U.S. patent application number 14/187732 was filed with the patent office on 2014-06-19 for trpm8 antagonists and their use in treatments.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Kaustav Biswas, James Brown, Jian J. Chen, Vijay Keshav Gore, Scott Harried, Daniel B. Horne, Matthew R. Kaller, Qingyian Liu, Vu Van Ma, Holger Monenschein, Thomas T. Nguyen, David J. St. Jean, JR., Chester Chenguang Yuan, Wenge Zhong.
Application Number | 20140171406 14/187732 |
Document ID | / |
Family ID | 46384521 |
Filed Date | 2014-06-19 |
United States Patent
Application |
20140171406 |
Kind Code |
A1 |
Biswas; Kaustav ; et
al. |
June 19, 2014 |
TRPM8 ANTAGONISTS AND THEIR USE IN TREATMENTS
Abstract
Compounds of Formula I are useful as antagonists of TRPM8. Such
compounds are useful in treating a number of TRPM8 mediated
disorders and conditions and may be used to prepare medicaments and
pharmaceutical compositions useful for treating such disorders and
conditions. Examples of such disorders include, but are not limited
to, migraines and neuropathic pain. Compounds of Formula I have the
following structure: ##STR00001## where the definitions of the
variables are provided herein.
Inventors: |
Biswas; Kaustav; (Agoura
Hills, CA) ; Brown; James; (Moorpark, CA) ;
Chen; Jian J.; (Camarillo, CA) ; Gore; Vijay
Keshav; (Aliso Viejo, CA) ; Harried; Scott;
(Pittsburgh, PA) ; Horne; Daniel B.; (Simi Valley,
CA) ; Kaller; Matthew R.; (Ventura, CA) ; Liu;
Qingyian; (Camarillo, CA) ; Ma; Vu Van; (Oak
Park, CA) ; Monenschein; Holger; (San Diego, CA)
; Nguyen; Thomas T.; (Newbury Park, CA) ; St.
Jean, JR.; David J.; (Camarillo, CA) ; Yuan; Chester
Chenguang; (Newbury Park, CA) ; Zhong; Wenge;
(Thousand Oaks, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Assignee: |
AMGEN INC.
Thousand Oaks
CA
|
Family ID: |
46384521 |
Appl. No.: |
14/187732 |
Filed: |
February 24, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13529860 |
Jun 21, 2012 |
8710043 |
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14187732 |
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61500843 |
Jun 24, 2011 |
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Current U.S.
Class: |
514/210.18 ;
514/230.5; 514/252.03; 514/265.1; 514/274; 514/300; 514/314;
514/335; 514/339 |
Current CPC
Class: |
A61P 25/06 20180101;
C07D 401/14 20130101; C07D 213/82 20130101; A61P 1/10 20180101;
A61P 25/04 20180101; A61P 43/00 20180101; C07D 213/61 20130101;
A61P 17/06 20180101; C07D 213/40 20130101; C07D 405/14 20130101;
A61P 11/00 20180101; C07D 403/12 20130101; A61P 25/00 20180101;
A61P 31/22 20180101; C07D 417/12 20130101; A61P 3/10 20180101; A61P
27/02 20180101; A61P 37/08 20180101; C07D 487/04 20130101; A61P
11/02 20180101; A61P 17/02 20180101; C07D 413/12 20130101; A61P
1/02 20180101; A61P 13/10 20180101; C07D 213/81 20130101; A61P 9/00
20180101; A61P 17/00 20180101; C07D 498/04 20130101; C07D 471/04
20130101; A61P 25/26 20180101; C07D 409/12 20130101; A61P 25/24
20180101; A61P 19/02 20180101; C07D 405/12 20130101; A61P 25/02
20180101; A61P 1/04 20180101; A61P 11/06 20180101; A61P 17/04
20180101; C07D 401/12 20130101; A61P 29/00 20180101 |
Class at
Publication: |
514/210.18 ;
514/230.5; 514/252.03; 514/265.1; 514/274; 514/300; 514/314;
514/335; 514/339 |
International
Class: |
C07D 487/04 20060101
C07D487/04; C07D 401/14 20060101 C07D401/14; C07D 401/12 20060101
C07D401/12; C07D 213/82 20060101 C07D213/82; C07D 413/12 20060101
C07D413/12; C07D 471/04 20060101 C07D471/04 |
Claims
1. A method of treating acute, inflammatory and neuropathic pain,
dental pain, general headache, migraine, cluster headache,
mixed-vascular and non-vascular syndromes, tension headache,
general inflammation, arthritis, rheumatic diseases,
osteoarthritis, inflammatory bowel disorders, depression, anxiety,
inflammatory eye disorders, inflammatory or unstable bladder
disorders, psoriasis, skin complaints with inflammatory components,
chronic inflammatory conditions, inflammatory pain and associated
hyperalgesia and allodynia, neuropathic pain and associated
hyperalgesia and allodynia, diabetic neuropathy pain, causalgia,
sympathetically maintained pain, deafferentation syndromes, asthma,
epithelial tissue damage or dysfunction, herpes simplex,
disturbances of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritus, vitiligo, general gastrointestinal disorders,
gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
induced by necrotising agents, hair growth, vasomotor or allergic
rhinitis, bronchial disorders or bladder disorders in a subject,
the method comprising: administering to the subject a compound of
Formula I or the pharmaceutically-acceptable salt thereof, the
tautomer thereof, the pharmaceutically-acceptable salt of the
tautomer, or the mixture thereof, wherein the compound of Formula I
has the structure: ##STR01179## wherein: m is 0, 1, 2 or 3; n is 0
or 1; X.sup.1 is C(R.sup.4) or N; X.sup.2 is CH, CF, or N; R.sup.1
is C.sub.1-6alk or a direct-bonded, C.sub.1-2alk-linked,
C.sub.1-2alkO-linked, saturated, partially-saturated or unsaturated
3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or
11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms
selected from N, O and S, but containing no more than one O or S
atom, the C.sub.1-6alk and ring being substituted by 0, 1, 2 or 3
substituents independently selected from halo, oxo, C.sub.1-6alk,
C.sub.1-6alkOH, C.sub.1-6alk-C(.dbd.O)R.sup.a,
C.sub.1-6alk-C(.dbd.O)OR.sup.a, C.sub.1-4haloalk, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, .dbd.S, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing
0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but
containing no more than one O or S atom, and substituted by 0, 1, 2
or 3 groups selected from halo, oxo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a; R.sup.2 is H, halo, cyano, R.sup.c,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalk, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 halo substituents and additionally
substituted by 0 or 1 substituents selected from R.sup.c; R.sup.3
is H, C.sub.1-8alk, C.sub.1-8alkOH, C.sub.1-4haloalk, halo, cyano,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a, or
--NR.sup.aC.sub.2-6alkOR.sup.a; R.sup.4 is independently, at each
instance, H, C.sub.1-6alk, --C.sub.1-3haloalk, --OC.sub.1-6alk,
--OC.sub.1-3haloalk, --N(C.sub.1-6alk)C.sub.1-6alk,
--NHC.sub.1-6alk, --NC(.dbd.O)C.sub.1-6alk,
--N(C.sub.1-6alk)C.sub.1-6alk, F, Cl, Br, CN, OH or NH.sub.2; or
R.sup.3 and R.sup.4 together form a four-atom unsaturated bridge
containing 0 or 1N atoms, wherein the bridge is substituted by 0, 1
or 2 R.sup.5 substituents; R.sup.5 is independently, in each
instance, halo, OR.sup.a, CH.sub.3 or CF.sub.3; R.sup.6 is F,
C.sub.1-6alk, or OR.sup.a; R.sup.a is independently, at each
instance, H or R.sup.b; R.sup.b is independently, at each instance,
phenyl, benzyl or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk
being substituted by 0, 1, 2 or 3 substituents selected from halo,
oxo, C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH,
--NH.sub.2, --OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk,
and --N(C.sub.1-4alk)C.sub.1-4alk; and R.sup.c is independently, at
each instance, a saturated, partially saturated or unsaturated 4-,
5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4
heteroatoms selected from N, O and S, wherein the C.sub.1-6alkyl
and ring are substituted by 0 or 1 oxo groups substituted by 0, 1,
2 or 3 substituents selected from C.sub.1-8alk, C.sub.1-4haloalk,
halo and cyano.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] This application is a divisional of, and claims priority to,
U.S. patent application Ser. No. 13/529,860, filed on Jun. 21,
2012, pending, which claims the benefit of, and priority to, U.S.
Provisional Application No. 61/500,843, filed on Jun. 24, 2011,
both of which are hereby incorporated by reference in their
entireties and for all purposes as if fully set forth herein.
FIELD OF THE INVENTION
[0002] The present invention relates to compounds that have TRPM8
antagonist properties and are useful in preparing medicaments and
compositions and in treating diseases and conditions such as those
mediated by TRPM8. The compounds and compositions may be used to
treat various diseases or conditions modulated by TRPM8 such as,
but not limited to, migraines and neuropathic pain.
BACKGROUND OF THE INVENTION
[0003] Cold sensation is derived from activation of the
somatosensory system by a cold stimulus. Calcium imaging and patch
clamp experiments in dissociated trigeminal and dorsal root ganglia
neurons have revealed cold stimuli induced calcium influx,
suggesting the direct opening of a calcium-permeable ion channels
by cold (Thut et al., 2003; Reid, 2005). A recently cloned
non-selective cation channel, TRPM8 (transient receptor potential
melastatin 8) or trp-p8 (identified as a prostate-specific gene,
up-regulated in prostate cancer and other malignancies, (Tsavaler
et al., 2001)) is activated by cold stimulus of 10 to 24.degree. C.
temperature (McKemy et al., 2002; Peier et al., 2002). In addition,
TRPM8 is also activated by compounds that elicit cool sensation
such as menthol, icilin (AG-3-5) (McKemy et al., 2002), and the
endogenous lipid PIP.sub.2 (Rohacs et al., 2005). Correlating with
the cold sensitivity of both A delta and C-fibers, TRPM8 is highly
expressed in sensory neurons of the trigeminal and dorsal root
ganglia (McKemy et al., 2002; Peier et al., 2002; Thut et al.,
2003). TRPM8 is also expressed in nerve fibers innervating urinary
bladder in guinea pigs (Tsukimi et al., 2005) and humans (Mukerji
et al., 2006) and believed to contribute to the bladder
hypersensitivity.
[0004] Activation mechanism of TRPM8 by menthol and icilin appears
to differ. Icilin requires calcium for robust activation of TRPM8,
whereas menthol and cold do not (Chuang et al., 2004). Typically,
activation by all these agonists follows a period of
calcium-dependent desensitization. The domain swap analysis of
chicken and rat TRPM8 and further mutational studies revealed that
determinants of icilin sensitivity map to a region of TRPM8 that
corresponds to the capsaicin binding site in TRPM1 transmembrane
domain 3 to 4 region (Chuang et al., 2004).
[0005] Cold allodynia and mechanical hyperalgesia are associated
with neuropathic pain in humans and in rodent models of neuropathic
and chemotherapy-induced pain. TRPM8 is shown to mediate the
analgesia by agonists such as menthol and icilin (by
desensitization of the receptor) during experimental neuropathic
pain in rodents (Proudfoot et al., 2006). Further, attenuation of
cold sensation and cold allodynia after chronic constriction injury
model of neuropathic pain in TRPM8 knockout mice (Colburn et al.,
2007; Dhaka et al., 2007) suggests that antagonists of TRPM8 may be
considered as pain therapeutics for chemotherapy-induced pain,
neuropathic pain and bladder disorders.
[0006] Mint oil that contains menthol, an agonist of TRPM8 has been
reported to alleviate pain in post-herpetic neuralgia (Davies et
al., 2002), a neuropathic pain condition. Furthermore, oral or
intracerebroventricular injection of menthol decreased nociceptive
responses to hot-plate test and acetic acid-induced writhing in
mice (Galeotti et al., 2002). These responses are believed to be
mediated by the activation and desensitization of the TRPM8. These
observations and the knockout mice studies indicate that TRPM8
modulation by antagonists might be beneficial for patients
experiencing neuropathic pain.
[0007] A need exists for TRPM8 antagonist compounds that can be
used to treat diseases and conditions mediated by TRPM8 such as,
but not limited to, migraines and neuropathic pain and those other
conditions described herein.
SUMMARY OF THE INVENTION
[0008] The present invention comprises a new class of compounds
useful in the treatment of diseases, such as TRPM8-mediated
diseases and other maladies, such as inflammatory or neuropathic
pain and diseases involving sensory nerve function such as asthma,
rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders,
urinary incontinence, migraine and psoriasis. In particular, the
compounds of the invention are useful for the treatment of acute,
inflammatory and neuropathic pain, dental pain, general headache,
migraine, cluster headache, mixed-vascular and non-vascular
syndromes, tension headache, general inflammation, arthritis,
rheumatic diseases, osteoarthritis, inflammatory bowel disorders,
anxiety, depression, inflammatory eye disorders, inflammatory or
unstable bladder disorders, psoriasis, skin complaints with
inflammatory components, chronic inflammatory conditions,
inflammatory pain and associated hyperalgesia and allodynia,
neuropathic pain and associated hyperalgesia and allodynia,
diabetic neuropathy pain, causalgia, sympathetically maintained
pain, deafferentation syndromes, asthma, epithelial tissue damage
or dysfunction, herpes simplex, disturbances of visceral motility
at respiratory, genitourinary, gastrointestinal or vascular
regions, wounds, burns, allergic skin reactions, pruritus,
vitiligo, general gastrointestinal disorders, gastric ulceration,
duodenal ulcers, diarrhea, gastric lesions induced by necrotising
agents, hair growth, vasomotor or allergic rhinitis, bronchial
disorders or bladder disorders. Accordingly, the invention also
comprises pharmaceutical compositions comprising the compounds,
methods for the treatment of TRPM8-receptor-mediated diseases, such
as inflammatory or neuropathic pain, asthma, rheumatoid arthritis,
osteoarthritis, inflammatory bowel disorders, urinary incontinence,
migraine and psoriasis diseases, using the compounds and
compositions of the invention, and intermediates and processes
useful for the preparation of the compounds of the invention.
[0009] In one aspect, the compounds of the invention are
represented by the following general structure:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, X.sup.1, X.sup.2, m
and n are defined below.
[0010] In another aspect, the invention provides compounds of
Formula I having the structure:
##STR00003##
a pharmaceutically-acceptable salt thereof, a tautomer thereof, a
pharmaceutically-acceptable salt of the tautomer, a stereoisomer
thereof, or a mixture thereof, wherein:
[0011] m is 0, 1, 2 or 3;
[0012] n is 0 or 1;
[0013] X.sup.1 is C(R.sup.4) or N;
[0014] X.sup.2 is CH, CF, or N;
[0015] R.sup.1 is C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S,
but containing no more than one O or S atom, the C.sub.1-6alk and
ring being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-6alkOH,
C.sub.1-6alk-C(.dbd.O)R.sup.a, C.sub.1-6alk-C(.dbd.O)OR.sup.a,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, .dbd.S, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing
0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but
containing no more than one O or S atom, and substituted by 0, 1, 2
or 3 groups selected from halo, oxo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0016] R.sup.2 is H, halo, cyano, R.sup.c, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalk, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 halo substituents and additionally
substituted by 0 or 1 substituents selected from R.sup.c;
[0017] R.sup.3 is H, C.sub.1-8alk, C.sub.1-8alkOH,
C.sub.1-4haloalk, halo, cyano, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a;
[0018] R.sup.4 is independently, at each instance, H, C.sub.1-6alk,
--C.sub.1-3haloalk, --OC.sub.1-6alk, --OC.sub.1-3haloalk,
--N(C.sub.1-6alk)C.sub.1-6alk, --NHC.sub.1-6alk,
--NC(.dbd.O)C.sub.1-6alk, --N(C.sub.1-6alk)C.sub.1-6alk, F, Cl, Br,
CN, OH or NH.sub.2; or R.sup.3 and R.sup.4 together form a
four-atom unsaturated bridge containing 0 or 1N atoms, wherein the
bridge is substituted by 0, 1 or 2 R.sup.5 substituents;
[0019] R.sup.5 is independently, in each instance, halo, OR.sup.a,
CH.sub.3 or CF.sub.3;
[0020] R.sup.6 is F, C.sub.1-6alk, or OR.sup.a;
[0021] R.sup.a is independently, at each instance, H or
R.sup.b;
[0022] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo, oxo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH, --NH.sub.2,
--OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0023] R.sup.c is independently, at each instance, a saturated,
partially saturated or unsaturated 4-, 5- or 6-membered monocyclic
ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and
S, wherein the C.sub.1-6alkyl and ring are substituted by 0 or 1
oxo groups substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-8alk, C.sub.1-4haloalk, halo and cyano.
[0024] In some such embodiments, the compound of Formula I has the
Formula IA:
##STR00004##
[0025] In some embodiments of the compounds of Formula IA,
[0026] X.sup.2 is selected from CH or N;
[0027] R.sup.1 is selected from C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S,
but containing no more than one O or S atom, the C.sub.1-6alk and
ring being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring
substituted by 0, 1, 2 or 3 groups selected from halo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0028] R.sup.3 is H, C.sub.1-8alk, C.sub.1-4haloalk, halo, cyano,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.3 and R.sup.4 together
form a four-atom unsaturated bridge containing 0 or 1N atoms,
wherein the bridge is substituted by 0, 1 or 2 R.sup.5
substituents;
[0029] R.sup.5 is independently, in each instance, F, CH.sub.3 or
CF.sub.3; and
[0030] R.sup.6 is F.
[0031] In another aspect, the invention provides pharmaceutical
compositions that include the compound of any of the embodiments or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, and a pharmaceutically-acceptable diluent or
carrier.
[0032] In yet another aspect, the invention provies methods of
treating acute, inflammatory and neuropathic pain, dental pain,
general headache, migraine, cluster headache, mixed-vascular and
non-vascular syndromes, tension headache, general inflammation,
arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel
disorders, depression, anxiety, inflammatory eye disorders,
inflammatory or unstable bladder disorders, psoriasis, skin
complaints with inflammatory components, chronic inflammatory
conditions, inflammatory pain and associated hyperalgesia and
allodynia, neuropathic pain and associated hyperalgesia and
allodynia, diabetic neuropathy pain, causalgia, sympathetically
maintained pain, deafferentation syndromes, asthma, epithelial
tissue damage or dysfunction, herpes simplex, disturbances of
visceral motility at respiratory, genitourinary, gastrointestinal
or vascular regions, wounds, burns, allergic skin reactions,
pruritus, vitiligo, general gastrointestinal disorders, gastric
ulceration, duodenal ulcers, diarrhea, gastric lesions induced by
necrotising agents, hair growth, vasomotor or allergic rhinitis,
bronchial disorders or bladder disorders in a subject. Such methods
typically include administering the compound according to any of
the embodiments or the pharmaceutically-acceptable salt thereof,
the tautomer thereof, the pharmaceutically-acceptable salt of the
tautomer, or the mixture thereof to the subject. In some such
embodiments, the subject is suffering from neuropathic paid whereas
in other embodiments the subject is suffering from migraines or
migraine pain.
[0033] The compounds of the invention may also be used to prepare
pharmaceutical compositions and medicaments. Therefore, in some
embodiments, the invention provides the use of the compound
according to any of the embodiments or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof in the preparation of a medicament.
[0034] In another aspect, the invention provides the use of the
compound according to any of the embodiments or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof for treating acute, inflammatory and neuropathic pain,
dental pain, general headache, migraine, cluster headache,
mixed-vascular and non-vascular syndromes, tension headache,
general inflammation, arthritis, rheumatic diseases,
osteoarthritis, inflammatory bowel disorders, depression, anxiety,
inflammatory eye disorders, inflammatory or unstable bladder
disorders, psoriasis, skin complaints with inflammatory components,
chronic inflammatory conditions, inflammatory pain and associated
hyperalgesia and allodynia, neuropathic pain and associated
hyperalgesia and allodynia, diabetic neuropathy pain, causalgia,
sympathetically maintained pain, deafferentation syndromes, asthma,
epithelial tissue damage or dysfunction, herpes simplex,
disturbances of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritus, vitiligo, general gastrointestinal disorders,
gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
induced by necrotising agents, hair growth, vasomotor or allergic
rhinitis, bronchial disorders or bladder disorders in a subject. In
some such embodiments, the compound is used to treat neuropathic
paid. In other embodiments, the compound is used to treat migraines
or migraine pain
[0035] 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, patent applications
and other publications recited herein are hereby incorporated by
reference in their entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The compounds of this invention may have in general several
asymmetric centers and are typically depicted in the form of
racemic mixtures. This invention is intended to encompass racemic
mixtures, partially racemic mixtures and separate enantiomers and
diasteromers.
[0037] Unless otherwise specified, the following definitions apply
to terms found in the specification and claims:
"C.sub..alpha.-.beta.alk" means an alkyl group comprising a minimum
of .alpha. and a maximum of .beta. carbon atoms in a branched,
cyclical or linear relationship or any combination of the three,
wherein .alpha. and .beta. represent integers. The alkyl groups
described in this section may also contain one or two double or
triple bonds. A designation of C.sub.0alk indicates a direct bond.
Examples of C.sub.1-6alkyl include, but are not limited to the
following:
##STR00005##
Where the term "C.sub..alpha.-.beta.alkyl" and
"C.sub..alpha.-.beta.cycloalkyl" are used, they relate to acyclic
saturated alkyls and cyclic saturated alkyls, respectively.
[0038] "Benzo group", alone or in combination, means the divalent
radical C.sub.4H.sub.4.dbd., one representation of which is
--CH.dbd.CH--CH.dbd.CH--, that when vicinally attached to another
ring forms a benzene-like ring--for example tetrahydronaphthylene,
indole and the like.
[0039] The terms "oxo" and "thioxo" represent the groups .dbd.O (as
in carbonyl) and .dbd.S (as in thiocarbonyl), respectively.
[0040] The term "cyano" refers to a nitrile group which may be
written as --C.dbd.N.
[0041] "Halo" or "halogen" means a halogen atoms selected from F,
Cl, Br and I.
[0042] "C.sub.V-Whaloalk" means an alk group, as described above,
wherein any number, but at least one, of the hydrogen atoms
attached to the alk chain are replaced by F, Cl, Br or I.
[0043] The group N(R.sup.a)R.sup.a and the like include
substituents where the two R.sup.a groups together form a ring,
optionally including a N, O or S atom, and include groups such
as:
##STR00006##
[0044] The group N(C.sub..alpha.-.beta.alk)C.sub..alpha.-.beta.alk,
wherein .alpha. and .beta. are as defined above, include
substituents where the two C.sub..alpha.-.beta.alk groups together
form a ring, optionally including a N, O or S atom, and include
groups such as:
##STR00007##
[0045] "Heterocycle" means a ring comprising at least one carbon
atom and at least one other atom selected from N, O and S. Examples
of heterocycles that may be found in the claims include, but are
not limited to, the following:
##STR00008## ##STR00009##
[0046] "Pharmaceutically-acceptable salt" means a salt prepared by
conventional means, and are well known by those skilled in the art.
The "pharmacologically acceptable salts" include basic salts of
inorganic and organic acids, including but not limited to
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic
acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric
acid, succinic acid, maleic acid, salicylic acid, benzoic acid,
phenylacetic acid, mandelic acid and the like. When compounds of
the invention include an acidic function such as a carboxy group,
then suitable pharmaceutically acceptable cation pairs for the
carboxy group are well known to those skilled in the art and
include alkaline, alkaline earth, ammonium, quaternary ammonium
cations and the like. For additional examples of "pharmacologically
acceptable salts," see infra and Berge et al., J. Pharm. Sci. 66:1
(1977).
[0047] "Saturated, partially-saturated or unsaturated" includes
substituents saturated with hydrogens, substituents completely
unsaturated with hydrogens and substituents partially saturated
with hydrogens.
[0048] "Leaving group" generally refers to groups readily
displaceable by a nucleophile, such as an amine, a thiol or an
alcohol nucleophile. Such leaving nucleophile, such as an amine, a
thiol or an alcohol nucleophile. Such leaving groups are well known
in the art. Examples of such leaving groups include, but are not
limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides,
triflates, tosylates and the like. Preferred leaving groups are
indicated herein where appropriate.
[0049] "Protecting group" generally refers to groups well known in
the art which are used to prevent selected reactive groups, such as
carboxy, amino, hydroxy, mercapto and the like, from undergoing
undesired reactions, such as nucleophilic, electrophilic,
oxidation, reduction and the like. Preferred protecting groups are
indicated herein where appropriate. Examples of amino protecting
groups include, but are not limited to, aralkyl, substituted
aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl,
allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl,
silyl and the like. Examples of aralkyl include, but are not
limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl,
which can be optionally substituted with halogen, alkyl, alkoxy,
hydroxy, nitro, acylamino, acyl and the like, and salts, such as
phosphonium and ammonium salts. Examples of aryl groups include
phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),
phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl
or substituted cycloalkylenylalkyl radicals, preferably have 6-10
carbon atoms, include, but are not limited to, cyclohexenyl methyl
and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl
groups include benzyloxycarbonyl, t-butoxycarbonyl,
iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl,
trifluoroacetyl, trichloro acetyl, phthaloyl and the like. A
mixture of protecting groups can be used to protect the same amino
group, such as a primary amino group can be protected by both an
aralkyl group and an aralkoxycarbonyl group. Amino protecting
groups can also form a heterocyclic ring with the nitrogen to which
they are attached, for example, 1,2-bis(methylene)benzene,
phthalimidyl, succinimidyl, maleimidyl and the like and where these
heterocyclic groups can further include adjoining aryl and
cycloalkyl rings. In addition, the heterocyclic groups can be
mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino
groups may also be protected against undesired reactions, such as
oxidation, through the formation of an addition salt, such as
hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the
like. Many of the amino protecting groups are also suitable for
protecting carboxy, hydroxy and mercapto groups. For example,
aralkyl groups. Alkyl groups are also suitable groups for
protecting hydroxy and mercapto groups, such as tert-butyl.
[0050] Silyl protecting groups are silicon atoms optionally
substituted by one or more alkyl, aryl and aralkyl groups. Suitable
silyl protecting groups include, but are not limited to,
trimethylsilyl, triethylsilyl, triisopropylsilyl,
tert-butyldimethylsilyl, dimethylphenylsilyl,
1,2-bis(dimethylsilyl)benzene, 1,2-bis(dimethylsilyl)ethane and
diphenylmethylsilyl. Silylation of an amino groups provide mono- or
di-silylamino groups. Silylation of aminoalcohol compounds can lead
to a N,N,O-trisilyl derivative. Removal of the silyl function from
a silyl ether function is readily accomplished by treatment with,
for example, a metal hydroxide or ammonium fluoride reagent, either
as a discrete reaction step or in situ during a reaction with the
alcohol group. Suitable silylating agents are, for example,
trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride,
phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or
their combination products with imidazole or DMF. Methods for
silylation of amines and removal of silyl protecting groups are
well known to those skilled in the art. Methods of preparation of
these amine derivatives from corresponding amino acids, amino acid
amides or amino acid esters are also well known to those skilled in
the art of organic chemistry including amino acid/amino acid ester
or aminoalcohol chemistry.
[0051] Protecting groups are removed under conditions which will
not affect the remaining portion of the molecule. These methods are
well known in the art and include acid hydrolysis, hydrogenolysis
and the like. A preferred method involves removal of a protecting
group, such as removal of a benzyloxycarbonyl group by
hydrogenolysis utilizing palladium on carbon in a suitable solvent
system such as an alcohol, acetic acid, and the like or mixtures
thereof. A t-butoxycarbonyl protecting group can be removed
utilizing an inorganic or organic acid, such as HCl or
trifluoroacetic acid, in a suitable solvent system, such as dioxane
or methylene chloride. The resulting amino salt can readily be
neutralized to yield the free amine. Carboxy protecting group, such
as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the
like, can be removed under hydrolysis and hydrogenolysis conditions
well known to those skilled in the art.
[0052] It should be noted that compounds of the invention may
contain groups that may exist in tautomeric forms, such as cyclic
and acyclic amidine and guanidine groups, heteroatom substituted
heteroaryl groups (Y'.dbd.O, S, NR), and the like, which are
illustrated in the following examples:
##STR00010##
and though one form is named, described, displayed and/or claimed
herein, all the tautomeric forms are intended to be inherently
included in such name, description, display and/or claim.
[0053] Prodrugs of the compounds of this invention are also
contemplated by this invention. A prodrug is an active or inactive
compound that is modified chemically through in vivo physiological
action, such as hydrolysis, metabolism and the like, into a
compound of this invention following administration of the prodrug
to a patient. The suitability and techniques involved in making and
using prodrugs are well known by those skilled in the art. For a
general discussion of prodrugs involving esters see Svensson and
Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of
Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion
include a variety of esters, such as alkyl (for example, methyl,
ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example,
benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example,
pivaloyloxymethyl). Amines have been masked as
arylcarbonyloxymethyl substituted derivatives which are cleaved by
esterases in vivo releasing the free drug and formaldehyde
(Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an
acidic NH group, such as imidazole, imide, indole and the like,
have been masked with N-acyloxymethyl groups (Bundgaard Design of
Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as
esters and ethers. EP 039,051 (Sloan and Little, Apr. 11, 1981)
discloses Mannich-base hydroxamic acid prodrugs, their preparation
and use.
[0054] The specification and claims contain listing of species
using the language like "selected from . . . and . . . " and "is .
. . or . . . " (sometimes referred to as Markush groups). When this
language is used in this application, unless otherwise stated it is
meant to include the group as a whole, or any single members
thereof, or any subgroups thereof. The use of this language is
merely for shorthand purposes and is not meant in any way to limit
the removal of individual elements or subgroups as needed.
[0055] One aspect of the current invention relates to compounds
having the general structure:
##STR00011##
or any pharmaceutically-acceptable salt thereof, wherein:
[0056] m is 0, 1, 2 or 3;
[0057] n is 0 or 1;
[0058] X.sup.1 is C(R.sup.4) or N;
[0059] X.sup.2 is C or N;
[0060] Y is NH or O;
[0061] R.sup.1 is selected from C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, the C.sub.1-6alk and ring
being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring
substituted by 0, 1, 2 or 3 groups selected from halo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0062] R.sup.2 is selected from H, halo, cyano, R.sup.c,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalk, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, or R.sup.2 is C.sup.1-6alk
substituted by 0, 1, 2 or 3 halo substituents and additionally
substituted by 0 or 1 substituents selected from R.sup.c;
[0063] R.sup.3 is H, C.sub.1-8alk, C.sub.1-4haloalk, halo, cyano,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a;
[0064] R.sup.4 is independently, at each instance, H, C.sub.1-6alk,
--C.sub.1-3haloalk, --OC.sub.1-6alk, --OC.sub.1-3haloalk,
--N(C.sub.1-6alk)C.sub.1-6alk, --NHC.sub.1-6alk,
--NC(.dbd.O)C.sub.1-6alk, --N(C.sub.1-6alk)C.sub.1-6alk, F, Cl, Br,
CN, OH or NH.sub.2; or R.sup.3 and R.sup.4 together form a
four-atom unsaturated bridge containing 0 or 1N atoms, wherein the
bridge is substituted by 0, 1 or 2 R.sup.5 substituents;
[0065] R.sup.5 is independently, in each instance, F, CH.sub.3 or
CF.sub.3;
[0066] R.sup.6 is F;
[0067] R.sup.a is independently, at each instance, H or
R.sup.b;
[0068] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo, oxo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH, --NH.sub.2,
--OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0069] R.sup.c is independently, at each instance, a saturated,
partially saturated or unsaturated 4-, 5- or 6-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,
wherein the C.sub.1-6alkyl and ring are substituted by 0 or 1 oxo
groups substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-8alk, C.sub.1-4haloalk, halo and cyano.
[0070] Another aspect of the current invention relates to compounds
having the general structure:
##STR00012##
or any pharmaceutically-acceptable salt thereof, wherein:
[0071] m is 0, 1, 2 or 3;
[0072] n is 0 or 1;
[0073] X.sup.1 is C(R.sup.4) or N;
[0074] R.sup.1 is selected from C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, the C.sub.1-6alk and ring
being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring
substituted by 0, 1, 2 or 3 groups selected from halo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0075] R.sup.2 is selected from H, halo, cyano, R.sup.c,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalk, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 halo substituents and additionally
substituted by 0 or 1 substituents selected from R.sup.c;
[0076] R.sup.3 is H, C.sub.1-8alk, C.sub.1-4haloalk, halo, cyano,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a;
[0077] R.sup.4 is independently, at each instance, H, C.sub.1-6alk,
--C.sub.1-3haloalk, --OC.sub.1-6alk, --OC.sub.1-3haloalk,
--N(C.sub.1-6alk)C.sub.1-6alk, --NHC.sub.1-6alk,
--NC(.dbd.O)C.sub.1-6alk, --N(C.sub.1-6alk)C.sub.1-6alk, F, Cl, Br,
CN, OH or NH.sub.2; or R.sup.3 and R.sup.4 together form a
four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the
bridge is substituted by 0, 1 or 2 R.sup.5 substituents;
[0078] R.sup.5 is independently, in each instance, F, CH.sub.3 or
CF.sub.3;
[0079] R.sup.6 is F;
[0080] R.sup.a is independently, at each instance, H or R.sup.b;
[0081] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo, oxo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH, --NH.sub.2,
--OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0082] R.sup.c is independently, at each instance, a saturated,
partially saturated or unsaturated 4-, 5- or 6-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,
wherein the C.sub.1-6alkyl and ring are substituted by 0 or 1 oxo
groups substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-6alk, C.sub.1-4haloalk, halo and cyano.
[0083] Another aspect of the current invention relates to compounds
having the general structure:
##STR00013##
or any pharmaceutically-acceptable salt thereof, wherein:
[0084] m is 0, 1, 2 or 3;
[0085] n is 0 or 1;
[0086] X.sup.2 is C or N;
[0087] R.sup.1 is selected from C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, the C.sub.1-6alk and ring
being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring
substituted by 0, 1, 2 or 3 groups selected from halo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0088] R.sup.2 is selected from H, halo, cyano, R.sup.c,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalk, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, or R.sup.2 is C.sup.1-6alk
substituted by 0, 1, 2 or 3 halo substituents and additionally
substituted by 0 or 1 substituents selected from R.sup.c;
[0089] R.sup.3 is H, C.sub.1-8alk, C.sub.1-4haloalk, halo, cyano,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a; [0090] R.sup.4 is independently, at
each instance, H, C.sub.1-6alk, --C.sub.1-3haloalk,
--OC.sub.1-6alk, --OC.sub.1-3haloalk,
--N(C.sub.1-6alk)C.sub.1-6alk, --NHC.sub.1-6alk,
--NC(.dbd.O)C.sub.1-6alk, --N(C.sub.1-6alk)C.sub.1-6alk, F, Cl, Br,
CN, OH or NH.sub.2;
[0091] R.sup.5 is F, CH.sub.3 or CF.sub.3;
[0092] R.sup.6 is F;
[0093] R.sup.a is independently, at each instance, H or
R.sup.b;
[0094] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo, oxo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH, --NH.sub.2,
--OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0095] R.sup.c is independently, at each instance, a saturated,
partially saturated or unsaturated 4-, 5- or 6-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,
wherein the C.sub.1-6alkyl and ring are substituted by 0 or 1 oxo
groups substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-8alk, C.sub.1-4haloalk, halo and cyano.
[0096] Another aspect of the current invention relates to compounds
having the general structure:
##STR00014##
or any pharmaceutically-acceptable salt thereof, wherein:
[0097] m is 0, 1, 2 or 3;
[0098] R.sup.1 is a direct-bonded, partially-saturated or
unsaturated 5- or 6-membered monocyclic ring containing 1 or 2
atoms selected from N, O and S, but containing no more than one O
or S atom, the C.sub.1-6alk and ring being substituted by 0, 1, 2
or 3 substituents independently selected from halo, oxo,
C.sub.1-6alk, C.sub.1-4haloalk and cyano;
[0099] R.sup.2 is selected from F and CF.sub.3;
[0100] R.sup.3 is CH.sub.3, CF.sub.3, F or Cl;
[0101] R.sup.4 is H or F;
[0102] R.sup.6 is F;
[0103] R.sup.a is independently, at each instance, H or
R.sup.b;
[0104] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo, oxo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH, --NH.sub.2,
--OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0105] R.sup.c is independently, at each instance, a saturated,
partially saturated or unsaturated 4-, 5- or 6-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,
wherein the C.sub.1-6alkyl and ring are substituted by 0 or 1 oxo
groups substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-8alk, C.sub.1-4haloalk, halo and cyano.
[0106] Another aspect of the current invention relates to compounds
having the general structure:
##STR00015##
or any pharmaceutically-acceptable salt thereof, wherein:
[0107] m is 0, 1, 2 or 3;
[0108] R.sup.1 is a direct-bonded, partially-saturated or
unsaturated 5- or 6-membered monocyclic ring containing 1 or 2
atoms selected from N, O and S, but containing no more than one O
or S atom, the C.sub.1-6alk and ring being substituted by 0, 1, 2
or 3 substituents independently selected from halo, oxo,
C.sub.1-6alk, C.sub.1-4haloalk and cyano; and
[0109] R.sup.2 is selected from F and CF.sub.3.
[0110] Another aspect of the current invention relates to compounds
having the general structure:
##STR00016##
or any pharmaceutically-acceptable salt thereof, wherein:
[0111] m is 0, 1, 2 or 3;
[0112] n is 0 or 1;
[0113] X.sup.1 is C(R.sup.4) or N;
[0114] X.sup.2 is C or N;
[0115] Y is NH or O;
[0116] R.sup.1 is selected from C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, the C.sub.1-6alk and ring
being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring
substituted by 0, 1, 2 or 3 groups selected from halo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0117] R.sup.2 is selected from H, halo, cyano, R.sup.c,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-4haloalk, halo, cyano, nitro, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, or R.sup.2 is C.sup.1-6 alk
substituted by 0, 1, 2 or 3 halo substituents and additionally
substituted by 0 or 1 substituents selected from R.sup.c;
[0118] R.sup.3 is H, C.sub.1-8alk, C.sub.1-4haloalk, halo, cyano,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a;
[0119] R.sup.4 is independently, at each instance, H, C.sub.1-6alk,
--C.sub.1-3haloalk, --OC.sub.1-6alk, --OC.sub.1-3haloalk,
--N(C.sub.1-6alk)C.sub.1-6alk, --NHC.sub.1-6alk,
--NC(.dbd.O)C.sub.1-6alk, --N(C.sub.1-6alk)C.sub.1-6alk, F, Cl, Br,
CN, OH or NH.sub.2;
[0120] R.sup.5 is F, CH.sub.3 or CF.sub.3;
[0121] R.sup.6 is F;
[0122] R.sup.a is independently, at each instance, H or
R.sup.b;
[0123] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo, oxo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH, --NH.sub.2,
--OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0124] R.sup.c is independently, at each instance, a saturated,
partially saturated or unsaturated 4-, 5- or 6-membered monocyclic
ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S,
wherein the C.sub.1-6alkyl and ring are substituted by 0 or 1 oxo
groups substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-8alk, C.sub.1-4haloalk, halo and cyano.
[0125] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is C.sub.1-6alk substituted by 0, 1, 2
or 3 substituents independently selected from halo, oxo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a.
[0126] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is C.sub.1-2alk-linked saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O
and S, but containing no more than one O or S atom, the ring being
substituted by 0, 1, 2 or 3 substituents independently selected
from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a.
[0127] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is a direct-bonded saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, but
containing no more than one O or S atom, the ring being substituted
by 0, 1, 2 or 3 substituents independently selected from halo, oxo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring
substituted by 0, 1, 2 or 3 groups selected from halo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a.
[0128] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is a direct-bonded partially-saturated
or unsaturated 5- or 6-membered monocyclic ring containing 1, 2, 3
or 4 atoms selected from N, O and S, but containing no more than
one O or S atom, the ring being substituted by 0, 1, 2 or 3
substituents independently selected from halo, oxo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a.
[0129] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is a direct-bonded partially-saturated
or unsaturated 6-membered monocyclic ring containing 1 or 2 N
atoms, substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano and
--OR.sup.a.
[0130] In another embodiment, in conjunction with any above or
below embodiments, R.sup.1 is a direct-bonded unsaturated
10-membered bicyclic ring containing 1 or 2 N atoms, substituted by
0, 1, 2 or 3 substituents independently selected from halo, oxo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano and --OR.sup.a.
[0131] Another aspect of the invention relates to a method of
treating acute, inflammatory and neuropathic pain, dental pain,
general headache, migraine, cluster headache, mixed-vascular and
non-vascular syndromes, tension headache, general inflammation,
arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel
disorders, depression, anxiety, inflammatory eye disorders,
inflammatory or unstable bladder disorders, psoriasis, skin
complaints with inflammatory components, chronic inflammatory
conditions, inflammatory pain and associated hyperalgesia and
allodynia, neuropathic pain and associated hyperalgesia and
allodynia, diabetic neuropathy pain, causalgia, sympathetically
maintained pain, deafferentation syndromes, asthma, epithelial
tissue damage or dysfunction, herpes simplex, disturbances of
visceral motility at respiratory, genitourinary, gastrointestinal
or vascular regions, wounds, burns, allergic skin reactions,
pruritus, vitiligo, general gastrointestinal disorders, gastric
ulceration, duodenal ulcers, diarrhea, gastric lesions induced by
necrotising agents, hair growth, vasomotor or allergic rhinitis,
bronchial disorders or bladder disorders, comprising the step of
administering a compound as described above.
[0132] Another aspect of the invention relates to a pharmaceutical
composition comprising a compound according to Claim 1 and a
pharmaceutically-acceptable diluent or carrier.
[0133] Another aspect of the invention relates to the use of a
compound according to any of the above embodiments as a
medicament.
[0134] Another aspect of the invention relates to the use of a
compound according to any of the above embodiments in the
manufacture of a medicament for the treatment of acute,
inflammatory and neuropathic pain, dental pain, general headache,
migraine, cluster headache, mixed-vascular and non-vascular
syndromes, tension headache, general inflammation, arthritis,
rheumatic diseases, osteoarthritis, inflammatory bowel disorders,
anxiety, depression, inflammatory eye disorders, inflammatory or
unstable bladder disorders, psoriasis, skin complaints with
inflammatory components, chronic inflammatory conditions,
inflammatory pain and associated hyperalgesia and allodynia,
neuropathic pain and associated hyperalgesia and allodynia,
diabetic neuropathy pain, causalgia, sympathetically maintained
pain, deafferentation syndromes, asthma, epithelial tissue damage
or dysfunction, herpes simplex, disturbances of visceral motility
at respiratory, genitourinary, gastrointestinal or vascular
regions, wounds, burns, allergic skin reactions, pruritus,
vitiligo, general gastrointestinal disorders, gastric ulceration,
duodenal ulcers, diarrhea, gastric lesions induced by necrotising
agents, hair growth, vasomotor or allergic rhinitis, bronchial
disorders or bladder disorders.
ADDITIONAL EMBODIMENTS
[0135] The embodiments listed below are presented in numbered form
for convenience and are in addition to the embodiments described
above.
[0136] 1. In a first additional embodiment, the invention procides
a compound of Formula I having the structure:
##STR00017##
a pharmaceutically-acceptable salt thereof, a tautomer thereof, a
pharmaceutically-acceptable salt of the tautomer, a stereoisomer
thereof, or a mixture thereof, wherein:
[0137] m is 0, 1, 2 or 3;
[0138] n is 0 or 1;
[0139] X.sup.1 is C(R.sup.4) or N;
[0140] X.sup.2 is CH, CF, or N;
[0141] R.sup.1 is C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S,
but containing no more than one O or S atom, the C.sub.1-6alk and
ring being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-6alkOH,
C.sub.1-6alk-C(.dbd.O)R.sup.a, C.sub.1-6alk-C(.dbd.O)OR.sup.a,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, .dbd.S, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing
0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but
containing no more than one O or S atom, and substituted by 0, 1, 2
or 3 groups selected from halo, oxo, C.sub.1-6alk,
C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0142] R.sup.2 is H, halo, cyano, R.sup.c, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a; or
[0143] R.sup.2 is C.sub.1-6alk substituted by 0, 1, 2 or 3
substituents selected from C.sub.1-4haloalk, halo, cyano, nitro,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)Rb --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, or R.sup.2 is C.sub.1-6alk
substituted by 0, 1, 2 or 3 halo substituents and additionally
substituted by 0 or 1 substituents selected from R.sup.c;
[0144] R.sup.3 is H, C.sub.1-8alk, C.sub.1-8alkOH,
C.sub.1-4haloalk, halo, cyano, --C(.dbd.O)R.sup.b,
--C(.dbd.O)OR.sup.b, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.b,
--OC(.dbd.O)NR.sup.aR.sup.a, --OC.sub.2-6alkNR.sup.aR.sup.a,
--OC.sub.2-6alkOR.sup.a, --SR.sup.a, --S(.dbd.O)R.sup.b,
--S(.dbd.O).sub.2R.sup.b, --S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.b,
--N(R.sup.a)C(.dbd.O)OR.sup.b, --N(R.sup.a)C(.dbd.)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a;
[0145] R.sup.4 is independently, at each instance, H, C.sub.1-6alk,
--C.sub.1-3haloalk, --OC.sub.1-6alk, --OC.sub.1-3haloalk,
--N(C.sub.1-6alk)C.sub.1-6alk, --NHC.sub.1-6alk,
--NC(.dbd.O)C.sub.1-6alk, --N(C.sub.1-6alk)C.sub.1-6alk, F, Cl, Br,
CN, OH or NH.sub.2; or R.sup.3 and R.sup.4 together form a
four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the
bridge is substituted by 0, 1 or 2 R.sup.5 substituents;
[0146] R.sup.5 is independently, in each instance, halo, OR.sup.a,
CH.sub.3 or CF.sub.3;
[0147] R.sup.6 is F, C.sub.1-6alk, or OR.sup.a;
[0148] R.sup.a is independently, at each instance, H or
R.sup.b;
[0149] R.sup.b is independently, at each instance, phenyl, benzyl
or C.sub.1-6alk, the phenyl, benzyl and C.sub.1-6alk being
substituted by 0, 1, 2 or 3 substituents selected from halo, oxo,
C.sub.1-4alk, C.sub.1-3haloalk, --OC.sub.1-4alk, --OH, --NH.sub.2,
--OC.sub.1-4alk, --OC.sub.1-4haloalk, --NHC.sub.1-4alk, and
--N(C.sub.1-4alk)C.sub.1-4alk; and
[0150] R.sup.c is independently, at each instance, a saturated,
partially saturated or unsaturated 4-, 5- or 6-membered monocyclic
ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and
S, wherein the C.sub.1-6alkyl and ring are substituted by 0 or 1
oxo groups substituted by 0, 1, 2 or 3 substituents selected from
C.sub.1-8alk, C.sub.1-4haloalk, halo and cyano.
[0151] 2. The compound of embodiment 1 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein the compound of Formula I has the Formula IA:
##STR00018##
[0152] 3. The compound of embodiment 2 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein
[0153] X.sup.2 is selected from CH or N;
[0154] R.sup.1 is selected from C.sub.1-6alk or a direct-bonded,
C.sub.1-2alk-linked, C.sub.1-2alkO-linked, saturated,
partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered
monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring
containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S,
but containing no more than one O or S atom, the C.sub.1-6alk and
ring being substituted by 0, 1, 2 or 3 substituents independently
selected from halo, oxo, C.sub.1-6alk, C.sub.1-4haloalk, cyano,
nitro, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.a, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC(.dbd.O)N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)R.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)OR.sup.a,
--S(.dbd.O).sub.2N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--NR.sup.aR.sup.a, --N(R.sup.a)C(.dbd.O)R.sup.a,
--N(R.sup.a)C(.dbd.O)OR.sup.a,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a and
--NR.sup.aC.sub.2-6alkOR.sup.a, wherein the ring is additionally
substituted by 0 or 1 directly bonded, SO.sub.2 linked, C(.dbd.O)
linked or CH.sub.2 linked saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring
substituted by 0, 1, 2 or 3 groups selected from halo,
C.sub.1-6alk, C.sub.1-4haloalk, cyano, nitro, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)NR.sup.aR.sup.a,
--C(.dbd.NR.sup.a)NR.sup.aR.sup.a, --OR.sup.a, --OC(.dbd.O)R.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.a, --S(.dbd.O).sub.2R.sup.a,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a, and
--N(R.sup.a)C(.dbd.O)R.sup.a;
[0155] R.sup.3 is H, C.sub.1-8alk, C.sub.1-4haloalk, halo, cyano,
--C(.dbd.O)R.sup.b, --C(.dbd.O)OR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.a, --C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--OR.sup.a, --OC(.dbd.O)R.sup.b, --OC(.dbd.O)NR.sup.aR.sup.a,
--OC.sub.2-6alkNR.sup.aR.sup.a, --OC.sub.2-6alkOR.sup.a,
--SR.sup.a, --S(.dbd.O)R.sup.b, --S(.dbd.O).sub.2R.sup.b,
--S(.dbd.O).sub.2NR.sup.aR.sup.a, --NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.O)R.sup.b, --N(R.sup.a)C(.dbd.O)OR.sup.b,
--N(R.sup.a)C(.dbd.O)NR.sup.aR.sup.a,
--N(R.sup.a)C(.dbd.NR.sup.a)NR.sup.aR.sup.a,
--N(R.sup.a)S(.dbd.O).sub.2R.sup.b,
--N(R.sup.a)S(.dbd.O).sub.2NR.sup.aR.sup.a,
--NR.sup.aC.sub.2-6alkNR.sup.aR.sup.a or
--NR.sup.aC.sub.2-6alkOR.sup.a; or R.sup.3 and R.sup.4 together
form a four-atom unsaturated bridge containing 0 or 1N atoms,
wherein the bridge is substituted by 0, 1 or 2 R.sup.5
substituents;
[0156] R.sup.5 is independently, in each instance, F, CH.sub.3 or
CF.sub.3; and
[0157] R.sup.6 is F.
[0158] 4. The compound of embodiment 3 or the
pharmaceutically-acceptable salt thereof.
[0159] 5. The compound of embodiment 1 or embodiment 2 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is the saturated, partially-saturated or
unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-,
10- or 11-membered bicyclic ring and the monocyclic or bicyclic
ring is substituted by 0, 1, 2, or 3 substituents, wherein the
substituents are selected from F, Cl, Br, I, oxo, cyano,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--C(H)(CH.sub.3).sub.2, --CH.sub.2C(H)(CH.sub.3).sub.2,
--CH.sub.2C(H).dbd.CH.sub.2, --CH.sub.2CO.sub.2H,
--CH.sub.2CF.sub.3, --C(OH)(CH.sub.3).sub.2,
--SO.sub.2N(H)CH.sub.3, --N(H)SO.sub.2CH.sub.3, --OCH.sub.3,
--OCF.sub.3, --OH, --OCH.sub.2CO.sub.2H, --CH.sub.2OH,
--CH.sub.2CH.sub.2OH, --CH.sub.2C(H)(CH.sub.3)OH, --CO.sub.2H,
--CO.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.3,
--CO.sub.2C(CH.sub.3).sub.3, --CO.sub.2NH.sub.2,
--CO.sub.2N(H)CH.sub.3, --SO.sub.2CH.sub.3, --OC(.dbd.O)CH.sub.3,
--NH.sub.2, --NHC(.dbd.O)CH.sub.3, --N(CH.sub.3).sub.2,
--N(H)CH.sub.2CH.sub.3, --CF.sub.3, --CHF.sub.2,
--CH.sub.2C(H)(CF.sub.3)OH, --CH.sub.2C(CH.sub.3).sub.2OH,
--CH.sub.2-phenyl, --C(.dbd.O)-phenyl, tetrazolyl, oxadiazolonyl,
pyridyl, oxetanyl,
##STR00019##
[0160] 6. The compound of embodiment 1 or embodiment 2 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a phenyl, pyridyl, pyridinonyl,
piperidinonyl, pyridazinonyl, pyrazinonyl, pyridazinyl,
pyrimidinyl, pyrazinyl, tetradyrofuranyl, tetrahydropyranyl,
thiazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, triazolyl,
oxazolyl, imidazolyl, pyrrolidinonyl, piperidinyl, cyclohexyl,
cyclohexanonyl, quinolinyl, isoquinolinyl, naphthyridinyl,
pyrrolopyridinyl, pyrrolopyrimidinyl, benzothiophenyl,
pyrazolopyrimidinyl, triazolopyrimidinyl, indazolyl,
tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl,
dihydropyrazolooxazinyl, indolinonyl, isoindolinonyl,
benzooxazolonyl, oxazolopyridinonyl, benzoimidazolonyl,
isoindolindionyl, tetrahydroquinolinyl, dihydroquinolinonyl,
benzooxazinonyl, dihydrobenzooxazinonyl, dihydroindenonyl,
benzothiazolyl, benzimidazolyl, imidazopyridinyl,
tetrazolopyridinyl, quinolinonyl, quinoxalinyl, or quinoxalindionyl
substituted by 0, 1, 2, or 3 substituents.
[0161] 7. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a phenyl substituted by 0, or 1
substituent.
[0162] 8. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a pyridinonyl substituted by 0, or 1
substituent.
[0163] 9. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a pyridyl substituted by 0, or 1
substituent.
[0164] 10. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a benzooxazolonyl substituted by 0, or
1 substituent.
[0165] 11. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a quinolinyl substituted by 0, or 1
substituent.
[0166] 12. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a benzimidazolyl substituted by 0, or 1
substituent.
[0167] 13. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a group of formula
##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024##
##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029##
##STR00030## ##STR00031## ##STR00032## ##STR00033##
and the symbol , when drawn across a bond, indicates the point of
attachment to the rest of the molecule.
[0168] 14. The compound of embodiment 1 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is a group of formula
##STR00034##
and the symbol , when drawn across a bond, indicates the point of
attachment to the rest of the molecule.
[0169] 15. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is
##STR00035##
and the symbol , when drawn across a bond, indicates the point of
attachment to the rest of the molecule.
[0170] 16. The compound of embodiment 6 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.1 is
##STR00036##
and the symbol , when drawn across a bond, indicates the point of
attachment to the rest of the molecule.
[0171] 17. The compound of any one of embodiments 1-3 or 4-16 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.5 is independently, in each
instance, F, C.sup.1, OR.sup.a, CH.sub.3 or CF.sub.3.
[0172] 18. The compound of embodiment 17 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.5 is F.
[0173] 19. The compound of any one of embodiments 1-3, or 5-18 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.6 is F, Me, or OMe.
[0174] 20. The compound of any one of embodiments 1-3 or 5-19 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein n is 1.
[0175] 21. The compound of any one of embodiments 1-3 or 5-20 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein m is 0 or 1.
[0176] 22. The compound of embodiment 21 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein m is 1.
[0177] 23. The compound of embodiment 21 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein m is 0.
[0178] 24. The compound of any one of embodiments 1-3 or 5-16 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein n is 0.
[0179] 25. The compound of embodiment 24 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.6 is F, Me, or OMe.
[0180] 26. The compound of any one of embodiments 1-3 or 5-25 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.2 is --H, halo, cyano,
--O--C.sub.1-C.sub.6alk, or C.sub.1-6alk substituted by 0, 1, 2 or
3 halo substituents.
[0181] 27. The compound of embodiment 26 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.2 is --H, --F, --Cl, --Br, cyano,
--CF.sub.3, --OCH.sub.3, or C.sub.1-6alk.
[0182] 28. The compound of embodiment 26 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.2 is --F, --Cl, --Br, cyano, --CF.sub.3,
--OCH.sub.3, or C.sub.1-6alk.
[0183] 29. The compound of embodiment 26 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.2 is --F.
[0184] 30. The compound of embodiment 26 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.2 is --CF.sub.3.
[0185] 31. The compound of any one of embodiments 1-3 or 5-25 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.2 is --CH.sub.3, --CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2CH.sub.3, --C(CH.sub.3).sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2--C(CH.sub.3).sub.3,
--CH.dbd.CH.sub.2, --CH.sub.2CH.dbd.CH.sub.2,
--C.ident.C--CH.sub.3, or a group of formula
##STR00037##
[0186] 32. The compound of any one of embodiments 1-3, or 5-31 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.3 is H, C.sub.1-8alk,
C.sub.1-8alkOH, C.sub.1-4haloalk, halo, or --OR.sup.a.
[0187] 33. The compound of embodiment 32 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.3 is H, --CH.sub.3, --CH.sub.2CH.sub.3, F,
Cl, Br, I, --OCH.sub.3, --OCF.sub.3, --CH(CH.sub.3)OH, or
--CF.sub.3.
[0188] 34. The compound of embodiment 33 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.3 is --CH.sub.3, --CH.sub.2CH.sub.3, F, Cl,
I, --OCH.sub.3, --OCF.sub.3, --CH(CH.sub.3)OH, or --CF.sub.3.
[0189] 35. The compound of embodiment 34 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.3 is --OCF.sub.3 or --CF.sub.3.
[0190] 36. The compound of embodiment 35 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.3 is --OCF.sub.3.
[0191] 37. The compound of embodiment 34 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.3 is --CF.sub.3.
[0192] 38. The compound of embodiment 21 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.3 is --H.
[0193] 39. The compound of any one of embodiments 1-3, or 5-38 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.4 is H.
[0194] 40. The compound of any one of embodiments 1-3, or 5-38 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.4 is F, Cl, C.sub.1-6alk,
--OC.sub.1-6alk, or --C.sub.1-3haloalk.
[0195] 41. The compound of embodiment 40 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.4 is F, Cl, CF.sub.3, CH.sub.3, or
OCH.sub.3.
[0196] 42. The compound of embodiment 41 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein R.sup.4 is F.
[0197] 43. The compound of any one of embodiments 1-3, or 5-31 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein R.sup.3 and R.sup.4 together form a
four-atom unsaturated bridge containing 0 or 1N atoms, wherein the
bridge is substituted by 0, 1 or 2 R.sup.5 substituents.
[0198] 44. The compound of any one of embodiments 1-3 or 5-43 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein X.sup.2 is N.
[0199] 45. The compound of any one of embodiments 1-3 or 5-43 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein X.sup.2 is CH or CF.
[0200] 46. The compound of embodiment 45 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein X.sup.2 is CH.
[0201] 47. The compound of embodiment 45 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein X.sup.2 is CF.
[0202] 48. The compound of any one of embodiments 1-3, or 5-47 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein X.sup.1 is N.
[0203] 49. The compound of any one of embodiments 1-3, or 5-47 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein X.sup.1 is C(R.sup.4).
[0204] 50. The compound of embodiment 49 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein X.sup.1 is CH.
[0205] 51. The compound of any one of embodiments 1-3, or 5-43 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein X.sup.1 is C(R.sup.4) and X.sup.2 is
N.
[0206] 52. The compound of any one of embodiments 1-3, or 5-43 or
the pharmaceutically-acceptable salt thereof, the tautomer thereof,
the pharmaceutically-acceptable salt of the tautomer, or the
mixture thereof, wherein X.sup.1 is N and X.sup.2 is N.
[0207] 53. The compound of embodiment 1 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, wherein X.sup.2 is N; R.sup.2 is F; m is 0; X.sup.1 is CH;
R.sup.4 is F or H; R.sup.3 is CF.sub.3 or OCF.sub.3; and R.sup.1
is
##STR00038##
and the symbol , when drawn across a bond, indicates the point of
attachment to the rest of the molecule.
[0208] 54. The compound of embodiment 1, wherein the compound is
[0209]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1-
,6-dihydropyridine-3-carboxamide; [0210]
(S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-
methyl)-1,6-dihydropyridine-3-carboxamide; [0211]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,-
6-dihydropyridine-3-carboxamide; [0212]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0213]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-2,-
3-dihydrobenzo[d]oxazole-5-carboxamide; [0214]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxo-2-
,3-dihydrobenzo[d]oxazole-5-carboxamide; [0215]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoin-
doline-5-carboxamide; [0216]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0217]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; or [0218]
(S)--N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)quinoline-7-carboxamide; or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0219] 55. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1-
,6-dihydropyridine-3-carboxamide or the pharmaceutically-acceptable
salt thereof, the tautomer thereof, the pharmaceutically-acceptable
salt of the tautomer, or the mixture thereof.
[0220] 56. The compound of embodiment 1, wherein the compound is
(S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-
methyl)-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0221] 57. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,-
6-dihydropyridine-3-carboxamide or the pharmaceutically-acceptable
salt thereof, the tautomer thereof, the pharmaceutically-acceptable
salt of the tautomer, or the mixture thereof.
[0222] 58. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-
-6-oxo-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0223] 59. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-2,-
3-dihydrobenzo[d]oxazole-5-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0224] 60. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxo-2-
,3-dihydrobenzo[d]oxazole-5-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0225] 61. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxoin-
doline-5-carboxamide or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0226] 62. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0227] 63. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0228] 64. The compound of embodiment 1, wherein the compound is
(S)--N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)quinoline-7-carboxamide orthe pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0229] 65. The compound of embodiment 1, wherein the compound is
[0230]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-6-oxo--
1,6-dihydropyridine-3-carboxamide; [0231]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-6-ox-
o-1,6-dihydropyridine-3-carboxamide; [0232]
(S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-2,3-dihydrob-
enzo[d]oxazole-5-carboxamide; [0233]
(S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-dihydrop-
yridine-3-carboxamide; [0234]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin--
2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0235]
(S)--N-((2-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0236]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1Hbenz-
o[d]imidazole-5-carboxamide; [0237]
(S)-5-fluoro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0238]
(S)--N-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; or [0239]
(S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)nicotinic acid; or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0240] 66. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-6-oxo--
1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0241] 67. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-6-ox-
o-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0242] 68. The compound of embodiment 1, wherein the compound is
(S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-2,3-dihydrob-
enzo[d]oxazole-5-carboxamide or the pharmaceutically-acceptable
salt thereof, the tautomer thereof, the pharmaceutically-acceptable
salt of the tautomer, or the mixture thereof.
