Note: Descriptions are shown in the official language in which they were submitted.
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
ISOXAZOLINES AS INHIBITORS OF FATTY ACID AMIDE HYDROLASE
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to United States provisional
patent application
serial numbers 61/179,280, 61/179,283, and 61/179,285 filed May 18, 2009, the
entirety of each
of which is hereby incorporated herein by reference.
BACKGROUND
[0002] Fatty acid amide hydrolase (FAAH), also referred to as oleamide
hydrolase and
anandamide amidohydrolase, is an integral membrane protein responsible for the
hydrolysis of
several important endogenous neuromodulating fatty acid amides (FAAs),
including anadamide,
oleoylethanolamide and palmitoylethanolamide, and is intimately involved in
their regulation.
Because these FAAs interact with cannabinoid and vanilliod receptors, they are
often referred to
as "endocannabinoids" or "endovanilliods". Initial interest in this area
focused on developing
FAAH inhibitors to augment the actions of FAAs and reduce pain. Further
investigation found
FAAH inhibitors, through interactions of the FAAs with unique extracellular
and intracellular
receptors, can be used to treat a variety of conditions that include, but are
not limited to,
inflammation, metabolic disorders (e.g., obesity-related conditions and
wasting conditions such
as cachexias and anorexia), disorders of the central nervous system (e.g.,
disorders associated
with neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord
injury, movement
disorders such as basal ganglia disorders, amylotrophic lateral sclerosis,
Alzheimer's disease,
epilepsy, mental disorders such as anxiety, depression, learning disorders and
Schizophrenia,
sleep disorders such as insomnia, nausea and/or emesis, and drug addiction),
cardiac disorders
(e.g., hypertention, circulatory shock, myocardial reperfusion injury and
atherosclerosis) and
glaucoma (Pacher et at., "The Endocannabinoid System as an Emerging Target of
Pharmacotherapy" Pharmacological Reviews (2006) 58:389-462; Pillarisetti et
at., "Pain and
Beyond: Fatty Acid Amides and Fatty Acid Amide Hydrolase Inhibitors in
Cardiovascular and
Metabolic Diseases" Drug Discovery Today (2009) 597:1-14).
1
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
SUMMARY
[0003] The present invention provides isoxazoline FAAH inhibitor compounds of
the
formula (I):
O Rd
N/
\ Rc
Rb
G'
Ra
(I)
or pharmaceutically acceptable forms thereof,
wherein:
(i) each of Ra, Rb, and Rc independently is selected from H, Ci_io alkyl and
CI-10
perhaloalkyl, Rd is the group -L-Z, and Z is selected from C6_14 aryl;
(ii) each of Ra, Rb, and Rc independently is selected from -H, C1_io alkyl and
Ci_io
perhaloalkyl, Rd is the group -L-Z, and Z is selected from 3-14 membered
heterocyclyl and 5-14 membered heteroaryl;
(iii) Ra and Rd are joined to form a C3_10 carbocycyl or 3-14 membered
heterocyclyl
fused ring, and Rb and R' are independently selected from -H, C1_10 alkyl and
Ci_
perhaloalkyl; or
(iv) R' and Rd are joined to form a C3_10 carbocycyl or 3-14 membered
heterocyclyl
spiro-fused ring, and Ra and Rb are independently selected from -H, Ci_io
alkyl
and CI-10 perhaloalkyl;
L is a covalent bond or a divalent C1 hydrocarbon group, wherein one, two or
three
methylene units of L are optionally and independently replaced with one or
more oxygen, sulfur
or nitrogen atoms;
G is selected from -CN, -NO2, -S(=O)Re, _S02R e, -SO2NRfRe, -PO2Re, -PO2ORe, -
PO2NRfRe, -(C=O)Re, -(C=O)ORe, -(C=O)NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -
ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -SRe, -OSO2Re, -NRfSO2Re, -
OPO2Re, -OPO2ORe, -NRfPO2Re, -NRfPO2ORC, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -
NRfRe, -NRf(C=O)Re,-NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NRf)NRfRe, -
O(C=NRf)NRfRe, -NRf(C=NRf)ORe, -[N(Rf)2Re]+X wherein Xis a counterion;
2
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
each Re is selected from Ci_io alkyl, C2_io alkenyl, C2_10 alkynyl, C3_10
carbocycyl, C6_14
aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each Rf
attached to a nitrogen
atom is, independently, selected from -H, CI-10 alkyl, or an amino protecting
group; or Re and Rf
are joined to form an 3-14 membered heterocyclyl ring or an 5-14 membered
heteroaryl ring.
[0004] The present invention also provides pharmaceutical compositions
comprising a
compound of formula (I), or a pharmaceutically acceptable form thereof, and a
pharmaceutically
acceptable excipient.
[0005] The present invention also provides methods for treating an FAAH-
mediated
condition in a subject comprising administering a therapeutically effective
amount of a
compound of formula (I), or a pharmaceutically acceptable form thereof, to a
subject in need
thereof.
[0006] The details of additional embodiments of the invention are set forth in
the
accompanying Detailed Description and Exemplification as described below.
Other features,
objects, and advantages of the invention will be apparent from this
description and from the
claims.
DEFINITIONS
[0007] Definitions of specific functional groups ad chemical terms are
described in more
detail below. The chemical elements are identified in accordance with the
Periodic Table of the
Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside
cover, and specific
functional groups are generally defined as described therein. Additionally,
general principles of
organic chemistry, as well as specific functional moieties and reactivity, are
described in
Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;
Smith and
March March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons,
Inc., New York,
2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New
York,
1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition,
Cambridge
University Press, Cambridge, 1987.
[0008] Certain compounds of the present invention can comprise one or more
asymmetric
centers, and thus can exist in various isomeric forms, e.g., enantiomers
and/or diastereomers.
The compounds provided herein can be in the form of an individual enantiomer,
diastereomer or
geometric isomer, or can be in the form of a mixture of stereoisomers,
including racemic
mixtures and mixtures enriched in one or more stereoisomer. In certain
embodiments, the
3
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
compounds of the invention are enantiopure compounds. In certain other
embodiments, mixtures
of stereoisomers are provided.
[0009] Furthermore, certain compounds, as described herein may have one or
more double
bonds that can exist as either the cis or trans, or the E or Z isomer, unless
otherwise indicated.
The invention additionally encompasses the compounds as individual isomers
substantially free
of other isomers, and alternatively, as mixtures of various isomers, e.g.,
racemic mixtures of E/Z
isomers or mixtures enriched in one E/Z isomer.
[0010] The terms "enantiomerically enriched," "enantiomerically pure" and "non-
racemic,"
as used interchangeably herein, refer to compositions in which the percent by
weight of one
enantiomer is greater than the amount of that one enantiomer in a control
mixture of the racemic
composition (e.g., greater than 1:1 by weight). For example, an
enantiomerically enriched
preparation of the (S)-enantiomer, means a preparation of the compound having
greater than
50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, more
preferably at least
75% by weight, and even more preferably at least 80% by weight. In some
embodiments, the
enrichment can be much greater than 80% by weight, providing a "substantially
enantiomerically
enriched," "substantially enantiomerically pure" or a "substantially non-
racemic" preparation,
which refers to preparations of compositions which have at least 85% by weight
of one
enantiomer relative to other enantiomer, more preferably at least 90% by
weight, and even more
preferably at least 95% by weight. In preferred embodiments, the
enantiomerically enriched
composition has a higher potency with respect to therapeutic utility per unit
mass than does the
racemic mixture of that composition. Enantiomers can be isolated from mixtures
by methods
known to those skilled in the art, including chiral high pressure liquid
chromatography (HPLC)
and the formation and crystallization of chiral salts; or preferred
enantiomers can be prepared by
asymmetric syntheses. See, for example, Jacques, et al., Enantiomers,
Racemates and
Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al.,
Tetrahedron 33:2725
(1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY,
1962); and
Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L.
Eliel, Ed., Univ. of
Notre Dame Press, Notre Dame, IN 1972).
[0011] When a range of values is listed, it is intended to encompass each
value and sub-
range within the range. For example "C1_6 alkyl" is intended to encompass, C1,
C2, C3, C4, C5,
C65 C1-65 C1-55 C1-45 C1-35 C1-25 C2_6, C2-55 C2-45 C2-35 C3_6, C3-55 C3_4, C4-
65 C4_5, and C5{ alkyl.
4
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0012] As used herein a "direct bond" or "covalent bond" refers to a single
bond joining two
groups.
[0013] As used herein, alone or as part of another group, "halo" and "halogen"
refer to
fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine
(iodo, -I).
[0014] As used herein, alone or as part of another group, "alkyl" refers to a
monoradical of a
straight-chain or branched saturated hydrocarbon group having from 1 to 10
carbon atoms ("C1_
1o alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1_9
alkyl"). In
some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1_8 alkyl"). In
some
embodiments, an alkyl group has 1 to 7 carbon atoms ("Ci 7 alkyl"). In some
embodiments, an
alkyl group has 1 to 6 carbon atoms ("C1-6 alkyl"). In some embodiments, an
alkyl group has 1
to 5 carbon atoms ("C1_5 alkyl"). In some embodiments, an alkyl group has 1 to
4 carbon atoms
("C1_4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms
("C1_3 alkyl"). In
some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1_2 alkyl"). In
some
embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some
embodiments, an alkyl
group has 2 to 6 carbon atoms ("C2_6 alkyl"). Examples of C1_6 alkyl groups
include methyl (C1),
ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-
butyl (C4), iso-butyl
(C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-
butanyl (C5),
tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups
include n-heptyl (C7),
n-octyl (Cg) and the like. Unless otherwise specified, each instance of an
alkyl group is
independently unsubstituted (an "unsubstituted alkyl") or substituted (a
"substituted alkyl") are
substituted with 1, 2, 3, 4, or 5 substituents as described herein. In certain
embodiments, the
alkyl group is an unsubstituted C1_io alkyl (e.g., -CH3). In certain
embodiments, the alkyl group
is a substituted CI-10 alkyl.
[0015] "Perhaloalkyl" as defined herein refers to an alkyl group having from 1
to 10 carbon
atoms wherein all of the hydrogen atoms are each independently replaced
halogen, e.g., selected
from fluoro, bromo, chloro or iodo ("C1_io perhaloalkyl"). In some
embodiments, the alkyl
moiety has 1 to 8 carbon atoms ("C1_8 perhaloalkyl"). In some embodiments, the
alkyl moiety
has 1 to 6 carbon atoms ("C1_6 perhaloalkyl"). In some embodiments, the alkyl
moiety has 1 to 4
carbon atoms ("C1-4 perhaloalkyl"). In some embodiments, the alkyl moiety has
1 to 3 carbon
atoms ("C1_3 perhaloalkyl"). In some embodiments, the alkyl moiety has 1 to 2
carbon atoms
("C1_2 perhaloalkyl"). In some embodiments, all of the hydrogen atoms are each
replaced with
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
fluoro. In some embodiments, all of the hydrogen atoms are each replaced with
chloro.
Examples of perhaloalkyl groups include -CF3, -CF2CF3, -CF2CF2CF3, -CC13, -
CFC12, -CF2C1
and the like.
[0016] As used herein, alone or as part of another group, "alkenyl" refers to
a monoradical of
a straight-chain or branched hydrocarbon group having from 2 to 10 carbon
atoms and one or
more carbon-carbon double bonds ("C2_10 alkenyl"). In some embodiments, an
alkenyl group
has 2 to 9 carbon atoms ("C2 9 alkenyl"). In some embodiments, an alkenyl
group has 2 to 8
carbon atoms ("C2_8 alkenyl"). In some embodiments, an alkenyl group has 2 to
7 carbon atoms
("C2_7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon
atoms ("C2-6
alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms
("C2_5 alkenyl"). In
some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl").
In some
embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2_3 alkenyl"). In
some
embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or
more carbon-
carbon double bonds can be internal (such as in 2-butenyl) or terminal (such
as in 1-butenyl).
Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-
propenyl (C3), 1-
butenyl (C4), 2-butenyl (C4), butadienyl (C4) and the like. Examples of C2_6
alkenyl groups
include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5),
pentadienyl (C5),
hexenyl (C6) and the like. Additional examples of alkenyl include heptenyl
(C7), octenyl (C8),
octatrienyl (Cg) and the like. Unless otherwise specified, each instance of an
alkenyl group is
independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
"substituted alkenyl")
with 1, 2, 3, 4, or 5 substituents as described herein. In certain
embodiments, the alkenyl group
is an unsubstituted C2_10 alkenyl. In certain embodiments, the alkenyl group
is a substituted C2_
alkenyl.
[0017] As used herein, alone or as part of another group, "alkynyl" refers to
a monoradical of
a straight-chain or branched hydrocarbon group having from 2 to 10 carbon
atoms and one or
more carbon-carbon triple bonds ("C2_10 alkynyl"). In some embodiments, an
alkynyl group has
2 to 9 carbon atoms ("C29 alkynyl"). In some embodiments, an alkynyl group has
2 to 8 carbon
atoms ("C2_8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7
carbon atoms ("C2 7
alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms
("C2_6 alkynyl"). In
some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2_5 alkynyl").
In some
embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2_4 alkynyl"). In
some embodiments,
6
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
an alkynyl group has 2 to 3 carbon atoms ("C2_3 alkynyl"). In some
embodiments, an alkynyl
group has 2 carbon atom ("C2 alkynyl"). The one or more carbon-carbon triple
bonds can be
internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples
Of C2-4 alkynyl
groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl
(C3), 1-butynyl
(C4), 2-butynyl (C4) and the like. Examples of C2_6 alkenyl groups include the
aforementioned
C2_4 alkynyl groups as well as pentynyl (C5), hexynyl (C6) and the like.
Additional examples of
alkynyl include heptynyl (C7), octynyl (Cg) and the like. Unless otherwise
specified, each
instance of an alkynyl group is independently unsubstituted (an "unsubstituted
alkynyl") or
substituted (a "substituted alkynyl") with 1, 2, 3, 4, or 5 substituents as
described herein. In
certain embodiments, the alkynyl group is an unsubstituted C2_10 alkynyl. In
certain
embodiments, the alkynyl group is a substituted C2_10 alkynyl.
[0018] A "divalent C1_6 hydrocarbon group" is a divalent C1_6 alkyl group,
divalent C1
alkenyl group or divalent C1 alkynyl group wherein one, two or three methylene
units (-CH2-)
of the hydrocarbon chain are optionally and independently replaced with one or
more oxygen,
sulfur or nitrogen atoms. In certain embodiments, the divalent C1_6
hydrocarbon group is a
divalent Cis alkyl group. In certain embodiments, the divalent C1_6
hydrocarbon group is an
unsubstituted divalent C1_6 hydrocarbon group (e.g., an unsubstituted divalent
C1 alkyl group).
[0019] As used herein, alone or as part of another group, "alkoxy" refers to
an alkyl group,
as defined herein, substituted with an oxygen atom, wherein the point of
attachment is the
oxygen atom. In certain embodiments, the alkyl group has 1 to 10 carbon atoms
("C1_10 alkoxy").
In some embodiments, the alkyl group has 1 to 8 carbon atoms ("CI-8 alkoxy").
In some
embodiments, the alkyl group has 1 to 6 carbon atoms ("Ci_6 alkoxy"). In some
embodiments,
the alkyl group has 1 to 4 carbon atoms ("Ci_4 alkoxy"). Examples of C1_4
alkoxy groups
include methoxy (C1), ethoxy (C2), propoxy (C3), isopropoxy (C3), butoxy (C4),
tert-butoxy (C5)
and the like. Examples of C1_6 alkoxy groups include the aforementioned C1_4
alkoxy groups as
well as pentyloxy (C5), isopentyloxy (C5), neopentyloxy (C5), hexyloxy (C6)
and the like.
Additional examples of alkoxy groups include heptyloxy (C7), octyloxy (Cg) and
the like.
Unless otherwise specified, each instance of the alkyl moiety of the alkoxy
group is
independently unsubstituted (an "unsubstituted alkoxy") or substituted (a
"substituted alkoxy")
are substituted with 1, 2, 3, 4, or 5 substituents as described herein. In
certain embodiments, the
7
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
alkoxy group is an unsubstituted C2_10 alkoxy (e.g., -OCH3). In certain
embodiments, the alkoxy
group is a substituted C2_10 alkoxy (e.g., perhaloalkoxy as defined herein).
[0020] "Perhaloalkoxy" refers to an alkoxy group wherein the all the hydrogen
atoms of the
alkyl moiety are each independently replaced with halogen atoms selected from
fluoro, chloro,
bromo and iodo. In certain embodiments, the alkyl moiety has 1 to 10 carbon
atoms ("C1-lo
perhaloalkoxy"). In some embodiments, the alkyl moiety has 1 to 8 carbon atoms
("CI-8
perhaloalkoxy"). In some embodiments, the alkyl moiety has 1 to 6 carbon atoms
("C1
perhaloalkoxy"). In some embodiments, the alkyl moiety has 1 to 4 carbon atoms
("C1
perhaloalkoxy"). In some embodiments, the alkyl moiety has 1 to 3 carbon atoms
("CI _3
perhaloalkoxy"). In some embodiments, the alkyl moiety has 1 to 2 carbon atoms
("Cl 2
perhaloalkoxy"). In some embodiments, all of the hydrogen atoms are each
replaced with fluoro.
In some embodiments, all of the hydrogen atoms are each replaced with chloro.
Examples of
perhaloalkoxy groups include, but are not limited to, -OCF3, -OCF2CF3, -
OCF2CF2CF3, -
OCC13, -OCFC12, -OCF2C1 and the like.
[0021] As used herein, alone or as part of another group, "carbocyclyl" refers
to a radical of
a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms
("C3_1o
carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some
embodiments, a
carbocyclyl group has 3 to 8 ring carbon atoms ("C3_8 carbocyclyl"). In some
embodiments, a
carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some
embodiments, a
carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6 carbocyclyl"). In some
embodiments, a
carbocyclyl group has 5 to 10 ring carbon atoms ("C5_10 carbocyclyl").
Examples of C3_6
carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclobutyl
(C4), cyclopentyl
(C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl
(C6) and the like.
Examples of C3_8 carbocyclyl groups include the aforementioned C3_6
carbocyclyl groups as well
as cycloheptyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl
(C8),
bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples Of C3-10
carbocyclyl
groups include the aforementioned C3_8 carbocyclyl groups as well as octahydro-
lH-indenyl,
decahydronaphthalenyl, spiro[4.5]decanyl and the like. As the foregoing
examples illustrate, in
certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic
carbocyclyl") or
polycyclic (e.g., containing a fused, bridged or spiro ring system such as a
bicyclic system
("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and
can be saturated or can
8
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also
includes ring
systems wherein the carbocyclyl ring, as defined above, is fused with one or
more aryl or
heteroaryl groups wherein the point of attachment is on the carbocyclyl ring.
Unless otherwise
specified, each instance of a carbocyclyl group is independently unsubstituted
(an "unsubstituted
carbocyclyl") or substituted (a "substituted carbocyclyl") with 1, 2, 3, 4, or
5 substituents as
described herein. In certain embodiments, the carbocyclyl group is an
unsubstituted C3_10
carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-
10 carbocyclyl.
[0022] In some embodiments, "carbocyclyl" is a monocyclic, saturated
carbocyclyl group
having from 3 to 10 ring carbon atoms ("C3_10 cycloalkyl"). In some
embodiments, a cycloalkyl
group has 3 to 8 ring carbon atoms ("C3_8 cycloalkyl"). In some embodiments, a
cycloalkyl
group has 3 to 6 ring carbon atoms ("C3_6 cycloalkyl"). In some embodiments, a
cycloalkyl
group has 5 to 6 ring carbon atoms ("C5_6 cycloalkyl"). In some embodiments, a
cycloalkyl
group has 5 to 10 ring carbon atoms ("C5_10 cycloalkyl"). Examples of C5_6
cycloalkyl groups
include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3_6 cycloalkyl
groups include the
aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and
cyclobutyl (C4).
Examples of C3_8 cycloalkyl groups include the aforementioned C3_6 cycloalkyl
groups as well as
cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each
instance of a cycloalkyl
group is independently unsubstituted (an "unsubstituted cycloalkyl") or
substituted (a
"substituted cycloalkyl") with 1, 2, 3, 4, or 5 substituents as described
herein. In certain
embodiments, the cycloalkyl group is an unsubstituted C3_10 cycloalkyl. In
certain embodiments,
the cycloalkyl group is a substituted C3_10 cycloalkyl.
[0023] As used herein, alone or as part of another group, "heterocyclyl"
refers to a radical of
a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to
4 ring
heteroatoms, wherein each heteroatom is independently selected from nitrogen,
oxygen and
sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one
or more
nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as
valency permits. A
heterocyclyl group can either be monocyclic ("monocyclic heterocyclyl") or
polycyclic (e.g., a
fused, bridged or spiro ring system such as a bicyclic system ("bicyclic
heterocyclyl") or
tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can
contain one or more
carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can
include one or
more heteroatoms in one or both rings. "Heterocyclyl" also includes ring
systems wherein the
9
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
heterocycyl ring, as defined above, is fused with one or more carbocycyl
groups wherein the
point of attachment is either on the carbocycyl or heterocyclyl ring, or ring
systems wherein the
heterocyclyl ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein
the point of attachment is on the heterocyclyl ring. In some embodiments, a
heterocyclyl group
is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4
ring
heteroatoms, wherein each heteroatom is independently selected from nitrogen,
oxygen and
sulfur ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl
group is a 5-8
membered non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms,
wherein each heteroatom is independently selected from nitrogen, oxygen and
sulfur ("5-8
membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered non-
aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms,
wherein each
heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6
membered
heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3
ring heteroatoms
selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6
membered
heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and
sulfur. In some
embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from
nitrogen,
oxygen and sulfur. Exemplary 3-membered heterocyclyls containing 1 heteroatom
include,
without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered
heterocyclyls
containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl.
Exemplary 5-membered heterocyclyls containing 1 heteroatom include, without
limitation,
tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl,
dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyls
containing 2
heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and
dithiolanyl. Exemplary 5-
membered heterocyclyls containing 3 heteroatoms include, without limitation,
triazolinyl,
oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups
containing 1
heteroatom include, without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and
thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms
include, without
limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-
membered heterocyclyl
groups containing 2 heteroatoms include, without limitation, triazinanyl.
Exemplary 7-
membered heterocyclyl groups containing 1 heteroatom include, without
limitation, azepanyl,
oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1
heteroatom
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary
bicyclic heterocyclyl
groups include, without limitation, indolinyl, isoindolinyl,
dihydrobenzofuranyl,
dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,
tetrahydroindolyl,
tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl,
decahydroisoquinolinyl,
octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-
1,8-
naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl,
naphthalimidyl,
chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-
b]pyrrolyl,
5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-
dihydro-4H-
thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-
dihydrofuro[2,3-
b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-
tetrahydrofuro[3,2-
c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-
naphthyridinyl,
and the like. Unless otherwise specified, each instance of heterocyclyl is
independently
unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted
heterocyclyl") with
1, 2, 3, 4, or 5 substituents as described herein. In certain embodiments, the
heterocyclyl group
is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the
heterocyclyl
group is a substituted 3-14 membered heterocyclyl.
[0024] As used herein, alone or as part of another group, "aryl" refers to a
radical of a
monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic ring system
(e.g., having 6, 10 or
14 it electrons shared in a cyclic array) having 6-14 ring carbon atoms and
zero heteroatoms
provided in the aromatic ring system ("C6_14 aryl"). In some embodiments, an
aryl group has 6
ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl
group has 10 ring
carbon atoms ("Clo aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
In some
embodiments, an aryl group has 14 ring carbon atoms ("C14 aryl"; e.g.,
anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is fused with
one or more
carbocyclyl or heterocyclyl groups wherein the radical or point of attachment
is on the aryl ring.
Unless otherwise specified, each instance of an aryl group is independently
unsubstituted (an
"unsubstituted aryl") or substituted (a "substituted aryl") with 1, 2, 3, 4,
or 5 substituents as
described herein. In certain embodiments, the aryl group is an unsubstituted
C6_14 aryl. In
certain embodiments, the aryl group is a substituted C6_14 aryl.
11
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0025] "Aralkyl" is a subset of "alkyl" and refers to an alkyl group, as
defined herein,
substituted by an aryl group, as defined herein, wherein the point of
attachment is on the alkyl
moiety.
[0026] As used herein, alone or as part of another group, "heteroaryl" refers
to a radical of a
5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) aromatic
ring system (e.g.,
having 6, 10 or 14 it electrons shared in a cyclic array) having ring carbon
atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each heteroatom is
independently
selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In
heteroaryl groups
that contain one or more nitrogen atoms, the point of attachment can be a
carbon or nitrogen
atom, as valency permits. Heteroaryl polycyclic ring systems can include one
or more
heteroatoms in one or both rings. "Heteroaryl" also includes ring systems
wherein the heteroaryl
ring, as defined above, is fused with one or more aryl groups wherein the
point of attachment is
either on the aryl or on the heteroaryl ring, or wherein the heteroaryl ring,
as defined above, is
fused with one or more carbocycyl or heterocycyl groups wherein the point of
attachment is on
the heteroaryl ring. For polycyclic heteroaryl groups wherein one ring does
not contain a
heteroatom (e.g., indolyl, quinolinyl, carbazolyl and the like) the point of
attachment can be on
either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or
the ring that does not
contain a heteroatom (e.g., 5-indolyl). In some embodiments, a heteroaryl
group is a 5-10
membered aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in
the aromatic ring system, wherein each heteroatom is independently selected
from nitrogen,
oxygen and sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a
5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms
provided in the aromatic ring system, wherein each heteroatom is independently
selected from
nitrogen, oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments,
a heteroaryl
group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4
ring
heteroatoms provided in the aromatic ring system, wherein each heteroatom is
independently
selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some
embodiments,
the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen,
oxygen and
sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring
heteroatoms selected
from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered
heteroaryl has 1
ring heteroatom selected from nitrogen, oxygen and sulfur. Exemplary 5-
membered
12
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
heteroaryls containing 1 heteroatom include, without limitation, pyrrolyl,
furanyl and thiophenyl.
Exemplary 5-membered heteroaryls containing 2 heteroatoms include, without
limitation,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
Exemplary 5-membered
heteroaryls containing 3 heteroatoms include, without limitation, triazolyl,
oxadiazolyl,
thiadiazolyl. Exemplary 5-membered heteroaryls containing 4 heteroatoms
include, without
limitation, tetrazolyl. Exemplary 6-membered heteroaryls containing 1
heteroatom include,
without limitation, pyridinyl. Exemplary 6-membered heteroaryls containing 2
heteroatoms
include, without limitation, pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary
6-membered
heteroaryls containing 3 or 4 heteroatoms include, without limitation,
triazinyl and tetrazinyl,
respectively. Exemplary 7 membered heteroaryls containing 1 heteroatom
include, without
limitation, azepinyl, oxepinyl and thiepinyl. Exemplary 5,6-bicyclic
heteroaryls include,
without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl,
isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,
benzoxazolyl,
benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl,
benzthiadiazolyl, indolizinyl,
and purinyl. Exemplary 6,6-bicyclic heteroaryls include, without limitation,
naphthyridinyl,
pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl
and quinazolinyl.
Exemplary tricyclic heteroaryls include, without limitation, phenanthridinyl,
dibenzofuranyl,
carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. Unless
otherwise specified,
each instance of a heteroaryl group is independently unsubstituted (an
"unsubstituted
heteroaryl") or substituted (a "substituted heteroaryl") with 1, 2, 3, 4, or 5
substituents as
described herein. In certain embodiments, the heteroaryl group is an
unsubstituted 5-14
membered heteroaryl. In certain embodiments, the heteroaryl group is a
substituted 5-14
membered heteroaryl.
[0027] "Heteroaralkyl" is a subset of "alkyl" and refers to an alkyl group, as
defined herein,
substituted by a heteroaryl group, as defined herein, wherein the point of
attachment is on the
alkyl moiety.
[0028] As used herein, the term "partially unsaturated" refers to a ring
moiety that includes
at least one double or triple bond. The term "partially unsaturated" is
intended to encompass
rings having multiple sites of unsaturation, but is not intended to include
aromatic groups (e.g.,
aryl or heteroaryl moieties) as herein defined.
13
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0029] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl
groups, as
defined herein, are optionally substituted (e.g., "substituted" or
"unsubstituted" alkyl,
"substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted"
alkynyl, "substituted"
or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl,
"substituted" or
"unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In
general, the term
"substituted", whether preceded by the term "optionally" or not, means that at
least one hydrogen
present on a group (e.g., a carbon or nitrogen atom etc.) is replaced with a
permissible
substituent, e.g., a substituent which upon substitution results in a stable
compound, e.g., a
compound which does not spontaneously undergo transformation such as by
rearrangement,
cyclization, elimination, or other reaction. Unless otherwise indicated, a
"substituted" group has
a substituent at one or more substitutable positions of the group, and when
more than one
position in any given structure is substituted, the substituent is either the
same or different at
each position.
[0030] Exemplary carbon atom substituents include, but are not limited to,
halogen (i.e.,
fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I)), -CN, -NO2, -N3, -SO2H,
-SO3H, -OH, -
ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X, -N(ORcc)Rbb -SH, -SR aa, _SSRcc, -
C(=O)Raa, -
CO2H, -CHO, -C(OR )z, -CO2R-, -OC(=O)Raa, -OCO2R-, -C(=O)N(Rbb)2, -
OC(=O)N(Rbb)z
-NRbbC(=O)Raa, -NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)R-, -C(=NRbb)ORaa, -
OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rb)2, -OC(=NRbb)N(Rbb)2, -
NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2R-, -NR1 SO2Raa, -SO2N(Rbb)2, -SO2Rt, -SO2OR-
, -
OSO2Rt, -S(=O)Raa, -OS(=O)Ra, -Si(R )3, -OSi(Raa )3 -C(=S)N(Rbb)2, -C(=O)SRaa,
-
C(=S)SRaa, _SC(S)SRaa, -P(=O)2Raa, -OP(=O)2R', -P(=O)(R')2, -OP(=O)(Rt)2, -
OP(=O)(ORc)2, -P(=O)2N(Rbb)2, -OP(=O)2N(Rbb)2, -P(=O)(NRbb)2, -OP(=O)(NRbb)2, -
NRbbP(=O)(OR )z, -NRbbP(=O)(NRbb)2, -P(Rcc)2, -P(Rcc)3, -OP(R )z, -OP(R )3,
-B(OR )z, -
BRaa(OR ), C1_io alkyl, C1_io perhaloalkyl, C2_10 alkenyl, C2_10 alkynyl,
C3_14 carbocyclyl, 3-14
membered heterocyclyl, C6_14 aryl, and 5-14 membered heteroaryl, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 Rdd groups;
or two geminal hydrogens on a carbon atom are replaced with the group =O, =S,
=NN(Rbb)2, =NNRbbC(=O)Rt, =NNRbbC(=O)ORt, =NNRbbS(=O)2R-, =NRb', =NOR';
14
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
each instance of R' is, independently, selected from CI-10 alkyl, CI-10
perhaloalkyl, C2_10
alkenyl, C2_10 alkynyl, C3_10 carbocyclyl, 3-14 membered heterocyclyl, C6_14
aryl, and 5-14
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, -OH, -OR", -
N(R66)2, -
CN, -C(=O)R`, -C(=O)N(Rcc)2, -C02R.., -S02R.., -C(=NRcc)ORa, -C(=NRcc)N(R66)2 -
S02N(Rcc)2, -S02RCC, -S02ORee, -SOR-, -C(=S)N(Ree)2, -C(=O)SR66, -C(=S)SRee -
P(=O)2R', -P(=O)(R')2, -P(=O)2N(Ree)2, -P(=O)(NR' )2, C1-lo alkyl, C1-lo
perhaloalkyl, C2-lo
alkenyl, C2_10 alkynyl, C3_1o carbocyclyl, 3-14 membered heterocyclyl, C6_14
aryl, and 5-14
membered heteroaryl, or two R66 groups attached to an N atom are joined to
form a 3-14
membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,
alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5
Rdd groups;
each instance of R66 is, independently, selected from hydrogen, C1_10 alkyl,
C1_10
perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, C3_1o carbocyclyl, 3-14 membered
heterocyclyl, C6-14
aryl, and 5-14 membered heteroaryl, or two R66 groups attached to an N atom
are joined to form
a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 Rdd groups;
each instance of Rdd is, independently, selected from halogen, -CN, -NO2, -N3,
-SO2H5 -
SO3H, -OH, -ORee, -ON(R')2, N(R')2, -N(R')3+X, -N(ORee)R', -SH, -SR ee, -
SSRee, -
C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(R)2, -OC(=O)N(R)2, -
NRRC(=O)Ree, -NRC02Ree, -NR"C(=O)N(R)2, -C(=NR")ORee, -OC(=NR')Ree, -
OC(=NR")ORee, -C(=NR')N(R')2, -OC(=NR')N(R')2, -NR C(=NR")N(R )2-NR SO2Ree, -
S02N(R')2, -S02Ree, -S02ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -
C(=S)N(R')2, -
C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, -P(=O)(Ree)2, -OP(=O)(Ree)2, -
OP(=O)(ORee)2, C1_6 alkyl, C1_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl,
C3_10 carbocyclyl, 3-10
membered heterocyclyl, C6_10 aryl, 5-10 membered heteroaryl, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 R11 groups, or two geminal Rdd substituents can be joined to form
=0 or =S;
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
each instance of Ree is, independently, selected from C1_6 alkyl, C1_6
perhaloalkyl, C2_6
alkenyl, C2 alkynyl, C3_10 carbocyclyl, C6-10 aryl, 3-10 membered
heterocyclyl, and 3-10
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
each instance of R' is, independently, selected from hydrogen, C1_6 alkyl,
C1_6
perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3_10 carbocyclyl, 3-10 membered
heterocyclyl, C6_10
aryl and 5-10 membered heteroaryl, or two R' groups attached to an N atom are
joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 Rgg groups; and
each instance of Rgg is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H,
-OH,
-OC1_6 alkyl, -ON(C1_6 alkyl)2, N(C1_6 alkyl)2, -N(C1-6 alkyl)3X, NH(C1_6
alkyl)2X, -
NH2(C1-6 alkyl)X, -NH3X, N(OC1-6 alkyl)(C1-6 alkyl), -N(OH)(C1 6 alkyl), -
NH(OH), -SH, -
SC1_6 alkyl, -SS(C1_6 alkyl), -C(=O)(C1-6 alkyl), -CO2H, -C02(C1-6 alkyl), -
OC(=O)(C1_6
alkyl), -0002(C1_6 alkyl), -C(=O)NH2, -C(=O)N(C1_6 alkyl)2, -OC(=O)NH(C1_6
alkyl), -
NHC(=O)( CI -6 alkyl), -N(C1 6 alkyl)C(=O)( CI -6 alkyl), -NHCO2(C1 6 alkyl), -
NHC(=O)N(C1_
6 alkyl)2, -NHC(=O)NH(C1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6 alkyl),-
OC(=NH)(C1-6
alkyl), -OC(=NH)OC1-6 alkyl, -C(=NH)N(C1-6 alkyl)2, -C(=NH)NH(C1-6 alkyl), -
C(=NH)NH2,
-OC(=NH)N(C1 6 alkyl)2, -OC(NH)NH(C1 6 alkyl), -OC(NH)NH2, -NHC(NH)N(C1 6
alkyl)2, -
NHC(=NH)NH2, -NHSO2(C1_6 alkyl), -SO2N(C1-6 alkyl)2, -SO2NH(C1_6 alkyl), -
SO2NH2,-
SO2C1-6 alkyl, -S020C1-6 alkyl, -OS02C1_6 alkyl, -SOC1_6 alkyl, -Si(C1_6
alkyl)3, -OSi(C1-6
alkyl) -C(=S)N(C1-6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, -C(=O)S(C1-6
alkyl), -
C(=S)SC1-6 alkyl, -SC(=S)SC1_6 alkyl, -P(=0)2(C1_6 alkyl), -P(=O)(C1_6
alkyl)2, -OP(=O)(C1-6
alkyl)2, -OP(=O)(OC1 6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl,
C2 alkynyl, , C3_10
carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl;
or two geminal
Rgg substituents can be joined to form =0 or =S;
wherein X is a counterion.
[0031] As used herein, a "counterion" is a negatively charged group associated
with a
positively charged quarternary amine in order to maintain electronic
neutrality. Exemplary
counterions include halide ions (e.g., F-, Cl-, Br , I-), N03-5 C104-5 OH-,
H2PO4 , HS04 ,
sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-
toluenesulfonate,
16
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-
l-sulfonic
acid-5-sulfonate, ethan-l-sulfonic acid-2-sulfonate, and the like) and
carboxylate ions (e.g.,
acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate,
glycolate, and the like).
[0032] Nitrogen atoms can be substituted or unsubstituted as valency permits,
and include
primary, secondary, tertiary and quartemary nitrogen atoms. Exemplary nitrogen
atom
substitutents include, but are not limited to, hydrogen, -OH, -OR", -N(R )2, -
CN, -C(=O)R ,
-C(=O)N(R )2, -CO2R.., -S02R", -C(=NRbb)Ra, -C(=NRc)ORaa, -C(=NRcc)N(Rcc)2 -
SO2N(Rcc)2, -SO2R6c, -SO2OR , -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, -C(=S)SR -
P(=0)2R', -P(=O)(Rt)2, -P(=O)2N(Rcc)2, -P(=O)(NR')2, C1-lo alkyl, C1_10
perhaloalkyl, C2-10
alkenyl, C2_10 alkynyl, C3_10 carbocyclyl, 3-14 membered heterocyclyl, C6_14
aryl, and 5-14
membered heteroaryl, or two R groups attached to an N atom are joined to
form a 3-14
membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,
alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5
Rdd groups, and wherein Rte, Rbb, R and Rdd are as defined above.
[0033] In certain embodiments, the substituent present on the nitrogen atom is
an amino
protecting group. Amino protecting groups include, but are not limited to, -
OH, -ORS, -
N(R )2, -C(=O)R-, -C(=O)N(Rcc)2, -CO2R ., -SO2R-, -C(=NRcc)Raa, -C(=NRcc)ORaa
, -
C(=NR`c)N(R66)2, -S02N(Rcc)2, -SO2R66, -SO2OR , -SORaa, -C(=S)N(Rcc)2, -
C(=O)SR66 -
C(=S)SR CI-10 alkyl (e.g., aralkyl groups), C2_10 alkenyl, C2_10 alkynyl,
C3_10 carbocyclyl, 3-14
membered heterocyclyl, C6_14 aryl, and 5-14 membered heteroaryl groups,
wherein each alkyl,
alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently
substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Rte, Rbb, R and
Rdd are as defined
above. Amino protecting groups are well known in the art and include those
described in detail
in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd
edition, John
Wiley & Sons, 1999, incorporated herein by reference.
[0034] For example, amino protecting groups such as amide groups (e.g., -
C(=O)Raa)
include, but are not limited to, formamide, acetamide, chloroacetamide,
trichloroacetamide,
trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-
pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-
phenylbenzamide, o-
nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-
dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-
17
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-
phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide,
o-
nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o-
(benzoyloxymethyl)benzamide.
[0035] Amino protecting groups such as carbamate groups (e.g., -C(=O)OR")
include, but
are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl
carbamate (Fmoc), 9-
(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-
butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-
Tmoc), 4-
methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-
trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-
adamantyl)-l-
methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-
dimethyl-2,2-
dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC),
1-methyl-l-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-l-
methylethyl
carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-
dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl
carbamate
(Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl
carbamate (Ipaoc),
cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl
carbamate, N-
hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-
methoxybenzyl
carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-
chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate
(Msz), 9-
anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl
carbamate, 2-
methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-
dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-
dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-
triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl
carbamate, m-
chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-
benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl
carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl
carbamate, 3,4-
dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-
amyl
carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl
carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-
decyloxybenzyl
18
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
carbamate, 2,2-dimethoxycarbonylvinyl carbamate, o-(N,N-
dimethylcarboxamido)benzyl
carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-
dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl
carbamate, 2-
iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl
carbamate, p-(p'-
methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-
methylcyclohexyl
carbamate, 1-methyl-l-cyclopropylmethyl carbamate, 1-methyl-l-(3,5-
dimethoxyphenyl)ethyl
carbamate, 1-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl-l-
phenylethyl
carbamate, 1-methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-
(phenylazo)benzyl
carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and
2,4,6-trimethylbenzyl carbamate.
[0036] Amino protecting groups such as sulfonamide groups (e.g., -S(=O)2Rt)
include, but
are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-
trimethyl-4-
methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-
dimethyl-
4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-
methoxybenzenesulfonamide
(Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide
(Mts), 2,6-
dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-
sulfonamide (Pmc), methanesulfonamide (Ms), 0-trimethylsilylethanesulfonamide
(SES), 9-
anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide
(DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
[0037] Other amino protecting groups include, but are not limited to,
phenothiazinyl-(10)-
carbonyl derivative, N' p-toluenesulfonylaminocarbonyl derivative, N'-
phenylaminothiocarbonyl derivative, N-benzoylphenylalanyl derivative, N-
acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide
(Dts), N-2,3-
diphenylmaleimide, N-2,5-dimethylpyrrole, N- 1, 1,4,4-
tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-
substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-
pyridone, N-
methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-
acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine,
quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-
dibenzosuberylamine, N-trip henylmethylamine (Tr), N-[(4-
methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-
2,7-
19
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-
picolylamino N'-
oxide, N- 1, 1 -dimethylthiomethyleneamine, N-benzylideneamine, N-p-
methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-
pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-
isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-
chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-
cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)amine, N-borane
derivative,
N-diphenylborinic acid derivative, N-[phenyl(pentacarbonylchromium- or
tungsten)carbonyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-
nitrosoamine,
amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),
diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl
phosphoramidate,
diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-
dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-
methoxybenzenesulfenamide, triphenylmethylsulfenamide and 3-
nitropyridinesulfenamide
(Npys).
[0038] As used herein, a "leaving group" is an art-understood term referring
to a molecular
fragment that departs with a pair of electrons in heterolytic bond cleavage,
wherein the molecular
fragment is an anion or neutral molecule. See, for example, Smith, March
Advanced Organic
Chemistry 6th ed. (501-502).
[0039] These and other exemplary substituents are described in more detail in
the Detailed
Description, the Exemplification and in the claims. The invention is not
intended to be limited in
any manner by the above exemplary listing of substituents.
[0040] As used herein, a "pharmaceutically acceptable form thereof' includes
pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers,
isomers, and/or
polymorphs of a compound of the present invention, as defined below and
herein.
[0041] As used herein, the term "pharmaceutically acceptable salt" refers to
those salts
which are, within the scope of sound medical judgment, suitable for use in
contact with the
tissues of humans and lower animals without undue toxicity, irritation,
allergic response and the
like, and are commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable
salts are well known in the art. For example, S. M. Berge et al., describe
pharmaceutically
acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.
Pharmaceutically
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
acceptable salts of the compounds of this invention include those derived from
suitable inorganic
and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic
acid addition
salts are salts of an amino group formed with inorganic acids such as
hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with
organic acids such
as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic
acid or malonic acid or
by using other methods used in the art such as ion exchange. Other
pharmaceutically acceptable
salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate,
butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,
digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate,
gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-
ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-
naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,
pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate,
sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate
salts, and the like. Salts
derived from appropriate bases include alkali metal, alkaline earth metal,
ammonium and N+(C1_
4alkyl)4 salts. Representative alkali or alkaline earth metal salts include
sodium, lithium,
potassium, calcium, magnesium, and the like. Further pharmaceutically
acceptable salts include,
when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations
formed using
counterions such as halide, hydroxide, carboxylate, sulfate, phosphate,
nitrate, lower alkyl
sulfonate and aryl sulfonate.
[0042] In certain embodiments, the pharmaceutically acceptable form thereof is
an isomer.
As used herein, the term "isomer" includes any and all geometric isomers and
stereoisomers.
For example, "isomers" include cis- and trans-isomers, E- and Z- isomers, R-
and S-
enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures
thereof, and other
mixtures thereof, as falling within the scope of the invention.
[0043] In certain embodiments, the pharmaceutically acceptable form thereof is
a tautomer.
As used herein, the term "tautomer" includes two or more interconvertable
compounds resulting
from at least one formal migration of a hydrogen atom and at least one change
in valency (e.g., a
single bond to a double bond, a triple bond to a single bond, or vice versa).
The exact ratio of the
tautomers depends on several factors, including temperature, solvent, and pH.
Tautomerizations
(i.e., the reaction providing a tautomeric pair) may catalyzed by acid or
base. Exemplary
21
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
tautomerizations include keto-to-enol; amide-to-imide; lactam-to-lactim;
enamine-to-imine;
and enamine-to-(a different) enamine tautomerizations.
[0044] In certain embodiments, the pharmaceutically acceptable form thereof is
a hydrate or
solvate. As used herein, the term "hydrate" refers to a compound non-
covalently associated with
one or more molecules of water. Likewise, "solvate" refers to a compound non-
covalently
associated with one or more molecules of an organic solvent.
[0045] In certain embodiments, the pharmaceutically acceptable form thereof is
a prodrug.
As used herein, the term "prodrug" refers to a derivative of a parent compound
that requires
transformation within the body in order to release the parent compound. In
certain cases, a
prodrug has improved physical and/or delivery properties over the parent
compound. Prodrugs
are typically designed to enhance pharmaceutically and/or pharmacokinetically
based properties
associated with the parent compound. The advantage of a prodrug can lie in its
physical
properties, such as enhanced water solubility for parenteral administration at
physiological pH
compared to the parent compound, or it enhances absorption from the digestive
tract, or it may
enhance drug stability for long-term storage.
[0046] In certain embodiments, the pharmaceutically acceptable form thereof is
a
polymorph. As used herein, "polymorph" refers to a compound having more than
one crystal
structure, e.g., resulting from differences in molecular packing and/or
molecular conformation of
the compound in the solid state.
SEQUENCE IDENTIFICATION NUMBERS
[0047] SEQ. ID. No.: Homo sapiens FAAH amino acid sequence:
MV QYEL WAALPGAS GVALAC CF VAAAVALRW S GRRTARGAV V RARQRQ RAGLENM
DRAAQRFRLQNPDLDSEALLALPLPQLVQKLHSRELAPEAVLFTYVGKAWEVNKGTNC
VTSYLADCETQLSQAPRQGLLYGVPVSLKECFTYKGQDSTLGLSLNEGVPAECDSVVVH
VLKLQGAVPFVHTNVPQSMFSYDCSNPLFGQTVNPWKSSKSPGGSSGGEGALIGSGGSP
LGLGTDIGGSIRFPSSFCGICGLKPTGNRLSKSGLKGCVYGQEAVRLSVGPMARDVESLA
LCLRALLCEDMFRLDPTVPPLPFREEVYTSSQPLRVGYYETDNYTMPSPAMRRAVLETK
QSLEAAGHTLVPFLPSNIPHALETLSTGGLFSDGGHTFLQNFKGDFVDPCLGDLVSILKLP
QWLKGLLAFLVKPLLPRLSAFLSNMKSRSAGKLWELQHEIEVYRKTVIAQWRALDLDV
22
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
VLTPMLAPALDLNAPGRATGAVSYTMLYNCLDFPAGVVPVTTVTAEDEAQMEHYRGY
FGDIWDKMLQKGMKKSVGLPVAVQCVALPWQEELCLRFMREVERLMTPEKQSS
DETAILED DESCRIPTION
I. Compounds
[0048] The present invention provides isoxazoline FAAH inhibitor compounds of
the
formula (I):
O Rd
N/
\ Rc
Rb
G Ra
(I)
or a pharmaceutically acceptable form thereof,
wherein:
(i) each of Ra, Rb, and Rc independently is selected from -H, Ci_io alkyl and
CI-10
perhaloalkyl, Rd is the group -L-Z, and Z is selected from C6_14 aryl;
(ii) each of Ra, Rb, and Rc independently is selected from -H, C1-lo alkyl and
Ci_io
perhaloalkyl, Rd is the group -L-Z, and Z is selected from 3-14 membered
heterocyclyl and 5-14 membered heteroaryl;
(iii) Ra and Rd are joined to form a C3_10 carbocycyl or 3-14 membered
heterocyclyl
fused ring, and Rb and R' are independently selected from -H, C1_10 alkyl and
Ci_
perhaloalkyl; or
(iv) R' and Rd are joined to form a C3_10 carbocycyl or 3-14 membered
heterocyclyl
spiro-fused ring, and Ra and Rb are independently selected from -H, Ci_io
alkyl
and CI-10 perhaloalkyl;
L is a covalent bond or a divalent C1_6 hydrocarbon group, wherein one, two or
three
methylene units of L are optionally and independently replaced with one or
more oxygen, sulfur
or nitrogen atoms;
G is selected from -CN, -NO2, -S(=O)Re, _S02R e, -SO2NRfRe, -PO2Re, -PO2ORe, -
PO2NRfRe, -(C=O)Re, -(C=O)ORe, -(C=O)NRfRe, -Br, -I, -F, -Cl, -ORe, -ONRfRe, -
23
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
ONRR(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRRPO2ORe, -SRe, -OSO2Re, -NR'SO2Re, -
OPO2Re, -OPO2ORe, -NR'PO2Re, -NR'PO2ORe, -OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -
NRfRe, -NR(C=O)Re,-NR(C=O)ORe, -O(C=O)NRRRe, -NRf(C=NRf)NRfRe, -
O(C=NRf)NRfRe, -NR(C=NRR)ORe, -[N(Rf)2Re]+X- wherein Xis a counterion; and
each Re is selected from C1_10 alkyl, C2-1o alkenyl, C2-1o alkynyl, C3_10
carbocycyl, C6_14
aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl; each Rf
attached to a nitrogen
atom is, independently, selected from -H, C1_10 alkyl, or an amino protecting
group; or Re and Rf
are joined to form an 3-14 membered heterocyclyl ring or an 5-14 membered
heteroaryl ring.
Group G
[0049] As defined above, G is selected from -CN, -NO2, -S(=O)Re, -S02Re, -
SO2NRfRe, -
PO2Re, -P02ORe, -PO2NRfRe, -(C=O)Re, -(C=O)ORe, -(C=O)NRfRe, -Br, -I, -F, -Cl,
-ORe, -
ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -SRe, -OS02Re, -
NRfSO2Re, -OP02Re, -OP02ORe, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe, _O(C=O)R e,
-
O(C=O)ORe, -NRfRe, -NRf(C=O)Re,-NRf(C=O)ORe, -O(C=O)NRfRe, -NRf(C=NR)NRfRe, -
O(C=NRf)NRfRe, -NRf(C=NRf)ORe, -[N(Rf)2Re]+X wherein Xis a counterion;
and wherein Re is selected from C1_10 alkyl, C2_10 alkenyl, C2-1o alkynyl,
C3_10
carbocycyl, C6_14 aryl, 3-14 membered heterocyclyl and 5-14 membered
heteroaryl; each Rf
attached to a nitrogen atom is, independently, selected from -H, C1_10 alkyl,
or an amino
protecting group; or Re and Rf are joined to form an 3-14 membered
heterocyclyl ring or an 5-14
membered heteroaryl ring.
[0050] In certain embodiments, G is not a leaving group, e.g., for example, G
is selected
from -F, -CN, -NO2, -S(=O)Re, -S02Re, -SO2NRfRe, -P02Re, -P020Re, -PO2NRfRe, -
(C=O)Re, -(C=O)ORe, and -(C=O)NRfRe.
[0051] In certain embodiments, G is selected from -CN and -NO2. In certain
embodiments,
G is -CN. In certain embodiments, G is -NO2.
[0052] In certain embodiments, G is selected from -S(=O)Re, -S02Re, and -
SO2NRfRe. In
certain embodiments, G is -S(=O)Re. In certain embodiments, G is -S02Re. In
certain
embodiments, G is -SO2NRfRe.
24
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0053] In certain embodiments, G is selected from -PO2Re, -P02ORe and -
PO2NRfRe. In
certain embodiments, G is -PO2Re. In certain embodiments, G is -PO2ORe. In
certain
embodiments, G is -PO2NRfRe.
[0054] In certain embodiments, G is selected from -(C=O)Re, -(C=O)ORe and -
(C=O)NRfRe. In certain embodiments, G is -(C=O)Re. In certain embodiments, G
is -
(C=O)ORe. In certain embodiments, G is -(C=O)NRfRe.
[0055] However, in certain embodiments, G is a leaving group, e.g., for
example, G is
selected from -Cl, -Br, -I, -ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -
ONRfPO2Re, -
ONRfPO2ORe, -SRe, -OS02Re, -NRfSO2Re, -OPO2Re, -OPO2ORe, -NRfP02Re, -
NRfP02ORe,
-OPO2NRfRe, -O(C=O)Re, -O(C=O)ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -
O(C=O)NRfRe, -NRf(C=NR)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NRf)ORe, and -[N(R)2Re]+X
wherein X is a counterion.
[0056] In certain embodiments, G is a halogen; i.e., selected from -F, -Cl, -
Br and -I. In
certain embodiments, G is -F. In certain embodiments, G is -Br. In certain
embodiments, G is -
1. In certain embodiments, G is -Cl. However, in certain embodiments, G is not
a halogen. For
example, in certain embodiments, G is not -Br. In certain embodiments, G is
not -I. In certain
embodiments, G is not -F. In certain embodiments, G is not -Cl.
[0057] In certain embodiments, G is selected from -ORe, -ONRfRe, -ONRf(C=O)Re,
-
ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -OSO2Re, -OPO2Re, -OP02ORe, -OPO2NRfRe, -
O(C=O)Re, -O(C=O)ORe, -O(C=O)NRfRe and -O(C=NRf)NRfRe. In certain embodiments,
G is
selected from -ORe, -O(C=O)Re, -O(C=O)ORe, -O(C=O)NRfRe and -O(C=NRf)NRfRe. In
certain embodiments, G is selected from -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -
ONRfPO2Re, -ONRfPO2ORe, -OPO2NRfRe, -O(C=O)NRfRe and -O(C=NRf)NRfRe. In
certain
embodiments, G is -ORe. In certain embodiments, G is -ONRfRe. In certain
embodiments, G is
-ONRf(C=O)Re. In certain embodiments, G is -ONRfSO2Re. In certain embodiments,
G is -
ONRfPO2Re. In certain embodiments, G is -ONRfPO2ORe. In certain embodiments, G
is -
OSO2Re. In certain embodiments, G is -OPO2Re. In certain embodiments, G is -
OPO2ORe. In
certain embodiments, G is -OPO2NRfRe. In certain embodiments, G is -O(C=O)Re.
In certain
embodiments, G is -O(C=O)ORe. In certain embodiments, G is -O(C=O)NRfRe. In
certain
embodiments, G is -O(C=NRf)NRfRe.
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0058] In certain embodiments, G is selected from -ORe and -SRe. In certain
embodiments,
G is selected from -ORe. In certain embodiments, G is -SRe.
[0059] In certain embodiments, G is selected from -NRfSO2Re, -NRfPO2Re, -
NRfPO2ORe, -
NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -NRf(C=NRf)NRfRe, -NRf(C=NR)ORe and -
[N(R)2Re]+X- wherein X- is a counterion. In certain embodiments, G is selected
from -
NRfSO2Re, -NRfP02Re, -NRfP020Re, -NRfRe, -NRf(C=O)Re and -NRf(C=O)ORe. In
certain
embodiments, G is selected from -NRfSO2Re, -NRfRe, -NRf(C=O)Re and -
NRf(C=O)ORe. In
certain embodiments, G is -NRfSO2Re. In certain embodiments, G is -NRfPO2Re.
In certain
embodiments, G is -NRfPO2ORe. In certain embodiments, G is -NRfRe. In certain
embodiments, G is -NRf(C=O)Re. In certain embodiments, G is -NRf(C=O)ORe. In
certain
embodiments, G is -NRf(C=NR)NRfRe. In certain embodiments, G is -NRf(C=NR)ORe.
In
certain embodiments, G is -[N(Rf)2Re]+X- wherein Xis a counterion.
[0060] Additional embodiments of G, included in the description of groups Re
and Rf, and
further exemplified in the Tables and Examples, is provided below and herein.
Re of Group G
[0061] As defined generally above, in certain embodiments, wherein G is
selected from -
S(=O)Re, -SO2Re, -SO2NRfRe, -PO2Re, -PO2ORe, -PO2NRfRe, -(C=O)Re, -(C=O)ORe, -
(C=O)NRfRe, -ORe, -ONRfRe, -ONRf(C=O)Re, -ONRfSO2Re, -ONRfPO2Re, -ONRfPO2ORe, -
SRe, -OSO2Re, -NRfSO2Re, -OPO2Re, -OPO2ORe, -NRfPO2Re, -NRfPO2ORe, -OPO2NRfRe,
-
O(C=O)Re, -O(C=O)ORe, -NRfRe, -NRf(C=O)Re, -NRf(C=O)ORe, -O(C=O)NRfRe, -
NRf(C=NRf)NRfRe, -O(C=NRf)NRfRe, -NRf(C=NR)ORe, and -[N(Rf)2Re]+X wherein X is
a
counterion, Re is selected from CI-10 alkyl, C2_10 alkenyl, C2_io alkynyl,
C3_io carbocycyl, C6_14
aryl, 3-14 membered heterocyclyl and 5-14 membered heteroaryl.
[0062] In certain embodiments, Re is selected from CI-10 alkyl, C2_10 alkenyl,
C2_10 alkynyl,
C3_io carbocycyl, C6-14 aryl, 3-14 membered heterocyclyl and 5-14 membered
heteroaryl,
wherein the alkyl, alkenyl, alkynyl, carbocycyl, aryl, heterocyclyl, and
heteroaryl groups are
substituted with 0, 1, 2, 3, 4 or 5 Rh groups, as defined below and herein.
[0063] In certain embodiments, Re is CI-10 alkyl. In certain embodiments, Re
is C1 alkyl.
In certain embodiments, Re is C1-6 alkyl substituted with 0, 1, 2, 3, 4 or 5
Rh groups. In certain
embodiments, Re is a C1_5 alkyl substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
In certain
26
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
embodiments, Re is a C1_4 alkyl substituted with 0, 1, 2, 3 or 4 Rh groups. In
certain
embodiments, Re is a C1_3 alkyl substituted with 0, 1, 2 or 3 Rh groups. In
certain embodiments,
Re is a C1 2 alkyl substituted with 0, 1 or 2 Rh groups. Exemplary alkyl
groups include, but are
not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tent-butyl, pentyl,
isopentyl, neopentyl, and hexyl, wherein such groups are substituted with 0,
1, 2, 3, 4 or 5 Rh
groups.
[0064] In certain embodiments, Re is a C1_6 perhaloalkyl. In certain
embodiments, Re is a C1_
perhaloalkyl. In certain embodiments, Re is a C1-4perhaloalkyl. In certain
embodiments, Re is
a C1_3 perhaloalkyl. In certain embodiments, Re is a C1_2 perhaloalkyl.
Exemplary Re
perhaloalkyl groups include, but are not limited to, -CF3, -CF2CF3, -
CF2CF2CF3, -CC13, -
CFC12, and -CF2C1.
[0065] In certain embodiments, Re is C2_1o alkenyl. In certain embodiments, Re
is C2-6
alkenyl. In certain embodiments, Re is a C2_6 alkenyl substituted with 0, 1,
2, 3, 4 or 5 Rh groups.
In certain embodiments, Re is a C2-5 alkenyl substituted with 0, 1, 2, 3, 4 or
5 Rh groups. In
certain embodiments, Re is a C2-3 alkenyl substituted with 0, 1, 2, or 3 Rh
groups. Exemplary
alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2
propenyl, 1-butenyl, 2-
butenyl, butadienyl, pentenyl, pentadienyl and hexenyl, wherein such groups
are substituted with
0, 1, 2, 3, 4 or 5 Rh groups.
[0066] In certain embodiments, Re is C2_10 alkynyl. In certain embodiments, Re
is C2-6
alkynyl. In certain embodiments, Re is C2_6 alkynyl substituted with 0, 1, 2,
3, 4 or 5 Rh groups.
In certain embodiments, Re is C2_5 alkynyl substituted with 0, 1, 2, 3, 4 or 5
Rh groups. In certain
embodiments, Re is C2_4 alkynyl substituted with 0, 1, 2, 3 or 4 Rh groups. In
certain
embodiments, Re is C2_3 alkynyl substituted with 0, 1, 2 or 3 Rh groups.
Exemplary Re alkynyl
groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-
butynyl, 2-butynyl,
pentynyl and hexynyl, wherein such groups are substituted with 0, 1, 2, 3, 4
or 5 Rh groups.
[0067] However, in certain embodiments, wherein G is -ORe, then Re is not C1{
alkyl (e.g.,
methyl, ethyl, propyl, isopropyl, aralkyl). In certain embodiments, wherein G
is -ORe, then Re is
not C2-6alkenyl (e.g., allyl).
[0068] In certain embodiments, wherein G is -SRe, then Re is not then Re is
not C1-6 alkyl
(e.g., methyl, ethyl, propyl, isopropyl, aralkyl).
27
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0069] In certain embodiments, wherein G is -NReRf and Rf is -H or Ci_3 alkyl
(e.g., methyl,
ethyl, aralkyl) then Re is not C1-6 alkyl.
[0070] In certain embodiments, Re is C6_14 aryl. In certain embodiments, Re is
C6_io aryl. In
certain embodiments, Re is C6_10 aryl substituted with 0, 1, 2, 3, 4 or 5 Rh
groups. In certain
embodiments, Re is C6 aryl (e.g., phenyl) substituted with 0, 1, 2, 3, 4 or 5
Rh groups. In certain
embodiments, Re is a Cio aryl (e.g., naphthyl) substituted with 0, 1, 2, 3, 4
or 5 Rh groups.
[0071] In certain embodiments, Re is phenyl. In certain embodiments, Re is
phenyl
substituted with 0, 1, 2, 3 or 4 Rh groups. In certain embodiments, Re is
phenyl substituted with
0, 1, 2 or 3 Rh groups. In certain embodiments, Re is phenyl substituted with
0, 1 or 2 Rh groups.
In certain embodiments, Re is phenyl substituted with 0 or 1 Rh groups. In
certain embodiments,
Re is a disubstituted phenyl (i.e., substituted with 2 Rh groups). In certain
embodiments, Re is a
monosubstituted phenyl (i.e., substituted with 1 Rh group). In certain
embodiments, Re is an
unsubstituted phenyl (i.e., substituted with 0 Rh groups).
[0072] In certain embodiments, Re is phenyl substituted with at least one
ortho Rh group. In
certain embodiments, Re is phenyl substituted with at least one meta Rh group.
In certain
embodiments, Re is phenyl substituted with at least one para Rh group.
