U.S. patent application number 15/354877 was filed with the patent office on 2017-09-21 for cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Jennifer R. ALLEN, Albert AMEGADZIE, Matthew P. BOURBEAU, James A. BROWN, Jian J. CHEN, Yuan CHENG, Michael J. FROHN, Angel GUZMAN-PEREZ, Paul E. HARRINGTON, Longbin LIU, Qingyian LIU, Jonathan D. LOW, Vu Van MA, James R. MANNING, Ana Elena MINATTI, Thomas T. NGUYEN, Nobuko NISHIMURA, Mark H. NORMAN, Liping H. PETTUS, Alexander J. PICKRELL, Wenyuan QIAN, Shannon RUMFELT, Robert M. RZASA, Aaron C. SIEGMUND, Markian M. STEC, Ryan D. WHITE, Qiufen XUE.
Application Number | 20170267673 15/354877 |
Document ID | / |
Family ID | 54150645 |
Filed Date | 2017-09-21 |
United States Patent
Application |
20170267673 |
Kind Code |
A1 |
ALLEN; Jennifer R. ; et
al. |
September 21, 2017 |
CYCLOPROPYL FUSED THIAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE
INHIBITORS AND METHODS OF USE
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, and each of R.sup.a, R.sup.b,
R.sup.1, R.sup.2, R.sup.3 and R.sup.7 of Formula I, independently,
are defined herein. The invention also provides pharmaceutical
compositions comprising the compounds, and 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
Formulas II and III, and sub-formula embodiments thereof,
intermediates and methods for preparing compounds of the
invention.
Inventors: |
ALLEN; Jennifer R.; (Newbury
Park, CA) ; AMEGADZIE; Albert; (Moorpark, CA)
; BOURBEAU; Matthew P.; (Woodland Hills, CA) ;
BROWN; James A.; (Moorpark, CA) ; CHEN; Jian J.;
(Camarillo, CA) ; CHENG; Yuan; (Newbury Park,
CA) ; FROHN; Michael J.; (Thousand Oaks, CA) ;
GUZMAN-PEREZ; Angel; (Belmont, MA) ; HARRINGTON; Paul
E.; (Camarillo, CA) ; LIU; Longbin; (Thousand
Oaks, CA) ; LIU; Qingyian; (Camarillo, CA) ;
LOW; Jonathan D.; (Reseda, CA) ; MA; Vu Van;
(Oak Park, CA) ; MANNING; James R.; (Pleasant
Hill, CA) ; MINATTI; Ana Elena; (Santa Monica,
CA) ; NGUYEN; Thomas T.; (Newbury Park, CA) ;
NISHIMURA; Nobuko; (West Hills, CA) ; NORMAN; Mark
H.; (Thousand Oaks, CA) ; PETTUS; Liping H.;
(Thousand Oaks, CA) ; PICKRELL; Alexander J.;
(Westlake Village, CA) ; QIAN; Wenyuan; (Thousand
Oaks, CA) ; RUMFELT; Shannon; (Camarillo, CA)
; RZASA; Robert M.; (Ventura, CA) ; SIEGMUND;
Aaron C.; (Ventura, CA) ; STEC; Markian M.;
(Moorpark, CA) ; WHITE; Ryan D.; (Somerville,
MA) ; XUE; Qiufen; (Thousand Oaks, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Assignee: |
AMGEN INC.
Thousand Oaks
CA
|
Family ID: |
54150645 |
Appl. No.: |
15/354877 |
Filed: |
November 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14819256 |
Aug 5, 2015 |
9550762 |
|
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15354877 |
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62035269 |
Aug 8, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/00 20180101; C07D 417/12 20130101; A61P 9/00 20180101; C07D
471/04 20130101; C07D 513/10 20130101; A61P 25/28 20180101; C07D
417/14 20130101; A61P 7/04 20180101; C07D 279/08 20130101; C07D
417/04 20130101 |
International
Class: |
C07D 417/12 20060101
C07D417/12; C07D 417/14 20060101 C07D417/14; C07D 471/04 20060101
C07D471/04; C07D 279/08 20060101 C07D279/08; C07D 417/04 20060101
C07D417/04; C07D 513/10 20060101 C07D513/10 |
Claims
1. A compound of Formula I ##STR00865## or a stereoisomer,
tautomer, hydrate, solvate or pharmaceutically acceptable salt
thereof, wherein A.sup.4 is CR.sup.4 or N; A.sup.5 is CR.sup.5 or
N; A.sup.6 is CR.sup.6 or N; A.sup.8 is CR.sup.8 or N, provided
that no more than two of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is
N; each of R.sup.a and R.sup.b, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH; R.sup.1 and either R.sup.a or R.sup.b
may optionally join to form a 5-membered saturated ring that
includes one S heteroatom; R.sup.1 is H, F, Cl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, --C.sub.1-6-alkylNH.sub.2,
--C.sub.1-6-alkylNHC.sub.1-6-alkyl,
--C.sub.1-6-alkylNHC(O)OC.sub.1-6-alkyl,
--C.sub.1-6-alkylNHC(O)NHC.sub.1-6-alkyl,
--C.sub.1-6-alkylNHC(O)C.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NH.sub.2, --CH.dbd.CHC(O)NHC.sub.1-6-alkyl,
--CH.dbd.CHC(O)N(C.sub.1-6-alkyl).sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl-OC.sub.1-6-alkyl,
--CH.dbd.CHC(O)-heterocyclyl,
--CH.dbd.C(CH.sub.3)C(O)-heterocyclyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHC(O)OC.sub.1-6-alkyl, --CH.dbd.CHCH.sub.2OH,
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
C.sub.1-6-alkyl-C(O)N(C.sub.1-6-alkyl).sub.2,
--C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl, --C(O)OH,
--C(O)OC.sub.1-C.sub.6alkyl, --C(O)NHC.sub.1-6-alkyl,
--C(O)N(C.sub.1-6-alkyl).sub.2, --C(O)NHC.sub.3-6cycloalkyl,
--C(O)NHOC.sub.1-6-alkyl, --C(O)N(C.sub.1-6-alkyl)OC.sub.1-6-alkyl,
--C(O)-heterocyclyl, --CH.sub.2-heteroaryl, or heteroaryl, wherein
the heterocyclyl groups of the --CH.dbd.CHC(O)-heterocyclyl,
--CH.dbd.C(CH.sub.3)C(O)-heterocyclyl, and --C(O)-heterocyclyl
groups are fully or partially unsaturated 3-, 4-, 5-, 6- or
7-membered monocyclic rings that include 1 heteroatom selected from
N, O, or S if the ring is a 3-membered ring, that include 1 or 2
heteroatoms independently selected from N, O, or S if the ring is a
4- or 5-membered ring, and include 1, 2, or 3 heteroatoms
independently selected from N, O, or S if the ring is a 6- or
7-membered ring, wherein the heteroaryl groups of the
--CH.sub.2-heteroaryl and heteroaryl groups is a 5- or 6-membered
ring that includes 1, 2, 3, or 4 heteroatoms selected from N, O, or
S, wherein each of the C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, and C.sub.3-6cycloalkyl portion of
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl,
C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--C(O)NHC.sub.1-6-alkyl, --C(O)N(C.sub.1-6-alkyl).sub.2,
--C(O)NHC.sub.3-6cycloalkyl, --CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl groups are optionally
substituted with 1-4 substituents of F, CN, methyl, oxo, or OH, and
further wherein each of the heterocyclyl groups of the
--CH.dbd.CHC(O)-heterocyclyl,
--CH.dbd.C(CH.sub.3)C(O)-heterocyclyl, and --C(O)heterocyclyl
groups is optionally substituted with 1-4 substituents
independently selected from F, methyl, OH, or OCH.sub.3, and
further wherein each of the heteroaryl groups of the
--CH.sub.2-heteroaryl and heteroaryl groups is optionally
substituted with 1-3 substituents independently selected from halo,
methyl, or OH; R.sup.2 is H, F, Cl, C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHCH.sub.2OH, C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl or --C(O)C.sub.1-6-alkenyl, wherein each of
the C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl, are optionally substituted
with 1-4 substituents of F, CN, oxo or OH; R.sup.3 is
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, CH.sub.2OH,
C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms; 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, C(O)C.sub.1-4-alkyl,
C(O)OC.sub.1-4-alkyl, or CH.sub.2OH; R.sup.7 is --NH--R.sup.9 or
--NH--C(.dbd.O)--R.sup.9; R.sup.9 is a fully or partially
unsaturated 3-, 4-, 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 ring is optionally substituted, independently, with 1-5
substituents of R.sup.10; each R.sup.10, independently, is H, halo,
haloalkyl, CN, OH, NO.sub.2, NH.sub.2, SF.sub.5, acetyl,
--C(O)NHC.sub.1-6-alkyl, --OCH.sub.2C(O)NHC.sub.1-6-alkyl,
--OCH.sub.2C(O)N(C.sub.1-6-alkyl).sub.2,
--OCH.sub.2CH.sub.2-pyrollidinonyl, oxo, cyclopropylmethoxy,
2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 3-pentynyloxy,
2-pentyloxy, 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, --OC.sub.2-C.sub.6alkenyl, C.sub.1-6thioalkoxyl,
--OCH.sub.2C.sub.3-6cycloaklyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl, dioxolyl,
--O-heterocyclyl, or --OCH.sub.2-heteroaryl, wherein the
heterocyclyl of the --O-heterocyclyl group is a 3-, 4-, 5-, 6- or
7-membered monocyclic saturated ring that includes 1 heteroatom
selected from N, O, or S if the heterocyclyl ring is a 3-membered
ring, that includes 1 or 2 heteroatoms independently selected from
N, O, or S if the heterocyclyl ring is a 4- or 5-membered ring, and
includes 1, 2, or 3 heteroatoms independently selected from N, O,
or S if the heterocyclyl ring is a 6- or 7-membered ring wherein
the heteroaryl group of the --OCH.sub.2-heteroaryl group is a 5- or
6-membered ring that includes 1, 2, 3, or 4 heteroatoms selected
from N, O, or S, and further wherein each of the
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 2-pentyloxy,
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,
--OCH.sub.2C.sub.3-6cycloaklyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolidinyl, oxetan-3-yl, dioxolyl, or
--OCH.sub.2-heteroaryl is optionally substituted independently with
1-5 substituents of F, Cl, Br, CN, NO.sub.2, NH.sub.2, OH, oxo,
CF.sub.3, CHF.sub.2, CH.sub.2F, methyl, methoxy, ethyl, ethoxy,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy,
tert-butoxy, isobutyl, sec-butyl, tert-butyl, cyclopentyl,
cyclohexyl, phenyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl,
tetrahydropyranyl, tetrahydropyrrolyl, oxetan-2-yl, or oxetan-3yl;
and the subscript o is selected from 0, 1, or 2.
2.-59. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to U.S.
Provisional Patent Application No. 62/035,269, filed on Aug. 8,
2014, which specification is hereby incorporated herein by
reference in its entirety and for all purposes as if specifically
set forth herein.
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
aging 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. Vassar & Yan, Lancet Neurology,
13:319-329 (2014). 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) (p 510) 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 compares 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, advanced to phase III 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. Vassar &
Yan, Lancet Neurology, 13:319-329 (2014). For example, each of the
following patent publications: WO14/098831, WO14/099794,
WO14/099788, WO14/097038, WO14/093190, WO14/066132, WO14/65434,
WO14/062553, WO14/062549, WO14/013076, WO13/182638, WO13/164730,
WO13/030713, WO13/028670, WO13/004676, WO2012162334, WO12/162330,
WO12/147762, WO2013139425, WO2012138734, US20120245157,
US20120245154, US20120238557, US2009082560, US2010160290,
US2010075957, WO2009151098, WO2011029803, WO2014045162,
WO201105738, WO2009134617, WO201013794, WO201013302, US20110152253,
US2009209755, EP 2703401 (equivalent of WO2012146762) and
EP01942105 describe inhibitors of BACE, useful for treating AD and
other beta-secretase mediated disorders. For Example, US20120245154
describes "Substituted Aminothiazine Derivative" as BACE inhibitors
for the treatment of neurological disorders of the general
formula:
##STR00002##
while EP2703401 describes "Pyridine Derivative and BACE1 Inhibitor
Containing Same" and discloses compounds of the general
formula:
##STR00003##
[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 multi-pathophysiological roles of CatD in tissue homeostasis
and organ development.
[0015] Inhibition of protein Cathepsin D has been implicated in
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
##STR00004##
wherein each of A.sup.4, A.sup.5, A.sup.6, A.sup.8, R.sup.a,
R.sup.b, R.sup.1, R.sup.2, R.sup.3 and R.sup.7 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 1 of the invention, there are provided
compounds, including stereoisomers, tautomers, hydrates, solvates
and pharmaceutically acceptable salts thereof, which are generally
defined by Formula I:
##STR00005##
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 two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0027] each of R.sup.a and R.sup.b, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0028] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHCH.sub.2OH, C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
C(O)C.sub.1-6-alkyl or --C(O)C.sub.1-6-alkenyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl, are optionally substituted
with 1-4 substituents of F, CN, oxo or OH;
[0029] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[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 or --NH--C(.dbd.O)--R.sup.9;
[0032] R.sup.9 is a fully or partially unsaturated 3-, 4-, 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 ring is 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl; and
[0034] the subscript o is selected from 0, 1, or 2.
[0035] In an alternative embodiment 1 of the invention, there are
provided compounds, including stereoisomers, tautomers, hydrates,
solvates and pharmaceutically acceptable salts thereof, which are
generally defined by Formula I:
##STR00006##
wherein
[0036] A.sup.4 is CR.sup.4 or N;
[0037] A.sup.5 is CR.sup.5 or N;
[0038] A.sup.6 is CR.sup.6 or N;
[0039] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0040] each of R.sup.a and R.sup.b, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0041] R.sup.1 and either R.sup.a or R.sup.b may optionally join to
form a 5-membered saturated ring that includes one S
heteroatom;
[0042] R.sup.1 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, --C.sub.1-6-alkylNH.sub.2,
--C.sub.1-6-alkylNHC.sub.1-6-alkyl,
--C.sub.1-6-alkylNHC(O)OC.sub.1-6-alkyl,
--C.sub.1-6-alkylNHC(O)NHC.sub.1-6-alkyl,
--C.sub.1-6-alkylNHC(O)C.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NH.sub.2, --CH.dbd.CHC(O)NHC.sub.1-6-alkyl,
--CH.dbd.CHC(O)N(C.sub.1-6-alkyl).sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl-OC.sub.1-6-alkyl,
--CH.dbd.CHC(O)-heterocyclyl,
--CH.dbd.C(CH.sub.3)C(O)-heterocyclyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHC(O)OC.sub.1-6-alkyl, --CH.dbd.CHCH.sub.2OH,
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
C.sub.1-6-alkyl-C(O)N(C.sub.1-6-alkyl).sub.2,
--C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl, --C(O)OH,
--C(O)OC.sub.1-C.sub.6alkyl, --C(O)NHC.sub.1-6-alkyl,
--C(O)N(C.sub.1-6-alkyl).sub.2, --C(O)NHC.sub.3-6cycloalkyl,
--C(O)NHOC.sub.1-6-alkyl, --C(O)N(C.sub.1-6-alkyl)OC.sub.1-6-alkyl,
--C(O)-heterocyclyl, --CH.sub.2-heteroaryl, or heteroaryl, wherein
the heterocyclyl groups of the --CH.dbd.CHC(O)-heterocyclyl,
--CH.dbd.C(CH.sub.3)C(O)-heterocyclyl, and --C(O)-heterocyclyl
groups are fully or partially unsaturated 3-, 4-, 5-, 6- or
7-membered monocyclic rings that include 1 heteroatom selected from
N, O, or S if the ring is a 3-membered ring, that include 1 or 2
heteroatoms independently selected from N, O, or S if the ring is a
4- or 5-membered ring, and include 1, 2, or 3 heteroatoms
independently selected from N, O, or S if the ring is a 6- or
7-membered ring, wherein the heteroaryl groups of the
--CH.sub.2-heteroaryl and heteroaryl groups is a 5- or 6-membered
ring that includes 1, 2, 3, or 4 heteroatoms selected from N, O, or
S, wherein each of the C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, and C.sub.3-6cycloalkyl portion of
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl,
C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--C(O)NHC.sub.1-6-alkyl, --C(O)N(C.sub.1-6-alkyl).sub.2,
--C(O)NHC.sub.3-6cycloalkyl, --CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl groups are optionally
substituted with 1-4 substituents of F, CN, methyl, oxo, or OH, and
further wherein each of the heterocyclyl groups of the
--CH.dbd.CHC(O)-heterocyclyl,
--CH.dbd.C(CH.sub.3)C(O)-heterocyclyl, and --C(O)heterocyclyl
groups is optionally substituted with 1-4 substituents
independently selected from F, methyl, OH, or OCH.sub.3, and
further wherein each of the heteroaryl groups of the
--CH.sub.2-heteroaryl and heteroaryl groups is optionally
substituted with 1-3 substituents independently selected from halo,
methyl, or OH;
[0043] R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHCH.sub.2OH, C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl or --C(O)C.sub.1-6-alkenyl, wherein each of
the C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl, are optionally substituted
with 1-4 substituents of F, CN, oxo or OH;
[0044] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0045] 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, C(O)C.sub.1-4-alkyl, C(O)OC.sub.1-4-alkyl, or
CH.sub.2OH;
[0046] R.sup.7 is --NH--R.sup.9 or --NH--C(.dbd.O)--R.sup.9;
[0047] R.sup.9 is a fully or partially unsaturated 3-, 4-, 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 ring is optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0048] each R.sup.10, independently, is H, halo, haloalkyl, CN, OH,
NO.sub.2, NH.sub.2, SF.sub.5, acetyl, --C(O)NHC.sub.1-6-alkyl,
--OCH.sub.2C(O)NHC.sub.1-6-alkyl,
--OCH.sub.2C(O)N(C.sub.1-6-alkyl).sub.2,
--OCH.sub.2CH.sub.2-pyrollidinonyl, oxo, cyclopropylmethoxy,
2-propynyloxy, 2-butynyloxy, 3-butynyloxy, 3-pentynyloxy,
2-pentyloxy, 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, --OC.sub.2-C.sub.6alkenyl, C.sub.1-6thioalkoxyl,
--OCH.sub.2C.sub.3-6cycloaklyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl, dioxolyl,
--O-heterocyclyl, or --OCH.sub.2-heteroaryl, wherein the
heterocyclyl of the --O-heterocyclyl group is a 3-, 4-, 5-, 6- or
7-membered monocyclic saturated ring that includes 1 heteroatom
selected from N, O, or S if the heterocyclyl ring is a 3-membered
ring, that includes 1 or 2 heteroatoms independently selected from
N, O, or S if the heterocyclyl ring is a 4- or 5-membered ring, and
includes 1, 2, or 3 heteroatoms independently selected from N, O,
or S if the heterocyclyl ring is a 6- or 7-membered ring wherein
the heteroaryl group of the --OCH.sub.2-heteroaryl group is a 5- or
6-membered ring that includes 1, 2, 3, or 4 heteroatoms selected
from N, O, or S, and further wherein each of the
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 2-pentyloxy,
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,
--OCH.sub.2C.sub.3-6cycloaklyl, morpholinyl, pyrazolyl, isoxazolyl,
dihydropyranyl, pyrrolidinyl, oxetan-3-yl, dioxolyl, or
--OCH.sub.2-heteroaryl is optionally substituted independently with
1-5 substituents of F, Cl, Br, CN, NO.sub.2, NH.sub.2, OH, oxo,
CF.sub.3, CHF.sub.2, CH.sub.2F, methyl, methoxy, ethyl, ethoxy,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy,
tert-butoxy, isobutyl, sec-butyl, tert-butyl, cyclopentyl,
cyclohexyl, phenyl, C.sub.1-3alkylamino-, C.sub.1-3dialkylamino,
C.sub.1-3thioalkoxyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, thienyl, furyl, pyrrolyl,
tetrahydropyranyl, tetrahydropyrrolyl, oxetan-2-yl, or oxetan-3yl;
and
[0049] the subscript o is selected from 0, 1, or 2.
[0050] In some embodiments of the alternative embodiment 1, the
invention provides compounds according to alternative embodiment 1,
or a stereoisomer or pharmaceutically acceptable salt thereof
wherein R.sup.1 is a --CH.sub.2-heteroaryl or a heteroaryl and the
heteroaryl groups of the --CH.sub.2-heteroaryl and heteroaryl is
selected from triazolyl, oxazolyl, or isoxazolyl optionally
substituted with 1 or 2 methyl groups. In some such embodiments,
R.sup.10 is a --OCH.sub.2-heteroaryl and the heteroaryl group of
the --OCH.sub.2-heteroaryl is selected from an oxadiazolyl,
thiadiazolyl, oxazolyl, thiazolyl, pyridinyl, or pyrimidinyl
optionally substituted independently with 1 or 2 F, Cl, Br, or
methyl groups.
[0051] In some embodiments of the alternative embodiment 1, the
invention provides compounds according to alternative embodiment 1,
or a stereoisomer or pharmaceutically acceptable salt thereof
wherein, R.sup.10 is a --OCH.sub.2-heteroaryl and the heteroaryl
group of the --OCH.sub.2-heteroaryl is selected from an
oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl,
pyridinyl, or pyrimidinyl optionally substituted independently with
1 or 2 F, Cl, Br, or methyl groups.
[0052] In embodiment 2, the invention provides compounds according
to embodiment 1, or a stereoisomer or pharmaceutically acceptable
salt thereof, wherein each of R.sup.1 and R.sup.2, independently,
is H, F, CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F, CHF.sub.2,
CF.sub.3, --C(O)NH.sub.2, --CH.dbd.CHC(O)NHC.sub.1-6alkyl,
--CH.dbd.CHC(O).sub.2H, --CH.dbd.CHCH.sub.2OH or
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl.
[0053] In embodiment 3, the invention provides compounds according
to any one of embodiments 1 and 2, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each of R.sup.a
and R.sup.b, independently, is H, F, CH.sub.3, CH.sub.2F, CHF.sub.2
or CF.sub.3.
[0054] In embodiment 4, the invention provides compounds according
to any one of embodiments 1, 2 and 3, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each of R.sup.1
and R.sup.2, independently, is H, F, CH.sub.2OCH.sub.3, or
CF.sub.3.
[0055] In embodiment 5, the invention provides compounds according
to any one of embodiments 1-4, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each of R.sup.a
and R.sup.b, independently, is H or F.
[0056] In embodiment 6, the invention provides compounds according
to any one of embodiments 1-5, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each of H, F,
CH.sub.2OCH.sub.3, or CF.sub.3; and each of R.sup.a and R.sup.b,
independently, is H or F.
[0057] In embodiment 6a, the invention provides compounds according
to any one of embodiments 1-5, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each of H or
CH.sub.2OCH.sub.3; and each of R.sup.a and R.sup.b, independently,
is H.
[0058] In embodiment 7, the invention provides compounds according
to any one of embodiments 1-6, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each of R.sup.1,
R.sup.2, R.sup.a and R.sup.b, independently, is H.
[0059] In embodiment 8, the invention provides compounds according
to any one of embodiments 1-7, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.3, CF.sub.3, CH.sub.2F or CHF.sub.2.
[0060] In embodiment 9, the invention provides compounds according
to any one of embodiments 1-8, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9;
##STR00007## [0061] wherein V is NR.sup.10, O or S; and [0062] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N.
[0063] In embodiment 10, the invention provides compounds according
to any one of embodiments 1 and 9, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
[0064] A.sup.4 is CR.sup.4 or N;
[0065] A.sup.5 is CR.sup.5 or N;
[0066] A.sup.6 is CR.sup.6 or N;
[0067] 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;
[0068] each of R.sup.a and R.sup.b, independently, is H, F, Cl,
CF.sub.3, OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3,
NHCH.sub.3, C(O)CH.sub.3 or CH.sub.2OCHF.sub.2;
[0069] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
CF.sub.3, OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3,
NHCH.sub.3, C(O)CH.sub.3, CH.sub.2OCH.sub.3 or
CH.sub.2OCHF.sub.2;
[0070] R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl; and
[0071] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.2H, CH.sub.2F, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3.
[0072] In embodiment 11, the invention provides compounds according
to any one of embodiments 1-9, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
[0073] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.2OCH.sub.3 or CF.sub.3;
[0074] each of R.sup.a and R.sup.b, independently, is H or F;
[0075] R.sup.3 is CH.sub.3, CF.sub.3, CH.sub.2F or CHF.sub.2;
and
[0076] R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00008## [0077] wherein V is NR.sup.10, O or S; and [0078] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N.
[0079] In embodiment 12, the invention provides compounds according
to any one of embodiments 1-11, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9.
[0080] In embodiment 13, the invention provides compounds according
to any one of embodiments 1-11, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
##STR00009## [0081] wherein V is NR.sup.10, O or S; and [0082] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N.
[0083] In embodiment 14, the invention provides compounds according
to any one of embodiments 1-13, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
[0084] A.sup.4 is CR.sup.4;
[0085] A.sup.5 is CR.sup.5 or N;
[0086] A.sup.6 is CR.sup.6; and
[0087] A.sup.8 is CR.sup.8 or N, provided only one of A.sup.5 and
A.sup.8 is N, and wherein each of R.sup.4, R.sup.5, R.sup.6 and
R.sup.8, independently, is H, F, Cl, CF.sub.3, CF.sub.2H, CH.sub.2F
or CH.sub.3.
[0088] In embodiment 15, the invention provides compounds,
including stereoisomers, tautomers, hydrates, solvates and
pharmaceutically acceptable salts thereof, which are generally
defined by Formula I:
##STR00010##
or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically
acceptable salt thereof, wherein
[0089] A.sup.4 is CH, CF or CCl;
[0090] A.sup.5 is CH, CF, CCl, CCH.sub.3 or N;
[0091] A.sup.6 is CH or CF;
[0092] A.sup.8 is CH, CF or N, provided that no more than one of
A.sup.5 and A.sup.8 is N;
[0093] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0094] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0095] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0096] R.sup.7 is --NH--R.sup.9 or --NH--C(.dbd.O)--R.sup.9;
[0097] or R.sup.7 is
##STR00011## [0098] wherein V is NR.sup.10, O or S; and [0099] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N;
[0100] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, pyrazolo[3,4-c]pyridinyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thienyl, wherein
the ring is optionally substituted with 1-5 substituents of
R.sup.10; and
[0101] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0102] In embodiment 16, the invention provides compounds,
including stereoisomers, tautomers, hydrates, solvates and
pharmaceutically acceptable salts thereof, which are generally
defined by Formula II:
##STR00012##
wherein
[0103] A.sup.4 is CR.sup.4 or N;
[0104] A.sup.5 is CR.sup.5 or N;
[0105] A.sup.6 is CR.sup.6 or N;
[0106] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0107] each of R.sup.a and R.sup.b, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0108] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHCH.sub.2OH, C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl or --C(O)C.sub.1-6-alkenyl, wherein each of
the C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl, are optionally substituted
with 1-4 substituents of F, CN, oxo or OH;
[0109] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0110] 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;
[0111] R.sup.7 is --NH--C(.dbd.O)--R.sup.9;
[0112] or R.sup.7 is
##STR00013## [0113] wherein V is NR.sup.10, O or S; and [0114] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N;
[0115] R.sup.9 is a fully or partially unsaturated 3-, 4-, 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 ring is optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0116] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl; and
[0117] the subscript o is selected from 0, 1, or 2.
[0118] In embodiment 17, the invention provides compounds according
any one of embodiments 1 and 16, or a stereoisomer, tautomer or
pharmaceutically acceptable salt thereof, wherein
[0119] A.sup.4 is CR.sup.4 or N;
[0120] A.sup.5 is CR.sup.5 or N;
[0121] A.sup.6 is CR.sup.6 or N;
[0122] A.sup.8 is CR.sup.8 or N, provided no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0123] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0124] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0125] R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl; and
[0126] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.2H, CH.sub.2F, CF.sub.3,
OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3.
[0127] In embodiment 18, the invention provides compounds according
to any one of embodiments 1-6, 7 and 16-17, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
[0128] A.sup.4 is CR.sup.4;
[0129] A.sup.5 is CR.sup.5;
[0130] A.sup.6 is CR.sup.6; and
[0131] 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,
CF.sub.2H, CH.sub.2F or CH.sub.3;
[0132] R.sup.3 is CH.sub.3, CF.sub.3, CH.sub.2F or CHF.sub.2;
and
[0133] R.sup.7 is --NH--C(.dbd.O)--R.sup.9 or
##STR00014## [0134] wherein V is NR.sup.10, O or S; and [0135] each
W, independently, is CH, CF, CCl or N.
[0136] In embodiment 19, the invention provides compounds according
to any one of embodiments 16-17, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9.
[0137] In embodiment 20, the invention provides compounds according
to any one of embodiments 16-18, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.7 is
##STR00015## [0138] wherein V is NR.sup.10, O or S; and [0139] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N.
[0140] In embodiment 21, the invention provides compounds according
to any one of embodiments 16-20, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each of H, F,
CH.sub.2OCH.sub.3 or CF.sub.3; and each of R.sup.a and R.sup.b,
independently, is H or F.
[0141] In embodiment 22, the invention provides compounds according
to any one of embodiments 1-12, or a stereoisomer or
pharmaceutically acceptable salt thereof, having a Formula I-A
##STR00016##
wherein
[0142] A.sup.4 is CR.sup.4 or N;
[0143] A.sup.5 is CR.sup.5 or N;
[0144] A.sup.6 is CR.sup.6 or N;
[0145] 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;
[0146] each of R.sup.a and R.sup.b, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH;
[0147] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHCH.sub.2OH, C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl or --C(O)C.sub.1-6-alkenyl, wherein each of
the C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl, are optionally substituted
with 1-4 substituents of F, CN, oxo or OH;
[0148] R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms;
[0149] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl or CH.sub.3;
[0150] R.sup.9 is a fully or partially unsaturated 3-, 4-, 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 ring is optionally
substituted, independently, with 1-5 substituents of R.sup.10;
[0151] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl; and
[0152] the subscript o is selected from 0, 1, or 2.
[0153] In embodiment 23, the invention provides compounds according
to any one of embodiments 1-3, 8-20 and 22, or a stereoisomer,
tautomer or pharmaceutically acceptable salt thereof, wherein
[0154] A.sup.4 is CR.sup.4;
[0155] A.sup.5 is CR.sup.5;
[0156] A.sup.6 is CR.sup.6;
[0157] 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.2H,
CH.sub.2F, CF.sub.3, OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3,
SCH.sub.3, NHCH.sub.3 or C(O)CH.sub.3;
[0158] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0159] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0160] R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or
CH.sub.2F;
[0161] R.sup.9 is a fully or partially unsaturated 3-, 4-, 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 ring is optionally
substituted, independently, with 1-5 substituents of R.sup.10;
and
[0162] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0163] In embodiment 24, the invention provides compounds according
to any one of embodiments 1-19 and 22-23, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
[0164] A.sup.4 is CR.sup.4 or N;
[0165] A.sup.5 is CR.sup.5 or N;
[0166] A.sup.6 is CR.sup.6 or N;
[0167] A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H, F, Cl or CH.sub.3,
provided no more than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8
is N;
[0168] each of R.sup.1, R.sup.2, R.sup.a and R.sup.b,
independently, is H; and
[0169] R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F.
[0170] In embodiment 25, the invention provides compounds according
to any one of embodiments 1-12, 16-19 and 22-24, or a stereoisomer
or pharmaceutically acceptable salt thereof, having a Formula
II-A
##STR00017##
wherein
[0171] A.sup.4 is CR.sup.4, wherein R.sup.4 is H, F or Cl;
[0172] A.sup.5 is CR.sup.5 or N, wherein R.sup.5 is H, F, Cl or
CH.sub.3;
[0173] A.sup.6 is CH;
[0174] A.sup.8 is CR.sup.8 or N, wherein R.sup.8 is H or F,
provided that no more than one of A.sup.5 and A.sup.8 is N;
[0175] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.2OCH.sub.3 or CF.sub.3;
[0176] each of R.sup.a and R.sup.b, independently, is H or F;
[0177] R.sup.3 is CH.sub.3, CF.sub.3, CH.sub.2F or CHF.sub.2;
[0178] R.sup.9 is a fully unsaturated 5- or 6-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 ring is 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, cyclopropylmethoxy, 2-propynyloxy,
2-butynyloxy, 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, pyrrolyl, pyrrolidinyl,
tetrahydropyrrolyl, piperazinyl, oxetan-3-yl, imidazo-pyridinyl or
dioxolyl, wherein each of the cyclopropylmethoxy, 2-propynyloxy,
2-butynyloxy, 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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0179] In embodiment 26, the invention provides compounds according
to embodiment 25, or a stereoisomer or pharmaceutically acceptable
salt thereof, wherein each of R.sup.a, R.sup.b, R.sup.1 and
R.sup.2, independently, is H.
[0180] In embodiment 27, the invention provides compounds according
ng any one of embodiments 25 and 26, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.3, CH.sub.2F or CHF.sub.2.
[0181] In embodiment 28, the invention provides compounds according
to any one of embodiments 25-27, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F or CHF.sub.2.
[0182] In embodiment 29, the invention provides compounds according
to any one of embodiments 25-28, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F.
[0183] In embodiment 30, the invention provides compounds according
to any one of embodiments 25-28, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CHF.sub.2.
[0184] In embodiment 31, the invention provides compounds according
to any one of embodiments 25-30, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is CF or
CCl;
[0185] A.sup.5 is CH, CF, CH.sub.3 or N;
[0186] A.sup.6 is CH; and
[0187] A.sup.8 is CH.
[0188] In embodiment 32, the invention provides compounds according
to any one of embodiments 25-31, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CF;
[0189] A.sup.5 is CH, CF or N;
[0190] A.sup.6 is CH; and
[0191] A.sup.8 is CH.
[0192] In embodiment 33, the invention provides compounds according
to any one of embodiments 25-31, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CCl;
[0193] A.sup.5 is CH or CF;
[0194] A.sup.6 is CH; and
[0195] A.sup.8 is CH.
[0196] In embodiment 34, the invention provides compounds according
to any one of embodiments 25-33, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
[0197] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, pyrazolo[3,4-c]pyridinyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thienyl, wherein
the ring is optionally substituted with 1-5 substituents of
R.sup.10; and
[0198] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0199] In embodiment 35, the invention provides compounds according
to any one of embodiments 25-33, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.9 is a ring
selected from pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
pyrazolyl, pyrazolo[3,4-c]pyridinyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl or thienyl, wherein the ring is optionally
substituted with 1-5 substituents of R.sup.10.
[0200] In embodiment 36, the invention provides compounds according
to any one of embodiments 25-35 or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.9 is
##STR00018##
and
[0201] each R.sup.10, independently, is H, F, Cl, Br, CF.sub.3,
CHF.sub.2, CH.sub.2F, CN, OH, --C(O)NHCH.sub.3, cyclopropylmethoxy,
2-propynyloxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkoxyl or
C.sub.1-6thioalkoxyl, wherein each of the cyclopropylmethoxy,
2-propynyloxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkoxyl and
C.sub.1-6thioalkoxyl is optionally substituted independently with
1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
CF.sub.3, CHF.sub.2, CH.sub.2F, methyl, methoxy, ethyl, ethoxy,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy,
tert-butoxy, isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxazolyl or
thiazolyl.
[0202] In embodiment 37, the invention provides compounds according
to any one of embodiments 25-36, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CHF.sub.2; and R.sup.9 is
##STR00019##
and
[0203] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0204] In embodiment 38, the invention provides compounds according
to any one of embodiments 25-36, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F; and R.sup.9 is
##STR00020##
and
[0205] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0206] In embodiment 39, the invention provides compounds according
to any one of embodiments 25-36, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CHF.sub.2; and R.sup.9 is
##STR00021##
and
[0207] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0208] In embodiment 40, the invention provides compounds according
to any one of embodiments 25-36, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F; and R.sup.9 is
##STR00022##
and
[0209] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0210] In embodiment 41, the invention provides compounds according
to any one of embodiments 1-11, 13-18 and 20-21, or a stereoisomer,
tautomer, hydrate, solvate or pharmaceutically acceptable salt
thereof, having a Formula II-B:
##STR00023##
wherein
[0211] A.sup.4 is CR.sup.4, wherein R.sup.4 is H, F or Cl;
[0212] A.sup.5 is CR.sup.5 or N, wherein R.sup.5 is H, F, Cl or
CH.sub.3;
[0213] A.sup.6 is CH;
[0214] A.sup.8 is CR.sup.8 or N, wherein R.sup.8 is H or F,
provided that no more than one of A.sup.5 and A.sup.8 is N;
[0215] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.2OCH.sub.3 or CF.sub.3;
[0216] each of R.sup.a and R.sup.b, independently, is H or F;
[0217] R.sup.3 is CH.sub.3, CF.sub.3, CH.sub.2F or CHF.sub.2;
[0218] R.sup.9 is a fully unsaturated 5- or 6-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 ring is optionally substituted, independently, with 1-5
substituents of R.sup.10; and
[0219] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
C.sub.1-6-alkyl, 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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl; and
[0220] each W, independently, is CH, CF, CCl, CCH.sub.3 or N.
[0221] In embodiment 42, the invention provides compounds according
according to embodiment 40, or a stereoisomer or pharmaceutically
acceptable salt thereof, wherein each of R.sup.a, R.sup.b, R.sup.1
and R.sup.2, independently, is H.
[0222] In embodiment 43, the invention provides compounds according
to any one of embodiments 41 and 42, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.3, CH.sub.2F or CHF.sub.2.
[0223] In embodiment 44, the invention provides compounds according
to any one of embodiments 41-43, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F or CHF.sub.2.
[0224] In embodiment 45, the invention provides compounds according
to any one of embodiments 41-44, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F.
[0225] In embodiment 46, the invention provides compounds according
to any one of embodiments 41-44, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CHF.sub.2.
[0226] In embodiment 47, the invention provides compounds according
to any one of embodiments 41-46, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is CF or
CCl;
[0227] A.sup.5 is CH, CF, CH.sub.3 or N;
[0228] A.sup.6 is CH; and
[0229] A.sup.8 is CH.
[0230] In embodiment 48, the invention provides compounds according
to any one of embodiments 41-47, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CF;
[0231] A.sup.5 is CH, CF or N;
[0232] A.sup.6 is CH; and
[0233] A.sup.8 is CH.
[0234] In embodiment 49, the invention provides compounds according
to any one of embodiments 41-47, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.4 is
CCl;
[0235] A.sup.5 is CH or CF;
[0236] A.sup.6 is CH; and
[0237] A.sup.8 is CH.
[0238] In embodiment 50, the invention provides compounds according
to any one of embodiments 41-49 or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein
##STR00024##
and
[0239] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0240] In embodiment 51, the invention provides compounds,
including stereoisomers, tautomers, hydrates, solvates and
pharmaceutically acceptable salts thereof, which are generally
defined by Formula III:
##STR00025##
wherein
[0241] A.sup.4 is CR.sup.4;
[0242] A.sup.5 is CR.sup.5 or N;
[0243] A.sup.6 is CR.sup.6;
[0244] A.sup.8 is CR.sup.8 or N, provided that no more than two of
A.sup.5 and A.sup.8 is N;
[0245] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0246] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0247] R.sup.3 is CH.sub.3, CF.sub.3, CH.sub.2F or CHF.sub.2;
[0248] R.sup.4 is F or Cl;
[0249] R.sup.5 is H, F, Cl or CH.sub.3;
[0250] each of R.sup.6 and R.sup.8, independently, is H or F;
[0251] R.sup.7 is --NH--C(.dbd.O)--R.sup.9, or
[0252] R.sup.7 is
##STR00026## [0253] wherein V is NR.sup.10, O or S; and [0254] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N;
[0255] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, pyrazolo[3,4-c]pyridinyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thienyl, wherein
the ring is optionally substituted with 1-5 substituents of
R.sup.10; and
[0256] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0257] In embodiment 52, the invention provides compounds including
stereoisomers, tautomers, hydrates, solvates and pharmaceutically
acceptable salts thereof, according to embodiment 51, which are
generally defined by Formula III-A:
##STR00027##
wherein
[0258] A.sup.4 is CR.sup.4, wherein R.sup.4 is H, F or Cl;
[0259] A.sup.5 is CR.sup.5 or N, wherein R.sup.5 is H, F, Cl or
CH.sub.3;
[0260] A.sup.6 is CH;
[0261] A.sup.8 is CR.sup.8 or N, wherein R.sup.8 is H or F,
provided that no more than one of A.sup.5 and A.sup.8 is N;
[0262] each of R.sup.a and R.sup.b, independently, is H or F;
[0263] each of R.sup.1 and R.sup.2, independently, is H,
CH.sub.2OCH.sub.3 or F;
[0264] R.sup.3 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0265] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyrazolyl, pyrazolo[3,4-c]pyridinyl, oxazolyl,
isoxazolyl, thiazolyl, isothiazolyl or thienyl, wherein the ring is
optionally substituted with 1-5 substituents of R.sup.10; and
[0266] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
C.sub.1-6-alkyl, 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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0267] In embodiment 53, the invention provides compounds according
to any one of embodiments 51-52 or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.9 is
##STR00028##
and
[0268] each R.sup.10, independently, is H, F, Cl, Br, CF.sub.3,
CHF.sub.2, CH.sub.2F, CN, OH, --C(O)NHCH.sub.3, cyclopropylmethoxy,
2-propynyloxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkoxyl or
C.sub.1-6thioalkoxyl, wherein each of the cyclopropylmethoxy,
2-propynyloxy, 2-butynyloxy, C.sub.1-6alkyl, C.sub.2-6alkenyl,
C.sub.2-6alkynyl, C.sub.3-6cycloalkyl, C.sub.1-6alkoxyl and
C.sub.1-6thioalkoxyl is optionally substituted independently with
1-5 substituents of F, Cl, CN, NO.sub.2, NH.sub.2, OH, oxo,
CF.sub.3, CHF.sub.2, CH.sub.2F, methyl, methoxy, ethyl, ethoxy,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl,
isopropoxy, cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy,
tert-butoxy, isobutyl, sec-butyl, tert-butyl, C.sub.1-3alkylamino-,
C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl, oxazolyl or
thiazolyl.
[0269] In embodiment 54, the invention provides compounds according
to any one of embodiments 51-53, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CHF.sub.2; and R.sup.9 is
##STR00029##
and
[0270] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0271] In embodiment 55, the invention provides compounds according
to any one of embodiments 51-53, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F; and R.sup.9 is
##STR00030##
and
[0272] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0273] In embodiment 56, the invention provides compounds according
to any one of embodiments 51-53 or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CHF.sub.2; and R.sup.9 is
##STR00031##
and
[0274] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0275] In embodiment 57, the invention provides compounds according
to any one of embodiments 51-53, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F; and R.sup.9 is
##STR00032##
and
[0276] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0277] In embodiment 58, the invention provides compounds,
including stereoisomers, tautomers, hydrates, solvates and
pharmaceutically acceptable salts thereof, which are generally
defined by Formula III-B:
##STR00033##
wherein
[0278] A.sup.4 is CR.sup.4, wherein R.sup.4 is H, F or Cl;
[0279] A.sup.5 is CR.sup.5 or N, wherein R.sup.5 is H, F, Cl or
CH.sub.3;
[0280] A.sup.6 is CH;
[0281] A.sup.8 is CR.sup.8 or N, wherein R.sup.8 is H or F,
provided that no more than one of A.sup.5 and A.sup.8 is N;
[0282] each of R.sup.a and R.sup.b, independently, is H or F;
[0283] each of R.sup.1 and R.sup.2, independently, is H,
CH.sub.2OCH.sub.3 or F;
[0284] R.sup.3 is CH.sub.3, CH.sub.2F or CHF.sub.2;
##STR00034##
and
[0285] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0286] In embodiment 59, the invention provides compounds of
formula III-A-1, or a pharmaceutically acceptable salt or tautomer
thereof,
##STR00035##
[0287] wherein, A.sup.4 is CF;
[0288] A.sup.5 is CH, CF, CCl, CCH.sub.3 or N;
[0289] A.sup.6 is CH;
[0290] A.sup.8 is CH or N, provided that no more than one of
A.sup.5 and A.sup.8 is N;
[0291] each of R.sup.a and R.sup.b, independently, is H;
[0292] each of R.sup.1 and R.sup.2, independently, is H,
CH.sub.2OCH.sub.3 or F;
[0293] R.sup.3 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0294] W is CR.sup.10 or N; 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0296] In embodiment 60, the invention provides compounds of
formula III-A-2, or a pharmaceutically acceptable salt or tautomer
thereof,
##STR00036##
[0297] wherein
[0298] A.sup.4 is CF or CCl;
[0299] A.sup.5 is CH, CF, CCl, CCH.sub.3 or N;
[0300] A.sup.8 is CH or N, provided no more than one of A.sup.5 and
A.sup.8 is N;
[0301] R.sup.1 is H, CH.sub.2OCH.sub.3 or F;
[0302] R.sup.3 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0303] W is CH or N; and
[0304] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0305] In embodiment 61, the invention provides compounds according
to any one of embodiments 59-60, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CHF.sub.2.
[0306] In embodiment 62, the invention provides compounds according
to any one of embodiments 59-60, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein R.sup.3 is
CH.sub.2F.
[0307] In embodiment 63, the invention provides compounds according
to any one of embodiments 59-62, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein W is CH.
[0308] In embodiment 64, the invention provides compounds according
to any one of embodiments 59-62, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein W is N.
[0309] In embodiment 65, the invention provides compounds according
to any one of embodiments 59-64, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each R.sup.10,
independently, is H, F, Cl, Br, CH.sub.3, CHF.sub.2, CH.sub.2F, CN,
2-propynyloxy, 2-butynyloxy or C.sub.1-2alkoxyl, wherein the
C.sub.1-2alkoxyl is optionally substituted independently with 1-5
substituents of F, oxazolyl or thiazolyl.
[0310] In embodiment 66, the invention provides compounds according
to any one of embodiments 59-65, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each R.sup.10,
independently, is H, F, Cl, Br, CH.sub.3, CHF.sub.2, CH.sub.2F, CN,
2-propynyloxy, 2-butynyloxy, --OCHF.sub.2 or --OCH.sub.3.
[0311] In embodiment 67, the invention provides compounds according
to any one of embodiments 59-66, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.8 is
CH.
[0312] In embodiment 68, the invention provides compounds according
to any one of embodiments 59-67, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is CH,
CF, CCl or CCH.sub.3.
[0313] In embodiment 68, the invention provides compounds according
to any one of embodiments 59-67, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is CH, CF
or CCH.sub.3.
[0314] In embodiment 68, the invention provides compounds according
to any one of embodiments 59-67, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is CH or
N.
[0315] In embodiment 69, the invention provides compounds of
formula III-A-3, or a pharmaceutically acceptable salt or tautomer
thereof,
##STR00037##
[0316] wherein
[0317] A.sup.5 is CH, CF, CCl, CCH.sub.3 or N;
[0318] R.sup.3 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0319] W is CH or N; and
[0320] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0321] In embodiment 70, the invention provides compounds according
to any one of embodiment 69, or a stereoisomer or pharmaceutically
acceptable salt thereof, wherein R.sup.3 is CHF.sub.2.
[0322] In embodiment 71, the invention provides compounds according
to any one of embodiment 69, or a stereoisomer or pharmaceutically
acceptable salt thereof, wherein R.sup.3 is CH.sub.2F.
[0323] In embodiment 72, the invention provides compounds according
to any one of embodiments 69-71, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein W is CH.
[0324] In embodiment 73, the invention provides compounds according
to any one of embodiments 69-71, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein W is N.
[0325] In embodiment 74, the invention provides compounds according
to any one of embodiments 69-74, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each R.sup.10,
independently, is H, F, Cl, Br, CH.sub.3, CHF.sub.2, CH.sub.2F, CN,
2-propynyloxy, 2-butynyloxy or C.sub.1-2alkoxyl, wherein the
C.sub.1-2alkoxyl is optionally substituted independently with 1-5
substituents of F, oxazolyl or thiazolyl.
[0326] In embodiment 75, the invention provides compounds according
to any one of embodiments 69-75, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein each R.sup.10,
independently, is H, F, Cl, Br, CH.sub.3, CHF.sub.2, CH.sub.2F, CN,
2-propynyloxy, 2-butynyloxy, --OCHF.sub.2 or --OCH.sub.3.
[0327] In embodiment 77, the invention provides compounds according
to any one of embodiments 69-76, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is CH,
CF, CCH.sub.3 or N.
[0328] In embodiment 78, the invention provides compounds according
to any one of embodiments 69-77, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is CH, CF
or N.
[0329] In embodiment 79, the invention provides compounds according
to any one of embodiments 69-78, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is CH or
N.
[0330] In embodiment 80, the invention provides compounds according
to any one of embodiments 69-79, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is
CH.
[0331] In embodiment 81, the invention provides compounds according
to any one of embodiments 69-79, or a stereoisomer or
pharmaceutically acceptable salt thereof, wherein A.sup.5 is N.
[0332] In embodiment 82, the invention provides compounds of
formula III-B-1, or a pharmaceutically acceptable salt or tautomer
thereof,
##STR00038##
[0333] wherein
[0334] A.sup.4 is CF;
[0335] A.sup.5 is CH, CF, CCl, CCH.sub.3 or N;
[0336] A.sup.6 is CH;
[0337] A.sup.8 is CH or N, provided that no more than one of
A.sup.5 and A.sup.8 is N;
[0338] R.sup.1 is H, CH.sub.2OCH.sub.3 or F;
[0339] R.sup.3 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0340] each W, independently, is CR.sup.10 or N, provided no more
than 2 W's are N; and
[0341] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0342] In embodiment 83, the invention provides compounds of
formula III-B-2, or a pharmaceutically acceptable salt or tautomer
thereof,
##STR00039##
[0343] wherein
[0344] A.sup.5 is CH, CF, CCl, CCH.sub.3 or N;
[0345] A.sup.8 is CH or N, provided no more than one of A.sup.5 and
A.sup.8 is N;
[0346] R.sup.3 is CH.sub.3, CH.sub.2F or CHF.sub.2;
[0347] each W, independently, is CR.sup.10 or N, provided no more
than 1 W is N; and
[0348] each R.sup.10, independently, is H, F, Cl, Br, CH.sub.3,
CHF.sub.2, CH.sub.2F, CN, 2-propynyloxy, 2-butynyloxy or
C.sub.1-2alkoxyl, wherein the C.sub.1-2alkoxyl is optionally
substituted independently with 1-5 substituents of F, Cl, methyl,
methoxy, ethyl, ethoxy, oxazolyl or thiazolyl.
[0349] Similarly, the invention provides compounds of sub-formulas
III-C, III-D, III-E and III-F, respectively, as described
below,
##STR00040##
in conjunction with any of the above or below embodiments,
including those described in embodiments A, A-1 to A-4, B, B-1 to
B-10, C, C-1 to C-10, D, D-1 to D-6, E, E-1 to E-5, F, F-1 to F-4,
G, G-1 to G-4, H, H-1 to H-4, I, I-1 to I-9, J, J-1 to J-8, K, K-1
to K-2, L, M, N-1 to N-2, O-1 to O-2, P-1 to P-2, Q and Q-1 to Q-2
described herein.
[0350] The present invention contemplates that the various
different embodiments of Formulas I, II and III, and sub-Formulas
I-A, I-B, I-C and III-A throught III-F 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, V and W, 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, V and W 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-4, B, B-1 to B10, C, C-1 to C-10, D, D-1 to D-6, E, E-1 to
E-5, F, F-1 to F-4, G, G-1 to G-4, H, H-1 to H-4, I, I-1 to I-9, J,
J-1 to J-8, K, K-1 to K-2, L, M, N-1 to N-2, O-1 to O-2, P-1 to
P-2, Q and Q-1 to Q-2 described herein, as it applies to general
Formulas I, II and III, and sub-formulas I-A, I-B and I-C and III-A
through III-F, also described herein.
[0351] In another embodiment A, the invention includes compounds
wherein each of R.sup.a and R.sup.b, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl or
--C(O)C.sub.1-6-alkyl, wherein each of the C.sub.1-6-alkyl,
C.sub.2-4alkenyl, C.sub.2-4alkynyl, and C.sub.1-6-alkyl portion of
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl and
--C(O)C.sub.1-6-alkyl are optionally substituted with 1-4
substituents of F, oxo or OH, in conjunction with any of the above
or below embodiments.
[0352] In another embodiment A-1, the invention includes compounds
wherein each of R.sup.a and R.sup.b, independently, is H, F, Cl,
CF.sub.3, OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3,
NHCH.sub.3, C(O)CH.sub.3 or CH.sub.2OCHF.sub.2, in conjunction with
any of the above or below embodiments.
[0353] In another embodiment A-2, the invention includes compounds
wherein each of R.sup.a and R.sup.b, independently, is H, F,
CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F, in conjunction with any
of the above or below embodiments.
[0354] In another embodiment A-3, the invention includes compounds
wherein R.sup.1 is H or F, in conjunction with any of the above or
below embodiments.
[0355] In another embodiment A-4, the invention includes compounds
wherein R.sup.1 is H, in conjunction with any of the above or below
embodiments.
[0356] In another embodiment B, the invention includes compounds
wherein R.sup.1 is each
[0357] of R.sup.1 and R.sup.2, independently, is H, F, Cl,
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, CN,
--CH.sub.2OC.sub.1-6-alkyl, --OC.sub.1-6-alkyl,
--S(O).sub.oC.sub.1-6-alkyl, --NHC.sub.1-6-alkyl, --C(O)NH.sub.2,
--CH.dbd.CHC(O) NHC.sub.1-6-alkyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHCH.sub.2OH, C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl,
--C(O)C.sub.1-6-alkyl or --C(O)C.sub.1-6-alkenyl, wherein each of
the C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl, C(O)C.sub.1-6-alkyl, --C(O)C.sub.1-6-alkenyl,
--CH.dbd.CHC(O)NHC.sub.1-6-alkyl and
C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl, are optionally substituted
with 1-4 substituents of F, CN, oxo or OH, in conjunction with any
of the above or below embodiments.
[0358] In another embodiment B-1, the invention includes compounds
wherein R.sup.1 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-3-alkyl,
--OC.sub.1-3-alkyl and --C(O)OC.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl and
C.sub.1-3-alkyl portion of --CH.sub.2OC.sub.1-3-alkyl,
--C(O)OC.sub.1-6-alkyl and --OC.sub.1-3-alkyl are optionally
substituted with 1-4 substituents of F and OH, in conjunction with
any of the above or below embodiments.
[0359] In another embodiment B-2, the invention includes compounds
wherein R.sup.1 is H, F, CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F,
CHF.sub.2, CF.sub.3, --C(O)NH.sub.2,
--CH.dbd.CHC(O)NHC.sub.1-6alkyl, --CH.dbd.CHC(O).sub.2H,
--CH.dbd.CHCH.sub.2OH or C.sub.1-6-alkyl-C(O)NHC.sub.1-6-alkyl, in
conjunction with any of the above or below embodiments.
[0360] In another embodiment B-3, the invention includes compounds
wherein R.sup.1 is H, F, CH.sub.3, C.sub.2H.sub.5, CF.sub.2H,
CH.sub.2F, or CH.sub.2OCH.sub.3, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H or CH.sub.2OCF.sub.3, in conjunction with any of
the above or below embodiments.
[0361] In another embodiment B-4, the invention includes compounds
wherein R.sup.1 is H, F, Cl, CF.sub.3, CH.sub.3, CF.sub.2H or
CH.sub.2F, in conjunction with any of the above or below
embodiments.
[0362] In another embodiment B-5, the invention includes compounds
wherein R.sup.1 is H, F, CF.sub.3, CH.sub.3, CF.sub.2H or
CH.sub.2F, in conjunction with any of the above or below
embodiments.
[0363] In another embodiment B-6, the invention includes compounds
wherein R.sup.1 is H, F, CH.sub.2OCH.sub.3 or CH.sub.2OH, in
conjunction with any of the above or below embodiments.
[0364] In another embodiment B-7, the invention includes compounds
wherein R.sup.1 is H or F, in conjunction with any of the above or
below embodiments.
[0365] In another embodiment B-8, the invention includes compounds
wherein R.sup.1 is H, in conjunction with any of the above or below
embodiments.
[0366] In another embodiment B-9, the invention includes compounds
wherein R.sup.1 is F, in conjunction with any of the above or below
embodiments.
[0367] In another embodiment B-10, the invention includes compounds
wherein R.sup.1 is H, CH.sub.2OCH.sub.3 or CH.sub.2OH, in
conjunction with any of the above or below embodiments.
[0368] In another embodiment C, the invention includes compounds
wherein R.sup.2 is H, F, Cl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl, CN, --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl or --C(O)C.sub.1-6-alkyl, wherein each of the
C.sub.1-6-alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, and
C.sub.1-6-alkyl portion of --CH.sub.2OC.sub.1-6-alkyl,
--OC.sub.1-6-alkyl, --S(O).sub.oC.sub.1-6-alkyl,
--NHC.sub.1-6-alkyl and --C(O)C.sub.1-6-alkyl are optionally
substituted with 1-4 substituents of F, oxo or OH, in conjunction
with any of the above or below embodiments.
[0369] In another embodiment C-1, the invention includes compounds
wherein R.sup.2 is H, F, Cl, C.sub.2-4alkenyl, C.sub.2-4alkynyl,
CN, --CH.sub.2OC.sub.1-3-alkyl, --OC.sub.1-3-alkyl, wherein each of
the C.sub.2-4alkenyl, C.sub.2-4alkynyl and C.sub.1-3-alkyl portion
of --CH.sub.2OC.sub.1-3-alkyl and --OC.sub.1-3-alkyl are optionally
substituted with 1-4 substituents of F, in conjunction with any of
the above or below embodiments.
[0370] In another embodiment C-2, the invention includes compounds
wherein R.sup.2 is H, F, Cl, CF.sub.3, OCF.sub.3, methyl, ethyl,
CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3, C(O)CH.sub.3 or
CH.sub.2OCHF.sub.2, in conjunction with any of the above or below
embodiments.
[0371] In another embodiment C-3, the invention includes compounds
wherein R.sup.2 is H, F, CH.sub.3, C.sub.2H.sub.5, CF.sub.2H,
CH.sub.2F, CH.sub.2OCH.sub.2F, CH.sub.2OCF.sub.2H or
CH.sub.2OCF.sub.3, in conjunction with any of the above or below
embodiments.
[0372] In another embodiment C-4, the invention includes compounds
wherein R.sup.2 is H, F, Cl, CF.sub.3, CH.sub.3, CF.sub.2H or
CH.sub.2F, in conjunction with any of the above or below
embodiments.
[0373] In another embodiment C-5, the invention includes compounds
wherein R.sup.2 is H, F, CF.sub.3, CH.sub.3, CF.sub.2H or
CH.sub.2F, in conjunction with any of the above or below
embodiments.
[0374] In another embodiment C-6, the invention includes compounds
wherein R.sup.2 is H, F or CF.sub.3, in conjunction with any of the
above or below embodiments.
[0375] In another embodiment C-7, the invention includes compounds
wherein R.sup.2 is H or F, in conjunction with any of the above or
below embodiments.
[0376] In another embodiment C-8, the invention includes compounds
wherein R.sup.2 is H, in conjunction with any of the above or below
embodiments.
[0377] In another embodiment C-9, the invention includes compounds
wherein R.sup.2 is F, in conjunction with any of the above or below
embodiments.
[0378] In another embodiment C-10, the invention includes compounds
wherein R.sup.2 is CF.sub.3, in conjunction with any of the above
or below embodiments.
[0379] In another embodiment D, the invention includes compounds
wherein R.sup.3 is C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl,
CH.sub.2OH, C.sub.1-4haloalkyl or cyclopropyl, wherein each of the
C.sub.1-4alkyl, CH.sub.2OC.sub.1-4alkyl, C.sub.1-4haloalkyl and
cyclopropyl is optionally substituted with 1-4 F atoms, in
conjunction with any of the above or below embodiments.
[0380] In another embodiment D-1, the invention includes compounds
wherein R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl, wherein each of the
C.sub.1-4alkyl, C.sub.1-4haloalkyl and cyclopropyl is optionally
substituted with 1-4 F atoms, in conjunction with any of the above
or below embodiments.
[0381] In another embodiment D-2, the invention includes compounds
wherein R.sup.3 is C.sub.1-4alkyl, CH.sub.2OH, CH.sub.2OCH.sub.2F,
CH.sub.2OCF.sub.2H, or cyclopropyl, wherein each of the
C.sub.1-4alkyl and cyclopropyl is optionally substituted with 1-2 F
atoms, in conjunction with any of the above or below
embodiments.
[0382] In another embodiment D-3, the invention includes compounds
wherein R.sup.3 is CH.sub.3, CF.sub.3, CF.sub.2H or CH.sub.2F, in
conjunction with any of the above or below embodiments.
[0383] In another embodiment D-4, the invention includes compounds
wherein R.sup.3 is CH.sub.3, CF.sub.2H or CH.sub.2F, in conjunction
with any of the above or below embodiments.
[0384] In another embodiment D-5, the invention includes compounds
wherein R.sup.3 is CH.sub.3 or CH.sub.2F, in conjunction with any
of the above or below embodiments.
[0385] In another embodiment D-6, the invention includes compounds
wherein R.sup.3 is CH.sub.2F, in conjunction with any of the above
or below embodiments.
[0386] In another embodiment E, 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.
[0387] In another embodiment E-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, methyl, ethyl, 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.
[0388] In another embodiment E-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.
[0389] In another embodiment E-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.
[0390] In another embodiment E-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.
[0391] In another embodiment E-5, the invention includes compounds
wherein A.sup.4 is N, in conjunction with any of the above or below
embodiments.
[0392] In another embodiment F, the invention includes compounds
wherein A.sup.5 is CR.sup.5 and 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.
[0393] In another embodiment F-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, methyl, ethyl, 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.
[0394] In another embodiment F-2, the invention includes compounds
wherein A.sup.5 is CR.sup.5 and R.sup.5 is H, F, Cl, CF.sub.3,
CF.sub.2H, CH.sub.2F, CH.sub.3 or N in conjunction with any of the
above or below embodiments.
[0395] In another embodiment F-3, the invention includes compounds
wherein A.sup.5 is CR.sup.5 and R.sup.5 is H, F, Cl or CH.sub.3, in
conjunction with any of the above or below embodiments.
[0396] In another embodiment F-4, the invention includes compounds
wherein A.sup.5 is N, in conjunction with any of the above or below
embodiments.
[0397] In another embodiment G, 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.
[0398] In another embodiment G-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, methyl, ethyl, 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.
[0399] In another embodiment G-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.
[0400] In another embodiment G-3, the invention includes compounds
wherein A.sup.6 is CR.sup.6 wherein R.sup.6 is H or F, in
conjunction with any of the above or below embodiments.
[0401] In another embodiment G-4, the invention includes compounds
wherein A.sup.6 is N, in conjunction with any of the above or below
embodiments.
[0402] In another embodiment H, 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.
[0403] In another embodiment H-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, methyl, ethyl, 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.
[0404] In another embodiment H-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.
[0405] In another embodiment H-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.
[0406] In another embodiment H-4, the invention includes compounds
wherein A.sup.8 is N, in conjunction with any of the above or below
embodiments.
[0407] In another embodiment I, the invention includes compounds
wherein no more than two 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.
[0408] In another embodiment I-1, 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.
[0409] In another embodiment I-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, in conjunction with any of the
above or below embodiments.
[0410] In another embodiment, the invention includes compounds
wherein A.sup.4 is CR.sup.4 or N, 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.
[0411] In another embodiment I-3, the invention includes compounds
wherein A.sup.4 is N, 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.
[0412] In another embodiment I-4, the invention includes compounds
wherein A.sup.4 is CR.sup.4, A.sup.5 is N, 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.
[0413] In another embodiment I-5, the invention includes compounds
wherein A.sup.4 is CR.sup.4, A.sup.5 is CR.sup.5, A.sup.6 is N, and
A.sup.8 is CR.sup.8, in conjunction with any of the above or below
embodiments.
[0414] In another embodiment I-6, the invention includes compounds
wherein A.sup.4 is CR.sup.5, A.sup.5 is CR.sup.5, A.sup.6 is
CR.sup.6, and A.sup.8 is N, in conjunction with any of the above or
below embodiments.
[0415] In another embodiment I-7, the invention includes compounds
of of Formulas I, II or III, wherein
[0416] A.sup.4 is CR.sup.4 or N;
[0417] A.sup.5 is CR.sup.5 or N;
[0418] A.sup.6 is CR.sup.6 or N;
[0419] 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;
[0420] each of R.sup.a and R.sup.b, independently, is H, F, Cl,
CF.sub.3, OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3,
NHCH.sub.3, C(O)CH.sub.3 or CH.sub.2OCHF.sub.2;
[0421] each of R.sup.1 and R.sup.2, independently, is H, F, Cl,
CF.sub.3, OCF.sub.3, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3,
NHCH.sub.3, C(O)CH.sub.3, C(O)OC.sub.1-3alkyl, CH.sub.2OCH.sub.3 or
CH.sub.2OCHF.sub.2;
[0422] R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl; and
[0423] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.2H, CH.sub.2F, CF.sub.3,
OCF.sub.3, methyl, ethyl, 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.
[0424] In another embodiment I-8, the invention includes compounds
of Formulas I, II or III, wherein
[0425] A.sup.4 is CR.sup.4;
[0426] A.sup.5 is CR.sup.5;
[0427] A.sup.6 is CR.sup.6; and
[0428] 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.
[0429] In another embodiment 1-9, the invention includes compounds
of Formulas I, II or III, wherein A.sup.4 is CH, CF or N, A.sup.5
is CH, CF or N, A.sup.6 is CH, CF or N, A.sup.8 is CH, CF or N, 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.
[0430] In another embodiment J, the invention includes compounds of
Formulas I, II or III, wherein R.sup.7 is --NH--R.sup.9 or
--NH--C(.dbd.O)--R.sup.9; or R.sup.7 is
##STR00041## [0431] wherein V is NR.sup.10, O or S; [0432] each W,
independently, is CH, CF, CCl, CCH.sub.3 or N; and [0433] each
R.sup.10 is as defined herein, in conjunction with any of the above
or below embodiments.
[0434] In another embodiment J-1, the invention includes compounds
of Formulas I, II or III, wherein R.sup.7 is --NH--R.sup.9,
--NH--C(.dbd.O)--R.sup.9 or
##STR00042##
[0435] wherein V is NR.sup.10, O or S; and
[0436] each W, independently, is CH, CF, CCl, CCH.sub.3 or N;
and
[0437] each R.sup.10 is as defined herein, in conjunction with any
of the above or below embodiments.
[0438] In another embodiment J-2, the invention includes compounds
of Formulas I, II or III, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9 or
##STR00043##
[0439] wherein V is NR.sup.10, O or S; and
[0440] each W, independently, is CH, CF, CCl or N; and
[0441] each R.sup.10 is as defined herein, in conjunction with any
of the above or below embodiments.
[0442] In another embodiment J-3, the invention includes compounds
of Formulas I, II or III, wherein R.sup.7 is
--NH--C(.dbd.O)--R.sup.9, in conjunction with any of the above or
below embodiments.
[0443] In another embodiment J-4, the invention includes compounds
of Formulas I, II or III, wherein R.sup.7 is --NH--R.sup.9, in
conjunction with any of the above or below embodiments.
[0444] In another embodiment J-5, the invention includes compounds
wherein R.sup.7 is
##STR00044## [0445] wherein V is NR.sup.10, O or S; and [0446] each
W, independently, is CH, CF, CCl, CCH.sub.3 or N, in conjunction
with any of the above or below embodiments.
[0447] In another embodiment J-6, the invention includes compounds
wherein R.sup.7 is
##STR00045##
[0448] wherein V is NR.sup.10, O or S; and
[0449] each W, independently, is CH, CF, CCl, CCH.sub.3 or N, in
conjunction with any of the above or below embodiments.
[0450] In another embodiment J-7, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9, in conjunction with any of the
above or below embodiments.
[0451] In another embodiment J-8, the invention includes compounds
wherein R.sup.7 is --NH--R.sup.9 or --NH--C(.dbd.O)--R.sup.9,
wherein R.sup.9 is a fully or partially unsaturated 3-, 4-, 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 ring is 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 K, 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,
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 K-1, the invention includes compounds
wherein each R.sup.9 is a ring selected from phenyl, pyridyl,
pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl,
pyrazolo[3,4-c]pyridinyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl or thienyl, wherein the ring is optionally substituted
with 1-5 substituents of R.sup.10, in conjunction with any of the
above or below embodiments.
[0454] In another embodiment K-2, the invention includes compounds
of Formulas I, II, and III, and any sub-formula thereof as
described herein, wherein R.sup.9 is a ring selected from the group
consisting of phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
pyrazolyl, isoxazolyl, thiazolyl, thienyl, furanyl and pyrrolyl,
wherein the ring is optionally substituted, independently, with 1-3
substituents of R.sup.10, wherein each R.sup.10, independently, is
F, Cl, CN, NO.sub.2, NH.sub.2, OH, CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.3, --OCH.sub.3, C.sub.2H.sub.5, --OC.sub.2H.sub.5,
--CH.sub.2CF.sub.3, --CH.sub.2CHF.sub.2, propyl, propoxy,
isopropyl, isopropoxy, cyclopropyl, butyl, butoxyl, cyclobutyl,
isobutoxy, tert-butoxy, isobutyl, sec-butyl, tert-butyl,
cyclopropylmethoxy, 2-butynyloxy or oxetan-3yl, in conjunction with
any of the above or below embodiments.
[0455] In another embodiment L, the present invention provides
compounds, and solvates, tautomers, hydrates, stereoisomers and
pharmaceutically acceptable salts thereof, as defined by Formulas
I, I-A, I-B, I-C or II, wherein
[0456] A.sup.4 is CR.sup.4 or N;
[0457] A.sup.5 is CR.sup.5 or N;
[0458] A.sup.6 is CR.sup.6 or N;
[0459] A.sup.8 is CR.sup.8 or N, provided no more than one of
A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0460] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0461] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0462] R.sup.3 is C.sub.1-4alkyl, C.sub.1-4haloalkyl, CH.sub.2OH,
CH.sub.2OCHF.sub.2 or cyclopropyl; and
[0463] each of R.sup.4, R.sup.5, R.sup.6 and R.sup.8,
independently, is H, F, Cl, CF.sub.2H, CH.sub.2F, CF.sub.3,
OCF.sub.3, methyl, ethyl, 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.
[0464] In another embodiment M, the present invention provides
compounds, and solvates, tautomers, hydrates, stereoisomers and
pharmaceutically acceptable salts thereof, as defined by Formulas I
and II, wherein
[0465] R.sup.7 is --NH--R.sup.9, --NH--C(.dbd.O)--R.sup.9 or
##STR00046## [0466] wherein V is NR.sup.10, O or S; and
[0467] each W, independently, is CH, CF, CCl, CCH.sub.3 or N, in
conjunction with any of the above or below embodiments.
[0468] In another embodiment N-1, the invention includes compounds
of Formula I-A wherein A.sup.4 is CR.sup.4;
[0469] A.sup.5 is CR.sup.5 or N;
[0470] A.sup.6 is CR.sup.6;
[0471] 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, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3;
[0472] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0473] R.sup.1 is H, F, CH.sub.3, CH.sub.2OCH.sub.3, CH.sub.2F,
CHF.sub.2 or CF.sub.3;
[0474] R.sup.2 is H, F, CH.sub.3, CH.sub.2F, CHF.sub.2 or
CF.sub.3;
[0475] R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or
CH.sub.2F;
[0476] R.sup.9 is acetyl, C.sub.1-6-alkyl, C.sub.2-4alkenyl,
C.sub.2-4alkynyl or a fully or partially unsaturated 3-, 4-, 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;
and
[0477] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0478] In another embodiment N-2, the invention includes compounds
of Formula I-A wherein A.sup.4 is CR.sup.4;
[0479] A.sup.5 is CR.sup.5;
[0480] A.sup.6 is CR.sup.6;
[0481] 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, OCF.sub.3,
methyl, ethyl, CN or OCH.sub.3;
[0482] each of R.sup.a and R.sup.b, independently, is H or F;
[0483] R.sup.1 is H, F, CH.sub.2OCH.sub.3 or CF.sub.3;
[0484] R.sup.2 is H, F or CF.sub.3;
[0485] R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F;
[0486] R.sup.9 is a ring selected from phenyl, pyridyl, pyrimidyl,
pyrazinyl, pyridazinyl, pyrazolyl, isoxazolyl, thiazolyl, furanyl,
thienyl and pyrrolyl, wherein the ring is optionally substituted,
independently, with 1-3 substituents of R.sup.10; and
[0487] 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,
cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy, 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, pyrrolyl, pyrrolidinyl, tetrahydropyrrolyl,
piperazinyl, oxetan-3-yl, imidazo-pyridinyl or dioxolyl, wherein
each of the cyclopropylmethoxy, 2-propynyloxy, 2-butynyloxy,
C.sub.1-6-alkyl, 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, CF.sub.3, CHF.sub.2,
CH.sub.2F, methyl, methoxy, ethyl, ethoxy, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, propyl, propoxy, isopropyl, isopropoxy,
cyclopropyl, butyl, butoxyl, cyclobutyl, isobutoxy, tert-butoxy,
isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl,
C.sub.1-3alkylamino-, C.sub.1-3dialkylamino, C.sub.1-3thioalkoxyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydropyrrolyl or
oxetan-3yl.
[0488] In another embodiment O-1, the invention includes compounds
of Formula I-B
[0489] wherein A.sup.4 is CR.sup.4;
[0490] A.sup.5 is CR.sup.5;
[0491] A.sup.6 is CR.sup.6;
[0492] 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, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3;
[0493] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0494] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3; and
[0495] R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or CH.sub.2F,
in conjunction with any of the above or below embodiments with
respect to Formula I-B.
[0496] In another embodiment O-2, the invention includes compounds
of Formula I-B wherein A.sup.4 is CR.sup.4 or N;
[0497] A.sup.5 is CR.sup.5 or N;
[0498] A.sup.6 is CR.sup.6 or N;
[0499] A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H or F and provided no more
than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0500] each of R.sup.1 and R.sup.2, independently, is H, F or
CF.sub.3;
[0501] each of R.sup.a and R.sup.b, independently, is H or F;
and
[0502] R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F, in
conjunction with any of the above or below embodiments with respect
to Formula I-B.
[0503] In another embodiment P-1, the invention includes compounds
of Formula I-C wherein A.sup.4 is CR.sup.4;
[0504] A.sup.5 is CR.sup.5;
[0505] A.sup.6 is CR.sup.6;
[0506] 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, methyl, ethyl, CN, OH, OCH.sub.3, SCH.sub.3, NHCH.sub.3
or C(O)CH.sub.3;
[0507] each of R.sup.a and R.sup.b, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3;
[0508] each of R.sup.1 and R.sup.2, independently, is H, F,
CH.sub.3, CH.sub.2F, CHF.sub.2 or CF.sub.3; and
[0509] R.sup.3 is CH.sub.3, C.sub.2H.sub.5, CF.sub.2H or CH.sub.2F,
in conjunction with any of the above or below embodiments with
respect to Formula I-C.
[0510] In another embodiment P-2, the invention includes compounds
of Formula I-C wherein A.sup.4 is CR.sup.4 or N;
[0511] A.sup.5 is CR.sup.5 or N;
[0512] A.sup.6 is CR.sup.6 or N;
[0513] A.sup.8 is CR.sup.8 or N, wherein each of R.sup.4, R.sup.5,
R.sup.6 and R.sup.8, independently, is H or F and provided no more
than one of A.sup.4, A.sup.5, A.sup.6 and A.sup.8 is N;
[0514] each of R.sup.1 and R.sup.2, independently, is H, F or
CF.sub.3;
[0515] each of R.sup.a and R.sup.b, independently, is H or F;
and
[0516] R.sup.3 is CF.sub.3, CH.sub.3, CF.sub.2H or CH.sub.2F, in
conjunction with any of the above or below embodiments with respect
to Formula I-C.
[0517] 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 taught and
described herein.
[0518] In another embodiment, the invention provides the compound
of Formula I, II or III, or a stereoisomer or pharmaceutically
acceptable salt thereof, selected from [0519]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0520]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-cyano-2-pyridinecarboxamide; [0521]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecarboxamide;
[0522]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide; and
[0523]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0524]
N-(3-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide; [0525]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-cyano-2-pyridinecarboxamide;
[0526]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0527]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-cyano-3-methyl-2-pyridinecarboxami-
de; [0528]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazineca-
rboxamide; [0529]
8-((3-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5--
yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0530]
N-(3-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecarboxamide;
[0531]
8-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-
-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0532]
4-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carb-
onitrile; [0533]
8-((3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carbon-
itrile; [0534]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4--
amine; [0535]
4-((3-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5--
yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitrile;
[0536]
8-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-5-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0537]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-5-yl)-4-fluorophenyl)-7-chloropyrido[3,2-d]pyrimidin-4-amine;
[0538]
4-((3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimid-
ine-7-carbonitrile; [0539]
((1S,5S,6S)-3-amino-5-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-f-
luorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)met-
hanol; [0540]
4-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-
-3-en-5-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitrile;
[0541]
((1S,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((3-(2-propyn-1-
-yloxy)-1,7-naphthyridin-8-yl)amino)phenyl)-2-thia-4-azabicyclo[4.1.0]hept-
-3-en-1-yl)methanol; [0542]
8-((3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carbon-
itrile; [0543]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[3,4-b]pyrazin--
5-amine; [0544]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazineca-
rboxamide; [0545]
((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]-
pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1--
yl)methanol; [0546]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyrazinecar-
boxamide; or [0547]
4-((3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7--
carbonitrile.
[0548] In another embodiment, the invention provides the compound
of Formula I or a tautomer, stereoisomer, or pharmaceutically
acceptable salt thereof selected from [0549]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b-
]pyrazin-5-amine; [0550]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido-
[3,4-b]pyrazin-5-amine; [0551]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-3-methyl-5-(2-propyn-1-yloxy)-2--
pyrazinecarboxamide; [0552]
8-((5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)amino)-1,7-naphthyridine-3-carbo-
nitrile; [0553]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-7-(1,3-oxazol-2-ylmethoxy)pyrido-
[3,2-d]pyrimidin-4-amine; [0554]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-5-(2-propyn-1-yloxy)-2-pyrazinec-
arboxamide; [0555]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-5-(1,3-oxazol-2-ylmethoxy)-2-pyr-
azinecarboxamide; [0556]
((1R,5S,6S)-3-amino-5-(2-fluoro-5-((7-(1,3-oxazol-2-ylmethoxy)pyrido[3,2--
d]pyrimidin-4-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]he-
pt-3-en-1-yl)acetonitrile; [0557]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-5-(2,2,3,3-tetrafluoropropoxy)-2-
-pyridinecarboxamide; [0558]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-5-(2,2,3,3-tetrafluoropropoxy)-2-
-pyrazinecarboxamide; [0559]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-methoxy-3-pyridinyl)-2-(2-propyn-1-yloxy)pyrido[3,4--
b]pyrazin-5-amine; [0560]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-methoxy-3-pyridinyl)-5-(2-propyn-1-yloxy)-2-pyrazine-
carboxamide; [0561]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-((.about.2.about.H_5_)-2-butyn-
-1-yloxy)pyrido[3,4-b]pyrazin-5-amine; [0562]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-
-2-pyrazinecarboxamide; [0563]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2,2,2-trifluoroethox-
y)-2-pyrazinecarboxamide; [0564]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-propy-
n-1-yl)oxy)-2-pyrazinecarboxamide; [0565]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-pro-
pyn-1-yl)oxy)-2-pyrazinecarboxamide; [0566]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy-
)-2-pyrazinecarboxamide; [0567]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-propyn--
1-yl)oxy)-2-pyrazinecarboxamide; [0568]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2--
pyrazinecarboxamide; [0569]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-propyn-1-
-yl)oxy)-2-pyrazinecarboxamide; [0570]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-prop-
yn-1-yl)oxy)-2-pyrazinecarboxamide; [0571]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2-
-pyrazinecarboxamide; [0572]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-methoxy-3-pyridinyl)-5-chloro-2-pyridinecarboxamide;
[0573]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-5-yl)-6-methoxy-3-pyridinyl)-7-(2-propyn-1-yloxy)pyri-
do[3,2-d]pyrimidin-4-amine; [0574]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-methoxy-3-pyridinyl)-2-(1,3-oxazol-2-ylmethoxy)pyrid-
o[3,4-b]pyrazin-5-amine; [0575]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]-
pyrazin-5-amine; [0576]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-4-ylmethoxy)pyrido[-
3,4-b]pyrazin-5-amine; [0577]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methoxy-1,7-naphthyridin-8-amin-
e; [0578]
N-(3-((1R,5S,6S)-3-amino-5-methyl-1-(methylsulfonyl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-propyn-1-yloxy)pyr-
ido[3,4-b]pyrazin-5-amine; [0579]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[-
3,4-b]pyrazin-5-amine; [0580]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3-
,4-b]pyrazin-5-amine; [0581]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyraz-
inecarboxamide; [0582]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2--
pyrazinecarboxamide; [0583]
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4-fluorophenyl)-2-(2-methoxyethoxy)pyrido[3,4-b]pyrazin-5--
amine; [0584]
N-(3-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-4,5-difluorophenyl)-7-fluoropyrido[3,2-d]pyrimidin-4-amine;
[0585]
N-(5-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-6-fluoro-3-pyridinyl)-5-chloro-2-pyridinecarboxamide; [0586]
5-((5-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5--
yl)-6-fluoro-3-pyridinyl)amino)pyrido[3,4-b]pyrazin-2(1H)-one;
[0587]
N-(5-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-6-fluoro-3-pyridinyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine;
[0588]
N-(5-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-
-en-5-yl)-6-fluoro-3-pyridinyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[3,4-b]pyr-
azin-5-amine; [0589]
8-((5-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5--
yl)-6-fluoro-3-pyridinyl)amino)-1,7-naphthyridine-3-carbonitrile;
[0590]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy)--
2-pyridinecarboxamide; [0591]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmetho-
xy)-2-pyridinecarboxamide; [0592]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy)-2-
-pyridinecarboxamide; [0593]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy-
)-2-pyridinecarboxamide; [0594]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethox-
y)-2-pyridinecarboxamide; [0595]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-pro-
pyn-1-yl)oxy)-2-pyridinecarboxamide; [0596]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-propyn--
1-yl)oxy)-2-pyridinecarboxamide; [0597]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-propyn-1-
-yl)oxy)-2-pyridinecarboxamide; [0598]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-prop-
yn-1-yl)oxy)-2-pyridinecarboxamide; [0599]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(((1S)-1-methyl-2-propyn-1--
yl)oxy)-2-pyridinecarboxamide; [0600]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy)-2--
pyridinecarboxamide; [0601]
N-(5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(2-propyn-1-yloxy)pyrido[3,4-
-b]pyrazin-5-amine; [0602]
N-(5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(1,3-oxazol-2-ylmethoxy)pyri-
do[3,4-b]pyrazin-5-amine; [0603]
N-(5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-5-chloro-2-pyridinecarboxamide-
; [0604]
8-((5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)amino)-N-(1-methylethy-
l)-1,7-naphthyridine-3-carboxamide; [0605]
8-((5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)amino)-1,7-naphthyridine-3-car-
bonitrile; [0606]
4-((5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)amino)pyrido[3,2-d]pyrimidine--
7-carbonitrile; [0607]
(1R)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-
-b]pyrazin-5-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hep-
t-3-en-1-yl)-2,2,2-trifluoroethanol; [0608]
(1S)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-
-b]pyrazin-5-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hep-
t-3-en-1-yl)-2,2,2-trifluoroethanol; [0609]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyri-
do[3,4-b]pyrazin-5-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-1-yl)methanol; [0610]
((1S,5S,6S)-3-amino-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]pyra-
zin-5-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en--
1-yl)methanol; [0611]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(1,3-oxazol-2-ylmethox-
y)pyrido[3,4-b]pyrazin-5-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-1-yl)methanol; [0612]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((7-(1,3-oxazol-2-ylmethox-
y)pyrido[3,2-d]pyrimidin-4-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-1-yl)methanol; [0613]
(1R)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((7-(2-propyn-1-yloxy)pyrido[3,2-
-d]pyrimidin-4-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-en-1-yl)-2,2,2-trifluoroethanol; [0614]
(1S)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((7-(2-propyn-1-yloxy)pyrido[3,2-
-d]pyrimidin-4-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-en-1-yl)-2,2,2-trifluoroethanol; [0615]
(1R)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((7-(1,3-oxazol-2-ylmethoxy)pyri-
do[3,2-d]pyrimidin-4-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-1-yl)-2,2,2-trifluoroethanol; [0616]
(1S)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((7-(1,3-oxazol-2-ylmethoxy)pyri-
do[3,2-d]pyrimidin-4-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-1-yl)-2,2,2-trifluoroethanol; [0617]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((3-(1,3-oxazol-2-ylmethox-
y)-1,7-naphthyridin-8-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-1-yl)methanol; [0618]
((1S,5S,6S)-3-amino-5-(2-fluoro-5-((7-(2-propyn-1-yloxy)pyrido[3,2-d]pyri-
midin-4-yl)amino)-3-pyridinyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-e-
n-1-yl)methanol; [0619]
(1R)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-
-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
-1-yl)-2,2,2-trifluoroethanol; [0620]
(1S)-1-((1S,5S,6S)-3-amino-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-
-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
-1-yl)-2,2,2-trifluoroethanol; [0621]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-((1R)-2,2,2-trifluoro-1-hydroxyethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-y-
loxy)-2-pyrazinecarboxamide; [0622]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-((1S)-2,2,2-trifluoro-1-hydroxyethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-y-
loxy)-2-pyrazinecarboxamide; [0623]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy-
)-2-pyridinecarboxamide; [0624]
N-(5-((1S,5S,6S)-3-amino-5-methyl-1-((1R)-2,2,2-trifluoro-1-methoxyethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(2-prop-
yn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine; [0625]
N-(5-((1S,5S,6S)-3-amino-5-methyl-1-((1S)-2,2,2-trifluoro-1-methoxyethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(2-prop-
yn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine; [0626]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-
-2-pyridinecarboxamide; [0627]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2,2,2-trifluoroethox-
y)-2-pyridinecarboxamide; [0628]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2-
-pyridinecarboxamide; [0629]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2--
pyridinecarboxamide; [0630]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-p-
yridinecarboxamide; [0631]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyrid-
inecarboxamide; [0632]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-py-
ridinecarboxamide;
[0633]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2-propyn-1-yl-
oxy)-2-pyridinecarboxamide; [0634]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyri-
dinecarboxamide; [0635]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-((1S)-1-(1,3-oxazol-2--
yl)ethoxy)-2-pyridinecarboxamide; [0636]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-((1R)-1-(1,3-oxazol-2--
yl)ethoxy)-2-pyridinecarboxamide; [0637]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2-p-
yridinecarboxamide; [0638]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyridi-
necarboxamide; [0639]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-chloro-5-(2-propyn-1-yloxy)-2-py-
ridinecarboxamide; [0640]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyridi-
necarboxamide; [0641]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-chloro-5-(2,2,2-trifluoroethoxy)-
-2-pyridinecarboxamide; [0642]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrid-
inecarboxamide; [0643]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyri-
dinecarboxamide; [0644]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyridine-
carboxamide; [0645]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyridineca-
rboxamide; [0646]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyridinec-
arboxamide; [0647]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy-
)-2-pyridinecarboxamide; [0648]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyrid-
inyl)carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3--
ene-1-carboxamide; [0649]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyraz-
inyl)carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3--
ene-1-carboxamide; [0650]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((3-methyl-5-(2,2,2-trifluoroethoxy-
)-2-pyridinyl)carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.-
0]hept-3-ene-1-carboxamide; [0651]
4-((3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(hydroxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrim-
idine-7-carbonitrile; [0652]
N-(3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(hydroxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarbo-
xamide; [0653]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(1,3-oxazol-2-ylmethox-
y)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-1-yl)methanol; [0654]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(1,3-oxazol-4-ylmethox-
y)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-1-yl)methanol; [0655]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyri-
do[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hep-
t-3-en-1-yl)methanol; [0656]
N-(3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(hydroxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,3,3-tetrafluoropr-
opoxy)-2-pyrazinecarboxamide; [0657]
4-((3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(methoxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrim-
idine-7-carbonitrile; [0658]
N-(3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(methoxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarbo-
xamide; [0659]
N-(3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(1-hydroxy-1-methylethyl)-5-methy-
l-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyr-
idinecarboxamide; [0660]
2-((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)py-
rido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-en-1-yl)-2-propanol; [0661]
(1R)-1-((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(2-propyn-1-ylo-
xy)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-1-yl)ethanol; [0662]
(1S)-1-((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((2-(2-propyn-1-ylo-
xy)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-1-yl)ethanol; [0663]
N-(3-((1S,5S,6S)-3-amino-1-(ethoxymethyl)-5-(fluoromethyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridinecar-
boxamide; [0664]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(methoxymethyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-cyano-3-methyl-2-pyridineca-
rboxamide; [0665]
8-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(methoxymethyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-3-ca-
rbonitrile; [0666]
N-(3-((1R,5S,6S)-3-amino-1-(cyanomethyl)-5-(fluoromethyl)-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0667]
8-((3-((1R,5S,6S)-3-amino-1-(cyanomethyl)-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)amino)-1,7-naphthyridine-
-3-carbonitrile; [0668]
((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)-
pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-2-thia-4-azabicyclo[4.1.0]hept-3-e-
n-1-yl)acetonitrile; [0669]
((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((2-(1,3-oxazol-2-ylme-
thoxy)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-2-thia-4-azabicyclo[4.1.0]he-
pt-3-en-1-yl)acetonitrile; [0670]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1H-1,2,3-triazol-1-ylmethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyri-
dinecarboxamide; [0671]
N-(3-((1S,5S,6S)-3-amino-1-(2-cyanoethyl)-5-(fluoromethyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide-
; [0672]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-((4-methyl-1H-1,2,3-t-
riazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophen-
yl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine; [0673]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-((5-methyl-1H-1,2,3-triazol-1-
-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-ch-
loro-2-pyridinecarboxamide; [0674]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(1,3-oxazol-5-ylmethoxy)-1,7-na-
phthyridin-8-amine; [0675]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(1,3-oxazol-2-ylmethoxy)-1,7-na-
phthyridin-8-amine; [0676]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(1,3-oxazol-4-ylmethoxy)-1,7-na-
phthyridin-8-amine; [0677]
((8-((3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicycl-
o[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridin-3-yl)ox-
y)acetonitrile; [0678]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(1,2,4-oxadiazol-3-ylmethoxy)-1-
,7-naphthyridin-8-amine; [0679]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(2,2,3,3-tetrafluoropropoxy)-1,-
7-naphthyridin-8-amine; [0680]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,3,3-tetrafluoropropoxy)-2--
pyridinecarboxamide; [0681]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(2-propyn-1-yloxy)-1,7-naphthyr-
idin-8-amine; [0682]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,3,3-tetrafluoropropoxy)-2--
pyrazinecarboxamide; [0683]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-((5-chloro-1,3-thiazol-2-yl)met-
hoxy)-1,7-naphthyridin-8-amine; [0684]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-((4-bromo-1,3-thiazol-2-yl)meth-
oxy)-1,7-naphthyridin-8-amine; [0685]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(1,3-thiazol-2-ylmethoxy)-1,7-n-
aphthyridin-8-amine; [0686]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(3,3,3-trifluoropropoxy)-2-pyra-
zinecarboxamide; [0687]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2-difluoropropoxy)-2-pyrazin-
ecarboxamide; [0688]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(3-fluoropropoxy)-2-pyrazinecar-
boxamide; [0689]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-((4,4,4-trifluoro-2-butyn-1-yl)-
oxy)-1,7-naphthyridin-8-amine; [0690]
N-(3-((1R,5S,6S)-3-amino-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0691]
N-(3-((1R,5S,6S)-3-amino-5-methyl-1-(methylsulfonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-py-
ridinecarboxamide; [0692]
N-(3-((1R,5S,6S)-3-amino-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinec-
arboxamide; [0693]
N-(3-((1R,5S,6S)-3-amino-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,3-oxazol-2-ylmethoxy)-2-pyr-
idinecarboxamide; [0694]
N-(3-((1R,5S,6S)-3-amino-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,3-oxazol-2-ylmethoxy)-2-pyr-
azinecarboxamide; [0695]
N-(3-((1R,5S,6S)-3-amino-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido-
[3,4-b]pyrazin-5-amine; [0696]
N-(3-((1R,5S,6R)-3-amino-7,7-difluoro-5-methyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0697]
N-(3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(hydroxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-p-
yrazinecarboxamide; [0698]
((1S,5S,6R)-3-amino-7,7-difluoro-5-(2-fluoro-5-((7-(1,3-oxazol-2-ylmethox-
y)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-1-yl)methanol; [0699]
N-(3-((1S,5S,6R)-3-amino-7,7-difluoro-1-(hydroxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,3,3-tetrafluoropr-
opoxy)-2-pyridinecarboxamide; [0700]
N-(3-((4S,4aR,7aS)-2-amino-4-(fluoromethyl)-4,4a,4b,5-tetrahydrothieno[3'-
,4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloro-2-pyr-
idinecarboxamide; [0701]
N-(3-((4S,4aS,7aR)-2-amino-4-(fluoromethyl)-4,4a,4b,5-tetrahydrothieno[3'-
,4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloro-2-pyr-
idinecarboxamide; [0702]
N-(3-((4S,4aS,7aR)-2-amino-4-(fluoromethyl)-4,4a,4b,5-tetrahydrothieno[3'-
,4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloro-2-pyr-
idinecarboxamide; [0703]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-3-chloropyrido[2,3-d]pyridazin-8-amine;
[0704] ethyl
(2E)-3-((1R,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)am-
ino)-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en--
1-yl)-2-propenoate; [0705]
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((1E)-3-hydroxy-1-propen-1-yl-
)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyr-
idinecarboxamide; [0706]
(2E)-3-((1R,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2-
-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)--
2-propenoic acid; [0707]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(3-hydroxypropyl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxam-
ide; [0708]
N-(3-((1R,5S,6S)-3-amino-1-((1E)-3-amino-3-oxo-1-propen-1-yl)-5-(fluorome-
thyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-
-pyridinecarboxamide; [0709]
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((1E)-3-(methylamino)-3-oxo-1-
-propen-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5--
chloro-2-pyridinecarboxamide; [0710]
N-(3-((1R,5S,6S)-3-amino-1-((1E)-3-(dimethylamino)-3-oxo-1-propen-1-yl)-5-
-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)--
5-chloro-2-pyridinecarboxamide; [0711]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amin-
e; [0712]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-7-(1,3-oxazol-2-ylmethoxy)pyrido[3,2-d-
]pyrimidin-4-amine; [0713]
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((1E)-3-(4-morpholinyl)-3-oxo-
-1-propen-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)--
5-chloro-2-pyridinecarboxamide; [0714]
N-(3-((1S,5S,6S)-3-amino-1-(3-(dimethylamino)-3-oxopropyl)-5-(fluoromethy-
l)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-py-
ridinecarboxamide; [0715]
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((1E)-3-(3-methoxy-1-azetidin-
yl)-3-oxo-1-propen-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluor-
ophenyl)-5-chloro-2-pyridinecarboxamide; [0716]
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((1E)-3-((2-methoxyethyl)amin-
o)-3-oxo-1-propen-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluoro-
phenyl)-5-chloro-2-pyridinecarboxamide; [0717]
(2E)-3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((2-(2-propyn-1-
-yloxy)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-2-thia-4-azabicyclo[4.1.0]h-
ept-3-en-1-yl)-N,N-dimethyl-2-propenamide; [0718]
(2E)-3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((2-(1,3-oxazol-
-2-ylmethoxy)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-1-yl)-N,N-dimethyl-2-propenamide; [0719]
(2E)-3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((3-(1,3-oxazol-
-2-ylmethoxy)-1,7-naphthyridin-8-yl)amino)phenyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)-N,N-dimethyl-2-propenamide;
[0720]
(2E)-3-((1R,5S,6S)-3-amino-5-(5-((3-(2-butyn-1-yloxy)-1,7-naphthyr-
idin-8-yl)amino)-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)-N,N-dimethyl-2-propenamide; [0721]
N-(3-((1R,5S,6S)-3-amino-1-((1E)-3-(3,3-difluoro-1-azetidinyl)-3-oxo-1-pr-
open-1-yl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fl-
uorophenyl)-5-chloro-2-pyridinecarboxamide; [0722]
N-(3-((1R,5S,6S)-3-amino-1-((1E)-3-(3,3-difluoro-1-azetidinyl)-3-oxo-1-pr-
open-1-yl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fl-
uorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine;
[0723]
N-(3-((1R,5S,6S)-3-amino-1-((1E)-3-(dimethylamino)-3-oxo-1-propen-1-yl)-5-
-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)--
5-(2-propyn-1-yloxy)-2-pyrazinecarboxamide; [0724]
(2E)-3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((7-(1,3-oxazol-
-2-ylmethoxy)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-1-yl)-N,N-dimethyl-2-prop enamide; [0725]
(2E)-3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((7-(2-propyn-1-
-yloxy)pyrido[3,2-d]pyrimidin-4-yl)amino)phenyl)-2-thia-4-azabicyclo[4.1.0-
]hept-3-en-1-yl)-N,N-dimethyl-2-propenamide; [0726]
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((1Z)-2-methyl-3-(4-morpholin-
yl)-3-oxo-1-propen-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluor-
ophenyl)-5-chloro-2-pyridinecarboxamide; [0727]
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((1E)-2-methyl-3-(4-morpholin-
yl)-3-oxo-1-propen-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluor-
ophenyl)-5-chloro-2-pyridinecarboxamide; [0728]
(1S,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)p-
yrido[3,4-b]pyrazin-5-yl)amino)phenyl)-N,N-dimethyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-ene-1-carboxamide; [0729]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,3-oxazol-5-yl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyra-
zinecarboxamide; [0730]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,3-oxazol-5-yl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(2-propyn-1-yloxy)pyrido[-
3,4-b]pyrazin-5-amine; [0731]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,3-oxazol-5-yl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-7-(2-propyn-1-yloxy)pyrido[-
3,2-d]pyrimidin-4-amine; [0732]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,3-oxazol-5-yl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(1,3-oxazol-2-ylmethoxy)--
2-pyrazinecarboxamide; [0733]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(4-methyl-1,3-oxazol-5-yl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-ylox-
y)-2-pyrazinecarboxamide; [0734]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1,3-oxazol-5-yl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxam-
ide; [0735]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(3-isoxazolyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide-
; [0736]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(4-methyl-1,3-oxazol--
5-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-
-pyridinecarboxamide; [0737]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(4-methyl-1,3-oxazol-5-yl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-7-(2-propyn-1-ylox-
y)pyrido[3,2-d]pyrimidin-4-amine; [0738]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(4-methyl-1,3-oxazol-5-yl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-ylox-
y)-2-pyridinecarboxamide; [0739]
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2-fluorop-
henyl)-5-(fluoromethyl)-N,N-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene--
1-carboxamide; [0740]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-((7-(2-propyn-1-yloxy)pyri-
do[3,2-d]pyrimidin-4-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-ene-1-carboxamide; [0741]
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2-fluorop-
henyl)-N-cyclopropyl-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbo-
xamide; [0742]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(3-isoxazolyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyridin-
ecarboxamide; [0743]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyri-
do[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hep-
t-3-ene-1-carboxamide; [0744]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-(((5-(2-propyn-1-yloxy)-2--
pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-
-ene-1-carboxamide; [0745]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-((2-(1,3-oxazol-2-ylmethox-
y)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxamide; [0746]
(1S,5S,6S)-3-amino-N-tert-butyl-5-(5-(((5-chloro-2-pyridinyl)carbonyl)ami-
no)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbox-
amide; [0747]
(1S,5S,6S)-3-amino-N-tert-butyl-5-(2-fluoro-5-(((5-(2-propyn-1-yloxy)-2-p-
yrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3--
ene-1-carboxamide; [0748]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-(((5-(1,3-oxazol-2-ylmetho-
xy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-ene-1-carboxamide; [0749]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethox-
y)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-ene-1-carboxamide; [0750]
4-((3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-ca-
rbonitrile; [0751]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[3-
,4-b]pyrazin-5-amine; [0752]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy-
)-2-pyrazinecarboxamide; [0753]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0754]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-propyn-1-yloxy)pyrid-
o[3,4-b]pyrazin-5-amine; [0755]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]p-
yrazin-5-amine; [0756]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinec-
arboxamide; [0757]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(1,3-oxazol-2-ylmethoxy)pyrido[3-
,2-d]pyrimidin-4-amine; [0758]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(1,3-oxazol-2-ylmethoxy)pyrido[-
3,2-d]pyrimidin-4-amine; [0759]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecar-
boxamide; [0760]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,3-oxazol-2-ylmethoxy)-2-pyraz-
inecarboxamide; [0761]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(1,3-oxazol-2-ylmethoxy)pyrido-
[3,2-d]pyrimidin-4-amine; [0762]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(2-propyn-1-yloxy)pyrido[3,2-d]p-
yrimidin-4-amine; [0763]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazi-
necarboxamide; [0764]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyraz-
inecarboxamide; [0765]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]pyr-
azin-5-amine; [0766]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[3,4-
-b]pyrazin-5-amine; [0767]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0768]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-7-(2-propyn-1-yloxy)pyrido[3,-
2-d]pyrimidin-4-amine; [0769]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecarbo-
xamide; [0770]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0771]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecarboxa-
mide; [0772]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]pyraz-
in-5-amine; [0773]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-7-(2-propyn-1-yloxy)pyrido[3,2-d]pyrim-
idin-4-amine; [0774]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[3,4-b-
]pyrazin-5-amine; [0775]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazineca-
rboxamide; [0776]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(((1S)-1-methyl-2-propyn-1-yl)oxy)py-
rido[3,4-b]pyrazin-5-amine; [0777]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-((5-methyl-1,2,4-oxadiazol-3-yl)meth-
oxy)pyrido[3,4-b]pyrazin-5-amine; [0778]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyrazi-
necarboxamide; [0779]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyra-
zinecarboxamide; [0780]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinec-
arboxamide; [0781]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyraz-
inecarboxamide; [0782]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0783]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazin-
ecarboxamide; [0784]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy)-2-
-pyrazinecarboxamide; [0785]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy)--
2-pyrazinecarboxamide; [0786]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4-fluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethoxy)-2--
pyrazinecarboxamide; [0787]
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,1-dideuterium-prop-2-yn-1-ylo-
xy)-2-pyrazinecarboxamide; [0788]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,1-dideuterium-prop-2-yn-1-y-
loxy)-2-pyrazinecarboxamide; [0789]
N-(3-((1S,5S,6S)-3-amino-1-(methoxy)-5-methyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,1-dideuterium-prop-2-yn-1-yloxy)py-
razine-2-carboxamide; [0790]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-2-(2-propyn-1-yloxy)pyrido[3,4-b]pyrazin-5--
amine; [0791]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido[3,4-b]pyra-
zin-5-amine; [0792]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-4-ylmethoxy)pyrido[3,4-b]pyra-
zin-5-amine; [0793]
N-(5-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-7-chloropyrido[3,2-d]pyrimidin--
4-amine; [0794]
N-(5-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-3-methyl-5-(2-propyn-1-yloxy)-2-
-pyrazinecarboxamide; [0795]
4-((5-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)amino)pyrido[3,2-d]pyrimidine-7-
-carbonitrile; [0796]
8-((5-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)amino)-1,7-naphthyridine-3-carb-
onitrile; [0797]
N-(5-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(2-propyn-1-yloxy)pyrido[3,4--
b]pyrazin-5-amine; [0798]
N-(5-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(1,3-oxazol-2-ylmethoxy)pyrid-
o[3,4-b]pyrazin-5-amine; [0799]
N-(5-((1S,5S,6S)-3-amino-5-methyl-1-(((.about.2.about.H_3_)methyloxy)meth-
yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-3-meth-
yl-5-(2-propyn-1-yloxy)-2-pyrazinecarboxamide; [0800]
N-(5-((1S,5S,6S)-3-amino-5-methyl-1-(((.about.2.about.H_3_)methyloxy)meth-
yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-5-(2-p-
ropyn-1-yloxy)-2-pyrazinecarboxamide; [0801]
N-(5-((1S,5S,6S)-3-amino-5-methyl-1-(((.about.2.about.H_3_)methyloxy)meth-
yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-7-chlo-
ropyrido[3,2-d]pyrimidin-4-amine; [0802]
N-(5-((1S,5S,6S)-3-amino-5-methyl-1-(((.about.2.about.H_3_)methyloxy)meth-
yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-(2-p-
ropyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine; [0803]
N-(5-((1S,5S,6S)-3-amino-5-methyl-1-(((.about.2.about.H_3_)methyloxy)meth-
yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-2-((1,-
1-.about.2.about.H_2_)-2-propyn-1-yloxy)pyrido[3,4-b]pyrazin-5-amine;
[0804] methyl
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2-fluoro--
3-(methoxycarbonyl)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxylate; [0805] methyl
(1S,5S,6S)-3-amino-5-(2-fluoro-3-(methoxycarbonyl)-5-((2-(2-propyn-1-ylox-
y)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxylate;
[0806] methyl
3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-5-yl)-2-fluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]pyrazin-5--
yl)amino)benzoate; [0807]
N-(3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluoro-5-(hydroxymethyl)phenyl)-5-chloro-2-pyridine-
carboxamide; [0808]
N-(5-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-5-(2-propyn-1-yloxy)-2-pyrazine-
carboxamide; [0809]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmetho-
xy)-2-pyrazinecarboxamide; [0810]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2--
pyrazinecarboxamide; [0811]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-p-
yrazinecarboxamide; [0812]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(1,3-oxazol-2-ylmethox-
y)-2-pyrazinecarboxamide; [0813]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-((1S)-1-(1,3-oxazol-2--
yl)ethoxy)-2-pyrazinecarboxamide; [0814]
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4-fluorophenyl)-2-(2-butyn-1-yloxy)pyrido[3,4-b]pyrazin-5--
amine; [0815]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyrido-
[3,4-b]pyrazin-5-amine; [0816]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-oxazol-4-ylmethoxy)pyrido-
[3,4-b]pyrazin-5-amine; [0817]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-butyn-1-yloxy)pyrido[3,4-b]-
pyrazin-5-amine; [0818]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-butyn-1-yloxy)pyrido[3,4-b]p-
yrazin-5-amine; [0819]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((2-methyl-1,3-oxazol-4-yl)met-
hoxy)pyrido[3,4-b]pyrazin-5-amine; [0820]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(3-fluoropropoxy)pyrido[3,4-b]-
pyrazin-5-amine; [0821]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2,2-difluoropropoxy)pyrido[3,-
4-b]pyrazin-5-amine; [0822]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((3-fluoro-2-pyridinyl)methoxy-
)pyrido[3,4-b]pyrazin-5-amine; [0823]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((4-methyl-2-pyrimidinyl)metho-
xy)pyrido[3,4-b]pyrazin-5-amine; [0824]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1,3-thiazol-4-ylmethoxy)pyrid-
o[3,4-b]pyrazin-5-amine; [0825]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(1-methylethoxy)pyrido[3,4-b]p-
yrazin-5-amine; [0826]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((5-methyl-1,3,4-oxadiazol-2-y-
l)methoxy)pyrido[3,4-b]pyrazin-5-amine; [0827]
2-((5-((3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2-
-yl)oxy)-N,N-dimethylacetamide; [0828]
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4-fluorophenyl)-2-(((1S)-1-methyl-2-propyn-1-yl)oxy)pyrido-
[3,4-b]pyrazin-5-amine; [0829]
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4-fluorophenyl)-2-((3-methyl-1,2,4-oxadiazol-5-yl)methoxy)-
pyrido[3,4-b]pyrazin-5-amine; [0830]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-pyrimidinylmethoxy)pyrido[3,-
4-b]pyrazin-5-amine; [0831]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((3-methyl-1,2,4-oxadiazol-5-yl-
)methoxy)pyrido[3,4-b]pyrazin-5-amine; [0832]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((5-methyl-1,2,4-oxadiazol-3-y-
l)methoxy)pyrido[3,4-b]pyrazin-5-amine; [0833]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(2-pyrimidinylmethoxy)pyrido[3-
,4-b]pyrazin-5-amine; [0834]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((5-methyl-1,2,4-oxadiazol-3-yl-
)methoxy)pyrido[3,4-b]pyrazin-5-amine; [0835]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((2,5-dimethyl-1,3-oxazol-4-yl-
)methoxy)pyrido[3,4-b]pyrazin-5-amine; [0836]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((3-methyl-1,2,4-oxadiazol-5-y-
l)methoxy)pyrido[3,4-b]pyrazin-5-amine; [0837]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((5-methyl-1,3-oxazol-2-yl)met-
hoxy)pyrido[3,4-b]pyrazin-5-amine; [0838]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2--
yl)methoxy)pyrido[3,4-b]pyrazin-5-amine; [0839]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(((1S)-1-methyl-2-propyn-1-yl)-
oxy)pyrido[3,4-b]pyrazin-5-amine; [0840]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((1R)-1-(1,3-oxazol-2-yl)ethox-
y)pyrido[3,4-b]pyrazin-5-amine; [0841]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((1S)-1-(1,3-oxazol-2-yl)ethox-
y)pyrido[3,4-b]pyrazin-5-amine; [0842]
1-(2-((5-((3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazi-
n-2-yl)oxy)ethyl)-2-pyrrolidinone; [0843]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((1S)-2-methoxy-1-methylethoxy-
)pyrido[3,4-b]pyrazin-5-amine; [0844]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5--
amine; [0845]
5-((3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,4-b]pyrazin-2(1H)-
-one; [0846]
N-(3-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-4,5-difluorophenyl)-7-methoxypyrido[3,2-d]pyrimidin-4-amine;
[0847] methyl
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2,-
3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxyl-
ate; [0848]
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2,3-diflu-
orophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic
acid; [0849]
N-(3-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-4,5-difluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine;
[0850]
(1S,5S,6S)-3-amino-5-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2,3--
difluorophenyl)-N-methoxy-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
e-1-carboxamide; [0851]
1-((1S,5S,6S)-3-amino-5-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-
,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)ethan-
one; [0852]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-3-(2-butyn-1-yloxy)-1,7-naphthyri-
din-8-amine; [0853]
4-((3-((1S,5S,6S)-1-acetyl-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hep-
t-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitri-
le; [0854]
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-
-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbo-
xamide; [0855]
N-(3-((1S,5S,6S)-1-acetyl-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-
-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0856]
4-((3-((1S,5S,6S)-3-amino-1-(1-hydroxyethyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7--
carbonitrile; [0857]
4-((3-((1R,2S,6S)-4-amino-6-((R)-1-hydroxyethyl)-2-methyl-3-azabicyclo[4.-
1.0]hept-3-en-2-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-car-
bonitrile; [0858]
4-((3-((1S,5S,6S)-3-amino-1-(1-hydroxy-1-methylethyl)-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyri-
midine-7-carbonitrile; [0859]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,3-oxazol-2-ylmethoxy)-2-pyra-
zinecarboxamide; [0860]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]p-
yrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carboxamide; [0861]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]p-
yrazin-5-yl)amino)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-
-ene-1-carboxamide; [0862]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2-propyn-1-yloxy)-2-pyrazinyl)-
carbonyl)amino)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
e-1-carboxamide; [0863]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2-propyn-1-yloxy)-2-pyrazinyl)-
carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxamide; [0864]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]p-
yrazin-5-yl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
e-1-carboxamide; [0865]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]p-
yrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carbonitrile; [0866]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((7-(2-propyn-1-yloxy)pyrido[3,2-d]p-
yrimidin-4-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene--
1-carboxamide; [0867]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((7-(1,3-oxazol-2-ylmethoxy)pyrido[3-
,2-d]pyrimidin-4-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-ene-1-carboxamide; [0868]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2-propyn-1-yloxy)-2-pyrazinyl)-
carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-car-
boxamide; [0869]
(1S,5S,6S)-3-amino-5-(5-((2-(2-butyn-1-yloxy)pyrido[3,4-b]pyrazin-5-yl)am-
ino)-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxamide; [0870]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((7-(2-propyn-1-yloxy)pyrido[3,2-d]p-
yrimidin-4-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene--
1-carbonitrile; [0871]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2,2,3,3-tetrafluoropropoxy)-2--
pyrazinyl)carbonyl)amino)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxamide; [0872]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((7-(1,3-oxazol-2-ylmethoxy)pyrido[3-
,2-d]pyrimidin-4-yl)amino)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.-
0]hept-3-ene-1-carboxamide; [0873]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecarboxamide;
[0874]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-(((1S)-1-methyl-2-propyn--
1-yl)oxy)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-N,N,5-trimethyl-2-thia-4--
azabicyclo[4.1.0]hept-3-ene-1-carboxamide; [0875]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyraz-
inyl)carbonyl)amino)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-
-3-ene-1-carboxamide; [0876]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecarboxamide;
[0877]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-((7-(2-propyn-1-yloxy)pyrido[3,2--
d]pyrimidin-4-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-e-
ne-1-carbonitrile; [0878]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide; [0879]
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2,3-diflu-
orophenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxam-
ide; [0880]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-(((1S)-1-methyl-2-propyn-1-yl)ox-
y)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carbonitrile; [0881]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide;
[0882]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(2-propyn-1-yloxy)pyri-
do[3,2-d]pyrimidin-4-amine; [0883]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-p-
yrazinecarboxamide; [0884]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarbo-
xamide; [0885]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(1,3-oxazol-2-ylmethox-
y)pyrido[3,2-d]pyrimidin-4-amine; [0886]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-(((1S)-1-methyl-2-prop-
yn-1-yl)oxy)pyrido[3,4-b]pyrazin-5-amine; [0887]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(1-pyrrolidinylcarbonyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-2-((1S)-1-(1,3-oxazol-2--
yl)ethoxy)pyrido[3,4-b]pyrazin-5-amine; [0888]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-((1S)-1-(1,3-oxazol-2-yl)ethoxy)-
pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carbonitrile; [0889]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxa-
mide; [0890]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-7-(2-propyn-1-yloxy)pyrido[3,2-d]pyrimidin-4-am-
ine; [0891]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(methoxymethyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-7-(2-propyn-1-yloxy)pyrido[3,-
2-d]pyrimidin-4-amine; [0892]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(2-propyn-1-yloxy)pyrido[3,2-d]-
pyrimidin-4-amine;
[0893]
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-5-yl)-6-fluoro-3-pyridinyl)-7-(2-propyn-1-yloxy)pyrid-
o[3,2-d]pyrimidin-4-amine; [0894]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(2-propyn-1-yloxy)pyrido[3,2-d-
]pyrimidin-4-amine; [0895]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-(2-methoxyethoxy)pyrido[3,2-d]p-
yrimidin-4-amine; [0896]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(methoxymethyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-7-(2-methoxyethoxy)pyrido[3,2-
-d]pyrimidin-4-amine; [0897]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-7-((2,5-dimethyl-1,3-oxazol-4-yl)-
methoxy)pyrido[3,2-d]pyrimidin-4-amine; [0898]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-fluoro-3-(1,3-oxazol-2-ylmetho-
xy)-1,7-naphthyridin-8-amine; [0899]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-fluoro-3-(1,3-oxazol-2-ylmethox-
y)-1,7-naphthyridin-8-amine; [0900]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-fluoro-3-(2-propyn-1-yloxy)-1,7-
-naphthyridin-8-amine; [0901]
(2E)-3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-5-(2-fluoro-5-((2-(2-pentyn-1-
-yloxy)pyrido[3,4-b]pyrazin-5-yl)amino)phenyl)-2-thia-4-azabicyclo[4.1.0]h-
ept-3-en-1-yl)-N,N-dimethyl-2-propenamide; [0902]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-((2,2,2-trifluoroethoxy)methy-
l)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-
-yloxy)-2-pyrazinecarboxamide; [0903]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-((2,2,2-trifluoroethoxy)methy-
l)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-py-
ridinecarboxamide; [0904]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-((1-methylethoxy)methyl)-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-
-2-pyrazinecarboxamide; [0905]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1H-1,2,3-triazol-4-yl)-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridineca-
rboxamide; [0906]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1H-1,2,3-triazol-4-yl)-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(1,3-oxazol-2-ylmet-
hoxy)pyrido[3,4-b]pyrazin-5-amine; [0907]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1-propyn-1-yl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(1,3-oxazol-2-ylmethoxy)pyr-
ido[3,4-b]pyrazin-5-amine; [0908]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1H-1,2,3-triazol-4-yl)-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)--
2-pyrazinecarboxamide; [0909]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1H-1,2,3-triazol-4-yl)-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-2-(2-propyn-1-yloxy)p-
yrido[3,4-b]pyrazin-5-amine; [0910]
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide; [0911]
4-((3-((1R,5S,6S)-3-amino-7,7-difluoro-1-(hydroxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrim-
idine-7-carbonitrile; or [0912]
N-(3-((4S,4aR,7aS)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide. [0913] In yet another embodiment, the invention
provides the compound of Formula I or a tautomer, stereoisomer, or
pharmaceutically acceptable salt thereof selected from [0914]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2,2,3,3-tetrafluoropropoxy)-2--
pyrazinyl)carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]he-
pt-3-ene-1-carboxamide; [0915]
N-(5-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-6-methoxy-3-pyridinyl)-5-(2-propyn-1-yloxy)-2-pyrazinecarboxami-
de; [0916]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(((1S)-1-methyl-2-propyn--
1-yl)oxy)-2-pyrazinecarboxamide; [0917]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(((1S)-1-methyl-2-propyn-1-yl)oxy)-
-2-pyrazinecarboxamide; [0918]
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(((1S)-1-methyl-2-propyn-1-yl)o-
xy)-2-pyrazinyl)carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-ene-1-carboxamide; [0919]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((1R)-2,2,2-trifluoro-1-methylethox-
y)-2-pyrazinecarboxamide; [0920]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((1S)-2,2,2-trifluoro-1-methylethox-
y)-2-pyrazinecarboxamide; [0921]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-((trideuteriummethyloxy)methyl)-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-ylo-
xy)-2-pyrazinecarboxamide; [0922]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((1S)-2-methoxy-1-methylethoxy)-2-p-
yrazinecarboxamide; [0923]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((1S)-2-methoxy-1-methylethoxy)-2--
pyrazinecarboxamide; [0924]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyrazinyl-
)carbonyl)amino)phenyl)-5-methyl-N-(2,2,2-trifluoroethyl)-2-thia-4-azabicy-
clo[4.1.0]hept-3-ene-1-carboxamide; [0925]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyrazinyl-
)carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene--
1-carboxamide; [0926]
(1S,5S,6S)-3-amino-N-((1S)-1,2-dimethylpropyl)-5-(2-fluoro-5-(((5-(2,2,2--
trifluoroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-ene-1-carboxamide; [0927] methyl
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2-propyn-1-yloxy)-2-pyrazinyl)-
carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-car-
boxylate; [0928]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyrazinyl-
)carbonyl)amino)phenyl)-5-methyl-N-(1-methylethyl)-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxamide; [0929]
(1S,5S,6S)-3-amino-N-ethyl-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-p-
yrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3--
ene-1-carboxamide; [0930]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(((1S)-1-methyl-2-propyn-1-yl)oxy)--
2-pyrazinyl)carbonyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-ene-1-carboxamide; [0931]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-((2-(2-propyn-1-yloxy)pyrido[3,4-b]pyraz-
in-5-yl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carboxamide; [0932] tert-butyl
(((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(((5-(2-propyn-1-yloxy)-2-pyraziny-
l)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl-
)methyl)carbamate; [0933]
N-(3-((1S,5S,6S)-3-amino-1-(aminomethyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecarb-
oxamide; [0934]
(1S,5S,6S)-3-amino-N-((1R)-2,2-difluorocyclopropyl)-5-(2-fluoro-5-(((5-(2-
,2,2-trifluoroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxamide; [0935]
(1S,5S,6S)-3-amino-N-((1S)-2,2-difluorocyclopropyl)-5-(2-fluoro-5-(((5-(2-
,2,2-trifluoroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxamide; [0936]
(1S,5S,6S)-3-amino-N-(2-fluoro-1,1-dimethylethyl)-5-(2-fluoro-5-(((5-(2,2-
,2-trifluoroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-ene-1-carboxamide; [0937]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyrazinyl-
)carbonyl)amino)phenyl)-N-methoxy-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-ene-1-carboxamide; [0938]
(1S,5S,6S)-3-amino-5-(5-(((5-chloro-2-pyridinyl)carbonyl)amino)-2-fluorop-
henyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide;
[0939]
(1S,5S,6S)-3-amino-N-tert-butyl-5-(5-(((5-cyano-2-pyridinyl)carbon-
yl)amino)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carboxamide; [0940]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(2-propyn-1-yloxy)-2-pyrazinyl)carb-
onyl)amino)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-car-
boxamide; [0941]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(((1R)-1-methyl-2-propyn-1-yl)oxy)--
2-pyrazinecarboxamide; [0942]
N-(5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-6-methoxy-3-pyridinyl)-5-(2-propyn-1-yloxy)-2-pyrazi-
necarboxamide; [0943]
N-(5-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-6-methoxy-3-pyridinyl)-5-chloro-2-pyridinecarboxamid-
e; [0944]
N-(3-((1S,5S,6S)-3-amino-1-(((3R)-3-fluoro-1-pyrrolidinyl)carbon-
yl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(-
2,2,2-trifluoroethoxy)-2-pyrazinecarboxamide; [0945]
N-(3-((1S,5S,6S)-3-amino-1-(((3
S)-3-fluoro-1-pyrrolidinyl)carbonyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]h-
ept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyrazinecarboxa-
mide; [0946]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-(((5-(((1S)-1-methyl-2-pro-
pyn-1-yl)oxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-ene-1-carboxamide; [0947]
(1S,5S,6S)-3-amino-N-tert-butyl-5-(2-fluoro-5-(((5-(((1S)-1-methyl-2-prop-
yn-1-yl)oxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyc-
lo[4.1.0]hept-3-ene-1-carboxamide; [0948]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((1S)-2,2,2-trifluoro-1-methylethox-
y)-2-pyrazinecarboxamide; [0949]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((1R)-2,2,2-trifluoro-1-methylethox-
y)-2-pyrazinecarboxamide; [0950]
(1S,5S,6S)-3-amino-N-((1R)-1,2-dimethylpropyl)-5-(2-fluoro-5-(((5-(2,2,2--
trifluoroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-ene-1-carboxamide; [0951]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(4-morpholinylcarbonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-p-
yrazinecarboxamide; [0952]
(1S,5S,6S)-3-amino-N-(2,2-difluoroethyl)-5-(2-fluoro-5-(((5-(2,2,2-triflu-
oroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-ene-1-carboxamide; [0953]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyrazinyl-
)carbonyl)amino)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-e-
ne-1-carboxamide; [0954]
(1S,5S,6S)-3-amino-N-cyclopropyl-5-(2-fluoro-5-(((5-((1S)-2-methoxy-1-met-
hylethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-ene-1-carboxamide; [0955]
(1S,5S,6S)-3-amino-N-tert-butyl-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy-
)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]he-
pt-3-ene-1-carboxamide; [0956]
(1S,5S,6S)-3-amino-N-tert-butyl-5-(2-fluoro-5-(((5-((1S)-2-methoxy-1-meth-
ylethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-ene-1-carboxamide; [0957]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(4-morpholinylcarbonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-py-
razinecarboxamide; [0958]
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(4-morpholinylcarbonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazi-
necarboxamide; [0959]
(1S,5S,6S)-3-amino-N-(2-fluoro-1,1-dimethylethyl)-5-(2-fluoro-5-(((5-(2-p-
ropyn-1-yloxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-ene-1-carboxamide; [0960]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyrazinecarboxamide;
[0961]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((3-methyl-1,2,4-oxadiazol-5-
-yl)methoxy)-2-pyrazinecarboxamide; [0962]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(((1S)-1-methyl-2-propyn-1-yl)o-
xy)-2-pyrazinecarboxamide; [0963]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-((1S)-2-methoxy-1-methylethoxy)-2-pyrazin-
ecarboxamide; [0964]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-(((1S)-1-methyl-2-propyn-1-yl)oxy)-2-pyra-
zinecarboxamide; [0965]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-(2,2,2-trifluoroethoxy)-2-pyridinecarboxa-
mide; [0966]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((5-methyl-1,2,4-oxadiazol-3-yl-
)methoxy)-2-pyrazinecarboxamide; [0967]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((3-methyl-1,2,4-oxadiazol-5-yl-
)methoxy)-2-pyrazinecarboxamide; [0968]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2,2,2-trifluoroethoxy)-2-pyridi-
necarboxamide; [0969]
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-3-methyl-5-(2-propyn-1-yloxy)-2-pyridinecar-
boxamide; [0970]
(1S,5S,6S)-3-amino-N-ethyl-5-(2-fluoro-5-(((5-(2-propyn-1-yloxy)-2-pyrazi-
nyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxamide; [0971]
(1S,5S,6S)-3-amino-5-(5-(((5-cyano-2-pyridinyl)carbonyl)amino)-2-fluoroph-
enyl)-N-(2-fluoro-1,1-dimethylethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]he-
pt-3-ene-1-carboxamide; [0972]
(1S,5S,6S)-3-amino-N-(2-fluoro-1,1-dimethylethyl)-5-(2-fluoro-5-(((5-(((1-
S)-1-methyl-2-propyn-1-yl)oxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-
-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide; [0973]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(cyclobutylmethoxy)-2-pyrazinec-
arboxamide; [0974]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(cyclopropylmethoxy)-2-pyrazine-
carboxamide; [0975]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(3-oxetanylmethoxy)-2-pyrazinec-
arboxamide; [0976]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(((2R)-2-methoxypropyl)oxy)-2-p-
yrazinecarboxamide; [0977]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(((2S)-2-methoxypropyl)oxy)-2-p-
yrazinecarboxamide;
[0978]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((1S)-2-methoxy-1-methyl-
ethoxy)-2-pyrazinecarboxamide; [0979]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2,2-difluoroethoxy)-2-pyrazine-
carboxamide; [0980]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((3,3-difluorocyclobutyl)methox-
y)-2-pyrazinecarboxamide; [0981]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-oxo-4,5-dihydro-2-pyrazinecarbo-
xamide; [0982]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-methylpropoxy)-2-pyrazinecar-
boxamide; [0983]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((2R)-2-oxetanylmethoxy)-2-pyra-
zinecarboxamide; [0984]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((2S)-2-oxetanylmethoxy)-2-pyra-
zinecarboxamide; [0985]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((2-methyl-2-propen-1-yl)oxy)-2-
-pyrazinecarboxamide; [0986]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((3-methyl-5-isoxazolyl)methoxy-
)-2-pyrazinecarboxamide; [0987]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((5-methyl-3-isoxazolyl)methoxy-
)-2-pyrazinecarboxamide; [0988]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(benzyloxy)-2-pyrazinecarboxami-
de; [0989]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(1,3-thiazol-2-ylmeth-
oxy)-2-pyrazinecarboxamide; [0990]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(((1R)-2,2-difluorocyclopropyl)-
methoxy)-2-pyrazinecarboxamide; [0991]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(((1S)-2,2-difluorocyclopropyl)-
methoxy)-2-pyrazinecarboxamide; [0992]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propen-1-yloxy)-2-pyrazineca-
rboxamide; [0993]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((5-methyl-1,3,4-oxadiazol-2-yl-
)methoxy)-2-pyrazinecarboxamide; [0994]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-ethoxy-2-pyrazinecarboxamide;
[0995]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((3-methyl-1,2,4-oxadiazol--
5-yl)methoxy)-2-pyrazinecarboxamide; [0996]
(1S,5S,6S)-3-amino-N-(2-fluoroethyl)-5-(2-fluoro-5-(((5-(2,2,2-trifluoroe-
thoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxamide; [0997]
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(((5-(2,2,2-trifluoroethoxy)-2-pyrazinyl-
)carbonyl)amino)phenyl)-5-methyl-N-(1-methylcyclopropyl)-2-thia-4-azabicyc-
lo[4.1.0]hept-3-ene-1-carboxamide; [0998]
N-(3-((1S,5S,6S)-1-((acetylamino)methyl)-3-amino-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyra-
zinecarboxamide; [0999]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-(2-propyn-1-yloxy)-2-pyraz-
inecarboxamide; [1000]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-((3-methyl-1,2,4-oxadiazol-
-5-yl)methoxy)-2-pyrazinecarboxamide; [1001]
(1S,5S,6S)-3-amino-N-((1R)-2,2-difluoro-1-methylethyl)-5-(2-fluoro-5-(((5-
-(2,2,2-trifluoroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide; [1002]
(1S,5S,6S)-3-amino-N-((1S)-2,2-difluoro-1-methylethyl)-5-(2-fluoro-5-(((5-
-(2,2,2-trifluoroethoxy)-2-pyrazinyl)carbonyl)amino)phenyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide; [1003]
N-(3-((1S,5S,6S)-3-amino-1-(ethoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-propyn-1-yloxy)-2-pyrazinecar-
boxamide; [1004]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(3-pentyn-1-yloxy)-2-pyrazinecarbox-
amide; [1005]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(3-butyn-1-yloxy)-2-pyrazinecarboxa-
mide; [1006]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((1-methylcyclopropyl)methoxy)-2-py-
razinecarboxamide; [1007]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((3-methyl-3-oxetanyl)methoxy)-2-py-
razinecarboxamide; [1008]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(((1R)-1-methyl-2-propen-1-yl)oxy)--
2-pyrazinecarboxamide; [1009]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(((1S)-1-methyl-2-propen-1-yl)oxy)--
2-pyrazinecarboxamide; [1010]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-fluoroethoxy)-2-pyrazinecarboxam-
ide; [1011]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(cyclopropylmethoxy)-2-pyrazinecarb-
oxamide; [1012]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(cyclobutylmethoxy)-2-pyrazinecarbo-
xamide; [1013]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(3-oxetanylmethoxy)-2-pyrazinecarbo-
xamide; [1014]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2-methylpropoxy)-2-pyrazinecarboxa-
mide; [1015]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2-difluoroethoxy)-2-pyrazinecarb-
oxamide; [1016]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((2R)-2-oxetanylmethoxy)-2-pyrazine-
carboxamide; [1017]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-((2S)-2-oxetanylmethoxy)-2-pyrazine-
carboxamide; [1018]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(3-pentyn-1-yloxy)-2-pyrazineca-
rboxamide; [1019]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(3-butyn-1-yloxy)-2-pyrazinecar-
boxamide; [1020]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((1-methylcyclopropyl)methoxy)--
2-pyrazinecarboxamide; [1021]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-((3-methyl-3-oxetanyl)methoxy)--
2-pyrazinecarboxamide; [1022]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(((1R)-1-methyl-2-propen-1-yl)o-
xy)-2-pyrazinecarboxamide; [1023]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(((1S)-1-methyl-2-propen-1-yl)o-
xy)-2-pyrazinecarboxamide; [1024]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(2-fluoroethoxy)-2-pyrazinecarb-
oxamide; [1025]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-(2,2,2-trifluoroethoxy)-2--
pyrazinecarboxamide; [1026]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-chloro-2-pyridinecarboxami-
de; [1027]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(oxetan-3-yloxy)pyrazine--
2-carboxamide; [1028]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(oxetan-3-yloxy)pyrazine-2-carb-
oxamide; [1029]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(neopentyloxy)pyrazine-2-carbox-
amide; [1030]
N-(3-((1S,5S,6S)-1-acetyl-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-
-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamid-
e; [1031]
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-(oxazol-2-ylmetho-
xy)pyrazine-2-carboxamide; [1032]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-(prop-2-yn-1-yloxy)pyrazi-
ne-2-carboxamide; [1033]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-(2,2,2-trifluoroethoxy)py-
razine-2-carboxamide; [1034]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-(oxazol-2-ylmethoxy)pyraz-
ine-2-carboxamide; or [1035]
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluoro-5-methylphenyl)-5-((3-methyl-1,2,4-oxadiazo-
l-5-yl)methoxy)pyrazine-2-carboxamide.
[1036] Additional generic and specific compounds representative of
the invention include:
##STR00047## ##STR00048##
[1037] In an additional embodiment, the invention provides a
compound, or a pharmaceutically acceptable salt or tautomer
thereof, selected from:
##STR00049## ##STR00050## ##STR00051##
[1038] Thus, in one embodiment, the invention provides the
compound
##STR00052##
or a pharmaceutically acceptable salt or tautomer thereof.
[1039] Thus, in one embodiment, the invention provides the
compound
##STR00053##
or a pharmaceutically acceptable salt or tautomer thereof.
[1040] Thus, in one embodiment, the invention provides the
compound
##STR00054##
or a pharmaceutically acceptable salt or tautomer thereof.
[1041] Thus, in one embodiment, the invention provides the
compound
##STR00055##
or a pharmaceutically acceptable salt or tautomer thereof.
[1042] Thus, in one embodiment, the invention provides the
compound
##STR00056##
or a pharmaceutically acceptable salt or tautomer thereof.
[1043] Thus, in one embodiment, the invention provides the
compound
##STR00057##
or a pharmaceutically acceptable salt or tautomer thereof.
[1044] Thus, in one embodiment, the invention provides the
compound
##STR00058##
or a pharmaceutically acceptable salt or tautomer thereof.
[1045] Thus, in one embodiment, the invention provides the
compound
##STR00059##
or a pharmaceutically acceptable salt or tautomer thereof.
[1046] Thus, in one embodiment, the invention provides the
compound
##STR00060##
or a pharmaceutically acceptable salt or tautomer thereof.
[1047] Thus, in one embodiment, the invention provides the
compound
##STR00061##
or a pharmaceutically acceptable salt or tautomer thereof.
[1048] Thus, in one embodiment, the invention provides the
compound
##STR00062##
or a pharmaceutically acceptable salt or tautomer thereof.
[1049] Thus, in one embodiment, the invention provides the
compound
##STR00063##
or a pharmaceutically acceptable salt or tautomer thereof.
[1050] Thus, in one embodiment, the invention provides the
compound
##STR00064##
or a pharmaceutically acceptable salt or tautomer thereof.
[1051] Thus, in one embodiment, the invention provides the
compound
##STR00065##
or a pharmaceutically acceptable salt or tautomer thereof.
[1052] In an additional embodiment, the invention provides a
compound, or a pharmaceutically acceptable salt or tautomer
thereof, selected from:
##STR00066## ##STR00067##
[1053] Thus, in one embodiment, the invention provides the
compound
##STR00068##
or a pharmaceutically acceptable salt or tautomer thereof.
[1054] Thus, in one embodiment, the invention provides the
compound
##STR00069##
or a pharmaceutically acceptable salt or tautomer thereof.
[1055] Thus, in one embodiment, the invention provides the
compound
##STR00070##
or a pharmaceutically acceptable salt or tautomer thereof.
[1056] Thus, in one embodiment, the invention provides the
compound
##STR00071##
or a pharmaceutically acceptable salt or tautomer thereof.
[1057] Thus, in one embodiment, the invention provides the
compound
##STR00072##
or a pharmaceutically acceptable salt or tautomer thereof.
[1058] Thus, in one embodiment, the invention provides the
compound
##STR00073##
or a pharmaceutically acceptable salt or tautomer thereof.
[1059] Thus, in one embodiment, the invention provides the
compound
##STR00074##
or a pharmaceutically acceptable salt or tautomer thereof.
[1060] Thus, in one embodiment, the invention provides the
compound
##STR00075##
or a pharmaceutically acceptable salt or tautomer thereof.
[1061] Thus, in one embodiment, the invention provides the
compound
##STR00076##
or a pharmaceutically acceptable salt or tautomer thereof.
[1062] In embodiment 84, the invention provides a compound, or a
pharmaceutically acceptable salt or tautomer thereof, selected
from:
##STR00077## ##STR00078## ##STR00079##
[1063] In embodiment 85, the invention provides each individual
compound according to embodiments 82-84, or a pharmaceutically
acceptable salt or tautomer thereof.
[1064] For instance, in embodiment 86, the invention provides the
compound
##STR00080##
or a pharmaceutically acceptable salt or tautomer thereof.
[1065] In embodiment 87, the invention provides the compound
##STR00081##
or a pharmaceutically acceptable salt or tautomer thereof.
[1066] In embodiment 88, the invention provides the compound
##STR00082##
or a pharmaceutically acceptable salt or tautomer thereof.
[1067] In embodiment 89, the invention provides the compound
##STR00083##
or a pharmaceutically acceptable salt or tautomer thereof.
[1068] In embodiment 90, the invention provides the compound
##STR00084##
or a pharmaceutically acceptable salt or tautomer thereof.
[1069] In embodiment 91, the invention provides the compound
##STR00085##
or a pharmaceutically acceptable salt or tautomer thereof.
[1070] In embodiment 92, the invention provides the compound
##STR00086##
or a pharmaceutically acceptable salt or tautomer thereof.
[1071] In embodiment 93, the invention provides the compound
##STR00087##
or a pharmaceutically acceptable salt or tautomer thereof.
[1072] In embodiment 94, the invention provides the compound
##STR00088##
or a pharmaceutically acceptable salt or tautomer thereof.
[1073] In embodiment 95, the invention provides the compound
##STR00089##
or a pharmaceutically acceptable salt or tautomer thereof.
[1074] In embodiment 96, the invention provides the compound
##STR00090##
or a pharmaceutically acceptable salt or tautomer thereof.
[1075] In embodiment 97, the invention provides the compound
##STR00091##
or a pharmaceutically acceptable salt or tautomer thereof.
[1076] In embodiment 98, the invention provides the compound
##STR00092##
or a pharmaceutically acceptable salt or tautomer thereof.
[1077] In the structures depicted hereinabove, an "--N" in the
1,3-oxazine head group is intended to be an --NH.sub.2 (an amine
groups); the "--N" in the amide linker is intended to be an --NH,
and lines ending without an atom are understood by persons of
ordinary skill in the art to be a --CH.sub.3 group.
[1078] All of the possible embodiments described herein for various
of the R groups of the compounds of Formula I may be applied, as
appropriate, to compounds of Formulas II and III, and any
sub-formulas thereof.
[1079] 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.
[1080] In another embodiment, the invention provides the
exemplified compounds described herein, and pharmaceutically
acceptable salt forms of each thereof.
Definitions
[1081] The following definitions should assist in understanding the
metes and bounds of the invention.
[1082] 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.
[1083] The compounds of the invention may contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C).
Radiolabeled compounds are useful as therapeutic or prophylactic
agents, research reagents, e.g., assay reagents, and diagnostic
agents, e.g., in vivo imaging agents. All isotopic variations of
the compounds of the invention, whether radioactive or not, are
intended to be encompassed within the scope of the invention. For
example, if a variable is said to be H, this means that variable
may also be deuterium (D) or tritium (T). However, in certain
deuterated compounds, if a structure is drawn showing D groups,
then this site is enriched with respect to D.
[1084] 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.
[1085] 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.
[1086] 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.
[1087] 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. Simlar
examples exist for such "alkynyl" radicals, as appreciated by those
skilled in the art.
[1088] 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.
[1089] 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.
[1090] 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.
[1091] 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.
[1092] 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.
[1093] The term "halo", when used alone or in combination, means
halogens such as fluorine, chlorine, bromine or iodine atoms.
[1094] 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.
[1095] 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--.
[1096] 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].
[1097] 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.
[1098] 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.
[1099] 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.
[1100] 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.
[1101] 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.
[1102] 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.
[1103] 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".
[1104] 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--).
[1105] 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.
[1106] As used herein and unless otherwise indicated, the term
"stereoisomer" or "stereomerically pure" means one stereoisomer of
a compound that is substantially free of other stereoisomers of
that compound. For example, a stereomerically pure compound having
one chiral center will be substantially free of the opposite
enantiomer of the compound. A stereomerically pure compound having
two chiral centers will be substantially free of other
diastereomers of the compound. A typical stereomerically pure
compound comprises greater than about 80% by weight of one
stereoisomer of the compound and less than about 20% by weight of
other stereoisomers of the compound, more preferably greater than
about 90% by weight of one stereoisomer of the compound and less
than about 10% by weight of the other stereoisomers of the
compound, even more preferably greater than about 95% by weight of
one stereoisomer of the compound and less than about 5% by weight
of the other stereoisomers of the compound, and most preferably
greater than about 97% by weight of one stereoisomer of the
compound and less than about 3% by weight of the other
stereoisomers of the compound. If the stereochemistry of a
structure or a portion of a structure is not indicated with, for
example, bold or dashed lines, the structure or portion of the
structure is to be interpreted as encompassing all stereoisomers of
it. A bond drawn with a wavy line indicates that both stereoisomers
are encompassed.
[1107] Various compounds of the invention contain one or more
chiral centers, and can exist as racemic mixtures of enantiomers,
mixtures of diastereomers or enantiomerically or optically pure
compounds. This invention encompasses the use of stereomerically
pure forms of such compounds, as well as the use of mixtures of
those forms. For example, mixtures comprising equal or unequal
amounts of the enantiomers of a particular compound of the
invention may be used in methods and compositions of the invention.
These isomers may be asymmetrically synthesized or resolved using
standard techniques such as chiral columns or chiral resolving
agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and
Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et
al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of
Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables
of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel,
Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
[1108] The present invention also includes tautomeric forms of
compounds of the invention. For example, the invention comprises
compounds of formula I as well as their tautomers, as shown:
##STR00093##
Similarly, tautomers of compounds of Formulas II and III, and of
compounds of sub-formulas of compounds of Formulas I, II and III,
are also included in the invention.
[1109] 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.
[1110] 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.
[1111] 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, TEA,
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.
[1112] 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.
[1113] 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.
[1114] The term "pharmaceutically-acceptable derivative" as used
herein, denotes a derivative which is pharmaceutically
acceptable.
[1115] 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.
[1116] 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.
[1117] 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.
[1118] 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.
[1119] 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
[1120] The present invention further comprises procedures for the
preparation of compounds of Formulas I-III. The compounds of
Formulas I-III can be synthesized according to the procedures
described in the following Schemes 1, 2, 3a, 3b, 4 and 5, 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.
[1121] The following list of abbreviations used throughout the
specification represent the following and should assist in
understanding the invention: [1122] CAN--acetonitrile [1123] Aq.,
aq.--aqueous [1124] Ar--argon (gas) [1125] Boc--tert-butoxycarbonyl
[1126] BOP--benzotriazol-1-yl-oxy [1127] Hexafluorophosphate [1128]
BuLi--Butyllithium [1129] Cs.sub.2CO.sub.3--cesium carbonate [1130]
CHCl.sub.3--chloroform [1131] CH.sub.2Cl.sub.2,
DCM--dichloromethane, methylene chloride [1132] Cu(1)I--copper(1)
iodide [1133] COMU
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium
hexafluorophosphate [1134] DCC--dicyclohexylcarbodiimide [1135]
DEA--diethylamine [1136] DIC--1,3-diisopropylcarbodiimide [1137]
DIEA, DIPEA--diisopropylethylamine [1138] DME--dimethoxyethane
[1139] DMF--dimethylformamide [1140] DMAP--4-dimethylaminopyridine
[1141] DMSO--dimethylsulfoxide [1142] EDC,
EDCI--1-(3-dimethylaminopropyl)-3-ethylcarbodiimide [1143]
Et.sub.2O--diethyl ether [1144] EtOAc--ethyl acetate [1145] EtOH
ethanol [1146] g, gm--gram [1147] h, hr--hour [1148]
H.sub.2--hydrogen (gas) [1149] H.sub.2O--water [1150]
HATU--O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluroniumhexafluoroph-
osphate [1151] HBr--hydrobromic acid [1152] HCl--hydrochloric acid
[1153] HMDS hexamethyldisilazane or bis(trimethylsilyl)amine [1154]
HOBt--1-hydroxybenzotriazole hydrate [1155] HOAc--acetic acid
[1156] HPLC--high pressure liquid chromatography [1157] IPA,
iPrOH--isopropyl alcohol [1158] K.sub.2CO.sub.3--potassium
carbonate [1159] KI--potassium iodide [1160] LDA--Lithium
diisopropylamide [1161] LG--leaving group [1162] LiHMDS lithium
bis(trimethylsilyl)amide [1163] LiOH--lithium hydroxide [1164]
MgSO.sub.4--magnesium sulfate [1165] MS--mass spectrum [1166]
MeOH--methanol [1167] N.sub.2--nitrogen (gas) [1168]
NaCNBH.sub.3--sodium cyanoborohydride [1169]
Na.sub.2CO.sub.3--sodium carbonate [1170] NaHCO.sub.3--sodium
bicarbonate [1171] NaH--sodium hydride [1172] NaI--sodium iodide
[1173] NaBH.sub.4--sodium borohydride [1174] NaOH--sodium hydroxide
[1175] Na.sub.2SO.sub.4--sodium sulfate [1176] NH.sub.4Cl--ammonium
chloride [1177] NH.sub.4OH--ammonium hydroxide [1178]
P(t-Bu).sub.3--tri(tert-butyl)phosphine [1179] Ph.sub.3P or
PPh.sub.3--triphenylphosphine [1180] Pd/C--palladium on carbon
[1181] Pd(PPh.sub.3).sub.4--palladium(0)triphenylphosphine tetrakis
[1182]
Pd(dppf)Cl.sub.2--palladium(1,1-bisdiphenylphosphinoferrocene)
[1183] II chloride [1184] Pd(PhCN).sub.2Cl.sub.2--palladium
di-cyanophenyl dichloride [1185] Pd(OAc).sub.2--palladium acetate
[1186] Pd.sub.2(dba).sub.3--tris(dibenzylideneacetone) dipalladium
[1187] PyBop--benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium
[1188] hexafluorophosphate [1189] RT, rt--room temperature [1190]
RBF, rbf--round bottom flask [1191] SEM
[2-(trimethylsilyl)ethoxy]methyl acetal [1192] SFC--Supercritical
fluid chromatography [1193] T3P propylphosphonic anhydride [1194]
TBAF--Tetrabutylammonium flouride [1195]
TBTU--O-benzotriazol-1-yl-N,N,N,N'-tetramethyluronium P0
tetrafluoroborate [1196] TEA, Et.sub.3N--triethylamine [1197]
TFA--trifluoroacetic acid [1198] THF--tetrahydrofuran [1199] TLC,
tlc--thin layer chromatography [1200] TMSCl trimethylsilyl chloride
or chlorotrimethylsilane [1201] UV--ultraviolet light
GENERAL SYNTHETIC SCHEMES AND EXAMPLES
[1202] The general synthetic schemes, starting materials, synthetic
intermediates and compounds (examples) representative of the
invention, ie., compounds of Formulas I-III, 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:
[1203] 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:
[1204] 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)
[1205] A typical run through the instrument included: eluting at 45
ml/min with a linear gradient of 10% (v/v) to 100% ACN (0.1% v/v
TFA) in water (0.1% TFA) over 10 minutes; conditions can be varied
to achieve optimal separations.
Proton NMR Spectra:
[1206] 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)
[1207] 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.
[1208] 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).
##STR00094## ##STR00095## ##STR00096## ##STR00097##
[1209] General Synthetic Scheme 1 describes an exemplary method for
preparing the key intermediate, aniline 1m. Beginning with Compound
1a, ketimine was converted to the corresponding sulfinamide using
(2-(tert-butoxy)-2-oxoethyl)zinc (II) chloride under suitable
conditions. The ester of Compound 1b was transformed to aldehyde by
either a two-step procedure (treatment with LiBH.sub.4 followed by
SO.sub.3-Pyridine) or reduction using DIBAL-H, to afford
intermediate 1c. The chiral auxiliary in 1c was removed with
PTSA/MeOH and the aldehyde converted to dimethyl acetal using
HCl/MeOH to give 1d. The treatment of 1d with PhCONCS followed by
heating in conc. sulfuric acid afforded thiazine 1e. The amino
group in 1e was protected with Boc and SEM to give 1f, which was
converted to ester 1g via a three-step procedure (lithiation,
carboxylic acid formation and esterification). Cyclopropanation of
1g gave a mixture 2 diastereomers, 1h (major product) and 1i (minor
product), which could be separated via silica gel chromatography in
most cases. Ester 1h was converted to aldehyde 1j (via treatment
with LiBH.sub.4 followed by SO.sub.3-Pyridine), which was treated
with chlorotris(triphenylphosphine)rhodium(I) (Wilkinson's) to
afford intermediate 1k.
[1210] Aniline 1m was derived from 1k (R.sup.4.dbd.H) via nitration
followed by nitro group reduction. In other cases, aniline 1m was
obtained from 1k (R.sup.4.dbd.Br) by a three-step procedure:
conversion of bromide to azide, azide reduction with
trimethylphosphine followed by removal of protecting groups with
TFA.
##STR00098##
##STR00099##
[1211] General Synthetic Scheme 3 describes exemplary methods for
preparing the biological testing Compounds 1n and 1o. Aniline 1m
was coupled with a carboxylic acid in the presence of
propylphosphonic anhydride (T3P) to afford amide 1n. Displacement
of the leaving group in 1q with aniline 1m in the presence of PTSA
gave Compound 1o. If aniline 1r was used instead of aniline 1m, an
acid (such as H.sub.2SO.sub.4 or PTSA) could be used to remove the
protecting groups (Boc and SEM) on the war head N-atom.
Syntheses of Intermediates
(R,Z)--N-(1-(2,3-Difluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sul-
finamide (201A)
##STR00100##
[1212] Preparation of 1-(2,3-difluorophenyl)-2-fluoroethanone
[1213] [Note: 3.times.10 g reactions were run separately. After
quenched with saturated NH.sub.4Cl, the reaction mixture were
combined and then purified.] To a solution of 1,2-difluorobenzene
(8.81 mL, 89 mmol) in THF (175 mL) at -78.degree. C. was added
dropwise n-BuLi (1.60 M in hexane, 61.50 mL, 98 mmol). After 2 h,
ethyl fluoroacetate (8.64 mL, 89 mmol) was added dropwise. The
reaction was stirred for 1 h at -78.degree. C. and quenched with
saturated NH.sub.4Cl and then warmed to RT. The three batches were
combined and extracted with EtOAc. The organic extracts were washed
with brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate
was concentrated and purified by silica gel column (0-30%
EtOAc/hexane) to afford 18.90 g of the desired product.
Preparation of Compound 201A
[1214] To a solution of 1-(2,3-difluorophenyl)-2-fluoroethanone
(18.9 g, 109.0 mmol) in THF (400 mL) was added
(R)-(+)-2-methyl-2-propanesulfinamide (26.3 g, 217.0 mmol) followed
by tetraisopropoxytitanium (93.0 g, 326.0 mmol). The reaction was
heated to reflux for 2 h. LCMS indicated complete consumption of
the starting ketone. The mixture was allowed to cool to room
temperature and then treated with brine (400 mL). The resulted
suspension was stirred for 15 min and filtered through Celite.RTM.
filter aid. The filter cake was washed with EtOAc. The filtrate was
extracted with EtOAc (2.times.). The organic extracts were washed
with brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate
was concentrated and purified by silica gel column (0-20%
EtOAc/hexanes) to afford
(R,E)-N-(1-(2,3-difluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sul-
finamide (12.3 g, 44.4 mmol, 40.9% yield) as a yellow oil.
Preparation of
(1S,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-3-amine (201)
##STR00101## ##STR00102##
[1215] Preparation of Compound 201B
[1216] 2-Tert-butoxy-2-oxoethylzinc chloride (0.5 M in THF, 24.2
mL, 12.1 mmol) was added dropwise over 5 min to a solution of
(R,Z)--N-(1-(2,3-difluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-su-
lfinamide (201A, 1.2 g, 4.33 mmol) in THF (15 mL) at 0.degree. C.
The solution was stirred at 0.degree. C. for 5 min then RT for 2 h.
The solution was then cooled back to 0.degree. C. and treated
dropwise with saturated aqueous ammonium chloride solution (7.5
mL), which resulted in a suspension. The suspension was filtered
through Celite.RTM. filter aid and the filter cake was washed with
EtOAc. The filtrate was concentrated in vacuo and the crude product
was adsorbed onto a plug of silica gel and purified by silica gel
chromatography, eluting with 0-50% EtOAc/hexanes gradient, to
provide (S)-tert-butyl
3-(2,3-difluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorobutan-
oate (201B, 1.55 g, 3.94 mmol, 91% yield) as an oil. LC/MS
(ESI.sup.-) m/z=394.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.24-7.31 (m, 1H) 7.08-7.21 (m, 2H) 5.37 (s,
1H) 5.17 (dd, J=47.14, 10.37 Hz, 1H) 4.86 (dd, J=46.56, 10.17 Hz,
1H) 3.20 (dd, J=16.24, 2.15 Hz, 1H) 3.01 (d, J=15.85 Hz, 1H)
1.37-1.41 (m, 9H) 1.25 (s, 9H).
Preparation of Compound 201C
[1217] Lithium borohydride (2.0 M solution in THF, 90.0 mL, 180.0
mmol) was added slowly over .about.6 min to a stirred solution of
(S)-tert-butyl
3-(2,3-difluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorobutan-
oate (201B, 35.4 g, 90.0 mmol) in THF (500 mL) in a 500 mL RBF
equipped with a thermometer. Anhydrous MeOH (29.2 mL, 720 mmol) was
then added over .about.4 min via addition funnel. The internal
temperature of the reaction rose to 41.degree. C. and bubbling
occurred. The reaction mixture was stirred for another 0.5 h, then
cooled to 0.degree. C. and quenched with saturated aqueous ammonium
chloride solution. The mixture was extracted two times with EtOAc
and the combined organic layers were washed with saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to provide
(R)--N--((S)-2-(2,3-difluorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-
-2-methylpropane-2-sulfinamide (201C, 27.8 g, 86 mmol, 96% crude
yield) as a white solid that was used without further purification.
LC/MS (ESI.sup.-) m/z=324.0 (M+H).sup.+.
[1218] N,N-Diisopropylethylamine (16.1 mL, 93 mmol) was added to a
stirred solution of
(R)--N--((S)-2-(2,3-difluorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2-methy-
lpropane-2-sulfinamide (10.00 g, 30.9 mmol, crude from reaction
above) in DCM (100 mL) and dimethyl sulfoxide (50.0 mL) at
-10.degree. C. Sulfur trioxide pyridine complex (7.38 g, 46.4 mmol)
was added in 4 portions over 8 min. The reaction mixture was
stirred at -10.degree. C. for another 8 min before being warmed to
0.degree. C. and stirred for 3 h. Additional sulfur trioxide
pyridine complex (0.74 g, 4.64 mmol) was added, and the reaction
mixture was stirred at 0.degree. C. for another 1 h. Additional
sulfur trioxide pyridine complex (1.48 g, 9.28 mmol) was added, and
the reaction mixture was stirred at 0.degree. C. for another 1 h.
Additional sulfur trioxide pyridine complex (2.96 g, 18.6 mmol) was
added, and the reaction mixture was stirred at 0.degree. C. for
another 1 h. The reaction mixture was diluted with water and
extracted with EtOAc. The organic layer was separated, washed with
saturated aqueous ammonium chloride, washed with saturated aqueous
sodium chloride solution, dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. The resulting material was
azeotroped with toluene to remove residual pyridine to give
(R)--N--((S)-2-(2,3-difluorophenyl)-1-fluoro-4-oxobutan-2-yl)-2-methylpro-
pane-2-sulfinamide as an oil (201C, 11.9 g, 37.0 mmol). LC/MS
(ESI.sup.-) m/z=322.1 (M+H).sup.+.
Preparation of Compound 201D
[1219] p-Toluenesulfonic acid monohydrate (0.35 g, 1.85 mmol) was
added to a stirred solution of the crude
(R)--N--((S)-2-(2,3-difluorophenyl)-1-fluoro-4-oxobutan-2-yl)-2-methylpro-
pane-2-sulfinamide (201C, 11.9 g, 37.0) in MeOH (150 mL). The
reaction mixture was heated to reflux for 3 h, then cooled to RT.
HCl (4.0 M solution in 1,4-dioxane, 9.25 mL, 37.0 mmol) was added.
The reaction mixture was stirred RT for 50 min, was partially
concentrated in vacuo, and then was quenched with saturated aqueous
sodium bicarbonate solution. The mixture was extracted with EtOAc
(2.times.), the combined organic extracts were washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. The
resulting oil was purified via silica gel chromatography, eluting
with 0-50% EtOAc/heptane gradient, to provide
(S)-2-(2,3-difluorophenyl)-1-fluoro-4,4-dimethoxybutan-2-amine
(201D, 6.25 g, 23.7 mmol, 64.1% yield for 2 steps) as a brown oil.
LC/MS (ESI.sup.-) m/z=264.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.36-7.44 (m, 1H) 7.07-7.19 (m, 2H) 4.68 (dd,
J=13.11, 8.80 Hz, 1H) 4.56 (ddd, J=13.11, 8.80, 4.11 Hz, 1H) 4.20
(dd, J=7.04, 4.30 Hz, 1H) 3.21 (d, J=4.89 Hz, 6H) 2.25-2.38 (m, 1H)
1.93-2.22 (m, 3H).
Preparation of Compound 201E
[1220] To a 1000 mL 3-neck RBF equipped with an internal
temperature probe was added
(S)-2-(2,3-difluorophenyl)-1-fluoro-4,4-dimethoxybutan-2-amine
(201D, 24.7 g, 94.0 mmol) and DCM (300 mL). The mixture was cooled
to 0.degree. C. and benzoyl isothiocyanate (13.9 mL, 103 mmol) was
added. After stirring at 0.degree. C. for 15 min, the mixture was
allowed to warm to RT and stirred for 2 h. The reaction was then
concentrated in vacuo to give a brown oil. Sulfuric acid (150 mL)
was added in 2 portions and then the mixture was stirred at
60.degree. C. for 6 h. The solution was cooled in an ice bath and
then poured into ice (2.times.2 L Erlenmeyer flasks, each with 700
mL ice in it) and these mixtures were carefully neutralized with
aqueous sodium hydroxide solution (10 N) while keeping the mixtures
near RT. The resulting solution was extracted with EtOAc,
(3.times.250 mL for each 2 L Erlenmeyer flask) and the combined
extracts were washed with water, saturated aqueous sodium chloride
solution, dried over anhydrous sodium sulfate, and then adsorbed
onto silica gel. Purification by silica gel chromatography, eluting
with 5-55% EtOAc/heptane gradient provided
(S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-amine
(201E, 19.8 g, 76.0 mmol, 82% yield) as a tan solid. LC/MS
(ESI.sup.-) m/z=259.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.29-7.39 (m, 1H) 7.14-7.25 (m, 2H) 6.60-6.73
(m, 3H) 6.27 (dd, J=9.59, 5.48 Hz, 1H) 4.35-4.78 (m, 2H).
Preparation of Compound 201F
[1221] To a 2000 mL, 3-neck, RBF equipped with an internal
temperature probe was added
(S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-amine
(201E, 19.7 g, 76 mmol) and THF (300 mL). di-tert-Butyl dicarbonate
(21.6 g, 99 mmol) was then added in portions, then the mixture was
heated at 50.degree. C. for 15 h. Additional di-tert-butyl
dicarbonate (3.2 g) was added, and the material was stirred for 2 h
at 50.degree. C. The mixture was allowed to cool to RT and then was
concentrated in vacuo. Purification by silica gel chromatography,
eluting with 0-40% EtOAc/hexane gradient, provided (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)carbamate
(201F, 26.5 g, 73.8 mmol, 97% yield LC/MS (ESI.sup.-) m/z=359.3
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.46 (br.
s., 1H) 7.18-7.42 (m, 3H) 6.69 (d, J=9.78 Hz, 1H) 6.18 (dd, J=9.00,
4.11 Hz, 1H) 4.47-4.83 (m, 2H) 1.44 (s, 9H).
Preparation of Compound 201G
[1222] To a 1000 mL RBF equipped with an internal temperature probe
was added (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)carbamate
(201F, 26.4 g, 73.7 mmol) and THF (220 mL). The mixture was cooled
to -10.degree. C. and lithium bis(trimethylsilyl)amide (1.0 M
solution in THF, 81.0 mL, 81.0 mmol) was added over 5 min, keeping
the internal temperature below -9.degree. C. After the addition was
complete, the solution was stirred at -10.degree. C. for 20 min and
then 2-(trimethylsilyl)ethoxymethyl chloride (14.3 mL, 81.0 mmol)
in 20 mL THF was added slowly, keeping the temperature below
-9.degree. C. The solution was stirred for 5 min at -10.degree. C.
and then the cooling bath was removed and the solution was allowed
to warm to RT. After 2 h, the solution was quenched with saturated
aqueous ammonium chloride solution and the resulting mixture was
extracted with EtOAc. The organic extracts were washed with
saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and adsorbed onto silica. Purification by silica
gel chromatography, eluting with 0 to 20% EtOAc/heptane gradient,
provided (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)((2-(trimeth-
ylsilyl)ethoxy)methyl)carbamate (201G, 32.4 g, 66.3 mmol, 90%
yield) as a colorless oil. LC/MS (ESI.sup.-) m/z=510.9
(M+Na).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.41 (dd,
J=9.88, 2.25 Hz, 1H) 7.16-7.25 (m, 2H) 6.83 (d, J=9.39 Hz, 1H) 6.18
(dd, J=9.39, 4.11 Hz, 1H) 5.19 (s, 2H) 4.59-4.90 (m, 2H) 3.57 (t,
J=8.02 Hz, 2H) 1.46 (s, 9H) 0.78-0.90 (m, 2H) -0.04 (s, 9H).
Preparation of Compound 201H
[1223] Lithium diisopropylamide (2.0 M solution in
THF/heptane/ethylbenzene) (2.58 mL, 5.16 mmol) was added dropwise
to a -78.degree. C. solution of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)((2-(trimeth-
ylsilyl)ethoxy)methyl)carbamate (201G, 1.94 g, 3.97 mmol) in THF
(18 mL). The mixture was stirred for 45 min before CO.sub.2 gas was
bubbled through the reaction at -78.degree. C. After 3 min, the
cold bath was removed, the addition of CO.sub.2 was stopped, and
the mixture was warmed to RT. The reaction was then quenched with
saturated aqueous ammonium chloride solution, and the product was
extracted into EtOAc (3.times.). The combined extracts were washed
with aqueous HCl solution (1 M, 2.times.), saturated aqueous sodium
chloride solution (1.times.), dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give a yellow
oil.
[1224] The oil was dissolved in (9:1) THF/MeOH (20 mL) and the
mixture was cooled to 0.degree. C. (Trimethylsilyl)diazomethane
(2.0 M in hexanes, 3.97 mL, 7.94 mmol) was added dropwise. This
mixture was stirred for 30 min, at which time HOAc (0.92 mL, 32.9
mmol) was added dropwise. The mixture was stirred at that
temperature until the solution became colorless. EtOAc and water
were added, the layers were separated, and the aqueous layer was
extracted with EtOAc (1.times.). The combined extracts were washed
with saturated aqueous sodium bicarbonate solution, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to
give a yellow oil. The oil was purified by silica gel
chromatography, eluting with 0 to 50% EtOAc/heptane gradient, to
give (S)-methyl
2-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-4-(2,3-d-
ifluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazine-6-carboxylate
(201H, 1.63 g, 3.0 mmol, 75% yield) as a colorless oil. LC/MS
(ESI.sup.-) m/z=547.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.17-7.17 (m, 1H) 6.98-7.25 (m, 3H) 5.29-5.36
(m, 2H) 4.90 (dd, J=46.95, 8.61 Hz, 1H) 4.68 (dd, J=47.14, 9.00 Hz,
1H) 3.84 (s, 3H) 3.65 (t, J=8.22 Hz, 2H) 1.54 (s, 9H) 0.89-0.96 (m,
2H) -0.01 (s, 9H).
Preparation of Compound 201I and Compound 202I
Preparation of Corey-Chaykovsky Reagent
[1225] Potassium tert-butoxide (3.42 g, 30.5 mmol) was added to a
stirred suspension of trimethylsulfoxonium iodide (7.32 g, 33.3
mmol) in DMSO (27 mL) under an argon atmosphere at RT. The mixture
was stirred for 1 h before being used as described below.
[1226] The ylide solution (13.5 mL, 15.3 mmol) was added to a
stirred solution of (S)-methyl
2-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-4-(2,3-d-
ifluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazine-6-carboxylate
(201H, 7.58 g, 13.87 mmol) in dimethyl sulfoxide (27 mL) under an
argon atmosphere. The reaction mixture was stirred at RT for 1.5 h.
An additional 2.0 mL of the ylide solution was added, and the
reaction mixture was stirred for another 2.5 h. The reaction
mixture was then quenched with saturated aqueous ammonium chloride
solution and then extracted with EtOAc. The organic extracts were
washed with water, saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate, filtered, and concentrated in vacuo to
give an oil. The oil was purified via silica gel chromatography,
eluting with 0 to 20% EtOAc/heptane gradient to provide
(1S,5S,6S)-methyl 3-((tert-butoxycarbonyl)((2-(trimethylsilyl)
ethoxy)methyl)amino)-5-(2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-ene-1-carboxylate (201I, 5.60 g, 10.0 mmol,
72% yield) and (1R,5S,6R)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-car-
boxylate (202I, 0.95 g, 1.70 mmol, 12% yield).
[1227] 201I: LC/MS (ESI.sup.-) m/z=561.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.46 (t, J=7.14 Hz, 1H) 7.08-7.20
(m, 2H) 5.31 (d, J=10.37 Hz, 1H) 5.08 (d, J=10.56 Hz, 1H) 4.72-5.02
(m, 2H) 3.81 (s, 3H) 3.65 (t, J=8.22 Hz, 2H) 2.68 (t, J=8.80 Hz,
1H) 1.62 (dd, J=9.98, 5.28 Hz, 1H) 1.51-1.56 (m, 9H) 1.14 (dd,
J=7.24, 5.48 Hz, 1H) 0.87-0.99 (m, 2H) 0.01 (s, 9H).
[1228] 202I: LC/MS (ESI.sup.-) m/z=561.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 7.02-7.18 (m, 3H) 5.24 (d, J=10.37
Hz, 1H) 5.07 (d, J=10.37 Hz, 1H) 4.92 (dd, J=46.95, 8.61 Hz, 1H)
4.71 (dd, J=46.95, 8.80 Hz, 1H) 3.80 (s, 3H) 3.58 (dd, J=9.00, 7.43
Hz, 2H) 2.85 (dd, J=9.88, 7.34 Hz, 1H) 1.73 (dd, J=9.78, 5.48 Hz,
1H) 1.59-1.64 (m, 1H) 1.51 (s, 9H) 0.89 (dd, J=9.10, 7.34 Hz, 2H)
-0.01-0.02 (m, 9H).
Preparation of Compound 201J
[1229] Lithium borohydride (2.0 M solution in THF, 9.9 mL, 19.8
mmol) was added slowly over .about.3 min to a stirred solution of
(1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-car-
boxylate (201I, 5.54 g, 9.9 mmol) in THF (60 mL) at RT under a
nitrogen atmosphere. Anhydrous MeOH (3.20 mL, 79 mmol) was then
added over .about.1 min. The reaction mixture was stirred for 30
min, cooled to 0.degree. C., and then saturated aqueous sodium
chloride. The mixture was extracted with EtOAc (2.times.), then the
combined extracts were washed with aqueous HCl solution (1 N),
washed with saturated aqueous sodium bicarbonate solution,
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo to provide
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)ca-
rbamate (5.93 g) as a colorless oil.
[1230] TEA (5.50 mL, 39.5 mmol) was added slowly via syringe to a
stirred solution of tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)ca-
rbamate (5.93 g, obtained from above reaction) in DCM (20 mL) and
dimethyl sulfoxide (20 mL). Sulfur trioxide pyridine complex (3.15
g, 19.8 mmol) was added, and the reaction mixture was stirred at RT
for 1 h. The reaction mixture was diluted with water and extracted
with EtOAc. The organic extracts were combined and then washed with
saturated aqueous ammonium chloride solution, water, saturated
sodium chloride solution, then dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to give an oil. The
resulting crude product was purified via silica gel chromatography,
eluting with 0 to 30% EtOAc/heptane gradient to provide tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(201J, 4.88 g, 9.2 mmol, 93% yield for 2 steps) LC/MS (ESI.sup.-)
m/z=531.2 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.16 (s, 1H) 7.40-7.45 (m, 1H) 7.08-7.21 (m, 2H) 5.34 (d, J=10.37
Hz, 1H) 5.14 (d, J=10.56 Hz, 1H) 4.92 (dd, J=46.75, 8.61 Hz, 1H)
4.72 (dd, J=46.75, 8.61 Hz, 1H) 3.66 (t, J=8.31 Hz, 2H) 2.57 (t,
J=8.71 Hz, 1H) 1.81 (dd, J=9.98, 5.67 Hz, 1H) 1.52-1.57 (m, 9H)
1.27 (dd, J=7.43, 5.67 Hz, 1H) 0.83-1.05 (m, 2H) -0.01-0.03 (m,
9H).
Preparation of Compound 201K
[1231] Chlorotris(triphenylphosphine)rhodium(I) (4.26 g, 4.61 mmol)
was added to a stirred solution of tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(201J, 1.63 g, 3.07 mmol) in 1,2-dichloroethane (20 mL). The
reaction mixture was heated to 80.degree. C. and stirred for 6 h.
