
optionally substituted (C3-C6)cycloalkyl, -(CH2)ri R", -CO-OR", -CO-R11, -
CON(R')(R"), -
N(R7)(R11), -SOR11 , -S02R" and optionally substituted straight or branched
(C1-C8)alkyl
chain.
In a seventeenth embodiment the invention provides a compound according to the
fourteenth through sixteenth embodiments wherein R1 is optionally substituted
phenyl,
optionally substituted furanyl, optionally substituted indolyl, optionally
substituted isoxazolyl,
optionally substituted pyrazolyl, optionally substituted pyridinyl, optionally
substituted
pyrimidinyl, optionally substituted pyrrolyl, unsubstituted (C2-C5)alkyl,
substituted (Ci-
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WO 2011/071570 PCT/US2010/046424
C6)alkyl, -COR11, -N(R7)(R), optionally substituted -O-(C1-C3)alkyl, or
optionally substituted
(C3-C6)cycloalkyl;
R2 and R6 may be the same or different and are independently H, -(C1-C4)alkyl,
-CF3, Cl
or F;
R3 is optionally substituted phenyl, optionally substituted piperidinyl
optionally
substituted pyrimidinyl, optionally substituted pyridinyl, optionally
substituted (C3-
C6)cycloalkyl, -(CH2)ri R11, optionally substituted straight or branched (C1-
C8)alkyl chain or
O
H
)t),
H ; or
-Y-R3 is
H
.,,
N
qrO
N -N~ -NH
OH OH 'OH
-N O
OH OH
OH or
OH
HO HO HO HO
--O O O
-N -N~ -N H
H H H
H HO HO HO
N ~GO O O
OH _ -N'0 _
H H or H
In an eighteenth embodiment the invention provides a compound according to the
fourteenth through seventeenth embodiments wherein R1 is optionally
substituted by one or more
substituents independently selected from Br, Cl, F, CF3, CN, oxo, -C(=O)H, -
N(R9)2, optionally
substituted (C1-C6)alkyl, optionally substituted (C2-C6)alkenyl, optionally
substituted (C2-
C6)alkynyl, optionally substituted azabicyclo[2.2.1]heptanyl, optionally
substituted (C3-
C6)cycloalkyl, -C(R9)2-optionally substituted (C3-C6)cycloalkyl, -C(R9)2-
optionally substituted
azetidinyl,, -CR92-optionally substituted piperidinyl, -C(R9)2-optionally
substituted pyrrolidinyl, -
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WO 2011/071570 PCT/US2010/046424
C(R9)2-N(R9)2, -C(O)-optionally substituted (C1-C6)alkyl, -C(O)-NR'-(C1-
C6)alkyl, -C(O)-O-
optionally substituted (C1-C6)alkyl, -C(R9)2-C(O)-O-optionally substituted (C1-
C6)alkyl, -NR9-
optionally substituted (C3-C6)cycloalkyl, -NR9-optionally substituted
azetidinyl, -NR9-furanyl, -
NR9-optionally substituted pyrrolidinyl, -NR9-C(O)-O-optionally substituted
(C1-C3)alkyl, -NR9-
optionally substituted (C1-C6)alkyl, -NR9-optionally substituted (C3-
C6)cycloalkyl, -NR9-C(O)-
azetidinyl, -NR9-C(O)-furanyl, -NR9-C(O)-pyridinyl, -NR9-C(O)-optionally
substituted
pyrrolidinyl, -NR9-S(0)2-optionally substituted phenyl, -0-optionally
substituted (C1-C6)alkyl, -
O-deuterated -(C2-C6)alkyl, -0-optionally substituted (C2-C6)alkenyl, -0-
optionally substituted
(C3-C6)cycloalkyl, -O-1H-benzo[d][1,2,3]triazolyl, -S(0)2-N(R9)2, -S(0)2-NR9-
optionally
substituted (C1-C4)alkyl, optionally substituted azetidinyl, optionally
substituted piperidinyl,
optionally substituted pyridinyl, optionally substituted pyrrolidinyl,
optionally substituted 1,2,4
oxadizaolyl, optionally substituted pyrrolidinyl, optionally substituted
tetrazolyl,
HO
H N --\ N _
-]<~ L-, L O
N
OH OH OH H
O HO
11 O
HN O O
OH
HO or -H
and
wherein each R9 is independently selected from H or optionally substituted (C1-
C6)alkyl.
In a nineteenth embodiment the invention provides a compound according to the
fourteenth through eighteenth embodiments wherein each substituent or optional
substituent is
independently one or more R10 groups wherein R10 is optionally substituted
alkyl, alkenyl,
optionally substituted alkoxy groups, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl,
alkoxycarbonylheterocycloalkoxy, alkyl, alkylamino, alkylcarbonyl, alkylester,
alkyl-O-C(O)-,
alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile, alkylsulfonyl, alkynyl,
amido groups,
optionally substituted amino, aminoalkyl, aminoalkoxy, aminocarbonyl,
optionally substituted
azabicyclo[2.2.1]heptanyl, carbonitrile, carbonylalkoxy, carboxamido, CF3, CN,
-C(O)OH, -
C(O)H, -C(O)-C(CH3)3, -OH, -C(0)0-alkyl, -C(0)0- optionally substituted
cycloalkyl, -C(0)0-
heterocyclyl, -C(O)-alkyl, -C(O)- optionally substituted cycloalkyl, -C(O)-
heterocyclyl, CN,
optionally substituted cycloalkyl, dialkylamino, dialkylaminoalkoxy,
dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, dialkylaminosulfonyl, -C(O)-
ORa, halogen,
optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally
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WO 2011/071570 PCT/US2010/046424
substituted heterocyclyloxy, hydroxy, hydroxyalkyl, nitro, oxo, optionally
substituted phenyl, -
SO2CH3, -SO2CF3, sulfonyl, tetrazolyl, thienylalkoxy,
trifluoromethylcarbonylamino,
trifluoromethylsulfonamido, heterocyclylalkoxy, heterocyclyl-S(O)p, optionally
substituted
cycloalkyl-S(O)p, optionally substituted alkyl-S-, optionally substituted
heterocyclyl-S,
heterocycloalkyl, cycloalkylalkyl, heterocycolthio, cycloalkylthio, N-
alkylamino and N,N-
dialkylamino where Ra is optionally substituted alkyl, optionally substituted
heterocycloalkyl, or
optionally substituted heterocyclyl and p is 1 or 2.
In a twentieth embodiment the invention provides a compound according to
fourteenth
through nineteenth embodiments wherein -Y-R3 is
-NN -N 1-kr 0 0 Q 0
OH OH OH
OH
3-O O H 0 HO
O O
OH OH N -N
H H
HO
HO HO O
O O H
N
O
H H -H
OH
HO HO
O
-N 0, -
H or H
In a twenty-first embodiment the invention provides a compound according to
fourteenth
through twentieth embodiments wherein the compound is
3- {3 -chloro-4- [5-(5 -chloro-6-isopropoxy-pyridin-3-yl)-[ 1 ,2,4]oxadiazol-3
-yl] -phenoxy} -
cyclobutanecarboxylic acid;
(1R,3S)-3-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid ;
WO 2011/071570 PCT/US2010/046424
(1 S,4R)-2-(3-(3-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-
methylphenyl)-2-azabicyclo[2.2.1 ]heptan-3-one;
(1R,3S)-3-(4-(3-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-
methylphenylamino)cyclopentanecarboxylic acid;
(1R,3S)-3-(4-(3-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-5-yl)-3-
(trifluoromethyl)phenylamino)cyclopentanecarboxylic acid;
1-amino-3-(3-chloro-4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-
yl)phenoxy)cyclopentanecarboxylic acid;
3- {3 -chloro-4- [5-(5 -chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-3 -
yl] -phenoxy} -
cyclobutanecarboxylic acid;
4- {3 -chloro-4- [5-(5 -chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-3 -
yl] -phenoxy} -
cyclohexanecarboxylic acid;
3- {3 -chloro-4- [3-(5 -chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-5 -
yl] -phenoxy} -
cyclobutanecarboxylic acid;
3-{3-chloro-4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-3-yl]-
phenoxy}-
cyclobutanecarboxylic acid;
3- {3 -chloro-4- [5-(5 -chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-3 -
yl] -phenoxy} -
cyclohexanecarboxylic acid;
4- {3 -chloro-4- [5-(5 -chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-3 -
yl] -phenoxy} -
cyclohexanecarboxylic acid;
cis- {3-chloro-4- [5 -(5 -chloro-6-isopropoxy-pyridin-3-yl)-[ 1,2,4]oxadiazol-
3-yl] -
phenoxy } -cyclopentanecarboxylic acid;
trans-3- {3 -chloro-4- [5 -(5-chloro-6-isopropoxy-pyridin-3 -yl)- [
1,2,4]oxadiazol-3 -yl]-
phenoxy } -cyclopentanecarboxylic acid; or
(1R,3S)-3-(4-(5-(5-bromo-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid.
In a twenty-second embodiment the invention provides a compound according to
Formula
(V)
O
NRaRb
R3 Y N
Formula (V)
Y is a bond
R3 is -3-((1aS,5aR)-1,1,2-Trimethyl-1,1a,5,5a-tetrahydro-3-thia-
cyclopropa[a]pentalenyl,
or optionally substituted thienyl;
Ra is H or optionally substituted (C1-C6)alkyl
Rb is H, optionally substituted (C1-C6)alkyl or optionally substituted (C3-
C6)cycloalkyl.
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WO 2011/071570 PCT/US2010/046424
In a twenty-third embodiment the invention provides a compound according to
the
twenty-second embodiment wherein the compound is
(1R,3S)-3-(4-(3-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid; or
(S)-3-{4-[3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia
cyclopropa[a]pentalen-
4-yl)-[1,2,4]oxadiazol-5-yl]-phenylamino}-cyclopentanecarboxylic acid.
In a twenty-fourth embodiment the invention provides a pharmaceutical
composition
comprising a compound according to any of the foregoing embodiments or a
pharmaceutically
acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or
stereoisomer thereof and a
pharmaceutically acceptable diluent or carrier.
In a twenty-fifth embodiment the invention provides for the use of one or more
compounds according to any of the foregoing embodiments or a pharmaceutically
acceptable salt,
solvate, hydrate, metabolite, prodrug or stereoisomer thereof for the
manufacture of a medicament
for treating an immune disorder.
In a twenty-sixth embodiment the invention provides for the use according the
twenty-
fifth embodiment wherein the immune disorder is active chronic hepatitis,
Addison's Disease,
ankylosing spondylitis, anti-phospholipid syndrome, asthma, atopic allergy,
autoimmune atrophic
gastritis, achlorhydra autoimmune, Celiac Disease, Crohn's Disease, Cushing's
Syndrome,
dermatomyositis, Goodpasture's Syndrome, Grave's Disease, Hashimoto's
thyroiditis, idiopathic
adrenal atrophy, idiopathic thrombocytopenia, juvenile rheumatoid arthritis,
Lambert-Eaton
Syndrome, lupoid hepatitis, lupus, mixed connective tissue disease, multiple
sclerosis,
pemphigoid, pemphigus vulgaris, pernicious anemia, phacogenic uveitis,
polyarteritis nodosa,
primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis,
Raynauds, Reiter's Syndrome,
relapsing polychondritis, Schmidt's Syndrome, Sjogren's Syndrome, sympathetic
ophthalmia,
Takayasu's Arteritis, temporal arteritis, thyrotoxicosis, rheumatoid
arthritis, Type B Insulin
Resistance, ulcerative colitis, or Wegener's granulomatosis.
In a twenty-seventh embodiment the invention provides for the use of one or
more
compounds according to any of the foregoing embodiments or a pharmaceutically
acceptable salt,
solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for
the manufacture of a
medicament for treating a central nervous system disorder.
In a twenty-eighth embodiment the invention provides for the use of one or
more
compounds according to any of the foregoing embodiments or a pharmaceutically
acceptable salt,
solvate, hydrate, metabolite, prodrug, enantiomer or stereoisomer thereof for
the manufacture of a
medicament for treating multiple sclerosis.
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WO 2011/071570 PCT/US2010/046424
In a twenty-ninth embodiment the invention provides for the use of one or more
compounds according to claims any of the foregoing embodiments or a
pharmaceutically
acceptable salt, solvate, hydrate, metabolite, prodrug, enantiomer or
stereoisomer thereof for the
manufacture of a medicament for treating rheumatoid arthritis.
In a thirtieth embodiment the invention provides a pharmaceutical composition
comprising one or more compounds according to Formula (I), (ta), (II), (III),
(IV), or (V) or
pharmaceutically acceptable salts, solvates, hydrates, metabolites, prodrugs
or stereoisomers
thereof and a pharmaceutically acceptable diluent or carrier. In a preferred
aspect, the invention
provides a pharmaceutical composition wherein the compound or compounds are
present in a
therapeutically effective amount.
In a thirty-first embodiment the invention provides a packaged pharmaceutical
comprising a one or more compounds according to Formula (1), (ta), (11),
(111), (IV), or (V) or
pharmaceutically acceptable salts, solvates, hydrates, metabolites, prodrugs
or stereoisomers
thereof and instructions for use. In one embodiment, the invention provides a
packaged
pharmaceutical wherein the compound or compounds are present in a
therapeutically effective
amount. In another embodiment, the invention provides a packaged
pharmaceutical wherein the
compound or compounds are present in a prophylactically effective amount.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
In this invention, the following definitions are applicable:
A "therapeutically effective amount" is an amount of a compound of Formula
(1), (11),
(111), (IV), or (V) or a combination of two or more such compounds, which
inhibits, totally or
partially, the progression of the condition or alleviates, at least partially,
one or more symptoms of
the condition. A therapeutically effective amount can also be an amount which
is prophylactically
effective. The amount which is therapeutically effective will depend upon the
patient's size and
gender, the condition to be treated, the severity of the condition and the
result sought. For a given
patient, a therapeutically effective amount can be determined by methods known
to those of skill
in the art.
"Physiologically acceptable salts" refers to those salts which retain the
biological
effectiveness and properties of the free bases and which are obtained by
reaction with inorganic
acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, and phosphoric
acid or organic acids such as sulfonic acid, carboxylic acid, organic
phosphoric acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric
acid, fumaric acid, maleic
acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acid
(e.g. (+) or (-)-tartaric acid
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WO 2011/071570 PCT/US2010/046424
or mixtures thereof), amino acids (e.g. (+) or (-)-amino acids or mixtures
thereof), and the like.
These salts can be prepared by methods known to those skilled in the art.
Certain compounds of Formula (I), (II), (III), (IV), or (V) which have acidic
substituents
may exist as salts with pharmaceutically acceptable bases. The present
invention includes such
salts. Examples of such salts include sodium salts, potassium salts, lysine
salts and arginine salts.
These salts may be prepared by methods known to those skilled in the art.
Certain compounds of Formula (I), (II), (III), (IV), or (V), and their salts
may exist in
more than one crystal form and the present invention includes each crystal
form and mixtures
thereof.
Certain compounds of Formula (I), (II), (III), (IV), or (V) and their salts
may also exist in
the form of solvates, for example hydrates, and the present invention includes
each solvate and
mixtures thereof.
Certain compounds of Formula (I), (II), (III), (IV), or (V) may contain one or
more chiral
centers, and exist in different optically active forms. When compounds of
Formula (I), (II), (III),
(IV), or (V) contain one chiral center, the compounds exist in two
enantiomeric forms and the
present invention includes both enantiomers and mixtures of enantiomers, such
as racemic
mixtures. The enantiomers may be resolved by methods known to those skilled in
the art, for
example by formation of diastereoisomeric salts which may be separated, for
example, by
crystallization; formation of diastereoisomeric derivatives or complexes which
may be separated,
for example, by crystallization, gas-liquid or liquid chromatography;
selective reaction of one
enantiomer with an enantiomer-specific reagent, for example enzymatic
esterification; or gas-
liquid or liquid chromatography in a chiral environment, for example on a
chiral support for
example silica with a bound chiral ligand or in the presence of a chiral
solvent. It will be
appreciated that where the desired enantiomer is converted into another
chemical entity by one of
the separation procedures described above, a further step may be used to
liberate the desired
enantiomeric form. Alternatively, specific enantiomers may be synthesized by
asymmetric
synthesis using optically active reagents, substrates, catalysts or solvents,
or by converting one
enantiomer into the other by asymmetric transformation.
When a compound of Formula (I), (Ia), (II), (III), (IV), or (V) contains more
than one
chiral center, it may exist in diastereoisomeric forms. The diastereoisomeric
compounds may be
separated by methods known to those skilled in the art, for example
chromatography or
crystallization and the individual enantiomers may be separated as described
above. The present
invention includes each diastereoisomer of compounds of Formula (I), (Ia),
(II), (III), (IV), or (V)
and mixtures thereof.
Certain compounds of Formula (I), (Ia), (II), (III), (IV), and (V) may exist
in different
tautomeric forms or as different geometric isomers, and the present invention
includes each
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WO 2011/071570 PCT/US2010/046424
tautomer and/or geometric isomer of compounds of Formula (I), (II), (III),
(IV), and (V) and
mixtures thereof.
Certain compounds of Formula (I), (Ia), (II), (III), (IV), and (V) may exist
in different
stable conformational forms which may be separable. Torsional asymmetry due to
restricted
rotation about an asymmetric single bond, for example because of steric
hindrance or ring strain,
may permit separation of different conformers. The present invention includes
each
conformational isomer of compounds of Formula (I), (Ia), (II), (III), (IV),
and (V), and mixtures
thereof.
Certain compounds of Formula (I), (Ia), (II), (III), (IV), and (V) may exist
in zwitterionic
form and the present invention includes each zwitterionic form of compounds of
Formula (I), (Ia),
(II), (III), (IV), and (V) and mixtures thereof.
As used herein the term "pro-drug" refers to an agent which is converted into
the parent
drug in vivo by some physiological chemical process (e.g., a prodrug on being
brought to the
physiological pH is converted to the desired drug form). Pro-drugs are often
useful because, in
some situations, they may be easier to administer than the parent drug. They
may, for instance, be
bioavailable by oral administration whereas the parent drug is not. The
prodrug may also have
improved solubility in pharmacological compositions over the parent drug. An
example, without
limitation, of a pro-drug would be a compound of the present invention wherein
it is administered
as an ester (the "pro-drug") to facilitate transmittal across a cell membrane
where water solubility
is not beneficial, but then it is metabolically hydrolyzed to the carboxylic
acid once inside the cell
where water solubility is beneficial
Pro-drugs have many useful properties. For example, a pro-drug may be more
water
soluble than the ultimate drug, thereby facilitating intravenous
administration of the drug. A pro-
drug may also have a higher level of oral bioavailability than the ultimate
drug. After
administration, the prodrug is enzymatically or chemically cleaved to deliver
the ultimate drug in
the blood or tissue.
Exemplary pro-drugs upon cleavage release the corresponding free acid, and
such
hydrolyzable ester-forming residues of the compounds of this invention include
but are not
limited to carboxylic acid substituents (e.g., -(CH2)C(O)OH or a moiety that
contains a carboxylic
acid) wherein the free hydrogen is replaced by (C1-C4)alkyl, (C2-
C12)alkanoyloxymethyl, (C4-
C9)1-(alkanoyloxy)ethyl, 1-methyl-l-(alkanoyloxy)-ethyl having from 5 to 10
carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-
(alkoxycarbonyloxy)ethyl having
from 4 to 7 carbon atoms, 1-methyl-l-(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms,
N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-
(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-
crotonolactonyl,
gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as f3-
WO 2011/071570 PCT/US2010/046424
dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1-C2)-alkylcarbamoyl-(C1-
C2)alkyl and
piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
Other exemplary pro-drugs release an alcohol of Formula (I), (Ia), (II),
(III), (IV), and (V)
wherein the free hydrogen of the hydroxyl substituent (e.g., R1 contains
hydroxyl) is replaced by
(C1-C6)alkanoyloxymethyl, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-l-((C1-
C6)alkanoyloxy)ethyl,
(C1-C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylamino-methyl,
succinoyl, (Ci-
C6)alkanoyl, a-amino(C1-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-
a-aminoacyl
wherein said a-aminoacyl moieties are independently any of the naturally
occurring L-amino
acids found in proteins, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or glycosyl (the
radical resulting from
detachment of the hydroxyl of the hemiacetal of a carbohydrate).
The term "heterocyclic" or "heterocyclyl", as used herein, include non-
aromatic, ring
systems, including, but not limited to, monocyclic, bicyclic and tricyclic
rings, which can be
completely saturated or which can contain one or more units of unsaturation,
for the avoidance of
doubt, the degree of unsaturation does not result in an aromatic ring system)
and have 3 to 12
atoms including at least one heteroatom, such as nitrogen, oxygen, or sulfur.
For purposes of
exemplification, which should not be construed as limiting the scope of this
invention, the
following are examples of heterocyclic rings: azabicyclo[2.2.1]heptanyl,
azepinyl, azetidinyl,
morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl,
pyrrolidinyl, quinicludinyl,
thiomorpholinyl, tetrahydropyranyl and tetrahydrofuranyl.
The term "heteroaryl" as used herein, include aromatic ring systems,
including, but not
limited to, monocyclic, bicyclic and tricyclic rings, and have 3 to 12 atoms
including at least one
heteroatom, such as nitrogen, oxygen, or sulfur. For purposes of
exemplification, which should
not be construed as limiting the scope of this invention: azaindolyl,
benzo(b)thienyl,
benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
benzotriazolyl,
benzoxadiazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl,
indazolyl, isoindolinyl,
isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, purinyl,
pyranyl, pyrazinyl,
pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl,
pyrazolo[3,4-
d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl,
tetrahydroindolyl,
tetrazolyl, thiadiazolyl, thienyl, thiomorpholinyl, triaozlyl or tropanyl.
When the term "substituted heterocyclic" (or heterocyclyl) or "substituted
heteroaryl" or
"substituted aryl" is used, what is meant is that the heterocyclic, heteroaryl
or aryl group is
substituted with one or more substituents that can be made by one of ordinary
skill in the art and
results in a molecule that is an agonist or antagonist of the sphingosine
receptor family. For
purposes of exemplification, which should not be construed as limiting the
scope of this
invention, preferred substituents for the heterocycle, heteroaryl or aryl
group of this invention are
each independently selected from the optionally substituted group consisting
of alkenyl, alkoxy,
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WO 2011/071570 PCT/US2010/046424
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylheterocycloalkoxy,
alkyl, alkylamino,
alkylcarbonyl, alkylester, alkyl-NH-alkyl, -alkyl-NH-cycloalkyl, alkyl-O-C(O)-
, -alkyl-
heterocyclyl, -alkyl-cycloalkyl, alkyl-nitrile, alkynyl, amido groups, amino,
aminoalkyl,
aminocarbonyl, carbonitrile, carbonylalkoxy, carboxamido, CF3, CN, -C(O)OH, -
C(O)H, -C(O)-
C(CH3)3, -OH, -C(O)O-alkyl, -C(O)O-cycloalkyl, -C(O)O-heterocyclyl, -C(O)O-
alkyl-aryl, -
C(O)-alkyl, -C(O)-cycloalkyl, -C(O)-heterocyclyl, cycloalkyl,
dialkylaminoalkoxy,
dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, halogen, heterocyclyl, a
heterocycloalkyl
group, heterocyclyloxy, hydroxy, hydroxyalkyl, nitro, OCF3, oxo, -0-alkyl, -0-
heteroaryl, -0-
heterocyclyl, -SO2CH3, -SO2NH2, -SO2NH-alkyl, -SO2N(alkyl)2, tetrazolyl,
thienylalkoxy,
trifluoromethylcarbonylamino, trifluoromethylsulfonamido, heterocyclylalkoxy,
heterocyclyl-
S(O)p, cycloalkyl-S(O)p, alkyl-S-, heterocyclyl-S, heterocycloalkyl,
cycloalkylalkyl,
heterocycolthio, cycloalkylthio, _Z105-C(O)N(R)2, -Z 105_N(R)_C(O)_Z200, _Z105
-N(R)-S(0)2-Z200, _
Z105-N(R)-C(O)-N(R)-Z200, -N(R), -N(H)-alkyl, -N(H)-cycloalkyl, -C(O)R, -N(R)-
C(O)OR, OR-
C(O)-heterocyclyl-OR, Re and -CH2ORei
wherein p is 0, 1 or 2;
where Re for each occurrence is independently hydrogen, optionally substituted
alkyl,
optionally substituted aryl, -(C1-C6)-NRdRe, -E-(CH2)t-NRdRe, -E-(CH2)t-O-
alkyl, -E-
(CH2)t-S-alkyl, or -E-(CH2)t-OH;
wherein t is an integer from about 1 to about 6;
Z105 for each occurrence is independently a covalent bond, alkyl, alkenyl or
alkynyl; and
Z200 for each occurrence is independently selected from an optionally
substituted group
selected from the group consisting of alkyl, alkenyl, alkynyl, phenyl, alkyl-
phenyl,
alkenyl-phenyl or alkynyl-phenyl;
E is a direct bond, 0, S, S(O), S(O)2, or NRf, wherein Rf is H or alkyl and Rd
and Re are
independently H, alkyl, alkanoyl or S02-alkyl; or Rd, Re and the nitrogen atom
to which
they are attached together to form a five- or six-membered heterocyclic ring.
An "heterocycloalkyl" group, as used herein, is a heterocyclic group that is
linked to a
compound by an aliphatic group having from one to about eight carbon atoms.
For example, a
morpholinomethyl group is an heterocycloalkyl group.
As used herein, "aliphatic" or "an aliphatic group" or notations such as "(CO-
C8)" include
straight chained or branched hydrocarbons which are completely saturated or
which contain one
or more units of unsaturation, and, thus, includes alkyl, alkenyl, alkynyl and
hydrocarbons
comprising a mixture of single, double and triple bonds. When the group is a
Co it means that the
moiety is not present or in other words, it is a bond. As used herein, "alkyl"
means C1-C8 and
includes straight chained or branched hydrocarbons, which are completely
saturated. Examples of
alkyls are methyl, ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. As
used herein,
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WO 2011/071570 PCT/US2010/046424
"alkenyl" and "alkynyl" means C2-C8 and includes straight chained or branched
hydrocarbons
which contain one or more units of unsaturation, one or more double bonds for
alkenyl and one or
more triple bonds for alkynyl.
As used herein, aromatic groups (or aryl groups) include aromatic carbocyclic
ring
systems (e.g. phenyl and cyclopentyldienyl) and fused polycyclic aromatic ring
systems (e.g.
naphthyl, biphenylenyl and 1,2,3,4-tetrahydronaphthyl).
As used herein, cycloalkyl means C3-C12 monocyclic or multicyclic (e.g.,
bicyclic,
tricyclic, etc.) hydrocarbons that is completely saturated or has one or more
unsaturated bonds but
does not amount to an aromatic group. Examples of a cycloalkyl group are
cyclopropyl,
cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.
As used herein, many moieties or substituents are termed as being either
"substituted" or
"optionally substituted". When a moiety is modified by one of these terms,
unless otherwise
noted, it denotes that any portion of the moiety that is known to one skilled
in the art as being
available for substitution can be substituted, which includes one or more
substituents, where if
more than one substituent then each substituent is independently selected.
Such means for
substitution are well-known in the art and/or taught by the instant
disclosure. For purposes of
exemplification, which should not be construed as limiting the scope of this
invention, some
examples of groups that are substituents are: alkenyl groups, alkoxy group
(which itself can be
substituted, such as -O-Cl-C6-alkyl-OR, -O-C1-C6-alkyl-N(R)2, and OCF3),
alkoxyalkoxy,
alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl groups (which itself
can also be
substituted, such as -Cl-C6-alkyl-OR, -C1-C6-alkyl-N(R)2, COOH, and -CF3),
alkylamino,
alkylcarbonyl, alkylester, alkylnitrile, alkylsulfonyl, amino, aminoalkoxy,
CF3, COH, COOH, CN,
cycloalkyl, dialkylamino, dialkylaminoalkoxy, dialkylaminocarbonyl,
dialkylaminocarbonylalkoxy, dialkylaminosulfonyl, esters (-C(O)-OR, where R is
groups such as
alkyl, heterocycloalkyl (which can be substituted), heterocyclyl, etc., which
can be substituted),
halogen or halo group (F, Cl, Br, I), hydroxy, morpholinoalkoxy,
morpholinoalkyl, -NH-C1-C6-
alkyl-COOH, nitro, oxo, OCF3, S(O)2CH3, S(O)2CF3, and sulfonyl, N-alkylamino
or N,N-
dialkylamino (in which the alkyl groups can also be substituted).
Methods of Use
The present invention provides compounds described by general Formula (I),
(Ia), (II),
(III), (IV), and (V), which are effective as antagonists or agonists of the G
protein-coupled SIP
receptor family. These compounds reduce the number of circulating and
infiltrating T- and 13-
lymphocytes affording a beneficial immunosuppressive effect.
The present invention also provides compounds that exhibit activity within the
SIP
receptor family.
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WO 2011/071570 PCT/US2010/046424
In a related aspect the invention provides a method for modulating receptors
of the SiP
family in a human subject suffering from a disorder in which modulation of SIP
activity is
beneficial, comprising administering to the human subject a compound of
Formula (I), (Ia), (II),
(III), (IV), and (V) such that modulation of SIP activity in the human subject
is triggered and
treatment is achieved.
In another related aspect the invention provides a method of modulating
sphingosine 1-
phosphate receptor 1 activity comprising contacting a cell with one or more
compounds of
Formula (I), (Ia), (II), (III), (IV), and (V).
A compound of Formula (I), (Ia), (II), (III), (IV), and (V) or a salt thereof
or
pharmaceutical compositions containing a therapeutically effective amount
thereof is useful in the
treatment of a disorder selected from the group comprising CNS system
disorders, arthritis,
rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, juvenile chronic
arthritis, Lyme
arthritis, psoriatic arthritis, reactive arthritis, and septic arthritis,
spondyloarthropathy, systemic
lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel
disease, insulin
dependent diabetes mellitus, thyroiditis, asthma, allergic diseases,
psoriasis, dermatitis
scleroderma, graft versus host disease, organ transplant rejection (including
but not limited to
bone marrow and solid organ rejection), acute or chronic immune disease
associated with organ
transplantation, sarcoidosis, atherosclerosis, disseminated intravascular
coagulation, Kawasaki's
disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome,
Wegener's
granulomatosis, Henoch-Schoenlein purpurea, microscopic vasculitis of the
kidneys, chronic
active hepatitis, uveitis, septic shock, toxic shock syndrome, sepsis
syndrome, cachexia,
infectious diseases, parasitic diseases, acquired immunodeficiency syndrome,
acute transverse
myelitis, Huntington's chorea, Parkinson's disease, Alzheimer's disease,
stroke, primary biliary
cirrhosis, hemolytic anemia, malignancies, heart failure, myocardial
infarction, Addison's disease,
sporadic, polyglandular deficiency type I and polyglandular deficiency type
11, Schmidt's
syndrome, adult (acute) respiratory distress syndrome, alopecia, alopecia
areata, seronegative
arthopathy, arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative
colitic arthropathy,
enteropathic synovitis, chlamydia, yersinia and salmonella associated
arthropathy, atheromatous
disease/arteriosclerosis, atopic allergy, autoimmune bullous disease,
pemphigus vulgaris,
pemphigus foliaceus, pemphigoid, linear IgA disease, autoimmune haemolytic
anaemia, Coombs
positive haemolytic anaemia, acquired pernicious anaemia, juvenile pernicious
anaemia, myalgic
encephalitis/Royal Free Disease, chronic mucocutaneous candidiasis, giant cell
arteritis, primary
sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired
Immunodeficiency Disease
Syndrome, Acquired Immunodeficiency Related Diseases, Hepatitis B, Hepatitis
C, common
varied immunodeficiency (common variable hypogammaglobulinaemia), dilated
cardiomyopathy,
female infertility, ovarian failure, premature ovarian failure, fibrotic lung
disease, chronic wound
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healing, cryptogenic fibrosing alveolitis, post-inflammatory interstitial lung
disease, interstitial
pneumonitis, connective tissue disease associated interstitial lung disease,
mixed connective tissue
disease associated lung disease, systemic sclerosis associated interstitial
lung disease, rheumatoid
arthritis associated interstitial lung disease, systemic lupus erythematosus
associated lung disease,
dermatomyositis/polymyositis associated lung disease, Sjogren's disease
associated lung disease,
ankylosing spondylitis associated lung disease, vasculitic diffuse lung
disease, haemosiderosis
associated lung disease, drug-induced interstitial lung disease, radiation
fibrosis, bronchiolitis
obliterans, chronic eosinophilic pneumonia, lymphocytic infiltrative lung
disease, postinfectious
interstitial lung disease, gouty arthritis, autoimmune hepatitis, type-1
autoimmune hepatitis
(classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis (anti-
LKM antibody
hepatitis), autoimmune mediated hypoglycaemia, type B insulin resistance with
acanthosis
nigricans, hypoparathyroidism, acute immune disease associated with organ
transplantation,
chronic immune disease associated with organ transplantation, osteoarthrosis,
primary sclerosing
cholangitis, psoriasis type 1, psoriasis type 2, idiopathic leucopaenia,
autoimmune neutropaenia,
renal disease NOS, glomerulonephritides, microscopic vasculitis of the
kidneys, Lyme disease,
discoid lupus erythematosus, male infertility idiopathic or NOS, sperm
autoimmunity, multiple
sclerosis (all subtypes), sympathetic ophthalmia, pulmonary hypertension
secondary to connective
tissue disease, Goodpasture's syndrome, pulmonary manifestation of
polyarteritis nodosa, acute
rheumatic fever, rheumatoid spondylitis, Still's disease, systemic sclerosis,
Sjogren's syndrome,
Takayasu's disease/arteritis, autoimmune thrombocytopaenia, idiopathic
thrombocytopaenia,
autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune
hypothyroidism
(Hashimoto's disease), atrophic autoimmune hypothyroidism, primary myxoedema,
phacogenic
uveitis, primary vasculitis, vitiligo, acute liver disease, chronic liver
diseases, alcoholic cirrhosis,
alcohol-induced liver injury, choleosatatis, idiosyncratic liver disease, Drug-
Induced hepatitis,
Non-alcoholic Steatohepatitis, allergy and asthma, group B streptococci (GBS)
infection, mental
disorders (e.g., depression and schizophrenia), Th2 Type and Thl Type mediated
diseases, acute
and chronic pain (different forms of pain), and cancers such as lung, breast,
stomach, bladder,
colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic
malignancies (leukemia
and lymphoma), and hematopoietic malignancies (leukemia and lymphoma),
Abetalipoprotemia,
Acrocyanosis, acute and chronic parasitic or infectious processes, acute
leukemia, acute
lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute or chronic
bacterial
infection, acute pancreatitis, acute renal failure, adenocarcinomas, aerial
ectopic beats, AIDS
dementia complex, alcohol-induced hepatitis, allergic conjunctivitis, allergic
contact dermatitis,
allergic rhinitis, allograft rejection, alpha-l- antitrypsin deficiency,
amyotrophic lateral sclerosis,
anemia, angina pectoris, anterior horn cell degeneration, anti cd3 therapy,
antiphospholipid
syndrome, anti-receptor hypersensitivity reactions, aordic and peripheral
aneuryisms, aortic
WO 2011/071570 PCT/US2010/046424
dissection, arterial hypertension, arteriosclerosis, arteriovenous fistula,
ataxia, atrial fibrillation
(sustained or paroxysmal), atrial flutter, atrioventricular block, B cell
lymphoma, bone graft
rejection, bone marrow transplant (BMT) rejection, bundle branch block,
Burkitt's lymphoma,
Burns, cardiac arrhythmias, cardiac stun syndrome, cardiac tumors,
cardiomyopathy,
cardiopulmonary bypass inflammation response, cartilage transplant rejection,
cerebellar cortical
degenerations, cerebellar disorders, chaotic or multifocal atrial tachycardia,
chemotherapy
associated disorders, chromic myelocytic leukemia (CML), chronic alcoholism,
chronic
inflammatory pathologies, chronic lymphocytic leukemia (CLL), chronic
obstructive pulmonary
disease (COPD), chronic salicylate intoxication, colorectal carcinoma,
congestive heart failure,
conjunctivitis, contact dermatitis, cor pulmonale, coronary artery disease,
Creutzfeldt-Jakob
disease, culture negative sepsis, cystic fibrosis, cytokine therapy associated
disorders, Dementia
pugilistica, demyelinating diseases, dengue hemorrhagic fever, dermatitis,
dermatologic
conditions, diabetes, diabetes mellitus, diabetic ateriosclerotic disease,
Diffuse Lewy body
disease, dilated congestive cardiomyopathy, disorders of the basal ganglia,
Down's Syndrome in
middle age, drug- induced movement disorders induced by drugs which block CNS
dopamine
receptors, drug sensitivity, eczema, encephalomyelitis, endocarditis,
endocrinopathy, epiglottitis,
epstein-barr virus infection, erythromelalgia, extrapyramidal and cerebellar
disorders, familial
hematophagocytic lymphohistiocytosis, fetal thymus implant rejection,
Friedreich's ataxia,
functional peripheral arterial disorders, fungal sepsis, gas gangrene, gastric
ulcer, glomerular
nephritis, graft rejection of any organ or tissue, gram negative sepsis, gram
positive sepsis,
granulomas due to intracellular organisms, hairy cell leukemia, Hallerrorden-
Spatz disease,
hashimoto's thyroiditis, hay fever, heart transplant rejection,
hemachromatosis, hemodialysis,
hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage,
hepatitis (A),
His bundle arrhythmias, HIV infection/HIV neuropathy, Hodgkin's disease,
hyperkinetic
movement disorders, hypersensitivity reactions, hypersensitivity pneumonitis,
hypertension,
hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis
evaluation, idiopathic
Addison's disease, idiopathic pulmonary fibrosis, antibody mediated
cytotoxicity, Asthenia,
infantile spinal muscular atrophy, inflammation of the aorta, influenza a,
ionizing radiation
exposure, iridocyclitis/uveitis/optic neuritis, ischemia- reperfusion injury,
ischemic stroke,
juvenile rheumatoid arthritis, juvenile spinal muscular atrophy, Kaposi's
sarcoma, kidney
transplant rejection, legionella, leishmaniasis, leprosy, lesions of the
corticospinal system,
lipedema, liver transplant rejection, lymphederma, malaria, malignamt
Lymphoma, malignant
histiocytosis, malignant melanoma, meningitis, meningococcemia,
metabolic/idiopathic, migraine
headache, mitochondrial multi.system disorder, mixed connective tissue
disease, monoclonal
gammopathy, multiple myeloma, multiple systems degenerations (Mencel Dejerine-
Thomas Shi-
Drager and Machado-Joseph), myasthenia gravis, mycobacterium avium
intracellulare,
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mycobacterium tuberculosis, myelodyplastic syndrome, myocardial infarction,
myocardial
ischemic disorders, nasopharyngeal carcinoma, neonatal chronic lung disease,
nephritis,
nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies ,
neutropenic fever, non-
hodgkins lymphoma, occlusion of the abdominal aorta and its branches,
occulsive arterial
disorders, okt3 therapy, orchitis/epidydimitis, orchitis/vasectomy reversal
procedures,
organomegaly, osteoporosis, pancreas transplant rejection, pancreatic
carcinoma, paraneoplastic
syndrome/hypercalcemia of malignancy, parathyroid transplant rejection, pelvic
inflammatory
disease, perennial rhinitis, pericardial disease, peripheral atherlosclerotic
disease, peripheral
vascular disorders, peritonitis, pernicious anemia, pneumocystis carinii
pneumonia, pneumonia,
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathy,
and skin changes syndrome), post perfusion syndrome, post pump syndrome, post-
MI cardiotomy
syndrome, preeclampsia, Progressive supranucleo Palsy, primary pulmonary
hypertension,
radiation therapy, Raynaud's phenomenon and disease, Raynaud's disease,
Refsum's disease,
regular narrow QRS tachycardia, renovascular hypertension, reperfusion injury,
restrictive
cardiomyopathy, sarcomas, scleroderma, senile chorea, Senile Dementia of Lewy
body type,
seronegative arthropathies, shock, sickle cell anemia, skin allograft
rejection, skin changes
syndrome, small bowel transplant rejection, solid tumors, specific arrythmias,
spinal ataxia,
spinocerebellar degenerations, streptococcal myositis, structural lesions of
the cerebellum,
Subacute sclerosing panencephalitis, Syncope, syphilis of the cardiovascular
system, systemic
anaphalaxis, systemic inflammatory response syndrome, systemic onset juvenile
rheumatoid
arthritis, T-cell or FAB ALL, Telangiectasia, thromboangitis obliterans,
thrombocytopenia,
toxicity, transplants, trauma/hemorrhage, type III hypersensitivity reactions,
type IV
hypersensitivity, unstable angina, uremia, urosepsis, urticaria, valvular
heart diseases, varicose
veins, vasculitis, venous diseases, venous thrombosis, ventricular
fibrillation, viral and fungal
infections, vital encephalitis/aseptic meningitis, vital-associated
hemaphagocytic syndrome,
Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection of any
organ or tissue, and
diseases involving inappropriate vascularization for example diabetic
retinopathy, retinopathy of
prematurity, choroidal neovascularization due to age-related macular
degeneration, and infantile
hemangiomas in human beings. In addition, such compounds may be useful in the
treatment of
disorders such as, edema, ascites, effusions, and exudates, including for
example macular edema,
cerebral edema, acute lung injury, adult respiratory distress syndrome (ARDS),
proliferative
disorders such as restenosis, fibrotic disorders such as hepatic cirrhosis and
atherosclerosis,
mesangial cell proliferative disorders such as glomerulonephritis, diabetic
nephropathy, malignant
nephrosclerosis, thrombotic microangiopathy syndromes, and glomerulopathies,
myocardial
angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis,
ischemia/reperfusion
injury, peptic ulcer Helicobacter related diseases, virally-induced angiogenic
disorders, Crow-
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Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever,
rubeosis,
neovascular glaucoma and retinopathies such as those associated with diabetic
retinopathy,
retinopathy of prematurity, age-related macular degeneration or a central
nervous system disorder.
In addition, these compounds can be used as active agents against solid
tumors, malignant ascites,
von Hippel Lindau disease, hematopoietic cancers and hyperproliferative
disorders such as
thyroid hyperplasia (especially Grave's disease), and cysts (such as
hypervascularity of ovarian
stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal
syndrome) and polycystic
kidney disease since such diseases require a proliferation of blood vessel
cells for growth and/or
metastasis.
Combination Therapy
Compounds of Formula (I), (Ia), (II), (III), (IV), and (V) of the invention
can be used
alone or in combination with another therapeutic agent to treat such diseases.
It should be
understood that the compounds of the invention can be used alone or in
combination with an
additional agent, e.g., a therapeutic agent, said additional agent being
selected by the skilled
artisan for its intended purpose. For example, the additional agent can be a
therapeutic agent art-
recognized as being useful to treat the disease or condition being treated by
the compound of the
present invention. The additional agent also can be an agent that imparts a
beneficial attribute to
the therapeutic composition e.g., an agent that affects the viscosity of the
composition.
It should further be understood that the combinations which are to be included
within this
invention are those combinations useful for their intended purpose. The agents
set forth below are
illustrative for purposes and not intended to be limited. The combinations,
which are part of this
invention, can be the compounds of the present invention and at least one
additional agent
selected from the lists below. The combination can also include more than one
additional agent,
e.g., two or three additional agents if the combination is such that the
formed composition can
perform its intended function.
Preferred combinations are non-steroidal anti-inflammatory drug(s) also
referred to as
NSAIDS which include drugs like ibuprofen. Other preferred combinations are
corticosteroids
including prednisolone; the well known side-effects of steroid use can be
reduced or even
eliminated by tapering the steroid dose required when treating patients in
combination with the
SIP receptor agonists or antagonists of this invention. Non-limiting examples
of therapeutic
agents for rheumatoid arthritis with which a compound of Formula (I), (Ia),
(II), (III), (IV), and
(V), of the invention can be combined include the following: cytokine
suppressive anti-
inflammatory drug(s) (CSAIDs); antibodies to or antagonists of other human
cytokines or growth
factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,
IL-12, IL-15, IL-16,
IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF. S/T kinase
inhibitors of the
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WO 2011/071570 PCT/US2010/046424
invention can be combined with antibodies to cell surface molecules such as
CD2, CD3, CD4,
CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA
or
their ligands including CD154 (gp39 or CD40L).
Preferred combinations of therapeutic agents may interfere at different points
in the
autoimmune and subsequent inflammatory cascade; preferred examples include TNF
antagonists
like chimeric, humanized or human TNF antibodies, D2E7 (HUMIRATM), (PCT
Publication No.
WO 97/29131), CA2 (REMICADETM), CDP 571, and soluble p55 or p75 TNF receptors,
derivatives, thereof, (p75TNFR1gG (ENBRELTM) or p55TNFR1gG (Lenercept), and
also TNFa
converting enzyme (TACE) inhibitors; similarly IL-1 inhibitors (Interleukin-l-
converting enzyme
inhibitors, IL-IRA etc.) may be effective for the same reason. Other preferred
combinations
include Interleukin 11. Yet other preferred combinations are the other key
players of the
autoimmune response which may act parallel to, dependent on or in concert with
IL- 18 function;
especially preferred are IL-12 antagonists including IL-12 antibodies or
soluble IL-12 receptors,
or IL-12 binding proteins. It has been shown that IL-12 and IL-18 have
overlapping but distinct
functions and a combination of antagonists to both may be most effective. Yet
another preferred
combination are non-depleting anti-CD4 inhibitors. Yet other preferred
combinations include
antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86 (B7.2) including
antibodies,
soluble receptors or antagonistic ligands.
A compound of Formula (I), (Ia), (II), (III), (IV), and (V) of the invention
may also be
combined with agents, such as methotrexate, 6-MP, azathioprine sulphasalazine,
mesalazine,
olsalazine chloroquinine/ hydroxychloroquine, pencillamine, aurothiomalate
(intramuscular and
oral), azathioprine, cochicine, corticosteroids (oral, inhaled and local
injection), beta-2
adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines
(theophylline,
aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium and
oxitropium, cyclosporin,
FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example,
ibuprofen,
corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine
agonists,
antithrombotic agents, complement inhibitors, adrenergic agents, agents which
interfere with
signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g. IRAK, NIK,
IKK , p38 or
MAP kinase inhibitors), IL-10 converting enzyme inhibitors, T-cell signalling
inhibitors such as
kinase inhibitors, metalloproteinase inhibitors, sulfasalazine, 6-
mercaptopurines, angiotensin
converting enzyme inhibitors, soluble cytokine receptors and derivatives
thereof (e.g. soluble p55
or p75 TNF receptors and the derivatives p75TNFRIgG (EnbrelTM and p55TNFRIgG
(Lenercept)), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines (e.g. IL-
4, IL-10, IL-11, IL-
13 and TGF(3), celecoxib, folic acid, hydroxychloroquine sulfate, rofecoxib,
etanercept,
infliximab, naproxen, valdecoxib, sulfasalazine, methylprednisolone,
meloxicam,
methylprednisolone acetate, gold sodium thiomalate, aspirin, triamcinolone
acetonide,
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WO 2011/071570 PCT/US2010/046424
propoxyphene napsylate/apap, folate, nabumetone, diclofenac, piroxicam,
etodolac, diclofenac
sodium, oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenac
sodium/misoprostol,
fentanyl, anakinra, tramadol HC1, salsalate, sulindac,
cyanocobalamin/fa/pyridoxine,
acetaminophen, alendronate sodium, prednisolone, morphine sulfate, lidocaine
hydrochloride,
indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl, sulfadiazine,
oxycodone
HC1/acetaminophen, olopatadine HCl misoprostol, naproxen sodium, omeprazole,
cyclophosphamide, rituximab, IL-1 TRAP, MRA, CTLA4-IG, IL-18 BP, anti-IL-12,
Anti-IL15,
BIRB-796, SCIO-469, VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, and
Mesopram. Preferred combinations include methotrexate or leflunomide and in
moderate or
severe rheumatoid arthritis cases, cyclosporine and anti-TNF antibodies as
noted above.
Non-limiting examples of therapeutic agents for inflammatory bowel disease
with which
a compound of Formula (I), (Ia), (II), (III), (IV), or (V) of the invention
can be combined include
the following: budenoside; epidermal growth factor; corticosteroids;
cyclosporin, sulfasalazine;
aminosalicylates; 6-mercaptopurine; azathioprine; metronidazole; lipoxygenase
inhibitors;
mesalamine; olsalazine; balsalazide; antioxidants; thromboxane inhibitors; IL-
1 receptor
antagonists; anti-IL-10 monoclonal antibodies; anti-IL-6 monoclonal
antibodies; growth factors;
elastase inhibitors; pyridinyl-imidazole compounds; antibodies to or
antagonists of other human
cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-
8, IL-12, IL-15, IL-
16, EMAP-II, GM-CSF, FGF, and PDGF; cell surface molecules such as CD2, CD3,
CD4, CD8,
CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;
cyclosporine;
FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, for example,
ibuprofen;
corticosteroids such as prednisolone; phosphodiesterase inhibitors; adenosine
agonists;
antithrombotic agents; complement inhibitors; adrenergic agents; agents which
interfere with
signalling by proinflammatory cytokines such as TNFa or IL-1 (e.g. IRAK, NIK,
IKK, or MAP
kinase inhibitors); IL-10 converting enzyme inhibitors; TNFct converting
enzyme inhibitors; T-
cell signalling inhibitors such as kinase inhibitors; metalloproteinase
inhibitors; sulfasalazine;
azathioprine; 6-mercaptopurines; angiotensin converting enzyme inhibitors;
soluble cytokine
receptors and derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-
1RI, sIL-1RII, sIL-
6R) and antiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGF(3).
Preferred
examples of therapeutic agents for Crohn's disease with which a compound of
Formula (I), (Ia),
(II), (III), (IV), or (V) can be combined include the following: TNF
antagonists, for example, anti-
TNF antibodies, D2E7 (PCT Publication No. WO 97/29131; HUMIRATM), CA2
(REMICADETM), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and
p55TNFRIgG (LenerceptTM)) inhibitors and PDE4 inhibitors. A compound of
Formula (I), (Ia),
(II), (III), (IV), or (V) can be combined with corticosteroids, for example,
budenoside and
dexamethasone; sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents
which interfere with
WO 2011/071570 PCT/US2010/046424
synthesis or action of proinflammatory cytokines such as IL-1, for example, IL-
10 converting
enzyme inhibitors and IL-lra; T cell signaling inhibitors, for example,
tyrosine kinase inhibitors
6-mercaptopurines; IL-11; mesalamine; prednisone; azathioprine;
mercaptopurine; infliximab;
methylprednisolone sodium succinate; diphenoxylate/atrop sulfate; loperamide
hydrochloride;
methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodone
bitartrate/apap;
tetracycline hydrochloride; fluocinonide; metronidazole; thimerosal/boric
acid;
cholestyramine/sucrose; ciprofloxacin hydrochloride; hyoscyamine sulfate;
meperidine
hydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;
promethazine
hydrochloride; sodium phosphate; sulfamethoxazole/trimethoprim; celecoxib;
polycarbophil;
propoxyphene napsylate; hydrocortisone; multivitamins; balsalazide disodium;
codeine
phosphate/apap; colesevelam HCl; cyanocobalamin; folic acid; levofloxacin;
methylprednisolone;
natalizumab and interferon-gamma.
Non-limiting examples of therapeutic agents for multiple sclerosis with which
a
compound of Formula (I), (Ia), (II), (III), (IV),or (V) can be combined
include the following:
corticosteroids; prednisolone; methylprednisolone; azathioprine;
cyclophosphamide;
cyclosporine; methotrexate; 4-aminopyridine; tizanidine; interferon-f31a
(Avonex ; Biogen);
interferon-f31b (Betaseron ; Chiron/Berlex); interferon a-n3) (Interferon
Sciences/Fujimoto),
interferon-a (Alfa Wassermann/J&J), interferon (31A-IF (Serono/Inhale
Therapeutics),
Peginterferon a 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1; Copaxone ;
Teva
Pharmaceutical Industries, Inc.); hyperbaric oxygen; intravenous
immunoglobulin; clabribine;
antibodies to or antagonists of other human cytokines or growth factors and
their receptors, for
example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16,
EMAP-II, GM-CSF,
FGF, and PDGF. A compound of Formula (I), (Ia), (II), (III), (IV), or (V) can
be combined with
antibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19, CD20,
CD25, CD28,
CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their ligands. A compound of
Formula (I),
(Ia), (II), (III), (IV), or (V) may also be combined with agents such as
methotrexate, cyclosporine,
FK506, rapamycin, mycophenolate mofetil, leflunomide, NSAIDs, for example,
ibuprofen,
corticosteroids such as prednisolone, phosphodiesterase inhibitors, adensosine
agonists,
antithrombotic agents, complement inhibitors, adrenergic agents, agents which
interfere with
signalling by proinflammatory cytokines such as TNFc or IL-1 (e.g. IRAK, NIK,
IKK, p38 or
MAP kinase inhibitors), IL-10 converting enzyme inhibitors, TACE inhibitors, T-
cell signaling
inhibitors such as kinase inhibitors, metalloproteinase inhibitors,
sulfasalazine, azathioprine, 6-
mercaptopurines, angiotensin converting enzyme inhibitors, soluble cytokine
receptors and
derivatives thereof (e.g. soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII,
sIL-6R) and
antiinflammatory cytokines (e.g. IL-4, IL-10, IL-13 and TGF(3).
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Preferred examples of therapeutic agents for multiple sclerosis in which a
compound of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined to include
interferon-(3, for example,
IFN(31a and IFN(31b; copaxone, corticosteroids, caspase inhibitors, for
example inhibitors of
caspase- 1, IL-1 inhibitors, TNF inhibitors, and antibodies to CD40 ligand and
CD80.
A compound of Formula (I), (Ia), (II), (III), (IV), or (V) may also be
combined with
agents, such as alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliproden
hydrochloride,
fampridine, glatiramer acetate, natalizumab, sinnabidol, a-immunokine NNSO3,
ABR-215062,
AnergiX.MS, chemokine receptor antagonists, BBR-2778, calagualine, CPI-1189,
LEM
(liposome encapsulated mitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298,
mesopram
(PDE4 inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidone
allotrap 1258
(RDP-1258), sTNF-Rl, talampanel, teriflunomide, TGF-beta2, tiplimotide, VLA-4
antagonists
(for example, TR-14035, VLA4 Ultrahaler, Antegran-ELAN/Biogen), interferon
gamma
antagonists and IL-4 agonists.
Non-limiting examples of therapeutic agents for angina with which a compound
of
Formula (I), (Ia), (II), (III), (IV), or (V) of the invention can be combined
include the following:
aspirin, nitroglycerin, isosorbide mononitrate, metoprolol succinate,
atenolol, metoprolol tartrate,
amlodipine besylate, diltiazem hydrochloride, isosorbide dinitrate,
clopidogrel bisulfate,
nifedipine, atorvastatin calcium, potassium chloride, furosemide, simvastatin,
verapamil HC1,
digoxin, propranolol hydrochloride, carvedilol, lisinopril, spironolactone,
hydrochlorothiazide,
enalapril maleate, nadolol, ramipril, enoxaparin sodium, heparin sodium,
valsartan, sotalol
hydrochloride, fenofibrate, ezetimibe, bumetanide, losartan potassium,
lisinopril/hydrochlorothiazide, felodipine, captopril and bisoprolol fumarate.
Non-limiting examples of therapeutic agents for ankylosing spondylitis with
which a
compound of Formula (I), (Ia), (II), (III), (IV), or (V) can be combined
include the following:
ibuprofen, diclofenac, misoprostol, naproxen, meloxicam, indomethacin,
diclofenac, celecoxib,
rofecoxib, sulfasalazine, methotrexate, azathioprine, minocyclin, prednisone,
etanercept, and
infliximab.
Non-limiting examples of therapeutic agents for asthma with which a compound
of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined include the
following: albuterol,
salmeterol/fluticasone, montelukast sodium, fluticasone propionate,
budesonide, prednisone,
salmeterol xinafoate, levalbuterol HC1, albuterol sulfate/ipratropium,
prednisolone sodium
phosphate, triamcinolone acetonide, beclomethasone dipropionate, ipratropium
bromide,
azithromycin, pirbuterol acetate, prednisolone, theophylline anhydrous,
methylprednisolone
sodium succinate, clarithromycin, zafirlukast, formoterol fumarate, influenza
virus vaccine,
amoxicillin trihydrate, flunisolide, allergy injection, cromolyn sodium,
fexofenadine
hydrochloride, flunisolide/menthol, amoxicillin/clavulanate, levofloxacin,
inhaler assist device,
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guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl, doxycycline
hyclate,
guaifenesin/d-methorphan, p-ephedrine/cod/chlorphenir, gatifloxacin,
cetirizine hydrochloride,
mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,
pe/hydrocodone/chlorphenir,
cetirizine HCl/pseudoephed, phenylephrine/cod/promethazine,
codeine/promethazine, cefprozil,
dexamethasone, guaifenesin/pseudoephedrine, chlorpheniramine/hydrocodone,
nedocromil
sodium, terbutaline sulfate, epinephrine, methylprednisolone and
metaproterenol sulfate.
Non-limiting examples of therapeutic agents for COPD with which a compound of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined include the
following: albuterol
sulfate/ipratropium, ipratropium bromide, salmeterol/fluticasone, albuterol,
salmeterol xinafoate,
fluticasone propionate, prednisone, theophylline anhydrous, methylprednisolone
sodium
succinate, montelukast sodium, budesonide, formoterol fumarate, triamcinolone
acetonide,
levofloxacin, guaifenesin, azithromycin, beclomethasone dipropionate,
levalbuterol HC1,
flunisolide, ceftriaxone sodium, amoxicillin trihydrate, gatifloxacin,
zafirlukast,
amoxicillin/clavulanate, flunisolide/menthol, chlorpheniramine/hydrocodone,
metaproterenol
sulfate, methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,
pirbuterol acetate,
p-ephedrine/loratadine, terbutaline sulfate, tiotropium bromide, (R,R)-
formoterol, TgAAT,
cilomilast and roflumilast.
Non-limiting examples of therapeutic agents for HCV with which a compound of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined include the
following: Interferon-alpha-
2a, Interferon-alpha-2b, Interferon-alpha conl, Interferon-alpha-nl, pegylated
interferon-alpha-2a,
pegylated interferon-alpha-2b, ribavirin, peginterferon alfa-2b + ribavirin,
ursodeoxycholic acid,
glycyrrhizic acid, thymalfasin, Maxamine, VX-497 and any compounds that are
used to treat
HCV through intervention with the following targets: HCV polymerase, HCV
protease, HCV
helicase, and HCV IRES (internal ribosome entry site).
Non-limiting examples of therapeutic agents for Idiopathic Pulmonary Fibrosis
with
which a compound of Formula (I), (Ia), (II), (III), (IV), or (V) can be
combined include the
following: prednisone, azathioprine, albuterol, colchicine, albuterol sulfate,
digoxin, gamma
interferon, methylprednisolone sod succ, lorazepam, furosemide, lisinopril,
nitroglycerin,
spironolactone, cyclophosphamide, ipratropium bromide, actinomycin d,
alteplase, fluticasone
propionate, levofloxacin, metaproterenol sulfate, morphine sulfate, oxycodone
HC1, potassium
chloride, triamcinolone acetonide, tacrolimus anhydrous, calcium, interferon-
alpha, methotrexate,
mycophenolate mofetil and interferon-gamma-1(3.
Non-limiting examples of therapeutic agents for myocardial infarction with
which a
compound of Formula (I), (Ia), (II), (III), (IV), or (V) can be combined
include the following:
aspirin, nitroglycerin, metoprolol tartrate, enoxaparin sodium, heparin
sodium, clopidogrel
bisulfate, carvedilol, atenolol, morphine sulfate, metoprolol succinate,
warfarin sodium, lisinopril,
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isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril,
tenecteplase, enalapril
maleate, torsemide, retavase, losartan potassium, quinapril HC1/mag Garb,
bumetanide, alteplase,
enalaprilat, amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazem
hydrochloride,
captopril, irbesartan, valsartan, propranolol hydrochloride, fosinopril
sodium, lidocaine
hydrochloride, eptifibatide, cefazolin sodium, atropine sulfate, aminocaproic
acid, spironolactone,
interferon, sotalol hydrochloride, potassium chloride, docusate sodium,
dobutamine HCl,
alprazolam, pravastatin sodium, atorvastatin calcium, midazolam hydrochloride,
meperidine
hydrochloride, isosorbide dinitrate, epinephrine, dopamine hydrochloride,
bivalirudin,
rosuvastatin, ezetimibe/simvastatin, avasimibe, and cariporide.
Non-limiting examples of therapeutic agents for psoriasis with which a
compound of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined include the
following: calcipotriene,
clobetasol propionate, triamcinolone acetonide, halobetasol propionate,
tazarotene, methotrexate,
fluocinonide, betamethasone diprop augmented, fluocinolone acetonide,
acitretin, tar shampoo,
betamethasone valerate, mometasone furoate, ketoconazole,
pramoxine/fluocinolone,
hydrocortisone valerate, flurandrenolide, urea, betamethasone, clobetasol
propionate/emoll,
fluticasone propionate, azithromycin, hydrocortisone, moisturizing formula,
folic acid, desonide,
pimecrolimus, coal tar, diflorasone diacetate, etanercept folate, lactic acid,
methoxsalen,
hc/bismuth subgal/znox/resor, methylprednisolone acetate, prednisone,
sunscreen, halcinonide,
salicylic acid, anthralin, clocortolone pivalate, coal extract, coal
tar/salicylic acid, coal
tar/salicylic acid/sulfur, desoximetasone, diazepam, emollient,
fluocinonide/emollient, mineral
oil/castor oil/na lact, mineral oil/peanut oil, petroleum/isopropyl myristate,
psoralen, salicylic
acid, soap/tribromsalan, thimerosal/boric acid, celecoxib, infliximab,
cyclosporine, alefacept,
efalizumab, tacrolimus, pimecrolimus, PUVA, UVB, and sulfasalazine.
Non-limiting examples of therapeutic agents for psoriatic arthritis with which
a
compound of Formula (I), (Ia), (II), (III), (IV), or (V) can be combined
include the following:
methotrexate, etanercept, rofecoxib, celecoxib, folic acid, sulfasalazine,
naproxen, leflunomide,
methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate,
prednisone, sulindac,
betamethasone diprop augmented, infliximab, methotrexate, folate,
triamcinolone acetonide,
diclofenac, dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen,
meloxicam,
methylprednisolone, nabumetone, tolmetin sodium, calcipotriene, cyclosporine,
diclofenac
sodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodium thiomalate,
hydrocodone
bitartrate/apap, ibuprofen, risedronate sodium, sulfadiazine, thioguanine,
valdecoxib, alefacept
and efalizumab.
Non-limiting examples of therapeutic agents for restenosis with which a
compound of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined include the
following: sirolimus,
paclitaxel, everolimus, tacrolimus, ABT-578, and acetaminophen.
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Non-limiting examples of therapeutic agents for sciatica with which a compound
of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined include the
following: hydrocodone
bitartrate/apap, rofecoxib, cyclobenzaprine HCl, methylprednisolone, naproxen,
ibuprofen,
oxycodone HCl/acetaminophen, celecoxib, valdecoxib, methylprednisolone
acetate, prednisone,
codeine phosphate/apap, tramadol hcl/acetaminophen, metaxalone, meloxicam,
methocarbamol,
lidocaine hydrochloride, diclofenac sodium, gabapentin, dexamethasone,
carisoprodol, ketorolac
tromethamine, indomethacin, acetaminophen, diazepam, nabumetone, oxycodone
HC1, tizanidine
HCl, diclofenac sodium/misoprostol, propoxyphene napsylate/apap,
asa/oxycod/oxycodone ter,
ibuprofen/hydrocodone bit, tramadol HCl, etodolac, propoxyphene HCl,
amitriptyline HCl,
carisoprodol/codeine phos/asa, morphine sulfate, multivitamins, naproxen
sodium, orphenadrine
citrate, and temazepam.
Preferred examples of therapeutic agents for SLE (Lupus) with which a compound
of
Formula (I), (Ia), (II), (III), (IV), or (V) can be combined include the
following: NSAIDS, for
example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin; COX2
inhibitors, for
example, celecoxib, rofecoxib, valdecoxib; anti-malarials, for example,
hydroxychloroquine;
steroids, for example, prednisone, prednisolone, budenoside, dexamethasone;
cytotoxics, for
example, azathioprine, cyclophosphamide, mycophenolate mofetil, methotrexate;
inhibitors of
PDE4 or purine synthesis inhibitor, for example Cellcept . A compound of
Formula (I), (Ia), (II),
(III), (IV), or (V) may also be combined with agents such as sulfasalazine, 5-
aminosalicylic acid,
olsalazine, Imuran and agents which interfere with synthesis, production or
action of
proinflammatory cytokines such as IL-1, for example, caspase inhibitors like
IL-10 converting
enzyme inhibitors and IL-lra. A compound of Formula (I), (Ia), (II), (III),
(IV), or (V) may also
be used with T cell signaling inhibitors, for example, tyrosine kinase
inhibitors; or molecules that
target T cell activation molecules, for example, CTLA-4-IgG or anti-B7 family
antibodies, anti-
PD-1 family antibodies. A compound of Formula (I), (Ia), (II), (III), (IV), or
(V) can be combined
with IL-11 or anti-cytokine antibodies, for example, fonotolizumab (anti-IFNg
antibody), or anti-
receptor receptor antibodies, for example, anti-IL-6 receptor antibody and
antibodies to B-cell
surface molecules. A compound of Formula (I), (Ia), (II), (III), (IV), or (V)
may also be used with
UP 394 (abetimus), agents that deplete or inactivate B-cells, for example,
Rituximab (anti-CD20
antibody), lymphostat-B (anti-B1yS antibody), TNF antagonists, for example,
anti-TNF
antibodies, D2E7 (PCT Publication No. WO 97/29131; HUMIRATM), CA2
(REMICADETM),
CDP 571, TNFR-Ig constructs, (p75TNFRIgG (ENBRELTM) and p55TNFRIgG
(LENERCEPTTM))
In the compositions of the present invention the active compound may, if
desired, be
associated with other compatible pharmacologically active ingredients. For
example, the
compounds of this invention can be administered in combination with another
therapeutic agent
WO 2011/071570 PCT/US2010/046424
that is known to treat a disease or condition described herein. For example,
with one or more
additional pharmaceutical agents that inhibit or prevent the production of
VEGF or angiopoietins,
attenuate intracellular responses to VEGF or angiopoietins, block
intracellular signal transduction,
inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent
the formation of
edema or neovascularization. The compounds of the invention can be
administered prior to,
subsequent to or simultaneously with the additional pharmaceutical agent,
whichever course of
administration is appropriate. The additional pharmaceutical agents include,
but are not limited
to, anti-edemic steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-IL 1
agents, antihistamines,
PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors,
Akt/PTB
inhibitors, IGF-1R inhibitors, PKC inhibitors, P13 kinase inhibitors,
calcineurin inhibitors and
immunosuppressants. The compounds of the invention and the additional
pharmaceutical agents
act either additively or synergistically. Thus, the administration of such a
combination of
substances that inhibit angiogenesis, vascular hyperpermeability and/or
inhibit the formation of
edema can provide greater relief from the deletrious effects of a
hyperproliferative disorder,
angiogenesis, vascular hyperpermeability or edema than the administration of
either substance
alone. In the treatment of malignant disorders combinations with
antiproliferative or cytotoxic
chemotherapies or radiation are included in the scope of the present
invention.
One or more compounds of the invention can be administered to a human patient
by
themselves or in pharmaceutical compositions where they are mixed with
biologically suitable
carriers or excipient(s) at doses to treat or ameliorate a disease or
condition as described herein.
Mixtures of these compounds can also be administered to the patient as a
simple mixture or in
suitable formulated pharmaceutical compositions. A therapeutically effective
dose refers to that
amount of the compound or compounds sufficient to result in the prevention or
attenuation of a
disease or condition as described herein. Techniques for formulation and
administration of the
compounds of the instant application may be found in references well known to
one of ordinary
skill in the art, such as "Remington's Pharmaceutical Sciences," Mack
Publishing Co., Easton,
PA, latest edition.
Pharmaceutical Compositions and Modes of Administration
Suitable routes of administration may, for example, include oral, eyedrop,
rectal,
transmucosal, topical, or intestinal administration; parenteral delivery,
including intramuscular,
subcutaneous, intramedullary injections, as well as intrathecal, direct
intraventricular, intravenous,
intraperitoneal, intranasal, or intraocular injections.
Alternatively, one may administer the compound in a local rather than a
systemic manner,
for example, via injection of the compound directly into an edematous site,
often in a depot or
sustained release formulation.
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WO 2011/071570 PCT/US2010/046424
Furthermore, one may administer the drug in a targeted drug delivery system,
for
example, in a liposome coated with endothelial cell-specific antibody.
The pharmaceutical compositions of the present invention may be manufactured
in a
manner that is itself known, e.g., by means of conventional mixing,
dissolving, granulating,
dragee-making, levigating, emulsifying, encapsulating, entrapping or
lyophilizing processes.
Pharmaceutical compositions for use in accordance with the present invention
thus may
be formulated in a conventional manner using one or more physiologically
acceptable carriers
comprising excipients and auxiliaries which facilitate processing of the
active compounds into
preparations which can be used pharmaceutically. Proper formulation is
dependent upon the route
of administration chosen.
For injection, the agents of the invention may be formulated in aqueous
solutions,
preferably in physiologically compatible buffers such as Hanks' solution,
Ringer's solution, or
physiological saline buffer. For transmucosal administration, penetrants
appropriate to the barrier
to be permeated are used in the formulation. Such penetrants are generally
known in the art.
For oral administration, the compounds can be formulated readily by combining
the
active compounds with pharmaceutically acceptable carriers well known in the
art. Such carriers
enable the compounds of the invention to be formulated as tablets, pills,
dragees, capsules,
liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion
by a patient to be treated.
Pharmaceutical preparations for oral use can be obtained by combining the
active compound with
a solid excipient, optionally grinding a resulting mixture, and processing the
mixture of granules,
after adding suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients
are, in particular, fillers such as sugars, including lactose, sucrose,
mannitol, or sorbitol; cellulose
preparations such as, for example, maize starch, wheat starch, rice starch,
potato starch, gelatin,
gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,
disintegrating agents
may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic
acid or a salt
thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose,
concentrated sugar
solutions may be used, which may optionally contain gum arabic, talc,
polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,
and suitable organic
solvents or solvent mixtures. Dyestuffs or pigments may be added to the
tablets or dragee
coatings for identification or to characterize different combinations of
active compound doses.
