U.S. patent application number 15/879792 was filed with the patent office on 2018-05-31 for benzoimidazol-1,2-yl amides as kv7 channel activators.
The applicant listed for this patent is Knopp Biosciences LLC. Invention is credited to Justin K. BELARDI, Charles A. FLENTGE, James S. HALE, Scott S. HARRIED, David A. MARESKA, Lynn RESNICK, George T. TOPALOV.
Application Number | 20180148419 15/879792 |
Document ID | / |
Family ID | 55454102 |
Filed Date | 2018-05-31 |
United States Patent
Application |
20180148419 |
Kind Code |
A1 |
RESNICK; Lynn ; et
al. |
May 31, 2018 |
BENZOIMIDAZOL-1,2-YL AMIDES AS Kv7 CHANNEL ACTIVATORS
Abstract
Optionally substituted benzoimidazol-1,2-yl amides, such as
compounds of Formula 1 or Formula 2, can be used to treat disorders
associated with a Kv7 potassium channel activator. Compositions,
medicaments, and dosage forms related to the treatment are also
disclosed herein.
Inventors: |
RESNICK; Lynn; (Pittsburgh,
PA) ; TOPALOV; George T.; (Pittsburgh, PA) ;
BELARDI; Justin K.; (Pittsburgh, PA) ; HALE; James
S.; (Pittsburgh, PA) ; HARRIED; Scott S.;
(Pittsburgh, PA) ; FLENTGE; Charles A.; (Mars,
PA) ; MARESKA; David A.; (McMurray, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Knopp Biosciences LLC |
Pittsburgh |
PA |
US |
|
|
Family ID: |
55454102 |
Appl. No.: |
15/879792 |
Filed: |
January 25, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15339590 |
Oct 31, 2016 |
9914708 |
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15879792 |
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14853815 |
Sep 14, 2015 |
9481653 |
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15339590 |
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62050023 |
Sep 12, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/06 20180101;
C07D 403/04 20130101; C07D 401/04 20130101; C07D 401/12 20130101;
A61P 25/08 20180101; A61P 29/00 20180101; C07D 405/12 20130101;
C07D 235/30 20130101; C07D 413/04 20130101 |
International
Class: |
C07D 235/30 20060101
C07D235/30; C07D 401/12 20060101 C07D401/12; C07D 403/04 20060101
C07D403/04; C07D 405/12 20060101 C07D405/12; C07D 413/04 20060101
C07D413/04; C07D 401/04 20060101 C07D401/04 |
Claims
1-21. (canceled)
22. A compound represented by a formula: ##STR00315## wherein: D is
optionally substituted cyclobutyl; A is C.sub.4 alkyl; X is
CF.sub.3; Y is H; R.sup.1 is C.sub.3 hydroxyalkyl; R.sup.2 and
R.sup.4 are H; and R.sup.3 is F.
23. A composition comprising a compound of claim 22, wherein the
composition is pharmaceutically acceptable and further comprises a
pharmaceutically acceptable excipient.
24. A method of treating a disorder associated with a Kv7 potassium
channel activator comprising administering an effective amount of a
compound of claim 22 to a mammal in need thereof.
25. The method of claim 24, wherein the disorder is selected from
epilepsy, pain, tinnitus, migraine, a disorder of neurotransmitter
release, a smooth muscle contractility disorder, a dyskinesia,
dystonia, mania, a hearing disorder, anxiety, substance abuse,
schizophrenia, a bladder disorder, a vasculature disorder,
neuropathic pain, inflammatory pain, persistent pain, cancer pain
and postoperative pain.
26. A compound represented by a formula: ##STR00316## wherein: D is
optionally substituted cyclobutyl; A is C.sub.4 alkyl; X is
CF.sub.3; Y is H; R.sup.1 is C.sub.3 hydroxyalkyl; and R.sup.2,
R.sup.3, and R.sup.4 are H.
27. A composition comprising a compound of claim 26, wherein the
composition is pharmaceutically acceptable and further comprises a
pharmaceutically acceptable excipient.
28. A method of treating a disorder associated with a Kv7 potassium
channel activator comprising administering an effective amount of a
compound of claim 26 to a mammal in need thereof.
29. The method of claim 28, wherein the disorder is selected from
epilepsy, pain, tinnitus, migraine, a disorder of neurotransmitter
release, a smooth muscle contractility disorder, a dyskinesia,
dystonia, mania, a hearing disorder, anxiety, substance abuse,
schizophrenia, a bladder disorder, a vasculature disorder,
neuropathic pain, inflammatory pain, persistent pain, cancer pain
and postoperative pain.
30. A compound represented by a formula: ##STR00317## wherein: D is
t-butyl; A is C.sub.5 alkyl; X is H; Y is H; R.sup.1 is CN; R.sup.2
and R.sup.4 are H; and R.sup.3 is F.
31. A composition comprising a compound of claim 30, wherein the
composition is pharmaceutically acceptable and further comprises a
pharmaceutically acceptable excipient.
32. A method of treating a disorder associated with a Kv7 potassium
channel activator comprising administering an effective amount of a
compound of claim 30 to a mammal in need thereof.
33. The method of claim 32, wherein the disorder is selected from
epilepsy, pain, tinnitus, migraine, a disorder of neurotransmitter
release, a smooth muscle contractility disorder, a dyskinesia,
dystonia, mania, a hearing disorder, anxiety, substance abuse,
schizophrenia, a bladder disorder, a vasculature disorder,
neuropathic pain, inflammatory pain, persistent pain, cancer pain
and postoperative pain.
34. A compound represented by a formula: ##STR00318## wherein: D is
t-butyl; A is C.sub.5 alkyl; X is H; Y is H; R.sup.1 is CN; R.sup.2
and R.sup.3 are F; and R.sup.4 is H.
35. A composition comprising a compound of claim 34, wherein the
composition is pharmaceutically acceptable and further comprises a
pharmaceutically acceptable excipient.
36. A method of treating a disorder associated with a Kv7 potassium
channel activator comprising administering an effective amount of a
compound of claim 34 to a mammal in need thereof.
37. The method of claim 36, wherein the disorder is selected from
epilepsy, pain, tinnitus, migraine, a disorder of neurotransmitter
release, a smooth muscle contractility disorder, a dyskinesia,
dystonia, mania, a hearing disorder, anxiety, substance abuse,
schizophrenia, a bladder disorder, a vasculature disorder,
neuropathic pain, inflammatory pain, persistent pain, cancer pain
and postoperative pain.
38. A compound represented by a formula: ##STR00319## wherein: D is
t-butyl; A is C.sub.4 alkyl; X is CF.sub.3; Y is H; R.sup.1 is CN;
R.sup.2 and R.sup.4 are H; and R.sup.3 is F.
39. A composition comprising a compound of claim 38, wherein the
composition is pharmaceutically acceptable and further comprises a
pharmaceutically acceptable excipient.
40. A method of treating a disorder associated with a Kv7 potassium
channel activator comprising administering an effective amount of a
compound of claim 38 to a mammal in need thereof.
41. The method of claim 40, wherein the disorder is selected from
epilepsy, pain, tinnitus, migraine, a disorder of neurotransmitter
release, a smooth muscle contractility disorder, a dyskinesia,
dystonia, mania, a hearing disorder, anxiety, substance abuse,
schizophrenia, a bladder disorder, a vasculature disorder,
neuropathic pain, inflammatory pain, persistent pain, cancer pain
and postoperative pain.
Description
CROSS-REFERENCE TO RELATED CASES
[0001] The present application is a continuation of U.S. patent
application Ser. No. 14/853,815, (U.S. Publication No. 2016-0075663
A1) filed Sep. 14, 2015, which claims the benefit of U.S.
Provisional application No. 62/050,023, filed Sep. 12, 2014, the
entire disclosure of which is incorporated herein by reference.
BACKGROUND
[0002] Potassium (K.sup.+) channels, present on the plasma
membranes of most cell types, are the most diverse class of all ion
channels and are associated with a wide range of physiological
functions including the regulation of the electrical properties of
excitable cells. The primary pore-forming (.alpha.) subunits of
these highly selective cation channels are divided into three
primary structural classes based on the number of transmembrane
(TM)-spanning regions and pore (P) regions: currently there are
known to be 6TM/1P, 2TM/1P and 4TM/2P K.sup.+ channels. The Kv7
genes (originally termed KCNQ, a name assigned by the HUGO Gene
Nomenclature Committee (HGNC)) were assigned to a subfamily of
voltage-gated K.sup.+ channels by the International Union of
Pharmacology (IUPHAR). The Kv7 subfamily consists of five
homologous pore-forming a subunits, Kv7.1-7.5, that have a
structure typical of voltage-gated K.sup.+ channels with
6TM-spanning regions (S1-S6) flanked by intracellular N-terminal
and C-terminal domains, a typical voltage-sensor domain located in
S4 comprised of alternating positively-charged residues and a
single P region between S5 and S6 of each subunit. The channels are
formed as tetramers of the primary a subunits, either as
homotetramers or heterotetramers. Neurons are known to express Kv7
channels comprised of Kv7.2-7.5.alpha. subunits. Some of these gene
products may be exclusively neuronal while others, such as Kv7.4
and Kv7.5, can be found in other tissues such as smooth and
skeletal muscle.
[0003] Native M-channels, and the corresponding macroscopic
M-current, were first characterized in amphibian sympathetic
neurons. M-channels were notable because they were slowly
activating and non-inactivating, active at membrane potentials at
or near the resting membrane potential of neurons and muscarinic
cholinergic agonists produced a reduction in the M-current,
demonstrating a direct and inhibitory link between G-protein
coupled receptors (GPCRs) and a physiological K.sup.+ current. It
was not until the cloning of this subfamily of genes that the
pharmacological and biophysical identity was established between
Kv7.2/7.3 (and likely Kv7.5/7.3) heteromultimers and the elusive
`M`-channel, providing significant new evidence for their
importance in neuronal regulation.
[0004] The distributions of these channels, both regionally and
developmentally, as well as their biophysical characteristics,
support their role in providing enduring resistance to depolarizing
excitatory influences. Under physiological conditions, as was
demonstrated with native M-channels, they can be very effective at
regulating the sub-threshold excitability of certain neuronal
populations with significant roles in regulating the frequency and
ultimately the pattern of action potential discharge in many types
of neurons. Their importance in neuronal regulation was punctuated
by the discovery that neuronal Kv7 mutations lead to benign
familial neonatal convulsions (BFNC) indicating that reduction or
removal of the influence of Kv7.2 and Kv7.3 channels can
dramatically alter neuronal excitability. Mutation analyses
demonstrated their involvement in BFNC and suggested their utility
as targets for anti-epileptic drugs (AEDs).
[0005] Unlike established pharmacological terminology for GPCRs,
the mode of action of K.sup.+ channel modulators, in particular
compounds that activate the channel, is still being refined. The
application of voltage-clamp techniques to the study of ion channel
pharmacology enabled detailed biophysical studies on either
whole-cell currents or single channels, allowing some
characterization of the nature of compound-channel interactions but
not preventing ongoing confusion around the terminology. The term
opener or activator is commonly used throughout the literature but
does not adequately describe the mode of action of all these
`positive modulator` compounds. In general, openers or activators
are expected to increase the open probability of the channel or
increase macroscopic current amplitude, but this nomenclature is
really too simplistic. For example, retigabine, the first publicly
disclosed Kv7 opener, has a complex and interesting profile in that
it has inhibitory activity at higher membrane potentials. Neuronal
Kv7 channel openers may work in concert with the activity of a
channel over the `normal` activation-voltage range and enhance
currents without significantly affecting the activation threshold
while others can significantly alter the activation threshold. In
addition, some openers appear to remove the voltage-dependence of
activation entirely. Whether these effects represent some continuum
is currently unclear since the effects are often
concentration-dependent. Clearly, the modes of interaction of
compounds that can increase channel current are complex and in most
cases not well understood and the implications of these profiles on
neuronal responsiveness and systems physiology are also unclear.
Retigabine is modestly potent, not highly specific, but it is a
very effective opener of Kv7.2, Kv7.5 and heteromultimeric Kv7
channels. Its effects are characterized by a significant increase
in channel current over a narrow voltage range. As mentioned above,
at more positive voltages the opener is less effective and under
some conditions channel current significantly decreases at more
positive voltages relative to control currents (this `crossover`
voltage-dependence of opener action is a characteristic of many
neuronal Kv7 channel openers). This effect is also
concentration-dependent and is more pronounced at higher
concentrations.
SUMMARY
[0006] Described herein are compounds that can be potent and/or at
least biased for the Kv7.2/7.3 heteromultimer over the Kv7.4
homomultimer. These compounds may have reduced untoward side
effects as compared to retigabine.
[0007] Some embodiments include a compound represented by Formula
1:
##STR00001##
[0008] wherein D is optionally substituted C.sub.3-6 carbocyclyl,
C.sub.2-5 heterocyclyl, or C.sub.1-4 alkyl; Bz is optionally
substituted benzoimidazol-1,2-diyl or optionally substituted
benzoimidazol-1,2,6-triyl; A is C.sub.1-8 alkyl; X is H, F,
CF.sub.3, optionally substituted phenyl, or optionally substituted
pyridinyl; and Y is H, F, Cl, Br, I, or a moiety having a molecular
weight of 15 Da to 300 Da and consisting of 2 to 5 chemical
elements, wherein the chemical elements are independently C, H, O,
N, S, F, Cl, or Br.
[0009] Some embodiments include a composition comprising a compound
described herein, such as a compound of Formula 1 or Formula 2,
wherein the composition is pharmaceutically acceptable.
[0010] Some embodiments include a pharmaceutical dosage form
comprising a compound described herein, such as a compound of
Formula 1 or Formula 2.
[0011] Some embodiments include a method of treating a disorder
associated with a Kv7 potassium channel activator comprising
administering an effective amount of a compound described herein,
such as a compound of Formula 1 or Formula 2, to a mammal in need
thereof.
[0012] Some embodiments include use of a compound of Formula 1 or
Formula 2, in the manufacture of a medicament for the treatment of
a disorder associated with a Kv7 potassium channel activator.
DETAILED DESCRIPTION
[0013] Unless otherwise indicated, when a compound or chemical
structural feature such as benzoimidazol-1,2-yl is referred to as
being "optionally substituted," it includes a feature that has no
substituents (i.e. unsubstituted), or a feature that is
"substituted," meaning that the feature has one or more
substituents. The term "substituent" has the broadest meaning known
to one of ordinary skill in the art and includes a moiety that
replaces one or more hydrogen atoms attached to a parent compound
or structural feature. In some embodiments, a substituent may be an
ordinary organic moiety known in the art, which may have a
molecular weight (e.g. the sum of the atomic masses of the atoms of
the substituent) of 15 Da to 50 Da, 15 Da to 100 Da, 15 Da to 150
Da, 15 Da to 200 Da, 15 Da to 300 Da, or 15 Da to 500 Da. In some
embodiments, a substituent comprises, or consists of: 0-30, 0-20,
0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0-10, or 0-5
heteroatoms, wherein each heteroatom may independently be: N, O, S,
Si, F, Cl, Br, or I; provided that the substituent includes one C,
N, O, S, Si, F, Cl, Br, or I atom. Examples of substituents
include, but are not limited to, alkyl, alkenyl, alkynyl,
heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl,
hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol,
alkylthio, cyano, halo, thiocarbonyl, O-carbamyl, N-carbamyl,
O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,
N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro,
silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl,
trihalomethanesulfonyl, trihalomethanesulfonamido, amino, etc.
[0014] For convenience, the term "molecular weight" is used with
respect to a moiety or part of a molecule to indicate the sum of
the atomic masses of the atoms in the moiety or part of a molecule,
even though it may not be a complete molecule.
[0015] The structures associated with some of the chemical names
referred to herein are depicted below. These structures may be
unsubstituted, as shown below, or a substituent may independently
be in any position normally occupied by a hydrogen atom when the
structure is unsubstituted. Unless a point of attachment is
indicated by
##STR00002##
attachment may occur at any position normally occupied by a
hydrogen atom.
##STR00003##
[0016] As used herein, the term "alkyl" has the broadest meaning
generally understood in the art and may include a moiety composed
of carbon and hydrogen containing no double or triple bonds. Alkyl
may be linear alkyl, branched alkyl, cycloalkyl, or a combination
thereof and in some embodiments, may contain from one to
thirty-five carbon atoms. In some embodiments, alkyl may include
C.sub.1-10 linear alkyl, such as methyl (--CH.sub.3), methylene
(--CH.sub.2--), ethyl (--CH.sub.2CH.sub.3), ethylene
(--C.sub.2H.sub.4--), propylene (--C.sub.3CH.sub.6--), n-butyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.3), n-pentyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), n-hexyl
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3), etc.;
C.sub.3-10 branched alkyl, such as C.sub.3H.sub.7 (e.g.
iso-propyl), C.sub.4H.sub.9 (e.g. branched butyl isomers),
C.sub.5H.sub.11 (e.g. branched pentyl isomers), C.sub.6H.sub.13
(e.g. branched hexyl isomers), C.sub.7H.sub.15 (e.g. heptyl
isomers), etc.; C.sub.3-10 cycloalkyl, such as C.sub.3H.sub.5 (e.g.
cyclopropyl), C.sub.4H.sub.7 (e.g. cyclobutyl isomers such as
cyclobutyl, methylcyclopropyl, etc.), C.sub.5H.sub.9 (e.g.
cyclopentyl isomers such as cyclopentyl, methylcyclobutyl,
dimethylcyclopropyl, etc.) C.sub.6H.sub.11 (e.g. cyclohexyl
isomers), C.sub.7H.sub.13 (e.g. cycloheptyl isomers), etc.; and the
like.
[0017] As used herein, the term "carbocyclyl" has the broadest
meaning generally understood in the art and includes rings free of
heteroatoms, such as cycloalkyl, e.g. cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, etc.; cycloalkenyl, e.g. cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclohexenyl; cycloalkynyl, e.g.
cyclopropynyl, cyclobutynyl, cyclopentynyl, cyclohexynyl; as well
as aryl rings free of heteroatoms.
[0018] As used herein the term "aryl" has the broadest meaning
generally understood in the art and may include an aromatic ring or
aromatic ring system such as phenyl, naphthyl, etc.
[0019] The term "heterocyclyl" includes any ring or ring system
containing a heteroatom such as N, O, S, P, etc. Heterocyclyl
includes heteroaryl rings or ring systems (such as those listed
below) and non-aromatic rings or ring systems. Examples of
non-aromatic heterocyclyl include azetidinyl, oxatanyl, thietanyl,
pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl,
pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,
isothiazolidinyl, dioxalanyl, dithiolanyl, tetrahydropyranyl,
piperidinyl, piperazinyl, morpholino, etc.
[0020] The term "heteroaryl" also has the meaning understood by a
person of ordinary skill in the art and includes an "aryl" which
has one or more heteroatoms in the ring or ring system, such as
pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl,
triazolyl, oxadiazolyl, isoxazolyl, indolyl, quinolinyl,
benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl,
benzoimidazolyl, etc.
[0021] Unless otherwise indicated, any reference to a compound
herein by structure, name, or any other means includes
pharmaceutically acceptable salts, such as HCl, HBr, HI,
H.sub.2SO.sub.4, acetate, citrate, sodium, potassium, and ammonium
salts; prodrugs, such as ester prodrugs; alternate solid forms,
such as polymorphs, solvates, hydrates, etc.; tautomers; or any
other chemical species that may rapidly convert to a compound
described herein under conditions in which the compounds are used
as described.
[0022] If stereochemistry is not indicated, a name or structural
representation includes any stereoisomer or any mixture of
stereoisomers.
[0023] With respect to Formula 1, Bz can be optionally substituted
benzoimidazol-1,2-yl. If the benzoimidazol-1,2-yl is substituted,
it may have 1, 2, 3, or 4 substituents. Any substituent may be
included on the benzoimidazol-1,2-yl. In some embodiments, some or
all of the substituents on the benzoimidazol-1,2-yl may have: from
0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each
heteroatom is independently: O, N, S, F, Cl, Br, or I (provided
that there is at least 1 non-hydrogen atom); and/or a molecular
weight of 15 g/mol to 500 g/mol. In some embodiments, some or all
of the substituents may each have a molecular weight of 15 Da to
200 Da, 15 Da to 100 Da, or 15 Da to 50 Da, and consist of 2 to 5
chemical elements, wherein the chemical elements are independently
C, H, O, N, S, F, Cl, or Br. In some embodiments, Bz can be
optionally substituted benzoimidazol-1,2-diyl. In some embodiments,
Bz can be optionally substituted benzoimidazol-1, 2, 6-triyl.
