Note: Descriptions are shown in the official language in which they were submitted.
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AMINAL DIONES AS POTASSIUM CHANNEL OPENERS
TECHNICAL FIELD
Novel aminal dione compounds and their derivatives can open potassium channels
and
are useful for treating a variety of medical conditions.
BACKGROUND OF INVENTION
Potassium channels play an important role in regulating cell membrane
excitability.
When the potassium channels open, changes in the electrical potential across
the cell
membrane occur and result in a more polarized state. A number of diseases or
conditions may
be treated with therapeutic agents that open potassium channels; see for
example (Lawson,
Pharmacol. Ther., v. 70, pp. 39-63 (1996)); (Gehlert et al., Prog. Neuro-
Psychopharmacol &
Biol. Psychiat., v. 18, pp. 1093-1102 (1994)); (Gopalakrishnan et al., Drug
Development
Research, v. 28, pp. 95-127 (1993)); (Freedman et al., The Neuroscientist, v.
2, pp. 145-152
(1996)); (Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991)); (Howe et al.,
J. Pharmacol. Exp.
Ther., v. 274 pp. 884-890 (1995)); (Spanswick et al., Nature, v. 390 pp. 521-
25 (December 4,
1997)); (Dompeling Vasa. Supplementum (1992) 3434); (W09932495); (Grover, J
Mol Cell
Cardiol. (2000) 32, 677); and (Buchheit, Pulmonary Pharmacology & Therapeutics
(1999) 12,
103). Such diseases or conditions include asthma, epilepsy, male sexual
dysfunction, female
sexual dysfunction, pain, bladder overactivity, stroke, diseases associated
with decreased
skeletal blood flow such as Raynaud's phenomenon and intermittent
claudication, eating
disorders, functional bowel disorders, neurodegeneration, benign prostatic
hyperplasia (BPH),
dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery
disease, angina
and ischemia.
Bladder overactivity is a condition associated with the spontaneous,
uncontrolled
contractions of the bladder smooth muscle. Bladder overactivity thus is
associated with
sensations of urgency, urinary incontinence, pollakiuria, bladder instability,
nocturia, bladder
hyerreflexia, and enuresis (Resnick, The Lancet (1995) 346, 94-99; Hampel,
Urology (1997)
50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 7-9).
Potassium channel
openers (KCOs) act as smooth muscle relaxants. Because bladder overactivity
and urinary
incontinence
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can result from the spontaneous, uncontrolled contractions of the smooth
muscle of the
bladder, the ability of potassium channel openers to hyperpolarize bladder
cells and relax
bladder smooth muscle may provide a method to ameliorate or prevent bladder
overactivity,
pollakiuria, bladder instability, nocturia, bladder hyperreflexia, urinary
incontinence, and
enuresis (Andersson, Urology (1997) SO (Suppl 6A), 74-84; Lawson, Pharmacol.
Ther., (1996)
70, 39-63; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp.
Ther., (1995) 274,
884-890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
The imitative symptoms of BPH (urgency, frequency, nocturia and urge
incontinence)
have been shown to be correlated to bladder instability (Pandita, The J. of
Urology (1999) 162,
943). Therefore the ability of potassium channel openers to hyperpolarize
bladder cells and
relax bladder smooth muscle may provide a method to ameliorate or prevent the
symptoms
associated with BPH. (Andersson, Prostate (1997) 30: 202-215).
The excitability of corpus cavernosum smooth muscle cells is important in the
male
erectile process. The relaxation of corporal smooth muscle cells allows
arterial blood to build
up under pressure in the erectile tissue of the penis leading to erection
(Andersson,
Pharmacological Reviews (1993) 45, 253). Potassium channels play a significant
role in
modulating human corporal smooth muscle tone, and thus, erectile capacity. By
patch clamp
technique, potassium channels have been characterized in human corporal smooth
muscle cells
(Lee, Int. J. Impot. Res. (1999) 11(4),179-188). Potassium channel openers are
smooth
muscle relaxants and have been shown to relax corpus cavernosal smooth muscle
and induce
erections (Andersson, Pharmacological Reviews (1993) 45, 253; Lawson,
Pharmacol. Ther.,
(1996) 70, 39-63, Vick, J. Urol. (2000) 163: 202). Potassium channel openers
therefore may
have utility in the treatment of male sexual dysfunctions such as male
erectile dysfunction,
impotence and premature ejaculation.
The sexual response in women is classified into four stages: excitement,
plateau,
orgasm and resolution. Sexual arousal and excitement increase blood flow to
the genital area,
and lubrication of the vagina as a result of plasma transudation. Topical
application of KCOs
like minoxidil and nicorandil have been shown to increase clitoral blood flow
(Kim, et al., J.
Urol. (2000) 163 (4): 240). KCOs may be effective for the treatment of female
sexual
dysfunction including clitoral erectile insufficiency, vaginismus and vaginal
engorgement
(Goldstein and Berman., Int. J. Impotence Res. (1998) 10:S84-S90), as KCOs can
increase
blood flow to female sexual organs.
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Potassium channel openers may have utility as tocolytic agents to inhibit
uterine
contractions to delay or prevent premature parturition in individuals or to
slow or arrest
delivery for brief periods to undertake other therapeutic measures (Sanborn,
Semin. Perinatol.
(1995) 19, 31-40; Mornson, Am. J. Obstet. Gynecol. (1993) 169(5), 1277-85).
Potassium
channel openers also inhibit contractile responses of human uterus and
intrauterine
vasculature. This combined effect would suggest the potential use of KCOs for
dysmenhorrea
(Kostrzewska, Acta Obstet. Gynecol. Scand. (1996) 75(10), 886-91). Potassium
channel
openers relax uterine smooth muscle and intrauterine vasculature and therefore
may have
utility in the treatment of premature labor and dysmenorrhoea (Lawson,
Pharmacol. Ther.,
(1996) 70, 39-63).
Potassium channel openers relax gastrointestinal smooth tissues and therefore
may be
useful in the treatment of functional bowel disorders such as irritable bowel
syndrome
(Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax airway smooth muscle and induce
bronchodilation.
Therefore potassium channel openers may be useful in the treatment of asthma
and airways
hyperreactivity (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit,
Pulmonary
Pharmacology & Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development
Research,
(1993) 28, 95-127).
Neuronal hyperpolarization can produce analgesic effects. The opening of
potassium
channels by potassium channel openers and resultant hyperpolarization in the
membrane of
target neurons is a key mechanism in the effect of opioids. The peripheral
antinociceptive
effect of morphine results from activation of ATP-sensitive potassium
channels, which causes
hyperpolarization of peripheral terminals of primary afferents, leading to a
decrease in action
potential generation (Rodrigues, Br. J. Pharmacol. (2000) 129(1), 110-4).
Opening of KATP
channels by potassium channel openers plays an important role in the
antinociception
mediated by alpha-2 adrenoceptors and mu opioid receptors. KCOs can potentiate
the
analgesic action of both morphine and dexmedetomidine via an activation of
KATP channels at
the spinal cord level (Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano,
Anesth. Analg.
(2000) 90(5), 1146-51). Thus, potassium channel openers can hyperpolarize
neuronal cells
and have shown analgesic effects. Potassium channel openers therefore may be
useful as
analgesics in the treatment of various pain states including but not limited
to migraine and
dyspareunia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug
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Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol.
& Biol.
Psychiat., (1994) 18, 1093-1102).
Epilepsy results from the propagation of nonphysiologic electrical impulses.
Potassium channel openers hyperpolarize neuronal cells and lead to a decrease
in cellular
excitability and have demonstrated antiepileptic effects. Therefore potassium
channel openers
may be useful in the treatment of epilepsy (Lawson, Pharmacol. Ther., (1996)
70, 39-63;
Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog.
Neuro-
Psychopharmacol. & Biol. Psychiat., (1994) 18, 1093-1102).
Neuronal cell depolarization can lead to excitotoxicity and neuronal cell
death. When
this occurs as a result of acute ischemic conditions, it can lead to stroke.
Long-term
neurodegeneration can bring about conditions such as Alzheimer's and
Parkinson's diseases.
Potassium channel openers can hyperpolarize neuronal cells and lead to a
decrease in cellular
excitability. Activation of potassium channels has been shown to enhance
neuronal survival.
Therefore potassium channel openers may have utility as neuroprotectants in
the treatment of
neurodegenerative conditions and diseases such as cerebral ischemia, stroke,
Alzheimer's
disease and Parkinson's disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63;
Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog.
Neuro-
Psychopharmacol & Biol. Psychiat., (1994) 18, 1093-1102; Freedman, The
Neuroscientist
(1996) 2, 145).
Potassium channel openers may have utility in the treatment of diseases or
conditions
associated with decreased skeletal muscle blood flow such as Raynaud's
syndrome and
intermittent claudication (Lawson, Pharmacol. Ther., (1996) 70, 39-63;
Gopalakrishnan, Drug
Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992)
3434;
and W09932495).
Potassium channel openers may be useful in the treatment of eating disorders
such as
obesity (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist
(1996) 2,
145).
Potassium channel openers have been shown to promote hair growth therefore
potassium channel openers have utility in the treatment of hair loss and
baldness also known
as alopecia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug
Development
Research, (1993) 28, 95-127).
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Potassium channel openers possess cardioprotective effects against myocardial
injury
during ischemia and reperfusion. (Garlid, Circ. Res. (1997) 81(6), 1072-82).
Therefore,
potassium channel openers may be useful in the treatment of heart diseases
(Lawson,
Pharmacol. Ther., (1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32,
677).
Potassium channel openers, by hyperpolarization of smooth muscle membranes,
can
exert vasodilation of the collateral circulation of the coronary vasculature
leading to increase
blood flow to ischemic areas and could be useful for the coronary artery
disease (Lawson,
Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research,
(1993) 28,
95-127).
US 3,636,105 discloses a group of 1-fluoroacetylamino-2,2,2-trichloroethyl
urea
rodenticide agents. US 4,146,646 discloses a group of bis-amides as fungicide
agents. ZA
695324 discloses a group of thioureas useful as insecticide, acaricidal, and
rodenticide agents.
US 5,397,790 discloses a group of substituted isoquinolinyl-1,2-
diaminocyclobutene-3,4-
diones as smooth muscle relaxants. US 5,401,753 and US 5,403,854 disclose
groups of
substituted N-heteroaryl-1,2-diaminocyclobutene-3,4-diones as smooth muscle
relaxants. US
5,403,853, US 5,466,712, and WO 98/33763 disclose groups of substituted N-aryl-
1,2-
diaminocyclobutene-3,4-diones. US 5,464,867 and US 5,512,585 disclose groups
of
substituted N-heteroaryl-N'-alkyl-1,2-diaminocyclobutene-3,4-diones as smooth
muscle
relaxants. US 5,506,252 and WO 96/15103 disclose groups of substituted N-aryl-
and N-
heteroaryl-1,2-diaminocyclobutene-3,4-diones as smooth muscle relaxants. US
5,750,574
discloses a group of substituted fluorinated N-arylmethylamino derivatives of
cyclobutene-
3,4-dione as agents for reducing the adverse effects of smooth muscle
contractions. US
5,763,474, US 5,780,505, US 5,846,999, and WO 98/02413 disclose groups of
substituted N-
arylmethylamino derivatives of cyclobutene-3,4-diones as smooth muscle
relaxants. US
5,872,139 and WO 97/48682 disclose groups ofN-heterocyclylmethylamino
derivatives of
cyclobutene-3,4-dione as agents for reducing the adverse effects of smooth
muscle
contractions. US 6,166,050 discloses a group of amino(heterocyclylanilino)-3-
cyclobutene-
1,2-diones as inhibitors of leukocyte adhesion mediated by VLA-4. WO 94/29277
discloses a
group of 3,4-diaminocyclobutene-1,2-diones as inhibitors of cGMP
phosphodiesterase. WO
00/51973 and WO 00/63160 discloses groups of substituted N-
(cyclohexylmethyl)amino-3-
cyclobutene-1,2-diones as inhibitors phosphodiesterase V. WO 00/73260
discloses a group of
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3,4-diamino-3-cyclobutene-1,2-diones as inhibitors of leukocyte adhesion
mediated by VLA-
4
Compounds of the present invention are novel, hyperpolarize cell membranes,
open
potassium channels, relax smooth muscle cells, inhibit bladder contractions
and may be useful
for treating diseases that can be ameliorated by opening potassium channels.
SUMMARY OF THE INVENTION
In its principle embodiment, the present invention discloses compounds having
formula (I)
R2 Rs Ra
R ~N~A~N~N~RS
1
Rs R~ O
(I),
or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of
0
O X O ~ O O ~ O and S(O)2,
X is selected from the group consisting of CHZ, O and N(Z);
Z is selected from the group consisting of hydrogen and alkyl;
R, is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R2, R3 and R4 are independently selected from hydrogen and alkyl;
RS is selected from aryl, arylalkenyl, arylalkyl, aryloxyalkyl, heterocycle
and
heterocyclealkyl;
R6 is selected from hydrogen, alkenyl, alkenyloxyalkyl,
alkenyloxy(alkenyloxy)alkyl,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl,
alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkylcarbonyl(halo)alkyl,
alkylcarbonyloxyalkyl, alkylsulfmylalkyl, alkylsulfonylalkyl, alkylthioalkyl,
alkynyl, aryl,
arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl,
arylcarbonyl,
arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl,
aryloxycarbonyl,
aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy,
carboxyalkyl,
carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl,
cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl,
cycloalkyloxyalkyl,
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cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl,
haloalkynyl,
heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl,
heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl,
sulfamylalkyl,
sulfamyl(halo)alkyl, (NR9Rlo)alkyl, (NR9R,o)carbonyl, and
(NR9R~o)carbonylalkyl;
R7 is selected from hydrogen, haloalkyl, and lower alkyl;
or
R6 and R7 taken together with the carbon atom to which they are attached,
together
form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered
carbocyclic ring is
optionally substituted with 1 or 2 substituents independently selected from
alkenyl, alkoxy,
alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
R9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl,
alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and
formyl.
DETAILED DESCRIPTION OF THE INVENTION
It is understood that the foregoing detailed description and accompanying
examples are
merely illustrative and are not to be taken as limitations upon the scope of
the invention,
which is defined solely by the appended claims and their equivalents. Various
changes and
modifications to the disclosed embodiments will be apparent to those skilled
in the art. Such
changes and modifications, including without limitation those relating to the
chemical
structures, substituents, derivatives, intermediates, syntheses, formulations
and/or methods of
use of the invention, may be made without departing from the spirit and scope
thereof.
All patents, patent applications, and literature references cited in the
specification are
herein incorporated by reference in their entirety.
In its principle embodiment, the present invention discloses compounds having
formula (I)
R2 Rs Ra
R ~N~A~N~N~Rs
i
Rs R~ O
(I),
or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of
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'~,' o
O X O , O p , O and S(O)Z,
X is selected from the group consisting of CHZ, O and N(Z);
Z is selected from the group consisting of hydrogen and alkyl;
R~ is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
RZ, R3 and R4 are independently selected from hydrogen and alkyl;
RS is selected from aryl, arylalkyl, aryloxyalkyl, heterocycle and
heterocyclealkyl;
R6 is selected from hydrogen, alkenyl, alkenyloxyalkyl,
alkenyloxy(alkenyloxy)alkyl,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl,
alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkylcarbonyl(halo)alkyl,
alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl,
alkynyl, aryl,
arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl,
arylcarbonyl,
arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl,
aryloxycarbonyl,
aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy,
carboxyalkyl,
carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl,
cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl,
cycloalkyloxyalkyl,
cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl,
haloalkynyl,
heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl,
heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl,
sulfamylalkyl,
sulfamyl(halo)alkyl, (NR9Rlo)alkyl, (NR9Rlo)carbonyl and
(NR9Rlo)carbonylalkyl;
R~ is selected from hydrogen, haloalkyl, and lower alkyl;
or
R4 and R7 taken together with the carbon atom to which they are attached,
together
form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered
carbocyclic ring is
optionally substituted with 1 or 2 substituents independently selected from
alkenyl, alkoxy,
alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
R9 and Rlo are independently selected from hydrogen, alkoxysulfonyl, alkyl,
alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and
formyl.
In another embodiment of the present invention, compounds have formula (I)
wherein
A is selected from
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O
O O ~ O and S(O)2; and
R,, R2, R3, R4, R5, R~ and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II)
R
R1,N, 2 R3 Ra
N~N R5
O R6 R
O
(II),
or a pharmaceutically acceptable salt thereof, wherein R~, R2, R3, R4, R5, R6
and R~ are as
defined in formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle; RS is aryl; and RZ, R3, R4, R~ and R7 are as defined in
formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein said heterocycle is selected from optionally
substituted pyridinyl
and optionally substituted pyrazinyl; RS is aryl wherein said aryl is
optionally substituted
phenyl; and RZ, R3, R4, R6 and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein said heterocycle is selected from optionally
substituted pyridinyl
and optionally substituted pyrazinyl; RZ is hydrogen; R3 is hydrogen; R4 is
hydrogen; RS is
aryl wherein said aryl is optionally substituted phenyl; R~ is selected from
hydrogen and alkyl;
and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is aryl wherein said aryl is optionally
substituted phenyl;
R6 is selected from arylalkyl and heterocyclealkyl wherein the aryl portion of
said arylalkyl is
optionally substituted phenyl and the heterocycle portion of said
heterocyclealkyl is optionally
substituted pyridinyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
R, is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; Rz is hydrogen;
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R3 is hydrogen; R4 is hydrogen; R5 is aryl wherein said aryl is optionally
substituted phenyl;
R6 is haloalkyl; and R~ is hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is aryl wherein said aryl is optionally
substituted phenyl;
R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, cyanoalkyl and
cycloalkylalkyl; and
R~ is hydrogen.
In another embodiment of the present invention, compounds have formula (IIj
wherein
Rl is heterocycle wherein heterocycle is optionally substituted pyridinyl; RS
is aryl wherein
aryl is selected from optionally substituted naphthyl and optionally
substituted fluorenyl; and
RZ, R3, R4, R~ and R7 are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein heterocycle is optionally substituted pyridinyl; RZ
is hydrogen; R3 is
hydrogen; R4 is hydrogen; R5 is aryl wherein aryl is selected from optionally
substituted
naphthyl and optionally substituted fluorenyl; R6 is selected from alkenyl,
alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said
arylalkyl is optionally
substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R~ is
hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is aryl wherein aryl is selected from
optionally substituted
naphthyl and optionally substituted fluorenyl 1; R6 is alkyl; and R7 is
hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is aryl; R5 is aryl; and R2, R3, R4, R6 and R~ are as defined in formula
(I).
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is aryl wherein said aryl is optionally substituted phenyl; RS is aryl
wherein said aryl is
optionally substituted phenyl; and R2, R3, R4, R~ and R~ are as defined in
formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is aryl wherein said aryl is optionally substituted phenyl; RZ is hydrogen;
R3 is hydrogen;
Ra is hydrogen; RS is aryl wherein said aryl is optionally substituted phenyl;
R6 is selected
from alkenyl, alkenyloxy(alkenyloxy)alkyl, alkyl, arylalkyl wherein the aryl
portion of said
arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl and
haloalkyl; and R7 is
hydrogen.
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In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is aryl wherein said aryl is optionally substituted phenyl; RZ is hydrogen;
R3 is hydrogen;
R4 is hydrogen; RS is aryl wherein said aryl is optionally substituted phenyl;
Rb is alkyl; and
R~ is hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
R, is heterocycle; RS is arylalkyl; and Rz, R3, R4, R6 and R7 are as defined
in formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RS is selected
from arylalkyl, arylalkenyl and aryloxyalkyl wherein the aryl portion of said
arylalkyl,
arylalkenyl, and aryloxyalkyl is optionally substituted phenyl; and R2, R3,
R4, R6 and R~ are as
defined in formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is selected from arylalkyl, arylalkenyl and
aryloxyalkyl
wherein the aryl portion of said arylalkyl is optionally substituted phenyl,
the aryl portion of
said arylalkenyl is optionally substituted phenyl and the aryl portion of said
aryloxyalkyl is
optionally substituted phenyl; Rb is selected from alkenyl,
alkenyloxy(alkenyloxy)alkyl,
arylalkyl wherein the aryl portion of said arylalkyl is optionally substituted
phenyl,
cyanoalkyl, cycloalkylalkyl and haloalkyl; and R~ is hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is selected from arylalkyl, arylalkenyl and
aryloxyalkyl
wherein the aryl portion of said arylalkyl is optionally substituted phenyl,
the aryl portion of
said arylalkenyl is optionally substituted phenyl and the aryl portion of said
aryloxyalkyl is
optionally substituted phenyl; R6 is selected from alkyl and arylalkyl wherein
the aryl portion
of said arylalkyl is optionally substituted phenyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle; R5 is heterocyclealkyl; and RZ, R3, R4, R6 and R7 are as
defined in formula
(I).
In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RS is
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heterocyclealkyl wherein the heterocycle portion of said heterocyclealkyl is
optionally
substituted pyridinyl; and RZ, R3, R4, R6 and R7 are as defined in formula
(I).
In another embodiment of the present invention, compounds have formula (II)
wherein
Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is heterocyclealkyl wherein the heterocycle
portion of said
heterocyclealkyl is optionally substituted pyridinyl; R6 is selected from
alkenyl,
alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein the aryl portion of said
arylalkyl is optionally
substituted phenyl, cyanoalkyl, cycloalkylalkyl and haloalkyl; and R~ is
hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
R, is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R~ is hydrogen; RS is heterocyclealkyl wherein the heterocycle
portion of said
heterocyclealkyl is optionally substituted pyridinyl; R~ is alkyl; and R7 is
hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is heterocycle; RS is heterocycle; and R2, R3, R4, R6 and R7 are as defined
in formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
R~ is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RS is heterocycle
wherein said heterocycle is selected from optionally substituted pyridinyl,
optionally
substituted thienyl and optionally substituted furyl; and R2, R3, R4, R6 and
R~ are as defined in
formula (I).
In another embodiment of the present invention, compounds have formula (II)
wherein
R1 is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is heterocycle wherein said heterocycle is
selected from
optionally substituted pyridinyl, optionally substituted thienyl and
optionally substituted furyl;
R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl wherein
the aryl portion of
said arylalkyl is optionally substituted phenyl, cyanoalkyl, cycloalkylalkyl
and haloalkyl; and
R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (II)
wherein
R1 is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is hydrogen;
R3 is hydrogen; R4 is hydrogen; RS is heterocycle wherein said heterocycle is
selected from
optionally substituted pyridinyl, optionally substituted thienyl and
optionally substituted furyl;
R6 is alkyl; and R7 is hydrogen.
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In another embodiment of the present invention, compounds have formula (III)
O R3 R4
R2~N~N~N~RS
R~ IOI R6 R~ IIO
(III),
or a pharmaceutically acceptable salt therof, wherein R,, Rz, R3, R4, R5, Rb
and R~ are as
defined in formula (I).
In another embodiment of the present invention, compounds have formula (III)
wherein R~ is heterocycle; RS is aryl; and RZ, R3, R4, R6 and R7 are as
defined in formula (I).
In another embodiment of the present invention, compounds have formula (III)
wherein R, is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RS is
aryl wherein said aryl is optionally substituted phenyl; and RZ, R3, R4, R~
and R~ are as defined
in formula (I).
In another embodiment of the present invention, compounds have formula (III)
wherein R, is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is
hydrogen; R3 is hydrogen; R4 is hydrogen; RS is aryl wherein said aryl is
optionally substituted
phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl
wherein the aryl
portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl,
cycloalkylalkyl and
haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (III)
wherein Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is
hydrogen; R3 is hydrogen; R4 is hydrogen; RS is aryl wherein said aryl is
optionally substituted
phenyl; R6 is alkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (IV)
R2 R3 Ra
N, ,N N R
R; ~S\\~~s
O OR/6\R~ IIO
(IV),
or a pharmaceutically acceptable salt therof, wherein Rl, R2, R3, R4, R5, R6
and R~ are as
defined in formula (I).
In another embodiment of the present invention, compounds have formula (IV)
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wherein Rl is heterocycle; RS is aryl; and R2, R3, R4, R6 and R~ are as
defined in formula (I).
In another embodiment of the present invention, compounds have formula (IV)
wherein RI is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RS is
aryl wherein said aryl is optionally substituted phenyl; and R2, R3, R4, R~
and R7 are as defined
in formula (I).
In another embodiment of the present invention, compounds have formula (IV)
wherein Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is
hydrogen; R3 is hydrogen; R4 is hydrogen; RS is aryl wherein said aryl is
optionally substituted
phenyl; R6 is selected from alkenyl, alkenyloxy(alkenyloxy)alkyl, arylalkyl
wherein the aryl
portion of said arylalkyl is optionally substituted phenyl, cyanoalkyl,
cycloalkylalkyl and
haloalkyl; and R7 is hydrogen.
In another embodiment of the present invention, compounds have formula (IV)
wherein Rl is heterocycle wherein said heterocycle is optionally substituted
pyridinyl; RZ is
hydrogen; R3 is hydrogen; R4 is hydrogen; RS is aryl wherein said aryl is
optionally substituted
phenyl; R6 is alkyl; and R7 is hydrogen.
Another embodiment of the present invention relates to pharmaceutical
compositions
comprising a therapeutically effective amount of a compound of formula I-N or
a
pharmaceutically acceptable salt, ester, amide, or prodrug thereof in
combination with a .
pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a method of treating
male
sexual dysfunction including, but not limited to, male erectile dysfunction
and premature
ejaculation, comprising administering a therapeutically effective amount of a
compound of
formula I-IV or a pharmaceutically acceptable salt, ester, amide, or prodrug
thereof.
Another embodiment of the present invention relates to a method of treating
female
sexual dysfunction including, but not limited to, female anorgasmia, clitoral
erectile
insufficiency, vaginal engorgement, dyspareunia, and vaginismus comprising
administering a
therapeutically effective amount of a compound of formula I-IV or a
pharmaceutically
acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the present invention relates to a method of treating
asthma,
epilepsy, Raynaud's syndrome, intermittent claudication, migraine, pain,
bladder overactivity,
pollakiuria, bladder instability, nocturia, bladder hyperreflexia, eating
disorders, urinary
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incontinence, enuresis, functional bowel disorders, neurodegeneration, benign
prostatic
hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection,
and ischemia
comprising administering a therapeutically effective amount of a compound of
formula I-IV or
a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the present invention relates to a process of preparing
a
compound of formula (V)
R
R~,N, 2 R3 Ra
N~N~RS
O~ IR6 IIO
O
(V),
wherein Rl is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
RZ, R3 and R4 are independently selected from hydrogen and alkyl;
RS is selected from aryl, arylalkyl, heterocycle and heterocyclealkyl;
R6 is selected from hydrogen, alkenyl, alkenyloxyalkyl,
alkenyloxy(alkenyloxy)alkyl,
alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl,
alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl,
alkylcarbonyl(halo)alkyl,
alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl,
alkynyl, aryl,
arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl,
arylcarbonyl,
arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl,
aryloxycarbonyl,
aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy,
carboxyalkyl,
carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl,
cycloalkenylalkyl, cycloalkyl,
cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl,
cycloalkyloxyalkyl,
cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl,
haloalkynyl,
heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl,
heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl,
sulfamylalkyl,
sulfamyl(halo)alkyl, (NR9Rlo)alkyl, (NR9R~o)carbonyl and
(NR9R,o)carbonylalkyl; and
R9 and Rio are independently selected from hydrogen, alkoxysulfonyl, alkyl,
alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl and
formyl;
the process comprising:
(a) reacting an aldehyde of formula (VI)
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O
R6" H
(VI),
with three components, an amide of formula (VII)
O
R5~ N. R4
H
(VII),
1H-benzotriazole-polystyrene resin and an acid in a first solvent at about 50
°C to about 80 °C,
wherein R4, RS and R6 are as defined above;
(b) reacting the product of step (a) with a base and a compound_of formula
(VIII)
R2 H
,N N
R~ !~ .R3
O O
(VIII)
in a second solvent wherein R~, RZ and R3 are as defined above to provide a
compound of
formula (V).
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) using an acid selected from para-toluenesulfonic acid
monohydrate
and acetic acid.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) using a first solvent selected from 1,4-dioxane, 2-
methoxyethanol,
tetrahydrofuran, trimethyl orthoformate and mixtures thereof.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) using a first solvent selected from tetrahydrofuran:2-
methoxyethanol in about a (1:1) ratio, tetrahydrofuranarimethyl orthoformate
in about a (1:1)
ratio and 1,4-dioxanearimethyl orthoformate in about a (1:0.3) to (1:3) ratio.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) wherein step (a) is conducted for a period of about 12
hours to
about 48 hours.
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In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) using a base selected from cesium carbonate, potassium
carbonate
and sodium carbonate.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) using a second solvent selected from
dimethylacetamide, N,N-
dimethylformamide, dimethylsulfoxide and mixtures thereof.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) wherein step (b) is conducted at about 15 °C to
about 50 °C.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) wherein step (b) is conducted for a period of about 24
hours to
about 168 hours.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) wherein the acid is para-toluenesulfonic acid
monohydrate; the first
solvent is tetrahydrofuran:2-methoxyethanol in about a (1:1) ratio; step (a)
is conducted at
about SO °C to about 80 °C and step (a) is conducted for a
period of about 12 hours to about 48
hours.
In another embodiment of the present invention is disclosed a process for
preparing a
compound of formula (V) wherein the acid is para-toluenesulfonic acid
monohydrate; the first
solvent is tetrahydrofuran:2-methoxyethanol in about a (1:1) ratio; step (a)
is conducted at
about 50 °C to about 80 °C; step (a) is conducted for a period
of about 12 hours to about 48
hours; the base is cesium carbonate; the second solvent is dimethylacetamide;
step (b) is
conducted at about 18 °C to about 23 °C; and step (b) is
conducted for a period of about 48
hours to about 168 hours.
Definition of Terms
As used throughout this specification and the appended claims, the following
terms
have the following meanings.
The term "alkenyl," as used herein, refers to a straight or branched chain
hydrocarbon
containing from 2 to 10 carbons and containing at least one carbon-carbon
double bond
formed by the removal of two hydrogens. Representative examples of alkenyl
include, but are
not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 1,1-
dimethyl-3-butenyl,
4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl.
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The term "alkenyloxy," as used herein, refers to an alkenyl group, as defined
herein,
appended to the parent molecular moiety through an oxy moiety, as defined
herein.
Representative examples of alkenyloxy include, but are not limited to,
allyloxy, 2-butenyloxy
and 3-butenyloxy .
The term "alkenyloxyalkyl," as used herein, refers to a alkenyloxy group, as
defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
Representative examples of alkenyloxyalkyl include, but are not limited to,
(allyloxy)methyl,
(2-butenyloxy)methyl and (3-butenyloxy)methyl.
The term "alkenyloxy(alkenyloxy)alkyl," as used herein, refers to 2
independent
alkenyloxy groups, as defined herein, appended to the parent molecular moiety
through an
alkyl group, as defined herein. Representative examples of
alkenyloxy(alkenyloxy)alkyl
include, but are not limited to, 1,2-bis(allyloxy)ethyl and l,1-
bis[(allyloxy)methyl]propyl.
The term "alkoxy," as used herein, refers to an alkyl group, as defined
herein,
appended to the parent molecular moiety through an oxy moiety, as defined
herein.
Representative examples of alkoxy include, but are not limited to, methoxy,
ethoxy, propoxy,
2-propoxy, butoxy and tert-butoxy.
The term "alkoxyalkyl," as used herein, refers to an alkoxy group, as defined
herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of alkoxyalkyl include, but are not limited to, tert-
butoxymethyl, 2-
ethoxyethyl, 2-methoxyethyl, methoxymethyl and 1,1-dimethyl-3-(methoxy)propyl.
The term "alkoxycarbonyl," as used herein, refers to an alkoxy group, as
defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
Representative examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl,
ethoxycarbonyl and tert-butoxycarbonyl.
The term "alkoxycarbonylalkyl," as used herein, refers to an alkoxycarbonyl
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of alkoxycarbonylalkyl include, but are not
limited to,
methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl and 1,1-
dimethyl-
2-(methoxycarbonyl)ethyl.
The term "alkoxycarbonyl(halo)alkyl," as used herein, refers to an
alkoxycarbonyl
group and at least one halogen, as defined herein, appended to the parent
molecular moiety
through an alkyl group, as defined herein. Representative examples of
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alkoxycarbonyl(halo)alkyl include, but are not limited to, 1,1-dichloro-2-
methoxy-2-oxoethyl,
l,l-difluoro-2-methoxy-2-oxoethyl, 1,1-dichloro-3-methoxy-3-oxopropyl and 1,1-
difluoro-3-
methoxy-3-oxopropyl.
The term "alkoxy(halo)alkyl," as used herein, refers to an alkoxy group and at
least one
halogen, as defined herein, appended to the parent molecular moiety through an
alkyl group,
as defined herein. Representative examples of alkoxy(halo)alkyl include, but
are not limited
to, dichloro(methoxy)methyl, dichloro(ethoxy)methyl, dichloro(tert-
butoxy)methyl, 1,1-
dichloro-2-ethoxyethyl, 1,1-dichloro-2-methoxyethyl, 1,1-dichloro-3-
methoxypropyl and 1,2-
dichloro-3-methoxypropyl.
The term "alkoxysulfonyl," as used herein, refers to an alkoxy group, as
defined herein,
appended to the parent molecular moiety through a sulfonyl group, as defined
herein.
Representative examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl
and ethoxysulfonyl.
The term "alkyl," as used herein, refers to a straight or branched chain
hydrocarbon
containing from 1 to 10 carbon atoms. Representative examples of alkyl
include, but are not
limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-
butyl, tert-butyl, n-
pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 1-ethylpropyl, 2,2-
dimethylpentyl, 2,3-
dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term "alkylcarbonyl," as used herein, refers to an alkyl group, as defined
herein,
appended to the parent molecular moiety through a carbonyl group, as defined
herein.
Representative examples of alkylcarbonyl include, but are not limited to,
acetyl, 1-oxopropyl,
2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
The term "alkylcarbonylalkyl," as used herein, refers to an alkylcarbonyl
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of alkylcarbonylalkyl include, but are not
limited to, 2-
oxopropyl, 1,1-dimethyl-3-oxobutyl, 3-oxobutyl and 3-oxopentyl.
The term "alkylcarbonyl(halo)alkyl," as used herein, refers to an
alkylcarbonyl group
and at least one halogen, as defined herein, appended to the parent molecular
moiety through
an alkyl group, as defined herein. Representative examples of
alkylcarbonyl(halo)alkyl
include, but are not limited to, 1,1-dichloro-2-oxopropyl, 1,1-dichloro-3-
oxobutyl, 1,1-
difluoro-3-oxobutyl and 1,1-dichloro-3-oxopentyl.
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The term "alkylcarbonyloxy," as used herein, refers to an alkylcarbonyl group,
as
defined herein, appended to the parent molecular moiety through an oxy moiety,
as defined
herein. Representative examples of alkylcarbonyloxy include, but are not
limited to,
acetyloxy and ethylcarbonyloxy.
The term "alkylcarbonyloxyalkyl," as used herein, refers to an
alkylcarbonyloxy group,
as defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of alkylcarbonyloxyalkyl include, but are not
limited to,
acetyloxymethyl and 2-(ethylcarbonyloxy)ethyl.
The term "alkylene" or "alkylene bridge" refers to a divalent group derived
from a
straight chain hydrocarbon of from 1 to 3 carbon atoms. Representative
examples of alkylene
or alkylene bridge include, -CHz- -CHZCHZ-, and -CHzCHzCH2-.
The term "alkylsulfmyl," as used herein, refers to an alkyl group, as defined
herein,
appended to the parent molecular moiety through a sulfinyl group, as defined
herein.
Representative examples of alkylsulfinyl include, but are not limited to,
methylsulfinyl and
ethylsulfinyl.
The term "alkylsulfinylalkyl," as used herein, refers to an alkylsulfinyl
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of alkylsulfinylalkyl include, but are not
limited to,
methylsulfinylmethyl and ethylsulfmylmethyl.
The term "alkylsulfonyl," as used herein, refers to an alkyl group, as defined
herein,
appended to the parent molecular moiety through a sulfonyl group, as defined
herein.
Representative examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and
ethylsulfonyl.
The term "alkylsulfonylalkyl," as used herein, refers to an alkylsulfonyl
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of alkylsulfonylalkyl include, but are not
limited to,
methylsulfonylmethyl and ethylsulfonylmethyl.
The term "alkylthio," as used herein, refers to an alkyl group, as defined
herein,
appended to the parent molecular moiety through a thio moiety, as defined
herein.
Representative examples of alkylthio include, but are not limited to,
methylsulfanyl,
ethylsulfanyl, propylsulfanyl, 2-propylsulfanyl and tent-butylsulfanyl.
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The term "alkylthioalkyl," as used herein, refers to an alkylthio group, as
defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
Representative examples of alkylthioalkyl include, but are not limited to,
tert-
butylsulfanylmethyl, 2-ethylsulfanylethyl, 2-methylsulfanylethyl and
methylsulfanylmethyl.
The term "alkynyl," as used herein, refers to a straight or branched chain
hydrocarbon
group containing from 2 to 10 carbon atoms and containing at least one carbon-
carbon triple
bond. Representative examples of alkynyl include, but are not limited to,
acetylenyl, 1-
propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.
The term "aryl," as used herein, refers to a monocyclic carbocyclic ring
system or a
bicyclic carbocyclic fused ring system having one or more aromatic rings.
Representative
examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl,
tetrahydronaphthyl and
fluorenyl.
The aryl groups of this invention may be substituted with 1, 2, 3, 4, or 5
substituents
independently selected from alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl,
alkoxysulfonyl,
alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl,
arylcarbonyloxy,
arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl,
carboxy, cyano,
halo, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, sulfamylalkyl, -NRARB,
(NRARB)alkyl,
(NRARB)carbonyl, (NRARB)carbonylalkyl, furyl, imidazolyl, isothiazolyl,
isoxazolyl,
naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl,
pyrimidinyl,
pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl,
thienyl, triazinyl, triazolyl,
benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothienyl,
benzoxadiazolyl,
benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl,
isobenzofuranyl,
isobenzothienyl, isoindolyl, isoquinolinyl and quinolinyl wherein said furyl,
imidazolyl,
isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,
pyrazolyl,
pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl,
thiadiazolyl, thiazolyl,
thienyl, triazinyl, triazolyl benzimidazolyl, benzothiazolyl,
benzothiadiazolyl, benzothienyl,
benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl,
cinnolinyl,
indolyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl,
isoquinolinyl, and
' quinolinyl may be substituted with l, 2 or 3 substituents independently
selected from alkenyl,
alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl,
alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkylsulfinyl, alkoxysulfonyl, alkylsulfonyl, alkynyl,
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arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy,
arylcarbonyloxyalkyl,
aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, cyano, halo, haloalkyl,
haloalkoxy, nitro,
sulfamyl, sulfamylalkyl, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and
(NRARB)carbonylalkyl as defined herein.
