U.S. patent application number 14/717339 was filed with the patent office on 2015-09-10 for bridged bicyclic amino thiazine dioxide compounds as inhibitors of beta-secretase and methods of use thereof.
The applicant listed for this patent is AMGEN INC.. Invention is credited to Jennifer R. ALLEN, James BROWN, Angel GUZMAN-PEREZ, Zihao HUA, Ted JUDD, Richard T. LEWIS, Qingyian LIU, Philip R. OLIVIERI, Karina ROMERO, Laurie SCHENKEL, John STELLWAGEN, Ryan WHITE.
Application Number | 20150252059 14/717339 |
Document ID | / |
Family ID | 51301366 |
Filed Date | 2015-09-10 |
United States Patent
Application |
20150252059 |
Kind Code |
A1 |
LEWIS; Richard T. ; et
al. |
September 10, 2015 |
BRIDGED BICYCLIC AMINO THIAZINE DIOXIDE COMPOUNDS AS INHIBITORS OF
BETA-SECRETASE AND METHODS OF USE THEREOF
Abstract
The present invention provides a new class of compounds useful
for the modulation of beta-secretase enzyme (BACE) activity. The
compounds have a general Formula I: ##STR00001## wherein variables
A.sup.4, A.sup.5, A.sup.6, A.sup.8, R.sup.1, R.sup.2, R.sup.3,
R.sup.7 and n of Formula I, independently, are defined herein. The
invention also provides pharmaceutical compositions comprising the
compounds, and corresponding uses of the compounds and compositions
for treatment of disorders and/or conditions related to A-beta
plaque formation and deposition, resulting from the biological
activity of BACE. Such BACE mediated disorders include, for
example, Alzheimer's Disease, cognitive deficits, cognitive
impairments, schizophrenia and other central nervous system
conditions. The invention further provides compounds of Formula II
and sub-formula embodiments thereof, compounds of Formula III,
intermediates and processes and methods useful for the preparation
of compounds of Formulas I-III, and sub-Formulas thereof.
Inventors: |
LEWIS; Richard T.; (Houston,
TX) ; ALLEN; Jennifer R.; (Newbury Park, CA) ;
BROWN; James; (Moorpark, CA) ; GUZMAN-PEREZ;
Angel; (Belmont, MA) ; HUA; Zihao; (Andover,
MA) ; JUDD; Ted; (Granada Hills, CA) ; LIU;
Qingyian; (Camarillo, CA) ; OLIVIERI; Philip R.;
(Charlestown, MA) ; ROMERO; Karina; (Burlington,
MA) ; SCHENKEL; Laurie; (Boston, MA) ;
STELLWAGEN; John; (Beverly, MA) ; WHITE; Ryan;
(Somerville, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Family ID: |
51301366 |
Appl. No.: |
14/717339 |
Filed: |
May 20, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14445498 |
Jul 29, 2014 |
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14717339 |
|
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61859923 |
Jul 30, 2013 |
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Current U.S.
Class: |
514/224.2 ;
544/47 |
Current CPC
Class: |
A61P 25/00 20180101;
A61P 25/28 20180101; C07D 519/00 20130101; C07D 513/06 20130101;
C07D 513/08 20130101 |
International
Class: |
C07D 513/08 20060101
C07D513/08; C07D 519/00 20060101 C07D519/00 |
Claims
1-32. (canceled)
33. A compound of formula ##STR00179## or a pharmaceutically
acceptable salt thereof.
34. A pharmaceutical composition comprising the compound of claim
33 and a pharmaceutically acceptable excipient.
35. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 33.
36. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 33.
37. A compound of formula ##STR00180## or a pharmaceutically
acceptable salt thereof.
38. A pharmaceutical composition comprising the compound of claim
37 and a pharmaceutically acceptable excipient.
39. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 37.
40. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 37.
41. A compound of formula ##STR00181## or a pharmaceutically
acceptable salt thereof.
42. A pharmaceutical composition comprising the compound of claim
41 and a pharmaceutically acceptable excipient.
43. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 41.
44. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 41.
45. A compound of formula ##STR00182## or a pharmaceutically
acceptable salt thereof.
46. A pharmaceutical composition comprising the compound of claim
45 and a pharmaceutically acceptable excipient.
47. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 45.
48. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 45.
49. A compound of formula ##STR00183## or a pharmaceutically
acceptable salt thereof.
50. A pharmaceutical composition comprising the compound of claim
49 and a pharmaceutically acceptable excipient.
51. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 49.
52. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 49.
53. A compound of formula ##STR00184## or a pharmaceutically
acceptable salt thereof.
54. A pharmaceutical composition comprising the compound of claim
53 and a pharmaceutically acceptable excipient.
55. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 53.
56. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 53.
57. A compound of formula ##STR00185## or a pharmaceutically
acceptable salt thereof.
58. A pharmaceutical composition comprising the compound of claim
57 and a pharmaceutically acceptable excipient.
59. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 57.
60. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 57.
61. A compound of formula ##STR00186## or a pharmaceutically
acceptable salt thereof.
62. A pharmaceutical composition comprising the compound of claim
61 and a pharmaceutically acceptable excipient.
63. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 61.
64. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 61.
65. A compound of formula ##STR00187## or a pharmaceutically
acceptable salt thereof.
66. A pharmaceutical composition comprising the compound of claim
65 and a pharmaceutically acceptable excipient.
67. A method of reducing beta amyloid peptide levels in the
cerebral spinal fluid of a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 65.
68. A method of treating Alzheimer's disease, cognitive impairment
or a combination thereof in a subject, the method comprising
administering to the subject a dose effective amount of the
compound of claim 65.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of, and claims priority
to, U.S. patent application Ser. No. 14/445,498, filed on Jul. 29,
2014, pending, which claims the benefit of U.S. Provisional Patent
Application No. 61/859,923, filed on Jul. 30, 2013, which
specification is hereby incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] The invention relates generally to pharmaceutically active
compounds, pharmaceutical compositions and methods of use thereof,
to treat beta-secretase mediated diseases and conditions,
including, without limitation, Alzheimer's disease, plaque
formation and associated central nervous system (CNS)
disorders.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD) affects greater than 12 million
people worldwide, and importantly, the number affected continues to
grow. AD accounts for the majority of dementias clinically
diagnosed after the age of 60. AD is generally characterized by the
progressive decline of memory, reasoning, judgement and
orientation. As the disease progresses, motor, sensory, and vocal
abilities are affected until there is global impairment of multiple
cognitive functions. The loss of cognitive function occurs
gradually, typically leading to a diminished cognition of self,
family and friends. Patients with severe cognitive impairment
and/or diagnosed as end-stage AD are generally bedridden,
incontinent, and dependent on custodial care. The AD patient
eventually dies in about nine to ten years, on average, after
initial diagnosis. Due to the incapacitating, generally humiliating
and ultimately fatal effects of AD, there is a need to treat AD
effectively upon diagnosis.
[0004] AD is characterized by two major physiological changes in
the brain. The first change, beta amyloid plaque formation,
supports the "amyloid cascade hypothesis" which conveys the thought
that AD is caused by the formation of characteristic beta amyloid
peptide (A-beta), or A-beta fragments thereof, deposits in the
brain (commonly referred to as beta amyloid "plaques" or "plaque
deposits") and in cerebral blood vessels (beta amyloid angiopathy).
A wealth of evidence suggests that beta-amyloid and accompanying
amyloid plaque formation is central to the pathophysiology of AD
and is likely to play an early role in this intractable
neurodegenerative disorder. The second change in AD is the
formation of intraneuronal tangles, consisting of an aggregate form
of the protein tau. Besides being found in patients with AD,
intraneuronal tangles are also found in other dementia-inducing
disorders. Joachim et al., Alz. Dis. Assoc. Dis., 6:7-34
(1992).
[0005] Several lines of evidence indicate that progressive cerebral
deposition of A-beta plays a seminal role in the pathogenisis of AD
and can precede cognitive symptoms by years or even decades.
Selkoe, Neuron, 6:487 (1991). Release of A-beta from neuronal cells
grown in culture and the presence of A-beta in cerebrospinal fluid
(CSF) of both normal individuals and AD patients has been
demonstrated. Seubert et al., Nature, 359:325-327 (1992). Autopsies
of AD patients have revealed large numbers of lesions comprising
these 2 factors in areas of the human brain believed to be
important for memory and cognition.
[0006] Smaller numbers of these lesions in a more restricted
anatomical distribution are found in the brains of most aged humans
who do not have clinical AD. Amyloid containing plaques and
vascular amyloid angiopathy were also found in the brains of
individuals with Down's Syndrome, Hereditary Cerebral Hemorrhage
with Amyloidosis of the Dutch-type (HCHWA-D), and other
neurodegenerative disorders.
[0007] It has been hypothesized that A-beta formation is a
causative precursor or factor in the development of AD. More
specifically, deposition of A-beta in areas of the brain
responsible for cognitive factors is believed to be a major factor
in the development of AD. Beta amyloid plaques are primarily
composed of amyloid beta peptide (A-beta peptide). A-beta peptide
is derived from the proteolytic cleavage of a large transmembrane
amyloid precursor protein (APP), and is a peptide comprised of
about 39-42 amino acid residues. A-beta 42 (42 amino acids long) is
thought to be the major component of these plaque deposits in the
brains of Alzheimer's Disease patients. Citron, Trends in
Pharmacological Sciences, 25(2):92-97 (2004).
[0008] Similar plaques appear in some variants of Lewy body
dementia and in inclusion body myositis, a muscle disease. A.beta.
also forms aggregates coating cerebral blood vessels in cerebral
amyloid angiopathy. These plaques are composed of a tangle of
regularly ordered fibrillar aggregates called amyloid fibers, a
protein fold shared by other peptides such as prions associated
with protein misfolding diseases. Research on laboratory rats
suggest that the dimeric, soluble form of the peptide is a
causative agent in the development of Alzheimer's and is the
smallest synaptotoxic species of soluble amyloid beta oligomer.
Shankar, G. M., Nature Medicine (Jun. 22, 2008) online doi 10:1038
nm 1782.
[0009] Several aspartyl proteases, including beta-secretase and
gamma-secretase, are thought to be involved in the processing or
cleavage of APP, resulting in the formation of A-beta peptide. Beta
secretase (BACE, also commonly referred to as memapsin) is thought
to first cleave APP to generate two fragments: (1) a first
N-terminus fragment (beta APP) and (2) a second C-99 fragment,
which is subsequently cleaved by gamma secretase to generate the
A-beta peptide. APP has also found to be cleaved by alpha-secretase
to produce alpha-sAPP, a secreted form of APP that does not result
in beta-amyloid plaque formation. This alternate pathway precludes
the formation of A-beta peptide. A description of the proteolytic
processing fragments of APP is found, for example, in U.S. Pat.
Nos. 5,441,870, 5,712,130 and 5,942,400.
[0010] BACE is an aspartyl protease enzyme comprising 501 amino
acids and responsible for processing APP at the beta-secretase
specific cleavage site. BACE is present in two forms, BACE 1 and
BACE 2, designated as such depending upon the specific cleavage
site of APP. Beta secretase is described in Sinha et al., Nature,
402:537-554 (1999) (p510) and PCT application WO 2000/17369. It has
been proposed that A-beta peptide accumulates as a result of APP
processing by BACE. Moreover, in vivo processing of APP at the beta
secretase cleavage site is thought to be a rate-limiting step in
A-beta production. Sabbagh, M. et al., Alz. Dis. Rev. 3:1-19
(1997). Thus, inhibition of the BACE enzyme activity is desirable
for the treatment of AD.
[0011] Studies have shown that the inhibition of BACE may be linked
to the treatment of AD. The BACE enzyme is essential for the
generation of beta-amyloid or A-beta. BACE knockout mice do not
produce beta-amyloid and are free from Alzheimer's associated
pathologies including neuronal loss and certain memory deficits.
Cole, S. L., Vasser, R., Molecular Degeneration 2:22, 2007. When
crossed with transgenic mice that over express APP, the progeny of
BACE deficient mice show reduced amounts of A-beta in brain
extracts as compared with control animals (Luo et al., Nature
Neuroscience, 4:231-232 (2001)). The fact that BACE initiates the
formation of beta-amyloid, and the observation that BACE levels are
elevated in this disease provide direct and compelling reasons to
develop therapies directed at BACE inhibition thus reducing
beta-amyloid and its associated toxicities. To this end, inhibition
of beta secretase activity and a corresponding reduction of A-beta
in the brain should provide a therapeutic method for treating AD
and other beta amyloid or plaque related disorders.
[0012] Consequently, the approach of regulating or reducing the
formation of A-beta peptide formation and deposition as a potential
treatment for AD has received tremendous attention, support and
commitment from both researchers and investors alike. A small
molecule gamma-secretase inhibitor, LY450139 ("Semagacestat"), an
A-beta lowering agent, is in phase II clinical trials for the
treatment of Alzheimer's Disease. The pharmacokinetics of
semagacestat in plasma, as well as the plasma and cerebral spinal
fluid (CSF) A-Beta peptide levels as pharmacodynamic responses to
semagacestat administration were evaluated in healthy human
subjects in single and multiple doses, and pharmacokinetic and
pharmacodynamic changes were also assessed in mild to moderate AD
patients in two (2) clinical trials (Expert Opin. Pharmacother.
(2009), 10 (10); Clin. Neuropharmacol. 2007; 30 (pgs 317-325); and
Neurology, 2006, 66 (pgs 602-624)).
[0013] Additional approaches have been taken in attempts to treat
AD and plaque-related disorders. One such approach to reduce the
formation of plaque deposits in the brain involves the inhibition
of and, therefore, the reduction of BACE activity. For example,
each of the following PCT publications: WO2012139425 and
WO2012162330 describe inhibitors of BACE, useful for treating AD
and other beta-secretase mediated disorders. WO20121623303
describes tricyclic thiazine compounds as inhibitors of beta
amyloid, formation having the general formula:
##STR00002##
wherein X is selected from the group consisting of CH.sub.2, O and
NR.sup.2.
[0014] The lysosomal aspartic protease Cathepsin D (CatD) is
ubiquitously expressed in eukaryotic organisms. CatD activity is
essential to accomplish the acid-dependent extensive or partial
proteolysis of protein substrates within endosomal and lysosomal
compartments therein delivered via endocytosis, phagocytosis or
autophagocytosis. CatD may also act at physiological pH on
small-size substrates in the cytosol and in the extracellular
milieu. Mouse and fruit fly CatD knock-out models have highlighted
the many or multiple pathophysiological roles of CatD in tissue
homeostasis and organ development.
[0015] Inhibition of Cathepsin D has been implicated in the
manifestation of undesirable side effects. For instance, the
inhibition of Cathepsin D is believed to be linked to adverse
retinal development and retinal atrophy. Particularly, in mice it
was found that cathepsin D is essential for the metabolic
maintenance of retinal photoreceptor cells and that its deficiency
induces apoptosis of the cells, while the loss of INL neurons is
mediated by nitric oxide release from microglial cells. However, in
the very same mice, it was also found that no atrophic change was
detected in the retina of mice deficient in cathepsin B or L. Mol.
Cell. Neurosci, 2003, February 22(2):146-161. Further, animal
models of Cathepsin D (CatD) deficiency are characterized by a
progressive and relentless neurodegenerative phenotype similar to
that observed in Neuronal Ceroid Lipofuscinoses (NCL), a group of
pediatric neurodegenerative diseases known collectively as Batten
Disease. It has been shown that the targeted deletion of the
pro-apoptotic molecule Bax prevents apoptotic markers but not
neuronal cell death and neurodegeneration induced by CatD
deficiency, which suggests that alterations in the
macroautophagy-lysosomal degradation pathway can mediate neuronal
cell death in NCL/Batten Disease in the absence of apoptosis.
Autophagy, 2007, September-October; 3(5):474-476. Finally, an
adverse effect of the inhibition of Cat D is evident from the data
presented in PLoS One, 2011; 6(7):e21908, published Jul. 1, 2011.
The authors of the PLoS One paper found that knock-down of
cathepsin D affects the retinal pigment epithelium, impairs
swim-bladder ontogenesis and causes premature death in zebrafish.
The main phenotypic alterations produced by CatD knock-down in
zebrafish were: 1. abnormal development of the eye and of retinal
pigment epithelium; 2. absence of the swim-bladder; 3. skin
hyper-pigmentation; 4. reduced growth and premature death. Rescue
experiments confirmed the involvement of CatD in the developmental
processes leading to these phenotypic alterations.
[0016] Moreover, such toxicity findings which, in view of the
literature, may have played a role in the termination of a human
Bace-mediated Alzheimer's Disease clinical trial. Eli Lilly
terminated a phase I clinical trial of LY 2811376 after rat
toxicology studies showed that a higher compound dose given for
three months damaged the pigment epithelium of the rat's eye. The
retinal layer had inclusions and extensive damage. The Ph I dosing
trial was terminated and people brought in for eye assessments did
not show any abnormalities. (Alzheimer's Research Forum News, Mar.
31, 2011 reporting on Martin Citron's presentation at the AD/PD
Conference 3-2011 in Barcelona, Spain)
[0017] Hence, it is desirable to provide compounds which modulate
the activity of and are reasonably selective for BACE, while not
suffering from undesirable side effects possibly due to
intervention with or the reduction and/or direct or indirect
inhibition of the expression and/or function of other proteins or
biological pathways.
BRIEF DESCRIPTION OF THE INVENTION
[0018] The present invention provides a new class of compounds
useful for the modulation of beta secretase activity, and as
treatment of AD. Particularly, the compounds of the invention are
useful for the regulation or reduction of the formation of A-beta
peptide and, consequently, the regulation and/or reduction of
formation of beta amyloid plaque both on the brain, as well as in
the CNS. To this end, the compounds are useful for the treatment of
AD and other beta secretase and/or plaque-related and/or mediated
disorders. For example, the compounds are useful for the
prophylaxis and/or treatment, acute and/or chronic, of AD and other
diseases or conditions involving the deposition or accumulation of
beta amyloid peptide, and formation of plaque, on the brain.
[0019] The compounds provided by the invention, including
stereoisomers, tautomers, hydrates, solvates and pharmaceutically
acceptable salts thereof, are generally defined by Formula I
##STR00003##
wherein each of A.sup.4, A.sup.5, A.sup.6, A.sup.8, R.sup.1,
R.sup.2, R.sup.3, R.sup.7 and n of Formula I are defined below. The
invention also provides procedures for making compounds of Formula
I, and sub-Formulas thereof, as well as intermediates useful in
such procedures.
[0020] The invention further provides pharmaceutical compositions
comprising compounds of the invention, and uses of these
compositions in the treatment of beta secretase mediated diseases.
For example, and in one embodiment, the invention provides a
pharmaceutical composition comprising an effective dosage amount of
a compound of Formula I in association with at least one
pharmaceutically acceptable excipient.
[0021] The foregoing merely summarizes certain aspects of the
invention and is not intended, nor should it be construed, as
limiting the invention in any way. All patents and other
publications recited herein are hereby incorporated by reference in
their entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0022] In embodiment A of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula I:
##STR00004##
or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically
acceptable salt thereof, wherein
[0023] A.sup.4 is CR.sup.4 or N;
[0024] A.sup.5 is CR.sup.5 or N;
[0025] A.sup.6 is CR.sup.6 or N;
[0026] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0027] each R.sup.1, independently, is H, F, Cl, C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, cyclopropyl or CN, wherein the
C.sub.1-4alkyl and CH.sub.2OC.sub.1-4alkyl are optionally
substituted with 1-3 substituents of F;
[0028] R.sup.2 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, CH.sub.2CN, C.sub.3-6cycloalkyl or CN, wherein each of
the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and C.sub.3-6cycloalkyl
is optionally substituted with 1-4 substituents of F;
[0029] each R.sup.3, independently, is H, halo, C.sub.1-4alkyl,
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH,
C.sub.1-4haloalkyl, cyclopropyl or CN, wherein each of the
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and cyclopropyl is
optionally substituted with 1-4 substituents of F;
[0030] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0031] R.sup.7 is --NH--R.sup.9, --NHC(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9 or --S--R.sup.9;
[0032] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed
of carbon atoms, said ring optionally including 1-4 heteroatoms if
monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms
selected from O, N or S, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0033] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, dioxolyl,
--NHC(O)R.sup.11-- or --C(O)NHR.sup.11--, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl;
[0034] R.sup.11 is C.sub.1-6alkyl, C.sub.1-6alkoxyl or
C.sub.3-6cycloalkyl; and
[0035] n is 0, 1 or 2.
[0036] In embodiment A-a of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment A, wherein each R.sup.10,
independently, is H, halo, haloalkyl, CN, OH, NO.sub.2, NH.sub.2,
SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, dioxolyl,
--NHC(O)R.sup.11-- or --C(O)NHR.sup.11--, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted
independently with 1-5 substituents of F, Cl, CN, NO.sub.2,
NH.sub.2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy,
isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl,
butoxyl, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxetan-3yl or a ring selected from oxazolyl, isoxazolyl, pyrazolyl,
thiazolyl, isothiazolyl or oxadiazolyl wherein the ring is
optionally substituted independently with 1-5 substituents of F,
Cl, CN or CH.sub.3.
[0037] In embodiment A-1 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment A, wherein o is 1 or 2.
[0038] In embodiment A-2 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A and A-1, wherein
[0039] A.sup.4 is CR.sup.4;
[0040] A.sup.5 is CR.sup.5;
[0041] A.sup.6 is CR.sup.6; and
[0042] A.sup.8 is CR.sup.8.
[0043] In embodiment A-3 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 and A-2, wherein each R.sup.1,
independently, is H, F, CH.sub.2OCH.sub.3, CH.sub.2F or
CH.sub.3.
[0044] In embodiment A-4 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-3, wherein R.sup.2 is
CH.sub.3, CH.sub.2F or CHF.sub.2.
[0045] In embodiment A-5 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-4, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9, --C(.dbd.O)NH--R.sup.9, --O--R.sup.9 or
--S--R.sup.9;
[0046] or R.sup.7 is
##STR00005## [0047] wherein V is NR.sup.10, O or S; and [0048] each
W, independently, is CH, CF, CCl or N.
[0049] In embodiment A-6 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-5, wherein A.sup.4 is
CR.sup.4;
[0050] A.sup.5 is CR.sup.5 or N;
[0051] A.sup.6 is CR.sup.6;
[0052] A.sup.8 is CR.sup.8;
[0053] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2;
[0054] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0055] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2; and
[0056] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3.
[0057] In embodiment A-7 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-6, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9 or
##STR00006## [0058] wherein V is NR.sup.10, O or S; and [0059] each
W, independently, is CH, CF, CCl or N.
[0060] In embodiment A-8 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-7, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9.
[0061] In embodiment A-9 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-7, wherein R.sup.7 is
##STR00007##
[0062] wherein V is NR.sup.10, O or S; and each W, independently,
is CH, CF, CCl or N.
[0063] In embodiment A-10 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-9, wherein
[0064] A.sup.4 is CR.sup.4;
[0065] A.sup.5 is CR.sup.5;
[0066] A.sup.6 is CR.sup.6; and
[0067] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, CF.sub.3, CF.sub.2H,
CH.sub.2F or CH.sub.3.
[0068] In embodiment A-11 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A through A-9, wherein
[0069] A.sup.4 is CR.sup.4 wherein R.sup.4 is F, Cl or
CH.sub.3;
[0070] A.sup.5 is CR.sup.5 wherein R.sup.5 is H, F, Cl or
CH.sub.3;
[0071] A.sup.6 is CH; and
[0072] A.sup.8 is CH.
[0073] In embodiment B of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula II:
##STR00008##
or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically
acceptable salt thereof, wherein
[0074] A.sup.4 is CR.sup.4 or N;
[0075] A.sup.5 is CR.sup.5 or N;
[0076] A.sup.6 is CR.sup.6 or N;
[0077] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0078] each R.sup.1, independently, is H, F, Cl, C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, cyclopropyl or CN, wherein the
C.sub.1-4alkyl and CH.sub.2OC.sub.1-4alkyl are optionally
substituted with 1-3 substituents of F;
[0079] R.sup.2 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, CH.sub.2CN, C.sub.3-6cycloalkyl or CN, wherein each of
the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and C.sub.3-6cycloalkyl
is optionally substituted with 1-4 substituents of F;
[0080] each R.sup.3, independently, is H, halo, C.sub.1-4alkyl,
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH,
C.sub.1-4haloalkyl, cyclopropyl or CN, wherein each of the
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and cyclopropyl is
optionally substituted with 1-4 substituents of F;
[0081] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0082] R.sup.7 is --NH--R.sup.9 or --NHC(.dbd.O)--R.sup.9;
[0083] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed
of carbon atoms, said ring optionally including 1-4 heteroatoms if
monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms
selected from O, N or S, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0084] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl, dioxolyl, --NHC(O)R.sup.11-- or --C(O)NHR.sup.11--,
wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
2-propynyloxy, 2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is
optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxetan-3yl or a ring
selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3; and
[0085] R.sup.11 is C.sub.1-6alkyl, C.sub.1-6alkoxyl or
C.sub.3-6cycloalkyl.
[0086] In embodiment B-1 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment B, wherein
[0087] A.sup.4 is CR.sup.4;
[0088] A.sup.5 is CR.sup.5;
[0089] A.sup.6 is CR.sup.6; and
[0090] A.sup.8 is CR.sup.8.
[0091] In embodiment B-2 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B and B-1, wherein each R.sup.1,
independently, is H, F, CH.sub.2OCH.sub.3, CH.sub.2F or
CH.sub.3.
[0092] In embodiment B-3 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B, B-1 and B-2, wherein R.sup.2 is
CH.sub.3, CH.sub.2F or CHF.sub.2.
[0093] In embodiment B-4 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B through B-3, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9 or --C(.dbd.O)NH--R.sup.9;
[0094] or R.sup.7 is
##STR00009## [0095] wherein V is NR.sup.10, O or S; and [0096] each
W, independently, is CH, CF, CCl or N.
[0097] In embodiment B-5 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B through B-4, wherein A.sup.4 is
CR.sup.4;
[0098] A.sup.5 is CR.sup.5 or N;
[0099] A.sup.6 is CR.sup.6;
[0100] A.sup.8 is CR.sup.8;
[0101] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2; R.sup.2 is
CH.sub.3, CH.sub.2F or CHF.sub.2;
[0102] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2; and
[0103] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3.
[0104] In embodiment B-6 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B through B-5, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9 or
##STR00010## [0105] wherein V is NR.sup.10, O or S; and [0106] each
W, independently, is CH, CF, CCl or N.
[0107] In embodiment B-7 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B through B-6, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9.
[0108] In embodiment B-8 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B through B-6, wherein R.sup.7 is
##STR00011## [0109] wherein V is NR.sup.10 or S; and [0110] each W,
independently, is CH, CF, CCl or N.
[0111] In embodiment B-9 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B through B-8, wherein A.sup.4 is
CR.sup.4;
[0112] A.sup.5 is CR.sup.5;
[0113] A.sup.6 is CR.sup.6; and
[0114] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, CF.sub.3, CF.sub.2H,
CH.sub.2F or CH.sub.3.
[0115] In embodiment B-10 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B through B-9, wherein A.sup.4 is
CR.sup.4 wherein R.sup.4 is F, Cl or CH.sub.3;
[0116] A.sup.5 is CR.sup.5 wherein R.sup.5 is H, F, Cl or
CH.sub.3;
[0117] A.sup.6 is CH; and
[0118] A.sup.8 is CH.
[0119] In embodiment B-A of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, of embodiments A,
A-1 through A-8, A-10, B, B-1 through B-7 and B-9-B-10, which are
generally defined by Formula II-A:
##STR00012##
wherein
[0120] A.sup.4 is CR.sup.4;
[0121] A.sup.5 is CR.sup.5 or N;
[0122] A.sup.6 is CR.sup.6;
[0123] A.sup.8 is CR.sup.8;
[0124] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CN, CH.sub.2F or
CHF.sub.2;
[0125] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0126] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0127] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0128] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, imidazo-pyridyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and
[0129] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0130] In embodiment B-A-a of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment B-A, wherein each R.sup.10,
independently, is H, halo, haloalkyl, CN, OH, NO.sub.2, NH.sub.2,
SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, dioxolyl,
--NHC(O)R.sup.11-- or --C(O)NHR.sup.11--, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted
independently with 1-5 substituents of F, Cl, CN, NO.sub.2,
NH.sub.2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy,
isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl,
butoxyl, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxetan-3yl or a ring selected from oxazolyl, isoxazolyl, pyrazolyl,
thiazolyl, isothiazolyl or oxadiazolyl wherein the ring is
optionally substituted independently with 1-5 substituents of F,
Cl, CN or CH.sub.3.
[0131] In embodiment B-A-1 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment B-A, wherein A.sup.4 is CR.sup.4;
[0132] A.sup.8 is CR.sup.8 or N;
[0133] A.sup.6 is CR.sup.6;
[0134] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CN or OCH.sub.3;
[0135] each R.sup.1, independently, is H, F, CH.sub.3, CF.sub.3,
CF.sub.2H or CH.sub.2F;
[0136] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0137] each R.sup.3, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CH.sub.2F, CF.sub.2H, CF.sub.3 or
CH.sub.2CF.sub.3;
[0138] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
imidazo-pyridyl, cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl, wherein the ring is optionally substituted,
independently, with 1-5 substituents of R.sup.10; and
[0139] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl, dioxolyl, --NHC(O)R.sup.11-- or --C(O)NHR.sup.11--,
wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
2-propynyloxy, 2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is
optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxetan-3yl or a ring
selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3; and
[0140] R.sup.11 is C.sub.1-6alkyl, C.sub.1-6alkoxyl or
C.sub.3-6cycloalkyl.
[0141] In embodiment B-A-2 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments B-A and B-A-1, wherein A.sup.4 is CH
or CF;
[0142] A.sup.5 is CH, CF or N;
[0143] A.sup.6 is CH or CF;
[0144] A.sup.8 is CH or CF;
[0145] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CF.sub.2H or CH.sub.2F;
[0146] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0147] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F.
[0148] In embodiment B-B of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, of embodiments A,
A-1 through A-7, A-9 through A-11, B, B-1 through B-6 and B-8
through B-10, which are generally defined by Formula II-B:
##STR00013##
wherein
[0149] A.sup.4 is CR.sup.4;
[0150] A.sup.5 is CR.sup.5 or N;
[0151] A.sup.6 is CR.sup.6;
[0152] A.sup.8 is CR.sup.8;
[0153] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CN, CH.sub.2F or
CHF.sub.2;
[0154] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0155] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0156] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3; and
[0157] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0158] In embodiment B-B-a of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment B-B, wherein each R.sup.10,
independently, is H, halo, haloalkyl, CN, OH, NO.sub.2, NH.sub.2,
SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, dioxolyl,
--NHC(O)R.sup.11-- or --C(O)NHR.sup.11--, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted
independently with 1-5 substituents of F, Cl, CN, NO.sub.2,
NH.sub.2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy,
isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl,
butoxyl, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxetan-3yl or a ring selected from oxazolyl, isoxazolyl, pyrazolyl,
thiazolyl, isothiazolyl or oxadiazolyl wherein the ring is
optionally substituted independently with 1-5 substituents of F,
Cl, CN or CH.sub.3; and
[0159] R.sup.11 is C.sub.1-6alkyl, C.sub.1-6alkoxyl or
C.sub.3-6cycloalkyl.
[0160] In embodiment B-B-1 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment B-B, wherein
[0161] A.sup.4 is CH or CF;
[0162] A.sup.5 is CH, CF or N;
[0163] A.sup.6 is CH or CF;
[0164] A.sup.8 is CH or CF;
[0165] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CF.sub.2H or CH.sub.2F;
[0166] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0167] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F.
[0168] In embodiment B-B-2 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment B-B and B-B-1, wherein A.sup.4 is CH
or CF;
[0169] A.sup.5 is CH or N;
[0170] A.sup.6 is CH;
[0171] A.sup.8 is CH;
[0172] each R.sup.1, independently, is H, F, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F;
[0173] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0174] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F.
[0175] In embodiment B-C of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 through A-7, A-9 through A-10,
B, B-1 through B-6, B-8 through B-9, B-A through B-A-2 and BB
through B-B-2, having a formula II-C
##STR00014##
wherein
[0176] A.sup.4 is CR.sup.4;
[0177] A.sup.5 is CR.sup.5 or N;
[0178] A.sup.6 is CR.sup.6;
[0179] A.sup.8 is CR.sup.8;
[0180] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CN, CH.sub.2F or
CHF.sub.2;
[0181] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0182] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0183] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0184] R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00015## [0185] wherein V is NR.sup.10, O or S; and [0186] each
W, independently, is CH, CF, CCl or N;
[0187] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, imidazo-pyridyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and
[0188] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl, dioxolyl, --NHC(O)R.sup.11-- or --C(O)NHR.sup.11--,
wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
2-propynyloxy, 2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is
optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxetan-3yl or a ring
selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3; and
[0189] R.sup.11 is C.sub.1-6alkyl, C.sub.1-6alkoxyl or
C.sub.3-6cycloalkyl.
[0190] In embodiment B-D of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 through A-7, A-9 through A-11,
B, B-1 through B-6, B-8 through B-10, B-A through B-A-2 and B-B
through B-B-2, having a formula II-C-1-A or Formula II-C-1-B
##STR00016##
wherein
[0191] A.sup.4 is CR.sup.4;
[0192] A.sup.5 is CR.sup.5 or N;
[0193] A.sup.6 is CR.sup.6;
[0194] A.sup.8 is CR.sup.8;
[0195] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CN, CH.sub.2F or
CHF.sub.2;
[0196] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0197] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0198] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0199] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, imidazo-pyridyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and
[0200] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl or dioxolyl, wherein each of the C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or
dioxolyl, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy,
tert-butoxy, 2-propynyloxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl oxetan-3yl or a ring selected from oxazolyl,
isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl or oxadiazolyl
wherein the ring is optionally substituted independently with 1-5
substituents of F, Cl, CN or CH.sub.3.
[0201] In embodiment B-E of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 through A-7, A-9 through A-11,
B, B-1 through B-6, B-8 through B-10, B-A through B-A-2, BB through
B-B-2, B-C and B-D, having a formula II-C-2
##STR00017##
wherein
[0202] A.sup.4 is CR.sup.4;
[0203] A.sup.5 is CR.sup.5 or N;
[0204] A.sup.6 is CR.sup.6;
[0205] A.sup.8 is CR.sup.8;
[0206] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CN, CH.sub.2F or
CHF.sub.2;
[0207] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0208] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0209] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0210] V is NR.sup.10, O or S;
[0211] each W, independently, is CH, CF, CCl or N; and
[0212] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl or dioxolyl, wherein each of the C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or
dioxolyl, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy,
tert-butoxy, 2-propynyloxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl oxetan-3yl or a ring selected from oxazolyl,
isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl or oxadiazolyl
wherein the ring is optionally substituted independently with 1-5
substituents of F, Cl, CN or CH.sub.3.
[0213] In embodiment B-E of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 through A-7, A-9 through A-11,
B, B-1 through B-6, B-8 through B-10, B-A through B-A-2, BB through
B-B-2, B-C and B-D, having a formula II-C-3
##STR00018##
wherein
[0214] A.sup.4 is CR.sup.4;
[0215] A.sup.5 is CR.sup.5 or N;
[0216] A.sup.6 is CR.sup.6;
[0217] A.sup.8 is CR.sup.8;
[0218] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CN, CH.sub.2F or
CHF.sub.2;
[0219] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0220] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0221] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0222] each W, independently, is CH, CF, CCl or N; and
[0223] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl or dioxolyl, wherein each of the C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or
dioxolyl, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy,
tert-butoxy, 2-propynyloxy, 2-butynyloxy, isobutyl, sec-butyl,
tert-butyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl oxetan-3yl or a ring selected from oxazolyl,
isoxazolyl, pyrazolyl, thiazolyl, isothiazolyl or oxadiazolyl
wherein the ring is optionally substituted independently with 1-5
substituents of F, Cl, CN or CH.sub.3.
[0224] In embodiment B-F of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 through A-7, A-9 through A-10,
B, B-1 through B-6, B-8 through B-9, B-A through B-A-2 and BB
through B-B-2, having a formula II-D
##STR00019##
wherein
[0225] A.sup.4 is CR.sup.4 wherein R.sup.4 is F, Cl or
CH.sub.3;
[0226] A.sup.5 is CR.sup.5 or N, wherein R.sup.5 is H, F, Cl or
CH.sub.3;
[0227] R.sup.1 is H, F, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2OCH.sub.3, CH.sub.2F or CHF.sub.2;
[0228] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0229] R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00020## [0230] wherein each W, independently, is CH, CF, CCl
or N;
[0231] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, furanyl,
thienyl or pyrrolyl, wherein ring is optionally substituted,
independently, with 1-5 substituents of R.sup.10; and
[0232] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl, dioxolyl, --NHC(O)R.sup.11-- or --C(O)NHR.sup.11--,
wherein each of the C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-,
C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl,
2-propynyloxy, 2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl, is
optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxetan-3yl or a ring
selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3; and
[0233] R.sup.11 is C.sub.1-6alkyl, C.sub.1-6alkoxyl or
C.sub.3-6cycloalkyl.
[0234] In embodiment C of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula III:
##STR00021##
wherein or a stereoisomer, tautomer, hydrate, solvate or
pharmaceutically acceptable salt thereof, wherein
[0235] A.sup.4 is CR.sup.4 or N;
[0236] A.sup.5 is CR.sup.5 or N;
[0237] A.sup.6 is CR.sup.6 or N;
[0238] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0239] each R.sup.1, independently, is H, F, Cl, C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, cyclopropyl or CN, wherein the
C.sub.1-4alkyl and CH.sub.2OC.sub.1-4alkyl are optionally
substituted with 1-3 substituents of F;
[0240] R.sup.2 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, CH.sub.2CN, C.sub.3-6cycloalkyl or CN, wherein each of
the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and C.sub.3-6cycloalkyl
is optionally substituted with 1-4 substituents of F;
[0241] each R.sup.3, independently, is H, halo, C.sub.1-4alkyl,
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH,
C.sub.1-4haloalkyl, cyclopropyl or CN, wherein each of the
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and cyclopropyl is
optionally substituted with 1-4 substituents of F;
[0242] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, halo, haloalkyl, haloalkoxyl, C.sub.1-4-alkyl,
CN, OH, OC.sub.1-4-alkyl, S(O).sub.oC.sub.1-4-alkyl,
NHC.sub.1-4-alkyl or C(O)C.sub.1-4-alkyl;
[0243] R.sup.7 is --NH--R.sup.9, --NHC(.dbd.O)--R.sup.9,
--C(.dbd.O)NH--R.sup.9, --O--R.sup.9 or --S--R.sup.9;
[0244] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed
of carbon atoms, said ring optionally including 1-4 heteroatoms if
monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms
selected from O, N or S, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0245] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, dioxolyl,
--NHC(O)R.sup.11-- or --C(O)NHR.sup.11--, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxyl, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl; and
[0246] R.sup.11 is C.sub.1-6alkyl, C.sub.1-6alkoxyl or
C.sub.3-6cycloalkyl.
[0247] In embodiment C-1 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment C, wherein
[0248] A.sup.4 is CR.sup.4;
[0249] A.sup.5 is CR.sup.5;
[0250] A.sup.6 is CR.sup.6; and
[0251] A.sup.8 is CR.sup.8.
[0252] In embodiment C-2 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C and C-1, wherein each R.sup.1,
independently, is H, F, CH.sub.2F or CH.sub.3.
[0253] In embodiment C-3 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C, C-1 and C-2, wherein R.sup.2 is
CH.sub.3, CH.sub.2F or CHF.sub.2.
[0254] In embodiment C-4 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C through C-3, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9 or --C(.dbd.O)NH--R.sup.9;
[0255] or R.sup.7 is
##STR00022## [0256] wherein V is NR.sup.10, O or S; and [0257] each
W, independently, is CH, CF, CCl or N.
[0258] In embodiment C-5 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C through C-4, wherein A.sup.4 is
CR.sup.4;
[0259] A.sup.5 is CR.sup.5 or N;
[0260] A.sup.6 is CR.sup.6;
[0261] A.sup.8 is CR.sup.8;
[0262] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2;
[0263] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0264] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2; and
[0265] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3.
[0266] In embodiment C-6 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C through C-5, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9 or
##STR00023## [0267] wherein V is NR.sup.10, O or S; and [0268] each
W, independently, is CH, CF, CCl or N.
[0269] In embodiment C-7 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C through C-6, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9.
[0270] In embodiment C-8 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C through C-6, wherein R.sup.7 is
##STR00024## [0271] wherein V is NR.sup.10 or S; and [0272] each W,
independently, is CH, CF, CCl or N.
[0273] In embodiment C-9 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C through C-8, wherein A.sup.4 is
CR.sup.4;
[0274] A.sup.5 is CR.sup.5;
[0275] A.sup.6 is CR.sup.6; and
[0276] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, CF.sub.3, CF.sub.2H,
CH.sub.2F or CH.sub.3.
[0277] In embodiment C-A of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, of embodiments A,
A-1 through A-8, A-10, C, C-1 through C-7 and C-9, which are
generally defined by Formula III-A:
##STR00025##
wherein
[0278] A.sup.4 is CR.sup.4;
[0279] A.sup.5 is CR.sup.5 or N;
[0280] A.sup.6 is CR.sup.6;
[0281] A.sup.8 is CR.sup.8;
[0282] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2;
[0283] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0284] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0285] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0286] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, imidazo-pyridyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and each R.sup.10, independently, is H, halo, haloalkyl,
CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3,
oxo, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl or dioxolyl, wherein each of the C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or
dioxolyl, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy,
tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxetan-3yl or a ring selected from oxazolyl, isoxazolyl, pyrazolyl,
thiazolyl, isothiazolyl or oxadiazolyl wherein the ring is
optionally substituted independently with 1-5 substituents of F,
Cl, CN or CH.sub.3.
[0287] In embodiment C-A-1 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment C-A, wherein A.sup.4 is CR.sup.4;
[0288] A.sup.5 is CR.sup.5 or N;
[0289] A.sup.6 is CR.sup.6;
[0290] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CN or OCH.sub.3;
[0291] each R.sup.1, independently, is H, F, CH.sub.3, CF.sub.3,
CF.sub.2H or CH.sub.2F;
[0292] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0293] each R.sup.3, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CH.sub.2F, CF.sub.2H, CF.sub.3 or
CH.sub.2CF.sub.3;
[0294] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, naphthyl,
quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl,
phthalazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, furanyl,
dihydrofuranyl, tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
imidazo-pyridyl, cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl, wherein the ring is optionally substituted,
independently, with 1-5 substituents of R.sup.10; and
[0295] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl or dioxolyl, wherein each of the C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or
dioxolyl, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy,
tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or a ring selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3.
[0296] In embodiment C-A-2 of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, of embodiments A,
A-1 through A-8, A-11, C, C-1 through C-7 and C-9, which are
generally defined by Formula III-A-1:
##STR00026##
wherein
[0297] A.sup.4 is CR.sup.4;
[0298] A.sup.5 is CR.sup.5 or N;
[0299] A.sup.6 is CR.sup.6;
[0300] A.sup.8 is CR.sup.8;
[0301] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2;
[0302] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0303] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0304] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0305] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, imidazo-pyridyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and
[0306] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl or dioxolyl, wherein each of the C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or
dioxolyl, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy,
tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or a ring selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3.
[0307] In embodiment C-A-2 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments C-A and C-A-1, wherein A.sup.4 is CH
or CF;
[0308] A.sup.5 is CH, CF or N;
[0309] A.sup.6 is CH or CF;
[0310] A.sup.8 is CH or CF;
[0311] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CF.sub.2H or CH.sub.2F;
[0312] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0313] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F.
[0314] In embodiment C-B of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, of embodiments A,
A-1 through A-7, A-9 through A-10, C, C-1 through C-6 and C-8
through C-9, which are generally defined by Formula III-B:
##STR00027##
wherein
[0315] A.sup.4 is CR.sup.4;
[0316] A.sup.5 is CR.sup.5 or N;
[0317] A.sup.6 is CR.sup.6;
[0318] A.sup.8 is CR.sup.8;
[0319] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2;
[0320] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0321] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
[0322] CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0323] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3,
[0324] CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0325] each W, independently, is CH, CF, CCl or N; and
[0326] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl or dioxolyl, wherein each of the C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or
dioxolyl, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxy, isobutoxy,
tert-butoxy, 2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or a ring selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3.
[0327] In embodiment C-B-1 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment C-B, wherein
[0328] A.sup.4 is CH or CF;
[0329] A.sup.5 is CH, CF or N;
[0330] A.sup.6 is CH or CF;
[0331] A.sup.8 is CH or CF;
[0332] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CF.sub.2H or CH.sub.2F;
[0333] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0334] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F.
[0335] In embodiment C-B-2 of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiment C-B and C-B-1, wherein A.sup.4 is CH
or CF;
[0336] A.sup.5 is CH or N;
[0337] A.sup.6 is CH;
[0338] A.sup.8 is CH;
[0339] each R.sup.1, independently, is H, F, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F;
[0340] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0341] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F.
[0342] In embodiment C-C of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 through A-7, A-9 through A-10,
C, C-1 through C-6, C-8 through C-9, C-A through C-A-2 and C-B
through C-B-2, having a formula III-C
##STR00028##
wherein
[0343] A.sup.4 is CR.sup.4;
[0344] A.sup.5 is CR.sup.5 or N;
[0345] A.sup.6 is CR.sup.6;
[0346] A.sup.8 is CR.sup.8;
[0347] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2;
[0348] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0349] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0350] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0351] R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00029## [0352] wherein V is NR.sup.10, O or S; and [0353] each
W, independently, is CH, CF, CCl or N;
[0354] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, imidazo-pyridyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and
[0355] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0356] In embodiment C-D of the invention, there are provided
compounds, including stereoisomers and pharmaceutically acceptable
salts thereof, of embodiments A, A-1 through A-7, A-9 through A-10,
C, C-1 through C-6, C-8 through C-9, C-A through C-A-2 and BB
through C-B-2, having a formula III-D
##STR00030##
wherein
[0357] A.sup.4 is CR.sup.4;
[0358] A.sup.8 is CR.sup.8 or N;
[0359] A.sup.6 is CR.sup.6;
[0360] A.sup.8 is CR.sup.8;
[0361] each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CN, CH.sub.2F or CHF.sub.2;
[0362] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0363] each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2;
[0364] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.3, OCF.sub.3, CH.sub.3,
CH.sub.2CH.sub.3, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3 or
C(O)CH.sub.3;
[0365] R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00031## [0366] wherein V is NR.sup.10, O or S; and [0367] each
W, independently, is CH, CF, CCl or N;
[0368] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl,
thiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl,
naphthyridinyl, phthalazinyl, pyranyl, dihydropyranyl,
tetrahydropyranyl, furanyl, dihydrofuranyl, tetrahydrofuranyl,
thienyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperidinyl,
piperazinyl, morpholinyl, azetidinyl,
8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl, aza-bicyclo[2.2.1]hept-5-yl,
2-oxo-7-aza-[3,5]-spironon-7-yl, imidazo-pyridyl, cyclopropyl,
cyclobutyl, cyclopentyl and cyclohexyl, wherein the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are
optionally substituted, independently, with 1-5 substituents of
R.sup.10; and
[0369] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-butynyloxy, morpholinyl,
pyrazolyl, isoxazolyl, dihydropyranyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl or dioxolyl, wherein
each of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, morpholinyl, pyrazolyl,
isoxazolyl, dihydropyranyl, pyrrolidinyl, oxetan-3-yl or dioxolyl,
is optionally substituted independently with 1-5 substituents of F,
Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl, methoxy, ethyl,
ethoxy, propyl, propoxy, isopropyl, isopropoxy, cyclopropyl,
cyclopropylmethoxy, butyl, butoxy, isobutoxy, tert-butoxy,
2-butynyloxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl
or oxetan-3yl.
[0370] Similarly, the invention provides compounds of sub-formulas
II-B-1 and II-B-2, respectively, as described below:
##STR00032##
[0371] wherein each of the variables listed in II-A-1, II-A-2,
II-B-1 and II-B-2, respectively, are as defined hereinabove and
below with respect to Formulas II, II-A and II-B, individually or
in conjunction with any of the above or below embodiments,
including those described in embodiments A, A-1 to A-11, B, B-1 to
B-10, B-A, B-A-1, B-A-2, B-B, B-B-1, B-B-2, B-C, B-D, B-E, D, D-1
to D-4, E, E-1 to E-8, F, F-1 to F-7, G, G-1 to G-3, H, H-1 to H-5,
I, I-1 to I-5, J, J-1 to J-5, K, K-1 to K-5, L, L-1 to L-8, M, M-1
to M-9, N, N-1, O, P and P-1 to P-2 described herein.
[0372] Similarly, the invention provides compounds of sub-formulas
III-A-1, III-A-2, III-B-1 and III-B-2, respectively, as described
below.
##STR00033##
[0373] wherein each of the variables listed in III-A-1, III-A-2,
III-B-1 and III-B-2, respectively, are as defined hereinabove and
below with respect to Formulas III, III-A and III-B, individually
or in conjunction with any of the above or below embodiments,
including those described in embodiments A, A-1 to A-11, C, C-1 to
C-9, C-A, C-A-1, C-A-2, C-B, C-B-1, C-B-2, C-C, C-D, C-E, D, D-1 to
D-4, E, E-1 to E-8, F, F-1 to F-7, G, G-1 to G-3, H, H-1 to H-5, I,
I-1 to I-5, J, J-1 to J-5, K, K-1 to K-5, L, L-1 to L-8, M, M-1 to
M-9, N, N-1, O and Q-1 to Q-2 described herein.
[0374] The present invention contemplates that the various
different embodiments of Formulas I, II and III, and sub-Formulas
thereof, described herein, may comprise the following embodiments
with respect to individual variables of A.sup.4, A.sup.5, A.sup.6,
A.sup.8, R.sup.1, R.sup.2, R.sup.3, R.sup.7, R.sup.9, R.sup.10, V,
W and o, where applicable, as described below. Hence, these
embodiments with respect to individual variables A.sup.4, A.sup.5,
A.sup.6, A.sup.8, R.sup.1, R.sup.2, R.sup.3, R.sup.7, R.sup.9,
R.sup.10, V, W and o, where applicable, may be applied "in
conjunction with any of the other {above and below} embodiments" to
create various embodiments of general Formulas I, II and III, and
each sub-formula thereof, which are not literally or identically
described herein. More specifically, the term "in conjunction with
any of the above or below embodiments" includes embodiments A, A-1
to A-10, B, B-1 to B-9, B-A, B-A-1, B-A-2, B-B, B-B-1, B-B-2, B-C,
B-D, B-E, C, C-1 to C-9, C-A, C-A-1, C-A-2, C-B, C-B-1, C-B-2, C-C,
C-D, C-E, D, D-1 to D-4, E, E-1 to E-8, F, F-1 to F-7, G, G-1 to
G-3, H, H-1 to H-5, I, I-1 to I-5, J, J-1 to J-5, K, K-1 to K-5, L,
L-1 to L-8, M, M-1 to M-9, N, N-1, O, P and P-1 to P-2 described
herein, as it applies to general Formulas I, II and III, and
sub-formulas thereof, also described herein (above and below).
[0375] In another embodiment D, the invention includes compounds of
Formula I, wherein n is 0, 1 or 2, in conjunction with any of the
above or below embodiments.
[0376] In another embodiment D-1, the invention includes compounds
of Formula I, wherein n is 1 or 2, in conjunction with any of the
above or below embodiments.
[0377] In another embodiment D-2, the invention includes compounds
of Formula I, wherein n is 2, in conjunction with any of the above
or below embodiments.
[0378] In another embodiment D-3, the invention includes compounds
of Formula I, wherein n is 1, in conjunction with any of the above
or below embodiments.
[0379] In another embodiment D-4, the invention includes compounds
of Formula I, wherein n is 0, in conjunction with any of the above
or below embodiments.
[0380] In another embodiment E, the invention includes compounds
wherein each R.sup.1, independently, is H, F, Cl, C.sub.1-4alkyl,
CH.sub.2OC.sub.1-4alkyl, cyclopropyl or CN, wherein the
C.sub.1-4alkyl and CH.sub.2OC.sub.1-4alkyl are optionally
substituted with 1-3 substituents of F;
[0381] In another embodiment E-1, the invention includes compounds
wherein each R.sup.1, independently, is H, F, Cl, CH.sub.3,
CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, cyclopropyl or CN, wherein the
CH.sub.3, CH.sub.2CH.sub.3 and CH.sub.2OCH.sub.3 are optionally
substituted with 1-3 substituents of F, in conjunction with any of
the above or below embodiments.
[0382] In another embodiment E-2, the invention includes compounds
wherein each R.sup.1, independently, is H, F, CH.sub.2OCH.sub.3,
CH.sub.2F or CH.sub.3, in conjunction with any of the above or
below embodiments.
[0383] In another embodiment E-3, the invention includes compounds
wherein each R.sup.1, independently, is H, F, Cl, CF.sub.3,
CH.sub.3, CH.sub.2CH.sub.3, CH.sub.2OCH.sub.3, CN, CH.sub.2F or
CHF.sub.2, in conjunction with any of the above or below
embodiments.
[0384] In another embodiment E-4, the invention includes compounds
wherein one R.sup.1 is CH.sub.3, CH.sub.2OCH.sub.3 or CH.sub.2F and
the other R.sup.1 is H, in conjunction with any of the above or
below embodiments.
[0385] In another embodiment E-5, the invention includes compounds
wherein each R.sup.1, independently, is CH.sub.2F in conjunction
with any of the above or below embodiments.
[0386] In another embodiment E-6, the invention includes compounds
wherein each R.sup.1, independently, is CH.sub.3, in conjunction
with any of the above or below embodiments.
[0387] In another embodiment F, the invention includes compounds
wherein R.sup.2 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, CH.sub.2CN, C.sub.3-6cycloalkyl or CN, wherein each of
the C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and C.sub.3-6cycloalkyl
is optionally substituted with 1-4 substituents of F, in
conjunction with any of the above or below embodiments.
[0388] In another embodiment F-1, the invention includes compounds
wherein R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2, in conjunction
with any of the above or below embodiments.
[0389] In another embodiment F-2, the invention includes compounds
wherein R.sup.2 is CH.sub.3 or CH.sub.2F, in conjunction with any
of the above or below embodiments.
[0390] In another embodiment F-3, the invention includes compounds
wherein R.sup.2 is CH.sub.3, CF.sub.3 or CH.sub.2F, in conjunction
with any of the above or below embodiments.
[0391] In another embodiment F-5, the invention includes compounds
wherein R.sup.2 is CF.sub.3 or CH.sub.3, in conjunction with any of
the above or below embodiments.
[0392] In another embodiment F-6, the invention includes compounds
wherein R.sup.2 is CH.sub.3, in conjunction with any of the above
or below embodiments.
[0393] In another embodiment F-7, the invention includes compounds
wherein R.sup.2 is CH.sub.2F, in conjunction with any of the above
or below embodiments.