Pharmaceutical preparations which can be used orally include push-fit capsules
made of
gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer,
such as glycerol or
sorbitol. The push-fit capsules can contain the active ingredients in
admixture with filler such as
lactose, binders such as starches, and/or lubricants such as talc or magnesium
stearate and,
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WO 2011/071570 PCT/US2010/046424
optionally, stabilizers. In soft capsules, the active compounds may be
dissolved or suspended in
suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene
glycols. In addition,
stabilizers may be added. All formulations for oral administration should be
in dosages suitable
for such administration.
For buccal administration, the compositions may take the form of tablets or
lozenges
formulated in conventional manner.
For administration by inhalation, the compounds for use according to the
present
invention are conveniently delivered in the form of an aerosol spray
presentation from pressurized
packs or a nebuliser, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other
suitable gas. In the
case of pressurized aerosol the dosage unit may be determined by providing a
valve to deliver a
metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler
or insufflator may be
formulated containing a powder mix of the compound and a suitable powder base
such as lactose
or starch.
The compounds can be formulated for parenteral administration by injection,
e.g. bolus
injection or continuous infusion. Formulations for injection may be presented
in unit dosage
form, e.g. in ampoules or in multi-dose containers, with an added
preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily or aqueous
vehicles, and may
contain formulatory agents such as suspending, stabilizing and/or dispersing
agents.
Pharmaceutical formulations for parenteral administration include aqueous
solutions of
the active compounds in water-soluble form. Additionally, suspensions of the
active compounds
may be prepared as appropriate oily injection suspensions. Suitable lipophilic
solvents or vehicles
include fatty oils such as sesame oil, or synthetic fatty acid esters, such as
ethyl oleate or
triglycerides, or liposomes. Aqueous injection suspensions may contain
substances which
increase the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or
dextran. Optionally, the suspension may also contain suitable stabilizers or
agents which increase
the solubility of the compounds to allow for the preparation of highly
concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution
with a suitable
vehicle, e.g., sterile pyrogen-free water, before use.
The compounds may also be formulated in rectal compositions such as
suppositories or
retention enemas, e.g., containing conventional suppository bases such as
cocoa butter or other
glycerides.
In addition to the formulations described previously, the compounds may also
be
formulated as a depot preparation. Such long acting formulations may be
administered by
implantation (for example subcutaneously or intramuscularly or by
intramuscular injection).
Thus, for example, the compounds may be formulated with suitable polymeric or
hydrophobic
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WO 2011/071570 PCT/US2010/046424
materials (for example as an emulsion in an acceptable oil) or ion exchange
resins, or as sparingly
soluble derivatives, for example, as a sparingly soluble salt.
An example of a pharmaceutical carrier for the hydrophobic compounds of the
invention
is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a
water-miscible organic
polymer, and an aqueous phase. The cosolvent system may be the VPD co-solvent
system. VPD
is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant
polysorbate 80, and
65% w/v polyethylene glycol 400, made up to volume in absolute ethanol. The
VPD co-solvent
system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water
solution. This co-
solvent system dissolves hydrophobic compounds well, and itself produces low
toxicity upon
systemic administration. Naturally, the proportions of a co-solvent system may
be varied
considerably without destroying its solubility and toxicity characteristics.
Furthermore, the
identity of the co-solvent components may be varied: for example, other low-
toxicity nonpolar
surfactants may be used instead of polysorbate 80; the fraction size of
polyethylene glycol may be
varied; other biocompatible polymers may replace polyethylene glycol, e.g.
polyvinyl
pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
Alternatively, other delivery systems for hydrophobic pharmaceutical compounds
may be
employed. Liposomes and emulsions are well known examples of delivery vehicles
or carriers
for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also
may be employed,
although usually at the cost of greater toxicity. Additionally, the compounds
may be delivered
using a sustained-release system, such as semipermeable matrices of solid
hydrophobic polymers
containing the therapeutic agent. Various sustained-release materials have
been established and
are well known by those skilled in the art. Sustained-release capsules may,
depending on their
chemical nature, release the compounds for a few weeks up to over 100 days.
Depending on the
chemical nature and the biological stability of the therapeutic reagent,
additional strategies for
protein stabilization may be employed.
The pharmaceutical compositions also may comprise suitable solid or gel phase
carriers
or excipients. Examples of such carriers or excipients include but are not
limited to calcium
carbonate, calcium phosphate, various sugars, starches, cellulose derivatives,
gelatin, and
polymers such as polyethylene glycols.
Many of the compounds of the invention may be provided as salts with
pharmaceutically
compatible counterions. Pharmaceutically compatible salts may be formed with
many acids,
including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric,
malic, succinic, etc.
Salts tend to be more soluble in aqueous or other protonic solvents than are
the corresponding free
base forms.
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WO 2011/071570 PCT/US2010/046424
Pharmaceutical compositions suitable for use in the present invention include
compositions wherein the active ingredients are contained in an effective
amount to achieve its
intended purpose. More specifically, a therapeutically effective amount means
an amount
effective to prevent development of or to alleviate the existing symptoms of
the subject being
treated. Determination of the effective amounts is well within the capability
of those skilled in
the art.
Dosage
For any compound used in a method of the present invention, the
therapeutically effective
dose can be estimated initially from cellular assays. For example, a dose can
be formulated in
cellular and animal models to achieve a circulating concentration range that
includes the EC50 as
determined in cellular assays (i.e., the concentration of the test compound
which achieves a half-
maximal inhibition of a given receptor activity). In some cases it is
appropriate to determine the
EC50 in the presence of 3 to 5% serum albumin since such a determination
approximates the
binding effects of plasma protein on the compound. Such information can be
used to more
accurately determine useful doses in humans. Further, advantageous compounds
for systemic
administration effectively modulate receptors of the SIP family in intact
cells at levels that are
safely achievable in plasma.
A therapeutically effective dose refers to that amount of the compound that
results in
amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of
such compounds can
be determined by standard pharmaceutical procedures in cell cultures or
experimental animals,
e.g., for determining the maximum tolerated dose (MTD) and the ED50 (effective
dose for 50%
maximal response). The dose ratio between toxic and therapeutic effects is the
therapeutic index
and it can be expressed as the ratio between MTD and ED50. Compounds which
exhibit high
therapeutic indices are preferred. The data obtained from these cell culture
assays and animal
studies can be used in formulating a range of dosage for use in humans. The
dosage of such
compounds lies preferably within a range of circulating concentrations that
include the ED50 with
little or no toxicity. The dosage may vary within this range depending upon
the dosage form
employed and the route of administration utilized. The exact formulation,
route of administration
and dosage can be chosen by the individual physician in view of the patient's
condition. (See e.g.
Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p1).
In the treatment of
crises, the administration of an acute bolus or an infusion approaching the
MTD may be
advantageous to obtain a rapid response.
Dosage amount and interval may be adjusted individually to provide plasma
levels of the
active moiety which are sufficient to modulate receptors of the SIP family, or
minimal effective
concentration (MEC). The MEC will vary for each compound but can be estimated
from in vitro
WO 2011/071570 PCT/US2010/046424
data; e.g. the concentration necessary to achieve 50-90% inhibition of binding
of the natural
ligand using the assays described herein. Dosages necessary to achieve the MEC
will depend on
individual characteristics and route of administration. However, HPLC assays
or bioassays can
be used to determine plasma concentrations.
Dosage intervals can also be determined using the MEC value. Compounds should
be
administered using a regimen which maintains plasma levels above the MEC for
10-90% of the
time, preferably between 30-90% and more preferably between 50-90% until the
desired
amelioration of symptoms is achieved. In cases of local administration or
selective uptake, the
effective local concentration of the drug may not be related to plasma
concentration.
The amount of composition administered will, of course, be dependent on the
subject
being treated, on the subject's weight, the severity of the affliction, the
manner of administration
and the judgment of the prescribing physician.
The compositions may, if desired, be presented in a pack or dispenser device
which may
contain one or more unit dosage forms containing the active ingredient. The
pack may for
example comprise metal or plastic foil, such as a blister pack. The pack or
dispenser device may
be accompanied by instructions for administration. Compositions comprising a
compound of the
invention formulated in a compatible pharmaceutical carrier may also be
prepared, placed in an
appropriate container, and labeled for treatment of an indicated condition.
Exemplary Formulations
In some formulations it may be beneficial to use the compounds of the present
invention
in the form of particles of very small size, for example as obtained by fluid
energy milling.
The use of compounds of the present invention in the manufacture of
pharmaceutical
compositions is illustrated by the following description. In this description
the term "active
compound" denotes any compound of the invention but particularly any compound
which is the
final product of one of the preceding Examples.
a) Capsules
In the preparation of capsules, 10 parts by weight of active compound and 240
parts by
weight of lactose can be de-aggregated and blended. The mixture can be filled
into hard gelatin
capsules, each capsule containing a unit dose or part of a unit dose of active
compound.
b) Tablets
Tablets can be prepared, for example, from the following ingredients:
Parts by weight
Active compound 10
Lactose 190
Maize starch 22
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Polyvinylpyrrolidone 10
Magnesium stearate 3
The active compound, the lactose and some of the starch can be de-aggregated,
blended
and the resulting mixture can be granulated with a solution of the
polyvinylpyrrolidone in ethanol.
The dry granulate can be blended with the magnesium stearate and the rest of
the starch. The
mixture is then compressed in a tabletting machine to give tablets each
containing a unit dose or a
part of a unit dose of active compound.
c) Enteric coated tablets
Tablets can be prepared by the method described in (b) above. The tablets can
be enteric
coated in a conventional manner using a solution of 20% cellulose acetate
phthalate and 3%
diethyl phthalate in ethanol:dichloromethane (1:1).
d) Suppositories
In the preparation of suppositories, for example, 100 parts by weight of
active compound
can be incorporated in 1300 parts by weight of triglyceride suppository base
and the mixture
formed into suppositories each containing a therapeutically effective amount
of active ingredient.
The present invention also comprises the use of a compound of Formula (I),
(Ia), (II),
(III), (IV), or (V) as a medicament.
A further aspect of the present invention provides the use of a compound of
Formula (I),
(Ia), (II), (III), (IV), or (V) or a salt thereof in the manufacture of a
medicament for treating
vascular hyperpermeability, angiogenesis-dependent disorders, proliferative
diseases and/or
disorders of the immune system in mammals, particularly human beings.
The present invention also provides a method of treating vascular
hyperpermeability,
inappropriate neovascularization, proliferative diseases and/or disorders of
the immune system
which comprises the administration of a therapeutically effective amount of a
compound of
Formula (I), (Ia), (II), (III), (IV), or (V) to a mammal, particularly a human
being, in need thereof.
The teachings of all references, including journal articles, patents and
published patent
applications, are incorporated herein by reference in their entirety.
S1P Receptor GTPyS Assays
The [35S]GTPyS binding assay can be run using both scintillation proximity
assay (SPA)
and filtration methods. Both formats are in 96 well plates and utilize
membranes from a stable or
transient CHO human cell lines overexpressing S1P1, S1P3, S1P4 or S1P5.
Compound stocks were
made up to 10 mM using DMSO and serial dilutions were carried out using 100%
DMSO.
Compounds were transferred to 96 well plates to yield a final DMSO
concentration of 1% for all
assays (lul for a 100 pl assay volume). Frozen membranes were thawed and
diluted in assay buffer
containing of 20 mM HEPES pH 7.4, 0.1% fatty acid-free BSA, 100mM NaCl, 5mM
MgC12 and
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M GDP. For the SPA assay membranes are premixed with WGA-SPA beads to yield a
final
concentration per well of 5 pg membrane and 500 pg of bead. For the filtration
assay, membranes
are added directly to the incubation plate at 5ug per well. The assay begins
with the addition of 50
pl of the membrane or membrane/bead mixture to each well of the assay plate.
Next, 50 l of 0.4
5 nM [35S]GTP1S is added to each well and incubated for 30 minutes.
Nonspecific binding is
measured using 10 pM unlabeled GTP1S. For the SPA, assay the plates are spun
and then read on
the Topcount. For the filtration assay the plate is harvested onto GF-C
filtration plates using a
Packard 96 well harvester.
10 Inhibition of [33P]S1P Binding to SIP Receptors
Radio ligand binding was carried out using membranes from transiently
transfected HEK
cells overexpressing SIP1, S1P3, S1P4 or S1P5. All compounds are dissolved in
DMSO and serial
dilutions were carried out in DMSO prior to addition to assay buffer. Final
assay DMSO
concentrations are 1% (v/v). [33P]S1P is purchased from Perkin Elmer and used
at 50 pM in all
assays. Frozen membranes are thawed and resuspended in assay buffer containing
50 mM
HEPES pH 7.4, 100 mM NaCl, 10 mM MgC12 and 0.1% fatty acid free BSA. Membrane
is added
to give 5-10 pg of membrane per well. Non-specific binding is determined in
the presence of cold
1 pM SIP. Incubations are carried out at room temperature for 45-60 minutes
before filtering
onto GF/C filtration plates using a Packard 96 well harvester. Plates are
dried before adding
Microscint to each well, sealed and counted on a Topcount.
Abbreviations
ACN Acetonitrile
Binap 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
CH2C12 dichloromethane
CHC13 Chloroform
CO2 Carbon dioxide
DAST Diethylaminosulfur trifluoride
DBAD Di-tent-butyl azodicarboxylate
DBU 1,8-Diazabicyclo(5.4.0)undec-7-ene
DCC N,N'-Dicyclohexylcarbodiimide
DCE Dicholorethane
DCM Dichloromethane
DIAD Diisopropyl azodicarboxylate
Dibal-H Diisobutylaluminum hydride
DIC N,N'-Diisopropylcarbodiimide
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DIEA N,N-Diisopropylethylamine
DMA N,N-Dimethylacetamide
DME 1,2-dimethoxyethane
DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
EA Ethyl acetate
EDC 1,2-dichloroethane
EDCI 1 -(3 -Dimethylaminopropyl)-3 -ethylcarbodiimide
EtOH Ethanol
EtOAc Ethyl acetate
Et3N Triethylamine
FCC Flash column chromatography
h hour(s)
HBTU O-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
Hexafluorophosaphate
HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
Hexafluorophosaphate
HCl Hydrochloric acid
HOBt 1-Hydroxybenzotriazole
HOAT 1-Hydroxy-7-azabenzotriazole
HPLC High Performance Liquid Chromatography
KHMDS Potassium hexamethyldisilazide
MeOH Methanol
Min Minutes
MW Microwave
NaOH Sodium hydroxide
NIS N-iodosuccinimide
NMP 1-methyl-2-pyrrolidone
PS-DCC Polymer-supported carbodiimide
PS-PPh3 Polymer-supported triphenylphosphine
RBF Round bottom flask
RP Reverse Phase
Rt Retention time
RT Room temperature
THE Tetrahydrofuran
i-PrOH 2-Propanol
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PPh3 Triphenylphosphine
SFC Supercritical fluid chromatography
SOC12 Thionyl chloride
Analytical Methods
Analytical data is defined either within the general procedures or in the
tables of
examples. Unless otherwise stated, all 1H or 13C NMR data were collected on a
Varian Mercury
Plus 400 MHz or a Bruker DRX 400 MHz instrument; chemical shifts are quoted in
parts per
million (ppm). High-pressure liquid chromatography (HPLC) analytical data are
either detailed
within the experimental or referenced to the table of HPLC conditions, using
the lower case
method letter, in Table 1.
Table 1. List of HPLC methods
HPLC Conditions
Method Unless indicated otherwise, mobile phase A was 10 mM ammonium acetate,
mobile
phase B was HPLC grade ACN.
a 5-95% B over 3.7 min with a hold at 95% B for 1 min (1.3 mL/min flow rate).
4.6 x
50 mm Zorbax XDB C18 column (5 pm particles). Detection methods are diode
array (DAD) and evaporative light scattering (ELSD) detection as well as
pos/neg
electrospray ionization.
b 5-60% B over 1.5 min then 60-95% B to 2.5 min with a hold at 95% B for 1.2
min
(1.3 mL/min flow rate). 4.6 x 30 mm Vydac Genesis C8 column (4 pm particles).
Detection methods are diode array (DAD) and evaporative light scattering
(ELSD)
detection as well as pos/neg electrospray ionization.
c 30-95% B over 2.0 min with a hold at 95% B for 1.7 min (1.0 mL/min flow
rate). 4.6
x 30 mm Vydac Genesis C8 column (4 pm particles). Detection methods are diode
array (DAD) and evaporative light scattering (ELSD) detection as well as
pos/neg
electrospray ionization.
d 30-95% B over 2.0 min with a hold at 95% B for 1.5 min (1.0 mL/min flow
rate).
UV 2 = 210-360 nm; Genesis C8, 4 m, 30 x 4.6 mm column; ESI +ve/-ve)
e A gradient of 10-100% ACN (B) and 0.1% trifluoroacetic acid in water (A) is
used,
at a flow rate of 1.5 mL/min (0-0.1 min 10% A, 0.1-3.1 min 10-100% B, 3.1-3.9
min
100-10% B, 3.9-4.0 min 100-10% B). 2.1mm x 30 mm Phenomenex Luna Combi-
HTS C8 (5 m particles). Detection methods are diode array (DAD) and
evaporative
light scattering (ELSD) detection as well as APCI ionization.
WO 2011/071570 PCT/US2010/046424
HPLC Conditions
Method Unless indicated otherwise, mobile phase A was 10 mM ammonium acetate,
mobile
phase B was HPLC grade ACN.
f Gradient was 5-35% B in 4 min then 35-95% B to 6 min with a hold at 95% B
for
1.7 min (1.3 mL/min flow rate). Mobile phase A was water with 0.1 % formic
acid,
mobile phase B was HPLC grade ACN. The column used for the chromatography
was a 4.6x30 mm Vydac Genesis C8 column (4 m particles). Detection methods
are diode array (DAD) and evaporative light scattering (ELSD) detection as
well as
pos/neg electrospray ionization.
g The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at
95%
B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10mM ammonium
acetate, mobile phase B was HPLC grade ACN. The column used for the
chromatography is a 4.6x50 mm MAC-MOD Halo C18 column (2.7 m particles).
Detection methods are diode array (DAD) and evaporative light scattering
(ELSD)
detection as well as positive/negative electrospray ionization.
h The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at
95%
B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10mM ammonium
acetate, mobile phase B was HPLC grade ACN. The column used for the
chromatography was a 4.6x50 mm MAC-MOD Halo C8 column (4 m particles).
Detection methods are diode array (DAD) and evaporative light scattering
(ELSD)
detection as well as positive/negative atmospheric pressure chemical
ionization
(APCI).
i The gradient was 30-60% B in 1.50 min then 60-95% B to 2.5 min with a hold
at
95% B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10mM ammonium
acetate, mobile phase B was HPLC grade ACN. The column used for the
chromatography is a 4.6x50 mm MAC-MOD Halo C8 column (2.7 m particles).
Detection methods are diode array (DAD) and evaporative light scattering
(ELSD)
detection as well as positive/negative electrospray ionization.
j The gradient was 5-60% B in 1.5 min then 60-95% B to 2.5 min with a hold at
95%
B for 1.2 min (1.3 mL/min flow rate). Mobile phase A was 10mM ammonium
acetate, mobile phase B was HPLC grade ACN. The column used for the
chromatography is a 4.6x50 mm MAC-MOD Halo C8 column (2.7 m particles).
Detection methods are diode array (DAD) and evaporative light scattering
(ELSD)
detection as well as positive/negative electrospray ionization.
56
WO 2011/071570 PCT/US2010/046424
HPLC Conditions
Method Unless indicated otherwise, mobile phase A was 10 mM ammonium acetate,
mobile
phase B was HPLC grade ACN.
k The gradient was 5-60% B in 0.75 min then 60-95% B to 1.15 min with a hold
at
95% B for 0.75 min (1.3 mL/min flow rate). Mobile phase A was 10mM ammonium
acetate, mobile phase B was HPLC grade ACN. The column used for the
chromatography is a 4.6x50 mm MAC-MOD Halo C8 column (2.7 m particles).
Detection methods are diode array (DAD) and evaporative light scattering
(ELSD)
detection as well as positive/negative electrospray ionization.
I Samples were purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um
100A AXIA column (30mm x 75mm). A gradient of ACN (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/min (0-0.5
min
10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min
linear gradient 100-10% A). Samples were injected in 1.5mL DMSO:MeOH (1:1).
m A gradient of 10-100% ACN (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A,
2.6-
2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay).
n 9 minute chromatogram. 5_95 NH4OAc 8m GC8 - The column used for the
chromatography was a 4.6x30 mm Vydac Genesis C8 column (4 mm particles). The
gradient was 5-35% B in 4 min then 35-95% B to 6 min with a hold at 95% B for
1.7
min (1.3 mL/min flow rate). Mobile phase A was 10 mM ammonium acetate,
mobile phase B was HPLC grade ACN. Detection methods are diode array (DAD)
and evaporative light scattering (ELSD) detection as well as pos/neg
electrospray
ionization.
0 6 minute chromatogram non polar 6 min GC8: The column used for the
chromatography was a 4.6x30 mm Vydac Genesis C8 column (4 mm particles). The
gradient was 30-95% B in 2 min then hold at 95% B to 5.7 min (1.3 mL/min flow
rate). Mobile phase A was 10 mM ammonium acetate, mobile phase B was HPLC
grade ACN. Detection methods are diode array (DAD) and evaporative light
scattering (ELSD) detection as well as pos/neg electrospray ionization.
p 5 minute chromatogram Purity QC method: The column used for the
chromatography was a 4.6x50 mm Zorbax XDB C18 column (5 mm particles). The
gradient was 5-95% B in 3.7 min with a hold at 95% B for 1 min (1.3 mL/min
flow
rate). Mobile phase A was 10mM ammonium acetate, mobile phase B was HPLC
grade ACN. Detection methods are diode array (DAD) and evaporative light
scattering (ELSD) detection as well as pos/neg electrospray ionization.
57
WO 2011/071570 PCT/US2010/046424
HPLC Conditions
Method Unless indicated otherwise, mobile phase A was 10 mM ammonium acetate,
mobile
phase B was HPLC grade ACN.
q HPLC Method: 80:20 0.1% H3PO4/ACN to 30:70% in 15 min then to 5:95 in 3 min,
hold for 4 min then increase to 80:20 in 0.1 min, keep at 80:20 for 5 min.
Column
Zorbax Eclipse XDB C18, 150X 4.6 mm, 3.5 micron, stop time 27 min, flow rate
1.5
mL/min, column temperature 25 C.
r HPLC 80:20 0.1% H3PO4/ACN to 30:70% in 15 min then to 5:95 in 3 min, keep
for
4 min then increase to 80:20 in 0.1 min, keep at 80:20 for 5 min. Column
Zorbax
Eclipse XDB C18, 150X 4.6 mm, 3.5 micron, stop time 27 min, flow rate 1.5
mL/min, column temperature 25 C.
Purification Methods
For the general procedures, the final compounds may be purified by any
technique or combination
of techniques known to one skilled in the art. Some examples that are not
limiting include flash
chromatography with a solid phase (e.g. silica gel, alumina, etc.) and a
solvent (or combination of
solvents) that elutes the desired compounds (e.g. heptane, EtOAc, DCM, MeOH,
MeCN, water,
etc.); preparatory TLC with a solid phase (e.g. silica gel, alumina etc.) and
a solvent (or
combination of solvents) that elutes the desired compounds (e.g. heptane,
EtOAc, DCM, MeOH,
MeCN, water, etc.); reverse phase HPLC (see Table 1 for some non-limiting
conditions);
recrystalization from an appropriate solvent (e.g. MeOH, EtOH, IPA, EtOAc,
toluene, etc.) or
combination of solvents (e.g. EtOAc/heptane, EtOAc/MeOH, etc.); chiral LC with
a solid phase
and an appropriate solvent (see Table 2 for some non-limiting conditions)to
elute the desired
compound; chiral SFC with a solid phase and CO2 with an appropriate modifier
(e.g. MeOH,
EtOH, IPA with or without additional modifier such as diethylamine, TFA,
etc.); precipitation
from a combination of solvents (e.g. DMF/water, DMSO/DCM, EtOAc/heptane,
etc.); trituration
with an appropriate solvent (e.g. EtOAc, DCM, MeCN, MeOH, EtOH, IPA, n-IPA,
etc.);
extractions by dissolving a compound in a liquid and washing with an
appropriately immiscible
liquid (e.g. DCM/water, EtOAc/water, DCM/saturated aqueous NaHCO3,
EtOAc/saturated
aqueous NaHCO3, DCM/10% aqueous HC1, EtOAc/10% aqueous HC1, etc.);
distillation (e.g.
simple, fractional, Kugelrohr, etc.); gas chromatography using an appropriate
temperature, carrier
gas and flow rate; sublimation at an appropriate temperature and pressure;
filtration through a
media (e.g. Florosil , alumina, Celite , silica gel, etc.) with a solvent
(e.g. heptane, hexanes,
EtOAc, DCM, MeOH, etc.) or combination of solvents; salt formation with solid
support (resin
based, e.g. ion exchange) or without. Some descriptions of these techniques
can be found in the
following references: Gordon, A. J. and Ford, R. A.. "The Chemist's
Companion", 1972; Palleros,
58
WO 2011/071570 PCT/US2010/046424
D. R. "Experimental Organic Chemistry", 2000; Still, W. C., Kahn and M. Mitra,
A. J. Org.
Chem. 1978, 43, 2923; Yan, B. "Analysis and Purification Methods in
Combinatorial Chemistry",
2003; Harwood, L. M., Moody, C. J. and Percy, J. M. "Experimental Organic
Chemistry:
Standard and Microscale, 2"d Edition", 1999; Stichlmair, J. G. and Fair, J. R.
"Distillation;
Principles and Practices", 1998; Beesley, T. E. and Scott, R. P. W. "Chiral
Chromatography",
1999; Landgrebe, J. A. "Theory and Practice in the Organic Laboratory, 4th
Ed.", 1993; Skoog, D.
A. and Leary, J. J. "Principles of Instrumental Analysis, 4th Ed.", 1992; G.
Subramanian, "Chiral
Separation Techniques, 3rd Edition", 2007; Y. Kazakevich, R. Lobrutto, "HPLC
for
Pharmaceutical Scientists", 2007.
Scheme A
NH O
' /R2
R1 i Re'- H ~~ N
N OH &1,
R
X X
X 1 2 3
A method for preparing di-substituted oxadiazole compounds of the invention is
illustrated in
Scheme A (X = CR3 or N). In Scheme A, step i, a suitably substituted nitrile
compound 1
(commercially available or made through General procedure A or B) is reacted
with
hydroxylamine to give compound 2. These types of reactions are well
established in the literature
(see, for example, Yan, et al., Bioorg & Med Chem Lett 2006, 16(14), 3679-
3683). This reaction
is typically conducted in a protic solvent (such as MeOH or EtOH) at
temperatures at or below
reflux (such as 60 C). The product 2 is typically isolated from the reaction
mixture as a solid by
concentrating the mixture. Compound 2 can be used as it is. Coupling of
compound 2 with a
suitable acid or acid chloride followed by ring closure to produce compound 3
is shown in step ii.
The coupling reaction is typically carried out with carboxylic acids in the
presence of a coupling
reagent (such as HOBt, DCC) or with acid chlorides in the presence of an
organic base (such as
DIEA, Et3N) at room temperature or elevated temperature (for example, 20 - 180
C) in a solvent
such as DMF or DMA. The subsequent ring closure reaction is complete in situ
at elevated
temperature (for example 160 C) (see, for example, Wang, et al., Org Lett
2005 7(5), 925 - 928).
The compounds 3 can then be isolated and purified using standard techniques
(such as reverse-
phase liquid chromatography or SFC).
General Synthetic Schemes
The general synthetic schemes that were utilized to construct the majority of
compounds
disclosed in this application are described below in (Schemes 1 - 3).
59
WO 2011/071570 PCT/US2010/046424
Scheme 1. General synthetic route to 4-alkoxy-benzonitrile (general procedure
A, B)
b__,~/N (A)or(B)
R ~O I ~
Scheme 2. General synthetic route to 3, 5-disubstituted oxadiazole (general
procedure C, D, and
E)
N NHZ N-O
i /
(C) ~N1OFi (D) or (E) \ N
R R R
X X
Scheme 3. General synthetic route to an acid chloride (general procedure F)
JL (F) A
R OH R CI
LIST OF GENERAL PROCEDURES
General Procedure A: Preparation of 4-alkoxy-benzonitrile using
triphenylphosphine
General Procedure B: Preparation of 4-alkoxy-benzonitrile using polymer-bound
triphenylphosphine
General Procedure C: Preparation of hydroxyamidine
General Procedure D: Oxadiazole formation from an acid
General Procedure E: Oxadiazole formation from an acid chloride
General Procedure F: Formation of an acid chloride from a carboxylic acid
General Procedure G: Formation of aldehyde from nitrite
General Procedure H: Amination of aldehyde
General Procedure I: Alkylation of indole with acrylate
General Procedure J: Alkylation of indole with an alkyl halide
General Procedure K: Deprotection of tert-butyl ester or ether
General Procedure L: Amination of aryl halide
General Procedure M: Alkylation of phenol with an alkyl halide
General Procedure N: Debenzylation
General Procedure 0: Deprotection of protected 1,2-diol
General Procedure P: Nucleophilic displacement of an aryl fluoride
WO 2011/071570 PCT/US2010/046424
General Procedure Q: Hydrolysis of an ester
General Procedure R: Mitsunobu coupling to a phenol
General Procedure S: Deprotection of phosphonate ester with or without
bromination
General Procedure T: Preparation of benzylic olefin from ketone
General Procedure U: Reduction of benzylic olefin
General Procedure V: Hydrolysis of ester
General Procedure W: Alkylation of a phenol
Example Of Use Of General Procedures
The general procedure letter codes constitute a synthetic route to the final
product. A worked
example of how the route is determined is given below using Example A.33 as a
non-limiting
illustration. Example A.33, 4-[3-(3-chloro-4-isopropoxy-phenyl)-[
1,2,4]oxadiazol-5-yl]-pyridine
was prepared from 3-chloro-N-hydroxy-4-isopropoxy-benzamidine using general
procedure D, as
represented in the following synthetic scheme:
1OH
N NCO
CI NH (D) CI I N N
~ I z ~OI /
The precursor to Example A.33, 3-chloro-N-hydroxy-4-isopropoxy-benzamidine was
prepared
using the route (A, Q. This translates into the following synthetic sequence,
where the
hydroxyamidine starting material used in general procedure D is the product by
the following the
procedure A and C, in the given order.
N NHZ
:icr' (A) () / o I O
1(D)
N-O
/
/\I I ~ N
ll JN
O
Preparations and Examples
The general synthetic methods used in each General Procedure follow and
include an illustration
of a compound that was synthesized using the designated General Procedure.
None of the
specific conditions and reagents noted herein are to be construed as limiting
the scope of the
invention and are provided for illustrative purposes only. All starting
materials are commercially
available from Sigma-Aldrich (including Fluka and Discovery CPR) unless
otherwise noted after
the chemical name. Reagent/reactant names given are as named on the commercial
bottle or as
61
WO 2011/071570 PCT/US2010/046424
generated by IUPAC conventions, CambridgeSoft ChemDraw Ultra 9Ø7,
CambridgeSoft
Chemistry E-Notebook 9Ø127, or AutoNom 2000.
General Procedure A: Preparation of 4-alkoxy-benzonitrile using
triphenylphosphine
Triphenylphosphine (1 - 3 equivalents, preferably 1.6 equivalents) and 4-
hydroxy-benzonitrile (1
- 3 equivalents, preferably 1 equivalent) are dissolved in an anhydrous
organic solvent such as
dichloromethane, toluene, or tetrahydrofuran (preferably tetrahydrofuran)
under an atmosphere of
nitrogen. After a brief stirring, an azodicarboxylate such as diethyl
azodicarboxylate, diisopropyl
azodicarboxylate, or di-tent-butyl azodicarboxylate (preferably di-tent-butyl
azodicarboxylate) (1
- 3 equivalents, preferably 1.6 equivalents) is added to the solution and the
mixture is stirred for a
few minutes before addition of an anhydrous alcohol (1 - 3 equivalents,
preferably 1.25
equivalents). The reaction mixture is stirred at 0 - 100 C (preferably about
23 C) under an
atmosphere of nitrogen for a period of about 2 - 24 hours (preferably 16
hours). The solvent is
removed under reduced pressure. The crude product can be further purified by
flash column
chromatography.
Exemplification of General Procedure A:
Preparation of 3-chloro-4-isopropoxy-benzonitrile
N / N
CI PPh31 DBAD CI
HO )OH THE O I /
Into a round bottom flask containing triphenylphosphine (27.3 g, 104 mmol) and
3-chloro-4-
hydroxy-benzonitrile (10 g, 65 mmol) was added anhydrous tetrahydrofuran (600
mL). The
mixture was stirred briefly under nitrogen, di-tent-butyl azodicarboxylate (24
g, 104 mmol) was
then added. The mixture was stirred for a few minutes, followed by addition of
anhydrous
isopropanol (6.23 mL, 81.4 mmol). The reaction mixture was stirred at room
temperature
overnight under nitrogen. The crude product was purified by flash
chromatography using 1:4 (v/v)
ethyl acetate/heptane as eluent. Fractions were dried to give 3-chloro-4-
isopropoxy-benzonitrile
(12.2 g, 91%) as a red-orange semi-solid.
LC/MS (Table 1, Method d) Rt = 2.36 min, m/z 152.1 (M+H) ; 1H NMR (400 MHz,
DMSO-d6) 6
7.74 (d, 1H), 7.61 (dd, 1H), 7.14 (d, 1H), 4.75 (sept., 1H), 1.34 (d, 6H)
General Procedure B: Preparation of 4-alkoxy-benzonitrile using polymer-bound
triphenylphosphine
To an alcohol (1 - 3 equivalents, preferably 1 equivalent) and 4-hydroxy-
benzonitrile (1 - 3
equivalents, preferably 1 equivalent) dissolved in a suitable solvent such as
dichloromethane,
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WO 2011/071570 PCT/US2010/046424
dichloroethane, tetrahydrofuran, or 1,4-dioxane (preferable tetrahydrofuran)
is added polymer-
bound triphenylphosphine (1 - 3 equivalents, preferably 2 equivalents) and an
azodicarboxylate
such as diethyl azodicarboxylate, DIAD, or di-tent-butyl azodicarboxylate
(preferably DIAD) (1 -
2 equivalents, preferably 1.5 equivalents). The mixture is shaken at about 0 -
100 C (preferably
about 23 C) for a period of 4 - 24 hours (preferably 16 hours). The crude
mixture is filtered and
the resin is washed with a suitable solvent such as dichloromethane,
dichloroethane, THF, or 1,4-
dioxane (preferably THF). The filtrate is concentrated to dryness under
reduced pressure and the
residue is subjected to General Procedure C.
Exemplification of General Procedure B:
Preparation of 3-chloro-4-(1-ethyl-propoxy)-benzonitrile
I //N
CI PS-PPh3, DIAD Cl
I;'OH THF
HO
Into a scintillation vial containing a solution of pentan-3-ol (22 mg, 0.25
mmol) dissolved in THF
(2 mL) was added a solution of 3-chloro-4-hydroxy-benzonitrile (38 mg, 0.25
mmol) in THF (2
mL) followed by PS-PPh3 resin (357 mg, 0.5 mmol, loading 1.4 mmol/g) and a
solution of DIAD
(76 mg, 0.375 mmol) in THF (2 mL). The vial was capped and shaken at room
temperature
overnight. The reaction mixture was filtered and the resin was washed with THF
(4 mL). The
filtrate was concentrated to dryness to give 3-chloro-4-(1-ethyl propoxy)-
benzonitrile.
General Procedure C: Preparation of hydroxyamidine
To a solution of benzonitrile (1-3 equivalents, preferably1 equivalent) in a
suitable solvent such as
methanol, ethanol, isopropanol, or water (preferably ethanol) is added (1 - 50
equivalents,
preferably 1.1 equivalents). The reaction mixture is heated at about 25 - 100
C (preferably 60 C)
for a period of about 2 - 24 hours (preferably 16 hours). The solvents are
removed under reduced
pressure. The crude product is dried under vacuum and then subjected to
General Procedure D or
E.
Exemplification of General Procedure C:
Preparation of 3-chloro-N-hydroxy-4-isopropoxy-benzamidine
NH2
CI ethanol Cl N 1OH
+ H Z N-OH
O O
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WO 2011/071570 PCT/US2010/046424
Into a round bottom flask was added 3-chloro-4-isopropoxy-benzonitrile (5.00
g, 25.6 mmol),
hydroxylamine (50% by weight in water, 1.86 mL, 28.1 mmol) and ethanol (150
mL). The
mixture was heated at about 60 C overnight. Upon completion of the reaction,
the mixture was
concentrated to dryness under reduced pressure to give 3-chloro-N-hydroxy-4-
isopropoxy-
benzamidine (5.76 g, 94%) as a light yellow solid.
LC/MS (Table 1, Method a) Rt = 2.09 min, m/z 229 (M+H) ; 1H NMR (400 MHz, DMSO-
d6) 6
9.58 (s, 1H), 7.70 (d, 1H), 7.59 (dd, 1H), 7.15 (d, 1H), 5.81 (s, 2H), 4.69
(sept., 1H), 1.29 (d, 6H)
General Procedure D: Oxadiazole formation from an acid
To a reaction vial is added a hydroxyamidine (0.9 - 1.5 equivalents,
preferably 1.1 equivalent), an
acid (0.9 - 1.5 equivalents, preferably 1 equivalent), a coupling reagent such
as HBTU, HATU,
HOBt, or polymer-bound HOBt (preferably HOBt) (1 - 2 equivalents, preferably 1
equivalent), a
carbodiimide such as PS, EDCI, DIC, DCC or polymer-bound DCC (preferably
polymer-bound
DCC) (1.5 - 3 equivalents, preferably 3 equivalents), a base such as
diisopropylethylamine,
triethylamine, or N-methylmorpholine (preferably diisopropylamine) (1 - 3
equivalents,
preferably 3 equivalents) and a suitable solvent such as DMF, DMA, or ACN
(preferably ACN).
The reaction vial is capped and heated (conventional heating or microwave
heating, preferably
microwave heating) at 100 - 200 C (preferably 160 C) for a period of 15 - 45
min (preferably
30 min). After cooling down to RT, the crude reaction mixture is filtered,
washed with a suitable
solvent such as DMF, DMA, or ACN (preferably ACN), and the filtrate is
concentrated to dryness
under reduced pressure. The crude product is further purified by
chromatography.
Exemplification of General Procedure D:
Preparation of 4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4] oxadiazol-5-yl]-3-
methyl-pyridine
NH, O N'O t
CI ~N,OH HO HOBt, PS-DCC CI I N N
/~O I / + I /N DI /~O
To a microwave vial charged with 3-chloro-N-hydroxy-4-isopropoxy-benzamidine
(75 mg, 0.328
mmol), 3-methyl-isonicotinic acid (41 mg, 0.298 mmol), HOBt (46 mg, 0.298
mmol), PS-
carbodiimide (720 mg, 0.894 mmol, loading 1.24 mmol/g) was added ACN (3.5 mL)
and
diisopropylethylamine (156 L, 0.894 mmol). The reaction vial was capped and
heated at about
160 C for about 30 min in a Biotage microwave. The reaction mixture was
filtered and the resin
was washed with ACN (4 mL). The filtrate was concentrated to dryness. The
crude product was
purified via reverse phase HPLC (30 - 90 % ACN, 30 minute ramp) to give 10.2
mg (10 %) of 4-
[3-(3-chloro-4-isopropoxy phenyl)-[1,2,4]oxadiazol-5 ylJ-3-methyl pyridine.
64
WO 2011/071570 PCT/US2010/046424
LC/MS (Table 1, Method c) Rt = 2.70 min, m/z 330 (M+H) ; 1H NMR (400 MHz, DMSO-
d6) 6
8.77 (s, 1H), 8.69 (d, 1H), 8.06 (d, 1H), 8.01 (dd, 2H), 7.39 (d, 1H), 4.83
(sept., 1H), 2.70 (s, 3H),
1.35 (d, 6H)
General Procedure E: Oxadiazole formation from an acid chloride
To a solution of a 3-chloro-N-hydroxy-4-alkoxy-benzamidine (1 - 3 equivalents,
preferably 1
equivalent) in pyridine is added a solution of an acid chloride (1-3
equivalents, preferably 2
equivalent) in pyridine. The reaction mixture is heated at 60 - 100 C
(preferably 100 C) for a
period of 8 - 24 h (preferably 20 h). The solvent is removed under reduced
pressure and the
residue is further purified by chromatography.
Exemplification of General Procedure E:
Preparation of 3-[3-chloro-4-(1-ethyl-propoxy)-phenyl]-5-o-tolyl-
[1,2,4]oxadiazole
NHZ O N'O b
CI "N,OH + CI I \ pyridine CI I \ I N
O / O
To a solution of 3-chloro-4-(1-ethyl-propoxy)-N-hydroxy-benzamidine (64 mg,
0.25 mmol)
(prepared by General procedure B) in pyridine (1 mL) was added a solution of 2-
methylbenzoyl
chloride (77 mg, 0.5 mmol) in pyridine (1 mL). The mixture was heated at about
100 C
overnight. The solvent was removed under reduced pressure and the crude
product was purified
via SFC (C02/pure MeOH; gradient: 5% hold for 0.5 min, ramp at 7.3% to 50%
over 6.5 min,
hold at 50% for 1 min) to give 3-[3-chloro-4-(1-ethyl propoxy) phenyl)-5-o-
tolyl-
[1,2,4Joxadiazole (16.5 mg, 18.5 %).
LC/MS (Table 1, Method b) Rt = 3.18 min, m/z 356.13 (M-H)-; 1H NMR (400 MHz,
CHC13) 6
8.19 (d, I H), 8.16 (dd, I H), 8.01 (dd, I H), 7.48 (m, I H), 7.37 (d, I H),
7.01 (d, I H), 4.28 (m, I H),
1.77 (m, 4H), 1.01 (t, 6H)
Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(3-chloropyridin-4-yl)-
[1,2,4]-oxadiazole
CI
NHZ O CI N'O
CI \ OH pyridine CI N N
/
1 N + CI 11
O
To a solution of 3-chloroisonicotinoyl chloride (about 2.6 mmol) (prepared by
General procedure
F) in pyridine (5 mL) was added 3-chloro-4-isopropoxy-N-hydroxy-benzamidine
(300 mg, 1.31
WO 2011/071570 PCT/US2010/046424
mmol) (prepared by General procedure B). The mixture was heated at about 100
C overnight.
The solvent was removed under reduced pressure and the crude product was
purified via normal
phase silica gel chromatography (0-50% ethyl acetate / heptane gradient over
30 min) to give 3-
(3-chloro-4-isopropoxyphenyl)-5-(3-chloropyridin-4-yl)-[1, 2, 4J-oxadiazole
(323 mg, 70.3 %).
LC/MS (Table 1, Method b) Rt = 3.88 min, m/z 349.04 (M-H)-; 1H NMR (400 MHz,
CHC13) 6 =
8.84 (d, 1H), 8.69 (d, 1H), 8.11 (d, 1H), 8.02 (d, 1H), 7.99 (dd, 1H), 7.02,
(d, 1H), 4.69 (m, 1H),
1.44 (d, 6H)
General Procedure F: Formation of an acid chloride from a carboxylic acid
To an acid (preferably 1 equivalent) in a suitable solvent, such as DCM or
dichloroethane
(preferably DCM) is added a chlorinating reagent such as thionyl chloride or
oxalyl chloride
(preferably thionyl chloride) (1 - 100 equivalents, preferably 3 equivalents).
The reaction mixture
is stirred at 20 - 80 C (preferably at about 23 C) for a period of 1 - 24
hours (preferably 3
hours). The solvent is removed under reduced pressure. The crude product is
dried under vacuum
and then subjected to General Procedure E.
Exemplification of General Procedure F:
Preparation of 3-methyl-isonicotinoyl chloride
HO 0 CI 0
SOCI2
DCM
N N
To 3-methylisonicotinic acid (100 mg, 0.729 mmol) suspended in DCM (2.5 mL)
was added
thionyl chloride (260 mg, 2.188 mmol). The reaction mixture was stirred at RT
for about 3 h. The
solvent was removed under reduced pressure and the residue was dried under
high vacuum for 1 h
to give 3-methyl-isonicotinoyl chloride.
Preparation of 3-chloro-isonicotinoyl chloride
HO O CI O
CI SOC12 CI
DCM I
N N
To 3-chloroisonicotinic acid (413 mg, 2.62 mmol) was added thionyl chloride (5
mL, 68.5 mmol).
The reaction mixture was stirred at RT for about 20 h. The solution was
concentrated under
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WO 2011/071570 PCT/US2010/046424
reduced pressure and the residue was dried under high vacuum for 1 h to give 3-
chloro-
isonicotinoyl chloride.
General Procedure G: Formation of aldehyde from nitrite
A mixture of a nitrile in a round bottom flask containing (0.9 - 1.2
equivalents, preferably 1.0
equivalents) in a suitable solvent such as dichloromethane or dichloroethane
(preferably
dichloromethane) was cooled to between 0 C and -60 C (preferably -40 C). A
solution of
Dibal-H (0.9 - 2.5 equivalents, preferably 2.0 equivalents) was added dropwise
and then the
solution was stirred for 15 - 240 minutes (preferably 120 minutes), quenched
with methanol,
warmed to ambient temperature and treated with a 10% solution of Rochelle's
salt. After
extraction with DCM the combined organic layers were stirred with dilute
aqueous acid
(preferably 1M aqueous HC1). The layers were separated and the aqueous layer
extracted with
DCM. The combined organic layers were washed with brine, dried over MgSO4 or
Na2SO4,
filtered and evaporated to dryness. The crude product is further purified by
chromatography.
Exemplification of General Procedure G:
Preparation of 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzonitrile
CI CI
o
a \ N N CN C1 &,, N O
"-~
To a 100 mL round bottom flask equipped with septa cap outfitted with nitrogen
inlet needle was
charged with 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzonitrile
(1.529 g, 3.27 mmol) in DCM (65.4 mL) to give an orange solution. The reaction
mixture was
cooled to about -40 C via an ACN-dry ice bath. Dibal-H (3.60 mL, 3.60 mmol)
was then added
dropwise at about -40 C. The resulting mixture was stirred for about 2 h at
about -40 C.
Methanol (0.5 mL, 12.36 mmol) was then added dropwise to the reaction mixture
at about -40 C.
The ice bath was removed and the reaction was left to warm to ambient
temperature then
Rochelle's salt solution (60 mL) was added. The resulting mixture was stirred
vigorously for
about 3 h. The aqueous layer was separated. The organic phase was washed with
brine, dried
(MgSO4) and concentrated to give crude yellow oil. The residue was purified
via Analogix FCC
system using RediSepTM RS 120g column, with a gradient of 0-15% EtOAc/Heptane
over 40 min.
at 40 mUmin then held at 15% until all peaks eluted. Fractions containing the
product were
combined and concentrated to yield 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5 yl)benzonitrile (0.791 g, 2.09 mmol). 1H NMR (400 MHz, CDC13) 6
ppm 10.09 (s,
1H), 8.35 (d, J = 8.02 Hz, 1H), 8.21 (d, J = 1.90 Hz, 1H), 8.09 (s, 1H), 8.03
(dd, J = 8.56, 1.86 Hz,
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WO 2011/071570 PCT/US2010/046424
1H), 7.94 (dd, J = 8.04, 0.79 Hz, 1H), 7.05 (d, J = 8.62 Hz, 1H), 4.69 (td, J
= 12.05, 6.04 Hz, 1H),
1.45 (t, J = 6.80 Hz, 6H).
General Procedure H: Amination of aldehyde
A mixture of an amine (0.9 - 1.2 equivalents, preferably 1.1 equivalents), an
aldehyde (0.9 - 1.2
equivalents, preferably 1.0 equivalents), a suitable reducing agent, such as
polymer supported
sodium cyanoborohydride or sodium cyanoborohydride (preferably polymer
supported sodium
cyanoborohydride )(1.5 - 3.0 equivalents, preferably 2.0 equivalents), acetic
acid (2 - 24 drops,
preferably 6 drops) and a suitable solvent such as DCM or methanol (preferably
DCM) was
stirred at ambient temperature for 4 - 72 h, preferably 17 h. The crude
product is further purified
by chromatography.
Alternate general procedure H
In a 2.5 microwave vial, a solution of aldehyde (25 mg, 1 eq) dissolved in 1:1
DCM : methanol
(1.5 mL) is added, followed by the addition of amine (35 mg, 1.2 eq.) also
dissolved in 1:1 DCM :
methanol solution (1.0 mL), followed by resin-bound cyanoborohydride (3 eq.)
and acetic acid
(10 eq.). The microwave vial was capped and heated at 90 C for 600 seconds per
reaction in
Biotage parallel microwave optimizer. The reaction was checked by LC/MS (Table
1, method m)
and concentrated to dryness. The residue was dissolved in 1:1 DMSO/MeOH and
purified by
reverse phase HPLC (Table 1, method L).
Examplification of General Procedure H:
Preparation of 1-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-yl)benzyl)-
3-methylazetidine-3-carboxylic acid
a a
H
N,O O N'O
N / 0_~ N
HN~ OH
~O O
CI CI
A 500 mL round bottom flask was charged with 3-chloro-4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)benzaldehyde (0.745 g, 1.975 mmol), ethyl 3-
methylazetidine-3-carboxylate
(0.566 g, 3.95 mmol) (Tetrahedron Letters 1991, 32, 36, 4795-4798) and
methanol (197 mL). To
this was added acetic acid (0.904 mL, 15.80 mmol). The resulting mixture was
stirred at ambient
temperature for about 1 h then sodium cyanoborohydride (0.095 g, 1.512 mmol)
was added in one
portion. The reaction was stirred for about 17 h at ambient temperature. The
progress of the
reaction was monitored by LC/MS. The reaction was concentrated in vacuo to
give crude dark
yellow oil. The residue was purified via Analogix FCC system using 120 g Redi-
Sep column,
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WO 2011/071570 PCT/US2010/046424
with a gradient of 0-40% EtOAc/Heptane over about 45 min. at 50 mL/min then
held at 40%
EtOAc until all peaks eluted. Fractions containing product were combined and
concentrated to
yield 0.820 g (1.626 mmol) of colorless oil. The material was dissolved in THE
(80 mL). To this
was added NaOH (9.0 mL, 9.00 mmol) as IN solution, followed by MeOH (about 25
mL). The
reaction was stirred at ambient temperature for about 3 h, after which the
LC/MS showed that
hydrolysis was complete. To the reaction mixture was added HC1 (9.0 mL, 9.00
mmol) as IN
solution dropwise to neutralize the pH. The reaction mixture was concentrated
in vacuo then
lyophilized to dryness. The crude white solid was triturated in diethyl ether
and DCM then
filtered. The resulting solid was washed with water then oven-dried overnight
to give 1-(3-chloro-
4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)benzyl)-3-
methylazetidine-3-carboxylic
acid (0.377 g, 0.75 mmol) as white solid. LC/MS (Table 1, Method a) Rt = 1.81
min.; MS m/z:
476.15 (M+H)+.1H NMR (400 MHz, DMSO) 6 ppm 12.67-12.25 (m, 1H), 8.24-7.93 (m,
3H),
7.73-7.32 (m, 3H), 4.90-4.76 (m, 1H), 3.69 (s, 2H), 3.43 (d, J = 6.51 Hz, 2H),
3.09 (d, J = 6.43
Hz, 2H), 1.45 (s, 3H), 1.35 (d, J = 5.75 Hz, 6H).
General Procedure I: Alkylation of indole with acrylate
To a solution of an indole (0.9 - 1.2 equivalents, preferably 1.0 equivalents)
in a suitable solvent
such as ACN at about 60 C was added an acrylate (1.0 - 2.0 equivalents,
preferably 1.5
equivalents) and a base such as DBU (0.3 - 1.0 equivalents, preferably 0.5
equivalents). The
mixture was stirred at about 50 C overnight. The solvent was removed under
reduced pressure
and the crude product was dissolved in DCM, washed with brine, dried over
MgS04 or Na2SO4,
filtered and the solvent was removed under reduced pressure. The crude product
is further purified
by chromatography or recrystallization.
Examplification of General Procedure I:
Preparation of tert-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-1H-
indol-1-yl)propanoate
N_O N_O
CI I ~ N CI I ~ N
O NH O O \ N 11 O-~
To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4-
oxadiazole (5.6 g,
15.83 mmol) in ACN (55.9 mL) at about 60 C was added tert-butyl acrylate
(3.45 mL, 23.74
mmol) dropwise, followed by DBU (1.193 mL, 7.91 mmol). The mixture was stirred
at about 50
C overnight. The solvent was removed under reduced pressure and the crude
product was
dissolved in DCM (150 mL), washed with brine (3xlOOmL) dried over MgS04,
filtered and the
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WO 2011/071570 PCT/US2010/046424
solvent removed under reduced pressure. Re-crystallization from 30-60 C
petroleum ether gave
tert-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-IH-
indol-1 yl) propanoate
(5.42 g, 69.6 %). LC/MS (Table 1, Method b) Rt = 3.03 min, m/z 482.26 (M+H)+.
General Procedure J: Alkylation of indole with an alkyl halide
To a solution of an indole (0.9 - 1.2 equivalents, preferably 1.0 equivalents)
in a suitable solvent
such as DMF was added NaH (0.9 - 1.2 equivalents, preferably 1.1 equivalents).
After about 15
min an alkyl halide (0.9 - 2.0 equivalents, preferably 1.5 equivalents) was
added and the reaction
mixture was heated to about 50 C. After about 24 h the reaction mixture was
cooled to ambient
temperature, evaporated to dryness and the crude product is further purified
by chromatography.
Exemplification of General Procedure J:
Preparation of tert-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-1H-
indol-1-yl)butanoate
N'O \ N'O
I i
N I\ N O1
O NH O
CI CI
To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-1,2,4-
oxadiazole (0.100 g,
0.283 mmol) in DMF (0.999 mL) was added NaH (0.012 g, 0.311 mmol). After about
15 min tert-
butyl 4-bromobutanoate (0.095 g, 0.424 mmol) was added and the reaction
mixture was heated to
about 50 C. After about 24 h the reaction mixture was cooled to ambient
temperature,
concentrated in vacuo and purified by chromatography on silica gel (eluting
with EtOAc/Hep) to
provide tert-butyl 4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5yl)-
IH-indol-l-
yl)butanoate (0.135 g, 93%) as a colorless oil that solidified on standing.
LC/MS (Table 1,
Method c) Rt = 3.50 min, m/z 496 (M+H)+.
General Procedure K: Deprotection of tert-butyl ester or ether
To a solution of a tert-butyl ester (0.9 - 1.2 equivalents, preferably 1.0
equivalents) in a suitable
solvent such as DCM was added trifluoroacetic acid (15 - 25 equivalents,
preferably 20
equivalents. The mixture was stirred at ambient temperature for about 1-10 h
(preferably 8 h). The
solvent was removed under reduced pressure and crude product was further
purified by
chromatography or recrystallization.
WO 2011/071570 PCT/US2010/046424
Examplification of General Procedure K:
Preparation of 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-
indol-l-
yl)propanoic acid
N-O
CI O
\ N
O~ TFA CI I \ N
N 0 O / OH
To a solution of tent-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-1H-indol-
1-yl) propanoate oxadiazole (5.25g, 10.89 mmol) in DCM (136 mL) was added
trifluoroacetic
acid (16.78 mL, 218 mmol). The mixture was stirred at ambient temperature for
about 8 h. The
solvent was removed under reduced pressure and the solid residue was
triturated with ether to
give 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)-IH-indol-1
yl)propanoic acid
(4.35g, 93.0 %). LC/MS (Table 1, Method b) Rt = 3.03 min, m/z 356.13 (M-H)-;
'H NMR (400
MHz, DMSO) 6 12.39 (s, 1H), 8.13 (m, 1H), 8.07 (m, 1H), 8.00 (d, IH), 7.94 (d,
1H), 7.7 (d, 1H),
7.41 (m, 2H), 7.18 (d, 1H), 4.84 (s, 1H), 4.53 (td, 2H), 2.82 (td, 2H), 1.36
(d, 6H).
General Procedure L: Amination of aryl halide
To a reaction vessel is added an aryl fluoride or bromide (preferably
fluoride) (0.9 - 1.2
equivalents, preferably 1.0 equivalents), an amine (0.9 - 1.5 equivalents,
preferably 1.1
equivalents) potassium carbonate (0.9 - 3.0 equivalents, preferably 2.0
equivalents) and a suitable
solvent such as DMF, DMA or DMSO (preferably DMF). The reaction vial is capped
and heated
either via microwave with cooling or in an oil bath (preferably via microwave)
at 110 - 200 C
(preferably 160 C) for 15 min to 4 days (preferably 30 min). The crude
product is optionally
isolated from the reaction mixture by dilution with water followed by
filtration or neutralization to
pH < 3 and extraction with a suitable organic solvent (ethyl acetate,
dichloromethane, diethyl
ether - preferably dichloromethane). The product can be further purified by
chromatography or
crystallization.
Examplification of General Procedure L:
Preparation of (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid
CO,H
CI N-O COZH -O
CI
O iI \N 1/ F HZN ~0 I N I/ N
H
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WO 2011/071570 PCT/US2010/046424
3-(3-Chloro-4-isopropoxyphenyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (360 mg,
1.082 mmol),
(1R,3S)-3-aminocyclopentanecarboxylic acid (154 mg, 1.190 mmol), potassium
carbonate (329
mg, 2.380 mmol) and DMF (2 mL) was heated with cooling at about 160 C on the
Biotage
microwave for about 30 min. The mixture was diluted with DMSO (6 mL) and ACN
(8 mL),
filtered and divided into 8 aliquots for purification by molecular ion
directed LC/MS. The
fractions were combined and evaporated to afford a pale brown solid that was
dried in vacuo at
about 60 C for about 3 h. This gave (JR,3S)-3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5 yl)phenylamino)cyclopentanecarboxylic acid (212 mg, 0.480 mmol,
44.3 % yield) as
a pale brown solid. LC/MS (Table 1, Method a) Rt = 3.49 min, m/z 440.20 (M-H)-
. 1H NMR
(400 MHz, DMS06 ppm 4.81 (s, 1H), 3.96-3.76 (m, 1H), 2.78 (s, 1H), 2.42-2.25
(m, 1H), 2.12-
1.95 (m, 1H), 1.89 (d, J = 7.72 Hz, 2H), 1.73-1.61 (m, 1H), 1.61-1.48 (m, 1H),
1.39-1.30 (m, 7H),
12.22-12.07 (m, 1H), 6.73 (d, J = 8.82 Hz, 2H), 6.87-6.79 (m, 1H), 7.36 (d, J
= 8.63 Hz, 1H), 7.87
(d, J = 8.59 Hz, 2H), 7.98 (ddd, J = 9.78, 1.97, 1.06 Hz, 2H).
General Procedure M: Alkylation of phenol with an alkyl halide
A phenol such as benzyl 4-hydroxybenzoate (0.9 - 1.2 equivalents, preferably 1
equivalents) and a
suitable base (such as potassium carbonate (1 - 5 equivalents, preferably 5
equivalents)) in an
organic solvent (such as acetone (about 100 mL)) were combined. An alkyl
bromide (such as tert-
butyl 2-bromoacetate (0.9 - 1.2 equivalents, preferably 1 equivalents)) was
added dropwise. The
solution was stirred at about 60 - 70 C, preferably about 65 C for 12-24 h,
preferably about 18 h.
The solution was cooled and the reaction mixture was filtered through a
sintered glass funnel. The
filtrate was concentrated in vacuo to afford a crude product which can be
further purified via
chromatography or crystallization.
Exemplification of General Procedure M:
Preparation of benzyl 4-(2-tert-butoxy-2-oxoethoxy)benzoate 0, Bn
O O.Bn
0
BrLOk O
OH OLO"~
In a 100 mL round bottomed flask benzyl 4-hydroxybenzoate (1.445 g, 6.33 mmol)
and potassium
carbonate (4.17 g, 30.1 mmol) in acetone (100 mL) were combined. Tert-butyl 2-
bromoacetate
(0.908 mL, 6.03 mmol) was added dropwise. The solution was stirred at about 65
C overnight.
The solution was cooled and the reaction mixture was filtered through a
sintered glass funnel. The
filtrate was concentrated to afford pale yellow oil, which was purified via
silica gel
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WO 2011/071570 PCT/US2010/046424
chromatography (40 g, 30% EtOAc:heptane) to afford benzyl 4-(2-tert-butoxy-2-
oxoethoxy)benzoate (2.06 g, 5.90 mmol, 98 % yield) as colorless oil. LC/MS
(Table 1, Method a)
Rt = 4.31 min.
General Procedure N: Debenzylation
A high-pressure flask was charged with 5-20% (preferably 10%) palladium on
carbon (0.9 - 1.2
equivalents, preferably 1.0 equivalents), a suitable solvent such as MeOH (200
mL), then a
benzoate ester (50 - 70 equivalents, preferably 60 equivalents) were added.
The resulting
suspension was allowed to shake under an atmosphere of hydrogen about 10-70
psi (preferably 47
psi) at ambient temperature for about 2 h. The mixture was filtered through
Celite and the
colorless filtrate was concentrated to afford the product.
Exemplification of General Procedure N:
Preparation of 4-(2-tert-butoxy-2-oxoethoxy)benzoic acid
O 01Bn 0 OH
H2 I \
O
JJ J~//
O~O~ I/\OIj\
A 500 mL high-pressure flask was charged with benzyl 4-(2-tert-butoxy-2-
oxoethoxy)benzoate
(2.06 g, 6.02 mmol) in methanol (100 mL). 10% Palladium on carbon (0.320 g,
0.301 mmol) was
added, the resulting suspension was allowed to shake under an atmosphere of
hydrogen (about 47
psi) at RT for about 6 h. The mixture was filtered through Celite , and the
colorless filtrate was
concentrated to afford 4-(2-tert-butoxy-2-oxoethoxy)benzoic acid (1.5 g, 5.95
mmol, 99 % yield)
as pale yellow solid. LC/MS (Table 1, Method a) Rt = 3.03 min.; MS m/z: 251.30
(M-H)-. 1H
NMR (400 MHz, d-DMSO) ppm 7.88 (d, J = 8.99 Hz, 2H), 6.98 (d, J = 9.00 Hz,
2H), 4.75 (s,
2H), 1.43 (s, 9H).
General Procedure 0: Deprotection of a protected 1,2 diol
To a solution of protected diol (0.9 - 1.2 equivalents, preferably 1.0
equivalents) in a suitable
solvent such as THE was added a solution of 1M HC1 (1.5 - 2.5 equivalents,
preferably 2.0
equivalents). The mixture was heated to about 70 C for about 2 h. After
cooling to ambient
temperature a solution of an aqueous base such as 1M NaOH was added and the
reaction mixture
was concentrated in vacuo. The resulting solid was washed with water and dried
in vacuo to
afford the product.
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WO 2011/071570 PCT/US2010/046424
Exemplification of General Procedure 0:
Preparation of 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)propane-1,2-diol
N'O N-O
i
CI I N O O ' l CI I I N/ O OH
O
X ~ /~O ~OH
3-(3-Chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-
yl)methoxy)phenyl)-1,2,4-
oxadiazole (0.1 g, 0.225 mmol) andp-toluenesulfonic acid monohydrate (8.55 mg,
0.045 mmol)
were added in methanol (2.4 mL). The reaction mixture was heated at about 70
C for about 16 h.
The solution was cooled, methanol (1.5 mL) was added to the mixture and
recrystallized, the
resulted suspension was filtered, the solid was washed with water to afford 3-
(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenoxy)propane-1,2-diol (0.08 g, 0.198
mmol, 88 %
yield) as white solid. LC/MS (Table 1, method g) Rt = 2.97 min.; MS m/z:
405.18 (M+H)+. 1H
NMR (400 MHz, DMSO-d6) 6 ppm 8.16-8.09 (m, 2H), 8.05 (d, J = 2.13 Hz, 1H),
7.99 (dd, J =
8.64, 2.15 Hz, 1H), 7.38 (d, J = 9.05 Hz, 1H), 7.25-7.16 (m, 2H), 5.03 (d, J =
5.19 Hz, 1H), 4.87-
4.78 (m, 1H), 4.72 (t, J = 5.68 Hz, 1H), 4.15 (dd, J = 3.97, 10.01 Hz, 1H),
4.01 (dd, J = 6.20,
10.03 Hz, 1H), 3.84 (dt, J = 4.04, 5.69, 5.91 Hz, 1H), 3.47 (t, J = 5.84 Hz,
2H), 1.35 (d, J = 6.03
Hz, 6H).
General Procedure P: Nucleophilic displacement of an aryl fluoride
A solution of an aryl fluoride in a dry, aprotic solvent such as DMF, THF,
toluene or 1,4-dioxane
(preferably THF) is treated with a base such as sodium hydride (1.0 to 3.0
equivalents, preferably
about 1.1 equivalents) at 0 - 50 C (preferably RT). The mixture is treated
dropwise with a
solution of an alcohol (1-10 equivalents, preferably 1.0 - 1.1 equivalents)
and then the reaction is
stirred at 20 - 150 C (preferably about 40 C) until the aryl fluoride is
consumed. The reaction is
then cooled and concentrated then purified by extractive workup,
crystallization or
chromatography. Optionally, when one component of the coupling is protected,
the crude
material may be deprotected by hydrolysis during the extractive workup.
Exemplification of General Procedure P:
Preparation of (R)-3-{3-Chloro-4-[3-(3-chloro-4-isopropoxy-phenyl)-
[1,2,4]oxadiazol-5
-yl] -phenoxy}-propane-1,2-diol
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WO 2011/071570 PCT/US2010/046424
CI CI OH
O IO
CI NIN CI NN O OH
O O
A solution of 5-(2-chloro-4-fluorophenyl)-3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-oxadiazole
(6.25g, 17.02 mmol) in dry THF (75.00mL) is treated with NaH (1.225 g, 20.42
mmol) at room
temperature. Neat (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (2.330 mL, 18.72
mmol) is added
dropwise at RT and the reaction is heated at about 40 C for about 4 h. The
reaction is cooled to
RT and treated with 2 N HC1 (75 mL) and allowed to stir 3 days at RT. The
mixture was diluted
with ethyl acetate (200 mL) and washed with saturated NaCl solution (3 X 100
mL), dried over
sodium sulfate, filtered and concentrated. Further purification by
crystallization from ethyl
acetate and heptane yielded (R)-3-{3-Chloro-4-[3-(3-chloro-4-isopropoxy
phenyl)-
[1,2,4]oxadiazol-5 ylJphenoxy}propane-1,2-diol (5.94g, 79%) as a white solid.
LC/MS (Table
1, Method A) Rt = 2.60 min.; MS m/z: 498 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 6
8.15 (d, J
= 8.8, 1H), 8.05 (d, J= 1.3, 1H), 8.08 - 7.95 (m, 1H), 7.39 (d, J= 8.7, 1H),
7.33 (d, J= 2.2, 1H),
7.19 (dd, J= 8.9, 2.4, 1H), 5.05 (d, J= 5.2, 1H), 4.87 - 4.78 (m, 1H), 4.72
(t, J= 5.7, 1H), 4.20-
4.02 (m, 2H), 3.83 (m, 1H), 3.46 (m, 2H), 1.35 (d, J= 6.0, 6H).
General Procedure Q: Hydrolysis of an ester
A solution of an ester in an organic solvent such as THF, MeOH, 1,4-dioxane,
methanol, ethanol,
DMF or DMSO (preferably THF, MeOH or 1,4-dioxane) is treated with an aqueous
base (1-10
equivalents, preferably about 1 equivalent) such as NaOH, LiOH or KOH and the
mixture is
stirred at 20 - 100 C (preferably RT) until the reaction is complete. The
reaction is neutralized
with an acid such as HC1, H2SO4, or acetic acid (preferably HC1), cooled,
concentrated and
purified by extractive workup, crystallization or chromatography.
Exemplification of General Procedure Q:
Preparation of 3-{3-Chloro-4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]
oxadiazol-3-yl]-
phenoxy}-cyclobutanecarboxylic acid
0 O
O-N CI O O-N CI OH
J~J(
_
CI CI I \ ~N / O
N N
WO 2011/071570 PCT/US2010/046424
To a solution of (1r,3r)-ethyl 3-(3-chloro-4-(5-(5-chloro-6-isopropoxypyridin-
3-yl)-1,2,4-
oxadiazol-3-yl)phenoxy)cyclobutanecarboxylate (118mg, 0.240 mmol) in 1,4-
dioxane (2.00 mL)
is added 2N NaOH (0.359 mL, 0.719 mmol) and the mixture is stirred at RT for
about 3 hours.
The reaction is neutralized by addition of 2N HC1 (360 L) and the mixture is
concentrated. Re-
crystallization from ACN and water yielded 3-{3-Chloro-4-[5-(5-chloro-6-
isopropoxy pyridin-3-
yl)-[1,2,4]oxadiazol-3 ylJphenoxy}-cyclobutanecarboxylic acid (72 mg, 65%) as
a white solid.
LC/MS (Table 1, Method a) Rt = 3.13 min.; MS m/z: 465 / 467 / 469 (M+H)+. 'H
NMR (400
MHz, DMSO-d6) 6 12.38 (bs, 1H), 8.91 (d, J = 2.2, 1H), 8.53 (d, J = 2.2, 1H),
7.99 - 7.92 (m,
1H), 7.15 - 7.10 (m, 1H), 7.08 - 7.01 (m, 1H), 5.48-5.42 (m, 2H), 5.01-4.94
(m, 2H), 3.17 - 3.05
(m, 1H), 2.74 - 2.66 (m, 3H), 2.46 - 2.28 (m, 2H), 1.42 - 1.32 (d, 6H).
Exemplification of General Procedure Q:
Preparation of deuterated methyl 5-chloro-6-isopropoxynicotinate
CI COOMe CI .` ^ COOH
~~: J J7I~ ~Jl
O N NaOH/MeOH O N
D+CD3 D+CD3
CD3 CD3
Methyl 5-chloro-6-hydroxynicotinate (3.86 g) was dissolved in about 21 mL
methanol and about
2.1 mL water was added. 1.74 g sodium hydroxide was added to the solution. The
mixture was
heated to about 50 C and mixed well to dissolve all NaOH and the solution was
stirred for about
1 h at the same temperature. The aqueous methanol solution was extracted with
hexane (2X10
mL) and the aqueous layer was adjusted to pH 4 using 6N HC1. Methanol was then
removed by
concentration and the aqueous slurry was adjusted to pH-1 using HC1 in an ice
bath. The
resulting slurry was stirred for about 30 min then filtered and washed with
water. The product
was further purified by drying under vacuum. Yield 3.64 g. HPLC purity 98%,
9.404 min.