The term "arylalkoxy," as used herein, refers to an aryl group, as defined
herein,
appended to the parent molecular moiety through an alkoxy group, as defined
herein.
Representative examples of arylalkoxy include, but are not limited to, 2-
phenylethoxy, 3-
naphth-2-ylpropoxy and 5-phenylpentyloxy.
The term "arylalkoxyalkyl," as used herein, refers to an arylalkoxy group, as
defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
Representative examples of arylalkoxyalkyl include, but are not limited to, 2-
phenylethoxymethyl, 2-(3-naphth-2-ylpropoxy)ethyl and S-phenylpentyloxymethyl.
The term "arylalkoxycarbonyl," as used herein, refers to an arylalkoxy group,
as
defined herein, appended to the parent molecular moiety through a carbonyl
group, as defined
herein. Representative examples of arylalkoxycarbonyl include, but are not
limited to,
benzyloxycarbonyl and naphth-2-ylmethyloxycarbonyl.
The term "arylalkoxycarbonylalkyl," as used herein, refers to an
arylalkoxycarbonyl
group, as defined herein, appended to the parent molecular moiety through an
alkyl group, as
defined herein. Representative examples of arylalkoxycarbonylalkyl include,
but are not
limited to, benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl and 2-(naphth-
2-
ylmethyloxycarbonyl)ethyl.
The term "arylalkyl," as used herein, refers to an aryl group, as defined
herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of arylalkyl include, but are not limited to, benzyl,
2-phenylethyl,
1,1-dimethyl-2-phenylethyl, 3-phenylpropyl and 2-naphth-2-ylethyl.
The term "arylalkylthio," as used herein, refers to an arylalkyl group, as
defined herein,
appended to the parent molecular moiety through a thio moiety, as defined
herein.
Representative examples of arylalkylthio include, but are not limited to,
2-phenylethylthio, 3-naphth-2-ylpropylthio and S-phenylpentylthio.
The term "arylalkylthioalkyl," as used herein, refers to an arylalkylthio
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of arylalkylthioalkyl include, but are not
limited to, 2-
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phenylethylsulfanylmethyl, 3-naphth-2-ylpropylsulfanylmethyl and 2-(5-
phenylpentylsulfanyl)ethyl.
The term "arylcarbonyl," as used herein, refers to an aryl group, as defined
herein,
appended to the parent molecular moiety through a carbonyl group, as defined
herein.
Representative examples of arylcarbonyl include, but are not limited to,
benzoyl and
naphthoyl.
The term "arylcarbonylalkyl," as used herein, refers to an arylcarbonyl group,
as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of arylcarbonylalkyl include, but are not
limited to, 2-oxo-3-
phenylpropyl and 1,1-dimethyl-3-oxo-4-phenylbutyl.
The term "arylcarbonyloxy," as used herein, refers to an arylcarbonyl group,
as defined
herein, appended to the parent molecular moiety through an oxy moiety, as
defined herein.
Representative examples of arylcarbonyloxy include, but are not limited to,
benzoyloxy and
naphthoyloxy.
The term "arylcarbonyloxyalkyl," as used herein, refers to an arylcarbonyloxy
group,
as defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of arylcarbonyloxyalkyl include, but are not
limited to,
benzoyloxymethyl, 2-(benzoyloxy)ethyl and 2-(naphthoyloxy)ethyl.
The term "aryl(halo)alkyl," as used herein, refers to an aryl group and at
least one
halogen, as defined herein, appended to the parent molecular moiety through an
alkyl group,
as defined herein. Representative examples of aryl(halo)alkyl include, but are
not limited to,
dichloro(phenyl)methyl, 1,1-dichloro-2-phenylethyl, 1,1-difluoro-2-
phenylethyl, 1,1-dichloro-
3-phenylpropyl and 1,1-difluoro-3-phenylpropyl.
The term "aryloxy," as used herein, refers to an aryl group, as defined
herein, appended
to the parent molecular moiety through an oxy moiety, as defined herein.
Representative
examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-
bromophenoxy,
4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.
The term "aryloxyalkyl," as used herein, refers to an aryloxy group, as
defined herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of aryloxyalkyl include, but are not limited to,
phenoxymethyl, 2-
phenoxyethyl, 3-naphth-2-yloxypropyl and 3-bromophenoxymethyl.
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The term "aryloxycarbonyl," as used herein, refers to an aryloxy group, as
defined
herein, appended to the parent molecular moiety through an oxy moiety, as
defined herein.
Representative examples of aryloxycarbonyl include, but are not limited to,
phenoxycarbonyl
and naphthyloxycarbonyl.
The term "aryloxycarbonylalkyl," as used herein, refers to an aryloxycarbonyl
group,
as defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of aryloxycarbonylalkyl include, but are not
limited to,
phenoxycarbonylmethyl, 2-(phenoxycarbonyl)ethyl and naphthyloxycarbonyl.
The term "arylsulfonyl," as used herein, refers to an aryl group, as defined
herein,
appended to the parent molecular moiety through a sulfonyl group, as defined
herein.
Representative examples of arylsulfonyl include, but are not limited to,
naphthylsulfonyl,
phenylsulfonyl and 4-fluorophenylsulfonyl.
The term "arylsulfonylalkyl," as used herein, refers to an arylsulfonyl group,
as defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
Representative examples of arylsulfonylalkyl include, but are not limited to,
1,1-dimethyl-3-
(phenylsulfonyl)propyl, naphthylsulfonylmethyl, 2-(phenylsulfonyl)ethyl,
phenylsulfonylmethyl and 4-fluorophenylsulfonylmethyl.
The term "arylthio," as used herein, refers to an aryl group, as defined
herein,
appended to the parent molecular moiety through a thio moiety, as defined
herein.
Representative examples of arylthio include, but are not limited
to,.phenylsulfanyl, naphth-2-
ylsulfanyl and 5-phenylhexylsulfanyl.
The term "arylthioalkyl," as used herein, refers to an arylthio group, as
defined herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of arylthioalkyl include, but are not limited to,
phenylsulfanylmethyl,
2-naphth-2-ylsulfanylethyl and 5-phenylhexylsulfanylmethyl.
The term "carbonyl," as used herein, refers to a -C(O)- group.
The term "carboxy," as used herein, refers to a -COZH group.
The term "carboxyalkyl," as used herein, refers to a carboxy group, as defined
herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of carboxyalkyl include, but are not limited to,
carboxymethyl, 2-
carboxyethyl, 3-carboxypropyl and 3-carboxy-l,l-dimethylpropyl .
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The term "carboxy(halo)alkyl," as used herein, refers to a carboxy group and
at least
one halogen, as defined herein, appended to the parent molecular moiety
through an alkyl
group, as defined herein. Representative examples of carboxy(halo)alkyl
include, but are not
limited to, carboxy(dichloro)methyl, carboxy(difluoro)methyl, 2-carboxy-1,1-
dichloroethyl
and 2-carboxy-1,1-difluoroethyl.
The term "cyano," as used herein, refers to a -CN group.
The term "cyanoalkyl," as used herein, refers to a cyano group, as defined
herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of cyanoalkyl include, but are not limited to,
cyanomethyl, 2-
cyanoethyl, 3-cyanopropyl, 3-cyano-l,l-dimethylpropyl and 3-cyano-1,1-
diethylpropyl .
The term "cyano(halo)alkyl," as used herein, refers to a cyano group and at
least one
halogen, as defined herein, appended to the parent molecular moiety through an
alkyl group,
as defined herein. Representative examples of cyano(halo)alkyl include, but
are not limited to,
3-cyano-1,1-difluoropropyl, 1,1-dichloro-3-cyanopropyl and 3-cyano-1,1-
bis(trifluoromethyl)propyl.
The term "cycloalkenyl," as used herein, refers to a cyclic hydrocarbon
containing
from 3 to 8 carbons and containing at least one carbon-carbon double bond
formed by the
removal of two hydrogens. Representative examples of cycloalkenyl include, but
are not
limited to, cyclohexene, 1-cyclohexen-2-yl, 3,3-dimethyl-1-cyclohexene,
cyclopentene and
cycloheptene.
The cycloalkenyl groups of this invention can be substituted with 1, 2, 3, 4,
or 5
substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkynyl,
arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy,
arylcarbonyloxyalkyl,
aryloxycarbonyl, aryloxycarbonylalkyl, halo, haloalkoxy, haloalkyl, hydroxy,
hydroxyalkyl,
sulfamylalkyl, -NRARB, (NRARB)alkyl, (NRARB)carbonyl and (NRARB)carbonylalkyl.
The term "cycloalkenylalkyl," as used herein, refers to a cycloalkenyl group,
as defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
Representative examples of cycloalkenylalkyl include, but are not limited to,
(2,6,6-trimethyl-
1-cyclohexen-1-yl)methyl, 1-cyclohexen-1-ylmethyl and 2-(2-cyclohepten-1-
yl)ethyl.
The term "cycloalkyl," as used herein, refers to a monocyclic, bicyclic, or
tricyclic ring
system. Monocyclic ring systems are exemplified by a saturated cyclic
hydrocarbon group
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containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems
include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Bicyclic ring
systems are exemplified by a bridged monocyclic ring system in which two non-
adjacent
carbon atoms of the monocyclic ring are linked by an alkylene bridge of
between one and
three carbon atoms. Representative examples of bicyclic ring systems include,
but are not
limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,
bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane. Tricyclic
ring systems
are exemplified by a bicyclic ring system in which two non-adjacent carbon
atoms of the
bicyclic ring are linked by a bond or an alkylene bridge of between one and
three carbon
atoms. Representative examples of tricyclic-ring systems include, but are not
limited to,
tricyclo[3.3.1.03'']nonane and tricyclo[3.3.1.13'']decane (adamantane).
The cycloalkyl groups of this invention can be substituted with 1, 2, 3, 4, or
5
substituents independently selected from alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl,
alkylsulfonylalkyl, alkynyl, alkylcarbonyloxy, arylalkoxycarbonyl,
arylalkoxycarbonylalkyl,
arylalkyl, arylcarbonyloxy, arylcarbonyloxyalkyl, aryloxycarbonyl,
aryloxycarbonylalkyl,
arylsulfonylalkyl, cyanoalkyl, cycloalkylalkyl, halo, haloalkoxy, haloalkyl,
heterocyclealkyl,
hydroxy, hydroxyalkyl, sulfamylalkyl, -NRARB, (NRARB)alkyl, (NRARB)carbonyl
and
(NRARB)carbonylalkyl.
The term "cycloalkylalkoxy," as used herein, refers to a cycloalkyl group, as
defined
herein, appended to the parent molecular moiety through an alkoxy group, as
defined herein.
Representative examples of cycloalkylalkoxy include, but are not limited to,
cyclopropylmethoxy, 2-cyclobutylethoxy, cyclopentylmethoxy, cyclohexylmethoxy
and 4-
cycloheptylbutoxy.
The term "cycloalkylalkoxyalkyl," as used herein, refers to a cycloalkylalkoxy
group,
as defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of cycloalkylalkoxyalkyl include, but are not
limited to,
cyclopropylmethoxymethyl, 2-cyclobutylethoxymethyl, cyclopentylmethoxymethyl,
2-
cyclohexylethoxymethyl and 2-(4-cycloheptylbutoxy)ethyl.
The term "cycloalkylalkyl," as used herein, refers to a cycloalkyl group, as
defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
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Representative examples of cycloalkylalkyl include, but are not limited to,
cyclopropylmethyl,
2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
The term "cycloalkylcarbonyl," as used herein, refers to a cycloalkyl group,
as defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
Representative examples of cycloalkylcarbonyl include, but are not limited to,
cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
The term "cycloalkyloxy," as used herein, refers to a cycloalkyl group, as
defined
herein, appended to the parent molecular moiety through an oxy moiety, as
defined herein.
Representative examples of cycloalkyloxy include, but are not limited to,
cyclohexyloxy and
cyclopentyloxy.
The term "cycloalkyloxyalkyl," as used herein, refers to a cycloalkyloxy
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of cycloalkyloxyalkyl include, but are not
limited to, 4-
(cyclohexyloxy)butyl and cyclohexyloxyrnethyl.
The term "cycloalkylalkylthio," as used herein, refers to a cycloalkylalkyl
group, as
defined herein, appended to the parent molecular moiety through a thio moiety,
as defined
herein. Representative examples of cycloalkylalkylthio include, but are not
limited to, (2-
cyclohexylethyl)sulfanyl and cyclohexylmethylsulfanyl.
The term "cycloalkylalkylthioalkyl," as used herein, refers to a
cycloalkylalkylthio
group, as defined herein, appended to the parent molecular moiety through an
alkyl group, as
defined herein. Representative examples of cycloalkylalkylthioalkyl include,
but are not
limited to, 2-[(2-cyclohexylethyl)sulfanyl]ethyl and (2-
cyclohexylethyl)sulfanylmethyl.
The term "cycloalkylthio," as used herein, refers to a cycloalkyl group, as
defined
herein, appended to the parent molecular moiety through a thio moiety, as
defined herein.
Representative examples of cycloalkylthio include, but are not limited to,
cyclohexylsulfanyl
and cyclopentylsulfanyl.
The term "cycloalkylthioalkyl," as used herein, refers to a cycloalkylthio
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of cycloalkylthioalkyl include, but are not
limited to, 4-
(cyclohexylsulfanyl)butyl and cyclohexylsulfanylmethyl.
The term "formyl," as used herein, refers to a -C(O)H group.
The term "halo" or "halogen," as used herein, refers to -C1, -Br, -I or -F.
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The term "haloalkoxy," as used herein, refers to at least one halogen, as
defined herein,
appended to the parent molecular moiety through an alkoxy group, as defined
herein.
Representative examples of haloalkoxy include, but are not limited to,
chloromethoxy, 2-
fluoroethoxy, 1,2-difluoroethoxy, trifluoromethoxy and pentafluoroethoxy.
The term "haloalkenyl," as used herein, refers to at least one halogen, as
defined
herein, appended to the parent molecular moiety through an alkenyl group, as
defined herein.
Representative examples of haloalkenyl include, but are not limited to, 2,2-
dichloroethenyl,
2,2-difluoroethenyl and 5-chloropenten-2-yl.
The term "haloalkyl," as used herein, refers to at least one halogen, as
defined herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of haloalkyl include, but are not limited to,
chloromethyl,
trichloromethyl, 1,1-dichloroethyl, 2-fluoroethyl, trifluoromethyl, 2,2,2-
trifluoroethyl, 2,2,2-
trifluoro-1-(trifluoromethyl)-1-(methyl)ethyl, pentafluoroethyl and 2-chloro-3-
fluoropentyl.
The term "haloalkylcarbonyl," as used herein, refers to a haloalkyl group, as
defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
Representative examples of haloalkylcarbonyl include, but are not limited to,
chloromethylcarbonyl, trichloromethylcarbonyl and trifluoromethylcarbonyl.
The term "haloalkylsulfonyl," as used herein, refers to a haloalkyl group, as
defined
herein, appended to the parent molecular moiety through a sulfonyl group, as
defined herein.
Representative examples of haloalkylsulfonyl include, but are not limited to,
chloromethylsulfonyl, trichloromethylsulfonyl and trifluoromethylsulfonyl.
The term "haloalkynyl," as used herein, refers to at least one halogen, as
defined
herein, appended to the parent molecular moiety through an alkynyl group, as
defined herein.
Representative examples of haloalkynyl include, but are not limited to and
4,4,4-
trichlorobutyn-2-yl.
The term "heterocycle," as used herein, refers to a monocyclic or a bicyclic
ring
system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring
containing 1,
2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and
sulfur. The 5-
membered ring has from 0-2 double bonds and the 6-membered ring has from 0-3
double
bonds. Representative examples of monocyclic ring systems include, but are not
limited to,
azetidinyl, azepinyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, 1,3-
dioxanyl, dithianyl,
furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl,
isothiazolidinyl,
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isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl,
oxadiazolinyl,
oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl,
pyranyl,
pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl,
pyridazinyl, pyrrolyl,
pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl,
tetrazolyl,
thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl,
thiazolidinyl, thienyl,
thiomorpholinyl, thiomorpholine sulfone, thiopyranyl, triazinyl, triazolyl and
trithianyl.
Bicyclic ring systems are exemplified by any of the above monocyclic ring
systems fused to
an aryl group as defined herein, a cycloalkyl group as defined herein, or
another monocyclic
ring system as defined herein. Representative examples of bicyclic ring
systems include but
are not limited to, for example, benzimidazolyl, benzothiazolyl,
benzothiadiazolyl,
benzothienyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, benzopyranyl,
benzothiopyranyl,
benzotriazolyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl,
indolyl, indolinyl,
indolizinyl, naphthyl, isobenzofuranyl, isobenzothienyl, isoindolyl,
isoindolinyl, 1-
isoindolinonyl, isoquinolinyl, 1-isoquinolinonyl, phthalazinyl,
pyranopyridinyl, quinolinyl,
quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl and
thiopyranopyridinyl.
The heterocycle groups of this invention can be substituted with 1, 2,or 3
substituents
independently selected from alkenyl, alkoxy, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl,
alkylcarbonyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylsulfinyl,
alkoxysulfonyl,
alkylsulfonyl, alkynyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl,
arylcarbonyloxy,
arylcarbonyloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl,
carboxy, cyano,
halo, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, sulfamylalkyl, -NRARB,
(NRARB)alkyl,
(NRARB)carbonyl, (NRARB)carbonylalkyl, furyl, imidazolyl, isothiazolyl,
isoxazolyl,
naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolyl, pyridinyl,
pyrimidinyl,
pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiazolyl,
thienyl, triazinyl, triazolyl,
benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl,
benzoxadiazolyl,
benzoxazolyl, benzofuranyl, cinnolinyl, indolyl, naphthyridinyl,
isobenzofuranyl,
isobenzothienyl, isoindolyl, isoquinolinyl, and quinolinyl wherein said furyl,
imidazolyl,
isothiazolyl, isoxazolyl, naphthyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,
pyrazolyl,
pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazinyl, tetrazolyl,
thiadiazolyl, thiazolyl,
thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl,
benzothiadiazolyl,
benzothiophenyl, benzoxadiazolyl, benzoxazolyl, benzofuranyl, cinnolinyl,
indolyl,
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naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl
and quinolinyl may
be substituted with 1 or 2 substituents independently selected from alkenyl,
alkoxy,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyloxy,
alkylcarbonyloxyalkyl, alkylsulfmyl, alkoxysulfonyl, alkylsulfonyl, alkynyl,
arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylcarbonyloxy,
arylcarbonyloxyalkyl,
aryloxycarbonyl, aryloxycarbonylalkyl, arylsulfonyl, carboxy, cyano, halo,
haloalkyl,
haloalkoxy, nitro, sulfamyl, sulfamylalkyl, -NRARB, (NRARB)alkyl,
(NRARB)carbonyl and
(NRARB)carbonylalkyl.
The term "heterocyclealkoxy," as used herein, refers to a heterocycle group,
as defined
herein, appended to the parent molecular moiety through an alkoxy group, as
defined herein.
Representative examples of heterocyclealkoxy include, but are not limited to,
2-pyrid-3-
ylethoxy, 3-quinolin-3-ylpropoxy and 5-pyrid-4-ylpentyloxy.
The term "heterocyclealkoxyalkyl," as used herein, refers to a
heterocyclealkoxy
group, as defined herein, appended to the parent molecular moiety through an
alkyl group, as
defined herein. Representative examples of heterocyclealkoxyalkyl include, but
are not
limited to, 2-pyrid-3-ylethoxymethyl, 2-(3-quinolin-3-ylpropoxy)ethyl and S-
pyrid-4-
ylpentyloxymethyl.
The term "heterocyclealkyl," as used herein, refers to a heterocycle, as
defined herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of heterocyclealkyl include, but are not limited to,
pyrid-3-ylmethyl
and pyrimidin-5-ylmethyl.
The term "heterocyclealkylthio," as used herein, refers to a heterocyclealkyl
group, as
defined herein, appended to the parent molecular moiety through a thio moiety,
as defined
herein. Representative examples of heterocyclealkylthio include, but are not
limited to, 2-
pyrid-3-ylethysulfanyl, 3-quinolin-3-ylpropysulfanyl and 5-pyrid-4-
ylpentylsulfanyl.
The term "heterocyclealkylthioalkyl," as used herein, refers to a
heterocyclealkylthio
group, as defined herein, appended to the parent molecular moiety through an
alkyl group, as
defined herein. Representative examples of heterocyclealkylthioalkyl include,
but are not
limited to, 2-pyrid-3-ylethysulfanylmethyl, 2-(3-quinolin-3-
ylpropysulfanyl)ethyl and 5-pyrid-
4-ylpentylsulfanylmethyl.
The term "heterocyclecarbonyl," as used herein, refers to a heterocycle, as
defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
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Representative examples of heterocyclecarbonyl include, but are not limited
to, pyrid-3-
ylcarbonyl, quinolin-3-ylcarbonyl and thiophen-2-ylcarbonyl.
The term "heterocycleoxy," as used herein, refers to a heterocycle group, as
defined
herein, appended to the parent molecular moiety through an oxy moiety, as
defined herein.
Representative examples of heterocycleoxy include, but are not limited to,
pyrid-3-yloxy and
quinolin-3-yloxy.
The term "heterocycleoxyalkyl," as used herein, refers to a heterocycleoxy
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of heterocycleoxyalkyl include, but are not
limited to, pyrid-
3-yloxymethyl and 2-quinolin-3-yloxyethyl.
The term "heterocyclethio," as used herein, refers to a heterocycle group, as
defined
herein, appended to the parent molecular moiety through a thio moiety, as
defined herein.
Representative examples of heterocyclethio include, but are not limited to,
pyrid-3-ylsulfanyl
and quinolin-3-ylsulfanyl.
The term "heterocyclethioalkyl," as used herein, refers to a heterocyclethio
group, as
defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of heterocyclethioalkyl include, but are not
limited to, pyrid-
3-ylsulfanylmethyl and 2-quinolin-3-ylsulfanylethyl.
The term "hydroxy," as used herein, refers to an -OH group.
The term "hydroxyalkyl," as used herein, refers to 1 or 2 hydroxy groups, as
defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
Representative examples of hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-
hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-ethyl-4-hydroxyheptyl, 2-
hydroxy-
1,1-dimethylethyl and 3-hydroxy-1,1-dimethylpropyl.
The term "lower alkyl," as used herein, is a subset of alkyl as defined herein
and refers
to a straight or branched chain hydrocarbon group containing from 1 to 6
carbon atoms.
Representative examples of lower alkyl include, but are not limited to,
methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl and tert-butyl.
The term "mercapto," as used herein, refers to a -SH group.
The term "mercaptoalkyl," as used herein, refers to a mercapto group, as
defined
herein, appended to the parent molecular moiety through an alkyl group, as
defined herein.
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Representative examples of mercaptoalkyl include, but are not limited to, 2-
sulfanylethyl and
3-sulfanylpropyl.
The term "-NR9R~o," as used herein, refers to two groups, R~ and Rlo, which
are
appended to the parent molecular moiety through a nitrogen atom. R9 and R~o
are
independently selected from hydrogen, alkoxysulfonyl, alkyl, alkylcarbonyl,
alkylsulfonyl,
aryl, arylalkyl, arylcarbonyl, arylsulfonyl and formyl, as defined herein.
Representative
examples of -NR9Rlo include, but are not limited to, acetylamino, amino,
methylamino,
(ethylcarbonyl)methylamino, ethylmethylamino, formylamino, methylsulfonylamino
and
phenylsulfonylamino.
The term "(NR9R,o)alkyl," as used herein, refers to a -NR9R,o group, as
defined herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of (NR9Rlo)alkyl include, but are not limited to,
acetylaminomethyl,
aminomethyl, 2-aminoethyl, 2-(methylamino)ethyl,
(ethylcarbonyl)methylaminomethyl, 3-
(ethylmethylamino)propyl, 1,1-dimethyl-3-(dimethylamino)propyl, 2-
(formylamino)ethyl,
methylsulfonylaminomethyl, 2-(phenylsulfonylamino)ethyl and
benzylsulfonylaminomethyl.
The term "(NR9R~o)carbonyl," as used herein, refers to a -NR9Rlo group, as
defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
Representative examples of (NR9Rlo)carbonyl include, but are not limited to,
aminocarbonyl,
dimethylaminocarbonyl, ethylaminocarbonyl and benzylaminocarbonyl.
The term "(NR9Rlo)carbonylalkyl," as used herein, refers to a (NR9R,o)carbonyl
group,
as defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of (NR9R~o)carbonylalkyl include, but are not
limited to,
aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl
and 3-
(benzylaminocarbonyl)propyl.
The term "-NRARB," as used herein, refers to two groups, R~ and RB, which are
appended to the parent molecular moiety through a nitrogen atom. RA and RB are
independently selected from hydrogen, alkyl, alkylcarbonyl and formyl, as
defined herein.
Representative examples of -NRARB include, but are not limited to,
acetylamino, amino,
methylamino, (ethylcarbonyl)methylamino, dimethylamino, ethylmethylamino and
formylamino.
The term "(1VRARB)alkyl," as used herein, refers to a -NRARa group, as defined
herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
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Representative examples of (NRARB)alkyl include, but are not limited to,
acetylaminomethyl,
aminomethyl, 2-aminoethyl, 2-(methylamino)ethyl,
(ethylcarbonyl)methylaminomethyl, 3-
(ethylmethylamino)propyl, 1,1-dimethyl-3-(dimethylamino)propyl and 2-
(formylamino)ethyl.
The term "(NRARB)carbonyl," as used herein, refers to a -NRARB group, as
defined
herein, appended to the parent molecular moiety through a carbonyl group, as
defined herein.
Representative examples of (NRARg)carbonyl include, but are not limited to,
aminocarbonyl,
dimethylaminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl and
diethylaminocarbonyl.
The term "(NRARB)carbonylalkyl," as used herein, refers to a (NRARB)carbonyl
group,
as defined herein, appended to the parent molecular moiety through an alkyl
group, as defined
herein. Representative examples of (NRARn)carbonylalkyl include, but are not
limited to,
aminocarbonylmethyl, dimethylaminocarbonylmethyl, 2-(ethylaminocarbonyl)ethyl
and 3-
(diethylaminocarbonyl)propyl.
The term "nitro," as used herein, refers to a -NOZ group.
The term "oxo," as used herein, refers to a (=O) moiety.
The term "oxy," as used herein, refers to a (-O-) moiety.
The term "sulfamyl," as used herein, refers to a -SOZNR94R9s group, wherein
R94 and
R~5 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as
defined herein.
Representative examples of sulfamyl include, but are not limited to,
aminosulfonyl,
methylaminosulfonyl, dimethylaminosulfonyl, phenylaminosulfonyl and
benzylaminosulfonyl.
The term "sulfamylalkyl," as used herein, refers to a sulfamyl group, as
defined herein,
appended to the parent molecular moiety through an alkyl group, as defined
herein.
Representative examples of sulfamylalkyl include, but are not limited to,
(aminosulfonyl)methyl, (dimethylaminosulfonyl)methyl, 2-(aminosulfonyl)ethyl,
3-
(aminosulfonyl)propyl and 3-aminosulfonyl-1,1-dimethylpropyl.
The term "sulfamyl(halo)alkyl," as used herein, refers to a sulfamyl group and
at least
one halogen, as defined herein, appended to the parent molecular moiety
through an alkyl
group, as defined herein. Representative examples of sulfamyl(halo)alkyl
include, but are not
limited to, (aminosulfonyl)dichloromethyl, (aminosulfonyl)difluoromethyl,
(dimethylaminosulfonyl)difluoromethyl, 2-(aminosulfonyl)-1,1-dichloroethyl, 3-
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(aminosulfonyl)-1,1-difluoropropyl, 3-aminosulfonyl-1,1-dichloropropyl and 3-
(aminosulfonyl)-1,2-difluoropropyl.
The term "sulfinyl," as used herein, refers to a -S(O)- group.
The term "sulfonyl," as used herein, refers to a -SOZ- group.
The term "thio," as used herein, refers to a (-S-) moiety.
Compounds of the present invention may exist as stereoisomers wherein,
asymmetric
or chiral centers are present. These stereoisomers are "R" or "S" depending on
the
configuration of substituents around the chiral carbon atom. The terms "R" and
"S" used
herein are configurations as defined in ILTPAC 1974 Recommendations for
Section E,
Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. The present
invention
contemplates various stereoisomers and mixtures thereof and are specifically
included within
the scope of this invention. Stereoisomers include enantiomers and
diastereomers, and
mixtures of enantiomers or diastereomers. In particular, the carbon atom
attached to R6 and
R~ of formula (I-IV), may be individually the (R) enantiomer or individually
the (S)
enantiomer or a mixture thereof. Individual stereoisomers of compounds of the
present
invention may be prepared synthetically from commercially available starting
materials which
contain asymmetric or chiral centers or by preparation of racemic mixtures
followed by
resolution well-known to those of ordinary skill in the art. These methods of
resolution are
exemplified by (1) attachment of a mixture of enantiomers to a chiral
auxiliary, separation of
the resulting mixture of diastereomers by recrystallization or chromatography
and liberation of
the optically pure product from the auxiliary or (2) direct separation of the
mixture of optical
enantiomers on chiral chromatographic columns.
Preferred compounds of the present invention include
3-chloro-N-(1- f [3,4-dioxo-2-(5-pyrimidinylamino)-1-cyclobuten-1-yl]amino)-
2,2-
dimethylpropyl)benzamide;
N-(1- f [3,4-dioxo-2-(5-pyrimidinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3,5-difluorobenzamide;
N-( 1- { [3,4-dioxo-2-(2-pyrazinylamino)-1-cyclobuten-1-yl] amino ) -2,2-
dimethylpropyl)-3,5-difluorobenzamide;
3-chloro-N-(1- f [3,4-dioxo-2-(2-pyrazinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)benzamide;
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3-chloro-N- { 1-[(3,4-dioxo-2- { [2-(trifluoromethyl)-3-pyridinyl] amino} -1-
cyclobuten-
1-yl)amino]-2,2-dimethylpropyl}benzamide;
3-chloro-N-[ 1-( {2-[(2-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-
y1 } amino)-2,2-dimethylpropyl]benzamide;
3,5-difluoro-N-[ 1-( {2-[(2-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-
1-
y1} amino)-2,2-dimethylpropyl]benzamide;
N-[2,2-dimethyl-1-( {2-[(2-methyl-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-
y1} amino)propyl]-3,5-difluorobenzamide;
3-chloro-N- { 1-[(3,4-dioxo-2- { [4-(trifluoromethyl)-3-pyridinyl] amino} -1-
cyclobuten-
1-yl)amino]-2,2-dimethylpropyl} benzamide;
3-chloro-N- { 1-[(3,4-dioxo-2- { [4-(trifluoromethyl)-3-pyridinyl] amino } -1-
cyclobuten-
1-yl)amino]-2,2-dimethyl-3-phenylpropyl} benzamide;
3-chloro-N-[ 1-( {2-[(2-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-
y1 } amino)-2,2-dimethyl-3-phenylpropyl]benzamide;
3-chloro-N- { 1-[(3,4-dioxo-2- { [2-(trifluoromethyl)-3-pyridinyl] amino } -1-
cyclobuten-
1-yl)amino]-2,2-dimethyl-3-phenylpropyl } benzamide;
N-[2,2-dimethyl-1-( {2-[(4-methyl-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-
y1 } amino)propyl]-3, 5-difluorobenzamide;
3,5-difluoro-N-[ 1-( {2-[(4-methoxy-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-
1-
y1 } amino)-2,2-dimethylpropyl]benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-(3-pyridinyl)propanamide;
3-chloro-N-[ 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethyl-3-(4-pyridinyl)propyl]benzamide;
4-(3-[(3-chlorobenzoyl)amino]-3- { [3,4-dioxo-2-(3-pyridinylamino)-1-
cyclobuten-1-
yl]amino}-2,2-dimethylpropyl)benzoic acid;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)nicotinamide;
5-bromo-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)nicotinamide;
3- { [( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)amino]carbonyl}benzoic acid;
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N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-( 1 H-tetraazol-5-yl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-(3-pyridinyl)benzamide and pharmaceutically acceptable salts
thereof.
The foregoing compounds, representative of formula (II), may be prepared by
one
skilled in the art using known synthetic methodology or by using synthetic
methodology
described in the Schemes and Examples contained herein.
Most preferred compounds of formula (I) include
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-4-methylbenzamide;
4-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-4-iodobenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-4-(2-furyl)benzamide;
3-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-methylbenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-fluorobenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-iodobenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3,4-dimethylbenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3,4-dimethoxybenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-1-naphthamide;
3,S-dichloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]
amino} -2,2-
dimethylpropyl)benzamide;
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N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3,5-dimethoxybenzamide;
(-) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3,5-dimethoxybenzamide;
(+) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3,5-dimethoxybenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3,5-difluorobenzamide;
4-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethyl-4-pentenyl)benzamide;
4-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethyl-3-phenylpropyl)benzamide;
4-chloro-N-~4-cyano-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]
amino } -
2,2-diethylbutyl)benzamide;
N-(2,2-bis[(allyloxy)methyl]-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-
1-
yl]amino}butyl)-4-chlorobenzamide;
4-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2-
ethylbutyl)benzamide;
4-chloro-N-(2-cyclohexyl-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
yl]amino}-2-methylpropyl)benzamide;
N-(2-( 1-adamantyl)-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
y1] amino } ethyl)-4-chlorobenzamide;
4-chloro-N-(2,2-dichloro-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
yl]amino}propyl)benzamide;
3-chloro-N-(2,2-dichloro-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
yl]amino}propyl)benzamide;
3-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2,3,3,3-
pentafluoropropyl)benzamide;
4-chloro-N-( 1- { [2-(3-fluoroanilino)-3,4-dioxo-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
4-chloro-N-( 1- { [2-(4-fluoroanilino)-3,4-dioxo-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
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4-chloro-N-[ 1-( {2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl
} amino)-
2,2-dimethylpropyl]benzamide;
N-[ 1-( {2-[(5-bromo-6-fluoro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl }
amino)-
2,2-dimethylpropyl]-4-chlorobenzamide;
4-chloro-N-[ 1-( {2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl}
amino)-
2,2-dimethyl-3-phenylpropyl]benzamide;
N-[ 1-( {2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethylpropyl]-3-methylbenzamide;
4-chloro-N-(2,2-dimethyl-1- { [(3-pyridinylamino)sulfonyl] amino }
propyl)benzamide;
N-(2,2-dimethyl-1- { [(3-pyridinylamino)sulfonyl] amino } propyl)-4-
iodobenzamide;
Nl- { 1-[(4-chlorobenzoyl)amino]-2,2-dimethylpropyl } -NZ-(3-
pyridinyl)ethanediamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-phenylpropanamide;
N-[ 1-( {2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethylpropyl]-3-(3-pyridinyl)propanamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-vinylbenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl) [ 1,1'-biphenyl]-3-carboxamide;
3-acetyl-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-2-pyridinecarboxamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-4-fluoro-3-(trifluoromethyl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-2-phenylacetamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-phenylprop-2-enamide;
4-chloro-N-(2,2-dichloro-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
y1] amino } pentyl)benzamide;
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4-chloro-N-( 1- { [3,4-dioxo-2-(4-pyridinylamino)-1-cyclobuten-1-yl] amino} -
2,2-
dimethylpropyl)benzamide;
4-chloro-N-( 1- { [3,4-dioxo-2-(2-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)benzamide;
(+) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3,5-difluorobenzamide;
(-) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3,5-difluorobenzamide;
N-(2,2-dichloro-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
y1] amino } propyl)-3, 5-difluorobenzamide;
4-chloro-N- { 1-[(3,4-dioxo-2- { [5-(trifluoromethyl)pyridin-3-yl] amino } -1-
cyclobuten-
1-yl)amino]-2,2-dimethylpropyl}benzamide;
3,5-dichloro-N- { 1-[(3,4-dioxo-2- { [5-(trifluoromethyl)pyridin-3-yl] amino }
-1-
cyclobuten-1-yl)amino]-2,2-dimethylpropyl } benzamide;
4-chloro-N- { 1-[(3,4-dioxo-2- { [5-(trifluoromethyl)pyridin-3-yl] amino } -1-
cyclobuten-
1-yl)amino]-2,2-dimethyl-3-phenylpropyl } benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)-3,5-difluorobenzamide;
(+) 3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-
2,2-
dimethylpropyl)benzamide;
(-) 3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-
2,2-
dimethylpropyl)benzamide;
3,5-dichloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino
} -2,2-
dimethyl-3-phenylpropyl)benzamide;
3-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethyl-3-phenylpropyl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)-3-methylbenzamide;
N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethyl-3-phenylpropyl]-3-methylbenzamide;
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4-chloro-N-[ 1-( {2-[(6-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}
amino)-
2,2-dimethylpropyl]benzamide;
4-chloro-N-[ 1-( {2-[(2-fluoropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}
amino)-
2,2-dimethylpropyl]benzamide;
3-chloro-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
3,3-
dimethylbutyl)benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)thiophene-2-carboxamide;
3-bromo-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
3-bromo-N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-
y1 } amino)-2,2-dimethylpropyl]benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-9-oxo-9H-fluorene-4-carboxamide;
methyl 3- { [( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino }
-2,2-
dimethylpropyl)amino]carbonyl } benzoate;
(+) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3-methylbenzamide;
(-) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3-methylbenzamide;
(+) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethyl-3-
phenylpropyl)-3-methylbenzamide;
(-) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethyl-3-
phenylpropyl)-3-methylbenzamide;
(+) N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-
2,2-
dimethylpropyl]-3-methylbenzamide;
(-) N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-
2,2-
dimethylpropyl]-3-methylbenzamide;
(+) N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethyl-3-
phenylpropyl)-3,5-difluorobenzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino} -2,2-
dimethylpropyl)-3-(2-furyl)benzamide;
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N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethylpropyl]-3-fluorobenzamide;
3,5-dichloro-N-[1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-1-en-1-
y1 } amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-[ 1-( {2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-
y1 } amino)-2,2-dimethylpropyl]benzamide;
N-[ 1-( {2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl } amino)-
2,2-
dimethylpropyl]-3-methylbenzamide;
3,5-difluoro-N-[ 1-( {2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-
1-
y1 } amino)-2,2-dimethylpropyl]benzamide;
N-[ 1-( {2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethyl-3-phenylpropyl]-3-methylbenzamide;
3-chloro-N-[ 1-( {2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-
y1 } amino)-2,2-dimethylpropyl]benzamide;
N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethyl-3-phenylpropyl]benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)benzamide;
N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethylpropyl]-3-phenylpropanamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-2-phenoxyacetamide;
N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
2,2-
dimethylpropyl]-2-phenoxyacetamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-2-methyl-2-phenylpropanamide;
3-chloro-N-( 1- { [3,4-dioxo-2-(pyrazin-2-ylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide;
N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl} amino)-
3,3-
dimethylbutyl]benzamide;
3-chloro-N-[ 1-( {2-[(6-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}
amino)-
2,2-dimethylpropyl]benzamide;
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3-chloro-N- { 1-[(3,4-dioxo-2- { [6-(trifluoromethyl)pyridin-3-yl] amino } -1-
cyclobuten-
1-yl)amino]-2,2-dimethylpropyl} benzamide;
3-chloro-N-[ 1-( {2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl
} amino)-
2,2-dimethylpropyl]benzamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)isonicotinamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)-3-phenylpropanamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)-2-methyl-2-phenylpropanamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)-2-phenoxyacetamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
phenylpropyl)nicotinamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)nicotinamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)isonicotinamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-2-furamide;
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethyl-3-
pyridin-4-ylpropyl)-3-methylbenzamide;
(-) 3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-
2,2-
dimethyl-3-phenylpropyl)benzamide;
(+) 3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino}-
2,2-
dimethyl-3-phenylpropyl)benzamide;
4-chloro-N-( { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
y1] amino } methyl)benzamide;
(+) 3,5-dichloro-N-[(1S)-1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-
1-en-
1-yl} amino)-2,2-dimethylpropyl]benzamide;
(-) 3,S-dichloro-N-[(1R)-1-({2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-
1-en-
1-yl} amino)-2,2-dimethylpropyl]benzamide;
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(+) N-(1-{[3,4-dioxo-2-(2-chloro3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3,5-difluorobenzamide;
(-) N-(1-{[3,4-dioxo-2-(2-chloro3-pyridinylamino)-1-cyclobuten-1-yl]amino}-2,2-
dimethylpropyl)-3,5-difluorobenzamide and pharmaceutically acceptable salts
thereof.