[0024] For example, with respect to Formula 1, the substituents of
Bz may be C.sub.1-10 optionally substituted alkyl, such as
CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7, cyclic C.sub.3H.sub.5,
C.sub.4H.sub.9, cyclic C.sub.4H.sub.7, C.sub.5H.sub.11, cyclic
C.sub.5H.sub.9, C.sub.6H.sub.13, cyclic C.sub.6H.sub.11, etc.,
which may be optionally substituted; C.sub.1-10 optionally
substituted alkoxy such as OCH.sub.3, OC.sub.2H.sub.5,
OC.sub.3H.sub.7, cyclic OC.sub.3H.sub.5, OC.sub.4H.sub.9, cyclic
OC.sub.4H.sub.7, OC.sub.5H.sub.11, cyclic OC.sub.5H.sub.9,
OC.sub.6H.sub.13, cyclic OC.sub.6H.sub.11, etc.; halo, such as F,
Cl, Br, I; OH; CN; NO.sub.2; C.sub.1-6 fluoroalkyl, such as
CF.sub.3, CF.sub.2H, C.sub.2F.sub.5, etc.; C.sub.1-6 fluoroalkoxy,
such as OCF.sub.3, OCF.sub.2H, OC.sub.2F.sub.5, etc.; a C.sub.1-10
ester such as --O.sub.2CCH.sub.3, --CO.sub.2CH.sub.3,
--O.sub.2CC.sub.2H.sub.5, --CO.sub.2C.sub.2H.sub.5,
--O.sub.2C-phenyl, --CO.sub.2-phenyl, etc.; a C.sub.1-10 ketone
such as --COCH.sub.3, --COC.sub.2H.sub.5, --COC.sub.3H.sub.7,
--CO-phenyl, etc.; or a C.sub.1-10 amine such as NH.sub.2,
NH(CH.sub.3), N(CH.sub.3).sub.2, N(CH.sub.3)C.sub.2H.sub.5, etc. In
some embodiments, a substituent of Bz may be F, Cl, Br, I, CN,
NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkyl-OH, C.sub.1-3 O-alkyl,
CF.sub.3, COH, C.sub.1-4 CO-alkyl, CO.sub.2H, C.sub.1-4
CO.sub.2-alkyl, NH.sub.2, or C.sub.1-4 alkylamino.
[0025] Some embodiments include a compound represented by Formula
2:
##STR00004##
[0026] With respect to any relevant structural representation, such
as Formula 1 or 2, D is optionally substituted C.sub.3-6
carbocyclyl or C.sub.2-5 heterocyclyl. If D is substituted
cyclobutyl, it may have 1, 2, 3, 4, 5, 6, or 7 substituents. If D
is substituted phenyl, it may have 1, 2, 3, 4, or 5 substituents.
If D is substituted isoxazolyl, it may have 1 or 2. D may include
any substituent. In some embodiments, some or all of the
substituents of D may have: from 0 to 10 carbon atoms and from 0 to
10 heteroatoms, wherein each heteroatom is independently: O, N, S,
F, Cl, Br, or I (provided that there is at least 1 non-hydrogen
atom); and/or a molecular weight of 15 g/mol to 500 g/mol. In some
embodiments, some or all of the substituents may each have a
molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to
50 Da, and consist of 2 to 5 chemical elements, wherein the
chemical elements are independently C, H, O, N, S, F, Cl, or
Br.
[0027] For example, with respect to any relevant structural
representation, such as Formula 1 or 2, the substituents of D may
be C.sub.1-10 optionally substituted alkyl, such as CH.sub.3,
C.sub.2H.sub.5, C.sub.3H.sub.7, cyclic C.sub.3H.sub.5,
C.sub.4H.sub.9, cyclic C.sub.4H.sub.7, C.sub.5H.sub.11, cyclic
C.sub.5H.sub.9, C.sub.6H.sub.13, cyclic C.sub.6H.sub.11, etc.,
which may be optionally substituted; C.sub.1-10 optionally
substituted alkoxy such as OCH.sub.3, OC.sub.2H.sub.5,
OC.sub.3H.sub.7, cyclic OC.sub.3H.sub.5, OC.sub.4H.sub.9, cyclic
OC.sub.4H.sub.7, OC.sub.5H.sub.11, cyclic OC.sub.5H.sub.9,
OC.sub.6H.sub.13, cyclic OC.sub.6H.sub.11, etc.; halo, such as F,
Cl, Br, I; OH; CN; NO.sub.2; C.sub.1-6 fluoroalkyl, such as
CF.sub.3, CF.sub.2H, C.sub.2F.sub.5, etc.; C.sub.1-6 fluoroalkoxy,
such as OCF.sub.3, OCF.sub.2H, OC.sub.2F.sub.5, etc.; a C.sub.1-10
ester such as --O.sub.2CCH.sub.3, --CO.sub.2CH.sub.3,
--O.sub.2CC.sub.2H.sub.5, --CO.sub.2C.sub.2H.sub.5,
--O.sub.2C-phenyl, --CO.sub.2-- phenyl, etc.; a C.sub.1-10 ketone
such as --COCH.sub.3, --COC.sub.2H.sub.5, --COC.sub.3H.sub.7,
--CO-phenyl, etc.; or a C.sub.1-10 amine such as NH.sub.2,
NH(CH.sub.3), N(CH.sub.3).sub.2, N(CH.sub.3)C.sub.2H.sub.5, etc. In
some embodiments, a substituent of D may be F, Cl, Br, I, CN,
NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkyl-OH, C.sub.1-3 O-alkyl,
CF.sub.3, COH, C.sub.1-4 CO-alkyl, CO.sub.2H, C.sub.1-4
CO.sub.2-alkyl, NH.sub.2, or C.sub.1-4 alkylamino.
[0028] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is:
##STR00005##
or optionally substituted C.sub.2-4 alkyl.
[0029] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is optionally substituted
cyclobutyl, optionally substituted phenyl, optionally substituted
isoxazolyl, or isopropyl.
[0030] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is optionally substituted
cyclobutyl. In some embodiments, D is cyclobutyl. In some
embodiments, D is
##STR00006##
[0031] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is isopropyl.
[0032] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is t-butyl, or
tert-butyl.
[0033] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is optionally substituted
phenyl. In some embodiments D
##STR00007##
[0034] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is optionally substituted
pyridinyl, such as optionally substituted pyridiny-2-yl,
pyridin-3-yl, or pyridin-4-yl. In some embodiments, D is
##STR00008##
[0035] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments, D is optionally substituted
isoxazolyl. In some embodiments, D is
##STR00009##
[0036] With respect to any relevant structural representation, such
as Formula 1 or 2, A is C.sub.2-8 alkyl, such as linear or
branched
##STR00010##
linear or branched
##STR00011##
linear or branched
##STR00012##
linear or branched
##STR00013##
linear or branched
##STR00014##
containing one ring,
##STR00015##
containing one ring,
##STR00016##
containing one ring,
##STR00017##
containing one ring, or
##STR00018##
containing a bicyclic ring system.
[0037] With respect to any relevant structural representation, such
as Formula 1 or 2, X is H, F, CF.sub.3, optionally substituted
phenyl, or optionally substituted pyridinyl. In some embodiments, X
is H. In some embodiments, X is F. In some embodiments, X is
CF.sub.3.
[0038] With respect to any relevant structural representation, such
as Formula 1 or 2, if X is substituted phenyl, it may have 1, 2, 3,
4, or 5, substituents. If X is substituted pyridinyl, it may have
1, 2, 3, or 4 substituents. In some embodiments, some or all of the
substituents of X may have: from 0 to 10 carbon atoms and from 0 to
10 heteroatoms, wherein each heteroatom is independently: O, N, S,
F, Cl, Br, or I (provided that there is at least 1 non-hydrogen
atom); and/or a molecular weight of 15 g/mol to 500 g/mol. In some
embodiments, some or all of the substituents may each have a
molecular weight of 15 Da to 200 Da, 15 Da to 100 Da, or 15 Da to
50 Da, and consist of 2 to 5 chemical elements, wherein the
chemical elements are independently C, H, O, N, S, F, Cl, or
Br.
[0039] For example, with respect to any relevant structural
representation, such as Formula 1 or 2, the substituents of X may
be C.sub.1-10 optionally substituted alkyl, such as CH.sub.3,
C.sub.2H.sub.5, C.sub.3H.sub.7, cyclic C.sub.3H.sub.5,
C.sub.4H.sub.9, cyclic C.sub.4H.sub.7, C.sub.5H.sub.11, cyclic
C.sub.5H.sub.9, C.sub.6H.sub.13, cyclic C.sub.6H.sub.11, etc.,
which may be optionally substituted; C.sub.1-10 optionally
substituted alkoxy such as OCH.sub.3, OC.sub.2H.sub.5,
OC.sub.3H.sub.7, cyclic OC.sub.3H.sub.5, OC.sub.4H.sub.9, cyclic
OC.sub.4H.sub.7, OC.sub.5H.sub.11, cyclic OC.sub.5H.sub.9,
OC.sub.6H.sub.13, cyclic OC.sub.6H.sub.11, etc.; halo, such as F,
Cl, Br, I; OH; CN; NO.sub.2; C.sub.1-6 fluoroalkyl, such as
CF.sub.3, CF.sub.2H, C.sub.2F.sub.5, etc.; C.sub.1-6 fluoroalkoxy,
such as OCF.sub.3, OCF.sub.2H, OC.sub.2F.sub.5, etc.; a C.sub.1-10
ester such as --O.sub.2CCH.sub.3, --CO.sub.2CH.sub.3,
--O.sub.2CC.sub.2H.sub.5, --CO.sub.2C.sub.2H.sub.5,
--O.sub.2C-phenyl, --CO.sub.2-- phenyl, etc.; a C.sub.1-10 ketone
such as --COCH.sub.3, --COC.sub.2H.sub.5, --COC.sub.3H.sub.7,
--CO-phenyl, etc.; or a C.sub.1-10 amine such as NH.sub.2,
NH(CH.sub.3), N(CH.sub.3).sub.2, N(CH.sub.3)C.sub.2H.sub.5, etc. In
some embodiments, a substituent of X may be F, Cl, Br, I, CN,
NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 alkyl-OH, C.sub.1-3 O-alkyl,
CF.sub.3, COH, C.sub.1-4 CO-alkyl, CO.sub.2H, C.sub.1-4
CO.sub.2-alkyl, NH.sub.2, or C.sub.1-4 alkylamino.
[0040] With respect to any relevant structural representation, such
as Formula 1 or 2, Y is H, F, Cl, Br, I, or a moiety having a
molecular weight of 15 Da to 300 Da and consisting of 2 to 5
chemical elements, wherein the chemical elements are independently
C, H, O, N, S, F, Cl, or Br. In some embodiments, Y is H, F, Cl,
Br, I, CN, --COH, C.sub.1-6 --CO-alkyl, CF.sub.3, OH, C.sub.1-5
O-alkyl, C.sub.0-6 amino, or C.sub.0-6 fluoroamino. In some
embodiments, Y is H, F, CF.sub.3, OH, C.sub.1-5 O-alkyl, C.sub.0-6
amino, or C.sub.0-6 fluoroamino. In some embodiments, Y is H. In
some embodiments, Y is OH. In some embodiments, Y is F. In some
embodiments, Y is CF.sub.3. In some embodiments, Y is C.sub.1-3
O-alkyl, such as --OCH.sub.3, OC.sub.2H.sub.5, OC.sub.3H.sub.7,
etc. In some embodiments, Y is C.sub.0-6 fluoroamino. In some
embodiments, Y is optionally substituted tetrahydropyranyl, such
as
##STR00019##
In some embodiments Y may include a C.sub.1-8 alkyl that may
include one or two C.sub.3-6 carbocyclyl rings. In some
embodiments, wherein Y includes at least one carbocyclyl rings, the
rings may be connected to each other. In some embodiments, Y is
--C(CF.sub.3).sub.2OH (or
1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl). In some embodiments Y
is
##STR00020##
(or methyl(2,2,2-trifluoroethyl)amino). In some embodiments, Y is
dimethylamino.
[0041] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00021##
is C.sub.2-8 alkyl, such as
##STR00022##
[0042] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00023##
is C.sub.2-8 hydroxyalkyl, such as
##STR00024##
[0043] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00025##
is C.sub.2-8 fluoroalkyl such as
##STR00026##
[0044] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00027##
is C.sub.2-8 alkoxyalkyl, such as
##STR00028##
[0045] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00029##
is C.sub.2-8 hydroxyfluoroalkyl, such as
##STR00030##
[0046] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00031##
is optionally substituted 2-hydroxy-2-phenylethyl, such as
##STR00032##
[0047] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00033##
is optionally substituted 2-hydroxy-2-phenylpyridinyl, such as
##STR00034##
[0048] With respect to any relevant structural representation, such
as Formula 1 or 2, in some embodiments
##STR00035##
is optionally substituted C.sub.2-8 fluoroaminoalkyl, such as
##STR00036##
[0049] Generally R.sup.1-18, may be H or any substituent, such as a
substituent having 0 to 12 atoms or 0 to 6 carbon atoms and 0 to 5
heteroatoms, wherein each heteroatom is independently: O, N, S, F,
Cl, Br, or I, and/or having a molecular weight of 15 g/mol to 300
g/mol. Any of R.sup.1-18 may comprise: a) 1 or more alkyl moieties
optionally substituted with, or optionally connected by or to, b) 1
or more functional groups, such as C.dbd.C, C.ident.C, CO,
CO.sub.2, CON, NCO.sub.2, OH, SH, O, S, N, N.dbd.C, F, Cl, Br, I,
CN, NO.sub.2, CO.sub.2H, NH.sub.2, etc.; or may be a substituent
having no alkyl portion, such as F, Cl, Br, I, NO.sub.2, CN,
NH.sub.2, OH, COH, CO.sub.2H, etc. In some embodiments, each of
R.sup.1-18 is independently H, F, Cl, Br, I, or a substituent
having a molecular weight of 15 Da to 300 Da, 15 Da to 200 Da, 15
Da to 100 Da, or 15 Da to 60 Da, and consisting of 2 to 5 chemical
elements, wherein the chemical elements are independently C, H, O,
N, S, F, Cl, or Br.
[0050] With respect to any relevant structural representation, such
as Formula 2, some non-limiting examples of R.sup.1-18 may include
R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3 fluoroalkyl, C.sub.1-4
hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B, COR.sup.A,
CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B, CONR.sup.AR.sup.B,
etc. In some embodiments, R.sup.1-18 may be H; F; Br; CN; C.sub.1-3
fluoroalkyl, such as CHF.sub.2, CF.sub.3, etc; OH; NH.sub.2;
C.sub.1-6 alkyl, such as methyl, ethyl, propyl isomers (e.g.
n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl
isomers (e.g. cyclobutyl and methylcyclopropyl), pentyl isomers,
cyclopentyl isomers, hexyl isomers, cyclohexyl isomers, etc.;
C.sub.1-6 alkoxy, such as --O-methyl, --O-ethyl, isomers of
--O-propyl, --O-- cyclopropyl, isomers of --O-butyl, isomers of
--O-cyclobutyl, isomers of --O-pentyl, isomers of --O-cyclopentyl,
isomers of --O-hexyl, isomers of --O-cyclohexyl, etc.; C.sub.1-4
hydroxyalkyl, such as --CH.sub.2OH, --C.sub.2H.sub.4--OH,
--C.sub.3H.sub.6--OH, C.sub.4H.sub.8--OH, etc.; C.sub.2-5
--CO.sub.2-alkyl, such as --CO.sub.2--CH.sub.3,
--CO.sub.2--C.sub.2H.sub.5, --CO.sub.2--C.sub.3H.sub.7,
--CO.sub.2--C.sub.4.H.sub.9, etc.
##STR00037##
[0051] With respect to any relevant structural representation, each
R.sup.A may independently be H, or C.sub.1-12 alkyl, including:
linear or branched alkyl having a formula C.sub.aH.sub.a+1, or
cycloalkyl having a formula C.sub.aH.sub.a-1, wherein a is 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl
of a formula: CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7,
C.sub.4H.sub.9, C.sub.5H.sub.11, C.sub.6H.sub.13, C.sub.7H.sub.15,
C.sub.8H.sub.17, C.sub.9H.sub.19, C.sub.10H.sub.21, etc., or
cycloalkyl of a formula: C.sub.3H.sub.5, C.sub.4H.sub.7,
C.sub.5H.sub.9, C.sub.6H.sub.11, C.sub.7H.sub.13, C.sub.8H.sub.15,
C.sub.9H.sub.17, C.sub.10H.sub.19, etc. In some embodiments,
R.sup.A may be H or C.sub.1-6 alkyl. In some embodiments, R.sup.A
may be H or C.sub.1-3 alkyl. In some embodiments, R.sup.A may be H
or CH.sub.3. In some embodiments, R.sup.A may be H.
[0052] With respect to any relevant structural representation, each
R.sup.B may independently be H, or C.sub.1-12 alkyl, including:
linear or branched alkyl having a formula C.sub.aH.sub.a+1, or
cycloalkyl having a formula C.sub.aH.sub.a-1, wherein a is 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl
of a formula: CH.sub.3, C.sub.2H.sub.5, C.sub.3H.sub.7,
C.sub.4H.sub.9, C.sub.5H.sub.11, C.sub.6H.sub.13, C.sub.7H.sub.15,
C.sub.8H.sub.17, C.sub.9H.sub.19, C.sub.10H.sub.21, etc., or
cycloalkyl of a formula: C.sub.3H.sub.5, C.sub.4H.sub.7,
C.sub.5H.sub.9, C.sub.6H.sub.11, C.sub.7H.sub.13, C.sub.8H.sub.15,
C.sub.9H.sub.17, C.sub.10H.sub.19, etc. In some embodiments,
R.sup.B may be H or C.sub.1-3 alkyl. In some embodiments, R.sup.B
may be H or CH.sub.3. In some embodiments, R.sup.B may be H.
[0053] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.1 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.1 is H, Cl, Br, CN, OCH.sub.3, CHF.sub.2, CF.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CH.sub.2OH,
##STR00038##
In some embodiments, R.sup.1 is H. In some embodiments, R.sup.1 is
Cl. In some embodiments, R.sup.1 is Br. In some embodiments,
R.sup.1 is CN. In some embodiments, R.sup.1 is OCH.sub.3. In some
embodiments, R.sup.1 is CHF.sub.2. In some embodiments, R.sup.1 is
CF.sub.3. In some embodiments, R.sup.1 is
--CO.sub.2CH.sub.2CH.sub.3. In some embodiments, R.sup.1 is
--CH.sub.2OH. In some embodiments, R.sup.1 is
##STR00039##
In some embodiments, R.sup.1 is
##STR00040##
In some embodiments, R.sup.1 is
##STR00041##
In some embodiments, R.sup.1 is
##STR00042##
In some embodiments, R.sup.1 is --OCH.sub.3, --CN, --CF.sub.3,
--CH.sub.2OH, --COOCH.sub.2CH.sub.3, --C(CH.sub.3).sub.2OH,
--CHOHCH.sub.2CH.sub.3, --CHOHCH.sub.3, --CH(CH.sub.3).sub.2,
--C(CH.sub.2CH.sub.3)OH, --CH.sub.2CO OCH.sub.2CH.sub.3,
--CH.sub.2C(CH.sub.3).sub.2OH, --CH.sub.2COOH, or
--CH.sub.2CON(CH.sub.3).sub.2.
[0054] With respect to the embodiments recited in this paragraph,
in some embodiments, the remaining groups of R.sup.1-18 may
independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0055] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.2 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.2 is H. In some embodiments, R.sup.2 is CH.sub.2OH. In some
embodiments, R.sup.2 is --CO.sub.2CH.sub.3. With respect to the
embodiments recited in this paragraph, in some embodiments, the
remaining groups of R.sup.1-18 may independently be R.sup.A, F, Cl,
Br, CN, OR.sup.A, C.sub.1-3 fluoroalkyl, C.sub.1-4 hydroxyalkyl,
NO.sub.2, NR.sup.AR.sup.B, COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A,
NR.sup.ACOR.sup.B, CONR.sup.AR.sup.B, etc. In some embodiments, the
remaining groups of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3
fluoroalkyl, OH, NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-4 --CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl. In some
embodiments, R.sup.2 is --CH.sub.2OH, --CO.sub.2Me, or
--C(CH.sub.3).sub.2OH.
[0056] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.3 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.3 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0057] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.4 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.4 is H. In some embodiments, R.sup.4 is CH.sub.3. In some
embodiments, R.sup.4 is CF.sub.3. With respect to the embodiments
recited in this paragraph, in some embodiments, the remaining
groups of R.sup.1-18 may independently be R.sup.A, F, Cl, Br, CN,
OR.sup.A, C.sub.1-3 fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2,
NR.sup.AR.sup.B, COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A,
NR.sup.ACOR.sup.B, CONR.sup.AR.sup.B, etc. In some embodiments, the
remaining groups of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3
fluoroalkyl, OH, NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-4 --CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0058] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.5 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.5 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0059] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.6 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.6 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0060] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.7 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.7 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0061] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.8 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.8 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0062] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.9 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.9 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0063] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.10 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.10 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0064] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.11 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.11 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0065] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.12 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.12 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0066] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.13 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4 alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.13 is H. With respect to the embodiments recited in this
paragraph, in some embodiments, the remaining groups of R.sup.1-18
may independently be R.sup.A, F, Cl, Br, CN, OR.sup.A, C.sub.1-3
fluoroalkyl, C.sub.1-4 hydroxyalkyl, NO.sub.2, NR.sup.AR.sup.B,
COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A, NR.sup.ACOR.sup.B,
CONR.sup.AR.sup.B, etc. In some embodiments, the remaining groups
of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3 fluoroalkyl, OH,
NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4
--CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0067] With respect to any relevant structural representation, such
as Formula 2, in some embodiments R.sup.14 is H, F, Cl, Br, CN,
OCH.sub.3, CHF.sub.2, CF.sub.3, C.sub.1-4 --CO.sub.2-alkyl,
C.sub.1-4alkyl, or C.sub.1-4 hydroxyalkyl. In some embodiments,
R.sup.14 is H. In some embodiments, R.sup.14 is F. With respect to
the embodiments recited in this paragraph, in some embodiments, the
remaining groups of R.sup.1-18 may independently be R.sup.A, F, Cl,
Br, CN, OR.sup.A, C.sub.1-3 fluoroalkyl, C.sub.1-4 hydroxyalkyl,
NO.sub.2, NR.sup.AR.sup.B, COR.sup.A, CO.sub.2R.sup.A, OCOR.sup.A,
NR.sup.ACOR.sup.B, CONR.sup.AR.sup.B, etc. In some embodiments, the
remaining groups of R.sup.1-18 may be H, F, Cl, Br, CN, C.sub.1-3
fluoroalkyl, OH, NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
C.sub.1-4 --CO.sub.2-alkyl, or C.sub.1-4 hydroxyalkyl.