[0073] In certain embodiments, Re is a phenyl group of the formula:
vw
~ i (Rh)x
(i-a)
wherein x is 0, 1, 2, 3, 4 or 5, and Rh is as defined below and herein. In
certain
embodiments, x is 0, 1, 2, 3 or 4. In certain embodiments, x is 0, 1, 2 or 3.
In certain
embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1. In certain
embodiments, x is 3.
In certain embodiments, Re is a disubstituted phenyl group (i.e., wherein x is
2). In certain
embodiments, Re is a monosubstituted phenyl group (i.e., wherein x is 1). In
certain
embodiments, Re is an unsubstituted phenyl group (i.e., wherein x is 0).
[0074] For example, in certain embodiments, Re is a substituted or
unsubstituted phenyl
group of any one of the formulae:
28
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309 R n R h Rh
\ I \ I \ Rn Rn \ Rn Rn Rn \ Rn \ Rn
R h Rn
Rn Rn \ I \ I Rh Rn Rn / Rn Rn Rn
Rh Rh Rh Rn \ I Rn Rn
Rh Rh Rn Rh Rn Rn Rh Rn
Rn / Rn
Rh Rh Rh Rn Rn Rh
Rn Rn Rn Rn Rn Rn Rn
or
wherein Rh is as defined below and herein.
[0075] In certain embodiments, Re is a naphthyl. In certain embodiments, Re is
a naphthyl
group of any one of the formulae:
(Rh)X or
(Rn)X
(i-b)
(i-c)
wherein x is 0, 1, 2, 3, 4 or 5, and Rh is as defined below and herein. In
certain
embodiments, x is 0, 1, 2, 3 or 4. In certain embodiments, x is 0, 1, 2 or 3.
In certain
embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1. In certain
embodiments, Re is a
trisubstituted naphthyl group (i.e., wherein x is 3). In certain embodiments,
Re is a disubstituted
naphthyl group (i.e., wherein x is 2). In certain embodiments, Re is a
monosubstituted naphthyl
group (i.e., wherein x is 1). In certain embodiments, Re is an unsubstituted
naphthyl group (i.e.,
wherein x is 0).
[0076] For example, in certain embodiments, Re is a substituted or
unsubstituted 1-naphthyl
group of any one of the formulae:
29
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Rh
Rh Rh Rh
Rh
h h R"
R / \ R \ / Rh
Rn \ I / \ I / \ I / \ / Rn Rh
Rh
Rh Rh
\ I / R" Rh or Rh
wherein Rh is as defined below and herein.
[0077] In certain embodiments, Re is a substituted or unsubstituted 2-naphthyl
group of any
one of the formulae:
wu
R h
\ I \ I \ I \ Rn Rh Rh
Rh
/ / / I \ \ \ R"
R" \ I \ I \ I R" R h Rn \ I \
\ I \ I \ Rh Rh Rh Rh
wu
\ I \ I Rh
R" Rh or Rh \
wherein Rh is as defined below and herein.
[0078] However, in certain embodiments, wherein G is -ORe, then Re is not Cio
aryl (e.g., 1-
naphthyl, 2-naphthyl).
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0079] In certain embodiments, Re is 5-14 membered heteroaryl. In certain
embodiments, Re
is a 5-10 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
In certain
embodiments, Re is a 5-8 membered heteroaryl substituted with 0, 1, 2, 3, 4 or
5 Rh groups. In
certain embodiments, Re is a 5-6 membered heteroaryl substituted with 0, 1, 2,
3 or 4 Rh groups.
In certain embodiments, Re is a 9-10 membered heteroaryl substituted with 0,
1, 2, 3, 4 or 5 Rh
groups.
[0080] Exemplary Re heteroaryl groups include, but are not limited to,
pyrrolyl, furanyl and
thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g., 2-pyridinyl, 3-
pyridinyl, 4-pyridinyl),
pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-
pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl), pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl,
thiepinyl, indolyl, isoindolyl,
indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,
benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
benzisothiazolyl,
benzthiadiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl,
quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl,
dibenzofuranyl, carbazolyl,
acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, wherein such groups
are substituted
with 0, 1, 2, 3, 4 or 5 Rh groups.
[0081] In certain embodiments, Re is a 5 -membered heteroaryl. In certain
embodiments, Re
is a 5-membered heteroaryl substituted with 0, 1, 2 or 3 Rh groups. In certain
embodiments, Re
is a 5-membered heteroaryl selected pyrrolyl, furanyl, thiophenyl, imidazolyl,
pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl,
thiadiazolyl and tetrazolyl,
wherein such groups are substituted with 0, 1, 2 or 3 Rh groups.
[0082] For example, in certain embodiments, Re is a 5-membered heteroaryl of
the formula:
Ya
\ b
aO/Y
Y NYC
(i-d)
wherein Ya, Yb, Ye and Yd are, independently, selected from CH, CRh, 0, S, N,
or NRk,
with the proviso that at least one of Ya, Yb, Ye and Yd is 0, S, N or NRk, and
wherein Rh and
Rkare defined below and herein.
31
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0083] In certain embodiments of the above formula (i-d), Ya is 0, S, N, or
NRk and yb, y,
and Yd are, independently, selected from CH, CRh, NRk or N. In certain
embodiments of the
above formula (i-d), Ya is 0, S, N, or NRk and Yb, Y and yd are,
independently, selected from
CH or CRh. In certain embodiments of the above formula (i-d), Ya is 0, S, or
NRk, Y is N and
Yb and Yd are, independently, selected from CH or CRh.
[0084] In certain embodiments of the above formula (i-d), Yb is 0, S, or NRk
and Ya, Y and
Yd are, independently, selected from CH, CRh or N. In certain embodiments of
the above
formula (i-d), Yb is 0, S, or NRk and Ya, Y and yd are, independently,
selected from CH or CRh.
In certain embodiments of the above formula (i-d), Yb is 0, S, or or NRk, yd
is N and Ya and Y'
are, independently, selected from CH or CRh.
[0085] In certain embodiments, Re is a substituted or unsubstituted 5-membered
heteroaryl
of any one of the formulae:
% L% fj~
LNk 6>(Rh). ~O
(Rh)x (Rh)x (Rh)x N / N (R h)
5 5
NRk
NRk
N (Rh)x N (Rh)x
N (Rh)x N (Rh)x
L
k
~N\ N, N, N,
N 0 S NRk
N (Rh). N (Rh)x N (Rh)x N (Rh)x
L4/ N-N~~
S /NRk NRk
N
(Rh)x N (Rh)x ~nj (Rh)x NN (Rh). NNR (Rh)x
or
wherein x is 0, 1 or 2, and Rh and Rk are as defined below and herein. In
certain
embodiments, Re is an unsubstituted 5-membered heteroaryl (i.e., wherein x is
0). In certain
embodiments, Re is a substituted 5-membered heteroaryl (e.g., wherein x is 1
or 2). In certain
embodiments, Re is a monosubstituted 5-membered heteroaryl (i.e., wherein x is
1). In certain
32
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
embodiments, Re is a disubstituted 5-membered heteroaryl (i.e., wherein x is
2). In certain
embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.
[0086] However, in certain embodiments, wherein G is -OR e, Re is not
thiazolyl, e.g., of the
formula:
,s~
>' (Rh)x
N
wherein x is 0, 1 or 2, and Rh and Rk are as defined below and herein.
[0087] In certain embodiments, Re is a 6-membered heteroaryl. In certain
embodiments, Re
is a 6-membered heteroaryl substituted with 0, 1, 2, 3 or 4 Rh groups. In
certain embodiments,
Re is a 6-membered heteroaryl selected from the group consisting of pyridinyl
(e.g., 2-pyridinyl,
3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl),
pyrimidinyl (e.g. 2-
pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl, triazinyl and
tetrazinyl, wherein such
groups are substituted with 0, 1, 2, 3 or 4 Rh groups.
[0088] For example, in certain embodiments, Re is a 6-membered heteroaryl
group of the
formula:
Wa_Wb
WC
We=Wd
(i-e)
wherein Wa, Wb, We, Wd and We are, independently, selected from CH, CRh or N,
with
the proviso that at least one of Wa, Wb, We, Wd, and We is N, and wherein Rh
is as defined below
and herein.
[0089] In certain embodiments, Re is a pyrindinyl group. In certain
embodiments, Re is a
pyrindinyl group substituted with 0, 1, 2, 3 or 4 Rh groups. For example, in
certain
embodiments, Re is a pyrindinyl group of the formula:
N
(R")X
wherein x is 0, 1, 2, 3 or 4, and Rh is as defined below and herein. In
certain
embodiments, Re is an unsubstituted pyrindinyl (i.e., wherein x is 0). In
certain embodiments, Re
33
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
is a substituted pyrindinyl (e.g., wherein x is 1, 2, 3 or 4). In certain
embodiments, Re is a
monosubstituted pyrindinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
pyrindinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted pyrindinyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[0090] In certain embodiments, Re is a 2-pyrindinyl group, e.g., of the
formula (i-e) wherein
Wa is N and Wb, We, Wd and We are, independently, CH or CRh. In certain
embodiments Re is a
3-pyrindinyl group, e.g., of the formula (i-e) wherein Wb is N and Wa, We, Wd
and We are,
independently, CH or CRh. In certain embodiments Re is a 4-pyrindinyl group,
e.g., of the
formula (i-e) wherein We is N and Wa, Wb, Wd and We are, independently, CH or
CRh.
[0091] In certain embodiments, Re is a substituted or unsubstituted 2-
pyridinyl group of any
one of the formulae:
n N Rn N
R 1jr N~ N R d-- N~ I &--,
\ I \ I R h Rh Rn \ Rn Rh
ww
Rn N N
N~ I N~ I \ Rn Rn \
Rn Rn Rn Rn Rn
or
wherein Rh is as defined below and herein.
[0092] In certain embodiments, Re is a substituted or unsubstituted 3-
pyridinyl group of any
one of the formulae:
6,1 R n N~ R 6,1 N~ I Rn Rn
N 1 N Rn Rn Rh N Rn
Rn Rn
N \ I Rn / Rh NN \ I Rn
Rn N I Rn N Rn
or
wherein Rh is as defined below and herein.
34
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0093] In certain embodiments, Re is a substituted or unsubstituted 4-
pyridinyl group of any
one of the formulae:
Rh RRh RRha::, N Rh N Rh or N Rh
wherein Rh is as defined below and herein.
[0094] In certain embodiments, Re is a pyridazinyl group. In certain
embodiments, Re is a
pyridazinyl group substituted with 0, 1, 2 or 3 Rh groups. For example, in
certain embodiments,
Re is a pyridazinyl group of the formula:
N
N
(R")X
wherein x is 0, 1, 2 or 3, and Rh is as defined below and herein. In certain
embodiments,
Re is an unsubstituted pyridazinyl (i.e., wherein x is 0). In certain
embodiments, Re is a
substituted pyridazinyl (e.g., wherein x is 1, 2 or 3). In certain
embodiments, Re is a
monosubstituted pyridazinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
pyridazinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted pyridazinyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[0095] In certain embodiments, Re is a 3-pyridazinyl group, e.g., of the
formula (i-e)
wherein Wa and Wb are N and We, Wd and We are, independently, CH or CRh. In
certain
embodiments Re is a 4-pyridazinyl group, e.g., of the formula (i-e) wherein Wb
and We are N
and Wa, Wd and We are, independently, CH or CRh.
[0096] In certain embodiments, Re is a substituted or unsubstituted 3-
pyridazinyl group of
any one of the formulae:
Rh
Rh Ni N/ Rh N N
N N i N- N N- Rh N
N I N I N Rh Rh N Rh Rh Rh
wherein Rh is as defined below and herein.
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0097] In certain embodiments, Re is a substituted or unsubstituted 4-
pyridazinyl group of
any one of the formulae:
Rh Rh Rh Rh Rh Rh
N N N N I h N N ~r'~~ h N I h
N N N 5 N R N R or N R
wherein Rh is as defined below and herein.
[0098] In certain embodiments, Re is a pyrimidinyl group. In certain
embodiments, Re is a
pyrimidinyl group substituted with 0, 1, 2 or 3 Rh groups. For example, in
certain embodiments,
Re is a pyrimidinyl group of the formula:
N
~Rh).
wherein x is 0, 1, 2 or 3, and Rh is as defined below and herein. In certain
embodiments,
Re is an unsubstituted pyrimidinyl (i.e., wherein x is 0). In certain
embodiments, Re is a
substituted pyrimidinyl (e.g., wherein x is 1, 2 or 3). In certain
embodiments, Re is a
monosubstituted pyrimidinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
pyridazinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted pyrimidinyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[0099] In certain embodiments, Re is a 2-pyrimidinyl group, e.g., of the
formula (i-e)
wherein Wa and We are N and Wb, We and Wd are, independently, CH or CRh. In
certain
embodiments Re is a 4-pyrimidinyl group, e.g., of the formula (i-e) wherein Wa
and We are N
and Wb, Wd and We are, independently, CH or CRh. In certain embodiments Re is
a 5-
pyrimidinyl group, e.g., of the formula (i-e) wherein Wb and Wd are N and Wa,
We and We are,
independently, CH or CRh.
[00100] In certain embodiments, Re is a substituted or unsubstituted 2-
pyrimidinyl group of
any one of the formulae:
N N N N
Ni N N N I Rh I N N
Rh Rh Rh or Rh Rh
36
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
wherein Rh is as defined below and herein.
[00101] In certain embodiments, Re is a substituted or unsubstituted 4-
pyrimidinyl group of
any one of the formulae:
INA"
Rn R" Rn
Rh N R" R" N R" N R" or R wherein Rh is as defined below and herein.
[00102] In certain embodiments, Re is a substituted or unsubstituted 5-
pyrimidinyl group of
any one of the formulae:
h
I / I R h r~l ,_R
NYN NYN
NON NON R h R h
, , , or
wherein Rh is as defined below and herein.
[00103] In certain embodiments, Re is a pyrazinyl group. In certain
embodiments, Re is a
pyrazinyl group substituted with 0, 1, 2 or 3 Rh groups. For example, in
certain embodiments, Re
is a pyrazinyl group of the formula:
N
N
(R h).
wherein x is 0, 1, 2 or 3, and Rh is as defined below and herein. In certain
embodiments, Re is an unsubstituted pyrazinyl (i.e., wherein x is 0). In
certain embodiments, Re
is a substituted pyrazinyl (e.g., wherein x is 1, 2 or 3). In certain
embodiments, Re is a
monosubstituted pyrazinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
pyrazinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted pyrazinyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[00104] In certain embodiments, Re is a substituted or unsubstituted pyrazinyl
group of any
one of the formulae:
37
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
n N Rn N Rn N
N R N N I N~-KRn N
N J N J N Rn Rn N Rn Rn Rn
or
wherein Rh is as defined below and herein.
[00105] In certain embodiments Re is a triazinyl group. In certain embodiments
Re is a
triazinyl group substituted with 0, 1 or 2 Rh groups. For example, in certain
embodiments, Re is
a triazinyl group of the formula:
/\ N
N
N (R")X
wherein x is 0, 1 or 2, and Rh is as defined below and herein. In certain
embodiments,
Re is an unsubstituted pyrazinyl (i.e., wherein x is 0). In certain
embodiments, Re is a substituted
pyrazinyl (e.g., wherein x is 1 or 2). In certain embodiments, Re is a
monosubstituted pyrazinyl
(i.e., wherein x is 1). In certain embodiments, Re is a disubstituted
pyrazinyl (i.e., wherein x is
2). In certain embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or
1.
[00106] In certain embodiments, Re is a substituted or unsubstituted triazinyl
group of any one
of the formulae:
Ni _N Ni N Ni N
`NJ `N~Rn or Rnl~ NRn
wherein Rh is as defined below and herein.
[00107] In certain embodiments Re is a tetrazinyl group. In certain
embodiments Re is a
tetrazinyl group substituted with 0 or 1 Rh groups. For example, in certain
embodiments, Re is a
tetrazinyl group of the formula:
N N
N ,, N
(R ")X
wherein x is 0 or 1, and Rh is as defined below and herein. In certain
embodiments,
Re is an unsubstituted pyrazinyl (i.e., wherein x is 0). In certain
embodiments, Re is a substituted
pyrazinyl (e.g., wherein x is 1). In certain embodiments, x is 0 or 1.
38
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00108] In certain embodiments, Re is a substituted or unsubstituted
tetrazinyl group of any
one of the formulae:
Ni N
Ni N N ~N
1 11 Y
N N or Rh
wherein Rh is as defined below and herein.
[00109] In certain embodiments, Re is a 9-membered heteroaryl (e.g., a 5,6-
bicyclic
heteroaryl). In certain embodiments, Re is a 5,6-bicyclic heteroaryl
substituted with 0, 1, 2, 3, 4
or 5 Rh groups. In certain embodiments, Re is a 5,6-bicyclic heteroaryl
selected from indolyl,
isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl,
benzofuranyl,
benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzoxadiazolyl, benzthiazolyl,
benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl, wherein such
groups are substituted
with 0, 1, 2, 3, 4 or 5 Rh groups.
[00110] For example, in certain embodiments, Re is a 5,6-bicyclic heteroaryl
of the formula:
YkY\Y"~Y
YJY'Yg
(i-f)
wherein ye, yf, Yg, Y', Y', yk and Ym are, independently, C, CH, CRh, 0, S, N,
or
NRk and Y" is C or N, with the proviso that at least one of ye, Yf, Yg is
selected from 0, S, N or
NRk wherein Rh and Rk are as defined below and herein.
[00111] In certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the
formula (i-f),
wherein ye is selected from 0, S, or NRk, Y" is C, and Yf, Yg, Y', Y', Yk and
Ym are,
independently, C, CH, or CRh. For example, in certain embodiments, Re is a 5,6-
bicyclic
heteroaryl group of the formulae:
ss" 0 S_ g ss NRk
Rh (Rh)x (Rh
( )x )x
or
wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined below and herein. In
certain
embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein x
is 0). In certain
39
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is
1, 2, 3, 4 or 5). In
certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 1). In
certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 2). In
certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 3). In
certain embodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or
2. In certain
embodiments, x is 0 or 1.
[00112] In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein Ye is
selected from
0, S, or NRk; Y' is N; Y' is C; Yf is C, CH, or CRh or N, and Y', Y', Yk and
Ym are,
independently, C, CH, or CRh. For example, in certain embodiments, Re is a 5,6-
bicyclic
heteroaryl group of the formulae:
s'~ 5 ~s s'~ / NRk N
Rh) (Rh)x (Rh)x (Rh)x N
N I N ~N , or `NR
wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined below and herein. In
certain
embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein x
is 0). In certain
embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is
1, 2, 3, 4 or 5). In
certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 1). In
certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 2). In
certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 3). In
certain embodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or
2. In certain
embodiments, x is 0 or 1.
[00113] In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein ye is
NRk, S or 0; Ym
is N; Y" is C; and Yf, Yg, Y', Y, and Yk are, independently, C, CH, or CRh.
For example, in
certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the formulae:
~.S`~
s" iN NRk N N O
Rh (Rh)x (Rh
)x )x
or
wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined below and herein. In
certain
embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein x
is 0). In certain
embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is
1, 2, 3, 4 or 5). In
certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 1). In
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 2). In
certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 3). In
certain embodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or
2. In certain
embodiments, x is 0 or 1.
[00114] In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein Y' is
0, S, or NRk;
Ym is N; Y" is C; and ye, Yf, Y', Y' and Yk are, independently, C, CH, or CRh.
For example, in
certain embodiments, Re is a 5,6-bicyclic heteroaryl group of the formulae:
s- ~N
r_ Q
N
(Rh)X I (Rh)X (Rh)x
~NR5 O or S
wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined below and herein. In
certain
embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein x
is 0). In certain
embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is
1, 2, 3, 4 or 5). In
certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 1). In
certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 2). In
certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 3). In
certain embodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or
2. In certain
embodiments, x is 0 or 1.
[00115] In certain embodiments, Re is a 5,6-bicyclic heteroaryl wherein ye is
selected from
N; Y" is N; and Yf, Y', Y', Yk and Ym are, independently, C, CH, or CRh. For
example, in certain
embodiments, Re is a 5,6-bicyclic heteroaryl group of the formula:
X.
-,-N
(Rh)x
wherein x is 0, 1, 2, 3, 4 or 5 and Rh and Rk are defined below and herein. In
certain
embodiments, Re is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein x
is 0). In certain
embodiments, Re is a substituted 5,6-bicyclic heteroaryl (e.g., wherein x is
1, 2, 3, 4 or 5). In
certain embodiments, Re is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 1). In
certain embodiments, Re is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 2). In
certain embodiments, Re is a trisubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein x is 3). In
41
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
certain embodiments, x is 0, 1, 2 or 3. In certain embodiments, x is 0, 1 or
2. In certain
embodiments, x is 0 or 1.
[00116] In certain embodiments, Re is a l0-membered heteroaryl (e.g., a 6,6-
bicyclic
heteroaryl). In certain embodiments, Re is a 6,6-bicyclic heteroaryl
substituted with 0, 1, 2, 3, 4
or 5 Rh groups. In certain embodiments, Re is a 6,6-bicyclic heteroaryl
selected from
naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl,
quinoxalinyl, phthalazinyl and
quinazolinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or 5 Rh
groups.
[00117] For example, in certain embodiments, Re is a 6,6-bicyclic heteroaryl
of the formula:
11 Wn Wf
W"' W9
C II
I I
W\ , Wh
W'
(i-g)
wherein Wf, Wg, Wh, W', W', Wk, Wm and W" are, independently, selected from C,
CH, CRh or N, with the proviso that at least one of Wf, Wg, Wh, W', Ww, Wk, Wm
and W" is N,
and wherein Rh is as defined below and herein.
[00118] In certain embodiments, Re is a quinolinyl group; e.g., of the formula
(i-g) wherein
W' is N and Wg, Wh, Wf, Wi, Wk, Wm and W" are, independently, C, CH, or CRh.
For example,
in certain embodiments, Re is a quinolinyl group of the formulae:
(Rh)x I \ \ (Rh)x
or
wherein x is 0, 1, 2, 3, 4 or 5, and Rh is as defined below and herein. In
certain
embodiments, Re is an unsubstituted quinolinyl (i.e., wherein x is 0). In
certain embodiments, Re
is a substituted quinolinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certain
embodiments, Re is a
monosubstituted quinolinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
quinolinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted quinolinyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[00119] In certain embodiments, Re is an isoquinolinyl group; e.g., of the
formula (i-g)
wherein Wh is N and Wf, Wg, W', W', Wk, Wm and W" are, independently, C, CH,
or CRh. For
example, in certain embodiments, Re is an isoquinolinyl group of the formulae:
42
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(Rh)x II (Rh)x
SS / ~N or
wherein x is 0, 1, 2, 3, 4 or 5, and Rh is as defined below and herein. In
certain
embodiments, Re is an unsubstituted isoquinolinyl (i.e., wherein x is 0). In
certain embodiments,
Re is a substituted isoquinolinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In
certain embodiments, Re is
a monosubstituted isoquinolinyl (i.e., wherein x is 1). In certain
embodiments, Re is a
disubstituted isoquinolinyl (i.e., wherein x is 2). In certain embodiments, Re
is a trisubstituted
isoquinolinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or
3. In certain
embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.
[00120] In certain embodiments, Re is a quinoxalinyl group; e.g., of the
formula (i-g) wherein
Wf and W' are N and Wg, Wh, W', Wk, Wm and W" are, independently, C, CH, or
CRh. For
example, in certain embodiments, Re is a quinoxalinyl group of the formulae:
\ N~ (Rh)x II \~ (Rh)x
or
wherein x is 0, 1, 2, 3, 4 or 5, and Rh is as defined below and herein. In
certain
embodiments, Re is an unsubstituted quinoxalinyl (i.e., wherein x is 0). In
certain embodiments,
Re is a substituted quinoxalinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In
certain embodiments, Re is
a monosubstituted quinoxalinyl (i.e., wherein x is 1). In certain embodiments,
Re is a
disubstituted quinoxalinyl (i.e., wherein x is 2). In certain embodiments, Re
is a trisubstituted
quinoxalinyl (i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or
3. In certain
embodiments, x is 0, 1 or 2. In certain embodiments, x is 0 or 1.
[00121] In certain embodiments, Re is a 3-14 membered heterocyclyl. In certain
embodiments, Re is a 3-14 membered heterocyclyl substituted with 0, 1, 2, 3, 4
or 5 Rh groups.
In certain embodiments, Re is a 5-10 membered heterocyclyl substituted with 0,
1, 2, 3, 4 or 5 Rh
groups. In certain embodiments, Re is a 5-8 membered heterocyclyl substituted
with 0, 1, 2, 3, 4
or 5 Rh groups. In certain embodiments, Re is a 5-6 membered heterocyclyl
substituted with 0,
1, 2, 3, 4 or 5 Rh groups. In certain embodiments, Re is a 9-10 membered
heterocyclyl
substituted with 0, 1, 2, 3, 4 or 5 Rh groups.
[00122] Exemplary heterocyclyl Re groups include, but are not limited to,
azirdinyl, oxiranyl,
thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl,
43
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl ,
pyrrolyl-2,5-dione,
dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl,
thiadiazolinyl, piperidinyl,
tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl,
dithianyl, dioxanyl,
triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl,
indolinyl, isoindolinyl,
dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl,
tetrahydrobenzofuranyl,
tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl,
decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
decahydronaphthyridinyl,
decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,
phthalimidyl,
naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-
tetrahydro-
pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-
furo[3,2-
b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-
b]pyridinyl,
2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-
b]pyridinyl, 4,5,6,7-tetra-
hydrofuro[3,2-c]pyridinyl, and 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,
1,2,3,4-tetrahydro-
1,6-naphthyridinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or
5 Rh groups.
[00123] In certain embodiments, Re is a 6-membered heterocyclyl substituted
with 0, 1, 2, 3,
4 or 5 Rh groups. In certain embodiments, Re is a 6-membered heterocyclyl
selected from
piperidinyl, tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl,
morpholinyl, dithianyl,
dioxanyl, and triazinanyl, wherein such groups are substituted with 0, 1, 2,
3, 4 or 5 Rh groups.
[00124] For example, in certain embodiments, Re is a 6-membered heterocyclyl
of the
formula:
WO-WP
q
Ws-Wr
(i-h)
wherein W , Wp, Wq, Wr, and Ws are, independently, selected from CH2, CHRh,
C(R)2,
NRk, 0 or S, and Wt is N, CH, CRh, with the proviso that at least one of W ,
Wp, Wq, Wr and Ws
is selected from N, NRk, 0 or S, and wherein Rh and Rk are defined below and
herein.
[00125] In certain embodiments, Re is a piperidinyl group. In certain
embodiments, Re is a
piperidinyl group substituted with 0, 1, 2, 3, 4 or 5 Rh groups, e.g., of the
formulae:
44
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
/~-~NRk
N(
\~\ h h
)x or (R )x
wherein x is 0, 1, 2, 3, 4 or 5, and Rh and Rk are as defined below and
herein. In certain
embodiments, Re is an unsubstituted piperidinyl (i.e., wherein x is 0). In
certain embodiments, Re
is a substituted piperidinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certain
embodiments, Re is a
monosubstituted piperidinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
piperidinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted piperidinyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[00126] In certain embodiments, Re is a 1-piperidinyl group, e.g., of the
formula (i-h)
wherein Wt is N and W , Wp, Wq, Wr, and Ws are, independently, selected from
CH2, CHRh,
C(Rh)2. In certain embodiments, Re is a 2-piperidinyl group, e.g., of the
formula (i-h) wherein
W is NRk; Wp, Wq, Wr, and Ws are, independently, CHRh, C(Rh)2, or CH2; and Wt
is CH or CRh.
In certain embodiments, Re is a 3-piperidinyl group, e.g., of the formula (i-
h) wherein WP is
NRk; W , Wq, Wr, and Ws are, independently, CHRh, C(Rh)2, or CH2; and Wt is CH
or CRh. In
certain embodiments, Re is a 4-piperidinyl group, e.g., of the formula (i-h)
wherein Wq is NRk;
W , WP, Wr, and Ws are, independently, CHRh, C(Rh)2, or CH2; and Wt is CH or
CRh.
[00127] In certain embodiments, Re is a piperazinyl group. In certain
embodiments, Re is a
piperazinyl group substituted with 0, 1, 2, 3 or 4 Rh groups, e.g., of the
formulae:
/-\ Nk
N NRk
Rh). or NRk,\(Rh)x
wherein x is 0, 1, 2, 3, 4 or 5, and Rh and Rk are as defined below and
herein. In certain
embodiments, Re is an unsubstituted piperazinyl (i.e., wherein x is 0). In
certain embodiments, Re
is a substituted piperazinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certain
embodiments, Re is a
monosubstituted piperazinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
piperazinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted piperazinyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[00128] In certain embodiments, Re is a 1-piperazinyl group, e.g., of the
formula (i-h)
wherein Wt is N, Wq is NRk and W , WP, Wr, and Ws are, independently, selected
from CH2,
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
CHRh, C(Rh)2. In certain embodiments, Re is a 2-piperazinyl group, e.g., of
the formula (i-h)
wherein W and Wr are independently NRk and WP, Wq, Wr, and Ws are,
independently, CHRh,
C(Rh)2, or CH2; and Wt is CH or CRh.
[00129] In certain embodiments, Re is a morpholinyl group. In certain
embodiments, Re is a
morpholinyl group substituted with 0, 1, 2, 3 or 4 Rh groups, e.g., of the
formulae:
/--NR k
-N O (\ >
\~Rh)x or O~\~Rh)x
wherein x is 0, 1, 2, 3, 4 or 5, and Rh and Rk are as defined below and
herein. In certain
embodiments, Re is an unsubstituted morpholinyl (i.e., wherein x is 0). In
certain embodiments,
Re is a substituted morpholinyl (e.g., wherein x is 1, 2, 3, 4 or 5). In
certain embodiments, Re is a
monosubstituted morpholinyl (i.e., wherein x is 1). In certain embodiments, Re
is a disubstituted
morpholinyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted morpholinyl
(i.e., wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1
or 2. In certain embodiments, x is 0 or 1.
[00130] In certain embodiments, Re is a morpholinyl group of the formula (i-h)
wherein Wt is
N, Wq is 0 and W , WP, Wr, and Ws are, independently, selected from CH2, CHRh,
C(Rh)2.
[00131] In certain embodiments, Re is a dioxanyl group. In certain
embodiments, Re is a
dioxanyl group substituted with 0, 1, 2, 3 or 4 Rh groups, e.g., of the
formulae:
o
h h
p- (R )X or 0-/"(R
)X
wherein x is 0, 1, 2, 3, 4 or 5, and Rh and Rk are as defined below and
herein. In certain
embodiments, Re is an unsubstituted dioxanyl (i.e., wherein x is 0). In
certain embodiments, Re is
a substituted dioxanyl (e.g., wherein x is 1, 2, 3, 4 or 5). In certain
embodiments, Re is a
monosubstituted dioxanyl (i.e., wherein x is 1). In certain embodiments, Re is
a disubstituted
dioxanyl (i.e., wherein x is 2). In certain embodiments, Re is a
trisubstituted dioxanyl (i.e.,
wherein x is 3). In certain embodiments, x is 0, 1, 2 or 3. In certain
embodiments, x is 0, 1 or 2.
In certain embodiments, x is 0 or 1.
[00132] In certain embodiments, Re is a dioxanyl group, e.g., of the formula
(i-h) wherein W
and Wr are 0 and WP, Wq, Wr, and Ws are, independently, CHRh, C(Rh)2, or CH2;
and Wt is CH
or CRh.
46
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00133] Other 6-membered heterocycyl Re groups encompassed by formula (i-h)
include
monosaccharide sugars, e.g., for example, pyranosides selected from ribose,
arabinose, xylose,
lyxose, allose, altrose, glucose, mannose, gulose, iodose, galactose and
talose.
[00134] In certain embodiments, Re is a C3_10 carbocycyl. In certain
embodiments, Re is a
C3-10 carbocycyl substituted with 0, 1, 2, 3, 4, or 5 Rh groups. In certain
embodiments, Re is a
C5-8 carbocycyl substituted with 0, 1, 2, 3, 4, or 5 Rh groups. In certain
embodiments, Re is a
C5-6 carbocycyl substituted with 0, 1, 2, 3 or 4 Rh groups. In certain
embodiments, Re is a C9-
carbocycyl substituted with 0, 1, 2, 3, 4, or 5 Rh groups.
[00135] Exemplary Re C3_io carbocycyl groups include, but are not limited to,
cyclopropyl,
cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,
cyclohexadienyl,
cycloheptyl, and cycloheptadienyl, wherein such groups are substituted with 0,
1, 2, 3, 4, or 5 Rh
groups.
Rf of Group G
[00136] As defined generally above, in certain embodiments, wherein G is
selected from -
SO2NRfRe, -PO2NRfRe, -(C=O)NRRe, -ONRfRe, -ONR(C=O)Re, -ONRfSO2Re, -ONRfPO2Re,
-ONRfPO2ORe, -NR'SO2Re, -NR'PO2Re, -NR'PO2ORe, -OPO2NRfRe,-NRfRe, -NR(C=O)Re,-
NRf(C=O)ORe, -O(C=O)NRRe, -NRf(C=NRf)NRfRe, -O(C=NR)NRRe, -NR(C=NRR)ORe,
and -[N(R)2Re]+X- wherein X is a counterion, each Rf attached to a nitrogen
atom is,
independently, selected from -H or CI-10 alkyl, or an amino protecting group,
or Re and Rf are
joined to form an 3-14 membered heterocyclyl ring or an 5-14 membered
heteroaryl ring.
[00137] In certain embodiments, Rf is H or a Ci_io alkyl group.
[00138] In certain embodiments, Rf is H.
[00139] In certain embodiments, Rf is a CI-10 alkyl group. In certain
embodiments, Rf is Ci_io
alkyl substituted with 0, 1, 2, 3, 4, or 5 Rh groups. Exemplary Rf alkyl
groups include, but are
not limited to, methyl, ethyl, propyl, allyl, and benzyl. In certain
embodiments, Rf an
unsubstituted methyl, i.e., -CH3. In certain embodiments, Rf an unsubstituted
ethyl, i.e., -
CH2CH3.
[00140] In certain embodiments, Rf is an amino protecting group. For example,
in certain
embodiments, Rf is selected from -OH, -OR', -N(R)2, -C(=O)W, -C(=O)N(Rk)2, -
CO2R', -
SO2R', -C(=NRk)R', -C(=NRk)OR', -C(=NRk)N(R)2, -SO2N(Rk)2, -SO2R', -SO2OR', -
SOW, -
47
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
C(=S)N(R)2, -C(=O)SR', -C(=S)SR', Ci_io alkyl (e.g., aralkyl), C2_io alkenyl,
C2_10 alkynyl, C3_
carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl, and 5-14 membered
heteroaryl groups,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl,
aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 Rm groups, wherein R', Rk,
Rm are as defined
below and herein.
[00141] However, in certain embodiments, G is -NReRf and Rf is -H or C1_3
alkyl, then Re is
not C1-6 alkyl or thiazolyl.
[00142] Moreover, in certain embodiments, wherein G is -OC(=O)NRfRe, then Re
and Rf are
not both -CH3.
[00143] Alternatively, in certain embodiments, Re and Rf are joined to form an
3-14
membered heterocyclyl ring or an 5-14 membered heteroaryl ring; e.g., for
example, when G is
-SO2NRfRe, -P02NRfRe' -(C=O)NRfRe, -ONRfRe, -OPO2NRfRe, -NRfRe, -O(C=O)NRfRe, -
NRf(C=NRf)NRfRe, -O(C=NR)NRfRe, and -[N(R)2Re]+X wherein X is a counterion. In
certain embodiments, wherein Re and Rf are joined to form an 3-14 membered
heterocyclyl ring
or an 5-14 membered heteroaryl ring, the heterocyclyl ring or heteroaryl ring
are substituted
with 0, 1, 2, 3, 4 or 5 Rh groups, as defined below and herein.
[00144] In certain embodiments, Re and Rf are joined to form an 3-14 membered
heterocyclyl
ring. In certain embodiments, Re and Rf are joined to form a 3-14 membered
heterocyclyl ring
substituted with 0, 1, 2, 3, 4 or 5 Rh groups. In certain embodiments, and Rf
are joined to form a
5-10 membered heterocyclyl ring substituted with 0, 1, 2, 3, 4, or 5 Rh
groups. In certain
embodiments, Re and Rf are joined to form a 5-8 membered heterocyclyl ring
substituted with 0,
1, 2, 3, 4, or 5 Rh groups. In certain embodiments, Re and Rf are joined to
form a 5-6 membered
heterocyclyl ring substituted with 0, 1, 2 or 3 Rh groups. In certain
embodiments, Re and Rf are
joined to form a 9-10 membered heterocyclyl ring substituted with 0, 1, 2, 3,
4, or 5 Rh groups.
[00145] In certain embodiments, Re and Rf are joined to form a heterocyclyl
group selected
from azirdinyl, azetidinyl, pyrrolidinyl, dihydropyrrolyl, pyrrolyl-2,5-dione,
triazolinyl,
oxadiazolinyl, thiadiazolinyl, piperidinyl, dihydropyridinyl, thianyl,
piperazinyl, morpholinyl,
triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, indolinyl, isoindolinyl,
tetrahydrobenzo-
thienyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl,
decahydroisoquinolinyl, indolinyl, and phthalimidyl, wherein such groups are
substituted with 0,
1, 2, 3, 4 or 5 Rh groups.
48
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00146] For example, in certain embodiments, Re and Rf are joined to form a 5-
membered
heterocyclyl ring selected from the group:
wv
0 N 0
I I I
N 0 N0 0 N0 zz: (Rh)X \(Rh) \(Rh and (Rh)X
wherein x is 0, 1, 2 or 3, wherein Rh and Rk are as defined below and herein.
[00147] In certain embodiments, Re and Rf are joined to form a 6-membered
heterocyclyl ring
selected from the group:
0 N 0 N 0 N / N
(Rh)X (Rh)X (Rh)X ~-N~\(Rh)X J /~(Rh)X
-N~ (Rh)X-N~ J Rk-NO-N S
Rk , (Rh)X (Rh)X and (Rh)X
wherein x is 0, 1, 2 or 3, wherein Rh and Rk are as defined below and herein.
[00148] However, in certain embodiments, wherein G is -NR eRf, then Re and Rf
are not
joined to form a pyrrolidinyl, piperidinyl or azepanyl ring.
[00149] In certain embodiments, Re and Rf are joined to form a 5-14 membered
heteroaryl
ring. In certain embodiments, Re and Rf are joined to form a 5-14 membered
heteroaryl ring
substituted with 0, 1, 2, 3, 4, or 5 Rh groups. In certain embodiments, Re and
Rf are joined to
form a 5-10 membered heteroaryl ring substituted with 0, 1, 2, 3, 4, or 5 Rh
groups. In certain
embodiments, Re and Rf are joined to form a 5-8 membered heteroaryl ring
substituted with 0, 1,
2, 3 or 4 Rh groups. In certain embodiments, Re and Rf are joined to form a 5-
6 membered
heteroaryl ring substituted with 0, 1, 2, 3 or 4 Rh groups. In certain
embodiments, Re and Rf are
joined to form a 9-10 membered heteroaryl ring substituted with 0, 1, 2, 3, 4,
or 5 Rh groups.
[00150] In certain embodiments, Re and Rf are joined to form a 5-membered
heteroaryl ring
selected from:
N N N N N N N'NN
h N' 1 h
~(Rh)X NJ~(Rh)X (Rh)X N~~(Rh)X N-N (R )X , ~N (R )X and (R%
wherein x is 0, 1 or 2, and Rh and Rk are as defined below and herein.
49
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00151] However, in certain embodiments, wherein G is -NRfRe, Re and Rf are
not joined to
form a 1,2,4-triazolyl ring, e.g. of the formula:
N
N`-N(Rh)X
wherein x is 0 or 1, and Rh is as defined below and herein.
[00152] In certain embodiments, Re and Rf are joined to form a 9-membered
heteroaryl ( "5,6-
bicyclic heteroaryl") ring selected from:
N NN NI N N_N N
\(Rh)X\-/ (Rh). N(Rh)X (Rh)X
and N J (Rh)X
wherein x is 0, 1, 2 or 3 and Rh and Rk are as defined below and herein.
Group G substituents
Embodiments ofRh
[00153] As used above and herein each instance of Rh is, independently,
selected from
halogen (fluoro (-F), bromo (-Br), chloro (-Cl), and iodo ( -I)), -CN5 -NO2, -
N3, -SO2H5 -
SO3H, -OH, -OR', -ON(R)2, -N(R)2, -N(R)3+X, -N(OR)Rk, -SH, -SR', -SSRj, -
C(=O)W,
-CO2H, -CHO, -CO2Ri, -OC(=O)R', -OCO2R', -C(=O)N(Rk)2, -OC(=O)N(R)2, -
NRkC(=O)R', -NRkC02R', -NRkC(=O)N(R)2, -C(=NR)R', -C(=NRk)OR', -OC(=NRk)R', -
OC(=NRk)OR', -C(=NRk)N(R)2, -OC(=NRk)N(R)2, -NRkC(=NRk)N(R)2, -C(=O)NRkS02R',
-NR" SO2Ri, -SO2N(Rk)2, -SO2R', -SO2OR', -OSO2R', -S(=O)R', -OS(=O)R', -
Si(R')3, -
OS'(Ri)3 -C(=S)N(R)2, -C(=O)SR', -C(=S)SR', -SC(S)SR', -P(=O)2R', -OP(=O)2R', -
P(=O)(R')2, -OP(=O)(R')2, -OP(=O)(OR')2, -P(=O)2N(R)2, -OP(=O)2N(R)2, -
P(=O)(NR)2, -
OP(=O)(NRk)2, -NRkP(=O)(OR')2, -NRkP(=O)(NRk)2, -P(R')2, -P(R')3, -OP(R')2, -
OP(R')3, -
B(OR')2, -BR'(OR'), C1_1o alkyl, C1_1o perhaloalkyl, C2_10 alkenyl, C2_10
alkynyl, C3_14
carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl, and 5-14 membered
heteroaryl, wherein
each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl
is independently
substituted with 0, 1, 2, 3, 4, or 5 Rm groups;
each instance of R' is, independently, selected from CI-10 alkyl, CI-10
perhaloalkyl, C2_10
alkenyl, C2_10 alkynyl, C3_10 carbocyclyl, 3-14 membered heterocyclyl, C6_14
aryl, and 5-14
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rm groups;
each instance of Rk is, independently, selected from hydrogen, -OH, -OR', -
N(R')2, -
CN, -C(=O)R', -C(=0)N(R')2, -CO2R', -SO2R', -C(=NR')0R', -C(=NR')N(R')2, -
S02N(Rj)2, -
SO2R', -S020RJ, -SOW, -C(=S)N(R')2, -C(=O)SR', -C(=S)SR', -P(=0)2R', -
P(=O)(R')2, -
P(=0)2N(R')2, -P(=O)(NR')2, C1_io alkyl, CI-10 perhaloalkyl, C2_10 alkenyl,
C2_10 alkynyl, C3_10
carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl, and 5-14 membered
heteroaryl, or two Rj
groups attached to an N atom are joined to foRm a 3-14 membered heterocyclyl
or 5-14
membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl,
and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rm
groups;
each instance of R' is, independently, selected from hydrogen, CI-10 alkyl, CI-
10
perhaloalkyl, C2_io alkenyl, C2_io alkynyl, C3_io carbocyclyl, 3-14 membered
heterocyclyl, C6-14
aryl, and 5-14 membered heteroaryl, or two Rj groups attached to an N atom are
joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 Rm groups;
each instance of Rm is, independently, selected from fluoro (-F), bromo (-Br),
chloro (-
Cl), and iodo ( -I), -CN5 -NO2, -N3, -SO2H, -SO3H, -OH, -ORo, -ON(R")2, -
N(Rn)2, -
N(Rn)3+X -N(ORo)Rn, -SH, -SR , -SSR , -C(=O)R , -CO2H, -C02R , -0C(=0)R , -
0002R , -C(=O)N(R")z, -OC(=O)N(R")z, -NRnC(=O)R , -NR"C02R , -NR"C(=O)N(R")z, -
C(=NR")OR , -0C(=NR")R , -0C(=NR")0R , -C(=NR")N(R")z, -OC(=NR")N(R")z, -
NR"C(=NR")N(R")2, NR"SO2R , -SO2N(R")2, -S02R , -S020R , -OS02R , -S(=O)R , -
Si(R )35 -0Si(R )3, -C(=S)N(R")z, -C(=O)SR , -C(=S)SR , -SC(=S)SR , -P(=0)2R ,
-
P(=O)(R )z, -0P(=0)(R )z, -OP(=O)(OR )z, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6
alkenyl, C2
alkynyl, C3_10 carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl, 5-14
membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 Rp groups, or two geminal
Rm substituents can
be joined to form =0 or =S;
each instance of R is, independently, selected from Ci_6 alkyl, Ci_6
perhaloalkyl, C2_6
alkenyl, C2 alkynyl, C3_10 carbocyclyl, C6_10 aryl, 3-10 membered
heterocyclyl, and 3-10
51
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 RP groups;
each instance of R" is, independently, selected from hydrogen, C1_6 alkyl, C1-
6
perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3_io carbocyclyl, 3-10 membered
heterocyclyl, C6_10
aryl and 5-10 membered heteroaryl, or two R" groups attached to an N atom are
joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 RP groups; and
each instance of RP is, independently, fluoro (-F), bromo (-Br), chloro (-Cl),
and iodo ( -
I), -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1_6 alkyl, -ON(C1_6 alkyl)2, -N(C1-6
alkyl)2, -
N(C1_6 alkyl)3X, -NH(C1_6 alkyl)2X, -NH2(C1_6 alkyl)X, -NH3X, -N(OC1_6
alkyl)(Ci_6 alkyl), -
N(OH)(C1_6 alkyl), -NH(OH), -SH, -SCIs alkyl, -SS(C1-6 alkyl), -C(=O)(C1-6
alkyl), -CO2H,
-C02(C1 6 alkyl), -OC(=O)(C1-6 alkyl), -0002(C1 6 alkyl), -C(=O)NH2, -
C(=O)N(C1-6 alkyl)2,
-OC(=O)NH(C16 alkyl), -NHC(=O)( C1-6 alkyl), -N(C1-6 alkyl)C(=O)( C1-6 alkyl),
-
NHCO2(C1 6 alkyl), -NHC(=O)N(C1 6 alkyl)2, -NHC(=O)NH(C1-6 alkyl), -
NHC(=O)NH2, -
C(=NH)O(C1 6 alkyl),-OC(=NH)(C1 6 alkyl), -OC(=NH)OC1-6 alkyl, -C(=NH)N(C1-6
alkyl)2, -
C(=NH)NH(C1 6 alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6 alkyl)2, -OC(NH)NH(C1-6
alkyl), -
OC(NH)NH2, -NHC(NH)N(C1 6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C1 6 alkyl), -SO2N(CI-
6
alkyl)2, -SO2NH(C1-6 alkyl), -SO2NH2,-SO2CI-6 alkyl, -S020C1-6 alkyl, -
OS02C1_6 alkyl, -
SOC1_6 alkyl, -Si(Ci_6 alkyl)3, -OSi(C1_6 alkyl)3 -C(=S)N(C1_6 alkyl)2,
C(=S)NH(C1_6 alkyl),
C(=S)NH2, -C(=O)S(C1_6 alkyl), -C(=S)SC1_6 alkyl, -SC(=S)SC1_6 alkyl, -
P(=O)2(C1-6 alkyl), -
P(=O)(C1_6 alkyl)2, -OP(=O)(Cis alkyl)2, -OP(=O)(OC1_6 alkyl)2, C1_6 alkyl,
C1_6 perhaloalkyl,
C2_6 alkenyl, C2 alkynyl, C3_10 carbocyclyl, C6_14 aryl, 3-14 membered
heterocyclyl, 5-14
membered heteroaryl; or two geminal Rp substituents can be joined to form =0
or =S;
wherein X is a counterion.
[00154] In certain embodiments, Rh is selected from fluoro (-F), bromo (-Br),
chloro (-Cl),
and iodo (-I), -CN, -NO2, -OH, -OR', -SR', -SO2H, -SO3H, -N(R)2, -N(Rk)3+X, -
C(=O)W,
-CO2H, -CHO, -CO2R', -OC(=O)R', -OCO2R', -C(=O)N(R)2, -OC(=O)N(R)2, -
NR'`C(=O)R',
-NRkCO2R', -NRkC(=O)N(R)2, -C(=NRk)R', -C(=NR)OR', -OC(=NR)R', -OC(=NRk)OR', -
C(=NRk)N(R)2, -OC(=NR)N(R)2, -NRkC(=NR)N(Rk)2, -C(=O)NRkSO2R', -NRkSO2Ri, -
SO2N(Rk)2, -SO2R', -SO2OR', -OSO2R', -S(=O)R', -OS(=O)R', -C(=S)N(Rk)2, -
C(=O)SR', -
52
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
C(=S)SR', -SC(S)SR', -P(=O)2R', -OP(=O)2R', -P(=O)(R')2, -OP(=O)(R')2, -
OP(=O)(OR')2, -
P(=O)2N(R)2, -OP(=O)2N(R)2, -P(=O)(NR)2, -OP(=O)(NR")2, -NR"P(=O)(OR')2, -
NRkP(=O)(NRk)2, -B(OR')2, -BR'(OR'), C1_io alkyl, -C1_io perhaloalkyl, C3_14
carbocyclyl, 3-14
membered heterocyclyl, C6_14 aryl, and 5-14 membered heteroaryl, wherein each
alkyl,
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5
Rm groups; and wherein X- is a counterion.
[00155] In certain embodiments, Rh is selected from fluoro (-F), bromo (-Br),
chloro (-Cl),
and iodo (-I), -CN, -NO2, -OH, -OR', -SR', -N(R)2, -N(Rk)3+X, -C(=O)R', -
CO2R', -CO2H,
-OC(=O)R', -OCO2R', -C(=O)N(R)2, -OC(=O)N(Rk)2, -NRkC(=O)R', -NRkCO2R', -
NRkC(=O)N(R)2, -C(=O)NRkSO2Ri, -NRkS02R', -SO2N(R)2, -SO2R', C1_io alkyl, C6
aryl, and
5-6 membered heteroaryl, wherein each alkyl, aryl, and heteroaryl is
independently substituted
with 0, 1, 2, 3 or 4 Rm groups; and wherein X- is a counterion.
[00156] In certain embodiments, Rh is -OR', e.g., selected from -OCH3, -OCF3, -
OCH2CH3,
-OCH2CF3, -OiPr and -OnBu.
[00157] In certain embodiments, Rh is -SR', e.g., selected from -SCH3.
[00158] In certain embodiments, Rh is -N(Rk)2 or -N(Rk)3'X , e.g., selected
from -NH2 and -
NH3+X
[00159] In certain embodiments, Rh is -C(=O)R', e.g., selected from -C(=O)CH3.
[00160] In certain embodiments, Rh is -CO2R', e.g., selected from -CO2CH3
[00161] In certain embodiments, Rh is -C(=O)N(Rk)2, e.g., selected from -
C(=O)NHOH, -
C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)NHCH2CF3 -
C(=O)NH(CH2)i-6NH3+X, -C(=O)NHCH2C(=O)OCH3, -C(=O)NHCH2C(=O)OH and -
C(=O)NHCH2CH2OH.
[00162] In certain embodiments, Rh is -OC(=O)R', e.g., selected from -
OC(=O)CH3.
[00163] In certain embodiments, Rh is -OCO2R', e.g., selected from -OCO2CH3.
[00164] In certain embodiments, Rh is -OC(=O)N(Rk)2, e.g., selected from -
OC(=O)NH2.
[00165] In certain embodiments, Rh is -NRkC(=O)R', e.g., selected from -
NHC(=O)CH3.
[00166] In certain embodiments, Rh is -NRkC02R', e.g., selected from -
NHC(=O)OCH3 and -
NHC(=O)OtBu.
[00167] In certain embodiments, Rh is -NRkC(=O)N(R)2, e.g., selected from
NHC(=O)NH2.
53
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00168] In certain embodiments, Rh is -C(=O)NR1 SO2R', e.g., selected from -
C(=O)NHSO2CH3, -C(=O)NHSO2CH2CH3, -C(=O)NHSO2C5H9 and -C(=O)NHSO2iBu.
[00169] In certain embodiments, Rh is -NRkS02R', e.g., selected from -
NHSO2CH3.
[00170] In certain embodiments, Rh is -SO2N(R)2, e.g., selected from -SO2NH2, -
SO2N(CH3)2.
[00171] In certain embodiments, Rh is -SO2R', e.g., selected from -SO2CH3, -
SO2CH2CH3, -
S02C5H9 and -SO2iBu.
[00172] In certain embodiments, Rh is Ci_io alkyl, e.g., selected from -CH3, -
CH2CH3, -iPr, -
nBu, -CF3, -CH2CH2CO2Me, -CH2CH2CO2H and -CH2CH2CO2NH2.
[00173] In certain embodiments, Rh is selected from -C(=O)R', -CO2H, and -
SO2R'. In
certain embodiments, Rh is -C(=O)W. In certain embodiments, Rh is -SO2R'. In
certain
embodiments, Rh is -CO2H or -SO2CH3. In certain embodiments, Rh is -CO2H. In
certain
embodiments, Rh is -SO2CH3.
[00174] In certain embodiments, each instance of Rh is, independently,
selected from fluoro
(-F), bromo (-Br), chloro (-Cl), iodo (-I), -NH2, -NH3+X, -CN, -NO2, -SO2CH3, -
SO2CH2CH3, -S02C5H9, -SO2iBu, -SO2NH2, -SO2N(CH3)2, -C(=O)NHSO2CH3, -
C(=O)NHSO2CH2CH3, -C(=O)NHSO2C5H9, -C(=O)NHSO2iBu, -C(=O)CH3, -CO2H, -
CO2CH3, -OC(=O)CH3, -OCO2CH3, -C(=O)NHOH, -C(=O)NH2, -C(=O)NHCH3, -
C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)NHCH2CF3 -C(=O)NH(CH2)16NH3+X, -
OC(O)NH2, -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)OtBu, -NHC(=O)NH2, -NHSO2CH3,
-CH3, -CH2CH3, -iPr, -nBu, -CF3, -OH, -OCH3, -SCH3, -OCF3, -OCH2CH3, -OCH2CF3,
-
OiPr, -OnBu, -CH2CH2CO2Me, -CH2CH2CO2H, -CH2CH2CO2NH2, -
C(=O)NHCH2C(=O)OCH3, -C(=O)NHCH2C(=O)OH, -C(=O)NHCH2CH2OH, C6 aryl
substituted with 0, 1, or 2 Rm groups and 5-6 membered heteroaryl substituted
with 0, 1, or 2 Rm
groups; and wherein X is a counterion.
[00175] In certain embodiments, Rh is a C6 aryl (e.g., phenyl) substituted
with 0, 1, or 2 Rm
groups. In certain embodiments, Rh is a C6 aryl (e.g., phenyl) substituted
with 1 Rm group, and
Rm is -CO2H, -CO2CH3, -CO2CH2CH3, and -C(=O)NH2.
[00176] In certain embodiments, Rh is a 5-6 membered heteroaryl substituted
with 0, 1, or 2
Rm groups. In certain embodiments, Rh is a 5 membered heteroaryl substituted
with 0, 1, or 2 Rm
groups. Exemplary 5 membered heteroaryl Rh groups include, but are not limited
to, pyrrolyl,
54
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, and tetrazolyl, wherein such groups are substituted
with 0 or 1 Rm
groups. In certain embodiments, the Rh 5 membered heteroaryl group is selected
from pyrazolyl
and oxadiazolyl, wherein such groups are substituted with 0 or 1 Rm groups.
Embodiments ofR
[00177] In certain embodiments, each instance of R' is, independently,
selected from CI-10
alkyl, CI-10 perhaloalkyl, C2_10 alkenyl, C2_10 alkynyl, C3_io carbocyclyl, 3-
14 membered
heterocyclyl, C6_14 aryl, and 5-14 membered heteroaryl, wherein each alkyl,
carbocyclyl,
heterocyclyl, aryl, and heteroaryl is unsubstituted.
[00178] In certain embodiments, R' is unsubstituted Ci_io alkyl. In certain
embodiments, R' is
Ci_io perhaloalkyl. In certain embodiments, R' is unsubstituted C2_10 alkenyl.
In certain
embodiments, R' is unsubstituted C2_io alkynyl. In certain embodiments, R' is
unsubstituted C3-1o
carbocyclyl. In certain embodiments, R' is unsubstituted 3-14 membered
heterocyclyl. In certain
embodiments, R' is unsubstituted C6_14 aryl. In certain embodiments, R' is
unsubstituted 5-14
membered heteroaryl.
Embodiments ofR'
[00179] In certain embodiments, each instance of Rm is, independently,
selected from fluoro
(-F), bromo (-Br), chloro (-Cl), and iodo (-I), -CN, -NO2, -SO2H, -SO3H, -OH, -
OR , -
ON(R")2, -N(R")2, -N(R)3+X, -N(OR )R", -SH, -SR , -SSR , -C(=O)R , -CO2H, -
C02R , -
OC(=O)R , -OC02R , -C(=O)N(Rn)2, -OC(=O)N(Rn)2, NR" C(=O)R , -NR.C02R , -
NR" C(=O)N(Rn)2, -C(=NRn)OR , -OC(=NRn)R , -OC(=NR1)OR , -C(=NRn)N(Rn)2, -
OC(=NRn)N(Rn)2, -NRnC(=NRn)N(Rn)2,-NRnSO2R , -SO2N(Rn)2, -S02R , -S020R , -
OSO2R , -S(=O)R , -C(=S)N(Rn)2, -C(=O)SR , -C(=S)SR , -SC(=S)SR , -P(=0)2R , -
P(=O)(R )2, -OP(=O)(R )2, -OP(=O)(OR )2, C1-6 alkyl, C1-6 perhaloalkyl, C3_io
carbocyclyl, 3-
14 membered heterocyclyl, C6_14 aryl, 5-14 membered heteroaryl, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 RI groups.
[00180] In certain embodiments, each instance of Rm is, independently,
selected from fluoro
(-F), bromo (-Br), chloro (-Cl), and iodo ( -I), -CN, -N02,-SO2H, -SO3H, -OH, -
OR , -
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
ON(R")2, -N(R")2, -N(R)3+X, -N(OR )R", -SH, -SR , -SSR , -C(=O)R , -CO2H, -
C02R , -
OC(=O)R , -OC02R , -C(=O)N(R")2, -OC(=O)N(R")2, -NRnC(=O)R , -NR"C02R , -
NR"C(=O)N(R")2, -C(=NR")OR , -OC(=NR")R , -OC(=NR")OR , -C(=NR")N(R")2, -
OC(=NR")N(R")2, -NR"C(=NR")N(R)2, NR"SO2R , -SO2N(R")2, -S02R , -S020R , -
OSO2R , -S(=O)R , -C(=S)N(R)2, -C(=O)SR , -C(=S)SR , -SC(=S)SR , -P(=0)2R , -
P(=O)(R )2, -OP(=O)(R )2, -OP(=O)(OR )2, C1_6 alkyl, C1_6 perhaloalkyl, C3_10
carbocyclyl, 3-
14 membered heterocyclyl, C6-14 aryl, 5-14 membered heteroaryl.
[00181] In certain embodiments, Rm is selected from fluoro (-F), bromo (-Br),
chloro (-Cl),
and iodo (-I), -NH2, -NH3+X, -CN, -NO2, -SO2CH3, -SO2CH2CH3, -S02C5H9, -
SO2iBu, -
SO2NH2, -SO2N(CH3)2, -C(=O)NHSO2CH3, -C(=O)NHSO2CH2CH3, -C(=O)NHSO2C5H9, -
C(=O)NHSO2iBu, -C(=O)CH3, -CO2H, -CO2CH3, -OC(=O)CH3, -OCO2CH3, -C(=O)NHOH, -
C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHCH2CH3, -C(=O)NHCH2CF3 -
C(=O)NH(CH2)1-6NH3+X, -OC(O)NH2, -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)OtBu, -
NHC(=O)NH2, -NHSO2CH3, -CH3, -CH2CH3, -iPr, -nBu, -CF3, -OH, -OCH3, -OCF3, -
OCH2CH3, -OCH2CF3, -OiPr, -OnBu, -CH2CH2CO2Me, -CH2CH2CO2H, -CH2CH2CO2NH2, -
C(=O)NHCH2C(=O)OCH3, -C(=O)NHCH2C(=O)OH, and -C(=O)NHCH2CH2OH.
Embodiments ofR k
[00182] As used above and herein each instance of Rk is, independently,
selected from -H, -
OH, -OR', -N(R)2, -C(=O)R', -C(=O)N(Rk)2, -CO2R', -SO2R', -C(=NRk)R', -
C(=NRk)OR', -
C(=NRk)N(R)2, -SO2N(Rk)2, -SO2R', -SO2OR', -SOW, -C(=S)N(R)2, -C(=O)SR', -
C(=S)SR',
Ci_io alkyl (e.g., aralkyl), C2_10 alkenyl, C2_10 alkynyl, C3_10 carbocyclyl,
3-14 membered
heterocyclyl, C6_14 aryl, and 5-14 membered heteroaryl groups, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently substituted with
0, 1, 2, 3, 4, or 5 Rm groups, wherein R', Rk, Rm are as defined above and
herein.
[00183] In certain embodiments, each instance of Rk is, independently,
selected from -H, -
C(=O)R', -C(=O)OR', -SO2R', or C1_6 alkyl. In certain embodiments, each
instance of Rk is,
independently, selected from -H or C1-6 alkyl. In certain embodiments, each
instance of Rk is,
independently, selected from -H and -CH3. In certain embodiments, each
instance of Rk is,
independently, selected from -H. In certain embodiments, each instance of Rk
is, independently,
selected from -CH3.
56
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Groups R", Rb, and R`
[00184] As generally defined above, wherein Rd is the group -L-Z, each of Ra,
Rb, and R'
independently is selected from -H, CI-10 alkyl and Ci_io perhaloalkyl.
[00185] In certain embodiments, each of Ra, Rb, and R' independently is
selected from -H,
C1_6 alkyl and C1_6 perhaloalkyl. In certain embodiments, each of Ra, Rb, and
R' independently
is selected from -H, Ci_3 alkyl and Ci_3 perhaloalkyl. In certain embodiments,
each of Ra, Rb,
and R' independently is selected from -H, -CH3, -CH2CH3 and -CF3. In certain
embodiments,
each of Ra, Rb, and R independently is selected from -H, -CH3, and -CF3.
[00186] In certain embodiments, Ra and Rb are H and R' is selected from Ci_3
alkyl and Ci_3
perhaloalkyl. In certain embodiments, Ra and Rb are H and R' is selected from -
CH3 and -CF3.