[0243] 69. The compound of embodiment 1, wherein the compound is
(S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-dihydrop-
yridine-3-carboxamide or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0244] 70. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin--
2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0245] 71. The compound of embodiment 1, wherein the compound is
(S)--N-((2-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0246] 72. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1Hbenz-
o[d]imidazole-5-carboxamide or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0247] 73. The compound of embodiment 1, wherein the compound is
(S)-5-fluoro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0248] 74. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0249] 75. The compound of embodiment 1, wherein the compound is
(S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)nicotinic acid or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0250] 76. The compound of embodiment 1, wherein the compound is
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-6-ox-
o-1,6-dihydropyridine-3-carboxamide; [0251]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-quin-
oline-7-carboxamide; [0252]
(S)--N-((3,4-dichlorophenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-6--
hydro-xynicotinamide; [0253]
(S)--N-((6-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)quinoline-7-carboxamide; [0254]
(S)--N-((4-(trifluoro-methoxy)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)--
methyl)quinoline-7-carboxamide; [0255]
(S)--N-((4-chloro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinol-
ine-7-carboxamide; [0256]
(S)--N-((8-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)quinoline-7-carboxamide; [0257]
(S)--N-((7-methoxyquinolin-3-yl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)-
-quinoline-7-carboxamide; [0258]
(S)--N-((5-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)quinoline-7-carboxamide; [0259]
(S)--N-((3,4-dichlorophenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-qu-
inoline-7-carboxamide; [0260]
(S)--N-((6-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)-isoquinoline-6-carboxamide; [0261]
(S)--N-(quinolin-3-yl(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline--
7-carboxamide; [0262]
(S)--N-((3-chloro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinol-
ine-7-carboxamide; [0263]
(S)--N-(p-tolyl(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carb-
oxamide; [0264]
(S)--N-(naphthalen-2-yl(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinolin-
e-7-carboxamide; [0265]
(S)--N-((6-chloro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)-6-hydro-xynicotinamide; [0266]
(S)--N-((3-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinol-
ine-7-carboxamide; [0267]
(S)--N-((3-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)quinoline-7-carboxamide; [0268]
(S)--N-((4-methoxyphenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quino-
line-7-carboxamide; [0269]
(S)--N-((8-fluoro-quinolin-3-yl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)quinoline-7-carboxamide; [0270]
(S)--N-(m-tolyl(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinoline-7-carb-
oxamide; [0271]
(S)--N-(quinolin-6-yl(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quinoline--
7-carboxamide; [0272]
(S)--N-((8-methoxyquinolin-3-yl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)-
-quinoline-7-carboxamide; [0273]
(S)--N-((3-methoxyphenyl)-(3-(trifluoro-methyl)pyridin-2-yl)methyl)-quino-
line-7-carboxamide; [0274]
(S)--N-((3-fluoro-4-methoxyphenyl)-(3-(trifluoro-methyl)pyridin-2-yl)meth-
yl)-quinoline-7-carboxamide; [0275]
N-((1S)-(4-(1-hydroxyethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-met-
hyl)quinoline-7-carboxamide; [0276]
(S)--N-((4-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinol-
ine-7-carboxamide; [0277]
(S)--N-((3-methoxypyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinol-
ine-7-carboxamide; [0278]
(S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-nicotinamide; [0279]
(S)-6-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-nicotinamide; [0280]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-pyridazine-3-carboxamide; [0281]
(S)-4-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-picolinamide;
[0282]
(S)-6-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)-
pyridin-2-yl)methyl)-picolinamide; [0283]
(S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-isonicotinamide; [0284]
N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-methoxyni-
cotinamide; [0285]
N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-methoxyni-
cotinamide; [0286]
(S)-6-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-pyridazine-3-carboxamide; [0287]
(S)-5-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-nicotinamide; [0288]
(S)-2-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-isonicotinamide; [0289]
(S)-6-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-nicotinamide; [0290]
(S)-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)-1,6-dihydropyridine-3-carboxamide; [0291]
(S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-pyrimidine-5-carboxamide; [0292]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; [0293]
(S)-2-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-isonicotinamide; [0294]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; [0295]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-meth-
oxynicotinamide; [0296]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-meth-
oxynicotinamide; [0297]
(S)-3-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-isonicotinamide; [0298]
(S)-1-methyl-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-py-
ridin-2-yl)-methyl)-1,2-dihydropyridine-4-carboxamide; [0299]
(S)-1-methyl-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-py-
ridin-2-yl)-methyl)-1,6-dihydropyridine-3-carboxamide; [0300]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-oxo--
1,6-dihydropyridine-3-carboxamide; [0301]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-meth-
ylnicotinamide; [0302]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-meth-
ylisonicotinamide; [0303]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1H-pyr-
rolo[2,3-b]pyridine-3-carboxamide; [0304]
(S)-4-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-nicotinamide; [0305]
(S)-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)indoline-5-carboxamide; [0306]
(S)-2-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-pyrimidine-5-carboxamide; [0307]
(S)-5-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-nicotinamide; [0308]
(S)-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)-1,2-dihydropyridine-3-carboxamide; [0309]
(S)-4-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-pyrimidine-5-carboxamide; [0310]
(S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-pyrimidine-5-carboxamide; [0311]
(S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-picolinamide; [0312]
(S)-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)-1,6-dihydropyridine-2-carboxamide; [0313]
(S)-5-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-picolinamide; [0314]
6-oxo-N--((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2--
yl)-methyl)-piperidine-3-carboxamide; [0315]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; [0316]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamide; [0317]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1-meth-
yl-6-oxo-1,6-dihydro-pyridine-3-carboxamide; [0318]
(S)-2-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)indoline-6-carboxamide; [0319]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxoi-
ndoline-5-carboxamide; [0320]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxoi-
ndoline-6-carboxamide; [0321]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo--
1,2-dihydropyridine-3-carboxamide; [0322]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-oxo--
3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide; [0323]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-(N-m-
ethylsulfamoyl)benzamide; [0324]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo--
3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide; [0325]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo--
2,3-dihydro-benzo[d]oxazole-5-carboxamide; [0326]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-oxo--
3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide; [0327]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo--
2,3-dihydro-benzo[d]oxazole-6-carboxamide; [0328]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-ox-
o-2,3-dihydro-benzo[d]oxazole-5-carboxamide; [0329]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-ox-
o-2,3-dihydro-benzo[d]oxazole-6-carboxamide; [0330]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-3-ox-
o-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide; [0331]
(S)--N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-6-oxo--
1,6-dihydro-pyridine-3-carboxamide; [0332]
(S)-1-methyl-N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl-
)-6-oxo-1,6-dihydro-pyridine-3-carboxamide; [0333]
(S)--N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-2-oxo--
2,3-dihydro-benzo[d]oxazole-5-carboxamide; [0334]
(S)--N-((3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-3-oxo--
3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide; [0335]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-imidaz-
o[1,2-a]pyridine-7-carboxamide; [0336]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-imidazo[1,2-a]pyridine-7-carboxamide; [0337]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-imid-
azo[1,2-a]pyridine-7-carboxamide; [0338]
S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-imida-
zo[1,2-a]pyridine-6-carboxamide; [0339]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-ox-
oindoline-6-carboxamide; [0340]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-2-ox-
oindoline-5-carboxamide; [0341]
(S)-6-oxo-N-((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)-phenyl-
)methyl)-1,6-dihydro-pyridine-3-carboxamide; [0342]
(S)--N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-meth-
yl)quinoline-6-carboxamide; [0343]
(S)-1,3-dioxo-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-isoindoline-5-carboxamide; [0344]
(S)-4-methoxy-N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phe-
nyl)methyl)-benzamide; [0345]
(S)-6-methoxy-N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phe-
nyl)methyl)-nicotinamide; [0346]
(S)--N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-meth-
yl)quinoline-7-carboxamide; [0347]
(S)--N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)-meth-
yl)-benzamide; [0348]
(S)-1,3-dioxo-2-(pyridin-2-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(triflu-
oro-methyl)pyridin-2-yl)methyl)-isoindoline-5-carboxamide; [0349]
(S)-2-bromo-4-(((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-carbamoyl)-benzoic acid; [0350]
(S)--N-((3-(3-methyloxetan-3-yl)ethynyl)-pyridin-2-yl)(4-(trifluoromethyl-
)-phenyl)methyl)-quinoline-6-carboxamide; [0351]
(S)--N-((3-fluoro-4-(trifluoro-methoxy)-phenyl)(3-fluoro-pyridin-2-yl)-me-
thyl)-6-oxo-1,6-dihydro-pyridine-3-carboxamide; [0352]
(S)--N-((3-fluoro-4-(trifluoro-methoxy)-phenyl)(3-fluoro-pyridin-2-yl)-me-
thyl)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxamide; [0353]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo--
1,2-dihydroquinoline-6-carboxamide; [0354]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-hydr-
o-xyquinoline-7-carboxamide; [0355]
(S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-quinoline-7-carboxamide; [0356]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-benzamide; [0357]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-quinoxaline-6-carboxamide; [0358]
(S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-quinoline-6-carboxamide; [0359]
(S)-4-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-quinoline-7-carboxamide; [0360]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-pyrazine-2-carboxamide; [0361]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-picolinamide; [0362]
(S)-4-chloro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl-
)quinoline-6-carboxamide; [0363]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-hydr-
o-xyquinoline-6-carboxamide; [0364]
(S)--N-((4-ethylphenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)quinolin-
e-7-carboxamide; [0365]
(S)-4-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-quinoline-6-carboxamide; [0366]
(S)-3-iodo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2--
yl)-methyl)-benzamide; [0367]
(S)-2-iodo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2--
yl)-methyl)-benzamide; [0368]
(S)--N--((S)-(3-fluoro-4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-py-
ridin-2-yl)-methyl)tetrahydrofuran-2-carboxamide; [0369]
(S)-4-chloro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl-
)quinoline-7-carboxamide; [0370]
(S)-4-(2-hydro-xypropan-2-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluo-
ro-methyl)pyridin-2-yl)methyl)-benzamide; [0371]
(S)-4-iodo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2--
yl)-methyl)-benzamide; [0372]
(R)--N--((S)-(3-fluoro-4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-py-
ridin-2-yl)-methyl)tetrahydrofuran-2-carboxamide; [0373]
(S)--N-((4-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-6-met-
hoxynicotinamide; [0374]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo--
1,2-dihydroquinoline-7-carboxamide; [0375]
(S)--N-((4-fluoro-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl)-benza-
mide; [0376]
(S)-4-isopropyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyri-
din-2-yl)methyl)-benzamide; [0377]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-1,8-naphthyridine-2-carboxamide; [0378]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-1,8-naphthyridine-2-carboxamide; [0379]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-quinoline-6-carboxamide; [0380]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-quinoline-7-carboxamide; [0381]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)quinoline-7-carboxamide; [0382]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)quinoline-6-carboxamide; [0383]
(S)-6-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-nicotinamide; [0384]
(S)-6-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-nicotinamide; [0385]
(S)-2-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-thiazole-4-carboxamide; [0386]
(S)-4-amino-2-methyl-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)--
pyridin-2-yl)-methyl)-pyrimidine-5-carboxamide; [0387]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-thiophene-2-carboxamide; [0388]
(S)-3-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-isonicotinamide; [0389] (S)-methyl
4-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)-carbamoyl)-benzoate; [0390]
(S)-4-(1H-tetrazol-5-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-me-
thyl)pyridin-2-yl)methyl)-benzamide; tert-butyl
3-(((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-2-yl)me-
thyl)-carbamoyl)-piperidine-1-carboxylate; [0391]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-1H-pyrazole-4-carboxamide; [0392]
(S)-6-(dimethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methy-
l)pyridin-2-yl)methyl)-nicotinamide; [0393]
(S)-3-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-picolinamide; [0394]
(S)-3-(4-methylthiazol-5-yl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoro-
methyl)-pyridin-2-yl)-methyl)-propanamide; [0395]
(S)-6-(ethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)p-
yridin-2-yl)methyl)-nicotinamide; [0396]
(S)-1-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-1H-imidazole-2-carboxamide; [0397]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-meth-
oxypyrimidine-5-carboxamide; [0398]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-pyrimidine-5-carboxamide; [0399]
(S)-6-acetamido-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyri-
din-2-yl)methyl)-nicotinamide; [0400]
(S)-5,7-dimethyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyr-
idin-2-yl)methyl)-pyrazolo[1,5-a]pyrimidine-2-carboxamide; [0401]
(S)-6-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)-1,6-dihydro-pyridazine-3-carboxamide; [0402]
(S)-5,7-dimethyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyr-
idin-2-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine-2-carboxamide;
[0403]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-tetrahydro-2H-pyran-4-carboxamide; [0404]
(S)-2-(5-methyl-1H-pyrazol-1-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trif-
luoro-methyl)pyridin-2-yl)methyl)-acetamide; [0405]
(S)-2-(2-oxooxazolidin-3-yl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoro-
methyl)-pyridin-2-yl)-methyl)-acetamide; [0406]
(S)-3-(1H-imidazol-4-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-me-
thyl)pyridin-2-yl)methyl)-propanamide; [0407]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-2-isobutylquinoline-4-carboxamide; [0408]
2-(tetrahydrofuran-3-yl)-N--((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifluo-
ro-methyl)pyridin-2-yl)methyl)-acetamide; [0409]
(S)-2-(1H-imidazol-4-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-me-
thyl)pyridin-2-yl)methyl)-acetamide; [0410]
(S)-3-amino-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-1H-1,2,4-triazole-5-carboxamide;
[0411]
(S)-2-(2-methyl-1H-imidazol-1-yl)-N-((4-(trifluoromethyl)-phenyl)(-
3-(trifluoromethyl)-pyridin-2-yl)-methyl)-acetamide; [0412]
(S)-2-(1H-imidazol-1-yl)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-me-
thyl)pyridin-2-yl)methyl)-acetamide; [0413]
2-acetamido-N--((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyr-
idin-2-yl)methyl)-propanamide; [0414]
5-oxo-N--((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2--
yl)-methyl)-pyrrolidine-3-carboxamide; [0415]
(S)-2-(2-(trifluoro-methoxy)-phenyl)-N-((4-(trifluoromethyl)-phenyl)(3-(t-
rifluoromethyl)-pyridin-2-yl)-methyl)-acetamide; [0416]
(S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-; [0417]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1H-ind-
azole-6-carboxamide; [0418]
(S)-4-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-
-benzamide; [0419]
(S)-3-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)be; [0420]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-meth-
oxybenzamide; [0421]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-quinox-
aline-6-carboxamide; [0422]
(S)-4-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-benzamide; [0423]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-meth-
oxybenzamide; [0424]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-5-hydr-
o-xypicolinamide; [0425]
(S)-4-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-carbamoyl)-phenyl acetate; [0426]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-1H-indazole-6-carboxamide; [0427]
(S)-2-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-benzamide; [0428]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-oxo--
2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide; [0429]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-isonicotinamide; [0430]
(S)-3-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-carbamoyl)-benzoic acid; [0431]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-benzam-
ide; [0432]
(S)-4-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-benzamide; [0433]
(S)-5-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-nicotinamide; [0434]
(S)-4-fluoro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-benzamide; [0435]
(S)-3-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-
-benzamide; [0436]
(S)-4-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-benzamide; [0437]
(S)-3-(dimethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methy-
l)pyridin-2-yl)methyl)-benzamide; [0438]
(S)-3-fluoro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl-
)-benzamide; [0439]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-nicotinamide; [0440] (S)-methyl
3-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-methyl-
)-carbamoyl)-benzoate; [0441]
(S)-4-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-oxazole-5-carboxamide; [0442]
(S)-3-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-benzamide; [0443]
(S)-1-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-1H-pyrazole-3-carboxamide; [0444]
N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-benzamide;
[0445]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-
-picolinamide; [0446]
(S)--N-((3-bromopyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)quinolin-
e-7-carboxamide; [0447]
(S)-4-(dimethylamino)-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methy-
l)pyridin-2-yl)methyl)-benzamide; [0448]
(S)-2-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-benzamide; [0449]
(S)-5-bromo-6-chloro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl-
)-methyl)-nicotinamide; [0450]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)furan-3-carboxamide; [0451]
4-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-ben-
zamide; [0452]
(S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethyl)-phenyl)methyl)-1,6-dihydro--
pyridine-3-carboxamide; [0453]
N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-quinoxaline-
-6-carboxamide; [0454]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-nicoti-
namide; [0455]
N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-quinoline-7-
-carboxamide; [0456]
(S)-5-bromo-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-picolinamide; [0457]
(S)-6-cyano-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin--
2-yl)methyl)-nicotinamide; [0458]
(S)-3-(((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-carbam-
oyl)-benzoic acid; [0459]
(S)-3-chloro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-benzamide; [0460]
3-fluoro-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)-methyl)-be-
nzamide; [0461]
(S)-5-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-picolinamide; [0462]
(S)-3-(trifluoro-methyl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluorometh-
yl)-pyridin-2-yl)-methyl)-benzamide; [0463]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-pyridazine-4-carboxamide; [0464]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-(met-
hylsulfonamido)benzamide; [0465]
N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-methoxybe-
nzamide; [0466]
(S)-1-methyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-1H-indazole-3-carboxamide; [0467]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-3-(met-
hylsulfonyl)-benzamide; [0468]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-(met-
hylsulfonyl)-benzamide; [0469]
(S)-2-phenyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-acetamide; [0470]
(S)-3-(trifluoro-methoxy)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromet-
hyl)-pyridin-2-yl)-methyl)-benzamide; [0471]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)isoxazole-5-carboxamide; [0472]
N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-4-methyloxa-
zole-5-carboxamide; [0473]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-benzo[b]thiophene-2-carboxamide; [0474]
3-oxo-N--((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2--
yl)-methyl)-cyclohexanecarboxamide; [0475]
(S)-3-methoxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-propanamide; [0476]
N--((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)tetrahydrofuran-3-carboxamide; [0477]
(S)-5-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-carbamoyl)-nicotinic acid; [0478]
(S)-3-fluoro-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridin-
-2-yl)methyl)-benzamide; [0479]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-picolinamide; [0480] (S)-tert-butyl
3-(2-oxo-2-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)amino)-ethyl)azetidine-1-carboxylate; [0481]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)quinoline-3-carboxamide; [0482]
(S)-4-(trifluoro-methoxy)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromet-
hyl)-pyridin-2-yl)-methyl)-benzamide; [0483]
N--((S)-(3-((R)-2,2-dimethylcyclopropyl)pyridin-2-yl)-(4-(trifluoro-methy-
l)phenyl)-methyl)quinoline-7-carboxamide; [0484]
N--((S)-(3-((R)-2,2-dimethylcyclopropyl)pyridin-2-yl)-(4-(trifluoro-methy-
l)phenyl)-methyl)quinoline-6-carboxamide; [0485]
(S)--N--((S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)tetrahydrofuran-2-carboxamide; [0486]
(S)--N--((S)-(3-allylpyridin-2-yl)-(4-(trifluoro-methyl)phenyl)-methyl)-2-
-phenylpropanamide; [0487]
(S)--N-((3-neopentylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)quino-
line-6-carboxamide; [0488]
3,3,3-trifluoro-2-methoxy-2-phenyl-N--((S)-(4-(trifluoromethyl)phenyl)(3--
(trifluoromethyl)-pyridin-2-yl)-methyl)-propanamide; [0489]
(S)-2-(pyridin-3-yl)-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)--
pyridin-2-yl)-methyl)-acetamide; [0490]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-benzo[d]thiazole-6-carboxamide; [0491]
(S)-2-methoxy-2-methyl-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl-
)-pyridin-2-yl)-methyl)-propanamide; [0492]
(1s,4R)-4-(hydro-xymethyl)-N--((S)-(4-(trifluoro-methyl)phenyl)-(3-(trifl-
uoro-methyl)pyridin-2-yl)methyl)-cyclohexanecarboxamide; [0493]
(S)-4-hydroxy-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-yl)methyl)-cyclohexanecarboxamide; [0494]
(S)-2,2-dimethyl-3-oxo-3-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethy-
l)-pyridin-2-yl)-methyl)amino)-propanoic acid; [0495]
(S)-4-(((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-carbamoyl)-cyclohexanecarboxylic acid; [0496]
(S)-3-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-y-
l)-methyl)-2,3-dihydro-1H-indene-5-carboxamide; [0497]
(S)-3-benzoyl-N-((4-(trifluoro-methyl)phenyl)-(3-(trifluoro-methyl)pyridi-
n-2-ylmethyl)-benzamide; [0498]
N-((3,4-dichloro-phenyl)(pyridin-2-ylmethyl)-isoquinoline-6-carboxamide;
[0499]
(S)--N-((3-chloro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0500]
(S)--N-((3-chloro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1-meth-
yl-6-oxo-1,6-dihydro-pyridine-3-carboxamide; [0501]
(S)--N-((3,4-dichlorophenyl)-(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihy-
dro-pyridine-3-carboxamide; [0502]
(S)--N-((3,4-dichlorophenyl)-(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-
-1,6-dihydro-pyridine-3-carboxamide; [0503]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl)-1-me-
thyl-6-oxo-1,6-dihydro-pyridine-3-carboxamide; [0504]
(S)--N-((3-fluoro-pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-imidaz-
o[1,2-a]pyridine-6-carboxamide; [0505]
(S)--N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-me-
thyl)-imidazo[1,2-a]pyridine-6-carboxamide; [0506]
(S)-1-ethyl-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methoxy)-phenyl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0507]
(S)--N-((2-bromophenyl)(4-(trifluoromethyl)-phenyl)methyl)-quinoline-6-ca-
rboxamide; [0508]
(S)--N-((3-fluoro-4-(trifluoro-methyl)phenyl)-(2-(trifluoro-methyl)phenyl-
)-methyl)quinoline-6-carboxamide; [0509]
(S)--N-((2,6-difluorophenyl)-(4-(trifluoro-methyl)phenyl)-methyl)-6-oxo-1-
,6-dihydro-pyridine-3-carboxamide; [0510]
(S)--N-((4-(trifluoromethyl)-phenyl)(4-(trifluoromethyl)-pyridin-3-yl)-me-
thyl)quinoline-6-carboxamide; [0511]
(S)-3-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-
methyl)isoindoline-5-carboxamide; [0512]
(S)-2-hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-
-yl)methyl)pyrimidine-5-carboxamide; [0513]
(S)-6-oxo-N-((3-propylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1,6-
-dihydropyridine-3-carboxamide; [0514]
(S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)p-
yridin-2-yl)methyl)isoindoline-5-carboxamide; [0515]
(S)-1,3-dioxo-2-propyl-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-
pyridin-2-yl)methyl)isoindoline-5-carboxamide; [0516]
(S)-2-methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-
pyridin-2-yl)methyl)isoindoline-5-carboxamide; [0517]
(S)-1-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-
methyl)isoindoline-5-carboxamide; [0518]
(S)-6-(((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoy-
l)nicotinic acid; [0519]
(S)--N2-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-N-5-met-
hylpyridine-2,5-dicarboxamide; [0520]
(S)--N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)-1,2,3,4-tetrahydroquinoline-7-carboxamide; [0521]
(S)-5-cyano-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-y-
l)methyl)picolinamide; [0522]
(S)--N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydro-
quinoline-7-carboxamide; [0523]
(S)-5-cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-
-oxo-1,6-dihydropyridine-3-carboxamide; [0524]
(S)--N-((3-cyanopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline--
7-carboxamide; [0525]
(S)-2-((6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carba-
moyl)pyridin-3-yl)oxy)acetic acid; [0526]
(S)-6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl-
)nicotinic acid; [0527]
(S)-6-(((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)carbamoyl)nicotinic acid; [0528]
(S)--N2-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)pyridine-
-2,5-dicarboxamide; [0529]
(S)-4-(((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)carbamoyl)benzoic acid; [0530]
(S)-3-(pyridin-2-yl)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)py-
ridin-2-yl)methyl)propanamide; [0531]
(S)-5-(((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)carbamoyl)picolinic acid; or [0532]
(S)--N-((3-(tert-butyl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)qui-
noline-7-carboxamide; or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof.
[0533] 77. The compound of embodiment 1, wherein the compound is
[0534]
(R)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,-
6-dihydropyridine-3-carboxamide; [0535]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-(pyridin-2-yl)acetamide; [0536]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-(pyridin-3-yl)acetamide; [0537]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-(pyridin-4-yl)acetamide; [0538]
(S)--N-((3,6-difluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-ox-
o-1,6-dihydropyridine-3-carboxamide; [0539]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(5-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0540]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-6-oxo--
1,6-dihydropyridine-3-carboxamide; [0541]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1-meth-
yl-6-oxo-1,6-dihydropyridine-3-carboxamide; [0542]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-6-ox-
o-1,6-dihydropyridine-3-carboxamide; [0543]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(2-fluorophenyl)methyl)-1-me-
thyl-6-oxo-1,6-dihydropyridine-3-carboxamide; [0544]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
[0545]
N--((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-((S)-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
[0546]
N--((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-((R)-2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
[0547]
N--((S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-((S)-2-
-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0548]
N--((S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-((R)-2-
-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0549]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
[0550]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-
-(2-hydroxy-2-methylpropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
[0551]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl-
)methyl)-1-(oxetan-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
[0552]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-(oxeta-
n-3-yl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0553]
(S)--N-(phenyl(3-(trifluoromethyl)pyridin-2-yl)methyl)quinoline-7-carboxa-
mide; [0554]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)tetrazolo-
[1,5-a]pyridine-6-carboxamide; [0555]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)tetrazolo-
[1,5-a]pyridine-7-carboxamide; [0556]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)tetrazol-
o[1,5-a]pyridine-6-carboxamide; [0557]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)tetrazol-
o[1,5-a]pyridine-7-carboxamide; [0558]
(S)--N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)tetrazolo[1,5-a]pyridine-6-carboxamide; [0559]
(S)--N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)tetrazolo[1,5-a]pyridine-7-carboxamide; [0560]
(S)--N-((3-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-2,-
3-dihydrobenzo[d]oxazole-6-carboxamide; [0561]
(S)--N-((3-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)imidazo[1-
,2-a]pyridine-6-carboxamide; [0562]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-(5-oxo-
-2,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide; [0563]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-4-(5-ox-
o-2,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide; [0564]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,-
6-dihydropyridazine-3-carboxamide; [0565]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-oxo-1,-
2,3,4-tetrahydroquinoline-6-carboxamide; [0566]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-5-oxo-4,-
5-dihydropyrazine-2-carboxamide; [0567]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6,7-dihy-
dro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide; [0568]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1,4,5,6--
tetrahydrocyclopenta[c]pyrazole-3-carboxamide; [0569]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4,5,6,7--
tetrahydro-1H-indazole-3-carboxamide; [0570]
(S)--N-((3-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-(5-oxo-
-2,5-dihydro-1,2,4-oxadiazol-3-yl)benzamide; [0571]
(S)--N-((3,5-dimethylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihyd-
ropyridine-3-carboxamide; [0572]
(S)--N-((3-fluoro-5-methylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6--
dihydropyridine-3-carboxamide; [0573]
(S)--N-((3-fluoro-5-methylphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-
-oxo-1,6-dihydropyridine-3-carboxamide; [0574]
(S)--N-((3-fluoro-5-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0575]
(S)--N-((3-fluoro-5-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-
-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; [0576]
(S)--N-((3,5-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihyd-
ropyridine-3-carboxamide; [0577]
(S)--N-((3,5-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo--
1,6-dihydropyridine-3-carboxamide; [0578]
(S)--N-((3,4-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihyd-
ropyridine-3-carboxamide; [0579]
(S)--N-((3,4-difluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo--
1,6-dihydropyridine-3-carboxamide; [0580]
(S)--N-((3-fluoropyridin-2-yl)(3-methyl-5-(trifluoromethyl)phenyl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0581]
(S)--N-((3-fluoro-4-methylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6--
dihydropyridine-3-carboxamide; [0582]
(S)--N-((3-fluoro-4-methylphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-
-oxo-1,6-dihydropyridine-3-carboxamide; [0583]
(S)--N-((3-fluoro-4-methoxyphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-
-dihydropyridine-3-carboxamide; [0584]
(S)--N-((3-fluoro-4-methoxyphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl--
6-oxo-1,6-dihydropyridine-3-carboxamide; [0585]
(S)--N-((4-fluoro-3-methylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6--
dihydropyridine-3-carboxamide; [0586]
(S)--N-((4-fluoro-3-methylphenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-
-oxo-1,6-dihydropyridine-3-carboxamide; [0587]
(S)--N-((4-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropy-
ridine-3-carboxamide; [0588]
(S)--N-((4-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-oxo-1,6--
dihydropyridine-3-carboxamide; [0589]
(S)--N-((3-fluoropyridin-2-yl)(4-methoxyphenyl)methyl)-6-oxo-1,6-dihydrop-
yridine-3-carboxamide; [0590]
(S)--N-((3-fluoropyridin-2-yl)(4-methoxyphenyl)methyl)-1-methyl-6-oxo-1,6-
-dihydropyridine-3-carboxamide; [0591]
(S)--N-((4-chloro-3-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6--
dihydropyridine-3-carboxamide; [0592]
(S)--N-((4-chloro-3-fluorophenyl)(3-fluoropyridin-2-yl)methyl)-1-methyl-6-
-oxo-1,6-dihydropyridine-3-carboxamide; [0593]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-oxoindoline-5-carboxamide; [0594]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0595]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl-
)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; [0596]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridazine-3-carboxamide; [0597]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1-
,6-dihydropyridazine-3-carboxamide; [0598]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxamide; [0599]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-2-oxo-1-
,2,3,4-tetrahydroquinoline-6-carboxamide; [0600]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-5-oxo-4,5-dihydropyrazine-2-carboxamide; [0601]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-5-oxo-4-
,5-dihydropyrazine-2-carboxamide; [0602]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide; [0603]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6,7-dih-
ydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxamide; [0604]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl-
)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide; [0605]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-methylpyridin-2-yl)methyl-
)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; [0606]
(S)--N-((3-methylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-6-oxo-1-
,6-dihydropyridine-3-carboxamide; [0607]
(S)-1-methyl-N-((3-methylpyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0608]
(S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-2,3-dihydrobe-
nzo[d]oxazole-5-carboxamide; [0609]
(S)-2-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-2,3-dihydrob-
enzo[d]oxazole-5-carboxamide; [0610]
(S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)-1,6--
dihydropyridine-3-carboxamide; [0611]
(S)-1-ethyl-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-
-oxo-1,6-dihydropyridine-3-carboxamide; [0612]
(S)--N-((3,4-dichlorophenyl)(3-fluoropyridin-2-yl)methyl)-1-ethyl-6-oxo-1-
,6-dihydropyridine-3-carboxamide; [0613]
(S)-1-ethyl-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl-
)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0614]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-isopro-
pyl-6-oxo-1,6-dihydropyridine-3-carboxamide; [0615]
(S)-5-bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-
-oxo-1,6-dihydropyridine-3-carboxamide; [0616]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methox-
y-6-oxo-1,6-dihydropyridine-3-carboxamide; [0617]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-(2-hyd-
roxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0618]
(S)-1-benzyl-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)--
6-oxo-1,6-dihydropyridine-3-carboxamide; [0619]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1--
(2,2,2-trifluoroethyl)-1,6-dihydropyridine-3-carboxamide; [0620]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-5-methyl-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0621]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)thiophen-
e-2-carboxamide; [0622]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)thiophene-
-2-carboxamide; [0623]
N-((4-iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-6-oxo-1,6-dihyd-
ropyridine-3-carboxamide; [0624]
(S)-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-dihydrop-
yridine-3-carboxamide; [0625]
(S)-1-methyl-6-oxo-N-(pyridin-2-yl(4-(trifluoromethoxy)phenyl)methyl)-1,6-
-dihydropyridine-3-carboxamide; [0626]
(S)--N-((3-fluoropyridin-2-yl)(p-tolyl)methyl)-6-oxo-1,6-dihydropyridine--
3-carboxamide; [0627]
(S)--N-((3,4-dimethylphenyl)(3-fluoropyridin-2-yl)methyl)-6-oxo-1,6-dihyd-
ropyridine-3-carboxamide; [0628]
(S)--N-((3-fluoropyridin-2-yl)(3-methyl-4-(trifluoromethoxy)phenyl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0629]
(S)--N-((3-bromopyridin-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0630]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin--
2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0631]
(S)--N-((3-bromopyridin-2-yl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-
-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; [0632]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)pyridin--
2-yl)methyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-5-carboxamide; [0633]
(S)--N-((2-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide 2,2,2-trifluoroacetate;
[0634]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-methyl-1H-imidazole-2-carboxamide 2,2,2-trifluoroacetate;
[0635]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-4-methyl-1H-imidazole-2-carboxamide 2,2,2-trifluoroacetate;
[0636]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-5-hydroxypicolinamide 2,2,2-trifluoroacetate; [0637]
(S)-4-acetamido-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin--
2-yl)methyl)-3-hydroxybenzamide; [0638]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-2-oxo--
2,3-dihydrobenzo[d]oxazole-6-carboxamide; [0639]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1H-benzo-
[d]imidazole-5-carboxamide; [0640]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)-1H-ben-
zo[d]imidazole-5-carboxamide; [0641]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-
-1H-benzo[d]imidazole-5-carboxamide; [0642]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-1-methyl-
-1H-benzo[d]imidazole-6-carboxamide; [0643]
(S)-1-(difluoromethyl)-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)pheny-
l)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0644]
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methyl-
-1H-benzo[d]imidazole-5-carboxamide; [0645] (S)-methyl
6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)car-
bamoyl)nicotinate;
[0646]
(S)-1-(difluoromethyl)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-f-
luoropyridin-2-yl)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide;
[0647]
(S)-5-fluoro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0648]
(S)-5-chloro-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0649]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide;
[0650]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-5-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide; [0651]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-5-methoxy-6-oxo-1,6-dihydropyridine-2-carboxamide; [0652]
(S)--N-((3-fluoro-4-(trifluoromethyl)phenyl)(3-fluoropyridin-2-yl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0653] (S)-methyl
6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(pyridin-2-yl)methyl)carbamoyl)n-
icotinate;
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-
-yl)methyl)-1-((1-hydroxycyclopropyl)methyl)-6-oxo-1,6-dihydropyridine-3-c-
arboxamide; [0654]
N--((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1-((S)-3,3,3-trifluoro-2-hydroxypropyl)-1,6-dihydropyridine-3-carb-
oxamide; [0655]
N--((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1-((R)-3,3,3-trifluoro-2-hydroxypropyl)-1,6-dihydropyridine-3-carb-
oxamide; [0656]
(S)--N-((3-fluoro-6-methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-
-6-oxo-1,6-dihydropyridine-3-carboxamide; [0657]
N-((3-fluoro-4-(trifluoromethoxy)phenyl)(4-fluorophenyl)methyl)-6-oxo-1,6-
-dihydropyridine-3-carboxamide; [0658]
N-((2,3-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-
-1,6-dihydropyridine-3-carboxamide; [0659]
N-((2,4-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-
-1,6-dihydropyridine-3-carboxamide; [0660]
N-((2,5-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-
-1,6-dihydropyridine-3-carboxamide; [0661]
(S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)picolinic acid trifluoroacetate; [0662]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-oxo-1,2-dihydropyridine-3-carboxamide; [0663]
N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluorophenyl)methyl)-6-oxo-1,6-
-dihydropyridine-3-carboxamide; [0664]
N-((2,6-difluorophenyl)(3-fluoro-4-(trifluoromethoxy)phenyl)methyl)-6-oxo-
-1,6-dihydropyridine-3-carboxamide; [0665]
(R)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-6-oxo-1,6-dihydropyridine-3-carboxamide; [0666]
N-((3-fluoro-4-(trifluoromethoxy)phenyl)(6-methoxypyridin-2-yl)methyl)-6--
oxo-1,6-dihydropyridine-3-carboxamide; [0667]
N-((3-fluoro-4-(trifluoromethoxy)phenyl)(5-methoxypyridin-2-yl)methyl)-6--
oxo-1,6-dihydropyridine-3-carboxamide; [0668]
N-((3-fluoro-4-(trifluoromethoxy)phenyl)(4-methoxypyridin-2-yl)methyl)-6--
oxo-1,6-dihydropyridine-3-carboxamide; [0669]
N-((3-fluoro-4-(trifluoromethoxy)phenyl)(4-methylpyridin-2-yl)methyl)-6-o-
xo-1,6-dihydropyridine-3-carboxamide; [0670]
N-((3-fluoro-4-(trifluoromethoxy)phenyl)(5-methylpyridin-2-yl)methyl)-6-o-
xo-1,6-dihydropyridine-3-carboxamide; [0671]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-5-carboxamide; [0672]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-oxo-1,2-dihydrooxazolo[5,4-b]pyridine-5-carboxamide; [0673]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxamide; [0674]
(S)-2-(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)met-
hyl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetic acid; [0675]
(S)-2-(5-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbam-
oyl)-2-oxopyridin-1(2H)-yl)acetic acid; [0676]
(S)--N-((3-ethylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6-
-dihydropyridine-3-carboxamide; [0677]
(S)-2-amino-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)c-
arbamoyl)phenyl acetate; [0678]
(S)-4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)benzoic acid; [0679]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)imidazo[1,2-a]pyridine-6-carboxamide; [0680]
(S)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)nicotinic acid; [0681]
(R)-6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)nicotinic acid; [0682]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-1-hydroxy-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide-
; [0683]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-c]pyridine-6-carboxamide; or
[0684]
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-2-oxo-2,3-dihydrooxazolo[4,5-c]pyridine-6-carboxamide; or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof.
[0685] 78. The compound or tautomer of any one of embodiments 1-3
or 5-77 in a neutral form.
[0686] 79. The compound of any one of embodiments 1-3 or 5-77 in a
neutral form.
[0687] 80. The pharmaceutically-acceptably salt of the compound or
the pharmaceutically acceptable salt of the tautomer of any one of
embodiments 1-3 or 5-77.
[0688] 81. The pharmaceutically-acceptably salt of the compound of
any one of embodiments 1-3 or 5-77.
[0689] 82. A pharmaceutical composition comprising the compound
according to any one of embodiments 1-3 or 5-77 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof, and a pharmaceutically-acceptable diluent or carrier.
[0690] 83. A method of treating acute, inflammatory and neuropathic
pain, dental pain, general headache, migraine, cluster headache,
mixed-vascular and non-vascular syndromes, tension headache,
general inflammation, arthritis, rheumatic diseases,
osteoarthritis, inflammatory bowel disorders, depression, anxiety,
inflammatory eye disorders, inflammatory or unstable bladder
disorders, psoriasis, skin complaints with inflammatory components,
chronic inflammatory conditions, inflammatory pain and associated
hyperalgesia and allodynia, neuropathic pain and associated
hyperalgesia and allodynia, diabetic neuropathy pain, causalgia,
sympathetically maintained pain, deafferentation syndromes, asthma,
epithelial tissue damage or dysfunction, herpes simplex,
disturbances of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritus, vitiligo, general gastrointestinal disorders,
gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
induced by necrotising agents, hair growth, vasomotor or allergic
rhinitis, bronchial disorders or bladder disorders in a subject,
the method comprising administering the compound according to any
one of embodiments 1-3 or 5-77 or the pharmaceutically-acceptable
salt thereof, the tautomer thereof, the pharmaceutically-acceptable
salt of the tautomer, or the mixture thereof to the subject.
[0691] 84. The method of embodiment 83, wherein the subject is
suffering from neuropathic pain.
[0692] 85. The method of embodiment 83, wherein the subject is
suffering from migraine pain.
[0693] 86. The use of the compound according to any one of
embodiments 1-3 or 5-77 or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof in the preparation of a
medicament.
[0694] 87. The use of the compound according to any one of
embodiments 1-3 or 5-77 or the pharmaceutically-acceptable salt
thereof, the tautomer thereof, the pharmaceutically-acceptable salt
of the tautomer, or the mixture thereof for treating acute,
inflammatory and neuropathic pain, dental pain, general headache,
migraine, cluster headache, mixed-vascular and non-vascular
syndromes, tension headache, general inflammation, arthritis,
rheumatic diseases, osteoarthritis, inflammatory bowel disorders,
depression, anxiety, inflammatory eye disorders, inflammatory or
unstable bladder disorders, psoriasis, skin complaints with
inflammatory components, chronic inflammatory conditions,
inflammatory pain and associated hyperalgesia and allodynia,
neuropathic pain and associated hyperalgesia and allodynia,
diabetic neuropathy pain, causalgia, sympathetically maintained
pain, deafferentation syndromes, asthma, epithelial tissue damage
or dysfunction, herpes simplex, disturbances of visceral motility
at respiratory, genitourinary, gastrointestinal or vascular
regions, wounds, burns, allergic skin reactions, pruritus,
vitiligo, general gastrointestinal disorders, gastric ulceration,
duodenal ulcers, diarrhea, gastric lesions induced by necrotising
agents, hair growth, vasomotor or allergic rhinitis, bronchial
disorders or bladder disorders in a subject.
[0695] 88. The use of embodiment 87, wherein the use is for
treating neuropathic pain.
[0696] 89. The use of embodiment 87, wherein the use is for
treating migraine.
[0697] 90. The compound according to any one of embodiments 1-3 or
5-71 or the pharmaceutically-acceptable salt thereof, the tautomer
thereof, the pharmaceutically-acceptable salt of the tautomer, or
the mixture thereof for treating acute, inflammatory and
neuropathic pain, dental pain, general headache, migraine, cluster
headache, mixed-vascular and non-vascular syndromes, tension
headache, general inflammation, arthritis, rheumatic diseases,
osteoarthritis, inflammatory bowel disorders, depression, anxiety,
inflammatory eye disorders, inflammatory or unstable bladder
disorders, psoriasis, skin complaints with inflammatory components,
chronic inflammatory conditions, inflammatory pain and associated
hyperalgesia and allodynia, neuropathic pain and associated
hyperalgesia and allodynia, diabetic neuropathy pain, causalgia,
sympathetically maintained pain, deafferentation syndromes, asthma,
epithelial tissue damage or dysfunction, herpes simplex,
disturbances of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritus, vitiligo, general gastrointestinal disorders,
gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
induced by necrotising agents, hair growth, vasomotor or allergic
rhinitis, bronchial disorders or bladder disorders in a
subject.
[0698] 91. The compound of embodiment 90 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof for treating neuropathic pain in a subject.
[0699] 92. The compound of embodiment 90 or the
pharmaceutically-acceptable salt thereof, the tautomer thereof, the
pharmaceutically-acceptable salt of the tautomer, or the mixture
thereof for treating migraine in a subject.
EXAMPLES
[0700] Unless otherwise noted, all materials were obtained from
commercial suppliers and used without further purification. All
parts are by weight and temperatures are in degrees centigrade
unless otherwise indicated. All microwave assisted reactions were
conducted with a Smith Synthesizer from Biotage. Mass spectral data
was determined by electrospray ionization technique. All examples
were purified to >90% purity as determined by high-performance
liquid chromatography. Unless otherwise stated, reactions were run
at room temperature.
The following abbreviations are used: [0701] AcOH--Acetic acid
[0702] DABCO--1,4-Diazabicyclo[2.2.2]octane [0703]
DCM--Dichloromethane [0704] DIPEA--Diisopropyl ethylamine [0705]
DMSO--Dimethyl sulfoxide [0706] DMF--N,N-dimethylformamide [0707]
THF--Tetrahydrofuran [0708] EDCI--1-Ethyl-3-(3-dimethylaminopropyl)
carbodiimide [0709] Et.sub.2O--Diethyl ether [0710] EtOAc--Ethyl
acetate [0711] EtOH--Ethyl alcohol [0712]
HATU--2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0713] MeCN--Acetonitrile [0714] MeOH--Methyl
alcohol [0715] n-BuLi--n-Butyllithium [0716]
NMP--N-Methyl-2-pyrrolidinone also known as
1-methyl-2-pyrrolidinone [0717] SFC--Supercritical fluid
chromatography [0718] TEA--Triethylamine [0719]
TFA--Trifluoroacetic acid [0720] TLC--Thin Layer Chromatography
[0721] pTSA--para-Toluenesulfonic acid [0722] h--Hour [0723]
min--Minute [0724] rt--Toom temperature (22-25.degree. C.) [0725]
mL Milliliters [0726] .mu.L Microliters [0727] g Grams [0728] .mu.g
Micrograms [0729] mg Milligrams [0730] .mu.moL Micromolars
General Method of Preparation
[0731] The compounds described herein are prepared using techniques
known to one skilled in the art through the reaction sequences
depicted in schemes 1-4 as well as by other methods. Furthermore,
in the following schemes, where specific acids, bases, reagents,
coupling agents, solvents, etc. are mentioned, it is understood
that other suitable acids, bases, reagents, coupling agents,
solvents, etc. may be used and are included within the scope of the
present invention.
[0732] Diarylamines used for the synthesis of compounds of the
present invention were prepared as described in Scheme 1.
2-Formylpyridines of the Formula (1) were treated with
2-methylpropane-2-sulfinamide and copper sulfate in DCM to give
2-methyl-N-(pyridin-2-ylmethylene)propane-2-sulfinamides of the
Formula (2a). The compounds of Formula (2a) were treated with aryl
or heteroaryl metal halides of Formula (3) at low temperature to
give sulfinamides of the Formula (4). Hydrolysis of sulfinamides
(4) with hydrochloric acid in MeOH gives diaryl amines of Formula
(5a).
##STR00039##
[0733] An alternative approach to diaryl amines of Formula (5a) is
shown in Scheme 2. Aryl or heteroaryl aldehydes of the Formula (6)
were treated with 2-methylpropane-2-sulfinamide and copper sulfate
in DCM to give sulfinimines of the Formula (7). The compounds of
Formula (7) were treated with aryl or heteroaryl metal halides of
Formula (8) at low temperature to give sulfinamides of the Formula
(4). Hydrolysis of sulfinamides (4) with hydrochloric acid in MeOH
gives diaryl amines of Formula (5a).
##STR00040##
[0734] The methods described in Scheme 1-2 can be adapted to a
asymmetric syntheses using the appropriate (R)- or
(S)-2-methylpropane-2-sulfinamides to give sulfinimines of the
Formula (2b) or (2c). Subsequent aryl metal addition and hydrolysis
gave chiral amines of Formula (5b) or (5c).
##STR00041##
[0735] The coupling reaction of diarylamines of Formula (5a-c) with
the various carboxylic acids of Formula (9) can be performed as
shown in Scheme 4. The coupling reaction can be mediated by a
suitable coupling agent such as HATU in the presence of a base in a
suitable solvent to afford compounds of the present invention
(Formula (1)).
##STR00042##
Experimentals for Intermediates
##STR00043##
[0736] Intermediate 1:
(S)-(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanami-
ne hydrochloride
##STR00044##
[0737] Step 1.
(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)-propane-2-s-
ulfinamide
[0738] To a solution of 3-(trifluoromethyl)picolinaldehyde
(Frontier Scientific, 9.80 g, 56.0 mmol) and DCM (50 mL) was added
(S)-2-methylpropane-2-sulfinamide (AK Scientific, 10.3 g, 85.0
mmol) and copper(II) sulfate (35.3 g, 221 mmol). After 1.5 h at rt,
the reaction was filtered through a pad of Celite.RTM. brand filter
agent and rinsed with DCM. The filtrate was concentrated in vacuo
to give a dark green oil. The oil thus obtained was loaded onto a
silica gel column and eluted with 30% EtOAc in hexanes to give
(S,E)-2-methyl-N-((3-(trifluoro-methyl)pyridin-2-yl)methylene)propane-2-s-
ulfinamide, as a golden oil. .sup.1H NMR (.delta. ppm, CDCl.sub.3,
300 MHz): 9.02 (d, J=4.3 Hz, 1H), 8.70 (d, J=1.3 Hz, 1H), 8.38 (d,
J=7.7 Hz, 1H), 7.79 (dd, J=7.9 & 4.8 Hz, 1H), 1.18 (s, 9H). MS
(ESI pos. ion) m/z: 279.1 (M+H).
##STR00045##
Step 2.
(S)-2-Methyl-N--((S)-(4-(trifluoromethyl)phenyl)(3-(trifluorometh-
yl)-pyridin-2-yl)methyl)propane-2-sulfinamide
[0739] To an oven-dried flask containing magnesium (3.46 g, 143
mmol) and Et.sub.2O(120 mL) was added diisobutylaluminum hydride
(0.950 mL, 0.950 mmol) and 1 mL of
1-bromo-4-(trifluoromethyl)benzene (12.5 mL, 91 mmol) dropwise. The
solution was stirred for .about.20 min, during which time the
reaction went from clear to a brownish tint. The reaction was
placed in an ice bath and the remaining
1-bromo-4-(trifluoromethyl)benzene was added dropwise over 20
minutes. In a separate flask, a solution of
(S,E)-2-methyl-N-((3-(trifluoromethyl)pyridin-2-yl)-methylene)propane-2-s-
ulfinamide (13.22 g, 47.5 mmol) and THF (80 mL) was cooled to
-78.degree. C. for 10 min and the Grignard solution was added over
30 min. After 1 h, the reaction was quenched with saturated aqueous
potassium sodium tartrate (10 mL). The reaction was then poured
into H.sub.2O (150 mL). The entire solution was filtered through a
pad of Celite.RTM. brand fliter agent and rinsed with THF and
EtOAc. The resulting filtrate was separated and the organics
concentrated in vacuo to give the product as a dark orange oil. The
oil thus obtained was adsorbed onto a plug of silica gel and
chromatographed through a Redi-Sep.RTM. pre-packed silica gel
column (120 g), eluting with 0% to 40% EtOAc in hexanes, to provide
(S)-2-methyl-N--((S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyrid-
in-2-yl)methyl)propane-2-sulfinamide as a golden oil. .sup.1H NMR
(6 ppm, DMSO-d.sub.6, 600 MHz): .delta. 8.93 (d, J=4.8 Hz, 1H),
7.25 (d, J=7.8 Hz, 1H), 7.71-7.67 (m, 2H), 7.61-7.59 (m, 1H), 7.54
(d, J=8.4 Hz, 2H), 6.08 (d, J=9 Hz, 1H), 5.90 (d, J=9 Hz, 1H), 1.20
(s, 9H). MS (ESI pos. ion) m/z: 425.1 (M+H).
##STR00046##
Step 3.
(S)-(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)--
methanamine hydrochloride
[0740] To a cooled (0.degree. C.) stirring solution of
((S)-2-methyl-N--((S)-(4-(trifluoro-methyl)phenyl)(3-(trifluoromethyl)pyr-
idin-2-yl)methyl)propane-2-sulfonamide (27 g, 63 mmol) in Et.sub.2O
(270 mL) was added 4.0 M HCl in 1,4-dioxane (157 mL, 630 mmol, 10
equiv.) at 0.degree. C., and the reaction mixture was stirred for
30 min at the same temperature. The reaction progress was monitored
by TLC (50% EtOAc in petroleum ether). After completion of the
reaction, the reaction mixture was concentrated under reduced
pressure and triturated with Et.sub.2O to get a white solid which
was filtered and dried to give
(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanami-
ne hydrochloride as a white solid. (.delta. ppm, DMSO-d.sub.6, 600
MHz): .delta. 9.26 (s, 3H), 9.08 (d, J=4.2 Hz, 1H), 8.35 (d, J=7.8
Hz, 1H), 7.82-7.77 (m, 3H), 7.67 (d, J=8.4 Hz, 2H), 5.94 (s, 1H).
MS (ESI pos. ion) m/z: 321.1 (M+H) for free base.
##STR00047##
Intermediate 2:
(S)-(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanami-
ne hydrochloride
##STR00048##
[0741] Step 1. 3-Fluoropicolinaldehyde
[0742] To a stirred solution of DABCO (262.4 g, 2342 mmol) in
anhydrous Et.sub.2O (2.1 L) at -25.degree. C. in a 10 L 3-neck
round bottom flask was added n-BuLi (2.5 M in hexane, 938 mL, 2342
mmol). The mixture was stirred between -25.degree. C. to
-10.degree. C. for 45 min. and then cooled to -70.degree. C. To the
above solution was added 3-fluoropyridine (206.7 g, 2129
mmol)dropwise, and the reaction was stirred between -70.degree. C.
to -60.degree. C. for 1.5 h before DMF (344 mL, 4258 mmol) was
added. The progress of the reaction was monitored by TLC (5% EtOAc
in Petroleum ether). After 1 h stirring at -70.degree. C., water
(800 mL) was added, and the reaction was allowed to warm to rt. The
layers were separated, and the aqueous layer was extracted with DCM
(5.times.1 L). The combined organic layers were washed with brine
and dried over sodium sulfate. After removal of solvent the
initially obtained product was purified by silica gel
chromatography using a gradient of EtOAc in hexane to give the
title compound as pale yellow oil. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 10.21 (s, 1H), 8.63 (t, J=2.2 Hz, 1H),
7.54-7.57 (m, 2H). MS (ESI pos. ion) m/z: 126.0 (M+H).
##STR00049##
Step 2.
(S,E)-N-((3-Fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfi-
namide
[0743] A mixture of 3-fluoropicolinaldehyde (300 g, 2400 mmol),
copper sulfate (572 g, 3600 mmol) and
(S)-2-methylpropane-2-sulfinamide (319 g, 2640 mmol) in DCM (3 L)
in a 10 L 3-neck round bottom flask was stirred for 3 h at rt. The
progress of the reaction was monitored by TLC (30% EtOAc in
petroleum ether). After completion of reaction, the solid was
filtered off and the filtrate was concentrated under vacuum. The
initially obtained product was purified by column chromatography
using silica (60-120 mesh) with 20% EtOAc in n-hexane as eluent to
give the title compound sulfinamide as yellow oil. .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. ppm 8.89 (s, 1H), 8.64 (s, 1H), 7.55 (t,
J=8.4 Hz, 1H), 7.46 (d, J=3.6 Hz, 1H), 1.29 (s, 9H). MS (ESI pos.
ion) m/z: 155.0 (M-O and t-Bu).
##STR00050##
Step-3.
(S)--N--((S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)met-
hyl)-2-methylpropane-2-sulfinamide
[0744] To a stirred suspension of magnesium (170 g, 2365 mmol) in
THF (1.35 L), was added 4-bromobenzotrifluoride (532 g, 2365 mmol).
Stirring was continued for 4 h (caution: slightly exothermic,
cooled with a water bath if needed). The solution was cannulated to
a stirred solution of
(S,E)-N-((3-fluoro-pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
(270 g, 1182 mmol) in THF (1.3 L) at -78.degree. C. dropwise.
Stirring was continued for 1 h. The progress of the reaction was
monitored by TLC (50% EtOAc in petroleum ether). After completion
of the reaction, the reaction mixture was quenched with saturated
aqueous NH.sub.4Cl (2.5 L), and the solution was extracted with
Et.sub.2O (5.times.500 mL). The organic layers were combined, dried
over Na.sub.2SO.sub.4, concentrated, and purified by column
chromatography using silica (100-200 mesh) with 25-30% EtOAc in
petroleum ether as eluent to give the title compound as a brown
oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.45 (d, J=3.6
Hz, 1H), 7.73-7.78 (m, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (m, 2H),
7.43-7.48 (m, 1H), 6.23 (d, J=6.8 Hz, 1H), 5.99 (d, J=6.8 Hz, 1H),
1.36 (s, 9H). MS (ESI pos. ion) m/z: 375.1 (M-O and t-Bu).
##STR00051##
Step 4.
(S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride
[0745] To a cooled (0.degree. C.) stirring solution of
(S)--N--((S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-m-
ethylpropane-2-sulfinamide (108 g, 288.8 mmol) in DCM:EtOH (1:1,
1080 mL), was added saturated HCl in 1,4-dioxane (216 mL). Stirring
was continued for 2 h at 0.degree. C. The progress of the reaction
was monitored by TLC (100% EtOAc). After completion of the
reaction, the reaction mixture was concentrated and triturated with
Et.sub.2O to give a white solid which was filtered and dried to
give the title compound as a white solid. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm 9.23 (s, 3H), 8.60 (d, J=4.8 Hz, 1H), 7.87
(d, J=1.2 Hz, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H),
7.59-7.63 (m, 1H), 6.09 (s, 1H). MS (ESI pos. ion) m/z: 270.1
(M+H).
##STR00052##
Intermediate 2a:
(4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine
hydrochloride
[0746] Following the procedure detailed above for Intermediate 2,
but replacing (S)-2-methylpropane-2-sulfinamide with racemic
2-methylpropane-2-sulfinamide in STEP 2 gave the title compound as
a white solid.
General Procedure for Preparation of Diarylmethanamines
(Intermediates 3-41)
[0747] Additional diarylmethanamies were prepared as described in
Scheme 5, Steps 2-3 or Scheme 6, Steps 3-4; substituting the
appropriate starting materials. Variations in methods applied in
Step 2 of the various intermediate syntheses are elaborated
below.
Method A:
##STR00053##
[0748] Intermediate 3:
(S)--N--((S)-(4-Methoxyphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2--
methylpropane-2-sulfinamide
[0749] Magnesium metal (0.095 g, 3.91 mmol) was activated using a
crystal of iodine prior to addition of THF (1 mL).
1-Bromo-4-methoxybenzene (0.400 g, 2.139 mmol) was added, and the
reaction was left without stirring for 5 minutes after which
initiation was observed. Additional THF (15 mL) was added and the
mixture was stirred for 2 hours.
(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-su-
lfinamide (0.500 g, 1.797 mmol) was added, and the mixture was
stirred for 10 minutes. The reaction was quenched by addition of
saturated aqueous NH.sub.4Cl (10 mL). H.sub.2O (100 mL) and EtOAc
(150 mL) were added, and the phases mixed and separated. The
organic layer was dried with MgSO.sub.4 and evaporated to dryness
under reduced pressure. Purification using silica chromatography
(hexane to EtOAc gradient) gave
(S)--N--((S)-(4-methoxyphenyl)-(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-
-methylpropane-2-sulfinamide.
[0750] The sulfinamide above was then subjected to the hydrolysis
conditions similar to those described above in Scheme 5, Step 3 to
give Intermediate 3 in Table 1 below.
Method B:
##STR00054##
[0751] Intermediate 4:
(S)--N--((S)-(3,4-Dichlorophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-
-2-methylpropane-2-sulfinamide
[0752]
(S,E)-2-Methyl-N-((3-(trifluoromethyl)pyridin-2-yl)methylene)propan-
e-2-sulfinamide (0.493 g, 1.772 mmol) was dissolved in dry THF (10
mL) and cooled in an ice bath. 3,4-Dichlorophenylmagnesium bromide
(Aldrich, 0.5 M solution in THF, 4.0 mL, 2.0 mmol) was added, and
the reaction was stirred for 5 minutes. Saturated aqueous
NH.sub.4Cl (10 mL), H.sub.2O (100 mL) and EtOAc (100 mL) were added
and the phases were mixed and separated. The organic layer was
dried with MgSO.sub.4 and evaporated to dryness under reduced
pressure. Purification using silica chromatography (hexane to EtOAc
gradient) gave
(S)--N--((S)-(3,4-dichloro-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl-
)-2-methylpropane-2-sulfinamide.
[0753] The sulfinamide above was then subjected to the hydrolysis
conditions similar to those described above in Scheme 5, Step 3 to
give Intermediate 4 in Table 1 below.
Method C:
##STR00055##
[0754] Intermediate 5:
(S)--N--((S)-(3-Fluoropyridin-2-yl)(4-(trifluoromethoxy)-phenyl)methyl)-2-
-methylpropane-2-sulfinamide
[0755] 1-Iodo-4-(trifluoromethoxy)benzene (1.00 g, 3.47 mmol) was
dissolved in dry THF (10 mL) and cooled in an ice bath.
Isopropylmagnesium chloride, lithium chloride complex (14% solution
in THF, Aldrich, 3.07 mL, 2.82 mmol) was added, and the mixture was
stirred for 10 min. A solution of
(S,E)-N-((3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
(0.643 g, 2.82 mmol) in dry THF (10 mL) was added and the reaction
was stirred. After 50 minutes, the reaction was quenched by
addition of saturated aqueous NH.sub.4Cl (10 mL). H.sub.2O (100 mL)
and EtOAc (150 mL) were added, and the phases were mixed and
separated. The organic layer was dried with MgSO.sub.4 and
evaporated to dryness under reduced pressure. Purification using
silica chromatography (hexane to EtOAc gradient) gave the desired
(S)--N--((S)-(3-fluoropyridin-2-yl)(4-(trifluoro-methoxy)phenyl)methyl)-2-
-methylpropane-2-sulfinamide.
[0756] The sulfinamide was then subjected to the hydrolysis
conditions similar to those described above in Scheme 6, Step 4 to
give Intermediate 5 in Table 1 below.
TABLE-US-00001 TABLE 1 Additional diarylmethanamines prepared
analogous to Scheme 5 and 6 (Intermediates 3-41). Unless otherwise
stateed, all amines in this table are hydrochloride salts. Aryl
Halide Mol. Inter- or Grignard Formula mediate Method in Step 2
Structure Name (Mol. Wt.) 3 A ##STR00056## ##STR00057## (S)-(4-
methoxyphenyl) (3-(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.14H.sub.13F.sub.3N.sub.2O (282.26) 4 B ##STR00058##
##STR00059## (S)-(3,4- dichloro- phenyl)(3- (trifluoro- methyl)-
pyridin-2-yl)- methanamine C.sub.13H.sub.9Cl.sub.2F.sub.3N.sub.2
(321.13) 5 C ##STR00060## ##STR00061## (S)-(4- (trifluoro-
methoxy)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)-
methanamine C.sub.14H.sub.10F.sub.6N.sub.2O (336.23) 6 A
##STR00062## ##STR00063## (S)-(3-fluoro- 4-(trifluoro- methoxy)-
phenyl)(3- fluoropyridin- 2-yl)- methanamine
C.sub.13H.sub.9F.sub.5N.sub.2O (304.22) 6b.sup.2 A ##STR00064##
##STR00065## (3-fluoro-4- (trifluoro- methoxy)- phenyl)(3-
fluoropyridin- 2-yl)- methanamine C.sub.13H.sub.9F.sub.5N.sub.2O
(304.22) 7 A ##STR00066## ##STR00067## (S)-(3-fluoro- 4-(trifluoro-
methyl)- phenyl)(3- (trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.14H.sub.9F.sub.7N.sub.2 (338.22) 8 C ##STR00068##
##STR00069## (S)-(3-fluoro- pyridin-2-yl)- (4-(trifluoro- methoxy)-
phenyl)- methanamine C.sub.14H.sub.10F.sub.4N.sub.2O (286.22) 9 C
##STR00070## ##STR00071## (S)-(6-chloro- quinolin-3-yl)-
(3-(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.16H.sub.11ClF.sub.3N.sub.3 (337.73) 10 C ##STR00072##
##STR00073## (S)-(4-chloro- phenyl)(3- trifluoro- methyl)-
pyridin-2-yl)- methanamine C.sub.13H.sub.10ClF.sub.3N.sub.2
(286.68) 11 C ##STR00074## ##STR00075## (S)-(8-chloro-
quinolin-3-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.16H.sub.11ClF.sub.3N.sub.3 (337.73) 12 C ##STR00076##
##STR00077## (S)-(7- methoxyquino- lin-3-yl)(3- (trifluoro-
methyl)- pyridin-2-yl)- methanamine C.sub.17H.sub.14F.sub.3N.sub.3O
(333.31) 13 C ##STR00078## ##STR00079## (S)-(5-chloro-
quinolin-3-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.16H.sub.11ClF.sub.3N.sub.3 (337.73) 14 C ##STR00080##
##STR00081## (S)-quinolin- 3-yl(3- (trifluoro- methyl)-
pyridin-2-yl)- methanamine C.sub.16H.sub.12F.sub.3N.sub.3 (303.28)
15 A ##STR00082## ##STR00083## (S)-(3-chloro- phenyl)(3-
(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.13H.sub.10ClF.sub.3N.sub.2 (286.68) 16 B ##STR00084##
##STR00085## (S)-p-tolyl(3- (trifluoro- methyl)- pyridin-2-yl)-
methanamine C.sub.14H.sub.13F.sub.3N.sub.2 (266.26) 17 A
##STR00086## ##STR00087## (S)- naphthalen-2- yl(3-(trifluoro-
methyl)- pyridin-2-yl)- methanamine C.sub.17H.sub.13F.sub.3N.sub.2
(302.29) 18 B ##STR00088## ##STR00089## (S)-(3-fluoro- phenyl)(3-
(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.13H.sub.10F.sub.4N.sub.2 (270.23) 19 A ##STR00090##
##STR00091## (S)-(3- (trifluoro- methyl)- phenyl)(3- (trifluoro-
methyl)- pyridin-2-yl)- methanamine C.sub.14H.sub.10F.sub.6N.sub.2
(320.23) 20 C ##STR00092## ##STR00093## (S)-(8-fluoro-
quinolin-3-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.16H.sub.11F.sub.4N.sub.3 (321.27) 21 B ##STR00094##
##STR00095## (S)-m-tolyl(3- (trifluoro- methyl)- pyridin-2-yl)-
methanamine C.sub.14H.sub.13F.sub.3N.sub.2 (266.26) 22 C
##STR00096## ##STR00097## (S)-quinolin- 6-yl(3- (trifluoro-
methyl)- pyridin-2-yl)- methanamine C.sub.16H.sub.12F.sub.3N.sub.3
(303.28) 23 C ##STR00098## ##STR00099## (S)-(5-chloro-
pyridin-2-yl)- (3-(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.12H.sub.9ClF.sub.3N.sub.3 (287.67) 24 C ##STR00100##
##STR00101## (S)-(8- methoxyquino- lin-3-yl)(3- (trifluoro-
methyl)- pyridin-2-yl)- methanamine C.sub.14H.sub.10F.sub.6N.sub.2
(333.31) 25 B ##STR00102## ##STR00103## (S)-(3- methoxyphenyl)
(3-(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.14H.sub.13F.sub.3N.sub.2O (282.26) 26 B ##STR00104##
##STR00105## (S)-(3-fluoro- 4-(trifluoro- methoxy)- phenyl)(3-
(trifluoro- methyl)- pyridin-2-yl)- methanamine
C.sub.14H.sub.9F.sub.7N.sub.2O (354.22) 27 B ##STR00106##
##STR00107## (S)-(4-fluoro- phenyl)(3- (trifluoro- methyl)-
pyridin-2-yl)- methanamine C.sub.13H.sub.10F.sub.4N.sub.2 (270.23)
28 B ##STR00108## ##STR00109## (S)-phenyl(3- (trifluoro- methyl)-
pyridin-2-yl)- methanamine C.sub.13H.sub.11F.sub.3N.sub.2 (252.24)
29 B ##STR00110## ##STR00111## (S)-(4- ethylphenyl)- (3-(trifluoro-
methyl)- pyridin-2-yl)- methanamine C.sub.15H.sub.15F.sub.3N.sub.2
(280.29) 30 A ##STR00112## ##STR00113## (S)-2-(3- (trifluoro-
methyl)- phenyl)-1-(3- (trifluoro- methyl)- pyridin-2-yl)-
ethanamine C.sub.15H.sub.12F.sub.6N.sub.2 (334.26) 31 B
##STR00114## ##STR00115## (S)-2-(3- chlorophenyl)- 1-(3-
(trifluoro- methyl)- pyridin-2-yl)- ethanamine
C.sub.14H.sub.12ClF.sub.3N.sub.2 (300.71) 32 B ##STR00116##
##STR00117## (S)-2-(3- methoxyphenyl)- 1-(3- (trifluoro- methyl)-
pyridin-2-yl)- ethanamine C.sub.15H.sub.15F.sub.3N.sub.2O (296.29)
33 B ##STR00118## ##STR00119## (S)-2-(2- chlorophenyl)- 1-(3-
(trifluoro- methyl)- pyridin-2-yl)- ethanamine
C.sub.14H.sub.12ClF.sub.3N.sub.2 (300.71) 34 B ##STR00120##
##STR00121## (S)-2-(2- methoxyphenyl)- 1-(3- (trifluoro- methyl)-
pyridin-2-yl)- ethanamine C.sub.15H.sub.15F.sub.3N.sub.2O (296.29)
35 A ##STR00122## ##STR00123## (S)-(3-chloro- pyridin-2-yl)-
(4-(trifluoro- methyl)- phenyl)- methanamine
C.sub.13H.sub.10ClF.sub.3N.sub.2 (286.68) 36 A ##STR00124##
##STR00125## (S)-(3,4- dichloro- phenyl)(3- fluoropyridin- 2-yl)-
methanamine C.sub.12H.sub.9Cl.sub.2FN.sub.2 (271.12) 37.sup.1 A
##STR00126## ##STR00127## (S)-(2- bromophenyl) (4-(trifluoro-
methyl)- phenyl)- methanamine C.sub.14H.sub.11BrF.sub.3N (330.14)
38.sup.1 A ##STR00128## ##STR00129## (S)-(3-fluoro- 4-(trifluoro-
methyl)- phenyl)(2- (trifluoro- methyl)- phenyl)- methanamine
C.sub.15H.sub.10F.sub.7N (337.24) 39.sup.1 A ##STR00130##
##STR00131## (S)-(2,6- difluoro- phenyl)(4- (trifluoro- methyl)-
phenyl)- methanamine C.sub.14H.sub.10F.sub.3N (287.23) 40.sup.2 A
##STR00132## ##STR00133## (5- bromothiazol- 4-yl)(4- (trifluoro-
methyl)- phenyl)- methanamine C.sub.11H.sub.8BrF.sub.3N.sub.2S
(337.16) 41 B ##STR00134## ##STR00135## (S)-3-phenyl- 1-(3-
(trifluoro- methyl)- pyridin-2-yl)- prop-2-yn-1- amine
C.sub.15H.sub.11F.sub.3N.sub.2 (276.26) .sup.1These amines were
prepared employing (R)-2-methylpropane-2-sulfinamide in the first
step (Scheme 5). For reversal of stereochemistry observed in the
Ellman sulfonylimine chemistry observed with 2-pyridyl substrates,
see Kuduk, S. D.; DiPardo, R. M.: Chang, R. K.; Ng, C.; Bock M. G.
Tetrahedraon Lett. 2004, 45, 6641-6643. .sup.2Prepared employng
racemic 2-methylpropane-2-sulfinamide in the first step (Scheme
5)
##STR00136##
Intermediate 42:
(S)-(4-(Trifluoromethyl)phenyl)(4-(trifluoromethyl)pyridin-3-yl)methanami-
ne
##STR00137##
[0757] Step 1:
N-Methoxy-N-methyl-4-(trifluoromethyl)nicotinamide
[0758] To a solution of 4-(trifluoromethyl)nicotinic acid (2.11 g,
11.04 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.077 g,
11.04 mmol) in DCM (20 mL) was added
N-ethyl-N-isopropylpropan-2-amine (3.78 mL, 22.08 mmol), and HATU
(4.20 g, 11.04 mmol). The reaction was stirred at rt under N.sub.2
for 5 h. The reaction was then diluted with H.sub.2O (50 mL) and
extacted with DCM (2.times.50 mL). The organic layers were
combined, dried (MgSO.sub.4), and concentrated to give the amide.
Purification by ISCO (80 g SiO.sub.2, 10-50% EtOAc/hexanes) gives
N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide as a yellow
oil.
##STR00138##
Step 2:
(R)-2-Methyl-N-((4-(trifluoromethyl)pyridin-3-yl)methylene)propan-
e-2-sulfinamide
[0759] To a solution of
N-methoxy-N-methyl-4-(trifluoromethyl)nicotinamide (1.50 g, 6.41
mmol) in THF (20 mL) at 0.degree. C. was added diisopropylaluminum
hydride (7.69 mL, 7.69 mmol) (1.0 M in hexanes). After addition,
the reaction was immersed in an ice/water bath and stirred for 1 h.
Additional diisopropylaluminum hydride (7.69 mL, 7.69 mmol) was
added, and the reaction was stirred 1 h at 0.degree. C. The
reaction was quenched by slow addition of H.sub.2O (2 mL) followed
by addition of saturated aqueous sodium potassium tartrate (100
mL). The reaction was diluted with Et.sub.2O and stirred at rt for
1 h. The organic layer was separated, and the aqueous layer was
extracted with Et.sub.2O. The combined organic layers were dried
(MgSO.sub.4), and the solution was concentrated to 10 mL in vacuo
to give a solution of the aldehyde which was used in the next step
without further purification.
[0760] To a the solution of 4-(trifluoromethyl)nicotinaldehyde from
above was added DCM (10 mL), (R)-2-methylpropane-2-sulfinamide
(1.553 g, 12.81 mmol; See Table 1, footnote 1) (AK Scientific) and
copper sulfate (4.09 g, 25.6 mmol) (Aldrich, anhydrous). The
suspension was stirred at rt under N.sub.2 for 68 h. The suspension
was then filtered through Celite.RTM. brand filter agent, and the
solid was washed with DCM (2.times.20 mL). The filtrates were
concentrated and purified by ISCO (40 g, SiO.sub.2, 10-50%
EtOAc/hexane) to give
(R)-2-methyl-N-((4-(trifluoromethyl)pyridin-3-yl)methylene)propane-2-sulf-
inamide as a light yellow oil.
##STR00139##
Step 3:
(S)-(4-(Trifluoromethyl)phenyl)(4-(trifluoromethyl)pyridin-3-yl)--
methanamine hydrochloride
[0761] Following the procuedure detailed above for Intermediate 2,
steps 3-4 gave the title compound as a white solid.
##STR00140##
Intermediate 43:
(S)-(3-Methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamine
##STR00141##
[0762] Step 1.
(S,E)-N-((3-Methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
[0763] To a solution of 3-methoxy-pyridine-2-carbaldehyde (2.95 g,
21.51 mmol) in DCM (26 mL) was added
(S)-2-methylpropane-2-sulfinamide (5.3 g, 43.7 mmol) and copper(II)
sulfate (6.95 g, 43.5 mmol). The suspension was stirred at rt under
argon for 18 hours, filtered, and the solid washed with DCM
(2.times.20 mL). The filtrates were concentrated, and the product
thus obtained was purified by silica gel flash column
chromatography (using a 80G ISCO cartridge) and eluted using
hexanes/EtOAc gradient followed by DCM/MeOH to yield the desired
product
(S,E)-N-((3-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
as a light-yellow solid after drying under high vacuum.
##STR00142##
Step 2.
(S)--N--((S)-(3-Methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)-m-
ethyl)-2-methylpropane-2-sulfinamide
[0764] To a 150 mL round-bottomed flask containing magnesium
turnings (0.370 g, 15.22 mmol) and Et.sub.2O (10 mL) was added
diisobutylaluminum hydride, 1.0M solution in THF (0.095 mL, 0.095
mmol) followed by dropwise addition of
1-bromo-4-(trifluoromethyl)benzene (0.8 mL, 5.71 mmol). The
solution was stirred for 2.0 hours during which it turned from
turbid to dark brown color. The reaction mixture was cooled to
-78.degree. C. in a dry ice/actone bath, then a solution of
(S,E)-N-((3-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
(0.920 g, 3.83 mmol) in THF (10 mL) was added dropwise over 5
minutes. The reaction was stirred for 14 hours during which it
warmed to rt. The reaction was then quenched with saturated aqueous
NH.sub.4Cl (30 mL) and H.sub.2O (25 mL) and extracted with EtOAc
(2.times.100 mL). The combined organic layers were dried over
anhydrous sodium sulfate and concentrated to yield the initial
product which was purified by silica gel flash column
chromatography (using a 40G ISCO cartridge) and eluted using
hexanes/EtOAc gradient to yield the desired product
(S)--N--((S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2--
methylpropane-2-sulfinamide as an yellow oil.
##STR00143##
Step 3.