[0068] Some embodiments include:
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067##
##STR00068##
[0069] The compounds described herein, such as a compound of
Formula 1 or Formula 2, (referred to hereafter as a "subject
compound" or "subject compounds") can be used to treat a disorder
associated with a Kv7 potassium channel activator. Treatment of a
disorder includes diagnosis, cure, mitigation, treatment, or
prevention of the disorder in man or other animals. In some
embodiments, the disorder is epilepsy, pain, migraine, a disorder
of neurotransmitter release, a smooth muscle contractility
disorder, a dyskinesia, dystonia, mania, or a hearing disorder. In
some embodiments, the disorder is epilepsy, neuropathic pain,
inflammatory pain, persistent pain, cancer pain, postoperative
pain, migraine, anxiety, substance abuse, schizophrenia, a bladder
disorder, a vasculature disorder, a dyskinesia, dystonia, mania, a
hearing disorder, or tinnitus.
[0070] Appropriate excipients for use in a pharmaceutical
composition comprising a subject compound (referred to hereafter as
"subject compositions" or a "subject composition") may include, for
example, one or more carriers, binders, fillers, vehicles,
disintegrants, surfactants, dispersion or suspension aids,
thickening or emulsifying agents, isotonic agents, preservatives,
lubricants, and the like or combinations thereof, as suited to a
particular dosage from desired. Remington's Pharmaceutical
Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co.,
Easton, Pa., 1980) discloses various carriers used in formulating
pharmaceutically acceptable compositions and known techniques for
the preparation thereof.
[0071] A subject composition may be formulated for any desirable
route of delivery including, but not limited to, parenteral,
intravenous, intradermal, subcutaneous, oral, inhalative,
transdermal, topical, transmucosal, rectal, interacisternal,
intravaginal, intraperitoneal, buccal, and intraocular.
[0072] Parenteral, intradermal or subcutaneous formulations may be
sterile injectable aqueous or oleaginous suspensions or solutions.
Acceptable vehicles, solutions, suspensions and solvents may
include, but are not limited to, water or other sterile diluent;
saline; Ringer's solution; sodium chloride; fixed oils such as
mono- or diglycerides; fatty acids such as oleic acid; polyethylene
glycols; glycerine; propylene glycol or other synthetic solvents;
antibacterial agents such as benzyl alcohol or methyl parabens;
antioxidants such as ascorbic acid or sodium bisulfate; chelating
agents such as ethylenediaminetetraacetic acid; buffers such as
acetates, citrates or phosphates; and agents for the adjustment of
tonicity such as sodium chloride or dextrose. The pH can be
adjusted with acids or bases, such as hydrochloric acid or sodium
hydroxide. A parenteral preparation may be enclosed in ampoules,
disposable syringes or multiple dose vials made of glass or
plastic.
[0073] Pharmaceutical compositions suitable for injectable use may
include sterile aqueous solutions or dispersions and sterile
powders for the extemporaneous preparation of sterile injectable
solutions or dispersion. For intravenous administration, suitable
carriers include, but are not limited to, saline, bacteriostatic
water, CREMOPHOR EL.RTM. (BASF, Parsippany, N.J.) or phosphate
buffered saline (PBS). The solvent or dispersion medium may
contain, for example, water, ethanol, polyol (for example,
glycerol, propylene glycol, and liquid polyethylene glycol, and the
like), and suitable mixtures thereof. Proper fluidity can be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersion and by the use of surfactants. Preventing growth of
microorganisms can be achieved by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, thimerosal, and the like. The composition may also
include isotonic agents such as, for example, sugars; polyalcohols
such as mannitol; sorbitol; or sodium chloride. Prolonged
absorption of injectable compositions can be enhanced by addition
of an agent that delays absorption, such as, for example, aluminum
monostearate or gelatin.
[0074] Oral compositions may include an inert diluent or an edible
carrier. They may be enclosed in gelatin capsules or compressed
into tablets. Tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose; a
disintegrating agent such as alginic acid, Primogel, or corn
starch; a lubricant such as magnesium stearate; a glidant such as
colloidal silicon dioxide; a sweetening agent such as sucrose or
saccharin; or a flavoring agent such as peppermint, methyl
salicylate, or orange flavoring.
[0075] In addition to oral or injected administration, systemic
administration may be by transmucosal or transdermal means. For
transmucosal or transdermal administration, penetrants may be used.
Such penetrants are generally known in the art and include, for
example, detergents, bile salts, and fusidic acid derivatives.
Transdermal administration may include a bioactive agent and may be
formulated into ointments, salves, gels, or creams as generally
known in the art. Transmucosal administration may be accomplished
through the use of nasal sprays or suppositories.
[0076] A subject compound may be administered in a therapeutically
effective amount, according to an appropriate dosing regimen. As
understood by a skilled artisan, an exact amount required may vary
from subject to subject, depending on a subject's species, age and
general condition, the severity of the infection, the particular
agent(s) and the mode of administration. In some embodiments, about
0.001 mg/kg to about 50 mg/kg, of the pharmaceutical composition
based on the subject's body weight is administered, one or more
times a day, to obtain the desired therapeutic effect. In other
embodiments, about 0.01 mg/kg to about 25 mg/kg, of the
pharmaceutical composition based on the subject's body weight is
administered, one or more times a day, to obtain the desired
therapeutic effect.
[0077] A total daily dosage of a subject compound can be determined
by the attending physician within the scope of sound medical
judgment. A specific therapeutically effective dose level for any
particular patient or subject will depend upon a variety of factors
including the disorder being treated and the severity of the
disorder; the activity of the specific compound employed; the
specific composition employed; the age, body weight, general
health, sex and diet of the patient or subject; the time of
administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment;
drugs used in combination or coincidental with the specific
compound employed; and other factors well known in the medical
arts.
Embodiments Section
[0078] The following example embodiments are contemplated.
Embodiment 1
[0079] A compound represented by a formula:
##STR00069##
[0080] wherein D is optionally substituted C.sub.3-6 carbocyclyl,
optionally substituted C.sub.2-5 heterocyclyl, isopropyl, or
t-butyl;
[0081] Bz is optionally substituted benzoimidazol-1,2-diyl;
[0082] A is C.sub.1-8 alkyl;
[0083] X is H, F, CF.sub.3, optionally substituted phenyl, or
optionally substituted pyridinyl;
[0084] and
[0085] Y is H, F, Cl, Br, I, or a moiety having a molecular weight
of 15 Da to 300 Da and consisting of 2 to 5 chemical elements,
wherein the chemical elements are independently C, H, O, N, S, F,
Cl, or Br.
Embodiment 2
[0086] The compound of embodiment 1, wherein each substituent of D,
Bz, or X, if present, independently has a molecular weight of 15 Da
to 200 Da and consists of 2 to 5 chemical elements, wherein the
chemical elements are independently C, H, O, N, S, F, Cl, or
Br.
Embodiment 3
[0087] The compound of embodiment 1 or 2, wherein Y is H, F, Cl,
Br, I, CN, --COH, C.sub.1-6 --CO-alkyl, CF.sub.3, OH, C.sub.1-5
O-alkyl, C.sub.0-6 amino, or C.sub.0-6 fluoroamino.
Embodiment 4
[0088] The compound of embodiment 1, 2, or 3, further represented
by a formula:
##STR00070##
[0089] wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently H, F, Cl, Br, I, or a substituent having a molecular
weight of 15 Da to 200 Da and consisting of 2 to 5 chemical
elements, wherein the chemical elements are independently C, H, O,
N, S, F, Cl, or Br.
Embodiment 5
[0090] The compound of embodiment 1, 2, 3, or 4, wherein Y is H, F,
CF.sub.3, OH, C.sub.1-5 O-alkyl, C.sub.0-6 alkylamino, optionally
substituted tetrahydropyranyl, or C.sub.0-6 fluoroalkylamino.
Embodiment 6
[0091] The compound of embodiment 4 or 5, wherein R.sup.1 is H, Cl,
Br, --OCH.sub.3, --CN, --CF.sub.3, --CH.sub.2OH,
--COOCH.sub.2CH.sub.3, --C(CH.sub.3).sub.2OH,
--CHOHCH.sub.2CH.sub.3, --CHOHC H.sub.3, --CHF.sub.2,
--CH(CH.sub.3).sub.2, --C(CH.sub.2CH.sub.3)OH,
--CH.sub.2COOCH.sub.2CH.sub.3, --CH.sub.2C(CH.sub.3).sub.2OH,
--CH.sub.2COO H, or --CH.sub.2CON(CH.sub.3).sub.2.
Embodiment 7
[0092] The compound of embodiment 4, 5, or 6, wherein R.sup.2 is H,
F, --CH.sub.2OH, --CO.sub.2Me, or --C(CH.sub.3).sub.2OH.
Embodiment 8
[0093] The compound of embodiment 4, 5, 6, or 7, wherein R.sup.3 is
H.
Embodiment 9
[0094] The compound of embodiment 4, 5, 6, 7, or 8, wherein R.sup.4
is H, --CH.sub.3, or --CF.sub.3.
Embodiment 10
[0095] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, or 9,
wherein D is optionally substituted cyclobutyl, optionally
substituted phenyl, optionally substituted isoxazolyl, optionally
substituted pyridinyl, isopropyl, or t-butyl.
Embodiment 11
[0096] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10,
wherein each substituent of D, X, and Y, if present, independently
has a molecular weight of 15 Da to 200 Da and consists of 2 to 5
chemical elements, wherein the chemical elements are independently
C, H, O, N, S, F, Cl, or Br.
Embodiment 12
[0097] The compound of embodiment 4, 5, 6, 7, 8, 9, 10, or 11,
wherein R.sup.1 is H, Cl, Br, CN, OCH.sub.3, CF.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, C.sub.1-4 alkyl, or C.sub.1-4
hydroxyalkyl.
Embodiment 13
[0098] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12, wherein D is optionally substituted cyclobutyl.
Embodiment 14
[0099] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12, wherein D is cyclobutyl.
Embodiment 15
[0100] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12, wherein D is optionally substituted phenyl.
Embodiment 16
[0101] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12, wherein D is optionally substituted isoxazolyl.
Embodiment 17
[0102] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12, wherein D is isopropyl.
Embodiment 18
[0103] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12, wherein D is t-butyl.
Embodiment 19
[0104] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12, wherein D is optionally substituted pyridinyl.
Embodiment 20
[0105] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is optionally
substituted phenyl.
Embodiment 21
[0106] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is CF.sub.3.
Embodiment 22
[0107] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is F.
Embodiment 23
[0108] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is optionally
substituted pyridinyl.
Embodiment 24
[0109] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein X is H.
Embodiment 25
[0110] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is H.
Embodiment 26
[0111] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is OH.
Embodiment 27
[0112] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is F.
Embodiment 28
[0113] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is CF.sub.3.
Embodiment 29
[0114] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is C.sub.1-3 O-alkyl.
Embodiment 30
[0115] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is C.sub.0-6 fluoroamino.
Embodiment 31
[0116] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is dimethylamino.
Embodiment 32
[0117] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is methyl(2,2,2-trifluoroethyl)amino.
Embodiment 33
[0118] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is optionally substituted tetrahydropyranyl.
Embodiment 34
[0119] The compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24, wherein
Y is 1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl.
Embodiment 35
[0120] The compound of embodiment 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
31, 32, 33, or 34, wherein A is C.sub.2-8 alkyl; and wherein at
least one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are
independently F, Cl, Br, I, or a substituent having a molecular
weight of 15 Da to 200 Da and consisting of 2 to 5 chemical
elements, wherein the chemical elements are independently C, H, O,
N, S, F, CI, or Br.
Embodiment 36
[0121] A compound represented by a formula:
##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075##
##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080##
##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085##
##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090##
##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095##
##STR00096##
Embodiment 37
[0122] A composition comprising a compound of embodiment 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36,
wherein the composition is pharmaceutically acceptable.
Embodiment 38
[0123] A pharmaceutical dosage form comprising a compound of
embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,
34, 35, or 36.
Embodiment 39
[0124] A method of treating a disorder associated with a Kv7
potassium channel activator comprising administering an effective
amount of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, or 36, to a mammal in need
thereof.
Embodiment 40
[0125] The method of embodiment 39, wherein the disorder is
epilepsy, pain, migraine, a disorder of neurotransmitter release, a
smooth muscle contractility disorder, a dyskinesia, dystonia,
mania, or a hearing disorder.
Embodiment 41
[0126] The method of embodiment 39, wherein the disorder is
epilepsy, neuropathic pain, inflammatory pain, persistent pain,
cancer pain, postoperative pain, migraine, anxiety, substance
abuse, schizophrenia, a bladder disorder, a vasculature disorder, a
dyskinesia, dystonia, mania, a hearing disorder, or tinnitus.
Embodiment 42
[0127] Use of a compound of embodiment 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33, 34, 35, or 36, in the manufacture of a
medicament for the treatment of a disorder associated with a Kv7
potassium channel activator.
Embodiment 43
[0128] The use of embodiment 42, wherein the disorder is epilepsy,
pain, migraine, a disorder of neurotransmitter release, a smooth
muscle contractility disorder, a dyskinesia, dystonia, mania, or a
hearing disorder.
Embodiment 44
[0129] The use of embodiment 42, wherein the disorder is epilepsy,
neuropathic pain, inflammatory pain, persistent pain, cancer pain,
postoperative pain, migraine, anxiety, substance abuse,
schizophrenia, a bladder disorder, a vasculature disorder, a
dyskinesia, dystonia, mania, a hearing disorder, or tinnitus.
EXPERIMENTAL SECTION
##STR00097##
[0131] Scheme 1 shows a general methodology for the synthesis of
1H-benzo[d]imidazol-2-yl amides 1.5. An appropriately substituted
1-fluoro-2-nitrobenzene 1.1 is reacted with a primary amine to
afford 1-amino-2-nitrobenzene 1.2. Alternatively, a
1-chloro-2-nitrobenzene is reacted with a primary amine under
palladium catalysis to provide the desired 1-amino-2-nitrobenzene
1.2. The nitro group may be reduced to the corresponding amine by a
variety of well-established methods to provide 1,2-diaminobenzenes
1.3. Reaction of 1.3 with cyanogen bromide affords
1H-benzo[d]imidazol-2-amines 1.4. Amide coupling with either an
appropriate carboxylic acid or acyl chloride can afford
1H-benzo[d]imidazol-2-yl amides such as 1.5.
##STR00098## ##STR00099##
##STR00100##
[0132] Scheme 2 and Scheme 3 describe general methodologies that
may be used to create novel Kv7 modulators after the initial amide
bond forming reaction has been used to synthesize
1H-benzo[d]imidazol-2-yl amides such as 2.3. Sulfuric acid-promoted
ethanolysis of the nitrile in
2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carbonitrile (2.1)
gives the ethyl ester 2.2. This amino-heterocycle may be used as
the amine in a standard amide bond forming reaction to give the
ester amide 2.3. The ethyl ester may serve as a synthetic handle to
access various other functional groups. The ester may be reduced
with DiBAL-H to the primary alcohol 2.4. Alternatively, excess
Grignard reagent may be used to generate a tertiary alcohol 2.7.
The primary alcohol 2.4 may be readily oxidized with the
Dess-Martin periodinane or a similar oxidant to generate an
intermediate aldehyde 2.5. The aldehyde 2.5 may serve as the input
for a difluorination reaction, for example using Xtal-FluorE
reagent, to provide the difluoromethyl-substituted amides 2.6 (see
Couturier, M, et al, J. Org. Chem. 2010, 75, 3401-3411). The
tertiary alcohols 2.7 may be reduced under the action of
triethylsilane and trifluoroacetic acid in dichloromethane to give
the branched benzylic alkyl groups present in amides 2.8. It is
noteworthy that the new molecules 2.4-2.8 are convenient as
intermediates for further conversion into additional benzo-ring
substituents, such as amides, ethers, and heterocycles, using known
methodologies.
[0133] A range of functional groups may be orthogonally transformed
in the presence of the amide functionality of
1H-benzo[d]imidazol-2-yl amides. Scheme 3 shows how the nitrile 3.1
may be selectively reacted with a Grignard reagent to produce an
aryl ketone 3.2. This ketone may be reduced with common hydride
reagents, such as sodium borohydride, to give the secondary alcohol
3.3. Such ketone reductions may be conducted in a
stereochemically-defined manner, using a variety of chiral reducing
reagents known in the literature (e.g. via CBS reagent, see Corey,
E J, Shibata, S, Bakshi, R K, J. Org. Chem. 1988, 53,
2861-2863).
##STR00101##
[0134] The general methodology of Scheme 1 may be used to
synthesize a wide range of functionalized 1H-benzo[d]imidazol-2-yl
amides. Bromide 4.1 in Scheme 4 is an example of a
halogenated-1H-benzo[d]imidazol-2-yl amide that also provides an
orthogonally reactive functional group. The bromide may be reduced
with the action of triethylsilane in chloroform and methanol with a
catalytic amount of palladium on charcoal to give the debrominated
product 4.2 (see Mandal, P K, McMurray, J S, J. Org. Chem. 2007,
72, 6599-6601). The aromatic bromide in 4.1 may also be used to
perform palladium cross coupling reactions such as Sonogashira,
Suzuki, or Stille reactions to provide alkynes, biaryl or other
cross coupled products.
##STR00102## ##STR00103##
[0135] Scheme 5 describes a general synthetic method for the
synthesis of chiral .alpha.-alkyl carboxylic acids that contain
.beta.-silyloxy ether protected acids 5.4 or ent-5.4. These
optically active acids are used as the acid component in amide
forming reaction (Step D of Scheme 1) to give .beta.-tertiary
alcohol amides. The diastereoselective bond construction via
titanium enolate chemistry described by Evans was used to condense
chiral imide 5.1 or ent-5.1 with a ketone or other electrophile to
give diastereomerically pure aldol adducts 5.2 or ent-5.2,
respectively (see Evans, D A, Urpi, F, Somers, T C, Clark, J S,
Bilodeau, M T, J. Am. Chem. Soc. 1990, 112, 8215-8216). The proper
choice of chiral imide 5.1 will give rise to the desired absolute
stereochemistry of the .alpha.-stereocenter in the carboxylic acids
5.4 or ent-5.4. Silyl ether protection of the aldol adducts 5.2 and
ent-5.2 with tert-butyldimethylsilyltriflate and
diisopropylethylamine gives the tert-butyldimethylsilyl ethers 5.3
and ent-5.3. Standard acyl oxazolidinone hydrolysis conditions
using lithium hydroxide and hydrogen peroxide in tetrahydrofuran
and water provides the desired acids 5.4 or ent-5.4 (see Evans, D
A, Britton, T C, Ellman, J A, Tetrahedron Lett. 1987, 28(49),
6141-6144). Proper selection of ketones or other electrophiles in
the titanium enolate chemistry will give rise to appropriately
substituted aldol adducts that vary in the nature of the R.sub.2
and R.sub.3 groups. Changing the R.sub.1 group of the starting
imides 5.1 and ent-5.1 may be used to vary the size and nature of
the R.sub.1 group in the acids 5.4 or ent-5.4. This methodology
allows one to synthesize a wide range of optically active acids
with absolute stereocontrol of the .alpha.-chiral center to the
carbonyl of the carboxylic acid.
##STR00104## ##STR00105##
[0136] A general synthetic method for the synthesis of
enantiomerically pure .alpha.-methyl-.beta.-branched chiral
carboxylic acids 6.4 or ent-6.4 is described in Scheme 6. Both of
the enantiomerically pure oxazolidinones
(S)-4-benzyloxazolidin-2-one 6.1 and (R)-4-benzyloxazolidin-2-one
ent-6.1 are commercially available. These oxazolidinones may be
readily acylated by deprotonation with n-butyl lithium followed by
reaction with acid chlorides 6.5 to give the chiral imides 6.2 and
ent-6.2, respectively. There are a large number of commercially
available acid chlorides 6.5 with wide variation about the R.sub.1,
R.sub.2 and R.sub.3 groups of this input. This allows for the rapid
synthesis of chiral imides 6.2 and ent-6.2 that have differing
substitution at the .beta.-position to the exocyclic carbonyl
group. The asymmetric alkylation reaction of chiral imide sodium
enolates as developed by Evans may then be used to introduce a
methyl group in a stereoselective fashion (see Evans, D A, Ennis, M
D, Mathre, D J, J. Am. Chem. Soc. 1982, 104, 1737-1739). The sodium
enolate of imide 6.2 may be produced by treatment of 6.2 with
sodium hexamethyldisilazide in tetrahydrofuran. The resultant
sodium enolate may then be stereoselectively methylated by the
addition of methyl iodide. The pure and single diastereomers 6.3
and ent-6.3 may be isolated by silica gel column chromatography.
