U.S. patent application number 14/734225 was filed with the patent office on 2015-11-26 for disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators.
The applicant listed for this patent is JANSSEN PHARMACEUTICA NV. Invention is credited to Wenying Chai, Akinola Soyode Johnson, Michael A. Letavic, Kiev S. Ly, Daniel J. Pippel, Dale A. Rudolph, Kathleen C. Sappey, Brad M. Savall, Chandravadan R. Shah, Brock T. Shireman, Emily M. Stocking, Devin M. Swanson.
Application Number | 20150335651 14/734225 |
Document ID | / |
Family ID | 43385633 |
Filed Date | 2015-11-26 |
United States Patent
Application |
20150335651 |
Kind Code |
A1 |
Chai; Wenying ; et
al. |
November 26, 2015 |
DISUBSTITUTED OCTAHYDROPYRROLO[3,4-c]PYRROLES AS OREXIN RECEPTOR
MODULATORS
Abstract
Disubstituted octahydropyrrolo[3,4-c]pyrrole compounds are
described, which are useful as orexin receptor modulators. Such
compounds may be useful in pharmaceutical compositions and methods
for the treatment of diseased states, disorders, and conditions
mediated by orexin activity, such as insomnia.
Inventors: |
Chai; Wenying; (San Diego,
CA) ; Letavic; Michael A.; (San Diego, CA) ;
Ly; Kiev S.; (San Diego, CA) ; Pippel; Daniel J.;
(Del Mar, CA) ; Rudolph; Dale A.; (San Diego,
CA) ; Sappey; Kathleen C.; (San Diego, CA) ;
Savall; Brad M.; (San Diego, CA) ; Shah; Chandravadan
R.; (San Diego, CA) ; Shireman; Brock T.;
(Poway, CA) ; Johnson; Akinola Soyode; (San Diego,
CA) ; Stocking; Emily M.; (Encinitas, CA) ;
Swanson; Devin M.; (La Jolla, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JANSSEN PHARMACEUTICA NV |
Beerse |
|
BE |
|
|
Family ID: |
43385633 |
Appl. No.: |
14/734225 |
Filed: |
June 9, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14138941 |
Dec 23, 2013 |
9079911 |
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14734225 |
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13503231 |
Apr 20, 2012 |
8653263 |
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PCT/US10/53606 |
Oct 21, 2010 |
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14138941 |
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61254509 |
Oct 23, 2009 |
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Current U.S.
Class: |
514/234.5 ;
514/245; 514/249; 514/256; 514/272; 514/275; 514/314; 514/338;
514/367; 544/122; 544/180; 544/321; 544/328; 544/356; 546/159;
546/276.7; 548/159 |
Current CPC
Class: |
A61K 31/428 20130101;
A61P 1/04 20180101; A61K 31/5377 20130101; A61P 11/00 20180101;
A61K 31/498 20130101; A61P 3/00 20180101; A61P 3/04 20180101; A61P
3/06 20180101; A61P 25/00 20180101; A61P 25/04 20180101; A61P 43/00
20180101; A61P 9/00 20180101; A61P 9/04 20180101; A61P 9/06
20180101; A61P 19/02 20180101; A61P 1/12 20180101; A61P 1/16
20180101; A61P 25/20 20180101; A61P 25/22 20180101; A61P 25/24
20180101; A61P 25/28 20180101; C07D 487/04 20130101; A61K 31/4439
20130101; A61P 5/50 20180101; A61P 15/00 20180101; A61K 31/53
20130101; A61P 9/12 20180101; A61P 3/10 20180101; A61P 25/14
20180101; A61P 25/16 20180101; A61P 25/18 20180101; A61K 31/506
20130101; A61P 1/00 20180101; A61K 31/4709 20130101 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/428 20060101 A61K031/428; A61K 31/53 20060101
A61K031/53; A61K 31/4709 20060101 A61K031/4709; A61K 31/4439
20060101 A61K031/4439; A61K 31/506 20060101 A61K031/506; A61K
31/498 20060101 A61K031/498 |
Claims
1. A compound selected from
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone; and
pharmaceutically acceptable salts thereof.
2.-34. (canceled)
35. The compound of claim 1, selected from:
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone; and
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone.cndot.HCl.
36. A compound which is
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone.
37. A pharmaceutical composition comprising a compound selected
from:
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone, and
pharmaceutically acceptable salts thereof; and a pharmaceutically
acceptable excipient.
38. A pharmaceutical composition comprising the compound of claim
36 and a pharmaceutically acceptable excipient.
39. A method of treating a subject suffering from or diagnosed with
a sleep disorder selected from the group consisting of sleep-wake
transition disorders, insomnia, restless legs syndrome, jet-lag,
disturbed sleep, and sleep disorders secondary to neurological
disorders, comprising administering to a subject in need of such
treatment an effective amount of a compound selected from
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)methanone, and pharmaceutically
acceptable salts thereof.
40. The method according to claim 39, wherein the sleep disorder is
selected from insomnia or a sleep disorder secondary to
depression.
41. The method according to claim 39, wherein the sleep disorder is
insomnia.
42. A method of treating a subject suffering from or diagnosed with
a sleep disorder selected from the group consisting of sleep-wake
transition disorders, insomnia, restless legs syndrome, jet-lag,
disturbed sleep, and sleep disorders secondary to neurological
disorders, comprising administering to a subject in need of such
treatment the pharmaceutical composition of claim 38.
43. The method according to claim 42, wherein the sleep disorder is
selected from insomnia or a sleep disorder secondary to
depression.
44. The method according to claim 42, wherein the sleep disorder is
insomnia.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. application Ser.
No. 14/138,941, filed Dec. 23, 2013, which is a continuation of
U.S. application Ser. No. 13/503,231, filed Apr. 20, 2012, which is
a national stage under 35 U.S.C. 371 of PCT International
Application No. PCT/US2010/053606 filed Oct. 21, 2010, which claims
benefit of priority under 35 U.S.C. .sctn.119(e) of U.S.
Provisional Application No. 61/254,509 filed Oct. 23, 2009, the
entire disclosures of which are hereby incorporated by reference in
their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to certain disubstituted
octahydropyrrolo[3,4-c]pyrrole compounds, pharmaceutical
compositions containing them, methods of making them, and methods
of using them for the modulation of the orexin receptor and for the
treatment of disease states, disorders, and conditions mediated by
orexin receptor activity.
BACKGROUND OF THE INVENTION
[0003] Orexin (or hypocretin) signaling is mediated by two
receptors and two peptide agonists. The two orexin peptides (orexin
A and orexin B) herein after referred to as orexins, bind to two
high affinity receptors, termed orexin-1 and orexin-2 receptors.
The orexin-1 receptor is selective in favor of orexin A, while the
orexin-2 receptor binds both orexins with similar affinities. The
orexins, are cleavage products of the same gene, prepro orexin. In
the central nervous system neurons expressing prepro-orexin, the
precursor from which orexin is produced, are found in the
perifornical nucleus, the dorsal hypothalamus and the lateral
hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23),
9996-10015). Orexinergic cells in these nuclei project to many
areas of the brain, extending rostrally to the olfactory bulbs and
caudally to the spinal cord (van den Pol, A. N. et al., J.
Neuroscience., 1999, 19(8), 3171-3182).
[0004] The broad CNS distribution of orexin projections and neurons
expressing orexin receptors is suggestive of orexin involvement in
a number of physiological functions including; feeding, drinking,
arousal, stress, reward, metabolism and reproduction (T. Sakurai,
Nature Reviews Neuroscience, 2007, 8(3), 171-181).
[0005] The targeted necrosis of cells expressing prepro-orexin
suggests the most physiologically important roles of the orexins
are likely to be effects on arousal, feeding and metabolism (J.
Hara et al., Neuron, 2001, 30, 345-354). A prominent orexin
neuronal projection via the vagus nerve probably mediates central
orexin effects on cardiac parameters (W. K. Samson et al., Brain
Res., 1999, 831, 248-253; T. Shirasaka et al., Am. J. Physiol.,
1999, 277, R1780-R1785; C.-T. Chen et al., Am. J. Physiol., 2000,
278, R692-R697), gastric acid secretion and gastric motility (A. L.
Kirchgessner and M.-T. Liu, Neuron, 1999, 24, 941-951; N. Takahashi
et al., Biochem. Biophys. Res. Commun., 1999, 254, 623-627).
[0006] Several lines of evidence indicate that the orexin system is
an important modulator of arousal. Rodents administered orexins
intracerebroventricularly spend more time awake (Piper et al., J.
Neurosci. 2000, 12, 726-730). Orexin-mediated effects on arousal
have been linked to orexin neuronal projections to histaminergic
neurons in the tuberomammillary nucleus (TMN) (Yamanaka et al.,
Biochem. Biophys. Res. Comm. 2002, 290, 1237-1245). TMN neurons
express the orexin-2 receptor primarily, and the orexin-1 receptor
to a lesser extent. Rodents whose prepro orexin gene has been
knocked out, or whose orexigenic neurons have been lesioned,
display altered sleep/wake cycles similar to narcolepsy (Chemelli
et al., Cell 1999, 98, 437-451; Hara et al., 2001, supra). Dog
models of narcolepsy have been shown to have mutant or
non-functional orexin-2 receptors (Lin et al., Cell 1999, 98,
365-376). Human narcolepsy appears to be linked to deficient orexin
signaling, likely related to immune ablation of orexinergic neurons
in the lateral hypothalamus (Mignot et al., Am. J. Hum. Genet.
2001, 68: 686-699; Minot & Thorsby, New England J. Med. 2001,
344, 692), or, in rare cases, to mutations in the orexin-2 gene
(Peyron et al., Nature Med. 2000, 6, 991-997). The disclosure that
rats, dogs and humans treated with the dual orexin-1/2 receptor
antagonist, ACT-078573 (Brisbare-Roch et al., Nature Medicine,
2007, 13, 150-155) exhibited decreased alertness together with
characteristic clinical and EEG (electroencephalographic) signs of
sleep provides evidence to support a role for the orexin system in
the regulation of arousal, sleep and wake states. EEG data
indicates that orexin-2 may be more important than orexin-1 in the
modulation of sleep/wake (P. Malherbe et al., Molecular
Pharmacology (2009) 76(3):618-31; C. Dugovic et al., J. Pharmacol.
Exp. Ther., 2009, 330(1), 142-151). Disorders of the sleep-wake
cycle are therefore likely targets for orexin-2 receptor antagonist
therapy. Examples of such disorders include sleep-wake transition
disorders, insomnia, restless legs syndrome, jet-lag, disturbed
sleep, and sleep disorders secondary to neurological disorders
(e.g., manias, depressions, manic depression, schizophrenia, and
pain syndromes (e.g., fibromyalgia, neuropathic pain).
[0007] The orexin system also interacts with brain dopamine
systems. Intracerebroventricular injections of orexins in mice
increase locomotor activity, grooming and stereotypy; these
behavioral effects are reversed by administration of D.sub.2
dopamine receptor antagonists (Nakamura et al., Brain Research,
873(1), 181-7). Therefore, orexin-2 modulators may be useful to
treat various neurological disorders; e.g., agonists or
up-regulators to treat catatonia, antagonists or down-regulators to
treat Parkinson's disease, Tourette's syndrome, anxiety, delerium
and dementias.
[0008] Recent evidence indicates a role for orexin in the
pathogenesis of Alzheimers disease (Kang et al, Science Express,
2009, 1-10). Brain interstitial fluid levels of amyloid-beta were
demonstrated to fluctuate diurnally in both humans and rodents with
sleep deprivation in rodents leading to significant increases in
brain interstitial fluid levels of amyloid-beta. Infusion of a dual
orexin antagonist in rodents suppressed interstitial levels of
amyloid-beta and abolished the natural diurnal variation of
amyloid-beta. The reduction of interstitial fluid amyloid-beta
levels is correlated with reduced amyloid plaque formation, a
hallmark of Alzheimer's disease, and consequently the regulation of
sleep time could potentially inhibit amyloid-beta aggregation and
slow the progression of Alzheimer's disease.
[0009] Orexin neurons project to many regions of the brain
associated with reward function (T. Sakurai, supra) and research,
focusing on animal models of drug intake, reward, and
reinstatement, has expanded the link between the orexin system and
addiction. A comprehensive set of data suggest that drugs of abuse
activate the orexin system, which in turn enhances drug reward or
drug seeking (G. Aston-Jones et al., Neuropharmacology, 2009, 56
(Suppl 1) 112-121. Thus interactions between nicotine (J. K. Kane
et al., Endocrinology, 2000, 141(10), 3623-3629; J. K. Kane et al.,
Neurosci. Lett., 2001, 298(1), 1-4), morphine (D. Georgescu, et
al., J.Neurosci., 2003, 23(8), 3106-3111) and amphetamine (C. J.
Winrow et al., Neuropharmacology, 2010, 58(1), 185-94) and the
orexin system have been demonstrated. Additional studies from a
number of laboratories have demonstrated an important relationship
between the Orexin system and ethanol consumption. As examples,
ethanol consumption in an alcohol-preferring strain of rat was
shown to up regulate Orexin mRNA in the lateral hypothalamus and
that an Orexin-1 receptor antagonist reduced operant responding for
ethanol (Lawrence, et. al., Br. J. Pharmacol., 2006, 148, 752-759).
Treatment with an orexin-1 antagonist has also been shown to
decrease operant responding for ethanol (Richards, et. al.,
Psychopharmacology, 2008, 199 (1), 109-117). Other studies have
demonstrated increased Fos activation of orexin neurons following
contextual reinstatement to ethanol seeking (Dayas, et. al., Biol.
Psychiatry, 2008, 63 (2), 152-157 and Hamlin, et. al.,
Neuroscience, 2007, 146, 525-536). Studies have also shown
increased ethanol consumption following Orexin infusion into the
paraventricular nucleus of the hypothalamus or in the lateral
hypothalamus (Schneider, et. al., Alcohol. Clin. Exp. Res., 2007,
31(11), 1858-1865). These studies provide evidence that modulation
of the Orexin system effects alcohol preference and therefore
Orexin receptor antagonists are likely to be useful for the
treatment of alcoholism.
[0010] Orexins and their receptors have been found in both the
myenteric and submucosal plexus of the enteric nervous system,
where orexins have been shown to increase motility in vitro
(Kirchgessner & Liu, Neuron 1999, 24, 941-951) and to stimulate
gastric acid secretion in vitro (Takahashi et al., Biochem.
Biophys. Res. Comm. 1999, 254, 623-627). Orexin mediated effects on
the gut may be driven by a projection via the vagus nerve (van den
Pol, 1999, supra), as vagotomy or atropine prevent the effect of an
intracerebroventricular injection of orexin on gastric acid
secretion (Takahashi et al., 1999, supra). Orexin receptor
antagonists or other down-regulators of orexin receptor-mediated
systems are therefore potential treatments for ulcers, irritable
bowel syndrome, diarrhea and gastroesophageal reflux.
[0011] Body weight may also be affected by orexin-mediated
regulation of appetite and metabolism (T. Sakurai et al., Cell,
1998, 92(4), 573-585; T. Sakurai, Reg. Pept., 1999, 85(1), 25-30).
Some effects of orexin on metabolism and appetite may be mediated
in the gut, where, as mentioned, orexins alter gastric motility and
gastric acid secretion. Orexin receptor antagonists therefore are
likely to be useful in treatment of overweight or obesity and
conditions related to overweight or obesity, such as insulin
resistance, type II diabetes, hyperlipidemia, gallstones, angina,
hypertension, breathlessness, tachycardia, infertility, sleep
apnea, back and joint pain, varicose veins and osteoarthritis.
Conversely, orexin receptor agonists are likely to be useful in
treatment of underweight and related conditions such as
hypotension, bradycardia, amenorrhea and related infertility, and
eating disorders such as anorexia and bulimia.
[0012] Intracerebroventricularly administered orexins have been
shown to increase mean arterial pressure and heart rate in freely
moving (awake) animals (Samson et al., Brain Res. 1999, 831,
248-253; Shirasaka et al., Am. J. Physiol. 1999, 277, R1780-R1785)
and in urethane-anesthetized animals (Chen et al., Am. J. Physiol.
2000, 278, R692-R697), with similar results. Orexin receptor
agonists may therefore be candidates for treatment of hypotension,
bradycardia and heart failure related thereto, while orexin
receptor antagonists may be useful for treatment of hypertension,
tachycardia and other arrhythmias, angina pectoris and acute heart
failure.
[0013] From the foregoing discussion, it can be seen that the
identification of orexin receptor modulators, in one embodiment
modulators of the orexin-2 receptor, will be of great advantage in
the development of therapeutic agents for the treatment of a wide
variety of disorders that are mediated through these receptor
systems.
[0014] Citation of a reference herein shall not be construed as an
admission that such reference is prior art to the present
invention. All publications referred to herein are incorporated by
reference in their entireties.
[0015] Various small-molecule orexin receptor modulators have been
reported e.g., N-aroyl cyclic amine derivatives (International
Publication No. WO2003002561, Jan. 9, 3003), ethylene diamine
derivatives (International Publication No. WO2003051872, Jun. 26,
2003), sulfonylamino-acetic acid derivatives (International
Publication No. WO2004033418, Apr. 22, 2004), N-aryl acetyl cyclic
amine derivatives (International Publication No. WO2004041791, May
21, 2004), diazepan derivatives (International Publication No.
WO2007126935, Nov. 8, 2007), amidoethylthioether derivatives
(International Publication No. WO2007126934, Nov. 8, 2007),
2-substituted proline bis-amide derivatives (International
Publication No. WO2008008551, Jan. 17, 2008), bridged diazepan
derivatives (International Publication No. WO2008008517, Jan. 17,
2008), substituted diazepan derivatives (International Publication
No. WO2008008518, Jan. 17, 2008; US20080132490, WO2009058238), oxo
bridged diazepan derivatives (International Publication No.
WO2008143856, Nov. 27, 2008), 1,2-diamido ethylene derivatives
(International Publication No. WO2009022311, Feb. 19, 2009),
heteroaryl derivatives (International Publication No.
WO20090163485, Jun. 25, 2009), methyl substituted piperidinyl
derivatives (International Publication No. WO2009124956, Oct. 15,
2009), N,N-disubstituted-1,4-diazepane derivatives (Cox et al,
Bioorganic& Medicinal Chemistry Letters, 2009, 19(11),
2997-3001), Orexin/Hypocretin receptor ligands (Boss, et al.,
Journal of Medicinal Chemistry, 2009, 52(4), 891-903)
3,9-diazabicyclo[4.2.1]nonanes (Coleman et al, Bioorganic &
Medicinal Chemistry Letters, 2010, 20(14), 4201-4205), the dual
orexin receptor antagonist,
[(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-meth-
yl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone, (Cox, et. al.,
Journal of Medicinal Chemistry, 2010 53(14) 5320-5332), pyridazine
carboxamide derivatives (International Publication No.
WO2010051238), 2,5-disubstituted benzamide derivatives
(International Publication No WO2010051237, May 6, 2010),
isonicotinamides (International Publication No WO2010051236),
heterocyclylbenzoylpiperazines derivatives (International
Publication No WO201048012), substituted diazepane derivatives
(International Publication No WO2010048017), substituted
pyrrolidine derivatives (International Publication No
WO2010048014), triazolylbenzoylpiperidine derivatives
(International Publication No WO2010048010),
triazolylbenzoylmorpholine derivatives (WO2010048013),
conformationally restrained N,N disubstituted 1,4-diazapane
derivatives (Coleman et al, Bioorganic & Medicinal Chemistry
Letters, 2010, 20(7), 2311-2315), tripyridyl carboxamide
derivatives (International Publication No WO2010017260),
imidazopyridylmethyl substituted piperidine derivatives
(International Publication No WO2010072722), imidazopyrazine
substituted piperidine derivatives (US2010160344, Jun. 24, 2010;
US20100160345, Jun. 24, 2010; International Publication No
WO2010060472, Jun. 3, 2010),
N-{[(1R,4S,6R)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methy-
l}-2-heteroarylamine derivatives (International Publication No
WO2010063663),
N-{[(1S,4S,6S)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methy-
l}-2-heteroarylamine derivatives (International Publication No
WO2010063662), imidazopyrimidine derivatives (International
Publication No WO2010060471), and imidazopyrazine derivatives
(International Publication No WO2010060470). There remains a need,
however, for potent orexin receptor modulators with desirable
pharmaceutical properties.
[0016] Substituted diaza-bicyclic compounds have been reported as
active central nervous system agents (International Publication No.
WO2001081347, Nov. 1, 2001; US2002/0019388, Feb. 14, 2002),
.alpha.7 acetylcholine receptor modulators (US2005/101602, May 12,
2005; US2005/0065178, Mar. 24, 2005 and Frost et al, Journal of
Medicinal Chemistry, 2006, 49(26), 7843-7853), proline transporter
inhibitors for the treatment of cognitive impairment (WO2008067121,
Jun. 5, 2008) and for improving cognition (WO 2006 124897, Nov. 23,
2006 and US20060258672, Nov. 16, 2006), as androgen receptor
ligands for the treatment of androgen receptor associated
conditions including cancer (WO2009081197, Jul. 2, 2009), and as
histone deacetylase inhibitors for the treatment of cancers,
neurodegenerative diseases and autoimmune diseases (WO20060123121,
Nov. 23, 2006).
SUMMARY OF THE INVENTION
[0017] Certain disubstituted octahydropyrrolo[3,4-c]pyrrole
derivatives have been found to have orexin-modulating activity.
Thus, the invention is directed to the general and preferred
embodiments defined, respectively, by the independent and dependent
claims appended hereto, which are incorporated by reference
herein.
[0018] In one general aspect, the invention is directed to a
chemical entity of Formula (I):
##STR00001##
wherein: R.sup.1 is a member selected from the group consisting of:
[0019] A) phenyl substituted or unsubstituted with one or two
R.sup.a members, and substituted in the ortho position with
R.sup.b; [0020] R.sup.a is independently selected from the group
consisting of: --H, halo, --C.sub.1-4alkyl, --C.sub.1-4alkoxy, and
--NO.sub.2, wherein two adjacent R.sup.a members may come together
to form a six membered aromatic ring; [0021] R.sup.b is a member
selected from the group consisting of: [0022] a) halo,
--C.sub.1-4alkoxy, --C.sub.1-4alkyl, --CF.sub.3, --OCF.sub.3, or
--CN; [0023] b) 5-membered heteroaryl ring containing one oxygen or
one sulfur members; [0024] c) 5-6 membered heteroaryl ring
containing one, two or three nitrogen members, optionally
containing one oxygen member, substituted or unsubstituted with
halo or --C.sub.1-4alkyl; and [0025] d) phenyl substituted or
unsubstituted with halo, --CH.sub.3, or --CF.sub.3; [0026] B)
pyridine substituted or unsubstituted with one or two R.sup.c
members and substituted with R.sup.d, wherein R.sup.d is positioned
adjacent to the point of attachment by R.sup.1; [0027] R.sup.c is
C.sub.1-4alkyl; [0028] R.sup.d is a member selected from the group
consisting of: [0029] a) 5-6 membered heteroaryl ring selected from
the group consisting of: 1H-1,2,3-triazol-1-yl,
2H-1,2,3-triazol-2-yl, 1H-pyrazol-5-yl,
3-methyl-1,2,4-oxadiazol-5-yl, pyridinyl, 3-methyl-pyridin-2-yl;
1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl), phenyl, and
pyrimidin-2-yl; and [0030] b) --CF.sub.3, --Br, and
--C.sub.1-4alkoxy; [0031] C) 5-membered heteroaryl ring selected
from the group consisting of: 2-methyl-1,3-thiazol-yl,
1H-pyrazol-5-yl, oxazole, isoxazolyl, thiophen-2-yl, and
furan-2-yl, each substituted with phenyl substituted or
unsubstituted with --F; and [0032] D) 5-13 membered aryl or
heteroaryl ring selected from the group consisting of:
3-methylfuran-2-yl, 9H-fluorene, quinoline, cinnoline;
3-(1H-pyrrol-1-yl)thiophen-2-yl,
8-[1,2,3]-triazol-2-yl-naphthalen-1-yl,
2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl,
4-fluoronaphthalen-1-yl, and naphthalen-1-yl; R.sup.2 is a member
selected from the group consisting of: [0033] A) 6-membered
heteroaryl ring containing two nitrogen members substituted with
one or more members independently selected from the group
consisting of: halo, --C.sub.1-4alkyl, --CD.sub.3, -D,
--C.sub.1-4alkoxy, cyclopropyl, morpholin-2-yl,
--CO.sub.2C.sub.1-4alkyl, --CO.sub.2H, --CH.sub.2OH,
--C(O)N(C.sub.1-4alkyl).sub.2, --CF.sub.3, --CN, --OH, --NO.sub.2,
--N(C.sub.1-4alkyl).sub.2, phenyl, furan-2-yl, thiophen-2-yl,
1H-pyrazol-4-yl, and pyrrolidin-1-yl; [0034] B) pyridine
substituted with one or two members independently selected from the
group consisting of: halo, --C.sub.1-4alkyl, --C.sub.1-4alkoxy, and
--CF.sub.3; [0035] C) 9-membered heteroaryl ring selected from the
group consisting of: benzooxazol-2-yl, 6-fluoro-1,3-benzothiazole,
1,3-benzothiazole, 6-methoxy-1,3-benzothiazole,
6-methyl-1,3-benzothiazole, 6-chloro-benzothiazol-2-yl, and
4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine; D) 10-membered
heteroaryl ring selected from the group consisting of:
quinoxalin-2-yl, 3-methylquinoxalin-2-yl,
6,7-difluoroquinoxalin-2-yl, 3-(trifluoromethyl)quinoxaline,
quinoline, 4-methylquinoline, and 6-fluoroquinazolin-2-yl; and
[0036] E) 4-methyl-1,3,5-triazin-2-yl or
2-methylpyrimidin-4(3H)-one. [0037] In another general aspect, the
invention is directed to a chemical entity of Formula (II):
##STR00002##
[0037] wherein [0038] R.sup.3 is phenyl substituted or
unsubstituted with a member independently selected from the group
consisting of: --C.sub.1-4alkoxy, and phenyl; and [0039] R.sup.4 is
a member selected from the group consisting of
(5-trifluoromethyl)-10 pyridin-2-yl,
(5-trifluoromethyl)-pyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, and
quinoxalin-2-yl.
[0040] Further embodiments are provided by pharmaceutically
acceptable salts of compounds of Formula (I) or Formula (II),
pharmaceutically acceptable prodrugs of compounds of Formula (I) or
Formula (II), and pharmaceutically active metabolites of compounds
of Formula (I) or Formula (II).
[0041] In certain embodiments, the compound of Formula (I) or
Formula (II) is a compound selected from those species described or
exemplified in the detailed description below.
[0042] In a further aspect, the invention relates to pharmaceutical
compositions for treating a disease, disorder, or medical condition
mediated by orexin receptor activity, comprising an effective
amount of at least one chemical entity selected from compounds of
Formula (I) or Formula (II), pharmaceutically acceptable salts of
compounds of Formula (I) or Formula (II), pharmaceutically
acceptable prodrugs of compounds of Formula (I) or Formula (II),
and pharmaceutically active metabolites of Formula (I) or Formula
(II).
[0043] Pharmaceutical compositions according to the invention may
further comprise one or more pharmaceutically acceptable
excipients.
[0044] In another aspect, the chemical embodiments of the present
invention are useful as orexin receptor modulators. Thus, the
invention is directed to a method for modulating orexin receptor
activity, including when such receptor is in a subject, comprising
exposing orexin receptor to an effective amount of at least one
chemical entity selected from compounds of Formula (I) or Formula
(II), pharmaceutically acceptable salts of compounds of Formula (I)
or Formula (II), pharmaceutically acceptable prodrugs of compounds
of Formula (I) or Formula (II), and pharmaceutically active
metabolites of compounds of Formula (I) or Formula (II).
[0045] In another aspect, the invention is directed to a method of
treating a subject suffering from or diagnosed with a disease,
disorder, or medical condition mediated by orexin receptor
activity, comprising administering to the subject in need of such
treatment an effective amount of at least one chemical entity
selected from compounds of Formula (I) or Formula (II),
pharmaceutically acceptable salts of compounds of Formula (I) or
Formula (II), pharmaceutically acceptable prodrugs of compounds of
Formula (I) or Formula (II), and pharmaceutically active
metabolites of compounds of Formula (I) or Formula (II). Additional
embodiments of methods of treatment are set forth in the detailed
description.
[0046] In another aspect, method of studying isotopically labeled
compounds in metabolic studies (preferably with .sup.14C), reaction
kinetic studies (with, for example .sup.2H or .sup.3H), detection
or imaging techniques [such as positron emission tomography (PET)
or single-photon emission computed tomography (SPECT)] including
drug or substrate tissue distribution assays, or in radioactive
treatment of patients. For example, an .sup.18F or .sup.11C labeled
compound may be particularly preferred for PET or an I.sup.123 for
SPECT studies.
[0047] An object of the present invention is to overcome or
ameliorate at least one of the disadvantages of the conventional
methodologies and/or prior art, or to provide a useful alternative
thereto. Additional embodiments, features, and advantages of the
invention will be apparent from the following detailed description
and through practice of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0048] FIG. 1 is a Powder X-Ray Diffraction of an exemplified
compound X
DETAILED DESCRIPTION
[0049] The invention may be more fully appreciated by reference to
the following description, including the following glossary of
terms and the concluding examples. For the sake of brevity, the
disclosures of the publications, including patents, cited in this
specification are herein incorporated by reference.
[0050] As used herein, the terms "including", "containing" and
"comprising" are used herein in their open, non-limiting sense.
[0051] The term "alkyl" refers to a straight- or branched-chain
alkyl group having from 1 to 12 carbon atoms in the chain. Examples
of alkyl groups include methyl (Me, which also may be structurally
depicted by the symbol, "I"), ethyl (Et), n-propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl,
tert-pentyl, hexyl, isohexyl, and groups that in light of the
ordinary skill in the art and the teachings provided herein would
be considered equivalent to any one of the foregoing examples.
[0052] The term "alkoxy" includes a straight chain or branched
alkyl group with a terminal oxygen linking the alkyl group to the
rest of the molecule. Alkoxy includes methoxy, ethoxy, propoxy,
isopropoxy, butoxy, t-butoxy, pentoxy and so on. "Aminoalkyl",
"thioalkyl", and "sulfonylalkyl" are analogous to alkoxy, replacing
the terminal oxygen atom of alkoxy with, respectively, NH (or NR),
S, and SO.sub.2.
[0053] The term "cyano" refers to the group --CN.
[0054] The term "cycloalkyl" refers to a saturated or partially
saturated, monocyclic, fused polycyclic, or spiro polycyclic
carbocycle having from 3 to 12 ring atoms per carbocycle.
Illustrative examples of cycloalkyl groups include the following
entities, in the form of properly bonded moieties:
##STR00003##
[0055] A "heterocycloalkyl" refers to a monocyclic ring structure
that is saturated or partially saturated and has from 4 to 7 ring
atoms per ring structure selected from carbon atoms and up to two
heteroatoms selected from nitrogen, oxygen, and sulfur. The ring
structure may optionally contain up to two oxo groups on sulfur
ring members. Illustrative entities, in the form of properly bonded
moieties, include:
##STR00004##
[0056] The term "aryl" refers to a monocyclic, or fused or spiro
polycyclic, aromatic carbocycle (ring structure having ring atoms
that are all carbon) having from 3 to 12 ring atoms per ring.
(Carbon atoms in aryl groups are sp.sup.2 hybridized.) Illustrative
examples of aryl groups include the following moieties:
##STR00005##
and the like.
[0057] The term "heteroaryl" refers to a monocyclic, fused
bicyclic, or fused polycyclic aromatic heterocycle (ring structure
having ring atoms selected from carbon atoms and up to four
heteroatoms selected from nitrogen, oxygen, and sulfur) having from
3 to 12 ring atoms per heterocycle. Illustrative examples of
heteroaryl groups include the following entities, in the form of
properly bonded moieties:
##STR00006## ##STR00007##
[0058] Those skilled in the art will recognize that the species of
heteroaryl, cycloalkyl, aryl and heterocycloalkyl groups listed or
illustrated above are not exhaustive, and that additional species
within the scope of these defined terms may also be selected.
[0059] The term "halogen" represents chlorine, fluorine, bromine or
iodine. The term "halo" represents chloro, fluoro, bromo or
iodo.
[0060] The term "substituted" means that the specified group or
moiety bears one or more substituents. The term "unsubstituted"
means that the specified group bears no substituents. The term
"optionally substituted" means that the specified group is
unsubstituted or substituted by one or more substituents. Where the
term "substituted" is used to describe a structural system, the
substitution is meant to occur at any valency-allowed position on
the system. In cases where a specified moiety or group is not
expressly noted as being optionally substituted or substituted with
any specified substituent, it is understood that such a moiety or
group is intended to be unsubstituted.
[0061] The terms "para", "meta", and "ortho" have the meanings as
understood in the art. Thus, for example, a fully substituted
phenyl group has substituents at both "ortho"(o) positions adjacent
to the point of attachment of the phenyl ring, both "meta" (m)
positions, and the one "para" (p) position across from the point of
attachment as illustrated below.
##STR00008##
[0062] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that, whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation to such given value that would reasonably be
inferred based on the ordinary skill in the art, including
equivalents and approximations due to the experimental and/or
measurement conditions for such given value. Whenever a yield is
given as a percentage, such yield refers to a mass of the entity
for which the yield is given with respect to the maximum amount of
the same entity that could be obtained under the particular
stoichiometric conditions. Concentrations that are given as
percentages refer to mass ratios, unless indicated differently.
[0063] The terms "buffered" solution or "buffer" solution are used
herein interchangeably according to their standard meaning.
Buffered solutions are used to control the pH of a medium, and
their choice, use, and function is known to those of ordinary skill
in the art. See, for example, G. D. Considine, ed., Van Nostrand's
Encyclopedia of Chemistry, p. 261, 5.sup.th ed. (2005), describing,
inter alia, buffer solutions and how the concentrations of the
buffer constituents relate to the pH of the buffer. See also
Handbook of Chemistry and Physics, 84.sup.th ed., pp. 8-37 to 8-44.
For example, a buffered solution is obtained by adding MgSO.sub.4
and NaHCO.sub.3 to a solution in a 10:1 w/w ratio to maintain the
pH of the solution at about 7.5.
[0064] Any formula given herein is intended to represent compounds
having structures depicted by the structural formula as well as
certain variations or forms. In particular, compounds of any
formula given herein may have asymmetric centers and therefore
exist in different enantiomeric forms. All optical isomers and
stereoisomers of the compounds of the general formula, and mixtures
thereof, are considered within the scope of the formula. Thus, any
formula given herein is intended to represent a racemate, one or
more enantiomeric forms, one or more diastereomeric forms, one or
more atropisomeric forms, and mixtures thereof. Furthermore,
certain structures may exist as geometric isomers (i.e., cis and
trans isomers), as tautomers, or as atropisomers.
[0065] The symbols and are used as meaning the same spatial
arrangement in chemical structures shown herein. Analogously, the
symbols and are used as meaning the same spatial arrangement in
chemical structures shown herein.
[0066] Additionally, any formula given herein is intended to refer
also to hydrates, solvates, and polymorphs of such compounds, and
mixtures thereof, even if such forms are not listed explicitly.
Certain compounds of Formula (I) or Formula (II) or
pharmaceutically acceptable salts of compounds of Formula (I) or
Formula (II) may be obtained as solvates. Solvates include those
formed from the interaction or complexation of compounds of the
invention with one or more solvents, either in solution or as a
solid or crystalline form. In some embodiments, the solvent is
water and then the solvates are hydrates. In addition, certain
crystalline forms of compounds of Formula (I) or Formula (II) or
pharmaceutically acceptable salts of compounds of Formula (I) or
Formula (II) may be obtained as co-crystals. In certain embodiments
of the invention, compounds of Formula (I) or Formula (II) were
obtained in a crystalline form. In other embodiments, crystalline
forms of compounds of Formula (I) or Formula (II) were cubic in
nature. In other embodiments, pharmaceutically acceptable salts of
compounds of Formula (I) or Formula (II) were obtained in a
crystalline form. In still other embodiments, compounds of Formula
(I) or Formula (II) were obtained in one of several polymorphic
forms, as a mixture of crystalline forms, as a polymorphic form, or
as an amorphous form. In other embodiments, compounds of Formula
(I) or Formula (II) convert in solution between one or more
crystalline forms and/or polymorphic forms.
[0067] Reference to a chemical entity herein stands for a reference
to any one of: (a) the actually recited form of such chemical
entity, and (b) any of the forms of such chemical entity in the
medium in which the compound is being considered when named. For
example, reference herein to a compound such as R--COOH,
encompasses reference to any one of, for example, R--COOH.sub.(s),
R--COOH.sub.(sol), and R--COO.sup.-.sub.(so). In this example,
R--COOH.sub.(s) refers to the solid compound, as it could be for
example in a tablet or some other solid pharmaceutical composition
or preparation; R--COOH.sub.(sol) refers to the undissociated form
of the compound in a solvent; and R--COO.sup.-.sub.(sol) refers to
the dissociated form of the compound in a solvent, such as the
dissociated form of the compound in an aqueous environment, whether
such dissociated form derives from R--COOH, from a salt thereof, or
from any other entity that yields R--COO.sup.- upon dissociation in
the medium being considered. In another example, an expression such
as "exposing an entity to compound of formula R--COOH" refers to
the exposure of such entity to the form, or forms, of the compound
R--COOH that exists, or exist, in the medium in which such exposure
takes place. In still another example, an expression such as
"reacting an entity with a compound of formula R--COOH" refers to
the reacting of (a) such entity in the chemically relevant form, or
forms, of such entity that exists, or exist, in the medium in which
such reacting takes place, with (b) the chemically relevant form,
or forms, of the compound R--COOH that exists, or exist, in the
medium in which such reacting takes place. In this regard, if such
entity is for example in an aqueous environment, it is understood
that the compound R--COOH is in such same medium, and therefore the
entity is being exposed to species such as R--COOH.sub.(aq) and/or
R--COO.sup.-.sub.(aq), where the subscript "(aq)" stands for
"aqueous" according to its conventional meaning in chemistry and
biochemistry. A carboxylic acid functional group has been chosen in
these nomenclature examples; this choice is not intended, however,
as a limitation but it is merely an illustration. It is understood
that analogous examples can be provided in terms of other
functional groups, including but not limited to hydroxyl, basic
nitrogen members, such as those in amines, and any other group that
interacts or transforms according to known manners in the medium
that contains the compound. Such interactions and transformations
include, but are not limited to, dissociation, association,
tautomerism, solvolysis, including hydrolysis, solvation, including
hydration, protonation, and deprotonation. No further examples in
this regard are provided herein because these interactions and
transformations in a given medium are known by any one of ordinary
skill in the art.
[0068] In another example, a zwitterionic compound is encompassed
herein by referring to a compound that is known to form a
zwitterion, even if it is not explicitly named in its zwitterionic
form. Terms such as zwitterion, zwitterions, and their synonyms
zwitterionic compound(s) are standard IUPAC-endorsed names that are
well known and part of standard sets of defined scientific names.
In this regard, the name zwitterion is assigned the name
identification CHEBI:27369 by the Chemical Entities of Biological
Interest (ChEBI) dictionary of molecular entities. As generally
well known, a zwitterion or zwitterionic compound is a neutral
compound that has formal unit charges of opposite sign. Sometimes
these compounds are referred to by the term "inner salts". Other
sources refer to these compounds as "dipolar ions", although the
latter term is regarded by still other sources as a misnomer. As a
specific example, aminoethanoic acid (the amino acid glycine) has
the formula H.sub.2NCH.sub.2COOH, and it exists in some media (in
this case in neutral media) in the form of the zwitterion
.sup.+H.sub.3NCH.sub.2COO.sup.-. Zwitterions, zwitterionic
compounds, inner salts and dipolar ions in the known and well
established meanings of these terms are within the scope of this
invention, as would in any case be so appreciated by those of
ordinary skill in the art. Because there is no need to name each
and every embodiment that would be recognized by those of ordinary
skill in the art, no structures of the zwitterionic compounds that
are associated with the compounds of this invention are given
explicitly herein. They are, however, part of the embodiments of
this invention. No further examples in this regard are provided
herein because the interactions and transformations in a given
medium that lead to the various forms of a given compound are known
by any one of ordinary skill in the art.
[0069] Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, fluorine, and chlorine, such as .sup.2H, .sup.3H,
.sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O,
.sup.31P, .sup.32P, .sup.35S, .sup.18F, .sup.36Cl, .sup.125I,
respectively. Such isotopically labeled compounds are useful in
metabolic studies (preferably with .sup.14C), reaction kinetic
studies (with, for example .sup.2H or .sup.3H), detection or
imaging techniques [such as positron emission tomography (PET) or
single-photon emission computed tomography (SPECT)] including drug
or substrate tissue distribution assays, or in radioactive
treatment of patients. In particular, an .sup.18F or .sup.11C
labeled compound may be particularly preferred for PET or an
I.sup.123 for SPECT studies. Further, substitution with heavier
isotopes such as deuterium (i.e., .sup.2H) may afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements. Isotopically labeled compounds of this invention and
prodrugs thereof can generally be prepared by carrying out the
procedures disclosed in the schemes or in the examples and
preparations described below by substituting a readily available
isotopically labeled reagent for a non-isotopically labeled
reagent.
[0070] When referring to any formula given herein, the selection of
a particular moiety from a list of possible species for a specified
variable is not intended to define the same choice of the species
for the variable appearing elsewhere. In other words, where a
variable appears more than once, the choice of the species from a
specified list is independent of the choice of the species for the
same variable elsewhere in the formula, unless stated
otherwise.
[0071] By way of a first example on substituent terminology, if
substituent S.sup.1.sub.example is one of S.sub.1 and S.sub.2, and
substituent S.sup.2.sub.example is one of S.sub.3 and S.sub.4, then
these assignments refer to embodiments of this invention given
according to the choices S.sup.1.sub.example is S.sub.1 and
S.sup.2.sub.example is S.sub.3; S.sup.1.sub.example is S.sub.1 and
S.sup.2.sub.example is S.sub.4; S.sup.1.sub.example is S.sub.2 and
S.sup.2.sub.example is S.sub.3; S.sup.1.sub.example is S.sub.2 and
S.sup.2.sub.example is S.sub.4; and equivalents of each one of such
choices. The shorter terminology "S.sup.1.sub.example is one of
S.sub.1 and S.sub.2, and S.sup.2.sub.example is one of S.sub.3 and
S.sub.4.sup." is accordingly used herein for the sake of brevity,
but not by way of limitation. The foregoing first example on
substituent terminology, which is stated in generic terms, is meant
to illustrate the various substituent assignments described herein.
The foregoing convention given herein for substituents extends,
when applicable, to members such as R.sup.1, R.sup.2, R.sup.3,
R.sup.4, A, R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.e, R.sup.f,
R.sup.g, R.sup.h, R.sup.i, R.sup.j, and R.sup.k, and any other
generic substituent symbol used herein.
[0072] Furthermore, when more than one assignment is given for any
member or substituent, embodiments of this invention comprise the
various groupings that can be made from the listed assignments,
taken independently, and equivalents thereof. By way of a second
example on substituent terminology, if it is herein described that
substituent S.sub.example is one of S.sub.1, S.sub.2, and S.sub.3,
this listing refers to embodiments of this invention for which
S.sub.example is S.sub.1; S.sub.example is S.sub.2; S.sub.example
is S.sub.3; S.sub.example is one of S.sub.1 and S.sub.2;
S.sub.example is one of S.sub.1 and S.sub.3; S.sub.example is one
of S.sub.2 and S.sub.3; S.sub.example is one of S.sub.1, S.sub.2
and S.sub.3; and S.sub.example is any equivalent of each one of
these choices. The shorter terminology "S.sub.example is one of
S.sub.1, S.sub.2, and S.sub.3" is accordingly used herein for the
sake of brevity, but not by way of limitation. The foregoing second
example on substituent terminology, which is stated in generic
terms, is meant to illustrate the various substituent assignments
described herein. The foregoing convention given herein for
substituents extends, when applicable, to members such as R.sup.1,
R.sup.2, R.sup.3, R.sup.4, A, R.sup.a, R.sup.b, R.sup.c, R.sup.d,
R.sup.e, R.sup.f, R.sup.g, R.sup.h, R.sup.i, R.sup.j, and R.sup.k,
and any other generic substituent symbol used herein.
[0073] The nomenclature "C.sub.i-j" with j>i, when applied
herein to a class of substituents, is meant to refer to embodiments
of this invention for which each and every one of the number of
carbon members, from i to j including i and j, is independently
realized. By way of example, the term C.sub.1-3 refers
independently to embodiments that have one carbon member (C.sub.1),
embodiments that have two carbon members (C.sub.2), and embodiments
that have three carbon members (C.sub.3).
[0074] The term C.sub.n-malkyl refers to an aliphatic chain,
whether straight or branched, with a total number N of carbon
members in the chain that satisfies n.ltoreq.N.ltoreq.m, with
m>n. Any disubstituent referred to herein is meant to encompass
the various attachment possibilities when more than one of such
possibilities are allowed. For example, reference to disubstituent
-A-B-, where A.noteq.B, refers herein to such disubstituent with A
attached to a first substituted member and B attached to a second
substituted member, and it also refers to such disubstituent with A
attached to the second substituted member and B attached to the
first substituted member.
[0075] According to the foregoing interpretive considerations on
assignments and nomenclature, it is understood that explicit
reference herein to a set implies, where chemically meaningful and
unless indicated otherwise, independent reference to embodiments of
such set, and reference to each and every one of the possible
embodiments of subsets of the set referred to explicitly.
[0076] Some embodiments are given by compounds of Formula (I) where
R.sup.1 is phenyl substituted with R.sup.a, where R.sup.a is --F,
--I, --Cl, --OCH.sub.3, --OCH.sub.2CH.sub.3, --CH.sub.3,
--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3 or --NO.sub.2.
[0077] In some of these embodiments, R.sup.1 is substituted phenyl
wherein R.sup.b is a --Br, --F, --I, --C.sub.1-4alkyl, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --CN, --CF.sub.3, or --OCF.sub.3.
[0078] In some of these embodiments, R.sup.1 is phenyl substituted
with R.sup.a, wherein R.sup.a is --H, --F, --Cl, --CH.sub.3,
--C(CH.sub.3).sub.3, --OCH.sub.3, or --OCH.sub.2CH.sub.3, and
R.sup.b is --Br, --F, --I, --C.sub.1-4alkyl, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --CN, --CF.sub.3, or --OCF.sub.3.
[0079] In some of these embodiments, R.sup.1 is substituted phenyl
where R.sup.b is 2-thiophen-2-yl or 2-furan-2-yl.
[0080] In some of these embodiments, R.sup.1 is substituted phenyl
where R.sup.b is phenyl, 3-chlorophenyl, 4-fluorophenyl,
3-fluorophenyl, 4-methylphenyl, or 4-trifluoromethylphenyl.
[0081] In some of these embodiments, R.sup.1 is substituted phenyl
where R.sup.b is 1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 1H-pyrazol-5-yl,
1H-imidazol-2-yl, 1-methyl-1H-imidazol-2-yl, 1H-1,2,3-triazol-1-yl,
2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-1-yl,
1H-1,2,4-triazol-5-yl, 2H-1,2,4-triazol-1-yl,
2H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-yl,
4H-1,2,4-triazol-4-yl, 1-methyl-1H-1,2,4-triazol-3-yl,
1-methyl-1H-1,2,4-triazol-5-yl or
1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl.
[0082] In some of these embodiments, R.sup.1 is substituted phenyl,
where R.sup.b is pyridin-2-yl, 3-chloropyridin-2-yl,
3-fluoropyridin-2-yl, 3-methylpyridin-2-yl, 4-methylpyridin-2-yl,
5-methylpyridin-2-yl, 6-methylpyridin-2-yl, 2-pyridin-3-yl, or
2-pyrimidin-2-yl.
[0083] In some of these embodiments, R.sup.1 is substituted phenyl,
where R.sup.b is 3-methyl-1,2,4-oxadiazol-5-yl or oxazol-2-yl.
[0084] In some of these embodiments, R.sup.1 is phenyl substituted
with R.sup.a, where R.sup.a is halo, --C.sub.1-4alkyl, or
--C.sub.1-4alkoxy, and R.sup.b is triazole or pyrimidine
substituted or unsubstituted with halo or --C.sub.1-4alkyl.
[0085] In some of these embodiments, R.sup.1 is
(1-methylethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl,
2-(1H-1,2,3-triazol-1-yl)phenyl, 2-(2H-1,2,3-triazol-2-yl)phenyl,
2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl,
2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl,
3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,
3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl,
3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl,
3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,
3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,
3-methyl-2-(1H-1,2,3-triazol-1-yl)phenyl,
4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,
4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,
4-methoxy-2-(1H-1,2,3-triazol-2-yl)phenyl,
4,5-dimethoxy-2-[1,2,3]triazol-1-yl-phenyl,
4,5-dimethoxy-2-[1,2,3]triazol-2-yl-phenyl,
5-[1,2,3]triazol-2-yl-benzo[1,3]dioxol-4-yl,
5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl,
5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,
5-iodo-2-(2H-1,2,3-triazol-2-yl)phenyl,
5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,
5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,
1-[1,2,3]triazol-2-yl-naphthalen-2-yl,
2-(1H-1,2,4-triazol-1-yl)phenyl, 2-(1H-1,2,4-triazol-5-yl)phenyl,
2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl,
2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl,
2-(4H-1,2,4-triazol-3-yl)phenyl, 2-(4H-1,2,4-triazol-4-yl)phenyl,
2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,
3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,
2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,
4,5-difluoro-2-(4H-1,2,4-triazol-4-yl)phenyl),
2-fluoro-6-pyrimidin-2-ylphenyl, 2-(pyrimidin-2-yl)pyridin-3-yl,
3-fluoro-2-pyrimidin-2-ylphenyl, 4-fluoro-2-(pyrimidin-2-yl)phenyl,
4-methoxy-2-(pyrimidin-2-yl)phenyl,
5-fluoro-2-pyrimidin-2-ylphenyl, or
5-methyl-2-pyrimidin-2-ylphenyl.
[0086] Some embodiments are given by compounds of Formula (I) where
R.sup.1 is substituted pyridine, where R.sup.d is --CF.sub.3, --Br,
or --OCH.sub.2CH.sub.2CH.sub.3.
[0087] In some of these embodiments, wherein R.sup.1 is substituted
pyridine, R.sup.d is 1H-pyrazol-5-yl, 2H-1,2,3-triazol-1-yl,
2H-1,2,3-triazol-2-yl, 4H-1,2,3-triazol-1-yl,
1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl, 3-methylpyridin-2-yl,
or 3-methyl-1,2,4-oxadiazol-5-yl.
[0088] In some of these embodiments, wherein R.sup.1 is substituted
pyridine, R.sup.d is 1H-pyrazol-5-yl, 2H-1,2,3-triazol-1-yl, or
2H-1,2,3-triazol-2-yl.
[0089] In some of these embodiments, wherein R.sup.1 is
1-phenyl-1H-pyrazol-5-yl, 3-phenylthiophen-2-yl,
3-phenylfuran-2-yl, 5-phenyl-1,3-oxazol-4-yl,
5-phenylisoxazol-4-yl,
5-(2-fluorophenyl)-2-methyl-1,3-thiazol-4-yl,
2-methyl-5-phenyl-thiazol-4-yl, or
5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl.
[0090] Some embodiments are given by compounds of Formula (I),
where R.sup.1 is 3-methylfuran-2-yl, 9H-fluorene, quinoline,
cinnoline; 3-(1H-pyrrol-1-yl)thiophen-2-yl,
8-[1,2,3]-triazol-2-yl-naphthalen-1-yl,
2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl,
4-fluoronaphthalen-1-yl, and naphthalen-1-yl and R.sup.2 is
selected from the group consisting of 4,6-dimethylpyrimidin-2-yl,
4-phenyl-pyrimidin-2-yl, quinoxaline, or
4-methoxypyrimidin-2-yl.
[0091] Some embodiments are given by compounds of Formula (I),
where R.sup.2 is pyrimidine substituted with --F, --Cl, -D,
-CD.sub.3, --CH.sub.3, ethyl, isopropyl, propyl, tert-butyl,
--CF.sub.3, --OCH.sub.3, --N(CH.sub.3).sub.2, --CN, --OH,
--CH.sub.2OH, --NO.sub.2, --CO.sub.2CH.sub.3, --CO.sub.2H,
--C(O)N(CH.sub.3).sub.2, phenyl, furan-2-yl, thiophen-2-yl,
1H-pyrazol-4-yl, cyclopropyl, pyrrolidin-1-yl, or
morpholin-4-yl.
[0092] In some of these embodiments, R.sup.2 is
4,6-dimethylpyrimidin-2-yl, 4,5-dimethylpyrimidin-2-yl,
4,6-dimethoxypyrimidin-2-yl, 4-phenyl-pyrimidin-2-yl,
4-furan-2-ylpyrimidin-2-yl, 4-methylpyrimidin-2-yl,
4-methoxypyrimidin-2-yl, 4-thiophen-2-ylpyrimidin-2-yl,
N,N,6-trimethyl-pyrimidin-4-amine,
4-(trifluoromethyl)pyrimidin-2-yl, 4,5,6-trimethylpyrimidin-2-yl,
4-(trifluoromethyl)pyrimidine-5-carboxylate,
4-(trifluoromethyl)pyrimidine-5-carboxylic acid,
5-nitro-pyrimidin-2-yl, 6-methylpyrimidine-4-carboxylic acid,
N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide,
N,N,6-trimethylpyrimidine-carboxamide,
6-methylpyrimidine-4-carbonitrile,
4,6-bis(trifluoromethyl)pyrimidin-2-yl, 6-methyl-pyrimidin-4-ol,
4-(furan-2-yl)-6-methylpyrimidin-2-yl,
5-fluoro-4-methylpyrimidin-2-yl, 5-fluoropyrimidin-2-yl,
4-methoxy-6-methylpyrimidin-2-yl, 4-ethyl-6-methylpyrimidin-2-yl,
4-isopropyl-6-methylpyrimidin-2-yl,
4-tertbutyl-6-methylpyrimidin-2-yl,
4-cyclopropyl-6-methylpyrimidin-2-yl,
4-methyl-6-morpholin-4-ylpyrimidin-2-yl,
5-chloro-4-methylpyrimidin-2-yl,
5-chloro-4,6-dimethylpyrimidin-2-yl,
5-fluoro-4,6-dimethylpyrimidin-2-yl,
5-trifluoromethylpyrimidin-2-yl,
4,6-bis[(.sup.2H3)methyl](.sup.2H)pyrimidin-2-yl, or
5-ethyl-4,6-dimethylpyrimidin-2-yl.
[0093] In some of these embodiments, R.sup.2 is pyrimidine
substituted with one or more --Cl, --F, --CH.sub.3, --CF.sub.3,
--N(CH.sub.3).sub.2, -D, or --CD.sub.3.
[0094] In some of these embodiments, R.sup.2 is
4,6-dimethylpyrimidin-2-yl, 4,5-dimethylpyrimidin-2-yl,
4,6-dimethoxypyrimidin-2-yl, 4-methylpyrimidin-2-yl,
4-methoxypyrimidin-2-yl, N,N,6-trimethyl-pyrimidin-4-amine,
4-(trifluoromethyl)pyrimidin-2-yl, 4,5,6-trimethylpyrimidin-2-yl,
4,6-bis(trifluoromethyl)pyrimidin-2-yl, 6-methyl-pyrimidin-4-ol,
5-fluoro-4-methylpyrimidin-2-yl, 5-fluoropyrimidin-2-yl,
4-methoxy-6-methylpyrimidin-2-yl, 5-chloro-4-methylpyrimidin-2-yl,
5-chloro-4,6-dimethylpyrimidin-2-yl,
5-fluoro-4,6-dimethylpyrimidin-2-yl,
5-trifluoromethylpyrimidin-2-yl, or
4,6-bis[(.sup.2H3)methyl](.sup.2H)pyrimidin-2-yl.
[0095] Some embodiments are given by compounds of Formula (I) where
R.sup.2 is pyrazine or triazine substituted with one or more
--CH.sub.3.
[0096] Some embodiments are given by compounds of Formula (I) where
R.sup.2 is pyridine substituted with one or more --F, --OCH.sub.3,
--OCH.sub.2CH.sub.3, --CH.sub.3, or --CF.sub.3.
[0097] In some of these embodiments, R.sup.2 is benzooxazol-2-yl,
2-methylpyrimidin-4(3H)-one and
4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine and R.sup.1 is
phenyl, substituted in the ortho position with R.sup.b, where
R.sup.b is 2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-1-yl,
3-methyl-1,2,4-oxadiazol-5-yl or 2-pyrimidin-2-yl.
[0098] Some embodiments are given by compounds of Formula (I) where
R.sup.2 is quinoxalin-2-yl, 3-methylquinoxalin-2-yl,
6,7-difluoroquinoxalin-2-yl, 3-(trifluoromethyl)quinoxaline,
4-methylquinoline, or 6-fluoroquinazolin-2-yl and R.sup.1 is phenyl
substituted in the ortho position with R.sup.b, where R.sup.b is
2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-1-yl,
3-methyl-1,2,4-oxadiazol-5-yl or 2-pyrimidin-2-yl.
[0099] Some embodiments are given by compounds of Formula (II)
where R.sup.3 is biphenyl or 2-methoxyphenyl and R.sup.4 is
(5-trifluoromethyl)-pyridin-2-yl,
(5-trifluoromethyl)-pyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, or
quinoxalin-2-yl.
[0100] Some embodiments are given by compounds of Formula (I)
wherein R.sup.1 is 2-(1H-1,2,3-triazol-1-yl)phenyl,
2-(2H-1,2,3-triazol-2-yl)phenyl,
2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl,
2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl,
3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,
3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl,
3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl,
3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,
3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,
3-methyl-2-(1H-1,2,3-triazol-1-yl)phenyl,
4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,
4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,
4-methoxy-2-(1H-1,2,3-triazol-2-yl)phenyl,
4,5-dimethoxy-2-[1,2,3]triazol-1-yl-phenyl,
4,5-dimethoxy-2-[1,2,3]triazol-2-yl-phenyl,
5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl,
5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,
5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,
5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,
2-(1H-1,2,4-triazol-1-yl)phenyl, 2-(1H-1,2,4-triazol-5-yl)phenyl,
2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl,
2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl,
2-(4H-1,2,4-triazol-3-yl)phenyl, 2-(4H-1,2,4-triazol-4-yl)phenyl,
2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,
3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,
2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,
4,5-difluoro-2-(4H-1,2,4-triazol-4-yl)phenyl),
2-fluoro-6-pyrimidin-2-ylphenyl, 2-(pyrimidin-2-yl)pyridin-3-yl,
3-fluoro-2-pyrimidin-2-ylphenyl, 4-fluoro-2-(pyrimidin-2-yl)phenyl,
4-methoxy-2-(pyrimidin-2-yl)phenyl,
5-fluoro-2-pyrimidin-2-ylphenyl, or 5-methyl-2-pyrimidin-2-ylphenyl
and R.sup.2 is 4,6-dimethylpyrimidin-2-yl,
4,5-dimethylpyrimidin-2-yl, 4,6-dimethoxypyrimidin-2-yl,
4-methylpyrimidin-2-yl, 4-methoxypyrimidin-2-yl,
N,N,6-trimethyl-pyrimidin-4-amine,
4-(trifluoromethyl)pyrimidin-2-yl, 4,5,6-trimethylpyrimidin-2-yl,
4,6-bis(trifluoromethyl)pyrimidin-2-yl, 6-methyl-pyrimidin-4-ol,
5-fluoro-4-methylpyrimidin-2-yl, 5-fluoropyrimidin-2-yl,
4-methoxy-6-methylpyrimidin-2-yl, 5-chloro-4-methylpyrimidin-2-yl,
5-chloro-4,6-dimethylpyrimidin-2-yl,
5-fluoro-4,6-dimethylpyrimidin-2-yl,
5-trifluoromethylpyrimidin-2-yl, or
4,6-bis[(.sup.2H3)methyl](.sup.2H)pyrimidin-2-yl.
[0101] Some embodiments are given by compounds of Formula (I)
wherein R.sup.1 is
3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,
6-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,
4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl, or
3-[1,2,3]triazol-2-yl-pyridin-2-yl and R.sup.2 is
4,6-dimethylpyrimidin-2-yl, 5-fluoro-4,6-dimethylpyrimidin-2-yl, or
5-fluoro-4-methylpyrimidin-2-yl.
[0102] Compounds of Formula (I) and Formula (II) and
pharmaceutically acceptable salts thereof are used, alone or in
combination with one or more additional active ingredients, to
formulate pharmaceutical compositions. A pharmaceutical composition
therefore comprises an effective amount of at least one a compound
of Formula (I) and Formula (II) or a pharmaceutically acceptable
salt thereof.
[0103] The invention includes also pharmaceutically acceptable
salts of the compounds of Formula (I) and Formula (II), preferably
of those described above and of the specific compounds exemplified
herein, and methods of treatment using such salts.
[0104] A "pharmaceutically acceptable salt" is intended to mean a
salt of a free acid or base of a compound represented by Formula
(I) and Formula (II), that is non-toxic, biologically tolerable, or
otherwise biologically suitable for administration to the subject.