The reaction mixture was concentrated in vacuo and the resulting
reddish-brown sludge was triturated in heptane and then filtered
through Celite.RTM. filter aid. The filter cake was washed multiple
times with 9:1 EtOAc/heptane, then with DCM. The filtrate was
concentrated in vacuo, slurried in DCM, and filtered. The yellow
solid that was collected was discarded, and the filtrate was again
concentrated in vacuo to give a brown oil. Heptane was added, the
resulting suspension was filtered, and the collected solid was
discarded. The filtrate was concentrated to give crude product,
which was purified via silica gel chromatography, eluting with 0 to
20% EtOAc/heptane gradient to give tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(201K, 1.54 g, 1.99 mmol, 65% yield) as a colorless oil. LC/MS
(ESI.sup.-) m/z=503.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.43 (t, J=7.24 Hz, 1H) 7.06-7.17 (m, 2H)
5.30 (d, J=10.56 Hz, 1H) 5.07 (d, J=10.56 Hz, 1H) 4.73-5.02 (m, 2H)
3.62-3.69 (m, 2H) 2.24-2.31 (m, 1H) 2.00-2.07 (m, 1H) 1.53 (s, 9H)
1.05 (ddd, J=9.15, 7.48, 5.87 Hz, 1H) 0.94 (dd, J=9.10, 7.53 Hz,
2H) 0.65 (q, J=5.87 Hz, 1H) -0.02-0.03 (m, 9H).
Preparation of Compound 201L
[1232] At RT, concentrated sulfuric acid (5 mL, 94 mmol) was added
to tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(201K, 1.00 g, 1.99 mmol). The mixture was stirred at RT for 15
min, then cooled to 0.degree. C. Sodium nitrate (0.24 g, 2.79 mmol)
was added. The reaction mixture was warmed to RT and stirred for 1
h. The reaction mixture was poured into ice and diluted with DCM.
K.sub.3PO.sub.4 (20 g) was added in portions over 15 min, and the
mixture was then brought to pH 7-8 with aqueous NaOH solution (10
N). The resulting biphasic mixture was separated, and the aqueous
layer was extracted DCM (2.times.). The combined organic extracts
were dried over anhydrous magnesium sulfate, filtered, and
concentrated in vacuo to give an oil. This oil was purified via
silica gel chromatography, eluting with 0 to 50% EtOAc/heptane
gradient to provide
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-5-(fluoromethyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-3-amine (201L, 0.54 g, 1.67 mmol, 85% yield)
as a light yellow solid. LC/MS (ESI.sup.-) m/z=318.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.51-8.56 (m, 1H) 8.05
(ddd, J=9.05, 6.41, 2.93 Hz, 1H) 4.73 (d, J=4.11 Hz, 4H) 2.25-2.36
(m, 1H) 1.92-2.06 (m, 1H) 1.07-1.18 (m, 1H) 0.66 (q, J=5.74 Hz,
1H).
Preparation of Compound 201
[1233] Zinc (nanopowder, 1.73 g, 26.5 mmol) was added to a stirred
mixture of
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-5-(fluoromethyl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-amine (201L, 1.68 g, 5.29 mmol) in HOAc
(12 mL) and trifluroacetic acid (6 mL). The reaction mixture was
stirred at RT for 45 min, then filtered through Celite.RTM. filter
aid. The filtrate was diluted with EtOAc and treated with saturate
sodium bicarbonate solution, and then the mixture was taken to
pH.about.7 w/aqueous sodium NaOH (10 N). The organic layer was
separated, and the aqueous layer was extracted once more with
EtOAc. The combined organic extracts were washed with saturated
sodium chloride solution, dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo. The resulting crude product
was purified via silica gel chromatography, eluting with 0 to 10%
MeOH/DCM gradient. The collected product was then dissolved in
EtOAc and then washed two times with saturated sodium carbonate
solution. The resulting organic solution was then washed with
saturated sodium chloride solution, dried over anhydrous magnesium
sulfate, filtered, and concentrated in vacuo to provide
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-3-amine (201, 1.29 g, 4.49 mmol, 85% yield)
as a yellow solid. LC/MS (ESI.sup.-) m/z=288.0 (M+H).sup.+. .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 6.66 (dt, J=4.84, 2.57 Hz,
1H) 6.38-6.45 (m, 1H) 4.78 (s, 4H) 3.61 (br. s., 2H) 2.26-2.34 (m,
1H) 1.78-1.89 (m, 1H) 1.05-1.14 (m, 1H) 0.53 (d, J=5.87 Hz,
1H).
(1R,5S,6R)-5-(5-Amino-2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-3-amine (202)
##STR00103##
[1235] This compound was prepared from 202I using the chemical
procedures similar to that described for intermediate 201. LC/MS
(ESI.sup.-) m/z=288.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 6.38-6.49 (m, 2H) 4.68-4.76 (m, 1H)
4.50-4.66 (m, 1H) 3.65 (br. s., 2H) 2.05-2.18 (m, 1H) 1.94-2.05 (m,
1H) 1.02-1.11 (m, 2H).
(R,E)-N-(1-(2,3-Difluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide
(203A)
##STR00104##
[1237] To a solution of 2,3-difluoroacetophenone (25.0 g, 160 mmol)
in THF (500 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide
(38.8 g, 320 mmol) followed by tetraisopropoxytitanium (142 mL, 480
mmol). The reaction was heated to reflux for 3 d. The mixture was
allowed to cool to RT and then treated with brine (550 mL). The
resulted suspension was stirred for 15 min and filtered through a
pad of Celite.RTM. filter aid. The filter cake was washed with
EtOAc. The filtrate was extracted with EtOAc (2.times.). The
organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and
purified by silica gel column (10-35% EtOAc/hexanes) to afford
(R,E)-N-(1-(2,3-difluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide
(203A, 35.6 g, 137 mmol, 86% yield) as yellow oil. MS m/z=260.1
[M+H].sup.+.
(1S,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-3-amine (203)
##STR00105## ##STR00106##
[1238] Preparation of Compound 203B
[1239] To a 3000 mL 3-neck RBF equipped with an addition funnel and
internal temperature probe was added
(R,E)-N-(1-(2,3-difluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide
(203A, 30 g, 116 mmol) and THF (450 mL). The mixture was cooled to
0.degree. C. and 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in
Et.sub.2O, 463 mL, 231 mmol) was added dropwise over 2 h keeping
the internal temperature under 2.degree. C. The reaction mixture
stayed homogeneous. After the addition was completed, the ice bath
was allowed to melt (about 2-3 h) and warm to RT overnight. The
reaction mixture was cooled with an ice bath and carefully quenched
with the slow addition sat. NH.sub.4Cl (200 mL). It was extracted
with EtOAc (3.times.250 mL). The combined extracts were washed with
brine (50 mL), dried (Na.sub.2SO.sub.4) and concentrated onto
silica. Purification by silica gel chromatography (5-35%
EtOAc/hexanes) afforded (S)-tert-butyl
3-(2,3-difluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate
(203B, 30.2 g, 80 mmol, 69.5% yield) as a colorless oil. LC/MS
(ESI.sup.-) m/z=376.1 (M+H).sup.+.
Preparation of Compound 203C
[1240] To a solution of (S)-tert-butyl
3-(2,3-difluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate
(203B, 11.6 g, 31.0 mmol) in 150 mL of THF in a 500 mL 3-neck RBF
equipped with an internal temperature probe at RT was added lithium
borohydride (2.0 M solution in THF, 31.0 mL, 62.0 mmol) over 5 min.
Anhydrous MeOH (10.0 mL, 248 mmol) was then added to the mixture
slowly over 5 min. The internal temperature of the reaction rose to
37.degree. C., and gentle bubbling ensued. The mixture was stirred
for 60 min. The reaction was chilled to 0.degree. C. and slowly
quenched with 80 mL of aq. NH.sub.4Cl. The mixture was then
extracted with 3.times.150 mL of EtOAc. The combined organic
extracts were dried over MgSO.sub.4, filtered, and concentrated in
vacuo to give
(R)--N--((S)-2-(2,3-difluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane--
2-sulfinamide (9.7 g) as an off-white amorphous solid which was
used without further purification. LC/MS (ESI.sup.-) m/z=306.2
(M+H).sup.+. N,N-diisopropylethylamine (21.6 mL, 124 mmol) was
added dropwise via a syringe to a solution of
(R)--N--((S)-2-(2,3-difluorophenyl)-4-hydroxybutan-2-yl)-2-methylpropane--
2-sulfinamide (9.7 g crude from above reaction) in DCM (60 mL) and
DMSO (30 mL) in 1000 mL RBF at -10.degree. C. Pyridine sulfur
trioxide (7.9 g, 49.6 mmol) was added in three portions over 1 min.
The mixture was stirred for 5 min, and then the cooling bath was
replaced with an ice bath. The mixture was stirred for 5 h at
.about.0.degree. C. It was treated with water (50 mL) and extracted
with 3.times.200 mL of DCM. The combined organic extracts were
washed with saturated aqueous NH.sub.4Cl (50 mL) followed by brine
(25 mL), and dried over sodium sulfate. The solution was filtered
and concentrated in vacuoto give the crude material. It was
adsorbed onto a plug of silica gel and chromatographed through a
Redi-Sep pre-packed silica gel column (220 g), eluting with a
gradient of 1-5% MeOH in DCM, to provide
(R)--N--((S)-2-(2,3-difluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-su-
lfinamide (203C, 9.6 g, 31.6 mmol, 102% yield) as an amorphous
solid. LC/MS (ESI.sup.-) m/z=304.1 (M+H).sup.+.
Preparation of Compound 203D
[1241] To a 1000 mL RBF equipped with a reflux condenser was added
(R)--N--((S)-2-(2,3-difluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-su-
lfinamide (203C, 9.40 g, 31 mmol), MeOH (80 mL) and
p-toluenesulfonic acid monohydrate (0.295 g, 1.550 mmol). The
reaction mixture was stirred at 65.degree. C. for 18 h. It was
cooled to RT and treated with HCl (4.0 M solution in 1,4-dioxane,
8.14 mL, 32.6 mmol) dropwise. After the reaction mixture was
stirred at RT for 3 h, it was concentrated in-vacuo, then diluted
with 300 mL of chloroform and treated with 50 mL of sat. aq.
NaHCO.sub.3. The layers were separated and the aqueous layer was
extracted with chloroform (2.times.100 mL). The combined organic
extracts were washed with 10 mL of brine, dried over magnesium
sulfate, filtered and concentrated in-vacuo to give light yellow
oil. It was purified by silica gel chromatography (2.times.110 g
Thomson column using a gradient of 1-8% MeOH in CH.sub.2Cl.sub.2)
to provide (S)-2-(2,3-difluorophenyl)-4,4-dimethoxybutan-2-amine
(203D, 6.05 g, 24.67 mmol, 80% yield) as a yellow oil. LC/MS
(ESI.sup.-) m/z=246.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.30 (m, 1H), 7.07 (m, 2H), 4.10 (m, 1H),
3.21 (s, 3H), 3.18 (s, 3H), 2.25-2.44 (m, 1H), 2.08 (m, 1H), 1.93
(br., 2H), 1.54 (s, 3H). .sup.19F NMR (376 MHz, CHLOROFORM-d)
.delta. -137.63 (d, J=20.16 Hz, 1 F), -139.03 (d, J=19.51 Hz, 1
F).
Preparation of Compound 203E
[1242] To a stirring solution of
(S)-2-(2,3-difluorophenyl)-4,4-dimethoxybutan-2-amine (203D, 6.08
g, 24.79 mmol) in CH.sub.2Cl.sub.2 (50 mL) at 0.degree. C. under
nitrogen was added a solution of benzoyl isothiocyanate (4.45 g,
27.3 mmol) in CH.sub.2Cl.sub.2 (12 mL) dropwise. It was stirred at
0.degree. C. for 20 min, and then treated with MeOH (1 mL). The
solvents were removed under reduced pressure to afford a tan syrup.
To the tan syrup at 0.degree. C. was added neat sulfuric acid (29.1
ml, 545 mmol). The warmed solution was stirred for 20 min then
heated to 50.degree. C. for 22 h. The reaction was cooled to RT
then poured onto 200 g of ice. To the slurry was added
CH.sub.2Cl.sub.2 (200 mL), the biphasic solutions were chilled to
0.degree. C. with external wet ice bath, then basified to pH=14
with very slow addition of 10 M NaOH. The organic layer was
separated and the aqueous was extracted with 9:1 CHCl.sub.3/IPA
(2.times.50 mL). The combined organics were dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (160 g) using a gradient of
20-75% EtOAc in hexanes to afford
(S)-4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine (203E,
3.24 g, 13.48 mmol, 54% yield) as a brown amorphous solid. LC/MS
(ESI.sup.-) m/z=241.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.19 (t, J=7.24 Hz, 1H), 6.98-7.09 (m, 2H),
6.26-6.32 (m, 2H), 5.00-4.00 (br., 2H), 1.74 (s, 3H). .sup.19F NMR
(377 MHz, CHLOROFORM-d) .delta. -138.00 (d, J=20.27 Hz, 1 F),
-138.75 (d, J=20.27 Hz, 1 F).
Preparation of Compound 203F
[1243] A solution of
(S)-4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine (203E,
3.06 g, 12.74 mmol) and 4-(dimethylamino)pyridine (0.039 g, 0.318
mmol) in THF (50 mL) at RT was treated with di-tert-butyl
dicarbonate (6.11 g, 28.0 mmol) in THF (10 mL) slowly via a
syringe. The solution was heated to 50.degree. C. in an oil bath
for 1 h. The LCMS suggested full conversion to the di-Boc. The
reaction mixture was cooled to 12.degree. C. and treated with water
(10 mL), lithium hydroxide monohydrate (1.603 g, 38.2 mmol), and
MeOH (10 mL). The reaction was heated to 50.degree. C. for 30 min.
The LCMS suggested 100% conversion to the mono-Boc. The reaction
was then partitioned between EtOAc (150 mL) and water (20 mL). Some
white solid precipitated from the mixture. It was filtered through
a fritted funnel. The solid was discarded (LCMS indicated no
desired product). The filtrate was transferred to a separatory
funnel. The aqueous was discarded. The organic layer was washed
with 5 mL of brine, dried over sodium sulfate and concentrated. The
residue was purified on a silica gel column (15-45% EtOAc in
hexanes) to give (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(203F, 4.28 g, 12.57 mmol, 99% yield) as a viscous brown oil. LC/MS
(ESI.sup.-) m/z=341.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 10.5 (br., 1H), 7.01-7.16 (m, 3H), 6.14-6.29
(m, 2H), 1.79 (br., 3H), 1.52 (s, 9H).
Preparation of Compound 203G
[1244] To a stirring solution of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(203F, 4.20 g, 12.34 mmol) in THF (50 mL) at -12.degree. C. (wet
ice/acetone) under nitrogen was added lithium
bis(trimethylsilyl)amide (1.0 M solution in THF, 16.04 mL, 16.04
mmol) at a rate not to exceed an internal temp of -5.degree. C.
After 15 min at -7.degree. C., to the reaction mixture was added a
solution of 2-(trimethylsilyl)ethoxymethyl chloride (2.84 mL, 16.04
mmol) in THF (10 mL) at a rate that did not exceed an internal temp
of -2.degree. C. After 15 min the cooling bath was removed and the
reaction mixture became a clear solution. The reaction was run for
18 h at RT. The reaction was quenched with sat NH.sub.4Cl (20 mL)
and extracted with EtOAc (2.times.100 mL). The organic solution was
washed with brine (10 mL), dried over MgSO.sub.4, concentrated
under reduced pressure. The residue was purified by silica gel
chromatography (5% EtOAc/Hextanes) to afford (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethylsilyl)-
ethoxy)methyl)carbamate (203G, 5.3 g, 11.26 mmol, 91% yield) as
viscous yellow oil. LC/MS (ESI.sup.-) m/z=471.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.23 (m, 1H), 7.08 (m,
2H), 6.33 (d, J=9.19 Hz, 1H), 6.08 (dd, J=3.42, 9.29 Hz, 1H), 5.32
(d, J=10.37 Hz, 1H), 5.23 (d, J=10.56 Hz, 1H), 3.67 (m, 2H), 1.73
(s, 3H), 1.54 (s, 9H), 0.94 (m, 2H), 0.00 (s, 9H). .sup.19F NMR
(377 MHz, CHLOROFORM-d) .delta. -138.14 (d, J=20.27 Hz, 1 F),
-138.73 (d, J=20.27 Hz, 1 F).
Preparation of Compound 203H
[1245] To a stirring solution of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethylsilyl)-
ethoxy)methyl) carbamate (203G, 10.6 g, 22.5 mmol) in THF (100 mL)
at -70.degree. C. was added lithium diisopropylamide (2.0 M in
heptane/THF/ethylbenzene, 13.51 mL, 27.0 mmol) at a rate that did
not exceed -68.degree. C. The dark solution was stirred for 20 min
at -72.degree. C. The reaction was then exposed to a gentle stream
of carbon dioxide from a lecture bottle in the head space of the
stirring solution (not submerged). The internal temp slowly climbed
to -60.degree. C. After 7 min the carbon dioxide stream was removed
and internal temp was -65.degree. C. The reaction was then slowly
quenched with sat. NH.sub.4Cl (10 mL). Once the suspension reached
5.degree. C., 1 M KH.sub.2PO.sub.4 (100 mL) was added. After the
bubbling subsided, the reaction was partitioned between EtOAc (400
mL) and 1 M KH.sub.2PO.sub.4 (100 mL). The organic layer was
separated, washed with brine (2.times.100 mL), dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
afford the acid as colorless oil. The oil was dissolved in THF (100
mL) and MeOH (10 mL), chilled to 16.degree. C. under nitrogen and
(trimethylsilyl)diazomethane (2 M in hexanes, 28.2 mL, 56.3 mmol)
added at a rate not to exceed 22.degree. C. The reaction was
stirred for 30 min then quenched with glacial HOAc (10 mL) with
reaction at 6.degree. C. The quench is exothermic with temp surging
to 19.degree. C. and gas evolution evident. The reaction was then
partitioned between 1:1 EtOAc/heptane (500 mL) and 1 M
KH.sub.2PO.sub.4 (100 mL). The organic layer was further washed
with both 5% NaHCO.sub.3 (100 mL) and brine (50 mL). The organic
layer was dried over MgSO.sub.4, filtered and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (330 g) eluting with a gradient of 0-10%
EtOAc/heptane to afford (S)-methyl
2-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-4-(2,3-d-
ifluorophenyl)-4-methyl-4H-1,3-thiazine-6-carboxylate (203H, 10.9
g, 20.62 mmol, 92% yield) as a colorless oil. LC/MS (ESI.sup.-)
m/z=529.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 7.27-7.33 (m, 1H), 7.01-7.13 (m, 3H), 5.30 (dd, J=10.37, 6.06
Hz, 1H), 5.18-5.23 (m, 1H), 3.82 (s, 3H), 3.62-3.68 (m, 2H), 1.76
(s, 3H), 1.52-1.55 (m, 9H), 0.86-0.95 (m, 2H), -0.01 (m, 9H).
Preparation of Compound 203I
[1246] Corey-Chaykovsky Reagent [0.2 M in DMSO] was prepared in
this fashion: To a stirring solution of trimethylsulfoxonium iodide
(8.39 g, 38.1 mmol) in dimethyl sulfoxide (200 mL) at 20.degree. C.
was added potassium tert-butoxide (4.28 g, 38.1 mmol) in one
portion. The internal temperature increased to 22.degree. C. The
solution was stirred for 1 h.
[1247] To a stirring solution of (S)-methyl
2-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-4-(2,3-d-
ifluorophenyl)-4-methyl-4H-1,3-thiazine-6-carboxylate (203H, 15.5
g, 29.3 mmol) in THF (200 mL) at 20.degree. C. under nitrogen was
added freshly prepared Corey-Chaykovsky Reagent [0.2 M in DMSO]
dropwise via addition funnel over a 10 min period. The reaction
remained in the 21-23.degree. C. temperature range. After stirring
at RT for 30 min, the reaction mixture was quenched with sat.
NH.sub.4Cl (50 mL) dropwise and diluted with water (400 mL). The
reaction mixture was extracted with 3:1 heptane/EtOAc (600 mL). The
aqueous was further extracted with 1:1 heptane/EtOAc (10 mL). The
organics were washed with water (200 mL) then brine (50 mL), dried
over MgSO.sub.4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (330 g) loading
material on with heptane and eluting products with 0-10%
EtOAc/heptane gradient to afford (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 12.7 g, 23.40 mmol, 80% yield) as colorless oil. LC/MS
(ESI.sup.-) m/z=543.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 7.37 (t, J=6.75 Hz, 1H) 7.01-7.12 (m, 2H)
5.26 (d, J=10.56 Hz, 1H) 5.01 (d, J=10.56 Hz, 1H) 3.78 (s, 3H)
3.59-3.69 (m, 2H) 2.61 (dd, J=8.71, 7.92 Hz, 1H) 1.76 (s, 3H)
1.50-1.55 (m, 9H) 1.46-1.50 (m, 1H) 1.21 (dd, J=7.43, 5.28 Hz, 1H)
0.90-0.96 (m, 2H) -0.03-0.00 (m, 9H).
Preparation of Compound 203J
[1248] At RT, a solution of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 4.1 g, 7.55 mmol) in 60 mL of THF was treated with lithium
borohydride (2 M solution in THF) (7.55 mL, 15.11 mmol) followed by
MeOH (2.45 mL, 60.4 mmol). The mixture was stirred for 1 h at RT
then cooled with an ice bath, and quenched with the dropwise
addition of 10 mL of aq. NH.sub.4Cl. The resulting biphasic mixture
was extracted with (3.times.50 mL) of EtOAc. The organic extracts
were washed sequentially with 10 mL of ice cold 1 N HCl, 5 mL of 1
N NaOH and 5 mL of brine, and dried over MgSO.sub.4. It was
filtered and concentrated under reduced pressure to provide
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(3.68 g, 7.15 mmol, 95% yield) as a clear viscous oil which was
used without further purification. LC/MS (ESI.sup.-) m/z=515.2
(M+H).sup.+. At RT, the above obtained crude tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(3.36 g, 6.53 mmol) was taken up in 25 mL of DCM and 8.3 mL of
DMSO. The solution was treated with Hunig's base (4.54 mL, 26.1
mmol) followed by pyridine-sulfur trioxide complex (2.078 g, 13.06
mmol). After 15 h, the mixture was diluted with 100 mL of DCM and
washed with (2.times.15 mL) of sat. NH.sub.4Cl followed by 10 mL of
brine, then dried over MgSO.sub.4. Filtration and concentration
under reduced pressure afforded a yellow oil which was purified on
a silica gel column (10-35% EtOAc in Hexanes) to provide tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-formyl-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(203J, 2.79 g, 5.44 mmol, 83% yield) as a yellow oil. LC/MS
(ESI.sup.-) m/z=513.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.91 (br., 1H), 7.45 (m, 2H), 7.27 (m, 1H),
5.19 (d, J=10.56 Hz, 1H), 5.00 (d, J=10.76 Hz, 1H), 3.58-3.65 (m,
2H), 2.82 (m, 1H), 1.87 (dd, J=5.87, 9.78 Hz, 1H), 1.71 (s, 3H),
1.50 (s, 9H), 1.25-1.40 (m, 2H), 0.90 (m, 1H), 0.02 (s, 9H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -139.15 (d, J=21.40
Hz, 1 F), -139.46 (d, J=21.46 Hz, 1 F).
Preparation of Compound 203K
[1249] To a stirring solution of tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-formyl-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(203J, 2.0 g, 3.90 mmol) in 1,2-dichloroethane (23.05 mL) at
20.degree. C. under nitrogen was added
chlorotris(triphenylphosphine)rhodium(i) (Wilkinson's reagent, 5.41
g, 5.85 mmol) then heated to vigorous reflux under nitrogen. After
3 h the LCMS suggested 80% conversion. To the reaction mixture was
added more Wilkinson's reagent (2.5 g) and returned to reflux for 1
h. It was cooled to RT and the solvents were removed under reduced
pressure. The residue was triturated in 6:1 heptane/EtOAc (75 mL)
by stirring for 20 h. The solid was further triturated in 6:1
heptane/EtOAc (2.times.50 mL) with the aid of sonication each time
capturing the solid through a bed of Celite.RTM. filter aid. The
resulting filtrate was concentrated under reduced pressure. The
resulting oil/solid was further triturated in 6:1 heptane/EtOAc
(2.times.50 mL) with the aid of sonication each time capturing the
solid through a bed of Celite.RTM. filter aid. The resulting
filtrate was concentrated under reduced pressure, loaded onto
silica with heptane, then purified by silica gel chromatography (80
g) eluting with a gradient of 0-10% EtOAc/heptane to afford
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-formyl-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(203K, 2.0 g, 3.90 mmol) as colorless oil. LC/MS (ESI.sup.-)
m/z=485.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 7.32-7.40 (m, 1H), 6.99-7.10 (m, 2H), 5.26 (d, J=10.56 Hz, 1H),
5.01 (d, J=10.37 Hz, 1H), 3.60-3.70 (m, 2H), 2.19 (td, J=8.36, 4.99
Hz, 1H), 1.94-2.05 (m, 1H), 1.78 (s, 3H), 1.51 (s, 9H), 0.90-0.98
(m, 2H), 0.83-0.90 (m, 1H), 0.70 (q, J=5.74 Hz, 1H), 0.00 (s,
9H).
Preparation of Compound 203L
[1250] At 0.degree. C., to tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hep-
t-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl) carbamate (203K,
1.29 g, 2.66 mmol) was added H.sub.2SO.sub.4 (6.38 mL, 120 mmol).
After 15 min, the ice bath was removed and syrup stirred for 30 min
at 20.degree. C. The reaction was cooled to 0.degree. C. and sodium
nitrate (0.317 g, 3.73 mmol) was added. The reaction was stirred
for 30 min at 0.degree. C. The ice bath was removed and reaction
stirred at 20.degree. C. for 15 min. The mixture was added to ice
(100 g) via a pipet. The acidic solution was cooled with an ice
bath and deluted with CH.sub.2Cl.sub.2 (50 mL). To the rapidly
stirred mixture was added potassium phosphate tribasic (16.95 g, 80
mmol) over 20 min, and the mixture was then brought to pH.about.8
with 1 M NaOH. The organic layer was separated, and the aqueous
layer was extracted with DCM (2.times.50 mL). The combined organic
layers were dried over MgSO.sub.4, filtered, concentrated under
reduced pressure. The residue was purified via silica gel flash
column chromatography eluting with a gradient of 0-25% EtOAc in
heptane to afford
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-3-amine (203L, 0.45 g, 1.504 mmol, 56.5% yield) as
tan oil. LC/MS (ESI.sup.-) m/z=300.0 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.44-8.50 (m, 1H), 7.98 (ddd, J=2.93,
6.31, 9.15 Hz, 1H), 4.04-4.95 (m, 2H), 2.24 (dt, J=5.28, 8.31 Hz,
1H), 1.84-1.99 (m, 1H), 1.77 (s, 3H), 0.85-0.97 (m, 1H), 0.64 (q,
J=5.74 Hz, 1H).
Preparation of Compound 203
[1251] To a stirring solution of
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-3-amine (203L, 0.46 g, 1.54 mmol) in glacial HOAc (5
mL) and TFA (5 mL) at 20.degree. C. was added zinc (nanopowder, 0.6
g, 9.22 mmol) in small portions. After 90 min, the reaction was
concentrated under reduced pressure to a thick oil/suspension. The
residue was partitioned between 9:1 CHCl.sub.3/IPA (50 mL) and 10%
NH.sub.4OH (50 mL). The separated aqueous layer was further
extracted with 9:1 CHCl.sub.3/IPA (20 mL). The combined organics
were washed with sat. NaCl (20 mL), dried over MgSO.sub.4,
concentrated under reduced pressure. The remaining solid was
purified by silica gel chromatography (12 g) eluting with a
gradient of 1-6% of 2 M NH.sub.3 in MeOH in DCM to afford
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-3-amine (203) (0.33 g, 1.22 mmol, 80% yield) as tan
foam. LC/MS (ESI.sup.-) m/z=270.0 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 6.69 (dt, J=4.99, 2.59 Hz, 1H),
6.32-6.40 (m, 1H), 3.81-4.58 (br., 2H), 3.58 (br. s., 2H), 2.18
(td, J=8.22, 5.09 Hz, 1H), 1.80-1.91 (m, 1H), 1.70-1.75 (m, 3H),
0.88-0.97 (m, 1H), 0.59 (q, J=5.67 Hz, 1H).
(R,Z)--N-(1-(5-Bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-
-sulfinamide (204A)
##STR00107##
[1252] Preparation of
1-(5-bromo-2-fluorophenyl)-2-fluoroethanone
[1253] A solution of 4-bromo-1-fluoro-2-iodobenzene (5.0 g, 116
mmol, Aldrich) in THF (60 mL) under nitrogen atmosphere was cooled
to -78.degree. C. A solution of n-BuLi (2.5 M in hexanes; 7.31 mL,
18.28 mmol, Aldrich) was added dropwise and the reaction was
stirred at -78.degree. C. for 1 h. Ethyl monofluoroacetate (2.1 g,
19.94 mmol, Aldrich) was added drop wise and the reaction was
stirred at -78.degree. C. for 1 h. The reaction was quenched with
aqueous saturated ammonium chloride solution and allowed to warm to
RT. The reaction was diluted with water and EtOAc. The organic
layer was separated, washed with brine, dried over magnesium
sulfate, and concentrated under reduced pressure. The material was
purified via silica gel flash chromatography using a gradient of
0-20% EtOAc in Hexanes to afford the title compound as an off white
solid (2.45 g, 10.42 mmol, 63% yield). MS m/z=234.9 M.sup.+.
Preparation of
(R)--N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2--
sulfinamide (204A
[1254] To a solution of 1-(5-bromo-2-fluorophenyl)-2-fluoroethanone
(14 g, 59.6 mmol) and (R)-2-methylpropane-2-sulfinamide (14.44 g,
119 mmol, AK Scientific) in THF (120 ml) was added
tetraethoxytitanium (27.2 g, 119 mmol, Aldrich). The reaction was
stirred at RT for 16 h. The reaction mixture was poured slowly into
vigorously stirring water (700 mL) and the resulting suspension was
stirred for 20 min. EtOAc (400 mL) was added and the suspension was
stirred for an additional 20 min. The suspension was filtered
through Celite.RTM. filter aid and the filter cake was washed with
additional EtOAc. The organic layer was separated, washed with
brine, dried over magnesium sulfate and concentrated under reduced
pressure. The material was purified via silica gel flash
chromatography using a gradient of 0-25% EtOAc in Hexanes to afford
the title compound as a yellow oil (204A, 15.35 g, 45.4 mmol, 76%
yield). MS m/z=338.0 M.sup.+.
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-3-amine (204)
##STR00108## ##STR00109##
[1255] Preparation of Compound 204B
[1256] To a 2000 mL 3-neck RBF equipped with an addition funnel and
internal temperature probe was added
(R,Z)--N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane--
2-sulfinamide (204A, 21.35 g, 63.1 mmol) and THF (200 mL). The
mixture was cooled to 0.degree. C. and 2-tert-butoxy-2-oxoethylzinc
chloride (0.5 M in Et.sub.2O, 253 mL, 126 mmol) was added dropwise
over 75 min keeping the internal temperature under 5.degree. C.
After the addition was completed, the ice bath was removed and the
reaction mixture was stirred at RT for 80 min. The reaction mixture
was carefully quenched with the slow addition of half-sat.
NH.sub.4Cl (100 mL) followed by water (200 mL). The layers were
separated and the aqueous phase was extracted with EtOAc (200 mL).
The combined organic extracts were washed with brine (300 mL),
dried (Na.sub.2SO.sub.4) and concentrated. Purification by silica
gel chromatography (5-50% EtOAc/hexanes) afforded (S)-tert-butyl
3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorob-
utanoate (204B, 22.33 g, 49.1 mmol, 78% yield) as a pale-yellow
oil, which solidified upon standing. LC/MS (ESI.sup.-) m/z=475.8
(M+Na).sup.+.
Preparation of Compound 204C
[1257] To a solution of (S)-tert-butyl
3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorob-
utanoate (204B, 22.3 g, 49.1 mmol) in THF (250 mL) in a 1000 mL
3-neck round-bottomed flask equipped with an internal temperature
probe at RT was added lithium borohydride (2.0 M solution in THF,
50.0 mL, 100 mmol) over 45 min. Anhydrous MeOH (16.0 mL, 395 mmol)
was then added to the mixture slowly over 55 min keeping the
internal temperature under 35.degree. C. The mixture was stirred
for 30 min. The reaction was slowly quenched with 100 mL of sat.
aq. NH.sub.4Cl. The mixture was stirred at RT for 15 min then
partitioned between water (100 mL) and EtOAc (100 mL). The aqueous
phase was extracted with EtOAc (100 mL). The combined organic
extracts were washed with brine (300 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. Purification
by silica gel chromatography (30-80% EtOAc/hexanes) afforded
((R)--N--((S)-2-(5-bromo-2-fluorophenyl)-1-fluoro-4-hydroxybutan-2-yl)-2--
methylpropane-2-sulfinamide (15.34 g, 39.9 mmol, 81%) as a white
foam. LC/MS (ESI.sup.-) m/z=383.8 (M+H).sup.+. This material was
dissolved in DCM (140 mL) and DMSO (70 mL) in a 1000 mL 3-neck RBF
equipped with an internal temperature probe. The mixture was cooled
in an ice/acetone bath to -10.degree. C. N,N-diisopropylethylamine
(21 mL, 121 mmol) was added dropwise via a syringe followed by
portion-wise addition of pyridine sulfur trioxide (9.51 g, 59.7
mmol) keeping the internal temperature below -5.degree. C. The
mixture was stirred for 5 min, and then the cooling bath was
replaced with an ice bath. The mixture was stirred for 1 h at
.about.0.degree. C. The mixture was poured into water (500 mL) and
EtOAc (300 mL) was added. The layers were separated and the aqueous
phase was extracted with EtOAc (3.times.150 mL). The combined
organic extracts were washed with saturated aqueous ammonium
chloride (2.times.500 mL), water (500 mL) and brine (500 mL). The
organic was dried over Na.sub.2SO.sub.4, filtered and concentrated
in vacuo to give the crude material. Purification by silica gel
chromatography (20-80% EtOAc/hexanes) afforded
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-1-fluoro-4-oxobutan-2-yl)-2-methy-
lpropane-2-sulfinamide (204C, 11.36 g, 29.7 mmol, 74.6% yield) as a
clear paste. LC/MS (ESI.sup.-) m/z=381.8 (M+H).sup.+. .sup.1H NMR
(300 MHz, CHLOROFORM-d) .delta. 9.76 (s, 1H), 7.65 (d, J=7.02 Hz,
1H), 7.39-7.53 (m, 1H), 6.96 (dd, J=8.92, 11.98 Hz, 1H), 4.70-5.18
(m, 3H), 3.31-3.55 (m, 2H), 1.23-1.29 (m, 9H). .sup.19F NMR (282
MHz, CHLOROFORM-d) .delta. -111.72 (s, 1 F), -217.48 (s, 1 F).
Preparation of Compound 204D
[1258] The mixture of
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-1-fluoro-4-oxobutan-2-yl)-2-methy-
lpropane-2-sulfinamide (2.44 g, 6.38 mmol) and 4-methylbenzene
sulfonic acid hydrate (0.085 g, 0.447 mmol) in MeOH (50 mL) was
heated at 80.degree. C. in 2 h. After 2 h, the reaction was cooled
to RT. To this mixture, stirred in an ice bath, was added HCl (1.6
mL of 4 M in dioxane solution, 6.38 mmol). After the addition, the
mixture was stirred at RT overnight. The mixture was concentrated
to dryness, saturated aqueous Na.sub.2CO.sub.3 was added, extracted
with EtOAc (3.times.). The extracts were dried over MgSO.sub.4,
concentrated to give
(S)-2-(5-bromo-2-fluorophenyl)-1-fluoro-4,4-dimethoxybutan-2-amine
(204D, 2.06 g, 100%) which was used in the next step without
further purification. LC/MS (ESI.sup.-) m/z=324.0 (M+H).sup.+.
Preparation of Compound 204E
[1259] To a stirred solution of
(S)-2-(5-bromo-2-fluorophenyl)-1-fluoro-4,4-dimethoxybutan-2-amine
(204D, 25.4 g, 78 mmol) in DCM (150 mL) at 0.degree. C. was added a
solution of benzoyl isothiocyanate (14.07 g, 86 mmol) in DCM (100
mL). After the addition, the ice bath was removed and stirred at RT
in 2 h. The mixture was concentrated to dryness to give a brown oil
which was treated with triflic acid (5.65 mL, 63.6 mmol). The
mixture was heated to 50.degree. C. for 3 h, then 70.degree. C. for
2 h. The reaction mixture was cooled, poured onto ice in a beaker,
basified with 10 N NaOH until pH=9. It was extracted with DCM
(3.times.). The extracts were dried over Na.sub.2SO.sub.4,
concentrated and purified by silica gel chromatography (0-50%
EtOAc/Hexanes) to give
(S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-amine
(204E, 1.59 g, 78%). .sup.1H NMR (CHLOROFORM-d) .delta.: 7.58 (dd,
J=6.8, 2.5 Hz, 1H), 7.37 (ddd, J=8.6, 4.3, 2.6 Hz, 1H), 6.92 (dd,
J=11.2, 8.7 Hz, 1H), 6.47 (d, J=9.6 Hz, 1H), 6.32 (dd, J=9.6, 5.3
Hz, 1H), 4.90 (br. s., 2H), 4.81 (d, J=8.0 Hz,), 0.5H), 4.70 (d,
J=8.0 Hz, 0.5H), 4.63 (d, J=8.6 Hz, 0.5H), 4.52 (d, J=8.6 Hz,
0.5H). LC/MS (ESI.sup.-) m/z=319.0 (M+H).sup.+.
Preparation of Compound 204F
[1260] A mixture of
(S)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-amine
(204E, 4.81 g, 15.07 mmol) and di-tert-butyl dicarbonate (6.58 g,
30.1 mmol) was heated neat at 50.degree. C. for 24 h. The reaction
mixture was cooled to RT and purified by silica gel chromatography
(0-20% EtOAc/Hexanes) to give (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)carbamat-
e (204F, 6.32 g, 100%). LC/MS (ESI.sup.-) m/z=362.9.0
(M+H).sup.+.
Preparation of Compound 204G
[1261] To a stirred solution of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)carbamat-
e (204F, 4 g, 9.54 mmol) in THF (20 mL) at -10.degree. C. was added
a solution of lithium bis(trimethylsilyl)amide (11.45 mL of 1 M
solution in THF, 11.45 mmol) dropwise. The mixture was stirred at
this temperature for 1 h, then a solution of
2-(trimethylsilyl)ethoxymethyl chloride (1.88 mL, 9.54 mmol) in THF
(10 mL) was added. The reaction mixture was gradually warmed to RT
and stirred for 16 h. It was treated with saturated aqueous
NH.sub.4Cl and extracted with hexanes. The combined extracts were
dried over Na.sub.2SO.sub.4, concentrated, then purified by silica
gel chromatography (0-20% EtOAc/Hexanes) to give (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)((2-(tri-
methylsilyl)ethoxy)methyl) carbamate (204G, 4.77 g, 91%). .sup.1H
NMR (DMSO-d.sub.6) .delta.: 7.54-7.72 (m, 2H), 7.28 (dd, J=11.6,
8.5 Hz, 1H), 6.85 (d, J=9.4 Hz, 1H), 6.17 (dd, J=9.6, 4.3 Hz, 1H),
5.16-5.31 (m, 2H), 4.56-4.96 (m, 2H), 3.63 (dd, J=8.6, 7.4 Hz, 2H),
1.50 (s, 9H), 0.69-1.03 (m, 2H), 0.03 (s, 9H). LC/MS (ESI.sup.-)
m/z=573.0 (M+Na).sup.+.
Preparation of Compound 204H
[1262] To a stirred solution of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)((2-(tri-
methylsilyl)ethoxy)methyl)carbamate (3.27 g, 5.71 mmol) in THF (30
mL) at -78.degree. C. was added LDA (3.71 mL of 1 M in THF
solution, 7.43 mmol) dropwise. After the addition, the mixture was
stirred at -78.degree. C. for 45 min, and then ethyl chloroformate
(6.58 mL, 68.6 mmol) was added in single portion. It was stirred at
-78.degree. C. for 10 min then quenched with saturated NH.sub.4Cl,
and extracted with EtOAc (3.times.). The organic extracts were
dried over Na.sub.2SO.sub.4, concentrated and purified by silica
gel chromatography (0-20% EtOAc/Hexanes to give (S)-ethyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimeth-
ylsilyl)ethoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazine-6-carboxylat-
e (204H, 1.75 g, 49.3%). 1H NMR (CHLOROFORM-d) .delta.: 7.57-7.69
(m, 1H), 7.65 (dd, J=6.8, 2.3 Hz, 1H), 7.19 (d, J=4.3 Hz, 1H), 6.97
(dd, J=11.0, 8.8 Hz, 1H), 5.35-5.44 (m, 1H), 5.24-5.33 (m, 1H),
4.78-4.99 (m, 1H), 4.55-4.75 (m, 1H), 4.30 (q, J=7.1 Hz, 2H),
3.63-3.73 (m, 2H), 1.52-1.60 (m, 9H), 1.34 (t, J=7.0 Hz, 3H),
0.87-1.04 (m, 2H), 0.03 (s, 9H). LC/MS (ESI.sup.-) m/z=643.1
(M+Na).sup.+.
Preparation of Compound 204I
[1263] To a stirred suspension of trimethylsulfoxonium iodide
(13.60 g, 61.8 mmol) in DMSO (30 mL) was added potassium
tert-butoxide (6.35 g, 56.6 mmol) in single portion. After the
addition, the mixture was stirred for 1 h. The resulting mixture
was added to a stirred solution of (S)-ethyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimeth-
ylsilyl)ethoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazine-6-carboxylat-
e (204H, 16 g, 25.7 mmol) in DMSO (70 mL). The reaction mixture was
stirred at RT for 1 h, the treated with saturated aqueous
NH.sub.4Cl, and extracted with EtOAc (3.times.). The extracts were
dried over Na.sub.2SO.sub.4, concentrated and purified by silica
gel chromatography (0-20% EtOAc/Hexanes) to give (1S,5S,6S)-ethyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-(f(1S,5S,6S)-ethyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxylateluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylat-
e (204I, 3.94 g, 24%). .sup.1H NMR (CHLOROFORM-d) .delta.: 7.84
(dd, J=6.8, 2.5 Hz, 1H), 7.41 (ddd, J=8.6, 4.3, 2.6 Hz, 1H), 6.98
(dd, J=11.5, 8.6 Hz, 1H), 5.29 (d, J=10.4 Hz, 1H), 5.04 (d, J=10.4
Hz, 1H), 4.59-4.99 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 3.67 (td,
J=8.4, 1.5 Hz, 2H), 2.63 (ddd, J=9.9, 7.7, 1.8 Hz, 1H), 1.56 (d,
J=4.9 Hz, 1H), 1.54 (s, 9H), 1.31 (t, J=7.1 Hz, 3H), 1.07 (dd,
J=7.5, 5.2 Hz, 1H), 0.97 (dd, J=9.2, 7.4 Hz, 2H), -0.01-0.02 (s,
9H). LC/MS (ESI.sup.-) m/z=657.2 (M+Na).sup.+.
Preparation of Compound 204J
[1264] To a stirred solution of (1S,5S,6S)-ethyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxylate (204I, 3.94 g, 6.20 mmol) in THF (40 mL) at RT was
added lithium borohydride (6.20 mL of 1 M in THF solution, 12.40
mmol) dropwise. After the addition, MeOH (2.0 mL, 49.6 mmol) was
added dropwise, and mixture stirred for 2 h. It was cooled in an
ice bath and quenched with saturated aqueous NH.sub.4Cl, extracted
with EtOAc (3.times.). The extracts were dried over
Na.sub.2SO.sub.4, concentrated to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate as a colorless oil (3.64 g, 99%). .sup.1H NMR
(CHLOROFORM-d) .delta.: 7.77 (dd, J=6.8, 2.5 Hz, 1H), 7.39 (ddd,
J=8.7, 4.2, 2.6 Hz, 1H), 6.96 (dd, J=11.6, 8.7 Hz, 1H), 5.32 (d,
J=10.6 Hz, 1H), 5.07 (d, J=10.6 Hz, 1H), 4.62-5.00 (m, 2H), 3.84
(dd, J=11.9, 4.3 Hz, 1H), 3.67 (dd, J=8.8, 7.8 Hz, 2H), 3.50-3.56
(m, 1H), 2.04 (t, J=6.0 Hz, 1H), 1.91 (ddd, J=9.5, 6.9, 2.2 Hz,
1H), 1.52 (s, 9H), 0.93-1.06 (m, 3H), 0.73 (t, J=6.3 Hz, 1H),
-0.02-0.04 (s, 9H). LC/MS (ESI.sup.-) m/z=617.2 (M+Na).sup.+.
[1265] TEA (3.41 mL, 24.46 mmol) was added dropwise via syringe to
a solution tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate (3.62 g, 6.12 mmol) in DCM (20 mL) and DMSO (20 mL) in
100 mL RBF. Pyridine sulfur trioxide (4.33 g, 12.23 mmol) was added
and the mixture was stirred for 2 h. Water was added and the
mixture was extracted with DCM (3.times.). The combined organic
extracts were washed with saturated aqueous ammonium chloride,
water, saturated aqueous sodium chloride, and dried over sodium
sulfate. The solution was filtered and concentrated in vacuo to
give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (204J, 3.62 g, 100%). .sup.1H NMR (CHLOROFORM-d) .delta.: 9.15
(s, 1H), 7.83 (dd, J=6.8, 2.5 Hz, 1H), 7.44 (ddd, J=8.7, 4.3, 2.5
Hz, 1H), 7.00 (dd, J=11.5, 8.8 Hz, 1H), 5.33 (d, J=10.4 Hz, 1H),
5.11 (d, J=10.4 Hz, 1H), 4.59-4.97 (m, 2H), 3.67 (dd, J=9.0, 7.6
Hz, 2H), 2.40-2.59 (m, 1H), 1.77 (dd, J=10.0, 5.7 Hz, 1H),
1.50-1.58 (s, 9H), 1.16-1.34 (m, 1H), 0.98 (dd, J=9.2, 7.4 Hz, 2H),
-0.03-0.04 (s, 9H). LC/MS (ESI.sup.-) m/z=615.0 (M+Na).sup.+.
Preparation of Compound 204K
[1266] A mixture of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (3.22 g, 5.44 mmol) and chlorotris(triphenylphosphine)
rhodium(i) (3.53 g, 3.81 mmol) in DCE (20 mL) was heated at
85.degree. C. for 4 h. The mixture was cooled, concentrated to
dryness, triturated in 40% EtOAc/Hexanes. The orange solid was
filtered off, washed with 40% EtOAc/Hexanes. The filtrate was
concentrated and purified by silica gel chromatography (0-20%
EtOAc/Hexanes) to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(204K, 1.75 g, 57%). .sup.1H NMR (CHLOROFORM-d) .delta.: 7.81 (dd,
J=7.0, 2.5 Hz, 1H), 7.39 (ddd, J=8.6, 4.2, 2.6 Hz, 1H), 6.96 (dd,
J=11.6, 8.7 Hz, 1H), 5.29 (d, J=10.4 Hz, 1H), 5.04 (d, J=10.4 Hz,
1H), 4.69-4.98 (m, 2H), 3.62-3.70 (m, 2H), 2.25 (ddd, J=8.9, 7.7,
5.3 Hz, 1H), 2.00 (tdd, J=9.2, 6.6, 2.7 Hz, 1H), 1.52 (s, 9H),
0.94-1.05 (m, 2H), 0.88 (t, J=6.8 Hz, 1H), 0.60 (q, J=5.9 Hz, 1H),
0.00 (s, 9H). LC/MS (ESI.sup.-) m/z=585.0 (M+Na).sup.+.
Preparation of Compound 204L
[1267] A mixture of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(3.31 g, 5.87 mmol), sodium
(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate
(0.291 g, 1.468 mmol), copper(I) iodide (0.280 g, 1.468 mmol),
sodium azide (1.145 g, 17.62 mmol), and
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.232 mL, 1.468
mmol) in EtOH/H.sub.2O (5:1, 60 mL) was heated at 85.degree. C. for
2 h. The reaction mixture was cooled, diluted with EtOAc, washed
with 10:1 saturated NH.sub.4Cl/NH.sub.4OH, brine, dried over
Na.sub.2SO.sub.4, and concentrated to give an oil.
[1268] A solution of the oil in 9:1 of THF/H.sub.2O (50 mL) was
added trimethylphosphine (6.46 mL of 1 M in THF, 6.46 mmol). After
stirring for 30 min, it was diluted with EtOAc, washed with
H.sub.2O, dried over Na.sub.2SO.sub.4, and concentrated to give
tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(204L, 2.85 g, 97%) as light brown oil. .sup.1H NMR (CHLOROFORM-d)
.delta.: 6.96 (dd, J=6.5, 2.9 Hz, 1H), 6.85 (dd, J=11.9, 8.6 Hz,
1H), 6.55 (dt, J=8.5, 3.4 Hz, 1H), 5.29 (d, J=10.6 Hz, 1H), 5.05
(d, J=10.6 Hz, 1H), 4.85-5.02 (m, 1H), 4.66-4.84 (m, 1H), 3.62-3.69
(m, 2H), 2.20-2.29 (m, 1H), 1.99 (tdd, J=9.2, 6.7, 2.3 Hz, 1H),
1.51 (s, 9H), 0.97-1.04 (m, 1H), 0.90-0.97 (m, 2H), 0.58 (q, J=5.7
Hz, 1H), -0.02-0.02 (s, 9H). LC/MS (ESI.sup.-) m/z=500.1
(M+H).sup.+.
Preparation of Compound 204
[1269] To a stirred solution of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(204L, 2.85 g, 5.70 mmol) in DCM (20 mL) was added TFA (4.39 mL,
57.0 mmol). The mixture was stirred at RT for 5 h then concentrated
to dryness. The residue was treated with H.sub.2O and basified with
saturated aqueous NaHCO.sub.3. The solid was collected, washed with
H.sub.2O, dried and purified by silica gel chromatography (0-40%
acetone/DCM) to give
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicycl-
o[4.1.0]hept-3-en-3-amine (204, 1.2 g, 78%). LC/MS (ESI.sup.-)
m/z=270.1 (M+H).sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
6.78-7.03 (m, 2H), 6.55 (td, J=3.45, 8.44 Hz, 1H), 4.01-5.31 (m,
4H), 3.08-3.97 (m, 2H), 2.29 (ddd, J=5.04, 7.53, 8.92 Hz, 1H), 1.87
(ddt, J=1.75, 6.87, 9.06 Hz, 1H), 1.08 (ddd, J=5.85, 7.38, 9.28 Hz,
1H), 0.50 (q, J=5.70 Hz, 1H).
(1S,5S,6S)-Methyl
3-amino-5-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyc-
lo[4.1.0]hept-3-ene-1-carboxylate (205)
##STR00110##
[1271] The title Compound was prepared from 201I using the chemical
procedures similar to that described for intermediate 206 (see
below). LC/MS (ESI.sup.-) m/z=318.0 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 6.59-6.65 (m, 1H) 6.39 (ddd,
J=12.57, 6.41, 2.74 Hz, 1H) 6.16 (s, 2H) 5.15 (s, 2H) 5.03 (t,
J=5.97 Hz, 1H) 4.52-4.71 (m, 2H) 3.52 (dd, J=11.64, 6.16 Hz, 1H)
3.39 (dd, J=11.74, 5.67 Hz, 1H) 1.51-1.60 (m, 1H) 0.98 (dd, J=9.39,
5.09 Hz, 1H) 0.44 (t, J=5.67 Hz, 1H).
((1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-1-yl)methanol (206)
##STR00111##
[1272] Preparation of Compound 206A
[1273] At RT, (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 2.00 g, 3.69 mmol) was treated with 4 mL of sulfuric acid
and stirred for 10 min, then chilled to 0.degree. C. Sodium nitrate
(0.41 g, 4.79 mmol) was added to the mixture. The mixture was
stirred for 1 h. Additional sodium nitrate (0.41 g, 4.79 mmol) was
added, and the mixture was warmed to RT. After 1 h, additional 3 mL
of sulfuric acid was added (to try and solublized the starting
material). The reaction was cooled to 0.degree. C. to suppress an
exotherm. After 30 min, the reaction mixture was poured into
.about.100 mL of wet ice. 50 mL of DCM was added. Potassium
phosphate tribasic (29.70 g, 140 mmol) was added to the mixture
over .about.20 min. Aq 10 N NaOH was then added until the pH
reached .about.8. The mixture was extracted three times with 100 mL
of 9:1 chloroform:IPA. The combined organic extracts were dried
over MgSO.sub.4. Filtration and concentration under reduced
pressure afforded (1S,5S,6S)-methyl
3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (LC/MS (ESI.sup.-) m/z=358.1 (M+H).sup.+)
as a sticky brown solid. The solid was taken up in 4 mL of HOAc and
2 mL of TFA. Zinc (nanopowder, 1.20 g, 18.43 mmol) was added to the
mixture. The mixture was stirred for 30 min, and then concentrated
under reduced pressure. The residue was taken up in 50 mL of 9:1
chloroform:IPA and basified to pH.about.8.0 with 1.0 N aq NaOH.
.about.10 mL of NH.sub.4OH was then added. The mixture was
partitioned and the aqueous portion was extracted three times with
100 mL of 9:1 chloroform:IPA. The combined organic extracts were
dried over MgSO.sub.4. Filtration and concentration under reduced
pressure, followed by flash chromatography on silica gel (40 g
Grace column, eluted with 40-90% EtOAc in DCM) afforded
(1S,5S,6S)-methyl
3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (206A, 0.63 g, 52% yield) as a yellow
solid. m/z (ESI, +ve ion) 328.1 (M+1).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 6.74 (d, J=5.35 Hz, 1H), 6.39 (m, 1H), 3.78
(s, 3H), 3.59 (br. s., 2H), 2.52 (m, 1H), 1.69 (s, 3H), 1.56 (br.,
2H), 1.54 (m, 1H), 1.11 (dd, J=5.18, 7.53 Hz, 1H).
Preparation of Compound 206
[1274] At RT, (1S,5S,6S)-methyl
3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (206A, 0.63 g, 1.92 mmol) was taken up in
10 mL of THF and treated with lithium borohydride (2.0 M solution
in THF, 4.81 ml, 9.62 mmol) followed by MeOH (1.56 mL, 38.5 mmol).
The mixture was stirred for 15 h. The reaction was cooled to
0.degree. C. and quenched by dropwise addition of 30 mL of sat aq
NH.sub.4Cl. The mixture was extracted twice with 20 mL of EtOAc and
the combined organic extracts were washed with 20 mL of brine and
dried over MgSO.sub.4. Filtration and concentration under reduced
pressure afforded
((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-1-yl)methanol (206, 0.54 g, 1.80 mmol, 94%
yield) as an off-white amorphous solid. m/z (ESI, +ve ion) 300.0
(M+1).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 6.68 (br.,
1H), 6.33 (m, 1H), 5.85 (br., 2H), 5.09 (br., 2H), 5.00 (t, J=5.87
Hz, 1H), 3.52 (dd, J=6.36, 11.64 Hz, 1H), 3.41 (dd, J=5.58, 11.64
Hz, 1H), 1.58 (m, 1H), 1.53 (s, 3H), 0.79 (m, 1H), 0.46 (t, J=5.58
Hz, 1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -140.52 (d,
J=23.35 Hz, 1 F), -155.98 (d, J=23.35 Hz, 1 F).
((1S,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-1-yl)methanol (207)
##STR00112##
[1275] Preparation of Compound 207A
[1276] At RT, the mixture of diastereomers 210B (3.92 g, 6.31 mmol)
was treated with conc. sulfuric acid (25 mL, 0.47 mol), and stirred
at RT for 10 min. The sticky mixture was added to ice (200 mL) and
EtOAc (50 mL). The pH was adjusted to 9 with 10 M NaOH. The aqueous
phase was extracted with EtOAc (3.times.) and the combined organic
extracts were washed with brine (1.times.), dried over MgSO.sub.4,
filtered, and concentrated to give (5S)-methyl
3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-ene-1-carboxylate (207A) as an off white foam that was
used in the next step without further purification. LC/MS (ESI)
m/z=391.0 (M+H).sup.+.
Preparation of Compound 207B and Compound 207C
[1277] To a mixture of copper(I) iodide (0.241 g, 1.27 mmol),
sodium azide (1.24 g, 19.1 mmol), and (5S)-methyl
3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-ene-1-carboxylate (207A, material prepared as described
above) at room temperature was added EtOH (9 mL) and water (4.5
mL). The reaction mixture was degassed by bubbling nitrogen through
the solution for 5 min and N,N''-dimethylcyclohexane-1,2-diamine
(0.200 mL, 1.27 mmol) was added. The reaction mixture was heated to
70.degree. C. for 1.5 h and cooled to room temperature. The mixture
was poured into 10:1 saturated NH.sub.4Cl/ammonium hydroxide, and
diluted with EtOAc. The aqueous phase was extracted with EtOAc
(3.times.) and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, concentrated to give a
dark yellow oil. The oil was dissolved in THF (20 mL) and water (7
mL) and trimethylphosphine (1.0 M solution in THF, 6.3 mL, 6.3
mmol) was added. The reaction mixture was stirred at RT for 15 min,
transferred to a separatory funnel, and diluted with water and
EtOAc. The aqueous phase was extracted with EtOAc (3.times.) and
the combined organic extracts were washed with brine (1.times.),
dried over MgSO.sub.4, filtered, and concentrated to give a yellow
foam. Purification by flash column chromatography on silica gel (80
g, eluted with 50% to 100% EtOAc in heptane gradient) gave
(1S,5S,6S)-methyl
3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-ene-1-carboxylate (207B, 1.62 g) as a white foam. LC/MS
(ESI) m/z=328.1 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 6.92 (d, J=6.40 Hz, 1H), 6.86 (dd, J=11.64, 8.51 Hz,
1H), 6.56 (dt, J=8.51, 3.47 Hz, 1H), 4.93 (dd, J=8.61, 1.17 Hz,
1H), 4.82 (dd, J=8.61, 1.37 Hz, 1H), 4.72 (d, J=9.39 Hz, 1H), 4.66
(s br, 2H), 4.61 (d, J=8.61 Hz, 1H), 3.77 (s, 3H), 3.56 (s br, 2H),
2.50-2.57 (m, 1H), 1.69 (dd, J=9.98, 5.09 Hz, 1H), 1.02 (dd,
J=7.24, 5.09 Hz, 1H). In addition, (1R,5S,6R)-methyl
3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-ene-1-carboxylate (207C, 0.280 g) was isolated as a
yellow foam. LC/MS (ESI) m/z=328.1 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 6.81-6.88 (m, 1H), 6.53-6.59 (m,
2H), 4.66 (s br, 2H), 4.53-4.83 (m, 2H), 3.74 (s, 3H), 3.52 (s br,
2H), 2.79 (dd, J=9.78, 7.43 Hz, 1H), 1.71 (dd, J=9.49, 5.38 Hz,
1H), 1.42-1.60 (m, 1H).
Preparation of Compound 207
[1278] To a solution of (1S,5S,6S)-methyl
3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-ene-1-carboxylate (207B, 1.24 g, 3.79 mmol) in THF (15
mL) at RT was added lithium borohydride (2.0 M solution in THF,
5.70 mL, 11.4 mmol) and MeOH (1.20 mL, 29.6 mmol). The reaction
mixture was stirred at room temperature for 4 h and quenched slowly
with saturated NH.sub.4Cl. After bubbling ceased, the mixture was
transferred to a separatory funnel and diluted with water, EtOAc,
and saturated NH.sub.4Cl. The aqueous phase was extracted with
EtOAc (4.times.) and the combined organic extracts were washed with
brine (1.times.), dried over MgSO.sub.4, filtered, concentrated.
Purification by flash column chromatography on silica gel (40 g,
eluted with 40% to 100% EtOAc [10% MeOH (2 M NH.sub.3)] in heptane
gradient) gave
((1S,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-1-yl)methanol (207, 1.06 g, 3.54 mmol,
93% yield) as a white solid. LC/MS (ESI) m/z=300.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 6.84 (dd, J=6.85, 2.93
Hz, 1H), 6.79 (dd, J=12.32, 8.61 Hz, 1H), 6.43 (dt, J=8.22, 3.52
Hz, 1H), 6.12 (s, 2H), 5.02 (t, J=5.97 Hz, 1H), 4.84 (s, 2H),
4.66-4.74 (m, 1H), 4.54-4.61 (m, 1H), 3.53 (dd, J=11.54, 6.26 Hz,
1H), 3.39 (dd, J=11.54, 5.48 Hz, 1H), 1.54-1.60 (m, 1H), 0.95 (dd,
J=9.49, 4.99 Hz, 1H), 0.41 (t, J=5.77 Hz, 1H).
(1S,5S,6S)-Methyl
3-amino-5-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyc-
lo[4.1.0]hept-3-ene-1-carboxylate (208)
##STR00113##
[1280] The title compound was prepared from 201I using the chemical
procedures described for intermediate 209 (see below), except LHMDS
was used in the place of NaHMDS. LC/MS (ESI.sup.-) m/z=332.0
(M+H).sup.+. .sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm (ddd,
J=5.18, 2.93, 1.86 Hz, 1H) 6.38-6.45 (m, 1H) 4.56-4.91 (m, 3H)
3.60-3.65 (m, 1H) 3.39 (s, 3H) 3.31-3.37 (m, 1H) 1.69-1.75 (m, 1H)
1.10 (dd, J=9.59, 5.67 Hz, 1H) 0.74 (t, J=6.16 Hz, 1H).
(1S,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-1-(methoxymethyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-3-amine (209)
##STR00114##
[1281] Preparation of Compound 209A
[1282] To a solution of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 2.70 g, 4.98 mmol) in THF (20 mL) at 20.degree. C. under
nitrogen was added lithium borohydride (2.0 M in THF, 4.98 mL, 9.95
mmol) followed by MeOH (2.01 mL, 49.8 mmol). Gas evolution was
noticed after addition of MeOH. After 15 min, the reaction was then
cooled to 0.degree. C. and carefully quenched with sat. NH.sub.4Cl
(20 mL). The reaction was then partitioned between 0.5 M KHPO.sub.4
(40 mL) and 1:1 EtOAc/heptane (75 mL). The aqueous layer was
further extracted with 1:1 EtOAc/heptane (25 mL). The combined
organic extracts were washed with saturated NaCl (2.times.20 mL),
dried over MgSO4, and then concentrated under reduced pressure to
afford the alcohol intermediate (2.70 g) as sticky oil. m/z (ESI,
+ve ion) 515.2 (M+1).sup.+.
[1283] To a solution of crude alcohol intermediate (2.70 g) in THF
(6 mL) at 0.degree. C. under nitrogen was added sodium
bis(trimethylsilyl)amide (1.0 M in THF, 6.47 mL, 6.47 mmol) at a
rate that did not exceed 5.degree. C. The solution was stirred for
5 min at 0.degree. C. then iodomethane (0.433 mL, 6.97 mmol) added
at a rate that did not exceed 7.degree. C. The cooling bath was
removed and reaction stirred for 2 h at 20.degree. C. The LCMS
suggested 95% conversion. The reaction was quenched with sat.
NH.sub.4Cl (10 mL) and then partitioned between 0.5 M KHPO.sub.4
(20 mL) with 1 M HCl (20 mL) and 1:1 EtOAc/heptane (75 mL). The
aqueous portion was further extracted with 1:1 EtOAc/heptane (25
mL). The combined organic extracts were washed with sat. NaCl
(2.times.20 mL), dried over MgSO.sub.4, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (120 g) eluting with a gradient of 0-15%
EtOAc/heptane to afford tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(209A, 2.00 g, 3.78 mmol, 76% yield) as colorless oil. m/z (ESI,
+ve ion) 529.3 (M+1).sup.+.
Preparation of Compound 209
[1284] At RT, to tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(209A, 2.0 g, 3.78 mmol) in a 250 mL round bottom flask equipped
with a magnetic stir bar and nitrogen line (no solvent) at
0.degree. C. was added chilled (0.degree. C.) neat sulfuric acid
(15 mL). The internal temperature reached to 5.degree. C., gas
evolution was evident, and a red color developed. After 15 min, the
reaction was cooled with an ice bath and treated with sodium
nitrate (0.35 g, 4.16 mmol) in one portion. After 10 min, the
reaction was poured onto wet ice (100 mL) contained in a 500 mL
Erylmeyer flask. That flask was then jacketed with a wet ice
cooling bath. To the mixture was added CH.sub.2Cl.sub.2 (50 mL)
followed by dropwise addition of NaOH (4 M, 150 mL) at a rate that
did not exceed an internal temp of 5.degree. C. until pH 14 was
achieved. To the flask was added 9:1 CHCl.sub.3/IPA (50 mL). The
mixture was transferred to a separatory funnel and the layers were
separated. The aqueous portion was further extracted with
CHCl.sub.3/IPA (2.times.50 mL). The combined organic extracts were
dried over MgSO.sub.4, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (120 g) eluting
with a 0-1.5% of 2 M NH.sub.3 in MeOH in CH.sub.2Cl.sub.2 to afford
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-1-(methoxymethyl)-5-m-
ethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.63 g, 1.83
mmol, 48% yield) as amber oil. m/z (ESI, +ve ion) 344.0
(M+1).sup.+.
[1285] To a stirring solution of
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-1-(methoxymethyl)-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.63 g, 1.83 mmol) in
glacial HOAc (5 mL) and TFA (5 mL) at 20.degree. C. was added
nanopowder zinc (0.67 g, 10.29 mmol). After 90 min the reaction was
concentrated under reduced pressure to a thick oil/suspension. The
residue was partitioned between 9:1 CHCl.sub.3/IPA (50 mL) and 10%
NH.sub.4OH (50 mL). The separated aqueous layer was further washed
with 9:1 CHCl.sub.3/IPA (20 mL). The combined organic solution was
washed with sat. NaCl (20 mL), dried over MgSO.sub.4, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography eluting with a gradient of 1-6% of 2 M
NH.sub.3 in MeOH in DCM to afford
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-1-(methoxymethyl)-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-3-amine (209, 0.53 g, 1.69 mmol,
92% yield) as tan foam. m/z (ESI, +ve ion) 314.1 (M+1).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 6.67 (br., 1H), 6.36
(m, 1H), 5.92 (br., 2H), 5.12 (br. s., 2H), 3.55 (d, J=10.95 Hz,
1H), 3.36 (d, J=10.95 Hz, 1H), 3.32 (s, 3H), 1.61 (br., 1H), 1.56
(s, 3H), 0.87 (br., 1H), 0.57 (br., 1H).
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-5-(fluoromethyl)-1-(methoxymethyl)-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (210)
##STR00115##
[1286] Preparation of Compound 210A
[1287] To a solution of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4H-1,3-thiazin-2-yl)((2-(tri-
methylsilyl)ethoxy)methyl)carbamate (204G, 40.2 g, 73.2 mmol) in
THF (270 mL) under N.sub.2 at -78.degree. C. was added lithium
diisopropylamide (2 M solution in THF/heptane/ethylbenzene, 36.6
mL, 73.2 mmol) dropwise at the rate where internal temperature did
not exceed -50.degree. C. After addition, the mixture was then
stirred at the same temperature for 45 min. CO.sub.2 (gas) was
bubbled into the mixture at the rate where internal temperature did
not exceed -50.degree. C. for 30 min. The mixture was warmed to RT
and was quenched with saturated ammonium chloride. It was diluted
with EtOAc and H.sub.2O. The organic layer was separated, washed
with HCl (1 N) followed by brine, dried over MgSO.sub.4, and
concentrated. The residue was dissolved in THF (220 mL) and MeOH
(24.44 mL) and cooled with an ice bath.
(Trimethylsilyl)diazomethane (2.0 M solutions in hexanes, 43.9 mL,
88 mmol) was added dropwise to the mixture. It was stirred at
0.degree. C. for 20 min and quenched with HOAc (5 mL). The mixture
was washed with saturated NaHCO.sub.3, brine, dried over
MgSO.sub.4, and concentrated. The residue was purified by silica
gel flash column chromatography using ISCO instrument (0%-15%
EtOAc/heptane) to give (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazine-6-carboxylate
(210A, 31.2 g, 51.4 mmol, 70% yield) as a white solid. LC/MS
(ESI.sup.-) m/z=607.1, 609.0, 629.0, 631.1. .sup.1H NMR
(CHLOROFORM-d) .delta.: 7.65 (dd, J=6.8, 2.5 Hz, 1H), 7.42 (ddd,
J=8.6, 4.3, 2.5 Hz, 1H), 7.22 (d, J=4.5 Hz, 1H), 6.96 (dd, J=11.2,
8.6 Hz, 1H), 5.27-5.43 (m, 2H), 4.55-4.96 (m, 2H), 3.84 (s, 3H),
3.63-3.72 (m, 2H), 1.56 (s, 9H), 0.95-1.02 (m, 2H), 0.00 (s,
9H).
Preparation of Compound 210B
[1288] To a solution of trimethylsulfoxonium iodide (8.74 g, 39.7
mmol) in dimethyl sulfoxide (39 mL) at 0.degree. C. under N.sub.2
was added potassium tert-butoxide (4.19 g, 37.3 mmol) in two
portions. The reaction mixture (A) was stirred at RT for 1 h. 20 mL
of reaction mixture (A) was added to a solution of (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazine-6-carboxylate
(210A, 12.06 g, 19.85 mmol) in DMSO (50 mL) dropwise. After
addition, the mixture was then stirred RT for 1 h. LCMS showed some
starting material. It was treated with additional 2 mL of the
mixture A and stirred at RT for overnight. LCMS showed some
starting material. It was treated with 4 mL of the mixture A and
stirred at RT for 4.5 h. LCMS showed no starting material. The
reaction mixture was quenched with saturated NH.sub.4Cl and
extracted with EtOAc (2.times.). The organic solution was washed
with brine, dried over MgSO.sub.4, and concentrated to give 13.16 g
of thick oil, 210B, as a mixture of (1R,5S,6R)-methyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxylate (minor product) and
(1S,5S,6S)-methyl-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2--
(trimethylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-ene-1-carboxylate (major product). LC/MS (ESI.sup.-)
m/z=621.0, 623.2
Preparation of Compound 210C
[1289] To a solution of 210B (6.1 g, 9.81 mmol) in THF (50 mL) at
0.degree. C. under N.sub.2 was added lithium borohydride (2 M
solution in THF, 9.81 mL, 19.63 mmol) dropwise followed by MeOH
(3.18 mL, 79 mmol). The mixture was stirred at 0.degree. C. for 1 h
and 45 min. It was quenched with saturated ammonium chloride,
washed with HCl (1 N), then saturated NaHCO.sub.3, brine, dried
over MgSO.sub.4, and concentrated. The residue was purified by
silica gel flash column chromatography using ISCO instrument
(0%-80% EtOAc/heptane) to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate (210C, 4.6 g, 7.75 mmol, 79% yield) as a light yellow
oil. LC/MS (ESI.sup.-) m/z=593.2, 595.1. .sup.1H NMR (CHLOROFORM-d)
.delta.: 7.77 (dd, J=6.8, 2.5 Hz, 1H), 7.40 (ddd, J=8.5, 4.3, 2.5
Hz, 1H), 6.96 (dd, J=11.5, 8.6 Hz, 1H), 5.28-5.31 (m, 1H), 5.07 (d,
J=10.6 Hz, 1H), 4.82-4.99 (m, 1H), 4.61-4.79 (m, 1H), 3.49-3.87 (m,
4H), 1.88-1.95 (m, 1H), 1.52 (s, 9H), 0.94-1.07 (m, 3H), 0.73 (t,
J=6.4 Hz, 1H), 0.00 (s, 9H)
Preparation of Compound 210D
[1290] To a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate (210C, 3.2 g, 5.39 mmol) in THF (20 mL) under N.sub.2
at 0.degree. C. was added lithium bis(trimethylsilyl)amide (1.0 M
solution in THF, 8.09 mL, 8.09 mmol) dropwise. After addition, the
mixture was stirred at 0.degree. C. for 30 min and iodomethane
(0.502 mL, 8.09 mmol) was added dropwise. It was stirred at
0.degree. C. for 20 min followed by RT overnight. The mixture was
quenched with saturated NH.sub.4Cl and diluted with H.sub.2O. It
was extracted with EtOAc (2.times.). The combined organic extracts
were washed with brine, dried over MgSO.sub.4, and concentrated.
The residue was purified by silica gel flash column chromatography
using ISCO instrument (10%-60% EtOAc/heptane) to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(methoxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate (210D, 3.17 g, 5.22 mmol, 97% yield) as a light yellow
oil. LC/MS (ESI.sup.-) m/z=607.1, 609.0. .sup.1H NMR (CHLOROFORM-d)
.delta.: 7.83 (dd, J=6.9, 2.4 Hz, 1H), 7.36-7.42 (m, 1H), 6.96 (dd,
J=11.6, 8.7 Hz, 1H), 5.01-5.32 (m, 2H), 4.64-4.96 (m, 2H),
3.63-3.69 (m, 2H), 3.39 (s, 3H), 1.87 (t, J=7.1 Hz, 1H), 1.52 (s,
9H), 0.94-1.06 (m, 3H), 0.77 (t, J=6.2 Hz, 1H), 0.00 (s, 9H)
Preparation of Compound 210E
[1291] To a RBF containing tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(methoxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate (210D, 3.17 g, 5.22 mmol) at 0.degree. C. was added
conc. sulfuric acid (13.90 mL, 261 mmol) dropwise. After the
addition, the mixture was stirred at 0.degree. C. for 30 min. It
was adjusted to pH=10-14 by 5 N NaOH. The mixture was extracted
with EtOAc (2.times.). The combined organic extracts were washed
with brine, dried over MgSO.sub.4, and concentrated. The residue
was purified by silica gel flash column chromatography using ISCO
instrument (0%-10% MeOH/DCM) to give
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(methoxymet-
hyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (210E, 1.73 g,
4.59 mmol, 88% yield) as a yellow solid. LC/MS (ESI.sup.-)
m/z=377.0, 379.0. .sup.1H NMR (CHLOROFORM-d) .delta.: 7.78 (dd,
J=7.0, 2.5 Hz, 1H), 7.38 (ddd, J=8.6, 4.2, 2.7 Hz, 1H), 6.94 (dd,
J=11.5, 8.6 Hz, 1H), 5.30 (s, 1H), 4.52-4.92 (m, 3H), 3.62 (d,
J=10.6 Hz, 1H), 3.39 (s, 3H), 3.35 (d, J=10.6 Hz, 1H), 1.77 (t,
J=8.2 Hz, 1H), 1.08 (dd, J=9.6, 5.9 Hz, 1H), 0.74 (t, J=6.3 Hz,
1H)
Preparation of Compound 210
[1292] To a solution of
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(methoxymethyl)--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (210E, 1.73 g, 4.59
mmol) in EtOH (3.0 mL), IPA (3.0 mL), and water (1.50 mL) was added
sodium azide (0.894 g, 13.76 mmol), copper(i) iodide (0.218 g,
1.146 mmol), sodium L-ascorbate (0.227 g, 1.146 mmol), and
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.181 mL, 1.146 mmol).
Then, N.sub.2 was bubbled into the mixture for 5 min. The mixture
was stirred at 70.degree. C. under N.sub.2 for 3 h. It was quenched
with saturated NH.sub.4Cl/NH.sub.4OH (10:1), extracted with EtOAc
(2.times.). The combined organic extracts were dried over
MgSO.sub.4 and concentrated. The residue was dissolved in
THF/H.sub.2O (9:1, 20 mL) and trimethylphosphine (1.0M solution in
THF) (4.59 mL, 4.59 mmol) was added. After the mixture was stirred
at RT for 30 min, it was quenched with saturated NaHCO.sub.3, and
extracted with EtOAc. The organic solution was washed with brine,
dried over MgSO.sub.4 and concentrated. The residue was purified by
silica gel flash column chromatography using ISCO instrument
(0%-20% MeOH/DCM) to give
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(methoxymethyl)--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (210, 1.07 g, 3.41
mmol, 74.5% yield) as a yellow solid. LC/MS (ESI.sup.-) m/z=314.1.
.sup.1H NMR (CHLOROFORM-d) .delta.: 6.89 (d, J=4.1 Hz, 1H), 6.84
(dd, J=11.6, 8.7 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.58-4.93 (m,
2H), 3.63 (d, J=10.6 Hz, 1H), 3.38 (s, 3H), 3.33 (d, J=10.4 Hz,
1H), 1.75 (t, J=8.1 Hz, 1H), 1.04-1.11 (m, 1H), 0.72 (t, J=6.3 Hz,
1H).
(1S,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-1-(difluoromethyl)-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-3-amine (211)
##STR00116##
[1293] Preparation of Compound 211B
[1294] At -10.degree. C. (ice/salt), to a stirred solution of
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-formyl-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(203J, 380 mg, 0.74 mmol) in 5 mL of DCM was added deoxo-fluor
(0.48 mL, 2.59 mmol). It was stirred at 0.degree. C. for 1 h then
RT for 2 h. It was diluted with 30 mL of DCM, washed with 20 mL of
sat NaHCO.sub.3 followed by 5 mL of brine. The organic solution was
dried over sodium sulfate and concentrated. The residue was
purified on a silica gel column (5-10% EtOAc in hexanes) to
give:
[1295] 1) 1.sup.st eluent, tert-butyl
((1R,5S,6S,8S)-5-(2,3-difluorophenyl)-1,8-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.2.0]oct-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)
carbamate (211A, 95 mg, 24% yield) as brown thick oil. m/z (ESI,
+ve ion) 535.1 (M+1).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 7.43 (t, J=7.40 Hz, 1H), 7.10 (m, 2H), 5.30 (d, J=10.76 Hz,
1H), 5.07-5.16 (m, 0.5H), 5.03 (d, J=8.61 Hz, 1H), 5.00 (m, 0.5H),
3.69 (m, 2H), 2.97 (m, 1H), 1.76 (m., 1H), 1.67 (s, 3H), 1.52 (s,
9H), 1.20 (m, 1H), 0.94 (m, 2H), 0.02 (s, 9H). .sup.19F NMR (376
MHz, CHLOROFORM-d) .delta. -112.71 (s, 1 F), -138.50 (d, J=19.94
Hz, 1 F), -139.76 (d, J=19.94 Hz, 1 F), -173.68 (s, 1 F).
[1296] 2) 2.sup.nd eluent, tert-butyl
((1S,5S,6S)-1-(difluoromethyl)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)
carbamate (211B, 249 mg, 0.46 mmol, 62% yield) as brown sticky oil.
m/z (ESI, +ve ion) 535.1 (M+1).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.34 (m, 1H), 7.07 (m, 2H), 5.55-5.88 (m,
1H), 5.29 (d, J=10.37 Hz, 1H), 5.05 (d, J=10.56 Hz, 1H), 3.65 (m,
2H), 2.11 (dd, J=7.73, 9.29 Hz, 1H), 1.78 (s, 3H), 1.52 (s, 9H),
1.23 (m, 1H), 0.95 (m, 3H), 0.00 (s, 9H). .sup.19F NMR (376 MHz,
CHLOROFORM-d) .delta. -118.00 (d, .sup.1J=280 Hz, 1 F), -120.01 (d,
.sup.1J=280 Hz, 1 F), -138.73 (d, .sup.2J=19.94 Hz, 1 F), -139.18
(d, .sup.2J=19.94 Hz, 1 F).
Preparation of Compound 211
[1297] At RT, sulfuric acid (1 mL, 18.76 mmol) was added to
tert-butyl
((1S,5S,6S)-1-(difluoromethyl)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(211B, 120 mg, 0.22 mmol). It was stirred at RT for 10 min. It was
cooled with an ice bath and treated with sodium nitrate (24.80 mg,
0.29 mmol). Ice bath was removed. The mixture was stirred at RT for
2 h. It was cooled with an ice bath, treated with ice cube followed
by 15 mL of DCM then potassium phosphate tribasic monohydrate (4.60
g, 20 mmol) in small portions. 2 mL of 2 N NaOH was added and pH
was about 10. It was extracted with 2.times.20 mL of
(9:1=CHCl.sub.3:iPrOH). The organic extracts were washed with 5 mL
of brine and concentrated. The resulting brown residue containing
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-1-(difluoromethyl)-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine was dissolved in 0.8 mL of
glacial HOAc and 0.4 mL of TFA and treated with zinc (nanopowder,
88 mg, 1.34 mmol) at RT. It was stirred at RT for 3 h then
concentrated under reduced pressure to remove TFA. The residue was
basified with 2 N NaOH until pH was about 10. The mixture was
extracted with 2.times.20 mL of (9:1=CHCl.sub.3:iPrOH). The organic
extracts were washed with 5 mL of brine and concentrated. The
residue was purified on a silica gel column (5% MeOH in DCM
followed by 5% 2 M NH.sub.3 in MeOH in DCM) to provide
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-1-(difluoromethyl)-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (211, 47 mg, 0.15 mmol,
65% yield) as a brown amorphous solid. m/z (ESI, +ve ion) 320.0
(M+1).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 6.52 (br.,
1H), 6.38 (m, 2H), 6.23 (br., 1H), 5.77-6.04 (m, 1H), 5.14 (br.,
2H), 1.84 (m, 1H), 1.59 (s, 3H), 1.30 (m, 1H), 0.67 (m, 1H).
.sup.19F NMR (376 MHz, CHLOROFORM-d) .delta. -118.06 (d,
.sup.1J=273 Hz, 1 F), -115.47 (d, .sup.1J=273 Hz, 1 F), -140.28 (d,
.sup.2J=22.54 Hz, 1 F), -155.35 (d, .sup.2J=22.64 Hz, 1 F).
(1S,5S,6S)-Ethyl
3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (212)
##STR00117##
[1298] Preparation of Compound 212A
[1299] In a 500 mL RBF, a solution of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethylsilyl)-
ethoxy)methyl)carbamate (3.05 g, 6.48 mmol) in 30 mL of THF at
-78.degree. C. was treated with lithium diisopropylamide (2 M
solution in heptane/THF/ethylbenzene) (4.21 mL, 8.42 mmol)
dropwise. The resulting mixture was stirred at -78.degree. C. for
45 min and treated with ethyl chloroformate (1.852 mL, 19.44 mmol)
via a syringe in one shot. The mixture was stirred for 30 min at
-78.degree. C., then quenched with 50 mL of aq. NH.sub.4Cl and
warmed to RT. It was extracted with (2.times.100 mL) of EtOAc. The
organic layers were combined, washed with 15 mL of brine, dried
over sodium sulfate and concentrated. The residue was purified via
flash chromatography on silica gel (80 g Grace column, eluted with
5-15% EtOAc in hexanes) to give (S)-ethyl
2-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-4-(2,3-d-
ifluorophenyl)-4-methyl-4H-1,3-thiazine-6-carboxylate (212A, 2.5 g,
4.61 mmol, 71% yield) as a colorless viscous oil. m/z (ESI, +ve
ion) 543.0 (M+1).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
7.32 (m, 1H), 7.03-7.16 (m, 3H), 5.32 (d, J=10.37 Hz, 1H), 5.22 (d,
J=10.37 Hz, 1H), 4.30 (m, 2H), 3.67 (m, 2H), 1.76 (s, 3H), 1.55 (s,
9H), 1.35 (t, J=7.14 Hz, 3H), 0.94 (m, 2H), 0.00 (s, 9H). .sup.19F
NMR (377 MHz, CHLOROFORM-d) .delta. -137.70 (d, J=20.27 Hz, 1 F),
-138.25 (d, J=20.27 Hz, 1 F).
Preparation of Compound 212B
[1300] Preparation of Corey Chykovsky Reagent (0.25 M in DMSO):
sodium hydride (60% wt.) (400 mg, 10 mmol) was added to a solution
of trimethylsulfoxonium iodide (2.22 g, 10 mmol) in DMSO (40 mL)
under argon. The mixture was stirred for 30 min before aliquots
were used for cyclopropanation.
[1301] At RT, to a solution of (S)-ethyl
2-((tert-butoxycarbonyl)((2-(trimethylsilyl)
ethoxy)methyl)amino)-4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazine-6-ca-
rboxylate (212A, 2.5 g, 4.61 mmol) in 15 mL of THF was added
freshly prepared Corey Chykovsky Reagent (0.25 M in DMSO) (27.6 mL,
6.91 mmol). The mixture was stirred at RT for 45 min. It was cooled
with an ice bath and quenched with 50 mL of aq NH.sub.4Cl, and
extracted with (2.times.75 mL) EtOAc. The organic extracts were
washed with 15 mL of brine, dried over MgSO.sub.4 and concentrated
under reduced pressure. The residue was purified via flash
chromatography on silica gel (40 g Grace column, elute with 1-15%
EtOAc in hexanes) to provide (1S,5S,6S)-ethyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(212B, 2.11 g, 3.79 mmol, 82% yield) as a thick oil. m/z (ESI, +ve
ion) 557.3 (M+1).sup.+.
Preparation of Compound 212C
[1302] At RT, sulphuric acid (5 mL, 94 mmol) was added to
(1S,5S,6S)-ethyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(2.03 g, 3.65 mmol). It was stirred at RT for 10 min then cooled
with an ice bath and treated with sodium nitrate (0.40 g, 4.74
mmol). Ice bath was removed. The mixture was stirred at RT for 45
min. It was cooled with an ice bath, treated with ice cube followed
by 15 mL of DCM then potassium phosphate tribasic monohydrate
(23.03 g, 100 mmol) in small portions. The mixture had a pH of
about 8; 5 mL of 1 N NaOH was added and pH was about 10. It was
extracted with (2.times.50 mL) (9:1=CHCl.sub.3:iPrOH). The organic
extracts were concentrated and the residue was purified on a 40 g
silica gel column (25-55% EtOAc in hexanes) to give
(1S,5S,6S)-ethyl
3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (212C, 1.21 g, 3.26 mmol, 89% yield) as a
brown amorphous solid. m/z (ESI, +ve ion) 372.0 (M+1).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.51-8.56 (m, 1H), 8.37
(dt, J=3.13, 6.36 Hz, 1H), 6.46 (s, 2H), 4.19 (q, J=7.11 Hz, 2H),
2.41 (t, J=8.51 Hz, 1H), 1.63 (s, 3H), 1.42 (dd, J=5.28, 9.59 Hz,
1H), 1.27 (m, 3H), 1.04 (m, 1H).
Preparation of Compound 212
[1303] Zinc (0.819 g, 12.52 mmol) was added to a stirred mixture of
(1S,5S,6S)-ethyl
3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (0.93 g, 2.50 mmol) in HOAc (4 mL) and
TFA (2 mL) at 0.degree. C. The reaction mixture was stirred at RT
for 45 min then concentrated under reduced pressure (to remove the
TFA). The residue was partitioned between 150 mL of EtOAc and 20 mL
of 5 N NaOH. The organic solution was washed with 5 mL of brine and
concentrated. The resulting crude product was purified via silica
gel flash column chromatography eluting with 2-5% MeOH in DCM to
give (1S,5S,6S)-ethyl
3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (212) (480 mg, 1.406 mmol, 56% yield) as
a tan solid. m/z (ESI, +ve ion) 342.0 (M+1).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 6.71 (d, J=5.73 Hz, 1H), 6.37 (m, 1H),
6.10 (s, 2H), 5.16 (s, 2H), 4.17 (q, J=7.11 Hz, 2H), 2.29 (m, 1H),
1.55 (s, 3H), 1.42 (dd, J=4.89, 9.78 Hz, 1H), 1.21 (t, J=7.14 Hz,
3H), 0.95 (dd, J=5.09, 7.24 Hz, 1H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -140.14 (d, J=20.20 Hz, 1 F), -156.28 (d,
J=20.20 Hz, 1 F).
(1R,5S,6S)-5-(5-Amino-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-3-amine (213)
##STR00118## ##STR00119##
[1304] Preparation of (S)-tert-butyl
3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate
(213B)
[1305] To a 3-L 3-neck RBF was added
(R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide (213A, 51 g, 159 mmol) and THF (400 mL). The flask was equipped
with a temperature probe, and an overhead stirrer. The solution was
cooled in a dry ice/acetone bath to an internal temperature of
-50.9.degree. C. (2-(tert-butoxy)-2-oxoethyl)zinc (II) chloride
(0.5 M in ether, 796 mL, 398 mmol, Rieke Metals) was added slowly
to the stirring solution over 45 min via cannula. After 20 min, the
dry ice/acetone bath was removed and the reaction warmed to ambient
temperature and stirred for 16 h. The flask was placed in an
ice/water bath and cooled to 5.degree. C. before slowly adding
saturated ammonium chloride (aq.) solution (300 mL) and water (300
mL). The reaction was extracted with EtOAc (2.times.300 mL). The
combined organic layers were washed sequentially with a 9:1
saturated ammonium chloride to saturated ammonium hydroxide
solution (2.times.) and brine before drying over magnesium sulfate
and concentrating under reduced pressure to afford crude
(S)-tert-butyl
3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate
(74.44 g, 171 mmol, 213b, 107% yield) as a yellow oil which
solidified upon sitting. The material was used in the next step
without further purification assuming theoretical yield. MS
m/z=436.0 M.sup.+.
Preparation of
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane--
2-sulfinamide (213C)
[1306] A 3-neck 3-L RBF was charged with a solution of
(S)-tert-butyl
3-(5-bromo-2-fluorophenyl)-3-((R)-1,1-dimethylethylsulfinamido)butanoate
(64.9 g, 149 mmol, 213b) in THF (400 mL). The flask was equipped
with an overhead stirrer, a 250 mL addition funnel, and a
temperature probe. The addition funnel was charged with LiBH.sub.4
(2.0 M in THF, 186 mL, 372 mmol, Sigma Aldrich) via cannula. The
LiBH.sub.4 was added to the stirring solution at room temperature.
The addition funnel was removed and replaced with a 125 mL addition
funnel which was subsequently charged with MeOH (30.1 mL, 744
mmol). The MeOH was added dropwise to the stirring solution at RT
via addition funnel. Evolution of gas observed and the internal
temperature of the reaction rose to 47.5.degree. C. over the course
of the reaction and then began to subside. Upon reaching an
internal temperature of 26.degree. C., a 250 mL addition funnel was
attached to the reaction flask and charged with an additional
portion of LiBH.sub.4 (186 mL of 2.0M in THF, 372 mmol, Sigma
Aldrich) via cannula. The LiBH.sub.4 was added to the reaction. The
addition funnel was removed and replaced with a 125 mL addition
funnel which was then with MeOH (30.1 mL, 744 mmol). The MeOH was
added dropwise to the stirring solution. Evolution of gas was
observed and the internal temperature increased to 35.degree. C.
and then subsided. After 20 min, the flask was placed in an
ice/water bath and carefully quenched with saturated ammonium
chloride (aq.) solution. The reaction was diluted with water and
EtOAc and stirred for 16 h. The solids were filtered off and washed
with EtOAc. The filtrate and washes were combined and transferred
to a separatory funnel. The organic layer was separated, washed
with brine, dried over magnesium sulfate and concentrated under
reduced pressure to afford
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-4-hydroxybutan-2-yl)-2-methylprop-
ane-2-sulfinamide (50.93 g) as a white solid. MS m/z=366.0 M.sup.+.
This material was used as crude.
[1307]
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-4-hydroxybutan-2-yl)-2-meth-
ylpropane-2-sulfinamide (5.5 g, 15.02 mmol) was taken up in DCM
(400 mL). Dess-martinperiodinane (DMP) (6.37 g, 15.02 mmol, Sigma
Aldrich) was added. After 30 min, the reaction was quenched with 50
mL of aq. Na.sub.2S.sub.2O.sub.3 and 50 mL of aq. NaHCO.sub.3. The
mixture was stirred for 10 min before partitioning. The aqueous
portion was extracted with DCM (100 mL) and the combined organic
layers were dried over MgSO.sub.4. Filtration and concentration
under reduced pressure, followed by silica gel flash chromatography
on silica gel using a gradient of 10-60% EtOAc in hexanes afforded
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane--
2-sulfinamide (213C, 3.3 g, 9.06 mmol, 60% yield) as a clear oil.
MS m/z=364.0 M.sup.+.
Preparation of
(S)-2-(5-bromo-2-fluorophenyl)-4,4-dimethoxybutan-2-amine
(213D)
[1308]
(R)--N--((S)-2-(5-bromo-2-fluorophenyl)-4-oxobutan-2-yl)-2-methylpr-
opane-2-sulfinamide (3.3 g, 9.06 mmol, 213c) was taken up in MeOH
(50 mL). p-toluenesulfonic acid monohydrate (0.086 g, 0.453 mmol,
Sigma Aldrich) was added, and the mixture was heated to 75.degree.
C. After 30 min, the mixture was cooled to RT and HCl (4.0 M in
1,4-dioxane, 3.40 mL, 13.59 mmol, Sigma Aldrich) was added. After 1
h, the solvent was removed under reduced pressure. The residue was
partitioned between a solution of 9:1 chloroform:IPA (50 mL) and
saturated aqueous NaHCO.sub.3 (50 mL). The aqueous portion was
extracted with 9:1 chloroform:IPA (50 mL). The combined organic
extracts were dried over MgSO.sub.4. Filtration and concentration
under reduced pressure afforded
(S)-2-(5-bromo-2-fluorophenyl)-4,4-dimethoxybutan-2-amine (213d,
2.7 g, 8.82 mmol, 97% yield) as a yellow oil. The product was
carried on without additional purification. MS m/z=306.1
M.sup.+.
Preparation of
(R)-4-(5-bromo-2-fluorophenyl)-4-methyl-4H-thiopyran-2-amine
(213E)
[1309] To a solution of
(S)-2-(5-bromo-2-fluorophenyl)-4,4-dimethoxybutan-2-amine (25.03 g,
82 mmol, 213d) in DCM (164 mL) was added benzoyl isothiocyanate
(11.00 mL, 82 mmol, Sigma Aldrich) at RT. The reaction was stirred
for 30 min then concentrated under reduced pressure. The residue
was taken up in sulfuric acid (96 mL, 1799 mmol) and the reaction
was heated to 50.degree. C. for 16 h. The reaction was cooled to
room temperature then carefully poured into an Erlenmeyer flask
containing wet ice. The flask was placed in a water bath and the
reaction was carefully basified to pH=14 by the slow addition of 10
N NaOH. The solution was extracted with DCM (3.times.). The
combined organic layers were washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure. The
crude residue was purified via silica gel flash chromatography
using a gradient of 0-5% 2 M ammonia in MeOH in DCM) to afford
(R)-4-(5-bromo-2-fluorophenyl)-4-methyl-4H-thiopyran-2-amine (213E,
12.5 g, 41.6 mmol, 51% yield) as a brown oil. MS m/z=301.0
M.sup.+.
Preparation of N,N-Bis Boc protected
(S)-4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine
(213F)
[1310] To a solution of di-tert-butyl dicarbonate (0.91 g, 4.16
mmol, Sigma Aldrich) in THF (4.6 mL) at room temperature was added
a solution of
(S)-4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine
(213E, 0.57 g, 1.89 mmol) and 4-(dimethylamino)-pyridine (5.78 mg,
0.05 mmol, Sigma Aldrich) in THF (4.6 mL) dropwise via syringe. The
reaction was stirred for one h. The reaction was diluted with water
and EtOAc. The organic layer was separated, washed with brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The crude residue was purified via silica gel flash
chromatography using a gradient of 0-20% EtOAc in Hexanes to afford
N,N-Bis Boc protected
(S)-4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine
(213F, 0.80 g, 1.59 mmol, 84% yield). MS m/z=501.0 M.sup.+.
Preparation of N,N-Bis Boc protected
(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (213G)
[1311] A sealable vial was charged with N,N-Bis Boc protected
(S)-4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine
(1.04 g, 2.07 mmol, 213F). THF was added to fully dissolve the
starting material. The reaction was then concentrated to near
dryness. Tetrabutylammonium bromide (0.07 g, 0.21 mmol, Sigma
Aldrich) was added followed by (bromodifluoromethyl)trimethylsilane
(2.11 g, 10.38 mmol, Synquest Laboratories). The vial was sealed
and heated to 65.degree. C. in an oil bath overnight. The reaction
was diluted with water and EtOAc. The organic layer was separated,
washed with brine, dried over magnesium sulfate and concentrated
under reduced pressure. The crude residue was purified via silica
gel flash chromatography using a gradient of 0-30% EtOAc in Hexanes
to afford N,N-Bis Boc protected
(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (213G, 0.103 g, 0.188 mmol, 9%
yield) as a pale yellow solid. MS m/z=551.0 M.sup.+.
Preparation of
(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (213H)
[1312] To a solution of N,N-Bis Boc protected
(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (0.103 g, 0.187 mmol, 213g) in DCM
(1.87 mL) was added TFA (0.475 mL, 6.16 mmol, Sigma Aldrich). The
reaction was stirred at room temperature for 3 h. The reaction was
concentrated under reduced pressure. The crude residue was taken up
in EtOAc and washed with saturated sodium bicarbonate (aq.)
solution and brine. The organic layer was dried over magnesium
sulfate and concentrated under reduced pressure to afford
(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (213H, 69 mg, 0.195 mmol,
105% yield) as a yellow oil. It was used without further
purification assuming theoretical yield. MS m/z=350.9 M.sup.+.
Preparation of
(1R,5S,6R)-5-(5-azido-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (213)
[1313] A sealable glass vial was charged with
(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (0.48 g, 1.37 mmol, 213H),
(+)-sodium L-ascorbate (0.054 g, 0.275 mmol, Sigma Aldrich),
copper(I) iodide (79 mg, 0.413 mmol, Sigma Aldrich), and sodium
azide (0.268 g, 4.13 mmol, Sigma Aldrich). The vial was sealed and
evacuated/backfilled with Nitrogen (3.times.). EtOH (4.8 mL) was
added followed by water (2.0 mL) and
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.043 mL, 0.27
mmol, Sigma Aldrich). The vial was stirred in a pre-heated
75.degree. C. oil bath for 5.5 h. The reaction was cooled to room
temperature. Additional sodium azide (0.268 g, 4.13 mmol),
copper(I) iodide (79 mg, 0.413 mmol) and
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.043 mL, 0.275
mmol) were added. The reaction was flushed with nitrogen and then
stirred in a pre-heated 85.degree. C. oil bath for an additional
1.5 h. The reaction was cooled to RT and poured into a separatory
funnel containing a solution of 9:1 aqueous saturated ammonium
chloride to aqueous saturated ammonium hydroxide. EtOAc was added
and the organic phase was separated and washed sequentially with
9:1 saturated aqueous ammonium chloride to saturated aqueous
ammonium hydroxide solution and brine. The organic layer was dried
over magnesium sulfate and concentrated under reduced pressure. The
crude residue was taken up in THF (5.2 ml) and water (1.7 mL).
Trimethylphosphine (1.0 M in THF, 1.376 mL, 1.376 mmol, Sigma
Aldrich) was added at RT. The reaction was stirred for 5 min. The
reaction was diluted with water and EtOAc. The organic layer was
separated, washed with brine, dried over magnesium sulfate and
concentrated under reduced pressure. The crude residue was purified
via silica gel flash chromatography using a gradient of 0-10% 2 M
ammonia in MeOH in DCM to afford
(1R,5S,6R)-5-(5-amino-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (213) (0.25 g, 0.86 mmol, 63%
yield). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.=7.04 (dd, J=2.9,
6.7 Hz, 1H), 6.87 (dd, J=8.5, 12.0 Hz, 1H), 6.54 (ddd, J=3.0, 3.8,
8.6 Hz, 1H), 2.89 (dd, J=8.3, 13.2 Hz, 1H), 2.74-2.60 (m, 1H), 1.69
(d, J=1.0 Hz, 3H) MS m/z=288.0 M.sup.+.
tert-Butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethox-
y)methyl) carbamate (214)
##STR00120## ##STR00121## ##STR00122##
[1314] Preparation of
(R,Z)--N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-s-
ulfinamide (214A)
[1315] A mixture of 1-(5-bromo-2-fluoropyridin-3-yl)ethanone
(prepared according to procedures described in WO2009016460; 11.0
g, 50.5 mmol), (R)-2-methylpropane-2-sulfinamide (AK Scientific,
12.2 g, 101.0 mmol) and titanium(IV) ethoxide (Aldrich, 26.1 mL,
126.0 mmol) in THF (100 mL) was heated to reflux for 2 h. The
mixture was cooled to room temperature, and brine (200 mL) was
added. The suspension was vigorously stirred for 10 min. The
suspension was filtered through a pad of silica gel and the organic
phase was separated. The aqueous phase was extracted with EtOAc.
The combined organic layers were washed with brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (gradient 0-20%
EtOAc/hexanes) to afford
(R,Z)--N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylprop-
ane-2-sulfinamide (214A) as a bright yellow oil (16 g, 49.8 mmol,
99% yield). MS m/z=320.8 [M+H].sup.+.
Preparation of (S)-tert-butyl
3-(5-bromo-2-fluoropyridin-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)buta-
noate (214B)
[1316] To a solution of
(R,Z)--N-(1-(5-bromo-2-fluoropyridin-3-yl)ethylidene)-2-methylpropane-2-s-
ulfinamide (214A, 41 g, 127 mmol) in THF (400 mL) in a 2 L flask at
0.degree. C. was cannulated slowly
(2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (0.5 M in Et.sub.2O,
611 mL, 305 mmol) within 1 h. The reaction mixture was stirred at
RT overnight, and then quenched with 200 mL of saturated NH.sub.4Cl
solution. The layers were separated. The aqueous layer was
extracted again with 200 mL of EtOAc. The combined organic layers
were then dried (Na.sub.2SO.sub.4) and concentrated to give an
orange oil that was purified by flash column (DCM to DCM/ethyl
acetate=10:1 to 5:1 to 3:1) to give (S)-tert-butyl
3-(5-bromo-2-fluoropyridin-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)buta-
noate (214B, 43 g, 98 mmol, 77% yield). LC/MS (ESI.sup.+) m/z=458.9
(M+Na). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.17 (dd,
J=1.61, 2.34 Hz, 1H), 8.03 (dd, J=2.48, 8.77 Hz, 1H), 5.44 (s, 1H),
3.18-3.29 (m, 1H), 2.98-3.11 (m, 1H), 1.82 (s, 3H), 1.33 (s, 9H),
1.30 (s, 9H).
Preparation of
(R)--N--((S)-2-(5-bromo-2-fluoropyridin-3-yl)-4-oxobutan-2-yl)-2-methylpr-
opane-2-sulfinamide (214C)
[1317] A solution of (S)-tert-butyl
3-(5-bromo-2-fluoropyridin-3-yl)-3-((R)-1,1-dimethylethylsulfinamido)buta-
noate (214B, 42 g, 96 mmol) in 200 mL of anhydrous DCM in a 2 L
round-bottom flask at -78.degree. C. was treated with
diisobutylaluminum hydride (1.0 M in hexanes) (211 mL, 211 mmol)
via a syringe dropwise along the inner wall of the flask within 1.5
h. The stirring was continued for 1 h. The reaction was quenched at
-78.degree. C. by slow addition of 25 mL of MeOH along the inner
wall of the flask. The reaction mixture was then taken out of the
dry ice-acetone bath, and treated with 300 mL of 1 M tartaric acid
solution. The mixture was stirred at RT for 1 h. A clear two phase
separation was achieved and the organic phase was isolated. The
aqueous was extracted with DCM (3.times.). The combined organic
phase was evaporated to dryness. The residue was purified via
silica gel chromatography (20-50% EtOAc in DCM) to Gi.RTM.
(R)--N--((S)-2-(5-bromo-2-fluoropyridin-3-yl)-4-oxobutan-2-yl)-2-methylpr-
opane-2-sulfinamide (214C, 31 g, 85 mmol, 88% yield) as a yellow
gum. LC/MS (ESI.sup.+) m/z=365.0 (M+H). .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 9.70 (s, 1H), 8.16 (dd, J=1.68, 2.41 Hz, 1H),
8.04 (dd, J=2.41, 8.84 Hz, 1H), 4.89 (s, 1H), 3.59-3.73 (m, 1H),
3.35-3.48 (m, 1H), 1.77 (s, 3H), 1.29 (s, 9H).
Preparation of
(S)-2-(5-bromo-2-fluoropyridin-3-yl)-4,4-dimethoxybutan-2-amine
(214D)
[1318] To a 1000 mL RBF equipped with a reflux condenser was added
(R)--N--((S)-2-(5-bromo-2-fluoropyridin-3-yl)-4-oxobutan-2-yl)-2-methylpr-
opane-2-sulfinamide (28.5 g, 78.0 mmol), MeOH (200 mL) and
p-toluenesulfonic acid monohydrate (0.7 g, 3.9 mmol). The solution
was stirred at 65.degree. C. overnight. It was cooled to RT and
treated with hydrogen chloride (4.0 M solution in 1,4-dioxane, 21.5
mL, 86.0 mmol) dropwise. After stirring at RT for 3 h, the mixture
was concentrated in vacuo. The residue was diluted with 300 mL of
chloroform and treated with 50 mL of sat. aq. NaHCO.sub.3. The
layers were separated and the aqueous layer was extracted with
EtOAc (50 mL). The chloroform extracts were washed with 10 mL of
brine. The EtOAc extracts were washed with 10 mL of brine. The
combined organic extracts were dried over magnesium sulfate,
filtered and concentrated in vacuo to give a light yellow oil. It
was purified by silica gel chromatography (50-100% EtOAc in DCM) to
give
(S)-2-(5-bromo-2-fluoropyridin-3-yl)-4,4-dimethoxybutan-2-amine
(214D, 20.6 g, 67.2 mmol, 86% yield) as a gum. LC/MS (ESI.sup.+)
m/z=307.0 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.26
(dd, J=2.48, 8.77 Hz, 1H), 8.12-8.19 (m, 1H), 4.10-4.19 (m, 1H),
3.23 (d, J=2.05 Hz, 6H), 2.24-2.45 (m, 1H), 1.79-2.14 (m, 1H), 1.75
(br. s., 2H), 1.54 (s, 3H).
Preparation of
(S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-amine
(214F)
[1319] To a solution of
(S)-2-(5-bromo-2-fluoropyridin-3-yl)-4,4-dimethoxybutan-2-amine
(214D, 20.5 g, 66.7 mmol) in DCM (100 mL) at 0.degree. C. under
nitrogen was added a solution of benzoyl isothiocyanate (9.4 mL,
70.1 mmol) in DCM (30 mL) dropwise. The reaction was kept below
5.degree. C. during the course of addition. After stirring at
0.degree. C. for 20 min, the reaction mixture was treated with MeOH
(1 mL). The solvents were removed under reduced pressure to afford
a tan syrup. To the tan syrup at 0.degree. C. was added neat
sulfuric acid (53.4 mL, 1001 mmol). The mixture was stirred at RT
for 20 min then heated at 60.degree. C. for 5 h, then 80.degree. C.
for 2 h, then 65.degree. C. overnight. LCMS indicated the ratio of
214E and 214F to be about 1:1. The mixture was heated at 85.degree.
C. for 3 h. The reaction was cooled to 20.degree. C. then poured
onto 200 g of ice. DCM (200 mL) was added to the slurry mixture.
The resulting biphasic solution was chilled to 0.degree. C. with
external wet ice bath, then basified to pH=8 with very slow
addition of 10 N NaOH solution. The organic layer was separated and
the aqueous portion was extracted with DCM (3.times.) and EtOAc
(1.times.). The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and then concentrated under reduced
pressure. The residue was purified by flash column (10-100% EtOAc
in DCM) to give two compounds. The first eluent was
(S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-amine
(214F, 12.0 g, 39.7 mmol, 59% yield) as a yellow solid. LC/MS
(ESI.sup.+) m/z=302.0 (M+H). .sup.1H NMR (CHLOROFORM-d) .delta.:
8.12 (dd, J=2.5, 1.6 Hz, 1H), 8.02 (dd, J=8.6, 2.5 Hz, 1H),
6.30-6.39 (m, 1H), 6.17-6.27 (m, 1H), 1.66 (d, J=1.0 Hz, 3H). The
second eluent was
(4S)-4-(5-bromo-2-fluoropyridin-3-yl)-6-methoxy-4-methyl-5,6-dihydro-4H-1-
,3-thiazin-2-amine (214E, 6.0 g, 17.9 mmol).
[1320] A mixture of
(4S)-4-(5-bromo-2-fluoropyridin-3-yl)-6-methoxy-4-methyl-5,6-dihydro-4H-1-
,3-thiazin-2-amine (214E, 6.0 g, 17.9 mmol) in 18 mL of
H.sub.2SO.sub.4 was heated at 80.degree. C. overnight. The reaction
mixture was cooled to 20.degree. C. then poured onto 200 g of ice.
To the slurry was added DCM (200 mL), the resulting biphasic
solution was chilled to 0.degree. C. with external wet ice bath,
then basified to pH=8 with very slow addition of 10 N NaOH
solution. The organic layer was separated and the aqueous portion
was extracted with DCM (3.times.) and EtOAc (1.times.). The
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column (10-30% EtOAc in DCM) to give
(S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-amine
(214F, 4 g) as a yellow solid.
Preparation of (S)-tert-butyl
(4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(214G)
[1321] Using a procedure similar to that described for Intermediate
203F,
(S)-4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-amine
(214F, 1.74 g, 5.76 mmol), 4-(dimethylamino)pyridine (0.04 g, 0.29
mmol), Boc anhydride (3.30 mL, 14.40 mmol) and lithium hydroxide
monohydrate (1.21, 28.80 mmol) were combined to afford the title
compound (2.17 g, 5.39 mmol, 94% yield). LC/MS (ESI.sup.+)
m/z=403.0 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
8.14-8.20 (m, 1H), 8.00 (br. s., 1H), 6.30 (d, J=9.79 Hz, 1H), 6.14
(d, J=6.87 Hz, 1H), 1.69 (s, 3H), 1.54 (s, 9H).
Preparation of (S)-tert-butyl
(4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trime-
thylsilyl)ethoxy)methyl)carbamate (214H)
[1322] Using a similar procedure described for 203G, (S)-tert-butyl
(4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(214G, 1.18 g, 2.93 mmol), lithium bis(trimethylsilyl)amide (3.8 mL
of 1.0 M solution in THF, 3.8 mmol) and
2-(chloromethoxy)ethyltrimethylsilane (0.7 mL, 3.8 mmol) were
combined to afford the title compound (214H, 1.5 g, 2.8 mmol, 95%
yield). LC/MS (ESI.sup.+) m/z=532.0/534.0 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta. 8.14-8.22 (m, 2H), 6.36 (d, J=9.50 Hz,
1H), 6.05-6.11 (m, 1H), 5.37 (d, J=10.38 Hz, 1H), 5.21 (d, J=10.38
Hz, 1H), 3.69 (dd, J=7.67, 8.84 Hz, 2H), 1.69 (d, J=1.17 Hz, 3H),
1.56 (s, 9H), 0.91-1.06 (m, 2H), 0.00 (s, 9H).
Preparation of (S)-methyl
4-(5-bromo-2-fluoropyridin-3-yl)-2-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylate
(214I)
[1323] LDA (2.0 M heptane/THF/ethylbenzene) (0.92 mL, 1.83 mmol)
was added dropwise to a solution of (S)-tert-butyl
(4-(5-bromo-2-fluoropyridin-3-yl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trime-
thylsilyl)ethoxy)methyl)carbamate (214H, 0.75 g, 1.41 mmol) in THF
(10 mL) at -78.degree. C. The mixture was stirred for 25 min before
CO.sub.2 gas was bubbled through the reaction mixture at
-78.degree. C. After 3 min, the cold bath was removed, the addition
of CO.sub.2 was stopped, and the reaction mixture was quenched with
saturated NH.sub.4Cl solution. The resulting solution was warmed to
RT and extracted with EtOAc (2.times.). The aqueous layer was
acidified to pH 4 with 1 N HCl solution and extracted again with
EtOAc. The combined extracts were dried over MgSO.sub.4, filtered,
and concentrated in vacuo to give a yellow oil.
[1324] The oil was taken up in DMF (2.0 mL) and potassium carbonate
(0.19 g, 1.41 mmol) and methyl iodide (0.09 mL, 1.41 mmol) were
added. The mixture was stirred at RT for 2 h, diluted with water
and extracted with EtOAc (2.times.). The combined organic extracts
were dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The residue was purified on an ISCO column using 0-15% EtOAc in
hexanes to afford (S)-methyl
4-(5-bromo-2-fluoropyridin-3-yl)-2-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylate
(214I, 0.40 g, 0.68 mmol, 48.1% yield). LC/MS (ESI.sup.+)
m/z=590.0/592.0 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
8.16-8.23 (m, 2H), 7.11 (d, J=3.07 Hz, 1H), 5.38 (d, J=10.38 Hz,
1H), 5.20 (d, J=10.38 Hz, 1H), 3.84 (s, 3H), 3.62-3.73 (m, 2H),
1.72 (d, J=1.02 Hz, 3H), 1.50-1.58 (m, 9H), 0.98 (dd, J=7.45, 8.92
Hz, 2H), -0.02 (s, 9H).
Preparation of (1S,5S,6S)-methyl
5-(5-bromo-2-fluoropyridin-3-yl)-3-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxylate (214J)
[1325] Using a similar procedure described for 210B,
trimethylsulfoxonium iodide (0.30 g, 1.36 mmol), potassium
tert-butoxide (0.15 g, 1.35 mmol), and (S)-methyl
4-(5-bromo-2-fluoropyridin-3-yl)-2-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylate
(214I, 0.40 g, 0.68 mmol) were combined to afford (1S,5S,6S)-methyl
5-(5-bromo-2-fluoropyridin-3-yl)-3-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxylate (214J, 0.27 g, 0.45 mmol, 65.9% yield). LCMS
m/z=604.0/606.0 [M+H].sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. 8.17-8.27 (m, 2H), 5.30 (d, J=10.52 Hz, 1H), 5.03 (d,
J=10.52 Hz, 1H), 3.82 (s, 3H), 3.62-3.74 (m, 2H), 2.68 (ddd,
J=1.53, 7.71, 9.61 Hz, 1H), 1.75 (d, J=1.17 Hz, 3H), 1.51-1.57 (m,
9H), 1.24-1.36 (m, 1H), 1.16 (dd, J=5.26, 7.60 Hz, 1H), 0.85-1.07
(m, 2H), -0.06 (s, 9H). .sup.19F NMR (282 MHz, CHLOROFORM-d)
.delta. -67.27 (s, 1 F).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(hydroxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (214K)
[1326] Using a similar procedure described for 210C,
(1S,5S,6S)-methyl
5-(5-bromo-2-fluoropyridin-3-yl)-3-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxylate (214J, 0.46 g, 0.76 mmol) and lithium borohydride (2.0 M
solution in THF, 0.76 mL, 1.52 mmol) and MeOH (0.12 mL, 3.04 mmol)
were combined to afford the title compound (214K, 0.42 g, 0.73
mmol, 96% yield). LC/MS (ESI+) m/z=576.0/578.0 (M+H).
Preparation of tert-butyl
((5S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)
carbamate (214M)
[1327] To a solution of tert-butyl
((5S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(hydroxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (0.46 g, 0.80 mmol) in hexanes (10.0 mL) at -78.degree. C. was
added Deoxo-Fluor (0.22 mL, 1.20 mmol) dropwise. The reaction
mixture was warmed to RT for 30 min and quenched with saturated
NaHCO.sub.3 solution. It was extracted with EtOAc (2.times.). The
organic extracts were concentrated under reduced pressure and the
residue purified by silica gel chromatography eluting products with
0-20% EtOAc/heptane gradient to afford:
[1328] 1.sup.st eluent, tert-butyl
((5S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-fluoro-5-methyl-2-thia-4-azabicy-
clo[4.2.0]oct-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(214L, 0.13 g, 0.22 mmol, 28.2% yield). LC/MS (ESI+)
m/z=578.0/580.0 (M+H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.
-67.71 (s, 1 F), -102.44 (s, 1 F).
[1329] 2.sup.nd eluent, tert-butyl
((5S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (214M, 0.17 g, 0.30 mmol, 37.0% yield). LC/MS (ESI+)
m/z=578.0/580.0 (M+H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.
-67.71 (s, 1 F), -213.42 (s, 1 F).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)
carbamate (214)
[1330] Using a similar procedure described for 210,
tert-butyl((5S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methy-
l-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)meth-
yl)carbamate (214M, 0.16 g, 0.28 mmol), sodium azide (0.05 g, 0.83
mmol), copper(I) iodide (13 mg, 0.07 mmol), sodium L-ascorbate (14
mg, 0.07 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (10.9
.mu.L, 0.07 mmol) and trimethylphosphine (1 M solution in THF, 0.41
mL, 0.41 mmol) were combined to afford tert-butyl
((5S)-5-(5-amino-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (214, 72 mg, 0.14 mmol, 51% yield). LC/MS (ESI.sup.-) m/z=515.2
(M+H).sup.+.
(1S,5S,6S)-5-(5-Amino-2-methoxypyridin-3-yl)-1-(fluoromethyl)-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (215)
##STR00123##
[1331] Preparation of Compound 215A
[1332] To a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)c-
arbamate (214M, 2.53 g, 4.37 mmol) in DMF (10 mL) was added sodium
methoxide (2.36 g, 43.7 mmol) at RT. The suspension was stirred at
RT for 6 h, diluted with water and extracted with EtOAc (2.times.).
The organic extracts were concentrated under reduced pressure and
the residue was purified on a silica gel column (0-20%
EtOAc/hexanes) to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-(fluoromethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (2.00 g, 3.39 mmol, 77% yield). LC/MS (ESI.sup.+)
m/z=590.2/592.1 (M+H).
Preparation of Compound 215B
[1333] To a round bottom flask containing tert-butyl
((1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-(fluoromethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (215A, 2.0 g, 3.4 mmol) at 0.degree. C. was added
concentrated sulfuric acid (4 mL, 72.0 mmol) dropwise. After the
addition, the mixture was stirred at RT for 30 min and the pH of
the reaction mixture was adjusted to pH=10-14 by the addition of 5
N NaOH solution. The mixture was extracted with EtOAc (2.times.).
The combined organic extracts were washed with brine, dried over
MgSO.sub.4, and concentrated to give
(1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-(fluoromethyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (1.2 g, 3.33 mmol, 98%
yield). LC/MS (ESI.sup.+) m/z=360.2/362.0 (M+H).
Preparation of Compound 215
[1334] A mixture of
(1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-(fluoromethyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (215B, 1.2 g, 3.33 mmol),
sodium azide (1.08 g, 16.66 mmol), copper(i) iodide (63 mg, 0.33
mmol), (+)-sodium L-ascorbate (0.13 g, 0.67 mmol), and
trans-N,N'-dimethylcyclohexane-1,2-diamine (0.10 mL, 0.67 mmol) in
EtOH/H.sub.2O (4:1, 20 mL) was heated in a closed capped vial at
85.degree. C. for 2 h. The reaction mixture was cooled, diluted
with water and extracted with EtOAc (2.times.). The organic
extracts were dried over Na.sub.2SO.sub.4 and concentrated.
[1335] The residue obtained was dissolved in a (8:2) mixture of
THF/H.sub.2O (10 mL) and trimethylphosphine (1 M solution in THF)
(6.66 mL, 6.66 mmol) was added. After stirring at RT for 1 h, the
reaction was quenched with saturated NaHCO.sub.3, and extracted
with EtOAc. The organic solution was concentrated and the residue
was purified by silica gel flash column chromatography (0-15%
MeOH/DCM) to give
(1S,5S,6S)-5-(5-amino-2-methoxypyridin-3-yl)-1-(fluoromethyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.25 g, 0.84 mmol, 25%
yield). LC/MS (ESI.sup.+) m/z=297.2 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.: 7.54 (d, J=2.93 Hz, 1H), 7.40 (d, J=2.93 Hz,
1H), 4.46-4.62 (m, 1H), 4.34-4.46 (m, 1H), 4.11-4.34 (m, 2H), 3.93
(s, 3H), 3.70-3.00 (br., 2H), 2.13 (ddd, J=0.98, 6.94, 9.68 Hz,
1H), 1.69 (s, 3H), 0.92 (dd, J=5.87, 9.59 Hz, 1H), 0.71 (dt,
J=4.30, 6.16 Hz, 1H). .sup.19F NMR (377 MHz, CHLOROFORM-d) .delta.
-212.20.
(1S,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-en-3-amine (216)
##STR00124##
[1336] Preparation of tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(216A)
[1337] At RT, to a solution of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 34.6 g, 63.8 mmol) in 300 mL of THF was added lithium
borohydride (2.0 M solution in THF, 63.8 mL, 128 mmol) dropwise via
an addition funnel. MeOH (20.66 mL, 510 mmol) was the added slowly
to the mixture over 20 min. The mixture was stirred at RT for 2 h,
during which time it warmed slightly (estimated .about.40.degree.
C.). The mixture was then chilled to 0.degree. C. and quenched by
dropwise addition of 250 mL of aq. NH.sub.4Cl. The reaction mixture
was then extracted with 500 mL of EtOAc and the organic extracts
were washed with 250 mL of brine and dried over MgSO.sub.4.
Filtration and concentration under reduced pressure afforded
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(30.7 g, 59.6 mmol, 94% yield) as a viscous yellow oil. MS (ESI,
positive ion) m/z: 515.3 (M+1). The crude material was used in the
next step without further purification.
[1338] At 0.degree. C., tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(4.9 g, 9.52 mmol) in 50 mL of DCM was treated with TEA (1.72 mL,
12.38 mmol) followed by methanesulfonyl chloride (0.85 mL, 10.95
mmol). The mixture was stirred for 30 min, then quenched with 30 mL
of aq. NaHCO.sub.3 and 30 mL of water. The layers were separated
and the aqueous portion was extracted with 25 mL of DCM. The
combined organic extracts were dried over MgSO.sub.4. Filtration
and concentration under reduced pressure afforded an oil that was
taken up in 20 mL of tBuOH. Cesium fluoride (4.34 g, 28.6 mmol) was
added, and the mixture as heated at 75.degree. C. for 10 h. The
mixture was cooled to RT and partitioned between 100 mL of EtOAc
and 100 mL of water. The organic portion was washed with 50 mL of
brine and dried over MgSO.sub.4. Filtration and concentration under
reduced pressure, followed by flash chromatography on silica gel
(5-25% EtOAc in heptanes) afforded tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(216A) (4.34 g, 8.40 mmol, 88% yield) as a clear oil. MS (ESI,
positive ion) m/z: 517.3 (M+1). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -139.35 (d, J=20.80 Hz, 1 F), -139.82 (d,
J=20.81 Hz, 1 F), -212.18 (s, 1 F).
Preparation of
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-1-(fluoromethyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-3-amine (216)
[1339] At 0.degree. C., tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(4.3 g, 8.32 mmol) was treated with sulfuric acid (15.97 mL, 300
mmol) dropwise. The mixture was stirred for 5 min, then warmed to
RT and stirred for 15 min. The mixture was chilled to 0.degree. C.
Sodium nitrate (0.70 g, 8.32 mmol) was added. The mixture was
warmed to RT and stirred for 40 min. The mixture was then chilled
to 0.degree. C., and sodium nitrate (0.70 g, 8.32 mmol) was added.
The mixture was warmed to RT. After 40 min, the mixture was chilled
to 0.degree. C. 200 mL of wet ice was added to the flask. Potassium
phosphate tribasic monohydrate (72.8 g, 316 mmol) was then added
slowly over 15 min. 10 N aq. NaOH was then added until the mixture
had reached a pH.about.9.0. The mixture was diluted with 100 mL of
water and 200 mL of chloroform:IPA (9:1), stirred for 5 min, then
filtered to remove all solid material. The filtrate was transferred
to a separatory funnel and the layers were separated. The aqueous
portion was extracted with 100 mL of DCM. The combined organic
extracts were then dried over MgSO.sub.4. Filtration and
concentration under reduced pressure, followed by flash
chromatography on silica gel (5-50% EtOAc/heptanes) afforded
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-1-(fluoromethyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-3-amine (1.44 g, 4.35 mmol, 52%
yield) as a sticky yellow solid. MS (ESI, positive ion) m/z: 332.1
(M+1).
[1340]
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-1-(fluoromethyl)-5-methyl-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (1.44 g, 4.35 mmol)
was taken up in HOAc (6 mL, 104 mmol) and TFA (3 mL, 40.4 mmol).
The mixture was cooled to 0.degree. C., and zinc (nanopowder, 0.85
g, 13.04 mmol) was added in four portions over 20 min. The mixture
was warmed to RT and stirred for 1 h. The solvents were removed
under reduced pressure and the residue was partitioned between 75
mL of 9:1 aq. NH.sub.4Cl:NH.sub.4OH and 75 mL of DCM. The aqueous
portion was extracted with 50 mL of DCM and the combined organic
extracts were dried over MgSO.sub.4. Filtration and concentration
under reduced pressure, followed by flash chromatography on silica
gel (1-5% MeOH/DCM) afforded
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-1-(fluoromethyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.85 g, 2.82 mmol, 65%
yield) as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 6.67 (m, 1H), 6.36 (m, 1H), 6.04 (br., 2H), 5.13 (br., 2H),
4.53 (m, 1H), 4.41 (m, 1H), 1.74 (m, 1H), 1.56 (s, 3H) 1.01 (m,
1H), 0.63 (m, 1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta.
-140.38 (d, J=23.41 Hz, 1 F), -155.86 (d, J=23.41 Hz, 1 F), -211.45
(s, 1 F). MS (ESI, positive ion) m/z: 302.0 (M+1).
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-amine (217)
##STR00125## ##STR00126##
[1341] Preparation of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethylsi-
lyl)ethoxy)methyl)carbamate (217G)
[1342] This intermediate was prepared in 9 steps from Compound 217A
in a fashion similar to that described for intermediate 204G.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.68 (dd, J=2.74, 7.04
Hz, 1H), 7.57 (ddd, J=2.74, 4.25, 8.66 Hz, 1H), 7.26 (dd, J=8.61,
11.54 Hz, 1H), 6.66 (d, J=9.39 Hz, 1H), 6.09 (dd, J=3.52, 9.39 Hz,
1H), 5.24 (d, J=10.56 Hz, 1H), 5.12 (d, J=10.76 Hz, 1H), 3.64 (m,
2H), 1.63 (s, 3H), 1.51 (s, 9H), 0.92 (m, 2H), -0.06 (s, 9H).
.sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -113.44 (s, 1 F). MS
(ESI, positive ion) m/z: 531/535 (M+1).
Preparation of (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylate
(217H)
[1343] To a stirring solution of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethylsi-
lyl)ethoxy)methyl)carbamate (217G) (15.0 g, 28.2 mmol) in THF (100
mL) at -78.degree. C. was added lithium diisopropylamide (14.1 mL
of 2 M in THF, 28.2 mmol) at a rate that the reaction temperature
did not exceed -65.degree. C. The light orange solution was stirred
for 20 min at -78.degree. C. The reaction was then exposed to
carbon dioxide (g), first as a stream above the level of the
solvent for 2 min, followed by the gas bubbled through the solvent
for 2 min. The reaction was then slowly quenched with sat.
NH.sub.4Cl (25 mL). Once the suspension reached RT, both EtOAc (200
mL) and water (25 mL) were added. The organic layer was separated
and the aqueous layer was extracted with EtOAc (lx). The combined
extracts were then dried over MgSO.sub.4 and concentrated under
reduced pressure to afford the crude
(S)-4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsily-
l)ethoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylic acid
as a thick oil. MS (ESI, positive ion) m/z: 575/577 (M+1).
[1344] The resulting thick oil was dissolved in DMF (100 mL) and
treated with potassium carbonate (7.8 g, 56.4 mmol) followed by
iodomethane (3.5 mL, 56.4 mmol) at RT. The mixture was then stirred
for 3 d at RT. The reaction mixture was diluted with 100 mL of
EtOAc, and then water (50 mL) was added. The resulting biphasic
mixture was separated and the aqueous layer was extracted with
EtOAc (1.times.). The combined organic extracts were washed with
water (2.times.), dried (MgSO.sub.4), filtered, and concentrated in
vacuo to give an oil. The crude material was loaded on a silica gel
column and eluted with a gradient of 0-10% EtOAc in hexanes to
afford (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylate (14.9 g,
46% yield) as a yellow viscous oil. .sup.1H NMR (CHLOROFORM-d)
.delta.: 7.73 (dd, J=7.0, 2.5 Hz, 1H), 7.39 (ddd, J=8.7, 4.3, 2.5
Hz, 1H), 7.11 (d, J=3.1 Hz, 1H), 6.97 (dd, J=11.3, 8.6 Hz, 1H),
5.34 (d, J=10.4 Hz, 1H), 5.21 (d, J=10.4 Hz, 1H), 3.83 (s, 3H),
3.58-3.73 (m, 2H), 1.71 (s, 3H), 1.56 (s, 9H), 0.87-1.08 (m, 2H),
0.00 (s, 9H). MS (ESI, positive ion) m/z: 589/591 (M+1).
Preparation of (1S,5S,6S)-methyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late (217I)
[1345] Corey-Chaykovsky Reagent [.about.0.25 M in DMSO]: To a
stirring solution of trimethylsulfoxonium iodide (12.46 g, 56.60
mmol) in DMSO (200 mL) at RT was added potassium tert-butoxide
(6.35 g, 56.60 mmol) in one portion. The solution was stirred for 1
h and then used in the reaction outlined below.
[1346] To a stirring solution of (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxylate (217H,
26.7 g, 45.3 mmol) in THF (200 mL) at RT was added freshly prepared
Corey-Chaykovsky Reagent (56.60 mmol) via a syringe dropwise. The
reaction mixture was stirred at RT for 1 h, then quenched with sat.
NH.sub.4Cl (300 mL) dropwise (exothermic!). It was extracted with
of EtOAc (2.times.300 mL). The combined organic extracts were
washed with water (2.times.30 mL) followed by brine (30 mL), dried
over MgSO.sub.4, and concentrated under reduced pressure. The
resulting oil was purified by silica gel chromatography (0-20%
EtOAc in hexanes) to give Compound 217I (24.05 g, 88% yield) as a
light yellow oil. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 7.77
(dd, J=2.63, 7.02 Hz, 1H), 7.35 (ddd, J=2.63, 4.24, 8.62 Hz, 1H),
6.95 (dd, J=8.62, 11.55 Hz, 1H), 5.25 (d, J=10.52 Hz, 1H), 5.00 (d,
J=10.52 Hz, 1H), 3.78 (s, 3H), 3.61-3.72 (m, 2H), 2.63 (ddd,
J=1.39, 7.86, 9.61 Hz, 1H), 1.72 (d, J=1.17 Hz, 3H), 1.51 (s, 9H),
1.46 (dd, J=5.19, 9.87 Hz, 1H), 1.17 (dd, J=5.33, 7.53 Hz, 1H),
0.88-1.03 (m, 2H), 0.00 (s, 9H). MS (ESI, positive ion) m/z:
603/605 (M+1).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (217K)
[1347] At RT, to a solution of (1S,5S,6S)-methyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late (217I, 8.7 g, 14.41 mmol) in 70 mL of THF was added lithium
borohydride (2 M solution in THF, 14.41 mL, 28.8 mmol) slowly. MeOH
(4.66 mL, 115 mmol) was then added to the mixture. The mixture
began to bubble and the temperature rose to .about.40.degree. C.
over 15 min. After the mixture was stirred for 1 h, it was cooled
to 0.degree. C. and quenched with 70 mL of sat. aq. NH.sub.4Cl. The
mixture was extracted with 2.times.200 mL of EtOAc. The organic
extracts were washed with 50 mL of brine and dried over MgSO.sub.4.
Filtration and concentration under reduced pressure afforded
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (217J) as a light yellow oil. It was azeotroped with 2.times.5
mL of toluene. MS (ESI, positive ion) m/z: 575/577 (M+1).
[1348] At 0.degree. C., to the crude alcohol (217J) in 50 mL of THF
was added sodium bis(trimethylsilyl)amide (16.58 mL of 1 M in THF
solution, 16.58 mmol) dropwise. The resulting mixture was stirred
at 0.degree. C. for 15 min, then treated with iodomethane (1.12 mL,
18.02 mmol). The mixture was stirred at 0.degree. C. for 1 h then
RT for 15 h. It was diluted with DCM (400 mL) and washed with sat.
NH.sub.4Cl (50 mL) followed by brine (50 mL), dried over
MgSO.sub.4, filtered and concentrated. The crude material was
purified by silica gel chromatography (5-15% EtOAc in hexanes) to
give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (217K) (6.61 g, 11.21 mmol, 78% yield). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -114.48 (s, 1 F). MS (ESI, positive ion) m/z:
589/591 (M+H).sup.+.
Preparation of Compound 217L
[1349] At RT, tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (6.60 g, 11.19 mmol) was treated with sulfuric acid (5.97 mL,
112 mmol). The brown reaction mixture was stirred at RT for 10 min,
then cooled with an ice bath and treated with 100 g of ice.
Potassium phosphate tribasic monohydrate (27.6 g, 120 mmol) was
added in small portions. The pH was then adjusted to 9 with 5 M
NaOH. The mixture was extracted with EtOAc (3.times.200 mL) and the
combined organic extracts were washed with brine (2.times.20 mL),
dried over MgSO.sub.4, filtered, and concentrated. Purification by
flash column chromatography on silica gel column (25-65% EtOAc in
DCM) gave
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-amine (3.31 g, 9.21 mmol, 82% yield)
as a pale yellow amorphous solid. .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -113.99 (s, 1 F). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.90 (dd, J=2.74, 7.24 Hz, 1H), 7.49 (m, 1H),
7.13 (m, 1H), 6.12 (br., 2H), 3.55 (d, J=10.95 Hz, 1H), 3.34 (d,
J=11.15 Hz, 1H), 3.28 (s, 3H), 1.70 (m, 1H), 1.55 (s, 3H), 0.82 (m,
1H), 0.53 (m, 1H). MS (ESI, positive ion) m/z: 359/361 (M+1).
Preparation of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-amine (217)
[1350] To a mixture of copper (I) iodide (0.41 g, 2.16 mmol),
sodium azide (1.97 g, 30.3 mmol), (+)-sodium L-ascorbate (0.09 g,
0.45 mmol), and
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-amine (217L, 3.11 g, 8.66 mmol) at RT
was added EtOH (20 mL) and water (10 mL). The reaction mixture was
degassed by bubbling nitrogen through the solution for 5 min and
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.31 g, 2.16
mmol) was added. The reaction mixture was heated to 70.degree. C.
for 1.5 h. The mixture was cooled to RT, poured into 30 mL of 10/1
mixed solution of saturated NH.sub.4Cl/ammonium hydroxide, and
extracted with EtOAc (2.times.150 mL). The combined organic
extracts were washed with brine (15 mL), dried over MgSO.sub.4,
filtered, and concentrated to give a green sticky oil which
contained
(1S,5S,6S)-5-(5-azido-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-amine. MS (ESI, positive ion) m/z:
322.0 (M+1). The green sticky oil was dissolved in THF (15 mL) and
water (5 mL) and trimethylphosphine (1.0 M solution in THF, 8.66
mL, 8.66 mmol) was added. The reaction mixture was stirred at RT
for 15 min, and then quenched by the addition of water (20 mL) and
EtOAc (100 mL). The layers were separated. The aqueous phase was
extracted with EtOAc (2.times.50 mL). The combined organic extracts
were washed with brine (15 mL), dried over MgSO.sub.4, filtered,
and concentrated. Purification by flash column chromatography on
silica gel (5-85% EtOAc in DCM followed by 5% MeOH in EtOAc) gave
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(methoxymethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-amine (217) (1.96 g, 6.64 mmol, 77%
yield) as a light yellow solid. MS (ESI, positive ion) m/z: 322.0
(M+1). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 6.92 (dd,
J=2.93, 7.24 Hz, 1H), 6.76 (dd, J=8.51, 12.42 Hz, 1H), 6.38 (td,
J=3.45, 8.36 Hz, 1H), 5.87 (br., 2H), 4.79 (br., 2H), 3.55 (d,
J=10.76 Hz, 1H), 3.38 (d, J=10.79 Hz, 1H), 3.35 (s, 3H), 1.63 (m,
1H), 1.54 (s, 3H), 0.81 (m, 1H), 0.54 (m, 1H). .sup.19F NMR (377
MHz, DMSO-d.sub.6) .delta. -128.23 (s, 1 F).
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-amine (218)
##STR00127##
[1351] Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-formyl-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(218A)
[1352] At RT, to tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (217J) (13.25 g, 23.03 mmol) in 45 mL of DCM and 15 mL of DMSO
was added diisopropylethylamine (16.02 mL, 92 mmol) followed by
pyridine sulfur trioxide (7.33 g, 46.1 mmol). The reaction mixture
was stirred at RT for 18 h. It was diluted with DCM (400 mL) and
washed with sat. NH.sub.4Cl (50 mL) followed by brine (50 mL),
dried over MgSO.sub.4, filtered and concentrated. The crude
material was purified by silica gel chromatography (5-15% EtOAc in
hexanes) to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-formyl-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(218A, 10.68 g, 18.62 mmol, 81% yield) as a colorless viscous oil.
MS (ESI, positive ion) m/z: 573/575 (M+1). .sup.19F NMR (377 MHz,
DMSO-d.sub.6) .delta. -114.00 (s, 1 F).
Preparation of
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-amine (218C)
[1353] At -10.degree. C. (ice/salt bath), to a stirring solution of
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-formyl-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(218A, 10.67 g, 18.60 mmol) in 160 mL of hexanes was added
Deoxo-Fluor (11.98 mL, 65.1 mmol). The reaction mixture was stirred
at 0.degree. C. for 1 h then RT overnight. The reaction mixture was
diluted with EtOAc (400 mL), cooled with an ice bath and quenched
with sat. NaHCO.sub.3 (100 mL) slowly over a period of 30 min. The
organic layer was separated, washed with brine (20 mL), dried over
sodium sulfate, filtered and concentrated. The crude material was
purified by column chromatography with 5-10% EtOAc in hexanes to
give a mixture of two compounds (10.49 g) as a sticky oil,
218BB:218B, in about 1:6 ratio. Both products had the mass of MS
(ESI, positive ion) m/z: 595/597 (M+1). The major product,
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carba-
mate (218B) had .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-114.34 (s, 1 F), -115.62 (d, .sup.1J=275.70 Hz, 1 F), -118.55 (d,
.sup.1J=275.70 Hz, 1 F).
[1354] To the above mixture of 218BB:218B (in about 1:6 ratio,
10.49 g) at RT was added sulfuric acid (9.91 mL, 186 mmol). The
reaction mixture was stirred at RT for 10 min. It was poured onto
100 g of ice.
[1355] The brown mixture was cooled with an ice bath and treated
with potassium phosphate tribasic monohydrate (43.8 g, 190 mmol) in
small portions (pH was about 7). The pH was adjusted to 9 with 5 M
NaOH. The aqueous phase was extracted with EtOAc (3.times.200 mL)
and the combined organic extracts were washed with brine
(2.times.20 mL), dried over MgSO.sub.4, filtered, and concentrated.
Purification by flash column chromatography on silica gel column
(25-65% EtOAc in DCM) gave
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-amine (218C, 3.69 g, 10.10 mmol, 54%
yield) as a pale yellow foam. MS (ESI, positive ion) m/z: 365/367
(M+1).
Preparation of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-amine (218)
[1356] To a mixture of copper (I) iodide (0.48 g, 2.52 mmol),
sodium azide (2.29 g, 35.3 mmol), (+)-sodium L-ascorbate (0.09 g,
0.45 mmol), and
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-amine (218C, 3.68 g, 10.08 mmol) at
RT was added EtOH (25 mL) and water (12.5 mL). The reaction mixture
was degassed by bubbling nitrogen through the solution for 5 min
and (1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.36 g, 2.52
mmol) was added. The reaction mixture was heated to 70.degree. C.
for 1.5 h. LCMS indicated the presence of 218C. Additional copper
(I) iodide (0.24 g, 0.22 mmol) and
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.18 g, 1.26
mmol) were added. Heating was resumed at 70.degree. C. for 0.5 h.
The mixture was cooled to RT, poured into 40 mL of 10:1 saturated
NH.sub.4Cl/ammonium hydroxide, and extracted with EtOAc
(2.times.150 mL). The combined organic extracts were washed with
brine (15 mL), dried over MgSO.sub.4, filtered, and concentrated to
give a brown sticky oil which contained
(1S,5S,6S)-5-(5-azido-2-fluorophenyl)-1-(difluoromethyl)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine. MS (ESI, positive
ion) m/z: 328.0 (M+1). The brown sticky oil was dissolved in THF
(15 mL) and water (5 mL) and trimethylphosphine (1.0 M solution in
THF) (10.08 mL, 10.08 mmol) was added. The reaction mixture was
stirred at RT for 15 min, and diluted with water (20 mL) and EtOAc
(100 mL). The layers were separated. The aqueous phase was
extracted with EtOAc (2.times.50 mL). The combined organic extracts
were washed with brine (15 mL), dried over MgSO.sub.4, filtered,
and concentrated. Purification by flash column chromatography on
silica gel column (5-85% EtOAc in DCM) gave: 1) The 1st eluent was
the recovered
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-amine (218C, 240 mg). MS (ESI,
positive ion) m/z: 365/367 (M+1). 2) The 2nd eluent was
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(difluoromethyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-amine (218) (1.77 g, 5.87 mmol, 58%
yield) as a light yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 6.75 (m, 2H), 6.36 (m, 1H), 6.17 (br., 2H), 5.76-6.04 (m,
1H), 4.80 (br., 2H), 1.81 (m, 1H), 1.57 (s, 3H), 1.25 (m, 1H), 0.63
(m, 1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -114.65 (d,
.sup.1J=274.10 Hz, 1 F), -118.13 (d, .sup.1J=274.10 Hz, 1 F),
-127.65 (s, 1 F). MS (ESI, positive ion) m/z: 302.1 (M+1).
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-amine (219)
##STR00128##
[1357] Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (219A)
[1358] This compound (3.40 g, 5.89 mmol, 70% yield) as a light
yellow sticky oil was prepared from 217I (5.07 g, 8.40 mmol)
according to the procedures similar to those described for
intermediate 216A. MS (ESI, positive ion) m/z: 577/579 (M+1).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -114.36 (s, 1 F),
-212.20 (s, 1 F)
Preparation of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-amine (219B)
[1359] This compound (1.69 g, 4.87 mmol, 85% yield) as a pale
yellow foam was prepared from tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (219A, 3.30 g, 5.71 mmol) according to the procedures similar to
those described for intermediate 217L. .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -113.80 (s, 1 F), -211.59 (s, 1 F). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.89 (dd, J=2.74, 7.24 Hz, 1H),
7.46 (m, 1H), 7.17 (dd, J=8.61, 11.93 Hz, 1H), 6.23 (br., 2H),
4.34-4.65 (m, 2H), 1.86 (m, 1H), 1.59 (s, 3H), 0.89 (m, 1H), 0.60
(m, 1H). MS (ESI, positive ion) m/z: 347/349 (M+1).
Preparation of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-amine (219)
[1360] This compound (1.08 g, 3.81 mmol, 79% yield) as a brown
amorphous solid was prepared from
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(fluoromethyl)-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-amine (219B, 1.68 g, 4.84 mmol)
according to the procedures similar to those described for
intermediate 217. .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-128.09 (s, 1 F), -211.32 (s, 1 F). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 6.88 (dd, J=2.74, 7.04 Hz, 1H), 6.76 (dd,
J=8.51, 12.42 Hz, 1H), 6.39 (td, J=3.42, 8.41 Hz, 1H), 5.98 (br.,
2H), 4.79 (br., 2H), 4.32-4.57 (m, 2H), 1.78 (m, 1H), 1.54 (s, 3H),
0.95 (m, 1H), 0.59 (q, J=5.15 Hz, 1H). MS (ESI, positive ion) m/z:
284.0 (M+1).
(1R,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-5-methyl-1-(methylsulfonyl)-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-3-amine (220)
##STR00129##
[1361] Preparation of (S)-tert-butyl
(4-(2,3-difluorophenyl)-6-iodo-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethy-
lsilyl)ethoxy)methyl)carbamate (220A)
[1362] A solution of lithium diisopropylamide (2.0 M in
THF/heptane/ethylbenzene) (4.2 mL, 8.4 mmol) was added dropwise to
a stirring solution of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethylsilyl)-
ethoxy)methyl)carbamate (203G, 3.3 g, 7.0 mmol) in THF (70 mL)
under a nitrogen atmosphere at -78.degree. C. The solution was
stirred at -78.degree. C. for 15 min and then a solution of iodine
(2.1 g, 8.4 mmol) in THF (15 mL) was added dropwise. The dark red
mixture was stirred at -78.degree. C. for another 10 min and the
reaction was quenched with saturated aqueous Na.sub.2S.sub.2O.sub.3
solution (40 mL). The mixture was allowed to warm to RT and then
diluted with water (40 mL) and extracted with EtOAc (2.times.75
mL). The combined organic extracts were washed with brine (40 mL),
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
The residue was purified by silica gel chromatography eluting with
a gradient of 2.5-10% EtOAc/heptane to give (S)-tert-butyl
(4-(2,3-difluorophenyl)-6-iodo-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethy-
lsilyl)ethoxy)methyl)carbamate as a yellow oil (220A, 4.2 g, 100%).
LC/MS (ESI.sup.+) m/z=597.0 (M+H). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.24-7.30 (m, 1H), 6.98-7.15 (m, 2H), 6.68
(d, J=3.13 Hz, 1H), 5.30-5.37 (m, 1H), 5.20-5.27 (m, 1H), 3.65 (t,
J=8.31 Hz, 2H), 1.72 (s, 3H), 1.55 (s, 9H), 0.91-0.96 (m, 2H), 0.00
(s, 9H).
Preparation of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-6-(methylsulfonyl)-4H-1,3-thiazin-2-yl)(-
(2-(trimethylsilyl)ethoxy)methyl)carbamate (220B)
[1363] (S)-tert-Butyl
(4-(2,3-difluorophenyl)-6-iodo-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethy-
lsilyl)ethoxy)methyl)carbamate (220A, 4.2 g, 7.0 mmol), potassium
metabisulfite (3.13 g, 14.1 mmol), tetrabutylammonium bromide (2.50
g, 7.74 mmol), sodium formate (1.05 g, 15.5 mmol), palladium(ii)
acetate (0.079 g, 0.35 mmol), triphenylphosphine (0.277 g, 1.06
mmol), 1,10-phenanthroline (0.190 g, 1.06 mmol) and DMSO (20 mL)
were combined under a nitrogen atmosphere. The mixture was degassed
by bubbling nitrogen through it for 10 min. The mixture was then
heated at 70.degree. C. for 1 h. The mixture was allowed to cool to
RT and then methyl iodide (0.66 mL, 10.6 mmol) was added. The
mixture was stirred at RT for 1 h. The reaction was then diluted
with water (40 mL) and extracted with EtOAc (3.times.30 mL). The
combined organic extracts were washed with brine (40 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by silica gel chromatography eluting with a
gradient of 0-35% EtOAc/heptane to give (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-6-(methylsulfonyl)-4H-1,3-thiazin-2-yl)(-
(2-(trimethylsilyl)ethoxy)methyl)carbamate as a yellow oil (220B,
1.8 g, 47%). LC/MS (ESI.sup.+) m/z=549.0 (M+H). .sup.1H NMR (400
MHz, chloroform-d) .delta. 7.29-7.32 (m, 1H), 7.04-7.18 (m, 3H),
5.32-5.37 (m, 1H), 5.22-5.28 (m, 1H), 3.65 (t, J=8.22 Hz, 2H), 3.03
(s, 3H), 1.79 (s, 3H), 1.57 (s, 9H), 0.91-0.95 (m, 2H), -0.01 (s,
9H).
Preparation of tert-butyl
((1R,5S,6S)-5-(2,3-difluorophenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(220C)
[1364] Potassium tert-butoxide (0.41 g, 3.6 mmol) was added to a
solution of trimethylsulfoxonium iodide (0.81 g, 3.6 mmol) in DMSO
(10 mL) at RT. The solution was stirred at RT for 1 h and then
added dropwise over 5 min by addition funnel to a solution of
(S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-6-(methylsulfonyl)-4H-1,3-thiazin-2-yl)(-
(2-(trimethylsilyl)ethoxy)methyl)carbamate (220B, 1.80 g, 3.28
mmol) in THF (10 mL). The solution was stirred at RT for 1 h. The
reaction was quenched with saturated aqueous NH.sub.4Cl (20 mL) and
diluted with water (20 mL). The mixture was extracted with 3:1
heptane:EtOAc (2.times.50 mL) and the combined organic extracts
were washed with water (30 mL), brine (30 mL), dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue was
purified by silica gel chromatography eluting with a gradient of
3-30% EtOAc/heptane to give tert-butyl
((1R,5S,6S)-5-(2,3-difluorophenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
as a yellow oil (220C, 1.55 g, 84%). LC/MS (ESI.sup.+) m/z=563.2
(M+H). .sup.1H NMR (400 MHz, chloroform-d) .delta. 7.30 (s, 1H),
7.01-7.19 (m, 2H), 5.37 (d, J=10.37 Hz, 1H), 5.13 (d, J=10.37 Hz,
1H), 3.66 (dt, J=2.54, 8.22 Hz, 2H), 3.12 (s, 3H), 2.55 (dd,
J=7.92, 10.07 Hz, 1H), 1.93 (dd, J=6.16, 10.47 Hz, 1H), 1.84 (s,
3H), 1.55 (s, 9H), 1.15 (t, J=6.85 Hz, 1H), 0.91-0.98 (m, 2H), 0.02
(s, 9H).
Preparation of
(1R,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-1-(methylsulfonyl)-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (220D)
[1365] This compound (900 mg, 89% yield) as a yellow solid was
prepared from intermediate 220C (1.5 g, 2.67 mmol) using the
procedures similar to those described for intermediate 203L. LC/MS
(ESI.sup.+) m/z=378.0 (M+H). .sup.1H NMR (400 MHz, chloroform-d)
.delta. 8.26 (ddd, J=1.96, 2.84, 5.77 Hz, 1H), 8.04 (ddd, J=2.74,
6.36, 9.10 Hz, 1H), 4.78 (br. s., 2H), 3.06 (s, 3H), 2.47 (ddd,
J=0.98, 7.73, 10.27 Hz, 1H), 2.04 (dd, J=6.26, 10.37 Hz, 1H), 1.83
(d, J=1.37 Hz, 3H), 1.03-1.09 (m, 1H).
Preparation of
(1R,5S,6S)-5-(5-amino-2,3-difluorophenyl)-5-methyl-1-(methylsulfonyl)-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (220)
[1366] This compound (420 mg, 51% yield) as a yellow crystalline
solid was prepared from intermediate 220D (900 mg, 2.39 mmol) using
the procedures similar to those described for intermediate 203.
LC/MS (ESI.sup.+) m/z=348.1 (M+H). .sup.1H NMR (400 MHz,
chloroform-d) .delta. 6.39 (ddd, J=2.74, 6.16, 11.25 Hz, 1H),
6.27-6.34 (m, 1H), 3.61 (br. s., 2H), 3.01 (s, 3H), 2.34 (dd,
J=7.63, 10.37 Hz, 1H), 2.14 (dd, J=6.16, 10.27 Hz, 1H), 1.82 (d,
J=0.98 Hz, 3H), 1.01-1.09 (m, 1H).
(1S,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-N-cyclopropyl-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (221) and tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(cyclopropylcarbamoyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (221D)
##STR00130##
[1367] Preparation of Acid 221A
[1368] A mixture of (1S,5S,6S)-methyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late (217I, 4.0 g, 6.63 mmol), and lithium hydroxide (19.88 mL of 1
M aqueous solution, 19.88 mmol) in MeOH (60 mL) was stirred at RT
in 16 h. The reaction mixture was concentrated, diluted with
H.sub.2O, cooled in an ice bath and acidified with 5 N HCl. The
solid (3.9 g, 100%) was collected, washed with H.sub.2O, dried and
used in the next step. MS (ESI, positive ion) m/z: 589/591
(M+1).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(cyclopropylcarbamoyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (221B)
[1369] To a solution of
(1S,5S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethyl-
silyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxylic acid (221A, 5.3 g, 9.0 mmol) in 40 mL dry THF was added
1,1'-carbonyldiimidazole (2.2 g, 13.5 mmol), and the resulting
cloudy mixture was stirred for 1 h. Additional
1,1'-carbonyldiimidazole (0.7 g) was added. It was stirred for 30
min then treated with cyclopropylamine (5 mL, 71.3 mmol). After the
mixture was stirred for 1.5 h, it was treated with 100 mL of EtOAc
and 100 mL of brine. The layers were separated. The organic layer
was washed 1 N HCl (10 mL) followed by with brine (2.times.10 mL),
dried over Na.sub.2SO.sub.4, filtered, and concentrated to give the
title compound (221B, 5.4 g, 96%). MS (ESI, positive ion) m/z:
628/630 (M+1).
Preparation of
(1S,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-N-cyclopropyl-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (221C)
[1370] At RT, concentrated sulfuric acid (20 mL) was added to
tert-butyl
((1S,5S)-5-(5-bromo-2-fluorophenyl)-1-(cyclopropylcarbamoyl)-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)ca-
rbamate (221B, 5.43 g, 8.64 mmol) dropwise. After the brown sticky
mixture was stirred for 10 min, it was added slowly to a mixture of
400 mL of DCM and 200 g of ice cooled with an ice bath. Solid
K.sub.3PO.sub.4 was added in small portions untill pH was about 7.
500 mL of water was added, and the mixtured was partitioned. The
layers were separated. The aqueous solution was extracted with a
mixed solvent of (400 mL DCM+50 mL MeOH). The combined organic
extracts were dried over Na.sub.2SO.sub.4 and evaporated to give
the title compound (1.23 g, 36%). MS (ESI, positive ion) m/z:
398/400 (M+1).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(cyclopropylcarbamoyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (221D)
[1371] A mixture of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(cyclopropylcarbamoyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (221B, 3.5 g, 5.57 mmol), sodium azide (1.08 g, 16.70
mmol), copper(i) iodide (318 mg, 1.67 mmol), (+)-sodium L-ascorbate
(0.33 g, 1.67 mmol), and
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.26 mL, 1.67
mmol) in EtOH/H.sub.2O (4:1, 50 mL) was heated at 90.degree. C. for
2 h. The reaction mixture was cooled to RT and treated with
NH.sub.4Cl/NH.sub.4OH (9:1, 20 mL) and stirred for 10 min. The
mixture was extracted with CHCl.sub.3 (3.times.). The organic
extracts were concentrated to dryness and dissolved in THF/H.sub.2O
(9:1, 40 mL) and added trimethylphosphine (1.0 M solution in THF,
8.35 mL, 8.35 mmol) and the mixture was stirred at RT overnight. It
was treated with saturated aqueous NH.sub.4Cl and extracted with
CHCl.sub.3 (3.times.). The extracts were dried over
Na.sub.2SO.sub.4 and concentrated to give the title compound (3.1
g, 99%). MS (ESI, positive ion) m/z: 564/566 (M+1).
Preparation of
(1S,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-N-cyclopropyl-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (221)
[1372] A mixture of
(1S,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-N-cyclopropyl-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (221C, 1.2 g, 3.01
mmol), sodium azide (0.59 g, 9.04 mmol), copper(I) iodide (0.14 g,
0.75 mmol), sodium
(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3--
olate (0.15 g, 0.75 mmol), and
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.147 ml, 0.753
mmol) in EtOH/H.sub.2O (5:1, 18 mL) was heated at 90.degree. C. for
16 h. The reaction mixture was cooled to RT and partitioned between
NH.sub.4Cl/NH.sub.4OH (9:1, 10 mL) and DCM (100 mL). The organic
layer was concentrated and the residue was dissolved in
THF/H.sub.2O (9:1, 20 mL). To this stirring solution was added
trimethylphosphine (3.01 mL of 1 M in THF solution, 3.01 mmol).
After the addition, the mixture was stirred for 1 h, diluted with
EtOAc, washed with H.sub.2O, brine, dried over MgSO.sub.4,
concentrated and the residue was purified by silica gel column
(10-20% MeOH/DCM) to give the title product (0.41 g, 41%). MS (ESI,
positive ion) m/z: 335 (M+1).
((1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-1-yl)(pyrrolidin-1-yl)methanone (222)
##STR00131##
[1374] tert-Butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-methyl-1-(pyrrolidine-1-carbonyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)c-
arbamate (222A, 3.1 g, 5.30 mmol, 100% yield) as colorless oil was
prepared according to the procedures described for intermediate
226B, starting from
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carboxylic acid (226A, 2.8 g, 5.30 mmol), CDI (1.29 g, 7.94 mmol)
and pyrrolidine (1.33 mL, 15.89 mmol). LC/MS (ESI.sup.-) m/z=582.2
(M+H).sup.+.
[1375]
((1S,5S,6S)-3-Amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)(pyrrolidin-1-yl)methanone (222B,
1.29 g, 3.25 mmol, 63% yield) as off white solid was prepared
according to the procedures described for intermediate 226C,
starting from tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-methyl-1-(pyrrolidine-1-carbonyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)c-
arbamate (222A, 3.0 g, 5.16 mmol). LC/MS (ESI.sup.-) m/z=397.1
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.31-8.38
(m, 2H), 6.51 (s, 2H), 3.60 (br., 2H), 3.28 (br., 2H), 2.14-2.20
(m, 1H), 1.83-1.93 (m, 2H), 1.81 (m, 2H), 1.70 (s, 3H), 1.31 (dd,
J=5.58, 9.49 Hz, 1H), 0.71-0.76 (m, 1H).
[1376]
((1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)(pyrrolidin-1-yl)methanone (222)
(0.78 g, 2.1 mmol, 98% yield) as white solid was prepared according
to the procedures described for intermediate 226, starting from
((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-1-yl)(pyrrolidin-1-yl)methanone (222B, 850
mg, 2.14 mmol). LC/MS (ESI.sup.-) m/z=367.1 (M+H). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 6.47-6.52 (m, 1H), 6.34 (ddd, J=2.84,
6.31, 12.57 Hz, 1H), 6.17 (br. s., 2H), 5.11 (s, 2H), 3.59 (d,
J=18.78 Hz, 2H), 3.29 (d, J=9.00 Hz, 2H), 1.95-2.03 (m, 1H), 1.86
(br. s., 2H), 1.80 (br. s., 2H), 1.63 (s, 3H), 1.30 (dd, J=5.28,
9.39 Hz, 1H), 0.60-0.67 (m, 1H).
(1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-N,5-dimethyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-ene-1-carboxamide (223)
##STR00132##
[1377] Preparation of Compound 223A
[1378] To a stirring solution of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carboxylic acid (226A, 13.0 g, 24.59 mmol) and
N,N-diisopropylethylamine (5.35 ml, 30.7 mmol) in CHCl.sub.3 (50
mL) and ACN (50 mL) at 20.degree. C. was added HATU (10.75 g, 28.3
mmol). The solution was stirred for 45 min at 20.degree. C. To the
reaction was added methylamine (2.0 M in THF, 36.9 mL, 73.8 mmol).
After 30 min the reaction was partitioned between EtOAc (300 mL)
and sat. NaHCO.sub.3 (200 mL). The organic layer was washed
sequentially with 1 M NaOH (150 mL), 1 M HCl (150 mL), and brine
(50 mL). The organic extract was then dried over MgSO.sub.4,
filtered, then concentrated under reduced pressure to afford light
oil. The material was then purified by silica gel chromatography
(330 g) eluting products with 0-25% EtOAc/heptane to afford
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-methyl-1-(methylcarbamoyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamat-
e (223A, 11.1 g, 20.49 mmol, 83% yield) as colorless tar. LC/MS
(ESI.sup.-) m/z=542.2 (M+H).
Preparation of Compound 223B
[1379] To a 500 mL flask containing tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-5-methyl-1-(methylcarbamoyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamat-
e (223A, 5.5 g, 10.15 mmol) at 0.degree. C. under nitrogen was
added sulfuric acid (16.24 mL, 305 mmol). Gas evolution was
evident. After 15 min, the reaction flask was removed from cooling
bath, swirled by hand, then allowed to stir at 20.degree. C. for 30
min. The mixture was chilled to 0.degree. C. and sodium nitrate
(0.86 g, 10.15 mmol) was added. The reaction was stirred for 15 min
at 0.degree. C. then more sodium nitrate (0.86 g, 10.15 mmol)
added. The reaction was stirred at 20.degree. C. for 45 min. The
reaction was then slowly poured onto wet ice (700 mL) and the
mixture along with CH.sub.2Cl.sub.2 (150 mL). To a rapidly stirred
mixture was added potassium phosphate tribasic monohydrate (105 g,
457 mmol) over 40 min (pH.about.8). The suspension was filtered and
the filtrate was transferred to a separatory funnel. The organic
layer was separated, and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (100 mL). The combined organic extracts were dried
over MgSO.sub.4, filtered, concentrated under reduced pressure,
then purified via silica gel chromatography (120 g) eluting the
products with a gradient of 0-50% EtOAc/CH.sub.2Cl.sub.2 to afford
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-nitrophenyl)-N,5-dimethyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-ene-1-carboxamide (223B, 2.2 g, 6.17 mmol,
60.8% yield) as off white solid. LC/MS (ESI.sup.-) m/z=357.0 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.45-8.50 (m, 1H), 8.36
(ddd, J=2.93, 6.36, 9.49 Hz, 1H), 7.73 (t, J=5.63 Hz, 1H), 6.41 (s,
2H), 2.64 (d, J=4.50 Hz, 3H), 2.25 (t, J=8.22 Hz, 1H), 1.64 (s,
3H), 1.39 (dd, J=5.28, 9.59 Hz, 1H), 0.84 (dd, J=5.48, 7.04 Hz,
1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -126.77 (d,
J=21.16 Hz, 1 F), --134.13 (d, J=21.16 Hz, 1 F).
Preparation of Compound 223
[1380] To a stirring solution of
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-nitrophenyl)-N,5-dimethyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-ene-1-carboxamide (223B, 2.2 g, 6.17 mmol)
in HOAc (20 mL) and TFA (5 mL) at 20.degree. C. was added zinc dust
(1.61 g, 24.69 mmol) in 4 portions over the period of 15 min. After
1 h, the suspension was filtered through a pad of Celite.RTM.
filter aid and the metallic residue was extensively washed with
CH.sub.2Cl.sub.2 (100 mL). The filtrate was then chilled to
0.degree. C. and 30% NH.sub.4OH (50 mL) was added drop wise via
addition funnel over a 10 min period. The mixture was partitioned,
and the aqueous portion was further extracted with CH.sub.2Cl.sub.2
(50 mL). The combined organic extracts were dried over MgSO.sub.4,
filtered, and concentrated under reduced pressure to afford
(1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-N,5-dimethyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-ene-1-carboxamide (223, 1.91 g, 5.85 mmol,
95% yield) as yellow foam. LC/MS (ESI.sup.-) m/z=327.1 (M+H).
(1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-ene-1-carbonitrile (224)
##STR00133##
[1381] Preparation of Compound 224A
[1382] To a solution of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carboxylic acid (226A, 4 g, 7.57 mmol) in THF (40 mL) at 20.degree.
C. was added 1,1'-carbonyldiimidazole (1.84 g, 11.35 mmol). The
suspension was stirred for 1 h at 20.degree. C. The solution was
chilled to 0.degree. C. and ammonia was introduced from a lecture
bottle. After 30 min, the reaction was partitioned between EtOAc
(30 mL) and 1 M HCl (30 mL). The organic extracts were washed with
brine (25 mL), dried over MgSO.sub.4, filtered, and concentrated
under reduced pressure to afford tert-butyl
((1S,5S,6S)-1-carbamoyl-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(224A, 4 g, 7.58 mmol, 100% yield) as colorless oil. LC/MS
(ESI.sup.-) m/z=528.2 (M+H).
[1383]
(1S,5S,6S)-3-Amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (224B, 1.4 g, 4.1 mmol,
54% yield) as tan foam was prepared according to the procedures
described for intermediate 223B, starting from tert-butyl
((1S,5S,6S)-1-carbamoyl-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(224A, 4.0 g, 7.58 mmol). LC/MS (ESI.sup.-) m/z=343.0 (M+H).
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.49 (d, J=5.60 Hz,
1H), 8.35 (ddd, J=2.93, 6.36, 9.49 Hz, 1H), 7.32 (br. s., 1H), 7.25
(br. s., 1H), 6.36 (s, 2H), 2.28 (t, J=8.41 Hz, 1H), 1.63 (s, 3H),
1.37 (dd, J=5.28, 9.59 Hz, 1H), 0.86 (dd, J=5.58, 6.94 Hz, 1H).
Preparation of Compound 224C
[1384] To a stirring solution of
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-ene-1-carboxamide (224B, 280 mg, 0.82 mmol) in
glacial HOAc (3 mL) and TFA (0.5 mL) at 20.degree. C. was added
zinc dust (270 mg, 4.09 mmol) in 5 portions. The suspension was
stirred for 30 min at 20.degree. C. then filtered. The metal
residue was extensively washed with CH.sub.2Cl.sub.2 (10 mL). The
filtrate was then chilled to 0.degree. C. and 30% NH.sub.4OH (5 mL)
was added drop wise via addition funnel over a 10 min period. After
separation of the organic the aqueous was further extracted with
9:1 CHCl.sub.3/IPA (3.times.20 mL). The combined organics were
dried over MgSO.sub.4 and concentrated under reduced pressure to
afford
(1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (224C, 295 mg, 0.944
mmol, 115% yield) as yellow foam. LC/MS (ESI.sup.-) m/z=313.1
(M+H).
Preparation of Compound 224D
[1385] To a stirring solution of
(1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-ene-1-carboxamide (224C, 250 mg, 0.80 mmol) and
N,N-diisopropylethylamine (2.08 mL, 12.01 mmol) in THF (10 mL) at
-70.degree. C. under nitrogen was added trifluoroacetic anhydride
(1.33 mL, 9.60 mmol). After 1 h, the reaction was quenched with
sat. NH.sub.4Cl (1 mL). The mixture was partitioned between EtOAc
(10 mL) and 5% NaHCO.sub.3 (10 mL). The organic layer was dried
over MgSO.sub.4, filtered, then concentrated under reduced pressure
to afford
N-((1S,5S,6S)-1-cyano-5-(2,3-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-
-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)-2,2,2-trifluoroacetami-
de (224D, 450 mg, 0.92 mmol, 116% yield) as tan oil. LC/MS
(ESI.sup.-) m/z=487.0 (M+H).
Preparation of Compound 224
[1386] A solution of
N-((1S,5S,6S)-1-cyano-5-(2,3-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-
-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)-2,2,2-trifluoroacetami-
de (224D, 375 mg, 0.771 mmol) in 2 M NH.sub.3 in MeOH (10 mL) was
stirred for 18 h at 42.degree. C. in a closed screw top vial. The
solvent was removed under reduced pressure and the residue was
purified by silica gel chromatography (12 g) eluting products with
a gradient of 1-5% 2 M NH.sub.3 in MeOH/CH.sub.2Cl.sub.2 to afford
(1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-ene-1-carbonitrile (224, 100 mg, 0.34 mmol, 44%
yield) as yellow film. LC/MS (ESI.sup.-) m/z=295.1 (M+H). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 6.49 (br. s., 2H), 6.34-6.44
(m, 2H), 5.11-5.21 (m, 2H), 2.29 (dd, J=8.02, 9.59 Hz, 1H), 1.87
(dd, J=5.87, 9.78 Hz, 1H), 1.68 (s, 3H), 0.96 (t, J=6.65 Hz,
1H).
tert-butyl
((1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-1-(tert-butylcarbamoyl)--
5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)etho-
xy)methyl)carbamate (225)
##STR00134##
[1387] Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(tert-butylcarbamoyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (225A)
[1388] To a mixture of
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimet-
hylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
e-1-carboxylic acid (221A, 5.19 g, 8.82 mmol), tert-butylamine
(1.20 mL, 11.47 mmol), and DIEA (2.03 mL, 11.47 mmol) in DMF (30
ML) was added HATU (4.02 g, 10.58 mmol). After the addition, the
mixture was stirred for 2 h. It was partitioned between H.sub.2O
(50 mL) and DCM (150). The extracts were dried over
Na.sub.2SO.sub.4, and concentrated to give the title compound (5.6
g, 100%). MS (ESI, positive ion) m/z: 644/646 (M+1).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-(tert-butylcarbamoyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (225)
[1389] The title compound (3.63 g, 71%) was prepared according to
the procedures described for intermediate 221D, starting from
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(tert-butylcarbamoyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (225A, 5.69 g, 8.83 mmol). MS (ESI, positive ion) m/z:
581 (M+1).
(1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-N,N,5-trimethyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (226)
##STR00135##
[1390] Preparation of Compound 226A
[1391] To a stirring solution of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 13.4 g, 24.7 mmol) in THF (100 mL) and MeOH (50 mL) was
added a solution of lithium hydroxide monohydrate (3.1 g, 74.1
mmol) in water (50 mL). The reaction was rapidly stirred at
35.degree. C. for 1 h. The reaction mixture was then partitioned
between EtOAc (400 mL) and 1 M HCl (200 mL). The organic layer was
washed with brine (2.times.50 mL), dried over MgSO.sub.4, filtered,
then concentrated under reduced pressure to afford
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)meth-
yl)amino)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-
-ene-1-carboxylic acid (226A, 13 g, 24.59 mmol, 100% yield) as
colorless oil. LC/MS (ESI.sup.-) m/z=529.1 (M+H).sup.+.
Preparation of Compound 226B
[1392] To a stirring solution of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1--
carboxylic acid (226A, 2.0 g, 3.8 mmol) in THF (20 mL) at RT under
nitrogen was added 1,1'-carbonyldiimidazole (0.9 g, 5.6 mmol). The
cloudy solution was stirred for 90 min at RT followed by addition
of dimethylamine (2.0 M in THF, 9.46 mL, 18.91 mmol). After 2 h the
reaction mixture was partitioned between EtOAc (60 mL) and 1 M HCl
(60 mL). The organic layer was washed with brine (25 mL), dried
over MgSO.sub.4, filtered, and concentrated under reduced pressure
to afford
tert-butyl((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(dimethylcarbamoyl)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)met-
hyl)carbamate (226B, 2.1 g, 3.78 mmol) as colorless oil. LC/MS
(ESI.sup.-) m/z=556.3 (M+H).sup.+.