In certain embodiments, Ra and Rb are H and R' is -CH3. In certain
embodiments, Ra and Rb are
H and R' is -CF3.
[00187] In certain embodiments, Rb and R are H and Ra is selected from C1_3
alkyl and C1_3
perhaloalkyl. In certain embodiments, Rb and R' are H and Ra is selected from -
CH3 and -CF3.
In certain embodiments, Rb and R' are H and Ra is -CH3. In certain
embodiments, kb and R' are
H and Ra is -CF3.
[00188] In certain embodiments, each of Ra, Rb, and R' independently is
selected from H, -
CH3 and -CF3. In certain embodiments, each of Ra, Rb, and R' independently is
selected from H
or -CH3. In certain embodiments, each of Ra, Rb, and R' is H.
Group Rd
[00189] As generally defined above, in certain embodiments, Rd is the group -L-
Z,
wherein L is a covalent bond or a divalent C1_6 hydrocarbon group, wherein
one, two or
three methylene units of L are optionally and independently replaced with one
or more oxygen,
sulfur or nitrogen atoms, and
Z is selected from C6_10 aryl, 3-14 membered heterocyclyl or 5-14 membered
heteroaryl.
Group L ofRd
57
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00190] As generally defined above, L is a covalent bond or a divalent C1
hydrocarbon
group, wherein one, two or three methylene units of L are optionally and
independently replaced
with one or more oxygen, sulfur or nitrogen atoms.
[00191] In certain embodiments, L is a covalent bond.
[00192] In certain embodiments, L is a divalent C1 hydrocarbon group, wherein
one, two or
three methylene units of L are optionally and independently replaced with one
or more oxygen (-
O-), sulfur (-S-) or nitrogen (e.g., -NR'-) atoms.
[00193] In certain embodiments, L is a divalent C1 hydrocarbon group, wherein
one, two or
three methylene units of L are optionally and independently replaced with one
or more oxygen (-
O-) atoms.
[00194] In certain embodiments, L is a divalent C1 hydrocarbon group, wherein
one, two or
three methylene units of L are optionally and independently replaced with one
or more sulfur (-
S-) atoms.
[00195] In certain embodiments, L is a divalent C1 hydrocarbon group, wherein
one, two or
three methylene units of L are optionally and independently replaced with one
or more nitrogen
(-NR'-) atoms. However, in certain embodiments, wherein L is a divalent Ci_6
hydrocarbon
group comprising one, two or three nitrogen atoms, then L is an unsubstituted
divalent Ci_6
hydrocarbon group and L is not the group -CH2NR'- wherein R1 is H, CI{ alkyl
or an amino
protecting group.
[00196] In certain embodiments, L is a divalent CI{ hydrocarbon group, wherein
one
methylene unit of L is optionally and independently replaced with an oxygen,
sulfur or nitrogen
atom. In certain embodiments, L is a divalent Ci_6 hydrocarbon group, wherein
one methylene
unit of L is optionally and independently replaced with an oxygen atom. In
certain
embodiments, L is a divalent C1 hydrocarbon group, wherein one methylene unit
of L is
optionally and independently replaced with a sulfur atom. In certain
embodiments, L is a
divalent Cis hydrocarbon group, wherein one methylene unit of L is optionally
and
independently replaced with a nitrogen atom.
[00197] In certain embodiments of L, the divalent Ci_6 hydrocarbon group is an
unsubstituted
divalent C1 hydrocarbon group. In certain embodiments of L, the divalent Ci-6
hydrocarbon
group contains one oxygen, sulfur or nitrogen atom. In certain embodiments,
the divalent Cis
58
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
hydrocarbon group is an unsubstituted divalent C1-6 hydrocarbon group (e.g.,
an unsubstituted
divalent C1-6alkyl group).
[00198] For example, in certain embodiments, L is an unsubstituted divalent
C1_6 alkyl group,
wherein one methylene unit of L is replaced with an oxygen, sulfur or nitrogen
atom. In certain
embodiments, L is an unsubstituted divalent C1_6 alkyl group, wherein one
methylene unit of L is
replaced with an oxygen atom. In certain embodiments, L is an unsubstituted
divalent C1 alkyl,
wherein one methylene unit of L is replaced with a sulfur atom. In certain
embodiments, L is an
unsubstituted divalent C 1-6 alkyl group, wherein one methylene unit of L is
replaced with a
nitrogen atom. However, in certain embodiments, wherein L is an unsubstituted
divalent C1-6
alkyl group, then L is not the group -CH2NR1- wherein R1 is H, C1-6 alkyl or
an amino
protecting group.
[00199] In certain embodiments, L is a divalent C1 hydrocarbon group, wherein
one
methylene unit of L is replaced with an oxygen, sulfur or nitrogen atom, e.g.,
L is selected from
oxygen (-0-), sulfur (-S-) or nitrogen (e.g., -NR'-). In certain embodiments,
L is oxygen (-0-).
In certain embodiments, L is sulfur (-S-). In certain embodiments, L is
nitrogen (e.g., -NR'-).
[00200] In certain embodiments, L is selected from the group consisting of -
(C(R10)2)m , -
(C(R'')2)m O-(C(R12)2)n , -(C(R1 )2)m S-(C(R12)2)n , or -(C(R'1)2)m NR'-(C(R1z
)2)ri ,wherein
m and n are, independently, 0, 1, 2, 3, 4, 5 or 6, and each instance of R10,
R" and R12 are,
independently, selected from H, halogen or C16 alkyl. In certain embodiments,
each of R10, R"
and R12 are -H.
[00201] In certain embodiments, L is -(C(R10)2)m . In certain embodiments, L
is selected
from -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2- and -
CH2CH2CH2CH2CH2CH2-.
[00202] In certain embodiments, L is -(C(R11)2)m O-(C(R12)2)ri . In certain
embodiments, L
is selected from -0-, -CH2O-, -OCH2-, -OCH2CH2-,-OCH2CH2-, -OCH2CH2CH2-, -
CH2CH2CH2O-, -CH2OCH2CH2-, and -CH2CH2OCH2-.
[00203] In certain embodiments, L is -(C(R11)2)m S-(C(R12)2)ri . In certain
embodiments, L
is selected from -S-, -CH2S-, -SCH2-, -SCH2CH2-,-CH2CH2S-, -SCH2CH2CH2-, -
CH2CH2CH2S-, -CH2SCH2CH2-, and -CH2CH2SCH2-.
[00204] In certain embodiments, L is -(C(R' 1)2)m NR'-(C(R12)2)ri . In certain
embodiments,
L is selected from -NR'-, -CH2NR'-, -NR'CH2-, -NR'CH2CH2-, -CH2CH2NR'-, -
59
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
NR'CH2CH2CH2-, -CH2CH2CH2NR'-, -CH2 NR'CH2CH2-, and -CH2CH2NR'CH2-, wherein
R1 is selected from H, an C1_6 alkyl or an amino protecting group.
[00205] In certain embodiments, R1 is selected from H or C1_6 alkyl. In
certain embodiments,
R1 is hydrogen. In certain embodiments, R1 is -CH3.
Embodiments wherein Group Z OR d is Aryl
[00206] As defined generally above, in certain embodiments, Z is C6_14 aryl.
[00207] In certain embodiments, Z is C6-14 aryl. In certain embodiments, Z is
C6_14 aryl. In
certain embodiments, Z is C6-14 aryl substituted with 0, 1, 2, 3, 4 or 5 R15
groups. In certain
embodiments, Z is C6 aryl (e.g., phenyl) substituted with 0, 1, 2, 3, 4 or 5
R15 groups. In certain
embodiments, Z is a C1o aryl (e.g., naphthyl) substituted with 0, 1, 2, 3, 4
or 5 R15 groups.
[00208] In certain embodiments, Z is phenyl. In certain embodiments, Z is
phenyl substituted
with 0, 1, 2, 3 or 4 R15 groups. In certain embodiments, Z is phenyl
substituted with 0, 1, 2 or 3
R15 groups. In certain embodiments, Z is phenyl substituted with 0, 1 or 2 R15
groups. In
certain embodiments, Z is phenyl substituted with 0 or 1 R15 groups. In
certain embodiments, Z
is a disubstituted phenyl (i.e., substituted with 2 R15 groups). In certain
embodiments, Z is a
monosubstituted phenyl (i.e., substituted with 1 R15 group). In certain
embodiments, Z is an
unsubstituted phenyl (i.e., substituted with 0 R15 groups).
[00209] In certain embodiments, Z is phenyl substituted with at least one
ortho R15 group. In
certain embodiments, Z is phenyl substituted with at least one meta R15 group.
In certain
embodiments, Z is phenyl substituted with at least one para R15 group.
[00210] In certain embodiments, Z is a monosubstituted phenyl substituted with
one ortho R15
group. In certain embodiments, Z is a monosubstituted phenyl substituted with
one meta R15
group. In certain embodiments, Z is a monosubstituted substituted with one
para R15 group.
[00211] In certain embodiments, Z is a disubstituted phenyl substituted with
an ortho R15
group and a meta R15 group. In certain embodiments, Z is a disubstituted
phenyl substituted with
an ortho R15 group and a para R15 group. In certain embodiments, Z is a
disubstituted phenyl
substituted with a meta R15 group and a para R15 group. In certain
embodiments, Z is a
disubstituted phenyl substituted with two meta R15 groups.
[00212] In certain embodiments, Z is a phenyl group of the formula:
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
wvw
~_(R1z
(ii-a)
wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and herein. In
certain
embodiments, z is 0, 1, 2, 3 or 4. In certain embodiments, z is 0, 1, 2 or 3.
In certain
embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1. In certain
embodiments, z is 3.
In certain embodiments, Z is a disubstituted phenyl group (i.e., wherein z is
2). In certain
embodiments, Z is a monosubstituted phenyl group (i.e., wherein z is 1). In
certain
embodiments, Z is an unsubstituted phenyl group (i.e., wherein z is 0).
[00213] For example, in certain embodiments, Z is a substituted or
unsubstituted phenyl group
of any one of the formulae:
uvw ww
R15 / \ I R15 / R15 fR15
\ I \ I \ R15 R15 R15 R15 \ R15 R15 R15
,nn u wvv ww wW
R15 ww "vvv / R15 R15 R15
&R 15 &R 15
R15 \ R15 R15
R15 R15 R15 R15 R15 R15 R15
Jvvv vw ww Juw
~vw R15 R15 R15 R15 R15 R15
R15 &R R15 / I :::: /
R15 R15 R15 5 \ R15 wherein
R15 is as defined below and herein.
[00214] In certain embodiments, Z is a naphthyl. In certain embodiments, Z is
a naphthyl
group of any one of the formulae:
\
(R 15),
or \
(11-b) (R15),
(ii-c)
61
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and herein. In
certain
embodiments, z is 0, 1, 2, 3 or 4. In certain embodiments, z is 0, 1, 2 or 3.
In certain
embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1. In certain
embodiments, Z is a
trisubstituted naphthyl group (i.e., wherein z is 3). In certain embodiments,
Z is a disubstituted
naphthyl group (i.e., wherein z is 2). In certain embodiments, Z is a
monosubstituted naphthyl
group (i.e., wherein z is 1). In certain embodiments, Z is an unsubstituted
naphthyl group (i.e.,
wherein z is 0).
[00215] For example, in certain embodiments, Z is a substituted or
unsubstituted 1-naphthyl
group of any one of the formulae:
R15r
R15
R15 R15 R15
.nnrv
,nnrv ,nnni ,iwv R15
15 15 R ~::, R15
R15 R15
w,nr .nnnr R15
ww R15 R15
R15 R15 or R15 , wherein R15 is as defined below and herein.
[00216] In certain embodiments, Z is a substituted or unsubstituted 2-naphthyl
group of any
one of the formulae:
R 15
\ I \ I \ I R15 \ \\ I \ 15
R
\ I \ I \ I \ R15 R15 R15
62
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
nn
R R15
\ \ I R15 I I I \
R15 R15
\ I \ R15 R15 R15 R15 R15 R15
or
\ R15
R15
wherein R15 is as defined below and herein.
Embodiments wherein Group Z ofRd is Heterocycyl or Heteroaryl
[00217] As generally defined above, in certain embodiments, Z is selected from
3-14
membered heterocycyl and 5-14 membered heteroaryl.
[00218] In certain embodiments, Z is 5-14 membered heteroaryl. In certain
embodiments, Z
is a 5-10 membered heteroaryl substituted with 0, 1, 2, 3, 4 or 5 R15 groups.
In certain
embodiments, Z is a 5-8 membered heteroaryl substituted with 0, 1, 2, 3, 4 or
5 R15 groups. In
certain embodiments, Z is a 5-6 membered heteroaryl substituted with 0, 1, 2,
3 or 4 R15 groups.
In certain embodiments, Z is a 9-10 membered heteroaryl substituted with 0, 1,
2, 3, 4 or 5 R15
groups.
[00219] Exemplary Z heteroaryl groups include, but are not limited to,
pyrrolyl, furanyl and
thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl (e.g., 2-pyridinyl, 3-
pyridinyl, 4-pyridinyl),
pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-
pyrimidinyl, 4-pyrimidinyl,
5-pyrimidinyl), pyrazinyl, triazinyl, tetrazinyl, azepinyl, oxepinyl,
thiepinyl, indolyl, isoindolyl,
indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,
benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
benzisothiazolyl,
benzthiadiazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl,
quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, phenanthridinyl,
dibenzofuranyl, carbazolyl,
acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl, wherein such groups
are substituted
with 0, 1, 2, 3,4or5R15groups.
63
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00220] In certain embodiments, Z is a 5-membered heteroaryl substituted with
0, 1, 2 or 3
R'5 groups. In certain embodiments, Z is a 5-membered heteroaryl selected
pyrrolyl, furanyl,
thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, triazolyl,
oxadiazolyl, thiadiazolyl and tetrazolyl, wherein such groups are substituted
with 0, 1, 2 or 3 R'5
groups.
[00221] For example, in certain embodiments, Z is a 5-membered heteroaryl of
the
formula:
Y2
4OX
Y3
(ii-d)
wherein Y', Y2, Y3 and Y4 are, independently, selected from CH, CR'5, O, S, N,
or NR",
with the proviso that at least one of Y', Y2, Y3 and Y4 are selected from 0,
S, N, or NR", and
wherein R'5 and Rig are defined below and herein.
[00222] In certain embodiments of the above formula (ii-d), Y' is 0, S, or
NR'8 and Y2, Y3
and Y4 are, independently, selected from CH, CR'5 or N. In certain embodiments
of the above
formula (ii-d), Y' is 0, S, or NR'8 and Y2, Y3 and Y4 are, independently,
selected from CH or
CR'5. In certain embodiments of the above formula (ii-d), Y' is 0, S, or or
NR'8, Y3 is N and
Y2 and Y4 are, independently, selected from CH or CR'5. In certain embodiments
of the above
formula (ii-d), Y' is S, Y3 is N, and Y2 and Y4 is CH or CR'5. In certain
embodiments of the
above formula (ii-d), Y' is S, Y3 is N, Y2 is CR'5 and Y4 is CH. In certain
embodiments of the
above formula (ii-d), Y' is S and Y2, Y3 and Y4 is CH or CR15
[00223] In certain embodiments of the above formula (ii-d), Y2 is 0, S, or
NR'8 and Y', Y3
and Y4 are, independently, selected from CH, CR'5 or N. In certain embodiments
of the above
formula (ii-d), Y2 is 0, S, or NR'8 and Y', Y3 and Y4 are, independently,
selected from CH or
CR'5. In certain embodiments of the above formula (ii-d), Y2 is 0, S, or or
NR'8, Y4 is N and Y'
and Y3 are, independently, selected from CH or CR15
[00224] In certain embodiments, Z is a 5-membered heteroaryl of any one of the
formulae:
64
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
~-S NR18 __S ~O
(R15)z (R15)z (R15)z N (R15)z >/(~ (R15)z
R18
L S NR1
N (R15)z N (R15% z N (R15)Z N (R15)z
NR18
N- Z N-N-N I I S NR18
N (R15)z N\/ (R15)z N~ (R15)z N (R15)z
r~r S NR18 N R18 N
L4o(R N/ N-~
15 (R15)z R15 N\ /(R15)z N\ /18 (R15)z
N )z N N ( )z )z N or NR
wherein R15 and Rib are as defined below and herein, and z is 0, 1 or 2.
wherein z is 0, 1 or 2, and R15 and Rib are as defined below and herein. In
certain
embodiments, Z is an unsubstituted 5-membered heteroaryl (i.e., wherein z is
0). In certain
embodiments, Z is a substituted 5-membered heteroaryl (e.g., wherein z is 1 or
2). In certain
embodiments, Z is a monosubstituted 5-membered heteroaryl (i.e., wherein z is
1). In certain
embodiments, Z is a disubstituted 5-membered heteroaryl (i.e., wherein z is
2). In certain
embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.
[00225] In certain embodiments, Zis a 6-membered heteroaryl substituted with
0, 1, 2, 3 or 4
Rh groups. In certain embodiments, Z is a 6-membered heteroaryl selected from
the group
consisting of pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl),
pyridazinyl (e.g., 3-
pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl, 5-
pyrimidinyl),
pyrazinyl, triazinyl and tetrazinyl, wherein such groups are substituted with
0, 1, 2, 3 or 4 R15
groups.
[00226] For example, in certain embodiments, Re is a 6-membered heteroaryl
group of the
formula:
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
W1-W2
W3
W5=W4
(ii-e)
wherein W1, W2, W3, W4 and W5 are, independently, selected from CH, CR15 or N,
with
the proviso that at least one of W1, W2, W3, W4, and W5 is N, and wherein R15
is as defined
below and herein.
[00227] In certain embodiments, Z is a pyrindinyl group. In certain
embodiments, Z is a
pyrindinyl group substituted with 0, 1, 2, 3 or 4 R15 groups. For example, in
certain
embodiments, Z is a pyrindinyl group of the formula:
N
(R15)z
wherein z is 0, 1, 2, 3 or 4, and R15 is as defined below and herein. In
certain
embodiments, Z is an unsubstituted pyrindinyl (i.e., wherein z is 0). In
certain embodiments, Z is
a substituted pyrindinyl (e.g., wherein z is 1, 2, 3 or 4). In certain
embodiments, Z is a
monosubstituted pyrindinyl (i.e., wherein z is 1). In certain embodiments, Z
is a disubstituted
pyrindinyl (i.e., wherein z is 2). In certain embodiments, Z is a
trisubstituted pyrindinyl (i.e.,
wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1 or 2.
In certain embodiments, z is 0 or 1.
[00228] In certain embodiments, Z is a 2-pyrindinyl group, e.g., of the
formula (ii-e) wherein
W1 is N and W2, W3, W4 and W5 are, independently, CH or CR15. In certain
embodiments Z is a
3-pyrindinyl group, e.g., of the formula (ii-e) wherein W2 is N and W1, W3, W4
and W5 are,
independently, CH or CR15. In certain embodiments Z is a 4-pyrindinyl group,
e.g., of the
formula (ii-e) wherein W3 is N and W1, W2, W4 and W5 are, independently, CH or
CR15
[00229] In certain embodiments, Re is a substituted or unsubstituted 2-
pyridinyl group of any
one of the formulae:
`$VW R15 wvv
wvv ,nnn. 15 N :::, N R15
N~ I &--, R N/ N/ N/ I N/
R15 15 R15 \ \ R15 R15 R15 \
66
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
N~ N I N/
R15 R15
R15 " R15 R15 R15 15
or , wherein R is defined below and herein.
[00230] In certain embodiments, Z is a substituted or unsubstituted 3-
pyridinyl group of any
one of the formulae:
15 15 R15
6,,1 / R / N-1 I R / N1 I R
N ~ N R15 R15 N , R15 Ni:
RR15 nnn, R15 n^^r
\ I R15 R15 R15 /
R15 N : R15 N or R15
wherein R15 is as defined below and herein.
[00231] In certain embodiments, Z is a substituted or unsubstituted 4-
pyridinyl group of the
formulae:
R15 ::,R1R15, R1R15 , N R15 N R15 or N R15
wherein R15 is as defined below and herein.
[00232] In certain embodiments, Z is a pyridazinyl group. In certain
embodiments, Z is a
pyridazinyl group substituted with 0, 1, 2 or 3 R15 groups. For example, in
certain embodiments,
Z is a pyridazinyl group of the formula:
N
~.~ N
15)z
wherein z is 0, 1, 2 or 3, and R15 is as defined below and herein. In certain
embodiments,
Z is an unsubstituted pyridazinyl (i.e., wherein z is 0). In certain
embodiments, Z is a substituted
pyridazinyl (e.g., wherein z is 1, 2 or 3). In certain embodiments, Z is a
monosubstituted
pyridazinyl (i.e., wherein z is 1). In certain embodiments, Z is a
disubstituted pyridazinyl (i.e.,
wherein z is 2). In certain embodiments, Z is a trisubstituted pyridazinyl
(i.e., wherein z is 3). In
67
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or
2. In certain
embodiments, z is 0 or 1.
[00233] In certain embodiments, Z is a 3-pyridazinyl group, e.g., of the
formula (ii-e)
wherein W1 and W2 are N and W3, W4 and W5 are, independently, CH or CR15. In
certain
embodiments Z is a 4-pyridazinyl group, e.g., of the formula (ii-e) wherein W2
and W3 are N
and W1, W4 and W5 are, independently, CH or CRh.
[00234] In certain embodiments, Z is a substituted or unsubstituted 3-
pyridazinyl group of
any one of the formulae:
wvv ,nnn, ,r`^^r ~`^^~ R15
N~ N R15 N~ N~ N~ R N~ R15 N
N I N N R15 R15 N R15 R15 R15
wherein R15 is as defined below and herein.
[00235] In certain embodiments, Z is a substituted or unsubstituted 4-
pyridazinyl group of
any one of the formulae:
R15 R15 R1 R15 R15 R15
N N N I N I 15 N,' N 15 N I 15
N 5 N N 5 N R 5 N 5 N R or N R
wherein R15 is as defined below and herein.
[00236] In certain embodiments, Z is a pyrimidinyl group. In certain
embodiments, Z is a
pyrimidinyl group substituted with 0, 1, 2 or 3 R15 groups. For example, in
certain embodiments,
Z is a pyrimidinyl group of the formula:
N (R15),
wherein z is 0, 1, 2 or 3, and R15 is as defined below and herein. In certain
embodiments,
Z is an unsubstituted pyrimidinyl (i.e., wherein z is 0). In certain
embodiments, Z is a substituted
pyrimidinyl (e.g., wherein z is 1, 2 or 3). In certain embodiments, Z is a
monosubstituted
pyrimidinyl (i.e., wherein z is 1). In certain embodiments, Z is a
disubstituted pyridazinyl (i.e.,
wherein z is 2). In certain embodiments, Z is a trisubstituted pyrimidinyl
(i.e., wherein z is 3).
68
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
In certain embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1
or 2. In certain
embodiments, z is 0 or 1.
[00237] In certain embodiments, Z is a 2-pyrimidinyl group, e.g., of the
formula (ii-e)
wherein W1 and W5 are N and W2, W3 and W4 are, independently, CH or CR15. In
certain
embodiments Z is a 4-pyrimidinyl group, e.g., of the formula (ii-e) wherein W1
and W3 are N
and W2, W4 and W5 are, independently, CH or CR15. In certain embodiments Z is
a 5-
pyrimidinyl group, e.g., of the formula (ii-e) wherein W2 and W4 are N and W1,
W3 and W5 are,
independently, CH or CR15
[00238] In certain embodiments, Z is a 2-pyrimidinyl group of any one of the
formulae:
N N N N
Ni N N N I R15 I N N
R15 R15 R15 or R15 R15
,
wherein R15 is as defined below and herein.
[00239] In certain embodiments, Re is a 4-pyrimidinyl group of any one of the
formulae:
R15 I R15 R15 N \ I I \ I \ I I \ I J
R15 N \N R15 R15 \N R15 \N R15 or R15 \N
5 wherein R15 is as defined below and herein.
[00240] In certain embodiments, Z is a 5-pyrimidinyl group of any one of the
formulae:
,nnn. w~ni R15
R15 / l I
/ I I II N~ N N~ N
NON NON YR15 or R15
wherein R15 is as defined below and herein.
[00241] In certain embodiments, Z is a pyrazinyl group. In certain
embodiments, Z is a
pyrazinyl group substituted with 0, 1, 2 or 3 R15 groups. For example, in
certain embodiments, Z
is a pyrazinyl group of the formula:
~--N
N
R15~z
69
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
wherein z is 0, 1, 2 or 3, and R15 is as defined below and herein. In certain
embodiments, Z is an unsubstituted pyrazinyl (i.e., wherein z is 0). In
certain embodiments, Z is
a substituted pyrazinyl (e.g., wherein z is 1, 2 or 3). In certain
embodiments, Z is a
monosubstituted pyrazinyl (i.e., wherein z is 1). In certain embodiments, Z is
a disubstituted
pyrazinyl (i.e., wherein z is 2). In certain embodiments, Z is a
trisubstituted pyrazinyl (i.e.,
wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1 or 2.
In certain embodiments, z is 0 or 1.
[00242] In certain embodiments, Z is a pyrazinyl group of any one of the
formulae:
.n w .nr~v R15
/ N 15
/ N
N R15 / N N N \lJ R NN NR15 N\
N J Nom/ N\/ R15 R15 Nom/ R15 R15 15 R15
wherein R15 is as defined below and herein.
[00243] In certain embodiments, Z is a triazinyl group. In certain
embodiments, Z is a
triazinyl group substituted with 0, 1 or 2 R15 groups. For example, in certain
embodiments, Z is
a triazinyl group of the formula:
N .
I J
(R15)z
wherein z is 0, 1 or 2, and R15 is as defined below and herein. In certain
embodiments, Z
is an unsubstituted pyrazinyl (i.e., wherein z is 0). In certain embodiments,
Z is a substituted
pyrazinyl (e.g., wherein z is 1 or 2). In certain embodiments, Z is a
monosubstituted pyrazinyl
(i.e., wherein z is 1). In certain embodiments, Z is a disubstituted pyrazinyl
(i.e., wherein z is 2).
In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.
[00244] In certain embodiments, Z is a substituted or unsubstituted triazinyl
group of any one
of the formulae:
Ni `N Ni N Ni N
`NJ I`NLR15 or R15" `N~R15
,
wherein R15 is as defined below and herein.
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00245] In certain embodiments Z is a tetrazinyl group. In certain embodiments
Z is a
tetrazinyl group substituted with 0 or 1 R15 groups. For example, in certain
embodiments, Z is a
tetrazinyl group of the formula:
N
N~~\
(R1%
wherein z is 0 or 1, and R15 is as defined below and herein. In certain
embodiments,
Z is an unsubstituted pyrazinyl (i.e., wherein z is 0). In certain
embodiments, Z is a substituted
pyrazinyl (e.g., wherein z is 1). In certain embodiments, z is 0 or 1.
[00246] In certain embodiments, Z is a tetrazinyl group of any one of the
formulae:
Ni N
~N
Ni 'N NY
N~IN or R
wherein R15 is as defined below and herein.
[00247] In certain embodiments, Z is a 9-membered heteroaryl (e.g., a 5,6-
bicyclic
heteroaryl). In certain embodiments, Z is a 5,6-bicyclic heteroaryl
substituted with 0, 1, 2, 3, 4
or 5 R15 groups. In certain embodiments, Z is a 5,6-bicyclic heteroaryl
selected from indolyl,
isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl,
benzofuranyl,
benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,
benzoxadiazolyl, benzthiazolyl,
benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl, wherein such
groups are substituted
with 0, 1, 2, 3, 4 or 5 R 15 groups.
[00248] For example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl of
the formula:
Y12
Y5
Y11~ Y13-~-
I I 6
Y1
Y9 Y7
(ii-f)
wherein y5' Y6 Y' Y9 Y10 Y" and Y12 are, independently, C, CH, CR'5, O S, N,
or
NR'8, and Y13 is C or N, with the proviso that at least one of Y5, Y6, Y7 are
selected from 0, S, N
or NR18, and wherein R15 and R18 are as defined herein.
71
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00249] In certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the
formula (ii-f),
wherein Y5 is selected from 0, S, or NR's, Y13 is C, and Y6, Y7, Y9, Y10, Y"
and Y'2 are,
independently, C, CH, or CR15. For example, in certain embodiments, Z is a 5,6-
bicyclic
heteroaryl group of the formulae:
NR 18 O S
(R15)Z (R15)Z (R15)Z
wherein z is 0, 1, 2, 3, 4 or 5 and R' 5 and R18 are defined below and herein.
In certain
embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
0). In certain
embodiments, Z is a substituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1,
2, 3, 4 or 5). In
certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 1). In
certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 2). In certain
embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
3). In certain
embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In
certain embodiments, z
is 0 or 1.
[00250] In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y5 is
selected from 0,
S, or NR'8; Y7 is N; Y13 is C; Y6 is C, CH, or CR15 or N, and Y9, Y' , Y" and
Y'2 are,
independently, C, CH, or CR15. For example, in certain embodiments, Z is a 5,6-
bicyclic
heteroaryl group of the formulae:
SS 18
S NR1s
R15 R15 R15 ~~NR R15 N
N -N N or
wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R18 are defined below and herein.
In certain
embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
0). In certain
embodiments, Z is a substituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1,
2, 3, 4 or 5). In
certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 1). In
certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 2). In certain
embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
3). In certain
embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In
certain embodiments, z
is 0 or 1.
72
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00251] In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y5 is
NRk, S or 0; Y12
is N; Y13 is C; and y6' Y' Y9 Y10 and Y" are, independently, C, CH, or CR'5.
For example, in
certain embodiments, Z is a 5,6-bicyclic hetersoaryl group of the formulae:
N NR18 ~_ ~N S N O
(R15) Z ( R I R15) Z
or
wherein z is 0, 1, 2, 3, 4 or 5 and R15 and R18 are defined below and herein.
In certain
embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
0). In certain
embodiments, Z is a substituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1,
2, 3, 4 or 5). In
certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 1). In
certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 2). In certain
embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
3). In certain
embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In
certain embodiments, z
is 0 or 1.
[00252] In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y7 is
0, S, or NR";
Y'2 is N; Y13 is C; and y5' Y6 Y9 Y1 and Y" are, independently, C, CH, or
CR'5. For example,
in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the formulae:
s' N X I., N X N
1
(R15)i ~R5) (R15)
~NR18, ~O or S
wherein z is 0, 1, 2, 3, 4 or 5 and R'5 and R18 are defined below and herein.
In certain
embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
0). In certain
embodiments, Z is a substituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1,
2, 3, 4 or 5). In
certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 1). In
certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 2). In certain
embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
3). In certain
embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In
certain embodiments, z
is 0 or 1.
[00253] In certain embodiments, Z is a 5,6-bicyclic heteroaryl wherein Y5 is
selected from 0,
S, or NR18; Y13 is N; and y6' Y' Yg Y9 and Y10 are, independently, C, CH, or
CR'5. For
example, in certain embodiments, Z is a 5,6-bicyclic heteroaryl group of the
formulae:
73
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
N-,N
(Rh)X
wherein z is 0, 1, 2, 3, 4 or 5 and R15 and Rib are defined below and herein.
In certain
embodiments, Z is an unsubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
0). In certain
embodiments, Z is a substituted 5,6-bicyclic heteroaryl (e.g., wherein z is 1,
2, 3, 4 or 5). In
certain embodiments, Z is a monosubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 1). In
certain embodiments, Z is a disubstituted 5,6-bicyclic heteroaryl (i.e.,
wherein z is 2). In certain
embodiments, Z is a trisubstituted 5,6-bicyclic heteroaryl (i.e., wherein z is
3). In certain
embodiments, z is 0, 1, 2 or 3. In certain embodiments, z is 0, 1 or 2. In
certain embodiments, z
is 0 or 1.
[00254] In certain embodiments, Z is a l0-membered heteroaryl (e.g., a 6,6-
bicyclic
heteroaryl). In certain embodiments, Z is a 6,6-bicyclic heteroaryl
substituted with 0, 1, 2, 3, 4
or 5 R15 groups. In certain embodiments, Z is a 6,6-bicyclic heteroaryl
selected from
naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl,
quinoxalinyl, phthalazinyl and
quinazolinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or 5 R15
groups.
[00255] For example, in certain embodiments, Z is a 6,6-bicyclic heteroaryl of
the formula:
W13 W6
W12 W7
W\ * W8
W10 W9
(ii-g)
wherein W6, W7, W8, W9 W10 Wll W12 and W13 are, independently, selected from
C,
CH, CR15 or N, with the proviso that at least one of W6, W7, W8, W9, W10, W",
W12 and W13 is
N, and wherein R15 is as defined below and herein.
[00256] In certain embodiments, Z is a quinolinyl group; e.g., of the formula
(ii-g) wherein
W9 is N and W6, W7, W8, W10Wll W12 and W13 are, independently, C, CH, or CR15.
For
example, in certain embodiments, Z is a quinolinyl group of the formulae:
(R15)z 5 (R15) z
55 ~N~ or5
74
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and herein. In
certain
embodiments, Z is an unsubstituted quinolinyl (i.e., wherein z is 0). In
certain embodiments, Z is
a substituted quinolinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certain
embodiments, Z is a
monosubstituted quinolinyl (i.e., wherein z is 1). In certain embodiments, Z
is a disubstituted
quinolinyl (i.e., wherein z is 2). In certain embodiments, Z is a
trisubstituted quinolinyl (i.e.,
wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1 or 2.
In certain embodiments, z is 0 or 1.
[00257] In certain embodiments, Z is an isoquinolinyl group; e.g., of the
formula (ii-g)
wherein W8 is N and W6, W7, W9, W10 W11, W12 and W13 are, independently, C,
CH, or CRIB
For example, in certain embodiments, Z is an isoquinolinyl group of the
formulae:
(R15 N (R15)7
N
or
wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and herein. In
certain
embodiments, Z is an unsubstituted isoquinolinyl (i.e., wherein z is 0). In
certain embodiments, Z
is a substituted isoquinolinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In
certain embodiments, Z is a
monosubstituted isoquinolinyl (i.e., wherein z is 1). In certain embodiments,
Z is a disubstituted
isoquinolinyl (i.e., wherein z is 2). In certain embodiments, Z is a
trisubstituted isoquinolinyl
(i.e., wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1
or 2. In certain embodiments, z is 0 or 1.
[00258] In certain embodiments, Z is a quinoxalinyl group; e.g., of the
formula (ii-g) wherein
W6 and W9 are N and W7, W8, W10, W", W'2 and W13 are, independently, C, CH, or
CR'5. For
example, in certain embodiments, Z is a quinoxalinyl group of the formulae:
\ N~ 15
R II \I I 15)
I~ ~ /J ( _(R N~ or
wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and herein. In
certain
embodiments, Z is an unsubstituted quinoxalinyl (i.e., wherein z is 0). In
certain embodiments, Z
is a substituted quinoxalinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certain
embodiments, Z is a
monosubstituted quinoxalinyl (i.e., wherein z is 1). In certain embodiments, Z
is a disubstituted
quinoxalinyl (i.e., wherein z is 2). In certain embodiments, Z is a
trisubstituted quinoxalinyl
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(i.e., wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1
or 2. In certain embodiments, z is 0 or 1.
[00259] In certain embodiments, Z is a 3-14 membered heterocyclyl. In certain
embodiments, Z is a 3-14 membered heterocyclyl substituted with 0, 1, 2, 3, 4
or 5 R'5 groups.
In certain embodiments, Z is a 5-10 membered heterocyclyl substituted with 0,
1, 2, 3, 4 or 5 R'5
groups. In certain embodiments, Z is a 5-8 membered heterocyclyl substituted
with 0, 1, 2, 3, 4
or 5 R'5 groups. In certain embodiments, Z is a 5-6 membered heterocyclyl
substituted with 0, 1,
2, 3, 4 or 5 R'5 groups. In certain embodiments, Z is a 9-10 membered
heterocyclyl substituted
with 0, 1, 2, 3,4or5R'5groups.
[00260] Exemplary heterocyclyl Z groups include, but are not limited to,
azirdinyl, oxiranyl,
thiorenyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydrofuranyl,
tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl ,
pyrrolyl-2,5-dione,
dioxolanyl, oxathiolanyl, dithiolanyl, triazolinyl, oxadiazolinyl,
thiadiazolinyl, piperidinyl,
tetrahydropyranyl, dihydropyridinyl, thianyl, piperazinyl, morpholinyl,
dithianyl, dioxanyl,
triazinanyl, azepanyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, thiocanyl,
indolinyl, isoindolinyl,
dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl,
tetrahydrobenzofuranyl,
tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
decahydroquinolinyl,
decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl,
decahydronaphthyridinyl,
decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,
phthalimidyl,
naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-
tetrahydro-
pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-
furo[3,2-
b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-
b]pyridinyl,
2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-
b]pyridinyl, 4,5,6,7-tetra-
hydrofuro[3,2-c]pyridinyl, and 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,
1,2,3,4-tetrahydro-
1,6-naphthyridinyl, wherein such groups are substituted with 0, 1, 2, 3, 4 or
5 R'5 groups.
[00261] In certain embodiments, Z is a 6-membered heterocyclyl. In certain
embodiments, Z
is a 6-membered heterocyclyl substituted with 0, 1, 2, 3, 4 or 5 R'5 groups.
In certain
embodiments, Z is a 6-membered heterocyclyl selected from piperidinyl,
tetrahydropyranyl,
dihydropyridinyl, thianyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, and
triazinanyl, wherein
such groups are substituted with 0, 1, 2, 3, 4 or 5 R'5 groups.
76
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00262] For example, in certain embodiments, Z is a 6-membered heterocyclyl of
the
formula:
W14_ W15
W19 W16
W18_ W17
(ii-h)
wherein W14, W15, W16, W17, Wig are, independently, CH2, CHR15, C(R15)2, NR18,
0 or
S, and W19 is N, CH or CR15, with the proviso that at least one of W14, W155
W165 W175 W185 and
W19 is N, NRI8, 0 or S, and wherein R15 and R18 are defined below and herein.
[00263] In certain embodiments, Z is a piperidinyl group. In certain
embodiments, Z is a
piperidinyl group substituted with 0, 1, 2, 3, 4 or 5 R15 groups, e.g., of the
formulae:
-- Z NR1$
lIl
15 R15
)~ ( ).
or
wherein z is 0, 1, 2, 3, 4 or 5, and R15 and R18 are as defined below and
herein. In certain
embodiments, Z is an unsubstituted piperidinyl (i.e., wherein z is 0). In
certain embodiments, Z
is a substituted piperidinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certain
embodiments, Z is a
monosubstituted piperidinyl (i.e., wherein z is 1). In certain embodiments, Z
is a disubstituted
piperidinyl (i.e., wherein z is 2). In certain embodiments, Z is a
trisubstituted piperidinyl (i.e.,
wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1 or 2.
In certain embodiments, z is 0 or 1.
[00264] In certain embodiments, Z is a 1-piperidinyl group, e.g., of the
formula (ii-h)
wherein W19 is N and W145 W155 W165 W17, and W18 are, independently, selected
from CH2,
CHR15, C(R15)2. In certain embodiments, Z is a 2-piperidinyl group, e.g., of
the formula (ii-h)
wherein W14 is NR18; W155 W165 W175 and W18 are, independently, CHR15,
C(R15)2, or CH2; and
W19 is CH or CR15. In certain embodiments, Z is a 3-piperidinyl group, e.g.,
of the formula (ii-
h) wherein W15 is NR18; W145 W165 W17 and W18 are, independently, CHR15,
C(R15)2, or CH2; and
W19 is CH or CR15. In certain embodiments, Z is a 4-piperidinyl group, e.g.,
of the formula (ii-
h) wherein W16 is NR18; W145 W155 W17 and W18 are, independently, CHR15,
C(R15)2, or CH2; and
W19 is CH or CRIB
77
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00265] In certain embodiments, Z is a piperazinyl group. In certain
embodiments, Z is a
piperazinyl group substituted with 0, 1, 2, 3 or 4 R15 groups, e.g., of the
formulae:
-N NR18 NR18 NR18
(R1 5). or (R15).
wherein x is 0, 1, 2, 3, 4 or 5, and R15 and Rib are as defined below and
herein. In
certain embodiments, Z is an unsubstituted piperazinyl (i.e., wherein z is 0).
In certain
embodiments, Z is a substituted piperazinyl (e.g., wherein z is 1, 2, 3, 4 or
5). In certain
embodiments, Z is a monosubstituted piperazinyl (i.e., wherein z is 1). In
certain embodiments,
Z is a disubstituted piperazinyl (i.e., wherein z is 2). In certain
embodiments, Z is a trisubstituted
piperazinyl (i.e., wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3.
In certain
embodiments, z is 0, 1 or 2. In certain embodiments, z is 0 or 1.
[00266] In certain embodiments, Z is a piperazinyl group, e.g., of the formula
(ii-h) wherein
W19 is N, W16 is NR18 and W14 W15 W16 W'7 and W'8 are, independently, CHR15
C(R15)2, or
CH2. In certain embodiments, Z is a piperazinyl group wherein W19 is CH or
CR15, W14 and W'7
are independently NR18, and W15, W16, and W18 are, independently, CHR15,
C(R15)2, or CH2.
[00267] In certain embodiments, Z is a morpholinyl group substituted with 0,
1, 2, 3 or 4 R15
groups, e.g., of the formulae:
7-NR18
-N O ~ c
O~~(R15)z
(R15)7
or
wherein z is 0, 1, 2, 3, 4 or 5, and R15 and R18 are as defined below and
herein. In certain
embodiments, Z is an unsubstituted morpholinyl (i.e., wherein z is 0). In
certain embodiments, Z
is a substituted morpholinyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certain
embodiments, Z is a
monosubstituted morpholinyl (i.e., wherein z is 1). In certain embodiments, Z
is a disubstituted
morpholinyl (i.e., wherein z is 2). In certain embodiments, Z is a
trisubstituted morpholinyl (i.e.,
wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1 or 2.
In certain embodiments, z is 0 or 1.
[00268] In certain embodiments, Z is a morpholinyl group; e.g., of the formula
(ii-h) wherein
W19 is N, W16 is 0 and W14, W15, W16, and W17 are, independently, selected
from CH2, CHR15,
78
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
C(R15)2. In certain embodiments, Z is a morpholinyl group wherein W19 is CH or
CR15, W14 and
W17 are independently selected from 0 and NRI8, and W15, W16, and W18 are,
independently,
CHR15, C(R15)2, or CH2.
[00269] In certain embodiments, Z is a dioxanyl group. In certain embodiments,
Z is a
dioxanyl group substituted with 0, 1, 2, 3 or 4 R15 groups, e.g., of the
formulae:
15 5),
0 (R )Z or O~ (R )z
wherein z is 0, 1, 2, 3, 4 or 5, and R15 is as defined below and herein. In
certain
embodiments, Z is an unsubstituted dioxanyl (i.e., wherein z is 0). In certain
embodiments, Z is
a substituted dioxanyl (e.g., wherein z is 1, 2, 3, 4 or 5). In certain
embodiments, Z is a
monosubstituted dioxanyl (i.e., wherein z is 1). In certain embodiments, Z is
a disubstituted
dioxanyl (i.e., wherein z is 2). In certain embodiments, Z is a trisubstituted
dioxanyl (i.e.,
wherein z is 3). In certain embodiments, z is 0, 1, 2 or 3. In certain
embodiments, z is 0, 1 or 2.
In certain embodiments, z is 0 or 1.
[00270] In certain embodiments, Z is a dioxanyl group, e.g., of the formula
(ii-h) wherein
W14 and W17 are 0 and W15, W16, and W18 are, independently, CHR15, C(R15)2, or
CH2; and W19
is CH or CR15. In certain embodiments, Z is a dioxanyl group wherein W19 is CH
or CR15, W14
and W16 are independently selected from 0, and W15, W17, and W18 are,
independently, CHR15,
C(R15)2, or CH2. In certain embodiments, Z is a dioxanyl group wherein W19 is
CH or CR'5, W15
and W17 are independently selected from 0, and W14, W16, and W18 are,
independently, CHR15,
C(R15)2, or CH2.
[00271] In certain embodiments, Z is a C3_,0 carbocycyl. In certain
embodiments, Z is a C3_,0
carbocycyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain
embodiments, Z is a C5_8
carbocycyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain
embodiments, Z is a C5_6
carbocycyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups. In certain
embodiments, Z is a C9-lo
carbocycyl substituted with 0, 1, 2, 3, 4 or 5 R15 groups.
79
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Embodiments Wherein R" and Rd are Joined (fused)
[00272] As generally defined above, in certain embodiments, Ra and Rd are
joined to form a
C3_io carbocycyl or 3-14 membered heterocyclyl fused ring, and Rb and R are
independently
selected from -H, C1_io alkyl and C1_io perhaloalkyl.
[00273] In certain embodiments, each of Rb and R' independently is selected
from -H, C1-6
alkyl and C1_6 perhaloalkyl. In certain embodiments, each of Rb and R'
independently is selected
from -H, Ci_3 alkyl and Ci_3 perhaloalkyl. In certain embodiments, each of Rb
and R'
independently is selected from -H, C1 alkyl and C1 perhaloalkyl. In certain
embodiments, each
of Rb and R' independently is selected from -H, -CH3 and -CF3. In certain
embodiments, each
of Rb and R' independently is selected from -H and -CH3. In certain
embodiments, each of Rb
and R' independently is selected from -H and -CF3. In certain embodiments, Rb
and R' are both
-H.
[00274] In certain embodiments, Ra and Rd are joined to form a C5_7 carbocycyl
or 5-7
membered heterocyclyl fused ring. In certain embodiments, Ra and Rd are joined
to form a C5 7
carbocycyl or 5-7 membered heterocyclyl fused ring of the formula:
W2o
W21
i I
W22
W23y
(iH)
wherein W20, W21, W22, and W23 are, independently, CH2, CHR15, C(R15)2 or
NR's, R15
and R 18 are as defined below and herein, s is 0, 1 or 2, and the dashed line
indicates ring fusion.
[00275] In certain embodiments, Ra and Rd are joined to form a C5_7 carbocycyl
fused ring.
For example, in certain embodiments of formula (ii-j), W205 W215 W22 and W23
are,
independently, CH2, CHR15 or C(R15)2. Exemplary C5_7 carbocycyl groups which
Ra and Rd can
be joined to form include, but are not limited to, cyclopentyl, cyclohexyl and
cycloheptyl,
wherein such groups are substituted with 0, 1, 2, 3, 4 or 5 R15 groups.
[00276] In certain embodiments, Ra and Rd are joined to form a 5-7 membered
heterocyclyl
fused ring. For example, in certain embodiments of formula (ii-j), W20 is
NR18, and W21, W22,
and W23 are, independently, CH2, CHR15 or C(R15)2. In certain embodiments of
formula (ii-j),
W21 is NR18, and W205 W22, and W23 are, independently, CH2, CHR15 or C(R15)2.
In certain
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
embodiments of formula ii-' W22 is NR", and W21, W21, and W23 are,
independently, CH2,
CHR15 or C(R15)2. Exemplary 5-7 membered heterocyclyl groups which Ra and Rd
can be joined
to form include, but are not limited to, pyrrolidinyl, pyrazolidinyl,
imidazolidinyl, piperidinyl,
piperazinyl and azepanyl, wherein such groups are substituted with 0, 1, 2, 3,
4 or 5 R15 groups.
[00277] In certain embodiments, wherein s is 0, Ra and Rd are joined to form a
C5 carbocycyl
or 5-membered heterocyclyl fused ring of the formula:
W2o
W2l
w22
(ii-k)
wherein W20, W21 and W22, are, independently, CH2, CHR15, C(R15)2 or NR18, R15
and
R 18 are as defined below and herein, and the dashed line indicates ring
fusion.
[00278] In certain embodiments of formula (ii-k), Ra and Rd are joined to form
a C5
carbocycyl fused ring (i.e., cyclopentyl) e.g., wherein W205 W21 and W22, are,
independently,
CH2, CHRIS C(R15)2
[00279] In certain embodiments of formula (ii-k), Ra and Rd are joined to form
a 5-membered
heterocycyl fused ring (e.g., pyrrolidinyl), e.g., wherein W21 is NR18 and W20
W22 and W23 are
,
independently, CH2, CHR15 or C(R15)2. In certain embodiments of formula (ii-
k), Ra and Rd are
joined to form a 5-membered heterocycyl fused ring (e.g., pyrrolidinyl), e.g.,
wherein W20 is
NR18, and W215 W22, and W23 are, independently, CH2, CHR15 or C(R15)2
[00280] In certain embodiments, wherein s is 1, Ra and Rd are joined to form a
C6 carbocycyl
or 6-membered heterocyclyl fused ring of the formula:
W2o
\W21
i
v22
W23
(ii-m)
wherein W205 W215 W22, and W23 are, independently, CH2, CHR15, C(R15)2 or
NR18,
R15 and R 18 are as defined below and herein, and the dashed line indicates
ring fusion.
81
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00281] In certain embodiments of formula (ii-m), Ra and Rd are joined to form
a C6
carbocycyl fused ring (i.e., cyclohexyl) e.g., wherein W20, W21, W22, and W23
are, independently,
CH2, CHR15 C(R15)2
[00282] In certain embodiments of formula (ii-m), Ra and Rd are joined to form
a 6-membered
heterocycyl fused ring (e.g., piperidinyl), e.g., wherein W21 is NR18 and W20,
W22, and W23 are
,
independently, CH2, CHR15 or C(R15)2. In certain embodiments of formula (ii-
m), Ra and Rd are
joined to form a 6-membered heterocycyl fused ring (e.g., piperidinyl), e.g.,
wherein W20 is
NR18, and W21, W22, and W23 are, independently, CH2, CHR15 or C(R15)2
[00283] In certain embodiments, wherein s is 2, Ra and Rd are joined to form a
C7 carbocycyl
or 7-membered heterocyclyl ring of the formula:
~W2 W21
W22
W23 w23
(ii-n)
wherein W20, W21, W22, and W23 are, independently, CH2, CHR15, C(R15)2 or
NRIg,
R15 and R 18 are as defined below and herein, and the dashed line indicates
ring fusion.
[00284] In certain embodiments of formula (ii-n), Ra and Rd are joined to form
a C7
carbocycyl ring (i.e., cycloheptyl) e.g., wherein W20, W21, W22, and W23 are,
independently, CH2,
CHR15, C(R15)2.
[00285] In certain embodiments of formula (ii-n), Ra and Rd are joined to form
a 7-membered
heterocycyl ring (e.g., azepanyl), e.g., wherein W21 is NR18, and W20, W22,
and W23 are,
independently, CH2, CHR15 or C(R15)2. In certain embodiments of formula (ii-
n), Ra and Rd are
joined to form a 7-membered heterocycyl ring (e.g., azepanyl), e.g., wherein
W22 is NR18, and
W2o, W21, and W23 are, independently, CH2, CHR15 or C(R15)2
Embodiments wherein Rc and Rd are Joined (spiro-fused)
[00286] As generally defined above, in certain embodiments, R' and Rd are
joined to form a
C3-io carbocycyl or 3-14 membered heterocyclyl spiro-fused ring, and Ra and Rb
are
independently selected from -H, C1_1o alkyl and C1_10 perhaloalkyl.
82
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00287] In certain embodiments, each of Ra and Rb independently is selected
from -H, C1-6
alkyl and C1_6 perhaloalkyl. In certain embodiments, each of Ra and Rb
independently is selected
from -H, Ci_3 alkyl and Ci_3 perhaloalkyl. In certain embodiments, each of Ra
and Rb
independently is selected from -H, C1 alkyl and C1 perhaloalkyl. In certain
embodiments, each
of Ra and Rb independently is selected from -H, -CH3 and -CF3. In certain
embodiments, each
of Ra and Rb independently is selected from -H and -CH3. In certain
embodiments, each of Ra
and Rb independently is selected from -H and -CF3. In certain embodiments, Ra
and Rb are both
-H.
[00288] In certain embodiments, R' and Rd are joined to form a C5_7
carbocycyl, a 5-7
membered heterocyclyl, a 5,6-bicyclic carbocycyl, a 6,6-bicyclic carbocycyl, a
5,6-bicyclic
heterocyclyl or a 6,6-bicyclic heterocyclyl spiro-fused ring.
[00289] For example, in certain embodiments, R' and Rd are joined to form a
C5_7 carbocycyl,
a 5-7 membered heterocyclyl, a 5,6-bicyclic carbocycyl or 5,6-bicyclic
heterocyclyl spiro-fused
ring of the formula:
\ W24 rW25
W26
w27
W29 W28
(iii-a)
wherein W24, W25, W26, W27, W28 and W29 are, independently, CH2, CHR15,
C(R15)2 or
NR'8, optionally wherein W25 and W26 are substituted with a fused C6 aryl ring
or fused 6-
membered heteroaryl ring; t and v are, independently, 0 or 1; and R15 and R18
are as defined
below and herein. In certain embodiments, t is 0 and v is 0. In certain
embodiments, t is 0 and v
is 1. In certain embodiments, t is 1 and v is 0. In certain embodiments, t is
1 and v is 1.
[00290] In certain embodiments, R' and Rd are joined to form a C5_7 carbocycyl
spiro-fused
ring. For example, in certain embodiments of formula (iii-a), W24, W25, W26,
W27, W 28 and W29
are, independently, CH2, CHR15, or C(R15)2. Exemplary C5_7 carbocycyl groups
which R' and Rd
can be joined to form include, but are not limited to, cyclopentyl, cyclohexyl
and cycloheptyl,
wherein such groups are substituted with 0, 1, 2, 3, 4 or 5 R15 groups.
83
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00291] In certain embodiments, R' and Rd are joined to form a 5-7 membered
heterocyclyl,
spiro-fused ring. For example, in certain embodiments of formula (iii-a), W25
is NR'8 and W26,
W27, W28 and W29 are, independently, CH2, CHR15, C(R15)2. In certain
embodiments of formula
(iii-a), W26 is NR's and W24, W25, W27, W28 and W29 are, independently, CH2,
CHR15, C(R15)2. In
certain embodiments of formula (iii-a), W27 is NR's and W24, W25, W26, W28 and
W29 are,
independently, CH2, CHR15, C(R15)2. Exemplary 5-7 membered heterocyclyl groups
which R'
and Rd can be joined to form include, but are not limited to, pyrrolidinyl,
pyrazolidinyl,
imidazolidinyl, piperidinyl, piperazinyl and azepanyl, wherein such groups are
substituted with
0,1,2, 3, 4 or 5 R15 groups.
[00292] In certain embodiments, wherein t is 0 and v is 0, R' and Rd are
joined to form a C5
carbocycyl or 5-membered heterocyclyl spiro-fused ring of the formula:
W2 _
W2s
W27
w28
(iii-b)
wherein W25, W26, W27 and W28 are, independently, CH2, CHR15, C(R15)2 or NR's,
and
R15 and R18 are as defined below and herein.
[00293] In certain embodiments, R and Rd are joined to form a C5 carbocycyl
spiro-fused ring
(e.g., cyclopentyl); e.g., of formula (iii-b) wherein W25 is NR18 and W26, W27
and W28 are,
independently, CH2, CHR15 or C(R15)2
[00294] In certain embodiments, R' and Rd are joined to form a 5-membered
heterocyclyl
spiro-fused ring; e.g., of formula (iii-b) wherein W26 is NR18 and W25, W27
and W28 are,
independently, CH2, CHR15 or C(R15)2
[00295] In certain embodiments, wherein t is 0 and v is 1, R' and Rd are
joined to form a C6
carbocycyl or 6-membered heterocyclyl spiro-fused ring of the formula:
w25-w26
w27
j w29-w28
(W-C)
84
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
wherein W25, W26, W27, W28 and W29 are, independently, CH2, CHR15, C(R15)2 or
NR18,
and R15 and Rib are as defined below and herein.
[00296] In certain embodiments, R and Rd are joined to form a C6 carbocycyl
spiro-fused ring
(e.g., cyclohexyl); e.g., of formula (iii-c) wherein W255 W26, W27, W28 and
W29 are,
independently, CH2, CHR15 or C(R15)2
[00297] In certain embodiments, R' and Rd are joined to form a 5-membered
heterocyclyl
spiro-fused ring; e.g., of formula (..-c) wherein W26 is NR18 and W25 W27 W28
and W29 are,
m independently, CH2, CHR15 or C(R15)2. In certain embodiments, R' and Rd are
joined to form a
5-membered heterocyclyl spiro-fused ring of formula (iii-c) wherein W27 is
NRIg and W255 W26,
W28 and W29 are, independently, CH2, CHR15 or C(R15)2
[00298] In certain embodiments, wherein t is 1 and v is 1, R' and Rd are
joined to form a C7
carbocycyl or 7-membered heterocyclyl spiro-fused ring of the formula:
W24/W2\
Wzs
W27
,-x W29-- Wes
(iii-d)
wherein W245 W255 W265 W27, W28 and W29 are, independently, CH2, CHR15,
C(R15)2 or
NRIg, and R15 and R18 are as defined below and herein.
[00299] In certain embodiments, R and Rd are joined to form a C7 carbocycyl
spiro-fused ring
(e.g., c clohe t 1 e.g., of formula (iii-d) wherein W24 W2s W26 W27 W28 and
W29 are,
independently, CH2, CHR15 or C(R15)2
[00300] In certain embodiments, R' and Rd are joined to form a 7-membered
heterocyclyl
spiro-fused ring; e.g., of formula (wherein W25 is NRI8 and W24 W26 W27, W28
and W29
(iii-d) are, independently, CH2, CHR15 or C(R15)2. In certain embodiments, R'
and Rd are joined to
form a 7-membered heterocyclyl spiro-fused ring wherein W26 is NRIg and W245
W255 W275 W28
and W29 are, independently, CH2, CHR15 or C(R15)2. In certain embodiments, R'
and Rd are
joined to form a 7-membered heterocyclyl spiro-fused ring wherein W27 is NR18
and W245 W255
W265 W28 and W29 are, independently, CH2, CHR15 or C(R15)2
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00301] In certain embodiments, R' and Rd are joined to form a 5,6-bicyclic
carbocycyl spiro-
fused ring or a 5,6-bicyclic heterocycyl spiro-fused ring. For example, in
certain embodiments
of formula (iii-a), t and v are both 0, W25 and W26 are substituted with a
fused C6 aryl ring or
fused 6-membered heteroaryl ring, and W27 is CH2, CHR15, C(R15)2, and NR18,
and and W28 is
CH2, CHR15 or C(R15)2. In certain embodiments of formula (iii-a), R' and Rd
are joined to form
a 5,6-bicyclic carbocycyl spiro-fused ring, e.g., wherein t and v are both 0,
W25 and W26 are
substituted with a fused C6 aryl ring or fused 6-membered heteroaryl ring, and
W27 and W28 are,
independently, CH2, CHR15 or C(R15)2. In certain embodiments, W25 and W26 are
substituted
with a fused C6 aryl ring.
[00302] For example, in certain embodiments, wherein t and v are both 0 and
W25 and W26 are
substituted with a fused C6 aryl ring, R' and Rd are joined to form a 5,6-
bicyclic carbocycyl
spiro-fused ring of the formula:
/ ~ (R15)z
W27
W28
(iii-d)
wherein W27 and W28 are, independently, CH2, CHR15, and C(R15)2, z is 0, 1, 2,
3 or
4; and R15 and is defined below and herein. In certain embodiments, W27 and
W28 are both CH2
groups. In certain embodiments, z is 0, 1, 2, 3 or 4. In certain embodiments,
z is 0, 1, 2 or 3. In
certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 2. In
certain embodiments, z is
1. In certain embodiments, z is 0.
[00303] In certain embodiments, R' and Rd are joined to form a 6,6-bicyclic
carbocycyl spiro-
fused ring or a 6,6-bicyclic heterocycyl spiro-fused ring. For example, in
certain embodiments
of formula (iii-a), t is 0 and v is 1, W25 and W26 are substituted with a
fused C6 aryl ring or fused
6-membered heteroaryl ring, and W27 and W28 are independently CH2, CHR15,
C(R15)2, and
NR18, and W29 is CH2, CHR15, C(R15)2. In certain embodiments of formula (iii-
a), R' and Rd are
joined to form a 6,6-bicyclic carbocycyl spiro-fused ring, e.g., wherein t is
0 and v is 1, W25 and
W26 are substituted with a fused C6 aryl ring or fused 6-membered heteroaryl
ring, and W27, W28
86
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
and W29 are, independently, CH2, CHR15 or C(R15)2. In certain embodiments, W25
and W26 are
substituted with a fused C6 aryl ring.
[00304] For example, in certain embodiments, wherein t is 0 and v is 1 and W25
and W26 are
substituted with a fused C6 aryl ring, R' and Rd are joined to form a 6,6-
bicyclic carbocycyl
spiro-fused ring of the formula:
(R'S)Z
W27
W29- W28
(iii-e)
wherein W27, W28 and W29 are, independently, CH2, CHR15, and C(R15)2, z is 0,
1, 2,
3 or 4, and R15 is as defined below and herein. In certain embodiments, W27,
W28 and W29 are
each CH2 groups. In certain embodiments, z is 0, 1, 2, 3 or 4. In certain
embodiments, z is 0, 1, 2
or 3. In certain embodiments, z is 0, 1 or 2. In certain embodiments, z is 2.
In certain
embodiments, z is 1. In certain embodiments, z is 0.
[00305] In another aspect, R' and Rd are joined to form a bridged carbocycyl
or bridged
heterocycyl spiro-fused ring of the formula:
W30,W3
X / W3l
W36 I
W32
W33--,W35
(iii-f)
wherein W30, W31, W32, W33 and W36 are, independently, CH2, CHR15, C(R15)2 or
NR18;
and W34 and W35 are, independently, CH or CR15, and and R15 and R18 are as
defined below and
herein.
[00306] In certain embodiments of formula (iii-f), W30, W31, W32, W33 are,
independently,
CH2, CHR15 or C(R15)2; W36 is NR18; and W34 and W35 are, independently, CH or
CR15. In
certain embodiments of formula (iii-f), W30, W31, W32, W33 and W36 are,
independently, CH2,
87
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
CHR15 or C(R15)2; and W34 and W35 are, independently, CH or CR15. In certain
embodiments of
formula (iii-f), W34 and W35 are CH.