HPLC (Table 1, Method q)
General Procedure R: Mitsunobu coupling to a phenol
A solution of a phenol and alcohol (1-3 equivalents, preferably about 1.1
equivalents) in a solvent
such as THF or 1,4-dioxane (preferably THF) is treated with a phosphine (1-5
equivalents) such
as triphenylphosphine or resin-bound triphenylphosphine (preferably resin-
bound
triphenylphosphine) and optionally with 4A molecular sieves and the mixture is
cooled to about 0
C. A solution of an alkylazodicarboxylate (1-2 equivalents, preferably about
1.1 equivalents)
such as diethylazodicarboxylate, diisopropylazodicarboxylate, or di-tert-
butylazodicarboxylate
(preferably di-tert-butylazodicarboxylate) in a solvent such as THF or 1,4-
dioxane (preferably
THF) is added dropwise and then the reaction is warmed to 20-70 C (preferably
RT) with stirring
76
WO 2011/071570 PCT/US2010/046424
for 1-24 h (preferably about 18 h). The reaction is filtered, concentrated and
purified by
chromatography on silica gel or crystallization.
Preparation of 3-(3-Chloro-4-cyano-phenoxy)-cyclobutanecarboxylic acid tert-
butyl ester
N
O O
CI O CI O
OH HO o
A solution of 2-chloro-4-hydroxybenzonitrile (5.00 g, 32.6 mmol) and (ls,3s)-
tert-butyl 3-
hydroxycyclobutanecarboxylate (6.17 g, 35.8 mmol) in THE (220 mL) is treated
with 4-A
molecular sieves (10g) and Ph3P-resin bound (32.6 mL, 98 mmol) for about 20
minutes at RT,
then cooled to about 0 C. A solution of di-tert-butyl azodicarboxylate (8.25
g, 35.8 mmol) in
THE (30 mL) is added dropwise while maintaining the reaction temperature below
about 4 C.
The reaction was stirred about 15 min at about 0 C and then allowed to warm to
RT for about 18
h. The reaction was filtered and the solids rinsed with methanol (3 x 50 mL)
and the combined
organic solutions were concentrated. The residue was purified on a silica gel
column using a
gradient from 10-30% ethyl acetate in heptane. The product fractions were
combined and
concentrated to a clear, colorless oil which solidifies on standing to afford
3-(3-chloro-4-cyano-
phenoxy)-cyclobutanecarboxylic acid tert-butyl ester. . LC/MS (Method a) Rt =
2.75 min.; 1H
NMR (400 MHz, DM SO-d6) 6 7.87 (d, J = 8.7, I H), 7.19 (d, J = 2.4, I H), 6.99
(dd, J = 8.7, 2.4,
1H), 4.99-4.92 (m, 1H), 3.11-3.04 (m, 1H), 2.69-2.63 (m, 2H), 2.40 - 2.28 (m,
2H), 1.44 (s, 9H).
General Procedure S: Deprotection of phosphonate ester with or without
bromination
To a solution of phosphonate ester (0.9 - 1.2 equivalents, preferably 1.0
equivalents) in an
anhydrous organic solvent such as DCM, or THE (preferably DCM) is added
bromotrimethylsilane (1 - 20 equiv, preferably 10 equiv). The reaction mixture
is stirred for about
2- 72 h (preferably 2-16 h). The reaction mixture is concentrated under
reduced pressure.
Intermediates and final compounds prepared via this General Procedure can be
optionally purified
using one or more of the Purification Methods described above.
Exemplification of General Procedure S
Example S.1 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)propylphosphonic acid
77
WO 2011/071570 PCT/US2010/046424
OH
O O N-O -P
CI N N \--& N~z - N~ CI I / N NH OH
O
0
To a solution of diethyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-
yl)phenylamino)propylphosphonate (Table D, #50, 0.060 g, 0.12 mmol) in DCM
(1.2 mL) was
added bromotrimethylsilane (0.15 mL, 1.18 mmol). The reaction mixture was
stirred at RT for
about 16 h. The reaction mixture was concentrated under reduced pressure. The
material was
purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN; 5-100% B over about
30.0 min
(21.0 mL/min flow rate); 21.2 x 250 mm Thermo Hyperprep C18 column, 8 pm
particles) to give
3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)propylphosphonic acid
(0.035 g, 65%): LC/MS (Table 1, Method b) Rt = 1.83 min; MS m/z 452 (M+H)+.
General Procedure T: Preparation of benzylic olefin from ketone
A suspension of 1-3 equivalents sodium hydride (60% in mineral oil, preferably
1.6 equivalent) in
about 5 mL DMSO was heated at about 80-100 C (preferably about 80 C) for
about 15-30 min
(preferably 15 min). The mixture was cooled down to about 0-5 C in an ice-
bath, (4-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)triphenylphosphonium
chloride
(preferably 1 equivalent) was added in one portion, the reaction mixture was
stirred at RT for 30
min. A solution of ketone (preferably 1.2 equivalents) in DMSO was added
dropwise. The
reaction mixture was heated at about 80 C for about 12-120 h (preferably 64
h). After cooling
down, the mixture was poured into ice water, acidified by HCl (6N), extracted
by DCM or ethyl
acetate, the organic layer was washed by HCl (1N) and brine, dried over
magnesium sulfate,
filtration and concentration afford a crude product, which is further purified
by chromatography.
Exemplification of General Procedure T:
Preparation of ethyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzylidene)cyclobutanecarb oxylate
CI N O P'Ph3Cl O NaH CI N-~
JOCOZEt O
\ /1\ CO2Et
78
WO 2011/071570 PCT/US2010/046424
Sodium hydride (0.036 g, 0.900 mmol) was added in DMSO (5.6 mL) under nitrogen
to give a
white suspension. The mixture was heated at about 80 C for about 18 min. It
was cooled down to
RT, then the reaction mixture was cooled down to about 0-5 C by an ice-bath.
(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzyl)triphenylphosphonium chloride
(0.422 g, 0.675
mmol) was added in one portion, the ice-bath was removed and DMSO (2 mL) was
added. It was
stirred at RT for about 30 min, a solution of ethyl 3-
oxocyclobutanecarboxylate (0.08 g, 0.563
mmol) in DMSO (1.0 mL) was added dropwise over about 5 min. The reaction
mixture was
heated at about 80 C for about 64 h. The mixture was cooled down, poured into
stirring ice-cold
water (60 mL), HC1 (6N, 20 mL) was added, the mixture was extracted by DCM (2x
75 mL), the
combined DCM layer was washed by HC1 (1N, 40 mL), water (50 mL), brine (30
mL), dried over
magnesium sulfate, filtered and concentrated afford 505 mg orange oil, which
was purified via
AnalogixTM FCC (0% 5 min, 0-10% over 10 min, 10-15% over 15 min, 15% over 5
min
EtOAc/Heptane; 80 g Redi-Sep silica gel column) to afford ethyl 3-(4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)benzylidene)cyclobutanecarboxylate
(0.106 g, 0.234
mmol, 41.6 % yield) as white solid. LC/MS (Table 1, Method g) Rt = 2.07 min,
m/z 453.12
(M+H)+. 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.10 (d, J = 8.41 Hz, 2H), 8.04 (d, J
= 2.10 Hz,
1H), 7.98 (dd, J = 8.63, 2.12 Hz, 1H), 7.46 (d, J = 8.46 Hz, 2H), 7.37 (s,
1H), 6.31 (d, J = 2.27
Hz, 1H), 4.81 (dt, J = 6.0, 12.0 Hz, 1H), 4.11 (q, J = 7.10 Hz, 2H), 3.41-3.22
(m, 3H), 3.17-3.03
(m, 2H), 1.34 (d, J = 6.02 Hz, 6H), 1.20 (t, J = 7.10 Hz, 3H).
General Procedure U: Reduction of benzylic olefin
A high-pressure flask was charged with a benzylic olefin (1 equivalent) and
palladium on carbon
(preferably 0.25 equivalents in ethyl acetate). The resulting suspension was
stirred under an
atmosphere of hydrogen (14 Psi) at ambient temperature for about 30-90 minutes
(preferably 60
minutes). The mixture was filtered through Celite and the colorless filtrate
was concentrated to
afford the product.
Exemplification of General Procedure U:
Preparation of Ethyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)cyclobutanecarboxylate
N-0 N-O
CI I \ i \ _ CI N N
0 0
C02Et C02Et
79
WO 2011/071570 PCT/US2010/046424
Ethyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzylidene)cyclobutanecarboxylate (0.08 g, 0.177 mmol) and 10% palladium
on carbon
(0.047 g, 0.044 mmol) in EtOAc (8.83 mL) were added to give a black
suspension. The reaction
mixture was allowed to stir under an atmosphere of hydrogen balloon at RT for
about 1 h. The
reaction mixture was diluted with ethyl acetate and filtered, the filtrate was
concentrated and the
residue was used as is in next step. LC/MS (Table 1, Method i) Rt = 2.08 min,
m/z 455.14
(M+H)+.
General Procedure V: Hydrolysis of ester
A solution of ester (1 equivalent) in ethyl alcohol/1,4-dioxane was combined
with a solution of
potassium/sodium hydroxide (1-10 equivalents, preferably 10 equivalent) in
water, the mixture
was heated at about 100 C for about 16 h. The reaction mixture was cooled
down, partitioned
between aqueous ammonium chloride (1.0 M) and ethyl acetate, the organic
layers were washed
by water and concentrated in vacuo, the resulting in crude product which was
further purified by
chromatography.
Exemplification of General Procedure V:
Preparation of 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)cyclobutanecarboxylic acid
N-O N-O
CI N CI I \ ' N
O IO
COZEt OH
O
Ethyl 3 -(4-(3 -(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -yl)b enzyl)
cyclobutanecarboxylate
(0.08 g, 0.176 mmol) in EtOH (5 mL) was added to give a colorless solution. A
solution of
potassium hydroxide (0.099 g, 1.758 mmol) in water (2.5 mL) was added while
stirring. The
reaction mixture was heated at about 100 C for about 16 h. The reaction
mixture was cooled
down, partitioned between aqueous ammonium chloride (1M, 40 mL) and EtOAc
(2x35 mL), the
combined organic layers were washed by water (2x30 mL), concentrated to afford
80 mg grey oil,
which was purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN; 30-100% B
over
30.0 min (21.0 mL/min flow rate); 21.2 x 250 mm Thermo Hyperprep C18 column, 8
m
particles) to afford 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)cyclobutanecarboxylic acid (0.049 g, 0.112 mmol, 64% yield) as white
solid. LC/MS
(Table 1, Method g) Rt = 3.13 min, m/z 427.24 (M+H)+. 1H NMR (400 MHz, DMSO-
d6) 6 ppm
WO 2011/071570 PCT/US2010/046424
8.12 - 8.03 (m, 2H), 8.00 (dd, J= 8.6, 2.1, 1H), 7.46 (t, J= 8.4, 1H), 7.39
(d, J= 8.9, 1H), 4.88 -
4.77 (m, 1H), 3.13 - 3.02 (m, 1H), 2.97 - 2.82 (m, 1H), 2.77 (d, J= 7.5, 1H),
2.70 - 2.55 (m, OH),
2.27-2.14 (m, 1H), 2.00-1.83 (m, 1H), 1.35 (d, J= 6.0, 6H).
General Procedure W: Alkylation of a phenol
A solution of ester (1 equivalent) in ethyl alcohol/1,4-dioxane or toluene is
combined with a
solution of potassium/sodium hydroxide or Ag2CO3 (1-10 equivalents, preferably
10 equivalent)
in water, the mixture is heated at about 60-100 C for about 16-20 hours. The
reaction mixture is
cooled down, and the resulting crude product mixture can be further purified
by extractive workup
and/or chromatography.
Exemplification of General Procedure W: Preparation of methyl 5-chloro-6-
isopropoxynicotinate
O O
CI Oi CI O
HO N
~O N
Methyl 5-chloro-6-hydroxynicotinate (8.91 g, 47.5 mmol) and 2-iodo-propane
(7.12 mL, 71.2
mmol) were combined in toluene (202 mL) under nitrogen to give a colorless
solution. Silver
carbonate (19.65 g, 71.2 mmol) was added and the reaction heated at about 60
C for about 4 h.
TLC in 1:1 EtOAc/heptane showed (uv light visualization) that the reaction was
not yet complete.
The temperature was reduced to about 50 C and the reaction stirred for about
an additional 16 h.
The reaction was allowed to cool to ambient temperature. The mixture was
filtered through a
buchner funnel and washed through with ethyl acetate. The solvents were
removed under reduced
pressure. The residue was purified by flash column chromatography (120 g Redi-
Sep column)
eluting with 5% ethyl acetate/heptane and the product fractions combined. The
solvents were
removed under reduced pressure to provide methyl 5-chloro-6-
isopropoxynicotinate (10.539 g,
45.9 mmol, 97% yield) as a colorless oil that solidified under vacuum to a
white solid: LC/MS
(Method g) Rt = 2.84 min.; MS m/z: 230.05 (M+H) ; 1H NMR (400 MHz, CDC13) 6
ppm 8.71
(d, J = 2.02 Hz, 1H), 8.22 (d, J = 1.93 Hz, 1H), 5.53-5.42 (m, 1H), 3.94 (s,
3H), 1.44 (d, J = 6.20
Hz, 6H).
Exemplification of General Procedure W: Preparation of methyl 5-chloro-6-
deutero-
isopropoxynicotinate
81
WO 2011/071570 PCT/US2010/046424
0 0
CI I Oi DDDCI 0
HO N D O N
D
Methyl-5-chloro-6-hydroxynicotinate (3.15 g), toluene (70 mL) and deuterated
isopropyl iodide
(4.445 g) are added together at room temperature. Ag2CO3 (6.95 g) is then
added and the reaction
mixture is heated at about 60 C for about 20h. The solids are removed by
filtration and washed
with toluene (2x20 mL). The filtrate is concentrated to dryness and
redissolved in with methanol
followed by concentration each time (3X20 mL). HPLC purity 98%, 14.031 min.
HPLC (Table
1, Method q)
Tables Utilizing General Procedures
Table A. Examples made using General Procedures C, D, E (Scheme 2)
The letter in parentheses below the nitrile precursors indicates the General
Procedure by which
the nitrile precursor was made.
NHZ N-O
jN OH Acid or ~ / R'
NH2OH N~ Acid Chloride N
R R R
X General X General X
Procedure Procedure
C DorE
Acid or
Ex # Nitrite acid Product Name Rr/min m/z
precursor chloride (method)
3-amino- 5-(3-(3-chloro-
1-methyl- 4
3-chloro-4- isopropoxyphen
1H- N'O N, 334.10
A.1 isopropoxy pyrazole- cl N yl)-1,2,4- 2.59 (g)
benzonitrile 5 NH2 oxadiazol-5- (M+H)
(A) carboxyli o yl)-1-methyl-
c acid 1H-pyrazol-3-
amine
3-(3-chloro-4-
A.2 3-chloro-4- 1H- isopropoxyphen
isopropoxy- indole-5- N " yl)-5-(1H- 1.62 (c) 354
benzonitrile carboxyli indol-5-yl)- (M+H)
(A) c acid CI 1,2,4-
oxadiazole
82
WO 2011/071570 PCT/US2010/046424
Acid or
Ex # Nitrite acid Product Name Rr/min y~/z
precursor chloride (method)
2-methyl-
3- (1S,4R)-2-(3-
((1S,4R)
3 oxo 2- (3-(5-chloro-6-
(E)-5 0 isopropoxypyri
chloro N'- azabicycl N din 3 yl) 1,2,4
A.3 0[2.2.1]h N o 439
hydroxy 6 oxadiazol-5
eptan-2 N 3.26 (a)
isopropoxy yl)-2- (M+H)+
nicotinimid yl)benzoi methylphenyl)-
amide (A) c acid ci 2-
(Preparati azabicyclo[2.2.
on 1]heptan-3-one
#64,65,66
,67)
H1NMR
(DMSO-d)
6 ppm 8.50
(s, 1H),
3-[3-(3-Chloro- 8.41 (d,
4-isopropoxy- 1H), 8.17
phenyl) (s, 1H),
A.4 3-chloro-4- 3- N o _
i N 7.98 (dd,
sopropoxy- cyanoben 4.66 (g)
benzonitrile zoylchlor I cN [1,2,4]oxadiazo 1H), 7.88
(A) ide
ci 1-5-y1]- (d, 1H),
benzonitril 7.68 (t,
e 1H), 7.03
(d, 1 H),
4.67 (m,
1H), 1.42
(d, 6H)
83
WO 2011/071570 PCT/US2010/046424
Table B. Examples made using General Procedures C, D or E, G and H
NH OH Acid or N-O RZ
~N z I-OH acid chloride ~ /
R General R \ NHZ General ReN CN
Procedure
Procedure
C
D or E
R2 NaCN(BH4)3 N-O RZ R3
N-O RZ DIBAL NO
\ I NN\R
CN General R e N/ \ General
CHO Re
R
C"T" Procedure Procedure
Procedure Procedure
G H
Acid or Rt/mi
Ex Nitrile acid Amine Structure Name m/z n
# precursor chloride (meth
od)
1-(4-(3-
(3-
chloro-4-
isopropo
3-chloro- 4 pyrroli a N-O xyphenyl
B.1 4 cyanoben dine-3- cN ) 1,2,4 442.13 1.97
isopropo carbox N oxadiazol (M+H) zoyl xybenzon chloride Ylic Qr OH -5- + (g)
itrile acid 0 yl)benzyl
)pyrrolidi
ne-3-
carboxyli
c acid
3-amino-
1-(4-(3-
3-(tent- (3-
butoxy chloro-4-
3-chloro- carbon a N-O isopropo
_
4- ylamin IN xyphenyl 457.14
4- 0-Y opo cyanoben o)pyrro N )-1,2,4- (M+H) 1.94
B.2 isopr
zoyl lidine- NHz oxadiazol (g)
xybenzon chloride 3- OH -5- +
itrile) carbox 0 yl)benzyl
ylic )pyrrolidi
acid ne-3-
carboxyli
c acid
1-((4-(3-
4-(4- 1- (4-(4-
fluoropip (amino fluoropip
eridin-l- 4- methyl eridin-l- 519.17
B.3 yl)-3- cyanoben )cyclop F N yl)-3-
OH (M+H) 2.18
(trifluoro zoyl ropane H ~' H o (trifluoro + (g)
methyl)b chloride carbox methyl)p
enzonitril ylic henyl)-
e acid 1,2,4-
oxadiazol
84
WO 2011/071570 PCT/US2010/046424
Acid or Rt/mi
Ex Nitrile acid Amine Structure Name m/z n
# precursor chloride (meth
od)
-5-
yl)benzyl
amino)m
ethyl)cyc
lopropan
ecarboxy
lic acid
(S)-1-(4-
(3-(3-
chloro-4-
isopropo
3-chloro- (~ 4- pyrroli of N-o xyphenyl
4 " )-1 2 4- 442.12
B.4 cyanoben dine-3- ' ' 1.97
isopropo oxadiazol (M+H)
xybenzon zoyl ri carbox OH -5- + (g)
itrile acid ad"o yl)benzyl
c
)pyrrolidi
ne-3-
carboxyli
c acid
(R)-1-(4-
(3-(3-
chloro-4-
isopropo
3-chloro- (R) 4- pyrroli of N-o xyphenyl
4 )-1,2,4- 442.08
B.5 cyanoben dine-3- 1.97
isopropo " oxadiazol (M+H)
xybenzon zoyl carbox a."#-OH -5- + (g)
itrile chloride ylic y1 )
ben l
acid )pyrrolidi
ne-3-
carboxyli
c acid
(S)-1-(4-
(3-(3-
chloro-4-
isopropo
3-chloro- 4- azetidi xyphenyl
B.6 4-
c anoben ne-2 O1 N n 'o )-1,2,4- 428.11( 1.96
isopropo y o "~ oxadiazol
xybenzon zoyl carbox off 5
itrile ac M+H)+ (g)
chloride y ic
acid yl)benzyl
)azetidin
e-2-
carboxyli
c acid
F
4-(4- 4- (R)- F N o (R) -I (4
B.7 fluoropip cyanoben pyrroli ~N ~, " (3 (4 (4 519.10( 2.10
eridin-l- zoyl dine-3- (") fluoropip M+H)+ (g)
yl)-3- chloride carbox o H eridin-l-
WO 2011/071570 PCT/US2010/046424
Acid or Rt/mi
Ex Nitrile acid Amine Structure Name m/z n
# precursor chloride (meth
od)
(trifluoro ylic yl)-3 -
methyl)b acid (trifluoro
enzonitril methyl)p
e henyl)-
1,2,4-
oxadiazol
-5-
yl)benzyl
)pyrrolidi
ne-3-
carboxyli
c acid
(S)-1-(4-
(3-(4-(4-
fluoropip
eridin-l -
4-(4- yl)-3-
fluoropip (S)- (trifluoro
eridin- I - 4- pyrroli F
" N o methyl)p
B.8 yl)-3- cyanoben dine-3 -0 henyl)- 519.09( 2.10
(trifluoro zoyl carbox"~ 1,2,4- M+H)+ (g)
methyl)b chloride ylic ` oro" oxadiazol
enzonitril acid -5-
e yl)benzyl
)pyrrolidi
ne-3-
carboxyli
c acid
1-(4-(3-
(4-(4-
fluoropip
eridin-l -
4-(4- yl)-3-
fluoropip 1- (trifluoro
eridin- I- 4- aminoc F F N o o methyl)p
B.9 yl)-3- cyanoben yclopro F ~N No henyl)- 505.08( 2.21
(trifluoro zoyl panecar F_CN 1,2,4- M+H)+ (g)
methyl)b chloride boxylic oxadiazol
enzonitril acid -5-
e yl)benzyl
amino)cy
clopropa
necarbox
ylic acid
86
WO 2011/071570 PCT/US2010/046424
Ex # Nitrile Acid or Name m/z
precursor acid Amine Structure ESI Rt
chloride (M+H)/ min
(M-H)
1-(4-
{3-[4-
(4-
Fluoro-
piperid
in-1-yl
)-3-
trifluor
3 -chloro- omethy
4- 4 Cyclop 1- 493.1
cyanoben phenyl] M+H 1.66
B.10 isopropo zoyl ropyl -[1,2,4] (m)
xybenzon n chloride glycine oxadia
zol-5-
yl}-
benzyl
amino)
-cyclop
ropane
carbox
ylic
acid
1-(4-
{3-[4-
(4-
Fluoro-
piperid
in-1-yl
-3-
trifluor
omethy 1.75
3-chloro-
4 4- Pyrroli C hen 1 519.1 (m)
M+H
isopropo cyanoben dine-3- o Y -[112,4]
zoyl carbox
B.11 xybenzon chloride ylate oxadia
itrile zol-5-
yl}-
benzyl)
pyrroli
dine
-3-
carbox
ylic
acid
87
WO 2011/071570 PCT/US2010/046424
Ex # Nitrile Acid or Name m/z
precursor acid Amine Structure ESI Rt
chloride (M+H)/ min
(M-H)
1-(4-
{3-[4-
(4-
Fluoro-
piperid
in-1-yl
)-3-
trifluor
omethy 1.73
3-chloro- PYrroli I N 1 (m)
4- dine-4 N No- phenyl]
4
iso cyanoben methyl N -[1,2,4] 533.1
propo
B.12 xybenzon chloride carbox oxadia M+H
itrile ylate y1}-
benzyl)
-4-
methyl
-py
rrolidin
e-3-
carbox
ylic
acid
(4-{3-
[4-(4-
Fluoro-
piperid
in-l-
yl)-
3-
HO, 477.1 1.71
3-chloro- 4 ~~ omethy M -H (m)
4 cyanoben Glycin 1
isopropo zo 1 e phenyl]
xybenzon y -
B.13 itrile chloride 1 2 4
[ õ ]
ox
adiazol
-5-yl}-
benzyl
amino)
-acetic
a
cid
88
WO 2011/071570 PCT/US2010/046424
Ex # Nitrile Acid or Name m/z
precursor acid Amine Structure ESI Rt
chloride (M+H)/ min
(M-H)
(4-{3-
[4-(4-
Fluoro-
piperid
in
-1-yl)-
3- 1.72
3-chloro- - trifluor 533.1 (m)
4 4- pyrroli omethy M+H
p p cyanoben din-2- ~ 1-
iso ro o
zoyl yl yl- F phenyl]
B.14 xybenzon chloride acetic F -[1
itrile acid ,2,4]ox
adiazol
-5-yl}-
benzyl)
-pyrrol
idin-2-
yl]-
acetic
acid
[1-(4-
{3-[4-
(4-
Fluoro-
piperid
in-1-y
1)-3-
trifluor 1.75
3 chloro 4 (1 H~, omethy 491.1 (m)
4- amino M+H
isopropo cyoben cyclopr phenyl]
-[1,2,4
B.15 xybenzon zOchloride opyl)m ]oxadia
itrile ethanol
zol-5-
yl}-
benzyl
amino)
-cyclo
propyl]
methan
of
89
WO 2011/071570 PCT/US2010/046424
Ex # Nitrile Acid or Name m/z
precursor acid Amine Structure ESI Rt
chloride (M+H)/ min
(M-H)
1-(4-
{3-[4-
(4-
Fluoro-
piperid
in-1-yl
)-3-
trifluor
omethy
4,4- H0 1- 1.78
3-chloro- 4_ dimeth o ~F phenyl] 547.1 (m)
4- yl- -[1,2,4] M+H
B.16 isopropo cyanoben
zoyl pyrroli F F oxadia
xybenzon chloride dine-3- zol-5-
itrile carbox y1}-
ylate benzyl)
-4,4-
dimeth
y
1-
pyrroli
dine-3-
carbox
ylic
acid
1-[(4-
{3-[4-
(4-
Fluoro-
piperid
in-1-y
1)-3-
trifluor 1.71
3-chloro- 1- omethy 491.1 (in)
4 OH
amino 1 M+H B.18 isopropo cyanoben methyl N FT phenyl]
xybenzon zoyl cyclopr -[1,2,4
itrile chloride opanol ]oxadia
zol-5-
yl}-
benzyl
amino)
-methy
1]-
cyclopr
opanol
WO 2011/071570 PCT/US2010/046424
Table C. Examples made using General Procedures C, D or E, I or J and K
NH OH Acid or N-O
R N 2 R N-OH acid chloride R i
General \ NH N
Procedure z General NH
Procedure
C D or E
R i X / I/ X
N-O TtH VN0 - TFA R N'O
\ General / X General I \ N /
Procedure \ N, Procedure \ N,RI
I or J F2 K CO2H
CO2tBu
Acid or tert-
Ex acid butyl Structure Name m/z min
# precursor curs chloride ester (method)
4-(4-(3-
(3-
chloro-4-
tert-
N-0 isopropo
3-chloro- 1H butyl
4 indole-4- 4- xyphenyl 440 2.95
C.1 isopropo o N off )-1 2 4
xybenzon carboxyli brom c, oxadiazol (M+H) (a)
itrile c acid obut-5-yl)-1H
noate -indol- l -
yl)butano
is acid
3-(4-(3-
(3-
chloro-4-
tert- isopropo
3-chloro- 1H- butyl N_o xyphenyl 4 indole-4- 2 v v ) 1'2'4_
444 2.19
C.2 isopropo F ox-yl)-l
carboxyli fluor QN H 5 (M+H)+ (a)
xybenzon c acid oacry ci o 5 yl)
itrile late 1H-indol-
l-yl)-2-
fluoropro
panoic
acid
3-(4-(3-
(3-
chloro-4-
isopropo
3-chloro- 1H tert- N-O xyphenyl
4 butyl v N )-1,2,4-
C.3 iso ro o indole-4- meth 442 2.47
/ II OH
xybenzon carboxyli acryl ci \ N o oxadiazol (M+H)+ (a)
itrile c acid ate 1H-indol-
1-yl)-2-
methylpr
opanoic
acid
91
WO 2011/071570 PCT/US2010/046424
Acid or tert-
Ex acid butyl Structure Name m/z min
# precursor curs chloride ester (method)
3-(4-(3-
(3-
ethyl chloro-4-
3- isopropo
3-chloro- chlor 0 xyphenyl IH- 4 indo e-4- o- " N )-1,2,4- 454 3.11
)0 Y( oH oxadiazol
C.4 isopropo yli 2,2- "
xybenzon carboxyli
0I ~ 0( -5-yl)-
itrile (a)
itrile c acid hylpr 1H-indol-
opan 1-yl)-2,2-
oate dimethyl
propanoi
c acid
3-(4-(3-
(3-
chloro-4-
isopropo
xyphenyl
3-chloro- 1H- tent N- )-1,2,4-
-
4 " - " oxadiazol
indole-4- butyl I 427 2.84
C.5 isopropo carboxyli acryl OH -5-yl)- (M+H)+ (a)
xybenzon c acid ate a 1H-
itrile pyrrolo[2
,3-
b]pyridin
-1-
yl)propan
oic acid
92
WO 2011/071570 PCT/US2010/046424
Table D. Examples made using General Procedures C, D or E and L
NH OH Acid or N-o
R iN R N-OH acid chloride R
General NH,
F
I \ N \ /
Procedure , General
C Procedure
D or E
R N-0 K2CO3 R H
iN 11~~ F N N
General
Procedure
L
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
(1R,3S)-3-
{4-[3-(5-
Chloro-6-
4- (1R 3S) isoprop
Chloro Fluoro- -3- o oxy-
-6-
2- aminoc N pyridin-3-
/
D.1 isoprop YD-[1 2 4] 458 3.29
methyl- yclope o N N ' ' (M- ( )
oxy- ~H oxadiazol- a
H)
nicotin benzoyl ntaneca a 5 yl] 3
onitri chlorid rboxyli
e c acid methyl-
le phenylamin
o} -cyclope
ntanecarbo
x lic acid
4-(4-(3-(3-
chloro-4-
3- 4- isopropoxy
chloro- 4- amino- N-o phenyl)-
4 fluorob 3,3- c 1,2,4- 444
D.2 isoprop enzoyl dimeth 1 N H off oxadiazol (M 2.84
oxyben chlorid ylbutan 0 5-yl)pheny H)+
zonitril e oic lamino)-
e acid 3,3-
dimethylbu
tanoic acid
4-(4-(3-(3-
3 Chloro-4-
chloro- 4- N-o isopropoxy
4 fluorob 4 c1 1 N NH phenyl) 416.1
D.3 aminob I 1,2,4- 7 2.81
isoprop enzoyl utanoic OH oxadiazol- (M+ (g)
oxyben chlorid acid 5-yl) H)+
zonitril e
phenylamin
e
o)butanoic
acid
93
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
1-(4-(3-(3-
chloro-4-
3- isopropoxy
chloro- 4- pyrroli N phenyl)-
D.4 4- fluorob dine-3- Cl H 1,2,4- 428.7
isoprop enzoyl carbox o oxadiazol- (M+ 2.87 (g)
oxyben chlorid ylic 5-yl) H)+
zonitril e acid phenyl)pyrr
e olidine-3 -
carboxylic
acid
2-(1-(4-(3-
(3-chloro-
3- 4-
chloro- 4- 2- NO Na o isopropoxy
D.5 4- fluorob (pyrroli Cl OH phenyl) 448.1 3.08
isoprop enzoyl din-3- O 1,2,4-
oxyben chlorid yl)aceti oxadiazol- (M+ (g)
zonitril e c acid 5-yl) H)
e phenyl)pyrr
olidin-3-yl)
acetic acid
(1R,3S)-3-
(4-(3 -(3 -
bromo-4-
3- (1R,3S) isopropoxy 486.1
bromo- 4- -3- N
11 ,o NH phenyl)- 9 &
D.6 4- fluorob aminoc Br N 1,2,4- 488.1 3.01
isoprop enzoyl yclope o oxadiazol- 2
oxyben chlorid ntaneca OH 5- (M+ (g)
zonitril e rboxyli yl)phenyla H)+
e c acid mino)cyclo
pentanecar
boxylic
acid
(1R,3S)-3-
(4-(3-(4-
isopropoxy
4- (1R,3S) 3
N,o (trifluorom 476.2
isoprop fluorob aminoc F H N NH ethyl)phen 8
D.7 oxy-3-
(trifluo enzoyl yclope o &,;~ OH yl) oxa-1,2,4diazol- (M+ 2.98
rometh chlorid ntaneca OH H) (g)
yl)benz e rboxyli 5
onitrile c acid yl)phenyla
mino)cyclo
pentanecar
boxylic
acid
94
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
(1R,3S)-3-
(4-(3-(5-
chloro-6-
5- (1R,3S) isopropoxy
chloro- 4- -3- N"o _ pyridin-3-
6- fluorob aminoc N L N NH yl)-1,2,4- 443 1.58
D.8 isoprop enzoyl yclope oxadiazol- (M+
(a)
oxynic chlorid ntaneca Cl ro 5- H)+
otinoni e rboxyli OH yl)phenyla
trile c acid mino)cyclo
pentanecar
boxylic
acid
(R)-1-(4-
(3-(3-
3- chloro-4-
chloro- 4- (R)- N-0 isopropoxy
4- fluorob pyrroli N N phenyl)- 399 1.98
D.9 isoprop enzoyl _ ~NH2 1,2,4- (M+
oxyben chlorid din-3 ~O oxadiazol- H)+ (a)
zonitril e amine Cl 5-
e yl)phenyl)p
yrrolidin-3-
amine
(1R,25')-2-
(1R 2S) (4-(3-(3-
chloro-4-
3- 2 isopropoxy
chloro- 4- aminoc
yclope N-0 phenyl)-
D.1 4- fluorob
ntaneca N NH o 1,2,4- 442 2.82
0 isoprop enzoyl ~Lo oxadiazol- (M+
oxyben chlorid rboxyli I0-9 H 5- H)+ (a) c acid, zonitril e hydro, o
yl)phenyla
e hloric mino)cyclo
acid pentanecar
boxylic
acid
(1S,2R)-2-
(1S,2R) (4-(3-(3-
-2- chloro-4-
3-
chloro- 4- aminoc isopropoxy
yclohe N-O o phenyl)-
D.1 4 fluorob 456
N ~ / ~~OH 1
1 isoprop enzoyl xanecar P '2'4- (M+ 2.94
oxyben chlorid boxylic o oxadiazol- H)+ (a)
zonitril e acid, Cl 5-
hydroc yl)phenyla
e hloric mino)cyclo
acid hexanecarb
ox lic acid
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
#
precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
(S)-1-(3-(4-
(3-(3-
3- (S)-1- chloro-4-
chloro- 4- (3- isopropoxy
D.1 4- fluorob aminop ' N \ phenyl) 441
N
2 isoprop enzoyl yrrolidi NH 1'2'4 (M+ 2 62
oxyben chlorid n-1- Cl ON oxadiazol- H)+ (a)
zonitril e yl)etha
e none yl)phenyla
mino)pyrro
lidin-l-
yl)ethanone
(1R,2R)-2-
(4-(3 -(3 -
3- (1R,2R chloro-4-
chloro- 4- )-2- N-O isopropoxy
D.1 4- fluorob aminoc v N / N" off phenyl)- 456 - 2.88
3 isoprop enzoyl yclohe ~ L5 1,2,4 (M+ ( (a)
a)
oxadiazol-
oxyben chlorid xanecar Cl 5 H)
zonitril e boxylic
e acid yl)phenyla
mino)cyclo
hexanecarb
oxylic acid
(1R,2S)-2-
(4-(3 -(3 -
3- (1R,2S) chloro-4-
chloro- 4- -2- isopropoxy
D.1 4- fluorob aminoc "-O, 0- phenyl)
N \ / NH OH 1,2,4- 456 2.94
4 isoprop enzoyl yclohe O (M+
oxyben chlorid xanecar c oxadiazol- H)+ (a)
zonitril e boxylic
e acid yl)phenyla
mino)cyclo
hexanecarb
oxylic acid
(1R,2S)-2-
(4-(3 -(3 -
chloro-4-
3 N_ isopropoxy
chloro 4 2- N \ NH 1-OH phenyl)-
aminoc 1,2,4-
D. 1 4- fluorob O 456
isoprop enzoyl yclohe Cl oxadiazol- (M+ 2.94 xanecr oxyben chlorid boxylac v
" \ N" cH yl)phenyla H)+ (a)
zonitril e acid mino)cyclo
e Cl
hexanecarb
oxylic acid
compound
with
96
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
(1S,2R)-2-
(4-(3 -(3 -
chloro-4-
isopropoxy
phenyl)-
1,2,4-
oxadiazol-
5-
yl)phenyla
mino)cyclo
hexanecarb
oxylic acid
L:1
(1R,2R)-2-
(4-(3 -(3 -
chloro-4-
isopropoxy
phenyl)-
1,2,4-
oxadiazol-
5-
yl)phenyla
mino)cyclo
3 _ N-O o hexanecarb
Chloro- 4- 2 N \/' NH OH oxylic acid
D.1 4- fluorob aminoc compound 456
yclohe Cl 2.88
)
6 isoprop enzoyl xanecar N-o with (M+ ( a
oxyben chlorid boxylic NH 0OH (1S,2S)-2- H)+
zonitril e acid 'JIo 'qAN (4-(3-(3-
e Cl chloro-4-
isopropoxy
phenyl)-
1,2,4-
oxadiazol-
5-
yl)phenyla
mino)cyclo
hexanecarb
oxylic acid
L:1
(1S,2R) (1S,2R)-2-
3- -2- (4-(3-(3-
chloro- 4- aminoc chloro-4-
D. 1 4- fluorob yclope N-o 0 isopropoxy 442
,_
ntaneca N / "oH phenyl)- 2.83
7 isoprop enzoyl rboxyli Jo 1,2,4- (M+ + (a)
oxyben chlorid H)
zonitril e c acid, Cl oxadiazol-
Hydroc 5-
e hloric yl)phenyla
Acid, mino)cyclo
97
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
0.5H2 pentanecar
O boxylic
acid
(1S,2S)-2-
(4-(3 -(3 -
3- (15,25) chloro-4-
chloro- 4- -2- isopropoxy
D.1 4- fluorob aminoc N-O o phenyl)- 456
N / N.H OH 1,2,4-
8 isoprop enzoyl yclohe \ (M+ 2.88
oxyben chlorid xanecar Cl oxadiazol- H)+ (a)
zonitril e boxylic
e acid yl)phenyla
mino)cyclo
hexanecarb
ox lic acid
(S)-N-(4-
(3-(3-
chloro-4-
3- (S)-1- isopropoxy
chloro- 4- (methy o phenyl)-
D.1 4- fluorob lsulfon N N / NH 1'24- 477
9 isoprop enzoyl yl)pyrr \ (M+ 2.78
oxyben chlorid olidin- Cl ON ~'c yl)phenyl)- H)+ (a)
zonitril e 3
e amine 1-
(methylsulf
onyl)pyrrol
idin-3-
amine
(S)-2-(3-(4-
(S)-2- (3-(3-
chloro-4-
3- (3 aminop isopropoxy
chloro- 4 y - o phenyl)-
D.2 4- fluorob n N NH 1,2,4- 457
2.15
0 isoprop enzoyl O oxadiazol- (M+
oxyben chlorid yl)aceti C N0 5- H)+ (a)
zonitril e c acid, o H yl)phenyla
e roaceti mino)pyrro
c Acid lidin-l-
yl)acetic
acid
3 (1R 3S) (1R,3S)-3-
chloro- 3 ovoff (2 bromo
D 2 4- bromo- amnoc 4-(3-(3- 522
1 isoprop 4 clo e N'-O- chloro-4- (M+ 3.31
oxyben fluorob y p a &Zr N NH isopropoxy O+ (g)
zonitril enzoic ntaneca phenyl)-
e e acid b acid roxyli 0 1,2,4-
(Gener oxadiazol-
98
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
al 5-
Proced yl)phenyla
ure A) mino)cyclo
pentanecar
boxylic
acid
(1R,3S)-3-
(2-bromo-
3-(3-(3-
chloro-4-
ch oro- 2 (1R3- isopropoxy
bromo- N_ phenyl)-
D.2 4- aminoc
3.17
2 isoprop 3 yclope a o 1,2 ,4 M+
oxyben fluorob ntan c a ~o Br HN,,. OH oxadiazol- ( H)+ (g)
zonitril enzoic rboxyli
e (A) acid c acid yl)phenyla
mino)cyclo
pentanecar
boxylic
acid
(1R,3S)-3-
(5-(3-(3-
chloro-4-
3 (1R,3S) ovoH isopropoxy
phenyl)-
D.2 -3- =
D.2 4- 6-
aminoc N "o 1'2'4 443.1
chloron oxadiazol 2.61
3 isoprop
N NH 7(M+ (g)
icotinic yclope Cl
oxyben ntaneca I N 5 H) +
zonitril acid rboxyli C e
c acid 2
ylamino)cy
clopentane
carboxylic
acid
(1R,3S)-3-
(4-(3 -(3 -
chloro-4-
3- (1R,3S) isopropoxy
chloro- -3- phenyl)-
D.2 4- 2 aminoc Cl N-0 , o 1'2'4 443.1
fluorois N oxadiazol- 2.73
4 isoprop yclope aH 6(M+
oxyben onicoti ntaneca C 0 HN 5- H)+
nic acid rboxyli yl)pyridin
zonitril (g)
e c acid 2
ylamino)cy
clopentane
carboxylic
acid
99
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
(3S)-3-(4-
(3-(3-
(3S)- chloro-4-
methyl isopropoxy
3-
chloro- 4- 3- o phenyl)-
D.2 4- fluorob amino- OH 1,2,4- 456.1 3.02,
1- N-o oxadiazol-
isoprop enzoyl C, N - NH 3(M+ 3.14
oxyben chlorid methyl 5- H)+ (g)
zonitril e cyclop o yl)phenyla
entanec mino)-1-
e arboxyl methylcycl
ate opentaneca
rboxylic
acid
2-((1R,3S)-
3-(4-(3-(3-
2- chloro-4-
chloro3- 4- ((1R,3S isopropoxy
D.2 4- fluorob ) 3 N-o phenyl)- 456.1
6 isoprop enzoyl aminoc Cl N i "" 0 1,2,4- 3(M+ 3.04
oxyben chlorid yclope ~oN oxadiazol- H)+ (g)
zoniti l e ntyl)ac 5-
etic yl)phenyla
e
acid mino)cyclo
pentyl)aceti
c acid
(1S,3S)-3-
(4-(3 -(3 -
(3S)- chloro-4-
3 methyl isopropoxy
chloro- 4- 3- o phenyl)-
D.2 4- fluorob amino OH 1,2,4- 456.1
1- N-o oxadiazol- 3.02
7 isoprop enzoyl methyl Cl N N" 5 3(M+
(g)
oxyben chlorid
zonitil e cyclop O yl)phenyla H)+
entanec mino)-1-
e arboxyl methylcycl
ate opentaneca
rboxylic
acid
(3S)- (1R,3S)-3-
3 methyl (4-(3-(3-
3- chloro 4 0 chloro-4-
chloro- isopropoxy
D.2 4- fluorob 456.1
1- N -'O phenyl)- 3(M+ 3.15
8 isoprop enzoyl methyl o' N \ / N" 1,2,4- (g)
oxyben chlorid
H)+
zonitril e cyclop O oxadiazol-
entanec - 5-
e arboxyl yl)phenyla
ate mino)-1-
100
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
methylcycl
opentaneca
rboxylic
acid
(3S)-3-(4-
(3-(3-
(3S)- chloro-4-
methyl isopropoxy
3 phenyl)-
D.2 ch4ro 3- o fluorob amino- OH 1,2,4- 460.1
1- N-O oxadiazol- 2.29
9 isoprop enzoyl Cl N NH 1(M+
~~' oxyben chlorid fluoroc 5 H)+ (g)
zoniti l e yclope o yl)phenyla
ntaneca mino)-1-
e rboxyla fluorocyclo
to pentanecar
boxylic
acid
(3S)-3-(4-
(3-(3-
(3S)- chloro-4-
methyl isopropoxy
3 3- phenyl)-
chloro- 4- o
D.3 4- fluorob amino , N \ NH 1'2'4
oxa 458.0 2.35,
1 diazol
0 isoprop enzoyl h drox Q H 5 9(M+ 2.39
oxyben chlorid ycyclooH yl)phenyla H)+ (g)
zonitril e
pentan mino)-1-
e ecarbo hydroxycyc
xylate lopentanec
arboxylic
acid
(1R,3S)-3-
(3-chloro-
4-(3-(3-
3- 2- (1R,3S) chloro-4-
chloro- chloro- -3- Cl isopropoxy
N phenyl)- 476.1
D.3 4- 4- aminoc NH
1 isoprop fluorob yclope clN 1,2,4- 4 3.13
oxyben enzoyl ntaneca o i oxadiazol- (M+ (g)
zonitril chlorid rboxyli OH 5- H)
e e c acid yl)phenyla
mino)cyclo
pentanecar
boxylic
acid
D.3 3- 2- (1R,3S) N_0 o (1R,3S)-3- 522.1
2 bromo- chloro- -3- Br L N N" (4-(3-(3- 4 3.17
4 4 aminoc O.,,,ro bromo-4- (M+ (g)
isoprop fluorob yclope OH isopropoxy H)+
101
WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
oxyben enzoic ntaneca phenyl)-
zonitril acid rboxyli 1,2,4-
e c acid oxadiazol-
5-yl)-3-
chlorophen
ylamino)cy
clopentane
carboxylic
acid
(1R,3S)-3-
(3-bromo-
4-(3-(3-
(1R 3S) chloro-4-
ch oro- 2- e isopropoxy
bromo- N-0 phenyl)- 522.1
D.3 4- aminoc
4- Cl N "-" 1,2,4- 4 2.88
3 isoprop fluorob yclope oxadiazol- (M+ (h)
oxyben enzoic ntaneca OH H)+
zonitril acdrboxyli y1)p hen y
la
e c acid mino)cyclo
pentanecar
boxylic
acid
(1R,3S)-3-
(4-(3 -(3 -
4 chloro-4-
3- fluoro- (1R,3S) isopropoxy
chloro- 3- -3- F F phenyl)-
D.3 4- (trifluor aminoc "-o F 1,2,4- 508.1
i , NH oxadiazol- 3 3.35
4 isoprop omethy yclope ci , \ / 5-yl)-2- (M- (g)
oxyben 1)benzo ntaneca 0"'e
zonitril yl rboxyli (trifluorom H)
e chlorid c acid ethyl)phen
ylamino)cy
e
clopentane
carboxylic
acid
4- (1R,3S)-3-
Phenyl (4-(3-(4-
-5- phenyl-5-
(trifluo (1R,3S) (trifluorom
rometh 4- -3- "-o ethyl)thiop
D.3 yl)thio Fluoro- aminoc F F s N hen-2 yl) 500.1 3.22
phene- benzoyl yclope F a., 1,2,4-
2- chlorid ntaneca OH oxadiazol- H))+ (g)
carbon e rboxyli 5- H
trile c acid yl)phenyla
(Prepar mino)cyclo
ation pentanecar
#82) boxylic
102
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Nitrile Acid
#
precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
acid
(laS,5a (S)-3-{4-
R)
[3-
1,1,2
Trimet ((laS,SaR)-
- 1,1,2-
hyl
1 hyl-
(1R,3S) ,1a,5,5a-
tetrahy 4- -3- tetrahydro-
tetrahy N-o 3-thia- 450.1
D.3 dro-3- Fluoro- aminoc NH
6 thia- benzoyl yclope N cyclopropa 5 3.31
cyclopr chlorid ntaneca " s[a]pentalen (M+ (g)
opa[a] e rboxyli OH -4-yl)- H) [1,2,4]oxad
pentale c acid
ne-4- iazol-5-yl]-
carboni phenylamin
trile o}-
(Prepar cyclopenta
ation necarboxyli
#83 c acid
(1R,3S)-3-
5- (4-(3-(5-
chloro- chloro-6-
6- 4- (1R,3S) isopropoxy 457.0
isoprop Fluoro -3- N-0 pyridin-3- 9
D.3 aminoc NH yl)-1,2,4-
oxynic 3 ci N 459.0 3.39
7 yclope ~ oxadiazol- 9
otinoni methyl ntaneca ~o N 5-yl)-2- (g)
trile benzoic rboxyli OH methylphen (M+
(Prepar acid c acid ylamino)cy H)
ation
#85) clopentane
carboxylic
acid
(1R,3S)-3-
(4-(3 -(3 -
4 chloro-4-
3- fluoro- (1R 3S) isopropoxy
chloro 2 3- ti H phenyl)-
D.3 4- (trifluor aminoc F3C 1,2,4
N"O oxadiazol- 510 3.02
8 isoprop omethy yclope Cl NH (M+
oxyben 1)benzo ntaneca 5-yl)-3- H)+ (g)
zonitril yl rboxyli (trifluorom
e chlorid c acid ethyl)phen
e ylamino)cy
clopentane
carboxylic
acid
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Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
(1R,3S)-3-
(4-(3-(5-
(Z)-5- 4- chloro-6-
chloro- fluoro- (1R,3S) isopropoxy
N'- 2- -3- OOH pyridin-3-
yl)-1,2,4-
D.3 hydrox (trifluor aminoc F3C 511
oxadiazol- 3.16
9 y-6- omethy yclope "" - (M+
isoprop 1)benzo ntaneca NH (trifluorom H)+ (g)
oxynic yl rboxyli o N ethyl)phen
otinimi chlorid c acid
damide e ylamino)cy
clopentane
carboxylic
acid
(1R,3S)-3-
(4-(3 -(3 -
chloro-4-
3- 4- (1R,3S) o off isopropoxy
chloro- fluoro- -3- phenyl)-
D.4 4- 2- aminoc N_o 1,2,4- 456
0 isoprop methyl yclope Cl N NH oxadiazol- (M+ 3.05
oxyben benzoyl ntaneca 5-yl)-3- H)+ (g)
zonitril chlorid rboxyli methylphen
e e c acid ylamino)cy
clopentane
carboxylic
acid
(1R,3S)-3-
(4-(3 -(3 -
chloro-4-
3- 4- (1R,3S) isopropoxy
chloro- fluoro- -3- H phenyl)-
D.4 4- 3- aminoc 1,2,4- 456
1 isoprop methyl yclope "~O oxadiazol (M+ 3.12
N N" 5-yl)-2- H)+ (g)
oxyben benzoyl ntaneca ~~ ) 12,
zonitril chlorid rboxyli o methylphen
e e c acid ylamino)cy
clopentane
carboxylic
acid
4- 4-(4-(3-(3-
3 amino- chloro-4-
chloro- 4- 2 isopropoxy
D.4 4- fluorob methyl N-o phenyl)- 430
2 isoprop enzoyl butanoi 'N ,NOH 1,2,4- (M+ 2.91
oxyben chlorid c acid o oxadiazol H)+ (g)
zonitril e (Prepay 5-
ation yl)phenyla
e #79- mino)-2-
81) methylbuta
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WO 2011/071570 PCT/US2010/046424
Nitrile Acid
Ex precurs chlorid Amine Structure Name m/z Rt/min
# (method)
or e
noic acid
tent-butyl
3- 2-(4-(3-(3-
chloro- 4- glycine chloro-4-
D4 4- fluorob tert N-0 isopropoxy
444
3 isoprop enzoyl butyl Cl N H 0 phenyl) (M+ 2.980)
oxyben chlorid ester o 1,2,4- H)+
zonitril e hydroc oxadiazol-
hloride 5-yl)
e phenylamin
o )acetate
tent-butyl
3-(4-(3-(3-
3- beta- chloro-4-
chloro- 4- alanine isopropoxy
D.4 4- fluorob tent- C1 o phenyl)- 458
4 isoprop enzoyl butyles N N' 0 1,2,4- (M+ 3.20 (j)
oxyben chlorid ter H oxadiazol- H)
zonitril e hydroc 5-
e hloride yl)phenyla
mino)propa
noate
(3-{4-[3-
(3-Chloro-
(3- 4-
3 Amino isopr ~oxy
chloro- 4- ~o o P
D.4 4- fluorob propyl) P nyl)- 508
isoprop enzoyl N,o [1,2,4}oxad (M+ 3.03
H
phosph c N
iazol-5-yl} (b)
oxyben chlorid onic e henYla H)
phenyla
e acid di 0 mino}-
e ethyl propyl)-
ester phosphonic
acid dieth
l ester
(3-{4-[3-
(3-Chloro-
(3- 4-
3 Amino ~o o isopr~oxy
chloro- 4- P
D.4 4- fluorob propyl) nyl) 508
6 isoprop enzoyl N-( [1,2,4}oxad (M+ 3.03
phosph c N iazol-5-yl} (b)
oxyben chlorid onic i phenyla H)
zonitril e acid di 0 mino}-
e ethyl propyl)-
ester phosphonic
acid dieth
yl ester
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WO 2011/071570 PCT/US2010/046424
Table E. Examples made using General Procedures R, K, D and V
OH
(CH )n O
z (C,H>4 0 O~ ~4 O-HZ)j4
R HO (CH2)n O-R General (CH2)n O-R General _ (CHz)n O-R
0 OtBu Procedure R2 Procedure \ R2
R O K HO
OtBu 0
NHZ (CH2)n 0 (CH2)n 0
R'--<\ O-~ \ O-~< /--//
N-OH - (CH2)n OR (CH2)n OH
General RZ Rz
General
Procedure N- N \
D R 0 Procedure
R-4 0 N
Nitrile Rt/min
#x precurs Phenol Alcohol Structure Name m/z (method)
or
3-{4-[3-(3-
chloro-4-
3 3- isopropoxy
chloro- benzyl hydroxy- 0 -phen
4 4 cyclobuta W- y) 429.0
E.1 isoprop hydrox necarbox o [1,2,4]oxad
oxyben ybenzo ylic aci iazol-5-yl]- (H+ 2.63 (a)
zonitril ate d tent- phenoxy}
butyl -
e
ester cyclobutan
ecarboxylic
acid
Table F. Examples made using General Procedures R, C, D and K
OH
/ (CHz`))n--y/,0 (CH2)n 0
R HO ( ) CH n O -R
CH n O-R CHzn O-R ( z)
( z) General General
CN Procedure \ R2 Procedure R 2
R NC C H2N \
N
0 (CH2)n HO
j o (CHz)> n 0
- (CH2)n O-R - (CH2)n OH
General Rz R2
Procedure jj General
\N Procedure N
D N
R 0 K R0.
106
WO 2011/071570 PCT/US2010/046424
Ex Benzon Alcohol Structure Name m/z Rt/nun
# itrile (method)
3-{3-Chloro-4-
2 3- [5-(5-chloro-6-
Chloro Hydroxy- o isopro
cyclobuta 0H poxy pyridin 3
-- O-N C1 F.1 4 necarbox p yl)- 464
hydrox ylic aci i " [1,2,4]oxadiazol (M+H)+ 2'72 (a)
Y- d tent- c', -3-yl]-phenoxy}-
itrile benzon butyl cyclobutanecarbo
ester xyl
is acid
4-{3-Chloro-4-
4- [5-(5-chloro-6-
2 Hydroxy- o isopro
4Chloro cyclohex C _ OH poxy-pyridin-3-
F.2 anecarbo 0
hydrox ~
xylic aci iiN~ [1,2,4]olxadiazol (M~+g0 ) 2.83 (a)
d tent- -3-yl]-phenoxy}-
benzon butyl cyclohexanecarb
itrile
ester oxyl
is acid
Table G. Examples made using General Procedures C, D or E, L and K
NHzOH Acid or R 2
N N_OH acid chloride O
II INI'
R General Rl NH2 General R ~N \ F
Procedure Procedure
C DorE
RZ Rz
O KZC03 O
I' (CH Z )n O
\ F /~ >O
R N / General N (CH2)n O-R
Procedure
L
Rz
General (CHZ)nO
Procedure R
K (CH2)n OH
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WO 2011/071570 PCT/US2010/046424
Nitrile Acid Rt/min
#x precurs chlorid alcohol Structure Name m/z (method)
or e (
3-{3-
Chloro-
4-[3-(5-
3 chloro-6-
5- 2- Hydrox isopro
Chloro Chloro y- poxy-
6 -4- cyclob pyridin-
G.1 isoprop fluoro- utaneca I o. o~ [1,2,4]ox 464 ( ) 10 oxy- benzoy rboxyli
N M H\ 2.99 a
nicotin 1 c aci adiazol \ l
onitri chlorid d tent- C1 no
le e butyl phenoxy}
ester
cyclobuta
necarbox
yl
is acid
3-{3-
Chloro-
4-[3-(5-
3 chloro-6-
5- 2- Hydrox isopro
Chloro Chloro y poxy-
-6- -4- cyclob Ci off pyridin-
G.2 isoprop fluoro- utaneca i-0~32y4) 464
oxy- benzoy rboxyli N 0 [1> ]ox (M-H) 2.99 (a)
nicotin 1 c aci adiazol
onitri chlorid d tent- C1 -5-yl]-
le e butyl phenoxy}
ester
cyclobuta
necarbox
yl
is acid
Table H. Examples made using General Procedures P, C, D and K or Q
F
R6 (CHz)n O Y (jH2). n 0 (CH2)n 0
R 2 Y Rs -R
(CH2)n O-R General ~(CH2)n O
General R s - (CH2)n O-R
CN Procedure R2 Procedure R2
P NC C H2N \
N
HO 0 Y-HZ)j--/( Y"2)
Rs - (CH2)n O Rs On
CH n OH
(
General \ Rz General R2
Procedure ~p\N Procedure
R K 5 R ON
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WO 2011/071570 PCT/US2010/046424
Ex Benzon Carbox Alcohol Rt/min
# itrile ylic or amine Structure Name m/z (method)
acid
3-{3-
Chloro-4-
[5-(5-
chloro-6-
isopro
poxy-
5- 3- pyridin-3-
Chloro 2 Chloro Hydroxy yl)
6 cyclobuta o_N ' 'E " [1,2,4]oxad 464
H.1 -4 iazol
isoprop necarbox --N (M+H) 2.86(a)
fluoro- 3-yl]- +
oxy- ylic aci
benzon nicotini d ethyl ' phenoxy}-
itrile c acid ester cyclobutan
ecarboxyl
is
acidphenox
y}-
cyclobutan
ecarboxyl
is acid
(1 r,4r)-4-
(3-chloro-
4-(5-(3-
2- 3- (lr,4r)- chloro-4-
Chloro Chloro tent-butyl isopropoxy
H.2 -4- -4- 4- OH
o N a phenyl)- 491 2.97
hydrox isoprop hydroxycN 0 1,2,4
y- oxy- yclohexa ~o oxadiazol- (M+H) (b)
benzon benzoi necarbox a 3-
itrile c acid ylate yl)phenoxy
)cyclohexa
necarboxyli
c acid
(1 r,4r)-4-
(4-(5-(5-
5- (lr,4r)- chloro-6-
3,4 Chloro tent butyl isopropoxy 6 4 OH pyridin-3-
H.3 difluor isoprop hydroxyc o-N 10 yl)-1,2,4- 476 2.81
obenzo N ~N oxadiazol- (M+H) (b)
nitrile oxy- yclohexa J.o F 3-yl)-2-
nicotini necarbox
c acid ylate fluorophen
oxy)cycloh
exanecarbo
xylic acid
109
WO 2011/071570 PCT/US2010/046424
Ex Benzon Carbox Alcohol Rt/min
# itrile ylic or amine Structure Name m/z (method)
acid
(ls,4s)-4-
(4-(5-(5-
5- (ls,4s)- chloro-6-
Chloro tent-butyl isopropoxy
3,4 6 4_ oõ pyridin-3-
H.4 difluor o N 0 yl)-1,2,4- 476 2.80
isoprop hydroxyc N o
obenzo oxadiazol- (M+H) (b)
nitrile oxy- yclohexa ~.o F 3 yl) 2
nicotini necarbox
c acid ylate fluorophen
oxy)cycloh
exanecarbo
xylic acid
(1 r,4r)-4-
(4-(5-(5-
5- (lr,4r)- chloro-6-
Chloro tent-butyl isopropoxy
4- _ mooõ pyridin-3-
H.5 fluorob 6 4 o-N Q yl)-1,2,4- 458 2.78
isoprop hydroxyc > 0-0
enzonit ox N oxadiazol- (M+H) (b)
Y- yclohexa o _
rile nicotini necarbox a 3
c acid ylate yl)phenoxy
)cyclohexa
necarboxyli
c acid
(1R,3S)-3-
(4-(5-(5-
chloro-6-
5- (1R,3S)- isopropoxy
Chloro 3- v H pyridin-3-
4 -6- Amino- 0 o yl)-1,2,4- 443 2.81
H.6 fluorob N
isoprop cyclopent NH oxadiazol-
enzonit
rile oxy- anecarbo " 3 (M+H) (b)
nicotini xy ci yl)phenyla
c acid lic acid mino)cyclo
pentanecar
boxylic
acid
(1R,3S)-3-
(4-(5-(5-
chloro-6-
5- (1R,3S)- isopropoxy
4 Chloro 3- * H pyridin-3-
fluorob
H.7 -6- Amino- yl)-1,2,4- 457 2.94
enrile rt isoprop cyclopent N N õ oxadiazol
oxy- anecarbo ~o 1 ~ 3-yl)-2- (M+H) (b)
Note H nicotini xy o methylphen
c acid lic acid ylamino)cy
clopentane
carboxylic
acid
110
WO 2011/071570 PCT/US2010/046424
Ex Benzon Carbox Alcohol Rt/min
# itrile ylic or amine Structure Name m/z (method)
acid
(IR,3S)-3-
(4-(5-(3-
chloro-4-
4 3- (IR,3S)- isopropoxy
Chloro 3- OOH phenyl)-
fluorob -4- Amino 1,2,4-
H.8 enzonit O -N 457 2.87
rile isoprop cyclopent NH oxadiazol- M+H b
oxy- anecarbo ~.o 3-yl)-2- ( ) ( )
Note H benzoi xy ci methylphen
c acid lic acid ylamino)cy
clopentane
carboxylic
acid
Note H: See Preparation of Additional Examples section for modification of
benzonitrile
intermediate
Table I. Examples made using General Procedures C, D or E, P, K, R and K or Q
HOB Acid or N RZ
N Rz NHZOH RZ acid chloride O
General H2N R1~N
F Procedure General
C D or E
RZ RZ RZ N -N
R,~N / F General R'N / O General R' N OH
Procedure Procedure
P K
- N RZ (CHz)n O ~0 RZ (CH2)n O
General R1 ~N O General R'' O~
Procedure (CH2)n procedure (CH )OH
n
R KorQ z
Nitrile
#x precurs Acid alcohol Structure Name m/z (method)
or
4-{3-
5 Hydrox Chloro-
4- Chloro 4-[5-(5-Y_ 0 Fluoro- -6- cycloh ci OH chloro-6- 3.26+
1.1 2- isoprop exanec o- isopro 492
chlorob oxy N ~N o pox y- H + 3.31 (a)
enzonit nicotini arboxyl pyridin ( ) Note F
ril c aci is aci ci 3-yl)-
d d ethyl ester [1,2,4]ox
adiazol
111
WO 2011/071570 PCT/US2010/046424
Nitrile Rt/min
#x precurs Acid alcohol Structure Name m/z (method)
or
-3-yl]-
phenoxy}
cyclohex
anecarbo
xyl
is acid
3-{3-
Chloro-
4-[5-(5-
chloro-6-
3- isopro
4- Chloro Hydrox o poxy-
Fluoro- -6- y- O -N c'oH pyridin-
1.2 2- isoprop cyclop N~ 0 3 yl) 478 3.18 +
chlorob oxy- entanec [1,2,4]ox MH)+ 3.25 (a)
enzonit nicotini arboxyl ci adiazol ( Note F.
ril c aci is ac 3 yl]
d id ethyl phenoxy}
ester -
cyclopent
anecarbo
xy
lic acid
3-{3-
Chloro-
4-[5-(5-
chloro-6-
3- isopro
5
4- Chloro Hydrox c poxy-
_
Fluoro- -6- y o-N pyridin-
L3 2- isoprop cycloh N
O
chlorob oxy- OH 3 yl) 478 3.31 +
exanec [1,2,4]ox (M-H) 3.38 (a)
enzonit nicotini arboxyl c, adiazol Note F.
ril c aci is aci -3-yl]-
d d ethyl phenoxy}
ester -
cyclohex
anecarbo
xyl
is acid
4- 4-{3-
4- Chloro Hydrox o Chloro-
Fluoro- -6- y off 4-[5-(5-
cycloh N c' chloro-6-
1.4 2- isoprop o 492
3.12 (a)
exanec o isopro M -H)-
chlorob oxy- 1-~- N \ / ( enzonit nicoti.m aicb aci l ~o c/ ppyridin-
ril c aci d tert- 3-yl)-
d butyl 1,2,4 ox
112
WO 2011/071570 PCT/US2010/046424
Nitrile Rt/min
#x precurs Acid alcohol Structure Name m/z (method)
or
ester adiazol
-3-yl]-
phenoxy}
cyclohex
anecarbo
xyl
is acid
(1R,3R)-
3-{3-
Chloro-
4-[5-(5-
chloro-
3- 6-
4- 5 Chloro Hydrox isopropo
Fluoro- -6- y o1 ~~(0 xy-
cyclop o- L/ '0H pyridin-
1.5 2- isoprop entanec o` 3-yl)- 478 2.78 (a)
chlorob oxy- (M-H)+ Note G
enzonit nicotini arboxyl [1,2,4]o
ril c aci is ac O1 xadiazol-
ril id ethyl 3-yl]-
d phenoxy }
cyclopent
an
ecarboxy
lic acid
(1R,3S)-
3-{3-
Chloro-
4-[5-(5-
chloro-
3- 6-
4- 5 Chloro Hydrox isopropo
Fluoro- -6- y 1 xy-
cyclop o-NoH pyridin-
1.6 2- isoprop entanec N C 3 yl) 478 2.74 (a)
chlorob oxy- bor (M-H)+ Note G
enzonit nicotini ar y1 [1,2,4]o
ril c aci is ac Cl xadiazol-
ril ethyl 3-yl]-
d ester phenoxy }
cyclopent
an
ecarboxy
lic acid
0
4- 5- 3 N C1 (1S,3S)-
L7 Fluoro- Chloro Hydrox OH 3-{3- 478 2.78 (a)
2- -6- y- Ni Chloro- (M-H)+ Note G
chlorob isoprop cyclop Cl 4-[5-(5-
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WO 2011/071570 PCT/US2010/046424
Nitrile Rt/min
#x precurs Acid alcohol Structure Name m/z (method)
or
enzonit oxy- entanec chloro-
ril nicotini arboxyl 6-
c aci is ac isopropo
d id ethyl xy-
ester pyridin-
3-yl)-
[1,2,4]o
xadiazol-
3-yl]-
phenoxy}
cyclopent
an
ecarboxy
lic acid
(IS,3R)-
3-{3-
Chloro-
4-[5-(5-
chloro-
3- 6-
4- 5 Chloro Hydrox isopropo
Fluoro- -6- Y C, xy-
cyclop o-N OH pyridin-
L8 2- isoprop entanec C 3_yl)_ 478 2.74 (a)
chlorob oxy box (M-H)+ Note G
enzonit nicotini ar Y1 'JI0 [1,2,4]o
ril e aci is ac C' xadiazol-
ril ethyl 3-yl]-
d ester phenoxy }
cyclopent
an
ecarboxy
lic acid
3-{3-
Chloro-
4-[5-(5-
3- Chloro-6-
Hydrox deutero-
2 Chloro ci isopro 21.717
Chloro -6 Ycyclob " / pox min,
deutero cis Y 98.8%
1.9 4 isoprop utaneca N pyridin- and
fluoro- oxy rboxyli 0N 0 3-yl)- 21.138
benzon nicotini c aci op HO [1,2,4]ox min
itrile c aci d tert- D D adiazol 1.19%(r)
d butyl -3-yl]-
ester phenoxy }
cyclobuta
necarbox
114
WO 2011/071570 PCT/US2010/046424
Nitrile Rt/min
#x precurs Acid alcohol Structure Name m/z (method)
or
yl
is
acidphen
oxy}-
cyclobuta
necarbox
yl
is acid
Note F: Mixture of isomers
Note G: Crude mixture of 4 isomers was separated using two orthogonal
preparative
chromatography methods. Method A: Isocratic elution using 0.12%
trifluoroacetic acid in
heptane (solvent B) and isopropanol (solvent A) in a ratio of 20% solvent A :
80% solvent B
on a Daicel ADH column (20 x 250mm) over 16.5 min, monitoring with UV (280
nm).
Method B: Gradient elution using 0.12% trifluoroacetic acid in heptane
(solvent B) and 1:1 /
ethanol:methanol (solvent A), 20-60% solvent A on a Daicel ADH column (20 x
250 mm)
over 19.5 minutes, monitoring with UV (280nm).
Table J. Examples made using General Procedures C, D or E, I or J and Q
NH OH Acid or N.o
R N ? R N-OH acid chloride
General NH
General
\~/ \ I I \ N \ / H
Procedure Pr
ocedure
C DorE
N-o N-0, R _o
i
N N I H General R\ N N General 6'1,~ N R
Procedure Ro R Procedure
COZH
I or J z z Q Acid or Rt/mi
Ex Nitrile # precursor acid ester Structure Name m/z (met
chloride
hod)
2-(6-(3-(3-
chloro-4-
3-chloro- _ ethyl o isopropoxyphe
4 4 2-
J. N off nyl) 1,2,4 428
1 isopropo fluoroben brom oxadiazol-5- (M+H) 2.55
xybenzon chloride oacet c' yl)-3,4- + (a)
itrile ate dihydroquinoli
n-1(211)-
1acetic acid
115
WO 2011/071570 PCT/US2010/046424
Acid or Rt/mi
Ex Nitrile # precursor acid ester Structure Name m/z (met
chloride
hod)
3-(6-(3-(3-
chloro-4-
3-chloro- ethyl isopropoxyphe
4- 4- 3- N-O nyl)-1,2,4- 443
J.2 iso ro o fluoroben brom ' N , /, N oxadiazol-5- M+H 2.78
ben on zoyl opro OOH yl)-3,4- ( + ) (a)
xy chloride pano C1 0 dihydroquinoli
itrile ate n-1(211)-
yl)propanoic
acid
Table K Examples made using Preparations #61, 62 and 63
The letter in parentheses below the phenol precursors indicates the General
Procedure by
which the phenol precursor was made.