[0394] In another embodiment G, the invention includes compounds
wherein each R.sup.3, independently, is H, halo, C.sub.1-4alkyl,
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH,
C.sub.1-4haloalkyl, cyclopropyl or CN, wherein each of the
OC.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl and cyclopropyl is
optionally substituted with 1-4 substituents of F, in conjunction
with any of the above or below embodiments.
[0395] In another embodiment G-1, the invention includes compounds
wherein each R.sup.3, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
CH.sub.2OCH.sub.2F or CH.sub.2OCHF.sub.2, in conjunction with any
of the above or below embodiments.
[0396] In another embodiment G-2, the invention includes compounds
wherein each R.sup.3, independently, is H, F, CH.sub.3,
C.sub.2H.sub.5, CH.sub.2F, CF.sub.2H, CF.sub.3 or CH.sub.2CF.sub.3,
in conjunction with any of the above or below embodiments.
[0397] In another embodiment G-3, the invention includes compounds
wherein each R.sup.3, independently, is H or F, in conjunction with
any of the above or below embodiments.
[0398] In another embodiment H, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0399] In another embodiment H-1, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3, in conjunction with any of
the above or below embodiments.
[0400] In another embodiment H-2, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0401] In another embodiment H-3, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is H or F, in
conjunction with any of the above or below embodiments.
[0402] In another embodiment H-4, the invention includes compounds
wherein A.sup.4 is CR.sup.4 wherein R.sup.4 is F, in conjunction
with any of the above or below embodiments.
[0403] In another embodiment I, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0404] In another embodiment I-1, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3, in conjunction with any of
the above or below embodiments.
[0405] In another embodiment I-2, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0406] In another embodiment I-3, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is H or F, in
conjunction with any of the above or below embodiments.
[0407] In another embodiment I-4, the invention includes compounds
wherein A.sup.5 is CR.sup.5 wherein R.sup.5 is F, in conjunction
with any of the above or below embodiments.
[0408] In another embodiment I-5, the invention includes compounds
wherein A.sup.5 is N, in conjunction with any of the above or below
embodiments.
[0409] In another embodiment J, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0410] In another embodiment J-1, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3, in conjunction with any of
the above or below embodiments.
[0411] In another embodiment J-2, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0412] In another embodiment J-3, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.5 is H or F, in
conjunction with any of the above or below embodiments.
[0413] In another embodiment J-4, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is F, in conjunction
with any of the above or below embodiments.
[0414] In another embodiment J-5, the invention includes compounds
wherein A.sup.6 is N, in conjunction with any of the above or below
embodiments.
[0415] In another embodiment K, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H, halo, haloalkyl,
haloalkoxyl, C.sub.1-4-alkyl, CN, OH, OC.sub.1-4-alkyl,
S(O).sub.oC.sub.1-4-alkyl, NHC.sub.1-4-alkyl or
C(O)C.sub.1-4-alkyl, in conjunction with any of the above or below
embodiments.
[0416] In another embodiment K-1, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3, in conjunction with any of
the above or below embodiments.
[0417] In another embodiment K-2, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H, F, CF.sub.3,
CF.sub.2H, CH.sub.2F or CH.sub.3, in conjunction with any of the
above or below embodiments.
[0418] In another embodiment K-3, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is H or F, in
conjunction with any of the above or below embodiments.
[0419] In another embodiment K-4, the invention includes compounds
wherein A.sup.8 is CR.sup.8 wherein R.sup.8 is F, in conjunction
with any of the above or below embodiments.
[0420] In another embodiment K-5, the invention includes compounds
wherein A.sup.8 is N, in conjunction with any of the above or below
embodiments.
[0421] In another embodiment L, the invention includes compounds
wherein no more than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8
is N, in conjunction with any of the above or below
embodiments.
[0422] In another embodiment L-1, the invention includes compounds
wherein no more than one of A.sup.5 and A.sup.6 is N, in
conjunction with any of the above or below embodiments.
[0423] In another embodiment L-2, the invention includes compounds
wherein A.sup.4 is CR.sup.4, A.sup.5 is CR.sup.5 or N, A.sup.6 is
CR.sup.6 and A.sup.8 is CR.sup.8 or N, in conjunction with any of
the above or below embodiments.
[0424] In another embodiment L-3, the invention includes compounds
wherein A.sup.4 is CR.sup.4, A.sup.5 is CR.sup.5, A.sup.6 is
CR.sup.6 and A.sup.8 is CR.sup.8, in conjunction with any of the
above or below embodiments.
[0425] In another embodiment L-4, the invention includes compounds
wherein
[0426] A.sup.4 is CR.sup.4 or N;
[0427] A.sup.5 is CR.sup.5 or N;
[0428] A.sup.6 is CR.sup.6 or N;
[0429] A.sup.8 is CR.sup.8 or N, provided that no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N; and each of A.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CH.sub.2CH.sub.3, CN, OH, OCH.sub.3,
SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3, in conjunction with any of
the above or below embodiments.
[0430] In another embodiment L-5, the invention includes compounds
wherein
[0431] A.sup.4 is CR.sup.4;
[0432] A.sup.5 is CR.sup.5;
[0433] A.sup.6 is CR.sup.6; and
[0434] A.sup.8 is CR.sup.8; wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, CF.sub.3, CF.sub.2H,
CH.sub.2F or CH.sub.3, in conjunction with any of the above or
below embodiments.
[0435] In another embodiment L-6, the invention includes compounds
wherein A.sup.4 is CR.sup.4; A.sup.5 is CR.sup.5 or N; A.sup.6 is
CR.sup.6; and A.sup.8 is CR.sup.8, wherein each of R.sup.4,
R.sup.5, R.sup.6 and R.sup.8, independently, is H, F, Cl, CF.sub.3,
OCF.sub.3, CH.sub.3, CN or OCH.sub.3, in conjunction with any of
the above or below embodiments.
[0436] In another embodiment L-7, the invention includes compounds
wherein A.sup.4 is CH or CF; A.sup.5 is CH, CF or N; A.sup.6 is CH
or CF; and A.sup.8 is CH or CF, in conjunction with any of the
above or below embodiments.
[0437] In another embodiment L-8, the invention includes compounds
wherein A.sup.4 is CH or CF; A.sup.5 is CH or N; A.sup.6 is CH; and
A.sup.8 is CH, in conjunction with any of the above or below
embodiments.
[0438] In another embodiment M-1, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9 or
##STR00034##
[0439] wherein V is NR.sup.10, O or S; and
[0440] each W, independently, is CH, CF, CCl or N, in conjunction
with any of the above or below embodiments.
[0441] In another embodiment M-2, the invention includes compounds
wherein R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00035##
[0442] wherein V is NR.sup.10, O or S; and
[0443] each W, independently, is CH, CF, CCl or N, in conjunction
with any of the above or below embodiments.
[0444] In another embodiment M-3, the invention includes compounds
wherein R.sup.7 is --NH--C(.dbd.O)--R.sup.9, in conjunction with
any of the above or below embodiments.
[0445] In another embodiment M-4, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, in conjunction with any of the
above or below embodiments.
[0446] In another embodiment M-5, the invention includes compounds
wherein R.sup.7 is
##STR00036## [0447] wherein V is NR.sup.10, O or S; and [0448] each
W, independently, is CH, CF, CCl or N, in conjunction with any of
the above or below embodiments.
[0449] In another embodiment M-6, the invention includes compounds
wherein R.sup.7 is selected from the group consisting of
##STR00037##
in conjunction with any of the above or below embodiments.
[0450] In another embodiment M-8, the invention includes compounds
wherein R.sup.7 is --NH--C(.dbd.O)--R.sup.9, wherein R.sup.9 is a
fully or partially unsaturated 5-, 6- or 7-membered monocyclic or
8-, 9- or 10-membered bicyclic ring formed of carbon atoms, said
ring optionally including 1-4 heteroatoms if monocyclic or 1-5
heteroatoms if bicyclic, said heteroatoms selected from O, N or S,
wherein the C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and
ring are optionally substituted, independently, with 1-5
substituents of R.sup.10, in conjunction with any of the above or
below embodiments.
[0451] In another embodiment N, the invention includes compounds
wherein R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 5-, 6- or
7-membered monocyclic or 8-, 9- or 10-membered bicyclic ring formed
of carbon atoms, said ring optionally including 1-4 heteroatoms if
monocyclic or 1-5 heteroatoms if bicyclic, said heteroatoms
selected from O, N or S, wherein the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl and ring are optionally
substituted, independently, with 1-5 substituents of R.sup.10, in
conjunction with any of the above or below embodiments.
[0452] In another embodiment N-1, the invention includes compounds
wherein each R.sup.9, independently, is a ring selected from
phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,
isoxazolyl, thiazolyl, naphthyl, quinolinyl, isoquinolinyl,
quinazolinyl, naphthyridinyl, phthalazinyl, pyranyl,
dihydropyranyl, tetrahydropyranyl, furanyl, dihydrofuranyl,
tetrahydrofuranyl, thienyl, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl,
azetidinyl, 8-oxo-3-aza-bicyclo[3.2.1]oct-3-yl,
aza-bicyclo[2.2.1]hept-5-yl, 2-oxo-7-aza-[3,5]-spironon-7-yl,
imidazo-pyridyl, cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl, wherein the C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl and ring are optionally substituted,
independently, with 1-5 substituents of R.sup.10, in conjunction
with any of the above or below embodiments.
[0453] In another embodiment O, the present invention provides
compounds, and solvates, tautomers, hydrates, stereoisomers and
pharmaceutically acceptable salts thereof, as defined by Formulas
I, II, II-A to II-E, III-A to III-E, II-A-1, II-A-2, II-B-1,
II-B-2, III-A-1, III-A-2, III-B-1 or III-B-2, wherein
[0454] A.sup.4 is CH or CF;
[0455] A.sup.5 is CH, CF or N;
[0456] A.sup.6 is CH or CF;
[0457] A.sup.8 is CH or CF;
[0458] one R.sup.1 is H, F, Cl, CF.sub.3, CH.sub.3, CF.sub.2H,
CH.sub.2F or CH.sub.2OCH.sub.3 and the other R.sup.1 is H;
[0459] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0460] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F, in conjunction with any of the above or
below embodiments.
[0461] In another embodiment P, the present invention provides
compounds, and solvates, tautomers, hydrates, stereoisomers and
pharmaceutically acceptable salts thereof, as defined by Formulas I
and II and each sub-Formula thereof, wherein
[0462] R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00038## [0463] wherein each W, independently, is CH, CF, CCl
or N, in conjunction with any of the above or below
embodiments.
[0464] In another embodiment P-1, the invention includes compounds
of Formula II-A, II-B, II-C, II-D or II-E, or a sub-formula
thereof, wherein
[0465] A.sup.4 is CH or CF;
[0466] A.sup.5 is CH, CF or N;
[0467] A.sup.6 is CH or CF;
[0468] A.sup.8 is CH or CF;
[0469] one R.sup.1 is H, F, Cl, CF.sub.3, CH.sub.3, CF.sub.2H,
CH.sub.2F or CH.sub.2OCH.sub.3 and the other R.sup.1 is H;
[0470] R.sup.2 is CH.sub.3 or CH.sub.2F; and
[0471] each R.sup.3, independently, is H, CF.sub.3, CH.sub.3,
CF.sub.2H or CH.sub.2F;
[0472] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, furanyl,
thienyl, pyrrolyl, wherein the ring is optionally substituted,
independently, with 1-5 substituents of R.sup.10; and
[0473] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHCH.sub.3, oxo,
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl, piperazinyl,
oxetan-3-yl, dioxolyl or --C(O)NHCH.sub.3, wherein each of the
C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy,
2-butynyloxy, morpholinyl, pyrazolyl, isoxazolyl, dihydropyranyl,
pyrrolidinyl, oxetan-3-yl or dioxolyl, is optionally substituted
independently with 1-5 substituents of F, Cl, CN, NO.sub.2,
NH.sub.2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy,
isopropyl, isopropoxy, cyclopropyl, cyclopropylmethoxy, butyl,
butoxyl, isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxetan-3yl or a ring selected from oxazolyl, isoxazolyl, pyrazolyl,
thiazolyl, isothiazolyl or oxadiazolyl wherein the ring is
optionally substituted independently with 1-5 substituents of F,
Cl, CN or CH.sub.3.
[0474] In embodiment P-2, the invention includes compounds of
Formula II-A-a,
##STR00039##
wherein
[0475] A.sup.9 is CR.sup.10 or N;
[0476] R.sup.1 is H, F, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2OCH.sub.3, CH.sub.2F or CHF.sub.2;
[0477] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2; and
[0478] each R.sup.10, independently, is H, F, Cl, Br, CN, OH,
NO.sub.2, NH.sub.2, acetyl, --C(O)NHCH.sub.3, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy or 2-butynyloxy, wherein each
of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy or
2-butynyloxy, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxyl, isobutoxy,
tert-butoxy, isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxetan-3yl or a ring
selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3.
[0479] In embodiment P-3, the invention includes compounds of
embodiment P-2 wherein A.sup.9 is CH or N; and R.sup.1 is H,
CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F or CHF.sub.2.
[0480] In embodiment P-4, the invention includes compounds of
Formula II-A-b,
##STR00040##
wherein
[0481] R.sup.1 is H, F, CF.sub.3, CH.sub.3, CH.sub.2CH.sub.3,
CH.sub.2OCH.sub.3, CH.sub.2F or CHF.sub.2;
[0482] R.sup.2 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0483] each W, independently, is CH, CF, CCl, CCH.sub.3 or N;
and
[0484] each R.sup.10, independently, is H, F, Cl, Br, CN, OH,
NO.sub.2, NH.sub.2, acetyl, --C(O)NHCH.sub.3, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.3-6cycloalkyl,
C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-, C.sub.1-6alkoxyl,
C.sub.1-6thioalkoxyl, 2-propynyloxy or 2-butynyloxy, wherein each
of the C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
C.sub.3-6cycloalkyl, C.sub.1-6alkylamino-, C.sub.1-6dialkylamino-,
C.sub.1-6alkoxyl, C.sub.1-6thioalkoxyl, 2-propynyloxy or
2-butynyloxy, is optionally substituted independently with 1-5
substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo, methyl,
methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, cyclopropylmethoxy, butyl, butoxyl, isobutoxy,
tert-butoxy, isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxetan-3yl or a ring
selected from oxazolyl, isoxazolyl, pyrazolyl, thiazolyl,
isothiazolyl or oxadiazolyl wherein the ring is optionally
substituted independently with 1-5 substituents of F, Cl, CN or
CH.sub.3.
[0485] In embodiment P-5, the invention includes compounds of
embodiment P-4 wherein each W is CH or N provided no more than one
W is N; and one R.sup.10 is H and the other R.sup.10 is as defined
in P-4.
[0486] All of the possible embodiments described herein for the
various A, R, V, W, X and Y groups of the compounds of Formula I
may be applied, as appropriate, to compounds of Formula II and any
sub-formulas thereof, as well as to a compound of Formulas III-A,
III-B, III-C and III-D.
[0487] In another embodiment, the invention provides each of the
Examplary compounds, and stereoisomers, tautomers, solvates,
pharmaceutically acceptable salts, derivatives or prodrugs thereof,
and related intermediates, described herein.
[0488] In another embodiment, the invention provides the
exemplified compounds described herein, and pharmaceutically
acceptable salt forms of each thereof.
[0489] In another embodiment, the invention provides one or more of
the compounds, or a pharmaceutically acceptable salt thereof, of
Formulas I, II and III, and sub-formulas thereof, as exemplified
and/or specifically disclosed or described herein.
[0490] In another embodiment, the invention provides a compound of
Formula I, II, II-A, II-B, II-C, II-C-1-A, II-C-1-B, II-C-2, II-C-3
or II-D, or a sub-Formula thereof, or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof, selected from [0491]
N-(3-((1R,2R,5S)-4-amino-2-methyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]o-
ct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0492]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicy-
clo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarbo-
xamide; [0493]
N-(3-((1R,2S,5S)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0494]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicy-
clo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-py-
ridinecarboxamide; [0495]
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0496]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicy-
clo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-3-methyl-5-(trifluoromethyl)-2-py-
ridinecarboxamide; [0497]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridine--
2-carboxamide; [0498]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-ami-
ne; [0499]
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azab-
icyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a-
]pyridine-2-carboxamide; [0500]
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-3-methyl-5-(trifluoromethyl)-2-pyridinec-
arboxamide; [0501]
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-8,8-dioxido-8-thia-3-azabicyclo[-
3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxami-
de; [0502]
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridin-
ecarboxamide; [0503]
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7-naphthyridin-8-ami-
ne; [0504]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azab-
icyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthy-
ridin-8-amine; and [0505]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide.
[0506] In another embodiment, the invention provides a compound of
Formula I, II, II-A, II-B, II-C, II-C-1-A, II-C-1-B, II-C-2, II-C-3
or II-D, or a sub-Formula thereof, or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof, selected from [0507]
4-((3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3--
azabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidi-
ne-7-carbonitrile; [0508]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyraz-
in-5-amine; [0509]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyridi-
necarboxamide; [0510]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyri-
dinecarboxamide; [0511]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-3-methoxy-1,7-naphthyridin--
8-amine; [0512]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-3-methyl-5-(2-propyn-1-ylox-
y)-2-pyrazinecarboxamide; [0513]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
[0514]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(1-propyn-1-yl)-2-pyridinecarboxamide;
[0515]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-t-
hia-3-azabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-
-pyrazinecarboxamide; [0516]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxam-
ide; [0517]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7-naphthyridin-8-am-
ine; [0518]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-methoxy-3-methyl-2-pyrazinecarboxamide-
; [0519]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabic-
yclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5--
amine; [0520]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2-pyrazinecarboxamid-
e; [0521]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-
-thia-3-azabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl--
2-pyridinecarboxamide; [0522]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-3-methyl-5-(trifluoromethyl-
)-2-pyridinecarboxamide; [0523]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridine-
carboxamide; [0524]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrim-
idin-4-amine; [0525]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimi-
din-4-amine; [0526]
8-((3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3--
azabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3--
carbonitrile; [0527]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methy-
l-2-pyridinecarboxamide; [0528]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethyl)-3-methyl-
-2-pyridinecarboxamide; [0529]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)p-
yrido[3,4-b]pyrazin-5-amine; [0530]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-3,5-dichloro-2-pyridinecarb-
oxamide; [0531]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-7-(trifluoromethyl)pyrido[3,2-d]pyrimidi-
n-4-amine; [0532]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-7-(trifluoromethyl)pyrido[3-
,2-d]pyrimidin-4-amine; [0533]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethyl)-2-pyrazi-
necarboxamide; [0534]
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(trifluoromethyl)-2-pyrid-
inecarboxamide; [0535]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
[0536]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicy-
clo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[-
3,4-b]pyrazin-5-amine; and [0537]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-2-((5-methyl-1,3-oxazol-2-yl)methoxy)pyr-
ido[3,4-b]pyrazin-5-amine
[0538] In another embodiment, the invention provides a compound of
Formula I, III, III-A, III-B, III-C, III-D or III-E, or a
sub-Formula thereof, or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof, selected from [0539]
N-(3-((1R,2R,5R)-4-amino-2-methyl-9,9-dioxido-9-thia-3-azabicyclo[3.3.1]n-
on-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0540]
N-(3-((1R,2R,5R)-4-amino-2-methyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridi-
necarboxamide; [0541]
N-(3-((1S,2R,5S)-4-amino-2-methyl-9,9-dioxido-9-thia-3-azabicyclo[3.3.1]n-
on-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0542]
N-(3-((1R,2R,5R)-4-amino-2-methyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine-
; [0543]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabic-
yclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5--
amine; [0544]
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3-
.1]non-3-en-2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0545]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicy-
clo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarbo-
xamide; [0546]
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3-
.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxamide;
[0547]
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicy-
clo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-py-
ridinecarboxamide; [0548]
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3-
.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridinec-
arboxamide; [0549]
N-(3-((1S,2R,5R)-4-amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecar-
boxamide; [0550]
N-(3-((1S,2R,5R)-4-amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2--
pyridinecarboxamide; [0551]
N-(3-((1R,2R,5S)-4-amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecar-
boxamide; [0552]
N-(3-((1R,2R,5S)-4-amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2--
pyridinecarboxamide; [0553]
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridinecarboxami-
de; [0554]
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-a-
zabicyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2-pyridin-
ecarboxamide; [0555]
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridi-
necarboxamide; [0556]
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methyl-2-pyridi-
necarboxamide; [0557]
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
and [0558]
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azab-
icyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamid-
e.
[0559] In another embodiment, the invention provides a compound of
Formula I, or a stereoisomer, tautomer or pharmaceutically
acceptable salt thereof, selected from
##STR00041## ##STR00042## ##STR00043## ##STR00044##
[0560] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00045##
[0561] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00046##
[0562] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00047##
[0563] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00048##
[0564] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00049##
[0565] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00050##
[0566] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00051##
[0567] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00052##
[0568] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00053##
[0569] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00054##
[0570] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00055##
[0571] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00056##
[0572] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00057##
[0573] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00058##
[0574] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00059##
[0575] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00060##
[0576] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00061##
[0577] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00062##
[0578] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00063##
[0579] In another embodiment, the invention provides the compound,
or a tautomer or pharmaceutically acceptable salt thereof, of
##STR00064##
DEFINITIONS
[0580] The following definitions should assist in understanding the
metes and bounds of the invention.
[0581] The term "A through A-10" with reference to embodiments is
intended to mean the same as the term "A, A-1 through A-10", both
terms of which are intended to encompass each embodiment listed
therein, individually, beginning with embodiment A, and including
each of embodiments A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9 and
A-10. Similarly, language with respect to other embodiments,
including embodiments B, C, etc. mean the same as with embodiment
A.
[0582] The term "comprising" is meant to be open ended, i.e., all
encompassing and non-limiting. It may be used herein synonymously
with "having." Comprising is intended to include each and every
indicated or recited component or element(s) while not excluding
any other components or elements.
[0583] The term "C.sub..alpha.-.beta.alkyl", when used either alone
or within other terms such as "haloalkyl" and "alkylamino",
embraces linear or branched radicals having .alpha. to .beta.
number of carbon atoms (such as C.sub.1-C.sub.10; C.sub.1-C.sub.6,
or C.sub.1-C.sub.4). Unless otherwise specified, one or more carbon
atoms of the "alkyl" radical may be substituted, such as with a
cycloalkyl moiety. Examples of "alkyl" radicals include methyl,
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, ethyl,
cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, n-propyl,
isopropyl, n-butyl, cyclopropylbutyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isoamyl, hexyl and the like.
[0584] The term "C.sub..alpha.-.beta.alkenyl", when used alone or
in combination, embraces linear or branched radicals having at
least one carbon-carbon double bond in a moiety having a number of
carbon atoms in the range from .alpha. and .beta.. Included within
alkenyl radicals are "lower alkenyl" radicals having two to about
six carbon atoms and, for example, those radicals having two to
about four carbon atoms. Examples of alkenyl radicals include,
without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and
4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace
radicals having "cis" and "trans" orientations, or alternatively,
"E" and "Z" orientations, as appreciated by those of ordinary skill
in the art.
[0585] The term "C.sub..alpha.-.beta.alkynyl", when used alone or
in combination, denotes linear or branched radicals having at least
one carbon-carbon triple bond in a moiety having a number of carbon
atoms in the range from .alpha. and .beta.. Examples of alkynyl
radicals include "lower alkynyl" radicals having two to about six
carbon atoms and, for example, lower alkynyl radicals having two to
about four carbon atoms. Examples of such radicals include, without
limitation, ethynyl, propynyl (propargyl), butynyl, and the
like.
[0586] The term "C.sub..alpha.-.beta.-alkyl",
"C.sub..alpha.-.beta.-alkenyl" and "C.sub..alpha.-.beta.alkynyl",
when used with other terms such as "wherein 1, 2 or 3 carbon atoms
of said C.sub..alpha.-.beta.-alkyl, C.sub..alpha.-.beta.-alkenyl or
C.sub.2.alpha.-.beta.-alkynyl is optionally replaced with a
heteroatom selected from O, S, S(O), S(O).sub.2 and N" embraces
linear or branched radicals wherein one or more of the carbon atoms
may be replaced with a heteroatom. Examples of such "alkyl"
radicals include --O-methyl, --O-ethyl, --CH.sub.2--O--CH.sub.3,
--CH.sub.2CH.sub.2--O--CH.sub.3, --NH--CH.sub.2,
--CH.sub.2CH.sub.2--N(CH.sub.3)--CH.sub.3,
--S--(CH.sub.2).sub.3CH.sub.2, --CH.sub.2CH.sub.2--S--CH.sub.3 and
the like. Accordingly, such radicals also include radicals
encompassed by --OR.sup.7 where R.sup.7 may be defined as a
C.sub..alpha.-.beta.-alkyl. Examples of such "alkenyl" radicals
include --NH--CH.sub.2CH.dbd.CH.sub.2,
--S--CH.sub.2CH.sub.2CH.dbd.CHCH.sub.3 and the like. Similar
examples exist for such "alkynyl" radicals, as appreciated by those
skilled in the art.
[0587] The term "C.sub..alpha.-.beta.alkoxyl" or
"--OC.sub..alpha.-.beta.alkyl" when used alone or in combination,
embraces linear or branched oxygen-containing alkyl radicals each
having .alpha. to .beta. number of carbon atoms (such as
C.sub.1-C.sub.10). The terms "alkoxy" and "alkoxyl", when used
alone or in combination, embraces linear or branched
oxygen-containing radicals each having alkyl and substituted alkyl
portions of one or more carbon atoms. Examples of such radicals
include methoxy, ethoxy, propoxy, butoxy, tert-butoxy and
neopentoxy. Alkoxy radicals may be further substituted with one or
more halo atoms, such as fluoro, chloro or bromo, to provide
"haloalkoxy" radicals or with other substitution. Examples of such
radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,
trifluoroethoxy, fluoroethoxy and fluoropropoxy.
[0588] The term "aryl", when used alone or in combination, means a
carbocyclic aromatic moiety containing one, two or even three rings
wherein such rings may be attached together in a fused manner.
Every ring of an "aryl" multi-ring system need not be aromatic, and
the ring(s) fused to the aromatic ring may be partially or fully
unsaturated and include one or more heteroatoms selected from
nitrogen, oxygen and sulfur. Thus, the term "aryl" embraces
aromatic radicals such as phenyl, naphthyl, indenyl,
tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,
benzodioxazinyl, and the like. The "aryl" group may be substituted,
such as with 1 to 5 substituents including lower alkyl, hydroxyl,
halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the
like. Phenyl substituted with --O--CH.sub.2--O-- or
--O--CH.sub.2--CH.sub.2--O-- forms an aryl benzodioxolyl
substituent.
[0589] The term "C.sub..alpha.-.beta.-cycloalkyl", also referred to
herein as "carbocyclic", when used alone or in combination, denotes
a partially or fully saturated ring radical having a number of
carbon atoms in the range from .alpha. and .beta.. The "cycloalkyl"
may contain one ("monocyclic"), two ("bicyclic") or even three
("tricyclic") rings wherein such rings may be attached together in
a fused manner and each formed from carbon atoms. Examples of
saturated carbocyclic radicals include saturated 3 to 6-membered
monocyclic groups such as cyclopropane, cyclobutane, cyclopentane
and cyclohexane. Cycloalkyls may be substituted as described
herein.
[0590] The terms "ring" and "ring system" refer to a ring
comprising the delineated number of atoms, the atoms being carbon
or, where indicated, a heteroatom such as nitrogen, oxygen or
sulfur. Where the number of atoms is not delineated, such as a
"monocyclic ring system" or a "bicyclic ring system", the numbers
of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring. The
ring itself, as well as any substitutents thereon, may be attached
at any atom that allows a stable compound to be formed. The term
"nonaromatic" ring or ring system refers to the fact that at least
one, but not necessarily all, rings in a bicyclic or tricyclic ring
system is nonaromatic.
[0591] The terms "partially or fully saturated or unsaturated" and
"saturated or partially or fully unsaturated" with respect to each
individual ring, refer to the ring either as fully aromatic (fully
unsaturated), partially aromatic (or partially saturated) or fully
saturated (containing no double or triple bonds therein). If not
specified as such, then it is contemplated that each ring
(monocyclic) in a ring system (if bicyclic or tricyclic) may either
be fully aromatic, partially aromatic or fully saturated, and
optionally substituted with up to 5 substituents. This includes
carbocyclics, heterocyclics, aryl and heteroaryl rings.
[0592] The term "halo", when used alone or in combination, means
halogens such as fluorine (F), chlorine (Cl), bromine (Br) or
iodine (I) atoms.
[0593] The term "haloalkyl", when used alone or in combination,
embraces radicals wherein any one or more of the alkyl carbon atoms
is substituted with halo as defined above. For example, this term
includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such
as a perhaloalkyl. A monohaloalkyl radical, for example, may have
either an iodo, bromo, chloro or fluoro atom within the radical.
Dihalo and polyhaloalkyl radicals may have two or more of the same
halo atoms or a combination of different halo radicals. Examples of
haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl
and dichloropropyl. "Perfluoroalkyl", as used herein, refers to
alkyl radicals having all hydrogen atoms replaced with fluoro
atoms. Examples include trifluoromethyl and pentafluoroethyl.
[0594] The term "heteroaryl", as used herein, either alone or in
combination, means a fully unsaturated (aromatic) ring moiety
formed from carbon atoms and having one or more heteroatoms
selected from nitrogen, oxygen and sulfur. The ring moiety or ring
system may contain one ("monocyclic"), two ("bicyclic") or even
three ("tricyclic") rings wherein such rings are attached together
in a fused manner. Every ring of a "heteroaryl" ring system need
not be aromatic, and the ring(s) fused thereto (to the
heteroaromatic ring) may be partially or fully saturated and
optionally include one or more heteroatoms selected from nitrogen,
oxygen and sulfur. The term "heteroaryl" does not include rings
having ring members of --O--O--, --O--S-- or --S--S--.
[0595] Examples of unsaturated heteroaryl radicals, include
unsaturated 5- to 6-membered heteromonocyclyl groups containing 1
to 4 nitrogen atoms, including for example, pyrrolyl, imidazolyl,
pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,
1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] and tetrazole; unsaturated
7- to 10-membered heterobicyclyl groups containing 1 to 4 nitrogen
atoms, including for example, quinolinyl, isoquinolinyl,
quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and the like;
unsaturated 5- to 6-membered heteromonocyclic group containing an
oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl,
etc.; unsaturated 5 to 6-membered heteromonocyclic group containing
a sulfur atom, for example, 2-thienyl, 3-thienyl, benzothienyl,
etc.; unsaturated 5- to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for
example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];
unsaturated 5 to 6-membered heteromonocyclic group containing 1 to
2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,
isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].
[0596] The terms "heterocycle" or "heterocyclic", when used alone
or in combination, means a partially or fully saturated ring moiety
containing one, two or even three rings wherein such rings may be
attached together in a fused manner, formed from carbon atoms and
including one or more heteroatoms selected from N, O or S. Examples
of saturated heterocyclic radicals include saturated 3 to
6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms
[e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,
piperazinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.
morpholinyl]; saturated 3 to 6-membered heteromonocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
thiazolidinyl]. Examples of partially saturated heterocyclyl
radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and
dihydrothiazolyl.
[0597] The term "heterocycle" also embraces radicals where
heterocyclic radicals are fused/condensed with aryl radicals:
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen
atoms, for example, indolyl, isoindolyl, indolizinyl,
benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,
tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen
atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,
benzoxadiazolyl]; unsaturated condensed heterocyclic group
containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,
benzothiazolyl, benzothiadiazolyl]; and saturated, partially
unsaturated and unsaturated condensed heterocyclic group containing
1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl,
2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples of
heterocyclic radicals include five to ten membered fused or unfused
radicals.
[0598] Examples of partially saturated and fully saturated
heterocyclyls include, without limitation, pyrrolidinyl,
imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl,
piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl,
dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl,
isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl,
chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl,
1,2,3,4-tetrahydro-quinolyl,
2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,
5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,
3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,
2,3-dihydro-1H-1.lamda.'-benzo[d]isothiazol-6-yl, dihydropyranyl,
dihydrofuryl and dihydrothiazolyl, and the like.
[0599] The term "a 3-8 membered monocyclic or 6-12 membered
bicyclic ring system, said ring system formed of carbon atoms
optionally including 1-3 heteroatoms if monocyclic or 1-6
heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,
wherein said ring system is optionally substituted" refers to a
single ring of 3-, 4-, 5-, 6-, 7- or 8-atom membered or a 6-, 7-,
8-, 9-, 10-, 11 or 12-atom membered bicyclic ring system comprising
the delineated number of atoms, the atoms being carbon or, where
indicated, a heteroatom such as nitrogen (N), oxygen (O) or sulfur
(S). Where the number of atoms is not delineated, such as a
"monocyclic ring system" or a "bicyclic ring system", the numbers
of atoms are 3-8 for a monocyclic and 6-12 for a bicyclic ring. The
ring or ring system may contain substitutents thereon, attached at
any atom that allows a stable compound to be formed. A bicyclic
ring is intended to include fused ring systems as well as
spiro-fused rings. This phrase encompasses carbocyclics,
heterocyclics, aryl and heteroaryl rings.
[0600] The term "alkylamino" includes "N-alkylamino" where amino
radicals are independently substituted with one alkyl radical.
Preferred alkylamino radicals are "lower alkylamino" radicals
having one to six carbon atoms. Even more preferred are lower
alkylamino radicals having one to three carbon atoms. Examples of
such lower alkylamino radicals include N-methylamino, and
N-ethylamino, N-propylamino, N-isopropylamino and the like.
[0601] The term "dialkylamino" includes "N,N-dialkylamino" where
amino radicals are independently substituted with two alkyl
radicals. Preferred alkylamino radicals are "lower alkylamino"
radicals having one to six carbon atoms. Even more preferred are
lower alkylamino radicals having one to three carbon atoms.
Examples of such lower alkylamino radicals include
N,N-dimethylamino, N,N-diethylamino, and the like.
[0602] The term "carbonyl", whether used alone or with other terms,
such as "aminocarbonyl", denotes --(C.dbd.O)--. "Carbonyl" is also
used herein synonymously with the term "oxo".
[0603] The term "alkylthio" or "thioalkoxy" embraces radicals
containing a linear or branched alkyl radical, of one to ten carbon
atoms, attached to a divalent sulfur atom. An example of
"alkylthio" or "thioalkoxy" is methylthio, (CH.sub.3S--).
[0604] The term "Formula I" includes any sub formulas, such as
Formulas II and III. Similar with Formulas II and III, in that they
include sub-formulas where described.
[0605] The term "pharmaceutically-acceptable" when used with
reference to a compound of Formulas I-III is intended to refer to a
form of the compound that is safe for administration. For example,
a salt form, a solvate, a hydrate, a prodrug or derivative form of
a compound of Formulas I-III, which has been approved for mammalian
use, via oral ingestion or other routes of administration, by a
governing body or regulatory agency, such as the Food and Drug
Administration (FDA) of the United States, is pharmaceutically
acceptable.
[0606] Included in the compounds of Formulas I-III are the
pharmaceutically acceptable salt forms of the free-base compounds.
The term "pharmaceutically-acceptable salts" embraces salts
commonly used to form alkali metal salts and to form addition salts
of free acids or free bases. As appreciated by those of ordinary
skill in the art, salts may be formed from ionic associations,
charge-charge interactions, covalent bonding, complexation,
coordination, etc. The nature of the salt is not critical, provided
that it is pharmaceutically acceptable.
[0607] Suitable pharmaceutically acceptable acid addition salts of
compounds of Formulas I-III may be prepared from an inorganic acid
or from an organic acid. Examples of such inorganic acids are
hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric,
carbonic, sulfuric and phosphoric acid. Appropriate organic acids
may be selected from aliphatic, cycloaliphatic, aromatic,
arylaliphatic, heterocyclic, carboxylic and sulfonic classes of
organic acids, examples of which include, without limitation,
formic, acetic, adipic, butyric, propionic, succinic, glycolic,
gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic,
maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,
mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic
(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,
benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic,
toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric,
camphorsulfonic, digluconic, cyclopentanepropionic,
dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic,
hexanoic, 2-hydroxy-ethanesulfonic, nicotinic,
2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric,
2-phenylpropionic, picric, pivalic propionic, succinic, thiocyanic,
undecanoic, stearic, algenic, .beta.-hydroxybutyric, salicylic,
galactaric and galacturonic acid. Suitable
pharmaceutically-acceptable base addition salts of compounds of
Formulas I-III include metallic salts, such as salts made from
aluminum, calcium, lithium, magnesium, potassium, sodium and zinc,
or salts made from organic bases including, without limitation,
primary, secondary and tertiary amines, substituted amines
including cyclic amines, such as caffeine, arginine, diethylamine,
N-ethyl piperidine, histidine, glucamine, isopropylamine, lysine,
morpholine, N-ethyl morpholine, piperazine, piperidine,
triethylamine, disopropylethylamine and trimethylamine. All of
these salts may be prepared by conventional means from the
corresponding compound of the invention by reacting, for example,
the appropriate acid or base with the compound of Formulas
I-III.
[0608] Also, the basic nitrogen-containing groups can be
quaternized with such agents as lower alkyl halides, such as
methyl, ethyl, propyl, and butyl chloride, bromides and iodides;
dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl
sulfates, long chain halides such as decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0609] Additional examples of such salts can be found in Berge et
al., J. Pharm. Sci., 66:1 (1977). Conventional methods may be used
to form the salts. For example, a phosphate salt of a compound of
the invention may be made by combining the desired compound free
base in a desired solvent, or combination of solvents, with
phosphoric acid in a desired stoichiometric amount, at a desired
temperature, typically under heat (depending upon the boiling point
of the solvent). The salt can be precipitated upon cooling (slow or
fast) and may crystallize (i.e., if crystalline in nature), as
appreciated by those of ordinary skill in the art. Further, hemi-,
mono-, di, tri- and poly-salt forms of the compounds of the present
invention are also contemplated herein. Similarly, hemi-, mono-,
di, tri- and poly-hydrated forms of the compounds, salts and
derivatives thereof, are also contemplated herein.
[0610] The term "pharmaceutically-acceptable derivative" as used
herein, denotes a derivative which is pharmaceutically
acceptable.
[0611] The compound(s) of Formulas I-III may be used to treat a
subject by administering the compound(s) as a pharmaceutical
composition. To this end, the compound(s) can be combined with one
or more excipients, including without limitation, carriers,
diluents or adjuvants to form a suitable composition, which is
described in more detail herein.
[0612] The term "excipient", as used herein, denotes any
pharmaceutically acceptable additive, carrier, adjuvant, or other
suitable ingredient, other than the active pharmaceutical
ingredient (API), which is typically included for formulation
and/or administration purposes. "Diluent" and "adjuvant" are
defined hereinafter.
[0613] The terms "treat", "treating," "treatment" and "therapy" as
used herein refer to therapy, including without limitation,
curative therapy, prophylactic therapy, and preventative therapy.
Prophylactic treatment generally constitutes either preventing the
onset of disorders altogether or delaying the onset of a
pre-clinically evident stage of disorders in individuals.
[0614] The phrase "effective dosage amount" is intended to quantify
the amount of each agent, which will achieve the goal of
improvement in disorder severity and the frequency of incidence
over treatment of each agent by itself, while avoiding adverse side
effects typically associated with alternative therapies.
Accordingly, this term is not limited to a single dose, but may
comprise multiple dosages required to bring about a therapeutic or
prophylactic response in the subject. For example, "effective
dosage amount" is not limited to a single capsule or tablet, but
may include more than one capsule or tablet, which is the dose
prescribed by a qualified physician or medical care giver to the
subject.
[0615] The term "leaving group" (also denoted as "LG") generally
refers to groups that are displaceable by a nucleophile. Such
leaving groups are known in the art. Examples of leaving groups
include, but are not limited to, halides (e.g., I, Br, F, Cl),
sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH.sub.3),
N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like.
Nucleophiles are species that are capable of attacking a molecule
at the point of attachment of the leaving group causing
displacement of the leaving group. Nucleophiles are known in the
art. Examples of nucleophilic groups include, but are not limited
to, amines, thiols, alcohols, Grignard reagents, anionic species
(e.g., alkoxides, amides, carbanions) and the like.
General Synthetic Procedures
[0616] The present invention further comprises procedures for the
preparation of compounds of Formulas I-III and sub-formulas
thereof. The compounds of Formulas I-III, including sub-formulas
thereof, can be synthesized according to the procedures described
in the following Schemes 1a, 1b, 2, 3a and 3b, wherein the
substituents are as defined for Formulas I-III above, except where
further noted. The synthetic methods described below are merely
exemplary, and the compounds of the invention may also be
synthesized by alternate routes utilizing alternative synthetic
strategies, as appreciated by persons of ordinary skill in the
art.
[0617] The following list of abbreviations used throughout the
specification represent the following and should assist in
understanding the invention: [0618] ACN, MeCN--acetonitrile [0619]
Aq., aq.--aqueous [0620] Ar--argon (gas) [0621]
BOC--tert-butoxycarbonyl [0622] BOP--benzotriazol-1-yl-oxy [0623]
Hexafluorophosphate [0624] BuLi--Butyllithium [0625]
Cs.sub.2CO.sub.3--cesium carbonate [0626] CHCl.sub.3--chloroform
[0627] CH.sub.2Cl.sub.2, DCM--dichloromethane, methylene chloride
[0628] Cu(1)I--copper(1) iodide [0629]
DCC--dicyclohexylcarbodiimide [0630] DEA--diethylamine [0631]
DIC--1,3-diisopropylcarbodiimide [0632] DIEA,
DIPEA--diisopropylethylamine [0633] DME--dimethoxyethane [0634]
DMF--dimethylformamide [0635] DMAP--4-dimethylaminopyridine [0636]
DMSO--dimethylsulfoxide [0637] EDC,
EDCI--1-(3-dimethylaminopropyl)-3-ethylcarbodiimide [0638]
Et.sub.2O--diethyl ether [0639] EtOAc--ethyl acetate [0640]
FC--flash (column) chromatography [0641] g, gm--gram [0642] h,
hr--hour [0643] H.sub.2--hydrogen (gas) [0644] H.sub.2O--water
[0645]
HATU--O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluoroph-
osphate [0646] HBr--hydrobromic acid [0647] HCl--hydrochloric acid
[0648] HOBt--1-hydroxybenzotriazole hydrate [0649] HOAc--acetic
acid [0650] HPLC--high pressure liquid chromatography [0651] IPA,
IpOH--isopropyl alcohol [0652] K.sub.2CO.sub.3--potassium carbonate
[0653] KI--potassium iodide [0654] LG--leaving group [0655]
LDA--Lithium diisopropylamide [0656] LiOH--lithium hydroxide [0657]
MgSO.sub.4--magnesium sulfate [0658] MS--mass spectrum [0659]
MeOH--methanol [0660] N.sub.2--nitrogen (gas) [0661]
NaCNBH.sub.3--sodium cyanoborohydride [0662]
Na.sub.2CO.sub.3--sodium carbonate [0663] NaHCO.sub.3--sodium
bicarbonate [0664] NaH--sodium hydride [0665] NaI--sodium iodide
[0666] NaBH.sub.4--sodium borohydride [0667] NaOH--sodium hydroxide
[0668] Na.sub.2SO.sub.4--sodium sulfate [0669] NH.sub.4Cl--ammonium
chloride [0670] NH.sub.4OH--ammonium hydroxide [0671]
P(t-bu).sub.3--tri(tert-butyl)phosphine [0672]
Ph.sub.3P--triphenylphosphine [0673] Pd/C--palladium on carbon
[0674] Pd(PPh.sub.3).sub.4--palladium(0)triphenylphosphine tetrakis
[0675]
Pd(dppf)Cl.sub.2--palladium(1,1-bisdiphenylphosphinoferrocene) II
chloride [0676] Pd(PhCN).sub.2Cl.sub.2--palladium di-cyanophenyl
dichloride [0677] Pd(OAc).sub.2--palladium acetate [0678]
Pd.sub.2(dba).sub.3--tris(dibenzylideneacetone) dipalladium [0679]
PyBop--benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium
hexafluorophosphate [0680] RCM--ring-closing metathesis [0681] RT,
rt--room temperature [0682] RBF, rbf--round bottom flask [0683]
TLC, tlc--thin layer chromatography [0684] TBAF--Tetrabutylammonium
flouride [0685]
TBTU--O-benzotriazol-1-yl-N,N,N,N'-tetramethyluronium
tetrafluoroborate [0686] TEA, Et.sub.3N--triethylamine [0687]
TFA--trifluoroacetic acid [0688] THF--tetrahydrofuran [0689]
UV--ultraviolet light
##STR00065##
[0690] Scheme 1-A describes an exemplary method for preparing
intermediate 10, enroute to preparing compounds of Formulas I, II
and III, wherein R.sup.7 is designated as R above and n can be
either 1 or 2. Beginning with starting material 1 (commercially
purchased or prepared), one of ordinary skill in the art may react
it with sodium methanesulfinate to afford the methylsulfonyl
intermediate (not shown. This intermediate can then be treated with
a desired halo-substituted olefin as shown, such as a bromo-butene
for example, in the presence of an appropriate base, such as cesium
carbonate or other suitable basem to provide the olefin adduct 2.
In addition, intermediate 3 (may be commercially purchased or
prepared by known methods in the literature) can be reacted with a
suitable titanium reagent and t-butyl sulfonamide to provide
intermediate 4 shown above. Intermediate 2 can be reacted with
intermediate 4 in the presence of a suitably strong base, such as a
lithium base and trimethyl aluminum to afford adduct 5. Ring
closure product 6 of aduct 5 can be accomplished in to presence of
a suitable acid, such as HCl, and a suitable catalyst, such as the
copper catalyst shown above in scheme 1. The amine of intermediate
6 can be boc protected by conventional methods or as shown, to
provide intermediate 7. The olefin group of boc-intermediate 7 can
be ozonolylated and reduced, and converted to the corresponding
iodine intermediate 8 as shown. Treatment of intermediate 8 with a
strong base, such as the lithium hexamethyl disilazide base as
whon, will afford the bridged ring closured adduct 9. The proton
aalpha to the sulfonyl group can be deprotonated using a strong
base, and the desired R1 group can be installed at this position to
afford product 10 as shown in scheme 1. Additional methods of
preparing intermediates can also be found in the intermediate
experimentals 1-14 described hereinbelow.
##STR00066##
[0691] Scheme 1-B describes an exemplary, alternative method for
preparing stereospecific, boc-protected compounds 10 of Formulas I,
II and III, wherein R.sup.7 is designated as R above and n can be
either 1 or 2. Beginning with compound 1 (See Scheme 1 above) one
of ordinary skill in the art may generate the corresponding OPG
sulfone intermediate 12 via techniques and reagents such as those
described in scheme 1 above, under suitable conditions. Similarly,
intermediate 13 can be generated using conditions as described
hereinabove in scheme 1 to close the ring. Ring closed intermediate
13 can be boc protected as shown in scheme 1, then
boc-amino-intermediate 14 can be converted to the corresponding
iodide 15 as shown, with a strong base, such as LiHMDS, under
suitable conditions to effect ring closed intermediate 16 (the
bridge of intermediate 16 is only one carbon. The present invention
also includes bridges of 2 or 3 carbons, as taught herein). The
desired R.sup.1 group can be installed similar to that taught in
scheme 1, to provide intermediate 10 above. Scheme 3 and 4 herein
further reveal how one may prepared desired R.sup.7-substituted
compounds of Formulas I, II, III and sub-Formulas thereof.
##STR00067## ##STR00068##
[0692] Compounds of Formulas I, II and III, and sub-Formulas
thereof, wherein A.sup.4 is CF, each of A.sup.5, A.sup.6 and
A.sup.8 is, independently CH, each R.sup.1 is H, R.sup.2 is
CH.sub.3 and each R.sup.3 is H, may be prepared as described in
scheme 2 above. The amine of the bromo-alcohol starting material 1
can be first protected with boc using known conditions, and the
protected intermediate (not shown) can be oxidized from the alcohol
to the ketone using conventional conditions, such as the
Dess-Martin periodane method shown above, to afford ketone
intermediate 18. Treatment of 18 with the suitable Grignard reagent
affords intermediate 19. The alcohol of 19 can be used to close the
ring to produce intermediate 20 using the conditions exemplified
above in scheme 2. The olefin of 20 can be converted to the
corresponding alcohol 21 using conventional reducing conditions,
such as borane as shown, and the resulting alcohol can be protected
to afford intermediate 22, as shown. Intermediate 22 can become the
ring closed adduct 23 using suitable oxidizing conditions in the
presence of a suitable catalyst, such as rhuthenium as shown.
Intermediate 23 can be opened to form intermediate 24, which can be
converted to the corresponding thio-ether 25 in the presence of a
suitable base, such as sodium methoxide. The thio-ether 25 can be
oxidized up to the corresponding sulfone using known conditions
such as sodium periodiate and ruthenium chloride. The sulfone ring
of 27 can be closed using a suitable acid, such as HCl, and the
amine can be protected with a suitable protecting group such as boc
by boc-anhydride under known, suitable conditions. Final ring
closure to afford intermediate 28 from intermediate 27 can be
accomplished converted in the alcohol in intermediate 27 to a more
suitable leaving group, such as the mesyl-chloride (not shown) in
the presence of a suitable base, such as cesium carbonate, to
afford the bridge ring closure intermediate 28. The bromide
intermediate 28 can then be used to prepare desired
R.sup.7-substituted compounds of Formulas I, II, III and
sub-Formulas thereof, using methods known in the art, or by the
techniques described hereinbelow in schemes 3 and 4.
##STR00069##
[0693] Scheme 3 describes an exemplary method for preparing
compounds of Formulas I, II, II-A through II-E and III, wherein
A.sup.4 is CF, each of A.sup.5, A.sup.6 and A.sup.8 is,
independently CH, each R.sup.1 is H, R.sup.2 is CH.sub.3 and each
R.sup.3 is H. Beginning with compound 28, the bromide can readily
be converted to the corresponding amino group using convention or
known methods, such as by the method described herein in
Intermediate 8. Then, one of ordinary skill in the art may activate
a desired R.sup.9-carboxylic acid in conjunction with an acid
activating reagent, such as HATU, DCC, TATU, DMTMM and the like
known in the art and commonly used acid activating agents/reagents
(see Example 3-28 and 32 described herein) and react it in the
presence of amine 29 to afford the desired boc-protected
amide-linked adduct 30. Compound 30 can be deprotected using known
conditions (not shown), such as with an acid, like TFA, to afford
final compounds of Formula I, II, II-A and III.
[0694] Acid activating agents convert the OH of the acid into a
strong leaving group "LG." Suitable leaving groups include halides,
such as an iodide, bromide, chloride or fluoride. The LG may also
be a non-halide moiety such as an alkylsulfonate or other known
groups which generally form an electrophilic species (E.sup.+).
Coupling reactions generally occur more readily in one or a
combination of solvents and a base. Suitable solvents include,
without limitation, generally non-nucleophilic, anhydrous solvents
such as toluene, CH.sub.2Cl.sub.2, THF, DMF, N,N-dimethylacetamide,
pyridine and the like. The solvent may range in polarity, as
appreciated by those skilled in the art. Suitable bases include,
for example, tertiary amine bases such as DIEA, TEA, carbonate
bases such as Na.sub.2CO.sub.3, K.sub.2CO.sub.3, Cs.sub.2CO.sub.3,
hydrides such as NaH, KH and the like, alkoxides such as
NaOCH.sub.3, and the like. The base itself may also serve as a
solvent. These coupling reactions are generally fast and conversion
occurs typically in ambient conditions. However, depending upon the
particular substrate, such reactions may require heat, as
appreciated by those skilled in the art.
##STR00070##
[0695] Similarly, and as shown in scheme 4, desired compounds 32 of
Formulas I, II and III can be prepared by treatment from
intermediate amine 29 (see scheme 3) with a desired bicyclic
R.sup.9 group having a suitable leaving group, such as a chloride
(Cl) or other aromatic leaving group, in the presence of a suitable
acid, such as in the presence of sulfuric acid. This allows
coupling of the bicycilc heteroaromatic R.sup.9 group to the amine
to form boc-protected intermediate 31. Intermediate 31 can then be
treated with acid, such as TFA, to afford the desired amine-linked
compounds of Formulas I, II and III, and sub-formulas thereof.
EXAMPLES
[0696] The Examples, described herein below, represent various
exemplary starting materials, intermediates and compounds of
Formulas I-III, which should assist in a better understanding and
appreciation of the scope of the present invention and of the
various methods which may be used to synthesize compounds of
Formulas I-III. It should be appreciated that the general methods
above and specific examples below are illustrative only, for the
purpose of assistance and of understanding the present invention,
and should not be construed as limiting the scope of the present
invention in any manner.
Chromatography:
[0697] Unless otherwise indicated, crude product-containing
residues were purified by passing the crude material or concentrate
through either a Biotage or Isco brand silica gel column
(pre-packed or individually packed with SiO.sub.2) and eluting the
product off the column with a solvent gradient as indicated. For
example a description of (330 g SiO.sub.2, 0-40% EtOAc/Hexane)
means the product was obtained by elution from the column packed
with 330 gms of silica, with a solvent gradient of 0% to 40% EtOAc
in Hexanes.
Preparative HPLC Method:
[0698] Where so indicated, the compounds described herein were
purified via reverse phase HPLC using one of the following
instruments: Shimadzu, Varian, Gilson; utilizing one of the
following two HPLC columns: (a) a Phenomenex Luna or (b) a Gemini
column (5 micron or 10 micron, C18, 150.times.50 mm)
[0699] A typical run through the instrument included: eluting at 45
ml/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v
TFA) in water (0.1% TFA) over 10 minutes; conditions can be varied
to achieve optimal separations.
Proton NMR Spectra:
[0700] Unless otherwise indicated, all .sup.1H NMR spectra were run
on a Bruker series 300 MHz instrument or a Bruker series 400 MHz
instrument. Where so characterized, all observed protons are
reported as parts-per-million (ppm) downfield from
tetramethylsilane (TMS) or other internal reference in the
appropriate solvent indicated.
Mass Spectra (MS)
[0701] Unless otherwise indicated, all mass spectral data for
starting materials, intermediates and/or exemplary compounds are
reported as mass/charge (m/z), having an (M+H.sup.+) molecular ion.
The molecular ion reported was obtained by electrospray detection
method (commonly referred to as an ESI MS) utilizing a PE SCIEX API
150EX MS instrument instrument or an Agilent 1100 series LC/MSD
system. Compounds having an isotopic atom, such as bromine and the
like, are generally reported according to the detected isotopic
pattern, as appreciated by those skilled in the art.
[0702] The compounds disclosed and described herein have been named
using either (1) the naming convention provided with Chem-Draw
Ultra 11.0 software, available in Chem Office, or (2) by the ISIS
database software (Advanced Chemistry Design Labs or ACD
software).