See, generally, G. S. Paulekuhn, et al., "Trends in Active
Pharmaceutical Ingredient Salt Selection based on Analysis of the
Orange Book Database", J. Med. Chem., 2007, 50:6665-72, S. M.
Berge, et al., "Pharmaceutical Salts", J Pharm Sci., 1977, 66:1-19,
and Handbook of Pharmaceutical Salts, Properties, Selection, and
Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.
Examples of pharmaceutically acceptable salts are those that are
pharmacologically effective and suitable for contact with the
tissues of patients without undue toxicity, irritation, or allergic
response. A compound of Formula (I) and Formula (II) may possess a
sufficiently acidic group, a sufficiently basic group, or both
types of functional groups, and accordingly react with a number of
inorganic or organic bases, and inorganic and organic acids, to
form a pharmaceutically acceptable salt.
[0105] bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt.
[0106] Examples of pharmaceutically acceptable salts include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,
phosphates, monohydrogen-phosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methylbenzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycolates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0107] When the compound of Formula (I) or Formula (II) contains a
basic nitrogen, the desired pharmaceutically acceptable salt may be
prepared by any suitable method available in the art, for example,
treatment of the free base with an inorganic acid, such as
hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid,
nitric acid, boric acid, phosphoric acid, and the like, or with an
organic acid, such as acetic acid, phenylacetic acid, propionic
acid, stearic acid, lactic acid, ascorbic acid, maleic acid,
hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,
fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic
acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a
pyranosidyl acid, such as glucuronic acid or galacturonic acid, an
alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric
acid, an amino acid, such as aspartic acid, glutaric acidor
glutamic acid, an aromatic acid, such as benzoic acid,
2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic
acid, such as laurylsulfonic acid, p-toluenesulfonic acid,
methanesulfonic acid, ethanesulfonic acid, any compatible mixture
of acids such as those given as examples herein, and any other acid
and mixture thereof that are regarded as equivalents or acceptable
substitutes in light of the ordinary level of skill in this
technology.
[0108] When the compound of Formula (I) or Formula (II) is an acid,
such as a carboxylic acid or sulfonic acid, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide, alkaline earth metal hydroxide, any
compatible mixture of bases such as those given as examples herein,
and any other base and mixture thereof that are regarded as
equivalents or acceptable substitutes in light of the ordinary
level of skill in this technology. Illustrative examples of
suitable salts include organic salts derived from amino acids, such
as N-methyl-D-glucamine, lysine, choline, glycine and arginine,
ammonia, carbonates, bicarbonates, primary, secondary, and tertiary
amines, and cyclic amines, such as tromethamine, benzylamines,
pyrrolidines, piperidine, morpholine, and piperazine, and inorganic
salts derived from sodium, calcium, potassium, magnesium,
manganese, iron, copper, zinc, aluminum, and lithium.
[0109] The invention also relates to pharmaceutically acceptable
prodrugs of the compounds of Formula (I) and Formula (II), and
treatment methods employing such pharmaceutically acceptable
prodrugs. The term "prodrug" means a precursor of a designated
compound that, following administration to a subject, yields the
compound in vivo via a chemical or physiological process such as
solvolysis or enzymatic cleavage, or under physiological conditions
(e.g., a prodrug on being brought to physiological pH is converted
to the compound of Formula (I) or Formula (II)). A
"pharmaceutically acceptable prodrug" is a prodrug that is
non-toxic, biologically tolerable, and otherwise biologically
suitable for administration to the subject. Illustrative procedures
for the selection and preparation of suitable prodrug derivatives
are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.
[0110] Exemplary prodrugs include compounds having an amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or
four) amino acid residues, covalently joined through an amide or
ester bond to a free amino, hydroxy, or carboxylic acid group of a
compound of Formula (I) or Formula (II). Examples of amino acid
residues include the twenty naturally occurring amino acids,
commonly designated by three letter symbols, as well as
4-hydroxyproline, hydroxylysine, demosine, isodemosine,
3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,
citrulline homocysteine, homoserine, ornithine and methionine
sulfone.
[0111] Additional types of prodrugs may be produced, for instance,
by derivatizing free carboxyl groups of structures of Formula (I)
or Formula (II) as amides or alkyl esters. Examples of amides
include those derived from ammonia, primary C.sub.1-6alkyl amines
and secondary di(C.sub.1-6alkyl) amines. Secondary amines include
5- or 6-membered heterocycloalkyl or heteroaryl ring moieties.
Examples of amides include those that are derived from ammonia,
C.sub.1-3alkyl primary amines, and di(C.sub.1-2alkyl)amines.
Examples of esters of the invention include C.sub.1-7alkyl,
C.sub.6-7cycloalkyl, phenyl, and phenyl(C.sub.1-6alkyl) esters.
Preferred esters include methyl esters. Prodrugs may also be
prepared by derivatizing free hydroxy groups using groups including
hemisuccinates, phosphate esters, dimethylaminoacetates, and
phosphoryloxymethyloxycarbonyls, following procedures such as those
outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19,
115-130. Carbamate derivatives of hydroxy and amino groups may also
yield prodrugs. Carbonate derivatives, sulfonate esters, and
sulfate esters of hydroxy groups may also provide prodrugs.
Derivatization of hydroxy groups as (acyloxy)methyl and
(acyloxy)ethyl ethers, wherein the acyl group may be an alkyl
ester, optionally substituted with one or more ether, amine, or
carboxylic acid functionalities, or where the acyl group is an
amino acid ester as described above, is also useful to yield
prodrugs. Prodrugs of this type may be prepared as described in
Robinson et al., J Med Chem. 1996, 39(I), 10-18. Free amines can
also be derivatized as amides, sulfonamides or phosphonamides. All
of these prodrug moieties may incorporate groups including ether,
amine, and carboxylic acid functionalities.
[0112] The present invention also relates to pharmaceutically
active metabolites of the compounds of Formula (I) or Formula (II),
which may also be used in the methods of the invention. A
"pharmaceutically active metabolite" means a pharmacologically
active product of metabolism in the body of a compound of Formula
(I) or Formula (II) or salt thereof. Prodrugs and active
metabolites of a compound may be determined using routine
techniques known or available in the art. See, e.g., Bertolini, et
al., J. Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci.
1997, 86 (7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230;
Bodor, Adv Drug Res. 1984, 13, 224-331; Bundgaard, Design of
Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application
of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et
al., eds., Harwood Academic Publishers, 1991).
[0113] The compounds of Formula (I) or Formula (II) and their
pharmaceutically acceptable salts, pharmaceutically acceptable
prodrugs, and pharmaceutically active metabolites of the present
invention are useful as modulators of the orexin receptor in the
methods of the invention. As such modulators, the compounds may act
as antagonists, agonists, or inverse agonists. The term
"modulators" include both inhibitors and activators, where
"inhibitors" refer to compounds that decrease, prevent, inactivate,
desensitize or down-regulate orexin receptor expression or
activity, and "activators" are compounds that increase, activate,
facilitate, sensitize, or up-regulate orexin receptor expression or
activity.
[0114] The term "treat" or "treating" as used herein is intended to
refer to administration of an active agent or composition of the
invention to a subject for the purpose of effecting a therapeutic
benefit through modulation of orexin receptor activity. Treating
includes reversing, ameliorating, alleviating, inhibiting the
progress of, or lessening the severity of a disease, disorder, or
condition, or one or more symptoms of such disease, disorder or
condition mediated through modulation of orexin receptor activity.
The term "subject" refers to a mammalian patient in need of such
treatment, such as a human.
[0115] Accordingly, the invention relates to methods of using the
compounds described herein to treat subjects diagnosed with or
suffering from a disease, disorder, or condition mediated by orexin
receptor activity, such as: disorders of the sleep-wake cycle,
metabolic disorders, neurological disorders and other disorders
(e.g., feeding, drinking, arousal, stress, addiction, metabolism
and reproduction). Symptoms or disease states are intended to be
included within the scope of "medical conditions, disorders, or
diseases."
[0116] Sleep disorders include, but are not limited to, sleep-wake
transition disorders, insomnia, restless legs syndrome, jet-lag,
disturbed sleep, and sleep disorders secondary to neurological
disorders (e.g., manias, depressions, manic depression,
schizophrenia, and pain syndromes (e.g., fibromyalgia,
neuropathic).
[0117] Metabolic disorders include, but are not limited to,
overweight or obesity and conditions related to overweight or
obesity, such as insulin resistance, type II diabetes,
hyperlipidemia, gallstones, angina, hypertension, breathlessness,
tachycardia, infertility, sleep apnea, back and joint pain,
varicose veins and osteoarthritis.
[0118] Neurological disorders include, but are not limited to,
Parkinson's disease, Alzheimer's disease, Tourette's Syndrome,
catatonia, anxiety, delirium and dementias.
[0119] Other disorders include, but are not limited to, ulcers,
irritable bowel syndrome, diarrhea and gastroesophageal reflux.
[0120] In treatment methods according to the invention, an
effective amount of a pharmaceutical agent according to the
invention is administered to a subject suffering from or diagnosed
as having such a disease, disorder, or condition. An "effective
amount" means an amount or dose sufficient to generally bring about
the desired therapeutic or prophylactic benefit in patients in need
of such treatment for the designated disease, disorder, or
condition. Effective amounts or doses of the compounds of the
present invention may be ascertained by routine methods such as
modeling, dose escalation studies or clinical trials, and by taking
into consideration routine factors, e.g., the mode or route of
administration or drug delivery, the pharmacokinetics of the
compound, the severity and course of the disease, disorder, or
condition, the subject's previous or ongoing therapy, the subject's
health status and response to drugs, and the judgment of the
treating physician. An example of a dose is in the range of from
about 0.001 to about 200 mg of compound per kg of subject's body
weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1
to 35 mg/kg/day, in single or divided dosage units (e.g., BID, TID,
QID). For a 70-kg human, an illustrative range for a suitable
dosage amount is from about 0.05 to about 7 g/day, or about 0.2 to
about 2.5 g/day.
[0121] Once improvement of the patient's disease, disorder, or
condition has occurred, the dose may be adjusted for preventative
or maintenance treatment. For example, the dosage or the frequency
of administration, or both, may be reduced as a function of the
symptoms, to a level at which the desired therapeutic or
prophylactic effect is maintained. Of course, if symptoms have been
alleviated to an appropriate level, treatment may cease. Patients
may, however, require intermittent treatment on a long-term basis
upon any recurrence of symptoms.
[0122] In addition, the active agents of the invention may be used
in combination with additional active ingredients in the treatment
of the above conditions. The additional active ingredients may be
coadministered separately with an active agent of compounds of
Formulas (I) and (II) or included with such an agent in a
pharmaceutical composition according to the invention. In an
exemplary embodiment, additional active ingredients are those that
are known or discovered to be effective in the treatment of
conditions, disorders, or diseases mediated by orexin activity,
such as another orexin modulator or a compound active against
another target associated with the particular condition, disorder,
or disease. The combination may serve to increase efficacy (e.g.,
by including in the combination a compound potentiating the potency
or effectiveness of an active agent according to the invention),
decrease one or more side effects, or decrease the required dose of
the active agent according to the invention.
[0123] The active agents of the invention are used, alone or in
combination with one or more additional active ingredients, to
formulate pharmaceutical compositions of the invention. A
pharmaceutical composition of the invention comprises: (a) an
effective amount of at least one active agent in accordance with
the invention; and (b) a pharmaceutically acceptable excipient.
[0124] A "pharmaceutically acceptable excipient" refers to a
substance that is non-toxic, biologically tolerable, and otherwise
biologically suitable for administration to a subject, such as an
inert substance, added to a pharmacological composition or
otherwise used as a vehicle, carrier, or diluent to facilitate
administration of an agent and that is compatible therewith.
Examples of excipients include calcium carbonate, calcium
phosphate, various sugars and types of starch, cellulose
derivatives, gelatin, vegetable oils, and polyethylene glycols.
[0125] Delivery forms of the pharmaceutical compositions containing
one or more dosage units of the active agents may be prepared using
suitable pharmaceutical excipients and compounding techniques known
or that become available to those skilled in the art. The
compositions may be administered in the inventive methods by a
suitable route of delivery, e.g., oral, parenteral, rectal,
topical, or ocular routes, or by inhalation.
[0126] The preparation may be in the form of tablets, capsules,
sachets, dragees, powders, granules, lozenges, powders for
reconstitution, liquid preparations, or suppositories. Preferably,
the compositions are formulated for intravenous infusion, topical
administration, or oral administration.
[0127] For oral administration, the compounds of the invention can
be provided in the form of tablets or capsules, or as a solution,
emulsion, or suspension. To prepare the oral compositions, the
compounds may be formulated to yield a dosage of, e.g., from about
0.05 to about 100 mg/kg daily, or from about 0.05 to about 35 mg/kg
daily, or from about 0.1 to about 10 mg/kg daily. For example, a
total daily dosage of about 5 mg to 5 g daily may be accomplished
by dosing once, twice, three, or four times per day.
[0128] Oral tablets may include a compound according to the
invention mixed with pharmaceutically acceptable excipients such as
inert diluents, disintegrating agents, binding agents, lubricating
agents, sweetening agents, flavoring agents, coloring agents and
preservative agents. Suitable inert fillers include sodium and
calcium carbonate, sodium and calcium phosphate, lactose, starch,
sugar, glucose, methyl cellulose, magnesium stearate, mannitol,
sorbitol, and the like. Exemplary liquid oral excipients include
ethanol, glycerol, water, and the like. Starch,
polyvinyl-pyrrolidone (PVP), sodium starch glycolate,
microcrystalline cellulose, and alginic acid are suitable
disintegrating agents. Binding agents may include starch and
gelatin. The lubricating agent, if present, may be magnesium
stearate, stearic acid or talc. If desired, the tablets may be
coated with a material such as glyceryl monostearate or glyceryl
distearate to delay absorption in the gastrointestinal tract, or
may be coated with an enteric coating.
[0129] Capsules for oral administration include hard and soft
gelatin capsules. To prepare hard gelatin capsules, compounds of
the invention may be mixed with a solid, semi-solid, or liquid
diluent. Soft gelatin capsules may be prepared by mixing the
compound of the invention with water, an oil such as peanut oil or
olive oil, liquid paraffin, a mixture of mono and di-glycerides of
short chain fatty acids, polyethylene glycol 400, or propylene
glycol.
[0130] Liquids for oral administration may be in the form of
suspensions, solutions, emulsions or syrups or may be lyophilized
or presented as a dry product for reconstitution with water or
other suitable vehicle before use. Such liquid compositions may
optionally contain: pharmaceutically-acceptable excipients such as
suspending agents (for example, sorbitol, methyl cellulose, sodium
alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
aluminum stearate gel and the like); non-aqueous vehicles, e.g.,
oil (for example, almond oil or fractionated coconut oil),
propylene glycol, ethyl alcohol, or water; preservatives (for
example, methyl or propyl p-hydroxybenzoate or sorbic acid);
wetting agents such as lecithin; and, if desired, flavoring or
coloring agents.
[0131] The active agents of this invention may also be administered
by non-oral routes. For example, the compositions may be formulated
for rectal administration as a suppository. For parenteral use,
including intravenous, intramuscular, intraperitoneal, or
subcutaneous routes, the compounds of the invention may be provided
in sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity or in parenterally acceptable oil.
Suitable aqueous vehicles include Ringer's solution and isotonic
sodium chloride. Such forms will be presented in unit-dose form
such as ampules or disposable injection devices, in multi-dose
forms such as vials from which the appropriate dose may be
withdrawn, or in a solid form or pre-concentrate that can be used
to prepare an injectable formulation. Illustrative infusion doses
may range from about 1 to 1000 .mu.g/kg/minute of compound, admixed
with a pharmaceutical carrier over a period ranging from several
minutes to several days.
[0132] For topical administration, the compounds may be mixed with
a pharmaceutical carrier at a concentration of about 0.1% to about
10% of drug to vehicle. Another mode of administering the compounds
of the invention may utilize a patch formulation to affect
transdermal delivery.
[0133] Compounds of the invention may alternatively be administered
in methods of this invention by inhalation, via the nasal or oral
routes, e.g., in a spray formulation also containing a suitable
carrier.
[0134] Exemplary compounds useful in methods of the invention will
now be described by reference to the illustrative synthetic schemes
for their general preparation below and the specific examples that
follow. Artisans will recognize that, to obtain the various
compounds herein, starting materials may be suitably selected so
that the ultimately desired substituents will be carried through
the reaction scheme with or without protection as appropriate to
yield the desired product. Alternatively, it may be necessary or
desirable to employ, in the place of the ultimately desired
substituent, a suitable group that may be carried through the
reaction scheme and replaced as appropriate with the desired
substituent. Unless otherwise specified, the variables are as
defined above in reference to Formula (I). Reactions may be
performed between the melting point and the reflux temperature of
the solvent, and preferably between 0.degree. C. and the reflux
temperature of the solvent. Reactions may be heated employing
conventional heating or microwave heating. Reactions may also be
conducted in sealed pressure vessels above the normal reflux
temperature of the solvent.
[0135] Abbreviations and acronyms used herein include the
following:
TABLE-US-00001 Term Acronym High-performance liquid chromatography
HPLC Thin layer chromatography TLC Diisopropylethylamine DIPEA
Tetrahydrofuran THF tert-Butylcarbamoyl BOC Carboxybenzyl CBz
Dichloromethane DCM Trifluoroacetic acid TFA Acetic Acid HOAc
N,N-Dimethylformamide DMF Methanol MeOH Isopropanol IPA Ethanol
EtOH Acetonitrile ACN Ethyl Acetate EtOAc, or EA Triethylamine TEA
2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3- HATU tetramethylaminium
hexafluorophosphate 1-Hydroxy-7-azabenzotriazole HOAT Methyl
Tertiary Butyl Ether MTBE N-(3-Dimethylaminopropyl)-N- EDCI
ethylcarbodiimide [1,1'- PdCl.sub.2(dppf)-dcm adduct
Bis(diphenylphosphino)ferrocene]palladium(II) Dichloride
Dichloromethane Adduct
##STR00009##
[0136] Intermediate compounds of formulae (VIa) and (VIb) are
readily prepared as outlined in Scheme A from a commercially
available or synthetically accessible compound of formula (IV).
Compounds of formula (Via) are obtained by reacting a compound of
formula (IV), where R.sup.a2 is --H, halo, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --NO.sub.2, --NHCOCH.sub.3, or two R.sup.a2
members may come together to form a 6-membered aryl ring, where X
is C or N (with the proviso that only one X member can be N), with
commercially available HET compounds of formula (V), where
HET is a 5-6 membered heteroaryl ring containing one to three
nitrogen members, in the presence of copper(I)iodide,
Cs.sub.2CO.sub.3 and N,N'-dimethylcyclohexane-1,2-diamine; in a
solvent such as DMF or dioxane, at temperatures ranging from
60.degree. C. to 100.degree. C. (using conventional or microwave
heating). One skilled in the art will recognize that 1,2,3-triazole
can exist in two tautomeric forms defined as 2H-[1,2,3]triazole and
1H-[1,2,3]triazole thus accounting for the formation of two
regioisomers.
[0137] Alternatively, compounds of formula (VIb) are prepared by
the reaction of halobenzonitrile compounds of formula (VII) with
HET, where HET is a 5-membered heteroaryl ring selected from the
group consisting of triazole or pyrazole, in a solvent such as DMF
and the like, in the presence of an inorganic base such as
K.sub.2CO.sub.3 and the like, at temperatures ranging from
100.degree. C. to 130.degree. C. Subsequent hydrolysis of the
nitrile using a base such as aqueous NaOH and the like, in a
solvent such as methanol provides compounds of formula (VIb).
[0138] Compounds of formula (VIb) are also prepared by the reaction
of halobenzonitrile compounds of formula (VII) with
HET-Sn(alkyl).sub.3, where HET-Sn(alkyl).sub.3 is a commercially
available or synthetically accessible trialkyltinheteroaryl
compound, in a solvent such as DME, in the presence of a palladium
catalyst such as Pd(PPh.sub.3).sub.4, in the presence or absence of
a catalytic amount of copper iodide, at temperatures ranging from
100.degree. C. to 160.degree. C., using conventional or microwave
heating. Subsequent hydrolysis of the nitrile using a base such as
aqueous NaOH and the like, in a solvent such as methanol provides
compounds of formula (VIb).
[0139] Compounds of formula (VIb) are also prepared by the reaction
of halobenzonitrile compounds of formula (VII) with HET-boronic
acid, where HET-boronic acid is a commercially available or
synthetically accessible heteroarylboronic acid, in a solvent such
as DME, in the presence of a base such as NaHCO.sub.3, a palladium
catalyst such as Pd(PPh.sub.3).sub.4, at temperatures ranging from
80.degree. C. to the reflux temperature of the solvent. Subsequent
hydrolysis using a base such as aqueous NaOH and the like, in a
solvent such as methanol provides compounds of formula (VIb).
[0140] Compounds of formula (I), where R.sup.b2 is --I, are further
elaborated to compounds of formula (I), where R.sup.b2 is HET,
where HET is a 5-6 membered heteroaryl ring containing one to three
nitrogen atoms optionally containing one oxygen member. Reaction of
compounds of formula (I), where R.sup.b2 is --I, with
HET-Sn(alkyl).sub.3, where HET-Sn(alkyl).sub.3 is a commercially
available or synthetically accessible trialkyltinheteroaryl
compound, in a solvent such as DME, in the presence of a palladium
catalyst such as Pd(PPh.sub.3).sub.4, in the presence or absence of
a catalytic amount of copper iodide, at temperatures ranging from
100.degree. C. to 160.degree. C., using conventional or microwave
heating, provides compounds of formula (I).
##STR00010##
[0141] According to Scheme B, compounds of formula (VIc) are
obtained from compounds of formula (IV), by first converting a
commercially available or synthetically accessible compound of
formula (IV), where R.sup.a2 is --H, halo, --C.sub.1-4alkyl,
--C.sub.1-4alkoxy, --CF.sub.3, or --NO.sub.2, and where X is C or N
(with the proviso that only one X may be N) to one of formula (IX)
under esterification conditions, for example by treating an alcohol
solution of a compound of formula (IV) with an acid. In a preferred
method the compound of formula (IV) is dissolved in a solvent such
as MeOH and treated with H.sub.2SO.sub.4 to afford a compound of
formula (IX). A compound of formula (X) is obtained by reacting a
suitable compound of formula (IX) with pinacol borane in the
presence of a phosphine and a palladium catalyst, in the presence
of an amine base, in a solvent such as THF, at temperatures ranging
from room temperature to 70.degree. C. In a preferred method the
phosphine is tri(o-tolyl)phosphine, the palladium catalyst is
Pd(OAc).sub.2 and the amine base is triethylamine.
[0142] A compound of formula (VIc) is obtained by reacting a
compound of formula (X) with a compound R.sup.b2--Cl, where
R.sup.b2--Cl is a suitable commercially available or synthetically
accessible 6-membered chloro-substituted heteroaryl compound, in
the presence of a palladium catalyst, a base such as
Na.sub.2CO.sub.3, and the like, in a solvent such as
2-methyl-tetrahydrofuran (2-methyl-THF), and the like, at
temperatures ranging from room temperature to 80.degree. C. In a
preferred method the palladium catalyst is PdCl.sub.2(dppf)-dcm
adduct, the base is Na.sub.2CO.sub.3 and the solvent is
2-methyl-THF. A compound of formula (VIc) is obtained from a
compound of formula (XI) via ester hydrolysis. In a preferred
method of hydrolysis, a compound of formula (XI) in methyl-THF is
treated with aqueous NaOH to afford a compound of formula
(VIc).
##STR00011##
[0143] According to SCHEME C, substituted heteroaryl compounds
R.sup.2Cl of formula (XIVa) and (XVIb) are prepared from
commercially available or synthetically accessible compounds of
formula (XIIIa) or (XIIIb). Pyrimidols of formula (XIIIa) or
formula (XIIIb) are commercially available or are prepared by
reacting substituted alkyl malonates of formula (XII), where
R.sup.e is halo, with urea in the presence of a base such as sodium
ethoxide and the like; in a suitable solvent such as ethanol, at
temperatures between room temperature and the reflux temperature of
the solvent. Chlorination of commercially available pyrimidinols of
formula (XIIIb) or synthetically accessible compounds of formula
(XIIIa) using a chlorinating agent such as oxalyl chloride and the
like; in a solvent such as CH.sub.2Cl.sub.2, in the presence of a
base such as N,N-dimethylaniline and the like; at temperatures
ranging between room temperature and the reflux temperature of the
solvent provides chloropyrimidines of formula (XIVa) or (XIVb).
Additionally, chloropyrimidines of formula (XIVa) or (XIVb) are
further elaborated. Chloropyrimidines of formula (XIVa) or (XIVb)
are reacted with Grignard reagents (R.sup.gMgBr) of formula (XV);
in the presence of a catalytic amount of Fe(acac).sub.3, in a
solvent such as Et.sub.2O at 0.degree. C., provides alkyl
chloropyrimidines of formula (XVIa) or (XVIb).
##STR00012##
[0144] According to Scheme D, compounds of formula (XX) are
obtained from synthetically accessible or commercially available
2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole by first protecting the
secondary nitrogen of 2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole as a
carbamate. In a preferred embodiment the carbamate is the
tert-butylcarbamate (boc) which is introduced by treating
2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole with
di-tert-butyl-dicarbonate, in a solvent such as DCM, affording
compound (XVII). Compound (XVIII) is obtained from treating
compound (XVII) with hydrogen gas, in the presence of a catalyst.
In a particularly preferred embodiment the catalyst is Pd on
carbon, in a solvent such as MeOH in the presence of AcOH. A
compound of formula (XIX) is obtained by treating compound (XVIII)
with a compound of formula R.sup.2Cl, where R.sup.2 is as defined
in formula (I). Commercially available or synthetically accessible
appropriately heteroaryl compounds of formula R.sup.2Cl are reacted
with compound (XVIII) in the presence of a suitably selected
tertiary organic or inorganic base such as Cs.sub.2CO.sub.3,
Na.sub.2CO.sub.3, TEA, and the like; in a solvent such as DMF,
dichloromethane, THF, n-butanol, and the like; at a temperature
between room temperature and the reflux temperature of the solvent,
using conventional or microwave heating, to afford compounds of
formula (XIX). In a preferred embodiment the base is
Cs.sub.2CO.sub.3 and the solvent is DMF. Removal of the
tert-butylcarbamate (boc) in compounds of formula (XIX) is
accomplished by using methods known to one skilled in the art, such
as, HCl, TFA, or p-toluenesulfonic acid, in a solvent such as
CH.sub.3OH, dioxane, or CH.sub.2Cl.sub.2. In a preferred
embodiment, a compound of formula (XIX) is treated with TFA in DCM
or HCl to afford a compound of formula (XX).
[0145] Compounds of formula (XX) are also obtained from
2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole. Referring to Scheme D,
2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole is treated with R.sup.2Cl,
where R.sup.2 is as defined in a compound of formula (I).
Commercially available or synthetically accessible suitably
substituted heteroaryl compounds of formula R.sup.2Cl are reacted
with compound 2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole in the
presence of a tertiary organic or inorganic base such as
Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3, TEA, and the like; in a solvent
such as DMF, dichloromethane, THF, and the like; at a temperature
between room temperature and the reflux temperature of the solvent
to afford a compound of formula (XXI). In a preferred embodiment
the base is Cs.sub.2CO.sub.3 and the solvent is DMF. A compound of
formula (XX) is obtained by treating a compound of formula (XXI)
with hydrogen gas, in the presence of a catalyst, in a solvent such
as AcOH. In a preferred embodiment the catalyst is Pd on
carbon.
##STR00013##
[0146] Referring to Scheme E, a compound of formula (I) is obtained
from a compound of formula (XIX), (XX), or (XXI) by reacting a
compound of formula (XIX), (XX), or (XXI) with a compound of
formula R.sup.1CO.sub.2H under amide formation conditions.
Compounds of formula R.sup.1CO.sub.2H, where R.sup.1 is as defined
in formula (I), are commercially available, as described, or
synthetically accessible appropriately substituted aryl or
heteroaryl carboxylic acids. In a preferred embodiment a compound
of formula (XIX), (XX), or (XXI), either as a free base or as an
acid salt, is reacted with a compound of formula R.sup.1CO.sub.2H,
in the presence of a dehydrating agent such as HOBt/EDAC, CDI,
HATU, HOAT; a suitably selected base such as DIPEA, TEA, and the
like; in an organic solvent or mixture thereof, such as toluene,
acetonitrile, ethyl acetate, DMF, THF, methylene chloride, and the
like; to afford a compound of formula (XXII), (XXIII) or (I). In a
particularly preferred embodiment the dehydrating agent is HATU,
and the base is DIPEA.
[0147] In an alternative embodiment, a compound of formula
R.sup.1CO.sub.2H (as described above) may be first converted to a
compound of formula R.sup.1COCl, or compound of formula R.sup.1COCl
is a commercially available substituted aryl sulfonyl chloride. In
a preferred embodiment, a compound of formula R.sup.1CO.sub.2H is
treated with thionyl chloride in a solvent such as toluene to
afford a compound of formula R.sup.1COCl. A compound of formula (I)
is obtained by treating a compound of formula R.sup.1COCl with a
compound of formula (XIX), (XX), or (XXI), a suitably selected
tertiary organic base such as TEA, and the like, in a solvent such
as dichloromethane, THF, and the like, at a temperature between
room temperature and the reflux temperature of the solvent. A
compound of formula (II) is obtained by treating a compound of
formula R.sup.1SO.sub.2Cl with a compound of formula (XIX), (XXI),
or (XXV), where R.sup.4 is (5-trifluoromethyl)-pyridin-2-yl,
(5-trifluoromethyl)-pyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, or
quinoxalin-2-yl; a suitably selected tertiary organic base such as
TEA, and the like, in a solvent such as dichloromethane, THF, and
the like, at a temperature between room temperature and the reflux
temperature of the solvent.
[0148] Referring to Scheme E, one skilled in the art will recognize
that the sequence of transformations shown in Schemes D and E may
be reordered such that amide bond formation may be the initial
reaction to give compounds of formulae (XXII) and (XXIII). Removal
of the N-benzyl group from a compound of formulae (XXII) or removal
of the carbamate from a compound of formula (XXIII) followed by the
reaction with a compound R.sup.2Cl, where R.sup.2Cl is as described
above gives a compound of formula (I).
##STR00014##
[0149] 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid and
2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid are prepared
according to SCHEME H. 3-Fluorophthalic anhydride was dissolved in
a solvent such as MeOH, at temperatures ranging from room
temperature to the reflux temperature of the solvent, to provide
acid-esters (XXVIIa) and (XXIIb). Conversion of the acid to the
acid chloride is accomplished under standard chlorination
conditions. In a preferred method the acid is heated with oxalyl
chloride in a solvent such as DCM. Subsequent reaction of the acid
chloride with N-hydroxyacetamide in a solvent such as
CH.sub.2Cl.sub.2 provides a mixture of esters (XXVIIIa) and
(XXVIIIb). Finally, esters (XXVIIIa) and (XXVIIIb) are converted to
a mixture of esters (XXIXa) and (XXIXb) and acids (XXXa) and (XXXb)
by treatment with a base, preferably sodium acetate, in the
presence of a solvent, preferably t-BuOH.
[0150] Alternately, acid (XXXa) is prepared by first converting
2-fluoro-6-iodobenzoic acid to the acid chloride by reaction with a
chlorinating agent such as oxalyl chloride, in a solvent such as
DCM, with a catalytic amount of DMF, at a temperature of 0.degree.
C. Subsequent reaction of the acid chloride with N-hydroxyacetamide
in a solvent such as CH.sub.2Cl.sub.2 provides
(Z)--N'-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide.
5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole is prepared by
reacting (Z)--N'-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide with
sodium acetate, in a solvent such as tert-butanol, at temperatures
ranging from 100.degree. C. to 110.degree. C.
3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa) is
prepared by reacting
5-(2-fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole with a grignard
reagent such as i-PrMgCl, in a suitable solvent such as THF and the
like, at a temperature of -78.degree. C. Subsequent addition of
CO.sub.2 gas, at a temperature of -78.degree. C. provides
3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa).
##STR00015##
[0151] Deuterated pyrimidine compounds of formula (XXXII) are
prepared according to Scheme H. Acetylacetone is reacted with an
inorganic base such as K.sub.2CO.sub.3 in deuterated water, at
temperatures ranging from 100.degree. C. to 120.degree. C. to
provide 1,1,1,3,3,3,5,5-octadeuteriopentane-2,4-dione.
1,1,1,3,3,3,5,5-Octadeuteriopentane-2,4-dione is subsequently
reacted with deuterated urea, in a solvent such as deuterated
ethanol, 35% wt. DCl in D.sub.2O, at temperatures ranging from
90.degree. C. to 100.degree. C. to provide deuterated pyrimidinols
of formula (XXXI). Chlorination under standard chlorinating
conditions provides chlorodeuteratedpyrimidine compounds of formula
(XXXII).
[0152] Compounds of formula (I) may be converted to their
corresponding salts using methods known to those skilled in the
art. For example, amines of formula (I) may be treated with
trifluoroacetic acid (TFA), HCl, maleic acid, or citric acid in a
solvent such as diethyl ether (Et.sub.2O), CH.sub.2Cl.sub.2,
tetrahydrofuran (THF), or methanol (MeOH) to provide the
corresponding salt forms. In a particularly preferred embodiment
the acid is HCl and the solvent is isopropanol.
[0153] Compounds prepared according to the schemes described above
may be obtained as single enantiomers, diastereomers, or
regioisomers, by enantio-, diastero-, or regiospecific synthesis,
or by resolution. Compounds prepared according to the schemes above
may alternately be obtained as racemic (1:1) or non-racemic (not
1:1) mixtures or as mixtures of diastereomers or regioisomers.
Where racemic and non-racemic mixtures of enantiomers are obtained,
single enantiomers may be isolated using conventional separation
methods known to one skilled in the art, such as chiral
chromatography, recrystallization, diastereomeric salt formation,
derivatization into diastereomeric adducts, biotransformation, or
enzymatic transformation. Where regioisomeric or diastereomeric
mixtures are obtained, single isomers may be separated using
conventional methods such as chromatography or crystallization.
[0154] The following examples are provided to further illustrate
the invention and various preferred embodiments.
EXAMPLES
Chemistry
[0155] In obtaining the compounds described in the examples below
and the corresponding analytical data, the following experimental
and analytical protocols were followed unless otherwise
indicated.
Unless otherwise stated, reaction mixtures were magnetically
stirred at room temperature (rt) under a nitrogen atmosphere. Where
solutions were "dried," they were generally dried over a drying
agent such as Na.sub.2SO.sub.4 or MgSO.sub.4. Where mixtures,
solutions, and extracts were "concentrated", they were typically
concentrated on a rotary evaporator under reduced pressure.
Reactions under microwave irradiation conditions were carried out
in a Biotage Initiator or CEM Discover instrument.
[0156] Normal-phase flash column chromatography (FCC) was performed
on silica gel (SiO.sub.2) using prepackaged cartridges, eluting
with the indicated solvents. Preparative reverse-phase high
performance liquid chromatography (HPLC) was performed on a Gilson
HPLC with an Xterra Prep RP.sub.18 or an XBridge C18 OBD (5 .mu.m,
30.times.100 mm, or 50.times.150 mm) column, and a gradient of 10
to 99% acetonitrile/water (20 mM NH.sub.4OH) over 12 to 18 min, and
a flow rate of 30 mL/min. Mass spectra (MS) were obtained on an
Agilent series 1100 MSD using electrospray ionization (ESI) in
positive mode unless otherwise indicated. Calculated (calcd.) mass
corresponds to the exact mass. Nuclear magnetic resonance (NMR)
spectra were obtained on Bruker model DRX spectrometers. The format
of the .sup.1H NMR data below is: chemical shift in ppm downfield
of the tetramethylsilane reference (multiplicity, coupling constant
J in Hz, integration).
[0157] Chemical names were generated using Chem Draw Ultra 6.0.2
(CambridgeSoft Corp., Cambridge, Mass.) or ACD/Name Version 9
(Advanced Chemistry Development, Toronto, Ontario, Canada).
Intermediate 1
5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00016##
[0159] 5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. To a solution
of 5-fluoro-2-iodo-benzoic acid (3.86 g, 14.65 mmol),
2H-[1,2,3]triazole (2.5 g, 36.2 mmol), Cs.sub.2CO.sub.3 (8.62 g,
24.5 mmol), trans-N,N'-dimethyl-cyclohexane-1,2-diamine (0.4 mL),
CuI (244 mg) and DMF (13 mL) were added to a microwave ready vessel
and heated to 100.degree. C. for 10 min. The mixture was cooled,
diluted with water, and extracted with EtOAc. The aqueous layer was
acidified and extracted with EtOAc. The organic layer was dried
over Na.sub.2SO.sub.4 and concentrated. Chromatography (DCM to 10%
MeOH/1% HOAc/DCM) gave the product as a white powder (2.14 g, 71%).
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.91 (s, 2H), 7.76 (dd, J=8.9,
4.8 Hz, 1H), 7.59 (dd, J=8.5, 2.9 Hz, 1H), 7.49-7.42 (m, 1H).
[0160] Intermediates 2-12 were prepared in a manner analogous to
Intermediate 1.
Intermediate 2
2-[1,2,3]Triazol-2-yl-benzoic acid
##STR00017##
[0161] The title compound was prepared in a manner analogous to
Intermediate 1, substituting 2-iodobenzoic acid for
5-fluoro-2-iodo-benzoic acid. Two products were formed in this
reaction, 2-[1,2,3]triazol-2-yl-benzoic acid and
2-[1,2,3]triazol-1-yl-benzoic acid, as a result of the tautomeric
forms of 1,2,3-triazole. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.91
(s, 2H), 7.85-7.82 (m, 1H), 7.75 (dd, J=8.1, 1.0 Hz, 1H), 7.69 (td,
J=7.7, 1.5 Hz, 1H), 7.60-7.55 (m, 1H).
Intermediate 3
2-[1,2,3]Triazol-1-yl-benzoic acid
##STR00018##
[0162] The title compound was isolated from the synthesis of
Intermediate 2. .sup.1H NMR (400 MHz, CD.sub.3OD): 6.70 (d, J=0.9
Hz, 1H), 6.50 (dd, J=7.7, 1.5 Hz, 1H), 6.30 (d, J=1.0 Hz, 1H),
6.24.6.18 (m, 1H), 6.17-6.11 (m, 1H), 6.01 (dd, J=7.8, 1.0 Hz,
1H).
Intermediate 4
4-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00019##
[0163] The title compound was prepared in a manner analogous to
Intermediate 1, substituting for 4-fluoro-2-iodo-benzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.93 (s, 2H), 7.88 (dd, J=8.7, 5.9 Hz, 1H), 7.56 (dd,
J=9.2, 2.5 Hz, 1H), 7.38-7.30 (m, 1H).
Intermediate 5
3-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00020##
[0164] The title compound was prepared in a manner analogous to
Intermediate 1, substituting for 3-fluoro-2-iodo-benzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.93 (s, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.63-7.58 (m,
1H), 7.29 (td, J=8.9, 0.9 Hz, 1H).
Intermediate 6
4-Chloro-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00021##
[0165] The title compound was prepared in a manner analogous to
Intermediate 1, substituting 4-chloro-2-iodo-benzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.93 (s, 2H), 7.84-7.78 (m, 2H), 7.59 (dd, J=8.3, 2.1
Hz, 1H).
Intermediate 7
5-Iodo-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00022##
[0166] The title compound was prepared in a manner analogous to
Intermediate 1, substituting 2-bromo-5-iodobenzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 8.09 (d, J=2.0, 1 H), 8.03-7.97 (m, 1H), 7.95-7.86 (m,
3H), 7.53 (d, J=8.4, 1 H).
Intermediate 8
5-Methyl-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00023##
[0167] The title compound was prepared in a manner analogous to
Intermediate 1, substituting for 2-iodo-5-methyl benzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.87 (s 2H), 7.66 (d, J=1.3 Hz, 1H), 7.59 (d, J=8.2
Hz, 1H), 7.53-7.46 (m, 1H), 2.45 (s, 3H).
Intermediate 9
5-Chloro-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00024##
[0168] The title compound was prepared in a manner analogous to
Intermediate 1, substituting 5-chloro-2-iodo-benzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.91 (s, 2H), 7.82-7.74 (m, 2H), 7.71-7.66 (m,
1H).
Intermediate 10
5-Methoxy-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00025##
[0169] The title compound was prepared in a manner analogous to
Intermediate 1, substituting for 2-iodo-5-methoxy benzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.81 (s, J=6.4, 2H), 7.55 (d, J=8.8, 1H), 7.33 (d,
J=2.9, 1H), 7.18 (dd, J=8.8, 2.9, 1H), 3.85 (s, 3H).
Intermediate 11
2-Methyl-6-[1,2,3]triazol-2-yl-benzoic acid
##STR00026##
[0170] The title compound was prepared in a manner analogous to
Intermediate 1, substituting for 2-iodo-6-methyl benzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.89 (s, 2H), 7.72 (d, J=8.1 Hz, 1H), 7.48 (t, J=7.9
Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 2.46 (s, 3H).
Intermediate 12
2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid
##STR00027##
[0172] Method A: The title compound was prepared in a manner
analogous to Intermediate 1, substituting 2-fluoro-6-iodo-benzoic
acid for 5-fluoro-2-iodo-benzoic acid. .sup.1H NMR (400 MHz,
CD.sub.3OD): 7.96 (s, 2H), 7.87-7.82 (m, 1H), 7.70 (td, J=8.1, 5.1
Hz, 1H), 7.59 (ddd, J=9.7, 8.4, 1.4 Hz, 1H).
[0173] Method B: 2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid. To a
2 L, 3-necked, round-bottomed flask equipped with an overhead
mechanical stirrer, thermocouple probe, heating mantle, reflux
condenser, and nitrogen inlet were added 2-fluoro-6-iodobenzoic
acid (127.6 g, 480 mmol), copper iodide (4.57 g, 24 mmol), and
Cs.sub.2CO.sub.3 (312.6 g, 959 mmol). To these solids were added
dioxane (640 mL), then water (2.6 mL, 144 mmol), then
1H-1,2,3-triazole (55.6 mL, 959 mmol), and finally
trans-1,2-dimethylcyclohexane-1,2-diamine (15.1 mL, 96 mmol). The
mixture was then warmed to 60.degree. C. for 30 min, then to
83.degree. C. for 30 min, and then to 100.degree. C. for 3 h. After
the 3 h at 100.degree. C., the mixture was cooled and then 1 L of
MTBE and 1 L of water were added. After vigorous mixing, the layers
were separated and the bottom aqueous layer was acidified to pH
1.72 with 148 mL of concentrated hydrochloric acid. The aqueous was
then extracted twice with EtOAc. The combined organic layers were
dried over Na.sub.2SO.sub.4, filtered, and concentrated to provide
a dark oil. The oil was stirred overnight in EtOAc (450 mL) and the
resulting precipitate was removed by filtration. The mother-liquors
were concentrated to a brown solid (106.21 g, 75 wt % by
quantitative HPLC, 79.7 g, 80%). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 8.22-8.13 (bs, 2H), 7.84-7.80 (m, 1H), 7.74-7.65 (m,
1H), 7.50-7.41 (m, 1H).
Intermediate 13
5-Fluoro-2-pyrimidin-2-yl-benzoic acid
##STR00028##
[0175] Step A: 5-Fluoro-2-iodo-benzoic acid methyl ester. To a 500
mL round-bottomed flask was added 5-fluoro-2-iodo-benzoic acid (23
g, 86.5 mmol) in methanol (230 mL). To the resulting solution was
added conc. sulfuric acid (2.3 mL, 43.2 mmol). The reaction mixture
was warmed to 65.degree. C. and stirred for 15 h. The resulting
mixture was concentrated under reduced pressure to give crude
product which was then was partitioned between EtOAc (250 mL) and a
half sat. Na.sub.2CO.sub.3(aq) solution (250 mL). The layers were
thoroughly mixed and then separated. The organic layer was dried
over magnesium sulfate, filtered, and concentrated under reduced
pressure to give a yellow oil (23 g, 95% yield). .sup.1H NMR (400
MHz, CDCl.sub.3): 7.94 (dd, J=8.7, 5.4 Hz, 1H), 7.54 (dd, J=9.0,
3.1 Hz, 1H), 6.93 (m, 1H), 3.94 (s, 3H).
[0176] Step B:
5-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic
acid methyl ester. To a 1 L round-bottomed flask equipped with a
reflux condenser, temperature probe, and nitrogen line, was added
5-fluoro-2-iodo-benzoic acid methyl ester (23 g, 82 mmol) in
anhydrous THF (250 mL). Anhydrous triethylamine (34 mL, 246.4 mmol)
was added and the resulting mixture was degassed with a nitrogen
sparge for 5 minutes. Pinacol borane (17.9 mL, 123.2 mmol) was
added and the reaction mixture was degassed once more for 5
minutes. Lastly, tri(o-tolyl)phosphine (1.25 g, 4.1 mmol) and
palladium acetate (461 mg, 2.053 mmol) were added. Again, the
reaction mixture was degassed with a nitrogen sparge. The mixture
was heated to 65.degree. C. and stirred for 1 h. After cooling to
room temperature, the reaction mixture was quenched with half sat.
ammonium chloride solution (250 mL), and the resulting layers were
separated. The aqueous layer was extracted with additional ethyl
acetate (250 mL) and the combined organics were dried over
magnesium sulfate. After filtration and concentration, the crude
product was obtained as a yellow oil (23 g). The crude product was
then slurried in 25% EtOAc/hexanes (250 mL). The resulting solids
were not desired product and were removed by filtration. The
resulting solution was then concentrated to a yellow oil (21 g, 75
wt % desired, 16.1 g actual product, 70% yield), which was used
directly in the next step. By .sup.1H-NMR, the crude product was
also found to contain 14 wt % pinacol, 6.5 wt % ligand, and 4 wt %
des-iodo starting material. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.61
(dd, J=9.5, 2.5 Hz, 1H), 7.52-7.45 (m, 1H), 7.21 (td, J=8.3, 2.5
Hz, 1H), 3.91 (s, 3H), 1.41 (s, 12H).
[0177] Step C: 5-Fluoro-2-pyrimidin-2-yl-benzoic acid methyl ester.
To a 250 mL round-bottomed flask, was added
5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic
acid methyl ester (5.9 g, 21.06 mmol) in 2-methyl-THF (50 mL). To
the resulting solution was added 2-chloropyrimidine (2.9 g, 25.28
mmol), sodium carbonate (6.7 g, 63.19 mmol), and water (17 mL). The
mixture was degassed for 30 minutes. PdCl.sub.2(dppf)-dcm adduct
(CAS#72287-26-4) (0.688 g, 0.843 mmol) was added and the reaction
mixture was degassed once more for 30 minutes. The reaction mixture
was warmed to 74.degree. C. and stirred overnight. To the resulting
solution was added diethyl ether (100 mL) and water (100 mL). The
layers were thoroughly mixed then separated. The aqueous layer was
extracted with additional diethyl ether (100 mL). The combined
organics were dried over magnesium sulfate, filtered, and
concentrated under reduced pressure to a brown crude material (5.85
g, 49% desired, 2.87 actual product). The crude product was further
purified through recrystallization in 10% EtOAc/hexanes. The
mixture was warmed to 70.degree. C. and cooled slowly to room
temperature. After filtration, the desired product was obtained as
a brown solid (1.72 g actual product, 35% yield overall after
recrystallization.) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.78 (d,
J=4.9 Hz, 2H), 8.09 (dd, J=8.7, 5.5 Hz, 1H), 7.39 (dd, J=8.6, 2.7
Hz, 1H), 7.30-7.20 (m, 2H), 3.77 (s, 3H).
[0178] Step D: 5-Fluoro-2-pyrimidin-2-yl-benzoic acid. To a
solution of 5-fluoro-2-pyrimidin-2-ylbenzoic acid methyl ester
(1.72 g, 7.407 mmol) in 2-methyl-THF (20 mL) was added sodium
hydroxide (0.74 g, 18.517 mmol) and water (20 mL). The mixture was
heated to 72.degree. C. and stirred for 2 h. The layers were
separated and the aqueous layer was extracted with additional MTBE.
A 50% HCl.sub.(aq) solution was then dripped into the aqueous layer
until a pH of 1 was reached. The resulting solids were filtered to
provide the desired product as an off-white solid (1.34 g, 83%
yield). .sup.1H NMR (400 MHz, CD.sub.3OD): 8.82 (d, J=5.0 Hz, 2H),
7.89 (dd, J=8.6, 5.4 Hz, 1H), 7.53 (dd, J=9.0, 2.7 Hz, 1H), 7.39
(m, 2H).
Intermediate 14
2-Fluoro-6-pyrimidin-2-yl-benzoic acid
##STR00029##
[0180] Step A: 2-Fluoro-6-iodo-benzoic acid methyl ester. To a 200
mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid
(7.5 g, 28.2 mmol), LiOH.H.sub.2O (1.42 g, 33.8 mmol), and THF (100
mL). The resulting mixture was warmed to 50.degree. C. and stirred
for 2 h. Dimethyl sulfate (4.03 mL, 42.3 mmol) was then added and
the mixture was warmed to 65.degree. C. After 2 h, the mixture was
cooled to room temperature and NH.sub.4Cl.sub.(aq) (50 mL, 13 wt %
solution) was added. The two resulting layers were thoroughly mixed
and then separated. The organic layer was dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure to a light brown
oil (7.79 g, 99% yield). .sup.1H NMR (400 MHz, CDCl.sub.3):
7.68-7.60 (m, 1H), 7.15-7.06 (m, 2H), 3.98 (s, 3H).
[0181] Step B:
2-Fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic
acid methyl ester. To a 500 mL round-bottomed flask were added
2-fluoro-6-iodo-benzoic acid methyl ester (7.29, 26.0 mmol) and
anhydrous THF (150 mL). This mixture was cooled to 0.degree. C. and
i-PrMgCl (13.7 mL, 2 M in THF, 27.3 mmol) was added dropwise. After
10 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.58
mL, 27.3 mmol) was added. The mixture was allowed to warm to room
temperature, and after 30 min NH.sub.4Cl.sub.(aq) (150 mL, 13 wt %
solution) was added. The layers were mixed and then separated, and
the aqueous layer was extracted with 100 mL of MTBE. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated to a final mass of 6.07 g (90% wt %, 75% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.47-7.38 (m, 2H), 7.17-7.11 (m,
1H), 3.92 (s, 3H), 1.36 (s, 12H).
[0182] Step C: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester.
To a 250 mL round-bottomed flask under nitrogen were added
2-fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic
acid methyl ester (5.46 g, 19.5 mmol) in 2-methyl-THF (50 mL),
2-chloropyrimidine (2.68 g, 23.4 mmol), and sodium carbonate (6.2
g, 58.5 mmol) in water (17 mL). PdCl.sub.2(dppf)-dcm adduct
(CAS#72287-26-4) (1.27 g, 1.56 mmol) was then added and the
reaction mixture was warmed to 74.degree. C. and stirred for 2.5 h.
After cooling, the mixture was diluted with MTBE (50 mL) and water
(80 mL). The layers were thoroughly mixed then separated. The
aqueous layer was extracted with additional MTBE (100 mL). The
combined organics were dried over magnesium sulfate, filtered,
concentrated and then purified by flash chromatography (0-25%
EA/hexanes) to provide the title compound (1.72 g, 72 wt %, 30%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.79 (d, J=4.9 Hz, 2H),
8.15 (d, J=7.9 Hz, 1H), 7.51 (td, J=8.1, 5.6 Hz, 1H), 7.28-7.20 (m,
2H), 3.92 (s, 3H).
[0183] Step D: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid. To a
solution of 2-fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester
(1.36 g, 5.85 mmol) in 2-methyl-THF (20 mL) was added sodium
hydroxide (2 M in water, 9.3 mL, 18.6 mmol). The mixture was heated
to 72.degree. C. and stirred for 9 h. The layers were separated and
the aqueous layer acidified to pH 2 by dropwise addition of 50%
HCl.sub.(aq) (3.1 mL). The resulting solids were stirred for 1 h,
filtered, washed with water, MTBE, and heptanes, and then dried to
provide the desired product as a white solid (1.12 g, 88% yield).
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.83 (d, J=4.9 Hz, 2H), 8.03
(dd, J=7.9, 0.8 Hz, 1H), 7.59 (td, J=8.1, 5.6 Hz, 1H), 7.40 (t,
J=4.9 Hz, 1H), 7.34 (ddd, J=9.4, 8.4, 1.0 Hz, 1H).
Intermediate 15
Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl
ester
##STR00030##
[0185] Step A.
5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
tert-butyl ester. To a solution of
2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole (5.62 g, 27.8 mmol) in DCM
(100 mL) was added (Boc).sub.2O (6.16 g, 28.2 mmol). The reaction
mixture was stirred for 24 hours at 23.degree. C. The solvent was
removed in vacuo and the resulting product was used in the next
step without further purification. MS (ESI) mass calcd. for
C.sub.18H.sub.26N.sub.2O.sub.2, 302.41; m/z found, 303.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.36-7.20 (m, 5H),
3.61-3.46 (m, 4H), 3.24 (br s, 2H), 2.85-2.72 (m, 2H), 2.70-2.63
(m, 2H), 2.43-2.30 (m, 2H), 1.50-1.42 (s, 9H).
[0186] Step B: Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
tert-butyl ester.
5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
tert-butyl ester (19.85 g, 65.6 mmol), MeOH (200 mL), HOAc (3 mL)
and 10% Pd/C Degussa type (400 mg) were charged to a Parr shaker
vial and shaken for 3 days at 70 psi hydrogen gas. The resulting
material was filtered through Celite.RTM. and concentrated. The
crude mixture was purified by flash column chromatography (FCC),
DCM to 10% MeOH/DCM containing 1% NH.sub.4OH, to afford the
product. MS (ESI) mass calcd. for C.sub.11H.sub.20N.sub.2O.sub.2,
212.29; m/z found, 213.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 3.60-3.55 (m, 2H), 3.38-3.25 (m, 4H), 2.95-2.86 (m,
4H), 1.47 (s, 9H).
Intermediate 16
(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2--
yl)methanone
##STR00031##
[0187] Method A:
[0188] Step A:
5-(2-Fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
e-2-carboxylic acid tert-butyl ester. In a 3-neck round bottom 100
mL flask was added toluene (8.5 mL), aqueous sodium carbonate (1.42
g in 10.7 mL water), and Intermediate 15 (0.905 mg, 4.26 mmol). The
biphasic mixture was cooled to 0.degree. C. After cooling to
0.degree. C., 2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl chloride was
poured over the stirring biphasic mixture of amine and aqueous
sodium carbonate. An exotherm was observed. The mixture was allowed
to warm to room temperature. After 1 h, a sample of the organic
layer was quenched into methanol and a small amount of acid
chloride was determined to remain (observed as its methyl ester).
Additional amine (.about.50 mg) was added and the mixture was
stirred overnight at room temperature. At the end of this period,
the layers were separated and 100 mL of methanol were added to the
organic layer. The organic was concentrated and purified using
flash column chromatography (FCC), gradient of 5-50% of a solution
of 10% MeOH, 0.1% NH.sub.4OH in DCM/DCM. The desired fractions were
combined and concentrated to provide a white foamy solid (1.327 g,
76.8%). MS (ESI): mass calculated for
C.sub.20H.sub.24FN.sub.5O.sub.3, 401.44, m/z found 346.2
[M+H-56].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.91-7.73 (m,
3H), 7.53-7.39 (m, 1H), 7.18-7.06 (m, 1H), 4.00-2.76 (m, 10H),
1.52-1.33 (m, 9H).
[0189] Step B:
(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-
-yl)-methanone.
5-(2-Fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrol-
e-2-carboxylic acid tert-butyl ester (1.3 g, 3.21 mmol) was taken
up in DCM (6.0 mL) and TFA (3.0 mL) was added. The mixture was
allowed to stir at rt for 1 hr. Solvent was removed and then taken
back up in DCM and basified with 1N aq. NaOH. The layers were
separated. The aqueous was extracted 2 more time with DCM (and a
small amount of MeOH). The organics were combined, dried
(Na.sub.2SO.sub.4), filtered, and concentrated to provide the
desired free base product,
(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-
-yl)-methanone, as a viscous/foamy residue that was found to be
very hydroscopic (950.6 mg, 93.3%). MS (ESI): mass calculated for
C.sub.15H.sub.16FN.sub.5O, 301.32, m/z found 302.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.90-7.73 (m, 3H), 7.54-7.42 (m,
1H), 7.19-7.10 (m, 1H), 3.85-2.65 (m, 10H).
Method B:
[0190] Step A: 2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (0.97 g,
4.71 mmol), hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid
tert-butyl ester (Intermediate 15, 1.0 g, 4.71 mmol), HATU (2.68 g,
7.06 mmol), in DMF (18.8 mL) was added DIEA (2.43 mL, 14.13 mmol).
The mixture was stirred at rt for 1 hr. The mixture was diluted
with EtOAc and washed with water. The aqueous layer was extracted
with EtOAc, the organic layers were combined, dried
(Na.sub.2SO.sub.4), filtered and concentrated to provide the crude
product. Purification (FCC) (5-50% of a solution 10% MeOH, 0.1%
NH.sub.4OH in DCM/EtOAc over 25 minutes, and 50-100% from 25-35
minutes) provided
5-(2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-
-c]pyrrole-2-carboxylic acid tert-butyl ester (0.376 g, 19.5%).
[0191] Step B:
(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-
-yl)-methanone. The title compound was prepared in a manner
analogous to Intermediate 16, Method A, Step B.
Intermediate 17
Biphenyl-2-yl-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone
##STR00032##
[0193] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting biphenyl-2-carboxylic acid
for 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A.
Intermediate 18
[5-(2-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-(hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl)-methanone
##STR00033##
[0195] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting
5-(2-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid for
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI):
mass calculated for C.sub.17H.sub.18FN.sub.3OS, 331.41, m/z found
332.1 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.54-7.45 (m,
1H), 7.40-7.32 (m, 1H), 7.21-7.10 (m, 2H), 3.79-3.70 (m, 1H),
3.61-3.50 (m, 2H), 3.22-3.13 (m, 1H), 3.12-3.05 (m, 1H), 3.03-2.94
(m, 1H), 2.85-2.45 (m, 8H).
Intermediate 19
(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(5-methyl-2-[1,2,3]triazol-2-yl-phen-
yl)-methanone
##STR00034##
[0197] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting
5-methyl-2-[1,2,3]triazol-2-yl-benzoic acid for
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI):
mass calculated for C.sub.17H.sub.19N.sub.5O, 297.36, m/z found
298.2 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88-7.76 (m,
3H), 7.36-7.29 (m, 1H), 7.22-7.18 (m, 1H), 3.81-2.59 (m, 10H), 2.42
(s, 3H).
Intermediate 20
2(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2-[1,2,3]triazol-2-yl-phenyl)-meth-
anone
##STR00035##
[0198] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting
2-[1,2,3]triazol-2-yl-benzoic acid for
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI):
mass calculated for C.sub.15H.sub.17N.sub.5O, 283.33, m/z found
284.1 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.99 (d,
J=8.2, 1 H), 7.55-7.51 (m, 1H), 7.48-7.36 (m, 2H), 3.99-2.42 (m,
11H).
Intermediate 21
(5-Fluoro-2-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2--
yl)-methanone
##STR00036##
[0199] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting
5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 97) for
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI):
mass calculated for C.sub.15H.sub.16FN.sub.5O, 301.32, m/z found
302.0 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.96 (dd,
J=9.0, 4.8, 1 H), 7.85-7.74 (m, 2H), 7.25-7.17 (m, 1H), 7.16-7.10
(m, 1H), 3.78-2.48 (m, 10H).
Intermediate 22
(4-Fluoro-2-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2--
yl)-methanone
##STR00037##
[0200] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting
4-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid for
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI):
mass calculated for C.sub.15H.sub.16FN.sub.5O, 301.32, m/z found
302.0 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.90-7.72 (m,
3H), 7.43-7.35 (m, 1H), 7.17-7.08 (m, 1H), 3.81-3.62 (m, 2H),
3.39-2.56 (m, 8H).
Intermediate 23
2-(4,6-Dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
##STR00038##
[0201] Method A:
[0202] Step A:
5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxy-
lic acid tert-butyl ester.
Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester
(1.20 g, 5.6 mmol), 2-chloro-4,6-dimethyl-pyrimidine (1.03 g, 7.2
mmol), Cs.sub.2CO.sub.3 (2.12 g, 6.5 mmol) and DMF (15 mL) were
combined and heated to 100.degree. C. for 24 hours. The reaction
was then allowed to cool and water and EtOAc were added. The
products were extracted into EtOAc, dried over Na.sub.2SO.sub.4,
and concentrated. The resulting crude mixture was purified by flash
column chromatography (EA/hex) to give the title compound (1.27 g,
71%). MS (ESI) mass calcd. for C.sub.17H.sub.26N.sub.4O.sub.2,
318.42; m/z found, 319.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 6.25 (s, 1H), 3.85-3.75 (m, 2H), 3.69-3.46 (m, 4H),
3.38-3.20 (m, 2H), 2.94 (br s, 2H), 2.29 (s, 6H), 1.44 (s, 9H).
[0203] Step B:
2-(4,6-Dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.