(S)-(3-Methoxypyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
[0765] A solution of
(S)--N--((S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-2-
-methylpropane-2-sulfinamide (0.576 g, 1.491 mmol) in MeOH (6 mL)
was treated with hydrochloric acid, 4.0 M solution in 1,4-dioxane
(0.75 mL, 3.00 mmol) and stirred at rt for 2 h. The reaction was
concentrated on the rotary evaporator resulting in a gummy residue
which was taken up in EtOAc (100 mL), saturated aqueous NaHCO.sub.3
(50 mL), and H.sub.2O (25 mL). The resulting mixture was
transferred to a separatory funnel and after vigorous extraction,
the organic layer was separated, dried over anhydrous sodium
sulfate, and concentrated to yield the product
(S)-(3-methoxypyridin-2-yl)(4-(trifluoromethyl)-phenyl)methanamine
as a light-brown oil which was used without further purification in
the next step.
##STR00144##
Intermediate 44:
(S)-(3-Methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamine
hydrochloride
##STR00145##
[0766] Step 1.
(S,E)-2-Methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide
[0767] To a solution of 3-methyl-2-pyridinecarboxaldehyde (3.243 g,
26.8 mmol) in DCM (18 mL) was added
(S)-2-methylpropane-2-sulfinamide (6.55 g, 54.0 mmol) and
copper(II) sulfate (8.72 g, 54.6 mmol). The suspension was stirred
at rt for 17 hours, filtered, and the solid was washed with DCM
(2.times.35 mL). The filtrates were concentrated, and the resulting
product was purified by silica gel flash column chromatography
(using a 80G ISCO cartridge) and eluted using DCM/MeOH gradient to
yield the desired product
(S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide
as a yellow solid.
##STR00146##
Step 2.
(S)-2-Methyl-N--((S)-(3-methylpyridin-2-yl)(4-(trifluoromethyl)-p-
henyl)methyl)propane-2-sulfinamide
[0768] A 250 mL round-bottomed flask containing magnesium turnings
(0.685 g, 28.2 mmol) and Et.sub.2O (25 mL) was added
diisobutylaluminum hydride 1.0 M solution in hexanes (0.18 mL,
0.180 mmol) followed by dropwise addition of
4-bromobenzotrifluoride (2.0 mL, 14.28 mmol). The solution was
stirred for 1.5 hours during which it turned from turbid to dark
brown in color. The reaction mixture was cooled to -78.degree. C.
in a dry ice/actone bath and then a solution of
(S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide
(2.15 g, 7.67 mmol) in THF (15 mL) was added dropwise over 5
minutes. The reaction was stirred for 5 hours during which it
warmed to rt. The reaction was quenched with saturated aqueous
NH.sub.4Cl (50 mL) and H.sub.2O (25 mL). The reaction mixture was
extracted with EtOAc (2.times.100 mL). The combined organic layers
were dried over anhydrous sodium sulfate and concentrated to yield
the initial product which was purified by silica gel flash column
chromatography (using a 80G ISCO cartridge) and eluted using
hexanes/EtOAc gradient to yield the desired product
(S)-2-methyl-N--((S)-(3-methylpyridin-2-yl)(4-(trifluoromethyl)ph-
enyl)methyl)-propane-2-sulfinamide as an yellow solid.
##STR00147##
Step 3.
(S)-(3-Methylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride
[0769] A solution of
(S)-2-methyl-N--((S)-(3-methylpyridin-2-yl)(4-(trifluoro-methyl)phenyl)me-
thyl)propane-2-sulfinamide (0.355 g, 0.958 mmol) in MeOH (10 mL)
was treated with hydrogen chloride, 4.0 M solution in 1,4-dioxane
(0.6 mL, 2.400 mmol) and stirred at rt. The reaction was
concentrated on the rotary evaporator resulting in a gummy residue.
The residue
(S)-(3-methylpyridin-2-yl)-(4-(trifluoromethyl)phenyl)methanamine
hydrochloride was used in the next steps without further
purification.
##STR00148##
Intermediate 45:
(S)-(3-Fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl-
)methanamine hydrochloride
##STR00149##
[0770] Step 1.
(S,E)-N-(3-Fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfi-
namide
[0771] To a solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde
(5.7 g, 29.7 mmol) in DCM (60 mL) was added
(S)-2-methylpropane-2-sulfinamide (7.19 g, 59.3 mmol) and copper
(II) sulfate (18.94 g, 119 mmol). The suspension was stirred at rt
under N.sub.2 for 20 h. The suspension was then filtered through
Celite.RTM. brand filter agent, and the solids were washed with DCM
(2.times.20 mL). The filtrates were concentrated and purified by
ISCO (120 g, SiO.sub.2, 10-50% EtOAc/hexanes) to give
(S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfi-
namide as a white solid.
##STR00150##
Step 2.
(S)--N--((S)-(3-Fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromet-
hyl)-pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide
[0772] To a solution of 2-(tributylstannyl)pyrimidine (425 mg,
1.151 mmol) in THF (3 mL) at -78.degree. C. was added
n-butyllithium (0.720 mL, 1.151 mmol) (1.6 M in hexanes). The
reaction was stirred at -78.degree. C. for 1.5 h and then
(S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfi-
namide (408 mg, 1.382 mmol) in THF (1 mL) was added. The cooling
bath was then removed as the reaction was allowed to warm to rt and
stirred for 1 h. LCMS showed 2 products with a ratio of 10:1. The
reaction was quenched with saturated aqueous NH.sub.4Cl (5 mL) and
H.sub.2O (5 mL). The reaction mixture was extracted with EtOAc
(2.times.5 mL). The organic layers were combined, dried
(MgSO.sub.4), and concentrated to give the product. Purification by
ISCO (12 g SiO.sub.2, 20-80% EtOAc/hexanes) gave the major product,
(S)--N--((S)-(3-fluoro-4-(trifluoromethyl)phenyl)-(pyrimidin-2-yl)methyl)-
-2-methylpropane-2-sulfinamide.
##STR00151##
Step 3.
(S)-(3-Fluoro-4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyrid-
in-2-yl)methanamine hydrochloride
[0773] To a solution of
(S)--N--((S)-(3-fluoro-4-(trifluoromethyl)phenyl)-(pyrimidin-2-yl)methyl)-
-2-methylpropane-2-sulfinamide (100 mg, 0.266 mmol) in MeOH (5 mL)
was added hydrogen chloride (0.200 mL, 0.799 mmol) (4.0 M in
1,4-dioxane). The reaction was stirred for 2 h at rt under N.sub.2
and then concentrated in vacuo to give the amine as the
hydrochloride salt which was used in the next step without further
purification.
##STR00152##
Intermediate 46:
(S)-(3-(Prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methanami-
ne hydrochloride
##STR00153##
[0774] Step-1. 3-Bromo-2-dibromethyl-pyridine
[0775] To a solution of 3-bromo-picoline (25 g, 0.145 mol) in
CCl.sub.4 was added N-bromosuccinimide (51.66 g, 0.29 mol) and
benzoylperoxide (2.5 g, 0.018 mol). The mixture was then gradually
heated to reflux and stirred for 30 h. The reaction miture was then
cooled to rt, the succinimide was removed by filtration, and the
filtrate was concentrated under reduced pressure. The resulting
product was purified by flash column chromatography using silica
(100-200 mesh) with EtOAc:hexane (0.1:09) as eluent to furnish pure
3-Bromo-2-dibromomethyl-pyridine. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta.7.66-7.68 (d, 1H), 7.84-7.88 (d, 1H), 7.13-7.17
(t, 2H).
##STR00154##
Step-2. 3-Bromo-pyridine-2-carbaldehyde
[0776] A suspension of 3-bromo-2-dibromomethyl-pyridine (10.0 g,
30.32 mmole) in morpholine (30.0 mL) was heated to 60.degree. C.
for 1 h. The reaction mixture was cooled to rt and diluted with
EtOAc (200 mL). The pH was adjusted to 4.0 by adding citric acid
(40.0 g). The reaction mixture was then extracted with EtOAc
(3.times.200 mL) and the combined organic layers were dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure. The
residue was purified by column chromatography using silica (100-200
mesh) using 3% EtOAc in hexane as eluent to give
3-bromo-pyridine-2-carbaldehyde. .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. 10.23 (s, 1H), 8.74-8.76 (d, 1H), 8.02-8.04 (d, 1H),
7.26-7.38 (t, 1H).
##STR00155##
Step 3.
(S,E)-N-((3-Bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfin-
amide
[0777] A mixture of 3-bromo piconaldehyde (10 g, 53.8 mmol), copper
sulfate (3.98 mL, 81 mmol) and (S)-2-methylpropane-2-sulfinamide
(6.84 g, 56.4 mmol) in DCM (100 mL) was stirred at rt overnight.
The solid was filtered off and the filtrate concentrated under
vacuum. The residue was purified by column chromatography using
silica (100-200 mesh) with 20% EtOAc in n-hexane as eluent to give
(S,E)-N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
as yellow oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.9.0 (s,
1H), 8.74-8.76 (d, 1H), 7.9-8.04 (d, 1H), 7.26-7.38 (t, 1H), 5.2
(d, 1H), 1.3 (s, 9H).
##STR00156##
Step 4. (S)-2-Methyl-propane-2-sulfinic acid
((3-bromo-pyridin-2-yl)-(4-trifluoromethyl-phenyl)-methyl)-amide
[0778] To a stirred suspension of magnesium (2.143 g, 88 mmol) in
THF (50 mL), was added 4-bromobenzotrifluoride (5.06 mL, 36.2
mmol). Stirring was continued for 4 h (caution: slightly
exothermic, cooled with a water bath if needed). The resulting
mixture was added to a stirred solution of
(S,E)-N-((3-bromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide
(5.1 g, 17.64 mmol) in THF (100 mL) at -78.degree. C. in a dropwise
fashion. The mixture was stirred for another hour after addition
and the reaction was then quenched with saturated aqueous
NH.sub.4Cl, extracted with Et.sub.2O (3.times.20 mL), dried over
Na.sub.2SO.sub.4,concentrated, and purified by column
chromatography using silica (100-200 mesh) with 5% EtOAc in hexane
as eluent to give the title compound as a brown oil.
##STR00157##
Step 5.
(S)-tert-Butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)me-
thyl)carbamate
[0779] To a cooled (0.degree. C.) stirred solution of
(S)-2-methyl-propane-2-sulfinic acid
((3-bromo-pyridin-2-yl)-(4-trifluoromethyl-phenyl)-methyl)-amide
(5.0 g, 11.49 mmol) in DCM/EtOH(1/1,60 mL) was added 4.0 M HCl in
1,4-dioxane (14.36 mL, 57.4 mmol). Stirring was continued for 2 h
and then DIPEA (10.00 mL, 57.4 mmol) was added, followed by
di-tert-butyl dicarbonate (4.00 mL, 17.23 mmol) added. The
resulting mixture was stirred at rt overnight, diluted with
H.sub.2O, and extracted with DCM (3.times.100 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The residue thus obtained was purified by
silica gel (100-200 mesh) column chromatography using 5% EtOAc in
hexane as eluent to give the title compound as a white solid.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 8.5 (dd, 1H), 7.81
(dd, 1H), 7.52 (s, 4H), 7.2 (dd, 1H) 6.51 (d, 1H), 6.32 (d. 1H),
1.41 (s, 9H).
##STR00158##
Step 6.
(S)-(3-Bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride
[0780] To a solution of (S)-tert-butyl
((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate
(2.0 g, 4.64 mmol) in MeOH (10 mL) was added hydrogen chloride
(3.48 mL, 13.91 mmol) (4.0 M in 1,4-dioxane). The reaction was
stirred for 27 h at rt under N.sub.2. The reaction was concentrated
in vacuo to give the amine which was used without further
purification in subsequent steps. MS (ESI pos. ion) m/z: 331.0,
332.9 (M+H).
##STR00159##
Intermediate 47:
(S)-(3-(Prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methanami-
ne hydrochloride
##STR00160##
[0781] Step 1. (S)-tert-Butyl
((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carba-
mate
[0782] To a microwave vial containing (S)-tert-butyl
((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate
(500 mg, 1.159 mmol) and a stir bar was added 1,4-dioxane (6 mL).
To this solution was added
tetrakis(triphenyl-phosphine)palladium(0) (67.0 mg, 0.058 mmol,
0.05 eq) and tributyl(prop-1-yn-1-yl)stannane (458 mg, 1.391 mmol,
1.2 eq). The vial was capped and irradiated in a microwave at
120.degree. C. for 20 min. The vial was allowed to cool, diluted
with hexanes (5 mL) and loaded directly to a normal phase silica
gel column (80 g ISCO, 0 to 40% EtOAc in hexanes) to provide
(S)-tert-butyl
((3-(prop-1-yn-1-yl)-pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carba-
mate as a white solid.
##STR00161##
Step 2.
(S)-(3-(Prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)-m-
ethanamine hydrochloride
[0783] To a 500 mL round bottom flask containing (S)-tert-butyl
((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbam-
ate (400 mg, 1.025 mmol) was added DCM (8 mL) and the mixture was
stirred at 23.degree. C. for 2 min. At this time, hydrogen chloride
(4N in 1,4-dioxane) (37.4 mg, 1.025 mmol) (4 mL) was added via
syringe. The reaction was stirred for 3 h then the volatiles were
removed via rotoryevaporator. The solid was placed on high vacuum
overnight to give
(S)-(3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanami-
ne hydrochloride as a white solid.
##STR00162##
Intermediate 48:
(S)-(3-((3-Methyloxetan-3-yl)ethynyl)pyridin-2-yl)(4-(trifluoromethyl)phe-
nyl)methanamine hydrochloride
[0784] To a microwave flask containing
trimethyl((3-methyloxetan-3-yl)-ethynyl)silane (0.585 g, 3.48 mmol)
was added THF (7.73 mL) and the mixture was stirred at 23.degree.
C. for 2 min. At this time, (S)-tert-butyl
((3-bromopyridin-2-yl)-(4-trifluoromethyl)phenyl)methyl)carbamate
(1.00 g, 2.319 mmol), tetrabutylammonium fluoride (0.909 g, 3.48
mmol), copper(I) iodide (0.022 g, 0.116 mmol) and lastly
tetrakis(triphenylphosphine)palladium(0) (0.134 g, 0.116 mmol) were
added to the flask. The flask was heated to 85.degree. C. for 90
min. The flask was allowed to cool and then subjected to a EtOAc
(100 mL) and NaHCO.sub.3 (sat, 1M, 100 mL) work up. The aq layer
was extracted with EtOAc (3.times.). The combined organics were
washed with brine, dried with sodium sulfate, filtered and
concentrated to give an oil (1.72 g). The oil thus obtained was
subjected to silica gel chromatography (120 g ISCO, 20 to 35% EtOAc
in hexanes) to give (S)-tert-butyl
((3-((3-methyloxetan-3-yl)ethynyl)pyridin-2-yl)(4-(trifluoromethyl)-pheny-
l)methyl)carbamate as a pale yellow oil.
[0785] (S)-tert-Butyl
((3-((3-methyloxetan-3-yl)ethynyl)pyridin-2-yl)(4-(trifluoro-methyl)pheny-
l)methyl)carbamate from above was prepared by following the
procedure described for the preparation of Intermediate 47, Step 2
to give the title compound as a white solid.
##STR00163##
Intermediate 49:
(1S)-(3-(2,2-Dimethylcyclopropyl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl-
)methanamine hydrochloride
[0786] A mixture of (S)-tert-butyl
(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate
(1.50 g, 3.48 mmol), potassium (2,2-dimethylcyclopropyl)
trifluoroborate (0.857 g, 4.87 mmol), potassium phosphate (2.58 g,
12.17 mmol), dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine
(0.314 g, 0.765 mmol), and palladium acetate (0.094 g, 0.417 mmol)
in toluene/H.sub.2O (10:1, 11 mL) was heated at 100.degree. C. for
24 h. The reaction mixture was cooled, diluted with H.sub.2O, and
extracted with EtOAc (3.times.). The combined extracts were dried
over MgSO.sub.4, concentrated and purified by ISCO (10%
EtOAc/hexanes) to give a colorless oil which was dissolved in DCM
(3 mL) and was treated with 4 mL of 4M HCl in 1,4-dioxane. The
solution was stirred at rt overnight and concentrated to dryness to
give the title compound as an off white solid. MS (ESI pos. ion)
m/z: 321.0 (M+H).
##STR00164##
Intermediate 50:
(S)-(3-Allylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride
[0787] A mixture of (S)-tert-butyl
(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate
(1.00 g, 2.319 mmol), allylboronic acid pinacol ester (0.507 mL,
3.01 mmol), cesium fluoride (0.171 mL, 4.64 mmol), and
(Ph.sub.3P).sub.4Pd (0.536 g, 0.464 mmol) in 1,4-dioxane (10 mL)
was heated by microwave at 125.degree. C. for 30 min. The mixture
was cooled, taken up in H.sub.2O, extracted with Et.sub.2O
(3.times.25 mL), the combined organic layers were dried over
MgSO.sub.4, concentrated and purified by ISCO (0-50%
EtOAc/hexanes). The residue was dissolved in DCM (10 mL) was added
HCl in 4M p-dioxane (4.64 mL, 18.55 mmol). Stirring was continued
for 2 h, and the solution concentrated to the dryness to give the
title compound as a white solid. MS (ESI pos. ion) m/z: 293.0
(M+H).
##STR00165##
Intermediate 51:
(S)-(3-Neopentylpyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamine
hydrochloride
[0788] A mixture of (S)-tert-butyl
(3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methylcarbamate
(0.500 g, 1.159 mmol), bis(tri-t-butylphosphine)-palladium (0)
(0.119 g, 0.232 mmol), and neopentylzinc(II) bromide (4.75 mL,
2.377 mmol) in THF (5 mL) was stirred at 135.degree. C. by
microwave for 30 min. The reaction mixture was cooled, quenched
with saturated aqueous NH.sub.4Cl, and extracted with EtOAc
(3.times.25 mL). The combined organic extracts were dried over
MgSO.sub.4, concentrated, and purified by ISCO (0-40%
EtOAc/hexanes) to give the carbamate intermediate. The carbamate
was dissolved in DCM (5 mL) and 4M HCl in 1,4-dioxane (2 mL) was
added. The reaction mixture was stirred at rt overnight, and
concentrated to dryness to give the title compound as a white
solid. MS (ESI pos. ion) m/z: 323.0 (M+H).
##STR00166##
Intermediate 52:
(S)-(3-Neopentylpyridin-2-yl)(4-(trifluoromethyl)phenyl)-methanamine
hydrochloride
##STR00167##
[0789] Step 1.
(E)-N-(3,4-Dichlorobenzylidene)-2-methylpropane-2-sulfinamide
[0790] A 1-L round-bottomed flask was charged with
3,4-dichlorobenzaldehyde (25.0 g, 143 mmol),
2-methylpropane-2-sulfinamide (17.3 g, 143 mmol), and 200 mL of
THF. To this was added Ti(OEt).sub.4 (65.2 g, 286 mmol) over 5 min.
The reaction was stirred at rt for 5 h and then poured onto brine.
The resulting white precipitate was removed by filtration, and the
filter cake was washed with EtOAc. The filtrate was transferred to
a separatory funnel and the layers were separated. The organic
layers were combined and dried (MgSO.sub.4), filtered, and
concentrated to give
(E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide as a
white solid.
##STR00168##
Step 2.
(S)-(3-Neopentylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methanami-
ne hydrochloride
[0791] A 250-mL round-bottomed flask was charged with
2-iodopyridine (1.0 g, 4.88 mmol) and 50 mL of THF. The resulting
mixture was cooled to -100.degree. C. and then n-BuLi (2.5 M in
hexanes, 5.3 mL, 13 mmol) was added at such a rate that the
internal temp did not rise above -97.degree. C. After 15 min at
-100.degree. C.,
(E)-N-(3,4-dichlorobenzylidene)-2-methylpropane-2-sulfinamide (1.36
g, 4.88 mmol) was added and stirring was continued for 1 h at
-100.degree. C. 30 mL of 1M HCl in ether was added, and the mixture
was allowed to warm to rt. Once at rt, 5 mL of MeOH was added and
the mixture was stirred for an additional 1 h. The resulting
precipitate was collected by filtration to give
(3,4-dichlorophenyl)(pyridin-2-yl)-methanamine hydrochloride as a
white solid.
##STR00169##
Intermediate 53:
1-(4-((S)-Amino(3-(trifluoromethyl)pyridin-2-yl)methyl)-phenyl)ethanol
hydrochloride
##STR00170##
[0792] Step 1.
(S)--N--((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-m-
ethylpropane-2-sulfinamide
[0793] Magnesium metal (0.200 g, 8.23 mmol) was activated using a
crystal of iodine followed by the addition of THF (4 mL).
1-Bromo-4-(diethoxymethyl)-benzene (2.0 g, 7.72 mmol) was added and
the mixture allowed to sit without stirring for 5 minutes. Gas
evolution was observed and the colour of the iodine mostly
disappeared. Stirring was then initiated and additional dry THF (20
mL) was added. After stirring for 2 hours, the mixture was allowed
to settle. The supernatant was added to a solution of
(S,E)-2-methyl-N-((3-(trifluoromethyl)-pyridin-2-yl)methylene)propane-2-s-
ulfinamide (0.450 g, 1.617 mmol) in dry THF (10 mL). The resulting
reaction mixturewas stirred overnight. Saturated aqueous NH.sub.4Cl
(10 mL) was added followed by H.sub.2O (80 mL) and EtOAc (100 mL).
The phases were mixed and separated. The organic layer was dried
with MgSO.sub.4 and evaporated to dryness under reduced pressure.
The acetal was further dried under high vacuum. The acetal was
dissolved in EtOAc (50 mL) and treated with 50% TFA in H.sub.2O (50
mL). The solution was stirred vigourously for 20 minutes. Water
(200 mL), EtOAc (100 mL), and Et.sub.2O (100 mL) were then added
and the phases separated. The aqueous layer was removed, and the
organic layer was washed with additional H.sub.2O (2.times.200 mL).
The organic layer was then washed with saturated aqueous
NaHCO.sub.3 (3.times.100 mL, strong gas evolution) followed by
H.sub.2O (100 mL) and finally brine (100 mL). The organic layer was
dried with MgSO.sub.4 and evaporated to dryness under reduced
pressure. Purification using silica chromatography (hexane to EtOAc
gradient) gave the desired
(S)--N--((S)-(4-formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-m-
ethylpropane-2-sulfinamide as an oil.
##STR00171##
Step 2.
1-(4-((S)-Amino(3-(trifluoromethyl)pyridin-2-yl)methyl)phenyl)-et-
hanol hydrochloride
[0794]
(S)--N--((S)-(4-Formylphenyl)(3-(trifluoromethyl)pyridin-2-yl)methy-
l)-2-methylpropane-2-sulfinamide (0.200 g, 0.520 mmol) was
dissolved in dry THF (30 mL) and cooled in an ice bath.
Methylmagnesium bromide (3M in Et.sub.2O, 0.50 mL, 1.50 mmol) was
added dropwise and the reaction stirred. The resulting mixture was
stirred for 1 h and then quenched by addition of saturated aqueous
NH.sub.4Cl (10 mL). H.sub.2O (100 mL) and EtOAc (100 mL) were
added, and the phases were mixed and separated. The organic layer
was dried with MgSO.sub.4 and evaporated to dryness under reduced
pressure. Purification using silica chromatography (hexane to EtOAc
gradient) gave impure material which was further purified using
reverse phase HPLC to give the desired
(S)--N-((1S)-(4-(1-hydroxyethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)m-
ethyl)-2-methylpropane-2-sulfinamide.
[0795] The sulfinamide was then subjected to the hydrolysis
conditions similar to those described above in Scheme 6, Step 4 to
give the title compound.
##STR00172##
Intermediate 54:
(S)-Pyridin-2-yl(4-(trifluoromethyl)phenyl)methanamine
bis(2,2,2-trifluoroacetate)
##STR00173##
[0796] Step 1. (S)-tert-Butyl
(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-carbamate
[0797] To a solution of (S)-tert-butyl
((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate
(2.24 g, 5.19 mmol) in MeOH (20 mL) was added palladium hydroxide,
(20 wt % Pd (dry basis) on carbon, wet, degussa type) (0.365 g,
2.60 mmol). The resulting mixture was then stirred at rt under
H.sub.2 overnight. The mixture was filtered through Celite.RTM.
brand filter agent and the solids were washed with a solution of
MeOH/EtOAc (1:1, 3.times.20 mL). The combined filtrates were
concentrated and dried to give the desired product as a yellow oil,
which was used in the next step without further purification.
##STR00174##
Step 2. (S)-Pyridin-2-yl(4-(trifluoromethyl)phenyl)methanamine
bis(2,2,2-trifluoroacetate)
[0798] To a solution of (S)-tert-butyl
(pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)carbamate (1.83 g,
5.19 mmol) in DCM (12 mL) was added TFA (3.86 mL, 51.9 mmol). The
resulting mixture was then stirred at rt for 1 h. The mixture was
then concentrated and dried to give the title compound as a yellow
oil which was used without further purification in the amide
coupling step.
##STR00175##
Intermediates 55-57: 4-Hydroxyquinoline-6-carboxylic acid (55),
4-chloro-quinoline-6-carboxylic acid (56), and 2-oxo-1,2,4a,
8a-tetrahydroquinoline-6-carboxylic acid (57)
##STR00176##
[0799] Step 1. Methyl quinoline-6-carboxylate
[0800] To a solution of quinoline-6-carboxylic acid (1.00 g, 5.77
mmol) in MeOH (10 mL) was added hydrogen chloride (2.00 mL, 8.00
mmol) (4.0M in 1,4-dioxane). The reaction was stirred 18 h at rt,
LCMS shows <10% conversion. Additional hydrogen chloride (2.00
mL, 8.00 mmol) was added and the reaction heated to 50.degree. C.
in an oil bath 36 h. The reaction was cooled to rt and concentrated
in vacuo. The solid was dissolved in DCM and extracted with sat.
aqueous NaHCO.sub.3 (2.times.50 mL). The organic layer was dried
(MgSO.sub.4), and concentrated to give the product which was used
without further purification in the next step.
##STR00177##
Step 2. 6-(Methoxycarbonyl)quinoline-N-oxide
[0801] To a solution of methyl quinoline-6-carboxylate from above
in DCM (10 mL) was added 3-chlorobenzoperoxoic acid (1.991 g, 11.54
mmol). The reaction was stirred 21 h at rt. The mixture was then
diluted with saturated aqueous NaHCO.sub.3 (40 mL), and the mixture
was extracted with DCM (2.times.30 mL). The organic layers were
combined, washed with saturated aqueous NaCl (40 mL), dried
(MgSO.sub.4), and concentrated. The N-oxide was isolated as an
orange solid which was used without purification in the next
step.
##STR00178##
Step 3. Methyl 4-chloroquinoline-6-carboxylate and methyl
2-chloro-quinoline-6-carboxylate
[0802] To 6-(methoxycarbonyl)quinoline-N-oxide from the above step
was added phosphoryl trichloride (5 mL, 54.6 mmol). The resulting
mixture was then stirred at rt under N.sub.2 for 2 h. The reaction
was then slowly quenched by addition to an ice cold solution of
saturated aqueous NaHCO.sub.3 (50 mL) in an ice bath with rapid
stirring. The aqueous solution was extracted with EtOAc (3.times.50
mL). The organic layers were combined, washed with saturated
aqueous NaHCO.sub.3 (25 mL), H.sub.2O (25 mL), dried (MgSO.sub.4),
and concentrated. Purification by ISCO (40 g SiO.sub.2, 0-50%
EtOAc/hexanes) gave as the major product, methyl
4-chloroquinoline-6-carboxylate (330 mg, 1.489 mmol, 25.8% yield
over 3 steps) (m/z=221.9) as a white solid. Also isolated was the
more polar, methyl 2-chloroquinoline-6-carboxylate with same mass
(m/z=221.9).
##STR00179##
Step 4a. 4-Hydroxyquinoline-6-carboxylic acid (55) and
4-chloroquinoline-6-carboxylic acid (56)
[0803] A solution of methyl 4-chloroquinoline-6-carboxylate (110
mg, 0.496 mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to
60.degree. C. in a heating block for 24 h. LCMS showed major
product with a 56-70% peak area corresponding to
4-hydroxyquinoline-6-carboxylic acid with hydrolysis of methyl
ester (M+H=189.9). Also present was a 18-34% peak area
corresponding to 4-chloroquinoline-6-carboxylic acid. The reaction
was concentrated and used in the subsequent amide coupling steps
without further purification.
##STR00180##
Step 4b. 2-Oxo-1,2,4a,8a-tetrahydroquinoline-6-carboxylic acid
(57)
[0804] A solution of methyl 2-chloroquinoline-6-carboxylate (60 mg,
0.271 mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to
60.degree. C. in a heating block. LCMS shows major product 86% peak
area corresponding to title compound with hydrolysis of methyl
ester (m/z=189.9). The reaction was concentrated and used in the
subsequent amide coupling steps without further purification.
##STR00181##
Intermediates 58-60: 4-Hydroxyquinoline-6-carboxylic acid,
4-chloro-quinoline-6-carboxylic acid (58),
2-oxo-1,2,4a,8a-tetrahydroquinoline-6-carboxylic acid (59), and
2-oxo-1,2-dihydroquinoline-7-carboxylic acid (60)
##STR00182##
[0805] Step 1. Methyl quinoline-7-carboxylate
[0806] To a solution of quinoline-7-carboxylic acid (1.00 g, 5.77
mmol) in MeOH (10 mL) was added hydrogen chloride (2.00 mL, 8.00
mmol) (4.0M in 1,4-dioxane). The reaction was stirred for 18 h at
rt (LCMS showed <10% conversion to the desired product).
Additional hydrogen chloride (2.00 mL, 8.00 mmol) was added, and
the reaction mixture was heated to 50.degree. C. in an oil bath for
36 h. The reaction was cooled to rt, and concentrated in vacuo. The
solid was dissolved in DCM, and washed with saturated aqueous
NaHCO.sub.3 (2.times.50 mL). The organic layer was dried
(MgSO.sub.4) and concentrated to give the product, which was used
without further purification in the next step.
##STR00183##
Step 2. 7-(Methoxycarbonyl)quinoline-N-oxide
[0807] To a solution of the methyl quinoline-7-carboxylate from
above in DCM (10 mL) was added 3-chlorobenzoperoxoic acid (1.991 g,
11.54 mmol). The reaction was stirred for 21 h at rt. The mixture
was then diluted with saturated aqueous NaHCO.sub.3 (40 mL) and the
mixture was extracted with DCM (2.times.30 mL). The organic layers
were combined, washed with saturated aqueous NaCl (40 mL), dried
(MgSO.sub.4), and concentrated. The N-oxide was isolated as an
orange solid which was used without purification in the next
step.
##STR00184##
Step 3. Methyl 4-chloroquinoline-7-carboxylate and methyl
2-chloro-quinoline-7-carboxylate
[0808] To the N-oxide from above was added phosphoryl trichloride
(10 mL, 109 mmol). The resulting reaction mixture was stirred at rt
under N.sub.2 or 2 h. The reaction was then quenched by slowly
adding it to an ice cold solution of saturated aqueous NaHCO.sub.3
(100 mL) in an ice bath with rapid stirring. The aqueous solution
was extracted with EtOAc (3.times.50 mL), the organic layers
combined, washed with saturated aqueous NaHCO.sub.3 (25 mL),
H.sub.2O (25 mL), dried (MgSO.sub.4), and concentrated.
Purification by ISCO (40 g SiO.sub.2, 0-50% EtOAc/hexanes) gave
methyl 4-chloroquinoline-7-carboxylate as a white solid and methyl
2-chloro-quinoline-7-carboxylate as a white solid.
##STR00185##
Step 4a. 4-Hydroxyquinoline-7-carboxylic acid (58) and
4-chloroquinoline-7-carboxylic acid (59)
[0809] A solution of methyl 4-chloroquinoline-7-carboxylate (110
mg, 0.496 mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to
60.degree. C. in a heating block or 22 h. LCMS showed formation of
product (40% peak area) with the mass of
4-hydroxyquinoline-7-carboxylic acid (m/z (M+H)=189.9). Additional
product 20% peak area corresponding to the mass of
4-chloroquinoline-7-carboxylic acid (m/z (M+H)=207.9). The reaction
was concentrated and used in the subsequent amide coupling steps
without further purification.
##STR00186##
Step 4b. 2-Oxo-1,2-dihydroquinoline-7-carboxylic acid (60)
[0810] A solution of methyl 2-chloroquinoline-7-carboxylate (150
mg, 0.677 mmol) in THF/5 N aqueous HCl (1:1, 2 mL) was heated to
60.degree. C. in a heating block or 24 h. LCMS showed major product
(47% peak area) corresponding to
2-oxo-1,2-dihydroquinoline-7-carboxylic acid (m/z (M+H)=189.9). The
reaction was concentrated and used in the subsequent amide coupling
steps without further purification.
EXAMPLES
General Amide Formation Procedure for Examples (1-261, 287-424)
[0811] To a solution of
(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanami-
ne (50 mg, 0.156 mmol), the corresponding carboxylic acid (0.156
mmol), and DIPEA (0.080 mL, 0.468 mmol) in DCM or DMF (1 mL) at rt
is added an amide coupling reagent such as (HATU, TBTU, or EDCI)
(0.156 mmol, 1.0 equiv.). The reaction was stirred 3 h at rt. The
reaction was diluted with DMF (1 mL), filtered through a syringe
filter, then purified by preperative reverse phase HPLC (gradient
elution 10-100% MeCN/0.1% TFA in H.sub.2O). The product containing
fractions were then combined and the solvent removed by
lyophilzation to provide the target compound as the TFA salt; or
the product was dissolved in MeOH (1 mL) and washed through
PL-HCO.sub.3 MP-resin, the resin was further washed with MeOH
(2.times.0.4 mL). The combined filtrates were then concentrated and
dried in vacuo to give the title compounds as free bases; or the
product containing fractions were concentrated, the solids
dissolved in DCM and the organic layer extracted with saturated
aqueous NaHCO.sub.3, the organic layer was dried, and concentrated
to provide the title compounds as free bases.
TABLE-US-00002 TABLE 2 Examples 1-261 prepared via amide formation
analogous to Scheme 4 MS Ex A- Product Product M + # mine Acid
Structure Structure Name H 1 8 ##STR00187## ##STR00188##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoro- methoxy)-
phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 408.0 2 8
##STR00189## ##STR00190## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoro- methoxy)- phenyl)methyl)- quinoline-7- carboxamide
442.0 3 4 ##STR00191## ##STR00192## (S)-N-((3,4- dichlorophenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)-6- hydroxy-
nicotinamide 442.0 4 9 ##STR00193## ##STR00194## (S)-N-((6-chloro-
quinolin-3-yl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)-
quinoline-7- carboxamide 493.0 5 5 ##STR00195## ##STR00196##
(S)-N-((4- (trifluoro- methoxy)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- quinoline-7- carboxamide 492.0 6 10
##STR00197## ##STR00198## (S)-N-((4-chloro- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- quinoline-7- carboxamide
442.0 7 11 ##STR00199## ##STR00200## (S)-N-((8-chloro-
quinolin-3-yl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)-
quinoline-7- carboxamide 493.0 8 12 ##STR00201## ##STR00202##
(S)-N-((7- methoxyquinolin- 3-yl)(3-(trifluoro- methyl)pyridin-2-
yl)methyl)- quinoline-7- carboxamide 489.0 9 13 ##STR00203##
##STR00204## (S)-N-((5-chloro- quinolin-3-yl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- quinoline-7- carboxamide 493.0 10 4
##STR00205## ##STR00206## (S)-N-((3,4- dichlorophenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- quinoline-7-
carboxamide 475.9 11 9 ##STR00207## ##STR00208## (S)-N-((6-chloro-
quinolin-3-yl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)-
isoquinoline-6- carboxamide 493.0 12 14 ##STR00209## ##STR00210##
(S)-N-(quinolin- 3-yl)(3-(trifluoro- methyl)pyridin-2- yl)methyl)-
quinoline-7- carboxamide 459.0 13 15 ##STR00211## ##STR00212##
(S)-N-((3-chloro- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- quinoline-7- carboxamide 442.0 14 16 ##STR00213##
##STR00214## (S)-N-(p-tolyl(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- quinoline-7- carboxamide 422.0 15 17 ##STR00215##
##STR00216## (S)-N- (naphthalen-2- yl(3-(trifluoro-
methyl)pyridin-2- yl)methyl)- quinoline-7- carboxamide 458.0 16 9
##STR00217## ##STR00218## (S)-N-((6-chloro- quinolin-3-yl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)-6- hydroxy- nicotinamide
458.9 17 18 ##STR00219## ##STR00220## (S)-N-((3-fluoro- phneyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- quinoline-7- carboxamide
426.0 18 19 ##STR00221## ##STR00222## (S)-N-((3- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)- quinoline-7-
carboxamide 476.0 19 3 ##STR00223## ##STR00224## (S)-N-((4-
methoxyphenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
quinoline-7- carboxamide 438.0 20 20 ##STR00225## ##STR00226##
(S)-N-((8-fluoro- quinolin-3-yl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- quinoline-7- carboxamide 477.0 21 21
##STR00227## ##STR00228## (S)-N-(m-tolyl(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- quinoline-7- carboxamide 422.0 22 22
##STR00229## ##STR00230## (S)-N-(quinolin- 6-yl(3-(trifluoro-
methyl)pyridin-2- yl)methyl)- quinoline-7- carboxamide 458.9 23 24
##STR00231## ##STR00232## (S)-N-((8- methoxyquinolin-
3-yl)(3-(trifluoro- methyl)pyridin-2- yl)methyl)- quinoline-7-
carboxamide 489.0 24 25 ##STR00233## ##STR00234## (S)-N-((3-
methoxyphenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
quinoline-7- carboxamide 438.0 25 26 ##STR00235## ##STR00236##
(S)-N-((3-fluoro- 4- methoxyphenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- quinoline-7- carboxamide 456.0 26 53
##STR00237## ##STR00238## N-((1S)-(4-(1- hydroxyethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- quinoline-7- carboxamide
452.0 27 27 ##STR00239## ##STR00240## (S)-N-((4-fluoro- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- quinoline-7- carboxamide
426.0 28 43 ##STR00241## ##STR00242## (S)-N-((3- methoxypyridin-
2-yl)(4-(trifluoro- methyl)phenyl)- methyl)- quinoline-7-
carboxamide 438.2 29 1 ##STR00243## ##STR00244## (S)-2-methoxy-
N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- nicotinamide 456.0 30 1 ##STR00245## ##STR00246##
(S)-6-methoxy- N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- nicotinamide 456.0 31 1 ##STR00247##
##STR00248## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- pyridazine-3-
carboxamide 427.1 32 1 ##STR00249## ##STR00250## (S)-4-methoxy-
N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- picolinamide 456.0 33 1 ##STR00251## ##STR00252##
(S)-6-methoxy- N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- picolinamide 456.0 34 1 ##STR00253##
##STR00254## (S)-2-methoxy- N-((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- isonicotinamide 456.0
35 2a ##STR00255## ##STR00256## N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 6- methoxynicotina- mide 406.1
36 2a ##STR00257## ##STR00258## N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 2- methoxynicotina- mide 406.1
37 1 ##STR00259## ##STR00260## (S)-6-methoxy- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
pyridazine-3- carboxamide 457.1 38 1 ##STR00261## ##STR00262##
(S)-5-methoxy- N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- nicotinamide 456.0 39 1 ##STR00263##
##STR00264## (S)-2-methyl-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- isonicotinamide 440.1
40 1 ##STR00265## ##STR00266## (S)-6-methyl-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
nicotinamide 440.1 41 1 ##STR00267## ##STR00268## (S)-6-oxo-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)-1,6- dihydropyridine- 3-carboxamide 442.1 42 1 ##STR00269##
##STR00270## (S)-2-methoxy- N-((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- pyrimidine-5-
carboxamide 457.1 43 1 ##STR00271## ##STR00272## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)-1H- pyrrolo[2,3- b]pyridine-3- carboxamide 465.0 44 1
##STR00273## ##STR00274## (S)-2-hydroxy-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
isonicotinamide 442.1 45 1 ##STR00275## ##STR00276## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)-7H- pyrrolo[2,3- d]pyrimidine-5- carboxamide 466.1 46 2
##STR00277## ##STR00278## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 6- methoxynicotina- mide 406.1
47 2 ##STR00279## ##STR00280## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 2- methoxynicotina- amide 406.1
48 1 ##STR00281## ##STR00282## (S)-3-methoxy- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
isonicotinamide 456.0 49 1 ##STR00283## ##STR00284##
(S)-1-methyl-2- oxo-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)-1,2- dihydropyridine-
4-carboxamide 456.0 50 1 ##STR00285## ##STR00286## (S)-1-methyl-6-
oxo-N-((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)-1,6- dihydropyridine- 3-carboxamide 456.0 51
2 ##STR00287## ##STR00288## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 392.1 52 2 ##STR00289## ##STR00290##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 6-methyl- nicotinamide 390.2 53 2 ##STR00291##
##STR00292## (S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 2-methyl- isonicotinamide- 390.2 54 2 ##STR00293##
##STR00294## (S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 1H-pyrrolo[2,3- b]pyridine-3- carboxamide 415.1 55
1 ##STR00295## ##STR00296## (S)-4-methoxy- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
nicotinamide 456.0 56 1 ##STR00297## ##STR00298## (S)-2-oxo-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)indoline- 5-carboxamide 480.0 57 1 ##STR00299## ##STR00300##
(S)-2-methyl-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- pyrimidine-5- carboxamide 441.0 58 1
##STR00301## ##STR00302## (S)-5-hydroxy-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
nicotinamide 442.1 59 1 ##STR00303## ##STR00304## (S)-2-oxo-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)-1,2- dihydropyridine- 3-carboxamide 442.1 60 1 ##STR00305##
##STR00306## (S)-4-methyl-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- pyrimidine-5-
carboxamide 441.0 61 1 ##STR00307## ##STR00308## (S)-4-hydroxy-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- pyrimidine-5- carboxamide 443.1 62 1 ##STR00309##
##STR00310## (S)-4-hydroxy-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- picolinamide 442.1 63
1 ##STR00311## ##STR00312## (S)-6-oxo-N-((4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)-1,6-
dihydropyridine- 2-carboxamide 442.1 64 1 ##STR00313## ##STR00314##
(S)-5-hydroxy-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- picolinamide 442.1
65 1 ##STR00315## ##STR00316## 6-oxo-N-((S)-(4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)- piperidine-3-
carboxamide 446.1 66 1 ##STR00317## ##STR00318## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)-1H- pyrrolo[2,3- b]pyridine-2- carboxamide 465.0 67 1
##STR00319## ##STR00320## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)-1H- pyrrolo[2,3-
b]pyridine-6- carboxamide 465.0 68 2 ##STR00321## ##STR00322##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 1-methyl-6-oxo- 1,6-dihydro- pyridine-3-
carboxamide 406.1 69 1 ##STR00323## ##STR00324## (S)-2-oxo-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)indoline- 6-carboxamide 480.2 70 2 ##STR00325## ##STR00326##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 2-oxoindoline-5- carboxamide 430.1 71 2
##STR00327## ##STR00328## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 2-oxoindoline-6- carboxamide
430.1 72 2 ##STR00329## ##STR00330## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 2-oxo-1,2-
dihydropyridine- 3-carboxamide 392.1 73 2 ##STR00331## ##STR00332##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxa- zine-7-
carboxamide 446.1 74 2 ##STR00333## ##STR00334## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 4-(N-
methylsulfamoyl) benzamide 468.0 75 2 ##STR00335## ##STR00336##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 2-oxo-3,4- dihydro-2H- benzo[b][1,4]oxa- zine-6-
carboxamide 446.1 76 2 ##STR00337## ##STR00338## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 2-oxo-2,3-
dihydro- benzo[d]oxazole- 5-carboxamide 432.0 77 2 ##STR00339##
##STR00340## (S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 3-oxo-3,4- dihydro-2H- benzo[b][1,4]oxa- zine-8-
carboxamide 446.1 78 2 ##STR00341## ##STR00342## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 2-oxo-2,3-
dihydro- benzo[d]oxazole- 6-carboxamide 432.2 79 8 ##STR00343##
##STR00344## (S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoro-
methoxy)- phenyl)methyl)- 2-oxo-2,3- dihydro- benzo[d]oxazole-
5-carboxamide 448.1 80 8 ##STR00345## ##STR00346##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoro- methoxy)-
phenyl)methyl)- 2-oxo-2,3- dihydro- benzo[d]oxazole- 6-carboxamide
448.1 81 8 ##STR00347## ##STR00348## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoro- methoxy)- phenyl)methyl)- 3-oxo-3,4-
dihydro-2H- benzo[b][1,4]oxa- zine-7- carboxamide 462.0 82 44
##STR00349## ##STR00350## (S)-N-((3- methylpyridin-2-
yl)(4-(trifluoro- methyl)phenyl)- methyl)-6-oxo- 1,6-dihydro-
pyridine-3- carboxamide 2,2,2- trifluoroacetate 388.1 83 44
##STR00351## ##STR00352## (S)-1-methyl-N- ((3- methylpyridin-2-
yl)(4-(trifluoro- methyl)phenyl)- methyl)-6-oxo- 1,6-dihydro-
pyridine-3- carboxamide 2,2,2- trifluoroacetate 402.2 84 44
##STR00353## ##STR00354## (S)-N-((3- methylpyridin-2-
yl)(4-(trifluoro- methyl)phenyl)- methyl)-2-oxo- 2,3-dihydro-
benzo[d]oxazole- 5-carboxamide 428.1 85 44 ##STR00355##
##STR00356## (S)-N-((3- methylpyridin-2- yl)(4-(trifluoro-
methyl)phenyl)- methyl)-3-oxo- 3,4-dihydro-2H- benzo[b][1,4]oxa-
zine-7- carboxamide 442.1 86 2 ##STR00357## ##STR00358##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- imidazo[1,2- a]pyridine-7- carboxamide 415.1 87 1
##STR00359## ##STR00360## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- imidazo[1,2-
a]pyridine-7- carboxamide 465.0 88 8 ##STR00361## ##STR00362##
(S)-N-(3-fluoro- pyridin-2-yl)(4- (trifluoro- methoxy)-
phenyl)methyl)- imidazo[1,2- a]pyridine-7- carboxamide 431.1 89 8
##STR00363## ##STR00364## S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoro- methoxy)- phenyl)methyl)- imidazo[1,2- a]pyridine-6-
carboxamide 2,2,2- trifluoroacetate 431.1 90 8 ##STR00365##
##STR00366## (S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoro-
methoxy)- phenyl)methyl)- 2-oxoindoline-6- carboxamide 446.1 91 8
##STR00367## ##STR00368## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoro- methoxy)- phenyl)methyl)- 2-oxoindoline-5- carboxamide
446.1 92 47 ##STR00369## ##STR00370## (S)-6-oxo-N-((3-
(prop-1-yn-1-yl)- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 1,6-dihydro- pyridine-3- carboxamide 412.1 93 47
##STR00371## ##STR00372## (S)-N-((3-(prop- 1-yn-1-yl)-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- quinoline-6-
carboxamide 446.2 94 1 ##STR00373## ##STR00374## (S)-1,3-dioxo-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- isoindoline-5- carboxamide 494.1 95 47 ##STR00375##
##STR00376## (S)-4-methoxy- N-((3-(prop-1- yn-1-yl)pyridin-
2-yl)(4-(trifluoro- methyl)phenyl)- methyl)- benzamide 2,2,2-
trifluoroacetate 425.2 96 47 ##STR00377## ##STR00378##
(S)-6-methoxy- N-((3-(prop-1- yn-1-yl)pyridin- 2-yl)(4-(trifluoro-
methyl)phenyl)- methyl)- nicotinamide 426.2 97 47 ##STR00379##
##STR00380## (S)-N-((3-(prop- 1-yn-1-yl)- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- quinoline-7- carboxamide 2,2,2-
trifluoroacetate 446.2 98 47 ##STR00381## ##STR00382##
(S)-N-((3-(prop- 1-yn-1-yl)- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- benzamide 395.1 99 1 ##STR00383## ##STR00384##
(S)-1,3-dioxo-2- (pyridin-2-yl)-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- isoindoline-5-
carboxamide 2,2,2- trifluoroacetate 571.1 100 1 ##STR00385##
##STR00386## (S)-2-bromo-4- (((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- carbamoyl)- benzoic
acid 549.0 101 48 ##STR00387## ##STR00388## (S)-N-((3-((3-
methyloxetan-3- yl)ethynyl)- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- quinoline-6- carboxamide 2,2,2- trifluoroacetate
502.2 102 6 ##STR00389## ##STR00390## (S)-N-((3-fluoro-
4-(trifluoro- methoxy)- phenyl)(3-fluoro- pyridin-2-yl)-
methyl)-6-oxo- 1,6-dihydro- pyridine-3- carboxamide 2,2,2-
trifluoroacetate 425.9 103 6 ##STR00391## ##STR00392##
(S)-N-((3-fluoro- 4-(trifluoro- methoxy)- phenyl)(3-fluoro-
pyridin-2-yl)- methyl)-1- methyl-6-oxo- 1,6-dihydro- pyridine-3-
carboxamide 439.9 104 2 57 ##STR00393## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 2-oxo-1,2-
dihydro- quinoline-6- carboxamide 441.8 105 2 58 ##STR00394##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 4-hydroxy- quinoline-7- carboxamide 2,2,2-
trifluoroacetate 441.8 106 1 58 ##STR00395## (S)-4-hydroxy-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- quinoline-7- carboxamide 2,2,2- trifluoroacetate 491.6
107 7 ##STR00396## ##STR00397## (S)-N-((3-fluoro- 4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
benzamide 443.0 108 7 ##STR00398## ##STR00399## (S)-N-((3-fluoro-
4-(trifluoro- methyl)phenyl)- 3-(trifluoro- methyl)pyridin-2-
yl)methyl)- quinoxaline-6- carboxamide 494.9 109 1 55 ##STR00400##
(S)-4-hydroxy-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- quinoline-6- carboxamide 2,2,2-
trifluoroacetate 491.6 110 1 59 ##STR00401## (S)-4-chloro-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- quinoline-7- carboxamide 2,2,2- trifluoroacetate 509.6
111 7 ##STR00402## ##STR00403## (S)-N-((3-fluoro- 4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
pyrazine-2- carboxamide 445.0 112 7 ##STR00404## ##STR00405##
(S)-N-((3-fluoro- 4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- picolinamide 443.9 113 2 56
##STR00406## (S)-4-chloro-N- ((3-fluoropyridin- 2-yl)(4-(trifluoro-
methyl)phenyl)- methyl)- quinoline-6- carboxamide 2,2,2-
trifluoroacetate 459.6 114 2 55 ##STR00407## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 4-hydroxy-
quinoline-6- carboxamide 2,2,2- trifluoroacetate 441.8 115 29
##STR00408## ##STR00409## (S)-N-((4- ethylphenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- quinoline-7- carboxamide
436.1 116 1 56 ##STR00410## (S)-4-chloro-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
quinoline-6- carboxamide 2,2,2- trifluoroacetate 509.6 117 1
##STR00411## ##STR00412## (S)-3-iodo-N-((4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)- benzamide
550.5 118 1 ##STR00413## ##STR00414## (S)-2-iodo-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- benzamide 550.5 119 7 ##STR00415## ##STR00416##
(S)-N-((S)-(3- fluoro-4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)THF-2- carboxamide 437.0
120 2 ##STR00417## ##STR00418## (S)-4-chloro-N- ((3-fluoropyridin-
2-yl)(4-(trifluoro- methyl)phenyl)- methyl)- quinoline-7-
carobxamide 2,2,2- trifluoroacetate 459.6 121 1 ##STR00419##
##STR00420## (S)-4-(2-hydro- xypropan-2-yl)- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
benzamide 483.0 122 1 ##STR00421## ##STR00422## (S)-4-iodo-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- benzamide 550.5 123 7 ##STR00423## ##STR00424##
(R)-N-((S)-(3- fluoro-4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)THF-2- carboxamide 437.0
124 27 ##STR00425## ##STR00426## (S)-N-((4-fluoro- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)-6- methoxynicotina- mide
406.1 125 2 60 ##STR00427## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- 2-oxo-1,2- dihydro- quinoline-7- carboxamide
441.8 126 27 ##STR00428## ##STR00429## (S)-N-((4-fluoro- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- benzamide 375.1 127 1
##STR00430## ##STR00431## (S)-4-isopropyl- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
benzamide 485.0 128 1 ##STR00432## ##STR00433## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)-1,8- naphthyridine-2- carboxamide 2,2,2- trifluoroacetate
476.9 129 7 ##STR00434## ##STR00435## (S)-N-(3-fluoro-
4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)-1,8- naphthyridine-2- carboxamide 2,2,2-
trifluoroacetate 494.9 130 7 ##STR00436## ##STR00437##
(S)-N-((3-fluoro- 4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
quinoline-6- carboxamide bis (2,2,2- trifluoroacetate) 494.0 131 7
##STR00438## ##STR00439## (S)-N-((3-fluoro- 4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
quinoline-7- carboxamide 494.0 132 1 ##STR00440## ##STR00441##
(S)-N-((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- quinoline-7- carboxamide 476.0 133 1
##STR00442## ##STR00443## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- quinoline-6- carboxamide
476.0 134 1 ##STR00444## ##STR00445## (S)-6-amino-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- nicotinamide 441.0 135 1 ##STR00446## ##STR00447##
(S)-6-chloro-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- nicotinamide 460.0 136 1 ##STR00448##
##STR00449## (S)-2-amino-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- thiazole-4-
carboxamide 2,2,2- trifluoroacetate 446.9 137 1 ##STR00450##
##STR00451## (S)-4-amino-2- methyl-N-((4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)- pyrimidine-5-
carboxamide 456.0 138 1 ##STR00452## ##STR00453## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- thiophene-2- carboxamide 430.9 139 1 ##STR00454##
##STR00455## (S)-3-amino-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- isonicotinamide 441.0
140 1 ##STR00456## ##STR00457## (S)-methyl 4- (((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
carbamoyl)- benzoate 482.9 141 1 ##STR00458## ##STR00459##
(S)-4-(1H- tetrazol-5-yl)-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- benzamide 493.0 142 1
##STR00460## ##STR00461## tert-butyl 3-(((S)- (4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
carbamoyl)- piperidine-1- carboxylate 554.0 (M + Na) 143 1
##STR00462## ##STR00463## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)-1H- pyrazole-4-
carboxamide 415.0 144 1 ##STR00464## ##STR00465## (S)-3-amino-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- picolinamide 441.0 145 1 ##STR00466## ##STR00467##
(S)-3-(4- methylthiazol-5- yl)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- propanamide 474.0 146 1
##STR00468## ##STR00469## (S)-1-methyl-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-1H-
imidazole-2- carboxamide 429.0 147 1 ##STR00470## ##STR00471##
(S)-N-((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- pyrimidine-5- carboxamide 427.0 148 1
##STR00472## ##STR00473## (S)-6-acetamido- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
nicotinamide 2,2,2- trifluoroacetate 482.9 149 1 ##STR00474##
##STR00475## (S)-5,7-dimethyl- N-((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- pyrazolo[1,5-
a]pyrimidine-2- carboxamide 494.0 150 1 ##STR00476## ##STR00477##
(S)-6-oxo-N-((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)-1,6- dihydro- pyridazine-3- carboxamide
443.0 151 1 ##STR00478## ##STR00479## (S)-5,7-dimethyl-
N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- [1,2,4]triazolo[1, 5-a]pyrimidine-2- carboxamide 2,2,2-
trifluoroacetate 495.0 152 1 ##STR00480## ##STR00481## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- tetrahydro-2H- pyran-4- carboxamide 433.0 153 1
##STR00482## ##STR00483## (S)-2-(5-methyl- 1H-pyrazol-1-yl)-
N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- acetamide 443.0 154 1 ##STR00484## ##STR00485##
(S)-2-(2- oxooxazolidin-3- yl)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)acetamide 448.0 155 1
##STR00486## ##STR00487## (S)-3-(1H- imidazol-4-yl)-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- lmethyl)pyridin-
2-yl)methyl)- propanamide 2,2,2- trifluoroacetate 443.0 156 7
##STR00488## ##STR00489## (S)-N-((3-fluoro- 4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-2-
isobutylquinoline- 4-carboxamide bis (2,2,2- trifluoroacetate)
550.0 157 1 ##STR00490## ##STR00491## 2-(THF-3-yl)-N-
((S)-(4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- acetamide 433.0 158 1 ##STR00492##
##STR00493## (S)-2-(1H- imidazol-4-yl)-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro_ methyl)pyridin-2- yl)methyl)-
acetamide 429.0 159 1 ##STR00494## ##STR00495## (S)-3-amino-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)-1H- 1,2,4-triazole-5- carboxamide 431.0 160 1
##STR00496## ##STR00497## (S)-2-(2-methyl- 1H-imidazol-1-
yl)-N-((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)acetamide 443.0 161 1 ##STR00498##
##STR00499## (S)-2-(1H- imidazol-1-yl)-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
acetamide 2,2,2- trifluoroacetate 428.9 162 1 ##STR00500##
##STR00501## 2-acetamido-N- ((S)-(4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- propanamide 434.0 163
1 ##STR00502## ##STR00503## 5-oxo-N-((S)-(4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)-
pyrrolidine-3- carboxamide 432.0 164 1 ##STR00504## ##STR00505##
(S)-2-(2- (trifluoro- methoxy)- phenyl)-N-((4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)acetamide 523.0
165 1 ##STR00506## ##STR00507## (S)-4-hydroxy-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- 441.0 166 2
##STR00508## ##STR00509## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 1H-indazole-6- carboxamide 415.1
167 2 ##STR00510## ##STR00511## (S)-4-cyano-N- ((3-fluoropyridin-
2-yl)(4-(trifluoro- methyl)phenyl)- methyl)- benzamide 400.1 168 1
##STR00512## ##STR00513## (S)-3-cyano-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)be 450.0
169 2 ##STR00514## ##STR00515## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 2-methoxy- benzamide 405.2 170 2
##STR00516## ##STR00517## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- quinoxazoline-6- carboxamide
427.1 171 1 ##STR00518## ##STR00519## (S)-4-methoxy-
N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- benzamide 455.1 172 2 ##STR00520## ##STR00521##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 4-methoxy- benzamide 405.0 173 2 ##STR00522##
##STR00523## (S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- 5-hydroxy- picolinamide 392.1 174 1 ##STR00524##
##STR00525## (S)-4-(((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- carbamoyl)- phenyl
acetate 483.0 175 1 ##STR00526## ##STR00527## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)-1H- indazole-6- carboxamide 465.0 176 1 ##STR00528##
##STR00529## (S)-2-methoxy- N-((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- benzamide 455.1 177 2
##STR00530## ##STR00531## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 2-oxo-2,3- dihydro-1H- benzo[d]
imidazole- 5-carboxamide 431.1 178 1 ##STR00532## ##STR00533##
(S)-N-((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- isonicotinamide 426.0 179 1 ##STR00534##
##STR00535## (S)-3-(((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- carbamoyl)- benzoic acid
469.1 180 2 ##STR00536## ##STR00537## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- benzamide 375.2
181 1 ##STR00538## ##STR00539## (S)-4-cyano-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
benzamide 450.0 182 1 ##STR00540## ##STR00541## (S)-5-methyl-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- nicotinamide 2,2,2- trifluoroacetate 440.1 183 1
##STR00542## ##STR00543## (S)-4-fluoro-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
benzamide 443.1 184 2 ##STR00544## ##STR00545## (S)-3-cyano-N-
((3-fluoropyridin- 2-yl)(4-(trifluoro- methyl)phenyl)- methyl)-
benzamide 400.1 185 1 ##STR00546## ##STR00547## (S)-4-chloro-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- benzamide 459.0 186 1 ##STR00548## ##STR00549## (S)-3-
(dimethylamino)- N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- benzamide 468.2 187 2 ##STR00550##
##STR00551## (S)-3-fluoro-N- ((3-fluoropyridin- 2-yl)(4-(trifluoro-
methyl)phenyl)- methyl)- benzamide 393.0 188 1 ##STR00552##
##STR00553## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- nicotinamide 426.0 189 1
##STR00554## ##STR00555## (S)-methyl 3- (((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
carbamoyl)- benzoate 483.0 190 1 ##STR00556## ##STR00557##
(S)-4-methyl-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- oxazole-5- carboxamide 430.1 191 1
##STR00558## ##STR00559## (S)-3-methoxy- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
benzamide 455.1 192 1 ##STR00560## ##STR00561## (S)-1-methyl-N-
((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)-1H- pyrazole-3- carboxamide 429.2 193 2a ##STR00562##
##STR00563## N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- benzamide 375.0 194 2 ##STR00564## ##STR00565##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- picolinamide 376.1 195 44 ##STR00566## ##STR00567##
(S)-N-((3- bromopyridin-2- yl)(4-(trifluoro- methyl)phenyl)-
methyl)- quinoline-7- carboxamide 486.0, 488.0 196 1 ##STR00568##
##STR00569## (S)-4- (dimethylamino)-
N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2-
yl)methyl)- benzamide 468.1 197 1 ##STR00570## ##STR00571##
(S)-2-cyano-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- benzamide 450.0 198 2 ##STR00572##
##STR00573## (S)-5-bromo-6- chloro-N-((3- fluoropyridin-2-
yl)(4-(trifluoro- methyl)phenyl)- methyl)- nicotinamidie 488.0,
490.0 199 1 ##STR00574## ##STR00575## (S)-N-((4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)furan-3-
carboxamide 415.1 200 2a ##STR00576## ##STR00577## 4-cyano-N-((3-
fluoropyridin-2- yl)(4-(trifluoro- methyl)phenyl)- methyl)-
benzamide 400.1 201 54 ##STR00578## ##STR00579## (S)-6-oxo-N-
(pyridin-2-yl(4- (trifluoromethyl)- phenyl)methyl)- 1,6-dihydro-
pyridine-3- carboxamide 2,2,2- trifluoroacetate 374.1 202 2a
##STR00580## ##STR00581## N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- quinoxaline-6- carboxamide 427.1
203 2 ##STR00582## ##STR00583## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- nicotinamide 376.1 204 2a
##STR00584## ##STR00585## N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- quinoline-7- carboxamide 426.2
205 1 ##STR00586## ##STR00587## (S)-5-bromo-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
picolinamide 505.0, 507.0 206 1 ##STR00588## ##STR00589##
(S)-6-cyano-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- nicotinamide 451.1 207 1 ##STR00590##
##STR00591## (S)-3-(((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- carbamoyl)- benzoic acid 419.1 208 1 ##STR00592##
##STR00593## (S)-3-chloro-N- ((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin-2- yl)methyl)- benzamide 460.1 209 2a
##STR00594## ##STR00595## 3-fluoro-N-((3- fluoropyridin-2-
yl)(4-(trifluoro- methyl)phenyl)- methyl)- benzamide 393.0 210 1
##STR00596## ##STR00597## (S)-5-methoxy- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
picolinamide 456.0 211 1 ##STR00598## ##STR00599##
(S)-3-(trifluoro- methyl)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- benzamide 493.1 212 1
##STR00600## ##STR00601## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- pyridazine-4-
carboxamide 427.1 213 2 ##STR00602## ##STR00603## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 4-(methyl-
sulfonamido)- benzamide 468.0 214 2a ##STR00604## ##STR00605##
N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)-
3-methoxy- benzamide 405.0 215 1 ##STR00606## ##STR00607##
(S)-1-methyl-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)-1H- indazole-3- carboxamide 479.1 216
2 ##STR00608## ##STR00609## (S)-N-((3-fluoro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 3- (methylsulfonyl)- benzamide
453.0 217 2 ##STR00610## ##STR00611## (S)-N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)- 4-
(methylsulfonyl)- benzamide 453.0 218 1 ##STR00612## ##STR00613##
(S)-2-phenyl-N- ((4-(trifluoro- methyl)phenyl)- (3-(trifluoro-
methyl)pyridin-2- yl)methyl)- acetamide 439.1 219 1 ##STR00614##
##STR00615## (S)-3-(trifluoro- methoxy)-N-((4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)- benzamide
509.1 220 1 ##STR00616## ##STR00617## (S)-N-((4- (trifluoromethyl)-
phenyl)(3- (trifluoromethyl)- pyridin-2-yl)- methyl)- isoxazole-5-
carboxamide 416.1 221 2a ##STR00618## ##STR00619## N-((3-fluoro-
pyridin-2-yl)(4- (trifluoromethyl)- phenyl)methyl)-
4-methyloxazole- 5-carboxamide 380.1 222 1 ##STR00620##
##STR00621## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)-benzo [b]thiophene-
2-carboxamide 481.1 223 1 ##STR00622## ##STR00623##
3-oxo-N-((S)-(4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- cyclohexane- carboxamide 445.1 224 1
##STR00624## ##STR00625## (S)-3-methoxy- N-((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
propanamide 407.1 225 1 ##STR00626## ##STR00627## N-((S)-(4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)THF-3- carboxamide 419.1 226 1 ##STR00628## ##STR00629##
(S)-5-(((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- carbamoyl)- nicotinic acid 470.1 227 1
##STR00630## ##STR00631## (S)-3-fluoro-N- ((4-(trifluoro-
methyl)phenyl)- (3-(trifluoro- methyl)pyridin-2- yl)methyl)-
benzamide 443.1 228 1 ##STR00632## ##STR00633## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- picolinamide 426.0 229 1 ##STR00634## ##STR00635##
(S)-tert-butyl 3- (2-oxo-2-(((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)amino)- ethyl)azetidine-1-
carboxylate 462.0 (M- tBu) 230 1 ##STR00636## ##STR00637##
(S)-N-((4- (trifluoromethyl)- phenyl)(3- (trifluoromethyl)-
pyridin-2-yl)- methyl)- quinoline-3- carboxamide 476.1 231 1
##STR00638## ##STR00639## (S)-4-(trifluoro- methoxy)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- benzamide 509.1 232 49 ##STR00640## ##STR00641##
N-((S)-(3-((R)- 2,2- dimethylcyclopro- pyl)pyridin-2-yl)-
(4-(trifluoro- methyl)phenyl)- methyl)- quinoline-7- carboxamide
476.0 233 49 ##STR00642## ##STR00643## N-((S)-(3-((R)- 2,2-
dimethylcyclopro- pyl)pyridin-2-yl)- (4-(trifluoro- methyl)phenyl)-
methyl)- quinoline-6- carboxamide 476.0 234 1 ##STR00644##
##STR00645## (S)-N-((S)-(4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)THF-2- carboxamide 419.0
235 50 ##STR00646## ##STR00647## (S)-N-((S)-(3- allylpyridin-2-
yl)(4-(trifluoro- methyl)phenyl)- methyl)-2- phenyl- propanamide
425.0 236 51 ##STR00648## ##STR00649## (S)-N-((3-neo-
pentylpyridin- 2-yl)(4- (trifluoro- methyl)phenyl) methyl)-
quinoline-6- carboxamide 478.0 237 1 ##STR00650## ##STR00651##
3,3,3-trifluoro- 2-methoxy-2- phenyl-N- ((S)-(4- (trifluoromethyl)
phenyl)(3-(tri- fluoromethyl)- pyridin-2-yl)- methyl)- propanamide
537.0 238 1 ##STR00652## ##STR00653## (S)-2-(pyridin-3-
yl)-N-((4-(tri- fluoromethyl)- phenyl)(3-(tri- fluoromethyl)-
pyridin-2-yl)- methyl) acetamide 440.0 239 1 ##STR00654##
##STR00655## (S)-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- benzo[d]thiazole-
6-carboxamide 481.9 240 1 ##STR00656## ##STR00657##
(S)-2-methoxy-2- methyl-N-((4- (trifluoromethyl)- phenyl)(3-
(trifluoromethyl)- pyridin-2-yl)- methyl)- propanamide 421.0 241 1
##STR00658## ##STR00659## (1s,4R)- 4-(hydroxy- methyl)-N-
((S)-(4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-
2-yl)methyl)- cyclohexane- carboxamide 461.0 242 1 ##STR00660##
##STR00661## (S)-4-hydroxy- N-((4-(trifluoro- methyl)phenyl)-
(3-(trifluoro- methyl)pyridin- 2-yl)methyl)- cyclohexane-
carboxamide 447.0 243 1 ##STR00662## ##STR00663## (S)-2,2-
dimethyl-3-oxo- 3-(((4-(trifluoro- methyl)- phenyl)(3-(tri-
fluoromethyl)- pyridin-2-yl)- methyl)amino)- propanoic acid 434.9
244 1 ##STR00664## ##STR00665## (S)-4-(((4- (trifluoro- methyl)-
phenyl)(3-(tri- fluoromethyl)- pyridin-2-yl)- methyl)- carbamoyl)-
cyclohexane- carboxylic acid 475.0 245 1 ##STR00666## ##STR00667##
(S)-3-oxo-N-((4- (trifluoro- methyl)- phenyl)(3-(tri-
fluoromethyl)- pyridin-2-yl)- methyl)-2,3- dihydro-1H- indene-5-
carboxamide 479.0 246 1 ##STR00668## ##STR00669## (S)-3-benzoyl-
N-((4-(trifluoro- methyl)phenyl)- (3-(trifluoro- methyl)pyridin-
2-yl)methyl)- benzamide 2,2,2- trifluoroacetate 529.0 247 52
##STR00670## ##STR00671## N-((3,4- dichloro- phenyl)(pyridin-
2-yl)methyl)- isoquinoline-6- carboxamide bis- hydrochloride 409.0,
410.0 248 35 ##STR00672## ##STR00673## (S)-N-((3- chloro-pyridin-
2-yl) (4-(trifluoro- methyl)- phenyl)methyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 2,2,2- trifluoroacetate 407.7 249 35
##STR00674## ##STR00675## (S)-N-((3-chloro- pyridin-2-yl)(4-
(trifluoromethyl)- phenyl)methyl)- 1-methyl-6-oxo- 1,6-dihydro-
pyridine-3- carboxamide 2,2,2- trifluoroacetate 421.9 250 36
##STR00676## ##STR00677## (S)-N-((3,4- dichlorophenyl)-
(3-fluoropyridin- 2-yl)methyl)-6- oxo-1,6-dihydro- pyridine-3-
carboxamide 2,2,2- trifluoroacetate 391.7 251 36 ##STR00678##
##STR00679## (S)-N-((3,4- dichlorophenyl)- (3-fluoropyridin-
2-yl)methyl)-1- methyl-6-oxo- 1,6-dihydro- pyridine-3- carboxamide
2,2,2- trifluoroacetate 405.8 252 8 ##STR00680## ##STR00681##
(S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoro- methoxy)-
phenyl)methyl)- 1-methyl-6-oxo- 1,6-dihydro- pyridine-3-
carboxamide 2,2,2- trifluoroacetate 422.1 253 2 ##STR00682##
##STR00683## (S)-N-((3-fluoro- pyridin-2-yl)(4- (trifluoromethyl)-
phenyl)methyl)- imidazo[1,2- a]pyridine-6- carboxamide 2,2,2-
trifluoroacetate 415.2 254 1 ##STR00684## ##STR00685## (S)-N-((4-
(trifluoromethyl)- phenyl)(3- (trifluoromethyl)- pyridin-2-yl)-
methyl)- imidazo[1,2- a]pyridine-6- carboxamide 2,2,2-
trifluoroacetate 465.1 255 8 ##STR00686## ##STR00687##
(S)-1-ethyl-N- ((3-fluoropyridin- 2-yl)(4-(trifluoro- methoxy)-
phenyl)methyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 436.1 256
37 ##STR00688## ##STR00689## (S)-N-((2- bromophenyl)(4-
(trifluoromethyl)- phenyl)methyl)- quinoline-6- carboxamide 2,2,2-
trifluoroacetate 484.9, 486.9 257 38 ##STR00690## ##STR00691##
(S)-N-((3-fluoro- 4-(trifluoro- methyl)phenyl)- (2-(trifluoro-
methyl)phenyl)- methyl)- quinoline-6- carboxamide 493.0 258 39
##STR00692## ##STR00693## (S)-N-((2,6- difluorophenyl)-
(4-(trifluoro- methyl)phenyl)- methyl)-6-oxo- 1,6-dihydro-
pyridine-3- carboxamide 408.8 259 40 ##STR00694## ##STR00695##
(S)-N-((5- bromothiazol-4- yl)(4-(trifluoro- methyl)phenyl)-
methyl)- quinoline-6- carboxamide 2,2,2- trifluoroacetate 491.8
493.9 260 42 ##STR00696## ##STR00697## (S)-N-((4-
(trifluoromethyl)- phenyl)(4- (trifluoromethyl)- pyridin-3-yl)-
methyl)- quinoline-6- carboxamide bis (2,2,2- trifluoroacetate)
476.0 261 41 ##STR00698## ##STR00699## (S)-N-(3-phenyl-
1-(3-(trifluoro- methyl)pyridin-2- yl)prop-2-yn-1- yl)quinoline-7-
carboxamide 432.0
Additional Examples
##STR00700##
[0812] Example 262
(S)-6-(Dimethylamino)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)py-
ridin-2-yl)methyl)nicotinamide
[0813] A glass microwave reaction vessel was charged with
(S)-6-chloro-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2--
yl)methyl)nicotinamide (50 mg, 0.109 mmol, example 135), DMF (1
mL), and 2 M diethylamine in THF (0.054 mL, 0.109 mmol). The
reaction mixture was stirred and heated in a Biotage Initiator at
100.degree. C. for 30 minutes. This was repeated at 150.degree. C.
for 30 minutes at a time until LC-MS indicated complete consumption
of starting material. The reaction product was purified by
reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini
column (5 micron, C18, 110 .ANG., Axia, 100.times.30 mm) eluting at
45 mL/min with a linear gradient of 20% to 70% MeCN (0.1% TFA) in
water (0.1% TFA) over 20 minutes. The desired fractions were poured
into 10% Na.sub.2CO.sub.3 and extracted with DCM (3.times.5 mL).