Alternatively, the single diastereomers may be obtained by
recrystallization of crystalline products 6.3 and ent-6.3. The
well-known chiral auxiliary hydrolysis conditions as described
above for Scheme 5 give the optically active .alpha.-methyl
.beta.-branched chiral carboxylic acids 6.4 or ent-6.4,
respectively.
##STR00106##
[0137] Scheme 7 shows a general methodology for the synthesis of
3-hydroxypropanoic acids such as 7.3. An appropriately substituted
2-bromoethanoic ester 7.1 is reacted with a ketone or aldehyde to
afford 3-hydroxypropanoic esters 7.2. The ester group may be
hydrolyzed to the corresponding acid by saponification to provide
3-hydroxypropanoic acids such as 7.3.
##STR00107##
[0138] Scheme 8 depicts additional methods for the preparation of
optionally substituted 3-hydroxypropanoic acids. An appropriately
substituted 3-acetyloxazolidin-2-one 8.1 is reacted with a ketone
or aldehyde to afford 3-(3-hydroxypropanoyl)oxazolidin-2-ones 8.2.
The hydroxyl group is functionalized with a protecting group to
provide diastereomers 8.3 that are separable by silica gel
chromatography. Each diastereomer 8.3 is then reacted in a two-step
sequence, in either order, of hydroxyl group deprotection and
oxazolidinone cleavage to provide 3-hydroxypropanoic acids such as
8.6.
##STR00108##
[0139] Scheme 9 describes methods that can be applied to the
syntheses of amino acid substituted 1H-benzo[d]imidazol-2-yl)
amides such as 9.4. Appropriately substituted
1H-benzo[d]imidazol-2-amines 9.1 may be coupled with
carbamate-protected amino acid derivatives such as 9.2 to afford
the corresponding amides 9.3. The carbamate protecting group can be
removed from the amine via one of a number of strongly acidic
reagents to afford amines like 9.4. Such secondary amines can then
be further functionalized under standard amine alkylation
conditions to provide tertiary amine-containing
1H-benzo[d]imidazol-2-yl)amides such as such as 9.5.
##STR00109##
[0140] Scheme 10 describes methods that can be employed to prepare
1H-benzo[d]imidazol-2-yl)amides substituted with
hydroxyl-containing amides such as 10.4. Appropriately substituted
1H-benzo[d]imidazol-2-amines 10.1 may be coupled with protected
alcohol derivatives such as 10.2 to afford the corresponding amides
10.3. The alcohol protecting group can be removed via several
methods including tetrabutylammonium fluoride to provide
alcohol-containing 1H-benzo[d]imidazol-2-yl) amides such as such as
10.4.
Synthetic Methods
Section 1. Representative Procedures for the Preparation of
1H-benzo[d]imidazol-2-amines Intermediates (Compounds 1.4, Scheme
1)
Method 1
##STR00110##
[0141] Step A. Preparation of
3-(cyclobutylamino)-4-nitrobenzonitrile
[0142] A 500 mL round-bottom flask was charged with of
3-fluoro-4-nitrobenzonitrile (5.00 g, 30.1 mmol) and
tetrahydrofuran (100 mL) and placed in a 0.degree. C. bath. After 5
minutes, cyclobutylamine hydrochloric acid (3.60 g, 33.0 mmol) was
added in one portion with stirring before the dropwise addition of
diisopropylethylamine (15 mL, 82 mmol). The mixture was allowed to
stir at 0.degree. C. for 1 hour. The ice bath was removed and the
flask was allowed to warm to room temperature and allowed to stir
overnight. The bulk of the tetrahydrofuran was removed on a rotary
evaporator before the mixture was diluted with EtOAc (200 mL). The
organic layer was washed with saturated aqueous ammonium chloride
twice, saturated aqueous sodium bicarbonate, and brine and then
dried over anhydrous sodium sulfate. The dried solution was
filtered and concentrated to give the desired product as a crude
orange solid (6.25 g). TLC R.sub.f=0.70-0.45 streak in 20% EtOAc in
hexanes. MS (ESI) m/z 218.0 (MH.sup.+). .sup.1H NMR (CDCl.sub.3):
.delta. 8.24 (d, J=8.68 Hz, 1H), 8.11 (bs, 1H), 7.01 (d, J=1.48 Hz,
1H), 6.86 (dd, J=8.72, 1.64, 1H), 4.09-4.00 (m, 1H), 2.60-2.51 (m,
2H), 2.11-1.88 (m, 4H).
##STR00111##
Step B. Preparation of 4-amino-3-(cyclobutylamino) benzonitrile
[0143] To a solution of 3-(cyclobutylamino)-4-nitrobenzonitrile
(6.50 g, 30.1 mmol) in EtOH (160 mL) was added iron powder (8.8 g,
150 mmol) and a solution of ammonium chloride (8.1 g, 150 mmol) in
water (30 mL). The mixture was heated in a sand bath at 90.degree.
C. for 16 hours while being exposed to air. The mixture was allowed
to cool, diluted with EtOAc (200 mL) and the resulting mixture was
filtered through Celite. The Celite was rinsed with saturated
aqueous sodium bicarbonate and EtOAc. The combined filtrates were
separated and the aqueous layer was extracted with EtOAc. The
combined organics were washed with brine, dried with anhydrous
sodium sulfate and concentrated to provide the crude title compound
(6.2 g). The material was subjected to a 120 g Isco silica gel
column (10 to 40% EtOAc in hexanes) to provide the desired product
(4.17 g) in a 74% yield for two steps as a pink colored solid. MS
(ESI) m/z 188.0 (MH.sup.+). .sup.1H NMR (CDCl.sub.3): .delta. 7.01
(dd, J=8.00, 1.76 Hz, 1H), 6.73 (d, J=1.72 Hz, 1H), 6.68 (d, J=8.0
Hz, 1H), 3.92-3.85 (m, 1H), 3.65-3.45 (br m, 2H), 2.53-2.44 (m,
2H), 1.88-1.83 (m, 4H).
##STR00112##
Step C. Preparation of
2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carbonitrile
[0144] To a solution of 4-amino-3-(cyclobutylamino) benzonitrile
(4.0 g, 21.3 mmol) in EtOH (100 mL) was added a solution of
cyanogen bromide (3 M in CH.sub.2Cl.sub.2, 14 mL, 42 mmol. The
mixture was stirred at room temperature for 18 hours and then
concentrated in vacuo. The residue was partitioned between EtOAc
(150 mL) and aqueous Na.sub.2CO.sub.3 (10%, 100 mL). The aqueous
layer was extracted twice with EtOAc. The combined organic layers
were washed with brine, dried (Na.sub.2SO.sub.4) and concentrated
to give a pink solid (4.5 g). The solid was subjected to a hexanes
and EtOAc trituration to provide the title compound as a pale pink
solid (3.1 g, 69%). R.sub.f=0.1 streak in 100% EtOAc. MS (ESI) m/z
213.2 (MH.sup.+). .sup.1H NMR (MeOH-d.sub.4): .delta. 7.78 (s, 1H),
7.38 (d, J=8.28, 1H), 7.28 (d, J=8.20, 1H), 4.92-4.81 (m, 1H),
2.88-2.78 (m, 2H), 2.54-2.45 (m, 2H), 2.08-1.78 (m, 2H). An
additional portion of the desired product (1.0 g) was recovered
from the trituration solvent and showed to be desired product with
>90% purity by .sup.1H NMR.
[0145] The following 1H-benzo[d]imidazol-2-amines were prepared
using the general procedures described in Section 1, Method 1, with
appropriate starting materials. Alternative procedures for certain
starting materials are described in the Methods 2-5.
[0146]
1-cyclobutyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine
##STR00113##
[0147] 6-bromo-1-cyclobutyl-1H-benzo[d]imidazol-2-amine
##STR00114##
[0148] 1-isopropyl-6-methoxy-1H-benzo[d]imidazol-2-amine
##STR00115##
[0149] methyl
2-amino-1-cyclobutyl-1H-benzo[d]imidazole-7-carboxylate
##STR00116##
[0150]
2-amino-1-(tert-butyl)-1H-benzo[d]imidazole-6-carbonitrile
##STR00117##
[0151]
2-amino-1-(1-methylcyclobutyl)-1H-benzo[d]imidazole-6-carbonitrile
##STR00118##
[0152] 6-chloro-1-(4-fluorophenyl)-1H-benzo[d]imidazol-2-amine
##STR00119##
[0153]
2-amino-1-cyclobutyl-5-methyl-1H-benzo[d]imidazole-6-carbonitrile
##STR00120##
[0154]
2-amino-1-(tert-butyl)-5-methyl-1H-benzo[d]imidazole-6-carbonitrile
##STR00121##
[0155]
1-cyclobutyl-7-fluoro-5-(trifluoromethyl)-1H-benzo[d]imidazol-2-ami-
ne
##STR00122##
[0156]
1-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imida-
zol-2-amine
##STR00123##
[0157]
1-(3,5-difluorophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-am-
ine
##STR00124##
[0158]
2-amino-1-(5-fluoropyridin-2-yl)-1H-benzo[d]imidazole-6-carbonitril-
e
##STR00125##
[0159]
1-(3,4-difluorophenyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-am-
ine
##STR00126##
[0160]
1-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H-benz-
o[d]imidazol-2-amine
##STR00127##
[0161]
1-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1H-benzo[d]imida-
zol-2-amine
##STR00128##
[0162] ethyl
2-(2-amino-1-cyclobutyl-7-fluoro-1H-benzo[d]imidazol-6-yl)acetate
##STR00129##
[0163] ethyl
2-(2-amino-7-fluoro-1-(4-fluorophenyl)-1H-benzo[d]imidazol-6-yl)acetate
##STR00130##
Method 2: Preparation of
3-((4-fluorophenyl)amino)-4-nitrobenzonitrile for Use in Method 1,
Step B
##STR00131##
[0165] A mixture of 3-fluoro-4-nitrobenzonitrile (2 g, 12 mmol),
triethylamine (1.7 mL, 1.5 equivalents) and 4-fluoroaniline (1.7
mL, 1.5 equivalents) was heated at 60.degree. C. under a nitrogen
atmosphere for 60 hours. The resulting solid red-brown mass was
cooled to ambient temperature and suspended in 50 mL of 1 N aqueous
hydrochloric acid. The mixture was extracted extensively with
dichloromethane and the organic extracts dried over anhydrous
magnesium sulfate. Concentration of the organic extracts under
reduced pressure afforded 2.9 g of a red solid, practically pure by
LC/MS. MS (ESI) m/z 256 (M-H.sup.-).
Method 3: Preparation of 5-chloro-N-cyclobutyl-2-nitroaniline for
Use in Method 1, Step B
##STR00132##
[0167] A mixture of cyclobutylamine hydrochloride (2.15 g),
triethylamine (2.8 mL), 2,4-dichloro-1-nitrobenzene (3.84 g, 20
mmol, limiting reagent) and tetrahydrofuran (40 mL) was heated in a
sealed vial at 100.degree. C. for 16 hours. The reaction mixture
was cooled to room temperature, and 0.2 equivalents of both
cyclobutylamine hydrochloride and triethylamine added, and the
resulting mixture was heated at 100.degree. C. for an additional 17
hours. The cooled reaction mixture was diluted with water,
extracted thoroughly with dichloromethane and ethyl acetate, the
organic extracts dried over anhydrous magnesium sulfate and
concentrated. Purification of the crude product by chromatography
on silica with 20% dichloromethane in hexanes as eluent afforded
the desired product (1.65 g) as an orange solid. .sup.1H NMR
(CDCl.sub.3): .delta. 8.16 (NH, bs), 8.12 (1H, d), 6.70 (1H, s),
6.60 (1H, d), 4.02 (1H, m), 2.53 (2H, m), 2.03 (2H, m), 1.92 (2H,
m).
Method 4: Preparation of
3-Methyl-N-(2-nitro-5-(trifluoromethyl)phenyl)isoxazol-5-amine for
Use in Method 5
##STR00133##
[0169] Palladium(II) acetate (1.00 g, 0.443 mmol) was added to
Xantphos (0.513 g, 0.887 mmol) in degassed dioxane (10 mL) and the
suspension was stirred for 15 minutes under N.sub.2. The resulting
solution was added to a mixture of
2-chloro-3-nitro-6-(trifluoromethyl)benzene (1.00 g, 4.43 mmol),
3-methylisoxazol-5-amine (0.522 g, 5.32 mmol) and K.sub.2CO.sub.3
(0.919 g, 6.65 mmol) in degassed dioxane (40 mL) and the reaction
mixture was refluxed overnight. Conversion was confirmed by TLC and
the solution was filtered through a plug of celite. The volatiles
were removed and the crude residue was purified by chromatography
on silica (0-100% EtOAc/hexanes) to give 0.811 g (63%) of the title
compound. MS (ESI) m/z 288 (MH.sup.+).
[0170] The following intermediates were prepared for use in Method
1, Step B using the general procedure described in Section 1,
Method 4, with appropriate starting materials. [0171]
3-((5-fluoropyridin-2-yl)amino)-4-nitrobenzonitrile [0172]
N-(3,5-difluorophenyl)-2-nitro-5-(trifluoromethyl)aniline [0173]
N-(3-fluoro-4-(trifluoromethoxy)phenyl)-2-nitro-5-(trifluoromethyl)anilin-
e [0174]
2-nitro-N-(4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)aniline
[0175]
N-(3,4-difluorophenyl)-2-nitro-5-(trifluoromethyl)aniline
Method 5: Preparation of
N.sup.1-(3-methylisoxazol-5-yl)-5-(trifluoromethyl)benzene-1,2-diamine
for Use in Method 1, Step C
##STR00134##
[0177] Sodium bicarbonate (0.410 g, 4.88 mmol) then sodium
hydrosulfite (1.27 g, 7.31 mmol) were added to a solution of the
nitro aromatic core (0.700 g, 2.44 mmol) in
tetrahydrofuran:H.sub.2O (2:1; 24 mL). The resulting reaction
mixture was allowed to stir for 4 hours, diluted with H.sub.2O and
then extracted with EtOAc. The combined organics were dried
(MgSO.sub.4) and the volatiles removed to leave a crude residue
that was purified by chromatography on silica (0-5%
MeOH/dichloromethane) to give 380 mg (61%) of the title compound.
MS (ESI) m/z 258 (MH.sup.+).
[0178] The following benzene-1,2-diamine was prepared using the
general procedures described in Section 1, Methods 4 and 5, with
appropriate starting materials, for use in Method 1, Step C:
[0179] 4-amino-3-((3-methylisoxazol-5-yl)amino)benzonitrile
##STR00135##
Method 6: Preparation of ethyl
2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carboxylate
##STR00136##
[0181] To a solution of 4-amino-3-(cyclobutylamino) benzonitrile
(1.5 g, 7.0 mmol) in EtOH (30 mL) was added water (3 mL) and
concentrated sulfuric acid (3 mL). The solution was placed in a
150.degree. C. sand bath with stirring for 4 days. The reaction was
allowed to cool to ambient temperature and carefully quenched by
pouring slowly into saturated aqueous sodium bicarbonate. The
mixture was diluted with EtOAc and the layers were separated. The
aqueous layer was back extracted with dichloromethane and the
combined organic layers were washed with brine, dried with sodium
sulfate, filtered and concentrated to give the title compound as a
tan solid (790 mg, 43% yield). MS (ESI) m/z 260.0 (MH.sup.+),
retention time=2.21 min (Method B).
Section 2. Representative Procedures for the Preparation of
1H-benzo[d]imidazol-2-yl Amides (1.5, Scheme 1)
Method 7: General Procedure for Amide Formation Using HATU
(1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole
3-oxide hexafluorophosphate(V)) as Coupling Reagent
##STR00137##
[0183] The appropriate carboxylic acid was dissolved in
dimethyformamide or THF (0.20-0.7 M) and diisopropylethylamine or
pyridine (2 equivalents) was added prior to the addition of
1-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazole
3-oxide hexafluorophosphate(V) (HATU, 1.2 equivalents) in one
portion. The reaction was allowed to stir at room temperature for 0
to 15 minutes prior to the addition of the required substituted
2-aminobenzimidazole (1 equivalent) and the flask was placed in a
heated sand bath (40-65.degree. C.) for 8 to 48 hours. The mixture
was diluted with EtOAc and washed sequentially with saturated
aqueous NH.sub.4Cl (2.times.), saturated aqueous NaHCO.sub.3
(2.times.), 10% aqueous Na.sub.2CO.sub.3 (2.times.), and brine. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by by chromatography on silica (0-100% EtOAc/hexanes
or 0-10% MeOH/dichloromethane) provided the title corresponding
1H-benzo[d]imidazol-2-yl amides.
Method 8: General Procedure for Amide Formation Using Acyl
Chlorides
##STR00138##
[0185] To a solution appropriate 1H-benzo[d]imidazol-2-amine
intermediate (0.22 mmol) in tetrahydrofuran (1 mL) was added
pyridine (1.5 equivalents) and acyl chloride (1.2 equivalents). The
reaction mixture was stirred for 18 hours. The mixture was
partitioned between EtOAc and water. The organic layer was dried
(Na.sub.2SO.sub.4) and concentrated. The residue was purified by
chromatography on silica (0-100% EtOAc/hexanes) to provide title
compounds.
Method 9: General Procedure for Amide Coupling Using Excess Acid
Chloride Followed by Treatment with Ammonia
Example 46. Preparation of
3,3-dimethyl-N-(1-(3-methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benzo[d]-
imidazol-2-yl)butanamide
##STR00139##
[0187] 3,3-Dimethylbutanoyl chloride (0.187 mL, 1.04 mmol) was
added dropwise to a 0.degree. C. solution of
1-(3-methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-amine
(0.030 g, 0.104 mmol) and triethylamine (0.180 mL, 1.56 mmol) in
CH.sub.2Cl.sub.2 (1 mL) and the reaction mixture was allowed to
warm to ambient temperature and stir for 30 minutes. Ammonia (2.0 M
in MeOH, 1 mL) was added and the mixture was stirred at 50.degree.
C. for two hours before quenching with saturated aqueous
NH.sub.4Cl. The aqueous portion was extracted with EtOAc, the
combined organics were dried (MgSO.sub.4) and the volatiles removed
to give a crude residue that was purified by chromatography on
silica (0-5% MeOH/DCM) to yield 0.017 g (43%) of the title
compound. MS (ESI) m/z 381 (MH.sup.+).
Method 10: General Procedure for Amide Formation Using EDC
(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and
HOBt (1-hydroxybenzotriazole) as Coupling Reagents
##STR00140##
[0189] A solution of the appropriate 1H-benzo[d]imidazol-2-amine
(0.13 mmol), carboxylic acid (0.16 mmol), EDC (0.19 mmol), HOBt
(0.19 mmol) and diisopropylethylamine (0.66 mmol) in
tetrahydrofuran (1 mL) was heated at 50.degree. C. under nitrogen
for 2-4 hours. The reaction was cooled to room temperature, diluted
with EtOAc and washed with water. The organic solution was
concentrated in vacuo and purified by flash column chromatography
(silica gel, 0-10% MeOH/DCM) to afford the title compounds.
Method 11: Representative Procedure for Amide Formation Using
Yamaguchi Conditions
Example 45. Preparation of
(S)-2,2-Dimethyl-N-(1-(3-methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benz-
o[d]imidazol-2-yl)cyclopropanecarboxamide
##STR00141##
[0191] (S)-2,2-Dimethylcyclopropyl carboxylic acid (0.018 g, 0.159
mmol), triethylamine (0.042 mL, 0.318 mmol) and
2,4,6-trichlorobenzoyl chloride (0.025 mL, 0.159 mmol) was stirred
in 1 mL tetrahydrofuran for 30 minutes.
1-(3-Methylisoxazol-5-yl)-6-(trifluoromethyl)-1H-benzo[d]imidazo-
l-2-amine (0.030 g, 0.106 mmol) and 4-(dimethylamino)pyridine
(0.003 g, 0.026 mmol) were added to the reaction mixture and the
resulting solution was heated to 50.degree. C. and stirred
overnight. The reaction was quenched with H.sub.2O, extracted
(EtOAc 3.times.) and the combined organics were dried (MgSO.sub.4)
and the volatiles removed to give a crude product that was purified
by chromatography on silica (0-100% EtOAc/hexanes) followed by HPLC
(0-100% MeCN/H.sub.2O) to yield 21 mg (71%) of the desired product.
MS (ESI) m/z 379 (MH.sup.+).
Method 12: General Procedure for Amide Formation Using
Acylbenzotriazoles
##STR00142##
[0193] A solution of appropriate 1H-benzo[d]imidazol-2-amine
intermediate (0.66 mmol) and triethylamine (0.5 mL, 3.3 mmol, 5
equivalents) in tetrahydrofuran (3 mL) was stirred for 5 min at
room temperature. To this solution was added a solution of an
appropriate acylbenzotriazole (0.7 M in dichloromethane, 3.0 mL,
2.0 mmol, 3 equivalents; see Katritzky, A R, et al, Synlett, 2005,
11, 1656) and the mixture was placed in a 50.degree. C. sand bath
for 12 hours. The mixture was allowed to cool to room temperature
and diluted with EtOAc (50 mL) and washed sequentially with
saturated aqueous Na.sub.2CO.sub.3 (three times) and brine. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated.
Purification by chromatography on silica (0-100% EtOAc/hexane or
0-10% MeOH/dichloromethane) provided the title compounds.