Abbreviations
Abbreviations which have been used in the descriptions of the schemes and the
examples that follow are: Ac for acetyl; COD for 1,4-cyclooctadiene; DMA
for'N,N-
dimethylacetamide; DMAP for 4-dimethylaminopyridine; DME for dimethoxyethane;
DMF
for N,N-dimethylformamide; DMSO for dimethylsulfoxide; dppf for 1,1'-
bis(diphenylphosphino)ferrocene; Et3N for triethylamine; Et20 for diethyl
ether; EtOAc for
ethyl acetate; EtOH for ethanol; HPLC for high pressure liquid chromatography;
MeOH for
methanol; NMP for 1-methyl-2-pyrrolidinone; pyr for pyridine; t-BuOH for tert-
butanol; Tf
for triflate or -OS(O)ZCF3; TFA for trifluoroacetic acid; THF for
tetrahydrofuran; and p-TsOH
or TsOH for para-toluenesulfonic acid monohydrate.
Preparation of Compounds of The Invention
The compounds and processes of the present invention will be better understood
in
connection with the following synthetic schemes and methods which illustrate a
means by
which the compounds of the invention can be prepared.
The compounds of this invention may be prepared by a variety of synthetic
routes.
Representative procedures are described in Schemes 1-16.
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Scheme 1
H Ra N~ N Ra
N~ CHO HN\ /RS PhCH3 N N R5
~N
N Rs O reflux
(1 ) (2) (3)
R~R2NH R3NHz
Rz 7 Rz Rs
RO~ ,OR ~ ~N~ ~O~ ~ »N~ ,NH
A EtOH R~ A R MeOH R A
(4) (6) ($)
Rz R3 N~ N Ra KZC03 Rz R3 Ra
R1 N~A~NH + ~ ~ N~N~RS M R~ N\A/N~N~RS
Rs O Rs O
(8) (3) (9)
A preferred route for preparing aminals of general formula (9), wherein Rl,
Rz, R3, Ra,
RS and R6 are as defined in formula (I) is described in Scheme 1. A three-
component
condensation including benzotriazole, aldehydes of general formula (1), and
amides of general
formula (2) in the presence of an acid catalyst such as, but not limited to, p-
toluenesulfonic
acid monohydrate as described in Katritzky, Urogdi, Mayence, J. Org. Chem.
(1990), SS,
2206); Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky, J. Heterocyclic
Chem. (1996),
33, 1935 provides benzotriazole adducts of general formula (3). Substitution
of a bis(ether)
precursor of general formula (4), wherein R is alkyl such as, but not limited
to, ethyl, with a
primary or secondary amine of general formula (5) provides adducts of general
formula (6)
which can undergo further substitution with ammonia or a primary amine of
general formula
(7) to provide amines of general formula (8). Benzotriazoles of general
formula (3) can be
treated with amines of general formula (8) as described in Katritzky, Urogdi,
Mayence, J. Org.
Chem. (1990), 55, 2206); Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky,
J.
Heterocyclic Chem. (1996), 33, 1935 in a polar, aprotic solvent such as, but
not limited to,
DMF in the presence of a base such as, but not limited to, potassium carbonate
or cesium
carbonate to provide aminals of general formula (9).
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Scheme 2
R~RZNH R2 R2
RO OR
_ (5) R1~N OR NH3 R; N
NH
EtOH ' MeOH
O~~O O O
(12) (13) O (14) O
Rz
Ra
N'N Na R5 CSC Ri N ~ N N R5
(14) ~ ~ ~ DMF O
O
(3) (15)
Squarate aminals of general formula (15), wherein Rl, R2, Ra, and RS are as
defined in
formula (I), and R4 is selected from alkyl such as, but not limited to, t-
butyl, arylalkyl such as,
but not limited to, phenethyl, or haloalkyl such as, but not limited to, -
CC12CH3 or -CFZCF3,
can be prepared as described in Scheme 2. Dialkyl squarate esters of general
formula (12),
wherein R is alkyl, such as, but not limited to, diethyl squarate can be
treated with amines of
general formula (5) in an alcoholic solvent such as, but not limited to,
ethanol as described in
Butera, J. Med. Chem. (2000), 43, 1187; and Gilbert, J. Med. Chem. (2000), 43,
1203 to
provide squarates of general formula (13). Squarates of general formula (13)
can be treated
with ammonia in an alcoholic solvent such as, but not limited to, methanol to
provide
squarates of general formula (14). Benzotriazoles of general formula (3) can
be treated with
squarates of general formula (14) in a polar, aprotic solvent such as, but not
limited to, DMF
in the presence of a base such as, but not limited to, cesium carbonate to
provide squarate
aminals of general formula (15).
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Scheme 3
H Ra
N~ CHO HN' /R5 p-TsOH
N + I
N R6 O
(17) (1 ) (2)
Rz
I
iN Rz
N~N R R' ~ NH2 N Ra
N Na R5 ° R~~ _ N N RS
\ / ~ ~ (14) ° °
0
(18) CszC03, DMA (15)
A process for the synthesis of squarate aminals of general formula (15),
wherein R~,
R2, and R5 are as defined in formula (I), Ra is hydrogen, and R~ is selected
from alkyl such as,
but not limited to, t-butyl, arylalkyl such as, but not limited to, phenethyl,
or haloalkyl such as,
but not limited to, -CC12CH3 or -CFZCF3, can be used as described in Scheme 3.
Commercially available 1H-benzotriazole-polystyrene resin (Novabiochem) can be
loaded in a
three-component condensation including aldehydes of general formula ( 1 ), and
amides of
general formula (2) in the presence of an acid catalyst, but not limited to, p-
toluenesulfonic
acid monohydrate as described in Katritzky, Belyakov, Tymoshenko, J. Comb.
Chem. (1999),
1, 173; and Paio, Zaramella, J. Comb. Chem. (1999), 1, 317 to provide
benzotriazole adducts
of general formula (18). Benzotriazole adducts of general formula (18) can
undergo
nucleophilic displacement of the resin bound benzotriazole moiety with
squarate amides of
general formula (14) in a solvent such as, but not limited to,
dimethylacetamide or a cosolvent
such as, but not limited to, THF and dimethylacetamide in the presence of a
base such as, but
not limited to, cesium carbonate to provide aminals of general formula (15).
In the polymer-bound benzotriazole method as described in Scheme 3, the
desired
components are bound to the resin allowing for efficient purification. In the
final product
formation, an excess of a squarate of general formula (14) can be used to
cleave only the
desired products off the resin. The process described in Scheme 3 also offers
the potential to
create a combinatorial library (array synthesis) of squarate aminals of
general formula (15) by
enabling diversity at Rl, RZ, Rs,and R6 to be explored.
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Scheme 4
Ra OR R6
HN' /Rs R6~OR' CI N R3
(20)
(2) SOCIz (21 )
pyridine
Rz
Rz ~N H Ra
+ R,iN NH CszC03 R~ ~ N\ /N\ /Rs
z ~ ~~
DMF p~ R6 O
O O
(14) O (15)
Squarate aminals of general formula (15), wherein R~, Rz, Ra, and RS are as
defined in
formula (I) and R4 is haloalkyl such as, but not limited to, -CC13 or -CF3,
can be prepared as
described in Scheme 4. Amides of general formula (2) can be treated with a-
haloaldehyde
hydrates or a-halohemiacetals of general formula (20), wherein R is hydrogen
and R' is
selected from hydrogen or alkyl, such as, but not limited to, 2,2,2-trichloro-
1,1-ethanediol or
1-ethoxy-2,2,2-trifluoro-1-ethanol, followed by addition of a chlorinating
agent such as, but
not limited to, thionyl chloride and a base such as, but not limited to,
pyridine to provide
chloroamides of general formula (21). Chloroamides of general formula (21) can
be treated
with squarates of general formula (14) in a polar, aprotic solvent such as,
but not limited to,
DMF in the presence of a base such as, but not limited to, cesium carbonate to
provide
squarate aminals of general formula (15).
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Scheme S
R2 R2
,N H H + ,N H
R~ ' N~N~R" H R~ _ N~NH2
O O Rs O ~ O O Rs
(23) (24)
CI R5 R2
( ) iN H H
25 R~ N N R
(i-Pr)2NEt, O ' ~ 5
CH2C12 O s
(15)
An alternate route for preparing squarate aminals of general formula (15),
wherein R,,
RZ, R5, and R6 are as defined in formula (I) is described in Scheme 5.
Squarate aminals of
general formula (23), wherein R" is alkoxy, can be prepared following the
strategy described
in Scheme 2. Squarate aminals of general formula (23) can be treated with an
acid such as,
but not limited to, hydrobromic acid or trifluoroacetic acid to provide
primary amines of
general formula (24). Amines of general formula (24) can be treated with acid
chlorides of
general formula (25) in the presence of a base such as, but not limited to,
diisopropylethylamine to provide squarate aminals of general formula (15).
Scheme 6
N~ N R4 R4
N N RS N~ H2N N R5
MeOH
(3) (27)
R2 R2 R
iN H ~ a
iN EtOH R~ N' /N\ /R
(27) + R~ ~ OR ~ ~ ~' ~ s
O O' \O Rs O
(13) O (15)
An alternate route for preparing squarate aminals of general formula (15),
wherein R~,
Rz, R4, R5, and R6 are as defined in formula (I) is described in Scheme 6.
Compounds of
general formula (3) can be treated with ammonia in an alcoholic solvent such
as, but not
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limited to, methanol as described in Katritzky, Urogdi, Mayence, J. Org. Chem.
(1990), 55,
2206; Katritzky, Chem. Rev. (1998), 98, 409; and Katritzky; J. Heterocyclic
Chem. (1996),
33, 1935 to provide aminoamides of general formula (27). Aminoamides of
general formula
(27) can be treated with squarates of general formula (13) in alcoholic
solvent such as, but not
limited to, ethanol or a polar, aprotic solvent such as, but not limited to,
acetonitrile to provide
squarate aminals of general formula (15).
Scheme 7
R4 RO OR
I
H2N\ /N\ /R5 EtOH
R6 O O O
(27) (12)
RO H R4 R~R2NH N2 H R4
N N R5 (5) R~~ ' N N R5
O ~ ~ EtOH O
O O
(29) (15)
Squarate aminals of general formula (15), wherein R~, RZ, R4, R5, and R6 are
as defined
in formula (I), can be prepared as described in Scheme 7. Aminoamides of
general formula
(27) can be treated with dialkyl squarates of general formula (12), wherein R
is alkyl, such as,
but not limited to, diethyl squarate in an alcoholic solvent such as, but not
limited to, ethanol
or a polar, aprotic solvent such as, but not limited to, acetonitrile to
provide squarates of
general formula (29). Squarates of general formula (29) can be treated with
amines of general
formula (5) in an alcoholic solvent such as, but not limited to, ethanol to
provide squarate
aminals of general formula (1 S).
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Scheme 8
O CI Rs O R
(25) a
NH2 O N Rs Phl(OAc)2
H2N ~ H2N~ ~ ---
R6 pyr, CH2CI2 R6 O HCI
(30)
(31)
21N Na Rs RO OR EtOH
i-Pr2NEt
O O
(27) (12)
R2
RO H Ra R~R2NH N H Ra
N N' /Rs (5) Ri ' N N Rs
O ~ O EtOH O
O O
(29) (15)
Squarate aminals of general formula (15), wherein R~, RZ, Ra, R5, and R6 are
as defined
in formula (I), can be prepared as described in Scheme 8. Aminoacetamides of
general
formula (30) can be treated with acid chlorides of general formula (25) in the
presence of a
base such as, but not limited to, pyridine or triethylamine to provide the
corresponding
acylaminoamides of general formula (31). Acylaminoamides of general formula
(31) can
undergo a Hofinann rearrangement as described in Wallis and Lane, Org. React.
(1946), 3,
267-306, and references contained therein with reagents such as, but not
limited to,
iodosobenzene diacetate as described in Loudon et al., Org. Chem. (1984), 49,
4272; Loudon
and Boutin, J. Org. Chem. (1984), 49, 4277; and Chan et al, Synth. Commun.
(1988), 53, 5158
to provide aminoamides of general formula (27), which can be typically
isolated as their
hydrochloride salts. Aminoamides of general formula (27) can be treated with
squarates of
general formula (12), wherein R is alkyl, such as, but not limited to, diethyl
squarate in an
alcoholic solvent such as, but not limited to, ethanol or a polar, aprotic
solvent such as, but not
limited to, acetonitrile to provide squarates of general formula (29).
Squarates of general
formula (29) can then be treated with amines of general formula (5) in an
alcoholic solvent
such as, but not limited to, ethanol to provide squarate aminals of general
formula (15).
SO
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Scheme 9
O p-TsOH Rs\ /N\ /R5
H2N\ /R5 ~ (CF3C0)20
Rs (34) R' pyridine R (35 O
(2) )
R2
I
~N
R~ ~ NH2 R
12
O ,N H H
(14) O Rt ~ N / \ N II Rs
Et3N O' ~p R6 R~ O
(36)
Geminally-substituted squarate aminals of general formula (36), wherein Rl,
R2, R5,
R6, and R~ are as defined in formula (I) and R6 = R~ or R6 and R7 taken
together with the
carbon atom to which they are attached, together form a S or 6 membered
carbocyclic ring,
can be prepared as described in Scheme 9 or as described in Steglich, Chem.
Ber. (1974), 107,
1488; and Burger, J. Fluorine Chem. (1982), 20, 813. Primary amides of general
formula (2)
can be treated with symmetrical ketones of general formula (34) in the
presence of a
dehydrating agent such as, but not limited to, trifluoroacetic anhydride and a
base such as, but
not limited to, pyridine to provide symmetrical imines of general formula
(35). Symmetrical
imines of general formula (35) can be treated with squarates of general
formula (14) in the
presence of a base such as, but not limited to, triethylamine to provide
geminally-substituted
squarate aminals of general formula (36).
Scheme 10
RZ R RZ R.
N Rs Ra / / N Rs Ra / /
R~~ ~ N N ~ ~ R'SnBu3 R~~ ~ N
O O Rs O Pd(0), AsPh3 O O Rs O
NMP
(37) R=Br, I or OTf (38)
Squarate aminals of general formula (38), wherein R~, R2, R3, R4 and R6 are as
defined
in formula (I) and R' is selected from alkoxycarbonyl, aryl, carboxy,
heterocycle and -NRARB
wherein RA and RB are as defined in formula (I), can be prepared as described
in Scheme 10.
Squarate aminals of general formula (37), wherein R is Br, I or -OS(O)ZCF3,
can be treated
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with a palladium catalyst, a trialkyltin reagent and triphenylarsine in a
solvent such as, but not
limited to, N-methylpyrrolidin-2-one as described in Farina and Baker, J. Org.
Chem. (1990),
55, 5833 to provide aminals of general formula (38). Alternatively, cross-
coupling reactions
and carbonylations can be done on squarate aminals of general formula (37)
using Buchwald,
Stille, Suzuki or Heck coupling reaction conditions, all of which are well
known to those
skilled in the art of organic chemistry.
Scheme 11
R R'
N-N R4 ~ /I R'SnBu3 N=N R4 ~ /I
N N ~ ~ N N
O Pd(0), AsPh3 ~ ~ R O
NMP
(40) (41 )
R=Br, I or OTf
R'
R2 N2 H Ra / /I
Cs2C03 R~ ' N ~ N w
(41 ) + R~ ~ NH2
O DMF O O R6 O
O
(14)
Scheme 11 describes a preferred method that provides squarate aminals of
general
formula (38), wherein Rl, RZ, R4, and R6 are as defined in formula (I) and R'
is selected from
alkoxycarbonyl, aryl, carboxy, heterocycle and -NRARB wherein RA and RB are as
defined in
formula (I). Benzotriazole compounds of general formula (40), wherein R is Br,
I or -
OS(O)ZCF3, can be treated with a palladium catalyst, a trialkyltin reagent and
triphenylarsine
in a solvent such as, but not limited to, N-methylpyrrolidin-2-one as
described in Farina and
Baker, J. Org. Chem. (1990), 55, 5833 to provide elaborated benzotriazoles of
general formula
(41). Alternatively, cross-coupling reactions and carbonylations can be done
on
benzotriazoles of general formula (40) using Buchwald, Stille, Suzuki or Heck
coupling
reaction conditions all of which are well known to those skilled in the art of
organic chemistry.
Benzotriazoles of general formula (41) can be treated with squarates of
general formula (14) in
a polar, aprotic solvent such as, but not limited to, DMF in the presence of a
base such as, but
not limited to, cesium carbonate to provide squarate aminals of general
formula (38).
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Scheme 12
H H
CISOZNCO N N O CF3COzH
RiNH2 -~ R~ ~S~
(42) t-BuOH p~ ~O O
(43 )
H N\N Ra K2C03 H H Ra
R; N~S~NH2 + N N R5 ~ R ,N~S~N N RS
v0 ~ ~ ~ DMF 1 ~i v0
R6 O R6 O
(44) (3) (45)
Sulfonylamino aminals of general formula (45), wherein R,, R4, R5, and R6 are
as
defined in formula (I), can be prepared as described in Scheme 12. Primary
amines of general
formula (42) can be treated with chlorosulfonyl isocyante in the presence of
an alcoholic
nucleophile such as, but not limited to, t-butanol as described in Abdaoui,
Bioorg. Med. Chem.
Lett. (1996), 4, 1227 to provide sulfonylamino carbamates of general formula
(43).
Sulfonylamino carbamates of general formula (43) can be treated with a protic
acid such as,
but not limited to, trifluoroacetic acid to provide amino sulfonamides of
general formula (44).
Amino sulfonamides of general formula (44) can be treated with benzotriazoles
of general
formula (3) in a polar, aprotic solvent such as, but not limited to, DMF in
the presence of a
base such as, but not limited to, potassium carbonate or cesium carbonate to
provide
sulfonylamino aminals of general formula (45).
Scheme 13
O RiNH2 O
CI~OR (42) R N II OR NH3
1 W J'~~/
O. Et3N, CH2CI2 H O MeOH
(47) (48)
O N, N Ra O Ra
I I Cs2C03 H I
R1~ NHZ + N N R5 ---~ R1~ ~N N R5
N II ~ ~ DMF N II
H O H O R6 O
(4g) (3) (50)
Ethanediamide aminals of general formula (50), wherein R~, R4, R5, and R6 ai-e
as
defined in formula (I) can be prepared as described in Scheme 13.
Chloroalkyloxalates of
general formula (47), wherein R is alkyl, such as, but not limited to,
chloroethyloxalate can be
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treated with primary amines of general formula (42) in the presence of a base
such as, but not
limited to, triethylamine to provide amidoesters of general formula (48).
Amidoesters of
general formula (48) can be treated with ammonia in an alcoholic solvent such
as, but not
limited to, methanol to provide oxalamides of general formula (49). Oxalamides
of general
formula (49) can be treated with benzotriazoles of general formula (3) in a
polar, aprotic
solvent such as, but not limited to, DMF in the presence of a base such as,
but not limited to,
potassium carbonate or cesium carbonate to provide ethanediamide aminals of
general formula
(50).
Scheme 14
CI CI R~NR2H2 R~R2N CI R~R2N NH2
(5) NH3
%~~O %~~O -~ %~~O
O O O O O O
(52) (53)
R~R2N H R4
O w NYN II R5
(53) ~ O~ Rs O
O
(54)
Aminals of general formula (54), wherein R1, R2, R4, RS and R6 are as defined
in
formula (I), can be prepared as described in Scheme 14. 3,4-Dichloro-2,5-
furandione,
purchased from Aldrich Chemical Company, can be treated with amines of general
formula
(5) as described in previous Schemes to provide furandiones of general formula
(52).
Furandiones of general formula (52) can be treated with ammonia as described
in previous
Schemes to provide compounds of general formula (53). Compounds of general
formula (53)
can be processed as described in Schemes 1-5 and Scheme 9 to provide aminals
of general
formula (54).
Alternatively, 3,4-dichloro-2,5-furandione can be processed as described in
Schemes
6-8 to provide aminals of general formula (54).
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Scheme 15
R~R2N NH2 R2R~N N N4 Rs
O N O N--~ Rs O
O
(55) (56)
R~RzN N H2 R2R~N H R4
O ~ N~N~RS
O O ~ Rs O
(5~) O
(58)
Aminals of general formula
(56), wherein Rl, R2,
R4, RS and R4 are as
defined in
formula (I), can be prepared as described in Scheme 15. Pyrrole diones of
general formula
(55) can be prepared as described in Augustin, Tetrahedron (1980) 36, 1801;
and Hanaineh-
Abdelnour, Tetrahedron (1999) 55, 11859 and then processed as described in
previous
Schemes to provide aminals of general formula (56).
Aminals of general formula (58), wherein R1, R2, R4, RS and R6 are as defined
in
formula (I), can be prepared as described in Scheme 15. Cyclopentene diones of
general
formula (57) can be prepared as described in Lee et al., JOC (1995) 60, 735;
and Yamamoto et
al., JACS (1995) 117, 9653 and then processed as described in previous Schemes
to provide
aminals of general formula (58).
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Scheme 16
HO OH CI CI
oxalyl chloride ROH
O O O O
(59) (60)
CI OR R~R2NH R2 R2
(5) iN NH3 ~N
R~ ~ OR ~ Ri ' NH2
NaHC03 MeOH
O O DMF O O
(61 ) (13) O (14) O
R2
I R
N\N N4 R CS2C03 RiiN _ N N4 R5
(14) + \ ~ ~ 5 DMF
R6 O O R6 O
O
(3) (15)
Squarate aminals of general formula (15), wherein R~, RZ, R4, and RS are as
defined in
formula (I) and R6 is selected from alkyl such as, but not limited to, t-
butyl, arylalkyl such as,
but not limited to, phenethyl, or haloalkyl such as, but not limited to, -
CC12CH3 or -CFZCF3,
can be prepared as described in Scheme 16. Squaric acid (59) can be treated
with oxalyl
chloride as described in Ohno et al., J. Chem. Soc., Perkin Trans. 1 (1993),
263; and
Yamamoto et al., Tetrahedron (2000), 50, 7783, to provide 3,4-dichloro-
cyclobut-3-ene-1,2-
dione (60) which can be treated with alcohols such as, but not limited to,
methanol as
described in Ohno et al., J. Chem. Soc., Perkin Trans. 1 (1993), 263, to
provide compounds of
general formula (61) wherein R is alkyl. Compounds of general formula (61) can
be treated
with amines of general formula (5) in the presence of a base such as, but not
limited to,
sodium bicarbonate in a polar aprotic solvent such as, but not limited to,
DMF, to provide
squarates of general formula (13). Squarates of general formula (13) can be
treated with
ammonia in an alcoholic solvent such as, but not limited to, methanol to
provide squarates of
general formula (14). Benzotriazoles of general formula (3) can be treated
with squarates of
general formula (14) in a polar, aprotic solvent such as, but not limited to,
DMF in the
presence of a base such as, but not limited to, cesium carbonate to provide
squarate aminals of
general formula (15).
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The compounds and processes of the present invention will be better understood
by
reference to the following examples, which are intended as an illustration of
and not a
limitation upon the scope of the invention.
Example 1
N~1-f[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~lamino~-2 2-
dimethypropyl)-4-
metl~lbenzamide
Example 1A
3-ethoxy-4-(3-pyridinylamino)-3-cyclobutene-1,2-dione
3-Aminopyridine (2.77 g, 29.4 mmol) in ethanol (30 mL) was added to a
refluxing
solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in
ethanol (100 mL)
over a period of 1 hour. The mixture was heated at reflux for 24 hours,
filtered, and the filtrate
removed under reduced pressure. The residue was purified by flash
chromatography on silica
gel (elution with 5% EtOH/EtOAc) to provide 4.42 g of the title compound as a
white powder.
MS (DCI/NH3) m/z 219 (M+H)+.
Example 1B
3-amino-4-(3-pyridinylamino)-3-cyclobutene-1,2-dione
The product from Example 1A (4.42 g, 20.2 mmol) in ethanol (80 mL) was treated
with 2.0M NH3 in methanol (30 mL) and stirred at ambient temperature for 16
hours. The
solvent was removed under reduced pressure and the residue was triturated with
diethyl ether
to provide 3.80 g of the title compound as a pale yellow powder.
MS (DCI/NH3) m/z 190 (M+H)+.
Example 1 C
N-( 1-~ 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl)-4-methylbenzamide
A suspension of p-toluamide (4.11 g, 30.4 mmol), pivaldehyde (2.62 g, 30.4
mmol),
and benzotriazole (3.62 g, 30.4 mmol) in toluene (200 mL) was treated with p-
toluenesulfonic
acid (286 mg, 1.52 mmol). The solution was heated at reflux under Dean-Stark
conditions for
hours, cooled gradually to ambient temperature, and further cooled to 5
°C. The white
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precipitate which formed was collected by filtration and was washed with 50%
diethyl
ether/hexanes (100 mL) to provide 6.67 g of the title compound as a white
solid.
MS (DCI/NH3) m/z 323 (M+H)+.
Example 1D
N-(1- f f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino}-2 2-
dimethylpropyl)-4-
methylbenzamide
The product from Example 1B (0.15 g, 0.79 mmol), and the product from Example
1C
(0.26 g, 0.79 mmol) in DMF (3 mL) were treated with KZC03 (0.55 g, 3.97 mmol).
The
reaction mixture was stirred at ambient temperature for 20 hours then diluted
with 25 mL H20
and extracted with EtOAc (2 x 50 mL). The combined extracts were dried over
Na2S04, and
EtOH (5 mL) was added. The crude reaction mixture was filtered through a 0.5
inch silica gel
plug and concentrated under reduced pressure to a volume of 20 mL. The title
compound
(0.13 g) was collected by filtration and dried under reduced pressure for 1
hour.
mp 258-259 °C;
MS (DCI/NH3) m/z 393 (M+H)+;
H NMR (DMSO-d6) 8 9.89 (s, 1 H), 8.5 8 (d, 1 H, J=3 Hz), 8.25 (d, 1 H, J=5
Hz), 8.06 (br s,
1H) 7.94 (dd, 1H, J=8, 1 Hz), 7.77 (d, 2H, J=8 Hz), 7.38 (dd, 1H, J=8, 5 Hz),
7.29 (d, 2H, J=8
Hz), 5.86 (t, 1H, J=8 Hz), 2.36 (s, 3H), 1.06 (s, 9H);
Anal. calcd for C22HzaNaO3: C, 67.33; H, 6.16; N, 14.28. Found: C, 66.99; H,
5.94; N, 14.20.
Example 2
4-chloro-N-(~[3,4-dioxo-2-(3-p r~idinylamino)-1-cyclobuten-1-yl]amino)-2 2-
dimeth~propyl)benzamide
Example 2A
N-( 1-( 1 H-1,2,3-benzotriazol-1-y1~2,2-dimethLrlpropyl)-4-chlorobenzamide
A suspension of 4-chlorobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic
acid was processed as described in Example 1 C to provide the title compound.
MS (DCI/NH3) m/z 343 (M+H)+.
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Example 2B
4-chloro-N-(1-{f3,4-dioxo-2-(3-p rr~ylamino~ 1-cyclobuten-1-yl]amino)-2 2-
dimethylpropyl)benzamide
A suspension of the product from Example 1B, the product from Example 2A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 257-258 °C;
MS (DCI/NH3) m/z 413 (M+H)+;
H NMR (DMSO-d6) 8 9.90 (br s, 1 H), 8.74 (d, 1 H, J=7 Hz), 8. 5 8 (d, 1 H, J=2
Hz), 8.25 (d,
1H, J=4 Hz), 8.06 (br s, 1H), 7.93 (d, 1H, J=8 Hz), 7.87 (d, 2H, J=8 Hz), 7.56
(d, 2H; J=8 Hz),
7.38 (dd, 1H, J=8, 5 Hz), 5.86 (s, 1H), 1.06 (s, 9H);
Anal. calcd for CZ1HZ~C1N403: C, 61.09; H, 5.13; N, 13.57. Found: C, 60.86; H,
5.07; N,
13.44.
Example 3
N-( 1- { [3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1-~] amino } -2,2-
dimethYlpro~yl)-4-
iodobenzamide
Example 3A
~~ 1 H-1,2,3-benzotriazol-1-yll-2,2-dimethylpropyl)-4-iodobenzamide
A suspension of 4-iodobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic
acid was processed as described in Example 1C to provide the title compound.
MS (DCI/NH3) m/z 435 (M+H)+.
Example 3B
1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ~ -2,2-
dimeth~propyl
iodobenzamide
A suspension of the product from Example 1B , the product from Example 3A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 256-257 °C;
MS (ESI+) m/z 505 (M+H)+;
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'H NMR (DMSO-d6) 8 9.90 (br s, 1H), 8.71 (d, 1H, J=8 Hz), 8.57 (d, 1H, J=3
Hz), 8.25 (dd,
1H, J=5, 1 Hz), 8.05 (br s, 1H), 7.93 (dd, 1H, J=8, 1 Hz), 7.88 (d, 2H, J=8
Hz), 7.63 (d, 2H,
J=8 Hz), 7.38 (dd, 1H, J=8, 5 Hz), 5.84 (br s, 1H), 1.05 (s, 9H);
Anal. calcd for Cz~H2~IN4O3: C, 50.01; H, 4.20; N, 11.11. Found: C, 50.37; H,
4.50; N, 10.80.
Example 4
N-( 1- ( f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino -2,2-
dimethylpropyl)-4-(2-
furyl)benzamide
Example 4A
N-~ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~propyl)-4-(2-fur~)benzamide
A solution of Example 3A (51 mg, 0.12 mmol) in N-methylpyrrolidinone (2 mL) at
23
°C was treated with 2-(tributylstannyl)furan (41 pL, 0.13 mmol)
followed by triphenylarsine
(3.7 mg, 0.012 mmol) and then tris(dibenzylideneacetone)dipalladium(0) (5.4
mg, 0.006
mmol). The reaction mixture was stirred for 3.5 hours then partitioned between
EtOAc (15
mL) and water (5 mL). The organic portion was washed with water (5 mL) then
brine (5 mL)
and dried (Na2S04). Filtration and concentration afforded a oily residue which
was purified
by flash chromatography (elution with 5% EtOAc/1:1 hexanes:CH2Clz) to provide
37 mg
(84%) of the title compound as a white solid.
MS (DCI/NH3) m/z 375 (M+H)+.
Example 4B
1- f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~]amino ) -2,2-
dimethylpropyl)-4-(2-
furyl)benzamide
A suspension of the product from Example 1B, the product from Example 4A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 230-232 °C;
MS (DCI/NH3) m/z 445 (M+H)+;
'H NMR (DMSO-d6) 8 9.88 (br s, 1H), 8.67 (br s, 1H), 8.55 (d, 1H, J=2.7 Hz),
8.23 (dd, 1H,
J=4.6, 1.0 Hz), 8.04 (br s, 1H), 7.96-7.87 (m, 3H), 7.83-7.77 (m, 3H), 7.37
(dd, 1H, J=8.5, 4.8
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Hz), 7.10 (d, 1H, J=3.4 Hz), 6.62 (dd, 1H, J=3.4, 2.0 Hz), 5.86 (br t, 1H,
J=6.8 Hz), 1.04 (s,
9H);
Anal. calcd for CZSH2aNa4a: C, 67.55; H, 5.44; N, 12.60. Found: C, 66.92; H,
5.46; N, 12.69.
Example 5
3-chloro-N-( 1- f f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yll amino ) -
2 2-
dimethylpropyl)benzamide
Example SA
N-( 1-( 1 H-1,2,3-benzotriazol-1-~)-2,2-dimeth~lprop~)-3-chlorobenzamide
A suspension of 3-chlorobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic
acid was processed as described in Example 1C to provide the title compound.
MS (DCI/NH3) m/z 343 (M+H)+.
Example SB
3-chloro-N-(1-f [3,4-dioxo-2-(3-p rr~ylamino)-1-cyclobuten-1-yl~amino)-2,2-
dimethylpropyl)benzamide
A suspension of the product from Example 1B, the product from Example SA, and
K2C03 was processed as described in Example 1D to provide the title compound.
MS (ESI) m/z 413 (M+H)+;
1H NMR (DMSO-d6) 8 9.73 (br s, 1H), 9.40 (br d, 1H, J=8.4 Hz), 8.77 (d, 1H,
J=2.5 Hz), 8.50
(d, 1H, J=8.4 Hz), 8.26 (dd, 1H, J=5.5, 1.1 Hz), 7.93 (br s, 1H), 7.79 (br s,
1H), 7.83 (d, 1H,
J=7.9 Hz), 7.61 (br d, 1H, J=8.6 Hz), 7.58 (t, 1H, J=8.2 Hz), 7.41 (dd, 1H,
J=8.7, 4.8 Hz), 5.47
(t, 1 H, J=8.5 Hz), 0.90 (s, 9H);
Anal. calcd forC21H5~C1N403: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.56; H,
5.02; N,
13.79.
Example 6
N-(1-f~j3,4-dioxo-2-(3-p r~ylamino)-1-c~lobuten-1-yl]amino-2,2-dimethylpropyl)-
3-
methylbenzamide
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Example 6A
N-( 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~prop~)-3-methylbenzamide
A suspension of m-toluamide, pivaldehyde, benzotriazole, and p-toluenesulfonic
acid
was processed as described in Example 1C to provide the title compound.
MS (DCI/NH3) m/z 323 (M+H)+.
Example 6B
N-( 1- ~ f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~] amino ) -2,2-
dimethylpropyl)-3-
methylbenzamide
A suspension of the product from Example 1B, the product from Example 6A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 236-237 °C;
MS (ESI+) m/z 393 (M+H)+;
IH NMR (DMSO-d6) 8 9.93 (br s, 1H), 8.64 (br d, 1H, J=7.1 Hz), 8.57 (d, 1H,
J=2.7 Hz), 8.25
(dd, 1H, J=4.7, 1.4 Hz), 8.08 (br s, 1H), 7.93 (br d, 1H, J=7.9 Hz), 7.66-7.60
(m, 2H), 7.41-
7.34 (m, 3H), 5.87 (br t, 1H, J=6.8 Hz), 2.37 (s, 3H), 1.05 (s, 9H);
Anal. calcd for CzzHzaNaOs: C, 67.33; H, 6.16; N, 14.28. Found: C, 66.98; H,
6.17; N, 14.10.
Example 7
N-(1-~~3,4-dioxo-2-(3-pyridinylamino -1-cyclobuten-1-yl]amino-2,2-
dimethylpropyl)-3-
fluorobenzamide
Exam 1p a 7A
N-( 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl)-3-fluorobenzamide
A suspension of 3-fluorobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic
acid was processed as described in Example 1 C to provide the title compound.
MS (DCI/NH3) m/z 327 (M+H)+.
Example 7B
N-(~,~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ) -2,2-
dimethylprop~)-3-
fluorobenzamide
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A suspension of the product from Example 1B, the product from Example 7A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 231-232 °C;
MS (DCI/NH3) m/z 397 (M+H)+;
'H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.75 (d, 1H, J=8 Hz), 8.59 (d, 1H, J=2 Hz),
8.26 (dd, 1H,
J=5, 1 Hz), 8.04 (br s, 1H), 7.94 (ddd, 1H, J=8, 3, 1 Hz), 7.71 (dt, 1H, J=8,
1 Hz), 7.66 (ddd,
1H, J=10, 3, 2 Hz), 7.55 (td, 1H, J=10, 6 Hz), 7.44-7.37 (m, 2H), 5.88 (t, 1H,
J=8 Hz), 1.07 (s,
9H);
Anal. calcd for CZ~HZ~FN403~O.SHzO: C, 62.21; H, 5.47; N, 13.82. Found: C,
62.12; H, 5.52;
N, 14.07.