Intermediate 1
##STR00071##
[0703] Synthesis of Imidodicarbonic acid,
2-[(5R)-2-(but-3-en-1-yl)-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dio-
xido-5,6-dihydro-2H-1,4-thiazin-3-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
Step 1: (+/-)-2-(Methylsulfonyl)propanenitrile
[0704] To a suspension of sodium methanesulfinate (8.44 g, 83 mmol)
in DMF (127 mL) was added 2-bromopropionitrile (5.5 mL, 63.6 mmol).
The reaction was stirred at 40.degree. C. After 16 hours, the
reaction mixture was diluted with water (1 L) and extracted with
ethyl acetate. The combined organic layers were washed with water
and brine and concentrated to provide the title compound (8.5 g,
quantitative yield).
Step 2: (+/-)-2-Methyl-2-(methylsulfonyl)hex-5-enenitrile
[0705] To a solution of 2-(methylsulfonyl)propanenitrile (8.47 g,
63.6 mmol) in ACN (200 mL) was added cesium carbonate (26.9 g, 83
mmol) and 4-bromo-1-butene (7.75 mL, 76 mmol). The reaction was
stirred at ambient temperature. After 16 hours, the reaction
mixture was filtered to remove inorganic salts, concentrated, and
partitioned between water and ethyl acetate. The organic layer was
washed with water and brine, dried over anhydrous magensium
sulfate, filtered, and concentrated to provide the title compound
(11.1 g, 93% yield).
Step 3:
(R)--N-((2R)-1-((2-cyanohex-5-en-2-yl)sulfonyl)-2-(2-fluoro-5-nitr-
ophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide
[0706] To a solution of 2-methyl-2-(methylsulfonyl)hex-5-enenitrile
(9.91 g, 52.9 mmol) in THF (100 mL) at -78.degree. C. was added a
2.8 N solution of n-buLi in heptane (18.76 mL, 52.9 mmol), and the
mixture was stirred for 30 minutes at -78.degree. C. Separately, a
solution of
(R,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide (10.1 g, 35.3 mmol) in THF (76 mL) was stirred for 10 minutes
at -78.degree. C. and then added to the sulfone anion via cannula,
and the reaction was stirred at -78.degree. C. for 3 hours. After 3
hours, the reaction was quenched with the addition of saturated
aqueous ammonium chloride and allowed to warm to RT. The reaction
mixture was partitioned between water and ethyl acetate. The
organic layer was concentrated and purified by column
chromagtography, eluting with 30-70% ethyl acetate in heptane, to
provide the title compound as an approximately 1:1 mixture of
diastereomers (8.17 g, 48.9% yield).
Step 4:
(3R)-5-amino-6-(but-3-en-1-yl)-3-(2-fluoro-5-nitrophenyl)-3,6-dime-
thyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0707] To a solution of
(R)--N-((2R)-1-((2-cyanohex-5-en-2-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl-
)propan-2-yl)-2-methylpropane-2-sulfinamide (8.17 g, 17.2 mmol) in
ethanol (100 mL) was added 4 N HCl in 1,4-dioxane (12.9 mL, 51.8
mmol). The reaction was stirred at ambient temperature for 30
minutes, and then concentrated at reduced pressure to about half of
the initial volume. To the reaction was added cuprous chloride (1.8
g, 18 mmol). The flask was sealed and stirred at 85.degree. C. for
two hours. The reaction mixture was concentrated, and the residue
was resuspended in EtOH (100 mL) and stirred at 85.degree. C. for
another 3 hours. The reaction mixture was concentrated and
partitioned between water and ethyl acetate; the aqueous layer was
neutralized with saturated aqueous sodium bicarbonate and extracted
with ethyl acetate. The combined organic layers were filtered
through a pad of silica gel (eluting with ethyl acetate) and
concentrated to provide the title compound as an approximately 1:1
mixture of diastereomers (7.24 g, quantitative yield).
Step 5: Imidodicarbonic acid,
2-[(5R)-2-(but-3-en-1-yl)-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dio-
xido-5,6-dihydro-2H-1,4-thiazin-3-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
[0708] To a solution of
(3R)-5-amino-6-(but-3-en-1-yl)-3-(2-fluoro-5-nitrophenyl)-3,6-dimethyl-3,-
6-dihydro-2H-1,4-thiazine 1,1-dioxide (6.4 g, 17.3 mmol) in DCM (87
mL) was added N,N-diisopropylethylamine (7.53 mL, 43.3 mmol),
di-tert-butyl dicarbonate (9.45 g, 43.3 mmol), and
N,N-dimethylpyridin-4-amine (1.27 g, 10.4 mmol). The reaction was
stirred at ambient temperature for 16 hours, diluted with DCM, and
washed with water (adjusted to pH-8 with HOAc). The resulting
emulsion was filtered through Celite, and the organic layer was
concentrated. The crude product was purified by column
chromatography, eluting with 20-60% ethyl acetate in heptane, to
provide the title compound as an approximately 1:1 mixture of
diastereomers (6.8 g, 68.9% yield). LC/MS (ESI.sup.+) m/z=592.2 D
(M+Na).
Intermediates 2A and 2B
##STR00072##
[0709] Synthesis of imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
Step 1: Imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-hydroxypropyl)-2,5-dimethyl-1,1-d-
ioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0710] To a solution of Intermediate 1 (0.84 g, 1.475 mmol) in DCM
(9.6 mL) and methanol (4.80 mL) was added sodium bicarbonate (0.248
g, 2.95 mmol), and the mixture was cooled to -78.degree. C. Ozone
was bubbled through the stirred reaction until the reaction mixture
turned light blue, and then purged with nitrogen until the color
dissipated. To the reaction was added sodium borohydride (0.112 g,
2.95 mmol), and the reaction was stirred at -78.degree. C. for 15
minutes and then allowed to warm slowly to 0.degree. C. After
stirring at 0.degree. C. for 30 minutes, the reaction was
partitioned between water and DCM; the organic layer was dried over
anhydrous magnesium sulfate, filtered, and concentrated to provide
the title compound as an approximately 1:1 mixture of diastereomers
(0.85 g, quantitative yield).
Step 2: Imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-(4-methylbenzenesulfonyloxy)-prop-
yl)-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0711] To a solution of imidodicarbonic acid,
2-[((5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-hydroxypropyl)-2,5-dimethyl-1,1--
dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester (0.9 g, 1.569 mmol) in DCM (15 mL)
was added triethylamine (0.262 mL, 1.88 mmol) and p-toluenesulfonyl
chloride (0.329 g, 1.73 mmol). The reaction was stirred at RT.
After 16 hours, 4-(N,N-dimethylamino)pyridine (0.019 g, 0.157 mmol)
was added, and the reaction was stirred at ambient temperature for
an additional six hours. The reaction mixture was washed with water
and purified by column chromatography on silica gel, eluting with
20-80% ethyl acetate in heptane, to provide the title compound as a
mixture of diastereomers (0.87 g, 1.195 mmol, 76% yield).
Step 3: Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-nitro-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-nitro-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
[0712] To a -78.degree. C. solution of imidodicarbonic acid,
2-[((5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-(4-methylbenzenesulfonyloxy)-pro-
pyl)-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester (0.87 g, 1.195 mmol) in THF (10
mL) was added a 1 N solution of potassium bis(trimethylsilyl)amide
in THF (1.79 mL, 1.79 mmol). The reaction was stirred at
-78.degree. C. for one hour, quenched with the addition of
saturated aqueous ammonium chloride, and warmed to ambient
temperature. The reaction mixture was partitioned between water and
ethyl acetate, and the crude product was purified by column
chromatography on silica gel, eluting with 20-80% ethyl acetate in
heptane, to provide the title compounds as a mixture of
diastereomers (0.6 g, 90% yield).
Step 4: Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
[0713] To a suspension of imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-nitro-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-nitro-2-fluorophenyl)-1,4-dimethyl-9,9-dioxido-9-thia--
3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester (350 mg, 0.630 mmol) in THF (8 mL) was added 10 wt %
palladium on carbon (134 mg, 0.126 mmol). A balloon filled with
hydrogen was installed, and the reaction vessel was evacuated and
backfilled with hydrogen twice. The reaction was stirred at ambient
temperature under a hydrogen atmosphere. After 16 hours, the
reaction mixture was diluted with THF and filtered through a Celite
plug, which was washed with methanol. The filtrate was concentrated
and purified by column chromatography on silica gel, eluting with
0-60% ethyl acetate in DCM, to provide the title compound (300 mg,
91% yield). LC/MS (ESI.sup.+) m/z=548.2 D (M+Na).
Intermediate 3
##STR00073##
[0714] Synthesis of imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-5-fluoro-1,4-dimethyl-9,9-dioxid-
o-9-thia-3-azabicyclo[3.3.1]non-2-en-2-yl]-,
1,3-bis(1,1-dimethylethyl) ester
Step 1: Imidodicarbonic acid,
2-[(5R)-2-(but-3-en-1-yl)-6-fluoro-5-(2-fluoro-5-nitrophenyl)-2,5-dimethy-
l-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0715] To a solution of Intermediate 1 (1.0 g, 1.76 mmol) in THF
(11.7 mL) at -78.degree. C. was added a 1.0-N solution of lithium
bis(trimethylsilyl)amide in THF (1.84 mL, 1.84 mmol). The reaction
was stirred at -78.degree. C. for 50 minutes, and then a solution
of N-fluorobenzenesulfonimide (0.664 g, 2.11 mmol) in THF (0.5 mL)
was added. The reaction was stirred at -78.degree. C. for 30
minutes, and then allowed to warm to ambient temperature. After 90
minutes, the reaction was quenched with saturated aqueous ammonium
chloride and partitioned between water and ethyl acetate. The
organic layer was concentrated and purified by column
chromatography on silica gel, eluting with 20-60% ethyl acetate in
heptane, to provide the title compound (0.89 g, 86% yield) as a
mixture of diastereomers.
Step 2: Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-5-fluoro-1,4-dimethyl-9,9-dioxid-
o-9-thia-3-azabicyclo[3.3.1]non-2-en-2-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0716] In a series of reactions analogous to those described in
Intermediate 2, Steps 1-4, imidodicarbonic acid,
2-[(5R)-2-(but-3-en-1-yl)-6-fluoro-5-(2-fluoro-5-nitrophenyl)-2,5-dimethy-
l-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester was converted to the title
compound. LC/MS (ESI.sup.+) m/z=566.3 D (M+Na).
Intermediate 4
##STR00074##
[0717] Synthesis of Imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-5-fluoro-1,4-dimethyl-9,9-dioxid-
o-9-thia-3-azabicyclo[3.3.1]non-2-en-2-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0718] Imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-5-fluoro-1,4-dimethyl-9,9-dioxid-
o-9-thia-3-azabicyclo[3.3.1]non-2-en-2-yl]-,
1,3-bis(1,1-dimethylethyl) ester. The title compound was also
isolated from the reaction described in Intermediate 3, Step 2.
LC/MS (ESI.sup.+) m/z=566.2 D (M+Na).
Intermediates 5A and 5B
##STR00075##
[0719] Synthesis of Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-9,9-dioxido-9-th-
ia-3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-9,9-dioxido-9-th-
ia-3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
Step 1: Imidodicarbonic acid,
2-[(5R)-2-(but-3-en-1-yl)-5-(2-fluoro-5-nitrophenyl)-2,5,6-trimethyl-1,1--
dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0720] To a solution of Intermediate 1 (1.0 g, 1.76 mmol) in THF
(11.7 mL) was added a 1.0-N solution of lithium
bis(trimethylsilyl)amide in THF (1.84 mL, 1.84 mmol). The reaction
was stirred at -78.degree. C. for 45 minutes, and then iodomethane
(0.131 mL, 2.11 mmol) was added. The reaction was stirred at
-78.degree. C. for 30 minutes, and then allowed to warm to RT.
After 1 hour, the reaction was quenched with saturated aqueous
ammonium chloride and partitioned between water and ethyl acetate.
The organic layer was concentrated and purified by column
chromatography on silica gel, eluting with 20-60% EtOAc in heptane,
to provide the title compound (1.02 g, 100% yield) as a mixture of
diastereomers.
Step 2: Imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-hydroxypropyl)-2,5,6-trimethyl-1,-
1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0721] In a sequence of reactions analogous to those described in
Intermediate 2, Step 1, imidodicarbonic acid,
2-[(5R)-2-(but-3-en-1-yl)-5-(2-fluoro-5-nitrophenyl)-2,5,6-trimethyl-1,1--
dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester was converted to the title
compound in 96% yield.
Step 3: Imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-iodopropyl)-2,5,6-trimethyl-1,1-d-
ioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester
[0722] To a solution of imidazole (0.337 g, 4.95 mmol) and
triphenylphosphine (0.520 g, 1.981 mmol) in DCM (8 mL) at 0.degree.
C. was added iodine (0.503 g, 1.981 mmol). The reaction was stirred
at 0.degree. C. for 2 minutes, and then a solution of
imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-hydroxypropyl)-2,5,6-trimethyl-1,-
1-dioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester (0.97 g, 1.651 mmol) in DCM (1 mL)
was added. The ice-bath was removed, and the reaction was allowed
to warm to ambient temperature. After 20 minutes, the reaction was
washed with saturated aqueous sodium bisulfite and concentrated.
The crude product was purified by column chromatography on silica
gel, eluting with 20-60% ethyl acetate in heptane, to provide the
title compound (0.85 g, 73.8% yield) as a mixture of
diastereomers.
Step 4: Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-9,9-dioxido-9-th-
ia-3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-9,9-dioxido-9-th-
ia-3-azabicyclo[3.3.1]non-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
[0723] In a sequence of reactions analogous to those described in
Intermediate 2, Step 3-4, imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(3-iodopropyl)-2,5,6-trimethyl-1,1-d-
ioxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-,
1,3-bis(1,1-dimethylethyl) ester was converted to the title
compounds. LC/MS (ESI.sup.+) m/z=562.3 D (M+Na).
Intermediate 6
##STR00076##
[0724] Synthesis of
(2S,3R)-5-Amino-3-(5-bromo-2-fluorophenyl)-2-(3-hydroxypropyl)-3-methyl-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
Step 1: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-1-oxopropan-2-yl)carbamate
[0725] To a solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-hydroxypropan-2-yl)carbamate (18.6 g,
53.4 mmol) in DCM (200 mL) at 0.degree. C. was added Dess-Martin
periodinane (24.9 g, 58.8 mmol) portionwise. The mixture was
stirred at 0.degree. C. for 10 minutes and at ambient temperature
for 90 minutes. After 90 minutes, the reaction was quenched with
the addition of saturated aqueous sodium bicarbonate and saturated
aqueous sodium bisulfite. Ether (50 mL) was added, and the reaction
was stirred for 30 minutes at ambient temperature. The layers were
separated, and the aqueous layer was extracted with ether. The
combined organic layers were dried over anhydrous magnesium
sulfate, filtered, and concentrated. The crude product was purified
by column chromatography on silica gel, eluting with 20-80% ethyl
acetate in heptane, to provide the title compound (14.6 g, 79%
yield).
Step 2: tert-Butyl
((2R)-2-(5-bromo-2-fluorophenyl)-3-hydroxyhex-5-en-2-yl)carbamate
[0726] To a solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-oxopropan-2-yl)carbamate (8.8 g, 25.4
mmol) in THF (100 mL) at 0.degree. C. was added a 2-N solution of
allylmagnesium chloride in THF (25.4 mL, 50.8 mmol) dropwise. The
mixture was stirred at 0.degree. C. for 15 minutes and at RT for 30
minutes. After 30 minutes, the reaction mixture was concentrated
and partitioned between water and ethyl acetate; the organic layer
was washed with brine, dried over anhydrous magnesium sulfate,
filtered, and concentrated to provide the title compound (9.6 g,
97% yield) as a mixture of diastereomers.
Step 3: (4R)-tert-Butyl
5-allyl-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carbo-
xylate 2-oxide
[0727] A solution of tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-3-hydroxyhex-5-en-2-yl)carbamate
(7.7 g, 19.8 mmol) in DCM (66 mL) was added dropwise to pre-cooled
mixture of pyridine (8.09 mL, 99 mmol) and thionyl chloride (2.89
mL, 39.7 mmol) at 0.degree. C. The mixture was allowed to warm to
RT. After 2 hours, the reaction mixture was partitioned between
water and DCM. The aqueous layer was extracted with DCM, and the
combined organic layers were concentrated and purified by column
chromatography on silica gel, eluting with 0-80% ethyl acetate in
DCM, to provide the title compound (7.85 g, 91% yield) as a mixture
of diastereomers.
Step 4: (4R)-tert-Butyl
4-(5-bromo-2-fluorophenyl)-5-(3-hydroxypropyl)-4-methyl-1,2,3-oxathiazoli-
dine-3-carboxylate 2-oxide
[0728] To a solution of (4R)-tert-butyl
5-allyl-4-(5-bromo-2-fluorophenyl)-4-methyl-1,2,3-oxathiazolidine-3-carbo-
xylate 2-oxide (0.2 g, 0.46 mmol) in THF (2 mL) at 0.degree. C. was
added a 1-M solution of borane in THF (0.55 mL, 0.55 mmol). The
mixture was allowed to warm to ambient temperature. After stirring
for 2 hours, a 3 N aqueous solution of NaOH (0.92 mL, 2.8 mmol) and
30% hydrogen peroxide in water (0.28 mL, 2.8 mmol) were added
dropwise. The reaction was stirred at ambient temperature for 2
hours, and then partitioned between water and ethyl acetate. The
organic layer was concentrated, and the crude product was purified
by column chromatography on silica gel, eluting with 0-100% ethyl
acetate in DCM, to provide the title compound (2.8 g, 42.2% yield)
as a mixture of diastereomers.
Step 5: tert-Butyl
((2R)-2-(5-bromo-2-fluorophenyl)-6-((tert-butyldimethylsilyl)oxy)-3-hydro-
xyhexan-2-yl)carbamate
[0729] To a solution of (4R)-tert-butyl
4-(5-bromo-2-fluorophenyl)-5-(3-hydroxypropyl)-4-methyl-1,2,3-oxathiazoli-
dine-3-carboxylate 2-oxide (84 mg, 0.207 mmol) and imidazole (15.48
mg, 0.227 mmol) in DCM (2 mL) was added
tert-butyldimethylchlorosilane (0.227 mL, 0.227 mmol). The mixture
was stirred at ambient temperature. After 1 hour, the reaction
mixture was partitioned between ethyl acetate and saturated aqueous
sodium bicarbonate. The organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated to provide the title
compound (0.15 g, quantitative yield) as a mixture of
diastereomers.
Step 6: (4R)-tert-Butyl
4-(5-bromo-2-fluorophenyl)-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-m-
ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide
[0730] A solution of tert-butyl
((2R)-2-(5-bromo-2-fluorophenyl)-6-((tert-butyldimethylsilyl)oxy)-3-hydro-
xyhexan-2-yl)carbamate (3.6 g, 6.92 mmol) in DCM (25 mL) was added
dropwise to pre-cooled mixture of pyridine (2.8 mL, 34.6 mmol) and
thionyl chloride (1.0 mL, 13.8 mmol) at 0.degree. C. The mixture
was stirred at RT for 1 hour, and then partitioned between water
and DCM. The aqueous layer was extracted with DCM, and the combined
organic layers were washed with aqueous copper sulfate, water, and
brine, and concentrated. The residue was redissolved in ACN (20
mL), and sodium meta-periodate (1.48 g, 6.92 mmol) was added,
followed by a solution of ruthenium (III) chloride hydrate (0.078
g, 0.346 mmol) in water (10 mL). The reaction was stirred at
ambient temperature. After 20 minutes, the reaction was partitioned
between water and DCM; the organic layer was filtered through a
silica-gel pad (eluting with DCM) and concentrated to the title
compound (2.75 g, 68.3% yield) as a mixture of diastereomers.
Step 7:
S-((9R)-9-(5-Bromo-2-fluorophenyl)-2,2,3,3,9,13,13-heptamethyl-11--
oxo-4,12-dioxa-10-aza-3-silatetradecan-8-yl) ethanethioate
[0731] To a solution of (4R)-tert-butyl
4-(5-bromo-2-fluorophenyl)-5-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-m-
ethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.66 g, 2.85
mmol) in DMF (15 mL) was added potassium thioacetate (3.25 g, 28.5
mmol). The reaction was stirred at 80.degree. C. After 90 minutes,
the reaction mixture was partitioned between water and 1:1 ethyl
acetate/heptane. The organic layer was concentrated, and the crude
product was purified by column chromatography on silica gel,
eluting with 5-50% ethyl acetate in heptanes, to provide the title
compound (1.1 g, 66.7% yield) as a mixture of diastereomers.
Step 8: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-6-((tert-butyldimethylsilyl)oxy)-3-((cyanomet-
hyl)thio)hexan-2-yl)carbamate
[0732] To a solution of
(R)--S-(9-(5-bromo-2-fluorophenyl)-2,2,3,3,9,13,13-heptamethyl-11-oxo-4,1-
2-dioxa-10-aza-3-silatetradecan-8-yl) ethanethioate (1.1 g, 1.9
mmol) in methanol (10 mL) was added a 0.5-M solution of sodium
methoxide in methanol (3.8 mL, 1.9 mmol). The mixture was stirred
at ambient temperature for 10 minutes, and then 2-bromoacetonitrile
(0.16 mL, 2.28 mmol) was added. The reaction was stirred at ambient
temperature for another 40 minutes and concentrated. The crude
product was purified by column chromatography on silica gel,
eluting with 5-50% ethyl acetate in heptane, to provide the title
compound (0.55 g, 50.3% yield) as a mixture of diastereomers.
Step 9: (R)-tert-Butyl
(2-(5-bromo-2-fluorophenyl)-6-((tert-butyldimethylsilyl)oxy)-3-((cyanomet-
hyl)sulfonyl)hexan-2-yl)carbamate
[0733] To a solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-6-((tert-butyldimethylsilyl)oxy)-3-((cyanomet-
hyl)thio)hexan-2-yl)carbamate (0.55 g, 0.955 mmol) in ACN (5 mL) at
0.degree. C. was added sodium periodate (0.409 g, 1.911 mmol),
followed by a solution of ruthenium (III) chloride hydrate (4.3 mg,
0.019 mmol) in water (2.500 mL). The mixture was stirred at
0.degree. C. for 5 minutes, and then diluted with water, quenched
with aqueous sodium thiosulfate, and extracted with DCM. The
organic layer was passed through a silica-gel pad and concentrated
to provide the title compound (0.534 g, 92% yield) as a mixture of
diastereomers.
Step 10:
(2S,3R)-5-amino-3-(5-bromo-2-fluorophenyl)-2-(3-hydroxypropyl)-3--
methyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0734] To a solution of (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-6-((tert-butyldimethylsilyl)oxy)-3-((cyanomet-
hyl)sulfonyl)hexan-2-yl)carbamate (0.534 g, 0.879 mmol) in
1,4-dioxane (5 mL) was added a 4-N solution of hydrochloric acid in
1,4-dioxane (2.2 mL, 8.8 mmol). The reaction mixture was stirred at
90.degree. C. for 2 hours, concentrated, and partitioned between
ethyl acetate and saturated aqueous sodium bicarbonate. The organic
layer was concentrated, and the crude product was purified by
column chromatography on silica gel, eluting with 0-10% methanol in
DCM, to provide the title compound (140 mg, 40.5% yield). LC/MS
(ESI.sup.+) m/z=393.0, 395.0 D (M+H; two bromine isotopes).
Intermediate 7
##STR00077##
[0735] Synthesis of
(2R,3R)-5-Amino-3-(5-bromo-2-fluorophenyl)-2-(3-hydroxypropyl)-3-methyl-3-
,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0736] The title compound was also isolated from the reaction
described in Intermediate 6, Step 10 (60 mg, 17.4% yield). LC/MS
(ESI.sup.+) m/z=393.0, 395.0 D (M+H; two bromine isotopes).
Intermediate 8
##STR00078##
[0737] Synthesis of tert-Butyl
((1S,4R,5R)-4-(5-amino-2-fluorophenyl)-4-methyl-9,9-dioxido-9-thia-3-azab-
icyclo[3.3.1]non-2-en-2-yl)carbamate
Step 1: tert-Butyl
((5R,6R)-5-(5-bromo-2-fluorophenyl)-6-(3-hydroxypropyl)-5-methyl-1,1-diox-
ido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate
[0738] To a solution of Intermediate 7 (140 mg, 0.356 mmol) in
1,4-dioxane (2 mL) was added a solution of sodium bicarbonate (35.9
mg, 0.427 mmol) in water (0.4 mL), followed by di-tert-butyl
dicarbonate (93 mg, 0.427 mmol). The mixture was stirred at RT for
16 hours, and then partitioned between water and EtOAc. The organic
layer was concentrated to provide the title compound (200 mg,
quantitative yield).
Step 2:
3-((2R,3R)-3-(5-Bromo-2-fluorophenyl)-5-((tert-butoxycarbonyl)amin-
o)-3-methyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-2-yl)propyl
methanesulfonate
[0739] To a solution of tert-butyl
((5R,6R)-5-(5-bromo-2-fluorophenyl)-6-(3-hydroxypropyl)-5-methyl-1,1-diox-
ido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate (175 mg, 0.355 mmol)
in DCM (3 mL) was added pyridine (0.087 mL, 1.064 mmol), followed
by methanesulfonyl chloride (0.041 mL, 0.532 mmol). The mixture was
stirred at RT for 16 hours, and then partitioned between water and
ethyl acetate. The organic layer was concentrated to provide the
title compound (220 mg, quantitative yield).
Step 3: tert-Butyl
((1S,4R,5R)-4-(5-bromo-2-fluorophenyl)-4-methyl-9,9-dioxido-9-thia-3-azab-
icyclo[3.3.1]non-2-en-2-yl)carbamate
[0740] To a solution of
3-((2R,3R)-3-(5-bromo-2-fluorophenyl)-5-((tert-butoxycarbonyl)amino)-3-me-
thyl-1,1-dioxido-3,6-dihydro-2H-1,4-thiazin-2-yl)propyl
methanesulfonate (200 mg, 0.350 mmol) in acetonitrile (5 mL) was
added cesium carbonate (342 mg, 1.050 mmol). The mixture was
stirred at RT for 48 hours, and then partitioned between water and
ethyl acetate. The organic layer was concentrated, and the crude
product was purified by column chromatography on silica gel,
eluting with 20-80% ethyl acetate in heptane, to provide the title
compound (166 mg, 100% yield).
Step 4: tert-Butyl
((1S,4R,5R)-4-(5-amino-2-fluorophenyl)-4-methyl-9,9-dioxido-9-thia-3-azab-
icyclo[3.3.1]non-2-en-2-yl)carbamate
[0741] A microwave vial was charged with copper (I) iodide (12.8
mg, 0.067 mmol), sodium azide (65 mg, 1.01 mmol), (+)-sodium
1-ascorbate (13 mg, 0.067 mmol), and tert-butyl
((1S,4R,5R)-4-(5-bromo-2-fluorophenyl)-4-methyl-9,9-dioxido-9-thia-3-azab-
icyclo[3.3.1]non-2-en-2-yl)carbamate (160 mg, 0.337 mmol). Water (1
mL), ethanol (2.3 mL), and
trans-N,N'-dimethyl-1,2-cyclohexanediamine (0.021 mL, 0.135 mmol),
were added, the vial was capped, and the reaction was irradiated at
50.degree. C. for 60 minutes. The reaction mixture was partitioned
between water and ethyl acetate. The organic layer was passed
through a silica-gel pad (eluting with ethyl acetate), and the
filtrate was concentrated. The residue was redissolved in THF (3
mL) and water (1 mL), and a 1-M solution of trimethylphosphine in
THF (0.34 mL, 0.34 mmol) was added. The reaction was stirred for 45
minutes at ambient temperature, and then partitioned between water
and ethyl acetate. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
crude product was purified by column chromatography on silica gel,
eluting with 50-100% ethyl acetate in heptane, to provide the title
compound (96 mg, 69.4% yield). LC/MS (ESI.sup.+) m/z=412.1 D
(M+H).
Intermediate 9
##STR00079##
[0742] Synthesis of tert-Butyl
((1R,4R,5S)-4-(5-amino-2-fluorophenyl)-4-methyl-9,9-dioxido-9-thia-3-azab-
icyclo[3.3.1]non-2-en-2-yl)carbamate
[0743] The titled compound was prepared in a series of reactions
analogous to those described in Intermediate 7, Steps 1-4, using
Intermediate 5. LC/MS (ESI.sup.+) m/z=412.1 D (M+H).
Intermediate 10
##STR00080##
[0744] Synthesis of tert-Butyl
((1S,4R,5R)-4-(5-amino-2-fluorophenyl)-4-methyl-8,8-dioxido-8-thia-3-azab-
icyclo[3.2.1]oct-2-en-2-yl)carbamate
Step 1:
(2R,3R)-5-Amino-3-(5-bromo-2-fluorophenyl)-2-(3-hydroxyethyl)-3-me-
thyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0745] In a series of reactions analogous to those described in
Intermediate 6, Steps 1-10, (R)-tert-butyl
(2-(5-bromo-2-fluorophenyl)-1-oxopropan-2-yl)carbamate and
vinylmagnesium bromide were converted to the title compound.
Step 2: tert-Butyl
((1S,4R,5R)-4-(5-amino-2-fluorophenyl)-4-methyl-8,8-dioxido-8-thia-3-azab-
icyclo[3.2.1]oct-2-en-2-yl)carbamate
[0746] In a series of reactions analogous to those described in
Intermediate 8, Steps 1-4,
(2R,3R)-5-amino-3-(5-bromo-2-fluorophenyl)-2-(3-hydroxyethyl)-3-methyl-3,-
6-dihydro-2H-1,4-thiazine 1,1-dioxide was converted to the title
compound. LC/MS (ESI.sup.+) m/z=398.1 D (M+H).
Intermediate 11
##STR00081##
[0747] Synthesis of Imidodicarbonic acid,
2-[(5R)-2-allyl-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dioxido-5,6-d-
ihydro-2H-1,4-thiazin-3-yl)]-, 1,3-bis(1,1-dimethylethyl) ester
Step 1: (+/-)-2-Methyl-2-(methylsulfonyl)pent-4-enenitrile
[0748] In an analogous reaction to that described for Intermediate
1, step 2, 2-(methylsulfonyl)propanenitrile and allyl bromide were
converted into the title.
Step 2:
(R)--N-((2R)-1-((2-Cyanopent-4-en-2-yl)sulfonyl)-2-(2-fluoro-5-nit-
rophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide
[0749] To a solution of
2-methyl-2-(methylsulfonyl)pent-4-enenitrile (0.91 g, 5.24 mmol) in
THF (14 mL) at -78.degree. C. was added a 2.7-N solution of
n-butyllithium in heptane (1.94 mL, 5.24 mmol) dropwise. The
reaction was stirred at -78.degree. C. for 30 minutes. In a
separate flask, a solution of
(R,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide (1 g, 3.49 mmol) in THF (15 mL) was cooled to -78.degree. C.
and added to the n-butyllithium solution via cannula. The reaction
was stirred at -78.degree. C. for 5 hours, quenched with saturated
ammonium chloride, and then warmed to 0.degree. C. The reaction
mixture was diluted with water and stirred at RT for 20 minutes,
and then partitioned between water and ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium sulfate,
filtered, and concentrated. The crude product was purified by
column chromatography on silica gel, eluting with 0-30% (3:1 ethyl
acetate:ethanol, 2% ammonium hydroxide) in heptanes, to provide the
title compound (0.88 g, 55% yield). LC/MS (ESI.sup.+) m/z=460.1
(M+H).
Step 3:
(3R)-6-Allyl-5-amino-3-(2-fluoro-5-nitrophenyl)-3,6-dimethyl-3,6-d-
ihydro-2H-1,4-thiazine 1,1-dioxide
[0750] To a solution of
(R)--N-((2R)-1-(2-cyanopent-4-en-2-yl)sulfonyl)-2-(2-fluoro-5-nitrophenyl-
)propan-2-yl)-2-methylpropane-2-sulfinamide (0.88 g, 1.92 mmol) in
dichloromethane (4.8 mL) and methanol (1.6 mL) was added a 4-N
solution of hydrochloric acid in dioxane (2.9 mL, 11.5 mmol) and
the reaction was stirred at RT for 2 hours. The reaction was then
concentrated, diluted with toluene, and reconcentrated. The residue
was redissolved in ethanol (12 mL) and transferred to a pressure
vessel. To this solution was added copper (I) chloride (0.20 g, 2.0
mmol) and the flask was sealed and stirred at 85.degree. C. for 4
hours. After cooling to ambient temperature, the reaction was
partitioned between water and ethyl acetate. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated, to provide the title compound (0.680 g,
quantitative yield). The isolated product was used in the next step
without further purification. LC/MS (ESI.sup.+) m/z=356.1
(M+H).
Step 4: Imidodicarbonic acid,
2-[(5R)-2-allyl-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dioxido-5,6-d-
ihydro-2H-1,4-thiazin-3-yl)]-, 1,3-bis(1,1-dimethylethyl) ester
[0751] To a solution of
(3R)-6-allyl-5-amino-3-(2-fluoro-5-nitrophenyl)-3,6-dimethyl-3,6-dihydro--
2H-1,4-thiazine 1,1-dioxide (0.68 g, 1.9 mmol) in DCM (6.4 mL) was
added di-tert-butyl dicarbonate (0.877 g, 4.0 mmol),
N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), and
N,N-dimethylpyridin-4-amine (0.070 g, 0.574 mmol), and the reaction
was stirred at ambient temperature for 1.5 hours. The reaction was
partitioned between water and ethyl acetate; the organic layer was
washed with brine, dried over anhydrous sodium sulfate, filtered,
and concentrated. The crude product was purified by column
chromatography on silica gel, eluting with 0-50% ethyl acetate in
heptanes, to provide the title compound (0.60 g, 56.4% yield).
LC/MS (ESI) m/z=578.2 (M+Na).
Intermediate 12
##STR00082##
[0752] Synthesis of Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-8,8-dioxido-8-thia--
3-azabicyclo[3.2.1]oct-2-en-2-yl)]-, 1,3-bis(1,1-dimethylethyl)
ester
Step 1: Imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dioxido-2-(2-oxoethyl-
)-5,6-dihydro-2H-1,4-thiazin-3-yl)]-, 1,3-bis(1,1-dimethylethyl)
ester
[0753] A solution of Intermediate 11 (3.1 g, 5.58 mmol) in
dichloromethane (18.60 mL) was cooled to -78.degree. C. and an
ozone/oxygen mixture was bubbled through the solution until the
reaction turned blue. Nitrogen was then bubbled through the
reaction until blue color disappeared. Triphenylphosphine (1.76 g,
6.70 mmol) was added and the mixture was stirred for 10 min at
-78.degree. C. and then allowed to reach room temperature. The
solution was concentrated, and the crude product was purified by
column chromatography on silica gel, eluting with 10-80% ethyl
acetate in heptanes, to provide the title compound (3.0 g, 96%
yield). LC/MS (ESI.sup.+) m/z=580.1 (M+Na).
Step 2: Imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(2-hydroxyethyl)-2,5-dimethyl-1,1-di-
oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)]-,
1,3-bis(1,1-dimethylethyl) ester
[0754] To a solution of imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dioxido-2-(2-oxoethyl-
)-5,6-dihydro-2H-1,4-thiazin-3-yl]-, 1,3-bis(1,1-dimethylethyl)
ester (3.0 g, 5.38 mmol) in THF (18 mL) at 0.degree. C. was added a
1 M solution of borane tetrahydrofuran complex in THF (8.07 mL,
8.07 mmol) dropwise. The mixture was stirred for 10 min at
0.degree. C., and then carefully quenched with aqueous saturated
ammonium chloride. The reaction was partitioned between water and
ethyl acetate. The organic layer was washed with water, brine, and
concentrated to afford the title compound (2.58 g, 86% yield) which
was used without further purification for the next step. LC/MS
(ESI.sup.+) m/z=582.2 (M+Na).
Step 3:
2-((5R)-3-((1,1-Bis-tert-butoxycarbonyl)amino)-5-(2-fluoro-5-nitro-
phenyl)-2,5-dimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-2-yl)ethyl
4-methylbenzenesulfonate
[0755] To a solution of imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2-(2-hydroxyethyl)-2,5-dimethyl-1,1-di-
oxido-5,6-dihydro-2H-1,4-thiazin-3-yl]-, 1,3-bis(1,1-dimethylethyl)
ester (2.58 g, 4.61 mmol) in DCM (15 mL) was added triethylamine
(1.29 mL, 9.22 mmol), p-toluenesulfonyl chloride (1.76 g, 9.22
mmol) and N,N-dimethylpyridin-4-amine (0.28 g, 2.3 mmol). The
reaction was stirred at RT for 1 hour, and partitioned between
water and dichloromethane. The organic layer was washed with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated.
The crude product was purified by column chromatography on silica
gel, eluting with 0-50% ethyl acetate in heptanes, to provide the
title compound (2.15 g, 65.3% yield). LC/MS (ESI.sup.+) m/z=736.2
(M+Na).
Step 4: Imidodicarbonic acid,
2-[(4R)-4-(2-fluoro-5-nitrophenyl)-1,4-dimethyl-8,8-dioxido-8-thia-3-azab-
icyclo[3.2.1]oct-2-en-2-yl)]-, 1,3-bis(1,1-dimethylethyl) ester
[0756] To a solution of 2-((5R)-3-((1,1-bis
tert-butoxycarbonyl)amino)-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-di-
oxido-5,6-dihydro-2H-1,4-thiazin-2-yl)ethyl
4-methylbenzenesulfonate (2.15 g, 3.01 mmol) in THF (25 mL) at
-78.degree. C. was added a 1-M solution of lithium
bis(trimethylsilyl)amide in THF (4.5 mL, 4.5 mmol). The reaction
was stirred at -78.degree. C. for 1.5 hours, quenched with the
addition of saturated aqueous ammonium chloride, and warmed to RT.
The reaction was partitioned between water and ethyl acetate, and
the organic layer was washed with brine, dried over anhydrous
sodium sulfate, filtered, and concentrated to provide the title
compound (1.5 g, 92% yield). The crude product was used in the next
reaction without further purification. LC/MS (ESI.sup.+) m/z=564.2
(M+Na).
Step 5: Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-8,8-dioxido-8-thia--
3-azabicyclo[3.2.1]oct-2-en-2-yl)]-, 1,3-bis(1,1-dimethylethyl)
ester
[0757] A RBF was charged with imidodicarbonic acid,
2-[(4R)-4-(2-fluoro-5-nitrophenyl)-1,4-dimethyl-8,8-dioxido-8-thia-3-azab-
icyclo[3.2.1]oct-2-en-2-yl)]-, 1,3-bis(1,1-dimethylethyl) ester
(1.5 g, 2.77 mmol) and palladium on carbon (10% by weight) (0.295
g, 0.277 mmol). Ethyl acetate was added (6.9 mL) followed by
addition of methanol (6.9 mL), and the flask was purged with
nitrogen. It was then evacuated and filled with hydrogen, and the
reaction was stirred at RT under a hydrogen atmosphere for 4 hours.
The mixture was filtered through Celite and washed with a
methanol/ethyl acetetate mixture. The filtrate was concentrated and
purified by reversed-phase HPLC on an 18.times.100 mm Waters
xBridge C18 column, 10-micron pore size. The flow rate was 40
mL/min, eluting with 25-100% (1% TFA in acetonitrile) in (1% TFA in
water). The product fractions were combined, neutralized with
aqueous sodium carbonate, and extracted into EtOAc. The organic
layer was washed with aqueous sodium carbonate, dried over
anhydrous sodium sulfate, filtered, and concentrated to provide the
title compound (266 mg, 0.52 mmol) as a white solid. LC/MS
(ESI.sup.+) m/z=534.2 (M+Na).
Intermediate 13
##STR00083##
[0758] Synthesis of Imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-1,4-dimethyl-8,8-dioxido-8-thia--
3-azabicyclo[3.2.1]oct-2-en-2-yl)]-, 1,3-bis(1,1-dimethylethyl)
ester
[0759] The title compound (120 mg, 0.235 mmol) was also isolated
from the reaction described in Intermediate 12, Step 5. LC/MS
(ESI.sup.+) m/z=534.2 (M+Na).
Intermediates 14A and 14B
##STR00084##
[0760] Synthesis of Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-8,8-dioxido-8-th-
ia-3-azabicyclo[3.2.1]oct-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-8,8-dioxido-8-th-
ia-3-azabicyclo[3.2.1]oct-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
Step 1:
(R)--N-((2R)-1-((2-Cyanopent-4-en-2-yl)sulfonyl)-2-(2-fluoro-5-nit-
rophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide
[0761] To a solution of
2-methyl-2-(methylsulfonyl)pent-4-enenitrile (7.8 g, 45.0 mmol) in
2-methyltetrahydrofuran (40 mL) under nitrogen at -75.degree. C.
was added a 1.6-M solution of n-butyllithium in hexane (28.9 mL,
46.2 mmol) dropwise. The mixture was stirred at -75.degree. C. for
30 minutes. Separately, a solution of
(R,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide (6.79 g, 23.70 mmol) in toluene was cooled to -35 to
-40.degree. C. and a 2.0 M solution of trimethylaluminum in toluene
(11.85 mL, 23.70 mmol) was added dropwise. The resulting mixture
was stirred for 15 min and transferred via cannula to the first
solution. The reaction mixture was stirred at -75.degree. C. for 2
hrs, and then quenched with brine (50 mL) and water (50 mL) and
warmed to RT. The mixture was extracted with ethyl acetate. The
combined organic extracts were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The crude
product was purified by silica-gel column chromatography, eluting
with 10% to 60% ethyl acetate in hexane, to provide the title
compound (9.3 g, 20.24 mmol, 85% yield) as light-yellow solid.
Step 2: Imidodicarbonic acid,
2-[(5R)-2-allyl-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dioxido-5,6-d-
ihydro-2H-1,4-thiazin-3-yl)]-, 1,3-bis(1,1-dimethylethyl) ester
[0762] Following the sequence of reactions described in
Intermediate 11, Steps 3-4,
(R)--N-((2R)-1-((2-cyanopent-4-en-2-yl)sulfonyl)-2-(2-fluoro-5-nitropheny-
l)propan-2-yl)-2-methylpropane-2-sulfinamide was converted to the
title compound.
Step 3: Imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2,5,6-trimethyl-1,1-dioxido-2-(2-oxoet-
hyl)-5,6-dihydro-2H-1,4-thiazin-3-yl)]-, 1,3-bis(1,1-dimethylethyl)
ester
[0763] To a solution of imidodicarbonic acid,
2-[(5R)-2-allyl-5-(2-fluoro-5-nitrophenyl)-2,5-dimethyl-1,1-dioxido-5,6-d-
ihydro-2H-1,4-thiazin-3-yl]-, 1,3-bis(1,1-dimethylethyl) ester
(2.01 g, 3.62 mmol) in THF (24 mL) at -78.degree. C. was added a
1-M solution of lithium bis(trimethylsilyl)amide in THF (3.80 mL,
3.80 mmol) and the solution was stirred at -78.degree. C. for 45
minutes. Iodomethane (0.270 mL, 4.34 mmol) was added and the
mixture was stirred at -78.degree. C. for 30 minutes. The reaction
was quenched with water and extracted with ethyl acetate. The
combined extracts were washed with brine, dried and concentrated.
The residue was redissolved in DCM (30 mL) and cooled to
-78.degree. C. A flow of ozone/oxygen mixture was bubbled through
the solution until the reaction turned blue. Nitrogen was then
bubbled through the reaction until blue color disappeared.
Triphenylphosphine (1.13 g, 4.30 mmol) was added and the mixture
was stirred for 5 minutes at -78.degree. C. and then allowed to
warm to ambient temperature. The mixture was concentrated and
purified by silica-gel column chromatography, eluting with 10-70%
ethyl acetate in heptanes, to provide the title compound (1.929 g,
94% yield).
Step 4:
2-((5R)-3-(bis(tert-butoxycarbonyl)amino)-5-(2-fluoro-5-nitropheny-
l)-2,5,6-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-2-yl)ethyl
4-methylbenzenesulfonate
[0764] To a solution of imidodicarbonic acid,
2-[(5R)-5-(2-fluoro-5-nitrophenyl)-2,5,6-trimethyl-1,1-dioxido-2-(2-oxoet-
hyl)-5,6-dihydro-2H-1,4-thiazin-3-yl]-, 1,3-bis(1,1-dimethylethyl)
ester (1.929 g, 3.37 mmol) in THF (17 mL) at 0.degree. C. was added
a 1 M solution of borane tetrahydrofuran complex in THF (5.06 mL,
5.06 mmol) dropwise. The mixture was stirred for 10 minutes at
0.degree. C. The reaction was carefully quenched with saturated
aqueous ammonium chloride, diluted with water, and extracted with
ethyl acetate. The organic layer was washed with water and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated.
The residue was redissolved in dichloromethane (34 mL), and
triethylamine (0.940 mL, 6.75 mmol), p-toluenesulfonyl chloride
(1.286 g, 6.75 mmol) and N,N-dimethylpyridin-4-amine (0.206 g,
1.687 mmol) were added. The mixture was stirred at RT for 16 hours
and then concentrated. The crude product was purified by silica-gel
column chromatography, eluting with 5-50% ethyl acetate in
heptanes, to provide the title (2.24 g, 91% yield).
Step 5: Imidodicarbonic acid,
2-[(4R)-4-(2-fluoro-5-nitrophenyl)-1,4,5-trimethyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
[0765] To a solution of
2-((5R)-3-(bis(tert-butoxycarbonyl)amino)-5-(2-fluoro-5-nitrophenyl)-2,5,-
6-trimethyl-1,1-dioxido-5,6-dihydro-2H-1,4-thiazin-2-yl)ethyl
4-methylbenzenesulfonate (0.52 g, 0.714 mmol) in THF (4.8 mL) at
-78.degree. C. was added a 1 M solution of potassium
bis(trimethylsilyl)amide in THF (0.93 mL, 0.93 mmol). The reaction
was stirred at -78.degree. C. for 30 minutes, and then quenched
with saturated aqueous ammonium chloride and warmed to RT. The
reaction mixture was partitioned between water and ethyl acetate.
The organic layer was concentrated and purified by silica-gel
column chromatography, eluting with 5-50% ethyl acetate in heptane,
to provide the title compound (0.26 g, 65.5% yield).
Step 6: Imidodicarbonic acid,
2-[(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-8,8-dioxido-8-th-
ia-3-azabicyclo[3.2.1]oct-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester and imidodicarbonic acid,
2-[(1S,4R,5R)-4-(5-amino-2-fluorophenyl)-1,4,5-trimethyl-8,8-dioxido-8-th-
ia-3-azabicyclo[3.2.1]oct-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl)
ester
[0766] To a solution of imidodicarbonic acid,
2-[(4R)-4-(2-fluoro-5-nitrophenyl)-1,4,5-trimethyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-2-en-2-yl]-, 1,3-bis(1,1-dimethylethyl) ester
(0.26 g, 0.468 mmol) in ethyl acetate (2.3 mL) was added 10% (w/w)
palladium on carbon (0.050 g, 0.047 mmol). A hydrogen balloon was
installed, the flask was evacuated and filled with hydrogen, and
the reaction mixture was stirred at RT under hydrogen atmosphere
for 17 hours. The reaction mixture was filtered through Celite and
the filter cake was washed with ethyl acetate. The filtrate was
concentrated and purified by silica-gel column chromatography,
eluting with 0.5% to 5% methanol in DCM, to provide the title
compounds (0.218 g, 89% yield).
Intermediate 15
##STR00085##
[0767] Synthesis of 3,8-Dichloro-1,7-naphthyridine
Step 1: 3-Bromo-5-chloropicolinonitrile
[0768] A microwave vial was charged with copper (I) cyanide (1.089
g, 12.16 mmol), 2,3-dibromo-5-chloropyridine (3 g, 11.06 mmol), and
propionitrile (15 mL). The vial was capped and irradiated in a
microwave reactor at 150.degree. C. for 2.5 hours. The solution was
concentrated, diluted with DCM (25 mL), and filtered. The filtrate
was concentrated, and the residue was purified by silica gel
chromatography, eluting with 0-30% EtOAc in heptanes, to afford the
title compound (2 g, 9.20 mmol). MS m/z=219 (M+H).
Step 2: 5-Chloro-3-((trimethylsilyl)ethynyl)picolinonitrile
[0769] A pressure vessel was charged with triethylamine (7.65 mL,
55.2 mmol), ethynyltrimethylsilane (2.32 mL, 16.6 mmol), copper (I)
iodide (0.263 g, 1.380 mmol), palladium (0)
tetrakis(triphenylphosphine) (0.558 g, 0.483 mmol),
3-bromo-5-chloropicolinonitrile (3.0 g, 13.8 mmol), and
N,N-dimethylformamide (50 ml). The vessel was flushed with argon,
sealed, stirred at ambient temperature for 15 minutes, and then
heated at 50.degree. C. for 4 hours. The solution was diluted with
water and extracted with ethyl acetate. The combined organic layers
were concentrated, and the residue was purified by silica-gel
chromatography, eluting 0-50% ethyl acetate in hexane, to afford
the title compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H).
Step 3: 5-Chloro-3-(2,2-dimethoxyethyl)picolinonitrile
[0770] A pressure vessel was charged with
5-chloro-3-((trimethylsilyl)ethynyl)picolinonitrile (2 g, 8.52
mmol) and sodium methoxide (0.5 M in methanol, 42.6 mL, 21.30
mmol), sealed, and stirred at 55.degree. C. for one hour. The
solution was concentrated, and the residue was purified via silica
gel chromatography, eluting with 10% methanol in DCM to afford the
title compound (1.7 g, 7.50 mmol). MS m/z=227 (M+H).
Step 4: 3-Chloro-1,7-naphthyridin-8(7H)-one
[0771] To a solution of
5-chloro-3-(2,2-dimethoxyethyl)picolinonitrile (1.7 g, 7.50 mmol)
in acetone (50 mL) and water (150 mL) was added aqueous saturated
sodium carbonate (37.5 mL, 113 mmol) and 30% aqueous hydrogen
peroxide (38.3 mL, 375 mmol). The reaction was stirred at RT for
one hour, concentrated to remove most of the acetone, and extracted
with dichloromethane. The combined organic layers were
concentrated.
[0772] To a solution of this intermediate (1.8 g, 7.36 mmol) in
benzene (20 mL) was added p-toluenesulfonic acid (0.350 g, 1.839
mmol) and the reaction was sonicated for 10 minutes. The solution
was stirred overnight at 80.degree. C. and concentrated. The crude
product was purified via silica gel, eluting with 0-100% (80/20/1
ethyl acetate/methanol/ammonium hydroxide) in ethyl acetate, to the
title intermediate (1.1 g, 6.1 mmol). MS m/z=181 (M+H).
Step 5: 3,8-Dichloro-1,7-naphthyridine
[0773] A suspension of -chloro-1,7-naphthyridin-8(7H)-one (250 mg,
1.384 mmol) in phosphorus oxychloride (1.94 mL, 20.8 mmol) was
stirred at 95.degree. C. for one hour. The solution was
concentrated to afford the title compound (276 mg, 1.39 mmol). MS
m/z=199 (M+H).
Intermediate 16
##STR00086##
[0774] Synthesis of 8-Chloro-3-methoxy-1,7-naphthyridine
Step 1: 3-chloro-5-methoxypicolinonitrile
[0775] To a solution of 3,5-dichloropicolinonitrile (22.5 g, 130
mmol) in DMF (500 mL) at 0.degree. C. was added sodium methoxide
(6.67 g, 124 mmol) slowly. The reaction was stirred for 5 minutes
at 0.degree. C., then allowed to warm to RT and stir for 30
minutes. The solution was partitioned between water and EtOAc. The
organic layer was washed with water and concentrated. The crude
product was purified via silica gel chromatography, eluting with
0-75% ethyl acetate in heptanes, to afford a 1:1 ratio of the
desired isomer 3-chloro-5-methoxypicolinonitrile and
5-chloro-3-methoxypicolinonitrile (7.0 g, 41.5 mmol). The material
was used without further purification. MS m/z=169 (M+H).
Step 2: 5-Methoxy-3-((triethylsilyl)ethynyl)picolinonitrile
[0776] A sealed vessel was charged with bis(acetonitrile)palladium
(II) chloride (0.154 g, 0.593 mmol),
dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine
(0.848 g, 1.780 mmol), cesium carbonate (25.1 g, 77 mmol), the
product of Intermediate 9, step 1 (5 g, 29.7 mmol), and ACN (60
mL). The vessel was flushed with argon, sealed, and stirred at RT
for 25 minutes. To the reaction was added triethyl(ethynyl)silane
(5.41 g, 38.6 mmol), and the vessel was resealed and stirred at
90.degree. C. for 3 hours. The solution was concentrated, and the
residue was purified via silica gel chromatography, eluting with
0-50% ethyl acetate in heptanes, to afford the title compound (3.8
g, 13.9 mmol). MS m/z=273 (M+H).
Step 3: 3-(2,2-Dimethoxyethyl)-5-methoxypicolinonitrile
[0777] A pressure vessel was charged with
5-methoxy-3-((triethylsilyl)ethynyl)picolinonitrile (3.8 g, 13.95
mmol) and sodium methoxide (0.5 M in methanol, 69.7 mL, 34.9 mmol).
The vessel was sealed and stirred at 55.degree. C. for 2 hours. The
reaction was concentrated to afford the title intermediate (3.1 g,
13.95 mmol).
Step 4: 8-chloro-3-methoxy-1,7-naphthyridine
[0778] Using an analogous sequence of reactions to those described
in Intermediate 8, steps 4-5,
3-(2,2-dimethoxyethyl)-5-methoxypicolinonitrile (3.4 g, 15.30 mmol)
was converted to the title compound (552 mg, 2.84 mmol). MS m/z=195
(M+H).
Intermediate 17
##STR00087##
[0779] Synthesis of 5-Chloro-2-methoxypyrido[3,4-b]pyrazine
Step 1: 5-Chloropyrido[3,4-b]pyrazin-2(1H)-one
[0780] A suspension 2-chloropyridine-3,4-diamine (2.5 g, 17.41
mmol) and a 50% solution of ethyl glyoxalate in toluene (3.45 mL,
17.41 mmol) in ethanol (34.8 mL) was stirred at reflux for 24
hours. The solution was cooled to -20.degree. C. for 16 hours, and
the resulting precipitate was collected by vacuum filtration and
rinsed with ethanol. The crude product was purified via
reverse-phase HPLC, eluting with 5-50% acetonitrile/0.1%
trifluoroacetic acid in water/0.1% trifluoroacetic acid, to afford
the title compound (570 mg, 3.14 mmol). MS m/z=182 (M+H).
Step 2: 2,5-Dichloropyrido[3,4-b]pyrazine
[0781] A suspension of 5-chloropyrido[3,4-b]pyrazin-2(1H)-one (0.57
g, 3.14 mmol) in phosphorus oxychloride (10.24 mL, 110 mmol) was
stirred at 110.degree. C. for two hours, and then concentrated. The
residue was dissolved in dichloromethane, washed with saturated
sodium bicarbonate, dried over anhydrous sodium sulfate, filtered,
and concentrated to afford the title compound (580 mg, 2.90 mmol).