Section 3. Exemplary Syntheses for Examples in Table 1 Involving
Further Transformation of 1H-benzo[d]imidazol-2-yl amides
Example 51. Preparation of
N-(1-cyclobutyl-6-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylb-
utanamide
##STR00143##
[0195] A CH.sub.2Cl.sub.2 (15 mL) solution of ethyl
1-cyclobutyl-2-(3,3-dimethylbutanamido)-1H-benzo[d]imidazole-6-carboxylat-
e (112 mg) was placed in a -78.degree. C. bath for 10 minutes prior
to the dropwise addition of diisobutylaluminum hydride (1.0 M in
CH.sub.2Cl.sub.2, 2 mL). The reaction was allowed to stir at
-78.degree. C. for 1 h before being quenched by the dropwise
addition of MeOH (2 mL). The quenched reaction was diluted with
CH.sub.2Cl.sub.2 (50 mL) and sodium/potassium tartrate (1 M, 50 mL)
was added and the mixture was allowed to vigorously stir overnight.
In this time frame, two clear layers developed and the aqueous
portion was extracted with CH.sub.2Cl.sub.2 (2.times.), the
combined organics were washed with brine, dried (Na.sub.2SO.sub.4)
and the volatiles removed to give a crude residue that was purified
via chromatography (Isco 12 g silica gel column, 0-10%
MeOH/CH.sub.2Cl.sub.2) to yield 56 mg (57%) of the title compound.
MS (ESI) m/z 316.4 (MH.sup.+), retention time=2.35 min. The
material was further purified by subjecting to another Isco 12 g
silica gel column (40 to 100% EtOAc in hexanes) to give 10 mg of
the title compound.
Example 53. Preparation of
N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-3,3-di-
methylbutanamide
##STR00144##
[0197] A tetrahydrofuran (2 mL) solution of ethyl
1-cyclobutyl-2-(3,3-dimethylbutanamido)-1H-benzo[d]imidazole-6-carboxylat-
e (50 mg, 0.14 mmol) was allowed to chill at 0.degree. C. for 10
minutes under nitrogen prior to the dropwise addition of
methylmagnesium bromide (2 M in ether, 0.3 mL). The reaction was
allowed to stir at 0.degree. C. for 1.5 hours and then quenched by
the addition of saturated sodium bicarbonate (25 mL) and EtOAc (25
mL). The aqueous layer was extracted twice with EtOAc and the
combined organics were washed with brine, dried with sodium
sulfate, filtered and concentrated to give a crude residue. The
crude material was subjected to column chromatography (two 4 g
silica gel Isco columns in series, 5 to 50% EtOAc in hexanes) to
give the title compound as a white solid (16 mg, 33% yield). MS
(ESI) m/z 344.4 (MH.sup.+), retention time=2.44 minutes (Method
B).
Example 57. Preparation of
N-(1-cyclobutyl-6-(1-hydroxyethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethyl-
butanamide
##STR00145##
[0198] Step A
[0199] A tetrahydrofuran (2 mL) solution of
N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide
(112 mg) was placed in a 0.degree. C. bath for 10 minutes prior to
the dropwise addition of ethylmagnesium bromide (3 M in diethyl
ether, 0.45 mL). The reaction was allowed to stir at 0.degree. C.
for 1 h and then allowed to warm up to room temperature. The
reaction was allowed to stir at room temperature overnight and then
placed back in a 0.degree. C. bath for 10 minutes before it was
quenched with MeOH (0.5 mL). After 5 minutes, the quenched reaction
was partioned between saturated aqueous ammonium chloride (25 mL)
and ethyl acetate (25 mL). The aqueous layer was extracted twice
with ethyl acetate. The combined organics were washed with brine
and dried with sodium sulfate. The dried reaction was filtered,
concentrated and subjected to a 12 g silica gel Isco column (15 to
100% EtOAc in hexanes) to give the ethyl ketone compound
N-(1-cyclobutyl-6-propionyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanam-
ide (75 mg, 70%) as a white solid. MS (ESI) m/z 342.4 (MH.sup.+),
retention time=3.51 minutes (Method B).
Step B
[0200]
N-(1-Cyclobutyl-6-propionyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylb-
utanamide (41 mg) was placed in a roundbottom flask with ethanol (6
mL) and the flask was allowed to chill in a 0.degree. C. bath for
10 minutes before the portionwise addition of sodium borohydride
(60 mg). The reaction was allowed to stir for 30 minutes and then
quenched by the slow addition of HCl (1.0 M, 10 mL). The quenched
reaction was diluted with EtOAc (30 mL) and allowed to stir for 1
hour. The aqueous layer was extracted with EtOAc (2.times.). The
combined organics were washed with saturated aqueous sodium
bicarbonate (40 mL), brine and dried with sodium sulfate. The dried
solution was filtered and concentrated to give a crude material
that was subjected to a 12 gram silica gel Isco column (20-50%
EtOAc in hexanes) to give the title compound (25 mg, 60%) as a
white solid. MS (ESI) m/z 344.4 (MH.sup.+), retention time=2.57
minutes (Method B).
Example 65. Preparation of
(S)--N-(1-cyclobutyl-6-isopropyl-1H-benzo[d]imidazol-2-yl)-2,3-dimethylbu-
tanamide
##STR00146##
[0202] Solid
(S)--N-(1-cyclobutyl-6-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-
,3-dimethylbutanamide (15 mL) was dissolved in dichloromethane (2
mL). TFA (1.5 mL) was added before the dropwise addition of neat
triethylsilane (1 mL). The reaction was allowed to stir overnight
and then diluted with dichloromethane (15 mL) and washed with
saturated sodium bicarbonate (20 mL). The aqueous layer was
extracted twice with dichloromethane. The combined organics were
washed with brine and dried with sodium sulfate. The dried solution
was filtered and concentrated to give a crude product. The crude
material was subjected to a high vacuum for 48 h prior to being
subjected to column chromatography (4 gram Isco silica gel, 0-5%
MeOH in dichloromethane) to give the title compound as a colorless
oil (9 mg, 63% yield). MS (ESI) m/z 328.4 (MH.sup.+), retention
time=3.36 min (Method B).
Example 66. Preparation of
N-(1-cyclobutyl-6-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethyl-
butanamide
##STR00147##
[0203] Step A
[0204] Solid
N-(1-cyclobutyl-6-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)-3,3-dimethylb-
utanamide (100 mg) was dissolved in dichloromethane (5 mL) and
solid sodium bicarbonate (106 mg, 4 equivalents) was added in one
portion before the addition of Dess-Martin periodinane (270 mg, 2
equivalents) in one portion. The reaction turned from colorless to
a red colored solution upon the addition of the Dess Martin
reagent. The reaction was allowed to stir at room temperature for 1
hour before sodium thiosulfate (10%, 25 mL) and EtOAc (25 mL) were
added to quench the reaction. The quenched reaction was allowed to
stir for 1 hour and in this time the red colored solution faded to
a colorless solution. The aqueous layer was extracted twice with
EtOAc. The combined organic phases were washed with sodium
bicarbonate, brine, and dried with sodium sulfate. The dried
solution was filtered and concentrated to give a crude product
which was subjected to column chromatography (12 gram Isco, 5 to
75% EtOAc in hexanes) to yield 83 mg (84%) of
N-(1-cyclobutyl-6-formyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide
that was used directly in the next reaction.
Step B
[0205] The freshly prepared aldehyde
(N-(1-cyclobutyl-6-formyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamid-
e, 37 mg, 0.118 mmol) from the above experimental was dissolved in
dichloromethane (2 mL) and TEA-3HF (58 mg, 3 equivalents) was added
before the portionwise addition of XtalFluor-E (81 mg, 3
equivalents) at room temperature. LC/MS analysis at 3 hours of
reaction time showed slow progression of the reaction. Therefore,
two more equivalents of each reagent were added to the reaction.
LC/MS analysis 4 hours later showed slow and clean conversion to
the desired product. The reaction was allowed to stir overnight and
then quenched by the addition of saturated sodium bicarbonate (20
mL) and diluted with dichloromethane (20 mL). The quenched reaction
was allowed to stir for 15 minutes and then extracted with
dichloromethane (3.times.) and the combined organics were washed
with brine, dried with sodium sulfate, filtered and concentrated to
give a crude material. The crude material was subjected to silica
gel chromatography (12 gram Isco, 0-25% EtOAc in hexanes, product
is higher in R.sub.f than the corresponding aldehyde) to give the
titled compound (7.5 mg, 19% yield) as a white solid. MS (ESI) m/z
336.4 (MH.sup.+), retention time=3.37 min (Method B). The
intermediate aldehyde was also recovered from the chromatography
(16 mg, 43%). (See: Couturier, M. et al, J. Org. Chem. 2010, 75,
3401-3411).
Example 1. Preparation of
N-(1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide
##STR00148##
[0207] Solid
N-(6-bromo-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3,3-dimethylbutanamide
(75 mg) was dissolved in chloroform (9 mL) and methanol (3 mL)
before the addition of palladium on carbon (10%, 30 mg). The
mixture was allowed to stir for 2 minutes before the dropwise
addition of triethylsilane (0.9 mL). The reaction was allowed to
stir for 30 minutes and then passed though filter paper. The
filtrate was concentrated and subjected to silica gel
chromatography (12 gram Isco column, 0 to 70% EtOAc in hexanes) to
give the desired product that contained an impurity. The material
was further purified by subjecting it to another silica gel column
(4 gram silica gel Isco, 0-10% MeOH in dichloromethane) to give a
pure sample of the titled compound (22 mg, 31% yield) as a foamy
white solid. MS (ESI) m/z 286.4 (MH.sup.+), retention time=2.71 min
(Method B). (see Mandal, P K, McMurray, J S, J. Org. Chem. 2007,
72, 6599-6601).
Example 22. Preparation of
(R)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methyl(2,2,2-tr-
ifluoroethyl)amino)propanamide
##STR00149##
[0208] Step A: Preparation of (R)-tert-butyl
(1-((6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)amino)-1-oxopropan-2-y-
l)(methyl)carbamate
[0209]
2-Amino-3-cyclobutyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (100
mg, 0.47 mmol) and
(R)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid (115 mg,
0.57 mmol) were used following Method 7 to provide the desired
product (112 mg, 59%).
Step B: Preparation of
(R)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methylamino)pro-
panamide Hydrochloride
[0210] To a solution of (R)-tert-butyl
(1-((6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)amino)-1-oxopropan-2-y-
l)(methyl)carbamate (112 mg, 0.30 mmol) from Step A in MeOH (4 mL)
was added concentrated aqueous hydrochloric acid (3 mL) at room
temperature. The mixture was stirred for one hour and then
concentrated in vacuo. The residue was concentrated twice from
methanol to provide the desired product (98 mg, 99%).
Step C: Preparation of
(R)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methyl(2,2,2-tr-
ifluoroethyl)amino)propanamide
[0211] DIEA (130 .mu.L, 0.76 mmol) was added to a room temperature
solution of
(R)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2-(methylamino)pro-
panamide hydrochloride from Step B in dimethylformamide (2 mL). The
mixture was stirred for several minutes and then was treated with
2,2,2-trifluoroethyl trifluoromethanesulfonate (55 .mu.L, 0.38
mmol). The mixture was stirred for eight hours with additional DIEA
(130 .mu.L, 0.76 mmol) and 2,2,2-trifluoroethyl
trifluoromethanesulfonate (55 .mu.L, 0.38 mmol) being added at two
hour intervals over the duration of the reaction. The mixture was
concentrated in vacuo and purified by silica gel chromatography
(10-50% EtOAc/hexanes) to provide the title compound (24 mg, 21%).
MS (ESI) m/z 380.4 (MH.sup.+).
Example 24. Preparation of
N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-(dimethylamino)-4,4,4-
-trifluorobutanamide
##STR00150##
[0213] To tert-butyl
(4-((6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)amino)-1,1,1-trifluoro-
-4-oxobutan-2-yl)carbamate (23 mg, 0.051 mmol, prepared according
to the procedure of Method 7 using
3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoic acid) in
CH.sub.2Cl.sub.2 (1 mL) was added CF.sub.3CO.sub.2H (1 mL) and the
mixture was stirred at room temperature for 1 hour. Solvents were
removed by rotary evaporation, the residue was dissolved in EtOAc,
washed sequentially with saturated NaHCO.sub.3, brine, then dried
(Na.sub.2SO.sub.4), filtered and concentrated to give
3-amino-N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-4,4,4-trifluoro-
butanamide (18 mg, 0.051 mmol) as a colorless oil. This material
was dissolved in 20:1 CH.sub.3OH/HOAc (0.5 mL) followed by
Et.sub.3N (9 .mu.L, 0.10 mmol) and formaldehyde solution (37% in
H.sub.2O, 12 .mu.L, 0.23 mmol). NaCNBH.sub.3 (18 mg, 0.51 mmol) was
added and the mixture was stirred at room temperature for 4 hours.
Solvent was concentrated by rotary evaporation, the residue was
distributed between saturated aqueous NaHCO.sub.3 and EtOAc and the
layers were separated. The aqueous layer was extracted with EtOAc,
the extracts were combined, dried (Na.sub.2SO.sub.4), filtered and
concentrated. Purification was run on a 4 g silica gel column
eluting with 0-50% EtOAc/hexanes to give the title compound (11.8
mg, 61%). MS (ESI) m/z 380.4 (MH.sup.+).
Section 4. Exemplary Syntheses for Examples in Table 1 Involving
Preparation of Branched Chiral 1H-benzo[d]imidazol-2-yl Amides
Example 18. Preparation of
(2S,3R)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2-me-
thyl-3-phenylbutanamide
##STR00151##
[0214] Step A: Preparation of
(2S,3R)-3-hydroxy-2-methyl-3-phenylbutanoic Acid
[0215] A solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (1.0
g, 4.3 mmol) in tetrahydrofuran (10 mL) was added dropwise to a
-78.degree. C. solution of LiN(TMS).sub.2 (1.0 M in
tetrahydrofuran, 4.5 mL, 4.5 mmol) in tetrahydrofuran (14 mL). The
mixture was stirred for 30 minutes at -78.degree. C. and then
acetophenone (0.53 mL, 4.5 mmol) was added over 10 minutes. The
-78.degree. C. mixture was stirred for two hours and then quenched
via the addition of saturated aqueous NH.sub.4Cl. The mixture was
warmed to room temperature and extracted twice with EtOAc. The
combined organics were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by silica gel chromatography
(0-20% EtOAc/hexanes) to provide partially separated mixtures of
the oxazolidinone starting material and four possible diastereomers
(R.sub.f=0.57 in 1:4 EtOAc/hexanes, 0.56 g, 37%, (2S,3S) containing
fraction; R.sub.f=0.50 in 1:4 EtOAc/hexanes, 0.26 g, 17%, (2S,3R)
containing fraction). Stereochemical assignment for the observed
two major diastereomers were made via extrapolation from data
reported in Bartroli, et al; J. Org. Chem., 1995, 60, 3000.
Step B: Preparation of
(R)-4-benzyl-3-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-pheny-
lbutanoyl)oxazolidin-2-one
[0216] tert-Butyldimethylsilyl trifluoromethanesulfonate (200
.mu.L, 0.88 mmol) was added dropwise to a solution of the
diastereomeric mixture containing
(2S,3R)-3-hydroxy-2-methyl-3-phenylbutanoic acid isolated from Step
A (0.26 g, 0.74 mmol) and Et.sub.3N (200 .mu.L, 1.5 mmol) in
CH.sub.2Cl.sub.2 (5 mL). The solution was stirred at room
temperature for one hour and then partitioned between EtOAc and
saturated aqueous NaHCO.sub.3. The phases were separated and the
organics were washed with saturated aqueous NaCl. The organics were
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue
was purified twice by silica gel chromatography (0-20%
EtOAc/hexanes and then 0-50% CH.sub.2Cl.sub.2/hexanes) to provide
the expected product (0.11 g, 32%).
Step C: Preparation of
(2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenylbutanoic
acid
[0217] Lithium hydroxide (29 mg, 1.2 mmol) and 30% aqueous hydrogen
peroxide (0.12 mL, 1.2 mmol) were added to a 0.degree. C. mixture
of
(R)-4-benzyl-3-((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-pheny-
lbutanoyl)oxazolidin-2-one from Step B (110 mg, 0.24 mmol) in 1:1
tetrahydrofuran/H.sub.2O (3 mL). The mixture was stirred at
0.degree. C. to room temperature overnight. The mixture was
adjusted to pH 2 via the addition of 1 M aqueous HCl and then
treated with solid NaCl until the solids failed to dissolve. The
mixture was then partitioned between saturated aqueous NaCl and
EtOAc. The phases were separated and the aqueous layer was
extracted again with EtOAc. The organics were combined, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by silica gel chromatography (0-50%
CH.sub.2Cl.sub.2/hexanes) to provide the expected product (10 mg,
24%).
Step D: Preparation of
(2S,3R)-3-((tert-butyldimethylsilyl)oxy)-N-(6-cyano-1-cyclobutyl-1H-benzo-
[d]imidazol-2-yl)-2-methyl-3-phenylbutanamide
[0218] A mixture of
2-amino-3-cyclobutyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile (7.0
mg, 0.032 mmol),
(2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenylbutanoic
acid from Step C (10 mg, 0.032 mmol), HOBt (7.0 mg, 0.049 mmol),
EDC (8.0 mg, 0.049 mmol) and diisopropylethylamine (17 .mu.L, 0.097
mmol) in dimethylformamide (2 mL) were stirred at 50.degree. C. for
3 days. The mixture was cooled to room temperature and partitioned
between water and EtOAc. The aqueous phase was extracted twice more
with EtOAc. The combined organics were washed with saturated
aqueous NaCl, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. This crude material was used as is in the next
step.
Step E: Preparation of
(2S,3R)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2-me-
thyl-3-phenylbutanamide
[0219] TBAF (1.0 M tetrahydrofuran, 160 .mu.L, 0.16 mmol) was added
to a solution of the crude product from Step D above in
tetrahydrofuran (0.32 mL). The mixture was stirred at 50.degree. C.
overnight, cooled to room temperature and concentrated. The residue
was purified by reverse phase chromatography (10%
CH.sub.3CN/H.sub.2O to CH.sub.3CN) to afford the title compound
(1.7 mg, 14% over two steps). MS (ESI) m/z 389.2 (MH.sup.+).
Example 29. Preparation of
(S)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenyl-
butanamide
##STR00152##
[0220] Step A: Preparation of
(S)-4-benzyl-3-((S)-3-hydroxy-3-phenylbutanoyl)oxazolidin-2-one
[0221] Lithium bis(trimethylsilyl)amide (1.0 M tetrahydrofuran, 9.2
mL, 9.2 mmol) was added over 15 minutes to a -78.degree. C.
suspension of (S)-3-acetyl-4-benzyloxazolidin-2-one (2.0 g, 9.2
mmol) in tetrahydrofuran (9 mL). The mixture was stirred at
-78.degree. C. for two hours. A solution of acetophenone (485
.mu.L, 4.2 mmol) in tetrahydrofuran (3 mL) was added over 35
minutes. The mixture was stirred at -78.degree. C. for one hour and
then quenched via the addition of aqueous 0.5 M HCl. The mixture
was warmed to room temperature and then extracted with
CH.sub.2Cl.sub.2. The layers were separated and the aqueous phase
was extracted twice more with CH.sub.2Cl.sub.2. The combined
organics were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified by silica gel chromatography
(0-30% EtOAc/hexanes) to provide the desired compound in a
partially purified fashion (1.6 g) that was used as is. The
stereochemistry was assigned as reported in Theurer, et al;
Tetrahedron, 2010, 66, 3814.
Step B: Preparation of
(S)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-3-phenylbutanoyl)oxa-
zolidin-2-one
[0222] tert-Butyldimethylsilyl trifluoromethanesulfonate (1.3 mL,
5.7 mmol) was added dropwise to a room temperature solution of the
residue prepared as described in Step A and Et.sub.3N (1.1 mL, 7.5
mmol) in CH.sub.2Cl.sub.2 (24 mL). The mixture was stirred at room
temperature overnight and then partitioned between EtOAc and
saturated aqueous NaHCO.sub.3. The phases were separated and the
organics were washed with saturated aqueous NaCl. The two aqueous
phases were then sequentially extracted twice with EtOAc. The
combined organics were dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The residue was purified twice by silica gel
chromatography (0-30% EtOAc/hexanes and then 0-50%
CH.sub.2Cl.sub.2/hexanes) to provide the expected product (0.57 g,
30% over two steps).
Step C: Preparation of
(S)-3-((tert-butyldimethylsilyl)oxy)-3-phenylbutanoic acid
[0223] Lithium hydroxide (150 mg, 6.3 mmol) and 30% aqueous
hydrogen peroxide (0.64 mL, 6.3 mmol) were added to a 0.degree. C.
mixture of
(S)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-3-phenylbutanoyl)oxa-
zolidin-2-one from Step B (570 mg, 1.3 mmol) in 1:1
tetrahydrofuran/H.sub.2O (13 mL). The mixture was stirred at
0.degree. C. to room temperature over 80 minutes. The mixture was
adjusted to pH 2 via the addition of 1 M aqueous HCl and then
treated with solid NaCl until the solids failed to dissolve. The
mixture was then partitioned between saturated aqueous NaCl and
EtOAc. The phases were separated and the aqueous layer was
extracted again with EtOAc. The organics were combined, dried over
anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was
purified by silica gel chromatography (0-60% EtOAc/hexanes) to
provide the expected product (0.21 g, 57%).