The combined DCM layers were washed with brine, dried over
MgSO.sub.4, and concentrated in vacuo to give the title compound as
a white solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. ppm 8.86
(d, J=3.8 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.02 (d, J=7.9 Hz, 2H),
7.92 (dd, J=9.1, 2.5 Hz, 1H), 7.54 (s, 4H), 7.45 (dd, J=7.7, 4.4
Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.49 (d, J=9.2 Hz, 1H), 3.14 (s,
6H) MS (ESI pos. ion) m/z: 469.0 (M+H).
##STR00701##
Example 263
(S)-6-(Ethylamino)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyrid-
in-2-yl)methyl)nicotinamide
[0814] A glass microwave reaction vessel was charged with
(S)-6-chloro-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2--
yl)methyl)nicotinamide (50 mg, 0.109 mmol, example 135), THF (1
mL), and 2 Methylamine in THF (0.054 mL, 0.109 mmol). The reaction
mixture was stirred and heated in a Biotage Initiator at
100.degree. C. for 30 minutes. This was repeated at 150.degree. C.
for 30 minutes at a time until LC-MS indicated complete consumption
of starting material. The reaction product was purified by
reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini
column (5 micron, C18, 110 .ANG., Axia, 100.times.30 mm) eluting at
45 mL/min with a linear gradient of 20% to 70% MeCN (0.1% TFA) in
water (0.1% TFA) over 20 minutes to give
(S)-6-(ethylamino)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyri-
din-2-yl)methyl)nicotinamide 2,2,2-trifluoroacetate as a white
solid after lypholization. .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta. ppm 10.41 (br. s., 1H), 8.93 (d, J=4.1 Hz, 1H), 8.12-8.39
(m, 3H), 8.05 (d, J=7.7 Hz, 1H), 7.41-7.63 (m, 5H), 6.71-6.86 (m,
2H), 3.25-3.49 (m, 2H), 1.37 (t, J=7.3 Hz, 3H) MS (ESI pos. ion)
m/z: 469.0 (M+H).
##STR00702##
Example 264
(S)--N-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-methoxy-
pyrimidine-5-carboxamide
[0815] To a solution of 2-methoxypyrimidine-5-carboxylic acid (80
mg, 0.519 mmol), DIPEA (0.25 mL, 1.435 mmol) in toluene (3 mL) was
added DPPA (0.19 mL, 0.882 mmol). The reaction was stirred at
80.degree. C. for 2 hours.
(S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
dihydrochloride (167 mg, 0.487 mmol) was then added as a solid in
one portion. After 24 hours, the reaction was concentrated in vacuo
and the residue was adsorbed onto a plug of silica gel and
chromatographed through a Redi-Sep.RTM. pre-packed silica gel
column (12 g), eluting with 0% to 80% EtOAc in hexane, to provide
the title compound as an off-white solid. .sup.1H NMR (DMSO-d6, 400
MHz) .delta. ppm 9.02 (d, J=4.7 Hz, 1H), 8.97 (d, J=8.6 Hz, 1H),
8.30 (d, J=7.8 Hz, 1H), 7.63-7.77 (m, 3H), 7.54 (d, J=8.2 Hz, 2H),
7.39 (s, 1H), 7.01 (s, 1H), 6.66 (d, J=8.6 Hz, 1H), 3.93 (s, 3H) MS
(ESI pos. ion) m/z: 407.0 (M+H).
##STR00703##
Example 265
(S)-3-Oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-
methyl)isoindoline-5-carboxamide
[0816] To a 25 mL round bottom flask containing
(S)-(4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanam-
ine hydrochloride (Intermediate 1) (120 mg, 0.336 mmol) was added
toluene (3 mL). The resulting mixture was stirred at rt for 2 min.
At this time, sodium carbonate (143 mg, 1.346 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.89 mg, 6.73
mol), palladium (II) acetate (1.5 mg, 6.7 mol) and
6-bromo-2,3-dihydro-isoindol-1-one (71.3 mg, 0.336 mmol) were added
to the flask. The reaction vessel was flushed with argon and then
left under 1.0 atm of carbon monoxide gas (from a lecture bottle,
in hood). The flask was heated to 85.degree. C. overnight, filtered
though Celite.RTM. brnad filter agent, and eluted with EtOAc.
Purification by reverse phase HPLC, and concentration of the
containing fractions gave
(S)-3-oxo-N-((4-(trifluoromethyl)-phenyl)(3-(trifluoromethyl)pyridin-2-yl-
)methyl)isoindoline-5-carboxamide as a yellow foamy solid. .sup.1H
NMR (300 MHz, CDCl.sub.3): .delta. ppm 8.92 (d, J=4.5 Hz, 1H), 8.40
(d, J=7.7 Hz, 1H), 7.60-7.56 (m, 5H), 7.46-7.48 (m, 2H), 6.90 (d,
J=7.6 Hz, 1H), 4.54 (s, 2H). MS (ESI pos. ion) m/z: 480.1
(M+H).
##STR00704##
Example 266
(S)-2-Hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-
-yl)methyl)pyrimidine-5-carboxamide
[0817] A 25 mL round-bottomed flask containing a suspension of
(S)-2-methoxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-
-yl)methyl)pyrimidine-5-carboxamide (Example 44) (0.094 g, 0.206
mmol) and sodium iodide, anhydrous (0.129 g, 0.861 mmol) in
anhydrous MeCN (3.5 mL) was treated with chlorotrimethylsilane,
redistilled (0.130 mL, 1.028 mmol). The resulting suspension was
stirred at rt for 17.5 h. The reaction was concentrated on the
rotary evaporator resulting in a gummy residue which was taken up
in DCM (55 mL), H.sub.2O (25 mL), and 10% aqueous sodium
thiosulfate (20 mL). The resulting mixture was transferred to a
separatory funnel and after vigorous extraction the organic layer
was separated, dried over anhydrous sodium sulfate, and
concentrated to yield the product. The product thus obtained was
dissolved in DMSO/MeOH(1/1) (3.5 mL) and loaded on a Gibson HPLC
system for purification using a MeCN/H.sub.2O/0.1% TFA gradient and
Phenomenex.TM. Gemini Axia-5.mu. C-18 column (150.times.30 mm). The
solvent was removed from the pure fractions in the Genevac.TM. and
the resulting product was dissolved in MeOH (3 mL), concentrated in
the Genevac.TM., and dried under high vacuum to yield
(S)-2-hydroxy-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-
-yl)-methyl)pyrimidine-5-carboxamide as an amorphous white solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.30 (d, J=7.6 Hz,
1H), 8.93 (d, J=3.9 Hz, 1H), 8.80 (s, 2H), 8.27 (dd, J=8.0, 1.2 Hz,
1H), 7.75-7.70 (m, 2H), 7.64 (dd, J=7.9, 5.0 Hz, 1H), 7.56-7.50 (m,
2H), 6.76 (d, J=7.6 Hz, 1H). MS (ESI pos. ion) m/z: 443.1
(M+H).
##STR00705##
Example 267
(S)-6-Oxo-N-((3-propylpyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-1,6-
-dihydropyridine-3-carboxamide
[0818] To a 250 mL round bottom flask containing
(S)-6-oxo-N-((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)m-
ethyl)-1,6-dihydropyridine-3-carboxamide (Example 94) (50 mg, 0.122
mmol), were added EtOAc (50 mL) and MeOH (10 mL). The resulting
mixture then stirred at 23.degree. C. for 2 min. At this time, Pd/C
(10%, 50 mg) was added and hydrogen was bubbled through the
reaction vessel for 15 min, and the reaction was stirred under 1.0
atm hydrogen for 3 h, filtered through a pad of Celite.TM., eluted
with EtOAc (150 mL), and concentrated to give (S)-tert-butyl
((3-(prop-1-yn-1-yl)pyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)carba-
mate as a foamy white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) 8
ppm 13.03 (br. s., 1H), 8.68 (d, J=6.9 Hz, 1H), 8.53 (dd, J=1.5,
4.7 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.95 (dd, J=2.6, 9.6 Hz, 1H),
7.62-7.41 (m, 5H), 7.33-7.20 (m, 1H), 6.60 (d, J=9.5 Hz, 1H), 6.52
(d, J=6.9 Hz, 1H), 2.73-2.57 (m, 1H), 2.56-2.39 (m, 1H), 1.87 (br.
s., 1H), 1.68-1.48 (m, 1H), 1.47-1.30 (m, 1H), 0.92 (t, J=7.3 Hz,
3H). MS (ESI pos. ion) m/z: 416.2 (M+H).
##STR00706##
Example 268
(S)-2-Allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)py-
ridin-2-yl)methyl)isoindoline-5-carboxamide
[0819] To a 25 mL pear-shaped flask was added solid
1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (200 mg, 1.041
mmol) and allylamine (234 .mu.L, 3.12 mmol, 3 eq) via syringe.
Toluene (2 mL) and AcOH (1 mL) were added via syringes and the
flask was refluxed for 12 h. The flask was allowed to cool and then
subjected to a DCM (75 mL) and HCl (1N, 50 mL) work up. The aqueous
layer was extracted with DCM (3.times.25 mL). The combined organic
layers were washed with brine, dried with sodium sulfate, filtered
and concentratred. The residue thus obtained was azeotropically
dried with toluene (2.times., 5 mL) and heptane (2.times.5 mL). The
resulting reside was placed on a high vacuum for 3 to give
2-allyl-1,3-dioxoisoindoline-5-carboxylic acid.
[0820] 2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then
coupled with Intermediate 1 using the general methods described
above for the amide coupling reaction (Table 2) to provide the
title compound,
(S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)p-
yridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.93 (d, J=3.9 Hz,
1H), 8.44 (d, J=7.6 Hz, 1H), 8.30-8.21 (m, 2H), 8.11-8.02 (m, 1H),
7.98-7.89 (m, 1H), 7.64-7.46 (m, 5H), 6.88 (d, J=7.6 Hz, 1H),
5.99-5.75 (m, 1H), 5.34-5.15 (m, 2H), 4.31 (d, J=5.7 Hz, 2H). MS
(ESI pos. ion) m/z: 534.1 (M+H).
##STR00707##
Example 269
(S)-1,3-Dioxo-2-propyl-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)p-
yridin-2-yl)methyl)isoindoline-5-carboxamide
[0821] To a 50 mL round bottom flask containing
(S)-2-allyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)p-
yridin-2-yl)methyl)isoindoline-5-carboxamide (Example 276) (160 mg,
0.300 mmol) was added EtOAc (15 mL). The resulting mixture was
stirred at 23.degree. C. for 2 min. At this time, Pd/C (10%, 50 mg)
was added and hydrogen was bubbled through the mixture for 10 min.
The reaction mixture was then left under 1 atm of hydrogen for 1 h.
The solid was filtered off on a pad of Celite.TM. and eluted with
EtOAc (75 mL). The solvent was evaporated to give
(S)-1,3-dioxo-2-propyl-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-
pyridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.93 (d, J=4.1 Hz,
1H), 8.42 (d, J=7.6 Hz, 1H), 8.30-8.19 (m, 2H), 8.11-8.01 (m, 1H),
7.91 (d, J=7.7 Hz, 1H), 7.64-7.45 (m, 5H), 6.88 (d, J=7.6 Hz, 1H),
3.68 (t, J=1.0 Hz, 2H), 1.72 (sxt, J=7.4 Hz, 2H), 0.95 (t, J=7.5
Hz, 3H). MS (ESI pos. ion) m/z: 536.2 (M+H).
##STR00708##
Example 270
(S)-2-Methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)p-
yridin-2-yl)methyl)isoindoline-5-carboxamide
[0822] To a microwave vial was added
1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (200 mg, 1.041
mmol), THF (2 mL) and methylamine (2.0M THF, 2.0 mL). The flask was
irradiated in a microwave at 100.degree. C. for 5 min. At this
time, AcOH (glacial, 0.4 mL) and an additional portion of
methylamine (2.0M THF, 2.0 mL) were added, and the flask was placed
in a the microwave at 100.degree. C. for 2 h. The flask was allowed
to cool and then azeotropically dried (toluene, 3.times.5 mL). The
flask was placed under a high vacuum for 12 h to provide
2-methyl-1,3-dioxoisoindoline-5-carboxylic acid which was used
directly in the amide coupling reaction without further
purification.
[0823] 2-Allyl-1,3-dioxoisoindoline-5-carboxylic acid was then
coupled with Intermediate 1 using the general methods described
above for the amide coupling reaction (Table 2) to provide the
title compound,
(S)-2-methyl-1,3-dioxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-
pyridin-2-yl)methyl)isoindoline-5-carboxamide as a white solid.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 8.95 (d, J=4.7 Hz,
1H), 8.44 (d, J=7.5 Hz, 1H), 8.31-8.20 (m, 2H), 8.08 (d, J=8.2 Hz,
1H), 7.93 (d, J=7.6 Hz, 1H), 7.65-7.42 (m, 5H), 6.88 (d, J=7.6 Hz,
1H), 3.22 (s, 3H). MS (ESI pos. ion) m/z: 508.1 (M+H).
##STR00709##
Example 271
(S)-1-Oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)-
methyl)isoindoline-5-carboxamide
##STR00710##
[0824] Step 1. Methyl 1-oxoisoindoline-5-carboxylate
[0825] To a 25 mL round bottom flask containing
5-bromo-2,3-dihydro-isoindol-1-one (500 mg, 2.36 mmol), was added
TEA. The resulting mixture was then stirred at 23.degree. C. for 2
min. At this time, MeOH (954 L, 23.58 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (54.6 mg, 0.094
mmol)(Xantphos) and palladium(II) acetate (10.59 mg, 0.047 mmol)
were added to the flask. The reaction mixture was then flushed with
argon and then with carbon monoxide. The flask was fitted with a
rubber septa and a balloon of carbon monoxide was inserted through
septa. The flask was stirred at 70.degree. C. overnight under
carbon monoxide, allowed to cool, diluted with EtOAc (50 mL) and
filtered through Celite.TM. eluting with EtOAc (300 mL). The solid
remaining on the Celite.TM. pad was washed with DCM (200 mL) and
DCM/MeOH (10:1)(150 mL) and the filtrates concentrated to give a
pale green solid (800 mg). A portion of this material was taken on
to the next reaction with no further purification.
##STR00711##
Step 2. 1-Oxoisoindoline-5-carboxylic Acid
[0826] To a 100 mL round bottom flask containing methyl
1-oxoisoindoline-5-carboxylate (200 mg, 1.046 mmol) was added THF
(6 mL) and H.sub.2O (2 mL) the mixture was stirred at 23.degree. C.
for 2 min. At this time, lithium hydroxide monohydrate (87 .mu.L,
3.14 mmol) was added and the flask was gently heated on aluminum
block for 5 min. The solid went into solution and LC/MS showed
product formation. The contents of the reaction were poured into
HCl (1 M, 15 mL) and extracted with DCM (15 mL). An emulsion
formed, the layers separated, and a white solid formed at the
boundary of the layers and stuck to the separatory funnel. This
material was collected, dissolved in MeOH, and concentrated. After
drying under high vacuum for 2 h, the 1-oxoisoindoline-5-carboxylic
acid thus obtained was taken on directly to the next reaction
without further purification.
##STR00712##
Step 3.
(S)-1-Oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyrid-
in-2-yl)methyl)isoindoline-5-carboxamide
[0827] 1-Oxoisoindoline-5-carboxylic acid was then coupled with
Intermediate 1 using the general methods described above for the
amide coupling reaction (Table 2) to provide the title compound,
(S)-1-oxo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-
methyl)isoindoline-5-carboxamide, as a white solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 8.92 (d, J=4.7 Hz, 1H), 8.36 (d,
J=7.4 Hz, 1H), 8.09-7.99 (m, 2H), 7.97-7.88 (m, 2H), 7.65-7.53 (m,
5H), 7.51 (dd, J=4.9, 7.8 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 4.54 (s,
2H). MS (ESI pos.ion) m/z: 480.2 (M+H).
##STR00713##
Example 272
(S)-6-(((3-Fluoropyridin-2-yl)(4-(trifluoromethoxy)phenyl)-methyl)carbamoy-
l)nicotinic acid
[0828] To a 150 mL round bottom flask containing (S)-methyl
6-(((3-fluoro-pyridin-2-yl)(4-(trifluoromethoxy)phenyl)methyl)carbamoyl)n-
icotinate (250 mg, 0.556 mmol) (prepared using the general coupling
procedure Table 2 with Intermediate 1 and
5-((methylperoxy)carbonyl)picolinic acid) were added THF (6 mL) and
H.sub.2O (2 mL). The resulting mixture was stirred at 23.degree. C.
for 2 min. At this time, lithium hydroxide monohydrate (61.8 .mu.L,
2.23 mmol) was added and the reaction was stirred for 3 h. The bulk
of the solvent was evaporated to give a foamy solid that oiled out.
The residue was dissolved in AcOH (8 mL). The solution was purified
by reverse phase HPLC and the product-containing fractions
concentrated to give the title compound as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. ppm 9.65 (d, J=7.3 Hz, 1H), 9.21
(s, 1H), 8.61 (d, J=4.1 Hz, 1H), 8.42 (d, J=7.3 Hz, 1H), 8.24 (d,
J=8.0 Hz, 1H), 7.63-7.42 (m, 3H), 7.39 (dd, J=4.2, 8.3 Hz, 1H),
7.20 (d, J=7.9 Hz, 2H), 6.74 (d, J=6.7 Hz, 1H). MS (ESI pos. ion)
m/z: 436.2 (M+H).
##STR00714##
Example 273
(S)--N.sup.2-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-N.-
sup.5-methylpyridine-2,5-dicarboxamide 2,2,2-trifluoroacetate
[0829] To a 50 mL round bottom flask containing
(S)-6-(((3-fluoropyridin-2-yl)-(4-(trifluoromethyl)phenyl)methyl)carbamoy-
l)nicotinic acid (Example 280) (86 mg, 0.205 mmol) was added DMF (3
mL). The resulting mixture was stirred at 23.degree. C. for 2 min.
At this time, DIPEA (143 .mu.L, 0.820 mmol), methylamine (2.0 M in
THF, 103 .mu.L, 0.205 mmol) and then HATU (78 mg, 0.205 mmol) were
added to the flask. The reaction was stirred for 1 h and then
directly purified by reverse phase HPLC. The pure fractions were
concentrated to give the title compound as a white solid. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. ppm 9.85 (d, J=7.2 Hz, 1H), 9.00
(s, 1H), 8.55 (d, J=4.4 Hz, 1H), 8.20 (s, 2H), 7.60 (s, 4H), 7.52
(t, J=8.7 Hz, 1H), 7.45-7.34 (m, 1H), 6.74 (d, J=7.3 Hz, 1H), 6.55
(br. s., 1H), 3.07 (d, J=4.5 Hz, 3H). MS (ESI pos. ion) m/z: 433.1
(M+H).
##STR00715##
Example 274
(S)--N-((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl-
)-1,2,3,4-tetrahydroquinoline-7-carboxamide
[0830] To a solution of
(S)--N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)meth-
yl)quinoline-7-carboxamide (Example 132) (0.500 g, 1.052 mmol) in
MeOH (6 mL) was added palladium hydroxide, (20 wt % Pd (dry basis)
on carbon, wet, degussa type) (0.148 g, 1.052 mmol). The resulting
mixture was then stirred at rt under H.sub.2 overnight. The
resulting mixture was filtered through Celite.RTM. brand filter
agent and the CeliteR filter agent was washed with MeOH (2.times.3
mL). The combined filtrates were concentrated and the mixture was
dissolved in DMSO (3 mL). The mixture was purified by preparative
HPLC (0%-100% MeCN 0.1% TFA/H.sub.2O 0.1% TFA) to give the desired
product, which was dissolved in MeOH (2 mL). The solution was
washed through PL_HCO.sub.3 MP-SPE resin and the resin was washed
with MeOH (2.times.2 mL). The combined filtrates were concentrated
and dried in vacuo to give the title compound as a yellow solid.
.sup.1H NMR (400 MHz, MeOH) .delta. ppm 8.94 (d, J=4.1 Hz, 1H),
8.22 (dd, J=8.0, 1.0 Hz, 1H), 7.50-7.70 (m, 5H), 6.94-7.02 (m, 3H),
6.90 (s, 1H), 3.24-3.31 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.86-1.99
(m, 2H). MS (ESI pos. ion) m/z: 480.2 (M+H).
##STR00716##
Example 275
(S)-5-Cyano-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-y-
l)methyl)picolinamide
[0831] To a solution of
(S)-5-bromo-N-((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2--
yl)methyl)picolinamide (Example 205) (0.100 g, 0.198 mmol) in DMF
(1.3 mL) was added zinc cyanide (0.050 mL, 0.793 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.020 mmol). The
resulting mixture was subjected to a microwave irradiation at
140.degree. C. for 20 min. The mixture was then purified by
preparative HPLC (0%-100% MeCN 0.1% TFA/H.sub.2O 0.1% TFA) to give
the title compound as a white solid. .sup.1H NMR (400 MHz, MeOH)
.delta. ppm 8.95-9.06 (m, 2H), 8.39 (dd, J=8.1, 2.1 Hz, 1H),
8.21-8.32 (m, 2H), 7.57-7.70 (m, 5H), 6.89 (s, 1H). MS (ESI pos.
ion) m/z: 451.1 (M+H).
##STR00717##
Example 276
(S)--N-(Pyridin-2-yl(4-(trifluoromethyl)phenyl)methyl)-1,2,3,4-tetrahydroq-
uinoline-7-carboxamide
[0832] To a solution of
(S)--N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)quinoline-
-7-carboxamide (Example 195) (0.130 g, 0.267 mmol) in MeOH (0.8 mL)
and EtOAc (0.800 mL) was added palladium hydroxide, (20 wt % Pd
(dry basis) on carbon, wet) (0.019 g, 0.134 mmol). The resulting
mixture was then stirred at rt under H.sub.2 (balloon) overnight.
The mixture was then filtered through Celite.RTM. brand filter
agent and the Celite.RTM. filter agent was washed with MeOH
(2.times.3 mL). The combined filtrates were concentrated, and the
residue was dissolved in MeOH (1 mL). The solution was purified by
preparative HPLC (0%-100% MeCN 0.1% TFA/H.sub.2O 0.1% TFA) to give
the desired product, which was dissolved in MeOH (1 mL). The
solution was washed through PL_HCO.sub.3 MP-SPE and the resin was
washed with MeOH (2.times.1 mL). The combined filtrates were
concentrated and dried in vacuo to give the title compound as a
yellow solid. .sup.1H NMR (400 MHz, MeOH) .delta. ppm 8.59 (d,
J=4.7 Hz, 1H), 7.84 (td, J=7.7, 1.6 Hz, 1H), 7.61-7.68 (m, 2H),
7.54-7.60 (m, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz,
1H), 6.93-7.07 (m, 3H), 6.44 (s, 1H), 3.25-3.30 (m, 2H), 2.78 (t,
J=6.4 Hz, 2H), 1.91 (dt, J=11.6, 6.0 Hz, 2H). MS (ESI pos. ion)
m/z: 412.1 (M+H).
##STR00718##
Example 277
(S)-5-Cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)-6-
-oxo-1,6-dihydropyridine-3-carboxamide
##STR00719##
[0833] Step 1.
(S)-5-Bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)--
6-oxo-1,6-dihydropyridine-3-carboxamide
[0834] To a solution of HATU (0.332 g, 0.874 mmol) in DCM (2 mL)
was added 5-bromo-6-hydroxynicotinic acid (0.191 g, 0.874 mmol) and
DIPEA (0.406 mL, 2.331 mmol). The resulting mixture was then
stirred at rt for 5 min, then
(S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride (Intermediate 2) (0.200 g, 0.583 mmol) was added. The
mixture was then stirred at rt overnight. The mixture was purified
by silica gel column chromatography using an ISCO instrument
(0%-100% EtOAc/hexane) to give the title compound as a brown
oil.
##STR00720##
Step 2.
(S)-5-Cyano-N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)--
methyl)-6-oxo-1,6-dihydropyridine-3-carboxamide
[0835] To a solution of
(S)-5-bromo-N-((3-fluoropyridin-2-yl)(4-(trifluoro-methyl)phenyl)methyl)--
6-oxo-1,6-dihydropyridine-3-carboxamide (0.080 g, 0.170 mmol) in
DMF (0.5 mL) was added zinc(II) cyanide (0.043 mL, 0.681 mmol) and
tetrakis(triphenylphosphine)palladium(0) (0.020 g, 0.017 mmol). The
resulting mixture was then subjected to a mirowave irradiation at
130.degree. C. for 30 min. Then, the mixture was purified by
preparative HPLC (0%-100% MeCN 0.1% TFA/H.sub.2O 0.1% TFA) to give
the title compound as a white solid. .sup.1H NMR (400 MHz, MeOH)
.delta. ppm 8.63 (d, J=2.5 Hz, 1H), 8.51 (d, J=4.7 Hz, 1H), 8.42
(d, J=2.5 Hz, 1H), 7.55-7.73 (m, 6H), 7.47 (dt, J=8.5, 4.4 Hz, 1H),
6.75 (s, 1H). MS (ESI pos. ion) m/z: 417.0 (M+H).
##STR00721##
Example 278
(S)--N-((3-Cyanopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)quinoline--
7-carboxamide
[0836] To a microwave vial were added
(S)--N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)quinoline--
7-carboxamide (Example 195) (0.100 g, 0.206 mmol), zinc cyanide
(0.026 mL, 0.411 mmol), tetrakis(triphenylphosphine)-palladium(0)
(0.024 g, 0.021 mmol), and DMF (1.3 mL). The resulting mixture was
then subjected to microwave irradiation at 130.degree. C. for 30
min. EtOAc (10 mL) and H.sub.2O (10 mL) were then added, and the
resulting mixture was stirred at rt for 5 min. The organic layer
was collected, dried over MgSO.sub.4 and concentrated. The residue
was then purified by preparative HPLC (0%-100% MeCN 0.1%
TFA/H.sub.2O 0.1% TFA) to give the desired product, which was
dissolved in MeOH (1 mL). The solution was washed through
PL_HCO.sub.3 MP-SPE resin and the resin was washed with MeOH
(2.times.1 mL). The combined filtrates were concentrated and dried
in vacuo to givethe title compound as a yellow solid. .sup.1H NMR
(400 MHz, MeOH) .delta. ppm 8.98 (dd, J=4.1, 1.6 Hz, 1H), 8.93 (dd,
J=4.9, 1.6 Hz, 1H), 8.60 (s, 1H), 8.46 (d, J=8.4 Hz, 1H), 8.25 (dd,
J=7.8, 1.6 Hz, 1H), 8.08 (s, 2H), 7.70-7.81 (m, 4H), 7.66 (dd,
J=8.4, 4.3 Hz, 1H), 7.58 (dd, J=7.8, 4.9 Hz, 1H), 6.91 (s, 1H). MS
(ESI pos. ion) m/z: 433.1 (M+H).
##STR00722##
Example 279
(S)-2-((6-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)carba-
moyl)pyridin-3-yl)oxy)acetic acid
[0837] To a solution of
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)-5-hydro-
xypicolinamide (Example 173) (0.145 g, 0.371 mmol) in DCM (2 mL)
and DMF (0.2 mL) were added bromoacetic acid t-butyl ester (0.072
mL, 0.445 mmol) and cesium carbonate (0.241 g, 0.741 mmol). The
resulting mixture was then stirred at rt for 2 h. Then, the mixture
was filtered and the solid was washed with DCM (1.times.1 mL) and
MeOH (1.times.1 mL). The combined filtrates were concentrated and
dried to give the desired product, which was used without further
purification in the next step.
[0838] To a solution of the (S)-tert-butyl
2-((6-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl-
)pyridin-3-yl)oxy)acetate from above in DCM (0.5 mL), was added TFA
(0.550 mL, 7.40 mmol). The resulting mixture was then stirred at rt
for 1 h. The mixture was then concentrated and MeOH (1 mL) was
added. The mixture was purified by preparative HPLC (0%-100% MeCN
0.1% TFA/H.sub.2O 0.1% TFA) to give the title compound as a white
solid. .sup.1H NMR (400 MHz, MeOH) .delta. ppm 8.55 (d, J=4.7 Hz,
1H), 8.42 (d, J=2.5 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.59-7.72 (m,
5H), 7.42-7.55 (m, 2H), 6.68 (d, J=1.6 Hz, 1H), 4.89 (s, 2H). MS
(ESI pos. ion) m/z: 450.2 (M+H).
##STR00723##
Example 280
(S)-6-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)carbamoyl-
)nicotinic acid
[0839] To a solution of 5-(methoxycarbonyl)picolinic acid (101 mg,
0.558 mmol) in DCM (4 mL) was added HATU (217 mg, 0.571 mmol) and
DIPEA (0.20 mL, 1.148 mmol). After stirring for 30 min at rt, the
reaction was treated with
(S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride (Intermediate 2) (125 mg, 0.364 mmol). After 16 h,
the reaction was concentrated in vacuo and then taken up in THF (3
mL), MeOH (1 mL), and 1M LiOH (1 mL). The resulting mixture was
stirred at rt for 2 h. The reaction mixture was concentrated in
vacuo, acidified with 1N HCl and extracted with EtOAc (3.times.5
mL). The combined EtOAc layers were concentrated in vacuo and
chromatographed through a Redi-Sep.RTM. pre-packed silica gel
column (4 g), eluting with 0% to 100% EtOAc in hexane, to provide
the title compound as an off-white solid. .sup.1H NMR
(CDCl.sub.3:CD.sub.3OD, 300 MHz) .delta. ppm 9.21 (d, J=1.5 Hz,
1H), 8.47 (d, J=4.7 Hz, 1H), 8.39 (dd, J=8.0, 1.9 Hz, 1H), 8.14 (d,
J=8.0 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.6 Hz, 2H), 7.42
(t, J=9.5 Hz, 1H), 7.27-7.32 (m, 1H), 6.63 (s, 1H). MS (ESI pos.
ion) m/z: 419.9 (M+H).
##STR00724##
Example 281
(S)-6-(((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methy-
l)carbamoyl)nicotinic acid
[0840] To a solution of 5-(methoxycarbonyl)picolinic acid (70.7 mg,
0.390 mmol) and DIPEA (0.20 mL, 1.148 mmol) in DMF (2 mL) were
added HATU (223 mg, 0.586 mmol) and
(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methanam-
ine hydrochloride (Intermediate 1) (125 mg, 0.390 mmol). The
resulting mixture was stirred at rt 16 h. The mixture was then
diluted with THF (10 mL), MeOH (3 mL), and 1M LiOH (2 mL). After a
further 16 h, the reaction was concentrated in vacuo, taken up in a
minimum of DMF and purified by reverse-phase preparative HPLC
(Shimadzu) on a Phenomenex Gemini.TM. column (5 micron, C18, 110
.ANG., Axia, 100.times.30 mm) eluting at 45 mL/min with a linear
gradient of 20% to 90% MeCN (0.1% TFA) in H.sub.2O (0.1% TFA) over
10 minutes to give the title compound as a white solid after
lypholization. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. ppm 9.74
(d, J=8.2 Hz, 1H), 9.25 (s, 1H), 8.97 (d, J=4.0 Hz, 1H), 8.47 (dd,
J=8.0, 2.1 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H),
7.61 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.46 (dd, J=7.5,
5.0 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H). MS (ESI pos. ion) m/z: 469.9
(M+H).
##STR00725##
Example 282
(S)--N.sup.2-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)pyri-
dine-2,5-dicarboxamide
[0841] To a solution of 5-cyanopicolinic acid (93 mg, 0.628 mmol)
in DCM (6 mL) were added DIPEA (0.3 mL, 1.722 mmol) and HATU (247
mg, 0.650 mmol). The solution was stirred at rt. After 20 minutes,
the reaction was treated with
(S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride (Intermediate 2) (115 mg, 0.426 mmol). After stirring
for 16 h, the reaction was poured into H.sub.2O (20 mL). The
aqueous layer was back-extracted with DCM (10 mL). The combined DCM
layers were concentrated in vacuo and taken up in 3 mL of
concentrated sulfuric acid. The mixture was stirred at rt for 4
hours and then was poured into 75 g of ice. After stirring for 1
hour, the reaction was filtered, and the solids were rinsed with
H.sub.2O. The solids were then taken up in EtOAc (30 mL) and washed
with saturated aqueous NaHCO.sub.3. The EtOAc layer was
concentrated in vacuo to give the title compound as an off-white
solid. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. ppm 9.93 (d, J=7.5
Hz, 1H), 9.07 (s, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.23-8.27 (m, 2H),
7.61 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz, 2H), 7.42 (td, J=8.2,
1.3 Hz, 1H), 7.27-7.35 (m, 1H), 6.69 (dd, J=7.8, 1.9 Hz, 1H), 5.92
(br s, 2H). MS (ESI pos. ion) m/z: 419.9 (M+H).
##STR00726##
Example 283
(S)-4-(((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methy-
l)carbamoyl)benzoic acid
[0842] To a solution of (S)-methyl
4-(((4-(trifluoromethyl)phenyl)(3-(trifluoro-methyl)pyridin-2-yl)methyl)c-
arbamoyl)benzoate (135 mg, 0.280 mmol, Example 140) and THF (7
mL):MeOH (3 mL) was added 1M LiOH (1 mL, 1.000 mmol). After 2 h,
the reaction was concentrated in vacuo. The off-white solid was
taken up in a minimum of DCM and eluted through a Redi-Sep.RTM.
pre-packed silica gel column (4 g) with EtOAc to provide the title
compound as a white solid. .sup.1H NMR (CD.sub.3OD, 300 MHz)
.delta. ppm 8.91 (d, J=4.8 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.03
(d, J=8.3 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.53-7.66 (m, 5H), 6.93
(s, 1H). MS (ESI pos. ion) m/z: 469.0 (M+H).
##STR00727##
Example 284
(S)-3-(Pyridin-2-yl)-N-((4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyr-
idin-2-yl)methyl)propanamide
[0843] To a solution of 3-(pyridin-2-yl)propanoic acid (89 mg,
0.586 mmol, Oakwood) and DCM (4 mL) were added CDI (95 mg, 0.586
mmol) and DIPEA (0.20 mL, 1.148 mmol). After 0.5 hours, the
reaction was treated with a solution of
(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)methanami-
ne hydrochloride (Intermediate 1) (125 mg, 0.390 mmol) in DCM (1.5
mL). The solution was stirred at rt. After 4 days, the resulting
product was adsorbed onto a plug of silica gel and chromatographed
through a Redi-Sep.RTM. pre-packed silica gel column (4 g), eluting
with 0% to 60% EtOAc in hexane, to provide the title compound as a
colorless oil. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. ppm 8.79
(d, J=3.8 Hz, 1H), 8.45 (d, J=4.8 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H),
7.78 (d, J=7.9 Hz, 1H), 7.44-7.52 (m, 3H), 7.34-7.43 (m, 3H),
7.03-7.12 (m, 2H), 6.63 (d, J=8.0 Hz, 1H), 3.11 (td, J=6.7 &
2.5 Hz, 2H), 2.74 (td, J=7.2 & 2.5 Hz, 2H). MS (ESI pos. ion)
m/z: 454.0 (M+H).
##STR00728##
Example 285
(S)-5-(((4-(Trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methy-
l)carbamoyl)picolinic acid 2,2,2-trifluoroacetate
[0844] To a solution of 6-(methoxycarbonyl)nicotinic acid (58.4 mg,
0.322 mmol) and DIPEA (0.20 mL, 1.148 mmol) in DMF (2 mL) were
added HATU (178 mg, 0.468 mmol) and
(S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)pyridin-2-yl)-methanam-
ine hydrochloride (Intermediate 1) (100 mg, 0.312 mmol). The
solution was stirred at rt for 2 h. The solution was then diluted
with THF (10 mL), MeOH (3 mL), and 1M LiOH (2 mL). After a further
16 h, the reaction was concentrated in vacuo, taken up in a minimum
of DMF and purified by reverse-phase preparative HPLC (Shimadzu) on
a Phenomenex Gemini.TM. column (5 micron, C18, 110 .ANG., Axia,
100.times.30 mm) eluting at 45 mL/min with a linear gradient of 20%
to 90% MeCN (0.1% TFA) in H.sub.2O (0.1% TFA) over 10 minutes to
the title compound as a yellow solid. .sup.1H NMR (CDCl.sub.3, 300
MHz) .delta. ppm 9.14 (s, 1H), 8.94 (d, J=4.4 Hz, 1H), 8.64 (d,
J=7.2 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 8.13
(d, J=7.9 Hz, 1H), 7.46-7.63 (m, 5H), 6.88 (d, J=7.0 Hz, 1H). MS
(ESI pos. ion) m/z: 469.9 (M+H).
##STR00729##
Example 286
(S)--N-((3-(tert-Butyl)pyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)qui-
noline-7-carboxamide 2,2,2-trifluoroacetate
[0845] To a -78.degree. C. solution
of(S)--N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)quinoli-
ne-7-carboxamide (97 mg, 0.199 mmol, Example 195) and THF (5 mL)
was added tert-butyllithium (1.7M in pentane, 0.35 mL, 0.595 mmol)
dropwise. After 30 seconds, the reaction was treated with acetone.
After 1 min, LC-MS shows a new peak with m/z=466 (MH+), .about.20%
conversion. The reaction was treated with more tert-butyllithium
(0.1 mL) and allowed to slowly warm to rt. Another reaction was
setup at the same scale and as described above. The reactions were
combined and concentrated in vacuo. The residue was taken up in
MeOH (3 mL) and purified by reverse-phase preparative HPLC
(Shimadzu) on a Phenomenex Gemini.TM. column (10 micron, C18, 110
.ANG., Axia, 100.times.50 mm) eluting at 90 mL/min with a linear
gradient of 20% to 90% MeCN (0.1% TFA) in H.sub.2O (0.1% TFA) over
10 minutes to give the title compound as an off-white solid after
lypholization. .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. ppm 9.85
(s, 1H), 9.44 (d, J=7.3 Hz, 1H), 8.79 (d, J=4.2 Hz, 1H), 8.64 (d,
J=8.8 Hz, 1H), 8.37 (d, J=8.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.98
(t, J=7.3 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.69-7.82 (m, 3H), 7.61
(d, J=8.2 Hz, 1H), 7.45-7.53 (m, 1H), 6.76 (d, J=7.3 Hz, 1H), 1.67
(s, 9H). MS (ESIpos. ion) m/z: 464.0 (M+H).
TABLE-US-00003 TABLE 3 Additional diarylmethanamines prepared
analogous to Scheme 5 and 6 (Intermediates 61-97). Unless otherwise
stated, all amines in this table are hydrochloride salts. Mol.
Inter- Aryl Halide or Formula mediate Method Grignard in Step 2
Structure Name (Mol. Wt.) 61 A ##STR00730## ##STR00731## (S)-(3,6-
difluoropyridin- 2-yl)(3-fluoro- 4-(trifluoro- methoxy)phenyl)
methanamine C.sub.13H.sub.8F.sub.6N.sub.2O (322.21) 62 A
##STR00732## ##STR00733## (S)-(3-fluoro-4- (trifluoromethoxy)
phenyl)(5- fluoropyridin-2- yl)methanamine
C.sub.13H.sub.9F.sub.5N.sub.2O (304.22) 63 A ##STR00734##
##STR00735## (S)-(3-fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2-
yl)methanamine C.sub.13H.sub.10F.sub.4N.sub.2O (286.22) .sup.
64.sup.1 A ##STR00736## ##STR00737## (S)-(3-fluoro-4-
(trifluoromethoxy) phenyl)(2- fluorophenyl) methanamine
C.sub.14H.sub.10F.sub.5NO (303.23) 65 C ##STR00738## ##STR00739##
(S)-(3,5- dimethylphenyl)(3- fluoropyridin-2- yl)methanamine
C.sub.14H.sub.15FN.sub.2 (230.28) 66 C ##STR00740## ##STR00741##
(S)-(3-fluoro-5- methylphenyl)(3- fluoropyridin-2- yl)methanamine
C.sub.13H.sub.12F.sub.2N.sub.2 (234.24) 67 C ##STR00742##
##STR00743## (S)-(3-fluoro-5- (trifluoromethyl) phenyl)(3-
fluoropyridin-2- yl)methanamine C.sub.13H.sub.9F.sub.5N.sub.2
(288.22) 68 C ##STR00744## ##STR00745## (S)-(3,5-
difluorophenyl)(3- fluoropyridin-2- yl)methanamine
C.sub.12H.sub.9F.sub.6N.sub.2 (238.21) 69 C ##STR00746##
##STR00747## (S)-(3,4- difluorophenyl)(3- fluoropyridin-2-
yl)methanamine C.sub.12H.sub.9F.sub.3N.sub.2 (238.21) 70 C
##STR00748## ##STR00749## (S)-(3- fluoropyridin- 2-yl)(3-methyl-5-
(trifluoromethyl) phenyl)methanamine C.sub.14H.sub.12F.sub.4N.sub.2
(284.25) 71 A ##STR00750## ##STR00751## (S)-(3-fluoro-4-
methylphenyl)(3- fluoropyridin-2- yl)methanamine
C.sub.13H.sub.12F.sub.2N.sub.2 (234.24) 72 A ##STR00752##
##STR00753## (S)-(3-fluoro-4- methoxyphenyl)(3- fluoropyridin-2-
yl)methanamine C.sub.13H.sub.12F.sub.2N.sub.2O (250.24) 73 B
##STR00754## ##STR00755## (S)-(4-fluoro-3- methylphenyl)(3-
fluoropyridin-2- yl)methanamine C.sub.13H.sub.12F.sub.2N.sub.2
(234.24) 74 B ##STR00756## ##STR00757## (S)-(4-fluorophenyl)
(3-fluoropyridin-2- yl)methanamine C.sub.12H.sub.10F.sub.2N.sub.2
(220.22) 75 B ##STR00758## ##STR00759## (S)-(3-fluoropyridin-
2-yl)(4-methoxy- phenyl)methanamine C.sub.13H.sub.13FN.sub.2O
(232.25) 76 B ##STR00760## ##STR00761## (S)-(4-chloro-3-
fluorophenyl)(3- fluoropyridin-2- yl)methanamine
C.sub.12H.sub.9ClF.sub.2N.sub.2 (254.66) 77 A ##STR00762##
##STR00763## (S)-(3-fluoro-4- (trifluoromethoxy) phenyl)(3-
methylpyridin-2- yl)methanamine C.sub.14H.sub.12F.sub.4N.sub.2O
(300.25) 78 A ##STR00764## ##STR00765## (S)-(3-methylpyridin-
2-yl)(4-(trifluoro- methoxy)phenyl) methanamine
C.sub.14H.sub.13F.sub.3N.sub.2O (282.26) 79 A ##STR00766##
##STR00767## (S)-pyridin-2- yl(4-(trifluoro- methoxy)phenyl)
methanamine C.sub.13H.sub.11F.sub.3N.sub.2O (268.23) 80 A
##STR00768## ##STR00769## (S)-(3-fluoropyridin- 2-yl)(p-tolyl)
methanamine C.sub.13H.sub.13FN.sub.2 (216.25) 81 A ##STR00770##
##STR00771## (S)-(3,4-dimethyl- phenyl)(3- fluoropyridin-2-
yl)methanamine C.sub.14H.sub.15FN.sub.2 (230.28) 82 A ##STR00772##
##STR00773## (S)-(3-fluoropyridin- 2-yl)(3-methyl-4-
(trifluoromethoxy) phenyl)methanamine
C.sub.14H.sub.12F.sub.4N.sub.2O (300.25) 83 A ##STR00774##
##STR00775## (S)-(3-bromopyridin- 2-yl)(3-fluoro-4-
(trifluoromethoxy) phenyl)methanamine
C.sub.13H.sub.9BrF.sub.4N.sub.2 (365.12) 84 A ##STR00776##
##STR00777## (S)-(2-fluoro-4- (trifluoromethoxy) phenyl)(3-
fluoropyridin-2- yl)methanamine C.sub.13H.sub.9F.sub.5N.sub.2O
(304.22) 85 A ##STR00778## ##STR00779## (S)-(3-fluoro-4-
(trifluoromethyl) phenyl)(3- fluoropyridin-2- yl)methanamine
C.sub.13H.sub.9F.sub.5N.sub.2 (288.22) 86 A ##STR00780##
##STR00781## (S)-(3-fluoro-4- (trifluoromethoxy)
phenyl)(3-fluoro-6- methylpyridin-2- yl)methanamine
C.sub.14H.sub.11F.sub.5N.sub.2O (318.24) .sup. 87.sup.2 A
##STR00782## ##STR00783## (3-fluoro-4- (trifluoromethoxy)
phenyl)(4- fluorophenyl) methanamine C.sub.14H.sub.10F.sub.5NO
(303.23) .sup. 88.sup.2 A ##STR00784## ##STR00785##
(2,3-difluorophenyl) (3-fluoro-4- (trifluoromethoxy)
phenyl)methanamine C.sub.14H.sub.9F.sub.6NO (321.22) .sup. 89.sup.2
A ##STR00786## ##STR00787## (2,4-difluorophenyl)
(3-fluoro-4-(trifluoro- methoxy)phenyl) methanamine
C.sub.14H.sub.9F.sub.6NO (321.22) .sup. 90.sup.2 A ##STR00788##
##STR00789## (2,5-difluorophenyl) (3-fluoro-4- (trifluoromethoxy)
phenyl)methanamine C.sub.14H.sub.9F.sub.6NO (321.22) .sup. 91.sup.2
A ##STR00790## ##STR00791## (3-fluoro-4- (trifluoromethoxy)
phenyl)(3- fluorophenyl) methanamine C.sub.14H.sub.10F.sub.5NO
(303.23) .sup. 92.sup.2 A ##STR00792## ##STR00793##
(2,6-difluorophenyl) (3-fluoro-4- (trifluoromethoxy)
phenyl)methanamine C.sub.14H.sub.9F.sub.6NO (321.21) .sup. 93.sup.2
A ##STR00794## ##STR00795## (3-fluoro-4- (trifluoromethoxy)
phenyl)(6- methoxypyridin-2- yl)methanamine
C.sub.14H.sub.12F.sub.4N.sub.2O.sub.2 (316.25) .sup. 94.sup.2 A
##STR00796## ##STR00797## (3-fluoro-4- (trifluoromethoxy)
phenyl)(5- methoxypyridin-2- yl)methanamine
C.sub.14H.sub.12F.sub.4N.sub.2O.sub.2 (316.25) .sup. 95.sup.2 A
##STR00798## ##STR00799## (3-fluoro-4- (trifluoromethoxy)
phenyl)(4- methoxypyridin-2- yl)methanamine
C.sub.14H.sub.12F.sub.4N.sub.2O.sub.2 (316.25) .sup. 96.sup.2 A
##STR00800## ##STR00801## (3-fluoro-4- (trifluoromethoxy)
phenyl)(4- methylpyridin-2- yl)methanamine
C.sub.14H.sub.12F.sub.4N.sub.2O (300.25) .sup. 97.sup.2 A
##STR00802## ##STR00803## (3-fluoro-4- (trifluoromethoxy)
phenyl)(5- methylpyridin-2- yl)methanamine
C.sub.14H.sub.12F.sub.4N.sub.2O (300.25) .sup.1Prepared employing
(R)-2-methylpropane-2-sulfinamide in the first step (Scheme 5). For
reversal of stereochemistry observed in the Ellman sulfonylimine
chemistry observed with 2-pyridyl substrates, see Kuduk, S.D.;
DiPardo, R. M.; Chang, R. K.; Ng, C.; Bock, M. G. Tetrahedron Lett.
2004, 45, 6641-6643. .sup.2Prepared employing racemic
2-methylpropane-2-sulfinamide in the first step (Scheme 5)
##STR00804##
Intermediate 98:
(4-Iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine
hydrochloride
##STR00805##
[0846] Step 1.
(E)-N-(4-Iodobenzylidene)-2-methylpropane-2-sulfinamide
[0847] To a solution of 4-(iodo)benzaldehyde (2.00 g, 8.62 mmol)
(BioNet Research) in DCM (20 mL) was added
2-methylpropane-2-sulfinamide (2.09 g, 17.2 mmol) (AK Scientific)
and copper (II) sulfate (2.75 g, 17.2 mmol) (Fluka). The suspension
was stirred at rt under N.sub.2 for 17 h. The suspension was then
filtered through Celite.RTM. brand filter agent, and the solids
were washed with DCM (2.times.20 mL). The filtrates were
concentrated and purified by ISCO (80 g, SiO.sub.2, 0-100%
EtOAc/hexanes) to give the title compound as a yellow solid.
##STR00806##
Step 2.
N-((4-Iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methy-
lpropane-2-sulfinamide
[0848] To a solution of 2-bromo-3-(trifluoromethyl)pyridine (750
mg, 3.32 mmol) (prepared as described in Schlosser, M. et al. Eur.
J. Org. Chem. 2003, 1559) in THF (5.0 mL) at -78.degree. C. was
added n-butyllithium (3.94 mL, 6.31 mmol, 1.6 M in n-hexane). The
resulting mixture was then stirred for 15 min.
N-(4-iodobenzylidene)-2-methylpropane-2-sulfinamide (556 mg, 1.66
mmol) in THF (5 mL) was added, and the reaction was allowed to warm
to rt and stirred for 4 h. The reaction was quenched with saturated
aqueous NH.sub.4Cl (10 mL) and stirred rapidly for 1 h. The aqueous
layer was extracted with EtOAc (2.times.10 mL) and the combined
organic layers were dried (MgSO.sub.4) and concentrated. The
product thus obtained was taken into the next step without further
purification.
##STR00807##
Step 3.
(4-Iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methanamine
[0849] To a solution of
N-((4-iodophenyl)(3-(trifluoromethyl)pyridin-2-yl)methyl)-2-methylpropane-
-2-sulfinamide in MeOH (5 mL) was added HCl (2.0 mL, 8.0 mmol) (4.0
M in 1,4-dioxane). The reaction was stirred at rt under N.sub.2 for
18 h. The reaction was then concentrated, and the residue was
purified by reverse-phase preparative HPLC (Shimadzu) on a
Phenomenex Gemini.TM. column (5 micron, C18, 110 .ANG., Axia,
100.times.30 mm) eluting at 45 mL/min with a linear gradient of 10%
to 100% MeCN (0.1% TFA) in H.sub.2O (0.1% TFA) over 20 minutes. The
product-containing fractions were combined, concentrated, dissolved
in DCM (5 mL) and extracted with saturated aqueous NaHCO.sub.3
(2.times.5 mL). The organic layer was dried and concentrated to
give (4-iodophenyl)(3-(trifluoromethyl)-pyridin-2-yl)methanamine as
a clear oil.
##STR00808##
Intermediate 99:
(S)-(4-(Trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methanamine
2,2,2-trifluoroacetate
##STR00809##
[0850] Step 1. (S)-tert-Butyl
((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamate
[0851] To a stirring solution of
(S)--N--((S)-(3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-2-me-
thylpropane-2-sulfinamide (Intermediate 40, Step 4, 0.6 g, 1.38
mmol) in 1,4-dioxane (6 mL) at 0.degree. C. was added HCl (4.0 M in
dioxane solution, 12 mL, 27.6 mmol). The resulting mixture was
warmed to room temperature and stirred for 1 h. The reaction
progress was monitored by TLC (20% EtOAc in petroleum ether). After
completion, Boc anhydride (0.76 g, 3.4 mmol) and DIPEA (0.28 g, 2
mmol) in 1,4-dioxane (5 mL) were added to the reaction mixture, and
the mixture was stirred at room temperature for 1 h. The reaction
progress was monitored by TLC (20% EtOAc in petroleum ether). After
completion of reaction, water (25 mL) was added to the reaction
mixture, and the product was extracted with DCM (3.times.25 mL).
The combined organic layers were dried over anhydrous sodium
sulfate and purified by column chromatography using silica (100-200
mesh) with 15-30% EtOAc in petroleum ether as an eluent to afford
the title compound as a white solid. MS (ESI pos. ion) m/z: 431.0
(M-100).
##STR00810##
Step 2. (S)-tert-Butyl
((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate
[0852] To a mixture of (S)-tert-butyl
((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate
(0.4 g, 0.93 mmol) in water (2 mL) and EtOH (8 mL) were added
K.sub.3PO.sub.4 (0.3 g, 1.3 mmol), vinyl boronic acid (4 mL, 9.3
mmol) and A.sup.-taPhos).sub.2PdCl.sub.2 (Guram, A. S. et al. Org.
Lett. 2006, 8, 1787; 0.13 g, 0.01 mmol). The resulting mixture was
stirred at 120.degree. C. for 1 h. Reaction progress was monitored
by TLC (20% EtOAc in petroleum ether). After completion of
reaction, water (50 mL) was added to the reaction mixture, and the
product was extracted with DCM (3.times.25 mL). The combined
organic layers were separated, dried over anhydrous sodium sulfate,
and purified by column chromatography using silica (100-200 mesh)
and using 15-30% EtOAc in petroleum ether as an eluent. In this
manner, (S)-tert-butyl
((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate
was obtained as an off-white solid. MS (ESI pos. ion) m/z: 378.9
(M+1).
##STR00811##
Step 3.
(S)-(4-(Trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methanamine
2,2,2-trifluoroacetate
[0853] To a 50 mL round bottom flask containing (S)-tert-butyl
((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)carbamate
(97 mg, 0.256 mmol) was added DCM (3 mL). The resulting mixture was
then stirred at 23.degree. C. for 2 min. At this time, TFA was
added (3 mL) and the reaction was stirred for 3 h. The solvent was
removed, and the material was immediately used with no further
purification. MS (ESI pos. ion) m/z: 279.1 (M+1).
##STR00812##
Intermediate 100:
(R)-1-(2-Hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic
acid
##STR00813##
[0854] STEP 1. (R)-Methyl
1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate
[0855] A solution of methyl coumalate (500 mg, 3.24 mmol) in MeOH
(10 mL) was treated with (R)-(-)-1-amino-2-propanol (0.319 mL, 4.06
mmol) and TEA (0.790 mL, 5.68 mmol). The reaction was stirred at
23.degree. C. under nitrogen. After 1 h, the reaction was
concentrated and purified by silica gel chromatography (eluent:
55-95% EtOAc/hexane), affording (R)-methyl
1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate as a
white solid. MS (ESI pos. ion) m/z: 212.1 (M+1).
##STR00814##
Step 2.
(R)-1-(2-Hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic
acid
[0856] A solution of (R)-methyl
1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (508
mg, 2.405 mmol) in 1,4-dioxane (12 mL) and MeOH (4.00 mL) was
treated with aqueous sodium hydroxide, 5.0 M (0.962 mL, 4.81 mmol).
The reaction was stirred at 23.degree. C. After 20 h, the reaction
was neutralized to pH=6.0 with 2 N HCl, and concentrated in vacuo.
The residue was azeotroped with toluene (3.times.10 mL), suspended
in a 1:1 MeOH:DCM solution (25 mL), and the white NaCl residue was
removed by filtration. The filtrate was concentrated, affording
(R)-1-(2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid
as a white solid. MS (ESI pos. ion) m/z: 198.1 (M+1).
TABLE-US-00004 TABLE 4 Additional carboxylic acids prepared from
methyl coumalate analogous to Scheme 16 (Intermediates 101-110)
Mol. Inter- Amine Formula mediate in Step 1 Structure Name (Mol.
Wt.) 101 ##STR00815## ##STR00816## 1-(2- hydroxyethyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxylic acid C.sub.8H.sub.9NO.sub.4 (183.16)
102 ##STR00817## ##STR00818## (S)-1-(2- hydroxypropyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxylic acid C.sub.9H.sub.11NO.sub.4 (197.19)
103 ##STR00819## ##STR00820## 1-(2-hydroxy-2- methylpropyl)-
6-oxo-1,6- dihydropyridine-3- carboxylic acid
C.sub.10H.sub.13NO.sub.4 (211.21) 104 ##STR00821## ##STR00822##
1-(oxetan-3-yl)- 6-oxo-1,6- dihydropyridine- 3-carboxylic acid
C.sub.9H.sub.9NO.sub.4 (195.17) 105 ##STR00823## ##STR00824##
1-ethyl-6-oxo- 1,6- dihydropyridine- 3-carboxylic acid
C.sub.8H.sub.9NO.sub.3 (167.16) 106 ##STR00825## ##STR00826##
1-isopropyl-6- oxo-1,6- dihydropyridine- 3-carboxylic acid
C.sub.9H.sub.11NO.sub.3 (181.19) 107 ##STR00827## ##STR00828##
6-oxo-1-(2,2,2- trifluoroethyl)- 1,6-dihydropyridine- 3-carboxylic
acid C.sub.8H.sub.6F.sub.3NO.sub.3 (221.13) 108 ##STR00829##
##STR00830## 1-((1-hydroxy- cyclopropyl)methyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxylic acid C.sub.10H.sub.11NO.sub.4
(209.20) 109 ##STR00831## ##STR00832## (S)-6-oxo-1-
(3,3,3-trifluoro-2- hydroxypropyl)-1,6- dihydropyridine-
3-carboxylic acid C.sub.9H.sub.8F.sub.3NO.sub.4 (251.16) 110
##STR00833## ##STR00834## (R)-6-oxo-1- (3,3,3-trifluoro-2-
hydroxypropyl)-1,6- dihydropyridine-3- carboxylic acid
C.sub.9H.sub.8F.sub.3NO.sub.4 (251.16)
##STR00835##
Intermediate 111: 1-Methoxy-6-oxo-1,6-dihydropyridine-3-carboxylic
acid
##STR00836##
[0857] Step 1. 2-Chloro-5-(methoxycarbonyl)pyridine 1-oxide
[0858] To a 500 mL round bottom flask containing methyl
6-chloronicotinate (4.50 g, 26.2 mmol) was added MeCN (100 mL). The
resulting mixture was then stirred at 0.degree. C. for 10 min. At
this time, urea hydrogen peroxide (4.93 g, 52.5 mmol) solid was
added before the dropwise addition of trifluoroacetic anhydride
(7.41 mL, 52.5 mmol). The reaction was stirred for 30 min and then
the ice bath was removed. The reaction was then stirred for 3 h and
then the bulk of MeCN was removed by rotary evaporation. The
residue was dissolved in EtOAc (150 mL) and washed with sodium
thiosulfate (aqueous, 0.5 M, 2.times.100 mL), water (100 mL), brine
(100 mL), dried with sodium sulfate and concentrated to a tan
solid. The solid thus obtained was dissolved in DCM (150 mL) and
MeOH (30 mL). The solid residue was removed by filtration, and the
filtrate was concentrated affording
2-chloro-5-(methoxycarbonyl)pyridine 1-oxide as a tan solid.
##STR00837##
Step 2. Methyl
1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate
[0859] To a 250 mL round bottom flask containing
2-chloro-5-(methoxycarbonyl)pyridine 1-oxide (2.45 g, 13.06 mmol)
was added MeCN (10 mL). The resulting mixture was stirred at
23.degree. C. for 5 min. At this time, trifluoroacetic anhydride
(20 mL) was added and the reaction was stirred 1 h. Solid
NaHCO.sub.3 (25 g) was added to the flask followed by MeOH (100
mL). The solid was filtered awau and the filtrate was concentrated
and subjected to silica gel chromatography (80 g ISCO column, 0-5%
MeOH in CHCl.sub.3) to give methyl
1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a yellow
solid.
##STR00838##
Step 3. Methyl
1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate
[0860] To a solution of methyl
1-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (0.75 g, 4.43
mmol) in 5 mL DMF at 23.degree. C., were added potassium carbonate
(1.8 g, 13.3 mmol) and MeI (1.5 g, 11 mmol). The resulting mixture
was stirred overnight and then MeOH (6 mL) was added and the
resulting mixture was stirred for 2 h. The volatiles were removed
under vacuum, and the resulting residue was dissolved in EtOAc (75
mL), washed with water (2.times.50 mL), brine (50 mL), dried
(MgSO.sub.4), and concentrated to give methyl
1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate as a brown
oil.
##STR00839##
Step 4. 1-Methoxy-6-oxo-1,6-dihydropyridine-3-carboxylic acid
[0861] A solution of methyl
1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylate (64 mg, 0.349
mmol) and potassium trimethylsilanolate (90 mg, 0.699 mmol) in THF
(6 mL) was stirred at 23.degree. C. for 20 min. MeOH (5 mL) was
added, and the mixture was filtered. The filtrate was concentrated
affording 1-methoxy-6-oxo-1,6-dihydropyridine-3-carboxylic acid as
a white solid.
##STR00840##
Intermediate 112:
1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid
##STR00841##
[0862] Step 1. Methy 6-acetamidonicotinate
[0863] To a mixture of methyl 6-aminopyridine-3-carboxylate (3 g,
19.72 mmol, Aldrich) in 1,4-ioxane (50 mL) was added acetic
anhydride (3.72 mL, 39.4 mmol, Aldrich). The resulting mixture was
then heated at 85.degree. C. for 3 h and at 100.degree. C. for an
additional 3 h. The mixture was then cooled to rt and diluted with
EtOAc (400 mL). The mixture was then washed with saturated
NaHCO.sub.3 solution (2.times.200 mL), brine (150 mL), dried over
MgSO.sub.4, and concentrated in vacuo to afford the title compound
as a white solid, which was used in the next step without
purification. MS (ESI, positive ion) m/z: 195 (M+H).
##STR00842##
Step 2. Methyl
1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate
[0864] A mixture of methyl 6-acetamidonicotinate (1.93 g, 9.94
mmol), sodium chlorodifluoroacetate (1.818 g, 11.93 mmol, Alfa
Aesar Avocado Lancaster) and 18-crown-6 (0.525 g, 1.988 mmol,
Aldrich) in MeCN (40 mL) was heated to 90.degree. C. (reflux) under
nitrogen. After 5 h, a solution of KHSO.sub.4 (1% in H.sub.2O, 10
mL) was added and the mixture was refluxed for 21 h. The mixture
was then cooled to room temperature and concentrated. The mixture
was diluted with EtOAc (250 mL), washed with 10% aqueous
hydrochloric acid (100 mL), and then with saturated aqueous
NaHCO.sub.3 (100 mL), and finally with brine (100 mL). The mixture
was dried (MgSO.sub.4) and concentrated in vacuo. The residue was
dissolved in DCM (5 mL), and the solution was purified by silica
gel flash column chromatography (5-30% EtOAc/hexane) to afford the
title compound as a white solid. MS (ESI, positive ion) m/z: 204
(M+H).
##STR00843##
Step 3. 1-(Difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic
acid
[0865] To a solution of methyl
1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (0.500
g, 2.461 mmol) in MeOH (12 mL) and water (4 mL) was added lithium
hydroxide hydrate (0.207 g, 4.92 mmol, Aldrich). The resulting
mixture was then stirred at room temperature for 4 h. Solvent
(MeOH) was removed in vacuok, and the remaining aqueous solution
was adjusted to pH=5-6 by addition of concentrated HCl. The mixture
was then extracted with EtOAc (3.times.10 mL). The combined organic
layers were dried (MgSO.sub.4), and the solvent removed to give the
title compound as a yellow solid. MS (ESI, positive ion) m/z: 190
(M+H).
##STR00844##
Intermediate 113: 5-Fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic
acid
##STR00845##
[0866] Step 1. Methyl
5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate
[0867] To a solution of methyl
6-oxo-1,6-dihydro-3-pyridinecarboxylate (2.00 g, 13.06 mmol, Bionet
Research) in MeCN (40 mL) was added SelectFluor.RTM. (4.63 g, 13.06
mmol, Aldrich). The resulting mixture was then heated at 65.degree.
C. for 18 h. Then, the mixture was cooled to rt and water (20 mL)
was added. The solvent, (MeCN) was removed and the remaining
aqueous solution was extracted with EtOAc (2.times.20 mL). The
combined organic extracts were dried (MgSO.sub.4) and concentrated
in vacuo. The residue was dissolved in MeOH (100 mL) and silica gel
was added. The mixture was concentrated and dried in vacuo.
Purification by silica gel flash column chromatography (0%-100%
EtOAc/hexane) gave the title compound as a white solid. MS (ESI,
positive ion) m/z: 172 (M+H).