R'5 Groups
[00307] As used herein, each instance of R15 is, independently, selected from
halogen (i.e.,
fluoro (-F), bromo (-Br), chloro (-Cl), and iodo (-I)), -CN, -NO2, -N3, -SO2H,
-SO3H, -OH, -
OR16 -ON(R'8)2, -N(R'8)2, -N(R'8)3X N(OR'7)R'8 SH SR16 SSR17 C(=O)R16
CO2H, -CHO, -C02R16, -OC(=O)R16, -OCO2R16, -C(=O)N(R18)2, -OC(=O)N(R18)2, -
NR18C(=O)R16, -NR18C02R16, -NR18C(=O)N(R'8)2, -C(=NR18)R16, -C(=NR18)OR16, -
OC(=NR18)R16, -OC(=NR18)OR16, -C(=NR18)N(R18)2, -OC(=NR'8)N(R18)2, -
NR18C(=NR18)N(R18)2, -C(=O)NR18SO2R16, -NR18SO2R16, -S02N(R18)2, -SO2R16, -
S02OR16, -
OSO2R16, -S(=O)R16, -OS(=O)R16, -Si(R16)3, -OSi(R16)3 -C(=S)N(R18)2, -
C(=O)SR16, -
C(=S)SR16, -SC(S)SR16, -P(=0)2R16 -OP(=0)2R16 -P(=O)(R16)2, -OP(=O)(R16)2, -
OP(=O)(OR17)2, -P(=O)2N(R18)2, -OP(=O)2N(R18)2, -P(=O)(NR18)2, -OP(=O)(NR18)2,
-
NR18P(=O)(OR17)2, -NR18P(=O)(NR18)2, -P(R17)2, -P(R17)3, -OP(R17)2, -OP(R17)3,
-B(OR17)2,
-BR 16(OR17), C,_1o alkyl, C,_,0 perhaloalkyl, C2_,0 alkenyl, C2_,0 alkynyl,
C3_,4 carbocyclyl, 3-
14 membered heterocyclyl, C6_,4 aryl, and 5-14 membered heteroaryl, wherein
each alkyl,
alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with
0, 1, 2, 3, 4, or 5 R19 groups; or two vicinal R15 groups are replaced with
the group -O(C(R2)2)1_
20- wherein each R2 is independently H, C1_6 alkyl or halogen;
each instance of R16 is, independently, selected from C,_1o alkyl, C,_1o
perhaloalkyl, C2_,0
alkenyl, C2_,0 alkynyl, C3_,0 carbocyclyl, 3-14 membered heterocyclyl, C6_,4
aryl, and 5-14
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R19 groups;
each instance of R18 is, independently, selected from hydrogen, -OH, -OR16, -
N(R'7)2, -
CN, -C(=O)R16 -C(=0)N(R 17)2, -C02R 16, -S02R 16, -C(=NR 17)OR 16, -
C(=NR17)N(R 17)
2, -
17171716 17) 1 17
SO2N(R )2, -SO2R , -S02OR , -SOR -C(=S)N(R 2, -C(_ -O)SR 7, -C(=S)SR , -
P(=0)2R16, -P(=0)(R16)2, -P(=O)2N(R17)2, -P(=O)(NR17)2, C1-1o alkyl, C1-1o
perhaloalkyl, C2-10
alkenyl, C2_10 alkynyl, C3_10 carbocyclyl, 3-14 membered heterocyclyl, C6_14
aryl, and 5-14
membered heteroaryl, or two R17 groups attached to an N atom are joined to
form a 3-14
membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,
alkenyl, alkynyl,
88
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted
with 0, 1, 2, 3, 4, or 5
R19 groups;
each instance of R17 is, independently, selected from hydrogen, C1_10 alkyl,
C1_10
perhaloalkyl, C2-lo alkenyl, C2-lo alkynyl, C3_1o carbocyclyl, 3-14 membered
heterocyclyl, C6_14
aryl, and 5-14 membered heteroaryl, or two R'7 groups attached to an N atom
are joined to form
a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 R19 groups;
each instance of R19 is, independently, selected from halogen, -CN, -NO2, -N3,
-SO2H5 -
SO3H, -OH, -OR20, -ON(R21)2, -N(R21)2, -N(R21)3+X, -N(OR20)R21, -SH, -SR20, -
SSR20, -
C(=O)R20, -CO2H, -C02R20, -OC(=O)R20, -0002R20, -C(=O)N(R21)2, -OC(=O)N(R21)2,
-
NR21C(=O)R20, -NR21CO2R20, -NR21C(=O)N(R21)2, -C(=NR21)OR20, -OC(=NR21)R20, -
OC(=NR21)OR20, -C(=NR21)N(R21)2, -OC(=NR21)N(R21)2, -NR21C(=NR21)N(R21)2,-
NR21S02R20, -S02N(R21)2, -S02R20, -S02OR20, -OS02R20, -S(=O)R20, -Si(R20)3, -
OSi(R20)3, -
C(=S)N(R21)2, -C(=O)SR20, -C(=S)SR20, -SC(=S)SR20, -P(=O)2R20 -P(=O)(R20)2, -
OP(=O)(R20)2, -OP(=O)(OR20)2, C1-6 alkyl, C1_6 perhaloalkyl, C2-6 alkenyl,
C2_6 alkynyl, C3_10
carbocyclyl, 3-10 membered heterocyclyl, C6_1o aryl, 5-10 membered heteroaryl,
wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently
substituted with 0, 1, 2, 3, 4, or 5 R22 groups, or two geminal R19
substituents can be joined to
form =0 or =S;
each instance of R20 is, independently, selected from C1-6 alkyl, C1-6
perhaloalkyl, C2-6
alkenyl, C2-6 alkynyl, C3_1o carbocyclyl, C6_1o aryl, 3-10 membered
heterocyclyl, and 3-10
membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R22 groups;
each instance of R21 is, independently, selected from hydrogen, C1_6 alkyl, C1-
6
perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, C3_1o carbocyclyl, 3-10 membered
heterocyclyl, C6_10
aryl and 5-10 membered heteroaryl, or two R21 groups attached to an N atom are
joined to form
a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each
alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently
substituted with 0, 1, 2,
3, 4, or 5 R22 groups; and
89
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
each instance of R22 is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H,
-OH,
-OC1_6 alkyl, -ON(C1_6 alkyl)2, N(C1_6 alkyl)2, -N(C1-6 alkyl)3X, NH(C1_6
alkyl)2X, -
NH2(C1_6 alkyl)X, -NH3X, N(OC1-6 alkyl)(C1-6 alkyl), -N(OH)(C, 6 alkyl), -
NH(OH), -SH, -
SC1_6 alkyl, -SS(C1_6 alkyl), -C(=O)(C1-6 alkyl), -CO2H, -C02(C1-6 alkyl), -
OC(=O)(C1_6
alkyl), -0002(C1_6 alkyl), -C(=O)NH2, -C(=O)N(C1_6 alkyl)2, -OC(=O)NH(C1_6
alkyl), -
NHC(=O)(Ci 6 alkyl), -N(C16 alkyl)C(=O)( Ci 6 alkyl), -NHCO2(C, 6 alkyl), -
NHC(=O)N(C,_
6 alkyl)2, -NHC(=O)NH(C1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C,-6 alkyl),-
OC(=NH)(C1-6
alkyl), -OC(=NH)OC1-6 alkyl, -C(=NH)N(C1-6 alkyl)2, -C(=NH)NH(C1_6 alkyl), -
C(=NH)NH2,
-OC(=NH)N(C16 alkyl)2, -OC(NH)NH(C16 alkyl), -OC(NH)NH2, -NHC(NH)N(C, 6
alkyl)2, -
NHC(=NH)NH2, -NHSO2(C,_6 alkyl), -SO2N(CI-6 alkyl)2, -SO2NH(C,_6 alkyl), -
SO2NH2,-
SO2CI_6 alkyl, -S020C1-6 alkyl, -OS02C1_6 alkyl, -SOC1_6 alkyl, -Si(Ci_6
alkyl)3, -OSi(C1-6
alkyl)3 -C(=S)N(C1_6 alkyl)2, C(=S)NH(C1-6 alkyl), C(=S)NH2, -C(=O)S(C1-6
alkyl), -
C(=S)SC1s alkyl, -SC(=S)SC,_6 alkyl, -P(=0)2(Ci_6 alkyl), -P(=O)(C,_6 alkyl)2,
-OP(=O)(C,-6
alkyl)2, -OP(=O)(OC16 alkyl)2, C1_6 alkyl, C1_6 perhaloalkyl, C2-6 alkenyl, C2
alkynyl, , C3_1o
carbocyclyl, C6-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl;
or two geminal
R22 substituents can be joined to form =0 or =S;
wherein X is a counterion.
[00308] In certain embodiments, each instance of R15 is, independently,
selected from fluoro
(-F), bromo (-Br), chloro (-Cl), and iodo ( -I), -OR16, -C(=O)N(R'8)2, -
S02N(Rl')2, CI-10
alkyl, C1_1o perhaloalkyl, C2_1o alkenyl, C2_1o alkynyl, C6_,4 aryl, and 5-14
membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl is independently
substituted with 0, 1,
2, 3, 4, or 5 R19 groups.
[00309] In certain embodiments, R15 is, independently, selected from fluoro (-
F), bromo (-
Br), chloro (-Cl), and iodo (-I), -OR16 and C1_1o perhaloalkyl. In certain
embodiments, R15 is,
independently, selected from fluoro (-F), bromo (-Br), chloro (-Cl), and iodo
(-I) and -OR16. In
certain embodiments, R15 is, independently, selected from fluoro (-F), bromo (-
Br), chloro (-
Cl), and iodo (-I) and C1_10 perhaloalkyl.
[00310] In certain embodiments, R15 is selected from -OR 16 and CI-10
perhaloalkyl.
[00311] In certain embodiments, R15 is -OR16. In certain embodiments, R16 is
selected from
C1-lo alkyl, C1-lo perhaloalkyl, C2-1o alkenyl, C2-1o alkynyl, C6_,0 aryl, and
5-6 membered
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
heteroaryl, wherein each alkyl, alkenyl, alkynyl, aryl, and heteroaryl is
independently substituted
with 0, 1, 2, 3, 4, or 5 R19 groups.
[00312] In certain embodiments, R15 is -OR16, and R16 is selected from C,_lo
alkyl. In certain
embodiments, R15 is -OR16, and R16 is selected from C1-6 alkyl. In certain
embodiments, R15 is -
OR16, and R16 is selected from C1_4 alkyl. In certain embodiments, R15 is -
OR16, and R16 is
selected from C1_2 alkyl. In certain embodiments, R15 is -OR16 and R16 is -
CH3, -Et, -iPr, -nBu, -
n-pentyl. In certain embodiments, R15 is -OR16 and R16 is -CH3.
[00313] In certain embodiments, R15 is -OR16, and R16 is selected from CI-10
perhaloalkyl. In
certain embodiments, R15 is -OR16, and R16 is selected from C1-6 perhaloalkyl.
In certain
embodiments, R15 is -OR16, and R16 is selected from C1_4 perhaloalkyl. In
certain embodiments,
R15 is -OR16, and R16 is selected from C1 2 perhaloalkyl. In certain
embodiments, R15 is -OR16
and R16 is -CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFC12, or -CF2C1. In certain
embodiments,
R15 is -OR16 and R16 is -CF3.
[00314] In certain embodiments, R15 is -OR16, and R16 is selected from C2_,0
alkenyl. In
certain embodiments, R15 is -OR16, and R16 is selected from C2 alkenyl. In
certain
embodiments, R15 is -OR16, and R16 is selected from C2 alkenyl. In certain
embodiments, R15
is -OR16, and R16 is selected from -CH2CHCH2 (i.e., allyl).
[00315] In certain embodiments, R15 is -OR16, and R16 is selected from C2_,0
alkynyl. In
certain embodiments, R15 is -OR16, and R16 is selected from C2_6 alkynyl. In
certain
embodiments, R15 is -OR16, and R16 is selected from C2_4 alkynyl. In certain
embodiments, R15 is
-OR16, and R16 is selected from -CH2CCH (i.e., propargyl).
[00316] In certain embodiments, R15 is -OR16, and R16 is selected from C6 aryl
(e.g., phenyl)
substituted with 0, 1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is -
OR16, and R16 is
phenyl substituted with 0, 1 or 2 R19 groups. In certain embodiments, R15 is -
OR16, and R16 is
phenyl substituted with 1 R19 groups. In certain embodiments, R15 is -OR16,
and R16 is phenyl
substituted with 0 R19 groups (i.e., -C6H5).
[00317] In certain embodiments, R15 is -OR 16, and R16 is selected from 5-6
membered
heteroaryl substituted with 0, 1, 2, 3 or 4 R19 groups. In certain
embodiments, R15 is -OR16, and
R16 is selected from a 6 membered heteroaryl substituted with 0, 1, 2, 3 or 4
R19 groups. In
certain embodiments, R15 is -OR16, and R16 is selected from pyridinyl (e.g., 2-
pyridinyl, 3-
pyridinyl, 4-pyridinyl) substituted with 0, 1, 2, 3 or 4 R19 groups. In
certain embodiments, R15 is
91
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
-OR16, and R16 is selected from pyrimidinyl (e.g., 2-pyrimidinyl, 4-
pyrimidinyl, 5-pyrimidinyl)
substituted with 0, 1, 2 or 3 R19 groups.
[00318] In certain embodiments, R15 is -C(=O)N(R'8)2.
[00319] In certain embodiments, R15 is -SO2N(RI8)2.
[00320] In certain embodiments, R15 is C,_lo perhaloalkyl. In certain
embodiments, R15 is C,_
6 perhaloalkyl. In certain embodiments, R15 is C1-4 perhaloalkyl. In certain
embodiments, R15 is
C,_2 perhaloalkyl. In certain embodiments, R15 is selected from -CF3, -CF2CF3,
-CF2CF2CF3, -
CC13, -CFC12, and -CF2C1. In certain embodiments, R15 is selected from -CF3.
[00321] In certain embodiments, R15 is C,_lo alkyl substituted with 0, 1, 2,
3, 4, or 5 R19
groups. In certain embodiments, R15 is C1-6 alkyl substituted with 0, 1, 2, 3,
4, or 5 R19 groups.
R15 is C1_4 alkyl substituted with 0, 1, 2, 3, 4, or 5 R19 groups. In certain
embodiments, the R15
alkyl group is unsubstituted (0 R19 groups). In certain embodiments, R15 is -
CH3, -Et, -iPr, -nBu,
-n-pentyl.
[00322] In certain embodiments, R15 is C2_,0 alkenyl substituted with 0, 1, 2,
3, 4, or 5 R19
groups. In certain embodiments, R15 is C2_6 alkenyl substituted with 0, 1, 2,
3 or 4 R19 groups. In
certain embodiments, R15 is C2_4 alkenyl substituted with 0, 1, 2 or 3 R19
groups. In certain
embodiments, the R15 alkenyl group is unsubstituted (0 R19 groups). In certain
embodiments, R15
is -CH2CHCH2 (i.e., allyl),
[00323] In certain embodiments, R15 is C2_,0 alkynyl substituted with 0, 1, 2,
3, 4, or 5 R19
groups. In certain embodiments, R15 is C2_6 alkynyl substituted with 0, 1, 2
or 3 R19 groups. In
certain embodiments, R15 is C2_4 alkynyl substituted with 0, 1 or 2 R19
groups. In certain
embodiments, the R15 alkynyl group is unsubstituted (0 R19 groups). In certain
embodiments, R15
is -CH2CCH (i.e., propargyl).
[00324] In certain embodiments, R15 is C6_,4 aryl. In certain embodiments, R15
is selected
from C6 aryl (e.g., phenyl) substituted with 0, 1, 2, 3 or 4 R19 groups. In
certain embodiments,
R15 is an unsubstituted phenyl. In certain embodiments, R15 is a
monosubstituted phenyl (i.e.,
substituted with 1 R19 group).
[00325] In certain embodiments, R15 is 5-14 membered heteroaryl substituted
with 0, 1, 2, 3,
4, or 5 R19 groups. In certain embodiments, R15 is 5-6 membered heteroaryl
substituted with 0, 1,
2, 3 or 4 R19 groups. In certain embodiments, R15 is a 6-membered heteroaryl
substituted with 0,
1, 2, 3 or 4 R19 groups. In certain embodiments, R15 is pyridinyl (e.g., 2-
pyridinyl, 3-pyridinyl, 4-
92
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
pyridinyl) substituted with 0, 1, 2, 3 or 4 R19 groups. In certain
embodiments, R15 is pyrimidinyl
(e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) substituted with 0, 1, 2
or 3 R19 groups. In
certain embodiments, the R15 heteroaryl group is unsubstituted (0 R19 groups).
R18 Groups
[00326] In certain embodiments, each instance of R18 is, independently,
selected from -H, -
OH, -OR16, -N(R'7)2, -C(=O)R16, -C(=O)N(R'7)2, -CO2R16, -SO2R16, -C(=NR17)R16,
-
C =NR17 OR16 17 17 17 16, 16, 16, 17
( ) , -C(=NR )N(R )z, -SOzN(R )z, -SOzR , -SOzOR , -SOR , -C(=S)N(R )z,
-C(=O)SR16, -C(=S)SR16, C1_1o alkyl (e.g., aralkyl), C2_1o alkenyl, C2_1o
alkynyl, C3_1o
carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl, and 5-14 membered
heteroaryl groups,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl,
aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R19 groups, wherein R16,
R17, R19 are as defined
above and herein.
[00327] In certain embodiments, each instance of R17 is, independently,
selected from -H, -
C(=O)R16, -C(=O)OR16, -SOZR16, or C1_6 alkyl. In certain embodiments, each
instance of R17 is,
independently, selected from -H or C1_6 alkyl. In certain embodiments, each
instance of R17 is,
independently, selected from -H and -CH3. In certain embodiments, each
instance of R17 is,
independently, selected from -H. In certain embodiments, each instance of R17
is,
independently, selected from -CH3.
Additional Embodiments of Compounds of Formula (I)
[00328] As defined generally above, the present invention provides compounds
of the formula
(I):
0 Rd
Rcb
9RF~
G Ra
(I)
or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, R' and Rd
are as
defined herein.
93
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00329] In one aspect, wherein Ra, Rb, R are each H, and Rd is the group Z,
the present
invention provides compounds of the formula (II):
L -Z
N
G
(II)
or a pharmaceutically acceptable form thereof, wherein G and Z are as defined
herein. In
certain embodiments, L is a covalent bond. In certain embodiments, G is -ORe.
In certain
embodiments, G is -Br. However, in certain embodiments, G is not halogen
(e.g., -Br, -Cl, -I).
[00330] For example, in certain embodiments, wherein L is a covalent bond, Ra,
Rb, R' are
each H, and G is the group -ORe, the present invention provides compounds of
the formula (II-
a):
O
Z
N
Re-0
(11-a)
or a pharmaceutically acceptable form thereof, wherein Re and Z are as defined
herein.
[00331] In certain embodiments, wherein Z is a phenyl ring, the present
invention provides
compounds of the formula (II-b):
N O L
R 15
(R )~
Rb
G Ra
(II-b)
or a pharmaceutically acceptable form thereof, wherein G, L, Ra, Rb, Rc, R'5
and z are as
defined herein. For example, in certain embodiments, z is 1 and R'5 is at the
ortho position. In
certain embodiments, z is 1 and R'5 is at the meta position. In certain
embodiments, z is 1 and
94
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
R15 is at the para position. In certain embodiments, z is 2 and R15 is at the
meta and para
position. In certain embodiments, L is a covalent bond. In certain
embodiments, G is -ORe. In
certain embodiments, G is -Br. However, in certain embodiments, G is not
halogen (e.g., -Br, -
Cl, -I). In certain embodiments, R15 is selected from -OR 16 and CI-10
perhaloalkyl.
[00332] For example, in certain embodiments, z is 1 and R15 is para to provide
compounds of
the formula (11-c):
0 L 0 R15
Rc
Rb
G Ra
(II-b)
or a pharmaceutically acceptable form thereof, wherein G, L, Ra, Rb, Re, R15
and z are as
defined herein. In certain embodiments, L is a covalent bond. In certain
embodiments, G is -
ORe. In certain embodiments, G is -Br. However, in certain embodiments, G is
not halogen
(e.g., -Br, -Cl, -I). In certain embodiments, R15 is selected from -OR16 and
C,_,0 perhaloalkyl.
[00333] For example, in certain embodiments, z is 2 and one R15 is meta and
one R15 is para to
provide compounds of the formula (II-c):
R15
L \ / R15
Rc
gF O
b
G Ra
(II-c)
or a pharmaceutically acceptable form thereof, wherein G, L, Ra, Rb, Rc, R15
and z are as
defined herein. In certain embodiments, L is a covalent bond. In certain
embodiments, G is -
ORe. In certain embodiments, G is -Br. However, in certain embodiments, G is
not halogen
(e.g., -Br, -Cl, -I). In certain embodiments, R15 is selected from -OR16 and
C,_,0 perhaloalkyl.
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00334] For example, in certain embodiments, wherein Z is an phenyl ring, and
G is the group
-ORe, the present invention provides compounds of the formula (II-d):
N/
Rc \ 15
\ (R ):
Rb
ReO Ra
(II-d)
or a pharmaceutically acceptable form thereof, wherein L, Ra, Rb, Re, R15, Re
and z are as
defined herein. For example, in certain embodiments, z is 1 and R15 is at the
ortho position. In
certain embodiments, z is 1 and R15 is at the meta position. In certain
embodiments, z is 1 and
R15 is at the para position. In certain embodiments, L is a covalent bond. In
certain
embodiments, R15 is selected from -OR 16 and CI-10 perhaloalkyl.
[00335] In certain embodiments, wherein Z is an phenyl ring, G is the group -
ORe, and Re is
an phenyl ring, the present invention provides compounds of the formula (II-
e):
Rc \ 15
gb
/ \ O Ra (R")X~
(II-e)
or a pharmaceutically acceptable form thereof, wherein L, Ra, Rb, Re, R'5, Rh,
x and z are
as defined herein. For example, in certain embodiments, z is 1 and R15 is at
the ortho position.
In certain embodiments, z is 1 and R15 is at the meta position. In certain
embodiments, z is 1 and
R15 is at the para position. In certain embodiments, L is a covalent bond. In
certain
embodiments, R15 is selected from -OR16 and C1-lo perhaloalkyl.
[00336] In certain embodiments, wherein Z is an phenyl ring, G is the group -
ORe, and Re is
an 5-membered heteroaryl ring, the present invention provides compounds of the
formula (II-
I):
96
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
O 0\/
N/
RC
\ (R'5).
Y d
YC / Rb
1 O O Ra
Yb___ Ya
(II-f)
or a pharmaceutically acceptable form thereof, wherein Ya, Yb, Ye, Yd, L, Ra,
Rb, Re, R15
and z are as defined herein. For example, in certain embodiments, z is 1 and
R15 is at the ortho
position. In certain embodiments, z is 1 and R15 is at the meta position. In
certain embodiments,
z is 1 and R15 is at the para position. In certain embodiments, L is a
covalent bond. In certain
embodiments, R15 is selected from -OR16 and Ci_io perhaloalkyl.
[00337] In certain embodiments, wherein Z is an phenyl ring, G is the group -
ORe, and Re is
an 6-membered heteroaryl ring, the present invention provides compounds of the
formula (II-
g):
N/O L 0\\ R
C Wb-Wa (R15)z
W~ \ O Ra Rb
Wd= We
(II-g)
or a pharmaceutically acceptable form thereof, wherein Wa, Wb, We, Wd, We, L,
Ra, Rb,
Re, R15 and z are as defined herein. For example, in certain embodiments, z is
1 and R15 is at the
ortho position. In certain embodiments, z is 1 and R15 is at the meta
position. In certain
embodiments, z is 1 and R15 is at the para position. In certain embodiments,
R15 is selected from
-OR16 and C1_1o perhaloalkyl. In certain embodiments, L is a covalent bond. In
certain
embodiments, Wb is N and Wa, We, Wd and We are selected from CH or CRh. In
certain
embodiments, In certain embodiments, Wb is N, We is CRh and Wa, We, Wd and We
are each CH.
In certain embodiments, Wb and Wd are N and Wa, We, Wd and We are selected
from CH or CRh.
97
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00338] In certain embodiments, wherein Z is a phenyl ring, G is the group -OR
e, and Re is an
9-membered heteroaryl ring, the present invention provides compounds of the
formula (11-h):
N~O L
YM Ye Rc \ \ (R15).
Y
k b
I J R
~ ` 9 O Ra
Y
Y' Y
(II-h)
or a pharmaceutically acceptable form thereof, wherein ye, Yf, Yg, Y', Y', Yk,
Ym, Y", L,
Ra, Rb, Rc, R15 and z are as defined herein. For example, in certain
embodiments, z is 1 and R15
is at the ortho position. In certain embodiments, z is 1 and R15 is at the
meta position. In certain
embodiments, z is 1 and R15 is at the para position. In certain embodiments,
R15 is selected from
-OR16 and CI-10 perhaloalkyl. In certain embodiments, L is a covalent bond.
[00339] In certain embodiments, wherein Z is a phenyl ring, G is the group -OR
e, and Re is an
l0-membered heteroaryl ring, the present invention provides compounds of the
formula (II-i):
N
n 0 L -\ ?
. Rc (R15).
W WM Wg R b
0 Ra
e Wh
W
(II-i)
or a pharmaceutically acceptable form thereof,
wherein Wf, Wg, W", W', Wj, Wk, Wm, WI L, Ra, Rb, Rc, R15 and z are as defined
herein.
For example, in certain embodiments, z is 1 and R15 is at the ortho position.
In certain
embodiments, z is 1 and R15 is at the meta position. In certain embodiments, z
is 1 and R15 is at
the para position. In certain embodiments, R15 is selected from -OR16 and C1-
lo perhaloalkyl.
In certain embodiments, L is a covalent bond.
98
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00340] In certain embodiments, wherein Z is a phenyl ring, and G is the group
-NR eRf, the
present invention provides compounds of the formula (II-j):
O L
gRTC
15 (R )z
b
Rem N Ra
\ f
(II-j)
or a pharmaceutically acceptable form thereof, wherein L, Ra, Rb, Rc, Re, Rf,
R15 and z
are as defined herein. For example, in certain embodiments, z is 1 and R15 is
at the ortho
position. In certain embodiments, z is 1 and R15 is at the meta position. In
certain embodiments,
z is 1 and R15 is at the para position. In certain embodiments, R15 is
selected from -OR16 and Ci_
perhaloalkyl. In certain embodiments, L is a covalent bond. In certain
embodiments, Re and
Rf are joined to forma 3-10 membered heterocycyl ring. In certain embodiments,
Re and Rf are
joined to form a 5-14 membered heteroaryl ring.
[00341] In certain embodiments of formulae (II), wherein Z is a 5-membered
heteroaryl ring,
the present invention provides compounds of the formula (111-a):
Y Y2
L QI
N/ a~Y3
Y
Rc
R G Ra
(III-a)
or a pharmaceutically acceptable form thereof, wherein Y', Y2, Y3, Y4, G, L,
Ra, Rb and
Re are as defined herein. In certain embodiments, L is a covalent bond. In
certain embodiments,
G is -ORe. In certain embodiments, G is -Br. However, in certain embodiments,
G is not
halogen (e.g., -Br, -Cl, -I). In certain embodiments, Y' is S, Y2 is CR'5, Y3
is N, and Y4 is CH or
99
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
CR15, wherein R15 is as defined above and herein. In certain embodiments, Y4
is CH. In certain
embodiments, the substituent present on Y2 is C6 aryl (e.g., phenyl).
[00342] In certain embodiments, wherein Z is a 6-membered heteroaryl ring, the
present
invention provides compounds of the formula (111-b):
W1- W2
L / >V3
0
N/ W5=w4
\ Rc
Rb
G Ra
(III-b)
or a pharmaceutically acceptable form thereof, wherein W', W2, W3, W4, G, L,
Ra, Rb and
R' are as defined herein. In certain embodiments, L is a covalent bond. In
certain embodiments,
G is -ORe. In certain embodiments, G is -Br. However, in certain embodiments,
G is not
halogen (e.g., -Br, -Cl, -I). In certain embodiments, the 6-membered
heteroaryl ring is pyridinyl
(e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl) or pyrimidinyl (e.g., 2-
pyrimidinyl, 4-pyrimidinyl, 5-
pyrimidinyl).
[00343] In certain embodiments, wherein Z is a 9-membered heteroaryl ring, the
present
invention provides compounds of the formula (III-c):
Y12
Y11/ \Y13___Y5
Ys
O Y1RC Y9 Y7
gRN
b
b
G Ra
(III-d)
or a pharmaceutically acceptable form thereof, wherein y5' Y6 Y' Y9 Y1o Yll
Yip Y13
G, L, Ra, Rb and R' are as defined herein. In certain embodiments, L is a
covalent bond. In
certain embodiments, G is -ORe. In certain embodiments, G is -Br. However, in
certain
embodiments, G is not halogen (e.g., -Br, -Cl, -I).
100
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00344] In certain embodiments, wherein Z is a 10-membered heteroaryl ring,
the present
invention provides compounds of the formula (III-e):
/W13 W6
W12 W7
s
~ W1\ ~W
W10W9
gFR~ 0 RL-1 I
b
b
G Ra
(III-e)
or a pharmaceutically acceptable form thereof, wherein W6, W7, W8, W9, W10,
W11, W12,
W13, G, L, Ra, Rb and R are as defined herein. In certain embodiments, L is a
covalent bond. In
certain embodiments, G is -ORe. In certain embodiments, G is -Br. However, in
certain
embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00345] In certain embodiments, wherein Z is a 6-membered heterocycyl, the
present
invention provides compounds of the formula (III-f):
W14_w15
/ \
0 L -W19 W16
gRN Rc\ 1s_W~
b
G Ra
(III-f)
or a pharmaceutically acceptable form thereof, wherein W14, W15, W16, W'7,
W'8, W19,
G, L, Ra, Rb and Re are as defined herein. In certain embodiments, L is a
covalent bond. In
certain embodiments, G is -ORe. In certain embodiments, G is -Br. However, in
certain
embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00346] In another aspect, wherein Ra and Rd are joined to form a C3-10
carbocycyl or 3-14
membered heterocycyl, the present invention provides compounds of the formula
(IV):
101
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Rc
W20
W21
N
z W23yv
Rb
G
(IV)
or a pharmaceutically acceptable form thereof, wherein s is 0, 1, or 2 and,
W20, W21, W22,
W23, G, Rc, Rd, R15 and Rig are as defined above and herein. In certain
embodiments, G is -ORe.
In certain embodiments, G is -Br. However, in certain embodiments, G is not
halogen (e.g., -
Br, -Cl, -I).
[00347] In certain embodiments, wherein s is 0, the present invention provides
compounds of
the formula (IV-a):
Rc
O W20
/ 2"21
Rb
G
(IV-a)
or a pharmaceutically acceptable form thereof, wherein G, Rb, Rc , W20, W21,
and W22 are
as defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is
-Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00348] In certain embodiments, wherein s is 0, W21 is NR18, and W20, W22, and
W23 are,
independently, CH2, CHRIS or C(R15)2, the present invention provides compounds
of the formula
(IV-b):
Rc
0 w20
N/ NR 18
W
Rb
102
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(IV-b)
or a pharmaceutically acceptable form thereof, wherein G, Rb, Re, Rig, and
R'5, are as
defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is -
Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00349] In certain embodiments, wherein s is 1, the present invention provides
compounds of
the formula (IV-c):
Rc
W20
j `--W2l
N I
Wzz
W23 ,- Rb
G
(IV-c)
or a pharmaceutically acceptable form thereof, wherein G, Rb, Re, W20, W21,
W22 and W23
are as defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G
is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -
I).
[00350] In certain embodiments, wherein s is 1, W21 is NR18, and W20, W22, and
W23 are,
independently, CH2, CHRIS or C(R15)2, the present invention provides compounds
of the formula
(IV-d):
Rc
W20
0 "- NR1s
N
W23 Wzz
Rb
G
(IV-d)
or a pharmaceutically acceptable form thereof, wherein G, Rb, Re, R18, and
R'5, are as
defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is -
Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00351] In certain embodiments, wherein s is 1, W22 is NR18, and W20, W21, and
W23 are,
independently, CH2, CHRIS or C(R15)2, the present invention provides compounds
of the formula
(IV-e):
103
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Rc
W20
W21
N
~NR1s
W23
Rb
G
(IV-e)
or a pharmaceutically acceptable form thereof, wherein G, Rb, Re, Rig, and
R'5, are as
defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is -
Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00352] In certain embodiments, wherein s is 2, the present invention provides
compounds of
the formula (IV-f):
Rc
O w2 W21
N/ W22
W23 __W23
Rb
G
(IV-f)
or a pharmaceutically acceptable form thereof, wherein G, Rb, Re, W20, W21,
W22 and W23
are as defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G
is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -
I).
[00353] In certain embodiments, wherein s is 2, W22 is NR18, and W20, W21, and
W23 are,
independently, CH2, CHRIS or C(R15)2, the present invention provides compounds
of the formula
(IV-g):
Rc
O W2 __ W21
N/ NR 18
W23
W23 _
Rb
G
(IV-g)
104
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
or a pharmaceutically acceptable form thereof, wherein G, Rb, Re, Rib, and
R15, are as
defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is -
Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00354] In still yet another aspect, wherein R' and Rd are joined to form a C3-
10 carbocycyl or
a 3-14 membered heterocycyl ring, the present invention provides compounds of
the formula
(V):
W25
r W24) W26
0 t
N/ W27
W29 W
Rb
G Ra
(V)
or a pharmaceutically acceptable form thereof,
wherein W24, W26, W27, W28 and W30 are, independently, CH2, CHR15, C(R15)2 or
NR18,
optionally wherein W25 and W26 are substituted with a fused C6 aryl ring or
fused 6-membered
heteroaryl ring; t and v are, independently, 0 or 1; wherein G, Ra, Rb, R15
and Rib are as defined
above and herein. In certain embodiments, G is -ORe. In certain embodiments, G
is -Br.
However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In
certain embodiments, t
is 0 and v is 0. In certain embodiments, t is 0 and v is 1. In certain
embodiments, t is 1 and v is
0. In certain embodiments, t is 1 and v is 1.
[00355] In certain embodiments, wherein t is 0 and v is 0, the present
invention provides
compounds of the formula (V-a):
W2 =
/p Wzs
N
I W27
W2s
G
Ra Rb
(V-a)
or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, W255 W26,
W27 and W28
are as defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments,
G is -Br. However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -
I). In certain
105
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
embodiments, W27 is NR18, and W25, W26 and W28 are, independently, CH2, CHR15
or C(R15)2
In certain embodiments, W25, W26, W27 and W28 are, independently, CH2, CHR15
or C(R15)2
[00356] In certain embodiments, wherein t is 0, v is 0, W27 is NR18, and W25,
W26 and W28
are, independently, CH2, CHR15 or C(R15)2, the present invention provides
compounds of the
formula (V-b):
/0 __W26
N
I ~NR1s
W2s
G
Ra Rb
(V-b)
or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, R15 and R18
are as
defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is -Br.
However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00357] In certain embodiments, wherein t is 0 and v is 1, the present
invention provides
compounds of the formula (V-c):
O w25_w26
~
N z7
W29_W2s
G
Ra Rb
(V-c)
or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, W25, W26,
W27, W2s
and W29 are as defined above and herein. In certain embodiments, G is -ORe. In
certain
embodiments, G is -Br. However, in certain embodiments, G is not halogen
(e.g., -Br, -Cl, -I).
In certain embodiments, W26 is NR18 and W25, W27, W28 and W29 are,
independently, CH2,
CHR15 or C(R15)2. In certain embodiments, W27 is NR18 and W25, W26, W28 and
W29 are,
independently, CH2, CHR15 or C(R15)2. In certain embodiments, W25, W26, W27,
W28 and W29
are, independently, CH2, CHR15 or C(R15)2
[00358] In certain embodiments, wherein t is 0, v is 1, W27 is NR18, and W25,
W26, W28 and
W29 are, independently, CH2, CHR15 or C(R15)2, the present invention provides
compounds of
the formula (V-d):
106
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
O w25 _ w26
N~
I \R18
W29_ Wzs
G
Ra Rb
(V-d)
or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, R15 and Rib
are as
defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is -Br.
However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00359] In certain embodiments, wherein t is 1 and v is 1, the present
invention provides
compounds of the formula (V-e):
W2
W24'\
/0 Wzs
N
I w27
W2 , W2s
G
Ra Rb
(V-e)
or a pharmaceutically acceptable form thereof, wherein G, W, Rb, Wz4, Wzs,
Wz6, Wz7,
W28 and W29 are as defined above and herein. In certain embodiments, G is -
ORe. In certain
embodiments, G is -Br. However, in certain embodiments, G is not halogen
(e.g., -Br, -Cl, -I).
In certain embodiments, W25 is NR18 and W24, W26, W27, W28 and W29 are,
independently, CH2,
CHR15 or C(R15)2. In certain embodiments, W26 is NR18 and W24, W25, W27, W28
and W29 are,
independently, CH2, CHR15 or C(R15)2. In certain embodiments, W27 is NR18 and
W24, W25, W26,
,
W28 and W29 are, independently, CH2, CHR15 or C(R15)2. In certain embodiments,
W24, W25
W26, W27, W28 and W29 are, independently, CH2, CHR15 or C(R15)2
[00360] In certain embodiments, wherein t is 1, v is 1, W27 is NR18 and W24,
W25, W26, W28
and W29 are, independently, CH2, CHR15 or C(R15)2, the present invention
provides compounds
of the formula (V-f):
107
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
iW2
0 W24\
Wes
)R18
/es
W29W
Ra Rb
(V-f)
or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb, R15 and Rig
are as
defined above and herein. In certain embodiments, G is -ORe. In certain
embodiments, G is -Br.
However, in certain embodiments, G is not halogen (e.g., -Br, -Cl, -I).
[00361] In certain embodiments, wherein t is 0, v is 0, W27 and W28 are,
independently, CH2,
CHRIS and C(R15)2, and W25 and W26 are substituted with a fused C6 aryl ring,
R' and Rd are
joined to form a 5,6-bicyclic carbocycyl spiro-fused ring of the formula (V-
g):
PR (R15)z
O
N 27
10,
G Ra
(V-g)
or a pharmaceutically acceptable form thereof, wherein G, Ra, Rb and R15 are
as
defined above and herein. In certain embodiments, Ra and Rb are -H. In certain
embodiments, z
is 1. In certain embodiments, G is -ORe. In certain embodiments, G is -Br.
However, in
certain embodiments, G is not halogen (e.g., -Br, -Cl, -I). In certain
embodiments, R15 is
selected from -OR16 and C,_,0 perhaloalkyl.
Exemplary Compouds of the Present Invention
[00362] Exemplary compounds of formulae (I) and (II), and subgenera thereof,
are set forth
in the Tables la-lm below, and are also described in more detail in Examples 1-
253, provided
108
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
herein. Compounds were assayed as inhibitors of human FAAH using the Method
described in
detail in Example 351.
[00363] In certain embodiments, the compound is any one of the compounds
provided in
Table 1a, or a pharmaceutically acceptable form thereof:
Table la.
O
N/ Rc & O
G
Ra
Compound G Ra Rc
1-10 -Br -H -H
1-17 -Cl -H -H
1-23 1/ I -H -H
1-24 -H -H
O
I-25 I -H -H
F \ O'
I-26 I -H -H
F3C \ O'
1-27 NC , -H -H
1-28 -H -H
CN
1-29 02N -H -H
I-30 Me, ,0 -H -H
OS
cc 1-31 Me , -H -H
FO"
1-32 OIN
-H -H H109
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table Ia.
-H -H
1-33 0 N'
1-34 -H -H
N~ N
~N
I-35 <:Nl\ -H -H
N
I-36 N I -H -H
1-37 -H -H
110
1-39 N -H -H
\ I ~
Me02C Oi
1-40 Me N -H -H
1-41 N -H -H
N~ I 0/
1-42 ~-N -H -H
1-43 N I -H -H
F O~
1-44 Me N -H -H
N
110 X
1-45 -OMe -H -H
1-47 ,N -H -H
H2N \ I 0
1-56 F3C N -H -H
I 0.
1-57 N -H -H
N 0
110
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table Ia.
1-58 CN -H -H
1-59 -H -H
1-60 CF3 -H -H
F
jo,
1-61 CO2Me -H -H
1-62 McO2C -H -H
, O
1-63 Me -H -H
o=s=o
\ 10 1-64 NH2 -H -H
O=S=O
6,0i
1-65 N -H -H
MeO \ O
1-66 MeO\ / N -H -H
N~ Oil
1-67 McO2C N -H -H
\ , Oi\
1-68 H
N -H -H
1-69 N -H -H
O \ Oiz
1-90 HZN.. -H -H _010
O
111
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table Ia.
1-92 BocH N\, N -H -H
"~:/ 'or
1-93 HZN f N -H -H
I-94 H N -H -H
Me~N
O O
I-98 O -H -H
UN
MeO
I-99 O -H -H
HO N
\ o,
I-100 O -H -H
H2N N
Oi z
1-110 HO2C N -H -H
I Oi
I-111 O -H -H
Me,N
N
Me Oiz
1-146 CO2H -H -H
oov' 1-147 HO2C -H -H
1-155 Me -H -H
/_O
N N
N \ I
O
1-159 Me -H -H
O
N ,
/
N
\ Oi z
112
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table Ia.
1-160 Me -H -H
N
O ,N
I-197 Me.. ,~ -H -H
OS N
1-243 HO-H -H
H
1-244 HO-,CN " -H -H
O Me
I-245 \ I N ,~ -H -H
H
OH
I-256 -H -H
GN
1-257 NON Me -H -H
F3C / O,\
1-260 O -H -H
Me O=
1-78 -Br -CH3 -H
(cis)
1-82 -Br -CH3 -H
(trans)
1-91 N -CH3 -H
(trans)
O
1-76 -Br -H -CH3
1-89 N -H -CH3
X
1-130 -Br -H -CF3
1-131 N -H -CF3
O'
1-95 -Br -H -CH2CH3
113
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00364] In certain embodiments, the compound is any one of the compounds
provided in
Table 1b, or a pharmaceutically acceptable form thereof:
Table 1b.
N
Rc OCF3
G
Ra
Compound G Ra Rc
1-14 -Br -H -H
I-46 -H -H
Me02C N 110
I-53 ,N -H -H
H2N \ I O~
1-54 ,N -H -H
Me N \ I 0
O
I-55 ;01 N -H -H
HO2C 10
I-70 N -H -H
O
1-71 ,N -H -H
Br \ O~
1-72 N -H -H
I-73 NH2 N -H -H
O I \ \ Oi~
I-83 a5l, -H -H
MeO N
O \ I O
114
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-84 i -H -H
EtO \ I N
O \ I O
1-85 -H -H
HO \ I N
O \ I Oi
1-86 -H -H
\ I N
Oiz
1-96 0 -H -H
N
MeO
\ 1-97 0 -H -H
HO N
\ I Oi
I-105 0 -H -H
MeO -11 ~N
IOI H \ I O 'X
1-106 0 -H -H
HO N
H I
O
1-107 0 -H -H
Me,N N
H \ 0A
1-108 0 -H -H
Me,N 1_,N,
Me Oiz
1-109 0 -H -H
HO~~ %N)
H
Oi
1-112 N -H -H
N, I Ol
1-118 0 -H -H
H2N ~N
H \ I iz
O
115
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-128 O -H -H
HO N
\ I
1-132 McSYN -H -H
N~ I Oi'z
I-133 Me,O -H -H
OSYN
N, Oi
1-134 MeS N -H -H
O
I-135 Me,SO N -H -H
1-136 MeO N -H -H
F \ I Oi.
I-151 N I -H -H
McO2C \ O~Z
I-152 -H -H
H02C \ O'
1-157 Me -H -H
/- O
N, N
N
1-161 Br N -H -H
O
1-162 S -H -H
N N~N
\I o-\
1-163 O -H -H
N
1-165 N- -H -H
HN N
I O
116
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-173 -H -H
H N
\ I O~
1-174 N=N -H -H
N NH
O
1-175 N-NH -H -H
N~
N
1-176 CO2H -H -H
1-177 HO2C -H -H
1-178 NC N -H -H
1-182 Et- IS'/ -H -H
N
O
1-183 J O -H -H
I-18
4 Me ,-H -H
N
~S
Me 0
\
1-186 -H -H
N
1-187 / 1-TN -H -H
Me
O I O1-188 HOC I -H -H
4 --
2 O
O
117
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-189 N/ I -H -H
N iN
Me \ O~
1-190 Me -H -H
N~ N
N
Me \ O
1-191 F3C -H -H
N I N
Me
1-192 Ny I -H -H
H N
\ O1
1-193 HOC I -H -H
2 S
1-194 N- -H -H
O N
\ Oi~
1-195 N-N -H -H
N N
H
O
1-199 Me\ -H -H
N
NN O
\ I Oi~
1-200 N= N -H -H
Me-N,
N
1-201 NCO -H -H
N 118
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-218 Me -H -H
N
NCI N
0
1-220 Me\ ,O 0 -H -H
S, N -11 O H \ I Oi
1-221 N-N -H -H
N
1-223 Me -H -H
N
O ,N
1-224 Me N -H -H
O, N
/
F \ Ol\
1-225 f--N -H -H
O ,N
FO
1-226 f--N -H -H
O ,N
F
\ Oi~
1-230 -H -H
0 N
/
N~ I O=
119
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-236 N-NH -H -H
N i N
0iz
I-246 \ I ,~ -H -H
N
H
OH
I-248 -H -H
os
I-249 -H -H
O
I-250 -H -H
0--s
p 'O
I-251 HO2C / I -H -H
I-253 / -H -H
JN
Me"
1-255 HO2C / I -H -H
N'
i
Me
1-258 -H -H
N
O &Zz~loA
~zl 1-75 -Br -H -CH3
1-88 N -H -CH3
1-113 HO2C
N -H -CH3
'~~l 0 A
1-114 0 -H -CH3
Me,N "-CN
H :~'~Jjo'\ 1
120
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-115 0 -H -CH3
N
Me^H
1-116 0 -H -CH3
F3CN U N
1-117 0 -H -CH3
HO,N UN
H OA
1-129 f ~ N I -H -CH3
N0
1-154 O I -H -CH3
N
\ Oi
1-156 Me -H -CH3
O
N N
N
\ Oiz
1-158 Me -H -CH3
S
N N
N 1I
1-164 S -H -CH3
N NUN
O
1-167 Mew 0 -H -CH3
OS N
OA
1-171 HO2CN'N -H -CH3
NJ
1-172 ("N_N -H -CH3
O'
121
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lb.
1-185 O -H -CH3
N NI
1-196 Et~s~ N -H -CH3
O
1-198 N -H -CH3
\ N N
1-222 Me -H -CH3
N
O N
1-227 -H -CH3
O N
F
1-228 -H -CH3
O &,"*," N N 1-229 Me -H -CH3
N
O ,N
N~ I OA
1-231 0 -H -CH3
NH
0 ,N
N~ Oi
122
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 1b.
1-232 /N -H -CH3
O .IN
\ I Oi~z
1-233 Me,N,Me -H -CH3
O=S=0
/
\ 10 1-234 Me. ,0 -H -CH3
OS
O
1-235 Me O -H -CH3
Me N-S
~ao
1-240 Me -H -CH3
N
N~ N
I 0A
1-241 N / I -H -CH3
N N
Me \ I OA
1-242 N OYN -H -CH3
N
H
O
1-261 McSN II -H -CH3
[00365] In certain embodiments, the compound is any one of the compounds
provided in
Table 1c, or a pharmaceutically acceptable form thereof:
Table lc.
N-O CFs
R(c;
G
Ra
123
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 1c.
Compound G Ra Rc
1-168 /N -H -H
Nr~,, Oi\
1-169 Mew ,? -H -H
S N
O
I O/
1-170 HO2C N -H -H
1-216 Br N -H -H
O >11
1-217 /N -H -H
O N
OoA
1-218 Me -H -H
N
N N
i
1-238 MeS .1,N -H -H
O
1-259 Me -H -H
N N
N
[00366] In certain embodiments, the compound is any one of the compounds
provided in
Table ld, or a pharmaceutically acceptable form thereof:
Table ld.
R15
GN~O~ OCF3
Ra
Compound G Ra Rc R15 = halogen
1-120 -Br -H -H -F
124
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table ld.
1-121 N -H -H -F
N ,-:,~0
1-122 McO2C N -H -H -F
1-123 HOZC N -H -H -F
I-124 -Br -H -H -Cl
1-125 N -H -H -Cl
N 0 '
[00367] In certain embodiments, the compound is any one of the compounds
provided in
Table le, or a pharmaceutically acceptable form thereof:
Table le.
N'O
Rc \ / O-R16
11
G
Ra
Compound G Ra Rc R1 = unsubstituted
alkyl, alk n l
1-142 -Br -H -H
1-143 N -H -H
N,
1-144 McO2C N -H -H
1-145 HO2C N -H -H
0
1-140 HO2C N -H -H Me
0 _Me
1-141 N N -H -H M )_Me
I
1-15 -Br -H -H Me
~_Me
125
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table le.
1-137 McO2C N -H -H n-butyl
1-138 HO2C N -H -H n-butyl
1-139 -H -H n-butyl
1-6 -Br -H -H -CH3
1-38 N -H -H -CH3
O
1-77 -Br -CH3 -H -CH3
(trans)
[00368] In certain embodiments, the compound is any one of the compounds
provided in
Table If, or a pharmaceutically acceptable form thereof:
Table 1f.
N R.aR15
G
Ra
Compound G Ra R` R'5 = alkyl, aryl
1-20 -Br -H -H n-butyl
1-180 ~N -H -H n-butyl
NU
O'
1-181 Me . 0 N -H -H n-butyl
o
1-179 -Br -H -H n- ent l
1-102 -Br -H -CH3 -C6H5
1-104 ~N -H -CH3 -C6H5
NU
O'
1-9 -Br -H -H -C6115
1-101 ,N -H -H -C6H5
1-103 N -H -H -C6H5
N~ Oi\
126
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00369] In certain embodiments, the compound is any one of the compounds
provided in
Table 1g, or a pharmaceutically acceptable form thereof:
Table 1 .
GN ~R15
Ra
Compound G R15 = halogen
1-3 -Br -Cl
1-153 N -Cl
N,,I Oil
1-148 -Br -Br
1-149 McO2C N -Br
1-150 HO2C N -Br
I-237 Mc, ,0 -Br
OS N
1-2 -Br -F
[00370] In certain embodiments, the compound is any one of the compounds
provided in
Table lh, or a pharmaceutically acceptable form thereof:
Table lh.
O
N' Rc~ ~ O
G
Ra N
Compound G Ra Rc
1-12 -Br -H -H
1-87 N -H -H
127
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00371] In certain embodiments, the compound is any one of the compounds
provided in
Table li, or a pharmaceutically acceptable form thereof:
Table li.
GN,O -
Rc\ /
Ra
Compound G Ra Rc
I-1 -Br -H -H
1-166 (N -H -H
N, ),,ON
[00372] In certain embodiments, the compound is any one of the compounds
provided in
Table 1j, or a pharmaceutically acceptable form thereof:
Table 1'.
R2
O~ R 2
N-O - O
R \ /
G
Ra
Compound G Ra Rc R2 = H, halogen
1-126 -Br -H -H -F, -F
1-127 ~N -H -H -F, -F
N~
O'
1-16 -Br -H -H -H
[00373] In certain embodiments, the compound is any one of the compounds
provided in
Table 1k, or a pharmaceutically acceptable form thereof:
Table 1k.
N,O O
G Rc , R18
Ra R18
Compound G Ra Rc R18
128
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 1k.
1-22 -Br -H -H H, -CH2Ph
1-214 Me- 0 N -H -H H, -CH2Ph
0
Oir
1-215 HO2C N -H -H H, -CH2Ph
1-203 -Br -H -H -CH3, -CH3
1-212 Me.. ,0 N -H -H -CH3, -CH3
OS
O
1-202 -Br -H -H
1-204 -Br -H -H -H, -CH3
1-208 -Br Oi-S
1-209 -Br -H -H
[00374] In certain embodiments, the compound is any one of the compounds
provided in
Table 11, or a pharmaceutically acceptable form thereof:
Table 11.
N,O O\/
18
G R N_R
Ra R18
Compound G Ra Rc R18
1-205 -Br -H -H
1-207 -Br -H -H -H, -CH3
1-206 -Br -H -H -CH3, -CH3
1-210 -Br -H -H Oi-S
1-211 -Br -H -H
129
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 11.
I-213 Me.. ,0 N -H -H -CH3, -CH3
OS /
O
[00375] In certain embodiments, the compound is any one of the compounds
provided in
Table lm, or a pharmaceutically acceptable form thereof:
Table lm.
CI CI
N,O - N-O -
I \ / 1 \ /
Br Br
1-4 I-5
OMe MeO
yao - N-O -
\ / I \ /
Br Br
1-7 1-8
N'O - N'O
Br O Br
I-11 1-13
F F N-O -
N ~ N,O 0
N
N,, O N
1-119 Me
1-18
O
N'0 N'N N-O C\DH1
I Br O I \ Br O -
i
1-19 \ /
1-21
"O
N'O, N
Br Br
1-49
1-48
N,O N,O
I \ /
O Br
Br I-51
I-50
130
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table lm.
N - 0 'N'O CO2Me
Br O Br
1-52 1-74
[00376] Further exemplified compounds of formulae (I), (II), (III), and
subgenera thereof, are
depicted in Tables 2a to 2e, provided below, and are also described in more
detail in Examples
254-284, provided herein. Compounds were assayed as inhibitors of human FAAH
using the
Method described in detail in Example 351.
[00377] In certain embodiments, the compound is any one of the compounds
provided in
Table 2a, or a pharmaceutically acceptable form thereof:
Table 2a.
N'0 / N
G R S \
Ra
Compound G Ra R` R'5 R19
11-6 -Br -H -H -H -H
II-21 N I -H -H -H -H
11-28 Me,S~ N -H -H -H -H
II-18 -Br -H -CH3 -H -H
II-22 N -H -CH3 -H -H
N 01\
11-23 N -H -CH3 -H -H
II-29 Mew ,0 -H -CH3 -H -H
DS '~'N
O
11-19 -Br -CH3 -H -H -H
(cis)
11-20 -Br -CH3 -H -H -H
(trans)
11-17 -Br -H -H -H -Cl
131
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00378] In certain embodiments, the compound is any one of the compounds
provided in
Table 2b, or a pharmaceutically acceptable form thereof:
Table 2b.
N'O
G Rc S \
Ra
N
Compound G Ra Rc
11-25 -Br -H -H
11-26 N I -H -H
11-27 H OZC , N I -H -H
\ "~/ 'Oi
[00379] In certain embodiments, the compound is any one of the compounds
provided in
Table 2c, or a pharmaceutically acceptable form thereof:
Table 2c.
N,O S
I
G Rc
Ra
Compound G Ra Rc
II-8 -Br -H -H
II-31 \ I N -H -H
H
OH
11-30 \ I N ,, -H -H
H
OH
[00380] In certain embodiments, the compound is any one of the compounds
provided in
Table 2d, or a pharmaceutically acceptable form thereof:
Table 2d.
N,
N-R18
G Rc
Ra
Compound G R18 Ra Rc
132
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
11-15 -Br-H -H
O
11-16 -Br 4 -H -H
O-~
[00381] In certain embodiments, the compound is any one of the compounds
provided in
Table 2e, or a pharmaceutically acceptable form thereof:
Table 2e.
NO - N,O -N
I /N
Br Br
II-1 11-2
N'O N- N O N
I \ / I \ II-3 N
Br Br
11-4
N'O S N'O
Br N Br S I \
II-5 11-7
NO -N
O - I \
Br
Br 11-10
11-9
O - O )-'E
Br J Br
N- N
II-11 Me
11-12
O O~
N' N' IOI
N
Br S ' N I O~ Br/-'
H N
11-13 O
O
11-14
133
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 2e.
Me N'C ~ N
N,o N
I I Br
Br Me s I \
CI
11-24 11-17
[00382] Additional exemplified compounds of formulae (I), (IV) and (V) and
subgenera
thereof, are depicted in Tables 3a to 3d, provided below, and are also
described in more detail in
Examples 285-350, provided herein. Compounds were assayed as inhibitors of
human FAAH
using the Method described in detail in Example 351.
[00383] In certain embodiments, the compound is any one of the compounds
provided in
Table 3a, or a pharmaceutically acceptable form thereof:
Table 3a.
N,O
\ /-\N-R 1s
G
Compound G R18
111-27 -Br
/ \ CI
111-48 -Cl
/ \ CI
111-51 N 0 ~ci
111-52 N
N 01\ cl
111-18 -Br 0
0
111-46 \ o
p O
134
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 3a.
III-59 10
-~
O
111-60 Me O
C ie O
111-16 -Br bo
III-58 Me., S~ N O
O
111-49 -Br
111-50 N
C-'1310
111-9 -Br O
O--
III-47 -Cl O
O--
III-53 N I //O
GAO-\ O
G
III-14 -Br -H
111-15 -Br Me
135
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 3a.
111-17 0
-Br -S
O
111-19
-Br / \
111-20
-Br /
CI
111-21
-Br /
OMe
111-22
-Br
111-23
-Br
111-24
-Br
Me
111-25
-Br CI
CI
111-26
-Br
CF3
111-28 -Br
111-29
-Br
111-30 -Br
136
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 3a.
111-31 -Br I \ / Br
111-32 ~-b
-Br
111-33 ~
-Br
111-34 O
-Br
111-35 0
-Br
H
OMe
III-36O
-Br O
~Me
Me
111-37 14
-Br
O \ /
111-38 O
-Br O /CI
CI CI
111-39 O
0-
-Br OMe
111-40 O
0-
-Br CI
111-41
Me
-Br 0
0
137
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 3a.
111-54 N O
N OA
111-55 0
N
N O
CI
111-56 N
N OA H N 0
III-57 N O
N JCF3
O
[00384] In certain embodiments, the compound is any one of the compounds
provided in
Table 3b, or a pharmaceutically acceptable form thereof:
138
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 3b.
N-O
G
N,R18
(cis ring fusion
Compound G R18
111-43 -Br Ox
111-44 -Br
O
111-45 -Br , CI
[00385] In certain embodiments, the compound is any one of the compounds
provided in
Table 3c, or a pharmaceutically acceptable form thereof:
Table 3c.
R15
O
G
Compound G R15
111-63 -Br 0
111-64 N O
N-/ `O
111-66 -Br -OCF3
111-67 MeS N -OCF3
111-68 Me.SO N -OCF3
O
O
139
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 3c.
111-70 Me -OCF3
N
N N
0
111-71 N I -OCF3
N N
Me \ I
O
111-73 [=N -OCF3
0 &1,111 0
-OCF3
111-74 0
)I_C)
HO N
[00386] In certain embodiments, the compound is any one of the compounds
provided in
Table 3d, or a pharmaceutically acceptable form thereof:
Table 3d.
N,O YI
DO
0+ 0 Br Br
III-1 111-2
~,,0 \ / N,O 01 jx D Br~ 0- Br O
111-3 111-4
N1O
N'0 0 -0
N
Br
Br /~- 0
111-8 0
III-10
)C0 N,O
N O I N
Br ~ Br Y 7&
0 O
III-11 111-12
140
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Table 3d.
N,O
O a
YIL> B
r + Br
111-13 111-42
(cis ring fusion)
O Q
jN-0
1 _J8
Br
111-62
[00387] However, in certain embodiments of formulae (I) and (II), or subgenera
thereof, any
one of the following compounds are specifically excluded:
OCH3
pC1 N/O NCO I
Br CI Br CH3
/ OCH3
0 I
NCO I NCO N/
NO2
Br Br Br F3C
OCH3
N/
N z 0 O
NO2
N N
H3C H3C
141
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
o
N
F3C
N NO / N\ O I
H3C MeO Et0
, , ,
O
N\
NO O N
c~yc' -O
-11 O H3C
N
N/O I N\ O '
N
N N
N/O \ I OCH3
3
O NO
O \ \
H3C--N H3C
CH3
CH3 0 0
O
N
or 0/ %fo
[00388] In certain embodiments of formulae (I) (II), and (III), or subgenera
thereof, any one
of the following compounds, wherein Rig is as defined herein, is specifically
excluded:
142
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
0-
0 O O
N\ N O N\ IV
Br Br Br
O O
N/ ~--O/O D
/O I
O N N
N N N
H3C H3C H3C
R\ 0
N
O O Ni0
N-R18
O N/ or Br
[00389] In certain embodiments of formulae (I), (IV) and (V), or subgenera
thereof, any one
of the following compounds, wherein Rig is as defined herein, and R'5 is -
OCH3, -CN, -CO2H, -
CO2CH3, -CO2CH2CH3, is specifically excluded:
N/O NO N/O NCO
MeO Meo MeO NC
NCO
O N_-O
;N
~-O
H3C--N
):0 Br
Br
Br
CH3
143
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
NCO CH3
NCO CH3 Br )__7 NCO
Br Br N~R18
NCO
O R15
NCO O ISLtr
Br
~R1s Br N Br N
~R1s ,R1s
N-_O
Br N1s )CN_R18
R15 or Br
H. Pharmaceutical Compositions
[00390] In certain embodiments, the present invention provides a
pharmaceutical composition
comprising a compound of the formula (I) or a pharmaceutically acceptable form
thereof, and a
pharmaceutically acceptable excipient.
[00391] Pharmaceutically acceptable excipients include any and all solvents,
diluents or other
liquid vehicles, dispersion or suspension aids, surface active agents,
isotonic agents, thickening
or emulsifying agents, preservatives, solid binders, lubricants and the like,
as suited to the
particular dosage form desired. General considerations in the formulation
and/or manufacture of
pharmaceutical compositions agents can be found, for example, in Remington's
Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa.,
1980), and
Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott
Williams & Wilkins,
2005).
[00392] Pharmaceutical compositions described herein can be prepared by any
method known
in the art of pharmacology. In general, such preparatory methods include the
steps of bringing
the active ingredient into association with a carrier and/or one or more other
accessory
ingredients, and then, if necessary and/or desirable, shaping and/or packaging
the product into a
desired single- or multi-dose unit.
144
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00393] Pharmaceutical compositions can be prepared, packaged, and/or sold in
bulk, as a
single unit dose, and/or as a plurality of single unit doses. As used herein,
a "unit dose" is
discrete amount of the pharmaceutical composition comprising a predetermined
amount of the
active ingredient. The amount of the active ingredient is generally equal to
the dosage of the
active ingredient which would be administered to a subject and/or a convenient
fraction of such a
dosage such as, for example, one-half or one-third of such a dosage.
[00394] Relative amounts of the active ingredient, the pharmaceutically
acceptable carrier,
and/or any additional ingredients in a pharmaceutical composition of the
invention will vary,
depending upon the identity, size, and/or condition of the subject treated and
further depending
upon the route by which the composition is to be administered. By way of
example, the
composition may comprise between 0.1 % and 100% (w/w) active ingredient.
[00395] Pharmaceutically acceptable excipients used in the manufacture of
provided
pharmaceutical compositions include inert diluents, dispersing and/or
granulating agents, surface
active agents and/or emulsifiers, disintegrating agents, binding agents,
preservatives, buffering
agents, lubricating agents, and/or oils. Excipients such as cocoa butter and
suppository waxes,
coloring agents, coating agents, sweetening, flavoring, and perfuming agents
may also be present
in the composition.
[00396] Exemplary diluents include calcium carbonate, sodium carbonate,
calcium phosphate,
dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium
phosphate lactose,
sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium
chloride, dry starch, cornstarch, powdered sugar, etc., and combinations
thereof.