[0224] The title compound was then prepared using the procedures
described in Step D and Step E of Example 18. MS (ESI) m/z 375
(MH.sup.+).
Example 30. Preparation of
(R)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-phenyl-
butanamide
##STR00153##
[0226] The same procedure was used to prepare the title compound as
was used for Example 29 with the exception of starting with
(R)-3-acetyl-4-benzyloxazolidin-2-one instead of the
(S)-enantiomer. MS (ESI) m/z 375 (MH.sup.+).
Example 20. Preparation of
(S)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-(pyrid-
in-2-yl)butanamide
##STR00154##
[0228] The same procedure was used to prepare the title compound as
was used for Example 29 with the exception of starting with
(R)-3-acetyl-4-benzyloxazolidin-2-one instead of the
(S)-enantiomer, and using 2-acetopyridine in place of acetophenone.
MS (ESI) m/z 376 (MH.sup.+). Stereochemical assignment based on
Peters R, et al., J. Org. Chem. 2006, 71, 7583-7595.
Example 21. Preparation of
(S)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-3-(pyrid-
ine-3-yl)butanamide
##STR00155##
[0230] The same procedure was used to prepare the title compound as
was used for Example 29 with the exception of starting with
(R)-3-acetyl-4-benzyloxazolidin-2-one instead of the (S)-enantiomer
and using 3-acetopyridine in place of acetophenone.
Example 23. Preparation of
(S)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2,3,3-trimethylbut-
anamide
##STR00156##
[0231] Step A: Preparation of
(S)-4-benzyl-3-(3,3-dimethylbutanoyl)oxazolidin-2-one
##STR00157##
[0233] A 1.0 L round bottom flask was charged with a stir bar,
tetrahydrofuran (200 mL, anhydrous) and
(S)-4-benzyloxazolidin-2-one (10.0 g, 56.4 mmol). The flask was
placed in a -78.degree. C. bath for 15 minutes prior to the
addition of n-BuLi (2.5 M in hexanes, 25.0 mL, 1.1 equivalents)
dropwise under a nitrogen atmosphere. The reaction was allowed to
stir for 1 hour prior to the addition of 3,3-dimethylbutanoyl
chloride (11.7 mL, 1.5 equivalents). The reaction was allowed to
stir at -78.degree. C. and then the cooling bath was removed and
the flask was allowed to slowly warm to room temperature and stir
overnight. The reaction was quenched by the addition of saturated
aqueous sodium bicarbonate (200 mL) and the bulk of the
tetrahydrofuran was removed by rotary evaporation. The remaining
residue was dissolved in ethyl acetate (300 mL) and washed
sequentially with saturated aqueous sodium bicarbonate (twice),
saturated aqueous sodium carbonate (twice), and brine and then
dried over sodium sulfate. The dried solution was filtered and
concentrated to give 20 g of crude product. The material was
recrystallized from warm ethyl acetate (approximately 30 mL) and
warm hexanes (approximately 70 mL) to give the first crop of the
desired product (9.0 g. 58% yield) as white crystals. An additional
second crop (3.8 g, 25% yield) was obtained from the mother liquor.
.sup.1H NMR (CDCl.sub.3): .delta. 7.36-7.22 (m, 5H), 4.73-4.67 (m,
1H), 4.18-4.12 (m, 2H), 3.34 (dd, J=13.28, 3.32 Hz, 1H), 2.99 (d,
J=14.9 Hz, 1H), 2.86 (d, J=14.9 Hz, 1H), 2.71 (dd, J=13.24, 10.00
Hz, 1H), 1.09 (br s, 9H).
Step B: Preparation of
(S)-4-benzyl-3-((S)-2,3,3-trimethylbutanoyl)oxazolidin-2-one
##STR00158##
[0235] Freshly recrystallized
(S)-4-benzyl-3-(3,3-dimethylbutanoyl)oxazolidin-2-one (8.75 g,
31.77 mmol) was azeotroped with dichloromethane (2.times., 30 mL)
and then placed under high vacuum for 10 minutes prior to being
dissolved in tetrahydrofuran (40 mL). In a 1.0 L round bottom flask
fitted with a balloon of nitrogen and a stir bar was placed NaHMDS
(1.0 M in tetrahydrofuran, 35 mL, 1.1 equivalents) and the flask
was placed in a -78.degree. C. bath. After being chilled for 15
minutes, the 40 mL tetrahydrofuran solution of
(S)-4-benzyl-3-(3,3-dimethylbutanoyl)oxazolidin-2-one was added
dropwise to the NaHMDS at -78.degree. C. The formation of the
sodium enolate was allowed to form over 1 hour at -78.degree. C.
and then methyl iodide (6 mL, 3 equivalents) was added via syringe.
The reaction was allowed to stir and slowly warm to room
temperature overnight. The reaction was quenched by the addition of
saturated aqueous sodium bicarbonate (150 mL) and the bulk of the
tetrahydrofuran was removed by rotary evaporation. The residue was
transferred to a separatory funnel using ethyl acetate and
saturated aqueous sodium bicarbonate. The layers were separated and
the organic layer was washed with 10% aqueous sodium thiosulfate
(150 mL) to remove the pale yellow color. The combined organic
layers were back extracted with ethyl acetate (2.times.). The
combined organics were washed with brine, dried with sodium
sulfate, filtered and concentrated to give a white solid (8.61 g,
94% yield). .sup.1H NMR analysis indicated complete conversion of
starting material to the methylated products and an approximately
15:1 diastereomeric ratio of products in favor of the desired
(S)-4-benzyl-3-((S)-2,3,3 trimethylbutanoyl)oxazolidin-2-one
diastereomer A. An attempt to enrich the diastereomeric ratio by
recrystallization from warm hexanes failed to improve the
diastereomeric ratio. Therefore, the initial solid product was
divided into three portions and each one was subjected to column
chromatography (Isco, 120 g silica gel, 0-10% EtOAc in hexanes).
The higher running R.sub.f fractions of the UV peak were cut off
from the later running fractions to give a product of improved
diastereomeric ratio (1.83 g, approximately 70:1 d.r.) as a white
solid. The chromatography was repeated on the original product to
give two samples of improved diastereomeric ratio (2.28 g, >20:1
d.r and 4.59 g, 30:1 d.r.) in favor of
(S)-4-benzyl-3-((S)-2,3,3-trimethylbutanoyl)oxazolidin-2-one
diastereomer. Major diastereomer A .sup.1H NMR (CDCl.sub.3):
.delta. 7.33-7.23 (m, 5H), 4.73-4.67 (m, 1H), 4.17-4.13 (m, 2H),
3.90 (q, J=7.00 Hz, 1H), 3.28 (dd, J=13.32, 3.20 Hz, 1H), 2.77 (dd,
J=13.32, 9.72 Hz, 1H), 1.20 (d, J=7.00 Hz, 3H), 1.02 (bs, 9H). The
latter running R.sub.f fraction were combined to give the desired
product in a diminished diastereomeric ratio (360 mg, 3:1 d.r.)
contaminated with the undesired
(S)-4-benzyl-3-((R)-2,3,3-trimethylbutanoyl)oxazolidin-2-one minor
diastereomer B (Reference: Evans, D A; Ennis, M D; Mathre, D J J.
Am. Chem. Soc. 1982, 104, 1737-1739).
Step C: Preparation of (S)-2,3,3-trimethylbutanoic Acid
##STR00159##
[0237] Solid
(S)-4-benzyl-3-((S)-2,3,3-trimethylbutanoyl)oxazolidin-2-one (2.24
g, 7.73 mmol, diastereomer A from Step B above, approx. 30:1 d.r)
was dissolved in tetrahydrofuran (50 mL) and water (10 mL) and the
flask was allowed to chill in a 0.degree. C. for 10 minutes prior
to the addition of lithium hydroxide (326 mg, 13.6 mmol, 2
equivalents) in one portion. After a few minutes, hydrogen peroxide
(30%, 6 mL) was added via syringe. After approximately 30 min, an
additional portion of tetrahydrofuran (60 mL) and water (10 mL)
were added to the flask. The reaction was allowed to stir at
0.degree. C. for 1 hour and then allowed to warm to room
temperature and stirred for 24 hours. The flask was rechilled to
0.degree. C. and then quenched by the addition of sodium sulfite
(19 g in 125 mL of water) and saturated aqueous sodium bicarbonate
(75 mL). The quenched reaction was allowed to stir for 1.5 hours
and then the bulk of the tetrahydrofuran was removed by rotary
evaporation. The mixture was transferred to a separatory funnel
using dichloromethane and saturated aqueous sodium bicarbonate. The
aqueous layer was extracted with dichloromethane (3.times.50 mL) to
remove the bulk of the chiral auxiliary. The aqueous layer was
carefully acidified with HCl (1 M, until pH=2) and then extracted
with dichloromethane (4.times.50 mL). The combined organics were
washed with brine and dried with sodium sulfate. The dried solution
was filtered and carefully evaporated to give the desired
carboxylic acid as an oil (925 mg, >100% yield, dichloromethane
impurity). The (S)-2,3,3-trimethylbutanoic acid was diluted up to a
volume of 9 mL with dichloromethane to make a stock solution that
was used directly in the amide coupling reaction. .sup.1H NMR
(CDCl.sub.3): .delta. 12.02 (br s, 1H), 2.29 (q, J=7.08 Hz, 1H),
1.13 (d, J=7.08 Hz, 3H), 0.99 (br s, 9H). (Reference: Evans, D A,
Britton, T C, Ellman, J A, Tetrahedron Left. 1987, 28(49),
6141-6144).
Step D: Preparation of
(S)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-2,3,3-trimethylbut-
anamide
[0238] The dichloromethane stock solution of
(S)-2,3,3-trimethylbutanoic acid from Step C above was transferred
to a tared flask and carefully evaporated. This acid was dissolved
in dimethylformamide and the standard amide coupling Method 7 was
followed to give the desired product.
Example 13. Preparation of
(S)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2,3-dime-
thylbutanamide
##STR00160##
[0239] Step A. Preparation of
(R)-4-benzyl-3-((S)-3-hydroxy-2,3-dimethylbutanoyl)oxazolidin-2-one
##STR00161##
[0241] Commercially available
(R)-4-benzyl-3-propionyloxazolidin-2-one (3.0 g, 12.85 mmol, 1.0
equivalents) was dissolved in dichloromethane (40 mL) and chilled
to 0.degree. C. for 10 minutes prior to the addition of TiCl.sub.4
(1.0 M in dichloromethane, 14.15 mL, 1.1 equivalents) via syringe
under an atmosphere of nitrogen. After 5 minutes,
diisopropylethylamine (2.5 mL, 1.1 equivalents) was added dropwise
via syringe. The reaction was allowed to stir at 0.degree. C. for 1
hour and a dark-red titanium enolate formed. At this time, acetone
(1.4 mL, 1.5 equivalents, dried over anhydrous potassium carbonate
for 24 hours) was added via syringe. The reaction was allowed to
stir at 0.degree. C. for 15 minutes and then slowly allowed to warm
to room temperature overnight. The reaction was quenched by the
addition of aqueous ammonium chloride (1 M, 100 mL) and extracted
with dichloromethane (three times). The combined organics were
washed with brine, dried with sodium sulfate, filtered and
concentrated to give 4.0 g of a crude oil. The crude oil was
subjected to column chromatography (Isco, 120 g silica gel, 0-25%
EtOAc in hexanes) to give the desired product (3.0 g, 80% yield) as
a white solid. NMR analysis indicated a single diastereomer of the
purified product. R.sub.f=0.75 in 20% EtOAc in hexanes. .sup.1H NMR
(CDCl.sub.3): .delta. 7.32-7.23 (m, 5H), 4.72-4.66 (m, 1H),
4.20-4.13 (m, 2H), 3.95 (q, J=7.00 Hz, 1H), 3.38-3.34 (m, 2H), 2.75
(dd, J=13.36, 9.88 Hz, 1H), 1.35 (s, 3H), 1.24-1.23 (m, 6H).
(Reference: Evans, D A, Urpi, F, Somers, T C. Clark, J S, Bilodeau,
M T, J. Am. Chem. Soc. 1990, 112, 8215-8216).
Step B: Preparation of
(R)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanoyl-
)oxazolidin-2-one
##STR00162##
[0243] The solid tertiary alcohol (1000 mg, 3.43 mmol, 1.0
equivalents) from the above procedure,
(R)-4-benzyl-3-((S)-3-hydroxy-2,3-dimethylbutanoyl)oxazolidin-2-one,
was dissolved in dichloromethane (10 mL) and diisopropylethylamine
(0.9 mL, 1.5 equivalents) was added via syringe. The flask was
chilled for 10 minutes in a 0.degree. C. bath prior to the drop
wise addition of tert-butyldimethylsilyl triflate (0.9 mL, 1.1
equivalents) via syringe. The reaction was allowed to stir
overnight and then quenched by the addition of saturated aqueous
sodium bicarbonate (50 mL). The aqueous layer was extracted twice
with dichloromethane. The combined organics were washed with brine,
dried with sodium sulfate, filtered and concentrated to give a
crude oil. The crude material was subjected to silica gel column
chromatography (Isco, 24 g silica gel, 0-20% EtOAc in hexanes) to
give the desired TBS ether (1.23 g, 95%) as a white solid.
R.sub.f=0.75 in 20% EtOAc in hexanes. .sup.1H NMR (CDCl.sub.3):
.delta. 7.24-7.12 (m, 5H), 4.57-4.51 (m, 1H), 4.10-3.93 (m, 3H),
3.33 (dd, J=13.08, 3.16 Hz, 1H), 2.47 (dd, J=13.00, 10.88 Hz, 1H),
1.25 (s, 3H), 1.24 (s, 3H), 1.07 (d, J=7.00 Hz, 3H), 0.76 (bs, 9H),
0.00 (d, J=5.72 Hz, 6H).
Step C: Preparation of
(S)-3-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanoic Acid
##STR00163##
[0245] Solid
(R)-4-benzyl-3-((S)-3-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbutanoyl-
)oxazolidin-2-one (3.8 g, 9.7 mmol, >30:1 d.r) was dissolved in
tetrahydrofuran (50 mL) and water (10 mL) and the flask was allowed
to chill in a 0.degree. C. for 5 minutes prior to the addition of
lithium hydroxide (450 mg, 18.7 mmol, 2 equivalents) in one
portion. After a few minutes, hydrogen peroxide (30%, 12 mL) was
added via syringe. The reaction was allowed to stir at 0.degree. C.
for 1 hour and then allowed to warm to room temperature and stirred
for 24 hours. The flask was rechilled to 0.degree. C. and then
quenched by the addition of sodium sulfite (12 g in 100 mL of
water). The quenched reaction was allowed to stir for 1.5 hours and
then the bulk of the tetrahydrofuran was removed by rotary
evaporation. The mixture was transferred to a separatory funnel
using dichloromethane and saturated aqueous sodium bicarbonate. The
aqueous layer was extracted with dichloromethane (2.times.50 mL).
This initial dichloromethane extract was found to contain both the
chiral auxiliary and the desired TBS ether acid. The combined
organics were washed with brine and dried with sodium sulfate,
filtered and concentrated to give the crude product as oil (3.1 g).
The crude material was subjected to silica gel column
chromatography (Isco, 40 g, 0-25% EtOAc in hexanes, ELSD detection)
to give the desired product as oil (1.2 g, 52% yield). R.sub.f=0.50
in 20% EtOAc in hexanes, purple to anisaldehyde stain and is not UV
active. .sup.1H NMR (CDCl.sub.3): .delta. 10.4-9.80 (br s, 1H),
2.32 (q, J=7.16 Hz, 1H), 1.19 (s, 3H), 1.14 (s, 3H), 1.03 (d,
J=7.16 Hz, 3H), 0.72 (s, 9H), 0.00 (s, 6H).
Step D: Preparation
(S)-3-((tert-butyldimethylsilyl)oxy)-N-(6-cyano-1-cyclobutyl-1H-benzo[d]i-
midazol-2-yl)-2,3-dimethylbutanamide
##STR00164##
[0247] Method 7 was used to provide the desired amide product (38
mg, 65% yield), isolated via column chromatography. The isolated
material was contaminated with the activated ester of the
corresponding carboxylic acid coupling partner. The material was
taken forward to the next step without any further
purification.
Step E: Preparation of
(S)--N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-hydroxy-2,3-dime-
thylbutanamide Via Deprotection of TBDMS Ether
##STR00165##
[0249] Crude
(S)-3-((tert-butyldimethylsilyl)oxy)-N-(6-cyano-1-cyclobutyl-1H-benzo[d]i-
midazol-2-yl)-2,3-dimethylbutanamide from Step D above (38 mg) was
dissolved in MeOH (4 mL) and HCl (3 M in diethyl ether, 2 mL) was
added to the reaction via syringe. The reaction was allowed to stir
at room temperature for 30 minutes when LC/MS analysis indicated a
slow and clean deprotection of the TBS ether. The flask was placed
in a 50.degree. C. sand bath and allowed to stir capped for 20
hours. The flask was allowed to cool and then quenched by the
careful addition of saturated aqueous sodium bicarbonate (30 mL)
and ethyl acetate (30 mL). The aqueous layer was extracted twice
with ethyl acetate. The combined organics were washed with brine,
dried with sodium sulfate, filtered and concentrated to give a
crude oil. The crude material was subjected to column
chromatography (Isco, 12 g silica gel, 5-75% EtOAc in hexanes) to
give the desired product (18 mg, 64% yield). MS (ESI) m/z 327.2
(MH.sup.+).
Example 12. Preparation of
N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-methoxy-3-methylbutan-
amide
##STR00166##
[0250] Step A. Preparation of 3-methoxy-3-methylbutanoic acid
##STR00167##
[0252] To a solution of 3-methoxy-3-methylbutan-1-ol (0.6 g, 5
mmol) in acetonitrile (20 mL) was added N-methyl morpholine N-oxide
monohydrate (6.8 g, 50 mmol, 10 equivalents) and the mixture was
allowed to stir at room temperature. After 5 min,
tetrapropylammonium perruthenate (175 mg, 0.5 mmol, 0.1
equivalents) was added in one portion and the reaction was allowed
to stir for 3 h before the bulk of the solvent was carefully
removed on a rotary evaporator (caution, the product is volatile).
The residue was purified by column chromatography (50-100%
EtOAc/hexanes). The hexanes and EtOAc were removed by both rotary
evaporator and a short period of time to high vacuum. The product
is volatile and must not be left under vacuum for more than 30 sec.
The resulting purified acid was diluted with dimethylformamide (7
mL) to make an approximately 0.2 M solution that was used for amide
coupling reaction as is. R.sub.f=0.4 to 0.8 streak in 100% EtOAc,
not UV active, stains purple to anisaldehyde. M-1=131.2. .sup.1H
NMR (CDCl.sub.3): .delta. 12.0-9.0 (bs, 1H), 3.30 (s, 3H), 2.57 (s,
2H), 1.32 (s, 6H). (Reference: Schmidt, A-K C, Stark, B W, Org.
Lett. 2011, 13, 4164-4167).
Step B. Preparation of
N-(6-cyano-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-methoxy-3-methylbutan-
amide
[0253] The title compound was prepared from
3-methoxy-3-methylbutanoic acid and 4-amino-3-(cyclobutylamino)
benzonitrile according to Method 7. MS (ESI) m/z 327
(MH.sup.+).
Example 103. Preparation of
(S)--N-(6-chloro-1-cyclobutyl-1H-benzo[d]imidazol-2-yl)-3-(4-fluorophenyl-
)-3-hydroxybutanamide
##STR00168##
[0254] Step A: Preparation of
(S)-4-benzyl-3-((S)-3-(4-fluorophenyl)-3-hydroxybutanoyl)oxazolidin-2-one
[0255] Lithium bis(trimethylsilyl)amide (1.0 M tetrahydrofuran, 6.6
mL, 6.6 mmol) was added over 15 minutes to a -78.degree. C.
suspension of (S)-3-acetyl-4-benzyloxazolidin-2-one (1.5 g, 6.6
mmol) in tetrahydrofuran (18 mL). The mixture was stirred at
-78.degree. C. for two hours. Acetophenone (330 .mu.L, 3.2 mmol)
was added dropwise over 5 minutes. The mixture was stirred at
-78.degree. C. for one hour and then quenched via the addition of
aqueous 0.5 M HCl. The mixture was warmed to room temperature and
then extracted with CH.sub.2Cl.sub.2. The layers were separated and
the aqueous phase was extracted twice more with CH.sub.2Cl.sub.2.
The combined organics were dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The residue was purified by silica gel
chromatography (0-30% EtOAc/hexanes) to provide the desired (0.80
g).
Step B: Preparation of (S)-3-(4-fluorophenyl)-3-hydroxybutanoic
Acid
[0256] Lithium hydroxide (210 mg, 9.0 mmol) was added to a
0.degree. C. mixture of
(S)-4-benzyl-3-((S)-3-(4-fluorophenyl)-3-hydroxybutanoyl)oxazolidin-2-one
(0.80 g, 2.2 mmol) and 50% aqueous hydrogen peroxide (0.51 mL, 9.0
mmol) in 1:1 tetrahydrofuran/H.sub.2O (9 mL). The mixture was
stirred at 0.degree. C. for 15 minutes, then at room temperature
for three hours. The mixture was adjusted to pH 7 via the addition
of 1 M aqueous HCl and then was diluted with EtOAc. The layers were
separated, the aqueous phase was adjusted to pH 2 via the addition
of 1 M aqueous HCl and then treated with solid NaCl until the
solids failed to dissolve. The mixture was then partitioned between
saturated aqueous NaCl and EtOAc. The phases were separated and the
aqueous layer was extracted again with EtOAc. The organics were
combined, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to
provide the expected product (0.35 g, 79%).sub..