5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxy-
lic acid tert-butyl ester (0.92 g, 2.9 mmol), DCM (10 mL) and TFA
(5 mL) were stirred at 23.degree. C. for 2 h. The mixture was
concentrated to remove the volatiles, diluted with EtOAc and 1N aq.
NaOH, and extracted with EtOAc (3.times.). The organic fractions
were dried and concentrated to give the title compound (0.61 g,
96%) that contained a small amount of DCM and was used as is. MS
(ESI) mass calcd. for C.sub.12H.sub.18N.sub.4, 218.30; m/z found,
219.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 6.27 (s, 1H),
3.81-3.70 (m, 2H), 3.55-3.48 (m, 2H), 3.16-3.07 (m, 2H), 2.94-2.78
(m, 4H), 2.29 (s, 6H).
Method B:
[0204] Step A: 2-Benzyl-5-(4,6-di
methyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole. To a 3 L,
3-necked, round-bottomed flask equipped with mechanical stirrer,
reflux condenser, temperature probe, and nitrogen inlet, was added
2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole (109 g, 538.8 mmol) in DMF
(1.6 L). To the resulting solution were added
2-chloro-4,6-methylpyrimidine (76.8 g, 538.8 mmol) and
Cs.sub.2CO.sub.3 (351.1 g, 1.08 mol). The heterogeneous mixture was
heated to 100.degree. C. and stirred for 15 h. After cooling to
room temperature, the mixture was diluted with ethyl acetate (1.5
L) and water (1.5 L). The layers were thoroughly mixed and
separated. The aqueous layer was extracted with additional ethyl
acetate (1.5 L). The combined organics were dried over sodium
sulfate, filtered, and concentrated under reduced pressure to a
brown solid (160 g, 96% yield). MS (ESI) mass calcd. for
C.sub.19H.sub.24N.sub.4, 308.20; m/z found 309 [M+H].sup.+.
.sup.1H-NMR (500 MHz, CDCl.sub.3): 7.32-7.26 (m, 4H), 7.25-7.20 (m,
1H), 6.27 (s, 1H), 3.81-3.73 (m, 2H), 3.58 (s, 2H), 3.54 (dd,
J=11.4, 3.5 Hz, 2H), 2.95-2.86 (m, 2H), 2.80-2.68 (m, 2H),
2.47-2.40 (m, 2H), 2.35-2.24 (s, 6H).
[0205] Step B:
2-(4,6-Dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.cndot.HOA-
c. To a 4 L high pressure autoclave equipped with mechanical
stirring, temperature probe, heating jacket, and gas inlet were
added 5% Pd/C (66.9 g, Johnson Matthey 5R338, 56.8% H.sub.2O, 3.45
mol %) and a solution of
2-benzyl-5-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(160 g, 519 mmol) and acetic acid (30 mL, 519 mmol) in ethanol (3.2
L). The mixture was stirred at 50.degree. C. under 50 psi of
H.sub.2(g) for 4 h. The catalyst was removed and the resulting
solution was then concentrated under reduced pressure to provide
the desired product as a white solid (144 g, quantitative yield) as
the HOAc salt. MS (ESI): mass calcd. for C.sub.12H.sub.18N.sub.4,
218.15; m/z found 219 [M+H].sup.+. .sup.1H-NMR (CDCl.sub.3, 400
MHz): 6.30 (s, 1H), 3.79-3.59 (m, 4H), 3.39 (m, 2H), 3.09-2.88 (m,
4H), 2.29 (s, 6H), 1.93 (s, 3H).
Intermediate 24
[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]dimethyl-
-amine
##STR00039##
[0207] Step A: Intermediate 24 was prepared in a manner analogous
to Intermediate 23, Method A, substituting
(4-chloro-6-methoxy-pyrimidin-2-yl)-dimethyl-amine for
2-chloro-4,6-dimethyl-pyrimidine in Step A to afford
5-(2-dimethylamino-6-methoxy-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrr-
ole-2-carboxylic acid tert-butyl ester.
[0208] Step B:
[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]dimethy-
l-amine. A mixture of
5-(2-dimethylamino-6-methoxy-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrr-
ole-2-carboxylic acid tert-butyl ester (700 mg) and TFA (10 mL) was
stirred in dioxane (30 mL) at room temperature for 18 h. Then the
acid and solvents were removed to yield the crude trifluoro acetic
acid salt of the title compound (1.3 g). The crude was purified by
flash column chromatography (FCC) using 0-10% MeOH (2 M NH.sub.3)
and DCM (gradient) to yield pure title compound (155 mg, 30.4%). MS
(ESI) mass calcd. for C.sub.13H.sub.21N.sub.5O, 263.34; m/z found
264.1 [M+H].sup.+. The intermediate was used without further
purification.
Intermediate 25
[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-
dimethyl-amine
##STR00040##
[0210] Step A: The title compound was prepared in a manner
analogous to Intermediate 23, Method A, substituting
(6-chloro-2-trifluoromethyl-pyrimidin-4-yl)-dimethyl-amine for
2-chloro-4,6-dimethyl-pyrimidine in Step A to afford
5-(6-dimethylamino-2-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,-
4-c]pyrrole-2-carboxylic acid tert-butyl ester.
[0211] Step B:
[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl-
]dimethyl-amine. A mixture of
5-(6-dimethylamino-2-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,-
4-c]pyrrole-2-carboxylic acid tert-butyl ester (600 mg) and TFA
(10.0 mL) was stirred in dioxane (30.0 mL) at room temperature for
18 h. Then the acid and solvents were removed to yield the crude
trifluoro acetic acid salt of the title compound (800 mg, 165%).
The crude was purified by flash column chromatography (FCC) using
0-10% MeOH (2M NH.sub.3) and DCM (gradient) to yield pure title
compound (260 mg, 53.5%). MS (ESI) mass calcd. for
C.sub.13H.sub.18F.sub.3N.sub.5, 301.32; m/z found 302.2
[M+H].sup.+. The intermediate was used as such in the subsequent
reactions.
Intermediate 26
2-(4-Phenyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
##STR00041##
[0212] The title compound was prepared in a manner analogous to
Intermediate 23, Method A, substituting
2-chloro-4-phenyl-pyrimidine for 2-chloro-4,6-dimethyl-pyrimidine
in Step A. MS (ESI) mass calcd. for C.sub.29H.sub.26N.sub.4O,
266.35; m/z found, 267.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): 6.78-6.70 (m, 1H), 6.55-6.49 (m, 2H), 5.97-5.82 (m,
3H), 5.60-5.47 (m, 1H), 2.30-2.20 (m, 2H), 2.02 (dd, J=11.6, 2.6
Hz, 2H), 1.58 (br s, 2H), 1.42 (br s, 2H), 1.23 (br s, 2H).
Intermediate 27
2-(4-Methyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
##STR00042##
[0213] The title compound was prepared in a manner analogous to
Intermediate 23, Method A, substituting
2-chloro-4-methyl-pyrimidine for 2-chloro-4,6-dimethyl-pyrimidine
in Step A. MS (ESI) mass calcd. for C.sub.11H.sub.16N.sub.4,
204.28; m/z found, 205.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.20-8.12 (m, 1H), 8.16 (d, J=5.0 Hz, 1H), 6.43-6.33
(m, 1H), 6.38 (d, J=5.0 Hz, 1H), 3.81-3.69 (m, 2H), 3.52 (dd,
J=11.6, 3.2 Hz, 2H), 3.16 (dd, J=11.1, 6.5 Hz, 2H), 2.97-2.77 (m,
5H), 2.33 (s, 3H).
Intermediate 28
2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-benzooxazole
##STR00043##
[0214] The title compound was prepared in a manner analogous to
Intermediate 23,
[0215] Method A, substituting 2-chloro-benzooxazole for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd.
for C.sub.11H.sub.16N.sub.4, 229.28; m/z found, 230.15 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.43-7.33 (m, 1H), 7.29-7.22 (m,
1H), 7.120-7.13 (m, 1H), 7.05-6.98 (m, 1H), 3.89-3.77 (m, 2H), 3.55
(dd, J=10.9, 3.2 Hz, 2H), 3.25-3.15 (m, 2H), 3.02-2.90 (m, 2H),
2.88-2.79 (m, 2H).
Intermediate 29
2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-3-methyl-quinoxaline
##STR00044##
[0216] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-3-methyl-quinoxaline for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd.
for C.sub.15H.sub.18N.sub.4, 254.34; m/z found, 255.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 7.78 (dd, J=8.2, 1.1 Hz, 1H),
7.73 (dd, J=8.3, 0.9 Hz, 1H), 7.59-7.54 (m, 1H), 7.48-7.43 (m, 1H),
3.78-3.69 (m, 2H), 3.58 (dd, J=11.0, 3.1 Hz, 2H), 3.18-3.12 (m,
2H), 2.99-2.90 (m, 2H), 2.81 (dd, J=11.6, 4.0 Hz, 2H), 2.75 (s,
3H).
Intermediate 30
2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-3-trifluoromethyl-quinoxaline
##STR00045##
[0217] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-3-trifluoromethyl-quinoxaline
for 2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass
calcd. for C.sub.15H.sub.15F.sub.3N.sub.4, 308.31; m/z found, 309.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.00-7.89 (m, 1H),
7.83-7.70 (m, 2H), 7.60-7.52 (m, 1H), 3.81-3.73 (m, 2H), 3.61 (dd,
J=11.3, 3.0 Hz, 2H), 3.18-3.13 (m, 2H), 2.99-2.92 (m, 2H), 2.78
(dd, J=11.6, 4.1 Hz, 2H).
Intermediate 31
2-(6-Methyl-2-trifluoromethyl-pyrimidin-4-yl)-octahydro-pyrrolo[3,4-c]pyrr-
ole
##STR00046##
[0219] The title compound was prepared in a manner analogous to
Intermediate 23 substituting
4-chloro-6-methyl-2-trifluoromethyl-pyrimidine for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd.
for C.sub.12H.sub.15F.sub.3N.sub.4, 272.27; m/z found, 273.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 6.48 (s, 1H),
3.90-3.24 (m, 4H), 3.20-3.10 (m, 2H), 3.00 (br s, 2H), 2.82-2.75
(m, 2H), 2.39 (s, 3H).
Intermediate 32
2-(4-Methoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
##STR00047##
[0220] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-4-methoxy-pyrimidine for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass
calculated for C.sub.11H.sub.16N.sub.4O, 220.27, m/z found 221.2
[M+1].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.00 (d, J=6.0, 1
H), 6.12 (d, J=6.0, 1 H), 4.23 (s, 1H), 3.94 (s, 3H), 3.84-3.75 (m,
2H), 3.70-3.59 (m, 4H), 3.28-3.15 (m, 4H).
Intermediate 33
2-(4-Trifluoromethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
##STR00048##
[0221] The title compound was prepared in a manner analogous to
Intermediate 24, substituting 2-chloro-4-trifluoromethyl-pyrimidine
for 2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass
calculated for C.sub.11H.sub.13F.sub.3N.sub.4, 258.25, m/z found
259.1 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.52 (d,
J=4.9, 1 H), 6.88-6.83 (m, 1H), 3.94-3.54 (m, 6H), 3.29-3.11 (m,
4H).
Intermediate 34
2-(3,6-Dimethyl-pyrazin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
##STR00049##
[0222] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 3-chloro-2,5-dimethyl-pyrazine for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass
calculated for C.sub.12H.sub.18N.sub.4, 218.30, m/z found 219.2
[M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 10.13-9.85 (m, 1H),
7.89 (s, 1H), 3.71-3.40 (m, 6H), 3.17 (s, 4H), 2.54 (s, 3H), 2.39
(s, 3H).
Intermediate 35
2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-quinoxaline
##STR00050##
[0223] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-quinoxaline for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass
calculated for C.sub.14H.sub.16N.sub.4, 240.31, m/z found 241.2
[M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.39-8.34 (m, 1H),
7.91-7.84 (m, 1H), 7.72-7.66 (m, 1H), 7.60-7.53 (m, 1H), 7.40-7.32
(m, 1H), 3.95-3.80 (m, 2H), 3.65-3.52 (m, 2H), 3.27-3.11 (m, 2H),
3.08-2.94 (m, 2H), 2.92-2.82 (m, 2H).
Intermediate 36
[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-
dimethyl-amine
##STR00051##
[0224] The title compound was prepared in a manner analogous to
Intermediate 23 substituting
(4-chloro-6-trifluoromethyl-pyrimidin-2-yl)-dimethyl-amine for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass
calculated for C.sub.34H.sub.18F.sub.3N.sub.5, 301.32, m/z found
302.1 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 5.92 (s, 1H),
3.91-3.54 (m, 2H), 3.50-3.24 (m, 2H), 3.21-3.05 (m, 9H), 2.99-2.75
(m, 4H).
Intermediate 37
(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2-thiophen-2-yl-phenyl)-methanone
##STR00052##
[0225] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting 2-thiophen-2-yl-benzoic
acid for 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS
(ESI): mass calculated for C.sub.17H.sub.18N.sub.2OS, 298.41, m/z
found 299.1 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.55-7.50 (m, 1H), 7.48-7.31 (m, 4H), 7.22-7.11 (m, 1H), 7.08-7.03
(m, 1H), 4.06-1.63 (m, 10H).
Intermediate 38
(2,4-Dimethoxy-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone
##STR00053##
[0226] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting 2,4-dimethoxybenzoic acid
for 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid and substituting
EDCl for HATU in Step A.
Intermediate 39
2-(4,6-Dimethoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
##STR00054##
[0227] The title compound was prepared in a manner analogous to
Intermediate 23 utilizing 2-chloro-4,6-dimethoxypyrimidine and
hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester
as starting materials.
Intermediate 40
6-Chloro-2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-25
benzothiazole
##STR00055##
[0228] The title compound was prepared in a manner analogous to
Intermediate 23 utilizing 2,6-dichloro-benzothiazole and
hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester
as starting materials.
Intermediate 41
(2,6-Dimethoxy-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone
##STR00056##
[0229] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting 2,6-dimethoxybenzoic acid
for 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A.
Intermediate 42
2-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00057##
[0230] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-4,5,6-trimethylpyrimidine
(Intermediate 56) for 2-chloro-4,6-dimethylpyrimidine in Step A. MS
(ESI): mass calculated for C.sub.24H.sub.25FN.sub.6O, 232.17; m/z
found 233.1 [M+H].sup.+.
Intermediate 43
6-Fluoro-2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinazoline
##STR00058##
[0231] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-6-fluoroquinazoline for
2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass
calculated for C.sub.24H.sub.25FN.sub.6O, 258.13; m/z found 259.1
[M+H].sup.+.
Intermediate 44
6,7-Difluoro-2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoxaline
##STR00059##
[0232] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-6,7-difluoroquinoxaline for
2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass
calculated for C.sub.24H.sub.25FN.sub.6O, 276.12; m/z found 277.1
[M+H].sup.+.
Intermediate 45
2-(4,6-Dimethoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00060##
[0233] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-4,6-dimethoxypyrimidine for
2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass
calculated for C.sub.12H.sub.18N.sub.4O.sub.2, 250.14; m/z found
251.2 [M+H].sup.+.
Intermediate 46
2-(5-Nitropyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00061##
[0234] The title compound was prepared in a manner analogous to
Intermediate 23 substituting 2-chloro-5-nitropyrimidine for
2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass
calculated for C.sub.10H.sub.13N.sub.5O.sub.2, 235.11; m/z found
236.2 [M+H].sup.+.
Intermediate 47
Methyl
2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)pyrim-
idine-5-carboxylate
##STR00062##
[0236] The title compound was prepared in a manner analogous to
Intermediate 23 substituting methyl
2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate for
2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass
calculated for C.sub.13H.sub.15F.sub.3N.sub.4O.sub.2, 316.11; m/z
found 317.2 [M+H].sup.+.
Intermediate 48
(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(-
1H)-yl)methanone
##STR00063##
[0237] The title compound was prepared in a manner analogous to
Intermediate 16, Method B, substituting
5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid for
3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid in the last step. MS
(ESI): mass calculated for C.sub.12H.sub.18N.sub.4, 218.30, m/z
found 219.2 [M+1].sup.+.
Intermediate 49
2-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidine-4-carbonitri-
le
##STR00064##
[0238] The title compound was prepared in a manner analogous to
Intermediate 23 substituting methyl
2-chloro-6-methylpyrimidine-4-carbonitrile for
2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass
calculated for C.sub.12H.sub.16N.sub.6, 229.3; m/z found 230.2
[M+H].sup.+.
Intermediate 50
3-Fluoro-2-(pyrimidin-2-yl)benzoic acid
##STR00065##
[0240] Step A: 3-Fluoro-2-(pyrimidin-2-yl)benzonitrile.
2-Iodo-3-fluorobenzonitrile (2.5 g, 10.3 mmol) and
2-tributylstannane pyrimidine (3.7 g, 10.0 mmol) were combined and
dissolved in degassed DME (18 ml) then purged with bubbling N.sub.2
for 5 minutes. The reaction was treated with Pd(PPh.sub.3).sub.4
(577 mg, 0.5 mmol) and then purged with bubbling for 5 minutes in a
sealed vessel and then heated in microwave at 160.degree. C. for 90
min. The reaction was cooled and filtered through celite and
concentrated to minimum volume and the ppt the formed was diluted
with hexanes (40 ml) and cooled to 0.degree. C. then filtered. The
solid purified (FCC) (20-100% EA/hex) to give
3-fluoro-2-(pyrimidin-2-yl)benzonitrile. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.93 (d, J=4.9 Hz, 2H), 8.14 (dd, J=9.6, 2.7 Hz, 1H),
7.86 (dd, J=8.6, 5.3 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 7.32-7.24 (m,
1H).
[0241] Step B: 3-Fluoro-2-(pyrimidin-2-yl)benzoic acid.
3-Fluoro-2-(pyrimidin-2-yl)benzonitrile (98 mg, 0.5 mmol) was
dissolved in MeOH (3 mL) and 2M NaOH (aq, 1 mL). The reaction was
heated at reflux for 15 h, then cooled to 23.degree. C., acidified
with 1N aq. HCl to pH=1 and extracted with EtOAc (2.times.). The
combined organics were washed with brine and dried over sodium
sulfate to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6): 8.89 (d, J=4.9 Hz, 1H), 7.74 (dd, J=7.6, 1.2 Hz,
1H), 7.63 (td, J=8.0, 5.5 Hz, 1H), 7.60-7.53 (m, 1H), 7.52 (t,
J=4.9 Hz, 1H).
Intermediate 51
5-Fluoro-2-(1H-pyrazol-5-yl)benzoic acid
##STR00066##
[0243] Step A: Methyl 2-bromo-5-fluorobenzoate (1.0 g, 4.2 mmol)
and (1H-pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined
and dissolved in degassed DME (15 ml) then treated with NaHCO.sub.3
(706 mg, 8.4 mmol) in water and the reaction purged with bubbling
N.sub.2 for 5 minutes. The reaction was treated with
Pd(PPh.sub.3).sub.4 (243 mg (0.2 mmol) and then purged with
bubbling for 5 minutes in a sealed vessel and then heated to reflux
for 2 h. The reaction mixture was cooled to 23.degree. C.,
filtered, and solid rinsed with EtOAc. The organic layers were
separated, dried and concentrated. Purification via FCC (ethyl
acetate/hexanes, 0-30%) afforded methyl
5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 44%).
[0244] Step B: A solution of methyl
5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 1.9 mmol) in EtOH (10
ml) was treated with 4.0 eq of LiOH and stirred and monitored for
two hours until the reaction was complete. The reaction mixture was
then made to pH=5, and then the solution concentrated under reduced
pressure, during which time a ppt formed. The solution was
concentrated to minimum volume and cooled in ice, filtered and
washed with ice water to give 5-fluoro-2-(1H-pyrazol-5-yl)benzoic
acid (172 mg, 44%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 13.03 (s,
1H), 7.71 (d, J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 5.6 Hz, 1H), 7.37
(td, J=8.6, 2.9 Hz, 2H), 6.44 (d, J=2.2 Hz, 1H).
Intermediate 52
3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid
##STR00067##
[0246] Step A: 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzonitrile and
3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile. A mixture of
2,3-difluorobenzonitrile (4.0 g, 28.8 mmol), 2H-1,2,3-triazole (1.9
g, 28.8 mmol) in DMF (85.0 mL) and K.sub.2CO.sub.3 (7.9 g, 57.5
mmol) were heated to 125.degree. C. for 1.5 h. After cooling to rt,
water was added and the mixture extracted with EtOAc (2.times.).
The combined organics were washed with brine and dried
(Na.sub.2SO.sub.4). Purification via FCC (10-100% EtOAc in hexanes)
gave two products. 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzonitrile
(1.6 g, 29%), .sup.1H NMR (CDCl.sub.3): 7.99 (s, J=6.6 Hz, 2H),
7.67-7.63 (m, 1H), 7.61-7.53 (m, 2H), 7.26 (s, 6H) and
3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile (2.0 g, 38%).sup.1H
NMR (CDCl.sub.3): 7.97 (dd, J=4.4, 2.8 Hz, 1H), 7.95 (d, J=1.2 Hz,
1H), 7.70 (tt, J=5.7, 2.8 Hz, 1H), 7.65 (td, J=8.1, 4.9 Hz, 1H),
7.62-7.57 (m, 1H).
[0247] Step B: 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. To
3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzonitrile (1.5 g, 8.0 mmol) in
MeOH (30 mL) was added 2M aq. NaOH (10 mL). The reaction was heated
at reflux for 15 h, then cooled to rt, acidified with 1N aq. HCl to
pH=1 and extracted with DCM (2.times.). The combined organics were
washed with brine and dried (Na.sub.2SO.sub.4). Purification via
Agilent (Reverse-Phase HPLC, basic conditions) gave the title
compound (290 mg, 18%). .sup.1H NMR (CDCl.sub.3): 7.90 (s, 2H),
7.89-7.85 (m, 1H), 7.63-7.56 (m, 1H), 7.50-7.44 (m, 1H) and
3-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 53,
140 mg, 8%).
Intermediate 53
3-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid
##STR00068##
[0248] The title compound was obtained during the synthesis of
Intermediate 52, Step B. .sup.1H NMR (CDCl.sub.3): 7.92-7.83 (m,
2H), 7.66 (dd, J=7.9, 1.3 Hz, 1H), 7.61-7.54 (m, 1H), 7.27 (dd,
J=8.4, 1.2 Hz, 1H), 3.82 (s, 3H).
Intermediate 54
4-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid
##STR00069##
[0249] The title compound was prepared in a manner analogous to
Intermediate 12, substituting 2-bromo-4-methoxybenzoic acid for
5-fluoro-2-iodo-benzoic acid in Step A. Upon purification, two
fractions were obtained, one containing pure
4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (.sup.1H NMR
(CDCl.sub.3): 7.99-7.90 (m, 1H), 7.83 (s, 2H), 7.20 (d, J=2.5 Hz,
1H), 7.03 (dd, J=8.8, 2.6 Hz, 1H), 3.89 (s, J=17.6 Hz, 3H), and the
other containing a mixture of
4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid and
4-methoxy-2-(1H-1,2,3-triazol-2-yl)benzoic acid.
Intermediate 55
2-Chloro-5-fluoro-4-methylpyrimidine
##STR00070##
[0250] To a solution of 2,4-dichloro-5-fluoropyrimidine (1.02 g,
6.08 mmol) in THF/NMP (38 mL/3 mL) was added Fe(acac).sub.3 (215
mg, 0.61 mmol) and the mixture was cooled to 0.degree. C. 3.0 M
methylmagnesium bromide in Et.sub.2O (3.04 mL, 9.12 mmol) was added
dropwise. After 30 min at 0.degree. C., the reaction was complete
and quenched with saturated aqueous NH.sub.4Cl solution. Et.sub.2O
was added and the layers were separated and the aqueous layer was
further extracted with several portions of Et.sub.2O. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. Chromatography (Hexanes to 10%
EtOAc/Hexanes) gave the desired product as a waxy white solid (430
mg, 48%). .sup.1H NMR (400 MHz, CDCl.sub.3): 8.35 (s, 1H), 2.55 (d,
J=2.5 Hz, 3H).
Intermediate 56
2-Chloro-4,5,6-trimethylpyrimidine
##STR00071##
[0251] To 4,5,6-trimethylpyrimidin-2-ol (3.69 g, 26.7 mmol) was
added POCl.sub.3 (21.7 mL, 26.7 mmol) followed by Et.sub.2NPh (2.17
mL, 13.6 mmol) dropwise. The mixture was heated at reflux for 48 h
and then added to ice dropwise. The aqueous layer was extracted
with EtOAc (2.times.). Extraction was difficult due to a large
amount of precipitate. The aqueous layer pH was adjusted to pH 4-5
with 28% NH.sub.4OH and was filtered through Celite.RTM.. The
aqueous layer was then extracted with DCM and the combined organic
extracts dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to a yellow solid. Chromatography (FCC) (0 to 30% EtOAc/Hex)
afforded 2-chloro-4,5,6-trimethylpyrimidine (4.26 g, 100%).
Intermediate 57
2-Chloro-4,5-dimethylpyrimidine
##STR00072##
[0252] The title compound was prepared in a manner analogous to
Intermediate 55, substituting 2,4-dichloro-5-methylpyrimidine for
2,4-dichloro-5-fluoropyrimidine. MS (ESI): mass calculated for
C.sub.6H.sub.7ClN.sub.2, 142.03, m/z found 143.1 [M+1].sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3): 8.32-8.25 (m, 1H), 2.52-2.46 (m,
3H), 2.28-2.22 (m, 3H).
Intermediate 58
2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro-pyrrolo[3,4-c]py-
rrol-2(1H)-yl)-6-methylpyrimidin-4-yl trifluoromethanesulfonate
##STR00073##
[0253] To a solution of
2-[5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl]-6-methylpyrimidin-4-ol (1.02 g, 2.5 mmol)
in THF (12 mL) was added 1.0 M KOtBu in THF (5 mL, 5 mmol) followed
by N-phenylbis(trifluoromethanesulfonimide) (0.893 g, 2.5 mmol).
The mixture was stirred at room temperature overnight and then
diluted with 2 M aq. K.sub.2CO.sub.3 solution and the layers
separated. The aqueous layer was extracted with DCM and the
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure. Chromatography (FCC,
Hexanes to 100% EtOAc) afforded the desired product (1.07 g, 79%)
plus a small amount of
2{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methoxy-6-meth-
ylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (55 mg, 5%) due to
residual MeOH in the pyrimidine starting material. MS (ESI): mass
calculated for C.sub.21H.sub.19F.sub.4N.sub.7O.sub.4S, 541.12, m/z
found 542.1 [M+1]+.
Intermediate 59
tert-Butyl
5-{[2-(4H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3-
,4-c]pyrrole-2(1H)-carboxylate
##STR00074##
[0254] To a solution of Intermediate 15 (1.0 g, 4.73 mmol) in DCM
(24 mL) was added 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid (895 mg,
4.73 mmol) followed by EDCl (1.36 g, 7.09 mmol), HOBt (959 mg, 7.09
mmol) and TEA (1.97 mL, 14.19 mmol). The mixture was stirred for 14
h at room temperature and then washed 2.times. with saturated
aqueous NH.sub.4Cl solution. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Chromatography (DCM to 8% 2M NH.sub.3 in MeOH/DCM) afforded the
desired product as a pale yellow foam (1.36 g, 75%). MS (ESI): mass
calculated for C.sub.20H.sub.25N.sub.5O.sub.3, 383.45, m/z found
384.1 [M+1].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 12.62 (s,
1H), 8.19-8.03 (m, 2H), 7.56-7.44 (m, 2H), 7.39-7.32 (m, 1H),
3.96-2.72 (m, 10H), 1.53-1.35 (m, 9H).
Intermediate 60
tert-Butyl
5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl]carbonyl}hexahydro-
pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
##STR00075##
[0255] To a heterogeneous mixture of NaH (60% dispersion in mineral
oil, 80 mg, 2 mmol) in DMF (4 mL) was added Intermediate 59 (641
mg, 1.67 mmol) in DMF (4 mL). 30 min after gas evolution had ceased
methyliodide (0.115 mL, 1.84 mmol) was added dropwise. The mixture
was diluted with H.sub.2O and extracted with EtOAc. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. Chromatography (DCM to 8% 2 M NH.sub.3 in
MeOH/DCM) afforded two products, tert-butyl
5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl]carbonyl}hexahydropyrrolo[3,-
4-c]pyrrole-2(1H)-carboxylate (120 mg, 18%) and tert-butyl
5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,-
4-c]pyrrole-2(1H)-carboxylate (454 mg, 68%) due to the tautomeric
nature of the 1,2,4-triazole moiety. MS (ESI): mass calculated for
C.sub.21H.sub.27N.sub.5O.sub.3, 397.21, m/z found 398.2
[M+1].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.90 (s, 1H),
7.61-7.41 (m, 4H), 3.83 (s, 3H), 3.74-3.36 (m, 5H), 3.29-3.12 (m,
3H), 2.88-2.75 (m, 2H), 1.47 (s, 9H).
Intermediate 61
tert-Butyl
5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydro-
pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
##STR00076##
[0256] The title compound was isolated from the synthesis of
Intermediate 60. MS (ESI): mass calculated for
C.sub.21H.sub.27N.sub.5O.sub.3, 397.21, m/z found 398.2
[M+1].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.15-8.07 (m, 1H),
8.03 (s, 1H), 7.49-7.40 (m, 2H), 7.37-7.29 (m, 1H), 3.97-3.86 (m,
3H), 3.86-3.27 (m, 6H), 3.18-2.73 (m, 4H), 1.54-1.36 (m, 9H).
Intermediate 62
tert-Butyl
5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydrop-
yrrolo[3,4-c]pyrrole-2(1H)-carboxylate
##STR00077##
[0257] The title compound was prepared in a manner analogous to
Intermediate 59 substituting
2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for
2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated
for C.sub.21H.sub.26N.sub.4O.sub.4, 398.20; m/z found, 399.2.
.sup.1H NMR (500 MHz, CDCl.sub.3): 8.12 (d, J=7.8 Hz, 1H), 7.63
(td, J=7.6 Hz, 1.2 Hz, 1H), 7.55 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.42
(d, J=7.5 Hz, 1H), 3.97-3.86 (m, 1H), 3.76-3.61 (m, 2H), 3.56-3.33
(m, 3H), 3.29-3.15 (m, 1H), 3.08-2.93 (m, 2H), 2.90-2.82 (m, 1H),
2.45 (s, 3H), 1.51-1.41 (m, 9H).
Intermediate 63
3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid
##STR00078##
[0258] Method A:
[0259] Step A: 2-Fluoro-6-(methoxycarbonyl)benzoic acid.
3-Fluorophthalic anhydride (377 mg, 2.27 mmol) was dissolved in
MeOH (6 mL) and heated to reflux for 15 h. The mixture was
concentrated in vacuo and the two products (400 mg, 89%),
2-fluoro-6-(methoxycarbonyl)benzoic acid and
3-fluoro-2-(methoxycarbonyl)benzoic acid, were taken on to the next
step without purification.
[0260] Step B: (Z)-Methyl
2-((((1-aminoethylidene)amino)oxy)carbonyl)-3-fluorobenzoate. To a
heterogeneous mixture of the two acids from step A (400 mg, 2 mmol)
at 0.degree. C. in DCM (5 mL) was added oxalyl chloride (0.244 mL,
2.32 mmol) followed by DMF (0.05 mL). Gas evolution commenced
immediately and after 5 min the ice bath was removed. When gas
evolution had ceased and the mixture was homogeneous an aliquot was
removed and quenched with MeOH. Formation of the methyl ester was
confirmed by HPLC and the mixture was concentrated in vacuo. The
viscous liquid was dissolved in fresh DCM (5 mL) and treated with
solid N-hydroxyacetamidine (165 mg, 2.22 mmol) in several portions
followed by TEA (0.351 mL, 2.52 mmol). After stirring for 14 h at
ambient temperature the mixture was concentrated in vacuo.
Chromatography (Hex to 100% EtOAc/Hex) afforded two products (477
mg, 94%), (Z)-methyl
2-((((1-aminoethylidene)amino)oxy)carbonyl)-3-fluorobenzoate and
(Z)-methyl
2-((((1-aminoethylidene)amino)oxy)carbonyl)-6-fluorobenzoate, which
were taken on to the next step as a mixture. MS (ESI) mass
calculated for C.sub.11H.sub.11FN.sub.2O.sub.4, 254.07; m/z found,
255.0.
[0261] Step C: 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic
acid. To the mixture of products from Step B (477 mg, 1.88 mmol) in
t-BuOH (9 mL) was added NaOAc (156 mg, 1.88 mmol). The mixture was
heated at 90.degree. C. for 50 h and then concentrated in vacuo.
This resulted in four products. The residue was dissolved in 1M aq.
K.sub.2CO.sub.3 and extracted with DCM to isolate methyl
2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate and methyl
3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate along with
unreacted (Z)-methyl
2-((((1-aminoethylidene)amino)oxy)carbonyl)-3-fluorobenzoate. The
aqueous layer was then acidified with concentrated HCl and
extracted with DCM. The combined organic layers from this
extraction were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The acid isomers were purified on a Prep
Agilent system with a XBridge C.sub.18 OBD 50.times.100 mm column
eluting with 5 to 99% 0.05% NH.sub.4OH in H.sub.2O/ACN over 17 min
to afford the desired product (63 mg, 15%) as a white solid after
acidification with 1M aq. HCl in Et.sub.2O. MS (ESI) mass
calculated for C.sub.10H.sub.7FN.sub.2O.sub.3, 222.04; m/z found,
223.0.
Method B:
[0262] Step A: (Z)--N'-((2-Fluoro-6-iodobenzoyl)oxy)acetimidamide.
To a heterogeneous mixture of 2-fluoro-6-iodobenzoic acid (1.51 g,
5.66 mmol) at 0.degree. C. in DCM (28 mL) was added oxalyl chloride
(0.635 mL, 7.36 mmol) followed by DMF (0.15 mL). Gas evolution
commenced immediately and after 5 min the ice bath was removed.
When gas evolution had ceased and the mixture was homogeneous an
aliquot was removed and quenched with MeOH. Formation of the methyl
ester was confirmed by HPLC and the mixture was concentrated in
vacuo. The viscous liquid was dissolved in fresh DCM (28 mL) and
treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) in
several portions followed by TEA (1.2 mL, 8.49 mmol) at 0.degree.
C. After stirring for 14 h at ambient temperature the mixture was
washed with saturated aqueous NaHCO.sub.3 solution. The combined
organic extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. Chromatography (Hex to 100% EtOAc/Hex)
afforded the desired product as a colorless oil (1.57 g, 86%). MS
(ESI) mass calculated for C.sub.9H.sub.8FIN.sub.2O.sub.2, 321.96;
m/z found, 323.0. 1H NMR (500 MHz, CDCl.sub.3): 7.70-7.65 (m, 1H),
7.15-7.11 (m, 2H), 4.87 (br s, 2H), 2.06 (s, 3H).
[0263] Step B: 5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole.
To a heterogeneous mixture of the product of Step A in t-BuOH (24
mL) was added NaOAc(603 mg, 7.27 mmol) in H.sub.2O (0.9 mL). The
mixture was then heated to 110.degree. C. for 12 days. The reaction
was concentrated in vacuo and then dissolved in toluene. The
toluene was then filtered to remove NaOAc and then concentrated in
vacuo. Chromatography (Hex to 40% EtOAc/Hex) afforded the desired
product as a colorless oil (1.21 g, 82%). MS (ESI) mass calculated
for C.sub.9H.sub.6FIN.sub.2O, 303.95; m/z found, 304.9. 1H NMR (500
MHz, CDCl3): 7.82-7.77 (m, 1H), 7.29-7.20 (m, 2H), 2.55 (s,
3H).
[0264] Step C: 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic
acid. To THF (15 mL) was added 2 M i-PrMgCl in THF (2.2 mL, 4.47
mmol). This mixture was cooled to -78.degree. C. and the product of
Step B (1.09 g, 3.58 mmol) was added dropwise in THF (20 mL). The
mixture was stirred for 30 min at -78.degree. C. and then CO.sub.2
from a lecture bottle was bubbled into the solution for 3 h while
allowing the temperature to slowly rise. When the temperature
reached -20.degree. C. the dry ice bath was replaced with an ice
bath, bubbling of CO.sub.2 was ceased and the mixture was allowed
to come to room temperature overnight. The mixture was quenched by
the addition of H.sub.2O and a small amount of Et.sub.2O. The
organic layer was washed 2.times. with 2N aq. NaOH and the combined
aqueous layers were then washed 3.times. with Et.sub.2O. The
aqueous layer was then acidified with concentrated HCl and
extracted with DCM. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the
desired product as a white solid (661 mg, 83%). MS (ESI) mass
calculated for C.sub.10H.sub.7FN.sub.2O.sub.3, 222.04; m/z found,
223.0. 1H NMR (500 MHz, CDCl.sub.3): 7.96 (d, J=7.8, 1 H),
7.72-7.64 (m, 1H), 7.50-7.44 (m, 1H), 2.56-2.48 (m, 3H).
Intermediate 64
2-Fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid
##STR00079##
[0265] The title compound was isolated from the synthesis of
Intermediate 63, Method A. MS (ESI) mass calculated for
C.sub.10H.sub.7FN.sub.2O.sub.3, 222.04; m/z found, 223.0. .sup.1H
NMR (500 MHz, CDCl.sub.3): 7.89 (d, J=7.7, 1 H), 7.65-7.59 (m, 1H),
7.44-7.38 (m, 1H), 2.50 (s, 3H).
Intermediate 65
2,5-Dichloro-4-methylpyrimidine
##STR00080##
[0266] The title compound was prepared in a manner analogous to
Intermediate 55, substituting 2,4,5-trichloropyrimidine for
2,4-dichloro-5-fluoropyrimidine. .sup.1H NMR (500 MHz, CDCl.sub.3):
8.47 (s, 1H), 2.61 (s, 3H).
Intermediate 66
2,5-Dichloro-4,6-dimethylpyrimidine
##STR00081##
[0267] To 5-chloro-4,6-dimethylpyrimidin-2-ol (992 mg, 6.26 mmol)
was added POCl.sub.3 (2.22 mL, 23.77 mmol) followed by Et.sub.2NPh
(0.75 mL, 4.69 mmol) dropwise. The mixture was heated at
125.degree. C. for 2 h. At approximately 2 h the reaction became
homogeneous and was checked by HPLC and it showed all starting
material had been consumed. The mixture was allowed to cool to room
temperature and was then added dropwise to ice. After the ice had
melted there was a white solid in a pink liquid. The aqueous layer
was extracted with DCM and the combined organic layers were dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Chromatography (Hex to 10% EtOAc/Hex) afforded the desired product
as a white solid (915 mg, 83%). .sup.1H NMR (500 MHz, CDCl.sub.3):
2.57 (s, 6H).
Intermediate 67
2-Chloro-5-ethyl-4,6-dimethylpyrimidine
##STR00082##
[0268] The title compound was prepared in a manner analogous to
Intermediate 56, substituting 5-ethyl-4,6-dimethylpyrimidin-2-ol
for 4,5,6-trimethylpyrimidin-2-ol. MS (ESI): mass calculated for
C.sub.8H.sub.11ClN.sub.2, 170.06, m/z found 171.1 [M+1].sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3): 2.65 (q, J=7.6 Hz, 2H), 2.50 (s,
6H), 1.15 (t, J=7.6 Hz, 3H).
Intermediate 68
(3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H-
)-yl)methanone
##STR00083##
[0270] Step A: tert-Butyl
5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1-
H)-carboxylate. tert-Butyl
5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1-
H)-carboxylate was prepared in a manner analogous to Intermediate
59 substituting 3-[1,2,3]triazol-2-yl-pyridine-2-carboxylic acid
(Intermediate 72) for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS
(ESI) mass calculated for C.sub.19H.sub.24N.sub.6O.sub.3, 384.19;
m/z found, 385.1.
[0271] Step B:
(3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1-
H)-yl)methanone. tert-Butyl
5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1-
H)-carboxylate (491 mg, 1.28 mmol) in DCM (6 mL) was added TFA (3
mL). After stirring for 2 h at room temperature the reaction was
complete and concentrated in vacuo. The TFA salt was purified on a
Prep Agilent system with a XBridge C.sub.18 OBD 50.times.100 mm
column eluting with 5 to 99% 0.05% NH.sub.4OH in H.sub.2O/ACN over
17 min to afford
(3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1-
H)-yl)methanone as a white solid (306 mg, 84%). MS (ESI) mass
calculated for C.sub.14H.sub.16N.sub.6O, 284.14; m/z found,
285.0.
Intermediate 69
2-Chloro-5-fluoro-4,6-dimethylpyrimidine
##STR00084##
[0273] Step A: 5-Fluoropyrimidine-2,4,6-triol. To a heterogeneous
mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate
(1.96 g, 10.67 mmol) in EtOH (11 mL) was added 2.68 M NaOEt in EtOH
(7.96 mL, 21.34 mmol). The mixture was heated at reflux for 60 h
and then allowed to cool to room temperature. The mixture was
filtered and the cake was then dissolved in warm water and the
resulting solution was acidified with concentrated HCl to pH 2. The
mixture was allowed to cool to room temperature and then cooled in
an ice bath before filtering. The cake was washed with water and
dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off
white solid (1.45 g, 93%).
[0274] Step B: 2,4,6-Trichloro-5-fluoropyrimidine. To POCl.sub.3
(4.49 mL, 48.15 mmol) was added 5-fluoropyrimidine-2,4,6-triol
(1.41 g, 9.63 mmol) in several portions. There was a 2.degree. C.
increase in temperature. The N,N-dimethylaniline (1.23 mL, 9.73
mmol) was then added dropwise and the mixture heated at 110.degree.
C. for 24 h. The reaction mixture was allowed to cool only briefly
and then was quenched by dropwise addition onto ice. When the ice
was melted the aqueous layer was extracted several times with
Et.sub.2O. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to a yellow
solid after storing in the refrigerator overnight. This material
was not purified further, but taken on to the next step without
further purification.
[0275] Step C: 2-Chloro-5-fluoro-4,6-dimethylpyrimidine was
prepared in a manner analogous to Intermediate 55, substituting
2,4,6-trichloro-5-fluoropyrimidine for
2,4-dichloro-5-fluoropyrimidine. .sup.1H NMR (500 MHz, CDCl.sub.3):
2.50 (d, J=2.7 Hz, 6H).
Intermediate 70
6-Methyl-2-[1,2,3]triazol-2-yl-nicotinic acid
##STR00085##
[0276] 6-Methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. To a 100 ml
round bottom flask containing 2-chloro-6-methylnicotinic acid (3 g,
17.4 mmol), copper iodide (0.16 g, 0.5 mol %), and cesium carbonate
(11.4 g, 35 mmol) was added a mixture of dioxane (20 mL) and
H.sub.2O (0.1 ml, 5.25 mmol). Next triazole (2.03 mL, 35 mmol) and
finally (R,R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine ligand (0.56
mL, 3.5 mmol) were added. The resulting clumpy yellow slurry was
stirred until evenly dispersed. Upon heating to 100.degree. C. the
reaction mixture changed from a yellow slurry to pale green. As
heating progressed the slurry became less thick and was stirred
more easily. The light green slurry was stirred for 4 hr at
100.degree. C. and left to stir at room temp overnight. At this
point the reaction mixture appeared as a cobalt blue slurry which
was then diluted with 20 mL ether and 20 mL H.sub.2O. The resulting
solution was thoroughly stirred and transferred to a seperatory
funnel then the RBF was subsequently rinsed with 20 mL ether and
H.sub.2O each. The aqueous layer was separated from the organic
layer and acidified to pH 1 with 6 mL conc. HCl. The now brown/lime
green aqueous layer was extracted twice with EtOAc. The bright
yellow organic layers were combined and dried with Na.sub.2SO.sub.4
and then conc. into a yellow powder under reduced pressure. To the
yellow powder was added EtOAc to form a yellow slurry. The solids
were filtered off and washed with EtOAc to give a very pale yellow
powder, which was found by .sup.1H NMR to be the Intermediate 71
(25% yield). The filtrate was conc. into a yellow solid and
purified (FCC, 0-5% MeOH in DCM w/0.5% AcOH) to give the title
product in a 20% yield. MS (ESI): mass calculated for
C.sub.9H.sub.8N.sub.4O.sub.2, 204.18; m/z found 205.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.21-8.18 (m, 1H), 7.98 (s, 2H),
7.51 (d, J=7.9 Hz, 1H), 2.64 (s, 3H).
Intermediate 71
6-Methyl-2-[1,2,3]triazol-1-yl-nicotinic acid
##STR00086##
[0277] The title compound was isolated as a byproduct from the
procedure used to prepare Intermediate 70 with a 25% yield. MS
(ESI): mass calculated for C.sub.9H.sub.8N.sub.4O.sub.2, 204.18;
m/z found 205.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD):
8.48 (d, J=1.1 Hz, 1H), 8.25 (dd, J=7.9, 3.8 Hz, 1H), 7.88 (d,
J=1.1 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 2.64 (s, 3H).
Intermediate 72
3-[1,2,3]Triazol-2-yl-pyridine-2-carboxylic acid
##STR00087##
[0278] The title compound was prepared in a manner analogous to
Intermediate 70 substituting 3-bromo-2-pyridinecarboxylic acid for
2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for
C.sub.8H.sub.6N.sub.4O.sub.2, 190.10; m/z found 191.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.77 (d, J=4.3 Hz, 1H), 8.26
(dt, J=6.5, 3.3 Hz, 1H), 7.88 (s, 2H), 7.65 (dd, J=8.2, 4.7 Hz,
1H).
Intermediate 73
1-[1,2,3]Triazol-2-yl-naphthalene-2-carboxylic acid
##STR00088##
[0279] The title compound was prepared in a manner analogous to
Intermediate 70 substituting 1-bromo-2-napthoic acid for
2-chloro-6-methylnicotinic acid. The title compound was obtained
(484 mg, 50%). MS (ESI): mass calculated for
C.sub.13H.sub.9N.sub.3O.sub.2, 239.23; m/z found 240.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.19 (d, J=8.7 Hz, 1H),
8.09-8.03 (m, 4H), 7.70-7.66 (m, 1H), 7.58 (ddd, J=8.2, 6.9, 1.2
Hz, 1H), 7.25 (d, J=8.6 Hz, 1H).
Intermediate 74
1-[1,2,3]Triazol-1-yl-naphthalene-2-carboxylic acid
##STR00089##
[0280] The title compound was isolated as a byproduct from the
preparation of Intermediate 73 (25% yield). MS (ESI): mass
calculated for C.sub.13H.sub.9N.sub.3O.sub.2, 239.23; m/z found
240.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.33 (d,
J=0.9 Hz, 1H), 8.24 (d, J=8.6 Hz, 1H), 8.14-8.07 (m, 2H), 8.01 (d,
J=0.9 Hz, 1H), 7.71 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.11
(d, J=8.5 Hz, 1H).
Intermediate 75
8-[1,2,3]Triazol-2-yl-naphthalene-1-carboxylic acid
##STR00090##
[0281] The title compound was prepared in a manner analogous to
Intermediate 70 substituting 8-bromo-2-napthoic acid for
2-chloro-6-methylnicotinic acid. The desired
8-[1,2,3]triazol-2-yl-naphthalene-1-carboxylic acid was obtained
(474 mg, 16%). MS (ESI): mass calculated for
C.sub.1H.sub.9N.sub.3O.sub.2, 239.20; m/z found 240.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.13 (t, J=9.0 Hz, 2H),
7.95-7.91 (m, 3H), 7.82 (dd, J=7.4, 1.0 Hz, 1H), 7.70 (dd, J=9.8,
5.8 Hz, 1H), 7.64-7.59 (m, 1H).
Intermediate 76
5-[1,2,3]Triazol-2-yl-benzo[1,3]dioxole-4-carboxylic acid
##STR00091##
[0283] The title compound was prepared in a manner analogous to
Intermediate 70 substituting 5-bromobenzo[1,3]dioxole-4-carboxylic
acid for 2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated
for C.sub.10H.sub.7N.sub.3O.sub.4, 233.18; m/z found 234.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.85 (s, 2H), 7.23
(d, J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.16 (s, 2H).
Intermediate 77
2,3-Dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid
##STR00092##
[0284] To a 20 ml microwave vial containing
2-bromo-4,5-dimethoxybenzoic acid (3 g, 11.5 mmol), copper iodide
(0.04 g, 0.5 mol %), cesium carbonate (7.5 g, 23 mmol), triazole
(1.33 mL, 23 mmol) and finally
(R,R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine ligand (0.36 mL, 2.3
mmol) was added DMF (12 mL). The resulting clumpy yellow slurry was
stirred until evenly dispersed then heated to 120.degree. C. for
10-20 min using a microwave. At this point the reaction mixture
appeared as a blue slurry which was then diluted with 20 mL ether
and 20 mL H.sub.2O. The resulting solution was thoroughly stirred
and transferred to a separatory funnel then the RBF was
subsequently rinsed with 20 mL ether and H.sub.2O each. The aqueous
layer was separated from the organic layer and acidified to pH 1
with 6 mL conc. HCl. The now brown/lime green aqueous layer was
extracted twice with EtOAc. The bright yellow organic layers were
combined and dried with Na.sub.2SO.sub.4 and then conc. into a
yellow powder under reduced pressure which was purified by FCC
(0-5% MeOH in DCM w/0.5% AcOH) to afford
2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid (60%) and
2,3-dimethoxy-6-[1,2,3]triazol-1-yl-benzoic acid (20%). Data for
2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid, MS (ESI): mass
calculated for C.sub.11H.sub.11N.sub.3O.sub.4, 249.23; m/z found
250.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.87 (s, 2H),
7.47 (s, 1H), 7.18 (s, 1H), 3.94 (s, 3H), 3.91 (s, 3H).
Intermediate 78
2,3-Dimethoxy-6-[1,2,3]triazol-1-yl-benzoic acid
##STR00093##
[0285] The title compound was isolated from the procedure used to
prepare Intermediate 77 with a 20% yield. MS (ESI): mass calculated
for C.sub.11H.sub.11N.sub.3O.sub.4, 249.23; m/z found 250.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.17 (d, J=1.0 Hz,
1H), 7.82 (d, J=1.0 Hz, 1H), 7.62 (s, 1H), 7.09 (s, 1H), 3.95 (s,
3H), 3.91 (s, 3H).
Intermediate 79
5-Acetylamino-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00094##
[0286] The title compound was prepared in a manner analogous to
Intermediate 70 substituting 5-acetamido-2-bromobenzoic acid for
2-bromo-4,5-dimethoxybenzoic acid. MS (ESI): mass calculated for
C.sub.11H.sub.10N.sub.4O.sub.3, 246.22; m/z found 247.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.09 (t, J=2.8 Hz,
1H), 7.92-7.86 (m, 3H), 7.66 (dd, J=8.7, 3.3 Hz, 1H), 2.17 (dd,
J=2.5, 1.3 Hz, 3H).
Intermediate 80
4-(1H-1,2,3-Triazol-1-yl)nicotinic acid
##STR00095##
[0287] The title compound was prepared in a manner analogous to
Intermediate 70 substituting 4-chloronicotinic acid for
2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for
C.sub.11H.sub.10N.sub.4O.sub.3, 246.22; m/z found 247.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.09 (t, J=2.8 Hz,
1H), 7.92-7.86 (m, 3H), 7.66 (dd, J=8.7, 3.3 Hz, 1H), 2.17 (dd,
J=2.5, 1.3 Hz, 3H).
Intermediate 81
3-Methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile
##STR00096##
[0289] To a mixture of 2-fluoro-3-methylbenzonitrile (4.0 g, 29.6
mmol) and 2H-1,2,3-triazole (2.04 g, 29.6 mmol) in DMF (80 mL) was
added potassium carbonate (8.26 g, 59.2 mmol). The resulting
mixture was heated to 120.degree. C. for 2 h. The mixture was
cooled, diluted with water and extracted with EtOAc. The organic
layers were combined, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was purified by FCC (SiO.sub.2, ethyl
acetate/hexanes, gradient 0-50%) to yield the title compound (1.5
g, 26%). MS (ESI) mass calcd. for C.sub.10H.sub.8N.sub.4, 184.2;
m/z found, 185.1 [M+H]+. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.95
(s, 2H), 7.66 (d, J=7.7, 0.7 Hz, 1H), 7.59 (d, J=7.8, 0.6 Hz, 1H),
7.50 (dd, J=9.8, 5.7 Hz, 1H), 2.20 (s, 3H).
Intermediate 82
3-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid
##STR00097##
[0290] To a solution of
3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile (1.4 g, 7.82 mmol)
in MeOH (15 mL) was added a 4N aqueous solution of NaOH (10 mL).
The resulting mixture was heated to 90.degree. C. After 15 h the
reaction mixture was cooled to ambient temperature then diluted
with water (50 mL). The aqueous layer was acidified to pH2 and
extracted with EtOAc (50 mL) three times. The organic layers were
combined, dried over Na.sub.2SO.sub.4, filtered and concentrated.
The residue was purified by FCC (SiO.sub.2, gradient DCM to 10%
MeOH/1% HOAc/DCM) to yield the title compound (1.3 g, 78%). .sup.1H
NMR (500 MHz, CDCl.sub.3): 7.90 (d, J=7.7, Hz, 1H), 7.83 (s, 2H),
7.57-7.53 (m, 1H), 7.49 (dd, J=9.7, 5.8 Hz, 1H), 2.10 (s, 3H).
Intermediate 83
3-Fluoro-2-(1H-pyrazol-5-yl)benzoic acid
##STR00098##
[0291] Method A:
[0292] Step A: 2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and
(1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and
dissolved in degassed DME (15 mL) then treated with NaHCO.sub.3
(1260 mg, 8.4 mmol) in water and the reaction purged with bubbling
N.sub.2 for 5 minutes. The reaction was treated with
Pd(PPh.sub.3).sub.4 (288 mg, 0.2 mmol) and then purged with
bubbling for 5 minutes in a sealed vessel and then heated to reflux
for 2 h. The reaction was then cooled to 23.degree. C. filtered and
the solids were rinsed with EtOAc and the layers separated. The
organic layers were combined, dried and concentrated under reduced
pressure. Chromatography (0-30% ethyl acetate/hexanes) afforded
3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%).
[0293] Step B: To 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile in MeOH
(3 mL) was added 2M aq. NaOH (1 mL). The reaction was heated at
reflux for 15 h, then cooled to rt, acidified with 1N aq. HCl to
pH=1 and extracted with EtOAc to give (210 mg, 99%) of
3-fluoro-2-(1H-pyrazol-5-yl)benzoic acid which was used crude.
Method B:
[0294] The title compound was prepared in a manner analogous to
Intermediate 51, substituting methyl 2-iodo-3-fluorobenzoate for
methyl 2-bromo-5-fluorobenzoate in Step A. MS (ESI): mass
calculated for C.sub.10H.sub.7FN.sub.2O.sub.2, 206.05; m/z found
207.0 [M+1].sup.+.
Intermediate 84
2-(1H-1,2,3-Triazol-1-yl)-6-(trifluoromethyl)nicotinic acid
##STR00099##
[0295] The title compound was prepared in a manner analogous to
Intermediate 13, substituting 2-chloro-6-(trifluoromethyl)nicotinic
acid for 5-fluoro-2-iodo-benzoic acid in step A, and substituting
1,4-dioxane for MeOH as the solvent, with 0.3 eq of water as an
additive. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 8.64 (s, 1H), 8.37
(d, J=7.6 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H), 7.93 (s, 1H).
Intermediate 85
5-Fluoro-2-(1H-pyrazol-5-yl)benzoic acid
##STR00100##
[0297] Step A: Methyl-2-fluoro-bromobenzoate (1.0 gram, 4.2 mmol)
and (1H-pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined
and dissolved in degassed DME (15 mL) then treated with NaHCO.sub.3
(706 mg, 8.4 mmol) in water and the reaction purged with bubbling
N.sub.2 for 5 minutes. The reaction was treated with
Pd(PPh.sub.3).sub.4 (243 mg (0.2 mmol) and then purged with
bubbling for 5 minutes in a sealed vessel and then heated to reflux
for 2 h. The reaction mixture was cooled to 23.degree. C.,
filtered, and the solid was rinsed with EtOAc and the layers
separated. The organic layers were combined, dried and
concentrated. Chromatography (ethyl acetate/hexanes, 0-30%) gave
methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 44%).
[0298] Step B: A solution of methyl
5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 1.9 mmol) in EtOH (10
mL) was treated with 4.0 eq of LiOH and stirred and monitored for
two hours the reaction was complete. Reaction was made to pH=5, and
then the solution concentrated under reduced pressure during which
time a ppt formed. The reactions was then concentrated to minimum
volume and cooled in ice, then filtered and washed with ice water
to give 5-fluoro-2-(1H-pyrazol-5-yl)benzoic acid (172 mg, 44%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): 13.03 (s, 1H), 7.71
(d, J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 5.6 Hz, 1H), 7.37 (td, J=8.6,
2.9 Hz, 2H), 6.44 (d, J=2.2 Hz, 1H).
Intermediate 86
3-Methyl-2-(1H-1,2,3-triazol-1-yl)benzoic acid
##STR00101##
[0299] The title compound was prepared in a manner analogous to
Intermediate 82, substituting
3-methyl-2-(1H-1,2,3-triazol-1-yl)benzonitrile for
3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile. .sup.1H NMR (500
MHz, CDCl.sub.3): 8.17 (s, 1H), 7.94 (s, 1H), 7.69 (d, J=6.8 Hz,
1H), 7.65 (d, J=7.7 Hz, 1H), 7.63-7.56 (m, 1H), 2.06 (s, 3H).
Intermediate 87
4-Fluoro-2-(pyrimidin-2-yl)benzoic acid
##STR00102##
[0300] Step A: 2-Iodo-4-fluorobenzonitrile (2.54 g, 10.3 mmol) and
2-tributylstannane pyrimidine (3.69 g, 10.0 mmol) were dissolved in
domethoxyethane (18 mL) and treated with tetrakistriphenylphosphine
palladium (0) (578 mg, 0.5 mmol) and copper (I) iodide (95 mg, 0.5
mmol). The reaction was then heated to 160.degree. C. for 90
minutes in the microwave. The reaction was cooled, concentrated
under reduced pressure. Chromatography (20-100% EA in hexanes) gave
the desired product. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.93 (d,
J=4.9 Hz, 2H), 8.14 (dd, J=9.6, 2.7 Hz, 1H), 7.86 (dd, J=8.6, 5.3
Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 7.32-7.23 (m, 1H).
[0301] Step: 4-Fluoro-2-(pyrimidin-2-yl)benzonitrile (85 mg, 0.4
mmol) was hydrolyzed to the acid in water (1 mL) by addition of 18
M H.sub.2SO.sub.4 (1 mL). The reaction was heated at 100.degree. C.
for 10 min, then cooled to 23.degree. C., and extracted with EtOAc
(3.times.5 mL). The combined organics were dried (Na.sub.2SO.sub.4)
and concentrated under reduced pressure. This material was used
crude in subsequent reactions.
Intermediate 88
4-Methoxy-2-(pyrimidin-2-yl)benzoic acid
##STR00103##
[0303] Step A: 4-Methoxy-2-(pyrimidin-2-yl)benzonitrile was
prepared in a manner analogous to Intermediate 87. .sup.1H NMR (400
MHz, CDCl.sub.3): 8.93 (d, J=4.9 Hz, 2H), 8.14 (dd, J=9.6, 2.7 Hz,
1H), 7.86 (dd, J=8.6, 5.3 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H),
7.32-7.23 (m, 1H).
[0304] Step B: 4-Methoxy-2-(pyrimidin-2-yl)benzonitrile (85 mg, 0.4
mmol) was dissolved in MeOH (20 mL) was treated with 2M aq NaOH (15
mL). The reaction was heated at reflux overnight, the reaction was
cooled to room temperature and filtered to remove the solids and
washed with cold MeOH. The filtrate was concentrated to minimum
volume and then acidified to pH=3 with 6 N aq. HCl and cooled to
0.degree. C. then filtered and washed with cold water. This
material was used crude in subsequent reactions.
Intermediate 89
2-Chloro-4,4,4,5,6,6,6-septadeuteriopyrimidine
##STR00104##
[0306] Step A: 1,1,1,3,3,3,5,5-Octadeuteriopentane-2,4-dione. To a
solution of acetylacetone (10 mL, 95.1 mmol) in D.sub.2O (90 mL)
was added K.sub.2CO.sub.3 (1.0 g, 7.29 mmol). The mixture was
heated at 120.degree. C. overnight. The aqueous layer was extracted
with DCM and the combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to an orange
liquid (Frediani et. al., Catalysis Comm. 2, 2001, 125).
[0307] Step B:
2-Deuteriohydroxy-4,4,4,5,6,6,6-septadeuteriopyrimidine. To a
solution of 1,1,1,3,3,3,5,5-Octadeuteriopentane-2,4-dione (product
of Step A) (1.60 g, 14.82 mmol) in EtOD (7 mL) was added
urea-d.sub.4 (0.95 g, 14.82 mmol) followed by 35% wt. DCl in
D.sub.2O (2 mL, 23.71 mmol). The mixture was heated at 90.degree.