MS m/z=200 (M+H).
Step 3: 5-Chloro-2-methoxypyrido[3,4-b]pyrazine
[0782] To a solution of 2,5-dichloropyrido[3,4-b]pyrazine (580 mg,
2.90 mmol) in N,N-dimethylformamide (10 mL) was added a 0.5-M
solution of sodium methoxide in methanol (6.09 mL, 3.04 mmol), and
the reaction was stirred at room temperature for 5 minutes. The
solution was diluted with water and extracted with ethyl acetate.
The organic layer was dried with sodium sulfate, filtered and
concentrated to afford the title compound (550 mg, 2.81 mmol). MS
m/z=196 (M+H).
Intermediate 18
##STR00088##
[0783] Synthesis of 8-Chloro-1,7-naphthyridine-3-carbonitrile
[0784] A screw-cap vial was charged with
3-chloro-1,7-naphthyridin-8(7H)-one (100 mg, 0.554 mmol), zinc
cyanide (52.7 .mu.l, 0.831 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (45.5 mg, 0.111
mmol), tris(dibenzylideneacetone)dipalladium(0) (40.6 mg, 0.044
mmol), DMF (2.74 mL) and water (28 .mu.L). The vial was purged with
argon, sealed, and stirred at 110.degree. C. for 1 hour. The
mixture was filtered through a pad of Celite, which was rinsed with
methanol and dimethylsulfoxide. The combined filtrates were
concentrated, and a few drops of water were added. The resulting
solids were collected by vacuum filtration, rinsed with water and
dried.
[0785] The solids were suspended in toluene (3.5 mL), and
phosphorus oxychloride (98 .mu.L, 1.052 mmol) and DIPEA (122 .mu.L,
0.701 mmol) were added. The reaction was stirred at 120.degree. C.
for 1.5 hours, cooled to RT, diluted with EtOAc, and washed with 2
M aqueous sodium carbonate. The organic portion was dried over
anhydrous sodium sulfate, filtered and concentrated. The crude
material was purified by silica gel chromatography, eluting with
5-50% EtOAc in heptanes, to provide the title compound (50 mg,
0.264 mmol) as a white solid. LC/MS (ESI.sup.+) m/z=190 (M+H).
Intermediate 19
##STR00089##
[0786] Synthesis of 3,8-Dichloro-5-fluoro-1,7-naphthyridine
Step 1:
3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one
[0787] A pressure bottle was charged with
3-chloro-1,7-naphthyridin-8(7H)-one (15 g, 83 mmol), methanol (34.6
mL), ACN (173 mL) and
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (30.9 g, 87 mmol), and the mixture was
heated at 45.degree. C. for 15 hours. Water and ethyl acetate were
added, and the layers were separated. The aqueous portion was
extracted twice with ethyl acetate and once with DCM, and the
combined organic layers were dried with anhydrous sodium sulfate,
filtered and concentrated. The crude solid was triturated with a
minimum amount of ethyl acetate and filtered. The title
intermediate was isolated as an off-white solid (15.34 g, 80%) as a
3:1 mixture of diastereomers.
Step 2: 3,8-dichloro-5-fluoro-1,7-naphthyridine
[0788] A vial was charged with
3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one
(7.5 g, 32.5 mmol), acetonitrile (130 mL) and phosphorus
oxychloride (9.09 mL, 98 mmol), and the mixture was stirred at
75.degree. C. for 15 hours. The mixture was concentrated, and the
crude material was purified by silica gel chromatography, eluting
with 0-50% ethyl acetate in heptanes, to provide the title compound
(5.57 g, 25.7 mmol, 79% yield) as a white solid. LC/MS (ESI.sup.+)
m/z=217 (M+H).
Intermediate 20
##STR00090##
[0789] Synthesis of
8-Chloro-5-fluoro-3-methoxy-1,7-naphthyridine
[0790] Using an analogous sequence of reactions to those described
for Intermediate 19, 3-,ethoxy-1,7-naphthyridin-8(7H)-one was
converted to the title compound. LC/MS (ESI.sup.+) m/z=213
(M+H).
Intermediate 21
##STR00091##
[0791] Synthesis of 4,7-Dichloropyrido[3,2-d]pyrimidine
Step 1: 3-Amino-5-chloropicolinamide
[0792] To a suspension of 5-chloro-2-cyano-3-nitropyridine (1.274
mL, 10.9 mmol) in water (22 mL) was added 28% aqueous ammonium
hydroxide (3.94 mL, 28.3 mmol), and the reaction was stirred at RT
for 20 minutes. Sodium hydrosulfite (2.68 mL, 32.7 mmol) was added,
and the reaction mixture was stirred at RT for 70 minutes. The
yellow precipitate was collected by vacuum filtration to provide
the title compound (1.097 g, 6.39 mmol) as yellow solid.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.88 (br. s, 1H),
.delta. 7.73 (s, 1H), .delta. 7.39 (br. s, 1H), .delta. 7.23 (s,
1H), .delta. 7.06 (br. s, 2H). LC/MS (ESI.sup.+) m/z=172 (M+H).
Step 2: 7-Chloropyrido[3,2-d]pyrimidin-4(1H)-one
[0793] A suspension of 3-amino-5-chloropicolinamide (1.1 g, 6.41
mmol) in triethyl orthoformate (15.99 mL, 96 mmol) was stirred at
155.degree. C. for 22 hours. After cooling to RT, the yellow
precipitate was collected by vacuum filtration and washed with
hexanes to yield the title intermediate (1.03 g, 5.67 mmol) as a
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.20
(s, 1H) 8.27 (d, J=2.35 Hz, 1H) 8.80 (d, J=2.25 Hz, 1H) 12.68 (br.
s., 1H). LC/MS (ESI.sup.+) m/z=182 (M+H).
Step 3: 4,7-Dichloropyrido[3,2-d]pyrimidine
[0794] To a mixture of 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one
(250 mg, 1.377 mmol) in toluene (12 mL) were added DIPEA (0.73 mL,
4.20 mmol) and phosphorus oxychloride (0.391 mL, 4.27 mmol), and
the reaction was stirred at reflux for 1 hour. After cooling to RT,
the reaction mixture was concentrated to provide the title
compound. LC/MS (ESI.sup.+) m/z=200 (M+H).
Intermediate 22
##STR00092##
[0795] Synthesis of 4-Chloro-7-methoxypyrido[3,2-d]pyrimidine
Step 1: 7-Methoxypyrido[3,2-d]pyrimidin-4(1H)-one
[0796] A microwave vial was charged with
7-chloropyrido[3,2-d]pyrimidin-4(1H)-one (110 mg, 0.606 mmol), a
0.5 M solution of sodium methoxide in methanol (3.65 mL, 1.817
mmol) and sodium methoxide (327 mg, 6.06 mmol). The vial was capped
and irradiated in a microwave reactor at 145.degree. C. for 30
minutes. The reaction was neutralized with saturated aqueous
ammonium chloride (3 mL), concentrated, and diluted with cold
water. The resulting precipitate was collected by vacuum filtration
and dried in vacuo to provide the title compound (107 mg, 0.604
mmol) as pink solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.95 (s, 3H) 7.49 (d, J=2.74 Hz, 1H) 8.11 (s, 1H) 8.47 (d,
J=2.74 Hz, 1H). LC/MS (ESI.sup.+) m/z=178 (M+H).
Step 2: 4-Chloro-7-methoxypyrido[3,2-d]pyrimidine
[0797] Using an analogous reaction to that described for
Intermediate 21, step 3,7-methoxypyrido[3,2-d]pyrimidin-4(1H)-one
was converted to the title compound. LC/MS (ESI.sup.+) m/z=196
(M+H).
Intermediate 23
##STR00093##
[0798] Synthesis of 4-Chloro-5-fluoro-7-methoxyquinazoline
Step 1: 2-Amino-6-fluoro-4-methoxybenzonitrile
[0799] Ammonia gas was bubbled through a solution of
2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in
dimethylsulfoxide (11.83 mL) for 10 minutes. The reaction was then
sealed and stirred at 90.degree. C. for 24 hours. The reaction
mixture was cooled to ambient temperature and concentrated in vacuo
to afford a tan residue. The residue was triturated with water,
collected be vacuum filtration, and dried in vacuo to afford the
title intermediate (0.9 g, 5.42 mmol) as a white solid. LC/MS
(ESI.sup.+) m/z=167 (M+H).
Step 2: 5-Fluoro-7-methoxyquinazolin-4-ol
[0800] To a mixture of formic acid (11.43 mL, 298 mmol) and
sulfuric acid (0.866 mL, 16.25 mmol) was added
2-amino-6-fluoro-4-methoxybenzonitrile (0.9 g, 5.42 mmol) in
portions. The reaction mixture was stirred at 100.degree. C. for 1
hour, cooled to ambient temperature, and poured into 80 mL of an
ice-water mixture. The resulting precipitate was collected by
vacuum filtration and dried in vacuo to provide the title
intermediate (0.8 g, 4.12 mmol) as an off-white solid. LC/MS
(ESI.sup.+) m/z=195 (M+H).
Step 3: 4-Chloro-5-fluoro-7-methoxyquinazoline
[0801] To a suspension of 5-fluoro-7-methoxyquinazolin-4-ol (0.125
g, 0.644 mmol) in thionyl chloride (1.410 mL, 19.31 mmol) was added
N,N-dimethylformamide (0.028 mL, 0.361 mmol). The reaction was
stirred at 80.degree. C. for 6 hours and concentrated in vacuo. The
residue was suspended in saturated aqueous sodium bicarbonate and
extracted with dichloromethane. The organic layer was concentrated
in vacuo to generate the title compound (0.13 g, 0.611 mmol) as a
yellow solid. LC/MS (ESI.sup.+) m/z=213 (M+H).
Intermediate 24
##STR00094##
[0802] Synthesis of 3-Aminothieno[3,2-b]pyridine-6-carbonitrile
Step 1: Sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate
[0803] To a suspension of NaH (60% dispersion in mineral oil, 2.52
g, 63.0 mmol) in diethylether (75 mL) was added
3,3-dimethoxypropanenitrile (6.17 mL, 55.0 mmol) followed by methyl
formate (6.74 mL, 110 mmol). The solution was stirred for 3 days at
RT. The resulting solid was collected by vacuum filtration and
washed with ether to afford sodium
(E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (4.2 g, 25.4 mmol).
Step 2: 3-Aminothieno[3,2-b]pyridine-6-carbonitrile
[0804] To a solution of sodium
(E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (1012 mg, 6.13 mmol) in
methanol (12 mL) was added concentrated hydrochloric acid (503
.mu.L 6.13 mmol). The solution was stirred for 5 minutes, and then
a solution of thiophene-3,4-diamine (700 mg, 6.13 mmol) in methanol
(12 mL) was added. The solution was stirred at reflux for 3 hours,
and then a solution of concentrated HCl (1.0 mL) in methanol (2 mL)
was added. The reaction was stirred at reflux for an additional two
hours, quenched with TEA (3 mL), and concentrated. The crude
product was purified via silica gel chromatography, eluting with
0-100% ethyl acetate in heptanes, to provide the title compound
(250 mg, 1.427 mmol). MS m/z=176 (M+H).
Intermediate 25
##STR00095##
[0805] Synthesis of 3-Methoxy-1,7-naphthyridin-8-amine
Step 1: 3-Methoxy-N-(4-methoxybenzyl)-1,7-naphthyridin-8-amine
[0806] To a solution of 8-chloro-3-methoxy-1,7-naphthyridine (1 g,
5.14 mmol) in N,N-dimethylformamide (10.28 mL) was added potassium
carbonate (1.42 g, 10.28 mmol) followed by 4-methoxybenzylamine
(1.47 ml, 11.3 mmol). The reaction was stirred at 100.degree. C.
for 24 hours and then concentrated to generate a brown residue.
This was partitioned between ethyl acetate and water. The organic
layer was concentrated and purified by silica-gel chromatography,
eluting with 1-5% methanol in DCM, to provide the title compound
(1.37 g, 4.63 mmol) as a tan solid. LC/MS (ESI.sup.+) m/z=296
(M+H).
Step 2: 3-methoxy-1,7-naphthyridin-8-amine
[0807] To a solution of
N-(4-methoxybenzyl)-1,7-naphthyridin-8-amine (340 mg, 1.15 mmol) in
1,2-dichloroethane (5.80 mL) was added TFA (2.67 mL, 34.5 mmol).
The reaction was stirred at 75.degree. C. for 8 hours and then
concentrated. The residue was partitioned between DCM and aqueous
sodium bicarbonate. The organic layer was concentrated and purified
by silica-gel chromatography, eluting with 50-100% EtOAc in DCM, to
provide the title compound (171.7 mg, 0.98 mmol) as an off-white
solid. LC/MS (ESI.sup.+) m/z=176 (M+H).
Intermediate 26
##STR00096##
[0808] Synthesis of 5-(Difluoromethyl)picolinic acid
Step 1: 5-Formylpicolinonitrile
[0809] A suspension of 2-bromo-5-formylpyridine (940 mg, 5.05 mmol)
and copper (I) cyanide (233 .mu.L, 7.58 mmol) in DMF (8.4 mL) was
stirred at 120.degree. C. for 1.5 hours, cooled to RT, and
partitioned between water and EtOAc. The solids were removed from
the aqueous layer by filtration, and the filtrate was extracted
with ethyl acetate. The combined organic layers were washed with
brine, dried over anhydrous magnesium sulfate, filtered and
concentrated. The crude product was purified by silica-gel
chromatography, eluting with a gradient of 40%-60% (40% ethyl
acetate in heptane) in heptane, to provide the title compound (236
mg, 1.786 mmol) as white solid. LC/MS (ESI.sup.+) m/z=133
(M+H).
Step 2: 5-(Difluoromethyl)picolinonitrile
[0810] To a solution of 5-formylpicolinonitrile (74 mg, 0.560 mmol)
in toluene (0.25 mL) was added bis(2-methoxyethyl)aminosulfur
trifluoride (0.258 mL, 1.400 mmol), and the reaction was stirred at
RT overnight. The reaction mixture was carefully quenched with
saturated aqueous sodium bicarbonate, diluted with water, and
extracted with DCM. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
crude material was purified by silica-gel chromatography, eluting
with a gradient of 40% to 60% (40% ethyl acetate/heptane) in
heptane, to provide the title compound (48 mg, 0.311 mmol) as white
solid. LC/MS (ESI.sup.+) m/z=155 (M+H).
Step 3: 5-(difluoromethyl)picolinic acid
[0811] A suspension of 5-(difluoromethyl)picolinonitrile (48 mg,
0.311 mmol) in 12 N aqueous hydrochloric acid (4.3 mL, 140 mmol)
was stirred at 110.degree. C. for 1.5 hours. After cooling to
ambient temperature, the reaction mixture was concentrated and
treated with DIPEA (2 mL). The mixture was concentrated and dried
in vacuo to provide the title compound in quantitative yield. LC/MS
(ESI.sup.+) m/z=174 (M+H).
Intermediate 27
##STR00097##
[0812] Synthesis of 2-Methoxyquinoxalin-5-amine
[0813] To a suspension of 5-aminoquinoxalin-2(1H)-one (440 mg, 2.73
mmol) in methanol (1 mL), DCM (8 mL) and acetonitrile (8 mL), at
0.degree. C., was added TEA (1.14 mL, 8.19 mmol), followed by
(trimethylsilyl)diazomethane (2 mL, 4.10 mmol; 2.0M in hexanes).
The reaction mixture was allowed to warm to RT and stirred for
additional 3 hours. The suspension was filtered, and the filtrate
was concentrated under reduced pressure. The crude product was
purified by silica gel chromatography, eluting with 10%-50% ethyl
acetate in hexane, to provide the title compound (167 mg, 0.953
mmol) as a light-yellow powder. LC/MS (ESI.sup.+) m/z=176
(M+H).
[0814] General amidation procedures: The following two (2) methods
may be used to couple the amine core intermediates (see examples
and intermediates 1-17; note that the bromide needs to be converted
to the corresponding amine to be used in the methods below).
Method A: HATU Procedure
[0815] To a solution of the aniline (1 equivalent) and the
carboxylic acid (1.1 equivalent) in DCM were added triethylamine
(1.5 eq) and
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxide hexafluorophosphate (HATU, 1.1 equivalent). The reaction
mixture was stirred at RT for 3 hours, diluted with DCM, and washed
with water and brine. The organic layer was concentrated.
[0816] The residue was redissolved in DCM, and TFA (up to 10
equivalents) was added. The reaction is stirred at RT for 1 hour,
diluted with DCM, and washed with saturated aqueous sodium
bicarbonate and brine, and concentrated. The crude product was
purified by silica-gel chromatography to provide the title
compound.
Method B: DMTMM Procedure
[0817] To a solution of the aniline (1 equivalent) and the
carboxylic acid (1.1 equivalent) in 2:1 tetrahydrofuran/methanol is
added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride (DMTMM, 1.5 equivalents). After about ten minutes, water
and saturated aqueous sodium bicarbonate is added, and the mixture
is extracted with DCM. The organic extract is washed with brine and
concentrated.
[0818] The residue is redissolved in DCM, and TFA (up to 10
equivalents) is added. The reaction is stirred at RT for 1 hour,
diluted with dichloromethane, and washed with saturated aqueous
sodium bicarbonate and brine, and concentrated. The crude product
is purified by silica-gel chromatography to provide the title
compound.
[0819] Note for purposes of Table 2 and for Methods C and D
described hereinbelow, the aniline intermediates use in Method A
and Method B are designated as intermediate R, while the carboxylic
acid intermediates are designated as intermediate L.
Example 1
##STR00098##
[0820] Synthesis of
(1R,4R,5S)-2-Amino-4-(2-fluoro-5-((2-methoxypyrido[3,4-b]pyrazin-5-yl)ami-
no)phenyl)-1,4-dimethyl-9-thia-3-azabicyclo[3.3.1]non-2-ene
9,9-dioxide
[0821] To a solution of Intermediates 2A and 2B (75 mg, 0.143 mmol)
and 5-chloro-2-methoxypyrido[3,4-b]pyrazine (27.9 mg, 0.143 mmol)
in 2-propanol (1.5 mL) was added concentrated sulfuric acid (7.6
.mu.L, 0.143 mmol). The reaction was stirred for 20 minutes at
100.degree. C. After 30 minutes, the reaction mixture was diluted
with DCM, washed with saturated aqueous sodium bicarbonate, and
concentrated. The residue was redissolved in DCM (2 mL), and TFA
(0.220 mL, 2.85 mmol) was added. The reaction was stirred at
ambient temperature for one hour, diluted with DCM, and washed with
saturated aqueous sodium bicarbonate. The organic layer was
purified by silica-gel column chromatography, eluting with 0-10%
methanol in DCM, to provide the title compound (23 mg, 33% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.43 (s, 1H), 8.55
(s, 1H), 8.21-8.25 (m, 2H), 8.12-8.16 (m, 1H), 7.14 (dd, J=11.7,
8.9 Hz, 1H), 7.06 (d, J=5.9 Hz, 1H), 5.99 (s, 2H), 4.07 (s, 3H),
3.56 (s, 1H), 2.04-2.14 (m, 1H), 1.91-1.98 (m, 2H), 1.72 (s, 3H),
1.38-1.58 (m, 6H). LC/MS (ESI.sup.+) m/z=485.1 D (M+H).
Example 2
##STR00099##
[0822] Synthesis of
(1S,4R,5R)-2-Amino-4-(2-fluoro-5-((2-methoxypyrido[3,4-b]pyrazin-5-yl)ami-
no)phenyl)-1,4-dimethyl-9-thia-3-azabicyclo[3.3.1]non-2-ene
9,9-dioxide
[0823] The title compound was also isolated from the reaction
described in Example 1 (10 mg, 14% yield). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 9.17 (s, 1H), 8.56 (s, 1H), 8.24 (d,
J=5.8 Hz, 2H), 8.03-8.07 (m, 1H), 7.80-7.85 (m, 1H), 7.05-7.10 (m,
2H), 6.11 (bs, 2H), 4.08 (s, 3H), 3.62 (bs, 1H), 2.37-2.46 (m, 1H),
2.22-2.30 (m, 1H), 2.00-2.06 (m, 2H), 1.76 (s, 3H), 1.57-1.67 (m,
5H). LC/MS (ESI.sup.+) m/z=485.1 D (M+H).
Example 3
##STR00100##
[0824] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3-
.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0825] To a solution of Intermediates 2A and 2B (150 mg, 0.285
mmol) and 5-chloro-3-methylpyridine-2-carboxylic acid (49 mg, 0.285
mmol) in methanol (1 mL) and THF (2 mL) was added
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium
chloride (88 mg, 0.300 mmol). The reaction was stirred at RT. After
3 hours, the reaction mixture was partitioned between water and
ethyl acetate; the organic layer was dried over anhydrous magnesium
sulfate, filtered, and concentrated. The residue was redissolved in
DCM (5 mL), and TFA (0.44 mL, 5.71 mmol) was added. The reaction
was stirred at RT for 2.5 hours, washed with saturated aqueous
sodium bicarbonate and brine, and concentrated. The crude product
was purified by silica-gel column chromatography, eluting with
2-10% methanol in DCM, to provide the title compound (56 mg, 41%
yield). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.54 (s,
1H), 8.57 (d, J=2.3 Hz, 1H), 8.02-8.06 (m, 2H), 7.85-7.89 (m, 1H),
7.16 (dd, J=11.7, 8.8 Hz, 1H), 5.96 (s, 2H), 3.57 (s, 1H), 2.57 (s,
3H), 2.03-2.14 (m, 1H), 1.89-1.96 (m, 2H), 1.70 (s, 3H), 1.50-1.53
(m, 1H), 1.48 (s, 3H), 1.21-1.35 (m, 2H). LC/MS (ESI.sup.+)
m/z=479.1 D (M+H).
Example 4
##STR00101##
[0826] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3-
.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0827] The title compound was also isolated from the reaction
described in Example 3 (41 mg, 30% yield). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.43 (s, 1H), 8.56 (d, J=1.8 Hz, 1H),
8.00 (d, J=1.6 Hz, 1H), 7.81-7.85 (m, 1H), 7.53 (dd, J=7.5, 2.7 Hz,
1H), 7.08 (dd, J=12.3, 8.9 Hz, 1H), 6.07 (s, 2H), 3.59 (s, 1H),
2.53 (s, 3H), 2.36-2.44 (m, 1H), 2.18-2.30 (m, 1H), 1.98-2.05 (m,
2H), 1.59-1.67 (m, 2H), 1.57 (s, 3H), 1.41 (s, 3H). LC/MS
(ESI.sup.+) m/z=479.1 D (M+H).
Example 5
##STR00102##
[0828] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3-
.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[0829] In a sequence of reactions analogous to those described in
Example 3, Intermediates 2A and 2B (150 mg, 0.285 mmol) and
5-(difluoromethoxy)-methylpyridine-2-carboxylic acid (58 mg, 0.285
mmol) were combined to provide the title compound (35 mg, 24%
yield). .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.50 (s,
1H), 8.42 (d, J=2.5 Hz, 1H), 8.05 (dd, J=7.2, 2.7 Hz, 1H),
7.86-7.90 (m, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.44 (t, J=73.0 Hz, 1H),
7.16 (dd, J=11.8, 8.8 Hz, 1H), 5.96 (s, 2H), 3.57 (s, 1H), 2.61 (s,
3H), 2.05-2.12 (m, 1H), 1.92-1.94 (m, 2H), 1.70 (s, 3H), 1.48-1.55
(m, 1H), 1.48 (s, 3H), 1.14-1.35 (m, 2H). LC/MS (ESI.sup.+)
m/z=511.1 D (M+H).
Example 6
##STR00103##
[0830] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2,5-dimethyl-9,9-dioxido-9-thia-3-azabicyclo[3.3-
.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[0831] The title compound was also isolated from the reaction
described in Example 5 (39 mg, 26% yield). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.39 (s, 1H), 8.41 (d, J=2.5 Hz, 1H),
7.81-7.85 (m, 1H), 7.70 (d, J=2.3 Hz, 1H), 7.54 (dd, J=7.5, 2.7 Hz,
1H), 7.43 (t, J=73.1 Hz, 1H), 7.08 (dd, J=12.3, 8.8 Hz, 1H), 6.07
(s, 2H), 3.59 (bs, 1H), 2.57 (s, 3H), 2.18-2.44 (m, 2H), 1.98-2.05
(m, 2H), 1.59-1.68 (m, 2H), 1.57 (s, 3H), 1.41 (s, 3H). LC/MS
(ESI.sup.+) m/z=511.1 D (M+H).
Example 7
##STR00104##
[0832] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0833] In a sequence of reactions analogous to those described in
Example 3, Intermediate 3 (64 mg, 0.118 mmol) and
5-chloro-3-methyl-pyridine-2-carboxylic acid (0.015 mL, 0.118 mmol)
were combined to provide the title compound (45 mg, 77% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.61 (s, 1H),
8.58 (d, J=1.9 Hz, 1H), 8.03-8.06 (m, 2H), 7.91-7.96 (m, 1H), 7.17
(dd, J=11.7, 8.8 Hz, 1H), 6.20 (s, 2H), 2.57 (s, 3H), 2.14-2.21 (m,
1H), 1.94-2.03 (m, 2H), 1.76 (d, J=3.1 Hz, 3H), 1.58-1.66 (m, 2H),
1.55 (s, 3H), 1.37-1.46 (m, 1H). LC/MS (ESI.sup.+) m/z=497.1 D
(M+H).
Example 8
##STR00105##
[0834] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0835] In a sequence of reactions analogous to those described in
Example 3, Intermediate 4 (40 mg, 0.074 mmol) and
5-chloro-3-methyl-pyridine-2-carboxylic acid (12.6 mg, 0.074 mmol)
were combined to provide the title compound (12 mg, 33% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.42 (s, 1H),
8.56 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.88-7.91 (m, 1H),
7.40-7.43 (m, 1H), 7.02 (dd, J=12.4, 8.9 Hz, 1H), 6.25 (s, 2H),
2.60-2.68 (m, 1H), 2.51 (s, 3H), 2.28-2.40 (m, 1H), 2.01-2.10 (m,
2H), 1.67-1.89 (m, 5H), 1.55 (s, 3H), 1.37-1.46 (m, 1H). LC/MS
(ESI.sup.+) m/z=497.1 D (M+H).
Example 9
##STR00106##
[0836] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpic-
olinamide
[0837] In a sequence of reactions analogous to those described in
Example 3, Intermediate 3 (64 mg, 0.118 mmol) and
5-(difluoromethoxy)-3-methylpicolinic acid (23.92 mg, 0.118 mmol)
were combined to provide the title compound (39 mg, 63% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.57 (s, 1H),
8.43 (d, J=2.4 Hz, 1H), 8.03-8.06 (m, 1H), 7.92-7.96 (m, 1H), 7.72
(d, J=2.2 Hz, 1H), 7.44 (t, J=73.1 Hz, 1H), 7.17 (dd, J=11.8, 8.8
Hz, 1H), 6.20 (s, 2H), 2.60 (s, 3H), 2.13-2.24 (m, 1H), 1.93-2.04
(m, 2H), 1.76 (d, J=3.1 Hz, 3H), 1.59-1.68 (m, 2H), 1.55 (s, 3H),
1.37-1.46 (m, 1H). LC/MS (ESI.sup.+) m/z=529.1 D (M+H).
Example 10
##STR00107##
[0838] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-1-fluoro-2,5-dimethyl-9,9-dioxido-9-thia-3-azabi-
cyclo[3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpic-
olinamide
[0839] In a sequence of reactions analogous to those described in
Example 3, Intermediate 4 (40 mg, 0.074 mmol) and
5-(difluoromethoxy)-3-methylpicolinic acid (14.95 mg, 0.074 mmol)
were combined to provide the title compound (15 mg, 39% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.38 (s, 1H),
8.42 (d, J=2.5 Hz, 1H), 7.88-7.92 (m, 1H), 7.72 (d, J=2.2 Hz, 1H),
7.42 (t, J=73.1 Hz, 1H), 7.40-7.44 (m, 1H), 7.03 (dd, J=12.2, 8.9
Hz, 1H), 6.25 (s, 2H), 2.60-2.68 (m, 1H), 2.55 (s, 3H), 2.29-2.40
(m, 1H), 2.04-2.09 (m, 1H), 1.67-1.89 (m, 6H), 1.52 (s, 3H). LC/MS
(ESI.sup.+) m/z=529.2 D (M+H).
Example 11
##STR00108##
[0840] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0841] In a sequence of reactions analogous to those described in
Example 3, Intermediates 5A and 5B (100 mg, 0.185 mmol) and
5-chloro-3-methyl-pyridine-2-carboxylic acid (31.8 mg, 0.185 mmol)
were combined to provide the title compound (14 mg, 15% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.63 (s, 1H),
8.58 (d, J=1.9 Hz, 1H), 8.02-8.05 (m, 2H), 7.89-7.93 (m, 1H), 7.15
(dd, J=12.8, 8.8 Hz, 1H), 5.92 (s, 2H), 2.54 (s, 3H), 2.00-2.20 (m,
2H), 1.71-1.87 (m, 6H), 1.50 (s, 3H), 1.46 (d, J=3.4 Hz, 3H). LC/MS
(ESI.sup.+) m/z=493.1 D (M+H).
Example 12
##STR00109##
[0842] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0843] The title compound was also isolated from the reaction
described in Example 11 (16 mg, 18% yield). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.36 (s, 1H), 8.57 (d, J=2.3 Hz, 1H),
8.00 (d, J=1.6 Hz, 1H), 7.88-7.91 (m, 1H), 7.29-7.33 (m, 1H), 7.00
(dd, J=12.8, 8.8 Hz, 1H), 5.95 (s, 2H), 2.51 (s, 3H), 2.21-2.29 (m,
1H), 1.90-2.10 (m, 4H), 1.58-1.79 (m, 6H), 1.50 (s, 3H), 1.46-1.56
(m, 1H). LC/MS (ESI.sup.+) m/z=493.1 D (M+H).
Example 13
##STR00110##
[0844] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinam-
ide
[0845] In a sequence of reactions analogous to those described in
Example 3, Intermediates 5A and 5B (100 mg, 0.185 mmol) and
5-(difluoromethoxy)-3-methylpicolinic acid (37.6 mg, 0.185 mmol)
were combined to provide the title compound (26 mg, 27% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.61 (s, 1H),
8.43 (d, J=2.4 Hz, 1H), 8.02-8.06 (m, 1H), 7.92-7.96 (m, 1H), 7.72
(d, J=2.2 Hz, 1H), 7.43 (t, J=73.1 Hz, 1H), 7.18 (bs, 1H), 5.93 (s,
2H), 2.58 (s, 3H), 1.96-2.12 (m, 3H), 1.69-1.89 (m, 6H), 1.44-1.58
(m, 6H). LC/MS (ESI.sup.+) m/z=525.2 D (M+H).
Example 14
##STR00111##
[0846] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinam-
ide
[0847] The title compound was also isolated from the reaction
described in Example 13 (7 mg, 7% yield). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.33 (s, 1H), 8.42 (d, J=2.4 Hz, 1H),
7.89-7.93 (m, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.41 (t, J=73.1 Hz, 1H),
7.31 (bs, 1H), 7.01 (dd, J=12.8, 8.9 Hz, 1H), 5.96 (s, 2H), 2.55
(s, 3H), 2.22-2.31 (m, 1H), 1.88-2.11 (m, 4H), 1.53-1.80 (m, 7H),
1.51 (s, 3H). LC/MS (ESI.sup.+) m/z=525.2 D (M+H).
Example 15
##STR00112##
[0848] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
[0849] In a sequence of reactions analogous to those described in
Example 3, Intermediates 5A and 5B (100 mg, 0.185 mmol) and
5-methoxypyrazine-2-carboxylic acid (28.6 mg, 0.185 mmol) were
combined to provide the title compound (19 mg, 21% yield).
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.63 (s, 1H),
8.89 (d, J=1.4 Hz, 1H), 8.42 (d, J=1.3 Hz, 1H), 8.21-8.23 (m, 1H),
7.86-7.89 (m, 1H), 7.15 (dd, J=12.8, 8.8 Hz, 1H), 5.93 (s, 2H),
4.02 (s, 3H), 1.70-2.06 (m, 8H), 1.50 (s, 3H), 1.47 (d, J=3.3 Hz,
3H). LC/MS (ESI.sup.+) m/z=476.1 D (M+H).
Example 16
##STR00113##
[0850] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-1,2,5-trimethyl-9,9-dioxido-9-thia-3-azabicyclo[-
3.3.1]non-3-en-2-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide
[0851] The title compound was also isolated from the reaction
described in Example 15 (24 mg, 27% yield). .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.16 (s, 1H), 8.87 (d, J=1.4 Hz, 1H),
8.42 (d, J=1.3 Hz, 1H), 7.80-7.84 (m, 1H), 7.48-7.53 (m, 1H), 7.00
(dd, J=12.8, 8.8 Hz, 1H), 5.95 (s, 2H), 4.02 (s, 3H), 2.23-2.30 (m,
1H), 1.90-2.08 (m, 4H), 1.57-1.82 (m, 7H), 1.50 (s, 3H). LC/MS
(ESI.sup.+) m/z=476.1 D (M+H).
Example 17
##STR00114##
[0852] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2-methyl-9,9-dioxido-9-thia-3-azabicyclo[3.3.1]n-
on-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0853] In a sequence of reactions analogous to those described in
Example 3, Intermediate 8 (30 mg, 0.073 mmol) and
5-chloro-3-methyl-pyridine-2-carboxylic acid (13.76 mg, 0.080 mmol)
were combined to provide the title compound (26 mg, 77% yield).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 9.94 (s, 1H), 8.36
(d, J=1.8 Hz, 1H), 7.93-7.97 (m, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.38
(dd, J=7.2, 2.7 Hz, 1H), 7.00 (dd, J=12.2, 8.9 Hz, 1H), 4.80 (bs,
2H), 3.73-3.78 (m, 1H), 3.46 (bs, 1H), 2.41-2.57 (m, 3H), 2.20-2.29
(m, 1H), 1.72 (s, 3H), 1.62-1.69 (m, 2H). LC/MS (ESI.sup.+)
m/z=465.1 D (M+H).
Example 18
##STR00115##
[0854] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2-methyl-9,9-dioxido-9-thia-3-azabicyclo[3.3.1]n-
on-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[0855] In a sequence of reactions analogous to those described in
Example 3, Intermediate 8 (30 mg, 0.073 mmol) and
5-(difluoromethoxy)-3-methylpicolinic acid (16.29 mg, 0.080 mmol)
were combined to provide the title compound (24 mg, 66% yield).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 9.98 (s, 1H), 8.22
(d, J=2.2 Hz, 1H), 7.91-7.95 (m, 1H), 7.39 (dd, J=7.2, 2.7 Hz, 1H),
7.35 (d, J=2.0 Hz, 1H), 7.01 (dd, J=12.1, 8.8 Hz, 1H), 6.59 (t,
J=72.3 Hz, 1H), 4.89 (bs, 2H), 3.77 (bs, 1H), 3.40 (bs, 1H),
2.40-2.56 (m, 3H), 2.18-2.27 (m, 1H), 1.72 (s, 3H), 1.62-1.70 (m,
2H). LC/MS (ESI.sup.+) m/z=497.1 D (M+H).
Example 19
##STR00116##
[0856] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2-(2-fluoro-5-((2-methoxypyrido[3,4-b]pyrazin-5--
yl)amino)phenyl)-2-methyl-9-thia-3-azabicyclo[3.3.1]non-3-ene
9,9-dioxide
[0857] To a suspension of Intermediate 8 (35 mg, 0.085 mmol) and
5-chloro-2-methoxypyrido[3,4-b]pyrazine (16.64 mg, 0.085 mmol) in
2-propanol (0.9 mL) was added concentrated sulfuric acid (4.5
.mu.L, 0.085 mmol). The reaction was stirred for 20 minutes at
100.degree. C., and then partitioned between saturated aqueous
sodium bicarbonate and DCM. The organic layer was concentrated and
purified by silica-gel column chromatography, eluting with 0-10%
methanol in DCM, to provide the title compound (20 mg, 50.0%
yield). .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.58 (s,
1H), 8.25 (s, 1H), 8.20 (d, J=5.9 Hz, 1H), 8.14-8.18 (m, 1H),
7.45-7.50 (m, 1H), 6.99 (d, J=5.9 Hz, 1H), 6.90-6.95 (m, 1H), 4.09
(s, 3H), 3.81-3.88 (m, 1H), 3.73 (bs, 1H), 2.43-2.61 (m, 3H),
2.26-2.34 (m, 1H), 1.76 (s, 3H), 1.65-1.74 (m, 2H). LC/MS
(ESI.sup.+) m/z=471.1 D (M+H).
Example 20
##STR00117##
[0858] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-2-methyl-9,9-dioxido-9-thia-3-azabicyclo[3.3.1]n-
on-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0859] In a sequence of reactions analogous to those described in
Example 3, Intermediate 9 (12 mg, 0.029 mmol) and
5-chloro-3-methyl-pyridine-2-carboxylic acid (5.50 mg, 0.032 mmol)
were combined to provide the title compound (8 mg, 59% yield).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 10.06 (s, 1H), 8.38
(d, J=2.0 Hz, 1H), 8.02-8.06 (m, 1H), 7.75 (dd, J=6.8, 2.6 Hz, 1H),
7.65 (d, J=1.7 Hz, 1H), 7.08 (dd, J=11.5, 8.8 Hz, 1H), 5.18 (bs,
2H), 3.71 (bs, 1H), 3.57 (bs, 1H), 2.40-2.52 (m, 1H), 2.16-2.37 (m,
2H), 1.91 (s, 3H), 1.70-1.79 (m, 1H), 1.18-1.36 (m, 2H). LC/MS
(ESI.sup.+) m/z=465.1 D (M+H).
Example 21
##STR00118##
[0860] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2-methyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.1]o-
ct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0861] In a sequence of reactions analogous to those described in
Example 3, Intermediate 10 (25 mg, 0.063 mmol) and
5-chloro-3-methyl-pyridine-2-carboxylic acid (10.79 mg, 0.063 mmol)
were combined to provide the title compound (16 mg, 57% yield).
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 9.99 (s, 1H), 8.37
(d, J=1.9 Hz, 1H), 7.99-8.03 (m, 1H), 7.62 (d, J=1.7 Hz, 1H), 7.44
(dd, J=7.1, 2.7 Hz, 1H), 7.03 (dd, J=12.0, 8.9 Hz, 1H), 5.44 (bs,
2H), 3.88 (bs, 1H), 3.67 (bs, 1H), 2.78 (s, 3H), 2.44-2.54 (m, 3H),
2.22-2.33 (m, 1H), 1.70 (s, 3H). LC/MS (ESI.sup.+) m/z=451.1 D
(M+H).
Example 22
##STR00119##
[0862] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0863] To a solution of Intermediate 12 (100 mg, 0.195 mmol) in
N,N-dimethylformamide (1.0 mL) was added 5-chloro-3-methylpicolinic
acid (43.6 mg, 0.254 mmol),
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) (111 mg, 0.293 mmol), and pyridine (0.047 mL,
0.586 mmol). The reaction was stirred at ambient temperature for 2
hours, and then partitioned between water and ethyl acetate. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate, filtered, and concentrated. The residue was redissolved in
DCM (0.5 mL) and TFA (0.301 mL, 3.91 mmol) was added. The reaction
was stirred at RT for an hour. The reaction was quenched with
saturated aqueous sodium carbonate, and partitioned between water
and ethyl acetate. The organic layer was washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated. The
crude product was purified by silica-gel column chromatography,
eluting with 0-50% (3:1 ethyl acetate:ethanol, 2% ammonium
hydroxide) in heptanes, to provide the title compound (62 mg, 68.2%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.28-1.34 (m, 1H)
1.46 (s, 3H) 1.68-1.72 (m, 1H) 1.74 (s, 3H) 1.87-2.09 (m, 2H) 2.57
(s, 3H) 3.68 (d, J=5.77 Hz, 1H) 6.03 (br. s., 2H) 7.17 (dd,
J=11.74, 8.90 Hz, 1H) 7.72-7.81 (m, 1H) 7.81-7.89 (m, 1H) 8.03 (dd,
J=2.25, 0.68 Hz, 1H) 8.52-8.61 (m, 1H) 10.54 (s, 1H). LC/MS
(ESI.sup.+) m/z=465.1 (M+H).
Example 23
##STR00120##
[0864] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-methylpicolinamide
[0865] In a sequence of reactions analogous to those described in
Example 22, Intermediate 12 (53 mg, 0.104 mmol) and
5-(difluoromethoxy)-methylpyridine-2-carboxylic acid (27 mg, 0.135
mmol) were combined to provide the title compound (16 mg, 31.1%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28-1.37
(m, 1H) 1.46 (s, 3H) 1.66-1.72 (m, 1H) 1.74 (s, 3H) 1.85-2.11 (m,
2H) 2.60 (s, 3H) 3.68 (d, J=5.67 Hz, 1H) 6.04 (br. s., 2H) 7.16
(dd, J=11.79, 8.75 Hz, 1H) 7.25-7.62 (m, 1H) 7.72 (d, J=2.25 Hz,
1H) 7.79 (dd, J=7.09, 2.69 Hz, 1H) 7.85 (dt, J=8.85, 3.50 Hz, 1H)
8.43 (d, J=2.54 Hz, 1H) 10.50 (s, 1H). LC/MS (ESI.sup.+) m/z=497.1
(M+H).
Example 24
##STR00121##
[0866] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-3-methyl-5-(trifluoromethyl)picolinamide
[0867] In a sequence of reactions analogous to those described in
Example 22, Intermediate 12 (68 mg, 0.133 mmol) and
3-methyl-5-(trifluoromethyl)picolinic acid (35 mg, 0.173 mmol) were
combined to provide the title compound (58 mg, 88% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.28-1.37 (m, 1H) 1.46 (s,
3H) 1.68-1.74 (m, 1H) 1.75 (s, 3H) 1.88-2.09 (m, 2H) 2.60 (s, 3H)
3.69 (d, J=5.48 Hz, 1H) 6.04 (br. s., 2H) 7.19 (dd, J=11.69, 8.75
Hz, 1H) 7.75-7.81 (m, 1H) 7.83-7.87 (m, 1H) 8.26-8.34 (m, 1H)
8.86-8.94 (m, 1H) 10.66 (s, 1H). LC/MS (ESI.sup.+) m/z=499.1
(M+H).
Example 25
##STR00122##
[0868] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridine--
2-carboxamide
[0869] In a sequence of reactions analogous to those described in
Example 22, Intermediate 12 (60 mg, 0.117 mmol) and
6-chloro-3-methylimidazo[1,2-c]pyridine-2-carboxylic acid (32 mg,
0.152 mmol) were combined to provide the title compound (52 mg, 88%
yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.30-1.36
(m, 1H) 1.48 (s, 3H) 1.68-1.74 (m, 1H) 1.76 (s, 3H) 1.87-2.01 (m,
1H) 2.05-2.19 (m, 1H) 2.81 (s, 3H) 3.67 (d, J=6.06 Hz, 1H) 6.10
(br. s, 2H) 7.15 (dd, J=11.74, 8.80 Hz, 1H) 7.43 (dd, J=9.63, 2.01
Hz, 1H) 7.69 (dd, J=9.63, 0.83 Hz, 1H) 7.84 (dd, J=7.14, 2.64 Hz,
1H) 7.87-7.94 (m, 1H) 8.69 (dd, J=1.96, 0.78 Hz, 1H) 10.19 (s, 1H).
LC/MS (ESI.sup.+) m/z=504.1 (M+H).
Example 26
##STR00123##
[0870] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0871] In a sequence of reactions analogous to those described in
Example 22, Intermediate 13 (80 mg, 0.156 mmol) and
5-chloro-3-methylpicolinic acid (35 mg, 0.203 mmol) were combined
to provide the title compound (15 mg, 21% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.24 (s, 1H) 1.42 (s, 3H) 1.50 (s,
3H) 1.82-1.94 (m, 1H) 2.14-2.28 (m, 2H) 2.36-2.45 (m, 1H) 2.56 (s,
3H) 3.76 (d, J=3.72 Hz, 1H) 6.04 (br. s., 1H) 7.12 (dd, J=12.18,
8.85 Hz, 1H) 7.63 (dd, J=7.38, 2.69 Hz, 1H) 7.77-7.89 (m, 1H) 8.02
(dd, J=2.30, 0.64 Hz, 1H) 8.50-8.62 (m, 1H) 10.42 (s, 1H). LC/MS
(ESI.sup.+) m/z=465.1 (M+H).
Example 27
N-(3-((1R,2R,5S)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2.-
1]oct-3-en-2-yl)-4-fluorophenyl)-3-methyl-5-(trifluoromethyl)picolinamide
##STR00124##
[0872] Synthesis of
N-(3-((1R,2R,5S)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyclo[3.2-
.1]oct-3-en-2-yl)-4-fluorophenyl)-3-methyl-5-(trifluoromethyl)picolinamide
[0873] In a sequence of reactions analogous to those described in
Example 22, Intermediate 13 (53 mg, 0.104 mmol) and
3-methyl-5-(trifluoromethyl)picolinic acid (27 mg, 0.135 mmol) were
combined to provide the title compound (36 mg, 70% yield). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.24 (s, 1H) 1.42 (s, 3H)
1.51 (s, 3H) 1.90 (d, J=12.42 Hz, 1H) 2.12-2.30 (m, 1H) 2.30-2.45
(m, 1H) 2.58 (s, 3H) 3.76 (d, J=5.87 Hz, 1H) 6.08 (s, 2H) 7.13 (dd,
J=12.08, 8.85 Hz, 1H) 7.63 (dd, J=7.43, 2.74 Hz, 1H) 7.79-7.92 (m,
1H) 8.29 (s, 1H) 8.89 (s, 1H) 10.58 (s, 1H). LC/MS (ESI.sup.+)
m/z=499.1 (M+H).
Example 28
##STR00125##
[0874]
N-(3-((1R,2R,5S)-4-Amino-2,5-dimethyl-8,8-dioxido-8-thia-3-azabicyc-
lo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyr-
idine-2-carboxamide
[0875] In a sequence of reactions analogous to those described in
Example 22, Intermediate 13 (35 mg, 0.068 mmol) and
6-chloro-3-methylimidazo[1,2-c]pyridine-2-carboxylic acid (18 mg,
0.088 mmol) were combined to provide the title compound (18 mg, 52%
yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.60 (s, 3H)
1.67 (s, 3H) 2.10 (ddd, J=12.57, 10.17, 4.35 Hz, 1H) 2.28-2.53 (m,
3H) 2.83 (s, 3H) 3.98 (d, J=5.58 Hz, 1H) 5.56 (br. s., 2H) 7.05
(dd, J=11.93, 8.80 Hz, 1H) 7.21 (dd, J=9.68, 1.96 Hz, 1H) 7.46-7.57
(m, 2H) 7.92 (ddd, J=8.80, 4.21, 2.84 Hz, 1H) 7.96 (dd, J=1.86,
0.78 Hz, 1H) 9.38 (s, 1H). LC/MS (ESI.sup.+) m/z=504.1 (M+H).
Example 29
##STR00126##
[0876] Synthesis of
(1R,4R,5S)-2-Amino-4-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino)--
2-fluorophenyl)-1,4-dimethyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene
8,8-dioxide
[0877] To a solution of Intermediate 12 (60 mg, 0.117 mmol), and
3,8-dichloro-5-fluoro-1,7-naphthyridine (28.0 mg, 0.129 mmol) in
2-propanol (0.78 mL) was added p-toluenesulfonic acid (66.9 mg,
0.352 mmol), and the mixture was stirred at 85.degree. C. for 5
hours. Saturated aqueous sodium bicarbonate and ethyl acetate were
added to the reaction and the layers were separated. The organic
portion was dried over anhydrous sodium sulfate, filtered and
concentrated. The crude product was purified by silica-gel column
chromatography, eluting with 0-80% (9:1 DCM/methanol) in DCM, to
provide the title compound (35 mg, 60.7% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.22-1.24 (m, 1H) 1.38-1.52 (m, 1H)
1.62 (br. s., 3H) 1.99 (br. s., 3H) 2.07 (br. s., 2H) 4.33 (d,
J=3.72 Hz, 1H) 7.20-7.38 (m, 1H) 8.04 (dd, J=7.24, 2.64 Hz, 1H)
8.19 (d, J=1.27 Hz, 1H) 8.33 (br. s., 1H) 8.63 (d, J=2.35 Hz, 1H)
9.02 (d, J=2.35 Hz, 1H) 9.85 (br. s., 1H) LC/MS (ESI.sup.+)
m/z=492.2 (M+H).
Example 30
##STR00127##
[0878] Synthesis of
(1S,4R,5S)-2-Amino-4-(5-((3-chloro-5-fluoro-1,7-naphthyridin-8-yl)amino)--
2-fluorophenyl)-1,4-dimethyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene
8,8-dioxide
[0879] In a sequence of reactions analogous to those described in
Example 29, Intermediate 13 (45 mg, 0.088 mmol) and
3,8-dichloro-5-fluoro-1,7-naphthyridine (21 mg, 0.097 mmol) were
combined to provide the title compound (7 mg, 16% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 1.58-1.66 (m, 2H) 1.72 (s,
2H) 2.08-2.21 (m, 2H) 2.34-2.54 (m, 3H) 4.04 (d, J=5.67 Hz, 1H)
5.31 (s, 1H) 5.38 (br. s., 3H) 7.08 (dd, J=11.98, 8.85 Hz, 1H) 7.63
(dd, J=7.24, 2.64 Hz, 1H) 8.02 (d, J=1.47 Hz, 1H) 8.16 (dt, J=7.24,
4.35 Hz, 1H) 8.25 (d, J=2.25 Hz, 1H) 8.73 (d, J=2.25 Hz, 1H). LC/MS
(ESI.sup.+) m/z=492.2 (M+H).
Example 31
##STR00128##
[0880] Synthesis of
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-8,8-dioxido-8-thia-3-azabicyclo[-
3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0881] To a solution of Intermediates 14A and 14B (0.218 g, 0.415
mmol) in dicholomethane (4 mL) were added
5-chloro-3-methylpicolinic acid (0.075 g, 0.435 mmol),
triethylamine (0.115 mL, 0.829 mmol) and
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) (0.173 g, 0.456 mmol). The mixture was stirred
at room temperature for 90 minutes and then concentrated. The crude
product was purified by silica-gel column chromatography, eluting
with 5% to 40% ethyl acetate in heptanes, to provide two
diastereomeric intermediates. The major diastereomer was
redissolved in DCM (1.0 mL), and trifluoroacetic acid (0.39 mL, 5.3
mmol) was added. The reaction was stirred at ambient temperature
for 30 minutes, concentrated, and partitioned between saturated
aqueous sodium bicarbonate and DCM. The organic layer was washed
with brine, dried over anhydrous sodium sulfate, filtered, and
concentrated to provide the title compound (48 mg, 24% yield).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.67 (s, 1H), 8.60 (d,
J=1.86 Hz, 1H), 8.03 (d, J=1.66 Hz, 1H), 7.90 (d, J=8.41 Hz, 1H),
7.64 (br. s., 1H), 7.06-7.25 (m, 1H), 6.01 (br. s., 2H), 2.56 (s,
3H), 2.25-2.42 (m, 1H), 1.83 (br. s., 3H), 1.71 (t, J=7.19 Hz, 2H),
1.56 (d, J=10.37 Hz, 1H), 1.50 (s, 3H), 1.41 (br. s., 3H). LC/MS
(ESI.sup.+) m/z=479.0 (M+H).
Example 32
##STR00129##
[0882] Synthesis of
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-8,8-dioxido-8-thia-3-azabicyclo[-
3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-chloro-3-methylpicolinamide
[0883] The minor diastereomer isolated from the reaction described
in Example 31 was redissolved in DCM (1.0 mL), and TFA (0.39 mL,
5.3 mmol) was added. The reaction was stirred at RT for 30 minutes,
concentrated, and partitioned between saturated aqueous sodium
bicarbonate and DCM. The organic layer was washed with brine, dried
over anhydrous sodium sulfate, filtered, and concentrated to
provide the title compound (42 mg, 21% yield). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.67 (s, 1H), 9.33 (br. s., 1H), 9.18
(br. s., 1H), 8.59 (d, J=1.76 Hz, 1H), 7.92-8.13 (m, 2H), 7.70 (d,
J=5.58 Hz, 1H), 7.19 (dd, J=8.90, 12.72 Hz, 1H), 2.73-2.89 (m, 1H),
2.67 (d, J=9.10 Hz, 1H), 2.54 (s, 3H), 2.01-2.19 (m, 2H), 1.97 (s,
3H), 1.64 (s, 3H), 1.45 (br. s., 3H). LC/MS (ESI.sup.+) m/z=479.0
(M+H).
[0884] The following compounds in Table 1 are examples of compounds
of Formulas I, II and III, and sub-formulas thereof, provided by
the present invention in Table 1 hereinabove. The methods used to
prepare the exemplary compounds are included in Table 1. Table I
further provides the mass and biological data (average nM
IC.sub.50's for the enzyme and cell assays) for each compound,
where available.