[0257] The title compound was then prepared using the procedures
described in Step D of Example 18, substituting
(S)-3-(4-fluorophenyl)-3-hydroxybutanoic acid for
(2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-methyl-3-phenylbutanoic
acid and 6-chloro-1-cyclobutyl-1H-benzo[d]imidazol-2-amine for
2-amino-1-cyclobutyl-1H-benzo[d]imidazole-6-carbonitrile. MS (ESI)
m/z 402 (MH.sup.+).
Preparation of 2-(1-hydroxycyclopentyl)acetic Acid
##STR00169##
[0258] Step A. Preparation of ethyl
2-(1-hydroxycyclopentyl)acetate
[0259] Chlorotrimethylsilane (181 .mu.L, 1.4 mmol) was added to a
suspension of zinc powder (1.2 g, 19 mmol) in Et.sub.2O (30 mL).
The mixture was stirred at room temperature for 15 minutes and then
refluxed for 15 minutes. The heat source was removed and ethyl
bromoacetate (1.8 mL, 14 mmol) was added dropwise to the warm
mixture. The mixture was then refluxed for one hour and then
stirred at room temperature for one hour. Cyclopentanone (1.0 g, 12
mmol) was then added dropwise. The resulting mixture was stirred
for one hour and then poured into ice cold concentrated aqueous
ammonia (80 mL). The layers were separated and the aqueous phase
was extracted with Et.sub.2O (3.times.40 mL). The combined organics
were dried (K.sub.2CO.sub.3) and concentrated to yield 1.7 g of a
colorless oil. This material was used as is in the next step.
Step B. Preparation of 2-(1-hydroxycyclopentyl)acetic acid
[0260] Lithium hydroxide (1.4 g, 58 mmol) was added to a room
temperature solution of the crude ester prepared as described in
the previous step (1.0 g, 5.8 mmol) in 1:1 EtOH:water (29 mL).
After 2 hours, the reaction was partitioned between water (100 mL)
and MTBE (100 mL). The aqueous layer was isolated and the pH was
adjusted to pH=2 with 1.0 N aqueous HCl. The aqueous mixture was
extracted three times with EtOAc. The combined organics were dried
(Na.sub.2SO.sub.4) and concentrated to afford the desired product
(500 mg, 60%). (ESI) m/z 143.2 (M-H).
[0261] The following carboxylic acids were prepared using an
analogous procedure to that described for preparation of
2-(1-hydroxycyclopentyl)acetic acid with appropriate starting
materials. [0262] 3,3-dicyclopropyl-3-hydroxypropanoic acid [0263]
3-cyclopentyl-3-hydroxybutanoic acid [0264]
3-cyclobutyl-3-hydroxybutanoic acid
Preparation of 3-hydroxy-2,2-dimethyl-3-phenylpropanoic Acid
##STR00170##
[0266] The preparation of 3-hydroxy-2,2-dimethyl-3-phenylpropanoic
acid is detailed in J. Org. Chem., 2012, 77 (11), 4885-4901.
Section 5. General Analytical Methods
[0267] LCMS was conducted on an Agilent 1100 MSD instrument
equipped with an Ascentis Express C18, 10 cm.times.4.6 mm.times.2.7
mm column, using the following methods:
[0268] HPLC Method A
[0269] Solvent A: 0.1% formic acid in water
[0270] Solvent B: Acetonitrile
[0271] Flow rate: 1.4 mL/min
[0272] Method:
[0273] 0-6.0 min gradient from B=10% to B=95%
[0274] 6.0-8.0 min, hold B=95%
[0275] 8.0-8.2 min, gradient from B=95% to B=10%
[0276] 8.2-10.0 min, hold B=10%
[0277] HPLC Method B:
[0278] Solvent A: 0.1% formic acid in water
[0279] Solvent B: Acetonitrile
[0280] Flow rate: 1.4 mL/min
[0281] Method:
[0282] 0-3.0 min gradient from B=10% to B=95%
[0283] 3.0-4.0 min, hold B=95%
[0284] 4.0-4.2 min, gradient from B=95% to B=10%
[0285] 4.2-6.0 min, hold B=10%
[0286] Table 1 shows the structures of the various Examples
prepared by these general methods, and indicates the general
coupling method used, together with a summary of the LCMS
analytical data.
TABLE-US-00001 TABLE 1 List of Examples, Synthetic Routes and
Analytical Data HPLC Re- Coupling tension Method/ HPLC time LCMS
Ex. Structure Name final step Method (min) m/z 1 ##STR00171##
N-(1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide
7 B 2.7 286 C.sub.17H.sub.23N.sub.3O 2 C.sub.19H.sub.21N.sub.3O
3,3-dimethyl-N-(1-phenyl-1H- 9 B 2.8 308 benzo[d]imidazol-2-
yl)butanamide 3 ##STR00172## 3-cyclopentyl-N-(1-isopropyl-
6-methoxy-1H- benzo[d]imidazol-2- yl)propanamide 12 A 5.5 330
C.sub.19H.sub.27N.sub.3O.sub.2 4 ##STR00173## (S)-N-(1-isopropyl-6-
methoxy-1H- benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide 7 B 2.7
304 C.sub.17H.sub.25N.sub.3O.sub.2 5 ##STR00174##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-
dimethylbutanamide 7 B 3.5 311 C.sub.18H.sub.22N.sub.4O 6
##STR00175## (S)-N-(6-cyano-1-cyclobutyl-
1H-benzo[d]imidazol-2-yl)- 2,3-dimethylbutanamide 7 B 3.5 311
C.sub.18H.sub.22N.sub.4O 7 ##STR00176##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-
2,3-dimethylbutanamide 7 A 4.9 311 C.sub.18H.sub.22N.sub.4O 8
##STR00177## N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-methylbutanamide 7 B 2.7 313
C.sub.17H.sub.20N.sub.4O.sub.2 9 ##STR00178##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-
difluorocyclobutane-1- carboxamide 7 B 3.5 331
C.sub.17H.sub.16F.sub.2N.sub.4O 10 ##STR00179##
(1S,2R,4R)-N-(6-cyano-1- cyclobutyl-1H- benzo[d]imidazol-2-
yl)bicyclo[2.2.1]heptane-2- carboxamide 7 B 3.6 335
C.sub.20H.sub.22N.sub.4O 11 ##STR00180##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-
2,2-dimethylcyclopropane-1- carboxamide 7 B 3.3 309
C.sub.18H.sub.20N.sub.4O 12 ##STR00181##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3- methoxy-3-
methylbutanamide 7 B 3.0 327 C.sub.18H.sub.22N.sub.4O.sub.2 13
##STR00182## (S)-N-(6-cyano-1-cyclobutyl-
1H-benzo[d]imidazol-2-yl)-3- hydroxy-2,3- dimethylbutanamide 7 B
2.9 327 C.sub.18H.sub.22N.sub.4O.sub.2 14 ##STR00183##
(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-
2,3-dimethylbutanamide 7 B 3.5 311 C.sub.18H.sub.22N.sub.4O 15
##STR00184## (1S,2S)-N-(6-cyano-1- cyclobutyl-1H-
benzo[d]imidazol-2-yl)-2-(2- hydroxypropan-2- yl)cyclopropane-1-
carboxamide 7 B 2.8 339 C.sub.19H.sub.22N.sub.4O.sub.2 16
##STR00185## (S)-N-(6-cyano-1-cyclobutyl-
1H-benzo[d]imidazol-2-yl)- 3,3,3-trifluoro-2-hydroxy-2-
methylpropanamide 7 B 3.8 353 C.sub.16H.sub.15F.sub.3N.sub.4O.sub.2
17 ##STR00186## N-(6-cyano-1-cyclobutyl-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7 B 3.4 375
C.sub.22H.sub.22N.sub.4O.sub.2 18 ##STR00187##
(2S,3R)-N-(6-cyano-1- cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-2-methyl-3- phenylbutanamide Ex 18 B 3.5 389
C.sub.23H.sub.24N.sub.4O.sub.2 19 ##STR00188##
(2S,3S)-N-(6-cyano-1- cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-2-methyl-3- phenylbutanamide Ex 19 B 3.8 389
C.sub.23H.sub.24N.sub.4O.sub.2 20 ##STR00189##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-(pyridin-2- yl)butanamide 7 (no base) A 2.9 376
C.sub.21H.sub.21N.sub.5O.sub.2 21 ##STR00190##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-(pyridin-3- yl)butanamide 7 B 2.3 376
C.sub.21H.sub.21N.sub.5O.sub.2 22 ##STR00191##
(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2-
(methyl(2,2,2- trifluoroethyl)amino)propan- amide 7 B 3.6 380
C.sub.18H.sub.20F.sub.3N.sub.5O 23 ##STR00192##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-
2,3,3-trimethylbutanamide 7 A 5.3 325 C.sub.19H.sub.24N.sub.4O 24
##STR00193## N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
(dimethylamino)-4,4,4- trifluorobutanamide 7 B 3.4 380
C.sub.18H.sub.20F.sub.3N.sub.5O 25 ##STR00194##
(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3- phenylpropanamide 7 B 3.1 361
C.sub.21H.sub.20N.sub.4O.sub.2 26 ##STR00195##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3- phenylpropanamide 7 B 3.1 361
C.sub.21H.sub.20N.sub.4O.sub.2 27 ##STR00196##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-2- (1-
hydroxycyclobutyl)propan- amide 7 B 3.1 339
C.sub.19H.sub.22N.sub.4O.sub.2 28 ##STR00197##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
cyclopropyl-3- hydroxybutanamide 7 B 3.1 339
C.sub.19H.sub.22N.sub.4O.sub.2 29 ##STR00198##
(S)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 10 B 3.4 375
C.sub.22H.sub.22N.sub.4O.sub.2 30 ##STR00199##
(R)-N-(6-cyano-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 10 B 3.4 375
C.sub.22H.sub.22N.sub.4O.sub.2 31 ##STR00200## N-(6-cyano-1-(4-
fluorophenyl)-1H- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7
B 3.5 351 C.sub.20H.sub.19FN.sub.4O 32 ##STR00201##
(S)-N-(6-cyano-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-2,3-
dimethylbutanamide 7 B 3.5 351 C.sub.20H.sub.19FN.sub.4O 33
##STR00202## (S)-N-(6-cyano-1-(4- fluorophenyl)-1H-
benzo[d]imidazol-2-yl)-2,2- dimethylcyclopropane-1- carboxamide 7 B
3.4 349 C.sub.20H.sub.17FN.sub.4O 34 ##STR00203##
N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7 B 3.9 354
C.sub.18H.sub.22F.sub.3N.sub.3O 35 ##STR00204## N-(1-cyclobutyl-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-methylbutanamide 7 B 3.2 356
C.sub.17H.sub.20F.sub.3N.sub.3O.sub.2 36 ##STR00205##
(S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide 7 B 4.0 354
C.sub.18H.sub.22F.sub.3N.sub.3O 37 ##STR00206##
(S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-2,2- dimethylcyclopropane-1- carboxamide 7 B
3.8 352 C.sub.18H.sub.20F.sub.3N.sub.3O 38 ##STR00207##
N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3,3- difluorocyclobutane-1- carboxamide 7 B
4.1 374 C.sub.17H.sub.16F.sub.5N.sub.3O 39 ##STR00208##
N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3-
(trifluoromethyl)butanamide 7 B 4.6 448
C.sub.17H.sub.14F.sub.9N.sub.3O 40 ##STR00209##
(R)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide 7 B 4.0 354
C.sub.18H.sub.22F.sub.3N.sub.3O 41 ##STR00210##
(1S,2S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-2-(2- hydroxypropan-2- yl)cyclopropane-1-
carboxamide 7 B 3.2 382 C.sub.19H.sub.22F.sub.3N.sub.3O.sub.2 42
##STR00211## (S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3,3,3- trifluoro-2-hydroxy-2-
methylpropanamide 7 B 4.3 396 C.sub.16H.sub.15F.sub.6N.sub.3O.sub.2
43 ##STR00212## (R)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3,3,3- trifluoro-2-hydroxy-2-
methylpropanamide 7 B 4.3 369 C.sub.16H.sub.15F.sub.6N.sub.3O.sub.2
44 ##STR00213## N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-2-(1- hydroxycyclobutyl)acetamide 7 B 3.4
368 C.sub.18H.sub.20F.sub.3N.sub.3O.sub.2 45 ##STR00214##
(S)-2,2-dimethyl-N-(1-(3- methylisoxazol-5-yl)-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)cyclopropane-1-
carboxamide 11 B 3.9 379 C.sub.18H.sub.17F.sub.3N.sub.4O.sub.2 46
##STR00215## 3,3-dimethyl-N-(1-(3- methylisoxazol-5-yl)-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)butanamide 9 B 3.9 381
C.sub.18H.sub.19F.sub.3N.sub.4O.sub.2 47 ##STR00216##
(S)-2,3-dimethyl-N-(1-(3- methylisoxazol-5-yl)-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)butanamide 11 B 3.9
381 C.sub.18H.sub.19F.sub.3N.sub.4O.sub.2 48 ##STR00217##
(S)-2,3,3-trimethyl-N-(1-(3- methylisoxazol-5-yl)-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)butanamide 11 B 4.0
395 C.sub.19H.sub.21F.sub.3N.sub.4O.sub.2 49 ##STR00218##
(S)-N-(6-cyano-1-(3- methylisoxazol-5-yl)-1H-
benzo[d]imidazol-2-yl)-2,3,3- trimethylbutanamide 11 B 3.6 352
C.sub.19H.sub.21N.sub.5O.sub.2 50 ##STR00219## ethyl
1-cyclobutyl-2-(3,3- dimethylbutanamido)-1H- benzo[d]imidazole-6-
carboxylate 7 B 3.7 358 C.sub.20H.sub.27N.sub.3O.sub.3 51
##STR00220## N-(1-cyclobutyl-6- (hydroxymethyl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7 A 2.4 316
C.sub.18H.sub.25N.sub.3O.sub.2 52 ##STR00221##
(S)-N-(1-cyclobutyl-6- (hydroxymethyl)-1H-
benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide 7 B 2.4 316
C.sub.18H.sub.25N.sub.3O.sub.2 53 ##STR00222##
N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7 B 2.5 344
C.sub.20H.sub.29N.sub.3O.sub.2 54 ##STR00223##
(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide 7 B 2.5 344
C.sub.20H.sub.29N.sub.3O.sub.2 55 ##STR00224##
N-(1-cyclobutyl-6-(1- hydroxyethyl)-1H- benzo[d]imidazol-2-yl)-3,3-
dimethylbutanamide 7 B 2.4 330 C.sub.19H.sub.27N.sub.3O.sub.2 56
##STR00225## (2S)-N-(1-cyclobutyl-6-(1- hydroxyethyl)-1H-
benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide 7 B 2.4 330
C.sub.19H.sub.27N.sub.3O.sub.2 57 ##STR00226##
N-(1-cyclobutyl-6-(1- hydroxypropyl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7 B 2.6 344
C.sub.20H.sub.29N.sub.3O.sub.2 58 ##STR00227##
(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-
2,2-dimethylcyclopropane-1- carboxamide 7 B 3.4 318
C.sub.17H.sub.20ClN.sub.3O 59 ##STR00228##
(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-
2,3-dimethylbutanamide 7 B 3.7 320 C.sub.17H.sub.22ClN.sub.3O 60
##STR00229## N-(6-chloro-1-cyclobutyl-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7 B 3.6 320
C.sub.17H.sub.22ClN.sub.3O 61 ##STR00230##
N-(6-chloro-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2- (3,3-
difluorocyclobutyl)acetamide 7 B 3.8 355
C.sub.17H.sub.18ClF.sub.2N.sub.3O 62 ##STR00231##
N-(6-chloro-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2-(1-
hydroxycyclobutyl)acetamide 7 B 3.0 334
C.sub.17H.sub.20ClN.sub.3O.sub.2 63 ##STR00232##
N-(6-bromo-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3,3-
dimethylbutanamide 7 B 3.8 366 C.sub.17H.sub.22BrN.sub.3O 64
##STR00233## N-(1-cyclobutyl-6-isopropyl-
1H-benzo[d]imidazol-2-yl)- 3,3-dimethylbutanamide 7 B 3.2 328
C.sub.20H.sub.29N.sub.3O 65 ##STR00234## (S)-N-(1-cyclobutyl-6-
isopropyl-1H- benzo[d]imidazol-2-yl)-2,3- dimethylbutanamide 7 B
3.4 328 C.sub.20H.sub.29N.sub.3O 66 ##STR00235## N-(1-cyclobutyl-6-
(difluoromethyl)-1H- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide
7 B 3.4 336 C.sub.18H.sub.23F.sub.2N.sub.3O 67 ##STR00236## methyl
1-cyclobutyl-2-(3,3- dimethylbutanamido)-1H- benzo[d]imidazole-7-
carboxylate 7 B 3.2 344 C.sub.19H.sub.25N.sub.3O.sub.3 68
##STR00237## N-(1-cyclobutyl-7- (hydroxymethyl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7 B 2.7 316
C.sub.18H.sub.25N.sub.3O.sub.2 69 ##STR00238## N-(6-cyano-1-(3-
methylisoxazol-5-yl)-1H- benzo[d]imidazol-2-yl)-3,3-
dimethylbutanamide 9 B 3.4 338 C.sub.18H.sub.19N.sub.5O.sub.2 70
##STR00239## (R)-N-(6-cyano-1-(4- fluorophenyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7 with (R)-
3-((tert- butyl- dimethyl- silyl)oxy)- 3- phenyl- butanoic acid as
acid, then procedure analagous to ex. 18, step E B 3.4 415
C.sub.24H.sub.19FN.sub.4O.sub.2 71 ##STR00240##
(S)-N-(6-cyano-1-(4- fluorophenyl)-1H-
benzo[d]imidazol-2-yl)-2,3,3- trimethylbutanamide 7 B 3.6 365
C.sub.21H.sub.21FN.sub.4O 72 ##STR00241##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-2,2-dimethyl-3- phenylpropanamide 7 B 3.8 389
C.sub.23H.sub.24N.sub.4O.sub.2 73 ##STR00242## (S)-N-(6-cyano-1-(5-
fluoropyridin-2-yl)-1H- benzo[d]imidazol-2-yl)-2,3-
dimethylbutanamide 7 B 3.4 352 C.sub.19H.sub.18FN.sub.5O 74
##STR00243## N-(6-cyano-1-(5- fluoropyridin-2-yl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 9 B 3.4 352
C.sub.19H.sub.18FN.sub.5O 75 ##STR00244## (S)-N-(6-cyano-1-(5-
fluoropyridin-2-yl)-1H- benzo[d]imidazol-2-yl)-2,3,3-
trimethylbutanamide 7 B 3.6 366 C.sub.20H.sub.20FN.sub.5O 76
##STR00245## (R)-N-(6-cyano-1-cyclobutyl-
1H-benzo[d]imidazol-2-yl)- 2,3,3-trimethylbutanamide 7 A 5.3 325
C.sub.19H.sub.24N.sub.4O 77 ##STR00246##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2,3,3-
trimethylbutanamide 7 A 5.3 325 C.sub.19H.sub.24N.sub.4O 78
##STR00247## N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
cyclobut-3- hydroxybutanamide 7 B 3.3 353
C.sub.20H.sub.24N.sub.4O.sub.2 79 ##STR00248## (S)-N-(6-cyano-1-(5-
fluoropyridin-2-yl)-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.3 416
C.sub.23H.sub.18FN.sub.5O.sub.2 80 ##STR00249##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-3-
cyclopentyl-3- hydroxybutanamide 7 B 3.5 367
C.sub.21H.sub.26N.sub.4O.sub.2 81 ##STR00250##
N-(6-cyano-1-cyclobutyl-1H- benzo[d]imidazol-2-yl)-2-(1-
hydroxycyclopentyl) acetamide 7 B 3.0 339
C.sub.19H.sub.22N.sub.4O.sub.2 82 ##STR00251##
N-(1-cyclobutyl-7-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7, followed by
method described for Ex. 53 with Ex. 67 as starting material B 3.5
344 C.sub.20H.sub.29N.sub.3O.sub.2 83 ##STR00252##
(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-2- (6,6-dimethyltetrahydro-2H-
pyran-2-yl)acetamide 7, followed by method described for Ex. 53 B
2.6 400 C.sub.23H.sub.33N.sub.3O.sub.3 84 ##STR00253##
(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7, followed by
method described for Ex. 53 B 2.7 408
C.sub.24H.sub.29N.sub.3O.sub.3 85 ##STR00254##
N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide 7, followed by
method described for Ex. 53 B 2.1 346
C.sub.19H.sub.27N.sub.3O.sub.3 86 ##STR00255##
(S)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-2,3,3- trimethylbutanamide 7, followed by
method described for Ex. 53 B 2.6 358
C.sub.21H.sub.31N.sub.3O.sub.2 87 ##STR00256##
N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-
yl)spiro[3.3]heptane-2- carboxamide 7, followed by method described
for Ex. 53 B 2.7 368 C.sub.22H.sub.29N.sub.3O.sub.2 88 ##STR00257##
(S)-N-(1-cyclobutyl-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7 B 3.9 418
C.sub.22H.sub.22F.sub.3N.sub.3O.sub.2 89 ##STR00258##
(R)-N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-2,2- dimethylcyclopropane-1- carboxamide 7,