[00397] Exemplary granulating and/or dispersing agents include potato starch,
corn starch,
tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus
pulp, agar, bentonite,
cellulose and wood products, natural sponge, cation-exchange resins, calcium
carbonate,
silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)
(crospovidone), sodium
carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-
linked sodium
carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized
starch (starch 1500),
microcrystalline starch, water insoluble starch, calcium carboxymethyl
cellulose, magnesium
aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium
compounds, etc., and
combinations thereof.
145
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00398] Exemplary surface active agents and/or emulsifiers include natural
emulsifiers (e.g.
acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux,
cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin),
colloidal clays (e.g. bentonite
[aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain
amino acid
derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl
alcohol, oleyl alcohol,
triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and
propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,
polyacrylic acid,
acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic
derivatives (e.g.
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose,
hydroxypropyl
cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty
acid esters (e.g.
polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan
[Tween 60],
polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span
40], sorbitan
monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate,
sorbitan monooleate
[Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj
45],
polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,
polyoxymethylene stearate,
and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters
(e.g. Cremophor),
polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]),
poly(vinyl-pyrrolidone),
diethylene glycol monolaurate, triethanolamine oleate, sodium oleate,
potassium oleate, ethyl
oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68,
Poloxamer 188,
cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, etc.
and/or combinations thereof.
[00399] Exemplary binding agents include starch (e.g. cornstarch and starch
paste), gelatin,
sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol,
mannitol, etc.), natural
and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss,
panwar gum, ghatti gum,
mucilage of isapol husks, carboxymethylcellulose, methylcellulose,
ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone),
magnesium aluminum
silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide,
polyethylene glycol,
inorganic calcium salts, silicic acid, polymethacrylates, waxes, water,
alcohol, etc., and/or
combinations thereof.
146
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00400] Exemplary preservatives include antioxidants, chelating agents,
antimicrobial
preservatives, antifungal preservatives, alcohol preservatives, acidic
preservatives, and other
preservatives.
[00401] Exemplary antioxidants include alpha tocopherol, ascorbic acid,
acorbyl palmitate,
butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol,
potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium
metabisulfite, and
sodium sulfite.
[00402] Exemplary chelating agents include ethylenediaminetetraacetic acid
(EDTA) and salts
and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium
edetate, calcium
disodium edetate, dipotassium edetate, and the like), citric acid and salts
and hydrates thereof
(e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof,
malic acid and salts
and hydrates thereof, phosphoric acid and salts and hydrates thereof, and
tartaric acid and salts
and hydrates thereof. Exemplary antimicrobial preservatives include
benzalkonium chloride,
benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium
chloride,
chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl
alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate,
propylene glycol, and thimerosal.
[00403] Exemplary antifungal preservatives include butyl paraben, methyl
paraben, ethyl
paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium
benzoate, potassium
sorbate, sodium benzoate, sodium propionate, and sorbic acid.
[00404] Exemplary alcohol preservatives include ethanol, polyethylene glycol,
phenol,
phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl
alcohol.
[00405] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin
E, beta-
carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic
acid, and phytic acid.
[00406] Other preservatives include tocopherol, tocopherol acetate, deteroxime
mesylate,
cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
ethylenediamine,
sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium
metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,
Phenonip,
methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In
certain
embodiments, the preservative is an anti-oxidant. In other embodiments, the
preservative is a
chelating agent.
147
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00407] Exemplary buffering agents include citrate buffer solutions, acetate
buffer solutions,
phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium
chloride, calcium
citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic
acid, calcium
glycerophosphate, calcium lactate, propanoic acid, calcium levulinate,
pentanoic acid, dibasic
calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate,
potassium acetate, potassium chloride, potassium gluconate, potassium
mixtures, dibasic
potassium phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium
acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate,
dibasic sodium
phosphate, monobasic sodium phosphate, sodium phosphate mixtures,
tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water,
isotonic saline,
Ringer's solution, ethyl alcohol, etc., and combinations thereof.
[00408] Exemplary lubricating agents include magnesium stearate, calcium
stearate, stearic
acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils,
polyethylene glycol,
sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl
sulfate, sodium
lauryl sulfate, etc., and combinations thereof.
[00409] Exemplary oils include almond, apricot kernel, avocado, babassu,
bergamot, black
current seed, borage, cade, camomile, canola, caraway, carnauba, castor,
cinnamon, cocoa butter,
coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening
primrose, fish, flaxseed,
geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba,
kukui nut, lavandin,
lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam
seed, mink,
nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut,
poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana,
savoury, sea
buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree,
thistle, tsubaki, vetiver,
walnut, and wheat germ oils. Exemplary oils include, but are not limited to,
butyl stearate,
caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate,
dimethicone 360,
isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil,
and combinations
thereof.
[00410] Liquid dosage forms for oral and parenteral administration include
pharmaceutically
acceptable emulsions, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to
the active ingredients, the liquid dosage forms may comprise inert diluents
commonly used in the
art such as, for example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl
148
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g.,
cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl
alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert
diluents, the oral
compositions can include adjuvants such as wetting agents, emulsifying and
suspending agents,
sweetening, flavoring, and perfuming agents. In certain embodiments for
parenteral
administration, the conjugates of the invention are mixed with solubilizing
agents such as
Cremophor, alcohols, oils, modified oils, glycols, polysorbates,
cyclodextrins, polymers, and
combinations thereof.
[00411] Injectable preparations, for example, sterile injectable aqueous or
oleaginous
suspensions can be formulated according to the known art using suitable
dispersing or wetting
agents and suspending agents. The sterile injectable preparation can be a
sterile injectable
solution, suspension or emulsion in a nontoxic parenterally acceptable diluent
or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can
be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride
solution. In
addition, sterile, fixed oils are conventionally employed as a solvent or
suspending medium. For
this purpose any bland fixed oil can be employed including synthetic mono- or
diglycerides. In
addition, fatty acids such as oleic acid are used in the preparation of
injectables.
[00412] The injectable formulations can be sterilized, for example, by
filtration through a
bacterial-retaining filter, or by incorporating sterilizing agents in the form
of sterile solid
compositions which can be dissolved or dispersed in sterile water or other
sterile injectable
medium prior to use.
[00413] In order to prolong the effect of a drug, it is often desirable to
slow the absorption of
the drug from subcutaneous or intramuscular injection. This can be
accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor water
solubility. The rate of
absorption of the drug then depends upon its rate of dissolution which, in
turn, may depend upon
crystal size and crystalline form. Alternatively, delayed absorption of a
parenterally
administered drug form is accomplished by dissolving or suspending the drug in
an oil vehicle.
[00414] Compositions for rectal or vaginal administration are typically
suppositories which
can be prepared by mixing the conjugates of this invention with suitable non-
irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a suppository wax
which are solid at
149
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
ambient temperature but liquid at body temperature and therefore melt in the
rectum or vaginal
cavity and release the active ingredient.
[00415] Solid dosage forms for oral administration include capsules, tablets,
pills, powders,
and granules. In such solid dosage forms, the active ingredient is mixed with
at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium citrate or
dicalcium phosphate
and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol, and silicic
acid, b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol,
d) disintegrating
agents such as agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates,
and sodium carbonate, e) solution retarding agents such as paraffin, f)
absorption accelerators
such as quaternary ammonium compounds, g) wetting agents such as, for example,
cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and bentonite clay,
and i) lubricants such
as talc, calcium stearate, magnesium stearate, solid polyethylene glycols,
sodium lauryl sulfate,
and mixtures thereof. In the case of capsules, tablets and pills, the dosage
form may comprise
buffering agents.
[00416] Solid compositions of a similar type can be employed as fillers in
soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as well as
high molecular weight
polyethylene glycols and the like. The solid dosage forms of tablets, dragees,
capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings and
other coatings
well known in the pharmaceutical formulating art. They may optionally comprise
opacifying
agents and can be of a composition that they release the active ingredient(s)
only, or
preferentially, in a certain part of the intestinal tract, optionally, in a
delayed manner. Examples
of embedding compositions which can be used include polymeric substances and
waxes. Solid
compositions of a similar type can be employed as fillers in soft and hard-
filled gelatin capsules
using such excipients as lactose or milk sugar as well as high molecular
weight polethylene
glycols and the like.
[00417] The active ingredients can be in micro-encapsulated form with one or
more
excipients as noted above. The solid dosage forms of tablets, dragees,
capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings,
release controlling
coatings and other coatings well known in the pharmaceutical formulating art.
In such solid
dosage forms the active ingredient can be admixed with at least one inert
diluent such as sucrose,
150
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
lactose or starch. Such dosage forms may comprise, as is normal practice,
additional substances
other than inert diluents, e.g., tableting lubricants and other tableting aids
such a magnesium
stearate and microcrystalline cellulose. In the case of capsules, tablets and
pills, the dosage
forms may comprise buffering agents. They may optionally comprise opacifying
agents and can
be of a composition that they release the active ingredient(s) only, or
preferentially, in a certain
part of the intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions
which can be used include polymeric substances and waxes.
[00418] Dosage forms for topical and/or transdermal administration of a
compound of this
invention may include ointments, pastes, creams, lotions, gels, powders,
solutions, sprays,
inhalants and/or patches. Generally, the active ingredient is admixed under
sterile conditions
with a pharmaceutically acceptable carrier and/or any needed preservatives
and/or buffers as can
be required. Additionally, the present invention contemplates the use of
transdermal patches,
which often have the added advantage of providing controlled delivery of an
active ingredient to
the body. Such dosage forms can be prepared, for example, by dissolving and/or
dispensing the
active ingredient in the proper medium. Alternatively or additionally, the
rate can be controlled
by either providing a rate controlling membrane and/or by dispersing the
active ingredient in a
polymer matrix and/or gel.
[00419] Suitable devices for use in delivering intradermal pharmaceutical
compositions
described herein include short needle devices such as those described in U.S.
Patents 4,886,499;
5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and
5,417,662. Intradermal
compositions can be administered by devices which limit the effective
penetration length of a
needle into the skin, such as those described in PCT publication WO 99/34850
and functional
equivalents thereof. Jet injection devices which deliver liquid vaccines to
the dermis via a liquid
jet injector and/or via a needle which pierces the stratum corneum and
produces a jet which
reaches the dermis are suitable. Jet injection devices are described, for
example, in U.S. Patents
5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911;
5,383,851;
5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639;
4,596,556;
4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO
97/13537.
Ballistic powder/particle delivery devices which use compressed gas to
accelerate vaccine in
powder form through the outer layers of the skin to the dermis are suitable.
Alternatively or
151
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
additionally, conventional syringes can be used in the classical mantoux
method of intradermal
administration.
[00420] Formulations suitable for topical administration include, but are not
limited to, liquid
and/or semi liquid preparations such as liniments, lotions, oil in water
and/or water in oil
emulsions such as creams, ointments and/or pastes, and/or solutions and/or
suspensions.
Topically-administrable formulations may, for example, comprise from about 1%
to about 10%
(w/w) active ingredient, although the concentration of the active ingredient
can be as high as the
solubility limit of the active ingredient in the solvent. Formulations for
topical administration
may further comprise one or more of the additional ingredients described
herein.
[00421] A pharmaceutical composition of the invention can be prepared,
packaged, and/or
sold in a formulation suitable for pulmonary administration via the buccal
cavity. Such a
formulation may comprise dry particles which comprise the active ingredient
and which have a
diameter in the range from about 0.5 to about 7 nanometers or from about 1 to
about 6
nanometers. Such compositions are conveniently in the form of dry powders for
administration
using a device comprising a dry powder reservoir to which a stream of
propellant can be directed
to disperse the powder and/or using a self propelling solvent/powder
dispensing container such
as a device comprising the active ingredient dissolved and/or suspended in a
low-boiling
propellant in a sealed container. Such powders comprise particles wherein at
least 98% of the
particles by weight have a diameter greater than 0.5 nanometers and at least
95% of the particles
by number have a diameter less than 7 nanometers. Alternatively, at least 95%
of the particles
by weight have a diameter greater than 1 nanometer and at least 90% of the
particles by number
have a diameter less than 6 nanometers. Dry powder compositions may include a
solid fine
powder diluent such as sugar and are conveniently provided in a unit dose
form.
[00422] Low boiling propellants generally include liquid propellants having a
boiling point of
below 65 F at atmospheric pressure. Generally the propellant may constitute
50 to 99.9% (w/w)
of the composition, and the active ingredient may constitute 0.1 to 20% (w/w)
of the
composition. The propellant may further comprise additional ingredients such
as a liquid non-
ionic and/or solid anionic surfactant and/or a solid diluent (which may have a
particle size of the
same order as particles comprising the active ingredient).
[00423] Pharmaceutical compositions of the invention formulated for pulmonary
delivery may
provide the active ingredient in the form of droplets of a solution and/or
suspension. Such
152
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
formulations can be prepared, packaged, and/or sold as aqueous and/or dilute
alcoholic solutions
and/or suspensions, optionally sterile, comprising the active ingredient, and
may conveniently be
administered using any nebulization and/or atomization device. Such
formulations may further
comprise one or more additional ingredients including, but not limited to, a
flavoring agent such
as saccharin sodium, a volatile oil, a buffering agent, a surface active
agent, and/or a preservative
such as methylhydroxybenzoate. The droplets provided by this route of
administration may have
an average diameter in the range from about 0.1 to about 200 nanometers.
[00424] The formulations described herein as being useful for pulmonary
delivery are useful
for intranasal delivery of a pharmaceutical composition of the invention.
Another formulation
suitable for intranasal administration is a coarse powder comprising the
active ingredient and
having an average particle from about 0.2 to 500 micrometers. Such a
formulation is
administered. by rapid inhalation through the nasal passage from a container
of the powder held
close to the nares.
[00425] Formulations suitable for nasal administration may, for example,
comprise from
about as little as 0.1% (w/w) and as much as 100% (w/w) of the active
ingredient, and may
comprise one or more of the additional ingredients described herein. A
pharmaceutical
composition of the invention can be prepared, packaged, and/or sold in a
formulation suitable for
buccal administration. Such formulations may, for example, be in the form of
tablets and/or
lozenges made using conventional methods, and may contain, for example, 0.1 to
20% (w/w)
active ingredient, the balance comprising an orally dissolvable and/or
degradable composition
and, optionally, one or more of the additional ingredients described herein.
Alternately,
formulations suitable for buccal administration may comprise a powder and/or
an aerosolized
and/or atomized solution and/or suspension comprising the active ingredient.
Such powdered,
aerosolized, and/or aerosolized formulations, when dispersed, may have an
average particle
and/or droplet size in the range from about 0.1 to about 200 nanometers, and
may further
comprise one or more of the additional ingredients described herein.
[00426] A pharmaceutical composition of the invention can be prepared,
packaged, and/or
sold in a formulation suitable for ophthalmic administration. Such
formulations may, for
example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w)
solution and/or
suspension of the active ingredient in an aqueous or oily liquid carrier. Such
drops may further
comprise buffering agents, salts, and/or one or more other of the additional
ingredients described
153
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
herein. Other opthalmically-administrable formulations which are useful
include those which
comprise the active ingredient in microcrystalline form and/or in a liposomal
preparation. Ear
drops and/or eye drops are contemplated as being within the scope of this
invention.
[00427] Although the descriptions of pharmaceutical compositions provided
herein are
principally directed to pharmaceutical compositions which are suitable for
administration to
humans, it will be understood by the skilled artisan that such compositions
are generally suitable
for administration to animals of all sorts. Modification of pharmaceutical
compositions suitable
for administration to humans in order to render the compositions suitable for
administration to
various animals is well understood, and the ordinarily skilled veterinary
pharmacologist can
design and/or perform such modification with ordinary experimentation. General
considerations
in the formulation and/or manufacture of pharmaceutical compositions can be
found, for
example, in Remington: The Science and Practice of Pharmacy 21st ed.,
Lippincott Williams &
Wilkins, 2005.
[00428] Still further encompassed by the invention are pharmaceutical packs
and/or kits.
Pharmaceutical packs and/or kits provided may comprise a provided composition
and a container
(e.g., a vial, ampoule, bottle, syringe, and/or dispenser package, or other
suitable container). In
some embodiments, provided kits may optionally further include a second
container comprising
a suitable aqueous carrier for dilution or suspension of the provided
composition for preparation
of administration to a subject. In some embodiments, contents of provided
formulation container
and solvent container combine to form at least one unit dosage form.
[00429] In some embodiments, a provided composition of the invention can be
useful in
conjunction with subject controlled analgesia (PCA) devices, wherein a subject
can administer,
for example, opioid analgesia as required for pain management.
[00430] Optionally, a single container may comprise one or more compartments
for
containing a provided composition, and/or appropriate aqueous carrier for
suspension or dilution.
In some embodiments, a single container can be appropriate for modification
such that the
container may receive a physical modification so as to allow combination of
compartments
and/or components of individual compartments. For example, a foil or plastic
bag may comprise
two or more compartments separated by a perforated seal which can be broken so
as to allow
combination of contents of two individual compartments once the signal to
break the seal is
generated. A pharmaceutical pack or kit may thus comprise such multi-
compartment containers
154
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
including a provided composition and appropriate solvent and/or appropriate
aqueous carrier for
suspension.
[00431] Optionally, instructions for use are additionally provided in such
kits of the invention.
Such instructions may provide, generally, for example, instructions for dosage
and
administration. In other embodiments, instructions may further provide
additional detail relating
to specialized instructions for particular containers and/or systems for
administration. Still
further, instructions may provide specialized instructions for use in
conjunction and/or in
combination with additional therapy. In one non-limiting example, the
formulations of the
invention can be used in conjunction with opioid analgesia administration,
which may,
optionally, comprise use of a subject controlled analgesia (PCA) device. Thus,
instructions for
use of provided formulations may comprise instructions for use in conjunction
with PCA
administration devices.
III Methods of Use and Treatment
[00432] The present invention provides methods for treating a FAAH-mediated
condition
comprising administering to a subject in need thereof a therapeutically
effective amount of a
compound of formula (I) or a pharmaceutically acceptable form thereof.
[00433] The present invention also provides methods for inhibiting FAAH in a
subject
comprising administering to a subject in need thereof a therapeutically
effective amount of a
compound of formula (I) or a pharmaceutically acceptable form thereof.
[00434] The present invention also provides a method of inhibiting activation
of the FAAH
pathway in vitro or ex vivo, comprising contacting a FAAH protein with a
compound of formula
(I) in an amount sufficient to reduce the activation of the FAAH pathway.
[00435] The present invention also provides use of a compound of formula (I)
for the
treatment of a FAAH-mediated condition in a subject.
[00436] The present invention also provides use of a compound of formula (I)
in the
manufacture of a medicament. In certain embodiments, the medicament is useful
for treating a
FAAH-mediated condition.
155
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00437] A "subject" to which administration is contemplated includes, but is
not limited to,
humans (i.e., a male or female of any age group, e.g., a pediatric subject
(e.g, infant, child,
adolescent) or adult subject (e.g., young adult, middle-aged adult or senior
adult)) and/or other
primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including
commercially
relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or
dogs; and/or birds,
including commercially relevant birds such as chickens, ducks, geese, and/or
turkeys.
[00438] As used herein, and unless otherwise specified, the terms "treat,"
"treating" and
"treatment" contemplate an action that occurs while a subject is suffering
from the specified
disease, disorder or condition, which reduces the severity of the disease,
disorder or condition, or
retards or slows the progression of the disease, disorder or condition.
[00439] As used herein, unless otherwise specified, the terms "prevent,"
"preventing" and
"prevention" contemplate an action that occurs before a subject begins to
suffer from the
specified disease, disorder or condition, which inhibits or reduces the
severity of the disease,
disorder or condition.
[00440] As used herein, and unless otherwise specified, the terms "manage,"
"managing" and
"management" encompass preventing the recurrence of the specified disease,
disorder or
condition in a subject who has already suffered from the disease, disorder or
condition, and/or
lengthening the time that a subject who has suffered from the disease,
disorder or condition
remains in remission. The terms encompass modulating the threshold,
development and/or
duration of the disease, disorder or condition, or changing the way that a
subject responds to the
disease, disorder or condition.
[00441] As used herein, and unless otherwise specified, a "therapeutically
effective amount"
of a compound is an amount sufficient to provide a therapeutic benefit in the
treatment or
management of a disease, disorder or condition, or to delay or minimize one or
more symptoms
associated with the disease, disorder or condition. A therapeutically
effective amount of a
compound means an amount of therapeutic agent, alone or in combination with
other therapies,
which provides a therapeutic benefit in the treatment or management of the
disease, disorder or
condition. The term "therapeutically effective amount" can encompass an amount
that improves
overall therapy, reduces or avoids symptoms or causes of disease or condition,
or enhances the
therapeutic efficacy of another therapeutic agent.
156
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00442] As used herein, and unless otherwise specified, a "prophylactically
effective amount"
of a compound is an amount sufficient to prevent a disease, disorder or
condition, or one or more
symptoms associated with the disease, disorder or condition, or prevent its
recurrence. A
prophylactically effective amount of a compound means an amount of therapeutic
agent, alone or
in combination with other agents, which provides a prophylactic benefit in the
prevention of the
disease, disorder or condition. The term "prophylactically effective amount"
can encompass an
amount that improves overall prophylaxis or enhances the prophylactic efficacy
of another
prophylactic agent.
[00443] As used herein "inhibition", "inhibiting", "inhibit" and "inhibitor",
and the like, refer
to the ability of a compound to reduce, slow, halt or prevent activity of a
particular biological
process (e.g., FAAH activity) in a cell relative to vehicle.
[00444] "FAAH-mediated condition" as used herein, refers to a disease,
disorder or condition
which is treatable by inhibition of FAAH activity. "Disease", "disorder" or
"condition" are
terms used interchangeably herein. FAAH-mediated conditions include, but are
not limited to,
painful conditions, inflammatory conditions, immune disorders, disorders of
the central nervous
system, metabolic disorders, cardiac disorders and glaucoma.
[00445] In certain embodiments, the FAAH-mediated condition is a painful
condition. As
used herein, a "painful condition" includes, but is not limited to,
neuropathic pain (e.g.,
peripheral neuropathic pain), central pain, deafferentiation pain, chronic
pain (e.g., chronic
nociceptive pain, and other forms of chronic pain such as post-operative pain,
e.g., pain arising
after hip, knee, or other replacement surgery), pre-operative pain, stimulus
of nociceptive
receptors (nociceptive pain), acute pain (e.g., phantom and transient acute
pain), non-
inflammatory pain, inflammatory pain, pain associated with cancer, wound pain,
bum pain, post-
operative pain, pain associated with medical procedures, pain resulting from
pruritus, painful
bladder syndrome, pain associated with premenstrual dysphoric disorder and/or
premenstrual
syndrome, pain associated with chronic fatigue syndrome, pain associated with
pre-term labor,
pain associated with withdrawl symptoms from drug addiction, joint pain,
arthritic pain (e.g.,
pain associated with crystalline arthritis, osteoarthritis, psoriatic
arthritis, gouty arthritis, reactive
arthritis, rheumatoid arthritis or Reiter's arthritis), lumbosacral pain,
musculo-skeletal pain,
headache, migraine, muscle ache, lower back pain, neck pain, toothache,
dental/maxillofacial
pain, visceral pain and the like.
157
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00446] One or more of the painful conditions contemplated herein can comprise
mixtures of
various types of pain provided above and herein (e.g. nociceptive pain,
inflammatory pain,
neuropathic pain, etc.). In some embodiments, a particular pain can dominate.
In other
embodiments, the painful condition comprises two or more types of pains
without one
dominating. A skilled clinician can determine the dosage to achieve a
therapeutically effective
amount for a particular subject based on the painful condition.
[00447] In certain embodiments, the painful condition is neuropathic pain. The
term
"neuropathic pain" refers to pain resulting from injury to a nerve.
Neuropathic pain is
distinguished from nociceptive pain, which is the pain caused by acute tissue
injury involving
small cutaneous nerves or small nerves in muscle or connective tissue.
Neuropathic pain
typically is long-lasting or chronic and often develops days or months
following an initial acute
tissue injury. Neuropathic pain can involve persistent, spontaneous pain as
well as allodynia,
which is a painful response to a stimulus that normally is not painful.
Neuropathic pain also can
be characterized by hyperalgesia, in which there is an accentuated response to
a painful stimulus
that usually is trivial, such as a pin prick. Neuropathic pain conditions can
develop following
neuronal injury and the resulting pain may persist for months or years, even
after the original
injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal
roots, spinal cord
or certain regions in the brain. Neuropathic pain conditions include, but are
not limited to,
diabetic neuropathy (e.g., peripheral diabetic neuropathy); sciatica; non-
specific lower back
pain; multiple sclerosis pain; carpal tunnel syndrome, fibromyalgia; HIV-
related neuropathy;
neuralgia (e.g., post-herpetic neuralgia, trigeminal neuralgia); pain
resulting from physical
trauma (e.g., amputation; surgery, invasive medical procedures, toxins, bums,
infection), pain
resulting from cancer or chemotherapy (e.g., chemotherapy-induced pain such as
chemotherapy-
induced peripheral neuropathy), and pain resulting from an inflammatory
condition (e.g., a
chronic inflammatory condition). Neuropathic pain can result from a peripheral
nerve disorder
such as neuroma; nerve compression; nerve crush, nerve stretch or incomplete
nerve
transsection; mononeuropathy or polyneuropathy. Neuropathic pain can also
result from a
disorder such as dorsal root ganglion compression; inflammation of the spinal
cord; contusion,
tumor or hemisection of the spinal cord; tumors of the brainstem, thalamus or
cortex; or trauma
to the brainstem, thalamus or cortex.
158
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00448] The symptoms of neuropathic pain are heterogeneous and are often
described as
spontaneous shooting and lancinating pain, or ongoing, burning pain. In
addition, there is pain
associated with normally non-painful sensations such as "pins and needles"
(paraesthesias and
dysesthesias), increased sensitivity to touch (hyperesthesia), painful
sensation following
innocuous stimulation (dynamic, static or thermal allodynia), increased
sensitivity to noxious
stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation
after removal of the
stimulation (hyperpathia) or an absence of or deficit in selective sensory
pathways (hypoalgesia).
[00449] In certain embodiments, the painful condition is non-inflammatory
pain. The types
of non-inflammatory pain include, without limitation, peripheral neuropathic
pain (e.g., pain
caused by a lesion or dysfunction in the peripheral nervous system), central
pain (e.g., pain
caused by a lesion or dysfunction of the central nervous system),
deafferentation pain (e.g., pain
due to loss of sensory input to the central nervous system), chronic
nociceptive pain (e.g., certain
types of cancer pain), noxious stimulus of nociceptive receptors (e.g., pain
felt in response to
tissue damage or impending tissue damage), phantom pain (e.g., pain felt in a
part of the body
that no longer exists, such as a limb that has been amputated), pain felt by
psychiatric subjects
(e.g., pain where no physical cause may exist), and wandering pain (e.g.,
wherein the pain
repeatedly changes location in the body).
[00450] In certain embodiments, the painful condition is inflammatory pain. In
certain
embodiments, the painful condition (e.g., inflammatory pain) is associated
with an inflammatory
condition and/or an immune disorder.
[00451] In certain embodiments, the FAAH-mediated condition is an inflammatory
condition.
The term "inflammatory condition" refers to those diseases, disorders or
conditions that are
characterized by signs of pain (dolor, from the generation of noxious
substances and the
stimulation of nerves), heat (calor, from vasodilatation), redness (rubor,
from vasodilatation and
increased blood flow), swelling (tumor, from excessive inflow or restricted
outflow of fluid),
and/or loss of function (functio laesa, which can be partial or complete,
temporary or permanent.
Inflammation takes on many forms and includes, but is not limited to, acute,
adhesive, atrophic,
catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous,
fibrosing, focal,
granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic,
obliterative,
parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent,
sclerosing,
159
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
seroplastic, serous, simple, specific, subacute, suppurative, toxic,
traumatic, and/or ulcerative
inflammation.
[00452] Exemplary inflammatory conditions include, but are not limited to,
inflammation
associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune
anaemia), asthma,
arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa,
Takayasu's arteritis), arthritis
(e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty
arthritis, reactive arthritis,
rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis,
amylosis, amyotrophic lateral
sclerosis, autoimmune diseases, allergies or allergic reactions,
atherosclerosis, bronchitis,
bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic
obstructive pulmonary
disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes
mellitus, type 2 diabetes
mellitus), a skin condition (e.g., psoriasis, eczema, bums, dermatitis,
pruritus (itch)),
endometriosis, Guillain-Barre syndrome, infection, ischaemic heart disease,
Kawasaki disease,
glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine
headaches, tension
headaches), ileus (e.g., postoperative ileus and ileus during sepsis),
idiopathic thrombocytopenic
purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal
disorder (e.g., selected
from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal
bleeding, eosinophilic
gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic
gastritis, eosinophilic
gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal
reflux disease (GORD,
or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,
ulcerative
colitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,
diversion colitis, Behcet's
syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)),
lupus, multiple
sclerosis, morphea, myeasthenia gravis, myocardial ischemia, nephrotic
syndrome, pemphigus
vulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primary biliary
cirrhosis,
neuroinflammation associated with brain disorders (e.g., Parkinson's disease,
Huntington's
disease, and Alzheimer's disease), prostatitis, chronic inflammation
associated with cranial
radiation injury, pelvic inflammatory disease, reperfusion injury, regional
enteritis, rheumatic
fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis,
spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation
rejection, tendonitis,
trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, bums,
physical injury),
vasculitis, vitiligo and Wegener's granulomatosis. In certain embodiments, the
inflammatory
disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory
bowel disease,
160
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial
cystitis and
prostatistis. In certain embodiments, the inflammatory condition is an acute
inflammatory
condition (e.g., for example, inflammation resulting from infection). In
certain embodiments, the
inflammatory condition is a chronic inflammatory condition (e.g., conditions
resulting from
asthma, arthritis and inflammatory bowel disease). The compounds may also be
useful in
treating inflammation associated with trauma and non-inflammatory myalgia. The
compounds
may also be useful in treating inflammation associated with cancer.
[00453] In certain embodiments, the FAAH-mediated condition is an immune
disorder.
Immune disorders, such as auto-immune disorders, include, but are not limited
to, arthritis
(including rheumatoid arthritis, spondyloarthopathies, gouty arthritis,
degenerative joint diseases
such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,
ankylosing spondylitis,
undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune
anaemias, multiple
sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder,
psoriatic, and juvenile
arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis,
bursitis, skin condition
(e.g., psoriasis, eczema, bums, dermatitis, pruritus (itch)), enuresis,
eosinophilic disease,
gastrointestinal disorder (e.g., selected from peptic ulcers, regional
enteritis, diverticulitis,
gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g.,
eosinophilic esophagitis,
eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis),
gastritis, diarrhea,
gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory
bowel disease
(IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis,
lymphocytic colitis,
ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate
colitis) and inflammatory
bowel syndrome (IBS)), and disorders ameliorated by a gastroprokinetic agent
(e.g., ileus,
postoperative ileus and ileus during sepsis; gastroesophageal reflux disease
(GORD, or its
synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic
gastroparesis; food
intolerances and food allergies and other functional bowel disorders, such as
non-ulcerative
dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-
chondritis)).
[00454] In certain embodiments, the inflammatory disorder and/or the immune
disorder is a
gastrointestinal disorder. In some embodiments, the gastrointestinal disorder
is selected from
gastrointestinal disorder (e.g., selected from peptic ulcers, regional
enteritis, diverticulitis,
gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g.,
eosinophilic esophagitis,
eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis),
gastritis, diarrhea,
161
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory
bowel disease
(IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis,
lymphocytic colitis,
ischaemic colitis, diversion colitis, Behcet's syndrome, indeterminate
colitis) and inflammatory
bowel syndrome (IBS)). In certain embodiments, the gastrointestinal disorder
is inflammatory
bowel disease (IBD).
[00455] In certain embodiments, the inflammatory condition and/or immune
disorder is a skin
condition. In some embodiments, the skin condition is pruritus (itch),
psoriasis, eczema, bums
or dermatitis. In certain embodiments, the skin condition is psoriasis. In
certain embodiments,
the skin condition is pruritis.
[00456] In certain embodiments, the FAAH-mediated condition is a disorder of
the central
nervous system (CNS) ("CNS disorder"). Exemplary CNS disorders include, but
are not limited
to, neurotoxicity and/or neurotrauma, stroke, multiple sclerosis, spinal cord
injury, epilepsy, a
mental disorder, a sleep condition, a movement disorder, nausea and/or emesis,
amyotrophic
lateral sclerosis, Alzheimer's disease and drug addiction.
[00457] In certain embodiments, the CNS disorder is neurotoxicity and/or
neurotrauma, e.g.,
for example, as a result of acute neuronal injury (e.g., tramatic brain injury
(TBI), stroke,
epilepsy) or a chronic neurodegenerative disorder (e.g., multiple sclerosis,
Parkinson's disease,
Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease). In
certain
embodiments, the compound of the present invention provides a neuroprotective
effect, e.g.,
against an acute neuronal injury or a chronic neurodegenerative disorder.
[00458] In certain embodiments, the CNS disorder is stroke (e.g., ischemic
stroke).
[00459] In certain embodiments, the CNS disorder is multiple sclerosis.
[00460] In certain embodiments, the CNS disorder is spinal cord injury.
[00461] In certain embodiments, the CNS disorder is epilepsy.
[00462] In certain embodiments, the CNS disorder is a mental disorder, e.g.,
for example,
depression, anxiety or anxiety-related conditions, a learning disability or
schizophrenia.
[00463] In certain embodiments, the CNS disorder is depression. "Depression,"
as used
herein, includes, but is not limited to, depressive disorders or conditions,
such as, for example,
major depressive disorders (e.g., unipolar depression), dysthymic disorders
(e.g., chronic, mild
depression), bipolar disorders (e.g., manic-depression), seasonal affective
disorder, and/or
depression associated with drug addiction (e.g., withdrawal). The depression
can be clinical or
162
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
subclinical depression. The depression can be associated with or prementrual
syndrome and/or
premenstrual dysphoric disorder.
[00464] In certain embodiments, the CNS disorder is anxiety. "Anxiety," as
used herein,
includes, but is not limited to anxiety and anxiety-related conditions, such
as, for example,
clinical anxiety, panic disorder, agoraphobia, generalized anxiety disorder,
specific phobia,
social phobia, obsessive-compulsive disorder, acute stress disorder, post-
traumatic stress
disorder, adjustment disorders with anxious features, anxiety disorder
associated with
depression, anxiety disorder due to general medical conditions, and substance-
induced anxiety
disorders, anxiety associated with drug addiction (e.g., withdrawal,
dependence, reinstatement)
and anxiety associated with nausea and/or emesis. This treatment may also be
to induce or
promote sleep in a subject (e.g., for example, a subject with anxiety).
[00465] In certain embodiments, the CNS disorder is a learning disorder (e.g.,
attention deficit
disorder (ADD)).
[00466] In certain embodiments, the CNS disorder is Schizophrenia.
[00467] In certain embodiments, the CNS disorder is a sleep condition. "Sleep
conditions"
include, but are not limited to, insomia, narcolepsy, sleep apnea, restless
legs syndrome (RLS),
delayed sleep phase syndrome (DSPS), periodic limb movement disorder (PLMD),
hypopnea
syndrome, rapid eye movement behavior disorder (RBD), shift work sleep
condition (SWSD),
and sleep problems (e.g., parasomnias) such as nightmares, night terrors,
sleep talking, head
banging, snoring, and clenched jaw and/or grinding of teeth (bruxism).
[00468] In certain embodiments, the CNS disorder is a movement disorder, e.g.,
basal ganglia
disorders, such as, for example, Parkinson's disease, levodopa-induced
dyskinesia, Huntington's
disease, Gilles de la Tourette's syndrome, tardive diskinesia and dystonia.
[00469] In certain embodiments, the CNS disorder is Alzheimer's disease.
[00470] In certain embodiments, the CNS disorder is amyotrophic lateral
sclerosis (ALS).
[00471] In certain embodiments, the CNS disorder is nausea and/or emesis.
[00472] In certain embodiments, the CNS disorder is drug addiction (e.g., for
instance,
addiction to opiates, nicotine, cocaine, psychostimulants or alcohol).
[00473] In still yet other embodiments, the FAAH-mediated condition is a
cardiac disorder,
e.g., for example, selected from hypertension, circulatory shock, myocardial
reperfusion injury
and atherosclerosis.
163
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00474] In certain embodiments, the FAAH-mediated condition is a metabolic
disorder (e.g.,
a wasting condition, an obesity-related condition or complication thereof).
[00475] In certain embodiments, the metabolic disorder is a wasting condition.
A "wasting
condition," as used herein, includes but is not limited to, anorexia and
cachexias of various
natures (e.g., weight loss associated with cancer, weight loss associated with
other general
medical conditions, weight loss associated with failure to thrive, and the
like).
[00476] In certain embodiments, the metabolic disorder is an obesity-related
condition or a
complication thereof. An "obesity-related condition" as used herein, includes,
but is not limited
to, obesity, undesired weight gain (e.g., from medication-induced weight gain,
from cessation of
smoking) and an over-eating disorder (e.g., binge eating, bulimia, compulsive
eating, or a lack of
appetite control each of which can optionally lead to undesired weight gain or
obesity).
"Obesity" and "obese" as used herein, refers to class I obesity, class II
obesity, class III obesity
and pre-obesity (e.g., being "over-weight") as defined by the World Health
Organization.
[00477] Reduction of storage fat is expected to provide various primary and/or
secondary
benefits in a subject (e.g., in a subject diagnosed with a complication
associated with obesity)
such as, for example, an increased insulin responsiveness (e.g., in a subject
diagnosed with Type
II diabetes mellitus); a reduction in elevated blood pressure; a reduction in
elevated cholesterol
levels; and/or a reduction (or a reduced risk or progression) of ischemic
heart disease, arterial
vascular disease, angina, myocardial infarction, stroke, migraines, congestive
heart failure, deep
vein thrombosis, pulmonary embolism, gall stones, gastroesophagael reflux
disease, obstructive
sleep apnea, obesity hypoventilation syndrome, asthma, gout, poor mobility,
back pain, erectile
dysfunction, urinary incontinence, liver injury (e.g., fatty liver disease,
liver cirrhosis, alcoholic
cirrhosis, endotoxin mediated liver injury) or chronic renal failure. Thus,
the method of this
invention is applicable to obese subjects, diabetic subjects, and alcoholic
subjects.
[00478] In some embodiments, treatment of an obesity-related condition or
complication
thereof involves reduction of body weight in the subject. In some embodiments,
treatment of an
obesity-related condition or complication thereof involves appetite control in
the subject.
[00479] In other embodiments, the FAAH-mediated condition is glaucoma.
164
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
IV. Administration
[0001] Provided compounds can be administered using any amount and any route
of
administration effective for treatment. The exact amount required will vary
from subject to
subject, depending on the species, age, and general condition of the subject,
the severity of the
infection, the particular composition, its mode of administration, its mode of
activity, and the
like.
[0002] Compounds provided herein are typically formulated in dosage unit form
for ease of
administration and uniformity of dosage. It will be understood, however, that
the total daily
usage of the compositions of the present invention will be decided by the
attending physician
within the scope of sound medical judgment. The specific therapeutically
effective dose level
for any particular subject or organism will depend upon a variety of factors
including the disease,
disorder, or condition being treated and the severity of the disorder; the
activity of the specific
active ingredient employed; the specific composition employed; the age, body
weight, general
health, sex and diet of the subject; the time of administration, route of
administration, and rate of
excretion of the specific active ingredient employed; the duration of the
treatment; drugs used in
combination or coincidental with the specific active ingredient employed; and
like factors well
known in the medical arts.
[0003] The compounds and compositions provided herein can be administered by
any route,
including oral, intravenous, intramuscular, intra-arterial, intramedullary,
intrathecal,
subcutaneous, intraventricular, transdermal, interdermal, rectal,
intravaginal, intraperitoneal,
topical (as by powders, ointments, creams, and/or drops), mucosal, nasal,
bucal, enteral,
sublingual; by intratracheal instillation, bronchial instillation, and/or
inhalation; and/or as an oral
spray, nasal spray, and/or aerosol. Specifically contemplated routes are
systemic intravenous
injection, regional administration via blood and/or lymph supply, and/or
direct administration to
an affected site. In general the most appropriate route of administration will
depend upon a
variety of factors including the nature of the agent (e.g., its stability in
the environment of the
gastrointestinal tract), the condition of the subject (e.g., whether the
subject is able to tolerate
oral administration), etc.
[0004] The exact amount of a compound required to achieve a therapeutically
effective
amount will vary from subject to subject, depending, for example, on species,
age, and general
165
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
condition of a subject, severity of the side effects or disorder, identity of
the particular
compound(s), mode of administration, and the like. The desired dosage can be
delivered three
times a day, two times a day, once a day, every other day, every third day,
every week, every two
weeks, every three weeks, or every four weeks. In certain embodiments, the
desired dosage can
be delivered using multiple administrations (e.g., two, three, four, five,
six, seven, eight, nine,
ten, eleven, twelve, thirteen, fourteen, or more administrations).
[0005] In certain embodiments, a therapeutically effective amount of a
compound for
administration one or more times a day to a 70 kg adult human may comprise
about 0.0001 mg
to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about
1000 mg, about
0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to
about 1000 mg,
about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about
1000 mg, or
about 100 mg to about 1000 mg, of an inventive compound per unit dosage form.
It will be
appreciated that dose ranges as described herein provide guidance for the
administration of
provided pharmaceutical compositions to an adult. The amount to be
administered to, for
example, a child or an adolescent can be determined by a medical practitioner
or person skilled
in the art and can be lower or the same as that administered to an adult.
[0006] It will be also appreciated that a compound or composition, as
described herein, can
be administered in combination with one or more additional therapeutically
active agents. The
compound or composition can be administered concurrently with, prior to, or
subsequent to, one
or more additional therapeutically active agents. In general, each agent will
be administered at a
dose and/or on a time schedule determined for that agent. In will further be
appreciated that the
additional therapeutically active agent utilized in this combination can be
administered together
in a single composition or administered separately in different compositions.
The particular
combination to employ in a regimen will take into account compatibility of the
inventive
compound with the additional therapeutically active agent and/or the desired
therapeutic effect to
be achieved. In general, it is expected that additional therapeutically active
agents utilized in
combination be utilized at levels that do not exceed the levels at which they
are utilized
individually. In some embodiments, the levels utilized in combination will be
lower than those
utilized individually.
[0007] The compounds or compositions can be administered in combination with
agents that
improve their bioavailability, reduce and/or modify their metabolism, inhibit
their excretion,
166
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
and/or modify their distribution within the body. It will also be appreciated
that therapy
employed may achieve a desired effect for the same disorder (for example, a
compound can be
administered in combination with an anti-inflammatory, anti-anxiety and/or
anti-depressive
agent, etc.), and/or it may achieve different effects (e.g., control of
adverse side-effects).
[0008] Exemplary active agents include, but are not limited to, anti-cancer
agents,
antibiotics, anti-viral agents, anesthetics, anti-coagulants, inhibitors of an
enzyme, steroidal
agents, steroidal or non-steroidal anti-inflammatory agents, antihistamine,
immunosuppressant
agents, anti-neoplastic agents, antigens, vaccines, antibodies, decongestant,s
sedatives, opioids,
pain-relieving agents, analgesics, anti-pyretics, hormones, prostaglandins,
progestational agents,
anti-glaucoma agents, ophthalmic agents, anti-cholinergics, anti-depressants,
anti-psychotics,
hypnotics, tranquilizers, anti-convulsants/anti-epileptics (e.g., Neurontin,
Lyrica, valproates
(e.g., Depacon), and other neurostabilizing agents), muscle relaxants, anti-
spasmodics, muscle
contractants, channel blockers, miotic agents, anti-secretory agents, anti-
thrombotic agents,
anticoagulants, anti-cholinergics, (3-adrenergic blocking agents, diuretics,
cardiovascular active
agents, vasoactive agents, vasodilating agents, anti-hypertensive agents,
angiogenic agents,
modulators of cell-extracellular matrix interactions (e.g. cell growth
inhibitors and anti-adhesion
molecules), or inhibitors/intercalators of DNA, RNA, protein-protein
interactions, protein-
receptor interactions, etc. Active agents include small organic molecules such
as drug
compounds (e.g., compounds approved by the Food and Drugs Administration as
provided in the
Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates,
monosaccharides,
oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins,
synthetic
polypeptides or proteins, small molecules linked to proteins, glycoproteins,
steroids, nucleic
acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense
oligonucleotides,
lipids, hormones, vitamins and cells.
[0009] In certain embodiments, the additional therapeutically active agent is
a pain-relieving
agent. Exemplary pain relieving agents include, but are not limited to,
analgesics such as non-
narcotic analgesics [e.g., salicylates such as aspirin, ibuprofen (MOTRIN ,
ADVIL ),
ketoprofen (ORUDIS ), naproxen (NAPROSYN ), acetaminophen, indomethacin] or
narcotic
analgesics [e.g., opioid analgesics such as tramadol, fentenyl, sufentanil,
morphine,
hydromorphone, codeine, oxycodone, and buprenorphine]; non-steroidal anti-
inflammatory
agents (NSAIDs) [e.g., aspirin, acetaminophen, COX-2 inhibitors]; steroids or
anti-rheumatic
167
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
agents; migraine preparations such as beta adrenergic blocking agents, ergot
derivatives; tricyclic
antidepressants (e.g., amitryptyline, desipramine, imipramine); anti-
epileptics (e.g., clonaxepam,
valproic acid, phenobarbital, phenytoin, tiagaine, gabapentin, carbamazepine,
topiramate, sodium
valproate); U2 agonists; selective serotonin reuptake inhibitors (SSRIs),
selective
norepinepherine uptake inhibitors; benzodiazepines; mexiletine (MEXITIL);
flecainide
(TAMBOCOR); NMDA receptor antagonists [e.g., ketamine, detromethorphan,
methadone]; and
topical agents [e.g., capsaicin (Zostrix), EMLA cream, lidocaine, prilocaine].
[0010] In other embodiments, the additional therapeutically active agent is an
anti-
inflammatory agent. Exemplary anti-inflammatory agents include, but are not
limited to, aspirin;
ibuprofen; ketoprofen; naproxen; etodolac (LODINE ); COX-2 inhibitors such as
celecoxib
(CELEBREX ), rofecoxib (VIOXX ), valdecoxib (BEXTRA ), parecoxib, etoricoxib
(MK663),
deracoxib, 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]
pyridazine, 4-(2-
oxo-3-phenyl-2,3-dihydrooxazol-4-yl)benzenesulfonamide, darbufelone,
flosulide, 4-(4-
cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzenesulfonamide), meloxicam,
nimesulide, 1-
Methylsulfonyl-4-(1,l-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-
yl)benzene, 4-(1,5-
Dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)-(2)-benzothiopyrano(4,3-
c)pyrazol-1-
yl)benzenesulfonamide, 4,4-dimethyl-2-phenyl-3-(4-methylsulfonyl)phenyl)cyclo-
butenone, 4-
Amino-N-(4-(2-fluoro-5-trifluoromethyl)-thiazol-2-yl)-benzene sulfonamide, 1-
(7-tert-butyl-2,3-
dihydro-3,3-dimethyl-5-benzo-furanyl)-4-cyclopropyl butan-l-one, or their
physiologically
acceptable salts, esters or solvates; sulindac (CLINORIL ); diclofenac
(VOLTAREN );
piroxicam (FELDENE ); diflunisal (DOLOBID ), nabumetone (RELAFEN ), oxaprozin
(DAYPRO ), indomethacin (INDOCIN ); or steroids such as PEDIAPED prednisolone
sodium
phosphate oral solution, SOLU-MEDROL methylprednisolone sodium succinate for
injection,
PRELONE brand prednisolone syrup.
[0011] Further examples of anti-inflammatory agents include naproxen, which is
commercially available in the form of EC-NAPROSYN delayed release tablets,
NAPROSYN ,
ANAPROX and ANAPROX DS tablets and NAPROSYN suspension from Roche Labs,
CELEBREX brand of celecoxib tablets, VIOXX brand of rofecoxib, CELESTONE
brand of
betamethasone, CUPRAMINE brand penicillamine capsules, DEPEN brand
titratable
penicillamine tablets, DEPO-MEDROL brand of methylprednisolone acetate
injectable
suspension, ARAVATM leflunomide tablets, AZULFIDIINE EN-tabs brand of
sulfasalazine
168
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
delayed release tablets, FELDENE brand piroxicam capsules, CATAFLAM
diclofenac
potassium tablets, VOLTAREN diclofenac sodium delayed release tablets,
VOLTAREN -XR
diclofenac sodium extended release tablets, or ENBREL etanerecept products.
V. Methods of Determining Biological Activity
[0012] Methods of determining the activity of the compounds provided herein
for various
therapeutic uses are known in the art. These include, but are not limited to,
high throughput
screening to identify compounds that bind to and/or modulate the activity of
isolated FAAH, as
well as in vitro and in vivo models of therapies.
[0013] Assays useful for screening the compounds provided herein may detect
the binding of
the inhibitor to FAAH or the release of a reaction product (e.g., fatty acid
amide or
ethanolamine) produced by the hydrolysis of a substrate such as
oleoylethanolamide or
ananadamide. The substrate can be labeled to facilitate detection of the
released reaction
products. U.S. Pat. No. 5,559,410 discloses high throughput screening methods
for proteins, and
U.S. Pat. Nos. 5,576,220 and 5,541,061 disclose high throughput methods of
screening for
ligand/antibody binding.
[0014] Methods for screening FAAH inhibitors for an antinociceptive effect are
known in the
art. For example, compounds can tested in the mouse hot-plate test and the
mouse formalin test,
and the nociceptive reactions to thermal or chemical tissue damage measured
(for example, see
U.S. Pat. No. 6,326,156 for a description of methods of screening for
antinociceptive activity;
see also Cravatt et at. Proc. Natl. Acad. Sci. U.S.A. (2001) 98:9371-9376).
[0015] Two pharmacologically validated animal models of anxiety are the
elevated zero
maze test, and the isolation-induced ultrasonic emission test. The zero maze
consists of an
elevated annular platform with two open and two closed quadrants and is based
on the conflict
between an animal's instinct to explore its environment and its fear of open
spaces (see, for
example, Bickerdike, M. J. et al., Eur. J. Pharmacol., (994) 271, 403-411;
Shepherd, J. K. et al.,
Psychopharmacology, (1994) 116, 56-64). Clinically used anxiolytic drugs, such
as the
benzodiazepines, increase the proportion of time spent in, and the number of
entries made into,
the open compartments.
[0016] A second test for an anti-anxiety compound is the ultrasonic
vocalization emission
model, which measures the number of stress-induced vocalizations emitted by
rat pups removed
169
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
from their nest (see, for example, Insel, T. R. et al., Pharmacol. Biochem.
Behav., 24, 1263-1267
(1986); Miczek, K. A. et al., Psychopharmacology, 121, 38-56 (1995); Winslow,
J. T. et al.,
Biol. Psychiatry, 15, 745-757 (1991).
[0017] The effect of the compounds provided herein in the treatment of
depression can be
tested in the model of chronic mild stress induced anhedonia in rats. This
model is based on the
observation that chronic mild stress causes a gradual decrease in sensitivity
to rewards, for
example consumption of sucrose, and that this decrease is dose-dependently
reversed by chronic
treatment with antidepressants. See, e.g., Willner, Paul, Psychopharmacology,
1997, 134, 319-
329.
[0018] Another test for antidepressant activity is the forced swimming test
(Nature 266, 730-
732, 1977). In this test, animals are administered an agent 30 or 60 minutes
before being placed
in container of water, and the time during which they remain immobile is
recorded. A decrease
in the immobility time of the mice is indicative of antidepressant activity.
[0019] A similar test for antidepressant activity is the mouse caudal
suspension test
(Psychopharmacology, 85, 367-370, 1985). In this test, animals are
administered an agent 30 or
60 minutes before being suspended by the tail, and their immobility time is
recorded. A decrease
in the immobility time of the mice is indicative of antidepressant activity.
[0020] Animal models are available for assessing anticonvulsant activity of
test compounds
(see, e.g., U.S. Pat. Nos. 6,309,406 and 6,326,156).
[0021] Inhibition of FAAH has been reported to induce sleep in test animals
(see, e.g., U.S.
Pat. No. 6,096,784). Methods for studying sleep inducing compounds are known
in the art (see,
e.g., U.S. Pat. Nos. 6,096,784 and 6,271,015). Compounds can be administered
to a test animal
(e.g., rat or mouse) or a human and the subsequent time (e.g., onset,
duration) spent sleeping
(e.g., eyes closed, motor quiescence) can be monitored. See also WO 98/24396.
[0022] Methods for screening FAAH inhibitors which induce catalepsy are also
well known
in the art (see, e.g., Quistand et al. in Toxicology and Applied Pharmacology
173: 48-55 (2001);
Cravatt et al. Proc. Natl. Acad. Sci. U.S.A. 98:9371-9376 (2001)).
[0023] Methods of assessing appetitive behavior are known in the art (see,
e.g., U.S. Pat. No.
6,344,474). One method of assessing the effect on appetite behavior is to
administer a FAAH
inhibitor to a rat and assess its effect on the intake of a sucrose solution
(see, e.g., W. C. Lynch et
al., Physiol. Behav., 1993, 54, 877-880).
170
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0024] Two pharmacologically validated animal models of neuropathic pain are
the rat spinal
nerve ligation model (Chung model) and a rat model of chemotherapy-induced
neuropathic pain.
After establishing neuropathy in these models, as a measure of mechanical
allodynia, paw
withdrawal thresholds were measured by stimulation with von Frey filaments
(see, for example,
Kim SH and Chung JM, Pain (1992) 50, 355-63; Nozaki-Taguchi N, et al., Pain
(2001) 93, 69-
76). Clinically used neuropathic pain drugs, such as the Gabapentin
(Neurontin), increase the
paw withdrawal threshold from stimulation with von Frey filaments.
[0025] Two pharmacologically validated animal models of inflammatory and
mechanical pain
are a joint compression model in rats treated with adjuvant or agents that
produce joint
degeneration. Treatment with clinically used anti-inflammatory agents such as
naproxen
increases the threshold of behavioral response to joint compression (see, for
example, Wilson
AW, et al., Eur. J. Pain (2006) 10, 537-49; Ivanavicius SA, et al., Pain
(2007) 128, 272-282).
[0026] A pharmacologically validated animal models of cancer pain is mouse
model where
implantation in the calcaneus bone of fibrosarcoma cells produces paw
hyperalgesia. Treatment
with clinically used analgesics agents such as morphine increases the
threshold of behavioral
response to mechanical algesia (see, for example, Khasabova, et al., J.
Neurscience (2008) 28,
11141-52).
EXEMPLIFICATION
[0027] The invention now being generally described, it will be more readily
understood by
reference to the following examples, which are included merely for purposes of
illustration of
certain aspects and embodiments of the present invention, and are not intended
to limit the
invention.
GENERAL SYNTHETIC METHODS
Method 1
HORN
Ra Rb II Ra Rb Br
Br Br
O
Rd R KHCO3 Rd R
[0028] General conditions for the preparation of 3-bromo-isoxazolines: Alkene
(1.2 equiv)
and potassium hydrogen carbonate (2.5 equiv) are suspended in ethyl acetate
(0.40 M with
171
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
respect to alkene). N,N-Dibromoformaldoxime (1.0 equiv) is added and the
reaction was
allowed to stir at 23 C for 14-28h. Upon completion as judged by thin layer
chromatography
analysis, the reaction was split between water and tent-butyl methyl ether,
and the organic layer
was washed with water and brine, dried over sodium sulfate, and concentrated
in vacuo. The
concentrated reaction mixture was purified by flash silica gel chromatography
(ethyl
acetate/hexanes) to provide the desired 3-bromo-isoxazoline.
Method 2
Ra Rb
Rb Br
0 HORN R R Ra
d c
OH + HONH2HCI II~ N
H
)~'~ ~ 11
HO OH CO2H NBS Rd = 0
R
[0029] General conditions for the preparation of 3-bromo-isoxazolines: A flask
is charged
with glyoxylic acid monohydrate (1.0 equiv) and hydroxylamine hydrochloride
(1.1 equiv). The
mixture was dissolved in water (2.0 M with respect to glyoxylic acid
monohydrate) and stirred at
23 C for 24h. The mixture was diluted with water and extracted with ethyl
acetate. The organic
layer was dried over sodium sulfate and concentrated to provide the desired
crude oxime which
was used directly in subsequent cycloaddition. The resulting oxime (1.1 equiv)
from the first
step is suspended in a 3:1 mixture of dimethoxyethane:water (v/v) (0.15 M with
respect to
oxime) and cooled to 0 C. N-Bromosuccinamide (NBS) (2.0 equiv) was added and
the reaction
was allowed to stir at 23 C for 20 min. The resulting mixture is then added
to a solution of
alkene (1.0 equiv) and potassium bicarbonate (2.5 equiv) in dimethoxyethane
(1.50 M with
respect to alkene) and the reaction is allowed to stir for 20 h at 23 C. Upon
completion as
judged by thin layer chromatography analysis, the reaction was split between
water and tert-
butyl methyl ether, and the organic layer was washed with brine, dried over
sodium sulfate, and
concentrated in vacuo. The concentrated reaction mixture was purified by flash
silica gel
chromatography (ethyl acetate / hexanes) to provide the desired 3-bromo-
isoxazoline.
Method 3
172
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
a Rb Br Rb ORe
R HORe Ra =
\N N
Rd = p NaOH Rd _ O
R R
[0030] General conditions for the preparation of 3-aryloxy-isoxazolines or 3-
heteroaryloxy-
isoxazolines: A microwave reaction vial is charged with a given 3-bromo-
isoxazoline (1.0
equiv) and an alcohol (e.g., a phenol or a hydroxypyridine) (3.0 equiv) and
dissolved in N-
methylpyrrolidine (0.50 M with respect to isoxazoline). Crushed sodium
hydroxide (2.0 equiv)
is added and the mixture was sealed and heated in a microwave reaction at 150
C for 30 min.
The reaction was then split between water and tent-butyl methyl ether, and the
organic layer was
washed with brine, dried over sodium sulfate, and concentrated in vacuo. The
concentrated
reaction mixture was purified by flash silica gel chromatography (ethyl
acetate / hexanes) to
provide the desired isoxazoline.
Method 4
Rb Br Rb ORe
Ra; HORe Ra =
N N
Rd=-O'
= O NaH Rd - O
Rc Rc
[0031] General conditions for the preparation of 3-aryloxy-isoxazolines or 3-
heteroaryloxy-
isoxazolines: A flask is charged with a given 3-bromo-isoxazoline (1.0 equiv)
and the alcohol
(e.g., a phenol or a hydroxypyridine) (2.0 equiv) and dissolved in N,N-
dimethylforamide (0.4 M
with respect to isoxazoline). Sodium hydride (2.0 equiv) is added and the
reaction is allowed to
stir for 10 min until all of the gas evolution ceases. The reaction is then
heated to 150 C for 1-
5h. After the reaction is determine to be complete by thin layer
chromatography analysis, the
reaction was then split between water and ethyl acetate, and the organic layer
was washed with
IN NaOH and brine, and then dried over sodium sulfate, and concentrated in
vacuo. The
concentrated reaction mixture was purified by flash silica gel chromatography
(ethyl
acetate/hexanes) to provide the desired isoxazoline.
Method 5
173
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
a Rb Br Rb ORe
R HORe Ra =
\N N
Rd = O Cs2CO3 Rd O
R R
[0032] General conditions for the preparation of 3-aryloxy-isoxazolines: A
flask is charged
with a given 3-bromo-isoxazoline (1.0 equiv) and the alcohol (e.g., a phenol
or a
hydroxypyridine) (2.0 equiv) and dissolved in N,N-dimethylforamide or N-
methylpyrrolidinone
(0.15 M with respect to isoxazole). Cesium carbonate (1.2 to 3 equiv) is added
and the reaction
is heated to 120 C in an oil bath for lh. The reaction was then split between
water and tert-
butyl methyl ether, and the organic layer was washed with brine, dried over
sodium sulfate, and
concentrated in vacuo. The concentrated reaction mixture was purified by flash
silica gel
chromatography (methanol/methylene chloride) to provide the desired
isoxazoline.
Method 6
NaHMDS
O P(Ph)3MeBr Ra Rb
Rd R Rd R
RA Rb
[0033] General conditions for the preparation of alkenes: under a nitrogen
atmosphere, 0.25
M methyltriphenylphosphonium bromide (1.1 equiv) dissolved in tetrahydrofuran
was cooled to
0 C after which the mixture was treated drop wise with sodium
hexamethyldisilazane
(NaHMDS) in tetrahydrofuran (1.0 M, 1.2 equiv). After stirring an additional
30 min at 0 C, a
given aldehyde or ketone is added and the reaction is allowed to warm slowly
to 23 C overnight.
The mixture was quenched saturated ammonium chloride and concentrated to
remove the
tetrahydrofuran. The mixture was then diluted with water and extracted with
ethyl acetate. The
organic layer was washed with brine, dried over sodium sulfate and
concentrated in vacuo. The
concentrated reaction mixture was purified by flash silica gel chromatography
(ethyl acetate /
hexanes) to provide the desired alkene.
Method 7
nBuLi
O P(Ph)3MeBr Ra Rb
Rd R O Rd R
Ra Rb
174
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0034] General conditions for the preparation of alkenes: under a nitrogen
atmosphere, 0.15
M methyltriphenylphosphonium bromide (1.5 equiv) dissolved in tetrahydrofuran
was cooled to
-78 C after which the mixture was treated drop wise with n-butyl lithium in
hexanes (2.5 M, 1.5
equiv). After stirring an additional lh at -78 C, a given aldehyde or ketone
is added and the
reaction is allowed to warm slowly to 23 C overnight. The mixture was
quenched saturated
ammonium chloride and concentrated to remove the tetrahydrofuran. The mixture
was then
diluted with water and extracted with ethyl acetate. The organic layer was
washed with brine,
dried over sodium sulfate and concentrated in vacuo. The concentrated reaction
mixture was
purified by flash silica gel chromatography (ethyl acetate / hexanes) to
provide the desired
alkene.
Method 8
KOtBu
O P(Ph)3MeBr Ra Rb
Rd R O Rd R
Ra Rb
[0035] General conditions for the preparation of alkenes: under a nitrogen
atmosphere, 0.12
M methyltriphenylphosphonium bromide (2.5 equiv) was dissolved in
tetrahydrofuran after
which potassium tert-butoxide (4.0 equiv) was added in six portions. After
stirring an additional
lh at 23 C, a given aldehyde or ketone is added and the reaction was heated
to 55 C for 2 h.