TABLE-US-00001 TABLE 1 BACE1 HEK FRET cell assay assay CatD Example
IC.sub.50 IC.sub.50 IC50 No Compound Name (uM) (uM) (.mu.M) 1
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-9,9- 0.037 0.057 45.8
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 2
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-9,9- 0.13 0.055 166
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 3
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-9,9- 0.002 0.007 119
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 4
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-9,9- 0.007 0.020 270
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 5
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-9,9- 0.003 0.004 105
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 6
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-9,9- 0.010 0.004 215
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 7
N-(3-((1S,2R,5R)-4-amino-1-fluoro-2,5- 0.007 0.22 22.6
dimethyl-9,9-dioxido-9-thia-3- azabicyclo[3.3.1]non-3-en-2-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 9
N-(3-((1S,2R,5R)-4-amino-1-fluoro-2,5- 0.007 0.149 19
dimethyl-9,9-dioxido-9-thia-3- azabicyclo[3.3.1]non-3-en-2-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3-methyl- 2-pyridinecarboxamide 8
N-(3-((1R,2R,5S)-4-amino-1-fluoro-2,5- 0.004 0.113 22.7
dimethyl-9,9-dioxido-9-thia-3- azabicyclo[3.3.1]non-3-en-2-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 10
N-(3-((1R,2R,5S)-4-amino-1-fluoro-2,5- 0.009 0.035 8.75
dimethyl-9,9-dioxido-9-thia-3- azabicyclo[3.3.1]non-3-en-2-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3-methyl- 2-pyridinecarboxamide
11 N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl- 0.006 0.031 51.5
9,9-dioxido-9-thia-3-azabicyclo[3.3.1]non-3-
en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl- 2-pyridinecarboxamide
12 N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl- 0.005 0.033 29.7
9,9-dioxido-9-thia-3-azabicyclo[3.3.1]non-3-
en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl- 2-pyridinecarboxamide
13 N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl- 0.013 0.006 8.64
9,9-dioxido-9-thia-3-azabicyclo[3.3.1]non-3-
en-2-yl)-4-fluorophenyl)-5- (difluoromethoxy)-3-methyl-2-
pyridinecarboxamide 14 N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-
0.009 0.002 17.7 9,9-dioxido-9-thia-3-azabicyclo[3.3.1]non-3-
en-2-yl)-4-fluorophenyl)-5- (difluoromethoxy)-3-methyl-2-
pyridinecarboxamide 15 N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-
0.049 0.027 138 9,9-dioxido-9-thia-3-azabicyclo[3.3.1]non-3-
en-2-yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 16
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl- 0.020 0.016 85.2
9,9-dioxido-9-thia-3-azabicyclo[3.3.1]non-3-
en-2-yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 17
N-(3-((1R,2R,5R)-4-amino-2-methyl-9,9- 0.015 0.064 2780
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 18
N-(3-((1R,2R,5R)-4-amino-2-methyl-9,9- 0.043 0.018 690
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 20
N-(3-((1S,2R,5S)-4-amino-2-methyl-9,9- 0.003 0.006 717
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 19
N-(3-((1R,2R,5R)-4-amino-2-methyl-9,9- 0.323 0.179 1210
dioxido-9-thia-3-azabicyclo[3.3.1]non-3-en-
2-yl)-4-fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 21
N-(3-((1R,2R,5S)-4-amino-2-methyl-8,8- 0.016 0.081 1640
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 33
N-(3-((1S,2R,5R)-4-amino-2-methyl-8,8- 8.46 >15.6 1540
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 22
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.002 0.002 1740
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 34
N-(3-((1R,2S,5S)-4-amino-2,5-dimethyl-8,8- 4.54 2.03 4310
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 23
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.002 0.001 117
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(difluoromethoxy)-3-
methyl-2-pyridinecarboxamide 35
(1R,4R,5S)-4-(5-amino-2-fluorophenyl)-1,4- 10.1 5.81 287
dimethyl-8-thia-3-azabicyclo[3.2.1]oct-2-en- 2-amine 8,8-dioxide 26
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.008 0.017 577
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 24
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.005 0.001 591
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-methyl-5-
(trifluoromethyl)-2-pyridinecarboxamide 25
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.021 0.004 318
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-6-chloro-3- methylimidazo[1,2-a]pyridine-2-
carboxamide 29 N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.001
0.052 733 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7- naphthyridin-8-amine 28
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.070 0.010 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-6-chloro-3- methylimidazo[1,2-a]pyridine-2-
carboxamide 27 N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.014
0.002 2040 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-methyl-5-
(trifluoromethyl)-2-pyridinecarboxamide 31
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl- 0.004 0.012 56.9
8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-
en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl- 2-pyridinecarboxamide
32 N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl- 0.007 0.017 131
8,8-dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-
en-2-yl)-4-fluorophenyl)-5-chloro-3-methyl- 2-pyridinecarboxamide
30 N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.033 0.163 4500
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7- naphthyridin-8-amine 36
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.002 0.006 5490
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7- naphthyridin-8-amine 37
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.004 0.001 1170
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide
Intermediate 28
##STR00130##
[0885] Synthesis of
5-((4,4-Dimethylpent-2-yn-1-yl)oxy)pyrazine-2-carboxylic acid
[0886] 3,3-Dimethyl-1-butyne (1.0 mL, 8.12 mmol) was dissolved in
dry tetrahydrofuran (5 mL) under nitrogen and cooled in a dry ice
bath. Butyllithium (2.5 M in hexanes, 3.25 mL, 8.12 mmol) was added
slowly and the reaction stirred for 20 minutes. The clear solution
was removed from the dry ice bath and placed in an acetone/ice bath
and stirred for another 5 minutes. Paraformaldehyde (0.200 g, 8.12
mmol) was added in one portion. The mixture was stirred for 3 hours
then quenched by addition of saturated ammonium chloride (20 mL).
Dichloromethane (100 mL) and water (100 mL) were added and the
phases mixed and separated. The organic was dried with magnesium
sulfate and evaporated to .about.2 mL. The crude solution of
4,4-dimethylpent-2-yn-1-ol was treated with lithium
bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran, 2.5
ml, 2.500 mmol) under nitrogen. Dry dimethylformamide (1 mL) was
added and the mixture heated in a 60.degree. C. bath. A solution of
methyl 5-chloro-2-pyrazinecarboxylate (0.250 g, 1.449 mmol) in dry
dimethylformamide (2 mL) was added dropwise over 30 minutes. Once
the addition was complete the reaction was cooled and water (50 mL)
and hexanes (100 mL) were added. The phases were mixed and
separated. The aqueous washed with DCM (50 mL) then concentrated to
.about.10 mL under reduced pressure. The pH was adjusted to 5 using
2 N HCl and the product extracted with ethyl acetate (3.times.50
mL). The combined ethyl acetate fractions were dried with magnesium
sulfate and evaporated to dryness under reduced pressure. The crude
5-((4,4-dimethylpent-2-yn-1-yl)oxy)pyrazine-2-carboxylic acid
(0.112 g, 0.478 mmol, 33.0% yield) was used without further
purification. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 1.23
(s, 9H) 5.05 (s, 2H) 8.30 (s, 1H) 8.90 (s, 1H). LC/MS (ESI.sup.+)
m/z=235.1 (M+H).
Intermediate 29
##STR00131##
[0887] Synthesis of
5-((2-Methylbut-3-yn-2-yl)oxy)pyrazine-2-carboxylic acid
Step 1. methyl
5-((2-methylbut-3-yn-2-yl)oxy)pyrazine-2-carboxylate
[0888] 5-Chloro-2-methoxycarbonyl pyrazine (0.250 g, 1.449 mmol),
2-methyl-3-butyn-2-ol (Fluka, 1.5 ml, 15.48 mmol),
1,8-diazabicyclo-[5.4.0]undec-7-ene (0.75 ml, 5.02 mmol), and
4-dimethylaminopyridine (0.102 g, 0.835 mmol) were combined in a
vial and heated in the microwave to 100.degree. C. for 10 minutes.
The vial was opened and the crude partitioned between water (75 mL)
and hexane (100 mL). The organic was dried with magnesium sulfate
and evaporated to dryness under reduced pressure to give methyl
5-((2-methylbut-3-yn-2-yl)oxy)pyrazine-2-carboxylate (0.210 g,
0.954 mmol, 65.8% yield) as an off white solid. .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta. ppm 1.86 (s, 6H) 2.55 (s, 1H) 3.98 (s,
3H) 8.23 (d, J=1.32 Hz, 1H) 8.91 (d, J=1.32 Hz, 1H).
Step 2. 5-((2-Methylbut-3-yn-2-yl)oxy)pyrazine-2-carboxylic
acid
[0889] Methyl 5-((2-methylbut-3-yn-2-yl)oxy)pyrazine-2-carboxylate
(0.210 g, 0.954 mmol) was dissolved in methanol (20 mL). A solution
of lithium hydroxide monohydrate (0.078 ml, 2.81 mmol) in water (5
mL) was added and the reaction stirred for 35 minutes then quenched
by addition of 1 N hydrochloric acid (2.8 mL). The solution was
evaporated to dryness under reduced pressure and the crude further
dried by azeotroping with toluene (3.times.30 mL). The crude solids
were used without further purification. LC/MS (ESI.sup.+) m/z=207.1
(M+H).
Intermediate 30
##STR00132##
[0890] Synthesis of 7-Bromo-4-chloropyrido[3,2-d]pyrimidine
Step 1. 3-amino-5-bromopicolinamide
[0891] 5-Bromo-2-cyano-3-nitropyridine (2.00 g, 8.77 mmol) was
dissolved in dioxane (10 mL). Water (5 mL) and ammonium hydroxide
(28% NH.sub.3 in water, 5.0 ml, 36.0 mmol) were added and the
mixture stirred for 10 minutes. Sodium hydrosulfite (5.0 g, 28.7
mmol) was added in 1 g portions every 5 minutes. After the addition
was complete, the mixture was stirred at RT for 2 hours. Additional
water (100 mL) and ethyl acetate (100 mL) were added and the phases
mixed and separated. The organic was dried with magnesium sulfate
and evaporated to dryness under reduced pressure. Purification
using silica chromatography (1-15% methanol in DCM gradient, dry
load on silica gel) gave 3-amino-5-bromopicolinamide (1.00 g, 4.63
mmol, 52.8% yield) as a light yellow solid.
Step 2. 3-amino-5-bromopicolinamide
[0892] 3-Amino-5-bromopicolinamide (1.00 g, 4.63 mmol) was
suspended in triethyl orthoformate (10 ml, 60.1 mmol) and heated in
a 145.degree. C. bath under nitrogen. The reaction was heated for
21/2 hours then the mixture was evaporated to dryness under reduced
pressure. The dark crude was azeotroped with toluene (3.times.50
mL) then further dried under high vacuum. The crude
7-bromopyrido[3,2-d]pyrimidin-4-ol (1.02 g, 4.51 mmol) was used
without purification.
Step 3. 7-bromopyrido[3,2-d]pyrimidin-4-ol
[0893] 7-Bromopyrido[3,2-d]pyrimidin-4-ol (1.02 g, 4.51 mmol) was
suspended in dry toluene (80 mL) under nitrogen. Phosphorus
oxychloride (5.0 mL, 54.6 mmol) was added and the mixture heated to
reflux under nitrogen. After 5 hours the reaction was cooled to RT.
The solution was placed in a water bath and saturated sodium
bicarbonate (50 mL) was added slowly with strong stirring. After 45
minutes the phases were separated and the organic evaporated to
dryness under reduced pressure. The crude
7-bromo-4-chloropyrido[3,2-d]pyrimidine (0.46 g, 1.89 mmol, 42%
yield) was used without further purification. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 8.59 (d, J=1.96 Hz, 1H) 9.11-9.15 (m,
2H). LC/MS (ESI.sup.+) m/z=243.8 (M+H).
Intermediate 31
##STR00133##
[0894] Synthesis of
2-(((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)oxazole
Step 1. 2,5-dichloropyrido[3,4-b]pyrazine
[0895] A mixture of 5-chloro-2-methoxypyrido[3,4-b]pyrazine (2.76
g, 14.11 mmol), phosphorus oxychloride (17.10 mL, 183 mmol) and DMF
(1.09 mL, 14.12 mmol) was heated at 100.degree. C. overnight. The
mixture was concentrated in vacuo. The residue was diluted with
EtOAc (150 mL) and cooled to 0.degree. C. It was treated with ice
water followed by solid NaHCO.sub.3 in small portions. The layers
were separated. The basic aqueous layer was extracted with EtOAc.
The combined organic solution was washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to afford
2,5-dichloropyrido[3,4-b]pyrazine (2.57 g, 12.85 mmol, 91% yield)
as a brown solid. LC/MS (ESI.sup.-) m/z=200, 202 (M+H).sup.+.
Step 2.
2-(((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)oxazole
[0896] At 0.degree. C., to a mixture of
2,5-dichloropyrido[3,4-b]pyrazine (1.64 g, 8.20 mmol),
oxazol-2-ylmethanol (1.19 g, 8.85 mmol) in THF (50 mL) under
N.sub.2 was added sodium hydride (60% wt. dispersion in mineral
oil) (0.35 g, 8.85 mmol) in batches. After 40 min, the reaction was
quenched with saturated NH.sub.4Cl (20 mL) and water (20 mL). The
mixture was diluted with EtOAc (150 mL) and the organic layer was
washed with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo. The solid was suspended in heptane-EtOAc
and filtered to afford
2-(((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)oxazole (1.89 g,
7.20 mmol, 88% yield) as a brown powder. LC/MS (ESC) m/z=263, 265
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) 6=8.70 (s, 1H),
8.51 (d, J=5.7 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H), 7.69-7.64 (m, 1H),
7.21 (s, 1H), 5.68 (s, 2H).
Intermediate 32
##STR00134##
[0897] Synthesis of
8-Chloro-3-(prop-2-yn-1-yloxy)-1,7-naphthyridine and
8-bromo-3-(prop-2-yn-1-yloxy)-1,7-naphthyridine
[0898] To a stirring solution of
8-chloro-3-methoxy-1,7-naphthyridine (0.75 g, 3.85 mmol) in
1,2-dichloroethane (40 mL) at 20.degree. C. under nitrogen was
added boron tribromide (3.71 mL, 38.5 mmol) dropwise. The reaction
mixture was then heated to 70.degree. C. for 2 h. The solvents were
removed under reduced pressure. The resulting solid was suspended
in CH.sub.2Cl.sub.2 (10 mL) and collected by filtration. The solid
was further washed with CH.sub.2Cl.sub.2 (10 mL). The solid was air
dried for 30 min to afford crude a tan solid which was used without
further purification. To a stirring suspension of the above crude
and cesium carbonate (6.31 g, 19.38 mmol) in DMF (5 mL) at
20.degree. C. under nitrogen was added propargyl bromide (691
.mu.L, 7.75 mmol) in one portion and stirred for 18 h. The reaction
mixture was partitioned between EtOAc (25 mL) and 5% NaHCO.sub.3
(50 mL). The organic layer was separated, washed with 5%
NaHCO.sub.3 (50 mL) and sat. NaCl (20 mL). The organic solution was
dried over MgSO.sub.4, concentrated under reduced pressure, then
purified by silica gel chromatography eluting with a gradient of
0-30% EtOAc/heptane to afford 540 mg of off-white solid, as a
mixture of 8-chloro-3-(prop-2-yn-1-yloxy)-1,7-naphthyridine (MS
m/z=219.1 [M+H].sup.+) and
8-bromo-3-(prop-2-yn-1-yloxy)-1,7-naphthyridine (MS m/z=263/265
[M+H].sup.+) in a ratio of about 3:2.
Intermediate 33
##STR00135##
[0899] Synthesis of
5-Chloro-2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazine
[0900] A solution of 3-propynol (0.62 mL, 10.72 mmol) in THF (1 mL)
was added under N.sub.2 to a slurry of sodium hydride (60% wt.
dispersion in mineral oil) (0.43 g, 10.72 mmol) in THF (30 mL) at
0.degree. C. The slurry was stirred for 15 min then added to a
mixture of 2,5-dichloropyrido[3,4-b]pyrazine (1.95 g, 9.75 mmol) in
THF (20 mL) at 0.degree. C. After 20 min, the reaction was quenched
with saturated NH.sub.4Cl (20 mL) and water (20 mL). The mixture
was diluted with EtOAc (200 mL) and the organic layer was washed
with brine (50 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The solid (2.26 g) was suspended in
heptane-DCM and filtered to afford the first batch of
5-chloro-2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazine as a brown
powder (1.81 g). The filtrate was concentrated in vacuo and was
purified by silica gel chromatography (40 g, 0-50% EtOAC in DCM) to
afford the second batch of
5-chloro-2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazine as a white
solid (0.32 g). LC/MS (ESI.sup.-) m/z=220, 222 (M+H).sup.+. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta.=8.66 (s, 1H), 8.50 (d, J=5.7
Hz, 1H), 7.67 (d, J=0.7 Hz, 1H), 5.18 (d, J=2.3 Hz, 2H), 2.58 (t,
J=2.4 Hz, 1H).
Intermediate 34
##STR00136##
[0901] Synthesis of tert-butyl
N-[(1R,2R,5S)-2-(5-amino-2-fluoro-phenyl)-5-(methoxymethyl)-2-methyl-8,8--
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-car-
bamate
Step 1: 2-(methylsulfonyl)pent-4-enenitrile
[0902] To a solution of (methanesulfonyl)acetonitrile (43 g, 361
mmol) in dry acetonitrile (350 mL) at 0.degree. C. was added cesium
carbonate (141 g, 433 mmol), followed by a solution of allyl
bromide (26.5 ml, 307 mmol) in acetonitrile (50 mL) dropwise. The
reaction was stirred at ambient temperature overnight, and then
concentrated. The residue was partitioned between ethyl acetate and
water, and 2N aqueous HCl was added slowly with stirring. When gas
evolution ceased, the layers were separated, and the aqueous layer
was extracted with ethyl acetate. The combined organic phases were
washed water and brine, and concentrated. The crude product was
dissolved in toluene and passed through a pad of silica-gel,
eluting first with 15% ethyl acetate in heptane to remove a higher
running impurity followed by 30% ethyl acetate in heptane to
provide the title compound (20.5 g, 129 mmol, 35.7% yield).
Step 2: 2-(methoxymethyl)-2-(methylsulfonyl)pent-4-enenitrile
[0903] To a solution of 2-(methylsulfonyl)pent-4-enenitrile (5 g,
31.4 mmol) in acetonitrile (50 mL) was added cesium carbonate
(10.23 g, 31.4 mmol) and methoxymethyl chloride (2.86 mL, 37.7
mmol). The reaction was stirred at RT. After 16 hours, the reaction
mixture was partitioned between water and ethyl acetate; the
organic layer was concentrated. The crude product was purified by
column chromatography, eluting with 5-50% ethyl acetate in heptane,
to the title compound (3.9 g, 19.19 mmol, 61.1% yield) as a
colorless oil.
Step 3:
(R)--N--((R)-1-(((S)-2-cyano-1-methoxypent-4-en-2-yl)sulfonyl)-2-(-
2-fluoro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide
[0904] To a solution of
2-(methoxymethyl)-2-(methylsulfonyl)pent-4-enenitrile (3.91 g,
19.24 mmol) in MeTHF (20 mL) at -78.degree. C. was added a 2.8 N
solution of n-butyllithium in heptane (7.00 mL, 19.75 mmol), and
the mixture was stirred for 30 minutes at -78.degree. C.
Separately, to a -40.degree. C. solution of
(R,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide (2.9 g, 10.13 mmol) in toluene (20 mL) was added a 2 M solution
of trimethylaluminum in toluene (5.06 mL, 10.13 mmol), and the
mixture was stirred for 15 minutes at -40.degree. C. The ketimine
mixture was transferred to the sulfone anion solution via syringe
at -78.degree. C., and the reaction was stirred at -78.degree. C.
After 3 hours, the reaction was quenched with the addition of
saturated aqueous ammonium chloride and allowed to warm to RT. The
reaction mixture was partitioned between water and ethyl acetate;
the organic layer was filtered through Celite to remove the
aluminum salts. The organic layer was concentrated, adsorbed onto a
silica-gel loading column, and purified by column chromagtography,
eluting with 30-70% ethyl acetate in heptane, to provide the title
compound (1.25 g, 2.55 mmol, 25.2% yield). LC/MS (ESI.sup.+)
m/z=490.0 (M+H).
Step 4: tert-butyl
N-[(1R,2R,5S)-2-(5-amino-2-fluoro-phenyl)-5-(methoxymethyl)-2-methyl-8,8--
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-car-
bamate
[0905] In a series of reactions analogous to those described in
Intermediate 11, steps 3-4 and Intermediate 12, steps 1-5,
(R)--N--((R)-1-(((S)-2-cyano-1-methoxypent-4-en-2-yl)sulfonyl)-2-(2-fluor-
o-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide was
converted to the title compound. LC/MS (ESI.sup.+) m/z=565.1
(M+Na).
Intermediate 35
##STR00137##
[0906] Synthesis of 4-(But-2-yn-1-yloxy)-2-fluorobenzoic acid
[0907] To a 0.degree. C. solution of methyl
2-fluoro-4-hydroxybenzoate (1.0 g, 5.88 mmol) and 2-butyn-1-ol
(0.824 mL, 11.76 mmol) in THF (25 mL) was added triphenylphosphine
(2.312 g, 8.82 mmol) and diisopropyl azodicarboxylate (1.732 mL,
8.82 mmol). The reaction was stirred at RT for 2 hours. After 2
hours, the reaction mixture was diluted with DCM and washed with
saturated aqueous sodium bicarbonate. The organic layer was
concentrated, and the crude product was purified by column
chromatography, eluting with 10-50% ethyl acetate in heptane. LC/MS
(ESI.sup.+) m/z=223.1 (M+H).
[0908] To a solution of methyl
4-(but-2-yn-1-yloxy)-2-fluorobenzoate (0.82 g, 3.69 mmol) in THF
(10 mL) and methanol (5 mL) was added lithium hydroxide monohydrate
(0.170 g, 4.06 mmol). The reaction was stirred at ambient
temperature. After 16 hours, another portion of LiOH (85 mg, 0.5
eq) was added, and the reaction was continued. After another 24
hours, the reaction mixture was concentrated and partitioned
between water and ethyl acetate. The aqueous layer was acidified to
pH<3 with 6 N aqueous HCl and extracted with ethyl acetate. The
combined organic layers were concentrated to provide the title
compound (0.78 g, 3.75 mmol, quantitative yield) as an off-white
solid. LC/MS (ESI.sup.+) m/z=209.1 (M+H).
Intermediate 36
##STR00138##
[0909] Synthesis of
3-(but-2-yn-1-yloxy)-8-chloro-5-fluoro-1,7-naphthyridine
Step 1: 8-chloro-5-fluoro-1,7-naphthyridin-3-ol
[0910] A 75 mL pressure-resistant vessel was charged with
8-chloro-5-fluoro-3-methoxy-1,7-naphthyridine (0.922 g, 4.34 mmol)
and DCE (10.84 ml). To this was added boron tribromide (2.460 ml,
26.0 mmol) dropwise via syringe. The resulting heterogeneous
mixture was placed in a 70.degree. C. preheated oil bath and
stirred for 6 hours. The reaction mixture was concentrated to
dryness, and the residue was washed with DCM. The solids were
purified by column chromatography, eluting with 2-10% MeOH in
DCM/1% ammonium hydroxide to give
8-chloro-5-fluoro-1,7-naphthyridin-3-ol (0.70 g, 3.52 mmol, 81%
yield). LC/MS (ESI.sup.+) m/z=199.1 (M+H).
Step 2:
3-(but-2-yn-1-yloxy)-8-chloro-5-fluoro-1,7-naphthyridine
[0911] To a 0.degree. C. solution of
8-chloro-5-fluoro-1,7-naphthyridin-3-ol (0.2 g, 1.007 mmol) and
2-butyn-1-ol (0.28 mL, 4.0 mmol) in THF (8 mL) was added
triphenylphosphine (0.53 g, 2.01 mmol) and diisopropyl
azodicarboxylate (0.40 mL, 2.01 mmol). The reaction was stirred at
ambient temperature. After 16 hours, the reaction mixture was
concentrated and purified by column chromatography, eluting with
10-50% ethyl acetate in heptane. The isolated product was
triturated with ether to provide the title compound (0.13 g, 0.519
mmol, 51.5% yield). LC/MS (ESI.sup.+) m/z=251.0 (M+H).
Intermediate 37
##STR00139##
[0912] Synthesis of
4-chloro-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidine
Step 1: 7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(3H)-one
[0913] A microwave vial was charged with cyclopropylmethanol (2231
.mu.l, 27.5 mmol), and 60% sodium hydride in mineral oil (413 mg,
10.33 mmol) was added slowly. The mixture was stirred at RT for 5
minutes, and then 7-chloropyrido[3,2-d]pyrimidin-4(3H)-one (250 mg,
1.377 mmol) was added. The vial was capped and irradiated in the
microwave for 30 minutes at 140.degree. C. After 30 minutes, the
reaction mixture was diluted with dichloromethane and purified by
column chromatography, eluting with 15-100% (90:10:1
DCM/methanol/ammonium hydroxide) in DCM, to provide the title
compound (66 mg, 0.304 mmol, 22.07% yield). LC/MS (ESI.sup.+)
m/z=218.1 (M+H).
Step 2: 4-chloro-7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidine
[0914] To a solution of
7-(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4(3H)-one (66 mg,
0.304 mmol) in toluene (2.2 mL) were added phosphorus oxychloride
(0.5 mL, 5.46 mmol) and Hunig's base (53 .mu.L, 0.304 mmol). A
reflux condenser was installed, and the mixture was stirred at
130.degree. C. for 40 minutes. The brown solution was concentrated,
diluted with dichloromethane, and the pH was adjusted to 6-7 with
saturated sodium bicarbonate. The reaction mixture was extracted
with DCM, and the organic layer was washed with water and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated to
yield the title compound as a dark brown solid, which was used
without further purification. LC/MS (ESI.sup.+) m/z=236.1
(M+H).
Synthetic Scheme for Intermediates 38 and 39
##STR00140## ##STR00141## ##STR00142##
[0915] Intermediate 38
##STR00143##
[0916] Synthesis of
(1S,2R,5R)-2-(5-amino-2-fluoro-phenyl)-5-(fluoromethyl)-2-methyl-8,8-diox-
o-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-amine
Step 1: 2-(methylsulfonyl)pent-4-enenitrile
[0917] To a suspension of (methanesulphonyl)acetonitrile (5 g, 42.0
mmol) in acetonitrile (210 mL) was added potassium carbonate (325
mesh; 7.54 g, 54.6 mmol). The reaction mixture was stirred for 5
minutes and to this was added a solution of allyl bromide (3.63 mL,
42.0 mmol) in 5 mL of acetonitrile. The reaction mixture was
stirred at RT for 24 hours. The reaction mixture was partitioned
between aqueous ammonium chloride and ethyl acetate. The organic
portion was dried over sodium sulfate and concentrated. The crude
product was purified by silica gel chromatography, eluting with
5-30% ethyl acetate in heptane to afford the title compound (3.78
g, 23.7 mmol, 56.6% yield) as a clear oil.
Step 2: 2-(hydroxymethyl)-2-(methylsulfonyl)pent-4-enenitrile
[0918] To a suspension of 2-(methylsulfonyl)pent-4-enenitrile
(3.324 g, 20.9 mmol) in 1,4-dioxane (20.9 mL) was added
formaldehyde (37% wt in water; 3.9 ml, 52.2 mmol) followed by a 1M
solution of TEA in THF (1.0 mL, 1.0 mmol). The reaction mixture was
stirred at 38.degree. C. for 4 hours. The reaction mixture was
partitioned between water and ethyl acetate. The organic portion
was dried over sodium sulfate and concentrated. The crude product
was purified by silica gel chromatography, eluting with 10-40%
ethyl acetate in heptane to afford the title compound (3.8 g, 20.1
mmol, 96% yield) as a tan oil.
Step 3: 2-(fluoromethyl)-2-(methylsulfonyl)pent-4-enenitrile
[0919] A solution of
2-(hydroxymethyl)-2-(methylsulfonyl)pent-4-enenitrile (3.32 g,
17.54 mmol) in DCM (88 mL) was placed in a water bath and stirred
for 5 minutes. To this was added a solution of deoxofluor (9.70 ml,
52.6 mmol) in 10 mL of dichloromethane followed by ethanol (0.205
mL, 3.51 mmol). The water bath was removed and the reaction was
stirred at RT for 24 hours. The reaction mixture was partitioned
between aqueous sodium bicarbonate solution and DCM. The organic
portion was dried over sodium sulfate and concentrated. The crude
product was purified by silica gel chromatography, eluting with
5-30% ethyl acetate in heptane to afford the title compound (2.55
g, 13.34 mmol, 76% yield) as a light yellow oil.
Step 4:
(R)--N-((2R)-1-((2-cyano-1-fluoropent-4-en-2-yl)sulfonyl)-2-(2-flu-
oro-5-nitrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide
[0920] A solution of n-butyllithium (2.61 M in THF; 8.75 mL, 22.84
mmol) was added dropwise to a solution of
2-(fluoromethyl)-2-(methylsulfonyl)pent-4-enenitrile (3.66 g, 19.16
mmol) in THF (46.1 mL) at -78.degree. C. The reaction mixture was
stirred at -78.degree. C. for 40 minutes. In a separate flask, a
solution of
(R,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide (4.22 g, 14.74 mmol) in toluene (46.1 ml) was cooled to
-40.degree. C. and charged with a solution of trimethylaluminum (2M
in toluene; 7.37 mL, 14.74 mmol) dropwise. The reaction mixture was
stirred at -40.degree. C. for 15 minutes and then transferred via
cannula to the alkyl-lithium solution. Upon complete addition, the
reaction was stirred at -40.degree. C. for 2 hours. The reaction
was quenched with aqueous saturated ammonium chloride solution and
diluted with water and ethyl acetate. The organic portion was dried
over sodium sulfate and concentrated. The crude product was
purified by silica gel chromatography, eluting with 10-50% ethyl
acetate in Heptane to provide the title compound (5.422 g, 11.35
mmol, 77% yield) as a yellow solid. LC/MS (ESI.sup.+) m/z=478.1
(M+H).
Step 5:
(3R)-6-allyl-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-3-methyl-
-1,1-dioxo-2H-1,4-thiazin-5-amine
[0921] To a solution of
(R)--N-((2R)-1-((2-cyano-1-fluoropent-4-en-2-yl)sulfonyl)-2-(2-fluoro-5-n-
itrophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide (5.422 g,
11.35 mmol) in DCM (56.8 mL) was added HCl (4N in Dioxane) (8.52
mL, 34.1 mmol). The resulting mixture was stirred at RT for 2
hours. The reaction mixture was concentrated and dried under high
vacuum for 16 hours. The crude solid was dissolved in ethanol (56.8
mL) and treated with copper (I) chloride (1.461 g, 14.76 mmol). The
reaction was stirred at 85.degree. C. for 4 hours. The mixture was
concentrated and partitioned between ethyl acetate (80 mL) and 10%
aq. ammonium hydroxide (15 mL). The organic portion was
concentrated to afford the title compound (4.2 g), which was taken
onto the next step without further purification. LC/MS (ESI.sup.+)
m/z=374.0 (M+H).
Step 6: tert-butyl
N-[(3R)-6-allyl-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-3-methyl-1,1-
-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
[0922] To a solution of
(3R)-6-allyl-5-amino-3-(2-fluoro-5-nitrophenyl)-6-(fluoromethyl)-3-methyl-
-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide (4.2 g, 11.25 mmol) in
dichloromethane (45.0 mL) was added DMAP (0.825 g, 6.75 mmol) and
boc anhydride (6.14 g, 28.1 mmol). The reaction mixture was stirred
vigorously at RT for 18 hours. The mixture was partitioned between
DCM and water. The organic portion was concentrated and the crude
was purified by silica gel chromatography, eluting with 0-40% ethyl
acetate in heptane to provide the title compound (3.73 g, 6.499
mmol, 58% yield) as an off-white foam. LC/MS (ESI.sup.+) m/z=596.2
(M+Na).
Step 7: tert-butyl
N-tert-butoxycarbonyl-N-[(3R)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl-
)-3-methyl-1,1-dioxo-6-(2-oxoethyl)-2H-1,4-thiazin-5-yl]carbamate
[0923] A suspension of tert-butyl
N-[(3R)-6-allyl-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl)-3-methyl-1,1-
-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (3.08
g, 5.36 mmol) in DCM (30.05 mL) and methanol (6.01 mL) was cooled
to -78.degree. C. and stirred at this temperature for 5 minutes. A
stream of ozone in oxygen was then bubbled through the solution for
30 min until the solution turned light blue. Nitrogen was then
passed through the reaction for 15 minutes until the solution
turned colorless. Triphenylphosphine (1.69 g, 6.44 mmol) was added
and the mixture was stirred for 5 minutes at -78.degree. C. and
then brought to RT. The reaction was stirred at RT for 30 minutes
and then concentrated under reduced pressure. The crude residue was
purified by silica gel chromatography, eluting with 0-40% ethyl
acetate in heptane to provide the title compound (2.94 g, 5.11
mmol, 95% yield) as a white foam. LC/MS (ESI.sup.+) m/z=598.1
(M+Na).
Step 8: tert-butyl
N-tert-butoxycarbonyl-N-[(3R)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl-
)-6-(2-hydroxyethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
[0924] A solution of borane tetrahydrofuran complex (1M in THF;
7.66 ml, 7.66 mmol) was added dropwise to a solution of tert-butyl
N-tert-butoxycarbonyl-N-[(3R)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl-
)-3-methyl-1,1-dioxo-6-(2-oxoethyl)-2H-1,4-thiazin-5-yl]carbamate
(2.94 g, 5.11 mmol) in THF (25.5 ml) at 0.degree. C. The mixture
was stirred at 0.degree. C. for 35 minutes. The reaction was
quenched with saturated ammonium chloride solution and then diluted
with water and ethyl acetate. The organic portion was washed with
brine and concentrated to afford the crude product. This was
purified by silica gel chromatography, eluting with 10-80% ethyl
acetate in heptane to provide the title compound (2.36 g, 4.09
mmol, 80% yield) as an off-white foam. LC/MS (ESI.sup.+) m/z=600.2
(M+Na).
Step 9: tert-butyl
N-tert-butoxycarbonyl-N-[(3R,6S)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phe-
nyl)-6-(2-iodoethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
and tert-butyl
N-tert-butoxycarbonyl-N-[(3R,6R)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phe-
nyl)-6-(2-iodoethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
[0925] To a suspension of imidazole (1.089 g, 16.00 mmol) and
triphenylphosphine (2.098 g, 8.00 mmol) in DCM (20.00 mL) was added
iodine (2.030 g, 8.00 mmol) at 0.degree. C. The reaction was
stirred at 0.degree. C. for 5 minutes and then a solution of
tert-butyl
N-tert-butoxycarbonyl-N-[(3R)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phenyl-
)-6-(2-hydroxyethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
(2.31 g, 4.00 mmol) in DCM (20.00 mL) was added dropwise via an
addition funnel. The ice bath was removed, and the reaction was
brought to RT. The resulting mixture was stirred at ambient
temperature for 16 hours and then concentrated to afford a crude
residue. This was purified by silica gel chromatography, eluting
with 10-40% ethyl acetate in heptane to provide the title
compounds. The first eluted peak (retention time at 3.00 minutes)
provided tert-butyl
N-tert-butoxycarbonyl-N-[(3R,6S)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phe-
nyl)-6-(2-iodoethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
(1.1 g, 1.60 mmol, 40.0% yield). The second eluted peak (retention
time at 2.95 minutes) provided tert-butyl
N-tert-butoxycarbonyl-N-[(3R,6R)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phe-
nyl)-6-(2-iodoethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
(1.41 g, 2.05 mmol, 51.3% yield). LC/MS (ESI.sup.+) m/z=710.0
(M+Na).
Step 10: tert-butyl
N-tert-butoxycarbonyl-N-[(1S,2R,5R)-5-(fluoromethyl)-2-(2-fluoro-5-nitro--
phenyl)-2-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbama-
te
[0926] To a solution of tert-butyl
N-tert-butoxycarbonyl-N-[(3R,6R)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phe-
nyl)-6-(2-iodoethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
(1.41 g, 2.05 mmol) in THF (17.04 mL) was added a solution of
lithium bis(trimethylsilyl)amide (1M in THF; 3.07 mL, 3.07 mmol) at
-78.degree. C. The reaction was stirred at -78.degree. C. for 1
hour and then quenched with aqueous ammonium chloride solution and
slowly warmed up to ambient temperature. The reaction mixture was
then diluted with water and ethyl acetate. The organic portion was
dried over sodium sulfate and concentrated to give a crude residue.
This was purified by silica gel chromatography, eluting with 10-60%
ethyl acetate in heptane to provide the title compound (1.14 g,
2.05 mmol, 100% yield) as a light yellow solid. LC/MS (ESI.sup.+)
m/z=582.2 (M+Na).
Step 11: tert-butyl
N-[(1S,2R,5R)-2-(5-amino-2-fluoro-phenyl)-5-(fluoromethyl)-2-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate
[0927] A sealable vessel was charged with tert-butyl
N-tert-butoxycarbonyl-N-[(1S,2R,5R)-5-(fluoromethyl)-2-(2-fluoro-5-nitro--
phenyl)-2-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbama-
te (1.14 g, 2.037 mmol) and purged with Nitrogen (g). 10% Pd/C
(0.434 g, 0.407 mmol) was added portion-wise followed by ethyl
acetate (5.28 mL) and ethanol (15.09 mL). The reaction mixture was
purged with Nitrogen (g) once more, then evacuated and backfilled
with Hydrogen (g). The reaction was stirred at RT for 5 hours. The
reaction mixture was filtered through a pad of celite and rinsed
with ethyl acetate and ethanol. The filtrate was concentrated to
provide the title compound (1.05 g, 1.99 mmol, 97% yield) as a
light yellow solid. LC/MS (ESI.sup.+) m/z=552.2 (M+Na).
Step 12:
(1S,2R,5R)-2-(5-amino-2-fluoro-phenyl)-5-(fluoromethyl)-2-methyl--
8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-amine
[0928] To a suspension of tert-butyl
N-[(1S,2R,5R)-2-(5-amino-2-fluoro-phenyl)-5-(fluoromethyl)-2-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate (0.17 g, 0.321 mmol) in dichloromethane (3 mL) was added
trifluoroacetic acid (0.247 ml, 3.21 mmol). The reaction mixture
was stirred at RT for 1 hour. The mixture was diluted with aqueous
sodium bicarbonate solution and stirred vigorously for 30 minutes.
The product was then extracted with DCM. The organic portion was
concentrated to dryness and the residue was dried under high vac.
for 2 hours. The residue was triturated with ethanol and the solids
were dried to afford the title compound (0.077 g, 0.234 mmol, 77%
yield) as a white solid. LC/MS (ESI.sup.+) m/z=330.0 (M+H).
Intermediate 39
##STR00144##
[0929] Synthesis of tert-butyl
N-[(1R,2R,5S)-2-(5-amino-2-fluoro-phenyl)-5-(fluoromethyl)-2-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate
Step 1: tert-butyl
N-tert-butoxycarbonyl-N-[(1R,2R,5S)-5-(fluoromethyl)-2-(2-fluoro-5-nitro--
phenyl)-2-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbama-
te
[0930] To a solution of tert-butyl
N-tert-butoxycarbonyl-N-[(3R,6S)-6-(fluoromethyl)-3-(2-fluoro-5-nitro-phe-
nyl)-6-(2-iodoethyl)-3-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate
(1.1 g, 1.60 mmol) in THF (13.33 mL) was added a solution of
lithium bis(trimethylsilyl)amide (1M in THF; 2.240 ml, 2.240 mmol)
at -78.degree. C. The reaction was stirred at -78.degree. C. for 1
hour and then quenched with aqueous ammonium chloride solution and
slowly warmed up to RT. The reaction mixture was then diluted with
water and ethyl acetate. The organic portion was dried over sodium
sulfate and concentrated to give a crude residue. This was purified
by silica gel chromatography, eluting with 10-60% ethyl acetate in
heptane to provide the title compound (0.895 g, 1.60 mmol, 100%
yield) as a light yellow solid. LC/MS (ESI.sup.+) m/z=582.2
(M+Na).
Step 2: tert-butyl
N-[(1R,2R,5S)-2-(5-amino-2-fluoro-phenyl)-5-(fluoromethyl)-2-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate
[0931] A sealable vessel was charged with tert-butyl
N-tert-butoxycarbonyl-N-[(1R,2R,5S)-5-(fluoromethyl)-2-(2-fluoro-5-nitro--
phenyl)-2-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbama-
te (0.77 g, 1.376 mmol) and purged with Nitrogen (g). 10% Pd/C
(0.293 g, 0.275 mmol) was added portion-wise followed by ethyl
acetate (3.44 mL) and ethanol (10.32 mL). The reaction mixture was
purged with Nitrogen (g) once more, then evacuated and backfilled
with H.sub.2 (g). The reaction was stirred at RT for 5 hours. The
reaction mixture was filtered through a pad of celite and rinsed
with ethyl acetate and ethanol. The filtrate was concentrated to
provide the title compound (0.70 g, 1.322 mmol, 96% yield) as a
light yellow solid. LC/MS (ESI.sup.+) m/z=552.2 (M+Na).
Intermediate 40
##STR00145##
[0933] 5-(Prop-2-yn-1-yloxy)picolinic acid was purchased from a
commercially available source, such as from Aurora Fine Chemicals
LLC.
Intermediate 41
##STR00146##
[0934] Synthesis of 5-(difluoromethoxy)-3-methylpicolinic acid
Step 1: Synthesis of
5-(difluoromethoxy)-3-methylpicolinonitrile
[0935] A mixture of 2-chloro-5-(difluoromethoxy)-3-methylpyridine
(12.4 g, 64.1 mmol), zinc cyanide (4.07 mL, 64.1 mmol),
1,1'-bis(diphenylphosphino)ferrocene (2.5 g, 4.51 mmol) and
1,1'-bis(diphenylphosphino)ferrocene (2.5 g, 4.51 mmol) in DMA (50
mL) was heated to 110.degree. C. under N.sub.2 for 18 h. The
reaction mixture was diluted with water and extracted with ethyl
acetate. The organic phase obtained was concentrated under reduced
pressure and the residue was purified by silica gel chromatography
eluting with 0-70% EtOAc/hex to give
5-(difluoromethoxy)-3-methylpicolinonitrile (5.88 g, 31.9 mmol,
49.8% yield). MS m/z: 185.0 [M+H].
Step 2: Synthesis of 5-(difluoromethoxy)-3-methylpicolinic acid
[0936] A solution of 5-(difluoromethoxy)-3-methylpicolinonitrile
(5.8 g, 31.5 mmol) and sodium hydroxide 1.0 normal (100 ml, 100
mmol) in EtOH (50 ml) was heated to 80.degree. C. for 18 h. The
reaction mixture was concentrated and diluted with water and
extracted with ether (2.times.). The aqueous layer was acidified to
pH 3 with 1N HCl solution and extracted with TBME (2.times.). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated to give desired product
5-(difluoromethoxy)-3-methylpicolinic acid (4.6 g, 22.64 mmol,
71.9% yield) as a tan solid. MS m/z: 204.1 [M+H].
Intermediate 42
##STR00147##
[0937] Synthesis of 5-Difluoromethyl-3-methyl-pyridine-2-carboxylic
acid
Step 1: 2-Chloro-5-difluoromethyl-3-methyl-pyridine
[0938] To a precooled solution of
6-chloro-5-methyl-pyridine-3-carbaldehyde (500 mg, 3.21 mmol) in
DCM (15 ml) was added at -78.degree. C. DAST (0.632 ml, 0.777 g,
4.82 mmol). The reaction mixture was stirred for 18 h at
-78.degree. C. to rt, then quenched at 0.degree. C. with saturated
aq. NaHCO.sub.3 solution, diluted with water and extracted with
DCM. The organic layer was washed with water and dried over sodium
sulfate, filtered, and concentrated.
2-Chloro-5-difluoromethyl-3-methyl-pyridine was obtained as a
yellow oil after flash chromatography on silica gel
(cyclohexane/EtOAc gradient 0-5 min 100:0, 5-40 min 100:0 to
80:20). ESI MS: 178 [M+H]; .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.=8.38 (d, 1H) 7.72 (d, 1H), 6.69 (t, 1H), 2.46 (s, 3H).
Step 2: 5-Difluoromethyl-3-methyl-pyridine-2-carbonitrile
[0939] A solution of 2-chloro-5-difluoromethyl-3-methyl-pyridine
(337 mg, 1.898 mmol), Zn(CN).sub.2 (159 mg, 1.328 mmol) and Pd
(PPh.sub.3).sub.4 (132 mg, 0.114 mmol) in DMF (10 ml) was stirred
for 10 min at 120.degree. C. in a microwave, filtered over hyflo
and washed with water and brine. The combined aqueous layers were
extracted with TBME, the combined organic layers were dried over
sodium sulfate, filtered and concentrated.
5-Difluoromethyl-3-methyl-pyridine-2-carbonitrile was obtained as a
yellow oil after flash chromatography on silica gel
(cyclohexane/EtOAc gradient 0-3 min 100:0, 3-35 min 100:0 to
80:20). ESI MS: 169 [M+H]; .sup.1H NMR (400 MHz, CDCl.sub.3):
.delta.=8.68 (s, 1H), 7.84 (s, 1H), 6.75 (t, 1H), 2.65 (s, 3H).
Step 3: 5-Difluoromethyl-3-methyl-pyridine-2-carboxylic acid
[0940] A solution of
5-difluoromethyl-3-methyl-pyridine-2-carbonitrile (209 mg, 0.787
mmol) in concentrated aqueous HCl solution (2 ml) was stirred for 2
h at 120.degree. C. in a sealed tube. The reaction mixture was
cooled to rt, diluted with TBME and extracted twice with water. The
combined aqueous layers were washed with TBME and lyophilized. The
residue was dissolved in water, 1M aqueous NaOH solution was added
to adjust the pH to 2 and the solution was extracted three times
with DCM. The combined organic layers were dried over sodium
sulfate, filtered and concentrated to afford
5-Difluoromethyl-3-methyl-pyridine-2-carboxylic acid. ESI MS: 188
[M+H]; .sup.1H NMR (400 MHz, CD.sub.3OD): .delta.=8.62 (s, 1H),
7.98 (s, 1H), 6.95 (t, 1H), 2.65 (s, 3H).
Intermediate 43
##STR00148##
[0941] Synthesis of 5-(methoxymethyl)picolinic acid
Step 1: 2-Chloro-5-(methoxymethyl)pyridine
[0942] To a solution of 2-chloro-5-hydroxymethylpyridine (1 g, 6.97
mmol) in THF (34.8 ml) was added sodium hydride (60% wt) (0.418 g,
10.45 mmol). The reaction was stirred for 10 minutes and treated
with methyl iodide (0.653 ml, 10.45 mmol). The reaction was stirred
at RT for 4 hrs. The reaction mixture was quenched with saturated
NH4Cl and extracted with EtOAc. The organic portion was
concentrated and purified in 10-40% EtOAc/Heptanes to give the
title compound (880 mg, 5.58 mmol, 80% yield) as a tan solid. MS
m/z=157.9 (M+H).
Step 2: 5-(Methoxymethyl)picolinonitrile
[0943] A mixture of 2-chloro-5-(methoxymethyl)pyridine (0.831 g,
5.27 mmol), tetrakis (1.219 g, 1.055 mmol), dicyanozinc (0.929 g,
7.91 mmol) and DMF (17.58 ml) was stirred at 100.degree. C. for 3
hrs. The reaction was treated with water and extracted with ethyl
acetate. The organic portion was dried over Na.sub.2SO.sub.4,
filtered, and concentrated in vacuo. The crude material was
purified by column chromatography, eluting with 10-40%
EtOAc/Heptanes to give the title compound (550 mg, 3.71 mmol,
70.4%). MS m/z=149.1 (M+H).
Step 3: 5-(Methoxymethyl)picolinic acid
[0944] A mixture of 5-(methoxymethyl)picolinonitrile (207 mg, 1.397
mmol) in NaOH (aq. 5N) (2794 .mu.l, 13.97 mmol) and EtOH (5588
.mu.l) was stirred at 80.degree. C. for 16 hrs. The reaction was
concentrated to half its volume and treated with 2N HCl until the
pH reached .about.5. The product was extracted with ethyl acetate.
The organic portion was dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give the title compound (210 mg, 1.26
mmol, 90%) as an off-white solid. MS m/z=167.9 (M+H).
Intermediate 44
##STR00149##
[0945] Synthesis of
4-chloro-7-(trifluoromethyl)pyrido[3,2-d]pyrimidine
Step 1: 3-Nitro-5-(trifluoromethyl)picolinonitrile
[0946] A microwave reaction vial was charged with
2-chloro-3-nitro-5-(trifluoromethyl)pyridine (2 g, 8.83 mmol), NMP
(4.41 ml) and CuCN (0.830 g, 9.27 mmol). The vial was sealed and
the mixture was irradiated in the MW at 175.degree. C. for 15 min.
Upon cooling to RT, the reaction mixture was poured onto ice and
EtOAc was added. The mixture was filtered through Celite, washing
with EtOAc and a small amount of MeOH. The layers of the filtrate
were separated, and the aqueous portion was extracted again with
EtOAc. The combined organic portions were dried with sodium
sulfate, filtered and concentrated. The crude material was purified
by silica gel chromatography, using a gradient of 0-30% EtOAc in
heptane to provide 3-nitro-5-(trifluoromethyl)picolinonitrile (645
mg, 2.97 mmol, 33.7% yield) as a yellow oil that solidified upon
standing. LC/MS (ESI.sup.+) m/z=218.1 (M+H).
Step 2: 3-Nitro-5-(trifluoromethyl)picolinamide
[0947] A round bottom flask was charged with
3-nitro-5-(trifluoromethyl)picolinonitrile (910 mg, 4.19 mmol) and
sulfuric acid (4192 .mu.l, 4.19 mmol), and the mixture was stirred
at 60.degree. C. for 16 h. Upon cooling to RT the crude mixture was
poured onto ice, and the resulting solids were filtered, washed
with water and dried. 3-nitro-5-(trifluoromethyl)picolinamide (850
mg, 3.62 mmol, 86% yield) was isolated as a light yellow solid.
LC/MS (ESI.sup.+) m/z=236.1 (M+H).
Step 3: 3-Amino-5-(trifluoromethyl)picolinamide
[0948] A round bottom flask was charged with
3-nitro-5-(trifluoromethyl)picolinamide (850 mg, 3.62 mmol) and wet
5 wt. % Pd/C (769 mg, 0.362 mmol) and was purged with nitrogen.
EtOAc (7230 .mu.l) and then MeOH (7230 .mu.l) were added, and the
flask was evacuated and filled with hydrogen. The reaction was
stirred at RT under hydrogen atmosphere for 17 h. The mixture was
filtered through Celite and washed with EtOAc and MeOH. The
filtrate was concentrated to provide
3-amino-5-(trifluoromethyl)picolinamide (720 mg, 3.51 mmol, 97%
yield) as a white solid. LC/MS (ESI.sup.+) m/z=206.1 (M+H).
Step 4: 7-(Trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one
[0949] A vial was charged with
3-amino-5-(trifluoromethyl)picolinamide (615 mg, 3.00 mmol) and
triethyl orthoformate (2496 .mu.l, 14.99 mmol). The vial was sealed
and the mixture was heated at 120.degree. C. for 17 h. Upon
cooling, the heterogeneous mixture was filtered and the solids were
washed with heptane.
7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (540 mg, 2.51
mmol, 84% yield) was isolated as a tan solid. LC/MS (ESI.sup.+)
m/z=216.0 (M+H).
Step 5: 4-Chloro-7-(trifluoromethyl)pyrido[3,2-d]pyrimidine
[0950] A pressure bottle was charged with
7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one (540 mg, 2.51
mmol), toluene (10.000 mL) and Hunig's base (1.315 mL, 7.53 mmol).
POCl.sub.3 (0.702 mL, 7.53 mmol) was added, and the bottle was
sealed. The mixture was heated to 115.degree. C. for 4 h. After
cooling to RT, the mixture was diluted with EtOAc and water, and
the layers were separated. The aqueous portion was extracted with
additional EtOAc, and the combined organic portions were washed
with saturated sodium bicarbonate, dried over sodium sulfate,
filtered and concentrated.
4-chloro-7-(trifluoromethyl)pyrido[3,2-d]pyrimidine (560 mg, 2.397
mmol, 96% yield) was isolated as a brown solid. LC/MS (ESI.sup.+)
m/z=234.0 (M+H).
Intermediate 45
##STR00150##
[0951] Synthesis of 5-(cyclopropylethynyl)picolinic acid
Step 1: Methyl 5-(cyclopropylethynyl)picolinate
[0952] To a microwave vial were added methyl
5-bromopyridine-2-carboxylate (0.285 mL, 2.083 mmol), THF (4 mL),
tetrakis(triphenylphosphine)palladium (193 mg, 0.167 mmol),
copper(i) iodide (3.53 .mu.l, 0.104 mmol), and triethylamine (2.318
mL, 16.66 mmol) under nitrogen. Cyclopropylacetylene (0.353 mL,
4.17 mmol) was added and the resulting yellow mixture was stirred
at 40.degree. C. overnight. The reaction mixture was diluted with
water and extracted with EtOAc. The organic extract was washed with
saturated NaCl and dried over MgSO4. The solution was filtered and
concentrated in vacuo to give the crude material as an orange oil.
The crude material was absorbed onto a plug of silica gel and
purified by chromatography through a silica gel column, eluting
with a gradient of 15% to 30% to 45% EtOAc in Heptane, to provide
methyl 5-(cyclopropylethynyl)picolinate (390 mg, 1.938 mmol, 93%
yield) as an orange solid. m/z (ESI) 202.2 (M+H).sup.+.
Step 2: 5-(Cyclopropylethynyl)picolinic acid
[0953] To a sealed tube were added methyl
5-(cyclopropylethynyl)picolinate (240 mg, 1.193 mmol), potassium
hydroxide (0.072 mL, 2.62 mmol), and MeOH (3.98 mL). The mixture
was stirred at 50.degree. C. for 20 minutes. The reaction was
cooled to RT and concentrated. The white solid salt was dissolved
in a minimum amount of water (.about.1.5 mL), and acidified by 6N
HCl to pH=2 (.about.0.6 mL). A light brown precipitate formed and
the resulting mixture was cooled to 0.degree. C. The precipitate
was collected by Buchner funnel to yield
5-(cyclopropylethynyl)picolinic acid (163 mg, 0.871 mmol, 73.0%
yield) as a light yellow solid. m/z (ESI) 188.1 (M+H).sup.+.
Intermediate 46
##STR00151##
[0954] Synthesis of 5-(pent-3-yn-2-yloxy)pyrazine-2-carboxylic
acid
[0955] A RBF was charged with 3-pentyn-2-ol (2.06 mL, 22.08 mmol)
and DMF (10 mL). Potassium t-butoxide, sublimed, 99.99% trace
metals basis (1.24 g, 11.04 mmol) was added portionwise (cooling
with water). The mixture was stirred at room temperature for 10 min
until all t-BuOK went into solution, then
5-chloropyrazine-2-carboxylic acid (0.500 g, 3.15 mmol) was added
in portions and the resulting brown suspension was heated at
75.degree. C. for 45 minutes. The mixture was cooled to RT and
diluted with water (.about.20 ml) until all solids dissolved, then
acidified with 2M HCl (.about.5.5 ml) to pH 2. The resulting
solution was extracted with EtOAc and the organic layer was washed
with water and brine, filtered through a pad of celite and
concentrated in vacuo. The resulting suspension was diluted with 3
mL heptane/EtOAc (20:1) mixture then filtered. The solid was washed
with heptane and dried in vacuo to afford
5-(pent-3-yn-2-yloxy)pyrazine-2-carboxylic acid (424 mg, 2.056
mmol, 65.2% yield) as a tan solid. m/z (ESI) 207.1 (M+H).sup.+.