C. for 36 h, cooled to room temperature and then chilled in an ice
bath before filtration and washing of the white solid with cold
EtOD to afford the desired product as the DCl salt (1.53 g,
61%).
[0308] Step C: 2-Chloro-4,4,4,5,6,6,6-septadeuteriopyrimidine. To
2-deuteriohydroxy-4,4,4,5,6,6,6-septadeuteriopyrimidine (product of
Step B) (1.53 g, 9.04 mmol) was added POCl.sub.3 (7.9 mL, 9.04
mmol) and the mixture was heated at reflux for 16 h. The mixture
was allowed to cool to room temperature and then added to ice drop
wise. The aqueous mixture was neutralized to pH 6 in an ice bath
with 5 N NaOH. The aqueous layer was extracted with DCM and the
combined organic layers were dried over Na.sub.2SO.sub.4, filtered
and concentrated in vacuo to afford the desired product as a yellow
solid (1.3 g, 96%). (ESI): mass calculated for
C.sub.6D.sub.7ClN.sub.2, 149.07; m/z found, 150.1.
Intermediate 90
tert-Butyl
5-{4,6-bis[(.sup.2H.sub.3)methyl](.sup.2H)pyrimidin-2-yl}hexahy-
dropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate
##STR00105##
[0310] A mixture of Intermediate 15 (294 mg, 1.38 mmol),
Intermediate 89 (207 mg, 1.38 mmol) and DIPEA (0.48 mL, 2.77 mmol)
in ACN (3.5 mL) was heated in the microwave at 150.degree. C. for 2
h. The mixture was concentrated in vacuo. The crude mixture was
purified by FCC (Hex to 50% EtOAc/Hex) to afford the title compound
(344 mg, 76%). MS (ESI): mass calculated for
C.sub.17H.sub.19D.sub.7N.sub.4O.sub.2, 325.25; m/z found 326.2
[M+1].sup.+. 1H NMR (500 MHz, CDCl.sub.3): 3.86-3.76 (m, 2H),
3.67-3.50 (m, 4H), 3.37-3.24 (m, 2H), 2.98-2.90 (m, 2H), 1.44 (s,
9H).
Intermediate 91
5-{4,6-Bis[(.sup.2H.sub.3)methyl](.sup.2H)pyrimidin-2-yl}hexahydropyrrolo[-
3,4-c]pyrrole
##STR00106##
[0312] Intermediate 90 (325 mg, 1 mmol), DCM (5 mL) and TFA (1 mL)
were stirred at room temperature for 2 h. The mixture was
concentrated in vacuo and was used as is. MS (ESI): mass calculated
for C.sub.12H.sub.11D.sub.7N.sub.4, 225.25; m/z found 225.2
[M+1].sup.+.
Intermediate 92
2-(4,6-Dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole,
bis-HCl salt
##STR00107##
[0314] A 150 mL EasyMax reactor was fitted with a mechanical
stirrer, a reflux condenser and a temperature probe and
2-chloro-4,6-dimethyl pyrimidine (7.10 g, 49.8 mmol), potassium
carbonate (9.77 g, 70.7 mmol), N-boc-3,7diazabicylco[3.3.0]octane
(10.03 g, 47.3 mmol) and 2-propanol (54.2 g) were added. The
reaction was slurried at 20.degree. C. for 5 minutes and then the
temperature was raised to 80.degree. C. over 30 minutes. The
reaction was then stirred at 80.degree. C. for 8 hours, cooled to
20.degree. C. within 30 minutes and allowed to stand overnight. To
the resulting mixture was added toluene (15.8 g) and the mixture
was stirred at 30.degree. C. for 30 minutes prior to removing all
salts by suction filtration. The reactor and filter cake were then
washed with toluene (20.2 g) and the resulting filtrates
(.about.115 mL) were added to a 150 mL EasyMax reactor held at a
temperature of 20.degree. C. 5-6 N HCl in 2-propanol (25.90 g) was
then added dropwise over a 30 minute period. The mixture was then
heated to 60.degree. C. over 20 minutes and stirred for 4 hours.
After approximately 1.5 hours crystallization of the product
started and the yellowish suspension was then cooled to 0-5.degree.
C. and was then stirred for another 1.5 hours. The product was then
isolated via suction filtration and washed with 2-propanol (25.0 g)
in two portions. The resulting wet product cake was dried in vacuo
at 50.degree. C. overnight then at 70.degree. C. for 4 hours to
obtain the title compound (11.52 g, 77%) as an off-white
crystalline solid. Purity was assessed by HPLC (99.5%, 99.7%, and
99.5area % (at 254, 235, and 280 nm, respectively). HCl content was
determined to be 25.26%.
Intermediate 93
3-Fluoro-2-(1H-pyrazol-1-yl)benzoic acid
##STR00108##
[0315] 3-Fluoro-2-(1H-pyrazol-1-yl)benzoic acid. To a mixture of
3-fluoro-2-iodobenzoic acid (1.4 g, 5.26 mmol), 1H-pyrazole (0.72
g, 10.5 mmol), trans-N,N'-dimethyl-cyclohexane-1,2-diamine (0.17
mL, 1.05 mmol), CuI (50.1 mg, 0.26 mmol), dioxane (50 mL) and water
(0.028 mL) was added Cs.sub.2CO.sub.3 (3.43 g, 10.5 mmol). The
reaction mixture was heated to 100.degree. C. for 1 h. The reaction
mixture was cooled to ambient temperature then diluted with water.
The aqueous layer was acidified to pH2 and extracted with EtOAc (30
mL) three times. The organic layers were combined, dried over
Na.sub.2SO.sub.4, filtered and concentrated. Purification (FCC),
(DCM to 10% MeOH/1% HOAC/DCM) afforded the title compound as a
colorless oil (790 mg, 72%). .sup.1H NMR (400 MHz, CDCl.sub.3):
7.85-7.73 (m, 1H), 7.54-7.44 (m, 1H), 7.44-7.34 (m, 1H), 6.55 (s,
1H).
Intermediate 94
3-Methyl-2-(1H-pyrazol-1-yl)benzoic acid
##STR00109##
[0316] The title compound was prepared in a manner analogous to
Intermediate 93 substituting 3-methyl-2-iodobenzoic acid for
3-fluoro-2-iodobenzoic acid. .sup.1H NMR (500 MHz, CDCl.sub.3):
7.79 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.5 Hz, 1H), 7.42 (t, J=7.6 Hz,
1H), 6.53 (s, 1H), 2.07 (s, 3H).
Intermediate 95
2-Fluoro-6-(pyrimidin-2-yl)benzoic acid
##STR00110##
[0318] Step A: 2-Fluoro-6-iodo-benzoic acid methyl ester. To a 200
mL round-bottomed flask were added 2-fluoro-6-iodo-benzoic acid
(7.5 g, 28.2 mmol), LiOH.cndot.H.sub.2O (1.42 g, 33.8 mmol), and
THF (100 mL). The resulting mixture was warmed to 50.degree. C. and
stirred for 2 h. Dimethyl sulfate (4.03 mL, 42.3 mmol) was then
added and the mixture was warmed to 65.degree. C. After 2 h, the
mixture was cooled to room temperature and NH.sub.4Cl.sub.ow (50
mL, 13 wt % solution) was added. The two resulting layers were
thoroughly mixed and then separated. The organic layer was dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure
to a light brown oil (7.79 g, 99% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.68-7.60 (m, 1H), 7.15-7.06 (m, 2H), 3.98 (s,
3H).
[0319] Step B:
2-Fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic
acid methyl ester. To a 500 mL round-bottomed flask were added
2-fluoro-6-iodo-benzoic acid methyl ester (7.29, 26.0 mmol) and
anhydrous THF (150 mL). This mixture was cooled to 0.degree. C. and
i-PrMgCl (13.7 mL, 2 M in THF, 27.3 mmol) was added dropwise. After
10 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.58
mL, 27.3 mmol) was added. The mixture was allowed to warm to room
temperature, and after 30 min NH.sub.4Cl.sub.(aq) (150 mL, 13 wt %
solution) was added. The layers were mixed and then separated, and
the aqueous layer was extracted with 100 mL of MTBE. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated to a final mass of 6.07 g (90% wt %, 75% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.47-7.38 (m, 2H), 7.17-7.11 (m,
1H), 3.92 (s, 3H), 1.36 (s, 12H).
[0320] Step C: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester.
To a 250 mL round-bottomed flask under nitrogen were added
2-fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic
acid methyl ester (5.46 g, 19.5 mmol) in 2-methyl-THF (50 mL),
2-chloropyrimidine (2.68 g, 23.4 mmol), and sodium carbonate (6.2
g, 58.5 mmol) in water (17 mL). PdCl.sub.2(dppf)-dcm adduct
(CAS#72287-26-4) (1.27 g, 1.56 mmol) was then added and the
reaction mixture was warmed to 74.degree. C. and stirred for 2.5 h.
After cooling, the mixture was diluted with MTBE (50 mL) and water
(80 mL). The layers were thoroughly mixed separated. The aqueous
layer was extracted with additional MTBE (100 mL). The combined
organics were dried over magnesium sulfate, filtered, concentrated
and then purified by flash chromatography (0-25% EA/hexanes) to
provide the title compound (1.72 g, 72 wt %, 30% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3): 8.79 (d, J=4.9 Hz, 2H), 8.15 (d, J=7.9
Hz, 1H), 7.51 (td, J=8.1, 5.6 Hz, 1H), 7.28-7.20 (m, 2H), 3.92 (s,
3H).
[0321] Step D: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid. To a
solution of 2-fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester
(1.36 g, 5.85 mmol) in 2-methyl-THF (20 mL) was added sodium
hydroxide (2 M in water, 9.3 mL, 18.6 mmol). The mixture was heated
to 72.degree. C. and stirred for 9 h. The layers were separated and
the aqueous layer acidified to pH 2 by dropwise addition of 50%
HCl.sub.(aq) (3.1 mL). The resulting solids were stirred for 1 h,
filtered, washed with water, MTBE, and heptanes, and then dried to
provide the desired product as a white solid (1.12 g, 88% yield).
.sup.1H NMR (400 MHz, CD.sub.3OD): 8.83 (d, J=4.9 Hz, 2H), 8.03
(dd, J=7.9, 0.8 Hz, 1H), 7.59 (td, J=8.1, 5.6 Hz, 1H), 7.40 (t,
J=4.9 Hz, 1H), 7.34 (ddd, J=9.4, 8.4, 1.0 Hz, 1H).
Intermediate 96
3-Methyl-2-(1H-1,2,3-triazol-1-yl)benzonitrile
##STR00111##
[0323] The title compound was a byproduct of the synthesis of
Intermediate 81 (3.1 g, 56%). MS (ESI) mass calcd. for
C.sub.10H.sub.8N.sub.4, 184.2; m/z found, 185.1 [M+H].sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3): 7.94 (d, J=2.1 Hz, 1H), 7.87 (d,
J=1.1 Hz, 1H), 7.71-7.67 (m, 1H), 7.67-7.62 (m, 1H), 7.56 (dd,
J=9.7, 5.8 Hz, 1H), 2.17 (s, 3H).
Intermediate 97
5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid
##STR00112##
[0324] 5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. To a solution
of 5-fluoro-2-iodo-benzoic acid (3.86 g, 14.65 mmol),
2H-[1,2,3]triazole (2.5 g, 36.2 mmol), Cs.sub.2CO.sub.3 (8.62 g,
24.5 mmol), trans-N,N.sup.1-dimethyl-cyclohexane-1,2-diamine (0.4
mL), CuI (244 mg) and DMF (13 mL) were added to a microwave ready
vessel and heated to 100.degree. C. for 10 min. The mixture was
cooled, diluted with water, and extracted with EtOAc. The aqueous
layer was acidified and extracted with EtOAc. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified by FCC (SiO.sub.2, gradient DCM to 10% MeOH/1% HOAc/DCM)
gave the product as a white powder, (2.14 g, 71%). .sup.1H NMR (400
MHz, CD.sub.3OD): 7.91 (s, 2H), 7.76 (dd, J=8.9, 4.8 Hz, 1H), 7.59
(dd, J=8.5, 2.9 Hz, 1H), 7.49-7.42 (m, 1H).
Example 1
4-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-6-methoxy-N,N-dimethylpyrimidin-2-amine
##STR00113##
[0325] A mixture of
[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimeth-
yl-amine (60.0 mg, 0.23 mmol),
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol),
HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was
stirred into DMF (4.0 mL) at room temperature for 30 minutes. The
reaction mixture was diluted with ethyl acetate (60.0 mL) and
washed with water (2.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated to dryness to yield
crude title compound (354.0 mg, 343%). The crude product was
purified using Agilent HPLC (Basic system) to yield pure title
compound (84.0 mg, 81.5%). MS (ESI) mass calcd. for
C.sub.22H.sub.25FN.sub.8O.sub.2, 452.49; m/z found 453.3
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.88-7.79 (m, 2H), 7.72 (d,
J=6.7, 1H), 7.54-7.41 (m, 1H), 7.19-7.08 (m, 1H), 5.02-4.92 (m,
1H), 3.96-3.86 (m, 1H), 3.87-3.83 (m, 3H), 3.81-3.50 (m, 5H),
3.43-3.19 (m, 2H), 3.15-3.09 (m, 6H)), 3.09-2.91 (m, 2H).
Example 2
N,N-Dimethyl-6-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrr-
olo[3,4-c]pyrrol-2(1H)-yl]-2-(trifluoromethyl)pyrimidin-4-amine
##STR00114##
[0327] A mixture of
[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl-
]dimethyl-amine (50 mg, 0.17 mmol), 2-[1,2,3]triazol-2-yl-benzoic
acid (34.5 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA
(0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room
temperature for 30 minutes. The reaction mixture was diluted with
ethyl acetate (60.0 mL) and washed with water (2.times.100 mL). The
organic phase was dried (Na.sub.2SO.sub.4), filtered and
concentrated to dryness. The crude product was purified using
Agilent HPLC (Basic system) to yield pure title compound (34.0 mg,
43.4%). MS (ESI) mass calcd. for C.sub.22H.sub.23F.sub.3N.sub.8O,
472.47; m/z found 473.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.98
(d, J=8.1, 1 H), 7.70-7.69 (m, 2H), 7.56-7.49 (m, 1H), 7.45-7.37
(m, 2H), 5.20-5.10 (m, 1H), 3.90-3.66 (m, 4H), 3.60-3.28 (m, 4H),
3.08 (s, 6H), 3.02-2.89 (m, 2H).
Example 3
6-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine
##STR00115##
[0328] A mixture of
[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl-
]dimethyl-amine (50 mg, 0.17 mmol),
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol),
HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF
(4.0 mL) was stirred at room temperature for 30 minutes. The
reaction mixture was diluted with ethyl acetate (60.0 mL) and
washed with water (2.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated to dryness. The crude
product was purified using Agilent HPLC (Basic system) to yield
pure title compound (19.0 mg, 23.4%). MS (ESI) mass calcd. for
C.sub.22H.sub.22F.sub.4N.sub.8O, 490.46; m/z found [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.89-7.79 (m, 2H), 7.74 (s, 1H),
7.55-7.37 (m, 1H), 7.21-7.05 (m, 1H), 5.25-5.09 (m, 1H), 4.25-3.51
(m, 6H), 3.50-2.95 (m, 10H).
Example 4
4-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-6-methoxy-N,N-dimethylpyrimidin-2-amine
##STR00116##
[0329] A mixture of
[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimeth-
yl-amine (60.0 mg, 0.23 mmol),
5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol),
HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was
stirred into DMF (4.0 mL) at room temperature for 30 minutes. The
reaction mixture was diluted with ethyl acetate (60.0 mL) and
washed with water (2.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated to dryness. The crude
product was purified using Agilent HPLC (Basic system) to yield
pure title compound (160.0 mg, 54%). MS (ESI) mass calcd. for
C.sub.22H.sub.25FN.sub.8O.sub.2, 452.49; m/z found 453.3
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.95 (dd, J=9.0, 4.8, 1H),
7.73 (s, 2H), 7.25-7.17 (m, 1H), 7.16-7.10 (m, 1H), 5.00-4.90 (m,
1H), 3.92-3.78 (m, 4H), 3.76-3.25 (m, 6H), 3.18-3.07 (m, 6H),
3.05-2.86 (m, 3H).
Example 5
4-Methoxy-N,N-dimethyl-6-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hex-
ahydropyrrolo-[3,4-c]pyrrol-2(1H)-yl]pyrimidin-2-amine
##STR00117##
[0330] A mixture of
[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimeth-
yl-amine (60.0 mg, 0.23 mmol), 2-[1,2,3]triazol-2-yl-benzoic acid
(47.4 mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12
mL, 0.68 mmol) was stirred into DMF (4.0 mL) at room temperature
for 30 minutes. The reaction mixture was diluted with ethyl acetate
(60.0 mL) and washed with water (2.times.100 mL). The organic phase
was dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness.
The crude product was purified using Agilent HPLC (Basic system) to
yield pure title compound (47.0 mg, 47.5%). MS (ESI) mass calcd.
for C.sub.22H.sub.26N.sub.8O.sub.2, 434.5; m/z found [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.98 (d, J=8.1, 1H), 7.73 (s, 2H), 7.75
(s, 2H), 7.55-7.47 (m, 1H), 7.45-7.37 (m, 2H), 5.00-4.90 (m, 1H),
3.91-3.80 (m, 5H), 3.70 (dd, J=12.5, 3.9, 2H), 3.60-3.29 (m, 4H),
3.19-3.04 (m, 8H).
Example 6
6-[5-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine
##STR00118##
[0331] A mixture of
[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl-
]dimethyl-amine (50 mg, 0.17 mmol),
4-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol),
HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF
(4.0 mL) was stirred at room temperature for 30 minutes. The
reaction mixture was diluted with ethyl acetate (60.0 mL) and
washed with water (2.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated to dryness. The crude
product was purified using Agilent HPLC (Basic system) to yield
pure title compound (42.0 mg, 51.6%). MS (ESI) mass calcd. for
C.sub.22H.sub.22F.sub.4N.sub.8O, 490.46; m/z found [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.90-7.65 (m, 3H), 7.57-7.35 (m, 1H),
7.18-7.02 (m, 1H), 5.23-5.05 (m, 1H), 4.02-3.20 (m, 7H), 3.16-2.84
(m, 9H).
Example 7
4-[5-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-6-methoxy-N,N-dimethylpyrimidin-2-amine
##STR00119##
[0332] A mixture of
[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimeth-
yl-amine (60.0 mg, 0.23 mmol),
4-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0 mg, 0.25 mmol),
HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) was
stirred into DMF (4.0 mL) at room temperature for 30 minutes. The
reaction mixture was diluted with ethyl acetate (60.0 mL) and
washed with water (2.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated to dryness. The crude
product was purified using Agilent HPLC (Basic system) to yield
pure title compound (52.0 mg, 50.5%). MS (ESI) mass calcd. for
C.sub.22H.sub.25FN.sub.8O.sub.2, 452.49; m/z found [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.83-7.66 (m, 3H), 7.42-7.36 (m, 1H),
7.16-7.08 (m, 1H), 5.00-4.89 (m, 1H), 3.90-3.78 (m, 4H), 3.77-3.19
(m, 6H), 3.17-2.82 (m, 9H).
Example 8
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-(1H-pyrrol-1-yl)thiophen-2-yl]carbony-
l}octahydro-pyrrolo[3,4-c]pyrrole
##STR00120##
[0334] A mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(60.0 mg, 0.28 mmol), 3-pyrrol-1-yl-thiophene-2-carboxylic acid
(58.4 mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6
mg, 0.83 mmol) was stirred into DMF (5.0 mL) at room temperature
for 30 minutes. The reaction mixture was diluted with ethyl acetate
(60.0 mL) and washed with water (2.times.100 mL). The organic phase
was dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness.
The crude product was purified using Agilent HPLC (Basic system) to
yield pure title compound (79.0 mg, 73%). MS (ESI) mass calcd. for
C.sub.21H.sub.23N.sub.5OS, 393.51; m/z found [M+H].sup.+. .sup.1H
NMR (CDCl.sub.3): 7.42-7.39 (m, 1H), 7.04-7.01 (m, 1H), 6.85 (t,
J=2.1, 2H), 6.29 (s, 1H), 6.14 (t, J=2.1, 2H), 3.88-3.73 (m, 2H),
3.66-3.52 (m, 2H), 3.50-3.41 (m, 1H), 3.32-3.20 (m, 1H), 3.00-2.86
(m, 2H), 2.80-2.66 (m, 1H), 2.60-2.47 (m, 1H), 2.34-2.25 (m,
6H).
Example 9
6-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine
##STR00121##
[0335] A mixture of
[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl-
]dimethyl-amine (50 mg, 0.17 mmol),
5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (37.8 mg, 0.18 mmol),
HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF
(4.0 mL) was stirred at room temperature for 30 minutes. The
reaction mixture was diluted with ethyl acetate (60.0 mL) and
washed with water (2.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated to dryness. The crude
product was purified using Agilent HPLC (Basic system) to yield
pure title compound (42.0 mg, 51.6%). MS (ESI) mass calcd. for
C.sub.22H.sub.22F.sub.4N.sub.8O, 490.46; m/z found [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.96 (dd, J=9.0, 4.8, 1H), 7.80-7.66 (m,
2H), 7.25-7.18 (m, 1H), 7.16-7.10 (m, 1H), 5.22-5.11 (m, 1H),
3.90-3.30 (m, 8H), 3.13-3.06 (m, 7H), 3.00 (s, 6H).
Example 10
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(1-phenyl-1H-pyrazol-5-yl)carbonyl]octah-
ydropyrrolo[3,4-c]pyrrole
##STR00122##
[0337] A mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(60.0 mg, 0.28 mmol), 2-phenyl-2H-pyrazole-3-carboxylic acid (56.9
mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg,
0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30
minutes. The reaction mixture was diluted with ethyl acetate (60.0
mL) and washed with water (2.times.100 mL). The organic phase was
dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness. The
crude product was purified using Agilent HPLC (Basic system) to
yield pure title compound (79.0 mg, 74%). MS (ESI) mass calcd. for
C.sub.22H.sub.24N.sub.6O, 388.47; m/z found 389.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.67 (d, J=1.7, 1 H), 7.50 (d, J=7.4,
2H), 7.37 (t, J=7.8, 2H), 7.29-7.23 (m, 1H), 6.56 (d, J=1.7, 1 H),
6.30 (s, 1H), 3.86-3.71 (m, 2H), 3.70-3.51 (m, 2H), 3.43-3.22 (m,
3H), 3.05-2.77 (m, 3H), 2.29 (s, 6H).
Example 11
8-{[5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]c-
arbonyl}-quinoline
##STR00123##
[0338] A mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(60.0 mg, 0.28 mmol), quinoline-8-carboxylic acid (52.4 mg, 0.30
mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol)
was stirred into DMF (5.0 mL) at room temperature for 30 minutes.
The reaction mixture was diluted with ethyl acetate (60.0 mL) and
washed with water (2.times.100 mL). The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated to dryness. The crude
product was purified using Agilent HPLC (Basic system) to yield
pure title compound (68.0 mg, 66.2%). MS (ESI) mass calcd. for
C.sub.22H.sub.23N.sub.5O, 373.46; m/z found 374.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 8.95 (s, 1H), 8.16 (d, J=7.9, 1H),
7.89-7.79 (m, 1H), 7.69 (d, J=6.8, 1 H), 7.61-7.49 (m, 1H), 7.41
(s, 1H), 6.26 (d, J=19.1, 1H), 4.29-4.03 (m, 1H), 3.96-3.59 (m,
4H), 3.65-3.29 (m, 2H), 3.21-2.84 (m, 3H), 2.37-2.18 (m, 6H).
Example 12
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-phenylthiophen-2-yl)carbonyl]octahydr-
opyrrolo[3,4-c]pyrrole
##STR00124##
[0339] A mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(60.0 mg, 0.28 mmol), 3-phenyl-thiophene-2-carboxylic acid (61.8
mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg,
0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30
minutes. The reaction mixture was diluted with ethyl acetate (60.0
mL) and washed with water (2.times.100 mL). The organic phase was
dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness. The
crude product was purified using Agilent HPLC (Basic system) to
yield pure title compound (30.0 mg, 27.0%). MS (ESI) mass calcd.
for C.sub.23H.sub.24N.sub.4OS, 404.54; m/z found 405.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.45-7.41 (m, 2H), 7.39 -(d, J=5.1, 1H),
7.34-7.27 (m, 2H), 7.18-7.14 (m, 1H), 7.13 (d, J=5.0, 1 H), 6.28
(s, 1H), 3.88-3.66 (m, 2H), 3.61-3.49 (m, 2H), 3.30 (dd, J=11.5,
5.1, 1H), 3.19-3.04 (m, 2H), 2.92-2.78 (m, 1H), 2.75-2.61 (m, 2H),
2.37-2.22 (m, 6H).
Example 13
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-phenylfuran-2-yl)carbonyl]octahydropy-
rrolo[3,4-c]pyrrole
##STR00125##
[0340] A mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(60.0 mg, 0.28 mmol), 3-phenyl-furan-2-carboxylic acid (61.8 mg,
0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83
mmol) was stirred into DMF (5.0 mL) at room temperature for 30
minutes. The reaction mixture was diluted with ethyl acetate (60.0
mL) and washed with water (2.times.100 mL). The organic phase was
dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness. The
crude product was purified using Dionex HPLC to yield pure title
compound (30.0 mg, 28.0%). MS (ESI) mass calcd. for
C.sub.23H.sub.24N.sub.4O.sub.2, 388.47; m/z found 389.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.56-7.50 (m, 2H), 7.46 (d,
J=1.8, 1H), 7.37-7.30 (m, 2H), 7.25-7.19 (m, 1H), 6.61 (d, J=1.8,
1H), 6.29 (s, 1H), 3.95-3.80 (m, 2H), 3.75-3.60 (m, 3H), 3.51 (dd,
J=11.6, 5.0 1H), 3.42 (dd, J=11.6, 4.1, 1 H), 3.33 (dd, J=11.6,
5.4, 1 H), 3.02-2.81 (m, 2H), 2.35-2.22 (m, 6H).
Example 14
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1H-1,2,4-triazol-5-yl)phenyl]carbony-
l}octahydro-pyrrolo[3,4-c]pyrrole
##STR00126##
[0341] A mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(60.0 mg, 0.28 mmol), 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid (57.2
mg, 0.30 mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg,
0.83 mmol) was stirred into DMF (5.0 mL) at room temperature for 30
minutes. The reaction mixture was diluted with ethyl acetate (60.0
mL) and washed with water (2.times.100 mL). The organic phase was
dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness. The
crude product was purified using Agilent HPLC (basic system) to
yield pure title compound (60.0 mg, 56%). MS (ESI) mass calcd. for
C.sub.21H.sub.23N.sub.7O, 389.46; m/z found 390.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 8.12 (d, J=7.5, 1 H), 8.05 (s, 1H),
7.53-7.39 (m, 2H), 7.37-7.31 (m, 1H), 6.28 (s, 1H), 3.95-3.77 (m,
2H), 3.76-3.55 (m, 3H), 3.48-3.33 (m, 2H), 3.19-3.03 (m, 1H),
3.02-2.95 (m, 1H), 2.91-2.82 (m, 1H), 2.36-2.19 (m, 6H).
Example 15
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00127##
[0342] A mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(437.3 mg, 2.0 mmol), 3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid
(415 mg, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DIPEA (777 mg, 6.0
mmol) was stirred into DMF (20 mL) at room temperature for 30
minutes. The reaction mixture was diluted with ethyl acetate (250
mL) and washed with water (2.times.500 mL). The organic phase was
dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness. The
crude product was purified using Agilent HPLC (basic system) to
yield pure title compound (458.0 mg, 56%). MS (ESI) mass calcd. for
C.sub.21H.sub.22FN.sub.7O, 407.45; m/z found 408.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.79 (s, 2H), 7.52-7.45 (m, 1H),
7.36-7.28 (m, 1H), 7.25-7.22 (m, 1H), 6.30 (s, 1H), 3.82 (dd,
J=11.6, 7.5, 1H), 3.75-3.66 (m, 2H), 3.58-3.41 (m, 4H), 3.13 (dd,
J=10.9, 5.2, 1H), 3.02-2.87 (m, 2H), 2.36-2.24 (m, 6H). Examples
16-106, 108-214 were prepared in a manner analogous to Example
15.
Example 16
2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
}-6-fluoro-1,3-benzothiazole
##STR00128##
[0343] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 38 and
2-chloro-6-fluoro-benzothiazole. MS (ESI) mass calcd. for
C.sub.22H.sub.22FN.sub.3O.sub.3S, 427.5; m/z found, 428.2
[M+H].sup.+.
Example 17
2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
}-1,3-benzothiazole
##STR00129##
[0345] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 38 and 2-chloro-benzothiazole. MS
(ESI) mass calcd. for C.sub.22H.sub.23N.sub.3O.sub.3S, 409.51; m/z
found, 410.2 [M+H].sup.+.
Example 18
2-[5-{[2-(1H-Pyrazol-1-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(-
1H)-yl]quinoxaline
##STR00130##
[0346] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-pyrazol-1-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.24H.sub.22N.sub.6O, 410.48;
m/z found, 411.2 [M+H].sup.+.
Example 19
2-{5-[(2-Thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)--
yl}quinoxaline
##STR00131##
[0347] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-thiophen-2-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.25H.sub.22N.sub.4OS, 426.54;
m/z found, 427.2 [M+H].sup.+.
Example 20
2-{5-[(2-Methylnaphthalen-1-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H-
)-yl}quinoxaline
##STR00132##
[0348] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and
2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.25H.sub.22N.sub.4OS, 426.54; m/z found, 427.2
[M+H].sup.+.
Example 21
2-(2,3-Dihydro-1,4-benzodioxin-5-ylcarbonyl)-5-(4-phenylpyrimidin-2-yl)oct-
ahydropyrrolo[3,4-c]pyrrole
##STR00133##
[0349] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and
2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid. MS (ESI) mass
calcd. for C.sub.25H.sub.24N.sub.4O.sub.3, 428.50; m/z found, 429.2
[M+H].sup.+.
Example 22
2-(4-Phenylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-py-
rrolo[3,4-c]pyrrole
##STR00134##
[0350] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and 2-thiophen-2-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.27H.sub.24N.sub.4OS, 452.58;
m/z found, 453.2 [M+H].sup.+.
Example 23
2-(4-Phenylpyrimidin-2-yl)-5-{[2-(1H-Pyrazol-1-yl)phenyl]carbonyl}octahydr-
o-pyrrolo[3,4-c]pyrrole
##STR00135##
[0351] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and 2-pyrazol-1-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.26H.sub.24N.sub.6, 436.52; m/z
found, 437.2 [M+H].sup.+.
Example 24
2-(4-Phenylpyrimidin-2-yl)-5-{[2-(1H-pyrrol-1-yl)phenyl]carbonyl}octahydro-
-pyrrolo[3,4-c]pyrrole
##STR00136##
[0352] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and 2-pyrrol-1-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.27H.sub.25N.sub.5O, 435.53;
m/z found, 436.3 [M+H].sup.+.
Example 25
2-[(2-Methylnaphthalen-1-yl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydrop-
yrrolo[3,4-c]pyrrole
##STR00137##
[0353] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and
2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.28H.sub.26N.sub.4O, 434.51; m/z found, 435.3 [M+H].sup.+.
Example 26
2-(5-Quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-15
benzonitrile
##STR00138##
[0354] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-cyano-benzoic acid. MS
(ESI): mass calculated for C.sub.22H.sub.19N.sub.5O, 369.43; m/z
found 370.3 [M+H].sup.+.
Example 27
2-[5-{[2-(1H-Pyrrol-1-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1-
H)-yl]quinoxaline
##STR00139##
[0355] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-pyrrol-1-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.25H.sub.23N.sub.5O, 409.49;
m/z found, 410.2 [M+H].sup.+.
Example 28
2-{5-[(4'-Fluorobiphenyl-2-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-
-yl}quinoxaline
##STR00140##
[0357] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and
4'-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.27H.sub.23FN.sub.4O, 438.51; m/z found, 439.2
[M+H].sup.+.
Example 29
2-{5-[(3'-Fluorobiphenyl-2-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-
-yl}quinoxaline
##STR00141##
[0358] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and
3'-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.27H.sub.23FN.sub.4O, 438.51; m/z found, 439.2
[M+H].sup.+.
Example 30
2-{5-[(2-Methylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quin-
oxaline
##STR00142##
[0359] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-methylbenzoic acid. MS
(ESI) mass calcd. for C.sub.22H.sub.22N.sub.4O, 358.45; m/z found,
359.2 [M+H].sup.+.
Example 31
2-(Biphenyl-2-ylcarbonyl)-5-(4-furan-2-ylpyrimidin-2-yl)octahydropyrrolo[3-
,4-c]pyrrole
##STR00143##
[0360] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-4-furan-2-yl-pyrimidine. MS (ESI) mass calcd. for
C.sub.27H.sub.24N.sub.4O.sub.2, 436.52; m/z found, 437.2
[M+H].sup.+.
Example 32
2-(4-Methylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-py-
rrolo[3,4-c]pyrrole
##STR00144##
[0362] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4-methyl-pyrimidine. MS (ESI) mass calcd. for
C.sub.22H.sub.22N.sub.4OS, 390.51; m/z found, 391.2
[M+H].sup.+.
Example 33
2-{5-[(2-Thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)--
yl}quinoline
##STR00145##
[0363] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and 2-chloro-quinoline. MS
(ESI) mass calcd. for C.sub.26H.sub.23N.sub.3OS, 425.56; m/z found,
426.2 [M+H].sup.+.
Example 34
2-(4-Furan-2-ylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydr-
o-pyrrolo[3,4-c]pyrrole
##STR00146##
[0364] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4-furan-2-yl-pyrimidine. MS (ESI) mass calcd. for
C.sub.26H.sub.22N.sub.4O.sub.2S, 442.50; m/z found, 443.2
[M+H].sup.+.
Example 35
2-{5-[(2-Ethylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quino-
xaline
##STR00147##
[0365] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-ethylbenzoic acid. MS
(ESI) mass calcd. for C.sub.23H.sub.24N.sub.4O, 372.46; m/z found,
373.2 [M+H].sup.+.
Example 36
2-[5-(1H-Indol-7-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxa-
line
##STR00148##
[0366] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 1H-indole-7-carboxylic
acid. MS (ESI) mass calcd. for C.sub.23H.sub.21N.sub.5O, 383.45;
m/z found, 384.2 [M+H].sup.+.
Example 37
2-[(2-Thiophen-2-ylphenyl)carbonyl]-5-(4-thiophen-2-ylpyrimidin-2-yl)octah-
ydro-pyrrolo[3,4-c]pyrrole
##STR00149##
[0367] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4-thiophen-2-yl-pyrimidine. MS (ESI) mass calcd. for
C.sub.25H.sub.22N.sub.4OS.sub.2, 458.60; m/z found, 459.1
[M+H].sup.+.
Example 38
2-(Biphenyl-2-ylcarbonyl)-5-(4-thiophen-2-ylpyrimidin-2-yl)octahydropyrrol-
o[3,4-c]pyrrole
##STR00150##
[0369] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-4-thiophen-2-yl-pyrimidine. MS (ESI) mass calcd. for
C.sub.27H.sub.24N.sub.4OS, 452.57; m/z found, 453.1
[M+H].sup.+.
Example 39
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(-
1-methyl-1H-imidazol-2-yl)-phenyl]-methanone
##STR00151##
[0370] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
2-(1-methyl-1H-imidazol-2-yl)-benzoic acid. MS (ESI) mass calcd.
for C.sub.23H.sub.26N.sub.6O, 402.50; m/z found, 403.2
[M+H].sup.+.
Example 40
2-[(2-Bromophenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-
-c]pyrrole
##STR00152##
[0371] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and 2-bromobenzoic acid. MS
(ESI) mass calcd. for C.sub.23H.sub.21BrN.sub.4O, 449.34; m/z
found, 449.1, 451.1 [M+H].sup.+.
Example 41
2-{5-[(3'-Chlorobiphenyl-2-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-
-yl}quinoxaline
##STR00153##
[0373] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and
3'-chloro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.27H.sub.23ClN.sub.4O, 454.95; m/z found, 455.1
[M+H].sup.+.
Example 42
2-{5-[(2-Bromophenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quino-
xaline
##STR00154##
[0374] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-bromobenzoic acid. MS
(ESI) mass calcd. for C.sub.21H.sub.19BrN.sub.4O, 423.31; m/z
found, 423.0, 425.0 [M+H].sup.+.
Example 43
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydr-
o-pyrrolo[3,4-c]pyrrole
##STR00155##
[0376] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4,6-dimethyl-pyrimidine. MS (ESI) mass calcd. for
C.sub.23H.sub.24N.sub.4OS, 404.53; m/z found, 405.1
[M+H].sup.+.
Example 44
2-(Biphenyl-2-ylcarbonyl)-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3-
,4-c]pyrrole
##STR00156##
[0377] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-4,6-dimethyl-pyrimidine. MS (ESI) mass calcd. for
C.sub.25H.sub.26N.sub.4O, 398.5; m/z found, 399.2 [M+H].sup.+.
Example 45
2-(4-Methoxypyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-p-
yrrolo[3,4-c]pyrrole
##STR00157##
[0378] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4-methoxy-pyrimidine. MS (ESI) mass calcd. for
C.sub.22H.sub.22N.sub.4O.sub.2S, 406.50; m/z found, 407.0
[M+H].sup.+.
Example 46
6-Fluoro-2-{5-[(2-thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrr-
ol-2(1H)-yl}-1,3-benzothiazole
##STR00158##
[0379] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-6-fluoro-benzothiazole. MS (ESI) mass calcd. for
C.sub.24H.sub.20FN.sub.3OS.sub.2, 449.57; m/z found, 450.0
[M+].sup.+.
Example 47
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-methylnaphthalen-1-yl)carbonyl]octahy-
dro-pyrrolo[3,4-c]pyrrole
##STR00159##
[0380] The title compound was prepared in a manner analogous to for
Example 15 utilizing Intermediate 23 and
2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.24H.sub.26N.sub.4O, 386.5; m/z found, 387.3 [M+H].sup.+.
Example 48
2-[(3'-Fluorobiphenyl-2-yl)carbonyl]-5-(4-methylpyrimidin-2-yl)octahydro-p-
yrrolo[3,4-c]pyrrole
##STR00160##
[0381] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 27 and
3'-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.24H.sub.23FN.sub.4O, 402.46; m/z found, 403.1
[M+H].sup.+.
Example 49
2-(4-Methoxypyrimidin-2-yl)-5-[(2-methylnaphthalen-1-yl)carbonyl]octahydro-
-pyrrolo[3,4-c]pyrrole
##STR00161##
[0382] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and
2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.23H.sub.24N.sub.4O.sub.2, 388.46; m/z found, 389.1
[M+H].sup.+.
Example 50
2-[(2-Methylnaphthalen-1-yl)carbonyl]-5-(4-methylpyrimidin-2-yl)octahydro--
pyrrolo[3,4-c]pyrrole
##STR00162##
[0383] The title compound was prepared in a manner analogous to
Example 15 utilizing and 2-methyl-naphthalene-1-carboxylic acid. MS
(ESI) mass calcd. for C.sub.23H.sub.24N.sub.4O, 372.46; m/z found,
373.1 [M+H].sup.+.
Example 51
2-[(3'-Fluorobiphenyl-2-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydro--
pyrrolo[3,4-c]pyrrole
##STR00163##
[0384] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and
3'-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.24H.sub.23FN.sub.4O.sub.2, 418.46; m/z found, 419.1
[M+H].sup.+.
Example 52
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3'-fluorobiphenyl-2-yl)carbonyl]octahyd-
ro-pyrrolo[3,4-c]pyrrole
##STR00164##
[0385] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
3'-fluoro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.25H.sub.25FN.sub.4O, 416.49; m/z found, 417.1
[M+H].sup.+.
Example 53
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-f-
luoro-phenyl)-methanone
##STR00165##
[0386] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-fluorobenzoic acid. MS
(ESI) mass calcd. for C.sub.19H.sub.21FN.sub.4O, 340.4; m/z found,
341.2 [M+H].sup.+.
Example 54
2-(4-Methoxypyrimidin-2-yl)-5-[(4'-methylbiphenyl-2-yl)carbonyl]octahydro--
pyrrolo[3,4-c]pyrrole
##STR00166##
[0387] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and
4'-methyl-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.25H.sub.26N.sub.4O.sub.2, 414.50; m/z found, 415.1
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.06 (d, J=5.7 Hz, 1H),
7.54-7.34 (m, 6H), 7.17 (s, 2H), 6.01 (d, J=5.7 Hz, 1H), 3.90 (s,
3H), 3.82-3.66 (m, 2H), 3.65-3.35 (m, 2H), 3.25-2.55 (m, 6H), 2.33
(s, 3H).
Example 55
2-[(3'-Chlorobiphenyl-2-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydro--
pyrrolo[3,4-c]pyrrole
##STR00167##
[0389] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and
3'-chloro-biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for
C.sub.24H.sub.23ClN.sub.4O.sub.2, 434.92; m/z found, 435.1
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.06 (d, J=5.6 Hz, 1H),
7.55-7.33 (m, 6H), 7.32-7.14 (m, 2H), 6.03 (d, J=5.7 Hz, 1H), 3.92
(s, 3H), 3.81-3.64 (m, 2H), 3.61-3.45 (m 2H), 3.14 (br s, 3H),
2.91-2.55 (m, 3H).
Example 56
2-[(2-Ethoxynaphthalen-1-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydro-
pyrrolo[3,4-c]pyrrole
##STR00168##
[0391] The title compound was prepared according to the procedure
used for Example 15 utilizing Intermediate 32 and
2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.24H.sub.26N.sub.4O.sub.3, 418.49; m/z found, 419.3
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): rotamers observed, 8.07 (t,
J=6.3 Hz, 1H), 7.89-7.76 (m, 2H), 7.74 (d, J=8.4 Hz, 0.6H), 7.66
(d, J=8.4 Hz, 0.4H), 7.50 (t, J=7.6 Hz, 0.6H), 7.46-7.32 (m, 1.5H),
7.31-7.22 (m, 1H), 6.05-6.00 (m, 1H), 4.32-3.81 (m, 7.7H),
3.80-3.52 (m, 3.0H), 3.43-3.31 (m, 1H), 3.27 (dd, J=11.1, 5.9 Hz,
0.6H), 3.19-3.07 (m, 1H), 3.05-2.92 (m 1.5H), 1.46 (t, J=7.0 Hz,
1.3H), 1.36 (t, J=6.9 Hz, 1.8H).
Example 57
2-[(4-Fluoronaphthalen-1-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydro-
-pyrrolo[3,4-c]pyrrole
##STR00169##
[0392] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and
4-fluoro-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.22H.sub.21FN.sub.4O.sub.2, 392.43; m/z found, 393.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.22-8.13 (m, 1H), 8.08 (d,
J=5.7 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.66-7.53 (m, 2H), 7.43 (dd,
J=7.8, 5.3 Hz, 1H), 7.17 (dd, J=10.1, 7.9 Hz, 1H), 6.04 (d, J=5.7
Hz, 1H), 4.11 (dd, J=12.8, 7.8 Hz, 1H), 4.00-3.80 (m, 5H),
3.80-3.63 (m, 2H), 3.57-3.39 m, 2H), 3.22-3.08 (m, 2H), 3.04-2.92
(m, 1H).
Example 58
2-(4-Methoxypyrimidin-2-yl)-5-(naphthalen-1-ylcarbonyl)octahydropyrrolo[3,-
4-c]pyrrole
##STR00170##
[0393] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and naphthalene-1-carboxylic
acid. MS (ESI) mass calcd. for C.sub.22H.sub.22N.sub.4O.sub.2,
374.44; m/z found, 375.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3):
8.08 (d, J=5.7 Hz, 1H), 7.95-7.81 (m, 3H), 7.59-7.46 (m, 4H), 6.04
(d, J=5.7 Hz, 1H), 4.13 (dd, J=12.8, 7.9 Hz, 1H), 4.00-3.80 (m,
5H), 3.80-3.65 (m, 2H), 3.55-3.40 (m, 2H), 3.22-3.09 (m, 2H),
3.05-2.91 (m, 1H).
Example 59
2-[(2-Ethoxyphenyl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3-
,4-c]pyrrole
##STR00171##
[0394] The title compound was prepared according to the procedure
used for Example 15 utilizing
2-(4-methoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and
2-ethoxybenzoic acid. MS (ESI) mass calcd. for
C.sub.20H.sub.24N.sub.4O.sub.3, 368.44; m/z found, 369.3
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.07 (d, J=5.7 Hz, 1H),
7.37-7.28 (m, 2H), 6.99 (t, J=7.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H),
6.02 (d, J=5.7 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 4.01-3.85 (m, 5H),
3.84-3.70 (m, 2H), 3.65-3.45 (m, 3H), 3.34-3.22 (m, 1H), 3.16-2.92
(m, 2H), 1.35 (t, J=6.8 Hz, 3H).
Example 60
2-[(2-Methoxynaphthalen-1-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydr-
opyrrolo[3,4-c]pyrrole
##STR00172##
[0395] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and
2-methoxy-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.23H.sub.24N.sub.4O.sub.3, 404.46; m/z found, 405.2
[M+H].sup.+. .sup.1H NMR (rotamers observed) 8.12-8.00 (m, 1H),
7.88 (d, J=9.1 Hz, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz,
0.6H), 7.63 (d, J=8.4 Hz, 0.4H), 7.49 (t, J=7.6 Hz, 0.6H),
7.45-7.23 (m, 3.4H), 6.06-5.97 (m, 1H), 4.16-4.02 (m, 1H),
3.99-3.79 (m, 7H), 3.80-3.62 (m, 2H), 3.61-3.47 (m, 1H), 3.41-3.28
(m, 1H), 3.25-3.06 (m, 2H), 2.98 (d, J=8.2 Hz, 2H).
Example 61
2-(Biphenyl-2-ylcarbonyl)-5-[4-(1H-pyrazol-4-yl)pyrimidin-2-yl]octahydro-p-
yrrolo[3,4-c]pyrrole
##STR00173##
[0397] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-4-(1H-pyrazol-3-yl)-pyrimidine. MS (ESI) mass calcd. for
C.sub.26H.sub.24N.sub.6O, 436.57; m/z found, 437.2 [M+H].sup.+.
Example 62
2-[4-(1H-Pyrazol-4-yl)pyrimidin-2-yl]-5-[(2-thiophen-2-ylphenyl)carbonyl]o-
ctahydro-pyrrolo[3,4-c]pyrrole
##STR00174##
[0398] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4-(1H-pyrazol-3-yl)-pyrimidine. MS (ESI) mass calcd. for
C.sub.24H.sub.22N.sub.6OS, 442.54; m/z found, 443.1
[M+H].sup.+.
Example 63
2-(3,6-Dimethylpyrazin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro--
pyrrolo[3,4-c]pyrrole
##STR00175##
[0399] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
3-chloro-2,5-dimethyl-pyrazine. MS (ESI) mass calcd. for
C.sub.23H.sub.24N.sub.4OS, 404.54; m/z found, 405.2
[M+H].sup.+.
Example 64
2-(Biphenyl-2-ylcarbonyl)-5-(3,5-dimethylpyrazin-2-yl)octahydropyrrolo[3,4-
-c]pyrrole
##STR00176##
[0400] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-3,5-dimethyl-pyrazine. MS (ESI) mass calcd. for
C.sub.25H.sub.26N.sub.4O, 398.50; m/z found, 399.2 [M+H].sup.+.
Example 65
2-Methyl-3-{5-[(2-thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrr-
ol-2(1H)-yl}quinoxaline
##STR00177##
[0401] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-3-methyl-quinoxaline. MS (ESI) mass calcd. for
C.sub.26H.sub.24N.sub.4OS, 440.56; m/z found, 441.1 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): rotamers observed 7.77 (d, J=7.9 Hz, 1H),
7.64 (d, J=7.9 Hz, 1H), 7.51-7.40 (m, 2H), 7.40-7.25 (m, 4H),
7.20-7.14 (m, 2H), 6.93 (br s, 1H), 3.86-3.74 (m, 2H), 3.70-3.60
(br m, 1.3H), 3.58-3.40 (br m, 1.6H), 3.26-3.10 (m, 1.7H),
2.95-2.82 (br m, 1.7H), 2.76 (br m, 1.5H), 2.62 (s, 3H).
Example 66
2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-meth-
ylquinoxaline
##STR00178##
[0402] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-3-methyl-quinoxaline. MS (ESI) mass calcd. for
C.sub.28H.sub.26N.sub.4O, 434.53; m/z found, 435.1 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 7.85-7.72 (m, 1H), 7.65 (br s, 1H),
7.53-7.30 (m, 9H), 7.21 (d, J=10.5 Hz, 2H), 3.80-3.54 (br m, 3.5H),
3.44-3.28 (br m, 1.5H), 3.15-2.90 broad (m, 2.5H), 2.85-2.70 (br m,
1.5H), 2.65-2.50 (m, 4H).
Example 67
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}octa-
hydro-pyrrolo[3,4-c]pyrrole
##STR00179##
[0403] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-pyrazol-1-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.24H.sub.24N.sub.6O, 388.47;
m/z found, 389.1 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): rotamers
observed, 7.73 (broad d, J=1.9 Hz, 1H), 7.52 (broad d, J=7.9 Hz,
1.6H), 7.48-7.39 (m, 1.3H), 7.38-7.29 (m, 2H), 6.31 (br s, 1H),
6.22 (s, 1H), 3.75-3.64 (m, 2H), 3.46 (dd, J=12.7, 4.4 Hz, 1.4H),
3.38 broad (s, 7H), 3.27 (dd, J=11.7, 4.2 Hz, 1.3H), 3.10 (br s,
1H), 2.90-2.65 (m, 3.3H), 2.23 (s, 6H).
Example 68
2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(2-fluoro-6-pyrimidin-2-ylphenyl)carbon-
yl]octahydropyrrolo[3,4-c]pyrrole
##STR00180##
[0404] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 14 and Intermediate 39. MS (ESI)
mass calcd. for C.sub.23H.sub.23FN.sub.6O.sub.3, 450.47; m/z found,
451.1 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): rotamers observed,
8.75-8.65 (m, 2H), 8.12-8.01 (m, 1H), 7.45-7.38 (m, 1H), 7.20-7.12
(m, 1H), 7.05 (t, J=4.9 Hz, 1H), 5.32 (s, 1H), 3.96-3.41 (m,
12.4H), 3.32-2.27 (m, 0.7H), 3.22-3.15 (m, 0.5H), 3.06-2.86 (m,
2.4H).
Example 69
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-pyridin-2-ylphenyl)carbonyl]octahydro-
-pyrrolo[3,4-c]pyrrole
##STR00181##
[0405] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-pyridin-2-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.24H.sub.25N.sub.5O, 399.49;
m/z found, 400.1 [M+H].sup.+.
Example 70
2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(2-pyridin-2-ylphenyl)carbonyl]octahydr-
o-pyrrolo[3,4-c]pyrrole
##STR00182##
[0406] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 39 and 2-pyridin-2-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.24H.sub.25N.sub.5O.sub.3,
431.49; m/z found, 432.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3):
8.49 (d, J=3.9 Hz, 1H), 7.69-7.49 (m, 3H), 7.48-7.29 (m, 3H),
7.15-7.04 (m, 1H), 5.32 (s, 1H), 3.92-3.61 (m, 8H), 3.60-3.40 (m,
2H), 3.35-3.15 (m, 3H), 2.98-2.65 (m, 3H).
Example 71
2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(5-fluoro-2-pyrimidin-2-ylphenyl)carbon-
yl]octahydropyrrolo[3,4-c]pyrrole
##STR00183##
[0407] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 39 and Intermediate 13. MS (ESI)
mass calcd. for C.sub.23H.sub.23FN.sub.6O.sub.3, 450.18; m/z found,
451.1 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.68 (d, J=4.9 Hz,
2H), 8.25 (dd, J=8.7, 5.5 Hz, 1H), 7.28-7.15 (m, 2H), 7.12 (dd,
J=8.6, 2.5 Hz, 1H), 5.31 (s, 1H), 3.84-3.65 (m, 7H), 3.63-3.33 (m,
5H), 3.13-2.86 (m, 4H).
Example 72
2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00184##
[0408] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 39 and Intermediate 1. MS (ESI)
mass calcd. for C.sub.22H.sub.22FN.sub.7O.sub.3, 439.18; m/z found,
440.1 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.89 (dd, J=8.9, 4.7
Hz, 1H), 7.66 (s, 1H), 7.25-7.01 (m, 2H), 5.32 (s, 1H), 3.77 (m,
8H), 3.67-3.54 (m, 2H), 3.52-3.26 (m, 3H), 3.01-2.78 (m, 3H).
Example 73
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-fluoro-6-pyrimidin-2-ylphenyl)carbony-
l]octahydropyrrolo[3,4-c]pyrrole
##STR00185##
[0409] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 14. MS (ESI)
mass calcd. for C.sub.23H.sub.23FN.sub.6O, 418.47; m/z found, 419.1
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.75-8.65 (m, 2H), 8.10-7.96
(m, 1.2H), 7.40 (dd, J=13.8, 8.0 Hz, 1.2H), 7.24-7.08 (m, 2.7H),
7.08-7.00 (m, 0.8H), 6.22 (s, 1H), 4.00-3.39 (m, 7H), 3.34-3.14 (m,
1H), 3.01 (d, J=6.8 Hz, 2H), 2.23 (s, 6H).
Example 74
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-fluoro-2-pyrimidin-2-ylphenyl)carbony-
l]octahydropyrrolo[3,4-c]pyrrole
##STR00186##
[0410] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 13. MS (ESI)
mass calcd. for C.sub.23H.sub.23FN.sub.6O, 418.47; m/z found, 419.1
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.81 (d, J=4.9 Hz, 2H), 8.36
(dd, J=8.8, 5.6 Hz, 1H), 7.44-7.14 (m, 3H), 6.44 (s, 1H), 6.44 (s,
1H), 3.98-3.75 (m, 2H), 3.76-3.48 (m, 5H), 3.24-2.97 (m, 3H), 2.32
(s, 6H).
Example 75
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00187##
[0411] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 1. MS (ESI):
mass calculated for C.sub.21H.sub.22FN.sub.7O, 407.45, m/z found
408.2 [M+1].sup.+. .sup.1H NMR (CDCl.sub.3) 7.97-7.92 (m, 1H), 7.73
(s, 2H), 7.23-7.06 (m, 2H), 6.30 (s, 1H), 3.90-3.80 (m, Hz, 2H),
3.72-3.55 (m, 5.9 Hz, 4H), 3.53-3.46 (m, Hz, 1H), 3.39 (br s, 1H),
3.08-2.87 (m, 4H), 2.30 (s, 6H).
Example 76
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-ethylphenyl)carbonyl]octahydropyrrolo-
[3,4-c]pyrrole
##STR00188##
[0412] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-ethylbenzoic acid. MS
(ESI) mass calcd. for C.sub.21H.sub.26N.sub.4O, 350.47; m/z found,
351.3 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.34-7.14 (m, 4H),
6.30 (s, 1H), 3.93 (m, 2H), 3.77 (dd, J=11.6, 7.3 Hz, 1H), 3.64 (m,
2H), 3.51-3.41 (m, 2H), 3.16-3.02 (m, 2H), 3.01-2.90 (m, 1H),
2.69-2.57 (m, 2H), 2.29 (s, 6H), 1.20 (t, J=7.6 Hz, 3H).
Example 77
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-ethoxynaphthalen-1-yl)carbonyl]octahy-
dro-pyrrolo[3,4-c]pyrrole
##STR00189##
[0413] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.25H.sub.28N.sub.4O.sub.2, 416.53; m/z found, 417.2
[M+H]+.
Example 78
2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}oct-
ahydro-pyrrolo[3,4-c]pyrrole
##STR00190##
[0414] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 39 and 2-pyrazol-1-yl-benzoic
acid. MS (ESI) mass calcd. for C.sub.22H.sub.24N.sub.6O.sub.3,
420.46; m/z found, 421.1 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3):
7.74 (d, J=2.0 Hz, 1H), 7.59-7.29 (m, 5H), 6.31 (br s, 1H), 5.32
(s, 1H), 3.90-3.64 (m, 7.8H), 3.61-3.41 (m, 2.2H), 3.40-3.05 (m,
3H), 2.95-2.65 (m, 3H).
Example 79
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-phenyl-1,3-oxazol-4-yl)carbonyl]octah-
ydro-pyrrolo[3,4-c]pyrrole
##STR00191##
[0415] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
5-phenyl-oxazole-4-carboxylic acid. MS (ESI) mass calcd. for
C.sub.22H.sub.23N.sub.5O.sub.2, 389.46; m/z found, 390.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.91 (m, 2H), 7.86 (s, 1H),
7.46-7.33 (m, 3H), 6.28 (s, 1H), 4.03-3.83 (m, 3H), 3.74 (m, 2H),
3.64-3.47 (m, 3H), 3.08-2.98 (m, 2H), 2.29 (m, 6H).
Example 80
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-phenylisoxazol-4-yl)carbonyl]octahydr-
o-pyrrolo[3,4-c]pyrrole
##STR00192##
[0416] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
5-phenyl-isoxazole-4-carboxylic acid. MS (ESI) mass calcd. for
C.sub.22H.sub.23N.sub.5O.sub.2, 389.46; m/z found, 390.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.37 (s, 1H), 7.84-7.75 (m,
2H), 7.49-7.36 (m, 3H), 6.30 (s, 1H), 4.00-3.80 (m, 2H), 3.73-3.62
(m, 2H), 3.59-3.42 (m, 2H), 3.36 (dd, J=11.7, 4.5 Hz, 1H),
3.16-2.85 (m, 3H), 2.37-2.22 (s, 6H).
Example 81
[5-(2-isopropyl-6-methyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2--
yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00193##
[0417] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
4-chloro-2-isopropyl-6-methyl-pyrimidine. MS (ESI): mass calculated
for C.sub.23H.sub.27N.sub.7O, 417.51, m/z found 418.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.99 (d, J=8.0 Hz, 1H), 7.73 (s,
2H), 7.59-7.38 (m, 3H), 5.92 (s, 1H), 3.97-2.85 (m, 10H), 2.35 (s,
3H), 1.33-1.21 (m, 6H).
Example 82
2-[(2-Bromophenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo-
[3,4-c]pyrrole
##STR00194##
[0418] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-bromobenzoic acid. MS
(ESI) mass calcd. for C.sub.19H.sub.21BrN.sub.4O, 401.31; m/z
found, 401.1, 403.1 [M+H].sup.+.
Example 83
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbony-
l}octahydropyrrolo[3,4-c]pyrrole
##STR00195##
[0419] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 2. MS (ESI)
mass calcd. for C.sub.21H.sub.23N.sub.7O, 389.46; m/z found, 374.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.98 (d, J=8.1 Hz, 1H), 7.74
(br s, 2H), 7.55-7.48 (m, 1H), 7.42 (d, J=4.1 Hz, 2H), 6.29 (s,
1H), 3.93-3.81 (m, 2H), 3.64 (m, 3H), 3.48 (dd, J=11.6, 4.2 Hz,
1H), 3.36 (br s, 1H), 3.08-2.86 (m, 3H), 2.30 (s, 6H).
Example 84
2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbon-
yl}octahydropyrrolo[3,4-c]pyrrole
##STR00196##
[0420] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
2-chloro-4,6-dimethoxypyrimidine. MS (ESI) mass calcd. for
C.sub.21H.sub.23N.sub.7O.sub.3, 421.46; m/z found, 422.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.05-7.95 (m, 2H), 7.75 (br
s, 1H), 7.57-7.48 (m, 1H), 7.46-7.41 (m, 2H), 5.39 (s, 1H),
3.93-3.79 (m, 5H), 3.76-3.62 (m, 2H), 3.56 (dd, J=11.8, 5.4 Hz,
1H), 3.49-3.33 (m, 2H), 2.96 (s, 3H), 2.89 (s, 3H).
Example 85
2-[5-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl]quinoxaline
##STR00197##
[0421] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and
2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calcd. for
C.sub.23H.sub.21N.sub.7O, 411.47; m/z found, 412.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 8.28 (s, 1H), 8.11 (d, J=8.1 Hz, 1H),
8.01 (br s, 1H), 7.89 (dd, J=8.2, 1.2 Hz, 1H), 7.69 (dd, J=8.4, 1.0
Hz, 1H), 7.59 (ddd, J=8.4, 7.0, 1.4 Hz, 1H), 7.55-7.43 (m, 2H),
7.42-7.33 (m, 2H), 3.89-4.00 (m, 2H), 3.82-3.72 (m, 2H), 3.71-3.64
(m, 1H), 3.55-3.42 (m, 2H), 3.20-2.98 (m, 3H).
Example 86
2-[5-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl]-1,3-benzoxazole
##STR00198##
[0422] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 28 and
2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for
C.sub.22H.sub.20N.sub.6O.sub.2, 400.43; m/z found, 401.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.15-8.02 (m 2H), 7.56-7.40
(m, 2H), 7.347-7.30 (m, 2H), 7.29-7.23 (m, 1H), 7.17 (td, J=7.7,
1.1 Hz, 1H), 7.05-6.98 (m, 1H), 3.98-3.42 (m, 7H), 3.26-2.93 (m,
3H).