The mixture was quenched saturated ammonium chloride and concentrated to
remove the
tetrahydrofuran. The mixture was then acidified to pH 5-6 with IN HC1 and
extracted with
methylene chloride. The organic layer was washed with brine and then dried
over sodium sulfate
and concentrated in vacuo. The concentrated reaction mixture was purified by
flash silica gel
chromatography (ethyl acetate / hexanes) to provide the desired alkene.
Method 9
CH2CHBF3K
Br 6"~
R15R15 [0036] General conditions for the preparation of styrenes: a dry flask
under argon
atmosphere was charged with aryl bromide (1.0 equiv), potassium
vinyltrifluoroborate (1.2
175
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
equiv), 1,1"-bis(diphenylphosphino)-ferrocenedichloropalladium(II) methylene
chloride adduct
(0.02 equiv) and triethylamine (1.0 equiv) and the mixture was suspended in
isopropanol (0.25
M with respect to aryl bromide) and heated at 80 C for 2-24 h. The mixture
was then diluted
with water and extracted with diethyl ether. The organic layer was washed with
brine and then
dried over magnesium sulfate and concentrated in vacuo. The concentrated
reaction mixture was
purified by flash silica gel chromatography (ethyl acetate / hexanes) to
provide the desired
styrene.
Method 10
Br
Sn(nBu)3CHCH2
z
R R15
[0037] General conditions for the preparation of styrenes: a dry flask under a
nitrogen
atmosphere was charged with aryl bromide (1.0 equiv), tributylvinyltin (1.1
equiv) and dissolved
in toluene (0.3 M with respect to bromide). The resulting mixture was further
purged with
nitrogen for 10 min after which tetrakis(triphenyphosphine)palladium (0.1
equiv) was added and
the reaction was refluxed for 1.5h. After the reaction was determined to be
complete by TLC
analysis, it was allowed to cool and loaded directly onto a silica gel column
where it was purified
by flash silica gel chromatography (ethyl acetate / hexanes) to provide the
desired styrene.
Method 11
Rh Rh
ROB- HO-ci)
RO N N
Rh Rh
ROB' HO-C'
RO N\> N
[0038] General conditions for the hydrolysis of pyridyl and pyrimidinyl
boronic acids to their
corresponding phenols: A flask is charged with a given boronic acid or ester
thereof (1.0 equiv)
and dissolved in tetrahydrofuran (1.1 M, 10 volumes). Sodium perborate (1.0
equiv) is dissolved
in water (1.1 M with respect to boronic acid, 10 volumes) and sonicated for 10
min. The
176
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
perborate suspension is then added to the THE solution using tetrahydrofuran
(1.6 volumes) to
rinse the remaining solid perborate into the reaction mixture. The reaction is
allowed to stir at
room temperature (reaction is mildly exothermic) after which ammonium chloride
is added in
three portions (10 equiv) and the reaction cooled back down to room
temperature. After 40 min,
the reaction was concentrated under vacuum until all of the tetrahydrofuran
was removed. The
resulting solid was collected by vacuum filtration, washed with excess waster
and dried in a
vacuum oven for 40 C for 3d to provide the desired phenol in 80% yield.
Chiral HPLC Method
[0039] Enantiomeric or diastereomeric mixtures of compounds can be separated
using
known methods, including chiral high pressure liquid chromatography (HPLC) and
chiral
supercritical fluid chromatography (SFC). Exemplary chiral columns found
useful in separating
such mixtures of compounds of the present invention include, but are not
limited to, ChiralPak
AD-H, ChiralPak OD-H, ChiralPak AY, RegisPackTM, and S,S WhelkO -l and LUXTM
Cellulose2 columns. One or more of these columns were used to separate
enantiomeric mixtures
of compounds of the present invention in order to obtain substantially
enantiomerically pure
compounds.
177
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
SYNTHESIS OF EXEMPLARY COMPOUNDS OF FORMULA I
[0040] Syntheses of exemplary compounds are set forth below. Compounds were
assayed as
inhibitors of human FAAH using the method described in detail in Example 351.
Activity
designated as "A" refers to compounds having a K; of less than or equal to 100
nM, "B" refers to
compounds having a K; of between 100 nM and 1 microM, and "C" refers to
compounds having
a K; of greater than or equal to 1 microM.
Example 1
'TI - N,Q -
I I
Br Br
I-1 a I-1 b
(I-1)
[0041] 3-bromo-4,5-dihydroisoxazole I-1a and I-lb were prepared in 1 step from
styrene
using Method 2. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 225.0 m/z.
Activity: B
Example 2
N,O N,O
I
Br Br
I-2a I-2b
(1-2)
[0042] 3-bromo-4,5-dihydroisoxazole I-2a and I-2b were prepared in 1 step from
4-
fluorostyrene using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein.
Activity: B
Example 3
O - CI N-O; - CI
Br N, Br""
I-3a I-3b
(1-3)
178
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0043] 3-bromo-4,5-dihydroisoxazole I-3a and I-3b were prepared in 1 step from
4-
chlorostyrene using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 259.0 m/z.
Activity: A
Example 4
CI CI
y[O - N,O, -
/ I
Br Br
I-4a I-4b
(1-4)
[0044] 3-bromo-4,5-dihydroisoxazole I-4a and I-4b were prepared in 1 step from
3-
chlorostyrene using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 258.9 m/z.
Activity: B
Example 5
CI CI
Br Br
I-5a I-5b
(1-5)
[0045] 3-bromo-4,5-dihydroisoxazole I-5a and I-5b were prepared in 1 step from
2-
chlorostyrene using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 258.9 m/z.
Activity: B
Example 6
O O
3c~&We N' ~"~ ~ OMe
Br Br
I-6a I-6b
(1-6)
179
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0046] 3-bromo-4,5-dihydroisoxazole I-6a and I-6b were prepared in 1 step from
4-
methoxystyrene using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
255.0 m/z. Activity: A
Example 7
We We
N-O - N-O, -
Br Br
I-7a I-7b
(1-7)
[0047] 3-bromo-4,5-dihydroisoxazole I-7a and I-7b were prepared in 1 step from
3-
methoxystyrene using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
255.0 m/z. Activity: B
Example 8
MeO MeO -0 0
I
~O ., I
Br Br
I-8a I-8b
(1-8)
[0048] 3-bromo-4,5-dihydroisoxazole I-8a and I-8b were prepared in 1 step from
2-
methoxystyrene using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
255.0 m/z. Activity: C
Example 9
O N-O,
N
Br Br
I-9a I-9b
180
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1-9)
[0049] 3-bromo-4,5-dihydroisoxazole I-9a and I-9b were prepared in 1 step from
4-
vinylbiphenyl using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 301.6 m/z.
Activity: A
Example 10
N-O - N'0,.
Br Br
I-1 Oa I-1 Ob
(1-10)
[0050] 3-bromo-4,5-dihydroisoxazole I-10a and I-10b were prepared in 1 step
from 4-
phenoxystyrene using Method 2. These compounds were separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 317.0 m/z.
Activity: A
Example 11
N'O - N'R -
Br O Br O
I-11 a I-11 b
(I-11)
[0051] 3-bromo-4,5-dihydroisoxazole I-Ila and I-llb were prepared in 2 steps
starting
with alkene formation from 3-phenoxybenzaldehyde using Method 8 followed by
cycloaddition
using Method 2. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-
317.0 m/z. Activity: A
Example 12
N,O N,O
I O O
Br Br
N N
1-1 2a I-12b
(1-12)
181
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0052] 3-bromo-4,5-dihydroisoxazole I-12a and I-12b were prepared in 2 steps
starting
with alkene formation from 4-(pyridin-3-yloxy)benzaldehyde using Method 8
followed by
cycloaddition using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 318.0 m/z.
Activity: A
Example 13
N-O N-O-
O O
Br ND-
1-1 -N Br N~N
3a I-13b
(1-13)
[0053] 3-bromo-4,5-dihydroisoxazole I-13a and I-13b were prepared in 2 steps
starting
with alkene formation from 4-(pyrimidin-2-yloxy)-benzaldehyde using Method 8
followed by
cycloaddition using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 319.0 m/z.
Activity: A
Example 14
O O NNBr Br
I-14a I-14b
(1-14)
[0054] 3-bromo-4,5-dihydroisoxazole I-14a and I-14b were prepared in 2 steps
starting
with alkene formation from 4-trifluoromethoxybenzaldehyde using Method 8
followed by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 309.6 m/z.
Activity: A
Example 15
Br -Me Br I lj /--Me
Me Me
I-15a I-15b
(1-15)
182
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0055] 3-bromo-4,5-dihydroisoxazole I-15a and I-15b were prepared in 2 steps
starting
with alkene formation from 4-isopropoxybenzaldehyde using Method 8 followed by
cycloaddition using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 238.0 m/z.
Activity: A
Example 16
J
Br O
\ - / J Br NI
O O
I-16a I-16b
(1-16)
[0056] 3-bromo-4,5-dihydroisoxazole I-16a and I-16b were prepared in 2 steps
starting
with alkene formation from piperonal using Method 7 followed by cycloaddition
using Method
2. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M-H]-= 269.0 m/z. Activity:
A
Example 17
N,O - N-O-.
O O
CI 6 CI
I-17a I-17b
(1-17)
[0057] 3-chloro-4,5-dihydroisoxazole I-17a and I-17b were prepared in using
the
analogous procedure as Example 10 except that N-chlorosuccinamide was used in
the place of
N-bromosuccinamide. These compounds can be separated using chiral HPLC methods
known
in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-=
273.1 m/z.
Activity: A
Example 18
NO N-O, -
I, - O I O
N N
Br Br
Me Me
I-18a I-18b
183
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1-18)
[0058] 3-bromo-4,5-dihydroisoxazole I-18a and I-18b were prepared in 2 steps
starting
with alkene formation from 3-(4-bromophenoxy)-6-methylpyridazine using Method
9 followed
by cycloaddition using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
333.0 m/z. Activity: B
Example 19
N-O NN N0, N'N
I I I I
Br O I \ Br O I \
I-19a I-19b
(1-19)
[0059] 3-bromo-4,5-dihydroisoxazole I-19a and I-19b were prepared in 2 steps
starting
with alkene formation from 2-(4-bromophenyl)-5-phenyl-1,3,4-oxadiazole using
Method 9
followed by cycloaddition using Method 2. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-
H]-= 369.0 m/z. Activity: A
Example 20
NO
Br - N'0,,.
I- ~ ~ O I ~ ~ O
Me Br Me
I-20a I-20b
(1-20)
[0060] 3-bromo-4,5-dihydroisoxazole I-20a and I-20b were prepared in 2 steps
starting
with alkene formation from 4-butoxybenzaldehyde using Method 8 followed by
cycloaddition
using Method 1. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 297.0 m/z.
Activity: A
184
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 21
N,O O N,O, O
Br O Br O
1-21 a 1) 1-21 b
(1-21)
[0061] 3-bromo-4,5-dihydroisoxazole I-21a and I-21b were prepared in 2 steps
starting
with the coupling between 4-vinylbenzoic acid and benzyl alcohol as follows: 4-
Vinylbenzoic
acid (1.0 equiv) is dissolved in N,N-dimethylforamide (0.20 M with respect to
acid). Benzyl
alcohol is added (2.0 equiv) followed by EDC (1.05 equiv) and a catalytic
amount of DMAP
(0.05 equiv). The reaction is allowed to stir at 23 C for 14h after which
point the the reaction
was split between water and tent-butyl methyl ether, and the organic layer was
washed with 0.5
M citric acid solution (2x) and saturated sodium bicarbonate solution (lx),
dried over magnesium
sulfate, and concentrated in vacuo. The concentrated reaction mixture was
purified by flash
silica gel chromatography (ethyl acetate/hexanes) to provide the desired
ester. This compound
was then converted to the desired 3-bromo-4,5-dihydroisoxazole using Method 1.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 359.8 m/z. Activity: A
Example 22
N,O O N,O, O
Br I \ / HN Br I \ / HN
1-22a 1-22b
(1-22)
[0062] 3-bromo-4,5-dihydroisoxazole I-22a and I-22b were prepared in using the
analogous procedure as Example 21 except that benzylamine was used in the
place of benzyl
alcohol. These compounds can be separated using chiral HPLC methods known in
the art. For
example, see chiral HPLC Method disclosed herein. [M-H]-= 358.9 m/z. Activity:
B
185
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 23
''b \ I O
I-23a I-23b
(1-23)
[0063] 3-phenoxy-4,5-dihydroisoxazole I-23a and I-23b were prepared in 1 step
from
compound 1-10 and phenol using Method 3. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-
H]-= 331.1 m/z. Activity: C
Example 24
F 0 O F p
O O
0 6 0
I-24a I-24b
(1-24)
[0064] 3-phenoxy-4,5-dihydroisoxazole I-24a and I-24b were prepared in 1 step
from
compound 1-10 and 4-fluorophenol using Method 4. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 350.3 m/z. Activity: C
Example 25
\ I YC~0 O \ I yc0 O
F O ~ ~ F O
I-25a I-25b
(1-25)
[0065] 3-phenoxy-4,5-dihydroisoxazole I-25a and I-25b were prepared in 1 step
from
compound 1-10 and 3-fluorophenol using Method 4. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 349.3 m/z. Activity: B
186
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 26
\ ~ N,O ~ ~ O \ ~ N'O' O
F3C O ~ ~ F3C O
I-26a I-26b
(1-26)
[0066] 3-phenoxy-4,5-dihydroisoxazole I-26a and I-26b were prepared in 1 step
from
compound 1-10 and 3-trifluoromethylphenol using Method 4. These compounds can
be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 400.3 m/z. Activity: C
Example 27
NC N,O - NC N,O,
\ I I O \ I I O
I-27a I-27b
(1-27)
[0067] 3-phenoxy-4,5-dihydroisoxazole I-27a and I-27b were prepared in 1 step
from
compound 1-10 and 4-cyanophenol using Method 3. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M-H]-= 356.1 m/z. Activity: A
Example 28
\ I N,O O 9i-O N,O O
CN CN
I-28a I-28b
(1-28)
[0068] 3-phenoxy-4,5-dihydroisoxazole I-28a and I-28b were prepared in 1 step
from
compound 1-10 and 2-cyanophenol using Method 4. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 357.3 m/z. Activity: C
187
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 29
02N N,O 02N / N-O,
\ I I O \ I O
6 6
I-29a I-29b
(1-29)
[0069] 3-phenoxy-4,5-dihydroisoxazole I-29a and I-29b were prepared in 1 step
from
compound 1-10 and 4-nitrolphenol using Method 4. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+= 376.8 m/z. Activity: B
Example 30
Me, ~P Me, ~P
iS N-O S N,O,
I-30a I-30b
(1-30)
[0070] 3-phenoxy-4,5-dihydroisoxazole I-30a and I-30b were prepared in 1 step
from
compound 1-10 and 4-methylsulfonylphenol using Method 4. These compounds can
be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 409.0 m/z. Activity: A
Example 31
O a Me / N,, -
Me / yc~
I O
\ I O \
F O F O
I-31 a I-31 b
(1-31)
[0071] 3-phenoxy-4,5-dihydroisoxazole I-31a and I-31b were prepared in 1 step
from
compound 1-10 and 4-methyl-3-fluorophenol using Method 4. These compounds can
be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 364.4 m/z. Activity: C
188
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 32
N,O O N0 O O
a 11 a
H H
I-32a I-32b
(1-32)
[0072] A microwave reaction vial is charged with racemic compound 1-10 (1.0
equiv) and
aniline (4.0 equiv). The mixture was sealed and heated in a microwave reactor
at 150 C for 2h.
The reaction was then split between water and tent-butyl methyl ether, and the
organic layer was
washed with brine, dried over sodium sulfate, and concentrated in vacuo. The
concentrated
reaction mixture was purified by flash silica gel chromatography (ethyl
acetate / hexanes) to
provide the desired 3-amino-4,5-dihydroisoxazole I-32a and I-32b. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 330.1 m/z. Activity: C.
Example 33
~' b ~1' b
I-33a 1-33b
(1-33)
[0073] 1-(4,5-dihydroisoxazol-3-yl)pyridin-2(1H)-one I-33a and I-33b were
prepared in
1 step from racemic compound 1-10 and 2-hydroxypyridine using Method 3. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M-H]-= 332.1 m/z. Activity: C
Example 34
N-O - N-O-
O O
N N N N
I-34a I-34b
189
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1-34)
[0074] A microwave reaction vial is charged with racemic ompound 1-10 (1.0
equiv) and the
sodium salt of 1,2,4-triazole (2.0 equiv). The reagents are dissolved in N-
methylpyrrolidine
(0.18 M with respect to compound I-10).The mixture was sealed and heated in a
microwave
reactor at 100 C for 30 min. Excess water is added and a brown solid crashes
out which is
isolated using vacuum filtration and dried to provide the desired 3-(1H-1,2,4-
triazol-1-yl)-
4,5-dihydroisoxazole I-34a and I-34b. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
306.1 m/z. Activity: C.
Example 35
N,O N-O,
O O
I-35a I-35b
(1-35)
[0075] Pyrazole (3.0 equiv) was dissolved in N,N-dimethylforamide (0.60 M with
respect to
pyraole) and NaH (60% dispersion in mineral oil, 3.0 equiv) was added and the
reaction was
allowed to stir under nitrogen for 5 min. After that point racemic compound 1-
10 was added.
The reaction was then heated to 90 C for 14 h after which it was cooled and
quenched with
methanol (0.30 M with prespect to pyrazole). The crude mixture was filtered
through cotton and
directly purified by semi-prep reverse phase chromatograpy to provide the
desired 3-(1H-
pyrazol-1-yl)-4,5-dihydroisoxazole I-35a and I-35b. These compounds can be
separated
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M+H]+= 306.4 m/z. Activity: C.
190
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 36
\ I N,O O Y s.D0 O 11 I-36a I-36b
(1-36)
[0076] 3-(pyridin-4-yloxy)-4,5-dihydroisoxazole I-36a and I-36b were prepared
in 1 step
from compound 1-10 and 4-hydroxypyridine using Method 3. These compounds can
be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 332.1 m/z. Activity: C
Example 37
N,O ~ ~ O OO'0O I-37a I-37b
(1-37)
[0077] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-37a and I-37b were prepared
in 1 step
from racemic compound 1-10 and 3-hydroxypyridine using Method 3 or Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M-H]-= 332.1 m/z. Activity: A
Example 38
N,O OMe U"I N~O- OMe
O O
I-38A I-38b
(1-38)
[0078] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-38a and I-38b were prepared
in 1 step
from racemic compound 1-6 and 3-hydroxypyridine using Method 3. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 270.1 m/z. Activity: B
191
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 39
- :U-~- I 11 \ / O N,O \ / O
\
Me02C O Me02CO
I-39a / \ I-39b
(1-39)
[0079] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-39a and I-39b were prepared
in 1 step
from racemic compound 1-10 and methyl 5-hydroxynicotinate using Method 3 or
Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 392.2 m/z. Activity: A
Example 40
Me N N,O Me N N0 -
\ I I \/ O \ I I \/ O
I-40a 6 I-40b
(1-40)
[0080] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-40a and I-40b were prepared
in 1 step
from racemic compound 1-10 and 5-hydroxy-2-methylpyridine using Method 4.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 346.1 m/z. Activity: A
Example 41
N N,O O N N N'O' O
v 'O v O
I-41 a - I-41 b -
(1-41)
[0081] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-41a and I-41b were
prepared in 1
step from racemic compound 1-10 and 5-hydroxypyrimidine using Method 3. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M-H]-= 333.1 m/z. Activity: A
192
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 42
N N,O N N,O \ / O
I-42a I-42b
(1-42)
[0082] 3-(quinolin-3-yloxy)-4,5-dihydroisoxazole I-42a and I-42b were prepared
in 1
step from racemic compound 1-10 and 3-hydroxyquinoline using Method 3. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M-H]-= 382.1 m/z. Activity: A
Example 43
\ I N0 O O I N,O O
FO -43a FO
- I-43b
(1-43)
[0083] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-43a and I-43b was prepared
in 1 step
from racemic compound 1-10 and 5-fluoro-3-hydroxypyridine using Method 3.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M-H]-= 350.1 m/z. Activity: A
Example 44
Me Me
N N 0 O \ N O
O O
O jO)L/-Ã
I-44a I-44b
(1-44)
[0084] 3-(1-methyl-lH-pyrrolo[2,3-b]pyridin-5-yloxy)-4,5-dihydroisoxazole I-
44a and
I-44b were prepared in 1 step from racemic compound 1-10 and 1-methyl-lH-
pyrrolo[2,3-
b]pyridin-5-ol using Method 3. These compounds can be separated using chiral
HPLC methods
193
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 385.1 m/z.
Activity: B
Example 45
N,O N-O, -
O I O
MeO 6 MeO
I-45a I-45b
(1-45)
[0085] A vial is charged with racemic compound 1-10 (1.0 equiv) and dissolved
in methanol
(0.05 M with respect to isoxazaole). Potassium carbonate (5.0 equiv) was added
and the reaction
was sealed and heated to 50 C for 24h. The reaction was then split between
water and ethyl
acetate, and the organic layer was washed with brine, dried over sodium
sulfate, and
concentrated in vacuo. The concentrated reaction mixture was purified by flash
silica gel
chromatography (ethyl acetate / hexanes) to provide the desired 3-methoxy-4,5-
dihydroisoxazole I-45a and I-45b. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
269.1 m/z. Activity: C.
Example 46
\ N,O OCF3 O OCF3
MeOZC O MeOZC O
I-46a I-46b
(1-46)
[0086] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-46a and I-46b were prepared
in 1 step
from racemic compound 1-14 and methyl 5-hydroxynicotinate using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 384.0 m/z. Activity: B
194
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 47
N O N ,O, N O N O
H N \ I \/ H N \ I \/
2 O / \ 2 O
0 I-47a - 0 I-47b -
(1-47)
[0087] Racemic compound 1-39 is dissolved in ammonia in methanol (7.0 M in
methanol,
0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir
at 23 C for 24h
after which point the solvent and excess ammonia are removed under a stream of
nitrogen to
provide a light brown solid which is triturated with hexanes to provide the
desired amide I-47a
and I-47b as a white solid. These compounds can be separated using chiral HPLC
methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 374.0 m/z.
Activity: B
Example 48
N"O-. N-O
I I
Br Br
I-48a I-48b
(1-48)
[0088] 3-bromo-4,5-dihydroisoxazole I-48a and I-48b were prepared in 1 step
from 3-
phenyl-l-propene using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
239.0 m/z. Activity: C
Example 49
N'0,,
Br Br
I-49a I-49b
(1-49)
[0089] 3-bromo-4,5-dihydroisoxazole I-49a and I-49b were prepared in 1 step
from 4-
phenyl-l-butene using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
253.0 m/z. Activity: B
195
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 50
N'O: P N'
I ~ I
Br O Br O
I-50a I-50b
(1-50)
[0090] Phenol (1.0 equiv) is dissolved in ethanol (0.5 M with respect to
phenol) and sodium
hydroxide (1.0 equiv) is added followed by the addition of 4-bromo-l-butene.
The mixture is
heated to reflux for lh after which the majority of the solvent is removed
under vacuum. The
reaction was then split between water and tent-butyl methyl ether, and the
organic layer was
washed with brine, dried over sodium sulfate, and concentrated in vacuo to
provide crude alkene
which was directly converted to the desired 3-bromo-4,5-dihydroisoxazole 1-50a
and 1-50b in
1 step using Method 2. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-=
269.0 m/z.
Activity: B
Example 51
N,O, N,O
O \ / I O \ /
Br Br
I-51 a I-51 b
(I-51)
[0091] Phenol (1.2 equiv) is dissolved in N,N-dimethylforamide (0.4 M with
respect to
phenol) and cesium carbonate (1.3 equiv) is added followed by the addition of
5-bromo-l-
pentene (1.0 equiv) and tetrabutylammonium iodide (0.10 equiv). The mixture is
heated to 50 C
for 16h. The reaction was then split between water and tent-butyl methyl
ether, and the organic
layer was washed with dilute sodium hydroxide solution, water, brine, dried
over sodium sulfate,
and concentrated in vacuo. The crude alkene was directly converted to the
desired 3-bromo-
4,5-dihydroisoxazole I-51a and I-51b in 1 step using Method 2. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 283.0 m/z. Activity: A
196
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 52
N~~ BrN
Br l-~~O
I-52a I-52b
(1-52)
[0092] 2-Phenylethanol (1.0 equiv) is dissolved in N,N-dimethylforamide (0.8 M
with
respect to alcohol) and crushed sodium hydroxide (2.0 equiv) is added followed
by the addition
of allyl bromide (1.0 equiv) and tetrabutylammonium iodide (0.10 equiv). The
mixture is stirred
at room temperature for 48 h. The reaction was then split between water and
tert-butylmethyl
ether, and the organic layer was washed with dilute Na2S2O3 solution and
brine, dried over
sodium sulfate, and concentrated in vacuo. The concentrated reaction mixture
was purified by
flash silica gel chromatography (ethyl acetate / hexanes) to provide the
desired alkene which was
directly converted to the desired 3-bromo-4,5-dihydroisoxazole I-52a and I-52b
in 1 step using
Method 1. These compounds can be separated using chiral HPLC methods known in
the art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 285.6 m/z.
Activity: B
Example 53
N NO OCF3 ~N I N,O OCF3
H2N O HZN \ O '-~
0 I-53a 0 I-53b
(1-53)
[0093] Racemic compound 1-46 is dissolved in ammonia in methanol (7.0 M in
methanol,
0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir
at 23 C for 72 h
after which point the solvent and excess ammonia are removed under a stream of
nitrogen to
provide a light brown solid which is triturated with hexanes to provide
desired amide I-53a and
I-53b as a white solid. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-=
366.0 m/z.
Activity: B
197
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 54
O OCF3 H N I NO
OCF3
H N Yi
I -a
Me' N O Me' N \ O
0 I-54a 0 I-54b
(1-54)
[0094] Racemic compound 1-46 is dissolved in ammonia in methylamine (2.0 M in
tetrahydrofuran, 0.02 M with respect to isoxazole). The reaction is sealed and
allowed to stir at
23 C for 72 h after which point the solvent and excess ammonia are removed
under a stream of
nitrogen to provide a light brown solid which is triturated with hexanes to
provide desired amide
I-54a and I-54b as a white solid. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
380.0 m/z. Activity: A
Example 55
\ N,O OCF3 Yc~aOCF3
OHOzC O HOzC O
I-55a I-55b
(1-55)
[0095] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-55a and I-55b were prepared
in 1 step
from racemic compound 1-46 and methyl 5-hydroxynicotinate using Method 5 and
was isolated
as a side product from the reaction during flash silica gel chromatography.
These compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M-H]-= 367.0 m/z. Activity: C
Example 56
F3C :11 N Na F3C N yc- O, a
0 0
I -56a - I-56b -
(1-56)
[0096] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-56a and I-56b was prepared
in 1 step
from racemic compound 1-10 and 5-hydroxy-2-trifluoromethylpyridine using
Method 5. These
198
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 401.5 m/z. Activity: A
Example 57
\ N,O O / \ JoL>-Ãb
H H
I-57a I-57b
(1-57)
[0097] 3-(IH-pyrrolo[3,2-b]pyridin-6-yloxy)-4,5-dihydroisoxazole 1-57a and 1-
57b
were prepared in 1 step from racemic compound 1-10 and 1H-pyrrolo[3,2-
b]pyridin-6-ol using
Method 5. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M-H]-= 370.0 m/z.
Activity: A
Example 58
CN CN
N,O \ N'O'
O
O
L
I-58a 1-58b
(1-58)
[0098] 3-phenoxy-4,5-dihydroisoxazole I-58a and I-58b were prepared in 1 step
from
racemic compound 1-10 and 3-cyanophenol using Method 4. These compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 356.8 m/z. Activity: B
Example 59
F F
I-59a I-59b
(1-59)
199
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[0099] 3-phenoxy-4,5-dihydroisoxazole I-59a and I-59b were prepared in 1 step
from
racemic compound 1-10 and 2-fluorophenol using Method 4. These compounds can
be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 350.3 m/z. Activity: B
Example 60
CF3 CF3
F\ U \ F\ ON,
I O O
I-60a I-60b
(1-60)
[00100] 3-phenoxy-4,5-dihydroisoxazole I-60a and I-60b were prepared in 1 step
from
racemic compound 1-10 and 4-fluoro-3-(trifluoromethyl)phenol using Method 4.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. Activity: C
Example 61
CO2Me CO2Me
\ I N,O N,O
O O
0 6 0
I-61 a I-61 b
(1-61)
[00101] 3-phenoxy-4,5-dihydroisoxazole I-61a and I-61b were prepared in 1 step
from
racemic compound 1-10 and methyl 3-hydroxybenzoate using Method 4. These
compounds can
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 390.5 m/z. Activity: A
200
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 62
McO2C N,O Mc02C / N,O,
6 6
I-62a I-62b
(1-62)
[00102] 3-phenoxy-4,5-dihydroisoxazole I-62a and I-62b were prepared in 1 step
from
racemic compound 1-10 and methyl 4-hydroxybenzoate using Method 4. These
compounds can
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 389.7 m/z. Activity: A
Example 63
Me Me
O=S=0 O=S=0
N-i0 O N'O' O
Y
/ 6 cb'o 6
I-63a I-63b
(1-63)
[00103] 3-phenoxy-4,5-dihydroisoxazole I-63a and I-63b were prepared in 1 step
from
racemic compound 1-10 and 3-(methylsulfonyl)phenol using Method 4. These
compounds can
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M-H]-= 409.0 m/z. Activity: C
Example 64
NH2 NH2
O=S=O O=S=O
b~o 11 N\ 6 6
I-64a I-64b
(1-64)
[00104] 3-phenoxy-4,5-dihydroisoxazole I-64a and I-64b were prepared in 1 step
from
racemic compound 1-10 and 3-hydroxybenzenesulfonamide using Method 4. These
compounds
201
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M-H]-= 409.0 m/z. Activity: C
Example 65
N,O N
O O O
McO1O 6 MeO
I-65a I-65b
(1-65)
[00105] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-65a and I-65b were prepared
in 1 step
from racemic compound 1-10 and 5-methoxypyridin-3-ol using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 363.2 m/z. Activity: A
Example 66
MeO N Yc O MeO N N-
N O NI O 6 6
I-66a I-66b
(1-66)
[00106] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-66a and I-66b were
prepared in 1
step from racemic compound 1-10 and 5-hydroxypyrimidine using Method 5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 364.6 m/z. Activity: A
Example 67
Me02C N N,O Me02C N N,O,
\ I I ~~ O \ I I ~~ O
I-67a 6 I-67b
(1-67)
[00107] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-67a and I-67b were prepared
in 1 step
from racemic compound 1-10 and methyl 5-hydroxypicolinate using Method 3.
These
202
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 392.1 m/z. Activity: A
Example 68
N N I Yc0 - O N N WI-68a 6 0 I-68b
(1-68)
[00108] 3-(IH-pyrrolo[2,3-b]pyridin-5-yloxy)-4,5-dihydroisoxazole 1-68a and 1-
68b
were prepared in 1 step from racemic compound 1-10 and 1H-pyrrolo[2,3-
b]pyridin-5-ol using
Method 5. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M-H]-= 370.0 m/z.
Activity: A
203
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 69
~O U~ 0
11 0 roxl"z" 110
I-69a I-69b
(1-69)
[00109] 6-(4,5-dihydroisoxazol-3-yloxy)furo[3,2-b]pyridine I-69a and I-69b
were
prepared in 2 steps from racemic compound 1-10 and furo[3,2-b]pyridin-6-ol
using Method 5
after furo[3,2-b]pyridin-6-ol is prepared from 6-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-
yl)furo[3,2-b]pyridine using Method 11. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
374.2 m/z. Activity: A
Example 70
I J OCF3 \ i/-_OCF3
IO O
I-70a I-70b
(1-70)
[00110] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-70a and I-70b were prepared
in 1 step
from racemic compound 1-14 and 3-hydroxypyridine using Method 5. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 324.1 m/z. Activity: A
Example 71
I N,O OCF3 N-O OCF3
Br ~O Br O
I-71 a I-71 b
(1-71)
[00111] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-71a and I-71b were prepared
in 1 step
from racemic compound 1-14 and 5-bromo-3-hydroxypyridine using Method 5. These
204
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 402.5 m/z. Activity: A
205
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 72
0jJL)cIOCF3 Yc0 O 0j,1LJ/COCF3
I-72a I-72b
(1-72)
[00112] Racemic compound 1-71 (1.0 equiv), phenyl boronic acid (1.1 equiv),
potassium
acetate (1.0 equiv), cesium carbonate (3.0 equiv), and dichloro[1,1'-
bis(diphenylphosphino)
ferrocene]palladium(II) dichloromethane adduct (14 mol %) were suspended in 1
mL DMSO and
purgetd with Ar. The resulting mixture was sealed and heated to 80 C for lh.
The crude
mixture was transferred to a separatory funnel with excess water and extracted
with methyl tert-
butylether (2x). The organic layers were combined, dried over Na2SO4 and
purified using flash
silica gel chromatography (gradient of 2-10% MeOH) to provided the desired 3-
(pyridin-3-
yloxy)-4,5-dihydroisoxazole I-72a and I-72b as a white solid. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 402.3 m/z. Activity: B
Example 73
O ONHZ N' OCF3 NHZ Y ' O I~ ~ O O I~ ~ O
I-73a I-73b
(1-73)
[00113] Racemic compound 1-71 (1.0 equiv), 3-carbamoylphenyl boronic acid (1.1
equiv),
potassium acetate (1.0 equiv), cesium carbonate (3.0 equiv), and dichloro[1,1'-
bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct (14 mol
%) were
suspended in 1 mL DMSO and purged with Ar. The resulting mixture was sealed
and heated to
80 C for lh. The crude mixture was transferred to a separatory funnel with
excess water and
extracted with methyl tert-butylether (2x). The organic layers were combined,
dried over
Na2SO4 and purified using flash silica gel chromatography (gradient of 2-10%
MeOH) to
provided the desired 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-73a and I-73b
as a white
206
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
solid. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M-H]-= 442.0 m/z. Activity:
A
Example 74
O O ~COWe
N/ COZMe Br Br
I-74a I-74b
(1-74)
[00114] 3-bromo-4,5-dihydroisoxazole I-74a and I-74b were prepared in 1 step
from
methyl 4-vinylbenzoate using Method 1. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
283.6 m/z. Activity: A
Example 75
OCF3 OCF3
N-O,% N-O,
I
Br Me Br Me
I-75a I-75b
(1-75)
[00115] 3-bromo-4,5-dihydroisoxazole I-75a and I-75b were prepared in 2 steps
starting
with alkene formation from 4'(trifluoromethoxy)acetophenone using Method 6
followed by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 323.0 m/z.
Activity: A
Example 76
0-- 0
O, ,O
Br N Me Br Me
I-76a I-76b
(1-76)
207
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00116] 3-bromo-4,5-dihydroisoxazole I-76a and I-76b were prepared in 2 steps
starting
with alkene formation from 4'-phenoxyacetophenone using Method 6 followed by
cycloaddition
using Method 2. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 331.0 m/z.
Activity: A
Example 77
OMe
Br N-0
O ~OMe YC-
BrrMe Me
I-77a I-77b
(1-77)
[00117] 3-bromo-4,5-dihydroisoxazole I-77a and I-77b were prepared in 1 step
from
trans-anethole using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 269.0 m/z.
Activity: C
Example 78 -0 0 'n-."O-O
Br~ Br
Me Me
I-78a I-78b
(1-78)
[00118] 3-bromo-4,5-dihydroisoxazole I-78a and I-78b were was prepared in 2
steps
starting with alkene formation from 4-phenoxybenzaldehyde using Method 6
(except that
ethyltriphenyphosphonium bromide is used in the place of
methyltriphenylphosphoium bromide)
followed by cycloaddition using Method 2. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-
H]-= 331.0 m/z. Activity: A
Example 79
208
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
O
Br BrN--~
Me
Me
I-82a I-82b
(1-82)
[00119] 3-bromo-4,5-dihydroisoxazole I-82a and I-82b were prepared in 3 steps
from 4-
phenoxybenzaldehyde as follows: 4-Phenoxybenzaldehyde (1.0 equiv) is dissolved
in
tetrahydrofuran (0.20 M with respect to tetrahydrofuran) and cooled to 0 C.
Ethyl magnesium
bromide (1.0 M in THF, 1.2 equiv) is added dropwise after which the reaction
is allowed to stir
at 23 C for 2h. The mixture was quenched with saturated ammonium chloride and
concentrated
to remove the tetrahydrofuran. The mixture was then diluted with water and
extracted with tert-
butyl methyl ether. The organic layer was washed with water and brine and then
dried over
sodium sulfate and concentrated in vacuo. The concentrated reaction mixture
was purified by
flash silica gel chromatography (ethyl acetate / hexanes) to provide the
desired alcohol 1-80.
[00120] The purified alcohol 1-80 is then dissolved in pyridine (0.80 M with
respect to
alcohol). Phosphorus oxychloride (1.1 equiv) is added and the mixture was
heated to reflux for
2h. After this point the reaction is cooled to 0 C and quenched with the
addition of excess
water. The mixture was then diluted with ethyl acetate. The organic layer was
washed with
water and brine and then dried over sodium sulfate and concentrated in vacuo.
The concentrated
reaction mixture was purified by flash silica gel chromatography (ethyl
acetate / hexanes) to
provide the desired alkene 1-81.
Me Me
OH
C 0 0 0
r 0", Cr
1-79 1-80 1-81
[00121] Alkene 1-81 was then converted to the desired 3-bromo-4,5-
dihydroisoxazole I-
82a and I-82b using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 331.0 m/z.
Activity: B.
209
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 80
Me0 I _N 0 O Me0 O _N 0
O 1 OCF3 OCF3
O O
I-83a I-83b
(1-83)
[00122] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-83a and I-83b were prepared
in 1 step
from racemic compound 1-14 and methyl 3-(5-hydroxypyridin-2-yl)benzoate using
Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 460.1 m/z. Activity: B
Example 81
Et0 al"I~N 0 O Et0 al',~N O,
O 1 OCF3 O 1 OCF3
O O
I-84a I-84b
(1-84)
[00123] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-84a and I-84b were prepared
in 1 step
from racemic compound 1-14 and ethyl 3-(5-hydroxypyridin-2-yl)benzoate using
Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 474.1 m/z. Activity: B
Example 82
HO \ I ~N N,O H O O j)_,i_oc \ IF3
O O
I-85a I-85b
(1-85)
[00124] Racemic compound 1-83 (1.0 equiv) was dissolved in 1:1
tetrahydrofuran/water (0.06
M) and lithium hydroxide (8.0 equiv) was added. The reaction was allowed to
stir at room
210
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
temperature for lh after which point the tetrahydrofuran was removed under a
stream of nitrogen
and the remaining solution was acidified to pH<2 with IN HC1 to provide the
desired acid I-85a
and I-85b as a white solid which was isolated via vacuum filtration. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 443.0 m/z. Activity: B
Example 83
N\ O
OCF3 OCF3
O O
I-86a I-86b
(1-86)
[00125] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-86a and I-86b were prepared
in 1 step
from racemic compound 1-14 and 6-phenylpyridin-3-ol using Method 5. These
compounds can
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 402.2 m/z. Activity: B
Example 84
N N,O N N/O' ~01 O O
N N
I-87a I-87b
(1-87)
[00126] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-87a and I- 87b were
prepared in 1
step from racemic compound 1-12 and 3-hydroxypyridine using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 333.5 m/z. Activity: A
Example 85
211
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
OCF3 OCF3
N N -O
N
O Me 0/ UM e
I-88a I-88b
(1-88)
[00127] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-88a and I-88b were prepared
in 1 step
from racemic compound 1-75 and 3-hydroxypyridine using Method 5. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 340.2 m/z. Activity: B
212
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 86
10- 0
N N,O, N N,O
Me O/~ Me
I-89a I-89b
(1-89)
[00128] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-89a and I-89b were prepared
in 1 step
from racemic compound 1-76 and 3-hydroxypyridine using Method 5. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 348.4 m/z. Activity: A
Example 87
H2N, ~P H2N, iP
OS N,O OS N
O O. O
I-90a - I-90b
(1-90)
[00129] 3-phenoxy-4,5-dihydroisoxazole I-90a and I-90b were prepared in 1 step
from
racemic compound 1-10 and 4-hydroxybenzenesulfonamide using Method 4. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 410.8 m/z. Activity: A
Example 88
N N-0 N N-0
-~O 0-0
YID
Me Me
I-91 a I-91 b
(1-91)
[00130] The trans 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-91a and I-91b
were
prepared in 1 step from either racemic compound 1-78 or 1-82 and 3-
hydroxypyridine using
213
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Method 5. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 346.2 m/z.
Activity: C
Example 89
BocHNkN N'0 O
BocHN N N'O \ / O 6 I
I-92a I-92b
(1-92)
[00131] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-92a and I-92b were prepared
in 2
steps from racemic compound 1-10 and (5-hydroxy-pyridin-2-yl)-carbamic acid
tert-butyl
ester using Method 5 after formation of (5-hydroxy-pyridin-2-yl)-carbamic acid
tert-butyl
ester from tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-
ylcarbamate
using Method 11. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 447.9 m/z.
Activity: C
Example 90
H2N N N-0 H2N N Y ,O,-. -a 0
6 0
6
I-93a I-93b
(1-93)
[00132] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-92 was dissolved in
trifluoroacetic acid (0.20 M with respect to isoxazole) and stirred at room
temperature for lh.
The solvent is then removed under vacuum and the crude residue is azeotroped
with toluene (2x)
to provide I-93a and I-93b as the TFA salt (white solid). These compounds can
be separated
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M+H]+ = 347.1 m/z. Activity: A
Example 91
214
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Me,'~ N N N,O O Me 11 N N I N~O O
O 6 6 O
I-94a I-94b
(1-94)
[00133] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-93 was dissolved in
methylene chloride (0.03 M with respect to isxozaole) after which
triethylamine (4.0 equiv) and
acetic anhydride (3.0 equiv are added). The reaction is allowed to stir for
16h after which point
is diluted with ethyl acetate and washed with saturated NaHCO3 (2x) and brine
(lx). The
organic layer is then dried over sodium sulfate and concentrated under vacuum
to provide acetate
I-94a and I-94b as a white solid. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
388.1 m/z. Activity: A
Example 92
10- 0
;NN OPEt N,O
)" Et
Br Br
I-95a I-95b
(1-95)
[00134] 3-bromo-4,5-dihydroisoxazole I-95a and I-95b were prepared in 2 steps
starting
with alkene formation from 1-(4-phenoxyphenyl)propan-l-one using Method 8
followed by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 347.7 m/z.
Activity: A
Example 93
O O
N O N O;
MeO YC~ - OCF3 MeO N OCF3
O ~ O
I-96a I-96b
(1-96)
215
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00135] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-96a and I-96b were prepared
in 1 step
from racemic compound 1-14 and 5-hydroxypicolinic acid methyl ester according
to the
following procedure: 3-bromo-5-(4-(trifluoromethoxy)phenyl)-4,5-
dihydroisoxazole (1.0
equiv), 5-hydroxypicolinic acid methyl ester (1.2 equiv), and cesium
hydrogencarbonate (1.50
equiv) are suspended in N,N-dimethylforamide (0.32 M with respect to
dihydroisoxazole. The
mixture is then degassed with argon after which it is heated to 130 C for 4 h
after which point
there is only desired product and corresponding acid visible by LC/MS. The
reaction is allowed
to cool to room temperature and quenched by pouring into a solution of
ammonium chloride in
water (30% by weight, 0.08 M with respect to dihydroisoxazole). The aqueous
phase is
extracted with ethyl acetate (2x), dried over sodium sulfate, filtered and
concentrated to product
a brown solid which could be recystallized from absolute ethanol to provide
racemic 3-(pyridin-
3-yloxy)-4,5-dihydroisoxazole 1-96 that was isolated by filtration as a white
solid (25% yield).
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 383.8 m/z. Activity: A
Example 94
O O
HO 11_CI N,O OCF3 HO UN N~O, OCF3
O O
I-97a I-97b
(1-97)
[00136] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-96 (1.0 equiv) was
dissolved
in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was
added. The
reaction was allowed to stir at room temperature for lh after which point the
tetrahydrofuran was
removed under a stream of nitrogen and the remaining solution was acidified to
pH<2 with IN
HC1 to provide the desired acid enantiomers I-97a and I-97b as a white solid
which was isolated
via vacuum filtration. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 369.3
m/z. Activity:
A
Example 95
216
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Me0 ,-N 0 O Me0 -11~N N,O,
O O
O O
I-98a I-98b
(1-98)
[00137] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-98a and I-98b were prepared
in 1 step
from racemic compound 1-10 and 3-(5-hydroxypyridin-2-yl)propanoic acid methyl
ester using
Method 5. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 418.1 m/z.
Activity: A
Example 96
O O
HO N'O - HO N N,O i O O O
I-99a I-99b
(1-99)
[00138] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-98 (1.0 equiv) was
dissolved
in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was
added. The
reaction was allowed to stir at room temperature for lh after which point the
tetrahydrofuran was
removed under a stream of nitrogen and the remaining solution was acidified to
pH<2 with IN
HC1 to provide the desired acid I-99a and I-99b as a white solid which was
isolated via vacuum
filtration. These compounds can be separated using chiral HPLC methods known
in the art. For
example, see chiral HPLC Method disclosed herein. [M-H]-= 402.8 m/z. Activity:
A
Example 97
-I~N
N1O O P H2N UN N,O \ / O P
H2N
O O
I-100a I-100b
(1-100)
217
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00139] Racemic compound 1-98 is dissolved in ammonia in methanol (7.0 M in
methanol,
0.02 M with respect to isoxazole). The reaction is sealed and allowed to stir
at 23 C for 72 h
after which point the solvent and excess ammonia are removed under a stream of
nitrogen to
provide a light brown solid which is triturated with hexanes to provide the
desired amide I-100a
and I-100b as a white solid. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 404.5 m/z.
Activity: A
Example 98
i0x3-c/o O0Xc/\/
1-101a I-101 b
(I-101)
[00140] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-101a and I-101b were
prepared in 1
step from racemic compound 1-9 and 3-hydroxypyridine using Method 5. These
compounds can
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+= 316.8 m/z. Activity: A
Example 99
\I \I
N-O N-O
Br Me Br Me
I-102a I-102b
(1-102)
[00141] 3-bromo-4,5-dihydroisoxazole I-102a and I-102b were prepared in 2
steps starting
with alkene formation from 1-(biphenyl-4-yl)ethanone using Method 8 followed
by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 315.7 m/z.
Activity: A
Example 100
218
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
NNI N,O N ,O
N YI'O'
~O
I-103a I-103b
(1-103)
[00142] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-103a and I-103b were
prepared in
1 step from racemic compound 1-9 and 5-hydroxyprimidine using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 318.7 m/z. Activity: A
Example 101
Na I N-O \ ~N I N-O `\ \
O Me 0 Me
I-104a I-104b
(1-104)
[00143] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-104a and I-104b were
prepared in
1 step from racemic compound 1-102 and 5-hydroxyprimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 332.6 m/z. Activity: A
Example 102
O O
Me0 O Me0 N O
; -
~H UN NOCF3 ~H N' OCF3
O O O \ O
I-105a I-105b
(I-105)
[00144] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-97 (1.0 equiv) was
dissolved
in methylene chloride (0.03 M with respect to isoxazole). Thionyl chloride is
added (2.0 equiv)
and the reaction was stirred for lh at room temperature after which point it
was concentrated
under vacuum to a beige solid which was azeotroped with toluene (2x). The
resultant solid was
219
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
redissolved in tetrahydrofuran (0.03 M with respect to isoxazole) after which
glycine methyl
ester (1.5 equiv) was added followed by triethylamine (3.0 equiv). The
reaction was stirred for
lh at room temperature after which point it was transferred to a separatory
funnel with excess
water and ethyl acetate. The organic layer was then washed with saturated
NaHCO3 solution and
brine, dried over magnesium sulfate and concentrated under vacuum to provide
crude material
which was purified using flash silica gel chromatography (ethyl
acetate/hexanes) to provide
amide I-105a and I-105b as a white solid. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-
H]-= 437.5 m/z. Activity: A
Example 103
O O
HO N O - HO ~H
N/ c OCF3 ~H Y:~N O- OCF3
O \ O O O
I-106a I-106b
(1-106)
[00145] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-105 (1.0 equiv) was
dissolved
in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was
added. The
reaction was allowed to stir at room temperature for lh after which point the
tetrahydrofuran was
removed under a stream of nitrogen and the remaining solution was acidified to
pH<2 with IN
HC1 to provide the desired acid I-106a and I-106b as a white solid which was
isolated via
vacuum filtration. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 423.7 m/z.
Activity: A
Example 104
O O
Me, N O - Me, N O, -
H I YOCF3 H N' \ OCF3
\ O \ O
I-107a I-107b
(1-107)
220
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00146] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-107a and I-107b were
prepared in
using the analogous procedure as Example 102 except that methylamine was used
in the place of
glycine methyl ester. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+= 382.5
m/z. Activity:
A
Example 105
O O
Me, N O Me, N O,
N I N' OCF3 N I N' OCF3
Me \ O Me \ O
I-108a I-108b
(1-108)
[00147] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-108a and I-108b were
prepared in
using the analogous procedure as Example 102 except that dimethylamine was
used in the place
of glycine methyl ester. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=
396.6 m/z.
Activity: B
Example 106
O O
HN UN N, HOB/- ~N N,O, -
H O -
I OCF3 H I I OCF3
O \ O
I-109a I-109b
(1-109)
[00148] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-109a and I-109b were
prepared in
using the analogous procedure as Example 102 except that ethanolamine was used
in the place of
glycine methyl ester. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 409.9
m/z. Activity:
A
Example 107
221
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
HOZC N N,O HOZC ;Oe N N,O
I-11 Oa - 1-110b -
(I-110)
[00149] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-67 (1.0 equiv) was
dissolved
in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was
added. The
reaction was allowed to stir at room temperature for lh after which point the
tetrahydrofuran was
removed under a stream of nitrogen and the remaining solution was acidified to
pH<2 with IN
HC1 to provide the desired acid I-110a and I-110b as a white solid which was
isolated via
vacuum filtration. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 376.5 m/z.
Activity: A
Example 108
O O
Me.N ~N N-O - Me,N ~N N,O,
Me \ I I O Me \ I I O
I-111 a I-111 b
(I-111)
[00150] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-67 is dissolved in
dimethylamine in methanol (2.0 M in tetrahydrofuran, 0.02 M with respect to
isoxazole). The
reaction is sealed and allowed to stir at 23 C for 72 h after which point the
solvent and excess
dimethylamine are removed under a stream of nitrogen to provide a light brown
solid which is
triturated with hexanes to provide the desired amide I-111a and I-111b as a
white solid. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 405.1 m/z. Activity: A
Example 109
N N ~ N,O OCF3 N N N~O; ~OCF,
O ~O
I-112a I-112b
(1-112)
222
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00151] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-112a and I-112b were
prepared in
1 step from racemic compound 1-14 and 5-hydroxypyrimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. Activity: A
Example 110
OCF3 OCF3
HOZC N N-O
H02C N NO 0 N~ I 1z"N
O Me O Me
I-113a I-113b
(1-113)
[00152] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-113a and I-113b were
prepared in 2
steps from racemic compound 1-75 and 5-hydroxypicolinic acid methyl ester
using Method 5
followed by hydrolysis under the same conditions as in example 94. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 380.7 m/z. Activity: A
Example 111
0 OCF3 0 OCF3
Me.N UN NO Me.N UNI N-O H I H ~I
p Me p Me
I-114a I-114b
(I-114)
[00153] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-114a and I-114b were
prepared from
racemic compound 1-113 by using the analogous procedure as Example 102 except
that
methylamine (2.OM in tetrahydrofuran) was used in the place of glycine methyl
ester. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+= 396.4 m/z. Activity: A
Example 112
223
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
p OCF3 p OCF3
Me^N iN NO, Me ^N N N-O . ~ I
H H ~I
~ p Me ~ p I'X Me
I-115a I-115b
(I-115)
[00154] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-115a and I-115b were
prepared from
racemic compound 1-113 by using the analogous procedure as Example 102 except
that
ethylamine was used in the place of glycine methyl ester. These compounds can
be separated
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M+H]+= 411.1 m/z. Activity: A
Example 113
p OCF3 p OCF3
F3CN iN N-O F3CN UN N'O H H
p Me p Me
I-116a I-116b
(I-116)
[00155] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-116a and I-116b were
prepared from
racemic compound 1-113 by using the analogous procedure as Example 102 except
that
trifluoroethylamine was used in the place of glycine methyl ester. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 461.7 m/z. Activity: B
Example 114
p OCF3 p OCF3
HO.N UN N HO.N UN N_O /
H H
p Me p Me
I-117a I-117b
(I-117)
[00156] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-117a and I-117b were
prepared from
racemic compound 1-113 by using the analogous procedure as Example 102 except
that
224
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
hydroxylamine hydrochloride was used in the place of glycine methyl ester.
These compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+- = 398.4 m/z. Activity: A
Example 115
O O
H2N N O HZN~ N ~N OOH UN
I OCF3 IOI H \ I I OCF3
O O
I-118a I-118b
(1-118)
[00157] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-105 is dissolved in
ammonia
in methanol (7.0 M in methanol, 0.02 M with respect to isoxazole). The
reaction is sealed and
allowed to stir at 23 C for 72 h after which point the solvent and excess
ammonia are removed
under a stream of nitrogen to provide a light brown solid which is triturated
with hexanes to
provide desired amide I-118a and I-118b as a white solid. These compounds can
be separated
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M+H]+ = 325.1 m/z. Activity: B
Example 116
F F F F
N N N,O N N 1 1 N -0,
~O
I-119a I-119b
(1-119)
[00158] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-119a and I-119b was
synthesized
in three steps starting with the conversion of 4-bromo-3,3'-difluorobiphenyl
to its corresponding
alkene using Method 9 followed by cycloaddition using Method 1 followed by
displacement
with 5-hydroxyprimidine using Method 5. These compounds can be separated using
chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 354.3 m/z. Activity: A
Example 117
225
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
F F
O - p
OCF3 Y ~ OCF3
Br Br
I-120a I-120b
(1-120)
[00159] 3-bromo-4,5-dihydroisoxazole I-120a and I-120b were prepared in 2
steps starting
with alkene formation from 3-fluoro-4-(trifluoromethoxy)benzaldehyde using
Method 8
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+= 327.5 m/z. Activity: A
Example 118
F F
N N,O OCF3 N I N-O OCF3
N ~/ 'O N ~/ O
I-121 a I-121 b
(1-121)
[00160] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-121a and I-121b were
prepared in
1 step from racemic compound 1-120 and 5-hydroxypyrimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 344.1 m/z. Activity: A
Example 119
F F
Me02C N N~p OCF Me02C " N~O OCF
3 3
O O
I-122a I-122b
(1-122)
[00161] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-122a and I-122b was
prepared in 1
step from racemic compound 1-120 and 5-hydroxypicolinic acid methyl ester
using Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 400.3 m/z. Activity: A
226
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 120
F F
HO2C N I 0 O OCF HOZC N N'O OCF
3 3
I-123a I-123b
(1-123)
[00162] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-122 (1.0 equiv) was
dissolved
in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was
added. The
reaction was allowed to stir at room temperature for lh after which point the
tetrahydrofuran was
removed under a stream of nitrogen and the remaining solution was acidified to
pH<2 with IN
HC1 to provide the desired acid I-123a and I-123b as a white solid which was
isolated via
vacuum filtration. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 386.3 m/z.
Activity: A
Example 121
CI CI
J OCF3 YO-6 OCF3
i5-6 O
Br Br
I-124a I-124b
(1-124)
[00163] 3-bromo-4,5-dihydroisoxazole I-124a and I-124b were prepared in 2
steps starting
with alkene formation from 3-chloro-4-(trifluoromethoxy)benzaldehyde using
Method 8
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 345.5 m/z. Activity: A
Example 122
CI CI
1 N N'O OCF3 N N'O OCF3
I-125a I-125b
227
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1-125)
[00164] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-125a and I-125b were
prepared in 1
step from racemic compound 1-124 and 5-hydroxypyrimidine using Method 5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 359.7 m/z. Activity: A
Example 123
F F
N-O - F N-O - O~F
I I
Br Br
I-126a I-126b
(I-126)
[00165] 3-bromo-4,5-dihydroisoxazole I-126a and I-126b were prepared in 2
steps starting
with alkene formation from 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde
using Method 8
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 305.6 m/z. Activity: A
Example 124
F F
O-[ F O~
F
N ~ N11 ,O ~~ O ~N I NOO
N O N --zz/ `O
I-127a I-127b
(I-127)
[00166] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-127a and I-127b were
prepared in 1
step from racemic compound 1-126 and 5-hydroxypyrimidine using Method 5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 321.8 m/z. Activity: B
Example 125
228
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
O O
HO UN N3O \ / O C F HO UN YC0~ OCF
O O
I-128a I-128b
(1-128)
[00167] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-128a and I-128b were
prepared in
analogous fashion to compound 1-99 in Example 96 except that racemic compound
1-14 was
used as starting material in place of racemic compound 1-10. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 398.2 m/z. Activity: A
Example 126
OCF3 OCF3
N N-O- N N-O
N N
Me O Me
I-129a I-129b
(1-129)
[00168] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-129a and I-129b were
prepared in
1 step from racemic compound 1-75 and 5-hydroxypyrimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 339.8 m/z. Activity: A
Example 127
O O
11
Br CF3 Br \ CF3
I-130a I-130b
(I-130)
[00169] 3-bromo-4,5-dihydroisoxazole I-130a and I-130b were prepared in 2
steps starting
with the coupling between 4-phenoxyphenylboronic acid and 2-bromo-3,3,3-
trifluoroprop-l-
ene as follows: A solution of toluene (0.25 M with respect to boronic acid) is
cooled to 0 C in a
229
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
sealed tube after which point 2-bromo-3,3,3-trifluoroprop-l-ene (0.83 equiv)
is added followed
by palladium tetrakis (2.5 mol%). The mixture is purged with Ar after which
point a 2.0 M
solution of sodium carbonate (1.5 equiv) is added followed by the boronic acid
(1.0 equiv) in
methanol (1.0 M with respect to boronic acid). The mixture was purged a second
time with Ar
after which point it was heated to 70 C in an oil bath for 20h. The reaction
was allowed to cool
after which it was transferred to a reparatory funnel with excess water and
ethyl acetate, washed
with a 2.OM solution of sodium carbonate (lx) and water (2x). The organic
layer was dried and
concentrated to provide a black oil which was purified by flash silica gel
chromatography (ethyl
acetate/hexanes) to provide the desired alkene as an oil in 35% yield which
was converted
directly to the desired racemic 3-bromo-4,5-dihydroisoxazole 1-130 using
Method 1. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 385.6 m/z. Activity: B
Example 128
N NI N~O \ I O N N O
N-O.~\ I I/
O CF3 O ,,CF3
I-131 a I-131 b
(I-131)
[00170] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-131a and I-131b were
prepared in
1 step from racemic compound 1-130 and 5-hydroxypyrimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 401.4 m/z. Activity: A
Example 129
MeS Y~N NO MeS N OI OCF3 I \ OCF3
O O
I-132a 1-132
(1-132)
[00171] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-132a and I-132b were
prepared in
1 step from racemic compound 1-14 and 2-(methylthio)pyrimidin-5-ol using
Method 5 after 2-
230
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(methylthio)pyrimidin-5-ol is first prepared from 2-(methylthio)pyrimidin-5-
ylboronic acid
using Method 11. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 372.2 m/z.
Activity: B
Example 130
Me. ~P Me. ~P
S N 0 O
O I I SVN 0
OCF3 O
N OCF3
O O
I-133a I-133b
(I-133)
[00172] Racemic 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole 1-132 was dissolved
in
methylene chloride (0.5 M with respect to isoxazole) after which point m-
chloroperbenzoic acid
(2.0 equiv) was added in 1 portion and the reaction was allowed to stir at
room temperature for
lh. After the reaction was determined to be complete by LC/MS, the solvent was
evaporated.
The crude mixture was then redissolved in tert-butylmethyl ether (.5 M) after
which hexane was
slowly added until a solid precipitated. The solid was then collected via
vacuum filtration and
washed with 1:1 hexanes/ tert-butylmethyl ether to provide the desired 3-
(pyridin-3-yloxy)-
4,5-dihydroisoxazole I-133a and I-133b as a white solid. These compounds can
be separated
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M+H]+ = 404.1 m/z. Activity: A
Example 131
MeS NMeS N YID-aOCF3
O O
I-134a I-134b
(I-134)
[00173] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-134a and I-134b were
prepared in 1
step from racemic compound 1-14 and 6-(methylthio)pyridin-3-ol using Method 5
after 6-
(methylthio)pyridin-3-ol is first prepared from 6-(methylthio)pyridin-3-
ylboronic acid using
Method 11. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 372.4 m/z.
Activity: A
231
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 132
Mew ~P Mew ~P
OS I U1N N0 O - OCF OS N N/O~' OCF
3 I 3
O O
I-135a I-135b
(1-135)
[00174] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-135a and I-135b were
prepared from
1-134 in analogous fashion to compound 1-133 in example 130. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 403.2 m/z. Activity: A
Example 133
MeO :~~O NO MeO N,O, - a
OCF3 D OCF3
F F O
I-136a I-136b
(I-136)
[00175] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-136a and I-136b were
prepared in 1
step from racemic compound 1-14 and 5-fluoro-6-methoxypyridin-3-ol using
Method 5 after
5-fluoro-6-methoxypyridin-3-ol is first prepared from 5-fluoro-6-
methoxypyridin-3-boronic
acid using Method 11. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 373.4
m/z. Activity:
B
Example 134
McO2C N N Mc02C N Y ,O,-&O' O'M~e O O
I-137a I-137b
(1-137)
[00176] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-137a and I-137b were
prepared in 3
steps from 4-butoxybenzaldehyde using Method 8 followed by cycloaddition using
Method 1.
The resuling bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic
acid methyl
232
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
ester using Method 5. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 370.1
m/z. Activity:
A
Example 135
HO2C N N0 H02C :11 N N0
\ I I \ / O Me \ I ~ ~ ~ O Me
O O
I-138a I-138b
(I-138)
[00177] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-138a and I-138b were
prepared in 1
step from compound 1-137 using the analogous hydrolysis conditions as in
Example 94. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 357.7 m/z. Activity: A
Example 136
~N N,0 - N N,O, -
I I \/ O Me N I I O Me
O O
I-139a I-139b
(I-139)
[00178] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-139a and I-139b was
prepared in 3
steps from 4-butoxybenzaldehyde using Method 8 followed by cycloaddition using
Method 1.
The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine
using
Method 5. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 314.9 m/z.