Example 8
N-(1- f f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino]-2,2-
dimethy_lpropyl)-3-
iodobenzamide
Example 8A
N-( 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl)-3-iodobenzamide
A suspension of 3-iodobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic
acid was processed as described in Example 1C to provide the title compound.
MS (DCI/NH3) m/z 435 (M+H)+.
Example 8B
N-(~j3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1-yl]amino-2,2-dimeth~propYl)-3-
iodobenzamide
A suspension of the product from Example 1B, the product from Example 8A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 234-236 °C;
MS (DCI/NH3) m/z 505 (M+H)+;
1H NMR (DMSO-db) 8 10.03 (br s, 1H), 8.77 (br d, 1H, J=7.0 Hz), 8.69 (d, 1H,
J=2.4 Hz),
8.3 3 (dd, 1 H, J=4. 8, 1.4 Hz), 8.15 (t, 1 H, J=1.4 Hz), 8.10 (br s, 1 H),
8.06 (ddd, 1 H, J=8. S, 2.7,
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1.4 Hz), 7.93 (br d, 1H, J=7.4 Hz), 7.83 (br d, 1H, J=7.9 Hz), 7.56 (dd, 1H,
J=8.5, 5.2 Hz),
7.80 (t, 1 H, J=7.8 Hz), 5.85 (br t, 1 H, J=6.9 Hz), 1.09 (s, 9H);
Anal. calcd for CZ~HZ1IN4O3: C, 50.01; H, 4.20; N, 11.11. Found: C, 49.56; H,
4.03; N,
10.86.
Example 9
N-(1-f f3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino-2,2-
dimeth~propyl)-3 4-
dimethylbenzamide
A mixture of 1H-benzotriazole polystyrene (purchased from Novabiochem, 1.33
mmol/g, 500 mg, 0.665 mmol), pivalaldehyde (580 mg, 6.70 mmol), 3,4-
dimethylbenzamide
(1.00 g, 6.70 mmol) and p-toluenesulfonic acid (50 mg, 0.30 mmol) in anhydrous
THF (3 mL)
and 2-methoxyethanol (3 mL) was heated at 65 °C for 24 hours. The resin
was filtered to
remove solvent and washed sequentially with DMF (3 x 0.5 mL), methanol (0.5
mL), DMF (3
x 0.5 mL), CHZCIz (3 x 0.5 mL), diethyl ether (2 x 0.5 mL) and dried.
The resin (126 mg, 0.133 mmol) was stirred with the product from Example 1B
(30
mg, 0.66 mmol) and cesium carbonate (100 mg, 0.310 mmol) in anhydrous
dimethylacetamide
(2 mL) for 7 days at 23 °C. The solution was filtered and the filtrate
concentrated under
reduced pressure. The residue was purified by preparative reverse-phase HPLC
(elution with
aqueous acetonitrile + 0.5% TFA) to provide 7 mg (13%) of the title compound.
MS (DCI/NH3) m/z 407 (M+H)+;
1H NMR (DMSO-d6) 8 13.19 (br s, 1 H), 11.67 (s, 1 H), 8.63 (br d, 1H, J=7.0
Hz), 8.55 (d,
1H, J=2.0 Hz), 8.13 (dd, 1H, J=8.8, 2.0 Hz), 7.98 (d, 1 H, J=9.2 Hz), 7.87 (br
d, 1H, J=0.8
Hz), 7.49-7.30 (m, 3H), 5.87 (br t, 1H, J=6.8 Hz), 2.34 (s, 6H), 1.06 (s, 9H).
Example 10
N-(1-f[3,4-dioxo-2-(3-pyridinylamino -1-cyclobuten-1-yl]amino-2,2-
dimethylpro~yl)-2,3-
dimethoxybenzamide
A suspension of resin-bound benzotriazole was treated with 2,3-
dimethoxybenzamide,
pivaldehyde, and p-toluenesulfonic acid and was then processed with the
product from
Example 1B and Cs2C03 as described in Example 9 to provide the title compound.
MS (ESI) m/z 439 (M+H)+;
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'H NMR (DMSO-d6) b 9.94 (s, 1H), 8.26 (d, 1H, J=8.5 Hz), 7.33-7.15 (m, SH),
7.08-7.03 (m,
2H), 6.23 (s, 1H), 5.73 (t, 1H, J=8.2 Hz), 3.79 (s, 6H), 1.08 (s, 9H).
Example 11
N-(1- f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~lamino)-2 2-
dimethylpropyl)-
1-naphthamide
A suspension of resin-bound benzotriazole was treated with 1-naphthamide,
pivaldehyde, and p-toluenesulfonic acid and was then processed with the
product from
Example 1B and CsZC03 as described in Example 9 to provide the title compound.
MS (ESI) m/z 429 (M+H)+;
1H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.75 (d, 1H, J=8 Hz), 8.59 (d, 1H, J=2 Hz),
8.31-8.17 (m,
3H), 8.26 (d, 1H, J=5Hz), 8.06 (br s, 1H), 7.94 (dd, 1H, J=8, 1 Hz), 7.74 (br
d, 1H, J=8 Hz),
7.71 (dt, 1H, J=8, 1 Hz), 7.66 (ddd, 1H, J=10, 3, 2 Hz), 7.42-7.34 (m, 1H),
7.35 (dd, 1H, J=8,
Hz), 5.88 (t, 1H, J=8 Hz), 1.07 (s, 9H).
Example 12
3,5-dichloro-N-(1-f~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino -
2,2-
dimethylpropyl)benzamide
Example 12A
N-( 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl)-3,5-dichlorobenzamide
A suspension of 3,5-dichlorobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic acid was processed as described in Example 1 C to provide the
title compound.
MS (DCI/NH3) m/z 377 (M+H)+.
Example 12B
3,5-dichloro-N-(1-{[3,4-dioxo-2-(3-p rr~ylamino)-1-cyclobuten-1-~lamino)-2,2-
dimeth~propyl)benzamide
A suspension of the product from Example 1B, the product from Example 12A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 260-262 °C;
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MS (ESI+) m/z 447 (M+H)+;
'H NMR (DMSO-d6) 8 9.88 (br s, 1H), 8.86 (d, 1H, J=7.8 Hz), 8.57 (d, 1H, J=2.7
Hz), 8.25
(dd, 1H, J=4.7, 1.3 Hz), 8.02 (br s, 1H), 7.86 (br d, 1H, J=8.4 Hz), 7.67 (s,
3H), 7.39 (dd, 1H,
J=8.1, 4.4 Hz), 5.84 (t, 1H, J=8.3 Hz), 1.06 (s, 9H);
Anal. calcd for CZ,HZOC12N4O3: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.16;
H, 4.49; N,
12.34.
Example 13
N-(1-([3,4-dioxo-2-(3-pyridinylamino -1-cyclobuten-1-yllamino~-2,2-
dimethylpro~yl)-3 5-
dimethoxybenzamide
Example 13A
N-( 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl)-3,5-
dimethoxybenzamide
A suspension of 3,5-dimethoxybenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic acid was processed as described in Example 1 C to provide the
title compound.
MS (ESI+) m/z 369 (M+H)+.
Example 13B
N-(~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino) -2,2-
dimeth~propyl)-3, 5-
dimethoxybenzamide
A suspension of the product from Example 1B, the product from Example 13A, and
KZC03 was processed as described in Example 1D to provide the title compound.
MS (ESI+) m/z 439 (M+H)+;
'H NMR (DMSO-d6) 8 10.82 (br s, 1H), 8.80 (d, 1H, J=2.4 Hz), 8.62 (d, 1H,
J=7.8 Hz), 8.56
(d, 1 H, J=7.9 Hz), 8.3 5 (d, 1 H, J=5 .1 Hz), 8.28 (br d, 1 H, J=8. 8 Hz),
7.66 (dd, 1 H, J=8.5, 5 .1
Hz), 6.92 (d, 2H, J=2.4 Hz), 6.67 (t, 1H, J=2.4 Hz), 5.82 (t, 1H, J=8.3 Hz),
3.82 (s, 6H), 1.07
(s, 9H);
Anal. calcd for C23H26N4O5: C, 63.00; H, 5.98; N, 12.78. Found: C, 62.76; H,
6.11; N, 12.98.
Example 14
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(-) N- 1~[3,4-dioxo-2-(3-~yridinylamino)-1-cyclobuten-1-yl]amino)-2,2-
dimethy~ropyl)-
3,5-dimethoxybenzamide
The product from Example 13B was chromatographed over a Daicel Chiral
Technologies Chiralcel AS chiral column (2.0 cmx25 cm) eluting with 7%
ethanol/hexanes
(flow rate=10 mL/minute) to provide of the title compound as the levorotatory
enantiomer.
[a]DZ3 = -14° (c 0.10, DMSO);
MS (ESI+) m/z 439 (M+H)+;
'H NMR (DMSO-d6) 8 10.82 (br s, 1H), 8.80 (d, 1H, J=2.4 Hz), 8.62 (d, 1H,
J=7.8 Hz), 8.56
(d, 1H, J=7.9 Hz), 8.35 (d, 1H, J=5.1 Hz), 8.28 (br d, 1H, J=8.8 Hz), 7.66
(dd, 1H, J=8.5, 5.1
Hz), 6.92 (d, 2H, J=2.4 Hz), 6.67 (t, 1 H, J=2.4 Hz), 5.82 (t, 1 H, J=8.3 Hz),
3.82 (s, 6H), 1.07
(s, 9H);
Example 15
(+~( 1 ~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino ) -2,2-
dimethylpropyl~
3,5-dimethoxybenzamide
The product from Example 13B was chromatographed over a Daicel Chiral
Technologies Chiralcel AS chiral column (2.0 cmx25 cm) eluting with 7%
ethanol/hexanes
(flow rate=10 mL/minute) to provide of the title compound as the
dextrorotatory enantiomer.
[a]p 3 = +16° (c 0.11, DMSO);
MS (ESI+) m/z 439 (M+H)+;
' H NMR (DMS O-d6) 8 10. 82 (br s, 1 H), 8 . 80 (d, 1 H, J=2.4 Hz), 8 . 62 (d,
1 H, J=7. 8 Hz), 8. S 6
(d, 1H, J=7.9 Hz), 8.35 (d, 1H, J=5.1 Hz), 8.28 (br d, 1H, J=8.8 Hz), 7.66
(dd, 1H, J=8.5, 5.1
Hz), 6.92 (d, 2H, J=2.4 Hz), 6.67 (t, 1 H, J=2.4 Hz), 5.82 (t, 1 H, J=8.3 Hz),
3.82 (s, 6H), 1.07
(s, 9H);
Example 16
N-(-1- f f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl~amino~-2,2-
dimethylpropyl)-3,5-
difluorobenzamide
Example 16A
N-(~ 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl)-3, 5-difluorobenzamide
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A suspension of 3,5-difluorobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic acid was processed as described in Example 1C to provide the
title compound.
MS (ESI+) m/z 345 (M+H)+.
Example 16B
N-(-1-~f3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino)-2 2-
dimeth~propyl)-3 S-
difluorobenzamide
A suspension of the product from Example 1B, the product from Example 16A, and
KZC03 was processed as described in Example 1D to provide the title compound.
MS (ESI+) m/z 415 (M+H)+;
1H NMR (DMSO-d6) 8 9.85 (br s, 1H), 8.76 (br d, 1H, J=8.2 Hz), 8.55 (d, 1H,
J=2.7 Hz), 8.23
(d, 1 H, J=4.5 Hz), 8.05-7.96 (m, 1 H), 7.91 (dd, 1 H, J=7.8, 1.0 Hz), 7. S 9-
7.42 (m, 3H), 7.3 8
(dd, 1H, J=8.5, 4.7 Hz), 5.83 (t, 1H, J=8.3 Hz), 1.06 (s, 9H);
Example 17
4-chloro-N-(-1-~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino 1-
2,2-dimethyl-4-
pentenyl)benzamide
Example 17A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-4-pentenyl]-4-
chlorobenzamide
A suspension of 4-chlorobenzamide, 2,2-dimethyl-4-pentenal, benzotriazole, and
p-
toluenesulfonic acid was processed as in Example 1C to provide the desired
compound.
MS (ESI+) m/z 369 (M+H)+.
Example 17B
4-chloro-N-(-1- ( [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~] amino} -
2,2-dimethyl-4-
pentenyl~benzamide
A suspension of the product from Example 1B, the product from Example 17A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 242-243 °C;
MS (DCI/NH3) m/z 439 (M+H)+;
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1H NMR (DMSO-db) b 9.87 (s, 1H), 8.74 (d, 1H, J= 6 Hz), 8.56 (d, 1H, J= 3 Hz),
8.25 (dd,
1H, J= 5, 1 Hz), 8.03 (br s, 1H), 7.93 (dd, 1H, J= 8, 1 Hz), 7.87 (d, 2H, J= 8
Hz), 7.57 (d, 2H,
J= 8 Hz), 7.38 (dd, 1H, J= 8, 5 Hz), 5.93-5.83 (m, 2H), 5.11-5.05 (m, 2H),
2.22 (dd, 1H, J= 14,
8 Hz), 2.12 (dd, 1H, J= 14, 8 Hz), 1.02 (s, 3H), 1.01 (s, 3H);
Anal. calcd for C23H23C1N4O3: C, 62.94; H, 5.28; N, 12.77. Found: C, 62.85; H,
5.20; N,
12.87.
Example 18
4-chloro-N-(-1-~[3,4-dioxo-2-(3-p r~idi~nylamino)-1-cyclobuten-1-yl]amino-2 2-
dimethyl-3-
phenylpropyl)benzamide
Example 18A
2,2-dimethyl-3-phen~propanal
To a solution of oxalyl chloride (10.1 g, 79.4 mmol) in methylene chloride (70
mL) at
-78 °C was added dimethylsufoxide (10.0 mL, 139 mmol). The solution was
stirred at-78 °C
for 10 minutes then a solution of 2,2-dimethyl-3-phenylpropanol (6.52 g, 39.7
mmol) in
methylene chloride (15 mL) was added. After stirring the reaction at -78
°C for 30 minutes,
triethylamine (20.1 g, 198 mmol) was added and the reaction mixture was
stirred for 10
minutes, then at 0 °C for 5 minutes. The reaction mixture was quenched
with saturated
aqueous ammonium chloride (20 mL) and the aqueous layer was extracted with
diethyl ether
(2 x 50 mL). The organic portions were individually washed with brine (15 mL),
dried over
anhydrous sodium sulfate, and concentrated under reduced pressure. The residue
was
redissolved in diethyl ether and the resulting precipitate was filtered
through a pad of Celite.
The filtrate was concentrated under reduced pressure to provide the title
compound (6.89 g) as
an oil.
Example 18B
N-[ 1-yl H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-3-phenylpropyl]-4-
chlorobenzamide
A suspension of p-chlorobenzamide (3.02 g, 20.0 mmol), the product from
Example
18A (3.24 g, 20.0 mmol), and benzotriazole (2.38 g, 20.0 mmol) in benzene (75
mL) was
treated with p-toluenesulfonic acid (190 mg, 1.00 mmol). The solution was
heated at reflux
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under Dean-Stark conditions for 10 hours, then cooled gradually to ambient
temperature. The
solvent was removed under vacuum and the residue was purified by flash
chromatography
(elution with 15% EtOAc/hexanes) to provide the title compound (3.63 g) as a
white solid.
MS (ESI) m/z 419 (M+H)+.
Example 18C
4-chloro-N-(-1- ~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino 1-
2,2-dimethyl-3-
phenylpro~yl)benzamide
A suspension of the product from Example 1B, the product from Example 18B, and
K2C03 was processed as described in Example 1D to provide the title compound.
mp 223-224 °C;
MS (ESI+) m/z 489 (M+H)+;
'H NMR (DMSO-d6) b 9.90 (br s, 1H), 8.84 (br s, 1H), 8.59 (d, 1H, J=3 Hz),
8.26 (dd, 1H,
J=5, 2 Hz), 8.14 (br s, 1H), 7.96-7.92 (m, 1H), 7.91 (d, 2H, J=8 Hz), 7.76 (d,
2H, J=8 Hz),
7.39 (dd, 1H, J=8, 5 Hz), 7.32-7.20 (m, SH), 5.95 (br s, 1H), 2.74 (ABq, 2H,
JAB=13 Hz,
4vAB=32 Hz), 0.97 (s, 3H), 0.95 (s, 3H);
Anal. calcd for C27H25C1N4O3'O.SHZO: C, 65.12; H, 5.26; N, 11.25. Found: C,
65.02; H, 5.39;
N, 11.36.
Example 19
4-chloro-N-(4-cyano-1- [3,4-dioxo-2-(3-per'~dinylamino)-1-cyclobuten-1-
yllamino)-2,2-
diethylbutyl)benzamide
Example 19A
4-ethyl-4-formylhexanenitrile
2,2-Diethyl-4-cyanobutanol, oxalyl chloride and dimethylsulfoxide were
processed as
described in Example 18A to provide the title compound.
Example 19B
N-f 1-(1H-1,2,3-benzotriazol-1-yl -2,2-diethyl-4-cyanobutyl]-4-chlorobenzamide
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The product from Example 19A, 4-chlorobenzamide, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1 C to provide the
title
compound.
MS (ESI) m/z 410(M+H)+.
Example 19C
4-chloro-N-(4-cyano-1-(~-3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
yllamino~-2 2-
diethylbutyl)benzamide
A suspension of the product from Example 1B, the product from Example 19B, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 242-243 °C;
MS (ESI+) m/z 480 (M+H)+;
~H NMR (DMSO-d6) 8 10.50 (br s, 1H), 9.04 (br s, 1H), 8.82-8.61 (m, 2H), 8.24
(d, 1H, J=4
Hz), 8.00-7.91 (m, 1H), 7.89 (d, 2H, J=8 Hz), 7.57 (d, 2H, J=8 Hz), 7.32 (dd,
1H, J=8, 5 Hz),
5.47 (br s, 1H), 2.90-2.51 (m, 2H), 1.85 (br s, 1H), 1.60 (br s, 1H), 1.48-
1.25 (m, 4H), 0.85 (t,
3H, J=8 Hz), 0.78 (t, 3H, J=8 Hz);
Anal. calcd for CZSHz6C1N503~1/3H20: C, 61.79; H, 5.53; N, 14.41. Found: C,
61.90; H, 5.34;
N, 14.16.
Example 20
X2,2-bis[(all~y)methyl]-1-f [3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1-
y1] amino ) butyl)-4-chlorobenzamide
Example 20A
2,2-bis[(allyloxy)meth~lbutanal
2,2-Bis(allyloxymethyl)-1-butanol, oxalyl chloride and dimethylsulfoxide were
processed as described in Example 18A to provide the title compound.
Example 20B
N-f2,2-bis[(allyloxy)methyll-1-(1H-1,2,3-benzotriazol-1-yl)butyll-4-
chlorobenzamide
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The product from Example 20A, 4-chlorobenzamide, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1 C to provide the
title
compound.
MS (ESI) m/z 469 (M+H)+.
Example 20C
N-(2,2-bisf (all~y)methyl]-1- f j3,4-dioxo-2-(3-~yridinylamino)-1-cyclobuten-1-
yll amino ~ butt)-4-chlorobenzamide
A suspension of the product from Example 1B, the product from Example 20B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 176-177 °C;
MS (ESI+) m/z 539 (M+H)+;
1 H NMR (DMSO-db) 8 9.79 (br s, 1 H), 8.69 (br s, 1 H), 8.56 (d, 1 H, J=3 Hz),
8.25 (dd, 1 H,
J=5, 1 Hz), 8.03 (br s, 1H), 7.90 (ddd, 1H, J=8, 2, 1 Hz), 7.78 (d, 2H, J=8
Hz), 7.58 (d, 2H,
J=8 Hz), 7.38 (dd, 1H, J=8, 5 Hz), 6.12 (br s, 1H), 5.95-5.84 (m, 2H), 5.31-
5.23 (m, 2H), 5.19-
5.14 (m, 2H), 4.00-3.94 (m, 4H), 3.56 (ABq, 2H, JAB=10 Hz, OvAB=43 Hz), 3.49-
3.45 (m, 2H),
1.60-1.49 (m, 2H), 0.88 (t, 3H, J=8 Hz);
Anal. calcd for CZ8H31C1N4O5: C, 62.39; H, 5.80; N, 10.39. Found: C, 62.33; H,
5.75; N,
10.39.
Example 21
4-chloro-N-(~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yll amino ~ -2-
eth 1~ ut~)benzamide
Example 21A
N-[ 1-(1H-1,2,3-benzotriazol-1-~)-2-ethylbutyl]-4-chlorobenzamide
A suspension of 4-chlorobenzamide, 2-ethylbutanal, benzotriazole, and p-
toluenesulfonic acid was processed as in Example 1 C to provide the title
compound.
MS (ESI+) m/z 357 (M+H)+.
Example 21B
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4-chloro-N-( 1- { f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yll amino } -
~-
ethylbutyl)benzamide
A suspension of the product from Example 1B, the product from Example 21A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 232-233 °C;
MS (DCI/NH3) m/z 427 (M+H)+;
1 H NMR (DMSO-d6) ~ 9.92 (br s, 1 H), 9.11 (br s, 1 H), 8.57 (d, 1 H, J=2 Hz),
8.24 (dd, 1 H,
J=5, 2 Hz), 8.20 (br s, 1H), 7.95-7.93 (m, 1H) 7.90 (d, 2H, J=8 Hz), 7.58 (d,
2H, J=8 Hz), 7.37
(dd, 1H, J=8, 5 Hz), 5.74 (br s, 1H), 1.99 (br s, 1H), 1.58-1.35 (m, 4H), 0.89
(q, 6H, J=7 Hz);
Anal. calcd for CZZH2sC1N4O3: C, 61.90; H, 5.43; N, 13.12. Found: C, 61.60; H,
5.30; N,
13.30.
Example 22
4-chloro-N-(2-cyclohexyl-1-{[3,4-dioxo-2-(3-p idinylamino)-1-cyclobuten-1-
yllaminol-2-
methylpropyl)benzamide
Example 22A
2-cyclohexyl-2-methylpropanal
2-Cyclohexyl-2-methyl-1-propanol, oxalyl chloride and dimethylsulfoxide were
processed as described in Example 18A to provide the title compound.
Example 22B
N-[~1H-1,2,3-benzotriazol-1-yl -~yclohexyl-2-methylpropyll-4-chlorobenzamide
The product from Example 22A, 4-chlorobenzamide, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1 C to provide the
title
compound.
MS (ESI) m/z 383 (M+H)+.
Example 22C
4-chloro-N-(2-c~clohexyl-1-f [3,4-dioxo-2-(3-p ry idinylamino -1-cyclobuten-1-
yl]aminol-2-
methylpro~yl~benzamide
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A suspension of the product from Example 1B, the product from Example 22B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 275-276 °C;
MS (ESI+) m/z 326 (M-C$HSC1N (amide))+;
1H NMR (DMSO-d6) 8 9.82 (br s, 1H), 8.61 (br s, 1H), 8.57 (d, 1H, J=3 Hz),
8.24 (dd, 1H,
J=5, 1 Hz), 7.95 (s, 1H), 7.94 (ddd, 1H, J=8, 3, 1 Hz), 7.85 (d, 2H, J=8 Hz),
7.57 (d, 2H, J=8
Hz), 7.38 (dd, 1H, J=8, 5 Hz), 6.13 (br s, 1H), 1.84-1.60 (m, 6H), 1.38 (t,
1H, J=12 Hz), 1.19-
1.00 (m, 4H), 0.99 (s, 3H), 0.92 (s, 3H);
Anal. calcd for C26H29C1N4O3: C, 64.92; H, 6.08; N, 11.65. Found: C, 64.56; H,
6.13; N,
11.54.
Example 23
N-(2-( 1-adamant)-1- f f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-y~
amino ~ethyl)-2-
chlorobenzamide
Example 23A
1-adamantylacetaldehyde
2-(1-Adamantyl)ethanol, oxalyl chloride and dimethylsulfoxide were processed
as
described in Example 18A to provide the title compound.
MS (DCI/NH3) m/z 179 (M+H)+.
Example 23B
N-[2-( 1-adamantyl)-1-( 1 H-1,2,3-benzotriazol-1-)ethyl]-4-chlorobenzamide
The product from Example 23A, 4-chlorobenzamide, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1 C to provide the
title
compound.
MS (ESn m/z 435 (M+H)+.
Example 23C
N-(2-( 1-adamantyl)-1- ( [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yll
amino ) ethyl)-2-
chlorobenzamide
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A suspension of the product from Example 1B, the product from Example 23B, and
KZC03 were processed as described in Example 1D to provide the title compound.
mp 224-225 °C;
MS (ESI+) m/z 505 (M+H)+;
'H NMR (DMSO-d6) 8 9.91 (br s, 1H), 9.16 (br s, 1H), 8.57 (d, 1H, J=3 Hz),
8.34 (br s, 1H),
8.23 (dd, 1H, J=S, 1 Hz), 7.94-7.90 (m, 1H), 7.90 (d, 2H, J=8 Hz), 7.58 (d,
2H, J=8 Hz), 7.37
(dd, 1H, J=8, 5 Hz), 5.96 (m 1H), 1.92 (br s, 1H), 1.73-1.57 (m, 14H);
Anal. calcd for Cz$H29C1N403~2/3Hz0: C, 65.05; H, 5.91; N, 10.84. Found: C,
64.94; H, 5.84;
N, 11.08.
Example 24
4-chloro-N-(2,2-dichloro-1- f [3,4-dioxo-2-(3-pyridinylamino -1-cyclobuten-1-
y1] amino } -propyl)benzamide
Example 24A
2,2-dichloropropionaldehyde
Chlorine gas was bubbled through dimethylformamide (14.7 g, 0.202 mmol) for 5
minutes. The solution was heated to 45-55 °C and a solution of
propionaldehyde (11.7, 0.202
mmol) in dimethylformamide (29.5 g, 0.404 mmol) was added slowly, maintaining
the
reaction temperature at 45-55 °C (a cooling bath was necessary to
control the temperature).
During the addition, C12 was bubbled through the reaction to maintain a yellow
color. After
the addition, the reaction mixture was heated at 45-55 °C for 30
minutes. The solution was
cooled to 0 °C and diethyl ether (100 mL) was added followed by cold
water (100 mL). The
organic portion was separated and washed with aqueous sodium bicarbonate (20
mL), brine
(20 mL), dried (sodium sulfate), and concentrated under reduced pressure to
provide 21.1 g of
the title compound as an oil.
Example 24B
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dichloroprop~]-4-chlorobenzamide
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4-Chlorobenzamide, the product from Example 24A, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1 C to provide the
title
compound.
MS (ESI) m/z 381 (M-H)~.
Example 24C
4-chloro-N-(2,2-dichloro-1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
yl]aminol propYl)benzamide
A suspension of the product from Example 1B, the product from Example 24B, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 201-202 °C;
MS (ESI+) m/z 453 (M+H)+;
1 H NMR (DMSO-d6) 8 10.24 (br s, 1 H), 9.44 (br d, 1 H, J=8.4 Hz); 8.59 (d, 1
H, J=2.4 Hz),
8.48 (d, 1 H, J=8.2 Hz), 8.28 (dd, 1 H, J=5.8, 1.1 Hz), 7.90-7.78 (m, 1 H),
7.81 (d, 2H, J=8.8
Hz), 7.61 (d, 2H, J=8.7 Hz), 7.41 (dd, 1H, J=8.6, 4.8 Hz), 6.66 (t, 1H, J=8.5
Hz), 2.22 (s, 3H);
Anal. calcd forC,9H15C13N4O3: C, 50.30; H, 3.33; N, 12.35. Found: C, 50.55; H,
3.52; N,
12.29.
Example 25
3-chloro-N-(2,2-dichloro-1- ( [3,4-dioxo-2-(3-pvrridinylamino)-1-cyclobuten-1-
~lamino~=prop~rl)benzamide
Example 25A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dichloropropyll-3-chlorobenzamide
3-Chlorobenzamide, the product from Example 24A, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1 C to provide the
title
compound.
MS (ESI) m/z 381 (M-H)-.
Example 25B
3-chloro-N-(2,2-dichloro-1- (~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
~lamino)-prop~)benzamide
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A suspension of the product from Example 1B, the product from Example 25A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 202-204 °C;
MS (ESI+) m/z 453 (M+H)+;
'H NMR (DMSO-d6) 8 10.23 (br s, 1H), 9.49 (br d, 1H, J=8.5 Hz); 8.59 (d, 1H,
J=2.7 Hz),
8.47 (d, 1 H, J=8.6 Hz), 8.29 (dd, 1 H, J=5.7, 0.9 Hz), 7.94 (br s, 1 H), 7.91
(br s, 1 H), 7.83 (d,
1 H, J=7. 8 Hz), 7.69 (br d, 1 H, J=8 . 5 Hz), 7. 5 7 (t, 1 H, J=8.1 Hz), 7.41
(dd, 1 H, J=8.6, 4. 8 Hz),
6.66 (t, 1 H, J=8.5 Hz), 2.19 (s, 3H);
Anal. calcd forCl~Hl5C13N403: C, 50.30; H, 3.33; N, 12.35;. Found: C, 50.48;
H, 3.40; N,
12.51.
Example 26
3-chloro-N-(1-fj3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1
yl] amino ) -2,2,3,3,3-pentafluoroprop~~l)benzamide
Example 26A
pentafluoropropanal
Pentafluoropropanol, oxalyl chloride and dimethylsulfoxide were processed as
described in Example 18A to provide the title compound.
MS (DCI/NH3) m/z 149 (M+H)+.
Example 26B
N-[ 1-(1H-1,2,3-benzotriazol-1-yl)-2,2,3,3,3-pentafluoro~ropyll-4-
chlorobenzamide
3-Chlorobenzamide, the product from Example 26A, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1 C to provide the
title
compound.
MS (ESI-) m/z 403 (M-H)-.
Example 26C
3-chloro-N-( 1-~-[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
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yllamino)-2,2,3,3,3-pentafluoropropyl)benzamide
A suspension of the product from Example 1C, the product from Example 26B, and
Cs2C03 was processed as described in Example 1D to provide the title compound.
mp 212-213 °C;
MS (ESI+) m/z 475 (M+H)+;
1 H NMR (DMSO-d6) 8 10.18 (br s, 1 H), 9.93 (br d, 1 H, J=8.4 Hz); 8.62 (d, 1
H, J=8.7 Hz),
8.57 (d, 1H, J=2.7 Hz), 8.28 (dd, 1H, J=5.8, 0.9 Hz), 7.91 (br s, 1H), 7.87
(br s, 1H), 7.83 (br
d, 1H, J=7.9 Hz), 7.70 (br d, 1H, J=8.6 Hz), 7.58 (t, 1H, J=8.1 Hz), 7.39 (dd,
1H, J=8.6, 4.8
Hz), 7.01-6.87 (m, 1 H);
Anal. calcd forC,9HIZC1F5N403: C, 48.07; H, 2.55; N, 11.80. Found: C, 48.13;
H, 2.61; N,
11.94.
Example 27
4-chloro-N-( 1 ~ j3,4-dioxo-2-(3-fluoroanilino)-1-cyclobuten-1
yl] amino ) -2,2-dimethylprop~)benzamide
Example 27A
3-Ethoxy-4-(3-fluoro-phenylamino)-cyclobut-3-ene-1,2-dione
A solution of 3-fluoroaniline and 3,4-diethoxy-3-cyclobutene-1,2-dione in
ethanol was
processed as described in Example 1A to provide the title compound.
MS (DCI/NH3) m/z 236 (M+H)+.
Example 27B
3-Amino-4-(3-fluoro-phenylamino)-cyclobut-3-ene-1,2-dione
A solution of the product from Example 27A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 207 (M+H)+.
Example 27B
4-chloro-N-( 1- ~j3,4-dioxo-2-(3-fluoroanilino)-1-cyclobuten-1
yl]amino-2,2-dimethylpropyl)benzamide
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A suspension of the product from Example 2A, the product from Example 27B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 271-272 °C;
MS (ESI+) m/z 430 (M+H)+;
IH NMR (DMSO-d6) 8 9.88 (s, 1H), 8.71 (d, 1H, J=7.2 Hz), 8.01-7.99 (m, 1H),
7.87 (d, 2H,
J=8.6 Hz), 7.56 (d, 2H, J=8.2 Hz), 7.48 (dt, 1H, J=10.7, 2.2 Hz), 7.37 (dt,
1H, J=8.4, 6.7 Hz),
7.13 (dd, 1H, J=8.3, 2.7 Hz), 6.85 (td, 1H, J=8.3, 2.2 Hz), 5.85 (t, 1H, J=8.1
Hz), 1.05 (s, 9H);
Anal. calcd for C22HZ~C1FN3O3: C, 61.47; H, 4.92; N, 9.78. Found: C, 61.31; H,
4.57; N, 9.99.
Example 28
4-chloro-N-( 1- f [3,4-dioxo-2-(4-fluoroanilino)-1-cyclobuten-1-
y1] amino ) -2,2-dimethyl~ropyl)benzamide
Example 28A
3-Ethoxy-4-(4-fluoro-phenylamino)-cyclobut-3-ene-1,2-dione
A solution of 4-fluoroaniline and 3,4-diethoxy-3-cyclobutene-1,2-dione in
ethanol was
processed as described in Example 1A to provide the title compound.
MS (DCI/NH3) m/z 236 (M+H)+.
Example 28B
3-Amino-4-(3-fluoro-phenylamino)-cyclobut-3-ene-1,2-dione
A solution of the product from Example 28A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 207 (M+H)+.
Example 28C
4-chloro-N-(~ [3,4-dioxo-2-(4-fluoroanilino)-1-cyclobuten-1-
yl]amino-2,2-dimeth~propyl)benzamide
A suspension of the product from Example 2A, the product from Example 288, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 247-249 °C;
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MS (ESI+) m/z 430 (M+H)+;
'H NMR (DMSO-db) 8 9.78 (br s, 1H), 8.72 (br d, 1H, J=6.8 Hz), 8.01-7.92 (m,
1H), 7.86 (d,
2H, J=8.6 Hz), 7.55 (d, 2H, J=8.4 Hz), 7.47-7.39 (m, 1H), 7.42 (dd, 1H, J=8.1,
4.8 Hz), 7.18
(t, 2H, J=8.8 Hz), 5.82 (t, 1H, J=8.0 Hz), 1.04 (s, 9H);
Anal. calcd for CZZHZ,C1FN303: C, 61.47; H, 4.92; N, 9.78. Found: C, 61.35; H,
4.99; N, 9.42.
N N IV ~ CH
3
O
O O
Example 29
4-chloro-N-[ 1-(~2-[(2-chloro-3-pyridin~)amino]-3,4-dioxo-1-cyclobuten-1-yl~
amino)-2,2-
dimethylprop~]benzamide
Example 29A
~2-Chloro-p',~ridin-3-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione
A solution of 2-chloro-3-aminopyridine and 3,4-diethoxy-3-cyclobutene-1,2-
dione in
ethanol was processed as described in Example 1A to provide the title
compound.
MS (DCI/NH3) m/z 253 (M+H)+.
Example 29B
3-Amino-4-(2-chloro-pyridin-3-ylamino)-cyclobut-3-ene-1,2-dione
A solution of the product from Example 29A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 224 (M+H)+.
Example 29C
4-chloro-N-f 1-( f 2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-
yl}amino)-2,2-
dimethylpropyllbenzamide
A suspension of the product from Example 2A, the product from Example 29B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 259-261 °C;
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MS (DCI/NH3) m/z 464 (M+H)+;
' H NMR (DMSO-db) 8 9.46 (br s, 1 H), 8.70 (d, 1 H, J=8.1 Hz), 8.48 (d, 1 H,
J=9.1 Hz), 8.10
(dd, 1H, J=4.6, 1.7 Hz), 8.00 (d, 1H, J=7.8 Hz), 7.85 (d, 2H, J=8.5 Hz), 7.55
(d, 2H, J=8.5
Hz), 7.42 (dd, 1H, J=8.1, 4.8 Hz), 5.88 (br t, 1H, J=8.3 Hz), 1.04 (s, 9H);
Anal. calcd for Cz,HZpC12N4O3: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.13;
H, 4.49; N,
12.38.
Example 30
N-[~ ~2-[(S-bromo-6-fluoro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yll
amino)-2,2-
dimeth~propyl]-4-chlorobenzamide
Example 30A
3-(5-Bromo-6-fluoro-pyridin-3-ylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione
A solution of 2-fluoro-3-bromo-5-aminopyridine and 3,4-diethoxy-3-cyclobutene-
1,2-
dione in ethanol was processed as described in Example 1A to provide the title
compound.
MS (DCI/NH3) m/z 315 (M+H)+.
Exam 1p a 30B
3-Amino-4-(5-bromo-6-fluoro-pyridin-3-ylamino)-cyclobut-3-ene-1,2-dione
A solution of the product from Example 30A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 286 (M+H)+.
Example 30C
N-[ 1-(~2-[(5-bromo-6-fluoro-3-pyridinyl)aminol-3,4-dioxo-1-cyclobuten-1-yll
amino)-2,2-
dimethylpropyll-4-chlorobenzamide
A suspension of the product from Example 2A, the product from Example 30B, and
K2C03 was processed as described in Example 1D to provide the title compound.
mp 249-252 °C;
MS (ESI+) m/z 509 (M+H)+;
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'H NMR (DMSO-d6) 8 10.00 (br s, 1H), 8.72 (br d, 1H, J=7.0 Hz), 8.47 (br d,
1H, J=7.2 Hz),
8.10 (t, 1H, J=15 Hz), 8.04 (br s, 1H), 7.87 (d, 2H, J=8.5 Hz), 7.58 (d, 2H,
J=8.5 Hz), 5.85 (br
t, 1 H, J=6.6 Hz), 1.05 (s, 9H);
Anal. calcd for CzlHi9BrC1FN403: C, 49.48; H, 3.76; N, 10.99. Found: C, 49.14;
H, 3.83; N,
10.71.