Intermediate 47
##STR00152##
[0956] Synthesis of 3-chloro-5-(prop-2-yn-1-yloxy)picolinic
acid
Step 1: Prop-2-yn-1-yl 3-chloro-5-(prop-2-yn-1-yloxy)picolinate
[0957] To a suspension of 3-chloro-5-hydroxypicolinic acid (0.400
g, 2.305 mmol, Afferchem) and potassium carbonate (1.115 g, 8.070
mmol) in DMF (10 mL) was added propargyl bromide, 80% solution in
toluene (0.565 mL, 5.070 mmol) dropwise at RT. The mixture was
heated to 45.degree. C. for 1 h, then diluted with EtOAc and washed
with water and brine. The organic solution was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was purified
by silica gel chromatography: 0-50% EtOAc-Hexane. The product
prop-2-yn-1-yl 3-chloro-5-(prop-2-yn-1-yloxy)picolinate was
obtained as yellow solid (0.449 g, 78% yield). LC/MS (ESI.sup.-)
m/z=250 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 2.53 (t, J=2.35 Hz, 1H) 2.63 (t, J=2.25 Hz, 1H) 4.81 (d, J=2.15
Hz, 2H) 4.98 (d, J=2.35 Hz, 2H) 7.41 (d, J=2.54 Hz, 1H) 8.37 (d,
J=2.54 Hz, 1H).
Step 2: 3-chloro-5-(prop-2-yn-1-yloxy)picolinic acid
[0958] A mixture of prop-2-yn-1-yl
3-chloro-5-(prop-2-yn-1-yloxy)picolinate (0.448 g, 1.795 mmol),
lithium hydroxide monohydrate (0.079 g, 1.884 mmol), THF (6 mL),
and water (2 mL) was stirred at RT for 1 h. LCMS showed the
reaction was complete. 1.9 mL of 1N HCl was added to neutralize the
base. The mixture was concentrated in vacuo and dried on vacuum.
The product was obtained as off-white solid (0.456 g, 1.795 mmol,
100% yield). LC/MS (ESI.sup.-) m/z=212 (M+H).sup.+. .sup.1H NMR
(400 MHz, MeOH-d4) .delta. ppm 3.06 (t, J=2.35 Hz, 1H) 4.85 (m, 2H)
7.52 (d, J=2.54 Hz, 1H) 8.01-8.30 (m, 1H).
Intermediate 48
##STR00153##
[0959] Synthesis of
5-chloro-2-(2,2,2-trifluoroethoxy)pyrido[3,4-b]pyrazine
[0960] To a RBF was added 2,2,2-trifluoroethanol (4.85 ml, 66.6
mmol, Sigma-Aldrich Chemical Company, Inc.) and sodium hydride
(0.200 g, 4.99 mmol, Sigma-Aldrich Chemical Company, Inc.) to stir
for 10 minutes. 2,5-Dichloropyrido[3,4-b]pyrazine (0.3329 g, 1.664
mmol) was added in batches to stir at rt. The reaction was allowed
to stir for 1 hour. The reaction was quenched with satd. ammonium
chloride. The reaction mixture was extracted with EtOAc. The
organic extract was washed with satd NaCl, dried over MgSO4,
filtered and concentrated in vacuo to give
5-chloro-2-(2,2,2-trifluoroethoxyl)pyrido[3,4-b]pyrazine (0.5104 g,
1.936 mmol, 116% yield). LCMS showed product peak at 2.13 min
(m+1=263.9). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 4.98
(q, J=8.18 Hz, 2H) 7.67 (d, J=5.70 Hz, 1H) 8.55 (d, J=5.70 Hz, 1H)
8.75 (s, 1H).
Intermediate 48A and 48B
##STR00154##
[0961] Synthesis of ten-butyl
N-[(1S,2S,5R)-2-(5-amino-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate and tert-butyl
N-[(1R,2R,5S)-2-(5-amino-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate
Step 1:
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-1-(((R)-2-cyanopent-4-en-2-
-yl)sulfonyl)-3-fluoropropan-2-yl)-2-methylpropane-2-sulfinamide
and
(R)--N--((R)-2-(5-bromo-2-fluorophenyl)-1-(((S)-2-cyanopent-4-en-2-yl)sul-
fonyl)-3-fluoropropan-2-yl)-2-methylpropane-2-sulfinamide
[0962] A RBF was charged with
2-methyl-2-(methylsulfonyl)pent-4-enenitrile (2.77 g, 15.97 mmol)
and THF (17.74 ml), and the solution was cooled to -78.degree. C.
under nitrogen. N-Butyl lithium (2.7 M, 5.91 ml, 15.97 mmol) was
added dropwise, and the mixture was stirred at -78.degree. C. for
30 min. A separate RBF was charged with
(R,E)-N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-
-sulfinamide (3 g, 8.87 mmol) and THF (17.74 ml) and the solution
was cooled to 0.degree. C. under nitrogen. BF.sub.3--OEt.sub.2
(1.124 ml, 8.87 mmol) was added and the mixture was stirred at
0.degree. C. for 15 min before being added dropwise via cannula to
the lithiate. After addition was complete, the reaction was stirred
at -78.degree. C. for 1.5 h. The reaction was quenched with
saturated aqueous NH.sub.4Cl and allowed to warm to RT. Water and
EtOAc were added, and the layers were separated. The aqueous
portion was washed with EtOAc, and the combined organics were
washed with brine, dried over sodium sulfate, filtered and
concentrated. The crude material was carried forward without
additional purification as part of a mixture of 4 diastereomers.
LC/MS (ESI.sup.+) m/z=511.0 (M+H).
Step 2:
(3S,6R)-6-allyl-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl-
)-6-methyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide and
(3R,6S)-6-allyl-5-amino-3-(5-bromo-2-fluorophenyl)-3-(fluoromethyl)-6-met-
hyl-3,6-dihydro-2H-1,4-thiazine 1,1-dioxide
[0963] Step 2 was carried out in analogy to Intermediate 11, Step 3
to provide the racemic title compound as part of a mixture of 4
diastereomers (1.5 g, 42% yield over 2 steps). LC/MS (ESI.sup.+)
m/z=408.0 (M+H).
Step 3: ten-butyl
N-[(3S,6R)-6-allyl-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-methyl--
1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate and
ten-butyl
N-[(3R,6S)-6-allyl-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-
-6-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
[0964] Step 3 was carried out in analogy to Intermediate 11, Step 4
to provide the racemic title compound as part of a mixture of 4
diastereomers (1.25 g, 56% yield). LC/MS (ESI.sup.+) m/z=629.0
(M+Na).
Step 4: tert-butyl
N-[(3S,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-methyl-1,1-diox-
o-6-(2-oxoethyl)-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-methyl-1,1-diox-
o-6-(2-oxoethyl)-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
[0965] Step 4 was carried out in analogy to Intermediate 12, Step 1
to provide the racemic title compound as part of a mixture of 4
diastereomers. (1.1 g, 88% yield). LC/MS (ESI.sup.+) m/z=631.0
(M+Na).
Step 5: tert-butyl
N-[(3S,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-hydroxyethyl-
)-6-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-hydroxyethyl-
)-6-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
[0966] Step 5 was carried out in analogy to Intermediate 12, Step 2
to provide the racemic title compound as part of a mixture of 4
diastereomers (1.05 g, 95% yield). LC/MS (ESI.sup.+) m/z=633.0
(M+Na).
Step 6: tert-butyl
N-[(3S,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
[0967] A RBF was charged with triphenylphosphine (0.901 g, 3.43
mmol), imidazole (0.468 g, 6.87 mmol) and 4.5 mL DCM, and the
mixture was cooled to 0.degree. C. Iodine (0.872 g, 3.43 mmol) was
added. The mixture became yellow and then brown. After stirring for
5 min, a solution of tert-butyl
N-[(3S,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-hydroxyethyl-
)-6-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-hydroxyethyl-
)-6-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
(1.05 g, 1.717 mmol) in 4.5 mL DCM was added. The reaction was
allowed to warm to RT and was stirred overnight. The mixture was
concentrated and was purified by silica gel chromatography, using a
gradient of 0-50% EtOAc/heptane. tert-butyl
N-[(3S,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
(520 mg, 0.721 mmol, 42.0% yield) eluted second, and was isolated
as a racemic mixture. LC/MS (ESI.sup.+) m/z=742.9 (M+Na).
Step 7: tert-butyl
N-[(1S,2S,5R)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate and tert-butyl
N-[(1R,2R,5S)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate
[0968] A RBF was charged with tert-butyl
N-[(3S,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
(520 mg, 0.721 mmol) and THF (3604 .mu.l) and the solution was
cooled to -78.degree. C. under nitrogen. LHMDS (1 M, 1081 .mu.l,
1.081 mmol) was added dropwise and the mixture was stirred at
-78.degree. C. for 20 min. The reaction was quenched with saturated
aqueous NH.sub.4Cl and allowed to warm to RT. Water and EtOAc were
added and the layers were separated. The aqueous portion was
extracted with additional EtOAc and the combined organics were
dried over sodium sulfate, filtered and concentrated to provide the
title compound as a mixture of enantiomers (428 mg, 100% yield).
LC/MS (ESI.sup.+) m/z=615.0 (M+Na).
Step 8: tert-butyl
N-[(1S,2S,5R)-2-(5-azido-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate and tert-butyl
N-[(1R,2R,5S)-2-(5-azido-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate
[0969] A vial was charged with tert-butyl
N-[(1S,2S,5R)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate and tert-butyl
N-[(1R,2R,5S)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate (387 mg, 0.652 mmol), CuI (8.84 .mu.l, 0.261 mmol), sodium
azide (183 .mu.l, 5.22 mmol), (+)-sodium 1-ascorbate (51.7 mg,
0.261 mmol), trans-n,n'-dimethyl-1,2-cyclohexanediamine (82 .mu.l,
0.522 mmol), EtOH (4658 .mu.l), and water (1863 .mu.l). The vial
was purged with argon and capped, and the reaction was heated to
60.degree. C. for 4.5 h. The mixture was poured into 10:1 saturated
aqueous NH.sub.4Cl:30% NH.sub.4OH and was extracted twice with
EtOAc. The combined organic extracts were dried over sodium
sulfate, filtered and concentrated. The crude material was
dissolved in THF (1629 .mu.l) and water (1629 .mu.l) in a RBF.
Trimethylphosphine (717 .mu.l, 0.717 mmol) was added, and the
reaction was stirred at RT for 15 min. Water and EtOAc were added,
and the layers were separated. The organic portion was dried over
sodium sulfate, filtered and concentrated to provide the title
compound as a mixture of enantiomers (345 mg, 100% yield). LC/MS
(ESI.sup.+) m/z=552.2 (M+Na).
Intermediate 49A and 49B
##STR00155##
[0970] Synthesis of
(1S,4S,5R)-2-amino-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-1-methyl-8-
-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide and
(1R,4R,5S)-2-amino-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-1-methyl-8-
-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide
Steps 1-6: tert-butyl
N-[(3S,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
[0971] Steps 1-6 were carried out as detailed for Intermediate 48,
steps 1-6. In the purification of Step 6, tert-butyl
N-[(3S,6S)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
and tert-butyl
N-[(3R,6R)-3-(5-bromo-2-fluoro-phenyl)-3-(fluoromethyl)-6-(2-iodoethyl)-6-
-methyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate
(598 mg, 0.829 mmol, 48.3% yield) eluted first, and was isolated as
a racemic mixture. LC/MS (ESI.sup.+) m/z=742.9 (M+Na).
Step 7: tert-butyl
N-[(1R,2S,5S)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate and tert-butyl
N-[(1S,2R,5R)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate
[0972] Step 7 was carried out in analogy to Intermediate 48, Step 7
to provide the title compound as a racemic mixture (468 mg, 99%
yield). LC/MS (ESI.sup.+) m/z=615.0 (M+Na).
Step 8: tert-butyl
N-tert-butoxycarbonyl-N-[(1R,2S,5S)-2-(fluoromethyl)-2-(2-fluorophenyl)-5-
-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbamate
And tert-butyl
N-tert-butoxycarbonyl-N-[(1S,2R,5R)-2-(fluoromethyl)-2-(2-fluorophenyl)-5-
-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbamate
[0973] A RBF was flushed with nitrogen and charged with wet Pd/C
(166 mg, 0.078 mmol), tert-butyl
N-[(1R,2S,55)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate and tert-butyl
N-[(1S,2R,5R)-2-(5-bromo-2-fluoro-phenyl)-2-(fluoromethyl)-5-methyl-8,8-d-
ioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]-N-tert-butoxycarbonyl-carbam-
ate (462 mg, 0.778 mmol), EtOAc (3892 .mu.l) and MeOH (3892 .mu.l).
The mixture was flushed with nitrogen, evacuated, and filled with
hydrogen. The reaction was stirred at RT under hydrogen atmosphere
overnight. The mixture was filtered through Celite and washed with
EtOAc. The filtrate was concentrated to provide the title compound
as a racemic mixture (400 mg, 99% yield). LC/MS (ESI.sup.+)
m/z=537.1 (M+Na).
Step 9:
(1S,4S,5R)-2-amino-4-(2-fluoro-5-nitrophenyl)-4-(fluoromethyl)-1-m-
ethyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide and
(1R,4R,5S)-2-amino-4-(2-fluoro-5-nitrophenyl)-4-(fluoromethyl)-1-methyl-8-
-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide
[0974] A RBF was charged with tert-butyl
N-tert-butoxycarbonyl-N-[(1R,2S,55)-2-(fluoromethyl)-2-(2-fluorophenyl)-5-
-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbamate
and tert-butyl
N-tert-butoxycarbonyl-N-[(1S,2R,5R)-2-(fluoromethyl)-2-(2-fluorophenyl)-5-
-methyl-8,8-dioxo-8-thia-3-azabicyclo[3.2.1]oct-3-en-4-yl]carbamate
(400 mg, 0.777 mmol) and potassium nitrate (39.1 .mu.l, 0.816
mmol). Sulfuric acid (1243 .mu.l, 23.32 mmol) was cooled to
0.degree. C. and was added, and the reaction was stirred at
0.degree. C. for 10 min. The reaction was allowed to warm to RT and
was stirred for 3 h. The mixture was cooled to 0.degree. C. and was
brought to pH 8 with saturated aqueous NaHCO.sub.3. Water and EtOAc
were added and the layers were separated. The aqueous portion was
extracted with EtOAc and the combined organic portions were dried
over sodium sulfate, filtered and concentrated to provide the title
compound as a mixture of enantiomers (275 mg, 98% yield). LC/MS
(ESI.sup.+) m/z=360.0 (M+H).
Step 10:
(1S,4S,5R)-2-amino-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-1--
methyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide and
(1R,4R,5S)-2-amino-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-1-methyl-8-
-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide
[0975] A RBF was purged with nitrogen and charged with Pd/C (wet)
(118 mg, 0.056 mmol),
(1S,4S,5R)-2-amino-4-(2-fluoro-5-nitrophenyl)-4-(fluoromethyl)-1-methyl-8-
-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide and
(1R,4R,5S)-2-amino-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-1-methyl-8-
-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide (100 mg, 0.278
mmol), EtOAc (696 .mu.l) and MeOH (696 .mu.l). The flask was
evacuated and filled with hydrogen and the reaction was stirred at
RT under hydrogen atmosphere for 2 h. The mixture was filtered
through Celite and washed with EtOAc. The filtrate was concentrated
and purified by silica gel chromatography, using a gradient of
0-70% 75/25/2 EtOAc/EtOH/NH.sub.4OH in heptane to provide the title
compound as a mixture of enantiomers (90 mg, 99% yield). LC/MS
(ESI.sup.+) m/z=330.0 (M+H).
Intermediate 50
##STR00156##
[0976] Synthesis of
3-Methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid
Step 1. Methyl 5-chloro-3-methylpyrazine-2-carboxylate
[0977] A solution of methyl 3-methylpyrazine-2-carboxylate (9.1 g,
59.8 mmol) in DCM (100 mL) was cooled to 0.degree. C. was added
urea hydrogen peroxide adduct (7.8 g, 83.0 mmol), followed by
dropwise addition of trifluoroacetic acid anhydride (10.8 mL, 78.0
mmol). The resulting mixture was stirred at 0.degree. C. for 1 h,
and at RT for 18 h, during which LCMS indicated a mixture of two
peaks corresponding to MS m/z=169.0 [M+H].sup.+. The reaction was
diluted with DCM and quenched with saturated Na.sub.2SO.sub.3
solution; the aqueous layer was back-extracted with DCM (2.times.).
The combined organic extracts were dried (MgSO.sub.4), filtered and
concentrated in vacuo. ISCO purification (20-80% EtOAc/hexanes)
afforded a mixture of two regioisomers, containing
3-(methoxycarbonyl)-2-methylpyrazine 1-oxide and
2-(methoxycarbonyl)-3-methylpyrazine 1-oxide (5.2 g, 30.9 mmol,
51.7% yield). The mixture of regioisomers was taken to next step
without further purification. MS m/z=169.0 [M+H].sup.+. A solution
of the mixture of 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide and
2-(methoxycarbonyl)-3-methylpyrazine 1-oxide (5.1 g, 15.2 mmol) in
toluene (50 mL) was cooled to 0.degree. C. and phosphorus
oxychloride (2.8 mL, 30.3 mmol) was added under nitrogen followed
by DMF (0.12 mL, 1.52 mmol). The reaction mixture was stirred at RT
for 4 h, and heated to 65.degree. C. for 18 h, cooled to RT,
diluted with EtOAc and washed with saturated NaHCO.sub.3 solution.
The aqueous layer was back-extracted with EtOAc (2.times.). The
combined organic extracts were dried (MgSO.sub.4), filtered and
concentrated in vacuo. ISCO purification (0-50% EtOAc/hexanes) with
care afforded both isomers: methyl
5-chloro-3-methylpyrazine-2-carboxylate (0.68 g) (minor product)
denoted by peak 1 and methyl
6-chloro-3-methylpyrazine-2-carboxylate (1.50 g) (major product)
denoted by peak 2. MS m/z=187.0 [M+H].sup.+. Peak 1: .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 8.73 (s, 1H), 3.91 (s, 3H), 2.71
(s, 3H). Peak 2: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.89
(s, 1H), 3.91 (s, 3H), 2.71 (s, 3H).
Step 2. Methyl
3-methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate
[0978] To a solution of methyl
5-chloro-3-methylpyrazine-2-carboxylate (750 mg, 4.02 mmol) and
propargyl alcohol (356 .mu.L, 6.03 mmol) in 3 mL of DMF was added
potassium carbonate (833 mg, 6.03 mmol). After 1 h, about 70%
desired conversion was detected by LCMS. Additional propargyl
alcohol (356 .mu.L, 6.03 mmol) was added and the reaction was
stirred overnight. The reaction was directly loaded to flash column
(hexanes/EtOAc=10:1 to 5:1 to 4:1) to give methyl
3-methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate (800 mg, 3.88
mmol, 97% yield) as a white gum. MS m/z=207.0 [M+H].sup.+. .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta. 8.18 (s, 1H), 5.06 (d, J=2.48
Hz, 2H), 3.97 (s, 3H), 2.80 (s, 3H), 2.52 (t, J=2.41 Hz, 1H).
Step 3 3-Methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid
[0979] A solution of methyl
3-methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate (800 mg, 3.88
mmol) in THF (10 mL) was treated with lithium hydroxide hydrate
(488 mg, 11.64 mmol) in 10 mL of water and the mixture was stirred
at RT for 3 h. The mixture was treated with 5 M aqueous HCl (2.4
mL), and extracted with DCM (3.times.50 mL). The combined organic
extracts were dried (Na.sub.2SO.sub.4) and concentrated to give
3-methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid (380 mg,
1.98 mmol, 51% yield) as a white solid. MS m/z=193.0 [M+H].sup.+.
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.05 (s, 1H), 5.09 (d,
J=2.48 Hz, 2H), 2.92 (s, 3H), 2.54 (t, J=2.41 Hz, 1H).
Scheme for Intermediate 51
##STR00157## ##STR00158##
[0980] Synthesis of 5-methoxy-3-methylpyrazine-2-carboxylic
acid
Step 1 3-Methylpyrazine-2-carboxylate
[0981] A solution of 3-methylpyrazine-2-carboxylic acid (10 g, 72.4
mmol) in MeOH (80 mL) and sulfuric acid, 95% (5 mL, 90 mmol) was
heated to 60.degree. C. for 4 hours. The solution was concentrated
to remove MeOH, the residue dissolved in 50 mL of water and
neutralized with 10% aq Na.sub.2CO.sub.3 solution to pH 12. The
resulting solution was extracted with ethyl acetate (2.times.). The
combine organic was dried and concentrated to give crude product
methyl 3-methylpyrazine-2-carboxylate (9.1 g, 59.8 mmol, 83%
yield). It was used for next step without further purification.
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 8.63 (1H, s), 8.53
(1H, s), 4.02 (3H, s), 2.87 (3H, s). MS m/z=153 [M+H].sup.+.
Calculated for C.sub.7H.sub.8N.sub.2O.sub.2: 152.0.
Step 2 3-(Methoxycarbonyl)-2-methylpyrazine 1-oxide and
2-(methoxycarbonyl)-3-methylpyrazine 1-oxide
[0982] A solution of methyl 3-methylpyrazine-2-carboxylate (9.1 g,
59.8 mmol) in CH.sub.2Cl.sub.2 (100 mL) was cooled to 0.degree. C.
was added urea hydrogen peroxide adduct, 97% (7.81 g, 83 mmol),
followed by dropwise addition of trifluoroacetic acid anhydride
(10.81 ml, 78 mmol). The resulting mixture was stirred at 0.degree.
C. for 1 h, and at RT for 18 h, during which LCMS indicated a
mixture of the desired product and the side product,
2-(methoxycarbonyl)-3-methylpyrazine 1,4-dioxide. The reaction was
diluted with CH.sub.2Cl.sub.2 and quenched with saturated
Na.sub.2SO.sub.3 solution; the aqueous layer was back-extracted
with CH.sub.2Cl.sub.2 (2.times.). The combined organic extracts
were dried (MgSO4), filtered and concentrated in vacuo. ISCO
purification (20% to 80% EtOAc/Hexanes) afforded mixture of two
regioisomers 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide and
2-(methoxycarbonyl)-3-methylpyrazine 1-oxide (5.2 g, 30.9 mmol,
51.7% yield). The mixture of regioisomers was taken to next step
without further purification. MS m/z=169.0 [M+H].sup.+. Calculated
for C.sub.7H.sub.8N.sub.2O.sub.3: 168.0.
Step 3: Methyl 5-chloro-3-methylpyrazine-2-carboxylate (and methyl
6-chloro-3-methylpyrazine-2-carboxylate
[0983] A solution of mixture of
3-(methoxycarbonyl)-2-methylpyrazine 1-oxide and
2-(methoxycarbonyl)-3-methylpyrazine 1-oxide (5.1 g, 15.17 mmol) in
toluene (50 mL) was cooled to 0.degree. C. and phosphorus
oxychloride (2.78 ml, 30.3 mmol) was added under nitrogen followed
by DMF (0.117 ml, 1.517 mmol). The reaction mixture was stirred at
RT for 4 h, and heated to 65.degree. C. for 18 h, cooled to RT,
diluted with EtOAc and washed with saturated NaHCO.sub.3 solution.
The aqueous layer was back-extracted with EtOAc (2.times.). The
combined organic extracts were dried (MgSO.sub.4), filtered and
concentrated in vacuo. ISCO purification (0% to 50% EtOAc/Hexanes)
with care afforded both isomers methyl
5-chloro-3-methylpyrazine-2-carboxylate (0.68 g) as the desired and
minor product denoted by peak 1 and methyl
6-chloro-3-methylpyrazine-2-carboxylate (1.5 g), as the undesired
and denoted by peak 2. MS m/z=187.0 [M+H].sup.+. Calculated for
C.sub.7H.sub.7C1N.sub.2O.sub.2: 186.0. Peak 1: .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.73 (s, 1H), 3.91 (s, 3H), 2.71 (s,
3H). Peak 2: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.89 (s,
1H), 3.91 (s, 3H), 2.71 (s, 3H)
Step 4: 5-Chloro-2-(methoxycarbonyl)-3-methylpyrazine 1-oxide and
5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide
[0984] To a solution of mixture of methyl
5-chloro-3-methylpyrazine-2-carboxylate and methyl
6-chloro-3-methylpyrazine-2-carboxylate (8.6 g, 46.1 mmol) and
hydrogen peroxide urea adduct (8.1 g, 86 mmol) in DCM (100 mL) was
added 2,2,2-trifluoroacetic anhydride (10.89 ml, 78 mmol) dropwise.
The resulting mixture was stirred at RT for 2 h, during which LCMS
indicated complete transformation to the desired products. The
reaction was diluted with CH.sub.2Cl.sub.2 and quenched with water.
The aqueous layer was back-extracted with CH.sub.2Cl.sub.2
(2.times.). The combined organic extracts were dried (MgSO.sub.4),
filtered, and concentrated in vacuo to give crude products
5-chloro-2-(methoxycarbonyl)-3-methylpyrazine 1-oxide and
5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (8.83 g, 43.6
mmol, 95% yield). MS m/z=203.0 [M+H].sup.+. Calculated for
C.sub.7H.sub.7C1N.sub.2O.sub.3: 202.0. The mixture of the crude
products were used without further purification.
Step 5 methyl 5,6-dichloro-3-methylpyrazine-2-carboxylate
[0985] A solution of mixture of
5-chloro-2-(methoxycarbonyl)-3-methylpyrazine 1-oxide and
5-chloro-3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (8.83 g, 43.6
mmol) in toluene (100 mL) was cooled to 0.degree. C. and phosphorus
oxychloride (10 ml, 109 mmol) was added under nitrogen followed by
DMF (1.0 mL, 12.91 mmol). The reaction mixture was stirred at RT
for 1 h, and at 85.degree. C. for 18 h, cooled to RT and
concentrated. The residue was diluted with EtOAc and washed with
saturated NaHCO.sub.3 solution (CAUTION--generation of CO.sub.2
gas, work up reaction batches as a precaution). The combined
organic extracts were dried (MgSO.sub.4), filtered and concentrated
in vacuo. The residue was purified by ISCO using silica eluting
with 0% to 10% EtOAc/Hexanes to give methyl
5,6-dichloro-3-methylpyrazine-2-carboxylate (6.51 g, 29.5 mmol,
67.6% yield). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 4.00
(3H, s), 2.83 (3H, s). MS m/z=221.0 [M+H].sup.+. Calculated for
C.sub.7H.sub.6Cl.sub.2N.sub.2O.sub.2: 219.9.
Step 6. Methyl
6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate
[0986] To a solution of methyl
5,6-dichloro-3-methylpyrazine-2-carboxylate (6.17 g, 27.9 mmol) in
anhydrous MeOH (100 ml, 2469 mmol) at 0.degree. C. was added slowly
potassium carbonate (4.30 g, 31.1 mmol). The suspension was stirred
at 0.degree. C. for 30 min and warmed to RT for 1 h. The reaction
was filtered and filtrate concentrated to give crude product methyl
6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate (6.2 g, 28.6
mmol, 103% yield). It was used in the next step without further
purification. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 4.11
(3H, s), 3.96 (3H, s), 2.78 (3H, s). MS m/z=217.0 [M+H].sup.+.
Calculated for C.sub.8H.sub.9C1N.sub.2O.sub.3: 216.0
Step 7. Methyl 5-methoxy-3-methylpyrazine-2-carboxylate
[0987] Acetone (200 mL) was added slowly and carefully to a mixture
of methyl 6-chloro-5-methoxy-3-methylpyrazine-2-carboxylate (6.5 g,
30.0 mmol) and 10% Pd/C (3.19 g, 3.00 mmol) in a 500 mL flask under
nitrogen. The flask was cooled to 0.degree. C. and triethylamine
(30 mL, 216 mmol) was added followed by formic acid, 96% (5.66 mL,
150 mmol) dropwise. The suspension was warmed to RT with stirring
and then heated at 40.degree. C. for 1 h. LCMS showed complete
conversion. The reaction mixture was concentrated, diluted with
saturated sodium hydrogenocarbonate solution and extracted with
dichloromethane (2.times.). The organic layer was dried and
concentrated. The crude product was purified by ISCO column
chromatography using 0-20% EtOAc in DCM to give methyl
5-methoxy-3-methylpyrazine-2-carboxylate (5.2 g, 28.5 mmol, 95%
yield). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 8.11 (1H,
s), 4.03 (3H, s), 3.97 (3H, s), 2.80 (3H, s). MS m/z=183.0
[M+H].sup.+. Calculated for C.sub.8H.sub.10N.sub.2O.sub.3:
182.0
Step 8. 5-Methoxy-3-methylpyrazine-2-carboxylic acid
[0988] To a solution of methyl
5-methoxy-3-methylpyrazine-2-carboxylate (5.1 g, 28.0 mmol) in MeOH
(50 mL) was added sodium hydroxide 1N solution (30.8 mL, 30.8
mmol). The reaction was heated to 40.degree. C. for 2 h. LCMS
showed complete conversion to product. The reaction mixture was
concentrated, diluted with water and the pH was adjusted to between
3-4 with 1N HCl solution. The solid that precipitated was filtered
and dried. The acidic filtrate was extracted with EtOAc (3.times.)
and later DCM (2.times.) while maintaining the pH between 3-4 by
addition of 1N HCl solution as necessary. The combined organic was
dried with Na.sub.2SO.sub.4, and concentrated in vacuo to give
another bacth of solid. The solids were combined and dried to give
product 5-methoxy-3-methylpyrazine-2-carboxylic acid (4.5 g, 26.8
mmol, 96% yield). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 13.00
(br. s., 1H), 8.19 (s, 1H), 3.96 (s, 3H), 2.68 (s, 3H). MS
m/z=169.0 [M+H].sup.+. Calculated for C.sub.7H.sub.8N.sub.2O.sub.3:
168.0.
Intermediate 52
##STR00159##
[0989] Synthesis of 5-Cyano-3-methylpicolinic acid
[0990] To a solution of tert-butyl 5-cyano-3-methylpicolinate
(synthesized according to procedure described in WO2012095521; 4.18
g, 19.15 mmol) in DCM (96 mL) was added TFA (Aldrich, 148 mL, 1915
mmol). The reaction mixture was stirred at RT for 2 h. The reaction
mixture was concentrated under reduced pressure and the residue was
triturated with EtOAc. The yellow slurry was concentrated under
reduced pressure. The residue was triturated with 30 mL of methyl
tert-butyl ether (30 mL) and of hexanes (50 mL) to yield
5-cyano-3-methylpicolinic acid (2.91 g, 17.95 mmol, 94% yield) as
yellow solid. MS m/z=163.2 [M+H].sup.+.
Intermediate 53
##STR00160##
[0991] Synthesis of 5-Chloro-3-methylpicolinic acid
Step 1. 5-Chloro-3-methylpicolinonitrile
[0992] A mixture of 2-bromo-5-chloro-3-methylpyridine (45 g, 218
mmol), zinc cyanide (8.30 mL, 131 mmol), tris
(dibenzylideneacetone) dipalladium (0) (4.99 g, 5.45 mmol), and
1,1'-bis(diphenylphosphino)ferrocene (6.04 g, 10.90 mmol) in
dimethylacetamide (40 mL) was heated to 110.degree. C. for 4 h. The
reaction mixture was cooled to RT, diluted with water and extracted
with ethyl acetate. The organic phase obtained was concentrated
under reduced pressure and residue purified by chromatography on
silica gel using ISCO eluting with 0-60% EtOAc/hexanes to afford
5-chloro-3-methylpicolinonitrile (25.4 g, 166 mmol, 76% yield).
LC/MS (ESI.sup.+) m/z=153.1 (M+H).
Step 2. 5-Chloro-3-methylpicolinic acid
[0993] To a solution of 5-chloro-3-methylpicolinonitrile (24.0 g,
157 mmol) in EtOH (100 mL) was added NaOH (110 mL of 5 N solution,
550 mmol). The resulting mixture was refluxed at 90.degree. C. for
18 h. After cooling to RT, the reaction mixture was concentrated.
The residue was diluted with water and the pH of the solution was
adjusted to 4 by addition of 5 N HCl. The solid that precipitated
was filtered and set aside. The filtrate was extracted with EtOAc
(2.times.). The aqueous layer was again acidified with 5 N HCl to
pH 4 and extracted with EtOAc (2.times.). The EtOAc extracts were
combined, dried, and concentrated. The solid obtained from all the
workup steps were combined and dried in a high vac oven at
40.degree. C. for 12 h to give 5-chloro-3-methylpicolinic acid
(268) (24.1 g, 140 mmol, 89% yield). LC/MS (ESI.sup.+) m/z=172.0
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 11.29
(br. s., 1H), 8.41 (d, J=1.76 Hz, 1H), 7.73 (d, J=1.76 Hz, 1H),
2.75 (s, 3H).
Intermediate 54
##STR00161##
[0995] The titled compound,
5-(but-2-yn-1-yloxy)pyrazine-2-carboxylic acid, was synthesized as
described in J. Med. Chem. 2013, 56, 3980.
General Methods
[0996] In addition to the general amidation procedures (Method A
and Method B) described above to couple the aniline core
intermediates R to carboxylic acid intermediates L, described below
are 2 general N-arylation procedures (Method C and Method D) that
may be used to couple the aniline core intermediates R to
heterocyclic intermediates L.
Method C: Sulfuric Acid and Deprotection Procedure
[0997] To a solution of intermediates L and R (1 equivalent each)
in 2-propanol is added concentrated sulfuric acid (1 equivalent).
The reaction is stirred for 20 minutes at 100.degree. C. After 30
minutes, the reaction mixture is diluted with DCM, washed with
saturated aqueous sodium bicarbonate, and concentrated.
[0998] The residue is redissolved in DCM, and TFA (up to 10
equivalents) is added. The reaction is stirred at RT for 1 hour,
diluted with DCM, and washed with saturated aqueous sodium
bicarbonate and brine, and concentrated. The crude product is
purified by silica-gel chromatography to provide the title
compound.
Method D: p-Toluenesulfonic Acid Procedure
[0999] To a solution of Intermediates L and R (1 equivalent each)
in 2-propanol was added p-toluenesulfonic acid (3 equivalents), and
the mixture was stirred at 85.degree. C. for 5 hours. Saturated
aqueous sodium bicarbonate and ethyl acetate were added to the
reaction and the layers were separated. The organic portion was
dried over anhydrous sodium sulfate, filtered and concentrated. The
crude product was purified by silica-gel column chromatography to
provide the title compound.
[1000] Additional methods used to exemplary prepare compounds of
the invention.
Example 38
Method E
##STR00162##
[1001] Synthesis of
N-(3-((1S,2R,5R)-4-Amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-((4,4-dimethylpent-2-yn-1-
-yl)oxy)pyrazine-2-carboxamide
[1002]
(1R,4R,5S)-2-Amino-4-(5-amino-2-fluorophenyl)-1-(fluoromethyl)-4-me-
thyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene 8,8-dioxide (0.100 g,
0.304 mmol) and
5-((4,4-dimethylpent-2-yn-1-yl)oxy)pyrazine-2-carboxylic acid
(0.078 g, 0.334 mmol) were dissolved in dry dimethylformamide (1
mL) under nitrogen and cooled in an ice bath. 1-Propanephosphonic
acid cyclic anhydride (Aldrich, 0.75 ml, 1.260 mmol) was added and
the reaction allowed to stir at RT. After 30 minutes water (50 mL),
saturated sodium bicarbonate (50 mL) and ethyl acetate (100 mL)
were added. The phases were mixed and separated. The organic was
dried with magnesium sulfate and evaporated to dryness under
reduced pressure. Purification using silica chromatography (0-5%
methanol in DCM gradient) gave
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2-methyl-8,8-dioxido-8-thia-3-a-
zabicyclo[3.2.1]oct-3-en-2-yl)-4-fluorophenyl)-5-((4,4-dimethylpent-2-yn-1-
-yl)oxy)pyrazine-2-carboxamide (0.035 g, 0.064 mmol, 21.13% yield)
as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.21-1.30 (m, 9H) 1.59-1.70 (m, 1H) 1.92 (s, 3H) 1.97-2.07 (m, 3H)
2.08-2.28 (m, 2H) 3.86 (d, J=5.28 Hz, 1H) 4.87-5.09 (m, 4H) 5.21
(dd, J=46.95, 10.37 Hz, 2H) 7.09 (dd, J=11.44, 8.90 Hz, 1H) 7.76
(dd, J=6.75, 2.64 Hz, 1H) 7.90 (dt, J=8.46, 3.59 Hz, 1H) 8.97 (s,
1H) 9.52 (s, 1H). LC/MS (ESI.sup.+) m/z=546.0 (M+H).
Example 39
Method F
##STR00163##
[1003] Synthesis of
(1R,4R,5S)-2-amino-4-(2-fluoro-5-((5-fluoro-3-hydroxy-1,7-naphthyridin-8--
yl)amino)phenyl)-1,4-dimethyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene
8,8-dioxide
[1004] A pressure-resistant vessel was charged with
(1R,4R,5S)-2-amino-4-(2-fluoro-5-((5-fluoro-3-methoxy-1,7-naphthyridin-8--
yl)amino)phenyl)-1,4-dimethyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene
8,8-dioxide (0.2 g, 0.410 mmol) and DCE (1.03 mL). To this solution
was added boron tribromide (0.40 mL, 4.10 mmol) dropwise via
syringe. The resulting heterogeneous mixture was placed in an
85.degree. C. preheated oil bath and stirred overnight. The
reaction was cooled to RT and slowly added to ice cold methanol.
The resulting yellow solution was concentrated down and the crude
material was eluted through a reverse phase column using 10-75% 1%
TFA in MeCN/1% TFA in water, extracted into ethyl acetate, washed
once with sodium carbonate, once with water, dried with sodium
sulfate, filtered through a fritted funnel, and concentrated to
yield
(1R,4R,5S)-2-amino-4-(2-fluoro-5-((5-fluoro-3-hydroxy-1,7-naphth-
yridin-8-yl)amino)phenyl)-1,4-dimethyl-8-thia-3-azabicyclo[3.2.1]oct-2-ene
8,8-dioxide as a light yellow solid. m/z (ESI) 474.0
(M+H).sup.+.
Examples 114, 118 and 120
[1005] Racemic intermediates 48A/48B were carried forward to final
compounds by the methods referred to in Table 2, and the final
compounds were purified by chiral SFC chromatography using a
Chiralpak AD-H column, 25% methanol with 0.2% diethylamine, to
provide single enantiomeric exemplary compounds:
Example 113--Peak 1--(ee>99%), Example 114--Peak 2--(ee>99%);
Example 117--Peak 1--(ee>99%), Example 118--Peak 2--(ee>99%);
and Example 119--Peak 1--(ee>99%), Example 120--Peak
2--(ee>99%).
Examples 115 and 116
[1006] Similarly, racemic intermediates 49A/49B were carried
forward to final compounds, and the final compounds were separated
by chiral SFC chromatography using a Chiralpak AD-H column, 25%
methanol with 0.2% diethylamine, to provide:
Example 116--Peak 1--(ee>99%) and, Example 115--Peak
2--(ee>99%).
[1007] The following compounds in Table 2 are examples 38-148 of
compounds of Formulas I, II and III, and sub-formulas thereof,
provided by the present invention. The methods used to prepare the
exemplary compounds, including intermediates L and R that were used
to prepare the compound example, are included in Table 2. Table 2
further includes the mass spec and NMR for each compound example
where available.
TABLE-US-00002 TABLE 2 Mass - Example Synthetic Observed No Method
Intermediate L Intermediate R [M + H].sup.+ NMR 40 D synthesized 39
484 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.60 (m, analogous 1
H) 1.92 (s, 3 H) 2.04-2.22 (m, 3H) 3.82 (m, 1 H) 4.88 to 18 (dd, J
= 46.37, 10.76 Hz, 1 H) 5.10 (dd, J = 47.4, 10.76 Hz, 1 H) 7.10
(dd, J = 11.34, 8.80 Hz, 1 H) 7.68 (dd, J = 6.75, 2.84 Hz, 1 H)
8.11 (m, 1 H) 8.46 (d, J = 1.76 Hz, 1 H) 8.72 (s, 1 H) 8.94 (d, J =
1.76 Hz, 1 H). 41 D 17 39 488.9 1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.65- 1.83 (m, 1 H) 1.95 (s, 3 H) 2.02-2.27 (m, 3 H)
3.88 (m, 1 H) 4.13 (s, 3 H) 4.93 (dd, J = 46.55, 10.37 Hz, 1 H)
5.17 (dd, J = 47.54, 10.37 Hz, 1 H) 7.05 (d, J = 5.87 Hz 2 H) 7.10
(dd, J = 11.54, 9.00 Hz, 1 H) 7.70 (dd, J = 6.85, 2.74 Hz, 1 H)
8.18-8.25 (m, 1 H) 8.22 (d, J = 5.87 Hz, 1 H) 8.29 (s, 1 H) 8.61
(s, 1 H). 42 A commercial 39 479 1H NMR (400 MHz, CHLOROFORM-d) a
ppm 1.65 (m, 1 H) 1.92 (s, 3 H) 1.96-2.25 (m, 3 H) 2.76 (s, 3 H)
3.86 (m, 1 H) 3.90 (s, 3 H) 4.91 (dd, J = 46.56, 10.37 Hz, 1 H)
5.14 (dd, J = 47.15, 10.56 Hz, 1 H) 7.02-7.10 (m, 2 H) 7.60 (dd, J
= 6.85, 2.54 Hz, 1 H) 7.94-8.01 (m, 1 H) 8.04 (d, J = 2.54 Hz, 1 H)
10.08 (s, 1H). 43 A commercial 39 482.9 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.60- 1.70 (m, 1 H) 1.92 (s, 3 H)
1.96-2.06 (m, 1 H) 2.09-2.26 (m, 2 H) 3.85 (d, J = 4.69 Hz, 1 H)
3.93 (s, 3 H) 4.96 (dd, J = 46.75, 10.56 Hz, 1 H) 5.19 (dd, J =
47.14, 10.56 Hz, 1 H) 6.92-7.14 (m, 2 H) 7.72-7.91 (m, 2 H) 8.05
(d, J = 1.96 Hz, 1 H) 9.68 (s, 1 H). 38 E 28 39 546 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 1.21- 1.30 (m, 9 H) 1.59-1.70
(m, 1 H) 1.92 (s, 3 H) 1.97-2.07 (m, 3 H) 2.08-2.28 (m, 2 H) 3.86
(d, J = 5.28 Hz, 1 H) 4.87-5.09 (m, 4 H) 5.21 (dd, J = 46.95, 10.37
Hz, 2 H) 7.09 (dd, J = 11.44, 8.90 Hz, 1 H) 7.76 (dd, J = 6.75,
2.64 Hz, 1 H) 7.90 (dt, J = 8.46, 3.59 Hz, 1 H) 8.97 (s, 1 H) 9.52
(s, 1 H). 44 E 29 39 518 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.59- 1.71 (m, 1 H) 1.83-1.95 (m, 9 H) 1.99-2.28 (m, 3
H) 2.57 (s, 1 H) 3.86 (d, J = 4.89 Hz, 1 H) 4.97 (dd, J = 46.56,
10.37 Hz, 2 H) 5.21 (dd, J = 47.14, 10.56 Hz, 1 H) 7.08 (dd, J =
11.44, 8.90 Hz, 1 H) 7.68 (dd, J = 6.65, 2.54 Hz, 1 H) 7.89-7.96
(m, 1 H) 8.09 (s, 1 H) 9.03 (s, 1 H) 9.50 (s, 1 H). 45 E
synthesized 39 504 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.60- analgous 1.73 (m, 4 H) 1.93 (s, 3 H) 1.99-2.32 (m, 3 H) 2.49
(d, to 29 J = 1.96 Hz, 1 H) 3.87 (d, J = 4.89 Hz, 1 H) 4.99 (dd, J
= 46.56, 10.56 Hz, 1 H) 5.21 (dd, J = 47.14, 10.56 Hz, 1 H) 5.83
(qd, J = 6.65, 1.96 Hz, 1 H) 7.09 (dd, J = 11.54, 8.80 Hz, 1 H)
7.73 (dd, J = 6.85, 2.74 Hz, 1 H) 7.90 (dt, J = 8.41, 3.62 Hz, 1 H)
8.14 (d, J = 0.98 Hz, 1 H) 9.01 (d, J = 1.17 Hz, 1 H) 9.54 (s, 1
H). 46 D 33 39 513 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.63- 1.78 (m, 1 H) 1.95 (s, 3 H) 2.00-2.28 (m, 3 H) 2.57 (t, J =
2.35 Hz, 1 H) 3.87 (d, J = 4.69 Hz, 1 H) 4.98 (dd, J = 46.56, 10.37
Hz, 1 H) 5.21 (dd, J = 47.34, 10.56 Hz, 1 H) 7.03-7.13 (m, 2 H)
7.70 (dd, J = 6.85, 2.74 Hz, 1 H) 8.18 (dt, J = 8.61, 3.62 Hz, 1 H)
8.22 (d, J = 5.87 Hz, 1 H) 8.32 (s, 1 H) 8.60 (s, 1 H) 47 D 30 39
536.9 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.62- 1.74
(m, 1 H) 1.96 (s, 3 H) 2.05-2.31 (m, 3 H) 3.89 (d, J = 4.93 Hz, 1
H) 5.00 (dd, J = 46.56, 10.37 Hz, 1 H) 5.23 (dd, J = 47.14, 10.37
Hz, 1 H) 7.09-7.20 (m, 1 H) 7.79- 7.86 (m, 1 H) 8.13-8.21 (m, 1 H)
8.35 (s, 1 H) 8.74 (s, 1 H) 8.80 (s, 1 H) 9.06 (br. s., 1 H). 48 A
commercial 14A 513.1 1H NMR (400 MHz, DMSO-d6) 10.93 (br. s., 1H),
9.44 (Anichem, NJ) (br. s., 1H), 9.32 (br. s., 1H), 8.93 (s, 1H),
8.35 (s, 1H), 8.25-8.27 (m, 1H), 8.12 (d, J = 14.77 Hz, 1H), 7.88
(br. s., 1H), 7.39 (d, J = 7.24 Hz, 1H), 2.70-2.62 (m, 2H), 2.65
(s, 3H), 2.08 (br. s., 3H), 1.96-2.05 (m, 1H), 1.86 (br. s., 1H),
1.68 (s, 3H), 1.52 (s, 3H) 49 A commercial 14B 513.1 1H NMR (400
MHz, DMSO-d6) d 10.88 (br. s., 1H), (Anichem, NJ) 10.79 (s, 1H),
9.46 (br. s., 1H), 9.19 (br. s., 1H), 8.91 (s, 1H), 8.31 (s, 1H),
7.94-8.16 (m, 1H), 7.68 (dd, J = 2.15, 7.34 Hz, 1H), 7.22 (dd, J =
9.00, 12.81 Hz, 1H), 2.74- 2.87 (m, 1H), 2.61-2.74 (m, 1H), 2.57
(s, 3H), 2.01-2.17 (m, 2H), 1.98-2.01 (m, 3H), 1.97 (s, 3H), 1.64
(s, 3H), 1.45 (s, 3H) 50 D 19 14A 506 1H NMR (400 MHz, DMSO-d6)
.delta. 9.83 (br. s., 1H), 9.01 (s, J = 5.35, 5.35 Hz, 1H), 8.59
(s, J = 5.22 Hz, 1H), 8.12 (s, J = 5.36, 5.36 Hz, 1H), 8.07 (br.