##STR00846##
Step 2. 5-Fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic Acid
[0868] To a solution of methyl
5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylate (0.876 g, 5.12
mmol) in MeOH (33 mL) and water (11 mL), was added lithium
hydroxide hydrate (1.074 g, 25.6 mmol). The resulting mixture was
then stirred at rt for 5 h. The mixture was concentrated and the pH
was adjusted to pH=5 using concentrated HCl. The mixture was then
concentrated and dried in vacuo. The resulting residue was
dissolved in MeOH (20 mL) and silica gel was added. The mixture was
concentrated and dried. The solid mixture was then purified by
silica gel flash column chromatography (30%-100% EtOAc/hexane, then
0%-100% MeOH/DCM) to give the title compound as an off-white solid.
MS (ESI, positive ion) m/z: 158 (M+H).
##STR00847##
Intermediate 114: 5-Chloro-6-oxo-1,6-dihydropyridine-3-carboxylic
Acid
[0869] To a solution of 6-hydroxy nicotinic acid (0.500 g, 3.59
mmol, TCI) in MeCN (20 mL), was added N-chlorosuccinimide (0.436
mL, 5.39 mmol, Aldrich). The resulting mixture was then heated at
80.degree. C. for 72 h. A white precipitatate was present. The
mixture was filtered and the white solid was washed with EtOAc
(2.times.1 mL) and dried in vacuo to afford the title compound as a
white solid. MS (ESI, positive ion) m/z: 174,176 (M+H).
##STR00848##
Intermediate 115:
6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridine-3-carboxylic acid
[0870] To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-ol
(0.960 g, 3.97 mmol, Aldrich) in THF (20 mL) at -78.degree. C.
under N.sub.2 was slowly added n-butyllithium solution, 1.6 M in
hexane (5.45 mL, 8.73 mmol). After addition, the mixture was
stirred at -78.degree. C. for 30 min. Then, dry ice was added and
the mixture was stirred at -78.degree. C. for 30 min and at rt for
30 min. Water (20 mL) was then added slowly, and the mixture was
stirred at rt for 15 min. The aqueous phase was collected and
acidified (pH=5-6) using concentrated HCl. The mixture was
extracted with EtOAc (3.times.15 mL). The combined organic layers
were dried (MgSO.sub.4), concentrated, and dried in vacuo to give
the title compound as a yellow solid. MS (ESI, positive ion) m/z:
208 (M+H).
##STR00849##
Intermediate 116: 5-Methyl-6-oxo-1,6-dihydropyridine-3-carboxylic
acid
##STR00850##
[0871] Step 1. 5-Bromo-3-methylpyridin-2(1H)-one
[0872] To a solution of 2-hydroxy-3-methylpyridine (0.500 g, 4.58
mmol, Acros Organics) in DCM (15 mL) was slowly added bromine
(0.282 mL, 5.50 mmol). After addition, the mixture was stirred at
rt for 18 h. The mixture was cooled to 0.degree. C. and was
quenched with saturated aqueous NaHCO.sub.3 (5 mL). The mixture was
then extracted with EtOAc (3.times.20 mL). The combined organic
layer were dried over MgSO.sub.4 and concentrated. The residue was
then dissolved in MeOH (20 mL) and silica gel was added. The
mixture was concentrated and dried in vacuo. The resulting mixture
was then purified by silica gel flash column chromatography (solid
loading, 0%-100% EtOAc/hexane) to afford the title compound as a
light pink solid. MS (ESI, positive ion) m/z: 188,190 (M+H).
##STR00851##
Step 2. 5-Methyl-6-oxo-1,6-dihydropyridine-3-carboxylic Acid
[0873] To a solution of 5-bromo-3-methylpyridin-2(1H)-one (0.400 g,
2.127 mmol) in THF (9 mL) at -78.degree. C. under N.sub.2 was
slowly added n-butyllithium solution, 1.6 M in hexane (5.32 mL,
8.51 mmol). After addition, the mixture was stirred at -78.degree.
C. for 20 min. The mixture was then quenched with dry ice and
allowed to warm to 0.degree. C. and stirred for 60 min. The mixture
was then immersed in a 0.degree. C. bath and the pH was adjusted to
pH=5-6 using concentrated HCl. The mixture was concentrated and
dried in vacuo to give the title compound as a light brown solid.
MS (ESI, positive ion) m/z: 154 (M+H).
##STR00852##
Intermediate 117: 5-Methoxy-6-oxo-1,6-dihydropyridine-2-carboxylic
acid
##STR00853##
[0874] Step 1. 6-Bromo-3-methoxypyridin-2(1H)-one
[0875] To a solution of 3-methoxy-2(1 h)-pyridone (1.00 g, 7.99
mmol, AstaTech, Inc) in DCM (26 mL) at 0.degree. C. was slowly
added bromine (0.819 mL, 15.98 mmol).
[0876] After addition, the mixture was stirred at rt for 18 h. The
mixture was then cooled to 0.degree. C. and saturated aqueous
NaHCO.sub.3 (4 mL) was slowly added. The mixture was then stirred
at rt for 30 min. The organic layer was collected and the aqueous
layer was extracted with EtOAc (1.times.20 mL). The combined
organic layers were dried over MgSO.sub.4 and concentrated in
vacuo. The residue was then dissolved in MeOH (20 mL) and silica
gel was added. The mixture was concentrated and dried in vacuo. The
solid mixture was purified by silica gel flash column
chromatography (solid loading, 0%-100% EtOAc/hexane) to give the
title compound as a tan solid. MS (ESI, positive ion) m/z: 204926
(M+H).
##STR00854##
Step 2. 5-Methoxy-6-oxo-1,6-dihydropyridine-2-carboxylic Acid
[0877] To a solution of 6-bromo-3-methoxypyridin-2(1H)-one (0.200
g, 0.980 mmol) in THF (3.5 mL) under N.sub.2 at -78.degree. C. was
added n-butyllithium solution, 1.6 M in hexanes (2.5 mL, 3.9 mmol)
slowly. After addition, the mixture was stirred at -78.degree. C.
for 20 min. Then, the mixture was quenched with dry ice at
-78.degree. C. The mixture was then stirred at 0.degree. C. for 1
h. The resulting mixture was adjusted to pH=5-6 using concentrated
HCl. The mixture was stirred at rt for 15 min. Then, the aqueous
layer was collected, concentrated, and dried in vacuo. Then, a
solution of DCM/MeOH (1:1, 20 mL) was added to the residue, and the
mixture was stirred at rt for 10 min. The mixture was filtered and
filtrate was collected, dried over MgSO.sub.4, concentrated, and
dried in vacuo to afford the title compound as a light brown solid.
MS (ESI, positive ion) m/z: 170 (M+H).
TABLE-US-00005 TABLE 5 Examples 287-424 prepared via amide
formation analogous to Scheme 4 MS Ex # Amine Acid Structure
Product Structure Product Name M + H .sup. 287.sup.1 2b
##STR00855## ##STR00856## (R)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 392.1 288 6 ##STR00857## ##STR00858## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-2- (pyridin-2- yl)acetamide 424.1 289 6 ##STR00859##
##STR00860## (S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
fluoropyridin-2- yl)methyl)-2- (pyridin-3- yl)acetamide 424.1 290 6
##STR00861## ##STR00862## (S)-N-((3- fluoro-4- (trifluoromethoxy)
phenyl)(3- fluoropyridin-2- yl)methyl)-2- (pyridin-4- yl)acetamide
424.0 291 61 ##STR00863## ##STR00864## (S)-N-((3,6-
difluoropyridin- 2-yl)(4- (trifluoromethyl) phenyl)methyl)-
6-oxo-1,6- dihydropyridine- 3-carboxamide 410.1 292 62 ##STR00865##
##STR00866## (S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(5-
fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-3-
carboxamide 426.0 293 63 ##STR00867## ##STR00868## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2- yl)methyl)-6-
oxo-1,6- dihydropyridine-3- carboxamide 408.0 294 63 ##STR00869##
##STR00870## (S)-N-((3- fluoro-4- (trifluoromethoxy)
phenyl)(pyridin-2- yl)methyl)-1- methyl-6-oxo-1,6-
dihydropyridine-3- carboxamide 422.1 295 64 ##STR00871##
##STR00872## (S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(2-
fluorophenyl) methyl)-6-oxo-1,6- dihydropyridine-3- carboxamide
425.1 296 64 ##STR00873## ##STR00874## (S)-N-((3- fluoro-4-
(trifluoromethoxy) phenyl)(2- fluorophenyl) methyl)-1-
methyl-6-oxo-1,6- dihydropyridine-3- carboxamide 439.1 297 6 101
##STR00875## (S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
fluoropyridin-2- yl)methyl)-1-(2- hydroxyethyl)- 6-oxo-1,6-
dihydropyridine-3- carboxamide 470.1 298 6 102 ##STR00876##
N-((S)-(3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-1- ((S)-2- hydroxypropyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 484.1 299 6 100 ##STR00877## N-((S)-(3- fluoro-4-
(trifluoromethoxy) phenyl)(3- fluoropyridin-2- yl)methyl)-1-
hydroxypropyl)- 6-oxo-1,6- dihydropyridine- 3-carboxamide 484.1 300
2 102 ##STR00878## N-((S)-(3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)- 1-((S)-2- hydroxypropyl)-
6-oxo-1,6- dihydropyridine- 3-carboxamide 450.1 301 2 100
##STR00879## N-((S)-(3- fluoropyridin-2- yl)(4- (trifluoromethyl)
phenyl)methyl)- 1-((R)-2 hydroxypropyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 450.1 302 6 103 ##STR00880##
(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-1-(2- hydroxy-2- methylpropyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 498.2 303 2 103 ##STR00881##
(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl)
phenyl)methyl)- 1-(2-hydroxy-2- methylpropyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 464.1 304 6 104 ##STR00882##
(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-1- (oxetan-3-yl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 482.1 305 2 104 ##STR00883## (S)-N-((3-
fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-
1-(oxetan-3- yl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 448.1
306 28 ##STR00884## ##STR00885## (S)-N- (phenyl(3-
(trifluoromethyl) pyridin-2- yl)methyl)quinoline- 7-carboxamide
408.0 307 2 ##STR00886## ##STR00887## (S)-N-((3- fluoropyridin-2-
yl)(4- (trifluoromethyl) phenyl)methyl) tetrazolo[1,5-a]
pyridine-6- carboxamide 417.2 308 2 ##STR00888## ##STR00889##
(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)
tetrazolo[1,5-a] pyridine-7- carboxamide 417.2 309 8 ##STR00890##
##STR00891## (S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy)
phenyl)methyl) tetrazolo[1,5-a] pyridine-6- carboxamide 433.1 310 8
##STR00892## ##STR00893## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethoxy) phenyl)methyl) tetrazolo[1,5-a] pyridine-7-
carboxamide 433.1 311 1 ##STR00894## ##STR00895## (S)-N-((4-
(trifluoromethyl) phenyl)(3- (trifluoromethyl) pyridin-2-
yl)methyl)tetrazolo [1,5-a]pyridine- 6-carboxamide 467.1 312 1
##STR00896## ##STR00897## (S)-N-((4- (trifluoromethyl) phenyl)(3-
(trifluoromethyl) pyridin-2- yl)methyl)tetrazolo [1,5-a]pyridine-
7-carboxamide 467.1 313 44 ##STR00898## ##STR00899## (S)-N-((3-
methylpyridin- 2-yl)(4- (trifluoromethyl) phenyl)methyl)-
2-oxo-2,3- dihydrobenzo[d] oxazole-6- carboxamide 428.1 314 44
##STR00900## ##STR00901## (S)-N-((3- methylpyridin- 2-yl)(4-
(trifluoromethyl) phenyl)methyl) imidazo[1,2-a] pyridine-6-
carboxamide 411.2 315 2 ##STR00902## ##STR00903## (S)-N-((3-
fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-
4-(5-oxo-2,5- dihydro-1,2,4- oxadiazol-3- yl)benzamide 459.0 316 8
##STR00904## ##STR00905## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethoxy) phenyl)methyl)- 4-(5-oxo- 2,5-dihydro-
1,2,4-oxadiazol- 3-yl)benzamide 475.1 317 2 ##STR00906##
##STR00907## (S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl)
phenyl)methyl)- 6-oxo-1,6- dihydropyridazine- 3-carboxamide 393.2
318 2 ##STR00908## ##STR00909## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)- 2-oxo-1,2,3,4-
tetrahydroquinoline- 6-carboxamide 444.2 319 2 ##STR00910##
##STR00911## (S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl)
phenyl)methyl)- 5-oxo-4,5- dihydropyrazine- 2-carboxamide 393.2 320
2 ##STR00912## ##STR00913## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)- 6,7-dihydro-5H- pyrazolo[5,1-b]
[1,3]oxazine- 2-carboxamide 421.1 321 2 ##STR00914## ##STR00915##
(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl)
phenyl)methyl)- 1,4,5,6- tetrahydrocyclopenta [c]pyrazole-3-
carboxamide 405.2 322 2 ##STR00916## ##STR00917## (S)-N-((3-
fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)- 4,5,6,7-
tetrahydro-1H- indazole-3- carboxamide 419.1 323 44 ##STR00918##
##STR00919## (S)-N-((3- methylpyridin- 2-yl)(4- (trifluoromethyl)
phenyl)methyl)- 4-(5-oxo-2,5- dihydro-1,2,4- oxadiazol-3-
yl)benzamide 455.1 324 65 ##STR00920## ##STR00921## (S)-N-((3,5-
dimethylphenyl)(3- fluoropyridin-2- yl)methyl)-6- oxo-1,6-
dihydropyridine- 3-carboxamide 352.1 325 66 ##STR00922##
##STR00923## (S)-N-((3- fluoro-5- methylphenyl) (3-fluoropyridin-
2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 356.1 326
66 ##STR00924## ##STR00925## (S)-N-((3- fluoro-5- methylphenyl)
(3-fluoropyridin- 2-yl)methyl)-1- methyl-6-oxo- 1,6-
dihydropyridine- 3-carboxamide 370.1 327 67 ##STR00926##
##STR00927## (S)-N-((3- fluoro-5- (trifluoromethyl) phenyl)(3-
fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 410.1 328 67 ##STR00928## ##STR00929## (S)-N-((3-
fluoro-5- (trifluoromethyl) phenyl)(3- fluoropyridin-2-
yl)methyl)-1- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide
424.1 329 68 ##STR00930## ##STR00931## (S)-N-((3,5-
difluorophenyl)(3- fluoropyridin-2- yl)methyl)-6- oxo-1,6-
dihydropyridine- 3-carboxamide 360.0 330 68 ##STR00932##
##STR00933## (S)-N-((3,5- difluorophenyl)(3- fluoropyridin-2-
yl)methyl)-1- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide
374.1 331 69 ##STR00934## ##STR00935## (S)-N-((3,4-
difluorophenyl)(3- fluoropydin-2- yl)methyl)-6- oxo-1,6-
dihydropyridine- 3-carboxamide 360.0 332 69 ##STR00936##
##STR00937## (S)-N-((3,4- difluorophenyl)(3- fluoropyridin-2-
yl)methyl)-1- methyl-6-oxo-1,6- dihydropyridine- 3-carboxamide
374.0 333 70 ##STR00938## ##STR00939## (S)-N-((3- fluoropyridin-2-
yl)(3-methyl-5- (trifluoromethyl) phenyl)methyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 406.1 334 71 ##STR00940##
##STR00941## (S)-N-((3- fluoro-4- methylphenyl) (3-fluoropyridin-
2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 356.0 335
71 ##STR00942## ##STR00943## (S)-N-((3- fluoro-4- methylphenyl)
(3-fluoropyridin- 2-yl)methyl)-1- methyl-6-oxo- 1,6-
dihydropyridine- 3-carboxamide 370.1 336 72 ##STR00944##
##STR00945## (S)-N-((3- fluoro-4- methoxyphenyl)(3-
fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 372.0 337 72 ##STR00946## ##STR00947## (S)-N-((3-
fluoro-4- methoxyphenyl)(3- fluoropyridin-2- yl)methyl)-1-
methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 386.0 338 73
##STR00948## ##STR00949## (S)-N-((4- fluoro-3- methylphenyl)
(3-fluoropyridin- 2-yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 356.0 339 73 ##STR00950## ##STR00951## (S)-N-((4-
fluoro-3- methylphenyl) (3-fluoropyridin- 2-yl)methyl)-1-
methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 370.1 340 74
##STR00952## ##STR00953## (S)-N-((4- fluorophenyl)(3-
fluoropyridin- 2-yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 342.0 341 74 ##STR00954## ##STR00955## (S)-N-((4-
fluorophenyl)(3- fluoropyridin- 2-yl)methyl)-1- methyl-6-oxo- 1,6-
dihydropyridine- 3-carboxamide 356.0 342 75 ##STR00956##
##STR00957## (S)-N-((3- fluoropyridin-2- yl)(4- methoxyphenyl)
methyl)-6-oxo- 1,6- dihydropyridine- 3-carboxamide 354.0 343 75
##STR00958## ##STR00959## (S)-N-((3- fluoropyridin-2- yl)(4-
methoxyphenyl) methyl)-1- methyl-6-oxo- 1,6- dihydropyridine-
3-carboxamide 368.0 344 76 ##STR00960## ##STR00961## (S)-N-((4-
chloro-3- fluorophenyl)(3- fluoropyridin- 2-yl)methyl)-6- oxo-1,6-
dihydropyridine- 3-carboxamide 376.0 345 76 ##STR00962##
##STR00963## (S)-N-((4- chloro-3- fluorophenyl)(3- fluoropyridin-
2-yl)methyl)-1- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide
390.0 346 6 ##STR00964## ##STR00965## (S)-N-((3- fluoro-4-
(trifluoromethoxy) phenyl)(3- fluoropyridin-2- yl)methyl)-2-
oxoindoline-5- carboxamide 464.0 347 77 ##STR00966## ##STR00967##
(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin-
2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 422.0
348 77 ##STR00968## ##STR00969## (S)-N-((3- fluoro-4-
(trifluoromethoxy) phenyl)(3- methylpyridin- 2-yl)methyl)-1-
methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide 436.0 349 6
##STR00970## ##STR00971## (S)-N-((3- fluoro-4- (trifluoromethoxy)
phenyl)(3- fluoropyridin-2- yl)methyl)-6- oxo-1,6-
dihydropyridazine-3- carboxamide 427.0 350 8 ##STR00972##
##STR00973## (S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy)
phenyl)methyl)- 6-oxo-1,6- dihydropyridazine-3- carboxamide 409.0
351 6 ##STR00974## ##STR00975## (S)-N-((3- fluoro-4-
(trifluoromethoxy) phenyl)(3- fluoropyridin-2- yl)methyl)-2-
oxo-1,2,3,4- tetrahydroquinoline- 6-carboxamide 478.0 352 8
##STR00976## ##STR00977## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethoxy) phenyl)methyl)- 2-oxo-1,2,3,4-
tetrahydroquinoline- 6-carboxamide 460.0 353 6 ##STR00978##
##STR00979## (S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
fluoropyridin-2- yl)methyl)-5- oxo-4,5- dihydropyrazine-
2-carboxamide 427.0 354 8 ##STR00980## ##STR00981## (S)-N-((3-
fluoropyridin-2- yl)(4- (trifluoromethoxy) phenyl)methyl)-
5-oxo-4,5- dihydropyrazine- -2-carboxamide 409.0 355 6 ##STR00982##
##STR00983## (S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
fluoropyridin-2- yl)methyl)-6,7- dihydro-5H- pyrazolo[5,1-
b][1,3]oxazine- 2-carboxamide 455.0 356 8 ##STR00984## ##STR00985##
(S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy)
phenyl)methyl)- 6,7-dihydro-5H- pyrazolo[5,1-b] [1,3]oxazine-
2-carboxamide 437.0 357 77 ##STR00986## ##STR00987## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin-
2-yl)methyl)-3- oxo-3,4- dihydro-2H- benzo[b][1,4] oxazine-7-
carboxamide 476.0 358 77 ##STR00988## ##STR00989## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(3- methylpyridin-
2-yl)methyl)-2- oxo-2,3- dihydrobenzo[d] oxazole-5- carboxamide
462.0 359 78 ##STR00990## ##STR00991## (S)-N-((3- methylpyridin-
2-yl)(4- (trifluoromethoxy) phenyl)methyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 404.0 360 78 ##STR00992##
##STR00993## (S)-1-methyl-N-((3- methylpyridin- 2-yl)(4-
(trifluoromethoxy) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 418.1 361 54 ##STR00994## ##STR00995## (S)-2-oxo-N-
(pyridin-2-yl(4- (trifluoromethyl) phenyl)methyl)- 2,3-
dihydrobenzo[d] oxazole-5- carboxamide 414.0 362 79 ##STR00996##
##STR00997## (S)-2-oxo-N- (pyridin-2-yl(4- (trifluoromethoxy)
phenyl)methyl)-2,3- dihydrobenzo[d] oxazole-5- carboxamide 430.0
363 99 ##STR00998## ##STR00999## (S)-6-oxo-N-((4- (trifluoromethyl)
phenyl)(3- vinylpyridin-2- yl)methyl)-1,6- dihydropyridine-
3-carboxamide 400.1 364 2 105 ##STR01000## (S)-1-ethyl-N- ((3-
fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-
6-oxo-1,6- dihydropyridine- 3-carboxamide 420.2 365 36 105
##STR01001## (S)-N-((3,4- dichlorophenyl)(3- fluoropyridin-2-
ethyl-6-oxo-1,6- dihydropyridine- 3-carboxamide 420.1 366 6 105
##STR01002## (S)-1-ethyl-N- ((3-fluoro-4- (trifluoromethoxy)
phenyl)(3- fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 454.1 367 2 106 ##STR01003## (S)-N-((3-
fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-
1-isopropyl-6- oxo-1,6- dihydropyridine- 3-carboxamide 434.1 368 2
##STR01004## ##STR01005## (S)-5-bromo-N-((3- fluoropyridin-2-yl)(4-
(trifluoromethyl) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 470 369 2 111 ##STR01006## (S)-N-((3-
fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-
1-methoxy-6- oxo-1,6- dihydropyridine- 3-carboxamide 422.1 370 2
101 ##STR01007## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)-1-(2- hydroxyethyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 436.2 371 2 ##STR01008##
##STR01009## (S)-1-benzyl-N-((3- fluoropyridin-2-yl)(4-
(trifluoromethyl) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 482.2 372 2 107 ##STR01010## (S)-N-((3-
fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-
6-oxo-1-(2,2,2- trifluoroethyl)-1,6- dihydropyridine- 3-carboxamide
474.1 373 2 116 ##STR01011## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)- 5-methyl-6- oxo-1,6-
dihydropyridine- 3-carboxamide 406.1 374 8 ##STR01012##
##STR01013## (S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethoxy)
phenyl)methyl) thiophene-2- carboxamide 397.1 375 2 ##STR01014##
##STR01015## (S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl)
phenyl)methyl) thiophene-2- carboxamide 381.1 376 98 ##STR01016##
##STR01017## N-((4- iodophenyl)(3- (trifluoromethyl) pyridin-2-
yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 499.5 377 79
##STR01018## ##STR01019## (S)-6-oxo-N- (pyridin-2-yl(4-
(trifluoromethoxy) phenyl)methyl)- 1,6- dihydropyridine-
3-carboxamide 389.7 378 79 ##STR01020## ##STR01021##
(S)-1-methyl-6- oxo-N-(pyridin- 2-yl(4- (trifluoromethoxy)
phenyl)methyl)- 1,6- dihydropyridine- 3-carboxamide 403.9 379 80
##STR01022## ##STR01023## (S)-N-((3- fluoropyridin-2-yl)-
(p-tolyl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 337.9
380 81 ##STR01024## ##STR01025## (S)-N-((3,4- dimethylphenyl)(3-
fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 351.8 381 81 ##STR01026## ##STR01027## (S)-N-((3-
fluoropyridin-2- yl)(3-methyl-4- (trifluoromethoxy) phenyl)methyl)-
6-oxo-1,6- dihydropyridine- 3-carboxamide 421.9 382 83 ##STR01028##
##STR01029## (S)-N-((3- bromopyridin- 2-yl)(3-fluoro-4-
(trifluoromethoxy) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 486.0 488.0 383 26 ##STR01030## ##STR01031##
(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
(trifluoromethyl) pyridin-2- yl)methyl)-6- oxo-1,6-
dihydropyridine- 3-carboxamide 476.0 384 83 ##STR01032##
##STR01033## (S)-N-((3- bromopyridin- 2-yl)(3-fluoro-4-
(trifluoromethoxy) phenyl)methyl)- 2-oxo-2,3- dihydrobenzo[d]
oxazole-5- carboxamide 526.0 528.0 385 26 ##STR01034## ##STR01035##
(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
(trifluoromethyl) pyridin-2- yl)methyl)-2- oxo-2,3- dihydrobenzo[d]
oxazole-5- carboxamide 516.0 386 84 ##STR01036## ##STR01037##
(S)-N-((2- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 2,2,2-
trifluoroacetate 426.0 387 6 ##STR01038## ##STR01039## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-1- methyl-1H- imidazole-2- carboxamide 2,2,2-
trifluoroacetate 413.0 388 6 ##STR01040## ##STR01041## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-4- methyl-1H- imidazole-2- carboxamide 2,2,2-
trifluoroacetate 413.0 389 6 ##STR01042## ##STR01043## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-5- hydroxypicolinamide 2,2,2- trifluoroacetate 426.0 390
6 ##STR01044## ##STR01045## (S)-4- acetamido-N- ((3-fluoro-4-
(trifluoromethoxy) phenyl)(3- fluoropyridin-2- yl)methyl)-3-
hydroxybenzamide 482.0 391 63 ##STR01046## ##STR01047## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2- yl)methyl)-2-
oxo-2,3- dihydrobenzo[d] oxazole-6- carboxamide 448.0 392 2
##STR01048## ##STR01049## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)-1H- benzo[d]imidazole-
5-carboxamide 415.1 393 63 ##STR01050## ##STR01051## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2- yl)methyl)-1H-
benzo[d]imidazole- 5-carboxamide 431.0 394 2 ##STR01052##
##STR01053## (S)-N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl)
phenyl)methyl)- 1-methyl-1H- benzo[d]imidazole- 5-carboxamide 429.0
395 2 ##STR01054## ##STR01055## (S)-N-((3- fluoropyridin-2- yl)(4-
(trifluoromethyl) phenyl)methyl)- 1-methyl-1H- benzo[d]imidazole-
6-carboxamide 429.0 396 2 112 ##STR01056## (S)-1- (difluoromethyl)-
N-((3- fluoropyridin-2- yl)(4- (trifluoromethyl) phenyl)methyl)-
6-oxo-1,6- dihydropyridine- 3-carboxamide 442.0 397 2 ##STR01057##
##STR01058## (S)-N-((3- fluoropyridin-2-yl)(4- (trifluoromethyl)
phenyl)methyl)- 2-methyl-1H- benzo[d]imidazole- 5-carboxamide 429.2
398 6 ##STR01059## ##STR01060## (S)-methyl 6- (((3-fluoro-4-
(trifluoromethoxy) phenyl)(3- fluoropyridin-2- yl)methyl)carbamoyl)
nicotinate 468.0 399 6 112 ##STR01061## (S)-1- (difluoromethyl)-
N-((3-fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropydin-2-
yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 476.0 400 6
113 ##STR01062## (S)-5-fluoro-N- ((3-fluoro-4- (trifluoromethoxy)
phenyl)(3- fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 444.0 401 6 114 ##STR01063## (S)-5-chloro-N-
((3-fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 462.0 402 6
115 ##STR01064## (S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
fluoropyridin-2- yl)methyl)-6- oxo-5- (trifluoromethyl)-1,6-
dihydropyridine- 3-carboxamide 494.0 403 6 116 ##STR01065##
(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-5- methyl-6-oxo- 1,6- dihydropyridine- 3-carboxamide
440.1 404 6 117 ##STR01066## (S)-N-((3- fluoro-4-
(trifluoromethoxy) phenyl)(3- fluoropyridin-2- yl)methyl)-5-
methoxy-6-oxo-1,6- dihydropyridine- 2-carboxamide 456.0 405 85
##STR01067## ##STR01068## (S)-N-((3- fluoro-4- (trifluoromethyl)
phenyl)(3- fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 410.0 406 63 ##STR01069## ##STR01070## (S)-methyl 6-
(((3-fluoro-4- (trifluoromethoxy) phenyl)(pyridin-2-
yl)methyl)carbamoyl) nicotinate 450.0 407 6 108 ##STR01071##
(S)-N-((3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-1-((1- hydroxycyclopropyl) methyl)-6- oxo-1,6-
dihydropyridine- 3-carboxamide 496.1 408 6 109 ##STR01072##
N-((S)-(3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-6- oxo-1-((S)- 3,3,3-trifluoro-2- hydroxypropyl)-1,6-
dihydropyridine- 3-carboxamide 538.1 409 6 110 ##STR01073##
N-((S)-(3- fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-6- oxo-1-((R)- 3,3,3-trifluoro-2- hydroxypropyl)-1,6-
dihydropyridine- 3-carboxamide 538.1 410 86 ##STR01074##
##STR01075## (S)-N-((3- fluoro-6- methylpyridin- 2-yl)(4-
(trifluoromethyl) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 406.1 411 87 ##STR01076## ##STR01077##
N-((3-fluoro-4- (trifluoromethoxy) phenyl)(4- fluorophenyl)
methyl)-6-oxo-1,6- dihydropyridine- 3-carboxamide 425.0
412 88 ##STR01078## ##STR01079## N-((2,3- difluorophenyl)
(3-fluoro-4- (trifluoromethoxy) phenyl)methyl)- 6-oxo-1,6-
dihydropyridine- 3-carboxamide 442.8 413 89 ##STR01080##
##STR01081## N-((2,4- difluorophenyl) (3-fluoro-4-
(trifluoromethoxy) phenyl)methyl)- 6-oxo-1,6- dihydropyridine-
3-carboxamide 442.8 414 90 ##STR01082## ##STR01083## N-((2,5-
difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methyl)-
6-oxo-1,6- dihydropyridine- 3-carboxamide 443.5 415 6 ##STR01084##
##STR01085## (S)-6-(((3- fluoro-4- (trifluoromethoxy) phenyl)(3-
fluoropyridin-2- yl)methyl)carbamoyl) picolinic acid
trifluoroacetate 454.1 416 6 ##STR01086## ##STR01087## (S)-N-((3-
fluoro-4- (trifluoromethoxy) phenyl)(3- fluoropyridin-2-
yl)methyl)-2- oxo-1,2- dihydropyridine- 3-carboxamide 426.0 417 91
##STR01088## ##STR01089## N-((3-fluoro-4- (trifluoromethoxy)
phenyl)(3- fluorophenyl) methyl)-6-oxo-1,6- dihydropyridine-
3-carboxamide 425.2 418 92 ##STR01090## ##STR01091## N-((2,6-
difluorophenyl) (3-fluoro-4- (trifluoromethoxy) phenyl)methyl)-
6-oxo-1,6- dihydropyridine- 3-carboxamide 442.8 .sup. 419.sup.2 6b
##STR01092## ##STR01093## (R)-N-((3- fluoro-4- (trifluoromethoxy)
phenyl)(3- fluoropyridin-2- yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 425.9 420 93 ##STR01094## ##STR01095##
N-((3-fluoro-4- (trifluoromethoxy) phenyl)(6- methoxypyridin-
2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 438.1 421
94 ##STR01096## ##STR01097## N-((3-fluoro-4- (trifluoromethoxy)
phenyl)(5- methoxypyridin- 2-yl)methyl)-6- oxo-1,6-
dihydropyridine- 3-carboxamide 438.3 422 95 ##STR01098##
##STR01099## N-((3-fluoro-4- (trifluoromethoxy) phenyl)(4-
methoxypyridin- 2-yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 438.5 423 96 ##STR01100## ##STR01101##
N-((3-fluoro-4- (trifluoromethoxy) phenyl)(4- methylpyridin-
2-yl)methyl)-6- oxo-1,6- dihydropyridine- 3-carboxamide 422.0 424
97 ##STR01102## ##STR01103## N-((3-fluoro-4- (trifluoromethoxy)
phenyl)(5- methylpyridin- 2-yl)methyl)-6- oxo-1,6- dihydropyridine-
3-carboxamide 422.0 .sup.1Purified via preparative SFC [using a
Chiralpak AS-H column (250 .times. 21 mm, 10 .mu.m); mobile phase
88:12 liquid CO.sub.2: MeOH at a flow rate of 65 mL/min] resulting
in Peak 1 and 2 fractions with enantiomeric excess >99%. Peak 1
correlates with the (S) enantiomer example 51, peak 2 was assigned
as the (R) enantiomer. .sup.2Purified via preparative SFC [using a
Chiralpak AS-H column (150 .times. 21 mm, 5 .mu.m); mobile phase
88:12 liquid CO.sub.2: MeOH (20 mM NH.sub.3) at a flow rate of 75
mL/min] resulting in Peak 1 and 2 fractions with enantiomeric
excess >99%. Peak 1 correlates with the (S) enantiomer example
102, peak 2 was assigned as the (R) enantiomer.
Additional Examples
##STR01104## ##STR01105##
[0878] Example 425
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-5-carboxamide
##STR01106##
[0879] Step 1. 3-Methoxy-6-methyl-2-nitropyridine
[0880] To a stirred mixture of 6-methyl-2-nitropyridin-3-ol (5 g,
0.032 mol, Sigma Aldrich) in DMF (50.0 mL) was added
K.sub.2CO.sub.3 (6.72 g, 0.048 mol, S.d.fine chemicals, India). The
reaction mixture was stirred for 30 min at room temperature. MeI (9
mL, 0.14 mol, Spectrochem, India) was then added at room
temperature, and the reaction mixture was stirred overnight. After
completion of the reaction (monitored by TLC, 30% EtOAc in hexane),
the reaction mixture was quenched with ice water, following which
the solid product precipitated. The solid was collected by
filtration and washed with n-hexane to give the title compound.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 7.88 (d, J=8.4 Hz,
1H), 7.64 (d, J=8.8 Hz, 1H), 3.92 (s, 3H), 2.44 (s, 3H). MS (ESI,
positive ion) m/z: 169 (M+H).
##STR01107##
Step 2. 5-Methoxy-6-nitropicolinic Acid
[0881] To a suspension of 3-methoxy-6-methyl-2-nitropyridine (7 g,
0.041 mol) in water (140.0 mL) was added KMnO.sub.4 (32.88 g, 0.208
mol, S.d.fine chemicals, India) at 80.degree. C. The reaction
mixture was stirred for 16 h at 100.degree. C. After completion of
the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction
mixture was filtered and the solids were washed with water. The
filtrate was acidified and extracted with EtOAc (500 mLx 2). The
organic layers were then dried over sodium sulfate and concentrated
under reduced pressure to afford the title compound as an off white
solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 13.6 (br. s.,
1H), 8.39 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.06 (s, 3H).
MS (ESI, positive ion) m/z: 199 (M+H).
##STR01108##
Step 3. (S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)
(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide
[0882] To a stirred solution of 5-methoxy-6-nitropicolinic acid
(200 mg, 0.001 mol) in DMF was added EDCI.HCl (231.6 mg, 0.0012
mol, Molekula, India) followed by HOBt (164.7 mg, 0.0012 mol,
Spectrochem, India), DIPEA (521.87 mg, 0.0040 mol, Spectrochem,
India) and (S)-(3-fluoro-4-(trifluoromethoxy) phenyl)
(3-fluoropyridin-2-yl)methanamine hydrochloride (349.83 mg, 0.0010
mmol, Intermediate 6) at 0.degree. C. The reaction mixture was
stirred at room temperature overnight. After completion of the
reaction (monitored by TLC, 50% EtOAc in hexane), water (20 mL) was
added to the reaction mixture, and the aqueous solution was
extracted with EtOAc (20 mL.times.2). The combined organic layers
were washed with water (100 mL.times.2). The organic layer was
dried and concentrated providing a residue which was purified by
silica gel (60-120 mesh) column chromatography eluting with 40-50%
EtOAc in petroleum ether to give the title compound as a solid.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 9.46 (d, J=7.6 Hz,
1H), 8.53 (d, J=4.4 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.12 (d, J=8.8
Hz, 1H), 7.83 (t, J=9.6 Hz, 1H), 7.58-7.55 (m, 3H), 7.35 (d, J=8.4
Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 4.04 (s, 3H). MS (ESI, positive
ion) m/z: 485 (M+H).
##STR01109##
Step 4.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-5-hydroxy-6-nitropicolinamide
[0883] To a stirred solution of
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)
(3-fluoropyridin-2-yl)methyl)-5-methoxy-6-nitropicolinamide (700
mg, 0.0011 mol) in NMP (7.0 mL) was added LiCl (183.79 mg, 0.0043
mol, Sigma Aldrich, India) followed by pTSA (746.63 mg, 0.0043 mol,
Sigma Aldrich, India) at room temperature. The reaction mixture was
stirred at 180.degree. C. for 2 h. After completion of the reaction
(monitored by TLC, 100% EtOAc), the reaction mixture was cooled to
room temperature and water (50 mL) was added and the aqueous
solution was extracted with EtOAc (25 mL.times.2). The organic
extracts were washed with water (25 mL.times.2) and brine (25 mL)
and dried over anhydrous sodium sulfate and concentrated. The
resulting material was purified by silica gel (60-120 mesh) column
chromatography eluting with 60-70% EtOAc in petroleum ether to give
the title compound as an off-white solid. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 12.77 (br. s., 1H), 9.43 (d, J=7.2 Hz, 1H),
8.57 (d, J=4.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 7.86-7.79 (m, 2H),
7.59-7.54 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H).
MS (ESI, positive ion) m/z: 471 (M+H).
##STR01110##
Step 5.
(S)-6-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyri-
din-2-yl)methyl)-5-hydroxypicolinamide
[0884] To a stirred suspension of Raney Nickel (0.2 g, Monarch,
India) in MeOH (10 mL), was added
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-5-hydroxy-6-nitropicolinamide (200 mg, 0.0004252 mol) at room
temperature. The temperature was raised to 56.degree. C. and
hydrazine hydrate (0.2 mL, Spectrochem, India) was added very
slowly over 5 min (exothermic reaction). The reaction mixture was
then stirred for 10 min at the same temperature. After completion
of the reaction, monitored by TLC (TLC eluent: 50% EtOAc in
petroleum ether, uv active), the mixture was cooled to room
temperature, filtered through Celite.RTM. brand filter agent and
concentrated under high vacuum to remove excess hydrazine hydrate.
The resulting product was triturated with petroleum ether to give
the title compound as a grey solid. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.23 (d, J=8 Hz, 1H), 8.57 (d, J=4.4 Hz,
1H), 7.87 (t, J=8.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.47 (d, J=11.6 Hz,
1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz,
1H), 6.57 (d, J=8 Hz, 1H), 5.53 (br. s., 2H). MS (ESI, positive
ion) m/z: 441 (M+H).
##STR01111##
Step 6.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-5-carboxamide
[0885] To a solution of
(S)-6-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl-
)methyl)-5-hydroxypicolinamide (300 mg, 0.681 mmol) in THF (10 mL)
was added TEA (689.4 mg, 0.00068 mmol, S.d fine, India) and
triphosgene (242 mg, 0.0008 mmol, Sigma Aldrich, India) at
0.degree. C. The reaction mixture was stirred for 2 h at room
temperature. After completion of the reaction, monitored by TLC
(TLC eluent: 50% EtOAc in petroleum ether), the reaction mixture
was quenched with sat'd NaHCO.sub.3 solution and extracted with
EtOAc (3.times.20 mL). The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate, concentrated and
purified by silica gel (60-120 mesh) column chromatography eluting
with 80-100% EtOAc in petroleum ether to afford the title compound
as an off white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
12.8 (br. s., 1H), 9.46 (d, J=7.2 Hz, 1H), 8.55 (d, J=4.4 Hz, 1H),
7.83-7.77 (m, 3H), 7.57-7.49 (m, 3H), 7.33 (d, J=8.4 Hz, 1H), 6.55
(d, J=6.8 Hz, 1H). MS (ESI, positive ion) m/z: 467.2 (M+H).
##STR01112## ##STR01113##
Example 426
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
-2-oxo-1,2-dihydrooxazolo[5,4-b]pyridine-5-carboxamide
##STR01114##
[0886] Step 1. 2-(Benzyloxy)-6-chloro-3-nitropyridine
[0887] To a stirred mixture of 6-chloro-3-nitropyridin-2-ol (5 g,
0.0286 mol, Combi Blocks) in toluene (50.0 mL) in a 250 mL sealed
tube, were added Ag.sub.2CO.sub.3 (11.84 g, 0.041 mol, Aldrich) and
benzyl bromide (5.8 g, 0.033 mol) in one lot. The reaction mixture
was capped, and the mixture was stirred for 12 h at 110.degree. C.
temperature. After completion of the reaction (monitored by TLC,
10% EtOAc in hexane), the reaction mixture was quenched with water
(50 mL) and extracted with EtOAc (50 mL.times.3). The organic
layers were combined, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to give a brown solid which was
further purified column chromatography, silica gel (60-120 mesh)
using 2-6% EtOAc in petroleum ether as an eluent to obtain the
title compound as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 8.30 (d, J=8.1 Hz, 1H), 7.54 (d, J=6.9 Hz, 2H), 7.42-7.26
(m, 3H), 7.09 (t, J=8.4 Hz, 1H), 5.58 (s, 2H).
##STR01115##
Step 2. 2-(Benzyloxy)-3-nitro-6-vinylpyridine
[0888] To a stirred mixture of
(2-(benzyloxy)-6-chloro-3-nitropyridine (3.2 g, 0.0123 mol) in
toluene (32.5 mL) in a 250 mL sealed tube, were added
Pd(PPh.sub.3).sub.4 (426 mg, 0.000369 mol, Aldrich) and vinyl
tributyltin (3.90 g, 0.0123 mol). The tube was purged with the
argon gas for 10 min, capped and stirred for 12 h at 110.degree. C.
After completion of the reaction (monitored by TLC, 10% EtOAc in
hexane), the reaction mixture was quenched with water (20 mL) and
extracted with EtOAc (50 mL.times.3). The organic layers were
combined, dried over anhydrous sodium sulfate, and purified by
column chromatography, silica gel (60-120 mesh) using 5-7% EtOAc in
petroleum ether as an eluent to afford the title compound as a
white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.47 (d,
J=8.1 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.43-7.27 (m, 3H), 7.20 (br.
s., 2H), 6.92-6.83 (m, 1H), 6.49 (dd, J=17.4, 1.5 Hz, 1H), 5.74
(dd, J=10.5, 1.5 Hz, 1H), 5.59 (s, 2H). MS (ESI, positive ion) m/z:
257 (M+H).
##STR01116##
Step 3. 6-(Benzyloxy)-5-nitropicolinaldehyde
[0889] To a cooled (0.degree. C.) stirred mixture of
(2-(benzyloxy)-3-nitro-6-vinylpyridine (0.5 g, 0.0019 mol) in
acetone:water (1:1, 5 mL), was added OsO.sub.4 (16.39 mg, 0.000064
mol, Aldrich) and NaIO.sub.4 (1.67 g, 0.0078 mol, Aldrich). The
reaction mixture was stirred for 4 h at room temperature. After
completion of the reaction (monitored by TLC, 10% EtOAc in hexane),
the reaction mixture was quenched with water (10 mL) and extracted
with EtOAc (5 mL.times.3). The organic layers were combined, dried
over anhydrous sodium sulfate and purified by column
chromatography, silica gel (60-120 mesh) using 5-7% EtOAc in
petroleum ether as an eluent to afford the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 10.00 (s, 1H), 8.38 (d, J=6 Hz,
1H), 7.69 (d, J=6 Hz, 1H), 7.54 (d, J=5.7 Hz, 2H), 7.41-7.37 (m,
3H), 5.69 (s, 2H).
##STR01117##
Step 4. 6-(Benzyloxy)-5-nitropicolinic acid
[0890] To a cooled (0.degree. C.) stirred mixture of
6-(benzyloxy)-5-nitropicolinaldehyde (0.5 g, 0.0019 mol) in
acetone:water (1:1, 5 mL), was added sulphamic acid (280 mg,
0.00029 mol, Aldrich) and NaClO.sub.2 (260 mg, 0.00029 mol,
Aldrich). The reaction mixture was stirred for 2 h at the same
temperature. After completion of the reaction (monitored by TLC,
10% EtOAc in hexane), the reaction mixture was quenched with water
(2 mL) and extracted with EtOAc (20 mL.times.3). The organic layers
were combined, dried over anhydrous sodium sulfate, and purified by
column chromatography, silica gel (60-120 mesh) using 5-9% EtOAc in
petroleum ether as an eluent to give the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 13.80 (br. s., 1H), 8.45 (d,
J=8.1 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.51 (d, J=7.2 Hz, 2H),
7.44-7.36 (m, 3H), 5.62 (s, 2H).
##STR01118##
Step 5.
(S)-6-(Benzyloxy)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluo-
ropyridin-2-yl)methyl)-5-nitropicolinamide
[0891] To a stirred solution of 6-(benzyloxy)-5-nitropicolinic acid
(500 mg, 0.0018 mol) in DMF (10 mL), were added
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (620 mg, 0.0018 mol, Intermediate 6), HATU (1 g,
0.0029 mol) and DIPEA (700 mg, 0.0054 mol). The reaction mixture
was then stirred for 12 h at room temperature. Progress was
monitored by TLC (100% EtOAc). After completion of reaction, water
(100 mL) was added and product was extracted with EtOAc (50
mL.times.3) and concentrated to obtain the product which was
purified by column chromatography, silica gel (100-200 mesh), using
80-100% EtOAc in petroleum ether as the eluent to afford the title
compound .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.75 (d,
J=7.6 Hz, 1H), 8.61-8.56 (m, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.59-7.54
(m, 5H), 7.35-7.32 (m, 4H), 6.60 (d, 1H), 5.77 (s, 2H).
##STR01119##
Step 6.
(S)-5-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyri-
din-2-yl)methyl)-6-hydroxypicolinamide
[0892] To a stirred mixture of
(S)-6-(benzyloxy)-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridi-
n-2-yl)methyl)-5-nitropicolinamide (800 mg, 0.0014 mol) in THF (8
mL), was added 10% Pd/C (800 mg, Aldrich). The reaction mixture was
stirred under hydrogen atmosphere in the form of hydrogen bladder
(.about.20-22 PSI) for 12 h at room temperature. After completion
of the reaction (monitored by TLC, 100% EtOAc), the reaction
mixture was filtered through Celite.RTM. brand filter agent, the
filtrate dried over anhydrous sodium sulfate and concentrated under
reduced pressure to afford the title compound. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta.: 11.00 (s, 1H), 9.13 (d, J=6 Hz, 1H),
8.46 (d, J=4 Hz, 1H), 7.79 (t, J=9.2 Hz, 1H), 7.57-7.46 (m, 3H),
7.33 (d, J=8.4 Hz, 1H), 7.08 (br. s., 1H), 6.62 (d, J=7.6 Hz, 1H),
6.40 (br. s., 1H), 5.83 (br. s., 2H). MS (ESI, positive ion) m/z:
440.9 (M+H).
##STR01120##
Step 7.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-b]pyridine-5-carboxamide
[0893] To a cooled (-78.degree. C.), stirred mixture of
(S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl-
)methyl)-6-hydroxypicolinamide (400 mg, 0.00098 mol) in THF (4 mL)
was added TEA (1.31 mL, 0.0090 mol, Spectrochem, India) and
triphosgene (323 mg, 0.0010 mol, Spectrochem, India) in one lot and
the reaction mixture was stirred for 2 h at the same temperature.
The reaction was slowly warmed to room temperature overnight. After
completion of the reaction (monitored by TLC, 50% EtOAc in hexane),
the reaction mixture was quenched with water (2 mL) and extracted
with EtOAc (2 mL.times.3). The combined organic layers were dried
over anhydrous sodium sulfate and purified by column
chromatography, silica (60-120 mesh) using 50-60% EtOAc in
petroleum ether as an eluent, and subsequently purified further
using Prep TLC plates, mobile phase 50% EtOAc in hexane to give the
title compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 12.40
(s, 1H), 9.53 (d, J=7.2 Hz, 1H), 8.59 (d, J=4.4 Hz, 1H), 7.90-7.80
(m, 2H), 7.61-7.53 (m, 4H), 7.35 (d, J=8.8 Hz, 1H), 6.54 (d, J=7.2
Hz, 1H). MS (ESI, positive ion) m/z: 467.1 (M+H).
##STR01121## ##STR01122##
Example 427
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxamide
##STR01123##
[0894] Step 1. Ethyl 5-hydroxynicotinate
[0895] To a stirred mixture of 5-hydroxynicotinic acid (25 g,
0.1797 mol, Combi Blocks) in EtOH (500 mL) was added a catalytic
amount of conc. H.sub.2SO.sub.4. The resulting reaction mixture was
stirred for 12 h at 110.degree. C. After completion of the reaction
(monitored by TLC, 10% MeOH in CHCl.sub.3), EtOH was removed under
reduced pressure and the reaction mixture was quenched with sat'd
NaHCO.sub.3 solution (50 mL) and extracted with EtOAc (50
mL.times.3). The combined organic layers were dried over anhydrous
sodium sulfate and concentrated under reduced pressure to afford
the title compound as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 11.00 (br.s., 1H), 8.74 (s, 1H), 8.42 (d, J=2.1 Hz, 1H),
7.90 (t, J=3.9 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J=6.9 Hz,
3H). MS (ESI, positive ion) m/z: 168 (M+H).
##STR01124##
Step 2. Ethyl 6-chloro-5-hydroxynicotinate
[0896] To a stirred mixture of ethyl 5-hydroxynicotinate (20 g,
0.119 mol, in DMF (200.0 mL) was added NCS (19.18 g, 0.143 mol,
Aldrich). The reaction mixture was stirred for 2 h at 80.degree. C.
After completion of the reaction (monitored by TLC, 30% EtOAc in
hexane), the reaction mixture was quenched with sat'd NaHCO.sub.3
solution (50 mL) and extracted with EtOAc (500 mL.times.3). The
combined organic layers were dried over anhydrous sodium sulfate,
and purified by column chromatography, silica gel (100-200 mesh),
using 10-15% EtOAc in petroleum ether as the eluent to give the
title compound as a solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 8.61 (d, J=2.1 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 5.94 (br.
s., 1H), 4.53 (q, J=6.9 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H). MS (ESI,
positive ion) m/z: 202.1 (M+H).
##STR01125##
Step 3. Ethyl 5-(benzyloxy)-6-chloronicotinate
[0897] To a stirred mixture of ethyl 6-chloro-5-hydroxynicotinate
(2 g, 0.01 mol) in Toluene (50.0 mL) were added K.sub.2CO.sub.3
(2.76 g, 0.02 mol, Rankem, India) and benzyl bromide (2 g, 0.0012
mol). The reaction mixture was stirred for 2 h at room temperature.
After completion of the reaction (monitored by TLC, 20% EtOAc in
hexane), the reaction mixture was quenched with water (50 mL),
extracted with EtOAc (50 mL.times.3). The combined organic layers
were dried over anhydrous sodium sulfate and purified by column
chromatography, silica gel (60-120 mesh) using 12-16% EtOAc in
petroleum ether as the eluent to give the title compound. MS (ESI,
positive ion) m/z: 292.2 (M+H).
##STR01126##
Step 4. Ethyl
5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinate
[0898] To a stirred mixture of ethyl
5-(benzyloxy)-6-chloronicotinate (2.1 g, 0.00719 mol) in THF (21
mL) in a 250 mL sealed tube, were added Pd.sub.2(dba).sub.3 (395
mg, 0.00043 mol, Aldrich), NH.sub.2Boc (1.68 g, 0.0143 mol,
Aldrich), X-phos (500 mg, 0.0010 mol, Aldrich) and K.sub.3PO.sub.4
(4.5 g, 0.0010 mol). The vessel was purged with argon gas for 10
min. The reaction mixture was then stirred for 12 h at 80.degree.
C. After completion of the reaction (monitored by TLC, 30% EtOAc in
hexane), the reaction mixture was quenched with water (50 mL) and
extracted with EtOAc (50 mL.times.3). The combined organic layers
were dried over anhydrous sodium sulfate, and purified by column
chromatography, silica gel (60-120 mesh) using 23-30% EtOAc in
petroleum ether as the eluent to give the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.22 (s, 1H), 8.46 (d, J=1.8
Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.53 (d, J=6.6 Hz, 2H) 7.42-7.33
(m, 3H), 5.22 (s, 2H), 4.36 (q, J=6.9 Hz, 2H), 1.44 (s, 9H), 1.36
(t, 3H).
##STR01127##
Step 5. 5-(Benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinic
acid
[0899] To a cooled (0.degree. C.) stirred mixture of ethyl
5-(benzyloxy)-6-((tert-butoxycarbonyl)amino) nicotinate (1.2 g,
0.0032 mol) in EtOH:water (1:1, 12 mL), was added LiOH (154 mg,
0.0064 mol, Aldrich). The reaction mixture was stirred for 2 h at
room temperature. After completion of the reaction (monitored by
TLC, 100% EtOAc), the reaction mixture was quenched with 1N HCl at
0.degree. C. temperature and extracted with EtOAc (2 mL.times.3).
The combined organic layers were dried over anhydrous sodium
sulfate and concentrated under reduced pressure to give the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 13.24 (s,
1H), 9.18 (s, 1H), 8.45 (d, J=1.2 Hz, 1H), 7.80 (d, J=1.5, Hz, 1H),
7.53 (d, J=5.4 Hz, 2H), 7.41-7.34 (m, 2H), 5.24 (s, 2H), 1.38 (s,
9H).
##STR01128##
Step 6. (S)-tert-Butyl
(2-(benzyloxy)-5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin--
2-yl)methyl)carbamoyl)pyridin-3-yl)carbamate
[0900] To a stirred solution of
5-(benzyloxy)-6-((tert-butoxycarbonyl)amino)nicotinic acid (800 mg,
0.0023 mol) in DMF (10 mL), were added
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (790 mg, 0.0023 mol, Intermediate 6), HATU (1.325
g, 0.0034 mol) and DIPEA (900 mg, 0.0069 mol). The reaction mixture
was then stirred for 12 h at rt. Reaction progress was monitored by
TLC (100% EtOAc). After completion of the reaction, water (8 mL)
was added, and the aqueous solution was extracted with EtOAc (5
mL.times.3) and concentrated to provide the product. The product
thus obtained was purified by column chromatography, silica gel
(100-200 mesh), using 80-100% EtOAc in petroleum ether as the
eluent to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta.: 9.52 (d, J=7.6 Hz, 1H), 9.10 (s, 1H), 8.47
(t, 7.5 Hz, 2H), 7.93 (d, J=1.8 Hz, 1H), 7.82 (dd, 0.9, 9.6 Hz,
1H), 7.63-7.46 (m, 4H), 7.40-7.33 (m, 4H), 6.75 (d, J=7.8 Hz, 1H),
5.20 (s, 2H), 1.40 (s, 9H).
##STR01129##
Step 7. ((S)-tert-Butyl
(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)ca-
rbamoyl)-2-hydroxypyridin-3-yl)carbamate
[0901] To a stirred mixture of (S)-tert-butyl
(2-(benzyloxy)-5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin--
2-yl)methyl)carbamoyl)pyridine)-carbamate (800 mg, 0.0012 mol) in
THF (8 mL) was added 10% Pd/C (800 mg, Aldrich). The reaction
mixture was stirred under a hydrogen atmosphere in the form of a
hydrogen bladder (.about.20-22 PSI) for 12 h at room temperature.
After completion of the reaction (monitored by TLC, 100% EtOAc),
the reaction mixture was filtered through Celite.RTM. brand filter
agent. The filtrate was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford the title compound.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 10.40 (br. s., 1H),
9.42 (d, J=7.8 Hz, 1H), 9.01 (s, 1H), 8.45 (d, J=4.8 Hz, 1H), 8.35
(d, J=1.8 Hz, 1H), 7.95 (s, 1H), 7.80 (t, 9.6 Hz, 1H), 7.61-7.45
(m, 4H), 7.37 (d, 8.4 Hz, 1H), 1.44 (s, 9H). MS (ESI, positive ion)
m/z: 541 (M+H).
##STR01130##
Step 8.
(S)-5-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyri-
din-2-yl)methyl)-6-hydroxynicotinamide
[0902] To a stirred mixture of ((S)-tert-butyl
(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)ca-
rbamoyl)-2-hydroxypyridin-3-yl)carbamate (600 mg, 0.0011 mol), in
DCM (6 mL) was added TFA (1.2 mL, 0.143 mol, Aldrich). The
resulting mixture was then stirred for 2 h at room temperature.
After completion of the reaction (monitored by TLC, 30% EtOAc in
hexane), the reaction mixture was quenched with sat'd NaHCO.sub.3
solution (50 mL) and extracted with EtOAc (50 mL.times.3). The
combined organic layers were dried over anhydrous sodium sulfate
and concentrated under reduced pressure to afford the title
compound. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 9.78 (s.,
1H), 9.00 (d, J=7.8 Hz, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.13 (d, J=1.8
Hz, 1H), 7.79 (dd, J=1.2, 9.9 Hz, 1H), 7.60-7.43 (m, 3H), 7.35 (d,
8.7 Hz, 1H), 7.26 (d, J=1.8 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.18
(br.s., 2H). MS (ESI, positive ion) m/z: 441.1 (M+H).
##STR01131##
Step 9.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-b]pyridine-6-carboxamide
[0903] To a cooled (-78.degree. C.) stirred mixture of
(S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)
(3-fluoropyridin-2-yl)methyl)-6-hydroxynicotinamide (400 mg,
0.00098 mol) in THF (4 mL), were added TEA (1.31 mL, 0.0090 mol,
Spectrochem, India) and triphosgene (323 mg, 0.0010 mol,
Spectrochem, India). The reaction mixture was stirred for 2 h at
the same temperature. The reaction was then slowly warmed to room
temperature overnight. After completion of the reaction (monitored
by TLC, 50% EtOAc in hexane), the reaction mixture was quenched
with water (2 mL) and extracted with EtOAc (2 mL.times.3). The
combined organic layers were dried over anhydrous sodium sulfate,
and purified by column chromatography, silica gel (60-120 mesh)
using 50-60% EtOAc in petroleum ether as an eluent, and purified
again using Prep TLC plates, mobile phase 50% EtOAc in hexane to
afford the title compound. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta.: 8.58 (s., 1H), 8.48 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.65
(t, J=9.6 Hz, 1H), 7.46-7.32 (m, 4H), 6.68 (s, 2H). MS (ESI,
positive ion) m/z: 467 (M+H).
##STR01132##
Example 428
(S)-2-(5-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)meth-
yl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetic acid
##STR01133##
[0904] Step 1. Benzyl 2-oxo-2H-pyran-5-carboxylate
[0905] A solution of coumalic acid (1.2 g, 8.57 mmol) in DCM (20
mL) and THF (20 mL) was treated with 4-dimethylaminopyridine (0.105
g, 0.857 mmol). The reaction was stirred under nitrogen at
23.degree. C. After 15 min, benzyl alcohol (0.886 mL, 8.57 mmol)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(1.642 g, 8.57 mmol) were added, and the stirring was continued.
After 5 h, the solution was diluted with DCM (200 mL) and the
mixture was washed with water (150 mL), dried over MgSO.sub.4,
concentrated in vacuo and purified by silica gel chromatography
(eluent: 5-25% EtOAc/hexane), affording the title compound as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.32 (s,
1H), 7.80 (dd, J=9.78, 2.15 Hz, 1H), 7.33-7.48 (m, 5H), 6.33 (d,
J=9.78 Hz, 1H), 5.31 (s, 2H). MS (ESI, positive ion) m/z: 231.1
(M+H).
##STR01134##
Step 2. Benzyl
1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate
[0906] A solution of benzyl 2-oxo-2H-pyran-5-carboxylate (906 mg,
3.94 mmol) and glycine tert butyl ester hydrochloride (726 mg, 4.33
mmol) in MeOH (20 mL) was treated with TEA (1.642 mL, 11.81 mmol).
The reaction was stirred at 23.degree. C. under nitrogen. After 1
h, the solution was concentrated in vacuo and purified by silica
gel chromatography (eluent: 10-50% EtOAc/hexane), affording the
title compound as a light yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.11 (d, J=2.35 Hz, 1H), 7.90 (dd, J=9.59,
2.54 Hz, 1H), 7.31-7.54 (m, 5H), 6.55 (d, J=9.59 Hz, 1H), 5.30 (s,
2H), 4.56 (s, 2H), 1.48 (s, 9H). MS (ESI, positive ion) m/z: 366.0
(M+H).
##STR01135##
Step 3.
1-(2-(tert-Butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carbox-
ylic acid
[0907] A solution of benzyl
1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate
(924 mg, 2.69 mmol) in EtOAc (20 mL) and EtOH (5 mL) was treated
with palladium 10 wt. % on activated carbon (143 mg, 0.135 mmol)
under nitrogen. The reaction vessel was purged through 3
vacuum-hydrogen cycles, and was stirred under a hydrogen balloon at
23.degree. C. After 45 min, the reaction was filtered through
Celite.RTM. brand filter agent, the filter cake washed with MeOH
(100 mL), the filtrates were combined and concentrated, affording
the title compound as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.02-13.68 (br. s., 1H), 8.49 (br. s.,
1H), 7.83 (d, J=9.39 Hz, 1H), 6.44 (d, J=9.19 Hz, 1H), 4.68 (br.
s., 2H), 1.41 (s, 9H). MS (ESI, positive ion) m/z: 276.0 (M+H).
##STR01136##
Step 4. (S)-tert-Butyl
2-(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
carbamoyl)-2-oxopyridin-1(2H)-yl)acetate
[0908] A solution of
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (400 mg, 1.174 mmol, Intermediate 6),
1-(2-(tert-butoxy)-2-oxoethyl)-6-oxo-1,6-dihydropyridine-3-carboxylic
acid (327 mg, 1.292 mmol) and HATU (491 mg, 1.292 mmol) in DMF (10
mL) was treated with TEA (0.490 mL, 3.52 mmol). The reaction was
then stirred at 23.degree. C. under nitrogen. After 17 h, the
solution was diluted with EtOAc (100 mL) and washed with brine (100
mL), dried over MgSO.sub.4, concentrated in vacuo and purified by
silica gel chromatography (eluent: 5-30% EtOAc/DCM), affording the
title compound as a colorless oil. The compound was taken forward
to the next step. MS (ESI, positive ion) m/z: 540.2 (M+H).
##STR01137##
Step 5.
(S)-2-(5-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin--
2-yl)methyl)carbamoyl)-2-oxopyridin-1(2H)-yl)acetic acid
[0909] A mixture of (S)-tert-butyl
2-(5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
carbamoyl)-2-oxopyridin-1(2H)-yl)acetate (633 mg, 1.173 mmol) and
silica gel 60 (70.5 mg, 1.173 mmol) in toluene (10 mL) was heated
to 110.degree. C. After 3 h, the reaction was cooled to 23.degree.
C. and filtered. The residue was washed with 10% MeOH/DCM (100 mL),
and the filtrates were combined and concentrated affording the
title compound as a tan solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 9.08 (d, J=7.8 Hz, 1H), 8.44 (br. s., 2H), 7.87-8.02
(m, 1H), 7.76 (s, 1H), 7.42-7.63 (m, 3H), 7.34 (d, J=8.4 Hz, 1H),
6.66 (d, J=7.4 Hz, 1H), 6.41 (d, J=9.6 Hz, 1H), 4.57 (d, J=3.7 Hz,
2H). MS (ESI, positive ion) m/z: 484.1 (M+H).
##STR01138##
Example 429
(S)-2-(5-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamo-
yl)-2-oxopyridin-1(2H)-yl)acetic acid
[0910] This compound was prepared by the same method as Example 428
employing amine intermediate 2 in Step 4. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.10 (d, J=7.6 Hz, 1H), 8.45 (br. s.,
2H), 7.94 (dd, J=9.4, 2.3 Hz, 1H), 7.67-7.83 (m, 3H), 7.61 (d,
J=8.0 Hz, 2H), 7.47 (dt, J=8.5, 4.3 Hz, 1H), 6.71 (d, J=7.6 Hz,
1H), 6.40 (d, J=9.6 Hz, 1H), 4.54 (d, J=4.1 Hz, 2H). MS (ESI,
positive ion) m/z: 450.0 (M+H).
##STR01139##
Example 430
(S)--N-((3-Ethylpyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-6-oxo-1,6--
dihydropyridine-3-carboxamide
[0911] To a 100 mL round bottom flask containing
(S)-6-oxo-N-((4-(trifluoromethyl)phenyl)(3-vinylpyridin-2-yl)methyl)-1,6--
dihydropyridine-3-carboxamide (40 mg, 0.100 mmol, Example 363) was
added EtOAc (20 mL). The resulting mixture was then stirred at
23.degree. C. for 2 min. At this time, Pd/C (10%, 20 mg) was added
before a balloon of hydrogen was bubbled through the mixture. The
reaction was stirred for 2 h under hydrogen (1 atm) and was then
filtered though a plug of Celite.RTM. brand filter agent and eluted
with EtOAc (50 mL). The solvent was removed, and the material was
placed on high vacuum for 1 h to give the title compound as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.67 (d, J=6.9
Hz, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.94 (dd,
J=9.6, 2.4 Hz, 1H), 7.36-7.67 (m, 5H), 7.27-7.36 (m, 1H), 6.60 (d,
J=9.5 Hz, 1H), 6.50 (d, J=6.7 Hz, 1H), 2.63-2.82 (m, 1H), 2.36-2.62
(m, 1H), 1.11 (t, J=7.5 Hz, 3H). MS (ESI, positive ion) m/z: 402.1
(M+H).
##STR01140##
Example 431
(S)-2-Amino-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)ca-
rbamoyl)phenyl acetate
##STR01141##
[0912] Step 1.
(S)--N-((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-hydrox-
y-3-nitrobenzamide
[0913] To a solution of 4-hydroxy-3-nitrobenzoic acid (285 mg,
1.556 mmol) and DMF (5 mL), were added DIPEA (0.69 mL, 3.96 mmol)
and HATU (612 mg, 1.611 mmol). After stirring for 45 min,
(S)-(3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methanamine
hydrochloride (380 mg, 1.239 mmol, Intermediate 2) was added in one
portion. The reaction was stirred at room temperature for 5 h and
was then diluted with water (50 mL). The aqueous solution was
extracted with EtOAc (3.times.20 mL). The combined EtOAc layers
were concentrated in vacuo and adsorbed onto a plug of silica gel
and chromatographed through a Redi-Sep.RTM.pre-packed silica gel
column (12 g), eluting with 0 to 75% EtOAc in hexane, to provide
the title compound as a yellow solid. MS (ESI pos. ion) m/z: 436.1
(M+H).
##STR01142##
Step 2.
(S)-4-(((3-Fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)c-
arbamoyl)-2-nitrophenyl acetate
[0914] To a solution of
(S)--N-((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)-4-hydrox-
y-3-nitrobenzamide (83 mg, 0.191 mmol) and DCM (5 mL) were added
acetic anhydride (0.2 mL, 2.120 mmol) and DIPEA (0.15 mL, 0.861
mmol). After stirring for 45 min, the reaction was quenched with
water and after stirring for 3 days, the aqueous solution was
filtered to give the title compound as a yellow solid. The
resulting product was used in the next step without further
purification. MS (ESI pos. ion) m/z: 478.1 (M+H).
##STR01143##
Step 3.
(S)-2-Amino-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)-
methyl)carbamoyl)phenyl acetate
[0915] To a round bottom flask purged with N.sub.2 was added 10%
Pd/C (20.29 mg, 0.019 mmol) and under a N.sub.2 atmosphere
(S)-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl-
)-2-nitrophenyl acetate (91 mg, 0.191 mmol) in EtOAc (10 mL) was
added. The solution was purged for a further 2 min, then capped
with a balloon of H.sub.2. After 5 h, the reaction was filtered
through a pad of Celite.RTM. brand filter agent and the Celite.RTM.
brand filter agent rinsed with EtOAc. The filtrate was concentrated
in vacuo and adsorbed onto a plug of silica gel and chromatographed
through a Redi-Sep.RTM. pre-packed silica gel column (4 g), eluting
with 0 to 75% EtOAc in hexane, to provide the title compound as a
white solid. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. ppm 9.85 (s,
1H), 8.35-8.54 (m, 2H), 8.19 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.59
(dd, J=8.5, 2.0 Hz, 1H), 7.55 (s, 4H), 7.38-7.47 (m, 1H), 7.32 (dt,
J=8.4, 4.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.62 (dd, J=6.9, 2.0
Hz, 1H), 2.20 (s, 3H). MS (ESI pos. ion) m/z: 448.1 (M+H).