Preparation of Compound 226C
[1393] To a 500 mL flask containing tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(dimethylcarbamoyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (226B, 2.0 g, 3.60 mmol) at 0.degree. C. was added sulfuric
acid (14.39 mL, 270 mmol). The reaction was periodically removed
from cooling bath, swirled by hand, and then allowed to stir at RT
for 1 hr. The material was chilled to 0.degree. C. and sodium
nitrate (0.31 g, 3.60 mmol) was added. The reaction was stirred for
15 min at 0.degree. C. then more sodium nitrate (0.31 g, 3.60 mmol)
added. The reaction was stirred at RT for 45 min, then poured onto
wet ice (700 mL) and the mixture along with CH.sub.2Cl.sub.2 (150
mL). To a rapidly stirred mixture was added potassium phosphate
tribasic monohydrate (83 g, 360 mmol) over 20 min. The suspension
was filtered and the filtrate transferred to a separatory funnel.
The organic layer was separated, and the aqueous layer was
extracted with 9:1 CHCl.sub.3/IPA (2.times.50 mL). The combined
organic layers were dried over MgSO.sub.4, filtered, concentrated
under reduced pressure, then purified via silica gel flash column
chromatography (40 g) eluting the products with a gradient of 0-50%
EtOAc/CH.sub.2Cl.sub.2 to afford
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-nitrophenyl)-N,N,5-trimethyl--
2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (226C, 0.89 g,
2.40 mmol, 66.8% yield) as off white solid. LC/MS (ESI.sup.-)
m/z=371.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.32 (br. s., 1H), 8.01 (ddd, J=2.74, 6.26, 9.00 Hz, 1H), 3.05 (br.
s., 6H), 2.43 (t, J=8.31 Hz, 1H), 1.90 (s, 3H), 1.40 (br. s., 1H),
0.99 (t, J=6.65 Hz, 1H).
Preparation of Compound 226
[1394] To a stirring solution of
(1S,5S,6S)-3-amino-5-(2,3-difluoro-5-nitrophenyl)-N,N,5-trimethyl-2-thia--
4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (226C, 200 mg, 0.540
mmol) in glacial HOAc (2 mL) and TFA (0.5 mL) was added zinc nano
powder (177 mg, 2.70 mmol) in five portions. The reaction was
stirred for 2 h at 20.degree. C. The reaction was then partitioned
between 9:1 CHCl.sub.3/IPA (30 mL) and 30% NH.sub.4OH (20 mL). The
aqueous was further extracted with 9:1 CHCl.sub.3/IPA (2.times.15
mL). The organics were then washed with brine (10 mL), dried over
MgSO.sub.4, filtered, then concentrated under reduced pressure to
afford
(1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-N,N,5-trimethyl-2-thia--
4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (226, 170 mg, 0.50
mmol, 92% yield) as colorless film. LC/MS (ESI.sup.-) m/z=341.0
(M+H).sup.+.
((1S,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-5-methyl-2-thia-4-azabicycl-
o[4.1.0]hept-3-en-1-yl)(pyrrolidin-1-yl)methanone (227)
##STR00136##
[1396] The title compound was prepared according to the synthetic
sequence described for intermediate 221, starting from
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimet-
hylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
e-1-carboxylic acid (221A). MS (ESI, positive ion) m/z: 349.0
(M+1). .sup.1H NMR (CHLOROFORM-d) .delta.: 6.82 (dd, J=11.6, 8.5
Hz, 1H), 6.76 (dd, J=6.6, 2.8 Hz, 1H), 6.49 (dt, J=8.2, 3.2 Hz,
1H), 3.65 (d, J=16.6 Hz, 4H), 3.46 (br. s., 2H), 2.11-2.26 (m, 1H),
1.91 (d, J=18.6 Hz, 4H), 1.81 (s, 3H), 1.43 (dd, J=9.7, 5.6 Hz,
1H), 0.79 (t, J=6.3 Hz, 1H).
tert-Butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamat-
e (228)
##STR00137##
[1397] Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-formyl-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(228A)
[1398] To a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(hydroxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (214K, 3.0 g, 5.20 mmol) in DCM (30 mL) and DMSO (10 mL)
was added diisopropylethylamine (3.8 mL, 21.85 mmol) and pyridine
sulfur trioxide (1.8 g, 11.31 mmol). After 18 h, the mixture was
diluted with EtOAc (200 mL) and washed with water (4.times.50 mL),
brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified by chromatography on silica using EtOAc in
heptane (5-35%) as eluent to give the desired product as a
colorless oil (2.31 g, 77%). LCMS (ESI, pos.) 574.0/576.0 (M+1).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.96 (s, 1H), 8.25 (dd,
J=2.54, 8.61 Hz, 1H), 8.15-8.20 (m, 1H), 5.23-5.33 (m, 1H), 5.03
(d, J=10.56 Hz, 1H), 3.58-3.70 (m, 2H), 2.59 (ddd, J=1.17, 7.82,
9.59 Hz, 1H), 1.71 (d, J=0.98 Hz, 3H), 1.58 (dd, J=5.97, 9.88 Hz,
1H), 1.52 (s, 9H), 1.30-1.41 (m, 1H), 0.91-1.01 (m, 2H), 0.00 (s,
9H). .sup.19F NMR (376 MHz, CHLOROFORM-d) .delta. -67.51 (s).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(228B)
[1399] A stream of Ar was bubbled through a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-formyl-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(0.99 g, 1.72 mmol) in 1,2-dichloroethane (8 mL) for 5 min before
Wilkinson's catalyst (1.59 g, 1.72 mmol) was added. The mixture was
heated at 90.degree. C. under N.sub.2. After 18 h, the mixture was
allowed to cool to RT and filtered. The filtrate was loaded
directly on a 220 g silica gel column. The remaining solids were
washed with DCM (5.times.3 mL) and the mother liquid was
concentrated and the residue was loaded to the silica gel column.
The column was eluted with EtOAc in heptane (5-25%) to give the
title compound as a colorless oil (0.60 g, 64%). LCMS (ESI, pos.)
546.0/548.0 (M+1). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.20
(dd, J=2.45, 8.51 Hz, 1H), 8.14 (s, 1H), 5.26 (d, J=10.56 Hz, 1H),
4.99 (d, J=10.56 Hz, 1H), 3.61-3.73 (m, 2H), 2.21 (dt, J=5.18, 8.26
Hz, 1H), 1.97-2.08 (m, 1H), 1.74 (s, 3H), 1.52 (s, 9H), 0.98 (dd,
J=7.43, 9.19 Hz, 2H), 0.81-0.92 (m, 1H), 0.63 (q, J=5.74 Hz, 1H),
0.01 (s, 9H). .sup.19F NMR (377 MHz, CHLOROFORM-d) .delta. -67.82
(s).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(228)
[1400] A mixture of (+)-sodium L-ascorbate (50 mg, 0.25 mmol),
sodium azide (200 mg, 3.08 mmol),
trans-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol),
copper(I) iodide (30 mg, 0.16 mmol) and tert-butyl
((5S)-5-(5-bromo-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate (600
mg, 1.10 mmol) was purged with N.sub.2 through vacuum-back fill
three times. EtOH (10 mL) and water 2.5 mL) were added. The blue
mixture was heated at 95.degree. C. under N.sub.2. After 1 h, more
(+)-sodium L-ascorbate (50 mg, 0.25 mmol), sodium azide (200 mg,
3.08 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14
mmol) and copper(I) iodide (30 mg, 0.158 mmol) were added. The
mixture was degassed with a stream of Ar for 5 min. The mixture was
heated at 95.degree. C. under N.sub.2. After 30 min, the mixture
was allowed to cool to RT. EtOAc (50 mL) was added and the mixture
was washed with ammonium hydroxide (5 mL) followed by saturated
NH.sub.4Cl (20 mL). The aqueous layer was extracted with DCM
(2.times.10 mL). The combined organic phases were concentrated. The
crude residue was suspended in THF (10 mL) and treated with
trimethylphosphine (1.0 M solution in THF, 1.5 mL, 1.5 mmol). After
2 h at RT, EtOAc (50 mL) was added. The mixture was washed with
saturated NH.sub.4Cl (20 mL) and brine (10 mL). The aqueous layer
was washed with DCM (2.times.10 mL). The combined organic phases
were dried over MgSO.sub.4, filtered, and concentrated. The residue
was purified by chromatography on silica using EtOAc in heptane
(10-70%) as eluent to give the title compound (0.49 g, 86%).
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.51 (d, J=2.35 Hz,
1H), 7.44 (dd, J=2.93, 8.41 Hz, 1H), 5.27 (d, J=10.56 Hz, 1H), 5.01
(d, J=10.56 Hz, 1H), 3.58-3.72 (m, 2H), 2.19 (dt, J=4.89, 8.31 Hz,
1H), 1.99-2.08 (m, 1H), 1.73 (d, J=0.78 Hz, 3H), 0.91-1.00 (m, 2H),
0.85 (dd, J=7.53, 15.16 Hz, 1H), 0.65 (q, J=5.87 Hz, 1H), 0.02 (s,
9H). .sup.19F NMR (376 MHz, CHLOROFORM-d) .delta. -77.66 (br.
s.).
((1S,5S,6R)-3-Amino-5-(5-amino-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (229)
##STR00138## ##STR00139##
[1401] Preparation of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(229A)
[1402] To a 250 mL round bottom flask charged with
(S)-4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-amine
(213E, 1.66 g, 5.51 mmol) and di-tert-butyl dicarbonate (1.20 g,
5.50 mmol, Sigma-Aldrich) was added THF (36 mL) and saturated
sodium bicarbonate aqueous solution (36 mL). The reaction was
stirred under Nitrogen for 48 h at RT. The reaction mixture was
diluted with water and EtOAc. The organic layer was separated,
washed with brine, dried over MgSO.sub.4 and concentrated under
reduced pressure. The crude residue was purified via silica gel
flash chromatography eluting with a gradient of 0-30% EtOAc in
hexanes to afford Compound 229A (2.08 g, 5.18 mmol, 94% yield) as a
light yellow oil. MS m/z=401.0/403 [M+H].sup.+.
Preparation of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)(4-methoxybenzyl-
)carbamate (229B)
[1403] To a solution of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(229A, 2.00 g, 4.98 mmol) in DMF (12.46 mL) was added potassium
carbonate (0.96 g, 6.98 mmol, Sigma-Aldrich), followed by
4-methoxybenzyl chloride (0.81 mL, 5.98 mmol, Sigma-Aldrich). The
reaction stirred at ambient temperature for 6 h. The reaction was
diluted with water and EtOAc and allowed to sit at RT for 72 h. The
organic layer was separated, washed with brine, dried over
MgSO.sub.4 and concentrated under reduced pressure. The crude
residue was purified via silica gel flash chromatography eluting
with a gradient of 0-25% EtOAc in hexanes to afford (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)(4-methoxybenzyl-
)carbamate (2.4 g, 4.60 mmol, 92% yield) as a clear oil. MS
m/z=521.0/523 [M+H].sup.+.
Preparation of (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino-
)-4-methyl-4H-1,3-thiazine-6-carboxylate (229C)
[1404] A flame dried round bottom flask was charged with
(S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)(4-methoxybenzyl-
)carbamate (0.53 g, 1.02 mmol) and THF (6 ml) The solution was
cooled to -78.degree. C. Lithium diisopropylamide (2.0 M in
heptane/THF/ethylbenzene, 0.66 mL, 1.33 mmol, Sigma-Aldrich) was
added drop wise and the mixture was stirred for 15 min. CO.sub.2
(generated by evaporation of dry ice) was passed over the reaction
head space for 15 min. The reaction was carefully quenched with
saturated ammonium chloride aqueous solution and the mixture was
warmed to RT. The mixture was diluted with 1.0 N HCl and extracted
with EtOAc. The organic layer was separated, washed with brine,
dried over MgSO4 and concentrated under reduced pressure. The
material was taken up in DMF (10 mL). Potassium carbonate (0.14 g,
1.02 mmol, Sigma-Aldrich) and methyl iodide (0.06 mL, 1.02 mmol,
Sigma-Aldrich) were added. The reaction was stirred at ambient
temperature for 1.5 h. The reaction was diluted with water and
EtOAc. The organic layer was separated and washed sequentially with
1 M LiCl aqueous solution and brine, dried over MgSO4 and
concentrated under reduced pressure. The crude residue was purified
via silica gel flash chromatography eluting with a gradient of
0-30% EtOAc in hexanes to afford (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino-
)-4-methyl-4H-1,3-thiazine-6-carboxylate (0.44 g, 0.75 mmol, 73%
yield). MS m/z=578.9/580.9 [M+H].sup.+.
Preparation of Diastereomers 229D
[1405] A flame dried sealed tube was charged with a solution of
(S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino-
)-4-methyl-4H-1,3-thiazine-6-carboxylate (229C, 3.03 g, 5.23 mmol)
in toluene (20.9 mL). The vial was sealed and nitrogen was bubbled
through the solution for 5 min. Tetrabutylammonium bromide (0.08 g,
0.26 mmol, Sigma-Aldrich) was added followed by
trimethyl(bromodifluoromethyl)silane (2.12 g, 10.46 mmol, SynQuest
Laboratories). The reaction was flushed with nitrogen and tightly
sealed. The reaction was heated to 110.degree. C. for 16 h then
cooled to RT. It was diluted with water and EtOAc. The organic
layer was separated, washed with brine, dried over MgSO4 and
concentrated under reduced pressure to afford an approximately
2:1:1 ratio of gemdifluorocyclopropyl carboxylic acid to
gemdifluorocyclopropyl methyl ester to unreacted starting material
by LC/MS. The crude material was taken up in DMF (35 mL). Potassium
carbonate (0.72 g, 5.23 mmol, Sigma-Aldrich) was added followed by
methyl iodide (0.33 mL, 5.23 mmol, Sigma-Aldrich). The reaction was
stirred at RT for 2 h. The reaction was diluted with water and
EtOAc. The organic layer was separated, washed with brine, and
dried over MgSO.sub.4. The crude material was purified via silica
gel flash chromatography eluting with a gradient of 0-30% EtOAc in
hexanes to afford 3.3 g of a mixture of (1S,5S,6R)-methyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino-
)-7,7-difluoro-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(229D: MS m/z=572.8/574.8 [M+H].sup.+) as a mixture of
diastereomers and (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino-
)-4-methyl-4H-1,3-thiazine-6-carboxylate (229C: MS m/z=578.9/580.9
M.sup.+). Note: the observed mass to charge ratio of 572.8/574.8
corresponds to the mass of the desired product (629.5) minus the
tert-butyl group of the Boc which is commonly observed under the
standard LC/MS method. The mixture was carried forward without
further purification.
Preparation of (1S,5S,6R)-methyl
5-(5-bromo-2-fluorophenyl)-7,7-difluoro-3-((4-methoxybenzyl)amino)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (229E) and
(1R,5S,6R)-methyl
5-(5-bromo-2-fluorophenyl)-7,7-difluoro-3-((4-methoxybenzyl)amino)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (229F)
[1406] To a flask charged with 3.3 g of the mixture containing
(5S)-methyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino-
)-7,7-difluoro-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(229D) and 229C from the previous step was added DCM (35 mL)
followed by TFA (13.3 mL, 173 mmol). The reaction was stirred at RT
for 1 h. The reaction was concentrated under reduced pressure. The
crude material was taken up in EtOAc (100 mL) and washed with
saturated sodium bicarbonate aqueous solution and brine. The
organic layer was dried over MgSO.sub.4 and concentrated under
reduced pressure. The crude residue was purified via silica gel
flash chromatography eluting with DCM to afford (1S,5S,6R)-methyl
5-(5-bromo-2-fluorophenyl)-7,7-difluoro-3-((4-methoxybenzyl)amino)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (1.4 g, 2.64
mmol, 229E, 50% yield and the diastereomer (1R,5S,6S)-methyl
5-(5-bromo-2-fluorophenyl)-7,7-difluoro-3-((4-methoxybenzyl)amino)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (0.3 g, 0.567
mmol, 229F, 11% yield). For both diastereomers: MS m/z=528.9/530.9
[M+H].sup.+.
Preparation of (1S,5S,6R)-methyl
3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-ene-1-carboxylate (229G)
[1407] To a solution of (1S,5S,6R)-methyl
5-(5-bromo-2-fluorophenyl)-7,7-difluoro-3-((4-methoxybenzyl)amino)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (229E, 1.4 g,
2.6 mmol) in TFA (17.6 mL) was added anisole (0.87 mL, 7.93 mmol)
followed by drop wise addition of sulfuric acid (1.4 mL, 26.4
mmol). The reaction was stirred at RT for 2 h. The sticky mixture
was poured into an Erlenmeyer flask containing wet ice. 10 N NaOH
was added to basify the reaction to pH=14. The basic aqueous layer
was extracted with EtOAc twice and the combined organic layers were
washed with brine, dried over MgSO4 and concentrated under reduced
pressure. The crude residue was purified via silica gel flash
chromatography eluting with a gradient of 10-55% EtOAc in hexanes
to afford (1S,5S,6R)-methyl
3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-ene-1-carboxylate (229G, 0.94 g, 2.29 mmol, 87%
yield) as a white solid. MS m/z=408.9/410.9 [M+H].sup.+.
Preparation of
((1S,5S,6R)-3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (229H)
[1408] To a solution of (1S,5S,6R)-methyl
3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-ene-1-carboxylate (229G, 0.98 g, 2.40 mmol) in THF
(17 mL) was added lithium borohydride (2.0 M solution in THF, 2.40
ml, 4.80 mmol) followed by MeOH (0.78 mL, 19.22 mmol). The solution
was stirred at ambient temperature for 2 h. The reaction was
quenched with water and EtOAc. The organic layer was separated,
washed with brine, dried over MgSO4 and concentrated under reduced
pressure to afford
((1S,5S,6R)-3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (0.83 g, 2.18 mmol,
91% yield) as a white solid. MS m/z=380.8/382.8 [M+H].sup.+.
Preparation of
((1S,5S,6R)-3-amino-5-(5-amino-2-fluorophenyl)-7,7-difluoro-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (229)
[1409] To a mixture of copper(I) iodide (0.05 g, 0.27 mmol,
Sigma-Aldrich), sodium azide (0.27 g, 4.11 mmol, Sigma-Aldrich),
and
((1S,5S,6R)-3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (229H, 0.52 g, 1.37
mmol) at RT was added EtOH (4.8 mL) and water (2.1 mL). The
reaction mixture was degassed by bubbling nitrogen through the
solution for 5 min then
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.27
mmol, Sigma-Aldrich) was added. The reaction mixture was heated to
80.degree. C. for 1.5 h then cooled to RT. The reaction was poured
into a separatory funnel containing a 9:1 solution of aqueous
saturated ammonium chloride to ammonium hydroxide. EtOAc was added
and the phases were mixed. The organic layer was separated, washed
sequentially with 9:1 saturated ammonium chloride to saturated
ammonium hydroxide solution and brine, then dried over MgSO4 and
concentrated under reduced pressure. The crude residue was taken up
in THF (6 mL) and water (3 mL). Trimethylphosphine (1.37 mL of 1.0
M solution in THF, 1.37 mmol) was added and the reaction was
stirred at RT for 1 h. It was diluted with water and EtOAc. The
organic layer was separated, washed with brine and dried over MgSO4
to afford
((1S,5S,6R)-3-amino-5-(5-amino-2-fluorophenyl)-7,7-difluoro-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (0.37 g, 1.12
mmol, 86% yield) as a glassy brown solid. MS m/z=318.0 [M+H].sup.+.
.sup.19F NMR (282 MHz, CHLOROFORM-d) .delta. -126.35 (s, 1 F),
-130.07 (d, J=157.75 Hz, 1 F), -141.94 (d, J=158.32 Hz, 1 F).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.03 (dd, J=2.9, 6.7 Hz,
1H), 6.87 (dd, J=8.6, 11.9 Hz, 1H), 6.55 (td, J=3.4, 8.5 Hz, 1H),
4.04-3.85 (m, 2H), 2.47 (dd, J=3.7, 15.8 Hz, 1H), 1.64 (s, 3H).
((1R,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (230)
##STR00140##
[1411] The title compound (230) was prepared following the
procedures described for intermediate 229, starting with
intermediate 229F. MS m/z=318.0 [M+H].sup.+. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 6.87 (dd, J=8.6, 11.9 Hz, 1H), 6.68 (dd, J=3.0,
6.8 Hz, 1H), 6.54 (ddd, J=3.0, 3.8, 8.6 Hz, 1H), 3.91-3.76 (m, 2H),
2.41 (dd, J=3.2, 16.2 Hz, 1H), 1.74 (s, 3H).
(1S,5S,6R)-5-(5-Amino-2-fluorophenyl)-7,7-difluoro-1-(methoxymethyl)-5-met-
hyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (231)
##STR00141##
[1412] Preparation of tert-butyl
((5S)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-1-(hydroxymethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)(4-methoxybenzyl)carbamate
(231A)
[1413] To a flask containing 0.94 g of intermediate 229D (not pure:
contaminated with 229C) in THF (10 mL) at RT was added lithium
borohydride (2.0 M solution in THF, 1.49 mL, 2.99 mmol). MeOH (0.48
mL, 11.95 mmol) was added dropwise. Evolution of gas was observed.
The reaction was stirred at RT for 15 min. It was quenched with
water and extracted with EtOAc. The organic layer was washed with
brine, dried over MgSO4 and concentrated under reduced pressure.
The crude residue was purified via silica gel flash chromatography
eluting with a gradient of 0-40% EtOAc in hexanes to afford 0.9 g
of a mixture of tert-butyl
((5S)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-1-(hydroxymethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)(4-methoxybenzyl)carbamate
as a mixture of diastereomers (231A). MS m/z=544.8/546.8
[M+H].sup.+. Note 1: the observed mass to charge ratio of
544.8/546.8 corresponds to the mass of the desired product (601.5)
minus the tert-butyl group of the Boc which is commonly observed
under the standard LC/MS method. Note 2: The product mixture
contains some of the allylic alcohol resulting from the reduction
of Compound 229C which was brought forward from the impure starting
material.
Preparation of tert-butyl
((5S)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-1-(methoxymethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)(4-methoxybenzyl)carbamate
(231B)
[1414] A solution of 0.9 g the above obtained intermediate 231A in
THF (7.5 mL) was cooled to 0.degree. C. Sodium
bis(trimethylsilyl)amide (2.1 mL of 1.0 M solution in THF, 2.1
mmol, Sigma-Aldrich) was added drop wise to the stirring solution
under nitrogen. The reaction was stirred for 20 min at 0.degree. C.
then methyl iodide (0.12 mL, 1.95 mmol) was added drop wise. The
reaction was stirred at RT for 16 h. It was quenched with aqueous
saturated ammonium chloride and diluted with water and EtOAc. The
organic layer was separated, washed with brine, dried over MgSO4
and concentrated under reduced pressure. The crude residue was
purified via silica gel flash chromatography eluting with a
gradient of 0-30% EtOAc in hexanes) to afford 0.77 g product
mixture containing tert-butyl
((5S)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-1-(methoxymethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)(4-methoxybenzyl)carbamate
as a mixture of diastereomers (231B). MS m/z=615.0/617.0
[M+H].sup.+.
Preparation of
(1S,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-N-(4-methoxybenzyl)-1--
(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(231C)
[1415] To a solution of 0.77 g of the above obtained intermediate
221C in DCM (10 mL) was added TFA (3.8 mL, 49.3 mmol). The reaction
was stirred at RT for 30 min then concentrated under reduced
pressure. The crude residue was taken up in EtOAc and washed with
saturated sodium bicarbonate 3 times followed by brine, dried over
MgSO.sub.4 and concentrated under reduced pressure. The material
was purified via silica gel flash chromatography eluting with DCM
to afford
(1S,5S,6R)-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-N-(4-methoxybenzyl)-1--
(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(231C, 0.41 g, 0.79 mmol, 63% yield) as a single diastereomer MS
m/z=515.0 [M+H].sup.+.
[1416] Intermediate 231D was prepared following the procedure
described in intermediate 229G, starting with intermediate 231C. MS
m/z=395/397 [M+H].sup.+.
Preparation of
(1S,5S,6R)-5-(5-amino-2-fluorophenyl)-7,7-difluoro-1-(methoxymethyl)-5-me-
thyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (231)
[1417] This compound was prepared following the procedure described
in intermediate 229, starting with intermediate 231D. MS m/z=332.0
[M+H].sup.+. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.05 (dd,
J=2.9, 6.7 Hz, 1H), 6.87 (dd, J=8.5, 12.0 Hz, 1H), 6.63-6.50 (m,
1H), 4.02-3.93 (m, 1H), 3.54 (dd, J=2.3, 11.3 Hz, 1H), 3.41 (s,
3H), 2.38 (dd, J=3.7, 15.4 Hz, 1H), 1.64 (d, J=1.0 Hz, 3H).
2-((1S,5S,6R)-3-Amino-5-(5-amino-2-fluorophenyl)-7,7-difluoro-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-1-yl)propan-2-ol (232)
##STR00142##
[1418] Preparation of Intermediate 232A
[1419] A flame dried round bottom flask was charged with
(1S,5S,6R)-methyl
3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-ene-1-carboxylate (229G, 0.28 g, 0.67 mmol). THF
(11.20 mL) was added and the solution was cooled to 0.degree. C.
Methylmagnesium bromide (3.0 M in Et.sub.2O, 2.24 mL, 6.72 mmol,
Sigma-Aldrich) was added drop wise to the stirring solution and the
reaction was stirred at 0.degree. C. for 5 min. The reaction was
carefully quenched with saturated ammonium chloride and diluted
with water and EtOAc. The organic layer was separated, washed with
brine, dried over MgSO4 and concentrated under reduced pressure.
Purification via silica gel flash chromatography eluting with a
gradient of 0-10% 2 M ammonia solution in MeOH in DCM afforded
2-((1S,5S,6R)-3-amino-5-(5-bromo-2-fluorophenyl)-7,7-difluoro-5--
methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)propan-2-ol (0.22
g, 0.55 mmol, 82% yield) as a pale yellow solid. MS m/z=409.0/411.0
[M+H].sup.+.
[1420]
2-((1S,5S,6R)-3-Amino-5-(5-amino-2-fluorophenyl)-7,7-difluoro-5-met-
hyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)propan-2-ol (232) was
prepared following the procedure described for intermediate 229,
starting with intermediate 232A. MS m/z=346.0 [M+H].sup.+. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 6.96 (dd, J=3.1, 6.8 Hz, 1H),
6.88 (dd, J=8.5, 11.8 Hz, 1H), 6.55 (td, J=3.6, 8.2 Hz, 1H),
3.12-3.01 (m, 1H), 1.68 (d, J=1.0 Hz, 3H), 1.49 (s, 3H), 1.47 (s,
3H).
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-5-(fluoromethyl)-1-((2,2,2-trifluoro-
ethoxy)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(233)
##STR00143##
[1421] Preparation of Compound 233A
[1422] To a solution of (1S,5S,6S)-methyl
3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-ene-1-carboxylate (207A1 purified from intermediate
207A via silica gel chromatography) (2.5 g, 6.39 mmol) in THF (60
mL) under N.sub.2 was added lithium borohydride (2 M solution in
THF, 6.39 mL, 12.78 mmol) via syringe followed by dropwise addition
of MeOH (2.07 mL, 51.10 mmol). The mixture was stirred at RT for 30
min. It was quenched with saturated NH.sub.4Cl, diluted with water,
and then extracted with EtOAc (3.times.). The combined organic
extracts were washed with water and brine, dried over
Na.sub.2SO.sub.4 and then filtered. The filtrate was concentrated
and purified by silica gel chromatography (1-8% MeOH (2 M NH.sub.3)
in DCM) to afford
((1S,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-1-yl)methanol (233A, 1.85 g, 5.09 mmol,
80% yield) as white solid. LC/MS (ESI.sup.+) m/z=363.0/365.0
(M+H).
Preparation of Compound 233B
[1423] To a solution of
((1S,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-1-yl)methanol (1.5 g, 4.13 mmol) in
1,4-dioxane (30 mL) was added di-tert-butyl dicarbonate (4.74 mL,
20.65 mmol) followed by saturated sodium bicarbonate (12 mL). The
reaction was stirred at ambient temperature for 16 h. The resulted
mixture was diluted with water and then extracted with EtOAc. The
organic layer was washed with brine, dried over Na.sub.2SO.sub.4
and filtered. The filtrate was concentrated and purified by silica
gel chromatography (0-70% EtOAc/hexanes) to afford tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (1.77 g, 3.82
mmol, 93% yield) as white foam. LC/MS (ESI.sup.+) m/z=463.0/465.0
(M+H).
Preparation of Compound 233C
[1424] To a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (0.10 g, 0.21
mmol) and (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (0.11 g,
0.43 mmol) in toluene (5 mL) at ambient temperature was added
tributylphosphine (0.11 mL, 0.43 mmol). After 10 min,
2,2,2-trifluoroethanol (0.16 mL, 2.16 mmol) was added and the
mixture was heated at 65.degree. C. for 2 h until the starting
material was fully consumed. The mixture was concentrated and the
residue was purified by Shimadzu HPLC to afford tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((2,2,2-trifluo-
roethoxy)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate
(40 mg, 0.07 mmol, 34% yield). LC/MS (ESI.sup.+) m/z=545.0/547.0
(M+H).
Preparation of Compound 233
[1425] To a pressure vial was charged tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((2,2,2-trifluo-
roethoxy)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate
(0.040 g, 0.073 mmol), sodium azide (0.014 g, 0.220 mmol),
copper(I) iodide (2.79 mg, 0.015 mmol), (+)-sodium L-ascorbate
(3.34 mg, 0.017 mmol), water (0.400 mL) and EtOH (2 mL). After
purged with N.sub.2, (1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine
(2 .mu.L, 0.015 mmol) was added. The mixture was heated to
80.degree. C. for 1.5 h. The reaction was quenched with saturated
NH.sub.4Cl and extracted with EtOAc. The organic extracts were
concentrated. The residue in THF (2 mL) and water (0.6 mL) was
treated with trimethylphosphine (1.0 M solution in THF, 0.073 mL,
0.073 mmol). After stirred at RT for 5 min, the reaction was
quenched with water and extracted with EtOAc. The organic extracts
were washed with brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The residue was dissolved in DCM (3 mL) and treated
with TFA (0.3 mL) at ambient temperature. After stirred for 25 min,
the mixture was concentrated and purified by Shimadzu HPLC to
afford
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((2,2,2-trifluor-
oethoxy)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (6.0
mg, 0.016 mmol, 21% yield). LC/MS (ESI.sup.+) m/z=382.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.77-6.91
(m, 2H), 6.54 (td, J=3.42, 8.41 Hz, 1H), 4.51-4.97 (m, 2H),
3.84-3.97 (m, 2H), 3.79 (d, J=10.56 Hz, 1H), 3.62 (d, J=10.76 Hz,
1H), 1.79 (m, 1H), 1.13 (dd, J=5.87, 9.59 Hz, 1H), 0.73 (t, J=6.26
Hz, 1H). The 2 sets of NH.sub.2 have broad peaks.
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-5-(fluoromethyl)-1-(isopropoxymethyl-
)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (234)
##STR00144##
[1426] Preparation of Compound 234A
[1427] To a 20 mL pressure vial was charged tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (0.58 g, 1.252
mmol), 2-iodopropane (1.00 mL, 10.01 mmol) and silver(i) oxide
(0.58 g, 2.50 mmol). After purged with N.sub.2 for 5 min, the vial
was sealed and stirred at ambient temperature with protection from
light for 140 h. At this point, LCMS detected no starting material.
The mixture was diluted with ether and DCM, and then filtered. The
filtrate was concentrated and purified by silica gel chromatography
(0-20% EtOAc/hexane) to afford tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(isopropoxymeth-
yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (0.20 g,
0.40 mmol, 31% yield). LC/MS (ESI.sup.+) m/z=505.1/507.1
(M+H).sup.+.
[1428] Intermediate 234 was synthesized using procedures analogous
to those described for intermediate 233, but using tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(isopropoxymeth-
yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (234A).
LC/MS (ESI.sup.+) m/z=342.2 (M+H).sup.+.
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-5-(fluoromethyl)-1-(1H-1,2,3-triazol-
-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (235)
##STR00145##
[1429] Preparation of Compound 235A
[1430] tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (204J, 3.85 g, 6.51 mmol) in MeOH (50 mL) was treated with
potassium carbonate (1.80 g, 13.02 mmol) followed by dimethyl
(1-diazo-2-oxopropyl)phosphonate (1.5 g, 7.81 mmol) at ambient
temperature. After stirred for 1.5 h, the reaction was quenched
with saturated NaHCO.sub.3 and extracted with EtOAc (2.times.). The
organic extracts were washed with brine, dried over
Na.sub.2SO.sub.4 and filtered. The filtrate was concentrated and
purified by silica gel chromatography (0-15% EtOAc in heptane) to
afford tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-ethynyl-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (3.44 g, 5.86 mmol, 90% yield) as colorless oil. LC/MS
(ESI.sup.+) m/z=609.0/611.0 (M+Na).sup.+.
Preparation of Compound 235B
[1431] To a pressure flask charged with tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-ethynyl-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (2.19 g, 3.73 mmol), sodium azide (0.73 g, 11.18 mmol),
copper(I) iodide (0.14 g, 0.74 mmol), (+)-sodium L-ascorbate (0.17
g, 0.85 mmol), water (4.00 mL) and EtOH (20 mL). After purged with
N.sub.2, (1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.12 mL,
0.74 mmol) was added. The reaction was heated to 75.degree. C. for
2 h, and then allowed to cool to RT. The reaction was quenched with
saturated NH.sub.4Cl and extracted with EtOAc. The organic extracts
were washed with brine, dried over Na.sub.2SO.sub.4 and filtered.
The filtrate was concentrated and purified by silica gel
chromatography on ISCO (0-30% EtOAc in heptane) to afford
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(1H-1,2,3-triaz-
ol-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)etho-
xy)methyl)carbamate (1.27 g, 2.01 mmol, 54% yield). LC/MS
(ESI.sup.+) m/z=630.2/632.2 (M+H).sup.+.
Preparation of Compound 235C
[1432] To a pressure flask was charged tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(1H-1,2,3-triaz-
ol-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)etho-
xy)methyl)carbamate (1.26 g, 1.99 mmol), p-toluenesulfonic acid
monohydrate (3.80 g, 19.98 mmol) and isopropanol (20 mL). The vial
was then sealed and heated in an 80.degree. C. oil bath for 16 h,
then at 90.degree. C. for additional 5 h until the reaction
progressed no further. The reaction mixture was allowed to cool to
RT and partitioned between EtOAc and water. The separated aqueous
layer was back extracted with EtOAc. The organic layers were
combined, washed with brine, dried over Na.sub.2SO.sub.4 and then
filtered. The filtrate was concentrated and purified by silica gel
chromatography (0-80% EtOAc in heptane) to afford
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(1H-1,2,3-
-triazol-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.49 g,
1.22 mmol, 61% yield) as light yellow oil. LC/MS (ESI.sup.+)
m/z=400.0/402.0 (M+H).sup.+.
Preparation of Compound 235
[1433] To a pressure flask charged with
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(1H-1,2,3-triazo-
l-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.49 g, 1.22
mmol), sodium azide (0.24 g, 3.67 mmol), copper(I) iodide (47 mg,
0.24 mmol), (+)-sodium L-ascorbate (56 mg, 0.28 mmol), water (1.50
mL) and EtOH (7.50 mL). After purged with N.sub.2,
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.24 mmol)
was added. The mixture was heated to 75.degree. C. for 23 h. The
reaction was quenched with saturated NH.sub.4Cl and extracted with
EtOAc. The organic extracts were washed with brine and
concentrated. To the residue in THF (10 mL) and water (3 mL) was
added trimethylphosphine (1.0 M solution in THF, 1.22 mL, 1.22
mmol). After stirred for 50 min, the reaction was quenched with
water and extracted with EtOAc. The organic extracts were
concentrated. The residue was triturated with DCM and then filtered
(repeated 3 times). The filter cake was rinsed with DCM and dried
in air to afford
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(1H-1,-
2,3-triazol-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (0.31
g, 0.91 mmol, 74% yield) as brown solid. LC/MS (ESI.sup.+)
m/z=337.1 (M+H).sup.+.
tert-Butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(prop-
-1-yn-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)e-
thoxy)methyl)carbamate (236)
##STR00146##
[1434] Preparation of Compound 236A
[1435] To a cooled (ice bath) solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-ethynyl-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbam-
ate (235A, 0.24 g, 0.401 mmol) in THF (4.0 mL) was added lithium
bis(trimethylsilyl)amide (0.61 mL of 1 M in THF, 0.61 mmol). After
stirred for 10 min, iodomethane (0.04 mL, 0.61 mmol) was added and
the mixture stirred for 1 h. The reaction was quenched with water
and extracted with EtOAc. The organic extracts were washed with
brine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate was
concentrated and purified by silica gel chromatography on ISCO
(0-15% EtOAc in heptane) to afford tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(prop-1-yn-1-yl-
)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)meth-
yl)carbamate (0.25 g, 0.42 mmol, 100% yield) as light yellow oil,
LC/MS (ESI.sup.+) m/z=601.1/603.1 (M+H).sup.+.
Preparation of Compound 236
[1436] To a pressure flask charged with tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(prop-1-yn-1-yl-
)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)meth-
yl)carbamate (0.25 g, 0.41 mmol), sodium azide (0.08 g, 1.24 mmol),
copper(I) iodide (16 mg, 0.08 mmol), (+)-sodium L-ascorbate (19 mg,
0.09 mmol), water (0.4 mL) and EtOH (2.0 mL). After purged with
N.sub.2, (1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.013 mL,
0.083 mmol) was added. The mixture was heated at 75.degree. C. for
2 h. The reaction was quenched with saturated NH.sub.4Cl and
extracted with EtOAc. The organic extracts were washed with brine
and concentrated. The residue was purified by silica gel
chromatography on ISCO (0-30% EtOAc in heptane) to afford
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(5-methyl-1H-1,-
2,3-triazol-4-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethyls-
ilyl)ethoxy)methyl)carbamate as colorless oil. LC/MS (ESI.sup.+)
m/z=564.2 (M+H).sup.+. To the colorless oil in THF (2 mL) and water
(0.6 mL) was added trimethylphosphine (0.41 mL of 1 M in THF, 0.41
mmol). After 50 min, the reaction was quenched with water and
extracted with EtOAc. The organic extracts were concentrated and
dried in vacuum to afford tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(prop-1-yn-1-yl-
)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)meth-
yl)carbamate (114 mg, 0.21 mmol, 51% yield). This material was used
without further purification. LC/MS (ESI.sup.+) m/z=538.3
(M+H).sup.+.
(1S,5S,6S)-Methyl
3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (237)
##STR00147##
[1437] Preparation of Compound 237A
[1438] To a 250 mL flask containing (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 2.00 g, 3.69 mmol) at 0.degree. C. under nitrogen was added
sulfuric acid (8.84 mL, 166 mmol). After 15 min, the ice bath was
removed and syrup stirred for 30 min at 20.degree. C. The reaction
was cooled to 0.degree. C. and sodium nitrate (0.44 g, 5.16 mmol)
was added. It was stirred at 0.degree. C. for 1 h then RT for 24 h.
The sticky mixture was pour onto ice (100 g). The mixture was
cooled with an ice bath, diluted with CH.sub.2Cl.sub.2 (50 mL) and
rapidly stirred. Solid potassium phosphate tribasic (23.47 g, 111
mmol) was added in small portions (over 20 min), and the mixture
was then brought to pH.about.8 with 1 M NaOH. The organic layer was
separated, and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (50 mL). The combined organic layers were dried
over MgSO.sub.4, filtered, concentrated under reduced pressure,
then purified via silica gel flash column chromatography (0-25%
EtOAc in heptane) to afford (1S,5S,6S)-methyl
3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (237A, 1.17 g, 3.27 mmol, 89% yield) as
tan oil. LC/MS (ESI.sup.-) m/z=485.1 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.51 (br. s., 1H), 8.02 (ddd, J=2.84,
6.31, 9.05 Hz, 1H), 4.26-4.91 (m, 2H), 3.79-3.83 (m, 3H), 1.70-1.82
(m, 3H), 1.49-1.66 (m, 1H), 1.03-1.26 (m, 1H), 0.92 (br. s.,
1H).
Preparation of Compound 237
[1439] To a stirring solution of (1S,5S,6S)-methyl
3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (237A, 1.17 g, 3.27 mmol) in glacial HOAc
(6 mL) and TFA (6 mL) at 20.degree. C. was added zinc nanopowder
(0.84 g, 13 mmol). After 90 min the reaction was concentrated under
reduced pressure to a thick oil/suspension. The reaction was then
partitioned between 9:1 CHCl.sub.3/IPA (50 mL) and 10% NH.sub.4OH
(50 mL). The separated aqueous layer was further extracted with 9:1
CHCl.sub.3/IPA (20 mL). The combined organics were then washed with
brine (20 mL). The organic was dried over MgSO.sub.4, concentrated
under reduced pressure, then purified by silica gel chromatography
(1-5% of 2 M NH.sub.3 in MeOH in CH.sub.2Cl.sub.2) to afford
(1S,5S,6S)-Methyl
3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (0.77 g, 2.35 mmol, 72% yield) as white
foam. LC/MS (ESI.sup.-) m/z=328.1 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 6.74 (d, J=5.24 Hz, 1H), 6.39 (ddd,
J=2.93, 6.06, 11.35 Hz, 1H), 3.89-4.84 (m, 2H), 3.78 (s, 3H), 3.60
(br. s., 2H), 2.50-2.56 (m, 1H), 1.68-1.72 (m, 3H), 1.55 (dd,
J=5.09, 9.78 Hz, 1H), 1.11 (dd, J=5.48, 7.43 Hz, 1H).
(1S,5S,6S)-3-Amino-5-(2,3-difluoro-5-nitrophenyl)-N-methoxy-N,5-dimethyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (238)
##STR00148##
[1440] Preparation of Compound 238A
[1441] To a stirring suspension of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 90 mg, 0.16 mmol) and N,O-dimethylhydroxylamine
hydrochloride (32 mg, 0.33 mmol) in THF (2 mL) at -20.degree. C.
under nitrogen was added isopropylmagnesium chloride (0.50 mL of 2
m in THF, 1.00 mmol) at a rate that did not exceed -15.degree. C.
internal temperature. After 15 min at -10.degree. C. the reaction
was quenched with sat NH.sub.4Cl. The reaction was then portioned
between 1:1 EtOAc/heptane (20 mL) and 5% NaHCO.sub.3 (10 mL). The
organic was dried over MgSO.sub.4, concentrated under reduced
pressure, then purified by silica gel chromatography (0-20% EtOAc
in heptane) to afford tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(methoxy(methyl)carbamoyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (238A, 57 mg, 0.10 mmol, 60% yield) as colorless film.
LC/MS (ESI.sup.-) m/z=572.2 (M+H).sup.+.
Preparation of
(1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-N-methoxy-N,5-dimethyl--
2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (238)
[1442] This compound (22 mg, 70 yield) as colorless film was
prepared according to the procedures described for intermediate
237, but starting from tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(methoxy(methyl)carbamoyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (238A, 50 mg). LC/MS (ESI.sup.-) m/z=357.0
(M+H).sup.+.
1-((1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-1-yl)ethanone (239)
##STR00149##
[1443] Preparation of Compound 239A
[1444] To a stirring solution of tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(methoxy(methyl)carbamoyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (238A, 1.04 g, 1.82 mmol) in THF (10 mL) at 0.degree. C.
under nitrogen was added methylmagnesium bromide (2.42 mL of 3.0 M
in Et.sub.2O, 7.28 mmol). After stirring for 15 min at 0.degree. C.
the reaction was slowly quenched with dropwise addition of sat.
NH.sub.4Cl (10 mL). The reaction was then partitioned between EtOAc
(75 mL) and 5% NaHCO.sub.3 (50 mL) along with water (50 mL). The
separated aqueous was extracted with EtOAc (25 mL). The combined
organics were dried over MgSO.sub.4, filtered, then concentrated
under reduced pressure to afford tert-butyl
((1S,5S,6S)-1-acetyl-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(239A, 0.93 g, 1.76 mmol, 97% yield) as colorless oil. LC/MS
(ESI.sup.-) m/z=527.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 7.38 (t, J=6.89 Hz, 1H), 7.02-7.13 (m, 2H),
5.27 (d, J=10.56 Hz, 1H), 5.04 (d, J=10.56 Hz, 1H), 3.60-3.70 (m,
2H), 2.53 (dd, J=8.02, 9.19 Hz, 1H), 2.25 (s, 3H), 1.67-1.83 (m,
3H), 1.57 (dd, J=5.38, 9.88 Hz, 1H), 1.54 (d, J=5.48 Hz, 1H),
1.49-1.52 (m, 9H), 0.89-0.97 (m, 2H), -0.02-0.01 (m, 9H).
Preparation of
1-((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-1-yl)ethanone (239)
[1445] This compound (290 mg, 0.93 mmol, 51% yield) as tan foam was
prepared according to the procedures described for intermediate
237, but starting from tert-butyl
((1S,5S,6S)-1-acetyl-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(239A, 0.95 g, 1.80 mmol). LC/MS (ESI.sup.-) m/z=312.1
(M+H).sup.+.
(S)-1-((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-1-yl)ethanol (240A) and
(R)-1-((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)ethanol (240B)
##STR00150##
[1447] To a stirring solution of
1-((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-1-yl)ethanone (intermediate 239, 104 mg,
0.33 mmol) in THF (3 mL) at RT under nitrogen was added lithium
borohydride (0.33 mL of 2.0 M in THF, 0.66 mmol) at a rate that did
not exceed an internal temperature of 25.degree. C. After 5 min,
MeOH (0.13 mL, 3.34 mmol) was added drop wise. The reaction was
cooled to 0.degree. C. and quenched with sat'd aqueous NH.sub.4Cl
(2 mL). The mixture was then partitioned between 9:1 CHCl.sub.3/IPA
(30 mL) and 0.5 M K.sub.2HPO.sub.4 (10 mL). The aqueous was further
extracted with 9:1 CHCl.sub.3/IPA (2.times.5 mL). The organic
solution was dried over MgSO.sub.4, filtered, concentrated under
reduced pressure. The residue was azeotroped with toluene
(2.times.25 mL). The residue was then purified by silica gel
chromatography (1-4% [2 M NH.sub.3 in MeOH] in CH.sub.2Cl.sub.2) to
afford separated diastereomers of arbitrary assignment. Oil
observed:
(R)-1-((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)ethanol (intermediate 240B, 45
mg, 0.14 mmol, 43% yield). LC/MS (ESI.sup.-) m/z=314.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.59 (td, J=2.52, 4.94
Hz, 1H), 6.36 (ddd, J=2.93, 6.06, 11.35 Hz, 1H), 3.49-3.65 (m, 2H),
3.40-3.49 (m, 2H), 3.05-3.34 (m, 2H), 1.70-1.74 (m, 4H), 1.24-1.33
(m, 3H), 0.93 (dd, J=5.77, 9.49 Hz, 1H), 0.71 (t, J=6.26 Hz, 1H).
Solid observed:
(S)-1-((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)ethanol (intermediate 240A, 15
mg, 0.05 mmol, 14% yield). LC/MS (ESI.sup.-) m/z=314.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.65-6.74 (m, 1H),
6.34-6.43 (m, 1H), 3.60 (br. s., 4H), 3.44-3.52 (m, 2H), 1.61-1.71
(m, 4H), 1.39 (d, J=6.26 Hz, 3H), 0.94 (dd, J=5.77, 9.49 Hz, 1H),
0.77 (t, J=6.06 Hz, 1H).
2-((1S,5S,6S)-3-Amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-1-yl)propan-2-ol (241)
##STR00151##
[1449] To a stirring solution of
1-((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-1-yl)ethanone (intermediate 239, 82 mg,
0.26 mmol) in THF (3 mL) at 0.degree. C. under nitrogen was added
methylmagnesium bromide (3.0 M in Et.sub.2O, 88 mL, 2.64 mmol) at a
rate not to exceed an internal temperature of 7.degree. C. After 15
min, the reaction was slowly quenched with sat NH.sub.4Cl then
partitioned between 0.1 M K.sub.2PO.sub.4 (20 mL) and 9:1
CHCl.sub.3/IPA (15 mL). The organic layer was dried over
MgSO.sub.4, concentrated under reduced pressure, then purified by
silica gel chromatography (0-5% [2 M NH.sub.3 in MeOH] in
CH.sub.2Cl.sub.2) to afford Compound 241 (9 mg, 0.03 mmol, 10%
yield) as colorless film. LC/MS (ESI.sup.-) m/z=328.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.62-6.69 (m, 1H),
6.33-6.40 (m, 1H), 3.85-4.77 (br., 2H), 3.60 (br. s., 2H), 1.86
(dd, J=7.34, 9.68 Hz, 1H), 1.59-1.79 (m, 3H), 1.30-1.36 (m, 6H),
1.23-1.30 (m, 1H), 1.12 (dd, J=5.67, 9.78 Hz, 1H), 0.61 (t, J=6.26
Hz, 1H).
tert-butyl
((1S,5S,6S)-5-(5-Amino-2-fluoropyridin-3-yl)-1-(methoxymethyl)--
5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)etho-
xy)methyl)carbamate (242)
##STR00152##
[1450] Preparation of Compound 242A
[1451] To a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(hydroxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (214K, 310 mg, 0.538 mmol) in THF (15 mL) under N.sub.2
at 0.degree. C. was added lithium bis(trimethylsilyl)amide (1.0 M
solution in THF, 0.86 mL, 0.86 mmol) dropwise. After addition, the
mixture was stirred at 0.degree. C. for 30 min and iodomethane
(0.053 mL, 0.860 mmol) was added. The mixture was stirred at
0.degree. C. for 20 min and at RT for overnight, then quenched with
saturated NH.sub.4Cl and diluted with H.sub.2O. The mixture was
extracted with EtOAc (2.times.). The combined organic extracts were
then washed with brine, dried over MgSO.sub.4, and concentrated.
The residue was purified by silica gel flash column chromatography
(DCM/EtOAc=5:1) to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(methoxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (242A, 220 mg, 0.37 mmol, 69% yield) as a light yellow
oil. LCMS (ESI.sup.+) m/z=590.5 (M+H).
Preparation of Compound 242
[1452] A microwave vial was charged with tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(methoxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (242A, 220 mg, 0.372 mmol), sodium azide (121 mg, 1.862
mmol), copper(I) iodide (14.19 mg, 0.074 mmol), sodium
(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate
(14.76 mg, 0.074 mmol), EtOH (3 mL) and water (1 mL). It was purged
with N.sub.2 and sealed. Then
(1R,2R)--N.sup.1,N.sup.2-dimethylcyclohexane-1,2-diamine (23 .mu.L,
0.15 mmol) was added. The mixture was heated to 80.degree. C. The
mixture was treated with saturated NH.sub.4Cl and diluted with
EtOAc. The organic layer was separated and the aqueous layer was
extracted twice with EtOAc. The organic solution was washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The
residue was dissolved in THF (3 mL) and water (1 mL) and treated
with trimethylphosphine (1.0 M solution in THF, 0.45 mL, 0.45
mmol). The mixture was evaporated to dryness purified by a silica
gel chromatography (DCM/EtOAc=10:1 to 5:1) to give tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-1-(methoxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (242, 130 mg, 0.25 mmol, 66% yield). LCMS (ESI.sup.+)
m/z=527.2 (M+H).
(1S,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-ene-1-carbonitrile (243)
##STR00153##
[1453] Preparation of Compound 243A
[1454] To a stirring solution of
(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimet-
hylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
e-1-carboxylic acid (221A, 1.90 g, 3.22 mmol) in THF (20 mL) at
20.degree. C. under nitrogen was added 1,1'-carbonyldiimidazole
(0.784 g, 4.83 mmol). The cloudy solution was stirred for 1 hr at
20.degree. C. followed by addition of ammonia (0.5 M in
1,4-dioxane, 19.34 mL, 9.67 mmol). After 1 h, the reaction mixture
was partitioned between EtOAc (60 mL) and 1 M HCl (60 mL). The
organic layer was washed with brine (25 mL), dried over MgSO.sub.4,
filtered and concentrated under reduced pressure to afford
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-carbamoyl-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(243A, 1.80 g, 3.06 mmol, 95% yield) as colorless oil. LC/MS
(ESI.sup.-) m/z=588.0/590.0 (M+H).sup.+.
Preparation of Compound 243B
[1455] A mixture of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-carbamoyl-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(243A, 1.90 g, 3.23 mmol), sodium azide (0.63 g, 9.68 mmol),
copper(i) iodide (0.18 g, 0.97 mmol),
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.19 g, 0.97
mmol), (+)-sodium L-ascorbate (0.19 g, 0.97 mmol) in 5:1
EtOH/H.sub.2O (20 mL) was purged with argon for 5 min. The blue
suspension was then heated at 70.degree. C. After 1 h, the reaction
mixture was chilled to 10.degree. C. and quenched with 9:1 (20 mL)
sat. NH.sub.4Cl/NH.sub.4OH (30%). The mixture was then extracted
with EtOAc (60 mL). The organic solution was washed with sat.
NH.sub.4Cl (10 mL) followed by brine (10 mL), dried over
MgSO.sub.4, and concentrated under reduced pressure. The residue
was dissolved in 5:1 THF/water (20 mL), chilled to 0.degree. C.,
then trimethylphosphine (4.84 mL of 1 M in THF, 4.84 mmol) was
added. The ice bath was removed and reaction stirred for 20 min at
20.degree. C. It was partitioned between EtOAc (40 mL) and 5%
NaHCO.sub.3 (20 mL). The organic layer was dried over MgSO.sub.4,
concentrated under reduced pressure, then purified by silica gel
chromatography (0-60% EtOAc in heptane) to afford tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-carbamoyl-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(243B, 0.81 g, 1.54 mmol, 48% yield) as colorless oil. LC/MS
(ESI.sup.-) m/z=525.2 (M+H).sup.+.
Preparation of Compound 243C
[1456] To a 100 mL flask containing tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1-carbamoyl-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(243B, 0.78 g, 1.48 mmol) at 0.degree. C. under nitrogen was added
sulfuric acid (5.95 mL). The flask was periodically removed from
cooling bath, swirled by hand, then allowed to stir at 20.degree.
C. for 1 h. The reaction mixture was then poured onto wet ice (300
mL) and the mixture along with DCM (100 mL). To the rapidly stirred
mixture was added potassium phosphate tribasic monohydrate (42.8 g,
186 mmol). The suspension was filtered and the filtrate transferred
to a separatory funnel. The organic layer was separated, and the
aqueous layer was extracted with 9:1 CHCl.sub.3/IPA (2.times.50
mL). The combined organic layers were dried over MgSO.sub.4,
filtered, concentrated under reduced pressure, then purified via
silica gel flash column chromatography (40 g) eluting the products
with a gradient of 0-50% EtOAc/CH.sub.2Cl.sub.2 to afford
(1S,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-ene-1-carboxamide (243C, 0.37 g, 1.25 mmol,
84% yield) as off white solid. LC/MS (ESI.sup.-) m/z=295.1
(M+H).sup.+.
Preparation of Compound 243D
[1457] To a stirring solution of
(1S,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-5-methyl-2-thia-4-azabicycl-
o[4.1.0]hept-3-ene-1-carboxamide (0.38 g, 1.291 mmol) and
N,N-diisopropylethylamine (243C, 1.80 mL, 10.33 mmol) in THF (10
mL) at -70.degree. C. under nitrogen was added
2,2,2-trifluoroacetic anhydride (1.08 mL, 7.75 mmol). After 10 min,
the reaction was quenched with sat. NH.sub.4Cl (1 mL). The reaction
was then partitioned between EtOAc (10 mL) and 5% NaHCO.sub.3 (10
mL). The organic was dried over MgSO.sub.4, filtered, then
concentrated under reduced pressure to afford
N-((1S,5S,6S)-1-cyano-5-(2-fluoro-5-(2,2,2-trifluoroacetamido)phenyl)-5-m-
ethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)-2,2,2-trifluoroacetamide
(243D, 0.60 g, 1.26 mmol) as tan solid. LC/MS (ESI.sup.-) m/z=421.0
(M+H).sup.+.
Preparation of Compound 243
[1458] A solution of
N-((1S,5S,6S)-1-cyano-5-(2-fluoro-5-(2,2,2-trifluoroacetamido)phenyl)-5-m-
ethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)-2,2,2-trifluoroacetamide
(243D, 600 mg, 1.28 mmol) in 2 M NH.sub.3 in MeOH (10 mL) was
stirred for 18 h at 37.degree. C. The solvent was removed under
reduced pressure and the residue was then purified by silica gel
chromatography (12 g) eluting products with a gradient of 1-5% 2 M
NH.sub.3 in MeOH/DCM to afford
(1S,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-5-methyl-2-thia-4-azabicycl-
o[4.1.0]hept-3-ene-1-carbonitrile (235 mg, 0.85 mmol, 66% yield) as
white foam. LC/MS (ESI.sup.-) m/z=277.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 6.80 (dd, J=8.41, 12.13 Hz, 1H),
6.63 (dd, J=2.93, 7.04 Hz, 1H), 6.38-6.50 (m, 3H), 4.84 (s, 2H),
2.28 (dd, J=7.92, 9.68 Hz, 1H), 1.83 (dd, J=5.87, 9.78 Hz, 1H),
1.67 (s, 3H), 0.92 (t, J=6.46 Hz, 1H).
(1R,5S,6R)-5-(5-Amino-2,3-difluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-amine (244)
##STR00154##
[1459] Synthesis of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)(4-methoxybenzyl)car-
bamate (244A)
[1460] To a solution of (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(203F, 1.00 g, 2.94 mmol) in DMF (6 mL) was added potassium
carbonate (568 mg, 4.1 mmol), followed by 4-methoxybenzyl chloride
(0.5 mL, 3.5 mmol). The reaction mixture was stirred overnight at
RT. It was partitioned between water and EtOAc. The aqueous phase
was separated and was back-extracted with EtOAc. The combined
organic extracts were dried over MgSO.sub.4, filtered and
concentrated in vacuo. The residue was purified by column
chromatography (SiO.sub.2, 0-30% EtOAc in hexanes) to afford the
title compound (244A, 1.00 g, 2.25 mmol, 76% yield) as a yellow
oil. LC/MS (ESI.sup.+) m/z=461.1 (M+H).sup.+; .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. ppm 1.49 (s, 9H) 1.69 (d, J=1.17 Hz, 3H) 3.79
(s, 3H) 5.06 (s, 2H) 6.07 (dd, J=9.50, 3.65 Hz, 1H) 6.26 (d, J=9.35
Hz, 1H) 6.84 (m, 2H) 6.89-7.13 (m, 3H) 7.27 (m, 2H).
Synthesis of tert-butyl
((1R,5S,6R)-5-(2,3-difluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-en-3-yl)(4-methoxybenzyl)carbamate (244B)
[1461] A sealable vial was charged with (S)-tert-butyl
(4-(2,3-difluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)(4-methoxybenzyl)car-
bamate (244A, 440 mg, 0.96 mmol) and toluene under nitrogen
atmosphere. Tetrabutylammonium bromide (9 mg, 0.029 mmol) was
added, followed by trimethyl(bromodifluoromethyl)silane (SynQuest
Laboratories, 291 mg, 1.43 mmol). The vial was sealed and heated to
110.degree. C. for 6 h. The residue was partitioned between water
and EtOAc. The aqueous phase was separated and was back-extracted
with EtOAc. The combined organic extracts were dried over
MgSO.sub.4, filtered and concentrated in vacuo. The residue was
purified by column chromatography (SiO.sub.2, 0-25% EtOAc in
hexanes) to afford the title compound as an oil (244B, 116 mg, 0.23
mmol, 24%). LC/MS (ESI.sup.+) m/z=533.2 (M+Na).sup.+.
Synthesis of Compound 244C
[1462] A solution of tert-butyl
((1R,5S,6R)-5-(2,3-difluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-en-3-yl)(4-methoxybenzyl)carbamate (244B, 380 mg,
0.74 mmol) in DCM (2.5 mL) was treated with TFA (1.7 mL, 22 mmol)
at RT. After 1 h, anisole (0.12 mL, 1.1 mmol) was added to the
reaction mixture, followed by drop-wise addition of concentrates
sulfuric acid (0.4 mL, 7.4 mmol). After 20 min, the reaction
mixture was poured into water and neutralized with aqueous,
saturated bicarbonate solution. The reaction mixture was
partitioned between water and EtOAc. The aqueous phase was
separated and was back-extracted with EtOAc. The combined organic
extracts were dried over MgSO.sub.4, filtered and concentrated in
vacuo. The crude material was purified by column chromatography
(SiO.sub.2, 5-55% EtOAc in hexanes) to afford
(1R,5S,6R)-5-(2,3-difluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-amine (87 mg, 0.30 mmol, 40% yield) as a waxy
yellow solid. LC/MS (ESI.sup.+) m/z=291.0 (M+H).sup.+; .sup.1H NMR
(300 MHz, CHLOROFORM-d) .delta. ppm 1.75 (d, J=1.17 Hz, 3H)
2.55-2.73 (m, 1H) 2.84-3.01 (m, 1H) 7.03-7.21 (m, 2H) 7.39-7.50 (m,
1H); .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta. ppm -149.49 (d,
J=158.90 Hz, 1 F) -140.44-138.72 (m, 1 F) -139.96-139.68 (m, 1 F)
-139.26-139.04 (m, 1 F) -121.99 (d, J=158.90 Hz, 1 F); The relative
stereochemistry was confirmed by COSY, HMBC and NOESY
correlations.
[1463] To a solution of
(1R,5S,6R)-5-(2,3-difluorophenyl)-7,7-difluoro-5-methyl-2-thia-4-azabicyc-
lo[4.1.0]hept-3-en-3-amine (87 mg, 0.30 mmol) in concentrated
sulfuric acid (1 mL) at 0.degree. C. was added potassium nitrate
(45 mg, 0.45 mmol). The reaction was stirred at for 5 min at
0.degree. C. and additional 5 min at RT. The reaction mixture was
poured into ice-water and solid potassium carbonate was added
portion wise until the reaction mixture reached pH>10. The
aqueous phase was extracted with three times EtOAc. The combined
organic extracts were dried over MgSO.sub.4. The solution was
filtered and concentrated in vacuo to give the crude
(1R,5S,6R)-5-(2,3-difluoro-5-nitrophenyl)-7,7-difluoro-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-amine (50 mg) as a yellow glass. The
product was taken onto the next step without further purification.
LC/MS (ESI.sup.+) m/z=336.0 (M+H).sup.+.
[1464] A flask containing a solution of
(1R,5S,6R)-5-(2,3-difluoro-5-nitrophenyl)-7,7-difluoro-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-en-3-amine (50 mg, 0.15 mmol) in HOAc (1
mL) was cooled in a water bath. TFA (0.08 mL) was added, followed
by zinc dust (50 mg, 0.75 mmol) in one portion. After 10 min, the
reaction mixture was basified with 1 N NaOH and then extracted with
EtOAc. The organic phase was washed with aqueous, saturated NaCl
solution, dried over MgSO.sub.4 and filtered. The filtrate was
concentrated to afford intermediate 244 as a yellow residue which
was taken on the next step without further purification. LC/MS
(ESI.sup.+) m/z=306.0 (M+H).sup.+.
(E)-3-((1R,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-1-yl)-N,N-dimethylacrylamide
(246)
##STR00155##
[1466] The title compound was prepared according to the procedures
describe for intermediate 767C (see the synthesis of Example 767).
MS (ESI, positive ion) m/z: 367 (M+1).sup.+.
(E)-3-((1R,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-th-
ia-4-azabicyclo[4.1.0]hept-3-en-1-yl)-1-(3,3-difluoroazetidin-1-yl)prop-2--
en-1-one (247)
##STR00156##
[1468] The title compound was prepared according to the procedures
describe for intermediate 767C (see the synthesis of Example 767).
MS (ESI, positive ion) m/z: 415 (M+1).sup.+.
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(oxazol-5-yl)-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (248)
##STR00157##
[1469] Preparation of Compound 248A
[1470] A mixture of p-toluenesulfonylmethyl isocyanide (0.79 g,
4.06 mmol), tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)
ethoxy)methyl)carbamate (2.00 g, 3.38 mmol), and potassium
carbonate (2.34 g, 16.90 mmol) in MeOH (4 mL) was stirred a RT for
16 h. The reaction mixture was concentrated to dryness. The residue
was diluted with H.sub.2O, and extracted with EtOAc (3.times.). The
organic extracts were dried over Na.sub.2SO.sub.4, concentrated and
purified by silica gel column to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(oxazol-5-yl)-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (248A, 1.37 g, 64%). .sup.1H NMR (CHLOROFORM-d) .delta.:
7.86 (dd, J=6.8, 2.5 Hz, 1H), 7.80 (s, 1H), 7.42 (ddd, J=8.7, 4.3,
2.7 Hz, 1H), 7.01 (s, 1H), 6.98 (dd, J=11.5, 8.6 Hz, 1H), 5.36 (d,
J=10.4 Hz, 1H), 5.10 (d, J=10.4 Hz, 1H), 4.89-5.06 (m, 1H),
4.68-4.85 (m, 1H), 3.62-3.72 (m, 2H), 2.30 (ddd, J=9.8, 7.4, 2.2
Hz, 1H), 1.53 (s, 9H), 1.50 (d, J=5.9 Hz, 1H), 1.12 (dd, J=7.0, 6.1
Hz, 1H), 0.98 (dd, J=9.0, 7.6 Hz, 2H), 0.00 (s, 9H). MS (ESI,
positive ion) m/z: 630/632 (M+1).sup.+.
Preparation of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(oxazol-5-yl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (248)
[1471] The title compound (0.58 g, 79%) was prepared in the same
method as described for 243C, but starting from 248A (1.37 g, 2.17
mmol). MS (ESI, positive ion) m/z: 337 (M+1).sup.+.
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-5-(fluoromethyl)-1-(4-methyloxazol-5-
-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (249)
##STR00158##
[1472] Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(4-methyloxazol-
-5-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy-
)methyl) carbamate (249A)
[1473] The title compound (2.41 g, 88%) was prepared in the same
method as that described for Example 248A, but starting from
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (204J, 2.50 g, 4.23 mmol), and 1-methyl-1-tosylmethyl isocyanide
(1.06 g, 5.07 mmol). MS (ESI, positive ion) m/z: 644/646
(M+1).sup.+.
[1474] Compound 249 (2.41 g, 88%) was prepared in the same method
as that described for intermediate 243C, but starting from Compound
249A (2.40 g, 3.71 mmol). MS (ESI, positive ion) m/z: 581
(M+1).
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-1,5-bis(fluoromethyl)-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-3-amine (450)
##STR00159##
[1475] Preparation of Compound 450A
[1476] To a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(hydroxymethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate (210C, 1.4 g, 2.4 mmol) and TEA (0.5 mL, 3.5 mmol) in
DCM (8 mL) at 0.degree. C. was added 4-methylbenzenesulfonyl
chloride (0.45 mL, 3.54 mmol) in DCM (7 mL). The resulting mixture
was stirred at RT for 4 h. LCMS showed some starting material.
4-(dimethylamino)-pyridine (0.14 g, 1.18 mmol) was added and the
mixture was stirred at RT for overnight. It was quenched saturated
NaHCO.sub.3. The organic layer was washed with brine, dried over
MgSO.sub.4, and concentrated. The residue was purified by silica
gel flash column chromatography (0-70% EtOAc/heptane) to give
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trime-
thylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-1-yl)methyl 4-methylbenzenesulfonate (450A, 1.12 g, 1.50
mmol, 64% yield) as a colorless oil. MS (ESI, positive ion) m/z:
747/749 (M+1).sup.+.
Preparation of Compound 450B
[1477] To a solution of
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trime-
thylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-1-yl)methyl 4-methylbenzenesulfonate (450A, 2.00 g, 2.67
mmol) (2.00 g, 2.67 mmol) in ACN (20 mL) at RT was added
tetrabutylammonium difluorotriphenylsilicate (8.74 g, 16.19 mmol).
The reaction mixture was heated to 75.degree. C. for 1 d and cooled
to RT. The mixture was diluted with EtOAc and transferred to a
separatory funnel. The aqueous layer was discarded and the organic
phase was washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. Purification by flash column chromatography on silica
gel (5-10% EtOAc in heptane) gave tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-1,5-bis(fluoromethyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(1.17 g, 1.96 mmol, 73% yield). MS (ESI, positive ion) m/z: 594/596
(M+1).sup.+.
Preparation of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-1,5-bis(fluoromethyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-amine (450)
[1478] The title compound was prepared in the same fashion as that
described for intermediate 452. MS (ESI, positive ion) m/z: 302.0
(M+1).sup.+.
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-1-(ethoxymethyl)-5-(fluoromethyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (451)
##STR00160##
[1480] The title compound was prepared in a fashion similar to that
described for intermediate 210. MS (ESI, positive ion) m/z: 328
(M+1).sup.+.
2-((1R,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-1-yl)acetonitrile (452)
##STR00161##
[1481] Preparation of Compound 452A
[1482] To a solution of
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trime-
thylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-1-yl)methyl 4-methylbenzenesulfonate (450A, 1.02 g, 1.36
mmol) in DMSO (anhydrous, 9 mL) was added potassium cyanide (0.13
g, 2.04 mmol). The resulting mixture was stirred at 55.degree. C.
under N.sub.2 overnight. It was cooled to RT, quenched with
saturated NaHCO.sub.3 (30 mL) and extracted with EtOAc (2.times.40
mL). The organic layer was then collected, washed with brine, dried
over MgSO.sub.4, and concentrated. The residue was purified by
silica gel flash column chromatography using ISCO instrument
(0-100% EtOAc/heptane) to give 783 mg of tert-butyl
((1R,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(cyanomethyl)-5-(fluoromethyl)-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate as a colorless oil. MS (ESI, positive ion) m/z:
602.2/604.1 (M+1).sup.+. .sup.1H NMR (CHLOROFORM-d) .delta.: 7.82
(dd, J=6.8, 2.5 Hz, 1H), 7.41 (dt, J=7.1, 4.3 Hz, 1H), 6.98 (dd,
J=11.6, 8.7 Hz, 1H), 5.34 (d, J=10.4 Hz, 1H), 5.08 (d, J=10.4 Hz,
1H), 4.83-5.01 (m, 1H), 4.61-4.77 (m, 1H), 3.63-3.69 (m, 2H), 3.48
(s, 1H), 2.77 (q, J=17.4 Hz, 2H), 2.04 (t, J=7.5 Hz, 1H), 1.53 (s,
9H), 1.11 (dd, J=10.0, 6.3 Hz, 1H), 0.97 (dd, J=9.3, 7.3 Hz, 2H),
0.81 (t, J=6.7 Hz, 1H), 0.00 (s, 9H).
Preparation of Compound 452
[1483] To a round bottom flask containing tert-butyl
((1R,5S,6S)-5-(5-bromo-2-fluorophenyl)-1-(cyanomethyl)-5-(fluoromethyl)-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (452A, 750 mg, 1.24 mmol) at 0.degree. C. was added
sulfuric acid (2 mL) dropwise. After addition, the mixture was
stirred at 0.degree. C. for 24 min and RT for 27 min. It was poured
into 50 g of ice and the mixture was adjusted to pH>10 by
saturated NaOH. The mixture was extracted with EtOAc (2.times.20
mL). The combined organic extracts were dried over MgSO.sub.4 and
concentrated. The residue was purified by silica gel flash column
chromatography using ISCO instrument (0-100% EtOAc/heptane) to give
2-((1R,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)acetonitrile (83 mg, 0.223 mmol,
18% yield) as a light yellow solid. MS (ESI, positive ion) m/z:
372.0/374.0 (M+1).sup.+.
[1484] To a solution of
2-((1R,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)acetonitrile (83 mg, 0.223 mmol)
in EtOH (0.5 mL) and water (0.25 mL) was added sodium azide (44 mg,
0.67 mmol), (+)-sodium L-ascorbate (11.0 mg, 0.05 mmol), copper(i)
iodide (10.6 mg, 0.05 mmol), and
trans-N,N'-dimethylcyclohexane-1,2-diamine (8.8 .mu.L, 0.05 mmol).
Then, N.sub.2 was bubbled in the solution mixture for 5 min. Then,
the mixture was then stirred at 70.degree. C. under N.sub.2 for 1
h. LCMS showed 80% conversion. Then, copper(i) iodide (10 mg),
(+)-sodium L-ascorbate (11 mg), and
trans-N,N'-dimethylcyclohexane-1,2-diamine (8.8 .mu.L) were added
and the mixture was stirred at 70.degree. C. for 45 min. LCMS
showed no starting material. The mixture was cooled to RT, quenched
with saturated NH.sub.4Cl/NH.sub.4OH (9:1, 5 mL), and extracted
with EtOAc (2.times.10 mL). The combined organic extracts were
dried over MgSO.sub.4 and concentrated in vacuo. The residue was
dissolved in THF/H.sub.2O (9:1, 1 mL) and trimethylphosphine (0.22
mL of 1.0 M solution in THF) was added. The resulting mixture was
then stirred at RT overnight. It was diluted with EtOAc and washed
with saturated NaHCO.sub.3 (5 mL). The organic layer was collected,
dried over MgSO.sub.4, and concentrated in vacuo. The residue was
purified by silica gel flash column chromatography using ISCO
instrument (0-20% MeOH/DCM) to give
2-((1R,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acetonitrile (56 mg, 0.182
mmol, 81% yield) as a yellow solid. MS (ESI, positive ion) m/z: 309
(M+1).sup.+.
3-((1S,5S,6S)-3-Amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-1-yl)propanenitrile (453)
##STR00162##
[1485] Preparation of Compound 453A
[1486] At 0.degree. C., sulfuric acid (5 mL) was added dropwise to
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trime-
thylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-1-yl)methyl 4-methylbenzenesulfonate (250A, 1.7 g, 2.3
mmol). The mixture was stirred at RT for 5 min then pour onto 50 g
of ice. The pH of the mixture was adjusted to >12 with the
addition of 5 N NaOH. The mixture was extracted with EtOAc
(2.times.50 mL). The combined organic extracts were dried over
MgSO.sub.4 and concentrated. The residue was purified by silica gel
flash column chromatography using ISCO instrument (0-100%
EtOAc/heptane) to give
((1S,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-1-yl)methyl 4-methylbenzenesulfonate
(851 mg, 1.64 mmol, 72% yield) as a light yellow solid. MS (ESI,
positive ion) m/z: 517.0, 518.9 (M+1).sup.+. .sup.1H NMR
(CHLOROFORM-d) .delta.: 7.80 (d, J=8.2 Hz, 2H), 7.61 (d, J=6.3 Hz,
1H), 7.43 (br. s., 1H), 7.38 (d, J=8.0 Hz, 2H), 6.91-7.00 (m, 1H),
4.57-4.87 (m, 2H), 4.01-4.17 (m, 2H), 1.89 (br. s., 1H), 1.25 (br.
s., 1H), 0.80 (t, J=6.7 Hz, 1H).
Preparation of Compound 453B
[1487] To a solution of
((1S,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-1-yl)methyl 4-methylbenzenesulfonate
(453A, 300 mg, 0.58 mmol) in DMF (3.7 mL) was added cesium
carbonate (416 mg, 1.27 mmol) and methyl 2-cyanoacetate (86 mg,
0.87 mmol). The resulting mixture was stirred at RT overnight. It
was quenched with saturated NaHCO.sub.3 (7 mL) and extracted with
EtOAc (2.times.20 mL). The combined organic extracts were dried
over MgSO.sub.4 and concentrated. The residue was purified by
silica gel flash column chromatography using ISCO instrument (0-40%
EtOAc/heptane), then by preparative HPLC (10% ACN 0.1% TFA/H.sub.2O
0.1% TFA). The desired fractions were concentrated and the residue
was treated with saturated NaHCO.sub.3 and extracted with EtOAc
(2.times.20 mL). The combined organic extracts were dried over
MgSO.sub.4, concentrated, and dried in vacuo to give a product as a
mixture of
(2R)-3-[(1R,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-1-yl]-2-cyanopropanoic acid and
(2S)-3-[(1R,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-1-yl]-2-cyanopropanoic acid. MS
(ESI, positive ion) m/z: 430, 432 (M+1).sup.+.
Preparation of Compound 453C
[1488] A mixture of
(2R)-3-[(1R,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-1-yl]-2-cyanopropanoic acid and
(2S)-3-[(1R,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2--
thia-4-azabicyclo[4.1.0]hept-3-en-1-yl]-2-cyanopropanoic acid
(453B, 249 mg, 0.58 mmol) in DMSO (1 mL) was stirred at 70.degree.
C. overnight. It was cooled to RT and saturated NaHCO3 (5 mL) was
added. The mixture was extracted with EtOAc (2.times.10 mL). The
combined organic extracts were dried over MgSO.sub.4, concentrated
and dried in vacuo to give
3-((1S,5S,6S)-3-amino-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)propanenitrile as a light yellow
oil which was used in the next step without purification
requirement. MS (ESI, positive ion) m/z: 386, 388 (M+1).sup.+.
Preparation of
3-((1S,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)propanenitrile (453)
[1489] The title compound (13 mg) as a yellow solid was prepared
from intermediate 453C (224 mg, 0.58 mmol) according to the
procedures described for intermediate 452. MS (ESI, positive ion)
m/z: 323 (M+1).sup.+.
(1S,5S,6S)-5-(5-Amino-2-fluorophenyl)-5-(fluoromethyl)-1-((5-methyl-1H-1,2-
,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(454)
##STR00163##
[1490] Preparation of Compound 454A
[1491] To a solution of potassium t-butoxide (0.82 g, 7.27 mmol) in
THF (8 mL) at 0.degree. C. under N.sub.2 was added a solution of
tert-butyl
((1S,5S,6S)-1-(azidomethyl)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (455A, 1.5 g, 2.42 mmol) in acetone (0.53 mL, 7.27 mmol)
and THF (7 mL) dropwise. After addition, the mixture was stirred at
0.degree. C. for 1 h and RT for 18 h. The mixture was poured onto
ice bath (50 mL) and saturated NaHCO.sub.3 (7 mL) was added. The
mixture was extracted with EtOAc (2.times.10 mL). The combined
organic extracts were washed with brine, dried over MgSO.sub.4, and
concentrated in vacuo. Chromatographic purification of the residue
(silica gel, 0%-100% EtOAc/heptane) provided tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((5-methyl-1H-1-
,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(tr-
imethylsilyl)ethoxy)methyl)carbamate (454A, 226 mg, 0.34 mmol, 14%
yield) as a yellow solid. MS (ESI, positive ion) m/z: 658.1/660.2
(M+H).sup.+.
Preparation of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((5-methyl-1H-1,-
2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(454)
[1492] The title compound (51 mg, 41% yield) as a yellow solid was
prepared from intermediate 454A (226 mg, 0.34 mmol) according to
the procedures described for intermediate 452. MS (ESI, positive
ion) m/z: 365.0 (M+1).sup.+.
2-((1R,5S,6S)-3-Amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-1-yl)acetonitrile (455)
##STR00164##
[1493] Preparation of Compound 455A
[1494] To a solution of
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trime-
thylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-1-yl)methyl 4-methylbenzenesulfonate (450A, 606 mg, 0.81
mmol) in DMSO (4.0 mL) was added sodium azide (58 mg, 0.89 mmol).
The resulting mixture was then stirred at RT overnight. The mixture
was quenched with saturated NH.sub.4Cl/NH.sub.4OH (10:1, 10 mL) and
extracted with EtOAc (2.times.15 mL). The combined organic extracts
were dried over MgSO.sub.4 and concentrated in vacuo. The residue
was purified by silica gel flash column chromatography using ISCO
instrument (0-100% EtOAc in heptane) to give tert-butyl
((1S,5S,6S)-1-(azidomethyl)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (501 mg, 0.81 mmol, 100% yield) as a colorless oil. MS
(ESI, positive ion) m/z: 618.0/620.2 (M+1).sup.+.
Preparation of Compound 455B
[1495] To a solution of tert-butyl
((1S,5S,6S)-1-(azidomethyl)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (501 mg, 0.81 mmol) in MTBE (4 mL) under N.sub.2 at
0.degree. C. was added 1-propynylmagnesium bromide (0.5 M in THF,
2.43 mL, 1.21 mmol). After addition, the mixture was stirred at RT
overnight. LCMS showed 15% conversion. Additional
1-propynylmagnesium bromide (0.5 M in THF, 2.43 mL, 1.21 mmol) was
added and the mixture was then stirred at RT for 4 h. LCMS showed
no starting material. The reaction was quenched with saturated
NH.sub.4Cl (50 mL) and extracted with EtOAc (2.times.70 mL). The
combined organic extracts were dried over MgSO.sub.4 and
concentrated in vacuo. The residue was purified by silica gel flash
column chromatography using ISCO instrument (0%-100% EtOAc/heptane)
to give tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((4-methyl-1H-1-
,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(tr-
imethylsilyl)ethoxy)methyl)carbamate (449 mg, 0.68 mmol, 84% yield)
as colorless oil. MS (ESI, positive ion) m/z: 658.1/660.0
(M+1).sup.+. .sup.1H NMR (CHLOROFORM-d) .delta.: 7.77 (dd, J=6.9,
2.4 Hz, 1H), 7.50 (s, 1H), 7.40 (ddd, J=8.7, 4.3, 2.5 Hz, 1H), 6.97
(dd, J=11.5, 8.6 Hz, 1H), 5.27 (d, J=10.4 Hz, 1H), 5.03 (d, J=10.4
Hz, 1H), 4.57-4.82 (m, 2H), 4.39-4.50 (m, 2H), 3.64 (dd, J=9.1, 7.3
Hz, 2H), 2.43 (s, 3H), 2.24 (t, J=7.6 Hz, 1H), 1.50 (s, 9H), 1.22
(dd, J=9.9, 6.2 Hz, 1H), 0.95 (dd, J=9.1, 7.5 Hz, 2H), 0.85 (t,
J=6.7 Hz, 1H), 0.00 (s, 9H).
Preparation of Compound 455
[1496] The title compound (185 mg, 87% yield) as a yellow solid was
prepared from intermediate 455B (449 mg, 0.68 mmol) according to
the procedures described for intermediate 452. MS (ESI, positive
ion) m/z: 365.0 (M+1). .sup.1H NMR (CHLOROFORM-d) .delta.: 7.46 (s,
1H), 6.84 (dd, J=11.7, 8.6 Hz, 1H), 6.75 (dd, J=6.6, 2.8 Hz, 1H),
6.51-6.58 (m, 1H), 4.73-4.90 (m, 1H), 4.52-4.69 (m, 1H), 4.33-4.51
(m, 2H), 2.38 (s, 3H), 2.04-2.06 (m, 1H), 1.35 (dd, J=9.8, 6.3 Hz,
1H), 1.26 (t, J=7.1 Hz, 1H). The 2 sets of NH.sub.2 have very broad
peaks.
8-Chloro-3-methoxy-1,7-naphthyridine (251)
##STR00165##
[1497] Preparation of
5-methoxy-3-((triethylsilyl)ethynyl)picolinonitrile (251A)
[1498] 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 min at
0.degree. C. then stirred at RT for 30 min. 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% EtOAc in heptane, 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). 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
mixture (1:1 ratio) of 3-chloro-5-methoxypicolinonitrile and
5-chloro-3-methoxypicolinonitrile (5 g, 29.7 mmol), and ACN (60
mL). The vessel was flushed with argon, and stirred at RT for 25
min. 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 h. The solution was concentrated, and the residue was
purified via silica gel chromatography, eluting with 0-50% EtOAc in
heptane, to afford the title compound (3.8 g, 13.9 mmol). MS
m/z=273 (M+H).sup.+.
Preparation of 3-(2,2-dimethoxyethyl)-5-methoxypicolinonitrile
(251B)
[1499] A pressure vessel was charged with
5-methoxy-3-((triethylsilyl)ethynyl) picolinonitrile (251A, 3.8 g,
13.95 mmol) and sodium methoxide (0.5 M in MeOH, 69.7 mL, 34.9
mmol). The vessel was sealed and stirred at 55.degree. C. for 2 h.
The reaction was concentrated to afford the title intermediate (3.1
g, 13.95 mmol).
Preparation of 3-Methoxy-1,7-naphthyridin-8(7H)-one (251C)
[1500] To a solution of
3-(2,2-dimethoxyethyl)-5-methoxypicolinonitrile (251B, 8.55 g, 38.5
mmol) in water (480 mL) and acetone (120 mL) was added an aqueous
solution of sodium carbonate (3 M; 154 mL, 462 mmol) followed by
hydrogen peroxide (35 wt. % solution in water; 138 mL, 1347 mmol).
The tan mixture was stirred vigorously at RT for 2 h. The organic
solvent was removed under reduced pressure and the aqueous residue
was extracted with DCM (3.times.). The combined organic fractions
were dried over sodium sulfate. The filtrate was concentrated under
reduced pressure to afford
3-(2,2-dimethoxyethyl)-5-methoxypicolinamide (8.2 g, 34.1 mmol, 89%
yield) as an off-white solid that was advanced without further
purification. MS m/z=263.2 (M+Na).sup.+.
[1501] To a mixture of 3-(2,2-dimethoxyethyl)-5-methoxypicolinamide
(6.74 g, 28.1 mmol) in toluene (112 mL) was added 4-methylbenzene
sulfonic acid (monohydrate; 0.534 g, 2.81 mmol). The reaction
mixture was heated to reflux for 20 h. The reaction mixture was
cooled to RT and concentrated in vacuo to a volume of ca. 15 mL.
The residue was triturated with heptane and filtered to afford
3-methoxy-1,7-naphthyridin-8(7H)-one (251C, 4.53 g, 25.7 mmol, 92%
yield) as a crude, tan solid that was advanced without further
purification. MS m/z=177.1 [M+H].sup.+
Preparation of 8-chloro-3-methoxy-1,7-naphthyridine (251)
[1502] To a mixture of 3-methoxy-1,7-naphthyridin-8(7H)-one (4.50
g, 25.5 mmol) in ACN (102 mL) was added phosphorus oxychloride
(11.69 mL, 128 mmol). The reaction mixture was heated to 85.degree.
C. for 5 h. The solution was cooled to RT and concentrated in
vacuo. The resulting brown residue was partitioned between DCM and
aqueous saturated NaHCO.sub.3 solution; the aqueous layer was
back-extracted with DCM (3.times.). The combined organic extracts
were dried over sodium sulfate. The filtrate was concentrated in
vacuo, and the residue was purified by silica gel chromatography
(5-30% of (9:1 DCM:MeOH) in DCM) to give
8-chloro-3-methoxy-1,7-naphthyridine (3.00 g, 15.41 mmol, 60%
yield) as an off-white solid. MS m/z=195 (M+H).sup.+.
3,8-Dichloro-1,7-naphthyridine (252)
##STR00166##
[1503] Preparation of 3-bromo-5-chloropicolinonitrile
[1504] 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 h. 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 heptane, to afford the
title compound (2 g, 9.20 mmol). MS m/z=219 (M+H).sup.+.
Preparation of
5-chloro-3-((trimethylsilyl)ethynyl)picolinonitrile
[1505] A pressure vessel was charged with TEA (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 DMF (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 h. The solution was diluted with water and
extracted with EtOAc. The combined organic layers were
concentrated, and the residue was purified by silica-gel
chromatography, eluting 0-50% EtOAc in hexane, to afford the title
compound (1.3 g, 5.5 mmol). MS m/z=235 (M+H).sup.+.
Preparation of 5-chloro-3-(2,2-dimethoxyethyl)picolinonitrile
[1506] A pressure vessel was charged with
5-chloro-3-((trimethylsilyl)ethynyl)picolinonitrile (2 g, 8.52
mmol) and sodium methoxide (0.5 M in MeOH, 42.6 mL, 21.30 mmol),
sealed, and stirred at 55.degree. C. for 1 h. The solution was
concentrated, and the residue was purified via silica gel
chromatography, eluting with 10% MeOH in DCM to afford the title
compound (1.7 g, 7.50 mmol). MS m/z=227 (M+H).sup.+.
Preparation of 3-chloro-1,7-naphthyridin-8(7H)-one
[1507] 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 DCM. The combined organic layers were concentrated.
[1508] 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
EtOAc/MeOH/ammonium hydroxide) in EtOAc, to the title intermediate
(1.1 g, 6.1 mmol). MS m/z=181 (M+H).sup.+.
Preparation of 3,8-dichloro-1,7-naphthyridine
[1509] 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).sup.+.
5-Chloro-2-methoxypyrido[3,4-b]pyrazine (253)
##STR00167##
[1510] Preparation of 5-chloropyrido[3,4-b]pyrazin-2(1H)-one
[1511] 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 EtOH (34.8 mL) was stirred at reflux for 24 h. The
solution was cooled to -20.degree. C. for 16 hours, and the
resulting precipitate was collected by vacuum filtration and rinsed
with EtOH. The crude product was purified via reverse-phase HPLC,
eluting with 5-50% ACN/0.1% TFA in water/0.1% TFA, to afford the
title compound (570 mg, 3.14 mmol). MS m/z=182 (M+H).sup.+.
Preparation of 2,5-dichloropyrido[3,4-b]pyrazine
[1512] 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 DCM, 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).sup.+.
Preparation of 5-chloro-2-methoxypyrido[3,4-b]pyrazine
[1513] To a solution of 2,5-dichloropyrido[3,4-b]pyrazine (580 mg,
2.90 mmol) in DMF (10 mL) was added a 0.5 M solution of sodium
methoxide in MeOH (6.09 mL, 3.04 mmol), and the reaction was
stirred at RT for 5 min. The solution was diluted with water and
extracted with EtOAc. 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).sup.+.
8-Chloro-1,7-naphthyridine-3-carbonitrile (254)
##STR00168##
[1515] 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.RTM. filter aid, which
was rinsed with MeOH and DMSO. 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. The solids were suspended in toluene (3.5 mL), and
phosphorus oxychloride (98 .mu.L, 1.052 mmol) and DIPEA (122 .mu.L,
0.70 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 heptane, to provide the title compound (50 mg, 0.264
mmol) as a white solid. LC/MS (ESI.sup.+) m/z=190 (M+H).sup.+.
4,7-Dichloropyrido[3,2-d]pyrimidine (255)
##STR00169##
[1516] Preparation of 3-amino-5-chloropicolinamide
[1517] To a suspension of 5-chloro-2-cyano-3-nitropyridine (1.274
mL, 10.9 mmol) in water (22 mL) was added 28% aqueous NH.sub.4OH
(3.94 mL, 28.3 mmol), and the reaction was stirred at RT for 20
min. 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).sup.+.
Preparation of 7-chloropyrido[3,2-d]pyrimidin-4(1H)-one
[1518] 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 h. 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).sup.+.
Preparation of 4,7-dichloropyrido[3,2-d]pyrimidine
[1519] 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 h. After cooling to RT,
the reaction mixture was concentrated to provide the title
compound. LC/MS (ESI.sup.+) m/z=200 (M+H).sup.+.
4-Chloropyrido[3,2-d]pyrimidine-7-carbonitrile (256)
##STR00170##
[1521] To a mixture of
4-oxo-1,4-dihydropyrido[3,2-d]pyrimidine-7-carbonitrile (prepared
according to the procedures described in US20090036430) (7.7 g,
44.7 mmol) in toluene (249 mL) were added N,N-diisopropylethylamine
(23.73 mL, 136 mmol) and phosphorus oxychloride (12.69 mL, 139
mmol). The resulting reaction mixture was refluxed at 130.degree.
C. for 20 min. It was concentrated under reduced pressure. The
residue was dissolved in EtOAc (150 mL) and neutralized with sat.
NaHCO.sub.3 until pH=6-7. It was diluted with water and filtered
through a pad of silica in a fritted funnel. The filtrate was
extracted with EtOAc (3.times.150 mL). The combined organic
extracts were washed sequentially with water, brine and dried over
MgSO.sub.4. The solution was filtered and concentrated in vacuo to
give a dark brown solid. It was triturated with 160 mL of heptane
and 20 mL of EtOAc to yield
4-chloropyrido[3,2-d]pyrimidine-7-carbonitrile (5.7 g, 29.9 mmol,
67% yield) as an orange solid. The filtrate was concentrated down
to .about.50 mL and the precipitated solid was collected to yield
0.3 g of 4-chloropyrido[3,2-d]pyrimidine-7-carbonitrile. MS
m/z=191.0 [M+H].sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
9.27 (d, J=2.0 Hz, 1H), 9.26 (s, 1H), 8.77 (d, J=2.0 Hz, 1H).
8-Chloro-5-fluoro-3-methoxy-1,7-naphthyridine (257)
##STR00171##
[1523] A mixture of 3-methoxy-1,7-naphthyridin-8(7H)-one (15.00 g,
85 mmol) and selectfluor fluorinating reagent (47.21 g, 133 mmol)
in ACN (360 mL)/MeOH (90 mL) was heated at 45.degree. C. for 3 h.
It was cooled to RT and the solvents were removed in vacuo. The
residue was partitioned between EtOAc (200 mL and saturated
NaHCO.sub.3 (200 mL). The aqueous layer was extracted with EtOAc
(2.times.200 mL) and DCM (2.times.200 mL). A white solid
precipitated from the combined organic layers and was filtered to
give 5-fluoro-3,6-dimethoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one
(10.20 g, MS m/z=227.0 [M+H].sup.+). The combined organic layers
were dried over MgSO.sub.4 where a white solid precipitate formed
on the MgSO.sub.4. The organic solution was filtered and the solid
was washed consecutively with water then Et.sub.2O. The remaining
solid (1.24 g) contained product
5-fluoro-3,6-dimethoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (MS
m/z=227.0 [M+H].sup.+). The combined dried organic layers were
concentrated in vacuo to give
5-fluoro-3,6-dimethoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one (7.41
g) of a light-tan solid.
[1524] The three batches of solid (18.85 g)
5-fluoro-3,6-dimethoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one were
slurried in toluene (150 mL), treated with phosphorus oxychloride
(80 mL, 874 mmol) and heated at 75.degree. C. overnight. The
mixture was cooled to RT and the solvents were removed in vacuo.
The residue was azeotroped with toluene, dissolved in DCM,
evaporated onto silica gel and purified by flash chromatography
eluting with EtOAc:hexanes (0:1.fwdarw.3:1) to give
8-chloro-5-fluoro-3-methoxy-1,7-naphthyridine (257) (11.21 g, 62%
yield) of a sticky yellow solid. MS m/z=212.9 [M+H].sup.+. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.85 (d, J=2.92 Hz, 1H), 8.23
(s, 1H), 7.54 (d, J=2.92 Hz, 1H), 4.05 (s, 3H). .sup.19F NMR (282
MHz, CDCl.sub.3) .delta. ppm -140.46.
5-Chloro-2-methoxypyrido[3,4-b]pyrazine (258)
##STR00172##
[1525] Preparation of 5-chloropyrido[3,4-b]pyrazin-2(1H)-one
(258A)
[1526] 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 EtOH (34.8 mL) was stirred at reflux for 24 h. The
solution was cooled to -20.degree. C. for 16 h, and the resulting
precipitate was collected by vacuum filtration and rinsed with
EtOH. The crude product was purified via reverse-phase HPLC,
eluting with 5-50% ACN/0.1% TFA in water/0.1% TFA, to afford the
title compound (570 mg, 3.14 mmol). MS m/z=182 (M+H).sup.+.
Preparation of 2,5-dichloropyrido[3,4-b]pyrazine (258B)
[1527] 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 h, and then concentrated. The
residue was dissolved in DCM, 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).sup.+.
Preparation of 5-chloro-2-methoxypyrido[3,4-b]pyrazine (258)
[1528] To a solution of 2,5-dichloropyrido[3,4-b]pyrazine (580 mg,
2.90 mmol) in DMF (10 mL) was added a 0.5 M solution of sodium
methoxide in MeOH (6.09 mL, 3.04 mmol), and the reaction was
stirred at RT for 5 min. The solution was diluted with water and
extracted with EtOAc. 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).sup.+.
2-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)oxazole (259)
##STR00173##
[1529] Preparation of Compound 259A
[1530] A mixture of 5-chloro-2-methoxypyrido[3,4-b]pyrazine (258,
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 (259A, 2.57 g, 12.85 mmol,
91% yield) as a brown solid. LC/MS (ESI.sup.-) m/z=200, 202
(M+H).sup.+.
Preparation of Compound 259
[1531] At 0.degree. C., to a mixture of
2,5-dichloropyrido[3,4-b]pyrazine (259A, 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 (259,
1.89 g, 7.20 mmol, 88% yield) as a brown powder. LC/MS (ESI.sup.-)
m/z=263, 265 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta.=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).
3-Bromo-8-chloropyrido[2,3-d]pyridazine (260)
##STR00174##
[1532] Preparation of Compound 260A
[1533] A vial was charged with methyl 5-bromo-3-methylpicolinate
(2.03 g, 8.82 mmol), carbon tetrachloride (22 mL), benzoyl peroxide
(0.107 g, 0.441 mmol) and NBS (3.14 g, 17.65 mmol). The mixture was
heated at 80.degree. C. for 2 h. Another equivalent of NBS and 50
mg benzoyl peroxide were added, and heating was continued for 16 h.
Upon cooling to RT the mixture was filtered through Celite.RTM.
filter aid and washed with DCM. The filtrate was concentrated, and
the crude material was purified by silica gel chromatography
(10-50% EtOAc/heptane) to provide methyl
5-bromo-3-(dibromomethyl)picolinate as a yellow oil (260A, 3.28 g,
8.46 mmol, 96% yield).
Preparation of 3-bromopyrido[2,3-d]pyridazin-8(7H)-one (260B)
[1534] A pressure bottle was charged with methyl
5-bromo-3-(dibromomethyl)picolinate (3.28 g, 8.46 mmol), EtOH
(16.91 mL) and hydrazine hydrate (4.19 mL, 85 mmol). The bottle was
sealed, and the mixture was heated at 80.degree. C. for 1.5 h. The
mixture was heterogeneous upon cooling, so the solids were
filtered, washed with MeOH and dried. The filtrate was concentrated
and was triturated in MeOH. The solids were filtered, rinsed with
MeOH and dried to give a second crop of product. The title compound
(1.72 g, 7.61 mmol, 90% yield) was isolated as a yellow solid.
Preparation of 3-bromo-8-chloropyrido[2,3-d]pyridazine (260)
[1535] A vial was charged with
3-bromopyrido[2,3-d]pyridazin-8(7H)-one (500 mg, 2.212 mmol) and
phosphorus oxychloride (4.1 mL, 44.2 mmol). The vial was capped and
the mixture was heated at 90.degree. C. for 2 h. The mixture was
concentrated and used without further purification. MS m/z=241
(M+MeOH adduct).sup.+.
8-Chloro-3-(prop-2-yn-1-yloxy)-1,7-naphthyridine and
8-chloro-3-(prop-2-yn-1-yloxy)-1,7-naphthyridine (261)
##STR00175##
[1537] To a stirring solution of
8-chloro-3-methoxy-1,7-naphthyridine (251) (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 8-chloro-1,7-naphthyridin-3-ol
(1.8 g, 9.97 mmol, 259% yield) as a tan solid which was used
without further purification.
[1538] To a stirring suspension of the above crude
8-chloro-1,7-naphthyridin-3-ol (700 mg, 3.88 mmol) 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 brine (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. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 8.85 (d, J=2.74 Hz, 1H),
8.29-8.35 (m, 1H), 7.54-7.58 (m, 1H), 7.47-7.52 (m, 1H), 4.90 (d,
J=2.54 Hz, 2H), 2.64 (t, J=2.45 Hz, 1H).
5-Chloro-2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazine (262)
##STR00176##
[1540] 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 NaH (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 (259A, 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=5.7 Hz, 1H), 5.18 (d, J=2.3 Hz, 2H), 2.58 (t,
J=2.4 Hz, 1H).
8-Chloro-3-(cyclopropylmethoxy)-1,7-naphthyridine (400)
##STR00177##
[1542] To a stirring solution of
8-chloro-3-methoxy-1,7-naphthyridine (251) (5.00 g, 25.7 mmol) and
tetrabutylammonium iodide (12.3 g, 33.4 mmol) in DCM (86 mL) at RT
under nitrogen was added a solution of boron trichloride (1.0 M in
DCM, 128 mL, 128 mmol). The dark red solution was stirred at RT for
5 h and then cooled to 0.degree. C. in an ice bath. The reaction
was carefully quenched by dropwise addition of water until bubbling
ceased with further addition of water. The ice bath was removed and
the mixture was then stirred for 30 min. DCM (250 mL) and water
(250 mL) were added and the mixture was carefully neutralized by
portion wise addition of solid sodium bicarbonate. The layers were
then separated and the aqueous layer was extracted with DCM
(3.times.150 mL). The combined organic extracts were washed with
brine (100 mL), dried over Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The residue was purified by silica gel
chromatography eluting with a gradient of 50-100% EtOAc/heptane to
give 8-chloro-1,7-naphthyridin-3-ol as a yellow solid (400A, 3.5 g,
75%). LC/MS (ESI.sup.+) m/z=181.1 (M+H).sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 11.30 (s, 1H), 8.75 (d, J=2.74 Hz, 1H),
8.22 (d, J=5.48 Hz, 1H), 7.77 (d, J=5.67 Hz, 1H), 7.58 (d, J=2.74
Hz, 1H).
[1543] To a stirring suspension of 8-chloro-1,7-naphthyridin-3-ol
(400A) (200 mg, 1.107 mmol) in THF (5 mL) under nitrogen, was added
cyclopropanemethanol (0.27 mL, 3.32 mmol). The mixture was then
cooled to 0.degree. C. in an ice bath and triphenylphosphine (871
mg, 3.32 mmol) was added. The reaction mixture was stirred at
0.degree. C. for 3 min then diisopropyl azodicarboxylate (0.65 mL,
3.32 mmol) was added dropwise by syringe over 2 min. The yellow
solution was then stirred at RT for 10-120 min. The reaction was
quenched with water (30 mL), and then diluted with EtOAc (25 mL).
The layers were separated and the aqueous layer was extracted with
EtOAc (20 mL). The combined organic extracts were washed with brine
(20 mL), dried over MgSO.sub.4, filtered through a fritted funnel
and concentrated in vacuo. The residue was purified by silica gel
chromatography eluting with a gradient of 0-80% EtOAc/heptane to
give 8-chloro-3-(cyclopropylmethoxy)-1,7-naphthyridine (400),
contaminated with DIAD byproduct as a white solid (280 mg, 108%).
LC/MS (ESI.sup.+) m/z=235.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 8.85 (d, J=2.74 Hz, 1H), 8.28 (dd, J=5.67,
6.65 Hz, 1H), 7.50 (dd, J=2.35, 5.48 Hz, 1H), 7.28 (d, J=2.74 Hz,
1H), 3.99 (d, J=7.04 Hz, 2H), 1.32 (m, 1H), 0.71-0.79 (m, 2H), 0.45
(q, J=5.02 Hz, 2H).
8-Chloro-3-(2-methoxyethoxy)-1,7-naphthyridine (401)
##STR00178##
[1545] The title compound was synthesized according to the
procedures similar to those described for intermediate 400, using
2-methoxyethanol to react with compound 400A. LC/MS (ESI.sup.+)
m/z=239.1 (M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
8.88 (d, J=2.93 Hz, 1H), 8.30 (dd, J=5.67, 6.65 Hz, 1H), 7.52 (m,
1H), 7.36 (dd, J=2.93, 6.85 Hz, 1H), 4.27-4.35 (m, 2H), 3.82-3.90
(m, 2H), 3.50 (s, 3H).
5-(((8-Chloro-1,7-naphthyridin-3-yl)oxy)methyl)oxazole (402)
##STR00179##
[1547] The title compound was synthesized according to the
procedures similar to those described for intermediate 400, using
5-oxazolemethanol to react with compound 400A. LC/MS (ESI.sup.+)
m/z=262.0 (M+H).sup.+.
2-(((8-Chloro-1,7-naphthyridin-3-yl)oxy)methyl)oxazole (403)
##STR00180##
[1549] The title compound was synthesized according to the
procedures similar to those described for intermediate 400, using
2-oxazolemethanol to react with compound 400A. LC/MS (ESI.sup.+)
m/z=262.1 (M+H).sup.+.
4-(((8-Chloro-1,7-naphthyridin-3-yl)oxy)methyl)oxazole (404)
##STR00181##
[1551] The title compound was synthesized according to intermediate
400, using oxazol-4-yl-methanol to react with compound 400A. The
product precipitated from the reaction mixture and was collected by
filtration, washed with THF and used without further purification.
LC/MS (ESI.sup.+) m/z=262.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.87 (d, J=2.74 Hz, 1H), 8.46 (s, 1H),
8.30-8.38 (m, 2H), 8.07 (d, J=2.74 Hz, 1H), 7.85 (d, J=5.48 Hz,
1H), 5.29 (s, 2H).
5-Chloro-2-(((8-chloro-1,7-naphthyridin-3-yl)oxy)methyl)thiazole
(405)
##STR00182##
[1553] Sodium borohydride (0.128 g, 3.39 mmol) was added to a
stirring solution of 5-chlorothiazole-2-carboxaldehyde (0.5 g, 3.39
mmol) in MeOH (6.78 mL) at RT. The mixture was stirred for 30 min
at RT and then concentrated in vacuo. The residue was taken up in
EtOAc (40 mL) and washed sequentially with water (30 mL) and brine
(20 mL). The organic layer was then dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give
(5-chlorothiazol-2-yl)methanol as a white solid that was used
without further purification (405A, 511 mg, 101%). LC/MS
(ESI.sup.+) m/z=150.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
chloroform-d) .delta. 7.54 (s, 1H), 4.88 (d, J=5.87 Hz, 2H), 2.57
(t, J=6.06 Hz, 1H).
[1554] The title compound was synthesized according to intermediate
400, using (5-chlorothiazol-2-yl)methanol (405A) to react with
Compound 400A. LC/MS (ESI.sup.+) m/z=311.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.94 (d, J=2.93 Hz, 1H), 8.34 (d,
J=5.67 Hz, 1H), 8.08 (d, J=2.74 Hz, 1H), 7.93 (s, 1H), 7.85 (d,
J=5.67 Hz, 1H), 5.66 (s, 2H).
4-Bromo-2-(((8-chloro-1,7-naphthyridin-3-yl)oxy)methyl)thiazole
(406)
##STR00183##
[1556] Sodium borohydride (99 mg, 2.60 mmol) was added to a
stirring solution of 5-chlorothiazole-2-carboxaldehyde (500 mg,
2.60 mmol) in MeOH (5.2 mL) at RT. The mixture was stirred for 30
min at RT and then concentrated in vacuo. The residue was taken up
in EtOAc (40 mL) and washed sequentially with water (30 mL) and
brine (20 mL). The organic layer was then dried over
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give
(4-bromothiazol-2-yl)methanol as a brown oil that was used without
further purification (406A, 499 mg, 99%). LC/MS (ESI.sup.+)
m/z=194.0 (M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta.
7.23 (s, 1H), 4.97 (d, J=6.06 Hz, 2H), 2.51 (t, J=5.38 Hz, 1H).
[1557] The title compound was synthesized according to intermediate
400, using (4-bromothiazol-2-yl)methanol (406A) to react with
Compound 400A. LC/MS (ESI.sup.+) m/z=358.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.96 (d, J=2.93 Hz, 1H), 8.35 (d,
J=5.48 Hz, 1H), 8.09 (d, J=2.93 Hz, 1H), 7.97 (s, 1H), 7.86 (d,
J=5.67 Hz, 1H), 5.71 (s, 2H).
2-(((8-Chloro-1,7-naphthyridin-3-yl)oxy)methyl)thiazole (407)
##STR00184##
[1559] The title compound was synthesized according to intermediate
400, using 1,3-thiazol-2-ylmethanol to react with Compound 400A.
LC/MS (ESI.sup.+) m/z=278.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.95 (d, J=2.93 Hz, 1H), 8.34 (d, J=5.48 Hz,
1H), 8.10 (d, J=2.93 Hz, 1H), 7.91 (d, J=3.13 Hz, 1H), 7.82-7.87
(m, 2H), 5.71 (s, 2H).
8-Chloro-3-((4,4,4-trideuterobut-2-yn-1-yl)oxy)-1,7-naphthyridine
(408)
##STR00185##
[1561] The title compound was synthesized according to intermediate
400, using 4,4,4-trideuterobut-2-yn-1-ol (prepared according to the
procedures reported in: J. Org. Chem. 2014, 79, 3572) to react with
Compound 400A. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.86 (d,
J=2.93 Hz, 1H), 8.32 (d, J=5.48 Hz, 1H), 7.56 (d, J=5.48 Hz, 1H),
7.48 (d, J=2.74 Hz, 1H), 4.86 (s, 2H).
2-((8-Chloro-1,7-naphthyridin-3-yl)oxy)acetonitrile (409) and
3-(((8-chloro-1,7-naphthyridin-3-yl)oxy)methyl)-1,2,4-oxadiazole
(410)
##STR00186##
[1563] To a stirring solution of 3-(chloromethyl)-1,2,4-oxadiazole
(361 mg, 3.05 mmol) in DMF (13.8 mL) was added
8-chloro-1,7-naphthyridin-3-ol (400A) (500 mg, 2.77 mmol),
tetrabutylammonium iodide (102 mg, 0.27 mmol) and potassium
carbonate (765 mg, 5.54 mmol). The suspension was heated at
70.degree. C. for 45 min and then cooled to RT. The mixture was
diluted with EtOAc (75 mL) and water (150 mL). The layers were
separated and the aqueous layer was extracted with EtOAc (75 mL).
The combined organic extracts were washed with brine (50 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by silica gel chromatography eluting with a
gradient of 20-80% EtOAc/heptane to give twp products: the 1.sup.st
eluent, 2-((8-chloro-1,7-naphthyridin-3-yl)oxy)acetonitrile (409)
as a white solid (325 mg, 53%). LC/MS (ESI.sup.+) m/z=220.1
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.89 (d,
J=2.93 Hz, 1H), 8.40 (d, J=5.48 Hz, 1H), 7.61 (d, J=5.48 Hz, 1H),
7.52 (d, J=2.93 Hz, 1H), 5.00 (s, 2H). The 2.sup.nd eluent,
3-(((8-chloro-1,7-naphthyridin-3-yl)oxy)methyl)-1,2,4-oxadiazole
(410) as a white solid (149 mg, 20%). LC/MS (ESI.sup.+) m/z=263.0
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.92 (d,
J=2.93 Hz, 1H), 8.84 (s, 1H), 8.34 (d, J=5.67 Hz, 1H), 7.53-7.59
(m, 2H), 5.47 (s, 2H).
5-(((8-Chloro-1,7-naphthyridin-3-yl)oxy)methyl)-1,2,4-oxadiazole
(411)
##STR00187##
[1565] To a stirring solution of 5-(chloromethyl)-1,2,4-oxadiazole
(361 mg, 3.05 mmol) in DMF (13.8 mL) was added
8-chloro-1,7-naphthyridin-3-ol (400A) (500 mg, 2.77 mmol),
tetrabutylammonium iodide (205 mg, 0.554 mmol) and potassium
carbonate (765 mg, 5.54 mmol). The suspension was heated at
70.degree. C. for 4 h and then cooled to RT. The mixture was
diluted with EtOAc (75 mL) and water (150 mL). The layers were
separated and the aqueous layer was extracted with EtOAc (75 mL).
The combined organic extracts were washed with brine (50 mL), dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
residue was purified by silica gel chromatography eluting with a
gradient of 0-20% MeOH/DCM to give
5-(((8-chloro-1,7-naphthyridin-3-yl)oxy)methyl)-1,2,4-oxadiazole
(411) as an oil (100 mg, 14%). LC/MS (ESI.sup.+) m/z=263.2
(M+H).sup.+.
8-Chloro-3-(2,2,3,3-tetrafluoropropoxy)-1,7-naphthyridine (412)
##STR00188##
[1567] To a stirring suspension of 2,2,3,3-tetrafluoroproyl
trifluoromethanesulfonate (377 mg, 1.43 mmol) and
8-chloro-1,7-naphthyridin-3-ol (400A) (258 mg, 1.43 mmol) in
acetone (4.5 mL) was added potassium carbonate (592 mg, 4.29 mmol).
The suspension was stirred at RT for 6 h, then diluted with MTBE
(25 mL) and filtered to remove the solids. The filtrate was
concentrated in vacuo and the residue was purified by silica gel
chromatography eluting with a gradient of 10-70% EtOAc/heptane to
give 8-chloro-3-(2,2,3,3-tetrafluoropropoxy)-1,7-naphthyridine
(412) as an off-white solid (343 mg, 81%). LC/MS (ESI.sup.+)
m/z=295.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.93 (d, J=2.93 Hz, 1H), 8.36 (d, J=5.48 Hz, 1H), 8.10 (d, J=2.93
Hz, 1H), 7.84 (d, J=5.67 Hz, 1H), 6.60-6.94 (m, 1H), 4.90 (t,
J=13.50 Hz, 2H).
8-Chloro-3-((4,4,4-trifluorobut-2-yn-1-yl)oxy)-1,7-naphthyridine
(413)
##STR00189##
[1569] A solution of lithium diisopropylamide (2.0 M in
THF/heptane/ethylbenzene) (0.73 mL, 1.47 mmol) was added dropwise
to a stirring solution of
8-chloro-3-(prop-2-yn-1-yloxy)-1,7-naphthyridine (261) (292 mg,
1.33 mmol) in THF (13.4 mL) under nitrogen at -78.degree. C. The
solution was stirred at -78.degree. C. for 5 min and then solid
S-(trifluoromethyl)dibenzothiophenium triflate (913 mg, 2.27 mmol)
was added in one portion. The cold bath was removed and the mixture
was allowed to warm to RT. The reaction was quenched with saturated
aqueous ammonium chloride solution (20 mL) and then diluted with
water (30 mL) and EtOAc (50 mL). The layers were separated and the
organic layer was dried over Na.sub.2SO.sub.4, filtered, and
concentrated in vacuo. The residue was purified by silica gel
chromatography eluting with a gradient of 10-35% EtOAc/heptane to
give
8-chloro-3-((4,4,4-trifluorobut-2-yn-1-yl)oxy)-1,7-naphthyridine
(413) as a white solid (88 mg, 23%). LC/MS (ESI.sup.+) m/z=287.1
(M+H).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.88 (d,
J=2.93 Hz, 1H), 8.37 (d, J=5.48 Hz, 1H), 7.59 (d, J=5.48 Hz, 1H),
7.44 (d, J=2.93 Hz, 1H), 5.02 (q, J=2.80 Hz, 2H). .sup.19F NMR (376
MHz, chloroform-d) .delta. -51.2.
3-(But-2-yn-1-yloxy)-8-chloro-1,7-naphthyridine (414)
##STR00190##
[1571] A suspension of 8-chloro-1,7-naphthyridin-3-ol (0.50 g, 2.77
mmol) with cesium carbonate (4.51 g, 13.84 mmol) and
1-bromo-2-butyne (0.73 g, 5.54 mmol) was stirred at RT for 15 min
then placed in a 40.degree. C. sand bath for 18 h. The reaction
mixture was partitioned between EtOAc (25 mL) and 0.5 M
K.sub.2HPO.sub.4 (50 mL). The organic layer was further washed with
0.5 M K.sub.2HPO.sub.4 (50 mL) and brine (20 mL). The organic layer
was dried over MgSO.sub.4, concentrated under reduced pressure,
then purified by silica gel chromatography (40 g) eluting products
with a gradient of 10-25% EtOAc/heptane to afford
3-(but-2-yn-1-yloxy)-8-chloro-1,7-naphthyridine (414) (370 mg) as a
white solid: m/z (APCI, pos. ion) 233.0. This material contained a
small amount of 8-bromo-3-(but-2-yn-1-yloxy)-1,7-naphthyridine: m/z
(APCI, pos. ion) 277.
4-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)oxazole (415)
##STR00191##
[1573] A mixture of 2,5-dichloropyrido[3,4-b]pyrazine (1.07 g, 5.35
mmol), oxazol-4-yl-methanol (0.42 mL, 5.35 mmol), and potassium
carbonate (1.48 g, 10.70 mmol) in DMF (18 mL) was heated at
50.degree. C. for 5 h. The reaction mixture was diluted with water
and extracted with EtOAc. The organic extract was washed with
brine, dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude product (1.2 g) was adsorbed onto a plug of silica
gel and chromatographed through a Biotage SNAP Ultra silica gel
column (50 g), eluting with isocratic 18% EtOH/EtOAc (25:75) in
hexanes, to the title compound (0.74 g, 2.82 mmol, 53% yield).
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 5.51 (s, 2H) 7.84
(d, J=5.70 Hz, 1H) 8.34 (d, J=0.73 Hz, 1H) 8.45 (s, 1H) 8.54 (d,
J=5.70 Hz, 1H) 8.80 (s, 1H). LC/MS (ESI.sup.+) m/z=263.0
[M+H].sup.+.
4-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-2-methyloxazole
(416)
##STR00192##
[1575] The title compound (0.94 g, 3.81 mmol, 73% yield) as a tan
solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.99 g, 4.98 mmol) and (2-methyloxazol-4-yl)methanol (0.56 g, 4.98
mmol). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 2.50 (s, 3H)
5.48 (s, 2H) 7.66 (d, J=5.70 Hz, 1H) 7.70 (s, 1H) 8.50 (d, J=5.70
Hz, 1H) 8.64 (s, 1H). LC/MS (ESI.sup.+) m/z=277.0 (M+H).sup.+.
4-(((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-5-methyloxazole
(417)
##STR00193##
[1577] The title compound (0.16 g, 0.58 mmol, 22% yield) as an
off-white solid was prepared according to the procedures described
for intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.51 g, 2.56 mmol) and (5-methyloxazol-4-yl)methanol (0.29 g, 2.56
mmol). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.47 (s, 3H)
5.45 (s, 2H) 7.81 (d, J=5.67 Hz, 1H) 8.26 (s, 1H) 8.53 (d, J=5.67
Hz, 1H) 8.79 (s, 1H). LC/MS (ESI.sup.+) m/z=277.1 (M+H).sup.+.
2-(But-2-yn-1-yloxy)-5-chloropyrido[3,4-b]pyrazine (418)
##STR00194##
[1579] The title compound (0.59 g, 2.56 mmol, 50% yield) as a light
brown solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
1.02 g, 5.11 mmol) and 3-pentyn-2-ol (0.48 mL, 5.11 mmol). .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 1.88 (t, J=2.34 Hz, 3H)
5.19 (q, J=2.34 Hz, 2H) 7.81 (d, J=5.70 Hz, 1H) 8.53 (d, J=5.55 Hz,
1H) 8.82 (s, 1H). LC/MS (ESI.sup.+) m/z=234.2 (M+H).sup.+.
5-Chloro-2-(pent-3-yn-2-yloxy)pyrido[3,4-b]pyrazine (419)
##STR00195##
[1581] The title compound (0.64 g, 2.61 mmol, 51% yield) as a solid
was prepared according to the procedures described for intermediate
259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A, 1.03 g, 5.15
mmol) and 2-butyn-1-ol (0.38 mL, 5.15 mmol). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.70 (d, J=6.65 Hz, 3H) 1.86 (d, J=2.15
Hz, 3H) 5.98 (m, 1H) 7.67 (d, J=5.67 Hz, 1H) 8.49 (d, J=5.67 Hz,
1H) 8.60 (s, 1H). LC/MS (ESI.sup.+) m/z=247.9 (M+H).sup.+.
5-Chloro-2-isopropoxypyrido[3,4-b]pyrazine (420)
##STR00196##
[1583] The title compound (0.56 g, 2.53 mmol, 100% yield) as a tan
solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.50 g, 2.53 mmol) and isopropanol (0.19 mL, 2.53 mmol). .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta. ppm 1.47 (d, J=6.14 Hz, 6H)
5.56 (dt, J=12.39, 6.16 Hz, 1H) 7.61 (d, J=5.70 Hz, 1H) 8.46 (d,
J=5.70 Hz, 1H) 8.53 (s, 1H). LC/MS (ESI.sup.+) m/z=224.0
(M+H).sup.+.
5-Chloro-2-(3-fluoropropoxy)pyrido[3,4-b]pyrazine (421)
##STR00197##
[1585] The title compound (0.40 g, 1.69 mmol, 66% yield) as a white
solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.51 g, 2.54 mmol) and 3-fluoropropan-1-ol (0.19 mL, 2.54 mmol).
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 2.18-2.41 (m, 2H)
4.56-4.83 (m, 4H) 7.64 (d, J=5.70 Hz, 1H) 8.49 (d, J=5.70 Hz, 1H)
8.61 (s, 1H). LC/MS (ESI.sup.+) m/z=242.0 (M+H).sup.+.
5-Chloro-2-(2,2,3,3-tetrafluoropropoxy)pyrido[3,4-b]pyrazine
(422)
##STR00198##
[1587] The title compound (0.63 g, 2.2 mmol, 85% yield) as a white
solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.50 g, 2.53 mmol) and 1H,1H,3H-tetrafluoro-1-propanol (0.20 mL,
2.53 mmol). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 5.11
(t, J=14.10 Hz, 2H) 6.52-6.99 (m, 1H) 7.83 (d, J=5.70 Hz, 1H) 8.57
(d, J=5.70 Hz, 1H) 8.92 (s, 1H). LC/MS (ESI.sup.+) m/z=295.9
(M+H).sup.+.
5-Chloro-2-(2,2-difluoropropoxy)pyrido[3,4-b]pyrazine (423)
##STR00199##
[1589] The title compound (0.34 g, 1.33 mmol, 52% yield) as a white
solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.51 g, 2.56 mmol) and 2,2-difluoro-propan-1-ol (0.20 mL, 2.56
mmol). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 1.83 (t,
J=18.64 Hz, 3H) 4.72 (t, J=11.84 Hz, 2H) 7.65 (d, J=5.70 Hz, 1H)
8.52 (d, J=5.55 Hz, 1H) 8.71 (s, 1H). LC/MS (ESI.sup.+) m/z=260.0
(M+H).sup.+.
4-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)thiazole
(424)
##STR00200##
[1591] The title compound (0.22 g, 0.78 mmol, 39% yield) as a tan
solid was prepared according to the procedures described for
intermediate 415 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.40 g, 2.00 mmol) and thiazole-4-methanol (0.23 g, 2.00 mmol).
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 5.78 (s, 2H) 7.55
(d, J=2.05 Hz, 1H) 7.68 (d, J=5.70 Hz, 1H) 8.51 (d, J=5.70 Hz, 1H)
8.68 (s, 1H) 8.91 (d, J=2.05 Hz, 1H). LC/MS (ESI.sup.+) m/z=278.9
(M+H).sup.+.
(S)-2-(1-((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)ethyl)oxazole
(425A) and
(R)-2-(1-((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)ethyl)oxazole
(425B)
##STR00201##
[1593] At 0.degree. C., a solution of 1-(oxazol-2-yl)ethanone (1.0
g, 9.00 mmol, J&W Pharmlab) in MeOH (40 mL) was treated with
sodium borohydride (0.39 g, 10.31 mmol) in 2 portions. After 15 min
the reaction was allowed to warm to RT for 2 h. The reaction was
quenched with water (5 mL). The mixture was partitioned between
brine/DCM and the aqueous layer was extracted with DCM (2.times.).
The combined organic layers were washed brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
920 mg (90%) of a light-yellow oil. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. ppm 7.62 (d, J=0.88 Hz, 1H), 7.07 (s, 1H), 4.97
(q, J=6.58 Hz, 1H), 1.62 (d, J=6.72 Hz, 3H). LC/MS (ESI.sup.+)
m/z=114.1 (M+H).sup.+.
[1594] 2-(1-((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)ethyl)oxazole
(6.00 g, 21.7 mmol, 88% yield) as a solid was prepared according to
the procedures described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 4.91 g, 24.57 mmol) and
1-(oxazol-2-yl)ethanol (2.7794 g, 24.57 mmol). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta. ppm 1.90 (d, J=6.72 Hz, 3H) 6.58 (q,
J=6.72 Hz, 1H) 7.14 (s, 1H) 7.63 (d, J=5.70 Hz, 1H) 7.67 (d, J=0.73
Hz, 1H) 8.49 (d, J=5.55 Hz, 1H) 8.67 (s, 1H). LC/MS (ESI.sup.+)
m/z=277.1 (M+H).sup.+. The racemic mixture was chromatographed
using supercritical CO.sub.2 (Organic modifier, 40% MeOH) on a
Chiracel AZ-H column (150.times.21 mm, 5 .mu.m) eluting at a flow
rate of 60 mL/min (220 bar pressure, 40.degree. C. column
temperature). The stereochemistry was arbitrarily assigned.
(S)-2-(1-((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)ethyl)oxazole
(425A, the first eluent, 2.97 g) and
(R)-2-(1-((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)ethyl)oxazole
(425B, the second eluent, 3.02 g) were obtained.
5-Chloro-2-((4-methylpyrimidin-2-yl)methoxy)pyrido[3,4-b]pyrazine
(426)
##STR00202##
[1596] The title compound (0.45 g, 1.58 mmol, 56% yield) as a light
yellow solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.56 g, 2.79 mmol) and 2-hydroxymethyl-4-methylpyrimidine (0.28 mL,
2.79 mmol). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 2.46
(s, 3H) 5.73 (s, 2H) 7.33 (d, J=5.28 Hz, 1H) 7.69 (d, J=5.67 Hz,
1H) 8.48 (d, J=5.67 Hz, 1H) 8.62 (d, J=5.09 Hz, 1H) 8.94 (s, 1H).
LC/MS (ESI.sup.+) m/z=287.9 (M+H).sup.+.
5-Chloro-2-((3-fluoropyridin-2-yl)methoxy)pyrido[3,4-b]pyrazine
(427)
##STR00203##
[1598] The title compound (0.74 g, 2.56 mmol, 101% yield) as a
light yellow solid was prepared according to the procedures
described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 0.51 g, 2.54 mmol) and
(3-fluoropyridin-2-yl)methanol (0.25 mL, 2.54 mmol). .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 5.74 (d, J=1.90 Hz, 2H) 7.55
(dt, J=8.59, 4.40 Hz, 1H) 7.74-7.90 (m, 2H) 8.46 (dt, J=4.60, 1.42
Hz, 1H) 8.52 (d, J=5.70 Hz, 1H) 8.86 (s, 1H). LC/MS (ESI.sup.+)
m/z=290.9 (M+H).sup.+.
4-(((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-2-methylthiazole
(428)
##STR00204##
[1600] The title compound (0.72 g, 2.48 mmol, 100% yield) as a tan
solid was prepared according to the procedures described for
intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.50 g, 2.49 mmol) and (2-methyl-1,3-thiazol-4-yl)methanol (0.32 g,
2.49 mmol). .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 5.59
(s, 2H) 7.71 (s, 1H) 7.83 (d, J=5.70 Hz, 1H) 8.53 (d, J=5.70 Hz,
1H). LC/MS (ESI.sup.+) m/z=293.0 (M+H).sup.+.
5-Chloro-2-(pyrimidin-2-ylmethoxy)pyrido[3,4-b]pyrazine (429)
##STR00205##
[1602] The title compound (1.11 g, 4.06 mmol, 77% yield) as a tan
crystalline solid was prepared according to the procedure described
for intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
1.06 g, 5.30 mmol) and pyrimidin-2-ylmethanol (0.59 g, 5.35 mmol,
Synthonix). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.81 (s,
1H), 8.76 (d, J=4.89 Hz, 2H), 8.45 (d, J=5.67 Hz, 1H), 7.56 (d,
J=5.67 Hz, 1H), 7.27-7.31 (m, 1H), 5.82 (s, 2H). LC/MS (ESI.sup.+)
m/z=274.1 (M+H).sup.+.
(S)-2-(But-3-yn-2-yloxy)-5-chloropyrido[3,4-b]pyrazine (430)
##STR00206##
[1604] The title compound (0.87 g, 3.72 mmol, 62% yield) as a tan
crystalline solid was prepared according to the procedure described
for intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
1.2 g, 6.0 mmol) and (S)-(-)-3-butyn-2-ol (0.50 mL, 0.443 g, 6.31
mmol, Sigma-Aldrich). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm
8.61 (s, 1H), 8.49 (d, J=5.70 Hz, 1H), 7.66 (d, J=5.70 Hz, 1H),
5.98 (qd, J=6.67, 2.05 Hz, 1H), 2.51 (d, J=2.05 Hz, 1H), 1.75 (d,
J=6.72 Hz, 3H). LC/MS (ESI.sup.+) m/z=234.1 (M+H).sup.+.
5-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-3-methyl-1,2,4-oxadiazo-
le (431)
##STR00207##
[1606] The title compound (0.95 g, 3.41 mmol, 68% yield) as a tan
amorphous solid was prepared according to the procedure described
for intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
1.0 g, 5.0 mmol) and (3-methyl-1,2,4-oxadiazol-5-yl)methanol (0.618
g, 5.42 mmol, Enamine). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
ppm 8.77 (s, 1H) 8.52 (d, J=5.55 Hz, 1H) 7.64 (d, J=5.70 Hz, 1H)
5.78 (s, 2H) 2.44 (s, 3H). LC/MS (ESI.sup.+) m/z=278.0
(M+H).sup.+.
4-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-2,5-dimethyloxazole
(432)
##STR00208##
[1608] The title compound (0.631 g, 2.17 mmol, 83% yield) as a
white crystalline solid was prepared according to the procedure
described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 0.520 g, 2.60 mmol) and
(2,5-dimethyloxazol-4-yl)methanol (0.380 g, 2.99 mmol, Frontier
Scientific). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.63 (s,
1H), 8.49 (d, J=5.70 Hz, 1H), 7.64 (d, J=5.70 Hz, 1H), 5.41 (s,
2H), 2.44 (s, 3H), 2.43 (s, 3H). LC/MS (ESI.sup.+) m/z=291.0
(M+H).sup.+.
2-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-5-methyloxazole
(433)
##STR00209##
[1610] The title compound (0.87 g, 3.17 mmol, 80% yield) as a tan
solid was prepared according to the procedures described for
intermediate 415 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.79 g, 3.96 mmol) and (5-methyloxazol-2-yl)methanol (0.36 mL, 3.96
mmol). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 2.37 (d,
J=1.02 Hz, 4H) 5.61 (s, 2H) 6.81 (d, J=1.17 Hz, 1H) 7.68 (d, J=5.70
Hz, 1H) 8.52 (d, J=5.70 Hz, 1H) 8.69 (s, 1H) LC/MS (ESI.sup.+)
m/z=2778.0 (M+H).sup.+.
3-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-5-methyl-1,2,4-oxadiazo-
le (434)
##STR00210##
[1612] The title compound (1.349 g, 4.86 mmol, 88% yield) as a
white crystalline solid was prepared according to the procedure
described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 1.10, 5.50 mmol) and
(5-methyl-1,2,4-oxadiazol-3-yl-methanol (0.656 g, 5.75 mmol,
Enamine). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.72 (s,
1H), 8.51 (d, J=5.70 Hz, 1H), 7.66 (d, J=5.70 Hz, 1H), 5.69 (s,
2H), 2.65 (s, 3H). LC/MS (ESI.sup.+) m/z=278.1 (M+H).sup.+.
1-(2-((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)ethyl)pyrrolidin-2-one
(435)
##STR00211##
[1614] The title compound (0.822 g, 2.81 mmol, 75% yield) as a
light-yellow crystalline solid was prepared according to the
procedure described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 0.750 g, 3.75 mmol) and
1-(2-hydroxyethyl)-2-pyrrolidinone (0.450 mL, 3.98 mmol,
Sigma-Aldrich). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.59
(s, 1H), 8.49 (d, J=5.55 Hz, 1H), 7.62 (d, J=5.70 Hz, 1H), 4.69 (t,
J=5.41 Hz, 2H), 3.79 (t, J=5.41 Hz, 2H), 3.57 (t, J=7.02 Hz, 2H),
2.34-2.47 (m, 2H), 1.98-2.17 (m, 2H). LC/MS (ESI.sup.+) m/z=293.0
(M+H).sup.+.
2-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-5-methyl-1,3,4-oxadiazo-
le (436)
##STR00212##
[1616] The title compound (0.860 g, 3.10 mmol, 68% yield) as a
white crystalline solid was prepared according to the procedure
described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 0.910 g, 4.55 mmol) and
(5-methyl-1,3,4-oxadiazol-2-yl)methanol (0.597 g, 5.23 mmol,
ChemBridge). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.71 (s,
1H) 8.54 (d, J=5.70 Hz, 1H) 7.69 (d, J=5.70 Hz, 1H) 5.77 (s, 2H)
2.60 (s, 3H) LC/MS (ESI.sup.+) m/z=278.1 (M+H).sup.+.
2-((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)-N,N-dimethylacetamide
(437)
##STR00213##
[1618] The title compound (0.555 g, 2.08 mmol, 59% yield) as a
light-orange crystalline solid was prepared according to the
procedure described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 0.706 g, 3.53 mmol) and
2-hydroxy-N,N-dimethylacetamide (0.372 g, 3.61 mmol, Enamine).
LC/MS (ESI.sup.+) m/z=267.0 (M+H).sup.+.
2-(((5-Chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)-5-methyl-1,3,4-thiadiaz-
ole (438)
##STR00214##
[1620] The title compound (0.191 g, 0.650 mmol, 34% yield) as a tan
crystalline solid was prepared according to the procedure described
for intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
0.380 g, 1.90 mmol) and (5-methyl-1,3,4-thiadiazol-2-yl)methanol
(0.261 g, 2.00 mmol, Enamine). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. ppm 8.68 (s, 1H) 8.54 (d, J=5.70 Hz, 1H) 7.70 (d, J=5.70
Hz, 1H) 5.96 (s, 2H) 2.81 (s, 3H). LC/MS (ESI.sup.+) m/z=294.2
(M+H).sup.+.
(S)-5-Chloro-2-((1-methoxypropan-2-yl)oxy)pyrido[3,4-b]pyrazine
(439)
##STR00215##
[1622] The title compound (0.794 g, 3.13 mmol, 84% yield) as a
light-yellow crystalline solid was prepared according to the
procedure described for intermediate 259 using
2,5-dichloropyrido[3,4-b]pyrazine (259A, 0.750 g, 3.75 mmol) and
(S)-(+)-1-methoxy-2-propanol (0.380 mL, 3.88 mmol, Fluka). .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.59 (s, 1H), 8.46 (d, J=5.70
Hz, 1H), 7.60 (d, J=5.55 Hz, 1H), 5.56-5.78 (m, 1H), 3.68 (dd,
J=10.67, 5.99 Hz, 1H), 3.62 (dd, J=10.67, 3.80 Hz, 1H), 3.42 (s,
3H), 1.45 (d, J=6.43 Hz, 3H). LC/MS (ESI.sup.+) m/z=254.0
(M+H).sup.+.
5-Chloro-2-(2-methoxyethoxy)pyrido[3,4-b]pyrazine (440)
##STR00216##
[1624] To a solution of 2-methoxyethanol (0.09 mL, 1.10 mmol) in
THF (1 mL) under nitrogen was added to a slurry of sodium hydride
(60% dispersion in mineral oil, 44 mg, 1.10 mmol) in THF (3 mL) at
0.degree. C. The slurry was stirred for 15 min, then was added to
the mixture of 2,5-dichloropyrido[3,4-b]pyrazine (0.20 g, 1.00
mmol) in THF (2 mL) at 0.degree. C. After 20 min, the reaction was
quenched with saturated NH.sub.4Cl solution (20 mL) and water (20
mL). The mixture was diluted with EtOAc (100 mL) and the organic
layer was washed with brine (50 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give
5-chloro-2-(2-methoxyethoxy)pyrido[3,4-b]pyrazine (0.24 g, 1.01
mmol, 100% yield). This material was used without further
purification. LC/MS (ESI.sup.-) m/z=240.1 (M+H).sup.+.
5-Chloro-2-((1,1-dideuteriumprop-2-yn-1-yl)oxy)pyrido[3,4-b]pyrazine
(441)
##STR00217##
[1626] A solution of 1,1-dideuteriumprop-2-yn-1-ol (0.22 g, 3.8
mmol) in THF (1 mL) was added to a slurry of sodium hydride (60%
dispersion in mineral oil, 0.11 g, 2.80 mmol) in THF (5 mL) at
0.degree. C. The slurry was stirred for 10 min. Solid
2,5-dichloropyrido[3,4-b]pyrazine (259A, 500 mg, 2.50 mmol) was
added to the alkoxide followed by THF rinsing of the stock flask
(.about.5 mL). After 10 min at 0.degree. C., the cooling bath was
removed and the mixture was stirred at RT for 20 min. It was
quenched with saturated NH.sub.4Cl solution and was extracted with
DCM (3.times.). The combined organic extracts were dried over
Na.sub.2SO.sub.4 and was passed through a silica gel pad with
excess of DCM/EtOAc=10:1. The filtrate was concentrated and the
resulting solid was triturated with hexanes-EtOAc (2:1, 6 mL, 5
times) and dried under vacuum to afford intermediate 441 (350 mg,
1.58 mmol, 63% yield) as an off-white powder. LCMS (ESI.sup.+)
m/z=221.6 (M+H).sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
8.66 (s, 1H), 8.50 (d, J=5.70 Hz, 1H), 7.67 (d, J=5.70 Hz, 1H),
2.57 (s, 1H).
5-Chloro-2-((1,1,4,4,4-pentadeuterobut-2-yn-1-yl)oxy)pyrido[3,4-b]pyrazine
(442)
##STR00218##
[1627] Preparation of Compound 442A
[1628] A solution of 1,1-dideutero-prop-2-yn-1-ol (0.8 g, 13.78
mmol) in DCM (5 mL) was added to a solution of
tert-butyl(chloro)diphenylsilane (5.37 mL, 20.66 mmol) and
imidazole (1.36 mL, 20.66 mmol) in DCM (5 mL) at RT. The mixture
was stirred at RT for 18 h, diluted with water, and extracted with
ether. The organic extract was washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography eluting with a gradient
of 0-10% EtOAc/heptane to give
tert-butyl((1,1-dideuteroprop-2-yn-1-yl)oxy)diphenylsilane (1.7 g,
41.6%) as a colorless oil. .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. 7.74 (dd, J=1.83, 7.67 Hz, 4H), 7.28-7.50 (m, 6H), 2.39 (s,
1H), 1.09 (s, 9H).
Preparation of Compound 442B
[1629] To a solution of
tert-butyl((1,1-dideuteroprop-2-yn-1-yl)oxy)diphenylsilane (1.7 g,
5.73 mmol) in THF (10 mL) was slowly added n-butyllithium solution
(1.6 M in hexanes) (4.66 mL, 7.45 mmol) at 0.degree. C. After 10
min, iodomethane-D3 (0.47 mL, 7.45 mmol) was slowly added and the
resulting mixture was stirred at RT overnight. The mixture was
diluted with EtOAc and washed with saturated aqueous NH.sub.4Cl
solution and then brine. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was
purified by flash column chromatography on silica gel using 0-10%
EtOAc in heptane to give
tert-butyl((1,14,4,4-pentadeuterobut-2-yn-1-yl)oxy)diphenylsilane
(1.23 g, 68.4%) as a pale yellow oil. LC/MS (ESI.sup.+) m/z=314.0
(M+H).sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 7.64-7.88
(m, 4H), 7.34-7.56 (m, 6H), 0.97-1.15 (m, 9H).
Preparation of
5-Chloro-2-((1,1,4,4,4-pentadeuterobut-2-yn-1-yl)oxy)pyrido[3,4-b]pyrazin-
e (442)
[1630] To a solution of
tert-butyl((1,14,4,4-pentadeuterobut-2-yn-1-yl)oxy)diphenylsilane
in THF (5 mL) was added TBAF solution (1M in THF) (1.91 mL, 1.9
mmol). The solution was stirred at RT for 1 h, quenched with water
and extracted with Et.sub.2O (2.times.). The combined organic
extracts were washed with brine, dried over Na.sub.2SO.sub.4,
filtered, and concentrated on the rotovap. The residue obtained
which contained 1,1,4,4,4-pentadeutero-but-2-yn-1-ol was dissolved
in THF (2 mL) at 0.degree. C. and was added sodium hydride (38 mg,
0.96 mmol). The slurry was stirred for 10 min and solid
2,5-dichloropyrido[3,4-b]pyrazine (259A, 0.17 g, 0.83 mmol) was
added. After stirring for 10 min at 0.degree. C., the cooling bath
was removed and the mixture was stirred at RT for 20 min. The
reaction mixture was quenched with saturated NH.sub.4Cl solution
and extracted with DCM. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The residue was purified by silica gel chromatography eluting with
a gradient of 0-60% EtOAc/heptane to give
5-chloro-2-((1,1,4,4,4-pentadeuterobut-2-yn-1-yl)oxy)pyrido[3,4-b]pyrazin-
e (0.035 g, 22.95%). LCMS (ESI.sup.+) m/z=239.0 (M+H).sup.+.
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.66 (s, 1H), 8.51 (d,
J=5.70 Hz, 1H), 7.68 (d, J=5.70 Hz, 1H).
5-Chloro-2-(pent-2-yn-1-yloxy)pyrido[3,4-b]pyrazine (443)
##STR00219##
[1632] The title compound (0.94 g, 3.81 mmol, 73% yield) as an
off-white solid was prepared according to the procedures described
for intermediate 259 using 2,5-dichloropyrido[3,4-b]pyrazine (259A,
1.04 g, 5.20 mmol) and 2-pentyn-1-ol (0.50 mL, 5.46 mmol). .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.18 (t, J=7.5 Hz, 3H),
2.28 (qt, J=7.5, 2.2 Hz, 2H), 5.17 (t, J=2.2 Hz, 2H), 7.66 (d,
J=5.7 Hz, 1H), 8.49 (d, J=5.7 Hz, 1H), 8.65 (s, 1H). LC/MS
(ESI.sup.+) m/z=248.2 (M+H).
4-Chloro-7-fluoropyrido[3,2-d]pyrimidine (444)
##STR00220##
[1633] Preparation of 5-fluoro-3-nitropicolinonitrile (444A)
[1634] Copper (I) cyanide (0.42 g, 4.73 mmol) was added to a
solution of 2-bromo-5-fluoro-3-nitropyridine (0.95 g, 4.30 mmol) in
DMF (15 mL) and the mixture was heated to 100.degree. C. for 4 h.
After cooling to RT, EtOAc (45 mL) was added followed by 9:1
NH.sub.4Cl/NH.sub.4OH (aq, 20 mL). The resulting biphasic mixture
was stirred for 10 min, and then the layers were separated. The
aqueous layer was extracted with EtOAc (2.times.) and then the
combined extracts were washed with water (2.times.), dried over
anhydrous MgSO.sub.4, filtered, and concentrated in vacuo to give
an oil. The oil was fused to silica gel and then purified by silica
gel chromatography (0-60% EtOAc/heptane gradient) to give the title
intermediate 444A (0.43 g, 2.60 mmol, 60% yield). .sup.1H-NMR (400
MHz, CHLOROFORM-d): .delta. ppm 8.90 (s, 1H) 8.35 (d, J=5.1 Hz,
1H). LC/MS (ESI.sup.+) m/z=168 (M+H).sup.+.
Preparation of 3-amino-5-fluoropicolinamide (444B)
[1635] Ammonium hydroxide (28% wt., 0.25 mL, 6.42 mmol) was added
to a suspension of 5-fluoro-3-nitropicolinonitrile (0.10 g, 0.62
mmol) in water (1.25 mL) and the mixture was stirred for 20 min.
Na.sub.2S.sub.2O.sub.4 (0.33 g, 1.87 mmol) was added portion wise
over 15 min. The resulting brown suspension was stirred for 2 h,
then filtered. The brown solid was washed with water three times,
then air-dried to give the title intermediate 444B (56 mg, 0.36
mmol, 58% yield). LC/MS (ESI.sup.+) m/z=156 (M+H).sup.+.
Preparation of 7-fluoropyrido[3,2-d]pyrimidin-4(3H)-one (444C)
[1636] 3-Amino-5-fluoropicolinamide (0.23 g, 1.49 mmol) was heated
to reflux in triethyl orthoformate (3.0 mL) for 4 h while
distillate was collected in a Dean-Stark trap. The mixture was
cooled to RT and the resulting suspension was filtered. The
collected solid was washed several times with heptane and then air
dried to give the title intermediate 444C (0.21 g, 1.26 mmol, 85%
yield) as a light brown solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.81 (d, J=2.74 Hz, 1H) 8.20 (s, 1H) 8.01 (dd, J=9.49,
2.64 Hz, 1H). LC/MS (ESI.sup.+) m/z=166 (M+H).sup.+.
Preparation of 4-Chloro-7-fluoropyrido[3,2-d]pyrimidine (444)
[1637] A mixture of 7-fluoropyrido[3,2-d]pyrimidin-4(3H)-one (0.20
g, 1.21 mmol), diisopropylethylamine (0.84 mL, 4.84 mmol), and
phosphorus oxychloride (0.44 mL, 4.84 mmol) in toluene (3 mL) was
heated to 110.degree. C. for 3 h, then cooled to RT. The mixture
was then carefully added to water that was being held at 10.degree.
C. This mixture was stirred vigorously for 30 min, and then the
product was extracted into EtOAc (3.times.). The combined extracts
were then dried over anhydrous MgSO4, filtered, and concentrated in
vacuo to give the title compound (68 mg, 31% yield) as a brown
solid. LC/MS (ESI.sup.+) m/z=184 (M+H).sup.+.
2-(((4-Chloropyrido[3,2-d]pyrimidin-7-yl)oxy)methyl)oxazole
(445)
##STR00221##
[1638] Preparation of
7-(oxazol-2-ylmethoxy)pyrido[3,2-d]pyrimidin-4(3H)-one (445A)
[1639] To a resealable vial was added
7-bromopyrido[3,2-d]pyrimidin-4(3H)-one (2.0 g, 8.85 mmol, D-L
Chiral Chemicals, LLC), cesium carbonate (8.65 g, 26.5 mmol),
2-(di-t-butylphosphono)-3-methoxy-6-methyl-2'-4'-6'-tri-i-propyl-1,1'-bip-
henyl (RockPhos) (0.21 g, 0.44 mmol, Strem Chemicals, Inc.), and
allylpalladium(II) chloride dimer (55 mg, 0.15 mmol, Sigma-Aldrich
Chemical Company, Inc.). The reaction vessel was carefully
evacuated and backfilled with N.sub.2. This was repeated twice. To
this mixture was added 1,4-dioxane (10 mL) and 2-oxazolemethanol
(2.81 mL, 35.4 mmol, Combi-Blocks, Inc.). Once again, the reaction
vessel was carefully evacuated and backfilled with N.sub.2. This
was repeated twice. The reaction mixture was heated at 90.degree.
C. for 6 h. The mixture was treated with sat NH.sub.4Cl and
extracted with 25% iPrOH/CHCl.sub.3. The solution needed to be
filtered through Celite.RTM. filter aid to achieve good extraction.
The combined extracts were dried and concentrated onto silica.
Purification by silica gel chromatography (3-20% MeOH/DCM) afforded
an off-white solid that was slurried with 50% EtOAc/heptane and
then dried under vacuum to afford the title compound (0.91 g, 42%).
MS m/z=245.0 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 5.50 (s, 2H) 7.31 (s, 1H) 7.70 (d, J=2.74 Hz, 1H) 8.13
(d, J=3.13 Hz, 1H) 8.21 (s, 1H) 8.54 (d, J=2.74 Hz, 1H) 12.43 (br
s, 1H).
Preparation of
2-(((4-chloropyrido[3,2-d]pyrimidin-7-yl)oxy)methyl)oxazole
(445)
[1640] To a 25 mL round-bottomed flask was added
7-(oxazol-2-ylmethoxy)pyrido[3,2-d]pyrimidin-4(3H)-one (0.45 g, 1.8
mmol), toluene (10 mL), N,N-diisopropylethylamine (0.96 mL, 5.5
mmol) and phosphorus oxychloride (1.0 mL, 11 mmol). The solution
was heated at 70.degree. C. for 1 h. The reaction mixture was
allowed to cool to RT and was pipetted into cold (.about.10.degree.
C.) sat NaHCO.sub.3. It was extracted with DCM (2.times.) and the
combined extracts were dried (Na.sub.2SO.sub.4) and concentrated.
The resulting solid was washed with heptane and then dried under
vacuum to afford the title compound as a tan solid (0.45 g, 1.7
mmol, 93% yield). MS m/z=263.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 5.39 (s, 2H), 7.22 (s, 1H), 7.75 (s, 1H),
7.79 (d, J=2.7 Hz, 1H), 8.92 (d, J=2.7 Hz, 1H), 9.05 (s, 1H).
4-Chloro-7-(prop-2-yn-1-yloxy)pyrido[3,2-d]pyrimidine (446)
##STR00222##
[1641] Preparation of
7-(2,2-dimethoxyethoxy)pyrido[3,2-d]pyrimidin-4(3H)-one (446A)
[1642] To a resealable vial was added
7-bromopyrido[3,2-d]pyrimidin-4(3H)-one (0.50 g, 2.2 mmol, D-L
Chiral Chemicals, LLC), cesium carbonate (2.2 g, 6.6 mmol),
2-(di-t-butylphosphono)-3-methoxy-6-methyl-2'-4'-6'-tri-i-propyl-1,1'-bip-
henyl (RockPhos) (0.062 g, 0.13 mmol, Strem Chemicals, Inc.) and
allylpalladium(II) chloride dimer (0.016 g, 0.044 mmol,
Sigma-Aldrich Chemical Company, Inc.). The reaction vessel was
carefully evacuated and backfilled with N.sub.2. This was repeated
twice. To the mixture was added 1,4-dioxane (5 mL) followed by
glycolaldehyde dimethyl acetal (1.41 g, 13.3 mmol). The reaction
mixture was stirred at 90.degree. C. for 2.5 h. After cooling to
RT, the solution was treated with sat NH.sub.4Cl and extracted with
25% iPrOH/CHCl.sub.3. The solution had to be filtered through
Celite.RTM. filter aid to prevent emulsion formation during
extraction. The combined extracts were dried and concentrated.
Purification by silica gel chromatography (0-10% MeOH/DCM) afforded
the title compound as a white solid (0.20 g, 36% yield). MS
m/z=252.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.37 (s, 6H), 4.21 (d, J=5.1 Hz, 2H), 4.76 (t, J=5.1 Hz, 1H),
7.57 (d, J=2.7 Hz, 1H), 8.12 (s, 1H), 8.49 (d, J=2.7 Hz, 1H), 12.40
(br. s., 1H).
Preparation of
2-((4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)oxy)acetaldehyde
(446B)
[1643] To a resealable vial was added
7-(2,2-dimethoxyethoxy)pyrido[3,2-d]pyrimidin-4(3H)-one (0.10 g,
0.40 mmol), THF (2 mL) and finally 2 N hydrochloric acid (2.0 mL).
The reaction mixture was heated at 60.degree. C. for 2 h. It was
allowed to cool to RT and then concentrated to afford the title
compound as a brown semi-solid which was carried on directly to the
next step. MS m/z=224.0 (M+H.sub.2O+H).sup.+.
Preparation of
7-(prop-2-yn-1-yloxy)pyrido[3,2-d]pyrimidin-4(3H)-one (446C)
[1644] To a 150 mL round bottomed flask was added
2-((4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-7-yl)oxy)acetaldehyde
(1.70 g, 8.29 mmol), potassium carbonate (4.58 g, 33.1 mmol) and
MeOH (80 mL). To this solution was added dimethyl
(1-diazo-2-oxopropyl)phosphonate (2.39 mL, 9.94 mmol, Astatech).
The reaction mixture was stirred at RT for 3 h. The solution was
poured into saturated NaHCO.sub.3 and then the pH was adjusted to 7
with 5 N HCl. The solution was extracted with 25% iPrOH/CHCl.sub.3.
There was an emulsion present that contained some solid. LC/MS
showed this solid to be product so it was filtered and dried under
vacuum to afford 0.28 g of product. The combined extracts were
dried (Na.sub.2SO.sub.4) and concentrated onto silica. Purification
by silica gel chromatography (0-10% MeOH/DCM) afforded 1.07 g (in
addition to the 0.28 g solid already isolated) of the title
compound as a white solid (1.35 g, 6.71 mmol, 81% yield). MS
m/z=201.9 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 3.71 (t, J=2.3 Hz, 1H), 5.06 (d, J=2.3 Hz, 2H), 7.58 (d, J=2.7
Hz, 1H), 8.13 (s, 1H), 8.50 (d, J=2.7 Hz, 1H), 12.43 (br s,
1H).
Preparation of
4-chloro-7-(prop-2-yn-1-yloxy)pyrido[3,2-d]pyrimidine (446)
[1645] To a solution of
7-(prop-2-yn-1-yloxy)pyrido[3,2-d]pyrimidin-4(3H)-one (0.86 g, 4.27
mmol) in toluene (20 mL) was added N,N-diisopropylethylamine (2.31
mL, 13.3 mmol) followed by phosphorus oxychloride (1.17 mL, 12.8
mmol, Sigma-Aldrich Chemical Company, Inc.). The reaction mixture
was heated at 65.degree. C. for 2.5 h. The solution was allowed to
cool to RT and then was slowly pipetted into sat NaHCO.sub.3 that
had been cooled to 10.degree. C. The solution was stirred
vigorously for 15 min and then was extracted with DCM (2.times.).
The combined extracts were dried (Na.sub.2SO.sub.4), filtered and
concentrated to afford the title compound as an off-white solid
(0.86 g, 3.9 mmol, 92% yield). MS m/z=219.9 (M+H).sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 2.66 (t, J=2.3 Hz, 1H), 4.94
(d, J=2.3 Hz, 2H), 7.74 (d, J=2.7 Hz, 1H), 8.88 (d, J=2.7 Hz, 1H),
9.05 (s, 1H).
2-(((8-Chloro-5-fluoro-1,7-naphthyridin-3-yl)oxy)methyl)oxazole
(447)
##STR00223##
[1647] Boron trichloride (4.99 mL of 1.0 M solution in DCM, 4.99
mmol) was added by syringe over 2 min to a stirring yellow solution
of 8-chloro-5-fluoro-3-methoxy-1,7-naphthyridine (212 mg, 0.99
mmol) and tetra-n-butylammonium iodide (479 mg, 1.29 mmol) in
anhydrous DCM (3.5 mL) under a nitrogen atmosphere at RT. The
mixture was stirred at RT for 4 h, then cooled with an ice bath
before the careful addition of water. After bubbling ceased with
addition of more water drops, the mixture was stirred for 30 min at
RT. The mixture was then diluted with DCM and water, then carefully
neutralized with portion wise addition of solid sodium bicarbonate.
The layers were separated and the aqueous layer was extracted with
DCM (3.times.150 mL). The combined extracts were washed with brine
(100 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to give a red oil. This oil was purified by ISCO (12 g Gold
silica gel column, 50-100% EtOAc in heptane) to give compound 447A
(123 mg, 62% yield) as a light yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 11.72 (br. s., 1H), 8.83 (d, J=2.7 Hz,
1H), 8.34 (d, J=1.2 Hz, 1H), 7.56 (d, J=2.7 Hz, 1H). MS m/z=199.0
(M+H).sup.+.
[1648] To a 15 mL round-bottomed flask was added
8-chloro-5-fluoro-1,7-naphthyridin-3-ol (Intermediate 447A) (0.58
g, 2.9 mmol), triphenylphosphine (0.996 g, 3.80 mmol), THF (15 mL),
and 2-oxazolemethanol (0.30 mL, 3.8 mmol, Combi-Blocks, Inc.). The
solution was cooled to 0.degree. C. and diisopropyl
azodicarboxylate (0.75 mL, 3.8 mmol, Sigma-Aldrich Chemical
Company, Inc.) was added slowly and then the solution was allowed
to warm to RT. After 1 h, the reaction mixture was poured into
water and extracted with EtOAc. The combined extracts were washed
with water and brine and then dried (Na.sub.2SO.sub.4) and
concentrated onto silica. Purification by silica gel chromatography
(0-80% EtOAc/heptane) afforded the title compound (0.68 g, 2.4
mmol, 83% yield). MS m/z=280.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 5.40 (s, 2H), 7.23 (s, 1H), 7.76 (s, 1H),
7.80 (d, J=2.9 Hz, 1H), 8.25 (s, 1H), 8.93 (d, J=2.9 Hz, 1H).
4-(((4-Chloropyrido[3,2-d]pyrimidin-7-yl)oxy)methyl)-2,5-dimethyloxazole
(448)
##STR00224##
[1650] Intermediate 448A (85 mg, 0.31 mmol, 35% yield) as a white
solid was prepared according to the procedures described for
intermediate 445A, starting from
7-bromopyrido[3,2-d]pyrimidin-4(3H)-one (0.20 g, 0.89 mmol) and
(2,5-dimethyloxazol-4-yl)methanol (0.450 g, 3.54 mmol, Frontier
Scientific, Inc.). MS m/z=273.2 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 2.35 (s, 3H) 2.35 (s, 3H) 5.12 (s, 2H)
7.66 (d, J=2.74 Hz, 1H) 8.12 (s, 1H) 8.48 (d, J=2.74 Hz, 1H) 12.40
(br s, 1H).
[1651] Intermediate 448 as a tan solid (0.057 g, 0.20 mmol, 86%
yield) was prepared according to the procedures described for
intermediate 445, starting from
7-((2,5-dimethyloxazol-4-yl)methoxy)pyrido[3,2-d]pyrimidin-4(3H)-one
(448A, 62 mg, 0.23 mmol). MS m/z=290.9 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 2.39 (s, 3H), 2.45 (s, 3H), 5.08
(s, 2H), 7.72 (d, J=2.7 Hz, 1H), 8.89 (d, J=2.7 Hz, 1H), 9.04 (s,
1H).
5-Methoxy-3-methylpyrazine-2-carboxylic acid (265)
##STR00225##
[1652] Preparation of Compound 265A
[1653] In a 2-L flask, 3-methylpyrazine-2-carboxylic acid (Matrix,
19.95 g, 144 mmol) was suspended in MeOH (500 mL). The suspension
was cooled in an ice-water bath, and concentrated sulfuric acid
(Fluka, 27.3 mL, 506 mmol) was added over a time period of 5 min.
The reaction mixture was heated to 80.degree. C. for 5 h. The
reaction mixture was concentrated under reduced pressure and the
residue was taken up in DCM (750 mL). The excess acid was
neutralized carefully with of aqueous NaOH (5 M, 200 mL). The
aqueous layer was separated and extracted with DCM (250 mL). The
combined organic layers were combined, dried over MgSO.sub.4 and
concentrated to afford 16.15 g of methyl
3-methylpyrazine-2-carboxylate (265A, 106 mmol, 73%). MS m/z=153
[M+H].sup.+.
Preparation of Compound 265B
[1654] In a 1-L flask, the methyl 3-methylpyrazine-2-carboxylate
(265A, 16.08 g, 106 mmol) was suspended in CHCl.sub.3 (300 mL).
3-Chlorobenzoperoxoic acid (Aldrich, 24.62 g, 143 mmol) was added.
The reaction mixture was heated to 70.degree. C. for 16 h. The
reaction mixture was quenched with saturated NaHCO.sub.3 (200 mL).
The layers were separated, and the aqueous layer was further
extracted with DCM (2.times.100 mL). The combined organic layers
were dried over MgSO.sub.4, and the filtrate was concentrated to
afford crude 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (17.77
g). MS m/z=169 [M+H].sup.+.
[1655] In a 1-L flask, the crude
3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (17.77 g, 106 mmol)
was dissolved in DMF (300 mL). Neat phosphoryl trichloride (29.6
mL, 317 mmol) was added. The reaction mixture was heated to
100.degree. C. After 1 h, the reaction mixture was concentrated to
remove most of the DMF. The flask was cooled in an ice water bath,
and 1 M aqueous Na.sub.2CO.sub.3 (300 mL) was added slowly,
followed by 80% EtOAc-hexane (400 mL). The mixture was filtered
through Celite.RTM. filter aid. The resulting filtrate was
partitioned and the aqueous phase was extracted further with 80%
EtOAc-hexane (2.times.250 mL). The combined organic layers were
dried over MgSO.sub.4 and concentrated. The material was purified
through silica gel using 11% EtOAc-hexane to afford methyl
5-chloro-3-methylpyrazine-2-carboxylate (265B, 4.29 g, 23 mmol,
22%). MS m/z=187 [M+H].sup.+.
Preparation of Compound 265
[1656] A flask was charged with sodium (0.813 g, 35.4 mmol), purged
with Argon, and placed in a room temperature water bath. MeOH (47.7
mL, 1179 mmol) was added slowly. After 40 min, methyl
5-chloro-3-methylpyrazine-2-carboxylate (265B, 2.2 g, 11.79 mmol)
was added. The vessel was sealed and heated to 45.degree. C. for
1.5 h. Sodium hydroxide (1 M, 12.97 mL, 12.97 mmol) was added and
heating was continued for 1.5 h. The reaction mixture was
concentrated under reduced pressure and the residue was dissolved
in a minimum amount of water (50 mL). The aqueous phase was
extracted with Et.sub.2O (15 mL), which was discarded. The aqueous
phase was acidified with HCl (5 M, 11 mL, 55 mmol). The mixture was
extracted with DCM (3.times.60 mL). The combined organic extracts
were dried over MgSO.sub.4 and the filtrate was concentrated to
afford 5-methoxy-3-methylpyrazine-2-carboxylic acid (265, 2.0 g,
100%). MS m/z=169 [M+H].sup.+. .sup.1H NMR in CDCl.sub.3 .delta.
10.70 (br, 1H), 7.98 (s, 1H), 4.00 (s, 3H), 2.91 (s, 3H).
3-Methyl-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid
(266)
##STR00226##
[1658] The title compound was synthesized according to Intermediate
265, using 2,2,2-trifluoroethanol (Aldrich) to react with Compound
265B. MS m/z=237 (M+H).sup.+.
5-Cyano-3-methylpicolinic acid (267)
##STR00227##
[1660] 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.+.
5-Chloro-3-methylpicolinic acid (268)
##STR00228##
[1662] 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 EtOAc. 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).
[1663] 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 vacuum 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).
5-(But-2-yn-1-yloxy)-3-methylpicolinic acid (269)
##STR00229## ##STR00230##
[1664] Preparation of Compound 269A
[1665] Iron powder (9.75 g, 0.17 mol) was added in portions over a
period of 2 h to a stirred solution of
2-chloro-3-methyl-5-nitropyridine (10 g, 58.00 mmol, Combi-blocks)
in HOAc/water (29 mL:88 mL). After 3 h, the reaction mixture was
filtered through Celite.RTM. filter aid and the filter cake was
washed with EtOAc. The organic layer was separated and the aqueous
layer was extracted with EtOAc. The combined organic layers were
washed with aqueous sodium bicarbonate, brine and dried over
Na2SO4. The solvent was removed under reduced pressure to yield
6-chloro-5-methylpyridine-3-amine as a brown solid (269A, 8.00 g;
97%). MS m/z=142.03 [M+H].sup.+. .sup.1H-NMR (300 MHz, DMSO-d6):
.delta.7.54 (d, J=30 Hz, 1H), 6.91-6.90 (dd, J=0.6 Hz & 2.7 Hz,
1H), 5.39 (s, 2H), 2.17 (s, 3H)
Preparation of Compound 269B
[1666] In a 100 mL RBF, boron trifluoride diethyl etherate (1.8 mL,
14.3 mmol, Sigma Aldrich) was added drop wise to a cooled mixture
(-15.degree. C.) of 6-chloro-5-methylpyridine-3-amine (269A, 1.0 g,
7.0 mmol) in DME (7.5 mL) and DCM (2.5 mL). Then tert-butyl nitrite
(850 mg, 8.2 mmol, Sigma-Aldrich) was added drop wise and the
reaction mixture was stirred at -10.degree. C. for 25 min. The
reaction mixture was allowed to warm to 0.degree. C. and stirred
for additional 20 min. The reaction mixture was diluted with
pentane (50 mL) and the tetrafluoroborate diazonium salt was
collected by filtration. The salt was dissolved in acetic anhydride
(10 mL) and heated at 95.degree. C. for 2 h. The reaction mixture
was cooled to ambient temperature and then partitioned between
EtOAc (50 mL) and sat. sodium bicarbonate solution (100 mL). The
aqueous solution was separated and extracted with EtOAc
(2.times.100 mL). The combined organic extracts were washed with
brine, dried over anhydrous sodium sulfate, filtered and
concentrated to afford a brown oil. This oil was purified by column
chromatography on silica gel, eluting with 5% EtOAc in petroleum
ether to give 6-chloro-5-methylpyridine-3-yl acetate as pale yellow
oil (269B, 780 mg, 62%). MS m/z=185.02 [M+H].sup.+. .sup.1H-NMR
(300 Mhz, DMSO-d.sub.6): .delta. 8.13 (d, J=2.4 Hz, 1H), 7.72 (d,
J=2.7 Hz 1H), 2.34 (s, 3H), 2.30 (s, 3H).
Preparation of Compound 269C
[1667] Potassium carbonate (1.1 g, 8.1 mmol) was added to a stirred
solution of 6-chloro-5-methylpyridine-3-yl acetate (269B, 750 mg,
4.0 mmol) in MeOH (15 mL) at RT. The reaction mixture was stirred
for 1 h at ambient temperature. The reaction mixture was
concentrated under reduced pressure and the residue was diluted
with minimum amounts of water and neutralized with 1 N HCl (15 mL).
After neutralization, the solution was extracted with EtOAc
(2.times.100 mL). The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate and concentrated to give
6-chloro-5-methylpyridine-3-ol (269C) as an off white solid (500
mg, 89%). MS m/z=143.01 [M+H].sup.+. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. 10.09 (s, 1H), 7.76 (d, J=3 Hz, 1H), 7.18
(d, J=3.6 Hz, 1H), 2.24 (s, 3H).
Preparation of Compound 269D
[1668] A mixture of 6-chloro-5-methylpyridin-3-ol (269C, 250 mg,
1.7 mmol), 1-(chloromethyl)-4-methoxybenzene (328 mg, 2.0 mmol,
Sigma Aldrich), and potassium carbonate (482 mg, 3.4 mol) in DMF (5
mL) was allowed to stir for 3 h at 60.degree. C. After completion
of the reaction, reaction mixture was cooled to RT and poured into
ice cold water (25 mL). The obtained solid was filtered, washed
with water (2.times.10 mL) and dried to obtain
2-chloro-5-((4-methoxybenzyl)oxy)-3-methylpyridine as an off white
solid (269D, 400 mg, 87%). MS m/z=263.9 [M+H].sup.+. .sup.1H-NMR
(300 MHz, CDCl.sub.3): .delta. 7.96 (d, J=2.7 Hz, 1H), 7.34 (d,
J=8.7 Hz, 2H), 7.15 (d, J=3 Hz, 1H), 6.94-6.89 (m, 2H), 4.99 (s,
2H), 3.81 (s, 3H), 2.33 (s, 3H).
Preparation of Compound 269E
[1669] A 25 mL sealable tube was charged with a mixture of
2-chloro-5-(difluoromethoxy)-3-methylpyridine (269D, 330 mg, 1.2
mmol), toluene (10 mL), and tributyl(vinyl)stannane (447 mg, 1.5
mmol). The reaction mixture was purged with Argon gas for 10 min.
Then Pd(PPh.sub.3).sub.4(144 mg, 0.2 mmol, Alfa-Aesar) was added
and the reaction mixture was allowed to stir for 16 h at
100.degree. C. The reaction mixture was cooled to RT and filtered
through Celite.RTM. filter aid. The filter cake was washed with
EtOAc and concentrated to get a crude residue. The residue was
purified by column chromatography using silica and eluting with
5-10% EtOAc in petroleum ether to give
5-((4-methoxybenzyl)oxy)-3-methyl-2-vinylpyridine as an off white
solid (269E, 250 mg, 65%). MS m/z=256.1 [M+H].sup.+. .sup.1H-NMR
(300 MHz, CDCl.sub.3): .delta. 8.20 (d, J=2.7 Hz, 1H), 7.37-7.33
(m, 2H), 7.02 (d, J=2.7 Hz, 1H), 6.94-6.87 (m, 3H), 6.21 (dd, J=1.8
Hz & 16.8 Hz, 1H), 5.39 (dd, J=2.1 Hz & 10.5 Hz, 1H), 5.01
(s, 2H), 3.81 (s, 3H), 2.33 (s, 3H).
Preparation of 5-methyl-6-vinylpyridin-3-ol (269F)
[1670] TFA (1.25 mL, 5 times) was added to a stirred solution of
5-((4-methoxybenzyl)oxy)-3-methyl-2-vinylpyridine (269E, 250 mg,
9.8 mmol) in anisole (0.5 mL). The reaction mixture was stirred for
2 h at ambient temperature. After completion of the reaction, the
mixture was concentrated and quenched with saturated NaHCO.sub.3
solution (2 mL). The reaction mixture was extracted with EtOAc
(2.times.10 mL) and the combined organic layers were washed with
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure. The crude residue was triturated with pentane to
afford 5-methyl-6-vinylpyridin-3-ol (269F) as an off white solid
(100 mg, 76%). MS m/z=136.15 [M+H].sup.+. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. 9.86 (s, 1H), 7.96 (d, J=2.8 Hz, 1H),
6.94-6.86 (m, 2H), 6.07 (dd, J=2.4 Hz, 16.8 Hz, 1H), 5.26 (dd,
J=2.8 Hz, 10.4 Hz, 1H), 2.25 (s, 3H).