Activity: A
Example 137
Me Me
H02C N N,0 - >-Me H02C N ,0 >-Me
I 10 \ 10
O O
I-140a I-140b
(I-140)
233
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00179] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-140a and I-140b were
prepared in 4
steps from 4-iso-propoxybenzaldehyde using Method 8 followed by cycloaddition
using Method
1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-
hydroxypicolinic acid methyl
ester using Method 5 followed by hydrolysis using the analogous conditions as
in Example 94
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 343.5 m/z. Activity: A
Example 138
Me M~
N ~ ,O ~Me ~N I N,O - O Me
NO N
O
1-141a I-141 b
(I-141)
[00180] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-141a and I-141b were
prepared in
3 steps from 4-iso-propoxybenzaldehyde using Method 8 followed by
cycloaddition using
Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-
hydroxypyrimidine
using Method 5. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 299.3 m/z.
Activity: A
Example 139
N-O - N'0,,
I ~-o I O
Br Br
I-142a I-142b
(1-142)
[00181] 3-bromo-4,5-dihydroisoxazole I-142a and I-142b were prepared in 3
steps from 4-
vinylphenyl acetate using the cycloaddition conditions in Method 1. The
resulting acetate is
dissolved in tetrahydrofuran (1.0 equiv, 0.18 M with respect to
bromoisoxazole) and cooled to 0
C in an ice bath. Lithium hydroxide (3.0 equiv, 1.0 M in water) is added and
the reaction is
allowed to stir for 30 min after which point it was transferred to a
separatory funnel with excess
water and ethyl acetate. The organic layer was extracted with saturated
ammonium chloride,
dried over sodium sulfate and evaporated to provide the desired phenol in
quantitative yield
234
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
which was used directly. The phenol (1.00 equiv) was dissolved in acetonitrile
(0.20 M with
respect to starting material) and cooled to 0 C in an ice bath. Propargyl
bromide (2.0 equiv) was
added followed by cesium carbonate (3.0 equiv). The reaction was allowed to
stir for 2h after
which it was quenched with saturated ammonium chloride and transferred to a
separatory funnel
with excess water and ethyl acetate. The organic layer was dried over sodium
sulfate and
evaporated to provide the desired racemic alkyne 1-142 which was purified by
flash silica gel
chromatography (ethyl acetate/hexanes) to provide the desired racemic compound
in 70% yield.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 279.7 m/z. Activity: A
Example 140
N N,O O N T[0 O
N\ N
O
I-143a I-143b
(1-143)
[00182] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-143a and I-143b were
prepared in
1 step from racemic compound 1-142 and 5-hydroxypyrimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 296.5 m/z. Activity: B
Example 141
McO2C N N Me02C N N0
I O \ I I O
O
I-144a I-144b
(1-144)
[00183] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-144a and I-144b were
prepared in 1
step from racemic compound 1-142 and 5-hydroxypicolinic acid methyl ester
using Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+= 353.5 m/z. Activity: A
Example 142
235
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
HO2C N N HO2C ~ 1 1 N N0
\ I I ~~ O \ I I ~~ O
O O
I-145a I-145b
(1-145)
[00184] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-145a and I-145b were
prepared in 1
step from racemic compound 1-144 using the analogous hydrolysis conditions as
in Example 94.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 338.8 m/z. Activity: A
Example 143
CO2H CO2H
N,O N ,O
\ I O bO)L' O
6 6
I-146a I-146b
(I-146)
[00185] 3-phenoxy-4,5-dihydroisoxazole I-146a and I-146b were prepared in 1
step from
racemic compound 1-61 using the analogous hydrolysis conditions as in Example
94. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M-H]-= 376.2 m/z. Activity: B
Example 144
HO2C N,O HO2C N-O,
O \ I I ~~
\ I I ~~ O
I-147a I-147b
(1-147)
[00186] 3-phenoxy-4,5-dihydroisoxazole I-147a and I-147b were prepared in 1
step from
racemic compound 1-62 using the analogous hydrolysis conditions as in Example
94. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 375.7 m/z. Activity: A
236
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 145
- N-O -
Br ' Br
Br IU Br
I-148a I-148b
(I-148)
[00187] 3-bromo-4,5-dihydroisoxazole I-148a and I-148b were prepared in 1 step
from 1-
bromo-4-vinylbenzene using Method 1. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
350.5 m/z. Activity: A
Example 146
McO2C ,, N N Mc02C ~N N,O, -
I Br D Br
O O
I-149a 1-149b
(I-149)
[00188] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-149a and I-149b were
prepared in 1
step from racemic compound 1-148 and 5-hydroxypicolinic acid methyl ester
using Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M-H]-= 378.4 m/z. Activity: A
Example 147
HO2C ;;" N N0 O HO2C ;;" N N,O,
\ I Br \ I I Br
O O
I-150a I-150b
(1-150)
[00189] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-150a and I-150b were
prepared in 1
step from racemic compound 1-149 using the analogous hydrolysis conditions as
in Example 94.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 362.6 m/z. Activity: A
Example 148
237
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
i
N N,O N YC~&OCF3
\ I C & OCF3 Me02C O Me02C \ O
1-151a I-151 b
(1-151)
[00190] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-151a and I-151b were
prepared in 1
step from racemic compound 1-14 and 4-hydroxypicolinic acid methyl ester using
Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+= 384.2 m/z. Activity: A
Example 149
N 0 O N 0
\ OCF3 OCF3
H02C O H02C \ O
I-152a I-152b
(1-152)
[00191] Racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-151 (1.0 equiv) was
dissolved
in 1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was
added. The
reaction was allowed to stir at room temperature for lh after which point the
tetrahydrofuran was
removed under a stream of nitrogen and the remaining solution was acidified to
pH<2 with IN
HC1 to provide the desired acid I-152a and I-152b as a white solid which was
isolated via
vacuum filtration. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 368.9 m/z.
Activity: A
Example 150
N,O CI CI
N,,` 'O Nv 'O
I-153a I-153b
(1-153)
[00192] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-153a and I-153b were
prepared in
2 steps 1-chloro-4-vinylbenzene using Method 1. The resulting bromo-4,5-
dihydroisoxazole
was reacted with 5-hydroxypyrimidine using Method 5. These compounds can be
separated
238
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M+H]+ = 277.3 m/z. Activity: B
Example 151
O OCF3 O OCF3
~ I N N-O \ I \ I N N'O ,. \ I
O Me O Me
I-154a I-154b
(1-154)
[00193] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-154a and I-154b were
prepared in 1
step from racemic compound 1-75 and 6-(furan-3-yl)pyridin-3-ol using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 406.3 m/z. Activity: A
Example 152
Me\\ Me\\
NN ~N \ / O NNN N,OO O Y[0 O
I-155a I-155b
(1-155)
[00194] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-155a and I-155b were
prepared from
racemic acid 1-110 according to the following procedure: in a microwave
reactor tube, acetyl
hydrazide (1.0 equiv) and acid 1-110 (1.0 equiv) were dissolved in dry
acetonitrile (0.1 M each).
Polystyrene-supported triphenylphosphine (3.0 equiv) and trichloroacetonitrile
(2.0 equiv) were
added, and the mixture was sealed and heated in a microwave reactor at 130 C
for 2 hours.
After this point the reaction was determined to be incomplete by LC/MS such
that 1.5 additional
equivalents of triphenylphosphine resin were added followed by 1.0 additional
equivalents of
trichloroacetonitrile. The vessel was resealed and heated for an additional 2h
at 130 C. On
completion, the concentrated reaction mixture was purified by flash silica gel
chromatography
(hexanes/ethyl acetate) to provide the desired racemic oxadiazole 1-155. These
compounds can
239
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+= 415.5 m/z. Activity: A
Example 153
Me Me
/-O OCF3 /- O OCF3
N%N iN I N N, N~ iN N-O
O Me pMe
I-156a I-156b
(1-156)
[00195] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-156a and I-156b were
prepared using
the analogous procedure to Example 152 except that racemic compound 1-113 was
used as the
starting acid. These compounds can be separated using chiral HPLC methods
known in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 422.0 m/z.
Activity: A
Example 154
Me Me
/-O /-O
O
OCF3
N N~ N YID-aO OCF3 N,N/ N YD-a
O O
I-157a I-157b
(1-157)
[00196] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-157a and I-157b were
prepared using
the analogous procedure to Example 152 except that racemic compound 1-97 was
used as the
starting acid. These compounds can be separated using chiral HPLC methods
known in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 407.2 m/z.
Activity: A
Example 155
240
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Me Me
g N OCF3 /-g N / OCF3
N N-O N N-O I
U I \ I `
O Me O Me
I-158a I-158b
(1-158)
[00197] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-158a and I-158b were
prepared from
racemic acid 1-113 according to the following procedure: acetyl hydrazide (1.0
equiv) and acid
1-113 (1.0 equiv) were dissolved in dry dichloromethane (0.1 M each) and
treated with EDC
(1.05 equiv) and DMAP (0.10 equiv) after which the reaction mixture was
allowed to stir at 23
C for 6h. After the reaction is complete it was diluted into a separatory
funnel with excess
dichloromethane and water and the organic layer was washed twice each with 0.5
M aqueous
citric acid and saturated aqueous sodium bicarbonate. The organic layer was
dried over
magnesium sulfate and concentrated to a white solid. This solid was dissolved
in dry THE and
1.2 equiv Lawesson's reagent is added. The mixture was sealed in a tube and
heated in a
microwave reactor at 115 C for 30 min. The concentrated reaction mixture was
purified by flash
silica gel chromatography (hexanes/ethyl acetate) to provide the desired
racemic thiadiazole I-
158. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 438.2 m/z.
Activity: A
Example 156
Me Me
\\ \\
N,N~ O N%N~
O O
YD-&O
I-159a I-159b
(1-159)
[00198] 3-phenoxy-4,5-dihydroisoxazole I-159a and I-159b were prepared using
the
analogous procedure to Example 152 except that racemic compound 1-147 was used
as the
starting acid. These compounds can be separated using chiral HPLC methods
known in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 413.6 m/z.
Activity: A
241
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 157
Me Me
N ~N
0 ,N 0 ,N
\ I N,O \ / O N,Q O
O
I-160a I-160b
(1-160)
[00199] 3-phenoxy-4,5-dihydroisoxazole I-160a and I-160b were prepared using
the
analogous procedure to Example 152 except that racemic compound 1-146 was used
as the
starting acid. These compounds can be separated using chiral HPLC methods
known in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 414.4 m/z.
Activity: A
Example 158
S
N O -
S N N' OCF3
Br ,N N-0 - C >Sn(n-Bu)3 O
1 OCF3 N S I-162a
p Pd(PPhs)a ~ N O
OCF3
1-161 N I yc~&
O
I-162b
(1-162)
[00200] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-162a and I-162b were
prepared
according to the following procedure: Racemic dihydroisoxazole I-161 was
prepared in 1 step
from compound 1-14 and 6-bromopyridin-3-ol using Method 5. Compound 1-161
placed in a
microwave vial and then dissolved in dioxane (0.02 M). 2-
(tributylstannyl)thiazole and
palladium tetrakis were added and the reaction was purged with Argon. At this
point the
reaction was heated in the microwave reactor for 20 min after which there was
no starting
material by TLC analysis. The mixture is concentrated and purified by flash
silica gel
chromatography (hexanes/ethyl acetate) to provide the desired racemic thiazole
1-162 in 50%
242
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
yield. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M-H]-= 407.3 m/z. Activity:
A
Example 159
N/ \ I O OCF3 N \ I O OCF3
O O
I-163a I-163b
(1-163)
[00201] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-163a and I-163b were
prepared using
the analogous procedure to Example 158 except that 2-(tributylstannyl)oxazole
was used in
place of 2-(tributylstannyl)thiazole. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
393.2 m/z. Activity: A
Example 160
S OCF3 S / OCF3
NUN N-O N N N-O I
p Me p Me
I-164a I-164b
(1-164)
[00202] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-164a and I-164b were
prepared using
the analogous procedure to Example 158 except that racemic compound 1-75 was
used in place
of compound 1-14 as starting material. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
423.4 m/z. Activity: A
Example 161
243
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
_ -
N HN N' N O
BocN ~
B0 O OCF3
Br N 1O - O pNc \
1\ / OCF3 \ 1-1 65a
O Pd(PPh3)4 N_
,O -
1-161 Na2CO3 HN N YI
O
CF3
O
I-165b
(1-165)
[00203] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-165a and I-165b were
prepared
according to the following procedure: racemic dihydroisoxazole I-161 and
sodium carbonate
(10.0 equiv) were placed in a microwave vial. A 2:2:1 mixture of toluene,
ethanol and water
(0.02 M with respect to 1-161) was added followed by tent-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)- 1H-pyrazole-l-carboxylateboronic acid (1.5 equiv). The
mixture was
purged with Ar for 20 min after which point palladium tetrakis (4 mol%) was
added, the reaction
was sealed and heated in an oil bath to 80 C for 17h. The reaction mixture
was then allowed to
cool after which it was transferred to a separatory funnel with excess ethyl
acetate and water.
The organic layer was washed with water and saturated sodium chloride. The
water layer was
back extracted with ethyl acetate. The organic layers were combined, dried
over sodium sulfate
and concentrated to provide a crude oil that was purified by flash silica gel
chromatography
(hexanes/ethyl acetate) to provide the desired racemic pyrazole 1-165 in 36%
yield. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 392.4 m/z. Activity: C
Example 162
~N N,O - ~N O;
\ / N,, N
o O
I-166a I-166b
(1-166)
[00204] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-166a and I-166b were
prepared in
1 step from racemic compound 1 and 5-hydroxypyrimidine using Method 5. [M-H]-=
241.5
m/z. Activity: B
244
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 163
0 OCF3 O OCF3
Me, % Me, ~/ /
N-q N-0
O Me O Me
I-167a I-167b
(1-167)
[00205] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-167a and I-167b were
prepared in
analogous fashion to compound 1-135 in example 132 except that racemic
compound 1-75 was
used as the bromo-isoxazole starting material. These compounds can be
separated using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 417.3 m/z. Activity: A
Example 164
O \ / CF3
/N I 0 O \ / CF3 N 0
N ~O N ~O
I-168a I-168b
(1-168)
[00206] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-168a and I-168b were
prepared in
2 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition
conditions from
Method 1. The resuling bromo-4,5-dihydroisoxazole was reacted with 5-
hydroxypyrimidine to
provide racemic compound 1-168 using Method 5. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 309.8 m/z. Activity: B
Example 165
Me, // Me, ~P
OS N N,O CF OS N N'O CF
3 I 3
O O
I-169a I-169b
(1-169)
245
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00207] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-169a and I-169b were
prepared in 3
steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition
conditions from Method
1. The resulting bromo-4,5-dihydroisoxazole was reacted with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation under analogous conditions to Example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 387.2 m/z. Activity: A
Example 166
HO2C N N0 O HO2C N N,O, -
\ I I CF3 I CF3
O O
I-170a I-170b
(1-170)
[00208] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-170a and I-170b were
prepared in 3
steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition
conditions from Method
5. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-
hydroxypicolinic acid methyl
ester using Method 5 followed by hydrolysis using the analogous conditions as
in example 94.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 353.0 m/z. Activity: A
Example 167
OCF3
OCF3 0-r
Q \ ~ N'O % 1 11
HO2C-CiN~N Me HO2C- i N~N~~/ Me
NJ NJ
I-171 a I-171 b
(1-171)
[00209] 1-(4,5-dihydroisoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylic acid I-
171a and I-
171b were prepared using the analogous procedure to Example 35 except that
racemic
compound 1-75 was used as the starting bromo-isoxazole and 1H-1,2,4-triazole-3-
carboxylic
acid methyl ester as the nucleophile Additionally, at some point during the
course of the reaction
or workup, the ester hydrolyzed to the corresponding acid. These compounds can
be separated
246
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M-H]-= 356.6 m/z. Activity: C
Example 168
OCF3 / OCF3
C N N N'O N N N'O
O Me O Me
I-172a I-172b
(1-172)
[00210] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-172a and I-172b were
prepared in 1
step from racemic compound 1-75 and pyrazolo[1,5-a]pyridin-2-ol using Method
5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 378.1 m/z. Activity: C
Example 169
N ~N YID0 - OCF N I ~N NO- OCF
H 3 H 3
~ O O
I-173a I-173b
(1-173)
[00211] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-173a and I-173b were
prepared using
the analogous procedure as Example 161 except that tent-butyl 2-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrrole-l-carboxylate was used in place of tent-butyl 4-
(4,4,5,5-
tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole-l-carboxylate. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 390.6 m/z. Activity: A
Example 170
247
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
N=N N=N
N IN NH N "I NH
\ N,O OCF3 N~O. OCF3
O O
I-174a I-174b
(1-174)
[00212] 3-phenoxy-4,5-dihydroisoxazole I-174a and I-174b were prepared in 1
step from
racemic compound 1-14 and 3-(1H-tetrazol-5-yl)phenol using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 392.3 m/z. Activity: B
Example 171
N-NH N-NH
N N~ N`N/ N~O-. OCF3
O Y[uOCF3 O
I-175a I-175b
(1-175)
[00213] 3-phenoxy-4,5-dihydroisoxazole I-175a and I-175b were prepared in 1
step from
racemic compound 1-14 and 4-(1H-tetrazol-5-yl)phenol using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 391.6 m/z. Activity: B
Example 172
COZH CO2H
\ ~ ~OCF3 \ I-176a I-176b
(1-176)
[00214] 3-phenoxy-4,5-dihydroisoxazole I-176a and I-176b were prepared in 2
steps from
racemic compound 1-14. Bromo-4,5-dihydroisoxazole 1-14 was reacted with 3-
hydroxybenzoic acid methyl ester using Method 5 followed by hydroysis using
the analogous
conditions as in example 94. [M+H]+ = 368.0 m/z. Activity: C
248
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 173
HO2C / N,O - HO2C N-O, -
\ I OCF3 OCF3
O O
I-177a I-177b
(1-177)
[00215] 3-phenoxy-4,5-dihydroisoxazole I-177a and I-177b were prepared in 2
steps from
racemic compound 1-14. Bromo-4,5-dihydroisoxazole 1-14 was reacted with 4-
hydroxybenzoic acid methyl ester using Method 5 followed by hydroysis using
the analogous
conditions as in Example 94. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 368.0 m/z.
Activity: B
Example 174
NC N NNC N NOO O
I-178a I-178b
(1-178)
[00216] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-178a and I-178b were
prepared in 2
steps from racemic compound 1-14 and 5-hydroxypicolinonitrile using Method 5
after 5-
hydroxypicolinonitrile was prepared from 5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-
yl)picolinonitrile using Method 11. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
350.0 m/z. Activity: B
Example 175
O N-O,
Br I Me Br Me
I-179a I-179b
(1-179)
249
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00217] 3-bromo-4,5-dihydroisoxazole I-179a and I-179b were prepared in 1 step
from 1-
pentyl-4-vinylbenzene using Method 1. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
283.6 m/z. Activity: A
Example 176
Yj ~M e YI:'j
Nom/ 'O
Nom/ 'O
I-180a I-180b
(1-180)
[00218] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-180a and I-180b were
prepared in
1 step from racemic compound 1-179 and 5-hydroxypyrimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 298.7 m/z. Activity: A
Example 177
Me- N 0 O - Me- N NO -
O Me j, Me
O
I-181 a I-181 b
(I-181)
[00219] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-181a and I-181b were
prepared in 2
steps from racemic compound 1-179 by first reacting 1-179 with 6-
(methylthio)pyridin-3-ol
(synthesized from 6-(methylthio)pyridin-3-ylboronic acid using Method 11)
using Method 5
followed by oxidiation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 375.4 m/z. Activity: A
Example 178
250
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
0 0
Et- N O Eta /i N O, -
jJtj__~_oc F30 \ I N~ OCF3
O O
I-182a I-182b
(1-182)
[00220] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-182a and I-182b were
prepared in 2
steps from racemic compound 1-14 by first reacting 1-14 with 6-
(ethylthio)pyridin-3-ol
(synthesized from 6-(ethylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidiation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 417.1 m/z. Activity: A
Example 179
N O 01 P/ N Q
0 N- 0 CF3 0 N~ O O
I-183a I-183b
(1-183)
[00221] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-183a and I-183b were
prepared in 2
steps from racemic compound 1-14 by first reacting 1-14 with 6-
(cyclopentylthio)pyridin-3-ol
(synthesized from 6-(cyclopentylthio)pyridin-3-ylboronic acid using Method 11)
using Method
followed by oxidation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 456.8 m/z. Activity: B
Example 180
O O
Me O N- OCF3 Me O \ I N OCF3
O O
I-184a I-184b
(1-184)
251
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00222] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-184a and I-184b were
prepared in 2
steps from racemic compound 1-14 by first reacting 1-14 with 6-(iso-
butylthio)pyridin-3-ol
(synthesized from 6-(iso-butylthio)pyridin-3-ylboronic acid using Method 11)
using Method 5
followed by oxidation under analogous conditions to Example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 444.7 m/z. Activity: B
Example 181
O OCF3 O OCF3
N ~ <1or><9'
p I-185a I-185b
(1-185)
[00223] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-185a and I-185b were
prepared using
the analogous procedure to Example 178 except that racemic compound 1-75 was
used in place
of compound 1-75 as starting material and 2-(tributylstannyl)oxazole was used
in place of 2-
(tributylstannyl)thiazole (as in Example 158). These compounds can be
separated using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 407.2 m/z. Activity: A
Example 182
/O I N 0 O OCF3 101 UN O OCF
O O
I-186a 1-1 86b
(1-186)
[00224] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-186a and I-186b were
prepared using
the analogous procedure as Example 161 except that 2-furylboronic acid was
used in place of
tent-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-l-
carboxylate.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 392.2 m/z. Activity: A
252
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 183
Me
I N O - Me N O, a
O
j \ OCF3 O I N' OCF3
O O
I-187a I-187b
(1-187)
[00225] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-187a and I-187b were
prepared using
the analogous procedure as Example 161 except that 5-methylfuran-2-ylboronic
acid was used
in place of tent-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole-l-
carboxylate. These compounds can be separated using chiral HPLC methods known
in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 406.3 m/z.
Activity: A
Example 184
_
HO2C O N 0 O HO
OCF3 2C O N I yO \ OCF3
O O
I-188a I-188b
(1-188)
[00226] The enantioners of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 1-188a and
1-188b
were prepared using the analogous procedure as Example 161 except that 5-
boronofuran-2-
carboxylic acid was used in place of tent-butyl 4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-
yl)-1H-pyrazole-l-carboxylate. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
435.5 m/z. Activity: C
Example 185
N I O _ N N Q 3
Me U,N N' \ OCF3 Me I N' \ OCF3
O O
I-189a I-189b
(1-189)
253
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00227] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-189a and I-189b were
prepared using
the analogous procedure as Example 161 except that 1-methyl-5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)- 1H-pyrazole was used in place of tent-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)- 1H-pyrazole-l-carboxylate. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 406.2 m/z. Activity: A
Example 186
Me Me
N N N 0 O Y_~I_OCF3 Me ~
O O
I-190a I-190b
(1-190)
[00228] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-190a and I-190b were
prepared using
the analogous procedure as Example 161 except that 1,3-dimethyl-lH-pyrazol-5-
ylboronic
acid was used in place of tent-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1H-
pyrazole-l-carboxylate. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ =
419.4 m/z.
Activity: A
Example 187
F3C F3C
NN N 0 O OCF NN I UN 0 OCF
Me O 3 Me O 3
I-191 a I-191 b
(I-191)
[00229] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-191a and I-191b were
prepared using
the analogous procedure as Example 161 except that 1-methyl-3-
(trifluoromethyl)-1H-
pyrazol-5-ylboronic acid was used in place of tent-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)- 1H-pyrazole-l-carboxylate. These compounds can be
separated using
254
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 473.3 m/z. Activity: C
Example 188
NHI 'IN 0 O OCF3 NHI UN 0
O OCF3
O O
I-192a I-192b
(1-192)
[00230] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-192a and I-192b were
prepared using
the analogous procedure as Example 161 except that 1H-pyrazol-5-ylboronic acid
was used in
place of tent-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole-l-
carboxylate. These compounds can be separated using chiral HPLC methods known
in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 391.4 m/z.
Activity: A
Example 189
HO2C S ~"N I Tc0 \ / OCF3 HO2C S ,N N"Q OCF3
O O
I-193a I-193b
(1-193)
[00231] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-193a and I-193b were
prepared using
the analogous procedure as Example 161 except that 5-boronothiophene-2-
carboxylic acid was
used in place of tent-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
pyrazole-l-
carboxylate. These compounds can be separated using chiral HPLC methods known
in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 450.6 m/z.
Activity: B
Example 190
255
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
N_
OCF3
O / O B'O N O
%
Br N N,O O YD-a
\ I OCF3 I-194a
0 PdC12(dppf)-CH2CI2 N-
1-161 K3PO4 O iN N- _ OCF
YID
3
O
I-194b
(1-194)
[00232] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-194a and I-194b were
prepared
according to the following procedure: racemic dihydroisoxazole I-161, tribasic
potassium
phosphate (3.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)isoxazole (1.2 equiv),
and the palladium catalyst (10 mol %) were placed in a microwave vial. Dioxane
(0.1 M with
respect to I-161) was added and the mixture was purged with Ar for 20 min
after which point the
reaction was sealed and heated in an oil bath to 85 C for 17h. The reaction
mixture was then
allowed to cool after which it was transferred to a separatory funnel with
excess ethyl acetate and
water. The organic layer was washed with water and saturated sodium chloride.
The water layer
was back extracted with ethyl acetate. The organic layers were combined, dried
over sodium
sulfate and concentrated to provide a crude oil that was purified by flash
silica gel
chromatography (hexanes/ethyl acetate) to provide the desired racemic pyrazole
1-194 in <5%
yield. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M+H]+= 392.2 m/z. Activity:
A
Example 191
IN- N ,N' N
N`H ~N I O OCF3 N`H 1 N NO, OCF
\ o ~ / \ o 3
I-195a I-195b
(I-195)
[00233] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-195a and I-195b were
prepared
according to the following procedure: racemic dihydroisoxazole 1-178 (1.0
equiv) was dissolved
in N,N-dimethylforamide (0.1 M with respect to isoxazole) after which ammonium
chloride (3.1
256
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
equiv) and sodium azide (1.5 equiv) were added. The reaction was then heated
in an oil bath to
120 C for 4h after which point it the reaction was transferred to a
separatory funnel with excess
ethyl acetate and water. The organic layer was washed with water and saturated
sodium
chloride, dried over sodium sulfate and concentrated to provide a crude oil
that was purified by
flash silica gel chromatography (hexanes/ethyl acetate) to provide the desired
racemic tetrazole
1-195. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 393.2 m/z.
Activity: A
Example 192
O OCF3 O OCF3
Eta Eta
N N
N_O \ ,S N-O
O Me O Me
I-196a I-196b
(1-196)
[00234] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-196a and I-196b were
prepared in 2
steps from racemic compound 1-75 by first reacting 1-75 with 6-
(ethylthio)pyridin-3-ol
(prepared from 6-(ethylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 431.3 m/z. Activity: A
Example 193
O O
Me, '/ Me, ii
S N N0 O S N ):U
O O
I-197a I-197b
(1-197)
[00235] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-197a and I-197b were
prepared in 2
steps from racemic compound 1-10 by first reacting 1-10 with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidiation under analogous conditions to example 130. These
compounds can be
257
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 411.4 m/z. Activity: A
Example 194
N OCF3 N OCF3
CN N CN N
N NI-0
0_'I
Me O Me
I-198a I-198b
(1-198)
[00236] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-198a and I-198b were
prepared in 1
step from racemic compound 1-75 and 6-(1H-pyrazol-1-yl)pyridin-3-ol using
Method 5 after
6-(1H-pyrazol-1-yl)pyridin-3-ol was synthesized from 2-(1H-pyrazol-l-yl)-5-
(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine using Method 11. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 405.3 m/z. Activity: A
Example 195
Me Me
N N
NN O N, O
\ I YID-&OCF3 O N,0," OCF3
O O
I-199a I-199b
(1-199)
[00237] 3-(phenoxy)-4,5-dihydroisoxazole I-199a and I-199b were prepared in 1
step from
racemic compound 1-14 and 3-(3-methyl-1,2,4-oxadiazol-5-yl)phenol using Method
5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 406.3 m/z. Activity: C
258
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 196
N=N N=N
Me-N, Me-N O
N ~ I N:UOCF3 N I ri_OCF3
O O
I-200a I-200b
(1-200)
[00238] 3-(Phenoxy)-4,5-dihydroisoxazole I-200a and I-200b were prepared in 1
step from
racemic compound 1-14 and 4-(2-methyl-2H-tetrazol-5-yl)phenol using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 406.4 m/z. Activity: B
Example 197
//-O //-O
OYID0
N N~ OCF3 N NYD-&OCF3
O O
I-201 a I-201 b
(1-201)
[00239] 3-(phenoxy)-4,5-dihydroisoxazole I-201a and I-201b were prepared in 1
step from
racemic compound 1-14 and 4-(1,3,4-oxadiazol-2-yl)phenol using Method 5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 392.2 m/z. Activity: A
Example 198
- - O
NO - O N O,
Br Br 0 0
-202a 0 I-202b 0
(1-202)
[00240] 3-bromo-4,5-dihydroisoxazole I-202a and I-202b were prepared in 2
steps
according to the following procedure: 4-vinylbenzoyl chloride (1.0 equiv) was
dissolved in
methylene chloride (0.375 M with respect to styrene) after which morpholine
(3.0 equiv) is
added. The reaction is allowed to stir at room temperature for 14h during
which time a white
259
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
precipitate began to form. The reaction was then transferred to a separatory
funnel with excess
water and methylene chloride. The organic layer was washed with water (lx), IN
HC1 (lx),
saturated sodium bicarbonate (lx) and brine (lx) after which point it was
dried over sodium
sulfate and concentrated to provide a yellow oil. This crude material was then
directly used to
form the desired racemic bromoisoxazole using Method 1. These compounds can be
separated
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M+H]+ = 338.7 m/z. Activity: B
Example 199
N-O O O
N-O,
Br I N-Me Br N-Me
Me Me
I-203b I-203b
(1-203)
[00241] 3-bromo-4,5-dihydroisoxazole I-203a and I-203b were prepared using the
analogous procedure as Example 198 except that dimethyl amine in
tetrahydrofuran (2.0 M) was
used in place of morpholine. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 299.3 m/z.
Activity: A
Example 200
N,O O N- O
Br I \ / HN-Me Br I \ / HN-Me
I-204a I-204b
(1-204)
[00242] 3-bromo-4,5-dihydroisoxazole I-204a and I-204b were prepared using the
analogous procedure as Example 198 except that methyl amine in tetrahydrofuran
(2.0 M) was
used in place of morpholine. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 282.6 m/z.
Activity: B
260
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 201
NO O, _ O N,O I I
, -N O
Br O \--/ Br I 11 c/
I-205a I-205b
(1-205)
[00243] 3-bromo-4,5-dihydroisoxazole I-205a and I-205b were prepared in 2
steps
according to the following procedure: 4-vinylbenzene-l-sulfonyl chloride (1.0
equiv) was
dissolved in methylene chloride (0.50 M with respect to styrene) after which
morpholine (3.0
equiv) is added. The reaction is allowed to stir at room temperature 90 min
after which point it
was transferred to a separatory funnel with excess water and methylene
chloride. The organic
layer was washed with water (lx), IN HC1 (lx), saturated sodium bicarbonate
(lx) and brine
(lx) after which point it was dried over sodium sulfate and concentrated to
provide a yellow oil.
This crude material was then directly used to form the desired racemic
bromoisoxazole using
Method 1. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 374.6 m/z.
Activity: A
Example 202
,O a 0 Me
O 0 Me YI-
S S
-N
Br O Me Br o Me
I-206a I-206b
(1-206)
[00244] 3-bromo-4,5-dihydroisoxazole I-206a and I-206b were prepared using the
analogous procedure as Example 201 except that dimethyl amine in THE (2.0 M)
was used in
place of morpholine. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 332.6
m/z. Activity:
A
Example 203
O O Me O - O Me
S-NH N S-NH
Br O Br O
I-207a I-207b
261
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1-207)
[00245] 3-bromo-4,5-dihydroisoxazole I-207a and I-207b were prepared using the
analogous procedure as Example 201 except that methyl amine in THE (2.0 M) was
used in
place of morpholine. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 318.6
m/z. Activity:
A
Example 204
N0 O - O N,O,
Br N~ Br N~
I-208a I-208b
(1-208)
[00246] 3-bromo-4,5-dihydroisoxazole I-208a and I-208b were prepared using the
analogous procedure as Example 198 except that piperidine was used in place of
morpholine.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 339.3 m/z. Activity: A
Example 205
N-O O N-O, O
Br N~ Br N~
I-209a v I-209b v
(1-209)
[00247] 3-bromo-4,5-dihydroisoxazole I-209a and I-209b were prepared using the
analogous procedure as Example 198 except that pyrrolidine was used in place
of morpholine.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 322.6 m/z. Activity: A
Example 206
262
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
S-ND D
Br O Br O
I-210a I-210b
(1-210)
[00248] 3-bromo-4,5-dihydroisoxazole I-210a and I-210b were prepared using the
analogous procedure as Example 201 except that piperidine was used in place of
morpholine.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 472.6 m/z. Activity: A
Example 207 - 11
O O ,,
II- N0 I --a S -NC]
I
Br Br
r
I-211 a I-211 b
(1-211)
[00249] 3-bromo-4,5-dihydroisoxazole I-211a and I-211b were prepared using the
analogous procedure as Example 201 except that pyrrolidine was used in place
of morpholine.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 358.6 m/z. Activity: A
Example 208
Me.// N N,O O Me~s~ N N0 O -
O N-Me O C I O N-Me
Me Me
I-212a I-212b
(1-212)
[00250] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-212a and I-212b were
prepared in 2
steps from racemic compound 1-203 by first reacting 1-203 with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 390.4 m/z. Activity: B
263
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 209
m e . Me.// N 0 O Me
S-N O I I \ S-N
O O Me O O Me
I-213a I-213b
(1-213)
[00251] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-213a and I-213b were
prepared in 2
steps from racemic compound 1-202 by first reacting 1-202 with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 426.2 m/z. Activity: A
Example 210
me. / N N,O O '' Me. ~~
N O O
OS \ N'
H\ / HN
LJO,L)N>'
O
I-214a I-214b
(1-214)
[00252] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-214a and I-214b were
prepared in 2
steps from racemic compound 1-21 by first reacting 1-21 with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 352.2 m/z. Activity: A
Example 211
HO2C N N'O O HO2C N ~0% O
O HN O HN
I-215a I-215b
264
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1-215)
[00253] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-215a and I-215b were
prepared in 2
steps compound from racemic compound 1-21. Bromo-4,5-dihydroisoxazole 1-21 was
reacted
with 5-hydroxy picolinic acid methyl ester using Method 5 followed by
hydrolysis using the
analogous conditions as in example 94. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
418.3 m/z. Activity: B
Example 212
Br N N-
Br N YID 0
CF3 -CF3
O O
I-216a I-216b
(1-216)
[00254] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-216a and I-216b were
prepared in 2
steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition
conditions from Method
1. The resulting bromo-4,5-dihydroisoxazole was reacted with 2-bromo-5-
hydroxypyridine
using Method 5 to provide racemic compound 1-216. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 389.1 m/z. Activity: B
Example 213
O 11N O ~N
O
\ N/ / CF3 \ ;Ile NOO O
I-217a I-217b
(1-217)
[00255] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-217a and I-217b were
prepared using
the analogous procedure as Example 212 except that 3-(1,3,4-oxadiazol-2-
yl)phenol was used
in place of 2-bromo-5-hydroxypyridine. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
376.4 m/z. Activity: A
265
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 214
Me Me
N N
N I ~N O OCF N I N N,O, - OCF
3 I / 3
O
O yc~& I-218a I-218b
(1-218)
[00256] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-218a and I-218b were
prepared using
the analogous procedure as Example 161 except that 1-methyl-4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole was used in place of tent-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)- 1H-pyrazole-l-carboxylate. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 404.8 m/z. Activity: A
Example 215
Me Me
N N
N ~N N,O - N I ~N NOCF3 CF3
O O
I-219a I-219b
(1-219)
[00257] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-219a and I-219b were
prepared using
the analogous procedure as Example 161 except that 1-methyl-4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole was used in place of tent-butyl 4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)- 1H-pyrazole-l-carboxylate and racemic bromopyridine 1-216
was used as
the starting material rather than 1-161. These compounds can be separated
using chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
390.3 m/z. Activity: A
Example 216
266
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Me. ~/ O Me. ~0 O
S`N QN O OCF S`N N N'O - OCF
O O
I-220a I-220b
(1-220)
[00258] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-220a and I-220b were
prepared
according to the following procedure: acid 1-97 (1.0 equiv) was dissolved in
methylene chloride
(0.08 M). Oxalyl chloride (1.5 equiv was added) followed by the addition of 1
drop of N,N-
dimethylforamide. The reaction was stirred at room temperature for 20 min
after which it was
concentrated under vacuum. The crude material was then redissolved in
methylene chloride after
which methanesulfonamide (1.2 equiv), DMAP (10 mol%) and triethylamine (1.5
equiv) were
added. After 3h, the reaction was determined to be complete by LC/MS analysis.
The reaction
mixture was then transferred to a separatory funnel with excess ethyl acetate
and water. The
organic layer was washed with IN HC1 and brine, drive over sodium sulfate and
concentrated
under vacuum to provide the desired sulfonamide. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 446.1 m/z. Activity: A
Example 217
N -N\\\\ N - N\\\\
N N
\ I N,O
. OCF3
O O
O
I-221 a I-221 b
(1-221)
[00259] 3-(phenoxy)-4,5-dihydroisoxazole I-221a and I-221b were prepared in 1
step from
racemic compound 1-14 and 3-(4H-1,2,4-triazol-4-yl)phenol using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 392.0 m/z. Activity: C
Example 218
267
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Me Me
N N
O OCF3 O , N OCF3
N-0,: / I 1N~O~
O Me & O'v Me
I-222a I-222b
(1-222)
[00260] 3-(phenoxy)-4,5-dihydroisoxazole I-222a and I-222b were prepared in 3
steps
according to the following procedures: 3-hydroxy benzoic acid methyl ester is
reacted with
racemic bromoisoxazole 1-75 using Method 5. The resulting methyl ester (1.0
equiv) is
dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight
in water) is
added and the reaction is allowed to stir for 14h. The reaction mixture is
then concentrated under
vacuum and used directly in the next step. Triethylorthoacetate (8.0 equiv) is
added and the
reaction is sealed and heated to reflux for 14h. The reaction is then
transferred to a separatory
funnel with excess ethyl acetate and water. The organic layer was washed water
and brine, drive
over sodium sulfate and concentrated under vacuum to provide crude material
which was
purified using flash silica gel chromatography (gradient ethyl
acetate/hexanes) to provide the
desired racemic oxadiazole 1-222. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
420.5 m/z. Activity: A
268
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 219
Me Me
N N
N
O ,N O &Zz~hlo
\ I 0 O OCF3 OOCF3
O I-223a I-223b
(1-223)
[00261] 3-(phenoxy)-4,5-dihydroisoxazole I-223a and I-223b were prepared using
the
analogous procedure as Example 218 except that racemic compound I-15 was used
in place of
compound 1-75 as starting material. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
406.5 m/z. Activity: A
Example 220
Me Me
O , O ,N
\ I 0 O OCF3 \ I O' \ / OCF3
F O F O
I-224a I-224b
(1-224)
[00262] 3-(phenoxy)-4,5-dihydroisoxazole I-224a and I-224b were prepared in 3
steps
according to the following procedures: 3-fluoro-5-hydroxybenzoic acid methyl
ester is reacted
with racemic bromoisoxazole 1-14 using Method 5. The resulting methyl ester
(1.0 equiv) is
dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight
in water) is
added and the reaction is allowed to stir for 14h. The reaction mixture is
then concentrated under
vacuum and used directly in the next step. Triethylorthoacetate (8.0 equiv) is
added and the
reaction is sealed and heated to reflux for 14h. The reaction is then
transferred to a separatory
funnel with excess ethyl acetate and water. The organic layer was washed water
and brine, drive
over sodium sulfate and concentrated under vacuum to provide crude material
which was
purified using flash silica gel chromatography (gradient ethyl
acetate/hexanes) to provide the
desired racemic oxadiazole 1-224. These compounds can be separated using
chiral HPLC
269
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
424.5 m/z. Activity: A
Example 221
O XN O XIN
O
OCF3
\ I 0 O OCF3 \ I YID-a
F O F O
I-225a I-225b
(1-225)
[00263] 3-(phenoxy)-4,5-dihydroisoxazole I-225a and I-225b were prepared using
the
analogous procedure as Example 220 except that triethylorthoformate was used
in place of
triethylorthoacetate to form the desired oxadiazole. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 410.3 m/z. Activity: A
Example 222
O "IN O ~N
F \ I 0 O OCF3 F \ O OCF3
O O
I-226a I-226b
(1-226)
[00264] 3-(phenoxy)-4,5-dihydroisoxazole I-226a and I-226b were prepared using
the
analogous procedure as Example 220 except that 4-fluoro-5-hydroxybenzoic acid
methyl ester
was used in place of 3-fluoro-5-hydroxybenzoic acid methyl ester in the first
step. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 410.4 m/z. Activity: A
Example 223
270
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
O N OCF3 O N OCF3
F F
/ I N-Q, 1N-O
O Me O'v Me
I-227a I-227b
(1-227)
[00265] 3-(phenoxy)-4,5-dihydroisoxazole I-227a and I-227b were prepared using
the
analogous procedure as Example 222 except that racemic compound 1-75 was used
in place of
compound 1-14 as starting material. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
424.2 m/z. Activity: A
Example 224
fN iN
O N OCF3 O N OCF3
N-Q N-0
N O Me N O Me
I-228a I-228b
(1-228)
[00266] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-228a and I-228b were
prepared in 3
steps according to the following procedures: 5-hydroxynicotinic acid methyl
ester is reacted
with racemic bromoisoxazole 1-75 using Method 5. The resulting methyl ester
(1.0 equiv) is
dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight
in water) is
added and the reaction is allowed to stir for 14h. The reaction mixture is
then concentrated under
vacuum and used directly in the next step. Triethylorthoformate (8.0 equiv) is
added and the
reaction is sealed and heated to reflux for 14h. The reaction is then
transferred to a separatory
funnel with excess ethyl acetate and water. The organic layer was washed water
and brine, drive
over sodium sulfate and concentrated under vacuum to provide crude material
which was
purified using flash silica gel chromatography (gradient ethyl
acetate/hexanes) to provide the
desired racemic oxadiazole 1-228. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
407.5 m/z. Activity: A
271
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 225
Me Me
N N
O &~" N OCF3 O N OCF3
N-Q, N-0
O Me N O~ Me
I-229a I-229b
(1-229)
[00267] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-229a and I-229b were
prepared using
the analogous procedure as Example 224 except that triethylorthoacetate was
used in place of
triethylorthoformate to form the desired oxadiazole. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 422.0 m/z. Activity: A
Example 226
fN ~N
N
0 O OCF3 O OCF3
O&,"*,' N O&z,
O O
I-230a I-230b
(1-230)
[00268] 3-(phenoxy)-4,5-dihydroisoxazole I-230a and I-230b were prepared using
the
analogous procedure as Example 224 except that racemic compound 1-14 was used
in place of
compound 75 as starting material. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
393.2 m/z. Activity: A
Example 227
272
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
0 0
NH NH
O ZN OCF3 O N OCF3
N-ON,O
O Me N O Me
I-231 a I-231 b
(1-231)
[00269] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-231a and I-231b were
prepared in 3
steps according to the following procedures: 5-hydroxynicotinic acid methyl
ester is reacted
with racemic bromoisoxazole 1-75 using Method 5. The resulting methyl ester
(1.0 equiv) is
dissolved in methanol (0.08 M) after which hydrazine (50 equiv, 50% by weight
in water) is
added and the reaction is allowed to stir for 14h. The reaction mixture is
then concentrated under
vacuum and used directly in the next step. The hydrazide is dissolved in
dioxane (0.12 M with
respect to hydrazide). N,N-Carbonydiimidazole (1.2 equiv) is added and the
reaction is sealed
and heated to reflux for 4h. The reaction is then transferred to a separatory
funnel with excess
ethyl acetate and water. The organic layer was washed water and brine, drive
over sodium
sulfate and concentrated under vacuum to provide crude material which was
purified using flash
silica gel chromatography (gradient methanol/dichloromethane) to provide the
desired racemic
1,3,4-oxadiazol-2(3H)-one 1-231. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
423.4 m/z. Activity: B
Example 228
N f -- N
O N OCF3 O N OCF3 loll / I N-Q; j-- -O~
O Me OMe
I-232a I-232b
(1-232)
[00270] 3-(phenoxy)-4,5-dihydroisoxazole I-232a and I-232b were prepared in 1
step from
racemic compound 1-75 and 4-(1,3,4-oxadiazol-2-yl)phenol using Method 5. These
273
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 406.5 m/z. Activity: A
Example 229
Me, N' Me Me, N' Me
O=S=0 / I OCF3 O=S=0 / I OCF3
10) Me 6'~'O'U-'Me
I-233a I-233b
(1-233)
[00271] 3-(phenoxy)-4,5-dihydroisoxazole I-233a and I-233b were prepared in 1
step from
racemic compound 1-75 and 3-hydroxy-N,N-dimethylbenzenesulfonamide using
Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 445.4 m/z. Activity: C
Example 230
OCF3 OCF3
Me,s~ Me~s~
NQ O \ I N0
0 Me O~v Me
I-234a I-234b
(1-234)
[00272] 3-(phenoxy)-4,5-dihydroisoxazole I-234a and I-234b were prepared in 1
step from
racemic compound 1-75 and 4-(methylsulfonyl)phenol using Method 5. These
compounds can
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 415.6 m/z. Activity: B
Example 231
Me OCF3 Me OCF3
õ~
Me' OS NO Me OS \ IO
Me I;'v~_
O Me
I-235a I-235b
274
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1-235)
[00273] 3-(phenoxy)-4,5-dihydroisoxazole I-235a and I-235b were prepared in 1
step from
racemic compound 1-75 and 4-hydroxy-N,N-dimethylbenzenesulfonamide using
Method 5.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 445.3 m/z. Activity: C
Example 232
,N-NH
1) - SiMe3 N N N,O OCF3
Pd(PPh3)4 O
Br ,,N Tc0 - Cul, DIEA
OCF3 I-236a N-NH
O 2) K2CO3 1,
3) TMSN3, mw N YID
O1-161 OCF3
O
I-236b
(1-236)
[00274] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-236a and I-236b were
prepared in 3
steps according to the following procedures: racemic dihydroisoxazole I-161
(1.0 equiv) was
dissolved in N,N-dimethylforamide (0.1 M). Copper iodide (1.0 equiv) was added
followed by
trimethylsilylacetylene (3.0 equiv) and N,N-diisopropyl ethylamine (2.0
equiv). Palladium
tetrakis (15 mol%) was added and the reaction was sealed and heated in a
microwave reactor at
100 C for lh. The reaction was allowed to cool after which it was transferred
to a separatory
funnel with ethyl acetate and water. The organic layer was then washed with
water and brine,
dried over sodium sulfate, concentrated and purified by flash silica gel
chromatography (gradient
ethyl acetate/hexanes). The TMS group was then deprotected by dissolving this
material in
methanol (0.07 M) and adding potassium carbonate (3.0 equiv). After stirring
for 4h at room
temperature, the reaction was transferred a separatory funnel with ethyl
acetate and water. The
organic layer was then washed with water and brine, dried over sodium sulfate,
concentrated and
purified by flash silica gel chromatography (gradient ethyl acetate/hexanes).
The resulting
alkyne was then converted to the desired triazole by first dissolving it in
neat trimethyl silylazide
(80 equiv), purging the reaction mixture with Argon and heating in a microwave
reactor to 110
C for 3h. After an additional 4h of heating the reaction was 60% complete by
LC/MS analysis
275
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
at which point it was concentrated and purified directly by flash silica gel
chromatography
(gradient methanol/methylene chloride) to provide the desired racemic triazole
1-236. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 392.9 m/z. Activity: A
Example 233
Me, /P Me, /P
S U11 N N0 O S N Y:U Br O \ Br
O
O
I-237a I-237b
(1-237)
[00275] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-237a and I-237b were
prepared in 2
steps from racemic compound 1-148 by first reacting 1-148 with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation under analogous conditions to example 130. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 396.6 m/z. Activity: A
Example 234
MeS .,N N,O - MeS N N,O; -
I CF3 \ I CF3
O O
I-238a I-238b
(1-238)
[00276] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-238a and I-238b were
prepared in 2
steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition
conditions from Method
1. The resulting bromo-4,5-dihydroisoxazole was reacted with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5 to
provide compound 1-238. These compounds can be separated using chiral HPLC
methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 355.3 m/z.
Activity: A
276
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 235
Me, OCF3
Me N Q,
Br Me]-McMeMe N-N O N,
Me
N + O, B ~O Pd(PPh3)4 75
Me I-240a
OCF3
Na2CO3 N Method 5 N a'~
OH N-N N N N,O Me OH I
1-239 p Me
I-240b
(1-240)
[00277] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-240a and I-240b were
prepared in 2
steps according to the following procedures: 6-bromopyridin-3-ol (1.0 equiv)
and sodium
carbonate (10.0 equiv) are added to a microwave vial. Toluene, ethanol, and
water (0.16 M,
2:2:1 v/v) are added followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-
1H-pyrazole (1.5 equiv). The mixture is purged with argon for 15 min followed
by the addition
of palladium tetrakis (4 mol%). The reaction tube is then covered with
aluminum foil and heated
to 80 C in an oil bath for 17h. After cooling the reaction was transferred to
a separatory funnel
with excess water and ethyl acetate. The organic layer was then washed with
water (lx),
saturated ammonium chloride (lx) and brine (lx). The aqueous layers were
combined and
washed with ethyl acetate (lx). The organic layers were then combined, dried
over sodium
sulfate, concentrated and purified using flash silica gel chromatography
(gradient
methanol/methylene chloride) to provide 6-(1-methyl-lH-pyrazol-4-yl)pyridin-3-
ol 1-239 as
a white solid. This compound is then reacted with racemic 3-bromo-4,5-
dihydroisoxazole 1-75
using Method 5 to provide the desired racemic compound 1-240. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 419.3 m/z. Activity: A
277
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 236
OCF3 CFN'I NUN
1-241a 1-241b
(1-241)
[00278] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-241a and I-241b were
prepared using
the analogous procedure as Example 235 except that 1-methyl-5-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)- 1H-pyrazole was used in place of 1-methyl-4-(4,4,5,5-
tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole as the boronoate in the first step. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 406.2 m/z. Activity: A
Example 237
OCF3 OCF3
N~ N N~ I N
N I N-R N-O Q
H H
O Me O Me
I-242a I-242b
(1-242)
[00279] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-242a and I-242b were
prepared using
the analogous procedure as Example 188 except that racemic compound 1-75 was
used in place
of compound 1-14 as starting material. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
406.3 m/z. Activity: A
Example 238
N,0
N-O 9
HN I O HO -' - I \ / O
H H
I-243a I-243b
(1-1243)
278
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00280] 2-(4,5-dihydroisoxazol-3-ylamino)ethanol I-243a and I-243b were
prepared in 2
steps according to the following procedures: racemic 3-bromo-4,5-
dihydroisoxazole 1-10 (1.0
equiv) was dissolved in n-butanol (0.57 M) followed by the addition of (tert-
butyldimethylsilyloxy)methanamine (1.2 equiv) and sodium carbonate (2.5
equiv). The reaction
was sealed and heated in a microwave reaction for lh at 150 C after which
point there was very
little product formation by LC/MS analysis. The reaction was then resealed and
heated for an
additional 24h at 120 C in the microwave after which it was transferred to a
separatory funnel
with excess water and tert-butylmethyl ether. The aqueous layer was washed
with tert-
butylmethyl ether (2x) and the combined organic layers were washed with brine,
dried over
magnesium sulfate and concentrate to provide a orange solid that was purified
using flash silica
gel chromatography (gradient ethyl acetate/hexane) to provide the desired
silyl ether. This
compound (1.0 equiv) was then dissolved in methanol (0.02 M) and cooled to 0
C in an ice bath.
Acetyl chloride (50 equiv) was added dropwise after which the reaction was
allowed to stir for
30 min at 0 C. The solvent and remaining acetyl chloride was then removed
under a stream of
nitrogen after which the crude material was purified by flash silica gel
chromatography (gradient
ethyl acetate/ methanol) to provide racemic 1-243. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 300.2 m/z. Activity: B
Example 239
Br S I \ Br S I \
II-7a II-7b
(1-244)
[00281] 2-((4,5-dihydroisoxazol-3-yl)(methyl)amino)acetic acid I-244a and I-
244b were
prepared in 2 steps according to the following procedure: racemic 3-bromo-4,5-
dihydroisoxazole 1-10 was converted to the corresponding 3-amino-4,5-
dihydroisoxazole by
reacting it with sarcosine ethyl ester under the same conditions as in Example
238. The ethyl
ester was then hydrolyzed using the analogous conditions as in Example 119 to
provide a
mixture of racemic 1-244. These compounds can be separated using chiral HPLC
methods
279
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 327.5 m/z.
Activity: B
Example 240
O 0c1j10U -ao
0--r N N
H H
OH I-245a OH I-245b
(1-245)
[00282] 2-(4,5-dihydroisoxazol-3-ylamino)alcohol I-245a and I-245b were
prepared in 1
step according to the following procedure: racemic 3-bromo-4,5-
dihydroisoxazole 1-10 (1.0
equiv) was dissolved in n-butanol (0.64 M) followed by the addition of (S)-2-
amino-l-
phenylethanol (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction is
the sealed and
heated in an oil bath to 120 C for 18h after which it allowed to cool and
then transferred to a
reparatory funnel with excess water and tert-butylmethyl ether. The aqueous
layer was washed
with tert-butylmethyl ether (2x) and the combined organic layers were washed
with brine, dried
over magnesium sulfate and concentrate to provide a orange solid that was
purified using flash
silica gel chromatography (gradient toluene/hexanes to toluene/ethyl acetate)
to provide racemic
1-245 as a white solid. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 374.20
m/z.
Activity: C
Example 241
O O
NOCF3 ID-/ OCF3
N N
H H
OH I-246a OH I-246b
(1-246)
[00283] 2-(4,5-dihydroisoxazol-3-ylamino)alcohol I-246a and I-246b were
prepared using
the analogous procedure as Example 240 except that racemic 3-bromo-4,5-
dihydroisoxazole I-
14 was used in place of 3-bromo-4,5-dihydroisoxazole 1-10 as starting material
and that (R)-2-
amino-l-phenylethanol was used in place of (S)-2-amino-l-phenylethanol. These
compounds
280
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 365.6 m/z. Activity: C
Example 242
O
N' ~ ~ OCF3
0-IS
HO. SH F3CO ", + NaH HO-õ I-248a
Br 'Al Br PhS SPh AgNO3 N~~= OCF
3
I-247
1-248b
(1-248)
[00284] 3-(phenylthio)-4,5-dihydroisoxazole I-248a and I-248b were prepared in
2 steps
according to the following procedure: N,N-dibromoformaldoxime (1.0 equiv) was
dissolved in
tetrahydrofuran. Thiophenol (2.0 equiv) was added followed by sodium hydride
(1.98 equiv).
After stirring for lh, the reaction is concentrated and purified by flash
silica gel chromatography
(gradient ethyl acetate/hexanes) to provide the desired diphenyl
hydroxycarbonimidodithioate I-
247. The dithioate (1.0 equiv) is then redissolved in acetonitrile (1.0 M)
followed by the
addition of 1-(trifluoromethoxy)-4-vinylbenzene (2.4 equiv), silver nitrate
(1.0 equiv) and
potassium carbonate (1.0 equiv). The reaction was allowed to stir for 3d at
room temperature
after which point it was concentrated and purified by flash silica gel
chromatography (gradient
ethyl acetate/hexanes) to provide racemic 3-(phenylthio)-4,5-dihydroisoxazole
1-248. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 339.9 m/z. Activity: C
Example 243
OCF3
yc~ OCF3
0-'S O \ yc ,
S
0 I-249a 0 I-249b
(1-249)
[00285] 3-(phenylsulfinyl)-4,5-dihydroisoxazole I-249a and I-249b were
prepared by the
oxidation of racemic 3-(phenylthio)-4,5-dihydroisoxazole 1-248. 3-(Phenylthio)-
4,5-
dihydroisoxazole 1-248 (1.0 equiv) was dissolved in ethanol (0.15 M) followed
by the addition
281
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
of excess hydrogen peroxide in water (30% by weight, >50 equiv) and IN HC1
(0.29 M). The
reaction was stirred at room temperature for 14h after which it was
transferred to a reparatory
funnel with excess water and methylene chloride. The water layer was extracted
with methylene
chloride (lx), dried over magnesium sulfate, and concentrated to provide crude
product that was
recrystallized from hexanes to provide the desired racemic 3-(phenylsulfinyl)-
4,5-
dihydroisoxazole 1-249. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ =
355.5 m/z.
Activity: C
Example 244
~ I NO N~O~. ~OCF3
a a
I-250a I-250b
(1-250)
[00286] 3-(phenylsulfonyl)-4,5-dihydroisoxazole I-250a and I-250b were
prepared by the
oxidation of racemic 3-(phenylsulfinyl)-4,5-dihydroisoxazole 1-249. 3-
(Phenylsulfinyl)-4,5-
dihydroisoxazole 1-249 is dissolved in methylene chloride (0.03 M). m-
Chloroperbenzoic acid
(77% by weight, 2.95 equiv) are added in two portions and the reaction is
allowed to stir at room
temperature for 14h after which it is transferred to a reparatory funnel with
excess water and
methylene chloride. The organic layer is washed with saturated sodium
bicarbonate (2x), dried
over magnesium sulfate, and concentrated to provide crude solid that is
recrystallized from
methylene chloride/hexanes to provide the desired racemic 3-(phenylsulfonyl)-
4,5-
dihydroisoxazole 1-250. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ =
371.7 m/z.
Activity: C
Example 245
HO2C / II N,O OCF3 HO2C / II N,O OCF3
S
I-251 a I-251 b
(1-251)
282
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00287] 3-(phenylthio)-4,5-dihydroisoxazole I-251a and I-251b were prepared
using the
analogous procedure as Example 242 except that methyl 4-mercaptobenzoate was
used in place
of thiophenol to form the requisite hydroxycarbonimidodithioate. The resulting
methyl ester
cycloadduct was then hydrolyzed using the analogous conditions as in example
94 to provide
racemic 3-(phenylthio)-4,5-dihydroisoxazole 1-251. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 384.1 m/z. Activity: C
Example 246
O
Me HO,N N/ OCF3
SH ~ HO, N
HNJ Br Br N OCF3 Me I-253a
NEt3 Me~N SPh O
52 OCF3
\ I 12P' h
N
Me I-253b
(1-253)
[00288] N-ethyl-N-phenyl-4,5-dihydroisoxazol-3-amine I-253a and I-253b were
prepared
in 2 steps according to the following procedure: N,N-dibromoformaldoxime (1.05
equiv) was
dissolved in acetonitrile. Thiophenol (1.0 equiv) and N-ethyl aniline (1.0
equiv) were added and
the reaction was allowed to stir at room temperature for 2.5h after which
point triethylamine (5.0
equiv) is added. After stirring for 1 h, the solids that have now precipitated
out of the reaction are
filtered and the filtrate is concentrated and purified directly by flash
silica gel chromatography
(gradient ethyl acetate/hexanes with 1 % triethylamine) to provide the desired
carbamimidothioate 1-252. The carbamimidothioate (1.0 equiv) is then
redissolved in
acetonitrile (1.0 M) followed by the addition of 1-(trifluoromethoxy)-4-
vinylbenzene (2.4
equiv), silver nitrate (1.07 equiv) and potassium carbonate (1.17 equiv). The
reaction was
allowed to stir for 1 d at room temperature after which point it was purified
by flash silica gel
chromatography (gradient ethyl acetate/hexanes with 1% triethylamine) to
provide racemic 4,5-
dihydroisoxazol-3-amine 1-253. These compounds can be separated using chiral
HPLC
283
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
352.1 m/z. Activity: C
Example 247
HO2C \ I N'O \ / OCF3
HO,N
N
HN'Me l
SH Br'\Br HO,N OCF3 Mel-255a
I
+ / I NEt3 Me-N'kSPh then HO2C / N-O, -
\ P,h hydrolysis 1 OCF3
COzMe I-254
Me
I-255b
(1-255)
[00289] N-methyl-N-phenyl-4,5-dihydroisoxazol-3-amine I-255a and I-255b were
prepared in 3 steps according to the following procedure: N,N-
dibromoformaldoxime (1.05
equiv) was dissolved in acetonitrile. Thiophenol (1.0 equiv) and 4-
(methylamino)benzoic acid
methyl ester (1.0 equiv) were added after which point triethylamine (3.0
equiv) is added in 3
portions. After stirring for 3h, the reaction was transferred to a reparatory
funnel with excess
water and methylene chloride. The organic layer was washed with IN HC1 (2x),
dried over
magnesium sulfate, concentrated and purified using flash silica gel
chromatography (gradient
ethyl acetate/hexanes with 0.5% triethyl amine followed by gradient
methanol/methylene
chloride with 0.5% triethyl amine) to provide the desired carbamimidothioate 1-
254. The
carbamimidothioate (1.0 equiv) is then redissolved in acetonitrile (1.0 M)
followed by the
addition of 1-(trifluoromethoxy)-4-vinylbenzene (1.8 equiv), silver nitrate
(2.3 equiv) and
potassium carbonate (2.1 equiv). The reaction was allowed to stir for 1 d at
room temperature
after which point it was purified by flash silica gel chromatography (gradient
ethyl
acetate/hexanes with 0.5% triethylamine followed by gradient
methanol/methylene chloride with
0.5% triethylamine. The resulting racemic methyl ester cycloadduct was then
hydrolyzed using
the analogous conditions as in Example 94 to provide racemic N-methyl-N-phenyl-
4,5-
dihydroisoxazol-3-amine 1-255. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
381.5 m/z. Activity: C
284
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 248
YO O NO
a /~N
I-256a v I-256b
(1-256)
[00290] 3-(pyrrolidin-1-yl)-4,5-dihydroisoxazole I-256a and I-256b were
prepared using
the analogous procedure as Example 238 except that pyrrolidine was used in
place of (S)-2-
amino-l-phenylethanol. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=
310.3 m/z.