##STR01144##
Example 432
(S)-4-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
caramoyl)benzoicmacid
##STR01145##
[0916] Step 1. (S)-Methyl
4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)car-
bamoyl)benzoate
[0917] To a solution of
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (100 mg, 0.294 mmol, Intermediate 6),
4-(methoxycarbonyl)benzoic acid (52.9 mg, 0.294 mmol), and DMF (2
mL) were added TEA (0.123 mL, 0.881 mmol) and 50% propylphosphonic
anhydride in EtOAc (0.175 mL, 0.587 mmol). The solution was stirred
at room temperature. After 2 h, the reaction was diluted with water
(30 mL), stirred for 30 min, and then filtered. The solids were
washed with water and dried in the funnel to give the title
compound as a white solid. MS (ESI pos. ion) m/z: 467.0 (M+H).
##STR01146##
Step 2.
(S)-4-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)carbamoyl)benzoic acid
[0918] To a solution of (S)-methyl
4-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)car-
bamoyl)benzoate (105 mg, 0.225 mmol) and THF (2 mL):MeOH (1 mL) was
added 1M LiOH (1 mL). The solution was stirred at room temperature.
After 16 h, the reaction was diluted with water. The aqueous
solution was acidified with 1N HCl to a pH of 7 and extracted with
EtOAc (3.times.15 mL). The combined EtOAc layers were dried over
MgSO.sub.4 and concentrated in vacuo to give the title compound as
a white solid. .sup.1H NMR (300 MHz, MeOH-d4) .delta. ppm 8.49 (d,
J=4.7 Hz, 1H), 8.06-8.15 (m, J=8.5 Hz, 2H), 7.89-8.00 (m, J=8.5 Hz,
2H), 7.64 (t, J=9.1 Hz, 1H), 7.31-7.51 (m, 4H), 6.70 (s, 1H). MS
(ESI pos. ion) m/z: 453.0 (M+H).
##STR01147##
Example 433
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
imidazo[1,2-a]pyridine-6-carboxamide
[0919] To a solution of
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (81 mg, 0.238 mmol, Intermediate 6) and EtOAc (3
mL) was added 50% propylphosphonic anhydride in EtOAc (0.28 mL,
0.470 mmol), imidazo[1,2-a]pyridine-6-carboxylic acid (47 mg, 0.290
mmol) and DIPEA (0.12 mL, 0.689 mmol). The solution was stirred at
room temperature. After 16 h, the reaction product was adsorbed
onto a plug of silica gel and chromatographed through a
Redi-Sep.RTM. pre-packed silica gel column (4 g), eluting with 0 to
100% EtOAc in hexane, to provide the title compound as a white
solid. .sup.1H NMR (300 MHz, MeOH-d4) .delta. ppm 9.06-9.16 (m,
1H), 8.44-8.55 (m, 1H), 7.96 (s, 1H), 7.76 (dd, J=9.5, 1.8 Hz, 1H),
7.56-7.71 (m, 3H), 7.42-7.51 (m, 2H), 7.32-7.42 (m, 2H), 6.68-6.76
(m, 1H). MS (ESI pos. ion) m/z: 449.0 (M+H).
##STR01148##
Example 434
(S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
carbamoyl)nicotinic acid
##STR01149##
[0920] Step 1. (S)-Methyl
6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)car-
badmoyl)nicotinate
[0921] To a solution of
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (17.0 g, 49.9 mmol, Intermediate
fluoropyridin-2-yl)methanamine hydrochloride (17.0 g, 49.9 mmol,
Intermediate 6) in DMF (166 mL, Aldrich) was added
5-(methoxycarbonyl)pyridine-2-carboxylic acid (9.94 g, 54.9 mmol,
Oakwood Products, Inc.), HATU (20.87 g, 54.9 mmol, Accela ChemBio,
Inc.), and DIPEA (18.23 mL, 105 mmol, EMD Biosciences, Inc.). The
resulting mixture was then stirred at room temperature for 18 h.
Water (400 mL) was then added and the mixture was extracted with
EtOAc (2.times.200 mL). The combined organic extracts were dried
over MgSO.sub.4 and concentrated in vacuo. The residue was then
dissolved in MeOH (500 mL) and silica gel was added. The mixture
was concentrated and dried in vacuo. The solid mixture was purified
by silica gel flash column chromatography using ISCO instrument
(solid loading, 0-100% EtOAc/hexane) to give the title compound as
a white solid. MS (ESI, positive ion) m/z: 468 (M+H).
##STR01150##
Step 2.
(S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)carbamoyl)nicotinic acid
[0922] To a solution of (S)-methyl
6-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)car-
bamoyl)nicotinate (11.5 g, 24.61 mmol) in MeOH (140 mL, Aldrich)
was added lithium hydroxide hydrate (2.065 g, 49.2 mmol, Aldrich).
The mixture was stirred at room temperature for 5 min followed by
the addition of THF (5 mL, Aldrich) and the mixture was stirred at
room temperature for 1 h. The mixture was concentrated in vacuo,
cooled to 0.degree. C. and was adjusted to pH=6-7 with concentrated
HCl. EtOAc (300 mL) was added to the adjusted pH mixture, and the
resulting mixture was stirred at room temperature for 15 min. The
organic layer was collected and the aqueous phase was extracted
with EtOAc (1.times.200 mL). The combined organic layers were dried
over MgSO.sub.4 and concentrated in vacuo. The residue was then
dissolved in MeOH (400 mL) and silica gel was added. The mixture
was concentrated and dried in vacuo. The solid mixture was then
purified by silica gel flash column chromatography using ISCO
instrument (solid loading, 40% EtOAc/hexane, then 10% MeOH in
EtOAc) to give the title compound as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 13.75 (br. s., 1H), 9.85 (d,
J=7.4 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.58 (d, J=4.7 Hz, 1H), 8.48
(dd, J=8.1, 2.1 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.83 (t, J=9.3 Hz,
1H), 7.50-7.61 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 6.58 (d, J=7.2 Hz,
1H). MS (ESI, positive ion) m/z: 454.0 (M+H)
##STR01151##
Example 435
(R)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
carbamoyl)nicotinic acid
[0923] This compound was prepared using the same procedure as
example 434, except the use of Intermediate 6b in Step 1. The
compound was purified via preparative SFC [using a Chiralpak AS-H
column (250.times.21 mm, 5 pm); mobile phase 92:8 liquid CO.sub.2:
EtOH with 0.2% diethylamine at a flow rate of 70 mL/min] resulting
in Peak 1 and 2 fractions with enantiomeric excess >99%. Peak 2
correlates with the (S) enantiomer (example 434), peak 1 was
assigned as the (R) enantiomer. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 9.78 (d, J=7.6 Hz, 1H), 9.05 (s, 1H), 8.59 (d, J=4.7
Hz, 1H), 8.31 (dd, J=7.9, 1.7 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.82
(t, J=9.2 Hz, 1H), 7.49-7.61 (m, 3H), 7.35 (d, J=8.6 Hz, 1H), 6.57
(d, J=7.0 Hz, 1H). MS (ESI, positive ion) m/z: 454.1 (M+H)
##STR01152##
Example 436
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
-1-hydroxy-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxamide
##STR01153##
[0924] Step 1.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-3-(methylamino)-4-nitrobenzamide
[0925] To a solution of
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (1.0 g, 2.94 mmol, intermediate 6) in DMF (20 mL,
Aldrich) was added 3-fluoro-4-nitrobenzenecarboxylic acid (0.543 g,
2.94 mmol, Bionet Research (A Trading Division of Key Organics
Ltd)), HATU (1.228 g, 3.23 mmol, Oakwood Products, Inc.), and DIPEA
(1.123 mL, 6.46 mmol, EMD Biosciences, Inc.). The resulting mixture
was then stirred at room temperature for 1 h. The mixture was
transferred to a pressure tube, and methylamine, 2.0M solution in
THF (7.34 mL, 14.68 mmol, Aldrich) and DIPEA (1.123 mL, 6.46 mmol,
EMD Biosciences, Inc.) were added. The resulting mixture was heated
at 55.degree. C. for 18 h, then cooled to room temperature. Water
(150 mL) was added and the mixture was extracted with EtOAc
(2.times.150 mL). The combined organic extracts were dried over
MgSO.sub.4 and concentrated in vacuo. The residue was dissolved in
DCM and the solution mixture was purified by silica gel flash
column chromatography using ISCO instrument (0-100% EtOAc/hexane)
to give the title compound as a yellow solid. MS (ESI, positive
ion) m/z: 483 (M+H).
##STR01154##
Step 2. (S)-Methyl
2-((5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)-2-nitrophenyl)(methyl)amino)-2-oxoacetate
[0926] To a solution of
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-3-(methylamino)-4-nitrobenzamide (1.28 g, 2.65 mmol) and DIPEA
(0.462 mL, 2.65 mmol, EMD Biosciences, Inc.) in DCM (7 mL, Aldrich)
at 0.degree. C. was added methyl chloro oxoacetate (0.268 mL, 2.92
mmol, Aldrich) in a drop-wise fashion. The resulting mixture was
stirred at 0.degree. C. for 2 h. Water (20 mL) was added, and the
mixture was stirred at room temperature for 5 min. The organic
layer was collected, and the aqueous layer was extracted with EtOAc
(1.times.20 mL). The combined organic layers were dried over
MgSO.sub.4 and concentrated in vacuo. The residue was dissolved in
DCM, and the mixture was purified by silica gel column
chromatography using ISCO instrument (35-100% EtOAc/hexane) to give
the title compound as a yellow solid. MS (ESI, positive ion) m/z:
569 (M+H).
##STR01155##
Step 3.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-1-hydroxy-4-methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-car-
boxamide
[0927] To a solution of (S)-methyl
2-((5-(((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)carbamoyl)-2-nitrophenyl)(methyl)amino)-2-oxoacetate (0.500 g,
0.880 mmol) in MeOH (3 mL, Aldrich), was added palladium, 10 wt. %
(dry basis) on activative carbon, wet, degussa type (0.047 g, 0.440
mmol, Aldrich). The resulting mixture was stirred at room
temperature under hydrogen (balloon) for 4 h. The mixture was
filtered through celite and the celite was washed with MeOH
(2.times.10 mL). The combined filtrates were concentrated in vacuo.
Dioxane (3.00 mL, Aldrich) and water (1 mL) were added, followed by
potassium phosphate (0.560 g, 2.64 mmol, Strem Chemical). The
mixture was heated at 90.degree. C. for 18 h. The mixture was then
cooled to room temperature and filtered. The solid was washed with
water (2.times.30 mL) and dried in vacuo to afford the title
compound as a yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 9.37 (d, J=7.8 Hz, 1H), 8.47 (d, J=4.5 Hz, 1H), 7.93
(br. s., 1H), 7.74-7.84 (m, 3H), 7.55-7.67 (m, 2H), 7.50 (dt,
J=8.5, 4.3 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H),
3.52-3.66 (m, 3H). MS (ESI, positive ion) m/z: 523 (M+H).
##STR01156## ##STR01157##
Example 437
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
-2-oxo-1,2-dihydrooxazolo[5,4-c]pyridine-6-carboxamide
##STR01158##
[0928] Step 1. 5-Methoxy-2-methylpyridine
[0929] To a stirred solution of 60% NaH (in mineral oil) (18.27 g,
0.458 mol, Aldrich, India) in DMSO (66 mL, Spectrochem., India) at
0.degree. C., was added 6-methylpyridin-3-ol (25.0 g, 0.229 mol)
dissolved in DMSO (100 mL) drop wise over a period of 15 min. After
complete addition, the reaction mixture was stirred at 0.degree. C.
for 40 min. Methyl iodide (29.5 mL, 0.458 mol, Spectrochem, India)
was added and the reaction mixture was stirred at rt for 2 h. The
reaction with water and Et.sub.2O (1:1, 200 mL). The organic layer
was separated and aqueous layer was back extracted with Et.sub.2O
(75 mL.times.3). The organic layers were combined, dried over
anhydrous sodium sulfate and concentrated to give the title
compound as a dark brown gummy oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.19 (d, J=2.8 Hz, 1H), 7.12-7.05 (m, 2H),
3.83 (s, 3H), 2.49 (s, 3H). MS (ESI, positive ion) m/z: 124.0
(M+H).
##STR01159##
Step 2. 5-Methoxy-2-methylpyridine 1-oxide
[0930] To a stirred solution of 5-methoxy-2-methylpyridine (15 g,
0.121 mol) in DCM (200 mL) was added 3-chloro peroxybenzoic acid
(23.14 g, 0.134 mol, Aldrich). The reaction was stirred at rt for 3
h. Reaction progress was monitored by TLC (50% EtOAc in petroleum
ether). After completion of reaction, the reaction mixture was
concentrated under reduced pressure providing the product as a
yellow oil. The oil was dissolved in EtOAc (50 mL) and passed
through a silica gel plug (60-120 mesh) and the plug eluted with
10% MeOH in CHCl.sub.3 to give the title compound as a colorless
liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.08 (d,
J=2.4 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 6.98 (dd, J=2.7 and 8.7 Hz,
1H), 3.78 (s, 3H), 2.26 (s, 3H). MS (ESI, positive ion) m/z: 140.0
(M+H).
##STR01160##
Step 3. 5-Methoxy-2-methyl-4-nitropyridine 1-oxide
[0931] To fuming nitric acid (20 mL, Spectrochem, India) was added
(5-methoxy-2-methylpyridine 1-oxide (14 g, 0.100 mol) in one lot
and the reaction was stirred at rt for 2 h. Reaction progress was
monitored by TLC (50% EtOAc in pet ether.). After completion of the
reaction, the reaction mixture was poured in to ice water (100 mL)
and neutralized with 40% NaOH solution (PH .about.7-7.5) to get a
yellow precipitate. The precipitate was stirred for 5-10 min, then
filtered and dried to give the title compound as a yellow solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.51 (s, 1H), 8.21
(s, 1H), 3.95 (s, 3H), 2.31 (s, 3H). MS (ESI, positive ion) m/z:
184.8 (M+H).
##STR01161##
Step 4. (5-Methoxy-4-nitropyridin-2-yl)methanol
[0932] 5-Methoxy-2-methyl-4-nitropyridine 1-oxide (7 g, 0.038 mol)
was dissolved in acetic anhydride (70 mL, Sdfine, India) and the
resulting solution was stirred for 3 h at 150.degree. C. The
reaction mixture was concentrated and Et.sub.2O (250 mL) was added
to the residue and it was neutralized with sat'd NaHCO.sub.3 (100
mL). The organic layer was separated and dried over anhydrous
sodium sulfate, concentrated to afford a pale yellow solid which
was dissolved in MeOH and THF (100 mL) and treated with LiOH (2.73
g, 0.113 mol). The reaction mixture was stirred for 2 h at rt. The
progress of the reaction was monitored by TLC (5% MeOH in
CHCl.sub.3). After completion of acetate hydrolysis, sat NH.sub.4Cl
(20 mL) was added and the product was extracted with EtOAc. The
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure to afford the title compound as
an off white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.71 (s, 1H), 7.81 (s, 1H), 5.62 (t, J=5.7 Hz, 1H), 4.59 (d, J=6
Hz, 2H), 4.04 (s, 3H). MS (ESI, positive ion) m/z: 185.1 (M+H).
##STR01162##
Step 5. 5-Methoxy-4-nitropicolinaldehyde
[0933] To a stirred solution of
(5-methoxy-4-nitropyridin-2-yl)methanol (4 g, 0.021 mol) in DCM (30
mL), was added Dess-Martin Periodinane (18.43 g, 0.043 mol,
Spectrochem, India) and reaction was stirred for 3 h at rt. The
reaction progress was monitored by TLC (50% EtOAc in petroleum
ether). After completion of the reaction, sat'd NaHCO.sub.3 (20 mL)
was added and the product was extracted with DCM (3.times.25 mL).
The combined organic layers were dried over anhydrous sodium
sulfate and concentrated to give the title compound as a pale
yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.95
(s, 1H), 9.02 (s, 1H), 8.36 (s, 1H), 4.19 (s, 3H). MS (ESI,
positive ion) m/z: 182.9 (M+H).
##STR01163##
Step 6. 5-Methoxy-4-nitropicolinic acid
[0934] To a stirred solution of 5-methoxy-4-nitropicolinaldehyde (4
g, 0.02 mol) in acetone and water (1:1, 100 mL) was added sodium
chlorite (5.9 g, 0.065 mol, spectrochem, india) and sulfamic acid
(6.3 g, 0.065 mol, Rankem, India) and the reaction mixture was
stirred for 1 h at rt. Reaction progress was monitored by TLC (50%
EtOAc in petroleum ether). After completion, the reaction mixture
was concentrated to get a white precipitate which was filtered and
dried to afford the title compound as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 13.6 (brs, 1H) 8.90 (s, 1H),
8.41 (s, 1H), 4.15 (s, 3H). MS (ESI, positive ion) m/z: 197.8
(M+H).
##STR01164##
Step 7.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-5-methoxy-4-nitropicolinamide
[0935] To a stirred solution of 5-methoxy-4-nitropicolinic acid (1
g, 0.005 mol) in DMF (10 mL) were added
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (1.8 g, 0.0055 mol, Intermediate 6), HATU (2.8 g,
0.0075 mol, molekula, India) and DIPEA (2.4 g, 0.02 mol, Aldrich).
The reaction mixture was stirred for 12 h at rt. The reaction
progress was monitored by TLC (50% EtOAc in pet ether). After
completion of reaction, water (10 mL) was added and product was
extracted with EtOAc (50 mL.times.3) and concentrated to get
initial product. The product thus obtained was purified by column
chromatography, silica gel (60-120 mesh), using 80-100% EtOAc in
petroleum ether as the eluent to give the title compound. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.74 (d, J=7.6 Hz, 1H),
8.94 (s, 1H), 8.56 (d, J=4.8 Hz, 1H), 8.38 (s, 1H), 7.82 (t, J=8.8
Hz, 1H), 7.57-7.53 (m, 3H), 7.35 (d, J=8.8 Hz, 1H), 6.55 (d, J=7.2
Hz, 1H), 4.16 (s, 3H). MS (ESI, positive ion) m/z: 485.1 (M+H).
##STR01165##
Step 8. (S)-4-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)
(3-fluoropyridin-2-yl)methyl)-5-methoxypicolinamide
[0936] To a stirred suspension of Raney Nickel (0.4 g, Monarch,
India) in MeOH (10 mL) was added
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-5-methoxy-4-nitropicolinamide (700 mg, 0.0014 mol) at rt. The
reaction mixture was stirred under a hydrogen balloon for 2 h.
After completion of the reaction, monitored by TLC (TLC eluent: 50%
EtOAc in petroleum ether), the reaction mixture was filtered
through Celite.RTM. brand filter agent and concentrated. The
resulting product was triturated with petroleum ether to give the
title compound as a white solid. MS (ESI, positive ion) m/z: 455.2
(M+H).
##STR01166##
Step 9.
(S)-4-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyri-
din-2-yl)methyl)-5-hydroxypicolinamide
[0937] To a stirred solution of
(S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)
(3-fluoropyridin-2-yl)methyl)-5-methoxypicolinamide (600 mg, 0.0013
mol) in NMP (10 mL) was added LiCl (168 mg, 0.0039 mol, Aldrich)
followed by pTSA (754 mg, 0.0039 mol, Aldrich) at rt. The reaction
mixture was stirred at 180.degree. C. for 2 h. After completion of
the reaction (monitored by TLC, 50% EtOAc in petroleum ether), the
reaction mixture was cooled to room temperature and sat'd
NaHCO.sub.3 (50 mL) was added and the aqueous solution was
extracted with EtOAc (25 mL.times.2). The combined organic layers
were washed with water (25 mL.times.2), saturated NaCl (25 mL) and
dried over anhydrous sodium sulfate. The product thus obtained was
purified by silica gel (60-120 mesh) column chromatography eluting
wih 60-70% EtOAc in petroleum ether to give the title compound as
an off-white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
9.90 (s, 1H), 9.51 (d, J=8 Hz, 1H), 8.55 (d, J=4.8 Hz, 1H),
7.82-7.78 (m, 2H), 7.56-7.50 (m, 2H), 7.46 (d, J=1.6 Hz, 10.4 Hz,
1H), 7.30 (d, J=12.8, 2H), 6.48 (d, J=4.4 Hz, 1H), 5.78 (s, 2H). MS
(ESI, positive ion) m/z: 441.3 (M+H).
##STR01167##
Step 10.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2--
yl)methyl)-2-oxo-1,2-dihydrooxazolo[5,4-c]pyridine-6-carboxamide
[0938] To a cooled (-78.degree. C.) stirred mixture of
(S)-4-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl-
)methyl)-5-hydroxypicolinamide (200 mg, 0.00045 mol) in THF (5 mL)
were added TEA (0.31 mL, 0.002 mol, Spectrochem, India) and
triphosgene (270 mg, 0.0009 mol, Spectrochem, India) in one lot and
the reaction mixture was stirred for 2 h at the same temperature,
warmed to rt and stirred for 12 h. After completion of the reaction
(monitored by TLC, 50% EtOAc in hexane), the reaction mixture was
quenched with sat'd NaHCO.sub.3 (5 mL), extracted with EtOAc (10
mL.times.3). The organic layers were combined and dried over
anhydrous sodium sulfate and concentrated. The product thus
obtained was purified by column chromatography, silica gel (60-120
mesh) using 50-60% EtOAc in petroleum ether as the eluent, and
further purified using Prep TLC plates, mobile phase 50% EtOAc in
hexanes to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.76 (d, J=7.6 Hz, 1H), 8.60 (s, 1H),
8.58 (d, J=4.8 Hz, 1H), 7.82 (t, J=8.8 Hz, 1H), 7.70 (s, 1H),
7.56-7.50 (m, 3H), 7.34 (d, J=8.4 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H).
MS (ESI, positive ion) m/z: 468.0 (M+H).
##STR01168## ##STR01169##
Example 438
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-
-2-oxo-2,3-dihydrooxazolo[4,5-c]pyridine-6-carboxamide
##STR01170##
[0939] Step 1. 2-Methyl-4-nitropyridine 1-oxide
[0940] A 25 mL round bottom flask was charged with conc.
H.sub.2SO.sub.4 (1 mL) and cooled to 0.degree. C. 2-Methylpyridine
1-oxide (0.4 g, 0.003 mol, Aldrich) was added in one portion,
followed bythe addition of fuming HNO.sub.3 (1 mL, spectrochem,
india) in a drop-wise fashion. The reaction was stirred at rt for
30 min and a further 12 h at 70.degree. C. Reaction progress was
monitored by TLC (50% EtOAc in petroleum ether). After completion
of the reaction, EtOAc (10 mL) was added to the reaction mixture
after cooling to 0.degree. C. and the reaction was neutralized to
pH.about.8-9 with 40% NaOH solution, and extracted with EtOAc
(2.times.10 mL). The combined organic layers were dried over
anhydrous sodium sulfate, filtered and concentrated to give the
title compound as a yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.82 (d, J=5.4 Hz, 1H), 8.03 (d, J=1.8
Hz, 1H), 7.92 (dd, J=1.8, 5.1 Hz, 1H), 2.64 (s, 3H).
##STR01171##
Step 2. 4-Methoxy-2-methylpyridine 1-oxide
[0941] To a stirred solution of 2-methyl-4-nitropyridine 1-oxide
(24 g, 0.155 mol) in MeOH (100 mL). Sodium methoxide (10 g, 0.187
mol, Aldrich) was added, and the reaction mixture was stirred for 2
h at 80.degree. C. Reaction progress was monitored by TLC (50%
EtOAc in petroleum ether). The reaction mixture was concentrated
and water (50 mL) was added and the aqueous solution was extracted
with EtOAc (4.times.50 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated to afford the title
compound as a brown liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.14 (d, J=7.2 Hz, 1H), 7.14 (d, J=3.3 Hz, 1H), 6.91
(dd, J=3.6, 7.2 Hz, 1H), 3.80 (s, 3H), 2.32 (s, 3H).
##STR01172##
Step 3. 4-Methoxy-2-methylpyridine
[0942] To a stirred solution of 4-methoxy-2-methylpyridine 1-oxide
(20 g, 0.143 mol) in AcOH (200 mL, sdfine, India), was added Fe (16
g, 0.287 mol, sdfine, India) and the reaction mixture was stirred
for 2 h at 120.degree. C. The reaction mixture was concentrated and
neutralized with sat'd NaHCO.sub.3. EtOAc was added to the mixture
and it was filtered through Celite.RTM. brand filter agent. The
organic layer was separated and the aqueous layer was extracted
with EtOAc (3.times.150 mL). The combined organic layers were dried
over sodium sulfate, filtered and concentrated to give the title
compound as a brown liquid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 8.33 (d, J=6 Hz, 1H), 6.68-6.64 (m, 2H), 3.84 (s, 3H),
2.52 (s, 3H). MS (ESI, positive ion) m/z: 124.0 (M+H).
##STR01173##
Step 4. 4-Methoxy-2-methyl-5-nitropyridine
[0943] To a stirred solution of 4-methoxy-2-methylpyridine (25 g,
0.148 mol) in conc. H.sub.2SO.sub.4 (17 mL, S. D. Fine, India), a
mixture of H.sub.2SO.sub.4 (17 mL, S.D. Fine, India) and 65%
HNO.sub.3 (22 mL, Rankem, India) was added in a drop-wise fashion
at 0.degree. C. over 30 min. The resulting solution was heated at
65.degree. C. for 12 h. After completion, the reaction mixture was
poured in to ice water and neutralized (PH.about.8) with 40% NaOH
solution to give a yellow precipitate. The precipitate was further
stirred and filtered, dried to give a mixture of 3-nitro (major
product) and the desired 5-nitro isomers. The product was isolated
by column chromatography, silica gel (230-400), eluting with 15%
EtOAc in petroleum ether to give the title compound as yellow
needles. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.: 8.86 (s, 1H),
7.33 (s, 1H), 3.99 (s, 3H), 2.52 (s, 3H). MS (ESI, positive ion)
m/z: 169.0 (M+H).
##STR01174##
Step 5. 4-Methoxy-5-nitropicolinic acid
[0944] To a stirred solution of 4-methoxy-2-methyl-5-nitropyridine
(2 g, 0.011 mol) in 1,4-dioxane (20 mL), was added SeO.sub.2 (3.2
g, 0.047 mol, Aldrich), and the reaction mixture was stirred for 12
h at 105.degree. C. The progress of reaction was monitored by TLC
(30% EtOAc in hexane). After completion, the reaction mixture was
cooled to rt and filtered. The filtrate was concentrated to afford
the aldehyde intermediate which was dissolved in acetone and water
(1:1, 5 mL) and treated with sodium chlorite (3.2 g, 0.035 mol,
Aldrich) and sulfamic acid (3.4 g, 0.035 mol, Aldrich). The
reaction mixture was stirred for 1 h at rt. The reaction progress
was monitored by TLC (50% EtOAc in petroleum ether). After
completion, the reaction mixture was concentrated to give a white
precipitate, which was filtered and dried to afford the title
compound as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 13.9 (br s, 1H), 9.06 (s, 1H), 7.92 (s, 1H), 4.10 (s,
3H). MS (ESI, positive ion) m/z: 197.0 (M+H).
##STR01175##
Step 6.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-4-methoxy-5-nitropicolinamide
[0945] To a stirred solution of 4-methoxy-5-nitropicolinic acid (1
g, 0.005 mol) in DMF (10 mL) were added
(S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamin-
e hydrochloride (1.8 g, 0.0055 mol, Intermediate 6), HATU (2.8 g,
0.0075 mol, Molicula, India) and DIPEA (2.4 g, 0.02 mol, Aldrich).
The reaction mixture was stirred for 12 h at rt. The reaction
progress was monitored by TLC (50% EtOAc in petroleum ether). After
completion of the reaction, water (100 mL) was added and aqueous
solution was extracted with EtOAc (50 mL.times.3) and concentrated
to give the product. The product thus obtained was purified by
column chromatography, silica gel (60-120 mesh), using 80-100%
EtOAc in petroleum ether as the eluent to give the title compound.
.sup.1H NMR (400 Mhz, DMSO-d.sub.6) .delta. ppm 9.89 (d, J=7.2 Hz,
1H), 9.13 (s, 1H), 8.57 (d, J=4.5 Hz, 1H), 7.92 (s, 1H), 7.82 (t,
J=8.7 Hz, 1H), 7.56 (t, J=4.8 Hz, 3H), 7.36 (d, J=8.4 Hz, 1H), 6.54
(d, J=6.3 Hz, 1H), 4.11 (s, 3H). MS (ESI, positive ion) m/z: 485.0
(M+H).
##STR01176##
Step 7.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-4-hydroxy-5-nitropicolinamide
[0946] To a solution of 30% HBr in AcOH (10 mL, Spectrochem, India)
was added
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)-
methyl)-4-methoxy-5-nitropicolinamide (1 g, 0.002 mol), and the
resulting reaction mixture was stirred for 12 h at 90.degree. C.
The reaction progress was monitored by TLC (50% EtOAc in petroleum
ether). After completion of the reaction, the reaction mixture was
concentrated and neutralized with sat'd NaHCO.sub.3 solution (pH
.about.7-7.5) and the aqueous solution was extracted with EtOAc
(3.times.10 mL). The combined organic layers were dried over
anhydrous sodium sulfate, and concentrated to afford the title
compound as a pale yellow solid. .sup.1H NMR (DMSO-d.sub.6)
.delta.: 9.84 (d, J=7.5 Hz, 1H), 8.77 (s, 1H), 8.53 (d, J=4.5 Hz,
1H), 7.83-7.70 (m, 1H), 7.57-7.49 (m, 3H), 7.38-7.31 (m, 2H), 6.56
(d, J=7.5 Hz, 1H). MS (ESI, positive ion) m/z: 471.4 (M+H).
##STR01177##
Step 8. ((S)-5-Amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)
(3-fluoropyridin-2-yl)methyl)-4-hydroxypicolinamide
[0947] To a stirred solution of
(S)--N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl-
)-4-hydroxy-5-nitropicolinamide (0.35 g, 0.0007 mol) in MeOH (10
mL) was added Raney Ni (0.3 g, Monarch), followed by hydrazine
hydrate (2 mL, Aldrich) added in a drop-wise fashion at rt. The
reaction mixture was stirred for 3 h. After completion of the
reaction (monitored by TLC, 50% EtOAc in hexane), the reaction
mixture was filtered through Celite.RTM. brand filter agent and
concentrated providing a residue. The residue was triturated with
Et.sub.2O, filtered dried under vacuum to give the title compound
as a brown solid. .sup.1H NMR (DMSO-d.sub.6) .delta.: 9.41 (d,
J=7.5 Hz, 1H), 8.55 (d, J=4.2 Hz, 1H), 7.83-7.78 (m, 2H), 7.54-7.44
(m, 3H), 7.27 (d, J=9.9 Hz, 2H), 6.46 (d, J=6.9 Hz, 1H), 5.29 (s,
2H).
##STR01178##
Step 9.
(S)--N-((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-y-
l)methyl)-2-oxo-2,3-dihydrooxazolo[4,5-c]pyridine-6-carboxamide
[0948] To a cooled (-78.degree. C.) and stirred mixture of
((S)-5-amino-N-((3-fluoro-4-(trifluoromethoxy)phenyl)
(3-fluoropyridin-2-yl)methyl)-4-hydroxypicolinamide (200 mg,
0.00045 mol) in THF (5 mL) was added TEA (0.31 mL, 0.002 mol,
Spectrochem, India) and triphosgene (270 mg, 0.0009 mol,
Spectrochem, India). The reaction mixture was stirred for 2 h at
same temperature, slowly warmed to rt and stirred overnight. After
completion of the reaction (monitored by TLC, 50% EtOAc in hexane),
the reaction mixture was quenched with sat'd NaHCO.sub.3 (5 mL),
extracted with EtOAc (10 mL.times.3). The combined organic layers
were dried over anhydrous sodium sulfate, concentrated and purified
by column chromatography, silica gel (60-120 mesh) using 50-60%
EtOAc in petroleum ether as the eluent, followed by further
purification using Prep TLC plates, mobile phase 50% EtOAc in
hexanes to give the title compound. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 9.79 (d, J=7.2 Hz, 1H), 9.00 (s, 1H),
8.53 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 8.08 (s, 1H), 7.44-7.35 (m,
1H), 7.35-7.31 (m, 3H), 7.26-7.21 (m, 1H), 6.64 (d, J=7.6 Hz, 1H).
MS (ESI, positive ion) m/z: 467.2 (M+H).
TABLE-US-00006 TABLE 6 .sup.1H NMR Data of Examples 1-261 and
287-424. Freq., Ex. # Solvent .sup.1HNMR Data (.delta. ppm) 1 400
MHz 8.38-8.52 (m, 1H), 8.14 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 9.6,
d.sub.4-MeOH 2.5 Hz, 1H), 7.59 (ddd, J = 9.7, 8.5, 1.2 Hz, 1H),
7.44-7.53 (m, J = 8.8 Hz, 2H), 7.41 (dt, J = 8.5, 4.4 Hz, 1H),
7.15-7.26 (m, J = 8.0 Hz, 2H), 6.66 (s, 1H), 6.44-6.57 (m, 1H) 2
400 MHz 8.97 (dd, J = 4.2, 1.5 Hz, 1H), 8.89 (d, J = 7.0 Hz, 1H),
8.62 (s, CDCl.sub.3 1H), 8.45-8.52 (m, 1H), 8.25 (d, J = 8.2 Hz,
1H), 8.09 (dd, J = 8.5, 1.7 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H),
7.49-7.58 (m, 3H), 7.46 (td, J = 8.6, 1.2 Hz, 1H), 7.28-7.39 (m,
1H), 7.17 (d, J = 8.6 Hz, 2H), 6.68-6.75 (m, 1H) 3 400 MHz 8.92 (d,
J = 4.1 Hz, 1H), 8.18 (dd, J = 8.0, 1.0 Hz, 1H), 8.14 (d,
d.sub.4-MeOH J = 2.5 Hz, 1H), 8.03 (dd, J = 9.6, 2.7 Hz, 1H), 7.58
(dd, J = 7.8, 4.9 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.45 (d, J =
8.2 Hz, 1H), 7.29 (dd, J = 8.4, 2.2 Hz, 1H), 6.78 (s, 1H), 6.52 (d,
J = 9.6 Hz, 1H), 4.86 (br s, 2H) 4 400 MHz 9.06-9.11 (m, 1H),
8.94-9.00 (m, 2H), 8.70 (d, J = 7.4 Hz, CDCl.sub.3 1H), 8.56 (s,
1H), 8.12-8.20 (m, 2H), 8.02-8.10 (m, 2H), 7.97 (d, J = 9.0 Hz,
1H), 7.88 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.59 (dd,
J = 9.0, 2.2 Hz, 1H), 7.44-7.53 (m, 2H), 7.06 (d, J = 7.4 Hz, 1H) 5
400 MHz 8.97 (dd, J = 4.2, 1.7 Hz, 1H), 8.87-8.92 (m, 1H),
CDCl.sub.3 8.49-8.56 (m, 2H), 8.21 (dd, J = 8.2, 0.8 Hz, 1H), 8.08
(dd, J = 8.5, 1.7 Hz, 1H), 8.03 (dd, J = 8.2, 0.6 Hz, 1H), 7.90 (d,
J = 8.6 Hz, 1H), 7.43-7.52 (m, 2H), 7.21-7.26 (m, 1H), 7.18 (dd, J
= 12.2, 2.1 Hz, 1H), 6.90 (t, J = 8.6 Hz, 1H), 6.83 (d, J = 7.8 Hz,
1H) 6 400 MHz 8.91 (d, J = 2.2 Hz, 1H), 8.85 (d, J = 4.7 Hz, 1H),
8.59 (d, J = 7.8 Hz, CDCl.sub.3 1H), 8.48 (s, 1H), 8.17 (d, J = 8.2
Hz, 1H), 7.96-8.04 (m, 2H), 7.86 (d, J = 8.6 Hz, 1H), 7.40-7.50 (m,
2H), 7.34-7.40 (m, 2H), 7.21-7.27 (m, 2H), 6.83 (d, J = 7.8 Hz, 1H)
7 400 MHz 9.17 (s, 1H), 8.97 (dd, J = 9.7, 4.4 Hz, 2H), 8.71 (d, J
= 7.2 Hz, CDCl.sub.3 1H), 8.56 (s, 1H), 8.33 (s, 1H), 8.19 (d, J =
8.2 Hz, 1H), 8.03-8.11 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.79 (d,
J = 7.4 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.40-7.54 (m, 3H), 7.08
(d, J = 7.4 Hz, 1H) 8 400 MHz 8.92-9.03 (m, 3H), 8.67 (d, J = 7.4
Hz, 1H), 8.56 (s, 1H), CDCl.sub.3 8.14-8.23 (m, 2H), 8.01-8.10 (m,
2H), 7.88 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.43-7.53
(m, 2H), 7.39 (br. s, 1H), 7.17 (dd, J = 9.0, 2.0 Hz, 1H), 7.04 (d,
J = 7.4 Hz, 1H), 3.92 (s, 3H) 9 400 MHz 9.19 (d, J = 1.8 Hz, 1H),
8.95-9.03 (m, 2H), 8.71 (d, J = 7.4 Hz, CDCl.sub.3 1H), 8.62 (s,
1H), 8.58 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.04-8.12 (m, 2H),
7.94-8.03 (m, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.57 (d,
J = 1.4 Hz, 1H), 7.44-7.54 (m, 2H), 7.12 (d, J = 7.6 Hz, 1H) 10 400
MHz 8.90-8.97 (m, 2H), 8.72 (d, J = 7.4 Hz, 1H), 8.52 (s, 1H),
d.sub.4-MeOH 8.25 (d, J = 8.2 Hz, 1H), 8.02-8.10 (m, 2H), 7.93 (d,
J = 8.6 Hz, 1H), 7.48-7.58 (m, 3H), 7.33-7.42 (m, 2H), 6.85 (d, J =
7.8 Hz, 1H) 11 400 MHz 9.19 (s, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.87
(d, J = 4.7 Hz, 1H), CDCl.sub.3 8.33-8.43 (m, 2H), 8.18 (d, J = 1.4
Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.98
(dd, J = 8.8, 1.4 Hz, 1H), 7.78-7.91 (m, 3H), 7.60 (dd, J = 9.0,
2.3 Hz, 1H), 7.52 (dd, J = 7.7, 5.0 Hz, 1H), 6.98-7.02 (m, 1H) 12
400 MHz 9.09 (d, J = 1.8 Hz, 1H), 8.92-9.00 (m, 2H), 8.70 (d, J =
7.6 Hz, CDCl.sub.3 1H), 8.56 (s, 1H), 8.25 (s, 1H), 8.17 (d, J =
8.2 Hz, 1H), 8.02-8.10 (m, 3H), 7.87 (d, J = 8.4 Hz, 1H), 7.79 (d,
J = 8.2 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.43-7.55 (m, 3H), 7.08
(d, J = 7.6 Hz, 1H) 13 400 MHz 8.89-8.96 (m, 2H), 8.72 (d, J = 7.8
Hz, 1H), 8.53 (s, 1H), CDCl.sub.3 8.26 (d, J = 8.2 Hz, 1H),
8.01-8.11 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.47-7.57 (m, 2H),
7.44 (s, 1H), 7.33-7.40 (m, 1H), 7.21-7.28 (m, 2H), 6.89 (d, J =
7.8 Hz, 1H) 14 400 MHz 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.87 (d, J =
4.1 Hz, 1H), 8.53 (s, CDCl.sub.3 1H), 8.44 (d, J = 7.8 Hz, 1H),
8.16 (dd, J = 8.2, 0.8 Hz, 1H), 8.07 (dd, J = 8.5, 1.7 Hz, 1H),
7.98 (dd, J = 8.0, 1.0 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.44 (dd,
J = 8.3, 4.2 Hz, 1H), 7.33-7.42 (m, 3H), 7.05-7.16 (m, 2H), 6.89
(d, J = 7.8 Hz, 1H), 2.28 (s, 3H) 15 400 MHz 8.94-8.99 (m, J = 4.3,
1.6 Hz, 1H), 8.92 (d, J = 4.7 Hz, 1H), CDCl.sub.3 8.61 (d, J = 7.8
Hz, 1H), 8.56 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.5,
1.7 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.74-7.90 (m, 5H), 7.65 (dd,
J = 8.6, 1.4 Hz, 1H), 7.38-7.49 (m, 4H), 7.09 (d, J = 8.0 Hz, 1H)
16 400 MHz 12.90 (br. s., 1H), 8.96-9.03 (m, 1H), 8.93 (d, J = 4.5
Hz, 1H), CDCl.sub.3 8.21 (d, J = 7.6 Hz, 1H), 8.00-8.12 (m, 3H),
7.96 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 9.6, 2.2 Hz, 1H), 7.74 (d,
J = 2.0 Hz, 1H), 7.59 (dd, J = 9.0, 2.2 Hz, 1H), 7.51 (dd, J = 7.7,
5.0 Hz, 1H), 6.92 (d, J = 7.4 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H) 17
400 MHz 8.97 (dd, J = 4.1, 1.4 Hz, 1H), 8.90 (d, J = 4.5 Hz, 1H),
8.54 (s, CDCl.sub.3 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 8.0
Hz, 1H), 8.09 (dd, J = 8.5, 1.5 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H),
7.89 (d, J = 8.6 Hz, 1H), 7.46 (td, J = 8.3, 4.6 Hz, 2H), 7.24-7.32
(m, 2H), 7.16 (d, J = 9.8 Hz, 1H), 6.85-6.99 (m, 2H) 18 400 MHz
8.98 (dd, J = 4.2, 1.5 Hz, 1H), 8.92 (d, J = 4.5 Hz, 1H),
CDCl.sub.3 8.50-8.58 (m, 2H), 8.20 (d, J = 8.2 Hz, 1H), 8.09 (dd, J
= 8.4, 1.6 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.4 Hz,
1H), 7.69-7.78 (m, 2H), 7.39-7.55 (m, 4H), 6.94 (d, J = 7.6 Hz, 1H)
19 400 MHz 8.93 (d, J = 3.3 Hz, 1H), 8.86 (d, J = 4.3 Hz, 1H),
8.46-8.58 (m, CDCl.sub.3 2H), 8.13 (d, J = 8.2 Hz, 1H), 8.06 (d, J
= 8.4 Hz, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.6 Hz, 1H),
7.34-7.48 (m, 4H), 6.79-6.92 (m, 3H), 3.73 (s, 3H) 20 400 MHz 9.12
(d, J = 1.8 Hz, 1H), 8.95-9.00 (m, 2H), 8.71 (d, J = 7.4 Hz,
CDCl.sub.3 1H), 8.57 (s, 1H), 8.31 (s, 1H), 8.20 (d, J = 8.0 Hz,
1H), 8.03-8.10 (m, 2H), 7.89 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.2
Hz, 1H), 7.40-7.55 (m, 3H), 7.35 (ddd, J = 10.2, 7.7, 0.9 Hz, 1H),
7.07 (d, J = 7.4 Hz, 1H) 21 400 MHz 8.96 (dd, J = 4.1, 1.2 Hz, 1H),
8.88 (d, J = 4.5 Hz, 1H), 8.54 (s, CDCl.sub.3 1H), 8.42 (d, J = 8.0
Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.08 (dd, J = 8.4, 1.4 Hz, 1H),
7.99 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.46 (dd, J =
8.3, 4.2 Hz, 1H), 7.40 (dd, J = 7.8, 4.9 Hz, 1H), 7.30 (s, 1H),
7.24 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H),
6.89 (d, J = 8.0 Hz, 1H), 2.31 (s, 3H) 22 400 MHz 8.97 (dd, J =
4.3, 1.6 Hz, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.87 (dd, CDCl.sub.3 J
= 4.1, 1.6 Hz, 1H), 8.64 (d, J = 7.8 Hz, 1H), 8.56 (s, 1H), 8.18
(d, J = 8.2 Hz, 1H), 8.13 (d, J = 7.6 Hz, 1H), 8.09 (dd, J = 8.6,
1.6 Hz, 1H), 8.05 (s, 1H), 8.03 (s, 1H), 7.93 (s, 1H), 7.83-7.91
(m, 2H), 7.44-7.51 (m, 2H), 7.37 (dd, J = 8.3, 4.2 Hz, 1H), 7.10
(d, J = 7.6 Hz, 1H) 23 400 MHz 9.05 (d, J = 2.0 Hz, 1H), 8.97 (dd,
J = 4.1, 1.6 Hz, 1H), 8.94 (d, d.sub.4-MeOH J = 4.5 Hz, 1H), 8.68
(d, J = 7.6 Hz, 1H), 8.57 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.18
(d, J = 8.2 Hz, 1H), 8.01-8.09 (m, 2H), 7.87 (d, J = 8.6 Hz, 1H),
7.44-7.50 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 8.2, 1.0
Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 4.03
(s, 3H) 24 400 MHz 8.88-8.95 (m, 1H), 8.76-8.82 (m, 1H), 8.51 (br.
s., 1H), CDCl.sub.3 8.11-8.25 (m, 2H), 7.94-8.09 (m, 2H), 7.87 (dd,
J = 8.5, 2.8 Hz, 1H), 7.44-7.51 (m, 1H), 7.38 (dt, J = 7.7, 3.7 Hz,
1H), 7.19-7.33 (m, 3H), 6.85-6.94 (m, 2H), 3.82 (s, 3H) 25 400 MHz
8.97 (dd, J = 4.2, 1.7 Hz, 1H), 8.89 (dd, J = 4.9, 0.8 Hz, 1H),
CDCl.sub.3 8.53 (s, 1H), 8.47 (d, J = 7.8 Hz, 1H), 8.18 (dd, J =
8.2, 0.8 Hz, 1H), 8.08 (dd, J = 8.5, 1.7 Hz, 1H), 8.02 (dd, J =
7.8, 0.8 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.41-7.49 (m, 2H),
7.21-7.26 (m, 1H), 7.19 (dd, J = 12.2, 2.1 Hz, 1H), 6.89 (t, J =
8.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 3.83 (s, 3H) 26 400 MHz 8.96
(dd, J = 4.1, 1.4 Hz, 1H), 8.88 (d, J = 4.3 Hz, 1H), 8.54 (s,
CDCl.sub.3 1H), 8.50 (d, J = 7.8 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H),
8.08 (dd, J = 8.5, 1.3 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.89 (d,
J = 8.4 Hz, 1H), 7.49 (dd, J = 8.2, 4.3 Hz, 1H), 7.39-7.47 (m, 3H),
7.28-7.35 (m, 2H), 6.89 (d, J = 7.8 Hz, 1H), 4.85 (q, J = 6.5 Hz,
1H), 2.47 (br. s., 1H), 1.44 (d, J = 6.5 Hz, 3H) 27 400 MHz 8.98
(d, J = 4.1 Hz, 1H), 8.89 (d, J = 4.7 Hz, 1H), 8.45-8.56 (m,
CDCl.sub.3 2H), 8.19 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H),
8.02 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.39-7.50 (m,
4H), 6.98 (t, J = 8.6 Hz, 2H), 6.88 (d, J = 7.8 Hz, 1H) 28 400 MHz,
9.50 (d, J = 7.8 Hz, 1H), 9.01 (dd, J = 4.2, 1.7 Hz, 1H), 8.61 (s,
DMSO-d.sub.6 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.23 (dd, J = 4.6, 1.1
Hz, 1H), 8.00-8.12 (m, 2H), 7.59-7.77 (m, 5H), 7.47-7.56 (m, 1H),
7.39 (dd, J = 8.4, 4.7 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.67 (s,
3H) 29 400 MHz, 9.73 (d, J = 7.6 Hz, 1H), 9.04 (d, J = 4.5 Hz, 1H),
8.35 (dd, J = 4.8, DMSO-d.sub.6 1.9 Hz, 1H), 8.29 (d, J = 7.6 Hz,
1H), 8.25 (dd, J = 7.4, 2.0 Hz, 1H), 7.66-7.77 (m, 3H), 7.57 (d, J
= 8.2 Hz, 2H), 7.16 (dd, J = 7.4, 4.9 Hz, 1H), 6.75 (d, J = 7.6 Hz,
1H), 4.06 (s, 3H) 30 400 MHz, 9.37 (d, J = 7.4 Hz, 1H), 8.91 (d, J
= 4.5 Hz, 1H), 8.71 (d, J = 2.3 Hz, DMSO-d.sub.6 1H), 8.25 (d, J =
7.4 Hz, 1H), 8.18 (dd, J = 8.7, 2.4 Hz, 1H), 7.66-7.76 (m, J = 8.2
Hz, 2H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H), 7.47-7.58 (m, J = 8.0 Hz,
2H), 6.86 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 3.89 (s,
3H) 31 400 MHz, 9.84 (d, J = 8.2 Hz, 1H), 9.45 (dd, J = 4.9, 1.6
Hz, 1H), 9.06 (d, DMSO-d.sub.6 J = 4.3 Hz, 1H), 8.32 (d, J = 7.8
Hz, 1H), 8.24 (dd, J = 8.5, 1.7 Hz, 1H), 7.95 (dd, J = 8.4, 5.1 Hz,
1H), 7.68-7.77 (m, 3H), 7.61 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.2
Hz, 1H) 32 400 MHz, 9.55 (d, J = 8.4 Hz, 1H), 9.04 (d, J = 4.3 Hz,
1H), 8.49 (d, J = 5.9 Hz, DMSO-d.sub.6 1H), 8.30 (d, J = 7.8 Hz,
1H), 7.65-7.76 (m, 3H), 7.48-7.60 (m, 3H), 7.20 (dd, J = 5.7, 2.7
Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H) 33 400 MHz, 9.54
(d, J = 8.4 Hz, 1H), 9.02 (d, J = 4.5 Hz, 1H), 8.31 (d, J = 7.6 Hz,
DMSO-d.sub.6 1H), 7.90 (t, J = 7.8 Hz, 1H), 7.67-7.75 (m, 3H), 7.65
(d, J = 7.2 Hz, 1H), 7.55 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.2 Hz,
1H), 6.72 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H) 34 400 MHz, 9.61 (d, J
= 7.4 Hz, 1H), 8.91 (d, J = 4.7 Hz, 1H), 8.20-8.32 (m, DMSO-d.sub.6
2H), 7.66-7.76 (m, J = 8.2 Hz, 2H), 7.63 (dd, J = 7.8, 4.9 Hz, 1H),
7.47-7.56 (m, J = 8.2 Hz, 2H), 7.38 (d, J = 5.3 Hz, 1H), 7.25 (s,
1H), 6.76 (d, J = 7.4 Hz, 1H), 3.87 (s, 3H) 35 400 MHz, 9.40 (d, J
= 7.8 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.45 (d, J = 4.7 Hz,
DMSO-d.sub.6 1H), 8.21 (dd, J = 8.7, 2.4 Hz, 1H), 7.74-7.80 (m,
1H), 7.72 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H), 7.48 (dt,
J = 8.5, 4.4 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.74 (d, J = 7.6
Hz, 1H), 3.91 (s, 3H) 36 400 MHz, 10.00 (d, J = 6.8 Hz, 1H), 8.60
(d, J = 4.5 Hz, 1H), 8.39 (dd, J = 4.9, DMSO-d.sub.6 2.0 Hz, 1H),
8.27 (dd, J = 7.4, 2.0 Hz, 1H), 7.82 (td, J = 9.2, 1.1 Hz, 1H),
7.68-7.77 (m, J = 8.2 Hz, 2H), 7.60-7.68 (m, J = 8.2 Hz, 2H), 7.54
(dt, J = 8.5, 4.4 Hz, 1H), 7.19 (dd, J = 7.4, 4.9 Hz, 1H), 6.60 (d,
J = 5.9 Hz, 1H), 4.15 (s, 3H) 37 400 MHz, 9.64 (d, J = 8.2 Hz, 1H),
9.05 (d, J = 4.3 Hz, 1H), 8.32 (d, J = 7.8 Hz, DMSO-d.sub.6 1H),
8.12 (d, J = 9.2 Hz, 1H), 7.66-7.79 (m, 3H), 7.59 (d, J = 8.2 Hz,
2H), 7.40 (d, J = 9.2 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 4.12 (s,
3H) 38 400 MHz, 9.62 (d, J = 7.4 Hz, 1H), 8.94 (d, J = 4.1 Hz, 1H),
8.67 (d, J = 1.6 Hz, DMSO-d.sub.6 1H), 8.44 (d, J = 2.9 Hz, 1H),
8.24-8.33 (m, 1H), 7.78-7.87 (m, 1H), 7.70-7.78 (m, J = 8.2 Hz,
2H), 7.65 (dd, J = 7.8, 4.9 Hz, 1H), 7.50-7.59 (m, J = 8.2 Hz, 2H),
6.83 (d, J = 7.4 Hz, 1H), 3.88 (s, 3H) 39 400 MHz, 9.58 (d, J = 6.7
Hz, 1H), 8.91 (d, J = 4.5 Hz, 1H), 8.55 (d, J = 5.1 Hz,
DMSO-d.sub.6 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.66-7.75 (m, 3H),
7.63 (dd, J = 7.8, 4.9 Hz, 1H), 7.58 (d, J = 4.9 Hz, 1H), 7.53 (d,
J = 8.2 Hz, 2H), 6.78 (d, J = 6.5 Hz, 1H), 2.51 (s, 3H) 40 400 MHz,
9.49 (d, J = 7.4 Hz, 1H), 8.87-8.97 (m, 2H), 8.26 (d, J = 7.2 Hz,
DMSO-d.sub.6 1H), 8.14 (dd, J = 8.2, 2.3 Hz, 1H), 7.67-7.75 (m, J =
8.2 Hz, 2H), 7.62 (dd, J = 7.8, 4.9 Hz, 1H), 7.49-7.57 (m, J = 8.2
Hz, 2H), 7.33 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 7.2 Hz, 1H), 2.51
(s, 3H) 41 400 MHz, 9.12 (d, J = 7.4 Hz, 1H), 8.92 (d, J = 3.9 Hz,
1H), 8.22-8.36 (m, DMSO-d.sub.6 1H), 8.17 (d, J = 2.5 Hz, 1H), 7.90
(dd, J = 9.7, 2.6 Hz, 1H), 7.68-7.75 (m, J = 8.2 Hz, 2H), 7.63 (dd,
J = 7.8, 4.9 Hz, 1H), 7.41-7.57 (m, J = 8.0 Hz, 2H), 6.76 (d, J =
7.4 Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H) 42 400 MHz, 9.62 (br. s.,
1H), 9.06 (s, 2H), 8.94 (d, J = 4.1 Hz, 1H), DMSO-d.sub.6 8.22-8.33
(m, 1H), 7.69-7.78 (m, J = 8.2 Hz, 2H), 7.65 (dd, J = 7.6, 4.9 Hz,
1H), 7.50-7.60 (m, J = 8.2 Hz, 2H), 6.81 (br. s., 1H), 3.99 (s, 3H)
43 400 MHz, 12.14 (br. s., 1H), 8.92 (d, J = 4.3 Hz, 1H), 8.84 (d,
J = 8.0 Hz, DMSO-d.sub.6 1H), 8.46 (s, 1H), 8.39 (dd, J = 7.8, 1.6
Hz, 1H), 8.17-8.32 (m, 2H), 7.66-7.75 (m, J = 8.4 Hz, 2H), 7.62
(dd, J = 7.9, 4.8 Hz, 1H), 7.46-7.58 (m, J = 8.0 Hz, 2H), 7.15 (dd,
J = 7.8, 4.7 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H) 44 400 MHz, 11.76
(br. s., 1H), 9.50 (d, J = 7.2 Hz, 1H), 8.90 (d, J = 4.5 Hz,
DMSO-d.sub.6 1H), 8.25 (d, J = 7.4 Hz, 1H), 7.66-7.75 (m, J = 8.2
Hz, 2H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H), 7.46-7.55 (m, J = 8.2 Hz,
2H), 7.42 (d, J = 6.8 Hz, 1H), 6.75-6.80 (m, 1H), 6.69 (d, J = 6.7
Hz, 1H), 6.44 (dd, J = 6.8, 1.4 Hz, 1H) 45 400 MHz, 12.42 (br. s.,
1H), 9.34 (s, 1H), 9.09 (d, J = 7.8 Hz, 1H), 8.95 (d, DMSO-d.sub.6
J = 4.3 Hz, 1H), 8.76-8.88 (m, 1H), 8.47-8.62 (m, 1H), 8.29 (d, (d
J = 7.8 Hz, 1H), 7.69-7.78 (m, J = 8.0 Hz, 2H), 7.65 (dd, J = 7.8,
4.9 Hz, 1H), 7.50-7.60 (m, J = 8.0 Hz, 2H), 6.91 (d, J = 7.8 Hz,
1H) 46 400 MHz, 9.41 (d, J = 7.8 Hz, 1H), 8.76 (d, J = 2.3 Hz, 1H),
8.40-8.53 (m, DMSO-d.sub.6 1H), 8.22 (dd, J = 8.8, 2.5 Hz, 1H),
7.76-7.82 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.2 Hz,
2H), 7.50 (dt, J = 8.5, 4.4 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.76
(d, J = 7.6 Hz, 1H), 3.93 (s, 3H) 47 400 MHz, 10.01 (d, J = 7.0 Hz,
1H), 8.60 (d, J = 4.7 Hz, 1H), 8.38 (dd, J = 4.9, DMSO-d.sub.6 2.0
Hz, 1H), 8.27 (dd, J = 7.4, 2.0 Hz, 1H), 7.82 (t, J = 8.9 Hz, 1H),
7.69-7.77 (m, J = 8.2 Hz, 2H), 7.60-7.69 (m, J = 8.0 Hz, 2H),
7.50-7.60 (m, 1H), 7.18 (dd, J = 7.6, 4.9 Hz, 1H), 6.60 (d, J = 6.3
Hz, 1H), 4.15 (s, 3H) 48 400 MHz, 9.72 (d, J = 7.6 Hz, 1H), 9.02
(d, J = 4.5 Hz, 1H), 8.59 (s, 1H), DMSO-d.sub.6 8.33 (d, J = 4.7
Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.68
(dd, J = 8.1, 5.0 Hz, 1H), 7.64 (d, J = 4.7 Hz, 1H), 7.57 (d, J =
8.2 Hz, 2H), 6.74 (d, J = 7.6 Hz, 1H), 4.08 (s, 3H) 49 400 MHz,
9.52 (d, J = 7.0 Hz, 1H), 8.90 (d, J = 4.7 Hz, 1H), 8.25 (d, J =
7.8 Hz, DMSO-d.sub.6 1H), 7.75 (d, J = 7.0 Hz, 1H), 7.67-7.73 (m, J
= 8.2 Hz, 2H), 7.62 (dd, J = 8.0, 4.9 Hz, 1H), 7.46-7.54 (m, J =
8.0 Hz, 2H), 6.83-6.92 (m, 1H), 6.70 (d, J = 7.0 Hz, 1H), 6.50 (dd,
J = 7.0, 1.8 Hz, 1H), 3.43 (s, 3H) 50 400 MHz, 9.05 (d, J = 7.6 Hz,
1H), 8.91 (d, J = 4.3 Hz, 1H), 8.50 (d, J = 2.5 Hz, DMSO-d.sub.6
1H), 8.25 (d, J = 7.4 Hz, 1H), 7.88 (dd, J = 9.6, 2.5 Hz, 1H),
7.66-7.74 (m, J = 8.4 Hz, 2H), 7.62 (dd, J = 7.9, 4.8 Hz, 1H),
7.46-7.55 (m, J = 8.2 Hz, 2H), 6.76 (d, J = 7.6 Hz, 1H), 6.37 (d, J
= 9.6 Hz, 1H), 3.45 (s, 3H) 51 400 MHz, 12.01 (br. s., 1H), 9.15
(d, J = 7.8 Hz, 1H), 8.46 (d, J = 4.5 Hz, DMSO-d.sub.6 1H), 8.19
(d, J = 2.5 Hz, 1H), 7.92 (dd, J = 9.7, 2.6 Hz, 1H), 7.77 (td, J =
9.3, 1.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz,
2H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.35
(d, J = 9.8 Hz, 1H) 52 400 MHz, 9.54 (d, J = 7.6 Hz, 1H), 8.96 (d,
J = 2.0 Hz, 1H), 8.45 (d, J = 4.7 Hz, DMSO-d.sub.6 1H), 8.21 (dd, J
= 8.1, 2.2 Hz, 1H), 7.74-7.81 (m, 1H), 7.69-7.74 (m, J = 8.2 Hz,
2H), 7.61-7.66 (m, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.3 Hz, 1H),
7.40 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 2.54 (s, 3H) 53
400 MHz, 9.69 (d, J = 7.6 Hz, 1H), 8.64 (d, J = 5.3 Hz, 1H), 8.45
(d, J = 4.7 Hz, DMSO-d.sub.6 1H), 7.82 (s, 1H), 7.77 (t, J = 9.8
Hz, 1H), 7.68-7.75 (m, 3H), 7.60-7.67 (m, 2H), 7.49 (dt, J = 8.5,
4.4 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 2.57 (s, 3H) 54 400 MHz,
12.15 (br. s., 1H), 8.90 (d, J = 8.0 Hz, 1H), 8.42-8.51 (m, 2H),
DMSO-d.sub.6 8.40 (dd, J = 8.0, 1.6 Hz, 1H), 8.26 (dd, J = 4.7, 1.6
Hz, 1H), 7.74-7.81 (m, 1H), 7.69-7.74 (m, J = 8.2 Hz, 2H),
7.60-7.67 (m, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.3 Hz, 1H), 7.16
(dd, J = 7.9, 4.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H) 55 400 MHz,
9.54 (d, J = 7.6 Hz, 1H), 9.02 (d, J = 4.3 Hz, 1H), 8.79 (s, 1H),
DMSO-d.sub.6 8.56 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 7.2 Hz, 1H),
7.65-7.74 (m, 3H), 7.56 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 5.9 Hz,
1H), 6.76 (d, J = 7.6 Hz, 1H), 4.03 (s, 3H) 56 400 MHz, 10.61 (br.
s., 1H), 9.07 (d, J = 7.4 Hz, 1H), 8.90 (d, J = 4.5 Hz,
DMSO-d.sub.6 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.75-7.84 (m, 2H),
7.66-7.73 (m, J = 8.2 Hz, 2H), 7.61 (dd, J = 7.9, 4.8 Hz, 1H),
7.47-7.55 (m, J = 8.2 Hz, 2H), 6.83 (d, J = 8.0 Hz, 1H), 6.78 (d, J
= 7.4 Hz, 1H), 3.51 (s, 2H) 57 400 MHz, 9.74 (d, J = 5.9 Hz, 1H),
9.08 (s, 2H), 8.92 (d, J = 4.3 Hz, 1H), DMSO-d.sub.6 8.27 (d, J =
8.0 Hz, 1H), 7.68-7.76 (m, J = 8.2 Hz, 2H), 7.63 (dd, J = 7.8, 4.9
Hz, 1H), 7.50-7.60 (m, J = 8.2 Hz, 2H), 6.80 (d, J = 5.5 Hz, 1H),
2.67 (s, 3H) 58 400 MHz, 10.34 (br. s., 1H), 9.47 (d, J = 7.4 Hz,
1H), 8.90 (d, J = 4.5 Hz, DMSO-d.sub.6 1H), 8.48 (d, J = 1.8 Hz,
1H), 8.25 (d, J = 7.4 Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 7.70 (d, J
= 8.4 Hz, 2H), 7.62 (dd, J = 7.8, 4.9 Hz, 1H), 7.48-7.56 (m, 3H),
6.77 (d, J = 7.4 Hz, 1H) 59 400 MHz, 12.46 (br. s., 1H), 11.21 (d,
J = 8.2 Hz, 1H), 8.96 (d, J = 4.5 Hz, DMSO-d.sub.6 1H), 8.32 (dd, J
= 7.2, 2.2 Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 7.66-7.78 (m, 3H),
7.64 (dd, J = 7.8, 4.9 Hz, 1H), 7.53 (d, J = 8.0 Hz, 2H), 6.80 (d,
J = 8.2 Hz, 1H), 6.47 (t, J = 6.7 Hz, 1H) 60 400 MHz, 9.77 (d, J =
6.7 Hz, 1H), 9.07 (s, 1H), 8.92 (d, J = 4.1 Hz, 1H), DMSO-d.sub.6
8.69 (s, 1H), 8.22-8.32 (m, 1H), 7.69-7.78 (m, J = 8.2 Hz, 2H),
7.63 (dd, J = 7.8, 4.9 Hz, 1H), 7.55-7.61 (m, J = 8.2 Hz, 2H), 6.74
(d, J = 6.3 Hz, 1H), 2.43 (s, 3H) 61 400 MHz, 10.88 (d, J = 8.0 Hz,
1H), 9.00 (d, J = 4.3 Hz, 1H), 8.63 (s, 1H), DMSO-d.sub.6 8.39-8.48
(m, 1H), 8.29 (d, J = 7.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.67
(dd, J = 7.9, 5.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 6.81 (d, J =
8.0 Hz, 1H) 62 400 MHz, 11.27 (br. s., 1H), 9.52 (d, J = 8.4 Hz,
1H), 9.04 (d, J = 4.5 Hz, DMSO-d.sub.6 1H), 8.21-8.41 (m, 2H),
7.64-7.79 (m, 3H), 7.53 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 2.2 Hz,
1H), 6.92 (d, J = 3.7 Hz, 1H), 6.71 (d, J = 8.6 Hz, 1H) 63 400 MHz,
11.39 (br. s., 1H), 9.26 (d, J = 8.0 Hz, 1H), 9.00 (d, J = 4.5 Hz,
DMSO-d.sub.6 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.62-7.84 (m, 4H), 7.51
(d, J = 8.0 Hz, 2H), 7.44 (d, J = 6.3 Hz, 1H), 6.82 (d, J = 8.2 Hz,
1H), 6.75 (d, J = 8.2 Hz, 1H) 64 400 MHz, 11.39 (br. s., 1H), 9.26
(d, J = 8.6 Hz, 1H), 9.03 (d, J = 4.5 Hz, DMSO-d.sub.6 1H), 8.29
(d, J = 7.8 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.90 (d, J = 8.4 Hz,
1H), 7.64-7.77 (m, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.29 (dd, J =
8.6, 2.7 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H) 65 400 MHz, 9.06 (dd, J
= 7.4, 5.9 Hz, 1H), 8.89 (d, J = 4.5 Hz, 1H), 8.24 (d, DMSO-d.sub.6
J = 8.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.61 (dd, J = 7.8, 4.9
Hz, 1H), 7.34-7.51 (m, 3H), 6.57 (d, J = 7.0 Hz, 1H), 3.20-3.27 (m,
1H), 2.72-2.86 (m, 1H), 2.03-2.24 (m, 2H), 1.85-2.00 (m, 1H),
1.64-1.85 (m, 2H) 66 400 MHz, 12.19 (br. s., 1H), 9.34 (d, J = 7.4
Hz, 1H), 8.94 (d, J = 4.5 Hz, DMSO-d.sub.6 1H), 8.33 (d, J = 3.5
Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.0 Hz, 1H),
7.68-7.78 (m, J = 8.2 Hz, 2H), 7.64 (dd, J = 7.8, 4.9 Hz, 1H),
7.52-7.59 (m, J = 8.2 Hz, 2H), 7.28 (s, 1H), 7.10 (dd, J = 7.8, 4.7
Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H) 67 400 MHz, 11.89 (br. s., 1H),
9.33 (d, J = 7.4 Hz, 1H), 8.92 (d, J = 4.5 Hz, DMSO-d.sub.6 1H),
8.74 (d, J = 2.0 Hz, 1H), 8.52 (d, J = 2.2 Hz, 1H), 8.26 (d, J =
7.8 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 7.8, 4.9 Hz,
1H), 7.51-7.59 (m, 3H), 6.84 (d, J = 7.4 Hz, 1H), 6.54 (d, J = 3.5
Hz, 1H) 68 400 MHz, 9.08 (d, J = 7.8 Hz, 1H), 8.51 (d, J = 2.5 Hz,
1H), 8.45 (d, J = 4.7 Hz, DMSO-d.sub.6 1H), 7.90 (dd, J = 9.5, 2.6
Hz, 1H), 7.68-7.82 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.47 (dt, J =
8.5, 4.4 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.39 (d, J = 9.4 Hz,
1H), 3.47 (s, 3H) 69 400 MHz, 10.49 (s, 1H), 9.27 (d, J = 7.4 Hz,
1H), 8.90 (d, J = 4.7 Hz, 1H), DMSO-d.sub.6 8.25 (d, J = 7.8 Hz,
1H), 7.70 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.0, 4.9 Hz, 1H),
7.45-7.56 (m, 3H), 7.21-7.33 (m, 2H), 6.78 (d, J = 7.4 Hz, 1H),
3.52 (s, 2H) 70 400 MHz, 10.62 (s, 1H), 9.13 (d, J = 7.8 Hz, 1H),
8.44 (d, J = 4.7 Hz, 1H), DMSO-d.sub.6 7.79-7.85 (m, 2H), 7.75 (t,
J = 9.3 Hz, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.2 Hz,
2H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.71
(d, J = 7.6 Hz, 1H), 3.53 (s, 2H) 71 400 MHz, 10.50 (s, 1H), 9.31
(d, J = 7.6 Hz, 1H), 8.45 (d, J = 4.7 Hz, 1H), DMSO-d.sub.6 7.76
(t, J = 9.3 Hz, 1H), 7.68-7.73 (m, J = 8.4 Hz, 2H), 7.59-7.65 (m, J
= 8.2 Hz, 2H), 7.51-7.56 (m, 1H), 7.45-7.51 (m, 1H), 7.32 (s, 1H),
7.28 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 3.53 (s, 2H) 72
400 MHz, 12.50 (br. s., 1H), 11.32 (d, J = 7.8 Hz, 1H), 8.47-8.55
(m, 1H), DMSO-d.sub.6 8.34 (dd, J = 7.2, 2.2 Hz, 1H), 7.69-7.85 (m,
4H), 7.59 (d, J = 8.0 Hz, 2H), 7.50 (dt, J = 8.5, 4.4 Hz, 1H), 6.69
(d, J = 7.4 Hz, 1H), 6.50 (dd, J = 7.0, 6.5 Hz, 1H) 73 400 MHz,
10.92 (s, 1H), 9.21 (d, J = 7.6 Hz, 1H), 8.44 (d, J = 4.7 Hz, 1H),
DMSO-d.sub.6 7.72-7.79 (m, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.61 (d,
J = 8.2 Hz, 2H), 7.53-7.59 (m, 2H), 7.47 (dt, J = 8.5, 4.3 Hz, 1H),
6.93 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H), 4.61 (s, 2H) 74
400 MHz, 9.60 (d, J = 7.8 Hz, 1H), 8.45 (d, J = 4.7 Hz, 1H),
8.05-8.15 (m, DMSO-d.sub.6 J = 8.4 Hz, 2H), 7.82-7.89 (m, J = 8.4
Hz, 2H), 7.74-7.81 (m, 1H), 7.69-7.74 (m, J = 8.2 Hz, 2H),
7.61-7.68 (m, J = 8.2 Hz, 2H), 7.58 (d, J = 5.1 Hz, 1H), 7.44-7.52
(m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 2.42 (d, J = 5.1 Hz, 3H) 75 400
MHz, 10.81 (s, 1H), 9.22 (d, J = 7.6 Hz, 1H), 8.44 (d, J = 4.7 Hz,
1H), DMSO-d.sub.6 7.73-7.79 (m, 1H), 7.68-7.73 (m, J = 8.2 Hz, 2H),
7.59-7.65 (m, J = 8.2 Hz, 2H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.47
(dt, J = 8.5, 4.4 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.00 (d, J =
8.4 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.63 (s, 2H) 76 400 MHz,
11.84 (br. s., 1H), 9.37 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 4.5 Hz,
DMSO-d.sub.6 1H), 7.73-7.80 (m, 1H), 7.71 (d, J = 8.2 Hz, 3H),
7.59-7.66 (m, 3H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 7.34 (d, J = 8.4
Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H) 77 400 MHz, 10.89 (s, 1H), 9.79
(d, J = 7.2 Hz, 1H), 8.57 (d, J = 4.7 Hz, 1H), DMSO-d.sub.6
7.75-7.82 (m, 1H), 7.68-7.74 (m, J = 8.4 Hz, 2H), 7.59-7.65 (m, J =
8.2 Hz, 2H), 7.51 (dt, J = 8.6, 4.4 Hz, 1H), 7.43 (dd, J = 6.7, 2.8
Hz, 1H), 7.00-7.11 (m, 2H), 6.58 (d, J = 6.7 Hz, 1H), 4.75-4.99 (m,
2H) 78 400 MHz, 9.28 (d, J = 7.8 Hz, 1H), 8.45 (d, J = 4.5 Hz, 1H),
7.87 (s, 1H), DMSO-d.sub.6 7.78 (t, J = 9.4 Hz, 2H), 7.69-7.74 (m,
3H), 7.59-7.67 (m,
2H), 7.43-7.53 (m, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 7.6
Hz, 1H) 79 400 MHz, 11.86 (br. s., 1H), 9.34 (d, J = 7.6 Hz, 1H),
8.46 (d, J = 4.7 Hz, DMSO-d.sub.6 1H), 7.68-7.82 (m, 2H), 7.65 (s,
1H), 7.54 (d, J = 8.6 Hz, 2H), 7.47 (dt, J = 8.5, 4.3 Hz, 1H), 7.35
(d, J = 8.2 Hz, 3H), 6.68 (d, J = 7.6 Hz, 1H) 80 400 MHz, 11.87
(br. s., 1H), 9.24 (d, J = 7.8 Hz, 1H), 8.37-8.52 (m, 1H),
DMSO-d.sub.6 7.89 (d, J = 1.4 Hz, 1H), 7.81 (dd, J = 8.2, 1.6 Hz,
1H), 7.76 (ddd, J = 10.0, 8.6, 1.2 Hz, 1H), 7.51-7.59 (m, J = 8.6
Hz, 2H), 7.44-7.51 (m, 1H), 7.31-7.40 (m, J = 8.0 Hz, 2H), 7.15 (d,
J = 8.0 Hz, 1H), 6.70 (d, J = 7.6 Hz, 1H) 81 400 MHz, 10.92 (br.