Preparation of 5-(but-2-yn-1-yloxy)-3-methyl-2-vinylpyridine
(269G)
[1671] A mixture of 5-methyl-6-vinylpyridin-3-ol (269F, 100 mg, 7.4
mmol), sodium 1-bromobut-2-yne (118 mg, 0.9 mmol, Alfa-Aesar) and
cesium carbonate (361 mg, 1.1 mmol) in DMF (2 mL) was stirred for 2
h at 80.degree. C. After completion of the reaction, reaction
mixture was cooled to ambient temperature, poured into ice-cold
water (10 mL) and extracted with EtOAc (3.times.10 mL). The
combined organic layers were washed with brine, dried over sodium
sulfate and concentrated under reduced pressure. The crude residue
was purified by column chromatography using silica gel and eluting
with 0-10% EtOAc in petroleum ether to give
5-(but-2-yn-1-yloxy)-3-methyl-2-vinylpyridine (269G) as an off
white solid (85 mg, 61%). MS m/z=188.3 [M+H].sup.+. .sup.1H-NMR
(400 MHz, CDCl.sub.3): .delta. 8.21 (d, J=2.8 Hz, 1H), 7.03 (d,
J=2.4 Hz, 1H), 6.96-6.89 (m, 1H), 6.22 (dd, J=2.4 Hz & 17.2 Hz,
1H), 5.40 (dd, J=2 Hz & 10.8 Hz, 1H), 4.68-4.67 (m, 2H), 2.35
(s, 3H), 1.85 (t, J=2.4 Hz, 3H).
Preparation of 5-(but-2-yn-1-yloxy)-3-methylpicolinaldehyde
(269H)
[1672] OsO.sub.4 (2.5 wt. % sol. in tert-butanol) (0.86 mL, 2.7
mmol) was added to a stirred solution of
5-(but-2-yn-1-yloxy)-3-methyl-2-vinylpyridine (5.1 g, 27 mmol) in
acetone/water (100/100 mL) at 0.degree. C. The reaction mixture was
allowed to stir for 30 min at ambient temperature. Then NaIO.sub.4
(23.2 g, 108.0 mmol) was added and the reaction mixture was allowed
to stir for additional 4 h at ambient temperature. The reaction
mixture was diluted with ice cold water (200 mL) and extracted with
EtOAc (3.times.200 mL). The combined organic layers were washed
with brine, dried over Na.sub.2SO.sub.4 and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography on silica gel, eluting with 5-10% EtOAc in petroleum
ether to give 5-(but-2-yn-1-yloxy)-3-methylpicolinaldehyde (269H,
3.6 g, 70%) as an off white solid. MS m/z=189.9 [M+H].sup.+.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. 10.10 (s, 1H), 8.37 (d,
J=2.8 Hz, 1H), 7.13 (d, J=2.8 Hz, 1H), 4.77 (d, J=2.4 Hz, 2H), 2.67
(s, 3H), 1.86 (t, J=2 Hz, 3H).
Preparation of Compound 269
[1673] A stirred solution of
5-(but-2-yn-1-yloxy)-3-methylpicolinaldehyde (269H, 3.6 g, 19.0
mmol) in water (216 mL)/acetone (36 mL) was treated with sulphamic
acid (2.5 g, 25.0 mmol) and 85% sodium chlorite (2.7 g, 29.0 mmol).
The reaction mixture was allowed to stir for 2 h at ambient
temperature. The reaction mixture was extracted with EtOAc
(2.times.100 mL). The combined organic layer were washed with
brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced
pressure. The crude residue was triturated with n-pentane to
provide 5-(but-2-yn-1-yloxy)-3-methylpicolinaldehyde (269) as an
off white solid (3.2 g, 82%). MS m/z=206.3 [M+H].sup.+. .sup.1H-NMR
(400 MHz, CD3OD): .delta. 8.16 (d, J=2.8 Hz, 1H), 7.38 (d, J=2.4
Hz, 1H), 4.84-4.82 (m, 2H), 2.63 (s, 3H), 1.83 (t, J=2 Hz, 3H).
3-Methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid
##STR00231##
[1674] Preparation of Compound 265B
[1675] A solution of methyl 3-methylpyrazine-2-carboxylate (265A,
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 (265B, 0.68 g) (minor
product) denoted by peak 1 and methyl
6-chloro-3-methylpyrazine-2-carboxylate (265B1, 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).
Preparation of Compound 270A
[1676] To a solution of methyl
5-chloro-3-methylpyrazine-2-carboxylate (265B, 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 (270A, 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).
Preparation of Compound 270
[1677] A solution of methyl
3-methyl-5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate (270A, 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 ambient temperature 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 (270) (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).
5-(2,2,2-Trifluoroethoxy)pyrazine-2-carboxylic acid (272)
##STR00232##
[1678] Preparation of tert-butyl 5-chloropyrazine-2-carboxylate
(272A)
[1679] A solution of 5-chloropyrazine-2-carboxylic acid (200.0 g,
1.26 mol) in THF (2.5 L) was treated with a solution of tert-butyl
2,2,2-trichloroacetimidate (460 mL, 2.57 mol) in cyclohexane (2.5
L). The reaction was stirred at 25.degree. C. for 5 min and then
treated with boron trifluoride dimethyl etherate (144.0 mL, 126
mmol). The resulting reaction mixture was stirred at 25.degree. C.
for 16 h and then diluted with EtOAc (5.0 L), washed with a
saturated aqueous sodium bicarbonate solution (4.0 L) followed by
water (5.0 L). The organic layer was dried over sodium sulfate,
filtered, and concentrated under reduced pressure. The crude
material was purified by column chromatography (Silica 60-120 mesh,
10% EtOAc in hexanes) to give tert-butyl
5-chloropyrazine-2-carboxylate (250 g, 92%) as a colorless oil. MS
(ESI, positive ion) m/z: 215.2 (M+1).sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.01 (d, J=1.3 Hz, 1H), 8.70 (d, J=1.3 Hz, 1H),
1.66 (s, 9H).
Preparation of tert-butyl
5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate (272B)
[1680] To a solution of 2,2,2-trifluoroethanol (2.70 mL, 37.00
mmol) in 30 mL of THF at 0.degree. C. was added potassium
tert-butoxide (4.47 g, 39.90 mmol) in small portions. The cloudy
mixture was stirred at RT for 15 min then cannulated to a solution
of tert-butyl 5-chloropyrazine-2-carboxylate (6.11 g, 28.50 mmol)
in 50 mL of THF at 0.degree. C. The mixture was stirred at
0.degree. C. for 30 min then quenched with 50 mL of saturated
NH.sub.4Cl. It was extracted with 200 mL of EtOAc. The organic
layer was washed with 25 mL of brine, dried (MgSO.sub.4), filtered,
and concentrated. The residue was purified on a silica gel column
(5-25% EtOAc in heptane) to afford tert-butyl
5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate (5.87 g, 21.10
mmol, 74% yield) as an off-white crystalline solid. .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. -72.16 (s, 1 F). .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.81 (d, J=1.37 Hz, 1H), 8.58 (d, J=1.17
Hz, 1H), 5.13 (q, J=8.80 Hz, 2H), 1.57 (s, 9H). m/z (ESI, +ve ion)
279.1
Preparation of 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid
(272)
[1681] At RT, a solution of tert-butyl
5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylate (5.85 g, 21.03
mmol) in 50 mL of DCM was treated with 2,2,2-trifluoroacetic acid
(24.14 mL) drop wise. The resulting mixture was stirred at RT for 3
h. The reaction mixture was concentrated under reduced pressure and
the crude product was azeotroped with toluene (3.times.5 mL). The
crude product was stirred with 5% EtOAc in hexanes (20 mL) for 1 h
and filtered. The filtrate was discarded. The white solid thus
obtained was washed with hexanes (2.times.10 mL) and collected to
afford 5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylic acid as a white
crystalline solid which was suspended in 10 mL of dioxane and
treated with 4 N HCl in dioxane (40 mmol, 10 mL) followed by 5 mL
of water. The mixture was stirred for 5 min at RT. It was
concentrated to dryness, then azeotroped with toluene (3.times.5
mL) to provide 5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid
(4.41 g, 19.85 mmol, 94% yield) as a white crystalline solid.
.sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -72.16. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 13.48 (br., 1H), 8.86 (d, J=1.17
Hz, 1H), 8.60 (d, J=1.17 Hz, 1H), 5.15 (q, J=9.00 Hz, 2H). m/z
(ESI, +ve ion) 223.1
5-(Prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid (273)
##STR00233##
[1682] Preparation of tert-butyl
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate
[1683] A solution of potassium tert-butoxide (272A, 78.0 g, 699
mmol) in 1,4-dioxane (2.5 L) was cooled to 0.degree. C. and
propargyl alcohol (39.2 g, 699 mmol) was added dropwise. The
resulting mixture was allowed to stir for 10 min. A solution of
tert-butyl 5-chloropyrazine-2-carboxylate (125 g, 582 mmol) in
1,4-dioxane (1.3 L) was added dropwise to the reaction mixture. The
mixture was allowed to slowly warm to ambient temperature and stir
for 4 h. The reaction mixture was quenched with sat. aq. NH.sub.4Cl
(2.0 L) and stirred for 10 min. The reaction mixture was diluted
with EtOAc (3.0 L) and water (2.5 L). The layers were separated and
the aqueous layer was extracted with EtOAc (3.times.2 L). The
combined organic extract was dried over sodium sulfate, filtered
and concentrated under reduced pressure to get the crude product
which was purified by column chromatography (silica gel 60-120
mesh, 10% EtOAc in hexanes) to afford tert-butyl
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate (70 g, 51%) as tan
solid. MS (ESI, positive ion) m/z: 235.2 (M+H).sup.+. .sup.1H NMR
(400 MHz, CDCl.sub.3) 8.83 (d, J=1.3 Hz, 1H), 8.35 (d, J=1.3 Hz,
1H), 5.06 (s, 2H), 2.54 (s, 1H), 1.64 (s, 9H).
Preparation of 5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid
(273)
[1684] A solution of tert-butyl
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate (140 g, 598 mol) in DCM
(480 mL) was cool to 0.degree. C. and TFA (1.4 L) was added
dropwise. The reaction mixture was stirred at ambient temperature
for 4 h. The reaction mixture was concentrated under reduced
pressure to obtain the crude material which was azeotroped with
toluene (3.times.1.0 L). The crude material was stirred with 10%
EtOAc in hexanes (2.0 L) for 1 h and filtered. The solid was washed
with hexane (3.0 L) to provide tert-butyl
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylate (103 g, 97%) as white
solid. MS (ESI, positive ion) m/z: 179.1 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-D.sub.6) .delta. 13.41 (s, 1H), 8.83 (d, J=1.3 Hz,
1H), 8.46 (d, J=1.3 Hz, 1H), 5.11 (d, J=2.4 Hz, 2H), 3.64 (s,
1H).
5-((1,1-dideuteriumprop-2-yn-1-yl)oxy)pyrazine-2-carboxylic acid
(274)
##STR00234##
[1685] Preparation of tert-butyl
5-((1,1-dideuterium-prop-2-yn-1-yl)oxy)pyrazine-2-carboxylate
(274A)
[1686] To a solution of 1,1-dideuterium-prop-2-yn-1-ol (1.81 g,
31.1 mmol) [cat # AM1043, Adesis Inc.] in 30 mL of THF at 0.degree.
C. was added potassium tert-butoxide (3.77 g, 33.60 mmol) in small
portions. The cloudy mixture was stirred at RT for 15 min then
cannulated to a solution of tert-butyl
5-chloropyrazine-2-carboxylate (5.34 g, 24.88 mmol) in 50 mL of THF
at 0.degree. C. The mixture was stirred at 0.degree. C. for 30 min
then treated with 50 mL of saturated NH.sub.4Cl followed by 200 mL
of EtOAc. The mixture was transferred to a separatory funnel and
the layers were separated. The organic layer was washed with 25 mL
of brine, dried (MgSO.sub.4), filtered, and concentrated. The
residue was purified on a silica gel column (5-25% EtOAc in
heptanes) to afford tert-butyl
5-((1,1-dideuterium-prop-2-yn-1-yl)oxy)pyrazine-2-carboxylate (1.40
g, 5.93 mmol, 24% yield) as a colorless viscous oil. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.81 (d, J=1.37 Hz, 1H), 8.46 (d,
J=1.37 Hz, 1H), 3.63 (s, 1H), 1.57 (s, 9H). m/z (ESI, +ve ion)
259.1 (M+23).sup.+.
Preparation of
5-((1,1-dideuteriumprop-2-yn-1-yl)oxy)pyrazine-2-carboxylic acid
(274)
[1687] At RT, a solution of tert-butyl
5-((1,1-dideuterium-prop-2-yn-1-yl)oxy)pyrazine-2-carboxylate (1.40
g, 5.93 mmol) in 10 mL of DCM was treated with
2,2,2-trifluoroacetic acid (5.44 mL, 71.1 mmol) drop wise. The
resulting mixture was stirred at RT for 4 h. The reaction mixture
was concentrated under reduced pressure and the crude product was
azeotroped with toluene (2.times.5 mL). The crude product was
stirred with 5% EtOAc in hexanes (20 mL) for 1 h and filtered. The
filtrate was discarded. The white solid thus obtained was washed
with hexanes (2.times.10 mL) and collected. .sup.19F-NMR of the
white solid indicated the presence of trace amount of
2,2,2-trifluoroacetic acid. The off white solid was suspended in 3
mL of dioxane and treated with 4 N HCl in dioxane (6 mmol, 1.5 mL)
followed by 1 mL of water. The mixture was stirred for 5 min at RT.
It was concentrated to dryness, then azeotroped with toluene (5 mL)
to provide
5-((1,1-dideuteriumprop-2-yn-1-yl)oxy)pyrazine-2-carboxylic acid
(1.0 g, 5.55 mmol, 94% yield) as a white crystalline solid.
.sup.19F-NMR of the white solid indicated the absence of
2,2,2-trifluoroacetic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 13.36 (br., 1H), 8.84 (d, J=1.17 Hz, 1H), 8.47 (d, J=1.17
Hz, 1H), 3.63 (s, 1H). m/z (ESI, +ve ion) 181.2 (M+H).sup.+.
5-(2,2,3,3-Tetrafluoropropoxy)pyrazine-2-carboxylic acid (275)
##STR00235##
[1689] To a solution of 2,2,3,3-tetrafluoro-1-propanol (1.1 mL, 8.4
mmol) in 5 mL of THF at 0.degree. C. was added a solution of
potassium tert-butoxide (1.0 M solution in THF (9.08 mL, 9.08
mmol)) by syringe over 2 min. The orange mixture was stirred at RT
for 15 min then cannulated to a solution of tert-butyl
5-chloropyrazine-2-carboxylate (272A, 1.5 g, 6.99 mmol) in 15 mL of
THF at 0.degree. C. The mixture was stirred at 0.degree. C. for 30
min. The reaction was quenched with saturated aqueous NH.sub.4Cl
(30 mL) and diluted with EtOAc (100 mL) and water (30 mL). The
layers were separated and the organic layer was washed with brine
(25 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The residue was purified by silica gel chromatography
eluting with a gradient of 0-30% EtOAc/heptane to give tert-butyl
5-(2,2,3,3-tetrafluoropropoxy)pyrazine-2-carboxylate as a yellow
solid (275A, 1.88 g, 87%). LC/MS (ESI.sup.+) m/z=333.1
(M+Na).sup.+. .sup.1H NMR (400 MHz, chloroform-d) .delta. 8.81 (d,
J=1.17 Hz, 1H), 8.41 (d, J=1.17 Hz, 1H), 5.83-6.17 (m, 1H), 4.84
(t, J=12.72 Hz, 2H), 1.65 (s, 9H).
[1690] 2,2,2-Trifluoroacetic acid (6.66 mL, 87 mmol) was added at
RT to a stirring solution of tert-butyl
5-(2,2,3,3-tetrafluoropropoxy)pyrazine-2-carboxylate (275A, 1.8 g,
5.8 mmol) in DCM (11.6 mL). The pink solution was stirred at RT for
3 h and then concentrated in vacuo. The residue was azeotroped with
toluene (2.times.25 mL) to give
5-(2,2,3,3-tetrafluoropropoxy)pyrazine-2-carboxylic acid (275) as a
white solid (1.38 g, 94%). LC/MS (ESI.sup.+) m/z=255.1 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.44 (br. s., 1H),
8.83 (d, J=1.37 Hz, 1H), 8.53 (d, J=1.17 Hz, 1H), 6.54-6.87 (m,
1H), 5.00 (t, J=14.08 Hz, 2H).
5-(3,3,3-Trifluoropropoxy)pyrazine-2-carboxylic acid (276)
##STR00236##
[1692] The title compound was synthesized according to intermediate
275, using 3,3,3-trifluoropropan-1-ol to react with tert-butyl
5-chloropyrazine-2-carboxylate 272A. LC/MS (ESI.sup.+) m/z=237.1
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.32 (br.
s., 1H), 8.83 (d, J=1.17 Hz, 1H), 8.41 (d, J=1.17 Hz, 1H), 4.63 (t,
J=5.97 Hz, 2H), 2.88 (m, 2H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -63.2.
5-(2,2-Difluoropropoxy)pyrazine-2-carboxylic acid (277)
##STR00237##
[1694] The title compound was synthesized according to intermediate
275, using 3,3,3-trifluoropropan-1-ol to react with tert-butyl
5-chloropyrazine-2-carboxylate 272A. LC/MS (ESI.sup.+) m/z=219.2
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.38 (br.
s., 1H), 8.82 (d, J=1.17 Hz, 1H), 8.51 (d, J=0.98 Hz, 1H), 4.70 (t,
J=13.20 Hz, 2H), 1.76 (t, J=19.27 Hz, 3H); .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -97.3.
5-(3-Fluoropropoxy)pyrazine-2-carboxylic acid (278)
##STR00238##
[1696] The title compound was synthesized according to intermediate
275, using 3,3,3-trifluoropropan-1-ol to react with tert-butyl
5-chloropyrazine-2-carboxylate 272A. LC/MS (ESI.sup.+) m/z=201.2
(M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.80 (d,
J=1.17 Hz, 1H), 8.38 (d, J=1.37 Hz, 1H), 4.67 (t, J=5.87 Hz, 1H),
4.55 (t, J=5.87 Hz, 1H), 4.49 (t, J=6.36 Hz, 2H), 2.08-2.23 (m,
2H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -74.5.
3-Methyl-5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylic acid (279)
##STR00239##
[1698] To a solution of tert-butyl
5-chloro-3-methylpyrazine-2-carboxylate (3.8 g, 16.62 mmol) and
oxazol-2-ylmethanol ((Combi-Blocks Inc., 3.29 g, 33.2 mmol) in 3 mL
of DMF was added potassium carbonate (4.59 g, 33.2 mmol). The
reaction mixture was stirred overnight. The contents were loaded
onto a flash column and eluted with a gradient of
(hexanes:EtOAc=5:1 to 2:1) to give tert-butyl
3-methyl-5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylate (279A, 4.16
g, 14.28 mmol, 86% yield) as a colorless oil. .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 8.20 (s, 1H), 7.69 (d, J=0.88 Hz, 1H), 7.16
(s, 1H), 5.53 (s, 2H), 2.71 (s, 3H), 1.63 (s, 9H). To the ester was
added TFA (18.52 mL, 249 mmol) dropwise and the mixture was stirred
at RT overnight. The TFA was removed in vacuo. The residue was
treated with 15 mL of 1 N aqueous HCl and azeotroped in vacuo to
remove the residual TFA (repeated twice). The residue was dried
under house vacuum overnight to give
3-methyl-5-(oxazol-2-ylmethoxy)pyrazine-2-carboxylic acid (3.6 g,
15.31 mmol, 92% yield) as a white solid. .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 8.10 (s, 1H), 7.71 (d, J=0.88 Hz, 1H), 7.18
(s, 1H), 5.59 (s, 2H), 2.91 (s, 3H). LC/MS (ESI.sup.+) m/z=236.0
(M+H).sup.+.
5-(Oxazol-2-ylmethoxy)pyrazine-2-carboxylic acid (280)
##STR00240##
[1700] Compound 280A (3.07 g, 11.07 mmol, 66% yield) as an off
white crystalline solid was prepared according to intermediate 272B
starting from 272A (3.59 g, 16.72 mmol) and oxazol-2-ylmethanol
(Combi-Blocks Inc., 1.99 g, 20.07 mmol). LC/MS (ESI.sup.+)
m/z=278.1 (M+H).sup.+.
[1701] Compound 280 (4.15 g, 18.76 mmol, 99% yield) as an off white
crystalline solid was prepared according to intermediate 272
starting from 280A (5.26 g, 18.97 mmol). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.81 (m, 1H), 8.50 (d, J=1.37 Hz, 1H), 8.18
(d, J=0.78 Hz, 1H), 7.28 (s, 1H), 5.58 (s, 2H), 4.55-5.55 (br.,
1H). LC/MS (ESI.sup.+) m/z=222.0 (M+H).sup.+.
3-Methyl-5-(oxazol-2-ylmethoxy)picolinic acid (281)
##STR00241##
[1702] Preparation of
2-(((6-bromo-5-methylpyridin-3-yl)oxy)methyl)oxazole (281A)
[1703] To a solution of 2-oxazolemethanol (1.12 g, 11.30 mmol,
Combi-Blocks Inc.) and triphenylphosphine (3.72 g, 14.18 mmol) in
THF (20 mL) was added 2-bromo-5-hydroxy-3-picoline (2.27 g, 12.07
mmol, AOB Chem USA). The mixture was cooled to 0.degree. C. and
1,2-ethoxycarbonyl diazene (2.5 mL, 13.72 mmol) was added slowly.
The solution was slowly allowed to warm to RT. After 21 h,
diisopropyl azodicarboxylate (1.5 mL, 7.63 mmol) was added to the
mixture. About 1.5 h later, a second batch of diisopropyl
azodicarboxylate (1.5 mL, 7.63 mmol) was added. The mixture was
stirred at RT for an additional 4 h and was diluted with EtOAc (50
mL). The solution was washed with NaOH (0.5 N, 10 mL), water,
brine, and then dried over Na.sub.2SO.sub.4 and concentrated. The
residue was purified by silica gel chromatography (10-50% EtOAc in
DCM) to afford 2-(((6-bromo-5-methylpyrid
in-3-yl)oxy)methyl)oxazole (3.8 g, .about.80% pure) as a white
solid that contained the hydrazine by-product as impurities (based
on .sup.1H-NMR). LCMS (ESI, pos.) 269.0 (M+1).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 8.02 (d, J=2.93 Hz, 1H), 7.70 (d,
J=0.78 Hz, 1H), 7.23 (d, J=2.74 Hz, 1H), 7.17 (s, 1H), 5.18 (s,
2H), 2.37 (s, 3H).
Preparation of methyl 3-methyl-5-(oxazol-2-ylmethoxy)picolinate
(281B)
[1704] To a mixture of palladium (II) acetate (63 mg, 0.28 mmol)
and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (327 mg, 0.56
mmol) under N.sub.2 was added
2-(((6-bromo-5-methylpyridin-3-yl)oxy)methyl)oxazole (281A, 3.8 g,
11.30 mmol, .about.80% pure) in MeOH (50 mL, 1233 mmol) and TEA
(18.90 mL, 136 mmol) in a 250 mL pressure tube. The mixture was
evacuated-purged with CO gas (balloon) 3-times. The valves were
closed and the mixture was heated at 70.degree. C. for 24 h. The
mixture was removed from the heater and was filtered through a pad
of Celite.RTM. filter aid. The Celite.RTM. filter aid was washed
with EtOAc (3.times.20 mL). The filtrate was concentrated in vacuo
and partitioned between EtOAc (60 mL) and saturated NaHCO.sub.3 (40
mL). The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. The crude material was purified by silica
gel chromatography using a gradient of 0-5% MeOH in EtOAc. The
product was obtained as a white solid (1.9 g, 68% over two steps).
LCMS (ESI, pos.) 249.1 (M+1).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.33 (d, J=2.74 Hz, 1H), 7.71 (s, 1H), 7.23
(d, J=2.54 Hz, 1H), 7.18 (s, 1H), 5.25 (s, 2H), 3.95 (s, 3H), 2.63
(s, 3H).
Preparation of 3-methyl-5-(oxazol-2-ylmethoxy)picolinic acid
(281)
[1705] To a solution of methyl
3-methyl-5-(oxazol-2-ylmethoxy)picolinate (281B, 1.9 g, 7.65 mmol)
in THF (20 mL) was added water (6 mL) followed by lithium hydroxide
monohydrate (350 mg, 8.34 mmol). After 3 h, the mixture was
concentrated to remove most of the THF. The pH of the aqueous layer
was adjusted to 3-4 by HCl (5 N). Solid NaCl was added to saturate
the solution. The mixture was extracted with 2% IPA in CHCl.sub.3
(5.times.30 mL). The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give a white solid
(1.74 g, 95%). LCMS (ESI, pos.) 235.1 (M+1).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.21 (d, J=2.35 Hz, 1H), 7.73 (s, 1H),
7.31 (d, J=2.15 Hz, 1H), 7.19 (s, 1H), 5.28 (s, 2H), 2.76 (s,
3H).
3-Methyl-5-(2,2,2-trifluoroethoxy)picolinic acid (282)
##STR00242##
[1707] To a solution of 5-hydroxy-3-methylpicolinonitrile (0.49 g,
3.63 mmol) in DMF (5 mL) were added cesium carbonate (1.54 g, 4.72
mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.01 mL,
4.36 mmol). The resulting suspension was stirred at RT overnight.
The reaction mixture was diluted with water and EtOAc. The organic
layer was washed with 1 M LiCl solution and brine, dried over MgSO4
and concentrating in vacuo. The crude
3-methyl-5-(2,2,2-trifluoroethoxy)picolinonitrile was taken up in
EtOH (20 mL) and 1 M NaOH (10.89 mL, 10.89 mmol) was added. The
reaction was heated at reflux until the conversion was complete.
The mixture was cooled to RT and diluted with ether and water. The
organic layer was washed with additional water and the combined
aqueous layers were acidified to pH=1 by the addition of 1 M HCl.
The aqueous layer was extracted with DCM twice and the combined
organics were washed with brine, dried over MgSO.sub.4 and
concentrated in vacuo to afford
3-methyl-5-(2,2,2-trifluoroethoxy)picolinic acid (0.75 g, 88%
yield). LC/MS (ESI.sup.-) m/z=236 (M+H).sup.+. .sup.1H NMR (300
MHz, DMSO-d6) .delta. ppm 2.50 (s, 3H) 4.94 (q, J=8.77 Hz, 2H) 7.53
(d, J=2.63 Hz, 1H) 8.28 (d, J=2.78 Hz, 1H).
3-Methyl-5-(prop-2-yn-1-yloxy)picolinic acid (283)
##STR00243##
[1709] To a suspension of methyl 5-hydroxy-3-methylpicolinate (1.00
g, 5.98 mmol) and potassium carbonate (1.24 g, 8.97 mmol) in DMF
(25 mL) was added propargyl bromide (80% solution in toluene, 0.80
mL, 7.18 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. Purification by silica gel chromatography
(40 g, 0-70% EtOAc in hexanes) afforded methyl
3-methyl-5-(prop-2-yn-1-yloxy)picolinate as yellow solid (1.21 g,
99% yield). LC/MS (ESI.sup.-) m/z=206 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 2.58 (t, J=2.45 Hz, 1H) 2.64 (s, 3H)
3.96 (s, 3H) 4.79 (d, J=2.54 Hz, 2H) 7.16 (d, J=2.54 Hz, 1H) 8.31
(d, J=2.74 Hz, 1H).
[1710] To a suspension of methyl
3-methyl-5-(prop-2-yn-1-yloxy)picolinate (1.21 g, 5.90 mmol) and
lithium hydroxide hydrate (0.26 g, 6.19 mmol) was added THF (16 mL)
and water (4 mL). The mixture was stirred at RT for 1.5 h, then
neutralized with 8.5 mL of 1 N HCl, and diluted with brine and a
mixed solvent of i-PrOH:CHCl.sub.3 (v/v 1:3). The aqueous layer was
further extracted with the mixed solvent. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated in vacuo to give
3-methyl-5-(prop-2-yn-1-yloxy)picolinic acid (1.10 g, 98% yield) as
off-white solid. LC/MS (ESI.sup.-) m/z=192 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 2.62 (br. s., 1H) 2.77 (s, 3H)
4.82 (br. s., 2H) 7.26 (br. s., 1H) 8.18 (br. s., 1H).
(S)-5-(But-3-yn-2-yloxy)-3-methylpyrazine-2-carboxylic acid
(284)
##STR00244##
[1711] Preparation of (S)-tert-butyl
5-(but-3-yn-2-yloxy)-3-methylpyrazine-2-carboxylate (284A)
[1712] To a solution of tert-butyl
5-chloro-3-methylpyrazine-2-carboxylate (2.50 g, 10.93 mmol) and
(S)-3-butyn-2-ol (0.95 mL, 12.03 mmol) in THF (10 mL) at 0.degree.
C. was added in portion wise sodium hydride (60% wt. in oil, 0.48
g, 12.03 mmol). The reaction was stirred at 0.degree. C. for 2 h,
treated with saturated NH.sub.4Cl solution (100 mL) and extracted
with EtOAc (200 mL). The organic solution was concentrated under
reduced pressure and the residue was purified via silica gel
chromatography (0-10% EtOAc in heptane) to afford (S)-tert-butyl
5-(but-3-yn-2-yloxy)-3-methylpyrazine-2-carboxylate (1.25 g, 4.77
mmol, 43% yield) as a colorless oil. LC/MS (ESI.sup.+) m/z=285.0
(M+23).sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.13 (s,
1H), 5.85 (dq, J=2.05, 6.67 Hz, 1H), 2.73 (s, 3H), 2.46 (d, J=2.05
Hz, 1H), 1.67 (d, J=6.72 Hz, 3H), 1.65 (s, 9H).
Preparation of Compound 284
[1713] TFA (20 mL, 269 mmol) was added at RT to a stirring solution
of (S)-tert-butyl
5-(but-3-yn-2-yloxy)-3-methylpyrazine-2-carboxylate (1.85 g, 7.05
mmol) in DCM (20 mL). The reaction mixture was stirred at RT for 4
h and then concentrated in vacuo. The residue was dissolved in 4 N
HCl in dioxane (5 mL) and 1 N HCl (10 mL), stirred at RT for 30 min
and concentrated in vacuo to give
(S)-5-(but-3-yn-2-yloxy)-3-methylpyrazine-2-carboxylic acid (1.3 g,
6.30 mmol, 89% yield). LC/MS (ESI.sup.+) m/z=207.2 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 13.10 (br. s., 1H),
8.22 (s, 1H), 5.80 (dq, J=2.05, 6.62 Hz, 1H), 3.56-3.59 (m, 1H),
2.69 (s, 3H), 1.60 (d, J=6.65 Hz, 3H).
Preparation of (S)-methyl 5-(but-3-yn-2-yloxy)-3-methylpicolinate
(285)
##STR00245##
[1714] Preparation of methyl 5-hydroxy-3-methylpicolinate
(285A)
[1715] To a mixture of 2-bromo-5-hydroxy-3-picoline (2.18 g, 11.59
mmol), TEA (19.39 mL, 139 mmol), and MeOH (30 mL, 740 mmol) in a
250 mL pressure tube was added
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (335 mg, 0.58 mmol)
and palladium (II) acetate (65 mg, 0.29 mmol). The mixture was
evacuated-purged with CO gas (balloon) 3-times. The valves were
closed and the mixture was heated at 70.degree. C. for 24 h. The
mixture was filtered through a pad of Celite.RTM. filter aid. The
Celite.RTM. filter aid was washed with MeOH. The filtrate was
concentrated in vacuo and dissolved in DCM (50 mL). The organic
solution was washed with saturated NaHCO.sub.3 (30 mL). The aqueous
layer was saturated with NaCl and extracted with 2% IPA in
CHCl.sub.3 (3.times.20 mL). The combined organic layers were dried
over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude was
purified by silica gel chromatography using 1-5% MeOH in DCM to
give the product as an off-white solid (1.65 g, 85%). LCMS (ESI,
pos.) 168.0 (M+1).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.57 (br. s., 1H), 8.02 (d, J=2.54 Hz, 1H), 7.08 (d,
J=2.15 Hz, 1H), 3.79 (s, 3H), 2.44 (s, 3H).
Preparation of (S)-methyl 5-(but-3-yn-2-yloxy)-3-methylpicolinate
(285B)
[1716] To a solution of (R)-(+)-3-butyn-2-ol (Sigma-Aldrich, 0.294
mL, 4.19 mmol), triphenylphosphine (1.2 g, 4.58 mmol) and methyl
5-hydroxy-3-methylpicolinate (285A, 0.7 g, 4.19 mmol) in THF (20
mL) at 0.degree. C. was added diisopropyl azodicarboxylate (1.0 mL,
5.09 mmol) slowly. The solution was allowed to warm to RT and
stirred overnight. About .about.1/4 of the theoretical amount of
the alcohol, PPh.sub.3, and DIAD were added and the mixture was
stirred for additional 1.5 h. The mixture was quenched with MeOH (2
mL) and concentrated. The residue was purified by silica gel
chromatography (10-50% EtOAc/heptane) to afford (S)-methyl
5-(but-3-yn-2-yloxy)-3-methylpicolinate (1.9 g, 8.67 mmol, 207%
yield) as a white foam that was contaminated by the hydrazine
by-product. LCMS (ESI, pos.) 220.1 (M+1).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.32 (d, J=2.74 Hz, 1H), 7.21 (d, J=2.54
Hz, 1H), 4.98 (m, 1H, overlapping with DIAD OC--H), 3.96 (s, 3H),
2.64 (s, 3H), 2.54 (d, J=1.96 Hz, 1H), 1.71 (d, J=6.46 Hz, 4H).
Preparation of (S)-methyl 5-(but-3-yn-2-yloxy)-3-methylpicolinate
(285)
[1717] A mixture of (S)-methyl
5-(but-3-yn-2-yloxy)-3-methylpicolinate prepared above (285B, 1.9 g
contaminated, theoretical 4.11 mmol) and lithium hydroxide (270 mg,
6.43 mmol) in MeOH (10 mL) and water (10 mL) was stirred at RT for
3 h. The mixture was concentrated to remove most of the MeOH. The
aqueous layer was extracted with DCM (3.times.10 mL) to remove
hydrazine carried from previous step. The aqueous layer was treated
with HCl (5 N, 1.5 mL) to bring the pH of the solution to
.about.3-4. Solid NaCl was added to saturate the solution. The
mixture was extracted with 2% IPA in CHCl.sub.3 (3.times.10 mL).
The combined organic phases were dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give a white solid that was still not
pure. The solid was dissolved in EtOAc (30 mL) and extracted with
saturated NaHCO.sub.3 (3.times.10 mL). The combined aqueous layers
were acidified with HCl (conc.) until the pH reached .about.3. The
solution was saturated with NaCl and extracted with 2% IPA in
CHCl.sub.3 (3.times.10 mL). The combined organic phases were dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The resulting
solid was suspended in ACN (5 mL) and water (2 mL) and was
lyophilized for 48 h to give a white powder (0.78 g, 92% yield over
two steps). LCMS (ESI, pos.) 206.0 (M+1).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.17 (d, J=2.35 Hz, 1H), 7.27 (d, J=2.15
Hz, 1H), 4.97 (dq, J=1.96, 6.52 Hz, 1H), 4.75 (s, 1H), 2.76 (s,
3H), 2.57 (d, J=2.15 Hz, 1H), 1.73 (d, J=6.46 Hz, 3H).
(S)-3-Methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylic acid
(286)
##STR00246##
[1718] Preparation of Compound 286A
[1719] To a solution of tert-butyl
5-chloro-3-methylpyrazine-2-carboxylate (7.0 g, 30.6 mmol) and
1-(oxazol-2-yl)ethanol (5.19 g, 45.9 mmol) in 5 mL of DMF was added
potassium carbonate (8.46 g, 61.2 mmol). The reaction was stirred
overnight. LCMS showed about 10-20% conversion. It was heated at
55.degree. C. for another 24 h. LCMS showed >90% conversion. The
reaction was directly loaded onto a silica gel column and eluted
with a gradient of (heptane/EtOAc=5:1 to 4:1 to 2:1) to give
tert-butyl 3-methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylate
as a colorless oil. This material (5.5 g) was chromatographed using
supercritical CO.sub.2 (additives 10% of 20 mM NH.sub.3 in IPOH) on
a AY-H column (30.times.250 mm, 5 .mu.m) eluting at a flow rate 100
mL/min (100 bar pressure). The absolute stereochemistry was
arbitrarily assigned. The first peak (retention time=1.0 min)
provided (S)-tert-butyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylate (286A,
2.25 g, 7.37 mmol, 24% yield). LCMS (ESI.sup.+) m/z=306
(M+H).sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.16 (s,
1H), 7.62 (d, J=0.73 Hz, 1H), 7.10 (s, 1H), 6.40 (q, J=6.72 Hz,
1H), 2.67 (s, 3H), 1.79 (d, J=6.58 Hz, 3H), 1.62 (s, 9H). The
second peak (retention time=3.2 min) provided (R)-tert-butyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylate (2.23 g,
7.30 mmol, 24% yield).
Preparation of Compound 286B
[1720] To (S)-tert-butyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylate (286A, 2.3
g, 7.53 mmol) was added TFA (8.39 mL, 113 mmol) dropwise and the
mixture was stirred at RT overnight. The TFA was removed in vacuo.
The residue was treated with 15 mL of 1 N aqueous HCl and
azeotroped in vacuo to remove the residual TFA (repeated twice).
The residue was dried under house vacuum overnight to give a gum.
LCMS showed that the gum not pure (some decomposition). The gum was
dissolved in DMF (3 mL), treated with iodomethane (0.56 mL, 9.04
mmol) and potassium carbonate (1.56 g, 11.30 mmol). After stirring
overnight, the reaction was diluted with water, extracted with
EtOAc, washed with sat. NaHCO.sub.3, dried and evaporated to
dryness. Flash column (DCM to DCM/EtOAc=10:1) gave (S)-methyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylate (286B, 540
mg, 2.051 mmol, 27% yield) as a gum. LCMS (ESI.sup.+) m/z=264.2
(M+H).sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.18 (s,
1H), 7.63 (d, J=0.73 Hz, 1H), 7.11 (s, 1H), 6.43 (q, J=6.72 Hz,
1H), 3.97 (s, 3H), 2.76 (s, 3H), 1.80 (d, J=6.72 Hz, 3H).
Preparation of Compound 286
[1721] A solution of (S)-methyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylate (286B, 520
mg, 1.97 mmol) in THF (10 mL) was treated with lithium hydroxide
hydrate (249 mg, 5.93 mmol) in 50 mL of water and the mixture was
stirred at ambient temperature for 3 h. The mixture was treated
with 5 M aqueous HCl (1.3 mL), and extracted with DCM (3.times.50
mL). The combined organic extracts were dried (Na.sub.2SO.sub.4)
and concentrated to give
(S)-3-methyl-5-(1-(oxazol-2-yl)ethoxy)pyrazine-2-carboxylic acid
(286, 490 mg, 1.97 mmol, 100% yield) as a white solid. LCMS
(ESI.sup.+) m/z=250.2 (M+H).sup.+. .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 10.64 (br. s., 1H), 8.05 (s, 1H), 7.64 (d,
J=0.73 Hz, 1H), 7.12 (d, J=0.73 Hz, 1H), 6.46 (q, J=6.67 Hz, 1H),
2.87 (s, 3H), 1.82 (d, J=6.72 Hz, 3H).
(S)-3-Methyl-5-(1-(oxazol-2-yl)ethoxy)picolinic acid (287) and
(R)-3-methyl-5-(1-(oxazol-2-yl)ethoxy)picolinic acid (288)
##STR00247##
[1722] Preparation of Compounds 287A and 288A
[1723] To a mixture of methyl 5-hydroxy-3-methylpicolinate (1.66 g,
9.93 mmol), triphenylphosphine (3.91 g, 14.90 mmol),
1-(oxazol-2-yl)ethanol (1.42 g, 11.92 mmol) in THF (40 mL) at
0.degree. C. was added diisopropyl azodicarboxylate (2.93 mL, 14.90
mmol) dropwise. The reaction was gradually warmed to RT and stirred
overnight. The mixture was treated with MeOH (2 mL) and
concentrated in vacuo. The residue was diluted with EtOAc (50 mL)
and washed sequentially with NaOH (0.5 N, 10 mL), water, and brine,
then dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The
residue was purified by silica gel chromatography (10-100% EtOAc in
heptane). The mixture of two enantiomers was obtained and
chromatographed using supercritical CO.sub.2 (additives 15% of EtOH
with 20 mM NH.sub.3) on an AY-H column (150.times.4.6 mm, 5 .mu.m)
eluting at a flow rate of 4 mL/min (100 bar pressure). The
stereochemistry was assigned arbitrarily. The first peak (retention
time=1.5 min) provided (S)-methyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)picolinate (287A, 1.29 g, 49%
yield). LC/MS (ESI.sup.-) m/z=263 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.82 (d, J=6.65 Hz, 3H) 2.59 (s, 3H)
3.94 (s, 3H) 5.57 (q, J=6.65 Hz, 1H) 7.11 (s, 1H) 7.20 (d, J=2.54
Hz, 1H) 7.63 (s, 1H) 8.28 (d, J=2.74 Hz, 1H). The second peak
(retention time=2.1 min) provided (R)-methyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)picolinate (288A, 1.11 g, 43%
yield). LC/MS (ESI.sup.-) m/z=263 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.82 (d, J=6.65 Hz, 3H) 2.59 (s, 3H)
3.94 (s, 3H) 5.57 (q, J=6.65 Hz, 1H) 7.11 (s, 1H) 7.20 (d, J=2.54
Hz, 1H) 7.63 (s, 1H) 8.28 (d, J=2.74 Hz, 1H).
Preparation of Compound 287
[1724] To a suspension of (S)-methyl
3-methyl-5-(1-(oxazol-2-yl)ethoxy)picolinate (287A, 1.29 g, 4.92
mmol) and lithium hydroxide hydrate (0.30 g, 7.28 mmol) was added
THF (16 mL) and water (4 mL). The mixture was stirred at RT for 1.5
h, then 8.5 mL of 1 N HCl was added and the mixture was diluted
with brine and a mixed solvent of i-PrOH:CHCl.sub.3 (v/v 1:3). The
aqueous layer was further extracted with the mixed solvent. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated in
vacuo to afford (S)-3-methyl-5-(1-(oxazol-2-yl)ethoxy)picolinic
acid as off-white solid (1.20 g, 98% yield). LC/MS (ESI.sup.-)
m/z=249 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 1.84 (d, J=6.65 Hz, 3H) 2.72 (s, 3H) 5.51-5.67 (m, 1H) 7.13 (s,
1H) 7.28 (d, J=2.35 Hz, 1H) 7.66 (s, 1H) 8.17 (d, J=2.54 Hz, 1H).
The acid-proton peak is broad.
Preparation of Compound 288
[1725] (R)-3-methyl-5-(1-(oxazol-2-yl)ethoxy)picolinic acid (288)
(1.20 g, 98% yield) as an off-white solid was synthesized in a
fashion similar to that of intermediate 287, but starting with
(R)-methyl 3-methyl-5-(1-(oxazol-2-yl)ethoxy)picolinate (288A, 1.11
g, 4.23 mmol). LC/MS (ESI.sup.-) m/z=249 (M+H).sup.+. .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 1.84 (d, J=6.46 Hz, 3H) 2.72
(s, 3H) 5.60 (q, J=6.52 Hz, 1H) 7.13 (s, 1H) 7.28 (d, J=1.76 Hz,
1H) 7.66 (s, 1H) 8.17 (d, J=2.35 Hz, 1H). The acid-proton peak is
broad.
3-Chloro-5-(prop-2-yn-1-yloxy)picolinic acid (289)
##STR00248##
[1727] To a suspension of 3-chloro-5-hydroxypicolinic acid
(Afferchem, 0.40 g, 2.30 mmol) and potassium carbonate (1.12 g,
8.07 mmol) in DMF (10 mL) was added propargyl bromide (0.56 mL,
5.07 mmol) dropwise at RT. The mixture was heated to 45.degree. C.
for 1 h. LCMS showed the reaction was complete. The mixture was
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 residue was purified by silica gel chromatography: 0-50%
EtOAc-Hexane. The product was obtained as yellow solid (0.45 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).
[1728] To a suspension of prop-2-yn-1-yl
3-chloro-5-(prop-2-yn-1-yloxy)picolinate (0.448 g, 1.795 mmol) and
lithium hydroxide monohydrate (0.079 g, 1.884 mmol) was added THF
(6 mL) and water (2 mL). The mixture was stirred at RT for 1 h.
LCMS showed the reaction was complete. 0.08 mL of 1 N HCl was added
and the mixture was concentrated in vacuo. The product was obtained
as off-white solid (0.456 g, 100% yield). LC/MS (ESI.sup.-) m/z=212
(M+H).sup.+.
5-(2,2,2-Trifluoroethoxy)picolinic acid (300)
##STR00249##
[1729] Preparation of ethyl 5-(2,2,2-trifluoroethoxy)picolinate
[1730] To a solution of methyl 5-hydroxypicolinate (0.50 g, 3.27
mmol, Frontier Scientific) in DMF (5 mL) were added cesium
carbonate (1.383 g, 4.24 mmol, Aldrich) and 2,2,2-trifluoroethyl
ester (0.909 ml, 3.92 mmol) and the resulting suspension was
stirred at RT for 1 h. The reaction was diluted with water and
EtOAc. The organic layer was washed with 1 M LiCl (aq) solution and
brine before drying over magnesium sulfate and concentrating under
reduced pressure to afford the crude title compound as a yellow
oil, which was used directly in the next step without further
purification. M/S m/z=236.0 [M+H].sup.+.
Preparation of Compound 300
[1731] The crude material from the previous reaction was taken up
in THF (5 mL) and lithium hydroxide (2.0 M of aq. Solution, 4.90
mL, 9.80 mmol) was added. The reaction was stirred at RT for 16 h.
The reaction was diluted with water and acidified with 1.0 N HCl
(aq.) solution was added until pH=1. The solution was extracted
with DCM and the organic layer was washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure to afford
the title compound as a white solid. (0.194 g, 0.877 mmol, 26.9%
yield). M/S m/z=221.9 [M+H].sup.+. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. ppm 5.00 (q, J=8.77 Hz, 2H) 7.66 (dd, J=8.77,
2.92 Hz, 1H) 8.07 (d, J=8.77 Hz, 1H) 8.50 (d, J=2.92 Hz, 1H) 13.00
(br. S., 1H).
3,8-Dichloro-5-fluoro-1,7-naphthyridine (301)
##STR00250##
[1733] A pressure bottle was charged with
3-chloro-1,7-naphthyridin-8(7H)-one (15 g, 83 mmol, Anichem), MeOH
(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 h. Water and EtOAc were added, and
the layers were separated. The aqueous portion was extracted twice
with EtOAc 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 EtOAc and
filtered. The title intermediate was isolated as an off-white solid
(15.34 g, 80%) as a 3:1 mixture of diastereomers.
[1734] 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), ACN (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% EtOAc in
heptanes, to provide Compound 301 (5.57 g, 25.7 mmol, 79% yield) as
a white solid. LC/MS (ESI.sup.+) m/z=217 (M+H).sup.+.
4-Chloro-5-fluoro-7-methoxyquinazoline (302)
##STR00251##
[1735] Preparation of 2-amino-6-fluoro-4-methoxybenzonitrile
[1736] Ammonia gas was bubbled through a solution of
2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in DMSO
(11.83 mL) for 10 minutes. The reaction was then sealed and stirred
at 90.degree. C. for 24 h. The reaction mixture was cooled to RT
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).sup.+.
Preparation of 5-fluoro-7-methoxyquinazolin-4-ol
[1737] To a mixture of formic acid (11.43 mL, 298 mmol) and
sulfuric acid (0.87 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
h, cooled to RT, 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).sup.+.
Preparation of 4-chloro-5-fluoro-7-methoxyquinazoline
[1738] To a suspension of 5-fluoro-7-methoxyquinazolin-4-ol (0.12
g, 0.64 mmol) in thionyl chloride (1.41 mL, 19.31 mmol) was added
DMF (0.028 mL, 0.36 mmol). The reaction was stirred at 80.degree.
C. for 6 h and concentrated in vacuo. The residue was suspended in
saturated aqueous sodium bicarbonate and extracted with DCM. The
organic layer was concentrated in vacuo to generate the title
compound (0.13 g, 0.61 mmol) as a yellow solid. LC/MS (ESI.sup.+)
m/z=213 (M+H).sup.+.
Difluoromethyl)picolinic acid (303)
##STR00252##
[1739] Step 1: 5-Formylpicolinonitrile
[1740] 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 EtOAc. 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% EtOAc 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).sup.+.
Step 2: 5-(Difluoromethyl)picolinonitrile
[1741] 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% EtOAc/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
[1742] 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 h. 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).sup.+.
5-Methoxy-3-methylpyrazine-2-carboxylic acid (304)
##STR00253##
[1743] Step 1: Methyl 3-methylpyrazine-2-carboxylate
[1744] In a 2-L flask, 3-methylpyrazine-2-carboxylic acid (Matrix,
19.95 g, 144 mmol) was suspended in MeOH (500 mL). The suspension
was cooled in an ice-water bath, and concentrated sulfuric acid
(Fluka, 27.3 mL, 506 mmol) was added over a time period of 5 min.
The reaction mixture was heated to 80.degree. C. for 5 h. The
reaction mixture was concentrated under reduced pressure and the
residue was taken up in DCM (750 mL). The excess acid was
neutralized carefully with of aqueous NaOH (5N or 5M, 200 mL). The
aqueous layer was separated and extracted with DCM (250 mL). The
combined organic layers were combined, dried over MgSO.sub.4 and
concentrated to afford 16.15 g of the title compound (106 mmol,
73%). MS m/z=153 [M+H].sup.+.
Step 2: 3-(Methoxycarbonyl)-2-methylpyrazine 1-oxide
[1745] In a 1-L flask, the methyl 3-methylpyrazine-2-carboxylate
(step 1, 16.08 g, 106 mmol) was suspended in CHCl.sub.3 (300 mL).
3-chlorobenzoperoxoic acid (Aldrich, 24.62 g, 143 mmol) was added.
The reaction mixture was heated to 70.degree. C. for 16 h. The
reaction mixture was quenched with saturated NaHCO.sub.3 (200 mL).
The layers were separated, and the aqueous layer was further
extracted with DCM (2.times.100 mL). The combined organic layers
were dried over MgSO.sub.4, and the filtrate was concentrated to
afford the title compound. MS m/z=169 [M+H].sup.+.
Step 3: Methyl 5-chloro-3-methylpyrazine-2-carboxylate
[1746] In a 1-L flask, the crude
3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (step 2, 17.77 g, 106
mmol) was dissolved in DMF (300 mL). Neat phosphoryl trichloride
(29.6 mL, 317 mmol) was added. The reaction mixture was heated to
100.degree. C. After 1 h, the reaction mixture was concentrated to
remove most of the DMF. The flask was cooled in an ice water bath,
and 1 M aqueous Na.sub.2CO.sub.3 (300 mL) was added slowly,
followed by 80% EtOAc-hexane (400 mL). The mixture was filtered
through Celite.RTM. filter aid. The resulting filtrate was
partitioned and the aqueous phase was extracted further with 80%
EtOAc-hexane (2.times.250 mL). The combined organic layers were
dried over MgSO.sub.4 and concentrated. The material was purified
through silica gel using 11% EtOAc-hexane to afford the title
compound (4.29 g, 23 mmol, 22%). MS m/z=187 [M+H].sup.+. .sup.1H
NMR in CDCl.sub.3 .delta.: 8.51 (s, 1H), 4.01 (s, 3H), 2.86 (s,
3H).
Step 4: 5-Methoxy-3-methylpyrazine-2-carboxylic acid
[1747] A flask was charged with sodium (0.813 g, 35.4 mmol), purged
with Argon. and placed in a room temperature water bath. MeOH (47.7
mL, 1179 mmol) was added slowly. After 40 min, methyl
5-chloro-3-methylpyrazine-2-carboxylate (step 3, 2.2 g, 11.79 mmol)
was added. The vessel was sealed and heated to 45.degree. C. for
1.5 hs. Sodium hydroxide (1M, 12.97 mL, 12.97 mmol) was added and
heating was continued for 1.5 hs. The reaction mixture was
concentrated unde reduced pressure and the residue was dissolved in
a minimum amount of water (50 mL). The aqueous phase was extracted
with Et.sub.2O (15 mL), which was discarded. The aqueous phase was
acidified with HCl (5M, 11 mL, 55 mmol). The mixture was extracted
with DCM (3.times.60 mL). The combined organic extracts were dried
over MgSO.sub.4 and the filtrate was concentrated to afford the
title compound (2.0 g, 100%). MS m/z=169 [M+H].sup.+. .sup.1H NMR
in CDCl.sub.3 .delta.: 10.70 (br, 1H), 7.98 (s, 1H), 4.00 (s, 3H),
2.91 (s, 3H).
5-Chloro-3-methoxypicolinic acid (305)
##STR00254##
[1749] In a 1-L flask, 5-chloro-3-nitropicolinonitrile (Oakwood,
6.67 g, 36.3 mmol) was dissolved in MeOH (185 mL). The solution was
cooled to 0.degree. C., and sodium hydroxide (3 M, 36.3 mL, 109
mmol) was added. The reaction mixture was warmed to RT and stirred
overnight. The reaction was concentrated under reduced pressure and
the residue was taken up in absolute EtOH (100 mL). NaOH (5 M, 3
equiv, 109 mmol, 22 mL) was added, and the reaction mixture was
heated to 100.degree. C. for 1 h. The reaction mixture was
concentrated under reduced pressure and the residue was taken up in
water (100 mL). The aqueous layer was extracted with Et.sub.2O (30
mL), which was discarded. The aqueous phase was acidified with HCl
(5 M, 55 mL), saturated with NaCl, and extracted with EtOAc
(5.times.75 mL). The combined organic extracts were dried over
MgSO.sub.4 and the filtrate was concentrated under reduced
pressure. The resulting solid was triturated with Et.sub.2O to
afford the title compound (5.63 g, 30 mmol, 83%). MS m/z=188
[M+H].sup.+. .sup.1H NMR in CDCl.sub.3 .delta.: 8.18 (d, 1H,
J=1.8), 7.49 (d, 1H, J=1.8), 4.03 (s, 3H).
5-Cyano-3-methoxypicolinic acid (306)
##STR00255##
[1750] Step 1: Methyl 5-chloro-3-methoxypicolinate
[1751] In a 350-mL resealable vessel, 5-chloro-3-methoxypicolinic
acid (intermediate 14, 7.51 g, 40.0 mmol) was dissolved in MeOH
(120 mL). The solution was cooled to 0.degree. C., and concentrated
sulfuric acid (7.57 mL, 140 mmol) was added. The vessel was sealed
and heated to 95.degree. C. for 1.5 h. The reaction mixture was
cooled to 0.degree. C., and quenched with Na.sub.2CO.sub.3 (1M, 140
mL). The reaction mixture was concentrated under reduced pressure
and the residue was extracted with EtOAc (3.times.100 mL). The
combined organics extracts were dried over MgSO.sub.4 and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel chromatography (gradient 20%-33%
EtOAc/hexane) to afford the title compound as a yellow solid (5.59
g, 27.7 mmol, 67%). MS m/z=202 [M+H].sup.+. .sup.1H NMR in
CDCl.sub.3 .delta.: 8.24 (d, 1H, J=1.9), 7.37 (d, 1H, J=1.9), 3.97
(s, 3H), 3.94 (s, 3H).
Step 2: Methyl 5-cyano-3-methoxypicolinate
[1752] In a 350-mL resealable vessel, Pd.sub.2dba.sub.3 (1.487 g,
1.623 mmol),
dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine (1.444
g, 3.52 mmol), dicyanozinc (3.18 g, 27.1 mmol), and methyl
5-chloro-3-methoxypicolinate (stepl, 5.455 g, 27.1 mmol) were taken
up in DMF (80 mL). The reaction mixture was purged with Argon and
subsequently heated to 120.degree. C. for 2 h. Upon cooling, the
reaction mixture was concentrated under reduced pressure. The
residue was filtered through Celite.RTM. filter aid, and the filter
cake was rinsed with 1% MeOH/DCM. The filtrate was concentrated
under reduced pressure and the residue was purified by silica gel
chromatography (33-40% EtOAc/hexane) to afford the title compound
as a white solid (4.51 g, 23.5 mmol, 87%)., MS m/z=193 [M+H].sup.-.
.sup.1H NMR in CDCl.sub.3 .delta.: 8.51 (d, 1H, J=1.6), 7.55 (d,
1H, J=1.6), 4.00 (s, 3H), 3.97 (s, 3H).
Step 3: 5-Cyano-3-methoxypicolinic acid
[1753] In a 1-L flask, the methyl 5-cyano-3-methoxypicolinate (step
2, 4.51 g, 23.5 mmol) was taken up in THF (74 mL). The suspension
was cooled to 0.degree. C., and sodium hydroxide (1M, 24.64 mL,
24.64 mmol) was added. After 1 h, the reaction was concentrated
under reduced pressure. The residue was taken up in 100 mL of
water, and the aqueous phase was extracted with Et.sub.2O (50 mL),
which was discarded. The aqueous phase was acidified with HCl (5M,
5.16 mL, 25.8 mmol). The aqueous phase was extracted with DCM
(11.times.150 mL). The combined organic extracts were dried over
MgSO.sub.4 and the filtrate was concentrated under reduced pressure
to afford the title compound as a white solid. MS m/z=179
[M+H].sup.+. .sup.1H NMR in CDCl.sub.3 .delta.: 8.48 (d, 1H,
J=1.6), 7.71 (d, 1H, J=1.6), 4.08 (s, 3H).
5-Cyano-3-methylpicolinic acid (307)
##STR00256##
[1755] 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 room temperature for 2
hrs. 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 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.+.
8-Chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (308)
##STR00257##
[1756] Step 1:
3-Chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one
[1757] A pressure bottle was charged with
3-chloro-1,7-naphthyridin-8(7H)-one (Anichem, 15 g, 83 mmol), MeOH
(34 ml), ACN (173 ml) and
1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium
tetrafluoroborate (Aldrich, 30.9 g, 87 mmol). The mixture was
heated to 45-50.degree. C. After 6 hs additional
1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diium
tetrafluoroborate (2.5 g) was added and heating was continued
overnight. Water and EtOAc were added to the cooled reaction
mixture and the layers were separated. The aqueous layer was
extracted with EtOAc, and the combined organic layers were dried
over MgSO.sub.4. The filtrate was concentrated under reduced
pressure and the residue was triturated with EtOAc. The solid was
filtered off and the title compound (15.34 g, 66.5 mmol, 80% yield)
was isolated as a white solid. MS m/z=231 [M+H].sup.+.
Step 2:
5-Fluoro-6-methoxy-8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridine-3-ca-
rbonitrile
[1758] A pressure bottle was charged with Pd(dba).sub.3 (Strem,
1.032 g, 1.127 mmol),
2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (Strem 1.157 g,
2.82 mmol), zinc cyanide (Alfa Aesar, 2.482 g, 21.14 mmol),
3-chloro-5-fluoro-6-methoxy-6,7-dihydro-1,7-naphthyridin-8(5H)-one
(step 1, 3.25 g, 14.09 mmol) and DMF (70 ml). The bottle was purged
with Argon and the reaction mixture was heated to 110.degree. C.
for 1 h. The crude reaction mixture was filtered through a pad of
Celite.RTM. filter aid and the filtercake was washed with MeOH. The
combined filtrates were concentrated under reduced pressure. The
residue was triturated with DCM. The solid was filtered off and
washed with DCM. The title compound (2.27 g, 10.26 mmol, 73% yield)
was obtained as an off white solid. MS m/z=222 [M+H].sup.+.
Step 3: 8-Chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile
[1759] A pressure bottle was charged with
5-fluoro-6-methoxy-8-oxo-5,6,7,8-tetrahydro-1,7-naphthyridine-3-carbonitr-
ile (step 3, 2.27 g, 10.26 mmol), ACN (41 ml) and phosphorus
oxychloride (Aldrich, 3.35 ml, 35.9 mmol). The bottle was sealed
and the reaction mixture was heated to 75.degree. C. overnight. The
reaction mixture was concentrated and the crude material was
purified by silica gel chromatography (gradient 0-20% (10 MeOH in
DCM)/DCM to afford the title compound (1.2 g, 5.78 mmol, 56% yield)
as a white solid. MS m/z=208 [M+H].sup.+.
5-(Cyanomethoxy)-3-methylpicolinic acid (309)
##STR00258##
[1760] Step 1: Methyl 5-(cyanomethoxy)-3-methylpicolinate
[1761] To a suspension of methyl 5-hydroxy-3-methylpicolinate
(0.8063 g, 4.82 mmol, step 3 intermediate 38) and cesium carbonate
(0.77 ml, 9.65 mmol, Alfa Aesar) in DMF (48.2 mL) was added
bromoacetonitrile (0.336 ml, 4.82 mmol, Sigma-Aldrich Chemical
Company, Inc.). The reaction mixture was stirred for 4 h at RT. The
reaction mixture was diluted with aqueous, saturated sodium
bicarbonate solution and extracted with EtOAc. The organic extract
was washed with aqueous, saturated sodium bicarbonate solution,
brine and dried over MgSO.sub.4. The filtrate was concentrated in
vacuo. MS m/z=207.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 2.67 (s, 3H) 3.98 (s, 3H) 4.88 (s, 2H)
7.20 (d, J=2.35 Hz, 1H) 8.32 (br. s., 1H)
Step 2: 5-(Cyanomethoxy)-3-methylpicolinic acid
[1762] To a solution of methyl 5-(cyanomethoxy)-3-methylpicolinate
(0.895 g, 4.34 mmol) and sodium iodide (0.354 ml, 8.68 mmol,
Sigma-Aldrich Chemical Company, Inc.) in ACN (4.34 ml) was added
chlorotrimethylsilane (1.102 ml, 8.68 mmol, Strem Chemicals, Inc.).
The reaction mixture was heated to 70.degree. C. and allowed to
stir overnight. The reaction mixture was concentrated under reduced
pressure and the residue was diluted with water and extracted with
EtOAc. The organic extract was washed with water, 10% sodium
thiosulfate solution and dried over MgSO.sub.4. The filtrate was
concentrated in vacuo to give 5-(cyanomethoxy)-3-methylpicolinic
acid which was used without further purification. MS m/z=192.9
[M+H].sup.+.
[1763] The following carboxylic acid intermediates were synthesized
according to existing literature procedures, as listed below:
TABLE-US-00001 Inter- mediate Literature No. Structure Reference
310 ##STR00259## WO2012095463 311 ##STR00260## WO2012095463 312
##STR00261## WO2012095521 313 ##STR00262## WO2012095521 314
##STR00263## WO2013061962 315 ##STR00264## WO2012138734 316
##STR00265## WO2011069934 317 ##STR00266## WO2011044181 318
##STR00267## WO 2011009898 319 ##STR00268## WO 2012147763 320
##STR00269## J. Med. Chem. 2013, 56, 3980 321 ##STR00270## J. Med.
Chem. 2013, 56, 3980
5-Cyanopyrimidine-2-carboxylic acid (322)
##STR00271##
[1764] Step 1: methyl 5-bromopyrimidine-2-carboxylate
[1765] To a solution of 5-bromopyrimidine-2-carboxylic acid (3.22
g, 15.9 mmol) in MeOH (50 mL) at room temperature was added acetyl
chloride (4.0 mL, 56.3 mmol). The reaction mixture was heated to
reflux for 15 min, cooled to room temperature and concentrated
under reduced pressure. The reaction mixture was diluted with
saturated NaHCO.sub.3 (30 mL) and EtOAc, and transferred to a
separatory funnel. The aqueous phase was extracted with EtOAc
(4.times.) and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, and concentrated to
give methyl 5-bromopyrimidine-2-carboxylate (2.30 g, 10.6 mmol, 67%
yield) as a white solid. LC/MS (ESI.sup.+) m/z=216.9 (M+H).
Calculated for C.sub.6H.sub.5BrN.sub.2O.sub.2 216.0.
Step 2: methyl 5-cyanopyrimidine-2-carboxylate
[1766] To a mixture of methyl 5-bromopyrimidine-2-carboxylate (2.30
g, 10.6 mmol) and copper (I) cyanide (1.92 g, 21.4 mmol) in a 100
mL round bottom flask was added DMA (21 mL). The reaction mixture
was degassed by bubbling nitrogen through the solution for 5 min.
The reaction mixture was heated to 110.degree. C. for 2 d and
cooled to room temperature. The reaction mixture was diluted with
EtOAc and water and filtered through a glass frit (medium). The
filtrate was transferred to a separatory funnel. The aqueous phase
was extracted with EtOAc (4.times.) and the combined organic
extracts were washed with brine (1.times.), dried over MgSO.sub.4,
filtered, concentrated to give a yellow oil. Purification by flash
column chromatography on silica gel (80 g, 5% to 50% EtOAc in
heptane) gave methyl 5-cyanopyrimidine-2-carboxylate (0.83 g, 5.08
mmol, 48% yield) as a white solid. LC/MS (ESI.sup.+) m/z=164.0
(M+H).
Step 3: 5-cyanopyrimidine-2-carboxylic acid
[1767] To a solution of methyl 5-cyanopyrimidine-2-carboxylate
(0.11 g, 0.644 mmol) in THF (2.6 mL) at 0.degree. C. was added a
solution of lithium hydroxide monohydrate (30 mg, 0.715 mmol) in
water (0.5 mL). The reaction mixture was stirred at 0.degree. C.
for 20 min and 1 M HCl (0.70 mL) was added. The reaction mixture
was concentrated under reduced pressure and dried under high vacuum
to give methyl 5-cyanopyrimidine-2-carboxylate (0.11 g, 0.644 mmol)
as a white solid that was used without further purification. LC/MS
(ESI.sup.+) m/z=148.0 (M-H).
5-Ethynylpicolinic acid (323)
##STR00272##
[1768] Step 1: Methyl 5-((triethylsilyl)ethynyl)picolinate
[1769] A glass microwave reaction vessel was charged with methyl
5-bromopyridine-2-carboxylate (0.95 mL, 6.94 mmol, Alfa Aesar),
(triethylsilyl) acetylene (3.73 mL, 20.81 mmol, Sigma-Aldrich),
tetrakis(triphenylphosphine) palladium (0.61 g, 0.527 mmol, Strem
Chemicals), TEA (4.82 mL, 34.7 mmol, Sigma-Aldrich Chemical), and
copper (I) iodide (198 mg, 1.04 mmol, Sigma-Aldrich). The reaction
mixture was stirred and heated in a Biotage Initiator microwave
reactor at 70.degree. C. for 30 min. The reaction mixture was
filtered through Celite.RTM. filter aid and concentrated. The
reaction mixture was diluted with saturated NH.sub.4Cl and
extracted with EtOAc. The organic extract was washed with water and
brine, dried over MgSO.sub.4, filtered and concentrated in vacuo.
The crude product was adsorbed onto a plug of silica gel and
chromatographed through a silica gel column, eluting with a
gradient of 0% to 40% EtOAc in hexane, to provide methyl
5-((triethylsilyl)ethynyl)picolinate (1.68 g, 6.09 mmol, 88%
yield). MS m/z [M+H].sup.+=276.0.
Step 2: 5-Ethynylpicolinic Acid
[1770] To a solution of methyl 5-((triethylsilyl)ethynyl)picolinate
(1.68 g, 6.05 mmol) in THF (12.11 ml) was added TBAF, 1.0M in THF
(6.68 ml, 6.68 mmol, Sigma Aldrich). The reaction was allowed to
stir for 6 hours at RT. The reaction was concentrated. The crude
product was adsorbed onto a plug of silica gel and chromatographed
through silica gel column eluting with a gradient of 10% to 100%
EtOAc in hexane followed by 1% HOAc in EtOAc, to afford
5-ethynylpicolinic acid (0.05 g, 0.37 mmol, 6% yield). MS m/z
[M+H].sup.+=147.9.
5-(Prop-1-yn-1-yl)picolinic acid (324)
##STR00273##
[1771] Step 1: Methyl 5-bromopicolinate
[1772] To a suspension of 5-bromopicolinic acid (2.0 g, 9.94 mmol)
in MeOH (2 ml)/toluene (20 ml) was added TMS-diazomethane (20M in
Et.sub.2O; 5.47 ml, 10.94 mmol, Matrix Scientific) dropwise. The
reaction was stirred at room temperature for 3 hours. An additional
0.2 eq (0.99 mL) of TMS-diazomethane was added and the reaction
stirred for 1.5 hours. The reaction was concentrated and the brown
solid was carried to next step without further work up. MS m/z
[M+H].sup.+=217.9.
Step 2: Methyl 5-(prop-1-yn-1-yl)picolinate
[1773] To a solution of methyl 5-bromopicolinate (0.60 g, 2.77
mmol) in toluene (50 mL) was added tributyl(prop-1-yn-1-yl)stannane
(1.01 mL, 3.32 mmol, Sigma Aldrich) and
tetrakis(triphenylphosphine)palladium (0.04 g, 0.036 mmol, Strem
Chemicals, Inc.). The reaction was stirred overnight at 100.degree.
C. The reaction was allowed to cool to RT and concentrated. The
residue was adsorbed onto a plug of 10% w/w KF Silica and
chromatographed with a silica gel column eluting with a gradient of
10% to 100% EtOAc in hexane, to provide methyl
5-(prop-1-yn-1-yl)picolinate (0.18, 1.05 mmol, 38% yield). MS m/z
[M+H].sup.+=176.0.
Step 3: 5-(Prop-1-yn-1-yl)picolinic acid
[1774] To a solution of methyl 5-(prop-1-yn-1-yl)picolinate (0.18
g, 1.05 mmol) in THF (3.48 ml) was added sodium hydroxide 1.0 N
solution (1.05 mL, 1.045 mmol, Sigma). The reaction was stirred for
1.5 hours at room temperature. Hydrogen chloride (4.0 M solution in
1,4-dioxane; 0.26 mL, 1.05 mmol, Sigma Aldrich) was added and the
reaction stirred for an additional 10 minutes. The reaction was
concentrated in vacuo to provide 5-(prop-1-yn-1-yl)picolinic acid
as a light yellow solid. The material was used without further
purification assuming theoretical yield. MS m/z
[M+H].sup.+=162.1.
(5S)-Methyl-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2-fluoro-3-methylphenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-e-
ne-1-carboxylate (456M)
##STR00274## ##STR00275## ##STR00276##
[1775] Preparation of 2-fluoro-N-methoxy-N,3-dimethylbenzamide
(456A)
[1776] To a solution of 2-fluoro-3-methylbenzoic acid (240 g, 1.16
mol) in DMF (2.0 L) was added DIPEA (542 mL, 3.12 mol) followed by
the addition of HATU (710 g, 1.87 mol) at 0.degree. C. The reaction
mixture was stirred for 10 min at 0.degree. C. and N,O-dimethyl
hydroxylamine hydrochloride (167 g, 1.71 mol) was added at
0.degree. C. The resulting reaction mixture was then stirred for 12
h at RT. The reaction mixture was then quenched with water (3.0 L)
and extracted with EtOAc (3.times.5.0 L). The combined organic
layera were dried over sodium sulfate and concentrated under
reduced pressure. The product thus obtained was purified using
silica gel chromatography (30% EtOAc in hexanes) to provide
compound 456A (270 g, 88%). .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 7.25-7.19 (m, 2H), 7.05 (t, J=3.6 Hz, 1H), 3.53 (s, 3H),
3.32 (s, 3H), 2.29 (s, 3H).
Preparation of 1-(2-fluoro-3-methylphenyl)ethanone (456B)
[1777] To a solution of compound 456A (270 g, 1.37 mol) in THF (2.7
L) was added methyl magnesium bromide (3.0 M in Et.sub.2O, 1.82 L,
5.48 mol) drop wise at -78.degree. C. The resulting mixture was
stirred for 1 h at -78.degree. C. The reaction mixture was then
quenched with saturated ammonium chloride (5.0 L) and extracted
with EtOAc (2.times.5.0 L). The combined organic layers were dried
over sodium sulfate and concentrated under reduced pressure. The
mixture thus obtained was purified by silica gel chromatography
(10% EtOAc in hexanes) to give compound 456B (200 g, 96%). .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 7.68-7.64 (m, 1H), 7.37-7.34
(m, 1H), 7.09 (t, J=7.0 Hz, 1H), 2.64 (s, 3H), 2.32 (s, 3H).
Preparation of
(R)--N-(1-(2-fluoro-3-methylphenyl)ethylidene)-2-methylpropane-2-sulfinam-
ide (456C)
[1778] To a solution of compound 456B (200.0 g, 1.32 mol) in THF
(2.0 L) was added (R)-2-methylpropane-2-sulfinamide (239 g, 1.97
mol) followed by addition of titanium tetraethoxide (899 g, 3.94
mol) at RT. The reaction mixture was stirred for 12 h at 70.degree.
C. It was then cooled to RT and quenched with brine (1 L). The
precipitates thus obtained were filtered and washed thoroughly with
EtOAc (3.times.1.0 L). The layers were separated, and the organic
layer was concentrated under reduced pressure to afford the initial
mixture which was purified by silica gel chromatography (30% EtOAc
in hexanes) to give compound 456C (230 g, 68%). .sup.1H NMR (300
MHz, Chloroform-d) .delta. 7.45 (t, J=7.0 Hz, 1H), 7.29-7.24 (m,
1H), 7.08-7.03 (m, 1H), 2.76 (s, 3H), 2.30 (s, 3H), 1.32 (s, 9H).
MS (ESI+ve ion) mlz: [M+1]=256.2.
Preparation of
(3S)-tert-butyl-3-(1,1-dimethylethylsulfinamido)-3-(2-fluoro-3-methylphen-
yl) butanoate (456D)
[1779] To a suspension of zinc powder (589 g, 9.01 mol) in THF (2.5
L) was added TMSCl (92 mL, 721.5 mmol). The reaction mixture was
then heated at 60.degree. C. for 45 min. Next, the reaction mixture
was cooled to 35.degree. C., and t-butyl bromo acetate (284 mL,
2.25 mol) was added over 6 h (internal temperature did not go above
above 45.degree. C.) and the reaction mixture was heated to
55.degree. C. for 60 min. The reaction mixture was then allowed to
cool to RT and stand for 30 min. The freshly prepared Zn-reagent
was cannulated to a solution of compound 456C (230 g, 901 mmol) in
THF (2.0 L) at 0.degree. C. dropwise. The resulting reaction
mixture was stirred for 12 h at RT. It was then quenched with
saturated NH.sub.4Cl (3.0 L) and stirred for 2 h (until all the
white precipitates were dissolved). The layers were separated and
the aqueous layer was extracted with EtOAc (3.times.3.0 L). The
combined organic layers were dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure to give an orange oil that was
purified by silica gel chromatography (25% EtOAc in hexanes) to
give compound 456D (270 g, 81%). .sup.1H NMR: (300 MHz, CDCl.sub.3)
.delta. 7.32-7.29 (m, 1H), 7.12-7.08 (m, 1H), 7.00-6.95 (m, 1H),
5.42 (s, 1H), 3.27-3.25 (m, 1H), 2.97-2.95 (m, 1H), 2.35 (s, 3H),
1.84 (s, 3H), 1.28 (s, 9H), 1.24 (s, 9H). MS (ESI+ve ion) m/z:
[M+1]=372.2.
Preparation of
(R)--N--((S)-2-(2-fluoro-3-methylphenyl)-4-hydroxybutan-2-yl)-2-methyl
propane-2-sulfinamide (456E)
[1780] To a solution of compound 456D (270 g, 727.2 mmol) in dry
THF (2.5 L) was adde LiBH.sub.4 (2.0 M solution in THF, 727 mL,
1454 mmol) dropwise at RT. The reaction mixture was stirred for 30
min at RT and was then cooled to 0.degree. C. MeOH (294 mL) was
slowly added. The reaction mixture was then stirred for 12 h at RT
and quenched with saturated ammonium chloride (2.5 L). The reaction
was then diluted with water and extracted with EtOAc (3.times.2.0
L). The organic layer was dried over sodium sulfate and
concentrated under reduced pressure. The material thus obtained was
triturated with hexanes (1.0 L) and filtered. The solid was
purified by silica gel chromatography (10% EtOAc in hexanes) to
give compound 456E (170 g, 78%). .sup.1H NMR (300 MHz, DMSO)
.delta. 7.31-7.28 (m, 1H), 7.19-7.17 (m, 1H), 7.04 (t, J=7.6 Hz,
1H), 5.56 (s, 1H), 4.74-4.71 (t, J=4.5 Hz, 1H), 3.46-3.43 (m, 1H),
3.26-3.22 (m, 1H), 2.20 (s, 3H), 2.17-2.08 (m, 2H), 1.71 (s, 3H),
1.11 (s, 9H). MS (ESI+ve ion) m/z: [M+1]=302.2.
Preparation of
N--((S)-2-(2-fluoro-3-methylphenyl)-4-oxobutan-2-yl)-2-methylpropane-2-su-
lfinamide (456F)
[1781] To a solution of compound 456E (170 g, 564.2 mmol, 1.0
equiv) in DMSO (850 mL) and DCM (1700 mL) at 0.degree. C. was added
DIPEA (295 mL, 1692.6 mmol) followed by pyridine sulphur trioxide
(135 g, 846.3 mmol). The reaction mixture was then stirred
overnight at RT, and then it was treated with water (2500 mL) and
extracted with DCM (3.times.2000 mL). The combined organic layers
were dried over sodium sulfate and concentrated under reduced
pressure. The product thus obtained was purified by silica gel
chromatography (50% EtOAc in hexanes) to give compound 456E (140 g,
83%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.62 (s, 1H),
7.30-7.20 (m, 1H), 7.06-7.04 (m, 1H), 6.99-6.96 (m, 1H), 4.81 (s,
1H), 3.40 (q, 2H), 2.20 (s, 3H), 1.74 (s, 3H), 1.21 (s, 9H). MS
(ESI+ve ion) m/z: [M+1]=300.2.
Preparation of
(S)-2-(2-fluoro-3-methylphenyl)-4,4-dimethoxybutan-2-amine
(456G)
[1782] To a solution of compound 456F (140 g, 468.6 mmol) in MeOH
(700 mL) was added p-toluene sulfonic acid monohydrate (4.03 g,
23.38 mmol). The reaction mixture was stirred at 65.degree. C. for
12 h. The solution was then allowed to cool to RT and treated with
HCl (4.0 M solution in 1,4-dioxane, 129 mL, 516 mmol) dropwise. The
reaction mixture was then stirred at RT for 3 h. The mixture was
concentrated under reduced pressure and the material thus obtained
was diluted with EtOAc (2 L) and treated with sat. aq. NaHCO.sub.3
(2 L). The layers were separated and the aqueous layer was
extracted with EtOAc (2.times.1 L). The combined organic extracts
were washed with brine (1 L), dried over magnesium sulfate,
filtered and concentrated under reduced pressure to give a
light-yellow oil which was purified by silica gel chromatography
(50% EtOAc in DCM) gave compound 456G (90 g, 80%). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.34-7.32 (m, 1H), 7.11-7.09 (m, 1H),
7.03-7.01 (m, 1H), 4.88-4.86 (m, 1H), 3.21 (s, 3H), 3.17 (s, 3H)
2.40-2.30 (m, 5H), 2.15-2.00 (m, 3H). The NH.sub.2 peak was very
broad. MS (ESI+ve ion) m/z: [M+1]=242.2.
Preparation of
(S)-4-(2-fluoro-3-methylphenyl)-4-methyl-4H-1,3-thiazin-2-amine
(456H)
[1783] To a stirring solution of compound 456G (60 g, 249.4 mmol)
in THF (600 mL) at 0.degree. C. under nitrogen, was added benzoyl
isothiocyanate (36.9 mL, 274.6 mmol) dropwise. The reaction
temperature was maintained between 0-5.degree. C. during the
addition. The reaction mixture was allowed to stir at 0.degree. C.
for 20 min. The solvents were then removed under reduced pressure,
and the residue was chilled with an ice bath. Concentrated sulfuric
acid (120 mL) was then added dropwise. The resulting solution was
stirred for 2 h at 70.degree. C. The mixture was then cooled to
0.degree. C. and poured onto ice. To the slurry was added EtOAc
(5.0 L), and the biphasic solution was chilled to 0.degree. C. and
basified to pH.about.12 with very slow addition of a 10 M aqueous
NaOH solution. The organic layer was separated and the aqueous
layer was extracted with EtOAc (3.times.5 L). The combined organic
extracts were dried over Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (hexanes:EtOAc=4:1) to give compound
456H (18.0 g, 31% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.27-7.25 (m, 1H), 7.09-7.05 (m, 1H), 6.97 (t, J=7.6 Hz, 1H),
6.35-6.20 (m, 2H), 2.26 (s, 3H), 1.72 (s, 3H). The NH.sub.2 peak
was very broad. MS (ESI+ve ion) m/z: [M+1]=237.0.
Preparation of (S)-tert-butyl
(4-(2-fluoro-3-methylphenyl)-4-methyl-4H-1,3-thiazin-2-yl)carbamate
(456I)
[1784] To a solution of compound 456H (21 g, 89.6 mmol) in THF (200
mL) was added di-tert-butyl carbonate (42.7 g, 196.2 mmol) and DMAP
(0.54 g, 4.4 mmol) at RT. The reaction mixture was then heated at
50.degree. C. for 3 h. The resulting mixture was cooled to RT and
treated with water (1 L) and extracted with EtOAc (3.times.1 L).
The organic extracts were dried over sodium sulfate and
concentrated under reduced pressure. The residue was taken in mixed
solvents of THF:MeOH:water (200 mL:100 mL:100 mL) and treated with
lithium hydroxide monohydrate (11.19 g, 269.0 mmol). The reaction
mixture was heated at 50.degree. C. for 40 min. The resulting
mixture was then cooled to RT and diluted with water (1 L) and
extracted with EtOAc (3.times.1 L). The combined organic layers
were dried over sodium sulfate. The resulting mixture was
concentrated under reduced pressure, and the product thus obtained
was purified by flash chromatography using 10% EtOAc in hexanes to
afford compound 456I (22 g, 73%). .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.15-7.10 (m, 2H), 7.01-6.96 (m, 1H), 6.24-6.17 (m, 2H),
2.27 (s, 3H), 1.80 (s, 3H), 1.53 (s, 9H). NH peak was not observed.
MS (ESI+ve ion) m/z: [M+1]=337.0.
Preparation of (S)-tert-butyl
(4-(2-fluoro-3-methylphenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethyls-
ilyl)ethoxy)methyl)carbamate (456J)
[1785] To a solution of compound 456I (22 g, 65.4 mmol) in THF (250
mL) was added LiHMDS (1.0 M in THF, 72 mL, 72 mmol) at -78.degree.
C. The reaction mixture was then stirred for 15 min at -78.degree.
C. and then treated with SEM chloride (12.0 g, 72.0 mmol). The
reaction mixture was slowly warmed to RT and stirred for 3 h at RT.
The resulting mixture was quenched with saturated ammonium chloride
solution and extracted with EtOAc (3.times.1 L). The organic layers
were combined and dried over sodium sulfate. The product thus
obtained was purified by flash chromatography using 5% EtOAc in
hexanes to afford compound 456J (25 g, 82%). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.36 (t, J=7.7 Hz, 1H), 7.10 (t, J=6.9 Hz, 1H),
7.00 (t, J=7.5 Hz, 1H) 6.29 (d, J=9.3 Hz, 1H), 6.09 (dd, J=3.6 Hz,
9.3 Hz, 1H), 5.30 (d, J=10.4 Hz, 1H), 5.24 (d, J=10.4 Hz, 1H),
3.69-3.61 (m, 2H), 2.30 (s, 3H), 1.72 (s, 3H), 1.54 (s, 9H),
0.97-0.95 (m, 2H), 0.03 (s, 9H). MS (ESI+ve ion) m/z:
[M+1]=467.2.
Preparation of
(S)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-4-(2-
-fluoro-3-methylphenyl)-4-methyl-4H-1,3-thiazine-6-carboxylic acid
(456K)
[1786] To a solution of compound 456J (24.0 g, 51.4 mmol) in THF
(250 mL) at -78.degree. C. was added a solution of LDA (2 M in THF,
64.5 mL, 129 mmol) and the reaction mixture was stirred for 20 min
at -78.degree. C. Carbon dioxide gas was purged to the reaction
mixture for 5 min and the resulting mixture was warm to RT. The
resulting mixture was quenched with sat. NH.sub.4Cl solution (200
mL) and extracted with EtOAc (3.times.500 mL). The combined organic
layers were dried over sodium sulfate and concentrated under
reduced pressure. The product thus obtained was purified by silica
gel chromatography (50% EtOAc in hexanes) to afford compound 456K
(17 g, 65%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.33-7.28
(m, 1H), 7.10-7.02 (m, 2H), 6.98-6.93 (m, 1H), 5.27 (d, J=10.6 Hz,
1H), 5.18 (d, J=10.6 Hz, 1H), 3.68-3.64 (m, 2H), 2.27 (s, 3H), 1.72
(s, 3H), 1.51 (s, 9H), 0.99-0.89 (m, 2H), 0.03 (s, 9H). --COOH
proton was not observed. MS (ESI+ve ion) m/z: [M+1]=511.2.
Preparation of
(S)-methyl-2-((tert-butoxycarbonyl)((2-trimethylsilyl)ethoxy)methyl)amino-
)-4-(2-fluoro-3-methylphenyl)-4-methyl-4H-1,3-thiazine-6-carboxylate
(456L)
[1787] To a solution of compound 456K (17.0 g, 33.3 mmol) in DMF
(150 mL) at RT was added potassium carbonate (9.20 g, 66.6 mmol)
followed by iodomethane (2.91 mL, 46.6 mmol). After the mixture was
stirred for 3 h at RT, it was quenched with water (1 L) and
extracted with Et.sub.2O (3.times.500 mL). The combined organic
layers were dried over sodium sulfate and concentrated under
reduced pressure. The product thus obtained was purified by flash
chromatography using 5% EtOAc in hexanes to give compound 456L
(13.0 g, 74%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.36-7.30
(m, 1H), 7.15-7.10 (m, 2H), 7.00 (t, J=7.6 Hz, 1H), 5.31 (d, J=10.5
Hz, 1H), 5.22 (d, J=10.5 Hz, 1H), 3.82 (s, 3H), 3.68-3.64 (m, 2H),
2.28 (s, 3H), 1.75 (s, 3H), 1.53 (s, 9H), 0.92-0.89 (m, 2H), 0.02
(s, 9H). MS (ESI+ve ion) m/z: [M+1]=525.2.
Preparation of
(5S)-methyl-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)ami-
no)-5-(2-fluoro-3-methylphenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3--
ene-1-carboxylate (456M)
[1788] To a solution of trimethylsulfoxonium iodide (6.0 g, 27.3
mmol) in DMSO (100 mL) at RT was added potassium tert-butoxide
(3.06 g, 27.3 mmol). The resulting mixture was stirred for 30 min
and then it was cannulated to a solution of compound 456L in THF
(150 mL) at RT. The reaction mixture was stirred for 1 h at RT and
then it was quenched with sat. NH.sub.4Cl solution, and extracted
with DCM (3.times.250 mL). The combined organic layers were dried
over sodium sulfate and concentrated. The crude product was
purified by flash column chromatography using 5% EtOAc in hexanes
to afford compound 456M (7.5 g, 56%). .sup.1H NMR: (400 MHz,
CDCl.sub.3) .delta. 7.45 (m, 1H), 7.15-7.11 (m, 1H), 7.03 (t, J=7.6
Hz, 1H), 5.30 (d, J=10.8 Hz, 1H), 5.06 (d, J=10.8 Hz, 1H), 3.83 (s,
3H), 3.71-3.67 (m, 2H), 2.71-2.67 (m, 1H), 2.32 (s, 3H), 1.77 (s,
3H), 1.54 (s, 9H), 1.26-1.22 (m, 2H), 0.98-0.94 (m, 2H), 0.02 (s,
9H). MS (ESI+ve ion) m/z: [M+1]=539.1
(1S,5S,6S)-5-(5-Amino-2-fluoro-3-methylphenyl)-1-(methoxymethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (456)
##STR00277##
[1790] The title compound was prepared from 456M using the
procedures described for intermediate 208. LC/MS (ESI.sup.-)
m/z=310.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
6.81 (dd, J=3.03, 6.16 Hz, 1H), 6.39 (dd, J=2.93, 5.67 Hz, 1H),
3.65 (d, J=10.56 Hz, 1H), 3.40 (s, 3H), 3.28-3.35 (m, 1H), 2.20 (d,
J=2.35 Hz, 3H), 1.76 (dd, J=7.24, 9.00 Hz, 1H), 1.68 (d, J=1.37 Hz,
3H), 0.87 (dd, J=5.87, 9.59 Hz, 1H), 0.72-0.82 (m, 1H).
(1S,5S,6S)-3-Amino-5-(5-amino-2-methoxypyridin-3-yl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-ene-1-carbonitrile (457)
##STR00278##
[1791] Preparation of
(1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-3-((teRT-butoxycarbonyl)((2--
(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]he-
pt-3-ene-1-carboxylic acid (457A)
[1792] To a solution of (1S,5S,6S)-methyl
5-(5-bromo-2-fluoropyridin-3-yl)-3-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxylate (214J, 2.80 g, 4.63 mmol) in DMF (10 mL) was added
anhydrous sodium methoxide powder (2.50 g, 46.3 mmol) in small
portions. The resulting suspension was stirred at RT for 18 h, and
then it was diluted with water and acidified to pH 4 with 5 N HCl.
The solid that formed was filtered and dried to give the title
compound (457A, 2.07 g, 3.44 mmol, 74% yield). The product thus
obtained was used in next step without further purification. LCMS
(ESI.sup.+) m/z=604.2 (M+2H).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-carbamoyl-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carba-
mate (457B)
[1793] The title compound 457B, (0.82 g, 1.36 mmol, 82% yield) was
prepared according to the procedure described for intermediate 243A
using
(1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-3-((tert-butoxycarbonyl)((2--
(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]he-
pt-3-ene-1-carboxylic acid, 457A, (1.00 g, 1.66 mmol) and
1,1'-carbonyldiimidazole (0.40 g, 2.49 mmol). LCMS (ESI.sup.+)
m/z=602.1/603.1 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.:
8.12 (d, J=2.49 Hz, 1H), 7.87 (d, J=2.34 Hz, 1H), 6.57-6.93 (m,
1H), 5.47-5.70 (m, 1H), 5.39 (d, J=10.52 Hz, 1H), 5.09 (d, J=10.52
Hz, 1H), 3.99-4.03 (m, 3H), 3.66-3.74 (m, 2H), 2.50 (dd, J=7.75,
9.65 Hz, 1H), 1.76-1.87 (m, 4H), 1.54-1.58 (m, 9H), 1.01 (ddd,
J=1.61, 6.94, 9.72 Hz, 2H), 0.78 (dd, J=5.12, 7.60 Hz, 1H), -0.07
(s, 9H).
Preparation of
(1S,5S,6S)-3-amino-5-(5-bromo-2-methoxypyridin-3-yl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-ene-1-carboxamide (457C)
[1794] The title compound 457C, (0.50 g, 1.34 mmol, 100% yield) was
prepared according to the procedures described for intermediate
218C using tert-butyl
((1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-carbamoyl-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carba-
mate, 457B (0.80 g, 1.33 mmol). LC/MS (ESI.sup.+) m/z=370.0/372.9
(M+H).
Preparation of
(1S,5S,6S)-3-amino-5-(5-bromo-2-methoxypyridin-3-yl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-ene-1-carbonitrile (457D)
[1795] The title compound 457D, (0.20 g, 0.56 mmol, 42% yield) was
prepared according to the procedure described for intermediate 243D
using
(1S,5S,6S)-3-amino-5-(5-bromo-2-methoxypyridin-3-yl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-ene-1-carboxamide, 457C, (0.50 g, 1.34 mmol),
diisopropylethylamine (1.64 mL, 9.43 mmol), 2,2,2-trifluoroacetic
anhydride (0.75 mL, 5.39 mmol), and 2 M ammonia in MeOH. LCMS
(ESI.sup.+) m/z=353.1/355.0 (M+H). .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.: 8.11 (d, J=2.15 Hz, 1H), 7.95 (d, J=2.35 Hz,
1H), 5.20-4.20 (br.s, 2H), 4.01 (s, 3H), 2.75 (dd, J=8.02, 9.98 Hz,
1H), 1.76 (s, 3H), 1.56 (dd, J=6.06, 9.98 Hz, 1H), 1.04 (dd,
J=6.16, 7.92 Hz, 1H).
Preparation of
(1S,5S,6S)-3-amino-5-(5-amino-2-methoxypyridin-3-yl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-ene-1-carbonitrile (457)
[1796] The title compound 457, (0.05 g, 0.17 mmol, 30% yield) was
prepared according to the procedure described for intermediate 218
using
(1S,5S,6S)-3-amino-5-(5-bromo-2-methoxypyridin-3-yl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-ene-1-carbonitrile, 457D, (0.20 g, 0.56
mmol), sodium azide (0.14 g, 2.26 mmol), copper(i) iodide (11 mg,
0.05 mmol), (+)-sodium L-ascorbate (22 mg, 0.11 mmol),
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine and 1 M
trimethylphosphine solution in THF (1.13 mL, 1.13 mmol). LC/MS
(ESI.sup.+) m/z=290.2 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta.: 7.56 (d, J=2.78 Hz, 1H), 7.24-7.30 (m, 1H), 3.95 (s, 3H),
3.78-4.04 (br.s, 4H), 2.70 (dd, J=8.11, 9.87 Hz, 1H), 1.78 (s, 3H),
1.60 (dd, J=6.14, 10.08 Hz, 1H), 0.99 (dd, J=6.14, 7.89 Hz,
1H).
(1S,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-1-(methoxytrideuteriomethyl)-5-m-
ethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (458)
##STR00279##
[1797] Preparation of Compound 458A
[1798] To a stirred solution of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2,3-d-
ifluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(203I, 36 g, 66.3 mmol) in THF (300 mL) at RT was added lithium
borohydride (2.0 M in THF, 66.3 mL, 133 mmol). The vessel was then
charged with MeOH (21.50 mL, 531 mmol) and gas evolution was
evident with the reaction temperature rising to 33.degree. C. The
solution was stirred for 1 h, cooled to 0.degree. C., and then it
was slowly quenched with 150 mL of 1/2 sat. aqueous NH.sub.4Cl
added via addition funnel. The mixture was then extracted twice
with 2:1 heptane/EtOAc (500 mL). The combined organic layers were
washed with sat. NaCl (2.times.50 mL), 1 M HCl (100 mL), followed
again by sat NaCl (2.times.50 mL). The organic layer was dried over
MgSO.sub.4, filtered, concentrated under reduced pressure, and then
purified by silica gel chromatography (0-15% EtOAc/heptane) to
afford tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(458A, 27.2 g, 52.8 mmol, 80% yield) as a light colorless oil that
crystalized upon setting. LC/MS (ESI.sup.-) m/z=515.2
(M+H).sup.+.
Preparation of Compound 458B
[1799] To a stirred solution of tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(458A, 1.05 g, 2.040 mmol) in THF (10 mL) at 0.degree. C. was added
sodium bis(trimethylsilyl)amide (1.0 M in THF, 2.44 mL, 2.44 mmol)
dropwise at a rate that did not exceed an internal temp of
6.degree. C. After 15 min, trideuteriomethyl iodide (0.17 mL, 2.65
mmol) was added. The resulting mixture was warmed to 20.degree. C.
and stirred for 18 h. The reaction was then quenched with aq.
NH.sub.4Cl (5 mL) and diluted with water (10 mL). The mixture was
extracted with 2:1 heptane/EtOAc (50 mL). The organic layer was
then washed with 1 M HCl (5 mL) followed by sat. NaCl (2.times.5
mL). The organic layer was then dried over MgSO.sub.4. Filtration
followed by concentration under reduced pressure afforded
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(methoxytrideuteriomethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (458B, 1.02 g, 1.92 mmol, 94% yield) as a colorless oil.
LC/MS (ESI.sup.-) m/z=532.3 (M+H).sup.+.
Preparation of Compound 458C
[1800] To a 100 mL single neck round bottom flask containing
tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(methoxytrideuteriomethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (458B, 1.02 g, 1.92 mmol) at 0.degree. C. under nitrogen
was added sulfuric acid (3.58 mL, 67.10 mmol). After 15 min, the
reaction was removed from the cooling bath, swirled by hand, then
allowed to stir at 20.degree. C. for 30 min. The material was
chilled to 0.degree. C. and sodium nitrate (0.16 g, 1.92 mmol) was
added. The reaction was stirred for 15 min at 0.degree. C. and then
more sodium nitrate (0.16 g, 1.92 mmol) was added. The reaction was
stirred at 20.degree. C. for 1 h, and then it was added dropwise to
a mixture of wet ice (300 mL)/DCM (100 mL). After addition, water
(500 mL) was added, and to the rapidly stirred mixture, was added
potassium phosphate tribasic (14.25 g, 67.10 mmol) over 30 min
periods (pH.about.7). The organic layer was separated, and the
aqueous layer was extracted with DCM (2.times.20 mL). The combined
organic layers were dried over MgSO.sub.4, filtered, concentrated
under reduced pressure, and then it was purified via silica gel
chromatography (40 g) eluting the products with a gradient of 0-30%
EtOAc/DCM to afford
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-1-(methoxytrideuteriomethyl)-5--
methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (458C, 0.48 g,
1.38 mmol, 72% yield) as a yellow crystaline solid. LC/MS
(ESI.sup.-) m/z=347.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.47-8.52 (m, 1H), 7.98 (ddd, J=2.93, 6.31,
9.15 Hz, 1H), 4.53 (br. s., 2H), 3.63 (d, J=10.56 Hz, 1H), 3.38 (d,
J=10.56 Hz, 1H), 1.78 (t, J=7.73 Hz, 1H), 1.73 (s, 3H), 0.90 (dd,
J=6.06, 9.19 Hz, 1H), 0.79-0.84 (m, 1H).
Preparation of Compound 458
[1801] To a stirring solution of
(1S,5S,6S)-5-(2,3-difluoro-5-nitrophenyl)-1-(methoxytrideuteriomethyl)-5--
methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (458C, 480 mg,
1.38 mmol) in HOAc (4 mL) and TFA (1 mL) at 20.degree. C. was added
zinc (453 mg, 6.93 mmol) in 2 portions. After 1 h, the suspension
was filtered and the metalic residue was extensively washed with
DCM (20 mL). The filtrate was then added dropwise to a chilled
(0.degree. C.) mixture of 30% NH.sub.4OH (10 mL) and DCM (10 mL).
After separation of the organic and aqueous layers, the aqueous
layer was further extracted with DCM (5 mL). The combined organic
layers were dried over MgSO.sub.4 and concentrated under reduced
pressure to afford
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-1-(methoxytrideuteriomethyl)-5--
methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine as a yellow
film. LC/MS (ESI.sup.-) m/z=317.1 (M+H).sup.+.
tert-Butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-methyl-1-(methylcarbam-
oyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)m-
ethyl)carbamate (459)
##STR00280##
[1803] The title compound was synthesized according to the
procedures described for intermediate 221D, using methylamine to
react with
(1S,5S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethyl-
silyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-
-carboxylic acid 221A. LC/MS (ESI.sup.+) m/z=539 (M+H).sup.+.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 6.92-7.03 (m, 1H), 6.85
(dd, J=8.61, 11.54 Hz, 1H), 6.70 (dd, J=2.93, 6.65 Hz, 1H), 6.50
(td, J=3.37, 8.51 Hz, 1H), 5.42 (d, J=10.56 Hz, 1H), 5.10 (d,
J=10.76 Hz, 1H), 3.57-3.76 (m, 2H), 3.50 (br. s., 2H), 2.86 (d,
J=4.69 Hz, 3H), 2.16 (dd, J=7.73, 9.29 Hz, 1H), 1.94 (dd, J=5.09,
9.59 Hz, 1H), 1.80 (d, J=0.78 Hz, 3H), 1.55 (s, 9H), 0.92-1.02 (m,
2H), 0.85 (dd, J=5.28, 6.46 Hz, 1H), 0.02 (s, 9H).
(1S,5S,6S)-5-(5-Amino-2-methoxypyridin-3-yl)-1-(difluoromethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (460)
##STR00281##
[1804] Preparation of
tert-butyl((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-formyl-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (460A)
[1805] The title compound (7.59 g, 13.21 mmol, 76% yield) was
prepared according to the procedure described for intermediate 218A
using tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(hydroxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate, 214K, (10 g, 17.34 mmol), TEA (12.06 mL, 87 mmol) and
pyridine-sulfur trioxide complex (6.90 g, 43.40 mmol). LCMS
(ESI.sup.+) m/z=574.1/576.1 (M+H).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(difluoromethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate (460B)
[1806] The title compound (7.43 g, 12.45 mmol, 94% yield) was
prepared according to the procedure described for intermediate 218B
using tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-formyl-5-methyl-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(460A, 7.59 g, 13.21 mmol) and deoxo-fluor solution (8.51 mL, 46.2
mmol). LCMS (ESI.sup.+) m/z=596.0/598.1 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.: 8.16-8.34 (m, 2H), 5.51-6.03 (m, 1H),
5.33 (d, J=10.08 Hz, 1H), 5.06 (d, J=10.52 Hz, 1H), 3.56-3.83 (m,
2H), 2.18 (t, J=8.62 Hz, 1H), 1.76 (s, 3H), 1.55 (s, 9H), 1.13-1.40
(m, 2H), 0.95-1.09 (m, 2H), -0.06 (s, 9H).
Preparation of
(1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-(difluoromethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (460C)
[1807] To a solution of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluoropyridin-3-yl)-1-(difluoromethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl-
)carbamate, 460B, (4.68 g, 7.84 mmol) in DMF (15 mL) was added
sodium methoxide (4.24 g, 78 mmol) portionwise. The suspension was
stirred at RT for 30 min, diluted with water and extracted with
EtOAc (2.times.). The combined organic layers were dried and
concentrated under vacuum to afford tert-butyl
((1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-(difluoromethyl)-5-methyl-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate. The product thus obtained in 5 mL of dioxane was
treated with p-toluenesulfonic acid monohydrate (1.87 g, 9.86
mmol). The reaction was heated to 85.degree. C. for 2 h, and it was
then diluted with water and extracted with EtOAc (2.times.). The
combined organic layers were concentrated, and the residue was
purified by flash column chromatography on silica gel (0-5% MeOH in
DCM) to afford the title compound (460C, 0.55 g, 1.45 mmol, 73%
yield). LCMS (ESI.sup.+) m/z=378.0/380.1 (M+H).
Preparation of
(1S,5S,6S)-5-(5-amino-2-methoxypyridin-3-yl)-1-(difluoromethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (460)
[1808] The title compound (0.17 g, 0.54 mmol, 41% yield) was
prepared according to the procedure described for 218 using
(1S,5S,6S)-5-(5-bromo-2-methoxypyridin-3-yl)-1-(difluoromethyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (460C, 0.50 g, 1.32
mmol), sodium azide (0.34 g, 5.3 mmol),
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.04 mL, 0.26
mmol), copper(I) iodide (25 mg, 0.13 mmol), and 1 M
trimethylphosphine solution in THF (3.97 mL, 3.97 mmol). LC/MS
(ESI.sup.+) m/z=315.2 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta.: 7.56 (s, 1H), 7.23 (br. s., 1H), 5.35-5.93 (m, 1H), 3.94
(s, 3H), 3.39 (br. s., 2H), 2.12-2.21 (m, 1H), 1.72-1.84 (m, 3H),
1.53 (s, 2H), 1.29 (d, J=13.59 Hz, 1H), 0.70 (br. s., 1H). .sup.19F
NMR (377 MHz, DMSO-d.sub.6) .delta.: -116.63 (d, .sup.1J=276.2 Hz,
1 F), -119.21 (d, .sup.1J=276.2 Hz, 1 F).
(1S,5S,6S)-Methyl
3-(di-tert-butoxycarbonyl)amino-5-(2,3-difluoro-5aminophenyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-ene-1-(morpholino)methanone
(461)
##STR00282##
[1809] Preparation of Compound 461A
[1810] To a stirred solution of di-tert-butyl dicarbonate (3.82 g,
17.49 mmol) in THF (15 mL) was added (1S,5S,6S)-methyl
3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (237A, 2.5 g, 7.00 mmol) in THF (15 mL)
at 20.degree. C. followed by DMAP (0.02 g, 0.17 mmol). After 30
min, MeOH (5 mL) was added to the mixture followed by an aqueous
solution of lithium hydroxide monohydrate (0.88 g, 20.99 mmol) in
water (10 mL). The suspension was stirred for 36 h at 20.degree. C.
The reaction was then partitioned between 1:1 EtOAc/heptane (150
mL) and 0.5 M KH.sub.2PO.sub.4 (50 mL). The organic layer was
further washed with brine (2.times.25 mL). The organic layer was
then dried over MgSO.sub.4, and concentrated under reduced pressure
to afford (1S,5S,6S)-methyl
3-(di-tert-butoxycarbonyl)amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid (461A, 3.76
g, 6.92 mmol, 99% yield) as white solid. LC/MS (ESI.sup.-)
m/z=566.2 (M+Na).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.40 (ddd, J=2.93, 6.50, 9.54 Hz, 1H), 8.12-8.21 (m, 1H), 3.60-3.66
(m, 1H), 2.29 (t, J=7.43 Hz, 1H), 1.63-1.71 (m, 3H), 1.42-1.52 (m,
18H), 1.06 (dd, J=3.91, 9.19 Hz, 1H), 0.75 (dd, J=4.11, 6.85 Hz,
1H).
Preparation of Compound 461B
[1811] To a stirred solution of (1S,5S,6S)-methyl
3-(di-tert-butoxycarbonyl)amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid (461A, 270
mg, 0.49 mmol) and diisopropylethylamine (112 .mu.L, 0.646\mmol) in
DMF (2 mL) at 20.degree. C. was added HATU (246 mg, 0.64 mmol). The
resulting solution was stirred for 20 min followed by addition of
morpholine (60 .mu.L, 0.69 mmol). Ater 18 h, the reaction was
quenched with sat. NH.sub.4Cl (2 mL) and was then partitioned
between 2:1 EtOAc/heptane (30 mL) and water (75 mL). The organic
layer was further washed with water (75 mL) and brine (10 mL),
dried over MgSO.sub.4, and conentrated under reduced pressure. The
residue was purified by silica gel chromatography (20-50%
EtOAc/heptane) to afford (1S,5S,6S)-methyl
3-(di-tert-butoxycarbonyl)amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-ene-1-(morpholino)methanone (461B,
300 mg, 0.49 mmol) as a white foam. LC/MS (ESI.sup.-) m/z=636.2
(M+Na).sup.+.
Preparation of Compound 461
[1812] To a stirred solution of (1S,5S,6S)-methyl
3-(di-tert-butoxycarbonyl)amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-ene-1-(morpholino)methanone (461C,
300 mg, 0.49 mmol) in glacial HOAc (2 mL) was added zinc (160 mg,
2.44 mmol). After 45 min, the reaction mixture was filtered, and
the solid was washed with DCM (30 mL). The filtrate was then
chilled to 0.degree. C., and 30% NH.sub.4OH (5 mL) was slowly added
followed by water (50 mL). The organic layer was separated, washed
with brine (10 mL), dried over MgSO.sub.4, concentrated under
reduced pressure, and then purified by silica gel chromatography
(0-2.5% MeOH/DCM) to afford (1S,5S,6S)-methyl
3-(di-tert-butoxycarbonyl)amino-5-(2,3-difluoro-5aminophenyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-ene-1-(morpholino)methanone (461, 92
mg, 0.15 mmol, 32% yield) as a colorless film. LC/MS (ESI.sup.-)
m/z=605.2 (M+Na).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
6.62 (br. s., 1H), 6.48 (br. s., 1H), 3.70 (br. s., 8H), 2.43 (t,
J=8.41 Hz, 1H), 1.81 (s, 3H), 1.51 (s, 18H), 1.33 (dd, J=5.58, 9.49
Hz, 1H), 1.13 (t, J=6.75 Hz, 1H).
(1S,5S,6S)-5-(5-Amino-2,3-difluorophenyl)-1-(ethoxymethyl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-en-3-amine (462)
##STR00283##
[1814] The title compound was prepared in a manner analogous to
that described for intermediate 458 with the substitution of
iodoethane. LC/MS (ESI.sup.-) m/z=328.1 (M+H).sup.+.
(1S,5S,6S)-5-(5-Amino-2-fluoro-3-methylphenyl)-1-(difluoromethyl)-5-methyl-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine (463)
##STR00284##
[1816] The title compound was prepared from 456 M using the
procedures described for intermediate 211. LC/MS (ESI.sup.-)
m/z=316.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
6.57-6.64 (m, 1H), 6.39 (dd, J=3.03, 5.77 Hz, 1H), 5.48-5.81 (m,
1H), 3.44 (br. s., 2H), 2.20 (d, J=2.54 Hz, 3H), 1.93 (dd, J=7.34,
9.88 Hz, 1H), 1.73-1.76 (m, 3H), 1.33 (dd, J=6.16, 9.88 Hz, 1H),
0.79-0.86 (m, 1H).
(S)-5-(But-3-yn-2-yloxy)pyrazine-2-carboxylic acid (290)
##STR00285##
[1818] To a solution of (S)-(-)-3-butyn-2-ol (Alfa Aesar, 0.91 mL,
11.46 mmol) in THF (15 mL) was added potassium tert-butoxide (1.36
g, 12.11 mmol). The resulting solution was stirred at RT for 15 min
and then a solution of tert-butyl 5-chloropyrazine-2-carboxylate
(272A, 2.00 g, 9.32 mmol) in THF (20 mL) was added at 0.degree. C.
The mixture was gradually warmed to RT and stirred for 5 h. The
reaction was quenched with sat. NH.sub.4Cl, and the mixture was
then extracted with EtOAc. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The material thus
obtained was purified by silica gel chromatography (0-50% EtOAc in
heptane) to provide a mixture of the desired product 290A and
trans-esterification product 290B as a colorless oil (1.35 g).
[1819] A suspension of the above product (1.35 g), lithium
hydroxide hydrate (0.46 g, 10.97 mmol), THF (30 mL) and water (10
mL) was heated at 50.degree. C. until the conversion was complete.
1 N HCl (12 mL) was added, and the resulting mixture was extracted
with DCM. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to give
(S)-5-(but-3-yn-2-yloxy)pyrazine-2-carboxylic acid (290) as a white
solid (0.96 g, 54% yield over two steps). LC/MS (ESI.sup.+) m/z=193
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.01 (d,
J=1.17 Hz, 1H), 8.20 (d, J=0.98 Hz, 1H), 5.83 (dq, J=2.05, 6.68 Hz,
1H), 2.49 (d, J=2.15 Hz, 1H), 1.71 (d, J=6.65 Hz, 3H).
(R)-5-(But-3-yn-2-yloxy)pyrazine-2-carboxylic acid (291)
##STR00286##
[1821] The title compound was synthesized according to the
procedures described for intermediate 290, using (R)-but-3-yn-2-ol
to react with tert-butyl 5-chloropyrazine-2-carboxylate 272A. LC/MS
(ESI.sup.+) m/z=193 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.01 (d, J=1.17 Hz, 1H), 8.21 (d, J=1.17 Hz,
1H), 5.83 (dq, J=2.05, 6.68 Hz, 1H), 2.50 (d, J=1.96 Hz, 1H), 1.71
(d, J=6.85 Hz, 3H).
(S)-5-((1-Methoxypropan-2-yl)oxy)pyrazine-2-carboxylic acid
(292)
##STR00287##
[1823] The title compound was synthesized according to the
procedures described for intermediate 290, using
(S)-(+)-1-methoxy-2-propanol to react with tert-butyl
5-chloropyrazine-2-carboxylate 272A. LC/MS (ESI.sup.+) m/z=213
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.95 (d,
J=1.37 Hz, 1H), 8.17 (d, J=1.37 Hz, 1H), 5.53 (dquin, J=3.72, 6.36
Hz, 1H), 3.52-3.68 (m, 2H), 3.40 (s, 3H), 1.39 (d, J=6.46 Hz,
3H).
5-((1,1,1-Trifluoropropan-2-yl)oxy)pyrazine-2-carboxylic acid
(293)
##STR00288##
[1825] The title compound was synthesized according to the
procedures described for intermediate 290, using
1,1,1-trifluoropropan-2-ol to react with tert-butyl
5-chloropyrazine-2-carboxylate 272A. LC/MS (ESI.sup.+) m/z=237
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.85-9.14
(m, 1H), 8.24-8.38 (m, 1H), 5.82 (m, 1H), 1.57 (d, J=6.46 Hz,
3H).
5-((3-Methyl-1,2,4-oxadiazol-5-yl)methoxy)pyrazine-2-carboxylic
acid (294)
##STR00289##
[1827] The title compound was synthesized according to the
procedures described for intermediate 274, using
(3-methyl-1,2,4-oxadiazol-5-yl)methanol to react with tert-butyl
5-chloropyrazine-2-carboxylate 272A. LC/MS (ESI.sup.+) m/z=237
(M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.97 (d,
J=1.17 Hz, 1H), 8.39 (d, J=1.17 Hz, 1H), 5.70 (s, 2H), 2.43 (s,
3H).
(1S,5S,6S)-3-((tert-Butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino-
)-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid
(295)
##STR00290##
[1828] (1S,5S,6S)-Methyl
5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late (295A)
[1829] The title compound (4.27 g, 7.91 mmol, 93% yield) was
prepared according to the procedure described for intermediate 218
using (1S,5S,6S)-methyl
5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late, 217I, (5.16 g, 8.55 mmol), sodium azide (2.78 g, 42.7 mmol),
copper(i) iodide (0.24 g, 1.282 mmol),
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (0.404 ml, 2.56
mmol), (+)-sodium L-ascorbate (0.508 g, 2.56 mmol) and 1.0 M
trimethylphosphine solution in THF (17.10 ml, 17.10 mmol). LCMS
(ESI.sup.+) m/z=540.2 (M+H).
(1S,5S,6S)-Methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2-flu-
oro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (295B)
[1830] To a mixture of (1S,5S,6S)-methyl
5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late, 295A, (4.27 g, 7.91 mmol),
5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxylic acid, 272, (2.28 g,
10.28 mmol) in DMF (15 mL) was added TEA (3.30 mL, 23.73 mmol) and
HATU (6.02 g, 15.82 mmol). The reaction was stirred at RT for 2 h
and was then diluted with water and extracted with EtOAc
(2.times.). The organic layers were combined and concentrated, and
the product was isolated using silica gel column chromatography
(0-20% EtOAc/heptane) to afford the title compound (5.16 g, 6.94
mmol, 88% yield). LCMS (ESI.sup.+) m/z=744.2 (M+H). .sup.1H NMR
(300 MHz, CHLOROFORM-d) .delta. 9.48 (s, 1H), 9.05 (s, 1H), 8.31
(s, 1H), 7.95-8.02 (m, 1H), 7.73 (dd, J=2.63, 6.72 Hz, 1H), 7.14
(dd, J=8.99, 11.62 Hz, 1H), 5.34 (d, J=10.52 Hz, 1H), 5.10 (d,
J=10.52 Hz, 1H), 4.89 (q, J=8.18 Hz, 2H), 3.82 (s, 3H), 3.67-3.78
(m, 2H), 2.71 (t, J=8.70 Hz, 1H), 1.79 (s, 3H), 1.56 (s, 9H),
1.47-1.54 (m, 2H), 1.21-1.36 (m, 1H), 0.94-1.02 (m, 2H), 0.00 (s,
9H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta. -73.61 (s, 3 F),
-116.70 (s, 1 F).
[1831] Compound 295 (1.3 g, 1.781 mmol, 96% yield) was prepared
according to the procedure for 221A using (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2-flu-
oro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate, 295B, (1.37 g,
1.85 mmol). LCMS (ESI.sup.+) m/z=730.1 (M+H).
5-(2,2,2-Trifluoroethoxy)picolinic acid (296)
##STR00291##
[1833] To a solution of methyl 5-hydroxypicolinate (0.50 g, 3.27
mmol, Frontier Scientific) in DMF (5 mL) were added cesium
carbonate (1.38 g, 4.24 mmol) and 2,2,2-trifluoroethyl
trifluoromethanesulfonate (0.91 mL, 3.92 mmol), The resulting
suspension was stirred at RT for 1 h. The reaction mixture was then
diluted with water and EtOAc. The organic layer was washed with
brine before drying over magnesium sulfate and concentrating under
reduced pressure to afford methyl
5-(2,2,2-trifluoroethoxy)picolinate as a yellow oil, which was used
directly in the next step without further purification. M/S
m/z=236.0 [M+H].sup.+.
[1834] The methyl 5-(2,2,2-trifluoroethoxy)picolinate from the
above reaction was taken up in THF (5 mL) and lithium hydroxide
(2.0 M, 4.90 mL, 9.80 mmol) was added. The reaction was stirred at
RT for 16 h. The resulting mixture was diluted with water and
acidified with 1.0 N HCl (aq) solution until pH=1 (by pH paper).
The solution was extracted with DCM, and the organic layer was
washed with brine, dried over magnesium sulfate and concentrated
under reduced pressure to afford 5-(2,2,2-Trifluoroethoxy)picolinic
acid (296) (0.19 g, 0.87 mmol, 27% yield) as a white solid. M/S
m/z=221.9 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
ppm 5.00 (q, J=8.77 Hz, 2H) 7.66 (dd, J=8.77, 2.92 Hz, 1H) 8.07 (d,
J=8.77 Hz, 1H) 8.50 (d, J=2.92 Hz, 1H) 13.00 (br., 1H).
General Amide Formation Procedures:
[1835] Method A, Method B, Method D, Method F1/2, Method H, and
Method J were used to couple an aniline core intermediate to a
desired acid as presented herein, to prepare the final compounds of
the invention.
General SNAr Amination Procedures:
[1836] Method C, Method E and Method G were used for the SNAr
displacement of the X in ArX intermediate (X=Cl or Br) with a
desired aniline core intermediate as presented herein, to prepare
the final compounds of the invention.
Method A: Propylphosphonic Anhydride (T3P) Procedure in DMF as
Solvent
Example 3: Synthesis of
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide
##STR00292##
[1838] To a solution of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicycl-
o[4.1.0]hept-3-en-3-amine (intermediate 204) (72 mg, 0.27 mmol) and
5-cyano-3-methylpicolinic acid (intermediate 267) (65 mg, 0.40
mmol) in DMF (5 mL) at 0.degree. C. was added propylphosphonic
anhydride solution (50 wt. % in EtOAc, 340 .mu.L, 0.53 mmol). The
reaction was stirred at 0.degree. C. for 30 min. LC/MS showed the
presence of the starting aniline (204). Another 34 .mu.L of
propylphosphonic anhydride solution (50 wt. % in EtOAc) was added.
The reaction was stirred at 0.degree. C. for another 30 min. It was
quenched with saturated NaHCO.sub.3 solution and extracted with DCM
(2.times.). The combined organic extracts were concentrated. The
residue was purified by flash chromatography (12 g ISCO RediSepRf
column, 0-60% EtOAc/hexanes) to provide
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4-fluorophenyl)-5-cyano-3-methylpicolinamide (Example 3,
72 mg, 0.17 mmol, 65% yield) as a white powder. MS m/z=414.2
[M+H].sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.=10.00 (s,
1H), 8.69 (d, J=1.4 Hz, 1H), 8.02 (ddd, J=3.0, 4.1, 8.8 Hz, 1H),
7.93 (d, J=1.2 Hz, 1H), 7.62 (dd, J=2.8, 6.7 Hz, 1H), 7.09 (dd,
J=8.8, 11.5 Hz, 1H), 4.98-4.67 (m, 2H), 4.59 (br. s., 2H), 2.85 (s,
3H), 2.34-2.25 (m, 1H), 1.93 (ddt, J=2.1, 6.7, 9.1 Hz, 1H),
1.11-1.02 (m, 1H), 0.54 (q, J=5.7 Hz, 1H).
[1839] Using procedures analogous or similar to the general
amidation Method A described above, the appropriate aniline and
carboxylic acid intermediates were reacted to provide the 44
examples listed in Table 1 and Table 1'.
TABLE-US-00002 TABLE 1 Observed Ex. No. Chemical Structure [M +
H].sup.+ 1 ##STR00293## 409.1 2 ##STR00294## 399.9 4 ##STR00295##
406.1 5 ##STR00296## 427.0 6 ##STR00297## 409.1 7 ##STR00298##
406.1 8 ##STR00299## 423.0 11 ##STR00300## 418.1 13 ##STR00301##
432.0 14 ##STR00302## 400.1 15 ##STR00303## 455.1 16 ##STR00304##
424.1 17 ##STR00305## 438.0 18 ##STR00306## 427.1 19 ##STR00307##
414.2 20 ##STR00308## 448.1 23 ##STR00309## 430.0 29 ##STR00310##
453.0 40 ##STR00311## 453.0 61 ##STR00312## 460.1 69 ##STR00313##
427.0 71 ##STR00314## 459.0 74 ##STR00315## 473.1 77 ##STR00316##
444.0 85 ##STR00317## 487.1 102 ##STR00318## 462.0 603 ##STR00319##
459.1 655 ##STR00320## 442 704 ##STR00321## 457 708 ##STR00322##
554 710 ##STR00323## 471 711 ##STR00324## 485 748 ##STR00325##
445.1 749 ##STR00326## 478.1 751 ##STR00327## 553.1 785
##STR00328## 476 790 ##STR00329## 480 906 ##STR00330## 451 910
##STR00331## 517 953 ##STR00332## 542.2 954 ##STR00333## 521.2 955
##STR00334## 502.2 956 ##STR00335## 476.1 959 ##STR00336##
497.1
TABLE-US-00003 TABLE 1' Ex. No. .sup.1H-NMR Chemical Name 1 .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. = 9.82
N-(3-((1S,5S,6S)-3-amino-5- (br. s., 1 H), 8.57-8.52 (m, 1 H), 8.24
(d, J = 8.4 (fluoromethyl)-2-thia-4- Hz, 1 H), 8.01 (ddd, J = 2.9,
4.1, 8.8 Hz, 1 H), azabicyclo[4.1.0]hept-3-en-5- 7.87 (dd, J = 2.3,
8.4 Hz, 1 H), 7.69 (dd, J = 2.8, yl)-4-fluorophenyl)-5-chloro-2-
6.7 Hz, 1 H), 7.09 (dd, J = 8.9, 11.6 Hz, 1 H), pyridinecarboxamide
4.98-4.83 (m, 1 H), 4.82-4.67 (m, 1 H), 4.60 (br s, 1 H), 2.30
(ddd, J = 5.1, 7.5, 8.9 Hz, 1 H), 1.93 (ddt, J = 2.0, 6.8, 9.1 Hz,
1 H), 1.60 (br s, 1 H), 1.11-1.03 (m, 1H), 0.55 (q, J = 5.8 Hz, 1
H). 2 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.85
N-(3-((1S,5S,6S)-3-amino-5- (s, 1H), 8.88 (d, J = 1.17 Hz, 1H),
8.42 (d, J = 8.04 (fluoromethyl)-2-thia-4- Hz, 1H), 8.20 (dd, J =
1.97, 8.11 Hz, 1H), 7.98- azabicyclo[4.1.0]hept-3-en-5- 8.07 (m,
1H), 7.73 (dd, J = 2.85, 6.80 Hz, 1H),
yl)-4-fluorophenyl)-5-cyano-2- 7.12 (dd, J = 8.92, 11.55 Hz, 1H),
4.19-5.32 (m, pyridinecarboxamide 4H), 2.25-2.37 (m, 1H), 1.87-2.00
(m, 1H), 1.03- 1.15 (m, 1H), 0.56 (q, J = 5.89 Hz, 1H). 4 .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 9.43-
N-(3-((1S,5S,6S)-3-amino-5- 9.56 (m, 1H), 9.03 (s, 1H), 8.16 (s,
1H), 7.94-8.05 (fluoromethyl)-2-thia-4- (m, 1H), 7.68 (dd, J =
2.84, 6.75 Hz, 1H), 7.10 (dd, azabicyclo[4.1.0]hept-3-en-5- J =
8.80, 11.54 Hz, 1H), 4.65-5.00 (m, 2H), 4.08
yl)-4-fluorophenyl)-5-methoxy- (s, 3H), 2.23-2.37 (m, 1H),
1.85-2.01 (m, 1H), 2-pyrazinecarboxamide 1.05-1.18 (m, 1H),
0.48-0.61 (m, 1H) 5 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
10.80 (s, N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.80 (d, J = 1.80 Hz, 1
H) 8.22 (dd, J = 8.61, (fluoromethyl)-2-thia-4- 2.35 Hz, 1 H) 8.17
(d, J = 8.40 Hz, 1 H) 7.99 (ddd, azabicyclo[4.1.0]hept-3-en-5- J =
12.37, 6.80, 2.54 Hz, 1 H) 7.89-7.93 (m, 1 H)
yl)-4,5-difluorophenyl)-5- 6.25 (s, 2 H) 4.74 (d, J = 47.73 Hz, 2
H) 2.38-2.45 chloro-2-pyridinecarboxamide (m, 1 H) 1.73-1.81 (m, 1
H) 1.06 (ddd, J = 8.80, 7.63, 5.28 Hz, 1 H) 0.46 (q, J = 5.15 Hz, 1
H) 6 .sup.1H NMR (400 MHz, CHLRORFORM-d) .delta. 9.69-
N-(3-((1S,5S,6S)-3-amino-5- 9.98 (m, 1H), 8.57 (d, J = 2.15 Hz,
1H), 8.25 (d, methyl-2-thia-4- J = 8.41 Hz, 1H), 8.02-8.12 (m, 1H),
7.90 (dd, azabicyclo[4.1.0]hept-3-en-5- J = 2.35, 8.41 Hz, 1H),
7.37-7.49 (m, 1H), 4.33 (br. yl)-4,5-difluorophenyl)-5- s., 2H),
2.21 (dt, J = 5.09, 8.31 Hz, 1H), 1.90-2.01
chloro-2-pyridinecarboxamide (m, 1H), 1.77 (s, 3H), 0.92 (dd, J =
7.43, 14.87 Hz, 1H), 0.63 (q, J = 5.87 Hz, 1H) 7 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 10.56 (s, N-(3-((1S,5S,6S)-3-amino-5- 1
H), 8.89 (d, J = 1.37 Hz, 1 H), 8.41 (d, J = 1.17 methyl-2-thia-4-
Hz, 1 H), 7.85-7.93 (m, 2 H), 5.91 (s, 2 H), 4.02
azabicyclo[4.1.0]hept-3-en-5- (s, 3 H), 2.29-2.35 (m, 1 H),
1.67-1.74 (m, 1 yl)-4,5-difluorophenyl)-5- H), 1.65 (s, 3 H),
0.83-0.90 (m, 1 H), 0.48 (q, methoxy-2-pyrazinecarboxamide J = 5.15
Hz, 1 H) 8 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.65 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H), 8.57 (d, J = 1.96 Hz, 1 H), 8.02
(d, J = 1.56 methyl-2-thia-4- Hz, 1 H), 7.91-7.95 (m, 1 H),
7.68-7.73 (m, 1 azabicyclo[4.1.0]hept-3-en-5- H), 5.92 (s, 2 H),
2.56 (s, 3 H), 2.29-2.36 (m, 1 yl)-4,5-difluorophenyl)-5- H), 1.73
(q, J = 7.82 Hz, 1 H), 1.64 (s, 3 H), 0.82- chloro-3-methyl-2- 0.90
(m, 1 H), 0.46 (q, J = 5.22 Hz, 1 H) pyridinecarboxamide 11 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. ppm 10.96 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 9.22 (d, J = 1.17 Hz, 1 H) 8.60
(dd, J = 8.22, (fluoromethyl)-2-thia-4- 1.96 Hz, 1 H) 8.30 (d, J =
8.22 Hz, 1 H) 7.99 (ddd, azabicyclo[4.1.0]hept-3-en-5- J = 12.18,
6.70, 2.25 Hz, 1 H) 7.91-7.96 (m, 1 H)
yl)-4,5-difluorophenyl)-5-cyano- 6.25 (s, 2 H) 4.74 (d, J = 47.54
Hz, 2 H) 2.38-2.46 2-pyridinecarboxamide (m, 1 H) 1.73-1.81 (m, 1
H) 1.06 (td, J = 8.07, 5.38 Hz, 1 H) 0.46 (q, J = 5.35 Hz, 1 H) 13
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.87 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.98 (d, J = 1.17 Hz, 1 H) 8.40
(d, J = 0.78 Hz, (fluoromethyl)-2-thia-4- 1 H) 7.96 (ddd, J =
12.18, 6.80, 2.54 Hz, 1 H) 7.68- azabicyclo[4.1.0]hept-3-en-5- 7.73
(m, 1 H) 6.24 (s, 2 H) 4.73 (d, J = 47.54 Hz,
yl)-4,5-difluorophenyl)-5-cyano- 2 H) 2.56 (s, 3 H) 2.37-2.44 (m, 1
H) 1.75 (q, 3-methyl-2-pyridinecarboxamide J = 7.96 Hz, 1 H) 1.04
(td, J = 8.22, 5.28 Hz, 1 H) 0.41 (q, J = 5.28 Hz, 1 H) 14 .sup.1H
NMR (400 MHz, CHLOROFORM-d) Shift N-(3-((1S,5S,6S)-3-amino-5- 9.88
(s, 1H), 8.85-8.94 (m, 1H), 8.41-8.48 (m, methyl-2-thia-4- 1H),
8.17-8.26 (m, 1H), 8.07 (ddd, J = 2.84, 6.75,
azabicyclo[4.1.0]hept-3-en-5- 11.74 Hz, 1H), 7.43 (td, J = 2.57,
5.23 Hz, 1H), yl)-4,5-difluorophenyl)-5-cyano- 2.17-2.30 (m, 1H),
1.92-2.02 (m, 1H), 1.75-1.80 2-pyridinecarboxamide (m, 3H),
0.89-0.98 (m, 1H), 0.62 (q, J = 5.87 Hz, 1H) 15 .sup.1H NMR (400
MHz, CHLOROFORM-d) Shift N-(3-((1S,5S,6S)-3-amino-5- 10.06 (br. s.,
1H), 8.32 (s, 1H), 8.01-8.13 (m, 1H), methyl-2-thia-4- 7.42 (s,
1H), 7.33 (br. s., 1H), 6.42-6.86 (m, 1H),
azabicyclo[4.1.0]hept-3-en-5- 2.84 (s, 3H), 2.15-2.28 (m, 1H),
1.88-2.01 (m, yl)-4,5-difluorophenyl)-5- 1H), 1.77 (s, 3H),
0.85-0.97 (m, 1H), 0.63 (q, (difluoromethoxy)-3-methyl-2- J = 5.80
Hz, 1H) pyridinecarboxamide 16 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 10.62 (s, N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.90 (d, J =
0.98 Hz, 1 H) 8.42 (d, J = 1.17 Hz, (fluoromethyl)-2-thia-4- 1 H)
7.96 (ddd, J = 12.37, 6.70, 2.45 Hz, 1 H) 7.87-
azabicyclo[4.1.0]hept-3-en-5- 7.91 (m, 1 H) 6.23 (s, 2 H) 4.73 (d,
J = 47.54 Hz, yl)-4,5-difluorophenyl)-5- 2 H) 4.03 (s, 3 H)
2.37-2.44 (m, 1 H) 1.71-1.79 methoxy-2-pyrazinecarboxamide (m, 1 H)
1.02-1.09 (m, 1 H) 0.45 (q, J = 5.28 Hz, 1 H) 17 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 10.56 (s, N-(3-((1S,5S,6S)-3-amino-5- 1
H) 8.24 (s, 1 H) 7.97 (ddd, J = 12.42, 6.85, 2.45
(fluoromethyl)-2-thia-4- Hz, 1 H) 7.72-7.76 (m, 1 H) 6.23 (s, 2 H)
4.72 azabicyclo[4.1.0]hept-3-en-5- (d, J = 47.54 Hz, 2 H) 4.00 (s,
3 H) 2.77 (s, 3 H) yl)-4,5-difluorophenyl)-5- 2.37-2.44 (m, 1 H)
1.75 (q, J = 8.15 Hz, 1 H) 1.01- methoxy-3-methyl-2- 1.08 (m, 1 H)
0.43 (q, J = 5.28 Hz, 1 H) pyrazinecarboxamide 18 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-5- 10.87
(s, 1 H) 8.79 (d, J = 1.76 Hz, 1 H) 8.12-8.24
(fluoromethyl)-2-thia-4- (m, 2 H) 7.94-8.07 (m, 2 H) 6.19 (s, 2 H)
4.73 azabicyclo[4.1.0]hept-3-en-5- (dd, J = 47.54, 8.61 Hz, 1 H)
4.49 (dd, J = 47.73, yl)-4,5-difluorophenyl)-5- 8.22 Hz, 1 H)
2.41-2.48 (m, 1 H) 1.86-1.96 (m, chloropicolinamide 1 H) 1.04-1.15
(m, 1 H) 0.84 (q, J = 5.15 Hz, 1 H) 19 .sup.1H NMR (400 MHz,
CHLOROFORM-d) Shift N-(3-((1S,5S,6S)-3-amino-5- 10.06 (s, 1H), 8.72
(d, J = 1.17 Hz, 1H), 8.07 (ddd, methyl-2-thia-4- J = 2.84, 6.75,
11.74 Hz, 1H), 7.95 (s, 1H), 7.31- azabicyclo[4.1.0]hept-3-en-5-
7.41 (m, 1H), 2.88 (s, 3H), 2.22 (dt, J = 5.09, 8.41
yl)-4,5-difluorophenyl)-5-cyano- Hz, 1H), 1.95 (td, J = 7.09, 8.90
Hz, 1H), 1.76 (s, 3-methyl-2-pyridinecarboxamide 3H), 0.84-0.98 (m,
1H), 0.62 (q, J = 5.74 Hz, 1H) 20 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 10.67 (s, N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.92 (d, J =
1.17 Hz, 1 H) 8.50 (d, J = 1.17 Hz, (fluoromethyl)-2-thia-4- 1 H)
7.97 (ddd, J = 12.32, 6.75, 2.64 Hz, 1 H) 7.89-
azabicyclo[4.1.0]hept-3-en-5- 7.93 (m, 1 H) 6.24 (s, 2 H) 5.16 (d,
J = 2.35 Hz, 2 yl)-4,5-difluorophenyl)-5-(2- H) 4.74 (d, J = 47.34
Hz, 2 H) 3.66 (t, J = 2.45 Hz, 1 propyn-1-yloxy)-2- H) 2.38-2.45
(m, 1 H) 1.72-1.80 (m, 1 H) 1.06 pyrazinecarboxamide (ddd, J =
8.85, 7.58, 5.09 Hz, 1 H) 0.46 (q, J = 5.28 Hz, 1 H) 23 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. ppm 10.60 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.90, (d, J = 1.17 Hz, 1 H), 8.48
(d, J = 0.98 methyl-2-thia-4- Hz, 1 H), 7.85-7.93 (m, 2 H), 5.92
(br. s., 2 H), azabicyclo[4.1.0]hept-3-en-5- 5.14 (d, J = 2.35 Hz,
2 H), 3.64 (t, J = 2.35 Hz, 1 H), yl)-4,5-difluorophenyl)-5-(2-
2.32 (td, J = 8.26, 4.99 Hz, 1 H), 1.68-1.74 (m, 1
propyn-1-yloxy)-2- H), 1.65 (s, 3 H), 0.87 (td, J = 8.12, 5.28 Hz,
1 H), pyrazinecarboxamide 0.48 (q, J = 5.28 Hz, 1 H) 29 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.74 (br., N-(3-((1S,5S,6S)-3-amino-1-
1H), 8.79 (d, J = 1.96 Hz, 1H), 8.14-8.23 (m, 2H),
(methoxymethyl)-5-methyl-2- 7.87-7.97 (m, 2H), 6.00 (br., 2H), 3.57
(d, thia-4-azabicyclo[4.1.0]hept-3- J = 10.95 Hz, 1H), 3.34 (m,
1H), 3.33 (s, 3H), 1.58 en-5-yl)-4,5-difluorophenyl)-5- (m, 1H),
1.66 (s, 3H), 0.90 (m, 1H), 0.65 (m, 1H)
chloro-2-pyridinecarboxamide 40 .sup.1H NMR (DMSO-d6) .delta.:
10.58 (s, 1H), 8.78 (d, N-(3-((1S,5S,6S)-3-amino-5- J = 2.0 Hz,
1H), 8.09-8.24 (m, 2H), 8.02 (d, J = 4.9 (fluoromethyl)-1- Hz, 1H),
7.83 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 11.7,
(methoxymethyl)-2-thia-4- 8.8 Hz, 1H), 6.25 (s, 2H), 4.57-4.78 (m,
2H), azabicyclo[4.1.0]hept-3-en-5- 3.32-3.60 (m, 2H), 3.28 (s, 3H),
1.64 (t, J = 8.2 Hz, yl)-4-fluorophenyl)-5-chloro-2- 1H), 1.04 (dd,
J = 9.3, 5.4 Hz, 1H), 0.58 (t, J = 5.8 pyridinecarboxamide Hz, 1H)
61 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.62 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.92 (d, J = 1.37 Hz, 1H), 8.50 (d, J =
1.37 Hz, 1H), (hydroxymethyl)-5-methyl-2- 7.89-7.98 (m, 2H), 5.95
(s, 2H), 5.16 (d, J = 2.35 thia-4-azabicyclo[4.1.0]hept-3- Hz, 2H),
5.05 (t, J = 5.97 Hz, 1H), 3.66 (t, J = 2.35
en-5-yl)-4,5-difluorophenyl)-5- Hz, 1H), 3.55 (dd, J = 6.36, 11.64
Hz, 1H), 3.45 (2-propyn-1-yloxy)-2- (dd, J = 5.58, 11.64 Hz, 1H),
1.63 (m, 1H), 1.61 (s, pyrazinecarboxamide 3H), 0.86 (dd, J = 5.09,
9.19 Hz, 1H), 0.57 (t, J = 5.77 Hz, 1H). 69 .sup.1H NMR (300 MHz,
CDCl3) Shift = 9.86 (br. s., N-(3-((1R,5S,6R)-3-amino-7,7- 1H),
8.58 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 7.9 Hz,
difluoro-5-methyl-2-thia-4- 1H), 8.06 (ddd, J = 2.8, 4.2, 8.9 Hz,
1H), 7.90 (dd, azabicyclo[4.1.0]hept-3-en-5- J = 2.3, 8.3 Hz, 1H),
7.76 (dd, J = 2.8, 6.9 Hz, 1H), yl)-4-fluorophenyl)-5-chloro-2-
7.12 (dd, J = 8.8, 11.8 Hz, 1H), 2.93 (dd, J = 8.3,
pyridinecarboxamide 13.1 Hz, 1H), 2.79-2.64 (m, 1H), 1.73 (s, 3H)
71 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.56 (br.,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.45 (d, J = 2.54 Hz, 1H), 8.15
(d, J = 8.80 Hz, (hydroxymethyl)-5-methyl-2- 1H), 7.915 (m, 1H),
7.88 (br., 1H), 7.69 (dd, thia-4-azabicyclo[4.1.0]hept-3- J = 2.64,
8.71 Hz, 1H), 5.97 (br., 2H), 5.00-5.11
en-5-yl)-4,5-difluorophenyl)-5- (m, 3H), 3.72 (s, 1H), 3.55 (m,
1H), 3.46 (m, 1H), (2-propyn-1-yloxy)-2- 1.66 (m, 1H), 1.61 (s,
3H), 0.87 (m, 1H), 0.59 (m, pyridinecarboxamide 1H). 74 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. ppm 10.54 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1 H), 8.43 (d, J = 2.74 Hz, 1 H), 8.13
(d, J = 8.61 (methoxymethyl)-5-methyl-2- Hz, 1 H), 7.89-7.99 (m, 1
H), 7.86 (d, J = 5.87 thia-4-azabicyclo[4.1.0]hept-3- Hz, 1 H),
7.67 (dd, J = 8.80, 2.93 Hz, 1 H), 6.00
en-5-yl)-4,5-difluorophenyl)-5-
(br. s., 2 H), 5.04 (d, J = 2.35 Hz, 2 H), 3.71 (t,
(2-propyn-1-yloxy)-2- J = 2.35 Hz, 1 H), 3.56 (d, J = 10.95 Hz, 1
H), 3.36 pyridinecarboxamide (d, J = 11.15 Hz, 1 H), 3.29-3.32 (m,
3 H), 1.56- 1.68 (m, 4 H), 0.90 (br. s., 1 H), 0.66 (d, J = 5.28
Hz, 1 H) 77 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.55 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H), 8.29 (s, 1 H), 7.91 (ddd, J =
12.42, 6.75, 2.54 methyl-2-thia-4- Hz, 1 H), 7.72 (d, J = 5.87 Hz,
1 H), 5.92 (s, 2 H), azabicyclo[4.1.0]hept-3-en-5- 5.11 (d, J =
2.35 Hz, 2 H), 3.61 (t, J = 2.35 Hz, 1 H),
yl)-4,5-difluorophenyl)-3- 2.75 (s, 3 H) 2.29-2.35 (m, 1 H),
1.67-1.78 (m, methyl-5-(2-propyn-1-yloxy)-2- 1 H), 1.64 (s, 3 H),
0.86 (td, J = 8.07, 5.38 Hz, 1 pyrazinecarboxamide H), 0.46 (q, J =
5.28 Hz, 1 H) 85 .sup.1H NMR (400 MHz, CHLOROFORM-d) Shift
N-(3-((1S,5S,6S)-3-amino-1- 10.10 (s, 1H), 8.17 (d, J = 2.54 Hz,
1H), 8.01-8.11 (hydroxymethyl)-5-methyl-2- (m, 1H), 7.29 (br. s.,
1H), 7.16 (d, J = 2.35 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1H),
4.55-4.82 (m, 2H), 3.59-3.80 (m, 2H), 2.80
en-5-yl)-4,5-difluorophenyl)-5- (s, 3H), 1.88 (t, J = 2.35 Hz, 3H),
1.79-1.86 (m, (2-butyn-1-yloxy)-3-methyl-2- 1H), 1.73 (s, 3H),
0.84-0.87 (m, 1H), 0.75-0.81 pyridinecarboxamide (m, 1H) 102
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1R,5S,6R)-3-amino-7,7- 1.72 (s, 3 H), 2.55 (s, 1 H),
2.65-2.82 (m, 1 H), difluoro-5-methyl-2-thia-4- 2.86-3.06 (m, 5 H),
4.58 (br., 2 H), 5.10 (s, 2 H), azabicyclo[4.1.0]hept-3-en-5-
7.03-7.19 (m, 1 H), 7.55-7.74 (m, 1 H), 7.96-
yl)-4-fluorophenyl)-3-methyl-5- 8.18 (m, 2 H), 9.81 (s, 1 H).
(prop-2-yn-1-yloxy)pyrazine-2- carboxamide 603 .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta. 9.83 N-(5-((1S,5S,6S)-3-amino-1- (s,
1H), 8.55-8.75 (m, 1H), 8.32 (dd, J = 2.70, 8.70
(fluoromethyl)-5-methyl-2-thia- Hz, 1H), 8.09 (s, 1H), 5.11 (d, J =
2.34 Hz, 2H), 4-azabicyclo[4.1.0]hept-3-en-5- 4.97-5.26 (br. s,
2H), 4.44-4.65 (m, 1H), 4.07- yl)-6-fluoro-3-pyridinyl)-3- 4.43 (m,
1H), 2.98 (s, 3H), 2.56 (t, J = 2.41 Hz,
methyl-5-(2-propyn-1-yloxy)-2- 1H), 1.85-2.13 (m, 1H), 1.74 (s,
3H), 1.02 (dd, pyrazinecarboxamide J = 6.14, 9.35 Hz, 1H),
0.84-0.93 (m, 1H). 655 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm N-(5-((1S,5S,6S)-3-amino-1- 0.84 (td, J = 6.60, 2.84 Hz, 1 H)
1.33 (dd, J = 9.88, (difluoromethyl)-5-methyl-2- 6.36 Hz, 1 H) 1.77
(s, 3 H) 1.97-2.08 (m, 1 H) thia-4-azabicyclo[4.1.0]hept-3-
5.47-5.86 (m, 1 H) 7.90 (dd, J = 8.41, 2.35 Hz, 1
en-5-yl)-6-fluoro-3-pyridinyl)-5- H) 8.23 (d, J = 8.22 Hz, 1 H)
8.35 (dd, J = 8.61, 2.74 chloro-2-pyridinecarboxamide Hz, 1 H)
8.53-8.63 (m, 2 H) 9.84 (s, 1 H). 704 .sup.1H NMR (300 MHz, CDCl3)
.delta. = 9.85 (s, 1H), N-(3-((1S,5S,6R)-3-amino-7,7- 8.58 (d, J =
2.3 Hz, 1H), 8.26 (d, J = 9.1 Hz, 1H),
difluoro-1-(hydroxymethyl)-5- 8.03 (ddd, J = 2.9, 4.2, 8.8 Hz, 1H),
7.90 (dd, methyl-2-thia-4- J = 2.3, 8.5 Hz, 1H), 7.77 (dd, J = 2.8,
6.9 Hz, 1H), azabicyclo[4.1.0]hept-3-en-5- 7.12 (dd, J = 8.8, 11.7
Hz, 1H), 4.04-3.97 (m, yl)-4-fluorophenyl)-5-chloro-2- 1H),
3.97-3.90 (m, 1H), 2.58-2.49 (m, 1H), pyridinecarboxamide 1.68 (s,
3H) 708 .sup.1H NMR (300 MHz, DMSO) .delta. = 10.48 (s, 1H),
N-(3-((1S,5S,6R)-3-amino-7,7- 8.91 (d, J = 1.3 Hz, 1H), 8.56 (d, J
= 1.3 Hz, 1H), difluoro-1-(hydroxymethyl)-5- 8.07 (dd, J = 2.7, 7.4
Hz, 1H), 7.83-7.73 (m, 1H), methyl-2-thia-4- 7.19 (dd, J = 8.9,
12.0 Hz, 1H), 6.92-6.53 (m, azabicyclo[4.1.0]hept-3-en-5- 1H), 6.13
(s, 2H), 5.43 (t, J = 5.8 Hz, 1H), 5.03 (t,
yl)-4-fluorophenyl)-5-(2,2,3,3- J = 14.3 Hz, 2H), 3.82 (br. s.,
1H), 3.65 (dd, J = 5.2, tetrafluoropropoxy)-2- 10.2 Hz, 1H), 1.52
(s, 3H) pyrazinecarboxamide 710 .sup.1H NMR (300 MHz, CDCl3)
.delta. = 9.87 (br. s., 1H), N-(3-((1S,5S,6R)-3-amino-7,7- 8.58 (s,
1H), 8.26 (d, J = 8.3 Hz, 1H), 8.13-8.02
difluoro-1-(methoxymethyl)-5- (m, 1H), 7.96-7.86 (m, 1H), 7.82-7.72
(m, 1H), methyl-2-thia-4- 7.21-7.05 (m, 1H), 3.98 (d, J = 11.0 Hz,
1H), 3.56 azabicyclo[4.1.0]hept-3-en-5- (d, J = 10.8 Hz, 1H), 3.42
(s, 3H), 2.44 (d, J = 15.9 yl)-4-fluorophenyl)-5-chloro-2- Hz, 1H),
1.70 (s, 3H) pyridinecarboxamide 711 .sup.1H NMR (300 MHz, CDCl3)
.delta. = 9.85 (s, 1H), N-(3-((1S,5S,6R)-3-amino-7,7- 8.62-8.53 (m,
1H), 8.27 (d, J = 9.1 Hz, 1H), 8.12- difluoro-1-(1-hydroxy-1- 8.00
(m, 1H), 7.90 (dd, J = 2.3, 8.5 Hz, 1H), 7.72
methylethyl)-5-methyl-2-thia-4- (dd, J = 2.8, 7.0 Hz, 1H), 7.13
(dd, J = 8.8, 11.6 Hz, azabicyclo[4.1.0]hept-3-en-5- 1H), 3.17-3.06
(m, 1H), 1.68 (d, J = 0.9 Hz, 3H), yl)-4-fluorophenyl)-5-chloro-2-
1.51 (s, 3H), 1.48 (s, 3H) pyridinecarboxamide 748 .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta. ppm N-(3-((1R,5S,6R)-3-amino-7,7- 1.75
(s, 3 H) 2.62-2.78 (m, 1 H) 2.90-3.02 (m,
difluoro-5-methyl-2-thia-4- 1 H) 7.37-7.50 (m, 1 H) 7.85-7.95 (m, 1
H) azabicyclo[4.1.0]hept-3-en-5- 8.11-8.20 (m, 1 H) 8.22-8.29 (m, 1
H) 8.49- yl)-4,5-difluorophenyl)-5- 8.63 (m, 1 H) 9.77-9.96 (m, 1
H) chloro-2-pyridinecarboxamide 749 .sup.1H NMR (300 MHz, DMSO-d6)
.delta. ppm 1.52 (br. N-(3-((1S,5S,6R)-3-amino-7,7- s., 3 H) 3.63
(br. s., 2 H) 3.82 (br. s., 1 H) 5.13 difluoro-1-(hydroxymethyl)-5-
(br. s., 2 H) 5.42 (br. s., 1 H) 6.12 (br. s., 2 H)
methyl-2-thia-4- 7.03-7.28 (m, 1 H) 7.76 (br. s., 1 H) 8.06 (d,
azabicyclo[4.1.0]hept-3-en-5- J = 4.82 Hz, 1 H) 8.47 (s, 1 H) 8.89
(s, 1 H) 10.43 yl)-4-fluorophenyl)-5-(2-propyn- (br. s., 1 H)
1-yloxy)-2-pyrazinecarboxamide 751 .sup.1H NMR (300 MHz, DMSO-d6)
.delta. ppm 1.52 (s, 3 N-(3-((1S,5S,6R)-3-amino-7,7- H) 2.38-2.48
(m, 1 H) 3.65 (dd, J = 12.57, 3.22 difluoro-1-(hydroxymethyl)-5-
Hz, 1 H) 3.78-3.90 (m, 1 H) 4.85 (t, J = 13.52 Hz, methyl-2-thia-4-
2 H) 5.43 (t, J = 5.77 Hz, 1 H) 6.14 (br. s., 2 H)
azabicyclo[4.1.0]hept-3-en-5- 6.45-6.96 (m, 1 H) 7.18 (dd, J =
12.06, 8.84 Hz, 1 yl)-4-fluorophenyl)-5-(2,2,3,3- H) 7.76 (dd, J =
8.77, 2.92 Hz, 1 H) 7.81 (dt, tetrafluoropropoxy)-2- J = 7.27, 4.26
Hz, 1 H) 8.03 (dd, J = 7.31, 2.78 Hz, 1 pyridinecarboxamide H) 8.14
(d, J = 8.77 Hz, 1 H) 8.49 (d, J = 2.63 Hz, 1 H) 10.31-10.46 (m, 1
H) 10.39 (s, 1 H) 785 .sup.1H NMR (DMSO-d6) .delta.: 10.74 (s, 1H),
8.89 (d, N-(3-((1S,5S,6S)-3-amino-5- J = 1.8 Hz, 1H), 8.43 (s, 1H),
8.28-8.33 (m, 1H), (fluoromethyl)-1-(1,3-oxazol-5- 8.22-8.28 (m,
1H), 8.13 (dd, J = 7.0, 2.7 Hz, 1H), yl)-2-thia-4- 7.97 (dt, J =
7.3, 4.2 Hz, 1H), 7.31 (dd, J = 11.7, 8.8
azabicyclo[4.1.0]hept-3-en-5- Hz, 1H), 7.23 (s, 1H), 6.62 (s, 2H),
4.74-5.01 (m, yl)-4-fluorophenyl)-5-chloro-2- 2H), 2.10-2.18 (m,
1H), 1.74 (dd, J = 9.7, 5.6 Hz, pyridinecarboxamide 1H), 1.03-1.11
(m, 1H), 1.03-1.11 (m, 1H) 790 .sup.1H NMR (DMSO-d6) .delta.: 10.62
(s, 1H), 9.73-10.99 (1S,5S,6S)-3-amino-5-(5-(((5- (m, 1H), 8.80 (d,
J = 1.8 Hz, 1H), 8.19-8.25 (m, chloro-2- 1H), 8.11-8.19 (m, 1H),
7.80-7.91 (m, 2H), 7.22 pyridinyl)carbonyl)amino)-2- (dd, J = 11.7,
8.8 Hz, 1H), 6.57 (s, 2H), 4.82 (q, fluorophenyl)-5-(fluoromethyl)-
J = 8.1 Hz, 1H), 4.61-4.75 (m, 1H), 2.97-3.18 (m,
N,N-dimethyl-2-thia-4- 3H), 2.88 (br. s., 3H), 2.04-2.05 (m, 1H),
2.06 (t, azabicyclo[4.1.0]hept-3-ene-1- J = 8.6 Hz, 1H), 1.50 (dd,
J = 9.5, 5.4 Hz, 1H), 0.69 carboxamide (t, J = 6.2 Hz, 1H). 906
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.79 (s, 1H),
N-(3-((1S,5S,6S)-1-acetyl-3- 8.79 (s, 1H), 8.15-8.23 (m, 2H),
7.92-8.02 (m, amino-5-methyl-2-thia-4- 2H), 6.17 (s, 2H), 2.33-2.41
(m, 1H), 2.11 (s, 3H), azabicyclo[4.1.0]hept-3-en-5- 1.74 (dd, J =
5.48, 9.78 Hz, 1H), 1.62 (s, 3H), 1.11- yl)-4,5-difluorophenyl)-5-
1.16 (m, 1H) chloro-2-pyridinecarboxamide 910 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.62 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.89
(d, J = 1.17 Hz, 1H), 8.54 (d, J = 1.17 Hz, 1H),
(methoxymethyl)-5-methyl-2- 8.20 (s, 1H), 7.88-7.94 (m, 2H), 7.30
(s, 1H), 5.99 thia-4-azabicyclo[4.1.0]hept-3- (s, 2H), 5.62 (s,
2H), 3.57 (d, J = 10.95 Hz, 1H), en-5-yl)-4,5-difluorophenyl)-5-
3.36 (d, J = 10.95 Hz, 1H), 3.31 (d, J = 2.54 Hz,
(1,3-oxazol-2-ylmethoxy)-2- 3H), 1.58-1.65 (m, 4H), 0.90 (dd, J =
5.18, 9.10 pyrazinecarboxamide Hz, 1H), 0.64 (t, J = 5.77 Hz, 1H)
953 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 0.77 (t, J = 6.26 Hz, 1 H) 1.13 (dd, J
= 9.68, 5.97 (fluoromethyl)-1-((2,2,2- Hz, 1 H) 1.80-1.88 (m, 1 H)
2.55 (t, J = 2.35 Hz, trifluoroethoxy)methyl)-2-thia- 1 H)
3.60-3.84 (m, 2 H) 3.90 (q, J = 8.61 Hz, 2 H)
4-azabicyclo[4.1.0]hept-3-en-5- 4.57-4.97 (m, 3 H) 5.09 (d, J =
2.35 Hz, 2 H) 7.09 yl)-4-fluorophenyl)-5-(2-propyn- (dd, J = 11.35,
8.80 Hz, 1 H) 7.68 (dd, J = 6.65, 2.74
1-yloxy)-2-pyrazinecarboxamide Hz, 1 H) 7.96 (dt, J = 8.31, 3.67
Hz, 1 H) 8.20 (d, J = 0.98 Hz, 1 H) 9.02 (d, J = 0.98 Hz, 1 H) 9.48
(s, 1H) 954 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 0.78 (t, J = 6.26 Hz, 1 H) 1.14 (dd, J
= 9.68, 5.97 (fluoromethyl)-1-((2,2,2- Hz, 1 H) 1.26 (br. s., 2 H)
1.83-1.89 (m, 1 H) trifluoroethoxy)methyl)-2-thia- 3.62-3.85 (m, 2
H) 3.90 (q, J = 8.74 Hz, 2 H) 4.60- 4-azabicyclo[4.1.0]hept-3-en-5-
4.96 (m, 2 H) 7.10 (dd, J = 11.54, 8.80 Hz, 1 H)
yl)-4-fluorophenyl)-5-chloro-2- 7.70 (dd, J = 6.85, 2.74 Hz, 1 H)
7.88 (dd, J = 8.41, pyridinecarboxamide 2.35 Hz, 1 H) 7.97 (dt, J =
8.75, 3.55 Hz, 1 H) 8.24 (d, J = 8.41 Hz, 1 H) 8.56 (d, J = 2.15
Hz, 1 H) 9.82 (s, 1 H) 955 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm N-(3-((1S,5S,6S)-3-amino-5- 0.75 (t, J = 5.97 Hz, 1 H)
1.09 (dd, J = 9.49, 5.77 (fluoromethyl)-1-((1- Hz, 1 H) 1.17 (t, J
= 6.36 Hz, 6 H) 1.75-1.81 (m, methylethoxy)methyl)-2-thia-4- 1 H)
2.55 (m, 1 H) 3.37 (d, J = 10.37 Hz, 1 H) 3.63
azabicyclo[4.1.0]hept-3-en-5- (dt, J = 12.13, 6.06 Hz, 1 H) 3.71
(d, J = 10.37 Hz, 1 yl)-4-fluorophenyl)-5-(2-propyn- H) 4.63-4.95
(m, 4 H) 5.08 (d, J = 1.96 Hz, 2 H) 1-yloxy)-2-pyrazinecarboxamide
7.09 (dd, J = 11.44, 9.10 Hz, 1 H) 7.70 (d, J = 4.30 Hz, 1 H)
7.93-8.05 (m, 1 H) 8.20 (s, 1 H) 9.02 (s, 1 H) 9.49 (br. s., 1 H)
956 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 1.14 (t, J = 6.36 Hz, 1 H) 1.77 (dd, J
= 9.59, 5.87 (fluoromethyl)-1-(1H-1,2,3- Hz, 1 H) 2.27 (t, J = 8.31
Hz, 1 H) 4.68-5.07 (m, triazol-4-yl)-2-thia-4- 2 H) 7.07-7.16 (m, 1
H) 7.66 (s, 1 H) 7.77 (d, azabicyclo[4.1.0]hept-3-en-5- J = 4.11
Hz, 1 H) 7.88 (d, J = 8.22 Hz, 1 H) 7.91-
yl)-4-fluorophenyl)-5-chloro-2- 7.99 (m, 1 H) 8.24 (d, J = 8.22 Hz,
1 H) 8.56 (s, 1 pyridinecarboxamide H) 9.85 (s, 1 H) 959 .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-5-
1.13 (t, J = 6.36 Hz, 1 H) 1.75 (dd, J = 9.39, 5.67
(fluoromethyl)-1-(1H-1,2,3- Hz, 1 H) 2.19-2.31 (m, 1 H) 2.55 (br.
s., 1 H) triazol-4-yl)-2-thia-4- 4.67-5.05 (m, 2 H) 5.09 (d, J =
2.15 Hz, 2 H) 7.11 azabicyclo[4.1.0]hept-3-en-5- (dd, J = 11.25,
9.29 Hz, 1 H) 7.66 (s, 1 H) 7.74 (d,
yl)-4-fluorophenyl)-5-(2-propyn- J = 4.30 Hz, 1 H) 7.86-8.01 (m, 1
H) 8.21 (s, 1 H) 1-yloxy)-2-pyrazinecarboxamide 9.03 (s, 1H) 9.51
(s, 1H)
Method B: Propylphosphonic Anhydride (T3P) Procedure in DMAc as
Solvent
Example 94:
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-(fluoromethyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-cyano-3-methylpicolina-
mide
##STR00337##
[1841] Propylphosphonic anhydride solution (50 wt. % in EtOAc, 279
mg, 0.44 mmol) was added to a stirred solution of
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-1-(difluoromethyl)-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (Intermediate 211, 70 mg,
0.22 mmol) and 5-cyano-3-methylpicolinic acid (Intermediate 267, 46
mg, 0.28 mmol) in DMAc (2 mL) at 0.degree. C. The reaction mixture
was stirred at 0.degree. C. for 0.5 h then RT for 2 h. The reaction
mixture was treated with additional 5-cyano-3-methylpicolinic acid
(15 mg, 0.09 mmol) followed by T3P (50 wt. % in EtOAc, 100 mg, 0.15
mmol) and stirred at RT for 48 h. It was quenched with sat'd
aqueous NaHCO.sub.3 and extracted with EtOAc. The organic layer was
separated, washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The resulting crude yellow oil was purified on a
silica gel column (35-65% EtOAc in DCM) to afford
N-(3-((1S,5S,6S)-3-amino-1-(difluoromethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-cyano-3-methylpicolinamide
(Example 94, 65 mg, 0.14 mmol, 64% yield) as an off-white solid. MS
m/z=464.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.86 (br., 1H), 8.99 (d, J=1.57 Hz, 1H), 8.41 (d, J=1.17 Hz, 1H),
7.94 (ddd, J=2.64, 6.75, 12.32 Hz, 1H), 7.62 (m, 1H), 6.31 (br.,
2H), 5.81-6.03 (m, 1H), 2.57 (s, 3H), 1.93 (m, 1H), 1.66 (s, 3H),
1.35 (m, 1H), 0.75 (m, 1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6)
.delta. -115.50 (d, .sup.1J=273.96 Hz, 1 F), -118.00 (d,
.sup.1J=273.90 Hz, 1 F), -137.95 (d, .sup.2J=22.56 Hz, 1 F),
-142.80 (d, .sup.2J=22.66 Hz, 1 F).
[1842] Using procedures analogous or similar to the general
amidation Method B described above, the appropriate aniline and
carboxylic acid intermediates were reacted to provide the 30
examples listed in Table 2 and Table 2'.