\\ \\
OH O-X O`XOH
1I CI \ N-0 N O
General 1I CI \ N-0 CI N
p Procedure M7 General ~O
Procedure
M8 and M9
Ex # Phenol Alkyl Product Name Rt/min m/Z
precursor Halide (method)
3-(3-(3- (E)-4-(3-(3-(3-
chloro-4- chloro-4-
isopropoxy (E)-ethyl a isopropoxyphen
K.1 phenyl)- N
4 O O yl)-1,2,4- 429
1,2,4- bromobut N O~LOH oxadiazol-5- 3.05 (g) (M+H)
oxadiazol -2-enoate yl)-2
5-yl)-2- methylphenoxy
methylphen )but-2-enoic
of A,C, E acid
3-(3-(3- 4-(3-(3-(3-
chloro-4- chloro-4-
isopropoxy (E)-ethyl cl isopropoxyphen
K.2 phenyl)- N-0 O 431
1,2,4- 4 0 N O'-'-)'OH yl)-1,2,4- 3.08 (g)
oxadiazol- bromobut oxadiazol-5- (M+H)
-2-enoate yl)-2-
5-yl)-2methylphen methylphenoxy
)butanoic acid
of (A,C, E
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Ex # Phenol Alkyl Product Name Rt/min m/z
precursor Halide (method)
3-(3-(3- 4-(3-(3-(3-
chloro-4
Cl chloro-4-
isopropoxy (E) ethyl isopropoxyphen __~ K.3 p1,2,4l- ) 4- - 0 " y1)-1>2>4 3.11
(g) 431
oxadiazol- bromobut oxadiazol-5 (M+H)
-2-enoate OH yl)-4-
5-yl)-2-
methylphen methylphenoxy
of (A,C, E )butanoic acid
Table L. Examples made using General Procedures C and D or E
R1 Rt
Acid or O -N R
R O N R
\\ /N NH2OH N-OH acid chloride I O N o
General r~\ NHZ N i~ General Procedure II Procedure o General OH
O Procedure
D or E R2 QorK
Carbox
ylic
Ex # acid Nitrile Structure Name m/z Rt/nun
(method)
precurs
or
(1R,3S)-
3 methyl 3- (1R,3S)-3-(4-(5-
chloro (4- Q (3-chloro-4-
4 cyanophe N NH isopropoxyphen
isoprop 442.27
L.1 oxyben nylamino Q / Q o yl)-1,2,4- (M+H) 2.94
zoic )cyclope OH oxadiazol-3- + (g)
acid ntane yl)phenylamino
carbox (Procedu )cyclopentaneca
ylate res #40 rboxylic acid
and 41)
Table M. Examples prepared using General Procedure S
Rt min m/z ESI+
Phosphonate ester Product Example # (Table 2, (M+H)+
Method)
diethyl 3-(4-(3-(3-
chloro-4- N-o isopropoxyphenyl)- Cl 1 ,2,4 oxadiazol 5 o H\ OH M 1 1.85 (b)
466
yl)benzylamino)propyl P'-OH
phosphonate (prepared 0
in table B entry 17,)
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Rt min m/z ESI+
Phosphonate ester Product Example # (Table 2, (M+H)+
Method
diethyl (1S,3R)-3-(4-
(3-(3-chloro-4- OH
isopropoxyphenyl)- O Ipl OH
M.2
1,2,4-oxadiazol-5- a N NH 2.01 (b) 478
1)phenylamino)cyclop
entylphosphonate O
(Preparation #68)
diethyl (1R,3R)-3-(4-
(3-(3-chloro-4- OH
isopropoxyphenyl)- O POOH
1,2,4-oxadiazol-5- a N NH M.3 1.97 (b) 478
1)phenylamino)cyclop
entylphosphonate O
(Preparation #68)
diethyl (1R,3R)-3-(4-
(3-(3-chloro-4- O
isopropoxyphenyl)- N_O _ a~P OH
1 ,2,4 oxadiazol 5 ci N \ N%i OH MA 2.18 (b) 556
1)phenylamino)cyclop X~' Br
O
entylphosphonate
(Preparation #68)
diethyl (1R,3S)-3-(4-
(3-(3-chloro-4-
isopropoxyphenyl)- N,O lV ~IOH
1,2,4-oxadiazol-5- ;IN'NHOH M'S 1.96 (b) 478
1)phenylamino)cyclop o
entylphosphonate
(Preparation #68)
diethyl (1R,3S)-3-(4-
3 3-chloro-4
OH
isopropoxyphenyl)- N-O ~P
1,2,4-oxadiazol-5- C1 N _ NH OH M.6
2.16 (b) 556
1)phenylamino)cyclop i Br
entylphosphonate
(Preparation #68)
diethyl (1S,3S)-3-(4-
(3-(3-chloro-4- OH
isopropoxyphenyl)-
~~.1.97 (b) 478
1,2,4-oxadiazol-5- ;IN'NH N O POOH
1)phenylamino)cyclop L ,
entylphosphonate O
(Preparation #68)
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Table N. Examples made using General Procedures T, U and V
N.O P+Ph3Cl- General N-O
CI \ I N Procedure CI )71I N
T
O I O O
n 1,2
OEt EtO
n 1,2
0
General H2, Pd/C
Procedure EtOAc, 1 hr
U
N'O N-O
I i
Cl I\ N OH Cl I\ I N
O General O
Procedure
n=1,2
O v O
HO EtO
Nitrile Acid or
Ex precurs acid Ketone Structure Name m/z Rt/min
# or chlorid (method)
e
3-(4-(3-(3-
chloro-4-
3- 4- isopropoxy
chloro- (chloro e t h y l 3- N-0 _ phenyl)-
N.1 4- methyl oxocyc c' -11)-, N 1,2,4- 427.24
isoprop )benzo lobutan oxadiazol- (M+H) 3.13 (g)
oxyben yl ecarbo 0 5- +
zonitril chlorid xylate HO yl)benzyl)c
e e yclobutane
carboxylic
acid
3-(4-(3-(3-
chloro-4-
3- 4- isopropoxy
chloro- (chloro e t h y l 3- N-0 phenyl)-
N.2 4- methyl oxocyc ci ' N 1,2,4- 441.11
isoprop )benzo lopenta oxadiazol- (M+H) 3.32 (g)
oxyben yl necarb 0 5- +
zonitril chlorid oxylate OH yl)benzyl)c
e e yclopentan
ecarboxylic
acid
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Table P: The following deuterated compounds could be prepared by those skilled
in the art:
Ex Nitrile Acid or
# precursor acid Amine Structure Name
chloride
Deutero- 1 -(4-
3-chloro- pyrroli ci N-O (3-(3-chloro-4-
4 N p isopropoxyphe
P.1 isopropo cyanobenz carbox N D nyl)-1,2,4-
xybenzon oyl ylic off oxadiazol-5-
itenz chloride acid o yl)benzyl)pyrro
lidine-3 -
carbox lic acid
Deutero-
(1R,3S)-3-{4-
[3-(5-Chloro-6-
Chloro- (1R,3S) isoprop
6 4 Fluoro 2 -3- N-O oxy-pyridin-3-
i ~ ~ NH y
isopropo methyl- aminoc N 1)-
P.2 Xy benzoyl yclope ON OH [1,2,4]oxadiazo
ntaneca C1 nicotinon chloride ___ 0 1
rboxyli 5-yl]-3-methyl-
ltrl c acid phenylamino}-
le cyclope
ntanecarboxyli
c acid
3 Deutero-3-{4-
hydrox [3-(3-chloro-4-
isopropoxy-
3-chloro- cyclob phen
4- benzyl 4- C1 N=O O yl)-
P.3 isopropo hydroxybe rboxye li N e [1,2,4]oxadiazo
xybenzon nzoate D 1-5-yl]-
itrile c aci d tert phenoxy}
-
butyl
ester cyclobutanecar
boxylic acid
Deutero-3-(4-
N-O _ p (3-(3-chloro-4-
3-chloro- ethyl 3- i , D 4- a N isopropoxyphe
P.4 isopropo (chloromet lobutan 0 nyl)-1,2,4-
hyl)benzoy oxadiazol-5 -
xybenzon 1 chloride ecarbo HO 0 yl)benzyl)cyclo
itrile xylate
butanecarboxyl
is acid
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Preparation of Additional Examples
Preparation # 1: Preparation of 3-chloro-4-isopropoxy-benzoic acid
0 0
CI I \ Oi 1). iPrOH, PPh3, DBAD CI )CT
OH
HO / 2). NaOH 5 Into a round bottom flask was added triphenylphosphine (62 g,
0.263 mol), 3-chloro-4-
hydroxy-benzoic acid methyl ester (10 g, 0.0535 mol) and anhydrous THE (500
mL). The
mixture was briefly stirred under nitrogen, then DBAD (19.75 g, 0.0858 mol)
was added. The
mixture was stirred for a few minutes before adding anhydrous isopropanol
(5.125 mL, 0.067
mol). After the reaction mixture was stirred at RT under an atmosphere of
nitrogen for about 3
h, DBAD (19.75 g, 0.0858 mol) and anhydrous isopropanol (5.125 mL, 0.067 mol)
were
added and the mixture was left to stir at RT overnight. The solvent was
removed under
reduced pressure. The residue was dissolved in a minimum amount of ethyl
acetate. Heptane
was added and the precipitate was removed by filtration. The filtrate was
brought up in
methanol. Water was added until the solution was cloudy. The precipitate was
filtered off. The
methanol/water precipitation procedure was repeated two more times. The
filtrate was taken
up in THE (200 mL) and 5 M NaOH (200 mL). The mixture was stirred at RT
overnight. The
organic solvent was removed under reduced pressure. The aqueous layer was
extracted three
times with ethyl acetate. The aqueous layer was further acidified to pH 1 - 2
with 2 M HC1.
The cloudy suspension was then extracted with ethyl acetate three times. The
organic layers
were combined, dried over magnesium sulfate, and concentrated to dryness to
give 3-chloro-
4-isopropoxy-benzoic acid (8.4 g, 71.4 %) as a white solid.
LC/MS (Table 1, Method b) Rt = 2.42 min, m/z (M-H)- 213; 1H NMR (400 MHz, DMSO-
d6)
612.95 (s, 1H), 7.87 (m, 2H), 7.25 (d, 1H), 4.79 (m, 1H), 1.32 (d, 6H)
Preparation #2: 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzonitrile
HNOH O N-O
CI NH CI CI N N
N O
3-Chloro-N-hydroxy-4-isopropoxybenzimidamide (10 g, 43.7 mmol) was dissolved
in DMF
(219 mL) under nitrogen. The mixture was heated at about 110 C for about 10
min. A
solution of 4-cyanobenzoyl chloride (7.24 g, 43.7 mmol) dissolved in DMF (30
mL) was
added dropwise over about 20 min and the reaction heated at about 110 C for
about 4 h until
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LC/MS showed the reaction was complete. The reaction was cooled in an ice bath
and poured
into rapidly stirred water (1000 mL). The resulting white precipitate was
collected by vacuum
filtration and washed with water. The precipitate was dissolved in methylene
chloride and
washed with 1 N HCl and then brine. The methylene chloride was dried over
sodium sulfate,
filtered, and evaporated. Heptane and DCM were added to the residue and the
mixture heated
until the DCM had boiled off after which the mixture was allowed to cool.
Solids did not
dissolve in hot heptane. The resulting solid was collected by vacuum
filtration and washed
with heptane to provide 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5
yl)benzonitrile
(12.568 g, 37.0 mmol, 85% yield) as a tan solid: LC/MS (Table 1, Method a) Rt
= 4.58 min.;
MS m/z: 340.20 (M+H)+.
Preparation #3: 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzaldehyde
N'O N-O O
CI N CI IN
O O
4-(3-(3-Chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzonitrile (10 g,
29.4 mmol) was
dissolved in dichloromethane (535 mL) under nitrogen. The reaction was cooled
to about -40
C in a dry ice/ACN bath measuring the temperature internally. A solution of
Dibal-H (58.9
mL, 58.9 mmol) was added dropwise and the reaction stirred for about 30 min.
and then
quenched with methanol. The mixture was stirred until the bubbles subsided.
The mixture
was then warmed to RT and stirred rapidly with a 10% solution of Rochelle's
salt. The
separated layers were extracted with DCM (3 x 100 mL). The combined extracts
were stirred
rapidly with about 100 mL of 1 N HCl and the solution turned from orange to
colorless. TLC
indicated the mixture had been cleaned up to just one spot with some baseline
material. The
layers were separated and the aqueous layer extracted with DCM (2 x 100 mL).
The
combined organic extracts were washed with brine, dried over sodium sulfate,
filtered, and
evaporated to dryness to afford an off white solid. The solid was stirred with
heptane and the
solvent removed carefully via pipette. The solid was dried under vacuum to
afford 4-(3-(3-
chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-yl)benzaldehyde (9.15 g, 26.7
mmol, 91%
yield) as white solid: LC/MS (Table 1, Method a) Rt = 4.59 min.; MS m/z:
343.26, 345.18
(M+H)+.
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Example #1: 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)azetidine-3-carboxylic acid
0\\
N-O O OOH
CI N OH N'O N
I/
O H JJJJ CI I ' N
Azetidine-3-carboxylic acid (3.72 g, 36.8 mmol) (Synchem) was dissolved in
acetic acid
(16.03 mL, 280 mmol) and methanol (2 mL). This was added to a stirred
suspension of 4-(3-
(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (12 g, 35.0
mmol) in
MeOH (600 mL). The reaction was stirred for about 18 h. Sodium
cyanoborohydride (5.50 g,
88 mmol) was added and the reaction stirred for about 4 h. The reaction was
cooled with an
ice bath and the precipitate was collected by vacuum filtration and washed
with ice cold
methanol and then ether. TLC showed impurities still present. The crude solid
was dissolved
in 1:1 EtOAc /(6:3:1 CHC13/MeOH/NH4OH) with a little extra added NH4OH.
Chromatography over silica gel in a mixture of 1:1 EtOAc/(6:3:1
CHC13/MeOH/NH4OH)
increasing to all 6:3:1 CHC13/MeOH/NH4OH eluted the product. The fractions
were
evaporated to dryness to afford a colorless film/oil. The mixture was
dissolved in methanol
and evaporated to dryness. The residue was resuspended in the minimum amount
of
methanol, water was added and the mixture filtered, washed with water and then
ether. The
residue was dried under vacuum at ambient temperature and then under vacuum at
about 60
C to remove trace methanol to afford 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)benzyl)azetidine-3-carboxylic acid (8.3 g, 19.40 mmol, 55.4%
yield) as a white
solid: LC/MS (Table 1, Method a) Rt = 2.94 min.; MS m/z: 428.31, 430.27 (M+H)
; mp
194.8-195.9 C; 1H NMR (400 MHz, DMSO-d) 6 ppm 8.12 (d, J = 8.34 Hz, 2H), 8.06
(d, J =
2.13 Hz, 1H), 8.00 (dd, J = 8.67, 2.15 Hz, 1H), 7.54 (d, J = 8.36 Hz, 2H),
7.39 (d, J = 9.06
Hz, 1H), 4.88-4.77 (m, 1H), 3.67 (s, 2H), 3.48-3.38 (m, 2H), 3.29-3.19 (m,
3H), 1.35 (d, J =
6.02 Hz, 6H).
Preparation #4: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(4-
fluorophenyl)-
1,2,4-oxadiazole
CI N-OH CI CI N-O
\ l NHz + O 1\ ~\ \ N 1\
O F O i / F
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(Z)-3-Chloro-N-hydroxy-4-isopropoxybenzimidamide (2.0 g. 8.75 mmol), 4-
fluorobenzoyl
chloride (2.1 g, 13.12 mmol) and pyridine (12 mL) are loaded into a 20 mL
microwave vial
equipped with a stir bar. The vessel is sealed and the reaction heated to
about 200 C with
cooling for about 25 min. The mixture was purified using normal phase
chromatography to
afford a pale brown solid. Analysis by LC/MS showed this to be a 35:30:21
mixture of 3-(3-
chloro-4-isopropoxyphenyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole, 2-chloro-4-(5-
(4-
fluorophenyl)-1,2,4-oxadiazol-3-yl)phenol and 4-fluorobenzoic acid. The
mixture was
purified a second time using normal phase chromatography to afford 5
fractions. Fractions 1,
2 and 3 were combined and evaporated to dryness to afford 3-(3-chloro-4-
isopropoxyphenyl)-
5-(4-fluorophenyl)-1,2,4-oxadiazole (420 mmol, 14%) as a white solid. LC/MS
(Table 1,
Method a) Rt = 2.85 min, m/z 333.10 (M-H)+
Preparation #5: Preparation of 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)benzonitrile
NOH CI O O CI
N'
I NHZ CI CI N
&"'
A
// O Ni
0
To a 250 mL round bottom flask equipped with a stir bar and charged with 2-
chloro-4-
cyanobenzoic acid (3.0 g, 16.52 mmol), was added anhydrous DCM (80 mL), and
DMF
(0.064 mL, 0.826 mmol). Oxalyl chloride (8.26 mL, 16.52 mmol) (2M solution in
DCM) was
then added slowly and the mixture was stirred under nitrogen at ambient
temperature. Upon
addition of the oxalyl chloride, gas evolution began and the suspended solid
began to dissolve.
After about 2-3 h, the reaction became translucent. The mixture was
concentrated in vacuo.
The resulting crude material was dissolved in pyridine (50 mL). To this was
added (Z)-3-
chloro-N-hydroxy-4-isopropoxybenzimidamide (1.258 g, 5.50 mmol). The mixture
was
heated to about 100 C under an atmosphere of nitrogen for about 16 h. The
resulting mixture
was cooled to ambient temperature. Pyridine was removed under reduced pressure
and the
resulting material was triturated in DCM and MeOH mixture (about 1:1). The
resulting
precipitate was left standing for a few minutes at ambient temperature then
was collected via
filtration, washed with a mixture of 1:1 DCM/MeOH, and then with straight MeOH
and dried
in a vacuum oven for about 48 h to yield 3-chloro-4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)benzonitrile (1.529g, 4.09 mmol, 25%) as a beige solid. 1H NMR
(400 MHz,
DMSO) 6 ppm 8.39 (d, J = 1.53 Hz, 1H), 8.35 (d, J = 8.15 Hz, 1H), 8.09 (dd, J
= 8.14, 1.53
Hz, 1H), 8.05 (d, J = 2.11 Hz, 1H), 8.00 (dd, J = 8.63, 2.12 Hz, 1H), 7.39 (d,
J = 8.82 Hz,
1H), 4.82 (sept, J = 6.04 Hz, 1H), 1.35 (d, J = 6.01 Hz, 6H).
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Example #2 :Preparation of 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)p rop an-2-amine
N-O N,O
CI I\ N CI I\ I N NHZ
lO / lO
Anhydrous cerium (III) chloride (5.57 g, 22.60 mmol) and anhydrous
tetrahydrofuran (20 mL)
were added to a dry 2-neck round bottom flask under nitrogen. The resulting
suspension was
sonicated for a few minutes and then stirred at room temperature for about 90
minutes. The
mixture was then cooled to about -50 C, and methylithium (14.13 mL, 22.60
mmol) was
added slowly. After about 60 min, and warming to about 0 C, the reaction was
cooled to
about -50 C and 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzonitrile (2.4g,
7.06 mmol) in 8 mL of anhydrous THE was added drop-wise, to keep the
temperature of the
reaction at about -50 C. The reaction was maintained at about -50 C for
about 1 h, then left
to warm to RT overnight. The next day the reaction was cooled to about -50 C,
and
quenched by the addition of 21 mL of 35% NH4OH. The quenched reaction was left
to warm
to RT over about two h. The mixture was filtered through Celite and washed
with DCM (4x
60 mL). The filtrate was collected and then washed with water and dried over
MgSO4.
Solvent was removed under reduced pressure and the crude material was purified
by RP-
HPLC (A = 50 mM ammonium acetate, B = ACN; 30-70% B over 30.0 min (21.0 mL/min
flow rate); 21.2 x 250 mm Thermo Hyperprep C18 column, 8 m particles) to give
2-(4-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenyl)propan-2-amine as the
acetic acid
salt (309 mg; 10.1%). LC/MS (Table 1, Method a) Rt = 2.61 min; 1H NMR (400
MHz,
DMSO-d6) 6 ppm 8.14-7.94 (m, 4H), 7.80 (d, J = 8.43 Hz, 2H), 7.37 (d, J = 8.81
Hz, 1H),
4.80 (sept, J = 6.04 Hz, 1H), 1.85 (s, 3H), 1.39 (s, 6H), 1.36-1.31 (d, J =
6.04 Hz, 6H)
Example #3: Preparation of methyl 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenyl)prop an-2-ylamino)p r op an oate
N-O N,O _
Cl \ I N CI \ , N
NH, I N O
O H~
-
2-(4-(3-(3-Chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2-
amine and
acetic acid (132 mg, 0.306 mmol) was added to a 5 mL microwave vial equipped
with a
stirring bar. Methyl acrylate (52.6 mg, 0.611 mmol), and MeOH (3.0 mL) were
added, the
vial capped, and the reaction heated to about 120 C for about 90 min under
microwave
irradiation (Biotage Optimizer, 300 W). After about 90 min another aliquot of
methyl
acrylate (52.6 mg, 0.611 mmol) was added and the reaction heated for about
another 60 min at
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WO 2011/071570 PCT/US2010/046424
about 120 C. The reaction was cooled and the solvent removed under reduced
pressure. The
crude material was purified by RP-HPLC (A = 50mM ammonium acetate, B = ACN; 30-
70%
B over 30.0 min (21.0 mL/min flow rate); 21.2 x 250 mm Thermo Hyperprep C18
column, 8
pm particles) to give methyl 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)propan-2-ylamino)propanoate (83.5 mg; 59.7%). LC/MS (Table 1, Method
a) Rt =
2.78 min, m/z = 458.29 (M=H)+.
Example #4: Preparation of 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)propan-2-ylamino)propanoic acid
N_O N_O
CI \ I N / CI \ I N \ /
H O / H
0 '1 10 0- 1_`_1 OH
Methyl 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)propan-2-
ylamino)propanoate (83mg, 0.181 mmol) was dissolved in ethanol (4 mL) and NaOH
(4 mL,
8.00 mmol) was added. The mixture was stirred at RT under nitrogen. After
about 20 min the
reaction was neutralized by drop-wise addition of acetic acid. The aqueous
mixture was then
frozen and lyophilized. DCM was added to the solid, filtered, and washed with
DCM. The
filtrate was concentrated and ether added to afford a slightly cloudy
solution. IN HCl in ether
was added dropwise until white precipitate formed. The material was collected
by filtration,
washed with ether, and dried in a vacuum oven to give 3-(2-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2ylamino)propanoic acid
as the
hydrochloric acid salt (61.5 mg; 70.6%). LC/MS (Table 1, Method a) Rt = 1.98
min, mlz =
444.29 (M=H) ; 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.32 (d, J = 8.57 Hz, 2H), 8.12
(d, J
= 2.08 Hz, 1H), 8.03 (dd, J = 8.64, 2.10 Hz, 1H), 7.85 (d, J = 8.59 Hz, 2H),
7.25 (d, J = 8.78
Hz, 1H), 4.79 (sept, J = 6.11 Hz, 1H), 2.95 (t, J = 6.20 Hz, 2H), 2.44 (t, J =
6.17 Hz, 2H), 1.84
(s, 6H), 1.40 (d, J = 6.04 Hz, 6H).
Example #5: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-4-yl)-
1,2,4-
oxadiazole
OH
N~ OH
Cl' 11 N-O
NHz + O J9 CI OH
\ NH Q
I'Ll
Under an atmosphere of nitrogen a mixture of 1H-indole-4-carboxylic acid (3.88
g, 24.05
mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.61 g,
24.05 mmol)
and benzotriazol-l-ol hydrate (3.68 g, 24.05 mmol) in anhydrous DMF (61.4 mL)
was stirred
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at ambient temperature for about 1 h. To the reaction mixture a solution of 3-
chloro-N-
hydroxy-4-isopropoxybenzamidine (5.0g, 21.87 mmol) in DMF (11.51 mL) was
added. The
mixture was stirred and heated at about 140 C for about 2 h. The mixture was
cooled to
ambient temperature and poured into water (1L). The product was partitioned
between ethyl
acetate and the aqueous phase. The organic layer washed with IN HCl (4 x 150
mL), IN
NaOH (2 x 150 mL) and water (2 x 300 mL), dried over MgSO4 and filtered. The
solvent was
removed under reduced pressure and the crude product was purified by elution
through
Florisil with heptane/ethyl acetate (2:1) to give 3-(3-chloro-4-
isopropoxyphenyl)-5-(IH-indol-
4-yl)-1,2,4-oxadiazole (2.76 g, 35.7 %). LC/MS (Table 1, Method b) Rt = 2.69
min, m/z
354.17 (M+H)+.
Preparation #6: Preparation of (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)methanol
N OH O N'O - OH
NH2 HO \ N
/~O / I / OH /`O I
CI CI
To a slurry of 4-(hydroxymethyl)benzoic acid (0.220 g, 1.443 mmol) in DMF
(1.640 mL) was
added EDC (0.277 g, 1.443 mmol) followed by HOBT hydrate (0.195 g, 1.443
mmol). After
about 45 min. a solution of (Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide
(0.300 g,
1.31 mmol) in DMF (1.640 mL) was added and the reaction mixture was heated to
about 140
C for about 2 h. After cooling to RT the reaction mixture was concentrated in
vacuo and
purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide
(4-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanol (0.336g, 71%)
as an off-
white solid. LC/MS (Table 1, Method c) Rt = 2.80 min, m/z 345 (M+H).
Preparation #7: Preparation of 5-(4-(azidomethyl)phenyl)-3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazole
N-O OH ~O)QN3
C1 C1
To a solution of (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)methanol
(0.100 g, 0.290 mmol) in THE (1.5 mL) was added DBU (0.048 mL, 0.319 mmol)
followed
by diphenyl phosphorazidate (0.069 mL, 0.319 mmol). After about 15 h the
reaction mixture
was poured into ether and saturated NaHCO3. The organic layer was separated,
washed with
brine, dried (MgSO4), concentrated in vacuo and purified by chromatography on
silica gel
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(eluting with EtOAc/Hep) to provide 5-(4-(azidomethyl)phenyl)-3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazole (0.066g, 60%) as a colorless solid. LC/MS
(Table 1,
Method c) Rt = 3.22 min, m/z 370 (M+H)+
Example #6: Preparation of (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-
yl)phenyl)methanamine
N-0 N3 N.O NH 2
N N \ j\`4
C1 C1
To a solution of 5-(4-(azidomethyl)phenyl)-3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-oxadiazole
(0.066 g, 0.178 mmol) in THE (3.40 mL) and water (0.170 mL) was added polymer-
supported
triphenylphosphine (0.237 g, 0.711 mmol). After about 2 h the reaction mixture
was heated to
about 60 C. After about 1 h the reaction mixture was cooled to RT, filtered,
concentrated in
vacuo and purified by chromatography on silica gel (eluting with MeOH:DCM) to
provide (4-
(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (40
mg, 64%) as
a colorless solid.
LC/MS (Table 1, Method c) Rt = 1.97 min, m/z 344 (M+H)+.
Preparation #8: 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)cyclopentanone
OH
N~ O N_0
NH2 HO N
O I / / O
CI O
CI
To a slurry of 3-oxocyclopentanecarboxylic acid (0.123 g, 0.962 mmol) in DMF
(1.0 mL) was
added EDC (0.184 g, 0.962 mmol) followed by HOBT hydrate (0.130 g, 0.962
mmol). After
about 1 h a solution of (Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide (0.2
g, 0.875
mmol) in DMF (0.5 mL) was added and the reaction mixture was heated to about
140 C for
about 45 min. After cooling to RT the reaction mixture was concentrated in
vacuo and
purified by chromatography on silica gel (eluting with EtOAc/Hep) to provide 3-
(3-(3-chloro-
4-isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)cyclopentanone (0.156 g, 56%) as a
yellow oil.
LC/MS (Table 1, Method c) Rt = 2.75 min, m/z 321 (M+H)+.
Example #7: 3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)cyclopentylamino)propanoic acid
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CO
CI NI-0 CI )-4 Ni
"~ N -(pH
O I L p p H O
To a slurry of 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)cyclopentanone
(0.178 g, 0.555 mmol) in MeOH (6.94 mL) and DCE (6.94 mL) was added acetic
acid (0.254
mL, 4.44 mmol) followed by 3-aminopropanoic acid (0.494 g, 5.55 mmol). After
about 1 h
sodium cyanoborohydride (0.017 g, 0.277 mmol) was added to the reaction
mixture. After
about 15 h the reaction mixture was filtered, rinsing with MeOH. The filtrate
was
concentrated in vacuo and purified by RP HPLC to provide 3-(3-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentylamino)propanoic acid. LC/MS
(Table 1,
Method c) Rt = 1.64 min, m/z 394 (M+H).
Example #8: 4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)cyclopentylamino)butanoic acid
N-O N-O
I I N/ H2N
~' \\ OH I
O O O N
H p
HO
3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)cyclopentanone (0.078
g, 0.243
mmol) was suspended in mixture of MeOH (3.04 mL) and DCE (3.04 mL). To this
was added
acetic acid (0.111 mL, 1.945 mmol) followed by 4-aminobutanoic acid (0.251 g,
2.432 mmol)
as solid. The solution was stirred at RT for 0.5-1 h. Sodium cyanoborohydride
(7.64 mg,
0.122 mmol) was then added in one portion. The reaction was stirred at RT
overnight and
LC/MS indicated reaction was complete. The excess amino acid was filtered off
and the
filtrate concentrated in vacuo. The crude oil was partitioned between ethyl
acetate and brine.
The organic layer was dried (MgS04) and concentrated to afford a residue that
was purified on
a Prep HPLC system using 30-100% ACN in 50 mM NH4OAc buffer at 21 mL/min.
Fractions 12-14 were combined and concentrated in vacuo. The resulting
material was
sonicated in MeOH. The suspended precipitate was filtered, rinsed with cold
MeOH and dried
to yield 4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-
yl)cyclopentylamino)butanoic acid, (11 mg, 0.025 mmol) as white solid. LC/MS
(Table 1,
Method c) Rt = 1.72 min, m/z 408.22 (M-H)+. 1H NMR (400 MHz, DMSO) 6 ppm 8.06 -
7.94 (d, 2H), 7.89 - 7.79 (dd, J = 1.99, 8.66Hz, 1H), 7.14 - 7.06 (d, J = 8.68
HZ, 1H), 4.78 -
4.65 (td, J = 6.08, 12.13 Hz, 1H), 4.09 - 3.96 (dd, J = 5.94, 10.14 Hz, 1H),
3.91 - 3.79 (m, 1H),
3.38 - 3.24 (t, J = 7.26 Hz, 2H), 2.73 - 2.65 (dd, J = 4.81 11.44 Hz, 2H),
2.65 - 2.56 (m, 1H),
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2.53 - 2.37 (m, 2H), 2.37 - 2.28 (m, 1H), 2.28 - 2.22 (m, 1H), 2.22 - 2.20 (s,
1H), 2.20 - 2.10
(m, 2H), [2.10 - 1.96 (m, 1H) andl.48 - 1.38 (d, J = 6.05 Hz, 6H)
Preparation #9: (R)-benzyl 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate
O O ' _ ' 1 0 O O
0
--
Ho",,,= 0 I / 0
O H 0"~,.= Co
In a 250 mL round bottom flask was added triphenylphosphine (6.54 g, 24.92
mmol) in THE
(79 mL) to give a colorless clear solution. The solution was cooled to about 0
C by ice-bath.
After stirring for about 15 min, diisopropyl azodicarboxylate (5.11 mL, 24.96
mmol) (orange
liquid) was added dropwise over about 5 min. The reaction mixture turned into
off-white
suspension in the process. The reaction mixture was stirred at about 0 C for
about 30 min.
Then a colorless solution of benzyl 4-hydroxybenzoate (5.69 g, 24.92 mmol) and
(R)-(2,2-
dimethyl-1,3-dioxolan-4-yl)methanol (3.00 mL, 23.73 mmol) in THE (39.5 mL) was
added to
the mixture, keeping the temperature at or below about 0 C. The solution
turned clear light
yellow. The solution was stirred for about 2 h at about 0 C then slowly
warmed to ambient
temperature and stirred over the weekend. The mixture was concentrated in
vacuo to give
crude yellow oil (-27 g). The crude oil was dissolved in ether. Then heptane
was added. The
resultant precipitate was sonicated and filtered. The filtrate was
concentrated and purified via
Analogix system using RediSepTM RS 120g column, with a gradient of 0-20%
EtOAc/Heptane over 10 min at 50 mL/min then hold at 20% ethyl acetate for 20
min.
Fractions containing product were combined and concentrated to afford (R)-
benzyl 4-((2,2-
dimethyl-1,3-dioxolan-4-yl)methoxy)benzoate as white solid (6.17 g, 23.73
mmol). LC/MS
(Table 1, Method c) Rt = 2.89 min, m/z 343.20 (M+H)+
Preparation #10: (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoic acid
O O '_'O I O OH
I I
0 0
Oar o" O"` ..CO/
A 500 mL high-pressure flask was charged with palladium on carbon (0.300 g,
0.282 mmol),
then MeOH (200 mL) was added, followed by (R)-benzyl 4-((2,2-dimethyl-1,3-
dioxolan-4-
yl)methoxy)benzoate (6.17 g, 18.02 mmol). The resulting suspension was allowed
to shake
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under an atmosphere of hydrogen (35 Psi) at ambient temperature for about 2 h.
The mixture
was filtered through Celite and the colorless filtrate was concentrated to
afford (R)-4-((2,2-
dimethyl-1,3-dioxolan-4 yl)methoxy)benzoic acid as white solid (4.45 g , 17.64
mmol).
LC/MS (Table 1, Method c) Rt = 2.15 min, m/z 253.14 (M+H)+
Preparation #11: (R)-3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-
dioxolan-
4-yl)methoxy)phenyl)-1,2,4-oxadi azole
,OH
N 11 ,O,
O (O O ~/
NH2 HO \ O
I
14 NIN
CI / O/
CI
To a slurry of (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoic acid
(0.303 g, 1.203
mmol) in DMF (1.367 mL) was added EDC (0.231 g, 1.203 mmol) followed by HOBT
hydrate (0.163 g, 1.203 mmol). After about 1.5 h a solution of (Z)-3-chloro-N-
hydroxy-4-
isopropoxybenzimidamide (0.250 g, 1.09 mmol) in DMF (1.367 mL) was added. The
reaction
mixture was heated to about 140 C for about 2 h. After cooling to RT the
reaction mixture
was concentrated in vacuo and purified by chromatography on silica gel
(eluting with
EtOAc/Hep) to provide (R)-3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-
1,3-
dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.339 g, 70%) as a colorless
solid. LC/MS
(Table 1, Method c) Rt = 3.36 min, m/z 445 (M+H)+.
Example #9: Preparation of (S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenoxy)propane-1,2-diol
O
L-) 0 HO OH
N-0 N-0
N / O I\ i N / O
CI CI
To a solution of (R)-3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-
dioxolan-4-
yl)methoxy)phenyl)-1,2,4-oxadiazole (0.339 g, 0.762 mmol) in THE (15.24 mL)
was added a
solution of IN HC1 (1.524 mL, 1.524 mmol). After about 48 h additional IN HC1
(2.286 mL,
2.286 mmol) was added and the reaction mixture was heated to about 70 C for
about 2 h.
After cooling to ambient temperature a solution of IN NaOH (3.81 mL, 3.81
mmol) was
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added and the reaction mixture was concentrated in vacuo. The resulting solid
was washed
with water and dried in vacuo to provide (S)-3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)phenoxy)propane-1,2-diol (0.294 g, 94%) as a colorless solid.
LC/MS (Table
1, Method c) Rt = 2.73 min, m/z 405 (M+H)+.
Example #10: Preparation of 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-yl)benzenesulfonamide
N= OH O N'O ~O
\INH2 HO N S~NH2
I O
O / ~ O
CI H2 CI
To a slurry of 4-sulfamoylbenzoic acid (1.452 g, 7.22 mmol) in DMF (8.20 mL)
was added
EDC (1.383 g, 7.22 mmol) followed by HOBT hydrate (0.975 g, 7.22 mmol). After
about 30
min a solution of (Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide in DMF
(8.20 mL)
was added. The reaction mixture was heated to about 140 C for about 2 h.
After cooling to
RT the reaction mixture was concentrated in vacuo and purified by purified by
chromatography on silica gel (eluting with EtOAc/Hep) to provide 4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)benzenesulfonamide (1.28 g, 50%) as a
colorless
solid. LC/MS (Table 1, Method c) Rt = 2.74 min, m/z 392 (M-H)-.
Preparation #12a: Preparation of tert-butyl3,3'-(4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)phenylsulfonylazanediyl)dipropanoate and tert-butyl 3-(4-
(3-(3-
chloro-4-is op rop oxyphenyl)-1,2,4-oxadiaz ol-5-yl)phenylsulfonamid o)pr op
anoate
N'O p p
ii p O N_O 1V"
Z \ N \/ O -N O O N 11x0
O O NH O
/ N \ / O N
CI 0 0 CI
To a solution of 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzenesulfonamide (0.500 g, 1.270 mmol) in DMF (3.17 mL) was added NaH
(0.056 g,
1.396 mmol). After about 10 min. tert-butyl 3-bromopropanoate (0.233 mL, 1.396
mmol) was
added and the reaction mixture was heated to about 60 C. After about 48 h the
reaction
mixture was cooled to RT and purified by chromatography on silica gel (eluting
with
EtOAc/Hep) to provide tert-butyl 3,3'-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-oxadiazol-5-
yl)phenylsulfonylazanediyl)dipropanoate (0.24 g, 29%) as a colorless solid.
LC/MS (Table 1,
Method c) Rt = 3.43 min, m/z 667 (M+NH4)+, in addition to tert-butyl 3-(4-(3-
(3-chloro-4-
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isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenylsulfonamido)propanoate (0.28 g,
42%) as a
colorless solid. LC/MS (Table 1, Method c) Rt = 3.13 min, m/z 521 (M-H)-.
Example #13: Preparation of 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenylsulfonamido)propanoic acid
0 0
N- O O N-OOH
' \ ~\H ~ I \ ' N 0\O O /
qH
CI CI
To a solution of tent-butyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenylsulfonamido)propanoate (0.28 g, 0.536 mmol) in dichloromethane (6.0
mL) was
added TFA (2.0 mL, 26.0 mmol). After about 3 h the reaction mixture was
concentrated in
vacuo and the resulting solid was triturated with ether, filtered and dried to
provide 3-(4-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5yl)phenylsulfonamido)propanoic
acid (0.176 g,
70%) as a colorless solid. LC/MS (Table 1, Method c) Rt = 2.54 min, m/z 466
(M+H).
Example #14: Preparation of 2,2'-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenylsulfonylazanediyl)diacetic acid
N-O O N-O O ~OH
~ ' N 0 0 \ ~ N ~ ON~
O / O~ O I / Ozz~'
CI -\/O CI OH
TFA (1.0 mL, 12.98 mmol) was added to a stirred mixture of tent-butyl2,2'-(4-
(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonylazanediyl)diacetate
(0.106 g, 0.170
mmol), dichlorom and then concentrated in vacuo. The resulting residue was
triturated with
diethyl ether, filtered and dried to give 2,2'-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)phenylsulfonylazanediyl)diacetic acid (63 mg, 0.122 mmol) as a
white solid.
LC/MS (Table 1, Method c) Rt = 1.84 min, m/z 508.38 (M-H)-.
Preparation #12b: Preparation of tert-butyl2,2'-(4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)phenylsulfonylazanediyl)diacetate and tert-butyl 2-(4-(3-
(3-chloro-4-
isoprop oxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)acetate
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N_O OHO N-O
- O -! NCO O ~(O
\ N O NH z N p -N O \ ' N S-N \\
O / O O~ /gyp / O H O
CI CI -~O
CI
Powdered K2CO3 (0.190 g, 1.374 mmol) was added dropwise to a stirred mixture
of 4-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzenesulfonamide (0.492 g,
1.249 mmol)
in anhydrous ACN (6.25 mL) under N2. Tert-butyl 2-bromoacetate (0.203 mL 1.374
mmol)
was then added and the mixture heated to about 80 C for about 3 h. The
reaction mixture
(suspension) was concentrated in vacuo and the resulting material triturated
in DCM and
filtered. The filtrate was concentrated and purified directly via AnalogiA
system using
RediSepTM RS 40g column, with a gradient of 0-40% EtOAc/Heptane over 40 min.
at 30
mL/min. Fractions containing product were combined and concentrated. This gave
tent-butyl
2,2 '-(4-(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-
yl)phenylsulfonylazanediyl)diacetate (249 mg, 0.400 mmol) as a sticky white
solid LC/MS
(Table 1, Method c) Rt = 3.17 min, m/z 639 (M+NH4)+ and tent-butyl 2-(4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenylsulfonamido)acetate (121 mg,
0.238 mmol) as
a white solid LC/MS (Table 1, Method c) Rt = 2.81 min, m/z 508 (M+H)+.
Example #16: Preparation of 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenylsulfonamido)acetic acid
o OH
A O N-O ~O
N N _ ' NZ
N'
O H O SH O
CI CI
TFA (2.0 mL, 26.0 mmol) was added dropwise to a stirred mixture of tent-butyl
2-(4-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylsulfonamido)acetate
(0.121 g, 0.238
mmol), DCM (5.0 mL) under N2. The mixture was stirred at ambient temperature
for about 3
h then concentrated in vacuo. The resulting solid was triturated in ether,
filtered and dried to
yield 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5yl)phenylsulfonamido)acetic
acid (46 mg, 0.102 mmol ) as a white solid. LC/MS (Table 1, Method c) Rt =
2.14 min, m/z
450.34 (M-H)-
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Preparation #12c: Preparation of tert-butyl 2-(5-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadi azol-5-yl)-3,4-dihydrois oquinolin-2 (1H)-yl)acetate
N-O N-O
CI NH CI q
O
To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-
tetrahydroisoquinolin-5-yl)-
1,2,4-oxadiazole (0.0726 g, 0.196 mmol) in DMF (1.963 mL) was added K2CO3
(0.054 g,
0.393 mmol) followed by tert-butyl bromoacetate (0.030 mL, 0.206 mmol). After
about 48 h
the reaction mixture was filtered, concentrated in vacuo and purified by
chromatography to
provide tert-butyl 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)-
3,4-
dihydroisoquinolin-2(IH)yl)acetate as a colorless oil that solidified on
standing. LC/MS
(Table 1, Method c) Rt = 3.41 min, m/z 486 (M+H)+.
Preparation #12d: Preparation of tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadi azol-5-yl)-3,4-dihydrois o quinoline-2 (1HH)-carb oxylate
NOH O
N.O
NH2 O N~O I N
O HO I J /
CI
/ O CI N
O
To a slurry of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-
carboxylic acid (0.380
g, 1.371 mmol) in DMF (1.662 mL) was added EDC (0.263 g, 1.371 mmol) followed
by
HOBT hydrate. After about 1 h a solution of (Z)-3-chloro-N-hydroxy-4-
isopropoxybenzimidamide (0.285 g, 1.246 mmol) in DMF (0.831 mL) was added and
the
reaction mixture was heated to about 140 C for about 1 h. The reaction
mixture was
concentrated in vacuo and purified by chromatography on silica gel to provide
tert-butyl 5-(3-
(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5 yl)-3, 4-dihydroisoquinoline-
2 (1 H)-
carboxylate (0.403 g, 69%) as a colorless oil. LC/MS (Table 1, Method c) Rt =
3.43 min, m/z
471 (M+H)+.
Example #19: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-
tetrahydrois o quinolin-5-yl)-1,2,4-oxadiaz ole
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N-O N-O
N \ / \ I N
O
N
CI 1 CI NH 01-
To a solution of tent-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-yl)-3,4-
dihydroisoquinoline-2(1H)-carboxylate (0.403 g, 0.858 mmol) in dioxane (17.15
mL) was
added a 4N solution of HC1 in 1,4-dioxane (3.86 mL, 15.44 mmol). After about
15 h the
reaction mixture was filtered. The resulting solid was partitioned between
EtOAc and
saturated NaHCO3. The organic layer was separated, dried (MgSO4) filtered and
concentrated
in vacuo to provide 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-
tetrahydroisoquinolin-5 yl)-
1,2,4-oxadiazole (0.230 g, 73%) as a colorless solid. LC/MS (Table 1, Method
c) Rt = 2.00
min, m/z 372 (M+H).
Example #20: Preparation of 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetic acid
N-O T N-O T
N I \ ' N
CI ~O CI N OH
O
To a solution of tent-butyl 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-3,4-
dihydroisoquinolin-2(1H)-yl)acetate (0.1319 g, 0.273 mmol) in dichloromethane
(10 mL was
added triisopropylsilane (0.056 mL, 0.273 mmol) followed by TFA (2 mL). After
about 15 h
reaction mixture was concentrated in vacuo. The resulting solid was triturated
in ether, filtered
and dried to provide 2-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)-3,4-
dihydroisoquinolin-2(IH)yl)acetic acid (0.138 g, 93%) as an off-white solid.
LC/MS (Table
1, Method c) Rt = 2.00 min, m/z 428 (M+H)+.
Preparation #12e: Preparation of tert-butyl 3-(5-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadi azol-5-yl)-3,4-dihydrois oquinolin-2 (1H)-yl)p rop ano ate
N-O N-O
'N" "~0'91N 0
CI T., CI N
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To 3-(3-chloro-4-isopropoxyphenyl)-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-
1,2,4-oxadiazole
(0.1088 g, 0.294 mmol) in DMF (2.94 mL) (briefly heated to about 40 C for
complete
dissolution) was added K2CO3 (0.081 g, 0.588 mmol) and tent-butyl 3-
bromopropanoate
(0.046 mL, 0.276 mmol) and the mixture stirred at ambient temperature for
about 2 h.
Additional tent-butyl 3-bromopropanoate (0.053 mL, 0.315 mmol) was added and
the reaction
was stirred at about 60 C over the weekend. Additional tent-butyl 3-
bromopropanoate (0.053
mL, 0.315 mmol) was added and the reaction continued heating at about 60 C
overnight.
Additional K2CO3 (0.041 g, 0.294 mmol) was added, followed by tent-butyl 3-
bromopropanoate (0.053 mL, 0.315 mmol). The reaction was heated at about 60 C
overnight.
The reaction mixture was filtered and the filtrate concentrated in vacuo to
give -179 mg of
crude yellow oil. The crude residue was purified via Analogix system using
RediSepTM RS
12g column, with a gradient of 0-45% EtOAc/Heptane over 35 min. at 15 mL/min.
Fractions
23-28 were combined and concentrated to yield tent-butyl 3-(5-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)-3,4-dihydroisoquinolin-2(JH)
yl)propanoate (91 mg,
0.183 mmol) as light yellow oil. LC/MS (Table 1, Method c) Rt = 3.39 min, m/z
500.72
(M+H)+.
Example #22: Preparation of 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)-3,4-dihydroisoquinolin-2(1H )-yl)propanoic acid, TFA salt
N-O N-O
#1 N N
O O "~O O
CI N_~-O
CI N\ OH
X
To tent-butyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3,4-
dihydroisoquinolin-2(1H)-yl)propanoate (0.091 g, 0.183 mmol) in
dichloromethane (6.0 mL)
TFA (1.5 mL) was added and the mixture stirred at ambient temperature
overnight. The
reaction mixture was concentrated in vacuo and the resulting crude product was
dissolved in
small amount of DCM. Ether was added until a solid precipitated out. The
mixture was
filtered, rinsed with ether and dried to give 3-(5-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-3,4-dihydroisoquinolin-2(JH)-yl)propanoic acid, TFA salt (74.7
mg, 0.134
mmol ) as light yellow solid. LC/MS (Table 1, Method c) Rt = 2.04 min, m/z
442.25 (M+H).
1H NMR (400 MHz, DMSO) 6 ppm 8.18 - 8.11 (dd, J = 2.07 6.76 Hz, 1H), 8.11 -
8.06 (d, J =
2.01 Hz, 1H), 8.06 - 7.99 (J = 2.02, 8.64 Hz, 1H), 7.61 - 7.53 (J = 6.58, 6.58
Hz, 1H), 7.45 -
7.37 (J = 8.8 Hz, 1H), 4.90 - 4.78 (m, 1H), 4.65 - 4.46 (s, 2H), 3.71 - 3.51
(s, 3H), 3.51 - 3.38
(J = 6.87, 6.87 Hz, 3H),2.91 - 2.81 (t, J = 7.32, 7.32 Hz, 2H) and 1.39 - 1.33
(d, 6H)
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Preparation #12: 4-isopropoxy-3-(trifluoromethyl)benzonitrile.
CF3 /CN
CF3CN
O
HO
Under an atmosphere of nitrogen a mixture of 4-hydroxy-3-
(trifluoromethyl)benzonitrile (5.89
g, 31.5 mmol) and triphenylphosphine (13.21 g, 50.4 mmol) in anhydrous THE
(200 mL) was
stirred for about 5 min at ambient temperature. To the solution DBAD (11.60 g,
50.4 mmol)
was added, stirred about 5 min before the addition of 2-propanol (3.03 mL,
39.3 mmol). The
mixture was stirred at ambient temperature for about 72 h. The solvent was
removed under
reduced pressure. The resulting oil was triturated with 30-60 C pet/ether
(200 mL), filtered to
remove phosphine oxide and the crude product was purified further by elution
through silica
with heptane/ethyl acetate (4:1). The isolated oil was dissolved in
dichloromethane (200 mL)
and stirred with TFA (4.85 mL, 63.0 mmol) for about 90 min at ambient
temperature. The
solution was basified with 2.5 N NaOH (30 mL) and the product was partitioned
between
DCM and the basic aqueous phase to give the crude 4-isopropoxy-3-
(trifluoromethyl)benzonitrile (6.56, 91%). LC/MS (Table 1, Method a) Rt = 2.32
min, 1H
NMR (400MHz, CDC13) 7.85 (d, 1H), 7.75 (dd, 1H), 7.06 (d, 1H), 4.73 (m, 1H),
1.41 (dd,
6H).
Preparation #13: (Z)-N'-hydroxy-4-isopropoxy-3-(trifluoromethyl)benzimidamide
OH
CF 3 /CN N
CF3I / NH
O Z
O
Under an atmosphere of nitrogen, 4-isopropoxy-3-(trifluoromethyl)benzonitrile
(6.5 g, 28.4
mmol) and 50% aqueous hydroxylamine (5.21 mL, 85 mmol) in EtOH (20.0 mL) was
heated
at about 60 C for about 18 h. Solvents were removed in vacuo and the residue
was
azeotroped with MeOH. The residual solid was purified by precipitation from an
ethyl acetate
/ 30-60 C pet/ether mixture (1: 2) to give (Z)-N'-hydroxy-4-isopropoxy-3-
(trifluoromethyl)benzimidamide (2.51g, 33.8%) LC/MS (Table 1, Method b) Rt =
1.89 min,
m/z 263.13 (M+H)+.
Preparation#14: (S)-3-chloro-4-(tetrahydrofuran-3-yloxy)benzonitrile.
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CI \ CN
CI \ CN
O
HO
O
Under an atmosphere of nitrogen, a mixture of 3-chloro-4-hydroxybenzonitrile
(8.70g, 56.7
mmol) and triphenylphosphine (23.77 g, 91 mmol) in anhydrous THE (218 mL) was
stirred
for about 5 min at ambient temperature. To the solution DBAD (20.87 g, 91
mmol) was
added, stirred about 5 min before the addition of (S)-(+)-3-
hydroxytetrahydrofuran (3.87 mL,
56.7 mmol) in THE (10 mL). The mixture was stirred at ambient temperature for
about 24 h.
The solvent was removed under reduced pressure. The residue was dissolved in
dichloromethane (200 mL) and stirred with TFA (21.82 mL, 283 mmol) for about
90 min. at
ambient temperature. The solution was basified with aqueous sodium hydroxide
and the
product was partitioned between DCM and the basic aqueous phase. The DCM was
dried over
magnesium sulphate, filtered and solvent removed under reduced pressure to
give an oil. The
oil was stirred with hot 30-60 C pet/ether (200 mL), cooled and filtered. The
solvent was
removed under reduced pressure to give the crude (S)-3-chloro-4-
(tetrahydrofuran-3-
yloxy)benzonitrile (11.2g). Rt 2.06 min, m/z 378.2 (M+H)+.
Preparation #15: (S,Z)-3-chloro-N'-hydroxy-4-(tetrahydrofuran-3-
yloxy)benzimidamide
N,OH
CI CN
CI I \ NH2
O
O
O 0
Under an atmosphere of nitrogen, (S)-3-chloro-4-(tetrahydrofuran-3-
yloxy)benzonitrile (11.2
g, 50.1 mmol) and 50% aqueous hydroxylamine (3.31 g, 50.1 mmol) in EtOH (150.0
mL) was
heated at about 60 C for about 18 h. Solvents were removed in vacuo and the
residue was
azeotroped with MeOH. The residual solid was purified by precipitation from an
ethyl acetate
/ 30-60 C pet/ether mixture (1:2) to give (S,Z)-3-chloro-N'-hydroxy-4-
(tetrahydrofuran-3-
yloxy)benzimidamide (5.3g) LC/MS (Table 1, Method b) Rt = 1.52 min, m/z 257.09
(M+H)+.
Preparation #16: 4-morpholino-3-(trifluoromethyl)benzonitrile
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F F N F F N
F \ low F~
F N
OJ
To a solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (15 g, 79 mmol) in
dimethylsulfoxide (160 mL) was added morpholine (13.8 mL, 159 mmol) and
potassium
carbonate (16.4 g, 119 mmol). The mixture was heated at about 90 C for about
18 h. The
mixture was cooled to ambient temperature and the solid was removed by
filtration. The
filtrate was partitioned between ethyl acetate (1.8 L) and water (1.5 L). The
organic layer was
washed with water (1.0 L) and brine (1.0 L) and dried over anhydrous magnesium
sulphate.
The solvent was removed in vacuo to give 4-morpholino-3-
(trifluoromethyl)benzonitrile
(17.25 g, 85 %).'H NMR (DMSO-d6, 400MHz) d ppm 8.18 (d, J = 2.05 Hz, 1H), 8.09
(dd,
J = 8.51, 2.06 Hz, 1H), 7.60 (d, J = 8.52 Hz, 1H), 3.69-3.75 (m, 4H), 2.97-
3.04 (m, 4H).
Preparation #17: N'-hydroxy-4-morpholino-3-(trifluoromethyl)benzimidamide
NOH
F F iN F VN
F F NH2
To a solution of 4-morpholino-3-(trifluoromethyl)benzonitrile (17.3 g, 67.3
mmol) in ethanol
(400 mL) was added a 50% aqueous solution of hydroxyl amine (4.9 mL, 74.1
mmol)
dropwise. The mixture was heated at about 65 C for about 24 h. The mixture
was cooled to
ambient temperature and the solid was removed by filtration. The filtrate was
partitioned
between ethyl acetate (1.8 L) and water (1.5 L). The organic layer was washed
with water (1.0
L) and brine (1.0 L) and dried over anhydrous magnesium sulphate. The solvent
was removed
in vacuo to give N'-hydroxy-4-morpholino-3-(trifluoromethyl)benzimidamide
(18.6 g, 91 %)
as a mixture of syn/anti isomers. LC/MS (Table 1, Method b) R, = 1.85 min, m/z
290.15
(M+H) ; 'H NMR (DMSO-d6, 400MHz) 6 ppm 9.75 (s, 1H), 8.09-8.16 (m, 1H), 7.89-
7.96
(m, 1H), 7.52-7.58 (m, 1H), 3.66-3.72 (m, 4H), 2.83-2.93 (m, 4H).
Preparation #18: 5-Methoxy-3,6-dihydro-2H-pyrazine-l-carboxylic acid benzyl
ester
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O O
/ I N rN
OUN OUN J
II II
O O
A solution of benzyl 3-oxopiperazine-l-carboxylate (2.50g, 10.67 mmol) in
CH2C12 (100 mL)
was cooled to about 0 C and treated with Na2CO3 (23.0 g, 217 mmol) for about
10 min. Neat
trimethyloxonium tetrafluoroborate (5.50 g, 37.2 mmol) was added in one
portion, then the
reaction is allowed to warm to RT for about 6 h. The reaction was poured into
water (100
mL), and the layers were separated. The aqueous layer was re-extracted with 50
mL CH2C12
and the combined organic layers were washed with brine (100 mL). The organic
layer was
dried over sodium sulfate, filtered and concentrated to yield 5-methoxy-3, 6-
dihydro-2H-
pyrazine-1-carboxylic acid benzyl ester (2.51g, 95%) as an oil. LC/MS (Table
1, Method a)
Rt = 3.00 min, m/z 249.24 (M+H)+ ; 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.36 (m,
5H),
5.16 (s, 2H), 3.96 (s, 2H), 3.68 (s, 3H), 3.54 (s, 2H), 3.47 (m, 2H)
Preparation #19: 3-Methyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-carboxylic
acid
benzyl ester
O
N
N N
"'O NJ \ O NJ
O Y
To a solution of 3-methoxy-5,6-dihydropyrazine-1(2H)-carboxylate (4.48 g,
18.03mmol) in
MeOH (200 mL) was added propargylamine (6.18 mL, 90 mmol) at RT. The mixture
was
heated at reflux for about 5 h, then cooled to RT and concentrated. The
residue was dissolved
in IN HC1 (100 mL) and washed with 3 x 75 mL ethyl acetate. The aqueous
solution was
neutralized with solid Na2CO3 and extracted with 2 x 100 mL ethyl acetate. The
combined
extracts were washed with 100 mL saturated NaCl solution, filtered and
concentrated. The
residue was triturate with ether, filtered and dried under reduced pressure to
yield 3-Methyl-
5,6-dihydro-8H-imidazo[1,2-aJpyrazine-7-carboxylic acid benzyl ester (2.91 g,
60%) as an
off-white solid. LC/MS (Table 1, Method a) Rt = 3.07 min, m/z 272.11 (M+H)+-;
1H NMR
(400 MHz, DMSO-d6) 6 ppm 7.30 (m, 5H), 6.58 (q, 1H), 5.13 (s, 2H), 4.55
(s,broad, 2H),
3.84 (s, 4H), 2.10 (s, 3H).
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Preparation #20: 2-Iodo-3-methyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-
carboxylic
acid benzyl ester
I
N~ N
~N ~N
OUN O N
I I Y
O O
To a solution of benzyl 3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(811)-
carboxylate
(1.085 g, 4.00 mmol) in 1,2-dichloroethane (60 mL) was added NIS (4.50 g,
20.00 mmol) and
the reaction was heated at reflux for about 1 h. The reaction was cooled to RT
and poured into
100 mL of saturated 5% sodium thiosulfate solution. The layers were separated
and the
aqueous layer was re-extracted with 1,2-dichloroethane (40 mL). The combined
organic
layers were washed with water (100 mL), dried over sodium sulfate, filtered
and concentrated.
Product was extracted from the residue by trituration with 3 x 50 mL portions
of ether. The
extract was filtered and concentrated to yield 2-Iodo-3-methyl-5,6-dihydro-8H-
imidazo[1,2-
aJpyrazine-7-carboxylic acid benzyl ester (1.42 g, 89%) as a pale yellow oil.
LC/MS (Table
1, Method a) Rt = 3.32 min, m/z 398.59 (M+H)+ ; 1H NMR (400 MHz, CHC13) 6 ppm
7.35
(m, 5H), 5.13 (s, 2H), 4.56 (s,broad, 2H), 4.38 (t, 2H), 3.82 (s, broad, 2H),
2.09 (s, 3H)
Preparation #21: 3-Methyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-2,7-
dicarboxylic acid
7-benzyl ester
O
O
N N
O N N
a Y J UN J
II II
O O
A solution of benzyl 2-iodo-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-
carboxylate
(900 mg, 2.266 mmol) in dry THE (25 mL) was cooled to about 0 C and ethyl
magnesiumbromide (1.888 mL, 5.66 mmol) was added at such a rate as to maintain
the
reaction temperature below about 2.5 C. The reaction was stirred under
nitrogen at about 0
C for about 15 min. then the reaction was quenched with a stream of carbon
dioxide. The
reaction was concentrated to solids and acetic acid (0.60 mL, 10.48 mmol)
ethyl acetate (50
mL) were added and the suspension was stirred vigorously at RT for about 15
min. The
resulting solid was filtered and washed with an additional 15 mL ethyl
acetate. The residue
was dissolved in 10 mL water plus 2 N HC1 to pH 4, then washed 2 times with 10
mL ether
then extracted with 4 x 20 mL CH2C12. The combined organic extracts were dried
over
sodium sulfate, filtered and evaporated under reduced pressure to yield 3-
Methyl-5, 6-dihydro-
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8H-imidazo[1,2-aJpyrazine-2,7-dicarboxylic acid 7-benzyl ester (374 mg, 52%)
as a foam.
LC/MS (Table 1, Method a) Rt = 2.28 min, m/z 316.10 (M+H)+-; 1H NMR (400 MHz,
DMSO-d6) 6 ppm 7.35 (m, 5H), 5.11 (s, 2H), 4.56 (s,broad, 2H), 3.88 (m, 2H),
3.83 (s, broad,
2H), 2.36 (s, 3H).
Preparation #22: Preparation of 2-[3-(3-Chloro-4-isopropoxy-phenyl)-
[1,2,4]oxadiazol-5-
yl]-3-methyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazine-7-carboxylic acid benzyl
ester
Y
o , o
0
O N- I
-N
N-?i CI
N N
01"'0 N,
I I N
N
0 Oy
I
I
O
To a solution of 7-(benzyloxycarbonyl)-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-
a]pyrazine-
2-carboxylic acid (370 mg, 1.173 mmol) in DCM (10 mL) was added oxalyl
chloride (2.054
mL, 23.47 mmol) and DMF (5 L). The reaction was stirred for about 1 h and
concentrated.
A solution of (E)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide (268 mg, 1.173
mmol) in
pyridine (10.00 mL) was added and the reaction was stirred at RT for about 30
min. The
reaction was treated with acetyl chloride (0.092 mL, 1.291 mmol) and then was
heated at 115
C under nitrogen for about 4 h. The reaction was cooled, concentrated and
partitioned
between saturated Na2CO3 and methylene chloride. The organic layer was washed
with water,
dried (sodium sulfate), filtered and concentrated under reduced pressure. The
residue was
purified on silica gel using 80:20 / methylene chloride:ethyl acetate as the
eluent to yield 2-[3-
(3-chloro-4-isopropoxyphenyl)-[1,2,4]oxadiazol-5 ylJ-3-methyl-5,6-dihydro-8H-
imidazo[1,2-
aJpyrazine-7-carboxylic acid benzyl ester (173 mg, 29%) as an off-white solid.
LC/MS
(Table 1, Method a) Rt = 4.34 min, m/z 508.24 (M+H)+-; 1H NMR (400 MHz, DMSO-
d6) 6
ppm 7.98 (d, 1H), 7.93 (d,d, 1H), 7.35 (m, 6H), 5.12 (s, 2H), 4.78 (m, 1H),
4.66 (s,broad, 2H),
3.99 (m, 2H), 3.88 (s, broad, 2H), 2.57 (s, 3H), 1.31 (d, 6H).
Example #23: Preparation of 2-[3-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]
oxadiazol-5-yl]-
3-methyl-5, 6,7,8-tetrahydro-imidazo [1,2-a] pyrazine
0
O)I- N NO`N N O-N
~ ~4N
O O1~
CI CI
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A solution of benzyl 2-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-
3-methyl-5,6-
dihydroimidazo[1,2-a]pyrazine-7(811)-carboxylate (160 mg, 0.315 mmol) in 33%
HBr
solution in acetic acid (2.00 mL) containing triisopropylsilane (0.065 mL,
0.315 mmol)) was
stirred at RT under nitrogen for about 10 min. Ether (20 mL) was added to
precipitate the
product. The resulting solid was filtered off, treated with saturated
bicarbonate solution (10
mL) and extracted with methylene chloride (2 x 10 mL). The combined organic
layers were
dried over sodium sulfate, filtered, concentrated to solids and dried under
reduced pressure to
yield 2-[3-(3-chloro-4-isopropoxy phenyl)-[1, 2, 4]oxadiazol-5-ylJ-3-methyl-5,
6, 7, 8-
tetrahydro-imidazo[1,2-a]pyrazine (113 mg, 96 %) as an off-white solid. LC/MS
(Table 1,
Method a) Rt = 3.14 min, m/z 374.24 (M+H)+ ; 1H NMR (400 MHz, DMSO-d6) 6 ppm
8.01
(d, 1H), 7.97 (d,d, 1H), 7.36 (d, 1H), 4.81 (m, 1H), 4.66 (s, 2H), 3.90 (s,
2H), 3.87 (t, 2H),
3.12 (t, 2H), 2.60 (s, 3H), 1.34 (d, 6H).
Example #24: Preparation of 1-{2-[3-(3-Chloro-4-isopropoxy-phenyl)-
[1,2,4]oxadiazol-5-
yl]-3-methyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl}-ethanone
0
N 'AN
N O`N N O`N
N~N I \ 30 N~N I \
CI CI
To a solution of 2-(3-chloro-4-isopropoxyphenyl)-3-methyl-5,6,7,8-
tetrahydroimidazo[1,2-
a]pyrazine (32 mg, 0.105 mmol) in methlyene chloride (2.0 mL) was added acetyl
chloride
(7.50 L, 0.105 mmol) at RT. The mixture was stirred at RT for 4 h and
concentrated. The
residue was purified by reverse phase HPLC to yield 1-{2-[3-(3-chloro-4-
isopropoxyphenyl)-
[1,2,4]oxadiazol-5 ylJ-3-methyl-5,6-dihydro-8H-imidazo[1,2-aJpyrazin-7 yl}-
ethanone (31
mg, 86%) as an off-white solid. LC/MS (Table 1, Method a) Rt = 3.46 min, m/z
416.20(M+H)+; 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.02 (d, 1H), 8.97 (d,d, 1H),
7.37 (d,
1H), 4.81 (m, 2H), 4.70 (s, 2H), 3.90 (s, 2H), 4.07 (tOm, 1H), 3.95 (m, 3H),
2.62 (s, 3H), 2.14
(m, 3H), 1.34 (d, 6H).
Preparation #22a: Preparation of {2-[3-(3-Chloro-4-isopropoxy-phenyl)-
[1,2,4]oxadiazol-
5-yl]-3-methyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl}-acetic acid tert-
butyl ester
O-N
/ O-N _ O\ CNC~
N N
N
CI a
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To a solution of 3-(3-chloro-4-isopropoxyphenyl)-5-(3-methyl-5,6,7,8-
tetrahydroimidazo[1,2-
a]pyrazin-2-yl)-1,2,4-oxadiazole (50.0 mg, 0.134 mmol) in DMF (1.0 mL) at RT
was added
sodium carbonate (28.4 mg, 0.267 mmol) and tent-butyl bromoacetate (0.021 mL,
0.140
mmol) at RT. The reaction was continued overnight. The reaction was filtered
and
concentrated. The residue was dissolved in ethyl acetate (10 mL), washed with
brine (10 mL),
dried over sodium sulphate, filtered and concentrated to yield {2-[3-(3-chloro-
4-isopropoxy-
phenyl)-[1,2,4]oxadiazol-5 ylJ-3-methyl-5,6-dihydro-8H-imidazo[1,2-aJpyrazin-7-
yl}-acetic
acid tent-butyl ester (35 mg, 54%) as an off-white foam which was used in the
next step
without further purification. LC/MS (Table 1, Method a) Rt = 4.32 min, m/z
488.29 (M+H)+
Example #26: Preparation of {2-[3-(3-Chloro-4-isopropoxy-phenyl)-
[1,2,4]oxadiazol-5-
yl]-3-methyl-5,6-dihydro-8H-imidazo[1,2-a]pyrazin-7-yl}-acetic acid,
triflouroacetic acid
salt
O~CT'N O-N O1N N O-N
~N I l
O N O 1\
O
CI CI
To a solution of tent-butyl 2-(2-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-3-
methyl-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)acetate (32 mg, 0.066 mmol)
and
triisopropylsilane (0.013 mL, 0.066 mmol) in methylene chloride (2.0 mL) was
added TFA
(2.0 mL) at RT for about 3 h. The reaction was diluted with ether (20 mL) and
the product
was filtered off and dried under reduced pressure. LC/MS (Table 1, Method a)
Rt = 2.99 min,
m/z 432.23 (M+H)+-; 1H NMR (400 MHz, DMSO-d6) 6 8.0 (m, 2H), 7.36 (m, 1H),
4.81 (m,
1H), 3.97 (m, 2H), 3.84 (m, 2H), 3.46 (m, 2H), 3.09 (m, 2H), 2.59 (s, 3H),
1.33 (d, 6H).
Preparation #23: 2-Methyl-imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester
\ N Na
NN
IIN_'
0
A solution of pyrazin-2-amine (3.6 g, 37.9 mmol) and ethyl 2-chloro-3-
oxobutanoate (5.24
mL, 37.9 mmol) in ethanol (30 mL) was heated at reflux for about 9 h. A 1 N
solution of HC1
in ether was added and the mixture was concentrated under reduced pressure.
The residue
was triturated with 3 x 50 mL ACN and filtered to yield crude 2-methyl-
imidazo[1,2-
aJpyrazin-3-carboxylic acid ethyl ester (4.5 g, 58%) as an amorphous solid
which was used
in the next step without further purification.
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Preparation #24: 2-Methyl-imidazo[1,2-a]pyrazine-3-carboxylic acid
N N a
O
O O
A solution of sodium hydroxide (1.754 g, 43.9 mmol) in water (25 mL) was added
to crude
ethyl 2-methylimidazo[1,2-a]pyrazine-3-carboxylate (4.5g, 21.93 mmol). The
reaction is
exothermic and goes to completion in minutes without additional heating. The
mixture was
acidified with concentrated HCl to about pH 5. The solution was injected onto
a preparative
C18 column and washed with water and then eluted with 20% CH3CN / water. The
product
fractions were combined and concentrate to yield 2-methyl-imidazo[1,2-
aJpyrazine-3-
carboxylic acid (250mg, 6%) as a tan solid. LC/MS (Table 1, Method a) Rt =
0.84 min, m/z
176.18 (M-H)-; 1H NMR (400 MHz, DMSO-d6) 6 9.12 (m, 2H), 8.12 (m, 1H), 2.66
(s, 3H).