Example 31
4-chloro-N-[1-( f 2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-
yl~amino)-2 2-
dimethyl-3-phenylpropyllbenzamide
A suspension of the product from Example 18B, the product from Example 29B,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 236-237 °C;
MS (DCI/NH3) m/z 523 (M+H)+;
'H NMR (DMSO-d6) 8 9.47 (br s, 1H), 8.71 (d, 1H, J=8.0 Hz), 8.48 (d, 1H, J=8.9
Hz), 8.10
(dd, 1H, J=4.7, 1.6 Hz), 8.02 (br d, 1H, J=8.3 Hz), 7.91-7.85 (m, 3H), 7.59-
7.48 (m, 2H), 7.42
(dd, 1H, J=7.8, 4.7 Hz), 7.32-7.16 (m, 4H), 5.88 (br t, 1H, J=8.3 Hz), 2.72
(ABq, 2H, JAB=12.2
Hz, wAB=28.5 Hz), 0.96 (s, 3H), 0.92 (s, 3H);
Anal. calcd for C27H24C1zN4O3: C, 61.96; H, 4.62; N, 10.70. Found: C, 61.55;
H, 4.66; N,
10.39.
Example 32
N-[1-( f 2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-}amino)-2,2-
dimethylpropyl]-3-methylbenzamide
A suspension of the product from Example 6A, the product from Example 29B, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 238-239 °C;
MS (ESI+) m/z 427 (M+H)+;
~ H NMR (DMSO-db) 8 9.47 (s, 1 H), 8.61 (d, 1 H, J=8 Hz), 8.52 (d, 1 H, J=9
Hz), 8.11 (dd,
1 H, J= 4, 2 Hz), 8.03 (d, 1 H, J=8 Hz), 7.67-7.61 (m, 2H), 7.44 (dd, 1 H,
J=8, 5 Hz), 7.39-
7.35 (m, 2H), 5.92 (t, 1H, J=8 Hz), 2.37 (s, 3H), 1.07 (s, 9H);
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Anal. calcd for C22H23C1N4O3'O.SH2O: C, 61.04; H, 5.51; N, 12.94. Found: C,
60.87; H, 5.51;
N, 12.90.
Example 33
4-chloro-N-(2,2-dimethyl-1- { [(3-pyridinylamino)sulfonyl]amino ~
propylbenzamide
Example 33A
tert-butyl 3-(3-pyridinyl)diazathiane-1-carboxylate 2,2-dioxide
tert-Butanol (2.0 mL, 21.1 mmol) was added to a solution of chlorosulfonyl-
isocyanate
(1.8 mL, 21.1 mmol) in CHZC12 (40 mL). The reaction mixture was stirred at
ambient
temperature for 0.5 hours and then treated with a solution of 3-aminopyridine
(2.00 g, 21.1
mmol) and triethylamine (4.4 mL, 31.6 mmol) in CHzCl2 (20 mL) via canula. The
reaction
mixture was stirred at ambient temperature for an additional 1.5 hours and
then filtered
through a 0.25 inch silica gel plug. The solvent was removed under reduced
pressure and the
residue was purified by flash chromatography on silica gel (elution with
EtOAc) to provide
1.17 g of the title compound as a white solid.
MS (ESI+) m/z 274 (M+H)+.
Exam 1p a 33B
~~yridinyl sulfamide
Trifluoroacetic acid (10 mL) was added to a solution of the product from
Example 33A
(1.17 g, 4.28 mmol) in CHZCI2 (40 mL). The reaction mixture was stirred at
ambient
temperature for 2 hours and then the solvent was removed under reduced
pressure. The crude
reaction mixture was diluted with EtOAc (25 mL) and washed with saturated
aqueous
NaHC03 (SO mL). The aqueous layer was extracted with EtOAc (25 mL) and the
organic
phases were combined, dried over NaZS04 and filtered. The filtrate was
concentrated under
reduced pressure and the residue was triturated from Et20/hexanes to provide
0.40 g of the
title compound as a white powder.
MS (DCI/NH3) m/z 174 (M+H)+.
CI
H H H
N,S,N N w
O O
N
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Exam 1p a 33C
4-chloro-N-(2 2-dimeth~f~3-R~idinylamino)sulfon'rllamino~propyl)benzamide
A suspension of the product from Example 33B , the product from Example 2A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 166-167 °C;
MS (ESI+) m/z 397 (M+H)+;
'H NMR (DMSO-db) 8 10.07 (s, 1H), 8.32 (d, 1H, J=2 Hz), 8.12, (d, 1H, J=9 Hz),
8.03 (dd,
1 H, J=5, 1 Hz), 7.62 (d, 1 H, J=9 Hz), 7.53 (d, 2H, J=9 Hz), 7.45 (ddd, 1 H,
J=8, 3, 2 Hz), 7.42
(d, 2H, J=8 Hz), 7.12 (dd, 1H, J=9, 5 Hz), 5.19 (t, 1H, J=9 Hz), 0.87 (s, 9H);
Anal. calcd for C17Hz1C1N403S: C, 51.45; H, 5.33; N, 14.12. Found: C, 51.44;
H, 5.56; N,
14.05.
Example 34
N-(2,2-dimethyl-1- f f (3-pyridinylamino)sulfonyllamino~propyl)-4-
iodobenzamide
A suspension of the product from Example 33B, the product from Example 3A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 177-178 °C;
MS (DCI/NH3) m/z 489 (M+H)+;
' H NMR (DMSO-d6) 8 10.06 (s, 1 H), 8.31 (d, 1 H, J=2 Hz), 8.10 (d, 1 H J=9
Hz), 8.03 (dd,
1H, J=5, 2 Hz), 7.74 (d, 2H, J=8 Hz), 7.60 (d, 1H, J=9 Hz), 7.46 (ddd, 1H,
J=8, 3, 2 Hz),
7.30 (d, 2H, J= 8 Hz), 7.13 (dd, 1H, J=9, 5 Hz), 5.18 (t, 1H, J=9 Hz), 0.86
(s, 9H);
Anal. calcd for Cl7HZlIN403S: C, 41.81; H, 4.33; N, 11.47. Found: C, 42.00; H,
4.37; N,
11.26.
Example 35
N'- (1-[(4-chlorobenzoyl amino]-2,2-dimeth~propyl -NZ-(3-
pyridinyl)ethanediamide
Example 35A
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ethyl oxo(3-pyridinylamino)acetate
To a solution 3-aminopyridine (3.00 g, 27.0 mmol) in methylene chloride ( 110
mL) at
23 °C was added triethylamine (7.53 mL mL, 54.0 mmol) and N,N-
dimethylaminopyridine
(330 mg, 2.70 mmol). The solution was cooled to 0 °C and
chloroethyloxalate 4.42 g, 32.4
mmol) was added in a dropwise fashion. The reaction mixture was stirred at 0
°C for 2 hours
and then quenched with water (30 mL) and partitioned. The organic portion was
washed with
10% sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate
and
concentrated under reduced pressure to provide 4.30 g of the title compound.
MS (ESI+) m/z 195 (M+H)+.
Example 35B
N~3-pyridin~l)ethanediamide
A solution of the product from Example 35A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (ESI-) m/z 164 (M-H)-.
Example 35C
N'- ~1-[(4-chlorobenzoyl)amino]-2,2-dimethylpropyl}-NZ-(3-p r~~)ethanediamide
A suspension of the product from Example 2A, the product from Example 35B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 168-170 °C;
MS (ESI+) m/z 389 (M+H)+; '
'H NMR (DMSO-db) 8 11.01 (s, 1H), 8.99 (d, 1H, J=2.3 Hz), 8.75 (d, 1H, J=9.2
Hz), 8.49 (d,
1H, J=8.8 Hz), 8.35 (dd, 1H, J=4.8, 1.4 Hz), 8.19 (br d, 1H, J=8.4 Hz), 7.88
(d, 2H, J=8.5 Hz),
7.60 (d, 2H, J=8.5 Hz), 7.41 (dd, 1 H, J=8.5, 4.8 Hz), 5.82 (t, 1 H, J=9.1
Hz), 0.94 (s, 9H);
Anal. calcd for C~9HZ~C1N403: C, 58.69; H, 5.44; N, 14.41. Found: C, 58.43; H,
5.41; N,
14.26.
Example 36
N-('1- ~[3,4-dioxo-2-(3-p~inylamino)-1-cyclobuten-1-yl] amino ~ -2,2-
dimethylpro_pyl)-3-
phenylpropanamide
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Example 36A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethKlpropyl]-3-pheny~ropanamide
A suspension of 3-phenyl-propionamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic acid was processed as described in Example 1 C to provide the
title compound.
MS (DCI/NH3) m/z 337 (M+H)+.
Example 36B
N-(1- f f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl)amino~-2,2-
dimeth~propyl)-3-
phenylp~ionamide
A suspension of the product from Example 1B, the product from Example 36A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 219-220 °C;
MS (ESI+) m/z 407 (M+H)+;
H NMR (DMSO-d6) 8 9.71 (s, 1 H), 8.57 (d, 1 H, J=3 Hz), 8.24 (dd, 1 H, J=S, 1
Hz), 8.17 (s,
1H), 7.95 (d, 1H, J=7 Hz), 7.89 (br s, 1H), 7.38 (dd, 1H, J=8, 5 Hz), 7.26-
7.13 (m, SH), 5.63
(br s, 1H), 2.83 (t, 2H, J=8 Hz), 2.61-2.43 (m, 2H), 0.94 (s, 9H),
Anal. calcd for Cz3Hz6Na03'0.2HZ0: C, 67.36; H, 6.49; N, 13.66. Found: C,
67.22; H, 6.44;
N, 13.95.
Example 37
N-[~~2-[(2-chloro-3-pyridine)amino]-3,4-dioxo-1-cyclobuten-1-~~amino -2,2-
dimethylpropyl)-3-(3-pyridinyl)propanamide
Example 37A
meth~3-pyridi~~propanoate
To a solution of 3-(3-pyridinyl)propanoic acid (2.50 g, 16.5 mmol) in CHZCIz
(110
mL) and MeOH (1 mL) was added DMAP (0.010 g, 0.082 mmol) and
diisopropylcarbodiimide (4.17 g, 33.1 mmol). The reaction was stirred for 2
hours at 23 °C
then saturated aqueous NaHC03 (100 mL) was added. The mixture was extracted
with
CHzCIz (100 mL) and the combined extracts were dried over NazS04, filtered,
and evaporated
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in vacuo. The residue was purified by flash chromatography on silica gel
(elution with 60%
EtOAc/hexanes) to provide 2.70 g (99%) of the desired product.
MS (DCI/NH3) m/z 166 (M+H)+.
Example 37B
3-(3-pyridinyl)propanamide
A solution of the product from Example 37A (2.70 g, 16.3 mmol) in NH3 (2.0 M
in
MeOH, 40 mL) was heated at 80 °C in a sealed vessel for 24 hours. The
mixture was allowed
to cool to 23 °C and the solvent was evaporated under reduced pressure.
The crude product
was recrystallized from EtOAc/hexanes to provide 1.71 g (69%) of the title
compound.
MS (DCI/NH3) m/z 151 (M+H)+.
Example 37C
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-3-(3-
pyridinyl)propanamide
A suspension of the product from Example 37B, pivaldehyde, benzotriazole, and
p-
toluenesulfonic acid was processed as described in Example 1 C to provide the
desired product.
MS (DCI/NH3) m/z 385 (M+H)+.
Example 37D
N-[1-( f 2-[(2-chloro-3-pyridinyl)amino]-3,4-dioxo-1-cyclobuten-1-yl)amino)-
2,2-
dimethylpropyl]-3-(3-pyridin~)propanamide
A suspension of the product from Example 29B (0.199 g, 0.889 mmol), the
product
from Example 37C (0.300 g, 0.889 mmol), and KZC03 (0.614 g, 4.45 mmol) in DMF
(3 mL)
was heated at 50 °C for 24 hours. The reaction mixture was allowed to
cool to 23 °C and then
applied to a silica gel column. Elution with 10% EtOH/EtOAc provided 14 mg
(4%) of the
title compound.
mp 179-180 °C;
MS (ESI+) m/z 442 (M+H)+;
~H NMR (DMSO-d6) b 9.31 (s, 1H), 8.44-8.38 (m, 3H), 8.18 (d, 1H, J=7 Hz), 8.10
(dd, 1H,
J=5, 1 Hz), 8.06 (d, 1H, J=8 Hz), 7.61 (d, 1H, J=8 Hz), 7.44 (dd, 1H, J=8, 5
Hz), 7.27 (dd, 1H,
J=8, 5 Hz), 5.67 (t, 1H, J=8 Hz), 2.85 (t, 2H, J=7 Hz), 2.65-2.46 (m, 2H),
0.93 (s, 9H);
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Anal. calcd for C22H24C1N503~0.8H20: C, 57.91; H, 5.65; N, 15.35. Found: C,
57.86; H, 5.51;
N, 15.18.
Example 38
N-(1- f f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-Xllamino~-2 2-
dimethylpro~yl)-3-
vinylbenzamide
Example 38A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-3-vinylbenzamide
The product from Example 8A (0.500 g, 1.15 mmol), tributyl(vinyl)tin 0.410 g,
1.27
mmol), triphenylarsine 0.035 g, 0.115 mmol), and
tris(dibenzylidineacetone)dipalladium(0)
(0.053 g, 0.058 mmol) were combined in anhydrous NMP (4 mL) and stirred at 23
°C for 18
hours. The reaction mixture was diluted with EtOAc (50 mL) and filtered
through a 0.25 inch
frit of Celite and the frit was washed with additional EtOAc (25 mL). The
filtrate was washed
with 100 mL brine and the brine back extracted with EtOAc (50 mL). The organic
phases
were combined, dried over Na2S04, filtered, and absorbed onto silica gel. The
crude material
was purified by flash chromatography on silica gel (elution with
EtOAc/CHzCIz/hexanes,
5:47.5:47.5) to provide 223 mg (58%) the title compound.
MS (DCI/NH3) m/z 335 (M+H)+.
Example 38B
N-( 1- ~ (3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-3-
vinylbenzamide
A suspension of the product from Example 1B, the product from Example 38A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 209-210 °C;
MS (ESI+) m/z 405 (M+H)+;
1 H NMR (DMSO-d6) b 9.89 (s, 1 H), 8.73 (d, 1 H, J=6 Hz), 8.59 (d, 1 H, J=2
Hz), 8.25 (dd, 1 H,
J=5, 1 Hz), 8.08 (br s, 1H), 7.94 (dd, 1H, J=1 Hz), 7.89 (s, 1H), 7.74 (d, 1H,
J=8 Hz), 7.67 (d,
1 H, J=8 Hz), 7.47 (t, 1 H, J=8 Hz), 7.39 (dd, 1 H, J=8, 5 Hz), 6.81 (dd, 1 H,
JAB=18 Hz, JAS=11
Hz), 5.92 (d, 1H, JAB=18 Hz), 5.87 (s, 1H), 5.36 (d, 1H, J=11 Hz), 1.07 (s,
9H);
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Anal. calcd for Cz3H24N403~0.1H20: C, 68.00; H, 6.00; N, 13.79. Found: C,
67.62; H, 5.67;
N, 13.88.
Example 39
N-(1-(~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino)-2 2-
dimeth~propyl)jl 1'
b~henyl]-3-carboxamide
Example 39A
N-f 1-(1H-1,2,3-benzotriazol-1-vl)-2,2-dimethvlnropvllf l,l'-binhenvll-3-
carboxamide
The product from Example 8A, trimethyl(phenyl)tin, triphenylarsine, and
tris(dibenzylidineacetone)dipalladium(0) were processed as described in
Example 38B to
provide the the title compound.
MS (DCI/NH3) m/z 385 (M+H)+.
Example 39B
N-( 1- f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino 1-2,2-
dimethylpropyl)[ 1 1'-
bi hen 1 -3-carboxamide
A suspension of the product from Example 1B, the product from Example 39A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 240-241 °C;
MS (ESI+) m/z 455 (M+H)+;
1H NMR (DMSO-d6) b 9.89 (s, 1H), 8.82 (d, 1H, J=7 Hz), 8.59 (d, 1H, J=3 Hz),
8.25 (dd, 1H,
J=5, 2 Hz), 8.10 (br s, 1H), 7.95 (ddd, 1H, J=8, 3, 1 Hz), 7.87-7.83 (m, 2H),
7.73 (dd, 2H, J=8,
1 Hz), 7.59 (t, 1H, J=8 Hz), 7.51 (t, 2H, J=7 Hz), 7.43-7.37 (m, 2H), 5.91 (br
s, 1H), 1.08 (s,
9H);
Anal. calcd for C27H26N4O3'O.15H20: C, 70.93; H, 5.80; N, 12.25. Found: C,
70.90; H, 5.66;
N, 12.25.
Example 40
3-acetyl-N-( 1- ~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -
2,2-
dimethylpropyl)benzamide
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Example 40A
3-acetyl-N-[1-(1H-1,2,3-benzotriazol-1-yl)-2 2-dimeth~propyllbenzamide
The product from Example 8A (0.500 g, 1.15 mmol), tributyl(1-ethoxyvinyl)tin
(0.459
g, 1.27 mmol), triphenylarsine (0.035 g, 0.115 mmol), and
tris(dibenzylidineacetone)dipalladium(0) (0.053 g, 0.058 mmol) were combined
in anhydrous
NMP (4 mL) and stirred at 23 °C for 18 hours. To this solution was
added 2 N HCl ( 10 mL)
and the reaction mixture was stirred for 30 minutes at 23 °C. The
mixture was extracted
EtOAc (2 x 25 mL) and the combined organic phases were dried (Na2S04),
filtered, and
absorbed onto silica gel. The crude material was purified by flash
chromatography on silica
gel (elution with 50% EtOAc/hexanes) to provide 207 mg (51 %) of the title
compound.
MS (ESI+) m/z 351 (M+H)+.
Example 40B
3-acetyl-N-(~[3,4-dioxo-2-(3-p rr~ylamino)-1-cyclobuten-1-~lamino~-2,2-
dimethylpropyl)benzamide
A suspension of the product from Example 1B, Example 40A, and KZC03 was
processed as described in Example 1D to provide the title compound.
mp 218-219 °C;
MS (ESI+) m/z 421 (M+H)+;
'H NMR (DMSO-d6) 8 10.28 (s, 1H), 8.89 (d, 1H, J=7 Hz), 8.62 (d, 1H, J=3 Hz),
8.35 (t, 1H,
J=2 Hz), 8.34 (br s, 1 H), 8.24 (dd, 1 H, J=5, 1 Hz), 8.11 (ddt, 2H, J=16, 8,
2 Hz), 7.96 (dd, 1 H,
J=8, 2 Hz), 7.65 (t, 1H, J=8 Hz), 7.38 (dd, 1H, J=8, 5 Hz), 5.90 (d, 1H, J=6
Hz), 2.64 (s, 3H),
1.08 (s, 9H);
Anal. calcd for C23HZaNaOa: C, 63.26; H, 5.95; N, 12.83. Found: C, 63.04; H,
5.62; N, 12.80.
Example 41
N~ 1- ~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino )-2,2-
dimeth~prop~)-2-
pyridinecarboxamide
Example 41A
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N-f 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimeth ly~propyl]-2-pyridinecarboxamide
A suspension of 2-pyridinecarboxamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic acid was processed as described in Example 1 C to provide the
desired product.
MS (DCI/NH3) m/z 310 (M+H)+.
Example 41B
~1~j3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~laminol-2,2-dimethylproR
1~)-2-
pyridinecarboxamide
A suspension of the product from Example 1B, the product from Example 41A, and
KzC03 was processed as described in Example 1D to provide the title compound.
MS (ESI+) m/z 380 (M+H)+;
'H NMR (DMSO-d~) 8 10.26 (s, 1H), 8.89 (d, 1H, J=8 Hz), 8.71 (d, 1H, J=3 Hz),
8.65 (d, 1H,
J=5 Hz), 8.37 (br s, 1H), 8.33 (d, 1H, J=5 Hz), 8.08 (dd, 1H, J=7, 1 Hz), 8.03-
7.97 (m, 2H),
7.64-7.58 (m, 2H), 5.88 (t, 1H, J=7 Hz), 1.06 (s, 9H).
Example 42
~~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~]amino ) -2,2-
dimeth~propyl)-4-
fluoro-3-(trifluoromethyl)benzamide
Example 42A
N-[~ 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~prop~]-4-fluoro-3-
(trifluoromethyl)benzamide
A suspension of 4-fluoro-3-(trifluoromethyl)benzamide, pivaldehyde,
benzotriazole,
and p-toluenesulfonic acid was processed as in Example 1 C to provide the
title compound.
MS (ESI+) m/z 395 (M+H)+.
Example 42B
N-( 1- J~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-4-
fluoro-3-(trifluoromethyl)benzamide
A suspension of the product from Example 1B, the product from Example 42A, and
KZC03 was processed as described in Example 1D to provide the title compound.
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MS (DCI/NH3) m/z 465 (M+H)+;
'H NMR (DMSO-db) 8 9.86 (s, 1H), 8.90 (d, 1H, J=7.8 Hz), 8.59 (d, 1H, J=2.7
Hz), 8.30-8.16
(m, 3H), 8.12-8.00 (m, 1H), 7.95 (ddd, 1H, J=8.4, 2.7, 1.4 Hz), 7.66 (t, 1H,
J=8.4 Hz), 7.39
(dd, 1 H, J=8.3, 4.6 Hz), 5.89 (t, 1 H, J=7.9 Hz), 1.67 (s, 9H).
Example 43
N-(~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ~ -2,2-
dimethylpro_pyl)-2-
phenylacetamide
Resin-bound benzotriazole, 2-phenylacetamide, pivaldehyde, p-toluenesulfonic
acid,
the product from Example 1B and CsZC03 were processed as described in Example
9 to
provide the title compound.
MS (ESI+) m/z 393 (M+H)+;
'H NMR (DMSO-db) 8 9.79 (s, 1H), 8.64 (s, 1H), 8.39 (br s, 1H), 8.29 (dd, 1H,
J=4.8, 1.5 Hz),
8.02 (br d, 1H, J=7.7 Hz), 7.98 (br s, 1H), 7.50 (dd, 1H, J=8.4, 4.8 Hz), 7.32-
7.24 (m, 4H),
7.23-7.19 (m, 1H), 5.61 (br s, 1H), 3.63-3.49 (m, 2H, Ph-CHZ, obscured), 0.98
(s, 9H).
Example 44
N-(1 ~f 3,4-dioxo-2-(3-pyridinylamino -1-cyclobuten-1-~]amino)-2,2-
dimeth~propyl)-3-
phenylprop-2-enamide
Resin-bound benzotriazole, 3-phenylacrylamide, pivaldehyde, p-toluenesulfonic
acid,
the product from Example 1B and CszC03 were processed as described in Example
9 to
provide the title compound.
MS (ESI+) m/z 405 (M+H)+;
' H NMR (DMSO-d6) 8 9.82 (s, 1 H), 8.67 (d, 1 H, J=2.6 Hz), 8.41 (br s, 1 H),
8.30 (dd, 1 H,
J=5.1, 1.1 Hz), 8.04 (ddd, 1H, J=8.4, 2.6, 1.1 Hz), 8.01 (br s, 1H), 7.60-7.55
(m, 2H), 7.55-
7.45 (m, 2H), 7.45-7.37 (m, 3H), 6.87 (d, 1H, J=15.7 Hz), 5.76 (br s, 1H),
1.04 (s, 9H).
Example 45
4-chloro-N-(2,2-dichloro-1-~~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
yl~amino~pentyl)benzamide
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Example 45A
N-f 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dichloro~entyl]-4-chlorobenzamide
A suspension of 4-chlorobenzamide, 2,2-dichloropentanal, benzotriazole, and p-
toluenesulfonic acid was processed as in Example 1C to provide the title
compound.
MS (ESI+) m/z 411 (M+H)+.
Example 45B
4-chloro-N-(2,2-dichloro-1-f~3,4-dioxo-2-(3pyridinvlamino -1-cyclobuten-1-
y1] amino ) pentyl)benzamide
A suspension of the product from Example 1B, the product from Example 45A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 258-259 °C;
MS (DCI/NH3) m/z 481 (M+H)+;
'H NMR (DMSO-d6) 8 10.21 (s, 1H), 9.37 (br d, 1H, J=8.0 Hz), 8.59-8.53 (m,
1H), 8.52-8.45
(m, 1H), 8.28 (br d, 1H, J=3.8 Hz), 7.93-7.88 (m, 3H), 7.63-7.58 (m, 2H), 7.41
(dd, 1H, J=8.2,
4.4 Hz), 6.69 (t, 1H, J=8.4 Hz), 2.32-2.23 (m, 2H), 1.77-1.68 (m, 2H), 0.97
(t, 3H, J=7.8 Hz);
Anal. calcd for C2,H,9C13N4O3: C, 52.35; H, 3.98; N, 11.63. Found: C, 52.45;
H, 3.84; N,
11.53.
Example 46
4-chloro-N-(~~[3,4-dioxo-2 ~4-pyridinylamino)-1-cyclobuten-1-yl]amino } -2,2-
dimethylpropyl)benzamide
Example 46A
3-ethoxy-4~4-pyridinylamino)-3-cyclobutene-1,2-dione
A solution of 4-aminopyridine and 3,4-diethoxy-3-cyclobutene-1,2-dione in
ethanol
was processed as described in Example 1A to provide the title compound.
MS (DCI/NH3) m/z 219 (M+H)+.
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Example 46B
3-amino-4-(4-~yridinylamino)-3-cyclobutene-1,2-dione
A solution of the product from Example 46A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 190 (M+H)+.
Example 46C
4-chloro-N-(~j3,4-dioxo-2-(4-pyridinylamino)-1-cyclobuten-1-yllaminor -2,2-
dimethylpropyl)benzamide
A suspension of the product from Example 46B, the product from Example 2A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 244-246 °C;
MS (ESI+) m/z 413 (M+H)+;
1 H NMR (DMSO-d6) 8 11.62 (br s, 1 H), 8.79 (d, 1 H, J=9.1 Hz), 8.72 (d, 1 H,
J=7.8 Hz), 8.60
(br d, 1 H, J=6.4 Hz), 7.97-7.79 (m, 4H), 7.5 5 (d, 1 H, J=8.4 Hz), 5 .87 (t,
1 H, J=8.1 Hz), 1.07
(s, 9H);
Anal. calcd for C2~HZ~C1N4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 60.95; H,
5.08; N,
13.51.
Example 47
4-chloro-N-( 1- f~ j3,4-dioxo-2-(2-pyridi~lamino)-1-cyclobuten-1-~l amino ) -
2,2-
dimethvlpropyl)benzamide
Example 47A
3-ethoxy-4-(2-p~rridinylamino)-3-cyclobutene-1,2-dione
A solution of 2-aminopyridine and 3,4-diethoxy-3-cyclobutene-1,2-dione in
ethanol
was processed as described in Example 1A to provide the title compound.
MS (DCI/NH3) m/z 219 (M+H)+.
Example 47B
3-amino-4-(2-pyridinylamino -~yclobutene-1,2-dione
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A solution of the product from Example 47A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 190 (M+H)+.
Example 47C
4-chloro-N-(1-1j3,4-dioxo-2-(2-pyridinylamino)-1-cyclobuten-1-yl~aminol-2 2-
dimeth~rlpropyl)benzamide
A suspension of the product from Example 47B, the product from Example 2A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 246-248 °C;
MS (ESI+) m/z 413 (M+H)+;
'H NMR (DMSO-db) b 10.95 (br s, 1H), 9.82 (d, 1H, J=9.8 Hz), 8.88 (d, 1H,
J=8.5 Hz), 8.31
(dd, 1H, J=5.1, 1.7 Hz), 7.86 (d, 2H, J=8.4 Hz), 7.85-7.77 (m, 2H), 7.57 (d,
1H, J=8.4 Hz),
7.23 (d, 1H, J=8.1 Hz), 7.08 (dd, 1H, J=6.8, S.1 Hz), 6.06 (t, 1H, J=8.1 Hz),
1.03 (s, 9H);
Anal. calcd for CZIHziC1N4O3: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.12; H,
5.24; N,
13.53.
Example 48
N-(~[3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1-~lamino -2,2-
dimeth~propyl)benzamide
Example 48A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~prop~]benzamide
A suspension of benzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic
acid
was processed as in Example 1 C to provide the title compound.
MS (ESI+) m/z 309 (M+H)+.
Example 48B
N-(1-ff3,4-dioxo-2-(3-pyridinylamino -~yclobuten-1-'il]amino~-2,2-
dimeth~propyl)benzamide
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A suspension of the product from Example 1B, the product from Example 48A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 246-247 °C;
MS (DCI/NH3) m/z 379 (M+H)+;
'H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.67 (br d, 1H, J=7.1 Hz), 8.57 (d, 1H, J=2.5
Hz), 8.23
(d, 1H, J=4.6 Hz), 8.04 (br s, 1H), 7.92 (br d, 1H, J=8.3 Hz), 7.83 (d, 2H,
J=7.4 Hz), 7.53 (t,
1H, J=7.2 Hz), 7.47 (t, 2H, J=7.2 Hz), 7.36 (dd, 1H, J=8.3, 4.6 Hz), 5.87 (br
s, 1H), 1.04 (s,
9H);
Anal. calcd for CZ1H22Na03~0.55 H20: C, 64.95; H, 6.00; N, 14.43. Found: C,
64.78; H, 5.69;
N, 14.14.
Example 49
(+) N- ~[3,4-dioxo-2-(3-p~ridinylamino)-1-cyclobuten-1-~]amino}-2,2-
dimethylproRyl)-
3,5-difluorobenzamide
The product from Example 16B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10%
ethanol/hexanes
(flow rate=10 mL/minute) to provide the title compound as the dextrorotatory
enantiomer.
[a]Da3 = +30 ° (c 0.013, DMSO);
MS (ESI+) m/z 415 (M+H)+;
'H NMR (DMSO-d6) b 9.87 (s, 1H), 8.78 (d, 1H, J=8.1 Hz), 8.57 (d, 1H, J=2.7
Hz), 8.25 (dd,
1 H, J=4.4, 1.4 Hz), 8.02 (br s, 1 H), 7.93 (ddd, 1 H, J=8.1, 2.7, 1.4 Hz),
7.62-7.45 (m, 3H), 7.40
(dd, 1H, J=8.1, 4.4 Hz), 5.85 (t, 1H, J=8.1 Hz), 1.06 (s, 9H).
Example SO
(-) N-(1-~[3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1-yl]amino)-2,2-
dimeth~pro~yl)-
3,5-difluorobenzamide
The product from Example 16B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10%
ethanol/hexanes
(flow rate=10 mL/minute) to provide the title compound as the levorotatory
enantiomer.
[a]DZ3 - -26 ° (c 0.013, DMSO);
MS (ESI+) m/z 415 (M+H)+;
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'H NMR (DMSO-d6) 8 9.87 (s, 1H), 8.78 (d, 1H, J=8.1 Hz), 8.57 (d, 1H, J=2.7
Hz), 8.25 (dd,
1H, J=4.4, 1.4 Hz), 8.02 (br s, 1H), 7.93 (ddd, 1H, J=8.1, 2.7, 1.4 Hz), 7.62-
7.45 (m, 3H), 7.40
(dd, 1H, J=8.1, 4.4 Hz), 5.85 (t, 1H, J=8.1 Hz), 1.06 (s, 9H).
Example 51
N~2,2-dichloro-1- ~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~] amino
~prop~)-3,5-
difluorobenzamide
Example 51 A
N-f 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dichloropropyll-3,5-difluorobenzamide
3,5-Difluorobenzamide, the product from Example 24A, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 1C to provide the
title
compound.
MS (ESI+) m/z 385 (M+H)+.
Example S1B
N-(2,2-dichloro-1-f[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-
yl]amino~propyl -3,5-
difluorobenzamide
A suspension of the product from Example 1B, the product from Example S1A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 231-232 °C;
MS (ESI+) m/z 455 (M+H)+;
'H NMR (DMSO-d6) b 10.22 (s, 1H), 9.50 (d, 1H, J=7.8 Hz), 8.58 (d, 1H, J=2.0
Hz), 8.46 (d,
1H, J=7.8 Hz), 8.28 (d, 1H, J=4.8 Hz), 7.91 (br d, 1H, J=7.8 Hz), 7.63-7.50 (,
3H), 7.41 (dd,
1 H, J=8.5, 4.7 Hz), 6.64 (t, 1 H, J=7.8 Hz), 2.24 (s, 3H);
Anal. calcd for C~9H14C12FZN4O3: C, 50.13; H, 3.10; N, 12.31. Found: C, 50.35;
H, 3.14; N,
12.31.
Example 52
4-chloro-N-fl-[(3,4-dioxo-2-~[~trifluoromethyl)pyridin-3-yl]amino -1-
cyclobuten-1-
yl)amino]-2,2-dimeth~propyl~ benzamide
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Example 52A
~trifluorometh~'~pyridin-3-, lad
A suspension of 4-chloro-5-trifluoromethyl pyridine (4.86 g, 26.8 mmol),
Ni(COD)z
(0.368 g, 1.34 mmol), Pd(dppf)Z~CHZC12 (2.19 g, 2.68 mmol), 1,1'-
bis(diphenylphosphino)ferrocene (1.00 g, 1.80 mmol), benzophenone imine (5.82
g, 32.1
mmol), and sodium tert-butoxide (3.60 g, 37.5 mmol) in toluene was heated at
reflux for 16
hours. The reaction mixture was cooled and evaporated in vacuo. The crude
material was
purified by chromatography, eluting with EtOAc/hexanes (1:1). The
chromatographed
product was dissolved in THF (200 mL) and 2 N HC1 (10 mL) was added and the
mixture
was stirred for 0.5 hours. The reaction mixture was partitioned between 0.5 M
HCl and (2:1 )
hexanes/EtOAc. The aqueous layer was separated and made alkaline with 10%
NaOH. The
product aniline was extracted with CHZC12, dried over anhydrous Na2S04 and
concentrated in
vacuo to provide 2.98 g (67 % yield) of white crystalline solid.
MS (DCI/NH3) m/z 163 (M+H)+.
Example 52B
3-ethox~ 5-trifluoromethyl-3-pyridinylamino)-cyclobut-3-ene-1,2-dione
A solution of the product from Example 52A (2.98 g, 18.4 mmol) and 3,4,-
diethoxy-3-
cyclobutene-1,2-dione (3.13 g, 18.4 mmol) in EtOH (50 mL) was heated at reflux
for 48
hours. The reaction mixture was filtered while still hot and the filtrate was
absorbed onto
silica gel. The crude material was purified by chromatography, eluting with
EtOAc/hexanes
(3:1) to provide 2.00 g (38 % yield) of the desired compound as colorless
crystals.
MS (DCI/NH3) m/z 287 (M+H)+.
Example 52C
3-amino-4-(5-trifluoromethyl-3-pyridinylamino)-cyclobut-3-ene-1,2-dione
The product from Example 52B (2.00 g, 6.99 mmol) was dissolved in 2.0 M NH3 in
MeOH and stirred in a sealed vessel for 5 hours. The reaction mixture was
concentrated in
vacuo to a volume of 15 mL and triturated with EtOAc. The product (1.59 g, 89
% yield) was
collected by filtration and used without further purification.
MS (DCI/NH3) m/z 258 (M+H)+.
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Example 52D
4-chloro-N- f 1- f (3,4-dioxo-2- ( f 5-(trifluoromethyl~pyridin-3-yllamino
~cyclobuten-1-
)amino]I-2,2-dimeth~propyl} benzamide
A suspension of the product from Example 52C, the product from Example 2A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 231-232 °C;
MS (ESI+) m/z 481 (M+H)+;
'H NMR (DMSO-d6) 8 10.13 (s, 1H), 8.75 (d, 1H, J=2.4 Hz), 8.72 (br s, 1H),
8.59 (d, 1H,
J=0.7 Hz), 8.34 (br s, 1H), 8.11 (br s, 1H), 7.87 (d, 2H, J=8.5 Hz), 7.57 (d,
2H, J=8.5 Hz), 5.86
(m, 1 H), 1.06 (s, 9H);
Anal. calcd for CZZH20C~3N4O3~ C~ 54.95; H, 4.19; N, 11.65. Found: C, 54.58;
H, 4.19; N,
11.99.
Example 53
3,5-dichloro-N- ~ 1-x(3,4-dioxo-2- f ~5-(trifluoromethyl)pyridin-3-~] amino ~ -
1-cyclobuten-1-
y1 amino]-2,2-dimethylprop~}benzamide
A suspension of the product from Example 52C, the product from Example 12A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 233-234 °C;
MS (ESI+) m/z 515 (M+H)+;
1H NMR (DMSO-d6) b 10.13 (s, 1H), 8.86 (d, 1H, J=6.9 Hz), 8.76 (d, 1H, J=2.4
Hz), 8.59 (s,
1H), 8.39 (s, 1H), 8.09 (br s, 1H), 7.85 (d, 2H, J=1.9 Hz), 7.82 (d, 1H, J=1.9
Hz), 5.86 (s, 1H),
1.07 (s, 1H);
Anal. calcd for CZZHi9C12FsNa03: C, 51.28; H, 3.72; N, 10.87. Found: C, 50.92;
H, 3.62; N,
11.05.
Example 54
4-chloro-N-(1-[~3,4-dioxo-2-fj5-(trifluoromethyl)pyridin-3-yl]amino -1-
cyclobuten-1-
yl)amino]-2,2-dimethyl-3-phenylpropyl}benzamide
A suspension of the product from Example 52C, the product from Example 18B,
and
KzC03 was processed as described in Example 1D to provide the title compound.
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mp 194-195 °C;
MS (ESI+) m/z 551 (M+H)+;
'H NMR (DMSO-d6) 8 10.14 (s, 1H), 8.84 (s, 1H), 8.77 (d, 1H, J=2.3 Hz), 8.60
(s, 1H), 8.41
(s, 1H), 8.21 (br s, 1H), 7.91 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=8.7 Hz), 7.32-
7.20 (m, 5H),
5.95 (br s, 1H), 2.75 (ABq, 2H, JAB=12.8 Hz, wAB=35.7 Hz), 0.98 (s, 3H), 0.95
(s, 3H);
Anal. calcd for Cz8Hz4C1F3N4O3: C, 60.38; H, 4.34; N, 10.06. Found: C, 60.36;
H, 4.46; N,
10.03.
Examine 55
N-j~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~lamino)-2,2-dimethyl-3-
phenylpro~~)-3,5-difluorobenzamide
Example 55A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-~)-2,2-dimethyl-3-phen~propyll-3,5-
difluorobenzamide
3,5-Difluorobenzamide, the product from Example 18A, benzotriazole, and p
toluenesulfonic acid were processed as described in Example 18B to provide the
title
compound.