Example 87
2-(4-Methylpyrimidin-2-yl)-5-{[2-(4H-1,2,4-triazol-3-yl)phenyl]carbonyl}oc-
tahydro-pyrrolo[3,4-c]pyrrole
##STR00199##
[0423] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 27 and
2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calcd. for
C.sub.20H.sub.21N.sub.7O, 375.55; m/z found, 376.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 8.18-8.04 (m, 3H), 7.55.7.42 (m, 2H),
7.39-7.33 (m, 1H), 6.39 (d, J=5.0 Hz, 1H), 3.96-3.79 (m, 2H),
3.77-3.63 (m, 2H), 3.62-3.55 (m, 1H), 3.46-3.37 (m, 2H), 3.15-3.06
(m, 1H), 3.05-2.98 (m, 1H), 2.95-2.90 (m, 1H), 2.33 (s, 3H).
Example 88
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-ethoxyphenyl)carbonyl]octahydropyrrol-
o[3,4-c]pyrrole
##STR00200##
[0424] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-ethoxybenzoic acid. MS
(ESI) mass calcd. for C.sub.21H.sub.26N.sub.4O.sub.2, 366.46; m/z
found, 367.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.37-7.21 (m,
2H), 7.03-6.91 (m, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.26 (d, J=20.0 Hz,
1H), 4.04 (q, J=7.0 Hz, 2H), 3.95-3.85 (m, 2H), 3.76 (dd, J=11.5,
7.3 Hz, 1H), 3.69-3.59 (m, 2H), 3.57-3.45 (m, 2H), 3.29-3.20 (m,
1H), 3.12-2.89 (m, 2H), 2.29 (s, 6H), 1.33 (t, J=7.0 Hz, 3H).
Example 89
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-fluoro-2-(trifluoromethyl)phenyl]carb-
onyl}octahydropyrrolo[3,4-c]pyrrole
##STR00201##
[0425] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
2-trifluoromethyl-4-fluorobenzoic acid. MS (ESI) mass calcd. for
C.sub.20H.sub.20F.sub.4N.sub.4O, 408.4; m/z found, 409.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.46-7.27 (m, 3H), 6.37-6.25
(m, 1H), 4.01-3.87 (m, 2H), 3.82-3.76 (m 1H), 3.67-3.57 (m, 2H),
3.53-3.38 (m, 2H), 3.14-3.04 (m, 2H), 3.04-2.96 m, 1H), 2.31 (s
6H).
Example 90
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(4-fluoronaphthalen-1-yl)carbonyl]octahy-
dro-pyrrolo[3,4-c]pyrrole
##STR00202##
[0426] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
4-fluoro-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for
C.sub.23H.sub.23FN.sub.4O, 390.45; m/z found, 391.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 8.16-8.10 (m 1H), 7.92-7.82 (m, 1H),
7.63-7.53 (m, 2H), 7.403-7.36 (m, 1H), 7.14 (dd, J=10.2, 7.8 Hz,
1H), 6.31 (s, 1H), 4.14-4.06 (m, 1H), 3.95-3.89 (m, 1H), 3.84-3.63
(m, 3H), 3.50-3.37 (m, 2H), 3.17-3.08 (m, 2H), 2.98-2.90 (m, 1H),
2.30 (s, 6H).
Example 91
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methylethyl)phenyl]carbonyl}octahy-
dro-pyrrolo[3,4-c]pyrrole
##STR00203##
[0428] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-isopropyl-benzoic acid.
MS (ESI) mass calcd. for C.sub.22H.sub.28N.sub.4O, 364.48; m/z
found, 365.3 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.37-7.30 (m,
2H), 7.23-7.10 (m, 2H), 6.30 (s, 1H), 4.00-3.86 (m, 2H), 3.79-3.73
(m, 1H), 3.71-3.58 (m, 2H), 3.51-3.40 (m, 2H), 3.19-2.89 (m, 4H),
2.30 (s, 6H), 1.29-1.17 (m, 6H).
Example 92
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-methoxy-2-methylphenyl)carbonyl]octah-
ydro-pyrrolo[3,4-c]pyrrole
##STR00204##
[0429] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 3-methoxy-2-methyl-benzoic
acid. MS (ESI) mass calcd. for C.sub.21H.sub.26N.sub.4O.sub.2,
366.47; m/z found, 367.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3):
7.19 (dd, J=14.3, 6.5 Hz, 1H), 6.81 (dd, J=14.3, 7.8 Hz, 2H), 6.30
(s, 1H), 4.01-3.85 (m, 2H), 3.83 (s, 3H), 3.77 (dd, J=11.6, 7.3 Hz,
1H), 3.69-3.58 (m, 2H), 3.50-3.39 (m, 2H), 3.15-3.00 (m, 2H),
3.00-2.90 (m, 1H), 2.30 (s, 6H), 2.14 (s, 3H).
Example 93
2-(4,6-Dimethylpyrimidin-2-yl)-5-(naphthalen-1-ylcarbonyl)octahydropyrrolo-
[3,4-c]pyrrole
##STR00205##
[0431] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and naphthalene-1-carboxylic
acid. MS (ESI) mass calcd. for C.sub.23H.sub.24N.sub.4O, 372.46;
m/z found, 373.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.91-7.79
(m, 3H), 7.54-7.40 (m, 4H), 6.30 (s, 1H), 4.11 (dd, J=12.8, 7.9 Hz,
1H), 3.92 (dd, J=11.6, 7.6 Hz, 1H), 3.80 (dd, J=12.8, 4.9 Hz, 1H),
3.75-3.64 (m, 2H), 3.49-3.36 (m, 2H), 3.17-3.06 (m, 2H), 2.97-2.87
(m, 1H), 2.31 (s, 6H).
Example 94
2-[5-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl]-3-(trifluoromethyl)quinoxaline
##STR00206##
[0432] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 30 and
2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for
C.sub.24H.sub.20F.sub.4N.sub.7O, 479.47; m/z found, 480.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.12-7.93 (m, 3H), 7.77 (dd,
J=8.5, 0.9 Hz, 1H), 7.69 (ddd, J=8.4, 6.8, 1.4 Hz, 1H), 7.52-7.41
(m, 3H), 7.38-7.34 (m, 1H), 4.01-3.79 (m, 3H), 3.78-3.66 (m, 2H),
3.49 (dd, J=23.0, 15.0 Hz, 2H), 3.16-2.88 (m, 3H).
Example 95
2-Methyl-3-[5-{[2-(4H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]quinoxaline
##STR00207##
[0433] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 29 and
2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for
C.sub.24H.sub.23N.sub.7O, 425.49; m/z found, 426.3 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 8.13 (d, J=7.3 Hz, 1H), 8.01 (s, 1H),
7.83 (dd, J=8.2, 1.1 Hz, 1H), 7.72 (dd, J=8.3, 1.0 Hz, 1H),
7.59-7.35 (m, 5H), 4.00-3.65 (m, 5H), 3.47 (s, 2H), 3.22-2.89 (m,
3H), 2.70 (s, 3H).
Example 96
2-[6-Methyl-2-(trifluoromethyl)pyrimidin-4-yl]-5-{[2-(4H-1,2,4-triazol-3-y-
l)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00208##
[0434] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 31 and
2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for
C.sub.21H.sub.20F.sub.3N.sub.7O, 443.43; m/z found, 444.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.11-7.99 (m, 2H), 7.55-7.42
(m, 2H), 7.37-7.29 (m, 1H), 6.17 (br s, 1H), 3.92-3.39 (m, 7H),
3.15-2.90 (m 3H), 2.42 (s, 3H).
Example 97
2-[6-Methyl-2-(trifluoromethyl)pyrimidin-4-yl]-5-{[2-(2H-1,2,3-triazol-2-y-
l)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00209##
[0435] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 31 and Intermediate 2. MS (ESI)
mass calcd. for C.sub.21H.sub.20F.sub.3N.sub.7O, 443.43; m/z found,
444.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.99 (d, J=8.0 Hz,
1H), 7.74 (s, 2H), 7.58-7.49 (m, 1H), 7.48-7.38 (m, 2H), 6.22 (br
s, 1H), 4.05-3.33 (m, 7H), 3.24-2.91 (m, 3H), 2.45 (s, 3H).
Example 98
2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[6-methyl-2-(trif-
luoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00210##
[0436] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 31 and Intermediate 12. MS (ESI)
mass calcd. for C.sub.21H.sub.19F.sub.4N.sub.7O, 461.42; m/z found,
462.1 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.91-7.78 (m, 2H),
7.72 (s, 1H), 7.54-7.43 (m, 1H), 7.20-7.10 (m, 1H), 6.30-6.20 (br
m, 1H), 4.07-3.52 (m, 6H), 3.42-3.02 (m, 4H), 2.47 (d, J=19.9 Hz,
3H).
Example 99
2-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[6-methyl-2-(trif-
luoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00211##
[0437] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 31 and Intermediate 4. MS (ESI)
mass calcd. for C.sub.21H.sub.19F.sub.4N.sub.7O, 461.42; m/z found,
462.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.76 (br s, 3H),
7.47-7.36 (m, 1H), 7.19-7.09 (m, 1H), 6.22 (br s, 1H), 4.05-3.32
(m, 7H), 2.98 (dd, J=40.7, 34.8 Hz, 3H), 2.44 (s, 3H).
Example 100
2-(6-Methylpyrazin-2-yl)-5-{[5-methyl-2-(2H-1,2,3-triazol-2
yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00212##
[0438] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 8 and 2-chloro-6-methyl-pyrazine.
MS (ESI): mass calculated for C.sub.21H.sub.23N.sub.7O, 389.46; m/z
found 390.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.87-7.81 (m, 1H), 7.75-7.53 (m, 4H), 7.35-7.29 (m, 1H), 7.24-7.18
(m, 1H), 3.94-3.83 (m, 1H), 3.80-3.66 (m, 2H), 3.64-3.54 (m, 1H),
3.50-3.30 (m, 3H), 3.12-2.90 (m, 3H), 2.41 (s, 2H), 2.38 (s,
3H).
Example 101
2-(3,6-Dimethylpyrazin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]-
carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00213##
[0439] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 34 and Intermediate 12. MS (ESI):
mass calculated for C.sub.21H.sub.22FN.sub.7O, 407.45; m/z found
408.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.90-7.80 (m,
2H), 7.78-7.71 (m, 2H), 7.54-7.44 (m, 1H), 7.20-7.12 (m, 1H),
3.97-3.90 (m, 1H), 3.86-3.40 (m, 6H), 3.32-3.22 (m, 1H), 3.13-2.91
(m, 2H), 2.55-2.49 (m, 3H), 2.39-2.33 (m, 3H).
Example 102
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-methyl-2-pyrimidin-2-ylphenyl)carbony-
l]octahydropyrrolo[3,4-c]pyrrole
##STR00214##
[0441] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated
for C.sub.24H.sub.26N.sub.6O, 414.51; m/z found 415.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.74 (d, J=4.9, 2H), 8.20 (d,
J=8.1, 1 H), 7.34-7.28 (m, 1H), 7.17-7.15 (m, 1H), 7.10-7.03 (m,
1H), 6.29 (s, 1H), 3.95-3.79 (m, 2H), 3.76-3.61 (m, 3H), 3.59-3.40
(m, 2H), 3.18-3.10 (m, 1H), 3.09-2.87 (m, 2H), 2.41 (s, 3H), 2.30
(s, 6H).
Example 103
2-(3,6-Dimethylpyrazin-2-yl)-5-[(5-methyl-2-pyrimidin-2-ylphenyl)carbonyl]-
octahydropyrrolo[3,4-c]pyrrole
##STR00215##
[0442] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 34 and
5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated
for C.sub.24H.sub.26N.sub.6O, 414.51; m/z found 415.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.77 (d, J=4.9, 2H), 8.22 (d,
J=8.1, 1 H), 7.73 (s, 1H), 7.34-7.29 (m, 1H), 7.21-7.16 (m, 1H),
7.11 (t, J=4.8, 1 H), 3.96-3.89 (m, 1H), 3.86-3.79 (m, 1H),
3.74-3.61 (m, 2H), 3.57-3.51 (m, 1H), 3.49-3.38 (m, 2H), 3.18-3.12
(m, 1H), 3.08-2.98 (m, 1H), 2.96-2.86 (m, 1H), 2.50 (s, 3H), 2.42
(s, 3H), 2.36 (s, 3H).
Example 104
2-(3,6-Dimethylpyrazin-2-yl)-5-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]-
carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00216##
[0443] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 34 and Intermediate 4. MS (ESI):
mass calculated for C.sub.21H.sub.22FN.sub.7O, 407.45; m/z found
408.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.83-7.72 (m,
4H), 7.42 (dd, J=8.5, 5.8, 1 H), 7.14 (ddd, J=8.5, 7.8, 2.5, 1 H),
3.94-3.86 (m, 1H), 3.82-3.74 (m, 1H), 3.73-3.60 (m, 2H), 3.56-3.47
(m, 1H), 3.42-3.31 (m, 2H), 3.10-2.82 (m, 3H), 2.50 (s, 3H), 2.36
(s, 3H).
Example 105
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-iodo-2-(2H-1,2,3-triazol-2-yl)phenyl]-
carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00217##
[0444] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 12. MS (ESI):
mass calculated for C.sub.21H.sub.22IN.sub.7O, 515.36; m/z found
516.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.87-7.80 (m,
1H), 7.79-7.67 (m, 4H), 6.30 (s, 1H), 3.94-3.82 (m, 2H), 3.74-3.56
(m, 3H), 3.53-3.30 (m, 2H), 3.13-2.85 (m, 3H), 2.29 (s, 6H).
Example 106
4-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine
##STR00218##
[0445] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 36 and Intermediate 12. MS (ESI):
mass calculated for C.sub.22H.sub.22F.sub.4N8O, 490.47; m/z found
491.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.89-7.64 (m,
3H), 7.56-7.44 (m, 1H), 7.19-7.10 (m, 1H), 6.01-5.74 (m, 1H),
4.10-2.86 (m, 16H).
Example 107
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-f-
luoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00219##
[0446] Method A:
[0447]
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-y-
l]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone. To a
3-necked, 3 L, round-bottomed flask equipped with a nitrogen line,
temperature probe, heating mantle, reflux condenser, mechanical
stirrer, and 1 N aq. NaOH scrubber were added
2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 12,
120.98 g, 75 wt %, 90.74 g actual, 438 mmol) and toluene (1 L). The
mixture was warmed to 50.degree. C. for 1 h with stirring. The
mixture was then cooled to 25.degree. C. and thionyl chloride (47.9
mL, 657 mmol) was added. The mixture was warmed back to 50.degree.
C. and held for 1 h. During this time, in a separate 5 L jacketed
reactor equipped with a mechanical stirrer and temperature probe
were added toluene (600 mL), aqueous sodium carbonate (185.7 g,
1.75 mol in 1.6 L water), and
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
HOAc (Intermediate 23, 122 g, 438 mmol). This biphasic mixture was
cooled to 0.degree. C. After cooling to 0.degree. C., the original
slurry was poured through a filter and over the stirring biphasic
mixture of amine and aqueous sodium carbonate. The mixture was
allowed to warm to room temperature. After 2 h, additional
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.cndot.HOA-
c (4 g, 14 mmol) was added and the mixture was stirred for 30
additional minutes. At the end of this period, the layers were
separated and 100 mL of methanol were added to the organic layer.
The organic layer was dried over MgSO.sub.4, filtered, and
concentrated to a white solid. This solid was taken up in ethanol
(1.4 L) and warmed to 77.degree. C. The mixture was then cooled to
55.degree. C. and seeded with previously crystallized material.
(Note: The seeds were generated from slurrying the initial product
in 2-propanol at room temperature [100 mg/mL]). The mixture was
cooled to room temperature at a rate of 5.degree. C. per hour.
After stirring at room temperature for 14 h, the mixture was
filtered and dried to provide the final product as a white
crystalline solid (136.84 g, 74%). .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.88-7.78 (m, 1.78H), 7.75-7.69 (s, 1.22H), 7.51-7.43
(m, 1H), 7.17-7.11 (m, 1H), 6.30-6.28 (m, 1H), 4.03-3.48 (m, 7H),
3.29-3.21 (m, 1H), 3.15-2.92 (m, 2H), 2.30 (s, 6H). MS (ESI) mass
calcd for C.sub.21H.sub.22FN.sub.7O, 407.19; m/z found, 408
[M+H].sup.+. Anal. calcd. for C.sub.21H.sub.22FN.sub.7O C, 61.90;
H, 5.44; N, 24.06. found C, 61.83; H, 5.42; N, 24.08.
Method B:
[0448] Step A: A one-piece EasyMax reactor was equipped with a
mechanical stirred, a temperature probe, a reflux condenser and an
NaOH scrubber. To the reactor was added 2-fluoro-6-triazol-2-yl
benzoic acid (15.01 g, 72.5 mmol) and toluene (150.0 g), N, N
dimethylformamide (0.06 g, 0.26 mmol) was then added, the reaction
was held at 20.degree. C. prior to the addition of thionyl chloride
(11.31 g, 94.1 mmol) via syringe pump. The reaction mixture was
then heated to 50.degree. C. over 15 minutes and then was stirred
at that temperature for 1.5 hours. The mixture was then heated to
55.degree. C. and 20.4 g of solvent were distilled in vacuo to give
139.4 g of acid chloride solution which was used as is in Step C
below.
[0449] Step B. In a 500 mL jacketed reactor equipped with a
mechanical stirrer, thermometer and reflux condenser was charged
with 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole,
bis-HCl salt (21.01 g, 72.1 mmol) and toluene (60.1 g) and the
slurry was stirred at 0.degree. C. Sodium carbonate (30.6 g, 288.7
mmol) was then separately dissolved in water (151.5 g) and then
added to the slurry over 15 minutes to give the crude amine
solution which was used directly in Step C.
[0450] Step C. To the crude amine solution from Step B in a 500 mL
reactor held at 0.degree. C. was added the crude acid chloride
solution from Step 1 and the reaction was held at 0.degree. C. for
another 15 minutes, then heated to 30.degree. C. over 30 minutes.
During this time the product started to precipitate and the aqueous
layer formed a slurry. The reaction was then cooled to 20.degree.
C. over 30 minutes and stirred at this temperature overnight. The
mixture was then heated to 75.degree. C. over 40 minutes and
stirred for 35 minutes. Stirring was then stopped and after 30
minutes the aqueous layer was removed. To the organic layer was
then added water (90.0 g) and the mixture was stirred for 20
minutes at 75.degree. C., then the stirrer was again stopped. After
10 minutes the aqueous layer was removed. To the remaining organic
layer was added water (90.0 g) and the mixture was again stirred at
75.degree. C. for 15 minutes, before the stirrer was again stopped,
and after 10 minutes the aqueous layer was again removed.
Distillation of the remaining toluene solution was then performed
(at 75.degree. C., 350 mbar) to remove 70 mL of solvent. The
remaining solution was then cooled to 50.degree. C., and stirred
for 20 minutes prior to the addition of Example 107 (0.04 g, seed
crystals to start the crystallization). The reaction was then
stirred at 50.degree. C. for 1.5 hour, then the thin suspension was
cooled to 30.degree. C. over 1 hour then cooled to 0.degree. C.
over 1 hour. After 90 minutes the product was isolated by suction
filtration, the filter cake was washed with cyclohexane (75 g),
then washed with water (85.0 g) and the wet product cake was dried
in vacuo at 55.degree. C. overnight to give the title compound
(25.21 g, 83%), Purity was assessed by HPLC (99.3%, 99.6%, and 99.3
area % (at 254, 235, and 280 nm, respectively).
[0451] Step D: The product of Step C (20.0 g, 48.9 mmol) was added
to a one-piece EasyMax reactor and activated charcoal (Norit CN1,
2.00 g), ethanol (120.0 g) and 2-propanol (20.0 g) were then added.
The mixture was heated to 85.degree. C. over 30 minutes, then
stirred for 45 minutes, then cooled to 75.degree. C. over 15
minutes. The mixture was then filtered via a glass fiber filter,
the filter was washed with 2-propanol (20.0 g) that was previously
heated to 70.degree. C., The filtrates were then placed into a 500
mL jacketed reactor equipped with a mechanical stirrer, reflux
condenser and thermometer and heated to 85.degree. C., stirred for
5 minutes, cooled to 55.degree. C. over 20 minutes and after 10
minutes at 55.degree. C. a suspension of Example 107 (0.02 g) in
2-propanol (0.20 g) was added. The resulting thin suspension was
stirred at 55.degree. C. for 1 hour, then was cooled to 45 over 1
hour and stirred for 30 minutes before it was cooled to 0.degree.
C. over 3 hours and was stirred at that temperature overnight.
After 13 hours, the product was isolated by suction filtration, the
filter cake was washed via the reactor with 2-propanol (40.0 g, at
10.degree. C.) to provide the wet product cake which was dried in
vacuo at 60.degree. C. overnight to give the title compound (18.18
g, 91.3%) as a white to off-white crystalline solid. Purity was
assessed by HPLC (99.7%, 99.8%, and 99.6 area % (at 254, 235, and
280 nm, respectively). Assays for residual solvents showed the
following: ethanol 1089 ppm, 2-propanol 348 ppm, toluene 202 ppm,
cyclohexane<20 ppm.
Example 108
N,N-Dimethyl-4-{5-[(5-methyl-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrr-
olo[3,4-c]pyrrol-2(1H)-yl}-6-(trifluoromethyl)pyrimidin-2-amine
##STR00220##
[0452] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 36 and
5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated
for C.sub.25H.sub.26F.sub.3N.sub.7O, 497.53; m/z found 498.0
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.67 (dd, J=20.0,
4.9, 2H), 8.20 (d, J=10.1, 1 H), 7.34-7.30 (m, 1H), 7.19-7.15 (m,
1H), 7.13-7.03 (m, 1H), 5.85 (br s, 1H), 3.98-2.83 (m, 16H), 2.42
(s, 3H).
Example 109
4-{5-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl}-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine
##STR00221##
[0453] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 36 and Intermediate 13. MS (ESI):
mass calculated for C.sub.24H.sub.23F.sub.4N.sub.7O, 501.49; m/z
found 502.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.70
(d, J=4.9, 2H), 8.38-8.31 (m, 1H), 7.24-7.17 (m, 1H), 7.14-7.02 (m,
2H), 5.86 (br s, 1H), 4.06-2.78 (m, 16H).
Example 110
4-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine
##STR00222##
[0454] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 36 and Intermediate 1. MS (ESI):
mass calculated for C.sub.22H.sub.22F.sub.4N.sub.8O, 490.46; m/z
found 490.9 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.00-7.92 (m, 1H), 7.78-7.64 (m, 2H), 7.26-7.20 (m, 1H), 7.17-7.11
(m, 1H), 5.87 (br s, 1H), 3.96-2.87 (m, 16H).
Example 111
[5-(2-Dimethylamino-6-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,-
4-c]pyrrol-2-yl]-(4-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00223##
[0455] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 36 and Intermediate 4. MS (ESI):
mass calculated for C.sub.22H.sub.22F.sub.4N.sub.8O, 490.46; m/z
found 490.9 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.84-7.64 (m, 3H), 7.45-7.36 (m, 1H), 7.20-7.07 (m, 1H), 5.87 (br
s, 1H), 4.04-2.79 (m, 16H).
Example 112
2-[(5-Methyl-2-pyrimidin-2-ylphenyl)carbonyl]-5-[6-methyl-2-(trifluorometh-
yl) pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00224##
[0456] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 31 and
5-methyl-2-pyrimidin-2-yl-benzoic acid. MS (ESI): mass calculated
for C.sub.24H.sub.23F.sub.3N.sub.6O, 468.48; m/z found 469.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.80-8.68 (m, 2H),
8.27-8.13 (m, 1H), 7.35-7.29 (m, 1H), 7.20-7.03 (m, 2H), 6.31-6.04
(m, 1H), 4.15-2.80 (m, 10H), 2.56-2.30 (m, 6H).
Example 113
2-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)oc-
tahydropyrrolo[3,4-c]pyrrole
##STR00225##
[0457] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and Intermediate 13. MS (ESI):
mass calculated for C.sub.27H.sub.23FN.sub.6O, 466.52; m/z found
467.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.72-8.66 (m,
2H), 8.44-8.29 (m, 2H), 8.16-8.02 (m, 2H), 7.53-7.45 (m, 3H),
7.21-7.14 (m, 1H), 7.10-7.06 (m, 1H), 7.01-6.98 (m, 1H), 6.87 (br
s, 1H), 4.05-3.50 (m, 7H), 3.31-2.98 (m, 3H).
Example 114
2-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[6-methyl-2-(trif-
luoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00226##
[0458] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 21 and
4-chloro-6-methyl-2-trifluoromethyl-pyrimidine. MS (ESI): mass
calculated for C.sub.21H.sub.19F.sub.4N.sub.7O, 461.42; m/z found
462.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.04-7.87 (m,
1H), 7.81-7.63 (m, 1H), 7.29-7.18 (m, 1H), 7.17-7.08 (m, 1H),
6.31-6.03 (m, 1H), 4.13-2.84 (m, 10H), 2.44 (s, 3H).
Example 115
[5-(2,6-Dimethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-f-
luoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00227##
[0459] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 21 and
4-chloro-2,6-dimethyl-pyrimidine. MS (ESI): mass calculated for
C.sub.21H.sub.22FN.sub.7O, 407.45, m/z found 408.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3) 7.97 (dd, J=9.0, 4.8 Hz, 1H), 7.73 (s,
2H), 7.25-7.19 (m, 1H), 7.16-7.10 (m, 1H), 5.94 (s, 1H), 3.95-2.88
(m, 10H), 2.50 (s, 3H), 2.34 (s, 3H).
Example 116
4-{5-[(2-Fluoro-6-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl}-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine
##STR00228##
[0460] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 36 and Intermediate 14. MS (ESI):
mass calculated for C.sub.24H.sub.23F.sub.4N.sub.7O, 501.49; m/z
found 502.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.86-8.63 (m, 2H), 8.22-8.05 (m, 1H), 7.56-7.40 (m, 1H), 7.29-7.18
(m, 1H), 7.12 (br s, 1H), 6.03-5.73 (m, 1H), 4.19-2.90 (m,
16H).
Example 117
2-[(2-Fluoro-6-pyrimidin-2-ylphenyl)carbonyl]-5-[6-methyl-2-(trifluorometh-
yl) pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00229##
[0461] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 31 and Intermediate 14. MS (ESI):
mass calculated for C.sub.23H.sub.20F.sub.4N.sub.6O, 472.45; m/z
found 473.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.81-8.72 (m, 2H), 8.21-8.01 (m, 1H), 7.54-7.42 (m, 1H), 7.27-7.20
(m, 1H), 7.18-7.10 (m, 1H), 6.36-6.04 (m, 1H), 4.19-2.93 (m, 10H),
2.60-2.29 (m, 3H).
Example 118
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00230##
[0462] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 1. MS (ESI):
mass calculated for C.sub.21H.sub.22FN.sub.7O, 408.45; m/z found
408.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.81-7.69 (m,
3H), 7.43-7.36 (m, 1H), 7.16-7.08 (m, 1H), 6.30 (s, 1H), 3.93-3.81
(m, 2H), 3.75-3.56 (m, 3H), 3.52-3.30 (m, 2H), 3.10-2.87 (m, 3H),
2.30 (s, 6H).
Example 119
N,N,6-Tri
methyl-2-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydro
pyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidin-4-amine
##STR00231##
[0463] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
(2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine. MS (ESI): mass
calculated for C.sub.22H.sub.26N.sub.8O, 418.50; m/z found 419.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.02-7.94 (m, 1H),
7.75 (s, 2H), 7.56-7.46 (m, 1H), 7.44-7.36 (m, 2H), 5.69 (s, 1H),
3.92-3.81 (m, 2H), 3.76-3.62 (m, 2H), 3.60-3.52 (m, 1H), 3.50-3.42
(m, 1H), 3.40-3.29 (m, 1H), 3.04 (s, 6H), 3.01-2.80 (m, 3H), 2.24
(s, 3H).
Example 120
N,N,4-Trimethyl-6-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydro
pyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidin-2-amine
##STR00232##
[0464] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
(4-chloro-6-methyl-pyrimidin-2-yl)-dimethyl-amine. MS (ESI): mass
calculated for C.sub.22H.sub.26N.sub.8O, 418.50; m/z found 419.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.01-7.95 (m, 1H),
7.80-7.65 (m, 2H), 7.57-7.48 (m, 1H), 7.45-7.35 (m, 2H), 5.51-5.39
(m, 1H), 3.91-2.85 (m, 19H).
Example 121
N,N-Dimethyl-4-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrr-
olo[3,4-c]pyrrol-2(1H)-yl]-6-(trifluoromethyl)pyrimidin-2-amine
##STR00233##
[0465] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
(4-chloro-6-trifluoromethyl-pyrimidin-2-yl)-15 dimethyl-amine. MS
(ESI): mass calculated for C.sub.22H.sub.23F.sub.3N.sub.8O, 472.47;
m/z found 473.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3:
8.02-7.95 (m, 1H), 7.73 (s, 2H), 7.57-7.50 (m, 1H), 7.46-7.39 (m,
2H), 5.97-5.75 (m, 1H), 3.99-2.80 (m, 16H).
Example 122
2-(2,6-Dimethylpyrimidin-4-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbony-
l}octahydropyrrolo[3,4-c]pyrrole
##STR00234##
[0466] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
4-chloro-2,6-dimethyl-pyrimidine. MS (ESI): mass calculated for
C.sub.21H.sub.23N.sub.7O, 408.45; m/z found 389.46 [M+H].sup.+; m/z
found 390.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.01-7.95 (m, 1H), 7.74 (s, 2H), 7.56-7.37 (m, 3H), 6.01-5.85 (m,
1H), 3.99-2.86 (m, 10H), 2.50 (s, 3H), 2.34 (s, 3H).
Example 123
[5-(3,6-Dimethyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-met-
hyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00235##
[0468] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 19 and
3-chloro-2,5-dimethyl-pyrazine. MS (ESI): mass calculated for
C.sub.22H.sub.25N.sub.7O, 413.49, m/z found 404.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3) 7.85 (d, J=8.3 Hz, 1H), 7.78-7.70 (m, 3H),
7.35-7.29 (m, 1H), 7.25-7.21 (m, 1H), 3.92-3.85 (m, 1H), 3.80-3.72
(m, 1H), 3.70-3.59 (m, 2H), 3.53-3.47 (m, 1H), 3.45-3.23 (m, 1H),
3.04-2.78 (m, 4H), 2.50 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H).
Example 124
2-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-N,N,6-trimethylpyrimidin-4-amine
##STR00236##
[0469] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 21 and
(2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine. MS (ESI): mass
calculated for C.sub.22H.sub.25FN.sub.8O, 435.49; m/z found 437.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.99-7.93 (m, 1H),
7.73 (s, 2H), 7.23-7.18 (m, 1H), 7.15-7.12 (m, 1H), 5.69 (s, 1H),
3.88-3.80 (m, 2H), 3.71-3.62 (m, 2H), 3.59-3.52 (m, 1H), 3.49-3.32
(m, 2H), 3.15-2.83 (m, 9H), 2.24 (s, 3H).
Example 125
2-(5-Methoxypyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrr-
olo[3,4-c]pyrrole
##STR00237##
[0470] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-5-methoxy-pyridine. MS (ESI): mass calculated for
C.sub.23H.sub.23N.sub.3O.sub.2S, 405.52; m/z found 406.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88 (d, J=2.7, 1
H), 7.54-7.47 (m, 1H), 7.45-7.31 (m, 4H), 7.25-7.19 (m, 1H),
7.18-7.12 (m, 1H), 7.06-6.88 (m, 1H), 6.30-6.13 (m, 1H), 3.94-2.47
(m, 13H).
Example 126
2-[(2-Ethoxynaphthalen-1-yl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydro
pyrrolo[3,4-c]pyrrole
##STR00238##
[0471] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and
2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI): mass calculated
for C.sub.29H.sub.28N.sub.4O.sub.2, 464.57; m/z found 465.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.42-8.33 (m, 1H),
8.14-7.98 (m, 2H), 7.89-7.61 (m, 3H), 7.53-7.43 (m, 3H), 7.41-7.18
(m, 3H), 7.01-6.95 (m, 1H), 4.31-2.91 (m, 12H), 1.49-1.23 (m,
3H).
Example 127
2-{[5-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-phenylpyrimidi-
n-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00239##
[0472] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 19 and
2-chloro-4-phenyl-pyrimidine. MS (ESI): mass calculated for
C.sub.26H.sub.25N.sub.7O, 451.53; m/z found 452.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.43-8.32 (m, 1H), 8.15-7.99 (m,
2H), 7.88-7.80 (m, 1H), 7.78-7.57 (m, 2H), 7.55-7.39 (m, 3H),
7.34-7.28 (m, 1H), 7.25-7.21 (m, 1H), 7.01-6.96 (m, 1H), 4.09-2.87
(m, 10H), 2.41 (s, 3H).
Example 128
(4-Chloro-2-[1,2,3]triazol-2-yl-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-h-
exahydro-pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00240##
[0473] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 6 and
2-chloro-4,6-dimethylpyrimidine. MS (ESI): mass calculated for
C.sub.21H.sub.22ClN.sub.7O, 423.91; m/z found 424.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.03 (t, J=10.1 Hz, 1H), 7.76
(s, 2H), 7.41-7.29 (m, 2H), 6.30 (s, 1H), 3.92-3.79 (m, 2H),
3.74-3.58 (m, 3H), 3.53-3.29 (m, 2H), 3.10-2.86 (m, 3H), 2.30 (s,
6H).
Example 129
2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00241##
[0474] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 19 and
2-chloro-4,6-dimethoxypyrimidine. MS (ESI): mass calculated for
C.sub.22H.sub.25N.sub.7O.sub.3, 435.49; m/z found 436.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.85 (d, J=8.3, 1
H), 7.72 (s, 2H), 7.34-7.29 (m, 1H), 7.24-7.21 (m, 1H), 5.39 (s,
1H), 3.99-3.60 (m, 10H), 3.57-3.27 (m, 3H), 3.08-2.82 (m, 3H), 2.41
(s, 3H).
Example 130
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00242##
[0476] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 19 and
2-chloro-4,6-dimethylpyrimidine. MS (ESI): mass calculated for
C.sub.22H.sub.25N.sub.7O, 403.49; m/z found 404.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.84 (d, J=8.3, 1 H), 7.72 (br
s, 2H), 7.33-7.29 (m, 1H), 7.23-7.20 (m, 1H), 6.29 (s, 1H),
3.91-3.80 (m, 2H), 3.73-3.54 (m, 3H), 3.50-3.24 (m, 2H), 3.07-2.81
(m, 3H), 2.40 (s, 3H), 2.29 (s, 6H).
Example 131
2-(4-Phenylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}oc-
tahydro pyrrolo[3,4-c]pyrrole
##STR00243##
[0477] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and Intermediate 2. MS (ESI):
mass calculated for C.sub.25H.sub.23N.sub.7O, 437.50; m/z found
438.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.46-8.31 (m,
1H), 8.21-7.91 (m, 3H), 7.82-7.59 (m, 2H), 7.58-7.39 (m, 6H),
7.01-6.97 (m, 1H), 4.04-3.31 (m, 7H), 3.17-2.86 (m, 3H).
Example 132
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-(2-fluorophenyl)-2-methyl-1,3-thiazol-
-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00244##
[0479] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 18 and
2-chloro-4,6-dimethylpyrimidine. MS (ESI): mass calculated for
C.sub.23H.sub.24FN.sub.5OS, 437.54; m/z found 438.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.50-7.44 (m, 1H), 7.32-7.23 (m,
1H), 7.16-7.04 (m, 2H), 6.29 (s, 1H), 3.93-3.80 (m, 2H), 3.76-3.67
(m, 2H), 3.61-3.54 (m, 1H), 3.51-3.37 (m, 2H), 3.29-3.22 (m, 1H),
3.03-2.87 (m, 2H), 2.73 (s, 3H), 2.30 (s, 6H).
Example 133
2-[(2-Thiophen-2-ylphenyl)carbonyl]-5-[6-(trifluoromethyl)pyridin-2-yl]oct-
ahydro pyrrolo[3,4-c]pyrrole
##STR00245##
[0480] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-6-trifluoromethyl-pyridine. MS (ESI): mass calculated for
C.sub.23H.sub.20F.sub.3N.sub.3OS, 443.49; m/z found 444.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.62-7.33 (m, 5H),
7.29-7.05 (m, 2H), 7.04-6.80 (m, 2H), 6.37 (s, 1H), 4.01-2.47 (m,
10H).
Example 134
2-(6-Methylpyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrro-
lo[3,4-c]pyrrole
##STR00246##
[0481] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-6-methyl-pyridine. MS (ESI): mass calculated for
C.sub.23H.sub.23N.sub.3OS, 389.52; m/z found 390.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.56-7.47 (m, 1H), 7.45-7.10 (m,
6H), 7.07-6.91 (m, 1H), 6.43 (d, J=7.2, 1 H), 6.04 (s, 1H),
3.96-2.57 (m, 10H), 2.38 (s, 3H).
Example 135
2-(4-Methylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}oc-
tahydro pyrrolo[3,4-c]pyrrole
##STR00247##
[0482] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
2-chloro-4-methyl-pyrimidine. MS (ESI): mass calculated for
C.sub.20H.sub.21N.sub.7O, 375.43; m/z found 376.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.17 (d, J=5.0, 1H), 7.98 (d,
J=8.1, 1H), 7.75 (s, 2H), 7.56-7.48 (m, 1H), 7.44-7.40 (m, 2H),
6.40 (d, J=5.0, 1 H), 3.94-3.81 (m, 2H), 3.75-3.54 (m, 3H),
3.52-3.31 (m, 2H), 3.10-2.88 (m, 3H), 2.35 (s, 3H).
Example 136
2-(4-Methylpyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrro-
lo[3,4-c]pyrrole
##STR00248##
[0483] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4-methyl-pyridine. MS (ESI): mass calculated for
C.sub.23H.sub.23N.sub.3OS, 389.52; m/z found 390.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.00 (d, J=5.2, 1 H), 7.56-7.47
(m, 1H), 7.45-7.31 (m, 3H), 7.25-7.11 (m, 2H), 7.09-6.90 (m, 1H),
6.42 (d, J=5.2, 1 H), 6.06 (br s, 1H), 3.98-2.59 (m, 10H), 2.27 (s,
3H).
Example 137
2-(6-Methoxypyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro
pyrrolo[3,4-c]pyrrole
##STR00249##
[0484] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-6-methoxy-pyridine. MS (ESI): mass calculated for
C.sub.23H.sub.23N.sub.3O.sub.2S, 405.52; m/z found 406.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.56-7.47 (m, 1H),
7.46-7.30 (m, 4H), 7.25-7.12 (m, 2H), 7.09-6.90 (m, 1H), 6.01 (d,
J=7.6, 1 H), 5.77 (br s, 1H), 3.85 (s, 3H), 3.71-2.59 (m, 10H).
Example 138
2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahyd-
ro pyrrolo[3,4-c]pyrrole
##STR00250##
[0485] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-4,6-dimethoxy-pyridine. MS (ESI): mass calculated for
C.sub.23H.sub.24N.sub.4O.sub.3S, 436.54; m/z found 437.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.52 (d, J=7.5, 1
H), 7.45-7.33 (m, 3H), 7.30-7.15 (m, 2H), 7.00 (br s, 1H), 5.38 (s,
1H), 3.97-2.60 (m, 16H).
Example 139
2-{5-[(2-Thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)--
yl}-1,3-benzoxazole
##STR00251##
[0487] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and 2-chloro-benzooxazole. MS
(ESI): mass calculated for C.sub.24H.sub.21N.sub.3O.sub.2S, 415.52;
m/z found 416.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.83-6.68 (m, 11H), 4.20-2.47 (m, 10H).
Example 140
2-[(2-Thiophen-2-ylphenyl)carbonyl]-5-[3-(trifluoromethyl)pyridin-2-yl]oct-
ahydro pyrrolo[3,4-c]pyrrole
##STR00252##
[0488] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 37 and
2-chloro-3-trifluoromethyl-pyridine. MS (ESI): mass calculated for
C.sub.23H.sub.20F.sub.3N.sub.3OS, 443.49; m/z found 444.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.28 (dd, J=4.7,
1.4, 1 H), 7.79 (dd, J=7.8, 1.8, 1 H), 7.55-7.49 (m, 1H), 7.46-7.33
(m, 3H), 7.30-7.19 (m, 2H), 7.01 (br s, 1H), 6.71 (dd, J=7.7, 4.7,
1 H), 3.98-2.54 (m, 10H).
Example 141
[5-(4-Phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(4H-[-
1,2,4]triazol-3-yl)-phenyl]methanone
##STR00253##
[0489] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and
2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI): mass calculated
for C.sub.25H.sub.23N.sub.7O, 437.50; m/z found 438.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 12.43 (br s, 1H), 8.36 (d, J=5.2
Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.08-7.91 (m, 3H), 7.60-7.42 (m,
5H), 7.39-7.31 (m, 1H), 6.98 (t, J=6.1 Hz, 1H), 4.01-3.87 (m, 2H),
3.85-3.65 (m, 3H), 3.61-3.40 (m, 2H), 3.28-2.89 (m, 3H).
Example 142
2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[5-(2-fluorophenyl)-2-methyl-1,3-thiazo-
l-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00254##
[0490] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 18 and
2-chloro-4,6-dimethoxypyrimidine. MS (ESI): mass calculated for
C.sub.23H.sub.24FN.sub.5O.sub.3S, 469.54; m/z found 470.0
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.47 (td, J=7.6,
1.7, 1 H), 7.32-7.24 (m, 1H), 7.17-7.11 (m, 1H), 7.10-7.03 (m, 1H),
5.39 (s, 1H), 3.94-3.78 (m, 8H), 3.75-3.65 (m, 2H), 3.61 (dd,
J=12.8, 4.3, 1 H), 3.45-3.35 (m, 2H), 3.24 (dd, J=11.4, 5.4, 1 H),
3.02-2.85 (m, 2H), 2.72 (s, 3H).
Example 143
2-(4-Thiophen-2-ylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carb-
onyl}octahydropyrrolo[3,4-c]pyrrole
##STR00255##
[0491] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
2-chloro-4-thiophen-2-yl-pyrimidine. MS (ESI): mass calculated for
C.sub.23H.sub.21N.sub.7OS, 443.53; m/z found 444.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.35-8.25 (m, 1H), 7.98 (d,
J=8.1, 1 H), 7.80-7.63 (m, 3H), 7.56-7.38 (m, 4H), 7.18-7.09 (m,
1H), 6.85 (d, J=5.2, 1H), 4.00-3.35 (m, 7H), 3.13-2.89 (m, 3H).
Example 144
2-[5-{[2-(2H-1,2,3-Triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl]-1,3-benzoxazole
##STR00256##
[0492] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and 2-chloro-benzooxazole. MS
(ESI): mass calculated for C.sub.22H.sub.20N.sub.6O.sub.2, 400.44;
m/z found 401.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.99 (d, J=8.1, 1 H), 7.74 (s, 2H), 7.57-7.49 (m, 1H), 7.46-7.40
(m, 2H), 7.40-7.36 (m, 1H), 7.30-7.25 (m, 1H), 7.21-7.15 (m, 1H),
7.06-7.01 (m, 1H), 4.00-3.85 (m, 2H), 3.83-3.72 (m, 2H), 3.68-3.61
(m, 1H), 3.59-3.41 (m, 2H), 3.19-2.97 (m, 3H).
Example 145
2-{5-[(2-Ethoxynaphthalen-1-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H-
)-yl}quinoxaline
##STR00257##
[0493] The title compound was prepared in a manner analogous to
Example 15 utilizing
2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-quinoxaline (Intermediate
35) and 2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI): mass
calculated for C.sub.27H.sub.26N.sub.4O.sub.2, 438.53; m/z found
439.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.32 (d,
J=16.4, 1 H), 7.95-7.55 (m, 6H), 7.52-7.17 (m, 4H), 4.34-2.94 (m,
12H), 1.49-1.19 (m, 3H).
Example 146
2-{5-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl}quinoxaline
##STR00258##
[0494] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and Intermediate 13. MS (ESI):
mass calculated for C.sub.25H.sub.21FN.sub.6O, 440.48; m/z found
441.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.71 (d,
J=4.9, 2H), 8.37-8.30 (m, 2H), 7.92-7.88 (m, 1H), 7.72-7.69 (m,
1H), 7.63-7.57 (m, 1H), 7.43-7.37 (m, 1H), 7.23-7.17 (m, 1H),
7.11-7.05 (m, 2H), 4.03-3.93 (m, 2H), 3.87-3.70 (m, 3H), 3.67-3.56
(m, 2H), 3.26-3.03 (m, 3H).
Example 147
2-(6-Ethoxypyridin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octa-
hydro pyrrolo[3,4-c]pyrrole
##STR00259##
[0495] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and 2-chloro-6-ethoxypyridine.
MS (ESI): mass calculated for C.sub.22H.sub.24N.sub.6O.sub.2,
404.47; m/z found 405.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.98 (d, J=8.1, 1 H), 7.72 (s, 2H), 7.56-7.49 (m, 1H),
7.46-7.33 (m, 3H), 6.00 (d, J=7.7, 1 H), 5.83 (d, J=7.9, 1 H),
4.33-4.23 (m, 2H), 3.93-3.82 (m, 1H), 3.79-3.67 (m, 2H), 3.59-3.49
(m, 1H), 3.47-3.33 (m, 2H), 3.32-3.25 (m, 1H), 3.11-2.86 (m, 3H),
1.38 (t, J=7.1, 3H).
Example 148
2-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-5-[4-(trifluoromethyl)pyrimi-
din-2-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00260##
[0496] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 33 and Intermediate 13. MS (ESI):
mass calculated for C.sub.22H.sub.18F.sub.4N.sub.6O, 459.42; m/z
found 459.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.74
(d, J=4.9, 2H), 8.60-8.28 (m, 2H), 7.23-7.04 (m, 3H), 6.84-6.75 (m,
1H), 4.03-2.97 (m, 10H).
Example 149
2-[5-{[2-(2H-1,2,3-Triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl]quinoxaline
##STR00261##
[0498] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and 2-chloroquinoxaline. MS
(ESI): mass calculated for C.sub.23H.sub.21N.sub.7O, 411.47; m/z
found 412.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.31
(s, 1H), 8.01-7.95 (m, 1H), 7.92-7.88 (m, 1H), 7.79-7.65 (m, 3H),
7.62-7.32 (m, 5H), 4.01-3.35 (m, 7H), 3.22-2.98 (m, 3H).
Example 150
2-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-5-(4-methoxypyrimidin-2-yl)o-
ctahydropyrrolo[3,4-c]pyrrole
##STR00262##
[0499] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and Intermediate 13. MS (ESI):
mass calculated for C.sub.22H.sub.21FN.sub.6O.sub.2, 420.45; m/z
found 421.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.73
(d, J=4.9, 2H), 8.35 (dd, J=8.8, 5.6, 1 H), 8.06 (d, J=5.7, 1 H),
7.23-7.02 (m, 3H), 6.01 (d, J=5.7, 1 H), 4.01-3.43 (m, 10H),
3.23-2.90 (m, 3H).
Example 151
2-(4-Furan-2-ylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbony-
l}octahydropyrrolo[3,4-c]pyrrole
##STR00263##
[0500] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
2-chloro-4-furan-2-yl-pyrimidine. MS (ESI): mass calculated for
C.sub.23H.sub.21N.sub.7OS, 427.47; m/z found 428.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.37-8.30 (m, 1H), 7.98 (d,
J=8.1, 1H), 7.80-7.37 (m, 6H), 7.20-7.11 (m, 1H), 6.89 (d, J=5.1, 1
H), 6.59-6.50 (m, 1H), 3.99-3.30 (m, 7H), 3.12-2.91 (m, 3H).
Example 152
2-(5-Fluoropyridin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octa-
hydro pyrrolo[3,4-c]pyrrole
##STR00264##
[0502] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and 2,5-difluoropyridine. MS
(ESI): mass calculated for C.sub.20H.sub.19FN.sub.6O, 378.41; m/z
found 379.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.03
(d, J=3.0, 1 H), 7.99 (d, J=8.1, 1 H), 7.73 (br s, 2H), 7.58-7.37
(m, 3H), 7.30-7.18 (m, 1H), 6.26 (dd, J=9.1, 3.3, 1 H), 3.95-3.84
(m, 1H), 3.77-3.24 (m, 6H), 3.13-2.89 (m, 3H).
Example 153
2-{[2-(2H-1,2,3-Triazol-2-yl)phenyl]carbonyl}-5-[4-(trifluoromethyl)pyrimi-
din-2-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00265##
[0503] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
2-chloro-4-trifluoromethyl-pyrimidine. MS (ESI): mass calculated
for C.sub.20H.sub.18F.sub.3N.sub.7O, 429.40; m/z found 430.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.58-8.40 (m, 1H),
7.99 (d, J=8.1, 1 H), 7.75 (br s, 2H), 7.56-7.48 (m, 1H), 7.45-7.39
(m, 2H), 6.80 (d, J=4.9, 1 H), 3.99-3.29 (m, 7H), 3.19-2.91 (m,
3H).
Example 154
2-(4-Methoxypyrimidin-2-yl)-5-{[2-(1H-1,2,4-triazol-5-yl)phenyl]carbonyl}o-
ctahydropyrrolo[3,4-c]pyrrole
##STR00266##
[0504] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and
2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI): mass calculated
for C.sub.20H.sub.21N.sub.7O, 391.44; m/z found 392.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.16-7.92 (m, 3H), 7.55-7.44 (m,
2H), 7.39-7.34 (m, 1H), 6.00 (d, J=5.8, 1 H), 4.02-3.33 (m, 10H),
3.20-2.83 (m, 4H).
Example 155
2-(3,6-Dimethylpyrazin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-
octa hydropyrrolo[3,4-c]pyrrole
##STR00267##
[0505] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
3-chloro-2,5-dimethyl-pyrazine. MS (ESI): mass calculated for
C.sub.20H.sub.21N.sub.7O.sub.2, 391.44; m/z found 390.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.00 (d, J=8.1, 1
H), 7.88-7.67 (m, 3H), 7.62-7.39 (m, 3H), 3.90 (dd, J=12.6, 7.6,
1H), 3.77 (dd, J=10.7, 7.5, 1H), 3.72-3.60 (m, 2H), 3.52 (dd,
J=10.8, 5.1, 1H), 3.43-3.28 (m, 2H), 3.10-2.97 (m, 2H), 2.95-2.85
(m, 1H), 2.51 (s, 3H), 2.36 (s, 3H).
Example 156
2-(4-Methoxypyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}o-
cta hydropyrrolo[3,4-c]pyrrole
##STR00268##
[0506] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
2-chloro-4-methoxypyrimidine. MS (ESI): mass calculated for
C.sub.20H.sub.21N.sub.7O.sub.2, 391.43; m/z found 392.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.08-8.03 (m, 1H),
7.99 (d, J=8.1, 1 H), 7.75 (s, 2H), 7.57-7.48 (m, 1H), 7.44-7.41
(m, 2H), 6.00 (d, J=5.7, 1 H), 3.97-3.79 (m, 5H), 3.77-3.63 (m,
2H), 3.61-3.53 (m, 1H), 3.50-3.30 (m, 2H), 3.09-2.89, (m, 3H).
Example 157
2-{[5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4,6-dimethylpyri-
midin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00269##
[0507] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 9. MS (ESI):
mass calculated for C.sub.21H.sub.22ClN.sub.7O, 423.91; m/z found
424.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.95 (d,
J=8.7, 1 H), 7.74 (s, 2H), 7.48 (dd, J=8.7, 2.3, 1 H), 7.40 (d,
J=2.3, 1 H), 6.30 (s, 1H), 3.94-3.81 (m, 2H), 3.75-3.57 (m, 3H),
3.55-3.29 (m, 2H), 3.11-2.78 (m, 3H), 2.30 (s, 6H).
Example 158
2-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(6-methylpyrazin--
2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00270##
[0509] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 22 and
2-chloro-6-methyl-pyrazine. MS (ESI): mass calculated for
C.sub.20H.sub.20FN.sub.7O, 393.43; m/z found 394.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.82-7.69 (m, 4H), 7.64 (s, 1H),
7.40 (dd, J=8.5, 5.8, 1 H), 7.17-7.10 (m, 1H), 3.97-3.83 (m, 1H),
3.81-3.68 (m, 2H), 3.65-3.55 (m, 1H), 3.53-3.29 (m, 3H), 3.18-2.88
(m, 3H), 2.38 (s, 3H).
Example 159
2-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methoxypyrimid-
in-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00271##
[0510] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 22 and
2-chloro-4-methoxypyrimidine. MS (ESI): mass calculated for
C.sub.20H.sub.20FN.sub.7O.sub.2, 409.43; m/z found 388.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.06 (d, J=5.7, 1
H), 7.88-7.62 (m, 3H), 7.45-7.37 (m, 1H), 7.18-7.10 (m, 1H), 6.01
(d, J=5.7, 1H), 4.00-3.81 (m, 5H), 3.70 (dd, J=20.4, 8.4, 2H),
3.62-3.53 (m, 1H), 3.51-3.28 (m, 2H), 3.13-2.84 (m, 3H).
Example 160
2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00272##
[0511] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 22 and
2-chloro-4,6-dimethoxypyrimidine. MS (ESI): mass calculated for
C.sub.21H.sub.22FN.sub.7O.sub.3, 439.45; m/z found 440.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.86-7.66 (m, 3H),
7.47-7.34 (m, 1H), 7.17-7.06 (m, 1H), 5.40 (s, 1H), 3.98-3.77 (m,
8H), 3.76-3.61 (m, 2H), 3.60-3.52 (m, 1H), 3.50-3.29 (m, 2H),
3.09-2.84 (m, 3H).
Example 161
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-m-
ethoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00273##
[0512] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and Intermediate 10. MS (ESI):
mass calculated for C.sub.22H.sub.25N.sub.7O.sub.2, 419.49; m/z
found 420.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.85
(d, 1H), 7.74-7.64 (m, 2H), 7.07-6.99 (m, 1H), 6.94-6.88 (m, 1H),
6.27 (s, J=20.0, 1 H), 3.94-3.75 (m, 5H), 3.73-3.25 (m, 5H),
3.08-2.81 (m, 3H), 2.32-2.27 (m, 6H).
Example 162
(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-[5-(4-methoxy-pyrimidin-2-yl)-hexa-
hydro-pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00274##
[0513] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 12 and
2-chloro-4-methoxypyrimidine. MS (ESI): mass calculated for
C.sub.20H.sub.20FN.sub.7O.sub.2, 409.42; m/z found 410.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.10-8.01 (m, 1H),
7.92-7.78 (m, 2H), 7.73 (s, 1H), 7.53-7.41 (m, 1H), 7.19-7.06 (m,
1H), 6.03-5.97 (m, 1H), 4.02-3.46 (m, 10H), 3.33-3.20 (m, 1H),
3.16-2.88 (m, 2H).
Example 163
6-Chloro-2-{5-[(2,4-dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-
-2(1H)-yl}-1,3-benzothiazole
##STR00275##
[0514] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 40 and 2,4-dimethoxybenzoic acid.
MS (ESI): mass calculated for C.sub.22H.sub.22ClN.sub.3O.sub.3S,
443.96; m/z found 444.2 [M+H].sup.+.
Example 164
2-(Biphenyl-2-ylcarbonyl)-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c-
]pyrrole
##STR00276##
[0515] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and biphenyl-2-carboxylic
acid. MS (ESI) mass calcd. for C.sub.29H.sub.26N.sub.4O, 446.56;
m/z found, 447.3 [M+H].sup.+.
Example 165
2-{5-[(2,6-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
}quinoxaline
##STR00277##
[0516] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2,6-dimethoxybenzoic acid.
MS (ESI) mass calcd. for C.sub.23H.sub.24N.sub.4O.sub.3, 404.47;
m/z found, 405.3 [M+H].sup.+.
Example 166
2-[(2,6-Dimethoxyphenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrro-
lo[3,4-c]pyrrole
##STR00278##
[0517] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and 2,6-dimethoxybenzoic acid.
MS (ESI) mass calcd. for C.sub.25H.sub.26N.sub.4O.sub.3, 430.51;
m/z found, 431.2 [M+H].sup.+.
Example 167
2-[(2,4-Dimethoxyphenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrro-
lo[3,4-c]pyrrole
##STR00279##
[0518] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and 2,4-dimethoxybenzoic acid.
MS (ESI) mass calcd. for C.sub.25H.sub.26N.sub.4O.sub.3, 430.51;
m/z found, 431.2 [M+H].sup.+.
Example 168
2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxa-
line
##STR00280##
[0519] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and biphenyl-2-carboxylic
acid. MS (ESI) mass calcd. for C.sub.27H.sub.24N.sub.4O, 420.52;
m/z found, 421.3 [M+H].sup.+.
Example 169
2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1,3-be-
nzothiazole
##STR00281##
[0520] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and 2-chloro-benzothiazole. MS
(ESI) mass calcd. for C.sub.26H.sub.23N.sub.3OS, 425.56; m/z found,
426.2 [M+H].sup.+.
Example 170
2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
}-4-methylquinoline
##STR00282##
[0521] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 38 and
2-chloro-4-methyl-quinoline. MS (ESI) mass calcd. for
C.sub.26H.sub.27N.sub.3O.sub.3, 417.51; m/z found, 418.3
[M+H].sup.+.
Example 171
2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
}-6-methoxy-1,3-benzothiazole
##STR00283##
[0522] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 38 and
2-chloro-6-methoxy-benzothiazole. MS (ESI) mass calcd. for
C.sub.23H.sub.25N.sub.3O.sub.4S, 439.54; m/z found, 440.2
[M+H].sup.+.
Example 172
2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
}-6-methyl-1,3-benzothiazole
##STR00284##
[0523] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 38 and
2-chloro-6-methyl-benzothiazole. MS (ESI) mass calcd. for
C.sub.23H.sub.25N.sub.3O.sub.3S, 423.54; m/z found, 424.2
[M+H].sup.+.
Example 173
2-(Biphenyl-2-ylcarbonyl)-5-(6-methylpyridin-2-yl)octahydropyrrolo[3,4-c]p-
yrrole
##STR00285##
[0524] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-6-methyl-pyridine. MS (ESI) mass calcd. for
C.sub.25H.sub.25N.sub.43O, 383.5; m/z found, 384.3 [M+H]+.
Example 174
2-(Biphenyl-2-ylcarbonyl)-5-(4-methylpyrimidin-2-yl)octahydropyrrolo[3,4-c-
]pyrrole
##STR00286##
[0525] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-4-methyl-pyrimidine. MS (ESI) mass calcd. for
C.sub.24H.sub.24N.sub.4O, 384.49; m/z found, 385.2 [M+H].sup.+.
Example 175
2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoli-
ne
##STR00287##
[0526] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and 2-chloro-quinoline. MS
(ESI) mass calcd. for C.sub.28H.sub.25N.sub.3O, 419.53; m/z found,
420.3 [M+H].sup.+.
Example 176
2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-fluo-
ro-1,3-benzothiazole
##STR00288##
[0528] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-6-fluoro-benzothiazole. MS (ESI) mass calcd. for
C.sub.26H.sub.22FN.sub.3OS, 443.55; m/z found, 444.2 [M+H]+.
Example 177
2-(Biphenyl-2-ylcarbonyl)-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3,4--
c]pyrrole
##STR00289##
[0529] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-4-methoxypyrimidine. MS (ESI) mass calcd. for
C.sub.24H.sub.24N.sub.4O.sub.2, 400.48; m/z found, 401.2
[M+H].sup.+.
Example 178
2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4-meth-
ylquinoline
##STR00290##
[0530] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-4-methyl-quinoline. MS (ESI) mass calcd. for
C.sub.29H.sub.27N.sub.3O, 433.56; m/z found, 434.3 [M+H].sup.+.
Example 179
(2,4-Dimethoxy-phenyl)-[5-(4-methoxy-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-
-c]pyrrol-2-yl]methanone
##STR00291##
[0531] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 38 and
2-chloro-4-methoxypyrimidine. MS (ESI): mass calculated for
C.sub.20H.sub.24N.sub.4O.sub.4, 384.43; m/z found 385.2
[M+H].sup.+.
Example 180
(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2-methoxy-phenyl-
)-methanone
##STR00292##
[0532] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 28 and 2-methoxybenzoic acid. MS
(ESI): mass calculated for C.sub.21H.sub.21N.sub.3O.sub.3, 363.42;
m/z found 364.2 [M+H].sup.+.
Example 181
(2-Pyridin-3-yl-phenyl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol--
2-yl)-methanone
##STR00293##
[0533] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2-pyridin-3-yl-benzoic
acid. MS (ESI): mass calculated for C.sub.26H.sub.23N.sub.5O,
421.51; m/z found 422.3 [M+H].sup.+.
Example 182
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(-
1H-imidazol-2-yl)-phenyl]-methanone
##STR00294##
[0534] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
2-(1H-imidazol-2-yl)-benzoic acid. MS (ESI) mass calcd. for
C.sub.22H.sub.24N.sub.6O, 388.47; m/z found, 398.2 [M+H].sup.+.