TABLE-US-00004 TABLE 2 Observed Ex. No. Chemical Structure [M +
H].sup.+ 31 ##STR00338## 457.1 37 ##STR00339## 439.1 43
##STR00340## 471.0 44 ##STR00341## 444.0 53 ##STR00342## 460.1 70
##STR00343## 462.0 72 ##STR00344## 474.0 75 ##STR00345## 450.1 76
##STR00346## 474.0 78 ##STR00347## 441.0 79 ##STR00348## 518.2 81
##STR00349## 437.1 83 ##STR00350## 478.1 84 ##STR00351## 462.0 86
##STR00352## 473.1 96 ##STR00353## 471.0 31 ##STR00354## 457.1 37
##STR00355## 439.1 43 ##STR00356## 471.0 44 ##STR00357## 444.0 673
##STR00358## 510 674 ##STR00359## 510 675 ##STR00360## 531 678
##STR00361## 519 679 ##STR00362## 537 715 ##STR00363## 472.1 716
##STR00364## 458.1 718 ##STR00365## 448.1 723 ##STR00366## 462 725
##STR00367## 504
TABLE-US-00005 TABLE 2' Ex. No. .sup.1H-NMR Chemical Name 31
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.79 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.79 (d, J = 1.76 Hz, 1 H) 8.21
(dd, J = 8.41, (fluoromethyl)-1- 2.35 Hz, 1 H) 8.16 (d, J = 8.61
Hz, 1 H) 7.98 (hydroxymethyl)-2-thia-4- (ddd, J = 12.23, 6.75, 2.54
Hz, 1 H) 7.89-7.93 azabicyclo[4.1.0]hept-3-en-5- (m, 1 H) 6.26 (s,
2 H) 5.08 (t, J = 5.97 Hz, 1 H) yl)-4,5-difluorophenyl)-5-
4.57-4.81 (m, 2 H) 3.54 (dd, J = 11.74, 6.26 Hz,
chloro-2-pyridinecarboxamide 1 H) 3.44 (dd, J = 11.74, 5.67 Hz, 1
H) 1.61-1.67 (m, 1 H) 1.04 (dd, J = 9.29, 5.18 Hz, 1 H) 0.57 (t, J
= 5.77 Hz, 1 H) 37 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 9.80 (br s, 1H), 8.54 (d, J = 2.15 Hz,
1H), 8.23 (d, (fluoromethyl)-1- J = 8.41 Hz, 1H), 7.94-8.01 (m,
1H), 7.87 (dd, (hydroxymethyl)-2-thia-4- J = 8.41, 2.35 Hz, 1H),
7.71 (d, J = 4.30 Hz, 1 H), azabicyclo[4.1.0]hept-3-en-5- 7.09 (dd,
J = 11.44, 8.90 Hz, 1H), 4.91 (dd, yl)-4-fluorophenyl)-5-chloro- J
= 46.95, 8.41 Hz, 1H), 4.77 (s br, 2H), 4.67 (dd,
2-pyridinecarboxamide J = 47.54, 8.80 Hz, 1H), 3.76 (d, J = 11.93
Hz, 1H), 3.60 (d, J = 11.74 Hz, 1H), 1.85 (t, J = 9.00 Hz, 1H),
1.77 (s br, 1H), 1.08 (dd, J = 9.59, 5.87 Hz, 1H), 0.71 (t, J =
6.26 Hz, 1H) 43 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.79
(s, N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.79 (d, J = 1.96 Hz, 1 H)
8.21 (dd, J = 8.41, (fluoromethyl)-1- 2.35 Hz, 1 H) 8.16 (d, J =
8.22 Hz, 1 H) 7.99 (methoxymethyl)-2-thia-4- (ddd, J = 12.37, 6.80,
2.54 Hz, 1 H) 7.88-7.93 azabicyclo[4.1.0]hept-3-en-5- (m, 1 H) 6.30
(s, 2 H) 4.60-4.78 (m, 2 H) 3.56 yl)-4,5-difluorophenyl)-5- (d, J =
10.76 Hz, 1 H) 3.35 (d, J = 10.95 Hz, 1 H)
chloro-2-pyridinecarboxamide 3.30 (s, 3 H) 1.63-1.69 (m, 1 H) 1.10
(dd, J = 9.49, 5.18 Hz, 1 H) 0.64 (t, J = 5.87 Hz, 1 H) 44 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. ppm 10.67 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1H), 8.98 (d, J = 1.37 Hz, 1H), 8.40
(d, J = 1.96 (fluoromethyl)-1- Hz, 1H), 7.90 (dd, J = 7.04, 2.74
Hz, 1H), 7.81- (hydroxymethyl)-2-thia-4- 7.87 (m, 1H), 7.19 (dd, J
= 11.93, 8.80 Hz, 1H), azabicyclo[4.1.0]hept-3-en-5- 6.22 (s, 2H),
5.06 (t, J = 5.87 Hz, 1H), 4.77 (dd, yl)-4-fluorophenyl)-5-cyano- J
= 26.41, 8.61 Hz, 1H), 4.65 (dd, J = 26.41, 9.19 3-methyl-2- Hz,
1H), 3.54 (dd, J = 11.54, 6.26 Hz, 1H), 3.43 pyridinecarboxamide
(dd, J = 11.74, 5.67 Hz, 1H), 2.56 (s, 3H), 1.64 (t, J = 7.82 Hz,
1H), 0.98 (dd, J = 9.49, 4.99 Hz, 1H), 0.50 (t, J = 5.67 Hz, 1H) 53
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 9.48 (s, 1H), 9.02 (d, J = 1.37 Hz,
1H), 8.20 (d, (fluoromethyl)-1- J = 1.37 Hz, 1H), 7.94-8.01 (m,
1H), 7.68 (dd, (hydroxymethyl)-2-thia-4- J = 6.75, 2.64 Hz, 1H),
7.09 (dd, J = 11.54, 8.80 azabicyclo[4.1.0]hept-3-en-5- Hz, 1H),
5.09 (d, J = 2.35 Hz, 2H), 4.91 (dd, yl)-4-fluorophenyl)-5-(2- J =
46.75, 7.82 Hz, 1H), 4.72 (s br, 2H), 4.66 (dd, propyn-1-yloxy)-2-
J = 47.73, 8.41 Hz, 1H), 3.76 (d, J = 11.74 Hz, 1H),
pyrazinecarboxamide 3.60 (d, J = 11.93 Hz, 1H), 2.55 (t, J = 2.35
Hz, 1H), 1.84 (t, J = 8.80 Hz, 1H), 1.68 (s br, 1H), 1.07 (dd, J =
9.68, 5.77 Hz, 1H), 0.71 (t, J = 6.26 Hz, 1H) 70 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 10.87 (s, N-(3-((1S,5S,6S)-3-amino-5- 1
H) 8.98 (d, J = 1.17 Hz, 1 H) 8.40 (d, J = 1.17 (fluoromethyl)-1-
Hz, 1 H) 7.97 (ddd, J = 12.37, 6.80, 2.54 Hz, 1 H)
(hydroxymethyl)-2-thia-4- 7.70-7.74 (m, 1 H) 6.26 (s, 2 H) 5.08 (t,
J = 5.97 azabicyclo[4.1.0]hept-3-en-5- Hz, 1 H) 4.57-4.82 (m, 2 H)
3.53 (dd, J = 11.74, yl)-4,5-difluorophenyl)-5- 6.26 Hz, 1 H) 3.43
(dd, J = 11.74, 5.67 Hz, 1 H) cyano-3-methyl-2- 2.56 (s, 3 H)
1.60-1.66 (m, 1 H) 1.02 (dd, pyridinecarboxamide J = 9.39, 5.09 Hz,
1 H) 0.53 (t, J = 5.77 Hz, 1 H) 72 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.42-10.79 N-(3-((1S,5S,6S)-3-amino-1- (m,
1H), 8.90 (d, J = 1.17 Hz, 1H), 8.48 (d,
(methoxymethyl)-5-methyl-2- J = 1.17 Hz, 1H), 7.70-8.03 (m, 2H),
5.99 (s, 2H), thia-4-azabicyclo[4.1.0]hept- 5.14 (d, J = 2.35 Hz,
2H), 3.64 (t, J = 2.45 Hz, 1H), 3-en-5-yl)-4,5- 3.57 (d, J = 10.95
Hz, 1H), 3.36 (d, J = 11.15 Hz, difluorophenyl)-5-(2-propyn- 1H),
3.30-3.31 (m, 3H), 1.57-1.70 (m, 4H), 0.90 1-yloxy)-2- (dd, J =
5.28, 9.19 Hz, 1H), 0.65 (t, J = 5.77 Hz, pyrazinecarboxamide 1H)
75 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 9.76 (s, 1H), 8.00 (dt, J = 8.56, 3.64
Hz, 1H), 7.97 (fluoromethyl)-1- (s, 1H), 7.58 (dd, J = 6.65, 2.74
Hz, 1H), 7.07 (dd, (hydroxymethyl)-2-thia-4- J = 11.54, 9.00 Hz,
1H), 4.91 (dd, J = 47.34, 8.22 azabicyclo[4.1.0]hept-3-en-5- Hz,
1H), 4.75 (s br, 2H), 4.64 (dd, J = 47.14, 8.41
yl)-4-fluorophenyl)-5- Hz, 1H), 4.04 (s, 3H), 3.75 (d, J = 11.93
Hz, 1H), methoxy-3-methyl-2- 3.60 (d, J = 11.93 Hz, 1H), 2.94 (s,
3H), 1.85 (t, pyrazinecarboxamide J = 8.20 Hz, 1H), 1.72 (s br,
1H), 1.06 (dd, J = 9.68, 5.77 Hz, 1H), 0.70 (t, J = 6.16 Hz, 1H) 76
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 9.75 (s, 1H), 8.05 (s, 1H), 8.01 (dt, J
= 8.80, 3.50 (fluoromethyl)-1- Hz, 1H), 7.58 (dd, J = 6.65, 2.54
Hz, 1H), 7.08 (hydroxymethyl)-2-thia-4- (dd, J = 11.54, 8.80 Hz,
1H), 5.08 (d, J = 2.35 Hz, azabicyclo[4.1.0]hept-3-en-5- 2H), 4.92
(dd, J = 47.34, 8.02 Hz, 1H), 4.70 (s br,
yl)-4-fluorophenyl)-3-methyl- 2H), 4.64 (dd, J = 46.95, 8.61 Hz,
1H), 3.76 (d, 5-(2-propyn-1-yloxy)-2- J = 11.93 Hz, 1H), 3.60 (d, J
= 11.93 Hz, 1H), 2.95 pyrazinecarboxamide (s, 3H), 2.53 (t, J =
2.35 Hz, 1H), 1.86 (t, J = 8.00 Hz, 1H), 1.70 (s br, 1H), 1.06 (dd,
J = 9.68, 5.77 Hz, 1H), 0.71 (t, J = 6.36 Hz, 1H) 78 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. ppm 10.70 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.57 (d, J = 2.15 Hz, 1 H) 8.03
(d, J = 1.76 (fluoromethyl)-2-thia-4- Hz, 1 H) 7.96 (ddd, J =
12.42, 6.85, 2.64 Hz, 1 H) azabicyclo[4.1.0]hept-3-en-5- 7.69-7.73
(m, 1 H) 6.22 (s, 2 H) 4.72 (d, yl)-4,5-difluorophenyl)-5- J =
47.73 Hz, 2 H) 2.56 (s, 3 H) 2.39 (ddd, chloro-3-methyl-2- J =
9.00, 7.63, 5.09 Hz, 1 H) 1.74 (m, J = 7.76, pyridinecarboxamide
7.76, 7.76 Hz, 1 H) 1.03 (ddd, J = 8.80, 7.63, 5.28 Hz, 1 H) 0.41
(q, J = 5.15 Hz, 1 H) 79 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm N-(3-((1S,5S,6S)-3-amino-5- 9.73 (s, 1H), 8.13 (s, 1H),
7.97-8.02 (m, 1H), (fluoromethyl)-1- 7.60 (d, J = 5.67 Hz, 1H),
7.08 (t, J = 10.04 Hz, (hydroxymethyl)-2-thia-4- 1H), 4.85 (q, J =
8.40 Hz, 2H), 4.82-4.98 (m, 1H), azabicyclo[4.1.0]hept-3-en-5- 4.71
(s br, 2H), 4.65 (dd, J = 47.14, 8.61 Hz, 1H),
yl)-4-fluorophenyl)-3-methyl- 3.76 (d, J = 11.74 Hz, 1H), 3.61 (d,
J = 11.74 Hz, 5-(2,2,2-trifluoroethoxy)-2- 1H), 2.95 (s, 3H), 1.85
(t, J = 8.12 Hz, 1H), 1.66 pyrazinecarboxamide (s br, 1H), 1.06
(dd, J = 9.59, 5.67 Hz, 1 H), 0.71 (t, J = 6.26 Hz, 1H) 81 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. ppm 10.51 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.22 (d, J = 2.54 Hz, 1 H) 7.98
(ddd, (fluoromethyl)-2-thia-4- J = 12.52, 6.85, 2.54 Hz, 1 H)
7.68-7.73 (m, 1 H) azabicyclo[4.1.0]hept-3-en-5- 7.41 (d, J = 2.54
Hz, 1 H) 6.23 (s, 2 H) 4.71 (d, yl)-4,5-difluorophenyl)-5- J =
47.73 Hz, 2 H) 3.91 (s, 3 H) 2.62 (s, 3 H) 2.36-
methoxy-3-methyl-2- 2.42 (m, 1 H) 1.69-1.81 (m, 1 H) 1.00-1.07
pyridinecarboxamide (m, 1 H) 0.43 (q, J = 5.15 Hz, 1 H) 83 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. ppm 10.67 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.92 (d, J = 1.17 Hz, 1 H) 8.50
(d, J = 1.37 (fluoromethyl)-1- Hz, 1 H) 7.97 (ddd, J = 12.32, 6.85,
2.74 Hz, 1 H) (hydroxymethyl)-2-thia-4- 7.90-7.94 (m, 1 H) 6.26 (s,
2 H) 5.16 (d, J = 2.35 azabicyclo[4.1.0]hept-3-en-5- Hz, 2 H) 5.09
(t, J = 5.87 Hz, 1 H) 4.58-4.82 (m, yl)-4,5-difluorophenyl)-5-(2- 2
H) 3.66 (t, J = 2.35 Hz, 1 H) 3.55 (dd, J = 11.74,
propyn-1-yloxy)-2- 6.26 Hz, 1 H) 3.45 (dd, J = 11.74, 5.48 Hz, 1 H)
pyrazinecarboxamide 1.62-1.68 (m, 1 H) 1.05 (dd, J = 9.29, 5.18 Hz,
1 H) 0.58 (t, J = 5.67 Hz, 1 H) 84 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 10.60 (s, N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.30 (s, 1
H) 7.97 (ddd, J = 12.32, 6.75, 2.25 (fluoromethyl)-2-thia-4- Hz, 1
H) 7.72-7.76 (m, 1 H) 6.23 (s, 2 H) 5.12
azabicyclo[4.1.0]hept-3-en-5- (d, J = 2.35 Hz, 2 H) 4.73 (d, J =
47.54 Hz, 2 H) yl)-4,5-difluorophenyl)-3- 3.62 (t, J = 2.15 Hz, 1
H) 2.76 (s, 3 H) 2.40 (td, methyl-5-(2-propyn-1-yloxy)- J = 8.12,
5.28 Hz, 1 H) 1.75 (q, J = 8.28 Hz, 1 H) 2-pyrazinecarboxamide 1.04
(td, J = 8.07, 5.58 Hz, 1 H) 0.43 (q, J = 5.28 Hz, 1 H) 86 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. ppm 10.67 (s,
N-(3-((1S,5S,6S)-3-amino-5- 1 H) 8.43 (d, J = 2.35 Hz, 1 H) 7.97
(ddd, (fluoromethyl)-2-thia-4- J = 12.42, 6.94, 2.35 Hz, 1 H)
7.71-7.75 (m, 2 H) azabicyclo[4.1.0]hept-3-en-5- 7.44 (t, J = 73.20
Hz, 1 H) 6.23 (s, 2 H) 4.73 (d, yl)-4,5-difluorophenyl)-5- J =
47.54 Hz, 2 H) 2.60 (s, 3 H) 2.37-2.44 (m, 1
(difluoromethoxy)-3-methyl- H) 1.75 (q, J = 8.22 Hz, 1 H) 1.05 (td,
J = 8.12, 2-pyridinecarboxamide 5.48 Hz, 1 H) 0.43 (q, J = 5.35 Hz,
1 H) 96 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1R,5S,6R)-3-amino-5- 9.80 (s, 1 H) 8.54 (d, J = 2.15 Hz, 1
H) 8.23 (d, (fluoromethyl)-1- J = 8.22 Hz, 1 H) 8.05 (ddd, J =
11.59, 6.80, 2.54 (methoxymethyl)-2-thia-4- Hz, 1 H) 7.89 (dd, J =
8.41, 2.15 Hz, 1 H) 7.44- azabicyclo[4.1.0]hept-3-en-5- 7.49 (m, 1
H) 4.56-4.91 (m, 2 H) 3.60 (d, yl)-4,5-difluorophenyl)-5- J = 10.56
Hz, 1 H) 3.50 (d, J = 10.76 Hz, 1 H) 3.41
chloro-2-pyridinecarboxamide (s, 3 H) 2.03-2.09 (m, 1 H) 1.23-1.30
(m, 4 H) 1.11 (dd, J = 9.49, 6.16 Hz, 1 H) 31 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 10.79 (s, N-(3-((1S,5S,6S)-3-amino-5- 1 H)
8.79 (d, J = 1.76 Hz, 1 H) 8.21 (dd, J = 8.41, (fluoromethyl)-1-
2.35 Hz, 1 H) 8.16 (d, J = 8.61 Hz, 1 H) 7.98
(hydroxymethyl)-2-thia-4- (ddd, J = 12.23, 6.75, 2.54 Hz, 1 H)
7.89-7.93 azabicyclo[4.1.0]hept-3-en-5- (m, 1 H) 6.26 (s, 2 H) 5.08
(t, J = 5.97 Hz, 1 H) yl)-4,5-difluorophenyl)-5- 4.57-4.81 (m, 2 H)
3.54 (dd, J = 11.74, 6.26 Hz, chloro-2-pyridinecarboxamide 1 H)
3.44 (dd, J = 11.74, 5.67 Hz, 1 H) 1.61-1.67 (m, 1 H) 1.04 (dd, J =
9.29, 5.18 Hz, 1 H) 0.57 (t, J = 5.77 Hz, 1 H) 37 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-5- 9.80 (br
s, 1H), 8.54 (d, J = 2.15 Hz, 1H), 8.23 (d, (fluoromethyl)-1- J =
8.41 Hz, 1H), 7.94-8.01 (m, 1H), 7.87 (dd,
(hydroxymethyl)-2-thia-4- J = 8.41, 2.35 Hz, 1H), 7.71 (d, J = 4.30
Hz, 1 H), azabicyclo[4.1.0]hept-3-en-5- 7.09 (dd, J = 11.44, 8.90
Hz, 1H), 4.91 (dd, yl)-4-fluorophenyl)-5-chloro- J = 46.95, 8.41
Hz, 1H), 4.77 (s br, 2H), 4.67 (dd, 2-pyridinecarboxamide J =
47.54, 8.80 Hz, 1H), 3.76 (d, J = 11.93 Hz, 1H), 3.60 (d, J = 11.74
Hz, 1H), 1.85 (t, J = 9.00 Hz, 1H), 1.77 (s br, 1H), 1.08 (dd, J =
9.59, 5.87 Hz, 1H), 0.71 (t, J = 6.26 Hz, 1H) 43 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 10.79 (s, N-(3-((1S,5S,6S)-3-amino-5- 1
H) 8.79 (d, J = 1.96 Hz, 1 H) 8.21 (dd, J = 8.41, (fluoromethyl)-1-
2.35 Hz, 1 H) 8.16 (d, J = 8.22 Hz, 1 H) 7.99
(methoxymethyl)-2-thia-4- (ddd, J = 12.37, 6.80, 2.54 Hz, 1 H)
7.88-7.93 azabicyclo[4.1.0]hept-3-en-5- (m, 1 H) 6.30 (s, 2 H)
4.60-4.78 (m, 2 H) 3.56 yl)-4,5-difluorophenyl)-5- (d, J = 10.76
Hz, 1 H) 3.35 (d, J = 10.95 Hz, 1 H) chloro-2-pyridinecarboxamide
3.30 (s, 3 H) 1.63-1.69 (m, 1 H) 1.10 (dd, J = 9.49, 5.18 Hz, 1 H)
0.64 (t, J = 5.87 Hz, 1 H) 44 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 10.67 (s, N-(3-((1S,5S,6S)-3-amino-5- 1H), 8.98 (d, J =
1.37 Hz, 1H), 8.40 (d, J = 1.96 (fluoromethyl)-1- Hz, 1H), 7.90
(dd, J = 7.04, 2.74 Hz, 1H), 7.81- (hydroxymethyl)-2-thia-4- 7.87
(m, 1H), 7.19 (dd, J = 11.93, 8.80 Hz, 1H),
azabicyclo[4.1.0]hept-3-en-5- 6.22 (s, 2H), 5.06 (t, J = 5.87 Hz,
1H), 4.77 (dd, yl)-4-fluorophenyl)-5-cyano- J = 26.41, 8.61 Hz,
1H), 4.65 (dd, J = 26.41, 9.19 3-methyl-2- Hz, 1H), 3.54 (dd, J =
11.54, 6.26 Hz, 1H), 3.43 pyridinecarboxamide (dd, J = 11.74, 5.67
Hz, 1H), 2.56 (s, 3H), 1.64 (t, J = 7.82 Hz, 1H), 0.98 (dd, J =
9.49, 4.99 Hz, 1H), 0.50 (t, J = 5.67 Hz, 1H) 673 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-5- 0.84 (t,
J = 6.46 Hz, 1 H) 1.04-1.13 (m, 1 H) methyl-1-((1R)-2,2,2- 1.75 (s,
3 H) 2.00-2.08 (m, 1 H) 2.55 (t, J = 2.45
trifluoro-1-hydroxyethyl)-2- Hz, 1 H) 3.23-3.64 (m, 3 H) 3.70 (q, J
= 6.39 Hz, thia-4-azabicyclo[4.1.0]hept- 1 H) 5.08 (d, J = 2.35 Hz,
2 H) 7.06 (dd, J = 11.54, 3-en-5-yl)-4-fluorophenyl)-5- 8.80 Hz, 1
H) 7.63 (dd, J = 6.85, 2.74 Hz, 1 H) (2-propyn-1-yloxy)-2-
7.75-7.86 (m, 1 H) 8.20 (d, J = 1.17 Hz, 1 H) pyrazinecarboxamide
9.01 (d, J = 1.17 Hz, 1 H) 9.48 (s, 1 H). 674 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-5- 0.91 (t, J =
6.65 Hz, 1 H) 1.16-1.25 (m, 1 H) methyl-1-((1S)-2,2,2-trifluoro-
1.74-1.88 (m, 4 H) 2.55 (t, J = 2.35 Hz, 1 H)
1-hydroxyethyl)-2-thia-4- 3.49 (q, J = 6.78 Hz, 1 H) 3.58-3.83 (m,
3 H) azabicyclo[4.1.0]hept-3-en-5- 5.08 (d, J = 2.35 Hz, 2 H) 7.05
(dd, J = 11.54, 8.80 yl)-4-fluorophenyl)-5-(2- Hz, 1 H) 7.59 (dd, J
= 6.85, 2.74 Hz, 1 H) 7.82 propyn-1-yloxy)-2- (dt, J = 8.46, 3.50
Hz, 1 H) 8.20 (d, J = 1.17 Hz, 1 pyrazinecarboxamide H) 9.01 (d, J
= 1.17 Hz, 1 H) 9.46 (s, 1 H). 675 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.78-0.83 (m,
1 H) 0.89 (dd, J = 9.39, 5.87 Hz, 1 (methoxymethyl)-5-methyl-2- H)
1.72 (s, 3 H) 1.77-1.85 (m, 1 H) 2.81 (s, 3
thia-4-azabicyclo[4.1.0]hept- H) 3.35 (d, J = 10.76 Hz, 1 H) 3.41
(s, 3 H) 3.67 3-en-5-yl)-4,5- (d, J = 10.76 Hz, 1 H) 4.47 (q, J =
7.89 Hz, 2 H) difluorophenyl)-3-methyl-5- 7.15 (d, J = 2.35 Hz, 1
H) 7.30-7.36 (m, 1 H) (2,2,2-trifluoroethoxy)-2- 8.09 (ddd, J =
12.03, 6.94, 2.74 Hz, 1 H) 8.18 (d, pyridinecarboxamide J = 2.54
Hz, 1 H) 10.05 (s, 1 H). 678 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.82-0.90 (m, 1 H) 1.00
(dd, J = 9.59, 6.06 Hz, 1 (fluoromethyl)-5-methyl-2- H) 1.73 (s, 3
H) 1.87-1.95 (m, 1 H) 2.81 (s, 3 thia-4-azabicyclo[4.1.0]hept- H)
4.19-4.90 (m, 6 H) 7.15 (d, J = 2.54 Hz, 1 H) 3-en-5-yl)-4,5-
7.30-7.36 (m, 1 H) 8.05 (ddd, J = 11.93, 6.85,
difluorophenyl)-3-methyl-5- 2.74 Hz, 1 H) 8.18 (d, J = 2.74 Hz, 1
H) 10.04 (s, (2,2,2-trifluoroethoxy)-2- 1 H). pyridinecarboxamide
679 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.80-0.88 (m, 1 H) 1.36 (dd, J = 9.98,
6.26 Hz, 1 (difluoromethyl)-5-methyl-2- H) 1.79 (s, 3 H) 1.98 (dd,
J = 9.68, 7.34 Hz, 1 H) thia-4-azabicyclo[4.1.0]hept- 2.80 (s, 3 H)
4.47 (q, J = 7.96 Hz, 2 H) 5.49-5.86 3-en-5-yl)-4,5- (m, 1 H)
7.11-7.20 (m, 2 H) 8.02 (ddd, difluorophenyl)-3-methyl-5- J =
11.93, 6.85, 2.74 Hz, 1 H) 8.14 (d, J = 2.74 Hz,
(2,2,2-trifluoroethoxy)-2- 1 H) 9.97 (s, 1 H). pyridinecarboxamide
715 .sup.1H NMR (CHLOROFORM-d) .delta.: 10.02 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.71 (s, 1H), 7.99-8.07 (m, 1H), 7.93
(s, 1H), (ethoxymethyl)-5- 7.62 (dd, J = 6.6, 2.4 Hz, 1H), 7.10
(dd, J = 11.4, (fluoromethyl)-2-thia-4- 8.9 Hz, 1H), 4.64-4.96 (m,
2H), 3.71 (d, J = 10.8 azabicyclo[4.1.0]hept-3-en-5- Hz, 1H),
3.50-3.59 (m, 2H), 3.38 (d, J = 10.6 Hz,
yl)-4-fluorophenyl)-5-cyano- 1H), 2.86 (s, 3H), 1.83 (d, J = 7.6
Hz, 1H), 1.22 3-methyl-2- (t, J = 7.0 Hz, 3H), 1.12 (dd, J = 9.4,
5.9 Hz, 1H), pyridinecarboxamide 0.78 (t, J = 6.2 Hz, 1H) 716
.sup.1H NMR (CHLOROFORM-d) .delta.: 10.02 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-5- 8.71 (s, 1H), 7.98-8.08 (m, 1H), 7.93
(s, 1H), (fluoromethyl)-1- 7.63 (dd, J = 6.7, 2.7 Hz, 1H), 7.10
(dd, J = 11.5, (methoxymethyl)-2-thia-4- 9.0 Hz, 1H), 4.64-4.96 (m,
2H), 3.64 (d, J = 10.6 azabicyclo[4.1.0]hept-3-en-5- Hz, 1H), 3.40
(s, 3H), 3.36 (d, J = 10.6 Hz, 1H), yl)-4-fluorophenyl)-5-cyano-
2.86 (s, 3H), 1.82 (t, J = 8.1 Hz, 1H), 1.09 (dd, 3-methyl-2- J =
9.7, 5.8 Hz, 1H), 0.76 (t, J = 6.3 Hz, 1H) pyridinecarboxamide 718
.sup.1H NMR (CHLOROFORM-d) .delta.: 9.81 (s, 1H),
N-(3-((1R,5S,6S)-3-amino-1- 8.55 (d, J = 2.2 Hz, 1H), 8.23 (d, J =
8.2 Hz, 1H), (cyanomethyl)-5- 7.92-7.99 (m, 1H), 7.88 (dd, J = 8.3,
2.2 Hz, 1H), (fluoromethyl)-2-thia-4- 7.70 (dd, J = 6.7, 2.6 Hz,
1H), 7.10 (dd, J = 11.3, azabicyclo[4.1.0]hept-3-en-5- 8.8 Hz, 1H),
4.54-5.03 (m, 3H), 2.76 (s, 2H), yl)-4-fluorophenyl)-5-chloro-
1.88-2.00 (m, 1H), 1.22 (dd, J = 9.8, 6.5 Hz, 1H),
2-pyridinecarboxamide 0.82 (t, J = 6.7 Hz, 1H) 723 .sup.1H NMR
(CHLOROFORM-d) .delta.: 9.84 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.56 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H),
(2-cyanoethyl)-5- 7.93-8.01 (m, 1H), 7.88 (dd, J = 8.4, 2.3 Hz,
1H), (fluoromethyl)-2-thia-4- 7.66 (dd, J = 6.7, 2.5 Hz, 1H), 7.12
(dd, J = 11.2, azabicyclo[4.1.0]hept-3-en-5- 8.9 Hz, 1H), 4.60-5.10
(m, 2H), 2.53-2.66 (m, yl)-4-fluorophenyl)-5-chloro- 2H), 1.91-2.00
(m, 1H), 1.84 (dd, J = 15.0, 6.6 2-pyridinecarboxamide Hz, 2H),
1.12-1.20 (m, 1H), 0.81 (t, J = 6.6 Hz, 1H) 725 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-5- 9.79 (1
H, s) 8.54 (1 H, d, J = 2.35 Hz) 8.22 (1 H,
(fluoromethyl)-1-((5-methyl- d, J = 8.41 Hz) 7.92-7.99 (1 H, m)
7.87 (1 H, dd, 1H-1,2,3-triazol-1-yl)methyl)- J = 8.41, 2.35 Hz)
7.64 (1 H, dd, J = 6.65, 2.74 Hz) 2-thia-4- 7.47 (1 H, s) 7.10 (1
H, dd, J = l 1.44, 8.90 Hz) azabicyclo[4.1.0]hept-3-en-5- 4.58-4.92
(2 H, m) 4.36-4.52 (2 H, m) 2.39 (3 yl)-4-fluorophenyl)-5-chloro-
H, s) 2.09-2.16 (1 H, m) 1.36 (1 H, dd, J = 9.78,
2-pyridinecarboxamide 6.26 Hz) 1.26 (1 H, s) 0.85 (1 H, t, J = 6.65
Hz). MS (ESI, positive ion) m/z: 504 (M + H)
Method C: SNAr in iPrOH
Example 54:
8-((3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carbon-
itrile
##STR00368##
[1844] A mixture of
((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-1-yl)methanol (Intermediate 206, 75 mg, 0.25
mmol), 8-chloro-1,7-naphthyridine-3-carbonitrile (Intermediate 254,
52 mg, 0.27 mmol) and p-toluenesulfonic acid monohydrate (52 mg,
0.27 mmol) in isopropyl alcohol (2.0 mL) was heated to 75.degree.
C. in an oil bath for 1 h. The reaction mixture was cooled to RT
and partitioned between CHCl.sub.3/iPrOH=9/1 (40 mL) and sat.
NaHCO.sub.3 (10 mL). The organic layer was dried over MgSO.sub.4,
filtered, and then concentrated under reduced pressure to afford a
yellow solid. It was purified by silica gel chromatography (12 g)
eluting with 35-75% EtOAc in DCM to afford
8-((3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carbon-
itrile (Example 54, 97 mg, 0.21 mmol, 86% yield) as yellow
crystalline solid. MS m/z=453.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.76 (br., 1H), 9.24 (d, J=1.76 Hz, 1H), 9.01
(d, J=1.76 Hz, 1H), 8.30 (m, 2H), 7.93 (br., 1H), 7.28 (d, J=5.87
Hz, 1H), 6.00 (br., 2H), 5.05 (t, J=5.58 Hz, 1H), 3.55 (m, 1H),
3.45 (m, 1H), 1.68 (m, 1H), 1.63 (s, 3H), 0.89 (m., 1H), 0.60 (m,
1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -138.70 (d,
J=22.59 Hz, 1 F), -146.08 (d, J=22.59 Hz, 1 F).
[1845] Using procedures analogous or similar to the general SNAr
Method C described above, the appropriate aniline and ArX (X=Cl/Br)
intermediates were reacted to provide the 195 examples listed in
Table 3 and Table 3'.
TABLE-US-00006 TABLE 3 Observed Ex. No. Chemical Structure [M +
H].sup.+ 21 ##STR00369## 423.0 22 ##STR00370## 451.0 24
##STR00371## 476.1 25 ##STR00372## 504.0 26 ##STR00373## 441.0 27
##STR00374## 441.0 32 ##STR00375## 452.0 33 ##STR00376## 467.1 34
##STR00377## 433.0 35 ##STR00378## 477.0 36 ##STR00379## 424.1 38
##STR00380## 423.0 39 ##STR00381## 433.1 45 ##STR00382## 462.0 46
##STR00383## 468.0 47 ##STR00384## 485.1 48 ##STR00385## 471.0 49
##STR00386## 463.1 50 ##STR00387## 453.0 51 ##STR00388## 424.1 52
##STR00389## 482.1 55 ##STR00390## 454.2 56 ##STR00391## 496.1 57
##STR00392## 471.0 58 ##STR00393## 459.0 65 ##STR00394## 473.1 66
##STR00395## 447.0 67 ##STR00396## 477.0/ 479.0 73 ##STR00397##
477.1 80 ##STR00398## 454.1 82 ##STR00399## 483.0 87 ##STR00400##
467.1 88 ##STR00401## 429.1 89 ##STR00402## 458.1 90 ##STR00403##
485.1 91 ##STR00404## 476.1 92 ##STR00405## 463.1 95 ##STR00406##
474.0 101 ##STR00407## 441.9 601 ##STR00408## 468 602 ##STR00409##
511 604 ##STR00410## 437.9 605 ##STR00411## 510.9 608 ##STR00412##
518 611 ##STR00413## 480.2 613 ##STR00414## 487.1 625 ##STR00415##
480.1 626 ##STR00416## 523.1 627 ##STR00417## 497.1 628
##STR00418## 540 629 ##STR00419## 472.2 630 ##STR00420## 531 631
##STR00421## 540.2 635 ##STR00422## 505.2 653 ##STR00423## 486 654
##STR00424## 529 656 ##STR00425## 516 657 ##STR00426## 456 658
##STR00427## 457 659 ##STR00428## 534 660 ##STR00429## 534 662
##STR00430## 466 663 ##STR00431## 545 665 ##STR00432## 534 666
##STR00433## 534 667 ##STR00434## 668 ##STR00435## 577 669
##STR00436## 544 670 ##STR00437## 466 671 ##STR00438## 533 672
##STR00439## 533 676 ##STR00440## 548 677 ##STR00441## 548 703
##STR00442## 472 705 ##STR00443## 544 706 ##STR00444## 544 707
##STR00445## 501 709 ##STR00446## 486 712 ##STR00447## 529 713
##STR00448## 515 714 ##STR00449## 515 717 ##STR00450## 467.1 719
##STR00451## 462 720 ##STR00452## 492 721 ##STR00453## 535.1 724
##STR00454## 548.2 726 ##STR00455## 539.1 727 ##STR00456## 539.1
728 ##STR00457## 539.1 729 ##STR00458## 497 730 ##STR00459## 540.1
731 ##STR00460## 572.1 733 ##STR00461## 496.1 735 ##STR00462##
589.1 736 ##STR00463## 633/635 737 ##STR00464## 555.1 741
##STR00465## 564.1 750 ##STR00466## 544.1 762 ##STR00467## 453 763
##STR00468## 496 768 ##STR00469## 550.1 769 ##STR00470## 593 770
##STR00471## 592 771 ##STR00472## 563 773 ##STR00473## 598 775
##STR00474## 776 ##STR00475## 550 779 ##STR00476## 524 781
##STR00477## 520 801 ##STR00478## 456.2 802 ##STR00479## 528 805
##STR00480## 503.1 806 ##STR00481## 485 808 ##STR00482## 528.2 809
##STR00483## 540.1 812 ##STR00484## 546 813 ##STR00485## 485.1 816
##STR00486## 485 817 ##STR00487## 528 819 ##STR00488## 485.1 823
##STR00489## 467 824 ##STR00490## 467
825 ##STR00491## 510 827 ##STR00492## 481.1 828 ##STR00493## 525
841 ##STR00494## 471 842 ##STR00495## 514.1 843 ##STR00496## 514.1
865 ##STR00497## 499 866 ##STR00498## 545.9 867 ##STR00499## 545.9
868 ##STR00500## 517 869 ##STR00501## 511 870 ##STR00502## 560 871
##STR00503## 525 872 ##STR00504## 542.9 873 ##STR00505## 574 874
##STR00506## 571 875 ##STR00507## 562 876 ##STR00508## 506.9 877
##STR00509## 560.9 878 ##STR00510## 550 879 ##STR00511## 499 880
##STR00512## 543 881 ##STR00513## 551 882 ##STR00514## 555 883
##STR00515## 561.2 884 ##STR00516## 557.3 885 ##STR00517## 555.2
886 ##STR00518## 574.2 887 ##STR00519## 561 888 ##STR00520## 560 2
889 ##STR00521## 577.2 890 ##STR00522## 517.3 891 ##STR00523## 560
892 ##STR00524## 560 893 ##STR00525## 576 894 ##STR00526## 536.9
895 ##STR00527## 479.1 896 ##STR00528## 465.2 897 ##STR00529## 429
898 ##STR00530## 467 900 ##STR00531## 429 901 ##STR00532## 520.1
903 ##STR00533## 510 904 ##STR00534## 466.1 907 ##STR00535## 468.1
908 ##STR00536## 468.1 909 ##STR00537## 482 911 ##STR00538## 496.1
912 ##STR00539## 524.1 917 ##STR00540## 496 918 ##STR00541## 539
923 ##STR00542## 567.1 928 ##STR00543## 460.1 931 ##STR00544## 492
933 ##STR00545## 550.1 936 ##STR00546## 593.2 937 ##STR00547## 564
938 ##STR00548## 607.1 941 ##STR00549## 453.2 942 ##STR00550## 497
944 ##STR00551## 468 945 ##STR00552## 503 946 ##STR00553## 517 947
##STR00554## 517.2 948 ##STR00555## 568 949 ##STR00556## 563 950
##STR00557## 557 2 951 ##STR00558## 514 952 ##STR00559## 578 957
##STR00560## 463.2 958 ##STR00561## 534.1 960 ##STR00562## 520.1
961 ##STR00563## 472
TABLE-US-00007 TABLE 3' Ex. No. .sup.1H-NMR Chemical Name 21
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.74 (s, 1 H),
8-((3-((1S,5S,6S)-3-amino-5- 9.23 (d, J = 1.96 Hz, 1 H), 9.00 (d, J
= 1.96 Hz, 1 H), methyl-2-thia-4- 8.34 (ddd, J = 12.96, 6.80, 2.74
Hz, 1 H), 8.27 (d, azabicyclo[4.1.0]hept-3-en-5- J = 5.87 Hz, 1 H),
7.91 (d, J = 5.35 Hz, 1 H), 7.27 (d, yl)-4,5-difluorophenyl)amino)-
J = 5.67 Hz, 1 H), 5.96 (s, 2 H), 2.29-2.37 (m, 1 H),
1,7-naphthyridine-3- 1.69-1.80 (m, 1 H), 1.66 (s, 3 H), 0.89 (td, J
= 8.12, carbonitrile 5.28 Hz, 1 H), 0.50 (q, J = 5.28 Hz, 1 H) 22
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.51 (s, 1 H)
N-(3-((1S,5S,6S)-3-amino-5- 8.96 (d, J = 2.35 Hz, 1 H) 8.75 (s, 1
H) 8.44 (d, J = 2.15 (fluoromethyl)-2-thia-4- Hz, 1 H) 8.18 (ddd, J
= 12.47, 6.80, 2.64 Hz, 1 H) 8.11- azabicyclo[4.1.0]hept-3-en-5-
8.14 (m, 1 H) 6.28 (s, 2 H) 4.66-4.84 (m, 2 H) 2.40-
yl)-4,5-difluorophenyl)-7- 2.47 (m, 1 H) 1.78 (q, J = 8.35 Hz, 1 H)
1.11 (ddd, chloropyrido[3,2-d]pyrimidin- J = 8.90, 7.53, 5.28 Hz, 1
H) 0.46 (q, J = 5.28 Hz, 1 H) 4-amine 24 .sup.1H NMR (400 MHz,
CHLOROFORM-d) Shift 9.01 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.70
(d, J = 1.76 Hz, 1H), 8.41-8.55 (m, 1H),
(methoxymethyl)-5-methyl-2- 8.16 (d, J = 5.87 Hz, 1H), 8.02 (d, J =
1.96 Hz, 1H), 7.40 thia-4-azabicyclo[4.1.0]hept-3- (d, J = 3.52 Hz,
1H), 6.95 (d, J = 5.67 Hz, 1H), 3.69 (d,
en-5-yl)-4,5-difluorophenyl)-3- J = 10.76 Hz, 1H), 3.43 (s, 3H),
3.36 (d, J = 10.76 Hz, chloro-1,7-naphthyridin-8- 1H), 1.78-1.90
(m, 1H), 1.75 (s, 3H), 0.92 (dd, J = 5.97, amine 9.29 Hz, 1H),
0.79-0.87 (m, 1H) 25 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.70
(s, 1H), 8.94 ethyl (1S,5S,6S)-3-amino-5-(5- (d, J = 2.35 Hz, 1H),
8.56 (d, J = 2.15 Hz, 1H), 8.40-8.48 ((3-chloro-1,7-naphthyridin-8-
(m, 1H), 8.20 (d, J = 5.87 Hz, 1H), 7.93-7.99 (m, 1H),
yl)amino)-2,3-difluorophenyl)- 7.23 (d, J = 5.67 Hz, 1H), 6.23 (s,
2H), 4.20 (q, J = 6.98 5-methyl-2-thia-4- Hz, 2H), 2.35 (t, J =
8.61 Hz, 1H), 1.65 (s, 3H), 1.52 azabicyclo[4.1.0]hept-3-ene-1-
(dd, J = 4.99, 9.68 Hz, 1H), 1.24 (t, J = 7.14 Hz, 3H), carboxylate
1.11 (dd, J = 5.09, 7.04 Hz, 1H) 26 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 9.82 (s, 1 H) 8-((3-((1S,5S,6S)-3-amino-5- 9.24 (d, J =
1.17 Hz, 1 H) 9.01 (d, J = 1.20 Hz, 1 H) 8.31-
(fluoromethyl)-2-thia-4- 8.39 (m, 1 H) 8.28 (d, J = 5.67 Hz, 1 H)
7.98-8.03 azabicyclo[4.1.0]hept-3-en-5- (m, 1 H) 7.28 (d, J = 5.67
Hz, 1 H) 6.28 (s, 2 H) 4.65- yl)-4,5-difluorophenyl)amino)- 4.84
(m, 2 H) 2.38-2.46 (m, 1 H) 1.73-1.82 (m, 1 H) 1,7-naphthyridine-3-
1.05-1.13 (m, 1 H) 0.42-0.49 (m, 1 H) carbonitrile 27 .sup.1H NMR
(400 MHz, CHLOROFORM-d) 8.89-8.96 8-((3-((1R,5S,6R)-3-amino-5- (m,
2 H) 8.39 (s, 1 H) 8.26-8.33 (m, 1 H) 8.22 (d,
(fluoromethyl)-2-thia-4- J = 5.87 Hz, 1 H) 7.38 (br. s., 1 H) 7.04
(d, J = 5.67 Hz, azabicyclo[4.1.0]hept-3-en-5- 1 H) 4.60-4.86 (m, 2
H) 2.17-2.24 (m, 1 H) 2.02- yl)-4,5-difluorophenyl)amino)- 2.14 (m,
1 H) 1.07-1.21 (m, 2 H) 1,7-naphthyridine-3- carbonitrile 32
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.96
N-(3-((1S,5S,6S)-3-amino-5- (s, 1 H), 8.47-8.56 (m, 2 H), 8.09 (d,
J = 5.87 Hz, 1 methyl-2-thia-4- H), 7.32-7.40 (m, 2 H), 7.13-7.20
(m, 1 H), 6.96 (d, azabicyclo[4.1.0]hept-3-en-5- J = 5.87 Hz, 1 H),
4.86 (d, J = 2.35 Hz, 2 H), 4.67 (br. s.,
yl)-4,5-difluorophenyl)-3-(2- 1 H), 2.62 (t, J = 2.45 Hz, 1 H),
2.17-2.28 (m, 1 H), propyn-1-yloxy)-1,7- 1.86-2.02 (m, 1 H),
1.74-1.85 (s, 3 H), 0.83-1.05 naphthyridin-8-amine (m, 1 H), 0.64
(q, J = 5.80 Hz, 1 H) 33 .sup.1H NMR (400 MHz, DMSO-d6) .delta.
9.76 (s, 1H), 9.24 8-((3-((1S,5S,6S)-3-amino-1- (d, J = 1.96 Hz,
1H), 9.01 (d, J = 1.96 Hz, 1H), 8.36 (m,
(methoxymethyl)-5-methyl-2- 1H), 8.25 (m, 1H), 7.94 (m, 1H), 7.28
(d, J = 5.87 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1H), 6.03 (br.,
2H), 3.58 (d, J = 10.95 Hz, 1H), 3.38 (m, en-5-yl)-4,5- 1H), 3.29
(s, 3H), 1.68 (m, 1H), 1.60 (s, 3H), 0.93 (dd,
difluorophenyl)amino)-1,7- J = 5.18, 9.29 Hz, 1H), 0.67 (t, J =
5.77 Hz, 1H). naphthyridine-3-carbonitrile 34 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 10.43 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-5-
8.94 (d, J = 2.15 Hz, 1 H), 8.73 (s, 1 H), 8.42 (d, J = 2.15
methyl-2-thia-4- Hz, 1 H), 8.13 (ddd, J = 12.42, 6.75, 2.74 Hz, 1
H), azabicyclo[4.1.0]hept-3-en-5- 8.04 (d, J = 5.91 Hz, 1 H), 5.94
(s, 2 H), 2.30-2.38 (m, yl)-4,5-difluorophenyl)-7- 1 H), 1.70-1.76
(m, 1 H), 1.67 (s, 3 H), 0.90 (td, chloropyrido[3,2-d]pyrimidin- J
= 8.17, 5.18 Hz, 1 H), 0.49 (q, J = 5.15 Hz, 1 H) 4-amine 35
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.46 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.96 (d, J = 2.15 Hz, 1H), 8.75 (s,
1H), 8.44 (d, J = 2.15 (methoxymethyl)-5-methyl-2- Hz, 1H), 8.16
(m, 1H), 8.07 (d, J = 5.84 Hz, 1H), 6.02
thia-4-azabicyclo[4.1.0]hept-3- (br., 2H), 3.58 (d, J = 10.76 Hz,
1H), 3.39 (m, 1H), 3.32 en-5-yl)-4,5-difluorophenyl)-7- (s, 3H),
1.69 (m, 1H), 1.65 (s, 3H), 0.94 (dd, J = 5.18,
chloropyrido[3,2-d]pyrimidin- 9.29 Hz, 1H), 0.67 (t, J = 5.77 Hz,
1H). 4-amine 36 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 10.58
(s, 1 H), 4-((3-((1S,5S,6S)-3-amino-5- 9.25 (d, J = 1.96 Hz, 1 H),
8.90 (d, J = 1.96 Hz, 1 H), methyl-2-thia-4- 8.80 (s, 1 H),
8.05-8.16 (m, 2 H), 5.95 (s, 2 H), 2.30-
azabicyclo[4.1.0]hept-3-en-5- 2.37 (m, 1 H), 1.70-1.76 (m, 1 H),
1.67 (s, 3 H), 0.90 yl)-4,5- (td, J = 8.17, 5.38 Hz, 1 H), 0.49 (q,
J = 5.28 Hz, 1 H) difluorophenyl)amino)pyrido[3,
2-d]pyrimidine-7-carbonitrile 38 .sup.1H NMR (DMSO-d6) .delta.:
9.62 (s, 1H), 9.22 (d, J = 1.8 8-((3-((1S,5S,6S)-3-amino-5- Hz,
1H), 8.98 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 5.7 Hz,
(fluoromethyl)-2-thia-4- 1H), 8.07-8.16 (m, 2H), 7.22 (d, J = 5.9
Hz, 1H), 7.17 azabicyclo[4.1.0]hept-3-en-5- (dd, J = 11.8, 8.5 Hz,
1H), 6.24 (s, 2H), 4.74-4.86 (m, yl)-4-fluorophenyl)amino)-1,7-
1H), 4.61-4.74 (m, 1H), 2.35-2.43 (m, 1H), 1.77 (q,
naphthyridine-3-carbonitrile J = 7.8 Hz, 1H), 0.99-1.08 (m, 1H),
0.39 (q, J = 5.2 Hz, 1H) 39 .sup.1H NMR (DMSO-d6) .delta.: 10.34
(s, 1H), 8.93 (d, J = 2.2 N-(3-((1S,5S,6S)-3-amino-5- Hz, 1H), 8.67
(s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.20 (fluoromethyl)-2-thia-4-
(dd, J = 7.0, 2.3 Hz, 1H), 7.78-7.99 (m, 1H), 7.21 (dd,
azabicyclo[4.1.0]hept-3-en-5- J = 11.8, 8.7 Hz, 1H), 6.23 (s, 2H),
4.75-4.88 (m, 1H), yl)-4-fluorophenyl)-7- 4.59-4.75 (m, 1H),
2.36-2.45 (m, 1H), 1.78 (q, J = 7.4 chloropyrido[3,2-d]pyrimidin-
Hz, 1H), 1.05 (ddd, J = 8.9, 7.6, 5.2 Hz, 1H), 0.40 (q, 4-amine J =
5.2 Hz, 1H) 45 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.49 (s,
1H), ((1S,5S,6S)-3-amino-5-(5-((3- 8.92 (d, J = 2.35 Hz, 1H), 8.52
(d, J = 2.35 Hz, 1H), chloro-1,7-naphthyridin-8- 8.13-8.19 (m, 2H),
8.10 (dd, J = 7.04, 2.74 Hz, 1H), yl)amino)-2-fluorophenyl)-5-
7.13-7.20 (m, 2H), 6.26 (s, 2H), 5.06 (t, J = 5.90 Hz,
(fluoromethyl)-2-thia-4- 1H), 4.78 (dd, J = 12.72, 8.80 Hz, 1H),
4.66 (dd, azabicyclo[4.1.0]hept-3-en-1- J = 12.91, 8.40 Hz, 1H),
3.56 (dd, J = 11.74, 6.06 Hz, yl)methanol 1H), 3.43 (dd, J = 11.64,
5.58 Hz, 1H), 1.67 (t, J = 8.20 Hz, 1H), 1.02 (dd, J = 9.19, 5.09
Hz, 1H), 0.53 (t, J = 5.70 Hz, 1H) 46 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 10.59 (s, 1 H), 4-((3-((1S,5S,6S)-3-amino-1-
9.25 (d, J = 1.96 Hz, 1 H), 8.90 (d, J = 1.96 Hz, 1 H),
(methoxymethyl)-5-methyl-2- 8.80 (s, 1 H), 8.06-8.17 (m, 2 H), 6.01
(br. s., 2 H), thia-4-azabicyclo[4.1.0]hept-3- 3.57 (d, J = 10.95
Hz, 1 H), 3.36 (d, J = 10.95 Hz, 1 H), en-5-yl)-4,5- 3.30 (s, 3 H),
1.60-1.68 (m, 4 H), 0.93 (dd, J = 9.19,
difluorophenyl)amino)pyrido[3, 5.28 Hz, 1 H), 0.65 (t, J = 5.77 Hz,
1 H) 2-d]pyrimidine-7-carbonitrile 47 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 9.84 (s, 1 H) 8-((3-((1S,5S,6S)-3-amino-5-
9.25 (d, J = 1.96 Hz, 1 H) 9.02 (d, J = 1.96 Hz, 1 H) 8.37
(fluoromethyl)-1- (ddd, J = 13.11, 6.85, 2.74 Hz, 1 H) 8.29 (d, J =
5.67 Hz, (methoxymethyl)-2-thia-4- 1 H) 8.01-8.04 (m, 1 H) 7.30 (d,
J = 5.87 Hz, 1 H) azabicyclo[4.1.0]hept-3-en-5- 6.35 (s, 2 H)
4.62-4.80 (m, 2 H) 3.58 (d, J = 10.95 Hz,
yl)-4,5-difluorophenyl)amino)- 1 H) 3.37 (d, J = 10.95 Hz, 1 H)
3.31 (s, 3 H) 1.66- 1,7-naphthyridine-3- 1.72 (m, 1H) 1.15 (dd, J =
9.49, 5.18 Hz, 1H) 0.67 (t, carbonitrile J = 5.87 Hz, 1 H) 48
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.84 (br. s., 1
8-((3-((1S,5S,6S)-3-amino-5- H) 9.24 (d, J = 1.17 Hz, 1 H) 9.01 (d,
J = 1.17 Hz, 1 H) (fluoromethyl)-1- 8.37 (ddd, J = 12.91, 6.50,
2.15 Hz, 1 H) 8.28 (d, (hydroxymethyl)-2-thia-4- J = 5.67 Hz, 1 H)
8.02 (br. s., 1 H) 7.29 (d, J = 5.67 Hz,
azabicyclo[4.1.0]hept-3-en-5- 1 H) 6.30 (br. s., 2 H) 5.10 (br. s.,
1 H) 4.59-4.86 (m, yl)-4,5-difluorophenyl)amino)- 2 H) 3.55 (dd, J
= 11.54, 6.06 Hz, 1 H) 3.45 (dd, 1,7-naphthyridine-3- J = 11.35,
5.28 Hz, 1 H) 1.68 (br. s., 1 H) 1.09 (br. s., 1 carbonitrile H)
0.60 (br. s., 1 H) 49 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 9.00 ((1S,5S,6S)-3-amino-5-(5-((7- (s, 1H), 8.72 (s, 1H), 8.68
(d, J = 2.15 Hz, 1H), 8.12- chloropyrido[3,2-d]pyrimidin- 8.20 (m,
2H), 7.79 (dd, J = 6.65, 2.74 Hz, 1H), 7.13
4-yl)amino)-2-fluorophenyl)-5- (dd, J = 11.35, 8.80 Hz, 1H), 4.93
(dd, J = 46.56, 8.41 (fluoromethyl)-2-thia-4- Hz, 1H), 4.79 (s br,
2H), 4.70 (dd, J = 47.34, 8.41 Hz, azabicyclo[4.1.0]hept-3-en-1-
1H), 3.76 (d, J = 11.93 Hz, 1H), 3.62 (d, J = 11.74 Hz, yl)methanol
1H), 1.85 (t, J = 7.92 Hz, 1H), 1.84 (s br, 1H), 1.10 (dd, J =
9.59, 5.87 Hz, 1H), 0.72 (t, J = 6.26 Hz, 1H) 50 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 9.63 (s, 1H),
8-((3-((1S,5S,6S)-3-amino-5- 9.23 (d, J = 1.96 Hz, 1H), 8.99 (d, J
= 1.96 Hz, 1H), 8.23 (fluoromethyl)-1- (d, J = 5.67 Hz, 1H),
8.11-8.17 (m, 2H), 7.23 (d, J = 5.86 (hydroxymethyl)-2-thia-4- Hz,
1H), 7.18 (dd, J = 11.74, 9.00 Hz, 1H), 6.26 (s,
azabicyclo[4.1.0]hept-3-en-5- 2H), 5.06 (t, J = 5.97 Hz, 1H), 4.78
(dd, J = 13.11, 9.00 yl)-4-fluorophenyl)amino)-1,7- Hz, 1H), 4.66
(dd, J = 14.08, 9.00 Hz, 1H), 3.56 (dd,
naphthyridine-3-carbonitrile J = 11.35, 6.26 Hz, 1H), 3.43 (dd, J =
11.93, 5.67 Hz, 1H), 1.66 (t, J = 8.60 Hz, 1H), 1.02 (dd, J = 9.39,
4.30 Hz, 1H), 0.53 (t, J = 5.70 Hz, 1H) 51 .sup.1H NMR (DMSO-d6)
.delta.: 10.50 (s, 1H), 9.25 (d, J = 1.8
4-((3-((1S,5S,6S)-3-amino-5- Hz, 1H), 8.88 (d, J = 2.0 Hz, 1H),
8.74 (s, 1H), 8.23 (fluoromethyl)-2-thia-4- (dd, J = 7.2, 2.7 Hz,
1H), 7.88-8.00 (m, 1H), 7.23 (dd, azabicyclo[4.1.0]hept-3-en-5- J =
11.7, 8.8 Hz, 1H), 6.23 (s, 2H), 4.75-4.87 (m, 1H), yl)-4-
4.64-4.75 (m, 1H), 2.37-2.46 (m, 1H), 1.73-1.86 (m,
fluorophenyl)amino)pyrido[3,2- 1H), 1.05 (ddd, J = 9.0, 7.5, 5.2
Hz, 1H), 0.40 (q, J = 5.3 d]pyrimidine-7-carbonitrile Hz, 1H) 52
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.89
((1S,5S,6S)-3-amino-5- (s, 1H), 8.52 (d, J = 2.74 Hz, 1H), 8.26
(dt, J = 8.36, 3.74 (fluoromethyl)-5-(2-fluoro-5- Hz, 1H), 8.05 (d,
J = 5.67 Hz, 1H), 7.69 (dd, J = 6.85, ((3-(2-propyn-1-yloxy)-1,7-
2.74 Hz, 1H), 7.37 (d, J = 2.74 Hz, 1H), 7.09 (dd, naphthyridin-8-
J = 11.54, 8.80 Hz, 1H), 6.92 (d, J = 5.87 Hz, 1H), 4.97
yl)amino)phenyl)-2-thia-4- (dd, J = 47.34, 8.41 Hz, 1H), 4.85 (d, J
= 2.35 Hz, 2H), azabicyclo[4.1.0]hept-3-en-1-
4.67 (s br, 2H), 4.66 (dd, J = 47.34, 8.61 Hz, 1H), 3.75
yl)methanol (d, J = 11.74 Hz, 1H), 3.60 (d, J = 11.93 Hz, 1H), 2.62
(t, J = 2.35 Hz, 1H), 1.86 (t, J = 8.20 Hz, 1H), 1.75 (s br, 1H),
1.08 (dd, J = 9.68, 5.77 Hz, 1H), 0.73 (t, J = 6.26 Hz, 1H) 55
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.65 (br., 1H),
4-((3-((1S,5S,6S)-3-amino-1- 9.32 (d, J = 1.76 Hz, 1H), 8.96 (d, J
= 1.96 Hz, 1H), 8.86 (hydroxymethyl)-5-methyl-2- (s, 1H), 8.12-8.23
(m, 2H), 6.02 (br., 2H), 5.10 (t, thia-4-azabicyclo[4.1.0]hept-3- J
= 5.97 Hz, 1H), 3.60 (m, 1H), 3.51 (m, 1H), 1.65-1.73 en-5-yl)-4,5-
(m, 4H), 0.94 (m, 1H), 0.63 (t, J = 5.67 Hz, 1H).
difluorophenyl)amino)pyrido[3, 2-d]pyrimidine-7-carbonitrile 56
.sup.1H NMR (DMSO-d6) .delta.: 9.41 (s, 1H), 8.66 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-5- 8.26 (d, J = 5.9 Hz, 1H), 8.23 (d, J =
0.8 Hz, 1H), 7.99- (fluoromethyl)-2-thia-4- 8.14 (m, 2H), 7.32 (d,
J = 0.8 Hz, 1H), 7.15 (dd, azabicyclo[4.1.0]hept-3-en-5- J = 11.7,
8.8 Hz, 1H), 7.06 (d, J = 5.9 Hz, 1H), 6.23 (s,
yl)-4-fluorophenyl)-2-(1,3- 2H), 5.68 (s, 2H), 4.75-4.88 (m, 1H),
4.61-4.74 (m, oxazol-2- 1H), 2.36-2.45 (m, 1H), 1.77 (q, J = 7.5
Hz, 1H), 1.04 ylmethoxy)pyrido[3,4- (ddd, J = 9.0, 7.4, 5.1 Hz,
1H), 0.39 (q, J = 5.1 Hz, 1H) b]pyrazin-5-amine 57 .sup.1H NMR
(DMSO-d6) 9.89 (s, 1 H) 9.25 (d, J = 1.96 Hz,
8-((3-((1R,5S,6R)-3-amino-5- 1 H) 9.03 (d, J = 1.96 Hz, 1 H) 8.28
(d, J = 5.67 Hz, 1 H) (fluoromethyl)-1- 8.15-8.22 (m, 2 H) 7.31 (d,
J = 5.87 Hz, 1 H) 6.24 (s, (hydroxymethyl)-2-thia-4- 2 H) 5.13 (t,
J = 5.77 Hz, 1 H) 4.80 (dd, J = 48.12, 9.39
azabicyclo[4.1.0]hept-3-en-5- Hz, 1 H) 4.51 (dd, J = 47.34, 9.19
Hz, 1 H) 3.77 (dd, yl)-4,5-difluorophenyl)amino)- J = 11.74, 6.65
Hz, 1 H) 3.56 (dd, J = 11.83, 5.18 Hz, 1 1,7-naphthyridine-3- H)
1.89 (dd, J = 9.19, 6.06 Hz, 1 H) 1.08 (dd, J = 9.39, carbonitrile
5.28 Hz, 1 H) 0.93 (t, J = 5.58 Hz, 1 H) 58 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.13 (br., 1H), ((1S,5S,6S)-3-amino-5-(2,3- 8.67
(m, 2H), 8.21 (m, 1H), 8.02 (br., 1H), 7.64 (br., difluoro-5-((7-
1H), 5.98 (br., 2H), 5.05 (t, J = 5.38 Hz, 1H), 4.02 (s,
methoxypyrido[3,2- 3H), 3.56 (m, 1H), 3.46 (m, 1H), 1.66 (m, 1H),
1.63 d]pyrimidin-4- (s, 3H), 0.90 (m, 1H), 0.60 (m, 1H).
yl)amino)phenyl)-5-methyl-2- thia-4-azabicyclo[4.1.0]hept-3-
en-1-yl)methanol 65 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
10.12 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-1- 8.66 (s, 1 H), 8.64 (s,
1 H), 8.18 (ddd, J = 12.62, 6.75, (methoxymethyl)-5-methyl-2- 2.74
Hz, 1 H), 7.98-8.03 (m, 1 H), 7.62 (d, J = 2.74
thia-4-azabicyclo[4.1.0]hept-3- Hz, 1 H), 6.00 (s, 2 H), 4.01 (s, 3
H), 3.57 (d, J = 10.95 en-5-yl)-4,5-difluorophenyl)-7- Hz, 1 H),
3.32-3.38 (m, 1 H), 3.30 (s, 3H), 1.58- methoxypyrido[3,2- 1.68 (m,
4 H), 0.92 (dd, J = 9.29, 5.18 Hz, 1 H), 0.66 (t,
d]pyrimidin-4-amine J = 5.77 Hz, 1 H) 66 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. ppm 10.19 (s, 1 H) N-(3-((1S,5S,6S)-3-amino-5-
8.69 (s, 1 H) 8.66 (d, J = 2.74 Hz, 1 H) 8.21 (ddd,
(fluoromethyl)-2-thia-4- J = 12.72, 6.85, 2.74 Hz, 1 H) 8.07-8.11
(m, 1 H) 7.64 azabicyclo[4.1.0]hept-3-en-5- (d, J = 2.74 Hz, 1 H)
6.27 (s, 2 H) 4.66-4.84 (m, 2 H) yl)-4,5-difluorophenyl)-7- 4.02
(s, 3 H) 2.40-2.46 (m, 1 H) 1.78 (m, J = 7.69, methoxypyrido[3,2-
7.69, 7.69 Hz, 1 H) 1.11 (ddd, J = 8.90, 7.53, 5.09 Hz, 1
d]pyrimidin-4-amine H) 0.46 (q, J = 5.28 Hz, 1 H) 67 .sup.1H NMR
(DMSO-d6) .delta.: 9.45 (s, 1H), 9.30 (d, J = 2.2
N-(3-((1S,5S,6S)-3-amino-5- Hz, 1H), 9.14 (s, 1H), 8.85 (d, J = 2.3
Hz, 1H), 8.17- (fluoromethyl)-2-thia-4- 8.26 (m, 1H), 7.98 (dd, J =
7.0, 2.7 Hz, 1H), 7.20 (dd, azabicyclo[4.1.0]hept-3-en-5- J = 11.8,
8.9 Hz, 1H), 6.18 (s, 2H), 4.76-4.87 (m, 1H),
yl)-4-fluorophenyl)-3- 4.63-4.75 (m, 1H), 2.35-2.44 (m, 1H),
1.74-1.85 (m, bromopyrido[2,3-d]pyridazin- 1H), 0.97-1.07 (m, 1H),
0.44 (q, J = 5.2 Hz, 1H) 8-amine 73 .sup.1H NMR (DMSO-d6) .delta.:
10.35 (s, 1H), 8.94 (d, J = 2.3 N-(3-((1S,5S,6S)-3-amino-5- Hz,
1H), 8.68 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.22 (fluoromethyl)-1-
(dd, J = 7.2, 2.7 Hz, 1H), 7.95 (dt, J = 8.8, 3.4 Hz, 1H),
(methoxymethyl)-2-thia-4- 7.22 (dd, J = 11.7, 8.8 Hz, 1H), 6.29 (s,
2H), 4.50-4.92 azabicyclo[4.1.0]hept-3-en-5- (m, 2H), 3.34-3.64 (m,
2H), 3.30 (s, 3H), 1.60-1.82 yl)-4-fluorophenyl)-7- (m, 1H), 1.10
(dd, J = 9.5, 5.2 Hz, 1H), 0.60 (t, J = 5.9
chloropyrido[3,2-d]pyrimidin- Hz, 1H) 4-amine 80 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 9.09 4-((3-((1S,5S,6S)-3-amino-5-
(s, 1H), 8.92 (d, J = 1.76 Hz, 1H), 8.80 (s, 1H), 8.48 (d,
(fluoromethyl)-1- J = 1.76 Hz, 1H), 8.19 (dt, J = 8.56, 3.55 Hz,
1H), 7.82 (hydroxymethyl)-2-thia-4- (dd, J = 6.65, 2.74 Hz, 1H),
7.16 (dd, J = 11.25, 8.90 Hz, azabicyclo[4.1.0]hept-3-en-5- 1H),
4.92 (dd, J = 47.14, 8.61 Hz, 1H), 4.78 (s br, 2H), yl)-4- 4.71
(dd, J = 47.54, 8.61 Hz, 1H), 3.76 (d, J = 11.93 Hz,
fluorophenyl)amino)pyrido[3,2- 1H), 3.62 (d, J = 11.74 Hz, 1H),
1.85 (t, J = 8.02 Hz, d]pyrimidine-7-carbonitrile 1H), 1.65 (s br,
1H), 1.10 (dd, J = 9.59, 5.87 Hz, 1H), 0.72 (t, J = 6.26 Hz, 1H) 82
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.55 (br., 1H), 8.64
((1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.28-8.35 (m, 2H), 7.91 (d, J
= 5.67 Hz, 1H), difluoro-5-((2-(2-propyn-1- 7.14 (d, J = 5.87 Hz,
1H), 5.97 (br. s., 2H), 5.21 (d, yloxy)pyrido[3,4-b]pyrazin-5- J =
2.35 Hz, 2H), 5.05 (t, J = 5.77 Hz, 1H), 3.68 (t,
yl)amino)phenyl)-5-methyl-2- J = 2.35 Hz, 1H), 3.56 (dd, J = 6.26,
11.54 Hz, 1H), 3.46 thia-4-azabicyclo[4.1.0]hept-3- (dd, J = 5.67,
11.74 Hz, 1H), 1.68 (m, 1H), 1.63 (s, en-1-yl)methanol 3H), 0.89
(m, 1H), 0.60 (m, 1H). 87 .sup.1H NMR (CHLOROFORM-d) .delta.: 9.02
(s, 1H), 8.90 (s, N-(3-((1S,5S,6S)-3-amino-5- 1H), 8.41 (d, J = 5.9
Hz, 1H), 7.95-8.04 (m, 2H), 7.32 (fluoromethyl)-2-thia-4- (d, J =
6.1 Hz, 1H), 7.15 (dd, J = 11.1, 9.1 Hz, 1H), 4.80-
azabicyclo[4.1.0]hept-3-en-5- 5.15 (m, 2H), 2.41-2.72 (m, 1H),
2.14-2.38 (m, 1H), yl)-4-fluorophenyl)-2- 1.28-1.49 (m, 1H), 0.69
(q, J = 5.9 Hz, 1H) (trifluoromethyl)pyrido[3,4- b]pyrazin-5-amine
88 .sup.1H NMR (DMSO-d6) .delta.: 10.00 (s, 1H), 8.63 (d, J = 2.5
N-(3-((1S,5S,6S)-3-amino-5- Hz, 1H), 8.60 (s, 1H), 8.17 (dd, J =
7.0, 2.7 Hz, 1H), (fluoromethyl)-2-thia-4- 7.91-8.01 (m, 1H), 7.61
(d, J = 2.7 Hz, 1H), 7.19 (dd, azabicyclo[4.1.0]hept-3-en-5- J =
11.8, 8.9 Hz, 1H), 6.22 (s, 2H), 4.74-4.85 (m, 1H),
yl)-4-fluorophenyl)-7- 4.63-4.73 (m, 1H), 4.01 (s, 3H), 2.34-2.44
(m, 1H), methoxypyrido[3,2- 1.77 (q, J = 8.0 Hz, 1H), 0.99-1.10 (m,
1H), 0.39 (q, d]pyrimidin-4-amine J = 5.3 Hz, 1H) 89 .sup.1H NMR
(400 MHz, CHLOROFORM-d) Shift 8.96 ((1S,5S,6S)-3-amino-5-(2,3- (s,
1H), 8.43-8.57 (m, 2H), 8.09 (d, J = 5.87 Hz, 1H),
difluoro-5-((3-methoxy-1,7- 7.31-7.41 (m, 1H), 7.25 (d, J = 2.74
Hz, 1H), 6.96 (d, naphthyridin-8- J = 5.67 Hz, 1H), 3.98 (s, 3H),
3.66-3.76 (m, 2H), 3.50 yl)amino)phenyl)-5-methyl-2- (s, 1H),
1.82-1.87 (m, 1H), 1.76 (s, 3H), 0.92 (dd,
thia-4-azabicyclo[4.1.0]hept-3- J = 6.06, 9.19 Hz, 1H), 0.81 (t, J
= 6.26 Hz, 1H) en-1-yl)methanol 90 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. ppm 9.80 (s, 1 H) 8-((3-((1R,5S,6R)-3-amino-5- 9.25 (d, J =
1.96 Hz, 1 H) 9.02 (d, J = 1.96 Hz, 1 H) 8.27 (fluoromethyl)-1- (d,
J = 5.67 Hz, 1 H) 8.18-8.25 (m, 1 H) 8.15-8.18
(methoxymethyl)-2-thia-4- (m, 1 H) 7.30 (d, J = 5.67 Hz, 1 H) 6.29
(s, 2 H) 4.44- azabicyclo[4.1.0]hept-3-en-5- 4.87 (m, 2 H) 3.72 (d,
J = 10.95 Hz, 1 H) 3.49 (d, yl)-4,5-difluorophenyl)amino)- J =
10.95 Hz, 1 H) 3.29 (s, 3 H) 1.92 (dd, J = 9.00, 6.26
1,7-naphthyridine-3- Hz, 1 H) 1.10 (dd, J = 9.39, 5.48 Hz, 1 H)
1.01 (t, carbonitrile J = 5.70 Hz, 1 H) 91 .sup.1H NMR (400 MHz,
CHLOROFORM-d) Shift 8.78 ((1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.55
(d, J = 2.74 Hz, 1H), 8.42 (ddd, J = 2.74, difluoro-5-((5-fluoro-3-
6.85, 12.72 Hz, 1H), 7.99 (d, J = 1.56 Hz, 1H), 7.48 (d,
methoxy-1,7-naphthyridin-8- J = 2.93 Hz, 1H), 7.31-7.40 (m, 1H),
3.98-4.05 (m, 3H), yl)amino)phenyl)-5-methyl-2- 3.65-3.79 (m, 2H),
3.50 (s, 1H), 1.81-1.88 (m, 1H), thia-4-azabicyclo[4.1.0]hept-3-
1.76 (s, 3H), 0.92 (dd, J = 5.87, 9.39 Hz, 1H), 0.80 (t,
en-1-yl)methanol J = 6.16 Hz, 1H) 92 .sup.1H NMR (400 MHz,
CHLOROFORM-d) Shift 9.07 ((1S,5S,6S)-3-amino-5-(5-((7- (s, 1H),
8.79 (s, 1H), 8.72 (d, J = 2.15 Hz, 1H), 8.37-
chloropyrido[3,2-d]pyrimidin- 8.50 (m, 1H), 8.18 (d, J = 2.15 Hz,
1H), 7.44-7.57 (m, 4-yl)amino)-2,3- 1H), 3.61-3.81 (m, 2H),
1.84-1.90 (m, 1H), 1.76 (s, difluorophenyl)-5-methyl-2- 3H), 0.92
(dd, J = 5.97, 9.10 Hz, 1H), 0.80 (t, J = 6.16
thia-4-azabicyclo[4.1.0]hept-3- Hz, 1H) en-1-yl)methanol 95 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 10.64 (br., 1H),
4-((3-((1S,5S,6S)-3-amino-1- 9.27 (d, J = 1.96 Hz, 1H), 8.92 (d, J
= 1.96 Hz, 1H), 8.82 (difluoromethyl)-5-methyl-2- (s, 1H),
8.07-8.16 (m, 2H), 6.35 (s, 2H), 5.81-6.09 (m,
thia-4-azabicyclo[4.1.0]hept-3- 1H), 1.94 (m, 1H), 1.70 (s, 3H),
1.39 (m, 1H), 0.77 en-5-yl)-4,5- (m, 1H).
difluorophenyl)amino)pyrido[3, 2-d]pyrimidine-7-carbonitrile 101
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm 1.77
4-((3-((1R,5S,6R)-3-amino-7,7- (s, 3 H) 2.67-2.80 (m, 1 H)
2.91-3.02 (m, 1 H) 4.66 difluoro-5-methyl-2-thia-4- (br., 2 H)
7.16-7.24 (m, 1 H) 7.86-7.94 (m, 1 H) azabicyclo[4.1.0]hept-3-en-5-
8.22-8.33 (m, 1 H) 8.47-8.57 (m, 1 H) 8.82-8.89 yl)-4- (m, 1 H)
8.92-9.00 (m, 1 H) 9.12-9.23 (m, 1 H)
fluorophenyl)amino)pyrido[3,2- d]pyrimidine-7-carbonitrile 601
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.92-8.96
N-(5-((1S,5S,6S)-3-amino-1- (m, 1H), 8.58 (s, 1H), 8.35-8.41 (m,
2H), 8.29 (d, (fluoromethyl)-5-methyl-2-thia- J = 5.99 Hz, 1H),
7.11 (d, J = 5.85 Hz, 1H), 5.18 (d, 4-azabicyclo[4.1.0]hept-3-en-5-
J = 2.34 Hz, 2H), 4.44-4.59 (m, 2H), 4.28-4.44 (m, 2H),
yl)-6-fluoro-3-pyridinyl)-2-(2- 2.59 (t, J = 2.41 Hz, 1H),
1.88-2.02 (m, 1H), 1.76 (s, propyn-1-yloxy)pyrido[3,4- 3H), 1.03
(dd, J = 6.14, 9.50 Hz, 1H), 0.80-0.96 (m, b]pyrazin-5-amine 1H).
602 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.92-8.96
N-(5-((1S,5S,6S)-3-amino-1- (m, 1H), 8.58 (s, 1H), 8.33-8.44 (m,
2H), 8.29 (d, (fluoromethyl)-5-methyl-2-thia- J = 5.99 Hz, 1H),
7.75 (d, J = 0.73 Hz, 1H), 7.21 (s, 1H),
4-azabicyclo[4.1.0]hept-3-en-5- 7.02-7.16 (m, 1H), 5.67 (s, 2H),
4.46-4.58 (m, 1H), yl)-6-fluoro-3-pyridinyl)-2- 4.28-4.43 (m, 1H),
3.75-5.00 (br. s, 2H), 1.94-2.03 (m, (1,3-oxazol-2- 1H), 1.76 (d, J
= 1.02 Hz, 3H), 0.94-1.08 (m, 1H), ylmethoxy)pyrido[3,4- 0.81-0.92
(m, 1H). b]pyrazin-5-amine 604 .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. 8.92-9.04 8-((5-((1S,5S,6S)-3-amino-1- (m, 3H), 8.40-8.47
(m, 2H), 8.29 (d, J = 5.70 Hz, 1H), (fluoromethyl)-5-methyl-2-thia-
7.09 (d, J = 5.85 Hz, 1H), 4.45-4.60 (m, 1H), 4.30-4.43
4-azabicyclo[4.1.0]hept-3-en-5- (m, 1H), 3.75-5.00 (br. s, 2H),
1.90-2.12 (m, 1H), 1.82 yl)-6-fluoro-3- (s, 3H), 1.11 (dd, J =
6.28, 9.50 Hz, 1H), 0.82-1.01 (m, pyridinyl)amino)-1,7- 1H).
naphthyridine-3-carbonitrile 605 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 8.92 (s, N-(5-((1S,5S,6S)-3-amino-1- 1H),
8.89 (s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.45 (dd,
(fluoromethyl)-5-methyl-2-thia- J = 2.45, 8.51 Hz, 1H), 7.74 (s,
1H), 7.61-7.64 (m, 1H),
4-azabicyclo[4.1.0]hept-3-en-5- 7.21 (s, 1H), 5.33 (s, 2H), 4.49
(q, J = 10.30 Hz, 1H), yl)-6-fluoro-3-pyridinyl)-7- 4.37 (q, J =
10.30 Hz, 1H), 4.25-4.75 (br. s, 2H), 1.96 (1,3-oxazol-2- (t, J =
8.12 Hz, 1H), 1.74 (s, 3H), 1.01 (dd, J = 6.36, 9.29
ylmethoxy)pyrido[3,2- Hz, 1H), 0.79-0.92 (m, 1H).
d]pyrimidin-4-amine 608 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
8.91 (s, ((1R,5S,6S)-3-amino-5-(2- 1H), 8.79-8.88 (m, 1H),
8.64-8.77 (m, 1H), 8.50-8.62 fluoro-5-((7-(1,3-oxazol-2- (m, 1H),
8.44 (dd, J = 2.78, 8.62 Hz, 1H), 7.68-7.82 (m,
ylmethoxy)pyrido[3,2- 1H), 7.50-7.67 (m, 1H), 7.10-7.25 (m, 1H),
5.32 (s, d]pyrimidin-4-yl)amino)-3- 2H), 4.33-5.09 (m, 2H),
2.56-2.90 (m, 2H), 1.96 (dd, pyridinyl)-5-methyl-2-thia-4- J =
7.16, 9.06 Hz, 1H), 1.61-1.81 (m, 3H), 0.99 (dd,
azabicyclo[4.1.0]hept-3-en-1- J = 6.36, 9.57 Hz, 1H), 0.81-0.94 (m,
1H). yl)acetonitrile 611 .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. 8.84-8.99 N-(5-((1S,5S,6S)-3-amino-1- (m, 1H), 8.37 (s,
2H), 8.18-8.31 (m, 1H), 7.99-8.19 (fluoromethyl)-5-methyl-2-thia-
(m, 1H), 6.95-7.09 (m, 1H), 5.17 (d, J = 2.34 Hz, 2H),
4-azabicyclo[4.1.0]hept-3-en-5- 4.45-4.63 (m, 1H), 4.27-4.44 (m,
1H), 4.05 (s, 3H), yl)-6-methoxy-3-pyridinyl)-2- 2.48-2.63 (m, 1H),
2.12-2.25 (m, 1H), 1.78 (s, 3H) (2-propyn-1-yloxy)pyrido[3,4- 1.28
(br. s. 2H), 0.94-1.05 (m, 1H), 0.73-0.85 (m, 1H) b]pyrazin-5-amine
613 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.81-9.06
N-(5-((1S,5S,6S)-3-amino-1- (m, 1H), 8.56 (s, 1H), 8.33-8.44 (m,
2H), 8.27 (d, (fluoromethyl)-5-methyl-2-thia- J = 5.99 Hz, 1H),
7.10 (d, J = 5.85 Hz, 1H), 4.45-4.64
4-azabicyclo[4.1.0]hept-3-en-5- (m, 1H), 4.26-4.44 (m, 1H),
3.50-5.00 (br. s., 2H), yl)-6-fluoro-3-pyridinyl)-2- 1.85-2.02 (m,
1H), 1.60-1.82 (m, 3H), 1.03 (dd, ((~2~H_5_)-2-butyn-1- J = 6.14,
9.50 Hz, 1H), 0.76-0.96 (m, 1H). yloxy)pyrido[3,4-b]pyrazin-5-
amine 625 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.72-8.83
N-(5-((1S,5S,6S)-3-amino-1- (m, 2H), 8.65 (s, 1H), 8.39-8.56 (m,
1H), 8.10-8.22 (fluoromethyl)-5-methyl-2-thia- (m, 1H), 7.48-7.58
(m, 1H), 5.29 (s, 1H), 4.85 (s, 2H),
4-azabicyclo[4.1.0]hept-3-en-5- 4.25-4.61 (m, 3H), 4.03 (s, 3H),
2.63 (s, 1H), 1.94- yl)-6-methoxy-3-pyridinyl)-7- 2.25 (m, 1H),
1.73 (s, 3H), 0.92 (dd, J = 6.07, 9.43 Hz,
(2-propyn-1-yloxy)pyrido[3,2- 1H), 0.71-0.82 (m, 1H)
d]pyrimidin-4-amine 626 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
8.92 (d, N-(5-((1S,5S,6S)-3-amino-1- J = 2.19 Hz, 1H), 8.40 (s,
2H), 8.24 (d, J = 5.85 Hz, 1H), (fluoromethyl)-5-methyl-2-thia-
8.12 (d, J = 2.19 Hz, 1H), 7.74 (s, 1H), 7.21 (s, 1H),
4-azabicyclo[4.1.0]hept-3-en-5- 7.03 (d, J = 5.85 Hz, 1H), 5.66 (s,
2H), 4.46-4.59 (m, yl)-6-methoxy-3-pyridinyl)-2- 1H), 4.19-4.43 (m,
3H), 4.05 (s, 3H), 2.15-2.24 (m, (1,3-oxazol-2- 1H), 1.77 (s, 3H),
0.98 (dd, J = 6.07, 9.43 Hz, 1H), ylmethoxy)pyrido[3,4- 0.75-0.88
(m, 1H) b]pyrazin-5-amine 627 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 8.67 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.45 (ddd, J =
2.84, 6.85, 12.62 Hz, 1H), 8.36 (s, (methoxymethyl)-5-methyl-2-
1H), 8.28 (d, J = 5.87 Hz, 1H), 7.34-7.38 (m, 1H), 7.08
thia-4-azabicyclo[4.1.0]hept-3- (d, J = 5.87 Hz, 1H), 5.16 (d, J =
2.54 Hz, 2H), 3.65-3.72 en-5-yl)-4,5-difluorophenyl)-2- (m, 1H),
3.43 (s, 3H), 3.36 (d, J = 10.56 Hz, 1H), 2.52-
(2-propyn-1-yloxy)pyrido[3,4- 2.61 (m, 1H), 1.79-1.85 (m, 1H), 1.75
(s, 3H), 0.92 b]pyrazin-5-amine (dd, J = 5.87, 9.39 Hz, 1H),
0.78-0.86 (m, 1H) 628 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.67 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.46 (ddd, J = 2.74,
6.90, 12.67 Hz, 1H), 8.32-8.39 (methoxymethyl)-5-methyl-2- (m, 1H),
8.28 (d, J = 5.87 Hz, 1H), 7.95 (s, 1H), 7.85 (s,
thia-4-azabicyclo[4.1.0]hept-3- 1H), 7.32-7.39 (m, 1H), 7.09 (d, J
= 5.87 Hz, 1H), 5.53 en-5-yl)-4,5-difluorophenyl)-2- (s, 2H), 3.68
(d, J = 10.56 Hz, 1H), 3.42 (s, 3H), 3.28- (1,3-oxazol-4- 3.39 (m,
1H), 1.79-1.85 (m, 1H), 1.75 (s, 3H), 0.91 ylmethoxy)pyrido[3,4-
(dd, J = 5.87, 9.59 Hz, 1H), 0.77-0.85 (m, 1H) b]pyrazin-5-amine
629 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.96 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.43-8.54 (m, 2H), 8.09 (d, J =
5.67 Hz, 1H), 7.38 (methoxymethyl)-5-methyl-2- (td, J = 2.47, 5.43
Hz, 1H), 7.25 (d, J = 2.74 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3-
6.96 (d, J = 5.87 Hz, 1H), 3.98 (s, 3H), 3.68 (d, J = 10.56
en-5-yl)-4,5-difluorophenyl)-3- Hz, 1H), 3.43 (s, 3H), 3.36 (d, J =
10.56 Hz, 1H), 1.81 methoxy-1,7-naphthyridin-8- (dd, J = 7.43, 8.61
Hz, 1H), 1.76 (d, J = 0.98 Hz, 3H), amine 0.91 (dd, J = 5.87, 9.59
Hz, 1H), 0.80-0.86 (m, 1H) 630 .sup.1H NMR (400 MHz, CHLOROFORM-d)
Shift 8.52- N-(3-((1R,5S,6S)-3-amino-5- 8.59 (m, 1H), 8.34 (s, 1H),
8.27-8.33 (m, 1H), 8.25 (d, methyl-1-(methylsulfonyl)-2- J = 6.06
Hz, 1H), 7.11-7.18 (m, 1H), 7.09 (d, J = 6.06
thia-4-azabicyclo[4.1.0]hept-3- Hz, 1H), 5.16 (d, J = 2.35 Hz, 2H),
3.03 (s, 3H), 2.57 (t, en-5-yl)-4,5-difluorophenyl)-2- J = 2.35 Hz,
1H), 2.41 (dd, J = 7.63, 10.37 Hz, 1H), 2.15
(2-propyn-1-yloxy)pyrido[3,4- (dd, J = 6.26, 10.37 Hz, 1H), 1.88
(s, 3H), 1.09 (t, b]pyrazin-5-amine J = 6.55 Hz, 1H) 631 .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 8.68 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.46 (ddd, J = 2.74, 7.04, 12.72
Hz, 1H), 8.41 (s, (methoxymethyl)-5-methyl-2- 1H), 8.29 (d, J =
6.06 Hz, 1H), 7.64-7.81 (m, 1H), 7.33-
thia-4-azabicyclo[4.1.0]hept-3- 7.43 (m, 1H), 7.20 (s, 1H),
7.05-7.13 (m, 1H), 5.59- en-5-yl)-4,5-difluorophenyl)-2- 5.71 (m,
2H), 3.68 (d, J = 10.56 Hz, 1H), 3.42 (s, 3H), (1,3-oxazol-2- 3.36
(d, J = 10.56 Hz, 1H), 1.78-1.84 (m, 1H), 1.75 (s,
ylmethoxy)pyrido[3,4- 3H), 0.92 (dd, J = 5.87, 9.39 Hz, 1H),
0.79-0.86 (m, b]pyrazin-5-amine 1H) 635 .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 9.37 (br., 1H), 8.57
N-(3-((1S,5S,6S)-3-amino-1,5- (s, 1H), 8.23 (d, J = 5.99 Hz, 1H),
7.97-8.13 (m, 2H), bis(fluoromethyl)-2-thia-4- 7.15 (dd, J = 8.77,
11.84 Hz, 1H), 7.04 (d, J = 5.85 Hz, azabicyclo[4.1.0]hept-3-en-5-
1H), 6.41 (br., 2H), 4.80 (m, 1H), 4.64 (m, 1H), 4.60
yl)-4-fluorophenyl)-2-(2- (m, 2H), 4.55 (m, 1H), 4.35 (m, 1H), 3.75
(m, 2H), methoxyethoxy)pyrido[3,4- 3.31 (s, 3H), 1.80 (m, 1H), 0.86
(m, 1H), 0.60 (m, b]pyrazin-5-amine 1H). 653 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.84 N-(5-((1S,5S,6S)-3-amino-1- (td, J =
6.60, 2.84 Hz, 1 H) 1.38 (dd, J = 9.88, 6.36 Hz, 1
(difluoromethyl)-5-methyl-2- H) 1.80 (s, 3 H) 2.01 (dd, J = 9.78,
7.24 Hz, 1 H) 2.58 thia-4-azabicyclo[4.1.0]hept-3- (t, J = 2.45 Hz,
1 H) 5.15 (d, J = 2.54 Hz, 2 H) 5.48-
en-5-yl)-6-fluoro-3-pyridinyl)- 5.88 (m, 1 H) 7.07 (d, J = 5.87 Hz,
1 H) 8.23 (d, J = 5.87 2-(2-propyn-1- Hz, 1 H) 8.30 (dd, J = 8.71,
2.64 Hz, 1 H) 8.33 (s, 1 H) yloxy)pyrido[3,4-b]pyrazin-5- 8.50 (s,
1 H) 8.81 (t, J = 2.15 Hz, 1 H). amine 654 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.82- N-(5-((1S,5S,6S)-3-amino-1- 0.90
(m, 1 H) 1.30-1.40 (m, 1 H) 1.79 (s, 3 H) 1.99-
(difluoromethyl)-5-methyl-2- 2.05 (m, 1 H) 5.50-5.83 (m, 3 H) 7.10
(d, J = 6.06 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1 H) 7.20 (s, 1 H)
7.73 (s, 1 H) 8.27 (d, J = 5.87 Hz, 1
en-5-yl)-6-fluoro-3-pyridinyl)- H) 8.33 (dd, J = 8.61, 2.74 Hz, 1
H) 8.41 (s, 1 H) 8.56 2-(1,3-oxazol-2- (s, 1 H) 8.85 (t, J = 2.25
Hz, 1 H). ylmethoxy)pyrido[3,4- b]pyrazin-5-amine 656 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm 0.83
8-((5-((1S,5S,6S)-3-amino-1- (td, J = 6.55, 2.74 Hz, 1 H) 1.36 (d,
J = 6.65 Hz, 6 H) (difluoromethyl)-5-methyl-2- 1.40 (dd, J = 9.88,
6.36 Hz, 1 H) 1.84 (s, 3 H) 2.01 (dd,
thia-4-azabicyclo[4.1.0]hept-3- J = 9.68, 7.34 Hz, 1 H) 4.37 (dq, J
= 13.74, 6.70 Hz, 1 H) en-5-yl)-6-fluoro-3- 5.50-5.86 (m, 1 H) 6.30
(d, J = 7.43 Hz, 1 H) 7.02 (d, pyridinyl)amino)-N-(1- J = 5.67 Hz,
1 H) 8.07 (d, J = 5.87 Hz, 1 H) 8.26-8.33 methylethyl)-1,7- (m, 2
H) 8.81 (t, J = 2.15 Hz, 1 H) 8.89 (s, 1 H) 8.97-
naphthyridine-3-carboxamide 9.04 (m, 1 H). 657 .sup.1H NMR (400
MHz, METHANOL-d4) .delta. ppm 0.78 8-((5-((1S,5S,6S)-3-amino-1-
(br. s., 1 H) 1.42 (dd, J = 9.49, 6.55 Hz, 1 H) 1.80 (s, 3
(difluoromethyl)-5-methyl-2- H) 1.86-1.96 (m, 1 H) 5.46-5.85 (m, 1
H) 7.09 (d, thia-4-azabicyclo[4.1.0]hept-3- J = 5.67 Hz, 1 H) 7.38
(d, J = 7.43 Hz, 1 H) 8.19 (d, en-5-yl)-6-fluoro-3- J = 5.67 Hz, 1
H) 8.28 (d, J = 8.61 Hz, 1 H) 8.48 (br. s., pyridinyl)amino)-1,7- 1
H) 8.80 (s, 1 H) 8.95 (s, 1 H). naphthyridine-3-carbonitrile 658
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.81-
4-((5-((1S,5S,6S)-3-amino-1- 0.90 (m, 1 H) 1.34-1.41 (m, 1 H) 1.81
(s, 3 H) 2.07 (difluoromethyl)-5-methyl-2- (dd, J = 9.78, 7.43 Hz,
1 H) 5.50-5.94 (m, 1 H) 8.44 thia-4-azabicyclo[4.1.0]hept-3- (dd, J
= 8.41, 2.74 Hz, 1 H) 8.53 (d, J = 1.96 Hz, 1 H)
en-5-yl)-6-fluoro-3- 8.84-8.86 (m, 1 H) 8.87 (s, 1 H) 8.97 (d, J =
1.96 Hz, pyridinyl)amino)pyrido[3,2- 1 H) 9.06 (s, 1 H).
d]pyrimidine-7-carbonitrile 659 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 0.90 (1R)-1-((1S,5S,6S)-3-amino-5- (t, J = 6.46 Hz, 1
H) 1.18-1.28 (m, 2 H) 1.82 (s, 3 H) (2-fluoro-5-((2-(2-propyn-1-
2.18 (t, J = 8.41 Hz, 1 H) 2.57 (t, J = 2.35 Hz, 1 H) 3.85
yloxy)pyrido[3,4-b]pyrazin-5- (br. s., 1 H) 5.16 (d, J = 2.54 Hz, 2
H) 7.11 (d, J = 5.87 yl)amino)-3-pyridinyl)-5- Hz, 1 H) 8.27 (d, J
= 5.87 Hz, 1 H) 8.32-8.39 (m, 2 H) methyl-2-thia-4- 8.58 (s, 1 H)
8.86 (br. s., 1 H). azabicyclo[4.1.0]hept-3-en-1-
yl)-2,2,2-trifluoroethanol 660 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 0.95 (1S)-1-((1S,5S,6S)-3-amino-5- (t, J = 6.85 Hz, 1
H) 1.23-1.30 (m, 2 H) 1.82 (s, 3 H) (2-fluoro-5-((2-(2-propyn-1-
1.92-1.99 (m, 1 H) 2.57 (t, J = 2.35 Hz, 1 H) 3.53 (q,
yloxy)pyrido[3,4-b]pyrazin-5- J = 6.72 Hz, 1 H) 5.16 (d, J = 2.35
Hz, 2 H) 7.11 (d, yl)amino)-3-pyridinyl)-5- J = 6.06 Hz, 1 H) 8.27
(d, J = 5.87 Hz, 1 H) 8.33-8.39 methyl-2-thia-4- (m, 2 H) 8.57 (s,
1 H) 8.85 (s, 1 H). azabicyclo[4.1.0]hept-3-en-1-
yl)-2,2,2-trifluoroethanol 662 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 0.78 ((1S,5S,6S)-3-amino-5-(2- (t, J = 6.26 Hz, 1 H)
0.90 (dd, J = 9.29, 5.97 Hz, 1 H) fluoro-5-((2-(2-propyn-1- 1.74
(s, 3 H) 1.84-1.92 (m, 1 H) 2.53-2.59 (m, 1 H)
yloxy)pyrido[3,4-b]pyrazin-5- 3.65-3.76 (m, 2 H) 5.16 (d, J = 2.35
Hz, 2 H) 7.10 (d, yl)amino)-3-pyridinyl)-5- J = 6.06 Hz, 1 H) 8.28
(d, J = 5.87 Hz, 1 H) 8.32-8.40 methyl-2-thia-4- (m, 2 H) 8.56 (s,
1 H) 8.94 (s, 1 H). azabicyclo[4.1.0]hept-3-en-1- yl)methanol 663
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 1.67
((1S,5S,6R)-3-amino-7,7- (s, 3 H) 2.52 (dd, J = 15.16, 2.64 Hz, 1
H) 3.88-4.05 difluoro-5-(2-fluoro-5-((2-(1,3- (m, 2 H) 4.51 (br.
s., 2 H) 5.65 (s, 2 H) 7.11 (d, J = 6.06 oxazol-2- Hz, 1 H) 7.20
(s, 1 H) 7.73 (s, 1 H) 8.29 (d, J = 5.87 ylmethoxy)pyrido[3,4- Hz,
1 H) 8.36 (dd, J = 8.61, 2.74 Hz, 1 H) 8.42 (s, 1 H)
b]pyrazin-5-yl)amino)-3- 8.59 (s, 1 H) 9.02 (t, J = 2.35 Hz, 1 H).
pyridinyl)-5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-1-
yl)methanol 665 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
0.87 (1R)-1-((1S,5S,6S)-3-amino-5- (t, J = 6.46 Hz, 1 H) 1.15 (dd,
J = 9.78, 6.06 Hz, 1 H) (2-fluoro-5-((7-(2-propyn-1- 1.77 (s, 3 H)
2.10-2.19 (m, 1 H) 2.64 (t, J = 2.35 Hz, 1
yloxy)pyrido[3,2-d]pyrimidin- H) 3.83 (q, J = 6.46 Hz, 1 H) 4.88
(d, J = 2.35 Hz, 2 H) 4-yl)amino)-3-pyridinyl)-5-
7.59 (d, J = 2.74 Hz, 1 H) 8.40-8.50 (m, 1 H) 8.55 (d,
methyl-2-thia-4- J = 2.74 Hz, 1 H) 8.72 (s, 1 H) 8.76-8.83 (m, 1 H)
azabicyclo[4.1.0]hept-3-en-1- 8.95 (s, 1 H).
yl)-2,2,2-trifluoroethanol 666 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 0.95 (1S)-1-((1S,5S,6S)-3-amino-5- (t, J = 6.75 Hz, 1
H) 1.82 (s, 3 H) 1.92-1.99 (m, 2 H) (2-fluoro-5-((7-(2-propyn-1-
2.64 (d, J = 1.57 Hz, 1 H) 3.56 (q, J = 6.52 Hz, 1 H) 4.04
yloxy)pyrido[3,2-d]pyrimidin- (br. s., 1 H) 4.89 (s, 2 H) 7.61 (s,
1 H) 8.44 (d, J = 8.61 4-yl)amino)-3-pyridinyl)-5- Hz, 1 H) 8.56
(s, 1 H) 8.74 (s, 1 H) 8.82 (br. s., 1 H) methyl-2-thia-4- 8.94 (s,
1 H). azabicyclo[4.1.0]hept-3-en-1- yl)-2,2,2-trifluoroethanol 667
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.85
(1R)-1-((1S,5S,6S)-3-amino-5- (t, J = 6.46 Hz, 1 H) 1.13 (dd, J =
9.59, 6.06 Hz, 1 H) (2-fluoro-5-((7-(1,3-oxazol-2- 1.77 (s, 3 H)
2.09-2.17 (m, 1 H) 3.81 (q, J = 6.39 Hz, ylmethoxy)pyrido[3,2- 1 H)
5.34 (s, 2 H) 7.17-7.23 (m, 1 H) 7.63 (d, J = 2.74
d]pyrimidin-4-yl)amino)-3- Hz, 1 H) 7.74 (s, 1 H) 8.44 (dd, J =
8.51, 2.64 Hz, 1 H) pyridinyl)-5-methyl-2-thia-4- 8.60 (d, J = 2.74
Hz, 1 H) 8.72 (s, 1 H) 8.79 (s, 1 H) azabicyclo[4.1.0]hept-3-en-1-
8.94 (s, 1 H). yl)-2,2,2-trifluoroethanol 668 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.94 (1S)-1-((1S,5S,6S)-3-amino-5- (t, J
= 6.94 Hz, 1 H) 1.19-1.25 (m, 1 H) 1.80 (s, 3 H)
(2-fluoro-5-((7-(1,3-oxazol-2- 1.94 (dd, J = 9.29, 7.53 Hz, 1 H)
3.54 (q, J = 6.65 Hz, 1 ylmethoxy)pyrido[3,2- H) 5.34 (s, 2 H) 7.21
(s, 1 H) 7.63 (d, J = 2.74 Hz, 1 H) d]pyrimidin-4-yl)amino)-3- 7.74
(s, 1 H) 8.42 (dd, J = 8.61, 2.74 Hz, 1 H) 8.61 (d,
pyridinyl)-5-methyl-2-thia-4- J = 2.74 Hz, 1 H) 8.74 (s, 1 H)
8.80-8.86 (m, 1 H) azabicyclo[4.1.0]hept-3-en-1- 8.92 (s, 1 H).
yl)-2,2,2-trifluoroethanol 669 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 1.68 ((1S,5S,6R)-3-amino-7,7- (s, 3 H) 2.51 (dd, J =
15.16, 2.84 Hz, 1 H) 3.87-4.05 difluoro-5-(2-fluoro-5-((3-(1,3- (m,
2 H) 4.71 (br. s., 2 H) 5.32 (s, 2 H) 6.98 (d, J = 5.87
oxazol-2-ylmethoxy)-1,7- Hz, 1 H) 7.21 (s, 1 H) 7.46 (d, J = 2.74
Hz, 1 H) 7.74 naphthyridin-8-yl)amino)-3- (s, 1 H) 8.09 (d, J =
5.87 Hz, 1 H) 8.39 (dd, J = 8.61, pyridinyl)-5-methyl-2-thia-4-
2.54 Hz, 1 H) 8.58 (d, J = 2.74 Hz, 1 H) 8.87 (s, 1 H)
azabicyclo[4.1.0]hept-3-en-1- 9.03 (s, 1 H). yl)methanol 670
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.78
((1S,5S,6S)-3-amino-5-(2- (t, J = 6.26 Hz, 1 H) 0.85-0.96 (m, 1 H)
1.74 (s, 3 H) fluoro-5-((7-(2-propyn-1- 1.86-1.92 (m, 1 H) 2.63 (t,
J = 2.35 Hz, 1 H) 3.63- yloxy)pyrido[3,2-d]pyrimidin- 3.81 (m, 2 H)
4.31-4.76 (m, 2 H) 4.88 (d, J = 2.35 Hz,
4-yl)amino)-3-pyridinyl)-5- 2 H) 7.60 (d, J = 2.74 Hz, 1 H) 8.43
(dd, J = 8.61, 2.74 methyl-2-thia-4- Hz, 1 H) 8.56 (d, J = 2.74 Hz,
1 H) 8.75 (s, 1 H) 8.88- azabicyclo[4.1.0]hept-3-en-1- 8.98 (m, 2
H). yl)methanol 671 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
0.82 (1R)-1-((1S,5S,6S)-3-amino-5- (t, J = 6.46 Hz, 1 H) 0.93 (dd,
J = 9.59, 6.06 Hz, 1 H) (2-fluoro-5-((2-(2-propyn-1- 1.76 (s, 3 H)
1.97-2.03 (m, 1 H) 2.56 (t, J = 2.35 Hz, 1
yloxy)pyrido[3,4-b]pyrazin-5- H) 2.88-3.49 (m, 3 H) 3.59 (q, J =
6.39 Hz, 1 H) 5.14 yl)amino)phenyl)-5-methyl-2- (d, J = 2.35 Hz, 2
H) 6.98-7.09 (m, 2 H) 7.58 (dd, thia-4-azabicyclo[4.1.0]hept-3- J =
6.94, 2.84 Hz, 1 H) 8.04 (dt, J = 8.51, 3.47 Hz, 1 H)
en-1-yl)-2,2,2-trifluoroethanol 8.20 (d, J = 5.87 Hz, 1 H) 8.32 (s,
1 H) 8.55 (s, 1 H). 672 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 0.92 (1S)-1-((1S,5S,6S)-3-amino-5- (t, J = 6.65 Hz, 1 H)
1.20-1.27 (m, 1 H) 1.76-1.85 (2-fluoro-5-((2-(2-propyn-1- (m, 4 H)
2.56 (t, J = 2.35 Hz, 1 H) 3.46 (q, J = 6.65 Hz, 1
yloxy)pyrido[3,4-b]pyrazin-5- H) 3.66 (br. s., 3 H) 5.14 (d, J =
2.54 Hz, 2 H) 6.97- yl)amino)phenyl)-5-methyl-2- 7.10 (m, 2 H) 7.60
(dd, J = 6.85, 2.74 Hz, 1 H) 8.03 (dt,
thia-4-azabicyclo[4.1.0]hept-3- J = 8.71, 3.37 Hz, 1 H) 8.20 (d, J
= 5.87 Hz, 1 H) 8.31 (s, en-1-yl)-2,2,2-trifluoroethanol 1 H) 8.54
(s, 1 H). 676 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.94
N-(5-((1S,5S,6S)-3-amino-5- (t, J = 6.46 Hz, 1 H) 1.09 (dd, J =
9.88, 5.97 Hz, 1 H) methyl-1-((1R)-2,2,2-trifluoro- 1.75 (s, 3 H)
2.04-2.10 (m, 1 H) 2.57 (t, J = 2.45 Hz, 1
1-methoxyethyl)-2-thia-4- H) 3.29 (q, J = 6.06 Hz, 1 H) 3.61 (s, 3
H) 5.16 (d, azabicyclo[4.1.0]hept-3-en-5- J = 2.54 Hz, 2 H) 7.10
(d, J = 5.87 Hz, 1 H) 8.28 (d, yl)-6-fluoro-3-pyridinyl)-2-(2- J =
5.87 Hz, 1 H) 8.35 (dd, J = 8.71, 2.84 Hz, 1 H) 8.37
propyn-1-yloxy)pyrido[3,4- (s, 1 H) 8.56 (s, 1 H) 8.87-8.96 (m, 1
H). b]pyrazin-5-amine 677 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. ppm 0.87 N-(5-((1S,5S,6S)-3-amino-5- (t, J = 6.65 Hz, 1 H)
1.08-1.17 (m, 1 H) 1.82 (s, 3 H) methyl-1-((1S)-2,2,2-trifluoro-
1.99 (dd, J = 9.39, 7.24 Hz, 1 H) 2.57 (t, J = 2.35 Hz, 1
1-methoxyethyl)-2-thia-4- H) 3.23 (q, J = 6.46 Hz, 1 H) 3.67 (s, 3
H) 5.15 (d, azabicyclo[4.1.0]hept-3-en-5- J = 2.54 Hz, 2 H) 7.09
(d, J = 5.87 Hz, 1 H) 8.25 (d, yl)-6-fluoro-3-pyridinyl)-2-(2- J =
5.87 Hz, 1 H) 8.31 (dd, J = 8.70, 2.64 Hz, 1 H) 8.35
propyn-1-yloxy)pyrido[3,4- (s, 1 H) 8.54 (s, 1 H) 8.87 (t, J = 2.15
Hz, 1 H). b]pyrazin-5-amine 703 .sup.1H NMR (300 MHz, CDCl3)
.delta. = 9.16 (s, 1H), 8.96 (d, 4-((3-((1S,5S,6R)-3-amino-7,7- J =
1.9 Hz, 1H), 8.85 (s, 1H), 8.50 (d, J = 1.9 Hz, 1H),
difluoro-1-(hydroxymethyl)-5- 8.28-8.19 (m, 1H), 7.90 (dd, J = 2.9,
6.9 Hz, 1H), 7.20 methyl-2-thia-4- (dd, J = 8.9, 11.7 Hz, 1H),
4.06-3.92 (m, 2H), 2.64- azabicyclo[4.1.0]hept-3-en-5- 2.54 (m,
1H), 1.76 (s, 3H) yl)-4- fluorophenyl)amino)pyrido[3,2-
d]pyrimidine-7-carbonitrile 705 .sup.1H NMR (300 MHz, CDCl3)
.delta. = 8.66 (s, 1H), 8.41 (s, ((1S,5S,6R)-3-amino-7,7- 1H), 8.27
(d, J = 5.8 Hz, 2H), 7.78-7.71 (m, 2H), 7.21
difluoro-5-(2-fluoro-5-((2-(1,3- (d, J = 0.7 Hz, 1H), 7.13 (dd, J =
8.9, 11.8 Hz, 1H), 7.06 oxazol-2- (d, J = 6.0 Hz, 1H), 5.66 (s,
2H), 4.06-3.92 (m, 2H), ylmethoxy)pyrido[3,4- 2.57 (dd, J = 2.6,
15.1 Hz, 1H), 1.73 (s, 3H) b]pyrazin-5-yl)amino)phenyl)-
5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-1- yl)methanol 706
.sup.1H NMR (300 MHz, DMSO) .delta. = 9.32 (s, 1H), 8.57 (s,
((1S,5S,6R)-3-amino-7,7- 1H), 8.45 (s, 1H), 8.33-8.31 (m, 1H), 8.25
(d, J = 5.8 difluoro-5-(2-fluoro-5-((2-(1,3- Hz, 1H), 8.15-8.03 (m,
2H), 7.16 (dd, J = 8.8, 11.9 Hz, oxazol-4- 1H), 7.10 (d, J = 5.8
Hz, 1H), 6.15 (s, 2H), 5.48 (s, 2H), ylmethoxy)pyrido[3,4- 5.43 (t,
J = 5.8 Hz, 1H), 3.90-3.80 (m, 1H), 3.71-3.62
b]pyrazin-5-yl)amino)phenyl)- (m, 1H), 1.54 (s, 3H)
5-methyl-2-thia-4- azabicyclo[4.1.0]hept-3-en-1- yl)methanol 707
.sup.1H NMR (300 MHz, DMSO) .delta. = 9.34 (s, 1H), 8.60 (s,
((1S,5S,6R)-3-amino-7,7- 1H), 8.25 (d, J = 5.8 Hz, 1H), 8.12 (dd, J
= 2.8, 7.2 Hz, difluoro-5-(2-fluoro-5-((2-(2- 1H), 8.08-8.02 (m,
1H), 7.16 (dd, J = 8.7, 11.9 Hz, propyn-1-yloxy)pyrido[3,4- 1H),
7.07 (d, J = 5.8 Hz, 1H), 6.15 (s, 2H), 5.43 (t,
b]pyrazin-5-yl)amino)phenyl)- J = 5.8 Hz, 1H), 5.19 (d, J = 2.5 Hz,
2H), 3.91-3.79 (m, 5-methyl-2-thia-4- 1H), 3.72-3.60 (m, 2H), 1.54
(s, 3H) azabicyclo[4.1.0]hept-3-en-1- yl)methanol 709 .sup.1H NMR
(300 MHz, CDCl3) .delta. = 9.18 (s, 1H), 8.96 (d,
4-((3-((1S,5S,6R)-3-amino-7,7- J = 1.9 Hz, 1H), 8.85 (s, 1H), 8.50
(d, J = 1.9 Hz, 1H), difluoro-1-(methoxymethyl)-5- 8.33-8.26 (m,
1H), 7.90 (dd, J = 2.8, 6.7 Hz, 1H), 7.20 methyl-2-thia-4- (dd, J =
8.9, 11.5 Hz, 1H), 4.04-3.97 (m, 1H), 3.58
azabicyclo[4.1.0]hept-3-en-5- (dd, J = 2.5, 11.3 Hz, 1H), 3.43 (s,
3H), 2.47 (dd, J = 2.3, yl)-4- 15.1 Hz, 1H), 1.74 (s, 3H)
fluorophenyl)amino)pyrido[3,2- d]pyrimidine-7-carbonitrile 712
.sup.1H NMR (300 MHz, CDCl3) .delta. = 8.65 (s, 1H), 8.37 (s,
2-((1S,5S,6R)-3-amino-7,7- 1H), 8.33-8.25 (m, 2H), 7.70 (dd, J =
2.8, 6.9 Hz, 1H), difluoro-5-(2-fluoro-5-((2-(2- 7.14 (dd, J = 8.9,
11.8 Hz, 1H), 7.05 (d, J = 5.8 Hz, 1H), propyn-1-yloxy)pyrido[3,4-
5.17 (d, J = 2.5 Hz, 2H), 3.17-3.07 (m, 1H), 2.58 (t,
b]pyrazin-5-yl)amino)phenyl)- J = 2.4 Hz, 1H), 1.74 (s, 3H), 1.51
(s, 3H), 1.48 (s, 3H), 5-methyl-2-thia-4- 1.49-1.46 (m, 3H)
azabicyclo[4.1.0]hept-3-en-1- yl)-2-propanol 713 .sup.1H NMR (300
MHz, CDCl3) .delta. = 8.66 (s, 1H), 8.37 (s,
(1R)-1-((1S,5S,6R)-3-amino- 1H), 8.34-8.28 (m, 1H), 8.27 (d, J =
5.8 Hz, 1H), 7.72 7,7-difluoro-5-(2-fluoro-5-((2- (dd, J = 2.9, 6.9
Hz, 1H), 7.13 (dd, J = 8.8, 11.8 Hz, 1H),
(2-propyn-1-yloxy)pyrido[3,4- 7.06 (d, J = 5.8 Hz, 1H), 5.17 (d, J
= 2.5 Hz, 2H), 4.09- b]pyrazin-5-yl)amino)phenyl)- 4.01 (m, 1H),
2.58 (t, J = 2.5 Hz, 1H), 2.38 (dd, J = 2.9, 5-methyl-2-thia-4-
15.6 Hz, 1H), 1.71 (s, 3H), 1.53 (d, J = 6.3 Hz, 3H)
azabicyclo[4.1.0]hept-3-en-1- yl)ethanol 714 .sup.1H NMR (300 MHz,
CDCl3) .delta. = 8.64 (s, 1H), 8.37 (s, (1S)-1-((1S,5S,6R)-3-amino-
1H), 8.27 (d, J = 5.8 Hz, 2H), 7.71 (dd, J = 2.9, 6.9 Hz,
7,7-difluoro-5-(2-fluoro-5-((2- 1H), 7.13 (dd, J = 8.9, 11.8 Hz,
1H), 7.05 (d, J = 6.0 Hz, (2-propyn-1-yloxy)pyrido[3,4- 1H), 5.17
(d, J = 2.5 Hz, 2H), 3.92 (dd, J = 2.5, 6.3 Hz,
b]pyrazin-5-yl)amino)phenyl)- 1H), 2.64 (dd, J = 2.4, 15.4 Hz, 1H),
2.58 (t, J = 2.5 Hz, 5-methyl-2-thia-4- 1H), 1.76 (s, 3H), 1.40 (d,
J = 6.4 Hz, 3H) azabicyclo[4.1.0]hept-3-en-1- yl)ethanol 717
.sup.1H NMR (CHLOROFORM-d) .delta. 9.01 (s, 1H), 8.93 (s,
8-((3-((1S,5S,6S)-3-amino-5- 1H), 8.37 (d, J = 1.8 Hz, 1H),
8.17-8.30 (m, 2H), 7.78 (fluoromethyl)-1- (dd, J = 6.7, 2.6 Hz,
1H), 7.13 (dd, J = 11.6, 8.9 Hz, 1H), (methoxymethyl)-2-thia-4-
7.00 (d, J = 5.7 Hz, 1H), 4.67-5.01 (m, 2H), 3.64 (d,
azabicyclo[4.1.0]hept-3-en-5- J = 10.6 Hz, 1H), 3.40 (s, 3H), 3.37
(d, J = 10.6 Hz, 1H), yl)-4-fluorophenyl)amino)-1,7- 1.84-1.93 (m,
1H), 1.12-1.19 (m, 1H), 0.81 (t, J = 5.9
naphthyridine-3-carbonitrile Hz, 1H) 719 .sup.1H NMR (DMSO-d6)
.delta. 9.65 (s, 1H), 9.22 (d, J = 2.0 8-((3-((1R,5S,6S)-3-amino-1-
Hz, 1H), 8.98 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 5.7 Hz,
(cyanomethyl)-5- 1H), 8.08-8.18 (m, 2H), 7.14-7.24 (m, 2H), 6.46
(s, (fluoromethyl)-2-thia-4- 2H), 4.58-4.85 (m, 2H), 2.89-3.14 (m,
2H), 1.76-1.88 azabicyclo[4.1.0]hept-3-en-5- (m, 1H), 1.16 (dd, J =
9.5, 5.4 Hz, 1H), 0.62 (t, J = 6.2 yl)-4-fluorophenyl)amino)-1,7-
Hz, 1H) naphthyridine-3-carbonitrile 720 .sup.1H NMR (DMSO-d6)
.delta.: 9.42 (s, 1H), 8.61 (s, 1H), ((1R,5S,6S)-3-amino-5- 8.25
(d, J = 5.9 Hz, 1H), 8.12 (dd, J = 7.1, 2.6 Hz, 1H),
(fluoromethyl)-5-(2-fluoro-5- 8.03-8.08 (m, 1H), 7.16 (dd, J =
11.8, 8.9 Hz, 1H), 7.07 ((2-(2-propyn-1- (d, J = 5.9 Hz, 1H), 6.45
(s, 2H), 5.19 (d, J = 2.5 Hz, yloxy)pyrido[3,4-b]pyrazin-5- 2H),
4.43-4.95 (m, 2H), 3.66 (t, J = 2.3 Hz, 1H), 2.84-
yl)amino)phenyl)-2-thia-4- 3.19 (m, 2H), 1.73-1.90 (m, 1H), 1.16
(dd, J = 9.6, 5.5 azabicyclo[4.1.0]hept-3-en-1- Hz, 1H), 0.61 (t, J
= 6.0 Hz, 1H) yl)acetonitrile 721 .sup.1H NMR (DMSO-d6) .delta.:
9.44 (s, 1H), 8.66 (s, 1H), ((1R,5S,6S)-3-amino-5- 8.27 (d, J = 5.9
Hz, 1H), 8.23 (s, 1H), 8.13 (dd, J = 7.0,
(fluoromethyl)-5-(2-fluoro-5- 2.7 Hz, 1H), 8.07 (dd, J = 8.3, 3.8
Hz, 1H), 7.32 (s, ((2-(1,3-oxazol-2- 1H), 7.17 (dd, J = 11.6, 8.9
Hz, 1H), 7.07 (d, J = 5.9 Hz, ylmethoxy)pyrido[3,4- 1H), 6.46 (s,
2H), 5.68 (s, 2H), 4.62-4.83 (m, 2H), b]pyrazin-5-yl)amino)phenyl)-
2.94-3.11 (m, 2H), 1.79-1.85 (m, 1H), 1.15-1.22 (m,
2-thia-4-azabicyclo[4.1.0]hept- 1H), 0.63 (t, J = 6.0 Hz, 1H)
3-en-1-yl)acetonitrile 724 .sup.1H NMR (CHLOROFORM-d) .delta.: 8.60
(s, 1H), 8.34 (s, N-(3-((1S,5S,6S)-3-amino-5- 1H), 8.23 (d, J = 6.1
Hz, 1H), 8.10-8.18 (m, 1H), 7.67 (fluoromethyl)-1-((4-methyl- (dd,
J = 6.9, 2.6 Hz, 1H), 7.48 (s, 1H), 7.10 (dd, J = 11.3,
1H-1,2,3-triazol-1-yl)methyl)- 8.8 Hz, 1H), 7.04 (d, J = 5.9 Hz,
1H), 5.14 (d, J = 2.5 Hz, 2-thia-4-azabicyclo[4.1.0]hept- 2H),
4.65-5.00 (m, 2H), 4.38-4.54 (m, 2H), 2.56 (t,
3-en-5-yl)-4-fluorophenyl)-2- J = 2.4 Hz, 1H), 2.40 (s, 3H), 2.18
(t, J = 8.1 Hz, 1H), (2-propyn-1-yloxy)pyrido[3,4- 1.41-1.45 (m,
1H), 0.91-0.97 (m, 1H) b]pyrazin-5-amine 726 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 8.96 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H),
8.54 (d, J = 2.74 Hz, 1H), 8.50 (dt, J = 2.74, 6.36
(methoxymethyl)-5-methyl-2- Hz, 1H), 8.11 (d, J = 5.87 Hz, 1H),
7.97 (s, thia-4-azabicyclo[4.1.0]hept-3- 1H), 7.37 (d, J = 2.74 Hz,
2H), 7.28 (s, 1H), 6.96 (d, en-5-yl)-4,5-difluorophenyl)-3- J =
5.87 Hz, 1H), 5.24 (s, 2H), 3.68 (d, J = 10.56 Hz,
(1,3-oxazol-5-ylmethoxy)-1,7- 1H), 3.42 (s, 3H), 3.36 (d, J = 10.76
Hz, 1H), naphthyridin-8-amine 1.79-1.85 (m, 1H), 1.76 (s, 3H), 0.92
(dd, J = 5.97, 9.49 Hz, 1H), 0.80-0.86 (m, 1H) 727 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 8.96 N-(3-((1S,5S,6S)-3-amino-1- (s,
1H), 8.58 (d, J = 2.74 Hz, 1H), 8.50 (ddd, J = 2.93,
(methoxymethyl)-5-methyl-2- 6.99, 12.76 Hz, 1H), 8.10 (d, J = 5.87
Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3- 7.74 (d, J = 0.78 Hz, 1H),
7.46 (d, J = 2.74 Hz, 1H), 7.37 en-5-yl)-4,5-difluorophenyl)-3-
(td, J = 2.52, 5.33 Hz, 1H), 7.21 (s, 1H), 6.96 (d, J = 5.67
(1,3-oxazol-2-ylmethoxy)-1,7- Hz, 1H), 5.33 (s, 2H), 3.68 (d,
naphthyridin-8-amine J = 10.56 Hz, 1H), 3.42 (s, 3H), 3.36 (d, J =
10.56 Hz, 1H), 1.81 (dd, J = 7.34, 8.71 Hz, 1H), 1.76 (s, 3H), 0.92
(dd, J = 5.77, 9.49 Hz, 1H), 0.78-0.87 (m, 1H) 728 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 8.96 N-(3-((1S,5S,6S)-3-amino-1- (s,
1H), 8.56 (d, J = 2.74 Hz, 1H), 8.50 (ddd, J = 2.93,
(methoxymethyl)-5-methyl-2- 6.94, 12.81 Hz, 1H), 8.10 (d, J = 5.87
Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3- 7.97 (s, 1H), 7.83 (d, J =
0.78 Hz, 1H), 7.40 (d, J = 2.74 en-5-yl)-4,5-difluorophenyl)-3- Hz,
1H), 7.38 (td, J = 2.54, 5.48 Hz, 1H), 6.96 (d,
(1,3-oxazol-4-ylmethoxy)-1,7- J = 5.87 Hz, 1H), 5.20 (s, 2H), 3.68
(d, naphthyridin-8-amine J = 10.37 Hz, 1H), 3.42 (s, 3H), 3.36 (d,
J = 10.76 Hz, 1H), 1.81 (ddd, J = 1.08, 6.75, 9.39 Hz, 1H), 1.75
(d, J = 0.98 Hz, 3H), 0.91 (dd, J = 5.87, 9.39 Hz, 1H), 0.79-0.86
(m, 1H) 729 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 8.97
((8-((3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.57 (d, J = 2.74 Hz, 1H),
8.51 (ddd, J = 2.64, (methoxymethyl)-5-methyl-2- 6.94, 12.72 Hz,
1H), 8.15 (d, J = 5.67 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3-
7.35-7.43 (m, 2H), 7.00 (d, J = 5.87 Hz, 1H), 4.95 (s,
en-5-yl)-4,5- 2H), 3.68 (d, J = 10.56 Hz, 1H), 3.43 (s, 3H), 3.36
(d, difluorophenyl)amino)-1,7- J = 10.56 Hz, 1H), 1.79-1.86 (m,
1H), 1.76 naphthyridin-3- (s, 3H), 0.92 (dd, J = 6.06, 9.39 Hz,
1H), 0.80-0.87 (m, yl)oxy)acetonitrile 1H), 0.80-0.87 (m, 1H) 730
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.73 (s, 1H), 9.47
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.71 (d, J = 2.93 Hz, 1H),
8.43 (ddd, J = 2.74, (methoxymethyl)-5-methyl-2- 6.80, 13.16 Hz,
1H), 8.10 (d, J = 5.87 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1H),
7.91 (d, J = 2.74 Hz, 1H), 7.81 (br. s., 1H), 7.15
en-5-yl)-4,5-difluorophenyl)-3- (d, J = 5.87 Hz, 1H), 6.03 (br. s.,
2H), 5.62 (s, 2H), 3.57 (1,2,4-oxadiazol-3-ylmethoxy)- (d, J =
10.76 Hz, 1H), 3.36 (d, J = 10.95 1,7-naphthyridin-8-amine Hz, 1H),
3.30 (s, 3H), 1.58-1.71 (m, 4H), 0.92 (br. s., 1H), 0.67 (t, J =
5.58 Hz, 1H) 731 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.50 (s,
1H), 8.72 N-(3-((1S,5S,6S)-3-amino-1- (d, J = 2.74 Hz, 1H), 8.44
(ddd, J = 2.84, 6.85, 13.20 Hz, (methoxymethyl)-5-methyl-2- 1H),
8.12 (d, J = 5.87 Hz, 1H), 7.93 (d, thia-4-azabicyclo[4.1.0]hept-3-
J = 2.74 Hz, 1H), 7.79-7.87 (m, 1H), 7.15 (d, J = 5.87
en-5-yl)-4,5-difluorophenyl)-3- Hz, 1H), 6.59-6.96 (m, 1H), 6.04
(br. s., 2H), 4.88 (t, (2,2,3,3-tetrafluoropropoxy)- J = 13.50 Hz,
2H), 3.58 (d, J = 10.76 Hz, 1,7-naphthyridin-8-amine 1H), 3.37 (d,
J = 11.15 Hz, 1H), 3.32 (s, 3H), 1.59-1.70 (m, 4H), 0.92 (dd, J =
5.28, 9.19 Hz, 1H), 0.68 (t, J = 5.87 Hz, 1H) 733 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.45 (s, 1H), 8.66
N-(3-((1S,5S,6S)-3-amino-1- (d, J = 2.74 Hz, 1H), 8.43 (ddd, J =
2.74, 6.85, 13.30 Hz, (methoxymethyl)-5-methyl-2- 1H), 8.10 (d, J =
5.87 Hz, 1H), 7.79-7.83 thia-4-azabicyclo[4.1.0]hept-3- (m, 1H),
7.78 (d, J = 2.74 Hz, 1H), 7.17 (d, J = 5.87 Hz,
en-5-yl)-4,5-difluorophenyl)-3- 1H), 6.03 (br. s., 2H), 5.06 (d, J
= 2.35 Hz, 2H), 3.72 (t, (2-propyn-1-yloxy)-1,7- J = 2.35 Hz, 1H),
3.57 (d, J = 10.95 Hz, naphthyridin-8-amine 1H), 3.36 (d, J = 10.95
Hz, 1H), 3.30 (s, 3H), 1.57-1.70 (m, 4H), 0.91 (dd, J = 5.28, 9.19
Hz, 1H), 0.66 (t, J = 5.77 Hz, 1H) 735 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 9.47 (s, 1H), 8.73 N-(3-((1S,5S,6S)-3-amino-1- (d,
J = 2.74 Hz, 1H), 8.43 (ddd, J = 2.74, 6.65, 13.30 Hz,
(methoxymethyl)-5-methyl-2- 1H), 8.10 (d, J = 5.67 Hz, 1H), 7.93
(s, thia-4-azabicyclo[4.1.0]hept-3- 1H), 7.91 (d, J = 2.74 Hz, 1H),
7.82 (br. s., 1H), 7.15 en-5-yl)-4,5-difluorophenyl)-3- (d, J =
5.87 Hz, 1H), 6.03 (br. s., 2H), 5.63 (s, 2H), 3.57
((5-chloro-1,3-thiazol-2- (d, J = 10.76 Hz, 1H), 3.36 (d, J = 10.95
yl)methoxy)-1,7-naphthyridin- Hz, 1H), 3.30 (s, 3H), 1.64-1.69 (m,
1H), 1.62 (s, 3H), 8-amine 0.91 (d, J = 8.61 Hz, 1H), 0.67 (t, J =
5.77 Hz, 1H) 736 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.47 (s,
1H), 8.74 N-(3-((1S,5S,6S)-3-amino-1- (d, J = 2.93 Hz, 1H), 8.43
(ddd, J = 2.93, 6.90, 13.25 Hz, (methoxymethyl)-5-methyl-2- 1H),
8.10 (d, J = 5.87 Hz, 1H), 7.96 (s, thia-4-azabicyclo[4.1.0]hept-3-
1H), 7.91 (d, J = 2.74 Hz, 1H), 7.82 (d, J = 5.67 Hz, 1H),
en-5-yl)-4,5-difluorophenyl)-3- 7.16 (d, J = 5.87 Hz, 1H), 6.03
(br. s., 2H), 5.69 (s, 2H), ((4-bromo-1,3-thiazol-2- 3.57 (d, J =
10.76 Hz, 1H), 3.36 (d, yl)methoxy)-1,7-naphthyridin- J = 10.95 Hz,
1H), 3.31 (s, 3H), 1.64-1.69 (m, 1H), 8-amine 1.62 (s, 3H),
0.88-0.95 (m, 1H), 0.67 (t, J = 5.67 Hz, 1H) 737 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.46 (s, 1H), 8.73
N-(3-((1S,5S,6S)-3-amino-1- (d, J = 2.74 Hz, 1H), 8.43 (ddd, J =
2.74, 6.75, 13.20 Hz, (methoxymethyl)-5-methyl-2- 1H), 8.10 (d, J =
5.67 Hz, 1H), 7.91 (dd, thia-4-azabicyclo[4.1.0]hept-3- J = 3.13,
5.67 Hz, 2H), 7.85 (d, J = 3.13 Hz, 1H), 7.77-
en-5-yl)-4,5-difluorophenyl)-3- 7.83 (m, 1H), 7.15 (d, J = 5.87 Hz,
1H), 6.04 (br. s., (1,3-thiazol-2-ylmethoxy)-1,7- 2H), 5.69 (s,
2H), 3.57 (d, J = 10.95 Hz, 1H), naphthyridin-8-amine 3.36 (d, J =
10.95 Hz, 1H), 3.30-3.32 (m, 3H), 1.67 (m, 1H), 1.62 (s, 3H), 0.91
(dd, J = 5.09, 9.19 Hz, 1H), 0.67 (t, J = 5.77 Hz, 1H) 741 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 9.47 (s, 1H), 8.71
N-(3-((1S,5S,6S)-3-amino-1- (d, J = 2.74 Hz, 1H), 8.42 (ddd, J =
2.84, 6.85, 13.20 Hz, (methoxymethyl)-5-methyl-2- 1H), 8.11 (d, J =
5.87 Hz, 1H), 7.85 (d, thia-4-azabicyclo[4.1.0]hept-3- J = 2.93 Hz,
1H), 7.78-7.84 (m, 1H), 7.18 (d, J = 5.87
en-5-yl)-4,5-difluorophenyl)-3- Hz, 1H), 6.03 (s, 2H), 5.39 (q, J =
3.06 Hz, 2H), 3.57 ((4,4,4-trifluoro-2-butyn-1- (d, J = 10.95 Hz,
1H), 3.36 (d, J = 10.95 Hz, yl)oxy)-1,7-naphthyridin-8- 1H), 3.30
(s, 3H), 1.63-1.69 (m, 1H), 1.62 (s, 3H), amine 0.91 (dd, J = 5.18,
9.29 Hz, 1H), 0.66 (t, J = 5.77 Hz, 1H) 750 .sup.1H NMR (300 MHz,
DMSO-d6) .delta. ppm 1.54 (s, 3 H) ((1S,5S,6R)-3-amino-7,7-
3.61-3.72 (m, 1 H) 3.83 (d, J = 4.68 Hz, 1 H) 5.43 (t,
difluoro-5-(2-fluoro-5-((7-(1,3- J = 5.26 Hz, 1 H) 5.54 (s, 2 H)
6.14 (br. s., 2 H) 7.20 oxazol-2- (dd, J = 11.91, 8.70 Hz, 1 H)
7.33 (s, 1 H) 7.80 (d, ylmethoxy)pyrido[3,2- J = 2.63 Hz, 1 H) 7.92
(dd, J = 8.18, 3.51 Hz, 1 H) 8.16- d]pyrimidin-4- 8.24 (m, 2 H)
8.60 (s, 1 H) 8.70 (d, J = 2.63 Hz, 1 H)
yl)amino)phenyl)-5-methyl-2- 10.01 (s, 1 H)
thia-4-azabicyclo[4.1.0]hept-3- en-1-yl)methanol 762 .sup.1H NMR
(DMSO-d6) .delta.: 9.39 (s, 1H), 8.61 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-5- 8.25 (d, J = 5.9 Hz, 1H), 8.00-8.14 (m,
2H), 7.14 (dd, (fluoromethyl)-2-thia-4- J = 11.8, 8.7 Hz, 1H), 7.07
(d, J = 5.9 Hz, 1H), 6.22 (s, azabicyclo[4.1.0]hept-3-en-5- 2H),
5.19 (d, J = 2.3 Hz, 2H), 4.73-4.87 (m, 1H), 4.59-
yl)-4-fluorophenyl)-2-(2- 4.73 (m, 1H), 3.66 (t, J = 2.4 Hz, 1H),
2.33-2.43 (m, propyn-1-yloxy)pyrido[3,4- 1H), 1.76 (q, J = 7.8 Hz,
1H), 0.97-1.08 (m, 1H), 0.38 b]pyrazin-5-amine (q, J = 5.1 Hz, 1H)
763 .sup.1H NMR (DMSO-d6) .delta.: 10.05 (s, 1H), 8.69 (d, J = 2.7
N-(3-((1S,5S,6S)-3-amino-5- Hz, 1H), 8.60 (s, 1H), 8.23 (d, J = 0.8
Hz, 1H), 8.17 (fluoromethyl)-2-thia-4- (dd, J = 7.2, 2.7 Hz, 1H),
7.91-8.00 (m, 1H), 7.80 (d, azabicyclo[4.1.0]hept-3-en-5- J = 2.7
Hz, 1H), 7.33 (d, J = 0.8 Hz, 1H), 7.18 (dd,
yl)-4-fluorophenyl)-7-(1,3- J = 11.7, 8.8 Hz, 1H), 6.21 (s, 2H),
5.54 (s, 2H), 4.73- oxazol-2- 4.85 (m, 1H), 4.61-4.72 (m, 1H),
2.34-2.42 (m, 1H), ylmethoxy)pyrido[3,2- 1.69-1.82 (m, 1H), 1.03
(ddd, J = 8.9, 7.4, 5.2 Hz, 1H), d]pyrimidin-4-amine 0.38 (q, J =
5.1 Hz, 1H) 768 .sup.1H NMR (DMSO-d6) .delta.: 9.44 (br. s., 1H),
8.61 (s, 1H), (2E)-3-((1R,5S,6S)-3-amino-5- 8.26 (d, J = 5.9 Hz,
1H), 8.14 (br. s., 1H), 8.02-8.10 (m, (fluoromethyl)-5-(2-fluoro-5-
1H), 7.17 (t, J = 9.8 Hz, 1H), 7.08 (d, J = 5.9 Hz, 1H),
((2-(2-propyn-1- 6.38-6.57 (m, 4H), 5.20 (d, J = 2.5 Hz, 2H),
4.57-4.89 yloxy)pyrido[3,4-b]pyrazin-5- (m, 2H), 3.66 (t, J = 2.3
Hz, 1H), 3.06 (s, 3H), 2.88 (s, yl)amino)phenyl)-2-thia-4- 3H),
1.93 (d, J = 12.3 Hz, 1H), 1.58 (br. s., 1H), 0.96
azabicyclo[4.1.0]hept-3-en-1- (br. s., 1H). yl)-N,N-dimethyl-2-
propenamide 769 .sup.1H NMR (DMSO-d6) .delta.: 9.45 (br. s., 1H),
8.66 (s, 1H), (2E)-3-((1R,5S,6S)-3-amino-5- 8.26 (d, J = 5.9 Hz,
1H), 8.22 (s, 1H), 8.11-8.16 (m, (fluoromethyl)-5-(2-fluoro-5- 1H),
8.07 (dt, J = 8.4, 3.6 Hz, 1H), 7.31 (s, 1H), 7.13-
((2-(1,3-oxazol-2- 7.22 (m, 1H), 7.06 (d, J = 5.9 Hz, 1H),
6.40-6.58 (m, ylmethoxy)pyrido[3,4- 4H), 5.67 (s, 2H), 4.57-4.89
(m, 2H), 3.06 (s, 3H), b]pyrazin-5-yl)amino)phenyl)- 2.88 (s, 3H),
1.89-1.99 (m, 1H), 1.58 (d, J = 4.3 Hz,
2-thia-4-azabicyclo[4.1.0]hept- 1H), 0.95 (br. s., 1H).
3-en-1-yl)-N,N-dimethyl-2- propenamide 770 .sup.1H NMR (DMSO-d6)
.delta.: 9.35 (s, 1H), 8.69 (d, J = 2.9
(2E)-3-((1R,5S,6S)-3-amino-5- Hz, 1H), 8.23 (d, J = 0.8 Hz, 1H),
8.18 (dt, J = 8.9, 3.4 (fluoromethyl)-5-(2-fluoro-5- Hz, 1H),
8.03-8.10 (m, 2H), 7.87 (d, J = 2.9 Hz, 1H),
((3-(1,3-oxazol-2-ylmethoxy)- 7.33 (s, 1H), 7.15 (dd, J = 11.7, 8.8
Hz, 1H), 7.10 (d, 1,7-naphthyridin-8- J = 5.9 Hz, 1H), 6.42-6.55
(m, 4H), 5.49 (s, 2H), 4.57- yl)amino)phenyl)-2-thia-4- 4.85 (m,
2H), 3.05 (s, 3H), 2.88 (s, 3H), 1.94 (t, J = 8.1
azabicyclo[4.1.0]hept-3-en-1- Hz, 1H), 1.56 (dd, J = 9.6, 5.5 Hz,
1H), 0.95 (t, J = 6.0 yl)-N,N-dimethyl-2-
Hz, 1H). propenamide 771 .sup.1H NMR (DMSO-d6) .delta.: 9.34 (s,
1H), 8.64 (d, J = 2.7 (2E)-3-((1R,5S,6S)-3-amino-5- Hz, 1H), 8.19
(dt, J = 8.4, 3.6 Hz, 1H), 8.01-8.11 (m,
(5-((3-(2-butyn-1-yloxy)-1,7- 2H), 7.73 (d, J = 2.7 Hz, 1H), 7.16
(dd, J = 11.7, 9.0 Hz, naphthyridin-8-yl)amino)-2- 1H), 7.12 (d, J
= 5.9 Hz, 1H), 6.43-6.56 (m, 4H), 5.00 fluorophenyl)-5- (d, J = 2.2
Hz, 2H), 4.59-4.86 (m, 2H), 3.06 (s, 3H), (fluoromethyl)-2-thia-4-
2.89 (s, 3H), 1.96 (t, J = 8.2 Hz, 1H), 1.87 (t, J = 2.2 Hz,
azabicyclo[4.1.0]hept-3-en-1- 3H), 1.57 (dd, J = 9.2, 5.1 Hz, 1H),
0.96 (t, J = 6.0 Hz, yl)-N,N-dimethyl-2- 1H). propenamide 773
.sup.1H NMR (DMSO-d6) .delta.: 9.45 (s, 1H), 8.62 (s, 1H),
N-(3-((1R,5S,6S)-3-amino-1- 8.27 (d, J = 5.9 Hz, 1H), 8.14 (dd, J =
6.9, 2.6 Hz, 1H), ((1E)-3-(3,3-difluoro-1- 8.05-8.11 (m, 1H), 7.18
(dd, J = 11.7, 9.0 Hz, 1H), 7.09 azetidinyl)-3-oxo-1-propen-1- (d,
J = 5.9 Hz, 1H), 6.61 (d, J = 15.3 Hz, 1H), 6.49 (s,
yl)-5-(fluoromethyl)-2-thia-4- 2H), 6.05 (d, J = 15.1 Hz, 1H), 5.21
(d, J = 2.3 Hz, 2H), azabicyclo[4.1.0]hept-3-en-5- 4.58-4.87 (m,
4H), 4.35 (br. s., 2H), 3.68 (t, J = 2.3 Hz,
yl)-4-fluorophenyl)-2-(2- 1H), 2.02 (t, J = 8.1 Hz, 1H), 1.61 (dd,
J = 9.6, 5.1 Hz, propyn-1-yloxy)pyrido[3,4- 1H), 0.96-1.02 (m, 1H).
b]pyrazin-5-amine 775 .sup.1H NMR (DMSO-d6) .delta.: 10.11 (s, 1H),
8.72 (d, J = 2.7 (2E)-3-((1R,5S,6S)-3-amino-5- Hz, 1H), 8.63 (s,
1H), 8.25 (s, 1H), 8.21 (dd, J = 7.0, (fluoromethyl)-5-(2-fluoro-5-
2.7 Hz, 1H), 7.98 (dt, J = 8.5, 3.5 Hz, 1H), 7.82 (d,
((7-(1,3-oxazol-2- J = 2.7 Hz, 1H), 7.35 (s, 1H), 7.22 (dd, J =
11.6, 8.9 Hz, ylmethoxy)pyrido[3,2- 1H), 6.43-6.57 (m, 4H), 5.56
(s, 2H), 4.58-4.88 (m, d]pyrimidin-4- 2H), 3.07 (s, 3H), 2.90 (s,
3H), 1.96 (t, J = 8.2 Hz, 1H), yl)amino)phenyl)-2-thia-4- 1.59 (dd,
J = 9.5, 5.2 Hz, 1H), 0.93-0.99 (m, 1H)
azabicyclo[4.1.0]hept-3-en-1- yl)-N,N-dimethyl-2- propenamide 776
.sup.1H NMR (DMSO-d6) .delta.: 10.10 (s, 1H), 8.68 (d, J = 2.7
(2E)-3-((1R,5S,6S)-3-amino-5- Hz, 1H), 8.63 (s, 1H), 8.21 (dd, J =
7.1, 2.6 Hz, 1H), (fluoromethyl)-5-(2-fluoro-5- 7.94-8.02 (m, 1H),
7.70 (d, J = 2.5 Hz, 1H), 7.22 (dd, ((7-(2-propyn-1- J = 11.7, 8.8
Hz, 1H), 6.43-6.58 (m, 4H), 5.13 (d, J = 2.3
yloxy)pyrido[3,2-d]pyrimidin- Hz, 2H), 4.60-4.88 (m, 2H), 3.75 (t,
J = 2.3 Hz, 1H), 4-yl)amino)phenyl)-2-thia-4- 3.07 (s, 3H), 2.90
(s, 3H), 1.92-2.01 (m, 1H), 1.59 (dd, azabicyclo[4.1.0]hept-3-en-1-
J = 9.6, 5.3 Hz, 1H), 0.91-1.01 (m, 1H) yl)-N,N-dimethyl-2-
propenamide 779 .sup.1H NMR (DMSO-d6) .delta.: 9.43 (s, 1H), 8.60
(s, 1H), (1S,5S,6S)-3-amino-5- 8.25 (d, J = 5.9 Hz, 1H), 8.09 (dd,
J = 7.1, 2.8 Hz, 1H), (fluoromethyl)-5-(2-fluoro-5- 7.97 (dt, J =
8.4, 3.7 Hz, 1H), 7.15 (dd, J = 11.5, 8.8 Hz, ((2-(2-propyn-1- 1H),
7.07 (d, J = 5.9 Hz, 1H), 6.60 (s, 2H), 5.19 (d,
yloxy)pyrido[3,4-b]pyrazin-5- J = 2.3 Hz, 2H), 4.75-4.89 (m, 1H),
4.62-4.75 (m, 1H), yl)amino)phenyl)-N,N- 3.66 (t, J = 2.3 Hz, 1H),
2.94-3.13 (m, 3H), 2.84 (br. s., dimethyl-2-thia-4- 3H), 2.03 (t, J
= 8.2 Hz, 1H), 1.50 (dd, J = 9.5, 5.4 Hz,
azabicyclo[4.1.0]hept-3-ene-1- 1H), 0.64 (t, J = 6.2 Hz, 1H)
carboxamide 781 .sup.1H NMR (DMSO-d6) .delta.: 9.47 (s, 1H), 8.62
(s, 1H), N-(3-((1S,5S,6S)-3-amino-5- 8.33 (s, 1H), 8.27 (d, J = 5.9
Hz, 1H), 8.18 (dd, J = 7.1, (fluoromethyl)-1-(1,3-oxazol-5- 2.8 Hz,
1H), 8.07 (dt, J = 8.7, 3.6 Hz, 1H), 7.18 (dd, yl)-2-thia-4- J =
11.6, 8.9 Hz, 1H), 7.13 (s, 1H), 7.09 (d, J = 5.9 Hz,
azabicyclo[4.1.0]hept-3-en-5- 1H), 6.56 (s, 2H), 5.21 (d, J = 2.5
Hz, 2H), 4.62-4.96 yl)-4-fluorophenyl)-2-(2- (m, 2H), 3.68 (t, J =
2.4 Hz, 1H), 2.01-2.13 (m, 1H), propyn-1-yloxy)pyrido[3,4- 1.69
(dd, J = 9.7, 5.4 Hz, 1H), 0.88-1.04 (m, 1H) b]pyrazin-5-amine 801
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.63 (s, 1H), 9.27
4-((3-((1S,5S,6S)-3-amino-1- (d, J = 1.96 Hz, 1H), 8.92 (d, J =
1.76 Hz, 1H), 8.82 (s, (fluoromethyl)-5-methyl-2-thia- 1H),
8.09-8.19 (m, 2H), 6.15 (s, 2H), 4.45-4.57 (m,
4-azabicyclo[4.1.0]hept-3-en-5- 2H), 1.84 (m, 1H), 1.66 (s, 3H),
1.09 (m, 1H), 0.73 yl)-4,5- (m, 1H). .sup.19F NMR (377 MHz,
DMSO-d.sub.6) .delta.-138.52 difluorophenyl)amino)pyrido[3, (d, J =
22.55 Hz, 1F), -143.20 (d, J = 22.55 Hz, 1F), -211.45
2-d]pyrimidine-7-carbonitrile (s, 1F). 802 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.57 (br., 1H), 8.67
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.30 (m, 2H), 8.22 (s, 1H),
7.91 (m, 1H), 7.32 (fluoromethyl)-5-methyl-2-thia- (s, 1H), 7.11
(t, J = 11.97 Hz, 1H), 6.13 (br., 2H), 5.67
4-azabicyclo[4.1.0]hept-3-en-5- (s, 2H), 4.55-4.46 (m, 2H), 1.80
(t, J = 7.92 Hz, 1H), yl)-4,5-difluorophenyl)-2-(1,3- 1.64 (s, 3H),
1.07 (dd, J = 5.48, 9.19 Hz, 1H), 0.73 (d, oxazol-2- J = 5.09 Hz,
1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -138.80
ylmethoxy)pyrido[3,4- (d, J = 22.53 Hz, 1F), -146.42 (d, J = 22.54
Hz, b]pyrazin-5-amine 1F), -211.42 (s, 1F). 805 .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.58 (br., 1H), 8.63
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.23-8.33 (m, 2H), 7.86-7.92
(m, 1H), 7.13 (d, (difluoromethyl)-5-methyl-2- J = 5.87 Hz, 1H),
6.32 (s, 2H), 5.79-6.07 (m, 1H), 5.20
thia-4-azabicyclo[4.1.0]hept-3- (d, J = 2.35 Hz, 2H), 3.67 (t, J =
2.45 Hz, 1H), 1.90 (m, en-5-yl)-4,5-difluorophenyl)-2- 1H), 1.68
(s, 3H), 1.37 (m, 1H), 0.77 (m, 1H). .sup.19F
(2-propyn-1-yloxy)pyrido[3,4- NMR (377 MHz, DMSO-d.sub.6) .delta.
-115.43 (d, .sup.1J = 273.86 b]pyrazin-5-amine Hz, 1F), -117.97 (d,
.sup.1J = 273.80 Hz, 1F), -138.76 (d, .sup.2J = 22.53 Hz, 1F),
-142.98 (d, .sup.2J = 22.53 Hz, 1F). 806 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.56 (br., 1H), 8.63
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.27-8.34 (m, 2H), 7.90 (m,
1H), 7.13 (d, (fluoromethyl)-5-methyl-2-thia- J = 5.87 Hz, 1H),
6.13 (br., 2H), 5.20 (d, J = 2.35 Hz,
4-azabicyclo[4.1.0]hept-3-en-5- 2H), 4.56 (m, 1H), 4.43 (m, 1H),
3.67 (t, J = 2.35 Hz, yl)-4,5-difluorophenyl)-2-(2- 1H), 1.80 (m,
1H), 1.63 (s, 3H), 1.07 (m, 1H), 0.73 propyn-1-yloxy)pyrido[3,4-
(m, 1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -138.80
b]pyrazin-5-amine (d, J = 23.41 Hz, 1F), -146.44 (d, J = 23.41 Hz,
1F), -211.42 (s, 1F). 808 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.19 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.73 (m, 1H),
8.67 (s, 1H), 8.24 (s, 1H), 8.19 (m, 1H),
(fluoromethyl)-5-methyl-2-thia- 8.04 (d, J = 5.67 Hz, 1H), 7.84 (d,
J = 2.74 Hz, 1H), 7.34 4-azabicyclo[4.1.0]hept-3-en-5- (s, 1H),
6.13 (br., 2H), 5.56 (s, 2H), 4.44-4.56 (m,
yl)-4,5-difluorophenyl)-7-(1,3- 2H), 1.80 (m, 1H), 1.64 (s, 3H),
1.08 (m, 1H), 0.74 oxazol-2- (m, 1H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -138.68 ylmethoxy)pyrido[3,2- (d, J = 23.45
Hz, 1F), -144.36 (d, J = 23.45 Hz,, 1F), -211.44
d]pyrimidin-4-amine (s, 1F). 809 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.18 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.67-8.73 (m, 2H), 8.15-8.25 (m, 2H), 8.02 (m, 1H),
(methoxymethyl)-5-methyl-2- 7.83 (d, J = 2.74 Hz, 1H), 7.34 (s,
1H), 6.01 (br., 2H), thia-4-azabicyclo[4.1.0]hept-3- 5.56 (s, 2H),
3.57 (d, J = 10.95 Hz, 1H), 3.38 (d,
en-5-yl)-4,5-difluorophenyl)-7- J = 10.95 Hz, 1 H), 3.29 (s, 3H),
1.67 (m, 1H), 1.63 (s, (1,3-oxazol-2- 3H), 0.93 (m, 1H), 0.67 (m,
1H). .sup.19F NMR (377 ylmethoxy)pyrido[3,2- MHz, DMSO-d.sub.6)
.delta. -138.72 (d, J = 22.54 Hz, 1F), -144.51 d]pyrimidin-4-amine
(d, J = 22.55 Hz, 1F). 812 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.23 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.64-8.78 (m,
2H), 8.25 (d, J = 0.78 Hz, 1H), 8.15 (m,
(difluoromethyl)-5-methyl-2- 1H), 8.04 (m, 1H), 7.85 (d, J = 2.74
Hz, 1H), 7.35 (s, thia-4-azabicyclo[4.1.0]hept-3- 1H), 6.34 (br.,
2H), 5.81-6.09 (m, 1H), 5.57 (s, 2H),
en-5-yl)-4,5-difluorophenyl)-7- 1.91 (m, 1H), 1.69 (s, 3H), 1.40
(m, 1H), 0.78 (m, (1,3-oxazol-2- 1H). .sup.19F NMR (377 MHz,
DMSO-d.sub.6) .delta. -116.84 (d, ylmethoxy)pyrido[3,2- J = 273.96
Hz, 1F), -117.94 (d, J = 273.96 Hz, 1F), -138.56
d]pyrimidin-4-amine (d, J = 22.55 Hz, 1F), -143.80 (d, J = 22.55
Hz, 1F). 813 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.20
(br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.69-8.70 (m, 2H), 8.20 (m,
1H), 8.05 (m, 1H), 7.72 (fluoromethyl)-5-methyl-2-thia- (d, J =
2.74 Hz, 1H), 6.15 (br., 2H), 5.13 (d, J = 2.35 Hz,
4-azabicyclo[4.1.0]hept-3-en-5- 2H), 4.45-4.61 (m, 2H), 3.75 (t, J
= 2.35 Hz, 1H), 1.82 yl)-4,5-difluorophenyl)-7-(2- (m, 1H), 1.66
(s, 3H), 1.09 (m, 1H), 0.74 (m, 1H). .sup.19F
propyn-1-yloxy)pyrido[3,2- NMR (377 MHz, DMSO-d.sub.6) .delta.
-138.66 (d, J = 22.54 d]pyrimidin-4-amine Hz, 1F), -144.04 (d, J =
22.54 Hz, 1F), -211.42 (s, 1F). 816 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.37 (br., 1H), 8.62
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.26 (d, J = 5.87 Hz, 1H),
7.95-8.10 (m, 2H), (difluoromethyl)-5-methyl-2- 7.15 (dd, J = 8.80,
11.74 Hz, 1H), 7.08 (m, 1H), 6.30 thia-4-azabicyclo[4.1.0]hept-3-
(br., 2H), 5.69-6.13 (m, 1H), 5.09-5.28 (m, 2H), 3.67
en-5-yl)-4-fluorophenyl)-2-(2- (t, J = 2.35 Hz, 1H), 1.92 (m, 1H),
1.68 (s, 3H), 1.32 propyn-1-yloxy)pyrido[3,4- (m, 1H), 0.75 (m,
1H). .sup.19F NMR (377 MHz, DMSO- b]pyrazin-5-amine d.sub.6)
.delta. -115.42 (d, .sup.1J = 273.10 Hz, 1F), -117.88 (d, .sup.1J =
273.10 Hz, 1F), -118.59 (s, 1F). 817 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.38 (br., 1H), 8.65
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.15-8.32 (m, 2H), 8.03 (m,
2H), 7.31 (s, 1H), (difluoromethyl)-5-methyl-2- 7.14 (dd, J = 8.51,
11.84 Hz, 1H), 7.05 (d, J = 5.87 Hz,
thia-4-azabicyclo[4.1.0]hept-3- 1H), 6.29 (br., 2H), 5.71-6.09 (m,
1H), 5.66 (s, 2H), en-5-yl)-4-fluorophenyl)-2- 1.91 (m, 1H), 1.66
(s, 3H), 1.30 (m, 1H), 0.70 (m, (1,3-oxazol-2- 1H). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. -115.10 (d, ylmethoxy)pyrido[3,4-
.sup.1J = 273.90 Hz, 1F), -118.10 (d, .sup.1J = 273.90 Hz, 1F),
-118.57 b]pyrazin-5-amine (s, 1F). 819 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.02 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.66 (d, J = 2.74 Hz, 1H), 8.61 (s, 1H), 8.12 (dd,
(difluoromethyl)-5-methyl-2- J = 2.74, 7.43 Hz, 1H), 7.91 (td, J =
3.67, 8.31 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3- 7.68 (d, J =
2.74 Hz, 1H), 7.20 (m, 1H), 6.28 (br., 2H),
en-5-yl)-4-fluorophenyl)-7-(2- 5.77-6.10 (m, 1H), 5.11 (d, J = 2.35
Hz, 2H), 3.74 (m, propyn-1-yloxy)pyrido[3,2- 1H), 1.90 (m, 1H),
1.67 (s, 3H), 1.33 (m, 1H), 0.73 d]pyrimidin-4-amine (m, 1H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -115.07 (d, .sup.1J =
273.70 Hz, 1F), -116.68 (s, 1F), -117.96 (d, .sup.1J = 273.70 Hz,
1F). 823 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.35 (br.,
1H), 8.62 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.25 (d, J = 5.87
Hz, 1H), 8.01-8.12 (m, 2H), (fluoromethyl)-5-methyl-2-thia- 7.14
(dd, J = 8.80, 11.93 Hz, 1H), 7.07 (d, J = 5.87 Hz,
4-azabicyclo[4.1.0]hept-3-en-5- 1H), 6.11 (br., 2H), 5.21 (d, J =
2.35 Hz, 2H), 4.29-4.66 yl)-4-fluorophenyl)-2-(2- (m, 2H), 3.67 (t,
J = 2.35 Hz, 1H), 1.82 (m, 1H), 1.63 propyn-1-yloxy)pyrido[3,4- (s,
3H), 1.03 (m, 1H), 0.70 (m, 1H). .sup.19F NMR (377
b]pyrazin-5-amine MHz, DMSO-d.sub.6) .delta. -119.06 (s, 1F),
-211.28 (s, 1F). 824 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.01 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.67 (d, J = 2.74 Hz,
1H), 8.62 (s, 1H), 8.15 (dd, (fluoromethyl)-5-methyl-2-thia- J =
2.84, 7.34 Hz, 1H), 7.95 (td, J = 3.67, 8.31 Hz, 1H),
4-azabicyclo[4.1.0]hept-3-en-5-
7.69 (d, J = 2.74 Hz, 1H), 7.19 (dd, J = 8.61, 11.93 Hz,
yl)-4-fluorophenyl)-7-(2- 1H), 6.10 (br., 2H), 5.12 (d, J = 2.35
Hz, 2H), 4.37-4.63 propyn-1-yloxy)pyrido[3,2- (m, 2H), 3.76 (m,
1H), 1.84 (m, 1H), 1.64 (s, 3H), d]pyrimidin-4-amine 1.03 (m, 1H),
0.70 (q, J = 5.35 Hz, 1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6)
.delta. -117.13 (s, 1F), -211.31 (s, 1F). 825 .sup.19F NMR (377
MHz, DMSO-d.sub.6) .delta. -119.04 (s, 1F), -211.28
N-(3-((1S,5S,6S)-3-amino-1- (s, 1F). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.37 (fluoromethyl)-5-methyl-2-thia- (br.,
1H), 8.66 (s, 1H), 8.18-8.31 (m, 2H), 7.95-8.11
4-azabicyclo[4.1.0]hept-3-en-5- (m, 2H), 7.32 (s, 1H), 7.14 (dd, J
= 9.19, 11.93 Hz, yl)-4-fluorophenyl)-2-(1,3- 1H), 7.06 (d, J =
5.67 Hz, 1H), 6.10 (br., 2H), 5.68 (s, oxazol-2- 2H), 4.30-4.70 (m,
2H), 1.80 (m, 1H), 1.63 (s, 3H), ylmethoxy)pyrido[3,4- 1.03 (m,
1H), 0.70 (m, 1H). b]pyrazin-5-amine 827 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.33 (br., 1H), 8.57
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.24 (d, J = 5.87 Hz, 1H),
8.00-8.11 (m, 2H), (fluoromethyl)-5-methyl-2-thia- 7.13 (dd, J =
8.80, 11.93 Hz, 1H), 7.01-7.08 (m, 1H),
4-azabicyclo[4.1.0]hept-3-en-5- 6.10 (br., 2H), 5.92 (dq, J = 1.76,
6.59 Hz, 1H), 4.31- yl)-4-fluorophenyl)-2-(((1S)-1- 4.64 (m, 2H),
3.60 (d, J = 1.96 Hz, 1H), 1.83 (t, J = 7.82 methyl-2-propyn-1- Hz,
1H), 1.66 (d, J = 6.46 Hz, 3H), 1.62 (s, 3H), 1.02
yl)oxy)pyrido[3,4-b]pyrazin-5- (m, 1H), 0.69 (m, 1H). .sup.19F NMR
(376 MHz, DMSO- amine d.sub.6) .delta. -119.12 (s, 1F), -211.30 (s,
1F). 828 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.37 (br.,
1H), 8.67 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.25 (d, J = 5.87
Hz, 1H), 7.99-8.12 (m, 2H), (fluoromethyl)-5-methyl-2-thia-
7.10-7.20 (m, 1H), 7.05 (d, J = 5.87 Hz, 1H), 6.11 (br.,
4-azabicyclo[4.1.0]hept-3-en-5- 2H), 5.58-5.71 (s, 2H), 4.35-4.70
(m, 2H), 2.65 (s, yl)-4-fluorophenyl)-2-((5- 3H), 1.87 (m, 1H),
1.63 (s, 3H), 1.03 (m, 1H), 0.70 methyl-1,2,4-oxadiazol-3- (m, 1H).
.sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -119.02 (s,
yl)methoxy)pyrido[3,4- 1F), -211.28 (s, 1F). b]pyrazin-5-amine 841
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.61 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-5- 8.64 (s, 1 H), 8.28-8.36 (m, 2 H),
7.94-8.00 (m, 1 (fluoromethyl)-2-thia-4- H), 7.14 (d, J = 5.87 Hz,
1 H), 6.27 (s, 2 H), 5.21 (d, azabicyclo[4.1.0]hept-3-en-5- J =
2.35 Hz, 2 H), 4.64-4.85 (m, 2 H), 3.68 (t, J = 2.35
yl)-4,5-difluorophenyl)-2-(2- Hz, 1 H), 2.38-2.47 (m, 1 H),
1.74-1.83 (m, 1 H), propyn-1-yloxy)pyrido[3,4- 1.10 (ddd, J = 8.75,
7.58, 5.18 Hz, 1 H), 0.46 (q, J = 5.28 b]pyrazin-5-amine Hz, 1 H)
842 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.62 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-5- 8.68 (s, 1 H), 8.27-8.36 (m, 2 H), 8.23
(d, J = 0.78 Hz, (fluoromethyl)-2-thia-4- 1 H), 7.94-8.00 (m, 1 H),
7.33 (d, J = 0.78 Hz, 1 H), azabicyclo[4.1.0]hept-3-en-5- 7.13 (d,
J = 5.87 Hz, 1 H), 6.27 (s, 2 H), 5.68 (s, 2 H),
yl)-4,5-difluorophenyl)-2-(1,3- 4.64-4.85 (m, 2 H), 2.38-2.47 (m, 1
H), 1.72-1.84 oxazol-2- (m, 1 H), 1.10 (ddd, J = 8.90, 7.53, 5.28
Hz, 1 H), 0.46 ylmethoxy)pyrido[3,4- (q, J = 5.28 Hz, 1 H)
b]pyrazin-5-amine 843 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 9.59 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-5- 8.61 (s, 1 H), 8.47
(s, 1 H), 8.28-8.37 (m, 3 H), 7.93- (fluoromethyl)-2-thia-4- 8.00
(m, 1 H), 7.17 (d, J = 5.87 Hz, 1 H), 6.27 (s, 2 H),
azabicyclo[4.1.0]hept-3-en-5- 5.49 (s, 2 H), 4.64-4.85 (m, 2 H),
2.39-2.46 (m, 1 yl)-4,5-difluorophenyl)-2-(1,3- H), 1.78 (q, J =
8.22 Hz, 1 H), 1.06-1.14 (m, 1 H), oxazol-4- 0.46 (q, J = 5.15 Hz,
1 H) ylmethoxy)pyrido[3,4- b]pyrazin-5-amine 865 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 0.57-0.68 N-(3-((1S,5S,6S)-3-amino-1,5-
(m, 1 H) 1.23 (dd, J = 9.59, 5.28 Hz, 1 H) 1.72-1.83
bis(fluoromethyl)-2-thia-4- (m, 1 H) 1.87 (t, J = 2.25 Hz, 3 H)
4.32-4.57 (m, 2 H) azabicyclo[4.1.0]hept-3-en-5- 4.58-4.85 (m, 2 H)
5.15 (d, J = 2.35 Hz, 2 H) 6.40 (s, yl)-4-fluorophenyl)-2-(2-butyn-
2 H) 7.06 (d, J = 5.67 Hz, 1 H) 7.15 (dd, J = 11.84, 8.90
1-yloxy)pyrido[3,4-b]pyrazin- Hz, 1 H) 8.05 (dt, J = 8.56, 3.55 Hz,
1 H) 8.11 (dd, 5-amine J = 7.24, 2.74 Hz, 1 H) 8.24 (d, J = 5.87
Hz, 1 H) 8.57 (s, 1 H) 9.39 (s, 1 H) 866 .sup.1H NMR (300 MHz,
DMSO-d6) .delta. ppm 0.70-0.82 N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H)
1.36 (dd, J = 9.50, 5.70 Hz, 1 H) 1.67 (s, 3 H)
(difluoromethyl)-5-methyl-2- 1.82-1.97 (m, 1 H) 5.66 (s, 2 H)
5.71-6.16 (m, 1 H) thia-4-azabicyclo[4.1.0]hept-3- 6.31 (s, 2 H)
7.11 (d, J = 5.85 Hz, 1 H) 7.31 (d, J = 0.73
en-5-yl)-4,5-difluorophenyl)-2- Hz, 1 H) 7.83-7.93 (m, 1 H) 8.21
(d, J = 0.73 Hz, 1 H) (1,3-oxazol-2- 8.25 (td, J = 6.58, 4.09 Hz, 1
H) 8.30 (d, J = 5.85 Hz, 1 ylmethoxy)pyrido[3,4- H) 8.67 (s, 1 H)
9.59 (s, 1 H) b]pyrazin-5-amine 867 .sup.1H NMR (300 MHz, DMSO-d6)
.delta. ppm 0.70-0.84 N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H) 1.36
(dd, J = 9.57, 5.92 Hz, 1 H) 1.66 (s, 3 H)
(difluoromethyl)-5-methyl-2- 1.81-1.95 (m, 1 H) 5.47 (s, 2 H)
5.62-6.18 (m, 1 H) thia-4-azabicyclo[4.1.0]hept-3- 6.31 (s, 2 H)
7.15 (d, J = 5.85 Hz, 1 H) 7.82-7.94 (m,
en-5-yl)-4,5-difluorophenyl)-2- 1 H) 8.24 (td, J = 6.54, 2.85 Hz, 1
H) 8.29-8.35 (m, 2 (1,3-oxazol-4- H) 8.44 (d, J = 0.73 Hz, 1 H)
8.58 (s, 1 H) 9.55 (s, 1 H) ylmethoxy)pyrido[3,4- b]pyrazin-5-amine
868 .sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm 0.77 (q,
N-(3-((1S,5S,6S)-3-amino-1- J = 5.75 Hz, 1 H) 1.29-1.44 (m, 1 H)
1.68 (s, 3 H) (difluoromethyl)-5-methyl-2- 1.88 (t, J = 2.34 Hz, 4
H) 5.16 (d, J = 2.48 Hz, 2 H) 5.69- thia-4-azabicyclo[4.1.0]hept-3-
6.16 (m, 1 H) 6.32 (s, 2 H) 7.12 (d, J = 5.99 Hz, 1 H)
en-5-yl)-4,5-difluorophenyl)-2- 7.81-7.94 (m, 1 H) 8.22-8.31 (m, 2
H) 8.60 (s, 1 H) (2-butyn-1-yloxy)pyrido[3,4- 9.56 (s, 1 H)
b]pyrazin-5-amine 869 .sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm
0.63-0.70 N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H) 0.92 (dd, J = 9.21,
5.26 Hz, 1 H) 1.60-1.70 (methoxymethyl)-5-methyl-2- (m, 4 H) 1.88
(t, J = 2.41 Hz, 3 H) 3.31 (s, 3 H) 3.31 (s,
thia-4-azabicyclo[4.1.0]hept-3- 3 H) 3.36 (d, J = 11.11 Hz, 1 H)
3.57 (d, J = 10.96 Hz, 1 en-5-yl)-4,5-difluorophenyl)-2- H) 5.16
(d, J = 2.34 Hz, 2 H) 6.01 (br. s., 2 H) 7.12 (d,
(2-butyn-1-yloxy)pyrido[3,4- J = 5.85 Hz, 1 H) 7.83-7.94 (m, 1 H)
8.22-8.39 (m, 2 b]pyrazin-5-amine H) 8.60 (s, 1 H) 9.52 (s, 1 H)
870 .sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm 0.67-0.84
N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H) 1.36 (dd, J = 9.72, 6.21 Hz, 1
H) 1.67 (s, 3 H) (difluoromethyl)-5-methyl-2- 1.78-1.97 (m, 1 H)
2.42 (s, 3 H) 5.40 (s, 2 H) 5.69- thia-4-azabicyclo[4.1.0]hept-3-
6.14 (m, 1 H) 6.31 (s, 2 H) 7.15 (d, J = 5.99 Hz, 1 H)
en-5-yl)-4,5-difluorophenyl)-2- 7.88 (d, J = 5.85 Hz, 1 H) 8.14 (s,
1 H) 8.21-8.32 (m, ((2-methyl-1,3-oxazol-4- 2 H) 8.58 (s, 1 H) 9.55
(s, 1 H) yl)methoxy)pyrido[3,4- b]pyrazin-5-amine 871 .sup.1H NMR
(300 MHz, DMSO-d6) .delta. ppm 0.77 (q, N-(3-((1S,5S,6S)-3-amino-1-
J = 5.65 Hz, 1 H) 1.38 (td, J = 10.05, 5.92 Hz, 1 H) 1.68
(difluoromethyl)-5-methyl-2- (s, 3H) 1.82-1.98 (m, 1 H) 2.12-2.34
(m, 2 H) 4.51- thia-4-azabicyclo[4.1.0]hept-3- 4.65 (m, 3 H) 4.75
(t, J = 5.85 Hz, 1 H) 5.68-6.18 en-5-yl)-4,5-difluorophenyl)-2- (m,
1 H) 6.32 (s, 2 H) 7.11 (d, J = 5.85 Hz, 1 H) 7.88
(3-fluoropropoxy)pyrido[3,4- (d, J = 6.14 Hz, 1 H) 8.20-8.35 (m, 2
H) 8.57 (s, 1 H) b]pyrazin-5-amine 9.55 (s, 1 H) 872 .sup.1H NMR
(300 MHz, DMSO-d6) .delta. ppm 0.76 (q, N-(3-((1S,5S,6S)-3-amino-1-
J = 5.65 Hz, 1 H) 1.36 (dd, J = 9.79, 5.70 Hz, 1 H) 1.67
(difluoromethyl)-5-methyl-2- (s, 3 H) 1.81 (t, J = 19.37 Hz, 4 H)
4.79 (t, J = 13.15 Hz, thia-4-azabicyclo[4.1.0]hept-3- 2 H)
5.67-6.15 (m, 1 H) 6.32 (s, 2 H) 7.12 (d, J = 5.85
en-5-yl)-4,5-difluorophenyl)-2- Hz, 1 H) 7.84-7.95 (m, 1 H)
8.17-8.36 (m, 2 H) (2,2- 8.68 (s, 1 H) 9.61 (s, 1 H)
difluoropropoxy)pyrido[3,4- b]pyrazin-5-amine 873 .sup.1H NMR (300
MHz, DMSO-d6) .delta. ppm 0.76 (q, N-(3-((1S,5S,6S)-3-amino-1- J =
5.85 Hz, 1 H) 1.36 (dd, J = 9.87, 5.92 Hz, 1 H) 1.67
(difluoromethyl)-5-methyl-2- (s, 3 H) 1.82-1.94 (m, 1 H) 5.71 (d, J
= 1.90 Hz, 2 H) thia-4-azabicyclo[4.1.0]hept-3- 5.72-6.14 (m, 1 H)
6.31 (s, 2 H) 7.10 (d, J = 5.85 Hz, en-5-yl)-4,5-difluorophenyl)-2-
1 H) 7.50-7.60 (m, 1 H) 7.77-7.93 (m, 2 H) 8.19- ((3-fluoro-2- 8.33
(m, 2 H) 8.42-8.50 (m, 1 H) 8.64 (s, 1 H) 9.56
pyridinyl)methoxy)pyrido[3,4- (s, 1 H) b]pyrazin-5-amine 874
.sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm 0.68-0.85
N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H) 1.36 (dd, J = 9.57, 5.77 Hz, 1
H) 1.67 (s, 3 H) (difluoromethyl)-5-methyl-2- 1.80-1.95 (m, 1 H)
2.46 (s, 3 H) 5.69 (s, 2 H) 5.72- thia-4-azabicyclo[4.1.0]hept-3-
6.15 (m, 1 H) 6.31 (s, 2 H) 7.00 (d, J = 5.85 Hz, 1 H)
en-5-yl)-4,5-difluorophenyl)-2- 7.33 (d, J = 5.12 Hz, 1 H) 7.88
(dd, J = 5.41, 2.78 Hz, 1 ((4-methyl-2- H) 8.17-8.33 (m, 2 H) 8.62
(d, J = 5.12 Hz, 1 H) 8.71 pyrimidinyl)methoxy)pyrido[3, (s, 1 H)
9.56 (s, 1 H) 4-b]pyrazin-5-amine 875 .sup.1H NMR (300 MHz,
DMSO-d6) .delta. ppm 0.70-0.83 N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H)
1.36 (dd, J = 9.72, 5.63 Hz, 1 H) 1.67 (s, 3 H)
(difluoromethyl)-5-methyl-2- 1.82-1.95 (m, 1 H) 5.67 (s, 2 H)
5.70-6.14 (m, 1 H) thia-4-azabicyclo[4.1.0]hept-3- 6.31 (s, 2 H)
7.15 (d, J = 5.85 Hz, 1 H) 7.89 (d, J = 6.28
en-5-yl)-4,5-difluorophenyl)-2- Hz, 1 H) 7.94 (d, J = 1.90 Hz, 1 H)
8.20-8.34 (m, 2 H) (1,3-thiazol-4- 8.62 (s, 1 H) 9.16 (d, J = 1.90
Hz, 1 H) 9.56 (s, 1 H) ylmethoxy)pyrido[3,4- b]pyrazin-5-amine 876
.sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm 0.76 (d,
N-(3-((1S,5S,6S)-3-amino-1- J = 6.28 Hz, 1 H) 1.30-1.47 (m, 7 H)
1.67 (s, 3 H) (difluoromethyl)-5-methyl-2- 1.88 (t, J = 7.82 Hz, 1
H) 5.39-5.55 (m, 1 H) 5.70- thia-4-azabicyclo[4.1.0]hept-3- 6.16
(m, 1 H) 6.31 (s, 2 H) 7.08 (d, J = 5.85 Hz, 1 H)
en-5-yl)-4,5-difluorophenyl)-2- 7.87 (br. s., 1 H) 8.20-8.34 (m, 2
H) 8.48 (s, 1 H) (1-methylethoxy)pyrido[3,4- 9.50 (s, 1 H)
b]pyrazin-5-amine 877 .sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm
0.69-0.82 N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H) 1.36 (dd, J = 9.57,
5.63 Hz, 1 H) 1.67 (s, 3 H) (difluoromethyl)-5-methyl-2- 1.89 (t, J
= 8.18 Hz, 1H) 2.54 (s, 3 H) 5.71-6.14 (m, 3
thia-4-azabicyclo[4.1.0]hept-3- H) 6.31 (s, 2 H) 7.12 (d, J = 5.85
Hz, 1 H) 7.89 (d, en-5-yl)-4,5-difluorophenyl)-2- J = 5.99 Hz, 1 H)
8.19-8.29 (m, 1 H) 8.31 (d, J = 5.99 ((5-methyl-1,3,4-oxadiazol-2-
Hz, 1 H) 8.68 (s, 1 H) 9.61 (s, 1 H) yl)methoxy)pyrido[3,4-
b]pyrazin-5-amine 878 .sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm
0.77 (d, 2-((5-((3-((1S,5S,6S)-3-amino- J = 4.82 Hz, 1 H) 1.38 (d,
J = 6.43 Hz, 1 H) 1.67 (s, 3 H) 1-(difluoromethyl)-5-methyl-2-
1.80-1.96 (m, 1 H) 2.85 (s, 4 H) 3.05 (s, 3 H) 5.30 (s,
thia-4-azabicyclo[4.1.0]hept-3- 2 H) 5.70-6.15 (m, 1 H) 6.32 (s, 2
H) 7.05 (d, J = 5.85 en-5-yl)-4,5- Hz, 1 H) 7.87 (br. s., 1 H) 8.27
(d, J = 5.85 Hz, 2 H) difluorophenyl)amino)pyrido[3,4- 8.66 (s, 1
H) 9.56 (s, 1 H) b]pyrazin-2-yl)oxy)-N,N- dimethylacetamide 879
.sup.1H NMR (300 MHz, DMSO-d6) .delta. ppm 9.40 (s, 1 H)
N-(3-((1S,5S,6S)-3-amino-1,5- 8.56 (s, 1 H) 8.24 (d, J = 5.85 Hz, 1
H) 8.00-8.15 (m, bis(fluoromethyl)-2-thia-4-
2 H) 7.15 (dd, J = 11.84, 8.77 Hz, 1 H) 7.06 (d, J = 5.85
azabicyclo[4.1.0]hept-3-en-5- Hz, 1 H) 6.40 (s, 2 H) 5.91 (qd, J =
6.63, 2.05 Hz, 1 H) yl)-4-fluorophenyl)-2-(((1S)-1- 4.69-4.86 (m, 1
H) 4.48-4.69 (m, 2 H) 4.30-4 methyl-2-propyn-1-
yl)oxy)pyrido[3,4-b]pyrazin-5- amine 880 .sup.1H NMR (300 MHz,
DMSO-d6) .delta. ppm 9.59 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-1,5-
8.85 (s, 1 H), 8.38 (d, J = 5.85 Hz, 1 H), 8.26 (dd,
bis(fluoromethyl)-2-thia-4- J = 7.16, 2.92 Hz, 1 H), 8.18 (ddd, J =
8.73, 4.13, 3.07 azabicyclo[4.1.0]hept-3-en-5- Hz, 1 H), 7.29 (dd,
J = 11.84, 8.92 Hz, 1 H), 7.14 (d, yl)-4-fluorophenyl)-2-((3- J =
5.85 Hz, 1 H), 6.54 (s, 2 H), 6.00 (s, 2 H), 4.63-
methyl-1,2,4-oxadiazol-5- 5.01 (m, 3 H), 4.46-4.59 (m, 1 H), 2.50
(s, 3 H), 1.86- yl)methoxy)pyrido[3,4- 2.01 (m, 1 H), 1.37 (dd, J =
9.50, 5.26 Hz, 1 H), 0.68- b]pyrazin-5-amine 0.84 (m, 1 H) 881
.sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.52 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-1- 8.81 (d, J = 4.89 Hz, 2 H), 8.72 (s, 1
H), 8.30 (ddd, (methoxymethyl)-5-methyl-2- J = 13.30, 6.65, 2.74
Hz, 1 H), 8.23 (d, J = 5.87 Hz, 1 H),
thia-4-azabicyclo[4.1.0]hept-3- 7.88 (m, J = 5.87 Hz, 1 H), 7.46
(t, J = 4.89 Hz, 1 H), en-5-yl)-4,5-difluorophenyl)-2- 6.97 (d, J =
5.87 Hz, 1 H), 6.00 (br. s., 2 H), 5.76 (s, 2 (2- H), 3.56 (d, J =
10.95 Hz, 1 H), 3.36 (d, J = 11.15 Hz, 1
pyrimidinylmethoxy)pyrido[3,4- H), 3.30 (s, 3 H), 1.57-1.69 (m, 4
H), 0.92 (dd, b]pyrazin-5-amine J = 8.61, 4.69 Hz, 1 H), 0.66 (t, J
= 5.58 Hz, 1 H) 882 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.58
(s, 1 H), N-(3-((1S,5S,6S)-3-amino-1- 8.73 (s, 1 H), 8.23-8.35 (m,
2 H), 7.83-7.94 (m, 1 (methoxymethyl)-5-methyl-2- H), 7.06 (d, J =
5.87 Hz, 1 H), 6.00 (br. s., 2 H), 5.87 (s,
thia-4-azabicyclo[4.1.0]hept-3- 2 H), 3.56 (d, J = 10.95 Hz, 1 H),
3.36 (d, J = 10.95 Hz, en-5-yl)-4,5-difluorophenyl)-2- 1 H), 3.27
(s, 3 H), 2.36 (s, 3 H), 1.55-1.71 (m, 4 H),
((3-methyl-1,2,4-oxadiazol-5- 0.92 (dd, J = 9.10, 5.38 Hz, 1 H),
0.66 (t, J = 5.58 Hz, 1 yl)methoxy)pyrido[3,4- H) b]pyrazin-5-amine
883 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 9.59 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-1- 8.67 (s, 1 H), 8.30 (d, J = 5.87 Hz, 1
H), 8.25 (ddd, (difluoromethyl)-5-methyl-2- J = 13.06, 6.80, 2.64
Hz, 1 H), 7.82-7.93 (m, 1 H), thia-4-azabicyclo[4.1.0]hept-3- 7.10
(d, J = 5.87 Hz, 1 H), 6.32 (br. s., 2 H), 5.93 (t,
en-5-yl)-4,5-difluorophenyl)-2- J = 55.40 Hz, 1 H), 5.69 (s, 2 H),
2.63 (s, 3 H), 1.81- ((5-methyl-1,2,4-oxadiazol-3- 1.96 (m, 1 H),
1.67 (s, 3 H), 1.37 (dd, J = 9.59, 5.87 Hz, yl)methoxy)pyrido[3,4-
1 H), 0.76 (q, J = 5.67 Hz, 1 H) b]pyrazin-5-amine 884 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. ppm 9.35-9.76
N-(3-((1S,5S,6S)-3-amino-1- (m, 1 H), 8.81 (d, J = 4.89 Hz, 2 H),
8.72 (s, 1 H), 8.18- (difluoromethyl)-5-methyl-2- 8.30 (m, 2 H),
7.83-7.92 (m, 1 H), 7.46 (t, J = 4.89
thia-4-azabicyclo[4.1.0]hept-3- Hz, 1 H), 6.98 (d, J = 5.87 Hz, 1
H), 6.32 (br. s., 2 H), en-5-yl)-4,5-difluorophenyl)-2-(2- 5.93 (t,
J = 55.60 Hz, 1 H), 5.75 (s, 2 H), 1.81-1.96
pyrimidinylmethoxy)pyrido[3,4- (m, 1 H), 1.67 (s, 3 H), 1.36 (dd, J
= 9.78, 5.87 Hz, 1 b]pyrazin-5-amine H), 0.76 (q, J = 5.74 Hz, 1 H)
885 .sup.1H NMR (400 MHz, CD3OD) .delta. ppm 8.56 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-1- 8.27 (d, J = 6.06 Hz, 1 H), 7.93-8.09
(m, 2 H), 7.16 (d, (methoxymethyl)-5-methyl-2- J = 5.87 Hz, 1 H),
5.73 (s, 2 H), 3.50-3.66 (m, 2 H), thia-4-azabicyclo[4.1.0]hept-3-
3.45 (s, 3 H), 2.66 (s, 3 H), 2.16 (dd, J = 9.10, 6.75 Hz,
en-5-yl)-4,5-difluorophenyl)-2- 1 H), 2.08 (s, 3 H), 1.63 (dd, J =
9.00, 6.65 Hz, 1 H), ((5-methyl-1,2,4-oxadiazol-3- 1.13 (t, J =
6.36 Hz, 1 H) yl)methoxy)pyrido[3,4- b]pyrazin-5-amine 886 .sup.1H
NMR (300 MHz, DMSO-d6) .delta. ppm 9.53 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-1- 8.56 (s, 1 H), 8.20-8.35 (m, 2 H),
7.80-7.93 (m, 1 (difluoromethyl)-5-methyl-2- H), 7.12 (d, J = 5.85
Hz, 1 H), 6.31 (s, 2 H), 5.93 (t, thia-4-azabicyclo[4.1.0]hept-3- J
= 55.50 Hz, 1 H), 5.34 (s, 2 H), 2.41 (s, 3 H), 2.35 (s,
en-5-yl)-4,5-difluorophenyl)-2- 3 H), 1.88 (t, J = 8.40 Hz, 1 H),
1.67 (s, 3 H), 1.36 (dd, ((2,5-dimethyl-1,3-oxazol-4- J = 9.50,
5.85 Hz, 1 H), 0.76 (q, J = 5.60 Hz, 1 H) yl)methoxy)pyrido[3,4-
b]pyrazin-5-amine 887 .sup.1H NMR (300 MHz, CD3OD) .delta. ppm 8.59
(s, 1 H), N-(3-((1S,5S,6S)-3-amino-1- 8.23 (d, J = 5.85 Hz, 1 H),
7.96 (dt, J = 5.96, 2.28 Hz, 1 (difluoromethyl)-5-methyl-2- H),
7.87 (ddd, J = 12.35, 6.80, 2.63 Hz, 1 H), 7.08 (d,
thia-4-azabicyclo[4.1.0]hept-3- J = 5.85 Hz, 1 H), 5.83 (s, 3 H),
5.81 (t, J = 55.80 Hz, 1 en-5-yl)-4,5-difluorophenyl)-2- H), 2.43
(dd, J = 9.35, 7.02 Hz, 1 H), 2.37 (s, 3 H), 2.06
((3-methyl-1,2,4-oxadiazol-5- (s, 3 H), 1.91 (dd, J = 9.50, 6.87
Hz, 1 H), 1.04-1.20 yl)methoxy)pyrido[3,4- (m, 1 H)
b]pyrazin-5-amine 888 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm
9.59 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-1- 8.65 (s, 1 H), 8.30 (d,
J = 5.87 Hz, 1 H), 8.25 (ddd, (difluoromethyl)-5-methyl-2- J =
13.01, 6.85, 2.64 Hz, 1 H), 7.89 (m, 1 H), 7.12 (d,
thia-4-azabicyclo[4.1.0]hept-3- J = 5.87 Hz, 1 H), 6.92 (d, J =
1.17 Hz, 1 H), 6.31 (br. s., en-5-yl)-4,5-difluorophenyl)-2- 2 H),
5.93 (t, J = 55.60 Hz, 1 H), 5.58 (s, 2 H), 2.33 (d,
((5-methyl-1,3-oxazol-2- J = 1.17 Hz, 3 H), 1.89 (t, J = 7.63 Hz, 1
H), 1.67 (s, 3 yl)methoxy)pyrido[3,4- H), 1.31-1.44 (m, 1 H), 0.77
(m, 1 H) b]pyrazin-5-amine 889 .sup.1H NMR (300 MHz, DMSO-d6)
.delta. ppm 9.61 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-1- 8.66 (s, 1
H), 8.32 (d, J = 5.99 Hz, 1 H), 8.25 (ddd,
(difluoromethyl)-5-methyl-2- J = 13.12, 6.83, 2.70 Hz, 1 H), 7.89
(dt, J = 5.92, 2.16 thia-4-azabicyclo[4.1.0]hept-3- Hz, 1 H), 7.15
(d, J = 5.85 Hz, 1 H), 6.32 (s, 2 H), 5.69-
en-5-yl)-4,5-difluorophenyl)-2- 6.15 (m, 3 H), 2.73 (s, 3 H),
1.80-1.96 (m, 1 H), ((5-methyl-1,3,4-thiadiazol-2- 1.67 (s, 3 H),
1.36 (dd, J = 9.57, 5.92 Hz, 1 H), 0.76 (q, yl)methoxy)pyrido[3,4-
J = 5.75 Hz, 1 H) b]pyrazin-5-amine 890 .sup.1H NMR (300 MHz,
DMSO-d6) .delta. ppm 9.57 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-1-
8.58 (s, 1 H), 8.18-8.36 (m, 2 H), 7.81-7.95 (m, 1
(difluoromethyl)-5-methyl-2- H), 7.12 (d, J = 5.85 Hz, 1 H), 6.32
(br. s., 2 H), 5.70- thia-4-azabicyclo[4.1.0]hept-3- 6.15 (m, 2 H),
3.60 (d, J = 2.05 Hz, 1 H), 1.81-1.97
en-5-yl)-4,5-difluorophenyl)-2- (m, 1 H), 1.56-1.78 (m, 6 H),
1.31-1.42 (m, 1 H), (((1S)-1-methyl-2-propyn-1- 0.77 (d, J = 5.55
Hz, 1 H) yl)oxy)pyrido[3,4-b]pyrazin-5- amine 891 .sup.1H NMR (300
MHz, DMSO-d6) .delta. ppm 9.57 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-1- 8.63 (s, 1 H), 8.19-8.35 (m, 2 H), 8.15
(d, J = 0.88 Hz, (difluoromethyl)-5-methyl-2- 1 H), 7.89 (dt, J =
4.02, 2.08 Hz, 1 H), 7.25 (d, J = 0.73
thia-4-azabicyclo[4.1.0]hept-3- Hz, 1 H), 7.07 (d, J = 5.85 Hz, 1
H), 6.43-6.59 (m, 1 en-5-yl)-4,5-difluorophenyl)-2- H), 6.31 (s, 2
H), 5.93 (t, J = 55.50 Hz, 1 H), 1.83- ((1R)-1-(1,3-oxazol-2- 1.95
(m, 1 H), 1.79 (d, J = 6.58 Hz, 3 H), 1.67 (s, 3 H),
yl)ethoxy)pyrido[3,4-b]pyrazin- 1.31-1.41 (m, 1 H), 0.76 (q, J =
5.75 Hz, 1 H) 5-amine 892 .sup.1H NMR (300 MHz, DMSO-d6) .delta.
ppm 9.57 (s, 1 H), N-(3-((1S,5S,6S)-3-amino-1- 8.63 (s, 1 H),
8.20-8.36 (m, 2 H), 8.15 (d, J = 0.88 Hz,
(difluoromethyl)-5-methyl-2- 1 H), 7.88 (dt, J = 3.95, 2.12 Hz, 1
H), 7.25 (d, J = 0.73 thia-4-azabicyclo[4.1.0]hept-3- Hz, 1 H),
7.07 (d, J = 5.85 Hz, 1 H), 6.43-6.60 (m, 1
en-5-yl)-4,5-difluorophenyl)-2- H), 6.32 (br. s., 2 H), 5.93 (t, J
= 55.50 Hz, 1 H), 1.83- ((1S)-1-(1,3-oxazol-2- 1.95 (m, 1 H), 1.79
(d, J = 6.72 Hz, 3 H), 1.67 (s, 3 H),
yl)ethoxy)pyrido[3,4-b]pyrazin- 1.32-1.42 (m, 1 H), 0.76 (q, J =
5.90 Hz, 1 H) 5-amine 893 .sup.1H NMR (300 MHz, DMSO-d6) .delta.
ppm 9.55 (s, 1 H), 1-(2-((5-((3-((1S,5S,6S)-3- 8.53 (s, 1 H),
8.20-8.34 (m, 2 H), 7.88 (dt, J = 6.03, amino-1-(difluoromethyl)-5-
2.17 Hz, 1 H), 7.09 (d, J = 5.85 Hz, 1 H), 6.31 (s, 2 H),
methyl-2-thia-4- 5.93 (t, J = 55.50 Hz, 1 H), 4.60 (t, J = 5.33 Hz,
2 H), azabicyclo[4.1.0]hept-3-en-5- 3.65 (t, J = 5.33 Hz, 2 H),
3.50 (t, J = 7.02 Hz, 2 H), 2.12- yl)-4,5- 2.23 (m, 2 H), 1.81-2.03
(m, 3 H), 1.67 (s, 3 H), difluorophenyl)amino)pyrido[3,4- 1.36 (dd,
J = 9.65, 5.85 Hz, 1 H), 0.76 (q, J = 5.70 Hz, 1
b]pyrazin-2-yl)oxy)ethyl)-2- H) pyrrolidinone 894 .sup.1H NMR (300
MHz, DMSO-d6) .delta. ppm 9.51 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-1- 8.52 (s, 1 H), 8.18-8.34 (m, 2 H),
7.78-7.92 (m, 1 (difluoromethyl)-5-methyl-2- H), 7.08 (d, J = 5.85
Hz, 1 H), 6.32 (s, 2 H), 5.93 (t, thia-4-azabicyclo[4.1.0]hept-3- J
= 55.70 Hz, 1 H), 5.47-5.64 (m, 1 H), 3.51-3.71 (m,
en-5-yl)-4,5-difluorophenyl)-2- 2 H), 1.83-1.95 (m, 1 H), 1.67 (s,
3 H), 1.29-1.43 ((1S)-2-methoxy-1- (m, 4 H), 0.76 (q, J = 5.70 Hz,
1 H) methylethoxy)pyrido[3,4- b]pyrazin-5-amine 895 .sup.1H NMR
(300 MHz, DMSO-d6) .delta. ppm 9.53 (s, 1 H),
N-(3-((1S,5S,6S)-3-amino-1- 8.56 (s, 1 H), 8.17-8.34 (m, 2 H), 7.87
(dt, J = 5.96, (difluoromethyl)-5-methyl-2- 2.28 Hz, 1 H), 7.12 (d,
J = 5.85 Hz, 1 H), 6.31 (s, 2 H), thia-4-azabicyclo[4.1.0]hept-3-
5.93 (t, J = 55.70 Hz, 1 H), 4.07 (s, 3 H), 1.82-1.95
en-5-yl)-4,5-difluorophenyl)-2- (m, 1 H), 1.67 (s, 3 H), 1.36 (dd,
J = 9.65, 5.85 Hz, 1 methoxypyrido[3,4-b]pyrazin- H), 0.76 (q, J =
5.80 Hz, 1 H) 5-amine 896 .sup.1H NMR (300 MHz, DMSO-d6) .delta.
ppm 12.58 (br. s., 1 5-((3-((1S,5S,6S)-3-amino-1- H), 9.22 (s, 1
H), 8.06-8.22 (m, 3 H), 7.76 (dt, (difluoromethyl)-5-methyl-2- J =
3.98, 2.03 Hz, 1 H), 6.65 (d, J = 5.70 Hz, 1 H), 6.29
thia-4-azabicyclo[4.1.0]hept-3- (br. s., 2 H), 5.92 (t, J = 55.50
Hz, 1 H), 1.80-1.94 (m, en-5-yl)-4,5- 1 H), 1.65 (s, 3 H), 1.35
(dd, J = 9.72, 5.92 Hz, 1 H), difluorophenyl)amino)pyrido[3,4- 0.75
(q, J = 5.75 Hz, 1 H) b]pyrazin-2(1H)-one 897 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.11 (s, 1H), 8.65- N-(3-((1S,5S,6S)-3-amino-5-
8.67 (m, 1H), 8.64 (s, 1H), 8.17 (ddd, J = 2.54, 6.70,
methyl-2-thia-4- 12.67 Hz, 1H), 8.00 (d, J = 5.99 Hz, 1H), 7.62 (d,
azabicyclo[4.1.0]hept-3-en-5- J = 2.74 Hz, 1H), 5.94 (br. s., 2H),
4.01 (s, 3H), 2.30- yl)-4,5-difluorophenyl)-7- 2.37 (m, 1H),
1.69-1.76 (m, 1H), 1.67 (s, 3H), 0.83- methoxypyrido[3,2- 0.98 (m,
1H), 0.50 (q, J = 5.28 Hz, 1H) d]pyrimidin-4-amine 898 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.79 (s, 1H), 8.79 methyl
(1S,5S,6S)-3-amino-5- (s, 1H), 8.14-8.22 (m, 2H), 7.93-8.00 (m,
2H), 6.20 (s, (5-(((5-chloro-2- J = 4.64 Hz, 2H), 3.72 (s, 3H),
2.32 (t, J = 8.51 Hz, 1H), pyridinyl)carbonyl)amino)-2,3- 1.62 (s,
3H), 1.50 (dd, J = 4.99, 9.68 Hz, 1H), 1.06 (dd,
difluorophenyl)-5-methyl-2- J = 5.09, 7.43 Hz, 1H)
thia-4-azabicyclo[4.1.0]hept-3- ene-1-carboxylate 900 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 9.48 (s, 1H), 8.56
N-(3-((1S,5S,6S)-3-amino-5- (s, 1H), 8.26-8.33 (m, 2H), 7.83-7.88
(m, 1H), 7.11 (d, methyl-2-thia-4- J = 5.87 Hz, 1H), 5.95 (br. s.,
2H), 4.08 (s, 3H), 2.29- azabicyclo[4.1.0]hept-3-en-5- 2.36 (m,
1H), 1.74 (q, J = 7.89 Hz, 1H), 1.66 (s, 3H),
yl)-4,5-difluorophenyl)-2- 0.89 (dt, J = 5.18, 8.17 Hz, 1H), 0.49
(q, J = 5.09 Hz, methoxypyrido[3,4-b]pyrazin- 1H) 5-amine
901 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.46 (s, 1H), 8.94
(1S,5S,6S)-3-amino-5-(5-((7- (d, J = 2.35 Hz, 1H), 8.73 (s, 1H),
8.42 (d, J = 2.15 Hz, chloropyrido[3,2-d]pyrimidin- 1H), 8.08 (ddd,
J = 2.64, 6.60, 12.47 Hz, 1H), 7.98-8.03 4-yl)amino)-2,3- (m, 1H),
6.26 (s, 2H), 3.71 (s, 3H), 3.14-3.19 (m, 3H),
difluorophenyl)-N-methoxy- 2.07-2.15 (m, 1H), 1.72 (s, 3H), 1.46
(dd, J = 5.48, 9.59 N,5-dimethyl-2-thia-4- Hz, 1H), 0.72-0.77 (m,
1H) azabicyclo[4.1.0]hept-3-ene-1- carboxamide 903 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.43 (s, 1H), 8.65
N-(3-((1S,5S,6S)-3-amino-1- (d, J = 2.93 Hz, 1H), 8.44 (ddd, J =
2.74, 6.85, 13.30 Hz, (methoxymethyl)-5-methyl-2- 1H), 8.09 (d, J =
5.87 Hz, 1H), 7.78-7.81 (m, 1H), 7.75
thia-4-azabicyclo[4.1.0]hept-3- (s, 1H), 7.17 (d, J = 5.87 Hz, 1H),
6.03 (s, 2H), 4.99 (d, en-5-yl)-4,5-difluorophenyl)-3- J = 2.35 Hz,
2H), 3.57 (d, J = 10.95 Hz, 1H), 3.36 (d, (2-butyn-1-yloxy)-1,7- J
= 10.95 Hz, 1H), 3.30 (s, 3H), 1.87 (t, J = 2.25 Hz,
naphthyridin-8-amine 3H), 1.66 (dd, J = 7.24, 8.80 Hz, 1H), 1.62
(s, 3H), 0.91 (dd, J = 5.18, 9.29 Hz, 1H), 0.66 (t, J = 5.87 Hz,
1H) 904 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.64 (s, 1H), 9.27
4-((3-((1S,5S,6S)-1-acetyl-3- (d, J = 1.76 Hz, 1H), 8.91 (d, J =
1.96 Hz, 1H), 8.82 (s, amino-5-methyl-2-thia-4- 1H), 8.20 (ddd, J =
2.74, 6.70, 12.47 Hz, 1H), 8.10-8.16 azabicyclo[4.1.0]hept-3-en-5-
(m, 1H), 6.19 (s, 2H), 2.40 (dd, J = 7.73, 9.49 Hz, 1H), yl)-4,5-
2.13 (s, 3H), 1.77 (dd, J = 5.38, 9.68 Hz, 1H), 1.64 (s,
difluorophenyl)amino)pyrido[3, 3H), 1.14 (dd, J = 5.87, 7.24 Hz,
1H) 2-d]pyrimidine-7-carbonitrile 907 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.60 (s, J = 5.99 4-((3-((1S,5S,6S)-3-amino-1-
Hz, 1H), 9.26 (d, J = 1.96 Hz, 1H), 8.90 (d, J = 1.96 Hz,
(1-hydroxyethyl)-5-methyl-2- 1H), 8.80 (s, 1H), 8.13 (ddd, J =
2.64, 6.70, 12.37 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1H),
8.05-8.09 (m, 1H), 5.96 (br. s., 2H), 5.00 (d, en-5-yl)-4,5- J =
3.91 Hz, 1H), 3.34-3.45 (m, 1H), 1.61 (s, 3H), 1.54-
difluorophenyl)amino)pyrido[3, 1.59 (m, 1H), 1.19-1.28 (m, 3H),
0.93 (dd, J = 4.99, d]pyrimidine-7-carbonitrile 9.29 Hz, 1H), 0.59
(t, J = 5.67 Hz, 1H) 908 .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.59 (s, 1H), 9.25 4-((3-((1R,2S,6S)-4-amino-6- (d, J = 1.76 Hz,
1H), 8.89 (d, J = 1.76 Hz, 1H), 8.79 (s,
((R)-1-hydroxyethyl)-2-methyl- 1H), 8.04-8.16 (m, 2H), 5.95 (br.
s., 2H), 4.91-5.00 3-azabicyclo[4.1.0]hept-3-en-2- (m, 1H),
3.41-3.50 (m, 1H), 1.59-1.70 (m, 4H), 1.12- yl)-4,5- 1.25 (m, 3H),
0.94 (dd, J = 4.99, 9.29 Hz, 1H), 0.53 (t,
difluorophenyl)amino)pyrido[3, J = 5.77 Hz, 1H)
2-d]pyrimidine-7-carbonitrile 909 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.14 (br. 4-((3-((1S,5S,6S)-3-amino-1- s.,
1H), 8.94 (d, J = 1.76 Hz, 1H), 8.86 (s, 1H), 8.50 (d,
(1-hydroxy-1-methylethyl)-5- J = 1.96 Hz, 1H), 8.39 (ddd, J = 2.74,
6.75, 11.84 Hz, methyl-2-thia-4- 1H), 7.48 (t, J = 3.65 Hz, 1H),
1.96 (dd, J = 7.43, 9.19 azabicyclo[4.1.0]hept-3-en-5- Hz, 1H),
1.67-1.81 (m, 3H), 1.38 (d, J = 5.28 Hz, 6H), yl)-4,5- 1.14 (dd, J
= 5.77, 9.88 Hz, 1H), 0.64 (t, J = 6.16 Hz,
difluorophenyl)amino)pyrido[3, 1H) 2-d]pyrimidine-7-carbonitrile
911 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.57 (s, 1H), 8.63
(1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.28-8.35 (m, 2H), 7.90 (d, J =
5.48 Hz, 1H), difluoro-5-((2-(2-propyn-1- 7.15-7.32 (m, 2H), 7.13
(d, J = 5.87 Hz, 1H), 6.12 (br. yloxy)pyrido[3,4-b]pyrazin-5- s.,
2H), 5.20 (d, J = 2.35 Hz, 2H), 3.67 (t, J = 2.35 Hz,
yl)amino)phenyl)-5-methyl-2- 1H), 2.17 (t, J = 8.31 Hz, 1H), 1.65
(s, 3H), 1.46 (dd, thia-4-azabicyclo[4.1.0]hept-3- J = 5.18, 9.49
Hz, 1H), 0.91 (t, J = 6.16 Hz, 1H) ene-1-carboxamide 912 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 9.55 (s, 1H), 8.62
(1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.22-8.32 (m, 2H), 7.86-7.90
(m, 1H), 7.12 (d, difluoro-5-((2-(2-propyn-1- J = 5.87 Hz, 1H),
6.28 (s, 2H), 5.20 (d, J = 2.35 Hz, 2H),
yloxy)pyrido[3,4-b]pyrazin-5- 3.67 (t, J = 2.45 Hz, 1H), 3.05 (br.
s., 3H), 2.90 (br. s., yl)amino)phenyl)-N,N,5- 3H), 1.99-2.07 (m,
1H), 1.72 (s, 3H), 1.36 (dd, J = 5.38, trimethyl-2-thia-4- 9.49 Hz,
1H), 0.79 (t, J = 6.26 Hz, 1H) azabicyclo[4.1.0]hept-3-ene-1-
carboxamide 917 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.20 (s,
1H), 8.68 (1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.69 (d, J = 3.44 Hz,
2H), 8.20 (ddd, J = 2.45, difluoro-5-((7-(2-propyn-1- 6.70, 12.57
Hz, 1H), 8.00-8.05 (m, 1H), 7.71 (d, yloxy)pyrido[3,2-d]pyrimidin-
J = 2.54 Hz, 1H), 7.29 (br. s., 1H), 7.22 (br. s., 1H),
4-yl)amino)phenyl)-5-methyl- 6.13 (br. s., 2H), 5.12 (d, J = 2.35
Hz, 2H), 3.74 (t, 2-thia-4-azabicyclo[4.1.0]hept- J = 2.35 Hz, 1H),
2.17 (t, J = 8.31 Hz, 1H), 1.65 (s, 3H), 3-ene-1-carboxamide 1.46
(dd, J = 5.18, 9.49 Hz, 1H), 0.91 (t, J = 5.97 Hz, 1H) 918 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 10.20 (s, 1H), 8.73
(1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.68 (s, 1H), 8.24 (s, 1H),
8.17-8.22 (m, 1H), difluoro-5-((7-(1,3-oxazol-2- 8.02 (d, J = 5.67
Hz, 1H), 7.84 (d, J = 2.74 Hz, 1H), ylmethoxy)pyrido[3,2- 7.25-7.36
(m, 2H), 7.21 (br. s., 1H), 6.12 (br. s., 2H), d]pyrimidin-4- 5.56
(s, 2H), 2.14-2.20 (m, 1H), 1.65 (s, 3H), 1.46 (dd,
yl)amino)phenyl)-5-methyl-2- J = 5.09, 9.59 Hz, 1H), 0.85-0.96 (m,
1H) thia-4-azabicyclo[4.1.0]hept-3- ene-1-carboxamide 923 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 10.19 (s, 1H), 8.72
(1S,5S,6S)-3-amino-5-(2,3- (d, J = 2.74 Hz, 1H), 8.68 (s, 1H), 8.24
(s, 1H), 8.10- difluoro-5-((7-(1,3-oxazol-2- 8.17 (m, 1H), 8.02
(br. s., 1H), 7.84 (d, J = 2.74 Hz, ylmethoxy)pyrido[3,2- 1H), 7.34
(s, 1H), 6.28 (br. s., 2H), 5.56 (s, 2H), 2.99- d]pyrimidin-4- 3.21
(m, 3H), 2.91 (br. s., 3H), 2.00-2.07 (m, 1H),
yl)amino)phenyl)-N,N,5- 1.72 (s, 3H), 1.36 (dd, J = 5.58, 9.29 Hz,
1H), 0.79 (t, trimethyl-2-thia-4- J = 6.26 Hz, 1H).
azabicyclo[4.1.0]hept-3-ene-1- carboxamide 928 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 10.06 (s, 1H), 8.66 (1S,5S,6S)-3-amino-5-(2-
(s, 1H), 8.61 (s, 1H), 8.10 (dd, J = 2.74, 7.24 Hz, 1H),
fluoro-5-((7-(2-propyn-1- 7.90 (td, J = 3.67, 8.51 Hz, 1H), 7.68
(d, J = 2.93 Hz, yloxy)pyrido[3,2-d]pyrimidin- 1H), 7.19 (dd, J =
8.80, 11.74 Hz, 1H), 6.57 (s, 2H), 4-yl)amino)phenyl)-5-methyl-
5.11 (d, J = 2.35 Hz, 2H), 3.74 (t, J = 2.25 Hz, 1H), 2.37
2-thia-4-azabicyclo[4.1.0]hept- (dd, J = 8.02, 9.59 Hz, 1H), 1.92
(dd, J = 5.87, 9.78 Hz, 3-ene-1-carbonitrile 1H), 1.77 (s, 3H),
1.00 (t, J = 6.65 Hz, 1H) 931 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 9.62 (s, 1H), 8.59 (1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.30
(d, J = 5.87 Hz, 1H), 8.25 (ddd, J = 2.74,
difluoro-5-((2-(((1S)-1-methyl- 6.85, 13.11 Hz, 1H), 7.85-7.90 (m,
1H), 7.12 (d, 2-propyn-1-yl)oxy)pyrido[3,4- J = 5.87 Hz, 1H), 6.60
(s, 2H), 5.92 (dq, J = 2.05, 6.62 b]pyrazin-5-yl)amino)phenyl)- Hz,
1H), 3.60 (d, J = 2.15 Hz, 1H), 2.37 (dd, J = 7.92,
5-methyl-2-thia-4- 9.68 Hz, 1H), 1.94 (dd, J = 5.97, 9.68 Hz, 1H),
1.78 (s, azabicyclo[4.1.0]hept-3-ene-1- 3H), 1.66 (d, J = 6.65 Hz,
3H), 1.07 (t, J = 6.75 Hz, 1H) carbonitrile 933 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 10.20 (s, 1H), 8.69
N-(3-((1S,5S,6S)-3-amino-5- (s, 2H), 8.15 (ddd, J = 2.74, 6.80,
12.57 Hz, 1H), 7.98- methyl-1-(1- 8.04 (m, 1H), 7.72 (d, J = 2.93
Hz, 1H), 6.30 (s, 2H), pyrrolidinylcarbonyl)-2-thia-4- 5.13 (d, J =
2.35 Hz, 2H), 3.75 (t, J = 2.35 Hz, 1H), 3.62
azabicyclo[4.1.0]hept-3-en-5- (d, J = 17.21 Hz, 2H), 3.32 (s, 2H),
2.03-2.10 (m, 1H), yl)-4,5-difluorophenyl)-7-(2- 1.89 (br. s., 2H),
1.82 (br. s., 2H), 1.74 (s, 3H), 1.39 propyn-1-yloxy)pyrido[3,2-
(dd, J = 5.38, 9.49 Hz, 1H), 0.74 (t, J = 6.16 Hz, 1H)
d]pyrimidin-4-amine 936 .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.20 (s, 1H), 8.73 N-(3-((1S,5S,6S)-3-amino-5- (s, 1H), 8.69 (s,
1H), 8.25 (d, J = 0.78 Hz, 1H), 8.14 methyl-1-(1- (ddd, J = 2.64,
6.65, 12.62 Hz, 1H), 8.01 (d, J = 5.92 Hz,
pyrrolidinylcarbonyl)-2-thia-4- 1H), 7.85 (d, J = 2.74 Hz, 1H),
7.35 (s, 1H), 6.30 (br. s., azabicyclo[4.1.0]hept-3-en-5- 2H), 5.57
(s, 2H), 3.62 (d, J = 15.26 Hz, 2H), 3.30
yl)-4,5-difluorophenyl)-7-(1,3- (br.s., 2H), 1.96-2.10 (m, 1H),
1.89 (br. s., 2H), 1.82 oxazol-2- (br. s., 2H), 1.74 (s, 3H), 1.40
(dd, J = 5.38, 9.49 Hz, ylmethoxy)pyrido[3,2- 1H), 0.74 (t, J =
6.06 Hz, 1H) d]pyrimidin-4-amine 937 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 9.56 (s, 1H), 8.60 N-(3-((1S,5S,6S)-3-amino-5- (s, 1H),
8.23-8.34 (m, 2H), 7.84-7.90 (m, 1H), 7.13 (d, methyl-1-(1- J =
5.87 Hz, 1H), 6.29 (br. s., 2H), 5.90-5.97 (m, 1H),
pyrrolidinylcarbonyl)-2-thia-4- 3.62 (d, J = 2.15 Hz, 3H), 3.32
(br. s., 2H), 2.01-2.10 azabicyclo[4.1.0]hept-3-en-5- (m, 1H), 1.89
(br. s., 2H), 1.82 (br. s., 2H), 1.73 (s,
yl)-4,5-difluorophenyl)-2- 3H), 1.68 (d, J = 6.65 Hz, 3H),
1.35-1.44 (m, 1H), 0.74 (((1S)-1-methyl-2-propyn-1- (t, J = 6.06
Hz, 1H) yl)oxy)pyrido[3,4-b]pyrazin-5- amine 938 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.58 (s, 1H), 8.65
N-(3-((1S,5S,6S)-3-amino-5- (s, 1H), 8.24-8.33 (m, 2H), 8.18 (s,
1H), 7.88 (d, methyl-1-(1- J = 5.81 Hz, 1H), 7.28 (s, 1H), 7.09 (d,
J = 5.87 Hz, 1H), pyrrolidinylcarbonyl)-2-thia-4- 6.54 (q, J = 6.65
Hz, 1H), 6.31 (br. s., 2H), 3.63 (d, azabicyclo[4.1.0]hept-3-en-5-
J = 15.65 Hz, 2H), 3.34 (s, 2H), 2.07 (t, J = 8.22 Hz,
yl)-4,5-difluorophenyl)-2-((1S)- 1H), 1.90 (br. s., 2H), 1.82 (d, J
= 6.65 Hz, 5H), 1.75 (s, 1-(1,3-oxazol-2- 3H), 1.40 (dd, J = 5.48,
9.39 Hz, 1H), 0.75 (t, J = 6.06 yl)ethoxy)pyrido[3,4-b]pyrazin- Hz,
1H) 5-amine 941 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.38 (q,
J = 5.1 N-(3-((1S,5S,6S)-3-amino-5- Hz, 1 H), 0.99-1.09 (m, 1 H),
1.76 (q, J = 8.3 Hz, 1 (fluoromethyl)-2-thia-4- H), 2.35-2.43 (m, 1
H), 3.73 (t, J = 2.3 Hz, 1 H), 4.60- azabicyclo[4.1.0]hept-3-en-5-
4.87 (m, 2 H), 5.11 (d, J = 2.3 Hz, 2 H), 6.21 (s, 2 H),
yl)-4-fluorophenyl)-7-(2- 7.18 (dd, J = 11.9, 8.8 Hz, 1 H), 7.68
(d, J = 2.7 Hz, 1 propyn-1-yloxy)pyrido[3,2- H), 7.91-8.00 (m, 1
H), 8.17 (dd, J = 7.1, 2.8 Hz, 1 H), d]pyrimidin-4-amine 8.60 (s, 1
H), 8.66 (d, J = 2.7 Hz, 1 H), 10.04 (s, 1 H) 942 .sup.1H NMR (400
MHz, DMSO-d6) .delta. ppm 0.58 (t, J = 5.9
N-(3-((1S,5S,6S)-3-amino-5- Hz, 1 H), 1.08 (dd, J = 9.4, 5.3 Hz, 1
H), 1.62-1.70 (m, (fluoromethyl)-1- 1 H), 3.28 (s, 3 H), 3.34 (d, J
= 10.8 Hz, 1 H), 3.55 (d, (methoxymethyl)-2-thia-4- J = 10.8 Hz, 1
H), 3.73 (t, J = 2.3 Hz, 1 H), 4.58-4.81
azabicyclo[4.1.0]hept-3-en-5- (m, 2 H), 5.11 (d, J = 2.3 Hz, 2 H),
6.27 (s, 2 H), 7.18 yl)-4-fluorophenyl)-7-(2- (dd, J = 11.7, 8.8
Hz, 1 H), 7.68 (d, J = 2.7 Hz, 1 H), propyn-1-yloxy)pyrido[3,2-
7.94-7.99 (m, 1 H), 8.18 (dd, J = 7.2, 2.7 Hz, 1 H),
d]pyrimidin-4-amine 8.60 (s, 1 H), 8.66 (d, J = 2.7 Hz, 1 H), 10.05
(s, 1 H) 944 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.63-0.72
N-(5-((1S,5S,6S)-3-amino-1- (m, 1 H), 1.05 (dd, J = 9.3, 5.4 Hz, 1
H), 1.61 (s, 3 H), (fluoromethyl)-5-methyl-2-thia- 1.79-1.88 (m, 1
H), 3.74 (t, J = 2.2 Hz, 1 H), 4.40-
4-azabicyclo[4.1.0]hept-3-en-5- 4.48 (m, 1 H), 4.51-4.60 (m, 1 H),
5.12 (d, J = 2.3 Hz, yl)-6-fluoro-3-pyridinyl)-7-(2- 2 H), 6.17 (s,
2 H), 7.70 (d, J = 2.7 Hz, 1 H), 8.64 (s, 1
propyn-1-yloxy)pyrido[3,2- H), 8.66-8.68 (m, 1 H), 8.69 (d, J = 2.7
Hz, 1 H), 8.73 d]pyrimidin-4-amine (dd, J = 9.2, 2.7 Hz, 1 H),
10.40 (s, 1 H) 945 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.77
(br. s., 1
N-(3-((1S,5S,6S)-3-amino-1- H), 1.38 (br. s., 1 H), 1.68 (s, 3 H),
1.90 (br. s., 1 H), (difluoromethyl)-5-methyl-2- 3.73 (t, J = 2.3
Hz, 1 H), 5.11 (d, J = 2.3 Hz, 2 H), 5.93
thia-4-azabicyclo[4.1.0]hept-3- (t, J = 55.5 Hz, 1 H), 6.32 (br.
s., 2 H), 7.70 (d, J = 2.7 en-5-yl)-4,5-difluorophenyl)-7- Hz, 1
H), 7.96-8.05 (m, 1 H), 8.15 (ddd, J = 12.6, 6.7,
(2-propyn-1-yloxy)pyrido[3,2- 2.5 Hz, 1 H), 8.62-8.74 (m, 2 H),
10.21 (s, 1 H) d]pyrimidin-4-amine 946 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.79- N-(3-((1S,5S,6S)-3-amino-1- 0.86
(m, 1 H), 0.92-1.01 (m, 1 H), 1.77 (s, 3 H), 1.79-
(methoxymethyl)-5-methyl-2- 1.87 (m, 1 H), 3.37 (d, J = 10.6 Hz, 1
H), 3.43 (s, 3 thia-4-azabicyclo[4.1.0]hept-3- H), 3.50 (s, 3 H),
3.66 (d, J = 10.6 Hz, 1 H), 3.82-3.93
en-5-yl)-4,5-difluorophenyl)-7- (m, 2 H), 4.25-4.35 (m, 2 H),
7.40-7.51 (m, 2 H), (2-methoxyethoxy)pyrido[3,2- 8.41 (ddd, J =
12.0, 6.9, 2.6 Hz, 1 H), 8.57 (d, J = 2.7 d]pyrimidin-4-amine Hz, 1
H), 8.73 (s, 1 H), 9.00 (s, 1 H). 947 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 0.77 N-(3-((1S,5S,6S)-3-amino-5- (t, J =
6.2 Hz, 1 H), 1.10 (dd, J = 9.7, 5.8 Hz, 1 H), 1.82
(fluoromethyl)-1- (t, J = 7.5 Hz, 1 H), 3.37 (d, J = 10.6 Hz, 1 H),
3.41 (s, 3 (methoxymethyl)-2-thia-4- H), 3.50 (s, 3 H), 3.67 (d, J
= 10.4 Hz, 1 H), 3.85-3.87 azabicyclo[4.1.0]hept-3-en-5- (m, 2 H),
4.25-4.36 (m, 2 H), 4.48-4.80 (m, 3 H), yl)-4-fluorophenyl)-7-(2-
4.80-5.01 (m, 1 H), 7.14 (dd, J = 11.6, 8.9 Hz, 1 H),
methoxyethoxy)pyrido[3,2- 7.43 (d, J = 2.7 Hz, 1 H), 7.78 (dd, J =
6.7, 2.8 Hz, 1 H), d]pyrimidin-4-amine 8.24 (dt, J = 8.5, 3.6 Hz, 1
H), 8.56 (d, J = 2.5 Hz, 1 H), 8.69 (s, 1 H), 8.96 (s, 1 H). 948
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm 0.78-
N-(3-((1S,5S,6S)-3-amino-1- 0.85 (m, 1 H), 0.91-1.00 (m, 1 H), 1.76
(s, 3 H), 1.79- (methoxymethyl)-5-methyl-2- 1.87 (m, 1 H), 2.38 (s,
3 H), 2.45 (s, 3 H), 3.37 (d, thia-4-azabicyclo[4.1.0]hept-3- J =
10.6 Hz, 1 H), 3.43 (s, 3 H), 3.67 (d, J = 10.6 Hz, 1
en-5-yl)-4,5-difluorophenyl)-7- H), 5.03 (s, 2 H), 7.40-7.50 (m, 1
H), 7.56 (d, J = 2.7 ((2,5-dimethyl-1,3-oxazol-4- Hz, 1 H), 8.42
(ddd, J = 12.0, 6.8, 2.8 Hz, 1 H), 8.56 (d, yl)methoxy)pyrido[3,2-
J = 2.5 Hz, 1 H), 8.75 (s, 1 H), 9.00 (s, 1 H) d]pyrimidin-4-amine
949 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.75 (q, J = 5.8
N-(3-((1S,5S,6S)-3-amino-1- Hz, 1 H), 1.36 (dd, J = 9.6, 5.9 Hz, 1
H), 1.67 (s, 3 H), (difluoromethyl)-5-methyl-2- 1.84-1.95 (m, 1 H),
5.59 (s, 2 H), 5.92 (t, J = 55.4 Hz,
thia-4-azabicyclo[4.1.0]hept-3- 1 H), 6.34 (br. s., 2 H), 7.34 (d,
J = 0.8 Hz, 1 H), 7.84- en-5-yl)-4,5-difluorophenyl)-5- 7.92 (m, 1
H), 7.96 (d, J = 2.7 Hz, 1 H), 8.16 (d, J = 1.6
fluoro-3-(1,3-oxazol-2- Hz, 1 H), 8.20-8.30 (m, 2 H), 8.78 (d, J =
2.9 Hz, 1 ylmethoxy)-1,7-naphthyridin-8- H), 9.47 (s, 1 H) amine
950 .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 0.65 (t, J = 5.8
N-(3-((1S,5S,6S)-3-amino-1- Hz, 1 H), 0.92 (dd, J = 8.7, 5.4 Hz, 1
H), 1.58-1.68 (m, (methoxymethyl)-5-methyl-2- 4 H), 3.30 (s, 3 H),
3.36 (d, J = 11.0 Hz, 1 H), 3.56 (d,
thia-4-azabicyclo[4.1.0]hept-3- J = 11.0 Hz, 1 H), 5.59 (s, 2 H),
6.02 (br. s., 2 H), 7.34 en-5-yl)-4,5-difluorophenyl)-5- (s, 1 H),
7.82-7.92 (m, 1 H), 7.96 (d, J = 2.7 Hz, 1 H),
fluoro-3-(1,3-oxazol-2- 8.16 (d, J = 1.6 Hz, 1 H), 8.24 (s, 1 H),
8.30 (ddd, ylmethoxy)-1,7-naphthyridin-8- J = 13.2, 6.7, 2.7 Hz, 1
H), 8.79 (d, J = 2.7 Hz, 1 H), 9.43 amine (s, 1 H) 951 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 0.65 (t, J = 5.8
N-(3-((1S,5S,6S)-3-amino-1- Hz, 1 H), 0.91 (dd, J = 9.3, 5.2 Hz, 1
H), 1.62 (s, 3 H), (methoxymethyl)-5-methyl-2- 1.64-1.68 (m, 1 H),
3.30 (s, 3 H), 3.36 (d, J = 11.0 Hz,
thia-4-azabicyclo[4.1.0]hept-3- 1 H), 3.56 (d, J = 11.0 Hz, 1 H),
3.75 (t, J = 2.3 Hz, 1 en-5-yl)-4,5-difluorophenyl)-5- H), 5.16 (d,
J = 2.3 Hz, 2 H), 6.02 (s, 2 H), 7.83 (d,
fluoro-3-(2-propyn-1-yloxy)- J = 2.9 Hz, 1 H), 7.84-7.91 (m, 1 H),
8.16 (d, J = 1.8 1,7-naphthyridin-8-amine Hz, 1 H), 8.31 (ddd, J =
13.2, 6.8, 2.7 Hz, 1 H), 8.75 (d, J = 2.9 Hz, 1 H), 9.43 (s, 1 H)
952 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 0.94 (br. s., 1
(2E)-3-((1R,5S,6S)-3-amino-5- H), 1.09 (t, J = 7.5 Hz, 3 H), 1.57
(br. s., 1 H), 1.94 (br. (fluoromethyl)-5-(2-fluoro-5- s., 1 H),
2.27 (qt, J = 7.5, 2.1 Hz, 2 H), 2.88 (s, 3 H), ((2-(2-pentyn-1-
3.05 (s, 3 H), 4.54-4.90 (m, 2 H), 5.16 (t, J = 2.1 Hz, 2
yloxy)pyrido[3,4-b]pyrazin-5- H), 6.35-6.60 (m, 4 H), 7.07 (d, J =
5.7 Hz, 1 H), 7.16 yl)amino)phenyl)-2-thia-4- (t, J = 10.1 Hz, 1
H), 8.06 (dt, J = 8.6, 3.5 Hz, 1 H), 8.12
azabicyclo[4.1.0]hept-3-en-1- (br. s., 1 H), 8.24 (d, J = 5.9 Hz, 1
H), 8.59 (s, 1 H), yl)-N,N-dimethyl-2- 9.41 (br. s., 1 H)
propenamide 957 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
1.13 N-(3-((1S,5S,6S)-3-amino-5- (br. s., 1 H) 1.75 (br. s., 1 H)
2.21 (t, J = 7.82 Hz, 1 H) (fluoromethyl)-1-(1H-1,2,3- 4.61-5.14
(m, 2 H) 5.65 (s, 2 H) 7.02 (d, J = 5.87 Hz,
triazol-4-yl)-2-thia-4- 1 H) 7.09 (t, J = 10.17 Hz, 1 H) 7.20 (s, 1
H) 7.61 (s, 1 azabicyclo[4.1.0]hept-3-en-5- H) 7.73 (br. s., 2 H)
8.12 (br. s., 1 H) 8.21 (d, J = 5.28 yl)-4-fluorophenyl)-2-(1,3-
Hz, 1 H) 8.35 (s, 1 H) 8.60 (br. s., 1 H) oxazol-2-
ylmethoxy)pyrido[3,4- b]pyrazin-5-amine 958 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.35 N-(3-((1S,5S,6S)-3-amino-5- (br. s.,
1 H) 1.75-1.93 (m, 4 H) 2.18 (d, J = 7.04 Hz, 1
(fluoromethyl)-1-(1-propyn-1- H) 4.65-5.10 (m, 3 H) 5.64 (br. s., 2
H) 7.02 (d, yl)-2-thia-4- J = 5.28 Hz, 1 H) 7.09 (t, J = 10.07 Hz,
1 H) 7.19 (br. s., azabicyclo[4.1.0]hept-3-en-5- 1 H) 7.65-7.80 (m,
2 H) 8.14-8.27 (m, 2 H) 8.36 yl)-4-fluorophenyl)-2-(1,3- (br. s., 1
H) 8.59 (br. s., 1 H) oxazol-2- ylmethoxy)pyrido[3,4-
b]pyrazin-5-amine 960 .sup.1H NMR (400 MHz, CD3OD) .delta. ppm 1.17
(t, J = 6.06 N-(3-((1S,5S,6S)-3-amino-5- Hz, 1 H) 1.81 (dd, J =
9.59, 5.67 Hz, 1 H) 2.16-2.24 (fluoromethyl)-1-(1H-1,2,3- (m, 1 H)
3.03 (t, J = 2.35 Hz, 1 H) 4.76-5.06 (m, 2 H)
triazol-4-yl)-2-thia-4- 5.21 (d, J = 2.54 Hz, 2 H) 7.08 (d, J =
5.87 Hz, 1 H) 7.15 azabicyclo[4.1.0]hept-3-en-5- (dd, J = 11.64,
8.90 Hz, 1 H) 7.80 (s, 1 H) 7.91-8.01 yl)-4-fluorophenyl)-2-(2- (m,
2 H) 8.19 (d, J = 5.87 Hz, 1 H) 8.46 (s, 1 H)
propyn-1-yloxy)pyrido[3,4- b]pyrazin-5-amine 961 .sup.1H NMR
(CDCl3, 300 MHz) .delta. = 9.09 (s, 1H), 8.96 (d,
4-((3-((1R,5S,6S)-3-amino-7,7- J = 1.9 Hz, 1H), 8.83 (s, 1H), 8.51
(d, J = 1.9 Hz, 1H), difluoro-1-(hydroxymethyl)-5- 7.96 (dt, J =
8.8, 3.4 Hz, 1H), 7.86 (dd, J = 7.0, 2.9 Hz, methyl-2-thia-4- 1H),
7.18 (dd, J = 11.5, 8.8 Hz, 1H), 3.81-3.94 (m, 2H),
azabicyclo[4.1.0]hept-3-en-5- 2.43 (dd, J = 15.9, 2.9 Hz, 1H), 1.81
ppm (s, 3H) yl)-4- fluorophenyl)amino)pyrido[3,2-
d]pyrimidine-7-carbonitrile
Method D: Propylphosphonic Anhydride (T3P) procedure in DCM as
solvent
Example 810:
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-carbox-
amide
##STR00564##
[1847] To a suspension of
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-1-(fluoromethyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-3-amine (intermediate 216, 110 mg,
0.36 mmol) and 5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid
(intermediate 273, 119 mg, 0.55 mmol) in DCM (4 mL) at 0.degree. C.
under nitrogen was added 1-propanephosphonic acid cyclic anhydride
(50 wt. % solution in EtOAc, 465 mg, 0.73 mmol). After 1 h, the
cooling bath was removed, and the hazy reaction mixture was stirred
for 18 h at RT. The reaction mixture was diluted with DCM (30 mL)
and poured into a 0.2 N NaOH solution (5 mL) that was cooled with
an ice bath. The mixture was stirred for 15 min then transferred to
a separatory funnel. The layers were separated. The aqueous layer
was further extracted with DCM (10 mL). The organic extracts were
combined and dried over MgSO.sub.4 then concentrated under reduced
pressure. The residue was purified by silica gel chromatography (12
g, using a gradient of 25-100% EtOAc in hexanes) to afford
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyr-
azine-2-carboxamide (Example 810, 101 mg, 0.219 mmol, 60% yield) as
an off white crystalline solid. MS m/z=462.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.64 (br., 1H), 8.92 (d,
J=1.37 Hz, 1H), 8.50 (d, J=1.17 Hz, 1H), 7.89-7.97 (m, 2H), 6.12
(br., 2H), 5.16 (d, J=2.35 Hz, 2H), 4.44-4.57 (m, 2H), 3.66 (t,
J=2.45 Hz, 1H), 1.80 (m, 1H), 1.63 (s, 3H), 1.05 (m, 1H), 0.72 (m,
1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -138.45 (d,
J=22.54 Hz, 1 F), -143.62 (d, J=22.54 Hz, 1 F), -211.57 (s, 1
F).
[1848] Using procedures analogous or similar to the general
amidation Method D described above, the appropriate aniline and
carboxylic acid intermediates were reacted to provide the 103
examples listed in Table 4 and Table 4'.
TABLE-US-00008 TABLE 4 Observed Ex. No. Chemical Structure [M + H]+
614 ##STR00565## 520.2 615 ##STR00566## 538.1 616 ##STR00567##
590.2 617 ##STR00568## 508.1 618 ##STR00569## 532.2 619
##STR00570## 490.1 620 ##STR00571## 514.1 621 ##STR00572## 484.1
622 ##STR00573## 592.1 623 ##STR00574## 520.1 633 ##STR00575##
509.1 634 ##STR00576## 553.1 642 ##STR00577## 518.2 643
##STR00578## 536.2 644 ##STR00579## 512.2 645 ##STR00580## 518.2
646 ##STR00581## 530.2 647 ##STR00582## 507.2 648 ##STR00583## 499
649 ##STR00584## 483.2 650 ##STR00585## 501.2 651 ##STR00586## 471
652 ##STR00587## 500.1 680 ##STR00588## 519 681 ##STR00589## 513
682 ##STR00590## 487 683 ##STR00591## 469 684 ##STR00592## 475 685
##STR00593## 493 686 ##STR00594## 475 687 ##STR00595## 544 688
##STR00596## 544 689 ##STR00597## 501 690 ##STR00598## 457 691
##STR00599## 495 692 ##STR00600## 505 693 ##STR00601## 539 694
##STR00602## 517 695 ##STR00603## 523 696 ##STR00604## 505 697
##STR00605## 487 698 ##STR00606## 499 699 ##STR00607## 570 700
##STR00608## 530 701 ##STR00609## 531 702 ##STR00610## 544 732
##STR00611## 549.1 734 ##STR00612## 550.1 738 ##STR00613## 532 739
##STR00614## 514.1 740 ##STR00615## 496.1 742 ##STR00616## 487 743
##STR00617## 507 744 ##STR00618## 508 745 ##STR00619## 550.1 746
##STR00620## 551 772 ##STR00621## 554 774 ##STR00622## 527 780
##STR00623## 497 783 ##STR00624## 540 792 ##STR00625## 474 795
##STR00626## 495 803 ##STR00627## 519.1 804 ##STR00628## 459 807
##STR00629## 480 811 ##STR00630## 505.1 814 ##STR00631## 506 815
##STR00632## 518 818 ##STR00633## 441 820 ##STR00634## 462 821
##STR00635## 423.2 822 ##STR00636## 440 826 ##STR00637## 488 829
##STR00638## 458 830 ##STR00639## 476 831 ##STR00640## 500 832
##STR00641## 470.1 833 ##STR00642## 435 834 ##STR00643## 456 835
##STR00644## 513 836 ##STR00645## 519 837 ##STR00646## 501 838
##STR00647## 464 839 ##STR00648## 482 840 ##STR00649## 476 860
##STR00650## 537.2 861 ##STR00651## 494 862 ##STR00652## 488.2 863
##STR00653## 531.2 864 ##STR00654## 545 913 ##STR00655## 501 914
##STR00656## 487.1 919 ##STR00657## 473 922 ##STR00658## 577.1 924
##STR00659## 455.1 926 ##STR00660## 545 927 ##STR00661## 437 929
##STR00662## 416 930 ##STR00663## 480 932 ##STR00664## 434 934
##STR00665## 527.1 935 ##STR00666## 506 940 ##STR00667## 499
TABLE-US-00009 TABLE 4' Ex. No. .sup.1H-NMR Chemical Name 614
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.79 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.16 (s, 1H), 8.08 (ddd, J = 2.78,
6.87, 11.98 (fluoromethyl)-5-methyl-2-thia-4- Hz, 1H), 7.32 (br.s.,
1H), 4.88 (q, J = 8.33 Hz, 2H), azabicyclo[4.1.0]hept-3-en-5-yl)-
4.44-4.62 (m, 1H), 4.21-4.44 (m, 1H), 4.00-5.00
4,5-difluorophenyl)-3-methyl-5- (br.s., 2H), 2.97 (s, 3H),
1.87-2.00 (m, 1H), 1.75 (2,2,2-trifluoroethoxy)-2- (d, J = 1.17 Hz,
3H), 1.03 (dd, J = 5.99, 9.50 Hz, 1H), pyrazinecarboxamide
0.84-0.93 (m, 1H). 615 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
9.77 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.16 (s, 1H), 8.06 (ddd,
J = 2.70, 6.87, 11.91 (difluoromethyl)-5-methyl-2-thia- Hz, 1H),
7.12-7.23 (m, 1H), 5.43-5.97 (m, 1H),
4-azabicyclo[4.1.0]hept-3-en-5- 4.88 (q, J = 8.33 Hz, 2H),
2.85-3.07 (s, 3H), 2.04 yl)-4,5-difluorophenyl)-3-methyl- (dd, J =
7.45, 9.65 Hz, 1H), 1.99 (br.s., 2H), 1.82
5-(2,2,2-trifluoroethoxy)-2- (s, 3H), 1.28-1.45 (m, 1H), 0.78-0.98
(m, 1H). pyrazinecarboxamide 616 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.80 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
8.08 (ddd, J = 2.74, 6.85, 11.93 Hz, 1H), 8.02
(fluoromethyl)-5-methyl-2-thia-4- (s, 1H), 7.25-7.27 (m, 3H), 5.89
(dd, J = 1.96, 6.65 azabicyclo[4.1.0]hept-3-en-5-yl)- Hz, 1H), 4.48
(d, J = 6.26 Hz, 1H), 4.35 (d, J = 6.06
4,5-difluorophenyl)-3-methyl-5- Hz, 1H), 2.95 (s, 3H), 2.47 (d, J =
2.15 Hz, 1H), (((1S)-1-methyl-2-propyn-1- 1.76 (s, 3H), 1.68 (d, J
= 6.85 Hz, 3H), 1.22-1.31 yl)oxy)-2-pyrazinecarboxamide (m, 1H),
1.05 (dd, J = 6.16, 9.68 Hz, 1H), 0.85-0.91 (m, 1H). 617 .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta. 9.78 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.01-8.11 (m, 2H), 7.18 (td, J =
2.36, 5.66 Hz, (difluoromethyl)-5-methyl-2-thia- 1H), 5.86-5.95 (m,
1H), 5.22-5.75 (m, 1H), 3.36- 4-azabicyclo[4.1.0]hept-3-en-5- 4.84
(m, 2H), 2.96 (s, 3H), 2.49 (d, J = 2.19 Hz,
yl)-4,5-difluorophenyl)-3-methyl- 1H), 2.02 (dd, J = 7.53, 9.57 Hz,
1H), 1.77-1.83 (m, 5-(((1S)-1-methyl-2-propyn-1- 3H), 1.70 (d, J =
6.72 Hz, 3H), 1.38 (dd, J = 6.28, yl)oxy)-2-pyrazinecarboxamide
9.94 Hz, 1H), 0.84-0.93 (m, 1H) 618 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 9.80 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
8.16 (s, 1H), 8.10 (ddd, J = 2.78, 6.87, 11.98
(methoxymethyl)-5-methyl-2- Hz, 1H), 7.33 (td, J = 2.41, 5.70 Hz,
1H), 4.87 (q, thia-4-azabicyclo[4.1.0]hept-3- J = 8.33 Hz, 2H),
4.00-4.50 (br.s., 2H), 3.67 (d, en-5-yl)-4,5-difluorophenyl)-3- J =
10.52 Hz, 1H), 3.43 (s, 3H), 3.37 (d, J = 10.67
methyl-5-(2,2,2-trifluoroethoxy)- Hz, 1H), 2.97 (s, 3H), 1.83 (ddd,
J = 1.39, 6.69, 2-pyrazinecarboxamide 9.32 Hz, 1H), 1.75 (d, J =
1.17 Hz, 3H), 0.94 (dd, J = 5.92, 9.43 Hz, 1H), 0.78-0.88 (m, 1H).
619 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.80 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.16 (s, 1H), 8.10 (ddd, J = 2.78,
6.87, 11.98 (difluoromethyl)-5-methyl-2-thia- Hz, 1H), 7.33 (td, J
= 2.41, 5.70 Hz, 1H), 4.87 (q, 4-azabicyclo[4.1.0]hept-3-en-5- J =
8.33 Hz, 2H), 3.67 (d, J = 10.52 Hz, 1H), 3.43 (s,
yl)-4-fluorophenyl)-3-methyl-5- 3H), 3.37 (d, J = 10.67 Hz, 1H),
2.97 (s, 3H), 1.83 (((1S)-1-methyl-2-propyn-1- (ddd, J = 1.39,
6.69, 9.32 Hz, 1H), 1.75 (d, J = 1.17 yl)oxy)-2-pyrazinecarboxamide
Hz, 3H), 0.94 (dd, J = 5.92, 9.43 Hz, 1H), 0.78-0.88 (m, 1H), NH2
broad at 4.5-4.0. 620 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
9.75 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.13 (s, 1H), 7.86-8.04
(m, 1H), 7.66 (dd, (methoxymethyl)-5-methyl-2- J = 2.78, 7.02 Hz,
1H), 7.07 (dd, J = 8.77, 11.69 Hz, thia-4-azabicyclo[4.1.0]hept-3-
1H), 4.86 (q, J = 8.33 Hz, 2H), 4.00-4.50 (br.s, 2H),
en-5-yl)-4-fluorophenyl)-3- 3.68 (d, J = 10.50 Hz, 1H), 3.42 (s,
3H), 3.35 (d, methyl-5-(2,2,2-trifluoroethoxy)- J = 10.52 Hz, 1H),
2.87-3.06 (m, 3H), 1.83 (ddd, 2-pyrazinecarboxamide J = 1.10, 6.80,
9.35 Hz, 1H), 1.73 (d, J = 1.17 Hz, 3H), 0.67-0.97 (m, 2H) 621
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.77 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 7.86-8.10 (m, 2H), 7.65 (dd, J =
2.85, 6.94 Hz, (methoxymethyl)-5-methyl-2- 1H), 6.90-7.15 (m, 1H),
5.89 (dq, J = 2.12, 6.65 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1H),
4.23-4.85 (br.s, 2H), 3.67 (d, J = 10.67 Hz,
en-5-yl)-4-fluorophenyl)-3- 1H), 3.39-3.49 (m, 3H), 3.35 (d, J =
10.67 Hz, 1H), methyl-5-(((1S)-1-methyl-2- 2.82-3.03 (m, 3H),
2.37-2.58 (m, 1H), 1.82 (ddd, propyn-1-yl)oxy)-2- J = 1.10, 6.83,
9.32 Hz, 1H), 1.72 (d, J = 1.17 Hz, pyrazinecarboxamide 3H), 1.69
(d, J = 6.72 Hz, 3H), 0.74-0.92 (m, 2H) 622 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 9.82 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
8.11 (ddd, J = 2.78, 6.87, 11.98 Hz, 1H), 8.03
(methoxymethyl)-5-methyl-2- (s, 1H), 7.32 (d, J = 4.97 Hz, 1H),
5.91 (dd, J = 2.05, thia-4-azabicyclo[4.1.0]hept-3- 6.72 Hz, 1H),
5.00-4.00 (br.s, 2H), 3.67 (d, en-5-yl)-4,5-difluorophenyl)-3- J =
10.52 Hz, 1H), 3.43 (s, 3H), 3.37 (d, J = 10.67
methyl-5-(((1S)-1-methyl-2- Hz, 1H), 2.96 (s, 3H), 2.49 (d, J =
2.05 Hz, 1H), propyn-1-yl)oxy)-2- 1.82 (ddd, J = 1.46, 6.72, 9.35
Hz, 1H), 1.75 (d, pyrazinecarboxamide J = 1.17 Hz, 3H), 1.70 (d, J
= 6.72 Hz, 3H), 0.93 (dd, J = 5.85, 9.50 Hz, 1H), 0.79-0.88 (m,
1H). 623 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.73 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.15 (s, 1H), 7.82-8.02 (m, 1H),
7.42 (dd, (difluoromethyl)-5-methyl-2-thia- J = 2.70, 6.94 Hz, 1H),
7.10 (dd, J = 8.77, 11.40 Hz, 4-azabicyclo[4.1.0]hept-3-en-5- 1H),
5.50 (s, 1H), 4.66-4.95 (m, 4H), 2.96 (s, 3H),
yl)-4-fluorophenyl)-3-methyl-5- 2.06 (dd, J = 6.80, 10.16 Hz, 1H),
1.88 (d, J = 0.73 (2,2,2-trifluoroethoxy)-2- Hz, 3H), 1.46 (dd, J =
6.43, 9.79 Hz, 1H), 0.75-1.03 pyrazinecarboxamide (m, 1H). 633
.sup.1H NMR (CHLOROFORM-d) Shift: 9.45 (br.s.,
N-(3-((1S,5S,6S)-3-amino-5- 1H), 9.02 (br.s., 1H), 8.19 (br.s.,
1H), 7.85 (br.s., methyl-1-(1- 1H), 7.60 (d, J = 3.9 Hz, 1H), 7.06
(t, J = 9.8 Hz, pyrrolidinylcarbonyl)-2-thia-4- 1H), 5.08 (br.s.,
2H), 3.35-3.81 (m, 4H), 2.28 (t, azabicyclo[4.1.0]hept-3-en-5-yl)-
J = 7.7 Hz, 1H), 1.79-2.08 (m, 7H), 1.41 (d, J = 8.2
4-fluorophenyl)-5-(2-propyn-1- Hz, 1H), 0.83 (br.s., 1H).
yloxy)-2-pyrazinecarboxamide 634 .sup.1H NMR (CHLOROFORM-d)
.delta.: 9.45 (br.s., 1H), N-(3-((1S,5S,6S)-3-amino-5- 9.01 (br.s.,
1H), 8.29 (br.s., 1H), 7.85 (br.s., 1H), methyl-1-(1- 7.60 (d, J =
4.3 Hz, 1H), 7.07 (t, J = 10.0 Hz, 1H),
pyrrolidinylcarbonyl)-2-thia-4- 4.86 (q, J = 8.0 Hz, 2H), 3.39-3.82
(m, 4H), 2.30 (t, azabicyclo[4.1.0]hept-3-en-5-yl)- J = 7.6 Hz,
1H), 1.87-2.02 (m, 4H), 1.85 (br.s., 4-fluorophenyl)-5-(2,2,2- 3H),
1.42 (d, J = 7.2 Hz, 1H), 0.84 (m, 1H). NH2 trifluoroethoxy)-2-
peak is broad. pyrazinecarboxamide 642 .sup.1H NMR (400 MHz,
CHLOROFORM-d) Shift N-(3-((1S,5S,6S)-3-amino-1- 9.99 (s, 1H), 8.21
(d, J = 2.54 Hz, 1H), 7.93 (ddd, (difluoromethyl)-5-methyl-2-thia-
J = 2.84, 4.11, 8.71 Hz, 1H), 7.72 (d, J = 0.78 Hz,
4-azabicyclo[4.1.0]hept-3-en-5- 1H), 7.48 (dd, J = 2.74, 7.04 Hz,
1H), 7.23 (d, yl)-4-fluorophenyl)-3-methyl-5- J = 2.54 Hz, 1H),
7.19 (s, 1H), 7.05 (dd, J = 8.80, (1,3-oxazol-2-ylmethoxy)-2- 11.54
Hz, 1H), 5.58 (t, J = 54.20 Hz, 1H), 5.26 (s, pyridinecarboxamide
2H), 2.79 (s, 3H), 1.96-2.03 (m, 1H), 1.78 (d, J = 0.78 Hz, 3H),
1.33 (dd, J = 6.26, 9.98 Hz, 1H), 0.81-0.90 (m, 1H). 643 .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 10.01
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.19 (s, 1H), 7.99-8.09 (m,
1H), 7.73 (s, (difluoromethyl)-5-methyl-2-thia- 1H), 7.24 (d, J =
2.54 Hz, 1H), 7.19 (s, 1H), 7.12- 4-azabicyclo[4.1.0]hept-3-en-5-
7.17 (m, 1H), 5.66 (t, J = 57.10 Hz, 1H), 5.26 (s,
yl)-4,5-difluorophenyl)-3-methyl- 2H), 2.78 (s, 3H), 1.98 (dd, J =
7.73, 9.49 Hz, 1H), 5-(1,3-oxazol-2-ylmethoxy)-2- 1.78 (s, 3H),
1.35 (dd, J = 6.36, 9.88 Hz, 1H), 0.85 pyridinecarboxamide (br.s.,
1H). 644 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.03
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.21 (d, J = 2.74 Hz, 1H),
7.94-7.99 (m, (methoxymethyl)-5-methyl-2- 1H), 7.72 (s, 1H), 7.62
(dd, J = 2.74, 7.04 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3- 7.23
(d, J = 2.54 Hz, 1H), 7.19 (s, 1H), 7.04 (dd,
en-5-yl)-4-fluorophenyl)-3- J = 8.80, 11.93 Hz, 1H), 5.26 (s, 2H),
3.66 (d, methyl-5-(1,3-oxazol-2- J = 10.56 Hz, 1H), 3.41 (s, 3H),
3.34 (d, J = 10.76 ylmethoxy)-2- Hz, 1H), 2.79 (s, 3H), 1.81 (dd, J
= 7.43, 8.80 Hz, pyridinecarboxamide 1H), 1.72 (d, J = 0.98 Hz,
3H), 0.88 (dd, J = 5.87, 9.39 Hz, 1H), 0.76-0.84 (m, 1H). 645
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.08
N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.22 (d, J = 2.74 Hz, 1H),
8.07 (ddd, (fluoromethyl)-5-methyl-2-thia-4- J = 2.93, 6.94, 12.03
Hz, 1H), 7.73 (d, J = 0.78 Hz, azabicyclo[4.1.0]hept-3-en-5-yl)-
1H), 7.30 (dd, J = 2.25, 5.58 Hz, 1H), 7.24 (d,
4,5-difluorophenyl)-3-methyl-5- J = 2.54 Hz, 1H), 7.19 (s, 1H),
5.27 (s, 2H), 4.48 (q, (1,3-oxazol-2-ylmethoxy)-2- J = 10.37 Hz,
1H), 4.35 (q, J = 10.30 Hz, 1H), 2.79 pyridinecarboxamide (s, 3H),
1.91 (dd, J = 7.63, 8.80 Hz, 1H), 1.74 (s, 3H), 1.01 (dd, J = 6.06,
9.39 Hz, 1H), 0.81-0.92 (m, 1H). 646 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 10.09 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H),
8.22 (d, J = 2.74 Hz, 1H), 8.05-8.15 (m,
(methoxymethyl)-5-methyl-2- 1H), 7.72 (s, 1H), 7.24 (d, J = 2.15
Hz, 2H), 7.19 (s, thia-4-azabicyclo[4.1.0]hept-3- 1H), 5.26 (s,
2H), 3.63 (d, J = 10.56 Hz, 1H), 3.41
en-5-yl)-4,5-difluorophenyl)-3- (s, 3H), 3.35 (d, J = 10.56 Hz,
1H), 2.79 (s, 3H), methyl-5-(1,3-oxazol-2- 1.79-1.85 (m, 1H), 1.77
(s, 3H), 0.90-1.01 (m, ylmethoxy)-2- 1H), 0.82 (t, J = 6.16 Hz, 1H)
pyridinecarboxamide 647 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
10.07 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.18 (d, J = 2.54 Hz,
1H), 8.06 (ddd, (difluoromethyl)-5-methyl-2-thia- J = 2.54, 6.94,
12.03 Hz, 1H), 7.21 (d, J = 2.54 Hz,
4-azabicyclo[4.1.0]hept-3-en-5- 1H), 7.11-7.17 (m, 1H), 5.66 (t, J
= 55.80 Hz, 1H), yl)-4,5-difluorophenyl)-3-methyl- 4.97 (dq, J =
1.96, 6.52 Hz, 1H), 2.79 (s, 3H), 2.56
5-(((1S)-1-methyl-2-propyn-1- (d, J = 1.96 Hz, 1H), 2.07-2.08 (m,
1H), 1.80 (s, yl)oxy)-2-pyridinecarboxamide 3H), 1.73 (d, J = 6.46
Hz, 4H), 1.38 (dd, J = 6.26, 9.78 Hz, 2H), 0.88 (br.s., 1H). 648
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.02
N-(3-((1S,5S,6S)-3-amino-1- (br.s., 1H), 8.19 (d, J = 2.54 Hz, 1H),
7.95 (dd, (difluoromethyl)-5-methyl-2-thia- J = 2.74, 9.39 Hz, 1H),
7.46 (dd, J = 2.64, 6.94 Hz, 4-azabicyclo[4.1.0]hept-3-en-5- 1H),
7.21 (d, J = 2.54 Hz, 1H), 7.06 (dd, J = 8.80,
yl)-4-fluorophenyl)-3-methyl-5- 11.54 Hz, 1H), 5.65 (t, J = 56.50
Hz, 1H), 4.96 (dq, (((1S)-1-methyl-2-propyn-1- J = 1.86, 6.55 Hz,
1H), 2.79 (s, 3H), 2.56 (d, J = 1.96 yl)oxy)-2-pyridinecarboxamide
Hz, 1H), 2.02 (dd, J = 7.43, 9.78 Hz, 1H), 1.81 (s, 3H), 1.72 (d, J
= 9.19 Hz, 3H), 1.31-1.43 (m, 1H), 0.87 (t, J = 7.40 Hz, 1H) 649
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.06
N-(3-((1S,5S,6S)-3-amino-1-
(s, 1H), 8.18 (d, J = 2.54 Hz, 1H), 7.99 (ddd,
(methoxymethyl)-5-methyl-2- J = 2.93, 4.01, 8.71 Hz, 1H), 7.61 (dd,
J = 2.74, 7.04 thia-4-azabicyclo[4.1.0]hept-3- Hz, 1H), 7.20 (d, J
= 2.54 Hz, 1H), 7.04 (dd, J = 8.80, en-5-yl)-4-fluorophenyl)-3-
11.93 Hz, 1H), 4.96 (dq, J = 1.96, 6.52 Hz, 2H),
methyl-5-(((1S)-1-methyl-2- 3.66 (d, J = 10.56 Hz, 1H), 3.41 (s,
3H), 3.34 (d, propyn-1-yl)oxy)-2- J = 10.76 Hz, 1H), 2.80 (s, 3H),
2.56 (d, J = 2.15 Hz, pyridinecarboxamide 1H), 1.81 (dd, J = 7.34,
8.90 Hz, 1H), 1.73 (s, 3H), 1.72 (d, J = 2.15 Hz, 3H), 0.89 (dd, J
= 5.97, 9.29 Hz, 1H), 0.78-0.84 (m, 1H). 650 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 10.11 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H),
8.18 (d, J = 2.54 Hz, 1H), 8.10 (ddd, (methoxymethyl)-5-methyl-2- J
= 2.74, 6.85, 12.13 Hz, 1H), 7.27-7.33 (m, 1H),
thia-4-azabicyclo[4.1.0]hept-3- 7.21 (d, J = 2.54 Hz, 1H), 4.97
(dq, J = 1.76, 6.52 Hz, en-5-yl)-4,5-difluorophenyl)-3- 1H), 3.65
(d, J = 10.76 Hz, 1H), 3.41 (s, 3H), 3.35
methyl-5-(((1S)-1-methyl-2- (d, J = 10.76 Hz, 1H), 2.79 (s, 3H),
2.56 (d, J = 1.96 propyn-1-yl)oxy)-2- Hz, 1H), 1.80 (dd, J = 7.04,
8.22 Hz, 1H), 1.73 (s, pyridinecarboxamide 3H), 1.72 (d, 3H), 0.91
(dd, J = 5.97, 9.29 Hz, 1H), 0.81 (t, J = 6.16 Hz, 1H). 651 .sup.1H
NMR (400 MHz, CHLOROFORM-d) .delta. 10.06
N-(3-((1S,5S,6S)-3-amino-1- (br.s., 1H), 8.20 (d, J = 2.35 Hz, 1H),
7.94-8.01 (m, (fluoromethyl)-5-methyl-2-thia-4- 1H), 7.41 (d, J =
4.89 Hz, 1H), 7.20 (br.s., 1H), azabicyclo[4.1.0]hept-3-en-5-yl)-
7.07 (t, J = 9.86 Hz, 1H), 4.92-5.00 (m, J = 6.06 Hz,
4-fluorophenyl)-3-methyl-5- 1H), 4.38 (d, J = 49.30 Hz, 2H), 2.78
(s, 3H), 2.55 (((1S)-1-methyl-2-propyn-1- (s, 1H), 1.94-2.00 (m, J
= 8.02 Hz, 1H), 1.90 (br.s., yl)oxy)-2-pyridinecarboxamide 3H),
1.72 (d, J = 6.46 Hz, 3H), 1.19-1.33 (m, 1H), 0.90-0.97 (m, 1H).
652 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 10.03
N-(3-((1S,5S,6S)-3-amino-1- (br.s., 1H), 8.22 (d, J = 2.54 Hz, 1H),
7.94-8.00 (m, (fluoromethyl)-5-methyl-2-thia-4- 1H), 7.72 (s, 1H),
7.47 (dd, J = 2.45, 6.94 Hz, 1H), azabicyclo[4.1.0]hept-3-en-5-yl)-
7.23 (d, J = 2.35 Hz, 1H), 7.19 (s, 1H), 7.06 (dd,
4-fluorophenyl)-3-methyl-5-(1,3- J = 8.90, 11.64 Hz, 1H), 5.26 (s,
2H), 4.39 (d, oxazol-2-ylmethoxy)-2- J = 46.17 Hz, 2H), 2.78 (s,
3H), 1.91-1.99 (m, 1H), pyridinecarboxamide 1.84 (s, 3H), 1.10-1.21
(m, J = 15.85 Hz, 1H), 0.87- 0.95 (m, 1H). 680 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1-
0.82-0.90 (m, 1 H) 1.32 (dd, J = 9.88, 6.16 Hz, 1
(difluoromethyl)-5-methyl-2-thia- H) 1.77 (d, J = 0.98 Hz, 3 H)
1.96-2.05 (m, 1 H) 4-azabicyclo[4.1.0]hept-3-en-5- 2.81 (s, 3 H)
4.47 (q, J = 7.82 Hz, 2 H) 5.48-5.91
yl)-4-fluorophenyl)-3-methyl-5- (m, 1 H) 7.06 (dd, J = 11.54, 8.80
Hz, 1 H) 7.14 (d, (2,2,2-trifluoroethoxy)-2- J = 2.35 Hz, 1 H) 7.53
(dd, J = 7.04, 2.74 Hz, 1 H) pyridinecarboxamide 7.86-7.96 (m, 1 H)
8.18 (d, J = 2.54 Hz, 1 H) 9.97 (s, 1 H). 681 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.78-0.84 (m,
1 H) 0.88 (dd, J = 9.49, 5.77 Hz, 1 (methoxymethyl)-5-methyl-2- H)
1.72 (d, J = 1.17 Hz, 3 H) 1.77-1.85 (m, 1 H)
thia-4-azabicyclo[4.1.0]hept-3- 2.82 (s, 3 H) 3.34 (d, J = 10.56
Hz, 1 H) 3.41 (s, 3 en-5-yl)-4-fluorophenyl)-3- H) 3.67 (d, J =
10.56 Hz, 1 H) 4.47 (q, J = 7.82 Hz, 2
methyl-5-(2,2,2-trifluoroethoxy)- H) 7.05 (dd, J = 11.83, 8.71 Hz,
1 H) 7.14 (d, 2-pyridinecarboxamide J = 2.54 Hz, 1 H) 7.64 (dd, J =
6.94, 2.84 Hz, 1 H) 7.96 (ddd, J = 8.80, 4.11, 2.93 Hz, 1 H) 8.18
(d, J = 2.74 Hz, 1 H) 10.00 (s, 1 H). 682 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.77-0.83 (m,
1 H) 0.89 (dd, J = 9.39, 5.87 Hz, 1 (methoxymethyl)-5-methyl-2- H)
1.72 (s, 3 H) 1.76-1.84 (m, 1 H) 2.60 (t,
thia-4-azabicyclo[4.1.0]hept-3- J = 2.35 Hz, 1 H) 2.81 (s, 3 H)
3.35 (d, J = 10.56 Hz, en-5-yl)-4,5-difluorophenyl)-3- 1 H) 3.41
(s, 3 H) 3.67 (d, J = 10.76 Hz, 1 H) 4.80
methyl-5-(2-propyn-1-yloxy)-2- (d, J = 2.35 Hz, 2 H) 7.18 (d, J =
2.74 Hz, 1 H) 7.29- pyridinecarboxamide 7.34 (m, 1 H) 8.09 (ddd, J
= 12.08, 6.90, 2.93 Hz, 1 H) 8.18 (d, J = 2.74 Hz, 1 H) 10.10 (s, 1
H). 683 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.77-0.91 (m, 2 H) 1.71 (d, J = 1.17
Hz, 3 H) 1.76- (methoxymethyl)-5-methyl-2- 1.85 (m, 1 H) 2.60 (t, J
= 2.35 Hz, 1 H) 2.81 (s, 3 thia-4-azabicyclo[4.1.0]hept-3- H) 3.34
(d, J = 10.76 Hz, 1 H) 3.41 (s, 3 H) 3.67 (d,
en-5-yl)-4-fluorophenyl)-3- J = 10.56 Hz, 1 H) 4.80 (d, J = 2.54
Hz, 2 H) 7.04 methyl-5-(2-propyn-1-yloxy)-2- (dd, J = 11.93, 8.80
Hz, 1 H) 7.18 (d, J = 2.35 Hz, 1 pyridinecarboxamide H) 7.64 (dd, J
= 6.94, 2.84 Hz, 1 H) 7.97 (ddd, J = 8.75, 4.06, 2.84 Hz, 1 H) 8.18
(d, J = 2.74 Hz, 1 H) 10.04 (s, 1 H). 684 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.83-0.90 (m,
1 H) 1.00 (dd, J = 9.59, 6.06 Hz, 1
(fluoromethyl)-5-methyl-2-thia-4- H) 1.73 (d, J = 0.98 Hz, 3 H)
1.86-1.95 (m, 1 H) azabicyclo[4.1.0]hept-3-en-5-yl)- 2.61 (t, J =
2.35 Hz, 1 H) 2.81 (s, 3 H) 4.29-4.41
4,5-difluorophenyl)-3-methyl-5- (m, 1 H) 4.42-4.53 (m, 1 H) 4.81
(d, J = 2.35 Hz, 2 (2-propyn-1-yloxy)-2- H) 7.19 (d, J = 2.74 Hz, 1
H) 7.32 (dt, J = 5.72, 2.32 pyridinecarboxamide Hz, 1 H) 8.07 (ddd,
J = 12.08, 6.90, 2.74 Hz, 1 H) 8.18 (d, J = 2.54 Hz, 1 H) 10.09 (s,
1 H). 685 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.86 (br.s., 1 H) 1.35 (dd, J = 9.78,
6.26 Hz, 1 H) (difluoromethyl)-5-methyl-2-thia- 1.78 (s, 3 H) 1.98
(dd, J = 9.39, 7.63 Hz, 1 H) 2.61 4-azabicyclo[4.1.0]hept-3-en-5-
(s, 1 H) 2.80 (s, 3 H) 4.80 (d, J = 2.15 Hz, 2 H) 5.49-
yl)-4,5-difluorophenyl)-3-methyl- 5.88 (m, 1 H) 7.15-7.21 (m, 2 H)
8.04 (ddd, 5-(2-propyn-1-yloxy)-2- J = 11.93, 6.94, 2.64 Hz, 1 H)
8.16 (d, J = 2.54 Hz, 1 pyridinecarboxamide H) 10.04 (s, 1 H). 686
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.78-0.87 (m, 1 H) 1.31 (dd, J = 9.88,
6.16 Hz, 1 (difluoromethyl)-5-methyl-2-thia- H) 1.77 (s, 3 H) 1.97
(dd, J = 9.78, 7.43 Hz, 1 H) 4-azabicyclo[4.1.0]hept-3-en-5-
2.57-2.63 (m, 1 H) 2.77 (s, 3 H) 4.67-4.98 (m, 3
yl)-4-fluorophenyl)-3-methyl-5- H) 5.42-5.89 (m, 1 H) 7.02 (dd, J =
11.64, 8.90 Hz, (2-propyn-1-yloxy)-2- 1 H) 7.15 (d, J = 2.35 Hz, 1
H) 7.51 (dd, J = 6.85, pyridinecarboxamide 2.74 Hz, 1 H) 7.88 (dt,
J = 8.46, 3.40 Hz, 1 H) 8.09 (d, J = 1.96 Hz, 1 H) 9.97 (s, 1 H).
687 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.76-0.83 (m, 1 H) 0.88 (dd, J = 9.39,
5.87 Hz, 1 (methoxymethyl)-5-methyl-2- H) 1.71 (s, 3 H) 1.74-1.81
(m, 1 H) 1.83 (d, thia-4-azabicyclo[4.1.0]hept-3- J = 6.46 Hz, 3 H)
2.75 (s, 3 H) 3.34 (d, J = 10.56 Hz,
en-5-yl)-4,5-difluorophenyl)-3- 1 H) 3.41 (s, 3 H) 3.66 (d, J =
10.76 Hz, 1 H) 4.11- methyl-5-((1S)-1-(1,3-oxazol-2- 4.11 (m, 1 H)
4.49 (br.s., 2 H) 5.58 (q, J = 6.52 Hz, yl)ethoxy)-2- 1 H) 7.13 (s,
1 H) 7.20 (d, J = 2.54 Hz, 1 H) 7.31 pyridinecarboxamide (dd, J =
5.09, 2.54 Hz, 1 H) 7.66 (s, 1 H) 8.07 (ddd, J = 11.93, 6.85, 2.54
Hz, 1 H) 8.15 (d, J = 2.35 Hz, 1 H) 10.07 (s, 1 H). 688 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1-
0.77-0.84 (m, 1 H) 0.88 (dd, J = 9.39, 5.87 Hz, 1
(methoxymethyl)-5-methyl-2- H) 1.71 (s, 3 H) 1.76-1.81 (m, 1 H)
1.83 (d, thia-4-azabicyclo[4.1.0]hept-3- J = 6.46 Hz, 3 H) 2.76 (s,
3 H) 3.34 (d, J = 10.56 Hz, en-5-yl)-4,5-difluorophenyl)-3- 1 H)
3.41 (s, 3 H) 3.66 (d, J = 10.56 Hz, 1 H) 4.23-
methyl-5-((1R)-1-(1,3-oxazol-2- 4.60 (m, 2 H) 5.58 (q, J = 6.65 Hz,
1 H) 7.13 (s, 1 yl)ethoxy)-2- H) 7.21 (d, J = 2.54 Hz, 1 H) 7.31
(dd, J = 5.28, 2.54 pyridinecarboxamide Hz, 1 H) 7.66 (s, 1 H) 8.07
(ddd, J = 12.13, 6.85, 2.74 Hz, 1 H) 8.17 (d, J = 2.54 Hz, 1 H)
10.06 (s, 1 H). 689 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.82-0.91 (m, 1 H) 0.98 (dd, J = 9.49,
5.97 Hz, 1 (fluoromethyl)-5-methyl-2-thia-4- H) 1.72 (d, J = 1.17
Hz, 3 H) 1.84-1.98 (m, 1 H) azabicyclo[4.1.0]hept-3-en-5-yl)- 2.82
(s, 3 H) 4.25-4.58 (m, 6 H) 7.06 (dd, 4-fluorophenyl)-3-methyl-5- J
= 11.74, 8.80 Hz, 1 H) 7.14 (d, J = 2.54 Hz, 1 H)
(2,2,2-trifluoroethoxy)-2- 7.64 (dd, J = 7.04, 2.74 Hz, 1 H)
7.90-8.01 (m, 1 pyridinecarboxamide H) 8.18 (d, J = 2.54 Hz, 1 H)
10.00 (s, 1 H). 690 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.81-0.91 (m, 1 H) 0.98 (dd, J = 9.49,
6.16 Hz, 1 (fluoromethyl)-5-methyl-2-thia-4- H) 1.72 (d, J = 0.98
Hz, 3 H) 1.85-1.97 (m, 1 H) azabicyclo[4.1.0]hept-3-en-5-yl)- 2.60
(t, J = 2.35 Hz, 1 H) 2.81 (s, 3 H) 4.26-4.59
4-fluorophenyl)-3-methyl-5-(2- (m, 4 H) 4.80 (d, J = 2.54 Hz, 2 H)
7.05 (dd, propyn-1-yloxy)-2- J = 11.74, 8.80 Hz, 1 H) 7.18 (d, J =
2.35 Hz, 1 H) pyridinecarboxamide 7.63 (dd, J = 7.04, 2.74 Hz, 1 H)
7.88-8.01 (m, 1 H) 8.19 (d, J = 2.54 Hz, 1 H) 10.04 (s, 1 H). 691
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.83-0.90 (m, 1 H) 1.00 (dd, J = 9.49,
6.16 Hz, 1 (fluoromethyl)-5-methyl-2-thia-4- H) 1.72 (d, J = 0.98
Hz, 3 H) 1.91 (dd, J = 8.90, 7.53 azabicyclo[4.1.0]hept-3-en-5-yl)-
Hz, 1 H) 2.65 (t, J = 2.45 Hz, 1 H) 4.27-4.57 (m, 4
4,5-difluorophenyl)-3-chloro-5- H) 4.83 (d, J = 2.35 Hz, 2 H)
7.30-7.35 (m, 1 H) (2-propyn-1-yloxy)-2- 7.45 (d, J = 2.54 Hz, 1 H)
8.10 (ddd, J = 11.93, 6.85, pyridinecarboxamide 2.74 Hz, 1 H) 8.26
(d, J = 2.54 Hz, 1 H) 9.85 (s, 1 H). 692 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.80-0.91 (m,
1 H) 1.01 (dd, J = 9.59, 6.06 Hz, 1
(fluoromethyl)-5-methyl-2-thia-4- H) 1.74 (s, 3 H) 1.84-1.96 (m, 1
H) 4.31-4.54 azabicyclo[4.1.0]hept-3-en-5-yl)- (m, 4 H) 7.36-7.44
(m, 2 H) 8.02 (ddd, J = 11.88, 4,5-difluorophenyl)-5-(2,2,2- 6.80,
2.64 Hz, 1 H) 8.26 (d, J = 8.61 Hz, 1 H) 8.32 trifluoroethoxy)-2-
(d, J = 2.93 Hz, 1 H) 9.81 (s, 1 H). pyridinecarboxamide 693
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.84-0.91 (m, 1 H) 1.04 (dd, J = 9.49,
6.16 Hz, 1 (fluoromethyl)-5-methyl-2-thia-4- H) 1.75 (s, 3 H)
1.89-1.96 (m, 1 H) 4.26-4.97 azabicyclo[4.1.0]hept-3-en-5-yl)- (m,
6 H) 7.30 (dt, J = 5.43, 2.47 Hz, 1 H) 7.40 (d,
4,5-difluorophenyl)-3-chloro-5- J = 2.54 Hz, 1 H) 8.11 (ddd, J =
11.93, 6.85, 2.74 Hz, (2,2,2-trifluoroethoxy)-2- 1 H) 8.28 (d, J =
2.54 Hz, 1 H) 9.80 (s, 1 H). pyridinecarboxamide 694 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1-
0.00-0.00 (m, 1 H) 0.78-0.84 (m, 1 H) 0.90 (dd,
(methoxymethyl)-5-methyl-2- J = 9.39, 5.87 Hz, 1 H) 1.72 (d, J =
1.17 Hz, 3 H) thia-4-azabicyclo[4.1.0]hept-3- 1.80 (ddd, J = 9.34,
6.80, 1.27 Hz, 1 H) 3.35 (d, en-5-yl)-4,5-difluorophenyl)-5- J =
10.56 Hz, 1 H) 3.41 (s, 3 H) 3.67 (d, J = 10.76
(2,2,2-trifluoroethoxy)-2- Hz, 1 H) 4.19-4.58 (m, 4 H) 7.36-7.46
(m, 2 H) pyridinecarboxamide 8.07 (ddd, J = 11.93, 6.85, 2.74 Hz, 1
H) 8.28 (d, J = 8.80 Hz, 1 H) 8.34 (d, J = 2.54 Hz, 1 H) 9.75-
9.88 (m, 1 H). 695 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-1- 0.82-0.91 (m, 1 H) 1.35 (dd, J = 9.88,
6.36 Hz, 1 (difluoromethyl)-5-methyl-2-thia- H) 1.78 (d, J = 0.78
Hz, 3 H) 1.99 (dd, J = 9.68, 7.53 4-azabicyclo[4.1.0]hept-3-en-5-
Hz, 1 H) 4.49 (q, J = 7.82 Hz, 4 H) 5.51-5.84 (m, 1
yl)-4,5-difluorophenyl)-5-(2,2,2- H) 7.27-7.32 (m, 1 H) 7.41 (dd, J
= 8.70, 2.84 Hz, trifluoroethoxy)-2- 1 H) 8.02 (ddd, J = 11.79,
6.80, 2.74 Hz, 1 H) 8.27 pyridinecarboxamide (d, J = 8.61 Hz, 1 H)
8.33 (d, J = 2.93 Hz, 1 H) 9.78 (s, 1 H). 696 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.80-0.89 (m,
1 H) 1.33 (dd, J = 9.88, 6.16 Hz, 1
(difluoromethyl)-5-methyl-2-thia- H) 1.78 (d, J = 0.78 Hz, 3 H)
2.00 (dd, J = 9.78, 7.24 4-azabicyclo[4.1.0]hept-3-en-5- Hz, 1 H)
4.22-4.88 (m, 4 H) 5.50-5.84 (m, 1 H) yl)-4-fluorophenyl)-5-(2,2,2-
7.07 (dd, J = 11.64, 8.71 Hz, 1 H) 7.40 (dd, J = 8.71,
trifluoroethoxy)-2- 2.84 Hz, 1 H) 7.63 (dd, J = 7.04, 2.74 Hz, 1 H)
7.85- pyridinecarboxamide 7.94 (m, 1 H) 8.28 (d, J = 8.61 Hz, 1 H)
8.33 (d, J = 2.74 Hz, 1 H) 9.77 (s, 1 H). 697 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.85-0.94 (m,
1 H) 1.05 (dd, J = 9.49, 6.16 Hz, 1
(fluoromethyl)-5-methyl-2-thia-4- H) 1.77 (d, J = 0.78 Hz, 3 H)
1.88-2.00 (m, 1 H) azabicyclo[4.1.0]hept-3-en-5-yl)- 4.30-4.54 (m,
4 H) 7.08 (dd, J = 11.54, 8.80 Hz, 1 4-fluorophenyl)-5-(2,2,2- H)
7.40 (dd, J = 8.80, 2.93 Hz, 1 H) 7.69 (dd, trifluoroethoxy)-2- J =
7.04, 2.74 Hz, 1 H) 7.94 (ddd, J = 8.80, 4.11, 2.93
pyridinecarboxamide Hz, 1 H) 8.28 (d, J = 8.61 Hz, 1 H) 8.34 (d, J
= 2.74 Hz, 1 H) 9.80 (s, 1 H). 698 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm N-(3-((1S,5S,6S)-3-amino-1- 0.84 (t, J =
6.36 Hz, 1 H) 0.94-1.02 (m, 1 H) 1.79 (methoxymethyl)-5-methyl-2-
(s, 3 H) 1.84 (dd, J = 8.61, 6.85 Hz, 1 H) 3.36 (d,
thia-4-azabicyclo[4.1.0]hept-3- J = 10.76 Hz, 1 H) 3.41 (s, 3 H)
3.63 (d, J = 10.76 en-5-yl)-4-fluorophenyl)-5-(2,2,2- Hz, 1 H) 4.48
(q, J = 7.82 Hz, 2 H) 7.08 (dd, trifluoroethoxy)-2- J = 11.74, 8.80
Hz, 1 H) 7.40 (dd, J = 8.80, 2.93 Hz, pyridinecarboxamide 1 H) 7.66
(dd, J = 6.85, 2.74 Hz, 1 H) 7.97 (ddd, J = 8.75, 4.06, 2.84 Hz, 1
H) 8.27 (d, J = 8.80 Hz, 1 H) 8.34 (d, J = 2.54 Hz, 1 H) 9.68-9.91
(m, 1 H). 699 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. ppm
N-(3-((1S,5S,6S)-3-amino-5- 0.86 (t, J = 6.36 Hz, 1 H) 1.42 (dd, J
= 9.59, 5.67 Hz, methyl-1-(1- 1 H) 1.60 (br.s., 2 H) 1.85 (s, 3 H)
1.89 (br.s., 4 pyrrolidinylcarbonyl)-2-thia-4- H) 2.25-2.34 (m, 1
H) 3.48 (br.s., 2 H) 3.67 (br.s., azabicyclo[4.1.0]hept-3-en-5-yl)-
2 H) 4.49 (q, J = 7.82 Hz, 2 H) 7.26-7.30 (m, 1
4,5-difluorophenyl)-5-(2,2,2- H) 7.40 (dd, J = 8.71, 2.84 Hz, 1 H)
8.01 (ddd, trifluoroethoxy)-2- J = 11.79, 6.80, 2.74 Hz, 1 H) 8.27
(d, J = 8.61 Hz, 1 pyridinecarboxamide H) 8.33 (d, J = 2.74 Hz, 1
H) 9.78 (s, 1 H). 700 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm (1S,5S,6S)-3-amino-5-(2,3- 0.73-0.83 (m, 1 H) 1.89 (s, 3 H)
2.00 (dd, J = 9.68, difluoro-5-(((5-(2,2,2- 4.99 Hz, 1 H) 2.22 (dd,
J = 9.39, 7.63 Hz, 1 H) 2.87 trifluoroethoxy)-2- (d, J = 4.89 Hz, 3
H) 4.49 (q, J = 7.82 Hz, 2 H) 6.61
pyridinyl)carbonyl)amino)phenyl)- (d, J = 4.69 Hz, 1 H) 6.99-7.13
(m, 1 H) 7.39 (dd, N,5-dimethyl-2-thia-4- J = 8.70, 2.84 Hz, 1 H)
7.77 (ddd, J = 11.74, 6.65, azabicyclo[4.1.0]hept-3-ene-1- 2.74 Hz,
1 H) 8.18 (d, J = 8.61 Hz, 1 H) 8.24 (d, carboxamide J = 2.74 Hz, 1
H) 9.53 (s, 1 H). 701 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm (1S,5S,6S)-3-amino-5-(2,3- 0.74-0.85 (m, 1 H) 1.85 (s, 3 H)
1.98 (dd, J = 9.59, difluoro-5-(((5-(2,2,2- 5.09 Hz, 1 H) 2.23 (dd,
J = 9.29, 7.73 Hz, 1 H) 2.87 trifluoroethoxy)-2- (d, J = 4.89 Hz, 3
H) 4.81-4.93 (m, 2 H) 6.54 (d, pyrazinyl)carbonyl)amino)phenyl)- J
= 4.70 Hz, 1 H) 7.06-7.19 (m, 1 H) 7.81 (ddd,
N,5-dimethyl-2-thia-4- J = 11.39, 6.70, 2.64 Hz, 1 H) 8.25 (d, J =
1.17 Hz, 1 azabicyclo[4.1.0]hept-3-ene-1- H) 8.96 (d, J = 1.17 Hz,
1 H) 9.29 (s, 1 H) carboxamide 702 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm (1S,5S,6S)-3-amino-5-(2,3- 0.79 (t, J =
5.87 Hz, 1 H) 1.88 (s, 3 H) 2.00 (dd,
difluoro-5-(((3-methyl-5-(2,2,2- J = 9.59, 5.09 Hz, 1 H) 2.22 (dd,
J = 9.39, 7.63 Hz, 1 trifluoroethoxy)-2- H) 2.77 (s, 3 H) 2.87 (d,
J = 4.69 Hz, 3 H) 4.47 (q, pyridinyl)carbonyl)amino)phenyl)- J =
7.82 Hz, 2 H) 6.59 (d, J = 4.69 Hz, 1 H) 6.83-
N,5-dimethyl-2-thia-4- 6.94 (m, 1 H) 7.14 (d, J = 2.54 Hz, 1 H)
7.88 (ddd, azabicyclo[4.1.0]hept-3-ene-1- J = 12.03, 6.75, 2.54 Hz,
1 H) 8.04 (d, J = 2.74 Hz, 1 carboxamide H) 9.75 (s, 1 H). 732
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.57 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.49 (d, J = 2.74 Hz, 1H), 8.15 (d, J =
8.61 Hz, 1H), (methoxymethyl)-5-methyl-2- 7.94 (ddd, J = 2.74,
6.75, 12.42 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3- 7.84-7.89 (m,
1H), 7.76 (dd, J = 2.84, 8.71 Hz, 1H),
en-5-yl)-4,5-difluorophenyl)-5- 6.56-6.89 (m, 1H), 5.99 (s, 2H),
4.85 (t, J = 13.40 (2,2,3,3-tetrafluoropropoxy)-2- Hz, 2H), 3.56
(d, J = 10.76 Hz, 1H), 3.35 (d, pyridinecarboxamide J = 10.95 Hz,
1H), 3.30 (s, 3H), 1.58-1.67 (m, 4H), 0.89 (dd, J = 5.18, 9.29 Hz,
1H), 0.65 (t, J = 5.87 Hz, 1H) 734 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 10.67 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.92 (d, J =
1.37 Hz, 1H), 8.57 (d, J = 1.37 Hz, 1H),
(methoxymethyl)-5-methyl-2- 7.86-7.97 (m, 2H), 6.56-6.89 (m, 1H),
5.99 (br.s., thia-4-azabicyclo[4.1.0]hept-3- 2H), 5.04 (t, J =
14.08 Hz, 2H), 3.57 (d, J = 10.76 en-5-yl)-4,5-difluorophenyl)-5-
Hz, 1H), 3.36 (d, J = 10.95 Hz, 1H), 3.31 (s, 3H),
(2,2,3,3-tetrafluoropropoxy)-2- 1.63-1.67 (m, 1H), 1.62 (s, 3H),
0.91 (br.s., pyrazinecarboxamide 1H), 0.61-0.69 (m, 1H) 738 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 10.60 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.89 (d, J = 1.37 Hz, 1H), 8.43 (d, J =
1.37 Hz, 1H), (methoxymethyl)-5-methyl-2- 7.84-7.96 (m, 2H), 5.98
(br.s., 2H), 4.65 (t, thia-4-azabicyclo[4.1.0]hept-3- J = 5.87 Hz,
2H), 3.56 (d, J = 10.95 Hz, 1H), 3.35 (d,
en-5-yl)-4,5-difluorophenyl)-5- J = 10.95 Hz, 1H), 3.30 (s, 3H),
2.89 (tq, J = 5.67, (3,3,3-trifluoropropoxy)-2- 11.35 Hz, 2H), 1.64
(br.s., 1H), 1.61 (s, 3H), pyrazinecarboxamide 0.89 (d, J = 8.41
Hz, 1H), 0.64 (t, J = 5.67 Hz, 1H) 739 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.63 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.89
(d, J = 1.37 Hz, 1H), 8.54 (d, J = 1.17 Hz, 1H),
(methoxymethyl)-5-methyl-2- 7.85-7.97 (m, 2H), 5.98 (s, 2H), 4.73
(t, J = 13.20 thia-4-azabicyclo[4.1.0]hept-3- Hz, 2H), 3.56 (d, J =
10.95 Hz, 1H), 3.35 (d, en-5-yl)-4,5-difluorophenyl)-5- J = 10.95
Hz, 1H), 3.30 (s, 3H), 1.78 (t, J = 19.27 Hz,
(2,2-difluoropropoxy)-2- 3H), 1.64 (br.s., 1H), 1.61 (s, 3H), 0.89
(dd, pyrazinecarboxamide J = 5.28, 9.19 Hz, 1H), 0.64 (t, J = 5.67
Hz, 1H) 740 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.58 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.88 (d, J = 1.37 Hz, 1H), 8.41 (d, J =
1.37 Hz, 1H), (methoxymethyl)-5-methyl-2- 7.86-7.95 (m, 2H), 5.99
(br.s., 2H), 4.70 (t, thia-4-azabicyclo[4.1.0]hept-3- J = 5.87 Hz,
1H), 4.58 (t, J = 5.87 Hz, 1H), 4.52 (t,
en-5-yl)-4,5-difluorophenyl)-5-(3- J = 6.36 Hz, 2H), 3.56 (d, J =
10.95 Hz, 1H), 3.36 (d, fluoropropoxy)-2- J = 11.15 Hz, 1H), 3.30
(s, 3H), 2.22 (quin, pyrazinecarboxamide J = 6.11 Hz, 1H), 2.15
(quin, J = 6.11 Hz, 1H), 1.65 (br.s., 1H), 1.61 (s, 3H), 0.90 (dd,
J = 5.18, 9.29 Hz, 1H), 0.64 (t, J = 5.67 Hz, 1H) 742 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.82 (s, 1H),
N-(3-((1R,5S,6S)-3-amino-5- 8.78 (d, J = 2.35 Hz, 1H), 8.17-8.23
(m, 1H), 8.11- methyl-1-(methylsulfonyl)-2-thia- 8.16 (m, 1H), 7.95
(ddd, J = 2.54, 6.80, 12.37 Hz, 4-azabicyclo[4.1.0]hept-3-en-5-
1H), 7.66-7.75 (m, 1H), 6.61 (s, 2H), 3.13 (s, 3H),
yl)-4,5-difluorophenyl)-5-chloro- 2.18 (dd, J = 7.82, 10.17 Hz,
1H), 1.92 (dd, J = 6.06, 2-pyridinecarboxamide 10.17 Hz, 1H), 1.73
(s, 3H), 0.95 (t, J = 6.75 Hz, 1H) 743 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.63 (s, 1H), N-(3-((1R,5S,6S)-3-amino-5- 8.44
(d, J = 2.93 Hz, 1H), 8.13 (d, J = 8.61 Hz, 1H),
methyl-1-(methylsulfonyl)-2-thia- 7.96 (ddd, J = 2.54, 6.85, 12.32
Hz, 1H), 4-azabicyclo[4.1.0]hept-3-en-5- 7.63-7.72 (m, 2H), 6.61
(s, 2H), 5.04 (d, J = 2.35 yl)-4,5-difluorophenyl)-5-(2- Hz, 2H),
3.71 (t, J = 2.25 Hz, 1H), 3.13 (s, 3H), propyn-1-yloxy)-2- 2.19
(dd, J = 7.63, 10.17 Hz, 1H), 1.92 (dd, J = 6.06,
pyridinecarboxamide 10.37 Hz, 1H), 1.73 (s, 3H), 0.96 (t, J = 6.85
Hz, 1H) 744 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.69 (s, 1H),
N-(3-((1R,5S,6S)-3-amino-5- 8.90 (d, J = 1.17 Hz, 1H), 8.48 (d, J =
1.37 Hz, 1H), methyl-1-(methylsulfonyl)-2-thia- 7.93 (ddd, J =
2.64, 6.85, 12.23 Hz, 1H), 7.71 (d, 4-azabicyclo[4.1.0]hept-3-en-5-
J = 5.87 Hz, 1H), 6.61 (s, 2H), 5.14 (d, J = 2.35 Hz,
yl)-4,5-difluorophenyl)-5-(2- 2H), 3.64 (t, J = 2.45 Hz, 1H), 3.13
(s, 3H), 2.19 propyn-1-yloxy)-2- (dd, J = 7.82, 10.17 Hz, 1H), 1.92
(dd, J = 6.06, pyrazinecarboxamide 10.17 Hz, 1H), 1.73 (s, 3H),
0.95 (t, J = 6.75 Hz, 1H) 745 .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 10.62 (s, 1H), N-(3-((1R,5S,6S)-3-amino-5- 8.49 (d, J =
2.74 Hz, 1H), 8.21 (d, J = 0.78 Hz, 1H),
methyl-1-(methylsulfonyl)-2-thia- 8.12 (d, J = 8.80 Hz, 1H), 7.95
(ddd, J = 2.64, 6.80, 4-azabicyclo[4.1.0]hept-3-en-5- 12.47 Hz,
1H), 7.75 (dd, J = 2.74, 8.80 Hz, 1H),
yl)-4,5-difluorophenyl)-5-(1,3- 7.64-7.71 (m, 1H), 7.31 (d, J =
0.78 Hz, 1H), 6.61 oxazol-2-ylmethoxy)-2- (s, 2H), 5.48 (s, 2H),
3.13 (s, 3H), 2.18 (dd, pyridinecarboxamide J = 7.82, 10.17 Hz,
1H), 1.92 (dd, J = 6.06, 10.17 Hz, 1H), 1.73 (s, 3H), 0.96 (t, J =
6.75 Hz, 1H) 746 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.70 (s,
1H), N-(3-((1R,5S,6S)-3-amino-5- 8.88 (d, J = 1.37 Hz, 1H), 8.53
(d, J = 1.17 Hz, 1H), methyl-1-(methylsulfonyl)-2-thia- 8.19 (d, J
= 0.78 Hz, 1H), 7.93 (ddd, J = 2.64, 6.85,
4-azabicyclo[4.1.0]hept-3-en-5- 12.42 Hz, 1H), 7.66-7.74 (m, 1H),
7.29 (s, 1H), yl)-4,5-difluorophenyl)-5-(1,3- 6.61 (s, 2H), 5.61
(s, 2H), 3.13 (s, 3H), 2.18 (dd, oxazol-2-ylmethoxy)-2- J = 7.73,
10.07 Hz, 1H), 1.92 (dd, J = 6.06, 10.17 Hz, pyrazinecarboxamide
1H), 1.73 (s, 3H), 0.94 (t, J = 6.75 Hz, 1H) 772 .sup.1H NMR
(DMSO-d6) .delta.: 10.63 (s, 1H), 8.80 (d,
N-(3-((1R,5S,6S)-3-amino-1- J = 2.0 Hz, 1H), 8.20-8.24 (m, 1H),
8.15-8.19 (m, ((1E)-3-(3,3-difluoro-1- 1H), 8.03 (dd, J = 7.0, 2.5
Hz, 1H), 7.83-7.90 (m, azetidinyl)-3-oxo-1-propen-1-yl)- 1H), 7.21
(dd, J = 11.7, 8.8 Hz, 1H), 6.61 (d, J = 15.3
5-(fluoromethyl)-2-thia-4- Hz, 1H), 6.46 (br.s., 2H), 6.04 (d, J =
15.1 Hz, 1H), azabicyclo[4.1.0]hept-3-en-5-yl)- 4.59-4.87 (m, 4H),
4.35 (m, 2H), 2.01 (t, J = 8.4 Hz, 4-fluorophenyl)-5-chloro-2- 1H),
1.56 (dd, J = 9.3, 4.8 Hz, 1H), 0.99 (t, J = 6.0
pyridinecarboxamide Hz, 1H). 774 .sup.1H NMR (DMSO-d6) .delta.:
10.49 (s, 1H), 8.90 (d, N-(3-((1R,5S,6S)-3-amino-1- J = 1.4 Hz,
1H), 8.48 (d, J = 1.4 Hz, 1H), 8.02 (dd,
((1E)-3-(dimethylamino)-3-oxo- J = 7.0, 2.5 Hz, 1H), 7.75-7.89 (m,
1H), 7.19 (dd,
1-propen-1-yl)-5-(fluoromethyl)- J = 11.5, 9.0 Hz, 1H), 6.40-6.55
(m, 4H), 5.14 (d, 2-thia-4-azabicyclo[4.1.0]hept-3- J = 2.3 Hz,
2H), 4.59-4.84 (m, 2H), 3.64 (t, J = 2.3
en-5-yl)-4-fluorophenyl)-5-(2- Hz, 1H), 3.06 (s, 3H), 2.88 (s, 3H),
1.87-1.97 (m, propyn-1-yloxy)-2- 1H), 1.53 (dd, J = 9.0, 4.9 Hz,
1H), 0.94 (t, J = 5.9 pyrazinecarboxamide Hz, 1H). 780 .sup.1H NMR
(DMSO-d6) .delta.: 10.50 (s, 1H), 8.89 (d,
N-(3-((1S,5S,6S)-3-amino-5- J = 1.2 Hz, 1H), 8.48 (d, J = 1.4 Hz,
1H), 8.32 (s, (fluoromethyl)-1-(1,3-oxazol-5- 1H), 8.02 (dd, J =
7.0, 2.7 Hz, 1H), 7.78-7.91 (m, yl)-2-thia-4- 1H), 7.19 (dd, J =
11.8, 8.7 Hz, 1H), 7.12 (s, 1H), azabicyclo[4.1.0]hept-3-en-5-yl)-
6.50 (s, 2H), 5.14 (d, J = 2.3 Hz, 2H), 4.61-4.90 (m,
4-fluorophenyl)-5-(2-propyn-1- 2H), 3.64 (t, J = 2.4 Hz, 1H),
1.98-2.08 (m, 1H), yloxy)-2-pyrazinecarboxamide 1.63 (dd, J = 9.8,
5.5 Hz, 1H), 0.89-1.00 (m, 1H) 783 .sup.1H NMR (DMSO-d6) .delta.:
10.62 (s, 1H), 8.99 (d, N-(3-((1S,5S,6S)-3-amino-5- J = 1.4 Hz,
1H), 8.64 (d, J = 1.4 Hz, 1H), 8.43 (s,
(fluoromethyl)-1-(1,3-oxazol-5- 1H), 8.30 (s, 1H), 8.13 (dd, J =
7.2, 2.7 Hz, 1H), yl)-2-thia-4- 7.95 (dt, J = 7.3, 4.2 Hz, 1H),
7.40 (d, J = 0.8 Hz, azabicyclo[4.1.0]hept-3-en-5-yl)- 1H), 7.30
(dd, J = 11.7, 8.8 Hz, 1H), 7.23 (s, 1H),
4-fluorophenyl)-5-(1,3-oxazol-2- 6.61 (s, 2H), 5.72 (s, 2H),
4.73-5.02 (m, 2H), 2.07- ylmethoxy)-2- 2.19 (m, 1H), 1.74 (dd, J =
9.7, 5.6 Hz, 1H), 0.96- pyrazinecarboxamide 1.12 (m, 1H) 792
.sup.1H NMR (DMSO-d6) .delta.: 10.55 (s, 1H), 8.78 (d,
(1S,5S,6S)-3-amino-5-(5-(((5- J = 2.3 Hz, 1H), 8.17-8.23 (m, 1H),
8.11-8.17 (m, chloro-2- 1H), 7.99 (dd, J = 7.4, 2.7 Hz, 1H),
7.77-7.85 (m, pyridinyl)carbonyl)amino)-2- 1H), 7.64 (d, J = 3.7
Hz, 1H), 7.16 (dd, J = 11.9, 8.8 fluorophenyl)-N-cyclopropyl-5- Hz,
1H), 6.09 (s, 2H), 2.65 (td, J = 7.3, 3.7 Hz, 1H), methyl-2-thia-4-
2.15 (dd, J = 9.3, 7.5 Hz, 1H), 1.61 (s, 3H), 1.38
azabicyclo[4.1.0]hept-3-ene-1- (dd, J = 9.7, 5.2 Hz, 1H), 0.79-0.87
(m, 1H), 0.56- carboxamide 0.65 (m, 2H), 0.43-0.51 (m, 2H) 795
.sup.1H NMR (DMSO-d6) d: 10.43 (br.s., 1H), 8.90 (s,
(1S,5S,6S)-3-amino-N- 1H), 8.48 (s, 1H), 8.00 (d, J = 4.9 Hz, 1H),
7.78 (br.s., cyclopropyl-5-(2-fluoro-5-(((5-(2- 1H), 7.64 (br.s.,
1H), 7.16 (br.s., 1H), 6.07 (br.s., propyn-1-yloxy)-2- 1H), 5.14
(d, J = 2.3 Hz, 2H), 3.64 (t, J = 2.3 Hz,
pyrazinyl)carbonyl)amino)phenyl)-5- 1H), 0.83 (br.s., 1H),
2.61-2.72 (m, 1H), 2.15 (t, methyl-2-thia-4- J = 8.4 Hz, 1H), 1.63
(s, 3H), 1.41 (dd, J = 9.7, 5.4 azabicyclo[4.1.0]hept-3-ene-1- Hz,
1H), 0.84 (t, J = 6.0 Hz, 1H), 0.60 (d, J = 5.1 Hz, carboxamide
2H), 0.39-0.51 (m, 2H) 803 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.58 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.35 (s, 1H),
8.19 (s, 1H), 7.93 (ddd, J = 2.45, 6.70,
(fluoromethyl)-5-methyl-2-thia-4- 12.37 Hz, 1H), 7.74 (d, J = 6.06
Hz, 1H), 7.29 (s, azabicyclo[4.1.0]hept-3-en-5-yl)- 1H), 6.12 (s,
2H), 5.59 (s, 2H), 4.40-4.55 (m, 2H),
4,5-difluorophenyl)-3-methyl-5- 2.74 (s, 3H), 1.80 (m, 1H), 1.61
(s, 3H), 1.03 (dd, (1,3-oxazol-2-ylmethoxy)-2- J = 5.48, 9.39 Hz,
1H), 0.69 (q, J = 5.35 Hz, 1H). .sup.19F pyrazinecarboxamide NMR
(376 MHz, DMSO-d.sub.6) .delta. -138.40 (d, J = 22.54 Hz, 1F),
-143.92 (d, J = 22.55 Hz,, 1F), -211.59 (s, 1F). 804 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.78 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.80 (s, 1H), 8.22 (m, 1H), 8.17 (m,
1H), 7.96 (m, (difluoromethyl)-5-methyl-2-thia- 1H), 7.83 (m, 1H),
6.30 (s, 2H), 5.81-6.09 (m, 1H), 4-azabicyclo[4.1.0]hept-3-en-5-
1.91 (m, 1H), 1.66 (s, 3H), 1.34 (m, 1H), 0.78 (m,
yl)-4,5-difluorophenyl)-5-chloro- 1H). .sup.19F NMR (376 MHz,
CHLOROFORM-d) 2-pyridinecarboxamide .delta. -115.56(d, .sup.1J =
273.96 Hz, 1F), -118.27 (d, .sup.1J = 273.77 Hz, 1F), -140.28 (d,
.sup.2J = 22.54 Hz, 1F), -155.35 (d, .sup.2J = 22.64 Hz, 1F). 807
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.65 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.91 (d, J = 1.17 Hz, 1H), 8.50 (d, J =
1.17 Hz, 1H), (difluoromethyl)-5-methyl-2-thia- 7.93 (m, 1H), 7.83
(d, J = 5.87 Hz, 1H), 6.29 (br., 4-azabicyclo[4.1.0]hept-3-en-5-
2H), 5.75-6.09 (m, 1H), 5.16 (d, J = 2.35 Hz, 2H),
yl)-4,5-difluorophenyl)-5-(2- 3.66 (t, J = 2.35 Hz, 1H), 1.91 (m,
1H), 1.66 (s, propyn-1-yloxy)-2- 3H), 1.34 (m, 1H), 0.77 (m, 1H).
.sup.19F NMR (377 pyrazinecarboxamide MHz, DMSO-d.sub.6) .delta.
-115.61 (d, .sup.1J = 273.96 Hz, 1F), -118.23 (d, .sup.1J = 273.90
Hz, 1F), -138.27 (d, .sup.2J = 22.55 Hz, 1F), -143.09 (d, .sup.2J =
22.55 Hz, 1F). 811 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.64 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.89 (d, J = 1.17 Hz,
1H), 8.54 (d, J = 1.17 Hz, 1H), (fluoromethyl)-5-methyl-2-thia-4-
8.20 (d, J = 0.78 Hz, 1H), 7.81-8.01 (m, 2H), 7.30
azabicyclo[4.1.0]hept-3-en-5-yl)- (s, 1H), 6.11 (br., 2H), 5.62 (s,
2H), 4.23-4.77 (m, 4,5-difluorophenyl)-5-(1,3- 2H), 1.80 (m, 1H),
1.62 (s, 3H), 1.04 (dd, J = 5.48, oxazol-2-ylmethoxy)-2- 9.39 Hz,
1H), 0.63-0.76 (m, 1H). .sup.19F NMR (376 pyrazinecarboxamide MHz,
DMSO-d.sub.6) .delta. -138.46 (d, J = 22.55 Hz, 1F), -143.62 (d, J
= 22.54 Hz, 1F), -211.59 (s, 1F). 814 .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.69 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.92 (d, J = 1.17 Hz, 1H), 8.62 (d, J = 1.37 Hz, 1H),
(fluoromethyl)-5-methyl-2-thia-4- 7.73-8.02 (m, 2H), 6.11 (s, 2H),
5.17 (q, J = 8.93 azabicyclo[4.1.0]hept-3-en-5-yl)- Hz, 2H),
4.11-4.73 (m, 2H), 1.79 (m, 1H), 1.62 (s,
4,5-difluorophenyl)-5-(2,2,2- 3H), 1.04 (m, 1H), 0.71 (m, 1H).
.sup.19F NMR (376 trifluoroethoxy)-2- MHz, DMSO-d.sub.6) .delta.
-72.13 (s, 3F), -138.44 (d, pyrazinecarboxamide J = 22.54 Hz, 1F),
-143.52 (d, J = 22.54 Hz, 1F), -211.59 (s, 1F). 815 .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.67 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.92 (d, J = 0.98 Hz, 1H), 8.62 (m,
1H), 7.95 (m, (methoxymethyl)-5-methyl-2- 2H), 5.99 (s, 2H), 5.17
(q, J = 9.00 Hz, 2H), 3.56 (d, thia-4-azabicyclo[4.1.0]hept-3- J =
11.15 Hz, 1H), 3.36 (d, J = 11.15 Hz, 1H), 3.31
en-5-yl)-4,5-difluorophenyl)-5- (s, 3H), 1.61 (m, 1H), 1.59 (s,
3H), 0.90 (m, 1H), (2,2,2-trifluoroethoxy)-2- 0.64 (m, 1H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -72.13
pyrazinecarboxamide (s, 3F), -138.52 (d, J = 22.54 Hz, 1F), -143.68
(d, J = 22.55 Hz, 1F). 818 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.55 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.78 (d, J =
2.35 Hz, 1H), 8.08-8.28 (m, 2H), 7.95
(difluoromethyl)-5-methyl-2-thia- (dd, J = 2.64, 7.34 Hz, 1H), 7.80
(td, J = 3.52, 8.61 4-azabicyclo[4.1.0]hept-3-en-5- Hz, 1H), 7.17
(dd, J = 8.70, 11.84 Hz, 1H), 6.25 yl)-4-fluorophenyl)-5-chloro-2-
(br., 2H), 5.77-6.11 (m, 1H), 1.91 (m, 1H), 1.64 (s,
pyridinecarboxamide 3H), 1.30 (m, 1H), 0.72 (m, 1H). .sup.19F NMR
(376 MHz, DMSO-d.sub.6) .delta. -115.55 (d, .sup.1J = 273.77 Hz,
1F), -116.11 (s, 1F), -118.80 (d, .sup.1J = 273.77 Hz, 1F). 820
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.44 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.91 (d, J = 1.37 Hz, 1H), 8.49 (d, J =
1.17 Hz, 1H), (difluoromethyl)-5-methyl-2-thia- 7.97 (dd, J = 2.74,
7.24 Hz, 1H), 7.78 (td, J = 3.72, 4-azabicyclo[4.1.0]hept-3-en-5-
8.22 Hz, 1H), 7.09 (m, 1H), 6.26 (br., 2H), 5.79-
yl)-4-fluorophenyl)-5-(2-propyn- 6.14 (m, 1H), 5.15 (d, J = 2.54
Hz, 2H), 3.65 (s, 1-yloxy)-2-pyrazinecarboxamide 1H), 1.93 (t, J =
8.22 Hz, 1H), 1.65 (s, 3H), 1.30 (m, 1H), 0.74 (m, 1H). .sup.19F
NMR (377 MHz, DMSO-d.sub.6) .delta. -115.51 (d, .sup.1J = 273.97
Hz, 1F), -116.19 (s, 1F), -118.54 (d, .sup.1J = 273.97 Hz, 1F). 821
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.54 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.78 (d, J = 1.76 Hz, 1H), 8.10-8.28
(m, 2H), 7.97- (fluoromethyl)-5-methyl-2-thia-4- 8.07 (m, 1H), 7.80
(td, J = 3.67, 8.31 Hz, 1H), 7.16 azabicyclo[4.1.0]hept-3-en-5-yl)-
(dd, J = 8.80, 12.13 Hz, 1H), 6.08 (br., 2H), 4.30-
4-fluorophenyl)-5-chloro-2- 4.65 (m, 2H), 1.82 (m, 1H), 1.60 (s,
3H), 0.99 (m, pyridinecarboxamide 1H), 0.68 (q, J = 5.28 Hz, 1H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -116.55 (s, 1F),
-211.46 (s, 1F). 822 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.43
(br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.91 (d, J = 1.17 Hz, 1H),
8.49 (d, J = 1.37 Hz, 1H), (fluoromethyl)-5-methyl-2-thia-4- 8.04
(dd, J = 2.74, 7.43 Hz, 1H), 7.78 (td, J = 3.47,
azabicyclo[4.1.0]hept-3-en-5-yl)- 8.51 Hz, 1H), 7.16 (dd, J = 8.80,
11.93 Hz, 1H), 4-fluorophenyl)-5-(2-propyn-1- 6.08 (br., 2H), 5.15
(d, J = 2.35 Hz, 2H), 4.34-4.65 yloxy)-2-pyrazinecarboxamide (m,
2H), 3.65 (t, J = 2.45 Hz, 1H), 1.78-1.87 (m, 1H), 1.61 (s, 3H),
1.00 (m, 1H), 0.69 (m, 1H). 826 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.49 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.93 (d, J =
1.37 Hz, 1H), 8.63 (d, J = 1.17 Hz, 1H),
(fluoromethyl)-5-methyl-2-thia-4- 8.05 (dd, J = 2.74, 7.43 Hz, 1H),
7.79 (td, J = 3.72, azabicyclo[4.1.0]hept-3-en-5-yl)- 8.22 Hz, 1H),
7.17 (dd, J = 8.80, 12.13 Hz, 1H), 4-fluorophenyl)-5-(2,2,2- 6.08
(br., 2H), 5.18 (q, J = 8.80 Hz, 2H), 4.33-4.66 trifluoroethoxy)-2-
(m, 2H), 1.83 (m, 1H), 1.61 (s, 3H), 1.00 (m, 1H),
pyrazinecarboxamide 0.68 (m, 1H). .sup.19F NMR (377 MHz,
DMSO-d.sub.6) .delta. -72.12 (s, 3F), -116.54 (s, 1F), -211.45 (s,
1F). 829 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.37 (br.,
1H), N-(3-((1S,5S,6S)-3-amino-1- 8.29 (s, 1H), 7.90-7.99 (m, 1H),
7.63-7.85 (m, (fluoromethyl)-5-methyl-2-thia-4- 1H), 7.14 (dd, J =
8.80, 12.13 Hz, 1H), 6.08 (br., azabicyclo[4.1.0]hept-3-en-5-yl)-
2H), 5.11 (d, J = 2.35 Hz, 2H), 4.25-4.64 (m, 2H),
4-fluorophenyl)-3-methyl-5-(2- 3.62 (t, J = 2.35 Hz, 1H), 2.76 (s,
3H), 1.82 (m, propyn-1-yloxy)-2- 1H), 1.60 (s, 3H), 0.99 (m, 1H),
0.66 (m, 1H). .sup.19F pyrazinecarboxamide NMR (376 MHz,
DMSO-d.sub.6) .delta. -116.96 (s, 1F), -211.47 (s, 1F). 830 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.39 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.30 (s, 1H), 7.71-7.81 (m, 2H), 7.17
(dd, J = 8.71, (difluoromethyl)-5-methyl-2-thia- 11.84 Hz, 1H),
6.26 (br., 2H), 5.79-6.14 (m, 1H), 4-azabicyclo[4.1.0]hept-3-en-5-
5.12 (d, J = 2.35 Hz, 2H), 3.63 (t, J = 2.35 Hz, 1H),
yl)-4-fluorophenyl)-3-methyl-5- 2.76 (s, 3H), 1.90 (m, 1H), 1.65
(s, 3H), 1.29 (m, (2-propyn-1-yloxy)-2- 1H), 0.72 (m, 1H). .sup.19F
NMR (377 MHz, DMSO-d.sub.6) pyrazinecarboxamide .delta. -115.05(d,
.sup.1J = 273.09 Hz, 1F), -116.49 (s, 1F), -118.18 (d, .sup.1J =
273.09 Hz, 1F). 831 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.46 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.91 (d, J = 1.17 Hz,
1H), 8.61 (d, J = 1.17 Hz, 1H), (methoxymethyl)-5-methyl-2- 8.04
(dd, J = 2.74, 7.24 Hz, 1H), 7.76 (m, 1H), 7.15
thia-4-azabicyclo[4.1.0]hept-3- (m, 1H), 5.95 (br., 2H), 5.15 (m,
2H), 3.56 (d, en-5-yl)-4-fluorophenyl)-5-(2,2,2- J = 10.76 Hz, 1H),
3.35 (d, J = 10.95 Hz, 2H), 3.32 trifluoroethoxy)-2- (s, 3H), 1.67
(m, 1H), 1.60 (s, 3H), 0.87 (m, 1H), pyrazinecarboxamide 0.62 (m,
1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -76.94 (s, 3F),
-116.69 (s, 1F). 832 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.37 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.30 (s, 1H), 7.92
(dd, J = 2.74, 7.24 Hz, 1H), 7.78 (methoxymethyl)-5-methyl-2- (m,
1H), 7.14 (dd, J = 8.90, 12.03 Hz, 1H), 5.97
thia-4-azabicyclo[4.1.0]hept-3- (br., 2H), 5.13 (d, J = 2.35 Hz,
2H), 3.63 (t, J = 2.35 en-5-yl)-4-fluorophenyl)-3- Hz, 1H), 3.57
(d, J = 10.76 Hz, 1H), 3.36 (d, methyl-5-(2-propyn-1-yloxy)-2- J =
11.15 Hz, 1H), 3.33 (s, 3H), 2.77 (s, 3H), 1.69 pyrazinecarboxamide
(m, 1H), 1.60 (s, 3H), 0.85 (dd, J = 5.28, 9.19 Hz, 1H), 0.61 (t, J
= 5.77 Hz, 1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta.
-117.09 (s, 1F). 833 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.54 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.79 (d, J = 2.35 Hz, 1H), 8.13-8.28
(m, 2H), 8.04 (methoxymethyl)-5-methyl-2- (dd, J = 2.84, 7.34 Hz,
1H), 7.81 (td, J = 3.67, 8.31 thia-4-azabicyclo[4.1.0]hept-3- Hz,
1H), 7.15 (m, 1H), 5.98 (br., 2H), 3.58 (d,
en-5-yl)-4-fluorophenyl)-5- J = 10.76 Hz, 1H), 3.40 (d, J = 10.76
Hz, 1H), 3.35 chloro-2-pyridinecarboxamide (s, 3H), 1.68 (t, J =
7.73 Hz, 1H), 1.61 (s, 3H), 0.86 (dd, J = 5.09, 8.61 Hz, 1H), 0.63
(t, J = 5.67 Hz, 1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta.
-116.67 (s, 1F). 834 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
10.41 (br., 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.91 (d, J = 1.37 Hz,
1H), 8.49 (d, J = 1.17 Hz, 1H), (methoxymethyl)-5-methyl-2- 8.05
(dd, J = 2.74, 7.43 Hz, 1H), 7.78 (td, J = 3.52,
thia-4-azabicyclo[4.1.0]hept-3- 8.41 Hz, 1H), 7.15 (dd, J = 8.80,
11.93 Hz, 1H), en-5-yl)-4-fluorophenyl)-5-(2- 5.97 (br., 2H), 5.15
(d, J = 2.35 Hz, 2H), 3.67 (m, propyn-1-yloxy)-2- 1H), 3.57 (d, J =
10.76 Hz, 1H), 3.42 (d, J = 10.76 pyrazinecarboxamide Hz, 1H), 3.4
(s, 3H), 1.68 (m, 1H), 1.61 (s, 3H), 0.85 (m, 1H), 0.67 (m, 1H).
.sup.19F NMR (377 MHz, DMSO-d.sub.6) .delta. -116.78 (s, 1F). 835
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.38 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.35 (s, 1H), 8.20 (d, J = 0.78 Hz,
1H), 7.92 (dd, (methoxymethyl)-5-methyl-2- J = 2.74, 7.43 Hz, 1H),
7.78 (td, J = 3.50, 8.66 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1H),
7.30 (m, 1H), 7.10 (m, 1H), 5.97 (br., 2H),
en-5-yl)-4-fluorophenyl)-3- 5.60 (s, 2H), 3.56 (d, J = 10.70 Hz,
1H), 3.37 (d, methyl-5-(1,3-oxazol-2- J = 10.70 Hz, 1H), 3.31 (s,
3H), 2.75 (s, 3H), 1.70 ylmethoxy)-2- (m, 1H), 1.60 (s, 3H), 0.80
(m, 1H), 0.60 (m, 1H). pyrazinecarboxamide .sup.19F NMR (377 MHz,
DMSO-d.sub.6) .delta. -113.44 (s, 1F). 836 .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -115.19 (d, N-(3-((1S,5S,6S)-3-amino-1- J =
273.96 Hz, 1F), -116.49 (s, 1F), -118.19 (d,
(difluoromethyl)-5-methyl-2-thia- J = 273.96 Hz, 1F). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 4-azabicyclo[4.1.0]hept-3-en-5-
10.39 (br., 1H), 8.34 (s, 1H), 8.19 (m, 1H), 7.74-
yl)-4-fluorophenyl)-3-methyl-5- 7.86 (m, 2H), 7.29 (m, 1H), 7.15
(dd, J = 8.71, (1,3-oxazol-2-ylmethoxy)-2- 11.84 Hz, 1H), 6.25
(br., 2H), 5.69-6.11 (m, 1H), pyrazinecarboxamide 5.58 (s, 2H),
2.73 (s, 3H), 1.90 (m, 1H), 1.63 (s, 3H), 1.27 (m, 1H), 0.68 (m,
1H). 837 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.38 (br.,
1H), N-(3-((1S,5S,6S)-3-amino-1- 8.34 (s, 1H), 8.19 (s, 1H), 7.91
(dd, J = 2.74, 7.43 (fluoromethyl)-5-methyl-2-thia-4- Hz, 1H), 7.78
(td, J = 3.64, 8.17 Hz, 1H), 7.29 (s,
azabicyclo[4.1.0]hept-3-en-5-yl)- 1H), 7.14 (dd, J = 8.80, 12.13
Hz, 1H), 6.08 (br., 4-fluorophenyl)-3-methyl-5-(1,3- 2H), 5.59 (s,
2H), 4.35-4.64 (m, 2H), 2.74 (s, 3H), oxazol-2-ylmethoxy)-2- 1.80
(m, 1H), 1.60 (s, 3H), 0.99 (dd, J = 5.38, 9.29 pyrazinecarboxamide
Hz, 1H), 0.66 (q, J = 5.28 Hz, 1H). .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -116.92 (s, 1F), -211.46 (s, 1F). 838 .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 10.62 (br., 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.91 (d, J = 0.98 Hz, 1H), 8.48 (d, J =
0.98 Hz, 1H), (fluoromethyl)-5-methyl-2-thia-4- 7.79-7.97 (m, 2H),
6.11 (br., 2H), 4.32-4.63 (m, azabicyclo[4.1.0]hept-3-en-5-yl)-
2H), 3.63 (s, 1H), 1.78 (m, 1H), 1.62 (s, 3H), 1.06
4,5-difluorophenyl)-5-(1,1- (m, 1H), 0.73 (m, 1H). .sup.19F NMR
(376 MHz, dideuterium-prop-2-yn-1-yloxy)- DMSO-d.sub.6) .delta.
-138.46 (d, J = 22.55 Hz, 1F), -143.63 2-pyrazinecarboxamide (d, J
= 22.55 Hz, 1F), -211.58 (s, 1F). 839 .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -115.45 (d, N-(3-((1S,5S,6S)-3-amino-1-
.sup.1J = 273.96 Hz, 1F), -118.24 (d, .sup.1J = 273.96 Hz,
(difluoromethyl)-5-methyl-2-thia- 1F), -138.30 (d, .sup.2J = 22.54
Hz, 1F), -143.10 (d, .sup.2J = 22.54
4-azabicyclo[4.1.0]hept-3-en-5- Hz, 1F). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.64 yl)-4,5-difluorophenyl)-5-(1,1- (br.,
1H), 8.90 (d, J = 1.17 Hz, 1H), 8.48 (d, J = 1.17
dideuterium-prop-2-yn-1-yloxy)- Hz, 1H), 7.92 (ddd, J = 2.54, 6.85,
12.32 Hz, 1H), 2-pyrazinecarboxamide 7.82 (d, J = 5.87 Hz, 1H),
6.28 (br., 2H), 5.68-6.13 (m, 1H), 3.63 (s, 1H), 1.90 (m, 1H), 1.65
(s, 3H), 1.33 (m, 1H), 0.76 (m, 1H). 840 .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -138.54 (d, N-(3-((1S,5S,6S)-3-amino-1- J =
22.54 Hz, 1F), -143.79 (d, J = 22.54 Hz, 1F). .sup.1H
(methoxy)-5-methyl-2-thia-4- NMR (400 MHz, DMSO-d.sub.6) .delta.
10.61 (s, 1H), 8.90 azabicyclo[4.1.0]hept-3-en-5-yl)- (d, J = 0.98
Hz, 1H), 8.48 (d, J = 1.17 Hz, 1H), 7.70-
4,5-difluorophenyl)-5-(1,1- 7.99 (m, 2H), 5.99 (br., 2H), 3.63 (s,
1H), 3.57 (d, dideuterium-prop-2-yn-1- J = 10.95 Hz, 1H), 3.36 (d,
J = 10.95 Hz, 1H), 3.32 yloxy)pyrazine-2-carboxamide (s, 3H), 1.63
(m, 1H), 1.61 (s, 3H), 0.90 (m, 1H), 0.65 (m, 1H). 860 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.60- N-(3-((1S,5S,6S)-3-amino-1-
9.83 (m, 1H), 8.08 (s, 1H), 8.03 (ddd, J = 2.74, 6.85,
(difluoromethyl)-5-methyl-2-thia- 11.93 Hz, 1H), 7.71 (d, J = 0.78
Hz, 1H), 7.12-7.21 4-azabicyclo[4.1.0]hept-3-en-5- (m, 2H),
5.42-5.96 (m, 1H), 5.57 (s, 2H), 2.93 (s,
yl)-4,5-difluorophenyl)-3-methyl- 3H), 1.99 (dd, J = 7.34, 9.68 Hz,
1H), 1.78 (s, 3H), 5-(1,3-oxazol-2-ylmethoxy)-2- 1.35 (dd, J =
6.26, 9.98 Hz, 1H), 0.85 (dt, J = 3.03, pyrazinecarboxamide 6.60
Hz, 1H) 861 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.75 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.05 (s, 1H), 7.97-8.14 (m, 1H),
7.17 (td, (difluoromethyl)-5-methyl-2-thia- J = 2.41, 5.70 Hz, 1H),
5.42-5.96 (m, 1H), 5.08 (d, 4-azabicyclo[4.1.0]hept-3-en-5- J =
2.34 Hz, 2H), 2.95 (s, 3H), 2.54 (t, J = 2.41 Hz,
yl)-4,5-difluorophenyl)-3-methyl- 1H), 1.95-2.06 (m, 1H), 1.78 (d,
J = 1.02 Hz, 3H), 5-(2-propyn-1-yloxy)-2- 1.35 (dd, J = 6.28, 9.79
Hz, 1H), 0.80-0.91 (m, 1H) pyrazinecarboxamide 862 .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta. 9.81 (s, N-(3-((1S,5S,6S)-3-amino-1-
1H), 8.02-8.14 (m, 2H), 7.21-7.30 (m, 1H), 5.08
(methoxymethyl)-5-methyl-2- (d, J = 2.48 Hz, 2H), 3.64 (d, J =
10.52 Hz, 1H), 3.41 thia-4-azabicyclo[4.1.0]hept-3- (s, 3H), 3.35
(d, J = 10.67 Hz, 1H), 2.95 (s, 3H),
en-5-yl)-4,5-difluorophenyl)-3- 2.53 (t, J = 2.41 Hz, 1H),
1.77-1.87 (m, 1H), 1.75 methyl-5-(2-propyn-1-yloxy)-2- (d, J = 1.17
Hz, 3H), 0.95 (dd, J = 5.85, 9.35 Hz, 1H), pyrazinecarboxamide
0.77-0.84 (m, 1H) 863 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.80 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.10 (s, 1H), 8.01-8.08
(m, 1H), 7.71 (d, (methoxymethyl)-5-methyl-2- J = 0.78 Hz, 1H),
7.30 (td, J = 2.37, 5.62 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3-
7.18 (s, 1H), 5.57 (s, 2H), 3.65 (d, J = 10.56 Hz,
en-5-yl)-4,5-difluorophenyl)-3- 1H), 3.41 (s, 3H), 3.35 (d, J =
10.76 Hz, 1H), 2.94 methyl-5-(1,3-oxazol-2- (s, 3H), 1.80 (ddd, J =
1.17, 6.65, 9.39 Hz, 1H), ylmethoxy)-2- 1.73 (d, J = 0.98 Hz, 3H),
0.91 (dd, J = 5.97, 9.49 Hz, pyrazinecarboxamide 1H), 0.76-0.84 (m,
1H) 864 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.79 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.00-8.19 (m, 2H), 7.64 (d, J =
0.88 Hz, 1H), (methoxymethyl)-5-methyl-2- 7.30 (td, J = 2.43, 5.52
Hz, 1H), 7.12 (d, J = 0.73 Hz, thia-4-azabicyclo[4.1.0]hept-3- 1H),
6.45 (q, J = 6.72 Hz, 1H), 3.66 (d, J = 10.38 Hz,
en-5-yl)-4,5-difluorophenyl)-3- 1H), 3.41 (s, 3H), 3.35 (d, J =
10.67 Hz, 1H), 2.90 methyl-5-((1S)-1-(1,3-oxazol-2- (s, 3H), 1.82
(d, J = 6.72 Hz, 4H), 1.72 (d, J = 1.02 yl)ethoxy)-2- Hz, 3H), 0.90
(dd, J = 5.85, 9.35 Hz, 1H), 0.75-0.84 pyrazinecarboxamide (m, 1H)
913 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.62 (s, 1H),
(1S,5S,6S)-3-amino-5-(2,3- 8.90 (d, J = 1.17 Hz, 1H), 8.49 (d, J =
1.17 Hz, 1H), difluoro-5-(((5-(2-propyn-1- 7.90 (ddd, J = 2.54,
6.85, 12.52 Hz, 1H), 7.82 (d, yloxy)-2- J = 5.87 Hz, 1H), 6.24 (s,
2H), 5.14 (d, J = 2.35 Hz, pyrazinyl)carbonyl)amino)phenyl)- 2H),
3.59-3.66 (m, 1H), 3.06 (br.s., 6H), 2.04 (t,
N,N,5-trimethyl-2-thia-4- J = 8.31 Hz, 1H), 1.69 (s, 3H), 1.32 (dd,
J = 5.48, azabicyclo[4.1.0]hept-3-ene-1- 9.59 Hz, 1H), 0.80 (t, J =
6.26 Hz, 1H) carboxamide 914 .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.64 (s, 1H), (1S,5S,6S)-3-amino-5-(2,3- 8.91 (d, J = 1.17 Hz,
1H), 8.49 (d, J = 1.37 Hz, 1H), difluoro-5-(((5-(2-propyn-1-
7.90-7.96 (m, 1H), 7.88 (d, J = 6.09 Hz, 1H), 7.68 yloxy)-2- (q, J
= 4.17 Hz, 1H), 6.14 (s, 2H), 5.14 (d, J = 2.35
pyrazinyl)carbonyl)amino)phenyl)- Hz, 2H), 3.65 (t, J = 2.35 Hz,
1H), 2.62 (d, J = 4.30 N,5-dimethyl-2-thia-4- Hz, 3H), 2.09-2.16
(m, 1H), 1.63 (s, 3H), 1.43 (dd, azabicyclo[4.1.0]hept-3-ene-1- J =
5.09, 9.59 Hz, 1H), 0.81-0.90 (m, 1H) carboxamide 919 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.64 (s, 1H),
(1S,5S,6S)-3-amino-5-(2,3- 8.91 (d, J = 1.17 Hz, 1H), 8.49 (d, J =
1.37 Hz, 1H), difluoro-5-(((5-(2-propyn-1- 7.87-7.97 (m, 2H), 7.28
(br.s., 1H), 7.21 (br.s., yloxy)-2- 1H), 6.10 (br.s., 2H), 5.15 (d,
J = 2.54 Hz, 2H), pyrazinyl)carbonyl)amino)phenyl)- 3.65 (t, J =
2.45 Hz, 1H), 2.16 (t, J = 8.51 Hz, 1H), 5-methyl-2-thia-4- 1.63
(s, 3H), 1.42 (dd, J = 4.99, 9.49 Hz, 1H), 0.89
azabicyclo[4.1.0]hept-3-ene-1- (t, J = 6.06 Hz, 1H) carboxamide 922
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.69 (s, 1H),
(1S,5S,6S)-3-amino-5-(2,3- 8.93 (d, J = 1.37 Hz, 1H), 8.58 (d, J =
1.17 Hz, 1H), difluoro-5-(((5-(2,2,3,3- 7.92 (ddd, J = 2.64, 6.75,
12.13 Hz, 1H), 7.84 (d, tetrafluoropropoxy)-2- J = 5.87 Hz, 1H),
6.57-6.90 (m, 1H), 6.25 (br.s., pyrazinyl)carbonyl)amino)phenyl)-
2H), 5.05 (t, J = 14.18 Hz, 2H), 3.07 (br.s., 3H),
N,N,5-trimethyl-2-thia-4- 2.94 (br.s., 3H), 2.05 (t, J = 8.22 Hz,
1H), 1.71 (s, azabicyclo[4.1.0]hept-3-ene-1- 3H), 1.34 (dd, J =
5.58, 9.49 Hz, 1H), 0.81 (t, carboxamide J = 6.16 Hz, 1H) 924
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.66 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.90 (d, J = 1.37 Hz, 1H), 8.48 (d, J =
1.37 Hz, 1H), cyano-5-methyl-2-thia-4- 7.91-7.94 (m, 1H), 7.75 (d,
J = 5.67 Hz, 1H), 6.54 azabicyclo[4.1.0]hept-3-en-5-yl)- (s, 2H),
5.14 (d, J = 2.35 Hz, 2H), 3.64 (t, J = 2.45
4,5-difluorophenyl)-5-(2-propyn- Hz, 1H), 2.38 (dd, J = 7.82, 9.59
Hz, 1H), 1.85-1.93 1-yloxy)-2-pyrazinecarboxamide (m, 1H), 1.75 (s,
3H), 1.03-1.10 (m, 1H) 926 .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.69 (s, 1H), (1S,5S,6S)-3-amino-5-(2,3- 8.93 (d, J = 1.17 Hz,
1H), 8.63 (d, J = 1.37 Hz, 1H), difluoro-5-(((5-(2,2,2- 7.92 (ddd,
J = 2.64, 6.80, 12.28 Hz, 1H), 7.84 (d, trifluoroethoxy)-2- J =
5.87 Hz, 1H), 6.25 (s, 2H), 5.18 (q, J = 8.80 Hz,
pyrazinyl)carbonyl)amino)phenyl)- 2H), 3.07 (br.s., 3H), 2.92
(br.s., 3H), 2.05 (t, N,N,5-trimethyl-2-thia-4- J = 8.31 Hz, 1H),
1.71 (s, 3H), 1.34 (dd, J = 5.38, azabicyclo[4.1.0]hept-3-ene-1-
9.49 Hz, 1H), 0.77-0.85 (m, 1H) carboxamide 927 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 10.47 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.90 (d, J = 1.37 Hz, 1H), 8.49 (d, J = 1.37 Hz, 1H),
cyano-5-methyl-2-thia-4- 7.90 (dd, J = 2.64, 7.34 Hz, 1H),
7.77-7.82 (m, 1H), azabicyclo[4.1.0]hept-3-en-5-yl)- 7.19 (dd, J =
8.80, 11.74 Hz, 1H), 6.53 (s, 2H), 5.15
4-fluorophenyl)-5-(2-propyn-1- (d, J = 2.35 Hz, 2H), 3.65 (t, J =
2.45 Hz, 1H), 2.38 yloxy)-2-pyrazinecarboxamide
(dd, J = 7.92, 9.68 Hz, 1H), 1.87 (dd, J = 5.87, 9.78 Hz, 1H), 1.75
(s, 3H), 1.03 (t, J = 6.55 Hz, 1H) 929 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.60 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.79
(d, J = 5.87 Hz, 1H), 8.12-8.24 (m, 2H), 7.90
cyano-5-methyl-2-thia-4- (dd, J = 2.74, 7.24 Hz, 1H), 7.80-7.86 (m,
1H), 7.20 azabicyclo[4.1.0]hept-3-en-5-yl)- (dd, J = 8.80, 11.74
Hz, 1H), 6.53 (s, 2H), 2.38 (dd, 4-fluorophenyl)-5-chloro-2- J =
7.92, 9.68 Hz, 1H), 1.87 (dd, J = 5.87, 9.78 Hz,
pyridinecarboxamide 1H), 1.75 (s, 3H), 1.03 (t, J = 6.55 Hz, 1H)
930 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.76 (s, 1H),
(1S,5S,6S)-3-amino-5-(5-(((5- 8.80 (s, 1H), 8.15-8.24 (m, 2H), 7.94
(ddd, J = 2.54, chloro-2- 6.80, 12.37 Hz, 1H), 7.83 (d, J = 5.58
Hz, 1H), 6.26 pyridinyl)carbonyl)amino)-2,3- (br.s., 2H), 3.09
(br.s., 3H), 2.93 (br.s., 3H), 2.06
difluorophenyl)-N,N,5-trimethyl- (t, J = 8.41 Hz, 1H), 1.71 (s,
3H), 1.34 (dd, J = 5.48, 2-thia-4-azabicyclo[4.1.0]hept-3- 9.59 Hz,
1H), 0.81 (t, J = 6.26 Hz, 1H) ene-1-carboxamide 932 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.81 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.80 (s, 1H), 8.19-8.24 (m, 1H),
8.14-8.19 (m, cyano-5-methyl-2-thia-4- 1H), 7.97 (ddd, J = 2.54,
6.80, 12.37 Hz, 1H), 7.74- azabicyclo[4.1.0]hept-3-en-5-yl)- 7.79
(m, 1H), 6.56 (s, 2H), 2.40 (dd, J = 7.82, 9.78
4,5-difluorophenyl)-5-chloro-2- Hz, 1H), 1.90 (dd, J = 6.06, 9.78
Hz, 1H), 1.77 (s, pyridinecarboxamide 3H), 1.09 (t, J = 6.75 Hz,
1H). 934 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.62 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-5- 8.90 (d, J = 1.17 Hz, 1H), 8.48 (d, J =
1.37 Hz, 1H), methyl-1-(1- 7.90 (ddd, J = 2.64, 6.75, 12.32 Hz,
1H), 7.78-7.82 pyrrolidinylcarbonyl)-2-thia-4- (m, 1H), 6.24 (s,
2H), 5.14 (d, J = 2.35 Hz, 2H), azabicyclo[4.1.0]hept-3-en-5-yl)-
3.53-3.71 (m, 3H), 3.31 (bs, 2H), 2.00-2.08 (m,
4,5-difluorophenyl)-5-(2-propyn- 1H), 1.87 (br.s., 2H), 1.81
(br.s., 2H), 1.70 (s, 1-yloxy)-2-pyrazinecarboxamide 3H), 1.34 (dd,
J = 5.38, 9.49 Hz, 1H), 0.70-0.76 (m, 1H) 935 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.74 (s, 1H), N-(3-((1S,5S,6S)-3-amino-5- 8.79
(d, J = 1.76 Hz, 1H), 8.13-8.23 (m, 2H), 7.92 methyl-1-(1- (ddd, J
= 2.54, 6.75, 12.42 Hz, 1H), 7.78-7.82 (m,
pyrrolidinylcarbonyl)-2-thia-4- 1H), 6.24 (s, 2H), 3.60 (br.s.,
2H), 3.31 (s, 2H), azabicyclo[4.1.0]hept-3-en-5-yl)- 2.03-2.09 (m,
1H), 1.87 (br.s., 2H), 1.81 (br.s., 4,5-difluorophenyl)-5-chloro-2-
2H), 1.70 (s, 3H), 1.34 (dd, J = 5.48, 9.39 Hz, 1H),
pyridinecarboxamide 0.71-0.76 (m, 1H) 940 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.72 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.92
(d, J = 1.17 Hz, 1H), 8.62 (d, J = 1.37 Hz, 1H),
cyano-5-methyl-2-thia-4- 7.94 (ddd, J = 2.64, 6.70, 12.37 Hz, 1H),
7.76 (d, azabicyclo[4.1.0]hept-3-en-5-yl)- J = 5.87 Hz, 1H), 6.54
(s, 2H), 5.17 (q, J = 9.00 Hz, 4,5-difluorophenyl)-5-(2,2,2- 2H),
2.33-2.41 (m, 1H), 1.89 (dd, J = 5.87, 9.78 Hz, trifluoroethoxy)-2-
1H), 1.75 (s, 3H), 1.07 (t, J = 6.85 Hz, 1H)
pyrazinecarboxamide
Method E: SNAr in 1,4-dioxane
Example 747:
(1R,5S,6S)-5-(2,3-difluoro-5-((2-(oxazol-2-ylmethoxy)pyrido[3,4-b]pyrazin-
-5-yl)amino)phenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-3-amine
##STR00668##
[1850] A mixture of
(1R,5S,6S)-5-(5-amino-2,3-difluorophenyl)-5-methyl-1-(methylsulfonyl)-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-3-amine (intermediate 220, 50 mg,
0.14 mmol),
2-(((5-chloropyrido[3,4-b]pyrazin-2-yl)oxy)methyl)oxazole
(intermediate 259, 42 mg, 0.16 mmol) and p-toluenesulfonic acid
monohydrate (27 mg, 0.14 mmol) in 1,4-dioxane (1.1 mL) was heated
to 60.degree. C. in an aluminum heating block for 1 h. The reaction
mixture was cooled to RT and diluted with EtOAc (25 mL) and
saturated aqueous NaHCO.sub.3 (20 mL). The layers were separated
and the aqueous layer was extracted with EtOAc (20 mL). The
combined organic layers were dried over Na.sub.2SO.sub.4, filtered,
and then concentrated under reduced pressure to afford a yellow
oil. It was purified by silica gel chromatography (0-8% MeOH in
DCM) to afford
(1R,5S,6S)-5-(2,3-difluoro-5-((2-(oxazol-2-ylmethoxy)pyrido[3,4-b]pyrazin-
-5-yl)amino)phenyl)-5-methyl-1-(methylsulfonyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-3-amine (Example 747, 20 mg, 0.035 mmol, 24% yield) as
yellow solid. MS m/z=574.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.67 (s, 1H), 8.66 (s, 1H), 8.30 (d, J=5.87
Hz, 1H), 8.13-8.23 (m, 2H), 7.89 (d, J=5.48 Hz, 1H), 7.31 (s, 1H),
7.11 (d, J=5.87 Hz, 1H), 6.66 (s, 2H), 5.66 (s, 2H), 3.11 (s, 3H),
2.17 (dd, J=7.63, 9.98 Hz, 1H), 1.91-2.00 (m, 1H), 1.76 (s, 3H),
0.94 (t, J=6.55 Hz, 1H).
[1851] Using procedures analogous or similar to the general SNAr
Method E described above, the appropriate aniline and ArX (X=Cl/Br)
intermediates were reacted to provide the 15 examples listed in
Table 5 and Table 5'.
TABLE-US-00010 TABLE 5 Observed Ex. No. Chemical Structure [M + H]+
632 ##STR00669## 532.1 661 ##STR00670## 502 664 ##STR00671## 545
782 ##STR00672## 520 788 ##STR00673## 534 791 ##STR00674## 518 794
##STR00675## 518 796 ##STR00676## 561 915 ##STR00677## 510 916
##STR00678## 478 920 ##STR00679## 510 921 ##STR00680## 478.1 925
##STR00681## 538.2 939 ##STR00682## 535.1 943 ##STR00683## 497
TABLE-US-00011 TABLE 5' Ex. No. .sup.1H-NMR Chemical Name 632
.sup.1H NMR (CHLOROFORM-d) Shift: 8.56 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-5- 8.32 (s, 1H), 8.23 (d, J = 5.9 Hz, 1H),
8.04-8.16 (m, methyl-1-(1- 1H), 7.57 (dd, J = 6.5, 2.3 Hz, 1H),
6.95-7.13 (m, 2H), pyrrolidinylcarbonyl)-2-thia- 5.15 (d, J = 2.0
Hz, 2H), 3.42-3.82 (m, 4H), 2.28 (t, 4-azabicyclo[4.1.0]hept-3-en-
J = 8.2 Hz, 1H), 1.84-2.00 (m, 7H), 1.45 (dd, J = 9.7, 5.8
5-yl)-4-fluorophenyl)-2-(2- Hz, 1H), 0.85 (t, J = 6.2 Hz, 1H)
propyn-1-yloxy)pyrido[3,4- b]pyrazin-5-amine 661 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 1.68 ((1S,5S,6R)-3-amino-7,7- (s, 3
H) 2.51 (dd, J = 15.06, 2.54 Hz, 1 H) 2.57 (t,
difluoro-5-(2-fluoro-5-((2-(2- J = 2.45 Hz, 1 H) 3.89-4.05 (m, 2 H)
4.56 (br s, 2 H) propyn-1-yloxy)pyrido[3,4- 5.16 (d, J = 2.35 Hz, 2
H) 7.10 (d, J = 5.87 Hz, 1 H) 8.28 b]pyrazin-5-yl)amino)-3- (d, J =
5.87 Hz, 1 H) 8.32-8.40 (m, 2 H) 8.58 (s, 1 H)
pyridinyl)-5-methyl-2-thia-4- 9.01 (t, J = 2.25 Hz, 1 H).
azabicyclo[4.1.0]hept-3-en-1- yl)methanol 664 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 1.68 ((1S,5S,6R)-3-amino-7,7- (s, 3 H)
2.51 (dd, J = 14.96, 2.64 Hz, 1 H) 3.86-4.07
difluoro-5-(2-fluoro-5-((7- (m, 2 H) 4.56 (br.s., 2 H) 5.34 (s, 2
H) 7.21 (s, 1 H) (1,3-oxazol-2- 7.63 (d, J = 2.74 Hz, 1 H) 7.74 (s,
1 H) 8.44 (dd, ylmethoxy)pyrido[3,2- J = 8.61, 2.74 Hz, 1 H) 8.61
(d, J = 2.74 Hz, 1 H) 8.75 d]pyrimidin-4-yl)amino)-3- (s, 1 H) 8.94
(s, 1 H) 8.96-8.98 (m, 1 H). pyridinyl)-5-methyl-2-thia-4-
azabicyclo[4.1.0]hept-3-en-1- yl)methanol 782 .sup.1H NMR (DMSO-d6)
.delta.: 10.11 (s, 1H), 8.67 (d, J = 2.7
N-(3-((1S,5S,6S)-3-amino-5- Hz, 1H), 8.62 (s, 1H), 8.32 (s, 1H),
8.23 (dd, J = 7.2, (fluoromethyl)-1-(1,3-oxazol- 2.7 Hz, 1H),
7.93-8.01 (m, 1H), 7.69 (d, J = 2.7 Hz, 5-yl)-2-thia-4- 1H), 7.22
(dd, J = 11.6, 8.9 Hz, 1H), 7.12 (s, 1H), 6.55
azabicyclo[4.1.0]hept-3-en-5- (s, 2H), 5.11 (d, J = 2.2 Hz, 2H),
4.64-4.93 (m, 2H), yl)-4-fluorophenyl)-7-(2- 3.74 (t, J = 2.3 Hz,
1H), 2.01-2.11 (m, 1H), 1.69 (dd, propyn-1-yloxy)pyrido[3,2- J =
9.6, 5.5 Hz, 1H), 0.89-1.02 (m, 1H) d]pyrimidin-4-amine 788 .sup.1H
NMR (DMSO-d6) .delta.: 10.10 (s, 1H), 8.67 (d, J = 2.7
N-(3-((1S,5S,6S)-3-amino-5- Hz, 1H), 8.62 (s, 1H), 8.24 (dd, J =
7.2, 2.7 Hz, 1H), (fluoromethyl)-1-(4-methyl- 8.19 (s, 1H), 8.00
(dt, J = 7.5, 4.3 Hz, 1H), 7.69 (d, 1,3-oxazol-5-yl)-2-thia-4- J =
2.7 Hz, 1H), 7.21 (dd, J = 11.7, 8.8 Hz, 1H), 6.48 (s,
azabicyclo[4.1.0]hept-3-en-5- 2H), 5.11 (d, J = 2.3 Hz, 2H),
4.68-5.00 (m, 2H), 3.74 yl)-4-fluorophenyl)-7-(2- (t, J = 2.3 Hz,
1H), 2.15 (s, 3H), 2.06-2.13 (m, 1H), propyn-1-yloxy)pyrido[3,2-
1.54 (dd, J = 9.7, 5.4 Hz, 1H), 0.94-1.03 (m, 1H)
d]pyrimidin-4-amine 791 .sup.1H NMR (DMSO-d6) .delta.: 10.02 (s,
1H), 8.66 (d, J = 2.7 (1S,5S,6S)-3-amino-N- Hz, 1H), 8.60 (s, 1H),
8.10 (dd, J = 7.2, 2.7 Hz, 1H), cyclopropyl-5-(2-fluoro-5- 7.94
(dt, J = 8.5, 3.6 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H),
((7-(2-propyn-1- 7.65 (d, J = 3.7 Hz, 1H), 7.18 (dd, J = 11.8, 8.7
Hz, 1H), yloxy)pyrido[3,2- 6.11 (br.s., 2H), 5.11 (d, J = 2.3 Hz,
2H), 3.74 (t, J = 2.3 d]pyrimidin-4- Hz, 1H), 2.65 (td, J = 7.3,
3.6 Hz, 1H), 2.16 (t, J = 8.4 yl)amino)phenyl)-5-methyl- Hz, 1H),
1.42 (dd, J = 9.3, 5.0 Hz, 1H), 0.84 (t, J = 6.0 2-thia-4- Hz, 1H),
0.57-0.65 (m, 2H), 0.44-0.51 (m, 2H) azabicyclo[4.1.0]hept-3-ene-
1-carboxamide 794 .sup.1H NMR (DMSO-d6) .delta.: 9.36 (s, 1H), 8.60
(s, 1H), (1S,5S,6S)-3-amino-N- 8.24 (d, J = 5.7 Hz, 1H), 7.98-8.09
(m, 2H), 7.64 (d, cyclopropyl-5-(2-fluoro-5- J = 3.7 Hz, 1H),
7.10-7.19 (m, 1H), 7.06 (d, J = 5.9 Hz, ((2-(2-propyn-1- 1H), 6.10
(s, 2H), 5.19 (d, J = 2.2 Hz, 2H), 3.66 (s, 1H), yloxy)pyrido
[3,4-b]pyrazin- 2.61-2.72 (m, 1H), 2.15 (t, J = 8.4 Hz, 1H), 1.63
(s, 5-yl)amino)phenyl)-5- 3H), 1.41 (dd, J = 9.7, 5.4 Hz, 1H), 0.84
(t, J = 6.0 Hz, methyl-2-thia-4- 1H), 0.61 (d, J = 4.7 Hz, 2H),
0.48 (d, J = 2.7 Hz, 2H) azabicyclo[4.1.0]hept-3-ene- 1-carboxamide
796 .sup.1H NMR (DMSO-d6) .delta.: 9.38 (s, 1H), 8.66 (s, 1H),
(1S,5S,6S)-3-amino-N- 8.25 (d, J = 5.7 Hz, 1H), 8.23 (d, J = 0.8
Hz, 1H), 7.94- cyclopropyl-5-(2-fluoro-5- 8.13 (m, 2H), 7.66 (d, J
= 3.9 Hz, 1H), 7.32 (d, J = 0.8 ((2-(1,3-oxazol-2- Hz, 1H), 7.15
(dd, J = 11.8, 8.7 Hz, 1H), 7.06 (d, J = 5.7 ylmethoxy)pyrido[3,4-
Hz, 1H), 6.12 (s, 2H), 5.68 (s, 2H), 2.61-2.72 (m, 1H),
b]pyrazin-5- 2.16 (dd, J = 9.5, 7.5 Hz, 1H), 1.64 (s, 3H), 1.43
(dd, yl)amino)phenyl)-5-methyl- J = 9.6, 5.1 Hz, 1H), 0.80-0.89 (m,
1H), 0.58-0.67 (m, 2-thia-4- 2H), 0.45-0.52 (m, 2H)
azabicyclo[4.1.0]hept-3-ene- 1-carboxamide 915 .sup.1H NMR (400
MHz, DMSO-d6) .delta. 9.59 (s, 1H), 8.64 (1S,5S,6S)-3-amino-5-(2,3-
(s, 1H), 8.28-8.35 (m, 2H), 7.91 (d, J = 5.83 Hz, 1H),
difluoro-5-((2-(2-propyn-1- 7.69 (t, J = 5.68 Hz, 1H), 7.14 (d, J =
5.87 Hz, 1H), 6.17 yloxy)pyrido[3,4-b]pyrazin- (br.s., 2H), 5.21
(d, J = 2.35 Hz, 2H), 3.68 (t, J = 2.45 5-yl)amino)phenyl)-N,5- Hz,
1H), 2.64 (d, J = 4.50 Hz, 3H), 2.14 (dd, J = 7.63,
dimethyl-2-thia-4- 9.19 Hz, 1H), 1.66 (s, 3H), 1.48 (dd, J = 5.09,
9.59 Hz, azabicyclo[4.1.0]hept-3-ene- 1H), 0.85-0.93 (m, 1H)
1-carboxamide 916 .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.63 (s,
1H), 8.62 (1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.30 (d, J = 5.87 Hz,
1H), 8.24 (ddd, J = 2.64, difluoro-5-((2-(2-propyn-1- 6.80, 13.06
Hz, 1H), 7.88 (d, J = 5.81 Hz, 1H), 7.13 (d,
yloxy)pyrido[3,4-b]pyrazin- J = 5.67 Hz, 1H), 6.60 (s, 2H), 5.20
(d, J = 2.35 Hz, 2H), 5-yl)amino)phenyl)-5- 3.67 (t, J = 2.45 Hz,
1H), 2.32-2.42 (m, 1H), 1.94 (dd, methyl-2-thia-4- J = 5.87, 9.78
Hz, 1H), 1.78 (s, 3H), 1.07 (t, J = 6.75 Hz,
azabicyclo[4.1.0]hept-3-ene- 1H) 1-carbonitrile 920 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 9.57 (s, J = 5.25,
(1S,5S,6S)-3-amino-5-(5-((2- 5.25 Hz, 1H), 8.62 (s, 1H), 8.29-8.37
(m, 2H), 7.91 (2-butyn-1-yloxy)pyrido[3,4- (br.s., 1H), 7.30
(br.s., 1H), 7.22 (br.s., 1H), 7.14 (d, b]pyrazin-5-yl)amino)-2,3-
J = 5.80 Hz, 1H), 6.13 (br.s., 2H), 5.15-5.19 (m, 2H),
difluorophenyl)-5-methyl-2- 2.18 (t, J = 8.51 Hz, 1H), 1.89 (t, J =
2.35 Hz, 3H), 1.66 thia-4-azabicyclo[4.1.0]hept- (s, 3H), 1.48 (d,
J = 4.30 Hz, 1H), 0.92 (br.s., 1H) 3-ene-1-carboxamide 921 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 10.25 (s, 1H), 8.68
(1S,5S,6S)-3-amino-5-(2,3- (s, 2H), 8.15 (ddd, J = 2.74, 6.70,
12.67 Hz, 1H), 7.99 difluoro-5-((7-(2-propyn-1- (d, J = 5.90 Hz,
1H), 7.71 (d, J = 2.93 Hz, 1H), 6.61 (s, yloxy)pyrido[3,2- 2H),
5.12 (d, J = 2.35 Hz, 2H), 3.74 (t, J = 2.25 Hz, 1H),
d]pyrimidin-4- 2.32-2.42 (m, 1H), 1.95 (dd, J = 6.06, 9.78 Hz, 1H),
yl)amino)phenyl)-5-methyl- 1.78 (s, 3H), 1.07 (t, J = 6.75 Hz, 1H)
2-thia-4- azabicyclo[4.1.0]hept-3-ene- 1-carbonitrile 925 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 9.56 (s, 1H), 8.60
(1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.24-8.33 (m, 2H), 7.88 (d, J =
5.48 Hz, 1H), difluoro-5-((2-(((1S)-1- 7.13 (d, J = 5.87 Hz, 1H),
6.29 (s, 2H), 5.94 (dq, methyl-2-propyn-1- J = 2.15, 6.59 Hz, 1H),
3.62 (d, J = 1.96 Hz, 1H), 3.04 yl)oxy)pyrido[3,4-b]pyrazin-
(br.s., 3H), 2.92 (br.s., 3H), 2.03-2.09 (m, 1H), 1.73
5-yl)amino)phenyl)-N,N,5- (s, 3H), 1.68 (d, J = 6.65 Hz, 3H), 1.37
(dd, J = 5.48, trimethyl-2-thia-4- 9.59 Hz, 1H), 0.81 (t, J = 6.16
Hz, 1H) azabicyclo[4.1.0]hept-3-ene- 1-carboxamide 939 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 9.63 (s, 1H), 8.63
(1S,5S,6S)-3-amino-5-(2,3- (s, 1H), 8.21-8.31 (m, 2H), 8.15 (d, J =
0.78 Hz, 1H), difluoro-5-((2-((1S)-1-(1,3- 7.87 (d, J = 5.87 Hz,
1H), 7.26 (s, 1H), 7.08 (d, J = 5.87 oxazol-2- Hz, 1H), 6.59 (s,
2H), 6.52 (q, J = 6.65 Hz, 1H), 2.37 yl)ethoxy)pyrido[3,4- (dd, J =
7.92, 9.68 Hz, 1H), b]pyrazin-5- yl)amino)phenyl)-5-methyl-
2-thia-4- azabicyclo[4.1.0]hept-3-ene- 1-carbonitrile 943 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. ppm 0.66 (t, J = 5.8
N-(3-((1S,5S,6S)-3-amino-1- Hz, 1 H), 0.92 (dd, J = 9.2, 5.3 Hz, 1
H), 1.57-1.71 (methoxymethyl)-5-methyl- (m, 4 H), 3.30 (s, 3 H),
3.36 (d, J = 11.0 Hz, 1 H), 3.57 2-thia-4- (d, J = 11.0 Hz, 1 H),
3.73 (t, J = 2.2 Hz, 1 H), 5.11 (d, azabicyclo[4.1.0]hept-3-en-5- J
= 2.3 Hz, 2 H), 6.00 (s, 2 H), 7.70 (d, J = 2.7 Hz, 1 H),
yl)-4,5-difluorophenyl)-7-(2- 7.97-8.06 (m, 1 H), 8.18 (ddd, J =
12.5, 6.8, 2.6 Hz, 1 propyn-1-yloxy)pyrido[3,2- H), 8.61-8.73 (m, 2
H), 10.16 (s, 1 H). d]pyrimidin-4-amine
Method F1: HATU Mediated Amide Formation Followed by Removal of the
Protecting Groups with H.sub.2SO.sub.4
Example 606:
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoropyridin-3-yl)-5-(prop-2-yn-1-yloxy)pyrazine-2--
carboxamide
##STR00684##
[1853] To a mixture of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)c-
arbamate (0.095 g, 0.185 mmol) and
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid (0.049 g, 0.277
mmol) in 1.0 mL of DMF was added TEA (0.051 mL, 0.369 mmol) and
HATU (0.140 g, 0.369 mmol). After stirring for 18 h, the reaction
was quenched with saturated NH.sub.4Cl solution, extracted with
EtOAc, dried over Na.sub.2SO.sub.4, filtered and evaporated to
dryness. It was purified by silica gel chromatography (12 g)
eluting with 0-50% EtOAc in hexanes to afford tert-butyl
((1S,5S,6S)-5-(2-fluoro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamido)py-
ridin-3-yl)-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en--
3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate as a brown solid.