Example #27: Preparation of 3-[3-(3-Chloro-4-isopropoxy-phenyl)-[1,2,4]
oxadiazol-5-yl]-
2-methyl-imidazo [1,2-a] pyrazine
CI
O N
I
O N-O ~N
0
A solution of 2-methylimidazo[1,2-a]pyrazine-3-carboxylic acid (250 mg, 1.411
mmol) in
DCE (5 mL) was treated with Hunig's Base (0.542 mL, 3.10 mmol) and HATU (590
mg,
1.552 mmol) at RT for about 15 min. and about 40 C for about 30 min. The
reaction was
concentrated and the residue was dissolved in acetic acid (10 mL) and heated
at about 100 C
for about 45 min. The reaction was cooled to RT and concentrated under reduced
pressure.
The residue was partitioned between saturated sodium carbonate solution (10
mL) and
methylene chloride (2 x 10 mL). The organic layers were dried with sodium
sulfate, filtered
and concentrated under reduced pressure. The residue was purified on silica
gel using 9:1 /
CH2C12:MeOH. The product fractions were combined and concentrated under
reduced
pressure to yield 3-[3-(3-chloro-4-isopropoxy phenyl)-[1,2,4]oxadiazol-5 ylJ-2-
methyl-
imidazo[1,2-aJpyrazine (133 mg, 25%) as a tan solid.
LC/MS (Table 1, Method a) Rt = 4.31 min, m/z 370.25 (M+H)+; 1H NMR (400 MHz,
DMSO-
d6) 6 9.43 (d,d, 1H), 9.26 (d, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 8.10 (d,d,
1H), 7.40 (d, 1H),
4.84 (m, 1H), 2.84 (s, 3H), 1.36 (d, 6H)
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Preparation #24a: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-
dimethyl-
1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole
0 CI
N-O
NO H CI O
N
&NH,
CI O "Co O
O'_'~o
In a 25 mL microwave tube 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoyl
chloride
(0.483 g, 1.784 mmol) and (Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide
(0.272 g,
1.189 mmol) in pyridine (15 mL) were combined to give an orange solution. The
vessel was
capped and the reaction heated at about 200 C for about 20 min under
microwave irradiation
(Biotage OptimizerTM, 300 W). The mixture was cooled, the solvent was removed
to afford a
yellow solid, which was partitioned between water (100 mL) and EtOAc (50 mL),
extracted
by EtOAc (2 x 30 mL), the combined EtOAC layer was washed by water (2 x 30
mL), and
concentrated to afford a yellow solid, which was purified via silica gel
chromatography (40 g,
30% EtOAc:Heptane) to afford 3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-
dimethyl-1, 3-
dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.3g, 0.674 mmol, 56.7 %
yield) as white
solid. LC/MS (30_95 NH4OAc 4m GC8.olp) Rt = 3.22 min.; MS m/z: 445.31 (M+H).
1H
NMR (400 MHz, d-DMSQ. 5 ppm 8.17-8.09 (m, 2H), 8.05 (d, J = 2.13 Hz, 1H), 7.99
(dd, J =
8.64, 2.15 Hz, 1H), 7.38 (d, J = 9.01 Hz, 1H), 7.26-7.19 (m, 2H), 4.88-4.77
(m, 1H), 4.45 (s,
1H), 4.23-4.07 (m, 3H), 3.79 (dd, J = 8.42, 6.29 Hz, 1H), 1.35 (m, 12H).
Preparation #25: tert-butyl 2-(4-(chlorocarbonyl)phenoxy)acetate
O OH OO O CI
CI CI
O O
O"'~'O j< O'_AOk
In a 100 mL round bottomed flask was 4-(2-tert-butoxy-2-oxoethoxy)benzoic acid
(0.76 g,
3.01 mmol) in dichloromethane (30.1 mL) to give a colorless suspension. Five
drops DMF
was added to the solution. The reaction mixture was cooled by ice-bath. Oxalyl
chloride
(0.396 mL, 4.52 mmol) was added dropwise. The ice-bath was removed, and the
solution was
stirred at RT for about 40 min. The reaction mixture was concentrated to
afford tent-butyl 2-
(4-(chlorocarbonyl)phenoxy)acetate (0.86 g, 3.18 mmol, 105 % yield) as
colorless oil. 1H
NMR (400 MHz, CDC13) dppm 8.10 (d, 2H), 6.95 (d, 2H), 4.61 (s, 2H), 1.49 (s,
9H)
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Example #29: Preparation of 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenoxy)acetic acid
0 CI
OH N'0
CI ' CI
/\ I \ NH2 O O
O
O I
O O OH
"k O
A 25 mL microwave reaction vial was charged with tent-butyl 2-(4-
(chlorocarbonyl)phenoxy)acetate (0.815 g, 3.01 mmol) and pyridine (15 mL), (Z)-
3-chloro-N'-
hydroxy-4-isopropoxybenzimidamide (0.459 g, 2.007 mmol) was added. The vessel
was
capped and the reaction heated at about 200 C for about 20 min under
microwave irradiation
(Biotage Optimizer, 300 W). The mixture was cooled, the reaction mixture was
poured into
stirring HC1 (10%, 100 mL), the resulting suspension was filtered, the solid
was washed by
HC1 (5%, 2x10 mL) and dried to afford grey solid, which was purified by RP-
HPLC (A =
50mM ammonium acetate, B = ACN; 30-95% B over 25.0 min (21.0 mL/min flow
rate); 21.2
x 250 mm Thermo Hyperprep C18 column, 8 pm particles) to give 2-(4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenoxy)acetic acid (0.246 g, 0.633
mmol, 31.5 %
yield) as white solid. LC/MS (Table 1, Method f) Rt = 2.08 min.; MS m/z:
389.14 (M+H)+.
1H NMR (400 MHz, d-DMSO 6 ppm 13.28-13.07 (m, 1H), 8.13 (d, J = 9.03 Hz, 2H),
8.05 (d,
J = 2.13 Hz, 1H), 7.99 (dd, J = 8.64, 2.15 Hz, 1H), 7.38 (d, J = 9.04 Hz, 1H),
7.18 (d, J =
9.06 Hz, 2H), 4.85 (s, 3H), 1.35 (d, J = 6.03 Hz, 6H).
Preparation #26: Preparation of 5-(6-(1H-benzo[d][1,2,3]triazol-1-
yloxy)pyridin-3-yl)-3-
(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole
N'0 -N
CI O
N N
0 / NI /
N
A 25 mL microwave reaction vial was charged with (Z)-3-chloro-N-hydroxy-4-
isopropoxybenzimidamide (0.1 g, 0.437 mmol), 6-bromonicotinic acid (0.097 g,
0.481 mmol),
and DCC (0.099 g, 0.481 mmol) in ACN (2.403 mL). HOBT (0.074 g, 0.481 mmol)
was
added in one portion, the resulting suspension was allowed to stir at RT for
about 10 min.
DIEA (0.168 mL, 0.962 mmol) was added dropwise, the reaction mixture was
heated at
about 120 C for about 30 min under microwave irradiation (Biotage Optimizer,
300 W). The
solution was cooled, the reaction mixture was partitioned between EtOAc (50
mL) and water
(50 mL), the organic layer was washed by water (2 x 50 mL), and concentrated
afforded
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yellow solid, which was purified via silica gel chromatography (12 g, 20%
EtOAc:Heptane) to
afford 5-(6-(IH-benzo[d][1,2,3]triazol-1 yloxy)pyridin-3-yl)-3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazole (0.128 g, 0.285 mmol, 65.2 % yield) as a
white solid.
LC/MS (Table 1, Method a) Rt = 3.74 min.; MS m/z: 449.18 (M+H)+. 1H NMR (400
MHz, d-
DMSO) ppm 8.88 (dd, J = 2.25, 0.65 Hz, 1H), 8.62 (dd, J = 8.68, 2.27 Hz, 1H),
8.15 (t, J =
5.28 Hz, 2H), 7.97 (dd, J = 8.62, 2.14 Hz, 1H), 7.55 (d, J = 0.96 Hz, 1H),
7.52-7.44 (m, 2H),
7.36 (dd, J = 8.68, 0.70 Hz, 1H), 7.03 (d, J = 8.87 Hz, 1H), 4.73-4.61 (m,
1H), 1.46-1.40 (m,
6H).
Preparation #27: (Z)-3-bromo-N'-hydroxy-4-isopropoxybenzimidamide
NOH
Br ~
NH2
3-Bromo-4-isopropoxybenzonitrile (0.68g, 2.83 mmol) and hydroxylamine (0.208
mL, 3.12
mmol) were combined in EtOH (20 mL). The reaction mixture was heated at about
65 C for
about 16 h. The reaction mixture was concentrated to afford (Z)-3-bromo-N'-
hydroxy-4-
isopropoxybenzimidamide (0.76 g, 2.78 mmol, 98 % yield) as pale yellow solid.
LC/MS
(Table 1, Method a) Rt = 2.89 min.; MS m/z: 275.00 (M+H)+.
Preparation #28: Preparation of 4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzonitrile
N-O _
Br ~N \ .N
O
A 25 mL microwave vial equipped with a stirring bar was charged with 4-
cyanobenzoyl
chloride (0.4 g, 2.416 mmol), (Z)-3-bromo-N-hydroxy-4-isopropoxybenzimidamide
(0.5 g,
1.831 mmol) and pyridine (15 mL) to give an orange solution. The vessel was
capped and the
reaction heated at about 200 C for about 20 min under microwave irradiation
(Biotage
Optimizer, 300 W). The solution was cooled, the reaction mixture was
partitioned between
aqueous HC1 (10%, 150 mL) and DCM (40 mL) mixture, the DCM layer was drained,
and the
aqueous layer was extracted by DCM (2x20 mL). The combined DCM layers were
washed by
water (2x20 mL) and concentrated to afford white solid, which was purified via
silica gel
chromatography (40 g, 40% EtOAc:Heptane) to afford 4-(3-(3-bromo-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)benzonitrile (0.638 g, 1.660 mmol, 91 % yield) as white
solid. LC/MS
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(Method c) Rt = 3.17 min.; MS m/z: 386.19 (M+H)+. 1H NMR (400 MHz, d-DMSO) ppm
8.40-8.32 (m, 2H), 8.23 (d, J = 2.13 Hz, 1H), 8.14 (dd, J = 8.14, 0.61 Hz,
2H), 8.05 (dd, J =
8.65, 2.15 Hz, 1H), 7.36 (d, J = 9.12 Hz, 1H), 4.89-4.77 (m, 1H), 1.35 (d, J =
6.03 Hz, 6H).
Preparation #29: Preparation of 4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzaldehyde
N-O
O
Br I i N
O
A 100 mL round bottom flask equipped with septa cap outfitted with nitrogen
inlet needle was
charged with 4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzonitrile (0.64 g,
1.666 mmol) in DCM (33.3 mL) to give a colorless solution. The reaction
mixture was cooled
to about -40 C by ACN-dry ice bath and it turned into a white suspension.
Dibal-H (3.33 mL,
3.33 mmol) was added dropwise over about 10 min. It was stirred for an extra
about 60 min at
about -40 C. Methanol (0.135 mL, 3.33 mmol) was added dropwise to quench the
reaction.
Then all of the mixture was poured into stirring Rochelle's salt (200 mL). It
was stirred at RT
for 4 h, then partitioned, the aqueous layer was extracted by DCM (2x50 mL),
the combined
DCM layers were washed by water (60 mL), dried over MgS04. Filtration and
concentration
afforded 1.04 g orange oil, which was purified via silica gel chromatography
(40 g, 40%
EtOAc:Heptane) to afford 4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzaldehyde (0.551 g, 1.423 mmol, 85 % yield) as pale yellow solid. LC/MS
(Method c)
Rt = 3.17 min.; MS m/z: 388.94 (M+H)+. 1H NMR (400 MHz, d-DMSO) ppm 10.15 (s,
1H),
8.41 (d, J = 8.20 Hz, 2H), 8.24 (d, J = 2.13 Hz, 1H), 8.20-8.14 (m, 2H), 8.06
(dd, J = 8.64,
2.15 Hz, 1H), 7.37 (d, J = 9.11 Hz, 1H), 4.89-4.78 (m, 1H), 1.36 (d, J = 6.03
Hz, 6H).
Preparation #30: Preparation of 3-(3-bromo-4-isopropoxyphenyl)-5-(4-
(dimeth oxymethyl)phenyl)-1,2,4-oxadiazole
N-O O-
Br I ' N
O-
O
4-(3-(3-Bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (0.551 g,
1.423
mmol), molecular sieve (4A, 8-12 mesh, 130 mg) and p-toluenesulfonic acid
monohydrate
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(0.037 g, 0.195 mmol) were added in trimethyl orthoformate (4 mL, 36.2 mmol)
and methanol
(6 mL), the reaction mixture was heated at about 80 C for about 16 h. The
solution was
cooled, the reaction mixture was concentrated to afford grey solid, which was
purified via
silica gel chromatography (12 g, 20% EtOAc:Heptane) to afford 3-(3-bromo-4-
isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.61 g,
1.366 mmol, 96
% yield) as white solid. LC/MS (Table 1, Method a) Rt = 3.31 min.; MS m/z:
435.03 (M+H)+.
1H NMR (400 MHz, d-DMSO) ppm 8.25-8.19 (m, 3H), 8.05 (dd, J = 8.63, 2.14 Hz,
1H), 7.67
(d, J = 8.18 Hz, 2H), 7.35 (d, J = 9.02 Hz, 1H), 5.52 (s, 1H), 4.86-4.78 (m,
1H), 3.30 (s, 6H),
1.35 (d, J = 6.02 Hz, 7H).
Preparation #31: Preparation of 5-(5-(4-(dimethoxymethyl)phenyl)-1,2,4-
oxadiazol-3-yl)-
2-isopropoxybenzonitrile
N-0 O-
N
O-
O
A 25 mL microwave vial equipped with a stirring bar was charged with 3-(3-
bromo-4-
isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.25g, 0.577
mmol),
copper(I) cyanide (0.133 g, 1.485 mmol) and pyridine (15 mL). The vessel was
capped and
the reaction heated to about 230 C for about 30 min under microwave
irradiation (Biotage
Optimizer, 300 W). The solution was cooled and the reaction mixture was
concentrated. To
the residue was added hydrated ferric chloride (0.8 g), concentrated
hydrochloric acid (2 mL)
and water (12 mL). The solution was heated at about 65 C for about 20 min,
the aqueous
mixture was extracted by DCM (3X30 mL), the combined DCM layers were washed
with
FeC13 solution (2x20 mL), then water (2x20 mL), dried (brine, MgS04) and
concentrated to
yield yellow solid, which was purified via silica gel chromatography (40 g,
20%
EtOAc:Heptane) to afford 5-(5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazol-3-
yl)-2-
isopropoxybenzonitrile (0.086 g, 0.227 mmol, 39.3 % yield) as pale yellow
solid which was
used in the next step without further purification.
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Preparation #32: Preparation of 5-(5-(4-formylphenyl)-1,2,4-oxadiazol-3-yl)-2-
is op r o p oxyb enzo nitr ile
N\\ N-0 N
O
5-(5-(4-(Dimethoxymethyl)phenyl)-1,2,4-oxadiazol-3-yl)-2-
isopropoxybenzonitrile (0.086 g,
0.227 mmol) and p-toluenesulfonic acid monohydrate (0.043 g, 0.227 mmol) were
added in
acetone (10 mL) to give a colorless solution. The reaction mixture was heated
at about 60 C
for about 2 h. The solution was cooled, the reaction mixture was concentrated,
the residue was
purified via silica gel chromatography (12 g, 50% EtOAc:Heptane) to afford 5-
(5-(4-
formylphenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.077 g, 0.231
mmol, 102 %
yield) as white solid. LC/MS (Table 1, Method f) Rt = 2.88 min.; MS m/z:
334.08 (M+H).
Example #30: Preparation of 1-(4-(3-(3-cyano-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzyl)azetidine-3-carboxylic acid
N-O
N
N
O
O
5-(5-(4-Formylphenyl)-1,2,4-oxadiazol-3-yl)-2-isopropoxybenzonitrile (0.077 g,
0.231 mmol)
and azetidine-3-carboxylic acid (0.028 g, 0.277 mmol) were combined in
methanol (11.55
mL) and DCE (11.55 mL) in a sealed vial. Acetic acid (0.066 mL, 1.155 mmol)
was added.
The reaction mixture was stirred at ambient temperature for about 2 h. MP-
cyanoborohydride
(0.265 g, 0.570 mmol) was added and the reaction stirred for about 24 h. The
solution was
filtered, the solid was washed with methylene chloride and methanol, and the
filtrate was
concentrated to afford a white solid, which was recrystallized by methanol (5
mL) to give 1-
(4-(3-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-5yl)benzyl)azetidine-3-
carboxylic acid
(0.025 g, 0.060 mmol, 25.9 % yield) as white solid: LC/MS (Table 1, Method a)
Rt = 2.10
min.; MS m/z: 420.26 (M+H)+. 1H NMR (400 MHz, d-DMSO) ppm 8.35-8.28 (m, 2H),
8.17-
8.11 (d, J = 8.00 Hz, 2H), 7.56-7.50 (m, 8.69 Hz, 3H), 4.98-4.89 (m, 1H), 3.68
(s, 2H), 3.43
(s, 2H), 3.25-3.23 (m, 3H), 1.38 (d, J = 6.03 Hz, 6H).
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Example #31: Preparation of 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)cyclop rop anecarb onitrile
1OH N-O
CI I \ ~\ CI N
NH2 + HON
O N
O
O
A 20 mL microwave vial was charged with 4-(1-cyanocyclopropyl)benzoic acid
(720 mg,
3.85 mmol), (Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide (880 mg, 3.85
mmol),
DCC (873 mg, 4.23 mmol), HOBT (648 mg, 4.23 mmol), ACN (10 mL), and DIEA
(1.478
mL, 8.46 mmol). The vial was capped and heated to about 160 C via microwave
irradiation
for about 25 min (max 300W). Solvent was removed under reduced pressure and
crude oil
was purified by flash column chromatography (AnalogiA system, heptane/ethyl
acetate, 0-
45% ethyl acetate over 30 min; 80 g column, 60 mL/min flow rate). Fractions
containing
product were combined, rotovapped, and dried in a vacuum oven overnight to
give 1-(4-(3-(3-
chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-
yl)phenyl)cyclopropanecarbonitrile (347 mg,
23.8%) as a yellow solid. LC/MS (Table 1, Method c) Rt = 3.19 min, m/z 380.43
(M+H)+; 'H
NMR (400 MHz, DMSO) ) 6 ppm 8.22-8.12 (m, 2H), 8.05 (d, 1H), 7.99 (dd, 2.14
Hz, 1H),
7.62-7.55 (m, 2H), 7.38 (d, 1H), 4.82 (td, 1H), 1.90 (q, 2H), 1.67 (q, 2H),
1.38-1.33 (m, 6H).
Preparation #32a: Preparation of 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-
5-yl)phenyl)cyclopropanecarbaldehyde
N-O N-O
lCI N lCI N
O N O O H
A 100 mL round bottom flask was charged with 1-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)phenyl)cyclopropanecarbonitrile (300 mg, 0.790 mmol) and
dichloromethane
(8 mL) and then cooled to about -40 C. Dibal-H (0.869 mL, 0.869 mmol) was
added slowly
via syringe and the reaction mixture left to warm to RT overnight. The
reaction was quenched
by addition of MeOH (4 mL), and aqueous Rochelle's salt (4 mL). Layers were
separated and
the aqueous layer was extracted with DCM (3x 25mL). Organic layers were washed
with
saturated sodium bicarbonate solution, then dried over MgS04, and
concentrated. To a
solution of the crude material in 3 mL of THE was added 3 mL of IN HC1. The
mixture was
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stirred at RT for about 1 h. The mixture was rotovapped to remove THF. The
material was
then purified via flash column chromatography (AnalogiA , 40g column, 0-40%
ethyl acetate
in heptane over 3 0min, 30 mL/min flow rate). The fractions containing product
were
combined and concentrated to give 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)cyclopropanecarbaldehyde (144 mg, 48%) as a tacky yellow solid.
LC/MS (Table
1, Method c) Rt = 3.11 min, m/z 383.50 (M+H).
Example #33: Preparation of 3-((1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-
5-yl)phenyl)cyclopropyl)methylamino)propanoic acid, Trifluoroacetic Acid
0
F
N-O N-0 F OH
Cl
N O CI N F
+ H
N
OI O H HzNOH 1O
11 /\ OH
A 20 mL vial was charged with 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)cyclopropanecarbaldehyde (46 mg, 0.120 mmol), methanol (2.5 mL), 3-
aminopropanoic acid (10.70 mg, 0.120 mmol) and acetic acid (0.034 mL, 0.601
mmol). The
vial was capped and the mixture stirred for about 30 min at RT. Next, sodium
cyanoborohydride (7.55 mg, 0.120 mmol) was added in one aliquot and the
reaction was
stirred overnight at RT. Solvents were removed under reduced pressure and the
crude
material was purified via RP-HPLC (A= 0.1% TFA, B = ACN; 30% to 95% B over 30
min
at 21.0 mL/min; UV 2 = 254 nm; Thermo Hyperprep HS C18, 8 m, 250 x 21.2 mm
column).
Fractions containing product were rotovapped and lyophilized to give 3-((1-(4-
(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5
yl)phenyl)cyclopropyl)methylamino)propanoic acid (27
mg, 40%) as the trifluroacetic acid salt. LC/MS (Table 1, Method c) Rt = 2.07
min, m/z
456.25 (M+H) ; 1H NMR (400 MHz, methanol) 6 ppm 8.22 (d, 2H), 8.11 (d, 1H),
8.03 (dd,
1H), 7.69 (d, J = 8.19 Hz, 2H), 7.24 (d, 1H), 4.80-4.76 (m, 1H), 3.36 (s, 2H),
3.13 (t,, 2H),
2.44 (t, 2H), 1.40 (d, 6H), 1.17 (d, 4H).
Example #34: Preparation of N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzyl)-1-(2,2-dimethyl-1,3-dioxolan-4-yl) methanamine
o
N_ CI
CI I I N H + HZN ~ N \ / N
H
O
'
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4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (150 mg,
0.438
mmol), (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (0.057 mL, 0.438 mmol),
methanol (4
mL), and acetic acid (0.125 mL, 2.188 mmol) were loaded into a 25 mL flask
equipped with a
stirring bar. The mixture was stirred for about 10 min at RT under nitrogen.
Sodium
cyanoborohydride (27.5 mg, 0.438 mmol) was added in one portion, and the
reaction mixture
was stirred at RT overnight. Solvent was removed under reduced pressure and
crude material
was purified by RP-HPLC (A = 50 mM ammonium acetate, B = ACN; 40% to 80% B
over
30 min at 21.0 mL/min; UV 2 = 254 nm; Thermo Hyperprep HS C18, 8 m, 250 x
21.2 mm
column). Fractions containing product were combined, rotovapped and
lyophilized to give N-
(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)benzyl)-1-(2,2-
dimethyl-1,3-
dioxolan-4-yl)methanamine (130.9mg, 64.7%) as a white solid. LC/MS (Table 1,
Method c)
Rt = 2.59 min, m/z 458.62 (M+H) ; 1H NMR (400 MHz, DMSO) 6 ppm 8.13 (d, 2H),
8.06 (d,
1H), 8.00 (dd, 1H), 7.61 (d, 2H), 7.39 (d, 1H), 4.82 (sept, 1H), 4.15 (p, 1H),
3.99 (dd, 1H),
3.84 (s, 2H), 3.63 (dd, 1H), 2.61 (ddd, 2H), 1.86 (s, 4H), 1.35 (d, 6H) 1.26
(s, 3H).
Example #35: Preparation of 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzylamino)p rop ane-1,2-diol
N_O N-O
CI :OA N CI I I \ /
O H ~ --- H
O OH
O-1< OH
To a solution of N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzyl)-1-(2,2-
dimethyl-1,3-dioxolan-4-yl)methanamine (108 mg, 0.236 mmol) in THE (4 mL) was
added
IN aqueous HC1 (0.778 mL, 0.778 mmol) The reaction was heated to about 65 C
under
nitrogen for about 90 min. Heating was stopped and the reaction was
neutralized by addition
of IN aqueous NaOH (0.778 mL, 0.778 mmol). THE was removed under reduced
pressure
and the remaining aqueous solution was basified (pH approx 9) by the addition
of O.1N
NaOH, at which point white precipitate formed. Solid was collected by vacuum
filtration, and
washed with 0.1N NaOH (3 x 10 mL). Solid was dried in a vacuum oven overnight
to give 3-
(4-(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-yl)benzylamino)propane-
1, 2-diol
(31.7mg, 32%) as an off-white solid. LC/MS (Table 1, Method c) Rt = 1.90 min,
m/z 418.47
(M+H) ; 1H NMR (400 MHz, methanol) 6 ppm 7.22 (d, J = 8.68 Hz, 1H), 7.60 (d,
2H), 8.01
(dd,, 1H), 8.10 (d, 1H), 8.16 (d, 2H), 4.78 (sept, 1H), 2.76 (dd, 1H), 2.63
(dd, 1H), 3.52 (d,
2H), 3.90 (d, 2H), 3.78 (m, 1H), 1.40 (d, 6H).
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Preparation #33: Preparation of (Z)-methyl 3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadi azol-5-yl)phenyl) ac rylate
0
0
N.O 0
Q// CI I \ N CI \ I N
H
O
A two-neck round bottom flask was charged with methyl 2-(bis(2,2,2-
trifluoroethoxy)phosphoryl)acetate (0.235 mL, 1.109 mmol), 18-crown-6 (1465
mg, 5.54
mmol) and THE (15 mL). The mixture was then cooled to about -78 C under an
atmosphere
of nitrogen. Potassium bis(trimethylsilyl)amide (221 mg, 1.109 mmol) was added
and the
mixture stirred for a few min. 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzaldehyde (380 mg, 1.109 mmol) was added and the mixture stirred at
about -78 C for
about 90 min and then left to warm to RT overnight. Reaction was quenched by
the addition
of saturated NH4C1 (aqueous). The mixture was separated and the aqueous layer
was
extracted with ether (3 x 10 mL). The combined organics were dried over MgSO4
and
concentrated to give an off-white solid. The solid was triturated with MeOH
and collected by
vacuum filtration and washed with MeOH (3 x 10 mL). The collected solid was
dried
overnight in a vacuum oven to give (Z)-methyl 3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)phenyl)acrylate (325 mg, 73.5%).
LC/MS (Table 1, Method c) Rt = 3.22 min, m/z 399.16 (M+H)+. 1H NMR (400 MHz,
DMSO)
6 ppm 8.18 (d, 2H), 8.06 (d, 1H), 8.01 (dd, 1H), 7.79 (d, 2H), 7.40 (d, 1H),
7.18 (d, 1H), 6.84
(d, 1H), 6.20 (d, 1H), 4.83 (sept, 1H), 3.67 (s, 3H), 1.35 (d, 6H).
Example #36: Preparation of Trans-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenyl)cyclopropanecarb oxylate
0 0 O
N-0 N-O
CI N CI \ N
To a stirred suspension of trimethylsulfoxonium iodide (234 mg, 1.065 mmol) in
DMSO (5.0
mL) under nitrogen, was added, in portions NaH (42.6 mg, 1.065 mmol), with a
water bath in
place to keep the reaction between about 25-30 C. Upon completion of hydrogen
evolution,
a solution of (Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-
yl)phenyl)acrylate (386mg, 0.968 mmol) in DMSO (5.00 mL) was added drop-wise,
keeping
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the reaction temperature at or below about 35 C. After addition was complete,
the reaction
was stirred at RT for about an hour and a half and then warmed to about 50 C
for about 2 h s.
50 mL of water was then added to the reaction, and the reaction left to stir
at RT overnight.
The reaction mixture was diluted with saturated aqueous sodium chloride, and
the aqueous
layer was extracted 3x with 75 mL EtOAc. Organic layers were combined, dried
over
MgSO4, and concentrated. The crude material was purified by RP-HPLC (A = 50 mM
ammonium acetate, B = ACN; 30% to 100% B over 30 min at 21.0 mL/min; UV 2 =
254 nm;
Thermo Hyperprep HS C18, 8 m, 250 x 21.2 mm column). Fractions containing
product
were combined, concentrated and lyophilized to give trans-methyl 2-(4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenyl)cyclopropanecarboxylate (155 mg,
39%) as a
white solid. LC/MS (Table 1, Method c) Rt = 3.27 min, m/z 413.17 (M+H)+. 'H
NMR (400
MHz, DMSO) 6 ppm 8.08 (d, 2H), 8.06 (d, 1H), 7.99 ( dd, 1H), 7.47 (d, 2H),
7.39 (d, 1H),
4.82 (sept, 1H), 3.66 (s, 3H), 2.59 (ddd, 1H), 2.12 (ddd, 1H), 1.58 (ddd, 1H),
1.53 (ddd, 1H),
1.35 (d, 6H).
Example #37: Preparation of Trans-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)phenyl)cyclopropanecarboxylic acid
0 OH
O O
N-O N-O
CI I\ I CI N \ N
To a suspension of (1S,2S)-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)cyclopropanecarboxylate (111mg, 0.269 mmol) in ethanol (5 mL) was
added 2 N
NaOH (5 mL, 10.00 mmol). The mixture was stirred under nitrogen at RT
overnight.
Reaction mixture was neutralized by addition of acetic acid, and then
acidified with a few
drops of 1 N aqueous HCl (pH about 2). White solid precipitated and was
collected by
filtration, washed with 0.1 N HCl (3 x 5 mL), and dried under vacuum to give
trans-2-(4-(3-
(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5yl)phenyl)cyclopropanecarboxylic acid (64
mg, 59%). LC/MS (Table 1, Method f) Rt = 2.99 min, m/z 399.16 (M+H)+. 'H NMR
(400
MHz, DMSO) 6 ppm 8.07 (d, 2H), 8.05 (d, 1H), 7.99 (dd, 1H), 7.45 (d, 2H), 7.38
(d, 1H),
4.82 (sept., 1H), 2.54 (m, 1H), 1.97 (m, 1H), 1.53 (td, 1H), 1.46 (ddd, 1H),
1.35 (d, 6H).
Example #38: Preparation of tert-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadi azol-5-yl)is oindoline-2-carb oxylate
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N1OH O N.O
CI NFi2 + HO y CI N
N O N
1 /
To a solution of 2-(tert-butoxycarbonyl)isoindoline-5-carboxylic acid (190 mg,
0.722 mmol)
in ACN (3 mL) in a 5 mL microwave vial was added HOBT (330 mg, 2.16 mmol), DCC
(298
mg, 2.16 mmol), and DIEA (0.115 mL, 0.656 mmol). The mixture was stirred RT
for about
16 h. Next, (Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide (150 mg, 0.656
mmol)
(prepared by General Procedure B) was added and the reaction was heated to
about 150 C
under microwave irradiation (max 300W) for about 20 min. After cooling, the
reaction
mixture was filtered, concentrated, and purified via Analogix FCC system using
RediSepTM
40g column, with a gradient of 0-40% EtOAc/Heptane over 30 min. at a flow rate
of
30mL/min. Fractions containing product were combined, rotovapped, and dried in
a vacuum
oven to give tent-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5
yl)isoindoline-
2-carboxylate (46.2 mg, 15.5%) LC/MS (Table 1, Method c) Rt = 3.40 min, m/z
456.22
(M+H) ; 1H NMR (400 MHz, DMSO) 6 ppm 8.16 (d, 1H), 8.10 (s, 1H), 8.05 (d, 1H),
7.61 (m,
1H), 7.39 (d, 1H), 4.82 (sept, 1H), 4.70 (d, 4H), 1.48 (s, 9H), 1.35 (d, 6H).
Example #39: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(isoindolin-5-
yl)-1,2,4-
oxadiazole, Trifluoroacetic Acid
O
N-0
N N-o F OH
CI I N -~ CI I N F F
~O I N` _
O~ NH
?IIIIf
To a solution of tent-butyl 5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-
yl)isoindoline-2-carboxylate (41 mg, 0.090 mmol) in DCM (2 mL) was added TFA
(0.5 mL,
6.49 mmol). The mixture was stirred at RT under nitrogen for about 30 min.
After 30 min,
ether was added slowly to the mixture, until it became cloudy and a white
precipitate formed.
The solid was collected by filtration and washed with ether (3 x 10 mL). The
collected solid
was then dried in vacuum oven to give 3-(3-chloro-4-isopropoxyphenyl)-5-
(isoindolin-5yl)-
1,2,4-oxadiazole as the TFA salt (26.7mg, 62.6%). LC/MS (Table 1, Method c) Rt
= 2.29
min, m/z 356.17 (M+H)+. 1H NMR (400 MHz, DMSO) 6 ppm 9.46 (s, 2H), 8.27 (s,
1H), 8.20
(d, 1H), 8.00 (d, 1H), 7.70 (d, 1H), 7.41 (d, 1H), 4.83 (sept, 1H), 4.64 (d,
4H), 1.35 (d, 6H).
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Preparation #34: Preparation of methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)isoindolin-2-yl)p rop anoate
N_O N_p
CI \ I N
CI N / + _\ u N
NH O
O
3-(3-Chloro-4-isopropoxyphenyl)-5-(isoindolin-5-yl)-1,2,4-oxadiazole (16.7 mg,
0.047 mmol)
was added to a 2 mL microwave vial equipped with a stirring bar. Methyl
acrylate (8.45 L,
0.094 mmol), and methanol (1.0 mL) were added, the vial capped, and the
reaction heated to
about 90 C for about 20 min under microwave irradiation (300W). After about
20 minutes,
another aliquot of methyl acrylate (8.45 L, 0.094 mmol) was added, the vial
was re-sealed,
and heated to about 110 C for about 40 min under microwave irradiation (300W).
The
reaction was then concentrated and dried under vacuum overnight to give crude
methyl 3-(5-
(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)isoindolin-2
yl)propanoate as a
yellow oil (21.6 mg, 104%). The product was used without further purification.
LC/MS
(Table 1, Method c) Rt = 2.85 min, m/z 442.45 (M+H)+
Example #41: Preparation of 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)isoindolin-2-yl)propanoic acid, Hydrochloric Acid
N-O N-O
CIH
CI I \ N ~ ~ CI \ I N
N
O o
To a solution of methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5-
yl)isoindolin-2-yl)propanoate (21mg, 0.048 mmol) in ethanol (1 mL) was added 2
M aqueous
NaOH (1 mL, 2.000 mmol). The reaction was stirred at RT under an atmosphere of
nitrogen
for about 4 h. Reaction mixture was then acidified to about a pH of 1 by
addition of 2 N HC1,
at which time a precipitate formed. The solid was collected by filtration and
washed with
water (3 x 5 mL). The solid was then dried in a vacuum oven overnight to give
3-(5-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5yl)isoindolin-2yl)propanoic acid
as the
hydrochloride salt (10.2 mg, 46.2%). LC/MS (Table 1, Method c) Rt = 1.86 min,
m/z 428.20
(M+H)+. 1H NMR (400 MHz, DMSO) 6 ppm 12.12 (m, 1H), 8.23 (s, 1H), 8.19 (d,
1H), 8.07
(d, 1H), 8.01 (dd, 1H), 7.68 (d, 1H), 7.41 (d, 1H), 4.83 (sept, 1H), 4.72 (s,
4H), 3.58 (t, 2H),
2.84 (t, 2H), 1.36 (d, 6H)
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Example #42: Preparation of (Z)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-
5-yl)phenyl)acrylic acid
O OH
O O O
NI/
To a solution of (Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)acrylate (30 mg, 0.075 mmol) in EtOH (2 mL) was added 2 N aqueous
NaOH (2
mL). The reaction was stirred at RT, under nitrogen, for about 2 h. The
reaction was
acidified via addition of 1 N HC1, until a precipitate formed. The solid was
collected by
filtration, washed with 0.2 N HC1, and dried in a vacuum oven to give (Z)-3-(4-
(3-(3-chloro-
4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)acrylic acid (8.2mg, 28.3%).
LC/MS (Table
1, Method c) Rt = 2.64 min, m/z 385.12 (M+H)+. 1H NMR (400 MHz, DMSO) 6 ppm
13.11-
12.20 (m, 1H), 8.15 (d, 2H), 8.04 (d, 1H), 7.99 (dd,, 1H), 7.78 (d, 2H), 7.37
(d, 1H), 7.03 (d,
1H), 6.12 (d, 1H), 4.81 (sept., 1H), 1.33 (d, 6H)
Preparation #35: Preparation of 3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)aniline
N OH O CI Y/:. CI
CI I I NH2 HO CI 0/>- NH2
O / NH2 /~O
(Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide (0.5 g, 2.187 mmol), 4-amino-
2-
chlorobenzoic acid (0.413 g, 2.405 mmol), DCC (0.496 g, 2.405 mmol), HOBT
(0.368 g,
2.405 mmol) were placed in an 80 mL microwave vial and ACN (12.01 mL) was
added. The
reaction mixture was stirred for about 5 min at RT before the addition of DIEA
(0.840 mL,
4.81 mmol). The reaction mixture was heated to about 120 C for about 30 min
in a
microwave. TLC (50%EA/Hept) indicated 4 spots Rf 0.8, 0.6, 0.5 and 0.3. LC/MS
(2007_9349) indicated by UV 16% (2.61 mins) to (M+H) 364.31. The solvent was
removed
and the crude material purified by FCC (50%EA/Hept) to afford 3-chloro-4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)aniline (534 mg, 1.466 mmol, 67.1 %
yield). LC/MS
(Table A, Method b) indicated a 99% by UV (3.10 mins) and 92% by ELSD (3.06
mins)
(M+H)+ 364.12
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Example #43: Preparation of 3-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid
0
CI O CI OH
N-O IOH N-O b
O'FI
C
I N / NHz CI N H
3-Chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (200
mg, 0.549
mmol) and 3-oxocyclobutanecarboxylic acid (62.7 mg, 0.549 mmol) in methanol
(1280 L) at
RT was added acetic acid (842 l, 14.72 mmol). The reaction mixture was
stirred at RT for
about 10 min before addition of sodium cyanoborohydride (17.25 mg, 0.275 mmol)
as a single
portion. The reaction mixture was stirred at RT overnight. The solvent was
removed and the
crude material purified by FCC (50%EA/Hept) to afford 3-(3-chloro-4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenylamino)cyclobutanecarboxylic acid
(135 mg,
0.292 mmol, 53.2 % yield) as a white solid. LC/MS (Table A, Method b)
indicated 100% by
UV (3.06 mins) to (M+H)+ 364.12.
Preparation #36: 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)aniline
NOH O N-0 _
CI NHz HO ICI I \ N NHz
o NHz /moo /
(Z)-3-chloro-N-hydroxy-4-isopropoxybenzimidamide (1 g, 4.37 mmol), 4-
aminobenzoic acid
(0.660 g, 4.81 mmol), HOBT (0.737 g, 4.81 mmol), DCC (0.992 g, 4.81 mmol) and
DIEA
(1.680 mL, 9.62 mmol) were combined in a microwave vial. The reaction mixture
was heated
in the microwave for about 20 min at about 150 C. The reaction mixture was
filtered to
remove the urea formed in the reaction and the solvent was removed in vacuo.
The crude
material was purified by FCC (50% ethyl acetate/heptane) to afford 4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (729 mg, 2.211 mmol, 50.6%
yield) as an off
white solid: LC/MS (Table A, Method b) 3.00 min, (M+H)+ 330.13.
Example #44: 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclobutanecarboxylic acid
0
OH
N'O O N-0 CI OH CI I NH
l I \ N NH2 0;1" 0
O
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4-(3-(3-Chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (250 mg, 0.531
mmol) in
methanol (1478 L) at RT was added 3-oxocyclobutanecarboxylic acid (60.5 mg,
0.531
mmol) followed by acetic acid (814 L, 14.22 mmol). The reaction mixture was
stirred at RT
for about 5 min before the addition of sodium cyanoborohydride (16.67 mg,
0.265 mmol). The
reaction mixture was stirred overnight at RT. The solvent was removed and the
crude material
purified by FCC (50% ethyl acetate/heptane) to afford 3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5 yl)phenylamino)cyclobutanecarboxylic acid (139 mg, 0.302
mmol, 56.9%
yield) as a white solid. LC/MS (Table A, Method b) 2.89 min, (M+H)+ 428.20.
Preparation #37: 3-Hydroxy-cyclobutanecarboxylic acid tert-butyl ester
O
O O
O
;J/ - ;?-
O
HO
A solution of tert-butyl 3-oxocyclobutanecarboxylate (prepared according to
R.P. Lemieux, J.
Org. Chem. (1993), Vol. 58, No. 1, pp. 100-110) (10.5g, 61.7 mmol) in EtOH
(110 mL) was
treated with sodium borohydride (2.173 mL, 61.7 mmol) portionwise at RT (cold
water bath
used to maintain reaction temperature below about 30 C) and the reaction was
stirred at room
temperature for about 2 h. The reaction was diluted with saturated NaCl
solution (300 mL)
and extracted with EtOAc (300 mL). The EtOAc layer was washed with saturated
salt solution
(3 x 200 mL), dried over sodium sulfate, filtered and concentrated. The crude
product was
further purified by distillation, taking the fraction that boils at about 88-
90 C at 3 Torr to yield
3-hydroxy-cyclobutanecarboxylic acid tert-butyl ester (7.37g, 70%) as
colorless oil.
LC/MS (Table 1, Method a), Rt = no peak, no parent ion; 1H NMR (400 MHz, DMSO-
d6) 6
ppm 5.12 (d, J= 6.9, 1H), 3.97-3.88 (m, 1H), 2.46-2.29 (m, 3H), 1.94-1.86 (m,
2H), 1.39 (s,
9H).
Preparation #38: 4-Hydroxy-cyclohexanecarboxylic acid tert-butyl ester
O O
HO " HO To a suspension of trans-4-hydroxycyclohexanecarboxylic acid (3.25 g,
22.54 mmol) in
dichloroethane (150 mL) was added tert-butyl 2,2,2-trichloroacetimidate (16.15
mL, 90
mmol) and mixture was heated at about 80 C under nitrogen for about 4 days.
The reaction
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was cooled to RT, filtered and the white solid was rinsed with 10 mL methylene
chloride.
The organic layer was washed with saturated sodium bicarbonate solution (100
mL), filtered
and concentrated. The residue was triturated twice with 10 mL of 80:20 /
heptane: ethyl
acetate and filtered. The filtrate was injected onto a silica gel column and
eluted with a
gradient from 20% to 60% ethyl acetate in heptane over about 40 min. The
combined product
fractions were concentrated to an oil that solidifies on drying to constant
weight under vacuum
to yield 4-hydroxy-cyclohexanecarboxylic acid tent-butyl ester (1.95g, 45%) as
a white solid.
LC/MS (Table 1, Method f) Rt = no peak, no parent ion; 1H NMR (400 MHz, DMSO-
d6) 6
ppm 4.52 (d, J= 4.3, 1H), 3.38-3.29 (m, 1H), 2.10-2.02 (m, 1H), 1.82-1.79 (m,
4H), 1.38 (s,
9H), 1.34-1.24 (m, 2H), 1.18-1.08 (m, 2H).
Preparation #39: 3-Hydroxy-cyclopentanecarboxylic acid ethyl ester
O O
OO~ HO~O
A solution of ethyl 3-oxocyclopentanecarboxylate (2.00 g, 12.81 mmol) in EtOH
(20 mL) was
treated with sodium borohydride (0.451 mL, 12.81 mmol) portionwise at RT (RT
water bath
to control exotherm) and the reaction was stirred overnight. The reaction was
quenched with
2N HC1 to about pH=2 and extracted with CH2C12, washed with water, dried over
sodium
sulfate, filtered and concentrated to oil. The crude product was further
purified on silica gel
using a gradient of 20-40% ethyl acetate in heptane. Pure product fractions
and concentrate
were combined to constant weight. NMR indicates an approximately 3:7 ratio of
isomers. 1H
NMR (400 MHz, DMSO-d6) 6 ppm 4.52-4.50 (m, 1H), 4.19-4.15 (m, 0.3H), 4.08-4.02
(m,
2.7H), 2.94-2.86 (m, 0.3H), 2.74-2.66 (m, 0.7H), 2.08-1.46 (m, 6H), 1.19-1.15
(m, 3H).
Preparation #40: (1R, 3S)-3-(4-cyanophenylamino) cyclopentane carboxylic acid
N N
H2N,,0O
OH
F OH H~, 0
To a round bottom flask was added 4-fluorobenzonitrile (1.705g, 14.08 mmol),
(1R, 3S)-3-
aminocyclopentanecarboxylic acid (2 g, 15.49 mmol), potassium carbonate (4.28
g, 31 mmol),
DMSO (45 mL) and water (1 mL). The mixture was heated at about 100 C for
about 16 h.
The mixture was then cooled to ambient temperature and partitioned between
water (250 mL)
and EtOAc (250 mL). The aqueous layer was extracted with EtOAc (2 x 100 mL).
The
combined organic layers were dried over Na2SO4, filtered and concentrated to
dryness to yield
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(JR, 3S)-3-(4-cyanophenylamino) cyclopentane carboxylic acid (1.83g, 7.87mmol,
55.9%) as
an off-white solid. LC/MS (Table 1, Method b) Rt = 1.94 min, m/z 231 (M+H) +.
1H NMR
(400 MHz, DMSO-d6) 6 ppm 12.1 (s, 1H), 7.44-7.42 (d, 2H), 6.74-6.72 (d, 1H),
6.63-6.61 (d,
2H), 3.81-3.74 (m, 1H), 2.79-2.71 (m, 1H), 2.37-2.27 (m, 1H), 2.01-1.93 (m,
1H), 1.89-1.83
(m, 2H), 1.65-1.58 (m, 1H), 1.54-1.45 (m, 1H).
Preparation #41: Preparation of (1R, 3S)-ethyl 3-(4-cyanophenylamino)
cyclopentane
carboxylate
N N
OH OEt
H O H O
A solution of (1R,3S)-3-(4-cyanophenylamino) cyclopentane carboxylic acid
(1.83 g, 7.87
mmol) in DMF (79 mL) was treated with DIEA (2.78 mL, 15.89 mmol) and HATU
(3.63g,
9.54 mmol) at RT. EtOH (0.696mL, 11.92mmol) was then added and the reaction
was stirred
for about 16 h. The reaction was concentrated under reduced pressure and the
residue was
partitioned between saturated sodium carbonate solution (100 mL) and EtOAc (2
x 100 mL).
The organic layers were dried over Na2SO4, filtered and concentrated under
reduced pressure.
The residue was purified by silica gel chromatography (120 g, 0-60%
EtOAc:Heptane) to
afford (JR,3S)-ethyl 3-(4-cyanophenylamino) cyclopentane carboxylate (1.66g,
6.43mmol,
81%) as an oil. LC/MS (Table 1, Method b) Rt = 2.38 min, m/z 259 (M+H) +. 1H
NMR (400
MHz, DMSO-d6) 6 ppm 7.44-7.42 (d, 2H), 6.74-6.72 (d, 1H), 6.63-6.61 (d, 2H),
4.08-4.03 (q,
2H), 3.82-3.77 (m, 1H), 2.87-2.79 (m, 1H), 2.35-2.28 (m, 1H), 2.03-1.94 (m,
1H), 1.90-1.85
(m, 2H), 1.63-1.59 (m, 1H), 1.53-1.47 (m, 1H), 1.18-1.14 (t, 3H).
Preparation #42: (1R, 3S)-ethyl 3-(2-bromo-4-cyanophenylamino) cyclopentane
carboxylate
OOEt Q<OEt
H O H O
Sodium perborate monohydrate (0.353 g, 3.54 mmol) was added dropwise to a
suspension of
KBr (0.481 g, 4.04 mmol), (1R,3S)-ethyl 3-(4-cyanophenylamino) cyclopentane
carboxylate
(0.870 g, 3.37 mmol) and ammonium molybdate tettrahydrate (0.017 mL, 0.034
mmol) in
acetic acid (11.2 mL). The reaction was stirred for about 16 h at RT and then
concentrated
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acetic acid was removed under reduced pressure. Saturated NaCO3 solution (50
mL) was
added and the residue was extracted with EtOAc (100 mL). The organic layer was
washed
with a saturated Na2CO3 solution, dried over Na2SO4, filtered and concentrated
under reduced
pressure to yield (JR,3S)-ethyl 3-(2-bromo-4-cyanophenylamino) cyclopentane
carboxylate
(1.112g, 3.30mmol, 98%) as a tan oil. LC/MS (Table 1, Method b) Rt = 2.64 min,
m/z 337
(M+H) +. 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.89 (d, 1H), 7.61-7.58 (dd, 1H),
6.85-6.82
(d, 1H), 5.77-5.75 (d, 1H), 4.10-4.05 (q, 2H), 4.04-395 (m, 1H), 2.94-2.86 (m,
1H), 2.29-2.24
(m, 1H), 2.02-1.80 (m, 4H), 1.71-1.63 (m, 1H), 1.19-1.16 (t, 3H).
Preparation #43: Preparation of (1R, 3S)-ethyl 3-(4-cyano-2-methylphenylamino)
cyclopentane carboxylate
N Br N4\
I / N\ 0 ~(OEt
N~ OOEt
H O H O O
A solution of (1R,3S)-ethyl 3-(2-bromo-4-cyanophenylamino) cyclopentane
carboxylate (1.12
g, 3.32 mmol), cesium carbonate (3.25 g, 9.96 mmol),trimethylboroxine (1.668
g, 6.64 mmol)
and bis(triphenylphosphine)palladium(II) chloride (0.117 g, 0.166 mmol) in DME
(16.6 mL)
and water (5. 5mL) was purged with nitrogen for about 15 min. The reaction was
stirred at
about 90 C and after about 4 h the reaction was cooled to ambient
temperature. DME was
removed under reduced pressure and the residue was partitioned between EtOAc
(25 mL) and
saturated NaCO3 solution (25 mL). The aqueous layer was extracted again with
EtOAc (50
mL) and the combined organic layers were dried over Na2SO4, filtered and
concentrated under
reduce pressure. The residue was purified by silica gel chromatography (120 g,
0-40%
EtOAc:Heptane) to yield (JR, 3S)-ethyl 3-(4-cyano-2-methylphenylamino)
cyclopentane
carboxylate (0.66g, 2.42mmol, 73%) as an oil. LC/MS (Table 1, Method b) Rt =
2.61 min,
m/z 273 (M+H) +. 1H NMR (400 MHz, DMSO-d6) 6 ppm 7.43-7.40 (dd, 1H), 7.33 (s,
1H),
6.66-6.63 (d, 1H), 5.55-5.53 (d, 1H), 4.09-4.04 (q, 2H), 3.95-3.87 (m, 1H),
2.82-2.90 (m, 1H),
2.31-2.24 (m, 1H), 2.08 (s, 3H), 2.00-1.87 (m, 3H), 1.85-1.77 (m, 1H), 1.68-
1.61 (m,1H),
1.19-1.15 (t, 3H).
Preparation #44: Preparation of 4-(4-fluoropiperidin-1-yl)-3-
(trifluoromethyl)benzonitrile:
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F F N
F F N + JjNH F
F ~
N
F O
F
F
In a 200 mL round bottom flask, 4-fluoro-3-trifluoromethyl-benzonitrile (5.43
g, 28.7 mmol),
4-fluoropiperidine hydrochloride (4.407 g, 31.6 mmol), and potassium carbonate
(9.92 g, 71.7
mmol) in DMF (50 mL) were added to give a tan suspension. The mixture was
heated at about
90 C for about 40 h. After cooling to ambient temperature, the reaction
mixture was
partitioned between water (75 mL) and ethyl acetate (75 mL). The organic layer
was washed
with water (50 mL) and brine (50 mL). The organic layer was dried over
anhydrous
magnesium sulfate and the solvent was removed in vacuo. The crude material was
purified
via gradient normal phase chromatography on silica gel (0% to 100% ethyl
acetate in heptane
over 6 column volumes) to afford 4-(4 fluoropiperidin-1 yl)-3-
(trifluoromethyl)benzonitrile
(4.87 g, 17.9 mmol, 62% yield). LC/MS Rf = 7.51 min.; MS m/z : (M+H+AcOH)+.
(Table 1,
Method n). 1H NMR (400 MHz, DMSO-d6) ppm 8.17 (d, J = 1.98, 1H), 8.06 (dd, J =
2.01,
8.51, 1H), 7.59 (d, J= 8.53, 1H), 4.87 (tdd, J= 3.26, 6.66, 48.35, 1H), 3.13
(t, J= 10.01, 2H),
3.02-2.92 (m, 2H), 2.07-1.78 (m, 4H).
Preparation #45: Preparation of (Z)-4-(4-fluoropiperidin-1-yl)-N'-hydroxy-3-
(trifluoromethyl)benzimidamide
DH
F F //N F N
F w F NH2
N O
F F
4-(4-Fluoro piperidin-1 yl)-N-hydroxy-3-trifluoromethyl-benzamidine Prepared
using General
procedure C. LC/MS Rf = 5.53 min.; MS m/z : 306.17 (M+H)+. (Table 1, Method n)
1H NMR (400 MHz, DMSO-d6) 6 9.74 (s, 1H), 7.95 (d, J= 1.8, 1H), 7.91 (dd, J=
1.8, 8.4,
1H), 7.53 (d, J= 8.4, 1H), 5.93 (s, 2H), 4.94-4.74 (m, 1H), 3.01 (t, J= 9.2,
2H), 2.88 - 2.78
(m, 2H), 2.06 - 1.90 (m, 2H), 1.84 (dqd, J= 3.7, 6.8, 13.5, 2H).
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Preparation #46: Preparation of 4-(3-(4-(4-fluoropiperidin-1-yl)-3-
(trifluor omethyl)phenyl)-1,2, 4-oxadiazol-5-yl)b enzonitrile.
F F N' OH O F N-O
F NH CI F N =N
Do ~)
4-{3-[4-(4-Fluoro piperidin-1 yl)-3-trifluoromethyl phenylJ-[1,2,4]oxadiazol-5
yl}-
benzonitrile Prepared using General procedure E. LC/MS Rf = 2.26 min.; MS m/z
: 417.18
(M+H)+ (Table 1, Method o) 1H NMR (400 MHz, DMSO-d6) 6 8.38 (d, J = 8.3, 2H),
8.32
(dd, J = 1.9, 8.4, I H), 8.29 (d, J = 1.9, I H), 8.14 (d, J= 8.3, 2H), 7.72
(d, J = 8.4, I H), 4.98 -
4.78 (m, 1H), 3.19 - 3.05 (m, 2H), 3.02 - 2.90 (m, 2H), 2.02 (dddd, J= 3.6,
6.3, 11.5, 13.4,
2H), 1.94 - 1.81 (m, 2H).
Preparation #47: Reaction to produce 4-(3-(4-(4-fluoropiperidin-1-yl)-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde.
F F N-O F N_0 O
F N F l i /
F N
F" v 0
F
4-{3-[4-(4-Fluoropiperidin-1 yl)-3-trifluoromethylphenylJ-[1,2,4]oxadiazol-
5yl}-
benzaldehyde Prepared using General Procedure G. LC/MS Rf = 4.20 min.; MS m/z
: 421.15
(M+H)+ (Table 1, Method p) 1H NMR (400 MHz, DMSO-d6) 6 10.16 (s, 1H), 8.42 (d,
J= 8.2,
2H), 8.33 (dd, J = 2.0, 8.4, I H), 8.30 (d, J = 2.0, I H), 8.17 (d, J = 8.6,
2H), 7.72 (d, J = 8.4,
1H), 4.88 (dtt, J = 3.3, 6.6, 48.4, 1H), 3.16 - 3.06 (m, 2H), 3.01 - 2.91 (m,
2H), 2.10 - 1.94
(m, 2H), 1.94 - 1.80 (m, 2H).
Example # 45: Preparation of 1-(4-(3-(4-(4-fluoropiperidin-1-yl)-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)benzyl)azetidine-3-carboxylic
acid,
Ammonium Acetate salt.
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o
F F N-O O OH F F N-
F ' N \ F j
' N N
O N
H F~O
F HO
1-(4-{3-[4-(4-Fluoro piperidin-1 yl)-3-trifluoromethyl phenylJ-
[1,2,4]oxadiazol-5 yl}-
benzyl)-azetidine-3-carboxylic acid Prepared using General Procedure H. LC/MS
Rt = 2.07
min.; MS m/z: 505.19 (M+H)+, (Table 1, Method g). 1H NMR (400 MHz, DMSO-d6). 6
ppm
8.33-8.26 (m, 2H), 8.15 (d, J = 8.35 Hz, 2H), 7.71 (d, J = 8.43 Hz, 1H), 7.55
(d, J = 8.43 Hz,
2H), 4.88 (dddd, J = 17.52, 10.37, 6.67, 3.53 Hz, 1H), 3.68 (s, 2H), 3.47-3.16
(m, 12H), 3.16-
3.06 (m, 2H), 2.98-2.90 (m, 2H), 2.09-1.81 (m, 1H), 1.91 (s, 3H).
Example # 46: Preparation of 5-((4-(3-(4-(4-fluoropiperidin-1-yl)-3-
(trifluor omethyl)p henyl)-1,2,4-oxadiazol-5-yl)b enzylamino) methyl)is oxazol-
3-ol.
O F N-O
F F N F
HO F I N
F N O N/ NHp HN
^ N
N
BrH
F F N OH
Prepared using General Procedure H. LC/MS Rt = 2.69 min.; MS m/z: 516.18 (M-H)-
Table1, method g. 1H NMR (400 MHz, CDCl3).6 ppm 8.50-8.42 (m, 1H), 8.28 (d, J
=1.11 Hz,1H),8.19(d,J=8.14Hz,2H),7.55(d,J=8.25Hz,3H),7.44(d,J=8.32
Hz, 1H), 5.89 (s, 1H), 4.96-4.74 (m, 1H), 3.94 (s, 2H), 3.86 (s, 2H), 3.25-
3.09 (m,
2H), 3.00-2.87 (m, 2H), 2.05 (m, 4H).
Example # 47: Preparation of 2-((4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-
1,2,4-
oxadiazol-5-yl)phen oxy)methyl) morpholine.
F N-O F N'O _ NH
F I ' F N F FI ' N
HO-_,~ O
In a 25 mL round bottom flask, 2-hydroxymethylmorpholine (0.096 g, 0.819 mmol)
(TYGER)
in THE (10 mL) was added to give a colorless solution. Sodium hydride (0.020
g, 0.819
mmol) was added and the mixture was stirred until hydrogen evolution ceased. 5-
(4-
fluorophenyl)-3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole
(0.300 g, 0.819
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mmol) was added and the mixture was stirred at ambient temperature under a
nitrogen
atmosphere then heated at reflux for about 4 days. The solvent was removed in
vacuo. The
crude material was purified by gradient normal phase chromatography using 0-
10%
methanol in dichloromethane as an eluent to afford 2-((4-(3-(4-isopropoxy-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5 yl)phenoxy)methyl)morpholine (0.032
g, 0.068
mmol, 8.4% yield). LC/MS Rt = 2.29 min.; MS m/z: 464.15 (M+H). (Table 1,
Method j).
1H NMR (400 MHz, DMSO) 6 ppm 8.27 (dd, J = 8.78, 2.11 Hz, 1H), 8.19 (d, J =
2.06 Hz,
1H), 8.11 (d, J = 8.95 Hz, 2H), 7.51 (d, J = 8.93 Hz, 1H), 7.18 (d, J = 8.98
Hz, 2H), 4.90
(td, J = 12.15, 6.07 Hz, 1H), 4.09-4.02 (m, 2H), 3.76-3.67 (m, 2H), 3.49-3.42
(m, 1H), 3.15
(d, J = 5.20 Hz, 1H), 2.86 (dd, J = 12.11, 2.23 Hz, 1H), 2.71-2.59 (m, 2H),
2.55-2.45 (m,
1H), 1.33 (d, J = 6.02 Hz, 6H).
Preparation #48 and 49: Preparation of (R)- and (S)-4-(tetrahydrofuran-3-
yloxy)-3-
(trifluoromethyl)benzonitrile according to Scheme AA
Scheme AA NOH
F3C CN F3C
NH2
OI O
0 AA3 AA4
F3C CN F3C CN (S)-Z :r
IZZZZ O I / HO I / N OH
AA1 AA2\ F3C CN F3C
I NH2
O : O
AA5 AA6
O O
(R)-
A mixture of 4-methoxy-3-(trifluoromethyl)benzonitrile (AA1, 24.88 g, 0.124
mol) and
pyridine hydrochloride (29.04 g, 0.251 mol) was stirred and heated at about
200 C for about
40 min. The mixture was cooled to ambient temperature before the addition of
water and the
resulting precipitate was filtered and dried to give 21.1 g of 4-hydroxy-3-
(trifluoromethyl)benzonitrile (AA2) which was used without further
purification. Yield: 91 %.
To a stirred mixture of 4-hydroxy-3-(trifluoromethyl)benzonitrile (AA2, 9.9 g,
53 mmol) and
PPh3 (23.6 g, 90 mmol) in THE (250 mL) at about 0 C, DIAD (17.7 mL ,90 mmol)
was
added The mixture was stirred for about 10 min. at about 0 C before (R)-(-)-3-
hydroxytetrahydrofuran (5 g, 56.7 mmol) in THE (20 mL) was added. The mixture
was stirred
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at ambient temperature overnight under an atmosphere of nitrogen. The solvent
was removed
in vacuo and the residue was purified by flash column chromatography
(EA/petroleum ether =
10-20%) to give (R)-4-(tetrahydrofuran-3-yloxy)-3-
(trifluoromethyl)benzonitrile (AA5, 8.8g,
65% yield) which was used without further purification.
19 mL (96 mmol) of diisopropyl azodicarboxylate was added to the mixture of 4-
hydroxy-3-
(trifluoromethyl)benzonitrile (AA2, 11 g, 59 mmol) and triphenylphosphine
(25.3 g, 96 mmol)
in THE (250 mL) at about 0 C. The mixture was stirred for about 10 min. at
about 0 C. (S)-
(+)-3-hydroxytetrahydrofuran (5 g, 56.7 mmol) in THE (20 mL) was added. The
mixture was
stirred at RT overnight under nitrogen. The solvent was removed in vacuo and
the residue was
purified by flash column chromatography (ethyl acetate/petroleum ether = 10-
20%) to afford
(S)-4-(tetrahydrofuran-3yloxy)-3-(trifluoromethyl)benzonitrile. (AA3, 9.2 g,
yield: 63%)
which was used without further purification.
A solution of (R)-4-(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)benzonitrile
(AA5, 8.6 g, 33
mmol) in ethanol (80 mL) was treaded with 50% aqueous hydroxylamine (8.1 mL).
The
mixture was stirred and heated at about 60 C for about 18 h. The solvents
were removed in
vacuo and the residue was purified by flash column chromatography
(methanol/chloroform =
5-15%) to give (R)-N'-hydroxy-4-(tetrahydrofuran-3yloxy)-3-
(trifluoromethyl)benzimidamide
(AA6, 5.4 g, yield: 56%) LC/MS (Table 1, Method c) Rt = 2.48 min, m/z 290.0
(M+H) ; 1H
NMR (400 MHz, DMSO-d6) 6 9.64 (s, 1H), 7.89 (m, 2H), 7.27 (d, 1H), 5.91 (s,
2H), 5.24 (m,
1H), 3.95 (dd, 1H), 3.79 (ddd, 3H), 2.24 (dtd, 1H), 1.98 (td, 1H).
A solution of (S)-4-(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)benzonitrile
(AA3, 9 g, 35
mmol) in ethanol (80 mL) was treaded with 50% aqueous hydroxylamine (8.5 mL).
The
mixture was stirred and heated at about 60 C overnight. The solvents were
removed in vacuo
and the residue was purified by flash column chromatography
(methanol/chloroform = 5-
15%) to afford N-Hydroxy-4-[(S)-(tetrahydro furan-3yl)oxyJ-3-trifluoromethyl-
benzamidine.
(AA4, 5.6 g, yield: 55%) which was used without further purification.
Preparation #50: (S)-5-(4-Fluorophenyl)-3-(4-(tetrahydrofuran-3-yloxy)-3-
(trifluor omethyl)p henyl)-1,2,4-oxadiazole
F F
-O
F F V
N-OH O F ON i CI N 1 F
NH2
F 6
O O
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(S,Z)-N-hydroxy-4-(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)benzimidamide
(500 mg,
1.723 mmol), 4-fluorobenzoyl chloride (0.207 mL, 1.723 mmol) and pyridine (5
mL) are
loaded into a microwave vial equipped with a stir bar. The vessel is sealed
and the reaction
heated to about 160 C with cooling for about 25 min. The mixture was diluted
with DMSO
(2 mL) and analyzed by LC/MS. MeCN (6 mL) was added and the mixture subjected
to
purification by molecular ion directed LC/MS to afford (S)-5-(4 fluorophenyl)-
3-(4-
(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole (413 mg,
1.047 mmol,
60.8 % yield) as an off-white solid. LC/MS (Table 1, Method g) Rt = 3.15 min.;
MS m/z: did
not ionize. 1H NMR (400 MHz, DMSO) dppm 8.42-8.14 (m, 4H), 7.60-7.43 (m, 3H),
5.35 (t,
J = 5.02 Hz, 1H), 3.98 (dd, J = 10.49, 4.40 Hz, 1H), 3.91-3.76 (m, 3H), 2.30
(dd, J = 13.95,
5.75 Hz, 1H), 2.11-1.96 (m, 1H).
Example #48: (1R,3S)-3-(4-(3-(4-((S)-Tetrahydrofuran-3-yloxy)-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid
F F N-O F OOH
F F N-O
`~
~/ O -NC '
1 /
N
OH O
O
6
6
(S)-5 -(4-fluorophenyl)-3 -(4-(tetrahydro furan-3 -yloxy)-3 -
(trifluoromethyl)phenyl)-1,2,4-
oxadiazole (350 mg, 0.888 mmol), (1R,3S)-3-aminocyclopentanecarboxylic acid
(115 mg,
0.888 mmol), potassium carbonate (270 mg, 1.953 mmol) and DMF (2 mL) was
heated with
cooling at about 160 C on the Biotage microwave for about 30 min. The mixture
was diluted
with DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots for
purification by
molecular ion directed LC/MS. The fractions were combined and evaporated to
afford a pale
brown solid that was dried in vacuo at about 60 C for about 3 h to afford
(JR,3S)-3-(4-(3-(4-
((S)-tetrahydrofuran-3 yloxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (43 mg, 0.083 mmol, 9.33 % yield)
as a pale
brown solid. NMR showed the presence of ammonium acetate and so the compound
was dried
in vacuo at about 100 C for about 3 h to afford (JR,3S)-3-(4-(3-(4-((S)-
tetrahydrofuran-3-
yloxy)-3-(trifluoromethyl)phenyl)-1, 2, 4-oxadiazol-5
yl)phenylamino)cyclopentanecarboxylic
acid (43 mg, 0.083 mmol, 9.33 % yield) as an off-white solid. LC/MS (Table 1,
Method g) Rt
= 2.61 min.; MS m/z: 504.2 (M+H)+. 1H NMR (400 MHz, DMSO) d ppm 7.48 (d, J =
8.85
Hz, 1H), 7.03-6.89 (m, 1H), 6.72 (d, J = 8.94 Hz, 2H), 7.87 (d, J = 8.88 Hz,
2H), 8.20 (d, J =
2.03 Hz, 1H), 8.27 (dd, J = 8.73, 2.06 Hz, 1H), 5.37-5.27 (m, 1H), 3.98 (dd, J
= 10.41, 4.47
Hz, 1H), 3.90-3.74 (m, 4H), 2.75 (t, J = 8.31 Hz, 1H), 2.30 (td, J = 11.68,
6.98 Hz, 2H), 2.10-
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1.92 (m, 2H), 1.92-1.81 (m, 2H), 1.68 (dd, J = 7.98, 4.74 Hz, 1H), 1.55 (dd, J
= 12.18, 6.65
Hz, 1 H).
Example #49: (1R,3S)-3-(4-(3-(4-(4-Fluoropiperidin-1-yl)-3-
(trifluoromethyl)phenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid
\-
F OH
F O
F
F N-OOH F N-O
/~ ~
I N F HzN. F-\~ H
F -l\/l
5 -(4-Fluorophenyl)-3 -(4-(4-fluoropiperidin- l -yl)-3 -
(trifluoromethyl)phenyl)-1,2,4-oxadiazol e
(420 mg, 1.026 mmol), (1R,3S)-3-aminocyclopentanecarboxylic acid (146 mg,
1.129 mmol),
potassium carbonate (312 mg, 2.257 mmol) and DMF (2 mL) was heated with
cooling at
about 160 C on the Biotage microwave for about 30 min. The mixture was
diluted with
DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots for
purification by
molecular ion directed LC/MS. The fractions were combined and evaporated to
afford a pale
brown solid that was dried in vacuo at about 60 C for about 3 h to afford
(JR,3S)-3-(4-(3-(4-
(4 fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (122 mg, 0.235 mmol, 22.93 % yield)
as an off-
white solid. LC/MS (Table 1, Method f) Rt = 3.05 min.; MS m/z: 517.17 (M-H)-.
1H NMR
(400 MHz, DMSO) 6 ppm 6.83 (d, J = 6.67 Hz, 1H), 6.72 (d, J = 8.92 Hz, 2H),
8.28-8.21 (m,
2H), 7.87 (d, J = 8.86 Hz, 2H), 7.67 (d, J = 8.40 Hz, 1H), 12.16-12.05 (m,
1H), 4.97-4.75 (m,
1H), 3.84 (d, J = 6.98 Hz, 1H), 3.08 (t, J = 9.04 Hz, 2H), 1.65 (d, J = 12.27
Hz, 1H), 1.52 (s,
1H), 2.31 (s, 1H), 2.11-1.92 (m, 3H), 1.92-1.79 (m, 4H), 2.97-2.85 (m, 2H),
2.83-2.69 (m,
1H).
Example #50: (1R,3S)-3-(4-(3-(4-(4,4-Difluoropiperidin-1-yl)-3-
(trifluoromethyl)phenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid acetate salt
O--OH
O F
F F N-O \\-OH F F\ N-O
F
0
N + ~ FN N / N.
F~N F H N=; H
z F
F
3-(4-(4,4-Difluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-5-(4-
fluorophenyl)-1,2,4-
oxadiazole (503 mg, 1.177 mmol), (1R,3S)-3-aminocyclopentanecarboxylic acid
(167 mg,
1.295 mmol), potassium carbonate (358 mg, 2.59 mmol) and DMF (2 mL) was heated
with
cooling at about 160 C on the Biotage microwave for about 30 min. The mixture
was diluted
with DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots for
purification by
molecular ion directed LC/MS. The fractions were combined and evaporated to
afford a pale
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brown solid that was dried in vacuo at about 60 C for about 3 h to afford
(IR,3S)-3-(4-(3-(4-
(4,4-difluoropiperidin-1 yl)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (243 mg, 0.453 mmol, 38.5 % yield)
as an off-
white solid as the acetate salt. LC/MS (Table 1, Method g) Rt = 3.06 min.; MS
m/z: 535.2
(M-H)-.