MS (DCI/NH3) m/z 421 (M+H)+.
Example 55B
~1-f j3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1-yl]aminol-2,2-dimethyl-3-
phenylpropyl)-3,5-difluorobenzamide
A suspension of the product from Example 1B, the product from Example 55A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 223-224 °C;
MS (ESI+) m/z 491 (M+H)+;
'H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.89 (d, 1H, J=7.4 Hz), 8.59 (d, 1H, J=2.6
Hz), 8.26 (dd,
1H, J=4.5, 1.2 Hz), 8.12 (br s, 1H), 7.95 (ddd, 1H, J=8.5, 2.3, 1.2), 7.63-
7.57 (m, 2H), 7.50 (tt,
1H, J=9.2, 2.4), 7.26 (ddd, 1H, J=8.5, 4.7, 0.7), 7.33-7.21 (m, 5H), 5.94 (s,
1H), 2.74 (ABq,
2H, JAB=12.7 Hz, OvAB=31.4 Hz), 0.97 (s, 3H), 0.95 (s, 3H);
Anal. calcd for Cz7Hz4F2N4O3: C, 66.11; H, 4.93; N, 11.42. Found: C, 65.87; H,
4.79; N,
11.40.
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Example 56
(+) 3-chloro-N-(1-f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino)-2
2-
dimeth~propyl)benzamide
The product from Example SB was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10%
ethanol/hexanes
(flow rate=10 mL/minute) to provide the title compound as the dextrorotatory
enantiomer.
[a]p ° _ +40° (c 0.11, DMSO);
MS (ESI+) m/z 413 (M+H)+;
~H NMR (DMSO-d6) 8 9.73 (br s, 1H), 9.40 (br d, 1H, J=8.4 Hz), 8.77 (d, 1H,
J=2.5 Hz), 8.50
(d, 1H, J=8.4 Hz), 8.26 (dd, 1H, J=5.5, 1.1 Hz), 7.93 (br s, 1H), 7.79 (br s,
1H), 7.83 (d, 1H,
J=7.9 Hz), 7.61 (br d, 1 H, J=8.6 Hz), 7.5 8 (t, 1 H, J=8.2 Hz), 7.41 (dd, 1
H, J=8.7, 4. 8 Hz), 5 .47
(t, 1 H, J=8.5 Hz), 0.90 (s, 9H);
Anal. calcd for CZIHsiC1N403: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.26; H,
4.99; N,
13.49.
Example 57
(-) 3-chloro-N-(~~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino-2,2-
dimethylpropyl)benzamide
The product from Example SB was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10%
ethanol/hexanes
(flow rate=10 mL/minute) to provide the title compound as the levorotatory
enantiomer.
[a]DZ° =-43° (c 0.09, DMSO);
MS (ESI+) m/z 413 (M+H)+;
'H NMR (DMSO-d6) 8 9.73 (br s, 1H), 9.40 (br d, 1H, J=8.4 Hz), 8.77 (d, 1H,
J=2.5 Hz), 8.50
(d, 1 H, J=8.4 Hz), 8.26 (dd, 1 H, J=5.5, 1.1 Hz), 7.93 (br s, 1 H), 7.79 (br
s, 1 H), 7.83 (d, 1 H,
J=7.9 Hz), 7.61 (br d, 1 H, J=8.6 Hz), 7. 5 8 (t, 1 H, J=8.2 Hz), 7.41 (dd, 1
H, J=8. 7, 4. 8 Hz), S .47
(t, 1H, J=8.5 Hz), 0.90 (s, 9H);
Anal. calcd for CZ~HS,CINqO3: C, 61.09; H, 5.13; N, 13.57. Found: C, 61.17; H,
5.00; N,
13.44.
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Example 58
3,5-dichloro-N-(1-~(3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino)-2
2-dimethyl-
3-phenylpropyl)benzamide
Example 58A
N-f 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-3-phenylpropyl]-3,5-
dichlorobenzamide
3,5-Dichlorobenzamide, the product from Example 18A, benzotriazole, and p
toluenesulfonic acid were processed as described in Example 18B to provide the
title
compound.
MS (DCI/NH3) m/z 453 (M+H)+.
Example 58B
3,5-dichloro-N-( 1- f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino
) -2,2-dimethyl-
3-phenylpropyl)benzamide
A suspension of the product from Example 1B, the product from Example 58A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 197-198 °C;
MS (ESI+) m/z 523 (M+H)+;
1H NMR (DMSO-d6) b 9.86 (s, 1H), 8.96 (d, 1H, J=7.6 Hz), 8.59 (d, 1H, J=2.8
Hz), 8.26 (dd,
1H, J=4.7, 1.4 Hz), 8.10 (br s, 1H), 7.94 (dd, 1H, J=8.3, 1.2 Hz), 7.87 (d,
2H, J=1.9 Hz), 7.85
(d, 1H, J=1.9 Hz), 7.39 (ddd, 1H, J=8.3, 4.8, 0.5 Hz), 7.32-7.20 (m, SH), 5.93
(t, 1H, J=7.3
Hz), 5.48 (ABq, JAB=13.0, OvAB=29.7 Hz), 0.97 (s, 3H), 0.96 (s, 3H);
Anal. calcd for CZ~H24C12N403~0.95 H20: C, 60.00; H, 4.83; N, 10.37. Found: C,
59.76; H,
4.59; N, 10.22.
Example 59
3-chloro-N-(~(3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~] amino ] -2,2-
dimethyl-3-
phen~propyl)benzamide
Example 59A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-3-phenylpropyl]-3-
chlorobenzamide
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3-Chlorobenzamide, the product from Example 18A, benzotriazole, and p-
toluenesulfonic acid were processed as described in Example 18B to provide the
title
compound.
MS (DCI/NH3) m/z 419 (M+H)+.
Example 59B
3-chloro-N-(1-f [3,4-dioxo-2-(3-pyridinylamino)-1-c;rclobuten-1-yl]amino)-2,2-
dimethyl-3-
phenylprop~)benzamide
A suspension of the product from Example 1B, the product from Example 59A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 178-179 °C; '
MS (ESI+) m/z 489 (M+H)+;
1H NMR (DMSO-d6) 8 9.87 (s, 1H), 8.90 (d, 1H, J=3.7 Hz), 8.60 (d, 1H, J=1.6
Hz), 8.26 (d,
1 H, J=4.2 Hz), 8.13 (br s, 1 H), 7.95 (dd, 1 H, J=8.3, 1.2 Hz), 7.90 (t, 1 H,
J=1.7 Hz), 7. 83 dt,
1 H, J=7. 8, 1.2 Hz), 7. 65 (ddd, 1 H, J=8 . 0, 2.1, 1.2 Hz), 7. 5 5 (t, 1 H,
J=8 .1 Hz), 7. 3 9 (dd, 1 H,
J=8.2, 4.7 Hz), 7.32-7.20 (m, SH), 5.95 (s, 1H), 2.74 (ABq, JAB=12.8,
4vAB=32.1 Hz), 0.97 (s,
3H), 0.95 (s, 3H);
Anal. calcd for C27HZSC1N403~0.5 H20: C, 65.12; H, 5.26; N, 11.25. Found: C,
65.19; H,
5.42; N, 11.26.
Example 60
N~~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino -2,2-dimethyl-3-
phenylpropyl -3-methylbenzamide
Example 60A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-~)-2,2-dimethyl-3-phenylpropyl]-3-
chlorobenzamide
m-Toluamide, the product from Example 18A, benzotriazole, and p-
toluenesulfonic
acid were processed as described in Example 18B to provide the title compound.
MS (DCI/NH3) m/z 399 (M+H)+.
Example 60B
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N-(1-f f3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino-2,2-dimethyl-3-
phenylpropyl)-3-methylbenzamide
A suspension of the product from Example 1B, the product from Example 60A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 234-235 °C;
MS (ESI+) m/z 469 (M+H)+;
' H NMR (DMSO-d6) 8 9.88 (s, 1 H), 8.74 (br s, 1 H), 8.60 (d, 1 H, J=2.6 Hz),
8.26 (dd, 1 H,
J=4.7, 1.1 Hz), 8.14 (br s, 1H), 7.95 (dd, 1H, J=8.3, 1.0 Hz), 7.67 (m, 2H),
7.41-7.37 (m, 3H),
7.32-7.20 (m, SH), 5.96 (br s, 1H), 5.48 (ABq, JAB=12.8, OvAB=33.8 Hz), 2.38
(s, 3H), 0.97 (s,
3H), 0.95 (s, 3H);
Anal. calcd for CZ8HZ8N403~0.1 H20: C, 69.12; H, 6.21; N, 11.51. Found: C,
69.21; H, 6.37;
N, 11.48.
Example 61
N-[ 1-( (2-[(2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl) amino)-
2,2-dimeth~rl-3-
phen~propyll-3-methylbenzamide
A suspension of the product from Example 29B, the product from Example 60A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 234-235 °C;
MS (ESI+) m/z 503 (M+H)+;
'H NMR (DMSO-d6) 8 9.47 (s, 1H), 8.73 (d, 1H, J=7.8 Hz), 8.62 (d, 1H, J=7.5
Hz), 8.12 (dd,
1H, J=4.8, 1.7 Hz), 8.05 (d, 1H, J=7.5 Hz), 7.70-7.65 (m, 2H), 7.45 (dd, 1H,
J=8.3, 4.8 Hz),
7.40-7.38 (m, 2H), 7.32-7.28 (m, 2H), 7.25-7.21 (m, 3H), 6.01 (br s, 1H), 2.75
(ABq,
JAB=12.8, 4vAB=38.7 Hz), 2.39 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H);
Anal. calcd for CZBHZ~C1N403~0.2 H20: C, 66.39; H, 5.45; N, 11.06. Found: C,
66.57; H,
5.67; N, 10.82.
Exam 1p a 62
4-chloro-N-f 1-(~2-[(6-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl;
amino -2,2-
dimethylpropyllbenzamide
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Example 62A
4-(6-chloro3-pyridinylamino)-3-ethoxy-cyclobut-3-ene-1,2-dione
5-Amino-2-chloropyridine (2.32 g, 18.0 mmol) in ethanol (SO mL) was added to a
solution of 3,4-diethoxy-3-cyclobutene-1,2-dione 3.07 g, 18.0 mmol) in ethanol
(200 mL) at
70 °C over a period of 6 hours. The mixture was then heated at 80
°C for an additional 18
hours, filtered, and the solvents removed in vacuo. The crude product was
suspended in 10%
EtOH/EtOAc (30 mL) and adsorbed onto silica gel (15 g). Purification by flash
chromatography on silica gel (eluted with S% EtOH/EtOAc) provided 1.98 g of
the desired
product as a pale yellow powder.
MS (DCI/NH3) m/z 253 (M+H)+.
Example 62B
3-amino-4-(6-chloro-3-pyridinylamino)-cyclobut-3-ene-1,2-dione
A solution of the product from Example 62A and ammonia in methanol was
processed
as described.in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 224 (M+H)+.
Example 62C
4-chloro-N-[1-(~2-[(6-chloropyridin-3-yl amino]-3,4-dioxo-1-cyclobuten-1-
~~amino)-2,2-
dimethylpropyl]benzamide
A suspension of the product from Example 62B, the product from Example 2A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 258-259 °C;
MS (ESI+) m/z 447 (M+H)+;
~H NMR (DMSO-d6) 8 9.96 (br s, 1H), 8.74 (br d, 1H, J=9.1 Hz), 8.08-7.97(m,
1H), 7.92-7.84
(m, 3H), 7.77 (d, 1H, J=7.8 Hz), 7.61-7.48 (m, 3H), 5.85 (dd, 1H, J=9.2, 7.8
Hz), 1.04 (s, 9H);
Anal. calcd for CZ~HZOC12N403: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.43;
H, 4.40; N,
12.46.
Example 63
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4-chloro-N-(1-(f2-[(2-fluoropyridin-3-yl)aminoL3,4-dioxo-1-cyclobuten-1-
yl~amino~-2 2-
dimeth 1y propyl]benzamide
Example 63A
3-amino-2-fluoropyridine
To a solution of 2-chloro-6-fluoro-5-nitropyridine (2.30 g, 13.0 mmol) in EtOH
(50
mL) and sodium acetate dihydrate (1.69 g, 14.3 mmol) was added 10% Pd/C (230
mg). The
suspension was hydrogenated (4 atm) at 23 °C for 5 hours then filtered
through Celite. The
filter cake was rinsed with EtOH and the filtrate concentrated to provide 1.34
g of the crude
product as an off yellow solid which was used without further purification.
MS (DCI/NH3) m/z 113 (M+H)+.
Example 63B
~2-fluoropyridin-3-ylamino)-3-ethox ~-~cyclobut-3-ene-1,2-dione
A solution of Example 63A and 3,4-diethoxy-3-cyclobutene-1,2-dione in ethanol
was
processed as described in Example 62A to provide the title compound.
MS (DCI/NH3) m/z 237 (M+H)+.
Example 63C
3-amino-4-(6-fluoro-3-pyridinylamino)-cyclobut-3-ene-1,2-dione
A solution of the product from Example 63B and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 208 (M+H)+.
Example 63D
4-chloro-N-[ 1-( (2-[(2-fluoropyridin-3-~)amino]-3,4-dioxo-1-cyclobuten-1-yl~
amino)-2,2-
dimeth~propyl]benzamide
A suspension of the product from Example 63C, the product from Example 2A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 231-234 °C;
MS (ESI+) m/z 431 (M+H)+;
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1H NMR (DMSO-d6) b 9.47 (br s, 1H), 8.72 (d, 1H, J=7.8 Hz), 8.50 (d, 1H, J=8.8
Hz), 8.11
(dd, 1H, J=4.4, 1.4 Hz), 8.02 (d, 1H, J=7.8 Hz), 7.87 (d, 2H, J=8.5 Hz), 7.57
(d, 2H, J=8.5
Hz), 7.44 (dd, 1H, J=8.1, 4.4 Hz), 5.89 (t, 1H, J=8.5 Hz), 1.06 (s, 9H);
Anal. calcd for CZIHZOC1FN403: C, 58.54; H, 4.68; N, 13.00. Found: C, 58.58;
H, 4.70; N,
13.18.
Example 64
3-chloro-N-(~ j3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~] amino ~ -3,3-
dimethylbutyl)benzamide
Example 64A
1-benzotriazol-1-yl-3,3-dimethYl-butyl)-3-chloro-benzamide
A suspension of 3-chlorobenzamide, 3,3-dimethyl-butyraldehyde, and
benzotriazole
were processed as described in Example 1 C to provide the desired product.
MS (DCI/NH3) m/z 357 (M+H)+.
Example 64B
3-chloro-N-(~[3,4-dioxo-2-(3-p r~ylamino)-1-cyclobuten-1-~laminoj-3,3-
dimethylbutyl)benzamide
A suspension of the product from Example 1B, the product from Example 64A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 238-239 °C;
MS (ESI+) m/z 427 (M+H)+;
1H NMR (DMSO-d6) 8 9.89 (s, 1H), 9.25 (s, 1H), 8.57 (d, 1H, J=2.6 Hz), 8.34
(br s, 1H),
8.27 (dd, 1H, J=4.5, 1.2 Hz), 7.95-7.91 (m, 2H), 7.85 (d, 1H, J=7.8 Hz), 7.64
(ddd, 1H, J=8.0,
2.1, 0.9 Hz), 7.54 (t, 1H, J=7.8 Hz), 7.37 (ddd, 1H, J=8.3, 4.7, 0.5 Hz), 5.99-
5.87 (m, 1H),
2.04 (dd, 1H, J=14.2, 6.4 Hz), 1.86 (dd, 1H, J=14.4, 6.3 Hz), 0.98 (s, 9H);
Anal. calcd for CZZH23C1N403: C, 61.90; H, 5.43; N, 13.12. Found: C, 62.00; H,
5.39; N,
12.89.
ExamRle 65
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N-( 1~,~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ~ -2,2-
dimethylpropyl)thio~hene-2-carboxamide
Example 65A
N-( 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~propyl)thiophene-2-carboxamide
A suspension of thiophene-2-carboxamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic acid was processed as in Example 1 C to provide the title
compound.
MS (ESI+) m/z 315 (M+H)+.
Example 65B
N-( 1- f~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino ~ -2,2-
dimeth~propyl)thiophene-2-carboxamide
A suspension of the product from Example 1B, the product from Example 65A, and
KZC03 was processed as described in Example 1D to provide the title compound.
MS (ESI+) m/z 385 (M+H)+;
'H NMR (DMSO-db) b 10.19 (s, 1H), 8.75 (br s, 1H), 8.57 (br d, 1H, J=5.2 Hz),
8.36 (d, 1H,
J=4.7 Hz), 8.24 (br s, 1 H), 8.11 (br d, 1 H, J=8.1 Hz), 7.94 (d, 1 H, J=3 .4
Hz), 7. 81 (d, 1 H,
J=5.0 Hz), 7.62 (dd, 1 H, J=8.4, 5.0 Hz), 7.18 (dd, 1 H, J=5.0, 3 .7 Hz), 5.81
(t, 1 H, J=7. 5 Hz),
1.05 (s, 9H).
Example 66
3-bromo-N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ~ -
2,2-
dimethylproRyl)benzamide
Example 66A
N-( 1-( 1 H-1,2,3-benzotriazol-1-~)-2,2-dimethylpropyl)-3-bromobenzamide
A suspension of 3-bromobenzamide, pivaldehyde, benzotriazole, and p-
toluenesulfonic
acid was processed as described in Example 1 C to provide the title compound.
MS (DCI/NH3) m/z 387 (M+H)+.
Example 66B
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3-bromo-N-(1-ff3,4-dioxo-2-(3-pyridinylamino~l-cyclobuten-1-~~amino)-2 2-
dimeth~prop~)benzamide
A suspension of the product from Example 1B, the product from Example 66A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 244-245 °C;
MS (ESI+) m/z 459 (M+H)+;
~ H NMR (DMSO-d6) 8 9.86 (br s, 1 H), 8.79 (d, 1 H, J=7.8 Hz), 8.57 (d, 1 H,
J=3.1 Hz), 8.11
(dd, 1 H, J=4.4, 1.4 Hz), 8.09-8.00 (m, 1 H), 7.99 (t, 1 H, J=1.7 Hz), 7.93
(ddd, 1 H, J=8.2, 2.6,
1.0 Hz), 7.83 (dt, 2H, J=7.8, 1.4 Hz), 7.76 (ddd, 1 H, J=8.2, 2.2, 1.0 Hz),
7.46 (t, 1 H, J=7.8
Hz), 7.38 (dd, 1H, J=8.5, 4.8 Hz), 5.86 (t, 1H, J=8.5 Hz), 1.06 (s, 9H);
Anal. calcd for CzlHziBrN403: C, 55.15; H, 4.63; N, 12.25. Found: C, 54.94; H,
4.45; N,
12.31.
Example 67
3-bromo-N-f 1-( f 2-((2-chloropyridin-3-~)amino)-3,4-dioxo-1-cyclobuten-1-yl)
amino)-2 2-
dimethy~ropyl)benzamide
A suspension of the product from Example 29B, the product from Example 66A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 257-259 °C;
MS (ESI+) m/z 493 (M+H)+;
1H NMR (DMSO-d6) 8 9.46 (br s, 1H), 8.78 (d, 1H, J=7.8 Hz), 8.48 (d, 1H, J=8.5
Hz), 8.11
(dd, 1H, J=4.4, 1.4 Hz), 8.05-8.02 (m, 1H), 8.00 (t, 1H, J=1.7 Hz), 7.84 (dt,
1H, J=7.8, 1.4
Hz), 7.76 (ddd, 1H, J=8.1, 2.0, 1.0 Hz), 7.46 (t, 1H, J=8.1 Hz), 7.44 (dd, 1H,
J=8.1, 3.4 Hz),
5.89 (t, 1 H, J=8.1 Hz), 1.07 (s, 9H);
Anal. calcd for CzlHzoBrC1N403~0.1 H20: C, 51.10; H, 4.12; N, 11.35. Found: C,
50.78; H,
3.78; N, 11.11.
Example 68
N-(1-~j3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino; -2,2-
dimethyl~ropyl)-9-oxo-
9H-fluorene-4-carboxamide
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Example 68A
9-oxo-9H-fluorene-4-carboxamide
9-Oxo-9H-fluorene-4-carbonyl chloride (5.00 g, 20.6 mmoL) in 200 mL of THF was
cooled to 0 °C and 100 mL of a solution of Hz0/NH40H (2:1) was added
dropwise over 10
minutes. The reaction mixture was warmed to 23 °C and stirred for 45
minutes then
concentrated in vacuo~to a volume of approximately 100 mL. The mixture was
filtered and
the filter cake was washed with 100 mL of H20 and 25 mL EtOAc/Et20 (1:l). The
product
was dried in vacuo and used without further purification.
MS (DCI/NH3) m/z 224 (M+H)+.
Example 68B
N-~ 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-9-oxo-9H-fluorene-4-
carboxamide
A suspension of the product from Example 68A, pivaldehyde, benzotriazole, and
p-
toluenesulfonic acid was processed as in Example 1 C to provide the title
compound.
MS (ESI+) m/z 411 (M+H)+.
Example 68C
1- ~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~] amino ~ -2,2-
dimeth~propyl)-9-oxo-
9H-fluorene-4-carboxamide
A suspension of the product from Example 1B, the product from Example 68B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 201-202 °C;
MS (ESI+) m/z 481 (M+H)+;
'H NMR (DMSO-d6) 8 9.89 (s, 1H), 9.23 (d, 1H, J=8.0 Hz), 8.61 (d, 1H, J=2.6
Hz), 8.27 (dd,
1 H, J=4.7, 1.2 Hz), 8.09 (br s, 1 H), 7.99 (ddd, 1 H, J=8.2, 2.6, 1.1 Hz),
7.72 (dd, 1 H, J=7.3,
1.2 Hz), 7.66-7.63 (m, 1H), 7.62 (d, 1H, J=7.1 Hz), 7.56 (dd, 1H, 7.5, 1.2
Hz), 7.49 (d, 1H,
J=7.3 Hz), 7.46-7.36 (m, 3H), 6.02 (t, 1H, J=8.7 Hz), 1.09 (s, 9H);
Anal. calcd for CZ8Hz4N4O4~ 1.05 H20: C, 67.34; H, 5.27; N, 11.22. Found: C,
67.68; H,
5.41; N, 10.85.
Example 69
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methyl 3-([(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~]amino -2 2-
dimethylpropyl)aminolcarbonyl benzoate
Example 69A
methyl 3-(aminocarbonyl)benzoate
3-(Methoxycarbonyl)benzoic acid (1.0 g, 5.55 mmol) and SOC12 (0.81 g, 11.1
mmol)
were dissolved in 20 mL of toluene. A catalytic amount of DMF (3 drops) was
added and the
reaction mixture was heated at 92 °C for 2.5 hours. The mixture was
cooled to 23 °C and the
solvent removed in vacuo. The crude material was dissolved in 25 mL THF and 3
mL
NH40H was added. The reaction was stirred for 10 minutes then diluted with 50
mL of
EtOAc and washed with 10 mL of 2 N HCI. The aqueous layer was extracted with
25 mL of
EtOAc and the combined extracts were washed with NaHC03, dried over Na2S04,
and filtered
through a 1/4" silica gel frit. The filtrate was concentrated in vacuo and the
crude material
was recrystallized from EtOAc/hexanes to provide the desired product (0.817 g,
82 % yield).
MS (DCI/NH3) m/z 180 (M+H)+.
Example 69B
meth 1y 3-(~jl-(1H-1,2,3-benzotriazol-1-~)-2,2-
dimethylpropyllamino~carbonyl)benzoate
A suspension of the product from Example 69A, pivaldehyde, benzotriazole, and
p-
toluenesulfonic acid was processed as in Example 1 C to provide the title
compound.
MS (ESI+) m/z 367 (M+H)+.
Example 69C
methyl 3- ~~(~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~l amino } -2,2-
dimethylprop~ amino~carbonyl}benzoate
A suspension of the product from Example 1B, the product from Example 69B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 228-229 °C;
MS (ESI+) m/z 437 (M+H)+;
1H NMR (DMSO-d6) 8 9.89 (s, 1H), 8.90 (d, 1H, J=7.6 Hz), 8.58 (d, 1H, J=2.4
Hz), 8.39 (t,
1 H, J=1.8 Hz), 8.25 (dd, 1 H, J=4.7, 1.4 Hz), 8.14-8.09 (m, 2H), 8.05 (br s,
1 H), 7.94 (ddd,
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1 H, J=8.5, 2.8, 1.4 Hz), 7.66 (t, 1 H, J=8.0 Hz), 7.39 (dd, 1 H, J=8.5, 4.7
Hz), 5.90 (br s, 1 H),
3.90 (s, 3H), 1.07 (s, 9H);
Anal. calcd for Cz3Hz4N4O5: C, 63.29; H, 5.54; N, 12.84. Found: C, 62.92; H,
5.61; N, 13.04.
Example 70
(+) N-(1-~ f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino)-2,2-
dimethylpropyl)-3-
methylbenzamide
The product from Example 6B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%
ethanol/hexanes
(flow rate=15 mL/minute) to provide the title compound as the dextrorotatory
enantiomer.
[a]DZS =+98° (c 0.25, EtOH);
HRMS (FAB) calcd for CzzHz5N4O3 (M+H)+ 393.1927, found 393.1917;
'H NMR (DMSO-d6) 8 9.93 (br s, 1H), 8.64 (br d, 1H, J=7.1 Hz), 8.57 (d, 1H,
J=2.7 Hz), 8.25
(dd, 1H, J=4.7, 1.4 Hz), 8.08 (br s, 1H), 7.93 (br d, 1H, J=7.9 Hz), 7.66-7.60
(m, 2H), 7.41-
7.34 (m, 3H), 5.87 (br t, 1H, J=6.8 Hz), 2.37 (s, 3H), 1.05 (s, 9H).
Example 71
~-) N-(~j3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino-2,2-
dimethylpropyl)-3-
methylbenzamide
The product from Example 6B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%
ethanol/hexanes
(flow rate=15 mL/minute) to provide the title compound as the levorotatory
enantiomer.
[a]DZS --96° (c 0.30, EtOH);
HRMS (FAB) calcd for CzzHzsNaO3 (M+H)+ 393.1927, found 393.1933;
'H NMR (DMSO-d6) 8 9.93 (br s, 1H), 8.64 (br d, 1H, J=7.1 Hz), 8.57 (d, 1H,
J=2.7 Hz), 8.25
(dd, 1H, J=4.7, 1.4 Hz), 8.08 (br s, 1H), 7.93 (br d, 1H, J=7.9 Hz), 7.66-7.60
(m, 2H), 7.41-
7.34 (m, 3H), 5.87 (br t, 1H, J=6.8 Hz), 2.37 (s, 3H), 1.05 (s, 9H).
Example 72
(+) N- 1 ~~[3,4-dioxo-2-(3-p r~ idinylamino)-1-cyclobuten-1-yl]amino-2,2-
dimethyl-3-
phenylprouyl)-3-methylbenzamide
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The product from Example 60B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%
ethanol/hexanes
(flow rate=15 mL/minute) to provide the title compound as the dextrorotatory
enantiomer.
[oc]pz3 =+105° (c 0.36, EtOH);
HRMS (FAB) calcd for Cz$Hz9N4O3 (M+H)+ 469.2240, found 469.2243;
'H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.74 (br s, 1H), 8.60 (d, 1H, J=2.6 Hz), 8.26
(dd, 1H,
J=4.7, 1.1 Hz), 8.14 (br s, 1H), 7.95 (dd, 1H, J=8.3, 1.0 Hz), 7.67 (m, 2H),
7.41-7.37 (m, 3H),
7.32-7.20 (m, 5H), 5.96 (br s, 1H), 5.48 (ABq, JAB=12.8, OvAB=33.8 Hz), 2.38
(s, 3H), 0.97 (s,
3H), 0.95 (s, 3H).
Example 73
(-)~1-~[3,4-dioxo-2-(3-p rr~ylamino)-1-cyclobuten-1-yl~amino; -2,2-dimethyl-3-
phenylpropyl)-3-methylbenzamide
The product from Example 60B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%
ethanol/hexanes
(flow rate=15 mL/minute) to provide the title compound as the levorotatory
enantiomer.
[oc]DZ3 _ _96° (c 0.34, EtOH);
HRMS (FAB) calcd for Cz8Hz9N4O3 (M+H)+ 469.2240, found 469.2252;
'H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.74 (br s, 1H), 8.60 (d, 1H, J=2.6 Hz), 8.26
(dd, 1H,
J=4.7, 1.1 Hz), 8.14 (br s, 1H), 7.95 (dd, 1H, J=8.3, 1.0 Hz), 7.67 (m, 2H),
7.41-7.37 (m, 3H),
7.32-7.20 (m, 5H), 5.96 (br s, 1H), 5.48 (ABq, JAB=12.8, OvAB=33.8 Hz), 2.38
(s, 3H), 0.97 (s,
3H), 0.95 (s, 3H).
Example 74
(+) N-[1-(~2~(2-chloropyridin-3-~)amino]-3,4-dioxo-1-cyclobuten-1-~~amino -2,2-
dimeth~prop.,~l]-3-methylbenzamide
The product from Example 32 was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%
ethanol/hexanes
(flow rate=15 mL/minute) to provide the title compound as the dextrorotatory
enantiomer.
[a]DZ3 = +77° (c 0.22, EtOH);
HRMS (FAB) calcd for Cz7Hz5F2N4O3 (M+H)+ 491.1895, found 491.1893;
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'H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.89 (d, 1H, J=7.6 Hz), 8.59 (d, 1H, J=2.4
Hz), 8.26 (dd,
1H, J=4.7, 1.0 Hz), 8.12 (br s, 1H), 7.95 (ddd, 1H, J=8.0, 2.5, 1.0 Hz), 7.63-
7.57 (m, 2H),
7.50 (dt, 1H, J=9.0, 2.4 Hz), 7.39 (dd, 1H, J=9.0, 4.7 Hz),7.33-7.27 (m, 2H),
7.26-7.19 (m,
3H), 5.94 (br s, 1H), 2.74 (ABq, J~=12.8, wAB=31.2 Hz), 0.97 (s, 3H), 0.95 (s,
3H).
Example 75
(-) N-[~~-[(2-chloropyridin-3-~)aminol-3,4-dioxo-1-cyclobuten-1-yl~amino)-2,2-
dimeth~propyll-3-methylbenzamide
The product from Example 32 was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%
ethanol/hexanes
(flow rate=15 mL/minute) to provide the title compound as the levorotatory
enantiomer.
[a]DZ3 _ _136° (c 0.27, EtOH);
HRMS (FAB) calcd for CzzHzaC1N4O3 (M+H)+ 427.1537, found 427.1529;
'H NMR (DMSO-d6) 8 9.47 (s, 1H), 8.61 (d, 1H, J=8.0 Hz), 8.52 (d, 1H, J=8.8
Hz), 8.11 (dd,
1 H, J=4.5, 1.6 Hz), 8.03 (d, 1 H, J=7.8 Hz), 7.67-7.61 (m, 2H), 7.44 (dd, 1
H, J=8.3, 4.7 Hz),
7.39-7.35 (m, 2H), 5.92 (t, 1H, J=8.0 Hz), 2.37 (s, 3H), 1.07 (s, 9H).
Example 76
~+) N-(1- f~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino)-2,2-
dimethyl-3-
phen~propyl)-3,5-difluorobenzamide
The product from Example 55B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 15%
ethanol/hexanes
(flow rate=15 mL/minute) to provide the title compound as the dextrorotatory
enantiomer.
[a,]DZ3 = +77° (c 0.22, EtOH);
HRMS (FAB) calcd for Cz7HzSF2N4O3 (M+H)+ 491.1895, found 491.1893;
'H NMR (DMSO-d6) 8 9.88 (s, 1H), 8.89 (d, 1H, J=7.6 Hz), 8.59 (d, 1H, J=2.4
Hz), 8.26 (dd,
1H, J=4.7, 1.0 Hz), 8.12 (br s, 1H), 7.95 (ddd, 1H, J=8.0, 2.5, 1.0 Hz), 7.63-
7.57 (m, 2H),
7.50 (dt, 1H, J=9.0, 2.4 Hz), 7.39 (dd, 1H, J=9.0, 4.7 Hz),7.33-7.27 (m, 2H),
7.26-7.19 (m,
3H), 5.94 (br s, 1H), 2.74 (ABq, J,e,B=12.8, OvAB=31.2 Hz), 0.97 (s, 3H), 0.95
(s, 3H).
Example 77
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N-( 1- ~ f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yll amino } -2,2-
dimethylpropyl)-3-(2-
furyl)benzamide
Examnle77A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyll-3-(2-furyl)benzamide
A solution of the product from Example 8A (0.50 g, 1.15 mmol), 2-
(tributylstannyl)furan (0.45 g, 1.27 mmol), triphenylarsinine (0.035 g, 0.115
mmol), and
tris(dibenzylideneacetone)dipalladium(0) (0.053 g, 0.058 mmol) in 6.0 mL NMP
was stirred at
23 °C for 16 hours. The mixture was diluted with 50 mL H20 and
extracted twice with 50 mL
of EtOAc. The combined extracts were dried over Na2S04, and absorbed onto
silica gel. The
crude product was purified by flash chromatography (eluting with EtOAc/hexanes
(1:4)) to
provide 0.34 g of the desired compound.
MS (DCI/NH3) m/z 375 (M+H)+.
Example 77B
N-( 1- ~ ~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino} -2,2-
dimethylpropyl)-3-(2-
fur~)benzamide
A suspension of the product from Example 1B, the product from Example 77A, and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 251-252 °C;
MS (ESI+) m/z 445 (M+H)+;
'H NMR (DMSO-d6) 8 9.89 (s, 1H), 8.80 (d, 1H, J=7.4 Hz), 8.59 (d, 1H, J=2.8
Hz), 8.25 (dd,
1H, J=4.6, 1.2 Hz), 8.11 (s, 1H), 8.09 (br s, 1H), 7.95 (ddd, 1H, J=8.3, 2.5,
1.2 Hz), 7.88(dt,
1H, J=8.0, 1.2 Hz), 7.80 (d, 1H, J=1.5 Hz), 7.75 (d, 1H, J=8.0 Hz), 7.55
(t,lH, J=8.0 Hz), 7.39
(dd, 1H, J=8.3, 4.6 Hz), 7.04 (d, 1H, J=3.4 Hz), 6.63 (dd, 1H, J=3.4, 1.8 Hz),
5.90 (t, 1H,
J=8.0 Hz), 1.08 (s, 9H);
Anal. calcd for CZSHZaNaOa~0.25 H20: C, 66.88; H, 5.50; N, 12.48. Found: C,
66.74; H, 5.55;
N, 12.69.
Example 78
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N-f 1-((2-~(2-chloropyridin-3-yl)amino]-3 4-dioxo-1-cyclobuten-1-yl)amino)-2 2-
dimethylpropyl]-3-fluorobenzamide
A suspension of the product from Example 29B, the product from Example 7A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 228-229 °C;
MS (ESI+) m/z 431 (M+H)+;
'H NMR (DMSO-d6) 8 9.47 (s, 1H), 8.72 (d, 1H, J=7.7 Hz), 8.51 (d, 1H, J=8.3
Hz), 8.12 (dd,
1 H, J=4.6, 1.5 Hz), 8.03 (d, 1 H, J=7.4 Hz), 7.71 (dt, 1 H, J=8.0, 1.2 Hz),
7.66 (ddd, 1 H, J=9.8,
2.5, 1.5 Hz), 7.55 (td, 1H, J=8.0, 5.8 Hz), 7.45 (dd, 1H, J=8.0, 4.6 Hz), 7.44-
7.39 (m, 1H),
5.91 (t, 1 H, J=8.0 Hz), 1.07 (s, 9H);
Anal. calcd for CZIHZOC1FN404: C, 58.54; H, 4.68; N, 13.00. Found: C, 58.35;
H, 4.90; N,
12.98.
Example 79
3,5-dichloro-N-[~ j2-[~2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-1-en-1-yl
) amino
2,2-dimethylpropyl]benzamide
A suspension of the product from Example 29B, the product from Example 12A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 233-234 °C;
MS (ESI+) m/z 482 (M+H)+;
'H NMR (DMSO-d6) b 9.45 (s, 1H), 8.86 (d, 1H, J=7.7 Hz), 8.47 (d, 1H, J=8.9
Hz), 8.12 (dd,
1H, J=4.6, 1.8 Hz), 8.03 (d, 1H, J=8.0 Hz), 7.86 (d, 2H, J=2.2 Hz), 7.82 (t,
1H, J=1.8 Hz), 7.45
(dd, 1 H, J=8.3, 4.6 Hz), 5.90 (t, 1 H, J=8.0 Hz), 1.08 (s, 9H);
Anal. calcd for CZiHi9C13Na4a: C, 52.35; H, 3.98; N, 11.63. Found: C, 52.32;
H, 4.04; N,
12.00.
Example 80
4-chloro-N-[ 1-( f 2-f (2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-
yl) amino)-2,2-
dimethyl~ropyl~benzamide
Example 80A
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3-ethoxy-4-f (2-methoxypyridin-3-yl)amino]cyclobut-3-ene-1 2-dione
A solution of 3-amino-2-methoxypyridine and 3,4-diethoxy-3-cyclobutene-1,2-
dione
in ethanol was processed as described in Example 62A to provide the title
compound.
MS (DCI/NH3) m/z 249 (M+H)+.
Example 80B
3-amino-4-[(2-methoxypyridin-3-vl)amino]cyclobut-3-ene-1 2-dione
A solution of the product from Example 80A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 220 (M+H)+.
Example 80C
4-chloro-N-[~~2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl
amino)-2 2-
dimethylpropyl]benzamide
A suspension of the product from Example 80B, the product from Example 2A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 239-241 °C;
MS (ESI+) m/z 443 (M+H)+;
'H NMR (DMSO-d6) 8 9.47 (br s, 1H), 8.70 (d, 1H, J=8.1 Hz), 8.49 (d, 1H, J=8.8
Hz), 8.07
(d, 1H, J=7.8 Hz), 7.90-7.82 (m, 3H), 7.56 (d, 2H, J=8.5 Hz), 7.01 (dd, 1H,
J=7.8, S.l Hz),
5.87 (t, 1H, J=8.1 Hz), 3.99 (s, 3H), 1.05 (s, 9H);
Anal. calcd for CZZHz3C1N4O4: C, 59.66; H, 5.23; N, 12.65. Found: C, 59.51; H,
5.13; N,
12.49.