s., 1H), 7.93 (s, 1H), 7.09- 7.16 (m, 1H), 5.97 (br. s., 2H),
2.48-2.61 (m, 2H), 1.84 (br. s., 3H), 1.68-1.79 (m, 1H), 1.52-1.61
(m, 1H), 1.52 (s, 3H), 1.44 (br. s., 3H) 51 D 19 14B 506 1H NMR
(400 MHz, DMSO-d6) d 9.08 (br. s., 1H), 9.04 (d, J = 1.96 Hz, 1H),
8.60 (d, J = 1.96 Hz, 1H), 8.17 (s, 1H), 8.06-8.16 (m, 1H), 7.59
(br. s., 1H), 7.05 (dd, J = 9.10, 12.32 Hz, 1H), 6.04 (br. s., 2H),
2.55-2.65 (m, 1H), 2.14-2.27 (m, 1H), 1.83 (d, J = 8.51 Hz, 2H),
1.70 (d, J = 3.91 Hz, 3H), 1.50 (s, 3H), 1.35 (d, J = 3.91 Hz, 3H)
52 A commercial 39 489 1H NMR (400 MHz, MeOH-d4) .delta. ppm 1.58
(m, 1 H) 1.92 (s, 3 H) 1.70-2.26 (m, 3 H) 3.09 (t, J = 2.15 Hz, 1
H) 3.83 (m, 1 H) 4.94 (d, J = 2.15 Hz, 2 H) 4.98-5.07 (m, 1 H)
5.08-5.23 (m, 1 H) 7.14 (dd, J = 11.74, 8.80 Hz, 1 H) 7.62 (dd, J =
8.61, 2.74 Hz, 1 H) 7.77-7.86 (m, 1 H) 7.90 (d, J = 5.09 Hz, 1 H)
8.17 (d, J = 8.80 Hz, 1 H) 8.40 (d, J = 2.74 Hz, 1 H). 53 D
synthesized 39 501 1H NMR (400 MHz, MeOH-d4) .delta. ppm 1.52-1.72
(m, 1 analogous H) 1.95 (s, 3 H) 1.75-2.29 (m, 3 H) 3.83 (m, 1 H)
5.03- to 18 5.11 (m, 1 H) 5.14-5.22 (m, 1 H) 7.12 (dd, J = 11.64,
8.90 Hz, 1 H) 7.93-8.02 (m, 1 H) 8.11 (m, 1 H) 8.14 (s, 1 H) 8.90
(s, 1 H) 9.15 (s, 1 H) 54 D 19 39 510 1H NMR (400 MHz, MeOH-d4)
.delta. ppm 1.53-1.72 (m, 1 H) 1.95 (s, 3 H) 1.75-2.28 (m, 3 H)
3.83 (m, 1 H) 4.98- 5.09 (m, 1 H) 5.10-5.21 (m, 1 H) 7.11 (dd, J =
11.74, 8.80 Hz, 1 H) 7.96-8.01 (m, 1 H) 8.02 (s, 1H) 7.99-8.14 (m,
2 H) 8.44 (d, J = 2.35 Hz, 1 H) 8.90 (d, J = 2.35 Hz, 1 H) 55 D
commercial 39 527.2 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.75
(m, 1 H) 2.00 (s, 3 H) 2.06-2.45 (m, 3 H) 3.93 (m, 1 H) 4.96 (dd, J
= 47.14, 10.56 Hz, 1 H) 5.20 (dd, J = 46.55, 10.37 Hz, 1 H) 7.15
(dd, J = 11.64, 8.90 Hz, 1 H) 7.36 (d, J = 6.06 Hz, 1 H) 7.83 (dd,
J = 6.85, 2.74 Hz, 1 H) 8.21-8.33 (m, 1 H) 8.42 (d, J = 6.06 Hz, 1
H) 8.93 (s, 1 H) 9.05 (s, 1 H). 56 D 16 39 488.1 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.63- 1.80 (m, 1 H) 1.95 (s, 3 H)
1.98-2.35 (m, 3 H) 3.87 (m, 1 H) 3.97 (s, 3 H) 4.92 (dd, J = 46.56,
10.56 Hz, 1 H) 5.16 (dd, J = 47.15, 10.56 Hz, 1 H) 6.93 (d, J =
5.87 Hz, 1 H) 7.08 (dd, J = 11.64, 8.90 Hz, 1 H) 7.23 (d, J = 2.74
Hz, 1 H) 7.31- 7.32 (m, 1 H) 7.70 (dd, J = 6.85, 2.74 Hz, 1 H) 8.05
(d, J = 5.67 Hz, 1 H) 8.26 (dt, J = 8.51, 3.67 Hz, 1 H) 8.49 (d, J
= 2.54 Hz, 1 H) 8.91 (s, 1 H). 57 A synthesized 39 548 1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.59- analogous 1.71 (m, 1 H) 1.92
(s, 3 H) 2.00-2.32 (m, 3 H) 2.96 (s, 3 to 50 H) 3.88 (m, 1 H) 4.85
(d, J = 8.41 Hz, 1 H) 4.89 (d, J = 8.41 Hz, 1 H) 4.93 (dd, J =
46.75, 10.56 Hz, 1 H) 5.15 (dd, J = 47.15, 10.37 Hz, 1 H) 7.08 (dd,
J = 11.54, 8.80 Hz, 1 H) 7.58 (dd, J = 6.85, 2.74 Hz, 1 H) 7.97
(dt, J = 8.71, 3.57 Hz, 1 H) 7.92-8.02 (m, 1 H) 8.15 (s, 1 H) 9.75
(s, 1 H). 58 D 15 39 492 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.69- 1.85 (m, 1 H) 1.99 (s, 3 H) 2.03-2.37 (m, 3 H) 3.91 (m, 1 H)
4.91 (dd, J = 46.56, 10.37 Hz, 1 H) 5.16 (dd, J = 47.34, 10.56 Hz,
1 H) 6.95 (d, J = 5.87 Hz, 1 H) 7.12 (dd, J = 11.54, 9.00 Hz, 1 H)
7.77 (dd, J = 6.85, 2.74 Hz, 1 H) 8.03 (d, J = 2.35 Hz, 1 H) 8.14
(d, J = 5.87 Hz, 1 H) 8.22- 8.33 (m, 1 H) 8.72 (d, J = 2.15 Hz, 1
H) 8.99 (s, 1 H). 59 A 50 39 504 1H NMR (400 MHz, CHLOROFORM-d)
.delta. = 9.77 (s, 1H), 8.07-8.00 (m, 1H), 7.93 (ddd, J = 2.9, 4.1,
8.8 Hz, 1H), 7.61 (dd, J = 2.7, 6.8 Hz, 1H), 7.07 (dd, J = 8.9,
11.4 Hz, 1H), 5.38-4.85 (m, 4H), 3.87 (d, J = 4.7 Hz, 1H), 2.93 (s,
3H), 2.54 (t, J = 2.3 Hz, 1H), 2.28-1.98 (m, 4H), 1.92 (d, J = 0.8
Hz, 3H), 1.72-1.58 (m, 1H). 60 A 47 39 523 1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.58- 1.72 (m, 1 H) 1.92 (s, 3 H)
1.97-2.04 (m, 1 H) 2.07-2.28 (m, 2 H) 2.65 (t, J = 2.35 Hz, 1 H)
3.86 (d, J = 4.50 Hz, 1 H) 4.82 (d, J = 2.35 Hz, 2 H) 4.87-5.31 (m,
2 H) 7.07 (dd, J = 11.54, 8.80 Hz, 1 H) 7.43 (d, J = 2.54 Hz, 1 H)
7.64 (dd, J = 6.85, 2.74 Hz, 1 H) 7.91-8.04 (m, 1 H) 8.21 (d, J =
2.54 Hz, 1H) 9.81 (s, 1H). 61 A commercial 12 448.1 1H NMR (400
MHz, DMSO-d6) a ppm 1.32 (t, J = l 1.20 Hz, 1 H) 1.49 (s, 3 H) 1.78
(br. s., 4 H) 1.98 (d, J = 8.80 Hz, 1 H) 2.11 (br. s., 1 H)
2.67-2.71 (m, 1 H) 3.63-3.84 (m, 1 H) 3.98-4.07 (m, 3 H) 5.83-6.33
(m, 1 H) 7.20 (t, J = 10.07 Hz, 1 H) 7.81-7.96 (m, 2 H) 8.42 (d, J
= 1.37 Hz, 1 H) 8.85-8.96 (m, 1 H) 10.51 (br. s., 1 H) 62 D
synthesized 12 509.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 1.23 (s, 3 H) 1.47 analogous (s, 3 H) 1.77 (s, 3 H) 1.87 (t, J
= 2.35 Hz, 3 H) 1.90-2.01 to 33 (m, 2 H) 3.66 (d, J = 6.36 Hz, 1 H)
5.15 (q, J = 2.35 Hz, 2 H) 5.93-6.23 (m, 1 H) 7.06 (d, J = 5.77 Hz,
1 H) 7.11-7.19 (m, 1 H) 7.96-8.02 (m, 1 H) 8.06-8.14 (m, 1 H) 8.21-
8.26 (m, 1 H) 8.55-8.61 (m, 1 H) 9.47 (s, 1 H) 63 D synthesized 13
509.1 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.21-
analogous 1.35 (m, 1 H) 1.44 (d, J = 6.26 Hz, 1 H) 1.59 (s, 3 H)
1.69 to 33 (d, J = 0.78 Hz, 3 H) 1.92 (t, J = 2.35 Hz, 3 H) 2.11
(ddd, J = 12.67, 10.22, 4.40 Hz, 1 H) 2.30-2.51 (m, 3 H) 4.01 (d, J
= 5.67 Hz, 1 H) 5.10 (q, J = 2.31 Hz, 2 H) 6.95-7.02 (m, 1 H) 7.07
(dd, J = 11.93, 8.90 Hz, 1 H) 7.60 (dd, J = 7.14, 2.74 Hz, 1 H)
8.12 (ddd, J = 8.78, 4.18, 2.89 Hz, 1 H) 8.21 (d, J = 5.87 Hz, 1 H)
8.29 (s, 1 H) 8.62 (s, 1 H) 64 A 45 12 481.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 0.78-0.87 (m, 2 H) 0.92-1.01 (m, 2 H)
1.19-1.37 (m, 2 H) 1.47 (s, 3 H) 1.65 (tt, J = 8.25, 5.05 Hz, 1 H)
1.71-1.79 (m, 4 H) 1.87- 2.01 (m, 1 H) 2.08 (td, J = 11.98, 4.99
Hz, 1 H) 3.67 (d, J = 5.67 Hz, 1 H) 6.06 (br. s., 1 H) 7.10-7.24
(m, 1 H) 7.88 (dd, J = 6.06, 3.42 Hz, 2 H) 7.99-8.05 (m, 1 H)
8.06-8.12 (m, 1 H) 8.69 (dd, J = 2.00, 0.83 Hz, 1 H) 10.62 (s, 1 H)
65 A 45 13 481.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
0.79-0.86 (m, 2 H) 0.93-1.00 (m, 2 H) 1.42 (s, 3 H) 1.50 (s, 3 H)
1.65 (tt, J = 8.25, 5.00 Hz, 1 H) 1.89 (d, J = 13.20 Hz, 1 H) 2.15-
2.29 (m, 3 H) 2.39 (d, J = 12.62 Hz, 1 H) 3.75 (br. s., 1 H) 6.04
(br. s., 1 H) 7.12 (dd, J = 12.03, 8.71 Hz, 1 H) 7.70- 7.88 (m, 2
H) 7.98-8.04 (m, 1 H) 8.05-8.12 (m, 1 H) 8.69 (dd, J = 2.05, 0.88
Hz, 1 H) 10.29-10.45 (m, 1 H) 66 A commercial 13 448.1 1H NMR (400
MHz, DMSO-d6) a ppm 1.42 (s, 3 H) 1.49 (s, 3 H) 1.75 (s, 1 H)
1.82-1.92 (m, 1 H) 2.12-2.28 (m, 2 H) 2.35-2.46 (m, 1 H) 3.75 (d, J
= 3.62 Hz, 1 H) 3.99- 4.05 (m, 3 H) 6.03 (br. s., 1 H) 7.11 (dd, J
= 12.08, 8.66 Hz, 1 H) 7.73-7.86 (m, 2 H) 8.41 (d, J = 1.37 Hz, 1
H) 8.88 (d, J = 1.27 Hz, 1 H) 10.24 (br. s., 1 H) 67 D synthesized
13 511.1 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.38-
analogous 0.47 (m, 2 H) 0.63-0.73 (m, 2 H) 1.32-1.42 (m, 1 H) to 31
1.62-1.67 (m, 3 H) 1.75 (s, 3 H) 2.02 (s, 3 H) 2.39-2.55 (m, 3 H)
4.06 (d, J = 5.18 Hz, 1 H) 5.39-5.69 (m, 2 H) 6.80-6.88 (m, 1 H)
6.94-6.99 (m, 1 H) 7.01-7.13 (m, 1 H) 7.54-7.67 (m, 1 H) 8.13-8.22
(m, 2 H) 8.58 (s, 1 H) 68 D synthesized 12 511.1 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 0.38- analogous 0.48 (m, 2 H)
0.63-0.75 (m, 2 H) 1.19-1.31 (m, 2 H) to 31 1.31-1.42 (m, 1 H)
1.55-1.58 (m, 3 H) 1.65 (s, 3 H) 1.67- 1.77 (m, 2 H) 1.93-2.00 (m,
4 H) 2.11-2.25 (m, 2 H) 3.88 (d, J = 5.58 Hz, 1 H) 7.00 (d, J =
5.87 Hz, 1 H) 7.05- 7.14 (m, 1 H) 7.71 (dd, J = 6.85, 2.74 Hz, 1 H)
8.16-8.25 (m, 2 H) 8.62 (s, 1 H) 69 A synthesized 12 455.1 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.31 (t, J = 11.84
analogous Hz, 1 H) 1.47 (s, 3 H) 1.68-1.80 (m, 4 H) 1.89-2.01 (m,
to 45 2 H) 2.04-2.12 (m, 1 H) 2.14 (s, 3 H) 3.68 (d, J = 5.87 Hz, 1
H) 6.06 (br. s., 2 H) 7.10-7.23 (m, 1 H) 7.85-7.94 (m, 2 H)
8.02-8.07 (m, 1 H) 8.08-8.14 (m, 1 H) 8.73 (d, J = 1.27 Hz, 1 H)
10.63 (s, 1 H) 70 A 46 12 500.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 0.81-0.91 (m, 1 H) 1.22-1.26 (s, 3 H) 1.28-1.37 (m, 1
H) 1.47 (s, 3 H) 1.59 (d, J = 6.65 Hz, 3 H) 1.75 (s, 3 H) 1.79-1.85
(m, 1 H) 1.88-2.01 (m, 1 H) 2.01-2.13 (m, 1 H) 3.67 (d, J = 6.06
Hz, 1 H) 5.75-5.83 (m, 1 H) 6.07 (br. s., 1 H) 7.17 (dd, J = 11.84,
8.71 Hz, 1 H) 7.85 (dd, J = 8.31, 4.01 Hz, 1 H) 7.91 (dd, J = 7.09,
2.69 Hz, 1 H) 8.41 (d, J = 1.37 Hz, 1 H) 8.90 (d, J = 1.37 Hz, 1 H)
10.49 (s, 1 H) 71 A 46 12 500.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 1.09-1.19 (m, 1 H) 1.23 (s, 3 H) 1.27-1.37 (m, 1 H)
1.47 (s, 3 H) 1.59 (d, J = 6.55 Hz, 3 H) 1.75 (s, 3 H) 1.79-1.83
(m, 1 H) 1.88- 2.01 (m, 1 H) 2.02-2.15 (m, 1 H) 3.67 (d, J = 6.36
Hz, 1 H) 5.73-5.85 (m, 1 H) 6.10 (s, 1 H) 7.17 (dd, J = 11.84, 8.71
Hz, 1 H) 7.81-7.95 (m, 2 H) 8.42 (d, J = 1.27 Hz, 1 H) 8.90 (d, J =
1.27 Hz, 1 H) 10.49 (s, 1 H) 72 A 53 49A 482.9 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 1.45 (s, 3 H) 1.84- 1.98 (m, 1 H)
1.85-1.97 (m, 1 H) 2.14-2.32 (m, 2 H)
2.37-2.47 (m, 1 H) 2.54-2.59 (m, 3 H) 3.99 (dd, J = 5.99, 2.57 Hz,
1 H) 4.44-4.54 (m, 1 H) 4.56-4.66 (m, 1 H) 7.12 (d, J = 8.86 Hz, 1
H) 7.15 (d, J = 8.91 Hz, 1 H) 7.77 (dd, J = 7.15, 2.70 Hz, 1 H)
7.85 (ddd, J = 8.86, 4.17, 2.98 Hz, 1 H) 8.02 (dd, J = 2.33, 0.78
Hz, 1 H) 8.56-8.66 (m, 1 H) 10.46 (s, 1 H) 73 A 53 49B 482.9
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 1.45 (s, 3 H) 1.82- 2.00
(m, 1 H) 2.12-2.32 (m, 2 H) 2.40 (br. s., 1 H) 2.54- 2.59 (m, 3 H)
3.98-4.05 (m, 1 H) 4.44-4.54 (m, 1 H) 4.56-4.66 (m, 1 H) 6.28 (br.
s., 1 H) 7.12 (d, J = 8.81 Hz, 1 H) 7.15 (d, J = 8.97 Hz, 1 H) 7.77
(dd, J = 7.36, 2.75 Hz, 1 H) 7.81-7.93 (m, 1 H) 8.00-8.12 (m, 1 H)
8.56-8.68 (m, 1 H) 10.46 (s, 1 H) 74 A commercial 49B 466 1H NMR
(400 MHz, DMSO-d6) .delta. ppm 1.37-1.51 (m, 3 H) 1.85-1.95 (m, 1H)
2.13-2.32 (m, 1 H) 2.18-2.30 (m, 1 H) 2.39-2.47 (m, 1 H) 3.40-3.44
(m, 1 H) 3.46-3.53 (m, 1 H) 4.01 (dd, J = 6.40, 2.36 Hz, 1 H) 4.03
(s, 3 H) 4.50- 4.60 (m, 1 H) 4.63 (s, 1 H) 7.14 (dd, J = 12.15,
8.84 Hz, 1 H) 7.79-7.86 (m, 1 H) 7.95 (dd, J = 7.31, 2.85 Hz, 1 H)
8.42 (d, J = 1.35 Hz, 1 H) 8.89 (d, J = 1.35 Hz, 1 H) 10.31 (s, 1
H) 75 A commercial 49A 466 1H NMR (400 MHz, DMSO-d6) .delta. ppm
1.41-1.50 (m, 3 H) 1.84-1.93 (m, 1 H) 2.18-2.31 (m, 2 H) 2.39-2.48
(m, 1 H) 3.40-3.44 (m, 1 H) 3.46-3.53 (m, 2 H) 4.01 (d, J = 5.23
Hz, 1 H) 4.03 (s, 3 H) 4.50-4.60 (m, 1 H) 7.14 (dd, J = 12.13, 8.86
Hz, 1 H) 7.79-7.86 (m, 1 H) 7.95 (dd, J = 7.15, 2.85 Hz, 1 H) 8.42
(d, J = 1.35 Hz, 1 H) 8.89 (d, J = 1.35 Hz, 1 H) 10.31 (s, 1 H) 39
F synthesized 12 474 1H NMR (400 MHz, DMSO-d6) .delta. 9.27 (s,
1H), 8.60 (d, analogous J = 2.70 Hz, 1H), 8.07-8.17 (m, 1H),
7.94-8.01 (m, 2H), to 20 7.44 (d, J = 2.70 Hz, 1H), 7.12 (dd, J =
8.81, 11.71 Hz, 1H), 4.28-4.40 (m, 1H), 3.66 (d, J = 6.84 Hz, 1H),
3.44 (q, J = 6.84 Hz, 2H), 2.05-2.17 (m, 1H), 1.88-2.01 (m, 1H),
1.76 (s, 3H), 1.68-1.75 (m, 1H), 1.47 (s, 3H), 1.37 (t, J = 13.58
Hz, 1H) 76 A 51 38 480 1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.43
(br. s, 1 H) 8.26 (s, 1 H) 7.80-7.88 (m, 1 H) 7.78 (d, J = 6.70 Hz,
1 H) 7.12-7.28 (m, 1 H) 6.22 (br. s., 2 H) 4.91-5.25 (m, 2 H) 4.00
(s, 3 H) 3.71-3.79 (m, 1 H) 2.78 (s, 3 H) 1.97-2.03 (m, 2 H) 1.76
(s, 3 H) 1.35-1.42 (m, 2 H) 77 A commercial 38 469 1H NMR (400 MHz,
DMSO-d6) .delta. ppm 10.66 (br. s, 1 H) 8.79 (dd, J = 2.31, 0.65
Hz, 1 H) 8.14-8.22 (m, 2 H) 7.78- 7.87 (m, 2 H) 7.15-7.26 (m, 1 H)
6.23 (br. s., 2 H) 4.89- 5.23 (m, 2 H) 3.71-3.80 (m, 1 H) 1.86-2.05
(m, 2 H) 1.78 (s, 3 H) 1.21-1.38 (m, 2 H) 78 D 20 12 488 1H NMR
(400 MHz, DMSO-d6) .delta. ppm 9.34 (s, 1 H) 8.72 (d, J = 2.74 Hz,
1 H) 8.07-8.14 (m, 2 H) 8.00 (dd, J = 7.24, 2.84 Hz, 1 H) 7.72 (d,
J = 2.84 Hz, 1 H) 7.14-7.22 (m, 1 H) 6.06 (br. s., 2 H) 4.05 (s, 3
H) 3.62-3.73 (m, 1 H) 1.92- 2.13 (m, 2 H) 1.77 (s, 3 H) 1.48 (s, 3
H) 1.19-1.41 (m, 2 H) 79 A 51 12 462 1H NMR (500 MHz, DMSO-d6)
.delta. ppm 10.38 (br. s., 1 H) 8.23 (s, 1 H) 7.81-7.87 (m, 1 H)
7.78 (d, J = 4.98 Hz, 1 H) 7.11-7.28 (m, 1 H) 6.01 (br. s., 2 H)
3.99 (s, 3 H) 3.63- 3.78 (m, 1 H) 2.76 (s, 3 H) 1.88-2.08 (m, 2 H)
1.74 (s, 3 H) 1.46 (s, 3 H) 1.22-1.39 (m, 2 H) 80 C 17 12 471.2 1H
NMR (400 MHz, DMSO-d6) .delta. ppm 9.51 (br. s., 1 H) 8.62 (s, 1 H)
8.28 (d, J = 5.77 Hz, 1 H) 8.10-8.20 (m, 1 H) 8.02-8.10 (m, 1 H)
7.10-7.26 (m, 2 H) 6.12 (br. s., 2 H) 4.16 (s, 3 H) 3.68-3.75 (m, 1
H) 1.94-2.24 (m, 2 H) 1.69-1.73 (m, 1 H) 1.80 (s, 3 H) 1.53 (s, 3
H) 1.34-1.39 (m, 1 H) 81 A 17 13 471.2 1H NMR (400 MHz, DMSO-d6)
.delta. ppm 9.12 (br. s., 1 H) 8.56 (s, 1 H) 8.25 (d, J = 6.03 Hz,
1 H) 8.11-8.18 (m, 1 H) 7.77-7.93 (m, 1 H) 7.03-7.16 (m, 2 H) 6.10
(br. s, 2 H) 4.08 (s, 3 H) 3.69-3.89 (m, 1 H) 2.38-2.42 (m, 1 H)
2.19-2.31 (m, 2 H) 1.86-1.74 (m, 1 H) 1.53 (s, 3 H) 1.42 (s, 3 H)
82 A 54 12 486.2 1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 9.45
(s, 1 H) 8.94 (s, 1 H) 8.11 (s, 1 H) 7.72-7.84 (m, 1 H) 7.64 (dd, J
= 6.85, 2.74 Hz, 1 H) 7.02 (dd, J = 11.49, 8.85 Hz, 1 H) 4.94-5.01
(m, 2 H) 3.74-3.79 (m, 1 H) 2.04-2.16 (m, 3 H) 1.87 (s, 3 H) 1.82
(s, 3 H) 1.56 (s, 3 H) 1.47- 1.52 (m, 1 H) 83 A 54 13 486.2 1H NMR
(400 MHz, DMSO-d6) .delta. ppm 10.32 (br. s., 1 H) 8.94 (s, 1 H)
8.51 (s, 1 H) 7.80-7.94 (m, 2 H) 7.12-7.22 (m, 1 H) 6.07 (br. s, 2
H) 5.08-5.16 (m, 2 H) 3.77-3.86 (m, 1 H) 2.40-2.51 (m, 1 H)
2.18-2.35 (m, 2 H) 1.95- 1.99 (m, 1 H) 1.88-1.93 (m, 3 H) 1.56 (s,
3 H) 1.48 (s, 3 H) 84 D 18 12 465 1H NMR (400 MHz, DMSO-d6) .delta.
ppm 9.72 (br. s, 1 H) 9.23 (d, J = 1.96 Hz, 1 H) 8.99 (d, J = 1.96
Hz, 1 H) 8.21 (d, J = 5.67 Hz, 1 H) 8.11-8.17 (m, 1 H) 8.02-8.05
(m, 1 H) 7.14-7.24 (m, 2 H) 6.07 (br. s., 2 H) 3.66-3.69 (m, 1 H)
2.07-2.13 (m, 1 H) 1.92-1.98 (m, 1 H) 1.78 (s, 3 H) 1.69-1.75 (m, 1
H) 1.48 (s, 3 H) 1.35-1.42 (m, 1 H) 85 D 18 13 465 1H NMR (400 MHz,
DMSO-d6) .delta. ppm 9.39 (br. s., 1 H) 9.23 (d, J = 1.96 Hz, 1 H)
8.99 (d, J = 1.96 Hz, 1 H) 8.24 (d, J = 5.77 Hz, 1 H) 8.14-8.20 (m,
1 H) 7.83-7.90 (m, 1 H) 7.23 (d, J = 5.77 Hz, 1 H) 7.09-7.16 (m, 1
H) 6.09 (br. s., 2 H) 3.71-3.81 (m, 1 H) 2.38-2.46 (m, 1 H)
2.16-2.30 (m, 2 H) 1.84-1.93 (m, 1 H) 1.54 (s, 3 H) 1.42 (s, 3 H)
86 C commercial 12 509.1 1H NMR (400 MHz, DMSO-d6) .delta. ppm
10.05 (br. s, 1 H) 9.37 (s, 1 H) 8.41 (d, J = 5.97 Hz, 1 H)
8.06-8.15 (m, 2 H) 7.37 (d, J = 5.87 Hz, 1 H) 7.18-7.26 (m, 1 H)
6.06 (br. s., 2 H) 3.65-3.71 (m, 1 H) 2.08-2.16 (m, 1 H) 1.91-2.01
(m, 1 H) 1.79 (s, 3 H) 1.69-1.76 (m, 1 H) 1.48 (s, 3 H) 1.30-1.44
(m, 1 H) 87 C commercial 13 509.1 1H NMR (400 MHz, DMSO-d6) .delta.
ppm 9.71 (br. s., 1 H) 9.37 (s, 1 H) 8.44 (d, J = 5.97 Hz, 1 H)
8.03-8.12 (m, 2 H) 7.36 (d, J = 5.87 Hz, 1 H) 7.11-7.19 (m, 1 H)
6.06 (br. s., 2 H) 3.73-3.82 (m, 1 H) 2.38-2.41 (m, 1 H) 2.15-2.28
(m, 2 H) 1.86-1.92 (m, 1 H) 1.53 (s, 3 H) 1.42 (s, 3 H) 88 A 53 38
483 1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.56 (br. s., 1 H)
8.58-8.61 (m, 1 H) 8.02-8.06 (m, 1 H) 7.81-7.89 (m, 1 H) 7.78 (d, J
= 6.10 Hz, 1 H) 7.19 (dd, J = 11.64, 8.71 Hz, 1 H) 6.22 (br. s., 2
H) 4.89-5.23 (m, 2 H) 3.71-3.77 (m, 1 H) 2.58 (s, 3 H) 1.82-1.99
(m, 2 H) 1.78 (s, 3 H) 1.69- 1.76 (m, 1 H) 1.29-1.41 (m, 1 H) 89 A
53 39 483 1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.46 (br. s, 1 H)
8.57 (d, J = 1.76 Hz, 1 H) 8.02 (d, J = 1.76 Hz, 1 H) 7.83- 7.91
(m, 1 H) 7.61-7.67 (m, 1 H) 7.09-7.17 (m, 1 H) 6.22 (br. s., 2 H)
4.86-5.27 (m, 2 H) 3.73-3.80 (m, 1 H) 2.56 (s, 3 H) 2.41-2.48 (m, 1
H) 2.17-2.28 (m, 1 H) 2.05- 2.17 (m, 1 H) 1.86-1.94 (m, 1 H) 1.52
(s, 3 H) 90 A 43 12 461.1 1H NMR (400 MHz, DMSO-d6) .delta. ppm
10.64 (br. s, 1 H) 8.68-8.71 (m, 1 H) 8.12-8.18 (m, 1 H) 7.98-8.02
(m, 1 H) 7.92 (d, J = 5.00 Hz, 2 H) 7.16-7.23 (m, 1 H) 6.07 (br.
s., 2 H) 4.60 (s, 2 H) 3.65-3.75 (m, 1 H) 3.38 (s, 3 H) 2.06-2.14
(m, 1 H) 1.91-2.02 (m, 1 H) 1.77 (s, 3 H) 1.72-1.76 (m, 1 H) 1.48
(s, 3 H) 1.32-1.39 (m, 1 H) 91 A 43 13 461.1 1H NMR (400 MHz,
DMSO-d6) .delta. ppm 10.40 (br. s., 1 H) 8.67-8.71 (m, 1 H)
8.11-8.15 (m, 1 H) 7.98-8.02 (m, 1 H) 7.78-7.90 (m, 2 H) 7.14 (dd,
J = 12.08, 8.75 Hz, 1 H) 6.06 (br. s., 2 H) 4.59 (s, 2 H) 3.73-3.85
(m, 1 H) 3.37 (s, 3 H) 2.38-2.42 (m, 1 H) 2.16-2.30 (m, 2 H)
1.84-1.94 (m, 1 H) 1.52 (s, 3 H) 1.44 (s, 3 H) 92 A commercial 38
517.1 1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.69 (br. s, 1 H)
8.91-8.93 (m, 1 H) 8.30-8.32 (m, 1 H) 7.84-7.92 (m, 1 H) 7.77-7.81
(m, 1 H) 7.18-7.23 (m, 1 H) 6.21 (br. s., 2 H) 4.91-5.24 (m, 2 H)
3.74-3.78 (m, 1 H) 2.62 (s, 3 H) 1.94-2.05 (m, 1 H) 1.81-1.91 (m, 2
H) 1.78 (s, 3 H) 1.32- 1.38 (m, 1 H) 93 A commercial 39 517.1 1H
NMR (400 MHz, DMSO-d6) .delta. ppm 10.62 (s, 1 H) 8.88-8.91 (m, 1
H) 8.27-8.31 (m, 1 H) 7.86-7.91 (m, 1 H) 7.65 (dd, J = 7.43, 2.74
Hz, 1 H) 7.11-7.15 (m, 1 H) 6.22 (br. s., 2 H) 4.84-5.27 (m, 2 H)
3.74-3.79 (m, 1 H) 2.59 (s, 3 H) 2.40-2.48 (m, 1 H) 2.21-2.25 (m, 1
H) 2.05-2.18 (m, 1 H) 1.86-1.95 (m, 1 H) 1.52 (s, 3 H) 94 A 54 38
504 1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.52 (br. s, 1 H) 8.91
(s, 1 H) 8.47 (s, 1 H) 7.84-7.92 (m, 2 H) 7.16-7.21 (m, 1 H) 6.23
(br. s, 2 H) 4.93-5.23 (m, 4 H) 3.73-3.78 (m, 1 H) 1.90-2.03 (m, 2
H) 1.87 (s, 3 H) 1.80-1.82 (m, 1 H) 1.79 (s, 3 H) 1.30-1.38 (m, 1
H) 95 A 54 39 504 1H NMR (500 MHz, DMSO-d6) .delta. ppm 10.30 (br.
s., 1 H) 8.88 (s, 1 H) 8.44 (s, 1 H) 7.71-7.88 (m, 2 H) 7.08-7.16
(m, 1 H) 6.24 (br. s., 2 H) 4.89-5.20 (m, 4 H) 3.69-3.85 (m, 1 H)
2.41-2.48 (m, 1 H) 2.17-2.29 (m, 1 H) 2.00- 2.15 (m, 1 H) 1.89-1.99
(m, 1 H) 1.86 (s, 3 H) 1.51 (s, 3 H) 96 A 52 38 474.2 1H NMR (400
MHz, DMSO-d6) .delta. ppm 10.71 (br. s, 1 H) 9.00 (s, 1 H) 8.41 (s,
1 H) 7.83-7.89 (m, 1 H) 7.76-7.81 (m, 1 H) 7.18-7.22 (m, 1 H) 6.21
(br. s., 2 H) 4.84-5.24 (m, 2 H) 3.74-3.78 (m, 1 H) 2.57 (s, 3 H)
1.91-2.04 (m, 1 H) 1.72-1.86 (m, 5 H) 1.29-1.34 (m, 1 H) 97 D 22 38
489 1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.15 (br. s, 1 H) 8.65
(d, J = 2.84 Hz, 1 H) 8.61 (s, 1 H) 7.99-8.09 (m, 2 H) 7.63 (d, J =
2.84 Hz, 1 H) 7.18-7.22 (m, 1 H) 6.24 (br. s., 2 H) 4.92-5.27 (m, 2
H) 4.01 (s, 3 H) 3.71-3.75 (m, 1 H) 1.94-2.05 (m, 2 H) 1.82 (s, 3
H) 1.73-1.79 (m, 1 H) 1.32-1.43 (m, 1 H) 98 Ex 29 21 38 493 1H NMR
(400 MHz, DMSO-d6) .delta. ppm 10.46 (br. s, 1 H) 8.95 (d, J = 2.35
Hz, 1 H) 8.67 (s, 1 H) 8.42 (d, J = 2.25 Hz, 1 H) 8.09 (dd, J =
7.24, 2.74 Hz, 1 H) 7.96-8.02 (m, 1 H) 7.21-7.25 (m, 1 H) 6.24 (br.
s., 2 H) 4.91-5.26 (m, 2 H) 3.72-3.77 (m, 1 H) 1.94-2.04 (m, 2 H)
1.81 (s, 3 H) 1.74-1.79 (m, 1 H) 1.30-1.40 (m, 1 H) 99 D 20 38
506.1 1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.39 (br. s, 1 H) 8.73
(d, J = 2.84 Hz, 1 H) 8.07-8.14 (m, 2 H) 8.02 (dd, J = 7.19, 2.79
Hz, 1 H) 7.73 (d, J = 2.84 Hz, 1 H) 7.12-7.16 (m, 1 H) 6.24 (br.
s., 2 H) 4.91-5.26 (m, 2 H) 4.05 (s, 3 H) 3.71-3.75 (m, 1 H)
1.92-2.03 (m, 2 H) 1.80 (s, 3 H) 1.72-1.78 (m, 1 H) 1.35-1.44 (m, 1
H) 100 D 18 38 483 1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.75 (s, 1
H) 9.23 (d, J = 2.07 Hz, 1 H) 8.99 (d, J = 2.07 Hz, 1 H) 8.12-8.23
(m, 2 H) 8.03 (dd, J = 7.26, 2.80 Hz, 1 H) 7.15-7.25 (m, 2 H) 6.25
(br. s., 2 H) 4.91-5.25 (m, 2 H) 3.72-3.76 (m, 1 H) 1.89-2.04 (m, 2
H) 1.80 (s, 3 H) 1.73-1.79 (m, 1 H) 1.35-1.45 (m, 1 H) 101 A
commercial 38 463.1 1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.59
(br. s., 1 H) (American 8.60-8.63 (m, 1 H) 8.09 (d, J = 8.11 Hz, 1
H) 7.86-7.95 Advanced (m, 3 H) 7.17-7.22 (m, 1 H) 6.25 (br. s., 2
H) 4.92-5.24 Scientific, (m, 2 H) 3.73-3.78 (m, 1 H) 2.76 (q, J =
7.53 Hz, 2 H) Inc) 1.89-2.05 (m, 2 H) 1.79 (s, 3 H) 1.71-1.76 (m, 1
H) 1.32- 1.40 (m, 1 H) 1.26 (t, J = 7.63 Hz, 3 H) 102 A 41 38 515
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.52 (br. s., 1 H)
8.44 (s, 1 H) 7.73 (m, 3 H) 7.45 (t, J = 73.06 Hz, 1 H) 7.15- 7.22
(m, 1 H) 6.22 (br. s., 2 H) 4.90-5.24 (m, 2 H) 3.73- 3.78 (m, 1 H)
2.62 (s, 3 H) 1.89-2.05 (m, 2 H) 1.83-1.89 (m, 1 H) 1.78 (s, 3 H)
1.32-1.38 (m, 1 H) 103 A 42 38 499.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.63 (s, 1 H) 8.73 (s, 1 H) 8.06 (s, 1
H) 7.84-7.90 (m, 1 H) 7.78-7.82 (m, 1 H) 7.09-7.37 (m, 2 H) 6.21
(br. s., 2 H) 4.91-5.24 (m, 2 H) 3.74-3.78 (m, 1 H) 2.61 (s, 3 H)
1.93-2.05 (m, 1 H) 1.81-1.92 (m, 2 H) 1.79 (s, 3 H) 1.33-1.38 (m, 1
H) 104 D 31 38 556 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
9.53 (s, 1 H) 8.66 (s, 1 H) 8.20-8.25 (m, 2 H) 8.05-8.12 (m, 1 H)
8.00 (dd, J = 7.20, 2.64 Hz, 1 H) 7.28-7.33 (m, 1 H) 7.12-7.16 (m,
1 H) 7.06 (d, J = 5.80 Hz, 1 H) 6.22 (br. s., 2 H) 5.66 (s, 2 H)
4.87-5.26 (m, 2 H) 3.71-3.76 (m, 1 H) 1.92-2.11 (m, 2 H) 1.80 (s, 3
H) 1.71-1.77 (m, 1 H) 1.33-1.47 (m, 1 H) 105 A commercial 38 503.9
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.76 (s, 1 H) 8.74
(matrix) (d, J = 2.07 Hz, 1 H) 8.45 (d, J = 2.07 Hz, 1 H) 7.80-7.86
(m, 1 H) 7.72-7.76 (m, 1 H) 7.18-7.22 (m, 1 H) 6.21 (br. s., 2 H)
4.90-5.24 (m, 2 H) 3.75-3.79 (m, 1 H) 1.92- 2.07 (m, 2 H) 1.80-1.84
(m, 1 H) 1.74 (s, 3 H) 1.30- 1.34 (m, 1 H) 106 D 44 38 509 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.59 (br. s, 1 H) 9.22 (d,
J = 2.28 Hz, 1 H) 8.75 (s, 1 H) 8.66 (s, 1 H) 8.12- 8.18 (m, 1 H)
7.96-8.02 (m, 1 H) 7.24-7.28 (m, 1 H) 6.05 (br. s., 2 H) 3.66-3.72
(m, 1 H) 1.78 (s, 3H) 1.72- 1.75 (m, 2 H) 1.48 (s, 3 H) 1.34-1.22
(m, 2 H) 107 D 44 38 527 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 10.61 (br. s, 1 H) 9.21 (d, J = 2.18 Hz, 1 H) 8.74 (s,
1 H) 8.66 (s, 1 H) 8.10 (d, J = 6.98 Hz, 1 H) 7.95-8.01 (m, 1 H)
7.23-7.29 (m, 1 H) 6.23 (br. s., 2 H) 5.01-5.13 (m, 2 H) 3.65-3.74
(m, 1 H) 1.92-2.02 (m, 2 H) 1.80 (s, 3 H) 1.71-1.76 (m, 2 H) 108 A
commercial 38 536.9 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
10.81 (s, 1 H) 9.01 (Matrix) (s, 1 H) 8.65 (s, 1 H) 7.72-7.81 (m, 1
H) 7.65-7.72 (m, 1 H) 7.13-7.20 (m, 1 H) 6.16 (br. s., 2 H)
4.80-5.18 (m, 2 H) 3.72 (m, 1 H) 1.84-2.05 (m, 1 H) 1.75-1.81 (m, 2
H) 1.72 (s, 3 H) 1.30-1.34 (m, 1 H) 109 A 26 38 485.9 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 10.91 (s, 1 H) 9.40 (s, 1 H)
9.10 (s, 1 H) 7.84-7.98 (m, 2 H) 7.19-7.38 (m, 2 H) 6.23 (br. s., 2
H) 4.92-5.25 (m, 2 H) 3.74-3.78 (m, 1 H) 1.87-2.04 (m, 2 H)
1.80-1.83 (m, 1 H) 1.79 (s, 3 H) 1.30-1.36 (m, 1 H) 110 A
commercial 38 503 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
10.87 (s, 1 H) 9.17
(s, 1 H) 8.55 (dd, J = 8.19, 1.87 Hz, 1 H) 8.39 (d, J = 8.24 Hz, 1
H) 7.92-7.96 (m, 2 H) 7.22-7.29 (m, 1 H) 6.28 (br. s., 2 H)
4.94-5.29 (m, 2 H) 3.77-3.80 (m, 1 H) 1.89- 2.07 (m, 2 H) 1.84 (s,
3 H) 1.76-1.80 (m, 1 H) 1.33- 1.41 (m, 1 H) 111 A commercial 38 460
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 10.82 (s, 1 H) 9.20
(s, 1 H) 8.58 (dd, J = 8.19, 2.02 Hz, 1 H) 8.28 (d, J = 8.66 Hz, 1
H) 7.86-7.91 (m, 2 H) 7.17-7.25 (m, 1 H) 6.22 (br. s., 2 H)
4.88-5.24 (m, 2 H) 3.72-3.76 (m, 1 H) 1.83- 2.08 (m, 3 H) 1.74 (s,
3 H) 1.30-1.34 (m, 1 H) 112 D 48 39 557.0 1H NMR (300 MHz, DMSO-d6)
.delta. ppm 1.31-1.47 (m, 1 H) 1.80 (s, 4 H) 1.88-2.05 (m, 2 H)
2.08 (s, 2 H) 3.73 (br. s., 1 H) 4.92 (d, J = 11.11 Hz, 1 H) 5.08
(d, J = 11.40 Hz, 1 H) 5.21 (q, J = 8.92 Hz, 3 H) 6.21 (br. s., 2
H) 7.09 (d, J = 5.85 Hz, 1 H) 7.16 (dd, J = 11.62, 8.84 Hz, 1 H)
7.95- 8.05 (m, 1 H) 8.08 (br. s., 1 H) 8.26 (d, J = 5.85 Hz, 1 H)
8.73 (s, 1 H) 9.58 (s, 1 H) 113 B commercial 48B 517.1 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 1.37-1.45 (m, 1 H) 1.48 (s, 3
H) 1.72-1.84 (m, 1 H) 1.98-2.13 (m, 2 H) 2.61 (s, 3 H) 3.85-3.93
(m, 1 H) 4.58-4.77 (m, 1 H) 4.91- 5.09 (m, 1 H) 6.24-6.37 (m, 2 H)
7.14-7.23 (m, 1 H) 7.84-7.91 (m, 2 H) 8.26-8.32 (m, 1 H) 8.87-8.92
(m, 1 H) 10.39-10.91 (m, 1 H) 114 B commercial 48A 517.1 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.37-1.45 (m, 1 H) 1.48 (s,
3 H) 1.72-1.84 (m, 1 H) 1.98-2.13 (m, 2 H) 2.61 (s, 3 H) 3.85-3.93
(m, 1 H) 4.58-4.77 (m, 1 H) 4.91- 5.09 (m, 1 H) 6.24-6.37 (m, 2 H)
7.14-7.23 (m, 1 H) 7.84-7.91 (m, 2 H) 8.26-8.32 (m, 1 H) 8.87-8.92
(m, 1 H) 10.39-10.91 (m, 1 H) 115 B, no commercial 49B 517.1
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.68 (s, 3 TFA H)
2.11-2.20 (m, 1 H) 2.43-2.56 (m, 2 H) 2.65-2.74 (m, 1 H) 2.86 (s, 3
H) 4.12-4.18 (m, 1 H) 4.46-4.63 (m, 1 H) 4.82-4.99 (m, 1 H)
7.06-7.15 (m, 1 H) 7.54-7.59 (m, 1 H) 7.85-7.88 (m, 1 H) 8.10-8.17
(m, 1 H) 8.67- 8.72 (m, 1 H) 10.13-10.18 (m, 1 H) 116 B, no
commercial 49A 517.1 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 1.68 (s, 3 TFA H) 2.11-2.20 (m, 1 H) 2.43-2.56 (m, 2 H)
2.65-2.74 (m, 1 H) 2.86 (s, 3 H) 4.12-4.18 (m, 1 H) 4.46-4.63 (m, 1
H) 4.82-4.99 (m, 1 H) 7.06-7.15 (m, 1 H) 7.54-7.59 (m, 1 H)
7.85-7.88 (m, 1 H) 8.10-8.17 (m, 1 H) 8.67- 8.72 (m, 1 H)
10.13-10.18 (m, 1 H) 117 B 53 48B 483 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 1.37-1.45 (m, 1 H) 1.46-1.50 (m, 3 H)
1.73-1.84 (m, 1 H) 1.98-2.14 (m, 2 H) 2.56-2.59 (m, 3 H) 3.83-3.93
(m, 1 H) 4.56- 4.76 (m, 1 H) 4.89-5.09 (m, 1 H) 6.26-6.38 (m, 2 H)
7.11-7.21 (m, 1 H) 7.81-7.90 (m, 2 H) 8.00-8.05 (m, 1 H) 8.53-8.61
(m, 1 H) 10.49-10.58 (m, 1 H) 118 B 53 48A 483 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.37-1.45 (m, 1 H) 1.46-1.50 (m, 3
H) 1.73-1.84 (m, 1 H) 1.98-2.14 (m, 2 H) 2.56-2.59 (m, 3 H)
3.83-3.93 (m, 1 H) 4.56- 4.76 (m, 1 H) 4.89-5.09 (m, 1 H) 6.26-6.38
(m, 2 H) 7.11-7.21 (m, 1 H) 7.81-7.90 (m, 2 H) 8.00-8.05 (m, 1 H)
8.53-8.61 (m, 1 H) 10.49-10.58 (m, 1 H) 119 B commercial 48B 466.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 1.35-1.46 (m, 1 H)
1.46-1.51 (m, 3 H) 1.72-1.83 (m, 1 H) 1.93-2.06 (m, 1 H) 2.07-2.18
(m, 1 H) 3.85-3.91 (m, 1 H) 4.02 (s, 3 H) 4.58-4.76 (m, 1 H)
4.91-5.10 (m, 1 H) 6.26-6.40 (m, 2 H) 7.09-7.22 (m, 1 H) 7.80-7.89
(m, 1 H) 7.95- 8.02 (m, 1 H) 8.39-8.44 (m, 1 H) 8.87-8.92 (m, 1 H)
10.33-10.85 (m, 1 H) 120 B commercial 48A 466.1 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 1.35-1.46 (m, 1 H) 1.46-1.51 (m, 3
H) 1.72-1.83 (m, 1 H) 1.93-2.06 (m, 1 H) 2.07-2.18 (m, 1 H)
3.85-3.91 (m, 1 H) 4.02 (s, 3 H) 4.58-4.76 (m, 1 H) 4.91-5.10 (m, 1
H) 6.26-6.40 (m, 2 H) 7.09-7.22 (m, 1 H) 7.80-7.89 (m, 1 H) 7.95-
8.02 (m, 1 H) 8.39-8.44 (m, 1 H) 8.87-8.92 (m, 1 H) 10.33-10.85 (m,
1 H) 121 B commercial 12 502.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. = 10.71 (s, 1H), 7.92- (Aldrich) 7.83 (m, 2H), 7.81-7.71
(m, 3H), 7.24-7.16 (m, 1H), 6.3 (br. s., 2H), 3.74 (d, J = 4.5 Hz,
1H), 2.04-1.89 (m, 2H), 1.81-1.72 (m, 4H), 1.47 (s, 3H), 1.43-1.22
(m, 1H) 122 B commercial 13 502.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. = 10.69 (s, 1H), 7.91- (Aldrich) 7.77 (m,
3H), 7.70 (d, J = 7.7 Hz, 1H), 7.60 (dd, J = 2.7, 7.4 Hz, 1H), 7.14
(dd, J = 8.8, 12.1 Hz, 1H), 3.83-3.75 (m, 1H), 2.52-2.42 (m, 1H),
2.33-2.15 (m, 2H), 1.96-1.85 (m, 1H), 1.52 (s, 3H), 1.43 (s, 3H)
123 B commercial 12 464.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. = 10.27 (s, 1H), 7.89- (Matrix) 7.69 (m, 2H), 7.64 (t, J =
8.6 Hz, 1H), 7.22 (m, 1H), 6.98 (dd, J = 2.0, 12.5 Hz, 1H), 6.91
(dd, J = 2.3, 8.7 Hz, 1H), 6.28-5.80 (m, 2H), 3.88-3.81 (m, 4H),
2.19-1.94 (m, 2H), 1.94-1.68 (m, 4H), 1.63-1.43 (m, 3H), 1.36 (m,
1H) 124 B commercial 13 464.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. = 10.22 (s, 1H), 7.75- (Matrix) 7.68 (m, 1H), 7.66-7.56 (m,
2H), 7.08 (dd, J = 8.8, 12.1 Hz, 1H), 6.95-6.86 (m, 2H), 6.32-5.86
(m, 2H), 3.75 (d, J = 6.2 Hz, 1H), 2.50-2.30 (m, 1H), 2.28-2.13 (m,
2H), 1.92-1.82 (m, 1H), 1.49 (s, 3H), 1.41 (s, 3H) 125 B commercial
12 530.0, 532.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 10.92
(s, 1H), 7.80- (Matrix) (2 Br 7.65 (m, 4H), 7.21 (dd, J = 8.9, 11.6
Hz, 1H), 6.30 (br. s., isotopes) 1H), 3.90-3.64 (m, 1H), 2.03-1.90
(m, 2H), 1.85-1.68 (m, 4H), 1.47 (s, 3H), 1.39-1.22 (m, 1H) 126 B
commercial 13 530.0, 532.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. = 10.86 (s, 1H), 7.84- (Matrix) (2 Br 7.78 (m, 1H),
7.67-7.62 (m, 2H), 7.50 (dd, J = 2.7, 7.3 Hz, isotopes) 1H), 7.12
(dd, J = 8.9, 12.1 Hz, 1H), 6.30 (br. s., 2H), 3.73 (d, J = 6.3 Hz,
1H), 2.45-2.32 (m, 1H), 2.28-2.13 (m, 2H), 1.92-1.82 (m, 1H), 1.49
(s, 3H), 1.41 (s, 3H) 127 B commercial 12 459.0 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. = 10.77 (s, 1H), 8.06 (d, (Matrix) J =
10.0 Hz, 1H), 7.87-7.76 (m, 4H), 7.25 (br. s., 1H), 2.10- 1.95 (m,
2H), 1.92-1.79 (m, 4H), 1.51 (br. s., 3H), 1.42- 1.30 (m, 1H) 128 B
commercial 13 459.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. =
10.73 (s, 1H), 8.03 (d, (Matrix) J = 9.9 Hz, 1H), 7.86-7.78 (m,
3H), 7.59 (dd, J = 2.7, 7.4 Hz, 1H), 7.13 (dd, J = 8.8, 12.1 Hz,
1H), 6.20 (br. s., 2H), 3.77 (d, J = 6.2 Hz, 1H), 2.47-2.35 (m,
1H), 2.30-2.15 (m, 2H), 1.96-1.75 (m, 1H), 1.51 (s, 3H), 1.42 (s,
3H) 129 B 35 13 502.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. =
10.26 (s, 1H), 7.75- 7.67 (m, 1H), 7.67-7.57 (m, 2H), 7.08 (dd, J =
8.8, 12.1 Hz, 1H), 6.98-6.88 (m, 2H), 6.10 (br. s., 2H), 4.87-4.82
(m, 2H), 3.75 (d, J = 6.7 Hz, 1H), 2.45-2.32 (m, 1H), 2.27- 2.13
(m, 2H), 1.92-1.79 (m, 4H), 1.49 (s, 3H), 1.41 (s, 3H) 130 C 21 12
475.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 10.41 (br. s.,
1H), 8.92 (d, J = 2.5 Hz, 1H), 8.65 (s, 1H), 8.39 (d, J = 2.3 Hz,
1H), 8.08 (dd, J = 2.8, 7.2 Hz, 1H), 7.97 (td, J = 3.7, 8.2 Hz,
1H), 7.21 (dd, J = 8.8, 11.7 Hz, 1H), 6.14 (br. s., 1H), 3.67 (d, J
= 6.0 Hz, 1H), 2.32-2.07 (m, 1H), 2.03-1.87 (m, 1H), 1.81-1.72 (m,
4H), 1.51-1.45 (m, 3H), 1.45-1.28 (m, 1H) 131 C 21 13 475.1 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. = 10.15 (br. s., 1H), 8.94 (d,
J = 2.2 Hz, 1H), 8.70 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.07 (d, J
= 4.7 Hz, 1H), 7.92 (br. s., 1H), 7.16 (dd, J = 8.8, 12.1 Hz, 1H),
6.04 (br. s., 2H), 3.77 (br. s., 1H), 2.48- 2.37 (m, 1H), 2.29-2.13
(m, 2H), 1.97-1.81 (m, 1H), 1.53 (s, 3H), 1.47-1.37 (m, 3H) 132 C
20 12 471.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 10.31
(br. s., 1H), 8.68- 8.62 (m, 2H), 8.41-8.19 (m, 1H), 8.04 (dd, J =
2.7, 7.3 Hz, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.34 (br. s., 1H), 4.01
(s, 3H), 2.22-1.88 (m, 3H), 1.61 (br. s., 4H), 1.48-1.35 (m, 1H),
1.32-1.19 (m, 3H) 133 C 20 13 471.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. = 10.03 (br. s., 1H), 8.64 (s, 2H), 8.22-7.98
(m, 2H), 7.62 (d, J = 2.7 Hz, 1H), 7.21 (t, J = 10.2 Hz, 1H),
4.02-3.98 (m, 4H), 2.64-2.53 (m, 1H), 2.38-2.21 (m, 1H), 2.12-1.94
(m, 1H), 1.77-1.60 (m, 4H), 1.51 (br. s., 3H) 134 D 36 12 526.1
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 9.35 (s, 1H), 8.72
(d, J = 2.8 Hz, 1H), 8.11 (dd, J = 3.6, 8.2 Hz, 1H), 8.08 (d, J =
1.7 Hz, 1H), 8.00 (dd, J = 2.8, 7.2 Hz, 1H), 7.77 (d, J = 2.8 Hz,
1H), 7.13 (dd, J = 8.9, 11.7 Hz, 1H), 6.06 (br. s., 2H), 5.10- 5.06
(m, 2H), 3.66 (d, J = 6.0 Hz, 1H), 2.16-2.04 (m, 1H), 2.01-1.89 (m,
1H), 1.87 (t, J = 2.3 Hz, 3H), 1.79-1.71 (m, 4H), 1.47 (s, 3H),
1.43-1.32 (m, 1H) 135 D 36 12 526.1 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. = 9.06 (br. s., 1H), 8.73 (d, J = 2.8 Hz,
1H), 8.18-8.12 (m, 1H), 8.11 (d, J = 1.8 Hz, 1H), 7.84-7.75 (m,
2H), 7.13-7.05 (m, J = 8.9, 12.1 Hz, 1H), 6.13 (br. s., 2H), 5.08
(d, J = 2.3 Hz, 2H), 3.76 (d, J = 4.1 Hz, 1H), 2.46-2.36 (m, 1H),
2.29-2.13 (m, 2H), 1.87 (t, J = 2.3 Hz, 4H), 1.52 (s, 3H), 1.42 (s,
3H) 136 D synthesized 13 528.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. = 9.03 (s, 1H), 8.73 (d, analogous J = 2.8 Hz, 1H),
8.19-8.13 (m, 1H), 8.08 (d, J = 1.8 Hz, to 36 1H), 7.79 (dd, J =
2.7, 7.2 Hz, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.09 (dd, J = 8.9, 12.1
Hz, 1H), 6.21 (br. s., 2H), 4.10 (d, J = 7.1 Hz, 2H), 3.77 (d, J =
5.5 Hz, 1H), 2.47-2.36 (m, 1H), 2.30-2.13 (m, 2H), 1.95-1.82 (m,
1H), 1.52 (s, 3H), 1.42 (s, 3H), 1.38-1.28 (m, 2H), 0.68-0.59 (m,
2H), 0.45- 0.37 (m, 2H) 137 D synthesized 12 528.2 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. = 9.33 (s, 1H), 8.72 (d, analogous J =
2.8 Hz, 1H), 8.16-8.08 (m, 1H), 8.08-8.03 (m, 1H), to 36 7.99 (dd,
J = 2.8, 7.2 Hz, 1H), 7.65 (d, J = 2.8 Hz, 1H), 7.13 (dd, J = 8.9,
11.7 Hz, 1H), 6.06 (br. s., 2H), 4.11 (d, J = 7.1 Hz, 2H), 3.66 (d,
J = 5.8 Hz, 1H), 2.17-2.03 (m, 1H), 2.01- 1.88 (m, 1H), 1.82-1.67
(m, 4H), 1.47 (s, 3H), 1.42- 1.26 (m, 2H), 0.69-0.60 (m, 2H),
0.46-0.38 (m, 2H) 138 B 35 12 502.2 .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. = 10.25 (br. s., 1H), 7.78 (d, J = 4.8 Hz,
1H), 7.72 (br. s., 1H), 7.63 (t, J = 8.5 Hz, 1H), 7.15 (dd, J =
9.0, 11.4 Hz, 1H), 7.02-6.87 (m, 2H), 5.99 (br. s., 2H), 4.85 (d, J
= 2.0 Hz, 2H), 3.74-3.62 (m, 1H), 1.97 (br. s., 2H), 1.85 (s, 3H),
1.81-1.68 (m, 4H), 1.46 (s, 3H), 1.32 (br. s., 1H) 139 C 37 12
511.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 10.09 (s, 1H),
8.64 (d, J = 2.7 Hz, 1H), 8.57 (s, 1H), 8.09-7.97 (m, 2H), 7.54 (d,
J = 2.7 Hz, 1H), 7.18 (dd, J = 8.8, 11.5 Hz, 1H), 6.06 (br. s.,
2H), 4.07 (d, J = 7.1 Hz, 2H), 3.68 (br. s., 1H), 2.20-2.06 (m,
1H), 2.00-1.87 (m, 1H), 1.81-1.69 (m, 4H), 1.47 (m, 3H), 1.40-1.26
(m, 2H), 0.69-0.57 (m, 2H), 0.43-0.37 (m, 2H) 140 D 31 12 538.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 9.50 (s, 1H), 8.65
(s, 1H), 8.26-8.19 (m, 2H), 8.13-8.05 (m, 1H), 8.00 (dd, J = 2.9,
7.3 Hz, 1H), 7.31 (d, J = 0.8 Hz, 1H), 7.15 (dd, J = 8.9, 11.8 Hz,
1H), 7.05 (d, J = 5.8 Hz, 1H), 6.11 (br. s., 2H), 5.66 (s, 2H),
3.67 (d, J = 6.0 Hz, 1H), 2.20-2.03 (m, 1H), 2.01-1.89 (m, 1H),
1.82-1.70 (m, 4H), 1.47 (s, 3H), 1.44-1.30 (m, 1H) 141 D 21 34
505.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 10.13 (br. s.,
1H), 8.92 (d, J = 2.3 Hz, 1H), 8.69 (s, 1H), 8.39 (d, J = 2.3 Hz,
1H), 8.04 (dd, J = 2.8, 7.5 Hz, 1H), 7.96-7.91 (m, 1H), 7.15 (dd, J
= 8.9, 12.1 Hz, 1H), 5.99 (br. s., 2H), 3.86 (q, J = 12.9 Hz, 2H),
3.74 (d, J = 6.1 Hz, 1H), 3.32 (s, 3H), 2.47-2.37 (m, 1H),
2.27-2.13 (m, 2H), 1.98-1.90 (m, 1H), 1.53 (s, 3H) 142 A 53 34
495.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 10.62 (br. s.,
1H), 8.56 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 0.6, 2.3 Hz, 1H), 7.94
(d, J = 8.8 Hz, 1H), 7.69 (dd, J = 2.4, 7.4 Hz, 1H), 7.20 (dd, J =
9.2, 11.5 Hz, 1H), 4.21-3.95 (m, 2H), 3.88 (d, J = 11.5 Hz, 1H),
3.32 (s, 3H), 2.60-2.52 (m, 4H), 2.49-2.30 (m, 2H), 2.14-2.02 (m,
1H), 1.71 (s, 3H) 143 D synthesized 12 513.2 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. = 9.44 (br. s., 1H), 8.55 analogous (s, 1H),
8.20 (d, J = 5.8 Hz, 1H), 8.18-8.06 (m, 1H), 7.98 to 31 (dd, J =
2.8, 7.3 Hz, 1H), 7.14 (dd, J = 8.9, 11.7 Hz, 1H), 7.04 (d, J = 5.8
Hz, 1H), 6.05 (br. s., 2H), 4.25 (d, J = 6.6 Hz, 2H), 3.66 (d, J =
5.9 Hz, 1H), 2.19-2.06 (m, 2H), 2.01- 1.88 (m, 1H), 1.82-1.70 (m,
4H), 1.47 (s, 3H), 1.43- 1.32 (m, 1H), 1.04 (d, J = 6.7 Hz, 6H) 144
D synthesized 12 499.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
= 9.43 (br. s., 1H), 8.53 analogous (s, 1H), 8.20 (d, J = 5.9 Hz,
1H), 8.14-8.07 (m, 1H), 7.98 to 31 (dd, J = 2.9, 7.3 Hz, 1H), 7.14
(dd, J = 8.8, 11.7 Hz, 1H), 7.03 (d, J = 5.8 Hz, 1H), 6.05 (br. s.,
2H), 4.42 (t, J = 6.7 Hz, 2H), 3.66 (d, J = 6.2 Hz, 1H), 2.17-2.05
(m, 1H), 1.99- 1.89 (m, 1H), 1.88-1.68 (m, 4H), 1.77 (s, 3H), 1.47
(s, 3H), 1.44-1.31 (m, 2H), 1.03 (t, J = 7.4 Hz, 3H) 145 D
synthesized 12 515.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. =
9.44 (br. s., 1H), 8.58 analogous (s, 1H), 8.21 (d, J = 5.8 Hz,
1H), 8.14-8.07 (m, 1H), 7.98 to 31 (dd, J = 2.9, 7.3 Hz, 1H), 7.14
(dd, J = 8.9, 11.7 Hz, 1H), 7.04 (d, J = 5.8 Hz, 1H), 6.04 (br. s.,
2H), 4.61-4.57 (m, 2H), 3.78-3.73 (m, 2H), 3.66 (d, J = 5.7 Hz,
1H), 3.32 (s,
3H), 2.17-2.06 (m, 1H), 2.00-1.89 (m, 1H), 1.81-1.68 (m, 4H), 1.47
(s, 3H), 1.42-1.31 (m, 1H) 146 D synthesized 12 551.9 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. = 9.48 (br. s., 1H), 8.64 analogous
(s, 1H), 8.23 (d, J = 5.9 Hz, 1H), 8.14-8.05 (m, 1H), 8.00 to 31
(dd, J = 2.8, 7.3 Hz, 1H), 7.14 (dd, J = 8.9, 11.7 Hz, 1H), 7.06
(d, J = 5.9 Hz, 1H), 6.92 (q, J = 1.1 Hz, 1H), 6.04 (br. s., 2H),
5.57 (s, 2H), 3.66 (d, J = 5.9 Hz, 1H), 2.33 (d, J = 1.2 Hz, 3H),
2.19-2.05 (m, 1H), 2.03-1.87 (m, 1H), 1.81- 1.70 (m, 1H), 1.77 (s,
3H), 1.47 (s, 3H), 1.37 (br. s., 1H) 147 D synthesized 12 551.0
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. = 9.46 (br. s., 1H),
8.55 analogous (s, 1H), 8.23 (d, J = 5.8 Hz, 1H), 8.10 (d, J = 6.6
Hz, 1H), to 31 7.99 (dd, J = 2.9, 7.3 Hz, 1H), 7.70 (d, J = 2.2 Hz,
1H), 7.15 (dd, J = 9.0, 11.7 Hz, 1H), 7.10 (d, J = 5.9 Hz, 1H),
6.41 (d, J = 2.2 Hz, 1H), 6.07 (br. s., 1H), 5.45 (s, 2H), 3.85 (s,
3H), 3.76-3.63 (m, 1H), 2.13 (br. s., 1H), 2.03-1.89 (m, 1H),
1.83-1.70 (m, 4H), 1.48 (s, 3H), 1.43-1.33 (m, 1H) 148 D
synthesized 38 475.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. =
9.20 (s, 1H), 8.10 (s, analogous 1H), 8.06 (d, J = 5.7 Hz, 1H),
8.02-7.96 (m, 1H), 7.87 (dd, to 17 J = 2.8, 7.3 Hz, 1H), 7.13 (dd,
J = 8.8, 11.7 Hz, 1H), 6.61 (d, J = 5.7 Hz, 1H), 5.25-4.89 (m, 2H),
3.73 (d, J = 4.9 Hz, 1H), 2.06-1.88 (m, 2H), 1.85-1.74 (m, 5H),
1.48-1.32 (m, 1H)
[1008] Table 3 hereinbelow includes the biological data (average
.mu.M IC.sub.50's for the BACE 1 enzyme and cell assays, BACE 2
enzyme assay and CatD enzyme assay) for each compound example,
where available.