1H NMR (400 MHz, DMSO) 6 ppm 7.73 (d, J = 8.23 Hz, 1H), 7.86 (d, J = 8.85 Hz,
2H),
8.29-8.21 (m, 2H), 2.81-2.68 (m, 1H), 2.30 (d, J = 12.64 Hz, 1H), 2.10 (ddd, J
= 13.96, 10.71,
5.50 Hz, 4H), 1.98 (s, 1H), 1.92-1.81 (m, 2H), 1.66 (d, J = 12.66 Hz, 1H),
1.52 (s, 1H), 3.09-
3.04 (m, 4H), 3.87-3.79 (m, 1H), 2.52 (s, 3H).
Example #51: (1S,3S)-3-(4-(3-(4-(4-fluoropiperidin-1-yl)-3-
(trifluoromethyl)phenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid acetate salt
OH
F F N_O F F N,O ~.,O
\ N OH
~ (^, ~ F ~ N NH
F' O HZ I O O /
F
5-(4-Fluorophenyl)-3-(4-(4-fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-
1,2,4-oxadiazole
(576 mg, 1.408 mmol), (1S,3S)-3-aminocyclopentanecarboxylic acid (200 mg,
1.549 mmol,
Afid Therapeutics), potassium carbonate (428 mg, 3.10 mmol) and DMF (2 mL) was
heated
with cooling at about 160 C on the Biotage microwave for about 30 min. The
mixture was
diluted with DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots
for
purification by molecular ion directed LC/MS. The fractions were combined and
evaporated
to afford a pale brown solid that was dried in vacuo at about 60 C for about
3 h to afford
(IS,3S)-3-(4-(3-(4-(4 fluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (47 mg, 0.082 mmol, 5.80 % yield)
as a pale
brown solid as the acetate salt. LC/MS (Table 1, Method g) Rt = 3.03 min.; MS
m/z: 517.2
(M-H)-. 1H NMR (400 MHz, DMSO) 6 ppm 8.23 (td, J = 5.39, 1.81 Hz, 2H), 7.65
(d, J =
8.39 Hz, 1H), 6.69 (dd, J = 9.02, 2.47 Hz, 2H), 6.79 (d, J = 6.44 Hz, 1H),
7.86 (d, J = 8.88
Hz, 2H), 4.97-4.87 (m, 1H), 4.83-4.74 (m, 1H), 3.96-3.79 (m, 2H), 3.07 (s,
2H), 2.97-2.85 (m,
2H), 2.85-2.72 (m, 1H), 2.20-1.43 (m, 13H).
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Example #52: (1R,3R)-3-(4-(3-(4-(4-fluoropiperidin-1-yl)-3-
(trifluoromethyl)phenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid acetate salt
OH
F F N'O F N-O _ ~
I i OH F
F N F + 0 O -- F N H
FJ:D HZN F~N
-(4-Fluorophenyl)-3 -(4-(4-fluoropiperidin- l -yl)-3 -(trifluoromethyl)phenyl)-
1,2,4-oxadiazol e
5 (576 mg, 1.408 mmol), (1R,3R)-3-aminocyclopentanecarboxylic acid (200 mg,
1.549 mmol,
Afid Therapeutics), potassium carbonate (428 mg, 3.10 mmol) and DMF (3 mL) was
heated
with cooling at about 160 C on the Biotage microwave for about 30 min. The
mixture was
diluted with DMSO (6 mL) and MeCN (8 mL), filtered and divided into 8 aliquots
for
purification by molecular ion directed LC/MS. The fractions were combined and
evaporated
to afford a pale brown solid that was dried in vacuo at about 60 C for about
3 hours to afford
(1R,3R)-3-(4-(3-(4-(4 fluoropiperidin-1 yl)-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (43 mg, 0.075 mmol, 5.30 % yield)
as an pale
brown solid as the acetate salt. LC/MS (Table 1, Method g Rt = 3.03 min.; MS
m/z: 517.2
(M-H)-. 1H NMR (400 MHz, DMSO) 6 ppm 8.27-8.18 (m, 2H), 7.85 (dd, J = 8.88,
3.58 Hz,
2H), 7.65 (d, J = 8.35 Hz, 1H), 6.79 (d, J = 6.47 Hz, 1H), 6.70 (d, J = 8.94
Hz, 2H), 4.91 (dd,
J = 6.64, 3.30 Hz, 1H), 4.82-4.73 (m, 1H), 3.87 (d, J = 5.83 Hz, 1H), 3.06 (t,
J = 8.93 Hz,
2H), 2.96-2.76 (m, 3H), 2.28-1.39 (m, 13H).
Example #53: (1S,3R)-3-(4-(5-(3-cyano-4-(4-fluoropiperidin-1-yl)phenyl)-1,2,4-
oxadiazol-
3-yl)-2-(trifluoromethyl)phenylamino)cyclopentanecarboxylic acid acetate salt
OH
O_N O-N O
N~\ N OH NH
Fi \/N
HZN; ii F
F\//
5-(3-(4-fluoro-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-2-(4-
fluoropiperidin-l-
yl)benzonitrile (500 mg, 1.151 mmol), (1S,3R)-3-aminocyclopentanecarboxylic
acid (164 mg,
1.266 mmol), potassium carbonate (350 mg, 2.53 mmol) and DMF (3 mL) was heated
with
cooling at about 160 C on the Biotage microwave for about 30 min. The mixture
was diluted
with DMSO (12 mL) and ACN (9 mL), filtered and divided in 8 aliquots for
purification by
molecular ion directed LC/MS. The fractions were combined and evaporated to
afford a pale
brown solid that was dried in vacuo at about 60 C for about 7 h to afford
(IS,3R)-3-(4-(5-(3-
cyano-4-(4 fluoropiperidin-1 yl)phenyl)-1,2,4-oxadiazol-3-yl)-2-
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(trifluoromethyl)phenylamino)cyclopentanecarboxylic acid (153 mg, 0.267 mmol,
23.23 %
yield) as a pale brown solid as the acetate salt.
LC/MS (Table 1, Method g) Rt = 2.93 min.; MS m/z: 542.1 (M-H)-.
6 H (400 MHz, DMSO) 8.32 (1 H, s), 8.19 (1 H, d, J 8.9), 8.01 (2 H, d, J 7.8),
7.31 (1 H, d, J
8.9), 7.03 (1 H, d, J 9.2), 5.96 (1 H, s), 5.05 - 4.79 (1 H, m), 4.12 - 3.97
(1 H, m), 3.44 (4 H, d,
J 29.9), 2.84 (1 H, s), 1.97 (11 H, d, J 73.3).
Example #54: (1S,3R)-3-(4-(5-(3-cyano-4-(4-fluoropiperidin-1-yl)phenyl)-1,2,4-
oxadiazol-
3-yl)phenylamino)cyclopentanecarboxylic acid acetate salt
OH
_
O-N \ O-N O..~ O
N~\ N I OH N~~ \ NH
NI 0 O
F" v Hg C
F ~\/
5-(3-(4-Fluorophenyl)-1,2,4-oxadiazol-5-yl)-2-(4-fluoropiperidin-1-
yl)benzonitrile (500 mg,
1.365 mmol), (1S,3R)-3-aminocyclopentanecarboxylic acid (194 mg, 1.501 mmol),
potassium
carbonate (415 mg, 3.00 mmol) and DMF (3 mL) was heated with cooling at about
160 C on
the Biotage microwave for about 30 min. The mixture was diluted with DMSO (12
mL) and
MeCN (9 mL), filtered and divided into 12 aliquots for purification by
molecular ion directed
LGMS. The fractions were combined and evaporated to afford a pale brown solid
that was
dried in vacuo at about 60 C for about 7 h to afford (IS,3R)-3-(4-(5-(3-cyano-
4-(4-
fluoropiperidin-1 yl)phenyl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid
(23 mg, 0.046 mmol, 3.40 % yield) as a pale yellow solid as the acetate salt.
LGMS (Table 1,
Method g) Rt = 2.59 min.; MS m/z: 474.2 (M-H)-.
6 H (400 MHz, DMSO) 8.33 (1 H, s), 8.24 - 8.17 (1 H, m), 7.75 (2 H, d, J 8.6),
7.34 (1 H, d, J
8.9), 6.65 (2 H, d, J 8.7), 5.03 - 4.83 (2 H, m), 3.84 - 3.72 (2 H, m), 3.55 -
3.32 (6 H, m), 2.75
- 2.58 (2 H, m), 1.83 (15 H, s).
Preparation #51 and 52: 5-[3-(4-Fluoro-phenyl)-[1,2,4] oxadiazol-5-yl]-2-(4-
fluoro-
piperidin-1-yl)-benzonitrile and 5-[3-(4-Fluoro-3-trifluoromethyl-phenyl)-
[1,2,4]oxadiazol-5-yl]-2-(4-fluoro-piperidin-1-yl)-benzonitrile according to
Scheme BB
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Scheme BB
II II I ' +
N" O" DAST, DCM fN" 0 \ HCI/Dioxane ZCI
HO" v -78C-0 C F\/ 25 C F'CH
BB1 BB2 BB3
N,OH
NC
\ HONH2HCI > H N I O,F
/ z
F EtOH, 65 C BB7
H I / CuCN, NMP H Al NaCIOZ, NaHZPO4OH /
\ FF \ F
Br 170 C HZO/t-BuOH, 25 C
O 0 N 0 N
BB4 BB5
F HO. NH2
F F
ONH HCI 3 N N I
K2CO3, DMF, 900C OH I / CN 1) PPh3, CCI3CN N F
MW100 C, 5min N-
F
o
2) DIEA, THF, CN
BB6 MW150 C, 15min BB9
NH2
CN N HONH2HCI IH
F EtOH, 65 C aw- F
F F F
F F F
BB8
NH2
N'
I / F /
CN OH F
O CF3 8
F-CN 1)HATU, DIEPA F3C N N F
OH DMF, 140 C NCO
BB6 BBIO CN
Preparation of BB2: 4-Fluoro-piperidine-l-carboxylic acid tert-butyl ester
NDAST, DCM N~O
HO, O -78t-0 C F~
BB1 BB2
The solution of 4-hydroxy-piperidine-l-carboxylic acid tent-butyl ester (BB1,
20.0 g, 99.4
mmol) in DCM (400mL) was cooled to about -78 C and to this the DAST (31.65
mL) was
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slowly added dropwise over about 30 min. The mixture was stirred at about -78
C for about
0.5 h and at about 0 C for about 0.5 h. The analysis by TLC showed the
formation of desired
product which was then quenched by addition of saturated NaHCO3 aqueous and
chloroform.
The organic layer was separated, dried over Na2SO4, and concentrated under
reduced pressure.
The crude product was further purified by silicon gel column chromatography to
afford 4-
Fluoro piperidine-l-carboxylic acid tert-butyl ester as colorless oil (BB2,
8.0 g).
Preparation of BB3: 4-Fluoro-piperidine hydrochloride
O
HCI/Dioxane NH2CI
F JD 25 C F J\/
BB2 BB3
To a solution of 4-fluoro-piperidine-l-carboxylic acid tent-butyl ester 2
(BB2, 23.0 g, 113.2
mmol) in DCM (460 mL) the solution of HCl/1,4-dioxane (2 N, 200 mL) was slowly
added
dropwise at about 0 T. The mixture was stirred at about 25 C overnight. The
analysis by
TLC indicated the completion of the reaction. The solution was concentrated
under reduced
pressure. The residue was washed with DCM, dried in vacuum to afford 4-fluoro-
piperidine
as white hydrochloride salt (BB3, 13.3 g).
Preparation of BB4: 2-Fluoro-5-formyl-benzonitrile
\ F F
CUCN, NMP
H I / H
Br 170 C II
O 0 N
BB4
3-Bromo-4-fluoro-benzaldehyde (15.0 g, 74 mmol) and CuCN (7.6 g, 84.4 mmol)
were mixed
with NMP (27 mL) under vigorously stirring at about 25 T. The mixture was
slowly heated
over several hours to reach about 170 C and stirred for about 24 h. The
analysis by TLC
showed the complete consumption of starting material and formation of new
product. The
temperature was cooled to about 80 C and EtOAc (250 mL) and water (150 mL) was
added.
The organic layer was separated and the aqueous was extracted with EtOAc (150
mL x 2).
The combined organic layers were dried over NaSO4 and concentrated. The
residue was
purified by silica gel column chromatography to afford 2-Fluoro-5formyl-
benzonitrile as a
white solid (BB4, 9.0 g).
Preparation of BBS: 3-Cyano-4-fluoro-benzoic acid
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F F
NaCIO2, NaH2PO4 H / I I H20/t-BuOH, 25 C OH /
O N O N
BB4 BB4
To a solution of the 2-fluoro-5-formyl-benzonitrile BB4 in mixed solvent of
H20/t-BuOH (48
mL/201 mL), the NaC1O2 (28.2 g, 223.5 mmol) and NaH2PO4 (22.2 g, 142.6 mmol)
was
added. The mixture was stirred vigorously at about 25 C and stood overnight.
The analysis
by TLC indicated the complete consumption of the starting material. The
solution was
adjusted to pH=3.5 by addition of 1 N aqueous HCl and extracted with DCM/i-
Propanol
(10:1, 200 mL x 3). The combined organic layer was dried over Na2SO4 and
concentrated in
vacuum. The residue was redissolved in aqueous NaHCO3 and extracted with DCM.
The
aqueous layer was acidified; the white precipitate was extracted with DCM,
dried over
Na2SO4 and concentrated under reduced pressure to afford 3-Cyano-4-fluoro-
benzoic acid as
white solid (BBS, 9.5 g).
Preparation of BB8: 4-Fluoro-N-hydroxy-benzamidine
CN NH2
HONH2HCI N
F DOH, 65 C UH
F
BB8
To a solution of the 4-fluoro-benzonitrile (10.0 g, 52.9 mmol) in ethanol (200
mL), the
solution of NH2OH=HCl (4.0 g, 58.2 mmmol) in H2O (4 mL) was added dropwise.
The
mixture was stirred vigorously at about 65 C and stood overnight. The
analysis by TLC
indicated the complete consumption of starting material. The solution was
concentrated to
remove the solvent. The residue was dissolved in DCM and washed with water,
brine, dried
over Na2SO4 and concentrated in vacuum to afford 4-Fluoro-N-hydroxy-
benzamidine as pale-
yellow solid (BB8).
Preparation of BB6: 3-Cyano-4-(4-fluoro-piperidin-1-yl)-benzoic acid:
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F
\ F ~ N
'ONH HCI BB3 OH I /
OH / CN
0 N K2CO3, DMF, 90 C 0
BB5 BB6
To a solution of the 3-cyano-4-fluoro-benzoic acid BB5 (14.3 g, 86.9 mmol) and
K2CO3 (36.3
g, 26.1 mmol) in DMF (150 mL) the 4-fluoro-piperidinium hydrochloride BB3
(13.3 g, 95.6
mmol) was added neat at about 25 T. The mixture was heated to about 90 C and
stirred
overnight. After about 24 h, the analysis by HPLC indicated there still
remained starting
material. The solution was stirred for another 24 h. The solution was quenched
by addition of
EtOAc and (300 mL) 1 N HC1. The organic layer was washed with brine, dried
over Na2SO4,
concentrated under reduced pressure. The residue was further purified by
silica gel column
chromatograph to afford 3-Cyano-4-(4 fluoro piperidin-1-yl)-benzoic acid as
white solid
(BB6).
Preparation of 5-[3-(4-Fluoro-phenyl)-[1,2,4] oxadiazol-5-yl]-2-(4-fluoro-
piperidin-1-yl)-
benzonitrile:
F NH2 F
HO.N
\ N , BB8
OH I / CN 1)HATU, DIEPA \ N \
N rF
DMF, 140 C N,O ~/
O
BB6 BB9 CN
A solution of the 3-cyano-4-(4-fluoro-piperidin-1-yl)-benzoic acid BB6 (0.5 g
x 18, 2 mmol)
and CC13CN (0.44 g x 18, 3 mmol) in dry THE (15 mL) was prepared and to this
the Ph3P
(1.58 g* 18, 6 mmol) was added under protection of nitrogen at about 25 T. The
mixture was
reacted in microwave add to abbreviation list at about 100 C for about 5 min,
then a solution
of 4-fluoro-N-hydroxy-benzamidine BB8 (0.34 g x 18, 2.2 mmol) and DIEA (0.52 g
x 18, 4
mmol) was added. The mixture was reacted in MW at about 150 C for about 15
min.
The analysis by TLC showed the formation of desired product, which was
purified by silica
gel column chromatograph to afford 5-[3-(4 fluorophenyl)-[1,2,4]oxadiazol-5-
ylJ-2-(4-
fluoropiperidin-1-yl)-benzonitrile as white solid (BB9). 1H NMR (400 MHz,
DMSO) 6 ppm
8.31(1H,m),8.19-8.17(1H,m),8.08-8.05(2H,m),7.41-7.36(2H,m),7.32-7.30(1H,
m), 4.97 - 4.85 (1H, m), 3.50 - 3.35 (4H, m), 2.07 - 1.91 (2H, m) and 1.89 -
1.85 (2H, m).
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Preparation of BB7: 4-Fluoro-N-hydroxy-3-trifluoromethyl-benzamidine:
OH
NC" CF3
HONH2HC1 H N N CF3
F EtOH, 65 C 2
F
BB7
To a solution of the 4-fluoro-3-trifluoromethyl-benzonitrile (20.0 g, 105.8
mmol) in ethanol
(400 mL) a solution of the NH2OH=HCl (8.0 g, 116.4 mmmol) which was adjusted
to pH=7.0
by addition of NaOH in H2O (8 mL) was added. The mixture was stirred
vigorously and
heated to about 65 C for about 16 h. The analysis by TLC indicated the
completion of the
reaction; it was concentrated to remove the solvent. The residue was
redissolved in DCM (200
mL) and washed with water, brine and dried over Na2SO4, concentrated in vacuum
to afford
4-Fluoro-N-hydroxy-3-trifluoromethyl-benzamidine (BB7) as pale-yellow solid.
1H NMR
(400 MHz, DMSO) 6 ppm 9.83 (1H, s), 8.00 - 7.98 (2H, m), 7.50 (1H, t) and 6.00
(2H, s).
Preparation of BB10: 5-[3-(4-Fluoro-3-trifluoromethyl-phenyl)-[1,2,4]
oxadiazol-5-yl]-2-
(4-fluo ro-pip eridin-1-yl)-benzonitrile:
F NH2
HO.N CF3 F
N BB8 I
F 10- F3C \ N
OH I / CN HATU, FIEPA, DMF
140 C NCO
O
BB6 BB10 CN
To a solution of compound BB6 (20 g, 80.6 mmol) in DMF (385 mL), the HATU(36.5
g, 96.7
mmol) , 4-fluoro-N-hydroxy-3-trifluoromethyl-benzamidine (21.5 g, 96.7 mmol)
and DIPA
(29.3 g, 227 mmol) was added. The analysis by HPLC indicated there was no
change starting
material. The solution was cooled to about 25 C and quenched by addition of
H20/DCM
(200 mL/500 mL). The organic layer was separated, washed with saturated
NaHCO3i brine
(200 mL x 2) dried over NaSO4 and concentrated. The crude product was isolated
by the pre-
HPLC to afford the product as white solid (BB10) 1H NMR (400 MHz, DMSO) 6 ppm
8.42 -
8.38 (2H, m), 8.32 - 8.30 (1H, m), 8.25 - 8.22 (1H, m), 7.75 (1H, t), 7.35
(1H, d), 5.01 - 4.87
(1H, m), 3.59 - 3.36 (4H, m), 2.12 - 2.02 (2H, m) and 1.92 - 1.74 (2H, m).
Preparation #53 and 54: Preparation of 5-(4-fluorophenyl)-3-(4-(4-
fluoropiperidin-1-yl)-
3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole and 3-(4-(4,4-difluoropiperidin-1-
yl)-3-
(trifluor omethyl)phenyl)-5-(4-fluor ophenyl)-1,2,4-oxadiazole
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F F V11- N HN~F F F N
F HCI F NHZOH
F KZCO3/DMF N EtOH
1 F
2
F N-OH F N-O
F Vj'~ O F, \ F
~\ F F N N
F N NH
Z CI ~I
~I F~/ Py/Toluene F~/
3
F F , N HNa F F F N
F \ F F NHZOH
N EtOH
F I KZC03 DMF F~
F~// wv/ 4
F
F N-OH F N-O
i F
F N
~ ~ '*-~ I / NHZ C1 F
F/ v O \ F F N I / N \
F
Py/Toluene
F 5 F
Preparation of 4-(4-fluoropiperidin-1-yl)-3-(trifluoromethyl)benzonitrile
(compound-2):
To a stirred solution of compound 1 (5.0 g, 0.026 mmol) and 4-fluoropiperidine-
HC1 (4.05 g,
0.029 mmol) in DMSO (50 mL), K2CO3 (9.12 g, 0.066 mmol) was added at RT. The
reaction
mixture was heated at about 100 C for about 12 h. Upon complete consumption
of starting
material, the reaction mixture was cooled to RT and poured into crushed ice.
The aqueous
layer was extracted with hexane (2 x 50 mL), washed with brine (50 mL), dried
over sodium
sulfate and concentrated under reduced pressure to yield a crude compound
which was
purified by column chromatography using 2 % EtOAc /Hexane to afford compound 2
as
colorless liquid (4.75 g, 67%). 'H NMR (200 MHz, CDC13): 6 1.94-2.01 (m, 2H),
2.04-2.12
(m, 2H), 2.92-3.03 (m, 2H), 3.13-3.25 (m, 2H), 4.70-5.10 (m, 1H), 7.32 (d, J=
8.4 Hz, 1H),
7.75 (dd, J= 8.4, 2.2 Hz, 1H), 7.89 (d, J= 2.2 Hz, 1H);
MS (ESI): 273 (M++H).
Preparation of 4-(4-fluoropiperidin-1-yl)-N'-hydroxy-3-(trifluoromethyl)
benzimidamide
(compound-3):
A stirred solution of compound 2 (4.75 g, 0.017 mmol) in EtOH (50 mL),
hydroxyl amine
(50% in water, 1.26 mL, 0.019 mmol) was added at RT. The reaction mixture was
heated at
about 65 C for about 4 h. Upon complete consumption of starting material, the
volatiles were
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removed under reduced pressure to afford crude 4-(4 fluoropiperidin-1 yl)-N'-
hydroxy-3-
(trifluoromethyl) benzimidamide 3 (5.4 g) which was used for the next step
without further
purification.
Preparation of 5-(4-fluorophenyl)-3-(4-(4-fluoropiperidin-1-yl)-3-
(trifluoromethyl)
phenyl)-1,2,4-oxadi azole:
A stirred solution of compound 3 (5.4 g, 0.017 mmol) in toluene (50 mL), 4-
fluorobenzoyl
chloride (2.33 mL, 0.019 mmol) and pyridine (1.56 mL, 0.019 mmol) were added
at RT. The
reaction mixture was heated at about 130 C for about 10 h. Upon complete
consumption of
starting material the toluene was removed and the crude product was dissolved
in EtOAc (100
mL). The organic layer was washed with water (50 mL), brine (50 mL), dried
over sodium
sulfate and concentrated under reduced pressure to get crude compound which
was purified by
column chromatography using 1 % EtOAc /Hexane to afford 5-(4 fluorophenyl)-3-
(4-(4-
fluoropiperidin-1 yl)-3-(trifluoromethyl) phenyl)-1,2,4-oxadiazole as white
solid (5.0 g, 69
%). 'H NMR (500 MHz, DMSO-d6): 6 1.83-1.90 (m, 2H), 1.95-2.04 (m, 2H), 2.49-
2.94 (m,
2H), 3.07-3.11 (m, 2H), 4.80-4.92 (m, 1H), 7.49 (t, J= 8.5 Hz, 2H), 7.68 (d,
J= 8.5 Hz, 1H),
8.24-8.29 (m, 4H).
13C NMR (125 MHz, DMSO-d6): 6 174.7, 166.9, 165.9, 163.9, 154.8, 131.8, 130.8,
125.8,
125.1, 124.8, 122.5, 121.8, 119.8, 116.8, 116.7, 88.2, 86.9, 49.4, 49.3, 31.5,
31.4.
Preparation of 4-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)benzonitrile
(compound-
4):
A solution stirred solution of compound 1 (5.0 g, 0.026 mmol) and 4,4-
difluoropiperidine,HC1 (4.58 g, 0.029 mmol) in DMSO (50 mL), K2CO3 (9.12 g,
0.066 mmol)
was added at RT. The reaction mixture was heated at about 100 C for about 12
h. Upon
complete consumption of starting material, the reaction mixture was cooled to
RT and poured
into crushed ice. The aqueous layer was extracted with EtOAc (2 x 100 mL),
washed with
water (60 mL), brine (60 mL), dried over sodium sulfate and concentrated under
reduced
pressure to get crude compound which was purified by column chromatography
using 2 %
EtOAc /Hexane to get compound 4 as white solid (3.2 g, 42 %). 'H NMR (200 MHz,
CDC13):
6 2.06-2.25 (m, 4H), 3.13 (t, J= 5.4 Hz, 4H), 7.36 (d, J= 8.4 Hz, 1H), 7.78
(dd, J= 8.4, 2.2
Hz, 1H), 7.92 (d, J= 2.2 Hz, 1H). MS (ESI): 290 (M++H).
Preparation of 4-(4,4-difluoropiperidin-1-yl)-N'-hydroxy-3-(trifluoromethyl)
benzimidamide (compound-5):
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A solution stirred solution of compound 4 (3.4 g, 0.0 11 mmol) in EtOH (65
mL), hydroxyl
amine (50% in water, 0.85 mL, 0.025 mmol) was added at RT. The reaction
mixture was
heated at about 65 C for about 3 h. Upon complete consumption of starting
material, the
volatiles were removed under reduced pressure to get crude compound 5 (3.78 g)
which was
used for the next step without further purification.
Preparation of 3-(4-(4,4-difluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-5-
(4-
fluor ophenyl)-1,2,4-oxadiazole:
A solution stirred solution of compound 5 (3.78 g, 0.011 mmol) in toluene (115
mL), 4-
fluorobenzoyl chloride (1.54 mL, 0.013 mmol) and pyridine (1.03 mL, 0.013
mmol) were
added at RT. The reaction mixture was heated at about 120 C for about 10 h.
Upon complete
consumption of starting material, the toluene was removed and crude mass was
dissolved in
EtOAc (150 mL). The organic layer was washed with water (50 mL), brine (50
mL), dried
over sodium sulfate and concentrated under reduced pressure to get crude
compound which
was purified by column chromatography using 1 % EtOAc /Hexane to afford 3-(4-
(4,4-
difluoropiperidin-1-yl)-3-(trifluoromethyl)phenyl)-5-(4 fluorophenyl)-1,2,4-
oxadiazole as
white solid (2.5 g, 50 %). 1H NMR (500 MHz, CDC13): 6 2.13-2.20 (m, 4H), 3.11
(m,4H),
7.23-7.44 (m, 2H), 7.48 (d, J = 8.5 Hz, 1H), 8.22-8.26 (m, 2H), 8.30 (dd, J =
8.5 Hz, 2.0 Hz,
1H), 8.45 (d, J = 2.0 Hz, 1H) 13C NMR (125 MHz, CDC13): 6 175.1, 167.7, 166.6,
164.5,
154.2, 131.6, 130.7, 130.6, 127.4, 127.1, 127.0, 126.9, 126.8, 124.7, 124.2,
123.6, 123.4,
122.5, 121.5, 120.4, 119.6, 116.6, 116.4, 50.5, 50.48, 50.4, 34.7, 34.6, 34.4.
Example #55: Preparation of 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzyl)-5-oxopyrrolidine-3-carboxylic acid
0
0
N_O NF12 N_O _ N OH
A
oj~AN O
CI CI
To a solution of (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)methanamine (27 mg, 0.079 mmol) (Example #6) in MeOH (1 mL) was
added
dimethyl 2-methylenesuccinate (12.42 mg, 0.079 mmol). After about 4 h
additional dimethyl
2-methylenesuccinate (124 mg, 0.79 mmol) was added and the reaction mixture
was heated to
about 50 C. After about 20 h the reaction mixture was cooled to RT and
lithium hydroxide
monohydrate (9.89 mg, 0.236 mmol) was added. After about 30 min a 1 N solution
of HCl (10
mL) and DCM (10 mL) were added to the reaction mixture. The organic layer was
removed,
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dried (Na2SO4) filtered and concentrated in vacuo. The oily residue was
suspended in Et20
(30 mL). After standing for about 30 min the resulting solid was collected by
filtration and
dried in vacuo to provide 1-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)benzyl)-
5-oxopyrrolidine-3-carboxylic acid (30 mg, 84 %) as a colorless solid. LC/MS
(Table 1,
Method a) Rt = 2.38 min, m/z 456 (M+H).
Example #56: Separation of (R)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)-1H-indol-1-yl)-2-methylpropanoic acid and (S)-3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)-2-methylpropanoic acid
0
I1 N N-O N-O
N
OH
N` ( OH )-O \
/\O ?~,N,OH //~~ _ O \
-1 11 - 11
ci o ci o ci o
The enatiomers of 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-
1H-indol-l-
yl)-2-methylpropanoic acid (example# C. 3) were separated by chiral
chromatography using a
Daicel AD-H (20 x 250 mm, 5 pm particle) column at a flow rate of 25 mL/min,
gradient
elution with 2-16% ethanol in heptane with 0.2% diethylamine modifier over 26
min. Elution
of compounds was monitored by UV detection at 254 nm with a column temperature
of about
C. Injection samples were prepared by dissolving the racemic acid in 80%
heptane:20%
ethanol: 0.2% diethylamine. Concentration of the fractions containing the
desired products
20 provided ((R)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-
lH-indol-1 yl)-2-
methylpropanoic acid (stereochemistry was arbitrarily assigned) LC/MS (Table
1, Method a)
Rt = 3.05 min, m/z 440 (M+H)+, or = neg. Followed by ((S)-3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5yl)-IH-indol-1 yl)-2-methylpropanoic acid
(stereochemistry was arbitrarily assigned) LC/MS (Table 1, Method a) Rt = 3.05
min, m/z 440
25 (M+H)+
Preparation #57: Preparation of (1R,2S)-methyl 2-(4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylate compound with (1S,2R)-
methyl 2-(4-(3-(3-chlo ro-4-isop rop oxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylate (1:1)
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OH H o
N
O/~ N I\ N O/~ N\ I
N-O CI N O
CI
O' -OH H O~
H -O
N I \\ N.,,~ O / \ N
CI N ,/ I \\
_ (\ I
-O CI / N-O
A 20 mL reaction vial was charged with (1R,2S)-2-(4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid compound with
(1S,2R)-2-(4-
(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic
acid (1:1) (0.265 g, 0.300 mmol) in methanol (1.934 mL) to give a cloudy
suspension. To the
reaction mixture was added thionyl chloride (0.044 mL, 0.600 mmol) dropwise.
The resulting
solution was stirred at about 60 C for about 15 hr. The mixture was cooled to
about ambient
temperature. The resulting white precipitate was filtered, rinsed with water
(5 mL) and oven
dried to provide (1R,2S)-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylate compound with (IS,2R)-methyl 2-(4-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)phenylamino)cyclopentanecarboxylate
(1:1) (0.165 g,
0.181 mmol, 60.3 % yield) as white solid. LC/MS (Table 1, Method a) Rt = 3.11
min, m/z 456
(M+H)+.
Example #58: Preparation of (1R,2R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic acid compound with (1S,2S)-2-
(4-
(3-(3-chlo ro-4-is op rop oxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (1:1)
O Ol H \-OH
/ CrN /~ N\ I ~
N-O CI N O
CI
O0 H OH
H
N
O / ~ N\ I ~ ,,'O O NO
N-O CI N
CI
A nitrogen-flushed 25 mL flask was charged sodium (0.398 mg, 0.017 mmol). The
flask was
cooled to about 0 C and methanol (5 mL) was added. The mixture was stirred
until all metal
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dissolved. A solution of (1R,2S)-methyl 2-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenylamino)cyclopentanecarboxylate compound with (1S,2R)-
methyl 2-(4-
(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylate (1:1) (0.158 g, 0.173 mmol) in methanol
(10 mL)
and DCM (3 mL) was added to the reaction mixture. After stirring at RT for
about 48 h water
(2 mL) was added to the reaction mixture. The mixture was concentrated in
vacuo and the
residue was partitioned between EtOAc (10 mL) and water (10 mL). The organic
phase was
dried (Na2SO4) filtered and concentrated. The crude material was purified by
RP-HPLC on a
Hyperprep HS C18 column using 0-95% ACN/Water (NH4OAc buffer) over 30 min at
21
mL/min. Fractions were concentrated in vacuo to provide (1R,2R)-2-(4-(3-(3-
chloro-4-
isopropoxyphenyl)-1, 2, 4-oxadiazol-5-yl)phenylamino)cyclopentanecarboxylic
acid compound
with (1 S, 2S)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (1:1) (0.0336 g, 0.038 mmol, 21.94
% yield) as
white solid. LC/MS (Table 1, Method a) Rt = 2.76 min, m/z 442 (M+H).
Example #59: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(1-methyl-
1,2,3,4-
tetrahydroquinolin-6-yl)-1,2,4-oxadiazole
N-O
N ,O~ N , / N
O O 'JIO
CI
CI
To a solution of tent-butyl 2-(6-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-3,4-
dihydroquinolin-1(211)-yl)acetate (0.117 g, 0.242 mmol) in DCM (2.015 mL) was
added TFA
(0.403 mL) dropwise. After about 24 h the reaction mixture was concentrated in
vacuo and the
crude material was purified by chromatography on silica gel (12 g) eluting
with
EtOAc/Heptane (0-15% ). Fractions containing product were combined and
concentrated to
yield 3-(3-chloro-4-isopropoxyphenyl)-5-(1-methyl-1,2,3,4-tetrahydroquinolin-6-
yl)-1,2,4-
oxadiazole (0.0405 g, 0.106 mmol, 43.6 % yield) as light yellow powder.
1H NMR (400 MHz, DMSO) d 8.00 (s, 1H), 7.94 (d, J= 8.7, 1H), 7.77 (d, J= 8.7,
1H), 7.66
(s, 1H), 7.34 (d, J= 8.7, 1H), 6.69 (d, J= 8.8, 1H), 4.84 - 4.75 (m, 1H), 3.40
- 3.32 (m, 2H),
2.96 (s, 3H), 2.77 (t, J= 6.1, 2H), 1.89 (s, 2H), 1.33 (d, J= 6.0, 6H).
LC/MS (Table 1, Method a) Rt = 3.26 min, m/z 384 (M+H)+.
Preparation #58: Preparation of (R)-5-(1H-indol-4-yl)-3-(4-(tetrahydrofuran-3-
yloxy)-3-
(trifluor omethyl)p henyl)-1,2,4-oxadiazole
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F N-OH F N-O
~ F I
F I\ N H 2 F N
O NH
O
O O
A mixture of 1H-indole-4-carboxylic acid (0.611 g, 3.79 mmol), EDCI
hydrochloride(0.727 g,
3.79 mmol) and HOBT hydrate (0.580 g, 3.79 mmol) in anhydrous DMF (9.66 ml)
was stirred
at RT for about 1 hour under an atmosphere of nitrogen. A solution of (R)-N'-
hydroxy-4-
(tetrahydrofuran-3-yloxy)-3-(trifluoromethyl)benzimidamide (1.00 g, 3.45 mmol)
in
anhydrous DMF (1.823 ml) was added and the reaction mixture was stirred at
approximately
140 C for about 2 hr. The reaction was cooled to RT and poured into water
(200mL). The
crude product was partitioned between EA and the aqueous phase. The combined
organic
extracts were washed with 20% brine solution and IN HC1 (2x5OmL), IN NaOH
(3x5OmL)
and water (3x5OmL), then dried over MgSO4, filtered and solvent removed to
yield a pale
brown solid 1.23g of (R)-5-(IH-indol-4 yl)-3-(4-(tetrahydrofuran-3 yloxy)-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazole LC/MS (Table 1, Method c) Rt = 2.36
min, m/z
416.1 (M+H) ; 1H NMR (400 MHz, DMSO-d6) 6 11.7 (d, 1H), 8.39 (dd, 1H), 8.31
(d, 1H),
8.15 (s, 1H), 7.99 (dd, 1H), 7.79 (td, 1H), 7.69 (m, 1H), 7.53 (d, 1H), 7.35
(m, 1H), 7.18 (ddd,
1H), 5.36 (m, 1H), 3.82 (m, 4H), 2.31 (dd, 2H), 1.99 (s, 2H).
Preparation #59: Preparation of (R)-tert-butyl 3-(4-(3-(4-(tetrahydrofuran-3-
yloxy)-3-
(trifluor omethyl)phenyl)-1,2, 4-oxadiazol-5-yl)-1H-indol-1-yl)p rop ano ate
F N-O F N-O
F \ I N F I\ I N
NH O O N.
O
O O
To a stirred solution of (R)-5-(1H-indol-4-yl)-3-(4-(tetrahydrofuran-3-yloxy)-
3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazole (0.4 g, 0.963 mmol) in ACN (5.0 mL)
(heated to
about 60 C till complete dissolution), tent-butyl acrylate (0.212 mL, 1.445
mmol) was added
dropwise, followed by DBU (0.072 mL, 0.482 mmol). The solution was stirred at
about 50 C
for about 18 h. The solvent was removed and the yellow solid was dissolved in
EtOAc (150
mL), washed with saturated brine (3 x 100mL), dried over MgSO4, filtered and
solvent
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removed to yield a yellow gum/solid (0.59g). The gum/solid was triturated with
EtOAc (5
mL), cooled to about 0-5 C and the resultant pale yellow solid was collected,
washed with
ice-cold EtOAc (2xlmL) and cold 30-60 C petroleum ether (2 x 1 mL) and dried
to afford
(R)-tent-butyl 3-(4-(3-(4-(tetrahydrofuran-3 yloxy)-3-(trifluoromethyl)phenyl)-
1,2,4-
oxadiazol-5-yl)-]H-indol-1 yl)propanoate. (0.27 g, 52% yield). LC/MS (Table 1,
Method c)
Rt = 2.76 min, m/z 544.22 (M+H) ; 1H NMR (400 MHz, DMSO-d6) 6 8.39 (dd, 1H),
8.3 (d,
I H), 8.01 (dd, I H), 7.94 (d, I H), 7.7 (d, I H), 7.53 (d, I H), 7.4 (m, I
H), 7.12 (dd, I H), 5.36
(d, 1H), 4.52 (t, 2H), 3.99 (dd, 1H), 3.84 (ddd, 3H), 2.81 (t, 2H), 2.31 (dd,
1H), 2.07 (s, 1H),
1.31 (s, 9H).
Example #60: Preparation of (R)-3-(4-(3-(4-(tetrahydrofuran-3-yloxy)-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)propanoic acid
F N-O F N'O
F \ I N F \ N
O I/ N O O I N OH
110 110
O O
A stirred solution of (R)-tert-butyl 3-(4-(3-(4-(tetrahydrofuran-3-yloxy)-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)-1H-indol-1-yl)propanoate (0.25
g, 0.460
mmol) in DCM (23 mL) was treated with trifluoroacetic acid (0.709 mL, 9.20
mmol) at
ambient temperature. The reaction mixture was stirred for about 20 h. The
solvent was
removed and the residue was diluted with water (50 mL). The product was
partitioned
between EtOAc (4 x 2 mL) and the acid aqueous phase. The extracts were
combined and
washed with saturated brine (4 x 30mL) and dried over MgSO4, filtered and the
solvent
removed in vacuo to yield a pale yellow solid (0.24 g). The solid was
recrystallized from can
(8 mL), cooled to ambient temperature before the solid was collected, washed
with ACN (2 x
2 mL), 30-60 C petroleum ether (2 x 2 mL) and dried to give a pale yellow
powdery solid of
(R)-3-(4-(3-(4-(tetrahydrofuran-3 yloxy)-3-(trifluoromethyl)phenyl)-1, 2, 4-
oxadiazol-5-yl)-1 H-
indol-1-yl)propanoic acid.(0.155g, 69%) LC/MS (Table 1, Method c) Rt = 2.12
min, m/z
486.11 (M-H)-. 1H NMR (400 MHz, DMSO-d6) 6 12.48 (m, 1), 8.38 (dd, 1H), 8.3
(d, 1H),
8.01 (dd, I H), 7.95 (d, I H), 7.71 (d, I H), 7.53 (d, I H), 7.4 (m, I H),
7.16 (dd, I H), 5.36 (dt,
1H), 4.53 (t, 2H), 3.99 (dd, 1H), 3.84 (ddd, 3H), 2.81 (t, 2H), 2.31 (m, 1H),
2.05 (m, 1H).
Examples #61, 62, 63 and 64: Preparation of (1R,3S)-3-[4-(5-biphenyl-2-yl-
[1,2,4] oxadiazol-3-yl)-2-methyl-phenylamino]-cyclopentanecarboxylic acid,
(1R,3S)-3-[4-
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(5-biphenyl-3-yl-[1,2,4] oxadiazol-3-yl)-2-methyl-phenylamino]-
cyclopentanecarboxylic
acid, (1R,3S)-3-[4-(5-biphenyl-4-yl-[1,2,4] oxadiazol-3-yl)-2-methyl-
phenylamino]-
cyclopentanecarboxylic acid and (1R,3S)-3-{4-[5-(4-cyclohexyl-phenyl)-
[1,2,4]oxadiazol-
3-yl]-2-methyl-phenylamino}-cyclopentanecarboxylic acid
0 NF - EtOH,DMF
H2N ,. O kOH DMSO,110 C N \ N", OH HAT~
DD1 DD2
H fO NH2OH, EtOH HO- \ - N
- 6 O--\ HZN O--\
DD3 O DD4
HO
HO-N H i
N~,. "ko/\ \ ~N NH
HZN - ff
DD4
DD5 ==,, f
LiOH/dioxane 0-
\ N NH
DD7 0,11~OH
/ \ \ / 'N
O
HO- \ - H O i O OH - N V0
HZN \ / N",10
DD4 DD6 H
LiOH/dioxane - N O
Cr \ N HO
DD8
H
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WO 2011/071570 PCT/US2010/046424
HO-N O HO
HpN / / \ O N N,,. O--\
~ I \
DD4 DD9
H 0
kOH
LiOHLiOH/ \ I /
DD11
O H", /I0
HO- N,,. I~ HO \ / I \ N N~., d~0~\
HpN 0-
DD4 DD10
/O
0__a
O.N N I`
H,,.
N O OH
DD12
LiOH/dioxane Synthesis of DD2: (1R,3S)-3-(4-Cyano-2-methyl-phenyla
mino)-cyclopentanecarboxylic acid
O N- F _ N H O
H2N~,. ~~~ - /
OH DMS0,110 C N OH
DD1 DD2
A solution of DD1 (IR,3S)-3-Amino-cyclopentanecarboxylic acid (5.89 g, 45.6
mmol) and 4-
fluoro-3-methylbenzonitrile (5.60g, 41.4 mmol) in DMSO (140 mL) and water
(11.67 mL)
was treated with potassium carbonate (12.60 g, 91 mmol) and the mixture was
heated to about
110 C under nitrogen overnight . The solution was cooled to room temperature
and diluted
with water, washed with ether then acidified to pH=2 with concentrated HC1.
The product
was extracted with ethyl acetate, the combined ethyl acetate layers were
washed with
saturated NaCl solution, dried over sodium sulfate, filtered and concentrated
to about 100 mL.
Hexane (100 mL) was added and the solution concentrated until product comes
out of
solution. Filtered off solids and concentrated the filtrate to a gum which was
dissolved in
methanol 40mL, and water and concentrated until crystals formed. A second crop
of solids
was filtered off combined with the first crop then dried in a vacuum overnight
to give 5.78 g
of (1R,3S)-3-(4-Cyano-2-methyl-phenylamino)-cyclopentanecarboxylic acid ( DD2,
57%
yield) LC/MS(ESI): m/z 245.2 (M+H), Rt: 0.78 min.
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Synthesis of DD3: (1R,3S)-3-(4-Cyano-2-methyl-phenylamino)-
cyclopentanecarboxylic acid
ethyl ester,
H O EtOH,DMF H O
0.,
OH HATU,DIPEA
DD2 DD3
In a 500 mL round bottom flask, (1R,3S)-3-(4-Cyano-2-methyl-phenylamino)-
cyclopentanecarboxylic acid (DD2 , 5.78 g, 23.7 mmol) in DMF (200 mL) was
added to give
orange solution. Molecule sieve (4A, 8-12 mesh, 4.4 g) was added. HATU (10.8
g, 28.4
mmol) was added in one portion, ethanol (2.08 mL, 35.6 mmol) was added. The
solution was
stirred at RT for about 30 min, then the mixture was cooled to about 0 C in
an ice bath. N,N-
ciisopropylethylamine (8.27 mL, 47.4 mmol) was added dropwise over about 10
min. The ice-
bath was removed, and the solution was stirred at RT overnight. The reaction
mixture was
filtered, washed with DMF, the combined filtrate was concentrated, the residue
was
partitioned between EtOAc and sat ammonium chloride, the organic layer was
washed with
saturated ammonium chloride, water, saturated sodium bicarbonate, and brine,
dried over
sodium sulfate, filtered and concentrated afforded 8.1 g of brown oil, which
was purified by
gel chromatography (0-30% EtOAc/ petroleum ether) to afford (1 R,3S)-3-(4-
Cyano-2-methyl-
phenylamino)-cyclopentanecarboxylic acid ethyl ester (DD3, 5.48 g, 20.1 mmol,
85% yield)
as orange oil. LC/MS(ESI): m/z 273.3 (M+H), Rt: 0.928 min.
Synthesis of DD4: (1 R,3 S)-3-[4-(N-Hydroxycarbamimidoyl)-2-methyl-
phenylamino]-
cyclopentanecarboxylic acid ethyl ester,
H~, 0 NH2OH, EtOH HO-N H
N O0-"N\ H N - N~,.O.,k0~
2
DD3 DD4
In a 250 mL round bottom flask, (1R,3S)-3-(4-Cyano-2-methyl-phenylamino)-
cyclopentanecarboxylic acid ethyl ester (DD3, 5.48 g, 20.1 mmol) and
hydroxylamine (4.92
mL, 80.4 mmol) in EtOH (86 mL) were added to give pale yellow solution. The
solution was
heated at about 50 C overnight. The reaction mixture was near colorless
solution, which was
concentrated, the residue was loaded into silica gel cartridge with the aid of
EtOAc, purified
by HPLC reverse phase (0% over 3 min, 0-95% MeOH/H20 over 30 min; 220 g silica
gel
column) to afford (1 R,3 S)-3-[4-(N-Hydroxycarbamimidoyl)-2-methyl-
phenylamino]-
cyclopentanecarboxylic acid ethyl ester (DD4, 4 g, 13.1 mmol, 65% yield) as
off-white slight
waxy solid. LC/MS(ESI): m/z 306 (M+H), Rt:1.80 min.
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Synthesis of DD5: (1R,3S)-3-[4-(5-Biphenyl-2-yl-[ 1,2,4]oxadiazol-3-yl)-2-
methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester
O
HO
HO-N H O O_N
N~ ko HOBT,EDC-HCI I \ ~N NH
HpN DCM
DD4 DD5 O
01
In a 250 mL round bottom flask, 2-biphenylcarboxylic acid (340 mg, 1.72 mmol)
and
HOBT (300 mg, 1.97 mmol) in DCM (5 mL) were added to give white suspension.
EDC-HC1
(377 mg, 1.97 mmol) was added in one portion, the reaction mixture became
mostly clear,
then it rapidly became a cloudy suspension. After about 1 h, the reaction
mixture was a cloudy
pale yellow suspension. (1 R,3 S)-3-[4-(N-Hydroxycarbamimidoyl)-2-methyl-
phenylamino]-
cyclopentanecarboxylic acid ethyl ester (DD4, 500 mg, 1.64 mmol) was added
with the aid of
5 mL DCM, and the reaction mixture became deep blue solution immediately. It
was stirred at
RT for about 150 min. The reaction mixture was diluted with DCM, washed with
brine, dried
over sodium sulfate overnight, filtered and concentrated to afford a waxy
yellow solid, which
was dissolved in 1,4-dioxane (10 mL) to form a deep red solution, Molecular
sieves (4A, 8-12
mesh, beads, 300 mg) were added. The solution was heated at about 110 C for
about 2 h. The
solution was cooled down, the reaction mixture was a black solution, it was
concentrated, the
residue was purified via silica gel chromatography (6/1 petroleum ether to
EtOAc) to
afford110 mg (14.4% yield) of (1R,3S)-3-[4-(5-Biphenyl-2-yl-[ 1,2,4]oxadiazol-
3-yl)-2-
methyl-phenylamino]-cyclopentanecarboxylic acid ethyl ester DD5. LC/MS(ESI):
m/z 468.2
(M+H), Rt: 2.49min.
Synthesis of DD6: (1R,3S)-3-[4-(5-Biphenyl-3-yl-[1,2,4] oxadiazol-3-yl)-2-
methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester
O / I O-N f0
Ni,.~
HO-N H o HO I
J O
HZN o-'\ HOBT,EDC-HCI
DCM
DD4 DD6
In a 250 mL round bottom flask, 3-biphenylcarboxylic acid (340 mg, 1.72 mmol)
and
HOBT (300 mg, 1.97 mmol) in DCM (5 mL) were added to give a white suspension.
EDC-
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HC1 (377 mg, 1.97 mmol) was added in one portion, the reaction mixture became
mostly
clear, then it rapidly became a cloudy suspension. After about 1 h, the
reaction mixture was a
cloudy pale yellow suspension. (1 R,3 S)-3-[4-(N-Hydroxycarbamimidoyl)-2-
methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester (DD10, 500 mg, 1.64 mmol)
was added
with the aid of 5 mL DCM. The reaction mixture became deep blue solution
immediately, it
was stirred at RT for about 150 min. The reaction mixture was diluted with
DCM, washed
with brine, dried over sodium sulfate overnight, filtered and concentrated to
afford a waxy
yellow solid, which was dissolved in 1,4-dioxane (10 mL) to form a deep red
solution, MS
(4A, 8-12 mesh, beads, 300 mg) was added. The solution was heated at about 110
C for
about 2 h. The solution was cooled down, the reaction mixture was a black
solution, it was
concentrated, the residue was purified via silica gel chromatography (6/1
petroleum ether to
EA) to afford 280 mg (36.6% yield) of compound DD6: (1R,3S)-3-[4-(5-Biphenyl-3-
yl-
[1,2,4]oxadiazol-3 yl)-2-methyl phenylaminoJ-cyclopentanecarboxylic acid ethyl
ester
LC/MS(ESI): m/z 468.2 (M+H), Rt: 2.57min.
Synthesis of DD9: (1R,3S)-3-[4-(5-Biphenyl-4-yl-[ 1,2,4]oxadiazol-3-yl)-2-
methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester
O p-N H
Hol
HpN Ni k o-'\ HOST EDC-HCI
DCM
DD4 DD9
In a 250 mL round bottom flask, 4-biphenylcarboxylic acid (340 mg, 1.72 mmol)
and
HOBT (300 mg, 1.97 mmol) in DCM (5 mL) were added to give a white suspension.
EDC-
HC1 (377 mg, 1.97 mmol) was added in one portion, the reaction mixture became
mostly
clear, then it rapidly became a cloudy suspension. After about 1 h, the
reaction mixture was a
cloudy pale yellow suspension. (1R,3S)-3-[4-(N-hydroxycarbamimidoyl)-2-methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester (DD4, 500 mg, 1.64 mmol)
was added
with the aid of 5 mL DCM. The reaction mixture became deep blue solution
immediately, it
was stirred at RT for about 150 min. The reaction mixture was diluted with
DCM, washed
with brine, dried over sodium sulfate overnight, filtered and concentrated to
afford a waxy
yellow solid, which was dissolved in 1,4-dioxane (10 mL) to form a deep red
solution, MS
(4A, 8-12 mesh, beads, 300 mg) was added. The solution was heated at about 110
C for
about 2 h. The solution was cooled down, the reaction mixture was black
solution, it was
concentrated, the residue was purified via silica gel chromatography (6/1
petroleum ether to
EA) to afford 320 mg (41.8% yield) of (JR,3S)-3-[4-(5-Biphenyl-4yl-[1,2,4]
oxadiazol-3-yl)-
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2-methyl phenylaminoJ-cyclopentanecarboxylic acid ethyl ester DD9 LC/MS(ESI):
mlz 468.2
(M+H), R,: 2.5 7min.
Synthesis of DD10: (1R,3S)-3-{4-[5-(4-Cyclohexyl-phenyl)-[1,2,4] oxadiazol-3-
yl]-2-
methyl-phenylamino}-cyclopentanecarboxylic acid ethyl ester
O-N
O NH
H I N
HO-N O
H
HZN O~ HOBT,EDC-HCI Oro
DCM
DD4 DD10 O
In a 250 mL round bottom flask, 4-cyclohexyl benzoic acid (340 mg, 1.72 mmol)
and
HOBt (300 mg, 1.97 mmol) in DCM (5 m") were added to give white suspension.
EDC-HC1
(377 mg, 1.97 mmol) was added in one portion, the reaction mixture became
mostly clear,
then it rapidly became a cloudy suspension. After about 1 h, the reaction
mixture was a cloudy
pale yellow suspension. (1R,3S)-3-[4-(N-hydroxycarbamimidoyl)-2-methyl-
phenylamino]-
cyclopentanecarboxylic acid ethyl ester (DD4, 500 mg, 1.64 mmol) was added
with the aid of
5 mL DCM. The reaction mixture became deep blue solution immediately, it was
stirred at RT
for about 150 min. The reaction mixture was diluted with DCM, washed with
brine, dried
over sodium sulfate overnight, filtered and concentrated to afforded a waxy
yellow solid,
which was dissolved in 1,4-dioxane (10 mL) to form a deep red solution, MS
(4A, 8-12 mesh,
beads, 300 mg) was added. The solution was heated at about 110 C for about 2
h. The
solution was cooled down, the reaction mixture was black solution, it was
concentrated, the
residue was purified via silica gel chromatography (6/1 petroleum ether to EA)
to afford 91
mg (11.3% yield) of compound DD10: (IR,3S)-3-{4-[5-(4-Cyclohexylphenyl)-
[1,2,4]oxadiazol-3 ylJ-2-methylphenylamino}-cyclopentanecarboxylic acid ethyl
ester
LC/MS(ESI): m/z 474.2 (M+H), Rt: 2.75 min.
Example #61: Preparation of DD7: (1R,3S)-3-[4-(5-biphenyl-2-yl-[1,2,4]
oxadiazol-3-yl)-
2-methyl-phenylamino]-cyclopentanecarboxylic acid
O-N LiOH/dioxane O-N
~_6 N NH \ N ~_6
NH
0 O"',OH
jr
DD5 O DD7 O
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A solution of DD5: (1R,3S)-3-[4-(5-Biphenyl-2-yl-[ 1,2,4]oxadiazol-3-yl)-2-
methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester (110 mg,0.235 mmol) in
1,4-dioxane
(10 mL) with LiOH(1M, 4 mL), stirred at RT for about 4 h, then the mixture was
acidified by
1.0 M HC1, diluted with EtOAc, washed by brine to pH=about 6,dried over
Na2SO4, and
concentrated. HPLC reverse phase purification gave 48.5 mg (47% yield) of DD7
(JR,3S)-3-
[4-(5-biphenyl-2-yl-[1,2,4]oxadiazol-3-yl)-2-methyl phenylaminoJ-
cyclopentanecarboxylic
acid.. 1HNMR(500MHz, CDC13, 6) 8.06(d,1H, J=7.6 Hz), 67.78(d, 1H, J=8.4Hz),
7.73(s,
1H), 7.61(t, 1H, J=7.0 Hz), 7.52-7.48(m, 2H), 7.36-7.35(m, 3H), 7.29-7.26(m,
2H),
6.65(d,1H, J=8.4Hz), 5.17 (br, 1H), 4.05-4.03(m,1H), 3.01-2.99(m,1H), 2.38-
2.29(m,1H),
2.14(s, 3H), 2.10-1.85 (m, 5H).
Example #62: Preparation of DD8: (1R,3S)-3-[4-(5-biphenyl-3-yl-[1,2,4]
oxadiazol-3-yl)-
2-methyl-phenylamino]-cyclopentanecarboxylic acid
O`N O\ LiOH/doxane KIII\_<iXtIT:_ \ ~O
Cr W 15 DD6 DD8
A solution of DD6: (1R,3S)-3-[4-(5-biphenyl-3-yl-[ 1,2,4]oxadiazol-3-yl)-2-
methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester (280 mg,0.599 mmol) in
1,4-dioxane (3
mL) with LiOH (1M, 2.4 mL), stirred at RT for about 4 h, then the mixture was
acidified by
1.0 M HC1, diluted with EtOAc, washed by brine to pH about 6, dried over
Na2SO4, and
concentrated. HPLC reverse phase purification gave 144.9 mg (55.1% yield) of
compound
DD8: (1R,3S)-3-[4-(5-Biphenyl-3 yl-[1,2,4]oxadiazol-3 yl)-2-methylphenylaminoJ-
cyclopentanecarboxylic acid. 1HNMR(500MHz, CDC13, 6) 8.43(s,1H), 8.18(d, 1H,
J=8.4Hz),
7.95 (d, 1H, J=8.4Hz), 7.88(s, 1H), 7.81 (d, 1H, J=8.OHz), 7.68 (d, 2H,
J=7.2Hz), 7.61(t, 1H,
J=7.8 Hz), 7.50(t, 2H, J=7.6Hz), 7.41(t, 1H, J=7.4Hz), 6.70(d,1H, J=4.4Hz),
3.07-
3.00(m,1H), 2.42-2.33(m,1H), 2.19(s, 3H), 2.14-1.88 (m, 5H).
Example #63: Preparation of DD11: (1R,3S)-3-[4-(5-biphenyl-4-yl-[1,2,4]
oxadiazol-3-yl)-
2-methyl-phenylamino]-cyclopentanecarboxylic acid
O' H o O' O
- l ~ - H
N
OH/dioxane \ N''
N~ O-\ Li N ~.,OH
DD7 I / DD11
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A solution of (1 R,3 S)-3-[4-(5-Biphenyl-4-yl-[1,2,4]oxadiazol-3-yl)-2-methyl-
phenylamino]-cyclopentanecarboxylic acid ethyl ester DD9 (105 mg,0.225 mmol)
in 1,4-
dioxane (3 mL) with LiOH(1M, 0.9 mL), stirred at RT for about 4 h, then the
mixture was
acidified by 1.0 M HCl, diluted with EA, washed by brine to about pH= 6,dried
over
Na2SO4,concentrated. HPLC reverse phase purification gave 90.9 mg (92% yield)
of
compound DD11: (JR,3S)-3-[4-(5-Biphenyl-4-yl-[1,2,4]oxadiazol-3 yl)-2-methyl-
phenylaminoJ-cyclopentanecarboxylic acid.. 1HNMR(500MHz, CDC13, 6) 8.26(d, 1H,
J=8.4Hz), 7.96 (d, 1H, J=8.4Hz), 7.89(s, 1H), 7.75 (d, 2H, J=8.4Hz), 7.65 (d,
2H, J=7.2Hz),
7.48(t, 1H, J=7.4 Hz), 7.41(t, 2H, J=7.4Hz), 6.76(d,1H, J=8.8Hz), 6.16(br,
1H), 4.13-
4.05(m,1H), 3.07-3.00(m,1H), 2.40-2.33(m,1H), 2.22(s, 3H), 2.15-1.88 (m, 5H).
Example #64: Preparation of DD12: (1R,3S)-3-{4-[5-(4-Cyclohexyl-phenyl)-
[1,2,4] oxadiazol-3-yl]-2-methyl-phenylamino}-cyclopentanecarboxylic acid
O
64~N N N
N UGH/dioxane
N N ,.~.,, O~\ I \ N O., OH
DD8 DD12
A solution of DD10: (1R,3S)-3-{4-[5-(4-cyclohexylcyclohexyl-phenyl)-[
1,2,4]oxadiazol-3-
yl]-2-methyl-phenylamino}-cyclopentanecarboxylic acid ethyl ester (129
mg,0.272 mmol) in
dioxane (10 mL) with LiOH(1M, 1.1 mL), was stirred at RT for about 4 h, then
the mixture
was acidified by 1.0 M HCl, diluted with EtOAc, washed by brine toabout pH= 6,
dried over
Na2SO4, and concentrated. HPLC reverse phase purification gave 97.1 mg (80%
yield) of
compound DD 12: (JR,3S)-3-{4-[5-(4-Cyclohexyl phenyl)-[],2,4Joxadiazol-3-ylJ-2-
methyl-
phenylamino}-cyclopentanecarboxylic acid. 1HNMR(500MHz, CDC13, 6) 8.10(d, 1H,
J=8.4Hz), 7.93 (d, 1H, J=7.6Hz), 7.89(s, 1H), 7.36 (d, 2H, J=8.4Hz), 6.82(d,
1H, J=8.OHz),
6.62(br, 1H), 4.13-4.04(m,1H), 3.10-2.97(m,1H), 3.61-2.56(m, 1H), 2.38-
2.31(m,1H), 2.24(s,
3H), 2.11-1.75 (m, 1OH), 1.50-1.25(m, 1H).
Example #65: Preparation of (1R,3S)-3-((4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenyl)(methyl)amino)cyclopentanecarboxylic acid
OOH
0,,,0H
N,O N-O
i
CI I\ I N NH I I N N
O
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A 20 mL reaction vial equipped with septa cap outfitted with nitrogen inlet
needle was
charged with (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentanecarboxylic acid (0.469 g, 1.061 mmol) and
formaldehyde
solution (0.398 mL, 5.31 mmol) in acetic acid (10.61 mL) to give a colorless
suspension.
Sodium triacetoxyborohidride (0.675 g, 3.18 mmol) was added in one portion.
The resulting
suspension was allowed to stir at RT for 1 day. The reaction mixture was
concentrated. The
sample was diluted with water and the resulting solid was collected by
filtration and dried
open to the air. The sample was further purified via automated silica gel
chromatography (5%
MeOH : CH2C12; EA -40g column, 18 x 150 mm test tubes). The fractions
containing product
were concentrated to give (JR,3S)-3-((4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)(methyl)amino)cyclopentanecarboxylic acid (101 mg, 21%) as a white
solid.
LC/MS (Table 1, Method g) Rt = 3.08 min, m/z 456 (M+H) ; 1H NMR (400 MHz,
DMSO) 6
8.04 - 7.82 (m, 4H), 7.35 (d, J= 8.9, 1H), 6.96 (d, J= 9.2, 2H), 4.80 (dt, J=
12.2, 6.0, 1H),
4.46 (dd, J= 17.1, 7.4, 1H), 2.87 (s, 3H), 2.84 - 2.74 (m, 1H), 2.16 - 2.05
(m, 1H), 2.05 -
1.60 (m, 6H), 1.33 (d, J= 6.0, 6H)
Preparation #60a: Preparation of Methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadi azol-5-yl)-1H-indol-1-yl)cyclopentanecarb oxylate
O /
0
N O N-O
' N NH \ I \ N
Br
O O
CI CI
A 100 mL round bottom flask equipped with rubber septum and nitrogen inlet
needle was
charged with 3-(3-chloro-4-isopropoxyphenyl)-5-(1H-indol-5-yl)-1,2,4-
oxadiazole (0.144 g,
0.407 mmol) in DMF (4.07 mL) to give a tan solution. The reaction mixture was
cooled at
about 0 C for about 10 min. Sodium hydride dispersion in mineral oil (0.020
g, 0.488 mmol)
was added in one portion. The resulting suspension was allowed to stir at
about 0 C for
about 20 min. Methyl 3-bromocyclopentanecarboxylate (0.101 g, 0.488 mmol) was
added in
one portion. The resulting yellow solution was allowed to stir at RT for 1
day. Additional
methyl 3-bromocyclopentanecarboxylate (0.169 g, 0.814 mmol) and sodium iodide
(0.031 g,
0.204 mmol) were each added sequentially in one portion. The resulting
solution was allowed
to stir at RT for an additional 18 h. The reaction mixture was concentrated
and the sample
was transferred in solution onto a prep HPLC column and eluted with 60%-100%
MeCN :
Water (NH4OAc buffer) over 30 min. The fractions containing product were
combined and
concentrated to afford methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-
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IH-indol-1-yl)cyclopentanecarboxylate (11 mg, 6%). LC/MS (Table 1, Method g)
Rt = 3.55
min, m/z 480 (M+H)+.
Example #67: Preparation of 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)-1H-indol-1-yl)cyclopentanecarboxylic acid
0 0
OH
N-O N-O
\ N N .PAN N
CI / CI
A 25 mL round bottom flask equipped with rubber septum and nitrogen inlet
needle was
charged with methyl 3-(5-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)-1H-indol-
1-yl)cyclopentanecarboxylate (0.011 g, 0.023 mmol) in (1,4?)dioxane (2.292 mL)
to give a
colorless solution. Sodium hydroxide solution (0.229 mL, 0.229 mmol) was added
dropwise
via syringe. The resulting solution was allowed to stir at RT for about 2 h.
The pH of the
solution was adjusted to pH= about 1 by dropwise addition of IN HC1 solution.
The mixture
was diluted with DCM and the solution was washed with H2O (1 x 10 mL). The
organic
phase was dried over MgS04, filtered and concentrated to give 3-(5-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)-IH-indol-1 yl)cyclopentanecarboxylic
acid (10 mg,
90%) as a colorless oil. LC/MS (Table 1, Method g) Rt = 3.12 min, m/z 466
(M+H) ; 1H
NMR (400 MHz, DMSO) 6 8.47 (d, J= 1.7, 1H), 8.10 - 7.92 (m, 3H), 7.79 (dd, J=
11.9, 8.6,
1H), 7.72 (dd, J = 7.8, 3.2, 1H), 7.40 (d, J = 8.8, 1H), 6.73 (t, J = 2.6,
1H), 5.14 - 5.00 (m,
1H), 4.88 - 4.78 (m, 1H), 3.13 - 2.93 (m, 2H), 2.31 - 2.08 (m, 4H), 2.10 -
1.94 (m, 2H), 1.39
- 1.33 (m, 6H).
Preparation #60: Preparation 3-(3-chloro-4-isopropoxyphenyl)-5-(4-fluoro-3-
((trimethylsilyl)ethynyl)phenyl)-1,2,4-oxadiazole
N'C
N-C F
Si-
'j'O ? Br CI
CI
A 25 mL round bottom flask equipped with reflux condenser outfitted with a
nitrogen inlet
adapter was charged with 5-(3-bromo-4-fluorophenyl)-3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazole (0.608 g, 1.477 mmol), bis(triphenylphosphine)palladium(II)
chloride (0.052
g, 0.074 mmol), copper(I) iodide(0.014 g, 0.074 mmol), evacuated and filled
with nitrogen
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(three cycles), and then THE was added to give a yellow solution.
Ethynyltrimethylsilane
(0.307 mL, 2.215 mmol) and triethylamine (0.618 mL, 4.43 mmol) were each added
sequentially in one portion. The reaction mixture was heated at about 60 C
for about 6 h.
The reaction mixture was allowed to cool to RT and concentrated. The sample
was deposited
onto silica gel and purified via automated silica gel chromatography (2% EtOAc
: Heptane;
EA -40g column, 18 x 150 mm test tubes). The fractions containing product were
combined
and concentrated to give 3-(3-chloro-4-isopropoxyphenyl)-5-(4 fluoro-3-
((trimethylsilyl)ethynyl)phenyl)-1,2,4-oxadiazole (321 mg, 51%) as a solid.
LC/MS (Table 1,
Method g) Rt = 2.43 min, m/z 429 (M+H).
Preparation #60b: Preparation of (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)-2-ethynylphenylamino)cyclopentanecarboxylic acid
O~yOH
N.O _ OOH
N-O
i N F Oi N NH
HZN, O I / \\
Si-
A 20 mL microwave reaction vial equipped with pressure-releasing septa cap was
charged
with 3-(3-chloro-4-isopropoxyphenyl)-5-(4-fluoro-3-
((trimethylsilyl)ethynyl)phenyl)-1,2,4-
oxadiazole (0.295 g, 0.688 mmol), (1R,3S)-3-aminocyclopentanecarboxylic acid
(0.098 g,
0.756 mmol), and potassium carbonate (0.209 g, 1.513 mmol) in water (0.344 mL)
and
DMSO (3.09 mL) to give a tan suspension. The reaction mixture was heated at
about 170 C
for about 1 h using simultaneous heating while cooling. The reaction mixture
was diluted
with 10 mL of water and diluted with EtOAc. The solution was washed with 1M
HC1 solution
(3 x 50 mL) and saturated NaCl solution (1 x 50 mL). The organic phase was
dried over
MgSO4, filtered and concentrated to give a solid that was triturated with
MeOH, filtered, and
dried open to the air to give 256 mg of a solid that was suspended in DMSO and
filtered,
washed with IN HC1 solution and dried open to the air to afford (JR,3S)-3-((4-
(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5
yl)phenyl)(methyl)amino)cyclopentanecarboxylic acid
(220 mg, 64%) as a white solid. LC/MS (Table 1, Method g) Rt = 1.63 min, m/z
466 (M+H)+.
Example #69: Preparation of (1R,3S)-3-(5-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)-1H-indol-1-yl)cyclopentanecarboxylic acid
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O
OOH \\-OH
N-O
N-O OI .:
cl N'--'-(NH
O
O
A 50 mL reaction vial equipped with septa cap outfitted with nitrogen inlet
needle was
charged with (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)-2-
ethynylphenylamino)cyclopentanecarboxylic acid (0.220 g, 0.113 mmol) and
gold(I) chloride
(2.63 mg, 0.011 mmol) in DCE (1.133 mL) to give a tan solution. The reaction
mixture was
heated at about 80 C for about 14 h. The reaction mixture was deposited onto
silica gel and
loaded onto a silica gel column and eluted with 40%-80% EtOAc : Heptane. The
fractions
containing product were combined and concentrated to give (JR,3S)-3-(5-(3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)-IH-indol-1 yl)cyclopentanecarboxylic
acid (5 mg,
2%) as a solid. LC/MS (Table 1, Method g) Rt = 3.12 min, m/z 466 (M+H) ; 1H
NMR (400
MHz, DMSO) 6 8.47 (d, J = 1.7, 1H), 8.10 - 7.92 (m, 3H), 7.79 (dd, J = 11.9,
8.6, 1H), 7.72
(dd, J = 7.8, 3.2, I H), 7.40 (d, J = 8.8, I H), 6.73 (t, J = 2.6, I H), 5.14 -
5.00 (m, I H), 4.88 -
4.78 (m, 1H), 3.13 - 2.93 (m, 2H), 2.31 - 2.08 (m, 4H), 2.10 - 1.94 (m, 2H),
1.39 - 1.33 (m,
6H).