followed by method described for Ex. 53 B 2.4 342
C.sub.20H.sub.27N.sub.3O.sub.2 90 ##STR00259##
N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-
yl)pivalamide 7, followed by method described for Ex. 53 B 2.9 330
C.sub.19H.sub.27N.sub.3O.sub.2 91 ##STR00260##
(R)-N-(1-(tert-butyl)-6-cyano- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.6 369
C.sub.22H.sub.24N.sub.4O.sub.2 92 ##STR00261##
(S)-N-(1-(tert-butyl)-6-cyano- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.6 369
C.sub.22H.sub.24N.sub.4O.sub.2 93 ##STR00262##
(S)-N-(1-(tert-butyl)-6-cyano- 1H-benzo[d]imidazol-2-yl)-
4,4,4-trifluoro-3-hydroxy-3- methylbutanamide 7 B 3.5 377
C.sub.17H.sub.19F.sub.3N.sub.4O.sub.2
94 ##STR00263## (R)-N-(1-(tert-butyl)-6-cyano-
1H-benzo[d]imidazol-2-yl)- 4,4,4-trifluoro-3-hydroxy-3-
methylbutanamide 7 B 3.5 377 C.sub.17H.sub.19F.sub.3N.sub.4O.sub.2
95 ##STR00264## (S)-N-(6-cyano-1-(1- methylcyclobutyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7 B 3.6 389
C.sub.23H.sub.24N.sub.4O.sub.2 96 ##STR00265## (R)-N-(6-cyano-1-(1-
methylcyclobutyl)-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.6 389
C.sub.23H.sub.24N.sub.4O.sub.2 97 ##STR00266##
N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-3,3- dicyclopropyl-3- hydroxypropanamide 7,
followed by method described for Ex. 53 B 2.6 398
C.sub.23H.sub.31N.sub.3O.sub.3 98 ##STR00267## N-(1-cyclobutyl-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3,3- dicyclopropyl-3-
hydroxypropanamide 7 B 4.0 408
C.sub.21H.sub.24F.sub.3N.sub.3O.sub.2 99 ##STR00268##
(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.8 384
C.sub.21H.sub.22ClN.sub.3O.sub.2 100 ##STR00269##
(R)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.7 384
C.sub.21H.sub.22ClN.sub.3O.sub.2 101 ##STR00270##
N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-
yl)spiro[2.3]hexane-1- carboxamide 7, followed by method described
for Ex. 53 B 2.5 354 C.sub.21H.sub.27N.sub.3O.sub.2 102
##STR00271## N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-3,3- difluorocyclopentane-1- carboxamide 7,
followed by method described for Ex. 53 B 2.7 378
C.sub.20H.sub.25F.sub.2N.sub.3O.sub.2 103 ##STR00272##
(S)-N-(6-chloro-1-cyclobutyl- 1H-benzo[d]imidazol-2-yl)-3-
(4-fluorophenyl)-3- hydroxybutanamide 7 B 3.9 402
C.sub.21H.sub.21ClFN.sub.3O.sub.2 104 ##STR00273##
N-(1-(4-fluorophenyl)-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7, followed by
method described for Ex. 53 B 2.7 384
C.sub.22H.sub.26FN.sub.3O.sub.2 105 ##STR00274##
N-(1-cyclobutyl-6-(2- hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-
yl)spiro[2.2]pentane-1- carboxamide 7, followed by method described
for Ex. 53 B 2.4 340 C.sub.20H.sub.25N.sub.3O.sub.2 106
##STR00275## N-(1-cyclobutyl-5-(3- hydroxypentan-3-yl)-1H-
benzo[d]imidazol-2- yl)spiro[2.2]pentane-1- carboxamide 7, followed
by method described for Ex. 53 with EtMgBr B 2.6 368
C.sub.22H.sub.29N.sub.3O.sub.2 107 ##STR00276##
(S)-N-(6-chloro-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.7 424
C.sub.23H.sub.19ClFN.sub.3O.sub.2 108 ##STR00277##
(R)-N-(6-chloro-1-(4- fluorophenyl)-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.7 424
C.sub.23H.sub.19ClFN.sub.3O.sub.2 109 ##STR00278##
N-(1-(4-fluorophenyl)-6-(2- hydroxypropan-2-yl)-1H-
benzo[d]imidazol-2- yl)spiro[2.2]pentane-1- carboxamide 7, followed
by method described for Ex. 53 B 2.5 380
C.sub.22H.sub.22FN.sub.3O.sub.2 110 ##STR00279## ethyl
2-(1-cyclobutyl-2-(3,3- dimethylbutanamido)-7-
fluoro-1H-benzo[d]imidazol- 6-yl)acetate 7 A 5.4 390
C.sub.21H.sub.28FN.sub.3O.sub.3 111 ##STR00280## ethyl
(S)-2-(1-cyclobutyl-2- (2,2-dimethylcyclopropane-1-
carboxamido)-7-fluoro-1H- benzo[d]imidazol-6- yl)acetate 7 B 3.6
388 C.sub.21H.sub.26FN.sub.3O.sub.3 112 ##STR00281## ethyl
2-(2-(3,3- dimethylbutanamido)-7- fluoro-1-(4-fluorophenyl)-1H-
benzo[d]imidazol-6- yl)acetate 7 B 3.7 430
C.sub.23H.sub.25F.sub.2N.sub.3O.sub.3 113 ##STR00282##
(S)-N-(1-cyclobutyl-7-fluoro- 6-(2-hydroxy-2- methylpropyl)-1H-
benzo[d]imidazol-2-yl)-2,2- dimethylcyclopropane-1- carboxamide 7 B
3.1 374 C.sub.21H.sub.28FN.sub.3O.sub.2 114 ##STR00283##
N-(1-cyclobutyl-7-fluoro-6-(2- hydroxy-2-methylpropyl)-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7, followed by
method described for Ex. 53 B 3.2 376
C.sub.21H.sub.30FN.sub.3O.sub.2 115 ##STR00284##
(S)-N-(7-fluoro-1-(4- fluorophenyl)-6-(2-hydroxy-2-
methylpropyl)-1H- benzo[d]imidazol-2-yl)-2,2-
dimethylcyclopropane-1- carboxamide 7, followed by method described
for Ex. 53 B 3.1 414 C.sub.23H.sub.25F.sub.2N.sub.3O.sub.2 116
##STR00285## N-(7-fluoro-1-(4- fluorophenyl)-6-(2-hydroxy-2-
methylpropyl)-1H- benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7,
followed by method described for Ex. 53 B 3.2 416
C.sub.23H.sub.27F.sub.2N.sub.3O.sub.2 117 ##STR00286##
2-(1-cyclobutyl-2-(3,3- dimethylbutanamido)-7-
fluoro-1H-benzo[d]imidazol- 6-yl)acetic acid 7 B 2.9 362
C.sub.19H.sub.24FN.sub.3O.sub.3 118 ##STR00287##
N-(1-cyclobutyl-6-(2- (dimethylamino)-2-oxoethyl)- 7-fluoro-1H-
benzo[d]imidazol-2-yl)-3,3- dimethylbutanamide 7 B 2.9 389
C.sub.21H.sub.29FN.sub.4O.sub.2 119 ##STR00288##
(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7 B 3.7 391
C.sub.23H.sub.26N.sub.4O.sub.2 120 ##STR00289##
(R)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-phenylbutanamide 7 B 3.7 391
C.sub.23H.sub.26N.sub.4O.sub.2 121 ##STR00290##
(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-
benzo[d]imidazol-2-yl)-3-(4- fluorophenyl)-3- hydroxybutanamide 7 B
3.8 409 C.sub.23H.sub.25FN.sub.4O.sub.2 122 ##STR00291##
(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-
benzo[d]imidazol-2-yl)-3-(2- fluorophenyl)-3- hydroxybutanamide 7 B
3.9 409 C.sub.23H.sub.25FN.sub.4O.sub.2 123 ##STR00292##
(S)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.5 389
C.sub.23H.sub.24N.sub.4O.sub.2 124 ##STR00293##
(R)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-phenylbutanamide 7 B 3.5 389
C.sub.23H.sub.24N.sub.4O.sub.2 125 ##STR00294##
(S)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H-
benzo[d]imidazol-2-yl)-3-(4- fluorophenyl)-3- hydroxybutanamide 7 B
3.6 407 C.sub.23H.sub.23FN.sub.4O.sub.2 126 ##STR00295##
(S)-N-(6-cyano-1-cyclobutyl- 5-methyl-1H-
benzo[d]imidazol-2-yl)-3-(2- fluorophenyl)-3- hydroxybutanamide 7 B
3.7 407 C.sub.23H.sub.23FN.sub.4O.sub.2 127 ##STR00296##
N-(1-(tert-butyl)-6-cyano-5- methyl-1H-benzo[d]imidazol-
2-yl)-3,3-dimethylbutanamide 7 B 3.9 327 C.sub.19H.sub.26N.sub.4O
128 ##STR00297## N-(1-(tert-butyl)-6-cyano-5-
methyl-1H-benzo[d]imidazol- 2-yl)-3-hydroxy-3- methylbutanamide 7 B
2.8 329 C.sub.18H.sub.24N.sub.4O.sub.2 129 ##STR00298##
N-(1-(tert-butyl)-6-cyano-5- methyl-1H-benzo[d]imidazol-
2-yl)-3,3-difluorocyclobutane- 1-carboxamide 7 B 3.9 347
C.sub.18H.sub.20F.sub.2N.sub.4O 130 ##STR00299##
N-(6-cyano-1-cyclobutyl-5- methyl-1H-benzo[d]imidazol-
2-yl)-3-hydroxy-3- methylbutanamide 7 B 2.8 327
C.sub.18H.sub.22N.sub.4O.sub.2 131 ##STR00300##
4,4,4-trifluoro-N-(1-(4- fluorophenyl)-6-(2-
hydroxypropan-2-yl)-1H- benzo[d]imidazol-2-yl)-3- hydroxy-3-
(trifluoromethyl)butanamide 7, followed by method described for Ex.
53 B 3.8 494 C.sub.21H.sub.18F.sub.7N.sub.3O.sub.3 132 ##STR00301##
(R)-N-(1-cyclobutyl-7-fluoro- 5-(trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3-hydroxy-3-
methylbutanamide 7 B 4.1 428 C.sub.17H.sub.16F.sub.7N.sub.3O.sub.2
133 ##STR00302## N-(1-cyclobutyl-7-fluoro-5- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide 7 B 3.5 374
C.sub.17H.sub.19F.sub.4N.sub.3O.sub.2 134 ##STR00303##
(S)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-
benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3-hydroxy-3-
methylbutanamide 7 B 3.8 383 C.sub.18H.sub.21F.sub.3N.sub.4O.sub.2
135 ##STR00304## (R)-N-(1-(tert-butyl)-6-cyano- 5-methyl-1H-
benzo[d]imidazol-2-yl)-4,4,4- trifluoro-3-hydroxy-3-
methylbutanamide 7 B 3.8 383 C.sub.18H.sub.21F.sub.3N.sub.4O.sub.2
136 ##STR00305## N-(1-(3,5-difluorophenyl)-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide 7 B 3.4 414
C.sub.19H.sub.16F.sub.5N.sub.3O.sub.2 137 ##STR00306##
3-hydroxy-3-methyl-N-(1-(4- (trifluoromethoxy)phenyl)-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)butanamide 7 B 3.5 462
C.sub.20H.sub.17F.sub.6N.sub.3O.sub.3 138 ##STR00307##
(S)-N-(6-cyano-1-(1- methylcyclobutyl)-1H-
benzo[d]imidazol-2-yl)-3-(4- fluorophenyl)-3- hydroxybutanamide 7 B
3.7 407
C.sub.23H.sub.23FN.sub.4O.sub.2 139 ##STR00308##
(S)-3-(2-chlorophenyl)-N-(6- cyano-1-(1- methylcyclobutyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxybutanamide 7 B 4.0 423
C.sub.23H.sub.23ClN.sub.4O.sub.2 140 ##STR00309##
(S)-3-(4-chlorophenyl)-N-(6- cyano-1-(1- methylcyclobutyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxybutanamide 7 A 5.7 423
C.sub.23H.sub.23ClN.sub.4O.sub.2 141 ##STR00310##
N-(1-(3,5-difluorophenyl)-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-2-(1- hydroxycyclobutyl)acetamide 7 B 3.6
426 C.sub.20H.sub.16F.sub.5N.sub.3O.sub.2 142 ##STR00311##
2-(1-hydroxycyclobutyl)-N-(1- (4-(trifluoromethoxy)phenyl)-
6-(trifluoromethyl)-1H- benzo[d]imidazol-2- yl)acetamide 7 B 3.8
474 C.sub.21H.sub.17F.sub.6N.sub.3O.sub.3 143 ##STR00312##
N-(1-(3,4-difluorophenyl)-6- (trifluoromethyl)-1H-
benzo[d]imidazol-2-yl)-3- hydroxy-3-methylbutanamide 7 B 3.4 414
C.sub.19H.sub.16F.sub.5N.sub.3O.sub.2 144 ##STR00313##
N-(1-(3-fluoro-4- (trifluoromethoxy)phenyl)-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-3-
hydroxy-3-methylbutanamide 7 B 3.8 480
C.sub.20H.sub.16F.sub.7N.sub.3O.sub.3 145 ##STR00314##
N-(1-(3-fluoro-4- (trifluoromethoxy)phenyl)-6-
(trifluoromethyl)-1H- benzo[d]imidazol-2-yl)-2-(1-
hydroxycyclobutyl)acetamide 7 B 3.9 492
C.sub.21H.sub.16F.sub.7N.sub.3O.sub.3
Biological Assay Methods
Kv7.2/7.3 Activation Assay
[0287] The ability of compounds to potentiate K-currents in
Kv7.2/7.3 containing HEK cells was assessed using planar
patch-clamp on the QPatch automated screening platform.
[0288] Cell Line:
[0289] The hKv7.2/7.3 cell line was obtained from Chantest
(Cleveland, Ohio 44128) cat. #CT6147. These HEK cells will express
the Kv7.2/7.3 ion channels when induced.
[0290] Cell Culture:
[0291] Cells were maintained in a media containing DMEM/F12; 50/50
(GIBCO cat. #11330), 10% Fetal Bovine Serum (FBS) (GIBCO cat.
#26140), 100 units/mL Penicillin-Streptomycin (GIBCO cat. #15140),
0.005 mg/mL Blasticidin (INVIVOGEN cat. # ant-bl-1), 0.5 mg/mL
Geneticin (GIBCO cat. #10131), 0.1 mg/mL Zeocin (GIBCO cat. #
R25001). Cells used in the electrophysiology assay were maintained
in a media without Blasticidin, Geneticin and Zeocin for 2 days and
channel expression was induced by adding tetracycline (BIOLINE cat.
# BIO-87030) at a final concentration of 1 mg/mL. Cells were grown
in T-175 flask to -75% confluency. Currents were recorded 24 hours
after channel induction.
[0292] Compound Plates:
[0293] Test compounds were prepared by performing serial dilutions
on a Biomek NX.sup.P (BECKMAN COULTER). Final dilutions were made
in external recording solution with a final DMSO concentration of
0.1% DMSO. For single concentration screens each plate had 10 .mu.M
retigabine as a positive control and 0.1% DMSO as a negative
control.
[0294] Electrophysiology:
[0295] On the day of the experiment cells were washed with Hank's
Balanced Salt Solution (HBBS) (GIBCO cat. #14175) and harvested
with Tryple (GIBCO cat. #12604). Cells were then centrifuged at
2000 rpm for 5 minutes and resuspended in CHO--S--SFM (GIBCO cat.
#12052) at .about.3.times.10.sup.6 cells/mL. Cells were stirred for
30 minutes before experiments were started. External recording
solution contained (in mM): NaCl (145), KCl (4), CaCl.sub.2 (2),
MgCl.sub.2 (1), HEPES (10) and Glucose (10); pH was adjusted to 7.4
with NaOH and the osmolarity was adjusted to 300-305 mOsM with
sucrose if necessary. Internal solution contained (in mM): KCl
(125), KF (10), EGTA (5), Na.sub.2ATP (5), MgCl.sub.2 (3.2), HEPES
(5); pH was adjusted to 7.2 with KOH and the osmolarity was
adjusted to 298-302 mOsM with sucrose.
[0296] Potassium channel activity was measured on the QPatch HTX
(Sophion Bioscience) using QPlates with 48-wells/plate. Each cell
was taken as an independent experiment and only one compound was
tested per well. Potassium channel activity was elicited by holding
at -80 mV and stepping to -30 mV for 2 s followed by a 100 ms pulse
to -120 mV.
[0297] Single Concentration Screen:
[0298] Baseline conditions were obtained by recording 5 sweeps in
the external solution only, this was repeated for three
applications of the external solution. The effect of test compounds
on elicited current was then assessed by recording 5 sweeps in the
presence of a 3 .mu.M compound solution. The steady-state current
at the end of the 2 s pulse to -30 mV was measured to determine the
fold increase from baseline.
TABLE-US-00002 TABLE 2 Kv7.2/7.3 Single Concentration Screen
Results. Example Kv7.2/7.3 Activity* 1 + 2 + 3 +++ 4 +/- 5 +++ 6 +
7 + 8 + 9 + 10 + 11 ++ 12 +/- 13 +/- 14 +/- 15 +/- 16 +/- 17 ++ 18
+ 19 + 20 + 21 +/- 22 +/- 23 ++ 24 + 25 +/- 26 +/- 27 +/- 28 +/- 29
+ 30 + 31 + 32 + 33 + 34 ++ 35 + 36 + 37 + 38 +/- 39 + 40 + 41 +/-
42 +/- 43 +/- 44 + 45 + 46 + 47 + 48 +++ 49 + 50 +/- 51 + 52 +/- 53
+ 54 ++ 55 + 56 ++ 57 + 58 + 59 + 60 + 61 + 62 + 63 ++ 64 ++ 65 +
66 ++ 67 +/- 68 + 69 + 70 +/- 71 + 72 +/- 73 +/- 74 + 75 ++ 76 + 77
+ 78 + 79 + 80 + 81 + 82 +/- 83 ++ 84 + 85 +/- 86 +++ 87 ++ 88 + 89
++ 90 +/- 91 +/- 92 + 93 + 94 +/- 95 ++ 96 ++ 97 +/- 98 + 99 + 100
+ 101 + 102 +/- 103 + 104 + (@ 1 .mu.M) 105 + 106 +/- 107 + 108 +/-
109 + 110 + 111 + 112 ++ 113 + 114 + 115 + 116 + 117 +/- 118 + 119
+/- 120 + 121 + 122 ++ 123 +/- 124 +/- 125 +/- 126 ++ 127 + 128 +/-
129 +/- 130 +/- 131 +/- 132 +/- 133 + 134 +/- 135 +/- 136 + 137 +
138 + 139 + 140 +/- 141 + 142 ++ 143 ++ 144 + 145 ++ *Increase in
current from Kv7.2/Kv7.3 co-expressing HEK cells, measured at
compound concentration of 3 .mu.M, as a range from <1.2-fold
increase over baseline (-) up to >6-fold increase over baseline
(+++).
[0299] Unless otherwise indicated, all numbers expressing
quantities of ingredients, properties such as molecular weight,
reaction conditions, and so forth used in the specification and
claims are to be understood as being modified in all instances by
the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary depending upon the
desired properties sought to be obtained. At the very least, and
not as an attempt to limit the application of the doctrine of
equivalents to the scope of the claims, each numerical parameter
should at least be construed in light of the number of reported
significant digits and by applying ordinary rounding
techniques.
[0300] The terms "a," "an," "the" and similar referents used in the
context of describing the invention (especially in the context of
the following claims) are to be construed to cover both the
singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g., "such as") provided
herein is intended merely to better illuminate the invention and
does not pose a limitation on the scope of any claim. No language
in the specification should be construed as indicating any
non-claimed element essential to the practice of the invention.
[0301] Groupings of alternative elements or embodiments disclosed
herein are not to be construed as limitations. Each group member
may be referred to and claimed individually or in any combination
with other members of the group or other elements found herein. It
is anticipated that one or more members of a group may be included
in, or deleted from, a group for reasons of convenience and/or
patentability. When any such inclusion or deletion occurs, the
specification is deemed to contain the group as modified thus
fulfilling the written description of all Markush groups used in
the appended claims.
[0302] Certain embodiments are described herein, including the best
mode known to the inventors for carrying out the invention. Of
course, variations on these described embodiments will become
apparent to those of ordinary skill in the art upon reading the
foregoing description. The inventor expects skilled artisans to
employ such variations as appropriate, and the inventors intend for
the invention to be practiced otherwise than specifically described
herein. Accordingly, the claims include all modifications and
equivalents of the subject matter recited in the claims as
permitted by applicable law. Moreover, any combination of the
above-described elements in all possible variations thereof is
contemplated unless otherwise indicated herein or otherwise clearly
contradicted by context.
[0303] In closing, it is to be understood that the embodiments
disclosed herein are illustrative of the principles of the claims.
Other modifications that may be employed are within the scope of
the claims. Thus, by way of example, but not of limitation,
alternative embodiments may be utilized in accordance with the
teachings herein. Accordingly, the claims are not limited to
embodiments precisely as shown and described.
* * * * *