TABLE-US-00003 TABLE 3 BACE1 BACE1 BACE2 Enzyme cell Enzyme assay
assay assay CatD IC.sub.50 IC.sub.50 IC.sub.50 IC50 Example No
Compound Name (uM) (uM) (uM) (.mu.M) 40
4-((3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.008 0.035 0.022
650.44 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7- carbonitrile 41
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.009 0.015 0.010
867.43 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-2-methoxypyrido[3,4-b]pyrazin- 5-amine 42
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.013 0.030 0.003
757.35 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-methoxy-3-methyl-2- pyridinecarboxamide 43
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.009 0.007 0.014
>400.0 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-fluoro-5-methoxy-2- pyridinecarboxamide 38
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.004 0.031 0.011
436.69 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-((4,4-dimethyl-2-pentyn-1-
yl)oxy)-2-pyrazinecarboxamide 44
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.034 0.153 0.283
>400.0 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-((1,1-dimethyl-2-propyn-1-
yl)oxy)-2-pyrazinecarboxamide 45
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.003 0.003 0.019
595.77 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(((1S)-1-methyl-2-propyn-1-
yl)oxy)-2-pyrazinecarboxamide 46
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.001 0.005 0.009
1003.7 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4- b]pyrazin-5-amine 47
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.007 0.036 0.002 174
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-7-bromopyrido[3,2-d]pyrimidin- 4-amine 48
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-8,8- 0.011 0.004 54.1
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-methyl-5-
(trifluoromethyl)-2-pyridinecarboxamide 49
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-8,8- 0.011 0.004 66.6
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-methyl-5-
(trifluoromethyl)-2-pyridinecarboxamide 50
N-(3-((1S,2R,5R)-4-amino-1,2,5-trimethyl-8,8- 0.004 0.28 12.05
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7- naphthyridin-8-amine 51
N-(3-((1R,2R,5S)-4-amino-1,2,5-trimethyl-8,8- 0.011 0.381 21.5
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-chloro-5-fluoro-1,7- naphthyridin-8-amine 52
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.001 0.004 0.018
810.63 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(2-propyn-1-yloxy)-2- pyridinecarboxamide 53
8-((3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.003 0.038 0.002
>14.8 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)amino)-5-fluoro-1,7- naphthyridine-3-carbonitrile 54
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.002 0.090 0.002
755.35 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-chloro-5-fluoro-1,7- naphthyridin-8-amine 55
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.018 0.351 0.024
>133.0 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-2-(trifluoromethyl)pyrido[3,4- b]pyrazin-5-amine 56
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.0188 0.0167 0.0185
>400.0 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-methoxy-1,7-naphthyridin-8- amine 57
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.003 0.048 0.076
>400.0 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4- fluorophenyl)-3-methyl-5-(2,2,2-
trifluoroethoxy)-2-pyrazinecarboxamide 58
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.001 0.046 0.002
341.92 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-chloro-1,7-naphthyridin-8- amine 59
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.001 0.001 0.003
836.73 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2- pyrazinecarboxamide
60 N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.001 0.008 0.010
952.92 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-chloro-5-(2-propyn-1-yloxy)-2- pyridinecarboxamide
61 N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.005 0.002 0.007
2498.7 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 62
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.001 0.001 0.007 123.65
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-(2-butyn-1-
yloxy)pyrido[3,4-b]pyrazin-5-amine 63
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.003 0.002 0.321 1175.4
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-(2-butyn-1-
yloxy)pyrido[3,4-b]pyrazin-5-amine 64
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.001 0.005 469.88
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(cyclopropylethynyl)-2- pyridinecarboxamide
65 N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.007 0.016 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(cyclopropylethynyl)-2- pyridinecarboxamide
66 N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.070 0.018 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 67
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.156 0.522 99.3
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2- (cyclopropylmethoxy)pyrido[3,4-b]pyrazin-5-
amine 68 N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.005 0.033
>400.0 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2- (cyclopropylmethoxy)pyrido[3,4-b]pyrazin-5-
amine 69 N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.002 0.003
>133.0, dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2- >400.0
yl)-4-fluorophenyl)-5-(1-propyn-1-yl)-2- pyridinecarboxamide 70
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.014 0.007 0.050
>400.0 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(((1R)-1-methyl-2-butyn-
1-yl)oxy)-2-pyrazinecarboxamide 71
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.003 0.0001 0.008
>400.0 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(((1S)-1-methyl-2-butyn-
1-yl)oxy)-2-pyrazinecarboxamide 72
N-(3-((1R,2S,5S)-4-amino-2-(fluoromethyl)-5- 0.024 0.111 >400.0
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 75
N-(3-((1R,2S,5S)-4-amino-2-(fluoromethyl)-5- 0.097 0.095 >400.0
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 39
8-((3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.001 0.009 191
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)amino)-5-fluoro-1,7- naphthyridin-3-ol 76
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.010 0.008 0.004
1061.2 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-methoxy-3-methyl-2- pyrazinecarboxamide 77
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.003 0.003 0.001
569.72 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-chloro-2-pyridinecarboxamide 78
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.003 0.012 0.005 3235.3
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-fluoro-3-methoxy-1,7- naphthyridin-8-amine 79
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.009 0.003 1828.1
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-methoxy-3-methyl-2- pyrazinecarboxamide 80
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.008 0.006 0.015
>400.0 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 81
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.225 0.062 >348.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-methoxypyrido[3,4- b]pyrazin-5-amine 82
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.0005 0.00007 0.003
717.19 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2- pyrazinecarboxamide 83
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.001 0.0005 0.082
1103.2 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(2-butyn-1-yloxy)-2- pyrazinecarboxamide 84
8-((3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.002 0.003 0.002
>118.0 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3- carbonitrile 85
8-((3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.013 0.011 0.024
1453.5 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3- carbonitrile 86
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.023 0.067 >44.4
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-
(trifluoromethyl)pyrido[3,4-b]pyrazin-5-amine 87
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.084 0.313 >44.4
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-
(trifluoromethyl)pyrido[3,4-b]pyrazin-5-amine 88
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.003 0.005 0.0008
684.74 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 89
N-(3-((1R,2R,5S)-4-amino-5-(fluoromethyl)-2- 0.016 0.053 0.006 1552
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 90
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.057 0.020 3416.5
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(methoxymethyl)-2- pyridinecarboxamide 91
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.255 0.046 3256.7
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-5-(methoxymethyl)-2- pyridinecarboxamide
92 N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.004 0.0050175
789.47 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-methyl-5-(trifluoromethyl)-2- pyridinecarboxamide
93 N-(3-((1R,2R,5S)-4-amino-5-(fluoromethyl)-2- 0.040 0.035 1589.4
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-methyl-5-(trifluoromethyl)-2- pyridinecarboxamide
94 N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.0005 0.0002
256.77 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(2-butyn-1-yloxy)-2- pyrazinecarboxamide 95
N-(3-((1R,2R,5S)-4-amino-5-(fluoromethyl)-2- 0.007 0.003 603.01
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(2-butyn-1-yloxy)-2- pyrazinecarboxamide 96
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.002 0.002 0.001
732.83 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-cyano-3-methyl-2- pyridinecarboxamide 97
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.007 0.007 0.02
359.18 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-7-methoxypyrido[3,2- d]pyrimidin-4-amine 98
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.005 0.015 286.13
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4- amine 99
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.006 0.028 317.37
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-fluoro-3-methoxy-1,7- naphthyridin-8-amine 100
8-((3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.001 0.004 0.0006
337.29 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)amino)-1,7-naphthyridine-3- carbonitrile 101
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.026 0.012 1851.3
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-ethyl-2-pyridinecarboxamide 102
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.004 0.002 0.008
451.06 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(difluoromethoxy)-3-methyl-2- pyridinecarboxamide
103 N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.009 0.007 890.76
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(difluoromethyl)-3-methyl-2- pyridinecarboxamide
104 N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.002 0.0009 0.003
799.04 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4- fluorophenyl)-2-(1,3-oxazol-2-
ylmethoxy)pyrido[3,4-b]pyrazin-5-amine 105
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.002 0.004 926.18
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3,5-dichloro-2- pyridinecarboxamide 106
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.011 0.006 0.067 317
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-7-
(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-amine 107
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.010 0.018 185
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-7-(trifluoromethyl)pyrido[3,2- d]pyrimidin-4-amine
108 N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.008 0.007
>400.0 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-chloro-5-(trifluoromethyl)-2- pyridinecarboxamide
109 N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.017 0.007 1036
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(difluoromethyl)-2- pyrazinecarboxamide 110
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.006 0.005 536.4
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-(trifluoromethyl)-2- pyridinecarboxamide 111
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.002 0.004 956.79
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-cyano-2-pyridinecarboxamide 112
N-(3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.008 0.188 0.058
1305.9 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4- fluorophenyl)-2-(2,2,2-
trifluoroethoxy)pyrido[3,4-b]pyrazin-5-amine 114
N-(3-((1S,2S,5R)-4-amino-2-(fluoromethyl)-5- 0.061 0.082 3455.6
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-methyl-5-(trifluoromethyl)-2- pyridinecarboxamide
116 N-(3-((1R,2S,5S)-4-amino-2-(fluoromethyl)-5- 0.044 0.047 254.74
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-3-methyl-5-(trifluoromethyl)-2- pyridinecarboxamide
118 N-(3-((1S,2S,5R)-4-amino-2-(fluoromethyl)-5- 0.017 0.062 0.002
>400.0 methyl-8,8-dioxido-8-thia-3-
azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 120
N-(3-((1S,2S,5R)-4-amino-2-(fluoromethyl)-5- 0.049 0.088 >400.0
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-methoxy-2- pyrazinecarboxamide 121
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.41 0.15 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-fluoro-4- (trifluoromethyl)benzamide 122
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.905 0.255 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-fluoro-4- (trifluoromethyl)benzamide 123
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.13 0.083 1621.7
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-fluoro-4- methoxybenzamide 124
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.588 0.103 4440.9
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-fluoro-4- methoxybenzamide 125
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.103 0.065 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-4-bromo-2,6- difluorobenzamide 126
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.315 0.073 2199.2
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-4-bromo-2,6- difluorobenzamide 127
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.056 0.025 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-4-cyano-2- fluorobenzamide 128
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.123 0.037 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-4-cyano-2- fluorobenzamide 129
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.061 0.044 7.0002
348.46 dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-4-(2-butyn-1-yloxy)-2- fluorobenzamide 130
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.005 0.004 363.3
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-7-chloropyrido[3,2- d]pyrimidin-4-amine 131
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.029 0.018 481.94
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-7-chloropyrido[3,2- d]pyrimidin-4-amine 132
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.006 0.003 0.051 964.56
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-7-methoxypyrido[3,2- d]pyrimidin-4-amine 133
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.096 0.026 1164.9
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-7-methoxypyrido[3,2- d]pyrimidin-4-amine 134
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.001 0.004 1605.4
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-5-
fluoro-1,7-naphthyridin-8-amine 135
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.003 0.021 613.76
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-(2-butyn-1-yloxy)-5-
fluoro-1,7-naphthyridin-8-amine 136
N-(3-((1R,2R,5S)-4-amino-2,5-dimethyl-8,8- 0.061 0.253 5341.8
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-(cyclopropylmethoxy)-5-
fluoro-1,7-naphthyridin-8-amine 137
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.003 0.0654 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-3-(cyclopropylmethoxy)-5-
fluoro-1,7-naphthyridin-8-amine 138
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.061 0.122 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-4-(2-butyn-1-yloxy)-2- fluorobenzamide 139
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.005 0.005 0.067 1281.1
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-7-
(cyclopropylmethoxy)pyrido[3,2-d]pyrimidin-4- amine 140
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.001 0.0004 0.020 855
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-(1,3-oxazol-2-
ylmethoxy)pyrido[3,4-b]pyrazin-5-amine 141
N-(3-((1R,2R,5S)-4-amino-5-(methoxymethyl)- 0.408 0.327 1185
2-methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4- amine 142
N-(3-((1R,2R,5S)-4-amino-5-(methoxymethyl)- 0.093 0.482 >400.0
2-methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)-5-chloro-3-methyl-2- pyridinecarboxamide 143
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.009 0.164 149.83
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-(2-
methylpropoxy)pyrido[3,4-b]pyrazin-5-amine 144
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.004 0.071 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-propoxypyrido[3,4- b]pyrazin-5-amine 145
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.003 0.002 0.065 1984.9
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-(2-
methoxyethoxy)pyrido[3,4-b]pyrazin-5-amine 146
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.001 0.001 416.78
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-((5-methyl-1,3-oxazol-2-
yl)methoxy)pyrido[3,4-b]pyrazin-5-amine 147
N-(3-((1S,2R,5R)-4-amino-2,5-dimethyl-8,8- 0.002 0.001 >400.0
dioxido-8-thia-3-azabicyclo[3.2.1]oct-3-en-2-
yl)-4-fluorophenyl)-2-((1-methyl-1H-pyrazol-3-
yl)methoxy)pyrido[3,4-b]pyrazin-5-amine 148
5-((3-((1S,2R,5R)-4-amino-5-(fluoromethyl)-2- 0.016 0.019 216.5
methyl-8,8-dioxido-8-thia-3- azabicyclo[3.2.1]oct-3-en-2-yl)-4-
fluorophenyl)amino)pyrido[3,4-b]pyrazin- 2(1H)-one
[1009] The present invention also provides methods for making
compounds of Formulas I-III, and sub-formulas therein. For example,
the compounds of the present invention and additional examples may
be made by the following methods, as similarly described in the
literature references mentioned below.
[1010] In one embodiment of the invention, there is provided a
process for preparing a compound according to any of Formula I, II
or III, of a sub-formula thereof, the process comprising the step
of reacting a compound 20
##STR00164##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, R.sup.1, R.sup.2,
R.sup.3 and o of compound 20 are as defined herein with respect to
Formulas I, II or III, with a compound having the structure or
R.sup.9--C(.dbd.O)OH or R.sup.9--Cl, wherein R.sup.9 is as defined
herein with respect to Formulas I, II or III, to prepare the
compound according to any of Formulas I, II or III, or a subformula
thereof.
[1011] In one embodiment of the invention, there is provided a
method of making a compound of Formula II-C-1 having a general
structure of
##STR00165##
the method comprising the step of reacting a compound 20
##STR00166##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, R.sup.2
and R.sup.3 of Formula II-C-1 are as defined herein, with a
compound having the structure R.sup.9--COOH, wherein R.sup.9 is as
defined herein, to make a compound of Formula II-C-1.
[1012] In one embodiment of the invention, there is provided a
method of making a compound of Formula II-C-3 having a general
structure of
##STR00167##
the method comprising the step of reacting a compound 20
##STR00168##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, R.sup.2,
each R.sup.3, Y and o of Formula II-B are as defined herein, with a
compound having the structure
##STR00169##
wherein each W and each R.sup.10 are, independently, as defined
herein, in the presence of acid to make a compound of Formula
II-B.
[1013] In one embodiment of the invention, there is provided a
method of making a compound of Formula II-C-2
##STR00170##
the method comprising the step of reacting a compound 20
##STR00171##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, R.sup.2
and each R.sup.3 of Formula II-E are as defined herein, with a
compound having the structure
##STR00172##
wherein V, each W and each R.sup.10 are, independently, as defined
herein, to make a compound of Formula II-C-2.
[1014] In another embodiment of the invention, there is provided a
method of making a compound of Formula III-A-1 having a general
formula of
##STR00173##
the method comprising the step of reacting a compound 20
##STR00174##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, R.sup.2
and each R.sup.3 of Formula III are as defined herein, with a
compound having either structure of R.sup.7--COOH in the presence
of a base or R.sup.7 in the presence of an acid, wherein R.sup.7 is
as defined herein, to make a compound of Formula III-A-1.
[1015] In another embodiment of the invention, there is provided a
method of making a compound of Formula II-C having a general
formula of
##STR00175##
the method comprising the step of reacting a compound 20
##STR00176##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, R.sup.2
and each R.sup.3 of Formula II are as defined herein, with a
compound having either structure of R.sup.9--COOH in the presence
of a base or R.sup.9 in the presence of an acid, wherein R.sup.9 is
as defined herein, to make a compound of Formula II-C.
[1016] In another embodiment of the invention, there is provided a
method of making a compound of Formula III-C having a general
formula of
##STR00177##
the method comprising the step of reacting a compound 20
##STR00178##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each R.sup.1, R.sup.2
and each R.sup.3 of Formula III-C are as defined herein, with a
compound having either structure of R.sup.9--COOH in the presence
of a base or R.sup.9 in the presence of an acid, wherein R.sup.9 is
as defined herein, to make a compound of Formula III-C.
[1017] As can be appreciated by the skilled artisan, the above
synthetic schemes and representative examples are not intended to
comprise a comprehensive list of all means by which the compounds
described and claimed in this application may be synthesized.
Further methods will be evident to those of ordinary skill in the
art. Additionally, the various synthetic steps described above may
be performed in an alternate sequence or order to give the desired
compounds.
[1018] For example, in these procedures, the steps may be preceded,
or followed, by additional protection/deprotection steps as
necessary. Particularly, if one or more functional groups, for
example carboxy, hydroxy, amino, or mercapto groups, are or need to
be protected in preparing the compounds of the invention, because
they are not intended to take part in a specific reaction or
chemical transformation, various known conventional protecting
groups may be used. For example, protecting groups typically
utilized in the synthesis of natural and synthetic compounds,
including peptides, nucleic acids, derivatives thereof and sugars,
having multiple reactive centers, chiral centers and other sites
potentially susceptible to the reaction reagents and/or conditions,
may be used.
[1019] Synthetic chemistry transformations and protecting group
methodologies (protection and deprotection) useful in synthesizing
the inhibitor compounds described herein are known in the art and
include, for example, those such as described in R. Larock,
Comprehensive Organic Transformations, VCH Publishers (1989); T. W.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3.sup.rd edition, John Wiley and Sons (1999); L. Fieser and M.
Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John
Wiley and Sons (1994); A. Katritzky and A. Pozharski, Handbook of
Heterocyclic Chemistry, 2.sup.nd edition (2001); M. Bodanszky, A.
Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag,
Berlin Heidelberg (1984); J. Seyden-Penne, Reductions by the
Alumino- and Borohydrides in Organic Synthesis, 2.sup.nd edition,
Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of
Reagents for Organic Synthesis, John Wiley and Sons (1995).
[1020] Salts, including pharmaceutically acceptable salts, of a
compound of the invention having a salt-forming group may be
prepared in a conventional manner or manner known to persons
skilled in the art. For example, acid addition salts of compounds
of the invention may be obtained by treatment with an acid or with
a suitable anion exchange reagent. A salt with two acid molecules
(for example a dihalogenide) may also be converted into a salt with
one acid molecule per compound (for example a monohalogenide); this
may be done by heating to a melt, or for example by heating as a
solid under a high vacuum at elevated temperature, for example from
50.degree. C. to 170.degree. C., one molecule of the acid being
expelled per molecule of the compound.
[1021] Acid salts can usually be converted to free-base compounds,
e.g. by treating the salt with suitable basic agents, for example
with alkali metal carbonates, alkali metal hydrogen carbonates, or
alkali metal hydroxides, typically potassium carbonate or sodium
hydroxide. Exemplary and suitable salts, and their preparation, are
described herein in the Definition section of the application.
[1022] All synthetic procedures described herein can be carried out
under known reaction conditions, advantageously under those
described herein, either in the absence or in the presence
(usually) of solvents or diluents. As appreciated by those of
ordinary skill in the art, the solvents should be inert with
respect to, and should be able to dissolve, the starting materials
and other reagents used. Solvents should be able to partially or
wholly solubilize the reactants in the absence or presence of
catalysts, condensing agents or neutralizing agents, for example
ion exchangers, typically cation exchangers for example in the
H.sup.+ form. The ability of the solvent to allow and/or influence
the progress or rate of the reaction is generally dependant on the
type and properties of the solvent(s), the reaction conditions
including temperature, pressure, atmospheric conditions such as in
an inert atmosphere under argon or nitrogen, and concentration, and
of the reactants themselves.
[1023] Suitable solvents for conducting reactions to synthesize
compounds of the invention include, without limitation, water;
esters, including lower alkyl-lower alkanoates, e.g., EtOAc; ethers
including aliphatic ethers, e.g., Et.sub.2O and ethylene glycol
dimethylether or cyclic ethers, e.g., THF; liquid aromatic
hydrocarbons, including benzene, toluene and xylene; alcohols,
including MeOH, EtOH, 1-propanol, IPOH, n- and t-butanol; nitriles
including CH.sub.3CN; halogenated hydrocarbons, including
CH.sub.2Cl.sub.2, CHCl.sub.3 and CCl.sub.4; acid amides including
DMF; sulfoxides, including DMSO; bases, including heterocyclic
nitrogen bases, e.g. pyridine; carboxylic acids, including lower
alkanecarboxylic acids, e.g., AcOH; inorganic acids including HCl,
HBr, HF, H.sub.2SO.sub.4 and the like; carboxylic acid anhydrides,
including lower alkane acid anhydrides, e.g., acetic anhydride;
cyclic, linear, or branched hydrocarbons, including cyclohexane,
hexane, pentane, isopentane and the like, and mixtures of these
solvents, such as purely organic solvent combinations, or
water-containing solvent combinations e.g., aqueous solutions.
These solvents and solvent mixtures may also be used in
"working-up" the reaction as well as in processing the reaction
and/or isolating the reaction product(s), such as in
chromatography.
[1024] Purification methods are known in the art and include, for
example, crystallization, chromatography (liquid and gas phase, and
the like), extraction, distillation, trituration, reverse phase
HPLC and the like. Reactions conditions such as temperature,
duration, pressure, and atmosphere (inert gas, ambient) are known
in the art and may be adjusted as appropriate for the reaction.
[1025] The invention further encompasses "intermediate" compounds,
including structures produced from the synthetic procedures
described, whether isolated or generated in-situ and not isolated,
prior to obtaining the finally desired compound. Structures
resulting from carrying out steps from a transient starting
material, structures resulting from divergence from the described
method(s) at any stage, and structures forming starting materials
under the reaction conditions are all "intermediates" included in
the invention. Further, structures produced by using starting
materials in the form of a reactive derivative or salt, or produced
by a compound obtainable by means of the process according to the
invention and structures resulting from processing the compounds of
the invention in situ are also within the scope of the
invention.
[1026] The invention also provides new starting materials and/or
intermediates, as well as processes for the preparation thereof. In
select embodiments, such starting materials are used and reaction
conditions so selected as to obtain the desired compound(s).
Starting materials of the invention, are either known, commercially
available, or can be synthesized in analogy to or according to
methods that are known in the art. Many starting materials may be
prepared according to known processes and, in particular, can be
prepared using processes described in the examples. In synthesizing
starting materials, functional groups may be protected with
suitable protecting groups when necessary. Protecting groups, their
introduction and removal are described above.
[1027] Compounds of the present invention can possess, in general,
one or more asymmetric carbon atoms and are thus capable of
existing in the form of optical isomers as well as in the form of
racemic or non-racemic mixtures thereof. While shown without
respect to stereochemistry in Formulas I-III, the present invention
includes such optical isomers and diastereomers, as well as the
racemic and resolved, enantiomerically pure R and S stereoisomers,
as well as other mixtures of R and S stereoisomers and
pharmaceutically acceptable salts thereof.
[1028] The optical isomers can be obtained by resolution of the
racemic mixtures according to conventional processes, e.g., by
formation of diastereoisomeric salts, by treatment with an
optically active acid or base. Examples of appropriate acids are
tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric,
and camphorsulfonic acid and then separation of the mixture of
diastereoisomers by crystallization followed by liberation of the
optically active bases from these salts. A different process for
separation of optical isomers involves the use of a chiral
chromatography column optimally chosen to maximize the separation
of the enantiomers. Still another available method involves
synthesis of covalent diastereoisomeric molecules by reacting
compounds of the invention with an optically pure acid in an
activated form or an optically pure isocyanate. The synthesized
diastereoisomers can be separated by conventional means such as
chromatography, distillation, crystallization or sublimation, and
then hydrolyzed to deliver the enantiomerically pure compound. The
optically active compounds of the invention can likewise be
obtained by using optically active starting materials. These
isomers may be in the form of a free acid, a free base, an ester or
a salt. All such isomeric forms of such compounds are expressly
included in the present invention.
[1029] The compounds of the invention may also be represented in
multiple tautomeric forms. Tautomers often exist in equilibrium
with each other, and interconvert under environmental and
physiological conditions. The compounds of the invention may also
occur in cis- or trans- or E- or Z-double bond isomeric forms. The
invention expressly includes all tautomeric forms of the compounds
described herein.
[1030] All crystal forms of the compounds described herein are
expressly included in the present invention.
[1031] The present invention also includes isotopically-labeled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H (deuterium), .sup.3H (tritium), .sup.13C,
.sup.14C, .sup.15N, .sup.16O, .sup.17O, .sup.31P, .sup.32P,
.sup.35S, .sup.18F, and .sup.36Cl.
[1032] Compounds of the present invention that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically-labeled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Deuterated (.sup.2H), Tritiated (.sup.3H) and carbon-14, i.e.,
.sup.14C, isotopes are particularly preferred for their ease of
preparation and detection. Further, substitution with heavier
isotopes such as deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements and, hence, may be preferred in some circumstances.
Isotopically labeled compounds of this invention can generally be
prepared by substituting a readily available isotopically labeled
reagent for a non-isotopically labeled reagent.
Biological Evaluation
[1033] The compounds of the invention may be modified by appending
appropriate functionalities to enhance selective biological
properties. The pharmacokinetic and pharmacodynamic properties of a
compound relate, directly and indirectly, to the ability of the
compound to be effective for its intended use.
[1034] Although the pharmacological properties of the compounds of
the invention (Formulas I-III) vary with structural change, in
general, activity possessed by compounds of Formulas I-III may be
demonstrated both in vitro as well as in vivo. The following
exemplified pharmacological assays have been carried out with the
compounds according to the invention, to assess and characterize
the compound's ability to modulate BACE activity and to regulate
the cleavage of amyloid beta precursor protein, thereby reducing or
inhibiting the production of amyloid beta.
In Vitro Enzymatic BACE FRET (Fluorescence Resonance Energy
Transfer) Assay (Enzyme Assay Data in the Example Table I)
[1035] The assay buffer used in this screen is 0.05 M acetate, pH
4.2, 10% DMSO final, 100 uM genapol (which is a nonionic detergent,
below its Critical Micelle Concentration). The Beta Secretase
enzyme (0.2 nM) is pre-incubated for one hour with inhibitors,
typically in about 1 uL of DMSO according to a serial dilution, are
added thereto. This assay is effectively started by the addition of
FRET substrate (50 nM) and the combination is incubated for one
hour. The FRET assay is terminated with by addition of Tris buffer,
which raises the pH to neutrality, and the fluorescence is
determined. The FRET substrate is a peptide with commercially
available fluorophore and quencher, on opposite sides of the BACE
cleavage site. Proteolytic cleavage of the FRET substrate releases
quenching of fluorescence (excitation 488 nm and emission 425
nm).
[1036] Where available, the in-vitro BACE FRET enzyme data for each
of the Examples is provided in Tables 1 and 3.
In Vitro BACE Cell-Based Assay
[1037] The cell-based assay measures inhibition or reduction of
A.beta.40 in conditioned medium of test compound treated cells
expressing amyloid precursor protein.
[1038] Cells stably expressing Amyloid Precursor Protein (APP) were
plated at a density of 40K cells/well in 96 well plates (Costar).
The cells were cultivated for 24 hours at 37.degree. C. and 5%
CO.sub.2 in DMEM supplemented with 10% FBS. The test compounds were
then added to cells in 10-point dose response concentrations with
the starting concentration being either 100 .mu.M or 10 .mu.M. The
compounds were diluted from stock solutions in DMSO and the final
DMSO concentration of the test compounds on cells was 0.1%. After
24 h of incubation with the test compounds the supernatant
conditioned media was collected and the A.beta. 40 levels were
determined using a sandwich ELISA. The IC.sub.50 of the compound
was calculated from the percent of control or percent inhibition of
A.beta. 40 as a function of the concentration of the test
compound.
[1039] The sandwich ELISA to detect A.beta. 40 was performed in 96
well microtiter plates, which were pre-treated with goat
anti-rabbit IgG (Pierce). The capture and detecting antibody pair
that were used to detect A.beta. 40 from cell supernatants were
affinity purified pAb40 (Biosource) and biotinylated 6E10 (Signet
Labs Inc.), respectively. The optimal concentration for the pAb40
antibody was 3 .mu.g/ml in Superblock/TBS (Pierce) that was
supplemented with 0.05% Tween 20 (Sigma). Optimal concentration for
the detection antibody 6E10-biotinylated was 0.5 .mu.g/ml in
Superblock/TBS (Pierce) that had been supplemented with 2% normal
goat serum and 2% normal mouse serum.
[1040] Cellular supernatants were incubated with the capture
antibody for 3 h at 4.degree. C., followed by 3 wash steps in
TBS-tween (0.05%). The detecting antibody incubation was for 2 h at
4.degree. C., again followed by the wash steps as described
previously. The final readout of the ELISA is Time-Resolved
Fluorescence (counts per minute) using Delfia reagents
Streptavidin-Europium and Enhancement solutions (Perkin Elmer) and
the Victor 2 multilabel counter (Perkin Elmer).
[1041] Where available, the in-vitro BACE cell based data for each
of the Examples is provided in Tables 1 and 3.
In Vitro Enzymatic BACE2 FRET (Fluorescence Resonance Energy
Transfer) Assay (Enzyme Assay Data in the Table 3)
[1042] The assay buffer used in this screen is 0.05 M acetate, pH
4.2, 10% DMSO final, 100 uM genapol (which is a nonionic detergent,
below its Critical Micelle Concentration). The Beta Secretase2
enzyme (human Bace2 protein with C-terminal V5 and 6-His tag; 0.2
nM) is pre-incubated for one hour with inhibitors, typically in
about 1 uL of DMSO according to a serial dilution, are added
thereto. This assay is effectively started by the addition of FRET
substrate (50 nM) and the combination is incubated for one hour.
Final assay concentration of about 0.64 nM. The FRET assay is
terminated with by addition of Tris buffer, which raises the pH to
neutrality, and the fluorescence is determined. The FRET substrate
is a peptide with commercially available fluorophore and quencher,
on opposite sides of the BACE cleavage site. Proteolytic cleavage
of the FRET substrate releases quenching of fluorescence
(excitation 488 nm and emission 425 nm).
[1043] Where available, the in-vitro BACE2 FRET enzyme data for
each of the Examples is provided in Table 3.
In Vitro Enzymatic Cathepsin D (Cat D) FRET (Fluorescence Resonance
Energy Transfer) Assay
[1044] Recombinant Cat D was expressed in CHO cells. The assay
buffer for CathepsinD is 0.05 M citrate pH 3.5, 10% DMSO final, 5
mM CHAPS. The Cat D enzyme (9 nM) is pre-incubated for one hour
with inhibitors, typically in about 1 uL of DMSO according to a
serial dilution, is added thereto. The assays are effectively
started by the addition of different FRET substrates (20 nM for Cat
D) and the combination is incubated for one hour. The FRET assay is
terminated with by addition of Tris buffer, which raises the pH to
neutrality, and the fluorescence is determined. The FRET substrate
is a peptide with commercially available fluorophore and quencher,
on opposite sides of the BACE cleavage site. The Cat D substrate
peptide sequence is based on sequence #1 of Table 1 from Gulnik et
al. FEBS Letters v413 p379-384 1997. Proteolytic cleavage of the
FRET substrate releases quenching of fluorescence (Cat D excitation
500 nm and emission 580 nm).
[1045] Alternatively, a Cat D assay may also be run according to
the procedure described in the article, Characterization of new
fluorgenic substrates for the rapid and sensitive assay of
cathepsin E and cathepsin D, J. Biochem., 125:1137, 1999. In
addition, the cathepsin D and cathepsin E assays are described in
PCT publication WO2011069934. This WIPO publication describes BACE
inhibitor compounds having an amide linker connecting two aromatic
groups with extremely poor cathepsin D and/or cathepsin E
inhibitory activity (see Table 2).
[1046] Where available, the in-vitro Cat D FRET assay data for each
of the Examples, conducted by the first procedure, is provided in
Tables 1 and 3. For example, the compound of example 28 has a Cat D
IC.sub.50 value of >400 uM. As shown by the high micromolar Cat
D data (very poorly active or inactive against Cat D), the
compounds of the present invention possess the unexpected property
of little to no ability to inhibit the activity of Cat D. The
compounds of the present invention are believed to minimize, reduce
or eliminate any risk of retinal atrophy and abnormal development
of the eye and of the retinal pigmented epithelium as it relates to
the normal function and activity of Cat D.
In Vivo Inhibition of Beta-Secretase
[1047] Several animal models, including mouse, rat, dog, and
monkey, may be used to screen for inhibition of beta-secretase
activity in vivo following administration of a test compound sample
Animals used in this invention can be wild type, transgenic, or
gene knockout animals. For example, the Tg2576 mouse model,
prepared and conducted as described in Hsiao et al., 1996, Science
274, 99-102, and other non-transgenic or gene knockout animals are
useful to analyze in vivo inhibition of Amyloid beta peptide
(Abeta) production in the presence of inhibitory test compounds.
Generally, 2 to 18 month old Tg2576 mice, gene knockout mice or
non-transgenic animals are administered test compounds formulated
in vehicles, such as cyclodextran, phosphate buffers, hydroxypropyl
methylcellulose or other suitable vehicles. One to twenty-four
hours following the administration of compound, animals are
sacrificed, and brains as well as cerebrospinal fluid (CSF) and
plasma are removed for analysis of A-beta levels and drug or test
compound concentrations (Dovey et al., 2001, Journal of
Neurochemistry, 76,173-181) Beginning at time 0, animals are
administered by oral gavage, or other means of delivery such as
intravenous injection, an inhibitory test compound of up to 100
mg/kg in a standard, conventional formulation, such as 2%
hydroxypropyl methylcellulose, 1% Tween80. A separate group of
animals receive 2% hydroxypropyl methylcellulose, 1% Tween80 alone,
containing no test compound, and serve as a vehicle-control group.
At the end of the test period, animals are sacrificed and brain
tissues, plasma or cerebrospinal fluid are collected. Brains are
either homogenized in 10 volumes (w/v) of 0.2% diethylamine (DEA)
in 50 mM NaCl (Best et al., 2005, Journal of Pharmacology and
Experimental Therapeutics, 313, 902-908), or in 10 volumes of 0.5%
TritonX-100 in Tris-buffered saline (pH at about 7.6). Homogenates
are centrifuged at 355,000 g, 4.degree. C. for 30 minutes. CSF or
brain supernatants are then analyzed for the presence of A-beta
peptide by specific sandwich ELISA assays based on ECL
(Electrochemiluminescence) technology. For example, rat Abeta40 is
measured using biotinylated-4G8 (Signet) as a capture antibody and
Fab40 (an in-house antibody specific to the C-terminal of Abeta40)
as a detection antibody. For example, 4 hours after administration
of 30 mg/kg oral dose of the test compound in 2% hydroxypropyl
methylcellulose, 1% Tween80 (pH2.2) to 200 g male Sprague Dawley
rats, amyloid beta peptide levels are measured for reduction by X %
and Y % in cerebrospinal fluid and brain, respectively, when
compared to the levels measured in the vehicle-treated or control
mice.
Actual vehicles used: Oral: 2% HPMC, 1% Tween80, pH 2.2 [1048] IV:
5% EtOH, 45% Propylene glycol in 5% Dextrose
[1049] The compounds of the invention may be shown to reduce the
formation and/or deposition of amyloid beta peptide in the
cerebrospinal fluid (CSF) as well as in the brain of a mouse or rat
at either 3 mpk, 10 mpk or 30 mpk (mpk=mg compound per kg weight of
the animal) dosing concentrations after 4 hrs. The following
examples exhibited the following percent Abeta 40 reductions at 10
mpk (unless otherwise noted) in the CSF and brain of the rat,
respectively.
TABLE-US-00004 Ex. % reduction of rat % reduction of rat brain No.
CSF levels at 10 pmk levels at 10 mpk 22 76 66 24 72 62 35 52 46 37
80 79 40 59 24 41 76 62 42 21 (3 mpk) 0 (3 mpk) 52 67 62 56 69 6-
59 80 76 61 80 79 69 42 9 76 76 66 77 77 67 78 52 46 79 71 62 80 72
63 82 71 56 88 77 70 92 73 67 96 60 (3 mpk) 39 (3 mpk) 97 75 76 98
70 74 100 67 59 102 67 68 103 62 58 104 74 71 105 74 71 106 59 29
107 53 43 109 70 57 110 65 54 132 70 50 140 41 39 146 35 13
Indications
[1050] According to the amyloid cascade hypothesis, cerebral
deposition of amyloid-beta peptide (A.beta.) is critical for
Alzheimer's disease (AD) pathogenesis. A.beta. generation is
initiated when .beta.-secretase (BACE1) cleaves the amyloid
precursor protein. De Meyer et al re-affirm the believed role which
the accumulation of beta-amyloid protein (A-beta) in cerebral
spinal fluid (CSF) in a subject plays in the progression of
symptoms, initially revealed as mild cognitive impairment, which
ultimately leads to AD. Arch Neurol. 67(8):949-956, 2010. Amyloid-b
(Ab) peptides generated from amyloid precursor protein (APP) by
proteolytic cleavage, such as by aspartyl protease enzymes
including beta-secreatase (BACE) and gamma-secretase, likely play a
causal role in AD pathogenesis (Tanzi and Bertram, Cell, (120):
545-555, 2005; Walsh and Selkoe, Neuron, (44): 181-193, 2004).
Although the precise mechanisms of Ab toxicity are unclear,
oligomeric forms of Ab may contribute to cognitive decline by
altering synaptic structure and function (Palop and Mucke, Nat.
Neuroscience, (13): 812-818, 2010; Selkoe, Behavioral Brain Res.,
(192): 106-113, 2008; Shankar et al., Nat. Medicine (14): 837-842,
2008). Transgenic mouse models that overexpress mutant APP and
produce high levels of Ab show amyloid plaque deposition, synaptic
deficits, learning and memory impairments, and other behavioral
abnormalities (Games et al., Nature, (373): 523-527, 1995;
Go{umlaut over ( )} tz et al., Molecular Psychiatry (9): 664-683,
2004; Hsia et al., Proc. Natl. Academy of Science USA (96):
3228-3233, 1999; Hsiao et al., Science (274): 99-102, 1996, citing
Harris et al, Neuron (68): 428-441, 2010).
[1051] For more than a decade, BACE1 has been a prime target for
designing drugs to prevent or treat AD. However, development of
such agents has turned out to be extremely challenging, with major
hurdles in cell penetration, oral bioavailability/metabolic
clearance, and brain access.
[1052] Bapineuzamab, a monoclonal amino-terminus specific
anti-amyloid antibody is presently in Phase III clinical trials for
the treatment of AD. Alzheimer's Research & Therapy, 1:2, 2009.
Each of the known genetic causes of AD is linked to A-beta.
Dementia, Down's Syndrome to APP over-production, are all believed
to be linked to the deposition of A-beta on the brain. With methods
for identifying brain amyloid deposition, positron emission
scanning (PET) and CSF measurements of Ab42, identification of AD
suffering individuals needing treatment is becoming easier and more
common. It is firmly believed that by reducing the formation of
A-beta, one can begin to pre-treat AD. Vassar et al, Journal of
Neuroscience, 29 (41):12787-12794, 2009. One published pathway for
treatment of AD is inhibition of beta-secretase. Tirrell, Bloomberg
News, The Boston Globe, Jan. 7, 2010.
[1053] The US biotech company CoMentis is developing an orally
bioavailable small molecule CTS-21166, a highly potent, highly
selective and efficacious brain-penetrating beta-secretase
inhibitor. CoMentis successfully completed a Phase I study of
CTS-21166 in healthy volunteers in 2008. Results indicated that
CTS-21166 was safe, well-tolerated and pharmacodynamically active
at all dose levels. All clinical subjects administered CTS-21166
showed area-under-curve (AUC) reduction in plasma A-Beta40
reductions ranging from 40-75%. Because of the urgent need for AD
treatment, Phase II studies for CTS-2166 are planned, or ongoing,
for AD patients. In preclinical studies, CTS-21166 exhibits
excellent efficacy, selectivity, brain penetration and
pharmacologic activity.
[1054] Using a fragment-based chemistry strategy, Eli Lilly and
company generated LY2811376
[(S)-4-(2,4-difluoro-5-pyrimidin-5-yl-phenyl)-4-methyl-5,6-dihydro-4H-[1,-
3]thiazin-2-ylamine], an orally available non-peptidic BACE1
inhibitor that produces profound A.beta.-lowering effects in
animals. The biomarker changes obtained in preclinical animal
models translate into man at doses of LY2811376 that were safe and
well tolerated in healthy volunteers (US Ph I Clinical
trial--www.clinicaltrials.gov). Prominent and long-lasting AP
reductions in lumbar CSF were measured after oral dosing of 30 or
90 mg of LY2811376. This represents the first translation of
BACE1-driven biomarker changes in CNS from preclinical animal
models to man. Because of toxicology findings identified in
longer-term preclinical studies, this compound is no longer
progressing in clinical development. However, BACE1 remains a
viable target because the potential adverse effects discussed
herein were recapitulated in LY2811376-treated BACE 1 KO mice and
thus are unrelated to BACE 1 inhibition. The magnitude and duration
of central A.beta. reduction obtainable with BACE1 inhibition
positions this protease as a tractable small-molecule target
through which to test the amyloid hypothesis in man. Neuroscience,
31(46):16507-16515, 2011
[1055] The compounds of the invention have been shown to modulate,
and specifically inhibit the activity of the beta-secretase enzyme,
thereby reducing the A-beta peptide fragments. Accordingly,
compounds of the invention are useful for, but not limited to, the
prevention or treatment of beta-secretase related diseases,
including Alzheimer's disease. The compounds of the invention have
the ability to modulate the activity of beta secretase enzyme,
thereby regulating the production of amyloid beta (Abeta peptide)
and reducing the formation and deposition of Abeta peptide in both
the cerebral spinal fluid as well as in the brain, resulting in a
decrease of amyloid plaque on the brain. In one embodiment of the
invention, there is provided a method of treating a disorder
related to a beta-secretase enzyme in a subject, the method
comprising administering to the subject an effective dosage amount
of a compound of Formulas I, II, III, and sub-formulae thereof. In
another embodiment, there is provided a method of reducing
production of amyloid beta, and of reducing plaque formation on the
brain. In another embodiment, there is provided a method for the
treatment, prevention or amelioration of a disease or disorder
characterized by the elevated beta-amyloid deposits or beta-amyloid
levels in a subject, the method comprising administering to the
subject a therapeutically effective amount of a compound according
to any of Formulas I-III. In yet another embodiment, the invention
provides a method of treating Alzheimer's disease, cognitive
impairment including mild, moderate and/or severe, Down's Syndrome,
cognitive decline, senile dementia, cerebral amyloid angiopathy or
a neurodegenerative disorder.
[1056] Accordingly, the compounds of the invention would be useful
in therapy as CNS agents in treating neurological disorders and
related conditions in subjects.
[1057] In one embodiment, the compounds of the invention are
provided for the manufacture of a medicament, or a pharmaceutical
composition, for the therapeutic and/or prophylactic treatment of
diseases and disorders characterized by elevated levels of
.beta.-amyloid and/or .beta.-amyloid oligomers and/or b-amyloid
plaques and further deposits, including Alzheimer's Disease. In
another embodiment, the invention provides compounds, in effective
dosage amounts, for the therapeutic and/or prophylactic treatment
of AD. Thus, the compounds of the invention may be used to treat
prodromol patients, i.e., subjects exhibiting the biomarkers and/or
hallmarks of developing AD.
[1058] Besides being useful for human treatment, the compounds of
the invention may be useful for veterinary treatment of companion
animals, exotic animals and farm animals, including mammals,
rodents, and the like. For example, animals including horses, dogs,
and cats may be treated with compounds provided herein.
Formulations and Method of Use
[1059] Treatment of diseases and disorders herein is intended to
also include therapeutic administration of a compound of the
invention, or a pharmaceutical salt thereof, or a pharmaceutical
composition of either to a subject (i.e., an animal, preferably a
mammal, most preferably a human) which may be in need of
preventative treatment, such as, for example, for pain,
inflammation and the like. Treatment also encompasses prophylactic
administration of a compound of the invention, or a pharmaceutical
salt thereof, or a pharmaceutical composition of either to a
subject (i.e., an animal, preferably a mammal, most preferably a
human). Generally, the subject is initially diagnosed by a licensed
physician and/or authorized medical practitioner, and a regimen for
prophylactic and/or therapeutic treatment via administration of the
compound(s) or compositions of the invention is suggested,
recommended or prescribed.
[1060] The amount of compound(s) which is/are administered and the
dosage regimen for treating neurological disorders and
beta-secretase mediated diseases with the compounds and/or
compositions of this invention depends on a variety of factors,
including the age, weight, sex and medical condition of the
subject, the type of disease, the severity of the disease, the
route and frequency of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. A daily dose of about
0.01 to 500 mg/kg, advantageously between about 0.01 and about 50
mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even
more advantageously between about 0.1 and about 10 mg/kg body
weight may be appropriate, and should be useful for all methods of
use disclosed herein. The daily dose can be administered in one to
four doses per day.
[1061] While it may be possible to administer a compound of the
invention alone, in the methods described, the compound
administered normally will be present as an active ingredient in a
pharmaceutical composition. Thus, in another embodiment of the
invention, there is provided a pharmaceutical composition
comprising a compound of this invention in combination with a
pharmaceutically acceptable excipient, which includes diluents,
carriers, adjuvants and the like (collectively referred to herein
as "excipient" materials) as described herein, and, if desired,
other active ingredients. A pharmaceutical composition of the
invention may comprise an "effective amount" of a compound of the
invention or an "effective dosage amount" of a compound of the
invention. An "effective dosage amount" of a compound of the
invention includes an amount less than, equal to or greater than an
effective amount of the compound. For example, a pharmaceutical
composition in which two or more unit dosages, such as in tablets,
capsules and the like, are required to administer an effective
amount of the compound, or alternatively, a multi-dose
pharmaceutical composition, such as powders, liquids and the like,
in which an effective amount of the compound is administered by
administering a portion of the composition.
[1062] The compound(s) of the present invention may be administered
by any suitable route, preferably in the form of a pharmaceutical
composition adapted to such a route, and in a dose effective for
the treatment intended. The compounds and compositions of the
present invention may, for example, be administered orally,
mucosally, topically, rectally, pulmonarily such as by inhalation
spray, or parentally including intravascularly, intravenously,
intraperitoneally, subcutaneously, intramuscularly intrasternally
and infusion techniques, in dosage unit formulations containing
conventional pharmaceutically acceptable carriers, adjuvants, and
vehicles.
[1063] For oral administration, the pharmaceutical composition may
be in the form of, for example, a tablet, capsule, suspension or
liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a particular amount of the active
ingredient. Examples of such dosage units are tablets or capsules.
For example, these may contain an amount of active ingredient from
about 1 to 2000 mg, advantageously from about 1 to 500 mg, and
typically from about 5 to 150 mg. A suitable daily dose for a human
or other mammal may vary widely depending on the condition of the
patient and other factors, but, once again, can be determined using
routine methods and practices.
[1064] For therapeutic purposes, the active compounds of this
invention are ordinarily combined with one or more adjuvants or
other "excipients" appropriate to the indicated route of
administration. If orally administered on a per dose basis, the
compounds may be admixed with lactose, sucrose, starch powder,
cellulose esters of alkanoic acids, cellulose alkyl esters, talc,
stearic acid, magnesium stearate, magnesium oxide, sodium and
calcium salts of phosphoric and sulfuric acids, gelatin, acacia
gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl
alcohol, to form the final formulation. For example, the active
compound(s) and excipient(s) may be tableted or encapsulated by
known and accepted methods for convenient administration. Examples
of suitable formulations include, without limitation, pills,
tablets, soft and hard-shell gel capsules, troches,
orally-dissolvable forms and delayed or controlled-release
formulations thereof. Particularly, capsule or tablet formulations
may contain one or more controlled-release agents, such as
hydroxypropylmethyl cellulose, as a dispersion with the active
compound(s).
[1065] Formulations for parenteral administration may be in the
form of aqueous or non-aqueous isotonic sterile injection solutions
or suspensions. These solutions and suspensions may be prepared
from sterile powders or granules using one or more of the carriers
or diluents mentioned for use in the formulations for oral
administration or by using other suitable dispersing or wetting
agents and suspending agents. The compounds may be dissolved in
water, polyethylene glycol, propylene glycol, ethanol, corn oil,
cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers. Other adjuvants
and modes of administration are well and widely known in the
pharmaceutical art. The active ingredient may also be administered
by injection as a composition with suitable carriers including
saline, dextrose, or water, or with cyclodextrin (ie. Captisol),
cosolvent solubilization (ie. propylene glycol) or micellar
solubilization (ie. Tween 80).
[1066] The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid
find use in the preparation of injectables.
[1067] The active ingredient may also be administered by injection
as a composition with suitable carriers including saline, dextrose,
or water. The daily parenteral dosage regimen will be from about
0.1 to about 30 mg/kg of total body weight, and preferably from
about 0.1 to about 10 mg/kg.
[1068] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[1069] The pharmaceutical compositions may be subjected to
conventional pharmaceutical operations such as sterilization and/or
may contain conventional adjuvants, such as preservatives,
stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and
pills can additionally be prepared with enteric coatings. Such
compositions may also comprise adjuvants, such as wetting,
sweetening, flavoring, and perfuming agents. Accordingly, in yet
another embodiment of the present invention, there is provided a
method of manufacturing a medicament, the method comprising
combining an amount of a compound according to Formulas I-III with
a pharmaceutically acceptable carrier to manufacture the
medicament.
[1070] In yet another embodiment, the invention provides a method
of manufacturing a medicament for the treatment of Alzheimer's
disease, the method comprising combining an amount of a compound
according to Formulas I-III with a pharmaceutically acceptable
carrier to manufacture the medicament.
Combinations
[1071] While the compounds of the invention can be dosed or
administered as the sole active pharmaceutical agent, they can also
be used in combination with one or more compounds of the invention
or in conjunction with other agents. When administered as a
combination, the therapeutic agents can be formulated as separate
compositions that are administered simultaneously or sequentially
at different times, or the therapeutic agents can be given as a
single composition.
[1072] The phrase "co-therapy" (or "combination-therapy"), in
defining use of a compound of the present invention and another
pharmaceutical agent, is intended to embrace administration of each
agent in a sequential manner in a regimen that will provide
beneficial effects of the drug combination, and is intended as well
to embrace co-administration of these agents in a substantially
simultaneous manner, such as in a single capsule having a fixed
ratio of these active agents or in multiple, separate capsules for
each agent.
[1073] Specifically, the administration of compounds of the present
invention may be in conjunction with additional therapies known to
those skilled in the art in the prevention or treatment of
beta-secretase, gamma-secretase and/or other reagents known in
influence the formation and/or deposition of amyloid beta,
otherwise responsible for the formation of plaque on the brain.
[1074] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the accepted dosage
ranges. Compounds of Formulas I, II and III may also be
administered sequentially with other known medicinal agents. The
invention is not limited in the sequence of administration;
compounds of the invention may be administered either prior to,
simultaneous with or after administration of the known
anti-inflammatory agent.
[1075] The foregoing description is merely illustrative of the
invention and is not intended to limit the invention to the
disclosed compounds, compositions and methods. Variations and
changes, which are obvious to one skilled in the art, are intended
to be within the scope and nature of the invention, as defined in
the appended claims. From the foregoing description, one skilled in
the art can easily ascertain the essential characteristics of this
invention, and without departing from the spirit and scope thereof,
can make various changes and modifications of the invention to
adapt it to various usages and conditions. All patents and other
publications recited herein are hereby incorporated by reference in
their entireties.
* * * * *