Preparation #61: Preparation of (E)-ethyl 4-(3-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadi azol-5-yl)-2-methylphenoxy)but-2-en oate
0
OH O N-O O
N~O ~I
' N B~~/"/~O'\ CO I N
CUI'
A 50 mL reaction vial equipped with septa cap outfitted with nitrogen inlet
needle was
charged with 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
methylphenol
(0.350 g, 1.015 mmol) and potassium carbonate (0.351 g, 2.54 mmol) in acetone
(5.08 mL) to
give a colorless suspension. (E)-ethyl 4-bromobut-2-enoate (0.275 mL, 2.030
mmol) was
added dropwise via syringe. The resulting suspension was allowed to stir at RT
for about 2
days. The reaction mixture was diluted with EtOAc and the solution was washed
with 1M
HC1 solution (1 x 50 mL), saturated NaHCO3 solution (1 x 50 mL), and saturated
NaCl
solution (1 x 50 mL). The organic phase was dried over MgSO4, filtered and
concentrated to
give 540 mg of a solid. The sample was purified via automated silica gel
chromatography
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(10%-20% EtOAc : Heptane; EA -40g column, 18 x 150 mm test tubes). The
fractions
containing product were combined and concentrated to afford (E)-ethyl 4-(3-(3-
(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-methylphenoxy)but-2-enoate (353 mg,
76%) as a
solid. LC/MS (Table 1, Method k) Rt = 1.98 min, m/z 457 (M+H)+.
Preparation #62: Preparation of Ethyl 4-(3-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadi azol-5-yl)-2-methylphenoxy)butanoate
o 0 N-O O O
C' I \ I N \ /
/\ I I N \
I
O
A 100 mL round bottom flask equipped with rubber septum and nitrogen inlet
needle was
charged with (E)-ethyl 4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)-2-
methylphenoxy)but-2-enoate (0.336 g, 0.735 mmol), copper(I) chloride (3.64 mg,
0.037
mmol), p-Tol-Binap (0.050 g, 0.074 mmol), sodium tert-butoxide (3.53 mg, 0.037
mmol),
evacuated and filled with nitrogen (three cycles), and then toluene (2.94 mL)
was added to
give a yellow solution. Poly(methylhydrosiloxane) (0.176 mL, 2.94 mmol) was
added in one
portion. The resulting solution was allowed to stir at RT for about 3 days.
EtOH (about 10
mL) was added dropwise. The solution was diluted with EtOAc. The solution was
washed
with saturated NaHCO3 solution (1 x 50 mL), H2O (1 x 50 mL), and saturated
NaCl solution
(1 x 50 mL). The organic phase was dried over MgSO4, filtered and concentrated
to give 590
mg of a solid. The sample was purified via automated silica gel chromatography
(10%-40%
EtOAc : Heptane; EA -40g column, 18 x 150 mm test tubes). The fractions
containing product
were combined and concentrated to afford ethyl 4-(3-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)-2-methylphenoxy)butanoate (178 mg, 53%) as an oil. LC/MS
(Table 1,
Method g) Rt = 3.74 min, m/z 459 (M+H).
Preparation #63: Preparation of (E)-4-(3-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)-2-methylphenoxy)but-2-enoic acid
ci ci
N-O O N'O O
/~/~OH
O /_ NO"~'Oi\ O N O-
A 25 mL round bottom flask equipped with rubber septum and nitrogen inlet
needle was
charged with (E)-ethyl 4-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)-2-
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methylphenoxy)but-2-enoate (0.255 g, 0.407 mmol) in (1,4?)dioxane (2.037 mL)
to give a
colorless solution. Sodium hydroxide solution (1.222 mL, 1.222 mmol) was added
in one
portion. The resulting solution was allowed to stir at RT for about 16 h. The
pH was adjusted
to pH=about 4 by dropwise addition of acetic acid. The solution was
concentrated and
triturated with water (1 x 20 mL). The solid was filtered through a sintered
glass funnel,
washed with water, and dried in vacuo to give (E)-4-(3-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5 yl)-2-methylphenoxy)but-2-enoic acid (39 mg, 22%) as a white
solid.
LC/MS (Table 1, Method g) Rt = 3.05 min, m/z 429 (M+H) ; 1H NMR (400 MHz,
DMSO) 6
8.04 (d, J= 2.0, 1H), 8.00 (d, J= 8.6, 1H), 7.77 (d, J= 7.7, 1H), 7.48 - 7.33
(m, 4H), 6.74 (d,
J = 5.8, I H), 5.07 (dd, J = 13.2, 7.1, I H), 4.86 - 4.75 (m, I H), 3.19 (d, J
= 7.0, 2H), 2.58 (s,
3H), 1.33 (d, J= 6.0, 6H).
Preparation #64: Preparation of Methyl 4-iodo-2-methoxybenzoate
O ", O O I'll O
HO NI O -11
A 250 mL round bottom flask equipped with nitrogen inlet adapter was charged
with 4-iodo-
2-methoxybenzoic acid (5.0 g, 17.98 mmol) in MeOH (36.0 mL) to give a
colorless solution.
The reaction mixture was cooled at about 0 C for about 20 min. Thionyl
chloride (3.94 mL,
53.9 mmol) was added slowly via syringe. The resulting solution was allowed to
stir at RT
for about 18 h. The solution was concentrated and dissolved in EtOAc. The
solution was
washed with saturated NaHCO3 solution (1 x 200 mL) and saturated NaCl solution
(1 x 200
mL). The organic phase was dried over MgS04, filtered and concentrated to give
methyl 4-
iodo-2-methoxybenzoate (5.2 g, 99%) as an oil. LC/MS (Table 1, Method g) Rt =
2.43 min;
1H NMR (400 MHz, DMSO) 6 7.47 (s, 1H), 7.38 (s, 2H), 3.81 (s, 3H), 3.75 (s,
3H).
Preparation #65: Preparation of Methyl 2-methoxy-4-((1R,4S)-3-oxo-2-
azabicyclo[2.2.1]hept-5-en-2-yl)benzoate
H
O O "IN'1/~N"-
O
NI O ~
HNl NI
H
A 50 mL round bottom flask equipped with reflux condenser outfitted with a
nitrogen inlet
adapter was charged with (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (1.480 g,
13.56 mmol),
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copper(I) iodide (0.129 g, 0.678 mmol), potassium phosphate tribasic (5.76 g,
27.1 mmol),
evacuated and filled with nitrogen (three cycles), and then toluene (27.1 mL)
was added to
give a white suspension. Methyl 4-iodo-2-methoxybenzoate (4.95 g, 16.95 mmol)
and N1,N2-
dimethylethane- 1,2-diamine (0.146 mL, 1.356 mmol) were each added
sequentially in one
portion. The reaction mixture was heated at about 110 C for about 18 h. The
reaction
mixture was filtered and deposited onto silica gel. The crude material was
purified via
automated silica gel chromatography (10%-50% EtOAc : Heptane; EA -80g column,
18 x 150
mm test tubes). The fractions containing product were combined and
concentrated to afford
methyl 2-methoxy-4-((IR,4S)-3-oxo-2-azabicyclo[2.2.IJhept-5-en-2 yl)benzoate
(2.69 g, 74%)
as a solid. LC/MS (Table 1, Method g) Rt =1.95 min, m/z 274 (M+H)+.
Preparation #66: Preparation of Methyl 2-methoxy-4-((1S,4R)-3-oxo-2-
azabicyclo[2.2.1]heptan-2-yl)benzoate
O 1~1 O O 1~1 O
O I S O O O
N N
H
A 250 mL round bottom flask was charged with methyl 2-methoxy-4-((1R,4S)-3-oxo-
2-
azabicyclo[2.2.1]hept-5-en-2-yl)benzoate (2.70 g, 9.88 mmol) in ethyl acetate
(99 mL) to give
a brown solution. Palladium on carbon (0.210 g, 0.198 mmol) was added in one
portion. The
resulting suspension was allowed to stir under an atmosphere of hydrogen
(balloon) at RT for
about 6 h. The suspension was filtered through a pad of Celite . The filtrate
was
concentrated to give methyl 2-methoxy-4-((JS,4R)-3-oxo-2-
azabicyclo[2.2.IJheptan-2-
yl)benzoate (2.73 g, 100%) as a solid. LC/MS (Table 1, Method g) Rt = 1.91
min, m/z 276
(M+H)+.
Preparation #67: Preparation of 2-Methoxy-4-((1S,4R)-3-oxo-2-
azabicyclo[2.2.1]heptan-
2-yl)benzoic acid
O 1-1 O O "1 O
O O HO O
N /
N
A 25 mL round bottom flask equipped with rubber septum and nitrogen inlet
needle was
charged with methyl 2-methoxy-4-((1S,4R)-3-oxo-2-azabicyclo[2.2.1]heptan-2-
yl)benzoate
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(0.610 g, 2.216 mmol) in EtOH (8.86 mL) to give a colorless solution. Barium
hydroxide
solution (8.12 mL, 2.437 mmol) was added dropwise. The resulting suspension
was allowed
to stir at RT for about 16 h. The pH was adjusted to pH= about 5 by dropwise
addition of
acetic acid. The solution was concentrated. The solid was triturated with
EtOAc (1 x 25
mL). The solid was removed via filtration through a sintered glass funnel, and
the filtrate was
dried in vacuo to give 2-methoxy-4-((1S,4R)-3-oxo-2-azabicyclo[2.2.IJheptan-2-
yl)benzoic
acid (378 mg, 65%) as an oil. LC/MS (Table 1, Method k) Rt = 1.7 1 min; 1H NMR
(400
MHz, DMSO) 6 7.67 (t, J= 7.8, 1H), 7.42 (dd, J= 5.5, 1.9, 1H), 7.14 - 7.06 (m,
1H), 4.71 (s,
1H), 3.79 (s, 3H), 2.83 (s, 1H), 1.95 (m, 3H), 1.69 (dd, J= 17.7, 12.0, 1H),
1.52 (dd, J= 17.4,
10.9, 2H).
Preparation #67a: Preparation of (1S,4R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadi azol-5-yl)-3-methoxyphenyl)-2-azabicyclo [2.2.1 ] heptan-3-one
N OH O O
O I L NHZ HO O
/I~ x O
CI CI
Suspended 2-methoxy-4-((1S,4R)-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl)benzoic
acid (0.340
g, 1.301 mmol), HOBt (0.299 g, 1.952 mmol), EDC (0.374 g, 1.952 mmol) in DMF
(2.169
mL) under nitrogen. The solution was stirred at RT for about 30 min. (Z)-3-
chloro-N-
hydroxy-4-isopropoxybenzimidamide (0.446 g, 1.952 mmol) was added as a
solution in DMF
(0.434 mL) and heated to about 140 C for about 4 h. The solution was allowed
to cool to RT
and precipitated with water. The solids were filtered and then dissolved in
EtOAc. The
organic phase was washed with IN HC1 solution (1 x 200 mL), saturated NaHCO3
solution (1
x 200 mL), and saturated NaCl solution (1 x 200 mL), dried over MgS04,
filtered and
concentrated to give (IS,4R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5 yl)-3-
methoxyphenyl)-2-azabicyclo[2.2.IJheptan-3-one (290 mg, 44%) as a solid. LC/MS
(Table 1,
Method g) Rt = 3.18 min, m/z 454 (M+H).
Example #71: Preparation of (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)-3-methoxyphenylamino)cyclopentanecarboxylic acid
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OOH
O O O
_O _O
N N I N NH
C1 C1
A 75 mL reaction vial equipped with septa cap outfitted with nitrogen inlet
needle was
charged with (1 S,4R)-2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)-3-
methoxyphenyl)-2-azabicyclo[2.2.1]heptan-3-one (0.290 g, 0.639 mmol) in THE
(6.39 mL) to
give a colorless solution. Sodium hydroxide solution (6.39 mL, 6.39 mmol) was
added
dropwise via syringe. The reaction mixture was heated at about 60 C for about
16 h. The pH
was adjusted to pH= about 2 by dropwise addition of IN HCl solution. The
aqueous
suspension was extracted with EtOAc (2 x 50 mL) and washed with saturated NaCl
solution
(1 x 50 mL). The organic phase was dried over MgS04, filtered and concentrated
to give an
oil. The sample was purified via automated silica gel chromatography (0%-5%
MeOH :
CH2C12;EA -40g column, 18 x 150 mm test tubes). The fractions containing
product were
combined and concentrated to afford 204 mg of a solid. The sample was
recrystallized from
ether, the solvent was decanted, and the solid was collected and washed with
ether, then dried
in vacuo to give (JR,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-
5 yl)-3-
methoxyphenylamino)cyclopentanecarboxylic acid (120 mg, 39%) as a solid. LC/MS
(Table
1, Method g) Rt = 2.85 min, m/z 472 (M+H) ; 1H NMR (400 MHz, DMSO) 6 7.98 (d,
J= 2.1,
1H), 7.92 (dd, J= 8.6, 2.1, 1H), 7.82 (d, J= 8.7, 1H), 7.34 (d, J= 9.0, 1H),
6.79 (d, J= 6.9,
1H), 6.33 (dd, J = 8.8, 2.0, 1H), 6.29 (d, J = 1.8, 1H), 4.85 - 4.73 (m, 1H),
3.95 - 3.83 (m,
4H), 2.82 - 2.71 (m, I H), 2.40 - 2.29 (m, I H), 2.01 (dd, J = 12.3, 7.0, I
H), 1.87 (dd, J = 15.3,
7.5, 2H), 1.70 - 1.60 (m, 1H), 1.53 (m, 1H), 1.33 (d, J= 6.0, 6H).
Example #72: Preparation of (R)-3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-
5-yl)-2-methylphenoxy)p rop ane-1,2-diol
OH HQ OH
N-O (O
C~ I ' N HO,,,. \/O O1 N.O
o \ 'N
O ~
A 50 mL reaction vial equipped with septa cap outfitted with nitrogen inlet
needle was
charged with 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-2-
methylphenol
(0.350 g, 1.015 mmol), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (0.139 mL,
1.117
mmol), and PS-triphenylphosphine (0.406 g, 1.218 mmol) in THE (5.08 mL) to
give a tan
suspension. 4 A molecular sieves were added in one portion. The resulting
suspension was
allowed to stir at RT for about 2 days. The reaction mixture was diluted with
about 20 mL of
ether and HCl (0.508 mL, 6.09 mmol) was added dropwise. The resulting
suspension was
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allowed to stir at RT for about 6 h. The suspension was filtered through a pad
of Celite with
the aid of EtOAc. The filtrate was concentrated and the resulting oil was
diluted with DCM
(5.08 mL). TFA (0.782 mL, 10.15 mmol) was added dropwise. The resulting
solution was
allowed to stir at RT for about 8 h. The mixture was concentrated and the
sample was
purified via automated silica gel chromatography (5%-20% EtOAc : Heptane; RS-
40g
column, 18 x 150 mm test tubes). The fractions containing product were
combined and
concentrated and then dissolved in MeOH. 100 mg of K2CO3 was added and the
suspension
was allowed to stir at RT for about 6 h. The solution was concentrated and
triturated with
water (2 x 50 mL), filtered and washed with water, then dried in vacuo to give
(R)-3-(3-(3-(3-
chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 yl)-2-methylphenoxy)propane-1,2-
diol (142
mg, 33%) as a white solid. LC/MS (Table 1, Method g) Rt = 3.35 min, m/z 457
(M+H) ; 1H
NMR (400 MHz, DMSO) 6 8.04 (d, J= 2.1, 1H), 7.99 (dd, J= 8.6, 2.1, 1H), 7.61
(d, J= 7.3,
1H), 7.39 (dd, J= 8.5, 5.8, 2H), 7.28 (d, J= 8.0, 1H), 4.98 (d, J= 5.1, 1H),
4.82 (d, J= 6.0,
1H), 4.68 (s, 1H), 4.06 (d, J= 4.5, 1H), 3.98 (d, J= 5.7, 1H), 3.84 (d, J=
5.1, 1H), 3.50 (d, J=
2.7, 2H), 2.54 (s, 3H), 1.34 (d, J = 6.0, 6H).
Preparation #68: Preparation of diethyl (1R,3R)-3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)cyclopentylphosphonate, diethyl (1S,3R)-3-(4-
(3-(3-
chloro-4-is op rop oxyphenyl)-1,2,4-oxadiaz ol-5-
yl)phenylamino)cyclopentylphosphonate,
diethyl (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonate and diethyl (1S,3S)-3-(4-(3-(3-chloro-4-
isoprop oxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclopentylphosphonate
_O
N-O \L/~ O
CI O
- /\ CIO N / NH
o
Q)
CI N ~ / NHz I P~ O
O O O P` O
N-0 0 N-0 0
CI N / NH o N / NH
O
A solution of 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline
(0.430 g, 1.30
mmol, 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline was
prepared from 3-
chloro-4-isopropoxybenzonitrile and 4-aminobenzoic acid by following General
Procedures C
and D.), diethyl 3-oxocyclopentylphosphonate (0.861 g, 3.91 mmol, prepared
according to
Journal of Medicinal Chemistry (1986), 29(10), 1988-95.), acetic acid (1.50
mL, 26.1
mmol), 4 A molecular sieves (1.5 g) in DCM (6.5 mL) and MeOH (6.52 mL) was
heated at
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WO 2011/071570 PCT/US2010/046424
about 40 C for about 6 h, then NaCNBH3 (0.041 g, 0.65 mmol) was added. The
reaction
mixture was stirred at RT for about 16 h. Water (20 mL) was added to the
reaction mixture.
After filtration, the filtrate was concentrated under reduced pressure and
purified on silica gel
(80 g) using (1-5% MeOH in DCM) followed by chiral chromatography (The
gradient was 0-
40% A in 19 min (20 mL/min flow rate). Mobile phase A was 200 proof ethanol,
mobile
phase B was HPLC grade heptane with 0.1% diethylamine added. The column used
for the
chromatography was a Daicel OD-H, 20 x 250 mm column (5 m particles).
Detection
methods were UV (330 nm) detection as well as optical rotation) to give
diethyl (IR,3R)-3-(4-
(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonate
[Rt 12.3 min, optical rotation=positive] (0.060 g, 9%): LC/MS (Table 1, Method
b) Rt = 2.87
min; MS m/z: 534 (M+H) ; diethyl (1 S,3R)-3-(4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)phenylamino)cyclopentylphosphonate [Rt 13.4 min, or=negative]
(0.065 g,
9%): LC/MS (Table 1, Method b) Rt = 2.82 min; MS m/z: 534 (M+H) ; diethyl
(IR,3S)-3-(4-
(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-
yl)phenylamino)cyclopentylphosphonate
[Rt 15.4 min, optical rotation=positive] (0.149 g, 21%): LC/MS (Table 1,
Method b) Rt = 2.87
min; MS m/z: 534 (M+H) ; diethyl (IS,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenylamino)cyclopentylphosphonate [Table 3, Method 9, Rt 13.4
min,
or=negative] (0.052 g, 7%): LC/MS (Table 1, Method b) Rt = 2.82 min; MS m/z:
534
(M+H)+.
Example #73: Preparation of N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)isonicotinamide
O
)XO
4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline was prepared
from 3-chloro-
4-isopropoxybenzonitrile and 4-aminobenzoic acid by following General
Procedures C and D.
Isonicotinic acid (0.112 g, 0.9 10 mmol) was dissolved in thionyl chloride (5
mL, 68.5 mmol)
to give a colorless solution. DMF (3 drops) was added, the reaction mixture
was heated at
about 70 C for about 16 h. Cooled down, the solvent was removed to afford
roughly 0.2 g
pale yellow solid. 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)aniline (0.15 g,
0.455 mmol) was dissolved in DCM (5 mL) to give a colorless solution, the
reaction mixture
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was cooled to about 0-5 C in an ice bath. The cloudy suspension of the 0.2 g
pale yellow
solid in DCM (5 mL) was added dropwise to the solution. The ice-bath was
removed, the
reaction mixture was stirred at RT overnight. The reaction mixture was
concentrated in vacuo,
the yellow residue was triturated by methanol (3 mL) and DMSO (3 mL), the
resulting
suspension was filtered, the solid was washed by methanol (2 x 5 mL). Dried in
oven
overnight to afford 0.18 g solid, to which was added DMSO (2 mL) and methanol
(2 mL),
heated at about 80 C for about 30 min. The solution was cooled down, the
mixture was
filtered, the solid was collected and washed by methanol (5 mL) and water (2 x
5 mL), and
dried to afford N-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenyl)isonicotinamide (0.12 g, 0.276 mmol, 60.7 % yield) as yellow powder:
LC/MS
(Table 1, Method a) Rt = 4.39 min.; MS m/z: 435.19 (M+H)+. 1H NMR (400 MHz,
DMSO-
d6) 6 ppm 11.17 (s, 1H), 8.96 (dd, J = 4.84, 1.50 Hz, 2H), 8.26-8.20 (m, 2H),
8.17 (dd, J =
4.82, 1.54 Hz, 2H), 8.14-8.09 (m, 2H), 8.06 (d, J = 2.11 Hz, 1H), 8.00 (dd, J
= 8.63, 2.13 Hz,
1 H), 7.40 (d, J = 8.8 8 Hz, 1 H), 4.91-4.75 (m, 1 H), 1.3 6 (d, J = 6.02 Hz,
6H).
Example #74: Preparation of 3-amino-l-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)benzyl)pyrrolidine-3-carboxylic acid
CI N-O
N-O O BocHN
__~A O)Cr
CI N O /1\ H N
N NHZ
OOH
O
3 -Amino-1-(4-(3 -(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -
yl)benzyl)pyrrolidine-3 -
carboxylic acid was made by General Procedures H and K. LC/MS (Table 1, Method
g) R, =
1.94 min, m/z 457.14 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.12 (d, J = 8.29
Hz,
2H), 8.05 (d, J = 2.11 Hz, 1H), 7.99 (dd, J = 8.64, 2.12 Hz, 1H), 7.65 (d, J =
8.28 Hz, 2H),
7.38 (d, J = 8.97 Hz, 1H), 4.81 (dt, J = 6.0, 12.0 Hz, 1H), 3.73 (dd, J =
24.40, 10.0 Hz, 2H),
2.96-2.90 (m, 1H), 2.75 (dd, J = 34.80, 10.0 Hz, 2H), 2.37-2.27 (m, 2H), 1.80-
1.72 (m, 1H),
1.34 (d, J = 6.02 Hz, 6H).
Preparation #69: Preparation of (1R,3S)-methyl 3-
(dibenzylamino)cyclopentanecarboxylate
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~ \ I
\ I N~
0-
Step 1
(1R, 3S)-Methyl 3-aminocyclopentanecarboxylate hydrochloride
HZNA, O SOCI2 H2N, O
0-1~ M HCI
OH MeOH O-
A solution of (1R,3S)-3-aminocyclopentanecarboxylic acid (0.115 g, 0.890 mmol)
(PepTech)
in MeOH (1.5 mL) was cooled to about 0 C in an ice bath. Thionyl chloride
(0.130 mL,
1.781 mmol) was added dropwise. The reaction mixture was stirred at about 0 C
for about 2
h, then the reaction mixture was heated at about 65 C for about 18 h until
TLC in (3:1:1 n-
BuOH/AcOH/water) showed (Ninhydrin/EtOH visualization) less polar spot forming
(Product's Rf=0.428, SM's Rf=0.345). The reaction mixture was cooled down and
concentrated to afford (JR, 3S)-Methyl 3-aminocyclopentanecarboxylate
hydrochloride (0.16
g, 0.89 mmol, 100 % yield) as a pale green solid.
Step 2
(1R, 3S)-Methyl 3-(dibenzylamino)cyclopentane carboxylate
HZN~. HCI 0.'' \ r-O
,
0-
A solution of sodium carbonate (0.296 g, 2.79 mmol) in water (0.840 mL) was
added DCM
(1.680 mL). (1R,3S)-Methyl 3-aminocyclopentanecarboxylate hydrochloric acid
(0.125 g,
0.698 mmol) was added, then benzyl bromide (0.170 mL, 1.431 mmol) was added.
The
reaction mixture was heated at about 40 C for about 7 h. The reaction mixture
was cooled
down, partitioned between EtOAc (30 mL) and water (30 mL), the organic layer
was washed
by brine (20 mL), dried over sodium sulfate, filtered and concentrated to
afford 237 mg pale
yellow oil, which was purified via Analogix (0-25% EtOAc/Heptane over 20 min;
12 g
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Redi-Sep silica gel column) to afford (1R,3S)-methyl 3-
(dibenzylamino)cyclopentanecarboxylate (0.195 g, 0.603 mmol, 86 % yield) as
colorless oil.
LC/MS (Table 1, Method g) Rt = 2.89 min, m/z 324.19 (M+H)+.
Preparation #70: Preparation of (3S)-methyl 3-amino-l-
fluorocyclopentanecarboxylate
H2N,, -O
[:)< O
F
Step 1
(3S)-Methyl 3-(dibenzylamino)-1-fluorocyclopentanecarboxylate
N
N, O
O
O- CX
A solution of (1R,3S)-methyl 3-(dibenzylamino)cyclopentanecarboxylate (0.139
g, 0.430
mmol) in THE (1.433 mL) was cooled to about -78 C in a dry ice/acetone bath.
Potassium
hexamethyldisiazide (0.945 mL, 0.473 mmol) (0.5 M in toluene) was added
dropwise over
about 5 min, the reaction mixture was stirred at about -78 C for about 50
min. A solution of
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.163 g, 0.516 mmol) in THE
(0.716 mL)
was added dropwise over about 1 min, then the cooling bath was removed, the
reaction
mixture was warmed up to RT. Hydrochloric acid (0.1 M, 4.30 mL, 0.430 mmol)
was added
to quench the reaction. The mixture was partitioned between water (30 mL) and
ether (30
mL), the aqueous layer was extracted by ether (2 x 15 mL), the combined ether
layer was
washed by brine (20 mL), dried over sodium sulfate, filtered and concentrated
to afford 198
mg yellow oil, which was purified via Analogix (0-30% EtOAc/Heptane over 20
min; 12 g
Redi-Sep silica gel column) to afford (3S)-methyl 3-(dibenzylamino)-1-
fluorocyclopentanecarboxylate (0.098 g, 0.287 mmol, 66.8 % yield) as colorless
oil. LC/MS
(Table 1, Method g) Rt = 3.11 min, m/z 342.15 (M+H)+.
Step 2
(3S)-Methyl 3-amino-l-fluorocyclopentanecarboxylate
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, O
o
ro 10 11,
0"N," H2N
Oi F
F
(3S)-Methyl 3-amino-1-fluorocyclopentanecarboxylate was made by General
Procedure N
and it used in the next step without further purification.
Preparation #71: Preparation of (3S)-methyl 3-amino-l-
methylcyclopentanecarboxylate
HZN, ^ O
x O
Step 1
(3S)-Methyl 3-(dibenzylamino)-1-methylcyclopentanecarb oxylate
O
N, O N
[3õ11% ~Oi
O-
A solution of diisopropylamine (0.521 mL, 3.65 mmol) in THE (2.77 mL) was
cooled to about
0 C in an ice bath, n-butyllithium (2.075 mL, 3.32 mmol) (1.6 M in hexane)
was added
dropwise over about 2 min. The solution was stirred at about 0 C for about 15
min. Then the
reaction mixture was cooled to about -78 C in a dry ice/acetone bath. A
solution of (1R,3S)-
methyl 3-(dibenzylamino)cyclopentanecarboxylate (0.358 g, 1.107 mmol) in THE
(1.384 mL)
was added dropwise over about 8 min. It was stirred at about -78 C for about
80 min. A
colorless solution of methyl iodide (0.415 mL, 6.64 mmol) in THE (1.384 mL)
was added
dropwise over about 13 min. The reaction mixture was stirred at about -78 C
for about 24
min. The cooling bath was removed, the reaction mixture was warmed to RT and
stirred at RT
overnight. The crude mixture was poured into saturated ammonium chloride (25
mL), rinsed
by some water, extracted by EtOAc (50 mL), the organic layer was washed by
water (20 mL)
and brine (20 mL), dried over sodium sulfate, filtered and concentrated to
afford 390 mg
orange oil, which was purified via Analogix (0-25% EtOAc/Heptane over 20 min;
40 g
Redi-Sep silica gel column) to afford (3S)-methyl 3-(dibenzylamino)-1-
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methylcyclopentanecarboxylate (0.34 g, 1.008 mmol, 91 % yield) as orange oil.
LC/MS
(Table 1, Method g) Rt = 3.11 min, m/z 338.19 (M+H)+.
Step 2
(3S)-Methyl 3-amino-l-methylcyclopentanecarboxylate
i
\ H2N,, O
O Oi
cx~
O
(3S)-Methyl 3-amino-l-methylcyclopentanecarboxylate was made using General
Procedure
N. TLC Rf = 0.545 in 3:1:1 n-BuOH/AcOH/water (KMnO4 visualization).
Preparation #72: Preparation of (3S)-methyl 3-amino-1-
hydroxycyclopentanecarboxylate
Step 1
N 0- KHMDS _ \ I O N; COZMe N''^ 'COZMe
~=~'CO2Me \ / ~OH v OH
A solution of KHMDS (0.557 mL, 0.278 mmol) in THE (2.441 mL) was cooled to
about -78
C in a dry ice/acetone bath. A solution of (1R,3S)-methyl 3-
(dibenzylamino)cyclopentanecarboxylate (0.06 g, 0.186 mmol) in THE (1.953 mL)
was added
dropwise over about 3 min. The reaction mixture turned into pink orange
gradually in the
addition process. The solution was stirred at about-78 C for about 70 min. A
solution of (R)-
3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (0.073 g, 0.278 mmol) (Organic
Syntheses, 1988,
66, 203) in THE (4.88 mL) was added dropwise over about 3 min. The solution
was stirred at
about -78 C for about 70 min, then saturated NH4C1 (0.5 mL) was added to
quench the
reaction and the reaction mixture was warmed to RT. The reaction mixture was
concentrated
in vacuo, to the aqueous residue was added EtOAc (15 mL) and water (5 mL), the
aqueous
layer was removed, the organic layer was washed by water (10 mL) and brine (10
mL), dried
over sodium sulfate, filtered and concentrated to afford 140 mg yellow solid,
which was
purified via Analogix (0-50% EtOAc/Heptane over 20 min; 40 g Redi-Sep silica
gel
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column) to afford 20 mg yellow oil. LC/MS showed a mixture of (3S)-methyl 3-
amino-l-
hydroxycyclopentanecarboxylate and N-oxide, LC/MS (Table 1, Method h) Rt =
2.09; 2.57
min, m/z 340.2; 356.2 (M+H). (3S)-methyl 3-amino-l-
hydroxycyclopentanecarboxylate is
used without further purification in next step.
Step 2
i t O \ I i I \ I HzN O
N N
~CO2Me ~"'~COzMe JH
"-0<
OH OH
(S)-3-Amino-1-hydroxy-cyclopentanecarboxylic acid methyl ester was made using
General
Procedure E. LC/MS (Table 1, Method h) Rt = 0.46 min, m/z 160.09 (M+H)+.
Example #75: Preparation of (3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-
5-yl)phenylamino)-1-hydroxycyclopentanecarboxylic acid
N-O N-O
CI N F HzN.,. OH CI N NH
COZMe OH
O OH
O
(35)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)-1-
hydroxycyclopentanecarboxylic acid was made using General Procedures P and Q
LC/MS
(Table 1, Method g) Rt = 2.39 min, m/z 458.09 (M+H)+. 1H NMR (400 MHz, DMSO-
d6) 6
ppm 8.02 (d, J= 1.9, 1H), 7.96 (dd, J= 8.7, 2.0, 1H), 7.87 (dd, J= 8.9, 2.9,
2H), 7.36 (d, J=
8.8, 1H), 6.93 - 6.86 (m, 1H), 6.82 (d, J= 6.9, 1H), 6.72 (d, J= 8.8, 2H),
4.88 - 4.74 (m, 1H),
4.11 - 3.87 (m, 2H), 2.59 - 2.52 (m, 1H), 2.31 - 2.08 (m, 2H), 2.05 - 1.89 (m,
1H), 1.89 -
1.67 (m, 2H), 1.68 - 1.50 (m, 1H), 1.35 (d, J= 6.0, 6H).
Preparation #73: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(4-
(chlo romethyl)phenyl)-1,2,4-oxadiazole
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N OH N'O CI
CI NH2 O CI \ N
I / CI ~ci I / O
3-(3-chloro-4-isopropoxyphenyl)-5-(4-(chloromethyl)phenyl)-1,2,4-oxadiazole
was made
using General Procedure E. LC/MS (Table 1, Method h) Rt = 3.15 min, m/z 365.09
(M+H)+.
1H NMR (400 MHz, DMSO-d6) 6 ppm 8.25-8.17 (m, 2H), 8.07 (d, J = 2.12 Hz, 1H),
8.01
(dd, J = 8.65, 2.13 Hz, 1H), 7.73 (d, J = 8.26 Hz, 2H), 7.40 (d, J = 8.87 Hz,
1H), 4.90 (s, 2H),
4.83 ((dt, J = 6.0, 12.0 Hz, 1H), 1.35 (d, J = 6.02 Hz, 6H).
Preparation #74: Preparation of (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)benzyl)triphenylphosphonium chloride
N-0 N.O - P+Ph3CI
CI CI
CI \ ~ N ~ ~ I \ N ~ ~
O
3-(3-chloro-4-isopropoxyphenyl)-5-(4-(chloromethyl)phenyl)-1,2,4-oxadiazole
(1.653 g, 4.55
mmol) and triphenylphosphine (1.790 g, 6.83 mmol) in Xylene (30.3 mL) were
added to give
a cloudy colorless solution. The solution was heated at about 140 C for about
18 h. The
solution was cooled, the white suspension was filtered, washed by heptane (3 x
8 mL), dried
in vacuo (at about 60 C) for about 3 h to afford (4-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-
oxadiazol-5-yl)benzyl)triphenylphosphonium chloride (1.812 g, 2.90 mmol, 63.7
% yield) as
white solid. LC/MS (Table 1, Method g) Rt = 2.89 min, m/z 589.11 (M+H)+. 1H
NMR (400
MHz, DMSO-d6) 6 ppm 8.06-8.02 (m, 3H), 8.00-7.86 (m, 4H), 7.78-7.67 (m, 12H),
7.38 (d, J
= 8.97 Hz, 1H), 7.23 (dd, J = 8.44, 2.35 Hz, 2H), 5.32 (d, J = 16.30 Hz, 2H),
4.81 (dt, J =
6.0, 12.0 Hz, 1H), 1.33 (d, J = 6.02 Hz, 6H).
Example #76: Preparation of (1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-3-yl)phenylamino)cyclopentanecarboxylic acid N -N
O N NH CI O
CI N NH
0
O" O H
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(1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid was prepared using General
Procedure Q
LC/MS (Table 1, Method g) Rt = 2.94 min, m/z 442.27 (M+H)+. 1H NMR (400 MHz,
DMSO-
d6) 6 ppm 12.10 (s, 1H), 8.14 (d, J = 2.09 Hz, 1H), 8.07 (dd, J = 8.67, 2.16
Hz, 1H), 7.78 (d,
J = 8.68 Hz, 2H), 7.42 (d, J = 8.90 Hz, 1H), 6.69 (d, J = 8.77 Hz, 2H), 6.40
(d, J = 6.66 Hz,
1H), 4.87 (dt, J = 6.0, 12.0 Hz, 1H), 3.86-3.77 (m, 1H), 2.83-2.72 (m, 1H),
2.37-2.30 (m, 1H),
2.05-1.96 (m, 1H), 1.93-1.82 (m, 2H), 1.69-1.61 (m, 1H), 1.57-1.49 (m, 1H),
1.36 (d, J = 6.01
Hz, 6H).
Example #77: Preparation of 1-Amino-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenoxy)cyclopentanecarboxylic acid
Step 1
Benzyl4-(3-(tert-butoxycarbonylamino)-3-
(ethoxycarbonyl)cyclopentyloxy)benzoate
0y*
OH O~O I -&7
\ I O I / HO NH
O O
O O
Benzyl 4-(3-(tert-butoxycarbonylamino)-3-
(ethoxycarbonyl)cyclopentyloxy)benzoate
was prepared using General Procedure R. LC/MS (Table 1, Method g) Rt = 3.05
min, m/z
484.14 (M+H)+.
Step 2
4-(3-(tert-butoxycarbonylamino)-3-(ethoxycarbonyl)cyclopentyloxy)benzoic acid
0~0 py0
0 I O NHO'/ \ O NH 0,_,,,
HO /
O 0
0 0
4-(3-(tert-butoxycarbonylamino)-3-(ethoxycarbonyl)cyclopentyloxy)benzoic acid
was
prepared using General Procedure N. LC/MS (Table 1, Method g) Rt = 2.16 min,
m/z 394.15
(M+H)+.
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Step 3
Ethyl 1-(tert-butoxycarb onylamino)-3-(4-(3-(3-chloro-4-isop rop oxyphenyl)-
1,2,4-
oxadi azol-5-yl)phenoxy)cyclopentanecarb oxylate
OH O 0 N'O
CI N/NH \ O NH CI N O OO11 z O
O HO I / O / NH
0
0 O
O
Ethyl 1-(tert-butoxycarbonylamino)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-
5-yl)phenoxy)cyclopentanecarboxylate was prepared using General Procedure D.
LC/MS
(Table 1, Method g) Rt = 3.78 min, m/z 586.22 (M+H)+.
Step 4
Ethyl 1-amino-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)cyclopentanecarboxylate
N-O _ N-O
CI N/ O O O CI I N O
10 NH N0O
O 0
Ethyl 1-amino-3 -(4-(3 -(3 -chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5 -
yl)phenoxy)cyclopentanecarboxylate was prepared using General Procedure K.
LC/MS (Table
1, Method g) Rt = 2.57 min, m/z 486.10 (M+H)+.
Step 5
1-Amino-3-{4-[3-(3-chloro-4-isopropoxy-phenyl)-[1,2,4] oxadiazol-5-yl]-
phenoxy}-
cyclopentanecarboxylic acid
N-O N-O
CI I\ ~~ N O
CI I\ ~~ N O KOH
NH ' v NH
O z O z
O OH
O
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1-Amino-3- {4-[3-(3-chloro-4-isopropoxy-phenyl)-[ 1,2,4]oxadiazol-5-yl]-
phenoxy}-
cyclopentanecarboxylic acid was prepared using General Procedure P. LC/MS
(Table 1,
Method g) Rt = 2.08 min, m/z 458.11 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 6 ppm
8.70-
8.20 (brs, 2H), 8.13 (d, J= 8.9, 2H), 8.04 (d, J= 2.1, 1H), 7.98 (dd, J= 8.6,
2.1, 1H), 7.38 (d,
J= 9.0, 1H), 7.21 (d, J= 8.9, 2H), 5.16 - 5.09 (m, 1H), 4.82 (kept, J= 6.1,
1H), 2.77 (dd, J=
14.7, 6.4, 1H), 2.44 - 2.19 (m, 2H), 2.20 - 2.02 (m, 3H), 1.35 (d, J= 6.0,
6H).
Example #78: Preparation of 1-Amino-3-(3-chloro-4-(5-(5-chloro-6-
isopropoxypyridin-3-
yl)-1,2,4-oxadiazol-3-yl)phenoxy)cyclopentanecarboxylic acid
Step 1
Ethyl 1-(tert-butoxycarb onylamino)-3-(3-chlo ro-4-(5-(5-chlor o-6-is opr op
oxypyridin-3-
yl)-1,2,4-oxadiazol-3-yl)phenoxy)cyclopentanecarboxylate
cl
CI \ O-N
O N \ O-N CI OO CI~N O OLNH
N HO ""
xNHO\/ O N OH v
O
Ethyl 1-(tent-butoxycarbonylamino)-3-(3-chloro-4-(5-(5-chloro-6-
isopropoxypyridin-3-yl)-
1,2,4-oxadiazol-3-yl)phenoxy)cyclopentanecarboxylate was prepared using
General
Procedure M. LC/MS (Table 1, Method i) Rt = 2.10 min, m/z 621.20 (M+H)+.
Step 2
Ethyl 1-amino-3-(3-chlo ro-4-(5-(5-chlor o-6-is op rop oxypyridin-3-yl)-1,2,4-
oxadiazol-3-
yl)phenoxy)cyclopentanecarb oxylate
CI CI
O-N O-N
CI N O O CI O
O N' NH O N NH2
o
O
O
Ethyl 1-amino-3-(3-chloro-4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-
oxadiazol-3-
yl)phenoxy)cyclopentanecarboxylate was prepared using General Procedure K.
LC/MS (Table
1, Method g) Rt = 2.90 min, m/z 521.09 (M+H).
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Step 3
1-Amino-3-(3-chlor o-4-(5-(5-chlo ro-6-is op rop oxypyridin-3-yl)-1,2,4-
oxadiazol-3-
yl)phenoxy)cyclopentanecarboxylic acid
CI CI
O-N O-N
O N O CI I -N / O 7','~ O N0 O N0
/1\ O /I\ O
HO
1-Amino-3-(3-chloro-4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-
yl)phenoxy)cyclopentanecarboxylic acid was prepared using General Procedure P.
LC/MS
(Table 1, Method g) Rt = 2.14 min, m/z 493.10 (M+H)+. 1HNMR (400 MHz, DMSO-d6)
6
ppm 8.91 (d, J= 2.1, 1H), 8.53 (d, J= 2.1, 1H), 7.97 (d, J= 8.7, 1H), 7.89 -
7.60 (brs, 2H),
7.2 5 (d, J = 2.4, 1 H), 7.15 (dd, J = 8.8, 2.4, 1 H), 5.51 - 5.3 9 (m, 1 H),
5.14 - 5.05 (m, 1 H),
2.65 (dd, J= 14.1, 6.1, 1H), 2.33 - 2.18 (m, 1H), 2.18 - 2.05 (m, 1H), 1.99 -
1.80 (m, 3H),
1.39 (d, J= 6.2, 6H).
Example #79: Preparation of (1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-3-yl)-3-methylphenylamino)cyclopentanecarboxylic acid
Step 1
2-Methyl-4-((1R, 4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-en-2-yl)benzonitrile
CN
CN
HN / N O
H
Br C~~
4-Bromo-2-methylbenzonitrile (10g, 51.0 mmol) and (1R, 4S)-2-
azabicyclo[2.2.1]hept-5-en-
3-one (4.64 g, 42.5 mmol) in toluene (85 mL) were added to give pale yellow
suspension.
N1,N2-dimethylethane-1,2-diamine (0.458 mL, 4.25 mmol) was added, the grinded
potassium
phosphate tribasic (18.05 g, 85 mmol) was added. The reaction mixture was
evacuated and
refilled with nitrogen for three times. Copper(I) iodide (0.405 g, 2.125 mmol)
was added. The
reaction mixture was evacuated and refilled with nitrogen for three times, a
condenser was put
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on under nitrogen. The resulting green suspension was heated at about 130 C
for about 16 h.
The reaction mixture was cooled and diluted with EtOAc (250 mL), washed with
water (3 x
100 mL), HC1 (1 N, 2 x 100 mL), and water (100 mL), the organic layer was
filtered through
Celite , and concentrated to afford 10.7 g yellow solid, which was purified
via Analogix
(10%-50% EtOAc/Heptane over 30 min; 120 g Redi-Sep silica gel column) to
afford 2-
methyl-4-((IR,4S)-3-oxo-2-azabicyclo[2.2.IJhept-5-en-2 yl)benzonitrile (4.12
g, 18.37 mmol,
43.2 % yield) as white solid. LC/MS (Table 1, Method g) Rt = 2.10 min, m/z
225.12 (M+H)+.
1H NMR (400 MHz, CDC13) 6 ppm 7.55 (d, J = 8.53 Hz, 1H), 7.44 (d, J = 2.00 Hz,
1H), 7.31
(dd, J = 8.53, 2.22 Hz, 1H), 7.02 (dd, J = 5.28, 1.91 Hz, 1H), 6.73 (ddd, J =
4.96, 3.23, 1.43
Hz, 1H), 4.85 (dd, J = 3.78, 1.88 Hz, 1H), 3.56-3.50 (m, 1H), 2.53 (s, 3H),
2.47 (td, J = 8.24,
1.63 Hz, 1H), 2.33 (td, J = 8.24, 1.54 Hz, 1H).
Step 2
Preparation of 2-Methyl-4-((1S,4R)-3-oxo-2-azabicyclo[2.2.1]heptan-2-
yl)benzonitrile
CN CN
N O N O
/
2-Methyl-4-((1S,4R)-3-oxo-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile was
prepared using
General Procedure N. LC/MS (Table 1, Method h) Rt = 2.10 min, m/z 227.13
(M+H)+.
Step 3
Preparation of (Z)-N'-hydroxy-2-methyl-4-((1S,4R)-3-oxo-2-
azabicyclo[2.2.1]heptan-2-
yl)benzimidamide
OH
CN Nll~ NH2
N O
r'~'T N O
r'~'T
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(Z)-N-hydroxy-2-methyl-4-((1S,4R)-3-oxo-2-azabicyclo [2.2.1 ]heptan-2-
yl)benzimidamide
was prepared using General Procedure C. LC/MS (Table 1, Method g) Rt = 1.33
min, m/z
260.17 (M+H)+.
Step 4
(1S,4R)-2-(4-(5-(3-chlo ro-4-is op rop oxyphenyl)-1,2,4-oxadi azol-3-yl)-3-
methylphenyl)-2-
azabicyclo[2.2.1]heptan-3-one
OH
N I'll NH2 O
O O'N N
HO aCI CI N
0 O
N O
r'"~T
(1 S,4R)-2-(4-(5 -(3 -chloro-4-isopropoxyphenyl)- 1,2,4-oxadiazol-3 -yl)-3 -
methylphenyl)-2-
azabicyclo [2.2. 1 ]heptan-3 -one was prepared using General Procedure D.
LC/MS (Table 1,
Method g) Rt = 3.45 min, m/z 438.14 (M+H)+. 1H NMR (400 MHz, DMSO-d6) 6 ppm
8.17
(d, J = 2.17 Hz, 1H), 8.10 (dd, J = 8.69, 2.17 Hz, 1H), 8.02 (d, J = 8.39 Hz,
1H), 7.66-7.60
(m, 2H), 7.44 (d, J = 8.96 Hz, 1H), 4.88 (td, J = 6.0, 1H), 4.73 (brs, 1H),
2.88-2.83 (m, 1H),
2.61 (s, 3H), 2.02-1.90 (m, 3H), 1.79-1.68 (m, 1H), 1.61-1.54 (m, 2H), 1.36
(d, J = 6.01 Hz,
6H), 1.29-1.20 (m, 1H), 0.89-0.83 (m, 1H).
Step 5
(1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-
methylphenylamino)cyclopentanecarboxylic acid
OOH
O
O'N N O-N
CI N CI N NH
O
(1R,3S)-3-(4-(5-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-3-
methylphenylamino)cyclopentanecarboxylic acid was prepared using General
Procedure P.
LC/MS (Table 1, Method g) Rt = 3.08 min, m/z 456.44 (M+H)+. 1HNMR (400 MHz,
DMSO-
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d6) 6 ppm 12.13 (brs, 1H), 8.14 (d, J = 2.16 Hz, 1H), 8.07 (dd, J = 8.70, 2.17
Hz, 1H), 7.82
(d, J = 8.52 Hz, 1H), 7.43 (d, J = 9.03 Hz, 1H), 6.55 (d, J = 7.93 Hz, 2H),
6.28 (d, J = 6.84
Hz, 1H), 4.87 (td, J= 6.0 Hz, 1H), 3.81 (sextet, J1 = 6.8 Hz, J2 = 7.2 Hz,
1H), 2.77 (quintet, J
= 8.2 Hz, 1H), 2.51 (s, 7H), 2.38-2.28 (m, 1H), 2.05-1.94 (m, 1H), 1.92-1.83
(m, 2H), 1.69-
1.58 (m, 1H), 1.58-1.45 (m, 1H), 1.36 (d, J = 6.02 Hz, 6H).
Example #80: Preparation of (1S,4R)-2-(4-(5-(5-chloro-6-isopropoxypyridin-3-
yl)-1,2,4-
oxadiazol-3-yl)-3-methylphenyl)-2-azabicyclo[2.2.1]heptan-3-one
O O O-N O
-
CI \ OH \ N CI N \
N
, N HO'
N N
NH2
(1 S,4R)-2-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-
methylphenyl)-
2-azabicyclo[2.2.1]heptan-3-one is prepared using General Procedure D. LC/MS
(Table 1,
Method g) Rt = 3.61 min, m/z 439.18 (M+H)+. 1H NMR (400 MHz, CDC13) 6 ppm 8.86
(d, J
= 2.12 Hz, 1H), 8.38 (d, J = 2.12 Hz, 1H), 8.09 (d, J = 8.60 Hz, 1H), 7.56 (d,
J = 2.18 Hz,
1H), 7.47 (dd, J = 8.58, 2.26 Hz, 1H), 5.49(td, J = 6.0, 1H),, 4.57-4.52 (m,
1H), 3.02-2.97 (m,
1H), 2.69 (s, 3H), 2.13-1.86 (m, 4H), 1.84-1.73 (m, 1H), 1.60-1.54 (m, 1H),
1.45 (d, J = 6.21
Hz, 6H).
Example #81: Preparation of (1R,3S)-3-(4-(5-(5-chloro-6-isopropoxypyridin-3-
yl)-1,2,4-
oxadiazol-3-yl)-3-methylphenylamino)cyclopentanecarboxylic acid
Q ,OH
O
0,N
0-N
I> - tk
H
CI N N _ CI N N U N H
O N 0 N
(1R,3S)-3-(4-(5-(5 -chloro-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-
methylphenylamino)cyclopentanecarboxylic acid is prepared using General
Procedure P.
LC/MS (Table 1, Method g) Rt = 3.23 min, m/z 457.15 (M+H)+. 1HNMR (400 MHz,
DMSO-
d6) 6 ppm 12.08 (brs, 1H), 8.88 (d, J = 2.10 Hz, 1H), 8.50 (d, J = 2.09 Hz,
1H), 7.83 (d, J =
8.66 Hz, 1H), 6.61-6.51 (m, 2H), 6.28 (d, J = 6.32 Hz, 1H), 5.44 (td, J= 6.0
Hz, 1H), 3.88-
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3.74 (m, 1H), 2.83-2.70 (m, 1H), 2.52 (s, 3H), 2.38-2.27 (m, 1H), 2.05-1.94
(m, 1H), 1.87 (dd,
J = 15.25, 7.64 Hz, 2H), 1.68-1.58 (m, 1H), 1.58-1.46 (m, 1H), 1.39 (d, J =
6.19 Hz, 6H).
Example #82: Preparation of 5-(3-(2H-tetrazol-5-yl)phenyl)-3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazole
O N-O
I i
CI N / CI I \ N
O CN N -N
N- NH
A mixture of 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzonitrile Table A,
entry A.4), sodium azide (0.036 g, 0.554 mmol), zinc bromide (0.074 g, 0.329
mmol), water
(2.83 mL) and THE (0.944 mL) was heated with stirring in a CEM microwave at
about 120 C
for about 105 min. The resulting suspension was acidified to a pH of about 1
using 1 N
aqueous HC1. Acetic acid and ethanol were added, after which the mixture was
stirred
overnight. The solution was then diluted with water and stirred to give a
white precipitate and
the resulting solid was collected by vacuum filtration and washed with water
to provide a
white solid. The crude solid was further purified by automated flash
chromatography (0 -
10% MeOH in DCM) to give the product, 5-(3-(2H-tetrazol-5-yl)phenyl)-3-(3-
chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazole (0.090 g; 78%). LC/MS (Table 1, Method g)
Rt = 2.14
min, m/z 383 (M+H) ; 1H NMR (400 MHz, DMSO-d6) 6 8.84 (s, 1H), 8.42 - 8.35 (m,
2H),
8.10 (d, J= 2.1, 1H), 8.04 (dd, J= 2.1, 8.6, 1H), 7.90 (t, J= 7.9, 1H), 7.41
(d, J= 8.8, 1H),
4.91 - 4.76 (m, 1H), 1.36 (d, J= 6.0, 6H).
Example #83: Preparation of methyl 2-(5-(3-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)phenyl)-2H-tetrazol-2-yl)acetate
O
N-O CI I
CI X \ I N \ N
O / _N N N O
N N,NH NIN
A mixture of 5-(3-(2H-tetrazol-5-yl)phenyl)-3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazole (0.114 g, 0.299 mmol), methyl bromoacetate (0.06 mL, 0.651 mmol)
and
potassium carbonate (0.061 g, 0.441 mmol) in DMF (2.3 mL) was stirred
overnight at RT.
The mixture was then concentrated to dryness and the residue was triturated
with water (10
mL). The resulting suspension was filtered through a sintered glass funnel and
the resulting
solid washed with water (3 x 15 mL), air dried, and resuspended in
dichloromethane/MeOH
(9:1; 5 mL). The suspension was filtered through a sintered glass funnel and
the filtrate then
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concentrated under reduced pressure. The residue was purified by automated
flash
chromatography (0-25% EtOAc/heptane) to give the product as a white solid:
methyl 2-(5-(3-
(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)-2H-tetrazol-2
yl)acetate
(0.082 g, 60.3 %). LC/MS (Table 1, Method g) Rt = 3.10 min, m/z 455 (M+H) ; 1H
NMR
(400 MHz, DMSO-d6) 6 8.82 (s, 1H), 8.40 (dd, J= 7.8, 19.8, 2H), 8.10 (d, J=
2.1, 1H), 8.05
(dd, J= 2.1, 8.6, 1H), 7.90 (t, J= 7.9, 1H), 7.40 (d, J= 8.8, 1H), 5.99 (s,
2H), 4.84 (dt, J= 6.2,
12.2, 1H), 3.78 (s, 3H), 1.36 (d, J= 6.0, 6H).
Preparation #85 : Preparation of 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)-N-hydroxybenzimidamide
N'O N-O
CI CI N N OH
O CN NH
HN
A mixture of 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)benzonitrile (0.101 g,
0.298 mmol), hydroxylamine hydrochloride (0.031 g, 0.445 mmol) and
triethylamine (0.095
mL, 0.684 mmol) in ethanol (2.98 mL) was heated to about reflux for about 20 h
in a 10 mL
round bottom flask. The reaction mixture was concentrated under reduced
pressure to provide
a crude solid, which was then triturated with water (5 mL) and then isolated
by vacuum
filtration, rinsed with water and dried in open air to afford 3-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5yl)-N-hydroxybenzimidamide (0.098 g, 88%),
which was
used without further purification. LC/MS (Table 1, Method j) Rt = 1.45 min,
m/z 373
(M+H)
Example #84: Preparation of 3-(3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenyl)-1,2,4-oxadiazol-5(2H)-one
N-O
N.O CI I / N
CI I N
OH O NH
0 HN NH NYO
0
To a mixture of 3-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-N-
hydroxybenzimidamide (0.098 g, 0.263 mmol) and 1,1'-carbonyldiimidazole (0.058
g, 0.345
mmol) in 1,4-dioxane (0.263 mL) was added DBU (0.042 mL, 0.281 mmol). The
resulting
solution was heated at about 105 C for about 4 h and monitored by LC/MS
(Table 1, method
j). Additional 1,1'-carbonyldiimidazole (0.021 g) and DBU (0.025 mL) were
added and
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heating continued for an additional 0.5 h, after which LC/MS (Table 1, method
j) indicated
complete conversion to the product. The reaction mixture was diluted with
water (6 mL),
extracted with ethyl acetate (5 mL), acidified to a pH of about 2 with aqueous
4 N HC1, and
again extracted with ethyl acetate (2 x 5 mL). The two organic layers were
combined,
concentrated under reduced pressure, and the resulting semisolid redissolved
in
dichloromethane and filtered to remove a white solid. The filtrate was
concentrated and then
purified by preparative HPLC (Varian ProStar with UV-Visible detector) using a
Thermo
Electron Hyperprep HS C18 column and the following gradient: A: Water; B:
Acetonitrile;
30%B to 70 %B over 45 min to give the product: 3-(3-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)phenyl)-1,2,4-oxadiazol-5(2H)-one (0.030 g, 28.6 %
yield). LC/MS
(Table 1, Method g) Rt = 2.61 min, m/z 397 (M-H)-; 1H NMR (400 MHz, DMSO-d6) 6
13.42
-13.04 (m, I H), 8.62 (s, I H), 8.40 (d, J= 8.0, I H), 8.15 (d, J= 8.0, I H),
8.09 (d, J= 1.9, I H),
8.03 (dd, J = 2.0, 8.6, 1 H), 7.8 7 (t, J = 7.9, 1 H), 7.41 (d, J = 8.6, 1 H),
4.92 - 4.74 (m, 1 H),
1.36 (d, J= 6.0, 6H).
Preparation #76: Preparation of 3-(4-fluorophenyl)-5-(4-isobutylphenyl)-1,2,4-
oxadiazole
0 HORN O-N -
CI + H2N II \ I \ ~N ~ ~ F
F
3-(4-Fluorophenyl)-5-(4-isobutylphenyl)-1,2,4-oxadiazole was prepared from 4-
isobutylbenzoyl chloride (prepared from 4-isobutylbenzoic acid [TCI] according
to General
Procedure F) and 4-fluorobenzamidoxime according to General Procedure E. LC/MS
(Table
1, Method h) Rt = 3.32 min, m/z 297 (M+H) ; 1H NMR (400 MHz, DMSO-d6) 6 8.25 -
8.06
(m, 4H), 7.52 - 7.39 (m, 4H), 2.59 (d, J = 7.2, 2H), 1.92 (dt, J = 6.8, 13.6,
1H), 0.89 (t, J =
8.5, 6H).
Example #85: Preparation of (1R,3S)-3-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-
3-
yl)phenylamino)cyclopentanecarboxylic acid
OOH
O-N / ~F
--------- ON
N C
N NH
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(1R,3S)-3-(4-(5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic
acid was prepared from 3-(4-fluorophenyl)-5-(4-isobutylphenyl)-1,2,4-
oxadiazole and
(1R,3S)-3-aminocyclopentanecarboxylic acid (Acros) according to General
Procedure L.
LC/MS (Table 1, Method g) Rt = 3.09 min, m/z 406 (M+H) ; 1H NMR (400 MHz,
CDC13) 6
8.13 - 8.07 (m, 2H), 8.00 - 7.93 (m, 2H), 7.31 (s, 1H), 7.29 (s, 1H), 6.66 (d,
J= 8.5, 2H), 3.99
(p, J = 5.5, I H), 3.03 - 2.91 (m, I H), 2.56 (d, J = 7.2, 2H), 2.38 (ddd, J =
6.6, 9.1, 13.6, I H),
2.12 - 1.87 (m, 5H), 1.80 (dd, J= 5.9, 11.6, 1H), 0.93 (d, J= 6.6, 6H).
Preparation #77: Preparation of 3-(3-chloro-4-isopropoxyphenyl)-5-(2-ethyl-4-
fluorophenyl)-1,2,4-oxadiazole
Br
O
CI N _ F CI N N F
L
A 5 mL microwave reaction vial equipped with pressure-releasing septa cap was
charged with
5-(2-bromo-4-fluorophenyl)-3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole
(0.500 g,
1.215 mmol, prepared from 3-chloro-N-hydroxy-4-isopropoxy-benzamidine and 2-
bromo-4-
fluorobenzoyl chloride according to General Procedure E), ethylboronic acid
(0.179 g, 2.429
mmol, Alfa Aesar), tetrakis(triphenylphosphine)palladium(0) (0.140 g, 0.121
mmol), and
potassium phosphate tribasic (0.516 g, 2.429 mmol) in 1,2-dimethoxyethane
(13.35 mL) to
give a orange suspension. The mixture was heated in a Biotage microwave at
about 150 C
for about 45 min. The reaction was concentrated to dryness to give an orange
residue, which
was purified by automated flash chromatography (0-10% EtOAc/heptane) to afford
3-(3-
chloro-4-isopropoxyphenyl)-5-(2-ethyl-4 fluorophenyl)-1,2,4-oxadiazole (0.224
g, 51.1 %
yield). LC/MS (Table 1, Method h) Rt = 3.33 min, m/z 361 (M+H) ; 1H NMR (400
MHz,
CDC13) 6 8.18 (d, J = 2.1, 1H), 8.13 (dd, J = 5.8, 8.7, 1H), 8.01 (dd, J =
2.1, 8.5, 1H), 7.15 -
7.02 (m, 3H), 4.73 - 4.63 (m, 1H), 3.23 - 3.14 (m, 2H), 1.44 (d, J = 6.0, 6H),
1.32 (t, J = 7.5,
3H).
Example #86: Preparation of (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)-3-ethylphenylamino)cyclopentanecarboxylic acid
OyOH
N'O
N-O
CI N CIO I / \ NH
N
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(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
ethylphenylamino)cyclopentanecarboxylic acid was prepared from 3-(3-chloro-4-
isopropoxyphenyl)-5-(2-ethyl-4-fluorophenyl)-1,2,4-oxadiazole and (1R,3S)-3-
aminocyclopentanecarboxylic acid (Acros) according to General Procedure L.
LC/MS (Table
1, Method g) Rt = 3.14 min, m/z 470 (M+H) ; 1H NMR (400 MHz, DMSO-d6) 6 12.32 -
11.86 (m, 1H), 8.01 (d, J = 2.1, 1H), 7.96 (dd, J = 2.1, 8.6, 1H), 7.89 - 7.82
(m, 1H), 7.38 (d, J
= 8.7, 1H), 6.61 - 6.55 (m, 2H), 4.81 (p, J = 6.0, 1H), 3.91 - 3.80 (m, 1H),
3.04 (q, J = 7.4,
2H), 2.75 (s, 1H), 2.33 - 2.23 (m, 1H), 2.02 - 1.92 (m, 1H), 1.92 - 1.82 (m,
2H), 1.72 - 1.60
(m, 1H), 1.60 - 1.48 (m, 1H), 1.35 (d, J = 6.0, 6H), 1.21 (d, J = 7.4, 4H).
Preparation #78: Preparation of 2-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)-5-fluo robenzonitrile
Br N
N ,L
O O
CI N F CI N' F
O \ I \ I N -
O
A suspension of 5-(2-bromo-4-fluorophenyl)-3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazole (0.500 g, 1.215 mmol) and copper(I) cyanide (0.163 g, 1.822 mmol)
in N-methyl-
2-pyrrolidinone (5.65 mL) was heated in a Biotage microwave at about 150 C
for about 15
min. The reaction was diluted with ethyl acetate (90 mL) and water (90 mL) was
added.
After separating the layers, the aqueous phase was extracted with ethyl
acetate (2 x 25 mL)
and the combined organic phases were washed with brine, dried over MgSO4,
filtered, and
concentrated under reduced pressure. The crude material was purified automated
flash
chromatography (0-15% EtOAc/Heptane) to give the product, 2-(3-(3-chloro-4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-5 fluorobenzonitrile (0.220 g, 50.6 %
yield). LC/MS
(Table 1, Method g) Rt = 3.06 min, m/z 358 (M+H) ; 1H NMR (400 MHz, CDC13) 6
8.35 (dd,
J = 5.2, 8.8, 1H), 8.20 (d, J = 2.1, 1H), 8.05 (dd, J = 2.1, 8.6, 1H), 7.66 -
7.48 (m, 2H), 7.05
(d, J = 8.6, 1H), 4.68 (dt, J = 6.0, 12.1, 1H), 1.45 - 1.38 (m, 6H).
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Example #87: Preparation of (1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-
1,2,4-
oxadiazol-5-yl)-3-cyanophenylamino)cyclopentanecarboxylic acid
N OOH
.~~ N
C .~C
O
/ N'O 0
CI N 11> F CI N NH
O
(1R,3S)-3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-3-
cyanophenylamino)cyclopentanecarboxylic acid was prepared from 2-(3-(3-chloro-
4-
isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)-5-fluorobenzonitrile and (1R,3S)-3-
aminocyclopentanecarboxylic acid (Acros) according to General Procedure L.
LC/MS (Table
1, Method g) Rt = 2.85 min, m/z 467 (M+H) ; 1H NMR (400 MHz, DMSO-d6) 6 12.31 -
12.02 (m, 1H), 8.04 (d, J = 6.8, 2H), 7.98 (dd, J = 2.1, 8.6, 1H), 7.43 - 7.38
(m, 1H), 7.38 -
7.3 0 (m, 1 H), 7.15 (d, J = 2.4, 1 H), 7.00 (dd, J = 2.4, 9.0, 1 H), 4.82 (p,
J = 6.0, 1 H), 3.92 (q, J
= 6.8, 1H), 2.82 - 2.72 (m, 1H), 2.38 - 2.28 (m, 1H), 2.03 (s, 1H), 1.94 -
1.84 (m, 2H), 1.68
(s, 1H), 1.55 (d, J = 7.1, 1H), 1.35 (d, J = 6.0, 6H).
Preparation #79: Preparation of (E)-ethyl 4-(1,3-dioxoisoindolin-2-yl)-2-
methylbut-2-
enoate
O
0 0
O
A 200 mL round bottom flask equipped with reflux condensor outfitted with a
nitrogen inlet
adapter was charged with ethyl tiglate (16.13 mL, 117 mmol), N-
bromosuccinimide (10.72
mL, 126 mmol), and benzoyl peroxide (0.012 g, 0.051 mmol) in carbon
tetrachloride (58.5
mL) to give a yellow suspension. The reaction mixture was heated at reflux for
about 1 day.
The reaction mixture was concentrated under reduced pressure via rotary
evaporation to give a
redish-brown oil. The reaction flask was then outfitted with a reflux
condensor and nitrogen
inlet adapter, and then was charged with potassium phthalimide (19.82 g, 107
mmol) and
DMF (86 mL) to give a purple solution. The mixture was heated in an oil bath
at about 140
C for about 18 h. The bath was removed and the reaction cooled to ambient
temperature,
filtered through a sintered glass funnel, and concentrated under reduced
pressure to about half
its original volume. The resulting dark brown solution was diluted with EtOAc
(450 mL) and
extracted with water (2 x 400 mL), 50% saturated aqueous NaCl (2 x 400 mL) and
brine (400
mL). The organic phase was dried over MgSO4, filtered and concentrated to give
a brown oil.
The crude material was purified by automated flash chromatography (10 - 50%
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WO 2011/071570 PCT/US2010/046424
EtOAc/heptane) to give a yellow semi-solid, from which the product was
isolated by
crystallization from cyclohexane: (E)-ethyl 4-(1,3-dioxoisoindolin-2 yl)-2-
methylbut-2-enoate
(4.0 g, 13.68 % yield). 1H NMR (400 MHz, CDC13) 6 7.90 - 7.83 (m, 2H), 7.77 -
7.70 (m,
2H), 6.69 - 6.61 (m, 1H), 4.44 (d, J = 6.8, 2H), 4.22 - 4.13 (m, 2H), 1.27
(td, J = 0.8, 7.1, 3H).
Preparation #80: Preparation of ethyl 4-(1,3-dioxoisoindolin-2-yl)-2-
methylbutanoate
C O O
O O
N\^~O/~
O `IT O IT
A solution of (E)-ethyl 4-(1,3-dioxoisoindolin-2-yl)-2-methylbut-2-enoate (4.0
g, 14.64
mmol) in methanol (150 mL) was passed through an H-Cube hydrogenation
apparatus
containing a 10% palladium on carbon cartridge at 1.5 mL/min under an
atmosphere of
hydrogen (about 20 bar) at about 20 C for about 90 min. The catalyst
cartridge was replaced
with a fresh one and the process repeated, after which the resulting solution
was concentrated
via rotary evaporation to afford ethyl 4-(1,3-dioxoisoindolin-2yl)-2-
methylbutanoate (4.03 g,
100 % yield), as a colorless oil. The material was used directly in the next
step without further
purification. LC/MS (Table 1, Method h) R, = 2.00 min, m/z 276 (M+H) ; 1H NMR
(400
MHz, CDC13) 6 7.92 - 7.79 (m, 2H), 7.77 - 7.64 (m, 2H), 4.12 (q, J = 7.2, 2H),
3.75 (t, J =
7.1, 2H), 2.47 (h, J= 7.1, 1H), 2.16 - 2.02 (m, 1H), 1.79 (dq, J= 6.9, 13.7,
1H), 1.34 - 1.13
(m, 6H).
Preparation #81: Preparation of 4-methyl-2-aminobutanoic acid
O
O ~O
N v Y O~~ H2N v Y 'OH
O I I
A 500 mL round bottom flask equipped with reflux condensor outfitted with a
nitrogen inlet
adapter was charged with ethyl 4-(1,3-dioxoisoindolin-2-yl)-2-methylbutanoate
(4.03 g, 14.64
mmol) in acetic acid (113 mL) and 6 N HC1 (227 mL) to give a colorless
solution. The
solution was heated at about 135 C for about 24 h. After cooling to RT, a
white precipitate
formed and was removed by vacuum filtration. The filtrate was concentrated
under reduced
pressure, filtered again to remove more solid, and further concentrated to
give a faintly yellow
residue. The residue was purified by ion exchange chromatography (Dowex 8 x 50
w H+
form; rinsed w/deionized water; prepared and loaded with 1 N aqueous HC1;
eluted
sequentially with deionized water followed by 1 M aqueous pyridine solution).
Collection
and evaporation of the appropriate fractions (identified using ninhydrin
stain) gave the
product, 4-amino-2-methylbutanoic acid (1.526 g,, 89 % yield), as a faintly
yellow solid. The
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WO 2011/071570 PCT/US2010/046424
material was used directly in the next step without further purification. 1H
NMR (400 MHz,
D20) 6 3.10 - 2.95 (m, 2H), 2.47 - 2.35 (m, 1H), 1.98 - 1.84 (m, 1H), 1.82 -
1.69 (m, 1H), 1.16
(dd, J = 1.1, 7.0, 3H).
Preparation #82: Preparation of 4-phenyl-5-(trifluoromethyl)thiophene-2-
carboxamide
Step 1
F F F F F F
F S O F S O F S O
OH \ CI I \ I NH2
4-Phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (5 g, 18.37 mmol)
(Maybridge) and
DMF (0.071 mL, 0.918 mmol) were combined in dichloromethane (184 mL) under
nitrogen to
give a colorless solution. Oxalyl chloride (1.768 mL, 20.20 mmol) was added
slowly and then
the reaction stirred for about 5 h. The solvents were removed under reduced
pressure.