Example 183
(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2,4-dimethoxy-ph-
enyl)-methanone
##STR00295##
[0535] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 28 and 2,4-dimethoxybenzoic acid.
MS (ESI): mass calculated for C.sub.22H.sub.23N.sub.3O.sub.4,
393.45; m/z found 394.2 [M+H].sup.+.
Example 184
(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-biphenyl-2-yl-met-
hanone
##STR00296##
[0536] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and 2-chloro-benzooxazole. MS
(ESI): mass calculated for C.sub.26H.sub.23N.sub.3O.sub.2, 409.49;
m/z found 410.2 [M+H].sup.+.
Example 185
(2,4-Dimethoxy-phenyl)-[5-(6-methyl-pyridin-2-yl)-hexahydro-pyrrolo[3,4-c]-
pyrrol-2-yl]methanone
##STR00297##
[0538] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 38 and
2-chloro-6-methyl-pyridine. MS (ESI): mass calculated for
C.sub.21H.sub.26N.sub.3O.sub.3, 367.45; m/z found 368.3
[M+H].sup.+.
Example 186
(2,4-Dimethoxy-phenyl)-[5-(4-methyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4--
c]pyrrol-2-yl]methanone
##STR00298##
[0539] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 38 and
2-chloro-4-methylpyrimidine. MS (ESI): mass calculated for
C.sub.20H.sub.24FN.sub.4O.sub.3, 368.43; m/z found 369.3
[M+H].sup.+.
Example 187
Biphenyl-2-yl-[5-(6-methoxy-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl]methanone
##STR00299##
[0540] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-6-methoxy-benzothiazole. MS (ESI): mass calculated for
C.sub.27H.sub.25N.sub.3O2S, 455.57; m/z found 456.2
[M+H].sup.+.
Example 188
Biphenyl-2-yl-[5-(6-methyl-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]methanone
##STR00300##
[0542] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 17 and
2-chloro-6-methyl-benzothiazole. MS (ESI): mass calculated for
C.sub.27H.sub.25N.sub.3OS, 439.57; m/z found 440.2 [M+H].sup.+.
Example 189
[5-(6-Chloro-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6--
dimethoxy-phenyl)-methanone
##STR00301##
[0543] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 40 and 2,6-dimethoxybenzoic acid.
MS (ESI): mass calculated for C.sub.22H.sub.22ClN.sub.3O.sub.3S,
443.96; m/z found 444.2 [M+H].sup.+.
Example 190
Biphenyl-2-yl-[5-(6-chloro-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrr-
ol-2-yl]methanone
##STR00302##
[0544] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 40 and biphenyl-2-carboxylic
acid. MS (ESI): mass calculated for
C.sub.26H.sub.22ClN.sub.3O.sub.3S, 459.99; m/z found 460.2
[M+H].sup.+.
Example 191
(2,4-Dimethoxy-phenyl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-
-yl)-methanone
##STR00303##
[0545] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 2,4-dimethoxybenzoic acid.
MS (ESI): mass calculated for C.sub.23H.sub.24N.sub.4O.sub.3,
404.47; m/z found 405.3 [M+H].sup.+.
Example 192
(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2,6-dimethoxy-ph-
enyl)-methanone
##STR00304##
[0546] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 41 and 2-chloro-benzooxazole. MS
(ESI): mass calculated for C.sub.22H.sub.23N.sub.3O.sub.4, 393.45;
m/z found 394.2 [M+H].sup.+.
Example 193
(4'-Methyl-biphenyl-2-yl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrro-
l-2-yl)-methanone
##STR00305##
[0547] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and
4'-methyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for
C.sub.28H.sub.26N.sub.4O, 434.55; m/z found 435.3 [M+H].sup.+.
Example 194
(5-Quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4'-trifluoromethy-
l-biphenyl-2-yl)-methanone
##STR00306##
[0548] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and
4'-trifluoromethyl-biphenyl-2-carboxylic acid. MS (ESI): mass
calculated for C.sub.28H.sub.23F.sub.3N.sub.4O, 488.50; m/z found
489.2 [M+H].sup.+.
Example 195
(4'-Methyl-biphenyl-2-yl)-[5-(4-phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3-
,4-c]pyrrol-2-yl]methanone
##STR00307##
[0549] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and
4'-methyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for
C.sub.30H.sub.28N.sub.4O, 460.58; m/z found 461.3 [M+H].sup.+.
Example 196
[5-(4-Phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4'-trif-
luoromethyl-biphenyl-2-yl)-methanone
##STR00308##
[0550] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and
4'-trifluoromethyl-biphenyl-2-carboxylic acid. MS (ESI): mass
calculated for C.sub.30H.sub.53F.sub.3N.sub.4O, 514.56; m/z found
515.3 [M+H].sup.+.
Example 197
(4-Methoxy-2-methyl-phenyl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl)-methanone
##STR00309##
[0552] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 4-methoxy-2-methyl-benzoic
acid. MS (ESI): mass calculated for C.sub.23H.sub.24N.sub.4O.sub.2,
388.47; m/z found 389.2 [M+H].sup.+.
Example 198
(3'-Chloro-biphenyl-2-yl)-[5-(4-phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3-
,4-c]pyrrol-2-yl]-methanone
##STR00310##
[0553] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 26 and
3'-chloro-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for
C.sub.29H.sub.25ClN.sub.4O, 480.99; m/z found 481.2
[M+H].sup.+.
Example 199
(2-Methoxy-phenyl)-[5-(4-methoxy-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]p-
yrrol-2-yl]methanone
##STR00311##
[0554] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 32 and 2-methoxybenzoic acid. MS
(ESI): mass calculated for C.sub.19H.sub.22N.sub.4O.sub.3, 354.41;
m/z found 355.2 [M+H].sup.+.
Example 200
(2-Methoxy-phenyl)-[5-(4-methyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]py-
rrol-2-yl]methanone
##STR00312##
[0555] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 27 and 2-methoxybenzoic acid. MS
(ESI): mass calculated for C.sub.19H.sub.22N.sub.4O.sub.2, 338.41;
m/z found 339.3 [M+H].sup.+.
Example 201
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-m-
ethoxy-phenyl)-methanone
##STR00313##
[0556] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-methoxybenzoic acid. MS
(ESI): mass calculated for C.sub.20H.sub.24N.sub.4O.sub.2, 352.44;
m/z found 353.3 [M+H].sup.+.
Example 202
2-[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbo-
nyl]-benzonitrile
##STR00314##
[0557] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-cyanobenzoic acid. MS
(ESI): mass calculated for C.sub.20H.sub.21N.sub.5O, 347.42; m/z
found 348.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.51-8.39 (m, 2H), 7.37-7.32 (m, 1H), 7.25-7.06 (m, 3H), 6.76 (t,
J=13.7 Hz, 1H), 4.18-3.96 (m, 3H), 3.48-3.33 (m, 1H), 3.05 (dd,
J=12.9, 6.4 Hz, 1H), 2.69-2.27 (m, 10H), 1.68-1.50 (m, 5H),
1.50-1.37 (m, 3H).
Example 203
Cinnolin-4-yl-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyr-
rol-2-yl]methanone
##STR00315##
[0558] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and cinnoline-4-carboxylic
acid. MS (ESI): mass calculated for C.sub.21H.sub.22N.sub.6O,
374.45; m/z found 375.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 9.26 (s, 1H), 8.61 (dd, J=8.4, 1.1 Hz, 1H), 7.96-7.85
(m, 2H), 7.83-7.74 (m, 1H), 6.33 (s, 1H), 4.13-4.07 (m, 1H), 3.92
(dd, J=11.7, 7.5 Hz, 1H), 3.84 (dd, J=13.0, 4.9 Hz, 1H), 3.78-3.68
(m, 2H), 3.54-3.42 (m, 2H), 3.20-3.09 (m, 2H), 3.04-2.98 (m, 1H),
2.29 (s, 6H).
Example 204
(5-Fluoro-2-pyrimidin-2-yl-phenyl)-[5-(6-methyl-2-trifluoromethyl-pyrimidi-
n-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00316##
[0560] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 13 and Intermediate 31. MS (ESI):
mass calculated for C.sub.23H.sub.20F.sub.4N.sub.6O, 472.45; m/z
found 473.2 [M+H].sup.+.
Example 205
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[-
1,2,3]triazol-1-yl-phenyl)-methanone
##STR00317##
[0561] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 3 and Intermediate 15 as starting
materials. In this case Intermediate C was coupled to Intermediate
15 first then the t-butylcarboxylate was removed prior to the
addition of 2-chloro-4,6-methylpyrimidine. (ESI): mass calculated
for C.sub.21H.sub.23N.sub.7O, 389.46; m/z found 390.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.99 (d, J=1.0 Hz, 1H), 7.79 (d,
J=0.9 Hz, 1H), 7.67-7.62 (m, 1H), 7.62-7.52 (m, 2H), 7.49-7.45 (m,
1H), 7.27 (s, 1H), 3.87-3.65 (m, 3H), 3.54-3.44 (m, 2H), 3.38-3.25
(m, 2H), 3.04-2.78 (m, 3H), 2.29 (s, 6H).
Example 206
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[-
1,2,4]triazol-1-yl-phenyl)-methanone
##STR00318##
[0562] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calcd. for
C.sub.21H.sub.23N.sub.7O, 389.46; m/z found, 390.2 [M+H].sup.+.
Example 207
[5-(4,6-Dimethoxy-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3--
phenyl-pyridin-2-yl)-methanone
##STR00319##
[0563] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 39 and
3-phenyl-pyridine-2-carboxylic acid. MS (ESI): mass calculated for
C.sub.24H.sub.25N.sub.5O.sub.3, 431.50; m/z found 432.3
[M+H].sup.+.
Example 208
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3-p-
henyl-pyridin-2-yl)-methanone
##STR00320##
[0564] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
3-phenyl-pyridine-2-carboxylic acid. MS (ESI): mass calculated for
C.sub.24H.sub.25N.sub.5O, 399.5; m/z found 400.3 [M+H].sup.+.
Example 209
[5-(6-Methyl-2-propyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-
-(2-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00321##
[0565] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
4-chloro-6-methyl-2-propyl-pyrimidine. MS (ESI): mass calculated
for C.sub.23H.sub.27N.sub.7O, 417.51; m/z found 418.2
[M+H].sup.+.
Example 210
[5-(2-Methyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,-
3]triazol-2-yl-phenyl)-methanone
##STR00322##
[0566] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
4-chloro-2-methyl-pyrimidine. MS (ESI): mass calculated for
C.sub.20H.sub.21N.sub.7O, 375.43; m/z found 376.2 [M+H].sup.+.
Example 211
[5-(6-Methyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,3]-
triazol-2-yl-phenyl)-methanone
##STR00323##
[0567] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
2-chloro-6-methyl-pyrazine. MS (ESI): mass calculated for
C.sub.20H.sub.21N.sub.7O, 375.43; m/z found 376.2 [M+H].sup.+.
Example 212
[5-(3,6-Dimethyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-flu-
oro-2-pyrimidin-2-yl-phenyl)-methanone
##STR00324##
[0569] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 34 and Intermediate 13. MS MS
(ESI): mass calculated for C.sub.23H.sub.23FN.sub.6O, 418.47; m/z
found 419.2 [M+H].sup.+.
Example 213
[5-(3,6-Dimethyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(2H-
-[1,2,4]triazol-3-yl)-phenyl]methanone
##STR00325##
[0570] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 34 and
2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI): mass calculated
for C.sub.21H.sub.23N.sub.7O, 389.46; m/z found 390.2
[M+H].sup.+.
Example 214
[5-(2-Pyrrolidin-1-yl-6-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[-
3,4-c]pyrrol-2-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00326##
[0571] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 20 and
4-chloro-2-pyrrolidin-1-yl-6-trifluoromethyl-pyrimidine acid. MS
(ESI): mass calculated for C.sub.24H.sub.26F.sub.3N.sub.8O, 498.51;
m/z found 499.2 [M+H].sup.+.
Example 215
2-(2,6-Dimethylpyrimidin-4-yl)-5-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00327##
[0572] The title compound was prepared in a manner analogous to
Intermediate 23, substituting
(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol--
2(1H)-yl)methanone (Intermediate 21) for
hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester
and 4-chloro-2,6-dimethylpyrimidine for
2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd for
C.sub.21H.sub.22FN.sub.7O, 407.19; m/z found, 408.2
[M+H].sup.+.
[0573] Prophetic Examples 216-218 may be synthesized using the
general schemes provided above.
Example 216
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-n-
itro-6-[1,2,3]triazol-2-yl-phenyl)-methanone
##STR00328##
[0575] MS (ESI) mass calcd. for C.sub.21H.sub.22N.sub.8O.sub.3,
434.45.
Example 217
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-f-
uran-2-yl-phenyl)-methanone
##STR00329##
[0577] MS (ESI) mass calcd. for C.sub.23H.sub.24N.sub.4O.sub.3,
388.46.
Example 218
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-m-
ethyl-5-phenyl-thiazol-4-yl)-methanone
##STR00330##
[0579] MS (ESI) mass calcd. for C.sub.23H.sub.25N.sub.5OS,
419.54.
Example 219
2-[(2,3-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropy-
rrolo[3,4-c]pyrrole
##STR00331##
[0580] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2,3-dimethylbenzoic acid.
MS (ESI): mass calculated for C.sub.21H.sub.26N.sub.4O, 350.47; m/z
found 351.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.16-7.05 (m, 2H), 7.02 (d, J=7.1 Hz, 1H), 6.30 (s, 1H), 4.00-3.86
(m, 2H), 3.78 (dd, J=11.6, 7.4 Hz, 1H), 3.70-3.58 (m, 2H),
3.49-3.38 (m, 2H), 3.17-3.02 (m, 2H), 2.99-2.92 (m, 1H), 2.35-2.28
(s, 6H), 2.27 (s, 3H), 2.19 (s, 3H).
Example 220
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-fluoro-2-methylphenyl)carbonyl]octahy-
dropyrrolo[3,4-c]pyrrole
##STR00332##
[0581] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 3-fluoro-2-methylbenzoic
acid. MS (ESI): mass calculated for C.sub.20H.sub.23FN.sub.4O,
354.4; m/z found 355.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.22-7.14 (m, 1H), 7.06-6.95 (m, 2H), 6.30 (s, 1H),
4.00-3.86 (m, 2H), 3.78 (dd, J=11.6, 7.3 Hz, 1H), 3.70-3.58 (m,
2H), 3.52-3.39 (m, 2H), 3.19-3.02 (m, 2H), 3.02-2.92 (m, 1H), 2.30
(s, 6H), 2.21 (d, J=2.0 Hz, 3H).
Example 221
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-fluoro-2-(trifluoromethyl)phenyl]carb-
onyl}octahydropyrrolo[3,4-c]pyrrole
##STR00333##
[0582] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
5-fluoro-2-(trifluoromethyl)benzoic acid. MS (ESI): mass calculated
for C.sub.20H.sub.20F.sub.4N.sub.4O, 408.4; m/z found 409.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.71 (dd, J=8.8,
5.0 Hz, 1H), 7.22-7.14 (m, 1H), 7.06 (dd, J=8.1, 2.3 Hz, 1H), 6.31
(s, 1H), 4.01-3.87 (m, 2H), 3.79 (dd, J=11.7, 7.3 Hz, 1H),
3.69-3.56 (m, 2H), 3.53-3.41 (m, 2H), 3.19-3.04 (m, 2H), 3.05-2.97
(m, 1H), 2.30 (s, 6H).
Example 222
2-[(4-Chloro-2-methoxyphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octah-
ydropyrrolo[3,4-c]pyrrole
##STR00334##
[0583] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 4-chloro-2-methoxybenzoic
acid. MS (ESI): mass calculated for
C.sub.20H.sub.23ClN.sub.4O.sub.2, 386.9; m/z found 389.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.18 (d, J=8.0 Hz,
1H), 6.97 (dd, J=8.0, 1.8 Hz, 1H), 6.89 (d, J=1.7 Hz, 1H), 6.29 (s,
1H), 3.98-3.82 (m, 2H), 3.80 (s, 3H), 3.78-3.73 (m, 1H), 3.68-3.59
(m, 2H), 3.55-3.44 (m, 2H), 3.19 (dd, J=11.1, 5.0 Hz, 1H),
3.13-2.90 (m, 2H), 2.29 (s, 6H).
Example 223
2-[(5-Chloro-2-methylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahy-
dropyrrolo[3,4-c]pyrrole
##STR00335##
[0585] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 5-chloro-2-methylbenzoic
acid. MS (ESI): mass calculated for C.sub.20H.sub.23ClN.sub.4O,
370.9; m/z found 371.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.26-7.21 (m, 1H), 7.18-7.13 (m, 2H), 6.31 (s, 1H),
4.00-3.86 (m, 2H), 3.79 (dd, J=11.6, 7.3 Hz, 1H), 3.68-3.57 (m,
2H), 3.51-3.42 (m, 2H), 3.17-2.94 (m, 3H), 2.30 (s, 6H), 2.26 (s,
3H).
Example 224
2-[(2,5-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropy-
rrolo[3,4-c]pyrrole
##STR00336##
[0587] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2,5-dimethylbenzoic acid.
MS (ESI): mass calculated for C.sub.21H.sub.26N.sub.4O, 350.5; m/z
found 351.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.11-7.03 (m, 2H), 6.99 (s, 1H), 6.30 (s, 1H), 4.00-3.87 (m, 2H),
3.78 (dd, J=11.5, 7.4 Hz, 1H), 3.70-3.58 (m, 2H), 3.50-3.42 (m,
2H), 3.15-2.90 (m, 3H), 2.32 (s, 3H), 2.32 (s, 3H), 2.24 (s,
3H).
Example 225
2-[(2,6-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropy-
rrolo[3,4-c]pyrrole
##STR00337##
[0588] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2,6-dimethylbenzoic acid.
MS (ESI): mass calculated for C.sub.21H.sub.26N.sub.4O, 350.5; m/z
found 351.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.13
(t, J=7.6 Hz, 1H), 7.51-7.00 (m, 2H), 6.30 (s, 1H), 4.15-3.87 (m,
2H), 3.85-3.75 (m, 1H), 3.73-3.67 (m, 1H), 3.63-3.55 (m, 1H),
3.50-3.44 (m, 1H), 3.40-3.33 (m, 1H), 3.08-2.90 (m, 3H), 2.28 (s,
6H), 2.21 (s, 3H), 1.80 (s, 3H).
Example 226
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-fluoro-2-methylphenyl)carbonyl]octahy-
dropyrrolo[3,4-c]pyrrole
##STR00338##
[0589] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 5-fluoro-2-methylbenzoic
acid. MS (ESI): mass calculated for C.sub.20H.sub.23FN.sub.4O,
354.4; m/z found 355.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.16 (dd, J=8.5, 5.4 Hz, 1H), 6.98-6.92 (m, 1H), 6.90
(dd, J=8.5, 2.7 Hz, 1H), 6.30 (s, 1H), 3.98-3.87 (m 2H), 3.79 (dd,
J=11.6, 7.3 Hz, 1H), 3.68-3.57 (m, 2H), 3.50-3.43 (m, 2H),
3.16-2.94 (m, 3H), 2.30 (s, 6H), 2.26 (d, J=8.6 Hz, 3H).
Example 227
2-[(2,4-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropy-
rrolo[3,4-c]pyrrole
##STR00339##
[0590] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2,4-dimethylbenzoic acid.
MS (ESI): mass calculated for C.sub.21H.sub.26N.sub.4O, 350.5; m/z
found 351.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.02
(s, 2H), 6.29 (s, OH), 3.92 (ddd, J=19.2, 12.2, 7.7 Hz, 2H), 3.77
(dd, J=11.6, 7.4 Hz, 0H), 3.63 (ddd, J=18.1, 12.2, 4.9 Hz, 1H),
3.52-3.39 (m, 1H), 3.06 (ddd, J=50.9, 27.4, 6.2 Hz, 0H), 2.30 (d,
J=6.6 Hz, 3H), 2.28-2.24 (m, 3H).
Example 228
2-[(2,5-Diethoxyphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropy-
rrolo[3,4-c]pyrrole
##STR00340##
[0592] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2,5-diethoxybenzoic acid.
MS (ESI): mass calculated for C.sub.23H.sub.30N.sub.4O.sub.3,
410.5; m/z found 411.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 6.89-6.77 (m, 3H), 6.28 (s, 1H), 4.04-3.83 (m, 6H),
3.80-3.74 (m, 1H), 3.70-3.44 (m, 4H), 3.27 (s, 1H), 3.13-2.90 (m,
2H), 2.26 (s, 6H), 1.44-1.23 (m, 6H).
Example 229
2-[(2,6-Diethoxyphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropy-
rrolo[3,4-c]pyrrole
##STR00341##
[0593] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2,6-diethoxybenzoic acid.
MS (ESI): mass calculated for C.sub.23H.sub.30N.sub.4O.sub.3,
410.5; m/z found 411.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.19 (t, J=8.4 Hz, 1H), 6.55-6.46 (m, 2H), 6.27 (s,
1H), 4.06 (q, J=7.0 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.94-3.82 (m,
2H), 3.79-3.65 (m, 2H), 3.61 (dd, J=11.6, 5.0 Hz, 1H), 3.57-3.42
(m, 2H), 3.17 (dd, J=11.0, 5.0 Hz, 1H), 3.11-2.87 (m, 2H),
2.31-2.27 (m, 6H), 1.44-1.25 (m, 6H).
Example 230
2-[(2-Chloro-6-methylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahy-
dropyrrolo[3,4-c]pyrrole
##STR00342##
[0594] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and 2-chloro-6-methylbenzoic
acid. MS (ESI): mass calculated for C.sub.20H.sub.23ClN.sub.4O,
370.9; m/z found 371.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): (rotamers observed) 7.24-7.14 (m, 2H), 7.15-7.07 (m,
1H), 6.31-6.28 (m, 1H), 4.06-3.85 (m, 2H), 3.85-3.75 (m, 1H),
3.74-3.36 (m, 1H), 3.65-3.52 (m, 2H), 3.45-3.51 (m, 1H), 3.37-3.30
(m, 1H), 3.25-3.14 (m, 1H), 3.14-2.94 (m, 2H), 2.37-2.23 (m,
9H).
Example 231
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00343##
[0595] The title compound was prepared in a manner analogous to
Example 15, substituting Intermediate 87 for
3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass calcd.
for C.sub.23H.sub.23FN.sub.6O, 418.47; m/z found, 419.2
[M+H].sup.+.
Example 232
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-iodophenyl)methanone
##STR00344##
[0596] The title compound was prepared in a manner analogous to
Example 15 substituting 2-iodo-3-fluorobenzoic acid for
3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass calcd.
for C.sub.19H.sub.20FIN.sub.4O, 466.3; m/z found, 467.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.36 (ddd, J=8.2,
7.5, 5.2 Hz, 1H), 7.04 (ddd, J=8.5, 7.7, 1.3 Hz, 2H), 6.30 (s, 1H),
3.94 (ddd, J=20.9, 12.2, 7.6 Hz, 2H), 3.79 (dd, J=11.7, 7.2 Hz,
1H), 3.69 (dd, J=12.8, 4.6 Hz, 1H), 3.64 (dd, J=11.7, 5.1 Hz, 1H),
3.58-3.51 (m, 1H), 3.47 (dd, J=10.8, 7.4 Hz, 1H), 3.16-2.98 (m,
3H), 2.29 (s, 6H).
Example 233
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(trifluoromethyl)pyridin-3-yl]carbony-
l}octahydropyrrolo[3,4-c]pyrrole
##STR00345##
[0598] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 23 and
2-(trifluoromethyl)nicotinic acid. MS (ESI): mass calculated for
C.sub.19H.sub.20F.sub.3N.sub.6O, 391.4; m/z found 392.9
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.77 (dd, J=4.7,
1.0 Hz, 1H), 7.74 (d, J=6.9 Hz, 1H), 7.55 (dd, J=12.4, 6.2 Hz, 1H),
6.31 (s, 1H), 3.99 (dd, J=12.8, 7.7 Hz, 1H), 3.90 (dd, J=11.7, 7.6
Hz, 1H), 3.80 (dd, J=11.6, 7.3 Hz, 1H), 3.71-3.57 (m, 2H),
3.50-3.41 (m, 2H), 3.16-3.06 (m, 2H), 3.06-2.97 (m, 1H), 2.34 (s,
5H).
Example 234
2-Bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]-
pyrrol-2(1H)-yl)methanone
##STR00346##
[0599] The title compound was prepared in a manner analogous to
Example 1 utilizing Intermediate 23 and
2-bromopyridine-3-carboxylic acid. MS (ESI): mass calculated for
C.sub.18H.sub.20BrN.sub.5O, 401.09; m/z found 402.9 [M+H].sup.+.
.sup.1H NMR (600 MHz, CDCl.sub.3): 8.41 (dd, J=4.7, 1.8, 1 H),
7.66-7.54 (m, 1H), 7.34 (dd, J=7.4, 4.8, 1 H), 6.38-6.24 (m, 1H),
3.94 (dd, J=12.1, 7.6, 2H), 3.80 (dd, J=11.5, 7.3, 1H), 3.74-3.46
(m, 4H), 3.31-3.01 (m, 3H), 2.40-2.23 (m, 6H).
Example 235
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(-
pyrimidin-2-yl)pyridin-3-yl)methanone
##STR00347##
[0601] To a solution of
2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c-
]pyrrol-2(1H)-yl)methanone (Example 234) (50 mg, 0.14 mmol),
2-tributylstannylpyrimidine (50 mg, 0.14 mmol), and copper iodide
(2.6 mg, 0.014 mmol) in 1,4 dioxane (1 mL) was added
Pd(PPh.sub.3).sub.4 (16 mg, 0.014 mmol). The reaction was
irradiated in a microwave reactor at 160.degree. C. for one hour.
The resulting solution was filtered through Celite.RTM., washed
with DCM, and concentrated. Purification (FCC) (MeOH
(NH.sub.3)/DCM) gave the title compound (35 mg, 64%). MS (ESI):
mass calculated for C.sub.22H.sub.23N.sub.7O, 401.20; m/z found
402.2 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.85 (s, 3H),
7.70 (d, J=6.7, 1 H), 7.48-7.42 (m, 1H), 7.21 (d, J=4.4, 1 H),
6.32-6.24 (m, 1H), 3.93-3.79 (m, 2H), 3.75-3.61 (m, 3H), 3.52 (s,
1H), 3.52-3.42 (m, 1H), 3.17 (dd, J=10.8, 5.0, 1 H), 3.09-2.88 (m,
2H), 2.37-2.22 (m, 6H).
Example 236
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(-
1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methanone
##STR00348##
[0602] To a solution of
2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c-
]pyrrol-2(1H)-yl)methanone (Example 234) (50 mg, 0.12 mmol),
4-(terahydropyran-2H-yl)-1H pyrazole-5 boronic acid pinacol ester
(35 mg, 0.12 mmol), TBAB (4.0 mg, 0.012 mmol), and PdCl.sub.2(dppf)
(10 mg, 0.012 mmol) in toluene (0.6 mL) was added 2N aq.
Na.sub.2CO.sub.3 (0.12 ml, 0.25 mmol). The reaction was irradiated
in a microwave reactor at 110.degree. C. for one hour. The
resulting solution was filtered through Celite.RTM., washed with
DCM, and concentrated. Purification (FCC) (MeOH (NH.sub.3)/DCM)
gave the title compound (52 mg, 88%). MS (ESI): mass calculated for
C.sub.26H.sub.31N.sub.7O.sub.2, 473.25; m/z found 474.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.72 (dd, J=4.7,
1.8, 1 H), 7.76 (dd, J=8.0, 1.7, 1 H), 7.62-7.45 (m, 1H), 7.34
(ddd, J=7.7, 4.8, 1.5, 1H), 6.56 (dd, J=18.2, 9.1, 1H), 6.33-6.23
(m, 1H), 3.91-3.71 (m, 2H), 3.72-3.53 (m, 3H), 3.53-3.36 (m, 2H),
3.36-3.06 (m, 3H), 2.98-2.70 (m, 3H), 2.65 (d, J=6.4, 1 H), 2.51
(d, J=10.0, 1 H), 2.28 (d, J=9.8, 6H), 2.18-2.01 (m, 2H), 1.94 (s,
3H).
Example 237
(2-(1H-Pyrazol-5-yl)pyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydrop-
yrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00349##
[0603] To a solution of
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2--
(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methanone
(Example 236) (210 mg, 0.43 mmol) in THF (10 mL) and H.sub.2O (1
mL) was added 4 N aq. HCl (1 mL). The reaction was let stir for 2
hours, neutralized with 3 N aq. NaOH, and extracted with DCM
(3.times.20 mL). The organics were combined, dried with
Na.sub.2SO.sub.4, and concentrated. Purification (FCC) (MeOH
(NH.sub.3)/DCM) gave the title compound (128 mg, 73%) (MS (ESI):
mass calculated for C.sub.21H.sub.23N.sub.7O, 389.20; m/z found
390.2 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.68-8.59 (m,
1H), 7.63 (d, J=9.1, 2H), 7.32-7.20 (m, 1H), 6.80 (d, J=2.2, 1 H),
6.33-6.19 (m, 1H), 3.92-3.55 (m, 5H), 3.54-2.78 (m, 5H), 2.37-2.24
(m, 6H).
Example 238
(2-(2H-1,2,3-Triazol-2-yl)pyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexa-
hydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00350##
[0605] To a solution of
2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c-
]pyrrol-2(1H)-yl)methanone (Example 234) (150 mg, 0.37 mmol),
1H-1,2,3 triazole (43 .mu.L, 0.75 mmol), CsCO.sub.3 (247 mg, 0.75
mmol), in H.sub.2O (2 .mu.L) and 1,4 dioxane (2 mL) was added
(R,R)-(-)-N,N'-dimethyl-1,2-cyclohexyldiamine (12 .mu.L, 0.75 mmol)
and CuI (3.5 mg, 0.86 mmol). The reaction mixture was irradiated in
a microwave reactor at 160.degree. C. for 2 h. The resulting
solution was filtered through Celite.RTM., washed with DCM, and
concentrated. Purification (FCC)(MeOH (NH.sub.3)/DCM) gave the
title compound (8 mg, 6%). MS (ESI): mass calculated for
C.sub.20H.sub.22N.sub.8O, 390.19; m/z found 391.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.65 (dd, J=4.8, 1.8, 1 H), 7.83
(dt, J=13.3, 6.6, 2H), 7.43 (dt, J=7.6, 4.5, 1 H), 6.38-6.23 (m,
2H), 4.02-3.28 (m, 6H), 3.10-3.06 (m, 4H), 2.42-2.22 (m, 6H).
Example 239
(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexah-
ydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00351##
[0606] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 42 and
3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI): mass calculated
for C.sub.24H.sub.25FN.sub.6O, 432.21; m/z found 433.3 [M+H].sup.+.
.sup.1H NMR (600 MHz, CDCl.sub.3): 8.41 (dd, J=4.7, 1.8, 2H),
7.66-7.54 (m, 2H), 7.34 (dd, J=7.4, 4.8, 2H), 3.94 (dd, J=12.1,
7.6, 2H), 3.80 (dd, J=11.5, 7.3, 1H), 3.74-3.46 (m, 4H), 3.31-3.01
(m, 3H), 2.40-2.13 (m, 9H).
Example 240
(3-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-y-
l)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00352##
[0607] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 42 and
3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.22H.sub.24FN.sub.7O, 421.20; m/z found 422.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.82-7.77 (m, 2H),
7.51-7.44 (m, 1H), 7.31 (ddd, J=9.8, 8.4, 1.3, 1 H), 7.25-7.20 (m,
1H), 3.86-3.60 (m, 3H), 3.59-3.42 (m, 4H), 3.14 (dd, J=10.9, 5.3,
1H), 2.94 (dd, J=10.9, 7.1, 2H), 2.38-2.27 (m, 6H), 2.07 (d, J=7.2,
3H).
Example 241
(5-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2--
yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00353##
[0608] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 42 and
5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.23H.sub.27N.sub.7O.sub.2, 433.22; m/z found
434.2 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.84 (d,
J=9.0, 1 H), 7.69 (s, 2H), 7.01 (dd, J=9.0, 2.8, 1 H), 6.91 (d,
J=2.8, 1 H), 3.91-3.74 (m, 5H), 3.70-3.58 (m, 2H), 3.55 (dd,
J=11.4, 5.2, 1 H), 3.47-3.28 (m, 2H), 3.04-2.82 (m, 3H), 2.41-2.25
(m, 5H), 2.13-2.01 (m, 4H).
Example 242
(3-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(6-fluoroquinazolin-2-yl)hexa-
hydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00354##
[0609] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 43 and
3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.23H.sub.19F.sub.2N.sub.7O, 447.16; m/z found
448.1 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.99 (s, 1H),
7.77 (d, J=15.8, 2H), 7.61 (dd, J=11.0, 5.5, 1 H), 7.53-7.43 (m,
2H), 7.37-7.29 (m, 2H), 7.24 (s, 1H), 3.93 (d, J=9.9, 1 H), 3.79
(dd, J=12.3, 7.4, 2H), 3.71-3.62 (m, 1H), 3.62 (s, 3H), 3.20 (dd,
J=11.0, 5.3, 1 H), 3.12-2.98 (m, 2H).
Example 243
(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(6-fluoroquinazolin-2-yl)hexahydropy-
rrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00355##
[0611] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 43 and
3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI): mass calculated
for C.sub.25H.sub.20F.sub.2N.sub.6O, 458.17; m/z found 459.1
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.98 (d, J=8.1, 1
H), 8.82-8.74 (m, 2H), 7.61 (dt, J=12.7, 6.4, 1 H), 7.53-7.41 (m,
2H), 7.31 (td, J=8.0, 2.7, 1 H), 7.25-7.18 (m, 2H), 7.15 (t, J=4.9,
1 H), 4.00-3.88 (m, 1H), 3.89-3.69 (m, 3H), 3.68-3.52 (m, 3H), 3.36
(dd, J=10.9, 4.6, 1 H), 3.14-2.97 (m, 2H).
Example 244
(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3--
fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00356##
[0612] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 44 and
3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.23H.sub.18F.sub.3N.sub.7O, 465.15; m/z found
466.1 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.28 (s, 1H),
7.75 (d, J=20.8, 2H), 7.65 (dd, J=10.6, 8.4, 1 H), 7.50 (tt, J=9.6,
4.8, 1 H), 7.43 (dd, J=11.4, 8.0, 1 H), 7.39-7.31 (m, 1H), 7.25
(dd, J=12.5, 4.9, 1H), 4.00-3.86 (m, 1H), 3.81 (dd, J=10.0, 5.6,
2H), 3.66-3.49 (m, 4H), 3.32-3.16 (m, 3H).
Example 245
(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5--
methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00357##
[0614] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 44 and
5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.24H.sub.21F.sub.2N.sub.7O.sub.2, 477.2; m/z
found 478.1 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.25
(s, 1H), 7.84 (t, J=7.6, 1H), 7.64 (dt, J=19.7, 10.8, 3H), 7.42
(dd, J=11.4, 8.0, 1 H), 7.03 (dd, J=9.0, 2.8, 1 H), 6.92 (d, J=2.8,
1 H), 3.97-3.84 (m, 5H), 3.64 (dd, J=18.2, 14.6, 5H), 3.12 (dd,
J=19.8, 8.6, 3H).
Example 246
(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2--
fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00358##
[0616] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 44 and
2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.23H.sub.18F.sub.3N.sub.7O, 465.2; m/z found
466.1 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.32-8.24 (m,
1H), 7.90-7.79 (m, 2H), 7.68 (s, 1H), 7.65 (ddd, J=10.7, 8.5, 4.2,
1H), 7.55-7.38 (m, 2H), 7.22-7.10 (m, 1H), 4.13-3.48 (m, 7H),
3.40-3.05 (m, 3H).
Example 247
(2-Bromo-3-fluorophenyl)(5-(6-fluoroquinazolin-2-yl)hexahydropyrrolo[3,4-c-
]pyrrol-2(1H)-yl)methanone
##STR00359##
[0618] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 43 and 2-bromo-3-fluorobenzoic
acid. MS (ESI): mass calculated for
C.sub.21H.sub.17BrF.sub.2N.sub.4O, 458.1; m/z found 459.0
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.95 (d, J=19.8, 1
H), 8.01 (s, 1H), 7.59 (dt, J=13.3, 6.7, 1 H), 7.52-7.40 (m, 1H),
7.40-7.28 (m, 1H), 7.18-7.05 (m, 2H), 4.01 (dt, J=12.8, 8.4, 2H),
3.95-3.85 (m, 1H), 3.80-3.48 (m, 4H), 3.27-3.04 (m, 3H).
Example 248
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(5-methylpyridin-2-yl)phenyl)methanone
##STR00360##
[0619]
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)--
yl)(4-fluoro-2-(5-methylpyridin-2-yl)phenyl)methanone. The title
compound was prepared in a manner analogous to Intermediate 50,
Step A, substituting
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4--
fluoro-2-iodophenyl)methanone for 2-iodo-3-fluorobenzonitrile,
5-methyl-2-(tributylstannyl)pyridine for 2-tributylstannane
pyrimidine, dioxane for DME and heating to 130.degree. C. for 60
minutes. The reactions were filtered through celite, rinsed with
EtOAc and then concentrated and purified on RP agilent HPLC and
fractions lyophilized. MS (ESI) mass calcd. for
C.sub.25H.sub.26FN.sub.5O, 431.21. found 432.2 [M+H].sup.+.
Example 249
(2-Bromopyridin-3-yl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,-
4-c]pyrrol-2(1H)-yl)methanone
##STR00361##
[0620] The title compound was prepared in a manner analogous to
Example 1 utilizing Intermediate 42 and
2-bromopyridine-3-carboxylic acid. MS (ESI): mass calculated for
C.sub.19H.sub.22BrN.sub.5O, 415.10; m/z found 416.1 [M+H].sup.+.
.sup.1H NMR (600 MHz, CDCl.sub.3): 8.44 (dd, J=4.7, 1.6, 1 H), 7.33
(dd, J=7.6, 4.7, 1 H), 6.38-6.24 (m, 1H), 3.94-3.90 (m, 2H),
3.88-3.84 (m, 1H), 3.74-3.50 (m, 4H), 3.31-3.01 (m, 3H), 2.40-2.23
(m, 6H), 2.12-2.06 (m, 3H).
Example 250
(2-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)(5-(4,5,6-tr-
imethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00362##
[0621] The title compound was prepared in a manner similar to
Example 236, utilizing Example 249 and 4-(terahydropyran-2H-yl)-1H
pyrazole-5 boronic acid pinacol ester. MS (ESI): mass calculated
for C.sub.27H.sub.33N.sub.7O.sub.2, 487.27; m/z found 488.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.78-8.72 (m, 1H),
7.80-7.75 (m, 1H), 7.62-7.45 (m, 1H), 7.34 (dd, J=4.8, 1.5, 1 H),
6.33-6.23 (m, 1H), 3.91-3.78 (m, 2H), 3.72-3.53 (m, 3H), 3.53-3.36
(m, 2H), 3.36-3.15 (m, 3H), 2.98-2.70 (m, 3H), 2.65 (d, J=6.8, 1
H), 2.38-2.27 (m, 6H), 2.10-2.06 (m, 3H), 2.18-2.01 (m, 2H), 1.94
(s, 3H).
Example 251
(2-(1H-Pyrazol-5-yl)pyridin-3-yl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahyd-
ropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00363##
[0623] The title compound was prepared in a manner similar to
Example 237, utilizing
(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)(-
5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)me-
thanone (Example 250). MS (ESI): mass calculated for
C.sub.23H.sub.18F.sub.3N.sub.7O, 403.21; m/z found 404.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 11.90 (s, 1H), 8.65
(dd, J=4.7, 1.5, 1 H), 7.65 (dd, J=7.7, 1.6, 1 H), 7.50 (d, J=7.0,
1 H), 7.34-7.21 (m, 1H), 6.81 (s, 1H), 3.66-3.60 (m, 6H), 3.26 (s,
4H), 2.39-2.25 (m, 6H), 2.09 (d, J=40.1, 3H).
Example 252
6-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-2-methylpyrimidin-4(3H)-one
##STR00364##
[0625] To a solution of Intermediate 16 (35.3 mg, 0.117 mmol) in
n-butanol (0.5 mL) was added triethylamine (0.065 mL, 0.47 mmol)
and 6-chloro-2-methylpyrimidin-4-ol (33.9 mg, 0.234 mmol). The
mixture was heated to 150.degree. C. in the microwave for 18
minutes. The reaction was concentrated and purified by reverse
phase HPLC to give the title compound (21.4 mg, 45%). MS (ESI):
mass calculated for C.sub.20H.sub.20FN.sub.7O.sub.2, 409.4; m/z
found [M+H].sup.+ 410.2. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.91-7.76 (m, 3H), 7.54-7.42 (m, 1H), 7.15 (t, J=8.5 Hz, 1H),
4.07-2.94 (m, 11H), 2.37 (d, J=8.8 Hz, 3H).
Example 253
2-(2,6-Dimethylpyrimidin-4-yl)-5-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-
-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00365##
[0626] To a solution of Intermediate 48 (15.8 mg, 0.048 mmol) was
added DMF (0.4 mL), 4-chloro-2,6-dimethylpyrimidine (8.2 mg, 0.057
mmol) and cesium carbonate (38.8 mg, 0.119 mmol). The mixture was
heated to 100.degree. C. for 18 hours, diluted with water and
extracte with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified by
reverse phase HPLC to give the title compound (12.9 mg, 62%). MS
(ESI): mass calculated for C.sub.23H.sub.24FN.sub.5OS, 437.5; m/z
found [M+H].sup.+438.2. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.51-7.41 (m, 2H), 7.06-6.95 (m, 2H), 6.29 (s, 1H), 3.892-3.76 (m,
2H), 3.73-3.51 (m, 3H), 3.44 (dd, J=11.6, 5.0 Hz, 1H), 3.32 (dd,
J=11.6, 4.5 Hz, 1H), 3.10 (dd, J=11.3, 5.3 Hz, 1H), 3.02-2.80 (m,
2H), 2.70 (s, 3H), 2.31 (d, J=20.0 Hz, 6H).
Example 254
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-
-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00366##
[0627] The title compound was prepared in a manner analogous to
Example 253 substituting 2-chloro-4,6-dimethylpyrimidine for
4-chloro-2,6-dimethylpyrimidine. MS (ESI): mass calculated for
C.sub.23H.sub.24FN.sub.5OS, 437.5; m/z found [M+H].sup.+ 438.2.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.53-7.41 (m, 2H), 7.06-6.97 (m,
2H), 6.29 (s, 1H), 3.90-3.76 (m, 2H), 3.69-3.49 (m, 3H), 3.44 (dd,
J=11.6, 5.0 Hz, 1H), 3.32 (dd, J=11.6, 4.5 Hz, 1H), 3.10 (dd,
J=11.3, 5.3 Hz, 1H), 3.02-2.82 (m, 2H), 2.70 (s, 3H), 2.29 (s,
6H).
Example 255
6-[5-{[5-(4-Fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}hexahydropyrr-
olo[3,4-c]pyrrol-2(1H)-yl]-2-methyl pyrimidin-4(3H)-one
##STR00367##
[0629] The title compound was prepared in a manner analogous to
Example 252 substituting Intermediate 48 for Intermediate 16. MS
(ESI): mass calculated for C.sub.22H.sub.22FN.sub.5O.sub.2S, 439.5;
m/z found 440.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
12.77 (s, 1H), 7.50-7.43 (m, 2H), 7.09-7.02 (m, 2H), 3.90-3.82 (m,
2H), 3.66-3.49 (m, 4H), 3.29-2.82 (m, 5H), 2.71 (s, 3H), 2.36 (s,
3H).
Example 256
6-{5-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl}-2-methylpyrimidin-4(3H)-one
##STR00368##
[0630] The title compound was prepared in a manner analogous to
Example 252, substituting
(5-fluoro-2-(pyrimidin-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-y-
l)methanone for Intermediate 16. MS (ESI): mass calculated for
C.sub.22H.sub.21FN.sub.6O.sub.2, 420.5; m/z found 421.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 12.85 (s, 1H), 8.73
(d, J=4.9 Hz, 2H), 8.35 (dd, J=8.8, 5.6 Hz, 1H), 7.24-7.13 (m, 2H),
7.07 (dd, J=8.4, 2.6 Hz, 1H), 3.90 (dd, J=12.6, 7.7 Hz, 1H),
3.76-3.65 (m, 3H), 3.55-3.48 (m, 2H), 3.24-2.90 (m, 4H), 2.36 (d,
J=8.7 Hz, 3H).
Example 257
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00369##
[0632] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and Intermediate 4. MS (ESI):
mass calculated for C.sub.23H.sub.24FN.sub.5O, 407.19; m/z found
408.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.80-7.68 (m,
3H), 7.39 (dd, J=8.4, 5.8, 1 H), 7.17-7.09 (m, 1H), 6.40 (s, 1H),
6.17 (s, 2H), 3.89 (dd, J=12.7, 7.6, 2H), 3.69 (dd, J=12.8, 4.3,
2H), 3.61-3.48 (m, 2H), 3.45-3.32 (m, 2H), 3.25 (dd, J=9.5, 5.0,
2H), 1.25 (s, 6H).
Example 258
(5-(4,6-Dimethoxypyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2--
fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00370##
[0634] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 45 and Intermediate 12. MS
(ESI): mass calculated for C.sub.21H.sub.22FN.sub.7O.sub.3, 439.18;
m/z found 440.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.89-7.80 (m, 2H), 7.73 (s, 1H), 7.53-7.43 (m, 1H), 7.15 (tdd,
J=8.4, 3.7, 0.9, 1 H), 5.39 (d, J=2.4, 1 H), 4.02-3.48 (m, 13H),
3.31-2.89 (m, 3H).
Example 259
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-m-
ethyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00371##
[0635] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and Intermediate 11. MS
(ESI): mass calculated for C.sub.22H.sub.25N.sub.7O, 403.21; m/z
found 404.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.84-7.75 (m, 2H), 7.69 (s, 1H), 7.38 (td, J=7.9, 2.4, 1 H),
7.25-7.22 (m, 1H), 6.29 (d, J=3.8, 1 H), 3.98-3.30 (m, 8H), 3.01
(dd, J=11.5, 6.6, 2H), 2.30 (d, J=3.6, 3H), 1.57 (s, 6H).
Example 260
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-m-
ethyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00372##
[0636] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and
3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 82).
MS (ESI): mass calculated for C.sub.22H.sub.25N.sub.7O, 403.21; m/z
found 404.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.76
(s, 1H), 7.44-7.34 (m, 2H), 7.25 (s, 1H), 7.24 (d, J=1.9, 1 H),
6.30 (s, 1H), 3.88-3.40 (m, 8H), 3.23 (dd, J=11.0, 4.9, 1 H),
3.00-2.83 (m, 1H), 2.36-2.26 (m, 3H), 2.24 (d, J=16.1, 3H), 1.63
(s, 3H).
Example 261
(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-nitropyrimidin-2-yl)hexahy-
dropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00373##
[0637] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 46 and Intermediate 12. MS
(ESI): mass calculated for C.sub.19H.sub.17FN.sub.8O.sub.3, 424.14;
m/z found 425.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
9.10 (ddd, J=9.9, 5.7, 3.3, 2H), 7.90-7.79 (m, 2H), 7.74 (d, J=6.6,
1 H), 7.55-7.44 (m, 1H), 7.22-7.10 (m, 1H), 4.13-3.60 (m, 7H),
3.40-3.07 (m, 3H).
Example 262
Methyl
2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,-
4-c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate
##STR00374##
[0639] A mixture of Intermediate 16 (30 mg, 0.9 mmol), methyl
2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (22 mg, 0.09
mmol), Cs.sub.2CO.sub.3 (92.4 mg, 0.28 mmol), in DMA (1 mL) was
heated to 100.degree. C. for 72 hours. The mixture was cooled to rt
diluted with H.sub.2O and extracted with EtOAc. The organics were
combined, dried and concentrated under reduced pressure.
Purification (FCC) (10% MeOH, 0.1% NH.sub.4OH in DCM/DCM) afforded
the title compound (19 mg, 37%) MS (ESI): mass calculated for
C.sub.22H.sub.19F4N.sub.7O.sub.3, 505.15; m/z found 506.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.98-8.85 (m, 1H),
7.92-7.78 (m, 2H), 7.73 (d, J=2.8, 1H), 7.54-7.42 (m, 1H), 7.15
(td, J=8.4, 4.9, 1H), 4.15-3.45 (m, 11H), 3.41-2.95 (m, 3H). The
aqueous layer was acidified with 1 N HCl and extracted with EtOAc.
The organics were combined, dried and concentrated under reduced
pressure. Purification (FCC) (0-100% soln of 5% MeOH, 0.5% HOAc in
DCM/DCM) to afford
2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]py-
rrol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (22
mg, 44%).
Example 263
2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid
##STR00375##
[0640] The title compound was isolated from the synthesis of
Example 262. MS (ESI): mass calculated for
C.sub.21H.sub.17F.sub.4N.sub.7O.sub.3, 491.13; m/z found 492.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 8.90 (t, J=11.7, 1
H), 7.97 (s, 1H), 7.94-7.79 (m, 2H), 7.69-7.58 (m, 1H), 7.29 (dt,
J=25.1, 12.6, 1 H), 4.05-3.50 (m, 7H), 3.18 (tdd, J=19.6, 13.8,
6.8, 3H).
Example 264
(2-(4H-1,2,4-Triazol-4-yl)phenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydrop-
yrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00376##
[0641] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and
2-(4H-1,2,4-triazol-4-yl)benzoic acid. MS (ESI): mass calculated
for C.sub.22H.sub.19F.sub.4N.sub.7O.sub.3, 505.15; m/z found 506.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.49 (s, 2H), 7.54
(dd, J=7.6, 1.9, 3H), 7.45-7.37 (m, 1H), 6.31 (d, J=11.3, 1 H),
3.88-3.65 (m, 4H), 3.50 (dd, J=12.0, 4.4, 2H), 3.33 (dt, J=11.2,
5.6, 1 H), 3.08-2.80 (m, 3H), 2.28-2.26 (m, 6H).
Example 265
2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl)-6-methylpyrimidine-4-carboxylic acid
##STR00377##
[0642] The title compound was prepared in a manner analogous to
Example 262, substituting methyl
2-chloro-6-methylpyrimidine-4-carboxylate for methyl
2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate. MS (ESI):
mass calculated for C.sub.21H.sub.20FN.sub.7O.sub.3, 437.16; m/z
found 438.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD): 7.96
(d, J=6.2, 1 H), 7.92-7.79 (m, 2H), 7.67-7.57 (m, 1H), 7.29 (d,
J=8.4, 1 H), 7.09 (s, 1H), 4.01-3.53 (m, 7H), 3.28-2.99 (m, 3H),
2.40-2.36 (m, 3H).
Example 266
(4,5-Difluoro-2-(4H-1,2,4-triazol-4-yl)phenyl)(5-(4,6-dimethylpyrimidin-2--
yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00378##
[0643] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and
4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.21H.sub.21F.sub.2N.sub.7O, 425.18; m/z found
425.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.86 (dd,
J=10.8, 7.0, 1H), 7.74 (s, 2H), 7.26-7.19 (m, 1H), 6.30 (s, 1H),
3.86 (dd, J=11.8, 7.6, 2H), 3.66-3.50 (m, 5H), 3.10-2.86 (m, 3H),
2.36-2.23 (m, 6H).
Example 267
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-m-
ethyl-2-(1H-1,2,3-triazol-1-yl)phenyl)methanone
##STR00379##
[0644] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and
3-methyl-2-(1H-1,2,3-triazol-1-yl)benzoic acid. MS (ESI): mass
calculated for C.sub.22H.sub.25N.sub.7O, 403.21; m/z found 404.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.87-7.77 (m, 1H),
7.52-7.38 (m, 2H), 7.25 (d, J=4.7, 2H), 6.28 (s, 1H), 3.76 (dd,
J=11.6, 7.2, 2H), 3.65-3.29 (m, 6H), 3.12 (dd, J=11.1, 4.9, 1H),
2.96-2.83 (m, 1H), 2.29 (s, 6H), 2.15 (d, J=18.1, 3H).
Example 268
2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl)-N,N,6-trimethylpyrimidine-4-carboxamide
##STR00380##
[0645] The title compound was prepared using Example 265 in a
manner analogous to Example 15 substituting dimethylamine for
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and
EDCl for HATU in the last step. MS (ESI): mass calculated for
C.sub.23H.sub.25FN.sub.8O.sub.2, 464.21; m/z found
464.4[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.90-7.79 (m,
2H), 7.73 (s, 1H), 7.53-7.41 (m, 1H), 7.18-7.09 (m, 1H), 6.57 (d,
J=9.8, 1 H), 4.05-3.48 (m, 8H), 3.31-2.91 (m, 10H), 2.38 (s, 4H),
1.60 (s, 3H).
Example 269
2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyr-
rol-2(1H)-yl)-N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide
##STR00381##
[0646] The title compound was prepared using Example 263 in a
manner analogous to Example 15 substituting dimethylamine for
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and
EDCl for HATU in the last step. MS (ESI): mass calculated for
C.sub.23H.sub.22F.sub.4N.sub.8O.sub.2, 518.18; m/z found 518.2
[M+H].sup.+.
Example 270
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(mes-
ityl)methanone
##STR00382##
[0647] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and 2,4,6-trimethylbenzoic
acid. MS (ESI): mass calculated for C.sub.22H.sub.28N.sub.4O,
364.23; m/z found 365.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 6.82 (d, J=8.5, 2H), 6.29 (s, 1H), 4.03-3.29 (m, 8H),
3.11-2.89 (m, 2H), 2.35-2.11 (m, 15H).
Example 271
(2,3-Difluorophenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]-
pyrrol-2(1H)-yl)methanone
##STR00383##
[0648] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and 2,3-difluorobenzoic acid.
MS (ESI): mass calculated for C.sub.19H.sub.20F.sub.2N.sub.4O,
358.16; m/z found 358.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.26-7.08 (m, 3H), 6.30 (s, 1H), 4.03-3.73 (m, 3H),
3.71-3.57 (m, 3H), 3.39 (dd, J=11.3, 5.0, 2H), 3.16-2.95 (m, 2H),
2.36-2.19 (m, 6H).
Example 272
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-m-
ethoxy-2-(pyrimidin-2-yl)phenyl)methanone
##STR00384##
[0649] The title compound was prepared in a manner analogous to
Example 15 substituting Intermediate 88 for
3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass calcd.
for C.sub.24H.sub.26N.sub.6O.sub.2, 430.5; m/z found, 431.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl3): 8.78 (t, J=4.6 Hz, 2H),
7.80 (d, J=2.6 Hz, 1H), 7.33-7.27 (m, 1H), 7.16 (q, J=4.7 Hz, 1H),
7.05 (dd, J=8.4, 2.7 Hz, 1H), 6.30 (s, 1H), 3.91 (d, J=3.6 Hz, 3H),
3.85 (ddd, J=11.7, 7.8, 3.4 Hz, 2H), 3.72-3.60 (m, 3H), 3.54 (dd,
J=11.6, 4.8 Hz, 1H), 3.47 (dd, J=11.0, 7.3 Hz, 1H), 3.16 (dd,
J=11.1, 4.9 Hz, 1H), 3.00-2.87 (m, 2H), 2.30 (s, 6H).
Example 273
(2,3-Dimethoxyphenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c-
]pyrrol-2(1H)-yl)methanone
##STR00385##
[0650] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and 2,3-dimethoxybenzoic
acid. MS (ESI): mass calculated for C.sub.21H.sub.26N.sub.4O.sub.3,
382.20; m/z found 383.4 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.09 (dd, J=17.8, 9.7, 1 H), 6.89 (dd, J=7.9, 1.4,
2H), 6.33-6.19 (m, 1H), 4.02-3.43 (m, 13H), 3.32-2.83 (m, 3H),
2.39-2.21 (m, 6H).
Example 274
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(-
trifluoromethoxy)phenyl)methanone
##STR00386##
[0652] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and
2-(trifluoromethoxy)benzoic acid. MS (ESI): mass calculated for
C.sub.20H.sub.21F.sub.3N.sub.4O.sub.2, 406.16; m/z found 407.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.49-7.27 (m, 4H),
6.30 (s, 1H), 4.08-3.36 (m, 8H), 3.28-2.80 (m, 3H), 2.40-2.19 (m,
6H).
Example 275
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(6-m-
ethyl-2-[1,2,3]triazol-2-yl-pyridin-3-yl)-methanone
##STR00387##
[0653] To a pale yellow solution of
2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
(Intermediate 23) (50 mg, 0.23 mmol) in 2 mL of DMF was added
6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid (Intermediate 70) (51
mg, 0.25 mmol) followed by HATU (131 mg, 0.34 mmol) and DIPEA
(0.118 mL, 0.69 mmol). The resulting solution was allowed to stir
at room temp for 1 h and turned progressively more intense yellow
as the reaction continued. The reaction was monitored via LCMS and
quenched with H.sub.2O once starting materials we no longer
observed. The resulting biphasic mixture was extracted with EtOAc
three times. The combined organic layers were washed with brine,
dried with Na.sub.2SO.sub.4 and conc. into a pale yellow oil under
reduced pressure. The yellow residue was purified via FCC using
5-50% 2M NH.sub.3/MeOH in DCM. Minor impurities remained so the
material was further purified via HPLC 0-99% CH.sub.3N to give the
desired product. MS (ESI) mass calcd. for C.sub.21H.sub.24N.sub.8O,
404.47; m/z found 405.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) 7.80 (s, 2H), 7.72 (d, J=7.7 Hz, 1H), 7.29-7.24 (m,
1H), 6.30 (s, 1H), 3.90-3.80 (m, 2H), 3.73-3.63 (m, 2H), 3.59 (dd,
J=11.6, 5.3 Hz, 1H), 3.47 (dd, J=11.6, 3.7 Hz, 1H), 3.33 (s, 1H),
3.00 (ddd, J=38.4, 21.7, 7.2 Hz, 3H), 2.68 (s, 3H), 2.30 (s,
6H).
Example 276
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-m-
ethoxy-4-methylphenyl)methanone
##STR00388##
[0654] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and 2-methoxy-4-methylbenzoic
acid. MS (ESI): mass calculated for C.sub.21H.sub.26N.sub.4O.sub.2,
366.21; m/z found 367.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.13 (d, J=7.6, 1H), 6.77 (d, J=7.6, 1H), 6.70 (s,
1H), 6.28 (s, 1H), 4.00-3.40 (m, 11H), 3.27-2.85 (m, 3H), 2.41-2.19
(m, 9H).
Example 277
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-m-
ethoxy-2-methylphenyl)methanone
##STR00389##
[0656] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and 4-methoxy-2-methylbenzoic
acid. MS (ESI): mass calculated for C.sub.21H.sub.26N.sub.4O.sub.2,
366.21; m/z found 367.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.11 (d, J=7.9, 1 H), 6.77-6.67 (m, 2H), 6.29 (s, 1H),
4.01-3.83 (m, 2H), 3.83-3.72 (m, 4H), 3.72-3.55 (m, 2H), 3.46 (dt,
J=11.9, 6.0, 2H), 3.21-2.89 (m, 3H), 2.37-2.25 (m, 9H).
Example 278
(2,6-Difluorophenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]-
pyrrol-2(1H)-yl)methanone
##STR00390##
[0657] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and 2,6-difluorobenzoic acid.
MS (ESI): mass calculated for C.sub.19H.sub.20F.sub.2N.sub.4O,
358.16; m/z found 359.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.34 (tt, J=8.4, 6.4, 1 H), 6.93 (s, 2H), 6.30 (s,
1H), 4.12-3.76 (m, 3H), 3.75-3.45 (m, 4H), 3.36-2.88 (m, 3H), 2.30
(s, 6H).
Example 279
2-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-6-methylpyrimidine-4-carbonitrile
##STR00391##
[0658] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 12 and Intermediate 49. MS
(ESI): mass calculated for C.sub.21H.sub.19F.sub.2N.sub.8O, 418.44;
m/z found 419.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.91-7.80 (m, 2H), 7.75 (s, 1H), 7.55-7.42 (m, 1H), 7.15 (ddd,
J=8.4, 6.6, 4.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.07-3.46 (m, 7H),
3.35-3.20 (m, 1H), 3.19-2.94 (m, 2H), 2.40 (s, 3H).
Example 280
2-[4,6-Bis(trifluoromethyl)pyrimidin-2-yl]-5-{[2-fluoro-6-(2H-1,2,3-triazo-
l-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00392##
[0660] Step A: Intermediate 16 (100 mg, 0.332 mmol) was diluted
with DCM (10 mL) and was treated with
1,3-di-boc-2-(trifluoromethylsulfonyl)guanidine (118.2 mg, 0.302
mmol) and triethyl amine (0.046 mL, 0.332 mmol). The reaction was
stirred at room temperature overnight, then was diluted with DCM
and water, extracted and concentrated to provide crude tert-butyl
(((tert-butoxycarbonyl)imino)(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoy-
l)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)carbamate (165 mg)
which was used as is in Step B. MS (ESI): mass calculated for
C.sub.26H.sub.34FN.sub.7O.sub.5, 543.60; m/z found 544.3
[M+H].sup.+.