Example 81
N-f 1-(~2-[(2-methoxypyridin-3-~)amino]-3,4-dioxo-1-cyclobuten-1-~~amino -2,2-
dimeth~prop~l-3-methylbenzamide
A suspension of the product from Example 80B, the product from Example 6A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 224-226 °C;
MS (ESI+) m/z 423 (M+H)+;
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'H NMR (DMSO-d6) 8 9.50 (br s, 1H), 8.61 (d, 1H, J=8.1 Hz), 8.52 (d, 1H, J=8.8
Hz), 8.07
(d, 1H, J=7.8 Hz), 7.83 (dd, 1H, J=4.8, 1.4 Hz), 7.66-7.59 (m, 2H), 7.39-7.33
(m, 2H), 7.00
(dd, 1H, J=7.8, 4.8 Hz), 5.89 (t, 1H, J=8.1 Hz), 3.99 (s, 3H), 2.37 (s, 3H),
1.05 (s, 9H);
Anal. calcd for CzzHz6Na4a: C, 65.39; H, 6.20; N, 13.28. Found: C, 65.45; H,
6.11; N, 13.28.
Example 82
3,5-difluoro-N-f 1-(~2-[(2-methoxynyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-
yl~amino~
2,2-dimethylpropvl]benzamide
A suspension of the product from Example 80B, the product from Example 16A,
and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 221-223 °C;
MS (ESI+) m/z 445 (M+H)+;
1 H NMR (DMSO-d6) 8 9.48 (br s, 1 H), 8.76 (d, 1 H, J=7.8 Hz), 8.47 (d, 1 H,
J=8.8 Hz), 8.06
(dd, 1 H, J=7. 8, 1.4 Hz), 7. 84 (dd, 1 H, J=4. 8, 1.4 Hz), 7. 61-7. 5 3 (m,
2H), 7.49 (tt, 1 H, J=9.2,
2.4 Hz), 7.01 (dd, 1H, J=7.8, 5.1 Hz), 5.87 (t, 1H, J=8.1 Hz), 3.99 (s, 3H),
1.06 (s, 9H);
Anal. calcd for CzzHzzFzNa4a: C, 59.45; H, 4.99; N, 12.61. Found: C, 59.33; H,
4.86; N,
12.66.
Example 83
N-[~~2-[~2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl] amino)-2,2-
dimethyl-
3-phenylpropyl]-3-methylbenzamide
A suspension of the product from Example 80B, the product from Example 60A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 233-235 °C;
MS (ESI+) m/z 499 (M+H)+;
1H NMR (DMSO-d6) 8 9.49 (br s, 1H), 8.73 (d, 1H, J=8.1 Hz), 8.61 (d, 1H, J=8.8
Hz), 8.08
(d, 1H, J=7.5 Hz), 7.84 (dd, 1H, J=5.1, 1.7 Hz), 7.69-7.63 (m, 2H), 7.41-7.36
(m, 2H), 7.34-
7.18 (m, SH), 7.01 (dd, 1H, J=7.8, S.l Hz), 5.97 (t, 1H, J=8.1 Hz), 4.00 (s,
3H), 2.73 (Abq,
2H, J~=12.5 Hz, wAB=26.8 Hz), 2.38 (s, 3H), 0.96 (s, 3H), 0.93 (s, 3H);
Anal. calcd for Cz9H3oN4O4: C, 69.86; H, 6.06; N, 11.24. Found: C, 69.73; H,
5.95; N, 11.18.
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Example 84
3-chloro-N-[1-(f2-[(2-methoxypyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl
amino)-2 2-
dimethylpro~yllbenzamide
A suspension of the product from Example 80B, the product from Example SA, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 208-210 °C;
MS (ESI+) m/z 443 (M+H)+;
~H NMR (DMSO-d6) 8 9.50 (br s, 1H), 8.77 (d, 1H, J=7.8 Hz), 8.53 (d, 1H, J=8.1
Hz), 8.06
(d, 1 H, J=7.4 Hz), 7. 87 (t, 1 H, J=1.8 Hz), 7.84 (dd, 1 H, J=5 .1, 1.7 Hz),
7.80 (br d, 1 H, J=7.8
Hz), 7.63 (br d, 1H, J=8.2 Hz), 7.52 (t, 1H, J=7.8 Hz), 7.00 (dd, 1H, J=7.8,
5.1 Hz), 5.88 (t,
1H, J=8.1 Hz), 3.99 (s, 3H), 1.05 (s, 9H);
Anal. calcd for CZZH23C1N4O4: C, 59.66; H, 5.23; N, 12.65. Found: C, 59.49; H,
5.04; N,
12.62.
Example 85
N-(1-(f2-((2-chloropyridin-3-~ amino]-3,4-dioxo-1-cyclobuten-1-yl)amino)-2,2-
dimet~l-3-
phen~pro~yllbenzamide
Example 85A
N-( 1-benzotriazol-1-yl-2,2-dimethyl-3-phenyl_propyl)-benzamide
A suspension of benzamide, the product from Example 18A, and benzotriazole
were
processed as described in Example I8B to provide the desired product.
MS (DCI/NH3) m/z 385 (M+H)+.
Example 85B
N-[1-(~2-[(2-chloropyridin-3-yl amino]-3,4-dioxo-1-cyclobuten-1-yl)amino)-2,2-
dimethyl-3-
phenylpropyl]benzamide
A suspension of the product from Example 29B, the product from Example 85A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 225-226 °C;
MS (ESI+) m/z 489 (M+H)+;
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1H NMR (DMSO-d6) 8 9.18 (s, 1H), 8.49 (d, 1H, J=6.8 Hz), 8.33 (d, 1H, J=6.8
Hz), 7.82 (dd,
1H, J=4.6, 1.5 Hz), 7.75 (d, 1H, J=7.7 Hz), 7.62-7.57 (m, 2H), 7.32-7.26 (m,
1H), 7.24-7.19
(m, 2H), 7.15 (dd, 1H, J=8.3, 4.6 Hz), 7.03-6.97 (m, 2H), 6.96-6.90 (m, 3H),
5.72 (br s, 1H),
2.46 (ABq, JAB= 12.9, OvAB= 37.8 Hz), 0.70 (s, 3H), 0.65 (s, 3H);
Anal. calcd for C27H25C1N4O4: C, 66.32; H, 5.15; N, 11.46. Found: C, 66.14; H,
5.03; N,
11.33.
Example 86
N-( 1- f,~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~l amino } -2,2-
dimethyl-3-
phen~prop~)benzamide
A suspension of the product from Example 1B, the product from Example 85A, and
K2C03 was processed as described in Example 1D to provide the title compound.
mp 237-238 °C;
MS (ESI+) m/z 455 (M+H)+;
H NMR (DMSO-db) 8 9.91 (s, 1 H), 8.80 (s, 1 H), 8.60 (d, 1 H, J=2.8 Hz), 8.26
(dd, 1 H, J=4.6,
1.2 Hz), 8.16 (br s, 1H), 7.98-7.92 (m, 1H), 7.90-7.86 (m, 2H), 7.61-7.55 (m,
1H), 7.54-7.48
(m, 2H), 7.39 (dd, 1H, J=8.3, 4.9 Hz), 7.33-7.27 (m, 2H), 7.25-7.19 (m, 3H),
5.96 (br s, 1H),
2.75 (ABq, JAB= 12.9, wAB= 32.8 Hz), 0.97 (s, 3H), 0.95 (s, 3H);
Anal. calcd for C27H26N404~0.85 H20: C, 69.02; H, 5.94; N, 11.92. Found: C,
68.73; H, 5.91;
N, 12.30.
Example 87
N-[1-( f2-[~2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl~amino)-2,2-
dimethylpropyl]-3 phen~propanamide
A suspension of the product from Example 29B, the product from Example 36A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 160-161 °C;
MS (ESI+) m/z 441 (M+H)+;
'H NMR (DMSO-d6) 8 9.32 (s, 1H), 8.42 (d, 1H, J=9.2 Hz), 8.17 (d, 1H, J=7.4
Hz), 8.10(dd,
1 H, J=4.6, 1.5 Hz), 8.07 (d, 1 H, J=7.7 Hz), 7.45 (dd, 1 H, J=8.0, 4.6 Hz),
7.28-7.13 (m, SH),
5.69 (t, 1H, J=8.0 Hz), 2.83 (t, 2H, J=7.7 Hz), 2.63-2.43 (m, 2H), 0.95 (s,
9H);
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Anal. calcd for C23HZSCIN4O3: C, 62.65; H, 5.71; N, 12.71. Found: C, 62.37; H,
5.63; N,
12.66.
Example 88
N-( 1- ~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~1 amino 1-2,2-
dimethylpropyl
phenox~acetamide
Example 88A
2-(phenoxy)acetamide
To a solution of phenoxyacetyl chloride (6.18 g, 36.2 mmol) in 175 mL of THF
was
added 75 mL of NH40H over 15 minutes. The reaction was stirred for 16 hours at
23 °C then
concentrated under reduced pressure. The crude product was dissolved in 200 mL
of EtOAc
and washed with 100 mL of 2 N HCI, 100 mL NaHC03, and 100 mL of brine. The
organic
phase was dried over Na2S04 and concentrated. The product was purified by
recrystallization
from EtOAc/hexanes to provide 4.05 g (74 % yield) of the desired product as a
white powder.
MS (DCI/NH3) m/z 152 (M+H)+.
Example 88B
N-L -( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyll-2-phenoxyacetamide
A suspension of the product from Example 88A, pivaldehyde, and benzotriazole
were
processed as described in Example 18B to provide the desired product.
MS (DCI/NH3) m/z 339 (M+H)+.
Example 88C
N-( 1- ~j3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino } -2,2-
dimethylpropyl)-2-
phenoxyacetamide
A suspension of the product from Example 1B, the product from Example 88B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 227-228 °C;
MS (ESI+) m/z 409 (M+H)+;
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'H NMR (DMSO-d6) 8 9.79 (s, 1H), 8.57 (d, 1H, J=2.8 Hz), 8.45 (d, 1H, J=8.0
Hz), 8.25 (dd,
1 H, J=4.6, 1.2 Hz), 8.02 (br s, 1 H), 7.93 (d, 1 H, J=8.0 Hz), 7.3 8 (dd, 1
H, J=8.3, 4.6 Hz), 7.29
(t, 2H, J=8.0 Hz), 6.98-6.91 (m, 3H), 5.68 (br s, 1H), 4.61 (ABq, JAB= 14.7,
OvAB= 21.8 Hz),
0.97 (s, 9H);
Anal. calcd for CzZHzaNaOa'0.2 HzO: C, 64.13; H, 5.97; N, 13.60. Found: C,
63.91; H, 5.89;
N, 13.89.
Example 89
N-[~~2-[(2-chloropyridin-3-~ amino]-3,4-dioxo-1-cyclobuten-1-yl~amino)-2,2-
dimethylpropyl]-2-phenoxyacetamide
A suspension of the product from Example 29B, the product from Example 88B,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 220-221 °C;
MS (ESI+) m/z 443 (M+H)+;
'H NMR (DMSO-d6) 8 9.37 (s, 1H), 8.50 (d, 1H, J=8.6 Hz), 8.44 (d, 1H, J=8.3
Hz), 8.11 (dd,
1H, J=4.6, 1.5 Hz), 8.03 (d, 1H, J=7.4 Hz), 7.44 (dd, 1H, J=8.3, 4.6 Hz), 7.29
(t, 2H, J=8.0
Hz), 6.98-6.91 (m, 3H), 5.72 (t, 1H, J=8.0 Hz), 4.62 (ABq, JAB= 14.7, OvAB=
22.1 Hz), 0.98 (s,
9H);
Anal. calcd for CZZH23C1N4O4: C, 59.66; H, 5.23; N, 12.65. Found: C, 59.55; H,
5.18; N,
12.68.
Example 90
N-(1-f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino-2,2-
dimeth~prop~)-2-
methyl-2-phen~propanamide
Example 90A
2-methyl-2 phenyl~ropanamide
To a solution of 2-methyl-2-phenylpropionic acid in 100 mL of CHzCIz was added
0.50 mL of DMF and oxalyl chloride (3.40 g, 26.8 mmol). The mixture was
stirred at 23 °C
for 4 hours then the solvent was removed under reduced pressure. The crude
material was
dissolved in 50 mL of THF and 30 mL of NH40H was added. The mixture was
stirred at 23
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°C for 1 hour then and the mixture was concentrated under reduced
pressure. The crude
product was dissolved in 150 mL of EtOAc and washed with 100 mL of 2 N HCI,
100 mL
NaHC03, and 100 mL of brine. The organic phase was dried over Na2S04 and
concentrated.
The product was purified by recrystallization from EtOAc/hexanes to provide
3.50 g (88
yield) of the desired product as a white powder.
MS (DCI/NH3) m/z 164 (M+H)+.
Example 90B
N-[ 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethylpropyl]-2-methyl-2-
phenylpropanamide
A suspension of the product from Example 90A, pivaldehyde, and benzotriazole
were
processed as described in Example 18B to provide the desired product.
MS (DCI/NH3) m/z 351 (M+H)+.
Example 90C
N-( 1- J~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ~ -2,2-
dimethylpropyl)-2-
methyl-2-phenylpropanamide
A suspension of the product from Example 1B, the product from Example 90B, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 247-248 °C;
MS (ESI+) m/z 421 (M+H)+;
1H NMR (DMSO-d6) 8 9.86 (s, 1H), 8.57 (d, 1H, J=2.6 Hz), 8.26 (d, 1H, J=4.6,
1.2 Hz), 7.97
(br s, 1H), 7.93 (d, 1H, J=8.0 Hz), 7.39 (d, 1H, J=8.3, 4.6 Hz), 7.39-7.28 (m,
5H), 7.26-7.19
(m, 1H), 5.58 (t, 1H, J=8.0 Hz), 1.49 (s, 3H), 1.48 (s, 3H), 0.85 (s, 9H);
Anal. calcd for C24H28N4O3: C, 68.55; H, 6.71; N, 13.32. Found: C, 68.34; H,
6.75; N, 13.35.
Example 91
3-chloro-N-( 1- ~~[3,4-dioxo-2-(pyrazin-2-ylamino)-1-cyclobuten-1-yl]amino ~ -
2,2-
dimethyl~ropyl)benzamide
Example 91A
3-ethoxy~2-pyrazinylamino)-3-cyclobutene-1,2-dione
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A solution of aminopyrazine and 3,4-diethoxy-3-cyclobutene-1,2-dione in
ethanol was
processed as described in Example 1A to provide the title compound.
MS (DCI/NH3) m/z 220 (M+H)+.
Example 91B
3-amino-4-(2-pyrazinylamino)-3-cyclobutene-1,2-dione
A solution of the product from Example 91A and ammonia in methanol was
processed
as described in Example 1B to provide the title compound.
MS (DCI/NH3) m/z 191 (M+H)+.
Example 91 C
3-chloro-N-( ~ [3,4-dioxo-2-(pyrazin-2-ylamino)-1-cyclobuten-1-~l amino ) -2,2-
dimeth~propyl)benzamide
A suspension of the product from Example 91B, the product from Example SA, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 245-247 °C;
MS (ESI+) m/z 414 (M+H)+;
1H NMR (DMSO-d6) 8 11.28 (br s, 1H), 8.88 (d, 1H, J=8.5 Hz), 8.83 (d, 1H,
J=10.2 Hz), 8.61
(d, 1H, J=1.4 Hz), 8.31-8.27 (m, 2H), 7.85 (t, 1H, J=1.7 Hz), 7.79 (dt, 1H,
J=7.5, 1.4 Hz), 7.63
(ddd, 1H, J=8.1, 2.2, 1.4 Hz), 7.53 (t, 1H, J=7.8 Hz), 6.05 (dd, 1H, J=9.0,
8.1 Hz), 1.03 (s,
9H);
Anal. calcd for CzoH2oC1N504: C, 58.04; H, 4.87; N, 16.92. Found: C, 57.67; H,
4.85; N,
16.89.
Example 92
N-[ 1-( f 2- f (2-chloropyridin-3-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl )
amino)-3,3-
dimethylbutyl]benzamide
Example 92A
N-[1-(1H-1,2,3-benzotriazol-1-yl)-3,3-dimeth l~yllbenzamide
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A suspension of benzamide, 3,3-dimethyl-butyraldehyde, and benzotriazole were
processed as described in Example 18B to provide the desired product.
MS (DCI/NH3) m/z 323 (M+H)+.
Example 92B
N-[ 1-( f 2-[(2-chloropyridin-3-yl)amino]'',-3,4-dioxo-1-cyclobuten-1-yl~~
amino)-3,3-
dimethylbutyl]benzamide
A suspension of the product from Example 29B, the product from Example 92A,
KzC03, and DMSO as the solvent was processed as described in Example 1D to
provide the
title compound.
mp 259-260 °C;
MS (ESI+) m/z 427 (M+H)+;
'H NMR (DMSO-d6) 8 9.47 (s, 1H), 9.07 (br s, 1H), 8.87 (br s, 1H), 8.08 (dd,
1H, J=4.6, 1.5
Hz), 8.03 (d, 1H, J=8.0 Hz), 7.87 (d, 1H, J=7.1 Hz), 7.58-7.52 (m, 1H), 7.51-
7.45 (m, 2H),
7.41 (dd, 1H, J=8.0, 4.6 Hz), 5.97 (br s, 1H), 2.07 (dd, 1H, J=14.1, 6.8 Hz),
1.83 (dd, 1H,
J=14.1, 5.8 Hz), 0.97 (s, 9H);
Anal. calcd for CZZHz3C1N4O3~O.7S C4HgOz: C, 60.91; H, 5.93; N, 11.36. Found:
C, 60.82; H,
5.76; N, 11.77.
Example 93
3-chloro-N-f 1-( {2-[(6-chloropyridin-3-yl)aminol-3,4-dioxo-1-cyclobuten-1-~)
amino)-2,2-
dimethylpropyllbenzamide
A suspension of the product from Example 62B, the product from Example SA, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 241-242 °C;
MS (ESI+) m/z 481 (M+H)+;
'H NMR (DMSO-d6) b 9.95 (s, 1H), 8.77 (d, 1H, J=7.7 Hz), 8.38 (d, 1H, J=2.9
Hz), 8.04 (br s,
1H), 7.99 (dd, 1H, J=8.8, 2.9 Hz), 7.87 (t, 1H, J=1.8 Hz), 7.80 (dt, 1H,
J=7.7, 1.5 Hz), 7.63
(ddd, 1H, J=8.1, 2.2, 1.1 Hz), 7.56-7.47 (m, 2H), 5.86 (t, 1H, J=8.4 Hz), 1.06
(s, 9H);
Anal. calcd for CZZHZOC12N403: C, 56.39; H, 4.51; N, 12.53. Found: C, 56.11;
H, 4.53; N,
12.33.
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Example 94
3-chloro-N- ( 1-[(3,4-dioxo-2- ~ j6-(trifluoromethyl)pyridin-3-yl] amino ) -1-
cyclobuten-1-
aminol-2,2-dimeth~propyl)benzamide
Example 94A
3,4-dichlorocyclobut-3-ene-1,2-dione
To a solution of squaric acid (5.00 g, 43.8 mmol) in 60 mL of CH2Clz and S
drops of
DMF was added oxalyl chloride (12.2 g, 96.4 mmol), dropwise. The reaction was
stirred at 23
°C for 10 minutes then heated at reflux for 16 hours. The mixture was
cooled to 23 °C and the
solvent removed under reduced pressure. The crude product was distilled at 80
°C (1 mm Hg)
to provide the product (5.92 g, 89 % yield) as a bright yellow solid upon
cooling which was
used immediately to avoid decomposition.
Example 94B
3-chloro-4-methoxycyclobut-3-ene-1,2-dione
To a solution of the product from Example 94A (5.92 g, 39.2 mmol) in 100 mL of
THF
was added MeOH (1.26 g, 39.2 mmol). The mixture was heated at reflux for 2
hours then
allowed to cool to ambient temperature. The solvent was removed under reduced
pressure and
the crude product was dissolved in 100 mL of EtOAc/hexanes (1:1). The mixture
was filtered
through a 1/2" silica gel frit and the frit was washed with an additional 50
mL of
EtOAc/hexanes (1:1). The solvent was removed in vacuo to provide a pale yellow
oil which
solidified on standing. The product (4.56 g, 80 % crude yield) was used
without further
purification.
Example 94C
3-methox~4- { [6-(trifluorometh~)pyridin-3-yl] amino ) -3-cyclobutene-1,2-
dione
Example 94B (1.51 g, 10.3 mmol) was dissolved in 3 mL of DMF and NaHC03 (0.865
g, 10.3 mmol) was added. A solution of 6-(trifluoromethyl)pyridin-3-ylamine
(1.67 g, 10.3
mmol) in 12 mL of CHZCIz was added dropwise and the mixture was stirred at
ambient
temperature for 16 hours. The mixture was diluted with 75 mL of EtOAc and
filtered through
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a pad of Celite. The filtrate was washed with 50 mL of H20 and the aqueous
layer was
extracted twice with SO mL of EtOAc. The combined organic extracts were washed
with 50
mL of brine, dried over Na2S04 and concentrated under reduced pressure. The
crude material
was purified by flash chromatography eluting with EtOAC/hexanes (3:2) to
provide the
desired product (0.281 g, 10 % yield) as a pale yellow powder.
MS (DCI/NH3) m/z 273 (M+H)+.
Example 94D
3-amino-4- i f 6-(trifluorometh~l)pyridin-3-yl]amino-3-c~clobutene-1,2-dione
Example 94C (0.281 g, 1.03 mmol) was dissolved in 20 mL 2.0 M NH3 in MeOH and
the mixture was stirred in a sealed vessel for 16 hours. The solvent was
removed under
reduced pressure and the crude material was triturated with Et20 to provide
the desired
product (0.230 g, 87 % yield) as a pale yellow powder.
MS (ESI+) m/z 258 (M+H)+.
Example 94E
3-chloro-N-~1-[(3,4-dioxo-2-f [6-(trifluoromethyl)pyridin-3-yl]amino -1-
cyclobuten-1-
amino]-2,2-dimethylpropyl)benzamide
A suspension of the product from Example 94D, the product from Example SA, and
K2C03 was processed as described in Example 1D to provide the title compound.
mp 226-227 °C;
MS (ESI+) m/z 481 (M+H)+;
1H NMR (DMSO-db) 8 10.16 (s, 1H), 8.78 (d, 1H, J=7.0 Hz), 8.68 (d, 1H, J=2.2
Hz), 8.21-
8.06 (m, 2H), 7.92-7.85 (m, 2H), 7.80 (d, 1H, J=7.7 Hz), 7.64 (ddd, 1H, J=8.1,
1.8, 1.1 Hz),
7.53 (t, 1H, J=7.8 Hz), 5.88 (br s, 1H), 1.07 (s, 9H);
Anal. calcd for CZZHZOF3N403: C, 54.95; H, 4.19; N, 11.65. Found: C, 54.80; H,
4.17; N,
11.52.
Example 95
3-chloro-N-[1-(~2-[~2-chloropyridin-3-yl)aminol-3,4-dioxo-1-cyclobuten-1-
yl}amino -
dimeth~propyl]benzamide
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A suspension of the product from Example 29B, the product from Example SA, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 213-214 °C;
MS (ESI+) m/z 448 (M+H)+;
'H NMR (DMSO-d6) 8 9.46 (s, 1H), 8.77 (d, 1H, J=8.1 Hz), 8.50 (d, 1H, J=8.8
Hz), 8.12 (dd,
1 H, J=4.4, 1.5 Hz), 8.03 (dd, 1 H, J=8.1, 1.5 Hz), 7.88 (t, 1 H, J=1.7 Hz),
7. 81 (dt, 1 H, J=7.7,
1.5 Hz), 7.63 (ddd, 1H, J=8.1, 1.8, 1.8 Hz), 7.57-7.48 (m, 1H), 7.44 (dd, 1H,
J=8.1, 4.8 Hz),
.91 (t, 1 H, J=8.1 Hz), 1.07 (s, 9H);
Anal. calcd for CZIHzoC12N403~0.65 H20: C, 54.95; H, 4.68; N, 12.21. Found: C,
54.80; H,
4.40; N, 11.92.
Exam In a 96
N-( 1- { [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ) -2,2-
dimethyl-3-
phenylpropyl)isonicotinamide
Example 96A
N-,[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-3-
phenylpropyllisonicotinamide
The product from Example 18A, isonicotinamide, benzotriazole, and p-
toluenesulfonic
acid in toluene were processed as described in Example 18B to provide the
title compound.
MS (ESI+) m/z 386 (M+H)+.
Example 96B
N-( 1- (~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ) -2,2-
dimethyl-3-
phenylprop~)isonicotinamide
A suspension of the product from Example 1B, the product from Example 96A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 251-254 °C;
MS (ESI+) m/z 456 (M+H)+;
1H NMR (DMSO-d6) b 9.92 (br s, 1H), 9.07 (br d, 1H, J=8.1 Hz), 8.79-8.75 (m,
2H), 8.58 (d,
1 H, J=2.7 Hz), 8.27 (dd, 1 H, J=4.7, 1.2 Hz), 8.19-8.11 (m, 1 H), 7.95 (br d,
1 H, J=7.1 Hz),
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7.78-7.75 (m, 2H), 7.40 (dd, 1H, J=8.5, 4.8 Hz), 7.34-7.19 (m, SH), 5.95 (t,
1H, J=7.8 Hz),
2.73 (ABq, 2H, JAB=12.9 Hz, OvAB=25.1 Hz), 0.96 (s, 3H), 0.94 (s, 3H);
Anal. calcd for C26H2sNs03: C, 68.56; H, 5.53; N, 15.37. Found: C, 68.37; H,
5.31; N, 15.20.
Ex~ 97
1- { [3,4-dioxo-2-(3-p~dinylamino)-1-cyclobuten-1-~1 amino } -2,2-dimethyl-3-
phenylpropyl)-3-phenylpropanamide
Example 97A
N-[ 1-( 1H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-3-phenylprop~]-3-
phenylpropionamide
A suspension of 3-(phenyl)propionamide, the product from Example 18A,
benzotriazole, and p-toluenesulfonic acid was processed as described in
Example 1C to
provide the title compound.
MS (DCI/NH3) m/z 413 (M+H)+.
Example 97B
N-(1- j3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino)-2,2-dimethyl-3-
phenYlpropyl)-3-phen~propanamide
A suspension of the product from Example 1B, the product from Example 97A, and
K2C03 was processed as described in Example 1D to provide the title compound.
mp 221-223 °C;
MS (ESI+) m/z 483 (M+H)+;
1H NMR (DMSO-d6) 8 9.73 (s, 1H), 8.57 (d, 1H, J=2.4 Hz), 8.34 (br s, 1H), 8.24
(dd, 1H,
J=4.8, 1.4 Hz), 8.06-7.90 (m, 2H), 7.39 (dd, 1H, J=8.1, 4.8 Hz), 7.33-7.09 (m,
10H), 5.70 (br
s, 1H), 2.91-2.81 (m, 2H), 2.69-2.54 (m, 4H), 0.85 (s, 3H), 0.81 (s, 3H);
Anal. calcd for C29H3pN4O3~ C, 72.18; H, 6.27; N, 11.61. Found: C, 71.86; H,
6.02; N, 11.41.
Example 98
N-( 1- f-[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~] amino) -2,2-dimeth
phenylpropyl)-2-methyl-2-phenylpropanamide
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Example 98A
N-f 1-(1H-1,2,3-benzotriazol-1-~~ 2 2-dimethyl-3-phen~propyl]-2-meth,
phenylpropanamide
A suspension of the product from Example 90A, the product from Example 18A,
benzotriazole, and p-toluenesulfonic acid was processed as described in
Example 1C to
provide the title compound.
MS (DCI/N 3) m/z 427 (M+H)+.
Example 98B
N-(1- ~[3,4-dioxo-2-(3-p rr~ylamino)-1-cyclobuten-1-yllamino)-2,2-dimeth.
phen~propyl)-2-methyl-2 phenylpropanamide
A suspension of the product from Example 1B, the product from Example 98A, and
KZC03 was processed as described in Example 92B to provide the title compound.
mp 228-231 °C;
MS (ESI+) m/z 497 (M+H)+;
'H NMR (DMSO-db) S 9.90 (s, 1H), 8.58 (d, 1H, J=2.7 Hz), 8.26 (dd, 1H, J=4.7,
1.4 Hz), 8.05
(br s, 1H), 7.94 (d, 1H, J=7.7 Hz), 7.51 (br s, 1H), 7.40 (dd, 1H, J=8.5, 4.8
z), 7.37-7.16 (m,
7H), 7.10-7.03 (m, 3H), 5.67 (br s, 1H), 2.51-2.44 (m, 2H, PhCH2 obscured),
1.50 (s, 6H),
0.74 (s, 3H), 0.72 (s, 3H);
Anal. calcd for C3pH32N4~3~ C, 72.56; H, 6.49; N, 11.28. Found: C, 72.72; H,
6.40; N, 11.26.
Example 99
N-( 1- { j3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ) -2,2-
dimethyl-3-
phen~propyl)-2-phenoxyacetamide
Example 99A
N-f 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-3-phenylpropyl)-2-
phenoxyacetamide
A suspension of the product from Example 88A, the product from Example 18A,
benzotriazole, and p-toluenesulfonic acid was processed as described in
Example 1 C to
provide the title compound.
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MS (DCI/NH3) m/z 415 (M+H)+.
Example 99B
N-(1-ff3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]aminol-2 2-dimethyl-3-
phenylpropyl)-2-phenoxyacetamide
A suspension of the product from Example 1B, the product from Example 99A, and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 249-250 °C;
MS (ESI+) m/z 485 (M+H)+;
~H NMR (DMSO-d6) 8 9.80 (s, 1H), 8.62 (d, 1H, J=7.5 Hz), 8.57 (d, 1H, J=2.4
Hz), 8.25 (dd,
1H, J=4.7, 1.4 Hz), 8.10 (br s, 1H), 7.93 (d, 1H, J=8.2 Hz), 7.39 (dd, 1H,
J=8.5, 4.7 Hz), 7.34-
7.18 (m, SH), 7.17-7.11 (m, 2H), 6.99-6.91 (m, 3H), 5.74 (br s, 1H), 4.66
(ABq, 2H, JAB= 14.6
Hz, OvAB= 20.7 Hz), 2.61 (d, 2H, J=4.4 Hz), 0.87 (s, 3H), 0.84 (s, 3H);
Anal. calcd for CZgH2gN4O4: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.51; H,
5.76; N, 11.44.
Example 100
N-( 1- { [3,4-dioxo-2-(3-p~ylamino)-1-cyclobuten-1-yll amino ) -2,2-dimethyl-3-
phenylpropyl)nicotinamide
Example 100A
N-[ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimethyl-3-phen~pro~yllnicotinamide
The product from Example 18A, nicotinamide, benzotriazole, and p-
toluenesulfonic
acid in xylene were processed as described in Example 18B to provide the title
compound.
MS (ESI+) m/z 386 (M+H)+.
Example 100B
~1- f~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino)-2,2-dimethyl-3-
3-
phen~propyl)nicotinamide
A suspension of the product from Example 1B, the product from Example 100A,
and
KzC03 was processed as described in Example 1D to provide the title compound.
mp 253-254 °C;
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MS (ESI+) m/z 456 (M+H)+;
'H NMR (DMSO-d6) 8 9.87 (s, 1H), 9.03 (d, 1H, J=2.1 Hz), 8.98 (br d, 1H, J=7.5
Hz), 8.75
(dd, 1 H, J=4.8, 1.7 Hz), 8.59 (d, 1 H, J=2.8 Hz), 8.25 (dd, 1 H, J=4.7, 1.4
Hz), 8.21 (dt, 1 H,
J=7.8, 1.7 Hz), 8.20-8.13 (m, 1H), 7.95 (br d, 1H, J=8.4 Hz), 7.55 (ddd, 1H,
J=8.1, 4.7, 0.7
Hz), 7.39 (dd, 1H, J=8.4, 4.7 Hz), 7.34-7.26 (m, 2H), 7.26-7.18 (m, 3H), 5.96
(t, 1H, J=7.5
Hz), 2.75 (ABq, 2H, J,~=12.9 Hz, 4vAB=25.8 Hz), 0.97 (s, 3H), 0.92 (s, 3H);
Anal. calcd for C26HzsNs03: C, 68.56; H, 5.53; N, 15.37. Found: C, 68.42; H,
5.52; N, 15.40.
Example 101
N-(1- f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-~lamino~-2,2-
dimethylpropyl)nicotinamide
Example lOlA
N-[ 1-(1H-1,2,3-benzotriazol-1-yl~-2,2-dimeth~propyl~nicotinamide
Nicotinamide, benzotriazole, pivaldehyde and p-toluenesulfonic acid in xylene
were
processed as described in Example 18B to provide the title compound.
MS (ESI+) m/z 310 (M+H)+.
Example lOlB
N-( 1- l~[3,4-dioxo-2 ~3-pyridinylamino)-1-cyclobuten-1-~l amino -2,2-dimethyl-
3-
phenylprop~)nicotinamide
A suspension of the product from Example 1B, the product from Example IOIA,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 233-234 °C;
MS (ESI+) m/z 380 (M+H)+;
'H NMR (DMSO-d6) 8 9.86 (br s, 1H), 8.98 (d, 1H, J=2.4 Hz), 8.87 (br d, 1H,
J=7.8 Hz), 8.73
(dd, 1H, J=4.7, 1.4 Hz), 8.57 (d, 1H, J=2.4 Hz), 8.25 (dd, 1H, J=4.7, 1.4 Hz),
8.17 (dt, 1H,
J=8.1, 2.0 Hz), 8.11-8.04 (m, 1H), 7.94 (ddd, 1H, J=9.2, 2.7, 1.0 Hz), 7.53
(dd, 1H, J=8.1, 4.7
Hz), 7.39 (dd, 1H, J=8.1, 4.7 Hz), 5.88 (t, 1H, J=7.8 Hz), 1.07 (s, 9H);
Anal. calcd for CZOH21N5O3: C, 63.61; H, 5.58; N, 18.43. Found: C, 63.61; H,
5.67; N, 18.43.
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Example 102
N~~[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino~-2 2-
dimethylpro~yl)isonicotinamide
Example 102A
N-f 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~propyl]isonicotinamide
Isonicotinamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid in
xylene were
processed as described in Example 18B to provide the title compound.
MS (ESI+) m/z 310 (M+H)+.
Example 102B
N-( 1- f ~3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yll amino 1-2,2-
dimethyl-3-
phenyl~ropyl)nicotinamide
A suspension of the product from Example 1B, the product from Example 102A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 220-222 °C;
MS (ESI+) m/z 380 (M+H)+;
'H NMR (DMSO-d6) 8 9.88 (br s, 1H), 8.95 (d, 1H, J=7.5 Hz), 8.76-.71 (m, 2H),
8.57 (d, 1H,
J=2.7 Hz), 8.25 (dd, 1H, J=4.7, 1.4 Hz), 8.05 (br s, 1H), 7.93 (ddd, 1H,
J=8.1, 2.7, 1.4 Hz),
7.74-7.71 (m, 2H), 7.39 (dd, 1H, J=8.5, 4.7 Hz), 5.86 (t, 1H, J=7.5 Hz), 1.06
(s, 9H);
Anal. calcd for CzpH2~N5O3: C, 63.61; H, 5.58; N, 18.46. Found: C, 63.31; H,
5.67; N, 18.47.
Example 103
N-(~ [3,4-dioxo-2-(3-p~-'~dinylamino)-1-cyclobuten-1-yl] amino~~ -2,2-
dimeth~propyl)-2-
furamide
Example 103A
N-f 1-(1H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~propyll-2-furamide
Furan-2-carboxamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid in
xylene
were processed as described in Example 18B to provide the title compound.
MS (ESI+) m/z 299 (M+H)+.
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Example 103B
N-(1-f f3,4-dioxo-2-(3-p ~dinylamino)-1-c~clobuten-1-yl]amino~-2 2-dimethyl-3-
phenylpropyl)nicotinamide
A suspension of the product from Example 1B, the product from Example 103A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 204-205 °C;
MS (ESI+) m/z 369 (M+H)+;
'H NMR (DMSO-d6) 8 9.95 (br s, 1H), 8.61 (br d, 1H, J=8.1 Hz), 8.57 (d, 1H,
J=2.7 Hz), 8.25
(dd, 1 H, J=4.7, 1.4 Hz), 8.18-8.08 (m, 1 H), 7.98-7.91 (m, 2H), 7.82 (dd, 1
H, J=S. l , 1.4 Hz),
7.38 (dd, 1H, J=8.1, 4.7 Hz), 7.18 (dd, 1H, J=5.1, 3.7 Hz), 5.80 (t, 1H, J=8.5
Hz), 1.05 (s, 9H);
Anal. calcd for Cl9HzoNaOa: C, 61.95; H, 5.47; N, 15.21. Found: C, 61.72; H,
5.33; N, 15.24.
Example 104
N-(1-f [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino~-2,2-dimethyl-3-
pyridin-4-
ylpropyl)-3-methylbenzamide
Example 104A
2,2-dimeth~pyridin-4-ylpropanal
4-(Bromomethyl)pyridine hydrobromide (5.00 g, 19.8 mmol) was suspended in
ethyl
acetate (40 mL) and water (20 mL) and washed with 10% aq. NaHC03 solution (35
mL) to
generated the free base. The layers were partitioned and the organic portion
was concentrated
and redissolved in benzene (30 mL). To this solution was added
tetrabutylammonium iodide
(112 mg, 0.303 mmol) and isobutyraldehyde (1.10 g, 15.2 mmol). The solution of
aledyde
and bromide was then added via addition funnel in dropwise fashion over a
period of 30
minutes to a stirred suspension of powdered NaOH (608 mg, 15.2 mmol) in
benzene (90 mL)
at 60 °C. The reaction was stirred at 60 °C for 5 hours then
cooled to ambient temperature.
EtOAc (40 mL) was added and the reaction mixture was washed with water (40
mL), satd. aq.
sodium bisulfate solution (2 x 25 mL), then brine (30 mL). The organic portion
was dried
(NazS04) and concentrated. Purification of the resulting oily residue by flash
chromatography
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(gradient elution: hexanes then 7% EtOH/hexanes) provided the title compound
(608 mg,
3.73 mmol) as a off yellow waxy solid.