s., 1H), 9.15 (d, J = 7.6 Hz, 1H), 8.44 (d, J = 4.5 Hz,
DMSO-d.sub.6 1H), 7.74 (t, J = 9.3 Hz, 1H), 7.54-7.59 (m, 2H),
7.48-7.54 (m, J = 8.6 Hz, 2H), 7.46 (dt, J = 8.5, 4.3 Hz, 1H),
7.26-7.39 (m, J = 8.4 Hz, 2H), 6.93 (d, J = 8.6 Hz, 1H), 6.65 (d, J
= 7.8 Hz, 1H), 4.61 (s, 2H) 82 400 MHz, 11.98 (br. s., 1H), 9.07
(d, J = 7.4 Hz, 1H), 8.46 (d, J = 4.3 Hz, DMSO-d.sub.6 1H), 8.15
(d, J = 2.3 Hz, 1H), 7.90 (dd, J = 9.7, 2.6 Hz, 1H), 7.76 (d, J =
7.4 Hz, 1H), 7.65-7.73 (m, J = 8.2 Hz, 2H), 7.53-7.60 (m, J = 8.2
Hz, 2H), 7.37 (dd, J = 7.4, 5.1 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H),
6.33 (d, J = 9.6 Hz, 1H), 2.24-2.40 (m, 3H) 83 400 MHz, 9.01 (d, J
= 7.4 Hz, 1H), 8.41-8.57 (m, 2H), 7.90 (dd, J = 9.5, DMSO-d.sub.6
2.6 Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.66-7.75 (m, J = 8.2 Hz,
2H), 7.54-7.63 (m, J = 8.2 Hz, 2H), 7.38 (dd, J = 7.3, 5.0 Hz, 1H),
6.62 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 3.46 (s, 3H),
2.35 (s, 3H) 84 400 MHz, 11.82 (br. s., 1H), 9.27 (d, J = 7.8 Hz,
1H), 8.43 (d, J = 3.9 Hz, DMSO-d.sub.6 1H), 7.68 (d, J = 8.4 Hz,
3H), 7.65 (d, J = 7.6 Hz, 1H), 7.56-7.62 (m, 3H), 7.33 (d, J = 8.4
Hz, 1H), 7.28 (dd, J = 7.6, 4.7 Hz, 1H), 6.47-6.69 (m, 1H),
2.22-2.41 (m, 3H) 85 400 MHz, 10.92 (br. s., 1H), 9.12 (d, J = 7.6
Hz, 1H), 8.43 (d, J = 4.3 Hz, DMSO-d.sub.6 1H), 7.68 (d, J = 8.2
Hz, 2H), 7.64 (d, J = 7.4 Hz, 1H), 7.50-7.60 (m, 4H), 7.27 (dd, J =
7.5, 4.8 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 7.6 Hz,
1H), 4.61 (s, 2H), 2.32 (s, 3H) 86 400 MHz 9.58 (d, J = 7.6 Hz, 1
H), 8.59-8.65 (m, 1 H), 8.45-8.51 (m, 1 DMSO-d.sub.6 H), 8.32 (s, 1
H), 8.09 (s, 1 H), 7.72-7.83 (m, 4 H), 7.66-7.70 (m, 2 H), 7.50
(dt, J = 8.5, 4.4 Hz, 1H), 7.37 (dd, J = 7.1, 1.7 Hz, 1H), 6.77 (d,
J = 7.6 Hz, 1H) 87 400 MHz 9.52 (d, J = 7.8 Hz, 1 H), 8.62 (d, J =
7.0 Hz, 1 H), 8.48 (d, J = 4.5 Hz, DMSO-d6 1 H), 8.31 (s, 1 H),
8.08 (s, 1 H), 7.72-7.82 (m, 2 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.49
(dt, J = 8.5, 4.3 Hz, 1 H), 7.37 (td, J = 4.8, 2.5 Hz, 3 H), 6.71
(d, J = 7.6 Hz, 1 H) 88 400 MHz 9.52 (d, J = 7.8 Hz, 1 H), 8.62 (d,
J = 7.0 Hz, 1 H), 8.48 (d, J = 4.5 Hz, DMSO-d.sub.6 1 H), 8.31 (s,
1 H), 8.08 (s, 1 H), 7.72-7.82 (m, 2 H), 7.58 (d, J = 8.6 Hz, 2 H),
7.49 (dt, J = 8.5, 4.3 Hz, 1 H), 7.37 (td, J = 4.8, 2.5 Hz, 3 H),
6.71 (d, J = 7.6 Hz, 1 H) 89 300 MHz 9.23 (s, 1H), 9.02 (d, J = 6.7
Hz, 1H), 8.54 (d, J = 4.5 Hz, 1H), CDCl.sub.3 8.14-8.33 (m, 2H),
7.94 (s, 2H), 7.56-7.70 (m, 1H), 7.37-7.54 (m, 3H), 7.17 (d, J =
8.2 Hz, 2H), 6.70 (d, J = 6.3 Hz, 1H) 90 300 MHz 10.50 (s, 1H),
9.25 (d, J = 7.7 Hz, 1H), 8.46 (d, J = 4.7 Hz, 1H), DMSO-d.sub.6
7.75 (ddd, J = 10.0, 8.5, 1.2 Hz, 1H), 7.42-7.64 (m, 4H), 7.20-7.39
(m, 4H), 6.66 (d, J = 6.9 Hz, 1H), 3.54 (s, 2H) 91 300 MHz 8.63
(br. s., 4H), 8.49 (d, J = 4.7 Hz, 5H), 8.39 (d, J = 7.2 Hz,
CDCl.sub.3 4H), 7.67-7.89 (m, 2H), 7.42-7.55 (m, 3H), 7.30-7.41 (m,
1H), 7.15 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.68 (dd,
J = 7.1, 1.7 Hz, 1H), 3.60 (s, 2H) 92 400 MHz 13.23 (br. s., 1H),
8.54 (dd, J = 4.9, 1.6 Hz, 1H), 8.43 (d, J = 6.8 Hz, CDCl.sub.3
1H), 8.11 (d, J = 2.5 Hz, 1H), 7.95 (dd, J = 9.6, 2.5 Hz, 1H), 7.69
(dd, J = 7.8, 1.6 Hz, 1H), 7.48-7.60 (m, 4H), 7.23 (dd, J = 7.8,
4.9 Hz, 1H), 6.69 (d, J = 6.8 Hz, 1H), 6.61 (d, J = 9.4 Hz, 1H),
2.11 (s, 3H) 93 400 MHz 8.99 (dd, J = 4.3, 1.6 Hz, 1H), 8.76 (d, J
= 6.8 Hz, 1H), 8.58 (dd, DMSO-d.sub.6 J = 4.9, 1.6 Hz, 1H), 8.41
(s, 1H), 8.28 (dd, J = 8.2, 1.6 Hz, 1H), 8.18 (s, 2H), 7.72 (dd, J
= 7.8, 1.6 Hz, 1H), 7.60-7.68 (m, J = 8.0 Hz, 2H), 7.52-7.59 (m, J
= 8.4 Hz, 2H), 7.47 (dd, J = 8.2, 4.3 Hz, 1H), 7.18-7.25 (m, 1H),
6.83 (d, J = 6.8 Hz, 1H), 2.15 (s, 3H) 94 300 MHz 8.94 (d, J = 4.4
Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.22-8.36 (m, CDCl.sub.3 2H),
8.16 (br. s., 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.94 (d, J = 7.7 Hz,
1H), 7.39-7.73 (m, 5H), 6.88 (d, J = 7.6 Hz, 1H) 95 300 MHz
8.60-8.92 (m, 2H), 8.03 (dd, J = 8.0, 1.2 Hz, 1H), 7.91 (d, J = 8.9
Hz, CDCl.sub.3 2H), 7.42-7.68 (m, 5H), 7.08 (d, J = 7.7 Hz, 1H),
6.93 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.17 (s, 3H) 96 400 MHz
8.73 (d, J = 2.3 Hz, 1H), 8.53 (dd, J = 4.8, 1.5 Hz, 2H),
CDCl.sub.3 8.06 (dd, J = 8.7, 2.4 Hz, 1H), 7.69 (dd, J = 7.8, 1.6
Hz, 1H), 7.44-7.63 (m, 4H), 7.22 (dd, J = 7.8, 4.9 Hz, 1H),
6.46-6.85 (m, 2H), 3.91-4.01 (m, 3H), 2.13 (s, 3H) 97 400 MHz
9.18-9.50 (m, 2H), 9.11 (br. s., 1H), 8.60-8.90 (m, 2H), CDCl.sub.3
8.38 (d, J = 8.4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.86-8.08 (m,
2H), 7.37-7.80 (m, 5H), 7.02 (d, J = 6.5 Hz, 1H), 2.18 (s, 3H) 98
300 MHz 8.49-8.69 (m, 2H), 7.83-8.06 (m, 2H), 7.76 (dd, J = 7.9,
1.6 Hz, CDCl.sub.3 1H), 7.37-7.66 (m, 7H), 7.26-7.32 (m, 1H), 6.86
(d, J = 7.2 Hz, 1H), 2.14 (s, 3H) 99 400 MHz 8.97 (d, J = 3.5 Hz,
1H), 8.65 (d, J = 3.5 Hz, 1H), 8.31-8.49 (m, d.sub.4-MeOH 2H), 8.24
(d, J = 7.6 Hz, 1H), 8.09 (d, J = 7.0 Hz, 2H), 7.32-7.92 (m, 7H),
6.98 (br. s., 1H) 100 400 MHz 8.93 (d, J = 4.7 Hz, 1H), 8.29 (d, J
= 7.8 Hz, 1H), 8.01-8.16 (m, CDCl.sub.3 2H), 7.95 (d, J = 8.2 Hz,
1H), 7.81 (dd, J = 8.1, 1.7 Hz, 1H), 7.39-7.65 (m, 5H), 6.87 (d, J
= 7.8 Hz, 1H) 101 300 MHz 9.33 (d, J = 4.2 Hz, 1H), 9.20 (d, J =
7.3 Hz, 1H), 8.88 (d, J = 8.3 Hz, CDCl.sub.3 1H), 8.65-8.79 (m,
2H), 8.43-8.65 (m, 2H), 8.05 (dd, J = 7.9, 1.3 Hz, 1H), 7.95 (dd, J
= 8.3, 5.1 Hz, 1H), 7.40-7.69 (m, 5H), 7.06 (d, J = 7.3 Hz, 1H),
4.91 (dd, J = 10.4, 5.6 Hz, 2H), 4.56 (dd, J = 5.6, 2.6 Hz, 2H),
1.75 (s, 3H) 102 300 MHz 8.48 (d, J = 4.5 Hz, 1H), 8.14 (d, J = 2.2
Hz, 1H), 8.04 (dd, J = 9.6, d.sub.4-MeOH 2.6 Hz, 1H), 7.63 (td, J =
9.1, 1.3 Hz, 1H), 7.34-7.51 (m, 3H), 7.26-7.34 (m, 1H), 6.65 (s,
1H), 6.53 (d, J = 9.6 Hz, 1H) 103 300 MHz 8.50 (d, J = 4.7 Hz, 1H),
8.42 (d, J = 2.6 Hz, 1H), 8.00 (dd, J = 9.4, d.sub.4-MeOH 2.6 Hz,
1H), 7.65 (td, J = 9.1, 1.2 Hz, 1H), 7.27-7.52 (m, 4H), 6.67 (s,
1H), 6.56 (d, J = 9.5 Hz, 1H), 3.63 (s, 3H) 104 300 MHz 8.70 (d, J
= 2.8 Hz, 1H), 8.51 (d, J = 4.7 Hz, 1H), 8.43 (s, 1H), d.sub.4-MeOH
7.99-8.11 (m, 2H), 7.85 (d, J = 2.6 Hz, 1H), 7.59-7.71 (m, 5H),
7.46 (dt, J = 8.4, 4.3 Hz, 1H), 6.81 (s, 1H) 105 300 MHz 8.50 (d, J
= 4.8 Hz, 1H), 8.01 (d, J = 9.5 Hz, 1H), 7.85 (s, 1H), d.sub.4-MeOH
7.69-7.82 (m, 2H), 7.58-7.69 (m, 5H), 7.46 (dt, J = 8.4, 4.3 Hz,
1H), 6.76 (s, 1H), 6.70 (d, J = 9.5 Hz, 1H) 106 300 MHz 8.93 (d, J
= 4.2 Hz, 1H), 8.21 (d, J = 6.9 Hz, 1H), 8.00 (d, J = 9.5 Hz,
d.sub.4-MeOH 1H), 7.80 (s, 1H), 7.72-7.78 (m, 1H), 7.51-7.71 (m,
6H), 6.93 (s, 1H), 6.69 (d, J = 9.6 Hz, 1H) 107 300 MHz 8.91 (d, J
= 4.8 Hz, 1H), 8.15-8.27 (m, 1H), 7.81-7.90 (m, d.sub.4-MeOH 2H),
7.64-7.70 (m, 1H), 7.51-7.64 (m, 2H), 7.41-7.51 (m, 2H), 7.31-7.41
(m, 2H), 6.90 (s, 1H) 108 300 MHz 8.89-9.01 (m, 3H), 8.60 (d, J =
1.8 Hz, 1H), 8.13-8.31 (m, 3H), d.sub.4-MeOH 7.55-7.73 (m, 2H),
7.36-7.48 (m, 2H), 6.96 (s, 1H) 109 300 MHz 8.94 (d, J = 4.4 Hz,
1H), 8.82 (d, J = 1.9 Hz, 1H), 8.13-8.32 (m, d.sub.4-MeOH 3H), 7.75
(d, J = 8.8 Hz, 1H), 7.53-7.70 (m, 5H), 6.96 (s, 1H), 6.59 (d, J =
7.3 Hz, 1H) 110 300 MHz 8.94 (d, J = 4.7 Hz, 1H), 8.90 (d, J = 2.5
Hz, 1H), 8.54 (s, 1H), d.sub.4-MeOH 8.48 (d, J = 1.9 Hz, 1H), 8.21
(d, J = 8.0 Hz, 1H), 7.96-8.10 (m, 2H), 7.55-7.69 (m, 5H), 6.98 (s,
1H) 111 300 MHz 9.26 (d, J = 1.2 Hz, 1H), 8.98 (d, J = 4.2 Hz, 1H),
8.81 (d, J = 2.5 Hz, d.sub.4-MeOH 1H), 8.65-8.75 (m, 1H), 8.23 (d,
J = 7.9 Hz, 1H), 7.58-7.71 (m, 2H), 7.30-7.45 (m, 2H), 6.86 (s, 1H)
112 300 MHz 8.98 (d, J = 4.1 Hz, 1H), 8.59-8.71 (m, 1H), 8.18-8.28
(m, d.sub.4-MeOH 1H), 8.11 (dt, J = 7.9, 1.0 Hz, 1H), 7.97 (td, J =
7.7, 1.7 Hz, 1H), 7.53-7.70 (m, 3H), 7.32-7.45 (m, 2H), 6.84 (s,
1H) 113 300 MHz 8.86-8.92 (m, 2H), 8.51 (d, J = 4.7 Hz, 1H), 8.34
(dd, J = 8.8, d.sub.4-MeOH 1.9 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H),
7.82 (d, J = 5.0 Hz, 1H), 7.63-7.71 (m, 5H), 7.46 (dt, J = 8.4, 4.3
Hz, 1H), 6.84 (s, 1H) 114 300 MHz 8.87 (d, J = 1.8 Hz, 1H), 8.51
(d, J = 4.7 Hz, 1H), 8.25 (dd, J = 8.7, d.sub.4-MeOH 2.1 Hz, 1H),
8.18 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.58-7.71 (m,
5H), 7.45 (dt, J = 8.5, 4.4 Hz, 1H), 6.79 (s, 1H), 6.56 (d, J = 7.3
Hz, 1H) 115 400 MHz 9.52 (d, J = 7.6 Hz, 1H), 8.93-8.99 (m, 2H),
8.59 (s, 1H), DMSO-d.sub.6 8.41 (d, J = 8.1 Hz, 1H), 8.21 (d, J =
8.0 Hz, 1H), 8.03 (s, 2H), 7.62 (m, 2H), 7.27 (d, J = 8 Hz, 2H),
7.18 (d, J = 8 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 2.59 (q, J = 8
Hz, 2H), 1.15 (t, J = 8 Hz, 3H) 116 300 MHz 8.94 (d, J = 4.8 Hz,
1H), 8.91 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 6.9 Hz, d.sub.4-MeOH
1H), 8.39 (dd, J = 8.9, 2.0 Hz, 1H), 8.16-8.27 (m, 1H), 7.98 (d, J
= 9.1 Hz, 1H), 7.53-7.70 (m, 5H), 7.03 (d, J = 6.9 Hz, 1H), 6.97
(s, 1H) 117 300 MHz 8.91 (d, J = 4.4 Hz, 1H), 8.11-8.27 (m, 2H),
7.84 (d, J = 7.9 Hz, d.sub.4-MeOH 1H), 7.89 (d, J = 7.9 Hz, 1H),
7.49-7.68 (m, 5H), 7.23 (t, J = 7.9 Hz, 1H), 6.89 (s, 1H) 118 300
MHz 8.88 (d, J = 4.2 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.87 (d, J
= 7.9 Hz, d.sub.4-MeOH 1H), 7.64 (s, 4H), 7.55 (dd, J = 7.7, 4.9
Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 6.6 Hz, 1H), 7.15
(t, J = 7.2 Hz, 1H), 6.90 (s, 1H) 119 300 MHz 8.93 (d, J = 4.2 Hz,
1H), 8.20 (d, J = 8.2 Hz, 1H), 7.52-7.74 (m, d.sub.4-MeOH 2H),
7.19-7.36 (m, 2H), 6.63 (s, 1H), 4.28-4.45 (m, 1H), 3.96-4.10 (m,
1H), 3.81-3.96 (m, 1H), 2.15-2.35 (m, 1H), 1.74-2.02 (m, 3H) 120
300 MHz 8.91 (d, J = 2.3 Hz, 1H), 8.60 (s, 1H), 8.46-8.54 (m, 2H),
d.sub.4-MeOH 8.10 (dd, J = 8.6, 1.7 Hz, 1H), 8.02 (d, J = 8.5 Hz,
1H), 7.58-7.72 (m, 5H), 7.46 (dt, J = 8.4, 4.4 Hz, 1H), 6.82 (s,
1H) 121 300 MHz 8.91 (d, J = 4.5 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H),
7.82 (d, J = 8.5 Hz, d.sub.4-MeOH 2H), 7.49-7.68 (m, 7H), 6.92 (s,
1H), 1.53 (s, 6H) 122 300 MHz 8.90 (d, J = 4.4 Hz, 1H), 8.19 (d, J
= 7.2 Hz, 1H), 7.84 (d, J = 8.5 Hz, d.sub.4-MeOH 2H), 7.50-7.67 (m,
7H), 6.90 (s, 1H) 123 300 MHz 8.92 (d, J = 4.1 Hz, 1H), 8.11-8.29
(m, 1H), 7.52-7.71 (m, d.sub.4-MeOH 2H), 7.28 (d, J = 9.9 Hz, 2H),
6.63 (s, 1H), 4.37 (dd, J = 8.3, 5.6 Hz, 1H), 3.77-4.04 (m, 2H),
2.14-2.35 (m, 1H), 1.70-2.03 (m, 3H) 124 600 MHz 9.32 (d, J = 7.6
Hz, 1H), 8.92 (d, J = 4.7 Hz, 1H), 8.71 (d, J = 2.1 Hz,
DMSO-d.sub.6 1H), 8.28-8.17 (m, 2H), 7.61 (dd, J = 7.9, 4.9 Hz,
1H), 7.34 (dd, J = 8.6, 5.5 Hz, 2H), 7.17 (t, J = 8.9 Hz, 2H), 6.87
(d, J = 8.7 Hz, 1H), 6.71 (d, J = 7.5 Hz, 1H), 3.90 (s, 3H) 125 300
MHz 8.50 (d, J = 4.7 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.23 (d, J
= 7.2 Hz, d.sub.4-MeOH 1H), 8.18 (d, J = 1.2 Hz, 1H), 7.96 (dd, J =
8.6, 1.5 Hz, 1H), 7.59-7.72 (m, 5H), 7.46 (dt, J = 8.6, 4.4 Hz,
1H), 6.79 (s, 1H), 6.58 (d, J = 7.2 Hz, 1H) 126 600 MHz 9.22 (d, J
= 7.2 Hz, 1H), 8.92 (d, J = 4.2 Hz, 1H), 8.23 (d, J = 7.8 Hz,
DMSO-d.sub.6 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.61 (dd, J = 7.8, 4.8
Hz, 1H), 7.54 (dd, J = 7.8, 1.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H),
7.34-7.37 (m, 2H), 7.16 (d, J = 9 Hz, 2H), 6.71 (d, J = 7.8 Hz, 1H)
127 300 MHz 8.91 (d, J = 4.2 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H),
7.78 (d, J = 8.2 Hz, d.sub.4-MeOH 2H), 7.50-7.71 (m, 2H), 7.23-7.45
(m, 4H), 6.89 (s, 1H), 2.96 (dt, J = 13.6, 6.8 Hz, 1H), 1.25 (d, J
= 6.9 Hz, 6H) 128 300 MHz 9.22 (dd, J = 4.4, 1.8 Hz, 1H), 9.00 (d,
J = 4.7 Hz, 1H), d.sub.4-MeOH 8.64-8.76 (m, 2H), 8.41 (d, J = 8.3
Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.84 (dd, J = 8.2, 4.4 Hz, 1H),
7.56-7.72 (m, 5H), 6.94 (s, 1H) 129 300 MHz 9.23 (dd, J = 4.5, 1.8
Hz, 1H), 9.01 (d, J = 4.4 Hz, 1H), d.sub.4-MeOH 8.63-8.76 (m, 2H),
8.42 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H),
7.85 (dd, J = 8.3, 4.5 Hz, 1H), 7.59-7.72 (m, 2H), 7.40-7.53 (m,
2H), 6.91 (s, 1H) 130 300 MHz 9.31 (d, J = 4.2 Hz, 1H), 8.96 (d, J
= 4.1 Hz, 1H), 8.81 (d, J = 8.3 Hz, CDCl.sub.3 1H), 8.49-8.69 (m,
3H), 8.35 (dd, J = 8.9, 1.8 Hz, 1H), 8.11 (d, J = 7.0 Hz, 1H), 7.90
(dd, J = 8.3, 4.8 Hz, 1H), 7.49-7.64 (m, 2H), 7.38 (d, J = 8.0 Hz,
1H), 7.30 (d, J = 11.4 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H) 131 300
MHz 9.26 (br. s., 1H), 8.77-9.14 (m, 4H), 8.39 (d, J = 8.6 Hz, 1H),
CDCl.sub.3 8.22 (d, J = 8.6 Hz, 1H), 7.91-8.16 (m, 2H), 7.46-7.65
(m, 2H), 7.28-7.46 (m, 2H), 6.84 (d, J = 7.0 Hz, 1H) 132 300 MHz
8.85-9.00 (m, 2 H), 8.52 (s, 1 H), 8.42 (d, J = 8.3 Hz, 1 H),
d.sub.4-MeOH 8.21 (d, J = 8.0 Hz, 1 H), 7.88-8.12 (m, 2 H),
7.48-7.73 (m, 6 H), 6.99 (s, 1 H) 133 300 MHz 8.93 (d, J = 4.1 Hz,
2 H), 8.38-8.56 (m, 2 H), 8.15-8.28 (m, 2 d.sub.4-MeOH H),
7.96-8.15 (m, 1 H), 7.50-7.71 (m, 6 H), 6.99 (s, 1 H) 134 400 MHz
8.95 (d, J = 7.4 Hz, 1H), 8.90 (d, J = 4.7 Hz, 1H), 8.51 (d, J =
2.0 Hz, DMSO-d.sub.6 1H), 8.24 (d, J = 7.8 Hz, 1H), 7.86 (dd, J =
8.6, 2.3 Hz, 1H), 7.66-7.73 (m, J = 8.2 Hz, 2H), 7.61 (dd, J = 7.8,
4.7 Hz, 1H), 7.46-7.55 (m, J = 7.8 Hz, 2H), 6.78 (d, J = 7.8 Hz,
1H), 6.51 (s, 2H), 6.40 (d, J = 8.6 Hz, 1H) 135 300 MHz 8.90 (d, J
= 3.9 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 7.6 Hz,
CDCl.sub.3 1H), 8.00-8.16 (m, 2H), 7.46-7.65 (m, 5H), 7.41 (d, J =
8.2 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H) 136 300 MHz 8.87 (d, J = 3.9
Hz, 1H), 8.75 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.0 Hz, CDCl.sub.3
1H), 7.62-7.74 (m, J = 8.2 Hz, 2H), 7.51-7.61 (m, J = 8.3 Hz, 2H),
7.43 (dd, J = 8.0, 4.9 Hz, 1H), 7.37 (s, 1H), 6.79 (d, J = 7.6 Hz,
1H), 6.34 (br s, 2H) 137 400 MHz 9.38 (d, J = 7.4 Hz, 1H), 8.90 (d,
J = 4.3 Hz, 1H), 8.66 (s, 1H), DMSO-d.sub.6 8.25 (d, J = 7.8 Hz,
1H), 7.70 (d, J = 7.8 Hz, 2H), 7.55-7.65 (m, 3H), 7.51 (d, J = 7.8
Hz, 3H), 6.74 (d, J = 7.4 Hz, 1H), 2.34 (s, 3H) 138 300 MHz 8.89
(d, J = 3.8 Hz, 1H), 7.93-8.11 (m, 2H), 7.58 (dd, J = 3.7,
CDCl.sub.3 1.1 Hz, 1H), 7.54 (s, 4H), 7.43-7.50 (m, 2H), 7.08 (dd,
J = 5.0, 3.8 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H) 139 400 MHz 9.35 (d,
J = 7.4 Hz, 1H), 8.91 (d, J = 4.3 Hz, 1H), 8.26 (d, J = 7.4 Hz,
DMSO-d.sub.6 1H), 8.12 (s, 1H), 7.67-7.76 (m, 3H), 7.63 (dd, J =
7.8, 5.1 Hz, 1H), 7.47-7.56 (m, 3H), 6.75 (d, J = 7.4 Hz, 1H), 6.37
(s, 2H) 140 300 MHz 8.90 (d, J = 3.8 Hz, 1H), 8.27 (d, J = 7.6 Hz,
1H), 8.07-8.14 (m, CDCl.sub.3 2H), 8.05 (d, J = 6.7 Hz, 1H),
7.83-7.94 (m, 2H), 7.55 (s, 4H), 7.48 (dd, J = 7.7, 4.8 Hz, 1H),
6.89 (d, J = 7.7 Hz, 1H), 3.94 (s, 3H) 141 300 MHz 8.98 (d, J = 4.2
Hz, 1H), 8.50 (d, J = 7.5 Hz, 1H), 8.13-8.18 (m, CDCl.sub.3 3H),
7.95 (d, J = 8.5 Hz, 2H), 7.49-7.69 (m, 5H), 6.95 (d, J = 7.3 Hz,
1H) 142 300 MHz 8.84 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H),
7.37-7.60 (m, CDCl.sub.3 6H), 6.66 (d, J = 7.6 Hz, 1H), 3.97-4.15
(m, 1H), 3.89 (d, J = 13.3 Hz, 1H), 2.95 (dd, J = 13.3, 10.4 Hz,
1H), 2.82 (br. s., 1H), 2.33 (d, J = 3.8 Hz, 1H), 1.88 (br. s.,
1H), 1.58-1.81 (m, 2H), 1.43 (d, J = 2.2 Hz, 9H) 143 400 MHz 13.13
(br. s., 1H), 8.81-8.99 (m, 2H), 8.34 (br. s., 1H), 8.25 (d,
DMSO-d.sub.6 J = 8.2 Hz, 1H), 7.98 (br. s., 1H), 7.66-7.75 (m, J =
8.2 Hz, 2H), 7.62 (dd, J = 8.0, 4.9 Hz, 1H), 7.44-7.51 (m, J = 8.2
Hz, 2H), 6.81 (d, J = 7.8 Hz, 1H) 144 400 MHz 9.44 (d, J = 8.6 Hz,
1H), 9.03 (d, J = 4.3 Hz, 1H), 8.30 (d, J = 8.2 Hz, DMSO-d.sub.6
1H), 7.80-7.86 (m, 1H), 7.64-7.76 (m, 3H), 7.54 (d, J = 8.2 Hz,
2H), 7.28 (dd, J = 8.6, 4.3 Hz, 1H), 7.18 (dd, J = 8.6, 1.2 Hz,
1H), 6.83 (br. s., 2H), 6.71 (d, J = 8.6 Hz, 1H) 145 400 MHz 8.96
(d, J = 8.2 Hz, 1H), 8.86 (d, J = 4.3 Hz, 1H), 8.73 (s, 1H),
DMSO-d.sub.6 8.22 (d, J = 7.8 Hz, 1H), 7.62-7.69 (m, J = 8.2 Hz,
2H), 7.59 (dd, J = 7.8, 4.7 Hz, 1H), 7.31-7.39 (m, J = 8.2 Hz, 2H),
6.58 (d, J = 7.8 Hz, 1H), 2.96 (q, J = 7.2 Hz, 2H), 2.52-2.61 (m,
2H), 2.23 (s, 3H) 146 400 MHz 9.02 (d, J = 4.7 Hz, 1H), 8.97 (d, J
= 8.6 Hz, 1H), 8.30 (d, J = 7.8 Hz, DMSO-d.sub.6 1H), 7.63-7.77 (m,
3H), 7.54 (d, J = 8.2 Hz, 2H), 7.39 (s, 1H), 7.01 (s, 1H), 6.66 (d,
J = 8.6 Hz, 1H), 3.93 (s, 3H) 147 300 MHz 9.33 (s, 1H), 9.16 (s,
2H), 8.91 (d, J = 4.2 Hz, 1H), 8.40 (d, J = 7.6 Hz, CDCl.sub.3 1H),
8.06 (d, J = 8.2 Hz, 1H), 7.56 (s, 4H), 7.51 (dd, J = 8.1, 4.8 Hz,
1H), 6.86 (d, J = 7.6 Hz, 1H) 148 300 MHz 8.90 (d, J = 4.1 Hz, 1H),
8.74 (d, J = 1.8 Hz, 2H), 8.31 (d, J = 8.8 Hz, CDCl.sub.3 1H), 8.23
(d, J = 7.7 Hz, 1H), 8.16 (dd, J = 8.8, 2.3 Hz, 1H), 8.05 (d, J =
7.0 Hz, 1H), 7.55 (s, 4H), 7.49 (dd, J = 7.8, 4.9 Hz, 1H), 6.87 (d,
J = 7.6 Hz, 1H), 2.23 (s, 3H) 149 400 MHz 8.92-9.06 (m, 2H), 8.30
(d, J = 8.2 Hz, 1H), 7.63-7.78 (m, DMSO-d.sub.6 3H), 7.55 (d, J =
8.2 Hz, 2H), 7.01-7.06 (m, 1H), 6.95-6.99 (m, 1H), 6.81 (d, J = 8.2
Hz, 1H), 2.68-2.76 (m, 3H) 150 400 MHz 9.00 (d, J = 4.3 Hz, 1H),
8.96 (d, J = 8.2 Hz, 1H), 8.30 (d, J = 8.2 Hz, DMSO-d.sub.6 1H),
7.81 (d, J = 9.8 Hz, 1H), 7.63-7.76 (m, 4H), 7.53 (d, J = 8.2 Hz,
2H), 6.94 (d, J = 9.8 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H) 151 400 MHz
9.34 (d, J = 7.8 Hz, 1H), 9.03 (br. s., 1H), 8.31 (d, J = 7.8 Hz,
DMSO-d.sub.6 1H), 7.65-7.78 (m, 4H), 7.58 (d, J = 8.2 Hz, 2H), 7.29
(d, J = 5.5 Hz, 1H), 6.76 (d, J = 8.2 Hz, 1H), 2.75 (s, 3H), 2.61
(s, 3H) 152 400 MHz 8.77-8.95 (m, 2H), 8.14-8.31 (m, 1H), 7.66-7.72
(m, J = 8.2 Hz, DMSO-d.sub.6 2H), 7.60 (dd, J = 7.8, 4.7 Hz, 1H),
7.36-7.53 (m, J = 7.8 Hz, 2H), 6.57 (d, J = 7.8 Hz, 1H), 3.75-3.92
(m, 2H), 3.21-3.31 (m, 2H), 2.56-2.67 (m, 1H), 1.47-1.66 (m, 4H)
153 400 MHz 9.23 (d, J = 7.8 Hz, 1H), 8.94 (d, J = 4.7 Hz, 1H),
8.26 (d, J = 7.8 Hz, DMSO-d.sub.6 1H), 7.68-7.77 (m, J = 8.2 Hz,
2H), 7.64 (dd, J = 7.8, 4.7 Hz, 1H), 7.46-7.55 (m, J = 7.8 Hz, 2H),
7.27 (s, 1H), 6.58 (d, J = 8.2 Hz, 1H), 6.00 (s, 1H), 4.77-4.99 (m,
2H), 2.15 (s, 3H) 154 400 MHz 9.21 (d, J = 8.2 Hz, 1H), 8.90 (d, J
= 4.3 Hz, 1H), 8.23 (d, J = 7.8 Hz, DMSO-d.sub.6 1H), 7.66-7.76 (m,
J = 8.2 Hz, 2H), 7.61 (dd, J = 8.0, 4.9 Hz, 1H), 7.43-7.53 (m, J =
7.8 Hz, 2H), 6.59 (d, J = 7.8 Hz, 1H), 4.25 (t, J = 8.0 Hz, 2H),
3.84-4.03 (m, 2H) 155 300 MHz 8.83 (d, J = 3.9 Hz, 1H), 8.36 (br.
s., 1H), 8.01 (d, J = 8.0 Hz, CDCl.sub.3 1H), 7.85 (d, J = 8.0 Hz,
1H), 7.36-7.61 (m, 5H), 7.05 (s, 1H), 6.64 (d, J = 7.5 Hz, 1H),
2.90-3.08 (m, 2H), 2.72 (d, J = 6.6 Hz, 2H) 156 300 MHz 8.95 (d, J
= 3.9 Hz, 1H), 8.16-8.32 (m, 3H), 8.11 (td, J = 7.8, d.sub.4-MeOH
1.2 Hz, 1H), 7.96 (s, 1H), 7.88 (td, J = 7.7, 1.1 Hz, 1H),
7.59-7.79 (m, 2H), 7.43-7.56 (m, 2H), 7.01 (s, 1H), 3.11 (d, J =
7.5 Hz, 2H), 2.19-2.44 (m, 1H), 1.06 (d, J = 6.6 Hz, 6H) 157 400
MHz 8.95 (dd, J = 8.0, 3.7 Hz, 1H), 8.89 (d, J = 4.7 Hz, 1H), 8.24
(d, DMSO-d.sub.6 J = 7.8 Hz, 1H), 7.64-7.75 (m, J = 8.2 Hz, 2H),
7.60 (dd, J = 7.8, 5.1 Hz, 1H), 7.38-7.52 (m, J = 7.4 Hz, 2H), 6.59
(d, J = 7.8 Hz, 1H), 3.63-3.74 (m, 2H), 3.59 (qd, J = 7.6, 2.3 Hz,
1H), 3.15-3.29 (m, 1H), 2.39-2.49 (m, 1H), 2.21-2.39 (m, 2H),
1.83-1.96 (m, 1H), 1.38-1.53 (m, 1H) 158 400 MHz 11.87 (br. s.,
1H), 9.08 (d, J = 8.2 Hz, 1H), 8.91 (d, J = 4.3 Hz, DMSO-d.sub.6
1H), 8.24 (d, J = 7.4 Hz, 1H), 7.65-7.72 (m, J = 8.2 Hz, 2H), 7.61
(dd, J = 8.0, 4.9 Hz, 2H), 7.44-7.49 (m, J = 8.2 Hz, 2H), 6.90 (br.
s., 1H), 6.60 (d, J = 8.2 Hz, 1H), 3.48 (br. s., 2H) 159 400 MHz
9.01 (d, J = 4.7 Hz, 1H), 8.65 (d, J = 8.2 Hz, 1H), 8.30 (d, J =
7.8 Hz, DMSO-d.sub.6 1H), 7.63-7.77 (m, 3H), 7.51 (d, J = 8.2 Hz,
2H), 6.66 (d, J = 8.6 Hz, 1H), 6.26 (br. s., 2H) 160 400 MHz 9.35
(d, J = 7.8 Hz, 1H), 8.94 (d, J = 4.3 Hz, 1H), 8.26 (d, J = 8.2 Hz,
DMSO-d.sub.6 1H), 7.69-7.76 (m, J = 8.2 Hz, 2H), 7.64 (dd, J = 7.8,
4.7 Hz, 1H), 7.46-7.56 (m, J = 7.8 Hz, 2H), 6.96 (s, 1H), 6.67 (s,
1H), 6.57 (d, J = 7.8 Hz, 1H), 4.61-4.83 (m, 2H), 2.13 (s, 3H) 161
300 MHz 9.12 (br. s., 1H), 8.84 (d, J = 3.9 Hz, 1H), 8.52 (d, J =
7.5 Hz, CDCl.sub.3 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.47-7.58 (m,
4H), 7.43 (dd, J = 7.8, 4.8 Hz, 1H), 7.32 (s, 1H), 6.60 (d, J = 7.3
Hz, 1H), 4.93-5.23 (m, 2H) 162 400 MHz 8.81-8.99 (m, 2H), 8.25 (dd,
J = 7.4, 2.7 Hz, 1H), 8.05 (dd, J = 19.0, DMSO-d.sub.6 7.6 Hz, 1H),
7.69 (dd, J = 8.2, 3.1 Hz, 2H), 7.58-7.66 (m, 1H), 7.45 (t, J = 7.4
Hz, 2H), 6.54 (dd, J = 17.8, 8.0 Hz, 1H), 4.32-4.56 (m, 1H), 1.81
(d, J = 7.4 Hz, 3H), 1.06-1.29 (m, 3H) 163 400 MHz 9.06-9.16 (m,
1H), 8.87-8.95 (m, 1H), 8.24 (d, J = 7.8 Hz, DMSO-d.sub.6 1H),
7.67-7.74 (m, J = 8.2 Hz, 2H), 7.62 (dd, J = 7.8, 4.7 Hz, 1H), 7.54
(d, J = 9.4 Hz, 1H), 7.42-7.49 (m, J = 8.2 Hz, 2H), 6.58 (dd, J =
7.8, 3.9 Hz, 1H), 3.41-3.49 (m, 1H), 3.11-3.25 (m, 1H), 2.29 (dd, J
= 7.8, 5.5 Hz, 1H), 2.24 (t, J = 8.4 Hz, 1H) 164 400 MHz 8.75 (br.
s., 1H), 7.98 (d, J = 6.8 Hz, 1H), 7.14-7.61 (m, 9H), CDCl.sub.3
6.66 (d, J = 6.8 Hz, 1H), 3.65 (br. s., 2H) 165 400 MHz 9.15 (d, J
= 4.9 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H), 8.00 (s, 2H), d.sub.4-MeOH
7.84-7.88 (m, 2H), 7.81-7.84 (m, 1H), 7.76-7.81 (m, 2H), 7.15 (s,
1H), 7.07 (d, J = 8.6 Hz, 2H) 166 400 MHz 8.53 (d, J = 4.7 Hz, 1H),
8.16 (s, 2H), 7.91 (d, J = 8.2 Hz, 1H), d.sub.4-MeOH 7.60-7.72 (m,
6H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.82 (s, 1H) 167 400 MHz 8.49
(d, J = 4.5 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz,
d.sub.4-MeOH 2H), 7.58-7.69 (m, 5H), 7.45 (dt, J = 8.5, 4.4 Hz,
1H), 6.72-6.79 (m, 1H) 168 400 MHz 8.93 (d, J = 4.9 Hz, 1H),
8.17-8.25 (m, 2H), 8.15 (d, J = 8.0 Hz, d.sub.4-MeOH 1H), 7.91 (d,
J = 7.6 Hz, 1H), 7.62-7.71 (m, 3H), 7.54-7.61 (m, 3H), 6.92 (s, 1H)
169 400 MHz 8.37 (d, J = 4.7 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H),
7.42-7.53 (m, d.sub.4-MeOH 5H), 7.33-7.42 (m, 1H), 7.28 (dt, J =
8.6, 4.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.91 (t, J = 7.5 Hz,
1H), 6.49 (s, 1H), 3.97 (s, 3H) 170 400 MHz 8.99 (d, J = 3.9 Hz,
2H), 8.68 (d, J = 1.6 Hz, 1H), 8.53 (d, J = 4.5 Hz, d.sub.4-MeOH
1H), 8.28-8.35 (m, 1H), 8.17-8.26 (m, 1H), 7.61-7.75 (m, 5H), 7.48
(dt, J = 8.5, 4.4 Hz, 1H), 6.85 (s, 1H) 171 400 MHz 8.94 (d, J =
4.1 Hz, 1H), 8.22 (dd, J = 8.0, 1.0 Hz, 1H), d.sub.4-MeOH 7.81-7.92
(m, 2H), 7.52-7.69 (m, 5H), 6.97-7.06 (m, 2H), 6.94 (s, 1H), 3.87
(s, 3H) 172 400 MHz 8.50 (d, J = 4.5 Hz, 1H), 7.90 (d, J = 9.0 Hz,
2H), 7.58-7.71 (m, d.sub.4-MeOH 5H), 7.45 (dt, J = 8.5, 4.4 Hz,
1H), 7.02 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 3.87 (s, 3H) 173 400
MHz 8.55 (d, J = 4.7 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 7.97 (d, J
= 8.6 Hz, d.sub.4-MeOH 1H), 7.60-7.70 (m, 5H), 7.47 (dt, J = 8.5,
4.4 Hz, 1H), 7.28 (dd, J = 8.5, 2.8 Hz, 1H), 6.67 (d, J = 1.6 Hz,
1H) 174 400 MHz 9.22 (d, J = 7.6 Hz, 1H), 8.93 (d, J = 4.5 Hz, 1H),
8.21 (d, J = 7.8 Hz, d.sub.4-MeOH 1H), 7.92 (d, J = 8.8 Hz, 2H),
7.50-7.71 (m, 5H), 7.23 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 7.6 Hz,
1H), 2.31 (s, 3H) 175 400 MHz 8.96 (d, J = 4.3 Hz, 1H), 8.24 (dd, J
= 8.0, 1.0 Hz, 1H), 8.12 (dd, d.sub.4-MeOH J = 12.6, 0.9 Hz, 2H),
7.88 (dd, J = 8.5, 0.7 Hz, 1H), 7.56-7.72 (m, 6H), 7.00 (s, 1H) 176
400 MHz 9.00 (d, J = 4.7 Hz, 1H), 8.22 (d, J = 7.8 Hz, 1H), 8.01
(dd, J = 7.8, d.sub.4-MeOH 1.6 Hz, 1H), 7.59-7.69 (m, 5H),
7.50-7.57 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.5 Hz,
1H), 6.91 (s, 1H), 4.07 (s, 3H) 177 400 MHz 10.90 (s, 1H), 10.83
(s, 1H), 9.20 (d, J = 7.6 Hz, 1H), 8.45 (d, J = 4.7 Hz,
d.sub.6-DMSO 1H), 7.69-7.83 (m, 3H), 7.58-7.66 (m, 3H), 7.53 (s,
1H), 7.48 (dt, J = 8.4, 4.3 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.73
(d, J = 8.2 Hz, 1H) 178 400 MHz 8.94 (d, J = 4.7 Hz, 1H), 8.65-8.76
(m, 2H), 8.23 (d, J = 8.0 Hz, d.sub.4-MeOH 1H), 7.79-7.88 (m, 2H),
7.65-7.70 (m, 2H), 7.56-7.64 (m, 3H), 6.94 (s, 1H)
179 400 MHz 8.95 (d, J = 4.3 Hz, 1H), 8.52 (s, 1H), 8.22 (dd, J =
7.2, 4.3 Hz, d.sub.4-MeOH 2H), 8.09 (d, J = 7.8 Hz, 1H), 7.51-7.71
(m, 6H), 6.90-7.01 (m, 1H) 180 400 MHz 8.50 (d, J = 4.7 Hz, 1H),
7.91 (d, J = 7.2 Hz, 2H), 7.61-7.71 (m, d.sub.4-MeOH 5H), 7.54-7.61
(m, 1H), 7.40-7.54 (m, 3H), 6.76 (s, 1H) 181 400 MHz 8.94 (d, J =
3.9 Hz, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.97-8.06 (m, d.sub.4-MeOH
2H), 7.81-7.90 (m, 2H), 7.64-7.70 (m, 2H), 7.57-7.63 (m, 3H), 6.94
(s, 1H) 182 400 MHz 8.94 (s, 2H), 8.68 (s, 1H), 8.45 (s, 1H), 8.21
(d, J = 8.0 Hz, 1H), d.sub.4-MeOH 7.63-7.69 (m, 2H), 7.55-7.62 (m,
3H), 6.93 (s, 1H), 2.51 (s, 3H) 183 400 MHz 8.93 (d, J = 4.5 Hz,
1H), 8.21 (d, J = 8.0 Hz, 1H), 7.93 (dd, J = 8.8, d.sub.4-MeOH 5.3
Hz, 2H), 7.62-7.68 (m, 2H), 7.54-7.62 (m, 3H), 7.21 (t, J = 8.7 Hz,
2H), 6.93 (s, 1H) 184 400 MHz 8.52 (d, J = 4.7 Hz, 1H), 8.27-8.33
(m, 1H), 8.21 (dt, J = 7.9, d.sub.4-MeOH 1.4 Hz, 1H), 7.95 (dt, J =
7.8, 1.3 Hz, 1H), 7.58-7.75 (m, 6H), 7.40-7.53 (m, 1H), 6.79 (s,
1H) 185 400 MHz 8.92 (d, J = 4.3 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H),
7.78-7.91 (m, d.sub.4-MeOH 2H), 7.61-7.68 (m, 2H), 7.54-7.61 (m,
3H), 7.46-7.51 (m, 2H), 6.91 (s, 1H) 186 400 MHz 8.93 (d, J = 4.7
Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.62-7.67 (m, d.sub.4-MeOH 2H),
7.54-7.62 (m, 3H), 7.26-7.34 (m, 1H), 7.22 (s, 1H), 7.14 (d, J =
7.6 Hz, 1H), 6.90-6.98 (m, 2H), 2.98 (s, 6H) 187 400 MHz 8.50 (d, J
= 4.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.59-7.69 (m, d.sub.4-MeOH
6H), 7.52 (td, J = 8.0, 5.8 Hz, 1H), 7.45 (dt, J = 8.5, 4.4 Hz,
1H), 7.32 (td, J = 8.4, 2.0 Hz, 1H), 6.76 (br. s., 1H) 188 400 MHz
8.99-9.05 (m, 1H), 8.94 (d, J = 4.1 Hz, 1H), 8.71 (dd, J = 4.9,
d.sub.4-MeOH 1.6 Hz, 1H), 8.26-8.33 (m, 1H), 8.22 (dd, J = 7.9, 0.9
Hz, 1H), 7.64-7.69 (m, 2H), 7.58-7.63 (m, 3H), 7.56 (ddd, J = 7.9,
5.0, 0.8 Hz, 1H), 6.96 (s, 1H) 189 400 MHz 8.94 (d, J = 4.5 Hz,
1H), 8.50 (s, 1H), 8.21 (t, J = 7.5 Hz, 2H), d.sub.4-MeOH 8.10 (d,
J = 7.6 Hz, 1H), 7.53-7.71 (m, 6H), 6.95 (s, 1H), 3.95 (s, 3H) 190
400 MHz 8.96 (d, J = 4.3 Hz, 1H), 8.24 (s, 1H), 8.20-8.23 (m, 1H),
d.sub.4-MeOH 7.60-7.70 (m, 3H), 7.55-7.59 (m, 2H), 6.87 (s, 1H),
2.47 (s, 3H) 191 400 MHz 8.94 (d, J = 4.1 Hz, 1H), 8.23 (d, J = 8.2
Hz, 1H), 7.63-7.68 (m, d.sub.4-MeOH 2H), 7.55-7.63 (m, 3H),
7.34-7.48 (m, 3H), 7.13 (dt, J = 6.7, 1.3 Hz, 1H), 6.94 (s, 1H),
3.86 (s, 3H) 192 400 MHz 8.95 (d, J = 4.7 Hz, 1H), 8.21 (d, J = 8.2
Hz, 1H), 7.51-7.69 (m, d.sub.4-MeOH 6H), 6.86 (s, 1H), 6.73 (d, J =
2.3 Hz, 1H), 3.96 (s, 3H) 193 400 MHz 8.51 (d, J = 4.7 Hz, 1H),
7.91 (d, J = 7.2 Hz, 2H), 7.62-7.70 (m, d.sub.4-MeOH 5H), 7.55-7.61
(m, 1H), 7.42-7.54 (m, 3H), 6.76 (s, 1H) 194 400 MHz 8.71 (d, J =
4.3 Hz, 1H), 8.54 (d, J = 4.5 Hz, 1H), 8.10 (d, J = 7.8 Hz,
d.sub.4-MeOH 1H), 7.97 (td, J = 7.7, 1.7 Hz, 1H), 7.55-7.70 (m,
6H), 7.46 (dt, J = 8.5, 4.4 Hz, 1H), 6.68 (s, 1H) 195 400 MHz 9.67
(d, J = 7.6 Hz, 1H), 9.01 (dd, J = 4.1, 1.8 Hz, 1H), d.sub.6-DMSO
8.59-8.71 (m, 2H), 8.45 (dd, J = 8.3, 0.9 Hz, 1H), 8.17 (dd, J =
8.1, 1.5 Hz, 1H), 8.08 (s, 2H), 7.71-7.80 (m, 2H), 7.59-7.69 (m,
3H), 7.38 (dd, J = 8.0, 4.7 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H) 196
400 MHz 8.94 (d, J = 4.1 Hz, 1H), 8.22 (d, J = 7.0 Hz, 1H),
7.73-7.84 (m, d.sub.4-MeOH 2H), 7.51-7.69 (m, 5H), 6.95 (s, 1H),
6.71-6.81 (m, 2H), 3.05 (s, 6H) 197 400 MHz 8.90 (d, J = 4.5 Hz,
1H), 8.20 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.6 Hz, d.sub.4-MeOH
1H), 7.71-7.79 (m, 2H), 7.60-7.70 (m, 5H), 7.57 (dd, J = 7.8, 4.9
Hz, 1H), 6.92 (s, 1H) 198 400 MHz 8.86 (d, J = 2.2 Hz, 1H), 8.61
(d, J = 2.2 Hz, 1H), 8.52 (d, J = 4.7 Hz, d.sub.4-MeOH 1H),
7.59-7.73 (m, 5H), 7.47 (dt, J = 8.5, 4.4 Hz, 1H), 6.78 (s, 1H) 199
400 MHz 8.78 (d, J = 4.1 Hz, 1H), 7.98-8.11 (m, 2H), 7.50 (d, J =
8.4 Hz, d.sub.4-MeOH 2H), 7.42-7.47 (m, 2H), 7.40 (d, J = 8.2 Hz,
2H), 6.77 (s, 1H), 6.74 (d, J = 1.0 Hz, 1H) 200 400 MHz 8.51 (d, J
= 4.7 Hz, 1H), 8.02-8.10 (m, 2H), 7.85-7.91 (m, d.sub.4-MeOH 2H),
7.62-7.72 (m, 5H), 7.47 (dt, J = 8.6, 4.4 Hz, 1H), 6.78 (s, 1H) 201
400 MHz 8.72 (dd, J = 5.3, 0.8 Hz, 1H), 8.15-8.25 (m, 2H), 8.08
(dd, J = 9.6, d.sub.4-MeOH 2.7 Hz, 1H), 7.71-7.78 (m, 3H), 7.69
(dd, J = 7.0, 5.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 6.54-6.63 (m,
2H) 202 400 MHz 8.95-9.05 (m, 2H), 8.69 (d, J = 2.0 Hz, 1H),
8.50-8.58 (m, d.sub.4-MeOH 1H), 8.32 (dd, J = 8.8, 2.0 Hz, 1H),
8.18-8.25 (m, 1H), 7.61-7.75 (m, 5H), 7.49 (dt, J = 8.5, 4.4 Hz,
1H), 6.86 (s, 1H) 203 400 MHz 9.05 (d, J = 1.8 Hz, 1H), 8.71 (dd, J
= 5.0, 1.5 Hz, 1H), 8.49 (d, d.sub.4-MeOH J = 4.7 Hz, 1H), 8.32
(dt, J = 8.0, 2.0 Hz, 1H), 7.59-7.69 (m, 5H), 7.56 (dd, J = 7.8,
5.1 Hz, 1H), 7.45 (dt, J = 8.5, 4.4 Hz, 1H), 6.78 (s, 1H) 204 400
MHz 8.99 (dd, J = 4.5, 1.6 Hz, 1H), 8.60 (s, 1H), 8.52 (d, J = 6.1
Hz, d.sub.4-MeOH 2H), 8.11 (s, 2H), 7.61-7.74 (m, 6H), 7.47 (dt, J
= 8.5, 4.4 Hz, 1H), 6.83 (s, 1H) 205 400 MHz 8.99 (d, J = 4.7 Hz,
1H), 8.78 (d, J = 1.8 Hz, 1H), 8.12-8.29 (m, d.sub.4-MeOH 2H), 8.05
(d, J = 8.2 Hz, 1H), 7.55-7.68 (m, 5H), 6.87 (s, 1H) 206 400 MHz
9.10 (d, J = 1.4 Hz, 1H), 8.92 (d, J = 4.5 Hz, 1H), 8.38 (dd, J =
8.1, d.sub.4-MeOH 2.2 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.97 (dd,
J = 8.0, 0.6 Hz, 1H), 7.62-7.69 (m, 2H), 7.55-7.62 (m, 3H), 6.92
(s, 1H) 207 400 MHz 8.55 (s, 1H), 8.50 (d, J = 4.7 Hz, 1H), 8.21
(d, J = 7.8 Hz, 1H), d.sub.4-MeOH 8.12 (d, J = 8.2 Hz, 1H),
7.55-7.70 (m, 6H), 7.45 (dt, J = 8.6, 4.3 Hz, 1H), 6.77 (s, 1H) 208
400 MHz 8.92 (d, J = 4.7 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.87
(s, 1H), d.sub.4-MeOH 7.79 (d, J = 7.8 Hz, 1H), 7.61-7.67 (m, 2H),
7.53-7.61 (m, 4H), 7.42-7.50 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H) 209
400 MHz 8.50 (d, J = 4.7 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H),
7.59-7.69 (m, d.sub.4-MeOH 6H), 7.53 (td, J = 8.0, 5.8 Hz, 1H),
7.46 (dt, J = 8.5, 4.4 Hz, 1H), 7.29-7.37 (m, 1H), 6.76 (s, 1H) 210
400 MHz 8.97 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 2.9 Hz, 1H), 8.21
(d, J = 7.2 Hz, d.sub.4-MeOH 1H), 8.07 (d, J = 8.6 Hz, 1H),
7.54-7.68 (m, 5H), 7.48 (dd, J = 8.7, 2.8 Hz, 1H), 6.86 (s, 1H),
3.94 (s, 3H) 211 400 MHz 8.94 (d, J = 4.1 Hz, 1H), 8.18-8.26 (m,
2H), 8.15 (d, J = 7.6 Hz, d.sub.4-MeOH 1H), 7.88 (d, J = 7.8 Hz,
1H), 7.64-7.74 (m, 3H), 7.55-7.64 (m, 3H), 6.96 (s, 1H) 212 400 MHz
9.53 (dd, J = 2.2, 1.3 Hz, 1H), 9.36 (dd, J = 5.3, 1.2 Hz, 1H),
d.sub.4-MeOH 8.93 (d, J = 4.5 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H),
8.06 (dd, J = 5.4, 2.2 Hz, 1H), 7.63-7.68 (m, 2H), 7.55-7.62 (m,
3H), 6.92 (s, 1H) 213 400 MHz 10.13 (s, 1H), 9.24 (d, J = 7.6 Hz,
1H), 8.45 (d, J = 4.7 Hz, 1H), d.sub.6-DMSO 7.92 (d, J = 8.8 Hz,
2H), 7.74-7.81 (m, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2
Hz, 2H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H),
6.73 (d, J = 7.6 Hz, 1H), 3.06 (s, 3H) 214 400 MHz .sup.1H NMR
(MeOH): 8.52 (d, J = 4.7 Hz, 1H), 7.61-7.71 (m, d.sub.4-MeOH 5H),
7.36-7.53 (m, 4H), 7.10-7.19 (m, 1H), 6.77 (s, 1H), 3.87 (s, 3H)
215 400 MHz 9.01 (d, J = 4.1 Hz, 1H), 8.17-8.28 (m, 2H), 7.59-7.69
(m, d.sub.4-MeOH 6H), 7.43-7.53 (m, 1H), 7.32 (t, J = 7.2 Hz, 1H),
6.98 (s, 1H), 4.18 (s, 3H) 216 400 MHz 8.50 (d, J = 4.7 Hz, 1H),
8.47 (s, 1H), 8.24 (d, J = 7.8 Hz, 1H), d.sub.4-MeOH 8.15 (d, J =
7.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.60-7.70 (m, 5H), 7.46 (dt,
J = 8.5, 4.4 Hz, 1H), 6.79 (s, 1H), 3.17 (s, 3H) 217 400 MHz 8.50
(d, J = 4.7 Hz, 1H), 8.10-8.14 (m, 2H), 8.05-8.10 (m, d.sub.4-MeOH
2H), 7.58-7.72 (m, 5H), 7.46 (dt, J = 8.5, 4.4 Hz, 1H), 6.77 (s,
1H), 3.17 (s, 3H) 218 400 MHz 8.86 (d, J = 4.3 Hz, 1H), 8.16 (d, J
= 8.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, d.sub.4-MeOH 2H), 7.55 (dd, J =
7.8, 4.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.20-7.35 (m, 5H), 6.70
(s, 1H), 3.64 (s, 2H) 219 400 MHz 8.94 (d, J = 3.9 Hz, 1H), 8.22
(dd, J = 8.0, 1.2 Hz, 1H), d.sub.4-MeOH 7.86-7.94 (m, 1H), 7.80 (s,
1H), 7.64-7.68 (m, 2H), 7.56-7.63 (m, 4H), 7.47-7.53 (m, 1H), 6.94
(s, 1H) 220 400 MHz 8.96 (d, J = 4.9 Hz, 1H), 8.54 (d, J = 1.8 Hz,
1H), 8.22 (d, J = 7.2 Hz, d.sub.4-MeOH 1H), 7.53-7.69 (m, 5H), 7.06
(d, J = 2.0 Hz, 1H), 6.88 (s, 1H) 221 400 MHz 8.50 (d, J = 4.5 Hz,
1H), 8.23 (s, 1H), 7.57-7.69 (m, 5H), d.sub.4-MeOH 7.46 (dt, J =
8.5, 4.4 Hz, 1H), 6.65 (s, 1H), 2.45 (s, 3H) 222 400 MHz 8.96 (d, J
= 4.5 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.10-8.15 (m, d.sub.4-MeOH
1H), 7.86-7.98 (m, 2H), 7.64-7.70 (m, 2H), 7.57-7.63 (m, 3H),
7.39-7.50 (m, 2H), 6.94 (s, 1H) 223 400 MHz 8.89 (d, J = 4.1 Hz,
1H), 8.17 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.8 Hz, d.sub.4-MeOH
2H), 7.47-7.58 (m, 3H), 6.69 (s, 1H), 2.82-3.02 (m, 1H), 2.48-2.72
(m, 1H), 2.24-2.45 (m, 2H), 1.14-2.18 (m, 5H) 224 400 MHz 8.89 (d,
J = 4.5 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.59-7.64 (m,
d.sub.4-MeOH 2H), 7.55-7.59 (m, 1H), 7.51-7.55 (m, 2H), 6.74 (s,
1H), 3.57-3.78 (m, 2H), 2.36-2.76 (m, 2H) 225 400 MHz 8.91 (d, J =
4.7 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.60-7.68 (m, d.sub.4-MeOH
2H), 7.50-7.60 (m, 3H), 6.73 (s, 1H), 3.64-4.17 (m, 4H), 3.21
(quin, J = 7.4 Hz, 1H), 2.00-2.21 (m, 2H) 226 400 MHz 9.27 (d, J =
2.0 Hz, 1H), 9.19 (d, J = 2.2 Hz, 1H), 8.95 (d, J = 3.9 Hz,
d.sub.4-MeOH 1H), 8.81 (t, J = 2.1 Hz, 1H), 8.23 (d, J = 7.4 Hz,
1H), 7.65-7.69 (m, 2H), 7.58-7.64 (m, 3H), 6.94-7.00 (m, 1H) 227
400 MHz 8.94 (d, J = 4.1 Hz, 1H), 8.22 (dd, J = 8.1, 0.9 Hz, 1H),
d.sub.4-MeOH 7.69-7.75 (m, 1H), 7.56-7.68 (m, 6H), 7.51 (td, J =
8.0, 5.6 Hz, 1H), 7.28-7.37 (m, 1H), 6.94 (s, 1H) 228 400 MHz 9.00
(d, J = 4.5 Hz, 1H), 8.68 (d, J = 4.7 Hz, 1H), 8.23 (d, J = 8.0 Hz,
d.sub.4-MeOH 1H), 8.14 (s, 1H), 7.99 (td, J = 7.7, 1.6 Hz, 1H),
7.53-7.69 (m, 6H), 6.90 (s, 1H) 229 400 MHz 8.91 (d, J = 4.5 Hz,
1H), 8.18 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, d.sub.4-MeOH
2H), 7.50-7.60 (m, 3H), 6.71 (s, 1H), 3.95-4.09 (m, 2H), 3.59-3.68
(m, 2H), 2.86-2.97 (m, 1H), 2.64 (d, J = 7.8 Hz, 2H), 1.44 (s, 9H)
230 400 MHz 9.28 (d, J = 2.2 Hz, 1H), 8.97 (d, J = 3.9 Hz, 1H),
8.89 (d, J = 1.6 Hz, d.sub.4-MeOH 1H), 8.24 (d, J = 7.2 Hz, 1H),
8.11 (t, J = 9.1 Hz, 2H), 7.84-7.97 (m, 1H), 7.57-7.77 (m, 6H),
7.03 (s, 1H) 231 400 MHz 8.94 (d, J = 4.3 Hz, 1H), 8.20-8.25 (m,
1H), 7.96-8.02 (m, d.sub.4-MeOH 2H), 7.64-7.70 (m, 2H), 7.55-7.63
(m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H) 232 300 MHz 8.94
(d, J = 3.1 Hz, 1 H), 8.56 (s, 1 H), 8.43 (d, J = 8.0 Hz, 1 H),
d.sub.4-MeOH 8.06 (s, 2 H), 7.53-7.74 (m, 6 H), 7.34 (dd, J = 7.6,
5.0 Hz, 1 H), 6.91 (s, 1 H), 1.70 (t, J = 7.1 Hz, 1 H), 1.52 (s, 3
H), 0.87-1.01 (m, 2 H), 0.83 (s, 3 H) 233 400 MHz 8.90-9.00 (m, 1
H), 8.44-8.62 (m, 3 H), 8.25 (dd, J = 8.9, 1.9 Hz, d.sub.4-MeOH 1
H), 8.13 (d, J = 8.8 Hz, 1 H), 7.52-7.73 (m, 6 H), 7.35 (dd, J =
7.7, 4.8 Hz, 1 H), 6.95 (s, 1 H), 1.62-1.76 (m, 1 H), 1.54 (s, 3
H), 0.86-0.98 (m, 2 H), 0.77-0.86 (m, 3 H) 234 400 MHz 8.94 (d, J =
4.5 Hz, 1 H), 8.20 (d, J = 8.0 Hz, 1 H), d.sub.4-MeOH 7.57-7.69 (m,
3 H), 7.51 (d, J = 8.0 Hz, 2 H), 6.68 (s, 1 H), 4.28-4.42 (m, 1 H),
4.03 (q, J = 6.5 Hz, 1 H), 3.91 (q, J = 6.8 Hz, 1 H), 2.18-2.36 (m,
1 H), 1.74-2.01 (m, 3 H) 235 400 MHz 8.37 (d, J = 4.5 Hz, 1H),
7.52-7.66 (m, 3H), 7.46 (d, J = 8.0 Hz, d.sub.4-MeOH 2H), 7.14-7.34
(m, 6H), 6.46 (s, 1H), 5.80 (ddt, J = 16.8, 10.4, 6.2 Hz, 1H), 4.97
(d, J = 10.0 Hz, 1H), 4.89 (d, J = 17.2 Hz, 1H), 3.81 (q, J = 7.0
Hz, 1H), 3.32-3.44 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H) 236 400 MHz
8.89-9.01 (m, 1 H), 8.56-8.61 (m, 1 H), 8.48-8.56 (m, 2 H),
d.sub.4-MeOH 8.23 (dd, J = 8.9, 1.9 Hz, 1 H), 8.13 (d, J = 8.8 Hz,
1 H),
7.70 (d, J = 7.8 Hz, 1 H), 7.54-7.66 (m, 5 H), 7.35 (dd, J = 7.6,
4.7 Hz, 1 H), 6.96 (s, 1 H), 2.93 (d, J = 13.7 Hz, 1 H), 2.51-2.78
(m, 1 H), 1.03 (s, 9 H) 237 300 MHz 8.86 (d, J = 4.5 Hz, 1 H), 8.17
(d, J = 8.0 Hz, 1 H), d.sub.4-MeOH 7.28-7.67 (m, 10 H), 6.68 (s, 1
H), 3.38 (s, 3 H) 238 300 MHz 8.87 (d, J = 4.5 Hz, 1 H), 8.45 (s, 1
H), 8.40 (d, J = 4.5 Hz, 1 H), d.sub.4-MeOH 8.14 (d, J = 7.9 Hz, 1
H), 7.75 (d, J = 7.7 Hz, 1 H), 7.57-7.63 (m, 2 H), 7.52-7.57 (m, 1
H), 7.44-7.52 (m, 2 H), 7.36 (dd, J = 7.7, 5.0 Hz, 1 H), 6.68 (s, 1
H), 3.68 (s, 2 H) 239 400 MHz 9.11 (s, 1H), 8.92 (d, J = 3.9 Hz,
1H), 8.52 (d, J = 1.5 Hz, 1H), CDCl.sub.3 8.32 (d, J = 7.7 Hz, 1H),
8.18 (d, J = 8.5 Hz, 1H), 8.02-8.09 (m, 1H), 7.95 (dd, J = 8.6, 1.7
Hz, 1H), 7.52-7.63 (m, 4H), 7.48 (dd, J = 7.7, 5.1 Hz, 1H), 6.93
(d, J = 7.7 Hz, 1H) 240 400 MHz 8.85 (dd, J = 4.7, 1.2 Hz, 1H),
8.32 (d, J = 7.9 Hz, 1H), 7.99 (dd, CDCl.sub.3 J = 8.0, 1.0 Hz,
1H), 7.44-7.58 (m, 4H), 7.41 (dd, J = 7.7, 5.0 Hz, 1H), 6.64 (d, J
= 8.2 Hz, 1H), 3.24 (s, 3H), 1.35 (s, 3H), 1.35 (s, 3H) 241 400 MHz
8.84 (d, J = 4.2 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.35-7.59 (m,
CDCl.sub.3 6H), 6.69 (d, J = 7.7 Hz, 1H), 3.51 (d, J = 6.9 Hz, 2H),
2.29-2.49 (m, 1H), 1.76-1.94 (m, 2H), 1.36-1.76 (m, 7H) 242 400 MHz
8.87 (d, J = 4.2 Hz, 1H), 8.13 (d, J = 7.7 Hz, 1H), 7.49-7.61 (m,
CDCl.sub.3 4H), 7.46 (d, J = 8.3 Hz, 2H), 6.70 (d, J = 7.7 Hz, 1H),
3.49-3.68 (m, 1H), 2.18 (tt, J = 11.9, 3.5 Hz, 1H), 1.86-2.10 (m,
3H), 1.42-1.65 (m, 2H), 1.17-1.38 (m, 2H) 243 400 MHz 8.84 (d, J =
4.2 Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 7.2 Hz,
CDCl.sub.3 1H), 7.35-7.62 (m, 5H), 6.65 (d, J = 7.5 Hz, 1H), 1.54
(s, 3H), 1.51 (s, 3H) 244 300 MHz 8.83 (d, J = 3.9 Hz, 1H), 8.01
(d, J = 8.2 Hz, 1H), 7.35-7.60 (m, CDCl.sub.3 6H), 6.68 (d, J = 7.9
Hz, 1H), 2.59 (t, J = 4.6 Hz, 1H), 2.20-2.38 (m, 1H), 2.01-2.20 (m,
2H), 1.75 (d, J = 5.1 Hz, 3H), 1.48-1.66 (m, 2H) 245 400 MHz 8.58
(d, J = 4.3 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.81-7.88 (m,
NCCD.sub.3 1H), 7.73-7.81 (m, 2H), 7.18-7.39 (m, 6H), 6.54 (d, J =
7.6 Hz, 1H), 2.81-2.92 (m, 2H), 2.32-2.41 (m, 2H) 246 400 MHz 9.58
(d, J = 7.4 Hz, 1H), 8.89 (d, J = 3.9 Hz, 1H), 8.22-8.30 (m,
d.sub.6-DMSO 2H), 8.19 (dt, J = 7.8, 1.3 Hz, 1H), 7.87 (dt, J =
7.7, 1.2 Hz, 1H), 7.48-7.78 (m, 11H), 6.81 (d, J = 7.4 Hz, 1H) 247
400 MHz 9.86 (s, 1H), 8.83 (s, 1H), 8.72 (d, J = 4.7 Hz, 1H),
d.sub.4-MeOH 8.64-8.70 (m, 1H), 8.56-8.64 (m, 2H), 8.43 (dd, J =
8.7, 1.5 Hz, 1H), 8.16 (td, J = 7.8, 1.6 Hz, 1H), 7.75 (d, J = 8.0
Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.61-7.67 (m, 1H), 7.58 (d, J =
8.4 Hz, 1H), 7.42 (dd, J = 8.3, 2.1 Hz, 1H), 6.58 (s, 1H) 248 300
MHz 9.10 (d, J = 7.7 Hz, 1H), 8.57 (dd, J = 4.7, 1.5 Hz, 1H), 8.15
(d, d.sub.6-DMSO J = 2.5 Hz, 1H), 7.97 (dd, J = 8.1, 1.4 Hz, 1H),
7.90 (dd, J = 9.6, 2.6 Hz, 1H), 7.64-7.76 (m, J = 8.3 Hz, 2H),
7.48-7.62 (m, J = 8.2 Hz, 2H), 7.43 (dd, J = 8.1, 4.6 Hz, 1H), 6.77
(d, J = 7.7 Hz, 1H), 6.33 (d, J = 9.6 Hz, 1H) 249 300 MHz 9.03 (d,
J = 7.7 Hz, 1H), 8.58 (dd, J = 4.6, 1.4 Hz, 1H), 8.50 (d,
d.sub.6-DMSO J = 2.5 Hz, 1H), 7.99 (dd, J = 8.2, 1.5 Hz, 1H), 7.90
(dd, J = 9.5, 2.6 Hz, 1H), 7.65-7.78 (m, J = 8.2 Hz, 2H), 7.51-7.62
(m, J = 8.2 Hz, 2H), 7.43 (dd, J = 8.2, 4.7 Hz, 1H), 6.79 (d, J =
7.9 Hz, 1H), 6.39 (d, J = 9.5 Hz, 1H), 3.47 (s, 3H) 250 300 MHz
9.10 (d, J = 7.7 Hz, 1H), 8.38-8.50 (m, 1H), 8.15 (d, J = 2.5 Hz,
d.sub.6-DMSO 1H), 7.89 (dd, J = 9.6, 2.8 Hz, 1H), 7.75 (ddd, J =
10.1, 8.6, 1.2 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 8.3
Hz, 1H), 7.42-7.54 (m, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 6.61
(d, J = 7.9 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H) 251 300 MHz 9.05 (d,
J = 7.9 Hz, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.40-8.47 (m,
d.sub.6-DMSO 1H), 7.90 (dd, J = 9.5, 2.6 Hz, 1H), 7.76 (ddd, J =
10.0, 8.5, 1.3 Hz, 1H), 7.69 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.3
Hz, 1H), 7.47 (dt, J = 8.6, 4.3 Hz, 1H), 7.39 (dd, J = 8.3, 2.0 Hz,
1H), 6.63 (d, J = 7.6 Hz, 1H), 6.40 (d, J = 9.5 Hz, 1H), 3.47 (s,
3H) 252 300 MHz 8.51 (d, J = 4.8 Hz, 1H), 8.44 (d, J = 7.0 Hz, 1H),
8.25 (d, J = 2.3 Hz, CDCl.sub.3 1H), 7.88 (dd, J = 9.5, 2.5 Hz,
1H), 7.53-7.65 (m, 1H), 7.36-7.50 (m, 3H), 7.17 (d, J = 8.2 Hz,
2H), 6.78 (d, J = 9.5 Hz, 1H), 6.66 (d, J = 7.2 Hz, 1H), 3.66 (s,
3H) 253 300 MHz 9.18 (s, 1H), 9.00 (d, J = 6.6 Hz, 1H), 8.52 (d, J
= 4.4 Hz, 1H), CDCl.sub.3 8.16-8.39 (m, 2H), 7.94 (d, J = 14.3 Hz,
2H), 7.49-7.73 (m, 5H), 7.36-7.49 (m, 1H), 6.68 (d, J = 5.4 Hz, 1H)
254 300 MHz 9.15 (s, 1H), 8.93 (d, J = 4.1 Hz, 1H), 8.77 (d, J =
7.2 Hz, 1H), CDCl.sub.3 8.04-8.38 (m, 3H), 7.94 (d, J = 18.1 Hz,
2H), 7.38-7.65 (m, 5H), 6.86 (d, J = 7.3 Hz, 1H) 255 300 MHz
8.39-8.56 (m, 1H), 8.08-8.34 (m, 2H), 7.72 (dd, J = 9.5, 2.6 Hz,
CDCl.sub.3 1H), 7.27-7.54 (m, 4H), 7.14 (d, J = 7.9 Hz, 2H),
6.35-6.73 (m, 2H), 4.03 (dd, J = 7.2, 3.7 Hz, 2H), 1.37 (t, J = 7.2
Hz, 3H) 256 300 MHz 9.09 (d, J = 3.5 Hz, 1H), 8.79 (d, J = 8.2 Hz,
1H), 8.64 (s, 1H), d.sub.4-MeOH 8.36 (d, J = 7.7 Hz, 1H), 8.19 (d,
J = 9.1 Hz, 1H), 7.83 (dd, J = 8.3, 4.7 Hz, 1H), 7.70 (d, J = 8.2
Hz, 3H), 7.52 (d, J = 8.2 Hz, 2H), 7.33-7.47 (m, 2H), 7.30 (d, J =
7.6 Hz, 1H), 6.88 (s, 1H) 257 400 MHz 8.97 (dd, J = 4.1, 1.6 Hz,
1H), 8.43 (s, 1H), 8.19-8.26 (m, 1H), CDCl.sub.3 8.07 (dd, J = 8.5,
1.7 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H),
7.60 (q, J = 7.0 Hz, 2H), 7.48-7.54 (m, 2H), 7.38 (d, J = 7.8 Hz,
1H), 7.11-7.25 (m, 2H), 6.83-6.93 (m, 2H) 258 300 MHz 9.03 (d, J =
7.7 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 8.04 (dd, J = 9.6,
d.sub.4-MeOH 2.6 Hz, 1H), 7.59-7.72 (m, J = 8.2 Hz, 2H), 7.46-7.54
(m, J = 8.2 Hz, 2H), 7.36-7.46 (m, 1H), 7.05 (t, J = 8.4 Hz, 2H),
6.87 (d, J = 4.8 Hz, 1H), 6.53 (d, J = 9.5 Hz, 1H) 259 300 MHz
9.01-9.16 (m, 2H), 8.80 (d, J = 8.3 Hz, 1H), 8.66 (s, 1H),
d.sub.4-MeOH 8.36 (d, J = 9.2 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H),
7.83 (dd, J = 8.5, 4.7 Hz, 1H), 7.57-7.73 (m, 4H), 6.79 (s, 1H) 260
300 MHz 9.14 (dd, J = 4.8, 1.3 Hz, 1H), 8.76-8.92 (m, 3H), 8.61 (s,
1H), d.sub.4-MeOH 8.17-8.32 (m, 2H), 7.92 (dd, J = 8.4, 4.9 Hz,
1H), 7.84 (d, J = 5.1 Hz, 1H), 7.68-7.79 (m, J = 8.2 Hz, 2H),
7.46-7.58 (m, J = 8.0 Hz, 2H), 6.99 (s, 1H) 261 400 MHz 9.00 (dd, J
= 4.2, 1.5 Hz, 1H), 8.84 (d, J = 4.7 Hz, 1H), 8.62 (s, CDCl.sub.3
1H), 8.26 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 7.6 Hz, 1H), 8.13 (dd,
J = 8.4, 1.6 Hz, 1H), 8.06 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.4
Hz, 1H), 7.44-7.51 (m, 2H), 7.35-7.42 (m, 2H), 7.20-7.30 (m, 3H),
6.79 (d, J = 8.0 Hz, 1H) 287 400 MHz 11.99 (br. s., 1H), 9.14 (d, J
= 7.8 Hz, 1H), 8.44 (d, J = 4.7 Hz, DMSO-d.sub.6 1H), 8.16 (d, J =
2.5 Hz, 1H), 7.90 (dd, J = 9.6, 2.7 Hz, 1H), 7.73-7.80 (m, 1H),
7.71 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.47 (dt, J =
8.5, 4.3 Hz, 1H), 6.69 (d, J = 7.8 Hz, 1H), 6.33 (d, J = 9.6 Hz,
1H) 288 400 MHz 9.31 (d, J = 8.0 Hz, 1H), 8.47 (t, J = 2.8 Hz, 2H),
7.37-7.42 (m, DMSO-d.sub.6 1H), 7.69-7.81 (m, 2H), 7.45-7.65 (m,
3H), 7.26-7.32 (m, 3H), 3.65 (s, 2H) 289 400 MHz 8.54 (s, 2H),
8.35-8.37 (d, J = 4.8 Hz, 1H), 7.78 (d, J = 6.8 Hz, DMSO-d.sub.6
1H), 7.67 (d, J = 7.6 Hz, 1H), 7.37-7.42 (m, 1H), 7.28-7.32 (m,
2H), 7.13-7.20 (m, 3H), 6.38 (dd, J = 6.8 Hz, 1H), 3.65 (s, 2H) 290
400 MHz 9.33 (d, J = 8.4 Hz, 1H), 8.45-8.46 (m, 3H), 7.76 (m, 1H),
DMSO-d.sub.6 7.50-7.55 (m, 1H), 7.46-7.48 (m, 2H), 7.25-7.28 (m,
3H), 6.47 (d, J = 8.0 Hz, 1H), 3.64 (s, 2H) 291 400 MHz 12.00 (s,
1H), 9.19 (d, J = 8.0 Hz, 1H), 8.19 (s, 1H), DMSO-d.sub.6 7.99-8.03
(m, 1H), 7.90 (dd, J = 9.6, 2.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H),
7.64 (d, J = 8.0 Hz, 2H), 7.27-7.29 (m, 1H), 6.65 (d, J = 7.6 Hz,
1H), 6.38 (d, J = 9.6 Hz, 1H) 292 400 MHz 12.05 (br. s., 1H), 9.07
(d, J = 8.0 Hz, 1H), 8.55 (d, J = 2.8 Hz, DMSO-d.sub.6 1H), 8.15
(br. s., 1H), 7.91 (dd, J = 9.6, 2.4 Hz, 1H,), 7.73-7.78 (m, 1H),
7.52-7.61 (m, 3H) 7.32 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 8.0 Hz,
1H), 6.35 (d, J = 9.6 Hz, 1H) 293 400 MHz 12.02 (br. s., 1H), 9.05
(d, J = 8.0 Hz, 1H), 8.55 (dd, J = 4.7, 0.8 Hz, DMSO-d.sub.6 1H),
8.16 (d, J = 2.3 Hz, 1H), 7.91 (dd, J = 9.7, 2.6 Hz, 1H), 7.82 (td,
J = 7.7, 1.8 Hz, 1H), 7.46-7.63 (m, 3H), 7.22-7.39 (m, 2H),
6.27-6.50 (m, 2H) 294 400 MHz 8.63 (d, J = 4.7 Hz, 1H), 8.38 (d, J
= 5.9 Hz, 1H), 8.14 (d, J = 2.3 Hz, CDCl.sub.3 1H), 7.64-7.84 (m,
2H), 7.27-7.32 (m, 1H), 7.16-7.25 (m, 3H), 6.60 (d, J = 9.6 Hz,
1H), 6.19 (d, J = 6.1 Hz, 1H), 3.60 (s, 3H) 295 400 MHz 12.02 (br.