To the brown solid was added conc. H.sub.2SO.sub.4 (0.5 mL) and the
mixture stirred at RT for 20 min. The reaction was poured onto iced
water and pH adjusted to 10-14 with 10 N NaOH solution. The
resulting basic solution was extracted with EtOAc (2.times.). The
organic phase was concentrated and the residue purified by flash
column chromatography on silica gel with ISCO eluting with 0-100%
EtOAc in hexanes to afford
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoropyridin-3-yl)-5-(prop-2-yn-1-yloxy)pyrazine-2--
carboxamide (Example 606, 18 mg, 22%). LCMS (ESI.sup.+) m/z=445.2
(M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.55 (s, 1H),
9.05 (d, J=1.32 Hz, 1H), 8.60-8.65 (m, 1H), 8.42 (dd, J=2.78, 8.62
Hz, 1H), 8.23 (d, J=1.32 Hz, 1H), 5.11 (d, J=2.48 Hz, 2H),
4.44-4.64 (m, 1H), 4.27-4.42 (m, 1H), 2.57 (t, J=2.41 Hz, 1H),
1.90-2.02 (m, 1H), 1.73 (d, J=1.17 Hz, 3H), 0.94-1.16 (m, 1H),
0.83-0.93 (m, 1H). NH.sub.2 peak is a broad peak between
3.25-4.75.
[1854] Using procedures analogous or similar to the general
amidation Method F1 described above, the appropriate aniline and
carboxylic acid intermediates were reacted to provide the 9
examples listed in Table 6 and Table 6'.
TABLE-US-00012 TABLE 6 Observed Ex. No. Chemical Structure [M + H]+
607 ##STR00685## 488 609 ##STR00686## 520.2 610 ##STR00687## 521
612 ##STR00688## 457.2 624 ##STR00689## 436.1 845 ##STR00690##
471.2 850 ##STR00691## 474 851 ##STR00692## 460.2 859 ##STR00693##
457.2
TABLE-US-00013 TABLE 6' Ex. No. .sup.1H-NMR Chemical Name 607
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.55
N-(5-((1S,5S,6S)-3-amino-1- (s, 1H), 9.03 (d, J = 1.32 Hz, 1H),
8.59-8.65 (m, (fluoromethyl)-5-methyl-2- 1H), 8.42 (dd, J = 2.78,
8.62 Hz, 1H), 8.26 (d, thia-4-azabicyclo[4.1.0]hept- J = 1.32 Hz,
1H), 7.72 (d, J = 0.73 Hz, 1H), 7.19 (s, 3-en-5-yl)-6-fluoro-3-
1H), 5.59 (s, 2H), 4.43-4.65 (m, 1H), 4.27-4.43
pyridinyl)-5-(1,3-oxazol-2- (m, 1H), 3.25-4.75 (br.s, 2H),
1.83-2.00 (m, 1H), ylmethoxy)-2- 1.72 (d, J = 1.02 Hz, 3H), 0.99
(dd, J = 6.21, 9.57 pyrazinecarboxamide Hz, 1H), 0.81-0.93 (m, 1H).
609 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.85
N-(5-((1S,5S,6S)-3-amino-1- (s, 1H), 8.65 (s, 1H), 8.66 (d, J =
3.18 Hz, 1H), (fluoromethyl)-5-methyl-2- 8.28-8.45 (m, 3H), 7.43
(dd, J = 2.85, 8.70 Hz, thia-4-azabicyclo[4.1.0]hept- 1H), 6.08 (m,
1H), 4.0-4.72 (br.s, 2H), 4.44-4.62 3-en-5-yl)-6-fluoro-3- (m, 2H),
4.21-4.44 (m, 1H), 1.93-2.06 (m, 1H), pyridinyl)-5-(2,2,3,3- 1.75
(s, 3H), 1.01 (dd, J = 6.07, 9.43 Hz, 1H), tetrafluoropropoxy)-2-
0.83-0.92 (m, 1H). pyridinecarboxamide 610 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.90 (s, 1H), N-(5-((1S,5S,6S)-3-amino-1- 8.95
(d, J = 1.37 Hz, 1H), 8.55-8.64 (m, 3H), 6.74
(fluoromethyl)-5-methyl-2- (m, 1H), 6.18 (br.s., 2H), 5.06 (t, J =
14.08 Hz, thia-4-azabicyclo[4.1.0]hept- 2H), 4.53-4.62 (m, 1H),
4.41-4.49 (m, 1H), 1.77- 3-en-5-yl)-6-fluoro-3- 1.91 (m, 1H), 1.61
(s, 3H), 1.03 (dd, J = 5.48, 9.19 pyridinyl)-5-(2,2,3,3- Hz, 1H),
0.68 (q, J = 5.28 Hz, 1H). tetrafluoropropoxy)-2-
pyrazinecarboxamide 612 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
9.38 N-(5-((1S,5S,6S)-3-amino-1- (s, 1H), 9.05 (d, J = 1.32 Hz,
1H), 8.66 (d, J = 2.63 (fluoromethyl)-5-methyl-2- Hz, 1H), 8.24 (d,
J = 1.32 Hz, 1H), 8.14 (d, J = 2.63 thia-4-azabicyclo[4.1.0]hept-
Hz, 1H), 5.11 (d, J = 2.48 Hz, 2H), 4.53 (m, 3H),
3-en-5-yl)-6-methoxy-3- 4.36 (q, J = 10.23 Hz, 1H), 4.05 (s, 3H),
2.57 (t, pyridinyl)-5-(2-propyn-1- J = 2.41 Hz, 1H), 2.16-2.25 (m,
1H), 1.74 (s, 3H), yloxy)-2-pyrazinecarboxamide 0.95 (dd, J = 5.99,
9.65 Hz, 1H), 0.75-0.85 (m, 1H). 624 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.69 N-(5-((1S,5S,6S)-3-amino-1- (s, 1H),
8.66 (d, J = 2.54 Hz, 1H), 8.54 (d, J = 2.15
(fluoromethyl)-5-methyl-2- Hz, 1H), 8.23 (d, J = 8.22 Hz, 1H), 8.16
(d, J = 2.74 thia-4-azabicyclo[4.1.0]hept- Hz, 1H), 7.86 (dd, J =
2.35, 8.41 Hz, 1H), 4.42- 3-en-5-yl)-6-methoxy-3- 4.64 (m, 3H),
4.29-4.42 (m, 1H), 4.02 (s, 3H), pyridinyl)-5-chloro-2- 2.18 (dd, J
= 7.24, 9.00 Hz, 1H), 1.71 (s, 3H), 0.90 pyridinecarboxamide (dd, J
= 5.97, 9.49 Hz, 1H), 0.72-0.83 (m, 1H). 845 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 9.81 N-(5-((1S,5S,6S)-3-amino-1- (s, 1H),
8.62-8.78 (m, 1H), 8.26 (dd, J = 2.70, 8.70
(methoxymethyl)-5-methyl-2- Hz, 1H), 8.07 (s, 1H), 5.08 (d, J =
2.48 Hz, 2H), thia-4-azabicyclo[4.1.0]hept- 3.65 (d, J = 10.67 Hz,
1H), 3.41 (s, 3H), 3.36 (d, 3-en-5-yl)-6-fluoro-3- J = 10.67 Hz,
1H), 2.96 (s, 3H), 2.54 (t, J = 2.41 Hz, pyridinyl)-3-methyl-5-(2-
1H), 1.82-1.89 (m, 1H), 1.73 (d, J = 0.88 Hz, 3H),
propyn-1-yloxy)-2- 0.92 (dd, J = 5.99, 9.35 Hz, 1H), 0.76-0.84 (m,
1H) pyrazinecarboxamide 850 .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. 9.81 N-(5-((1S,5S,6S)-3-amino-5- (s, 1H), 8.59-8.74 (m,
1H), 8.28 (dd, J = 2.70, 8.70 methyl-1- Hz, 1H), 8.07 (s, 1H), 5.08
(d, J = 2.48 Hz, 2H), (((~2~H_3_)methyloxy)methyl)- 3.66 (d, J =
10.08 Hz, 1H), 3.35 (d, J = 10.67 Hz, 2-thia-4- 1H), 2.96 (s, 3H),
2.54 (t, J = 2.41 Hz, 1H), 1.85 azabicyclo[4.1.0]hept-3-en-5- (ddd,
J = 1.39, 6.72, 9.28 Hz, 1H), 1.71 (d, J = 1.17
yl)-6-fluoro-3-pyridinyl)-3- Hz, 3H), 0.89 (dd, J = 5.99, 9.35 Hz,
1H), 0.74- methyl-5-(2-propyn-1-yloxy)- 0.83 (m, 1H)
2-pyrazinecarboxamide 851 .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. 9.52 N-(5-((1S,5S,6S)-3-amino-5- (s, 1H), 9.04 (d, J = 1.32
Hz, 1H), 8.65 (dd, methyl-1- J = 1.90, 2.63 Hz, 1H), 8.36 (dd, J =
2.78, 8.62 Hz, (((~2~H_3_)methyloxy)methyl)-2- 1H), 8.23 (d, J =
1.32 Hz, 1H), 5.10 (d, J = 2.48 Hz, thia-4- 2H), 3.66 (d, J = 10.08
Hz, 1H), 3.36 (d, J = 10.67 azabicyclo[4.1.0]hept-3-en-5- Hz, 1H),
2.55 (t, J = 2.41 Hz, 1H), 1.79-1.92 (m,
yl)-6-fluoro-3-pyridinyl)-5-(2- 2H), 1.71 (d, J = 1.17 Hz, 3H),
0.86-0.96 (m, 1H), propyn-1-yloxy)-2- 0.72-0.83 (m, 1H)
pyrazinecarboxamide 859 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.52 N-(5-((1S,5S,6S)-3-amino-1- (s, 1H), 9.04 (s, 1H), 8.65 (s,
1H), 8.37 (dd, (methoxymethyl)-5-methyl-2- J = 2.15, 8.41 Hz, 1H),
8.22 (s, 1H), 5.10 (d, thia-4-azabicyclo[4.1.0]hept- J = 2.54 Hz,
2H), 3.66 (d, J = 10.56 Hz, 1H), 3.41 3-en-5-yl)-6-fluoro-3- (s,
3H), 3.36 (d, J = 10.56 Hz, 1H), 2.56 (t, J = 2.45
pyridinyl)-5-(2-propyn-1- Hz, 1H), 1.80-1.90 (m, 1H), 1.71 (s, 3H),
0.86- yloxy)-2-pyrazinecarboxamide 0.92 (m, 1H), 0.74-0.82 (m,
1H)
Method F2: HATU Mediated Amide Formation Followed by Removal of the
Protecting Groups with PTSA
Example 784:
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(4-methyloxazol-5-yl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(prop-2-yn-1-yloxy)py-
razine-2-carboxamide
##STR00694##
[1856] To a stirred mixture of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(4-methyloxazol-
-5-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy-
)methyl)carbamate (189 mg, 0.325 mmol),
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid (249, 70 mg, 0.39
mmol), and EtNiPr.sub.2 (0.06 mL, 0.32 mmol) in DMF (4 mL) was
added HATU (148 mg, 0.39 mmol). The reaction mixture was stirred at
RT for 2 h. H.sub.2O was added, the solid was collected, dried and
dissolved in p-dioxane (4 mL) and added PTSA (186 mg, 0.97 mmol)
and heated at 70.degree. C. for 2 h. The mixture was concentrated,
added H.sub.2O, neutralized with saturated aqueous NaHCO.sub.3. The
solid was filtered, dried, purified by preparative reverse phase
HPLC. The pure fractions were concentrated to dryness, dissolved in
MeOH and passed through Pl-HCO.sub.3 MP SPE (200 mg per tube) to
give the title compound (69 mg, 48%). .sup.1H NMR (DMSO-d6)
.delta.: 10.49 (s, 1H), 8.90 (d, J=1.4 Hz, 1H), 8.48 (d, J=1.2 Hz,
1H), 8.20 (s, 1H), 8.06 (dd, J=7.2, 2.7 Hz, 1H), 7.84 (dt, J=8.6,
3.5 Hz, 1H), 7.20 (dd, J=11.7, 8.8 Hz, 1H), 6.45 (s, 2H), 5.14 (d,
J=2.3 Hz, 2H), 4.66-4.99 (m, 2H), 3.64 (t, J=2.4 Hz, 1H), 2.15 (s,
3H), 2.04-2.11 (m, 1H), 1.50 (dd, J=9.7, 5.4 Hz, 1H), 0.94-1.02 (m,
1H). MS (ESI, positive ion) m/z: 511 (M+1).
[1857] Using procedures analogous or similar to the general
amidation Method F2 described above, the appropriate aniline and
carboxylic acid intermediates were reacted to provide the 7
examples listed in Table 7 and Table 7'.
TABLE-US-00014 TABLE 7 Observed Ex. No. Chemical Structure [M +
H].sup.+ 787 ##STR00695## 490 789 ##STR00696## 510 793 ##STR00697##
496 797 ##STR00698## 490 798 ##STR00699## 511 799 ##STR00700## 538
800 ##STR00701## 539
TABLE-US-00015 TABLE 7' Ex. No. .sup.1H-NMR Chemical Name 787
.sup.1H NMR (DMSO-d6) .delta.: 10.62 (s, 1H), 8.78 (d,
N-(3-((1S,5S,6S)-3-amino- J = 2.3 Hz, 1H), 8.18-8.23 (m, 2H),
8.13-8.17 (m, 5-(fluoromethyl)-1-(4- 1H), 8.06 (dd, J = 7.2, 2.7
Hz, 1H), 7.84-7.90 (m, methyl-1,3-oxazol-5-yl)-2- 1H), 7.20 (dd, J
= 11.9, 8.8 Hz, 1H), 6.46 (s, 2H), thia-4- 4.66-5.07 (m, 2H), 2.15
(s, 3H), 2.05-2.11 (m, 1H), azabicyclo[4.1.0]hept-3-en- 1.50 (dd, J
= 9.6, 5.5 Hz, 1H), 0.94-1.01 (m, 1H)
5-yl)-4-fluorophenyl)-5-chloro-2- pyridinecarboxamide 789 .sup.1H
NMR (DMSO-d6) 5:10.44 (s, 1H), 8.44 (d, N-(3-((1S,5S,6S)-3-amino- J
= 2.7 Hz, 1H), 8.20 (s, 1H), 8.14 (d, J = 8.6 Hz, 1H),
5-(fluoromethyl)-1-(4- 8.04 (dd, J = 7.2, 2.7 Hz, 1H), 7.88 (dt, J
= 8.7, 3.5 methyl-1,3-oxazol-5-yl)-2- Hz, 1H), 7.67 (dd, J = 8.8,
2.9 Hz, 1H), 7.19 (dd, thia-4- J = 11.9, 8.8 Hz, 1H), 6.46 (s, 2H),
5.04 (d, J = 2.3 Hz, azabicyclo[4.1.0]hept-3-en- 2H), 4.68-4.98 (m,
2H), 3.71 (t, J = 2.3 Hz, 1H), 2.15 5-yl)-4-fluorophenyl)-5-(2- (s,
3H), 2.06-2.12 (m, 1H), 1.50 (dd, J = 9.7, 5.4 Hz,
propyn-1-yloxy)-2- 1H), 0.96-1.02 (m, 1H) pyridinecarboxamide 793
.sup.1H NMR (CHLOROFORM-d) .delta.: 9.86 (s, 1H), 8.38
N-(3-((1S,5S,6S)-3-amino- (d, J = 1.6 Hz, 1H), 8.34 (d, J = 2.7 Hz,
1H), 8.25 (d, 5-(fluoromethyl)-1-(3- J = 8.6 Hz, 1H), 7.97-8.03 (m,
1H), 7.74 (dd, J = 6.8, isoxazolyl)-2-thia-4- 2.7 Hz, 1H), 7.45
(dd, J = 8.7, 2.8 Hz, 1H), 7.11 (dd, azabicyclo[4.1.0]hept-3-en- J
= 11.3, 8.8 Hz, 1H), 6.38 (d, J = 1.8 Hz, 1H), 4.89-
5-yl)-4-fluorophenyl)-5-(2- 5.06 (m, 1H), 4.83 (d, J = 2.3 Hz, 2H),
4.63-4.80 (m, propyn-1-yloxy)-2- 1H), 2.61 (t, J = 2.4 Hz, 1H),
2.30 (t, J = 8.7 Hz, 1H), pyridinecarboxamide 1.82-1.89 (m, J =
9.8, 6.1 Hz, 1H), 1.19 (t, J = 6.7 Hz, 1H) 797 .sup.1H NMR
(DMSO-d6) .delta.: 10.55 (s, 1H), 8.72-8.80
(1S,5S,6S)-3-amino-N-tert- (m, 1H), 8.17-8.21 (m, 1H), 8.12-8.16
(m, 1H), 7.92 butyl-5-(5-(((5-chloro-2- (dd, J = 7.3, 2.8 Hz, 1H),
7.76-7.82 (m, 1H), 7.15 pyridinyl)carbonyl)amino)- (dd, J = 11.7,
8.8 Hz, 1H), 6.80 (s, 1H), 6.17 (s, 2H),
2-fluorophenyl)-5-methyl-2- 2.07 (dd, J = 9.3, 7.5 Hz, 1H), 1.63
(s, 3H), 1.45 (dd, thia-4- J = 9.6, 4.9 Hz, 1H), 1.27 (s, 9H), 0.73
(dd, J = 6.7, azabicyclo[4.1.0]hept-3- 5.2 Hz, 1H)
ene-1-carboxamide 798 .sup.1H NMR (DMSO-d6) .delta.: 10.42 (s, 1H),
8.89 (d, (1S,5S,6S)-3-amino-N-tert- J = 1.4 Hz, 1H), 8.48 (d, J =
1.4 Hz, 1H), 7.93 (dd, butyl-5-(2-fluoro-5-(((5-(2- J = 7.3, 2.6
Hz, 1H), 7.77 (dt, J = 8.4, 3.6 Hz, 1H), propyn-1-yloxy)-2- 7.16
(dd, J = 11.9, 8.8 Hz, 1H), 6.81 (s, 1H), 6.17 (s,
pyrazinyl)carbonyl)amino)phenyl)- 2H), 5.14 (d, J = 2.3 Hz, 2H),
3.64 (t, J = 2.3 Hz, 1H), 5-methyl-2-thia-4- 2.07 (dd, J = 9.2, 7.6
Hz, 1H), 1.63 (s, 3H), 1.46 (dd, azabicyclo[4.1.0]hept-3- J = 9.7,
5.0 Hz, 1H), 1.28 (s, 9H), 0.57-0.83 (m, 1H) ene-1-carboxamide 799
.sup.1H NMR (DMSO-d6) .delta.: 10.57 (s, 1H), 9.00 (d,
(1S,5S,6S)-3-amino-N- J = 1.4 Hz, 1H), 8.70 (d, J = 1.4 Hz, 1H),
8.09 (dd, cyclopropyl-5-(2-fluoro-5- J = 7.3, 2.8 Hz, 1H),
7.83-7.93 (m, 1H), 7.73 (d, (((5-(1,3-oxazol-2- J = 3.9 Hz, 1H),
7.25 (dd, J = 11.9, 8.8 Hz, 1H), 6.16 ylmethoxy)-2- (s, 2H), 5.25
(q, J = 9.0 Hz, 2H), 2.69-2.81 (m, 1H),
pyrazinyl)carbonyl)amino)phenyl)- 2.23 (dd, J = 9.4, 7.6 Hz, 1H),
1.70 (s, 3H), 1.46 (dd, 5-methyl-2-thia-4- J = 9.7, 5.2 Hz, 1H),
0.91 (dd, J = 6.7, 5.4 Hz, 1H), azabicyclo[4.1.0]hept-3- 0.69 (dd,
J = 7.2, 2.3 Hz, 2H), 0.46-0.60 (m, 2H). ene-1-carboxamide 800
.sup.1H NMR (DMSO-d6) .delta.: 10.57 (s, 1H), 9.00 (d,
(1S,5S,6S)-3-amino-N- J = 1.4 Hz, 1H), 8.70 (d, J = 1.4 Hz, 1H),
8.09 (dd, cyclopropyl-5-(2-fluoro-5- J = 7.3, 2.8 Hz, 1H),
7.83-7.93 (m, 1H), 7.73 (d, (((5-(2,2,2-trifluoroethoxy)- J = 3.9
Hz, 1H), 7.25 (dd, J = 11.9, 8.8 Hz, 1H), 6.16 2- (s, 2H), 5.25 (q,
J = 9.0 Hz, 2H), 2.69-2.81 (m, 1H),
pyrazinyl)carbonyl)amino)phenyl)- 2.23 (dd, J = 9.4, 7.6 Hz, 1H),
1.70 (s, 3H), 1.46 (dd, 5-methyl-2-thia-4- J = 9.7, 5.2 Hz, 1H),
0.91 (dd, J = 6.7, 5.4 Hz, 1H), azabicyclo[4.1.0]hept-3- 0.69 (dd,
J = 7.2, 2.3 Hz, 2H), 0.46-0.60 (m, 2H) ene-1-carboxamide
Method G: SNAr in iPrOH Followed by Removal of the Protecting
Groups with H.sub.2SO.sub.4
Example 844:
(1S,5S,6S)-5-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-fluoropyri-
din-3-yl)-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-
-amine
##STR00702##
[1859] A mixture of 4,7-dichloropyrido[3,2-d]pyrimidine (31.3 mg,
0.157 mmol), tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-1-(methoxymethyl)-5-methyl-2-
-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)-
carbamate (55 mg, 0.10 mmol), p-toluenesulfonic acid monohydrate
(39 mg, 0.20 mmol) in isopropanol (3 mL) in a microwave vial was
heated at 80.degree. C. under N.sub.2 for 1 h. LCMS showed the
desired product peak, together with partial deprotections. The
solvent was evaporated and the residue was treated with sulfuric
acid (0.14 mL, 2.61 mmol) and was stirred at RT for 20 min. It was
quenched by slow addition of saturated NaHCO.sub.3 till pH=8. The
aqueous layer was extracted with EtOAc. The organic phase was dried
over Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by chromatography on silica using EtOAc in DCM (30-100%)
as eluent to give Example 844 (44 mg, 0.096 mmol, 92% yield) as a
yellow solid. LCMS (ESI.sup.+) m/z=459.2 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta. 9.00 (s, 1H), 8.93 (dd, J=1.97, 2.70 Hz,
1H), 8.79 (s, 1H), 8.73 (d, J=2.19 Hz, 1H), 8.44 (dd, J=2.78, 8.48
Hz, 1H), 8.19 (d, J=2.34 Hz, 1H), 3.67 (d, J=10.08 Hz, 1H), 3.42
(s, 3H), 3.37 (d, J=10.67 Hz, 1H), 1.86 (ddd, J=1.39, 6.69, 9.32
Hz, 1H), 1.74 (d, J=1.32 Hz, 3H), 0.91 (dd, J=5.85, 9.35 Hz, 1H),
0.75-0.84 (m, 1H).
[1860] Using procedures analogous or similar to the general SNAr
Method G described above, the appropriate aniline and ArX (X=Cl/Br)
intermediates were reacted to provide the 8 examples listed in
Table 8 and Table 8'.
TABLE-US-00016 TABLE 8 Observed Ex. No. Chemical Structure [M + H]+
641 ##STR00703## 406 846 ##STR00704## 451 847 ##STR00705## 450.2
848 ##STR00706## 480.1 849 ##STR00707## 523.2 852 ##STR00708## 463
853 ##STR00709## 483.2 854 ##STR00710## 485.2
TABLE-US-00017 TABLE 8' Ex. No. .sup.1H-NMR Chemical Name 641
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.97 (s, 1H, NH),
8-((5-((1S,5S,6S)-3-amino-5- 9.92-10.02 (m, 1H), 9.92-10.02 (m,
1H), 9.23 (d, methyl-2-thia-4- J = 1.96 Hz, 1H), 9.00 (d, J = 1.96
Hz, 1H), 8.78 (s, azabicyclo[4.1.0]hept-3-en-5- 1H), 8.70 (dd, J =
2.74, 9.00 Hz, 1H), 8.24 (d, J = 5.67 yl)-6-fluoro-3- Hz, 1H), 7.26
(d, J = 5.67 Hz, 1H), 5.99 (br.s., 2H, pyridinyl)amino)-1,7- NH2),
2.34 (d, J = 9.00 Hz, 1H), 1.73-1.82 (m, 1H),
naphthyridine-3-carbonitrile 1.65 (s, 3H), 0.88 (dd, J = 2.15,
10.17 Hz, 1H), 0.46 (d, J = 4.89 Hz, 1H). 846 .sup.1H NMR
(CHLOROFORM-d) .delta.: 9.08 (br.s., 1H),
4-((5-((1S,5S,6S)-3-amino-1- 8.97 (d, J = 1.9 Hz, 1H), 8.94 (dd, J
= 2.8, 1.9 Hz, (methoxymethyl)-5-methyl- 1H), 8.87 (s, 1H), 8.53
(d, J = 1.9 Hz, 1H), 8.45 (dd, 2-thia-4- J = 8.4, 2.8 Hz, 1H), 3.67
(d, J = 10.7 Hz, 1H), 3.42 (s, azabicyclo[4.1.0]hept-3-en-5- 3H),
3.37 (d, J = 10.7 Hz, 1H), 1.87 (ddd, J = 9.4, 6.7, yl)-6-fluoro-3-
1.5 Hz, 1H), 1.74 (d, J = 1.0 Hz, 3H), 0.92 (dd,
pyridinyl)amino)pyrido[3,2- J = 9.1, 6.1 Hz, 1H), 0.79 (t, J = 6.3
Hz, 1H) d]pyrimidine-7-carbonitrile 847 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 8.99- 8-((5-((1S,5S,6S)-3-amino-1- 9.04 (m,
1H), 8.92-8.98 (m, 2H), 8.35-8.44 (m, 2H),
(methoxymethyl)-5-methyl- 8.27 (d, J = 5.70 Hz, 1H), 7.07 (d, J =
5.85 Hz, 1H), 2-thia-4- 3.66 (d, J = 10.67 Hz, 1H), 3.42 (s, 3H),
3.37 (d, azabicyclo[4.1.0]hept-3-en-5- J = 10.67 Hz, 1H), 1.87
(ddd, J = 1.32, 6.72, 9.35 Hz, yl)-6-fluoro-3- 1H), 1.76 (d, J =
1.02 Hz, 3H), 0.94 (dd, J = 5.99, 9.35 pyridinyl)amino)-1,7- Hz,
1H), 0.76-0.85 (m, 1H). naphthyridine-3-carbonitrile 848 .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta. 8.89-
N-(5-((1S,5S,6S)-3-amino-1- 8.98 (m, 1H), 8.57 (s, 1H), 8.31-8.42
(m, 2H), 8.28 (methoxymethyl)-5-methyl- (d, J = 5.85 Hz, 1H), 7.10
(d, J = 5.85 Hz, 1H), 5.16 2-thia-4- (d, J = 2.34 Hz, 2H), 3.66 (d,
J = 10.52 Hz, 1H), 3.42 azabicyclo[4.1.0]hept-3-en-5- (s, 3H), 3.36
(d, J = 10.67 Hz, 1H), 2.57 (t, J = 2.41
yl)-6-fluoro-3-pyridinyl)-2- Hz, 1H), 1.80-1.90 (m, 1H), 1.74 (s,
3H), 0.87-0.99 (2-propyn-1- (m, 1H), 0.75-0.84 (m, 1H)
yloxy)pyrido[3,4-b]pyrazin- 5-amine 849 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 8.89- N-(5-((1S,5S,6S)-3-amino-1- 8.99 (m,
1H), 8.58 (s, 1H), 8.41 (s, 1H), 8.35 (dd,
(methoxymethyl)-5-methyl- J = 2.78, 8.62 Hz, 1H), 8.28 (d, J = 5.85
Hz, 1H), 7.73 2-thia-4- (d, J = 0.73 Hz, 1H), 7.20 (s, 1H), 7.09
(d, J = 5.99 azabicyclo[4.1.0]hept-3-en-5- Hz, 1H), 5.65 (s, 2H),
3.66 (d, J = 10.38 Hz, 1H), yl)-6-fluoro-3-pyridinyl)-2- 3.41 (s,
3H), 3.36 (d, J = 10.67 Hz, 1H), 1.80-1.90 (1,3-oxazol-2- (m, 1H),
1.74 (d, J = 1.02 Hz, 3H), 0.88-0.99 (m, ylmethoxy)pyrido[3,4- 1H),
0.76-0.84 (m, 1H) b]pyrazin-5-amine 852 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 9.00 (s, N-(5-((1S,5S,6S)-3-amino-5- 1H),
8.93 (dd, J = 1.90, 2.78 Hz, 1H), 8.79 (s, 1H), methyl-1- 8.73 (d,
J = 2.19 Hz, 1H), 8.44 (dd, J = 2.78, 8.62 Hz,
(((~2~H_3_)methyloxy)methyl)-2- 1H), 8.19 (d, J = 2.19 Hz, 1H),
3.67 (d, J = 10.67 Hz, thia-4- 1H), 3.37 (d, J = 10.67 Hz, 1H),
1.86 (ddd, J = 1.39, azabicyclo[4.1.0]hept-3-en-5- 6.69, 9.32 Hz,
1H), 1.74 (d, J = 1.17 Hz, 3H), 0.87- yl)-6-fluoro-3-pyridinyl)-7-
0.99 (m, 1H), 0.75-0.84 (m, 1H) chloropyrido[3,2-
d]pyrimidin-4-amine 853 .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
8.87- N-(5-((1S,5S,6S)-3-amino-5- 9.02 (m, 1H), 8.57 (s, 1H),
8.31-8.40 (m, 2H), 8.27 methyl-1- (d, J = 5.99 Hz, 1H), 7.09 (d, J
= 5.99 Hz, 1H), 5.16 (((~2~H_3_)methyloxy)methyl)-2- (d, J = 2.48
Hz, 2H), 3.66 (d, J = 10.23 Hz, 1H), 3.36 thia-4- (d, J = 10.67 Hz,
1H), 2.57 (t, J = 2.48 Hz, 1H), 1.84 azabicyclo[4.1.0]hept-3-en-5-
(ddd, J = 1.24, 6.72, 9.28 Hz, 1H), 1.74 (d, J = 1.17
yl)-6-fluoro-3-pyridinyl)-2- Hz, 3H), 0.87-0.97 (m, 1H), 0.74-0.84
(m, 1H) (2-propyn-1- yloxy)pyrido[3,4-b]pyrazin- 5-amine 854
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 8.91-
N-(5-((1S,5S,6S)-3-amino-5- 9.03 (m, 1H), 8.57 (s, 1H), 8.32-8.40
(m, 2H), 8.28 methyl-1- (d, J = 5.85 Hz, 1H), 7.10 (d, J = 5.85 Hz,
1H), 3.66 (((~2~H_3_)methyloxy)methyl)- (d, J = 10.52 Hz, 1H), 3.36
(d, J = 10.67 Hz, 1H), 2.55 2-thia-4- (s, 1H), 1.85 (ddd, J = 1.17,
6.65, 9.43 Hz, 1H), 1.75 azabicyclo[4.1.0]hept-3-en-5- (d, J = 1.02
Hz, 3H), 0.93 (dd, J = 5.92, 9.43 Hz, 1H),
yl)-6-fluoro-3-pyridinyl)-2- 0.77-0.84 (m, 1H)
((1,1-~2~H_2_)-2-propyn-1- yloxy)pyrido[3,4-b]pyrazin- 5-amine
Miscellaneous Methods
Example 12:
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide
##STR00711##
[1861] Preparation of
3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (Example 9)
[1862] (1S,5S,6S)-ethyl
3-Amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0-
]hept-3-ene-1-carboxylate (intermediate 212, 225 mg, 0.66 mmol) was
taken up in 3.2 mL of DMAc and chilled to 0.degree. C.
5-Chloro-2-pyridinecarboxylic acid (125 mg, 0.79 mmol) and
propylphosphonic anhydride solution (50 wt. % in EtOAc, 839 mg,
1.32 mmol) were added to the mixture. The mixture was stirred for
20 min at 0.degree. C. then RT for 4 h. The reaction was diluted
with 25 mL of EtOAc, cooled with an ice bath and quenched with 10
mL of aq. NaHCO.sub.3. The organic layer was separated. The aqueous
was extracted with 15 mL of EtOAc. The combine organic extracts
were washed with 5 mL of brine, dried over sodium sulfate and
concentrated. The residue was purified by silica gel flash
chromatography (1-5% MeOH/DCM) to afford (1S,5S,6S)-ethyl
3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (Example 9, 289 mg, 0.60
mmol, 91% yield) as an off white crystalline solid. MS m/z=481.0
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.80 (s,
1H), 8.81 (d, J=1.76 Hz, 1H), 8.16-8.24 (m, 2H), 7.97 (m, 2H), 6.20
(br., 2H), 4.20 (q, J=7.17 Hz, 2H), 2.34 (d, J=8.22 Hz, 1H), 1.64
(s, 3H), 1.50 (m, 1H), 1.23 (t, J=7.14 Hz, 3H), 1.08 (m, 1H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -138.11 (d, J=20.20
Hz, 1 F), -143.69 (d, J=20.20 Hz, 1 F).
Preparation of
N-(3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide
(Example 10)
[1863] At RT, (1S,5S,6S)-ethyl
3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (Example 9, 289 mg, 0.60
mmol) in 5 mL of THF was treated with lithium borohydride (2.0 M
solution in THF (0.60 mL, 1.20 mmol) followed by MeOH (0.24 mL,
6.01 mmol). After 1 h at RT, the reaction mixture was cooled with
an ice bath and quenched with dropwise addition of 15 mL of aq.
NH.sub.4Cl. The resulting biphasic mixture was extracted with
2.times.40 mL of EtOAc. The organic extracts were washed with 20 mL
of brine and dried over MgSO.sub.4. Filtration and concentration
under reduced pressure afforded a brown oil. It was purified on a
silica gel column (15-45% EtOAc in hexanes) to provide
N-(3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide
(Example 10, 173 mg, 0.39 mmol, 66% yield) as an off-white
crystalline solid. MS m/z=439.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.74 (br., 1H), 8.79 (d, J=1.96 Hz, 1H),
8.14-8.23 (m, 2H), 7.87-7.98 (m, 2H), 5.95 (br., 2H), 5.05 (br.,
1H), 3.55 (m, 1H), 3.44 (m, 1H), 1.70 (m, 1H), 1.61 (s, 3H), 0.86
(br., 1H), 0.58 (br., 1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -138.50 (d, J=20.18 Hz, 1 F), -143.58 (d, J=20.18 Hz, 1
F).
Preparation of
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide
(Example 12)
[1864] To a solution of
N-(3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide
(Example 10, 75 mg, 0.17 mmol) in 3 mL of DCM at -30.degree. C.
(dry ice/acetone) was added diethylaminosulfur trifluoride (1 M in
DCM) (342 .mu.L, 0.34 mmol). The mixture was stirred at -30.degree.
C. for 5 min then RT for 0.5 h. The reaction mixture was cooled
with an ice bath and treated with a saturated solution of
NaHCO.sub.3, extracted with DCM (3.times.50 mL), dried over
MgSO.sub.4, filtered and concentrated. The crude residue was
purified on a silica gel column, using a gradient of 25-80% EtOAc
in DCM, to provide
N-(3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide
(Example 12, 31 mg, 0.07 mmol, 41% yield) as an off-white
crystalline solid. MS m/z=441.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.75 (s, 1H), 8.79 (d, J=1.96 Hz, 1H),
8.14-8.23 (m, 2H), 7.87-7.98 (m, 2H), 6.12 (br., 2H), 4.56 (m, 1H),
4.44 (m, 1H), 1.79 (m, 1H), 1.62 (s, 3H), 1.04 (dd, J=5.48, 9.19
Hz, 1H), 0.71 (m, 1H). .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-138.40 (d, J=20.22 Hz, 1 F), -143.48 (d, J=20.22 Hz, 1 F), -211.58
(s, 1 F).
Example 28:
4-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-
-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitril-
e
##STR00712##
[1866]
(1S,5S,6S)-5-(5-((7-Chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2,3-di-
fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(Example 22, 84 mg, 0.19 mmol), zinc cyanide (33 mg, 0.28 mmol),
tris(dibenzylideneacetone) dipalladium(0) (14 mg, 0.02 mmol), and
2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (15 mg, 0.04
mmol) were added to a round bottom flask and placed under an argon
atmosphere. DMF (2 mL) and water (0.02 mL) were added, and the
reaction mixture was stirred at 120.degree. C. for 1 h. The
reaction mixture was cooled to RT, diluted with water, and
extracted with EtOAc. The organic layer was separated, washed with
saturated aqueous sodium chloride, dried over magnesium sulfate,
filtered, and concentrated in vacuo. The resulting crude residue
was purified via silica gel flash column chromatography (0-100%
EtOAc/heptane) to afford
4-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-
-3-en-5-yl)-4,5-difluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitril-
e (Example 28, 68 mg, 0.15 mmol, 83% yield) as a light yellow
solid. MS m/z=442.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 10.66 (s, 1H) 9.27 (d, J=1.76 Hz, 1H)
8.92 (d, J=1.96 Hz, 1H) 8.82 (s, 1H) 8.13-8.21 (m, 2H) 6.28 (s, 2H)
4.67-4.84 (m, 2H) 2.40-2.47 (m, 1H) 1.79 (q, J=7.89 Hz, 1H) 1.11
(ddd, J=8.85, 7.48, 5.18 Hz, 1H) 0.46 (q, J=5.28 Hz, 1H).
Example 30:
((1S,5S,6S)-3-amino-5-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2,3-difl-
uorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol
##STR00713##
[1868] At RT, (1S,5S,6S)-ethyl
3-amino-5-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2,3-difluorophenyl)--
5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
(Example 25, 236 mg, 0.47 mmol) in 4 mL of THF was treated with
lithium borohydride (2.0 M solution in THF, 0.47 mL, 0.94 mmol)
followed by MeOH (0.19 mL, 4.68 mmol). The reaction mixture was
stirred at RT for 1 h. LCMS indicated the presence of the starting
ester. Additional lithium borohydride (0.47 mL of the 2 M in THF
solution, 0.94 mmol) and MeOH (0.19 mL, 4.68 mmol) were added to
the reaction mixture. It was stirred at RT for 18 h. The reaction
mixture was cooled with an ice bath and quenched with dropwise
addition of 15 mL of aq. NH.sub.4Cl. The resulting biphasic mixture
was extracted with 2.times.40 mL of EtOAc. The organic extracts
were washed with 20 mL of brine and dried over MgSO.sub.4.
Filtration and concentration under reduced pressure afforded a
brown oil. The residue was purified on a silica gel column (15-45%
EtOAc in hexanes) to provide
((1S,5S,6S)-3-amino-5-(5-((3-chloro-1,7-naphthyridin-8-yl)amino)-2,3-difl-
uorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol
(29 mg, 0.06 mmol, 13% yield) as a yellow crystalline solid. m/z
(ESI, +ve ion) 462.0 (M+1).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 9.65 (br., 1H), 8.93 (d, J=2.35 Hz, 1H), 8.55
(d, J=2.35 Hz, 1H), 8.39 (ddd, J=2.74, 6.85, 13.11 Hz, 1H), 8.20
(d, J=5.87 Hz, 1H), 7.90 (br., 1H), 7.22 (d, J=5.87 Hz, 1H), 6.01
(br., 2H), 5.07 (br., 1H), 3.56 (dd, J=6.26, 11.74 Hz, 1H), 3.47
(dd, J=5.48, 11.74 Hz, 1H), 1.68 (m, 1H), 1.64 (s, 3H), 0.91 (br.,
1H), 0.62 (br., 1H).
Example 41:
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamide
##STR00714##
[1870] To a solution of
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(hydroxymethyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicolinamide
(Example 37, 0.25 g, 0.58 mmol) in DCM (2.5 mL) at -78.degree. C.
was added Deoxo-Fluor (0.33 mL, 1.79 mmol). The reaction mixture
was warmed from -78.degree. C. to room temperature over 3 h,
stirred at room temperature for 20 min and quenched with saturated
NaHCO.sub.3. After bubbling ceased, the mixture was transferred to
a separatory funnel and diluted with water, EtOAc, and saturated
NaHCO.sub.3. The aqueous phase was extracted with EtOAc (3.times.)
and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, and concentrated to
give a light yellow solid. Purification by flash column
chromatography on silica gel (24 g, eluted with 5-60% EtOAc in
heptane) gave
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicolinamide (Example
41, 47 mg, 0.11 mmol, 18% yield) as an off-white solid. LC/MS (ESI)
m/z=441.0 (M+H).sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 9.80 (br., 1H), 8.54 (s, 1H), 8.23 (d, J=8.61 Hz, 1H),
7.92-8.01 (m, 1H), 7.87 (d, J=8.41 Hz, 1H), 7.69 (d, J=6.85 Hz,
1H), 7.09 (t, J=11.20 Hz, 1H), 4.87 (dd, J=47.54, 9.00 Hz, 1H),
4.69 (dd, J=47.14, 8.61 Hz, 1H), 4.64 (br., 2H), 4.48 (dd, J=47.93,
10.17 Hz, 1H), 4.36 (dd, J=46.95, 9.78 Hz, 1H), 1.89 (t, J=8.02 Hz,
1H), 1.17-1.24 (m, 1H), 0.80 (br., 1H).
Example 42:
N-(3-((1R,5S,6R)-3-amino-5-(fluoromethyl)-1-(hydroxymethyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamid-
e
##STR00715##
[1871] Preparation of
((1R,5S,6R)-3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-1-yl)methanol (42A)
[1872] To a solution of (1R,5S,6R)-methyl
3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4-
.1.0]hept-3-ene-1-carboxylate (207C, 0.28 g, 0.86 mmol) in THF (3.5
mL) at room temperature was added lithium borohydride (2.0 M
solution in THF, 1.30 mL, 2.60 mmol) and MeOH (0.28 mL, 6.91 mmol).
The reaction mixture was stirred at room temperature for 4.5 h and
quenched slowly with saturated NH.sub.4Cl. After bubbling ceased,
the mixture was transferred to a separatory funnel and diluted with
water, EtOAc, and saturated NH.sub.4Cl. The aqueous phase was
extracted with EtOAc (3.times.) and the combined organic extracts
were washed with brine (1.times.), dried over MgSO.sub.4, filtered,
concentrated. Purification by flash column chromatography on silica
gel (24 g, eluted with 1-8% MeOH (2 M NH.sub.3) in DCM) gave
((1R,5S,6R)-3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4--
azabicyclo[4.1.0]hept-3-en-1-yl)methanol (42A, 0.17 g, 0.57 mmol,
66% yield) as a white solid. LC/MS (ESI) m/z=300.0 (M+H).sup.+.
Preparation of
N-(3-((1R,5S,6R)-3-amino-5-(fluoromethyl)-1-(hydroxymethyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyridinecarboxamid-
e (Example 42)
[1873] To a solution of 5-chloro-2-pyridinecarboxylic acid (94 mg,
0.59 mmol) and
((1R,5S,6R)-3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol (42A, 159 mg,
0.53 mmol) in DMAc (1.5 mL) at room temperature was added
1-propylphosphonic acid cyclic anhydride (50 wt. % solution in
EtOAc, 0.35 mL, 0.59 mmol). The reaction mixture was stirred at
room temperature for 18 h and quenched with 1 M NaOH. The mixture
was diluted with EtOAc and water (pH=10) and transferred to a
separatory funnel. The aqueous phase was extracted with EtOAc
(3.times.) and the combined organic extracts were washed with brine
(1.times.), dried over MgSO.sub.4, filtered, concentrated.
Purification by flash column chromatography on silica gel (24 g,
eluted with 60-100% EtOAc [10% MeOH (2 M NH.sub.3)] in heptane)
gave
N-(3-((1R,5S,6R)-3-amino-5-(fluoromethyl)-1-(hydroxymethyl)-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicolinamide
(Example 42, 145 mg, 0.33 mmol, 62% yield) as a white solid. LC/MS
(ESI) m/z=439.1 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
ppm 10.62 (s, 1H), 8.80 (d, J=2.35 Hz, 1H), 8.22 (dd, J=8.41, 2.35
Hz, 1H), 8.17 (dd, J=8.41, 0.78 Hz, 1H), 8.04 (dd, J=7.14, 2.64 Hz,
1H), 7.78-7.84 (m, 1H), 7.16 (dd, J=11.93, 8.80 Hz, 1H), 6.16 (s,
2H), 5.07 (dd, J=6.55, 5.18 Hz, 1H), 4.78 (dd, J=47.93, 8.41 Hz,
1H), 4.49 (dd, J=47.54, 8.61 Hz, 1H), 3.81 (dd, J=11.54, 6.65 Hz,
1H), 3.50 (dd, J=11.74, 5.09 Hz, 1H), 1.82 (dd, J=9.19, 6.26 Hz,
1H), 1.05 (dd, J=9.29, 5.18 Hz, 1H), 0.90 (t, J=5.58 Hz, 1H).
Example 59:
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide
##STR00716##
[1875] Deoxo-fluor (0.13 mL, 0.71 mmol) was added to a stirred
suspension of
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(hydroxymethyl)-2-thia-4-a-
zabicyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropicolinamide
(Example 31, 108 mg, 0.24 mmol) in DCM (1 mL) at -78.degree. C.
under a nitrogen atmosphere. The reaction mixture was allowed to
slowly warm up to room temperature over 1.5 h. The reaction mixture
was quenched with saturated aqueous sodium bicarbonate and
extracted with EtOAc. The organic layer was separated, washed with
saturated aqueous sodium chloride, dried over magnesium sulfate,
filtered, and concentrated in vacuo. The resulting crude residue
was purified via silica gel flash column chromatography (0-70%
EtOAc/heptane) to afford
N-(3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloro-2-pyridinecarboxamide
(Example 59, 33 mg, 0.07 mmol, 30% yield) as a white solid. MS
m/z=459.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
ppm 9.82 (s, 1H) 8.55 (d, J=1.96 Hz, 1H) 8.22 (d, J=8.22 Hz, 1H)
8.06-8.12 (m, 1H) 7.89 (dd, J=8.41, 2.15 Hz, 1H) 7.34-7.38 (m, 1H)
4.63-4.92 (m, 2H) 4.30-4.54 (m, 2H) 1.90 (t, J=8.22 Hz, 1H)
1.22-1.28 (m, 1H) 0.80-0.86 (m, 1H).
Example 60:
8-((3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carboni-
trile
##STR00717##
[1877] At 0.degree. C.,
8-((3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3-carbon-
itrile (Example 54, 47 mg, 0.10 mmol) in 4 mL of DCM was treated
with diethylaminosulfur trifluoride (1 M in DCM) (0.22 mL, 0.22
mmol). It was stirred at 0.degree. C. for 30 min then RT for 1 h.
LCMS indicated the presence of the staring alcohol. The reaction
mixture was cooled with an ice bath and treated with additional
diethylaminosulfur trifluoride (1 M in DCM) (55 .mu.L, 55 .mu.mol)
and stirred at RT for 18 h. It was quenched with 10 mL of saturated
NaHCO.sub.3 and extracted with CHCl.sub.3/iPrOH (2.times.15 mL,
9/1). The combined organic extracts was washed with 5 mL of brine,
dried over Na.sub.2SO.sub.4 and concentrated. The residue was
purified on a silica gel column (50-75% EtOAc in DCM) to afford 33
mg of yellow solid that contained the desired product [m/z (ESI,
+ve ion) 455.1 (M+1).sup.+] in about 91% purity as judged by LCMS.
The material was purified on a silica gel column (65% EtOAc in DCM)
to afford
8-((3-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)amino)-1,7-naphthyridine-3--
carbonitrile (Example 60, 10 mg, 0.02 mmol, 21% yield) as a brown
crystalline solid. m/z (ESI, +ve ion) 455.1 (M+1).sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.78 (br., 1H), 9.24 (d, J=4.66
Hz, 1H), 9.01 (d, J=1.96 Hz, 1H), 8.25-8.39 (m, 2H), 7.95 (d,
J=5.67 Hz, 1H), 7.29 (d, J=5.61 Hz, 1H), 6.15 (br., 2H), 4.56-4.41
(m, 2H), 1.86 (m, 1H), 1.64 (s, 3H), 1.07 (m, 1H), 0.75 (m, 1H).
.sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -138.65 (d, J=22.70
Hz, 1 F), -145.98 (d, J=22.69 Hz, 1 F), -211.43 (s, 1 F).
Example 62 and Example 63:
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine
and
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-2-(1-methylethoxy)pyrido[3,4-b]pyrazin-5-am-
ine
##STR00718##
[1879]
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-amine (Intermediate 201, 65 mg, 0.23
mmol), 5-chloro-2-methoxypyrido[3,4-b]pyrazine (49 mg, 0.25 mmol),
and p-toluenesulfonic acid monohydrate (86 mg, 0.45 mmol) were
mixed in isopropanol (1 mL) in a sealed tube. The reaction mixture
was stirred at 80.degree. C. for 2 h. It was cooled to RT, quenched
with saturated aqueous sodium bicarbonate and extracted with EtOAc.
The organic layer was separated, washed with saturated aqueous
sodium chloride, dried over magnesium sulfate, filtered, and
concentrated in vacuo. The resulting crude residue was purified via
silica gel flash column chromatography (0-100% EtOAc/heptane) to
afford two products.
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-2-(1-methylethoxy)pyrido[3,4-b]pyrazin-5-am-
ine (Example 63, 17 mg, 36 .mu.mol, 16% yield) was the first
product to elute and was isolated as a yellow solid. MS m/z=475.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.53
(s, 1H) 8.49 (s, 1H) 8.33 (ddd, J=13.25, 6.80, 2.64 Hz, 1H) 8.27
(d, J=5.87 Hz, 1H) 7.92-7.96 (m, 1H) 7.09 (d, J=5.87 Hz, 1H) 6.26
(s, 2H) 5.48 (spt, J=6.19 Hz, 1H) 4.64-4.83 (m, 2H) 2.38-2.45 (m,
1H) 1.77 (q, J=8.35 Hz, 1H) 1.42 (d, J=6.26 Hz, 6H) 1.05-1.12 (m,
1H) 0.44 (q, J=5.22 Hz, 1H).
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-2-methoxypyrido[3,4-b]pyrazin-5-amine
(Example 62, 25 mg, 56 .mu.mol, 25% yield) was the second product
to elute and was isolated as a yellow solid. MS m/z=447.0
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.56
(s, 1H) 8.57 (s, 1H) 8.30-8.35 (m, 1H) 8.29 (d, J=5.87 Hz, 1H)
7.93-7.97 (m, 1H) 7.13 (d, J=5.87 Hz, 1H) 6.26 (s, 2H) 4.64-4.83
(m, 2H) 4.08 (s, 3H) 2.38-2.45 (m, 1H) 1.73-1.81 (m, 1H) 1.05-1.12
(m, 1H) 0.44 (q, J=5.28 Hz, 1H).
Example 64:
(1S,5S,6S)-5-(2,3-difluoro-5-((7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino-
)phenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-a-
mine
##STR00719##
[1881] At -60.degree. C. to a solution of
((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((7-methoxypyrido[3,2-d]pyrimidin-4-
-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methan-
ol (Example 58, 75 mg, 0.16 mmol) in 4 mL of DCM was added
diethylaminosulfur trifluoride (1 M in DCM) (0.22 mL, 0.22 mmol).
The reaction mixture was slowly warmed to RT in 3 h. LCMS indicated
the presence of the starting alcohol. The reaction mixture was
cooled to -20.degree. C. and treated with deoxo-fluor (0.03 mL,
0.16 mmol). The cold bath was removed and the mixture stirred at RT
for 1 h. It was quenched with 10 mL of sat NaHCO.sub.3 and
extracted with CHCl.sub.3/iPrOH (9/1, 2.times.15 mL). The combined
organic extracts was washed with 5 mL of brine, dried over
Na.sub.2SO.sub.4 and concentrated. The residue was purified on a
silica gel column (50-100% EtOAc in hexanes followed by 5% MeOH in
EtOAc) to afford
(1S,5S,6S)-5-(2,3-difluoro-5-((7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino-
)phenyl)-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-a-
mine (15 mg, 19% yield) as an off-white crystalline solid. m/z
(ESI, +ve ion) 461.1 (M+1).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.16 (br., 1H), 8.68 (s, 1H), 8.66 (s, 1H),
8.20 (m, 1H), 8.04 (m, 1H), 7.64 (d, J=2.74 Hz, 1H), 6.14 (br.,
2H), 4.41-4.57 (m, 2H), 4.02 (s, 3H), 1.80 (m, 1H), 1.65 (s, 3H),
1.09 (m, 1H), 0.74 (m, 1H). .sup.19F NMR (377 MHz, DMSO-d.sub.6)
.delta. -138.67 (d, J=22.61 Hz, 1 F), -144.46 (d, J=22.70 Hz, 1 F),
-211.43 (s, 1 F).
Example 93:
((1S,5S,6S)-3-Amino-5-(2,3-difluoro-5-((2-methoxypyrido[3,4-b]pyrazin-5-y-
l)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol
##STR00720##
[1883] A mixture of
((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-1-yl)methanol (intermediate 206, 40 mg, 0.13
mmol), 5-chloro-2-methoxypyrido[3,4-b]pyrazine (intermediate 258,
29 mg, 0.15 mmol) and p-toluenesulfonic acid monohydrate (28 mg,
0.15 mmol) were taken up in 2 mL of MeOH in a sealable vial with a
pressure relief septa. The vial was sealed and heated to 55.degree.
C. for 2 h. The mixture was cooled to RT and diluted with 20 mL of
EtOAc. The mixture was washed with 10 mL of aq. NaHCO.sub.3 and 10
mL of brine. The organic layer was dried over MgSO.sub.4, filtered,
then concentrated under reduced pressure. The residue was purified
by silica gel chromatography (4 g) eluting with 1-5% MeOH in DCM to
afford
((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-((2-methoxypyrido[3,4-b]pyrazin-5-y-
l)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methanol
(Example 93, 27 mg, 59 .mu.mol, 44% yield) as a yellow solid. MS
m/z=459.1 [M+H].sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
8.65 (s, 1H), 8.46 (br. s., 1H), 8.31 (s, 1H), 8.24-8.28 (m, 1H),
7.34 (br. s., 1H), 7.08 (d, J=5.87 Hz, 1H), 4.13 (s, 3H), 3.62-3.77
(m, 2H), 3.50 (s, 1H), 1.82-1.89 (m, 1H), 1.76 (s, 3H), 0.86-0.97
(m, 1H), 0.73-0.83 (m, 1H).
Example 97: Synthesis of
4-((3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[4.1.0-
]hept-3-en-5-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbonitri-
le. (Method PH-3)
##STR00721##
[1885] To a suspension of
4-((3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(hydroxymethyl)-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-
-7-carbonitrile (Example 80, 0.30 g, 0.66 mmol) in hexanes (15 mL)
at -78.degree. C. was added bis(2-methoxyethyl)aminosulfur
trifluoride (0.19 mL, 1.03 mmol). The reaction mixture was warmed
from -78.degree. C. to RT over 2 h. DCM (3 mL) was added and the
reaction mixture was stirred at room temperature for 1.5 h and
additional DCM (6 mL) was added. The reaction mixture was stirred
at room temperature for 15 h and quenched with saturated
NaHCO.sub.3. The mixture was diluted with EtOAc and water and
transferred to a separatory funnel. The aqueous phase was extracted
with EtOAc (3.times.) and the combined organic extracts were washed
with brine (1.times.), dried over MgSO.sub.4, filtered, and
concentrated to give a yellow solid. Purification by flash column
chromatography on silica gel (40 g, eluted with 10% to 60% EtOAc
(10% MeOH) in heptane) gave
4-((3-((1S,5S,6S)-3-amino-1,5-bis(fluoromethyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-5-yl)-4-fluorophenyl)amino)pyrido[3,2-d]pyrimidine-7-carbo-
nitrile (Example 97, 0.12 g, 0.26 mmol, 40% yield) as a yellow
solid. LC/MS (ESI) m/z=456.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. ppm 9.05 (s, 1H), 8.90 (d, J=1.76 Hz, 1H),
8.76-8.82 (m, 1H), 8.47 (d, J=1.56 Hz, 1H), 8.16 (dt, J=8.61, 3.50
Hz, 1H), 7.75-7.84 (m, 1H), 7.14 (dd, J=11.25, 8.90 Hz, 1H), 4.88
(dd, J=47.34, 8.22 Hz, 1H), 4.86 (br., 2H), 4.75 (dd, J=47.34, 8.61
Hz, 1H), 4.48 (dd, J=36.97, 9.98 Hz, 1H), 4.36 (dd, J=36.19, 9.98
Hz, 1H), 1.89 (t, J=8.12 Hz, 1H), 1.24 (dd, J=9.68, 5.97 Hz, 1H),
0.77-0.84 (m, 1H).
Example 98:
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-5-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamide
##STR00722##
[1886] Preparation of Compound 98A
[1887] To a mixture of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-1-(fluoromethyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)c-
arbamate (intermediate 214, 70 mg, 0.14 mmol),
5-chloropyridine-2-carboxylic acid (28 mg, 0.18 mmol), and TEA
(0.06 mL, 0.41 mmol) in DMF (1.0 mL) at RT was added HATU (78 mg,
0.20 mmol). The reaction mixture was stirred at RT for 2 h, then
diluted with water and extracted with EtOAc (2.times.). The organic
extracts were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by ISCO eluting with 0-40%
EtOAc in heptane to afford tert-butyl
((1S,5S,6S)-5-(5-(5-chloropicolinamido)-2-fluoropyridin-3-yl)-1-(fluorome-
thyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsily-
l)ethoxy)methyl)carbamate (98A, 66 mg, 0.10 mmol, 74% yield). LCMS
m/z=654.0 [M+H].sup.+. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.
9.85 (s, 1H), 8.68-8.76 (m, 1H), 8.57 (d, J=1.90 Hz, 1H), 8.38 (dd,
J=2.78, 8.62 Hz, 1H), 8.26 (d, J=8.18 Hz, 1H), 7.91 (dd, J=2.41,
8.40 Hz, 1H), 5.31-5.44 (d, J=10.52 Hz, 1H), 5.14 (d, J=10.52 Hz,
1H), 4.50 (d, 2H), 3.70 (t, J=8.26 Hz, 2H), 2.01-2.14 (m, 1H), 1.77
(s, 3H), 1.56 (s, 9H), 0.88-1.06 (m, 4H), 0.01 (s, 9H). .sup.19F
NMR (282 MHz, CHLOROFORM-d) .delta. -69.42 (s, 1 F), -213.24 (s, 1
F).
Preparation of Example 98
[1888] At RT, concentrated sulfuric acid (0.4 mL, 7.2 mmol) was
added to tert-butyl
((1S,5S,6S)-5-(5-(5-chloropicolinamido)-2-fluoropyridin-3-yl)-1-(fluorome-
thyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsily-
l)ethoxy)methyl)carbamate (98A, 60 mg, 0.09 mmol) and the mixture
stirred at RT for 15 min. It was poured onto ice and the pH was
adjusted to 13 by addition of 5 N NaOH (.about.3.0 mL). The
resulting solution was extracted with EtOAc (2.times.). The
combined organic extracts were dried with sodium sulfate, filtered
and concentrated in vacuo. The residue was purified by silica gel
chromatography using ISCO (0-80% EtOAc in heptane) to afford
N-(5-((1S,5S,6S)-3-amino-1-(fluoromethyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-5-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamide
(Example 98, 28 mg, 0.07 mmol, 72% yield). LC/MS (ESI.sup.+)
m/z=424.0 (M+H).
[1889] .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.88 (s, 1H),
8.54-8.66 (m, 2H), 8.44 (dd, J=2.78, 8.62 Hz, 1H), 8.24 (d, J=8.33
Hz, 1H), 7.90 (dd, J=2.34, 8.33 Hz, 1H), 4.43-4.63 (m, 1H),
4.26-4.42 (m, 1H), 1.84-2.00 (m, 1H), 1.73 (d, J=1.17 Hz, 3H), 0.98
(d, J=6.14 Hz, 1H), 0.86 (dt, J=4.09, 6.36 Hz, 1H). The peak for
NH.sub.2 is broad, over 4.75-3.75 ppm. .sup.19F NMR (282 MHz,
CHLOROFORM-d) .delta. -68.62 (s, 1 F), -212.75 (s, 1 F).
Example 100: Synthesis of
N-(5-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamide
##STR00723##
[1890] Preparation of Compound 99A
[1891] A microwave vial was charged with (1S,5S,6S)-methyl
5-(5-bromo-2-fluoropyridin-3-yl)-3-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxylate (214I, 240 mg, 0.39 mmol), sodium azide (129 mg, 1.98
mmol), copper(I) iodide (30 mg, 0.16 mmol), sodium
(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate
(15 mg, 0.08 mmol), EtOH (2.0 mL) and water (0.2 mL), then purged
with N.sub.2 and sealed. Then
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (25 .mu.L, 0.16
mmol) was added via a syringe. The mixture was heated at 80.degree.
C. for 1 h, cooled to RT, treated with saturated NH.sub.4Cl and
diluted with EtOAc. The organic layer was separated and the aqueous
layer was extracted twice with EtOAc. The combined organic solution
was washed with brine, dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. The crude material was used in next step
directly.
[1892] To a solution of the above crude product in THF (3 mL) and
water (1 mL) was added trimethylphosphine (1.0 M solution in THF,
0.47 mL, 0.47 mmol). After 10 min, LCMS showed the reaction was
complete. The mixture was evaporated to dryness and the residue was
purified by a quick silica gel chromatography (0-50% EtOAc in DCM)
to give (1S,5S,6S)-methyl
5-(5-amino-2-fluoropyridin-3-yl)-3-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxylate (99A, 150 mg, 0.28 mmol, 70% yield) as a white solid
(containing about 10% of the ethyl ester). LCMS m/z=540.72
[M+H].sup.+. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.51 (d,
J=2.35 Hz, 1H), 7.43 (dd, J=2.93, 8.41 Hz, 1H), 5.27 (d, J=10.76
Hz, 1H), 5.01 (d, J=10.56 Hz, 1H), 3.78 (s, 3H), 3.64 (t, J=8.22
Hz, 2H), 2.58-2.74 (m, 1H), 1.70 (s, 3H), 1.51 (s, 10H), 1.45 (dd,
J=5.18, 9.88 Hz, 1H), 1.14 (dd, J=5.28, 7.43 Hz, 1H), 0.87-0.99 (m,
2H), 0.00 (s, 9H).
Preparation of Compound 99B
[1893] To a mixture of (1S,5S,6S)-methyl
5-(5-amino-2-fluoropyridin-3-yl)-3-((tert-butoxycarbonyl)((2-(trimethylsi-
lyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxylate (99A, 50 mg, 0.09 mmol) and
5-chloro-2-pyridinecarboxylic acid (29 mg, 0.18 mmol) in 0.5 mL of
DMF was added HATU (70 mg, 0.18 mmol) and diisopropylethylamine (32
.mu.L, 0.18 mmol). After stirring overnight, the reaction was
quenched with sat. NH.sub.4Cl, extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered, and evaporated to dryness. The residue
was purified by flash column (10-100% EtOAc in DCM) to afford
(1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(5-(5--
chloropicolinamido)-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxylate (99B, 51 mg, 0.07 mmol, 81% yield) as a
gum. LCMS m/z=680.0 [M+H].sup.+. .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta. 9.86 (s, 1H), 8.72 (d, J=1.90 Hz, 1H), 8.59
(d, J=1.90 Hz, 1H), 8.41 (dd, J=2.70, 8.55 Hz, 1H), 8.27 (d, J=8.33
Hz, 1H), 7.93 (dd, J=2.34, 8.33 Hz, 1H), 5.38 (d, J=10.52 Hz, 1H),
5.13 (d, J=10.52 Hz, 1H), 3.83 (s, 3H), 3.71 (t, J=8.26 Hz, 2H),
2.73 (t, J=8.70 Hz, 1H), 1.80 (s, 3H), 1.57 (s, 9H), 1.48-1.55 (m,
1H), 1.18-1.25 (m, 1H), 0.99 (dd, J=6.80, 9.43 Hz, 2H), 0.00 (s,
9H).
Preparation of Example 99
[1894] To (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(5-(5--
chloropicolinamido)-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxylate (99A, 50 mg, 0.07 mmol) at RT was added
sulfuric acid (157 .mu.L, 2.94 mmol). After stirring for 15 min,
the reaction was quenched by slow addition of saturated NaHCO.sub.3
solution (until pH was about 8). The mixture was extracted with
EtOAc three times, dried over Na.sub.2SO.sub.4, filtered and
evaporated to dryness. Flash chromatography (10-90% EtOAc in DCM)
gave (1S,5S,6S)-methyl
3-amino-5-(5-(5-chloropicolinamido)-2-fluoropyridin-3-yl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (Example 99, 31 mg,
94% yield) as a white solid. LCMS m/z=449.9 [M+H].sup.+. .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta. 9.87 (s, 1H), 8.61-8.68 (m,
1H), 8.57 (d, J=2.34 Hz, 1H), 8.47 (dd, J=2.78, 8.62 Hz, 1H),
8.21-8.30 (m, 1H), 7.90 (dd, J=2.34, 8.33 Hz, 1H), 3.80 (s, 3H),
2.62 (ddd, J=1.24, 7.67, 9.79 Hz, 1H), 1.72 (d, J=1.32 Hz, 3H),
1.53 (dd, J=5.19, 9.72 Hz, 1H), 1.13 (dd, J=5.26, 7.45 Hz, 2H).
Preparation of Example 100
[1895] To a solution of (1S,5S,6S)-methyl
3-amino-5-(5-(5-chloropicolinamido)-2-fluoropyridin-3-yl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (Example 99, 26 mg,
0.06 mmol) in 5 mL of THF at RT was added lithium borohydride (72
.mu.L of 2 M solution in THF, 0.14 mmol) followed by two drops of
methanol. After stirring for 1 h, the reaction was quenched by the
careful addition of satd. NH.sub.4Cl. It was extracted with EtOAc
(2.times.). The combined organic extracts were dried
(Na.sub.2SO.sub.4), filtered, and concentrated in vacuo. Flash
chromatography (10-90% EtOAc in DCM) gave
N-(5-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-6-fluoropyridin-3-yl)-5-chloropicolinamide
(Example 100, 12 mg, 49% yield) as a white solid. LCMS m/z=422.0
[M+H].sup.+. .sup.1H NMR (300 MHz, MeOH) .delta. 8.74 (d, J=2.34
Hz, 1H), 8.62 (dd, J=1.75, 2.63 Hz, 1H), 8.52 (dd, J=2.63, 8.77 Hz,
1H), 8.20-8.28 (m, 1H), 8.11 (dd, J=2.34, 8.48 Hz, 1H), 3.59-3.76
(m, 2H), 1.79-1.86 (m, 1H), 1.78 (d, J=1.32 Hz, 3H), 1.03 (dd,
J=5.70, 9.35 Hz, 1H), 0.77 (t, J=5.99 Hz, 1H).
Example 636:
(1S,5S,6S)-5-(2,3-difluoro-5-((7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-
phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
##STR00724##
[1897] A mixture of
(1S,5S,6S)-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.-
1.0]hept-3-en-3-amine (0.05 g, 0.18 mmol) and
4-chloro-7-fluoropyrido[3,2-d]pyrimidine (0.068 g, 0.37 mmol) in
HOAc (0.5 mL) was heated to 80.degree. C. for 3 h. The mixture was
cooled to RT, diluted with EtOAc, and then washed with saturated
aqueous sodium bicarbonate solution several times. The resulting
organic solution was then dried over anhydrous magnesium sulfate,
filtered, and concentrated in vacuo to give an oil. The oil was
purified by silica gel chromatography (0-5% MeOH in DCM) to give
the title compound as a yellow solid. .sup.1H NMR (CHLOROFORM-d)
.delta. ppm 9.08 (br. s., 1H) 8.78 (s, 1H) 8.67 (d, J=2.74 Hz, 1H)
8.34-8.41 (m, 1H) 7.82 (dd, J=8.80, 2.54 Hz, 1H) 7.47 (dd, J=5.38,
2.45 Hz, 1H) 2.20-2.27 (m, 1H) 1.91-2.01 (m, 1H) 1.80 (s, 3H)
0.90-1.01 (m, 1H) 0.63 (dd, J=11.35, 5.67 Hz, 1H). MS m/z=417.0
[M+H].sup.+.
Example 637:
N-(5-((1S,5S,6S)-3-Amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-y-
l)-6-fluoropyridin-3-yl)-5-chloropicolinamide
##STR00725##
[1899] Flask A: A mixture of CDI (35 mg, 0.22 mmol) and
5-chloro-2-pyridinecarboxylic acid (34 mg, 0.22 mmol) in DMF (0.6
mL) was stirred as gas evolution occurred in .about.1 min. The
mixture was heated at 60.degree. C. for 10 min then cooled to RT.
Flask B: at RT, a solution of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(intermediate 228) (30 mg, 0.06 mmol) in DMF (0.5 mL) was treated
with the solution from Flask A (0.2 mL, .about.1.15 equiv). The
mixture in Flask B was heated at 60.degree. C. for 30 min.
Additional portion of the solution from Flask A (0.1 mL) was added
to Flask B. After heating for 2 days, the mixture in Flask B was
diluted with EtOAc (10 mL) and washed sequentially with water (2
mL), saturated NaHCO.sub.3 (2 mL) and brine (2 mL). The aqueous
layer was extracted with EtOAc (5 mL). The combined organic layer
was dried over Na.sub.2SO.sub.4, filtered, and concentrated to give
a yellow oil. LCMS (ESI, pos.) 622 (M+1). At RT, the yellow oil was
treated with sulfuric acid (0.25 mL, 4.69 mmol). After 20 min, the
mixture was quenched with ice (5 g) and treated with NaOH (5 N)
until the pH reached >12. The mixture was extracted with DCM
(3.times.5 mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by chromatography on silica using [10% (2 N NH.sub.3 in
MeOH) in DCM] in heptane (10-50%) as the eluent to give the product
which was lyophilized (ACN-water) to afford Example 637 as a white
flake (15 mg, 63%). LCMS (ESI, pos.) 392 (M+1). .sup.1H NMR (400
MHz, ACETONITRILE-d3) .delta. 9.99 (br. s., 1H, NH), 8.67 (d,
J=1.76 Hz, 1H), 8.52-8.57 (m, 1H), 8.48 (dd, J=2.74, 8.80 Hz, 1H),
8.19 (d, J=8.41 Hz, 1H), 8.02 (dd, J=2.35, 8.41 Hz, 1H), 4.88 (br.,
2H, NH2), 2.26 (ddd, J=4.89, 7.63, 9.19 Hz, 2H), 1.84-1.92 (m, 1H),
1.67 (d, J=1.17 Hz, 3H), 0.80-0.90 (m, 1H), 0.43-0.51 (m, 1H).
Examples:
5-((5-((1S,5S,6S)-3-amino-5-methyl-2-thia-4-azabicyclo[4.1.0]hep-
t-3-en-5-yl)-6-fluoropyridin-3-yl)amino)pyrido[3,4-b]pyrazin-2(1H)-one
(638) and
(1S,5S,6S)-5-(2-fluoro-5-((2-(prop-2-yn-1-yloxy)pyrido[3,4-b]py-
razin-5-yl)amino)pyridin-3-yl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-e-
n-3-amine (639)
##STR00726##
[1901] A mixture of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluoropyridin-3-yl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(intermediate 228) (82 mg, 0.17 mmol),
5-chloro-2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazine (intermediate
262) (53 mg, 0.24 mmol), and p-toluenesulfonic acid (60 mg, 0.315
mmol) in IPA (2 mL) was heated at 80.degree. C. for 1 h. The
solvent was concentrated and the residue was treated with sulfuric
acid (0.25 mL, 4.69 mmol) and heated at 50.degree. C. for 1 h. The
mixture was quenched with ice (5 g) and treated with NaOH (5 N)
until the pH reached >12. The mixture was extracted with DCM
(3.times.5 mL). The combined organic phase was dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
chromatography on silica using a gradient of [10% (2 N NH.sub.3 in
MeOH) in EtOAc] in DCM (10-70%) to give two fractions: 1.sup.st
fraction was a mixture of Example 639 and Example 638; the 2.sup.nd
fraction was the pure Example 638 (9 mg, 12% yield) as a yellow
solid. The analytical data for Example 638: .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.57 (br. s., 1H), 9.41 (s, 1H), 8.42-8.69 (m,
2H), 7.99-8.18 (m, 2H), 6.63 (d, J=5.67 Hz, 1H), 5.96 (br. s., 2H),
2.26-2.40 (m, 1H), 1.68-1.82 (m, 1H), 1.63 (s, 3H), 0.86 (d, J=4.69
Hz, 1H), 0.37-0.51 (m, 1H). LCMS (ESI, pos.) 398.0 (M+1).
[1902] The mixture of Example 639 and Example 638 was purified by
reverse-phase preparative HPLC (Gilson GX281) using a Phenomenex
Gemini column, 5 micron, C18, 110 .ANG., 150.times.30 mm, 0.1% TFA
in CH.sub.3CN/H.sub.2O, gradient 5% to 60% over 16 min. The
fraction containing Example 639 was concentrated and partitioned
between saturated NaHCO.sub.3 (5 mL) and IPA (3%) --CH.sub.3Cl (10
mL). The organic phase was washed again with saturated NaHCO.sub.3
(5 mL) and concentrated. This material was dried (lyophilized from
ACN-water) to provide
(1S,5S,6S)-5-(2-fluoro-5-((2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazin-5-yl-
)amino)pyridin-3-yl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(Example 639, 26 mg, 38% yield) as a yellow flake. .sup.1H NMR (400
MHz, ACETONITRILE-d3) .delta. 8.83 (s, 1H), 8.75 (t, J=2.35 Hz,
1H), 8.62 (dd, J=2.74, 9.00 Hz, 1H), 8.47 (s, 1H), 8.29 (d, J=5.87
Hz, 1H), 7.11 (d, J=5.87 Hz, 1H), 5.19 (d, J=2.35 Hz, 2H), 4.85
(br. s., 1H), 2.90 (t, J=2.45 Hz, 1H), 2.30 (ddd, J=4.99, 7.58,
9.34 Hz, 1H), 1.86-1.94 (m, 1H), 1.71 (d, J=1.17 Hz, 3H), 0.90
(ddd, J=5.38, 7.58, 8.95 Hz, 1H), 0.48-0.57 (m, 1H). LCMS (ESI,
pos.) 436.1 (M+1).
Example 722:
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(1H-1,2,3-triazol-1-ylmethyl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloro-2-pyri-
dinecarboxamide
##STR00727##
[1903] Preparation of Compound 722A
[1904] To a solution of Compound 250A, as a mixture of
[(1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-[(tert-butoxycarbonyl){[2-(trime-
thylsilyl)ethoxy]methyl}amino]-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]-
hept-3-en-1-yl]methyl 4-methylbenzenesulfonate (major) and
[(1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-3-[(tert-butoxycarbonyl)
{[2-(trimethylsilyl)ethoxy]methyl}amino]-5-(fluoromethyl)-2-thia-4-azabic-
yclo[4.1.0]hept-3-en-1-yl]methyl 4-methylbenzenesulfonate (minor),
(1.1 g, 1.471 mmol) in DMSO (9 mL) was added sodium azide (0.115 g,
1.765 mmol). After addition, the mixture was then stirred at RT
overnight. (+)-Sodium L-ascorbate (0.073 g, 0.368 mmol), copper
(ii) sulfate pentahydrate (0.367 g, 1.471 mmol), and
(trimethylsilyl)-acetylene (0.416 mL, 2.940 mmol) were added. After
the mixture was then stirred at RT for 2 h, it was quenched with
NH.sub.4Cl/NH.sub.4OH (10:1, 5 mL) and extracted with EtOAc
(2.times.10 mL). The combined organic extracts were dried over
MgSO.sub.4 and concentrated. The residue was purified by silica gel
flash column chromatography using ISCO instrument (0-100%
EtOAc/heptane) to give Compound 722A as a mixture of diastereomers,
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((4-(trimethyls-
ilyl)-1H-1,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3--
yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate and tert-butyl
((1R,5S,6R)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((4-(trimethyls-
ilyl)-1H-1,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3--
yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate (725 mg, 1.011 mmol,
69% yield) as a colorless solid. MS (ESI, positive ion) m/z: 716,
718 (M+1).
Preparation of Compound 722B
[1905] To a solution of 722A (720 mg, 1.004 mmol) in EtOH (3.0 mL)
and water (1.0 mL) was added sodium azide (196 mg, 3.01 mmol),
copper(i) iodide (47.8 mg, 0.25 mmol) and (+)-sodium L-ascorbate
(49.7 mg, 0.25 mmol). The mixture was then bubbled through N.sub.2
for 5 min and then trans-N,N'-dimethylcyclohexane-1,2-diamine
(0.040 mL, 0.251 mmol) was added. The resulting mixture was then
stirred at 70.degree. C. for 2 h under N.sub.2. It was quenched
with saturated NH.sub.4Cl/NH.sub.4OH (10:1, 5 mL), extracted with
EtOAc (2.times.). The combined organic extracts were dried over
MgSO.sub.4 and concentrated. The residue was then dissolved in
THF/H.sub.2O (9:1, 5 mL) and trimethylphosphine (1.0 M solution in
THF, 1.00 mL, 1.00 mmol) was added dropwise. After the addition,
the mixture was stirred at RT under N.sub.2 for 72 h.
Trimethylphosphine (1.0 M solution in THF, 0.5 mL) was added to the
mixture and stirring was continued for 30 min. The mixture was
treated with saturated NaHCO.sub.3 (5 mL) extracted with EtOAc
(2.times.5 mL). The combined organic extracts were dried over
MgSO.sub.4 and concentrated. The residue was purified by silica gel
flash column chromatography using ISCO instrument (0-100%
EtOAc/heptane) to give a product (547 mg, 0.84 mmol, 83% yield) as
a mixture of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((4-(trimethyls-
ilyl)-1H-1,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3--
yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate and tert-butyl
((1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((4-(trimethyls-
ilyl)-1H-1,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3--
yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate as a colorless oil.
MS (ESI, positive ion) m/z: 653.3 (M+1).
Preparation of Compound 722C
[1906] To a round bottom flask containing 722B (540 mg, 0.83 mmol)
at 0.degree. C. was added sulfuric acid (3.08 mL) dropwise. After
the addition, the mixture was stirred at RT for 20 min, and treated
with 20 g of ice. The mixture was cooled with an ice bath and
treated with 5 N NaOH till pH>12. It was extracted with EtOAc
(2.times.10 mL). The combined organic extracts were then dried over
MgSO.sub.4, concentrated, and dried in vacuo to give 722C as a
yellow oil, as a mixture of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((4-(trimethylsi-
lyl)-1H-1,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-a-
mine and
(1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((4-(tri-
methylsilyl)-1H-1,2,3-triazol-1-yl)methyl)-2-thia-4-azabicyclo[4.1.0]hept--
3-en-3-amine which was used in the next step without purification
requirement. MS (ESI, positive ion) m/z: 423.0 (M+1).
Preparation of Compound 722D
[1907] To a solution of 722C (67 mg, 0.159 mmol) in THF (0.3 mL)
was added TBAF solution (1.0 M in THF, 0.317 mL, 0.317 mmol). Then,
the mixture was stirred at 60.degree. C. for 9 h. It was cooled to
RT, treated with saturated NaHCO.sub.3 (1 mL) and saturated
NH.sub.4Cl (1 mL). The mixture was extracted with EtOAc (2.times.4
mL). The combined organic extracts were dried over MgSO.sub.4,
concentrated. The residue was purified by silica gel flash column
chromatography using ISCO instrument (0-30% MeOH/DCM) to give 68 mg
of 722D as a yellow oil, as a mixture of
(1S,5S,6S)-1-((1H-1,2,3-triazol-1-yl)methyl)-5-(5-amino-2-fluorophenyl)-5-
-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine and
(1R,5S,6R)-1-((1H-1,2,3-triazol-1-yl)methyl)-5-(5-amino-2-fluorophenyl)-5-
-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine. MS
(ESI, positive ion) m/z: 351.0 (M+1).
Preparation of Example 722
[1908] To a solution of 722D (16.2 mg, 0.10 mmol) in DMA (1.2 mL)
was added 5-chloro-2-pyridinecarboxylic acid (16.2 mg, 0.10 mmol).
The mixture was cooled to 0.degree. C. and propylphosphonic
anhydride solution (50 wt. % in EtOAc, 0.082 mL, 0.128 mmol) was
added. After addition, the mixture was stirred at RT overnight,
then quenched with saturated NaHCO.sub.3 (2 mL) and extracted with
EtOAc (2.times.5 mL). The combined organic extracts were dried over
MgSO.sub.4 and concentrated. The residue was purified by
preparative HPLC (0%-100% ACN 0.1% TFA/H.sub.2O 0.1% TFA). The
desired fractions were concentrated and the residue was treated
with saturated NaHCO.sub.3 (7 mL). The mixture was extracted with
EtOAc (2.times.10 mL). The combined organic extracts were dried
over MgSO.sub.4, concentrated, and dried in vacuo to give
N-(3-((1S,5S,6S)-1-((1H-1,2,3-triazol-1-yl)methyl)-3-amino-5-(fluoromethy-
l)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicol-
inamide (15 mg, 0.031 mmol, 24% yield) as a yellow solid. MS (ESI,
positive ion) m/z: 490 (M+1). 1H NMR (MeOH) .delta.: 8.70 (d, J=2.2
Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.04-8.10 (m, 2H), 7.80-7.86 (m,
1H), 7.74-7.80 (m, 2H), 7.17 (dd, J=11.5, 8.8 Hz, 1H), 4.50-4.83
(m, 4H), 2.18-2.26 (m, 1H), 1.52 (dd, J=9.6, 5.9 Hz, 1H), 0.85 (t,
J=6.4 Hz, 1H).
Examples: 752 (mixture of diastereomers), 753 and 962
N-(3-((4S,4aS,7aR)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide (753) and
N-(3-((4S,4aR,7aS)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide (962)
##STR00728##
[1909] Synthesis of
(S)-(4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsil-
yl)ethoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazin-6-yl)methyl
3-oxobutanoate (752A)
[1910] A solution of diisobutylaluminum hydride in THF (1.0 M; 13.7
mL, 13.7 mmol) was added drop wise to a solution of (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazine-6-carboxylate
(5.56 g, 9.15 mmol, 210A) in THF (100 ml) at 0.degree. C. under
nitrogen atmosphere. After 1 h, additional 13 mL DIBALH (1 M in
THF) was added. The reaction mixture was allowed to stir for
additional 20 min and was then slowly treated with MeOH. The
reaction mixture was partitioned between EtOAc and water. The
organic extract was separated, washed with brine and dried over
MgSO.sub.4. The solution was filtered and concentrated in vacuo to
give the crude material. The crude material was absorbed onto a
plug of silica gel and purified by column chromatography
(SiO.sub.2), eluting with a gradient of 10-80% (EtOAc in hexanes),
to provide (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(hydroxymethyl)-4H-1,3-thi-
azin-2-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate (5.3 g, 9.1
mmol, 99% yield) as a yellow oil. LC/MS (ESI.sup.+) m/z=589.0/581.2
(M+H).
[1911] A round-bottom flask was charged with (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-6-(hydroxymethyl)-4H-1,3-thi-
azin-2-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate (5.37 g, 9.27
mmol), 2-xylene (4 mL) and 2,2,6-trimethyl-1,3-dioxin-4-one (1.4
mL, 11 mmol). The reaction mixture was heated to 135.degree. C.
(internal temp 123.degree. C.) for 40 min. The reaction mixture was
cooled to RT and absorbed onto a plug of silica gel. Purification
by column chromatography (SiO.sub.2), eluting with a gradient of
10-70% (EtOAc in hexanes), afforded the title compound as a red oil
(752A; 4.4 g, 6.6 mmol, 71% yield). LC/MS (ESI.sup.+)
m/z=663.2/665.2 (M+H). The ketone compound exists in equilibrium
with the corresponding enol.
Synthesis of
(S)-(4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsil-
yl)ethoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazin-6-yl)methyl
2-diazoacetate (752B)
[1912] A solution of 4-acetamidobenzenesulfonyl azide (0.73 g, 3.0
mmol) in ACN (3 mL) was added drop wise to a stirred solution of
(S)-(4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsil-
yl)ethoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazin-6-yl)methyl
3-oxobutanoate (752A; 1.0 g, 1.5 mmol) and TEA (0.64 mL, 4.57 mmol)
in ACN (5 mL). The reaction mixture was stirred at RT for 1.5 h. An
aqueous LiOH solution (2 M, 2.3 mL, 4.57 mmol) was added and the
reaction mixture was stirred overnight at RT. The reaction mixture
was diluted with water and extracted with EtOAc. The organic phase
was washed with aqueous saturated ammonium chloride solution and
dried over MgSO.sub.4. The solution was filtered and concentrated
in vacuo to give the crude material. The crude material was
absorbed onto a plug of silica gel and purified by column
chromatography (SiO.sub.2) eluting with a gradient of 5-60% (EtOAc
in hexanes), to provide the title compound (752B; 700 mg, 1.08
mmol, 71% yield) as a yellow oil. LC/MS (ESI.sup.+) m/z=647.2
(M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. ppm -0.02-0.05
(m, 9H) 0.99 (dd, J=8.92, 7.60 Hz, 2H) 1.56 (s, 9H) 3.69 (td,
J=8.22, 0.80 Hz, 2H) 4.50-4.94 (m, 5H) 5.26-5.34 (m, 1H) 5.36-5.44
(m, 1H) 6.19 (d, J=3.80 Hz, 1H) 6.96 (dd, J=11.25, 8.62 Hz, 1H)
7.41 (ddd, J=8.66, 4.28, 2.56 Hz, 1H) 7.67 (dd, J=6.87, 2.48 Hz,
1H)
Synthesis of 752C
[1913] A solution of
(S)-(4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)((2-(trimethylsil-
yl)ethoxy)methyl)amino)-4-(fluoromethyl)-4H-1,3-thiazin-6-yl)methyl
2-diazoacetate (752B, 0.32 g, 0.49 mmol) in dichloroethane (4 mL)
was added drop wise (addition rate 1.3 mL/h) to a refluxing
solution of bis(2-((E)-(tert-butylimino)methyl)phenoxy)copper (10.0
mg, 0.025 mmol, synthesized according to J. Org. Chem. 1957, 22,
677) in toluene (15 mL). The reaction mixture was allowed to stir
for one more hour at the same temperature after completed addition
(5 h total reaction time). The solvent was removed under reduced
pressure and the residue was dissolved in THF (4 mL). A solution of
lithium borohydride in THF (2.0 M in THF; 0.32 mL, 0.64 mmol) was
added drop wise at 0.degree. C. The reaction mixture was allowed to
warm to RT. Additional lithium borohydride solution (0.32 mL, 0.64
mmol) were added drop wise. The reaction mixture was allowed to
stir overnight. The reaction mixture was then cooled to 0.degree.
C. and quenched by the addition of aqueous HCl solution (1 M). The
aqueous phase was extracted with EtOAc. The organic extract was
washed with brine and dried over MgSO.sub.4. The solution was
filtered and concentrated in vacuo to give the crude material. The
crude material was absorbed onto a plug of silica gel and purified
by column chromatography (SiO.sub.2), eluting with a gradient of
5-75% (EtOAc in hexanes), to provide a 65:35 mixture of tert-butyl
((1R,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1,7-bis(hydroxyme-
thyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)-
methyl)carbamate and tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1,7-bis(hydroxyme-
thyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)-
methyl)carbamate (752C) (0.12 g, 0.20 mmol, 40% yield) as an oil.
LC/MS (ESI.sup.+) m/z=645.2/647.2 (M+Na, for both isomers).
Retention time of minor isomer=1.58 min; Retention time of major
isomer=1.61 min on LC.
Synthesis of 752D
[1914] A 65:35 mixture of tert-butyl
((1R,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1,7-bis(hydroxyme-
thyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)-
methyl)carbamate and tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1,7-bis(hydroxyme-
thyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)-
methyl)carbamate (752C; 143 mg, 0.22 mmol) was dissolved in DCM
(1.5 mL) and cooled to 0.degree. C. TEA (96 .mu.L, 0.69 mmol) was
added, followed by methanesulfonyl chloride (36 .mu.L, 0.46 mmol).
The reaction was warmed to RT and, aqueous saturated bicarbonate
solution was added after 10 min, followed by EtOAc. The organic
extract was washed with brine and dried over MgSO.sub.4. The
solution was filtered and concentrated in vacuo to give the crude
material. The crude material was dissolved in DMSO (1 mL) and
sodium sulfide (54 mg, 0.69 mmol) was added at RT. The suspension
was diluted after 20 min with H.sub.2O (30 mL) and extracted three
times with EtOAc. The combined organic extracts were dried over
MgSO.sub.4, filtered and concentrated to under reduced pressure.
The crude material was absorbed onto a plug of silica gel and
purified by column chromatography (SiO.sub.2), eluting with a
gradient of 5-100% EtOAc in hexanes, to provide a mixture of
tert-butyl
((4S,4aS,7aR)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4a,4b,5,7-tetra-
hydro-4H-thieno[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-2-yl)((2-(trimethy-
lsilyl)ethoxy)methyl)carbamate and tert-butyl
((4S,4aR,7aS)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4a,4b,5,7-tetra-
hydro-4H-thieno[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-2-yl)((2-(trimethy-
lsilyl)ethoxy)methyl)carbamate (752D) as a colorless oil. LC/MS
(ESI.sup.+) m/z=643.1/645.0 (M+Na, for both isomers, same retention
time). The ratio of isomers was not determined.
Synthesis of 752E
[1915] A resealable tube was charged with a mixture of tert-butyl
((4S,4aS,7aR)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4a,4b,5,7-tetra-
hydro-4H-thieno[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-2-yl)((2-(trimethy-
lsilyl)ethoxy)methyl)carbamate and tert-butyl
((4S,4aR,7aS)-4-(5-bromo-2-fluorophenyl)-4-(fluoromethyl)-4a,4b,5,7-tetra-
hydro-4H-thieno[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-2-yl)((2-(trimethy-
lsilyl)ethoxy)methyl)carbamate (752D; 117 mg, 0.19 mmol), copper(I)
iodide (7 mg, 0.04 mmol), sodium azide (37 mg, 0.57 mmol),
(+)-sodium L-ascorbate (7.5 mg, 0.04 mmol). The reaction vessel was
evacuated and backfilled with nitrogen. EtOH (1.3 mL) and water
(0.57 mL) were added and the reaction mixture was degassed by
bubbling nitrogen through the solution for 5 min.
(1R,2R)-(-)-N,N''-dimethylcyclohexane-1,2-diamine (6.0 .mu.L, 0.04
mmol) was added and the reaction mixture was heated to 80.degree.
C. for 30 min. The reaction mixture was cooled to RT and poured
into a solution of saturated ammonium chloride and saturated
ammonium hydroxide (9:1). The mixture was extracted three times
with EtOAc. The organic layers were combined and concentrated under
reduced pressure. The residue was dissolved in THF (3 mL) and
H.sub.2O (1.5 mL). A solution of trimethylphosphine in THF (0.21 mL
of 1.0 M in THF, 0.21 mmol) was added at RT. The reaction was
stirred for 15 min. The reaction was diluted with water and EtOAc.
The organic layer was separated, washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure. The
crude mixture (752E; 100 mg) was used directly in the next step
without further purification. LC/MS (ESI.sup.+) m/z=558.2 (M+H,
same for both isomers same retention time). The ratio of isomers
was not determined.
Synthesis of Example 752 (a Mixture of Diastereomers)
[1916] A flask was charged with the crude product from the former
step (752E; 100 mg, 0.18 mmol), 5-chloro-2-pyridinecarboxylic acid
(34 mg, 0.21 mmol) and DMF (0.9 mL). The solution was cooled to
0.degree. C. and
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-meth-
ylmethanaminium hexafluorophosphate N-oxide (HATU, 119 mg, 0.31
mmol) and diisoproyl-ethyl-amine (55 .mu.L, 0.31 mmol) were added.
The reaction mixture was poured into water after 10 min reaction
time. A white solid precipitated and was filtered off. The solid
was washed with water and dried under reduced pressure. The solid
was subsequently dissolved in concentrated H.sub.2SO.sub.4 (1 mL)
and stirred vigorously at RT for 20 min. The reaction mixture was
poured into water and the pH was adjusted to 10 with aqueous 5 M
NaOH solution. A white solid precipitated and was filtered off. The
solid was dissolved in EtOAc and dried over MgSO.sub.4. The
solution was filtered and concentrated in vacuo to give a mixture
of
N-(3-((4S,4aR,7aS)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide and
N-(3-((4S,4aS,7aR)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide as a white solid (47 mg, 0.1 mmol, 56%). The ratio of
isomers was determined to be 63:37 by analytical superfluid
chromatography using supercritical CO.sub.2 (additives 35% of 20 mM
NH.sub.3 in MeOH) on a Chiracel AD column (100.times.2.1 mm, 3
.mu.m) eluting at a flow rate 1 mL/min (105 bar pressure,
25.degree. C. column temperature). LC/MS (ESI.sup.+) m/z=467.4
(M+H, for both isomers). .sup.1H NMR (400 MHz, CHLOROFORM-d;
overlapping signals) .delta. ppm 1.49 (t, J=4.89 Hz, 1H) 2.16-2.22
(m, 1H) 2.46 (d, J=2.93 Hz, 1H) 2.70 (d, J=5.28 Hz, 1H) 2.93 (d,
J=11.15 Hz, 1H) 3.03-3.26 (m, 4H) 3.30-3.39 (m, 1H) 4.60-4.98 (m,
3H) 7.13 (dd, J=11.35, 8.80 Hz, 2H) 7.64-7.72 (m, 1H) 7.89 (dd,
J=8.41, 2.35 Hz, 2H) 7.94-8.03 (m, 1H) 8.20-8.30 (m, 2H) 8.57 (d,
J=1.96 Hz, 2H) 9.83 (s, 1H).
[1917] The mixture of
N-(3-((4S,4aR,7aS)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide and
N-(3-((4S,4aS,7aR)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide (Example 752) (39 mg) was chromatographed using
supercritical CO.sub.2 (additives 30% of 20 mM NH.sub.3 in MeOH) on
a Chiracel AD column (250.times.21 mm, 10 .mu.m) eluting at a flow
rate 70 mL/min (158 bar pressure, 40.degree. C. column
temperature). The first peak (retention time=3.1 min) provided
N-(3-((4S,4aS,7aR)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide
(Example 753; 17 mg, >99% ee), and the second peak (retention
time=3.8 min) provided
N-(3-((4S,4aR,7aS)-2-amino-4-(fluoromethyl)-4a,4b,5,7-tetrahydro-4H-thien-
o[3',4':2,3]cyclopropa[1,2-e][1,3]thiazin-4-yl)-4-fluorophenyl)-5-chloropi-
colinamide (Example 962; 8 mg, >99% ee). LC/MS (ESI.sup.+)
m/z=467.4 (M+H, for both isomers). .sup.1H NMR (400 MHz,
DMSO-d.sub.6, Example 753) .delta. ppm 1.40 (t, J=4.40 Hz, 1H) 2.16
(d, J=3.52 Hz, 1H) 2.85 (d, J=11.15 Hz, 1H) 3.00-3.08 (m, 1H)
3.10-3.22 (m, 3H) 4.52-4.79 (m, 2H) 6.39 (br. s., 2H) 7.19 (dd,
J=11.74, 9.00 Hz, 1H) 7.82 (dt, J=8.71, 3.57 Hz, 1H) 8.00 (dd,
J=7.14, 2.64 Hz, 1H) 8.13-8.16 (m, 1H) 8.17-8.23 (m, 1H) 8.78 (d,
J=2.35 Hz, 1H) 10.61 (s, 1H); .sup.1H NMR (400 MHz, DMSO-d.sub.6,
Example 962) .delta. ppm 1.96 (br. s., 1H) 2.35 (br. s., 1H)
2.94-3.08 (m, 2H) 3.45 (d, J=10.95 Hz, 2H) 4.45-4.65 (m, 1H)
4.72-4.95 (m, 1H) 6.32 (br. s., 2H) 7.11-7.23 (m, 1H) 7.78 (br. s.,
1H) 8.13-8.25 (m, 3H) 8.81 (d, J=1.37 Hz, 1H) 10.78 (s, 1H); The
relative stereochemistry was confirmed by COSY, HMBC and NOESY
correlations.
Example 754:
(1S,5S,6S)-5-(5-((3-chloropyrido[2,3-d]pyridazin-8-yl)amino)-2-fluorophen-
yl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
##STR00729##
[1918] Preparation of 5-chloro-N-phenylpicolinamide (754A)
[1919] To a stirred solution of 5-chloropicolinic acid (1.5 g, 9.52
mmol), aniline (1.13 mL, 12.38 mmol), and EtNiPr.sub.2 (2.16 mL,
12.38 mmol) in DMF (15 mL) was added HATU (4.05 g, 10.66 mmol).
After the addition, the mixture was stirred for 2 h. H.sub.2O was
added and the white solid was collected, washed with H.sub.2O,
dried to give the title compound (2.05 g, 93%). .sup.1H NMR
(CHLOROFORM-d) .delta.: 9.82 (br. s., 1H), 8.57 (d, J=2.0 Hz, 1H),
8.26 (d, J=8.4 Hz, 1H), 7.88 (dd, J=8.4, 2.3 Hz, 1H), 7.76 (dd,
J=8.6, 1.0 Hz, 2H), 7.39 (t, J=7.9 Hz, 2H), 7.07-7.21 (m, 1H). MS
(ESI, positive ion) m/z: 233 (M+1).
Preparation of
3-chloro-5-hydroxy-6-phenyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one
(754B)
[1920] To a stirred solution of 5-chloro-N-phenylpicolinamide
(754A, 1.00 g, 4.30 mmol) in THF (10 mL) at -78.degree. C. was
added lithium diisopropylamide (4.73 mL of 2 M in THF, 9.46 mmol)
dropwise. After stirring at -78.degree. C. for 1 h, DMF (1.99 mL,
25.8 mmol) was added and continued to stirred at -78.degree. C. for
another 2 h, then warmed to RT, and quenched with saturated
NH.sub.4Cl. The mixture was extracted with EtOAc (3.times.). The
extracts were dried over Na.sub.2SO.sub.4, concentrated. The
residue was triturated in EtOH, and the solid (0.78 g, 69%) was
filtered, dried and used in the next step. MS (ESI, positive ion)
m/z: 261 (M+1).
Preparation of 3-chloropyrido[2,3-d]pyridazin-8(7H)-one (754C)
[1921] A mixture of
3-chloro-5-hydroxy-6-phenyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one
(754B, 1.10 g, 4.22 mmol) and hydrazine (3.97 mL, 127 mmol) was
stirred at RT overnight. The solid (0.65 g, 85%) was collected,
washed with EtOH, and used in the next step. .sup.1H NMR (DMSO-d6)
.delta.: 13.01 (br. s., 1H), 9.07 (d, J=2.3 Hz, 1H), 8.58 (d, J=2.3
Hz, 1H), 8.34 (s, 1H). MS (ESI, positive ion) m/z: 182 (M+1).
Preparation of 3,8-dichloropyrido[2,3-d]pyridazine (754D)
[1922] A mixture of 3-chloropyrido[2,3-d]pyridazin-8(7H)-one (754C,
1.80 g, 9.91 mmol) and phosphorus oxychloride (9.24 mL, 99 mmol)
was heated at 90.degree. C. for 3 h. The reaction mixture was
cooled, poured onto ice in a beaker and neutralized with saturated
NaHCO.sub.3. The solid (0.45 g, 22%) was collected dried and used
in the next step. MS (ESI, positive ion) m/z: 200 (M+1).
Preparation of
(1S,5S,6S)-5-(5-((3-chloropyrido[2,3-d]pyridazin-8-yl)amino)-2-fluorophen-
yl)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-amine
(754)
[1923] A mixture of
(1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-thia-4-azabicycl-
o[4.1.0]hept-3-en-3-amine (754D, 0.10 g, 0.37 mmol),
3,8-dichloropyrido[2,3-d]pyridazine (204) (0.074 g, 0.371 mmol),
4-methylbenzenesulfonic acid hydrate (0.071 g, 0.371 mmol) in EtOH
(4 mL) was heated at 80.degree. C. in 4 h. The mixture was cooled,
saturated aqueous NaHCO.sub.3 was added, the solid was collected,
dried and purified by silica gel column to give the title compound
(25 mg, 16%). .sup.1H NMR (DMSO-d6) .delta.: 9.46 (s, 1H), 9.24 (d,
J=2.3 Hz, 1H), 9.15 (s, 1H), 8.71 (d, J=2.3 Hz, 1H), 8.18-8.28 (m,
1H), 7.92-8.02 (m, 1H), 7.21 (dd, J=11.8, 9.1 Hz, 1H), 6.19 (br.
s., 2H), 4.75-4.89 (m, 1H), 4.63-4.75 (m, 1H), 2.39 (d, J=4.5 Hz,
1H), 1.79 (d, J=7.2 Hz, 1H), 1.03 (d, J=6.1 Hz, 1H), 0.44 (d, J=5.3
Hz, 1H). MS (ESI, positive ion) m/z: 433/435 (M+1).
Example 755: (E)-ethyl
3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluo-
romethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylate
##STR00730##
[1924] Preparation of (E)-ethyl
3-((1R,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(tri-
methylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)acrylate (755A)
[1925] To a stirred solution of triethyl phosphonoacetate (0.227
mL, 1.014 mmol) in THF (5 mL) was added potassium tert-butoxide
(1.0 M solution in THF, 1.014 mL, 1.014 mmol) dropwise. After the
addition, the mixture was stirred for 30 min., then a solution of
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (4.01 mL, 0.84 mmol) was added and stirred for another 30 min.
It was treated with saturated aqueous NH.sub.4Cl and extracted with
EtOAc (3.times.). The extracts were washed with brine, dried over
Na.sub.2SO.sub.4, and concentrated to give Compound 755A (2.98 g,
100%). .sup.1H NMR (CHLOROFORM-d) .delta.: 7.82 (dd, J=6.8, 2.5 Hz,
1H), 7.41 (ddd, J=8.6, 4.3, 2.7 Hz, 1H), 6.97 (dd, J=11.7, 8.6 Hz,
1H), 6.66 (d, J=15.5 Hz, 1H), 6.03 (d, J=15.5 Hz, 1H), 5.31 (d,
J=10.4 Hz, 1H), 5.06 (d, J=10.6 Hz, 1H), 4.78-4.97 (m, 1H),
4.62-4.78 (m, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.67 (dd, J=9.4, 7.4 Hz,
2H), 2.16 (ddd, J=9.7, 7.5, 2.0 Hz, 1H), 1.54 (s, 8H), 1.25-1.35
(m, 4H), 1.12 (dd, J=7.1, 6.0 Hz, 1H), 0.97 (dd, J=9.3, 7.3 Hz,
2H), 0.00 (s, 9H). MS (ESI, positive ion) m/z: 661 (M+1).
Preparation of (E)-ethyl
3-((1R,5S,6S)-5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(tri-
methylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)acrylate (755B)
[1926] A mixture of (E)-ethyl
3-((1R,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(tri-
methylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)acrylate (2.98 g, 4.50 mmol), sodium
(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate
(0.223 g, 1.126 mmol), copper(I) iodide (0.214 g, 1.126 mmol),
sodium azide (0.88 g, 13.51 mmol), and
(1R,2R)--N1,N2-dimethylcyclohexane-1,2-diamine (0.178 ml, 1.126
mmol) in EtOH/H.sub.2O (5:1, 33 mL) was heated at 85.degree. C. in
2 h. The reaction mixture was cooled to RT, and partitioned between
EtOAc and saturated NH.sub.4Cl/NH.sub.4OH (10/1). The organic phase
was washed brine, dried over Na.sub.2SO.sub.4, and concentrated to
give the oil. The oil was dissolved in 9:1 of THF/H.sub.2O (30 mL)
and treated with trimethylphosphine (6.99 mL of 1 M in THF
solution, 6.99 mmol). After stirring for 30 min, it was diluted
with EtOAc and H.sub.2O. The organic solution was dried over
Na.sub.2SO.sub.4, and concentrated. The resulting brown oil was
purified on silica gel column to give Compound 755B as a light
yellow gum (1.48 g, 53%). MS (ESI, positive ion) m/z: 598
(M+1).
Preparation of (E)-ethyl
3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluo-
romethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylate
(755)
[1927] To a stirred mixture of (E)-ethyl
3-((1R,5S,6S)-5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(tri-
methylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)acrylate (2.02 g, 3.38 mmol),
5-chloro-2-pyridinecarboxylic acid (0.57 g, 3.72 mmol),
EtNiPr.sub.2 (0.76 mL, 4.39 mmol) in DMF (20 mL) was added HATU
(1.54 g, 4.05 mmol). After the addition, the mixture was stirred at
RT overnight, then treated with H.sub.2O and extracted with EtOAc
(3.times.). The organic extracts were dried over Na.sub.2SO.sub.4,
and concentrated to give (E)-ethyl
3-((1R,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)a-
mino)-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylate a light brown oil (755C,
2.44 g, 98%) as a brown oil, which was used in the next step
without further purification. MS (ESI, positive ion) m/z: 737
(M+1).
Preparation of (E)-ethyl
3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluo-
romethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylate
(755)
[1928] To a stirred neat (E)-ethyl
3-((1R,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)a-
mino)-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluoromethyl)-2-thia--
4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylate (77 mg, 0.10 mmol) at
0.degree. C. was added H.sub.2SO.sub.4/TFA (1:4, 1 mL). The
stirring was continued for 15 min at 0.degree. C., then basified
with saturated Na.sub.2CO.sub.3 until pH=9. It was extracted with
DCM (3.times.). The organic extracts were dried over
Na.sub.2SO.sub.4, and concentrated to give Example 755 (43 mg,
81%). .sup.1H NMR (DMSO-d6) .delta.: 10.61 (s, 1H), 8.78 (d, J=2.2
Hz, 1H), 8.17-8.21 (m, 1H), 8.12-8.16 (m, 1H), 7.97 (dd, J=7.1, 2.6
Hz, 1H), 7.85 (dd, J=8.0, 3.5 Hz, 1H), 7.08-7.26 (m, 1H), 6.73 (d,
J=15.5 Hz, 1H), 6.50 (br. s., 2H), 5.92 (d, J=15.5 Hz, 1H),
4.51-4.84 (m, 2H), 4.09-4.17 (m, 2H), 1.60 (dd, J=9.0, 4.9 Hz, 1H),
1.22 (t, J=7.1 Hz, 3H), 0.93-1.01 (m, 1H), 0.82-0.89 (m, 1H). MS
(ESI, positive ion) m/z: 507 (M+1).
Example 756:
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-3-hydroxyprop-1-en-1-yl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicolin-
amide
##STR00731##
[1930] To a stirred solution of (E)-ethyl
3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluo-
romethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylate (35 mg,
0.07 mmol) in THF (2 mL) at 0.degree. C. was added DIBAL-H (0.24 mL
of 1 M in THF, 0.24 mmol). After the addition, the reaction mixture
was stirred at RT for 2 h, then cooled with an ice bath and slowly
quenched with saturated Rochelle's salt. It was extracted with
EtOAc (3.times.). The organic extracts were dried over
Na.sub.2SO.sub.4, concentrated and the residue purified on a silica
gel column to give the title compound as an off white solid (15 mg,
16%). .sup.1H NMR (DMSO-d6) .delta.: 10.59 (s, 1H), 8.78 (d, J=2.3
Hz, 1H), 8.17-8.22 (m, 1H), 8.11-8.16 (m, 1H), 8.05 (dd, J=7.2, 2.9
Hz, 1H), 7.84 (dt, J=7.3, 4.3 Hz, 1H), 7.18 (dd, J=11.9, 8.8 Hz,
1H), 6.31 (s, 2H), 5.65-5.75 (m, 1H), 5.54-5.62 (m, 1H), 4.70-4.80
(m, 2H), 4.59-4.68 (m, 1H), 3.95 (t, J=4.4 Hz, 2H), 1.73 (t, J=8.0
Hz, 1H), 1.20 (dd, J=9.5, 5.2 Hz, 1H), 0.67-0.81 (m, 1H). MS (ESI,
positive ion) m/z: 465 (M+1).
Example 757:
(E)-3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(-
fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylic
acid
##STR00732##
[1932] To a stirred solution of (E)-ethyl
3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluo-
romethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylate (159
mg, 0.31 mmol) in EtOH (5 mL) was added lithium hydroxide (1.57 mL
of 1 M in water, 1.57 mmol). After the mixture was stirred for 16 h
at RT, it was concentrated. The residue was diluted with H.sub.2O
and acidified with 1 N HCl. The precipitated tan solid was
collected, washed with H.sub.2O, and dried to give Example 757 (83
mg, 55%). .sup.1H NMR (DMSO-d6) .delta.: 12.35 (br. s., 1H), 10.62
(s, 1H), 8.79 (d, J=1.8 Hz, 1H), 8.18-8.23 (m, 1H), 8.11-8.17 (m,
1H), 7.99 (dd, J=7.1, 2.6 Hz, 1H), 7.85 (dt, J=8.8, 3.4 Hz, 1H),
7.20 (dd, J=11.7, 8.8 Hz, 1H), 6.65 (d, J=15.5 Hz, 1H), 6.48 (s,
2H), 5.85 (d, J=15.5 Hz, 1H), 4.58-4.83 (m, 2H), 2.02 (t, J=8.8 Hz,
1H), 1.55 (dd, J=9.5, 5.2 Hz, 1H), 0.92-1.01 (m, 1H). MS (ESI,
positive ion) m/z: 479 (M+1).
Example 758:
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(3-hydroxypropyl)-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicolinamide
##STR00733##
[1934] To a stirred solution of (E)-ethyl
3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(fluo-
romethyl)-2-thia-4-azabicyclo[44.1.0]hept-3-en-1-yl)acrylate (34.7
mg, 0.07 mmol) in THF (2 mL) was added lithium borohydride (2.0 M
solution in THF (0.05 mL, 0.10 mmol). followed by MeOH (0.023 mL,
0.55 mmol). After the addition, the mixture was stirred was stirred
for 1 h. Another 0.05 mL of LiBH.sub.4 was added and the mixture
was continued to stir overnight. It was slowly quenched with
saturated aqueous NH.sub.4Cl, extracted with DCM (3.times.). The
organic extracts were dried over Na.sub.2SO.sub.4, concentrated and
the residue purified by ISCO (40-80% EtOAc in hexanes) to give the
title compound (19 mg, 59%) as an off white solid. .sup.1H NMR
(DMSO-d6) .delta.: 10.57 (s, 1H), 8.74-8.80 (m, 1H), 8.17-8.23 (m,
1H), 8.12-8.16 (m, 1H), 8.03 (dd, J=7.1, 2.6 Hz, 1H), 7.78-7.88 (m,
1H), 7.16 (dd, J=11.8, 8.9 Hz, 1H), 6.21 (s, 2H), 4.75 (s, 1H),
4.63 (s, 1H), 4.42 (t, J=5.1 Hz, 1H), 3.41 (q, J=5.4 Hz, 2H),
1.45-1.73 (m, 5H), 0.85 (dd, J=9.3, 5.0 Hz, 1H), 0.53 (t, J=5.6 Hz,
1H). MS (ESI, positive ion) m/z: 467/469 (M+1).
Example 759:
N-(3-((1R,5S,6S)-3-amino-1-((E)-3-amino-3-oxoprop-1-en-1-yl)-5-(fluoromet-
hyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropic-
olinamide
##STR00734##
[1936] To a stirred mixture of
(E)-3-((1R,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-5-(-
fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)acrylic acid
(45 mg, 0.10 mmol), DIEA (21.63 .mu.L, 0.12 mmol), and ammonia
(70.5 .mu.L, 0.14 mmol) in DMF (2 mL) was added HATU (42.9 mg, 0.11
mmol). After the reaction mixture was stirred at RT for 2 h, it was
treated with H.sub.2O and extracted with EtOAc (3.times.). The
organic extracts were dried over Na.sub.2SO.sub.4, concentrated,
and the residue was purified by reverse phase HPLC. The pure
fractions were concentrated to dryness. The residue was dissolved
in MeOH, and passed through PL-HCO.sub.3 MP SPE (200 mg per 6 mL
tube) to give the title compound (24.3 mg, 54%) as a yellow solid.
.sup.1H NMR (DMSO-d6) .delta.: 10.62 (s, 1H), 8.80 (d, J=1.8 Hz,
1H), 8.19-8.25 (m, 1H), 8.14-8.19 (m, 1H), 8.07 (dd, J=7.2, 2.7 Hz,
1H), 7.83-7.93 (m, 1H), 7.49 (br. s., 1H), 7.21 (dd, J=11.7, 8.8
Hz, 1H), 7.01 (br. s., 1H), 6.39-6.49 (m, 3H), 6.04 (d, J=15.5 Hz,
1H), 4.59-4.84 (m, 2H), 1.97 (t, J=8.0 Hz, 1H), 1.41 (dd, J=9.7,
5.2 Hz, 1H), 0.89-1.02 (m, 1H). MS (ESI, positive ion) m/z: 478
(M+1).
Example 760:
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-3-(methylamino)-3-oxopro-
p-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-c-
hloropicolinamide
##STR00735##
[1938] The title compound (23 mg, 59%) was prepared in the same
method as described in Example 759. .sup.1H NMR (DMSO-d6)
.delta.:10.62 (s, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.20-8.24 (m, 1H),
8.15-8.18 (m, 1H), 8.07 (dd, J=7.2, 2.7 Hz, 1H), 7.96-8.03 (m, 1H),
7.87 (dt, J=8.7, 3.5 Hz, 1H), 7.21 (dd, J=11.9, 8.8 Hz, 1H),
6.40-6.48 (m, 3H), 6.04 (d, J=15.3 Hz, 1H), 4.71-4.83 (m, 1H),
4.58-4.70 (m, 1H), 2.66 (d, J=4.7 Hz, 3H), 1.96 (t, J=8.3 Hz, 1H),
1.41 (dd, J=9.6, 5.3 Hz, 1H), 0.94-1.00 (m, 1H). MS (ESI, positive
ion) m/z: 492 (M+1).
Example 761:
N-(3-((1R,5S,6S)-3-amino-1-((E)-3-(dimethylamino)-3-oxoprop-1-en-1-yl)-5--
(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-
-chloropicolinamide
##STR00736##
[1940] The title compound (16 mg, 36%) was prepared in the same
method as described in Example 759. .sup.1H NMR (DMSO-d6) .delta.:
10.63 (s, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.19-8.25 (m, 1H), 8.13-8.18
(m, 1H), 8.03 (dd, J=7.1, 2.6 Hz, 1H), 7.87 (dt, J=7.3, 4.2 Hz,
1H), 7.21 (dd, J=11.9, 8.8 Hz, 1H), 6.40-6.58 (m, 4H), 4.73-4.84
(m, 1H), 4.61-4.72 (m, 1H), 3.07 (s, 3H), 2.90 (s, 3H), 1.95 (t,
J=8.2 Hz, 1H), 1.54 (dd, J=9.4, 5.3 Hz, 1H), 0.86-1.00 (m, 1H). MS
(ESI, positive ion) m/z: 506 (M+1).
Example 764:
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-3-morpholino-3-oxoprop-1-
-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chlo-
ropicolinamide
##STR00737##
[1942] The title compound (31 mg, 54%) was prepared in the same
method as described in Example 759. .sup.1H NMR (DMSO-d6)
.delta.:10.61 (s, 1H), 10.59 (s, 1H), 8.79 (d, J=1.8 Hz, 1H),
8.18-8.23 (m, 1H), 8.12-8.17 (m, 1H), 8.00 (dd, J=7.1, 2.6 Hz, 1H),
7.85 (dt, J=8.7, 3.5 Hz, 1H), 7.20 (dd, J=11.7, 8.8 Hz, 1H),
6.56-6.62 (m, 1H), 6.45-6.50 (m, 1H), 6.44 (s, 2H), 4.71-4.84 (m,
1H), 4.60-4.71 (m, 1H), 3.47-3.64 (m, 8H), 1.88-1.98 (m, 1H), 1.55
(dd, J=9.7, 5.2 Hz, 1H), 0.90-0.97 (m, 1H). MS (ESI, positive ion)
m/z: 548 (M+1).
Example 765:
N-(3-((1S,5S,6S)-3-amino-1-(3-(dimethylamino)-3-oxopropyl)-5-(fluoromethy-
l)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicol-
inamide
##STR00738##
[1944] To a stirred solution of
N-(3-((1R,5S,6S)-3-amino-1-((E)-3-(dimethylamino)-3-oxoprop-1-en-1-yl)-5--
(fluoromethyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-
-chloropicolinamide (31.5 mg, 0.062 mmol) in THF (2 mL) was added
lithium borohydride (2.0 M solution in THF, 62.3 .mu.L, 0.125
mmol). After 4 h, the reaction was slowly quenched with saturated
NH.sub.4Cl and extracted with DCM (3.times.). The organic extracts
were dried over Na.sub.2SO.sub.4, concentrated and purified by
reverse phase HPLC. The pure fractions were concentrated to
dryness. The residue was dissolved in MeOH and passed through a
PL-HCO3 MP SPE (200 mg per tube) to give the title compound (19.4
mg, 61%). .sup.1H NMR (DMSO-d6) .delta.:10.60 (s, 1H), 8.80 (d,
J=1.8 Hz, 1H), 8.20-8.25 (m, 1H), 8.15-8.19 (m, 1H), 8.04 (dd,
J=7.1, 2.6 Hz, 1H), 7.86 (dt, J=8.5, 3.5 Hz, 1H), 7.19 (dd, J=11.7,
8.8 Hz, 1H), 6.26 (s, 2H), 4.62-4.80 (m, 2H), 3.01 (s, 3H), 2.85
(s, 3H), 2.41-2.50 (m, 2H), 1.84-1.98 (m, 1H), 1.68-1.78 (m, 1H),
1.59-1.67 (m, 1H), 0.92 (dd, J=9.4, 5.1 Hz, 1H), 0.54 (t, J=5.7 Hz,
1H). MS (ESI, positive ion) m/z: 508 (M+1).
Example 766:
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-3-(3-methoxyazetidin-1-y-
l)-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluoro-
phenyl)-5-chloropicolinamide
##STR00739##
[1946] The title compound (14.5 mg, 25%) was prepared in the same
method as described in Example 759. 1H NMR (DMSO-d6) .delta.: 10.64
(br. s., 1H), 8.81 (d, J=2.2 Hz, 1H), 8.21-8.26 (m, 1H), 8.15-8.20
(m, 1H), 8.03 (br. s., 1H), 7.89 (br. s., 1H), 7.22 (br. s., 1H),
6.54 (d, J=15.1 Hz, 1H), 6.47 (br. s., 2H), 6.04 (d, J=15.3 Hz,
1H), 4.78 (d, J=16.8 Hz, 1H), 4.66 (d, J=17.2 Hz, 1H), 4.41 (br.
s., 1H), 4.24 (br. s., 1H), 4.09 (dd, J=17.3, 10.9 Hz, 2H), 3.72
(d, J=7.2 Hz, 1H), 3.25 (s, 3H), 1.98 (br. s., 1H), 1.46-1.62 (m,
1H), 0.98 (br. s., 1H). MS (ESI, positive ion) m/z: 548 (M+1).
Example 767:
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-3-((2-methoxyethyl)amino-
)-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorop-
henyl)-5-chloropicolinamide
##STR00740##
[1947] Preparation of
(E)-3-((1R,5S,6S)-5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2--
(trimethylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-en-1-yl)acrylic acid (767A)
[1948] To a stirred solution of (E)-ethyl
3-((1R,5S,6S)-5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(tri-
methylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)acrylate (2.60 g, 4.35 mmol) in EtOH (40 mL) was
added lithium hydroxide (21.75 mL of 1 M in water, 21.75 mmol). The
reaction mixture was stirred at RT in 16 h then concentrated. The
residue was diluted with H.sub.2O, cooled in an ice bath and
neutralized with 5 N HCl. The solid (2.32 g, 94%) was collected,
washed with H.sub.2O, dried, and used in the next step. MS (ESI,
positive ion) m/z: 570 (M+1).
Preparation of tert-butyl
((1R,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((E)-3-((2-meth-
oxyethyl)amino)-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-
-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate (767B)
[1949] The title compound (154 mg, 54%) was prepared in the same
method as described in Example 759. MS (ESI, positive ion) m/z: 627
(M+1).
Preparation of
(E)-3-((1R,5S,6S)-3-amino-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-2-t-
hia-4-azabicyclo[4.1.0]hept-3-en-1-yl)-N-(2-methoxyethyl)acrylamide
(767C)
[1950] tert-Butyl
((1R,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-((E)-3-((2-meth-
oxyethyl)amino)-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-
-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate (767B, 154 mg, 0.25
mmol) was cooled in an ice bath and treated with
TFA/H.sub.2SO.sub.4 (4:1, 5 mL) and stirred for 15 min. The mixture
was concentrated to remove all the excess of TFA, then cooled in an
ice bath, basified with saturated Na.sub.2CO.sub.3, and extracted
with DCM (3.times.). The organic extracts were dried over
Na.sub.2SO.sub.4, concentrated and used in the next step. MS (ESI,
positive ion) m/z: 397 (M+1).
Preparation of
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-3-((2-methoxyethyl)amino-
)-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorop-
henyl)-5-chloropicolinamide (767)
[1951] The title compound (25.2 mg, 52%) was prepared using the
amide formation Method D (T3P mediated amide formation in DCM as
the solvent). .sup.1H NMR (DMSO-d6) .delta.: 10.61 (s, 1H), 8.79
(d, J=2.2 Hz, 1H), 8.19-8.23 (m, 1H), 8.12-8.18 (m, 2H), 8.06 (dd,
J=7.2, 2.7 Hz, 1H), 7.84-7.89 (m, 1H), 7.20 (dd, J=11.9, 8.8 Hz,
1H), 6.42-6.46 (m, 1H), 6.41 (br. s., 2H), 6.09 (d, J=15.3 Hz, 1H),
4.70-4.82 (m, 1H), 4.58-4.70 (m, 1H), 3.34-3.41 (m, 2H), 3.26-3.30
(m, 2H), 3.25 (s, 3H), 1.96 (t, J=8.4 Hz, 1H), 1.40 (dd, J=9.7, 5.2
Hz, 1H), 0.93-1.00 (m, 1H). MS (ESI, positive ion) m/z: 536
(M+1).
Examples
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((Z)-2-methyl-3-morph-
olino-3-oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-flu-
orophenyl)-5-chloropicolinamide (777) and
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-2-methyl-3-morpholino-3--
oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluoropheny-
l)-5-chloropicolinamide (778)
##STR00741## ##STR00742##
[1952] Preparation of (E/Z)-ethyl
3-((1R,5S,6S)-5-(5-bromo-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(tri-
methylsilyl)ethoxy)methyl)amino)-5-(fluoromethyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-1-yl)-2-methylacrylate (777A)
[1953] To a stirred solution of triethyl 2-phosphonopropionate
(1.33 g, 5.58 mmol) in THF (20 mL) at 0.degree. C. was added
potassium tert-butoxide (1.0 M solution in THF, 5.32 mL, 5.32 mmol)
dropwise. After stirring at 0.degree. C. for 30 min., a solution of
tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (3 g, 5.07 mmol) in THF (30 mL) was added dropwise from dropping
funnel. The reaction mixture was stirred for 2 h. Saturated aqueous
NH.sub.4Cl was added and the mixture was extracted with EtOAc
(3.times.). The organic extracts were dried over Na.sub.2SO.sub.4,
concentrated and purified by silica gel column to give 777A (2.47,
72%) as a mixture of E and Z-isomers. MS (ESI, positive ion) m/z:
697/699 (M+1).
[1954] Compound 777B as a mixture of E and Z-isomers (1.55 g, 59%)
was prepared in the same method as described in Example 755B, but
starting from Compound 777A. MS (ESI, positive ion) m/z: 612
(M+1).
[1955] Compound 777C as a mixture of E and Z-isomers (0.58 g, 65%)
was prepared in the same method as described for Example 767B, but
starting from Compound 777B. MS (ESI, positive ion) m/z: 653
(M+1).
Preparation of Example 777 and Example 778
[1956] Intermediate 777C was converted to the amide as a mixture of
E and Z-isomers following the general Method-F1 (HATU mediated
amide formation followed by removal of protecting groups with
H.sub.2SO.sub.4), which were separated by SFC (chiralPak OX-H).
N-(3-((1R,5S,6S)-3-Amino-5-(fluoromethyl)-1-((Z)-2-methyl-3-morpholino-3--
oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluoropheny-
l)-5-chloropicolinamide (777) (18 mg, 8%) was obtained. .sup.1H NMR
(DMSO-d6) .delta.: 10.68 (s, 1H), 8.85-8.91 (m, 1H), 8.27-8.34 (m,
1H), 8.21-8.27 (m, 1H), 8.10 (dd, J=7.1, 2.8 Hz, 1H), 7.93 (dt,
J=7.3, 4.3 Hz, 1H), 7.27 (dd, J=11.9, 8.8 Hz, 1H), 6.39 (s, 2H),
5.65 (d, J=1.4 Hz, 1H), 4.87 (q, J=9.1 Hz, 1H), 4.60-4.79 (m, 1H),
3.59-3.76 (m, 4H), 3.44-3.59 (m, 4H), 1.91 (d, J=1.4 Hz, 3H), 1.81
(br. s., 1H), 1.25-1.32 (m, 1H), 0.76 (t, J=6.1 Hz, 1H). MS (ESI,
positive ion) m/z: 562 (M+1).
N-(3-((1R,5S,6S)-3-amino-5-(fluoromethyl)-1-((E)-2-methyl-3-morpholino-3--
oxoprop-1-en-1-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluoropheny-
l)-5-chloropicolinamide (778) (96.5 mg, 45%) was obtained. .sup.1H
NMR (DMSO-d6) .delta.: 10.59 (s, 1H), 8.67-8.84 (m, 1H), 8.17-8.23
(m, 1H), 8.10-8.17 (m, 1H), 8.02 (dd, J=7.2, 2.7 Hz, 1H), 7.80-7.87
(m, 1H), 7.18 (dd, J=11.9, 8.8 Hz, 1H), 6.32 (s, 2H), 5.67 (d,
J=1.4 Hz, 1H), 4.78-4.88 (m, 1H), 4.66-4.76 (m, 1H), 3.51-3.63 (m,
4H), 3.41 (br. s., 4H), 1.90 (d, J=1.4 Hz, 3H), 1.77 (t, J=8.0 Hz,
1H), 1.15-1.22 (m, 1H), 0.81 (t, J=5.9 Hz, 1H). MS (ESI, positive
ion) m/z: 562 (M+1).
Example 786:
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(isoxazol-3-yl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicolinamide
##STR00743##
[1957] Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((E)-(hydroxyim-
ino)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)e-
thoxy)methyl)carbamate (786A)
[1958] A mixture of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-formyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbama-
te (2.00 g, 3.38 mmol), hydroxylamine hydrochloride (0.352 g, 5.07
mmol), and NaHCO.sub.3 (0.71 g, 8.45 mmol) in EtOH (30 mL) was
stirred at RT for 16 h. The reaction mixture was concentrated to
dryness. The residue was added H.sub.2O. The white solid (1.62 g,
80%) was collected, washed with H.sub.2O, dried and used in the
next step. .sup.1H NMR (CHLOROFORM-d) .delta.: 7.84 (dd, J=7.0, 2.5
Hz, 1H), 7.41 (ddd, J=8.7, 4.3, 2.7 Hz, 1H), 7.28 (s, 1H), 7.13
(br. s., 1H), 6.97 (dd, J=11.6, 8.7 Hz, 1H), 5.30 (d, J=10.6 Hz,
1H), 5.06 (d, J=10.6 Hz, 1H), 4.83-4.98 (m, 1H), 4.66-4.82 (m, 1H),
3.67 (td, J=8.3, 1.2 Hz, 2H), 2.19 (ddd, J=9.6, 7.4, 2.0 Hz, 1H),
1.52 (s, 9H), 1.38 (dd, J=9.9, 6.0 Hz, 1H), 1.04-1.12 (m, 1H), 0.98
(dd, J=9.2, 7.4 Hz, 2H), 0.00 (s, 9H). (ESI, positive ion) m/z:
606/608 (M+1).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-(5-(trimethylsi-
lyl)isoxazol-3-yl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethyl-
silyl)ethoxy)methyl)carbamate (786B)
[1959] To a stirred mixture of tert-butyl
((1S,5S,6S)-5-(5-bromo-2-fluorophenyl)-5-(fluoromethyl)-1-((E)-(hydroxyim-
ino)methyl)-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)e-
thoxy)methyl)carbamate (1.62 g, 2.67 mmol),
(trimethylsilyl)-acetylene (1.13 mL, 8.00 mmol), and
bis(tributylstannyl)oxide (2.04 mL, 4.00 mmol) in DCM (3 mL) at
0.degree. C. was added tert-butyl hypochlorite (0.45 mL, 4.00
mmol). After the addition, the reaction mixture was gradually
warmed to RT and stirred for 24 h. The reaction was diluted with
DCM and washed with H.sub.2O followed by brine, dried over
Na.sub.2SO.sub.4, and concentrated. The residue was purified by
silica gel column to give the title compound (1.15 g, 61%).
Preparation of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-(fluoromethyl)-1-(isoxazol-3-yl)-
-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methy-
l)carbamate (786C)
[1960] The title compound (286 mg, 28%) was prepared in the same
manner as described for Example 755B. MS (ESI, positive ion) m/z:
567 (M+1).
Preparation of
N-(3-((1S,5S,6S)-3-amino-5-(fluoromethyl)-1-(isoxazol-3-yl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-chloropicolinamide
(786)
[1961] The title compound (25 mg, 60%) was prepared in the same
manner as described for Example 784 (Method-F1: HATU mediated amide
formation followed by removal of protecting groups with PTSA).
.sup.1H NMR (DMSO-d6) .delta.: 10.63 (s, 1H), 8.92 (d, J=1.6 Hz,
1H), 8.79 (d, J=2.3 Hz, 1H), 8.19-8.23 (m, 1H), 8.13-8.18 (m, 1H),
8.08 (dd, J=7.0, 2.7 Hz, 1H), 7.89 (dt, J=8.2, 3.7 Hz, 1H), 7.21
(dd, J=11.7, 8.8 Hz, 1H), 6.63 (d, J=1.8 Hz, 1H), 6.49 (s, 2H),
4.62-4.89 (m, 2H), 2.08-2.16 (m, 1H), 1.63 (dd, J=9.8, 5.5 Hz, 1H),
1.08-1.16 (m, 1H). MS (ESI, positive ion) m/z: 476 (M+1).
Examples: 855, 856, 857 and 858
##STR00744## ##STR00745##
[1962] Preparation of Compound 855A
[1963] To a solution of (S)-tert-butyl
(4-(5-bromo-2-fluorophenyl)-4-methyl-4H-1,3-thiazin-2-yl)((2-(trimethylsi-
lyl)ethoxy)methyl)carbamate (217G, 1.23 g, 2.31 mmol) in THF (10
mL) under N.sub.2 at -78.degree. C. was added lithium
diisopropylamide (2.0 M solution in THF/heptane/ethylbenzene, 3.47
mL, 6.94 mmol) dropwise. After addition, the mixture was then
stirred at -78.degree. C. for 45 min. Then, the mixture was bubbled
CO.sub.2 gas for 3 min. The mixture was warmed to RT and quenched
with saturated ammonium chloride. It was extracted with EtOAc
(3.times.20 mL). The combined organic extracts were dried over
MgSO4, and concentrated. LCMS indicated that the crude material was
a mixture of two products, in a ratio of about 2:1. To the residue
in 2 mL of DMF was added potassium carbonate (1.92 g, 13.88 mmol)
and methyl iodide (0.86 mL, 13.88 mmol). The reaction mixture was
stirred overnight. It was quenched with sat. NH.sub.4Cl, extracted
with EtOAc, dried and concentrated. Flash column (5-20% EtOAc in
DCM) gave (S)-methyl
4-(5-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)
((2-(trimethylsilyl)ethoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carbo-
xylate (920 mg, 1.56 mmol, 67% yield) and (S)-methyl
4-(5-bromo-2-fluoro-3-(methoxycarbonyl)phenyl)-2-((tert-butoxycarbonyl)((-
2-(trimethylsilyl)ethoxy)methyl)amino)-4-methyl-4H-1,3-thiazine-6-carboxyl-
ate (855A, 470 mg, 0.726 mmol, 31% yield) as a yellow oil. LCMS
(ESI.sup.+) m/z=647.5 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta. 7.84-8.06 (m, 2H), 7.14 (d, J=3.65 Hz, 1H), 5.31-5.44 (m,
1H), 5.20 (d, J=10.38 Hz, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.68
(dd, J=7.67, 8.84 Hz, 2H), 1.74 (d, J=1.02 Hz, 3H), 1.56 (s, 9H),
0.84-1.06 (m, 2H), 0.00 (s, 9H).
Preparation of Compound 855B
[1964] This intermediate was prepared from 855A in a fashion
similar to that described for intermediate 217I. LCMS (ESI.sup.+)
m/z=661.5 (M+H). .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 7.99
(dd, J=2.74, 6.26 Hz, 1H), 7.95 (dd, J=2.64, 5.77 Hz, 1H), 5.26 (d,
J=10.56 Hz, 1H), 4.99 (d, J=10.56 Hz, 1H), 3.94 (s, 3H), 3.78 (s,
3H), 3.60-3.70 (m, 2H), 2.70 (t, J=8.22 Hz, 1H), 1.74 (s, 3H), 1.52
(s, 9H), 1.45 (dd, J=5.28, 9.78 Hz, 1H), 1.13 (dd, J=5.38, 7.53 Hz,
1H), 0.91-1.01 (m, 2H), 0.00 (s, 9H).
Preparation of 855C
[1965] A microwave vial was charged with (1S,5S,6S)-methyl
5-(5-bromo-2-fluoro-3-(methoxycarbonyl)phenyl)-3-((tert-butoxycarbonyl)((-
2-(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-ene-1-carboxylate (855B, 320 mg, 0.48 mmol), sodium azide
(94 mg, 1.45 mmol), copper(I) iodide (13.82 mg, 0.073 mmol), sodium
(R)-2-((S)-1,2-dihydroxyethyl)-4-hydroxy-5-oxo-2,5-dihydrofuran-3-olate
(14.37 mg, 0.07 mmol), EtOH (3 mL) and water (1 mL) was purged with
N.sub.2 and sealed. Then
(1R,2R)--N.sub.1,N.sub.2-dimethylcyclohexane-1,2-diamine (0.023 mL,
0.145 mmol) was added. The mixture was heated to 80.degree. C.
After 60 min, LCMS showed most of the bromide was consumed. The
mixture was treated with saturated NH.sub.4Cl and diluted with
EtOAc. The organic layer was separated and the aqueous layer was
extracted twice with EtOAc. The organic solution was washed with
brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. To
the residue in THF (3 mL) and water (1 mL) was added
trimethylphosphine (1.0 M solution in THF, 0.58 mL, 0.58 mmol).
After 10 min, the mixture was evaporated to dryness and purified by
a quick silica gel chromatography (10-20% EtOAc in DCM) to give
(1S,5S,6S)-methyl
5-(5-amino-2-fluoro-3-(methoxycarbonyl)phenyl)-3-((tert-butoxycarbonyl)((-
2-(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-ene-1-carboxylate (855C, 130 mg, 0.21 mmol, 45% yield) which
was used directly in the next step.
Preparation of Example 855
[1966] To a mixture of (1S,5S,6S)-methyl
5-(5-amino-2-fluoro-3-(methoxycarbonyl)phenyl)-3-((tert-butoxycarbonyl)((-
2-(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-ene-1-carboxylate (50 mg, 0.084 mmol) and
5-chloro-2-pyridinecarboxylic acid (855C, 26.4 mg, 0.167 mmol) in
0.5 mL of DMF was added HATU (63.6 mg, 0.167 mmol) and
diisopropylethylamine (29.1 .mu.L, 0.167 mmol). After stirring
overnight, LCMS showed about 80% conversion. The reaction was
quenched with sat. NH.sub.4Cl, extracted with EtOAc, dried over
Na.sub.2SO.sub.4, filtered and evaporated to dryness. Flash column
(0-10% EtOAc in DCM) afforded (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(5-(5--
chloropicolinamido)-2-fluoro-3-(methoxycarbonyl)phenyl)-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-ene-1-carboxylate (40 mg, 0.054 mmol, 64.9%
yield) as a gum. .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.88
(s, 1H), 8.58 (d, J=2.05 Hz, 1H), 8.49 (dd, J=2.92, 5.70 Hz, 1H),
8.28 (d, J=8.48 Hz, 1H), 8.10 (dd, J=3.00, 6.21 Hz, 1H), 7.92 (dd,
J=2.34, 8.33 Hz, 1H), 5.38 (d, J=10.52 Hz, 1H), 5.13 (d, J=10.52
Hz, 1H), 3.99 (s, 3H), 3.82 (s, 3H), 3.72 (dd, J=7.75, 8.77 Hz,
2H), 2.79 (t, J=8.70 Hz, 1H), 1.82 (s, 3H), 1.57 (s, 9H), 1.52 (dd,
J=5.26, 9.79 Hz, 1H), 1.21 (dd, J=5.33, 7.53 Hz, 1H), 0.93-1.07 (m,
2H), 0.00 (s, 9H).
[1967] To the neat (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(5-(5--
chloropicolinamido)-2-fluoro-3-(methoxycarbonyl)phenyl)-5-methyl-2-thia-4--
azabicyclo[4.1.0]hept-3-ene-1-carboxylate (40 mg, 0.054 mmol) was
added 0.2 mL of concentrated H.sub.2SO.sub.4 and the mixture was
stirred at RT for 20 min. It was quenched with sat NaHCO.sub.3 to
pH=8, extracted with EtOAc, dried and evaporated to dryness. Flash
column (DCM/EtOAc=3:1 to 2:1 to 1:1) gave (1S,5S,6S)-methyl
3-amino-5-(5-(5-chloropicolinamido)-2-fluoro-3-(methoxycarbonyl)phenyl)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (855, 33
mg, 0.065 mmol, 78% yield) as an off-white solid. LCMS (ESI.sup.+)
m/z=507.0 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta. 9.87
(s, 1H), 8.56 (d, J=2.34 Hz, 1H), 8.42 (dd, J=3.07, 5.70 Hz, 1H),
8.25 (d, J=8.48 Hz, 1H), 8.16 (dd, J=2.92, 6.28 Hz, 1H), 7.89 (dd,
J=2.34, 8.33 Hz, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 2.61-2.74 (m,
1H), 1.75 (d, J=1.32 Hz, 3H), 1.52 (dd, J=5.12, 9.79 Hz, 1H), 1.12
(dd, J=5.41, 7.45 Hz, 1H).
Preparation of Example 858
[1968] A solution of lithium tetrahydroborate (0.12 mL of 2 M in
THF, 0.24 mmol) was added dropwise to a solution of
(1S,5S,6S)-methyl
3-amino-5-(5-(5-chloropicolinamido)-2-fluoro-3-(methoxycarbonyl)phenyl)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (Example
855, 30 mg, 0.06 mmol) under argon at RT, followed by addition of
MeOH (15 mg, 0.47 mmol). The mixture was stirred for 1 h (slight
exotherm), at which time LCMS suggested complete conversion. The
reaction was quenched by the careful addition of satd. NH.sub.4Cl
and the product was extracted into EtOAc (2.times.). The combined
extracts were dried (Na.sub.2SO.sub.4), filtered, and concentrated
in vacuo and submit to flash column (DCM/MeOH=10:1 to 5:1) to give
product as a solid
N-(3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluoro-5-(hydroxymethyl)phenyl)-5-chloropicolinamid-
e (Example 858, 15 mg, 0.03 mmol, 56% yield). LCMS (ESI.sup.+)
m/z=451.0 (M+H). .sup.1H NMR (400 MHz, MeOH) .delta. 8.73 (d,
J=2.15 Hz, 1H), 8.22 (d, J=8.41 Hz, 1H), 8.10 (dd, J=2.45, 8.51 Hz,
1H), 7.83-7.94 (m, 2H), 4.75 (s, 2H), 3.66 (s, 2H), 1.88-1.97 (m,
4H), 1.25 (dd, J=6.06, 9.19 Hz, 1H), 0.90 (t, J=6.16 Hz, 1H).
Preparation of Example 856
[1969] To a mixture of
5-chloro-2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazine (38.6 mg, 0.176
mmol) and (5S)-methyl
5-(5-amino-2-fluoro-3-(methoxycarbonyl)phenyl)-3-((tert-butoxycarbonyl)((-
2-(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-ene-1-carboxylate (855C, 70 mg, 0.117 mmol) in 3 mL of iPrOH
was added p-toluenesulfonic acid monohydrate (66.8 mg, 0.351 mmol)
and the mixture was stirred at 80.degree. C. for 2 h. The solvent
was evaporated and the residue was treated with 0.2 mL of
concentrated H.sub.2SO.sub.4 and stirred at RT for 20 min. The
reaction was quenched with sat. NaHCO.sub.3, extracted with EtOAc,
dried and evaporated. Flash column (DCM/EtOAc=3:1 to 2:1) gave
(1S,5S,6S)-methyl
3-amino-5-(2-fluoro-3-(methoxycarbonyl)-5-((2-(prop-2-yn-1-yloxy)pyrido[3-
,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3--
ene-1-carboxylate (Example 856, 35 mg, 0.06 mmol, 54% yield) as a
light yellow solid. LCMS (ESI.sup.+) m/z=551.0 (M+H). .sup.1H NMR
(300 MHz, CHLOROFORM-d) .delta. 8.72 (ddd, J=1.46, 3.11, 5.66 Hz,
1H), 8.65 (s, 1H), 8.35 (d, J=1.75 Hz, 1H), 8.29 (dd, J=1.02, 5.85
Hz, 1H), 7.99-8.16 (m, 1H), 7.07 (dd, J=1.32, 5.99 Hz, 1H), 5.15
(dd, J=0.80, 2.41 Hz, 2H), 3.97 (s, 3H), 3.78 (s, 3H), 2.67 (t,
J=8.77 Hz, 1H), 2.57 (t, J=2.48 Hz, 1H), 1.77 (s, 3H), 1.50-1.61
(m, 1H), 1.07-1.18 (m, 1H).
Preparation of Example 857
[1970] A solution of LiBH.sub.4 (0.11 mL of 2 M THF solution, 0.22
mmol) was added dropwise to a solution of (1S,5S,6S)-methyl
3-amino-5-(2-fluoro-3-(methoxycarbonyl)-5-((2-(prop-2-yn-1-yloxy)pyrido[3-
,4-b]pyrazin-5-yl)amino)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3--
ene-1-carboxylate (Example 856, 30 mg, 0.05 mmol) under argon at
RT, followed by addition of MeOH (14 mg, 0.43 mmol). The mixture
was stirred for 1 h, then quenched by the careful addition of sat.
NH.sub.4Cl. The mixture was extracted with EtOAc (2.times.). The
combined extracts were dried (Na.sub.2SO.sub.4), filtered, and
concentrated in vacuo and submit to flash column (DCM/MeOH=10:1 to
5:1) to give methyl
3-((1S,5S,6S)-3-amino-1-(hydroxymethyl)-5-methyl-2-thia-4-azabicyclo[4.1.-
0]hept-3-en-5-yl)-2-fluoro-5-((2-(prop-2-yn-1-yloxy)pyrido[3,4-b]pyrazin-5-
-yl)amino)benzoate (Example 857, 15 mg, 0.03 mmol, 53% yield) as an
off-white solid. LCMS (ESI.sup.+) m/z=523.0 (M+H). .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 8.68 (dd, J=2.93, 5.67 Hz, 1H), 8.64 (s,
1H), 8.35 (s, 1H), 8.29 (d, J=5.87 Hz, 1H), 8.03 (dd, J=2.93, 6.26
Hz, 1H), 7.07 (d, J=5.87 Hz, 1H), 5.15 (d, J=2.54 Hz, 2H), 3.97 (s,
3H), 3.61-3.74 (m, 2H), 2.57 (t, J=2.45 Hz, 1H), 1.91 (dd, J=7.34,
8.90 Hz, 1H), 1.79 (s, 3H), 0.90-0.98 (m, 1H), 0.76 (t, J=6.26 Hz,
1H).
Example 899: lithium
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate
##STR00746##
[1972] A suspension of (1S,5S,6S)-methyl
3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-methyl-2-thia-4-
-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (Example 898, 25 mg,
0.05 mmol) and lithium hydroxide monohydrate (3 mg, 0.05 mmol) in
THF (0.4 mL), MeOH (0.2 mL), and water (0.2 mL) was stirred at
40.degree. C. sand bath for 48 h. The solvents were then removed
via positive pressure of nitrogen to afford lithium
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (899, 25 mg,
0.05 mmol, 100%) as white solid. LC/MS (ESI.sup.-) m/z=453.0
(M+H).sup.+ [expected for the acid]. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.71 (s, 1H), 8.66 (br. s., 1H), 8.15-8.23
(m, 1H), 8.11 (br. s., 1H), 7.80-8.00 (m, 1H), 7.70 (br. s., 1H),
5.56 (br. s., 2H), 2.04 (t, J=7.53 Hz, 1H), 1.52 (s, 3H), 0.92 (dd,
J=3.52, 9.00 Hz, 1H), 0.47 (dd, J=3.42, 6.36 Hz, 1H).
Example 902:
1-((1S,5S,6S)-3-amino-5-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-
,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)ethan-
one
##STR00747##
[1974] To a stirring solution of
(1S,5S,6S)-3-amino-5-(5-((7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2,3--
difluorophenyl)-N-methoxy-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-
e-1-carboxamide (901, 50 mg, 0.09 mmol) in THF (1 mL) at -8.degree.
C. (wet ice/ACN) under nitrogen was added methylmagnesium bromide
(0.6 mL of 3.0 M in Et.sub.2O, 1.8 mmol). The reaction was slowly
quenched with sat NH.sub.4Cl. The reaction was then partitioned
between 5% NaHCO.sub.3 (15 mL), water (15 mL) and EtOAc (15 mL).
The organic layer was dried over MgSO.sub.4, concentrated under
reduced pressure, then purified by silica gel chromatography (0-60%
ACN in CH.sub.2Cl.sub.2) to afford Example 902 (12 mg, 0.025 mmol,
26% yield) as white solid. LC/MS (ESI.sup.-) m/z=475.0 (M+H).sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.49 (br. s., 1H),
8.95 (d, J=2.15 Hz, 1H), 8.75 (s, 1H), 8.43 (d, J=1.96 Hz, 1H),
8.22 (br. s., 1H), 8.11 (br. s., 1H), 6.18 (br. s., 2H), 2.12 (s,
3H), 1.77 (br. s., 1H), 1.64 (br. s., 3H), 1.25 (br. s., 1H), 1.15
(d, J=5.28 Hz, 1H), 0.86 (t, J=6.75 Hz, 1H).
Example 905:
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide
##STR00748##
[1975] Preparation of Compound 905A
[1976] To a stirring suspension of lithium
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-meth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (899) (220
mg, 0.40 mmol) in DMF (2 mL) at 20.degree. C. under nitrogen was
added di-tert-butyl dicarbonate (131 mg, 0.60 mmol) and DMAP (2
mg). The suspension was heated in a 50.degree. C. sand bath. After
15 min, the reaction was exposed to K.sub.2CO.sub.3 (150 mg) and
MeOH (3 mL). After 10 min the reaction was partitioned between
EtOAc (20 mL) and 1 M HCl (50 mL). The aqueous was further
extracted with EtOAc (20 mL). The combined organics were dried over
MgSO.sub.4, filtered, then and concentrated under reduced pressure
to afford
(1S,5S,6S)-3-((tert-butoxycarbonyl)amino)-5-(5-(5-chloropicolinamido)-2,3-
-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxyli-
c acid (905A, 265 mg, 0.48 mmol) as colorless oil. LC/MS
(ESI.sup.-) m/z=553.1 (M+H).sup.+.
Preparation of Compound 905B
[1977] To a stirring solution of
(1S,5S,6S)-3-((tert-butoxycarbonyl)amino)-5-(5-(5-chloropicolinamido)-2,3-
-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxyli-
c acid (905A, 250 mg, 0.452 mmol) in DMF (1 mL) was added
1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 0.86 mL,
1.36 mmol). The solution was stirred for 20 min at 20.degree. C.
then ammonia (7 M in MeOH, 0.45 mL, 3.15 mmol) added. The resulting
suspension was stirred for 3 days at 20.degree. C. The reaction was
then partitioned between 9:1 CHCl.sub.3/IPA (20 mL) and 5%
NaHCO.sub.3 (10 mL). The organic was dried over MgSO.sub.4,
filtered, concentrated under reduced pressure, and then purified by
silica gel chromatography (12 g) eluting products with 0-6%
MeOH/CH.sub.2Cl.sub.2 to afford tert-butyl
((1S,5S,6S)-1-carbamoyl-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (905B,
19 mg, 0.034 mmol, 7% yield) as white solid. LC/MS (ESI.sup.-)
m/z=552.0 (M+H).sup.+.
Preparation of Example 905
[1978] At RT, TFA (1 mL) was added to tert-butyl
((1S,5S,6S)-1-carbamoyl-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-3-yl)carbamate (905B,
19 mg, 0.034 mmol). The solution was stirred for 20 min at
20.degree. C. The TFA was removed under reduced pressure and the
residue was partitioned between 9:1 CHCl.sub.3/IPA (20 mL) and 1 M
K.sub.2HPO.sub.4 (10 mL). The separated aqueous was further
extracted with 9:1 CHCl.sub.3/IPA (2.times.5 mL). The combined
organics were dried over MgSO.sub.4, filtered, and concentrated
under reduced pressure. The resulting solid was suspended in 1:1
H.sub.2O/ACN (2 mL), frozen, then lyophilized to afford
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2,3-difluorophenyl)-
-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide (905,
14 mg, 0.031 mmol, 90% yield) as fluffy white powder. LC/MS
(ESI.sup.-) m/z=452.0 (M+H).sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 10.77 (br. s., 1H), 8.79 (d, J=1.76 Hz, 1H),
8.11-8.25 (m, 2H), 7.95 (br. s., 1H), 7.88 (t, J=4.62 Hz, 1H), 7.28
(br. s., 1H), 7.21 (br. s., 1H), 6.10 (br. s., 2H), 2.17 (br. s.,
1H), 1.57-1.69 (m, 3H), 1.45 (dd, J=7.43, 15.06 Hz, 1H), 0.79-0.92
(m, 1H).
[1979] Using procedures analogous or similar to the general
amidation Method D described previously, the appropriate aniline
and carboxylic acid intermediates were reacted to provide the 20
examples listed in Table 9 and Table 9'.
TABLE-US-00018 TABLE 9 Observed Ex. No. Chemical Structure [M +
H].sup.+ 963 ##STR00749## 563 964 ##STR00750## 450.2 965
##STR00751## 470 966 ##STR00752## 476 967 ##STR00753## 501 968
##STR00754## 514 969 ##STR00755## 477 970 ##STR00756## 490 971
##STR00757## 496 975 ##STR00758## 488 979 ##STR00759## 492 988
##STR00760## 470 989 ##STR00761## 475.2 990 ##STR00762## 454.2 1007
##STR00763## 454 1008 ##STR00764## 514 1009 ##STR00765## 488 1014
##STR00766## 532 1024 ##STR00767## 508 1039 ##STR00768## 520
TABLE-US-00019 TABLE 9' Ex. No .sup.1H-NMR Chemical Name 963 1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.34-9.47
(1S,5S,6S)-3-amino-5-(2,3- (m, 1H), 9.01 (d, J = 1.17 Hz, 1H), 8.26
(d, J = 1.17 Hz, difluoro-5-(((5-(2,2,3,3- 1H), 7.90 (ddd, J =
2.74, 6.65, 11.54 Hz, 1H), 7.10-7.18 tetrafluoropropoxy)-2- (m,
1H), 6.46 (d, J = 4.30 Hz, 1H), 5.77-6.16 (m, 1H),
pyrazinyl)carbonyl)amino)phenyl)- 4.87 (t, J = 12.72 Hz, 2H), 2.88
(d, J = 4.89 Hz, 3H), 2.21- N,5-dimethyl-2-thia-4- 2.32 (m, 1H),
1.95 (dd, J = 5.09, 9.78 Hz, 1H), 1.81 (s,
azabicyclo[4.1.0]hept-3-ene-1- 3H), 0.75-0.87 (m, 1H) carboxamide
964 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.35 (s, 1H),
N-(5-((1S,5S,6S)-3-amino-1- 9.02 (s, 1H), 8.52 (d, J = 2.54 Hz,
1H), 8.21 (d, J = 1.17 cyano-5-methyl-2-thia-4- Hz, 1H), 8.13 (d, J
= 2.54 Hz, 1H), 5.09 (d, J = 2.35 Hz, azabicyclo[4.1.0]hept-3-en-5-
2H), 4.04 (s, 3H), 4.00-3.50 (br.s., 2H), 2.76 (dd,
yl)-6-methoxy-3-pyridinyl)-5-(2- J = 8.02, 9.98 Hz, 1H), 2.55 (t, J
= 2.45 Hz, 1H), 1.79-1.84 propyn-1-yloxy)-2- (m, 3H), 1.60 (dd, J =
6.26, 9.98 Hz, 1H), 1.06 (dd, pyrazinecarboxamide J = 6.26, 7.82
Hz, 1H). 965 1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.49 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.02 (d, J = 1.17 Hz, 1H), 8.14
(d, J = 0.78 Hz, 1H), (methoxymethyl)-5-methyl-2- 7.94 (td, J =
3.52, 8.61 Hz, 1H), 7.73 (dd, J = 2.84, 6.94
thia-4-azabicyclo[4.1.0]hept-3- Hz, 1H), 7.06 (dd, J = 8.80, 11.74
Hz, 1H), 5.83 (dq, en-5-yl)-4-fluorophenyl)-5- J = 1.96, 6.65 Hz,
1H), 4.46 (br.s., 2H), 3.66 (d, J = 10.76
(((1S)-1-methyl-2-propyn-1- Hz, 1H), 3.41 (s, 3H), 3.34 (d, J =
10.76 Hz, 1H), 2.49 (d, yl)oxy)-2-pyrazinecarboxamide J = 2.15 Hz,
1H), 1.80 (dd, J = 7.34, 8.71 Hz, 1H), 1.72 (d, J = 0.78 Hz, 3H),
1.70 (d, J = 6.65 Hz, 3H), 0.87 (dd, J = 5.87, 9.39 Hz, 1H),
0.77-0.83 (m, 1H) 966 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.44 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 9.02 (s, 1H), 8.14 (d, J
= 1.17 Hz, 1H), 7.80-7.93 (m, (difluoromethyl)-5-methyl-2- 1H),
7.61 (dd, J = 2.74, 6.85 Hz, 1H), 7.06 (dd, J = 8.80,
thia-4-azabicyclo[4.1.0]hept-3- 11.54 Hz, 1H), 5.81-5.88 (m, 1H),
5.50-5.81 (m, 1H), en-5-yl)-4-fluorophenyl)-5- 4.62 (br s, 2H),
2.49 (d, J = 2.15 Hz, 1H), 1.99 (dd, (((1S)-1-methyl-2-propyn-1- J
= 7.24, 9.78 Hz, 1H), 1.78 (s, 3H), 1.70 (d, J = 6.65 Hz,
yl)oxy)-2-pyrazinecarboxamide 3H), 1.33 (dd, J = 6.16, 9.88 Hz,
1H), 0.84 (dt, J = 2.74, 6.46 Hz, 1H) 967 1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.31 (s, (1S,5S,6S)-3-amino-5-(2,3- 1H), 8.96
(d, J = 1.37 Hz, 1H), 8.11 (d, J = 1.37 Hz, 1H),
difluoro-5-(((5-(((1S)-1-methyl- 7.71-7.88 (m, 1H), 7.13 (dd, J =
2.45, 5.18 Hz, 1H), 6.55 2-propyn-1-yl)oxy)-2- (d, J = 4.69 Hz,
1H), 5.83 (dq, J = 2.05, 6.68 Hz, 1H), 2.87
pyrazinyl)carbonyl)amino)phenyl)- (d, J = 4.69 Hz, 3H), 2.50 (d, J
= 1.96 Hz, 1H), 2.22 (dd, N,5-dimethyl-2-thia-4- J = 7.63, 9.39 Hz,
1H), 1.98 (dd, J = 5.09, 9.59 Hz, 1H),
azabicyclo[4.1.0]hept-3-ene-1- 1.85 (s, 3H), 1.70 (d, J = 6.65 Hz,
3H), 0.73-0.84 (m, 1H) carboxamide 968 1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.48 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
9.01 (d, J = 1.17 Hz, 1H), 8.24 (d, J = 0.98 Hz, 1H),
(methoxymethyl)-5-methyl-2- 7.89-8.01 (m, 1H), 7.72 (td, J = 2.74,
6.85 Hz, 1H), 7.07 thia-4-azabicyclo[4.1.0]hept-3- (dd, J = 8.71,
11.64 Hz, 1H), 5.81 (spt, J = 6.42 Hz, 1H),
en-5-yl)-4-fluorophenyl)-5- 3.67 (d, J = 10.76 Hz, 1H), 3.41 (s,
3H), 3.35 (d, J = 10.56 ((1,1,1-trifluoropropan-2- Hz, 1H), 1.81
(dd, J = 7.43, 8.80 Hz, 1H), 1.72 (d, J = 0.98
yl)oxy)pyrazine-2-carboxamide Hz, 3H), 1.56 (d, J = 6.65 Hz, 3H),
0.88 (dd, J = 5.87, 9.39 Hz, 1H), 0.78-0.83 (m, 1H) 969 1H NMR (400
MHz, DMSO-d6) .delta. 10.61 (s, 1H), 8.90
N-(3-((1S,5S,6S)-3-amino-5- (d, J = 1.17 Hz, 1H), 8.48 (d, J = 1.17
Hz, 1H), 7.88-7.94 methyl-1- (m, 2H), 5.99 (s, 2H), 5.14 (d, J =
2.35 Hz, 2H), 3.64 (t, (((trideuterium)methyl- J = 2.45 Hz, 1H),
3.56 (d, J = 10.95 Hz, 1H), 3.36 (d, oxy)methyl)-2-thia-4- J =
10.95 Hz, 1H), 1.58-1.65 (m, 4H), 0.90 (dd, J = 5.28,
azabicyclo[4.1.0]hept-3-en-5- 9.19 Hz, 1H), 0.64 (t, J = 5.77 Hz,
1H) yl)-4,5-difluorophenyl)-5-(2- propyn-1-yloxy)-2-
pyrazinecarboxamide 970 1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.49
(s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.97 (s, 1H), 8.12 (s, 1H),
7.88-7.99 (m, 1H), 7.73 (methoxymethyl)-5-methyl-2- (dd, J = 2.45,
6.94 Hz, 1H), 7.06 (dd, J = 8.90, 11.64 Hz,
thia-4-azabicyclo[4.1.0]hept-3- 1H), 5.45-5.56 (m, 1H), 4.45
(br.s., 2H), 3.54-3.69 (m, en-5-yl)-4-fluorophenyl)-5- 3H), 3.41
(s, 6H), 3.34 (d, J = 10.76 Hz, 1H), 1.76-1.86 ((1S)-2-methoxy-1-
(m, 1H), 1.72 (s, 3H), 1.39 (d, J = 6.26 Hz, 3H), 0.87 (dd,
methylethoxy)-2- J = 5.87, 9.39 Hz, 1H), 0.77-0.83 (m, 1H)
pyrazinecarboxamide 971 1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.42
(s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.94 (d, J = 1.37 Hz, 1H),
8.08 (d, J = 1.37 Hz, 1H), (difluoromethyl)-5-methyl-2- 7.76-7.87
(m, 1H), 7.62 (dd, J = 2.84, 6.94 Hz, 1H), 7.03
thia-4-azabicyclo[4.1.0]hept-3- (dd, J = 8.61, 11.54 Hz, 1H),
5.46-5.82 (m, 2H), 4.78 (br. en-5-yl)-4-fluorophenyl)-5- s., 2H),
3.54-3.67 (m, 2H), 3.41 (s, 3H), 1.97 (dd, ((1S)-2-methoxy-1- J =
7.24, 9.78 Hz, 1H), 1.79 (d, J = 0.98 Hz, 3H), 1.39 (d,
methylethoxy)-2- J = 6.46 Hz, 3H), 1.33 (dd, J = 6.16, 9.88 Hz,
1H), 0.78- pyrazinecarboxamide 0.88 (m, 1H) 975 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. ppm 9.51 methyl (1S,5S,6S)-3-amino-5-
(br., 1 H), 9.02 (d, J = 1.37 Hz, 1 H), 8.20 (d, J = 1.37 Hz,
(2,3-difluoro-5-(((5-(2-propyn-1- 1 H), 8.02 (ddd, J = 11.74, 6.85,
2.74 Hz, 1 H), 7.47 (dt, yloxy)-2- J = 5.50, 2.50 Hz, 1 H), 5.09
(d, J = 2.54 Hz, 2 H), 3.79 (s, pyrazinyl)carbonyl)amino)phenyl)- 3
H), 2.54-2.61 (m, 2 H), 1.73 (d, J = 0.78 Hz, 3 H),
5-methyl-2-thia-4- 1.54 (dd, J = 9.78, 5.28 Hz, 1 H), 1.13 (dd, J =
7.43, 5.28 azabicyclo[4.1.0]hept-3-ene-1- Hz, 1 H). NH.sub.2 peak
is broad. .sup.19F NMR (377 MHz, carboxylate CHLOROFORM-J) .delta.
ppm -135.85 (d, J = 20.86 Hz, 1 F) -142.34 (d, J = 21.46 Hz, 1 F).