Toluene was added and the solvents removed. The residue was taken up in ethyl
acetate (10
mL) and added dropwise to a rapidly stirred mixture of ethyl acetate (150 mL)
and
concentrated ammonium hydroxide (100 mL). The mixture was stirred for 1 h. The
layers
were separated and the aqueous layer extracted with ethyl acetate (50 mL). The
combined
extracts were washed with brine, dried over sodium sulfate, filtered, and
evaporated to a white
solid: LC/MS (Method g) Rt = 2.24 min.; MS m/z: 270.06 (M-H)-, 1H NMR (400
MHz,
DMSO-d6) 6 ppm 8.24 (s, 1H), 7.90-7.87 (m, 1H), 7.80 (s, 1H), 7.52-7.42 (m,
5H)
Step 2
Preparation of 4-phenyl-5-(trifluoromethyl)thiophene-2-carbonitrile
F F F F
F S O F S
I / -N
NH2
4-phenyl-5-(trifluoromethyl)thiophene-2-carboxamide (1.400 g, 5.16 mmol) was
dissolved in
1,2-dichloroethane (51 mL) under nitrogen to give a colorless solution.
Burgess reagent (4.92
g, 20.64 mmol) (Acros) was added and the reaction heated at about 60 C for
about 4 h. The
reaction was allowed to cool to ambient temperature. Methylene chloride (50
mL) and water
(50 mL) were added and the layers separated. The aqueous layer was extracted
with
methylene chloride (1 x 25 mL). The combined extracts were washed with brine,
dried over
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sodium sulfate, filtered, and evaporated to a colorless solid. The residue was
purified by flash
column chromatography (40 g Redi-Sep) eluting with 20-50% ethyl
acetate/heptane and the
product fractions combined. The solvents were removed under reduced pressure
to provide 4-
phenyl-5-(trifluoromethyl)thiophene-2-carbonitrile (1.227 g, 4.85 mmol, 94%
yield) as a
white solid: LC/MS (Method H) Rt = 2.74 min.; 1H NMR (400 MHz, DMSO-d6) 6 ppm
8.27-
8.17 (m, 1H), 7.55-7.40 (m, 6H).
Step 3
Preparation of (Z)-N'-hydroxy-4-phenyl-5-(trifluoromethyl)thiophene-2-
carboximidamide
F F F F
F S F S IN-OH
-N \ I /
NH2
4-Phenyl-5-(trifluoromethyl)thiophene-2-carbonitrile (1.22 g, 4.82 mmol) was
dissolved in
ethanol (48 mL) under nitrogen to give a colorless suspension. Hydroxylamine
(0.947 mL,
19.27 mmol) was added and the reaction heated at about 60 C for about 5 h.
TLC in 1:1
EtOAc/heptane showed (uv light visualization) that the reaction was complete.
The reaction
was allowed to cool to ambient temperature. The solvents were removed under
reduced
pressure. The residue was purified by flash column chromatography (40 g Redi-
Sep column)
eluting with 20-50% ethyl acetate/heptane and the product fractions combined.
The solvents
were removed under reduced pressure to provide (Z)-N'-hydroxy-4 phenyl-5-
(trifluoromethyl)thiophene-2-carboximidamide (1.397 g, 4.88 mmol, 101% yield)
as a white
solid: LC/MS (Method g) Rt = 2.19 min.; MS m/z: 287.08 (M+H) ; 1H NMR (400
MHz,
DMSO) 6 ppm 9.98 (s, 1H), 7.65-7.63 (m, 1H), 7.51-7.41 (m, 5H), 6.15 (s, 2H).
Preparation #83: Preparation of (laS,5aR)-1,1,2-Trimethyl-1,1a,5,5a-tetrahydro-
3-thia-
cyclopropa[a]pentalene-4-carboxylic acid amide
Step 1
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H H H H H H
S I S / S
OH CI NH2
O 0 O
(1 aS,5 aR)-1,1,2-Trimethyl-1,1 a,5,5a-tetrahydro-3-thia-
cyclopropa[a]pentalene-4-carboxylic
acid (0.39 g, 1.754 mmol) (Prepared according to W02006/010379) and DMF (6.79
l, 0.088
mmol) were combined in dichloromethane (17 mL) under nitrogen to give an
orange solution.
Oxalyl chloride (0.169 mL, 1.930 mmol) was added and the reaction stirred for
about 4 h.
The solvents were removed under reduced pressure and the residue dried under
vacuum for
about 30 minutes. The residue was dissolved in ethyl acetate (15 mL).
Concentrated
ammonium hydroxide (10 mL) was added with rapid stirring and the mixture was
stirred for
about 45 min. The layers were separated and the aqueous layer extracted with
ethyl acetate
(15 mL). The combined organic extracts were washed with brine, dried over
sodium sulfate,
filtered, and evaporated to an orange oil. The residue was purified by flash
column
chromatography (40 g Redi-Sep column) eluting with 1:1 EtOAc/heptane and the
product
fractions combined. The solvents were removed under reduced pressure to
provide
(1 aS, 5aR)-1, 1, 2-Trimethyl-1, la, 5, 5a-tetrahydro-3-thia-
cyclopropa[aJpentalene-4-carboxylic
acid amide (0.324 g, 1.464 mmol, 83% yield) as an orange oil: LC/MS (Method g)
Rt = 2.12
min.; MS m/z: 222.12 (M+H)+.
Step 2
Preparation of (1aS,5aR)-1,1,2-Trimethyl-1,la,5,5a-tetrahydro-3-thia-
cyclopropa[a]pentalene-4-carbonitrile
H H H H
S S
NH2 XX
O N
(1 aS,5aR)-1,1,2-Trimethyl-1,1 a,5,5 a-tetrahydro-3-thia-
cyclopropa[a]pentalene-4-carboxylic
acid amide (0.324 g, 1.464 mmol) was dissolved in 1,2-dichloroethane (14 mL)
under
nitrogen to give an orange solution. Burgess reagent (0.698 g, 2.93 mmol)
(Acros) was added
and the reaction stirred for about 18 h. Methylene chloride (20 mL) and water
(15 mL) were
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added and the layers separated. The aqueous layer was extracted with methylene
chloride (1 x
mL). The combined extracts were washed with brine, dried over sodium sulfate,
decanted,
and evaporated to an orange oil. The oil was purified by flash column
chromatography (40 g
Redi-Sep) eluting with 0-10% ethyl acetate/heptane and the product fractions
combined. The
5 solvents were removed under reduced pressure to provide (1 aS, 5aR)-1,1, 2-
Trimethyl-
1,1 a, 5, 5a-tetrahydro-3-thia-cyclopropa[aJpentalene-4-carbonitrile (0.26 g,
1.279 mmol, 87
% yield) as a colorless oil: LC/MS (Method h) Rt = 2.84 min.; MS m/z: 204.09
(M+H)+.
Step 3
10 Preparation of (1aS,5aR)-N-Hydroxy-1,1,2-trimethyl-1,la,5,5a-tetrahydro-3-
thia-
cyclopropa[a] pentalene-4-carboxamidine
H H H H
S
NH2
N N,
OH
(1aS,5aR)-1,1,2-Trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-
carbonitrile
(0.26 g, 1.279 mmol) and hydroxylamine (50% solution in water) (0.302 mL, 5.12
mmol)
were combined in ethanol (12.8 mL) under nitrogen to give a colorless
solution. The mixture
was heated at about 60 C for about 5 h. TLC in 1:1 EtOAc/heptane showed (uv
light
visualization) that the reaction was complete. The solvents were removed under
reduced
pressure. The residue was purified by flash column chromatography (40 g Redi-
Sep column)
eluting with 20-50% ethyl acetate/heptane and the product fractions combined.
The solvents
were removed under reduced pressure to provide (IaS,5aR)-N-Hydroxy-1,1,2-
trimethyl-
1, l a, 5, 5a-tetrahydro-3-thia-cyclopropa[aJpentalene-4-carboxamidine (0.284
g, 1.202 mmol,
94% yield) as a sticky white solid: LC/MS (Method g) Rt = 2.16 min.; MS m/z:
237.09
(M+H)+.
Preparation #84: Preparation of (2R,4R)-1-tert-butyl 2-methyl 4-(4-(3-(3-
chloro-4-
isoprop oxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)pyrrolidine-1,2-
dicarboxylate
Step 1
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WO 2011/071570 PCT/US2010/046424
HZN N-O
N-0 (^1 1 i N I
^
CI N N F HCI `N~'===GO ~pI C
O" O~p 10- p-ll O-
O
3-(3-Chloro-4-isopropoxyphenyl)-5-(4-fluorophenyl)-1,2,4-oxadiazole (0.4 g,
1.202 mmol),
(2R,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate
hydrochloride (0.506 g,
1.803 mmol) (Acesys Pharmatech) , and potassium carbonate (0.498 g, 3.61 mmol)
were
combined in DMSO (4.01 mL) in a sealed vial to give a white suspension. The
mixture was
heated at about 100 C for about 20 h. Ethyl acetate (20 mL) and water (20 mL)
were added
and the layers separated. The ethyl acetate layer was washed with water (2 x
10 mL). The
ethyl acetate layer was washed with brine, dried over sodium sulfate,
filtered, and evaporated
to a yellow oil. The residue was purified by flash column chromatography (40 g
Redi-Sep
column) eluting with 10-50% ethyl acetate/heptane and the product fractions
combined. The
solvents were removed under reduced pressure to provide (2R,4R)-1-tert-butyl 2-
methyl 4-(4-
(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-oxadiazol-5-
yl)phenylamino)pyrrolidine-1, 2-
dicarboxylate (0.085 g, 0.153 mmol, 12.69% yield) as a off-white solid: LC/MS
(Method h)
Rt = 3.10 min.; MS m/z: 557.24 (M+H)+, NMR (400 MHz, ) 6 8.21 (d, J = 2.0,
1H), 8.08 -
7.99 (m, 3H), 7.05 (d, J= 8.7, 1H), 6.75 - 6.66 (m, 2H), 4.75 - 4.63 (m, 1H),
4.41 (dd, J=
8.6, 35.3, 1H), 4.31 - 4.19 (m, 1H), 3.90 - 3.54 (m, 5H), 2.66 - 2.42 (m, 1H),
2.26 - 2.10 (m,
1H), 1.47 (t, J= 12.3, 16H).
Step 2
Preparation of (2R,4R)-1-(tert-butoxycarbonyl)-4-(4-(3-(3-chloro-4-
isopropoxyphenyl)-
1,2,4-oxadiazol-5-yl)phenylamino)pyrrolidine-2-carboxylic acid
N'O N'O
CI I i NHn ICI i
NHn
O O
/gyp I N \ / ==, /gyp I N \ / =
O_p 0- O-.~p
41
(2R,4R)-1-tert-butyl 2-methyl 4-(4-(3 -(3 -chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)pyrrolidine-1,2-dicarboxylate (0.085 g, 0.153 mmol) was
dissolved in a
mixture of THE (2.0 mL) and water (1.0 mL) under nitrogen to give a colorless
solution.
Lithium hydroxide (15 mg, 0.626 mmol) was added and the reaction stirred for
about 48 h.
The solvents were removed under reduced pressure. Ethyl acetate (15 mL) and 1
N HCl (3
mL) were added and the layers separated. The aqueous layer was extracted with
ethyl acetate
(1 x 10 mL). The combined extracts were washed with brine, dried over sodium
sulfate,
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WO 2011/071570 PCT/US2010/046424
filtered, and evaporated to a white solid. The residue was purified by flash
column
chromatography (40 g Redi-Sep column) eluting with 50-100% ethyl
acetate/heptane and the
product fractions combined. The solvents were removed under reduced pressure
to provide
(2R, 4R)-1-(tent-butoxycarbonyl)-4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1, 2, 4-
oxadiazol-5-
yl)phenylamino)pyrrolidine-2-carboxylic acid (0.036 g, 0.066 mmol, 43.4%
yield) as an off-
white solid: LC/MS (Method g) Rt = 2.71 min.; MS m/z: 543.15 (M+H)+, NMR (400
MHz, )
6 8.21 (d, J= 1.6, 1H), 8.08 - 7.98 (m, 3H), 7.05 (d, J= 8.6, 1H), 6.63 (d, J=
8.5, 2H), 4.76 -
4.64 (m, 1H), 4.59 (d, J = 8.8, 1H), 4.28 - 4.17 (m, 1H), 3.68 - 3.46 (m, 2H),
2.73 (d, J =
13.4, 1H), 2.50 - 2.36 (m, 1H), 1.53 (s, 9H), 1.50 (m, obscured, 1 H), 1.45
(d, J= 6.0, 6H).
Example #88: (2R,4R)-4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-
yl)phenylamino)pyrrolidine-2-carboxylic acid
N-O N-O
CI ~ NH CI
I IIZ~Z N NH
Nn
N
OH H OH
O O
(2R,4R)-1-(tent-butoxycarbonyl)-4-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)pyrrolidine-2-carboxylic acid (0.036 g, 0.066 mmol) was
dissolved in
dichloromethane (0.663 mL) under nitrogen to give a colorless solution.
Trifluoroacetic acid
(0.663 mL) was added and the reaction stirred for about 18 h. The solvents
were removed
under reduced pressure. The residue was purified by flash column
chromatography (4 g Redi-
sep) eluting with 1:1 EtOAc/(6:3:1 CHC13/MeOH/NH4OH) and the product fractions
combined. The solvents were removed under reduced pressure. Ether was added
and the
resulting solid was collected by vacuum filtration and washed with ether to
provide (2R, 4R)-4-
(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5
yl)phenylamino)pyrrolidine-2-
carboxylic acid (0.043 g, 0.097 mmol, quantitative yield) as a white solid on
drying under
vacuum at 55 C: LC/MS (Method g) Rt = 2.00 min.; MS m/z: 443.11 (M+H) ; 1H
NMR
(400 MHz, DMSO) 6 ppm 8.00-7.95 (m, 1H), 7.95-7.89 (m, 1H), 7.86 (d, J = 8.41
Hz, 2H),
7.33 (d, J = 8.58 Hz, 1H), 6.86 (d, J = 6.34 Hz, 1H), 6.72 (d, J = 6.34 Hz,
2H), 4.84-4.72 (m,
1H), 4.19-4.08 (m, 1H), 3.81 (t, J = 8.15 Hz, 1H), 3.47-3.39 (m, 1H), 3.13-
3.06 (m, 1H), 2.62-
2.51 (m, 1H), 1.96-1.85 (m, 1H), 1.33 (d, J = 5.81 Hz, 6H).
Preparation #85: Preparation of methyl 5-chloro-6-hydroxynicotinate
Step 1
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WO 2011/071570 PCT/US2010/046424
O O
CI CI
OH O
HO N HO I N
5-Chloro-6-hydroxynicotinic acid (10.2 g, 58.8 mmol) (Alfa Aesar) was
dissolved in methanol
(102 mL) under nitrogen to give a white suspension. Sulfuric acid (15.66 mL,
294 mmol) was
added dropwise (exotherm observed) and the reaction heated at about 65 C for
about 6 h.
The reaction was cooled to about ambient temperature and stirred overnight.
The resulting
solid was collected by vacuum filtration and washed with methanol (2 x 10 mL)
and ether (2 x
mL) to provide methyl 5-chloro-6-hydroxynicotinate (8.911 g, 47.5 mmol, 81%
yield) as a
white solid on drying under vacuum at 60 C: LC/MS (Method g) Rt = 1.45 min.;
MS m/z:
10 188.00 (M+H)+, 1H NMR (400 MHz, CDC13) 6 ppm 12.71 (s, 1H), 8.06-8.03 (m,
1H), 8.00-
7.98 (m, 1H), 3.76 (s, 3H)
Step 2
Preparation of methyl 5-chloro-6-isopropoxynicotinate
O O
CI Oi CI &N-
Methyl O15 HO N O 5-chloro-6-hydroxynicotinate (8.91 g, 47.5 mmol) and 2-iodo-
propane (7.12 mL, 71.2
mmol) were combined in toluene (202 mL) under nitrogen to give a colorless
solution. Silver
carbonate (19.65 g, 71.2 mmol) was added and the reaction heated at about 60
C for about 4
h. TLC in 1:1 EtOAc/heptane showed (uv light visualization) that the reaction
was not yet
complete. The temperature was reduced to about 50 C and the reaction stirred
for about an
additional 16 h. The reaction was allowed to cool to ambient temperature. The
mixture was
filtered through a buchner funnel and washed through with ethyl acetate. The
solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography
(120 g Redi-Sep column) eluting with 5% ethyl acetate/heptane and the product
fractions
combined. The solvents were removed under reduced pressure to provide methyl 5-
chloro-6-
isopropoxynicotinate (10.539 g, 45.9 mmol, 97% yield) as a colorless oil that
solidified under
vacuum to a white solid: LC/MS (Method g) Rt = 2.84 min.; MS m/z: 230.05 (M+H)
; 1H
NMR (400 MHz, CDC13) 6 ppm 8.71 (d, J = 2.02 Hz, 1H), 8.22 (d, J = 1.93 Hz,
1H), 5.53-
5.42 (m, 1H), 3.94 (s, 3H), 1.44 (d, J = 6.20 Hz, 6H).
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WO 2011/071570 PCT/US2010/046424
Step 3
Preparation of 5-chloro-6-isopropoxynicotinamide
O O
CI &N~ O/ CI I NH2
O ~O N
Methyl 5-chloro-6-isopropoxynicotinate (5.19 g, 22.60 mmol) was stirred in
ammonia (7 M in
methanol) (75 mL, 525 mmol) in a pressure vessel (with relief valve) to give a
white
suspension. The mixture was heated at about 60 C for about 48 h. The reaction
was cooled
to about 0-5 C in an ice bath and the reaction vessel opened. The solvents
were removed
under reduced pressure. The resulting white solid was taken up in water (100
mL) and stirred
rapidly for about 2 h. The resulting solid was collected by vacuum filtration
and washed with
water and then pentane to provide 5-chloro-6-isopropoxynicotinamide (4.45 g,
20.73 mmol,
92% yield) as a white solid: LC/MS (Method g) Rt = 1.91 min.; MS m/z: 215.04
(M+H),
NMR (400 MHz, ) 6 8.58 (d, J = 2.2, 1H), 8.24 (d, J = 2.2, 1H), 8.00 (s, 1H),
7.48 (s, 1H),
5.42 - 5.27 (m, 1H), 1.32 (d, J= 6.2, 6H).
Step 4
Preparation of 5-chloro-6-isopropoxynicotinonitrile
O
N
CI CI
NH2 ,J\ J
o &N' O N
5-Chloro-6-isopropoxynicotinamide (6 g, 28.0 mmol) was dissolved in 1,2-
dichloroethane
(140 mL) under nitrogen to give a white suspension. Burgess reagent (13.32 g,
55.9 mmol)
(Alfa Aesar) was added and the reaction stirred for about 16 h. As the
reaction progressed all
the solids dissolved (within an hour or two). The solvents were removed under
reduced
pressure. The residue was purified by flash column chromatography (80 g Redi-
Sep column)
eluting with 10% ethyl acetate/heptane and the product fractions combined. The
solvents
were removed under reduced pressure to provide 5-chloro-6-
isopropoxynicotinonitrile (5.36
g, 27.3 mmol, 98% yield) as a white solid: LC/MS (Method g) Rt = 2.60 min.; MS
m/z:
196.07 (M+H)+, 1H NMR (400 MHz, DMSO) 6 ppm 8.63 (d, J = 2.03 Hz, 1H), 8.45
(d, J =
2.04 Hz, 1H), 5.41-5.31 (m, 1H), 1.33 (d, J = 6.17 Hz, 6H)
Step 5
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WO 2011/071570 PCT/US2010/046424
Preparation of (Z)-5-chloro-N'-hydroxy-6-isopropoxynicotinimidamide
iiN ' OH
CI
CI
NH2
O N "~O N
5-Chloro-6-isopropoxynicotinonitrile (5.36 g, 27.3 mmol) was dissolved in
ethanol (136 mL)
under nitrogen to give a colorless solution. Hydroxylamine (50% in water)
(6.43 mL, 109
mmol) was added and the reaction heated at about 60 C for about 3 h. TLC in
1:1
EtOAc/heptane showed (uv light visualization) that the reaction was complete.
The reaction
was concentrated under vacuum to a thick, colorless oil. Heptane was added to
give a
biphasic system. The oil was seeded with previously made product and
crystallization formed
a heavy precipitate. The precipitate was collected by vacuum filtration and
washed with
heptane. The mother liquor contained more product that precipitated. The
mother liquor was
concentrated, heptane added, and seeded to give a second crop. The crops
looked the same by
TLC and were combined to give (Z)-5-chloro-N'-hydroxy-6-
isopropoxynicotinimidamide
(6.108 g, 26.6 mmol, 98% yield) as a white solid on drying under vacuum at
about 60 C over
phosphorous pentoxide: LC/MS (Method g) Rt = 1.89 min.; MS m/z: 230.05 (M+H),
1H
NMR (400 MHz, DMSO) 6 = 9.71 (s, 1H), 8.36 (d, J=2.1, 1H), 8.02 (d, J=2.1,
1H), 5.91 (s,
2H), 5.37 - 5.24 (m, 1H), 1.31 (d, J=6.2, 6H).
Example #89: 2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-
5-
yl)phenylamino)p rop an-l -ol
Step 1
Preparation of N-(1-(benzyloxy)propan-2-yl)-4-(3-(4-isopropoxy-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)aniline
F N-O F N'O H
' N 7 0 /
F N \ F HZN O F N
O
O
5-(4-Fluorophenyl)-3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazole
(1.794 g,
4.90 mmol), 1-(benzyloxy)propan-2-amine (0.890 g, 5.39 mmol), and potassium
carbonate
(1.489 g, 10.77 mmol) were combined in DMSO (17 mL) and water (1.4 mL) under
nitrogen
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to give a white suspension. The mixture was heated at about 110 C for about
72 h. TLC in
1:1 EtOAc/heptane showed (uv light visualization) slow conversion to a more
polar spot. The
reaction was allowed to cool to ambient temperature. Ethyl acetate (75 mL) and
water (50
mL) were added and the layers separated. The ethyl acetate was washed with
water (2 x 25
mL). The combined extracts were washed with brine, dried over sodium sulfate,
filtered, and
evaporated to an off-white solid. This mixture was transferred to a microwave
vial and 2
equivalents of the amine added (1.9 g). DMSO (15 mL) and water (1.2 mL) were
added and
the vial capped. The reaction was heated in a Biotage microwave (heating with
cooling) at
about 180 C for about 30 minutes. TLC showed better progress toward product.
Heating for
about an additional 30 minutes gave approximately 50% conversion as judged by
TLC. The
reaction was heated for about an additional 60 minutes. The reaction was
poured into water
(50 mL) and ethyl acetate (150 mL). The ethyl acetate was washed with water (2
x 50 mL).
The ethyl acetate was washed with brine, dried over sodium sulfate, filtered,
and evaporated
to a brown oil. With the aid of a small amount of methylene chloride the oil
was transferred
onto a column and was purified by flash column chromatography (80 g Redi-Sep
column)
eluting with 10-40% ethyl acetate/heptane and the product fractions combined.
The solvents
were removed under reduced pressure to provide N-(1-(benzyloxy)propan-2-yl)-4-
(3-(4-
isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5 yl)aniline (1.475 g,
2.88 mmol,
58.9% yield) as an orange oil: LC/MS (Method g) Rt = 3.75 min.; MS m/z: 512.14
(M+H);
1H NMR (400 MHz, CDC13) 6 = 8.39 (s, 1H), 8.27 (d, J=8.7, 1H), 8.02 (d, J=8.6,
2H), 7.43 -
7.30 (m, 5H), 7.12 (d, J=8.8, 1H), 6.68 (d, J=8.7, 2H), 4.82 - 4.70 (m, 1H),
4.59 (s, 2H), 4.43
(d, J=8.0, 1H), 3.88 - 3.76 (m, 1H), 3.57 (d, J=4.6, 2H), 1.44 (d, J=6.0, 6H),
1.33 (d, J=6.5,
3H).
Step 2
Preparation of 2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenylamino)p rop an-l -ol
F N' H F N-O H
F N~ I FI ~~ N I N
F O OH
N-(1-(benzyloxy)propan-2-yl)-4-(3-(4-isopropoxy-3 -(trifluoromethyl)phenyl)-
1,2,4-
oxadiazol-5-yl)aniline (1.111 g, 2.172 mmol) was dissolved in dichloromethane
(145 mL)
under nitrogen to give a colorless solution. The reaction was cooled to about
0-5 C in an ice
bath. A solution of boron tribromide (1.0 M in dichloromethane) (4.34 mL, 4.34
mmol) was
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added slowly and the reaction stirred for about 30 min. TLC in 1:1
EtOAc/heptane showed
(uv light visualization) reaction complete having formed a more polar spot.
The reaction was
quenched by addition of 1 N HCl (10 mL). The cooling was removed and the
reaction stirred
for about 30 min. Saturated sodium bicarbonate (30 mL) was added and the
layers separated.
The aqueous layer was extracted with methylene chloride (1 x 30 mL). The
combined
extracts were washed with brine, dried over sodium sulfate, filtered, and
evaporated to a
yellow/tan solid. The residue (dissolved in methylene chloride) was purified
by flash column
chromatography (40 g Redi-Sep column) eluting with 20-60% ethyl
acetate/heptane and the
product fractions combined. The solvents were removed under reduced pressure.
Pentane
was added and the solid scraped from the sides of the flask. The resulting
solid was collected
by vacuum filtration and washed with pentane to provide 2-(4-(3-(4-isopropoxy-
3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5 yl)phenylamino)propan-l-ol (0.771
g, 1.830
mmol, 84 % yield) as a white solid on drying under vacuum at about 70 C over
phosphorous
pentoxide: LC/MS (Method g) Rt = 2.95 min.; MS m/z: 422.14 (M+H) ; 1H NMR (400
MHz,
DMSO) 6 = 8.24 (dd, J=2.1, 8.8, 1H), 8.17 (d, J=2.1, 1H), 7.85 (d, J=8.8, 2H),
7.49 (d, J=8.9,
1H), 6.73 (d, J=8.9, 2H), 6.52 (d, J=7.9, 1H), 4.97 - 4.81 (m, 1H), 4.76 (t,
J=5.6, 1H), 3.62 -
3.49 (m, 1H), 3.49 - 3.40 (m, 1H), 3.36 - 3.30 (m, 1H), 1.32 (d, J=6.0, 6H),
1.14 (d, J=6.4,
3H).
Example #90: (R)-2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenoxy)propanoic acid
Step 1
Preparation of (R)-benzyl 4-(1-ethoxy-l-oxopropan-2-yloxy)benzoate
O
O
I~ HO o ~ ~
OH
0
Benzyl 4-hydroxybenzoate (10 g, 43.8 mmol), (S)-ethyl 2-hydroxypropanoate
(6.21 g, 52.6
mmol), and triphenylphosphine (14.36 g, 54.8 mmol) were combined in
tetrahydrofuran (110
mL) under nitrogen to give a colorless solution. Molecular sieves 4A beads (4-
8 mesh) (5 g)
were added and the reaction stirred for about 30 min. The reaction was cooled
to about 0-5 C
in an ice bath. Di-tertbutylazodicarboxylate (12.61 g, 54.8 mmol) was added
(exotherm
observed) and the reaction stirred for about 18 h. TLC in 1:1 EtOAc/heptane
showed (uv light
visualization) that the reaction was complete. The mixture was filtered
through Celite and
washed through with ethyl acetate. The solvents were removed under reduced
pressure.
Heptane was added and the sides scraped to induce crystallization of
triphenylphosphine oxide
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and reduced di-tertbutylazodicarboxylate. The flask was swirled until a thick
precipitate had
formed. After standing overnight the solids were removed by vacuum filtration
and the solid
washed with heptane until no further product eluted as judged by TLC. The
solvents were
removed under reduced pressure. The residue was purified by flash column
chromatography
(120 g Redi-Sep column) eluting with 10-20%ethyl acetate/heptane and the
product fractions
combined. The product fractions were concentrated to provide (R)-benzyl 4-(1-
ethoxy-l -
oxopropan-2-yloxy)benzoate (16.3 g, 49.6 mmol, 113% yield) as a colorless oil:
LC/MS
(Method g) Rt = 2.83 min.; MS m/z: 329.15 (M+H) ; 1H NMR (400 MHz, CDC13) 6
8.05 (d,
J= 8.9, 2H), 7.60 - 7.21 (m, 5H), 6.91 (d, J= 8.8, 2H), 5.36 (s, 2H), 4.84 (q,
J= 6.8, 1H), 4.24
(q, J= 7.1, 2H), 1.67 (d, J= 6.8, 3H), 1.27 (t, J= 7.1, 3H).
Step 2
Preparation of (R)-4-(1-ethoxy-l-oxopropan-2-yloxy)benzoic acid
0
0
N~Z N~ = ~ HO
o~ 0~
o
(R)-benzyl 4-(1-ethoxy-l-oxopropan-2-yloxy)benzoate (14.39 g, 43.8 mmol) was
dissolved in
methanol (438 mL). Palladium hydroxide on carbon (20%) (3.08 g, 4.38 mmol) was
added,
the reaction was flushed with hydrogen, and hydrogenated at atmospheric
pressure for about 3
h. TLC in 1:1 EtOAc/heptane showed (uv light visualization) that the reaction
was complete.
The reaction was flushed with nitrogen. The mixture was filtered through
Celite and washed
through with methanol. The solvents were removed under reduced pressure. Ethyl
acetate
was added and the solvents removed again to remove any remaining methanol
providing a
white solid. Heptane was added and the solid scraped from the sides of the
flask. The
resulting solid was collected by vacuum filtration and washed with heptane to
provide (R)-4-
(1-ethoxy-l-oxopropan-2-yloxy)benzoic acid (8.83 g, 37.1 mmol, 85% yield) as a
white solid:
LC/MS (Method g) Rt = 1.88 min.; MS m/z: 237.08 (M+H)+, 1H NMR (400 MHz, DMSO)
6
12.67 (m, 1H), 7.85 (d, J = 8.9, 2H), 6.94 (d, J = 8.9, 2H), 5.06 (d, J = 6.8,
1H), 4.13 (q, J =
7.1, 2H), 1.51 (d, J= 6.8, 3H), 1.15 (t, J= 7.1, 3H).
Step 3
Preparation of (R)-ethyl 2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-
1,2,4-
oxadi azol-5-yl)phenoxy)p rop anoate
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O F F NOH F F N'O
11 i O O
HO F
O0\/ F / NHZ
O O-\
O
O
(R)-4-(1-ethoxy-l-oxopropan-2-yloxy)benzoic acid (1 g, 4.20 mmol) and HOBt
(0.884 g, 4.62
mmol) were combined in methylene chloride (20.99 mL) under nitrogen to give a
white
suspension. EDC (0.885 g, 4.62 mmol) was added and the reaction stirred for
about 4 h. TLC
in 1:1 EtOAc/heptane showed (uv light visualization) a less polar spot had
formed.
Methylene chloride (20 mL) and water (20 mL) were added and the layers
separated. The
methylene chloride was washed with water (2 x 15 mL). The combined extracts
were washed
with brine, dried over sodium sulfate, filtered, and evaporated to a white
solid. The solid was
dissolved in DMF (20 mL) and (Z)-N-hydroxy-4-isopropoxy-3-
(trifluoromethyl)benzimidamide (1.101 g, 4.20 mmol) was added. The reaction
was heated at
about 60 C for about 72 h. TLC showed formation of an intermediate spot and a
non-polar
spot. LC/MS showed this to be the uncyclized intermediate and the oxadiazole
product. The
reaction temperature was increased to about 90 C and the reaction progressed
more rapidly.
A further increase to about 110 C for about 4 h completed the reaction. The
reaction was
cooled to ambient temperature and poured into water (about 200 mL). The
aqueous mixture
was extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate
extracts were
washed with 5% lithium chloride solution (3 x 30 mL). The ethyl acetate was
then washed
with brine, dried over sodium sulfate, filtered and evaporated. The resulting
residue was
purified by flash column chromatography (80 g Redi-sep column) eluting with
ethyl
acetate/heptane and the product fractions combined. The solvents were removed
under
reduced pressure to provide (R)-ethyl 2-(4-(3-(4-isopropoxy-3-
(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-yl)phenoxy)propanoate (1.373 g, 2.96 mmol, 70.4%) as an off white
solid:
LC/MS (Method g) Rt = 3.50 min.; MS m/z: 465.15 (M+H)+, 1H NMR (400 MHz,
CDC13) 6
8.40 (s, I H), 8.28 (d, J = 8.7, I H), 8.18 (d, J = 7.7, 2H), 7.13 (d, J =
8.6, I H), 7.04 (d, J = 7.8,
2H), 4.89 (dd, J= 6.7, 13.5, 1H), 4.83 - 4.70 (m, 1H), 4.28 (q, J= 7.1, 2H),
1.71 (d, J= 5.8,
3H), 1.45 (d, J= 4.9, 6H), 1.30 (t, J= 7.1, 3H).
Step 4
Preparation of (R)-2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenoxy)propanoic acid
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F' F N-0)
0O F N-
F O
F O O
F \ N
O I OH
(R)-ethyl 2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)propanoate (0.5 g, 1.077 mmol) was dissolved in ethanol (10 mL)
open to the air
to give a white suspension. Sodium hydroxide (1 M) (2.153 mL, 2.153 mmol) was
added and
the reaction stirred for about 2 h. The starting material was not very
soluble. Tetrahydrofuran
(5 mL) was added and the reaction sonicated. All the material dissolved and
the reaction
stirred for about an additional 30 min. TLC in 1:1 EtOAc/heptane showed (uv
light
visualization) that the reaction was complete. The solvents were removed under
reduced
pressure. 1 N HCl (2.5 mL) was added and the aqueous layer was extracted with
ethyl acetate
(2 x 10 mL). The combined extracts were washed with brine, dried over sodium
sulfate,
filtered, and evaporated to a white solid. The residue was purified by flash
column
chromatography (40 g Redi-Sep column) eluting with 5-10% methanol in methylene
chloride
and the product fractions combined. The solvents were removed under reduced
pressure to
provide (R)-2-(4-(3-(4-isopropoxy-3-(trfuoromethyl)phenyl)-1, 2, 4-oxadiazol-5-
yl)phenoxy)propanoic acid (0.286 g, 0.655 mmol, 60.9% yield) as a white solid
on drying
under vacuum at about 60 C: LC/MS (Method g) Rt = 2.31 min.; MS m/z: 437.11
(M+H)
1H NMR (400 MHz, DMSO) 6 13.16 (s, OH), 8.26 (dd, J = 2.1, 8.8, 1H), 8.19 (d,
J = 2.1,
1H), 8.11 (d, J = 8.9, 2H), 7.51 (d, J = 8.9, 1H), 7.11 (d, J = 9.0, 2H), 5.02
(q, J = 6.7, 1H),
4.96 - 4.85 (m, 1H), 1.54 (d, J= 6.8, 3H), 1.32 (d, J= 6.0, 6H).
Example #91: (R)-N-(2-hydroxyethyl)-2-(4-(3-(4-isopropoxy-3-
(trifluoromethyl)phenyl)-
1,2,4-oxadiazol-5-yl)phenoxy)p rop anamide
F N-O \/ O F N'O
F O F O O
F N F I\ N ~-U
O OH O HN--\-OH
(R)-2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)propanoic acid (0.05 g, 0.115 mmol) and HOBT (0.021 g, 0.115 mmol)
were
combined in dichloromethane (2.29 mL) in a sealed vial to give a colorless
solution. EDC
(0.022 g, 0.115 mmol) was added and the reaction stirred for about 30 min.
Ethanolamine (30
l, 0.496 mmol) was added and the reaction stirred for about 30 min. TLC in
EtOAc showed
(uv light visualization) that the reaction was complete. Methylene chloride (5
mL) and water
(5 mL) were added and the layers separated. The methylene chloride was washed
with 1 N
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HCl (1 x 5 mL). The methylene chloride was washed with brine, dried over
sodium sulfate,
filtered, and evaporated to a colorless oil. The residue was purified by flash
column
chromatography (40 g Redi-Sep column) eluting with 50-80% ethyl
acetate/heptane and the
product fractions combined. The solvents were removed under reduced pressure.
The residue
was triturated with pentane and the resulting solid was collected by vacuum
filtration and
washed with pentane to provide (R)-N-(2-hydroxyethyl)-2-(4-(3-(4-isopropoxy-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5 yl)phenoxy)propanamide (0.043 g,
0.090 mmol,
78% yield) as a white solid: LC/MS (Method g) Rt = 2.64 min.; MS m/z: 480.17
(M+H) ; 1H
NMR (400 MHz, DMSO) 6 8.27 (dd, J= 2.1, 8.8, 1H), 8.22 - 8.18 (m, 1H), 8.15
(t, J= 5.9,
1H), 8.13 - 8.09 (m, 1H), 7.56 - 7.46 (m, 1H), 7.19 - 7.11 (m, 2H), 4.96 -
4.84 (m, 2H), 4.67
(q, J = 5.4, 1H), 3.42 - 3.33 (m, 2H), 3.20 - 3.11 (m, 2H), 1.46 (d, J = 6.6,
3H), 1.32 (d, J =
6.0, 6H).
Example #92: (1R,3S)-3-(4-(5-(5-bromo-6-isopropoxypyridin-3-yl)-1,2,4-
oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid
Step 1
Preparation of methyl 5-bromo-6-hydroxynicotinate
0 O
Br OH Br rN
OHO N HO 20
5-Bromo-6-hydroxynicotinic acid (4.9 g, 22.48 mmol) (Combi-Blocks) was stirred
in
methanol (39.0 mL) under nitrogen to give a off-white suspension. Sulfuric
acid (5.99 mL,
112 mmol) was added slowly and the reaction heated at about 60 C for about 20
h. The
reaction was allowed to cool to ambient temperature. The resulting solid was
collected by
vacuum filtration and washed with methanol and then ether to provide methyl 5-
bromo-6-
hydroxynicotinate (4.041 g, 17.42 mmol, 77% yield) as a off-white solid on
drying under
vacuum at 50 C: LC/MS (Method g) Rt = 1.55 min.; MS m/z: 233.95 (M+H) ; 1H
NMR
(400 MHz, DMSO) 6 12.66 (s, 1H), 8.16 (d, J= 2.4, 1H), 8.07 (d, J= 2.4, 1H),
3.76 (s, 3H).
Step 2
Preparation of methyl 5-bromo-6-isopropoxynicotinate
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O O
B r O/ Br I Oi
O N
r )"
HO N
Methyl 5-bromo-6-hydroxynicotinate (4 g, 17.24 mmol) and 2-iodopropane (2.58
mL, 25.9
mmol) (Alfa Aesar) were combined in toluene (73 mL) and equipped with a reflux
condensor
under nitrogen to give a white suspension. Silver carbonate (7.13 g, 25.9
mmol) (Alfa Aesar)
was added and the reaction heated at about 60 C for about 24 h. The mixture
was filtered
through Celite and washed through with ethyl acetate until no further product
came out as
judged by TLC. The solvents were removed under reduced pressure to provide
methyl 5-
bromo-6-isopropoxynicotinate (4.809 g, 17.54 mmol, 102% yield) as a white
solid: LC/MS
(Method g) Rt = 2.92 min.; MS m/z: 274.00, 276.00 (M+H)+, 1H NMR (400 MHz,
DMSO) 6
8.67 (d, J= 2.1, 1H), 8.35 (d, J= 2.1, 1H), 5.42 - 5.30 (m, 1H), 3.83 (s, 3H),
1.33 (d, J= 6.2,
6H).
Step 3
Preparation of 5-bromo-6-isopropoxynicotinic acid
0 O
Br 177 O OH
BrO
O N
Methyl 5-bromo-6-isopropoxynicotinate (4.8 g, 17.51 mmol) and sodium hydroxide
(1.401 g,
35.0 mmol) were combined in methanol (31 mL) and water (3.5 mL) under nitrogen
to give a
cloudy colorless solution. The mixture was heated at about 50 C for about 6
h. The reaction
was allowed to cool to ambient temperature. The solvents were removed under
reduced
pressure. The residue was dissolved in water. The mixture was acidified to
about pH = 1 with
1 N HCl causing a thick white precipitate to form. The resulting solid was
collected by
vacuum filtration and washed with water to provide 5-bromo-6-
isopropoxynicotinic acid
(4.155 g, 15.98 mmol, 91% yield) as a white solid on drying under vacuum at
about 50 C
over phosphorous pentoxide: LC/MS (Method g) Rt = 1.92 min.; MS m/z: 257.98,
259.97
(M-H)-; 1H NMR (400 MHz, DMSO) 6 13.26 (s, 1H), 8.65 (d, J= 2.0, 1H), 8.31 (d,
J= 2.1,
1H), 5.35 (dt, J= 6.2, 12.4, 1H), 1.33 (d, J= 6.2, 6H).
Step 4
Preparation of (1R,3S)-ethyl 3-(4-(5-(5-bromo-6-isopropoxypyridin-3-yl)-1,2,4-
oxadiazol-3-yl)phenylamino)cyclopentanecarboxylate
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O
HO-N pN
Br OH H NH Br N NH
ZN
O N 0
==,~j0 ~O N a=.,~0
O-\ O--\
5-Bromo-6-isopropoxynicotinic acid (0.1 g, 0.384 mmol), HOBt (0.081 g, 0.423
mmol), and
molecular sieves 4A (4-8 mesh beads) (0.5 g) were combined in DMF (1.922 mL)
under
nitrogen to give a colorless suspension. EDC (0.081 g, 0.423 mmol) and N,N-
Diisoproplylethylamine (0.074 mL, 0.423 mmol) were added and the reaction
stirred for about
30 min. (1R,3S)-ethyl 3-(4-((Z)-N-
hydroxycarbamimidoyl)phenylamino)cyclopentanecarboxylate (0.101 g, 0.346 mmol)
was
added and the reaction heated at about 100 C for about 6 h. Ethyl acetate (15
mL) and water
(10 mL) were added and the layers separated. The ethyl acetate was washed with
water (2 x 5
mL). The combined extracts were washed with brine, dried over sodium sulfate,
filtered, and
evaporated to a brown oil. The residue was purified by flash column
chromatography (40 g
Redi-Sep) eluting with 10-20% ethyl acetate/heptane and the product fractions
combined.
The solvents were removed under reduced pressure to provide (IR,3S)-ethyl 3-(4-
(5-(5-
bromo-6-isopropoxypyridin-3 yl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylate
(0.023 g, 0.045 mmol, 11.6% yield): LC/MS (Method g) Rt = 3.94 min.; MS m/z:
515.11,
517.11 (M+H)+, 1H NMR (400 MHz, DMSO) 6 8.89 (d, J = 2.1, 1H), 8.60 (d, J =
2.1, 1H),
7.77 (d, J= 8.6, 2H), 6.68 (d, J= 8.7, 2H), 6.41 (d, J= 6.7, 1H), 5.47 - 5.35
(m, 1H), 4.05 (dd,
J= 7.1, 14.2, 2H), 3.87 - 3.75 (m, 1H), 2.89 - 2.76 (m, 1H), 2.38 - 2.28 (m,
1H), 2.06 - 1.94
(m, 1H), 1.88 (dd, J = 7.6, 15.2, 2H), 1.69 - 1.59 (m, 1H), 1.58 - 1.47 (m,
1H), 1.36 (d, J =
6.2, 6H), 1.15 (t, J= 7.1, 3H).
Step 5
Preparation of (1R,3S)-3-(4-(5-(5-bromo-6-isopropoxypyridin-3-yl)-1,2,4-
oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid
O_N NH p-N
r N Br NH
N
O N =, O I i a., O
O N
O-\ OH
(1R,3S)-Ethyl 3-(4-(5-(5-bromo-6-isopropoxypyridin-3-yl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylate (0.023 g, 0.045 mmol) was dissolved in
ethanol
(0.446 mL) in a sealed vial to give a white suspension. A solution of sodium
hydroxide (1 M)
(0.179 mL, 0.179 mmol) was added in one portion and the reaction stirred for
about 4 h. THE
(1 mL) was added and the reaction cleared. LC/MS indicated that the reaction
was complete.
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The solvents were removed under reduced pressure. The residue was dissolved in
water
(about 3 mL) and 1 N HC1 (0.2 mL) was added with rapid stirring causing a
white precipitate
to form. The mixture was stirred for about 1 h to ensure complete
precipitation. The resulting
solid was collected by vacuum filtration and washed with water and pentane to
provide
(JR,3S)-3-(4-(5-(5-bromo-6-isopropoxypyridin-3 yl)-1,2,4-oxadiazol-3-
yl)phenylamino)cyclopentanecarboxylic acid (0.02 g, 0.041 mmol, 92% yield) as
an off-white
solid on drying under vacuum at 50 C over phosphorous pentoxide: LC/MS
(Method g) Rt =
3.14 min.; MS m/z: 487.1 (M+H) ; 1H NMR (400 MHz, DMSO) 6 12.03 (s, 1H), 8.89
(d, J=
2.1, 1H), 8.60 (d, J = 2.1, 1H), 7.77 (d, J = 8.6, 2H), 6.68 (d, J = 8.7, 2H),
6.41 (d, J = 6.6,
1H), 5.46 - 5.34 (m, 1H), 3.86 - 3.74 (m, 1H), 2.81 - 2.70 (m, 1H), 2.38 -
2.26 (m, 1H), 2.06 -
1.92 (m, 1H), 1.86 (dd, J= 7.6, 15.2, 2H), 1.71 - 1.57 (m, 1H), 1.57 - 1.46
(m, 1H), 1.36 (d, J
= 6.2, 6H).
Example #93: Preparation of (R)-2-(4-(3-(4-isopropoxy-3-
(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-yl)phenoxy)propanal
Step 1 F F
F
OiO O F~ _ LI OiO F~ _ LI OiO F F ~-.-~/ F \ N F \ N
IO ' O~ OH O
(R)-ethyl 2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)propanoate (0.608 g, 1.309 mmol) was dissolved in tetrahydrofuran
(13.09 mL)
under nitrogen to give a colorless solution. The reaction was cooled to about
0-5 C in an ice
bath. A solution of lithium aluminum hydride (2 M in THF) (1.309 mL, 2.62
mmol) was
added dropwise and the reaction stirred for about 30 min. TLC in 1:1
EtOAc/heptane showed
(uv light visualization) conversion to a more polar spot. The reaction was
quenched by
addition of water (100 uL) and the reaction stirred for about 15 min. 10% NaOH
(300 uL)
was added and the reaction stirred for about 30 minutes. Water (100 L) was
added and the
reaction stirred for about 30 min. The mixture was filtered through Celite
and washed
through with ethyl acetate. The solution was then dried over sodium sulfate,
filtered and
concentrated. The residue was dissolved in dichloromethane (13.09 mL). Dess-
Martin
periodinane (1.111 g, 2.62 mmol) was added and the reaction stirred for about
5 h. The
reaction was quenched by addition of saturated sodium bicarbonate (1 mL) and
methylene
chloride (5 mL). The layers were separated. The aqueous layer was extracted
with
methylene chloride (1 x 2 mL). The combined extracts were washed with brine,
dried over
sodium sulfate, filtered, and evaporated to a colorless oil. The residue was
purified by flash
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column chromatography (40 g Redi-Sep column) eluting with 20-40% ethyl
acetate/heptane
and the product fractions combined. The solvents were removed under reduced
pressure to
provide (R)-2-(4-(3-(4-isopropoxy-3-(trfuoromethyl)phenyl)-1, 2, 4-oxadiazol-5-
yl)phenoxy)propanal (0.281 g, 0.668 mmol, 51.1% yield) as a off-white solid:
LC/MS
(Method g) Rt = 2.77 min.; MS m/z: 439.14 (M+H2O) ; 1H NMR (400 MHz, DMSO) 6
9.68
(s, 1H), 8.26 (dd, J= 2.0, 8.8, 1H), 8.19 (d, J= 2.0, 1H), 8.11 (d, J= 8.8,
2H), 7.50 (d, J= 8.9,
1H), 7.19 (d, J = 8.8, 2H), 5.23 (q, J = 7.0, 1H), 4.96 - 4.85 (m, 1H), 1.46
(d, J = 7.0, 3H),
1.32 (d, J= 6.0, 6H).
Step 2
Preparation of (R,E)-ethyl 4-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-
1,2,4-
oxadi azol-5-yl)phenoxy)-2-methylpent-2-enoate
F F N O)O
F F N'O O
F N F O
O O
(R)-2-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)propanal
(0.281 g, 0.668 mmol) was dissolved in dichloromethane (6.68 mL) under
nitrogen to give a
colorless solution. Ethyl 2-(triphenylphosphoranylidene)propionate (0.266 g,
0.735 mmol)
was added and the reaction stirred for about 18 h. The solvents were removed
under reduced
pressure. The residue was purified by flash column chromatography (40 g Redi-
Sep column)
eluting with 20-40% ethyl acetate/heptane and the product fractions combined.
The solvents
were removed under reduced pressure to provide (R,E)-ethyl 4-(4-(3-(4-
isopropoxy-3-
(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)phenoxy)-2-methylpent-2-enoate
(0.281 g, 0.557
mmol, 83% yield) as a white solid: LC/MS (Method g) Rt = 3.93 min.; MS m/z:
505.17
(M+H) ; 1H NMR (400 MHz, DMSO) 6 8.26 (dd, J= 2.1, 8.7, 1H), 8.19 (d, J= 2.0,
1H), 8.11
(d, J= 8.8, 2H), 7.50 (d, J= 8.9, 1H), 7.11 (d, J= 8.9, 2H), 6.56 (dd, J= 1.3,
7.9, 1H), 5.52 -
5.42 (m, 1H), 4.96 - 4.84 (m, 1H), 4.10 (qd, J= 1.6, 7.1, 2H), 1.94 (d, J=
1.0, 3H), 1.42 (d, J
= 6.3, 3H), 1.32 (d, J= 6.0, 6H), 1.19 (t, J= 7.1, 3H).
Step 3
Preparation of (RE)-ethyl 4-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-
1,2,4-
oxadi azol-5-yl)phenoxy)-2-methylpent-2-enoate
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F N.O _ F F N O
O
F
N O F I N \/ O
Op
OO
(R,E)-ethyl 4-(4-(3 -(4-isopropoxy-3 -(trifluoromethyl)phenyl)-1,2,4-oxadiazol-
5 -yl)phenoxy)-
2-methylpent-2-enoate (0.281 g, 0.557 mmol) was dissolved in ethyl acetate
(11.14 mL).
Palladium on carbon (10%) (0.059 g, 0.056 mmol) was added, the reaction was
flushed with
hydrogen, and hydrogenated at atmospheric pressure for about 4 h. LC/MS showed
product
and oxadiazole opening. The mixture was filtered through a syringe filter and
washed through
with ethyl acetate. The solvents were removed under reduced pressure. The
residue was
purified by flash column chromatography (40 g Redi-Sep column) eluting with 20-
40% ethyl
acetate/heptane and the product fractions combined. The solvents were removed
under
reduced pressure to provide (4R)-ethyl 4-(4-(3-(4-isopropoxy-3-
(trifluoromethyl)phenyl)-
1,2,4-oxadiazol-5 yl)phenoxy)-2-methylpentanoate (0.105 g, 0.207 mmol, 37.2%
yield) as a
colorless oil: LC/MS (Method i) Rt = 2.17 min.; MS m/z: 507.18 (M+H)+, iH NMR
(400 MHz,
DMSO) 6 8.26 (dd, J= 2.1, 8.8, 1H), 8.19 (d, J= 2.0, 1H), 8.09 (d, J= 8.9,
2H), 7.50 (d, J=
8.9, 1H), 7.12 (d, J = 8.9, 2H),4.95 - 4.84 (m, 1H), 4.69 - 4.56 (m, 1H), 4.10
- 3.92 (m,
2H),2.68 - 2.50 (m, 2H), 2.11 - 2.02 (m, 1H), 1.97 - 1.76 (m, 2H), 1.69 - 1.61
(m, 1H), 1.32
(d, J = 6.0, 6H), 1.26 (d, J = 6.0, 3H), 1.15 - 1.01 (m, 3H) major
diastereomer, minor
diastereomer observed at 6 8.10 (d, J= 9.0, 2H), 7.14 (d, J= 8.9, 2H).
Step 4
Preparation of (R)-4-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-
oxadiazol-5-
yl)phenoxy)-2-methylpentanoic acid
F F N o F N-O
F
O
F N \/ O F ~O
O
OH
I'Ll
(4R)-ethyl 4-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-
yl)phenoxy)-
2-methylpentanoate (0.105 g, 0.207 mmol) was dissolved in ethanol (2.073 mL)
under
nitrogen to give a colorless solution. A solution of sodium hydroxide (1 M)
(0.829 mL, 0.829
mmol) was added in one portion and the reaction stirred for about 20 h. On
addition of the
sodium hydroxide the reaction turned cloudy but it became homogeneous after
reacting
overnight. The solvents were removed under reduced pressure. The residue was
dissolved in
water (about 5 mL) with sonication. 1 N HCl (900 uL) was added to bring the
mixture to
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about pH = 1. A white precipitate formed and was stirred for about 2 h. The
resulting solid
was collected by vacuum filtration and washed with water and a small amount of
pentane to
provide (R)-4-(4-(3-(4-isopropoxy-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5
yl)phenoxy)-
2-methylpentanoic acid (0.081 g, 0.169 mmol, 82% yield) as a white solid:
LC/MS (Method
g) Rt = 3.24 min.; MS m/z: 479.16 (M+H)+ (major diastereomer) and Rt = 3.20
min.; MS m/z:
479.16 (M+H)+ (minor diastereomer), iH NMR (400 MHz, DMSO) 6 12.10 (s, 1H),
8.27 (dd, J =
1.9, 8.7, 1H), 8.19 (d, J= 1.9, 1H), 8.10 (d, J= 8.8, 2H), 7.51 (d, J= 8.9,
1H), 7.19 - 7.09 (m, 2H), 4.97
- 4.84 (m, 1H), 4.69 - 4.57 (m, 1H), 2.59 - 2.50 (m, 1H), 1.97 - 1.84 (m, 1H),
1.75 (d, J= 19.4, 1H),
1.33 (d, J = 6.0, 6H), 1.27 (d, J = 6.0, 3H), 1.10 (d, J = 7.1, 3H). Minor
diastereomer observed at
2.13 - 2.02 (m, 1H), 1.66 - 1.53 (m, 1H), 1.31 (d, J= 6.0, 6H), 1.08 (d, J=
7.1, 3H).
Preparation #86: Preparation of 5-chloro-6-isopropoxynicotinic acid
0 O
CI CI
O OH
&N'
O ~
O N
Methyl 5-chloro-6-isopropoxynicotinate (24 g, 105 mmol) was stirred in
methanol (190 mL)
and water (19.00 mL) under nitrogen to give a colorless solution. Sodium
hydroxide (5.43 g,
136 mmol) was added and the reaction heated at about 60 C for about 6 h. TLC
in EtOAc
showed (uv light visualization) that the reaction was complete. The reaction
was allowed to
cool to ambient temperature. The solvents were removed under reduced pressure.
The white
residue was redissolved in water (about 250 mL) to give a cloudy solution. The
mixture was
filtered through Celite and washed through with water (about 200 mL). The
clear aqueous
solution was acidified to about pH 2 with 1 N HCl (140 mL) causing a heavy
white precipitate
to form. The resulting solid was collected by vacuum filtration and washed
with water and
then pentane to provide 5-chloro-6-isopropoxynicotinic acid (21.946 g, 102
mmol, 97% yield)
as a white solid on drying under vacuum at about 50 C over phosphorous
pentoxide: LC/MS
(Table 1, Method g) Rt = 1.91 min.; MS m/z: 214.02, 216.04 (M-H)-, 1H NMR (400
MHz,
DMSO) 6 ppm 13.29 (s, 1H), 8.62 (d, J= 2.0, 1H), 8.18 (d, J= 2.0, 1H), 5.44 -
5.31 (m, 1H),
1.33 (d, J = 6.2, 6H).
Preparation #87: 3-(3-Chloro-4-cyano-phenoxy)-cyclobutanecarboxylic acid tert-
butyl
ester
O CN
O
CI CI
O O
HO OH O,.
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A solution of 2-chloro-4-hydroxybenzonitrile (5.00 g, 32.6 mmol) and (ls,3s)-
tert-butyl 3-
hydroxycyclobutanecarboxylate described in W020070607 (6.17 g, 35.8 mmol) in
THE (220
mL) is treated with 4A molecular sieves (10g) and Ph3P-Resin bound (32.6 mL,
98 mmol) for
20 min. at RT, then cooled to about 0 C. A solution of di-tert-butyl
azodicarboxylate (8.25 g,
35.8 mmol) in THE (30 mL) is added dropwise while maintaining the reaction
temperature
below about 4 C. The reaction is stirred about 15 minutes at about 0 C and
then allowed to
warm to RT for about 18 h. The reaction was filtered and the solids rinsed
with methanol (3 x
50 mL) and the combined organic solutions were concentrated. The residue was
purified on a
silica gel column using a gradient from 10-30% ethyl acetate in heptane. The
product
fractions were combined and concentrated to a clear, colorless oil which
solidified on standing
to yield 3-(3-Chloro-4-cyano-phenoxy)-cyclobutanecarboxylic acid tert-butyl
ester, (6.03g,
60%) as a white solid. LC/MS (Table 1, Method a) Rt = 2.75 min.; MS m/z: No
parent mass.
1 H NMR (400 MHz, DMSO) 6 ppm 7.87 (d, J = 8.7, I H), 7.19 (d, J = 2.4, I H),
6.99 (dd, J =
8.7, 2.4, 1H), 4.99-4.92 (m, 1H), 3.11-3.04 (m, 1H), 2.69-2.63 (m, 2H), 2.40 -
2.28 (m, 2H),
1.44 (s, 9H).
Preparation #88: 3-[3-Chloro-4-(N-hydroxycarbamimidyl)-phenoxy]
cyclobutanecarboxylic acid tert-butyl ester
CI O
O H2N CI
O
NC /
/
O HO-N/
O~
Into a round bottom flask was added (lr,3r)-tert-butyl 3-(3-chloro-4-
cyanophenoxy)
cyclobutanecarboxylate (5.98g, 19.43 mmol), hydroxylamine (50% by weight in
water, 6.88
mL, 117 mmol) and ethanol (50 mL). The mixture was heated at 60 C overnight.
Upon
completion of the reaction, the mixture was cooled to room temperature,
diluted with 150 mL
water and extracted with 150 mL ethyl acetate. The organic layer was washed
with saturated
NaCl solution (100mL), dried over sodium sulfate, filtered and concentrated to
solids. The
crude product was triturated with ether to obtain 3-[3-Chloro-4-(N-
hydroxycarbamimidoyl)-
phenoxyJ-cyclobutanecarboxylic acid tert-butyl ester (5.43g, 82%) as a white
solid.
LC/MS (Table 1, Method a) R, = 2.15min, m/z 341 (M+H) ; 1H NMR (400 MHz, DMSO-
d6)
6 ppm 9.37 (s, 1H), 7.30 (d, J= 8.5, 1H), 6.89 (d, J= 2.5, 2H), 6.81 (dd, J=
8.5, 2.5, 1H),
5.71 (s, 2H), 4.91 - 4.81 (m, 1H), 3.12 - 3.01 (m, 1H), 2.63 (m, 2H), 2.37 -
2.26 (m, 2H),
1.44 (s, 9H).
Preparation #89: 3-{3-Chloro-4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]
oxadiazol
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WO 2011/071570 PCT/US2010/046424
-3-y1]-phenoxy}-cyclobutanecarboxylic acid tert-butyl ester
H N CI O~ N\ CI O-N CI O
,E~
HO_N CI I OH \ \N\ / \ O0,0
0 X/
O
A solution of 5-chloro-6-isopropoxynicotinic acid (3.42 g, 15.87 mmol) and 1H-
benzo[d][1,2,3]triazol-1-ol hydrate (2.430 g, 15.87 mmol) in CH2C12 (100 mL)
was treated
with EDC (3.04 g, 15.87 mmol) and the reaction was stirred at RT for 2 h. The
mixture was
washed twice with water (50 mL), dried over sodium sulfate, filtered and
concentrated. The
residue was dissolved in NMP (100 mL) and (lr,3r)-tent-butyl 3-(3-chloro-4-
((Z)-N-
hydroxycarbamimidoyl)phenoxy)cyclobutanecarboxylate (5.23g, 14.43 mmol) was
added and
the mixture was heated at about 110 C for about 18 h. The reaction was cooled
to room
temperature, diluted with water (200 mL) and extracted with ethyl acetate (200
mL). The
ethyl acetate layer was washed with saturated sodium bicarbonate solution (100
mL),
saturated ammonium chloride solution (100 mL) and with saturated NaCl solution
(100mL).
The organic layer was dried over sodium sulfate, filtered and concentrated.
The residue was
further purified on silica gel using a gradient 10% to 20% ethyl
acetate/heptane. Product
fractions were concentrated to about 100 mL and filtered to yield 3-{3-Chloro-
4-[5-(5-chloro-
6-isopropoxypyridin-3-yl)-[1,2,4]oxadiazol-3 ylJphenoxy}-cyclobutanecarboxylic
acid tert-
butyl ester (6.52g, 87%) as off white solid product. LC/MS (Table 1, Method c)
Rt = 3.30 min,
m/z 520 (M+H) ; 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.91 (d, J = 2.1, 1H), 8.53
(d, J =
2.1, I H), 7.95 (d, J = 8.7, I H), 7.12 (d, J = 2.5, I H), 7.03 (dd, J = 8.8,
2.5, I H), 5.50-5.40 (m,
1H), 5.02 - 4.90 (m, 1H), 3.13-3.06 (m, 1H), 2.73 - 2.63 (m, 2H), 2.43 - 2.32
(m, 2H), 1.45
(s, 9H), 1.39 (d, J= 6.2, 6H).
Example #94: 3-{3-Chloro-4-[5-(5-chloro-6-isopropoxy-pyridin-3-yl)-[1,2,4]
oxadiazol-3-
yl]-phenoxy}-cyclobutanecarboxylic acid
0 O
CI O-N CI - ON CI OH
\ / ~Er El'
O CI
O N \~ I\ N \~ .
N O~ O
A solution of (1r,3r)-tent-butyl 3-(3-chloro-4-(5-(5-chloro-6-
isopropoxypyridin-3-yl)-1,2,4-
oxadiazol-3-yl)phenoxy)cyclobutanecarboxylate (6.42 g, 12.34 mmol) in
DCM(100.0 mL)
was treated with triisopropylsilane (2.53 mL, 12.34 mmol) and then TFA (100
mL) at RT for
about 45 min. The mixture was concentrated to yield an oil and purified on
silica gel using a
gradient from 0-10% MeOH. Product fractions were combined and concentrated.
The
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WO 2011/071570 PCT/US2010/046424
residue was triturated with 1:1/MeOH water (50 mL), filtered, washed with
water and dried
under vacuum to yield 3-{3-Chloro-4-[5-(5-chloro-6-isopropoxy pyridin-3-yl)-
[1,2,4]oxadiazol-3 ylJphenoxy}-cyclobutanecarboxylic acid (5.26g, 92%) as
white solid.
LC/MS (Table 1, Method c) Rt = 2.70 min, m/z 464 (M+H) ; 1H NMR (400 MHz, DMSO-
d6)
6 ppm 12.36 (s, 1H), 8.88 (d, J= 2.1, 1H), 8.50 (d, J= 2.1, 1H), 7.94 (d, J=
8.7, 1H), 7.11 (d,
J = 2.5, 1 H), 7.03 (dd, J = 8.8, 2.5, 1 H), 5.50 - 5.38 (m, 1 H), 5.03 - 4.90
(m, 1 H), 3.12 (m,
1H), 2.71 (m, 2H), 2.43 - 2.32 (m, 2H), 1.39 (d, J= 6.2, 6H).
Preparation #90: (1R, 3S)-ethyl 3-(4-((Z)-N'-hydroxycarbamimidoyl)
phenylamino)
cyclopentane carboxylate
NH2
N~~ HORN
Et OEt
H O H O
Into a round bottom flask was added (1R, 3S)-ethyl 3-(4-cyanophenylamino)
cyclopentane
carboxylate (0.5 g, 1.936 mmol), hydroxylamine (50% by weight in water, 0.457
mL, 7.74
mmol) and ethanol (6 mL). The mixture was heated at about 60 C for about 16
h. Upon
completion of the reaction, the mixture was concentrated to dryness under
reduced pressure to
give (JR, 3S)-ethyl 3-(4-((Z)-N'-hydroxycarbamimidoyl) phenylamino)
cyclopentane
carboxylate (0.506 g, 1.737mmo1, 90%) as an oil. LC/MS (Table 1, Method b) Rt
= 1.62 min,
m/z 292 (M+H) +; 1H NMR (400 MHz, DMSO-d6) 6 ppm 9.18 (s, 1H), 7.39-7.37 (d,
2H),
6.53-6.50 (d, 2H), 5.84-5.83 (d, 1H), 5.52 (s, 2H), 4.08-4.03 (q, 2H), 3.79-
3.71 (m, 1H), 2.86-
277 (m, 1H), 2.35-2.28 (m, 1H), 2.01-1.93 (m, 1H), 1.89-1.84 (m, 2H), 1.64-
1.56 (m, 1H),
1.54-1.47 (m, 1H), 1.18-1.15 (t, 3H).
Preparation #91: (1R, 3S)-ethyl 3-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1,
2, 4-
oxadiazol-3-yl) phenylamino) cyclopentane carboxylate
a O NH2 O-N
,,(OEt
OH HO.N Et CI\ ^ \ .,"\\
N H O
O I + I N''~ O N
H O
To a solution of (1R, 3S)-Ethyl 3-(4-((Z)-N'-hydroxycarbamimidoyl)
phenylamino)
cyclopentane carboxylate (0.506 g, 1.737 mmol), EDC (0.366 g, 1.910 mmol),
DIEA (0.334
mL, 1.910 mmol) and HOBT (0.293 g, 1.910 mmol) in DMF (10 mL) was added
solution 5-
chloro-6-isopropoxynicotinic acid (0.412 g, 1.910 mmol) and the reaction was
stirred at RT
under nitrogen for about 1 h and then heated at about 100 C for about 16 h.
The reaction was
cooled and concentrated under reduced pressure and the residue was taken up in
EtOAc (25
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WO 2011/071570 PCT/US2010/046424
mL) and sequentially washed with a saturated NH4C1 solution (20 mL), a
saturated Na2CO3
solution (20 mL) and water (20 mL). The organic layer was dried over Na2SO4,
filtered and
concentrated under reduced pressure. The residue was purified on silica gel
using a gradient
of 15-50% EtOAc in Heptane to afford (JR,3S)-ethyl 3-(4-(5-(5-chloro-6-
isopropoxypyridin-
3-yl)-1,2,4-oxadiazol-3-yl) phenylamino) cyclopentane carboxylate (0.170 g,
0.361 mmol,
20.8%) as a pale yellow solid. LC/MS (Table 1, Method b) Rt = 3.21 min, m/z
471 (M+H) +;
1H NMR (400 MHz, DMSO-d6) 6 ppm 8.88 (d, 1H), 8.50 (d, 1H), 7.80-7.78 (d, 2H),
6.71-
6.69 (d, 2H), 6.43-6.42 (d, 1H), 5.48-5.41 (m, 1H), 4.09-4.04 (q, 2H), 3.87-
3.78 (m, 1H),
2.89-2.81 (m, 1H), 2.39-2.32 (m, 1H), 2.06-1.97 (m, 1H), 1.92-1.87 (m, 2H),
1.70-1.62 (m,
1H), 1.57-1.50 (m, 1H), 1.39-1.38 (d, 6H), 1.19-1.15 (t, 3H).
Example #95: (1R, 3S)-3-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-1, 2, 4-
oxadiazol-3-yl)
phenylamino) cyclopentane carboxylic acid
O-N O-N
OEt OH
CI (( CI
N N
H O HO
O N O N
To a solution of (1R,3S)-ethyl 3-(4-(5-(5-chloro-6-isopropoxypyridin-3-yl)-
1,2,4-oxadiazol-3-
yl) phenylamino) cyclopentane carboxylate (170 mg, 0.361 mmol) in dioxane (3.6
mL) was
added 2 M potassium hydroxide (0.722 mL, 1.444 mmol) and the mixture was
stirred at RT
for about 16 h. The reaction was neutralized by addition of 2 M HC1 (750 L)
and the
mixture is concentrated. The residue was triturated with water and aqueous
ammonium
acetate solution. The resulting solid was filtered and washed with water and
dried to yield (JR,
3S)-3-(4-(5-(5-chloro-6-isopropoxypyridin-3 yl)-1, 2, 4-oxadiazol-3-yl)
phenylamino)
cyclopentane carboxylic acid (141.6 mg, 0.317 mmol, 88%) as a tan solid. LC/MS
(Table 1,
Method b) Rt = 2.81 min, m/z 433 (M+H) +; 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.88-
87
(d, 1H), 8.50-8.49 (d, 1H), 7.81-7.79 (d, 2H), 6.74-6.71 (d, 2H), 5.49-5.40
(m, 1H), 3.85-3.78
(m, 1H), 2.82-2.73 (m, 1H), 2.37-2.30 (m, 1H), 2.05-1.96 (m, 1H), 1.91-1.85
(m, 2H), 1.69-
1.62 (m, 1H), 1.58-1.50 (m, 1H), 1.39-1.38 (d, 6H).
Preparation #1-1: Isomerization
o o
N CI OH
CI O -N C1 OE CI
CI NN LiOD CI ON / N 1. NaOH \ \N\ / \ O
N THE/EtOH O O 2. HCI Oj N
n-BuLi (about 1 equivalent) is added to about 20 mL THE at 0 C, followed by
ethanol and
trans-tert-butyl 3 -(4-(5 -(5 -chloro-6-isopropoxypyridin-3 -yl)-1,2,4-
oxadiazol-3 -
yl)phenoxy)cyclobutanecarboxylate. Warmed to about room temperature over about
5 h then
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WO 2011/071570 PCT/US2010/046424
stirred about 18 h. NaOH (4 eq, 5% in water) is added. The reaction is stirred
for about 4 h at
rt and the pH is adjusted to about 2 with about 12 N HC1. The precipitate is
filtered, washed
with water and 1:1 ethanol water then dried. Yield 1.32 g. 82:14 cis/trans
products identical to
those described above (74% yield).
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