Activity: C
Example 249
Me O N -N' O N-N" N- O ~(-N" NO
F3C-- /~ O F3C ~O v I-257a I-257b
(1-257)
[00291] 3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yloxy)-4,5-
dihydroisoxazole I-
257a and I-257b were prepared in 1 step from compound 1-10 and 1-methyl-3-
(trifluoromethyl)-1H-pyrazol-5-01 using Method 5. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 403.7 m/z. Activity: B
Example 250
iN rN
O "IN 0 ',IN
\ I N'O &OCF3 N'O~" OCF3
O O
I-258a I-258b
(1-258)
285
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00292] 3-(phenoxy)-4,5-dihydroisoxazole I-258a and I-258b were prepared in 1
step from
racemic compound 1-14 and 3-(1,3,4-oxadiazol-2-yl)phenol using Method 5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 392.4 m/z. Activity: A
Example 251
Me Me
/- O /-O
N`N N ~ 0 O CF3 N`N N ~5- Q CF3
~
I-259a I-259b
(1-259)
[00293] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-259a and I-259b were
prepared using
the analogous procedure to Example 152 except that racemic compound 1-170 was
used as the
starting acid. These compounds can be separated using chiral HPLC methods
known in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 390.7 m/z.
Activity: A
Example 252
O 1Q-o LO-
, Me O Me O
I-260a I-260b
(1-260)
[00294] 4,5-dihydroisoxazol-3-yl acetate I-260a and I-260b were prepared in 3
steps
according to the following procedures: racemic bromoisoxazole 1-10 was (1.0
equiv) was
dissolved in tetrahydrofuran (1.0 M). IN Sodium hydroxide solution is added
(4.0 equiv)
followed by allyl alcohol (45 equiv). The reaction was sealed and heated to 60
C for 3h. The
reaction mixture was allowed to cool and then transferred to a separatory
funnel with excess
water and ethyl acetate. The organic layer was washed water and brine, drive
over sodium
sulfate and concentrated under vacuum to provide crude material which was
purified using flash
silica gel chromatography (gradient ethyl acetate/hexanes). The resulting
allyl ether (1.0 equiv)
286
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
was then dissolved in tetrahydrofuran (0.2 M). Formic acid (5.0 equiv) was
added followed by
palladium tetrakis (10 mol%) after which the reaction was allowed to stir for
2h at room
temperature. The reaction mixture was transferred to a separatory funnel with
excess water and
ethyl acetate. The organic layer was washed with saturated sodium bicarbonate
and brine, dried
over sodium sulfate and purified using flash silica gel chromatography
(gradient ethyl
acetate/hexanes). The resulting isoxazolidin-3-one (1.0 equiv) was dissolved
in methylene
chloride (0.3 M) after which N,N-dimethyamino pyridine (1.0 equiv) and acetic
anhydride (1.0
equiv) were added. After stirring at room temperature for 14h, the reaction
was transferred to a
separatory funnel with excess water and ethyl acetate. The organic layer was
washed with IN
HC1 and brine, dried over sodium sulfate and concentrated to provide the
desired racemic acetate
1-260. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 297.8 m/z.
Activity: D
Example 253
OCF3 OCF3
MeS N N_O MeS LLO,LY\Me
I-261 a I-261 b
(1-261)
[00295] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-261a and I-261b were
prepared in 1
step from racemic compound 1-75 and 6-(methylthio)pyridin-3-ol using Method 5
after 6-
(methylthio)pyridin-3-ol is first prepared from 6-(methylthio)pyridin-3-
ylboronic acid using
Method 11. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 386.2 m/z.
Activity: A
Example 254
O
0
N N
I ~ ~N
Br Br
II-1a II-1 b
(II-1)
287
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00296] 3-bromo-4,5-dihydroisoxazole II-1a and II-1b were prepared in 1 step
from 4-
vinylpyridine using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 226.0 m/z.
Activity: C
Example 255
-
N YC 0 N
\
ya0
B r Br
II-2a II-2b
(11-2)
[00297] 3-bromo-4,5-dihydroisoxazole II-2a and II-2b were was prepared in 1
step from
3-vinylpyridine using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
226.0 m/z. Activity: C
Example 256
N-O N- l O NI /
Br Br
II-3a II-3b
(11-3)
[00298] 3-bromo-4,5-dihydroisoxazole II-3a and II-3b were prepared in 1 step
from 2-
vinylpyridine using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 226.0 m/z.
Activity: C
Example 257
O N YC) N
N \ N
Br Br
11-4a 11-4b
(11-4)
288
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00299] 3-bromo-4,5-dihydroisoxazole II-4a and II-4b were prepared in 2 steps
starting
with alkene formation from 1-phenyl-lH-pyrazole-4-carbaldehyde using Method 8
followed
by cycloaddition using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
291.0 m/z. Activity: B
Example 258
N'O / S N-R / S
Br N I \ Br N I \
11-5a 11-5b
(11-5)
[00300] 3-bromo-4,5-dihydroisoxazole II-5a and II-5b were prepared in 2 steps
starting
with alkene formation from 2-phenyl-1,3-thiazole-4-carbaldehyde using Method 8
followed by
cycloaddition using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 308.0 m/z.
Activity: C
Example 259
N'0 N N-OS' N
Br Br S I \
II-~SAO II-6b
(11-6)
[00301] 3-bromo-4,5-dihydroisoxazole II-6a and II-6b were prepared in 2 steps
starting
with alkene formation from 2-phenyl-1,3-thiazole-5-carbaldehyde using Method 8
followed by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 308.0 m/z.
Activity: A
Example 260
289
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Br S I \ Br S I \
II-7a II-7b
(11-7)
[00302] 3-bromo-4,5-dihydroisoxazole II-7a and II-7b were prepared in 2 steps
starting
with alkene formation from 5-phenylthiophene-2-carbaldehyde using Method 8
followed by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 309.6 m/z.
Activity: A
Example 261
N I -O S N I -O; S
Br I \ Br
II-8a II-8b
(11-8)
[00303] 3-bromo-4,5-dihydroisoxazole II-8a and II-8b were prepared in 2 steps
starting
with alkene formation from 4-phenylthiophene-2-carbaldehyde using Method 8
followed by
cycloaddition using Method 2. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 307.0 m/z.
Activity: A
Example 262
O - N-O,
N I N
Br Br
II-9a II-9b
(11-9)
[00304] 3-bromo-4,5-dihydroisoxazole II-9a and II-9b were prepared in 2 steps
starting
with alkene formation from 6-quinolinecarbaldehyde using Method 8 followed by
cycloaddition
using Method 2. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 276.0 m/z.
Activity: A
290
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 263
):~-Cb Br Br I
II-10a II-10b
(11-10)
[00305] 3-bromo-4,5-dihydroisoxazole II-10a and II-10b were prepared in 2
steps starting
with alkene formation from 3-quinolinecarbaldehyde using Method 8 followed by
cycloaddition
using Method 2. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 276.0 m/z.
Activity: A
Example 264
O - N-Q
Br Br
11-11a II-11 b
(11-11)
[00306] 3-bromo-4,5-dihydroisoxazole II-11a and II-11b were prepared in 2
steps starting
with alkene formation from 6-bromoquinoxaline using Method 10 followed by
cycloaddition
using Method 2. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 277.0 m/z.
Activity: A
Example 265
N-O - N-O; -
Br I I I Br I I
N N
Me Me
II-12a II-12b
(11-12)
[00307] 3-bromo-4,5-dihydroisoxazole II-12a and II-12b were prepared in 2
steps starting
with alkene formation from 5-bromo-l-methyl-lH-indole using Method 9 followed
by
cycloaddition using Method 2. These compounds can be separated using chiral
HPLC methods
291
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 278.0 m/z.
Activity: A
Example 266
N-O - N-O, - IIII
Br S~N'J~'O~ Br S 1111 0-1<
H H
II-13a II-13b
(11-13)
[00308] 3-bromo-4,5-dihydroisoxazole II-13a and II-13b were prepared in 2
steps starting
with the Boc-protection of 2-amino-6-bromobenzothiazole as follows: The
benzothiazole (1.0
equiv) is dissolved in methylene chloride (0.12 M with respect to thiazole).
Di-tent-butyl
dicarbonate (3.0 equiv) is then added followed by the addition of DMAP (0.20
equiv) in five
portions. The reaction was allowed to stir for 2h at 23 C after which point
there was no more
SM by TLC analysis. The reaction was quenched with the addition of methanol
(75 equiv) and
allowed to stir for 10 min after which the reaction was split between water
and methylene
chloride, and the organic layer was washed with 0.5 M citric acid solution
(2x) and saturated
sodium bicarbonate solution (lx), dried over magnesium sulfate, and
concentrated in vacuo to
provide a crude solid which was converted directly to the desired 3-bromo-4,5-
dihydroisoxazole using Method 9 followed by Method 2. These compounds can be
separated
using chiral HPLC methods known in the art. For example, see chiral HPLC
Method disclosed
herein. [M-H]-= 397.0 m/z. Activity: B
Example 267
N/- N'O., 1 -0 Br Br/~\'
ON N
O ~-O
II-14a0
II-14b
(11-14)
292
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00309] 1-Allylpiperazine is dissolved in methylene chloride (1.1 M with
respect to
piperazine). Potassium carbonate (1.5 equiv) was added followed by di-tent-
butyl dicarbonate
(1.1 equiv). The reaction was allowed to stir for 16h after which it was then
split between water
and tent-butyl methyl ether, and the organic layer was washed with brine,
dried over sodium
sulfate, and concentrated in vacuo to provide crude alkene which was directly
converted to the
desired 3-bromo-4,5-dihydroisoxazole II-14a and II-14b in 1 step using Method
1. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M-H]-= 347.1 m/z. Activity: A
Example 268
N,O N N,O,
Br O Br O
II-15a II-15b
(11-15)
[00310] 3-bromo-4,5-dihydroisoxazole II-15a and II-15b were prepared in 2
steps starting
with alkene formation from benzyl 4-formylpiperidine-l-carboxylate using
Method 8 followed
by cycloaddition using Method 2. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-H]-=
366.1 m/z. Activity: B
Example 269
N,O N0 ~IN~
,O Br O Br O
II-16a II-16b
(11-16)
[00311] 3-bromo-4,5-dihydroisoxazole II-16a and II-16b were prepared in 2
steps starting
with alkene formation from tent-butyl 4-formylpiperidine-l-carboxylate using
Method 8
followed by cycloaddition using Method 2. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-
H]-= 332.1 m/z. Activity: A
293
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 270
N'O CS N N'0.N
Br Br I S
CI CI
II-17a II-17b
(11-17)
[00312] 3-bromo-4,5-dihydroisoxazole II-17a and II-17b were prepared in 2
steps starting
with alkene formation from 2-(4-chlorophenyl)thiazole-5-carbaldehyde using
Method 8
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 342.5 m/z. Activity: A
Example 271
N N'C ,.[N
S
Br Me Br /i~ ~. /~Me
II-18a II-18b
(11-18)
[00313] 3-bromo-4,5-dihydroisoxazole II-18a and II-18b were prepared in 2
steps starting
with alkene formation from 1-(2-phenylthiazol-5-yl)ethanone using Method 8
followed by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+
= 322.3 m/z.
Activity: A
Example 272
N'O N N'O N
Br S \ Br~' 1 S \
Me Me
II-19a II-19b
(11-19)
294
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00314] 3-bromo-4,5-dihydroisoxazole II-19a and II-19b were prepared in 2
steps starting
with alkene formation from 2-phenylthiazole-5-carbaldehyde using Method 8
except that
ethyltriphenylphosphoium bromide was used in place of
methyltriphenylphosphoium bromide
followed by cycloaddition using Method 1. [M+H]+ = 325.1 m/z. Activity: A
Example 273
N'O ~ N N,O ri N
S
Br S \ Br \
Me Me
II-20a II-20b
(11-20)
[00315] 3-bromo-4,5-dihydroisoxazole II-20a and II-20b were isolated as the
trans
diastereomers which also formed during the cycloaddition in Example 272. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 324.9 m/z. Activity: C
Example 274
N N,O N (0x5-cr~
I I
S I\ O II-21 a II-21 b
(11-21)
[00316] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-21a and II-21b were
prepared in 1
step from racemic compound 11-6 and 3-hydroxypyridine using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 325.1 m/z. Activity: A
Example 275
U"o'Z N N N N'O NNS
S N
N Me Me
II-22a II-22b
295
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(11-22)
[00317] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-22a and II-22b were
prepared in 1
step from racemic compound 11-18 and 5-hydroxyprimidine using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 340.4 m/z. Activity: A
Example 276
N
O Me O "Ix
I I
Me
II-23a II-23b
(11-23)
[00318] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-23a and II-23b were
prepared in 1
step from racemic compound 11-18 and 3-hydroxypyridine using Method 5. These
compounds
can be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 339.3 m/z. Activity: A
Example 277
Me N Me N
0: S N'O ,,.I S
l'
Br Me gr Me
II-24a II-24b
(11-24)
[00319] 3-bromo-4,5-dihydroisoxazole II-24a and II-24b were prepared in 2
steps starting
with alkene formation from 1-(4-methyl-2-phenylthiazol-5-yl)ethanone using
Method 8
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 339.0 m/z. Activity: B
Example 278
296
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
N,O N,Q
Br \ Br S I \
II-25a N II-25b N
(11-25)
[00320] 3-bromo-4,5-dihydroisoxazole II-25a and II-25b were prepared in 2
steps starting
with alkene formation from 5-pyridin-3-ylthiophen-2-carbaldehyde using Method
8 followed
by cycloaddition using Method 1. These compounds can be separated using chiral
HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
310.3 m/z. Activity: A
Example 279
IN N'O N'O /
N ,N `O 8 \ N ~/ `O
N N
II-26a II-26b
(11-26)
[00321] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole II-26a and II-26b were
prepared in 1
step from racemic compound 11-25 and 5-hydroxypyrimidine using Method 5. These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 325.1 m/z. Activity: A
Example 280
HOZC N I N'O / I HOZC N N-01
~O O S
II-27a N II-27b N
(11-27)
[00322] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-27a and II-27b were
prepared in 2
steps from racemic compound 11-25 according to the following procedure: 5-
hydroxypicolinic
acid methyl ester was reacted using Method 5 followed by methyl ester
hydrolysis. The methyl
297
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
ester of racemic 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole 11-27 (1.0 equiv)
was dissolved in
1:1 tetrahydrofuran/water (0.06 M) and lithium hydroxide (8.0 equiv) was
added. The reaction
was allowed to stir at room temperature for lh after which point the
tetrahydrofuran was
removed under a stream of nitrogen and the remaining solution was acidified to
pH<2 with IN
HC1 to provide desired acid II-27a and II-27b as a white solid which was
isolated via vacuum
filtration. These compounds can be separated using chiral HPLC methods known
in the art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 367.5 m/z.
Activity: A
Example 281
Mew ~~ Mew ~,
p I
!3,U-<1 S ,, N
O S
II-28a II-28b
(11-28)
[00323] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-28a and II-28b were
prepared in 2
steps from racemic compound 11-6 by first reacting 11-6 with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation according to the following procedure: racemic 3-(6-
(methylthio)pyridin-
3-yloxy)-4,5-dihydroisoxazole was dissolved in methylene chloride (0.5 M with
respect to
isoxazole) after which point m-chloroperbenzoic acid (2.0 equiv) was added in
1 portion and the
reaction was allowed to stir at room temperature for 1h. After the reaction
was determined to be
complete by LC/MS, the solvent was evaporated. The crude mixture was then
redissolved in
tert-butylmethyl ether (.5 M) after which hexane was slowly added until a
solid precipitated.
The solid was then collected via vacuum filtration and washed with 1:1
hexanes/MTBE to
provide the desired 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-29a and II-29b
as a white
solid. These compounds can be separated using chiral HPLC methods known in the
art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 404.1 m/z.
Activity: A
298
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 282
Me % Me
OS
;; U-I
N N-O ,.CS
N N- S OS - U"I
p Me p Me
11-29a 11-29b
(11-29)
[00324] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole II-29a and II-29b were
prepared in 2
steps from racemic compound 11-18 by first reacting 11-18 with 6-
(methylthio)pyridin-3-ol
(prepared from 6-(methylthio)pyridin-3-ylboronic acid using Method 11) using
Method 5
followed by oxidation under analogous conditions to Example 281. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 417.9 m/z. Activity: A
Example 283
S
oCNx3-cr7
N
H H
H
OH II-30a OH II-30b
(11-30)
[00325] 2-(4,5-dihydroisoxazol-3-ylamino)alcohol II-30a and II-30b were
prepared in 1
step according to the following procedure: racemic 3-bromo-4,5-
dihydroisoxazole 1-8 (1.0
equiv) was dissolved in n-butanol (0.64 M) followed by the addition of (S)-2-
amino-l-
phenylethanol (1.2 equiv) and sodium carbonate (2.5 equiv). The reaction is
the sealed and
heated in an oil bath to 120 C for 18h after which it allowed to cool and
then transferred to a
separatory funnel with excess water and tert-butylmethyl ether. The aqueous
layer was washed
with tert-butylmethyl ether (2x) and the combined organic layers were washed
with brine, dried
over magnesium sulfate and concentrate to provide a orange solid that was
purified using flash
silica gel chromatography (gradient toluene/hexanes to toluene/ethyl acetate)
to provide racemic
11-30 as a white solid. These compounds can be separated using chiral HPLC
methods known in
the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ = 374.20
m/z.
Activity: C
299
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 284
o o
N N
H H
OH II-31a OH II-31b
(11-31)
[00326] 2-(4,5-dihydroisoxazol-3-ylamino)alcohol II-31a and II-31b were
prepared using
the analogous procedure as Example 283 except that (R)-2-amino-l-phenylethanol
was used in
place of (S)-2-amino-l-phenylethanol. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
366.4 m/z. Activity: C
Example 285
N,O
Br
(III-1)
[00327] 3-Bromo-4,5-dihydroisoxazole III-1 was prepared in 1 step from
methylenecyclohexane using Method 1. [M-H]-= 217.0 m/z. Activity: A.
Example 286
N'0 N'~
0
Br Br
III-2a III-2b
(111-2)
[00328] 3-bromo-4,5-dihydroisoxazole III-2a and III-2b were prepared in 2
steps starting
with alkene formation from 4-tert-butylcyclohexanone using Method 6 followed
by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 273.1 m/z.
Activity: B
300
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 287
,Q ~ ~ N,Q 0 -1 ~ ~
BrN Br
III-3a III-3b
(111-3)
[00329] 3-bromo-4,5-dihydroisoxazole III-3a and III-3b was prepared in 2 steps
starting
with alkene formation from 4-phenylcyclohexanone using Method 6 followed by
cycloaddition
using Method 1. These compounds can be separated using chiral HPLC methods
known in the
art. For example, see chiral HPLC Method disclosed herein. [M-H]-= 293.0 m/z.
Activity: A.
Example 288
c~o
OBr (111-4)
[00330] 3-Bromo-4,5-dihydroisoxazole 111-4 was prepared in 2 steps starting
with alkene
formation from 1,4-dioxaspiro[4.5]decan-8-one using Method 6 followed by
cycloaddition
using Method 1. [M-H]-= 275.0 m/z. Activity: C.
Example 289
31~O O, 0%
Br
Br 0
-0 -0
III-8a III-8b
(111-8)
[00331] 4-Methylenecyclohexanecarboxylic acid ethyl ester is prepared from the
Wittig
reaction on ethyl 4-oxocyclohexanecarboxylate using Method 3. This ester is
reduced to
compound 111-5 according to the following procedure: To a solution of lithium
aluminum
hydride (4.0 equiv) in diethyl ether (1.0 M with respect to hydride) is added
ethyl 4-
oxocyclohexanecarboxylate in diethyl ether (2.0 M with respect to ester) . The
reaction is heated
to reflux for 2h after which it is cooled in an ice bath and quenched with by
subsequent additions
of isopropanol, 50% NaOH in water, and water. The mixture is then filtered and
the filter cake is
washed with excess diethyl ether. The filtrate is then washed with water and
brine, dried over
301
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
sodium sulfate, and concentrated in vacuo to provide a clear oil that is used
without further
purification.
[00332] Compound 111-5 (1.0 equiv) is then dissolved in pyridine (0.90 M with
respect to the
alcohol). p-Toluenesulfonyl chloride (1.1 equiv) is added and the reaction is
allowed to stir for
16h after which it was quenched with a few drops of water, diluted with excess
methylene
chloride and washed with water, dilute HC1 and brine. The organic layer is
then dried over
sodium sulfate and concentrated in vacuo to provide a off-white solid which
was used directly
without further purification.
[00333] Phenol (1.2 equiv) is then dissolved in N,N-dimethylforamide (0.20 M
with respect
to tosylate). Cesium carbonate (1.3 equiv) is added follwed by compound 111-6
(1.0 equiv) and
TBAI (0.10 equiv). The reaction is heated to 40 C for 19h after which point
it was diluted with
tert-butylmethyl ether and washed with dilute NaOH, water and brine and then
dried over
sodium sulfate. Concentration under vacuum provides compound 111-7 as a clear
oil which is
used without further purification.
O
O OEt OH OTs
111-5 111-6 b
111-7
[00334] The crude alkene was directly converted to the desired diastereomers 3-
bromo-4,5-
dihydroisoxazole III-8a and III-8b in 1 step using Method 2. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 323.6 m/z. Activity: A
Example 290
N-0 -/O
Br O+
(111-9)
302
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00335] 3-Bromo-4,5-dihydroisoxazole 111-9 was prepared in 2 steps starting
with alkene
formation from 1-(tert-butoxycarbonyl)-4-piperidone using Method 7 followed by
cycloaddition using Method 1 or Method 2. [M-H]-= 318.1 m/z. Activity: A.
Example 291
O O
-N N N
Br Br
O O
O X O (
III-10a \ III-10b \
(111-10)
[00336] 3-bromo-4,5-dihydroisoxazole III-10a and III-10b was prepared in 2
steps starting
with alkene formation from 1-(tert-butoxycarbonyl)-3-piperidone using Method 7
followed by
cycloaddition using Method 1. These compounds can be separated using chiral
HPLC methods
known in the art. For example, see chiral HPLC Method disclosed herein. [M-H]-
= 318.1 m/z.
Activity: C
Example 292
'O N-O,
Br' O Bri~'I ~N O
III-11a III-11 b
(111-11)
[00337] 3-bromo-4,5-dihydroisoxazole III-11a and III-11b were prepared in 2
steps
starting with alkene formation from N-(tert-butoxycarbonyl)-3-pyrrolidinone
using Method 7
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein.
[M+H]+ = 304.7 m/z. Activity: B
303
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 293
NON,O
Br N-fO/ Br' N
O nO
III-12a III-12b
(111-12)
[00338] 3-bromo-4,5-dihydroisoxazole III-12a and III-12b were prepared in 2
steps
starting with alkene formation from 1-(tert-butoxycarbonyl)-4-oxoazepane using
Method 7
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-
H]-= 332.1 m/z. Activity: A
Example 294
N'O N -0, 0
Br~~ 0 Br 0
III-13a III-13b
(111-13)
[00339] 3-bromo-4,5-dihydroisoxazole III-13a and III-13b were prepared in 2
steps
starting with alkene formation from N-(tert-butoxycarbonyl)-nortropinone using
Method 7
followed by cycloaddition using Method 1. These compounds can be separated
using chiral
HPLC methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M-
H]-= 344.1 m/z. Activity: C
Example 295
N-O NH
Br
(111-14)
[00340] 3-Bromo-4,5-dihydroisoxazole 111-9 was dissolved in trifluoroacetic
acid (0.20 M
with respect to isoxazole) and stirred at room temperature for lh. The solvent
is then removed
under vacuum and the crude residue is azeotroped with toluene (2x) to provide
111-14 as the
TFA salt (white solid). [M-H]-= 218.0 m/z. Activity: C.
304
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 296
N,O O
4
Br Me
(111-15)
[00341] 3-Bromo-4,5-dihydroisoxazole 111-14 is dissolved in methylene chloride
(0.03 M
with respect to isxozaole) after which triethylamine (4.0 equiv) and acetic
anhydride (3.0 equiv
are added). The reaction is allowed to stir for 16h after which point is
diluted with ethyl acetate
and washed with dilute HC1, dilute NaOH and then brine. The organic layer is
then dried over
sodium sulfate and concentrated under vacuum to provide crude material which
was purfied
using flash silica gel chromatography (ethyl acetate/hexanes) to provide
acetate III-15 as a white
solid. [M-H]-= 260.0 m/z. Activity: C.
Example 297
NO O
Br
(111-16)
[00342] 3-Bromo-4,5-dihydroisoxazole 111-14 is dissolved in methylene chloride
(0.05 M
with respect to isxozaole) after which triethylamine (4.0 equiv) and benzoyl
chloride (1.25 equiv
are added). The reaction is allowed to stir for 16h after which point is
diluted with ethyl acetate
and washed with dilute HC1, dilute NaOH and then brine. The organic layer is
then dried over
sodium sulfate and concentrated under vacuum to provide acetate 111-16 as a
white film. [M-
H]-= 332.0 m/z. Activity: A.
Example 298
N'O 0
N-S
Br O
(111-17)
305
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00343] 3-Bromo-4,5-dihydroisoxazole 111-14 is dissolved in methylene chloride
(0.05 M
with respect to isxozaole) after which triethylamine (4.0 equiv) and
benzenesulfonyl chloride
(1.25 equiv are added). The reaction is allowed to stir for 16 h after which
point is diluted with
ethyl acetate and washed with dilute HC1, dilute NaOH and then brine. The
organic layer is then
dried over sodium sulfate and concentrated under vacuum to provide sulfonamide
111-17 as a
white solid. [M-H]-= 358.0 m/z. Activity: B.
Example 299
N-O ~/O
i~1 UCN \
Br O
(111-18)
[00344] 3-Bromo-4,5-dihydroisoxazole 111-14 is dissolved in methylene chloride
(0.05 M
with respect to isxozaole) after which triethylamine (4.0 equiv) and benzyl
chloroformate (1.25
equiv are added). The reaction is allowed to stir for 16h after which point is
diluted with ethyl
acetate and washed with dilute HC1, dilute NaOH and then brine. The organic
layer is then dried
over sodium sulfate and concentrated under vacuum to provide crude material
which was
purified using flash silica gel chromatography (ethyl acetate/hexanes) to
provide carbamate III-
18 as a white solid. [M-H]-= 352.0 m/z. Activity: A.
Example 300
N/O
Br
(111-19)
[00345] 3-Bromo-4,5-dihydroisoxazole 111-14 is dissolved in methylene chloride
(0.06 M
with respect to isxozaole) after which triethylamine (2.5 equiv) and
benzaldehyde (1.25 equiv)
are added followed by sodium triacetoxyborohydride (1.5 equiv). The reaction
is allowed to stir
for 16h after which point is diluted with ethyl acetate and washed with dilute
NaOH and then
brine. The organic layer is then dried over sodium sulfate and concentrated
under vacuum to
306
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
provide crude material which was purified using flash silica gel
chromatography (ethyl
acetate/hexanes) to provide N-benzylpiperidine 111-19 as a white solid. [M-H]-
= 308.1 m/z.
Activity: A.
Example 301
N-0
N
Br
CI
(111-20)
[00346] 3-Bromo-4,5-dihydroisoxazole 111-20 was prepared in using the
analogous
procedure as Example 300 except that 4-chlorobenzaldehyde was used in the
place of
benzaldehyde. [M+H]+ = 342.6 m/z. Activity: A.
Example 302
N/O
Br
OMe
(111-21)
[00347] 3-Bromo-4,5-dihydroisoxazole 111-21 was prepared in using the
analogous
procedure as Example 300 except that 4-methoxybenzaldehyde was used in the
place of
benzaldehyde. [M+H]+= 338.7 m/z. Activity: A.
Example 303
N/O
Br N
(111-22)
[00348] 3-Bromo-4,5-dihydroisoxazole 111-22 was prepared in using the
analogous
procedure as Example 300 except that 2-pyridinecarboxaldehyde was used in the
place of
benzaldehyde. [M+H]+ = 312.1 m/z. Activity: B.
307
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 304
N'0
Br
N
(111-23)
[00349] 3-Bromo-4,5-dihydroisoxazole 111-23 was prepared in using the
analogous
procedure as Example 300 except that 3-pyridinecarboxaldehyde was used in the
place of
benzaldehyde. [M+H]+ = 312.4 m/z. Activity: B.
Example 305
N N
Br
Me
(111-24)
[00350] 3-Bromo-4,5-dihydroisoxazole 111-24 was prepared in using the
analogous
procedure as Example 300 except that 4-methylbenzaldehyde was used in the
place of
benzaldehyde. [M+H]+ = 322.5 m/z. Activity: A.
Example 306
N-0
Br
Q-CI
CI
(111-25)
[00351] 3-Bromo-4,5-dihydroisoxazole 111-25 was prepared in using the
analogous
procedure as Example 300 except that 3,4-dichlorobenzaldehyde was used in the
place of
benzaldehyde. [M+H]+= 378.6 m/z. Activity: A.
308
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 307
N'0 N
Br
CF3
(111-26)
[00352] Bromo-4,5-dihydroisoxazole 111-26 was prepared in using the analogous
procedure
as Example 300 except that 4-trifluoromethylbenzaldehyde was used in the place
of
benzaldehyde. [M+H]+ = 376.6 m/z. Activity: A.
Example 308
O
N" CN
Br \
CI
(111-27)
[00353] 3-Bromo-4,5-dihydroisoxazole 111-27 was prepared in using the
analogous
procedure as Example 300 except that 3-chlorobenzaldehyde was used in the
place of
benzaldehyde. [M+H]+ = 342.6 m/z. Activity: A.
Example 309
N- N -
Br
(111-28)
[00354] 3-Bromo-4,5-dihydroisoxazole 111-28 was prepared in using the
analogous
procedure as Example 300 except that hydrocinnamaldehyde was used in the place
of
benzaldehyde. [M+H]+ = 336.7 m/z. Activity: A.
Example 310
N'O
Br
309
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(111-29)
[00355] 3-Bromo-4,5-dihydroisoxazole 111-14 is dissolved in N,N-
dimethylforamide (0.05
M with respect to isoxazole) after which potassium carbonate (3.0 equiv) was
added followed by
potassium iodide (0.2 equiv) and 2-bromoethylbenzene (3.0 equiv). The reaction
was heated to
70 C in an oil bath for 16h after which point it was purified directly using
flash silica gel
chromatography (ethyl acetate/hexanes) to provide amine 111-29 as an oil.
[M+H]+ = 324.6 m/z.
Activity: A.
Example 311
N,O
Br
(111-30)
[00356] 3-Bromo-4,5-dihydroisoxazole 111-30 was prepared in using the
analogous
procedure as Example 290 except that 1-phenyl-4-piperidone was used in the
place of 1-(tert-
butoxycarbonyl)-4-piperidone. [M+H]+ = 297.0 m/z. Activity: B.
Example 312
N'O N Br )LA-/ -&
Br
(111-31)
[00357] 3-Bromo-4,5-dihydroisoxazole 111-30 is dissolved in chloroform (0.01 M
with
respect to isoxazole) after which bromine (1.0 equiv) is added. The reaction
is allowed to stir for
16h after which point is diluted with water and washed with saturated Na2CO3.
The organic
layer is then dried over sodium sulfate and concentrated under vacuum to
provide 111-31 as a
yellow solid. [M+H]+ = 377.0 m/z. Activity: B.
Example 313
O
N" N
Br
(111-32)
310
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00358] 3-Bromo-4,5-dihydroisoxazole 111-32 was prepared in using the
analogous
procedure as Example 300 except that cyclohexanecarboxaldehyde was used in the
place of
benzaldehyde. [M+H]+ = 390.5 m/z. Activity: A.
Example 314
N'O
Br
(111-33)
[00359] 3-Bromo-4,5-dihydroisoxazole 111-33 was prepared in using the
analogous
procedure as Example 300 except that pivaldehyde was used in the place of
benzaldehyde.
[M+H]+ = 290.5 m/z. Activity: B.
Example 315
N-0 0
I N
Br
(111-34)
[00360] 3-Bromo-4,5-dihydroisoxazole 111-34 was prepared in using the
analogous
procedure as Example 297 except that hydrocinnamaldehyde was used in the place
of benzoyl
chloride. [M+H]+ = 352.8 m/z. Activity: A.
Example 316
N-0 0
Y 1 N
Br OMe
(111-35)
[00361] 3-Bromo-4,5-dihydroisoxazole 111-35 was prepared in using the
analogous
procedure as Example 299 except that methyl chloroformate was used in the
place of benzyl
chloroformate. [M+H]+ = 378.8 m/z. Activity: B.
311
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 317
N,O O
Br OM~-Me
(111-36)
[00362] 3-Bromo-4,5-dihydroisoxazole 111-36 was prepared in using the
analogous
procedure as Example 299 except that iso-butyl chloroformate was used in the
place of benzyl
chloroformate. [M+H]+ = 318.7 m/z. Activity: A.
Example 318
N,O O
Br O
(111-37)
[00363] 3-Bromo-4,5-dihydroisoxazole 111-37 was prepared in using the
analogous
procedure as Example 299 except that phenyl chloroformate was used in the
place of benzyl
chloroformate. [M+H]+ = 340.7 m/z. Activity: A.
Example 319
N,O O
iJ~ ~J~~N~
Br O~CI
CI CI
(111-38)
[00364] 3-Bromo-4,5-dihydroisoxazole 111-38 was prepared in using the
analogous
procedure as Example 299 except that 2,2,2-trichloroethyl chloroformate was
used in the place
of benzyl chloroformate. [M+H]+ = 394.5 m/z. Activity: B.
312
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 320
N-0 0
I N
Br O
OMe
(111-39)
[00365] 3-Bromo-4,5-dihydroisoxazole 111-14 is dissolved in methylene chloride
(0.05 M
with respect to isoxazole) after which triethylamine (5.0 equiv) and carbonyl
diimidazole (1.25
equiv) are added. The reaction is allowed to stir for 2h after which point
anisyl alcohol (2.5
equiv) was added followed by catalytic tetrabutylammonium hydrogensulfate and
50% aqueous
sodium hydroxide (0.10 M with respect to isoxazole). The heterogeneous mixture
is allowed to
stir for 16h after which point it was diluted with ethyl acetate. The water
layer was washed two
additional times with ethyl acetate after which the organic layers were
combined, dried over
sodium sulfate and concentrated under vacuum to provide crude material which
was purified
using flash silica gel chromatography (ethyl acetate/hexanes) to provide
carbamate 111-39 as a
white solid. [M+H]+ = 382.9 m/z. Activity: A.
Example 321
N-0 0
I N
Br O
CI
(111-40)
[00366] 3-Bromo-4,5-dihydroisoxazole 111-40 was prepared in using the
analogous
procedure as Example 320 except that 4-chlorobenzyl alcohol was used in the
place of anisyl
alcohol. [M+H]+ = 388.8 m/z. Activity: A.
313
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 322
NO O N'O
i~~ ~~N Me i~~ Uci Me
Br ~~----// O- Br O
41 a 41 b
(111-41)
[00367] 3-bromo-4,5-dihydroisoxazole III-41a and III-41b were prepared in
using the
analogous procedure as Example 320 except that racemic sec-phenethyl alcohol
was used in the
place of anisyl alcohol. These compounds can be separated using chiral HPLC
methods known
in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+ =
368.8 m/z.
Activity: A
Example 323
N,
O H
0 O H N,O H N'ao
Br Br
Br BrH H ,
H O
III-42a III-42b III-42c III-42d
(111-42)
[00368] 3-Cylopentene-l-ol (1.0 equiv) is dissolved in N,N-dimethylformide
(0.80 M with
respect to the alcohol) and treated with TBAI (0.10 equiv) followed by crushed
sodium
hydroxide (2.0 equiv). Benzyl bromide (1.2 equiv) is then added and the
reaction is allowed to
stir for 48h at room temperature. The reaction is then diluted with tent-butyl
methyl ether and
washed with dilute Na2S2O3 and brine. The organic layer is then dried over
sodium sulfate and
concentrated under vacuum to provide crude material which was purified using
flash silica gel
chromatography (ethyl acetate/hexanes) to provide the desired cycloalkene as a
colorless oil.
This compound was then converted to the desired 3-bromo-4,5-dihydroisoxazole
111-42 using
the cycloaddition procedures outlined in Method 1. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M-H]-= 295.0 m/z. Activity: B.
314
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 324
N-O H N,O H
Br
H NOX Br N~OX
O O
III-43a III-43b
(111-43)
[00369] 3-bromo-4,5-dihydroisoxazole III-43a and III-43b were prepared in 1
step from
N-(tert butoxycarbonyl)-2,5-dihydro-lH-pyrrole using Method 1. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M-H]-= 290.0 m/z. Activity: B.
Example 325
N-O H N0 O H
Br N O Br'N O \
H O H O
III-44a III-44b
(111-44)
[00370] Racemic 3-bromo-4,5-dihydroisoxazole 111-43 was dissolved in
trifluoroacetic acid
(0.20 M with respect to isoxazole) and stirred at room temperature for lh. The
solvent is then
removed under vacuum and the crude residue is azeotroped with toluene (2x) to
provide a the
trifluoroacetic acid salt as a white solid which was dissolved in methylene
chloride (0.05 M with
respect to isozaole) after which triethylamine (4.0 equiv) and benzyl
chloroformate (1.25 equiv
are added). The reaction is allowed to stir for 16h after which point is
diluted with ethyl acetate
and washed with dilute HC1, dilute NaOH and then brine. The organic layer is
then dried over
sodium sulfate and concentrated under vacuum to provide crude material which
was purified
using flash silica gel chromatography (ethyl acetate/hexanes) to provide
carbamate 111-44 as a
white solid. These compounds can be separated using chiral HPLC methods known
in the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 324.6 m/z.
Activity: A
315
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 326
N"O CI NO H / CI
BrIN I Br
H
III-45a III-45b
(111-45)
[00371] Racemic 3-bromo-4,5-dihydroisoxazole 111-43 was dissolved in
trifluoroacetic acid
(0.20 M with respect to isoxazole) and stirred at room temperature for lh. The
solvent is then
removed under vacuum and the crude residue is azeotroped with toluene (2x) to
provide a the
trifluoroacetic acid salt as a white solid which is then is dissolved in
methylene chloride (0.06 M
with respect to isoxozaole) after which triethylamine (2.5 equiv) and 4-
chlorobenzaldehyde
(1.25 equiv) are added followed by sodium triacetoxyborohydride (1.5 equiv).
The reaction is
allowed to stir for 16h after which point is diluted with ethyl acetate and
washed with dilute
NaOH and then brine. The organic layer is then dried over sodium sulfate and
concentrated
under vacuum to provide crude material which was purified using flash silica
gel
chromatography (ethyl acetate/hexanes) to provide N-benzylpiperidine 111-45 as
a white solid.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+= 316.6 m/z. Activity: C
Example 327
N N"O O
N4
o
(111-46)
[00372] 3-(Pyridin-3-yloxy)-4,5-dihydroisoxazole 111-46 was prepared in 1 step
from
compound 111-18 and 3-hydroxypyridine using Method 5. [M+H]+ = 369.4 m/z.
Activity: A
Example 328
N
Y ~~C -O
CI O
316
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(111-47)
[00373] 3-Chloro-4,5-dihydroisoxazole 111-47 was prepared in 2 steps starting
with alkene
formation from 1-(tert-butoxycarbonyl)-4-piperidone using Method 6 followed by
cycloaddition using Method 2 except that N-chlorosuccinamide was used in place
of N-
bromosuccinamide. [M+H]+ = 274.9 m/z. Activity: A
Example 329
N-0
CI
CI
(111-48)
[00374] 3-Chloro-4,5-dihydroisoxazole 111-48 was prepared in using the
analogous
procedure as Example 301 except that 3-chloro-4,5-dihydroisoxazole 111-47 was
used in the
place of 3-bromo-4,5-dihydroisoxazole 111-9. [M+H]+ = 298.6 m/z. Activity: A
Example 330
O
N~ N
Br
(111-49)
[00375] 3-Bromo-4,5-dihydroisoxazole 111-49 was prepared in using the
analogous
procedure as Example 300 except that 4-ethynylcarboxaldehyde was used in the
place of
benzaldehyde. [M+H]+ = 335.1 m/z. Activity: A
Example 331
(N N-O N
317
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(111-50)
[00376] 3-(Pyridin-3-yloxy)-4,5-dihydroisoxazole III-50 was prepared in 1 step
from
compound 111-49 and 3-hydroxypyridine using Method 5. [M+H]+ = 348.6 m/z.
Activity: A
Example 332
,N ~ N-O N
CI
(111-51)
[00377] 3-(Pyridin-3-yloxy)-4,5-dihydroisoxazole 111-51 was prepared in 1 step
from
compound 111-20 and 3-hydroxypyridine using Method 5. [M-H]-= 358.1 m/z.
Activity: A
Example 333
I N N/O
N,, O
CI
(111-52)
[00378] 3-(Pyrimidin-5-yloxy)-4,5-dihydroisoxazole 111-52 was prepared in 1
step from
compound 111-20 and 5-hydroxypyrimidine using Method 5. [M+H]+ = 360.2 m/z.
Activity: A
Example 334
~N I Ni~\~/~N- O (N I N,O O
N~ O I N
N~
111-53 111-54
[00379] 3-(Pyrimidin-5-yloxy)-4,5-dihydroisoxazole 111-54 was prepared in 3
steps from
compound 111-9 starting with the synthesis of 3-(pyridin-3-yloxy)-4,5-
dihydroisoxazole III-
53 from compound 111-9 and 5-hydroxypyrimidine using Method 5. Compound 111-53
is then
deprotected using analogous conditions to Example 295 and then converted to
desired product
318
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
111-54 using the analogous procedure as Example 297 except that
hydrocinnamaldehyde was
used in the place of benzoyl chloride. [M+H]+ = 367.6 m/z. Activity: B
Example 335
~
CI
(111-55)
[00380] 3-(Pyrimidin-5-yloxy)-4,5-dihydroisoxazole 111-55 was prepared in 3
steps from
compound 111-9 using the analogous procedure as Example 334 except that 4-
chlorobenzoyl
chloride was used in the place of hydrocinnamaldehyde. [M-H]-= 372.9 m/z.
Activity: A
Example 336
~VN N,O 4O
N HN
(111-56)
[00381] 3-(Pyrimidin-5-yloxy)-4,5-dihydroisoxazole 111-56 was synthesized in
two steps
from compound 111-53 starting with deprotection using analogous conditions to
Example 295.
The resulting trifluoroacetic acid salt (1.0 equiv) is then dissolved in
methylene chloride (0.11 M
with respect to isoxazole) after which phenyl isocyanate (1.5 equiv) is added
followed by
pyridine (5.0 equiv). The reaction is allowed to stir overnight at room
temperature after which
point the reaction was transferred to a separatory funnel with excess water
and methylene
chloride. The organic layer was washed with saturate sodium bicarbonate (2x),
dried over
magnesium sulfate, and concentrated to provide a white solid which was
purified by flash silica
gel chromatography (gradient of ethyl acetate/methanol). [M+H]+ = 353.6 m/z.
Activity: C
Example 337
N O O
N' NCF3
Nom/ `O
(111-57)
319
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00382] 3-(Pyridin-3-yloxy)-4,5-dihydroisoxazole 111-57 was synthesized in two
steps from
compound 111-53 starting with deprotection using analogous conditions to
Example 295. The
resulting trifluoroacetic acid salt (1.0 equiv) is then dissolved in methylene
chloride (0.11 M with
respect to isoxazole after which 5,5,5-trifluoropentanoic acid (1.5 equiv),
EDC (1.5 equiv) and
triethylamine (3.0 equiv) are added. The reaction is allowed to stir for 14h
at room temperature
after which point the reaction was transferred to a separatory funnel with
excess water and
methylene chloride. The organic layer was washed with saturate sodium
bicarbonate (2x), dried
over magnesium sulfate, and concentrated to provide a white solid which was
purified by flash
silica gel chromatography (gradient of ethyl acetate/methanol). [M+H]+ = 373.7
m/z. Activity:
C
Example 338
Me., s~ N N,O O
i~l 1N
I-)
(111-58)
[00383] 3-(Pyridin-3-yloxy)-4,5-dihydroisoxazole 111-58 was prepared in 3
steps from
compound 111-16 according to the following procedures: 6-(methylthio)pyridin-3-
ol is prepared
from 6-(methylthio)pyridin-3-ylboronic acid using Method 11. 3-Bromo-4,5-
dihydroixoazole
111-16 was then reacted with 6-(methylthio)pyridin-3-ol using Method 5. The
resulting 3-
(pyridin-3-yloxy)-4,5-dihydroisoxazole was dissolved in methylene chloride
(0.5 M with
respect to isoxazole) after which point m-chloroperbenzoic acid (2.0 equiv)
was added in 1
portion and the reaction was allowed to stir at room temperature for 1h. After
the reaction was
determined to be complete by LC/MS, the reaction was transferred to a
separatory funnel with
excess water and methylene chloride. The organic layer was washed with
saturate sodium
bicarbonate (2x), and IN NaOH (lx), dried over magnesium sulfate, and
concentrated to provide
a white solid which was purified by flash silica gel chromatography (gradient
of ethyl
acetate/methanol). [M+H]+ = 415.8 m/z. Activity: B
320
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 339
I U~IN-~ T- O-P
CT
(111-59)
[00384] 3-(Pyrrolidin-1-yl)-4,5-dihydroisoxazole 111-59 was prepared in 1 step
according to
the following procedure: 3-bromo-4,5-dihydroisoxazole 111-18 (1.0 equiv) was
dissolved in
n-butanol (0.64 M) followed by the addition of pyrollidine (1.2 equiv) and
sodium carbonate
(2.5 equiv). The reaction is the sealed and heated in an oil bath to 120 C
for 18h after which it
allowed to cool and then transferred to a separatory funnel with excess water
and tert-
butylmethyl ether. The aqueous layer was washed with tert-butylmethyl ether
(2x) and the
combined organic layers were washed with brine, dried over magnesium sulfate
and concentrate
to provide a orange solid that was purified using flash silica gel
chromatography (gradient ethyl
acetate/hexanes) to provide 111-59 as a white solid. [M+H]+ = 345.4 m/z.
Activity: C
Example 340
Me
1)CN
~ -
% O
ci I
(111-60)
[00385] 1-(4,5-Dihydroisoxazol-3-yl)-l-methylpyrrolidinium iodide 111-60 was
synthesized according to the following procedure: 3-(pyrrolidin-1-yl)-4,5-
dihydroisoxazole
111-59 was dissolved in methanol (0.044 M) followed by the addition of methyl
iodide (0.022
M). The reaction was allowed to sit for 72h after which it was concentrated
and purified using
high pressure liquid chromatography (0.1 % formic acid). The desired fractions
were lyophilized
to provide the desired product plus some impurities which were removed by
washing the solid
with hexanes. Activity: C
321
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 341
Br
N-
O 0 O
/ 1)Method III-62a
2) Method 1 Br
HO N-
111-61 O1,
0
III-62b
(111-62)
[00386] 3-bromo-4,5-dihydroisoxazole III-62a and III-62b were synthesized in
three steps
according to the following procedures: phenyl boronic acid (2.0 equiv) is
suspended in toluene
(0.23 M with respect to boronic acid) and heated until a solution results. The
solvent is
evaporated and this process is repeated. The resulting anhydride is then
redissolved in
methylene chloride (0.23 M). 6-Hydroxy-3,4-dihydronaphthalen-1(2H)-one (1.0
equiv),
triethylamine (5.0 equiv) and copper acetate (0.95 equiv) are added and the
reaction is sealed and
stirred for 16h at room temperature. The mixture is then transferred to a
separatory funnel with
excess methylene chloride and water. The organic layer is then washed with
water, dilute
sodium hydroxide, and brine. The organic layer is dried with sodium sulfate,
and concentrated to
provide 111-61 as a brown oil which is converted directly to racemic 3-bromo-
4,5-
dihydroisoxazole 111-62 using Method 5 followed by Method 1. These compounds
can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 359.5 m/z. Activity: A
Example 342
N Br N Br
O Y O
ao
III-63a III-63b
322
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(111-63)
[00387] 3-bromo-4,5-dihydroisoxazole III-63a and III-63b was prepared using
the
analogous procedure as Example 341 except that 5-hydroxy-2,3-dihydro-lH-inden-
l-one was
used in place of 6-hydroxy-3,4-dihydronaphthalen-1(2H)-one as the starting
material in the
first step. These compounds can be separated using chiral HPLC methods known
in the art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 343.7 m/z.
Activity: A
Example 343
N
ONYO ) ONE 0
ao
III-64a III-64b
(111-64)
[00388] 3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole III-60a and III-60b were
prepared in
1 step from racemic compound 111-63 and 5-hydroxypyrimidine using Method 5.
These
compounds can be separated using chiral HPLC methods known in the art. For
example, see
chiral HPLC Method disclosed herein. [M+H]+ = 361.2 m/z. Activity: A
Example 344
Y Br
NI
O 0 F3CO
F3CO OH 1) I 1) Method III-66a
2) AIC13 F3CO - 2) Method 1 N Br
0
111-65
11
F3CO
III-66b
(111-66)
[00389] 3-bromo-4,5-dihydroisoxazole III-66a and III-66b were synthesized in
four steps
according to the following procedures: A 250 mL round bottom flask with 10/30
thermometer
port is fitted with a stir bar, analog thermometer, and Allihn condenser. 3-(3-
323
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(Trifluoromethoxy)phenyl)propanoic acid (0.22 mol, 1.0 equiv) is added,
dissolved in thionyl
chloride (6.0 equiv), and refluxed in an oil bath during I h during which time
the internal temp
78-82 C across the hour. At this time, the condenser is replaced with a short-
path head and the
thermometer with an inlet for a stream of dry argon, and the volatiles removed
by distillation.
When distillation is complete, cyclohexane (100 mL) is added to the pot and is
distilled out in the
same manner to provide the desired acid chloride in quantitative yield as a
brown oil that is used
directly. A 2L 3-necked round bottom flask is then fitted with a mechanical
stirrer,
thermocouple probe, and a 250-mL pressure-equalized dropping funnel. It is
charged with
aluminum trichloride (0.233 mol, 1.08 equiv) and methylene chloride (0.24 M),
then stirred 45
min to dissolve as much as possible. The reaction is then chilled in an ice
bath to an internal
temp of <2.5 C. A solution of acid chloride (1.0 equiv, 0.215 mol) in 200 ml
methylene chloride
is added via an addition funnel over 15 min. After the addition is complete,
the ice is removed
from the bath and replaced with room-temperature water (bath temperature at 18
C) and the
reaction allowed to proceed for 2h more, at which point the reaction is
indicated to be complete
by TLC and LC/MS analysis. The reaction mixture is then treated with ice (500
g, and then
water (600 mL) after which the mixture stirred for lh until all solids have
dissolved. The layers
are separated and the water layer is extracted with diethyl ether (350 mL).
The combined
organics are washed with water (250 mL, lx), half-saturated sodium bicarbonate
(250 mL, lx),
brine (250 mL, lx), dried over magnesium sulfate and concentrated to provide 5-
(trifluoromethoxy)-2,3-dihydro-lH-inden-l-one 111-65 as a pink solid in
quantitative yield.
This material is then is converted directly to racemic 3-bromo-4,5-
dihydroisoxazole 111-66
using Method 5 followed by Method 1. These compounds can be separated using
chiral HPLC
methods known in the art. For example, see chiral HPLC Method disclosed
herein. [M+H]+ _
335.6 m/z. Activity: A
Example 345
N ` O -N N O -01, tl- ~ = SMe SMe
F3CO F3CO
III-67a III-67b
(111-67)
324
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00390] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-67a and III-67b were
prepared in 2
step from racemic compound 111-66 and 6-(methylthio)pyridin-3-ol using Method
5 after 6-
(methylthio)pyridin-3-ol is first prepared from 6-(methylthio)pyridin-3-
ylboronic acid using
Method 11. These compounds can be separated using chiral HPLC methods known in
the art.
For example, see chiral HPLC Method disclosed herein. [M+H]+ = 396.7 m/z.
Activity: A
Example 346
N ~ N N O ~ N
O I o O, I / o
`` e S. S.
Me OMe
F3CO F3CO
III-68a III-68b
(111-68)
[00391] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-68a and III-68b were
prepared in 1
step from racemic compound 111-67 using analogous oxidation conditions as in
Example 338.
These compounds can be separated using chiral HPLC methods known in the art.
For example,
see chiral HPLC Method disclosed herein. [M+H]+ = 429.4 m/z. Activity: A
Example 347
O N~YO I N
Br Me McMeMe N-N Me I ~~ N-Me
N 0,B.0 Pd(PPh3)4 111-66 F3CO III-70a
\ Na2CO3 N Method 5 N 0 - N
OH N-N 0 I /
_ N-Me
'Me OH
III-69 F3CO III-70b
(111-70)
[00392] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-70a and III-70b were
prepared in 2
steps according to the following procedures: 6-bromopyridin-3-ol (1.0 equiv)
and sodium
carbonate (10.0 equiv) are added to a microwave vial. Toluene, ethanol, and
water (0.16 M,
2:2:1 v/v) are added followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-
1H-pyrazole (1.5 equiv). The mixture is purged with argon for 15 min followed
by the addition
325
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
of palladium tetrakis (4 mol%). The reaction tube is then covered with
aluminum foil and heated
to 80 C in an oil bath for 17h. After cooling the reaction was transferred to
a separatory funnel
with excess water and ethyl acetate. The organic layer was then washed with
water (lx),
saturated ammonium chloride (lx) and brine (lx). The aqueous layers were
combined and
washed with ethyl acetate (lx). The organic layers were then combined, dried
over sodium
sulfate, concentrated and purified using flash silica gel chromatography
(gradient
methanol/methylene chloride) to provide 6-(1-methyl-lH-pyrazol-4-yl)pyridin-3-
ol 111-69 as
a white solid. This compound is then reacted with racemic 3-bromo-4,5-
dihydroisoxazole III-
66 using Method 5 to provide the desired racemic compound 111-70. These
compounds can be
separated using chiral HPLC methods known in the art. For example, see chiral
HPLC Method
disclosed herein. [M+H]+ = 430.0 m/z. Activity: A
Example 348
N7 O ~ N Me N O N Me
O I I/ 01, I/ N
I /N /N
F3CO F3CO
III-71 a 111-71b
(111-71)
[00393] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-71a and III-71b were
prepared
using the analogous procedure as Example 347 except that 1-methyl-5-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used in place of 1-methyl-4-(4,4,5,5-
tetramethyl-
1,3,2-dioxaborolan-2-yl)-1H-pyrazole as the boronoate in the first step. These
compounds can
be separated using chiral HPLC methods known in the art. For example, see
chiral HPLC
Method disclosed herein. [M+H]+ = 430.0 m/z. Activity: A
326
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
Example 349
NTO ~N
O
,III /
CO2Me O N F CO N 0
1) H2NNH2 111-66 3 III-73a NJ
N 2) HC(OEt)2 Method 5
OH N O N
N
OH O
III-72
F3CO N ~ 0
III-73b NJ
(111-73)
[00394] 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-73a and III-73b were
prepared in 3
steps according to the following procedures: 5-hydroxynicotinic acid methyl
ester is reacted
with (1.0 equiv) is dissolved in methanol (0.08 M) after which hydrazine (50
equiv, 50% by
weight in water) is added and the reaction is allowed to stir for 14h. The
reaction mixture is then
concentrated under vacuum and used directly in the next step.
Triethylorthoformate (8.0 equiv)
is added and the reaction is sealed and heated to reflux for 14h. The reaction
is then transferred
to a separatory funnel with excess ethyl acetate and water. The organic layer
was washed water
and brine, drive over sodium sulfate and concentrated under vacuum to provide
crude material
which was purified using flash silica gel chromatography (gradient
methanol/methylene chloride.
to provide the desired oxadiazole 111-72. This compound is then reacted with
racemic 3-
bromo-4,5-dihydroisoxazole 111-66 using Method 5 to provide the desired
racemic compound
111-73. These compounds can be separated using chiral HPLC methods known in
the art. For
example, see chiral HPLC Method disclosed herein. [M+H]+ = 419.5 m/z.
Activity: A
Example 350
N 0 N 0 01. =,% C02H CO2H
F3CO F3CO
III-74a III-74b
(111-74)
327
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00395] The enantiomers of 3-(pyridin-3-yloxy)-4,5-dihydroisoxazole III-74a
and III-74b
were prepared in 2 steps according to the following procedures: racemic 3-
bromo 4,5-
dihydroisoxazole 111-66 was reacted with 5-hydroxynicotinic acid methyl ester
using Method 5.
The resulting ester (1.0 equiv) was dissolved in 1:1 tetrahydrofuran/water
(0.06 M) and lithium
hydroxide (8.0 equiv) was added. The reaction was allowed to stir at room
temperature for lh
after which point the tetrahydrofuran was removed under a stream of nitrogen
and the remaining
solution was acidified to pH<2 with IN HC1 to provide the racemic desired acid
111-74 as a
white solid which was isolated via vacuum filtration. These compounds can be
separated using
chiral HPLC methods known in the art. For example, see chiral HPLC Method
disclosed herein.
[M+H]+ = 395.5 m/z. Activity: A
Example 351
Inhibition of Human FAAH
[00396] Human FAAH Preparation: COS-7 cells were split the day before, 1:5
into 150 mm x
25 mm cell culture dishes (Coming Inc., Cat. No. 430599). Transient
transfection took place at
30-40% confluency according to FuGENE 6 Transfection Reagent (Roche, Cat. No.
11814 443
001).
[00397] Transfection Procedure: The FuGENE transfection 6 reagent (45uL) was
added to
1410 gL of media (DMEM, serum free without pen/strep) in a 15 mL conical tube
and incubated
at room temp for 5 minutes, followed by the addition of FAAH plasmid DNA (15
g) (OriGene
Cat. No. TC119221, Genbank Accession No. NM001441.1, 0.67 ug/uL) and a further
incubation of 15 minutes at room temperature. The resulting solution was added
into one dish of
30-40% confluent COS-7 cells in a drop-wise manner. The COS-7 cell dish was
subsequently
incubated for 48 hours. The cells are then harvested.
[00398] Harvest procedure: Media was aspirated from the dishes and the cells
rinsed with
lOmL PBS. The PBS was removed and 3 mL of PBS added to the dish. The dish was
scraped to
resuspend the cells, and the subsequent cell suspension collected into a 15 mL
conical tube. The
cells were pelleted by centrifugation at 1200 rpm for 5 minutes in a bench top
centrifuge. PBS
was removed and the cell pellet snap frozen in liquid nitrogen and stored at -
80 C.
[00399] COS-7 cells - FAAH purification:
328
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
(1) Fractionation: Frozen cell pellets from transient transfections were
thawed on ice and
resuspended in 12.5mM Hepes pH 8.0, 100mM NaCl, 1mM EDTA (10 mL/0.2 g cell
pellet). The pellets were dounce homogenized and then sonicated to produce
cell extract.
The cell extract was subsequently centrifuged at 1000 g to remove cellular
debris. The
pellet was discarded and the supernatant centrifuged at 13,000 g for 20
minutes. The
pellet contained membrane bound FAAH. The supernatant was discarded and the
pellet
resolubilized.
(2) Re-solubilization: The fraction of interest, (13,000g, membrane fraction)
was re-
suspended in 2.3 mL re-suspension buffer (20mM Hepes pH 7.8, 10%v/v Glycerol,
1
mM EDTA, 1% Triton X-100) and the sample incubated on ice for 1 hour and then
centrifuged to remove any particulate matter. The supernatant containing
solubilized
human FAAH was aliquoted and snap frozen in liquid nitrogen and stored at -80
C until
use.
(3) Characterization: Protein Concentration determined by Bradford assay.
SDS gel and Western blot to confirm presence of FAAH
FAAH activity assay
Km determination - 96-well assay
Linear dependence - 96-well assay
Standard compound Ki determination - 384-well assay
[00400] Human FAAH assay; Experimental Protocol: A 0.1 mg/mL Human FAAH
solution
was made up in FAAH reaction buffer, and 24 ul pipeted into a 384 well plate.
To this was added
1 gL of a 3 fold serially diluted inhibitor from a DMSO stock solution. The
FAAH solution and
inhibitor were incubated for 30 minutes at room temperature. The FAAH reaction
was initiated
by the addition of 25 gL of 40 gM AMC Arachidonoyl Amide in FAAH reaction
buffer,
yielding a final reaction human FAAH preparation concentration of 0.05 mg/ml
and AMC-
Arachidonoyl substrate concentration of 20 M, reaction volume 50 L. The
reaction was
allowed to proceed for 4 hours at room temperature. The reaction was stopped
by the addition of
25 gL 12 gM a-ketoheterocycle (Cayman Chemicals, catalogue # 10435). The
microtiter plate
was read in the envision plate reader.
329
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
[00401] The raw fluorescence was plotted on the y axis and the inhibitor
concentration on the
x axis to give a dose response inhibition curve. The data was fitted to a
single site competitive
inhibition equation, fixing the Km for the human enzyme to 12 gM and 9 gM
respectively.
[00402] Other assays which can be used to determine the inhibition of FAAH by
the
compounds of the present invention include: (1) a fluorescence-based assay for
fatty acid amide
hydrolase compatible with high-throughput screening as described in Manjunath
et at.,
Analytical Biochemistry (2005) 343:143-151; and (2) a high-throughput
screening for the
discovery of inhibitors of fatty acid amide hydrolase using a microsome-based
fluorescent assay.
Wang et at., Biomolecular Screening (2006) 1-9.
Example 352
Evidence for Covalent Complex Formation between Serine-241 of FAAH and
Isoxazolines
[00403] Treatment of rat FAAH protein with the active site-directed
irreversible inhibitor
methoxy arachidonyl fluorophosphonate results in a crystal structure wherein
methoxy
arachidonyl phosphonate is covalently bound to the side chain of Ser-241
(Bracey et at., Science
(2002) 298:1793-1796).
[00404] Based on this data, it is hypothesized that the isoxazoline compounds
of the present
invention form covalent complexes with the nucleophilic side chain of Ser-241.
This hypothesis
is consistent with the kinetic data, with the proposed binding involving
nucleophilic attack of the
isoxazoline electrophile by the active site Ser-241, resulting in the
elimination of the leaving
group from the cytosolic port, and the subsequent formation of a covalent
enzyme-isoxazoline
adduct. Recovery of activity would subsequently involve a deacylation
reaction, which would
occur inefficiently, if at all, for the covalent enzyme-isoxazoline adduct.
[00405] Recovery of activity experiments were performed via a jump dilution
method which
involved rapidly diluting the enzyme-inhibitor complex 5-fold below its
apparent Ki, and
measuring activity as a function of time. Little or no enzyme activity was
regained over a period
of two hours, indicating essentially irreversible inhibition, or a very slowly
hydrolysable
complex, supporting the above hypothesis.
330
CA 02762527 2011-11-17
WO 2010/135360 PCT/US2010/035309
OTHER EMBODIMENTS
[00406] Those skilled in the art will recognize, or be able to ascertain using
no more than
routine experimentation, many equivalents to the specific embodiments of the
invention
described herein. Such equivalents are intended to be encompassed by the
following claims.
331