MS (DCI/NH3) m/z 164 (M+H)+.
Example 104B
N-~ 1-( 1 H-1,2,3-benzotriazol-1-yl)-2,2-dimeth~(pyridin-4-yl)propyl]-3-
methylbenzamide
The product from Example 104A, m-toluamide, benzotriazole, and p-
toluenesulfonic
acid were processed as described in Example 1 C to provide the title compound.
MS (DCI/NH3) m/z 400 (M+H)+.
Example 104C
N-(~ [3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yll amino ) -2,2-dimethyl-
3-pyridin-4-
ylpropyl)-3-methylbenzamide
A suspension of the product from Example 1B, the product from Example 104B,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 219-221 °C;
MS (ESI+) m/z 470 (M+H)+;
1H NMR (DMSO-d6) 8 8.81 (br s, 1H), 8.59 (br d, 1H, J=2.4 Hz), 8.50-8.43 (m,
2H), 8.24 (dd,
1H, J=4.7, 1.4 Hz), 7.98-7.86 (m, 2H), 7.71-7.62 (m, 3H), 7.44 (dd, 1H, J=6.4,
3.1 Hz), 7.41-
7.23 (m, 4H), 5.99-5.92 (m, 1H), 2.84 (ABq, 2H, JAB=11.2, wAB=22.0 Hz), 2.41
(s, 3H), 0.99
(s, 3H), 0.91 (s, 3H);
Anal. calcd for C27H27NSO3: C, 69.07; H, 5.80; N, 14.92. Found: C, 68.90; H,
5.88; N, 14.77.
Example 105
(-) 3-chloro-N-(1-{[3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yllamino)-
2,2-dimethyl-
3-phenylpropyl)benzamide
The product from Example 59B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10%
ethanol/hexanes
(flow rate=10 mL/minute) to provide the title compound as the levorotatory
enantiomer.
[a,~p2o - _80° (c 0.20, DMSO);
mp 178-179 °C;
MS (ESI+) m/z 489 (M+H)+;
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'H NMR (DMSO-d6) ~ 9.87 (s, 1H), 8.90 (d, 1H, J=3.7 Hz), 8.60 (d, 1H, J=1.6
Hz), 8.26 (d,
1H, J=4.2 Hz), 8.13 (br s, 1H), 7.95 (dd, 1H, J=8.3, 1.2 Hz), 7.90 (t, 1H,
J=1.7 Hz), 7.83 dt,
1H, J=7.8, 1.2 Hz), 7.65 (ddd, 1H, J=8.0, 2.1, 1.2 Hz), 7.55 (t, 1H, J=8.1
Hz), 7.39 (dd, 1H,
J=8.2, 4.7 Hz), 7.32-7.20 (m, 5H), 5.95 (s, 1H), 2.74 (ABq, JAB=12.8,
OvAB=32.1 Hz), 0.97 (s,
3H), 0.95 (s, 3H).
Example 106
(+) 3-chloro-N-(1-f f3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl]amino-2
2-dimethyl-
3-phen~propyl)benzamide
The product from Example 59B was chromatographed over a Daicel Chiral
Technologies Chiralpak AS chiral column (2.0 cm x 25 cm) eluting with 10%
ethanol/hexanes
(flow rate=10 mL/minute) to provide the title compound as the dextrorotatory
enantiomer.
[a.]D2o = +78~ (c 0.24, DMSO);
mp 178-179 °C;
MS (ESI+) m/z 489 (M+H)+;
'H NMR (DMSO-d6) b 9.87 (s, 1H), 8.90 (d, 1H, J=3.7 Hz), 8.60 (d, 1H, J=1.6
Hz), 8.26 (d,
1H, J=4.2 Hz), 8.13 (br s, 1H), 7.95 (dd, 1H, J=8.3, 1.2 Hz), 7.90 (t, 1H,
J=1.7 Hz), 7.83 dt,
1H, J=7.8, 1.2 Hz), 7.65 (ddd, 1H, J=8.0, 2.1, 1.2 Hz), 7.55 (t, 1H, J=8.1
Hz), 7.39 (dd, 1H,
J=8.2, 4.7 Hz), 7.32-7.20 (m, 5H), 5.95 (s, 1H), 2.74 (ABq, JAB=12.8,
OvAB=32.1 Hz), 0.97 (s,
3H), 0.95 (s, 3H);
Anal. calcd for C27HZSC1N403~0.5 HzO: C, 65.12; H, 5.26; N, 11.25. Found: C,
65.19; H,
5.42; N, 11.26.
Example 107
4-chloro-N-( ~ f 3,4-dioxo-2-(3-p~dinylamino)-1-cyclobuten-1-yl] amino,
methyl)benzamide
Example 107A
1 H-1,2,3-benzotriazol-1-ylmethYl)-4-chlorobenzamide
4-Chlorobenzamide, paraformaldehyede, benzotriazole, and p-toluenesulfonic
acid
were processed as described in Example 18B to provide the title compound.
MS (DCI/NH3) m/z 287 (M+H)+.
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Example 107B
4-chloro-N-( { f 3,4-dioxo-2-(3-pyridinylamino)-1-cyclobuten-1-yl] amino ~
methyl)benzamide
A suspension of the product from Example 1B, the product from Example 107A,
and
KZC03 was processed as described in Example 1B to provide the title compound.
mp 174-176 °C;
MS (ESI+) m/z 357 (M+H)+;
IH NMR (DMSO-d6) 8 9.99 (br t, 1H, J=6.1 Hz), 8.04 (br d, 2H, J=8.4 Hz), 7.91
(d, 2H, J=8.8
Hz), 7.63-7.52 (m, 4H), 7.43 (d, 1H, J=8.1 Hz), 7.40 (d, 1H, J=8.1 Hz), 6.21
(app d, 2H, J=6.4
Hz);
Anal. calcd for C17H13N4O3: C, 57.23; H, 3.67; N, 15.70. Found: C, 56.85; H,
3.65; N, 16.10.
Example 108
(+) 3,5-dichloro-N-[(1S)-1- f2-[(2-chloropyridin-3-yl)amino]-3,4-dioxocyclobut-
1-en-1-
~~ amino)-2,2-dimethylpropyllbenzamide
The product from Example 79 was chromatographed over a Regis Technologies
Whelk-O1 chiral column (2.0 cm x 25 cm) using gradient elution (10% methanol-
CHZCl2
(2:1)/hexanes to 30% methanol-CHZCIz (2:1)/hexanes, flow rate=10 mL/minute) to
provide
the title compound.
[a]p ° _ +45° (c 0.15, DMSO);
mp 233-234 °C;
MS (ESI+) m/z 482 (M+H)+;
HRMS (FAB) calcd for C2~HZpCI3N4O3 (M+H)+ 481.0601; found 481.0581;
'H NMR (DMSO-d6) 8 9.45 (s, 1H), 8.86 (d, 1H, J=7.7 Hz), 8.47 (d, 1H, J=8.9
Hz), 8.12 (dd,
1H, J=4.6, 1.8 Hz), 8.03 (d, 1H, J=8.0 Hz), 7.86 (d, 2H, J=2.2 Hz), 7.82 (t,
1H, J=1.8 Hz), 7.45
(dd, 1H, J=8.3, 4.6 Hz), 5.90 (t, 1H, J=8.0 Hz), 1.08 (s, 9H);
Anal. calcd for Cz~H,9C13N4O3: C, 52.35; H, 3.98; N, 11.63. Found: C, 52.38;
H, 3.84; N,
11.82.
Example 109
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(-) 3,S-dichloro-N-f(1R)-1-(f2-f(2-chloropyridin-3-Xl)amino]-3,4-dioxocyclobut-
1-en-1
yl ~ amino)-2,2-dimethylpro~yl]'benzamide
The product from Example 79 was chromatographed over a Regis Technologies
Whelk-O1 chiral column (2.0 cm x 25 cm) using gradient elution (10% methanol-
CHzCl2
(2:1)/hexanes to 30% methanol-CHZC12 (2:1)/hexanes, flow rate=10 mL/minute) to
provide
the title compound. The absolute stereochemistry was determined by x-ray
diffraction.
[a]DZO =--46~ (c 0.15, DMSO);
mp 233-234 °C;
Crystal data: Single crystals suitable for x-ray diffraction were grown by
slow evaporation
from hexanes:CH2C12:methanol, crystal dimensions 0.40X0.40X0.10 mm,
orthorhombic,
P2,2,21 (#19), a=8.344(1) ~, b=11.832(2) A, c=24.993(3) ~, V=2467.3(5) A3,
Z=4,
Dcaic 1.383 g/cm3. Crystallographic data were collected using Mo K a radiation
(~,=0.71069
~); Refinement of the structure using full matrix least squares refinement was
based on 4011
observed reflections (I>3.OOa(I)) and 298 variable parameters, R=0.069, Rw
0.088;
MS (ESI+) m/z 482 (M+H)+;
'H NMR (DMSO-d6) b 9.45 (s, 1H), 8.86 (d, 1H, J=7.7 Hz), 8.47 (d, 1H, J=8.9
Hz), 8.12 (dd,
1H, J=4.6, 1.8 Hz), 8.03 (d, 1H, J=8.0 Hz), 7.86 (d, 2H, J=2.2 Hz), 7.82 (t,
1H, J=1.8 Hz), 7.45
(dd, 1H, J=8.3, 4.6 Hz), 5.90 (t, 1H, J=8.0 Hz), 1.08 (s, 9H).
Example 110
(+) N-(1-~[3,4-dioxo-2-(2-chloro3-pyridinylamino)-1-cyclobuten-1-~lamino}-2,2-
dimethylprop~l-3,5-difluorobenzamide
Example 110A
N-(1- f j3,4-dioxo-2-(2-chloro3-pyridinylamino)-1-cyclobuten-1-yllamino -2,2-
dimethylpropyl)-3,5-difluorobenzamide
A suspension of the product from Example 29B, the product from Example 16A,
and
KZC03 was processed as described in Example 1D to provide the title compound.
mp 215-217 °C;
MS (ESI+) m/z 449 (M+H)+;
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'H NMR (DMSO-d6) 8 9.47 (s, 1H), 8.77 (d, 1H, J=8.1 Hz), 8.48 (d, 1H, J=8.8
Hz), 8.11 (dd,
1H, J=4.8, 1.7 Hz), 8.02 (dd, 1H, J=8.1, 1.4 Hz), 7.62-7.42 (m, 4H), 5.89 (t,
1H, J=8.1 Hz),
1.08 (s, 9H).
Example 1 lOB
(+) N-(1-f f3,4-dioxo-2-(2-chloro3-p, ryridinylamino)-1-cyclobuten-1-yl]amino)-
2 2-
dimethylpropyl)-3,5-difluorobenzamide
The product from Example 1 10A was chromatographed over a Regis Technologies
Whelk-O1 chiral column (2.0 cm x 25 cm) using gradient elution (10% methanol-
CHZC12
(2:1)/hexanes to 30% methanol-CHZCl2 (2:1)/hexanes, flow rate=10 mL/minute) to
provide
the title compound as the dextrororotatory enantiomer.
Via,]D2o - +73° (c 0.13, DMSO);
mp 215-216 °C;
MS (ESI+) m/z 449 (M+H)+;
'H NMR (DMSO-d6) 8 9.47 (s, 1H), 8.77 (d, 1H, J=8.1 Hz), 8.48 (d, 1H, J=8.8
Hz), 8.11 (dd,
1H, J=4.8, 1.7 Hz), 8.02 (dd, 1H, J=8.1, 1.4 Hz), 7.62-7.42 (m, 4H), 5.89 (t,
1H, J=8.1 Hz),
1.08 (s, 9H);
Anal. calcd for CZ~H19FC1zNqO3: C, 56.19; H, 4.27; N, 12.48. Found: C, 56.00;
H, 4.23; N,
12.29.
Example 111
(-) N-(1-(~3,4-dioxo-2-(2-chloro3-p ryridinylamino -1-cyclobuten-1-yl]amino)-
2,2-
dimethylpropyl)-3,5-difluorobenzamide
The product from Example 1 10A was chromatographed over a Regis Technologies
Whelk-O1 chiral column (2.0 cm x 25 cm) using gradient elution (10% methanol-
CHzCl2
(2:1)/hexanes to 30% methanol-CHZCIz (2:1)/hexanes, flow rate=10 mL/minute) to
provide
the title compound as the levororotatory enantiomer.
[a,]DZO _ _69° (c 0.20, DMSO);
mp 21 S-217 °C;
MS (ESI+) m/z 449 (M+H)+;
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1 H NMR (DMSO-d6) 8 9.47 (s, 1 H), 8.77 (d, 1 H, J=8.1 Hz), 8.48 (d, 1 H, J=8.
8 Hz), 8.11 (dd,
1 H, J=4. 8, 1.7 Hz), 8.02 (dd, 1 H, J=8.1, 1.4 Hz), 7.62-7.42 (m, 4H), 5. 89
(t, 1 H, J=8.1 Hz),
1.08 (s, 9H);
Anal. calcd for CZ,H~9FC1ZN403: C, 56.19; H, 4.27; N, 12.48. Found: C, 55.93;
H, 4.48; N,
12.20.
Determination of Potassium Channel Opening Activity
Membrane Hyperpolarization Assays
Compounds were evaluated for potassium channel opening activity using primary
cultured guinea-pig urinary bladder (GPB) cells.
For the preparation of urinary bladder smooth muscle cells, urinary bladders
were
removed from male guinea-pigs (Hartley, Charles River, Wilmington, MA)
weighing 300-400
g and placed in ice-cold Ca2+-free Krebs solution (composition, mM: KCI, 2.7;
KHZP04, 1.5;
NaCI, 75; Na2HP04, 9.6; NaZHP04~7HZ0, 8; MgS04, 2; glucose, 5; HEPES, 10; pH
7.4).
Cells were isolated by enzymatic dissociation as previously described with
minor
modifications (Klockner and Isenberg, Pflugers Arch. (1985), 405, 329-339),
hereby
incorporated by reference. The bladder was cut into small sections and
incubated in 5 mL of
the Kreb's solution containing 1 mg/mL collagenase (Sigma, St. Louis, MO) and
0.2 mg/mL
pronase (Calbiochem, La Jolla, CA) with continuous stirring in a cell
incubator for 30
minutes. The mixture was then centrifuged at 1300 x g for 5 minutes, and the
pellet
resuspended in Dulbecco's PBS (GIBCO, Gaithersburg, MD) and recentrifuged to
remove
residual enzyme. The cell pellet was resuspended in 5 mL growth media
(composition:
Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum,
100
units/mL penicillin, 100 units/mL streptomycin and 0.25 mg/mL amphotericin B)
and further
dissociated by pipetting the suspension through a flame-polished Pasteur
pipette and passing it
through a polypropylene mesh membrane (Spectrum, Houston, TX). The cell
density was
adjusted to 100,000 cells/mL by resuspension in growth media. Cells were
plated in clear-
bottomed black 96-well plates (Packard) for membrane potential studies at a
density of 20,000
cells/well and maintained in a cell incubator with 90% air:10% COZ until
confluent. Cells
were confirmed to be of smooth muscle type by cytoskeletal staining using a
monoclonal
mouse anti human-a-smooth muscle actin (Biomeda, Foster City, CA).
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Functional activity at potassium channels was measured by evaluating changes
in
membrane potential using the bis-oxonol dye DiBAC(4)3 (Molecular Probes) in a
96-well cell-
based kinetic assay system, Fluorescent Imaging Plate Reader (FLIPR) (K.S.
Schroeder et al.,
J. Biomed. Screen., v. 1 pp. 75-81 (1996)), hereby incorporated by reference.
DiBAC(4)3 is
an 'anionic potentiometric probe which partitions between cells and
extracellular solution in a
membrane potential-dependent manner. With increasing membrane potential (for
example, K+
depolarization), the probe further partitions into the cell; this is measured
as an increase in
fluorescence due to dye interaction with intracellular lipids and proteins.
Conversely,
decreasing membrane potential (hyperpolarization by potassium channel openers)
evokes a
decrease in fluorescence.
Confluent guinea-pig urinary bladder cells cultured in black clear-bottomed 96-
well
plates were rinsed twice with 200 mL assay buffer (composition, mM: HEPES, 20;
NaCI,
120; KCI, 2; CaCl2, 2; MgCl2, 1; glucose, 5; pH 7.4 at 25 °C)
containing 5 ~M DiBAC(4)3
and incubated with 180 mL of the buffer in a cell incubator for 30 minutes at
37 °C to ensure
dye distribution across the membrane. After recording the baseline
fluorescence for 5
minutes, the reference or test compounds, prepared at 10 times the
concentration in the assay
buffer, were added directly to the wells. Changes in fluorescence were
monitored for an
additional 25 minutes. Hyperpolarization responses were corrected for any
background noise
and were normalized to the response observed with 10 ~M of the reference
compound P 1075
(assigned as 100%), a potent opener of smooth muscle KATP channels (Quast et
al., Mol.
Pharmacol., v. 43 pp. 474-481 (1993)).
Routinely, five concentrations of P1075 or test compounds (log or half log
dilutions)
were evaluated and the maximal steady-state hyperpolarization values
(expressed as % relative
to P1075) plotted as a function of concentration. The ECSO (concentration that
elicites 50% of
the maximal response for the test sample) values were calculated by non-linear
regression
analysis using a four parameter sigmoidal equation. The maximal response of
each compound
(expressed as % relative to P1075) is reported. Stock solutions of compounds
were prepared
in 100% DMSO and further dilutions were carned out in the assay buffer and
added to a 96-
well plate.
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Table 1
Membrane Hyperpolarization (MHP) in Guinea-Pig Bladder (GPB) Cells
Maximal MHP GPB
Response ECso
xample # (% P 1075)(p,M)
1 91 0.15
2 108 0.16
17 96 0.18
18 97 0.51
19 <20 >10
20 98 0.58
60 83 0.093
In Vitro Functional Models
Compounds were evaluated for functional potassium channel opening activity
using
tissue strips obtained from Landrace pig bladders.
Landrace pig bladders were obtained from female Landrace pigs of 9-30 kg.
Landrace
pigs were euthanized with an intraperitoneal injection of pentobarbital
solution, Somlethal~ ,
J.A. Webster Inc., Sterling MA. The entire bladder was removed and immediately
placed into
Krebs Ringer bicarbonate solution (composition, mM: NaCI, 120; NaHC03, 20;
dextrose, 11;
KCI, 4.7; CaCl2, 2.5; MgS04, 1.5; KHzP04, 1.2; KZEDTA, 0.01, equilibrated with
5%
COz/95% Oz pH 7.4 at 37 °C). Propranolol (0.004 mM) was included in all
of the assays to
block (3-adrenoceptors. The trigonal and dome portions were discarded. Strips
3-5 mm wide
and 20 mm long were prepared from the remaining tissue cut in a circular
fashion. The
mucosal layer was removed. One end was fixed to a stationary glass rod and the
other to a
Grass FT03 transducer at a basal preload of 1.0 gram. Two parallel platinum
electrodes were
included in the stationary glass rod to provide field stimulation of 0.05 Hz,
0.5 mini-seconds at
20 volts. This low frequency stimulation produced a stable twitch response of
100-500
centigrams. Tissues were allowed to equilibrate for at least 60 minutes and
primed with 80
mM KCI. A control concentration response curve (cumulative) was generated for
each tissue
using the potassium channel opener P1075 as the control agonist. P1075
completely
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eliminated the stimulated twitch in a dose dependent fashion over a
concentration range of 10-9
to 10-5 M dissolved in DMSO using 1/2 log increments. After a 60 minute
rinsing period, a
concentration response curve (cumulative) was generated for the test agonist
in the same
fashion as that used for the control agonist P1075. The maximal efficacy of
each compound
(expressed as % relative to P1075) is reported. The amount of agent necessary
to cause 50%
of the agent's maximal response (EDso) was calculated using "ALLFIT" (DeLean
et al., Am.
J. Physiol., 235, E97 (1980)), hereby incorporated by reference. Agonist
potencies were also
expressed as an index relative to P 1075. The index was calculated by dividing
the EDSO for
P1075 by the EDso for the test agonist in a given tissue. Each tissue was used
for only one test
agonist, and the indices obtained from each tissue were averaged to provide an
average index
of potency. These data are shown in Table 2.
Table 2
Functional Potassium Channel Opening Activity in Isolated Bladder Strips
Landrace
Pig
Bladder
EfficacyEDso
Example (%P1075)(pM) Index
#
1 54 19 0.008
2 79 6.9 0.047
3 73 2.2 0.062
98 0.38 0.059
6 100 1.0 0.067
7 89 8.4 0.025
8 84 2.8 0.047
12 78 2.6 0.12
13 75 0.37 0.57
16 94 3.8 0.046
17 92 5.8 0.028
18 62 17 0.055
21 68 4.0 0.092
26 64 0.42 0.64
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29 81 3.0 0.028
31 76 2.9 0.039
32 99 1.3 0.076
36 99 0.97 0.063
49 100 1.2 0.071
50 79 6.8 0.14
51 96 1.4 0.080
55 75 2.3 0.053
56 94 2.2 0.028
57 81 4.0 0.015
59 57 1.7 0.062
60 88 0.68 0.87
61 64 0.47 0.50
64 76 4.2 0.025
66 74 4.2 0.040
67 72 2.5 0.029
78 98 0.84 0.18
79 60 4.6 0.024
86 85 0.64 0.24
87 96 1.9 0.039
108 89 4.2 0.033
As shown by the data in Tables 1 and 2, the compounds of this invention reduce
stimulated contractions of the bladder by opening potassium channels and
therefore can have
utility in the treatment of diseases prevented by or ameliorated with
potassium channel
openers.
The term "pharmaceutically acceptable carrier," as used herein, means a non-
toxic,
inert solid, semi-solid or liquid filler, diluent, encapsulating material or
formulation auxiliary
of any type. Some examples of materials which can serve as pharmaceutically
acceptable
carriers are sugars such as lactose, glucose and sucrose; starches such as
corn starch and potato
starch; cellulose and its derivatives such as sodium carboxymethyl cellulose,
ethyl cellulose
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and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients
such as cocoa butter
and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil,
sesame oil, olive
oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such
as ethyl oleate and
ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum
hydroxide;
alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and
phosphate buffer solutions, as well as other non-toxic compatible lubricants
such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents, releasing
agents, coating
agents, sweetening, flavoring and perfuming agents, preservatives and
antioxidants can also be
present in the composition, according to the judgment of the formulator.
The present invention provides pharmaceutical compositions which comprise
compounds of the present invention formulated together with one or more non-
toxic
pharmaceutically acceptable Garners. The pharmaceutical compositions can be
formulated for
oral administration in solid or liquid form, for parenteral injection or for
rectal administration.
Further included within the scope of the present invention are pharmaceutical
compositions comprising one or more of the compounds of formula I-IV prepared
and
formulated in combination with one or more non-toxic pharmaceutically
acceptable
compositions. The pharmaceutical compositions can be formulated for oral
administration in
solid or liquid form, for parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered to
humans and
other mammals orally, rectally, parenterally, intracisternally,
intravaginally, intraperitoneally,
topically (as by powders, ointments or drops), bucally or as an oral or nasal
spray. The term
"parenterally," as used herein, refers to modes of administration which
include intravenous,
intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular
injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection
comprise
pharmaceutically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions
or emulsions and sterile powders for reconstitution into sterile injectable
solutions or
dispersions. Examples of suitable aqueous and nonaqueous Garners, diluents,
solvents or
vehicles include water, ethanol, polyols (propylene glycol, polyethylene
glycol, glycerol, and
the like), suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic
esters such as ethyl oleate. 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
dispersions, and by the use of surfactants.
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These compositions can also contain adjuvants such as preservative agents,
wetting
agents, emulsifying agents, and dispersing agents. Prevention of the action of
microorganisms
can be ensured by various antibacterial and antifungal agents, for example,
parabens,
chlorobutanol, phenol, sorbic acid, and the like. It can also be desirable to
include isotonic
agents, for example, sugars, sodium chloride and the like. Prolonged
absorption of the
injectable pharmaceutical form can be brought about by the use of agents
delaying absorption,
for example, aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of a drug, it is often desirable
to slow the
absorption of the drug from subcutaneous or intramuscular injection. This can
be
accomplished by the use of a liquid suspension of crystalline or amorphous
material with poor
water solubility. The rate of absorption of the drug then depends upon its
rate of dissolution
which, in turn, may depend upon crystal size and crystalline form.
Alternatively, delayed
absorption of a parenterally administered drug form is accomplished by
dissolving or
suspending the drug in an oil vehicle.
Suspensions, in addition to the active compounds, may contain suspending
agents, as,
for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar,
tragacanth, and
mixtures thereof.
If desired, and for more effective distribution, the compounds of the present
invention
can be incorporated into slow-release or targeted-delivery systems such as
polymer matrices,
liposomes, and microspheres. They may be sterilized, for example, by
filtration through a
bacteria-retaining filter or by incorporation of sterilizing agents in the
form of sterile solid
compositions, which may be dissolved in sterile water or some other sterile
injectable medium
immediately before use.
The active compounds can also be in micro-encapsulated form, if appropriate,
with one
or more excipients as noted above. The solid dosage forms of tablets, dragees,
capsules, pills,
and granules can be prepared with coatings and shells such as enteric
coatings, release
controlling coatings and other coatings well known in the pharmaceutical
formulating art. In
such solid dosage forms the active compound can be admixed with at least one
inert diluent
such as sucrose, lactose, or starch. Such dosage forms may also comprise, as
is normal
practice, additional substances other than inert diluents, e.g., tableting
lubricants and other
tableting aids such a magnesium stearate and microcrystalline cellulose. In
the case of
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capsules, tablets and pills, the dosage forms may also comprise buffering
agents. They may
optionally contain opacifying agents and can also be of such composition that
they release the
active ingredients) only, or preferentially, in a certain part of the
intestinal tract in a delayed
manner. Examples of embedding compositions which can be used include polymeric
substances and waxes.
Injectable depot forms are made by forming microencapsulated matrices of the
drug in
biodegradable polymers such as polylactide-polyglycolide. Depending upon the
ratio of drug
to polymer and the nature of the particular polymer employed, the rate of drug
release can be
controlled. Examples of other biodegradable polymers include poly(orthoesters)
and
poly(anhydrides) Depot injectable formulations are also prepared by entrapping
the drug in
liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration
through a
bacterial-retaining filter or by incorporating sterilizing agents in the form
of sterile solid
compositions which can be dissolved or dispersed in sterile water or other
sterile injectable
medium just prior to use.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable
dispersing or
wetting agents and suspending agents. The sterile injectable preparation may
also be a sterile
injectable solution, suspension or emulsion in a nontoxic, parenterally
acceptable diluent or
solvent such as a solution in 1,3-butanediol. Among the acceptable vehicles
and solvents that
may be employed are water, Ringer's solution, U.S.P. and isotonic sodium
chloride solution.
In addition, sterile, fixed oils are conventionally employed as a solvent or
suspending medium.
For this purpose any bland fixed oil can be employed including synthetic mono-
or
diglycerides. In addition, fatty acids such as oleic acid are used in the
preparation of
injectables.
Solid dosage forms for oral administration include capsules, tablets, pills,
powders, and
granules. In such solid dosage forms, the active compound is mixed with at
least one inert,
pharmaceutically acceptable excipient or Garner such as sodium citrate or
dicalcium phosphate
and/or a) fillers or extenders such as starches, lactose, sucrose, glucose,
mannitol, and silicic
acid; b) binders such as carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone,
sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents
such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain silicates,
and sodium
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carbonate; e) solution retarding agents such as paraffin); f) absorption
accelerators such as
quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and
glycerol
monostearate;) absorbents such as kaolin and bentonite clay; and i) lubricants
such as talc,
calcium stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and
mixtures thereof. In the case of capsules, tablets and pills, the dosage form
may also comprise
buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft
and hard-
filled gelatin capsules using such excipients as lactose or milk sugar as well
as high molecular
weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can
be
prepared with coatings and shells such as enteric coatings and other coatings
well known in
the pharmaceutical formulating art. They may optionally contain opacifying
agents and can
also be of a composition that they release the active ingredients) only, or
preferentially, in a
certain part of the intestinal tract in a delayed manner. Examples of
embedding compositions
which can be used include polymeric substances and waxes.
Compositions for rectal or vaginal administration are preferably suppositories
which
can be prepared by mixing the compounds of this invention with suitable non-
irritating
excipients or Garners such as cocoa butter, polyethylene glycol or a
suppository wax which are
solid at ambient temperature but liquid at body temperature and therefore melt
in the rectum or
vaginal cavity and release the active compound.
Liquid dosage forms for oral administration include pharmaceutically
acceptable
emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the
active compounds, the liquid dosage forms may contain inert diluents commonly
used in the
art such as, for example, water or other solvents, solubilizing agents and
emulsifiers such as
ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in
particular,
cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures
thereof. Besides
inert diluents, the oral compositions can also include adjuvants such as
wetting agents,
emulsifying and suspending agents, sweetening, flavoring, and perfuming
agents.
Dosage forms for topical or transdermal administration of a compound of this
invention include ointments, pastes, creams, lotions, gels, powders,
solutions, sprays, inhalants
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or patches. The active component is admixed under sterile conditions with a
pharmaceutically
acceptable Garner and any needed preservatives or buffers as may be required.
Ophthalmic
formulation, ear drops, eye ointments, powders and solutions are also
contemplated as being
within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active
compound
of this invention, excipients such as animal and vegetable fats, oils, waxes,
paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc
and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this
invention,
excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium
silicates and
polyamide powder, or mixtures of these substances. Sprays can additionally
contain
customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery
of a
compound to the body. Such dosage forms can be made by dissolving or
dispensing the
compound in the proper medium. Absorption enhancers can also be used to
increase the flux
of the compound across the skin. The rate can be controlled by either
providing a rate
controlling membrane or by dispersing the compound in a polymer matrix or gel.
Compounds of the present invention may also be administered in the form of
liposomes. As is known in the art, liposomes are generally derived from
phospholipids or
other lipid substances. Liposomes are formed by mono- or mufti-lamellar
hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable
and metabolizable lipid capable of forming liposomes may be used. The present
compositions
in liposome form may contain, in addition to the compounds of the present
invention,
stabilizers, preservatives, excipients, and the like. The preferred lipids are
the natural and
synthetic phospholipids and phosphatidylcholines (lecithins) used separately
or together.
Methods to form liposomes are known in the art. See, for example, Prescott,
Ed.,
Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y., (1976),
p 33 et
seq.
The term "pharmaceutically acceptable salt," as used herein, refers to salts
that are well
known in the art. Examples of pharmaceutically acceptable, nontoxic acid
addition salts are
salts of an amino group formed with inorganic acids such as hydrochloric acid,
hydrobromic
acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids
such as acetic
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acid, oxalic acid, malefic acid, tartaric acid, citric acid, succinic acid, or
malonic acid or by
using other methods used in the art such as ion exchange. Other
pharmaceutically acceptable
salts include nitrate, bisulfate, borate, formate, butyrate, valerate, 3-
phenylpropionate,
camphorate, adipate, benzoate, oleate, palmitate, stearate, laurate, lactate,
fumarate, ascorbate,
aspartate, nicotinate, p-toluenesulfonate, camphorsulfonate, methanesulfonate,
2-
hydroxyethanesulfonate, gluconate, glucoheptonate, lactobionate,
glycerophosphate, pectinate,
lauryl sulfate, and the like, metal salts such as sodium, potassium, magnesium
or calcium salts
or amino salts such as ammonium, triethylamine salts, and the like, all of
which may be
prepared according to conventional methods.
Dosage forms for topical administration of a compound of this invention
include
powders, sprays, ointments and inhalants. The active compound is mixed under
sterile
conditions with a pharmaceutically acceptable carrier and any needed
preservatives, buffers or
propellants which can be required. Opthalmic formulations, eye ointments,
powders and
solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical compositions
of this
invention can be varied so as to obtain an amount of the active compounds)
which is effective
to achieve the desired therapeutic response for a particular patient,
compositions and mode of
administration. The selected dosage level will depend upon the activity of the
particular
compound, the route of administration, the severity of the condition being
treated and the
condition and prior medical history of the patient being treated. However, it
is within the skill
of the art to start doses of the compound at levels lower than required for to
achieve the
desired therapeutic effect and to gradually increase the dosage until the
desired effect is
achieved.
The present invention contemplates compounds of formula I-IV formed by
synthetic
means or formed by in vivo biotransformation.
The compounds of the invention, including but not limited to those specified
in the
examples, possess potassium channel opening activity in mammals (especially
humors). ,As
potassium channel openers, the compounds of the present invention may be
useful for the
treatment and prevention of diseases such as asthma, epilepsy, male sexual
dysfunction,
female sexual dysfunction, pain, bladder overactivity, stroke, diseases
associated with
decreased skeletal blood flow such as Raynaud's phenomenon and intermittent
claudication,
eating disorders, functional bowel disorders, neurodegeneration, benign
prostatic hyperplasia
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(BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary
artery disease,
angina and ischemia.
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat bladder overactivity, sensations of
incontinence
urgency, urinary incontinence, pollakiuria, bladder instability, nocturia,
bladder hyeneflexia,
and enuresis may be demonstrated by (Resnick, The Lancet (1995) 346, 94-99;
Hampel,
Urology (1997) 50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl
2), 7-9;
Andersson, Urology (1997) 50 (Suppl 6A), 74-84; Lawson, Pharmacol. Ther.,
(1996) 70, 39-
63; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther.,
(1995) 274, 884-
890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat male sexual dysfunction such as male
erectile
dysfunction, impotence and premature ejaculation may be demonstrated by
(Andersson,
Pharmacological Reviews (1993) 45, 253; Lee, Int. J. Impot. Res. (1999)
11(4),179-188;
Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther.,
(1996) 70,
39-63, Vick, J. Urol. (2000) 163: 202).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat female sexual dysfunction such as
clitoral erectile
insufficiency, vaginismus and vaginal engorgement may be demonstrated by (Kim
et al., J.
Urol. (2000) 163 (4): 240; Goldstein and Berman., Int. J. Impotence Res.
(1998) 10:S84-S90).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat benign prostatic hyperplasia (BPH)
may be
demonstrated by (Pandita, The J. of Urology (1999) 162, 943; Andersson,
Prostate (1997) 30:
202-215).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat premature labor and dysmenorrhoea
may be
demonstrated by (Sanborn, Semin. Perinatol. (1995) 19, 31-40; Morrison, Am. J.
Obstet.
Gynecol. (1993) 169(5), 1277-85; Kostrzewska, Acta Obstet. Gynecol. Scand.
(1996) 75(10),
886-91; Lawson, Pharmacol. Ther., (1996) 70, 39-63).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat functional bowel disorders such as
irntable bowel
syndrome may be demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
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The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat asthma and airways hyperreactivity
may be
demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit,
Pulmonary
Pharmacology & Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development
Research,
(1993) 28, 95-127).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat various pain states including but
not limited to
migraine and dyspareunia may be demonstrated by (Rodrigues, Br. J. Pharmacol.
(2000)
129(1), 110-4; Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth.
Analg. (2000)
90(5), 1146-51; Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan,
Drug
Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol.
& Biol.
Psychiat., (1994) 18, 1093-1102).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat epilepsy may be demonstrated by
(Lawson,
Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research,
(1993) 28,
95-127; Gehlert, Prog. Neuro-Psychopharmacol & Biol. Psychiat., (1994) 18,
1093-1102).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat neurodegenerative conditions and
diseases such as
cerebral ischemia, stroke, Alzheimer's disease and Parkinson's disease may be
demonstrated
by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug
Development
Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. & Biol.
Psychiat.,
(1994) 18, 1093-1102; Freedman, The Neuroscientist (1996) 2, 145).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat diseases or conditions associated
with decreased
skeletal muscle blood flow such as Raynaud's syndrome and intermittent
claudication may be
demonstrated by (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan,
Drug
Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992)
3434;
W09932495).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat eating disorders such as obesity may
be demonstrated
by (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996)
2, 145).
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The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat alopecia may be demonstrated by
(Lawson,
Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research,
(1993) 28,
95-127).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat myocardial injury during ischemia
and reperfusion
may be demonstrated by (Garlid, Circ Res (1997) 81(6), 1072-82; Lawson,
Pharmacol. Ther.,
(1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677).
The ability of the compounds of the present invention, including but not
limited to
those specified in the examples, to treat coronary artery disease may be
demonstrated by
(Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakrishnan, Drug Development
Research,
(1993) 28, 95-127).
Aqueous liquid compositions of the present invention are particularly useful
for the
treatment and prevention of asthma, epilepsy, hypertension, Raynaud's
syndrome, male sexual
dysfunction, female sexual dysfunction, migraine, pain, eating disorders,
urinary incontinence,
functional bowel disorders, neurodegeneration and stroke.
When used in the above or other treatments, a therapeutically effective amount
of one
of the compounds of the present invention can be employed in pure form or,
where such forms
exist, in pharmaceutically acceptable salt, ester, amide or prodrug form.
Alternatively, the
compound can be administered as a pharmaceutical composition containing the
compound of
interest in combination with one or more pharmaceutically acceptable
excipients. The phrase
"therapeutically effective amount" of the compound of the invention means a
sufficient
amount of the compound to treat disorders, at a reasonable benefit/risk ratio
applicable to any
medical treatment. It will be understood, however, that the total daily usage
of the compounds
and compositions of the present invention will be decided by the attending
physician within
the scope of sound medical judgement. The specific therapeutically effective
dose level for
any particular patient will depend upon a variety of factors including the
disorder being treated
and the severity of the disorder; activity of the specific compound employed;
the specific
composition employed; the age, body weight, general health, sex and diet of
the patient; 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 like factors well known in the medical arts.
For example, it
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is well within the skill of the art to start doses of the compound at levels
lower than required to
achieve the desired therapeutic effect and to gradually increase the dosage
until the desired
effect is achieved.
The total daily dose of the compounds of this invention administered to a
human or
lower animal may range from about 0.003 to about 50 mg/kg/day. For purposes of
oral
administration, more preferable doses can be in the range of from about 0.01
to about 25
mg/kg/day. If desired, the effective daily dose can be divided into multiple
doses for purposes
of administration; consequently, single dose compositions may contain such
amounts or
submultiples thereof to make up the daily dose.
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