979 1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.48 (s,
(1S,5S,6S)-3-amino-5-(2-fluoro- 1H), 8.29 (s, 1H), 8.19 (d, J =
5.87 Hz, 1H), 8.00 (td, 5-((2-(2-propyn-1- J = 3.45, 8.75 Hz, 1H),
7.48 (dd, J = 2.74, 6.85 Hz, 1H), yloxy)pyrido[3,4-b]pyrazin-5-
7.05 (dd, J = 8.80, 11.35 Hz, 1H), 7.00 (d, J = 5.87 Hz,
yl)amino)phenyl)-N,5-dimethyl- 1H), 6.59 (d, J = 4.69 Hz, 1H), 5.14
(d, J = 2.54 Hz, 2H), 2-thia-4-azabicyclo[4.1.0]hept- 2.87 (d, J =
4.89 Hz, 3H), 2.56 (t, J = 2.35 Hz, 1H), 2.24 3-ene-1-carboxamide
(dd, J = 7.73, 9.49 Hz, 1H), 1.99 (dd, J = 4.99, 9.68 Hz, 1H), 1.85
(s, 3H), 0.81-0.87 (m, 1H) 988 1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.50 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.02 (d, J = 1.37
Hz, 1H), 8.14 (d, J = 1.37 Hz, 1H), (methoxymethyl)-5-methyl-2-
7.89-7.99 (m, 1H), 7.74 (dd, J = 2.84, 6.94 Hz, 1H), 7.06
thia-4-azabicyclo[4.1.0]hept-3- (dd, J = 8.80, 11.74 Hz, 1H), 5.83
(dq, J = 1.96, 6.65 Hz, en-5-yl)-4-fluorophenyl)-5- 1H), 3.66 (d, J
= 10.56 Hz, 1H), 3.41 (s, 3H), 3.34 (d, (((1R)-1-methyl-2-propyn-1-
J = 10.76 Hz, 1H), 2.50 (d, J = 2.15 Hz, 1H), 1.80 (ddd,
yl)oxy)-2-pyrazinecarboxamide J = 0.88, 7.43, 8.71 Hz, 1H), 1.72
(d, J = 0.98 Hz, 3H), 1.69 (d, J = 6.65 Hz, 3H), 0.87 (dd, J =
5.87, 9.39 Hz, 1H), 0.76-0.83 (m, 1H) 989 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta.: 9.36 (s, N-(5-((1S,5S,6S)-3-amino-1- 1H),
9.04 (s, 1H), 8.60 (d, J = 2.48 Hz, 1H), 8.23 (s, 1H),
(difluoromethyl)-5-methyl-2- 8.05 (d, J = 2.48 Hz, 1H), 5.42-5.92
(m, 1H), 5.10 (d, thia-4-azabicyclo[4.1.0]hept-3- J = 2.19 Hz, 2H),
4.04 (s, 3H), 3.96-4.10 (br.s., 2H), 2.57 en-5-yl)-6-methoxy-3- (t,
J = 2.19 Hz, 1H), 2.18-2.32 (m, 1H), 1.80 (s, 3H), 1.29
pyridinyl)-5-(2-propyn-1-yloxy)- (dd, J = 6.14, 10.23 Hz, 1H),
0.72-1.02 (m, 1H). .sup.19F 2-pyrazinecarboxamide NMR (282 MHz,
CHLOROFORM-d) .delta.: -116.81 (d, .sup.1J = 276.36 Hz, 1F),
-119.51 (d, .sup.1J = 276.36 Hz, 1F). 990 .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta.: 9.67 (s, N-(5-((1S,5S,6S)-3-amino-1- 1H),
8.49-8.65 (m, 2H), 8.23 (d, J = 8.33 Hz, 1H), 8.07
(difluoromethyl)-5-methyl-2- (d, J = 2.05 Hz, 1H), 7.83-7.93 (m,
1H), 5.42-5.94 (m, thia-4-azabicyclo[4.1.0]hept-3- 1H), 4.09-4.68
(br.s., 2H), 4.03 (s, 3H), 2.21 (dd, en-5-yl)-6-methoxy-3- J =
7.60, 9.65 Hz, 1H), 1.79 (s, 3H), 1.23-1.35 (m, 1H),
pyridinyl)-5-chloro-2- 0.69-0.92 (m, 1H). .sup.19F NMR (282 MHz,
pyridinecarboxamide CHLOROFORM-d) .delta.: -116.81 (d, .sup.1J =
277.07 Hz, 1F), -119.56 (d, .sup.1J = 277.07 Hz, 1F). 1007 1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.51 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.26 (d, J = 1.37 Hz, 1H), 8.57
(d, J = 1.37 Hz, 1H), (methoxymethyl)-5-methyl-2- 8.04 (ddd, J =
2.84, 6.70, 11.59 Hz, 1H), 7.43 (td, J = 2.47,
thia-4-azabicyclo[4.1.0]hept-3- 5.43 Hz, 1H), 4.41 (br.s., 2H),
3.66 (d, J = 10.56 Hz, en-5-yl)-4,5-difluorophenyl)-5- 1H), 3.41
(s, 3H), 3.35 (d, J = 10.76 Hz, 1H), 1.80 (ddd,
chloro-2-pyrazinecarboxamide J = 1.37, 6.80, 9.24 Hz, 1H), 1.72 (d,
J = 0.98 Hz, 3H), 0.90 (dd, J = 5.87, 9.39 Hz, 1H), 0.76-0.82 (m,
1H) 1008 1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.49 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.00 (d, J = 1.17 Hz, 1H), 8.33
(d, J = 1.17 Hz, 1H), (methoxymethyl)-5-methyl-2- 7.90-8.01 (m,
1H), 7.71 (dd, J = 2.74, 6.85 Hz, 1H), 7.07
thia-4-azabicyclo[4.1.0]hept-3- (dd, J = 8.70, 11.64 Hz, 1H), 5.68
(s, 2H), 3.67 (d, en-5-yl)-4-fluorophenyl)-5-((3- J = 10.56 Hz,
1H), 3.41 (s, 3H), 3.35 (d, J = 10.76 Hz, 1H),
methyl-1,2,4-oxadiazol-5- 2.43 (s, 3H), 1.77-1.85 (m, 1H), 1.72 (s,
3H), 0.88 (dd, yl)methoxy)-2- J = 5.87, 9.39 Hz, 1H), 0.77-0.84 (m,
1H) pyrazinecarboxamide 1009 1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.51 (br.s., N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.03 (s, 1H), 8.17
(s, 1H), 8.00-8.12 (m, 1H), 7.39 (methoxymethyl)-5-methyl-2-
(br.s., 1H), 5.84 (q, J = 6.19 Hz, 1H), 3.67 (d, J = 10.76
thia-4-azabicyclo[4.1.0]hept-3- Hz, 1H), 3.41 (s, 3H), 3.35 (d, J =
10.37 Hz, 1H), 2.49 (s, en-5-yl)-4,5-difluorophenyl)-5- 1H), 1.80
(t, J = 7.92 Hz, 1H), 1.69-1.73 (m, 6H), 0.85-
(((1S)-1-methyl-2-propyn-1- 0.93 (m, 1H), 0.76-0.84 (m, 1H)
yl)oxy)-2-pyrazinecarboxamide 1014 1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.50 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.98 (d, J = 1.37
Hz, 1H), 8.32 (d, J = 1.17 Hz, 1H), (methoxymethyl)-5-methyl-2-
8.03 (ddd, J = 2.74, 6.70, 11.69 Hz, 1H), 7.42 (dd,
thia-4-azabicyclo[4.1.0]hept-3- J = 2.45, 5.18 Hz, 1H), 5.68 (s,
2H), 5.63-5.74 (m, 2H), en-5-yl)-4,5-difluorophenyl)-5- 3.66 (d, J
= 10.56 Hz, 1H), 3.41 (s, 3H), 3.35 (d, J = 10.56
((3-methyl-1,2,4-oxadiazol-5- Hz, 1H), 2.43 (s, 3H), 1.75-1.83 (m,
1H), 1.72 (s, 3H), yl)methoxy)-2- 0.89 (dd, J = 5.87, 9.39 Hz, 1H),
0.75-0.83 (m, 1H) pyrazinecarboxamide 1024 1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.51 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
8.97 (d, J = 1.17 Hz, 1H), 8.12 (d, J = 1.17 Hz, 1H),
(methoxymethyl)-5-methyl-2- 8.05 (ddd, J = 2.74, 6.80, 11.79 Hz,
1H), 7.40 (dd, thia-4-azabicyclo[4.1.0]hept-3- J = 2.54, 5.28 Hz,
1H), 5.51 (dquin, J = 3.91, 6.26 Hz, 1H),
en-5-yl)-4,5-difluorophenyl)-5- 4.09-4.84 (m, 2H), 3.50-3.73 (m,
3H), 3.41 (s, 6H), 3.35
((1S)-2-methoxy-1- (d, J = 10.56 Hz, 1H), 1.75-1.83 (m, 1H), 1.72
(s, 3H), methylethoxy)-2- 1.39 (d, J = 6.46 Hz, 3H), 0.89 (dd, J =
5.87, 9.39 Hz, 1H), pyrazinecarboxamide 0.77-0.83 (m, 1H) 1039 1H
NMR (400 MHz, CHLOROFORM-d) .delta. 9.44 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.98 (s, 1H), 8.32 (s, 1H),
7.81-7.92 (m, 1H), 7.61 (difluoromethyl)-5-methyl-2- (dd, J = 2.35,
6.85 Hz, 1H), 7.07 (dd, J = 9.00, 11.35 Hz,
thia-4-azabicyclo[4.1.0]hept-3- 1H), 5.49-5.87 (m, 3H), 2.43 (s,
3H), 1.95-2.05 (m, 1H), en-5-yl)-4-fluorophenyl)-5-((3- 1.78 (s,
3H), 1.33 (dd, J = 6.26, 9.78 Hz, 1H), 0.84 (br.s.,
methyl-1,2,4-oxadiazol-5- 1H) yl)methoxy)-2-
pyrazinecarboxamide
Example 978:
(1S,5S,6S)-3-amino-5-(5-(5-((S)-but-3-yn-2-yloxy)pyrazine-2-carboxamido)--
2-fluorophenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbox-
amide
##STR00769##
[1981] The title compound (67 mg, 0.14 mmol, 63% yield) was
obtained as an off white crystalline solid and was made via General
Method F2, using Intermediate 290 (51 mg, 0.26 mmol) and
Intermediate 459 (120 mg, 0.22 mmol) as the starting materials.
LC/MS (ESI.sup.+) m/z=483 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.25 (s, 1H), 8.92 (s, 1H), 8.05 (s, 1H),
7.58-7.73 (m, 1H), 7.44 (dd, J=2.54, 6.85 Hz, 1H), 6.90 (t, J=9.88
Hz, 1H), 6.67 (d, J=4.30 Hz, 1H), 5.82 (dq, J=1.86, 6.62 Hz, 1H),
2.85 (d, J=4.69 Hz, 3H), 2.51 (d, J=1.96 Hz, 1H), 2.20 (dd, J=7.82,
9.19 Hz, 1H), 1.98 (dd, J=4.89, 9.59 Hz, 1H), 1.87 (s, 3H), 1.70
(d, J=6.65 Hz, 3H), 0.76 (t, J=6.06 Hz, 1H).
Method H: Preformation of Acid Chloride with Ghosez Reagent
Followed by Amide Coupling in ACN and Water
Example 1010:
N-(3-((1S,5S,6S)-3-amino-1-cyano-5-methyl-2-thia-4-azabicyclo[4.1.0]hept--
3-en-5-yl)-4,5-difluorophenyl)-5-(((S)-1-methoxypropan-2-yl)oxy)pyrazine-2-
-carboxamide
##STR00770##
[1983] A suspension of
(S)-5-((1-methoxypropan-2-yl)oxy)pyrazine-2-carboxylic acid (292,
38.4 mg, 0.18 mmol) in ACN (0.25 mL) and
1-chloro-N,N,2-trimethyl-1-propenylamine (23.9 .mu.L, 0.18 mmol)
was stirred for 10 min at 20.degree. C. and formed a solution. This
freshly prepared acid chloride was then added to a solution of
(1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-azabi-
cyclo[4.1.0]hept-3-ene-1-carbonitrile (224, 38 mg, 0.13 mmol) and
HOAc (7.5 .mu.L, 0.13 mmol) in 1:1 ACN/water (1.0 mL) at 0.degree.
C. The reaction mixture was stirred for 5 min and then quenched
with sat. NH.sub.4Cl. The mixture was then partitioned between 9:1
CHCl.sub.3/IPA (10 mL) and 1 M NaOH (4 mL). The aqueous layer was
further extracted with 9:1 CHCl.sub.3/IPA (5 mL). The organic
layers were dried over MgSO.sub.4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (0-6% MeOH in DCM) to afford Example 1010 (45 mg,
0.09 mmol, 71% yield) as a white solid. LCMS (ESI.sup.+) m/z=489.1
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.62 (s, 1H),
8.86 (d, J=1.17 Hz, 1H), 8.37 (d, J=1.37 Hz, 1H), 7.94 (ddd,
J=2.54, 6.80, 12.37 Hz, 1H), 7.74 (d, J=5.79 Hz, 1H), 6.54 (s, 2H),
5.38-5.48 (m, 1H), 3.51-3.62 (m, 2H), 3.30 (s, 3H), 2.38 (dd,
J=7.82, 9.59 Hz, 1H), 1.89 (dd, J=5.87, 9.78 Hz, 1H), 1.75 (s, 3H),
1.29-1.34 (m, 3H), 1.07 (t, J=6.85 Hz, 1H).
[1984] Using procedures analogous or similar to the general
amidation Method H described above, the appropriate aniline and
carboxylic acid intermediates were reacted to provide the 15
examples listed in Table 10 and Table 10'.
TABLE-US-00020 TABLE 10 Observed Ex. No. Chemical Structure [M +
H].sup.+ 1011 ##STR00771## 469.1 1012 ##STR00772## 498 1015
##STR00773## 512.1 1016 ##STR00774## 468 1043 ##STR00775## 470 1044
##STR00776## 528 1046 ##STR00777## 488 1065 ##STR00778## 514 1066
##STR00779## 449 1068 ##STR00780## 472.1 1071 ##STR00781## 513 1072
##STR00782## 476 1073 ##STR00783## 520 1074 ##STR00784## 519 1075
##STR00785## 534
TABLE-US-00021 TABLE 10' Ex. No .sup.1H-NMR Chemical Name 1011
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 10.67 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.91 (d, J = 1.37 Hz, 1H), 8.46 (d, J =
1.37 Hz, 1H), cyano-5-methyl-2-thia-4- 7.96 (ddd, J = 2.64, 6.80,
12.28 Hz, 1H), 7.76 (d, azabicyclo[4.1.0]hept-3-en-5- J = 5.78 Hz,
1H), 6.56 (s, 2H), 5.82 (dq, J = 1.96,
yl)-4,5-difluorophenyl)-5-(((1S)- 6.65 Hz, 1H), 3.61 (d, J = 2.15
Hz, 1H), 2.34-2.43 1-methyl-2-propyn-1-yl)oxy)-2- (m, 1H), 1.90
(dd, J = 5.97, 9.68 Hz, 1H), 1.76 (s, pyrazinecarboxamide 3H), 1.64
(d, J = 6.65 Hz, 3H), 1.08 (t, J = 6.85 Hz, 1H) 1012 .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 10.66 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.53 (d, J = 2.54 Hz, 1H), 8.17 (d, J =
8.80 Hz, 1H), cyano-5-methyl-2-thia-4- 7.95-8.06 (m, 1H), 7.68-7.80
(m, 2H), 6.56 (s, azabicyclo[4.1.0]hept-3-en-5- 2H), 5.04 (q, J =
8.80 Hz, 2H), 2.40 (dd, J = 7.82, yl)-4,5-difluorophenyl)-5-(2,2,2-
9.59 Hz, 1H), 1.90 (dd, J = 5.87, 9.78 Hz, 1H), 1.76
trifluoroethoxy)-2- (s, 3H), 1.10 (t, J = 6.85 Hz, 1H)
pyridinecarboxamide 1015 .sup.1H NMR (400 MHz, DMSO-d6) .delta.
10.57 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.34 (d, J = 2.74 Hz,
1H), 7.96 (ddd, J = 2.45, 6.80, cyano-5-methyl-2-thia-4- 12.47 Hz,
1H), 7.56-7.61 (m, 2H), 6.55 (s, 2H), azabicyclo[4.1.0]hept-3-en-5-
4.99 (q, J = 8.80 Hz, 2H), 2.61 (s, 3H), 2.38 (dd,
yl)-4,5-difluorophenyl)-3- J = 7.92, 9.68 Hz, 1H), 1.88 (dd, J =
6.06, 9.78 Hz, methyl-5-(2,2,2- 1H), 1.75 (s, 3H), 1.08 (t, J =
6.85 Hz, 1H). trifluoroethoxy)-2- pyridinecarboxamide 1016 .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 10.55 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.27 (d, J = 2.54 Hz, 1H), 7.93-8.00
(m, 1H), 7.58 cyano-5-methyl-2-thia-4- (d, J = 5.67 Hz, 1H), 7.47
(d, J = 2.35 Hz, 1H), 6.54 azabicyclo[4.1.0]hept-3-en-5- (s, 2H),
5.00 (d, J = 2.35 Hz, 2H), 3.69 (t, J = 2.35
yl)-4,5-difluorophenyl)-3- Hz, 1H), 2.61 (s, 3H), 2.38 (dd, J =
7.82, 9.59 Hz, methyl-5-(2-propyn-1-yloxy)-2- 1H), 1.88 (dd, J =
5.87, 9.78 Hz, 1H), 1.75 (s, 3H), pyridinecarboxamide 1.08 (t, J =
6.85 Hz, 1H). 1043 .sup.1H NMR (400 MHz, CHLOROFORM-d) Shift
N-(3-((1S,5S,6S)-3-amino-1- 9.44 (s, 1H), 8.91-9.08 (m, 1H), 8.20
(d, J = 1.37 (methoxymethyl)-5-methyl-2- Hz, 1H), 7.85 (dd, J =
2.64, 6.16 Hz, 1H), 7.52 (dd, thia-4-azabicyclo[4.1.0]hept-3- J =
2.84, 6.36 Hz, 1H), 5.08 (d, J = 2.54 Hz, 2H), en-5-yl)-4-fluoro-5-
3.67 (d, J = 10.56 Hz, 1H), 3.41 (s, 3H), 3.34 (d,
methylphenyl)-5-(2-propyn-1- J = 10.76 Hz, 1H), 2.54 (t, J = 2.45
Hz, 1H), 2.29- yloxy)-2-pyrazinecarboxamide 2.38 (m, 3H), 1.77-1.88
(m, 1H), 1.71 (s, 3H), 0.85-0.93 (m, 1H), 0.77-0.83 (m, 1H) 1044
.sup.1H NMR (400 MHz, CHLOROFORM-d) Shift
N-(3-((1S,5S,6S)-3-amino-1- 9.43 (s, 1H), 8.99 (d, J = 1.17 Hz,
1H), 8.33 (d, (methoxymethyl)-5-methyl-2- J = 1.37 Hz, 1H), 7.85
(dd, J = 2.74, 6.26 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3- 7.52
(dd, J = 2.84, 6.36 Hz, 1H), 5.68 (s, 2H), 3.67
en-5-yl)-4-fluoro-5- (d, J = 10.76 Hz, 1H), 3.41 (s, 3H), 3.35 (d,
J = 10.76 methylphenyl)-5-((3-methyl- Hz, 1H), 2.43 (s, 3H), 2.32
(d, J = 2.35 Hz, 3H), 1,2,4-oxadiazol-5-yl)methoxy)- 1.82 (dd, J =
7.24, 8.61 Hz, 1H), 1.71 (s, 4H), 0.88 2-pyrazinecarboxamide (dd, J
= 5.87, 9.39 Hz, 1H), 0.75-0.83 (m, 1H) 1046 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.62 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.92
(d, J = 1.17 Hz, 1H), 8.50 (d, J = 1.37 Hz, 1H),
(ethoxymethyl)-5-methyl-2-thia- 7.89-7.96 (m, 2H), 5.99 (s, 2H),
5.16 (d, J = 2.35 4-azabicyclo[4.1.0]hept-3-en-5- Hz, 2H), 3.66
(td, J = 2.89, 5.18 Hz, 2H), 3.45-3.57
yl)-4,5-difluorophenyl)-5-(2- (m, 2H), 3.38 (d, J = 11.15 Hz, 1H),
1.59-1.66 (m, propyn-1-yloxy)-2- 4H), 1.14 (t, J = 6.94 Hz, 3H),
0.91 (dd, J = 5.28, pyrazinecarboxamide 9.19 Hz, 1H), 0.66 (t, J =
5.77 Hz, 1H) 1065 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.30-
N-(3-((1S,5S,6S)-3-amino-1- 9.63 (m, 1H), 9.02 (d, J = 1.17 Hz,
1H), 8.30 (d, (methoxymethyl)-5-methyl-2- J = 1.37 Hz, 1H), 7.84
(dd, J = 2.74, 5.87 Hz, 1H), thia-4-azabicyclo[4.1.0]hept-3- 7.54
(dd, J = 2.74, 6.46 Hz, 1H), 4.86 (q, J = 8.35 Hz,
en-5-yl)-4-fluoro-5- 2H), 3.67 (d, J = 10.56 Hz, 1H), 3.41 (s, 3H),
3.35 methylphenyl)-5-(2,2,2- (d, J = 10.56 Hz, 1H), 2.33 (d, J =
2.35 Hz, 3H), trifluoroethoxy)-2- 1.77-1.89 (m, 1H), 1.72 (s, 3H),
0.88 (dd, J = 5.87, pyrazinecarboxamide 9.39 Hz, 1H), 0.76-0.82 (m,
1H) 1066 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.63-
N-(3-((1S,5S,6S)-3-amino-1- 9.87 (m, 1H), 8.55 (d, J = 2.15 Hz,
1H), 8.24 (d, (methoxymethyl)-5-methyl-2- J = 8.22 Hz, 1H),
7.81-7.89 (m, 2H), 7.52-7.62 (m, thia-4-azabicyclo[4.1.0]hept-3-
1H), 3.67 (d, J = 10.56 Hz, 1H), 3.41 (s, 3H), 3.35
en-5-yl)-4-fluoro-5- (d, J = 10.76 Hz, 1H), 2.27-2.39 (m, 3H), 1.82
(dd, methylphenyl)-5-chloro-2- J = 7.24, 8.80 Hz, 1H), 1.72 (d, J =
0.98 Hz, 3H), pyridinecarboxamide 1.69-1.74 (m, 3H), 0.88 (dd, J =
5.87, 9.39 Hz, 1H), 0.75-0.83 (m, 1H) 1068 .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 10.66 (s, 1H), N-(3-((1S,5S,6S)-1-acetyl-3- 8.91
(d, J = 1.37 Hz, 1H), 8.49 (d, J = 1.37 Hz, 1H),
amino-5-methyl-2-thia-4- 7.92-7.99 (m, 2H), 6.16 (s, 2H), 5.15 (d,
J = 2.35 azabicyclo[4.1.0]hept-3-en-5- Hz, 2H), 3.65 (t, J = 2.45
Hz, 1H), 2.33-2.41 (m, yl)-4,5-difluorophenyl)-5-(prop- 1H), 2.11
(s, 3H), 1.74 (dd, J = 5.48, 9.78 Hz, 1H), 2-yn-1-yloxy)pyrazine-2-
1.62 (s, 3H), 1.11-1.17 (m, 1H) carboxamide 1071 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.44 (s, N-(3-((1S,5S,6S)-3-amino-1-
1H), 9.02 (d, J = 1.37 Hz, 1H), 8.17-8.28 (m, 1H),
(methoxymethyl)-5-methyl-2- 8.17-8.28 (m, 1H), 8.17-8.28 (m, 1H),
7.87 (dd, thia-4-azabicyclo[4.1.0]hept-3- J = 2.64, 6.16 Hz, 1H),
7.71 (d, J = 0.78 Hz, 1H), en-5-yl)-4-fluoro-5- 7.52 (dd, J = 2.74,
6.46 Hz, 1H), 7.18 (s, 1H), 5.58 methylphenyl)-5-(oxazol-2- (s,
2H), 4.38 (br.s., 2H), 3.67 (d, J = 10.56 Hz, 1H),
ylmethoxy)pyrazine-2- 3.41 (s, 3H), 3.34 (d, J = 10.76 Hz, 1H),
2.32 (d, carboxamide J = 2.35 Hz, 3H), 1.82 (dd, J = 7.24, 8.80 Hz,
1H), 1.71 (d, J = 0.98 Hz, 3H), 0.88 (dd, J = 5.77, 9.49 Hz, 1H),
0.78-0.83 (m, 1H) 1072 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.40 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.03 (d, J = 1.17 Hz,
1H), 8.21 (d, J = 1.17 Hz, (difluoromethyl)-5-methyl-2- 1H), 7.79
(dd, J = 2.54, 6.06 Hz, 1H), 7.41 (dd,
thia-4-azabicyclo[4.1.0]hept-3- J = 2.74, 6.26 Hz, 1H), 5.46-5.90
(m, 1H), 5.09 (d, en-5-yl)-4-fluoro-5- J = 2.35 Hz, 2H), 2.55 (t, J
= 2.45 Hz, 1H), 2.32 (d, methylphenyl)-5-(prop-2-yn-1- J = 2.35 Hz,
3H), 2.00 (dd, J = 7.43, 9.78 Hz, 1H), yloxy)pyrazine-2-carboxamide
1.77 (s, 4H), 1.30-1.37 (m, 1H), 0.85 (br.s., 1H) 1073 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.39 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.01 (d, J = 1.37 Hz, 1H), 8.30
(d, J = 1.37 Hz, (difluoromethyl)-5-methyl-2- 1H), 7.78 (dd, J =
2.93, 6.06 Hz, 1H), 7.43 (dd, thia-4-azabicyclo[4.1.0]hept-3- J =
2.74, 6.46 Hz, 1H), 5.42-5.87 (m, 1H), 4.86 (q,
en-5-yl)-4-fluoro-5- J = 8.22 Hz, 2H), 2.25-2.40 (m, 3H), 2.01 (dd,
methylphenyl)-5-(2,2,2- J = 7.34, 9.88 Hz, 1H), 1.77 (s, 3H),
1.29-1.39 (m, trifluoroethoxy)pyrazine-2- 1H), 0.81-0.88 (m, 1H)
carboxamide 1074 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.41
(s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 9.02 (d, J = 1.17 Hz, 1H),
8.25 (d, J = 1.17 Hz, (difluoromethyl)-5-methyl-2- 1H), 7.79 (dd, J
= 2.64, 6.16 Hz, 1H), 7.71 (s, 1H), thia-4-azabicyclo[4.1.0]hept-3-
7.40 (dd, J = 2.84, 6.36 Hz, 1H), 7.18 (s, 1H), 5.48-
en-5-yl)-4-fluoro-5- 5.84 (m, 3H), 2.27-2.37 (m, 3H), 2.00 (dd, J =
7.24, methylphenyl)-5-(oxazol-2- 9.78 Hz, 1H), 1.77 (s, 3H), 1.33
(dd, J = 6.16, 9.88 ylmethoxy)pyrazine-2- Hz, 1H), 0.85 (d, J =
9.39 Hz, 1H) carboxamide 1075 1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.40 N-(3-((1S,5S,6S)-3-amino-1- (s, 1H), 8.99 (d, J = 1.37
Hz, 1H), 8.33 (d, J = 1.17 (difluoromethyl)-5-methyl-2- Hz, 1H),
7.78 (dd, J = 2.35, 6.06 Hz, 1H), 7.42 (dd,
thia-4-azabicyclo[4.1.0]hept-3- J = 2.93, 6.26 Hz, 1H), 5.42-5.90
(m, 3H), 2.43 (s, en-5-yl)-4-fluoro-5- 3H), 2.28-2.36 (m, 3H), 2.01
(dd, J = 7.24, 9.78 Hz, methylphenyl)-5-((3-methyl- 1H), 1.77 (s,
3H), 1.31-1.36 (m, 1H), 0.82-0.87 1,2,4-oxadiazol-5- (m, 1H).
yl)methoxy)pyrazine-2- carboxamide
Method J: COMU Mediated Amide Formation Followed by Removal of the
Protecting Groups with PTSA
Example 985:
(1S,5S,6S)-3-amino-5-(5-(5-chloropicolinamido)-2-fluorophenyl)-N,5-dimeth-
yl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide
##STR00786##
[1986] To a mixture of tert-butyl
((1S,5S,6S)-5-(5-amino-2-fluorophenyl)-5-methyl-1-(methylcarbamoyl)-2-thi-
a-4-azabicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carb-
amate (intermediate 459) (0.032 g, 0.059 mmol), 5-chloropicolinic
acid (0.014 g, 0.089 mmol), and
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium
hexafluorophosphate (COMU, 0.038 g, 0.089 mmol) in DMF (0.5 mL) was
added N-ethyl-N-isopropylpropan-2-amine (0.021 mL, 0.119 mmol)
dropwise. The mixture was stirred at RT overnight. The reaction
mixture was diluted with sat'd Na.sub.2CO.sub.3 and EtOAc. The
organic layer was washed with water followed by brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (0-100% EtOAc in heptane)
to give product 985A (0.040 g, 0.059 mmol) as a white solid. LC/MS
(ESI.sup.+) m/z=678 (M+H).sup.+.
[1987] A mixture of 985A (0.040 g, 0.059 mmol) andp-toluenesulfonic
acid monohydrate (0.024 g, 0.124 mmol) in 1,4-dioxane (1.5 mL) was
stirred at 90.degree. C. for 1 h. The mixture was diluted with
saturated NaHCO.sub.3 and extracted with EtOAc. The organic
solution was washed with water and brine, dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was
purified by silica gel chromatography (0-100% EtOAc in DCM) to
provide Example 985 as an off-white solid (0.020 g, 78% yield over
two steps). LC/MS (ESI.sup.+) m/z=448 (M+H).sup.+. .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.67 (s, 1H), 8.48 (d, J=2.15 Hz, 1H),
8.17 (d, J=8.41 Hz, 1H), 7.84 (dd, J=2.35, 8.41 Hz, 1H), 7.72 (td,
J=3.57, 8.31 Hz, 1H), 7.50 (dd, J=2.74, 6.85 Hz, 1H), 6.99 (dd,
J=8.80, 11.15 Hz, 1H), 6.68 (d, J=4.30 Hz, 1H), 4.38 (br. s., 2H),
2.86 (d, J=4.69 Hz, 3H), 2.25 (dd, J=7.73, 9.29 Hz, 1H), 2.00 (dd,
J=5.09, 9.59 Hz, 1H), 1.87 (s, 3H), 0.74-0.87 (m, 1H).
[1988] Using procedures analogous or similar to the general
amidation Method J described above, the appropriate aniline and
carboxylic acid intermediates were reacted to provide the 7
examples listed in Table 11 and Table 11'.
TABLE-US-00022 TABLE 11 Observed Ex. No. Chemical Structure [M +
H].sup.+ 986 ##STR00787## 481 987 ##STR00788## 469 993 ##STR00789##
509 994 ##STR00790## 525 1001 ##STR00791## 529 1002 ##STR00792##
555 1003 ##STR00793## 545
TABLE-US-00023 TABLE 11' Ex. No. .sup.1H-NMR Chemical Name 986
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.70 (s,
(1S,5S,6S)-3-amino-N-tert- 1H), 8.81 (d, J = 1.17 Hz, 1H), 8.35 (d,
J = 8.02 Hz, 1H), butyl-5-(5-(((5-cyano-2- 8.17 (dd, J = 1.96, 8.22
Hz, 1H), 7.69-7.82 (m, 1H), pyridinyl)carbonyl)amino)-2- 7.52 (dd,
J = 2.74, 6.85 Hz, 1H), 7.00 (dd, J = 8.80,
fluorophenyl)-5-methyl-2- 11.15 Hz, 1H), 6.36 (s, 1H), 4.39-4.83
(m, 2H), 2.19 thia-4-azabicyclo[4.1.0]hept- (dd, J = 7.92, 9.29 Hz,
1H), 1.90 (dd, J = 4.99, 9.68 Hz, 3-ene-1-carboxamide 1H), 1.86 (s,
3H), 1.36 (s, 9H), 0.72 (dd, J = 5.38, 6.36 Hz, 1H) 987 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.39 (s, (1S,5S,6S)-3-amino-5-(2-
1H), 9.00 (s, 1H), 8.19 (s, 1H), 7.70-7.87 (m, 1H),
fluoro-5-(((5-(2-propyn-1- 7.49 (dd, J = 2.45, 6.75 Hz, 1H), 7.04
(dd, J = 9.00, yloxy)-2- 11.15 Hz, 1H), 6.54 (d, J = 4.11 Hz, 1H),
5.08 (d, pyrazinyl)carbonyl)amino)phenyl)- J = 2.35 Hz, 2H), 2.87
(d, J = 4.69 Hz, 3H), 2.55 (s, 1H), N,5-dimethyl-2-thia-4-
2.15-2.31 (m, 2H), 1.96 (dd, J = 4.89, 9.59 Hz, 1H),
azabicyclo[4.1.0]hept-3-ene-1- 1.83 (s, 3H), 0.73-0.88 (m, 1H)
carboxamide 993 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.38
(s, (1S,5S,6S)-3-amino-N- 1H), 9.00 (s, 1H), 8.14 (s, 1H), 7.76
(br.s., 1H), 7.48 cyclopropyl-5-(2-fluoro-5- (d, J = 4.69 Hz, 1H),
6.94-7.12 (m, 1H), 6.58 (br.s., (((5-(((1S)-1-methyl-2- 1H),
5.71-6.02 (m, 1H), 2.73 (d, J = 3.33 Hz, 1H), 2.49
propyn-1-yl)oxy)-2- (s, 1H), 2.19-2.29 (m, 1H), 1.95 (dd, J = 5.38,
9.88 Hz, pyrazinyl)carbonyl)amino)phenyl)- 1H), 1.82 (s, 3H), 1.70
(d, J = 6.65 Hz, 3H), 0.80 (d, 5-methyl-2-thia-4- J = 6.65 Hz, 3H),
0.55 (d, J = 4.11 Hz, 2H) azabicyclo[4.1.0]hept-3-ene-1-
carboxamide 994 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.40
(s, (1S,5S,6S)-3-amino-N-tert- 1H), 9.01 (s, 1H), 8.14 (s, 1H),
7.78 (br.s., 1H), 7.50 butyl-5-(2-fluoro-5-(((5- (d, J = 6.46 Hz,
1H), 6.98-7.12 (m, 1H), 6.30 (s, 1H), (((1S)-1-methyl-2-propyn-1-
5.84 (d, J = 7.63 Hz, 1H), 5.78-5.90 (m, 1H), 2.49 (s, yl)oxy)-2-
1H), 2.18 (t, J = 8.22 Hz, 1H), 1.86 (dd, J = 5.28, 9.59
pyrazinyl)carbonyl)amino)phenyl)- Hz, 1H), 1.81 (s, 3H), 1.70 (d, J
= 6.65 Hz, 3H), 1.37 5-methyl-2-thia-4- (s, 10H), 0.75 (d, J = 6.65
Hz, 1H), 0.70-0.78 (m, 1H) azabicyclo[4.1.0]hept-3-ene-1-
carboxamide 1001 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.39
(s, (1S,5S,6S)-3-amino-N- 1H), 8.95 (d, J = 1.37 Hz, 1H), 8.10 (d,
J = 1.37 Hz, 1H), cyclopropyl-5-(2-fluoro-5- 7.70-7.83 (m, 1H),
7.49 (dd, J = 2.74, 6.85 Hz, 1H), (((5-((1S)-2-methoxy-1- 7.04 (dd,
J = 8.80, 11.35 Hz, 1H), 6.59 (d, J = 2.15 Hz, methylethoxy)-2-
1H), 5.51 (dquin, J = 3.81, 6.28 Hz, 1H), 3.52-3.69 (m,
pyrazinyl)carbonyl)amino)phenyl)- 2H), 3.41 (s, 3H), 2.73 (qt, J =
3.62, 7.09 Hz, 1H), 2.24 5-methyl-2-thia-4- (dd, J = 7.92, 9.29 Hz,
1H), 1.95 (dd, J = 5.09, 9.78 Hz, azabicyclo[4.1.0]hept-3-ene-1-
1H), 1.82 (s, 3H), 1.39 (d, J = 6.46 Hz, 3H), 0.74-0.86 carboxamide
(m, 3H), 0.49-0.59 (m, 2H) 1002 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.42 (s, (1S,5S,6S)-3-amino-N-tert- 1H), 9.01 (d, J = 1.37
Hz, 1H), 8.29 (d, J = 1.37 Hz, 1H), butyl-5-(2-fluoro-5-(((5-
7.71-7.89 (m, 1H), 7.53 (dd, J = 2.64, 6.75 Hz, 1H),
(2,2,2-trifluoroethoxy)-2- 7.07 (dd, J = 8.80, 11.15 Hz, 1H), 6.28
(s, 1H), 4.77- pyrazinyl)carbonyl)amino)phenyl)- 4.98 (m, 2H),
2.15-2.24 (m, 1H), 1.86 (dd, J = 4.89, 5-methyl-2-thia-4- 9.78 Hz,
1H), 1.80 (d, J = 0.98 Hz, 3H), 1.37 (s, 9H),
azabicyclo[4.1.0]hept-3-ene-1- 0.75 (dd, J = 5.48, 7.04 Hz, 1H)
carboxamide 1003 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.41
(s, (1S,5S,6S)-3-amino-N-tert- 1H), 8.96 (d, J = 1.17 Hz, 1H), 8.12
(d, J = 1.17 Hz, 1H), butyl-5-(2-fluoro-5-(((5-((1S)- 7.72-7.85 (m,
1H), 7.51 (dd, J = 2.74, 6.85 Hz, 1H), 2-methoxy-1-methylethoxy)-
7.05 (dd, J = 8.80, 11.35 Hz, 1H), 6.29 (s, 1H), 5.44- 2- 5.59 (m,
1H), 3.51-3.69 (m, 2H), 3.41 (s, 3H), 2.14-
pyrazinyl)carbonyl)amino)phenyl)- 2.23 (m, 1H), 1.86 (dd, J = 5.09,
9.78 Hz, 1H), 1.80 (s, 5-methyl-2-thia-4- 3H), 1.39 (d, J = 6.46
Hz, 3H), 1.37 (s, 9H), 0.75 (dd, azabicyclo[4.1.0]hept-3-ene-1- J =
5.18, 6.55 Hz, 1H) carboxamide
Example 972:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-5-methyl-N-(2,2,2-trifluoroethyl)-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxamide
##STR00794##
[1990] To a mixture of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)--
5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid,
295, (0.17 g, 0.27 mmol) and 2,2,2-trifluoroethylamine (0.04 mL,
0.40 mmol) in DMF (1.0 mL) was added TEA (0.11 mL, 0.81 mmol) and
HATU (0.20 g, 0.53 mmol). The reaction mixture was stirred at RT
for 2 h, and then it was quenched with saturated NH.sub.4Cl
solution and extracted with EtOAc. The organic layer was
concentrated to dryness. The residue containing tert-butyl
((1S,5S,6S)-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamid-
o)phenyl)-5-methyl-1-((2,2,2-trifluoroethyl)carbamoyl)-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
was dissolved in dioxane (2 mL) and treated with p-toluenesulfonic
acid monohydrate (0.15 g, 0.80 mmol). The resulting mixture was
heated at 85.degree. C. for 2 h. The reaction mixture was diluted
with water and extracted with EtOAc (2.times.). The organic phase
was concentrated and the residue purified by flash column
chromatography on silica gel (0-60% EtOAc in heptane) to afford
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-5-methyl-N-(2,2,2-trifluoroethyl)-2-thia-4-azabicyclo[4.1-
.0]hept-3-ene-1-carboxamide (972) (72 mg, 0.12 mmol, 46% yield).
LC/MS (ESI.sup.+) m/z=581.2 (M+H). .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta.: 9.39 (s, 1H), 9.00 (s, 1H), 8.29 (s, 1H),
7.71-7.78 (m, 1H), 7.48-7.54 (m, 1H), 6.93-7.11 (m, 2H), 4.88 (q,
J=8.28 Hz, 2H), 3.98-4.23 (m, 1H), 3.88 (ddd, J=5.99, 8.88, 14.94
Hz, 1H), 2.82 (s, 2H), 2.24-2.32 (m, 1H), 2.04-2.12 (m, 1H), 1.89
(s, 3H), 0.86-0.94 (m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d)
.delta.: -72.37 (s, 3 F), -73.64 (s, 3 F), -113.23 (s, 1 F).
Example 973:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbo-
xamide
[1991] The title compound 973 (45 mg, 0.09 mmol, 33% yield) was
prepared according to the procedure described for 972 using
compound 295 (0.20 g, 0.27 mmol) and 2.0 M methylamine solution in
THF (0.20 mL, 0.40 mmol). LC/MS (ESI.sup.+) m/z=513.2 (M+H).
.sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.: 9.37 (s, 1H), 8.99 (s,
1H), 8.27 (s, 1H), 7.71-7.80 (m, 1H), 7.51 (dd, J=2.19, 6.72 Hz,
1H), 7.03 (dd, J=9.06, 10.82 Hz, 1H), 6.60 (d, J=4.38 Hz, 1H), 4.88
(q, J=8.28 Hz, 2H), 3.50-4.50 (br. s., 2H), 2.81-2.95 (m, 3H), 2.26
(t, J=8.55 Hz, 1H), 1.99 (dd, J=4.97, 9.65 Hz, 1H), 1.86 (s, 3H),
0.78-0.95 (m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.:
-73.64 (s, 3 F), -113.35 (s, 1 F).
Example 974:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-5-methyl-N--((S)-3-methylbutan-2-yl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-ene-1-carboxamide
[1992] The title compound 974 (0.045 g, 0.079 mmol, 29% yield) was
prepared according to the procedure described for 972 using
compound 295 (0.196 g, 0.269 mmol) and
(S)-(+)-3-methyl-2-butylamine (0.035 mL, 0.403 mmol). LC/MS
(ESI.sup.+) m/z=569.3 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta.: 9.41 (s, 1H), 9.01 (s, 1H), 8.29 (s, 1H), 7.78-7.85 (m,
1H), 7.52-7.58 (m, 1H), 7.07 (t, J=9.90 Hz, 1H), 6.34 (d, J=8.62
Hz, 1H), 4.88 (q, J=8.28 Hz, 2H), 3.80-3.93 (m, 1H), 2.82 (s, 2H),
2.25 (t, J=8.62 Hz, 1H), 1.95 (dd, J=4.97, 9.65 Hz, 1H), 1.84 (s,
3H), 1.76 (dd, J=6.65, 13.23 Hz, 1H), 1.13 (d, J=6.72 Hz, 3H), 0.93
(dd, J=3.22, 6.58 Hz, 6H), 0.77-0.88 (m, 1H). .sup.19F NMR (282
MHz, CHLOROFORM-d) .delta.: -73.63 (s, 3 F), -113.78 (s, 1 F).
Example 976:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-N-isopropyl-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-
-1-carboxamide
##STR00795##
[1994] The title compound 976 (0.045 g, 0.083 mmol, 40% yield) was
prepared according to the procedure described for 972 using
compound 295 (0.150 g, 0.206 mmol) and isopropylamine (0.026 mL,
0.308 mmol). LCMS (ESI.sup.+) m/z=541.3 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.: 9.36 (s, 1H), 8.97 (s, 1H), 8.25 (s,
1H), 7.73-7.83 (m, 1H), 7.49 (dd, J=2.34, 6.72 Hz, 1H), 7.28 (s,
1H), 7.02 (dd, J=8.92, 10.96 Hz, 1H), 6.34 (d, J=7.60 Hz, 1H),
5.02-5.44 (m, 1H), 4.87 (q, J=8.28 Hz, 2H), 4.00-4.18 (m, 1H), 2.25
(t, J=8.55 Hz, 1H), 1.96 (dd, J=4.97, 9.65 Hz, 1H), 1.87 (s, 3H),
1.20 (dd, J=4.38, 6.28 Hz, 6H), 0.76-0.86 (m, 1H).
Example 977:
(1S,5S,6S)-3-amino-N-ethyl-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazi-
ne-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-c-
arboxamide
##STR00796##
[1996] The title compound 977 (0.061 g, 0.116 mmol, 43% yield) was
prepared according to the procedure for 972 using compound 295
(0.196 g, 0.269 mmol) and 2.0 M ethylamine solution in THF (0.671
mL, 1.343 mmol). LCMS (ESI.sup.+) m/z=527.3 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.: 9.29 (s, 1H), 8.92 (s, 1H), 8.20 (s,
1H), 7.62-7.72 (m, 1H), 7.47 (dd, J=2.34, 6.72 Hz, 1H), 6.94 (dd,
J=9.13, 10.74 Hz, 1H), 6.63 (t, J=5.33 Hz, 1H), 5.43 (br. s., 2H),
4.87 (q, J=8.18 Hz, 2H), 3.23-3.42 (m, 2H), 2.23 (t, J=8.48 Hz,
1H), 1.93-2.07 (m, 1H), 1.89 (s, 3H), 1.17 (t, J=7.23 Hz, 3H), 0.78
(t, J=6.14 Hz, 1H).
Example 981:
N-(3-((1S,5S,6S)-3-amino-1-(aminomethyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-car-
boxamide
##STR00797## ##STR00798##
[1997] Preparation of Compound 980A
[1998] To a stirred solution of tert-butyl
((1S,5S,6S)-5-(2,3-difluorophenyl)-1-(hydroxymethyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(458A, 4.60 g, 8.94 mmol) and TEA (1.49 mL, 10.72 mmol) in
CH.sub.2Cl.sub.2 (100 mL) at 0.degree. C. under nitrogen was added
methanesulfonyl chloride (0.76 mL, 9.83 mmol). The resulting
suspension was stirred for 20 min and then quenched with sat
NH.sub.4Cl (5 mL). The reaction was diluted with sat NaHCO.sub.3
(200 mL) and CH.sub.2Cl.sub.2 (50 mL). The organic layer was
further washed with brine (10 mL) and then it was dried over
MgSO.sub.4, filtered, and concentrated under reduced pressure to
afford
((1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)ami-
no)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1--
yl)methyl methanesulfonate (980A, 4.95 g, 8.35 mmol, 93% yield) as
a colorless oil. LC/MS (ESI.sup.-) m/z=593.2.
Preparation of Compound 980B
[1999] A suspension of
((1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)ami-
no)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1--
yl)methyl methanesulfonate (980A, 4.95 g, 8.35 mmol) and sodium
azide (0.81 g, 12.53 mmol) in dry DMF (30 mL) was heated at
80.degree. C. for 90 min. The reaction mixture was then partitioned
between dimethylether (150 mL) and water (250 mL). The separated
organic solution was washed with 1 M LiCl (100 mL) followed by
brine (10 mL). It was dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography (0-10% EtOAc in heptane) to afford
tert-butyl
((1S,5S,6S)-1-(azidomethyl)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(980B, 4.40 g, 8.15 mmol, 98% yield) as a colorless oil. LC/MS
(ESI.sup.-) m/z=540.2.
Preparation of Compound 980C
[2000] To a stirred solution of tert-butyl
((1S,5S,6S)-1-(azidomethyl)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(980B, 4.2 g, 7.78 mmol) in THF (40 mL) at 20.degree. C. was added
trimethylphosphine (1 M in THF, 9.73 mL, 9.73 mmol) in 1 mL
aliquots over a course of 10 min. To the reaction after 90 min was
slowly added 1 M HCl (30 mL) and the resulting mixture was stirred
at high speed for 1 h. The reaction mixture was then partitioned
between EtOAc (250 mL) and water (300 mL). The organic layer was
further washed with brine (2.times.50 mL), dried over MgSO.sub.4,
filtered, and then concentrated under reduce pressure to afford
tert-butyl
((1S,5S,6S)-1-(aminomethyl)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(980C, 3.5 g, 6.81 mmol, 88% yield) as a white foam. LC/MS
(ESI.sup.-) m/z=514.2.
Preparation of Compound 980D
[2001] To tert-butyl
((1S,5S,6S)-1-(aminomethyl)-5-(2,3-difluorophenyl)-5-methyl-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
(980C, 3.50 g, 6.81 mmol) at 0.degree. C. was added sulfuric acid
(50.1 g, 511 mmol). The acid slowly digested the starting material
and gas evolution was evident. After 15 min, the reaction was
removed from the cooling bath, swirled by hand, and then allowed to
stir at 20.degree. C. for 30 min. The material was chilled to
0.degree. C. and sodium nitrate (1.16 g, 13.63 mmol) was added in 2
portions over a course of 5 min. The reaction was then stirred for
45 min at 0.degree. C. The reaction was then slowly poured onto wet
ice (300 mL) along with CH.sub.2Cl.sub.2 (100 mL). Water (1200 mL)
was added, followed by portion wise addition of potassium phosphate
(181 g, 852 mmol) over 15-20 min period (pH.about.9). The organic
layer was separated, and the aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.50 mL). The combined organic layers were
dried over MgSO.sub.4, filtered, concentrated under reduced
pressure, and then purified by silica gel chromatography (0-10% [2
M NH.sub.3 in MeOH] in CH.sub.2Cl.sub.2 to give
(1S,5S,6S)-1-(aminomethyl)-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-en-3-amine (980D, 1.48 g, 4.51 mmol, 66%
yield) as a white foam. LC/MS (ESI.sup.-) m/z=329.1. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.46-8.51 (m, 1H), 8.31 (ddd,
J=2.93, 6.36, 9.49 Hz, 1H), 6.21 (s, 2H), 2.64-2.77 (m, 2H), 1.72
(t, J=6.85 Hz, 1H), 1.61 (s, 3H), 1.58 (br. s., 2H), 0.79 (dd,
J=5.28, 9.19 Hz, 1H), 0.48 (t, J=5.77 Hz, 1H).
Preparation of Compound 980E
[2002] To a stirred solution of tert-butyl
(((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-1-yl)methyl)carbamate (980D, 1.50 g, 3.50
mmol) in glacial AcOH (15 mL) at 20.degree. C. was added zinc (0.68
g, 10.50 mmol) in 0.20 g portions that kept the reaction temp in
the range of 35-42.degree. C. To the reaction, after 45 min, was
added TFA (0.5 mL). After 4 h, the reaction was cooled to 0.degree.
C., CH.sub.2Cl.sub.2 (50 mL) added, and 30% NH.sub.4OH (80 mL) was
added dropwise to the reaction mixture. The organic layer was
separated and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(2.times.25 mL). The organic extracts were dried over MgSO.sub.4,
filtered, and then concentrated under reduced pressure to afford
tert-butyl(((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methyl)carbamate (980E, 1.3
g, 3.4 mmol, 98% yield) as a yellow foam. LC/MS (ESI.sup.-)
m/z=399.2.
Preparation of Compound 980F
[2003] To a stirred solution of
(1S,5S,6S)-1-(aminomethyl)-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-en-3-amine (980E, 1.40 g, 4.26 mmol) in
THF (20 mL) at 0.degree. C. was added di-tert-butyl dicarbonate
(2.88 g, 13.22 mmol) followed by DMAP (10 mg). The solution was
stirred for 15 min and then quenched with sat NH.sub.4Cl (10 mL).
The reaction was diluted with EtOAc (50 mL) and water (20 mL). The
separated organic was dried over MgSO.sub.4, filtered, concentrated
under reduced pressure, and then purified by silica gel
chromatography (0-25% EtOAc in CH.sub.2Cl.sub.2) to afford
tert-butyl
(((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-nitrophenyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-1-yl)methyl)carbamate (980F, 1.50 g, 3.50
mmol, 82% yield) as a yellow tar. The material thus obtained
crystallized upon sitting overnight. LC/MS (ESI.sup.-) m/z=429.1.
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.44 (br. s., 1H), 7.98
(ddd, J=2.93, 6.31, 9.15 Hz, 1H), 4.90 (br. s., 1H), 4.23-4.78 (bs,
2H), 3.33 (d, J=6.26 Hz, 2H), 1.99 (br. s., 1H), 1.72 (s, 3H), 1.47
(s, 9H), 0.90 (br. s., 1H), 0.75 (t, J=6.36 Hz, 1H).
Preparation of Example 980
[2004] To a stirred solution of tert-butyl
(((1S,5S,6S)-3-amino-5-(5-amino-2,3-difluorophenyl)-5-methyl-2-thia-4-aza-
bicyclo[4.1.0]hept-3-en-1-yl)methyl)carbamate (980F, 70 mg, 0.17
mmol) in CH.sub.2Cl.sub.2 (1 mL) at 0.degree. C. under nitrogen was
added 1-propanephosphonic acid cyclic anhydride (224 mg of 50%
solution in EtOAc, 0.35 mmol) in CH.sub.2Cl.sub.2 (1 mL). The
mixture was stirred for 18 h at 20.degree. C. The reaction was then
quenched with sat. NH.sub.4Cl (2 mL) and stirred for 10 min. The
reaction was then partitioned between 9:1 CHCl.sub.3/IPA (10 mL)
and 5% NaHCO.sub.3 (10 mL). The aqueous layer was further extracted
with 9:1 CHCl.sub.3/IPA (2 mL). The combined organic layers were
further washed with 1 M NaOH (10 mL). The aqueous layer was further
extracted with 9:1 CHCl.sub.3/IPA (2 mL). The combined organics
were then dried over MgSO.sub.4, concentrated under reduced
pressure onto dry silica (5 g), and then purified by silica gel
chromatography (12 g) eluting products with a gradient of 1-4% MeOH
in CH.sub.2Cl.sub.2 to afford
tert-butyl(((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(5-(prop-2-yn-1-yloxy)py-
razine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en--
1-yl)methyl)carbamate (980, 14 mg, 0.025 mmol, 14% yield) as a
colorless film. This film was suspended in 1:1 ACN/water (1 mL),
frozen, and then lyophilized to afford product as a white fluffy
solid. LC/MS (ESI.sup.-) m/z=559.1. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.50 (s, 1H), 9.02 (d, J=1.37 Hz, 1H), 8.21
(s, 1H), 8.03 (ddd, J=2.64, 6.80, 11.69 Hz, 1H), 7.34-7.39 (m, 1H),
5.09 (d, J=2.54 Hz, 2H), 4.87 (br. s., 1H), 3.49 (s, 1H), 3.32 (d,
J=5.87 Hz, 2H), 2.55 (t, J=2.45 Hz, 1H), 1.93 (t, J=7.63 Hz, 1H),
1.71 (s, 3H), 1.43-1.52 (m, 9H), 0.81-0.94 (m, 1H), 0.74 (t, J=6.26
Hz, 1H).
Preparation of Example 981
[2005] A solution of tert-butyl
(((1S,5S,6S)-3-amino-5-(2,3-difluoro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-c-
arboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-en-1-yl)methy-
l)carbamate (980, 12 mg, 0.02 mmol) in TFA was stirred for 30 min
at 20.degree. C. The reaction was concentrated under reduced
pressure then partitioned between 9:1 CHCl.sub.3/IPA (10 mL) and 1
M NaCl (5 mL). The aqueous was further extracted with 9:1
CHCl.sub.3/IPA (2.times.5 mL). The combined organics were dried
over MgSO.sub.4, and concentrated under reduced pressure. The
resulting residue was suspended in 1:1 ACN/water (1 mL), frozen,
and then lyophilized affording
N-(3-((1S,5S,6S)-3-amino-1-(aminomethyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-car-
boxamide (8 mg, 0.017 mmol, 81% yield) as a white fluffy powder.
LC/MS (ESI.sup.-) m/z=459.0. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.53 (s, 1H), 8.83 (d, J=1.17 Hz, 1H), 8.41 (d, J=1.17 Hz,
1H), 7.80-7.86 (m, 2H), 5.86 (s, 2H), 5.07 (d, J=2.54 Hz, 2H), 3.57
(t, J=2.45 Hz, 1H), 2.54-2.70 (m, 3H), 1.47-1.60 (m, 4H), 0.75 (dd,
J=5.18, 9.49 Hz, 1H), 0.46 (t, J=5.67 Hz, 1H).
Example 982:
(1S,5S,6S)-3-amino-N-(2,2-difluorocyclopropyl)-5-(2-fluoro-5-(5-(2,2,2-tr-
ifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-ene-1-carboxamide
[2006] The title compound 982 (0.008 g, 0.014 mmol, 5% yield) was
prepared according to the procedure for 972 using compound 295
(0.196 g, 0.269 mmol) and 2,2-difluorocyclopropylamine
hydrochloride (0.049 g, 0.376 mmol). LC/MS (ESI.sup.+) m/z=575.2
(M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.: 9.39 (s, 1H),
9.00 (s, 1H), 8.29 (s, 1H), 7.72-7.81 (m, 1H), 7.49 (t, J=5.55 Hz,
1H), 6.98-7.12 (m, 1H), 6.94 (br. s., 1H), 4.88 (q, J=8.18 Hz, 2H),
4.00-4.50 (br. s., 2H), 3.38 (br. s., 1H), 2.29 (t, J=8.48 Hz, 1H),
1.97-2.11 (m, 1H), 1.81-1.94 (m, 4H), 1.34-1.68 (m, 1H), 0.81-0.99
(m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.: -73.63 (s, 3
F), -113.22 (s, 1 F), -131.06 (d, J=160.74 Hz, 1 F), -143.91 (d,
J=160.74 Hz, 1 F).
Example 983:
(1S,5S,6S)-3-amino-N-(1-fluoro-2-methylpropan-2-yl)-5-(2-fluoro-5-(5-(2,2-
,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabic-
yclo[4.1.0]hept-3-ene-1-carboxamide
##STR00799##
[2008] To a mixture of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)--
5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid,
295, (0.15 g, 0.20 mmol), 2-fluoro-1,1-dimethyl-ethylamine
hydrochloride (52 mg, 0.41 mmol), and diisopropylethylamine (0.18
mL, 1.03 mmol) in DMF (2 mL) was added
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium
hexafluorophosphate, COMU, (0.17 g, 0.41 mmol). The reaction
mixture was stirred at RT for 18 h, quenched with saturated
NH.sub.4Cl, and extracted with EtOAc. The organic layer was
concentrated to dryness. The residue of tert-butyl
((1S,5S,6S)-1-((1-fluoro-2-methylpropan-2-yl)carbamoyl)-5-(2-fluoro-5-(5--
(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-az-
abicyclo[4.1.0]hept-3-en-3-yl)((2-(trimethylsilyl)ethoxy)methyl)carbamate
was dissolved in dioxane (2 mL) and added to p-toluenesulfonic acid
monohydrate (0.15 g, 0.80 mmol). The resulting mixture was then
heated at 85.degree. C. for 2 h. The reaction was diluted with
water and extracted with EtOAc (2.times.). The organic phase was
concentrated and the residue purified by flash column
chromatography on silica gel (0-5% MeOH in DCM) to afford
(1S,5S,6S)-3-amino-N-(1-fluoro-2-methylpropan-2-yl)-5-(2-fluoro-
-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thi-
a-4-azabicyclo[4.1.0]hept-3-ene-1-carboxamide, 983, (0.04 g, 0.07
mmol, 34% yield). LCMS (ESI.sup.+) m/z=573.2 (M+H). .sup.1H NMR
(300 MHz, CHLOROFORM-d) .delta.: 9.41 (s, 1H), 9.01 (s, 1H), 8.29
(s, 1H), 7.77-7.85 (m, 1H), 7.50 (dd, J=2.34, 6.72 Hz, 1H), 7.07
(t, J=9.92 Hz, 1H), 6.45 (s, 1H), 4.88 (q, J=8.28 Hz, 2H),
4.45-4.62 (m, 1H), 4.28-4.43 (m, 1H), 3.88-4.26 (br. s., 2H),
2.18-2.27 (m, 1H), 1.80-1.96 (m, 4H), 1.33-1.45 (m, 6H), 0.76-0.88
(m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.: -73.63 (s, 3
F), -113.56 (s, 1 F), -225.38 (s, 1 F).
Example 984:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-N-methoxy-N,5-dimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-e-
ne-1-carboxamide
##STR00800##
[2010] The title compound 984 (0.060 g, 0.111 mmol, 53% yield) was
prepared according to the procedure for 983 using compound 295,
(0.150 g, 0.206 mmol), and N,O-dimethyl hydroxylamine hydrochloride
(0.040 g, 0.411 mmol). LCMS (ESI.sup.+) m/z=543.2 (M+H). .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta.: 9.45 (s, 1H), 9.02 (s, 1H),
8.31 (s, 1H), 7.86-7.93 (m, 1H), 7.55 (dd, J=2.48, 6.72 Hz, 1H),
6.96-7.18 (m, 1H), 4.88 (q, J=8.28 Hz, 2H), 3.92-4.65 (br. s., 2H),
3.79 (s, 3H), 3.26 (s, 3H), 2.46 (t, J=8.62 Hz, 1H), 1.88 (s, 3H),
1.51 (dd, J=5.55, 9.79 Hz, 1H), 0.93 (t, J=6.43 Hz, 1H). .sup.19F
NMR (282 MHz, CHLOROFORM-d) .delta.: -73.64 (s, 3 F), -114.39 (s, 1
F).
Example 991:
N-(3-((1S,5S,6S)-3-amino-1-((R)-3-fluoropyrrolidine-1-carbonyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluo-
roethoxy)pyrazine-2-carboxamide
##STR00801##
[2012] The title compound 991 (0.060 g, 0.105 mmol, 51% yield) was
prepared according to the procedure for 983 using compound 295,
(0.150 g, 0.206 mmol) and (R)-(-)-3-fluoropyrrolidine hydrochloride
(0.052 g, 0.411 mmol). LCMS (ESI.sup.+) m/z=571.2 (M+H). .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta.: 9.47 (s, 1H), 9.03 (s, 1H),
8.31 (s, 1H), 7.83-7.91 (m, 1H), 7.57-7.64 (m, 1H), 6.99-7.19 (m,
1H), 5.10-5.55 (m, 1H), 4.88 (q, J=8.33 Hz, 2H), 3.28-4.46 (br. m.,
7H), 2.35 (br. s., 1H), 2.15-2.31 (m, 1H), 1.91 (s, 3H), 1.60 (dd,
J=5.92, 9.57 Hz, 1H), 0.86 (br. s., 1H). .sup.19F NMR (282 MHz,
CHLOROFORM-d) .delta.: -73.63 (s, 3 F), -114.61 (s, 1 F), -177.70
(s, 1 F).
Example 992:
N-(3-((1S,5S,6S)-3-amino-1-((S)-3-fluoropyrrolidine-1-carbonyl)-5-methyl--
2-thia-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluo-
roethoxy)pyrazine-2-carboxamide
##STR00802##
[2014] The title compound 992 (0.057 g, 0.100 mmol, 48% yield) was
prepared according to the procedure for 983 using compound 295,
(0.150 g, 0.206 mmol) and (S)-(-)-3-fluoropyrrolidine hydrochloride
(0.052 g, 0.411 mmol). LCMS (ESI.sup.+) m/z=571.2 (M+H). .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta.: 9.47 (s, 1H), 9.03 (s, 1H),
8.31 (s, 1H), 7.84-7.92 (m, 1H), 7.62 (d, J=4.53 Hz, 1H), 7.09 (s,
1H), 5.10-5.50 (m, 1H), 4.88 (q, J=8.18 Hz, 2H), 3.90-4.62 (m, 3H),
3.76 (br. s., 4H), 2.46 (s, 2H), 1.89 (s, 3H), 1.42 (dd, J=5.63,
9.72 Hz, 1H), 0.93 (t, J=6.28 Hz, 1H). .sup.19F NMR (282 MHz,
CHLOROFORM-d) .delta.: -73.63 (s, 3 F), -114.67 (s, 1 F), -177.55
(s, 1 F).
Example 995 and Example 996
##STR00803##
[2016] Example 968 (40 mg, a mixture of two diastereomers) was
chromatographed using supercritical CO.sub.2 (additives 15% of EtOH
with 20 mM NH.sub.3) on an OD-H column (250.times.21 mm, 5 m)
eluting at a flow rate of 70 mL/min. The first peak (retention
time=3.6 min) provided
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(((S)-1,1,1-trifluoropropan-2-yl)ox-
y)pyrazine-2-carboxamide 995 (18 mg, 45% yield). The second peak
(retention time=4.5 min) provided
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(((R)-1,1,1-trifluoropropan-2-yl)ox-
y)pyrazine-2-carboxamide 996 (18 mg, 45% yield). The absolute
stereochemistry was arbitrarily assigned. Analytical data for
Example 995: .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.48 (s,
1H), 9.01 (d, J=1.17 Hz, 1H), 8.23 (d, J=1.17 Hz, 1H), 7.87-8.00
(m, 1H), 7.72 (dd, J=2.74, 7.04 Hz, 1H), 7.07 (dd, J=8.80, 11.74
Hz, 1H), 5.81 (m, 1H), 3.67 (d, J=10.37 Hz, 1H), 3.41 (s, 3H), 3.35
(d, J=10.76 Hz, 1H), 1.81 (ddd, J=1.17, 6.70, 9.34 Hz, 1H), 1.72
(d, J=1.17 Hz, 3H), 1.56 (d, J=6.46 Hz, 3H), 0.88 (dd, J=5.87, 9.39
Hz, 1H), 0.77-0.84 (m, 1H). LC/MS (ESI.sup.+) m/z=514 (M+H).sup.+.
Analytical data for Example 996: .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.48 (s, 1H), 9.01 (d, J=1.37 Hz, 1H), 8.24
(d, J=1.17 Hz, 1H), 7.95 (td, J=3.47, 8.71 Hz, 1H), 7.71 (dd,
J=2.74, 6.85 Hz, 1H), 7.08 (dd, J=8.61, 11.74 Hz, 1H), 5.74-5.89
(m, 1H), 3.67 (d, J=10.56 Hz, 1H), 3.41 (s, 3H), 3.35 (d, J=10.56
Hz, 1H), 1.82 (dd, J=7.04, 8.41 Hz, 1H), 1.73 (s, 3H), 1.57 (d,
J=6.46 Hz, 3H), 0.89 (dd, J=5.87, 9.39 Hz, 1H), 0.76-0.83 (m, 1H).
LC/MS (ESI.sup.+) m/z=514 (M+H).sup.+.
Example 997:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-5-methyl-N--((R)-3-methylbutan-2-yl)-2-thia-4-azabicyclo[-
4.1.0]hept-3-ene-1-carboxamide
##STR00804##
[2018] The title compound 997 (0.042 g, 0.074 mmol, 36% yield) was
prepared according to the procedure for 983 using compound 295,
(0.150 g, 0.206 mmol) and (R)-(-)-2-amino-3-methylbutylamine (0.027
mL, 0.308 mmol). LCMS (ESI.sup.+) m/z=569.3 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.: 9.39 (s, 1H), 8.98 (s, 1H), 8.26 (s,
1H), 7.74-7.81 (m, 1H), 7.54 (dd, J=2.41, 6.80 Hz, 1H), 7.04 (dd,
J=8.92, 10.96 Hz, 1H), 6.39 (d, J=8.77 Hz, 1H), 4.87 (q, J=8.33 Hz,
2H), 4.71 (br. s., 2H), 3.80-3.93 (m, 1H), 2.24 (t, J=8.55 Hz, 1H),
1.95 (dd, J=4.97, 9.65 Hz, 1H), 1.85 (s, 3H), 1.72-1.81 (m, 1H),
1.12 (d, J=6.72 Hz, 3H), 0.89-0.97 (m, 6H), 0.78-0.88 (m, 1H).
.sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.: -73.63 (s, 3 F),
-113.63 (s, 1 F).
Example 998:
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyra-
zine-2-carboxamide
##STR00805##
[2020] To a solution of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-carboxamido)phenyl)--
5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid,
295, (0.15 g, 0.20 mmol) in DCM (3 mL) was added
1-chloro-N,N,2-trimethyl-1-propenylamine (0.20 mL, 1.49 mmol).
After the reaction mixture was stirred at RT for 2 h, additional
1-chloro-N,N,2-trimethyl-1-propenylamine (0.20 mL, 1.49 mmol) was
added and the reaction was stirred for another 12 h. The reaction
mixture was then concentrated under vacuum. To the residue in DMF
(1 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.03 mmol) and
morpholine (0.02 mL, 0.21 mmol). The reaction was stirred at RT for
30 min, diluted with water and extracted with EtOAc (2.times.). The
combined organic extracts were concentrated to dryness. The residue
was dissolved in dioxane (2 mL) and treated with p-toluenesulfonic
acid monohydrate (0.12 g, 0.62 mmol). The resulting mixture was
heated in an oil bath at 85.degree. C. for 2 h. The reaction was
then diluted with water and extracted with EtOAc (2.times.). The
organic extracts were concentrated and the residue was purified by
flash column chromatography on silica gel (0-5% MeOH in DCM) to
afford
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(2,2,2-trifluoroethoxy)pyra-
zine-2-carboxamide, 998, (77 mg, 0.14 mmol, 66% yield). LCMS
(ESI.sup.+) m/z=569.2 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta.: 9.46 (s, 1H), 9.02 (s, 1H), 8.29 (s, 1H), 7.81-7.89 (m,
1H), 7.64-7.71 (m, 1H), 7.04-7.13 (m, 1H), 4.88 (q, J=8.18 Hz, 2H),
4.25 (br. s., 2H), 3.70 (br. s., 8H), 2.36 (t, J=8.48 Hz, 1H), 1.86
(s, 3H), 1.36 (dd, J=5.70, 9.65 Hz, 1H), 0.92 (t, J=6.43 Hz, 1H).
.sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.: -73.36 (s, 3 F),
-114.91 (s, 1 F).
Example 999:
(1S,5S,6S)-3-amino-N-(2,2-difluoroethyl)-5-(2-fluoro-5-(5-(2,2,2-trifluor-
oethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]-
hept-3-ene-1-carboxamide
##STR00806##
[2022] The title compound 999 (0.100 g, 0.178 mmol, 65% yield) was
prepared according to the procedure for 998 using compound 295
(0.200 g, 0.274 mmol) and 2,2-difluoroethylamine (0.022 mL, 0.274
mmol). LCMS (ESI.sup.+) m/z=563.1 (M+H). .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta.: 9.28 (s, 1H), 8.93 (s, 1H), 8.22 (s, 1H),
7.62-7.73 (m, 1H), 7.46 (d, J=6.72 Hz, 1H), 6.87-7.04 (m, 2H),
5.60-6.14 (m, 1H), 5.26 (br. s., 2H), 4.88 (q, J=8.28 Hz, 2H),
3.51-3.82 (m, 2H), 2.18-2.28 (m, 1H), 2.04 (dd, J=5.12, 9.35 Hz,
1H), 1.90 (s, 3H), 0.84 (t, J=6.14 Hz, 1H). .sup.19F NMR (282 MHz,
CHLOROFORM-d) .delta.: -73.63 (s, 3 F), -113.09 (s, 1 F), -122.91
(s, 1 F), -122.92 (s, 1 F).
Example 1000:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-N,N,5-trimethyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-ca-
rboxamide
##STR00807##
[2024] The title compound (0.109 g, 0.207 mmol, 76% yield) was
prepared according to the procedure for 983 using compound 295,
(0.200 g, 0.274 mmol) and dimethylamine hydrochloride (0.045 g,
0.548 mmol). LCMS (ESI+) m/z=527.2 (M+H). .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta.: 9.42 (s, 1H), 8.98 (s, 1H), 8.24 (s, 1H),
7.79-7.87 (m, 1H), 7.62 (dd, J=2.12, 6.65 Hz, 1H), 7.03 (dd,
J=9.21, 10.96 Hz, 1H), 4.86 (q, J=8.28 Hz, 4H), 3.06 (br. s., 6H),
2.31 (t, J=8.40 Hz, 1H), 1.88 (s, 3H), 1.38 (dd, J=5.70, 9.65 Hz,
1H), 0.88 (t, J=6.43 Hz, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d)
.delta.: -73.63 (s, 3 F), -114.70 (s, 1 F).
Example 1004:
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyra-
zine-2-carboxamide
##STR00808##
[2026] To a stirred solution of (1S,5S,6S)-methyl
3-(di-tert-butoxycarbonyl)amino-5-(2,3-difluoro-5aminophenyl)-5-methyl-2--
thia-4-azabicyclo[4.1.0]hept-3-ene-1-(morpholino)methanone (461, 83
mg, 0.142 mmol) and diisopropylethylamine (99 .mu.L, 0.57 mmol) in
DMF (0.5 mL) at 20.degree. C. was added HATU (81 mg, 0.21 mmol).
The solution was stirred for 30 min and then
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid hydrochloride (273,
46 mg, 0.21 mmol) was added. The solution was stirred for 1 h and
then partitioned between 9:1 CHCl.sub.3/IPA (20 mL) and 5%
NaHCO.sub.3. The organic layer was washed with brine, dried over
MgSO.sub.4, filtered, and then concentrated under reduced pressure.
The residue was azeotroped with toluene (3.times.5 mL) followed by
stirring in TFA (1 mL) for 30 min. The solvent was removed under
reduced pressure and the residue was partitioned between 9:1
CHCl.sub.3/IPA (20 mL) and 1 M NaOH (10 mL). The organic layer was
washed with brine, dried over MgSO.sub.4, filtered, and then
concentrated under reduced pressure. The resulting white solid was
triturated with EtOH (2.times.2 mL) and then dried under reduced
pressure to afford Example 1004 (42 mg, 0.08 mmol, 54% yield) as a
white solid. LC/MS (ESI.sup.-) m/z=543.0 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.62 (s, 1H), 8.90 (d, J=1.17 Hz,
1H), 8.48 (d, J=1.37 Hz, 1H), 7.91 (ddd, J=2.54, 6.80, 12.37 Hz,
1H), 7.84 (d, J=5.87 Hz, 1H), 6.25 (s, 2H), 5.14 (d, J=2.35 Hz,
2H), 3.49-3.68 (m, 8H), 2.04-2.10 (m, 1H), 1.68 (s, 4H), 1.37 (dd,
J=5.48, 9.59 Hz, 1H), 0.78-0.84 (m, 1H).
Example 1005:
N-(3-((1S,5S,6S)-3-amino-5-methyl-1-(morpholine-4-carbonyl)-2-thia-4-azab-
icyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-
-2-carboxamide
##STR00809##
[2027] Preparation of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2-flu-
oro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (1005A)
[2028] To a mixture of (1S,5S,6S)-methyl
5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late, 295A, (0.570 g, 1.056 mmol),
5-(prop-2-yn-1-yloxy)pyrazine-2-carboxylic acid, 273, (0.226 g,
1.267 mmol), and diisopropylethylamine (0.551 mL, 3.17 mmol) in DMF
(1 mL) was added
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocar-
benium hexafluorophosphate, COMU, (0.905 g, 2.112 mmol). The
reaction mixture was stirred at RT for 2 h and was then quenched
with saturated NH.sub.4Cl solution and extracted with EtOAc. The
organic layer was concentrated to dryness and the residue was
purified by flash column chromatography on silica gel (0-40% EtOAc
in heptane) to afford compound 1005A (0.510 g, 0.729 mmol, 69%
yield). LCMS (ESI.sup.+) m/z=700.3 (M+H).
Preparation of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2-fluoro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamido)phenyl)-5-me-
thyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid
(1005B)
[2029] The title compound (0.486 g, 0.709 mmol, 99% yield) was
prepared according to the procedure for 221A using
(1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(2-flu-
oro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-
-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate 1005A, (0.500 g, 0.714
mmol). LCMS (ESI.sup.+) m/z=686.3 (M+H).
[2030] Example 1005 (0.043 g, 0.082 mmol, 70% yield) was prepared
according to the procedure for 998 using compound
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(2-fluoro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-carboxamido)phenyl)-5-me-
thyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid, 1005B,
(0.080 g, 0.117 mmol) and morpholine (0.020 mL, 0.233 mmol). LCMS
(ESI.sup.+) m/z=525.2 (M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d)
.delta.: 9.46 (s, 1H), 9.02 (s, 1H), 8.20 (s, 1H), 7.81-7.88 (m,
1H), 7.68 (dd, J=2.41, 6.80 Hz, 1H), 7.07 (dd, J=8.99, 11.33 Hz,
1H), 5.09 (d, J=1.90 Hz, 2H), 4.39 (br. s., 2H), 3.70 (br. s., 8H),
2.56 (s, 1H), 2.35 (t, J=8.48 Hz, 1H), 1.85 (s, 3H), 1.35 (dd,
J=5.77, 9.72 Hz, 1H), 0.91 (t, J=6.43 Hz, 1H). .sup.19F NMR (282
MHz, CHLOROFORM-d) .delta.: -115.18 (s, 1 F).
Example 1006:
(1S,5S,6S)-3-amino-N-(1-fluoro-2-methylpropan-2-yl)-5-(2-fluoro-5-(5-(pro-
p-2-yn-1-yloxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-ene-1-carboxamide
##STR00810##
[2032] The title compound (0.040 g, 0.076 mmol, 52% yield) was
prepared according to the procedure for 998 using compound 1005B
(0.100 g, 0.146 mmol) and 2-fluoro-1,1-dimethyl-ethylamine
hydrochloride (0.026 g, 0.204 mmol). LCMS (ESI.sup.+) m/z=529.1
(M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.: 9.40 (s, 1H),
9.01 (s, 1H), 8.19 (s, 1H), 7.76-7.84 (m, 1H), 7.50 (dd, J=2.27,
6.65 Hz, 1H), 7.00-7.10 (m, 1H), 6.46 (s, 1H), 5.10 (s, 2H),
4.45-4.65 (m, 3H), 4.26-4.44 (m, 1H), 2.57 (s, 1H), 2.20 (t, J=8.55
Hz, 1H), 1.81-1.94 (m, 4H), 1.39 (s, 6H), 0.75-0.90 (m, 1H).
.sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.: -113.80 (s, 1 F),
-225.37 (s, 1 F).
Example 1017:
(1S,5S,6S)-3-amino-N-ethyl-5-(2-fluoro-5-(5-(prop-2-yn-1-yloxy)pyrazine-2-
-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carbo-
xamide
##STR00811##
[2034] The title compound 1017 (0.035 g, 0.073 mmol, 45% yield) was
prepared according to the procedure for 998 using compound 1005B
(0.110 g, 0.160 mmol) and 2.0 M ethylamine solution in THF (0.241
mL, 0.481 mmol). LCMS (ESI.sup.+) m/z=483.2 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.: 9.42 (s, 1H), 9.02 (s, 1H), 8.21 (s,
1H), 7.76-7.84 (m, 1H), 7.47-7.54 (m, 1H), 7.07 (dd, J=9.06, 10.96
Hz, 1H), 6.55 (br. s., 1H), 5.10 (d, J=2.19 Hz, 2H), 3.73-4.52 (br.
s., 2H), 3.35 (m, 2H), 2.57 (s, 1H), 2.28 (t, J=8.55 Hz, 1H), 1.99
(dd, J=5.04, 9.57 Hz, 1H), 1.86 (s, 3H), 1.20 (t, J=7.23 Hz, 3H),
0.79-0.93 (m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.:
-113.63 (s, 1 F).
Example 1018:
(1S,5S,6S)-3-amino-5-(5-(5-cyanopicolinamido)-2-fluorophenyl)-N-(1-fluoro-
-2-methylpropan-2-yl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carb-
oxamide
##STR00812##
[2035] Preparation of (1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(5-(5--
cyanopicolinamido)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-
-3-ene-1-carboxylate (1018A)
[2036] The title compound (0.215 g, 0.321 mmol, 79% yield) was
prepared according to the procedure described for 1005A using
(1S,5S,6S)-methyl
5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late, 295A, (0.218 g, 0.404 mmol) and 5-cyano-2-pyridinecarboxylic
acid (0.072 g, 0.485 mmol). LCMS (ESI.sup.+) m/z=670.2 (M+H).
Preparation of
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(5-(5-cyanopicolinamido)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-ene-1-carboxylic acid (1018B)
[2037] The title compound (0.181 g, 0.276 mmol, 98% yield) was
prepared according to the procedure for 221A using
(1S,5S,6S)-methyl
3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-(5-(5--
cyanopicolinamido)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-
-3-ene-1-carboxylate, 1018A, (0.188 g, 0.281 mmol). LCMS
(ESI.sup.+) m/z=656.2 (M+H).
[2038] Example 1018 (0.039 g, 0.078 mmol, 34% yield) was prepared
according to the procedure for 998 using
(1S,5S,6S)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amin-
o)-5-(5-(5-cyanopicolinamido)-2-fluorophenyl)-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-ene-1-carboxylic acid, 1018B, (0.150 g, 0.229 mmol)
and 2-fluoro-1,1-dimethyl-ethylamine hydrochloride (0.041 g, 0.320
mmol). LCMS (ESI.sup.+) m/z=499.2 (M+H). .sup.1H NMR (300 MHz,
CHLOROFORM-d) .delta.: 9.76 (s, 1H), 8.87 (s, 1H), 8.41 (d, J=8.18
Hz, 1H), 8.20 (d, J=8.01 Hz, 1H), 7.79-7.88 (m, 1H), 7.54 (dd,
J=2.63, 6.87 Hz, 1H), 7.07 (dd, J=8.92, 11.11 Hz, 1H), 6.44 (s,
1H), 4.29-4.66 (m, 4H), 2.16-2.27 (m, 1H), 1.78-1.95 (m, 4H),
1.33-1.47 (m, 6H), 0.74-0.99 (m, 1H). .sup.19F NMR (282 MHz,
CHLOROFORM-d) .delta.: -113.05 (s, 1 F), -225.39 (s, 1 F).
Example 1019:
(1S,5S,6S)-3-amino-5-(5-(5-((S)-but-3-yn-2-yloxy)pyrazine-2-carboxamido)--
2-fluorophenyl)-N-(1-fluoro-2-methylpropan-2-yl)-5-methyl-2-thia-4-azabicy-
clo[4.1.0]hept-3-ene-1-carboxamide
##STR00813##
[2039] Preparation of (1S,5S,6S)-methyl
5-(5-(5-((S)-but-3-yn-2-yloxy)pyrazine-2-carboxamido)-2-fluorophenyl)-3-(-
(tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate (1019A)
[2040] The title compound (0.188 g, 0.263 mmol, 71% yield) was
prepared according to the procedure described for 1005A using
(1S,5S,6S)-methyl
5-(5-amino-2-fluorophenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)et-
hoxy)methyl)amino)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxy-
late, 295A, (0.200 g, 0.371 mmol) and
(S)-5-(but-3-yn-2-yloxy)pyrazine-2-carboxylic acid, 290, (0.085 g,
0.445 mmol). LCMS (ESI.sup.+) m/z=714.2 (M+H).
Preparation of
(1S,5S,6S)-5-(5-(5-((S)-but-3-yn-2-yloxy)pyrazine-2-carboxamido)-2-fluoro-
phenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid
(1019B)
[2041] The title compound 1019B (0.181 g, 0.259 mmol, 98% yield)
was prepared according to the procedure for 221A using
(1S,5S,6S)-methyl
5-(5-(5-((S)-but-3-yn-2-yloxy)pyrazine-2-carboxamido)-2-fluorophenyl)-3-(-
(tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-methyl-2-t-
hia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylate, 1019A, (0.188 g,
0.263 mmol). LCMS (ESI.sup.+) m/z=700.3 (M+H).
[2042] Example 1019 (0.062 g, 0.114 mmol, 44% yield) was prepared
according to the procedure for 998 using
(1S,5S,6S)-5-(5-(5-((S)-but-3-yn-2-yloxy)pyrazine-2-carboxamido)-2-fluoro-
phenyl)-3-((tert-butoxycarbonyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-5-
-methyl-2-thia-4-azabicyclo[4.1.0]hept-3-ene-1-carboxylic acid,
1019B, (0.180 g, 0.257 mmol) and 2-fluoro-1,1-dimethyl-ethylamine
hydrochloride (0.049 g, 0.386 mmol). LCMS (ESI.sup.+) m/z=543.2
(M+H). .sup.1H NMR (300 MHz, CHLOROFORM-d) .delta.: 9.40 (s, 1H),
9.02 (s, 1H), 8.15 (s, 1H), 7.78-7.86 (m, 1H), 7.46 (dd, J=2.34,
6.72 Hz, 1H), 7.05 (dd, J=8.99, 10.89 Hz, 1H), 6.47 (s, 1H), 5.85
(q, J=6.43 Hz, 1H), 4.45-4.62 (m, 1H), 4.26-4.44 (m, 2H), 2.51 (s,
1H), 2.21 (t, J=8.62 Hz, 1H), 1.92 (dd, J=4.97, 9.65 Hz, 1H), 1.86
(s, 3H), 1.72 (d, J=6.72 Hz, 3H), 1.39 (s, 6H), 1.08-1.24 (m, 1H),
0.75-0.88 (m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.:
-113.79 (s, 1 F), -225.37 (s, 1 F).
Example 1020:
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(cyclobutylmethoxy)pyrazine-2-c-
arboxamide
##STR00814##
[2044] To a mixture of
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropyrazine-2-carboxamide
(Example 1007) (0.022 g, 0.047 mmol) and cyclobutanemethanol (0.061
mL, 0.711 mmol) in THF (0.5 mL) was added cesium carbonate (0.046
g, 0.142 mmol). The reaction mixture was then heated at 50.degree.
C. for 2 h. The resulting mixture was then diluted with water and
extracted with EtOAc. The organic layer was washed with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The residue was purified by silica gel chromatography (0-100% EtOAc
in DCM) to afford Example 1020 (20 mg, 86% yield) as an off-white
solid. LC/MS (ESI.sup.+) m/z=504 (M+H).sup.+. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.51 (s, 1H), 8.97 (d, J=1.17 Hz, 1H), 8.12
(d, J=0.98 Hz, 1H), 8.05 (ddd, J=2.54, 6.75, 11.84 Hz, 1H),
7.35-7.42 (m, 1H), 4.40 (d, J=6.85 Hz, 2H), 3.66 (d, J=10.56 Hz,
1H), 3.41 (s, 3H), 3.35 (d, J=10.56 Hz, 1H), 2.81 (m, 1H),
2.10-2.22 (m, 2H), 1.84-2.05 (m, 4H), 1.76-1.82 (m, 1H), 1.72 (s,
3H), 0.90 (dd, J=5.77, 9.49 Hz, 1H), 0.77-0.83 (m, 1H).
[2045] Using procedures analogous or similar to the procedures
described above for Example 1020, the appropriate alcohol and
N-(3-((1S,5S,6S)-3-amino-1-(methoxymethyl)-5-methyl-2-thia-4-azabicyclo[4-
.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-chloropyrazine-2-carboxamide
(Example 1007) were reacted to provide the 39 examples listed in
Table 12 and Table 12'.
TABLE-US-00024 TABLE 12 Observed Ex. No. Chemical Structure [M +
H].sup.+ 1013 ##STR00815## 532 1021 ##STR00816## 490 1022
##STR00817## 506 1023 ##STR00818## 508 1025 ##STR00819## 500 1026
##STR00820## 540 1027 ##STR00821## 436 1028 ##STR00822## 492 1029
##STR00823## 506 1030 ##STR00824## 490 1031 ##STR00825## 531 1032
##STR00826## 531 1033 ##STR00827## 526 1034 ##STR00828## 533 1035
##STR00829## 526 1036 ##STR00830## 476 1037 ##STR00831## 532 1038
##STR00832## 464 1047 ##STR00833## 484 1048 ##STR00834## 470 1049
##STR00835## 486 1050 ##STR00836## 502 1051 ##STR00837## 472 1052
##STR00838## 464 1053 ##STR00839## 472 1054 ##STR00840## 486 1055
##STR00841## 488 1056 ##STR00842## 474 1057 ##STR00843## 482 1058
##STR00844## 488 1059 ##STR00845## 502 1060 ##STR00846## 488 1061
##STR00847## 504 1062 ##STR00848## 520 1063 ##STR00849## 490 1064
##STR00850## 482 1067 ##STR00851## 474 1068 ##STR00852## 492 1069
##STR00853## 506
TABLE-US-00025 TABLE 12' Ex. No. .sup.1H-NMR Chemical Name 1013
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.51 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 9.02 (d, J = 1.17 Hz, 1H), 8.27 (d, J =
1.17 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J = 2.74,
6.80, 11.79 Hz, 1H), 7.40 (dd, J = 2.54,
thia-4-azabicyclo[4.1.0]hept- 5.28 Hz, 1H), 5.59 (s, 2H), 3.66 (d,
J = 10.76 Hz, 1H), 3-en-5-yl)-4,5- 3.62-3.71 (m, 1H), 3.41 (s, 3H),
3.35 (d, J = 10.56 Hz, difluorophenyl)-5-((5-methyl- 1H), 2.64 (s,
3H), 1.76-1.84 (m, 1H), 1.72 (s, 3H), 0.89 1,2,4-oxadiazol-3- (dd,
J = 5.87, 9.39 Hz, 1H), 0.76-0.84 (m, 1H), 0.76-0.84 yl)methoxy)-2-
(m, 1H) pyrazinecarboxamide 1021 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.51 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.96 (d, J = 1.17 Hz, 1H), 8.14 (d, J = 1.17 Hz, 1H), 8.05
(methoxymethyl)-5-methyl-2- (ddd, J = 2.74, 6.85, 11.93 Hz, 1H),
7.40 (td, J = 2.37, 5.23 thia-4-azabicyclo[4.1.0]hept- Hz, 1H),
4.27 (d, J = 7.24 Hz, 2H), 3.66 (d, J = 10.56 Hz, 3-en-5-yl)-4,5-
1H), 3.41 (s, 3H), 3.35 (d, J = 10.56 Hz, 1H), 1.76-1.83
difluorophenyl)-5- (m, 1H), 1.72 (s, 3H), 1.27-1.38 (m, 1H), 0.89
(dd, (cyclopropylmethoxy)-2- J = 5.87, 9.39 Hz, 1H), 0.75-0.83 (m,
1H), 0.62-0.70 (m, pyrazinecarboxamide 2H), 0.36-0.44 (m, 2H) 1022
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.50 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.98 (d, J = 1.37 Hz, 1H), 8.15 (d, J =
1.37 Hz, 1H), 8.04 (methoxymethyl)-5-methyl-2- (ddd, J = 2.74,
6.80, 11.79 Hz, 1H), 7.36-7.45 (m, 1H),
thia-4-azabicyclo[4.1.0]hept- 4.90 (dd, J = 6.26, 7.82 Hz, 2H),
4.67 (d, J = 6.65 Hz, 2H), 3-en-5-yl)-4,5- 4.59 (t, J = 6.06 Hz,
2H), 3.66 (d, J = 10.56 Hz, 1H), 3.45- difluorophenyl)-5-(3- 3.56
(m, 1H), 3.41 (s, 3H), 3.35 (d, J = 10.76 Hz, 1H),
oxetanylmethoxy)-2- 1.76-1.82 (m, 1H), 1.72 (s, 3H), 0.90 (dd, J =
5.77, 9.49 pyrazinecarboxamide Hz, 1H), 0.75-0.83 (m, 1H) 1023
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.51 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.97 (d, J = 0.98 Hz, 1H), 8.18 (d, J =
0.78 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J = 2.64,
6.80, 11.69 Hz, 1H), 7.33-7.45 (m, 1H),
thia-4-azabicyclo[4.1.0]hept- 4.34-4.51 (m, 2H), 3.72-3.83 (m, 1H),
3.66 (d, J = 10.56 3-en-5-yl)-4,5- Hz, 1H), 3.44 (s, 3H), 3.41 (s,
3H), 3.35 (d, J = 10.56 Hz, difluorophenyl)-5-(2- 1H), 1.76-1.82
(m, 1H), 1.72 (s, 3H), 1.29 (d, J = 6.46 methoxypropoxy)pyrazine-2-
Hz, 3H), 0.89 (dd, J = 5.87, 9.39 Hz, 1H), 0.76-0.84 (m,
carboxamide 1H). 1025 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.
9.50 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 9.00 (d, J = 1.17 Hz,
1H), 8.24 (d, J = 1.17 Hz, 1H), 8.04 (methoxymethyl)-5-methyl-2-
(ddd, J = 2.74, 6.80, 11.79 Hz, 1H), 7.41 (dd, J = 2.25,
thia-4-azabicyclo[4.1.0]hept- 5.38 Hz, 1H), 5.93-6.37 (m, 1H), 4.66
(dt, J = 3.91, 13.40 3-en-5-yl)-4,5- Hz, 2H), 3.66 (d, J = 10.56
Hz, 1H), 3.41 (s, 3H), 3.35 (d, difluorophenyl)-5-(2,2- J = 10.76
Hz, 1H), 1.75-1.84 (m, 1H), 1.72 (s, 3H), 0.89 difluoroethoxy)-2-
(dd, J = 5.87, 9.39 Hz, 1H), 0.80 (t, J = 6.16 Hz, 1H)
pyrazinecarboxamide 1026 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.50 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.98 (d, J = 0.78
Hz, 1H), 8.14 (d, J = 0.78 Hz, 1H), 8.04
(methoxymethyl)-5-methyl-2- (ddd, J = 2.64, 6.80, 11.69 Hz, 1H),
7.36-7.48 (m, 1H), thia-4-azabicyclo[4.1.0]hept- 4.48 (d, J = 6.46
Hz, 2H), 3.66 (d, J = 10.76 Hz, 1H), 3.41 3-en-5-yl)-4,5- (s, 3H),
3.35 (d, J = 10.76 Hz, 1H), 2.62-2.86 (m, 3H),
difluorophenyl)-5-((3,3- 2.41-2.57 (m, 2H), 1.76-1.83 (m, 1H), 1.72
(s, 3H), 0.90 difluorocyclobutyl)methoxy)- (dd, J = 5.77, 9.29 Hz,
1H), 0.74-0.83 (m, 1H) 2-pyrazinecarboxamide 1027 .sup.1H NMR (400
MHz, CHLOROFORM-d) .delta. 9.27 (br.s., N-(3-((1S,5S,6S)-3-amino-1-
1H), 7.90-8.57 (m, 4H), 7.55-7.74 (m, 2H), 7.23 (br.s.,
(methoxymethyl)-5-methyl-2- 1H), 3.44 (d, J = 9.78 Hz, 1H), 3.33
(s, 4H), 1.97 (br.s., thia-4-azabicyclo[4.1.0]hept- 3H), 1.82 (d, J
= 7.04 Hz, 1H), 1.16-1.50 (m, 1H), 0.80 3-en-5-yl)-4,5- (br.s., 1H)
difluorophenyl)-5-oxo-4,5- dihydro-2- pyrazinecarboxamide 1028
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.51 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.97 (d, J = 0.98 Hz, 1H), 8.13 (d, J =
1.17 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J = 2.74,
6.80, 11.79 Hz, 1H), 7.40 (dd, J = 2.45,
thia-4-azabicyclo[4.1.0]hept- 5.18 Hz, 1H), 4.20 (d, J = 6.65 Hz,
2H), 3.66 (d, J = 10.56 3-en-5-yl)-4,5- Hz, 1H), 3.41 (s, 3H), 3.35
(d, J = 10.76 Hz, 1H), 2.14 difluorophenyl)-5-(2- (quind, J = 6.67,
13.42 Hz, 1H), 1.76-1.82 (m, 1H), 1.72 methylpropoxy)-2- (s, 3H),
1.05 (d, J = 6.85 Hz, 6H), 0.89 (dd, J = 5.87, 9.39
pyrazinecarboxamide Hz, 1H), 0.77-0.84 (m, 1H) 1029 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.52 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.98 (d, J = 1.17 Hz, 1H), 8.22 (d, J =
1.17 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J = 2.74,
6.65, 11.74 Hz, 1H), 7.41 (dd, J = 2.45,
thia-4-azabicyclo[4.1.0]hept- 5.18 Hz, 1H), 5.14-5.24 (m, 1H),
4.71-4.78 (m, 1H), 3-en-5-yl)-4,5- 4.66 (td, J = 6.14, 9.05 Hz,
1H), 4.61 (d, J = 4.30 Hz, 2H), difluorophenyl)-5-(oxetan-2- 3.66
(d, J = 10.56 Hz, 1H), 3.41 (s, 3H), 3.35 (d, J = 10.56
ylmethoxy)pyrazine-2- Hz, 1H), 2.75-2.88 (m, 1H), 2.65 (tdd, J =
7.04, 8.97, carboxamide 11.17 Hz, 1H), 1.76-1.83 (m, 1H), 1.72 (s,
3H), 0.90 (dd, J = 5.87, 9.39 Hz, 1H), 0.76-0.84 (m, 1H) 1030
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.51 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.99 (d, J = 1.17 Hz, 1H), 8.17 (d, J =
1.17 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J = 2.74,
6.80, 11.79 Hz, 1H), 7.40 (dd, J = 2.25,
thia-4-azabicyclo[4.1.0]hept- 5.38 Hz, 1H), 4.97-5.14 (m, 2H), 4.86
(s, 2H), 3.66 (d, 3-en-5-yl)-4,5- J = 10.56 Hz, 1H), 3.41 (s, 3H),
3.35 (d, J = 10.76 Hz, 1H), difluorophenyl)-5-((2-methyl- 1.86 (s,
3H), 1.76-1.83 (m, 1H), 1.72 (s, 3H), 0.89 (dd,
2-propen-1-yl)oxy)-2- J = 5.87, 9.39 Hz, 1H), 0.76-0.83 (m, 1H)
pyrazinecarboxamide 1031 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.50 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.94-9.09 (m,
1H), 8.21 (d, J = 1.17 Hz, 1H), 8.05 (ddd,
(methoxymethyl)-5-methyl-2- J = 2.74, 6.85, 11.74 Hz, 1H), 7.40
(td, J = 2.27, 5.43 Hz, thia-4-azabicyclo[4.1.0]hept- 1H), 6.24 (s,
1H), 5.54 (s, 2H), 3.66 (d, J = 10.56 Hz, 3-en-5-yl)-4,5- 1H), 3.41
(s, 3H), 3.35 (d, J = 10.56 Hz, 1H), 2.32 (s,
difluorophenyl)-5-((3-methyl- 3H), 1.79 (dt, J = 0.98, 8.02 Hz,
1H), 1.72 (d, J = 0.78 Hz, 5-isoxazolyl)methoxy)-2- 3H), 0.85-0.93
(m, 1H), 0.76-0.82 (m, 1H) pyrazinecarboxamide 1032 .sup.1H NMR
(400 MHz, CHLOROFORM-d) .delta. 9.50 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 9.02 (s, 1H), 8.20 (s, 1H), 8.05 (ddd,
J = 2.64, 6.80, 11.69 (methoxymethyl)-5-methyl-2- Hz, 1H),
7.34-7.48 (m, 1H), 6.11 (s, 1H), 5.53 (s, 2H),
thia-4-azabicyclo[4.1.0]hept- 4.40 (br s, 2H), 3.66 (d, J = 10.76
Hz, 1H), 3.41 (s, 3H), 3-en-5-yl)-4,5- 3.35 (d, J = 10.56 Hz, 1H),
2.45 (s, 3H), 1.76-1.83 (m, difluorophenyl)-5-((5-methyl- 1H), 1.72
(s, 3H), 0.89 (dd, J = 5.87, 9.39 Hz, 1H), 0.77-
3-isoxazolyl)methoxy)-2- 0.83 (m, 1H) pyrazinecarboxamide 1033
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.51 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 9.02 (d, J = 1.17 Hz, 1H), 8.18 (d, J =
1.17 Hz, 1H), 8.06 (methoxymethyl)-5-methyl-2- (ddd, J = 2.74,
6.80, 11.79 Hz, 1H), 7.45-7.50 (m, 2H),
thia-4-azabicyclo[4.1.0]hept- 7.34-7.44 (m, 4H), 5.49 (s, 2H), 3.66
(d, J = 10.76 Hz, 3-en-5-yl)-4,5- 1H), 3.41 (s, 3H), 3.35 (d, J =
10.56 Hz, 1H), 1.76-1.83 difluorophenyl)-5- (m, 1H), 1.72 (s, 3H),
0.89 (dd, J = 5.77, 9.49 Hz, 1H), (benzyloxy)-2- 0.77-0.83 (m, 1H)
pyrazinecarboxamide 1034 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.51 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 9.04 (d, J = 1.17
Hz, 1H), 8.26 (d, J = 1.37 Hz, 1H), 8.05
(methoxymethyl)-5-methyl-2- (ddd, J = 2.74, 6.80, 11.79 Hz, 1H),
7.84 (d, J = 3.33 Hz, thia-4-azabicyclo[4.1.0]hept- 1H), 7.35-7.44
(m, 2H), 5.80 (s, 2H), 3.66 (d, J = 10.76 3-en-5-yl)-4,5- Hz, 1H),
3.41 (s, 3H), 3.35 (d, J = 10.56 Hz, 1H), 1.79
difluorophenyl)-5-(1,3-thiazol- (ddd, J = 1.08, 6.75, 9.19 Hz, 1H),
1.72 (d, J = 0.78 Hz, 2-ylmethoxy)-2- 3H), 0.86-0.93 (m, 1H),
0.76-0.83 (m, 1H) pyrazinecarboxamide 1035 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .TM. 9.51 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.98
(d, J = 1.37 Hz, 1H), 8.17 (d, J = 1.37 Hz, 1H),
(methoxymethyl)-5-methyl-2- 8.05 (ddd, J = 2.74, 6.75, 11.83 Hz,
1H), 7.34-7.45 (m, thia-4-azabicyclo[4.1.0]hept- 1H), 4.53-4.65 (m,
1H), 4.37-4.48 (m, 1H), 3.66 (d, 3-en-5-yl)-4,5- J = 10.56 Hz, 1H),
3.41 (s, 3H), 3.35 (d, J = 10.76 Hz, 1H), difluorophenyl)-5-((2,2-
2.16 (qt, J = 7.63, 12.03 Hz, 1H), 1.79 (ddd, J = 1.17, 6.80,
difluorocyclopropyl)methoxy) 9.24 Hz, 1H), 1.72 (d, J = 0.78 Hz,
3H), 1.54-1.67 (m, pyrazine-2-carboxamide 1H), 1.33 (tdd, J = 3.86,
7.65, 16.90 Hz, 1H), 0.89 (dd, J = 5.87, 9.39 Hz, 1H), 0.76-0.83
(m, 1H) 1036 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.53 (s,
1H), N-(3-((1S,5S,6S)-3-amino-1- 8.98 (d, J = 1.37 Hz, 1H), 8.15
(d, J = 1.17 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J =
2.74, 6.85, 11.74 Hz, 1H), 7.37 (dd, J = 2.45,
thia-4-azabicyclo[4.1.0]hept- 5.18 Hz, 1H), 6.02-6.17 (m, 1H), 5.45
(dd, J = 1.37, 17.21 3-en-5-yl)-4,5- Hz, 1H), 5.34 (dd, J = 1.17,
10.37 Hz, 1H), 4.95 (d, difluorophenyl)-5-(2-propen- J = 5.67 Hz,
2H), 3.64 (d, J = 10.56 Hz, 1H), 3.41 (s, 3H), 1-yloxy)-2- 3.35 (d,
J = 10.76 Hz, 1H), 1.80 (dd, J = 7.43, 8.61 Hz, pyrazinecarboxamide
1H), 1.75 (s, 3H), 0.94 (dd, J = 5.87, 9.39 Hz, 1H), 0.78- 0.84 (m,
1H), 0.00-0.00 (m, 1H) 1037 .sup.1H NMR (400 MHz, CHLOROFORM-d)
.delta. 9.51 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 9.03 (d, J = 1.37
Hz, 1H), 8.27 (d, J = 1.37 Hz, 1H), 8.06
(methoxymethyl)-5-methyl-2- (ddd, J = 2.74, 6.85, 11.74 Hz, 1H),
7.29-7.37 (m, 1H), thia-4-azabicyclo[4.1.0]hept- 5.66 (s, 2H), 3.64
(d, J = 10.56 Hz, 1H), 3.41 (s, 3H), 3-en-5-yl)-4,5- 3.35 (d, J =
10.76 Hz, 1H), 2.58 (s, 3H), 1.77-1.82 (m,
difluorophenyl)-5-((5-methyl- 1H), 1.75 (d, J = 0.78 Hz, 3H),
0.92-1.00 (m, 1H), 0.80 (t, 1,3,4-oxadiazol-2- J = 6.26 Hz, 1H)
yl)methoxy)-2- pyrazinecarboxamide 1038 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.51 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.98 (d, J = 1.17 Hz, 1H), 8.11 (d, J = 1.17 Hz, 1H), 8.06
(methoxymethyl)-5-methyl-2- (ddd, J = 2.74, 6.80, 11.79 Hz, 1H),
7.39 (td, J = 2.40, 5.38 thia-4-azabicyclo[4.1.0]hept- Hz, 1H),
4.49 (q, J = 7.04 Hz, 2H), 3.66 (d, J = 10.56 Hz, 3-en-5-yl)-4,5-
1H), 3.41 (s, 3H), 3.35 (d, J = 10.76 Hz, 1H), 1.79 (ddd,
difluorophenyl)-5-ethoxy-2- J = 0.98, 7.38, 8.66 Hz, 1H), 1.72 (d,
J = 0.78 Hz, 3H), pyrazinecarboxamide 1.45 (t, J = 7.04 Hz, 3H),
0.89 (dd, J = 5.87, 9.39 Hz, 1H), 0.75-0.84 (m, 1H) 1047 .sup.1H
NMR (500 MHz, DMSO-d6) .delta. 10.36 (s, 1H), 8.86 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.42 (s, 1H), 8.02 (dd, J = 2.59,
7.20 Hz, 1H), 7.64- (methoxymethyl)-5-methyl-2- 7.86 (m, 1H), 7.13
(dd, J = 8.95, 11.87 Hz, 1H), 5.94 (br.
thia-4-azabicyclo[4.1.0]hept- s., 2H), 4.45 (t, J = 6.59 Hz, 2H),
3.55 (d, J = 10.96 Hz,
3-en-5-yl)-4-fluorophenyl)-5- 1H), 3.33-3.36 (m, 1H), 3.30 (br.s.,
3H), 2.66 (d, J = 2.60 (3-pentyn-1-yloxy)-2- Hz, 2H), 1.75 (t, J =
2.21 Hz, 3H), 1.66 (t, J = 7.66 Hz, pyrazinecarboxamide 1H), 1.59
(s, 3H), 0.84 (br.s., 1H), 0.61 (br.s., 1H) 1048 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 10.36 (s, 1H), 8.87 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.42 (s, 1H), 8.02 (dd, J = 2.53,
7.20 Hz, 1H), 7.71- (methoxymethyl)-5-methyl-2- 7.79 (m, 1H), 7.12
(dd, J = 8.86, 11.84 Hz, 1H), 5.94 (br.
thia-4-azabicyclo[4.1.0]hept- s., 2H), 4.49 (t, J = 6.46 Hz, 2H),
3.55 (d, J = 10.96 Hz, 3-en-5-yl)-4-fluorophenyl)-5- 1H), 3.34 (d,
J = 10.96 Hz, 1H), 3.30 (br.s., 3H), 2.91 (t, (3-butyn-1-yloxy)-2-
J = 2.50 Hz, 1H), 2.72 (dt, J = 2.47, 6.39 Hz, 2H), 1.61-
pyrazinecarboxamide 1.72 (m, 1H), 1.59 (s, 3H), 0.84 (dd, J = 5.03,
8.99 Hz, 1H), 0.61 (t, J = 5.55 Hz, 1H) 1049 .sup.1H NMR (500 MHz,
DMSO-d6) .delta. 10.34 (s, 1H), 8.83 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.43 (s, 1H), 8.02 (dd, J = 2.50,
7.23 Hz, 1H), 7.67- (methoxymethyl)-5-methyl-2- 7.86 (m, 1H), 7.12
(dd, J = 8.82, 11.87 Hz, 1H), 5.94 (br.
thia-4-azabicyclo[4.1.0]hept- s., 2H), 4.22 (s, 2H), 3.55 (d, J =
10.90 Hz, 1H), 3.34 (d, 3-en-5-yl)-4-fluorophenyl)-5- J = 11.22 Hz,
1H), 3.30 (br.s., 3H), 1.62-1.69 (m, 1H), ((1- 1.59 (s, 3H),
1.14-1.25 (m, 3H), 0.84 (dd, J = 5.29, 9.24
methylcyclopropyl)methoxy)- Hz, 1H), 0.55-0.65 (m, 3H), 0.43 (s,
2H) 2-pyrazinecarboxamide 1050 .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 10.37 (s, 1H), 8.88 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
8.44 (s, 1H), 8.03 (dd, J = 2.56, 7.17 Hz, 1H), 7.74-
(methoxymethyl)-5-methyl-2- 7.80 (m, 1H), 7.12 (dd, J = 8.89, 11.87
Hz, 1H), 5.94 (br. thia-4-azabicyclo[4.1.0]hept- s., 2H), 4.47-4.58
(m, 4H), 4.33 (d, J = 5.84 Hz, 2H), 3.55
3-en-5-yl)-4-fluorophenyl)-5- (d, J = 10.90 Hz, 1H), 3.33-3.36 (m,
1H), 3.30 (br.s., ((3-methyl-3- 3H), 1.62-1.69 (m, 1H), 1.59 (s,
3H), 1.39 (s, 3H), 0.84 oxetanyl)methoxy)-2- (dd, J = 5.19, 9.15
Hz, 1H), 0.61 (t, J = 5.68 Hz, 1H) pyrazinecarboxamide 1051 .sup.1H
NMR (500 MHz, DMSO-d6) .delta. 10.34 (s, 1H), 8.84 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.38 (s, 1H), 8.02 (d, J = 5.06
Hz, 1H), 7.76 (d, (methoxymethyl)-5-methyl-2- J = 8.43 Hz, 1H),
7.12 (dd, J = 8.79, 11.90 Hz, 1H), 5.97-
thia-4-azabicyclo[4.1.0]hept- 6.07 (m, 1H), 5.94 (br.s., 2H),
5.70-5.78 (m, 1H), 5.34 3-en-5-yl)-4-fluorophenyl)-5- (d, J = 17.32
Hz, 1H), 5.20 (d, J = 10.64 Hz, 1H), 3.55 (d,
(((1R)-1-methyl-2-propen-1- J = 10.90 Hz, 1H), 3.33-3.36 (m, 1H),
3.30 (br.s., 3H), yl)oxy)-2- 1.61-1.70 (m, 1H), 1.59 (s, 3H), 1.45
(d, J = 6.42 Hz, pyrazinecarboxamide, N-(3- 3H), 0.83 (dd, J =
5.13, 9.28 Hz, 1H), 0.60 (t, J = 5.77 Hz, ((1S,5S,6S)-3-amino-1-
1H) (methoxymethyl)-5-methyl-2- thia-4-azabicyclo[4.1.0]hept-
3-en-5-yl)-4-fluorophenyl)-5- (((1S)-1-methyl-2-propen-1-
yl)oxy)-2- pyrazinecarboxamide 1052 .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 10.37 (s, 1H), 8.87 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
8.47 (s, 1H), 8.02 (dd, J = 2.56, 7.10 Hz, 1H), 7.73-
(methoxymethyl)-5-methyl-2- 7.79 (m, 1H), 7.13 (dd, J = 8.79, 11.97
Hz, 1H), 5.94 (br. thia-4-azabicyclo[4.1.0]hept- s., 2H), 4.83-4.90
(m, 1H), 4.73-4.80 (m, 1H), 4.67-4.73 3-en-5-yl)-4-fluorophenyl)-5-
(m, 1H), 4.62-4.67 (m, 1H), 3.55 (d, J = 10.83 Hz, 1H),
(2-fluoroethoxy)-2- 3.34 (d, J = 11.03 Hz, 1H), 3.30 (br.s., 3H),
1.61-1.68 pyrazinecarboxamide (m, 1H), 1.59 (s, 3H), 0.84 (dd, J =
5.16, 9.24 Hz, 1H), 0.60 (t, J = 5.68 Hz, 1H) 1053 .sup.1H NMR (500
MHz, DMSO-d6) .delta. 10.34 (s, 1H), 8.84 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.41 (s, 1H), 7.95-8.10 (m, 1H),
7.68-7.84 (m, 1H), (methoxymethyl)-5-methyl-2- 7.12 (dd, J = 8.76,
11.87 Hz, 1H), 5.94 (br.s., 2H), 4.26 thia-4-azabicyclo[4.1.0]hept-
(d, J = 7.27 Hz, 2H), 3.55 (d, J = 10.90 Hz, 1H), 3.33-3.36
3-en-5-yl)-4-fluorophenyl)-5- (m, 1H), 3.30 (br.s., 3H), 1.66 (t, J
= 7.72 Hz, 1H), 1.59 (cyclopropylmethoxy)-2- (s, 3H), 1.30 (br.s.,
1H), 0.84 (br.s., 1H), 0.56-0.65 (m, pyrazinecarboxamide 3H), 0.39
(d, J = 4.41 Hz, 2H) 1054 .sup.1H NMR (500 MHz, DMSO-d6) .delta.
10.36 (s, 1H), 8.86 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.42 (s,
1H), 8.02 (dd, J = 2.59, 7.20 Hz, 1H), 7.64-
(methoxymethyl)-5-methyl-2- 7.86 (m, 1H), 7.13 (dd, J = 8.95, 11.87
Hz, 1H), 5.94 (br. thia-4-azabicyclo[4.1.0]hept- s., 2H), 4.45 (t,
J = 6.59 Hz, 2H), 3.55 (d, J = 10.96 Hz,
3-en-5-yl)-4-fluorophenyl)-5- 1H), 3.33-3.36 (m, 1H), 3.30 (br.s.,
3H), 2.66 (d, J = 2.60 (cyclobutylmethoxy)-2- Hz, 2H), 1.75 (t, J =
2.21 Hz, 3H), 1.66 (t, J = 7.66 Hz, pyrazinecarboxamide 1H), 1.59
(s, 3H), 0.84 (br.s., 1H), 0.61 (br.s., 1H) 1055 .sup.1H NMR (500
MHz, DMSO-d6) .delta. 10.36 (s, 1H), 8.87 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.41 (s, 1H), 8.02 (d, J = 6.99
Hz, 1H), 7.76 (d, (methoxymethyl)-5-methyl-2- J = 8.21 Hz, 1H),
7.12 (dd, J = 8.82, 12.00 Hz, 1H), 5.94
thia-4-azabicyclo[4.1.0]hept- (br.s., 2H), 4.72 (dd, J = 6.20, 7.75
Hz, 2H), 4.64 (d, 3-en-5-yl)-4-fluorophenyl)-5- J = 6.68 Hz, 2H),
4.47 (t, J = 6.07 Hz, 2H), 3.55 (d, (3-oxetanylmethoxy)-2- J =
10.96 Hz, 1H), 3.46 (td, J = 6.86, 13.27 Hz, 1H), 3.33-
pyrazinecarboxamide 3.36 (m, 1H), 3.30 (br.s., 3H), 1.63-1.68 (m,
1H), 1.59 (s, 3H), 0.81-0.88 (m, J = 4.80 Hz, 1H), 0.59-0.67 (m,
1H) 1056 .sup.1H NMR (500 MHz, DMSO-d6) .delta. 10.34 (s, 1H), 8.85
(s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.40 (s, 1H), 8.02 (dd, J =
2.34, 7.20 Hz, 1H), 7.73- (methoxymethyl)-5-methyl-2- 7.79 (m, 1H),
7.12 (dd, J = 8.86, 11.97 Hz, 1H), 5.94 (br.
thia-4-azabicyclo[4.1.0]hept- s., 2H), 4.19 (d, J = 6.62 Hz, 2H),
3.55 (d, J = 10.96 Hz, 3-en-5-yl)-4-fluorophenyl)-5- 1H), 3.34 (d,
J = 10.96 Hz, 1H), 3.29 (br.s., 3H), 2.10 (2-methylpropoxy)-2- (td,
J = 6.60, 13.40 Hz, 1H), 1.61-1.71 (m, 1H), 1.59 (s,
pyrazinecarboxamide 3H), 1.00 (d, J = 6.68 Hz, 6H), 0.84 (dd, J =
4.93, 9.02 Hz, 1H), 0.61 (t, J = 5.84 Hz, 1H) 1057 .sup.1H NMR (500
MHz, DMSO-d6) .delta. 10.41 (s, 1H), 8.89 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.53 (s, 1H), 8.01-8.08 (m, 1H),
7.74-7.79 (m, 1H), (methoxymethyl)-5-methyl-2- 7.13 (dd, J = 8.82,
11.94 Hz, 1H), 6.47 (t, J = 54.17 Hz, thia-4-azabicyclo[4.1.0]hept-
1H), 5.94 (br.s., 2H), 4.74 (dt, J = 3.15, 15.07 Hz, 2H),
3-en-5-yl)-4-fluorophenyl)-5- 3.55 (d, J = 10.83 Hz, 1H), 3.33-3.36
(m, 1H), 3.30 (br. (2,2-difluoroethoxy)-2- s., 3H), 1.61-1.68 (m,
1H), 1.59 (s, 3H), 0.84 (dd, pyrazinecarboxamide J = 5.22, 9.12 Hz,
1H), 0.60 (t, J = 5.64 Hz, 1H) 1058 .sup.1H NMR (500 MHz, DMSO-d6)
.delta. 10.37 (s, 1H), 8.86 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H),
8.46 (s, 1H), 7.98-8.05 (m, 1H), 8.02 (dd, J = 2.47,
(methoxymethyl)-5-methyl-2- 7.27 Hz, 1H), 7.73-7.80 (m, 1H), 7.13
(dd, J = 8.92, 11.77 thia-4-azabicyclo[4.1.0]hept- Hz, 1H), 5.95
(br.s., 2H), 5.08 (br.s., 1H), 4.46-4.63
3-en-5-yl)-4-fluorophenyl)-5- (m, 4H), 3.55 (d, J = 10.96 Hz, 1H),
3.34 (d, J = 11.09 Hz, (oxetan-2- 1H), 3.30 (br.s., 3H), 2.73 (td,
J = 8.35, 17.16 Hz, 1H), ylmethoxy)pyrazine-2- 2.54-2.62 (m, 1H),
1.64-1.70 (m, 1H), 1.59 (s, 3H), 0.84 carboxamide (br.s., 1H), 0.61
(br.s., 1H) 1059 .sup.1H NMR (500 MHz, DMSO-d6) .delta. 10.57 (s,
1H), 8.87 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.42 (s, 1H),
7.86-7.94 (m, 2H), 5.98 (br.s., 2H), (methoxymethyl)-5-methyl-2-
4.45 (t, J = 6.58 Hz, 2H), 3.56 (d, J = 10.90 Hz, 1H), 3.35
thia-4-azabicyclo[4.1.0]hept- (d, J = 11.09 Hz, 1H), 3.30 (br.s.,
3H), 2.66 (d, J = 2.53 3-en-5-yl)-4,5- Hz, 2H), 1.71-1.80 (m, 3H),
1.56-1.66 (m, 4H), 0.89 difluorophenyl)-5-(3-pentyn- (dd, J = 5.32,
9.08 Hz, 1H), 0.64 (t, J = 5.81 Hz, 1H) 1-yloxy)-2-
pyrazinecarboxamide 1060 .sup.1H NMR (500 MHz, DMSO-d6) .delta.
10.58 (s, 1H), 8.87 (s, N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.43 (s,
1H), 7.84-7.93 (m, 2H), 5.97 (br.s., 2H),
(methoxymethyl)-5-methyl-2- 4.50 (t, J = 6.46 Hz, 2H), 3.56 (d, J =
10.96 Hz, 1H), 3.34- thia-4-azabicyclo[4.1.0]hept- 3.37 (m, 1H),
3.30 (br.s., 3H), 2.91 (t, J = 2.43 Hz, 1H), 3-en-5-yl)-4,5- 2.72
(dt, J = 2.59, 6.39 Hz, 2H), 1.58-1.65 (m, 4H), 0.89
difluorophenyl)-5-(3-butyn-1- (dd, J = 5.03, 9.18 Hz, 1H),
0.62-0.68 (m, 1H) yloxy)-2-pyrazinecarboxamide 1061 .sup.1H NMR
(500 MHz, DMSO-d6) .delta. 10.56 (s, 1H), 8.84 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.43 (s, 1H), 7.87-7.93 (m, 2H),
5.98 (br.s., 2H), (methoxymethyl)-5-methyl-2- 4.22 (s, 2H), 3.56
(d, J = 10.96 Hz, 1H), 3.35 (d, J = 11.16
thia-4-azabicyclo[4.1.0]hept- Hz, 1H), 3.30 (br.s., 3H), 1.60 (s,
4H), 1.20 (s, 3H), 3-en-5-yl)-4,5- 0.89 (dd, J = 5.22, 9.18 Hz,
1H), 0.58-0.65 (m, 3H), 0.43 difluorophenyl)-5-((1- (s, 2H)
methylcyclopropyl)methoxy)- 2-pyrazinecarboxamide 1062 .sup.1H NMR
(500 MHz, DMSO-d6) .delta. 10.59 (s, 1H), 8.88 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.45 (s, 1H), 7.84-7.94 (m, 2H),
5.98 (br.s., 2H), (methoxymethyl)-5-methyl-2- 4.46-4.59 (m, 4H),
4.33 (d, J = 5.90 Hz, 2H), 3.56 (d, thia-4-azabicyclo[4.1.0]hept- J
= 10.77 Hz, 1H), 3.33-3.39 (m, 1H), 3.30 (br.s., 3H),
3-en-5-yl)-4,5- 1.57-1.66 (m, 4H), 1.39 (s, 3H), 0.89 (dd, J =
5.19, 9.21 difluorophenyl)-5-((3-methyl- Hz, 1H), 0.64 (t, J = 5.74
Hz, 1H) 3-oxetanyl)methoxy)-2- pyrazinecarboxamide 1063 .sup.1H NMR
(500 MHz, DMSO-d6) .delta. 10.55 (s, 1H), 8.85 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.39 (s, 1H), 7.83-7.93 (m, 2H),
5.92-6.07 (m, 3H), (methoxymethyl)-5-methyl-2- 5.74 (t, J = 6.10
Hz, 1H), 5.34 (d, J = 17.32 Hz, 1H), 5.20
thia-4-azabicyclo[4.1.0]hept- (d, J = 10.64 Hz, 1H), 3.56 (d, J =
10.96 Hz, 1H), 3.35 (d, 3-en-5-yl)-4-fluorophenyl)-5- J = 11.16 Hz,
1H), 3.30 (br.s., 3H), 1.57-1.66 (m, 4H),
(but-3-en-2-yloxy)pyrazine-2- 1.45 (d, J = 6.42 Hz, 3H), 0.89 (dd,
J = 5.29, 9.31 Hz, 1H), carboxamide 0.64 (t, J = 5.81 Hz, 1H) 1064
.sup.1H NMR (500 MHz, DMSO-d6) .delta. 10.59 (s, 1H), 8.87 (s,
N-(3-((1S,5S,6S)-3-amino-1- 1H), 8.47 (s, 1H), 7.85-7.93 (m, 2H),
5.97 (s, 2H), 4.83- (methoxymethyl)-5-methyl-2- 4.89 (m, 1H),
4.74-4.81 (m, 1H), 4.67-4.73 (m, 1H), thia-4-azabicyclo[4.1.0]hept-
4.61-4.67 (m, 1H), 3.56 (d, J = 10.96 Hz, 1H), 3.34-3.37
3-en-5-yl)-4,5- (m, 1H), 3.30 (br.s., 3H), 1.58-1.65 (m, 4H), 0.89
(dd, difluorophenyl)-5-(2- J = 5.13, 9.28 Hz, 1H), 0.62-0.68 (m,
1H) fluoroethoxy)-2- pyrazinecarboxamide 1067 .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta. 9.51 (s, 1H), N-(3-((1S,5S,6S)-3-amino-1-
8.89-8.97 (m, 1H), 8.93 (d, J = 1.17 Hz, 1H), 8.23 (d,
(methoxymethyl)-5-methyl-2- J = 1.17 Hz, 1H), 7.94 (td, J = 3.57,
8.31 Hz, 1H), 7.64 thia-4-azabicyclo[4.1.0]hept- (dd, J = 2.74,
7.04 Hz, 1H), 7.08 (dd, J = 8.90, 11.64 Hz,
3-en-5-yl)-4-fluorophenyl)-5- 1H), 5.71 (quin, J = 5.72 Hz, 1H),
5.03 (t, J = 7.14 Hz, (oxetan-3-yloxy)pyrazine-2- 2H), 4.77 (dd, J
= 5.28, 7.82 Hz, 2H), 3.62 (d, J = 10.56 carboxamide Hz, 1H), 3.41
(s, 3H), 3.36 (d, J = 10.76 Hz, 1H), 1.83 (dd, J = 7.14, 9.10 Hz,
1H), 1.79 (s, 3H), 0.99 (dd, J = 5.87, 9.39 Hz, 1H), 0.82 (t, J =
6.26 Hz, 1H). 1068 .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.50
(s, 1H), N-(3-((1S,5S,6S)-3-amino-1- 8.94 (d, J = 1.17 Hz, 1H),
8.23 (d, J = 1.37 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J
= 2.84, 6.75, 11.74 Hz, 1H), 7.39 (dd, J = 2.25,
thia-4-azabicyclo[4.1.0]hept- 5.58 Hz, 1H), 5.72 (quin, J = 5.67
Hz, 1H), 5.04 (t, 3-en-5-yl)-4,5- J = 7.14 Hz, 2H), 4.77 (dd, J =
5.28, 8.22 Hz, 2H), 3.66 (d,
difluorophenyl)-5-(oxetan-3- J = 10.56 Hz, 1H), 3.41 (s, 3H), 3.35
(d, J = 10.56 Hz, 1H), yloxy)pyrazine-2-carboxamide 1.77-1.82 (m,
1H), 1.72 (s, 3H), 0.86-0.94 (m, 1H), 0.76-0.83 (m, 1H). 1069
.sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 9.51 (s, 1H),
N-(3-((1S,5S,6S)-3-amino-1- 8.98 (d, J = 1.37 Hz, 1H), 8.15 (d, J =
1.37 Hz, 1H), 8.05 (methoxymethyl)-5-methyl-2- (ddd, J = 2.74,
6.75, 11.83 Hz, 1H), 7.35-7.45 (m, 1H),
thia-4-azabicyclo[4.1.0]hept- 4.10 (s, 2H), 3.67 (d, J = 10.56 Hz,
1H), 3.41 (s, 3H), 3-en-5-yl)-4,5- 3.35 (d, J = 10.56 Hz, 1H), 1.79
(dd, J = 7.24, 8.80 Hz, difluorophenyl)-5- 1H), 1.72 (s, 3H), 1.06
(s, 9H), 0.90 (dd, J = 5.87, 9.39 (neopentyloxy)pyrazine-2- Hz,
2H), 0.76-0.84 (m, 1H). carboxamide
Example 1040:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-N-(2-fluoroethyl)-5-methyl-2-thia-4-azabicyclo[4.1.0]hept-
-3-ene-1-carboxamide
##STR00854##
[2047] The title compound 1040 (0.024 g, 0.044 mmol, 30% yield) was
prepared according to the procedure for 998 using compound 295
(0.106 g, 0.145 mmol) and 2-fluoroethylamine hydrochloride (0.019
g, 0.189 mmol). LCMS (ESI.sup.+) m/z=545.2 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.: 9.38 (s, 1H), 8.99 (d, J=1.32 Hz, 1H),
8.28 (d, J=1.32 Hz, 1H), 7.78 (ddd, J=2.85, 4.06, 8.73 Hz, 1H),
7.49 (dd, J=2.70, 6.80 Hz, 1H), 6.91-7.10 (m, 2H), 4.74-5.22 (m,
4H), 4.62 (t, J=4.75 Hz, 1H), 4.46 (t, J=4.75 Hz, 1H), 3.50-3.77
(m, 2H), 2.19-2.31 (m, 1H), 1.95-2.07 (m, 1H), 1.84-1.92 (m, 3H),
0.81-0.94 (m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.:
-73.63 (s, 3 F), -113.22 (s, 1 F), -224.15 (s, 1 F).
Example 1041:
(1S,5S,6S)-3-amino-5-(2-fluoro-5-(5-(2,2,2-trifluoroethoxy)pyrazine-2-car-
boxamido)phenyl)-5-methyl-N-(1-methylcyclopropyl)-2-thia-4-azabicyclo[4.1.-
0]hept-3-ene-1-carboxamide
##STR00855##
[2049] The title compound 1041 (0.031 g, 0.056 mmol, 38% yield) was
prepared according to the procedure for 998 using compound 295
(0.106 g, 0.145 mmol) and (1-methylcyclopropyl)amine (0.015 g,
0.218 mmol). LCMS (ESI.sup.+) m/z=553.1 (M+H). .sup.1H NMR (300
MHz, CHLOROFORM-d) .delta.: 9.34 (s, 1H), 8.96 (d, J=1.17 Hz, 1H),
8.24 (d, J=1.31 Hz, 1H), 7.67-7.82 (m, 1H), 7.49 (dd, J=2.70, 6.80
Hz, 1H), 7.00 (dd, J=8.77, 11.25 Hz, 1H), 6.82 (s, 1H), 4.87 (q,
J=8.18 Hz, 4H), 2.21 (dd, J=7.75, 9.35 Hz, 1H), 1.95 (dd, J=4.90,
9.72 Hz, 1H), 1.86 (s, 3H), 1.38 (s, 3H), 0.72-0.87 (m, 3H),
0.63-0.72 (m, 2H). .sup.19F NMR (282 MHz, CHLOROFORM-d) .delta.:
-73.63 (s, 3 F), -113.37 (s, 1 F).
Example 1042:
N-(3-((1S,5S,6S)-1-(acetamidomethyl)-3-amino-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-
-carboxamide
##STR00856##
[2051] To a stirred solution of
N-(3-((1S,5S,6S)-3-amino-1-(aminomethyl)-5-methyl-2-thia-4-azabicyclo[4.1-
.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-car-
boxamide (Example 981, 120 mg, 0.26 mmol) and diisopropylethylamine
(0.045 mL, 0.262 mmol) in CH.sub.2Cl.sub.2 (4 mL) at -30.degree. C.
was added acetic anhydride (0.025 mL, 0.262 mmol) in
CH.sub.2Cl.sub.2 (0.5 mL). The reaction was stirred for 2 h at
-30.degree. C. then quenched with sat. NH.sub.4Cl (1 mL). The
reaction mixture was then partitioned between CH.sub.2Cl.sub.2 (10
mL) and 1 M NaOH (5 mL). The organic layer was dried over
MgSO.sub.4, concentrated under reduced pressure, and then purified
by silica gel chromatography (4 g) eluting products with a gradient
of 20-50% of (3:1 EtOAc/EtOH) in heptane to afford
N-(3-((1S,5S,6S)-1-(acetamidomethyl)-3-amino-5-methyl-2-thia-4-azabicyclo-
[4.1.0]hept-3-en-5-yl)-4,5-difluorophenyl)-5-(prop-2-yn-1-yloxy)pyrazine-2-
-carboxamide (1042, 52 mg, 0.104 mmol, 40% yield) as a white solid.
LC/MS (ESI.sup.-) m/z=501.1. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.61 (s, 1H), 8.90 (d, J=1.17 Hz, 1H), 8.48 (d, J=1.17 Hz,
1H), 8.14 (t, J=6.06 Hz, 1H), 7.87-7.94 (m, 2H), 5.96 (s, 2H), 5.14
(d, J=2.35 Hz, 2H), 3.64 (t, J=2.35 Hz, 1H), 3.32-3.38 (m, 1H),
3.21 (dd, J=5.58, 14.38 Hz, 1H), 1.85 (s, 3H), 1.74 (dd, J=7.04,
8.61 Hz, 1H), 1.59 (s, 3H), 0.86 (dd, J=5.28, 9.19 Hz, 1H), 0.57
(t, J=5.77 Hz, 1H).
Example 1045:
(1S,5S,6S)-3-amino-N-(1,1-difluoropropan-2-yl)-5-(2-fluoro-5-(5-(2,2,2-tr-
ifluoroethoxy)pyrazine-2-carboxamido)phenyl)-5-methyl-2-thia-4-azabicyclo[-
4.1.0]hept-3-ene-1-carboxamide
##STR00857##
[2053] The title compound 1045 (0.022 g, 0.038 mmol, 26% yield) was
prepared according to the procedure for 983 using compound 295
(0.106 g, 0.145 mmol) and 1,1-difluoropropan-2-amine hydrochloride
(0.029 g, 0.218 mmol). LCMS (ESI.sup.+) m/z=577.1 (M+H). .sup.1H
NMR (300 MHz, CHLOROFORM-d) .delta.: 9.34 (s, 1H), 8.97 (d, J=1.32
Hz, 1H), 8.25 (d, J=1.32 Hz, 1H), 7.73 (ddd, J=2.78, 3.98, 8.73 Hz,
1H), 7.48 (dd, J=2.70, 6.80 Hz, 1H), 7.01 (dd, J=8.84, 11.18 Hz,
1H), 6.63 (d, J=8.62 Hz, 1H), 5.83 (dt, J=2.05, 55.10 Hz, 1H), 4.88
(q, J=8.33 Hz, 2H), 4.23-4.61 (m, 3H), 2.24 (dd, J=7.89, 9.50 Hz,
1H), 2.00 (dd, J=4.97, 9.65 Hz, 1H), 1.88 (s, 3H), 1.23-1.34 (m,
3H), 0.81-0.95 (m, 1H). .sup.19F NMR (282 MHz, CHLOROFORM-d)
.delta.: -73.63 (s, 3 F), -113.31 (s, 1 F), -126.66 (d, J=283 Hz, 1
F), -132.70 (d, J=283 Hz, 1 F).
[2054] Table 13A contains representative compounds of the invention
(Examples 1-102 presented herein), Table 13B contains
representative compounds of the invention (Examples 601-962
presented herein), and Table 13C contain representative compounds
of the invention (Examples 963-1075 presented herein). These tables
also include the mass observed and associated biological data. The
data presented includes BACE1 enzyme assay, BACE1 cell assay, BACE2
enzyme assay and Cathepsin D (Cat D) assay, inhibitory data
expressed as .mu.M IC.sub.50's. The assays procedures and data
measurements are described below.
TABLE-US-00026 TABLE 13A IC.sub.50 IC.sub.50 IC.sub.50 IP (.mu.M)
IP (.mu.M) IP (.mu.M) IC.sub.50 Oberved BACE1 BACE1 BACE2 IP
(.mu.M) Ex. No. [M + H].sup.+ enzyme cell enzyme CatD 1 409.1
0.00551 0.00871 0.0022 74.5 2 399.9 0.00747 0.00437 0.0129 >400
3 414.2 0.00838 0.00522 0.0108 437 4 406.1 0.0696 0.0164 1845 5
427.0 0.00855 0.0326 0.00154 1421 6 409.1 0.0123 0.0124 0.00184 750
7 406.1 0.0141 0.00636 719 8 423.0 0.00528 0.0563 418 9 481.0
0.00679 0.0232 366 10 439.1 0.00235 0.00196 1246 11 418.1 0.0104
0.0119 0.0275 >400 12 441.0 0.00128 0.00242 <0.00203 425 13
432.0 0.00548 0.00899 0.00618 >400 14 400.1 0.0109 0.00569 797
15 455.1 0.0124 0.00994 506 16 424.1 0.0145 0.00908 875 17 438.0
0.026 0.0548 863 18 427.1 0.0172 0.0169 34.3 19 414.2 0.00545
0.00431 669 20 448.1 0.0006 0.00064 0.0394 47.1 21 423.0 0.0145
0.0164 0.00534 >133 22 451.0 0.0149 0.0533 331 23 430.0 0.00047
0.00062 0.0374 81.9 24 476.1 0.00188 0.0191 189 25 504.0 0.0025
0.571 48.7 26 441.0 0.0107 0.0213 >133 27 441.0 0.0235 0.013
33.5 28 442.1 0.0276 0.0204 0.0497 466 29 453.0 0.00209 0.00212
<0.00203 282 30 462.0 0.00152 0.00851 <0.00203 958 31 457.1
0.00206 0.00226 0.00109 1396 32 452.0 0.0212 0.0836 0.304 138 33
467.1 0.00203 0.00383 0.00169 >400 34 433.0 0.0198 0.0317 0.0136
295 35 477.0 0.00386 0.00288 0.00363 213 36 424.1 0.0267 0.00767
0.0562 250 37 439.1 0.00332 0.0014 0.00161 >400 38 423.0 0.0157
0.0144 0.00728 >133 39 433.1 0.0234 0.024 0.0278 1222 40 453.0
0.00553 0.0065 0.00121 2806 41 441.0 0.00227 0.00596 <0.00203
>400 42 439.1 0.00601 0.00576 0.0039 95.6 43 471.0 0.00235
0.00995 0.00163 755 44 444.0 0.00255 0.00215 0.00147 >400 45
462.0 0.00299 0.00427 <0.00203 >400 46 468.0 0.00631 0.00352
0.0301 252 47 485.1 0.00318 0.0162 0.00187 >400 48 471.0 0.00357
0.0149 0.00323 >400 49 463.1 0.00631 0.0084 0.00749 1764 50
453.0 0.00225 0.00505 0.00286 >133 51 424.1 0.033 0.00344 0.0983
1346 52 482.1 0.0105 0.00455 0.23 >400 53 460.1 0.00045 0.00045
0.0156 349 54 453.2 0.00139 0.00196 <0.00203 >44.4 55 454.2
0.00399 0.00457 0.014 227 56 496.1 0.00538 0.0135 0.27 >400 57
471.0 0.00563 0.0225 0.0235 29.5 58 459.0 0.00397 0.00306 0.0308
975 59 459.0 0.00114 0.0229 <0.00203 >400 60 455.1 0.00135
0.00767 0.00174 204 61 460.1 0.0003 0.00035 0.0201 59.7 62 447.0
0.0289 0.14 0.0885 295 63 475.1 0.1365 4.65 3.75 494 64 461.1
0.00448 0.00281 0.025 268 65 473.1 0.0133 0.00781 0.0836 1229 66
447.0 0.0171 0.0525 0.132 >400 67 477.0/479.0 0.0137 0.0208
0.00616 738 68 457.0 0.00588 0.0201 0.00568 47.0 69 427.0 0.0152
0.114 0.00302 939 70 462.0 0.00116 0.0035 0.00247 >400 71 459.0
0.00047 0.00156 0.0375 329 72 474.0 0.00044 0.00082 0.0212 81.6 73
477.1 0.00911 0.0177 0.00296 >400 74 473.1 0.00095 0.00219
0.0473 932 75 450.1 0.012 0.0136 0.0295 >400 76 474.0 0.00095
0.00271 0.0174 1494 77 444.0 0.0047 0.0217 0.0461 949 78 441.0
0.00464 0.0917 0.00126 627 79 518.2 0.00489 0.0284 0.143 >400 80
454.1 0.00913 0.00851 0.0251 >400 81 437.1 0.0219 0.047 0.0116
1392 82 483.0 0.00043 0.00354 0.0099 >133 83 478.1 0.00046
0.00092 0.0138 105 84 462.0 0.00125 0.0216 0.0228 974 85 487.1
0.00062 0.00216 0.0435 1550 86 473.1 0.00763 0.0501 0.0206 715 87
467.1 0.114 22.6 0.271 2809 88 429.1 0.0416 0.0264 0.137 >400 89
458.1 0.0228 0.0198 0.0364 >400 90 485.1 0.00682 0.128 0.0112
34.1 91 476.1 0.00524 0.0256 0.0111 1208 92 463.1 0.00520 0.0102
0.00373 414 93 459.1 0.01 0.0108 0.0342 1376 94 464.0 0.00053
0.00304 <0.00203 559 95 474.0 0.00426 0.0138 0.00837 133 96
471.0 0.00726 0.0174 0.0024 40.4 97 456.0 0.0118 0.0312 0.0632 752
98 424.0 0.00665 0.0056 0.0032 3140 99 449.9 0.00659 0.0659 0.00824
1130 100 422.0 0.0225 0.0112 0.0038 >400 101 441.9 0.0197 0.094
0.023 720 102 462.0 0.00433 0.058 0.019 361
TABLE-US-00027 TABLE 13B IC.sub.50 IC.sub.50 IC.sub.50 IP (.mu.M)
IP (.mu.M) IP (.mu.M) IC.sub.50 Oberved BACE1 BACE1 BACE2 IP
(.mu.M) Ex. No. [M + H].sup.+ enzyme cell enzyme CatD 601 468
0.000589 0.00235 0.0361 1679 602 511 0.000871 0.00204 0.0371 605
603 459.1 0.0016 0.0037 0.0132 336 604 437.9 0.00624 0.00933
0.00378 571 605 510.9 0.00178 0.00149 0.114 1290 606 445.2 0.00032
0.000849 0.00931 278 607 488 0.000975 0.000956 0.0237 >400 608
518 0.00285 0.00174 0.154 >400 609 520.2 0.00344 0.0194 0.466
>400 610 521 0.00178 0.00597 0.193 >400 611 480.2 0.00663
0.00649 0.208 >400 612 457.2 0.00115 0.00103 0.0544 196 613
487.1 0.000555 0.00098 0.0123 709 614 520.2 0.00361 0.0755 0.101
340 615 538.1 0.00273 0.0788 0.117 102 616 590.2 0.00342 0.0329
0.124 905 617 508.1 0.00357 0.0652 0.158 >400 618 532.2 0.00606
0.0557 0.0161 1015 619 490.1 0.00439 0.0352 0.175 655 620 514.1
0.00832 0.0437 0.245 >400 621 484.1 0.0113 0.0197 0.148 710 622
592.1 0.00492 0.0438 0.225 946 623 520.1 0.00575 0.0671 0.0485 641
624 436.1 0.0298 0.0435 0.00394 >400 625 480.1 0.0309 0.014
0.401 730 626 523.1 0.0164 0.00509 0.2 1077 627 497.1 0.00114
0.00428 0.0384 1389 628 540 0.00324 0.0148 0.0383 443 629 472.2
0.0365 0.0205 0.0582 2884 630 531 0.000443 0.00528 0.00547 74.9 631
540.2 0.00173 0.00325 0.055 475 632 532.1 0.000715 0.000535 0.00302
961 633 509.1 0.00036 0.000224 0.00165 67.5 634 553.1 0.000758
0.000616 0.00951 660 635 505.2 0.00832 0.0208 0.192 >400 636 417
0.0918 0.411 0.0298 996 637 392 0.0213 0.0121 0.00261 >400 638
398 0.0625 0.0517 0.0314 >400 639 436.1 0.00157 0.00213 0.0401
381 640 479 0.00553 0.00251 0.101 646 641 406 0.0188 0.00799
0.00815 1428 642 518.2 0.00642 0.0351 0.114 434 643 536.2 0.00246
0.0328 0.134 751 644 512.2 0.014 0.0137 0.207 >400 645 518.2
0.00337 0.0246 0.143 477 646 530.2 0.00656 0.013 0.211 865 647
507.2 0.0236 0.259 0.342 389 648 499 0.0433 0.222 0.522 196 649
483.2 0.0646 0.131 0.284 803 650 501.2 0.0389 0.344 0.556 777 651
471 0.0589 0.139 0.397 1033 652 500.1 0.00756 0.0256 0.142 >400
653 486 0.000544 0.00151 0.0192 260 654 529 0.000931 0.00166 0.0291
861 655 442 0.00455 0.006 <0.00203 1723 656 516 0.387 0.624 2.35
998 657 456 0.00369 0.00533 0.00303 306 658 457 0.0107 0.0136
0.0293 705 659 534 0.000774 0.0013 0.00425 462 660 534 0.00133
0.00345 0.0235 554 661 502 0.000765 0.00244 0.00392 795 662 466
0.000437 0.00049 0.0199 1060 663 545 0.00048 0.00338 0.0174 601 664
545 0.000274 0.0143 0.046 >400 665 534 0.00165 0.00737 0.0383
1110 666 534 0.00201 0.00772 0.177 1693 667 0.00262 0.00362 0.0599
1162 668 577 0.0033 0.00697 0.233 1966 669 544 0.00119 0.00593
0.036 1136 670 466 0.0024 0.000969 0.17 730 671 533 0.000943
0.00177 0.0236 1045 672 533 0.00142 0.007 0.0685 638 673 510
0.000389 0.000398 0.00602 101 674 510 0.000368 0.000776 0.0133 149
675 531 0.0124 0.0519 0.703 1014 676 548 0.00155 0.0033 0.0157 337
677 548 0.0016 0.00305 0.00948 306 678 519 0.00612 0.0286 0.579 747
679 537 0.00435 0.0495 0.746 375 680 519 0.0139 0.0153 0.846 1110
681 513 0.0109 0.0555 0.789 1454 682 487 0.00182 0.0175 0.0195 800
683 469 0.00391 0.008 0.0267 2099 684 475 0.00146 0.00684 0.0332
1038 685 493 0.00112 0.0197 0.018 463 686 475 0.00167 0.00967
0.0221 496 687 544 0.117 0.569 2.52 >400 688 544 0.548 3.89
0.709 1320 689 501 0.0105 0.0464 0.819 >400 690 457 0.00418
0.00779 0.026 675 691 495 0.000673 0.00563 0.0231 728 692 505
0.0053 0.0453 0.29 >400 693 539 0.00294 0.0489 0.246 1197 694
517 0.00615 0.0517 0.401 1691 695 523 0.00272 0.0883 0.263 >400
696 505 0.0062 0.0707 0.324 846 697 487 0.00629 0.0315 0.338
>400 698 499 0.0086 0.0116 0.316 >400 699 570 0.00106 0.0352
0.0524 138 700 530 0.00115 0.00826 0.224 569 701 531 0.000943
0.00309 0.0782 587 702 544 0.000986 0.0344 0.269 362 703 472
0.00594 0.0153 0.011 340 704 457 0.002 0.00557 <0.00203 141 705
544 0.00186 0.0035 0.0184 183 706 544 0.00292 0.0086 0.0294 354 707
501 0.000636 0.00422 0.0185 550 708 554 0.000969 0.0215 0.107 438
709 486 0.0092 0.104 0.0257 148 710 471 0.00599 0.055 <0.00203
379 711 485 0.00311 0.014 <0.00203 753 712 529 0.000782 0.00904
0.0516 476 713 515 0.000864 0.00543 0.00394 547 714 515 0.00102
0.0109 0.00913 613 715 472.1 0.00409 0.00635 0.00881 918 716 458.1
0.00216 0.00431 0.00196 2288 717 467.1 0.0072 0.0239 0.00332
>400 718 448.1 0.00367 0.04 0.00131 921 719 462 0.00442 0.0138
0.00397 1490 720 492 0.000935 0.00151 0.0273 648 721 535.1 0.00162
0.00474 0.0677 2126 722 490.1 0.0118 0.0209 <0.00203 684 723 462
0.00169 0.00431 <0.00203 282 724 548.2 0.00208 0.00712 0.0746
1080 725 504 0.00565 0.0148 0.00251 1164 726 539.1 0.179 0.406
0.641 >400 727 539.1 0.00798 0.009625 0.359 779 728 539.1 0.0238
0.0127 0.553 859 729 497 0.0282 0.0457 0.385 856 730 540.1 0.0157
0.0759 1.03 1376 731 572.1 0.0668 1.3 3.83 1097 732 549.1 0.00339
0.034 0.737 600 733 496.1 0.00638 0.014 0.0642 1520 734 550.1
0.00173 0.017 0.188 2107 735 589.1 0.0412 1.76 0.978 1646 736
633/635 0.0317 1.07 0.765 151 737 555.1 0.0325 0.274 0.693 1497 738
532 0.0169 0.0667 0.562 648 739 514.1 0.00421 0.0169 0.158 1464 740
496.1 0.0055 0.0194 0.209 927 741 564.1 0.0269 1.14 0.658 94.4 742
487 0.000719 0.0149 <0.00203 846 743 507 0.000395 0.00971
0.00543 >133 744 508 0.00029 0.000872 0.0183 46.5 745 550.1
0.000898 0.0175 0.0257 972 746 551 0.000628 0.00356 0.00522 880 747
574.1 0.00242 0.0123 0.0115 1186 748 445.1 0.00807 0.597 0.00284
129 749 478.1 0.000319 0.00121 0.00979 101 750 544.1 0.0019 0.00301
0.0404 246 751 553.1 0.00203 0.0338 0.255 292 752 467.4 0.0068
0.0522 0.00709 26.4 753 467.4 0.00339 0.0964 0.00304 420 754 433
0.0454 0.0781 0.00588 844 755 507 0.00147 0.00838 <0.00203 250
756 465 0.00373 0.00659 <0.00203 >400 757 479 0.000176 0.0498
<0.00203 458 758 467 0.00156 0.00195 <0.00203 2066 759 478
0.00101 0.00265 <0.00203 >400 760 492 0.000415 0.00265
<0.00203 779 761 506 0.000794 0.00152 <0.00203 364 762 453
0.00303 0.0142 0.0384 669 763 496 0.00849 0.0048 0.239 1110 764 548
0.00073 0.000856 <0.00203 518 765 508 0.000706 0.0011
<0.00203 1074 766 548 0.00105 0.0031 <0.00203 848 767 536
0.00102 0.00143 <0.00203 602 768 550.1 0.00119 0.00113 0.00612
406 769 593 0.00143 0.00121 0.023 224 770 592 0.00294 0.00281 0.143
311 771 563 0.00204 0.00146 0.0786 282 772 554 0.000429 0.000972
<0.00203 82 773 598 0.000423 0.00148 <0.00203 113 774 527
0.000313 0.000583 0.00575 7.95 775 0.00112 0.00323 0.0602 22.8 776
550 0.001197 0.00305 0.0264 293 777 562 0.000274 0.000416
<0.00203 834 778 562 0.00558 0.0134 0.0026 557 779 524 0.000728
0.00082 <0.00203 >400 780 497 0.00022 0.00126 <0.0061 116
781 520 0.000422 0.00577 0.00329 397 782 520 0.000577 0.0197 0.0245
792 783 540 0.000501 0.00485 0.00245 >400 784 511 0.000318
0.00152 <0.00203 166 785 476 0.00112 0.0102 <0.00203 621 786
476 0.000976 0.0464 <0.00203 584 787 490 0.000847 0.0139
<0.00203 1233 788 534 0.00127 0.0161 0.0122 485 789 510 0.000528
0.0259 0.00936 835 790 480 0.000338 0.0028 <0.00203 792 791 518
0.000658 0.00183 0.0712 317 792 474 0.00075 0.000971 <0.00203
134 793 496 0.000293 0.0153 0.00477 482 794 518 0.000846 0.0012
0.0397 316 795 495 0.0003 0.000608 0.0104 16.6 796 561 0.000859
0.00354 0.0628 543 797 490 0.00452 0.0211 <0.00203 147 798 511
0.000294 0.000715 0.0272 4.72 799 538 0.000382 0.00075 0.015 349
800 539 0.000711 0.00659 0.0841 293 801 456.2 0.00613 0.0137 0.0163
145 802 528 0.000992 0.00497 0.0334 310 803 519.1 0.000643 0.00228
0.0157 1063 804 459 0.00111 0.008 <0.00203 319 805 503.1
0.000222 0.00497 0.0189 27 806 485 0.000489 0.00772 0.0242 122 807
480 0.000228 0.000722 0.00736 43.9 808 528.2 0.000866 0.00111
0.0383 127 809 540.1 0.000974 0.00181 0.0358 123 810 462 0.000268
0.141 0.012 67.8 811 505.1 0.000676 0.00126 0.0207 297 812 546
0.000827 0.00167 0.0642 118 813 485.1 0.0009 0.002 0.0258 447 814
506 0.000829 0.00608 0.0601 595 815 518 0.000847 0.00349 0.0395 396
816 485 0.000244 0.00122 0.0183 73.6 817 528 0.000706 0.00171
0.0319 124 818 441 0.000587 0.00164 <0.00203 152 819 485.1
0.000821 0.00175 0.0412 34.2 820 462 0.000319 0.000495 0.0162 60.4
821 423.2 0.00298 0.00428 <0.00203 1174 822 440 0.000264
0.000378 0.0147 150 823 467 0.000791 0.00186 0.0296 351 824 467
0.00299 0.00128 0.0842 1840 825 510 0.00357 0.00111 0.0542 526 826
488 0.00174 0.00331 0.0778 395 827 481.1 0.000771 0.0207 0.263 810
828 525 0.00496 0.00446 0.207 995 829 458 0.000776 0.0019 0.00801
354 830 476 0.000566 0.00221 0.0101 121 831 500 0.00299 0.00359
0.118 >400 [2] 832 470.1 0.00299 0.00213 0.013 778 833 435
0.0041 0.0137 0.0061 >400 834 456 0.000404 0.000489 0.0127 318
835 513 0.00305 0.00392 0.0249 >400 836 519 0.00209 0.00389
0.0362 >400 837 501 0.00253 0.00325 0.0259 1074 838 464 0.000209
0.000355 0.00751 49.1 839 482 <0.00203 0.00105 0.0106 56.6 840
476 <0.00203 0.0006 0.0163 153 841 471 0.00114 0.0216 0.0449 598
842 514.1 0.00256 0.0217 0.119 >400
843 514.1 0.00378 0.0493 0.115 432 844 460.2 0.0219 0.0145 0.0108
1784 845 471.2 0.0026 0.00473 0.0257 1709 846 451 0.0282 0.0111
0.0494 >400 847 450.2 0.0113 0.00675 0.00955 1906 848 480.1
0.00136 0.00134 0.0335 773 849 523.2 0.00343 0.0017 0.0463 1534 850
474 0.00121 0.00207 0.00886 1146 851 460.2 0.000574 0.000624 0.0184
468 852 463 0.0127 0.0101 0.00758 1685 853 483.2 0.000878 0.000961
0.0244 791 854 485.2 0.00144 0.00134 0.0383 1236 855 507.2 0.198
0.294 0.0224 >400 856 551 0.071 0.249 0.657 116 857 523 0.0678
0.0156 0.346 2523 858 451 0.00085 0.000487 <0.00203 >400 859
457.2 0.000799 0.000762 0.0194 590 860 537.2 0.00276 0.00853 0.0286
1007 861 494 0.000889 0.00754 0.0176 146 862 488.2 0.000598 0.0072
0.017 129 863 531.2 0.00228 0.00635 0.0249 467 864 545 0.0609 0.172
0.652 621 865 499 0.000236 0.00301 0.0123 325 866 545.9 0.000941
0.0115 0.0285 >400 867 545.9 0.00171 0.011 0.0549 299 868 517
0.000671 0.0147 0.0211 >400 869 511 0.000725 0.00155 0.0173 127
870 560 0.00156 0.02 0.0326 91.3 871 525 0.0183 1.17 0.517 352 872
542.9 0.0193 2.66 0.441 239 873 574 0.00175 0.287 0.0358 95.1 874
571 0.00361 0.0245 0.0755 956 875 562 0.00296 0.0272 0.0352 295 876
506.9 0.0801 0.587 0.912 223 877 560.9 0.011 0.0294 0.338 343 878
550 0.231 1.07 0.353 171 879 499 0.00107 0.0179 0.282 2688 880 543
0.00452 0.0193 0.27 1106 881 551 0.00936 0.00819 0.14 349 882 555
0.00778 0.0204 0.381 911 883 561.2 0.000316 0.0133 0.091 363 884
557.3 0.00427 0.0119 0.13 >400 885 555.2 0.00223 0.00823 0.143
592 886 574.2 0.0011 0.0411 0.0278 136 887 561 0.00295 0.0442 0.317
>400 888 560.2 0.00209 0.0218 0.0581 71.9 889 577.2 0.0418 0.252
1.41 306 890 517.3 0.001 0.0257 0.2 517 891 560 0.177 2.88 1.09 984
892 560 0.00278 0.056 0.848 873 893 576 0.149 1.66 3.86 518 894
536.9 0.00372 0.05 0.464 >133 895 479.1 0.0053 0.113 0.0254 167
896 465.2 0.018 0.135 0.0223 128 897 429 0.035 0.038 0.184 1443 898
467 0.00454 0.111 0.00268 673 899 453 0.00889 2.45 0.00258 >400
900 429 0.0324 0.195 0.0972 559 901 520.1 0.00192 0.0167 0.00203
603 902 475 0.0148 0.0796 0.0125 479 903 510 0.00195 0.00785 0.109
1219 904 466.1 0.0141 0.0132 0.0355 380 905 452.2 0.000606 0.000893
<0.00203 856 906 451 0.00404 0.014 0.00174 693 907 468.1 0.00747
0.00413 0.0102 381 908 468.1 0.00801 0.00812 0.0255 360 909 482
0.0257 0.0144 0.183 6.84 910 517 0.00124 0.00117 0.0337 1459 911
496.1 0.000649 0.0038 0.00714 >400 912 524.1 0.000467 0.000795
0.00101 >400 913 501 0.000303 0.000278 0.000795 45.1 914 487.1
0.000464 0.000534 0.0108 79.4 915 510 0.000426 0.00195 0.0101
>400 916 478 0.000515 0.00974 0.00399 84.2 917 496 0.000633
0.000857 0.0355 373 918 539 0.000861 0.000733 0.0389 86.9 919 473
0.000199 0.000298 0.00428 21.2 920 510 0.000201 0.000644 0.00604
1077 921 478.1 0.00198 0.0206 0.0627 172 922 577.1 0.00155 0.00155
0.00839 1089 923 567.1 0.000863 0.000338 0.00253 121 924 455.1
0.000249 0.00138 <0.00203 17.8 925 538.2 0.001405 0.00308
0.00387 >400 926 545 0.0021 0.00113 0.00491 695 927 437 0.000266
0.000667 0.00448 126 928 460.1 0.00141 0.00723 0.0129 439 929 416
0.000567 0.00363 <0.00203 >400 930 480 0.000417 0.000688
<0.00203 797 931 492 0.000902 0.0386 0.0551 633 932 434 0.00188
0.045 <0.00203 >400 933 550.1 0.000526 0.000709 0.00491 315
934 527.1 0.000393 0.000378 <0.00203 12.9 935 506 0.000498
0.000889 <0.00203 254 936 593.2 0.00385 0.000847 0.0182 115 937
564 0.00207 0.00624 0.0102 872 938 607.1 0.00129 0.00508 0.0633 162
939 535.1 0.000867 0.165 0.127 209 940 499 0.004 0.015 0.0224 1388
941 453.2 0.00962 0.0129 0.2 780 942 497 0.00314 0.00518 0.0417
1090 943 497 0.00223 0.00593 0.101 571 944 468 0.00102 0.00216
0.0696 >400 945 503 0.00105 0.00709 0.0661 381 946 517 0.0268
0.0174 0.517 352 947 517.2 0.0282 0.0337 0.519 595 948 568 0.00304
0.0102 0.144 80.9 949 563 0.00245 0.0841 0.0588 336 950 557.2
0.0051 0.104 0.118 384 951 514 0.00233 0.0603 0.0497 915 952 578
0.00126 0.0108 0.00755 16.3 953 542.2 0.00028 0.00149 0.0267 61.9
954 521.2 0.00579 0.0144 0.00382 715 955 502.2 0.000805 0.00178
0.0501 48 956 476.1 0.000927 0.019 <0.00203 341 957 463.2
0.000621 0.00616 0.00538 1255 958 534.1 0.0012 0.04 0.0662 354 959
497.1 0.0000901 0.00152 <0.00203 44.1 960 520.1 0.000507 0.00624
0.00422 >400 961 472 0.012 0.0214 0.0223 171 962 467.4 0.01
0.104 0.0199 21
TABLE-US-00028 TABLE 13C IC.sub.50 IC.sub.50 IC.sub.50 IP (.mu.M)
IP (.mu.M) IP (.mu.M) IC.sub.50 Oberved BACE1 BACE1 BACE2 IP
(.mu.M) Ex. No. [M + H].sup.+ enzyme cell enzyme CatD 963 563
0.000194 0.0026 0.0631 267 964 450.2 0.000737 0.00154 0.00887 98.9
965 470 0.000618 0.00287 0.0638 >400 966 476 0.000385 0.00182
0.0419 735 967 501 0.00011 0.000539 0.0149 269 968 514 0.129 0.12
1.1 >400 969 477 0.000197 0.000687 0.0115 158 970 490 0.0085
0.021 0.333 >400 971 496 0.00522 0.0185 0.38 611 972 581
0.000454 0.00455 0.0794 138 973 513 0.000404 0.00192 0.0476 1568
974 569.1 0.00132 0.00257 0.014 14.5 975 488 0.000565 0.00551
0.0562 212 976 541 0.000527 0.0101 0.268 260 977 527 0.000782
0.00439 0.0876 577 978 483 0.000344 0.000648 0.0195 >400 979 492
0.000315 0.000859 0.0201 >400 980 559.1 0.000455 0.000747 0.013
19.8 981 459.1 0.00315 0.00074 0.0575 106 982 575 0.000679 0.00329
0.032 175 983 573.1 0.00151 0.00736 0.174 172 984 543 0.000858
0.00125 0.0217 1111 985 448 0.000276 0.000709 <0.00203 1119 986
481 0.00113 0.00141 0.00598 172 987 469 0.00014 0.000229 0.0079
49.9 988 470 0.0216 0.0532 0.336 >400 989 475.2 0.000518 0.00067
0.0406 174 990 454.2 0.02075 0.026 0.00465 67 991 571 0.000297
0.000265 0.0097 664 992 571 0.000776 0.000338 0.0125 954 993 509
0.00048 0.000566 0.061 255 994 525 0.00069 0.00116 0.0689 215 995
514 0.10105 0.164 1.77 1943 996 514 0.123 0.1202 0.807 1636 997
569.3 0.000893 0.00672 0.0509 9.48 998 569.3 0.000146 0.0017 0.0754
>400 999 563.1 0.00009 0.00613 0.0755 180 1000 527.2 0.00007
0.000921 0.00345 1003 1001 529 0.000059 0.00589 0.356 492 1002 555
0.00177 0.00484 0.165 82.7 1003 545 0.00565 0.021 0.48 297 1004 543
0.0001 0.000324 0.00235 14.9 1005 525.2 0.000384 0.00108 0.00516
72.1 1006 529.2 0.000885 0.000575 0.0213 7.08 1007 454 0.00702 0.73
0.00484 460 1008 514 0.00471 0.0022 0.195 >400 1009 488 0.000695
0.00254 0.0436 936 1010 489.1 0.0032 0.0309 0.0669 >400 1011
469.1 0.000465 0.00353 0.00908 741 1012 498 0.00399 0.111 0.095
>400 1013 532 0.00139 0.00144 0.0541 959 1014 532 0.000879
0.00289 0.192 2555 1015 512.1 0.00497 0.00686 0.185 >400 1016
468 0.00104 0.0119 0.00764 >400 1017 483.1 0.000266 0.000106
0.00982 22.5 1018 499.2 0.00116 0.00113 0.00651 211 1019 543.2
0.000937 0.00109 0.073 271 1020 504.2 0.00118 0.0248 0.0998 783
1021 490 0.000918 0.0116 0.0808 776 1022 506 0.00572 0.0331 0.579
>400 1023 508 0.00319 0.0135 0.204 1357 1024 508 0.00214 0.0222
0.313 884 1025 500 0.00169 0.0142 0.13 1697 1026 540 0.00496 0.0936
0.115 475 1027 436 0.0196 0.136 0.0565 981 1028 492 0.00195 0.0293
0.226 135 1029 506 0.00741 0.0541 0.459 1139 1030 490 0.00213
0.0414 0.072 243 1031 531 0.00107 0.152 0.0897 775 1032 531 0.00106
0.0323 0.0465 1017 1033 526 0.00105 0.101 0.0323 230 1034 533
0.0014 0.0109 0.0118 1395 1035 526 0.00258 0.022 0.1 1207 1036 476
0.00184 0.0445 0.0681 1275 1037 532 0.000803 0.0467 0.128 785 1038
464 0.00363 0.0364 0.0947 1295 1039 520 0.000941 0.00251 0.171 725
1040 545 0.000426 0.00284 0.0555 212 1041 553.2 0.00176 0.00692
0.222 324 1042 501 0.000317 0.00621 0.0159 55.6 1043 470 0.000352
0.0138 0.00931 196 1044 528 0.001 0.017 0.0987 291 1045 577.2
0.00181 0.0738 0.288 194 1046 488 0.00037 0.0162 0.0307 43.5 1047
484 0.0054 0.015 0.189 >400 1048 470 0.0078 0.0095 0.152 -- 1049
486 0.0054 0.0035 0.180 >400 1050 502 0.030 0.035 1.19 >400
1051 472 0.033 0.035 0.345 >400 1052 464 0.016 0.0083 0.146
>400 1053 472 0.0059 0.0029 0.108 1420 1054 486 0.0014 0.011
0171 862 1055 488 0.0079 0.022 0.498 1330 1056 474 0.0014 0.018
0.317 1240 1057 482 0.0023 0.0033 0.158 >400 1058 488 >0.016
0.010 0.498 >400 1059 502 0.011 0.020 0.069 1320 1060 488 0.0074
0.0076 0.130 >400 1061 504 0.0047 0.0039 0.170 >400 1062 520
>16 0.022 0.658 >400 1063 490 0.037 0.100 0.555 >400 1064
482 0.0027 0.0047 0.081 >400 1065 514 0.000256 0.00294 0.0636
1578 1066 449 0.00161 0.00347 0.00099 >400 1067 474 0.0264
0.0238 1.63 2051 1068 492 0.0165 0.0271 1.51 >400 1069 506
0.0174 0.2145 0.878 1058 1068 472.1 0.000178 0.000127 0.0136 170
1071 513 0.000768 0.00025 0.0304 1429 1072 476 0.00032 0.000345
0.00983 143 1073 520 0.000842 0.00323 0.0515 1296 1074 519 0.00057
0.000489 0.0167 1328 1075 534 0.00152 0.00153 0.198 1250
[2055] 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.
[2056] In one embodiment of the invention, there is provided a
method of making a compound of Formula I-A having a general
structure of
##STR00858##
the method comprising the step of reacting a compound 20
##STR00859##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each of R.sup.a,
R.sup.b, R.sup.1, R.sup.2 and R.sup.3 of Formula I-A 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
I-A.
[2057] In one embodiment of the invention, there is provided a
method of making a compound of Formula I-B having a general
structure of
##STR00860##
the method comprising the step of reacting a compound 20
##STR00861##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each of R.sup.a,
R.sup.b, R.sup.1, R.sup.2 and R.sup.3 of Formula I-B are as defined
herein, with a compound having the structure
##STR00862##
wherein each W and each R.sup.10 are, independently, as defined
herein, in the presence of acid to make a compound of Formula
I-B.
[2058] In another embodiment of the invention, there is provided a
method of making a compound of Formula II having a general formula
of
##STR00863##
the method comprising the step of reacting a compound 30
##STR00864##
wherein A.sup.4, A.sup.5, A.sup.6, A.sup.8, each of R.sup.a,
R.sup.b, R.sup.1, R.sup.2 and 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--Cl in the presence of an acid or
phosphonic anhydride, wherein R.sup.9 is as defined herein, to make
a compound of Formula II.
[2059] 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.
[2060] 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.
[2061] 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).
[2062] 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.
[2063] 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.
[2064] 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 solublize 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.
[2065] 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.
[2066] 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.
[2067] 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.
[2068] 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.
[2069] 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.
[2070] 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.
[2071] 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.
[2072] All crystal forms of the compounds described herein are
expressly included in the present invention.
[2073] 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.
[2074] 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
[2075] 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.
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 BACE1 and BACE2 FRET (Fluorescence Resonance
Energy Transfer) Assays (Enzyme Assay Data in the Example
Tables)
[2076] The cDNAs for both human recombinant BACE1 and BACE2 with
C-terminal 6-His Tags were cloned into transient protein expression
vectors, which were subsequently transfected into mammalian cell
lines. These recombinant proteins were further purified using
Ni-NTA affinity chromatography (Qiagen). The assay buffer used in
these screens is 0.05 M acetate, pH 4.5, 8% DMSO final, 100 uM
genapol (which is a nonionic detergent, below its Critical Micelle
Concentration). The Beta Secretase enzyme (0.02 nM for BACE1 and
0.64 nM for BACE2) 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 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 590
nm).
[2077] Where available, the in-vitro BACE FRET enzyme data for each
of the Examples is provided in Tables 13A, 13B, and 13C.
In Vitro BACE-1 Cell-Based Assay
[2078] The cell-based assay measures inhibition or reduction of
AP40 in conditioned medium of test compound treated cells
expressing amyloid precursor protein. 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.
[2079] 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.
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).
[2080] Where available, the in-vitro BACE cell based data for each
of the Examples is provided in Tables 13A, 13B, and 13C.
In Vitro Enzymatic Cathepsin D (Cat D) FRET (Fluorescence Resonance
Energy Transfer) Assay
[2081] 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 p 379-384 1997. Proteolytic cleavage of the
FRET substrate releases quenching of fluorescence (Cat D excitation
500 nm and emission 580 nm).
[2082] 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).
[2083] Where available, the in-vitro Cat D FRET assay data for each
of the Examples, conducted by the first procedure, is provided. For
example, the compound of Example 43 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. It was surprisingly found that
incorporation of an amino- or amido-linker between the core of the
compounds and the R.sup.7 and R.sup.9 groups, respectively, has
conferred a significantly reduced, poor or no potency on the
protein Cat D. Thus, with this surprising selectivity profile, the
compounds of the present invention are believed to minimize, reduce
or completely 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
[2084] 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 [2085] IV:
5% EtOH, 45% Propylene glycol in 5% Dextrose
[2086] 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 h. The following examples
in Table 14A, Table 14B, and Table 14C exhibited the following
percent Abeta 40 reductions at 10 mpk (unless otherwise noted) in
the CSF and brain of the rat, respectively.
TABLE-US-00029 TABLE 14A % A.beta. 40 reduction % A.beta. 40
reduction Ex. No. in rat CSF at 10 mpk in rat brain at 10 mpk 1 58
28 2 72 67 4 40 18 5 43 19 6 78 68 11 41 (3 mpk) 25 (3 mpk) 12 75
65 13 70 56 20 80 76 21 61 40 23 70 (3 mpk) 61 (3 mpk) 26 38 34 28
42 26 33 65 53 35 63 50 36 74 46 38 66 44 39 50 23 45 17 0 46 73 67
49 24 14 51 23 (3 mpk) 17 (3 mpk) 52 16 0 54 18 19 56 50 32 72 85
84 82 48 23 84 40 8 95 69 60
TABLE-US-00030 TABLE 14B % A.beta. 40 reduction % A.beta. 40
reduction Ex. No. in rat CSF at 10 mpk in rat brain at 10 mpk 707
27 25 712 52 32 708 13 -4 660 38 26 689 38 10 678 40 11 662 40 37
679 20 6 680 30 8 631 52 47 698 15 -7 931 8 3 770 22 6 941 41 2 911
21 20 803 59 45 915 51 47 945 68 55 924 84 76 913 84 78 612 84 82
697 35 13 645 53 34 627 59 50 628 59 50 921 70 64 795 76 70 843 51
16 842 51 25 841 58 44 705 28 1 828 24 10 831 49 16 727 38 18 827
41 19 728 31 23 808 44 26 812 52 38 815 50 43 802 59 50 813 68 50
805 59 53 806 70 65 801 74 68 814 76 68 823 78 78 834 83 83 807 80
(3 mpk) 66 (3 mpk) 810 79 (3 mpk) 74 (3 mpk)
TABLE-US-00031 TABLE 14C % A.beta. 40 reduction % A.beta. 40
reduction Ex. No. in rat CSF at 10 mpk in rat brain at 10 mpk 965
33 20 966 67 68 969 79 (3 mpk) 79 (3 mpk) 976 36 16 1021 44 25 1039
13 16
Indications
[2087] 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
(A.beta.) 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 A.beta. toxicity are unclear,
oligomeric forms of A.beta. 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; Gotz 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).
[2088] 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.
[2089] MK-8931, a small molecule inhibitor of BACE (structure
unknown) was tested in a two-part randomised, double-blind,
placebo-controlled phase 1 clinical trial in 88 healthy individuals
(18-45 years old). MK-8931 seemed to be generally well tolerated
(66 patients), and no serious adverse events were reported. A major
goal of the trial was to determine whether MK-8931 was able to
enter the brain and block .beta. secretase. To monitor this,
biomarkers of BACE1 activity in the CSF were measured, including
A.beta.40 and A.beta.42, as was soluble peptide APP (sAPP.beta.), a
direct product of BACE1 cleavage of APP. MK-8931 significantly
reduced CSF A.beta. concentrations in a sustained and
dose-dependent manner. At 36 h post-dose, a single dose of 100 mg
reduced CSF A.beta.40 concentrations by 75% and a single dose of
550 mg by 92%. Similar reductions of CSF concentrations of
A.beta.42 and sAPP.beta., the BACE1-cleaved ectodomain of APP, were
also observed. Vassar & Yan, Lancet Neurology, 13:319-329
(2014). Currently, MK-8931 is enrolling mild-to-moderate
Alzheimer's Disease patients in a Ph 2/3 trial; and enrolling
participants with prodomal Alzheimer's disease in a Ph III safety
and efficacy trial. (US clinical trials; Merck Newsroom, 2014).
[2090] Bapineuzamab, a monoclonal amino-terminus specific
anti-amyloid antibody was 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.
[2091] The US biotech company CoMentis has been 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.
[2092] 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 A.beta.
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 adverse effects reported here were
recapitulated in LY2811376-treated BACE1 KO mice and thus are
unrelated to BACE1 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
[2093] 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. Accordingly, the compounds of the
invention would be useful in therapy as CNS agents in treating
neurological disorders and related conditions in subjects.
[2094] 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 (AD).
In another embodiment, the invention provides compounds, in
effective dosage amounts, for the therapeutic and/or prophylactic
treatment of AD. The compounds of the invention are useful for
treating various stages and degrees of AD, including without
limitation, mild, moderate and sever AD. Additionally, the
compounds of the invention may be used to treat prodomal patients,
i.e., subjects exhibiting the biomarkers and/or hallmarks of
developing AD, without exhibiting any symptoms of AD.
[2095] 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
[2096] 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.
[2097] 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.
[2098] 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.
[2099] 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.
[2100] 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.
[2101] 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).
[2102] 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).
[2103] 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.
[2104] 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.
[2105] For pulmonary administration, the pharmaceutical composition
may be administered in the form of an aerosol or with an inhaler
including dry powder aerosol.
[2106] 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.
[2107] 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
[2108] 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.
[2109] 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.
[2110] 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.
[2111] 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.
[2112] 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.
* * * * *