[0661] Step B: Crude tert-butyl
(((tert-butoxycarbonyl)imino)(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoy-
l)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)carbamate was
dissolved in dioxin (8 mL) and TFA (3 mL) was added and the
reaction was stirred at room temperature overnight to form crude
5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrro-
le-2(1H)-carboximidamide (214 mg) as a TFA salt which was used
directly in Step C.
[0662] Step C: Crude
5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrr-
ole-2(1H)-carboximidamide TFA salt (66 mg) was diluted with
n-butanol (4 mL) and treated with sodium methoxide (51.9 mg, 0.961
mmol). The reaction is heated to reflux for 1 hour, then cooled and
1,1,1,5,5,5-hexafluoropentane-2,4-dione (400 mg, 1.92 mmol) is
added prior to re-heating the reaction to reflux for 19 hours. The
mixture was then cooled and concentrated, then diluted with DCM and
saturated sodium bicarbonate. Extract with DCM and concentrate.
Reverse phase HPLC gave the title compound (4.6 mg). MS (ESI): mass
calculated for C.sub.21H.sub.16F.sub.7N.sub.7O, 515.39; m/z found
416.2 [M+H].sup.+. Rotamers observed in .sup.1H NMR.
Example 281
2-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-6-methylpyrimidin-4-ol
##STR00393##
[0663] The title compound was prepared in a manner analogous to
Example 280, substituting methyl acetoacetate for
1,1,1,5,5,5-hexafluoropentane-2,4-dione in Step C. MS (ESI): mass
calculated for C.sub.20H.sub.20FN.sub.7O.sub.2, 409.42; m/z found
410.2 [M+H].sup.+. Rotamers observed in .sup.1H NMR.
Example 282
(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-(furan-2-yl)-6-methylpyrim-
idin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00394##
[0664] The title compound was prepared in a manner analogous to
Example 280, substituting 1-(furan-2-yl)butane-1,3-dione for
1,1,1,5,5,5-hexafluoropentane-2,4-dione in the Step C. MS (ESI):
mass calculated for C.sub.24H.sub.22FN.sub.7O.sub.2, 459.49; m/z
found 460.2 [M+H].sup.+. .sup.1H NMR very broad peaks due to
rotamers.
Example 283
2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-fluoro-2-pyrimidin-2-ylphenyl)carbony-
l]octahydropyrrolo[3,4-c]pyrrole
##STR00395##
[0665] To a mixture of
2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole
(1.4 g, 6.5 mmol), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (1.4 g,
6.5 mmol), and TEA (1.3 mL, 9.7 mmol) in DMF (32.0 mL) was added
HATU (2.7 g, 7.1 mmol). After 1 h, the reaction mixture was diluted
with EtOAc and washed with water. The aqueous layer was then
extracted with EtOAc (1.times.). The combined organic phases were
dried (Na.sub.2SO.sub.4), filtered and concentrated to dryness. The
crude product was purified using silica gel chromatography (0-5%
MeOH in EtOAc) to yield pure title compound (1.2 g, 44%). MS (ESI)
mass calcd. For C.sub.23H.sub.23FN.sub.6O, 418.48; m/z found 419.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.91-8.56 (m, 2H), 7.47-7.42
(m, 1H), 7.24-7.14 (m, 3H), 6.30 (s, 1H), 3.81 (dd, J=11.6, 7.2 Hz,
1H), 3.72 (ddd, J=9.0, 7.2, 2.2 Hz, 2H), 3.68-3.47 (m, 4H), 3.31
(dd, J=11.0, 4.8 Hz, 1H), 3.05-2.89 (m, 2H), 2.31 (s, 6H).
Example 284
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(1H-pyrazol-5-yl)phenyl]carb-
onyl}octahydropyrrolo[3,4-c]pyrrole
##STR00396##
[0666] The title compound was prepared in a manner analogous to
Example 283, substituting Intermediate 86 for
3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd.
C.sub.22H.sub.23FN.sub.6O, 406.47; m/z found 407.2 [M+H].sup.+.
.sup.1H NMR (CDCl.sub.3): 11.33 (s, 1H), 7.50 (m, 1H), 7.35-7.31
(m, 1H), 7.21-7.08 (m, 2H), 6.64 (s, 1H), 6.28 (s, 1H), 3.82-2.71
(m, 10H), 2.30 (s, 6H).
Example 285
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-methoxy-2-(2H-1,2,3-triazol-2-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00397##
[0667] The title compound was prepared in a manner analogous to
Example 283, substituting
3-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid for
3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd.
C.sub.22H.sub.25N.sub.7O.sub.2, 419.49; m/z found 420.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.74 (d, J=6.6 Hz, 2H),
7.51-7.45 (m, 1H), 7.09 (dd, J=8.4, 1.0 Hz, 1H), 7.00 (dd, J=7.6,
1.1 Hz, 1H), 6.29 (s, 1H), 3.87-3.76 (m, 4H), 3.66 (ddd, J=19.8,
12.1, 7.0 Hz, 2H), 3.58-3.50 (m, 2H), 3.47-3.37 (m, 2H), 3.22 (dd,
J=11.0, 5.1 Hz, 1H), 2.97-2.86 (m, 2H), 2.28 (s, J=20.1 Hz,
6H).
Example 286
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-methoxy-2-(1H-1,2,3-triazol-1-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00398##
[0669] Step A: To 3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile
(2.1 g, 11.2 mmol) in MeOH (30 mL) was added 2 M aq. NaOH (10 mL).
The reaction was heated at reflux until determined complete by HPLC
then cooled to room temperature, acidified with 1 N aq. HCl to pH=1
and extracted with DCM (2.times.). The combined organics were
washed with brine and dried (Na.sub.2SO.sub.4) resulting in a
mixture of two products, 3-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic
acid and 3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzoic acid, which were
used without further purification in the next step.
[0670] Step B:
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-methoxy-2-(1H-1,2,3-triazol-1-yl)phe-
nyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole. Example 286 was
prepared in a manner analogous to Example 283, utilizing a mixture
of 3-methoxy-2-(1H-1,2,3-triazol-2-yl)benzoic acid and
3-fluoro-2-(1H-1,2,3-triazol-2-yl)benzoic acid in place of
3-fluoro-2-(pyrimidin-2-yl)benzoic acid which gave 2 products,
Example 286 and Example 287. For Example 286: MS (ESI) mass calcd.
C.sub.22H.sub.23N.sub.7O.sub.2, 419.49; m/z found 420.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.87 (d, J=1.0 Hz, 1H), 7.77
(d, J=1.0 Hz, 1H), 7.52-7.45 (m, 1H), 7.09 (dd, J=8.5, 1.0 Hz, 1H),
7.00 (dd, J=7.7, 1.1 Hz, 1H), 6.29 (s, J=5.2 Hz, 1H), 3.89-3.81 (m,
4H), 3.79-3.65 (m, 3H), 3.54-3.46 (m, 2H), 3.43-3.36 (m, 1H), 3.24
(dt, J=12.4, 6.1 Hz, 1H), 3.02-2.91 (m, 2H), 2.29 (s, 6H).
Example 287
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(1H-1,2,3-triazol-1-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00399##
[0671] The title compound was isolated from Step B in Example 286.
MS (ESI) mass calcd. C.sub.21H.sub.22FN.sub.7O, 407.45; m/z found
408.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.96-7.91 (m, 1H),
7.84-7.80 (m, 1H), 7.58-7.49 (m, 1H), 7.37-7.30 (m, 1H), 7.26-7.23
(m, 1H), 6.29 (s, 1H), 3.88-3.85 (m, 1H), 3.80-3.71 (m, 2H),
3.71-3.64 (m, 1H), 3.57-3.42 (m, 3H), 3.23 (dd, J=11.0, 5.0 Hz,
1H), 3.04-2.94 (m, 2H), 2.29 (s, 6H).
Example 288
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00400##
[0673] Step A:
(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-tr-
iazol-2-yl)phenyl)methanone. To a mixture of
2-benzyloctahydropyrrolo[3,4-c]pyrrole (282 mg, 1.4 mmol),
4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (306 mg, 1.4 mmol),
and TEA (0.21 mL, 1.5 mmol) in DMF (7.5 mL) was added HATU (583 mg,
1.5 mmol). After 1 h, the reaction mixture was diluted with EtOAc
and washed with water. The aqueous layer was then extracted with
EtOAc (1). The combined organics were dried (Na.sub.2SO.sub.4) and
concentrated to give a residue. Purification via Agilent prep
system (Basic) gave 327 mg (58%) of the title compound as a clear
oil. .sup.1H NMR (CDCl.sub.3): 7.79 (s, J=6.5 Hz, 2H), 7.50 (d,
J=5.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.34-7.21 (m, 5H), 6.95 (dd,
J=8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.86-3.72 (m, 1H), 3.65-3.46 (m,
3H), 3.13 (s, 1H), 2.90-2.74 (m, 2H), 2.74-2.59 (m, 2H), 2.57-2.39
(m, 2H), 2.16 (dd, J=9.2, 4.2 Hz, 1H).
[0674] Step B:
(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2--
yl)phenyl)methanone.
(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-tr-
iazol-2-yl)phenyl)methanone in EtOH (20 mL) and AcOH (1 mL) was
continuously flowed through a 20 wt % Pd(OH).sub.2/C cartridge at a
rate of 1 mL/min for 2 h at 50.degree. C. and 50 bar using a H-cube
apparatus. Then the reaction was concentrated and neutralized with
5% Na.sub.2CO.sub.3 (aq), and extracted with CH.sub.2Cl.sub.2
(3.times.). Combined organics and dried (Na.sub.2SO.sub.4) to give
(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2--
yl)phenyl)methanone as a clear oil that was used without further
purification. .sup.1H NMR (CDCl.sub.3):7.83-7.80 (m, 2H), 7.50 (d,
J=2.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.96 (dd, J=8.5, 2.5 Hz,
1H), 3.89 (s, 3H), 3.75-3.63 (m, 2H), 3.27 (s, 1H), 3.08 (dd,
J=11.9, 8.1 Hz, 1H), 2.94 (dt, J=11.4, 5.7 Hz, 2H), 2.88-2.75 (m,
2H), 2.69 (dd, J=17.8, 14.3 Hz, 1H), 2.56 (dd, J=11.4, 3.9 Hz,
1H).
[0675] Step C:
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phe-
nyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole. To
(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2--
yl)phenyl)methanone (185 mg, 0.4 mmol) in DMF (2.2 mL) was added
2-chloro-4,6-dimethylpyrimidine (61 mg, 0.4 mmol). The flask was
heated to 120.degree. C. for 18 h. The flask was allowed to cool to
rt, diluted with EtOAc and washed with H.sub.2O. The aq was
back-extracted with EtOAc (1.times.). The combined organics were
washed with brine and dried (Na.sub.2SO.sub.4) to give an oil.
Purification via silica gel (15-75% EtOAc in hexanes) gave 175 mg
(97%) of the title compound. MS (ESI) mass calcd.
C.sub.22H.sub.25N.sub.7O.sub.2, 419.49; m/z found 420.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.73 (s, 2H), 7.49 (d, J=7.8
Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 6.29
(s, 1H), 3.93-3.80 (m, 5H), 3.72-3.63 (m, 2H), 3.58 (dd, J=11.6,
5.2 Hz, 1H), 3.46 (dd, J=11.6, 4.3 Hz, 1H), 3.39-3.28 (m, 1H),
3.05-2.84 (m, 3H), 2.33 (s, 6H).
Example 289
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(1H-1,2,3-triazol-2-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00401##
[0677] The title compound was prepared in a manner analogous to
Example 283, utilizing a mixture of
4-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic acid and
4-methoxy-2-(2H-1,2,3-triazol-1-yl)benzoic acid obtained from the
synthesis of Intermediate 54. Purification of the final compounds
gave the title compound as an oil. MS (ESI) mass calcd.
C.sub.22H.sub.25N.sub.7O.sub.2, 419.49; m/z found 420.2
[M+H].sup.+1H NMR (CDCl.sub.3): 7.98 (s, J=2.9 Hz, 1H), 7.77 (s,
J=4.1 Hz, 1H), 7.42-7.36 (m, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.06 (dd,
J=8.5, 2.5 Hz, 1H), 6.29 (s, 1H), 3.90 (s, J=7.6 Hz, 3H), 3.83-3.66
(m, 3H), 3.50-3.42 (m, 2H), 3.30 (dd, J=11.6, 4.7 Hz, 1H), 3.22
(dd, J=11.1, 7.3 Hz, 1H), 2.99-2.76 (m, 3H), 2.28 (d, J=16.2 Hz,
6H).
Example 290
2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]ca-
rbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00402##
[0678] A mixture of Intermediate 20 (86 mg, 0.30 mmol),
Intermediate 55 (44 mg, 0.3 mmol) and DIPEA (0.16 mL, 0.91 mmol) in
ACN (1 mL) was heated in the microwave at 200.degree. C. for 2 h.
The mixture was concentrated in vacuo and chromatography (Hex to
100% EtOAc/Hex) afforded the title compound (82 mg, 69%). MS (ESI):
mass calculated for C.sub.20H.sub.20FN.sub.7O, 393.17, m/z found
394.2 [M+1].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.06 (d,
J=1.7 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.75 (s, 2H), 7.57-7.48 (m,
1H), 7.43 (d, J=6.2 Hz, 2H), 3.93-3.77 (m, 2H), 3.74-3.60 (m, 2H),
3.59-3.51 (m, 1H), 3.46-3.33 (m, 2H), 3.09-2.88 (m, 3H), 2.37 (d,
J=2.5 Hz, 3H).
Example 291
2-(2-Chloro-5-fluoropyrimidin-4-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]ca-
rbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00403##
[0679] The title compound was prepared in a manner analogous to
Example 290 utilizing Intermediate 20 and substituting
2,4-dichloro-5-fluoropyrimidine for Intermediate 55. MS (ESI) mass
calculated for C.sub.19H.sub.17CIFN.sub.7O, 413.85; m/z found,
414.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.01 (d,
J=8.3 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.79 (s, 2H), 7.58-7.51 (m,
1H), 7.48-7.39 (m, 2H), 4.04-3.93 (m, 1H), 3.92-3.70 (m, 4H),
3.68-3.59 (m, 1H), 3.46 (br s, 1H), 3.13-2.88 (m, 3H).
Example 292
2-(5-Fluoropyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]ca-
rbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00404##
[0680] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 16 for Intermediate 20 and
2-chloro-5-fluoropyrimidine for Intermediate 55. MS (ESI) mass
calculated for C.sub.19H.sub.17F.sub.2N.sub.7O, 397.39; m/z found,
398.2. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.26-8.17 (m, 2H),
7.89-7.78 (m, 2H), 7.73 (s, 1H), 7.53-7.44 (m, 1H), 7.19-7.10 (m,
1H), 4.02-3.45 (m, 7H), 3.30-3.23 (m, 1H), 3.17-2.97 (m, 2H).
Example 293
2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)-
phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00405##
[0681] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 16 for Intermediate 20. MS
(ESI) mass calculated for C.sub.20H.sub.19F.sub.2N.sub.7O, 411.42;
m/z found, 412.2. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.09-8.03 (m,
1H), 7.88-7.79 (m, 2H), 7.72 (s, 1H), 7.51-7.43 (m, 1H), 7.18-7.10
(m, 1H), 4.01-3.45 (m, 7H), 3.30-3.21 (m, 1H), 3.15-2.95 (m, 2H),
2.37 (d, J=2.4 Hz, 3H).
Example 294
2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4,5,6-trimethylp-
yrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00406##
[0682] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 16 for Intermediate 20 and
Intermediate 56 for Intermediate 55. MS (ESI) mass calculated for
C.sub.22H.sub.24FN.sub.7O, 421.48; m/z found, 422.2. .sup.1H NMR
(500 MHz, CDCl.sub.3): 7.88-7.79 (m, 2H), 7.72 (s, 1H), 7.50-7.43
(m, 1H), 7.17-7.10 (m, 1H), 3.93-3.47 (m, 7H), 3.28-3.21 (m, 1H),
3.11-2.93 (m, 2H), 2.33 (s, 6H), 2.07 (s, 3H).
Example 295
2-(4,5-Dimethylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00407##
[0683] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 16 for Intermediate 20 and
Intermediate 57 for Intermediate 55. MS (ESI) mass calculated for
C.sub.21H.sub.22FN.sub.7O, 407.45; m/z found, 408.2. .sup.1H NMR
(400 MHz, CDCl.sub.3): 7.99 (s, 1H), 7.89-7.78 (m, 2H), 7.72 (s,
1H), 7.53-7.42 (m, 1H), 7.19-7.08 (m, 1H), 4.02-3.46 (m, 7H),
3.31-3.21 (m, 1H), 3.15-2.95 (m, 2H), 2.32 (s, 3H), 2.09 (s,
3H).
Example 296
2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methoxy-6-meth-
ylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00408##
[0684] The title compound was isolated from the synthesis of
Intermediate 58. MS (ESI) mass calculated for
C.sub.21H.sub.22FN.sub.7O.sub.2, 423.45; m/z found, 424.0. .sup.1H
NMR (500 MHz, CDCl.sub.3): 7.88-7.80 (m, 2H), 7.72 (s, 1H),
7.52-7.44 (m, 1H), 7.18-7.11 (m, 1H), 5.87 (d, J=4.3 Hz, 1H),
4.00-3.50 (m, 10H), 3.30-3.22 (m, 1H), 3.13-2.93 (m, 2H), 2.28 (s,
3H).
Example 297
2-(4-Ethyl-6-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)p-
henyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00409##
[0685] The title compound was prepared in a manner analogous to
Intermediate 55 substituting Intermediate 58 for
2,4-dichloro-5-fluoropyrimidine and 1.0 M EtMgBr in THF for 3.0 M
MeMgBr in Et.sub.2O. MS (ESI) mass calculated for
C.sub.22H.sub.24FN.sub.7O, 421.48; m/z found, 422.0. .sup.1H NMR
(500 MHz, CDCl.sub.3): 7.88-7.79 (m, 2H), 7.71 (s, 1H), 7.51-7.43
(m, 1H), 7.18-7.11 (m, 1H), 6.29 (d, J=7.2 Hz, 1H), 4.01-3.50 (m,
7H), 3.31-3.22 (m, 1H), 3.13-2.94 (m, 2H), 2.56 (q, J=7.6 Hz, 2H),
2.31 (d, J=1.6 Hz, 3H), 1.27-1.21 (m, 3H).
Example 298
2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-methyl-6-(1-me-
thylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00410##
[0686] The title compound was prepared in a manner analogous to
Intermediate 55 substituting Intermediate 58 for
2,4-dichloro-5-fluoropyrimidine and 2.0 M iPrMgBr in THF for 3.0 M
MeMgBr in Et.sub.2O. Three products were formed in this reaction,
2-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-methyl-6-(1-m-
ethylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole,
2-[4-methyl-6-(1-methylethyl)pyrimidin-2-yl]-5-{[2-(2H-1,2,3-triazol-2-yl-
)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole and
2-{[5-(1-Methylethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-meth-
yl-6-(1-methylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole.
MS (ESI) mass calculated for C.sub.23H.sub.26FN.sub.7O, 435.51; m/z
found, 436.2. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.89-7.79 (m, 2H),
7.72 (s, 1H), 7.52-7.43 (m, 1H), 7.18-7.10 (m, 1H), 6.32-6.25 (m,
1H), 4.01-3.49 (m, 7H), 3.31-3.21 (m, 1H), 3.13-2.93 (m, 2H),
2.82-2.70 (m, 1H), 2.32 (d, J=2.1 Hz, 3H), 1.27-1.20 (m, 6H).
Example 299
2-[4-Methyl-6-(1-methylethyl)pyrimidin-2-yl]-5-{[2-(2H-1,2,3-triazol-2-yl)-
phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00411##
[0687] The title compound was isolated from the synthesis of
Example 298. MS (ESI) mass calculated for C.sub.23H.sub.27N.sub.7O,
417.52; m/z found, 418.2. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.98
(d, J=8.1 Hz, 1H), 7.73 (s, 2H), 7.55-7.48 (m, 1H), 7.45-7.39 (m,
2H), 6.29 (s, 1H), 3.91-3.83 (m, 2H), 3.74-3.64 (m, 2H), 3.63-3.57
(m, 1H), 3.50-3.44 (m, 1H), 3.42-3.27 (m, 1H), 3.07-2.88 (m, 3H),
2.81-2.59 (m, 1H), 2.31 (s, 3H), 1.25-1.21 (m, 6H).
Example 300
2-{[5-(1-Methylethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-methy-
l-6-(1-methylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole
##STR00412##
[0688] The title compound was isolated from the synthesis of
Example 298. MS (ESI) mass calculated for C.sub.26H.sub.33N.sub.7O,
459.6; m/z found, 460.3. .sup.1H NMR (400 MHz, CDCl.sub.3):
7.84-7.72 (m, 2H), 7.67 (s, 1H), 7.51-7.32 (m, 2H), 6.32-6.25 (m,
1H), 3.92-3.31 (m, 7H), 3.16-2.70 (m, 5H), 2.31 (d, J=4.7 Hz, 3H),
1.28-1.14 (m, 12H).
Example 301
2-(4-tert-Butyl-6-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-
-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00413##
[0689] The title compound was prepared in a manner analogous to
Intermediate 55 substituting Intermediate 58 for
2,4-dichloro-5-fluoropyrimidine and 1.0 M tBuMgBr in THF for 3.0 M
MeMgBr in Et.sub.2O. MS (ESI) mass calculated for
C.sub.24H.sub.28FN.sub.7O, 449.54; m/z found, 450.3. .sup.1H NMR
(500 MHz, CDCl.sub.3): 7.93-7.72 (m, 3H), 7.54-7.45 (m, 1H),
7.20-7.11 (m, 1H), 6.66-6.59 (m, 1H), 4.23-3.60 (m, 7H), 3.38-3.06
(m, 3H), 2.67-2.43 (m, 3H), 1.29 (s, 9H).
Example 302
2-(4-Cyclopropyl-6-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol--
2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00414##
[0690] The title compound was prepared in a manner analogous to
Intermediate 55 substituting Intermediate 58 for
2,4-dichloro-5-fluoropyrimidine and 0.5 M cyclopropylmagnesium
bromide in THF for 3.0 M MeMgBr in Et.sub.2O. MS (ESI) mass
calculated for C.sub.23H.sub.24FNO, 433.49; m/z found, 434.2.
.sup.1H NMR (500 MHz, CDCl.sub.3): 7.87-7.80 (m, 2H), 7.71 (s, 1H),
7.51-7.43 (m, 1H), 7.18-7.11 (m, 1H), 6.31-6.26 (m, 1H), 3.99-3.79
(m, 2H), 3.79-3.72 (m, 1H), 3.69-3.45 (m, 4H), 3.27-3.20 (m, 1H),
3.10-2.91 (m, 2H), 2.29 (s, 3H), 1.82-1.74 (m, 1H), 1.10-1.00 (m,
2H), 0.95-0.88 (m, 2H).
Example 303
2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methyl-1,3,5-t-
riazin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00415##
[0692] Step A: tert-Butyl
5-(4-chloro-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo-
xylate. To a solution of 2,4-dichloro-1,3,5-triazine (150 mg, 0.953
mmol) in ACN (5 mL) was added a solution of Intermediate 15 (202
mg, 0.953 mmol) and DIPEA (0.33 mL, 1.91 mmol) in ACN (5 mL) at
0.degree. C. dropwise. After 10 min the mixture was diluted with
saturated aqueous NH.sub.4Cl solution. The aqueous layer was then
extracted with DCM and the combined organic extracts were dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Chromatography (Hexanes to 80% EtOAc/Hexanes) afforded the desired
product as a white solid (137 mg, 44%). MS (ESI) mass calculated
for C.sub.14H.sub.20ClN.sub.5O.sub.2, 325.13; m/z found, 326.1.
[0693] Step B: tert-Butyl
5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo-
xylate. tert-Butyl
5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo-
xylate was prepared in a manner analogous to Intermediate 55
substituting the product of Step A for
2,4-dichloro-5-fluoropyrimidine. MS (ESI) mass calculated for
C.sub.15H.sub.23N.sub.5O.sub.2, 305.18; m/z found, 306.0.
[0694] Step C:
2-(4-Methyl-1,3,5-triazin-2-yl)octahydropyrrolo[3,4-c]pyrrole.
tert-Butyl
5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbo-
xylate (43 mg, 0.142 mmol), DCM (1.4 mL) and TFA (0.71 mL) were
stirred at room temperature for 2 h. The mixture was concentrated
in vacuo and taken on to the next step without further
purification.
[0695] Step D:
2{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methyl-1,3,5-t-
riazin-2-yl)octahydropyrrolo[3,4-c]pyrrole. Example 303 was
prepared in a manner analogous to Intermediate 59 substituting the
product of Step C for Intermediate 15 and Intermediate 12 for
2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated
for C.sub.19H.sub.19FN.sub.8O, 394.41; m/z found, 395.0. .sup.1H
NMR (500 MHz, CDCl.sub.3): 8.51-8.42 (m, 1H), 7.89-7.81 (m, 2H),
7.75 (d, J=3.5 Hz, 1H), 7.54-7.45 (m, 1H), 7.20-7.11 (m, 1H),
4.02-3.51 (m, 8H), 3.32-3.23 (m, 1H), 3.17-3.00 (m, 2H), 2.50-2.40
(m, 3H).
Example 304
2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methyl-6-morph-
olin-4-ylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00416##
[0696] A mixture of Intermediate 58 (137 mg, 0.254 mmol) and
morpholine (1.3 mL) was stirred 14 h at room temperature. The
mixture was concentrated in vacuo. Chromatography (DCM to 8% 2 M
NH.sub.3 in MeOH/DCM) afforded the desired product as a pale yellow
foam (95 mg, 78%). MS (ESI) mass calculated for
C.sub.24H.sub.27FN.sub.8O.sub.2, 478.53; m/z found, 479.3. .sup.1H
NMR (500 MHz, CDCl.sub.3): 7.86-7.78 (m, 2H), 7.72 (s, 1H),
7.51-7.44 (m, 1H), 7.18-7.10 (m, 1H), 5.77-5.72 (m, 1H), 3.99-3.47
(m, 13H), 3.28-3.21 (m, 1H), 3.09-2.91 (m, 2H), 2.90-2.86 (m, 2H),
2.25 (s, 3H).
Example 305
2-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpyrimidin--
2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00417##
[0698] Step A:
(2-(4H-1,2,4-Triazol-3-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-
methanone.
(2-(4H-1,2,4-Triazol-3-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-
-2(1H)-yl)methanone was prepared in a manner analogous to Example
303, substituting Intermediate 59 for the product of Example 303 in
Step C. MS (ESI) mass calculated for C.sub.15H.sub.17NO, 283.14;
m/z found, 284.2.
[0699] Step B:
2-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpyrimidin-
-2-yl)octahydropyrrolo[3,4-c]pyrrole. The product of Step A (167
mg, 0.421 mmol), Intermediate 56 (66 mg, 0.421 mmol) and DIPEA
(0.29 mL, 1.68 mmol) were heated for 2 h at 200.degree. C. in ACN
(1.4 mL) in the microwave. The mixture was concentrated in vacuo.
The crude product was purified using Agilent HPLC (basic system) to
yield impure material. This material was subsequently purified
using normal phase chromatography (DCM to 8% 2M NH.sub.3 in
MeOH/DCM) to afford the title compound (49 mg, 29%). MS (ESI) mass
calculated for C.sub.22H.sub.25N.sub.7O, 403.49; m/z found, 404.2.
.sup.1H NMR (500 MHz, CDCl.sub.3): 8.16 (d, J=7.8 Hz, 1H), 8.06 (s,
1H), 7.54-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.35 (d, J=7.5 Hz, 1H),
3.96-3.89 (m, 1H), 3.85-3.77 (m, 1H), 3.74-3.68 (m, 1H), 3.68-3.55
(m, 2H), 3.42 (br s, 2H), 3.16 (br s, 1H), 3.04-2.96 (m, 1H), 2.89
(br s, 1H), 2.32 (s, 6H), 2.05 (s, 3H).
Example 306
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl-
]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00418##
[0701] The title compound was prepared in a manner analogous to
Intermediate 59 substituting Intermediate 23 for Intermediate 15
and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for
2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated
for C.sub.22H.sub.24N.sub.6O.sub.2, 404.48; m/z found, 405.2.
.sup.1H NMR (500 MHz, CDCl.sub.3): 8.10 (dd, J=7.9 Hz, 0.9 Hz, 1H),
7.62 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.53 (td, J=7.7 Hz, 1.3 Hz, 1H),
7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 6.28 (s, 1H), 3.99-3.88 (m, 2H),
3.80-3.75 (m, 1H), 3.74-3.65 (m, 2H), 3.53-3.48 (m, 1H), 3.46-3.40
(m, 1H), 3.12-3.04 (m, 2H), 3.01-2.93 (m, 1H), 2.42 (s, 3H), 2.28
(s, 6H).
Example 307
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00419##
[0703] Step A:
(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(1-methyl-1H-1,2,4-triazol-5-y-
l)phenyl)methanone. Intermediate 60 (100 mg, 0.252 mmol), DCM (2.5
mL), TFA (0.5 mL) were stirred at room temperature for 2 h and then
concentrated in vacuo. The residue was dissolved in DCM and treated
with Dowex 550 A resin. After stirring for 2 h the resin was
removed by filtration and the filtrate was concentrated in vacuo to
a colorless oil which was taken on to the next step without further
purification. MS (ESI) mass calculated for
C.sub.16H.sub.19N.sub.5O, 297.16; m/z found, 298.0.
[0704] Step B:
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole. Example 307 was
prepared in a manner analogous to Example 290 substituting the
product of Step A for Intermediate 20 and
2-chloro-4,6-dimethylpyrimidine for Intermediate 55. MS (ESI) mass
calculated for C.sub.22H.sub.25N.sub.7O, 403.21; m/z found, 404.2.
.sup.1H NMR (500 MHz, CDCl.sub.3): 7.83 (s, 1H), 7.58-7.49 (m, 2H),
7.47-7.42 (m, 2H), 6.28 (s, 1H), 3.85-3.80 (m, 4H), 3.75-3.69 (m,
2H), 3.55-3.45 (m, 4H), 3.24-3.19 (m, 1H), 2.99-2.88 (m, 2H), 2.29
(s, 6H).
Example 308
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)pheny-
l]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00420##
[0705] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 61 for Intermediate 60 in
Step A. MS (ESI) mass calculated for C.sub.22H.sub.26N.sub.7O,
403.21; m/z found, 404.2. .sup.1H NMR (500 MHz, CDCl.sub.3):
8.12-8.06 (m, 1H), 7.93 (s, 1H), 7.49-7.38 (m, 2H), 7.37-7.29 (m,
1H), 6.27 (s, 1H), 3.95-3.83 (m, 5H), 3.78-3.60 (m, 3H), 3.47-3.38
(m, 2H), 3.08-2.98 (m, 2H), 2.95-2.86 (m, 1H), 2.29 (s, 6H).
Example 309
2-{[2-(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpy-
rimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00421##
[0706] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 62 for Intermediate 60 in
Step A, and Intermediate 56 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for
C.sub.23H.sub.26N.sub.6O.sub.2, 418.21; m/z found, 419.3. .sup.1H
NMR (500 MHz, CDCl.sub.3): 8.09 (dd, J=7.9 Hz, 0.9 Hz, 1H), 7.60
(td, J=7.6 Hz, 1.2 Hz, 1H), 7.52 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.41
(dd, J=7.6 Hz, 1.0 Hz, 1H), 3.98-3.93 (m, 1H), 3.90-3.84 (m, 1H),
3.79-3.73 (m, 1H), 3.70-3.61 (m, 2H), 3.50-3.44 (m, 1H), 3.44-3.38
(m, 1H), 3.10-3.02 (m, 2H), 2.98-2.91 (m, 1H), 2.42 (s, 3H), 2.30
(s, 6H), 2.06 (s, 3H).
Example 310
2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)p-
henyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00422##
[0708] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 62 for Intermediate 60 in
Step A, and Intermediate 55 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for
C.sub.21H.sub.21FN.sub.6O.sub.2, 408.17; m/z found, 409.2. .sup.1H
NMR (500 MHz, CDCl.sub.3): 8.10 (dd, J=7.9 Hz, 0.9 Hz, 1H), 8.04
(d, J=1.8 Hz, 1H), 7.61 (td, J=7.6 Hz, 1.3 Hz, 1H), 7.53 (td, J=7.7
Hz, 1.3 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 4.00-3.94 (m,
1H), 3.90-3.83 (m, 1H), 3.79-3.74 (m, 1H), 3.71-3.60 (m, 2H),
3.47-3.41 (m, 2H), 3.13-3.06 (m, 2H), 3.02-2.94 (m, 1H), 2.41 (s,
3H), 2.35 (d, J=2.5 Hz, 3H).
Example 311
2-{[2-(1-Methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}-5-(4,5,6-trimethylp-
yrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00423##
[0709] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 61 for Intermediate 60 in
Step A, and Intermediate 56 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for C.sub.23H.sub.27N.sub.7O,
417.23; m/z found, 418.2. .sup.1H NMR (500 MHz, CDCl.sub.3):
8.11-8.04 (m, 1H), 7.93 (s, 1H), 7.47-7.38 (m, 2H), 7.34-7.30 (m,
1H), 3.94-3.79 (m, 5H), 3.75-3.69 (m, 1H), 3.66-3.56 (m, 2H),
3.43-3.36 (m, 2H), 3.07-2.97 (m, 2H), 2.92-2.85 (m, 1H), 2.32 (s,
6H), 2.06 (s, 3H).
Example 312
2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)-
phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00424##
[0710] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 61 for Intermediate 60 in
Step A, and Intermediate 55 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for C.sub.21H.sub.22FN.sub.7O,
407.19; m/z found, 408.2. .sup.1H NMR (500 MHz, CDCl.sub.3): 8.09
(dd, J=7.5 Hz, 1.5 Hz, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.94 (s, 1H),
7.47-7.39 (m, 2H), 7.34-7.30 (m, 1H), 3.97-3.85 (m, 4H), 3.85-3.78
(m, 1H), 3.76-3.70 (m, 1H), 3.66-3.55 (m, 2H), 3.45-3.36 (m, 2H),
3.09-3.00 (m, 2H), 2.97-2.88 (m, 1H), 2.35 (d, J=2.5 Hz, 3H).
Example 313
2-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[-
3,4-c]pyrrol-2(1H)-yl]-4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine
##STR00425##
[0711] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 16 for Intermediate 20 and
2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine for
Intermediate 55. MS (ESI) mass calculated for
C.sub.23H.sub.24FN.sub.7O, 433.20; m/z found, 434.2. 1H NMR (500
MHz, CDCl.sub.3): 7.87-7.78 (m, 2H), 7.72 (s, 1H), 7.49-7.42 (m,
1H), 7.17-7.09 (m, 1H), 4.01-3.84 (m, 2H), 3.82-3.49 (m, 5H),
3.29-3.22 (m, 1H), 3.13-2.93 (m, 2H), 2.86-2.79 (m, 2H), 2.78-2.72
(m, 2H), 2.28 (s, 3H), 2.09-2.00 (m, 2H).
Example 314
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5--
yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00426##
[0712] The title compound was prepared in a manner analogous to
Intermediate 59 substituting Intermediate 23 for Intermediate 15
and Intermediate 63 for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS
(ESI) mass calculated for C.sub.22H.sub.23FN.sub.6O.sub.2, 422.19;
m/z found, 423.2. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.62-7.56 (m,
1H), 7.31-7.26 (m, 1H), 7.24-7.20 (m, 1H), 6.29 (s, 1H), 3.93-3.86
(m, 2H), 3.77-3.62 (m, 3H), 3.57-3.47 (m, 2H), 3.21-3.16 (m, 1H),
3.10-2.96 (m, 2H), 2.43 (s, 3H), 2.28 (s, 6H).
Example 315
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5--
yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00427##
[0713] The title compound was prepared in a manner analogous to
Intermediate 59 substituting Intermediate 23 for Intermediate 15
and Intermediate 64 for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS
(ESI) mass calculated for C.sub.22H.sub.23FN.sub.6O.sub.2, 422.19;
m/z found, 423.2. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.96-7.86 (m,
1H), 7.55-7.47 (m, 1H), 7.38-7.29 (m, 1H), 6.32-6.23 (m, 1H),
3.99-3.46 (m, 7H), 3.27-2.95 (m, 3H), 2.49-2.37 (m, 3H), 2.36-2.21
(m, 6H).
Example 316
2-(5-Chloro-4-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)-
phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00428##
[0714] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 16 for Intermediate 20 and
Intermediate 65 for Intermediate 55. MS (ESI) mass calculated for
C.sub.20H.sub.19CIFN.sub.7O, 427.13; m/z found, 428.1. 1H NMR (500
MHz, CDCl.sub.3): 8.13 (d, J=1.3 Hz, 1H), 7.87-7.79 (m, 2H), 7.71
(s, 1H), 7.51-7.43 (m, 1H), 7.17-7.11 (m, 1H), 4.00-3.54 (m, 7H),
3.28-3.23 (m, 1H), 3.14-2.97 (m, 2H), 2.43 (s, 3H).
Example 317
2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-
-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00429##
[0715] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 16 for Intermediate 20 and
Intermediate 66 for Intermediate 55. MS (ESI) mass calculated for
C.sub.21H.sub.21CIFN.sub.7O, 441.15; m/z found, 442.1. 1H NMR (500
MHz, CDCl.sub.3): 7.87-7.79 (m, 2H), 7.71 (s, 1H), 7.50-7.44 (m,
1H), 7.17-7.11 (m, 1H), 4.00-3.73 (m, 3H), 3.70-3.46 (m, 4H),
3.27-3.22 (m, 1H), 3.12-2.94 (m, 2H), 2.42 (s, 6H).
Example 318
2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[2-(3-methyl-1,2,4-oxadiazol-5--
yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00430##
[0716] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 62 for Intermediate 60 in
Step A, and Intermediate 66 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for
C.sub.22H.sub.23ClN.sub.6O.sub.2, 438.16; m/z found, 439.2. 1H NMR
(500 MHz, CDCl.sub.3): 8.11 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.62 (td,
J=7.6 Hz, 1.2 Hz, 1H), 7.54 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.42 (dd,
J=7.6 Hz, 1.2 Hz, 1H), 3.99-3.92 (m, 1H), 3.90-3.84 (m, 1H),
3.80-3.74 (m, 1H), 3.70-3.61 (m, 2H), 3.50-3.41 (m, 2H), 3.12-3.04
(m, 2H), 3.02-2.94 (m, 1H), 2.46-2.36 (m, 9H).
Example 319
4-Methyl-2-[5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydro-
pyrrolo[3,4-c]pyrrol-2(1H)-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine
##STR00431##
[0717] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 62 for Intermediate 60 in
Step A, and
2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine for
2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI) mass calculated
for C.sub.24H.sub.26N.sub.6O.sub.2, 430.21; m/z found, 431.2.
.sup.1H NMR (500 MHz, CDCl.sub.3): 8.10 (dd, J=7.9 Hz, 0.9 Hz, 1H),
7.61 (td, J=7.6 Hz, 1.3 Hz, 1H), 7.53 (td, J=7.6 Hz, 1.3 Hz, 1H),
7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 3.99-3.87 (m, 2H), 3.80-3.74 (m,
1H), 3.73-3.65 (m, 2H), 3.52-3.47 (m, 1H), 3.45-3.39 (m, 1H),
3.11-3.05 (m, 2H), 3.01-2.93 (m, 1H), 2.83-2.72 (m, 4H), 2.43 (s,
3H), 2.26 (s, 3H), 2.08-2.00 (m, 2H).
Example 320
2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-
-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00432##
[0718] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 61 for Intermediate 60 in
Step A, and Intermediate 66 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for C.sub.22H.sub.24ClN.sub.7O,
437.17; m/z found, 438.2. .sup.1H NMR (500 MHz, CDCl.sub.3):
8.12-8.06 (m, 1H), 7.95 (s, 1H), 7.47-7.40 (m, 2H), 7.34-7.31 (m,
1H), 3.96-3.85 (m, 4H), 3.85-3.78 (m, 1H), 3.77-3.70 (m, 1H),
3.65-3.57 (m, 2H), 3.45-3.38 (m, 2H), 3.08-3.00 (m, 2H), 2.95-2.87
(m, 1H), 2.41 (s, 6H).
Example 321
2-(5-Chloro-4-methylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)-
phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00433##
[0719] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 61 for Intermediate 60 in
Step A, and Intermediate 65 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for C.sub.21H.sub.22ClN.sub.7O,
423.16; m/z found, 424.2. .sup.1H NMR (500 MHz, CDCl.sub.3):
8.15-8.06 (m, 2H), 7.96 (s, 1H), 7.48-7.40 (m, 2H), 7.36-7.30 (m,
1H), 3.96-3.80 (m, 5H), 3.79-3.70 (m, 1H), 3.67-3.55 (m, 2H),
3.47-3.37 (m, 2H), 3.10-3.01 (m, 2H), 2.99-2.90 (m, 1H), 2.41 (s,
3H).
Example 322
2-(5-Ethyl-4,6-dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3--
yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00434##
[0720] The title compound was prepared in a manner analogous to
Example 307 substituting Intermediate 61 for Intermediate 60 in
Step A, and Intermediate 67 for 2-chloro-4,6-dimethylpyrimidine in
Step B. MS (ESI) mass calculated for C.sub.24H.sub.29N.sub.7O,
431.24; m/z found, 432.2. .sup.1H NMR (500 MHz, CDCl.sub.3):
8.11-8.05 (m, 1H), 7.95 (s, 1H), 7.48-7.39 (m, 2H), 7.35-7.30 (m,
1H), 3.96-3.79 (m, 5H), 3.77-3.70 (m, 1H), 3.66-3.55 (m, 2H),
3.43-3.35 (m, 2H), 3.08-2.97 (m, 2H), 2.94-2.86 (m, 1H), 2.52 (q,
J=7.5 Hz, 2H), 2.34 (s, 6H), 1.08 (t, J=7.5 Hz, 3H).
Example 323
2-{[3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl]carbonyl}-5-(4,5,6-trimethylpyri-
midin-2-yl)octahydropyrrolo[3,4-c]pyrrole
##STR00435##
[0721] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 68 for Intermediate 20 and
Intermediate 56 for Intermediate 55. MS (ESI) mass calculated for
C.sub.21H.sub.24N.sub.8O, 404.21; m/z found, 405.2. .sup.1H NMR
(500 MHz, CDCl.sub.3): 8.62 (dd, J=4.7 Hz, 1.4 Hz, 1H), 8.33 (dd,
J=8.3 Hz, 1.4 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7 Hz,
1H), 3.96-3.84 (m, 2H), 3.78-3.63 (m, 4H), 3.60-3.54 (m, 1H),
3.29-3.23 (m, 1H), 3.12-2.98 (m, 2H), 2.33 (s, 6H), 2.07 (s,
3H).
Example 324
2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[3-(2H-1,2,3-triazol-2-yl)pyrid-
in-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00436##
[0722] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 68 for Intermediate 20 and
Intermediate 66 for Intermediate 55. MS (ESI) mass calculated for
C.sub.20H.sub.21ClN.sub.8O, 424.15; m/z found, 425.1. .sup.1H NMR
(500 MHz, CDCl.sub.3): 8.62 (dd, J=4.7 Hz, 1.4 Hz, 1H), 8.33 (dd,
J=8.3 Hz, 1.4 Hz, 1H), 7.81 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7 Hz,
1H), 3.95-3.89 (m, 1H), 3.89-3.83 (m, 1H), 3.79-3.74 (m, 1H),
3.73-3.64 (m, 3H), 3.60-3.53 (m, 1H), 3.28-3.23 (m, 1H), 3.13-2.98
(m, 2H), 2.42 (s, 6H).
Example 325
2-(5-Fluoro-4,6-dimethylpyrimidin-2-yl)-5-{[3-(2H-1,2,3-triazol-2-yl)pyrid-
in-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00437##
[0723] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 68 for Intermediate 20 and
Intermediate 69 for Intermediate 55. MS (ESI) mass calculated for
C.sub.20H.sub.21FN.sub.8O, 408.18; m/z found, 409.1. .sup.1H NMR
(500 MHz, CDCl.sub.3): 8.62 (dd, J=4.7 Hz, 1.4 Hz, 1H), 8.34 (dd,
J=8.3 Hz, 1.4 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7 Hz,
1H), 3.97-3.89 (m, 1H), 3.88-3.82 (m, 1H), 3.78-3.73 (m, 1H),
3.72-3.62 (m, 3H), 3.57-3.51 (m, 1H), 3.29-3.23 (m, 1H), 3.12-2.99
(m, 2H), 2.33 (d, J=2.6 Hz, 6H).
Example 326
2-(4,6-Dimethylpyrimidin-2-yl)-5-(9H-fluoren-4-ylcarbonyl)octahydropyrrolo-
[3,4-c]pyrrole
##STR00438##
[0724] The title compound was prepared in a manner analogous to
Example 15 substituting 9H-fluorene-4-carboxylic acid for
3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass
calculated for C.sub.20H.sub.21FN.sub.8O, 410.52; m/z found, 411.2.
.sup.1H NMR (400 MHz, CDCl.sub.3): 7.68-7.61 (m, 1H), 7.58-7.51 (m,
2H), 7.35-7.23 (m, 4H), 6.28 (s, 1H), 4.13 (dd, J=12.8, 7.9 Hz,
1H), 3.94-3.87 (m, 3H), 3.80 (dd, J=12.8, 5.0 Hz, 1H), 3.73-3.64
(m, 2H), 3.46 (s, 2H), 3.11 (dtd, J=12.5, 7.5, 4.9 Hz, 2H),
2.97-2.86 (m, 1H), 2.28 (s, 6H).
Example 327
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-[-
1,2,3]triazol-2-yl-benzo[1,3]dioxol-4-yl)-methanone
##STR00439##
[0725] The title compound was prepared in a manner analogous to
Example 275 substituting
5-[1,2,3]triazol-2-yl-benzo[1,3]dioxole-4-carboxylic acid
(Intermediate 76) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic
acid. MS (ESI) mass calcd. for C.sub.22H.sub.23N.sub.7O.sub.3,
433.47; m/z found 434.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 7.75 (s, 1H), 7.64 (s, 1H), 7.42 (t, J=8.7 Hz, 1H),
6.89 (d, J=8.5 Hz, 1H), 6.29 (d, J=3.4 Hz, 1H), 6.13-5.99 (m, 2H),
3.95-3.75 (m, 3H), 3.74-3.50 (m, 5H), 3.26 (ddd, J=43.0, 10.7, 5.1
Hz, 1H), 3.09-2.92 (m, 2H), 2.30 (s, 6H).
Example 328
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(8-[-
1,2,3]triazol-2-yl-naphthalen-1-yl)-methanone
##STR00440##
[0726] The title compound was prepared in a manner analogous to
Example 275 substituting
8-[1,2,3]triazol-2-yl-naphthalene-1-carboxylic acid (Intermediate
75) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI)
mass calcd. for C.sub.2H.sub.25N.sub.7O, 439.41; m/z found 440.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (m, J=11.0,
7.1, 2.7 Hz, 2H), 7.80 (m, J=51.6 Hz, 2H), 7.69-7.49 (m, 4H), 6.31
(m, J=12.7 Hz, 1H), 3.91 (m, J=11.6, 7.7 Hz, 1H), 3.85-3.62 (m,
4H), 3.57-3.47 (m, 2H), 3.38-3.28 (m, 1H), 3.18 (m, J=10.9, 5.9 Hz,
1H), 3.06-2.93 (m, 2H), 2.30 (m, J=8.3 Hz, 6H).
Example 329
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-[-
1,2,3]triazol-1-yl-pyridin-3-yl)-methanone
##STR00441##
[0727] The title compound was prepared in a manner analogous to
Example 275 substituting 4-(1H-1,2,3-triazol-1-yl)nicotinic acid
(Intermediate 81) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic
acid. MS (ESI) mass calcd. for C.sub.20H.sub.22N.sub.8O, 390.40;
m/z found 391.4 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.83 (d, J=5.4 Hz, 1H), 8.75 (s, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.82
(d, J=0.9 Hz, 1H), 7.69 (d, J=5.4 Hz, 1H), 6.31 (s, 1H), 3.86 (ddd,
J=16.6, 12.3, 7.7 Hz, 2H), 3.75-3.67 (m, 1H), 3.56 (ddd, J=16.5,
12.3, 4.8 Hz, 2H), 3.35 (dt, J=14.9, 7.7 Hz, 2H), 3.04-2.86 (m,
3H), 2.30 (s, 6H).
Example 330
(5-tert-Butyl-2-methoxy-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-
-pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00442##
[0728] The title compound was prepared in a manner analogous to
Example 275 substituting 5-tert-butyl-2-methoxybenzoic acid for
6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd.
for C.sub.24H.sub.32N.sub.4O.sub.2, 408.54; m/z found 409.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.34 (dd, J=8.7,
2.5 Hz, 1H), 7.27-7.24 (m, 1H), 6.82 (d, J=8.7 Hz, 1H), 6.29 (s,
1H), 3.96 (dd, J=12.7, 7.9 Hz, 1H), 3.87 (dd, J=11.6, 7.4 Hz, 1H),
3.80-3.73 (m, 4H), 3.67-3.60 (m, 2H), 3.57-3.45 (m, 2H), 3.21 (dd,
J=11.0, 4.7 Hz, 1H), 3.09-3.00 (m, 1H), 2.99-2.91 (m, 1H), 2.29 (s,
6H), 1.28 (s, 9H).
Example 331
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(1-[-
1,2,3]triazol-2-yl-naphthalen-2-yl)-methanone
##STR00443##
[0729] The title compound was prepared in a manner analogous to
Example 275 substituting
1-[1,2,3]triazol-2-yl-naphthalene-2-carboxylic acid (Intermediate
73) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI)
mass calcd. for C.sub.25H.sub.25N.sub.7O, 439.52; m/z found 440.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.02 (d, J=8.4 Hz,
1H), 7.95-7.91 (m, 1H), 7.88 (s, 2H), 7.72 (d, J=8.3 Hz, 1H), 7.56
(dddd, J=14.9, 8.2, 6.9, 1.3 Hz, 2H), 7.52-7.48 (m, 1H), 6.30 (s,
1H), 3.83 (dd, J=11.6, 7.5 Hz, 1H), 3.72 (ddd, J=14.6, 12.2, 7.1
Hz, 2H), 3.56-3.45 (m, 4H), 3.19 (dd, J=11.0, 5.4 Hz, 1H),
3.00-2.87 (m, 3H), 2.31 (s, 6H).
Example 332
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3-[-
1,2,3]triazol-2-yl-pyridin-2-yl)-methanone
##STR00444##
[0730] The title compound was prepared in a manner analogous to
Example 275 substituting
3-[1,2,3]triazol-2-yl-pyridine-2-carboxylic acid (Intermediate 72)
for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. Excess amounts
of acetic acid from the purification of the acid (in previous
steps) still remained and allowed the acetamide to be formed in
significant quantities as a byproduct, which was isolated in
addition to the title compound. MS (ESI) mass calcd. for
C.sub.20H.sub.22N.sub.8O, 390.44; m/z found 391.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): 8.62 (dd, J=4.7, 1.3 Hz, 1H),
8.33 (dd, J=8.3, 1.3 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3, 4.7
Hz, 1H), 6.28 (s, 1H), 3.92 (td, J=12.5, 7.4 Hz, 2H), 3.80-3.57 (m,
5H), 3.26 (dd, J=10.8, 5.3 Hz, 1H), 3.12-2.98 (m, 2H), 2.30 (s,
6H).
Example 333
(2-Bromo-4,5-dimethoxy-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro--
pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00445##
[0732] The title compound was prepared in a manner analogous to
Example 275 substituting 5-acetamido-2-bromobenzoic acid for
6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd.
for C.sub.21H.sub.25BrN.sub.4O.sub.3, 461.35; m/z found 463.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 6.98 (s, 1H), 6.77
(s, 1H), 6.30 (s, 1H), 3.98-3.89 (m, 2H), 3.86 (d, J=9.2 Hz, 6H),
3.79 (dd, J=11.6, 7.2 Hz, 1H), 3.67-3.59 (m, 2H), 3.53 (dd, J=11.5,
4.4 Hz, 2H), 3.22 (s, 1H), 3.12-2.96 (m, 2H), 2.29 (s, 6H).
Example 334
(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-[5-(4,6-dimethyl-pyrimidin-2-y-
l)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00446##
[0733] The title compound was prepared in a manner analogous to
Example 275 substituting
3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylic acid for
6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd.
for C.sub.22H.sub.26N.sub.4O.sub.3, 394.47; m/z found 395.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 6.99 (dd, J=7.9,
1.9 Hz, 1H), 6.93 (t, J=7.6 Hz, 1H), 6.88 (dd, J=7.4, 1.9 Hz, 1H),
6.29 (s, 1H), 4.20 (s, 2H), 3.90 (ddd, J=19.1, 12.1, 7.6 Hz, 2H),
3.81-3.73 (m, 1H), 3.68-3.58 (m, 2H), 3.57-3.45 (m, 2H), 3.23 (dd,
J=10.9, 4.7 Hz, 1H), 3.09-2.90 (m, 2H), 2.29 (s, 6H), 2.14 (d,
J=5.9 Hz, 2H).
Example 335
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(6-methylpyridin-2-yl)phenyl)methanone
##STR00447##
[0734] The title compound was prepared in a manner analogous to
Example 248, substituting 6-methyl-2-(tributylstannyl)pyridine for
5-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.25H.sub.26FN.sub.5O, 431.21. found 432.2 [M+H].sup.+.
Example 336
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(6-m-
ethyl-2-[1,2,3]triazol-1-yl-pyridin-3-yl)-methanone
##STR00448##
[0735] The title compound was prepared in a manner analogous to
Example 275 substituting 6-methyl-2-[1,2,3]triazol-1-yl-nicotinic
acid (Intermediate 71) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic
acid. MS (ESI) mass calcd. for C.sub.21H.sub.24N.sub.8O, 404.47;
m/z found 405.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3):
8.45 (d, J=0.7 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.26
(t, J=3.9 Hz, 1H), 6.29 (s, 1H), 4.01 (dd, J=12.6, 7.7 Hz, 1H),
3.91 (dd, J=11.6, 7.7 Hz, 1H), 3.76 (dd, J=11.6, 7.2 Hz, 1H),
3.65-3.58 (m, 2H), 3.51 (ddd, J=16.0, 11.1, 5.9 Hz, 2H), 3.15 (dt,
J=10.1, 5.1 Hz, 1H), 3.12-2.95 (m, 2H), 2.61 (s, 3H), 2.30 (s,
6H).
Example 337
(1-Bromo-naphthalen-2-yl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrro-
lo[3,4-c]pyrrol-2-yl]-methanone
##STR00449##
[0736] The title compound was prepared in a manner analogous to
Example 275 substituting 5-acetamido-2-bromobenzoic acid for
6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd.
for C.sub.23H.sub.23BrN.sub.4O, 451.36; m/z found 451.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.29 (d, J=7.1 Hz,
1H), 7.85 (t, J=7.5 Hz, 2H), 7.64 (t, J=7.4 Hz, 1H), 7.60-7.54 (m,
1H), 7.33 (s, 1H), 6.30 (s, 1H), 4.03 (s, 1H), 3.91 (s, 1H), 3.77
(dt, J=14.9, 7.4 Hz, 2H), 3.66 (dd, J=11.6, 5.0 Hz, 1H), 3.51 (d,
J=52.5 Hz, 2H), 3.18 (d, J=65.6 Hz, 2H), 2.98 (d, J=21.2 Hz, 1H),
2.30 (s, 6H).
Example 338
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3-m-
ethoxy-naphthalen-2-yl)-methanone
##STR00450##
[0737] The title compound was prepared in a manner analogous to
Example 275 substituting 3-methoxy-2-naphthoic acid for
6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd.
for C.sub.24H.sub.26N.sub.4O.sub.2, 402.49; m/z found 403.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.78-7.70 (m, 3H),
7.49-7.43 (m, 1H), 7.39-7.32 (m, 1H), 7.15 (s, 1H), 6.29 (s, 1H),
3.99 (dd, J=12.7, 7.9 Hz, 1H), 3.93-3.85 (m, 4H), 3.79-3.62 (m,
3H), 3.56-3.45 (m, 2H), 3.21 (dd, J=11.1, 4.9 Hz, 1H), 3.11-3.02
(m, 1H), 2.99-2.90 (m, 1H), 2.30 (s, 6H).
Example 339
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(8-[-
1,2,3]triazol-2-yl-naphthalen-1-yl)-methanone
##STR00451##
[0738] The title compound was prepared in a manner analogous to
Example 275 substituting
1-[1,2,3]triazol-1-yl-naphthalene-2-carboxylic acid (Intermediate
74) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI)
mass calcd. for C.sub.25H.sub.25N.sub.7O, 439.52; m/z found 440.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.08 (d, J=8.4 Hz,
1H), 8.01 (d, J=0.8 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.92 (d, J=0.8
Hz, 1H), 7.65-7.59 (m, 1H), 7.56 (ddd, J=8.1, 7.0, 1.2 Hz, 1H),
7.51-7.47 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.29 (s, 1H), 3.82 (dd,
J=11.6, 7.3 Hz, 1H), 3.76-3.63 (m, 2H), 3.56 (dd, J=11.2, 7.1 Hz,
1H), 3.49 (dd, J=11.5, 3.8 Hz, 1H), 3.45-3.36 (m, 2H), 3.14 (dd,
J=11.2, 4.9 Hz, 1H), 2.96-2.84 (m, 2H), 2.29 (s, 6H).
Example 340
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(1-m-
ethoxy-naphthalen-2-yl)-methanone
##STR00452##
[0739] The title compound was prepared in a manner analogous to
Example 275 substituting 1-methoxy-2-naphthoic acid for
6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd.
for C.sub.24H.sub.26N.sub.4O.sub.2, 402.49; m/z found 403.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.19-8.12 (m, 1H),
7.84 (dt, J=6.2, 2.6 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.56-7.49 (m,
2H), 7.36 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 4.07-3.97 (m, 4H), 3.91
(dd, J=11.5, 7.5 Hz, 1H), 3.80-3.55 (m, 4H), 3.48 (dd, J=11.5, 4.6
Hz, 1H), 3.33 (s, 1H), 3.13-3.04 (m, 1H), 3.01-2.92 (m, 1H), 2.30
(s, 6H).
Example 341
(4,5-Dimethoxy-2-[1,2,3]triazol-1-yl-phenyl)-[5-(4,6-dimethyl-pyrimidin-2--
yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00453##
[0740] The title compound was prepared in a manner analogous to
Example 275 substituting
2,3-dimethoxy-6-[1,2,3]triazol-1-yl-benzoic acid (Intermediate 78)
for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass
calcd. for C.sub.23H.sub.27N.sub.7O3, 449.51; m/z found 450.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.93 (s, 1H), 7.77
(s, 1H), 7.17 (s, 1H), 6.92 (s, 1H), 6.29 (s, 1H), 3.95 (d, J=1.6
Hz, 6H), 3.74 (ddd, J=29.3, 15.1, 7.9 Hz, 3H), 3.46 (d, J=8.6 Hz,
2H), 3.28 (d, J=7.5 Hz, 1H), 3.14 (d, J=7.4 Hz, 1H), 2.89 (s, 2H),
2.77 (d, J=6.0 Hz, 1H), 2.29 (s, 6H).
Example 342
(4,5-Dimethoxy-2-[1,2,3]triazol-2-yl-phenyl)-[5-(4,6-dimethyl-pyrimidin-2--
yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]methanone
##STR00454##
[0741] The title compound was prepared in a manner analogous to
Example 275 substituting
2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 77)
for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass
calcd. for C.sub.23H.sub.27N.sub.7O.sub.3, 449.51; m/z found 450.3
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.70 (s, 2H), 7.45
(s, 1H), 6.89 (s, 1H), 6.29 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H),
3.84 (dt, J=11.6, 7.6 Hz, 2H), 3.65 (dd, J=12.5, 4.1 Hz, 2H), 3.55
(dd, J=11.5, 5.2 Hz, 1H), 3.44 (dd, J=11.6, 3.8 Hz, 1H), 3.27 (s,
1H), 3.03-2.93 (m, 1H), 2.85 (d, J=24.5 Hz, 2H), 2.30 (s, 6H).
Example 343
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(4-methylpyridin-2-yl)phenyl)methanone
##STR00455##
[0742] The title compound was prepared in a manner analogous to
Example 248 substituting 4-methyl-2-(tributylstannyl)pyridine for
5-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.25H.sub.26FN.sub.5O, 431.21; m/z found 432.2 [M+H].sup.+.
Example 344
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-p-
ropoxypyridin-2-yl)methanone
##STR00456##
[0743] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 23 and 2-propoxynicotinic acid.
MS (ESI) mass calcd. C.sub.21H.sub.27N.sub.5O.sub.2, 381.48; m/z
found 382.0 [M+H].sup.+. .sup.1H NMR (CD.sub.3OD): 8.47 (d, J=5.5
Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.06 (dd, J=8.9, 5.5 Hz, 1H), 6.83
(s, 1H), 4.36-4.24 (m, 2H), 4.10-3.97 (m, 3H), 3.81-3.67 (m, 4H),
3.50-3.44 (m, 1H), 3.39-3.33 (m, 1H), 3.30-3.22 (m, 1H), 2.54 (s,
6H), 1.92-1.80 (m, 2H), 1.03 (t, J=7.4 Hz, 3H). The following
prophetic example may be prepared using the procedures described in
the previous examples.
Example 345
(3-Propoxypyridin-2-yl)(5-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrr-
olo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00457##
[0745] MS (ESI) mass calcd. For
C.sub.20H.sub.23F.sub.3N.sub.5O.sub.2, 421.17.
Example 346
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(3-fluoropyridin-2-yl)phenyl)methanone
##STR00458##
[0746] The title compound was prepared in a manner analogous to
Example 248, substituting 3-fluoro-2-(tributylstannyl)pyridine for
5-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.24H.sub.23F.sub.2N.sub.5O, 435.19. found 436.2 [M+H].sup.+.
Prophetic examples 347-348 may be prepared using the procedures
described in the previous examples.
Example 347
(3-Propoxypyridin-2-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2-
(1H)-yl)methanone
##STR00459##
[0748] MS (ESI) mass calcd. For C.sub.23H.sub.25N.sub.5O.sub.2,
403.20.
Example 348
2-(5-([1,1'-biphenyl]-2-ylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-
quinoxaline
##STR00460##
[0749] The title prophetic compound may be synthesized using
biphenylsulfonylchloride and Intermediate 35. MS (ESI) mass calcd.
for C.sub.26H.sub.24N.sub.4O.sub.2S, 456.16.
Example 349
2-[(2,6-Dimethoxyphenyl)carbonyl]-5-[5-(trifluoromethyl)pyridin-2-yl]octah-
ydropyrrolo[3,4-c]pyrrole
##STR00461##
[0750] The title compound was prepared in a manner analogous to
Example 15, utilizing
5-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrrole and
2,6-dimethoxybenzoic acid. MS (ESI) mass calcd.
C.sub.21H.sub.22F.sub.3N.sub.3O.sub.3, 421.42; m/z found 422.0
[M+H].sup.+. .sup.1H NMR (CD.sub.3OD): 8.23 (s, 1H), 8.12 (d, J=8.9
Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.27 (d, J=9.2 Hz, 1H), 6.72-6.66
(m, 2H), 4.03-3.48 (m, 14H), 3.28-3.22 (m, 2H).
Example 350
(2,6-Dimethoxyphenyl)(5-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrol-
o[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00462##
[0751] The title prophetic compound may be synthesized in a manner
analogous to Example 15 utilizing
5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole
and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. For
C.sub.20H.sub.21F.sub.3N.sub.4O.sub.3, 422.16.
Example 351
(2,6-Dimethoxyphenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c-
]pyrrol-2(1H)-yl)methanone
##STR00463##
[0752] The title compound was prepared in a manner analogous to
Example 15 utilizing in a manner analogous to Example 15, utilizing
Intermediate 23 and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd.
C.sub.21H.sub.26N.sub.4O.sub.3, 382.47; m/z found 383.1
[M+H].sup.+. .sup.1H NMR (CD.sub.3OD): 7.38 (t, J=8.4 Hz, 1H), 6.81
(s, 1H), 6.81-6.70 (m, 2H), 4.04-3.89 (m, 3H), 3.84 (s, 3H), 3.79
(s, 3H), 3.76-3.55 (m, 4H), 3.27-3.13 (m, 3H), 2.53 (s, 6H).
Example 352
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-m-
ethylfuran-2-yl)methanone
##STR00464##
[0753] The title compound was prepared in a manner analogous to
Example 15, substituting 3-methylfuran-2-carboxylic acid for
3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass calcd.
For C.sub.18H.sub.22N.sub.4O.sub.2, 326.17. m/z found 327.2
[M+H].sup.+.
Example 353
2-[(3-Methylfuran-2-yl)carbonyl]-5-[5-(trifluoromethyl)pyridin-2-yl]octahy-
dropyrrolo[3,4-c]pyrrole
##STR00465##
[0754] The title compound was prepared in a manner analogous to
Example 15, utilizing
2-(5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole
and 3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd.
C.sub.18H.sub.18F.sub.3N.sub.3O.sub.2, 365.36; m/z found 366.0
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.39 (s, 1H), 7.62 (d, J=9.1
Hz, 1H), 7.32 (d, J=1.4 Hz, 1H), 6.39 (d, J=8.8 Hz, 1H), 6.32 (d,
J=1.4 Hz, 1H), 4.17 (brs, 1H), 3.94 (brs, 1H), 3.81 (brs, 3H),
3.71-3.67 (m, 1H), 3.50 (brs, 2H), 3.11 (brs, 2H), 2.37 (s,
3H).
Example 354
(3-Methylfuran-2-yl)(5-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00466##
[0755] The title prophetic compound may be prepared analogous to
Example 15, utilizing
5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole
and 3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd. For
C.sub.17H.sub.17F.sub.3N.sub.4O.sub.2, 366.13.
Example 355
(3-Methylfuran-2-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H-
)-yl)methanone
##STR00467##
[0756] The title compound was prepared in a manner analogous to
Example 15 utilizing Intermediate 35 and 3-methylfuran-2-carboxylic
acid. MS (ESI) mass calcd. For C.sub.20H.sub.20N.sub.4O.sub.2,
348.16; m/z found 349.0 [M+H].sup.+.
Example 356
2-([1,1'-Biphenyl]-2-ylsulfonyl)-5-(5-(trifluoromethyl)pyridin-2-yl)octahy-
dropyrrolo[3,4-c]pyrrole
##STR00468##
[0757] The title compound may be prepared using
biphenylsulfonylchloride and
5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole. MS
(ESI) mass calcd. For C.sub.24H.sub.22F.sub.3N.sub.3O.sub.2S,
473.14; m/z found 474.1 [M+H].sup.+.
Example 357
2-([1,1'-Biphenyl]-2-ylsulfonyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)octa-
hydropyrrolo[3,4-c]pyrrole
##STR00469##
[0758] The title prophetic compound may be prepared using
biphenylsulfonylchloride and
5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole MS
(ESI) mass calcd. For C.sub.23H.sub.21F.sub.3N.sub.4O.sub.2S,
474.13.
Example 358
2-([1,1'-Biphenyl]-2-ylsulfonyl)-5-(4,6-dimethylpyrimidin-2-yl)octahydropy-
rrolo[3,4-c]pyrrole
##STR00470##
[0759] The title compound was prepared using
biphenylsulfonylchloride and
4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole. MS (ESI)
mass calcd. For C.sub.24H.sub.26N.sub.4O.sub.2S, 434.18; m/z found
435.2 [M+H].sup.+.
Example 359
2-(4,6-Dimethylpyrimidin-2-yl)-5-((2-methoxyphenyl)sulfonyl)octahydropyrro-
lo[3,4-c]pyrrole
##STR00471##
[0760] The title compound was prepared using
2-methoxyphenyl)sulfonylchloride and Intermediate 23. MS (ESI) mass
calcd. For C.sub.19H.sub.24N.sub.4O.sub.3S, 388.16; m/z found 389.2
[M+H].sup.+.
Example 360
2-((2-Methoxyphenyl)sulfonyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)octahyd-
ropyrrolo[3,4-c]pyrrole
##STR00472##
[0761] The title prophetic compound may be prepared using
2-methoxyphenyl)sulfonylchloride and
5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole.
MS (ESI) mass calcd. For C.sub.18H.sub.19F.sub.3N.sub.4O.sub.3S,
428.11.
Example 361
2-((2-Methoxyphenyl)sulfonyl)-5-(5-(trifluoromethyl)pyridin-2-yl)octahydro-
pyrrolo[3,4-c]pyrrole
##STR00473##
[0762] The title compound was prepared using
2-methoxyphenyl)sulfonylchloride and
5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole. MS
(ESI) mass calcd. For C.sub.19H.sub.20F.sub.3N.sub.3O.sub.3S,
427.12; m/z found 428.2 [M+H].sup.+.
Example 362
2-(5-((2-Methoxyphenyl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)qui-
noxaline
##STR00474##
[0763] The title compound was prepared using
2-methoxyphenyl)sulfonylchloride and Intermediate 35. MS (ESI) mass
calcd. For C.sub.21H.sub.22N.sub.4O.sub.3S, 410.14; m/z found 411.1
[M+H].sup.+. Prophetic Examples 363-365 may be prepared as
previously described.
Example 363
(3,6'-Dimethyl-[2,3'-bipyridin]-2'-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00475##
[0765] MS (ESI) mass calcd. For C.sub.27H.sub.26N.sub.6O,
450.22.
Example 364
(3,6'-Dimethyl-[2,3'-bipyridin]-2'-yl)(5-(5-(trifluoromethyl)pyrimidin-2-y-
l)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00476##
[0767] MS (ESI) mass calcd. For C.sub.27H.sub.23F.sub.3N.sub.6O,
468.19.
Example 365
(3,6'-Dimethyl-[2,3'-bipyridin]-2'-yl)(5-(5-(trifluoromethyl)pyridin-2-yl)-
hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00477##
[0769] MS (ESI) mass calcd. For C.sub.25H.sub.24F.sub.3N.sub.5O,
467.19.
Example 366
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(pyridin-2-yl)phenyl)methanone
##STR00478##
[0770] The title compound was prepared in a manner analogous to
Example 367 substituting
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4--
fluoro-2-iodophenyl)methanone for
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3--
fluoro-2-iodophenyl)methanone, with the addition of catalytic CuI,
substituting dioxane for DME, heating 130.degree. C. in microwave
for 60 min. The reaction was filtered through celite, rinsed with
EtOAc and then concentrated and purified on RP agilent HPLC and
fractions lyophilized. MS (ESI) mass calcd. for
C.sub.24H.sub.24FN.sub.5O, 417.20; m/z found, 418.2
[M+H].sup.+.
Example 367
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(pyridin-2-yl)phenyl)methanone
##STR00479##
[0771]
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)--
yl)(3-fluoro-2-(pyridin-2-yl)phenyl)methanone.
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3--
fluoro-2-iodophenyl)methanone (51 mg, 0.11 mmol) and
2-tributylstannane pyridine (57 mg, 0.13 mmol) were combined and
dissolved in degassed DME then purged with bubbling N.sub.2 for 5
minutes. The reaction was treated with Pd(PPh.sub.3).sub.4 and then
purged with bubbling for 5 minutes in a sealed vessel and then
heated to 160.degree. C. in microwave for 90 min. Reaction was
filtered through celite, concentrated and purified on 16 g
SiO.sub.2 with 0-3.5% NH.sub.3 MeOH/CH.sub.2Cl.sub.2. MS (ESI) mass
calcd. for C.sub.24H.sub.24FN.sub.5O, 417.49; m/z found, 418.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.71-7.64 (m, 1H),
7.57-7.52 (m, 1H), 7.46 (dddd, J=8.2, 5.6, 2.8, 1.2 Hz, 1H), 7.37
(td, J=7.9, 5.5 Hz, 1H), 7.30-7.24 (m, 2H), 7.20 (ddd, J=9.0, 2.5,
1.5 Hz, 1H), 7.11 (tdd, J=8.4, 2.6, 1.0 Hz, 1H), 6.31 (s, 1H), 3.97
(dd, J=12.7, 7.8 Hz, 1H), 3.89 (dd, J=11.5, 7.7 Hz, 1H), 3.82-3.70
(m, 2H), 3.70-3.60 (m, 2H), 3.50 (dd, J=11.5, 4.6 Hz, 1H), 3.40
(dd, J=10.9, 5.4 Hz, 1H), 3.07 (d, J=7.2 Hz, 1H), 3.03-2.94 (m,
1H), 2.30 (s, 6H).
Example 368
[2,3'-bipyridin]-2'-yl(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4--
c]pyrrol-2(1H)-yl)methanone
##STR00480##
[0772] The title prophetic example may be synthesized according to
a procedure as previously described. MS (ESI) mass calcd. for
C.sub.23H.sub.24N.sub.6O, 400.48
Example 369
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-f-
luoro-2-(oxazol-2-yl)phenyl)methanone
##STR00481##
[0773] The title compound was prepared in a manner analogous to
Example 248, substituting 2-(tri-N-butylstannyl)oxazole for
2-tributylstannane pyrimidine. MS (ESI) mass calcd. for
C.sub.22H.sub.22FN.sub.5O.sub.2, 407.18. found 408.2
[M+H].sup.+.
Example 370
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(6-methylpyridin-2-yl)phenyl)methanone
##STR00482##
[0774] The title compound was prepared in a manner analogous to
Example 367, substituting 6-methyl-2-(tributylstannyl)pyridine for
2-tributylstannane pyridine. MS (ESI) mass calcd. for
C.sub.25H.sub.26FN.sub.5O, 431.51; m/z found, 432.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, CDCl.sub.3): 7.60 (t, J=7.7 Hz, 1H),
7.43-7.35 (m, 2H), 7.21-7.15 (m, J=13.8, 4.5 Hz, 2H), 7.05 (d,
J=7.7 Hz, 1H), 6.30 (s, 1H), 3.84-3.73 (m, J=20.1, 12.0, 7.6 Hz,
2H), 3.67 (dd, J=11.5, 7.0 Hz, 1H), 3.63-3.53 (m, 1H), 3.40 (t,
J=13.3 Hz, 2H), 3.30-3.20 (m, 1H), 3.10 (dd, J=10.8, 5.7 Hz, 1H),
2.98-2.84 (m, 2H), 2.43 (s, 3H), 2.30 (s, 6H).
Example 371
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(3-methylpyridin-2-yl)phenyl)methanone
##STR00483##
[0775] The title compound was prepared in a manner analogous to
Example 367. MS (ESI) mass calcd. for C.sub.25H.sub.26FN.sub.5O,
431.51; m/z found, 432.2 [M+H].sup.+. .sup.1H NMR (500 MHz,
CDCl.sub.3): 8.37 (d, J=40.0 Hz, 1H), 7.56-7.49 (m, 1H), 7.41 (td,
J=7.9, 5.3 Hz, 1H), 7.23-7.04 (m, J=19.5, 9.7 Hz, 3H), 6.30 (s,
1H), 3.96-3.45 (m, 6H), 3.46-3.19 (m, J=11.6, 7.6 Hz, 2H),
3.01-2.85 (m, 2H), 2.31 (s, 6H), 2.23 (s, 3H).
Example 372
(2-(3-Chloropyridin-2-yl)-3-fluorophenyl)(5-(4,6-dimethylpyrimidin-2-yl)he-
xahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00484##
[0777] The title compound was prepared in a manner analogous to
Example 367. MS (ESI) mass calcd. for C.sub.24H.sub.23ClFN.sub.5O,
451.93; m/z found, 452.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.51 (d, J=3.7 Hz, 1H), 7.71 (dd, J=28.1, 8.0 Hz, 1H),
7.45 (td, J=7.9, 5.3 Hz, 1H), 7.25-7.14 (m, J=10.6, 7.7 Hz, 3H),
6.30 (s, 1H), 3.77 (s, 2H), 3.72-3.59 (m, J=23.3, 9.8 Hz, 2H),
3.59-3.53 (m, 1H), 3.45 (dd, J=33.2, 12.0 Hz, 2H), 3.37-3.11 (m,
J=59.6 Hz, 1H), 3.02-2.88 (m, 2H), 2.31 (s, 6H).
Example 373
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(4-methylpyridin-2-yl)phenyl)methanone
##STR00485##
[0778] The title compound was prepared in a manner analogous to
Example 367. MS (ESI) mass calcd. for C.sub.25H.sub.26FN.sub.5O,
431.51; m/z found, 432.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.44 (d, J=5.0 Hz, 1H), 7.43-7.40 (m, 1H), 7.40-7.34
(m, 1H), 7.21-7.14 (m, J=2.7, 1.1 Hz, 2H), 6.99 (d, J=4.5 Hz, 1H),
6.29 (s, 1H), 3.79 (dd, J=11.5, 7.3 Hz, 1H), 3.69 (ddd, J=8.7, 7.1,
2.1 Hz, 2H), 3.58-3.50 (m, 2H), 3.46 (dd, J=12.6, 4.3 Hz, 1H), 3.40
(dd, J=10.9, 4.2 Hz, 1H), 3.25 (dd, J=11.0, 5.1 Hz, 1H), 2.99-2.85
(m, 2H), 2.34 (s, 3H), 2.31 (s, 6H).
Example 374
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(5-methylpyridin-2-yl)phenyl)methanone
##STR00486##
[0779] The title compound was prepared in a manner analogous to
Example 367. MS (ESI) mass calcd. for C.sub.25H.sub.26FN.sub.5O,
431.51; m/z found, 432.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.42 (s, 1H), 7.53-7.48 (m, 2H), 7.42-7.33 (m, 1H),
7.21-7.12 (m, 2H), 6.29 (s, 1H), 3.81 (dd, J=11.5, 7.3 Hz, 1H),
3.76-3.67 (m, J=11.3, 7.2, 4.3 Hz, 2H), 3.58-3.39 (m, 4H), 3.28
(dd, J=10.9, 4.8 Hz, 1H), 3.01-2.86 (m, 2H), 2.31 (s, 9H).
Example 375
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(3-fluoropyridin-2-yl)phenyl)methanone
##STR00487##
[0780] The title compound was prepared in a manner analogous to
Example 367 substituting 3-fluoro-2-(tributylstannyl)pyridine for
2-tributylstannane pyridine. MS (ESI) mass calcd. for
C.sub.24H.sub.23F.sub.2N.sub.5O, 435.48; m/z found, 436.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): 8.45 (dt, J=4.6,
1.5 Hz, 1H), 7.49-7.39 (m, 2H), 7.29-7.16 (m, 3H), 6.30 (s, 1H),
3.85-3.60 (m, 5H), 3.53-3.42 (m, 2H), 3.38 (dd, J=10.9, 4.4 Hz,
1H), 3.03-2.91 (m, 2H), 2.31 (s, 6H).
Example 376
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(oxazol-2-yl)phenyl)methanone
##STR00488##
[0781] The title compound was prepared in a manner analogous to
Example 367 substituting 2-(tri-N-butylstannyl)oxazole for
2-tributylstannane pyridine. MS (ESI) mass calcd. for
C.sub.22H.sub.22FN.sub.5O.sub.2, 407.45; m/z found, 408.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.73 (d, J=0.6 Hz,
1H), 7.51-7.44 (m, 1H), 7.25-7.20 (m, 2H), 7.18 (dd, J=7.6, 0.9 Hz,
1H), 6.29 (s, 1H), 3.90-3.83 (m, 2H), 3.74-3.60 (m, 3H), 3.52 (dd,
J=11.6, 4.4 Hz, 1H), 3.45 (dd, J=10.9, 7.5 Hz, 1H), 3.11 (dd,
J=10.9, 5.4 Hz, 1H), 3.08-3.00 (m, 1H), 3.00-2.93 (m, 1H), 2.30 (s,
6H).
Example 377
2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl-
)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00489##
[0782]
(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-tria-
zol-2-yl)phenyl)methanone (Example 288-step B, 33 mg, 0.10 mmol),
2-chloro-5-fluoro-4-methylpyrimidine (Intermediate 55, 15 mg, 0.10
mmol) and DIPEA (54 .mu.L, 0.3 mmol) in ACN (1 mL) were heated in a
microwave reactor for 2 h at 200.degree. C. Then the reaction
mixture was concentrated and purified via prep HPLC (Agilent,
basic) gave the title compound as a clear oil. MS (ESI) mass calcd.
C.sub.21H.sub.22FN.sub.7O.sub.2, 423.45; m/z found 424.2
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.06 (d, J=1.8 Hz, 1H), 7.74
(s, 2H), 7.50 (d, J=5.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd,
J=8.5, 2.5 Hz, 1H), 3.93-3.76 (m, 5H), 3.71-3.59 (m, 2H), 3.53 (dd,
J=11.4, 5.2 Hz, 1H), 3.44-3.30 (m, 2H), 3.07-2.87 (m, 3H), 2.37 (t,
J=4.9 Hz, 3H).
Example 378
2-(5-Chloro-4-methylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl-
)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00490##
[0784] The title compound was prepared in a manner analogous to
Example 377, utilizing 2,5-dichloro-4-methylpyrimidine
(Intermediate 65) in place of 2-chloro-5-fluoro-4-methylpyrimidine.
MS (ESI) mass calcd. C.sub.21H.sub.22ClN.sub.7O.sub.2, 439.91; m/z
found 440.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.13 (s, 1H),
7.74 (s, 2H), 7.51 (d, J=10.9 Hz, 1H), 7.32 (d, J=6.8 Hz, 1H), 6.94
(dd, J=20.6, 10.3 Hz, 1H), 3.93-3.78 (m, 5H), 3.73-3.60 (m, 2H),
3.59-3.50 (m, 1H), 3.47-3.30 (m, 2H), 3.08-2.87 (m, 3H), 2.44 (s,
J=11.6 Hz, 3H).
Example 379
2-(5-Fluoro-4,6-dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol--
2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00491##
[0785] The title compound was prepared in a manner analogous to
Example 377, utilizing 2-chloro-5-fluoro-4,6-dimethylpyrimidine
(Intermediate 69) in place of 2-chloro-5-fluoro-4-methylpyrimidine.
MS (ESI) mass calcd. C.sub.22H.sub.24FN.sub.7O.sub.2, 437.48; m/z
found 438.2 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.74 (s, 2H),
7.50 (d, J=2.5 Hz, 1H), 7.35-7.30 (m, 1H), 6.95 (dd, J=8.5, 2.5 Hz,
1H), 3.92-3.75 (m, 5H), 3.70-3.58 (m, 2H), 3.53 (dd, J=11.5, 5.2
Hz, 1H), 3.43-3.29 (m, 2H), 3.04-2.84 (m, 3H), 2.32 (d, J=6.7 Hz,
6H).
Example 380
2-(4,5-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phen-
yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00492##
[0786] The title compound was prepared in a manner analogous to
Example 377, utilizing 2-chloro-4,5-dimethylpyrimidine
(Intermediate 57) in place of 2-chloro-5-fluoro-4-methylpyrimidine.
MS (ESI) mass calcd. C.sub.22H.sub.25N.sub.7O.sub.2, 419.49; m/z
found 420.1 [M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.99 (s, 1H),
7.74 (s, 2H), 7.49 (d, J=7.3 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.94
(dd, J=8.5, 2.5 Hz, 1H), 3.92-3.78 (m, 5H), 3.72-3.61 (m, 2H), 3.54
(dd, J=11.4, 5.2 Hz, 1H), 3.42 (dd, J=11.4, 4.2 Hz, 1H), 3.34 (s,
1H), 3.07-2.85 (m, 3H), 2.32 (s, 3H), 2.09 (s, 3H).
Example 381
2-[(3-Propoxypyridin-2-yl)carbonyl]-5-[5-(trifluoromethyl)pyridin-2-yl]oct-
ahydropyrrolo[3,4-c]pyrrole
##STR00493##
[0788] The title compound was prepared in a manner analogous to
Example 15, utilizing
5-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrrole and
2-propoxynicotinic acid. MS (ESI) mass calcd.
C.sub.21H.sub.23F.sub.3N.sub.4O.sub.2, 420.40; m/z found 421.1
[M+H].sup.+. .sup.1H NMR (CD.sub.3OD): 8.31 (s, 2H), 8.19 (dd,
J=9.6, 2.3 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.26 (d, J=9.4 Hz,
1H), 4.22-4.17 (m, 2H), 4.07-3.93 (m, 3H), 3.79-3.60 (m, 4H),
3.44-3.35 (m, 3H), 1.88-1.77 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).
Example 382
2-{4,6-Bis[(.sup.2H.sub.3)methyl](.sup.2H)pyrimidin-2-yl}-5-{[2-fluoro-6-(-
2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00494##
[0789] To a solution of Intermediate 91 (150 mg, 0.26 mmol) in DCM
(2.6 mL) was added Intermediate 12 (55 mg, 0.26 mmol) followed by
EDCl (76 mg, 0.4 mmol), HOBt (54 mg, 0.4 mmol) and TEA (0.15 mL,
1.06 mmol). The mixture was stirred for 14 h at room temperature
and an additional amount of EDCl (76 mg, 0.4 mmol) and TEA (0.15
mL, 1.06 mmol) were added. After an additional 24 h at room
temperature the mixture was concentrated in vacuo and
chromatography (Hex to 100% EtOAc/Hex) afforded the desired product
as a colorless foam (63 mg, 58%). MS (ESI): mass calculated for
C.sub.21H.sub.15D.sub.7FN.sub.7O, 414.23; m/z found 415.2
[M+1].sup.+. 1H NMR (500 MHz, CDCl.sub.3): 7.87-7.80 (m, 2H), 7.71
(s, 1H), 7.51-7.44 (m, 1H), 7.18-7.10 (m, 1H), 4.01-3.50 (m, 7H),
3.32-3.21 (m, 1H), 3.12-2.94 (m, 2H).
Example 383
2-{4,6-Bis[(.sup.2H.sub.3)methyl](.sup.2H)pyrimidin-2-yl}-5-{[3-fluoro-2-(-
3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrro-
le
##STR00495##
[0790] The title compound was prepared in a manner analogous to
Example 382 substituting Intermediate 63 for Intermediate 12. MS
(ESI): mass calculated for C.sub.22H.sub.16D.sub.7FN.sub.6O.sub.2,
429.23; m/z found 430.2 [M+1].sup.+. 1H NMR (500 MHz, CDCl.sub.3):
7.63-7.57 (m, 1H), 7.31-7.27 (m, 1H), 7.24-7.21 (m, 1H), 3.94-3.87
(m, 2H), 3.78-3.62 (m, 3H), 3.58-3.48 (m, 2H), 3.22-3.15 (m, 1H),
3.12-2.96 (m, 2H), 2.43 (s, 3H).
Example 384
2-{4,6-Bis[(.sup.2H.sub.3)methyl](.sup.2H)pyrimidin-2-yl}-5-{[4-methoxy-2--
(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00496##
[0791] The title compound was prepared in a manner analogous to
Example 382 substituting Intermediate 54 for Intermediate 12. MS
(ESI): mass calculated for C.sub.22H.sub.18D.sub.7N.sub.7O.sub.2,
426.25; m/z found 427.3 [M+1].sup.+. 1H NMR (500 MHz, CDCl.sub.3):
7.73 (s, 2H), 7.50 (d, J=2.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95
(dd, J=8.5 Hz, 2.5 Hz, 1H), 3.94-3.80 (m, 5H), 3.71-3.63 (m, 2H),
3.61-3.55 (m, 1H), 3.49-3.43 (m, 1H), 3.38-3.29 (m, 1H), 3.05-2.86
(m, 3H).
Example 385
2-(5-Ethyl-4,6-dimethylpyrimidin-2-yl)-5-{[3-(2H-1,2,3-triazol-2-yl)pyridi-
n-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00497##
[0793] The title compound was prepared in a manner analogous to
Example 290 substituting Intermediate 68 for Intermediate 20 and
Intermediate 67 for Intermediate 55. MS (ESI) mass calculated for
C.sub.22H.sub.26N.sub.8O, 418.22; m/z found, 419.2. 1H NMR (500
MHz, CDCl.sub.3): 8.62 (dd, J=4.7 Hz, 1.3 Hz, 1H), 8.33 (dd, J=8.3
Hz, 1.4 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7 Hz, 1H),
3.97-3.84 (m, 2H), 3.78-3.63 (m, 4H), 3.59-3.55 (m, 1H), 3.29-3.23
(m, 1H), 3.13-2.98 (m, 2H), 2.52 (q, J=7.5 Hz, 2H), 2.38 (s, 6H),
1.08 (t, J=7.5 Hz, 3H).
Example 386
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridi-
n-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole
##STR00498##
[0795] Step A: 2-(Methoxycarbonyl)nicotinic acid.
2,3-Pyridinecarboxylic anhydride (2.32 g, 15.55 mmol) was dissolved
in MeOH (11 mL) and heated to reflux for 14 h. The mixture was
concentrated in vacuo to a white solid that was a mixture of
2-(methoxycarbonyl)nicotinic acid and 3-(methoxycarbonyl)picolinic
acid. This mixture was used as is. MS (ESI) mass calculated for
C.sub.8H.sub.7NO.sub.4, 181.04; m/z found, 181.9.
[0796] Step B: (E)-Methyl
3-((((1-aminoethylidene)amino)oxy)carbonyl) picolinate. To the
product of Step A (250 mg, 1.38 mmol) in THF (7 mL) at 0.degree. C.
was added ethyl chloroformate (0.17 mL, 1.38 mmol) followed by TEA
(0.29 mL, 2.07 mmol). After 10 min the ice bath was removed and
after 2 h N-hydroxyacetamidine (102 mg, 1.38 mmol) was added in one
portion. After 14 h at room temperature the mixture was
concentrated in vacuo and chromatography (Hex to 100% EtOAc/Hex)
afforded the desired (E)-methyl
3-((((1-aminoethylidene)amino)oxy)carbonyl)picolinate (200 mg, 70%)
and (E)-methyl
2-((((1-aminoethylidene)amino)oxy)carbonyl)nicotinate (60 mg, 18%).
MS (ESI) mass calculated for C.sub.10H.sub.11N.sub.3O.sub.4,
237.08; m/z found, 238.1. 1H NMR (500 MHz, CDCl.sub.3): 8.79 (dd,
J=4.8 Hz, 1.6 Hz, 1H), 8.28 (dd, J=7.9 Hz, 1.6 Hz, 1H), 7.58-7.51
(m, 1H), 3.99 (s, 3H), 2.04 (s, 3H).
[0797] Step C: 3-(3-Methyl-1,2,4-oxadiazol-5-yl)picolinic acid. To
the product of Step B (180 mg, 0.76 mmol) was added t-BuOH (4 mL)
followed by NaOAc (94 mg, 1.14 mmol) and the mixture was heated at
100.degree. C. for 14 h. The mixture was allowed to cool to room
temperature and filtered to afford
3-(3-methyl-1,2,4-oxadiazol-5-yl)picolinic acid (60 mg, 39%) as a
white solid.
[0798] Step D:
2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-(3-methyl-1,2,4-oxadiazol-5-yl)pyrid-
in-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole. To a solution of
the product of Step C (60 mg, 0.30 mmol) in DCM (3 mL) was added
Intermediate 23 (65 mg, 0.30 mmol) followed by EDCl (85 mg, 0.44
mmol), HOBt (60 mg, 0.44 mmol) and TEA (0.08 mL, 0.59 mmol). The
mixture was stirred at room temperature for 14 h and then
concentrated in vacuo. Chromatography (DCM to 8% 2 M NH.sub.3 in
MeOH/DCM) afforded the desired compound as a colorless foam (49 mg,
41%). MS (ESI) mass calculated for C.sub.21H.sub.23N.sub.7O.sub.2,
405.19; m/z found, 406.2. 1H NMR (500 MHz, CDCl.sub.3): 8.82-8.75
(m, 1H), 8.42-8.36 (m, 1H), 7.52-7.47 (m, 1H), 6.31-6.26 (m, 1H),
4.02-3.90 (m, 2H), 3.86-3.79 (m, 1H), 3.76-3.69 (m, 2H), 3.66-3.54
(m, 2H), 3.24-3.18 (m, 1H), 3.14-2.99 (m, 2H), 2.48-2.42 (m, 3H),
2.33-2.24 (m, 6H).
Example 387
(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3--
fluoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00499##
[0799] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 44 and Intermediate 50 in the
last step MS (ESI): mass calculated for
C.sub.25H.sub.19F.sub.3N.sub.6O, 476.16; m/z found 477.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.74 (t, J=12.5,
2H), 8.25 (d, J=20.5, 1H), 7.65 (dd, J=10.5, 8.4, 1H), 7.52-7.40
(m, 2H), 7.26-7.12 (m, 3H), 3.97-3.74 (m, 3H), 3.73-3.52 (m, 4H),
3.38 (dd, J=11.1, 4.6, 1 H), 3.22-3.02 (m, 2H).
Example 388
(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3--
fluoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00500##
[0800] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 43 and Intermediate 54 in the
last step MS (ESI): mass calculated for
C.sub.24H.sub.22FN.sub.7O.sub.2, 459.18; m/z found 460.2
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.97 (s, 1H), 7.71
(s, 2H), 7.59 (dd, J=9.0, 4.7, 1 H), 7.47 (ddd, J=17.7, 9.5, 2.6,
2H), 7.37-7.28 (m, 2H), 6.95 (dd, J=8.5, 2.5, 1 H), 4.01-3.85 (m,
5H), 3.74 (ddt, J=17.0, 11.6, 8.8, 3H), 3.64-3.33 (m, 2H),
3.12-2.93 (m, 3H).
Example 389
(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4--
methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00501##
[0802] The title compound was prepared in a manner analogous to
Example 15, utilizing Intermediate 44 and Intermediate 54 in the
last step MS (ESI): mass calculated for
C.sub.24H.sub.21F.sub.2N.sub.7O.sub.2, 477.17; m/z found 478.1
[M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3) 8.26 (d, J=14.7, 1
H), 7.71 (s, 2H), 7.63 (dd, J=10.6, 8.5, 1 H), 7.49 (t, J=7.1, 1
H), 7.41 (dd, J=11.4, 8.0, 1 H), 7.33 (t, J=6.7, 1 H), 6.95 (dt,
J=8.4, 4.2, 1 H), 3.99-3.85 (m, 5H), 3.83-3.69 (m, 2H), 3.70-3.57
(m, 1H), 3.52 (dd, J=11.0, 3.5, 1 H), 3.44 (s, 1H), 3.19-3.09 (m,
1H), 3.09-2.97 (m, 2H).
Example 390
(5-(6-(Dimethylamino)pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00502##
[0803] The title compound was prepared utilizing
(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2--
yl)phenyl)methanone (Example 288, product from Step B) and
6-chloro-N,N-dimethylpyrimidin-4-amine. MS (ESI) mass calcd.
C.sub.22H.sub.26N.sub.8O.sub.2, 434.49; m/z found 435.2
[M+H].sup.+.
Example 391
(5-(6-(Dimethylamino)-2-methylpyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-
-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
##STR00503##
[0804] The title compound was prepared utilizing
(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2--
yl)phenyl)methanone (Example 288, product from Step B) and
6-chloro-N,N,2-trimethylpyrimidin-4-amine. MS (ESI) mass calcd.
C.sub.23H.sub.28N.sub.8O.sub.2, 448.52; m/z found 449.2
[M+H].sup.+. Prophetic examples 392-398 may be made using the
procedures described previously.
Example 392
(5-(6-(Dimethylamino)-2-methylpyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-
-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00504##
[0805] The title prophetic compound may be synthesized utilizing
6-chloro-N,N,2-trimethylpyrimidin-4-amine and MS (ESI) mass calcd.
C.sub.24H.sub.26FN.sub.7O, 447.51
Example 393
(5-(6-(Dimethylamino)pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00505##
[0806] The title prophetic compound may be synthesized utilizing
3-fluoro-2-(pyrimidin-2-yl)benzoic acid and
6-chloro-N,N-dimethylpyrimidin-4-amine. MS (ESI) mass calcd.
C.sub.23H.sub.24FN.sub.7O, 433.48
Example 394
(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl-
)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00506##
[0807] The title prophetic compound may be synthesized utilizing
3-fluoro-2-(pyrimidin-2-yl)benzoic acid and
2-chloro-5-fluoro-4,6-dimethylpyrimidine. MS (ESI) mass calcd.
C.sub.23H.sub.22F.sub.2N.sub.6O, 436.46
Example 395
(5-(5-Chloro-4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H-
)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00507##
[0808] The title prophetic compound may be synthesized utilizing
3-fluoro-2-(pyrimidin-2-yl)benzoic acid and
2,5-dichloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd.
C.sub.23H.sub.22ClFN.sub.6O.sub.2, 452.91
Example 396
(5-(5-Chloro-4-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl-
)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00508##
[0809] The title prophetic compound may be synthesized utilizing
3-fluoro-2-(pyrimidin-2-yl)benzoic acid and
2,5-dichloro-4-methylpyrimidine. MS (ESI) mass calcd.
C.sub.22H.sub.20ClN.sub.6O, 438.89.
Example 397
(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(5-fluoro-4-methylpyrimidin-2-yl)hex-
ahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00509##
[0810] The title prophetic compound may be synthesized utilizing
3-fluoro-2-(pyrimidin-2-yl)benzoic acid and
2-chloro-5-fluoro-4-methylpyrimidine. MS (ESI) mass calcd.
C.sub.22H.sub.20F.sub.2N.sub.6O, 434.49.
Example 398
(5-(4,5-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-f-
luoro-2-(pyrimidin-2-yl)phenyl)methanone
##STR00510##
[0812] MS (ESI) mass calcd. C.sub.23H.sub.23FN.sub.6O, 418.47
Example 399
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-f-
luoro-2-(6-methylpyridin-2-yl)phenyl)methanone
##STR00511##
[0813] The title compound was prepared in a manner analogous to
Example 248, substituting
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5--
fluoro-2-iodophenyl)methanone for
(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4--
fluoro-2-iodophenyl)methanone and
6-methyl-2-(tributylstannyl)pyridine for 2-tributylstannane
pyrimidine, with the addition of CuI. MS (ESI) mass calcd. for
C.sub.25H.sub.26FN.sub.5O, 431.21; m/z found 432.2 [M+1].sup.+.
Example 400
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-f-
luoro-2-(4-methylpyridin-2-yl)phenyl)methanone
##STR00512##
[0814] The title compound was prepared in a manner analogous to
Example 399, substituting 4-methyl-2-(tributylstannyl)pyridine for
6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.25H.sub.26FN.sub.5O, 431.21; m/z found 432.2 [M+1].sup.+.
Example 401
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-f-
luoro-2-(5-methylpyridin-2-yl)phenyl)methanone
##STR00513##
[0815] The title compound was prepared in a manner analogous to
Example 399, substituting 5-methyl-2-(tributylstannyl)pyridine for
6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.25H.sub.26FN.sub.5O, 431.21; m/z found 432.2 [M+1].sup.+.
Example 402
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-f-
luoro-2-(3-fluoropyridin-2-yl)phenyl)methanone
##STR00514##
[0816] The title compound was prepared in a manner analogous to
Example 399, substituting 3-fluoro-2-(tributylstannyl)pyridine for
6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.24H.sub.23F.sub.2N.sub.5O, 435.19; m/z found 436.2
[M+1].sup.+.
Example 403
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-f-
luoro-2-(pyridin-2-yl)phenyl)methanone
##STR00515##
[0817] The title compound was prepared in a manner analogous to
Example 399, substituting 2-tri-N-butylstannylpyridine for
6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.24H.sub.24FN.sub.5O, 417.20; m/z found 418.2 [M+1].sup.+.
Example 404
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-f-
luoro-2-(oxazol-2-yl)phenyl)methanone
##STR00516##
[0818] The title compound was prepared in a manner analogous to
Example 399, substituting 2-(tri-N-butylstannyl)oxazole for
6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. for
C.sub.22H.sub.22FN.sub.5O.sub.2, 407.18; 1H .sup.1H NMR (400 MHz,
CDCl.sub.3): 8.04 (dd, J=8.8, 5.3 Hz, 1H), 7.65 (s, 1H), 7.20-7.13
(m, 2H), 7.07 (dd, J=8.3, 2.6 Hz, 1H), 6.29 (s, 1H), 3.95 (dd,
J=12.6, 7.6 Hz, 1H), 3.88 (dd, J=11.6, 7.6 Hz, 1H), 3.78-3.63 (m,
3H), 3.51-3.45 (m, 1H), 3.41 (dd, J=10.8, 7.5 Hz, 1H), 3.11-3.02
(m, 2H), 3.00-2.90 (m, 1H), 2.29 (s, 6H). Prophetic examples
405-410 may be made using the procedures described previously.
Example 405
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-f-
luoro-2-(6-methylpyridin-2-yl)phenyl)methanone
##STR00517##
[0820] MS (ESI) mass calcd. for C.sub.25H.sub.26FN.sub.5O,
431.21;
Example 406
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-f-
luoro-2-(4-methylpyridin-2-yl)phenyl)methanone
##STR00518##
[0822] MS (ESI) mass calcd. for C.sub.25H.sub.26FN.sub.5O,
431.21;
Example 407
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-f-
luoro-2-(5-methylpyridin-2-yl)phenyl)methanone
##STR00519##
[0824] MS (ESI) mass calcd. for C.sub.25H.sub.26FN.sub.5O,
431.21;
Example 408
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-f-
luoro-2-(3-fluoropyridin-2-yl)phenyl)methanone
##STR00520##
[0826] MS (ESI) mass calcd. for C.sub.24H.sub.23F.sub.2N.sub.5O,
435.19;
Example 409
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-f-
luoro-2-(pyridin-2-yl)phenyl)methanone
##STR00521##
[0828] MS (ESI) mass calcd. for C.sub.24H.sub.24FN.sub.5O,
417.20;
Example 410
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-f-
luoro-2-(oxazol-2-yl)phenyl)methanone
##STR00522##
[0830] MS (ESI) mass calcd. for C.sub.22H.sub.22FN.sub.5O.sub.2,
407.18;
Example 411
(3,6'-Dimethyl-[2,3'-bipyridin]-2'-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo-
[3,4-c]pyrrol-2(1H)-yl)methanone
##STR00523##
[0832] MS (ESI) mass calcd. For C.sub.27H.sub.26N.sub.6O,
450.22.
Example 412
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-f-
luoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone.cndot.HCl.cndot.1.65H.sub.2O
##STR00524##
[0833] To a mixture of
[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone (200 mg, 0.47 mmol)
and IPA (1.5 mL) at room temperature was added 6 M HCl.sub.(aq) (83
.mu.L, 0.5 mmol). The mixture was warmed to 75.degree. C. and then
slowly cooled to 35.degree. C. The mixture was then seeded with
solids formed previously [The seeds were formed as follows: To a
mixture of
[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2--
fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone (200 mg, 0.47 mmol)
and IPA (2 mL) at room temperature was added 5 M HCl in IPA (100
.mu.L, 0.5 mmol). The mixture became homogeneous and was stirred at
room temperature for 3 weeks. Solids formed when the solvent was
allowed to evaporate under an ambient atmosphere.]. Once seeded,
the mixture was cooled to room temperature and stirred for 3 days.
The resulting solids were filtered and washed with IPA (0.5 mL).
The solids were then dried in a vacuum oven for 2 h at 45.degree.
C. to give the title compound as a white solid (201.9 mg, 91%).
.sup.1H NMR (600 MHz, DMSO-d.sub.6): 8.16 (s, 0.8H), 8.05 (s,
1.2H), 7.83 (d, J=8.2, 0.4H), 7.79 (d, J=8.2, 0.6H), 7.70-7.64 (m,
1H), 7.48-7.41 (m, 1H), 6.71 (bs, 1H), 4.0-3.4 (m, 7H), 3.25-2.96
(m, 3H), 2.48-2.33 (m, 6H). Anal. Calcd. For
C.sub.21H.sub.22FN.sub.7O.cndot.HCl.cndot.1.65H.sub.2O C, 53.25; H,
5.60; N, 20.70; Cl, 7.49. found C, 53.54; H, 5.64; N, 21.04; Cl,
7.10. Water calculated, 6.28%. found by Karl-Fisher titration,
6.32%.
Biological Assays
[0834] The in vitro affinity of the compounds for the human
orexin-1 and orexin-2 receptors was determined by competitive
radioligand binding using [.sup.3H]SB SB674042
(1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-14(S)-2-(5-phenyl-(1,3,4)o-
xadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone) (Langmead et al.,
British Journal of Pharmacology 2004, 141:340-346.) and
[.sup.3H]EMPA
(N-ethyl-2[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-
-3-ylmethyl acetamide) (Malherbe et al., British Journal of
Pharmacology, 2009, 156(8), 1326-1341), respectively. The in vitro
functional antagonism of the compounds on the human orexin-1 and
orexin-2 receptors was determined using fluorometric imaging plate
reader (FLIPR) based calcium assays.
Human Orexin 1 Receptor Radioligand Binding Studies
[0835] Chinese ovary cells (CHO) stably expressing human orexin 1
receptor (Genebank accession number NM.sub.--001526) were grown to
confluency in DMEM/F12 (Gibco, Cat #11039), 10% FBS, 1.times.
Pen/Strep, 600 .mu.g/mL G418 media on 150 cm.sup.2 tissue culture
plates, washed with 5 mM EDTA in PBS (HyClone Dulbecco's Phosphate
Buffered Saline 1.times. with Calcium and Magnesium, Cat #
SH30264.01, hereafter referred to simply as PBS) and scraped into
50 ml tubes. After centrifugation (2K.times.G, 10 min at 4.degree.
C.), the supernatant was aspirated and the pellets frozen and
stored at 80.degree. C. Cells were resuspended in PBS in the
presence of 1 tablet of protease inhibitor cocktail (Roche, Cat.
#11836145001) per 50 mL. Each cell pellet from a 15 cm plate was
resuspended in 10 mL, stored on ice, and vortexed for 45 sec prior
to addition to the reactions. Competition binding experiments in 96
well polypropylene plates were performed using [.sup.3H]-SB674042
(Moravek Corporation, specific activity=35.3 Ci/mmol), diluted to a
10 nM concentration in PBS (4 nM final). Compounds were solubilized
in 100% DMSO (Acros Organics, Cat. #61042-1000) and tested over a
range of 7 concentrations (from 0.1 nM to 10 .mu.M). The final
concentration of DMSO in the reactions is equal to or less than
0.1%. Total and nonspecific binding was determined in the absence
and presence of 10 .mu.M
(1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea,
CAS Registry #288150-92-5). The total volume of each reaction is
200 .mu.L (20 .mu.L of diluted compounds, 80 .mu.L of
[.sup.3H]-SB674042 diluted in PBS and 1004 of the cell suspension).
Reactions were run for 60 min at room temperature and terminated by
filtration through GF/C filter plates (PerkinElmer, Cat. #6005174)
presoaked in 0.3% polyethylenimine using the cell harvester
(PerkinElmer Filtermate). The plates were washed 3 times by
aspirating 30 ml PBS through the plates. Plates were dried in
55.degree. C. oven for 60 min, scintillation fluid was added, and
the radioactivity was counted on a Topcount (Packard). IC.sub.50
values (i.e. concentration of unlabelled compound required to
compete for 50% of specific binding to the radioligand) were
calculated using the GraphPad Prism software (GraphPad Prism
Software Inc., San Diego, Calif.) with a fit to a sigmoidal
dose-response curve. Apparent K.sub.i values were calculated as
K.sub.i=IC.sub.50/(1+C/K.sub.d), where C is concentration of
radioligand and K.sub.d=4 nM.
Human Orexin 2 Receptor Radioligand Binding Studies
[0836] HEK293 stably expressing human orexin-2 receptor (Genebank
accession number NM.sub.--001526) were grown to confluency in
DMEM/F12 (Gibco, Cat #11039), in DMEM, 10% FBS, 1.times. Pen/Strep,
1.times. NaPyruvate, 1.times. HEPES, 600 ug/ml G418 media on 150
cm.sup.2 tissue culture plates, washed with 5 mM EDTA in PBS
(HyClone Dulbecco's Phosphate Buffered Saline 1.times. with Calcium
and Magnesium, Cat # SH30264.01, hereafter referred to simply as
PBS) and scraped into 50 ml tubes. After centrifugation
(2K.times.G, 10 min at 4.degree. C.), the supernatant was aspirated
and the pellets frozen and stored at -80.degree. C. Cells were
resuspended in PBS in the presence of 1 tablet of protease
inhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cell
pellet from a 15 cm plate was resuspended in 10 mL, stored on ice,
and vortexed for 45 sec just prior to addition to the reactions.
Competition binding experiments in 96 well polypropylene plates
were performed using [.sup.3H]-EMPA (Moravek Corporation, specific
activity=27 Ci/mmol), diluted to a 20 nM concentration in PBS (5 nM
final concentration). Compounds were solubilized in 100% DMSO
(Acros Organics, Cat. #61042-1000) and tested over a range of 7
concentrations (from 0.1 nM to 10 .mu.M). The final concentration
of DMSO in the reactions is equal to or less than 0.1%. Total and
nonspecific binding was determined in the absence and presence of
10 .mu.M
(N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylnaphthalene-1-carboxamide,
CAS Registry #1089563-88-1). The total volume of each reaction is
200 .mu.L (20 .mu.L of diluted compounds, 80 .mu.L of
[.sup.3H]-EMPA diluted in PBS and 100 .mu.L of the cell
suspension). Reactions were run for 60 min at room temperature and
terminated by filtration through GF/C filter plates (PerkinElmer,
Cat. #6005174) presoaked in 0.3% polyethylenimine using the cell
harvester (PerkinElmer Filtermate). The plates were washed 3 times
by aspirating 30 ml PBS through the plates. Plates were dried in
55.degree. C. oven for 60 min, scintillation fluid was added, and
the radioactivity was counted on a Topcount (Packard). IC.sub.50
values (i.e. concentration of unlabelled compound required to
compete for 50% of specific binding to the radioligand) were
calculated using the GraphPad Prism software (GraphPad Prism
Software Inc., San Diego, Calif.) with a fit to a sigmoidal
dose-response curve. Apparent K.sub.i values were calculated as
K.sub.i=IC.sub.50/(1+C/K.sub.d), where C is concentration of
radioligand and K.sub.d=2 nM.
Human Orexin 1 Receptor Ca.sup.2+ Mobilization Assay
[0837] CHO cells stably transfected with the human orexin-1
receptor (Genebank accession number NM.sub.--001526) were grown to
confluency in DMEM/F12, 10% FBS, 1.times. Na Pyruvate, 1.times.
pen-strep, 400 .mu.g/ml G418. Cells were seeded on to 96-well
Packard viewplates at a density of 50,000 cells/well and incubated
overnight at 37.degree. C., 5% CO.sub.2. The cells were dye-loaded
with 4 .mu.M Ca.sup.2+ dye Fluo-3AM in serum-free DMEM/F-12 with
2.5 mM probenecid and incubated at 37.degree. C., 5% CO.sub.2 for
one hour. Cells were pre-incubated with compounds (diluted in
DMEM/F-12) for 30 minutes before agonist (orexin A, 10 nM)
stimulation. Ligand-induced Ca.sup.2+ release was measured using a
Fluorometric Imaging Plate Reader (FLIPR, Molecular Devices,
Sunnyvale, Calif.). Functional responses were measured as peak
fluorescence intensity minus basal. The concentration of agonist
that produced a half-maximal response is represented by the
EC.sub.50 value. Antagonistic potency values were converted to
apparent pK.sub.B values using a modified Cheng-Prusoff correction.
Apparent pK.sub.B=-log IC.sub.50/1+[conc agonist/EC.sub.50]. Data
are expressed as mean.+-.S.E.M.
Human Orexin 2 Receptor Ca.sup.2+ Mobilization Assay
[0838] PFSK cells endogenously expressing the human orexin 2
receptor were grown to confluency in RPMI 1640, 10% FBS, 1.times.
pen-strep. Cells were seeded on to 96-well Packard viewplates at a
density of 50,000 cells/well and incubated overnight at 37.degree.
C., 5% CO.sub.2. The cells were dye-loaded with 4 .mu.M Ca.sup.2+
dye Fluo-3AM in serum-free DMEM/F-12 with 2.5 mM probenecid and
incubated at 37.degree. C., 5% CO.sub.2 for one hour. Cells were
pre-incubated with compounds (diluted in DMEM/F-12) for 30 minutes
before agonist (orexin B, 100 nM) stimulation. Ligand-induced
Ca.sup.2+ release was measured using a Fluorometric Imaging Plate
Reader (FLIPR, Molecular Devices, Sunnyvale, Calif.). Functional
responses were measured as peak fluorescence intensity minus basal.
The concentration of agonist that produced a half-maximal response
is represented by the EC.sub.50 value. Antagonistic potency values
were converted to apparent pK.sub.B values using a modified
Cheng-Prusoff correction. Apparent pK.sub.B=-log IC.sub.50/1+[conc
agonist/EC.sub.50]. Data are expressed as mean.+-.S.E.M, the
designation of NT means not tested.
TABLE-US-00002 OR 2 Ki OR 2 OR 1 Ki Ex # (nM) Kb (nM) 1 37 10 100 2
33 16 189 3 42 14 127 4 65 32 447 5 14 5 63 6 67 25 154 7 42 13 139
8 542 NT 10000 9 101 56 691 10 170 NT 6708 11 1438 NT 10000 12 46
32 4378 13 89 79 10000 14 28 9 2780 15 13 2 1824 16 300 NT 10000 17
730 NT NT 18 519 NT 1264 19 24 31 77 20 92 129 263 21 352 NT 1091
22 70 158 303 23 364 NT 677 24 415 NT 1544 25 110 99 162 26 8999 NT
NT 27 740 NT NT 28 575 NT 1787 29 135 NT 1009 30 790 NT NT 31 425
NT 651 32 47 32 8999 33 250 NT 488 34 79 NT 143 35 722 NT 4370 36
449 NT 1459 37 181 NT 137 38 515 NT 887 39 8999 NT 10000 40 559 NT
1433 41 356 NT 2512 42 616 NT 5000 43 7 10 422 44 142 63 10000 45
36 10 723 46 132 NT 294 47 38 32 1124 48 716 NT 10000 49 78 32 1692
50 215 NT 10000 51 644 NT 10000 52 65 50 8999 53 5000 NT 10000 54
769 NT 5000 55 744 NT 8999 56 80 40 800 57 167 NT 2323 58 227 NT
5000 59 778 NT 8999 60 173 NT 2644 61 224 NT 2272 62 42 40 689 63
44 20 2171 64 579 NT 10000 65 228 NT 207 66 449 NT 415 67 119 NT
10000 68 13 16 225 69 17 8 3082 70 52 40 2630 71 1000 NT 10000 72
318 NT 8999 73 7 5 69 74 14 10 4275 75 119 32 9226 76 237 NT 10000
77 25 16 547 78 550 NT 10000 79 480 NT 8999 80 314 NT 8999 81 1223
NT 6708 82 379 NT 10000 83 12 4 1766 84 53 25 1322 85 98 63 1162 86
256 NT 2603 87 509 NT 10000 88 75 25 8999 89 452 NT 10000 90 38 25
1734 91 541 NT 10000 92 766 NT 8999 93 64 40 5000 94 551 NT 847 95
215 NT 774 96 68 50 2429 97 25 16 354 98 28 10 275 99 15 16 180 100
238 NT 10000 101 48 25 4234 102 17 6 463 103 38 32 2280 104 42 25
3604 105 20 20 2451 106 26 20 212 107 9 2 868 108 57 25 80 109 46
25 65 110 52 32 350 111 28 16 153 112 95 20 122 113 50 63 90 114
224 NT 3061 115 5000 NT 10000 116 22 13 61 117 24 8 42 118 19 5
1843 119 51 13 3568 120 71 13 2867 121 15 13 42 122 865 NT 10000
123 44 79 10000 124 422 NT 10000 125 901 NT 8999 126 95 100 75 127
55 20 40 128 18 4 1250 129 111 100 1538 130 32 16 3438 131 75 79
131 132 125 79 7071 133 291 NT 390 134 102 12 2722 135 90 40 10000
136 104 50 8999 137 50 25 891 138 30 40 231 139 63 63 83 140 119 NT
1538 141 1034 NT 415 142 315 NT 2318 143 81 79 150 144 87 63 537
145 45 32 70 146 27 16 137 147 85 63 2946 148 129 NT 947 149 173 NT
142 150 92 40 5000 151 184 NT 504 152 125 NT 10000 153 75 40 2645
154 241 NT 9654 155 33 16 8999 156 39 16 5000 157 69 16 5000 158 55
8 5000 159 45 8 2447 160 58 20 659 161 46 7 5317 162 43 5 5000 163
380 501 NT 164 289 200 722 165 852 NT 4637 166 465 NT 752 167 411
631 2803 168 66 126 851 169 595 NT 1784 170 945 NT NT 171 780 NT NT
172 450 NT NT 173 950 NT NT 174 729 NT NT 175 669 NT 1391 176 236
158 923 177 339 NT NT 178 123 126 762 179 8999 NT NT 180 2300 NT NT
181 3564 NT 8999 182 2198 NT 10000 183 5000 NT NT 184 1037 NT 879
185 8999 NT NT 186 10000 NT NT 187 2283 NT NT 188 2608 NT NT 189
1600 NT NT 190 1300 NT 5000 191 2658 NT NT 192 1015 NT NT 193 1156
NT 814 194 10000 NT NT 195 1099 NT 646 196 10000 NT NT 197 1163 NT
NT 198 1312 NT 2012 199 3777 NT NT 200 10000 NT 10000 201 1372 NT
10000 202 5000 NT 10000 203 5000 NT 10000 204 50 20 169 205 3189 NT
10000 206 1266 NT 10000 207 8999 NT 10000 208 2100 NT 10000 209
8999 NT 10000 210 3000 NT 10000 211 44 25 10000 212 33 32 5000 213
56 50 10000 214 1227 NT 1077 215 5000 NT 10000 219 404 NT 10000 220
500 NT 10000 221 2211 NT 10000 222 3621 NT 10000 223 340 NT 10000
224 635 NT 10000 225 423 NT 10000 226 836 NT 10000 227 1472 NT
10000 228 184 NT 10000 229 319 NT 10000 230 254 NT 10000 231 68 7
1613 232 52 7 2078 233 2100 NT 10000 234 10000 NT 10000 235 560 NT
10000 236 10000 NT 10000 237 69 18 8247 238 243 NT 10000 239 7 4
173 240 7 3 460 241 17 7 978 242 39 13 633 243 16 6 358 244 18 5
660 245 58 15 369 246 11 11 208 247 650 NT 4399 248 170 NT 1400
249 NT NT NT 250 NT NT NT 251 25 2 1470 252 10000 NT 10000 253 5000
NT 10000 254 2200 NT 10000 255 10000 NT 10000 256 10000 NT 10000
257 19 5 1843 258 46 25 927 259 8 3 335 260 90 16 8999 261 477 NT
10000 262 500 NT 10000 263 10000 NT 10000 264 10000 NT 10000 265
8999 NT 10000 266 127 NT 8999 267 10000 NT 10000 268 265 NT 10000
269 10000 NT 10000 270 1033 NT 10000 271 5000 NT 10000 272 33 7 598
273 5000 NT 10000 274 61 16 8999 275 487 NT 10000 276 2947 NT 10000
277 680 NT 10000 278 2274 NT 10000 279 23 10 1603 280 41 63 71 281
8999 NT 10000 282 858 NT 1436 283 10 2 978 284 8 2 587 285 1500 NT
10000 286 10000 NT 10000 287 1400 NT 10000 288 11 3 1606 289 1800
NT 10000 290 19 7 2150 291 266 NT 10000 292 428 NT 10000 293 19 79
2186 294 4 3 125 295 24 10 1100 296 9 3 235 297 6 NT 261 298 9 NT
160 299 15 NT 389 300 290 NT 2800 301 36 20 114 302 17 8 173 303
1700 NT 10000 304 3100 NT 10000 305 7 NT 775 306 39 13 2300 307
10000 NT 10000 308 26 5 1743 309 7 6 414 310 64 15 4996 311 7 3 312
312 79 11 3472 313 7 3 128 314 13 4 958 315 38 10 2837 316 10 8 306
317 3 3 34 318 5 3 89 319 18 7 537 320 4 2 54 321 29 10 816 322 10
5 378 323 25 4 2474 324 16 4 388 325 16 2 1662 326 8 4 151 327 103
50 5500 328 112 40 6345 329 10000 NT 10000 330 10000 NT 10000 331
81 32 3791 332 114 63 10000 333 10000 NT 10000 334 277 NT 10000 335
59 NT 3200 336 288 NT 10000 337 513 NT 10000 338 1604 NT 10000 339
8999 NT 10000 340 1521 NT 10000 341 10000 NT 10000 342 9486 NT
10000 343 36 NT 2900 344 1500 NT 10000 346 25 NT 1800 347 3100 NT
10000 349 10000 NT 10000 351 1200 NT 10000 352 10000 NT 3111 353
10000 NT 10000 355 10000 NT 10000 356 10000 NT 10000 358 230 NT
10000 359 180 NT 10000 361 4399 NT 10000 362 1800 NT 2700 366 23 NT
1900 367 15 3 839 369 19 NT 1200 370 84 7 7874 371 3400 NT 10000
372 109 NT 8000 373 42 5 10000 374 73 12 1049 375 21 4 3186 376 17
NT 1591 377 17 2 2186 378 10 2 508 379 9 5 202 380 15 5 2039 381
10000 NT 10000 382 14 3 854 383 13 4 920 384 10 5 1385 385 42 8
3688 386 940 NT 10000 387 16 9 437 388 30 NT 694 389 22 14 492 390
190 NT 10000 391 28 NT 1200 399 570 NT 10000 400 510 NT 10000 401
830 NT 10000 402 120 NT 10000 403 180 NT 10000 404 19 NT 1200
Powder X-Ray Diffraction
[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-f-
luoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone
[0839] Powder X-Ray Diffraction of the reference compound was
performed on a Philips X'PERT PRO with X'Celerator Cu detector
equipped with a real time multiple strips X-ray detection
technology to obtain the X-ray powder patterns in FIG. 1. The
samples were scanned from 4.degree. to 40.degree.2.theta., at a
step size 0.0167 .degree.20 and a time per step of 29.8450 seconds.
The tube voltage and current were 45 kV and 40 mA, respectively.
The samples were placed onto zero background holders and analyzed
on a spinning stage.
* * * * *