s., 1H), 9.02 (d, J = 7.4 Hz, 1H), 8.14 (br. s., 1H), DMSO-d.sub.6
7.90 (d, J = 9.4 Hz, 1H), 7.51-7.65 (m, 1H), 7.30-7.50 (m, 3H),
7.12-7.29 (m, 3H), 6.58 (d, J = 7.4 Hz, 1H), 6.35 (d, J = 9.4 Hz,
1H) 296 400 MHz 8.15 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 9.6, 2.5
Hz, 1H), CDCl.sub.3 7.30-7.42 (m, 2H), 6.97-7.26 (m, 5H), 6.71 (d,
J = 8.0 Hz, 1H), 6.55 (dd, J = 8.8, 4.1 Hz, 2H), 3.60 (s, 3H) 297
400 MHz 9.08 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 20.0 Hz, 2H), 7.94
(d, J = 9.2 Hz, DMSO-d.sub.6 1H), 7.77 (br. s., 1H), 7.43-7.65 (m,
3H), 7.33 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 7.0 Hz, 1H), 6.40 (d, J
= 8.8 Hz, 1H), 4.91 (br. s., 1H), 3.97 (br. s., 2H), 3.63 (br. s.,
2H) 298 400 MHz 9.10 (d, J = 7.8 Hz, 1H), 8.31-8.60 (m, 2H), 7.94
(dd, J = 9.5, DMSO-d.sub.6 2.6 Hz, 1H), 7.77 (ddd, J = 9.9, 8.6,
1.1 Hz, 1H), 7.42-7.66 (m, 3H), 7.33 (d, J = 8.4 Hz, 1H), 6.69 (d,
J = 7.6 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 4.94 (d, J = 5.3 Hz,
1H), 4.08 (dd, J = 12.9, 3.3 Hz, 1H), 3.82-3.97 (m, 1H), 3.55 (dd,
J = 12.8, 8.5 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H) 299 400 MHz 9.07
(d, J = 7.0 Hz, 1H), 8.32-8.59 (m, 2H), 7.95 (d, J = 9.6 Hz,
DMSO-d.sub.6 1H), 7.76 (t, J = 9.1 Hz, 1H), 7.39-7.63 (m, 3H), 7.33
(d, J = 8.2 Hz, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.39 (d, J = 9.4 Hz,
1H), 4.91 (br. s., 1H), 4.07 (d, J = 12.7 Hz, 1H), 3.90 (br. s.,
1H), 3.59 (d, J = 10.2 Hz, 1H), 1.08 (d, J = 3.5 Hz, 3H) 300 400
MHz 9.13 (d, J = 7.8 Hz, 1H), 8.34-8.54 (m, 2H), 7.95 (dd, J = 9.6,
DMSO-d.sub.6 2.7 Hz, 1H), 7.65-7.87 (m, 3H), 7.60 (d, J = 8.2 Hz,
2H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.39
(d, J = 9.6 Hz, 1H), 4.94 (d, J = 5.3 Hz, 1H), 4.07 (dd, J = 12.8,
3.2 Hz, 1H), 3.90 (td, J = 5.8, 2.5 Hz, 1H), 3.55 (dd, J = 12.9,
8.4 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H) 301 400 MHz 9.09 (d, J = 7.0
Hz, 1H), 8.26-8.63 (m, 2H), 7.95 (d, J = 9.4 Hz, DMSO-d.sub.6 1H),
7.67-7.82 (m, 3H), 7.60 (d, J = 7.0 Hz, 2H), 7.48 (d, J = 3.9 Hz,
1H), 6.71 (d, J = 6.8 Hz, 1H), 6.39 (d, J = 9.6 Hz, 1H), 4.91 (br.
s., 1H), 4.07 (d, J = 12.7 Hz, 1H), 3.90 (br. s., 1H), 3.46-3.70
(m, 1H), 1.08 (d, J = 2.9 Hz, 3H) 302 400 MHz 9.08 (d, J = 7.8 Hz,
1H), 8.24-8.60 (m, 2H), 7.97 (dd, J = 9.5, DMSO-d.sub.6 2.6 Hz,
1H), 7.76 (ddd, J = 10.0, 8.6, 1.2 Hz, 1H), 7.42-7.63 (m, 3H), 7.33
(d, J = 8.6 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.41 (d, J = 9.6 Hz,
1H), 4.80 (s, 1H), 3.92 (s, 2H), 1.06 (s, 6H) 303 400 MHz 9.12 (d,
J = 7.8 Hz, 1H), 8.43-8.53 (m, 1H), 8.39 (d, J = 2.5 Hz,
DMSO-d.sub.6 1H), 7.98 (dd, J = 9.6, 2.7 Hz, 1H), 7.68-7.84 (m,
3H), 7.60 (d, J = 8.2 Hz, 2H), 7.37-7.54 (m, 1H), 6.71 (d, J = 7.6
Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H), 4.81 (s, 1H), 3.92 (s, 2H), 1.06
(s, 6H) 304 400 MHz 9.30 (d, J = 7.8 Hz, 1H), 8.36-8.55 (m, 2H),
7.94 (dd, J = 9.5, DMSO-d.sub.6 2.4 Hz, 1H), 7.68-7.84 (m, 1H),
7.44-7.65 (m, 3H), 7.33 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 7.8 Hz,
1H), 6.42 (d, J = 9.6 Hz, 1H), 5.50 (t, J = 7.2 Hz, 1H), 4.57-5.03
(m, 4H) 305 400 MHz 9.35 (d, J = 7.8 Hz, 1H), 8.31-8.61 (m, 2H),
7.94 (dd, J = 9.6, DMSO-d.sub.6 2.5 Hz, 1H), 7.68-7.84 (m, 3H),
7.60 (d, J = 8.2 Hz, 2H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 6.76 (d,
J = 7.8 Hz, 1H), 6.42 (d, J = 9.6 Hz, 1H), 5.51 (t, J = 7.2 Hz,
1H), 4.57-5.03 (m, 4H)
306 400 MHz 8.94 (dd, J = 4.1, 1.4 Hz, 1H), 8.87 (d, J = 4.3 Hz,
1H), 8.53 (s, CDCl.sub.3 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.15 (d, J
= 7.8 Hz, 1H), 8.07 (dd, J = 8.4, 1.6 Hz, 1H), 7.99 (d, J = 7.6 Hz,
1H), 7.85 (d, J = 8.6 Hz, 1H), 7.36-7.51 (m, 4H), 7.20-7.33 (m,
3H), 6.93 (d, J = 8.0 Hz, 1H) 307 400 MHz 9.95 (s, 1 H), 9.82 (br.
s., 1 H), 8.47 (d, J = 4.7 Hz, 1 H), DMSO-d.sub.6 8.19-8.30 (m, 2
H), 7.72-7.83 (m, 3 H), 7.66-7.71 (m, 2 H), 7.50 (dt, J = 8.5, 4.4
Hz, 1 H), 6.78 (br. s., 1 H) 308 400 MHz 9.93 (br. s., 1 H), 9.38
(d, J = 7.2 Hz, 1 H), 8.82 (s, 1 H), DMSO-d.sub.6 8.47 (d, (d J =
4.7 Hz, 1 H), 7.72-7.83 (m, 4 H), 7.66-7.71 (m, 2 H), 7.50 (dt, J =
8.5, 4.4 Hz, 1 H), 6.77 (br. s., 1 H) 309 400 MHz 9.95 (s, 1 H),
9.72-9.81 (m, 1 H), 8.47 (d, J = 4.5 Hz, 1 H), DMSO-d.sub.6
8.19-8.29 (m, 2 H), 7.78 (t, J = 9.2 Hz, 1 H), 7.59 (m, J = 8.6 Hz,
2 H), 7.48 (dt, J = 8.4, 4.3 Hz, 1 H), 7.37 (m, J = 8.2 Hz, 2 H),
6.69-6.75 (m, 1 H) 310 400 MHz 9.87 (d, J = 7.4 Hz, 1 H), 9.38 (d,
J = 7.0 Hz, 1 H), 8.81 (s, 1 H), DMSO-d.sub.6 8.47 (d, J = 4.5 Hz,
1 H), 7.73-7.82 (m, 2 H), 7.58 (m, J = 8.6 Hz, 2 H), 7.45-7.52 (m,
1 H), 7.37 (m, J = 8.2 Hz, 2 H), 6.71 (d, J = 7.4 Hz, 1 H) 311 400
MHz 9.94 (s, 1 H), 9.82 (br. s., 1 H), 8.94 (d, J = 4.5 Hz, 1 H),
DMSO-d.sub.6 8.18-8.31 (m, 3 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.65
(dd, J = 7.8, 4.9 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 2 H), 6.82 (s, 1
H) 312 400 MHz 9.93 (s, 1 H), 9.37 (d, J = 7.0 Hz, 1 H), 8.94 (d, J
= 4.3 Hz, 1 H), DMSO-d.sub.6 8.80 (s, 1 H), 8.28 (d, J = 7.4 Hz, 1
H), 7.78 (dd, J = 7.1, 1.5 Hz, 1 H), 7.73 (m, J = 8.2 Hz, 2 H),
7.65 (dd, J = 8.0, 4.9 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 2 H), 6.81
(s, 1 H) 313 400 MHz 9.17 (d, J = 7.6 Hz, 1 H), 8.43 (d, J = 4.3
Hz, 1 H), 7.81 (s, 1 H), DMSO-d.sub.6 7.75 (d, J = 8.0 Hz, 1 H),
7.62-7.71 (m, 3 H), 7.59 (d, J = 8.2 Hz, 2 H), 7.27 (dd, J = 7.5,
4.8 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 6.61 (d, J = 7.6 Hz, 1 H),
2.33 (s, 3 H) 314 400 MHz 9.35 (d, J = 7.6 Hz, 1 H), 9.22 (s, 1 H),
8.44 (d, J = 4.1 Hz, 1 H), DMSO-d.sub.6 8.04 (s, 1 H), 7.56-7.72
(m, 8 H), 7.28 (dd, J = 7.5, 4.8 Hz, 1 H), 6.65 (d, J = 7.6 Hz, 1
H), 2.36 (s, 3 H) 315 400 MHz 13.09 (br. s., 1 H), 9.58 (d, J = 7.6
Hz, 1 H), 8.42-8.52 (m, 1 H), DMSO-d.sub.6 8.12 (m, 2 H), 7.92 (m,
2 H), 7.72-7.83 (m, 3 H), 7.64-7.69 (m, 2 H), 7.50 (dt, J = 8.5,
4.4 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H) 316 400 MHz 13.09 (br. s.,
1 H), 9.52 (d, J = 7.8 Hz, 1 H), 8.45-8.51 (m, 1 H), DMSO-d.sub.6
8.11 (m, 2 H), 7.92 (m, 2 H), 7.78 (ddd, J = 10.0, 8.6, 1.2 Hz, 1
H), 7.57 (m, 2 H), 7.49 (dt, J = 8.5, 4.3 Hz, 1 H), 7.37 (m, 2 H),
6.71 (d, J = 7.6 Hz, 1 H) 317 400 MHz 13.51 (s, 1 H), 9.22 (d, J =
7.4 Hz, 1 H), 8.53 (d, J = 4.7 Hz, 1 H), DMSO-d.sub.6 7.76-7.85 (m,
2 H), 7.70 (m, 2 H), 7.60 (m, 2 H), 7.53 (dt, J = 8.6, 4.4 Hz, 1
H), 6.98 (dd, J = 9.9, 2.2 Hz, 1 H), 6.51 (d, J = 6.5 Hz, 1 H) 318
400 MHz 10.31 (s, 1 H), 9.14 (d, J = 7.8 Hz, 1 H), 8.42-8.50 (m, 1
H), DMSO-d.sub.6 7.83 (s, 1 H), 7.70-7.81 (m, 4 H), 7.63 (d, J =
8.2 Hz, 2 H), 7.49 (dt, J = 8.5, 4.4 Hz, 1 H), 6.90 (d, J = 8.4 Hz,
1 H), 6.74 (d, J = 7.6 Hz, 1 H), 2.94 (t, J = 7.5 Hz, 2 H),
2.47-2.51 (m, 2H) 319 400 MHz 12.76 (br. s., 1 H), 9.29 (d, J = 7.6
Hz, 1 H), 8.58 (d, J = 4.7 Hz, 1 DMSO-d.sub.6 H), 8.06 (d, J = 1.2
Hz, 1 H), 7.99 (s, 1 H), 7.82 (ddd, J = 9.9, 8.6, 1.1 Hz, 1 H),
7.72 (m, 2 H), 7.60 (m, 2 H), 7.54 (dt, J = 8.5, 4.4 Hz, 1 H), 6.55
(dd, J = 7.4, 1.4 Hz, 1 H) 320 400 MHz 8.80 (d, J = 7.6 Hz, 1 H),
8.52-8.58 (m, 1 H), 7.81 (ddd, J = 10.0, DMSO-d.sub.6 8.5, 1.3 Hz,
1 H), 7.72 (m, 2 H), 7.58 (m, 2 H), 7.53 (dt, J = 8.6, 4.4 Hz, 1
H), 6.54 (dd, J = 7.6, 1.2 Hz, 1 H), 5.88 (s, 1 H), 4.27-4.37 (m, 2
H), 4.21 (t, J = 6.7 Hz, 2 H), 2.16-2.28 (m, 2 H) 321 400 MHz 8.80
(d, J = 7.6 Hz, 1 H), 8.52-8.58 (m, 1 H), 7.81 (ddd, J = 10.0,
DMSO-d.sub.6 8.5, 1.3 Hz, 1 H), 7.72 (m, 2 H 7.58 (m, 2 H), 7.53
(dt, J = 8.6, 4.4 Hz, 1 H), 6.54 (dd, J = 7.6, 1.2 Hz, 1 H), 5.88
(s, 1 H), 4.27-4.37 (m, 2 H), 4.21 (t, J = 6.7 Hz, 2 H), 2.16-2.28
(m, 2 H) 322 400 MHz 12.86 (br. s., 1 H), 8.82 (d, J = 7.6 Hz, 1
H), 8.56 (d, J = 4.7 Hz, 1 DMSO-d.sub.6 H), 7.81 (ddd, J = 9.9,
8.5, 1.2 Hz, 1 H), 7.72 (m, 2 H), 7.59 (m, 2 H), 7.53 (dt, J = 8.6,
4.4 Hz, 1 H), 6.54 (d, J = 7.2 Hz, 1 H), 2.61 (t, J = 5.7 Hz, 4 H),
1.61-1.77 (m, 4 H) 323 400 MHz 13.08 (br. s., 1 H), 9.47 (d, J =
7.6 Hz, 1 H), 8.47 (d, J = 4.1 Hz, 1 DMSO-d.sub.6 H), 8.09 (m, 2
H), 7.90 (m, 2 H), 7.67-7.76 (m, 3 H), 7.61 (d, J = 8.2 Hz, 2 H),
7.34 (dd, J = 7.5, 4.8 Hz, 1 H), 6.65 (d, J = 7.4 Hz, 1 H), 2.35
(s, 3 H) 324 400 MHz 11.98 (br. s., 1 H), 8.95 (d, J = 8.0 Hz, 1
H), 8.45 (d, J = 4.5 Hz, 1 DMSO-d.sub.6 H), 8.17 (d, J = 2.3 Hz, 1
H), 7.90 (dd, J = 9.6, 2.5 Hz, 1 H), 7.70 (t, J = 9.3 Hz, 1 H),
7.43 (dt, J = 8.5, 4.3 Hz, 1 H), 6.97 (s, 2 H), 6.90 (s, 1 H), 6.52
(d, J = 7.8 Hz, 1 H), 6.31 (d, J = 9.6 Hz, 1 H), 2.23 (s, 6 H) 325
400 MHz 12.00 (br. s., 1 H), 9.05 (d, J = 8.0 Hz, 1 H), 8.43-8.49
(m, 1 H), DMSO-d.sub.6 8.18 (d, J = 2.5 Hz, 1 H), 7.92 (dd, J =
9.6, 2.7 Hz, 1 H), 7.74 (ddd, J = 10.1, 8.5, 1.2 Hz, 1 H), 7.46 (1
dt, J = 8.5, 4.3 Hz, 1 H), 7.00-7.07 (m, 2 H), 6.95 (d, J = 9.6 Hz,
1 H), 6.59 (d, J = 7.8 Hz, 1 H), 6.35 (d, J = 9.6 Hz, 1 H), 2.30
(s, 3 H) 326 400 MHz 8.98 (d, J = 8.0 Hz, 1 H), 8.52 (d, J = 2.3
Hz, 1 H), 8.46 (d, J = 4.7 Hz, DMSO-d.sub.6 1 H), 7.91 (dd, J =
9.4, 2.5 Hz, 1 H), 7.74 (t, J = 9.3 Hz, 1 H), 7.46 (dt, J = 8.5,
4.4 Hz, 1 H), 7.00-7.07 (m, 2 H), 6.95 (d, J = 9.6 Hz, 1 H), 6.60
(d, J = 8.0 Hz, 1 H), 6.40 (d, J = 9.6 Hz, 1 H), 3.48 (s, 3 H),
2.29 (s, 3 H) 327 400 MHz 12.01 (br. s., 1 H), 9.20 (d, J = 7.8 Hz,
1 H), 8.42-8.48 (m, 1 H), DMSO-d.sub.6 8.17 (d, J = 2.5 Hz, 1 H),
7.91 (dd, J = 9.6, 2.7 Hz, 1 H), 7.78 (ddd, J = 10.0, 8.5, 1.3 Hz,
1 H), 7.58-7.70 (m, 3 H), 7.49 (dt, J = 8.5, 4.4 Hz, 1 H), 6.76 (d,
J = 7.8 Hz, 1 H), 6.36 (d, J = 9.6 Hz, 1 H) 328 400 MHz 9.16 (d, J
= 7.8 Hz, 1 H), 8.50 (d, J = 2.3 Hz, 1 H), 8.44 (d, J = 4.7 Hz,
DMSO-d.sub.6 1 H), 7.91 (dd, J = 9.5, 2.4 Hz, 1 H), 7.78 (t, J =
9.3 Hz, 1 H), 7.59-7.69 (m, 3 H), 7.49 (dt, J = 8.5, 4.3 Hz, 1 H),
6.76 (d, J = 7.6 Hz, 1 H), 6.41 (d, J = 9.4 Hz, 1 H), 3.48 (s, 3 H)
329 400 MHz 12.01 (br. s., 1 H), 9.10 (d, J = 8.0 Hz, 1 H), 8.45
(dt, J = 4.5, 1.3 Hz, DMSO-d.sub.6 1 H), 8.18 (d, J = 2.5 Hz, 1 H),
7.91 (dd, J = 9.7, 2.6 Hz, 1 H), 7.77 (ddd, J = 10.1, 8.5, 1.2 Hz,
1 H), 7.49 (dt, J = 8.5, 4.3 Hz, 1 H), 7.10-7.22 (m, 3 H), 6.65 (d,
J = 7.6 Hz, 1 H), 6.36 (d, J = 9.6 Hz, 1 H) 330 400 MHz 9.05 (d, J
= 7.8 Hz, 1 H), 8.52 (d, J = 2.5 Hz, 1 H), 8.43-8.49 (m,
DMSO-d.sub.6 1 H), 7.92 (dd, J = 9.5, 2.6 Hz, 1 H), 7.78 (ddd, J =
10.0, 8.6, 1.2 Hz, 1 H), 7.49 (dt, J = 8.4, 4.4 Hz, 1 H), 7.10-7.23
(m, 3 H), 6.67 (d, J = 7.6 Hz, 1 H), 6.41 (d, J = 9.4 Hz, 1 H),
3.49 (s, 3 H) 331 400 MHz 12.01 (br. s., 1 H), 9.07 (d, J = 8.0 Hz,
1 H), 8.44 (d, J = 4.5 Hz, 1 DMSO-d.sub.6 H), 8.16 (d, J = 2.5 Hz,
1 H), 7.90 (dd, J = 9.6, 2.5 Hz, 1 H), 7.74 (t, J = 9.3 Hz, 1 H),
7.34-7.56 (m, 3 H), 7.19-7.27 (m, 1 H), 6.61 (d, J = 7.8 Hz, 1 H),
6.34 (d, J = 9.6 Hz, 1 H) 332 400 MHz 9.02 (d, J = 7.8 Hz, 1 H),
8.50 (d, J = 2.5 Hz, 1 H), 8.45 (d, J = 4.5 Hz, DMSO-d.sub.6 1 H),
7.90 (dd, J = 9.5, 2.6 Hz, 1 H), 7.75 (ddd, J = 10.0, 8.6, 1.0 Hz,
1 H), 7.35-7.56 (m, 3 H), 7.19-7.28 (m, 1 H), 6.63 (d, J = 7.6 Hz,
1 H), 6.40 (d, J = 9.4 Hz, 1 H), 3.48 (s, 3 H) 333 400 MHz 11.95
(br. s., 1 H), 9.15 (d, J = 8.0 Hz, 1 H), 8.45 (d, J = 4.5 Hz, 1
DMSO-d.sub.6 H), 8.16 (d, J = 2.5 Hz, 1 H), 7.90 (dd, J = 9.6, 2.7
Hz, 1 H), 7.69-7.78 (m, 1 H), 7.53 (d, J = 9.6 Hz, 2 H), 7.41-7.49
(m, 2 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.33 (d, J = 9.6 Hz, 1 H),
2.37 (s, 3 H) 334 400 MHz 11.97 (br. s., 1 H), 9.02 (d, J = 7.8 Hz,
1 H), 8.43 (d, J = 4.7 Hz, 1 DMSO-d.sub.6 H), 8.16 (d, J = 2.3 Hz,
1 H), 7.90 (dd, J = 9.7, 2.6 Hz, 1 H), 7.67-7.76 (m, 1 H), 7.44
(dt, J = 8.5, 4.4 Hz, 1 H), 7.19-7.26 (m, 1 H), 7.16 (d, J = 11.2
Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 6.57 (d, J = 7.8 Hz, 1 H),
6.33 (d, J = 9.6 Hz, 1 H), 2.19 (s, 3 H) 335 400 MHz 8.95 (d, J =
7.8 Hz, 1 H), 8.51 (d, J = 2.5 Hz, 1 H), 8.44 (d, J = 4.5 Hz,
DMSO-d.sub.6 1 H), 7.90 (dd, J = 9.5, 2.6 Hz, 1 H), 7.68-7.77 (m, 1
H), 7.44 (dt, J = 8.5, 4.3 Hz, 1 H), 7.20-7.27 (m, 1 H), 7.17 (d, J
= 11.0 Hz, 1 H), 7.09 (d, J = 7.8 Hz, 1 H), 6.59 (d, J = 7.8 Hz, 1
H), 6.39 (d, J = 9.4 Hz, 1 H), 3.47 (s, 3 H), 2.19 (s, 3 H) 336 400
MHz 11.96 (br. s., 1 H), 8.99 (d, J = 8.0 Hz, 1 H), 8.44 (d, J =
4.7 Hz, 1 DMSO-d.sub.6 H), 8.15 (d, J = 2.5 Hz, 1 H), 7.89 (dd, J =
9.7, 2.6 Hz, 1 H), 7.66-7.76 (m, 1 H), 7.43 (dt, J = 8.5, 4.4 Hz, 1
H), 7.21-7.29 (m, 1 H), 7.07-7.15 (m, 2 H), 6.53 (d, J = 7.8 H, 1
Hz), 6.33 (d, J = 9.6 Hz, 1 H), 3.80 (s, 1 H) 337 400 MHz 8.92 (d,
J = 8.0 Hz, 1 H), 8.50 (d, J = 2.3 Hz, 1 H), 8.44 (d, J = 4.5 Hz,
DMSO-d.sub.6 1 H), 7.89 (dd, J = 9.6, 2.5 Hz, 1 H), 7.72 (t, J =
9.0 Hz, 1 H), 7.44 (dt, J = 8.5, 4.3 Hz, 1 H), 7.22-7.29 (m, 1 H),
7.06-7.17 (m, 2 H), 6.54 (d, J = 7.8 Hz, 1 H), 6.39 (d, J = 9.6 Hz,
1 H), 3.81 (s, 3 H), 3.47 (s, 3 H) 338 400 MHz 11.97 (br. s., 1 H),
9.00 (d, J = 8.0 Hz, 1 H), 8.44 (d, J = 4.7 Hz, 1 DMSO-d.sub.6 H),
8.15 (d, J = 2.5 Hz, 1 H), 7.90 (dd, J = 9.7, 2.6 Hz, 1 H,
7.67-7.75 (m, 1 H), 7.43 (dt, J = 8.5, 4.4 Hz, 1 H), 7.26-7.33 (m,
1 H), 7.16-7.24 (m, 1 H), 7.03-7.12 (m, 1 H), 6.55 (d, J = 7.8 Hz,
1 H), 6.33 (d, J = 9.6 Hz, 1 H), 2.08-2.30 (m, 3 H) 339 400 MHz
8.93 (d, J = 7.8 Hz, 1 H), 8.50 (d, J = 2.5 Hz, 1 H), 8.45 (d, J =
4.5 Hz, DMSO-d.sub.6 1 H), 7.90 (dd, J = 9.5, 2.6 Hz, 1 H),
7.67-7.76 (m, 1 H), 7.44 (dt, J = 8.4, 4.4 Hz, 1 H), 7.26-7.34 (m,
1 H), 7.17-7.25 (m, 1 H), 7.09 (t, J = 9.1 Hz, 1 H), 6.56 (d, J =
7.8 Hz, 1 H), 6.39 (d, J = 9.6 Hz, 1 H), 3.47 (s, 3 H), 2.17-2.23
(m, 3 H) 340 400 MHz 11.94 (br. s., 1 H), 9.03 (d, J = 7.8 Hz, 1
H), 8.44 (d, J = 4.7 Hz, 1 DMSO-d.sub.6 H), 8.16 (d, J = 2.5 Hz, 1
H), 7.89 (dd, J = 9.6, 2.5 Hz, 1 H), 7.67-7.76 (m, 1 H), 7.36-7.48
(m, 3 H), 7.16 (t, J = 8.8 Hz, 2 H), 6.59 (d, J = 7.8 Hz, 1 H),
6.32 (d, J = 9.6 Hz, 1 H) 341 400 MHz 8.97 (d, J = 8.0 Hz, 1 H),
8.50 (d, J = 2.5 Hz, 1 H), 8.45 (d, J = 4.7 Hz, DMSO-d.sub.6 1 H),
7.90 (dd, J = 9.5, 2.6 Hz, 1 H), 7.73 (ddd, J = 10.0, 8.6, 1.2 Hz,
1 H), 7.38-7.49 (m, 3 H), 7.12-7.21 (m, 2 H), 6.61 (d, J = 7.8 Hz,
1 H), 6.39 (d, J = 9.4 Hz, 1 H), 3.47 (s, 3 H) 342 400 MHz 11.96
(br. s., 1 H), 8.97 (d, J = 7.8 Hz, 1 H), 8.43 (d, J = 4.7 Hz, 1
DMSO-d.sub.6 H), 8.15 (d, J = 2.5 Hz, 1 H), 7.90 (dd, J = 9.7, 2.6
Hz, 1 H), 7.64-7.73 (m, 1 H), 7.41 (dt, J = 8.4, 4.4 Hz, 1 H), 7.28
(m, 2 H), 6.88 (m, 2 H), 6.52 (d, J = 7.6 Hz, 1 H), 6.32 (d, J =
9.6 Hz, 1 H), 3.72 (s, 3 H) 343 400 MHz 8.88 (d, J = 7.8 Hz, 1 H),
8.48-8.53 (m, 1 H), 8.44 (d, J = 4.3 Hz, DMSO-d.sub.6 1 H), 7.90
(dd, J = 9.5, 2.2 Hz, 1 H), 7.70 (t, J = 9.2 Hz, 1 H), 7.42 (dt, J
= 8.3, 4.3 Hz, 1 H), 7.29 (m, 2 H), 6.89 (m, 2 H), 6.54 (d, J = 7.6
Hz, 1 H), 6.38 (d, J = 9.4 Hz, 1 H), 3.72 (s, 3 H), 3.47 (s, 3 H)
344 400 MHz 12.00 (br. s., 1 H), 9.08 (d, J = 7.8 Hz, 1 H), 8.43
(d, J = 4.7 Hz, 1 DMSO-d.sub.6 H), 8.15 (d, J = 2.3 Hz, 1 H), 7.89
(dd, J = 9.6, 2.7 Hz, 1 H), 7.75 (ddd, J = 10.0, 8.6, 1.2 Hz, 1 H),
7.55 (t, J = 8.0 Hz, 1 H), 7.42-7.50 (m, 2 H), 7.21-7.27 (m, 1 H),
6.62 (d, J = 7.8 Hz, 1 H), 6.33 (d, J = 9.8 Hz, 1 H) 345 400 MHz
9.03 (d, J = 7.8 Hz, 1 H), 8.49 (d, J = 2.5 Hz, 1 H), 8.44 (d, J =
4.5 Hz, DMSO-d.sub.6 1 H), 7.89 (dd, J = 9.6, 2.7 Hz, 1 H), 7.75
(ddd, J = 10.0,
8.6, 1.2 Hz, 1 H), 7.56 (t, J = 8.0 Hz, 1 H), 7.43-7.51 (m, 2 H),
7.25 (dd, J = 8.2, 1.6 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H), 6.39
(d, J = 9.4 Hz, 1 H), 3.47 (s, 3 H) 346 400 MHz 10.65 (br. s., 1
H), 9.14 (d, J = 7.8 Hz, 1 H), 8.37-8.54 (m, 1 H), DMSO-d.sub.6
7.81-7.86 (m, 2 H), 7.77 ddd, J = 10.0, 8.6, 1.2 Hz, 1 H),
7.53-7.63 (m, 2 H), 7.49 (dt, J = 8.5, 4.4 Hz, 1 H), 7.37 (d, J =
8.4 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H),
3.55 (s, 2 H) 347 400 MHz 11.96 (br. s., 1 H), 9.01 (d, J = 8.0 Hz,
1 H), 8.39-8.43 (m, 1 H), DMSO-d.sub.6 8.14 (d, J = 2.5 Hz, 1 H),
7.89 (dd, J = 9.6, 2.7 Hz, 1 H), 7.63 (d, J = 6.8 Hz, 1 H),
7.46-7.54 (m, 2 H), 7.23-7.32 (m, 2 H), 6.55 (d, J = 7.8 Hz, 1 H),
6.32 (d, J = 9.6 Hz, 1 H), 2.35 s, 3 H) 348 400 MHz 8.96 (d, J =
7.8 Hz, 1 H), 8.49 (d, J = 2.5 Hz, 1 H), 8.38-8.45 (m, DMSO-d.sub.6
1 H), 7.89 (dd, J = 9.5, 2.6 Hz, 1 H), 7.61-7.67 (m, 1 H),
7.47-7.55 (m, 2 H), 7.22-7.33 (m, 2 H), 6.56 (d, J = 7.8 Hz, 1 H),
6.38 (d, J = 9.6 Hz, 1 H), 3.46 (s, 3 H), 2.36 (s, 3 H) 349 400 MHz
13.38-13.60 (m, 1 H), 9.22 (d, J = 7.2 Hz, 1 H), 8.52 (d, J = 4.7
Hz, DMSO-d.sub.6 1 H), 7.75-7.86 (m, 2 H), 7.48-7.58 (m, 3 H), 7.33
(d, J = 8.6 Hz, 1 H), 6.98 (dd, J = 9.9, 2.2 Hz, 1 H), 6.47-6.52
(m, 1 H) 350 400 MHz 13.38-13.60 (m, 1 H), 9.17 (d, J = 7.4 Hz, 1
H), 8.53 (d, J = 4.7 Hz, DMSO-d.sub.6 1 H), 7.75-7.85 (m, 2 H),
7.46-7.56 (m, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 6.98 (dd, J = 9.9,
2.1 Hz, 1 H), 6.47 (dd, J = 7.3, 1.5 Hz, 1 H) 351 400 MHz 10.29 (s,
1 H), 9.12 (d, J = 7.8 Hz, 1 H), 8.44 (d, J = 4.7 Hz, 1 H),
DMSO-d.sub.6 7.70-7.83 (m, 3 H), 7.50-7.62 (m, 2 H), 7.47 (dt, J =
8.5, 4.4 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.2 Hz,
1 H), 6.69 (d, J = 7.8 Hz, 1 H), 2.92 (t, J = 7.5 Hz, 2 H),
2.44-2.50 (m, 2 H) 352 400 MHz 10.29 (1 H, s, 1 H), 9.07 (1 H, d, J
= 7.8 Hz, 1 H), 8.45 (1 H, d, DMSO-d.sub.6 J = 4.7 Hz, 1 H),
7.67-7.84 (3 H, m, 3 H), 7.52 (2 H, m, 2 H), 7.46 (1 H, dt, J =
8.5, 4.4 Hz, 1 H), 7.34 (2 H, m, 2 H), 6.88 (1 H, d, J = 8.4 Hz, 1
H), 6.67 (1 H, d, J = 7.6 Hz, 1 H), 2.91 (2 H, t, J = 7.5 Hz, 2 H),
2.44-2.49 (2 H, m, 2 H) 353 400 MHz 12.78 (br. s., 1 H), 9.25 (d, J
= 7.4 Hz, 1 H), 8.55 (d, J = 4.7 Hz, 1 DMSO-d.sub.6 H), 8.02-8.07
(m, 1 H), 7.97 (br. s., 1 H), 7.76-7.84 (m, 1 H), 7.46-7.57 (m, 3
H), 7.30 (d, J = 8.4 Hz, 1 H), 6.49 (dd, J = 7.4, 1.4 Hz, 1 H) 354
400 MHz 12.78 (br. s., 1 H), 9.23 (d, J = 7.6 Hz, 1 H), 8.55 (d, J
= 4.7 Hz, 1 DMSO-d.sub.6 H), 8.05 (d, J = 1.2 Hz, 1 H), 7.97 (s, 1
H), 7.79 (ddd, J = 9.9, 8.6, 1.1 Hz, 1 H), 7.44-7.56 (m, 3 H), 7.32
(d, J = 8.0 Hz, 2 H), 6.48 (dd, J = 7.6, 1.6 Hz, 1 H) 355 400 MHz
8.79 (1 H, d, J = 7.6 Hz, 1 H), 8.52 (1 H, d, J = 4.7 Hz, 1 H),
DMSO-d.sub.6 7.74-7.84 (1 H, m, 1 H), 7.44-7.58 (3 H, m, 3 H), 7.29
(1 H, d, J = 8.6 Hz, 1 H), 6.50 (1 H, dd, J = 7.6, 1.2 Hz, 1 H),
5.87 (1 H, s, 1 H), 4.28-4.33 (2 H, m, 2 H), 4.18 (2 H, t, J = 6.4
Hz, 2 H), 2.16-2.25 (m, 1 H) 356 400 MHz 8.72 (1 H, d, J = 7.8 Hz,
1 H), 8.53 (1 H, d, J = 4.7 Hz, 1 H), DMSO-d.sub.6 7.69-7.85 (1 H,
m, 1 H), 7.44-7.54 (3 H, m, 3 H), 7.33 (2 H, d, J = 8.2 Hz, 2 H),
6.44-6.52 (1 H, m, 1 H), 5.86 (1 H, s, 1 H), 4.28-4.33 (2 H, m, 2
H), 4.19 (2 H, t, J = 6.3 Hz, 2 H), 2.16-2.25 (2 H, m, 2 H) 357 400
MHz 10.92 (s, 1 H), 9.11 (d, J = 7.6 Hz, 1 H), 8.44 (d, J = 3.7 Hz,
1 H), DMSO-d.sub.6 7.67 (d, J = 7.6 Hz, 1 H), 7.45-7.59 (m, 4 H),
7.26-7.34 (m, 2 H), 6.93 (d, J = 8.0 Hz, 1 H), 6.56 (d, J = 7.6 Hz,
1 H), 4.61 (s, 2 H), 2.34 (s, 3 H) 358 400 MHz 11.83 (s, 1 H), 9.27
(d, J = 7.6 Hz, 1 H), 8.44 (d, J = 3.7 Hz, 1 H), DMSO-d.sub.6
7.66-7.74 (m, 2 H), 7.63 (d, J = 1.6 Hz, 1 H), 7.47-7.58 (m, 2 H),
7.26-7.39 (m, 3 H), 6.59 (d, J = 7.8 Hz, 1 H), 2.35 (s, 3 H) 359
300 MHz 11.92 (br. s., 1 H), 9.01 (d, J = 7.7 Hz, 1 H), 8.39-8.46
(m, 1 H), DMSO-d.sub.6 8.14 (d, J = 2.5 Hz, 1 H), 7.90 (dd, J =
9.6, 2.6 Hz, 1 H), 7.57-7.66 (m, 1 H), 7.46 (d, J = 8.8 Hz, 2 H),
7.21-7.35 (m, 3 H), 6.53 (d, J = 7.9 Hz, 1 H), 6.32 (d, J = 9.6 Hz,
1 H), 2.31 (s, 3 H) 360 300 MHz 8.94 (d, J = 7.9 Hz, 1 H), 8.50 (d,
J = 2.3 Hz, 1 H), 8.44 (d, J = 3.8 Hz, DMSO-d.sub.6 1 H), 7.89 (dd,
J = 9.5, 2.5 Hz, 1 H), 7.63 (d, J = 7.0 Hz, 1 H), 7.47 (d, J = 8.6
Hz, 2 H), 7.21-7.36 (m, 3 H), 6.55 (d, J = 7.9 Hz, 1 H), 6.39 (d, J
= 9.4 Hz, 1 H), 3.47 (s, 3 H), 2.33 (s, 3 H) 361 400 MHz 9.35 (d, J
= 8.0 Hz, 1 H), 8.57 (d, J = 4.1 Hz, 1 H), 7.83 (td, J = 7.7,
DMSO-d.sub.6 1.7 Hz, 1 H), 7.68-7.75 (m, 3 H), 7.61-7.67 (m, 3 H),
7.54 (d, J = 7.8 Hz, 1 H), 7.29-7.40 (m, 2 H), 6.51 (d, J = 8.0 Hz,
1 H) 362 400 MHz 10.84-12.61 (m, 1 H), 9.30 (d, J = 8.2 Hz, 1 H),
8.57 (d, J = 4.3 Hz, DMSO-d.sub.6 1 H), 7.83 (td, J = 7.7, 1.8 Hz,
1 H), 7.71 (dd, J = 8.2, 1.6 Hz, 1 H), 7.62-7.66 (m, 1 H), 7.53 (d,
J = 8.4 Hz, 3 H), 7.28-7.38 (m, 4 H), 6.46 (d, J = 8.2 Hz, 1 H) 363
300 MHz 13.05 (br. s., 1H), 8.45-8.87 (m, 2H), 8.09 (d, J = 2.5 Hz,
1H), CDCl.sub.3 7.94 (dd, J = 9.6, 2.6 Hz, 1H), 7.81 (dd, J = 7.9,
1.5 Hz, 1H), 7.40-7.63 (m, 4H), 7.32 (dd, J = 7.7, 4.8 Hz, 1H),
6.92 (dd, J = 17.2, 11.0 Hz, 1H), 6.44-6.71 (m, 2H), 5.65 (d, J =
17.2 Hz, 1H), 5.44 (d, J = 11.3 Hz, 1H) 364 300 MHz 8.47 (d, J =
4.5 Hz, 1H), 8.32 (d, J = 6.6 Hz, 1H), 8.15 (d, J = 2.6 Hz,
CDCl.sub.3 1H), 7.73 (dd, J = 9.5, 2.6 Hz, 1H), 7.56 (s, 4H),
7.39-7.48 (m, 1H), 7.29-7.38 (m, 1H), 6.44-6.65 (m, 2H), 4.02 (qd,
J = 7.1, 4.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H) 365 300 MHz 8.46
(dt, J = 4.6, 1.2 Hz, 1H), 8.26 (d, J = 6.7 Hz, 1H), 8.15 (d, J =
2.5 Hz, CDCl.sub.3 1H), 7.72 (dd, J = 9.6, 2.7 Hz, 1H), 7.27-7.58
(m, 5H), 6.58 (d, J = 9.5 Hz, 1H), 6.47 (dd, J = 6.7, 2.0 Hz, 1H),
3.91-4.10 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H) 366 300 MHz 8.47 (d, J
= 4.7 Hz, 1H), 8.26 (d, J = 6.6 Hz, 1H), 8.16 (d, J = 2.5 Hz,
CDCl.sub.3 1H), 7.72 (dd, J = 9.5, 2.6 Hz, 1H), 7.41-7.52 (m, 1H),
7.31-7.40 (m, 1H), 7.16-7.27 (m, 3H), 6.37-6.64 (m, 2H), 4.04 (qd,
J = 7.2, 4.0 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H) 367 300 MHz 8.47 (d,
J = 4.7 Hz, 1H), 8.35 (d, J = 6.6 Hz, 1H), 8.22 (d, J = 2.3 Hz,
CDCl.sub.3 1H), 7.70 (dd, J = 9.5, 2.6 Hz, 1H), 7.56 (s, 4H),
7.39-7.48 (m, 1H), 7.28-7.39 (m, 1H), 6.34-6.67 (m, 2H), 5.11-5.34
(m, 1H), 1.37 (dd, J = 6.7, 4.2 Hz, 6H) 368 300 MHz 13.23 (br. s.,
1H), 8.50 (d, J = 4.5 Hz, 1H), 8.30-8.42 (m, 2H), CDCl.sub.3 8.18
(d, J = 2.2 Hz, 1H), 7.50-7.67 (m, 4H), 7.31-7.49 (m, 2H), 6.57
(dd, J = 6.6, 1.8 Hz, 1H) 369 300 MHz 11.69 (dd, J = 13.2, 6.9 Hz,
1H), 8.55 (d, J = 4.7 Hz, 1H), CDCl.sub.3 7.60-7.70 (m, 2H),
7.53-7.59 (m, 2H), 7.40-7.50 (m, 2H), 7.29-7.38 (m, 1H), 6.91 (d, J
= 9.8 Hz, 1H), 6.07 (d, J = 6.7 Hz, 1H), 5.84 (d, J = 9.6 Hz, 1H),
4.03 (s, 3H) 370 400 MHz 9.12 (d, J = 7.8 Hz, 1H), 8.35-8.51 (m,
2H), 7.94 (dd, J = 9.5, d.sub.6-DMSO 2.6 Hz, 1H), 7.66-7.84 (m,
3H), 7.60 (d, J = 8.2 Hz, 2H), 7.36-7.54 (m, 1H), 6.71 (d, J = 7.8
Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 4.91 (t, J = 5.5 Hz, 1H),
3.85-4.27 (m, 2H), 3.63 (q, J = 5.5 Hz, 2H) 371 300 MHz 8.36-8.52
(m, 1H), 8.30 (d, J = 6.6 Hz, 1H), 8.16 (d, J = 2.5 Hz, CDCl.sub.3
1H), 7.73 (dd, J = 9.6, 2.6 Hz, 1H), 7.53 (s, 4H), 7.27-7.47 (m,
7H), 6.62 (d, J = 9.5 Hz, 1H), 6.54 (dd, J = 6.7, 1.9 Hz, 1H), 5.15
(d, J = 3.7 Hz, 2H) 372 300 MHz 8.41-8.51 (m, 1H), 8.35 (d, J = 6.7
Hz, 1H), 8.10 (d, J = 2.3 Hz, CDCl.sub.3 1H), 7.77 (dd, J = 9.7,
2.6 Hz, 1H), 7.49-7.65 (m, 5H), 7.39-7.48 (m, 1H), 7.30-7.39 (m,
1H), 6.66 (d, J = 9.6 Hz, 1H), 6.57 (dd, J = 6.7, 2.0 Hz, 1H), 4.64
(q, J = 8.5 Hz, 2H) 373 300 MHz 12.78 (br. s., 1H), 8.48 (d, J =
4.7 Hz, 1H), 8.27 (d, J = 6.7 Hz, CDCl.sub.3 1H), 8.02 (d, J = 2.3
Hz, 1H), 7.80 (d, J = 1.0 Hz, 1H), 7.55 (s, 4H), 7.39-7.49 (m, 1H),
7.29-7.39 (m, 1H), 6.60 (dd, J = 6.8, 2.0 Hz, 1H), 2.22 (s, 3H) 374
300 MHz 8.45 (d, J = 3.4 Hz, 1H), 8.28 (d, J = 5.8 Hz, 1H), 7.64
(d, J = 2.3 Hz, CDCl.sub.3 1H), 7.21-7.56 (m, 5H), 6.97-7.20 (m,
3H), 6.61 (d, J = 6.4 Hz, 1H) 375 300 MHz 8.47 (br. s., 1H), 8.32
(br. s., 1H), 7.21-7.88 (m, 8H), 7.10 (br. CDCl.sub.3 s., 1H), 6.63
(d, J = 5.7 Hz, 1H) 376 300 MHz 11.97 (br. s., 1H), 9.02 (d, J =
7.7 Hz, 1H), 8.90 (d, J = 3.7 Hz, d.sub.6-DMSO 1H), 8.22 (d, J =
8.2 Hz, 1H), 8.13 (br. s., 1H), 7.88 (dd, J = 9.6, 2.8 Hz, 1H),
7.65-7.75 (m, J = 8.3 Hz, 2H), 7.60 (dd, J = 7.8, 4.6 Hz, 1H),
6.99-7.14 (m, J = 8.3 Hz, 2H), 6.61 (d, J = 7.3 Hz, 1H), 6.31 (d, J
= 9.4 Hz, 1H) 377 300 MHz 9.03 (d, J = 8.2 Hz, 1H), 8.55 (dd, J =
4.8, 0.9 Hz, 1H), 8.16 (d, d.sub.6-DMSO J = 2.5 Hz, 1H), 7.91 (dd,
J = 9.6, 2.7 Hz, 1H), 7.81 (td, J = 7.7, 1.9 Hz, 1H), 7.42-7.56 (m,
3H), 7.24-7.40 (m, 3H), 6.39 (d, J = 8.2 Hz, 1H), 6.33 (d, J = 9.6
Hz, 1H) 378 300 MHz 9.00 (d, J = 8.0 Hz, 1H), 8.57 (dd, J = 4.9,
0.8 Hz, 1H), 8.50 (d, d.sub.6-DMSO J = 2.6 Hz, 1H), 7.92 (dd, J =
9.5, 2.6 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.44-7.57 (m,
3H), 7.28-7.40 (m, 3H), 6.33-6.49 (m, 2H) 379 300 MHz 8.39-8.50 (m,
1H), 8.13 (d, J = 2.6 Hz, 1H), 8.04 (dd, J = 9.5, d.sub.4-MeOH 2.6
Hz, 1H), 7.54-7.66 (m, 1H), 7.41 (dt, J = 8.6, 4.4 Hz, 1H),
7.20-7.31 (m, J = 8.2 Hz, 2H), 7.09-7.20 (m, J = 8.0 Hz, 2H), 6.59
(s, 1H), 6.53 (d, J = 9.5 Hz, 1H), 2.30 (s, 3H) 380 300 MHz 8.44
(d, J = 4.7 Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 8.04 (dd, J = 9.6,
d.sub.4-MeOH 2.7 Hz, 1H), 7.58 (ddd, J = 9.9, 8.5, 1.2 Hz, 1H),
7.40 (dt, J = 8.6, 4.3 Hz, 1H), 7.13 (s, 1H), 7.01-7.11 (m, 2H),
6.47-6.59 (m, 2H), 2.22 (s, 6H) 381 300 MHz 8.46 (dt, J = 4.8, 1.2
Hz, 1H), 8.10-8.18 (m, 1H), 8.04 (dd, d.sub.4-MeOH J = 9.6, 2.7 Hz,
1H), 7.60 (ddd, J = 9.9, 8.4, 1.3 Hz, 1H), 7.42 (dt, J = 8.5, 4.4
Hz, 1H), 7.34-7.38 (m, 1H), 7.29 (dd, J = 8.6, 2.0 Hz, 1H), 7.20
(dd, J = 8.5, 1.3 Hz, 1H), 6.58-6.65 (m, 1H), 6.53 (dd, J = 9.6,
0.6 Hz, 1H), 2.28 (s, 3H) 382 300 MHz 8.57-8.68 (m, 1H), 8.13 (d, J
= 2.5 Hz, 1H), 7.97-8.09 (m, d.sub.4-MeOH 2H), 7.23-7.44 (m, 4H),
6.77 (s, 1H), 6.53 (d, J = 9.6 Hz, 1H) 383 300 MHz 8.90 (d, J = 4.1
Hz, 1H), 8.13-8.23 (m, 1H), 8.11 (d, J = 2.2 Hz, d.sub.4-MeOH 1H),
8.01 (dd, J = 9.6, 2.7 Hz, 1H), 7.57 (dd, J = 7.7, 5.1 Hz, 1H),
7.30-7.42 (m, 2H), 7.19-7.30 (m, 1H), 6.80 (s, 1H), 6.51 (d, J =
9.6 Hz, 1H) 384 300 MHz 8.65 (br. s., 1H), 8.08 (d, J = 8.2 Hz,
1H), 7.69 (d, J = 8.0 Hz, d.sub.4-MeOH 1H), 7.59 (br. s., 1H),
7.19-7.48 (m, 5H), 6.81 (s, 1H) 385 300 MHz 8.92 (br. s., 1H), 8.20
(d, J = 6.3 Hz, 1H), 7.66 (d, J = 7.5 Hz, d.sub.4-MeOH 1H), 7.57
(br. s., 2H), 7.36 (br. s., 2H), 7.28 (br. s., 2H), 6.84 (br. s.,
1H) 386 300 MHz 8.43 (dt, J = 4.6, 1.3 Hz, 1H), 8.10-8.19 (m, 1H),
8.04 (dd, J = 9.6, d.sub.4-MeOH 2.7 Hz, 1H), 7.57-7.70 (m, 1H),
7.38-7.54 (m, 2H), 7.06-7.18 (m, 2H), 6.91 (s, 1H), 6.48-6.59 (m,
1H) 387 300 MHz 8.45-8.57 (m, 1H), 7.64 (ddd, J = 9.8, 8.4, 1.2 Hz,
1H), d.sub.4-MeOH 7.31-7.52 (m, 5H), 7.28 (d, J = 1.2 Hz, 1H), 6.59
(s, 1H), 4.03 (s, 3H) 388 300 MHz 8.46-8.58 (m, 1H), 7.64 (ddd, J =
9.8, 8.5, 1.3 Hz, 1H), d.sub.4-MeOH 7.29-7.53 (m, 4H), 7.22 (s,
1H), 6.62 (s, 1H), 2.27-2.42 (m, 3H) 389 300 MHz 8.53 (d, J = 4.7
Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 7.98 (d, J = 8.6 Hz,
d.sub.4-MeOH 1H), 7.64 (td, J = 9.1, 1.2 Hz, 1H), 7.26-7.51 (m,
6H), 6.53-6.64 (m, 1H) 390 300 MHz 8.47-8.52 (m, 1H), 7.95 (d, J =
8.9 Hz, 1H), 7.64 (ddd, J = 9.8, d.sub.4-MeOH 8.5, 1.3 Hz, 1H),
7.30-7.48 (m, 7H), 6.63-6.66 (m, 1H), 2.20 (s, 3H) 391 400 MHz 9.21
(d, J = 8.0 Hz, 1H), 8.52-8.63 (m, 1H), 7.73-7.93 (m, d.sub.6-DMSO
3H), 7.50-7.65 (m, 3H), 7.40 (d, J = 8.6 Hz, 1H), 7.34 (ddd, J =
7.5, 4.8, 1.0 Hz, 1H), 7.16 (s, 1H), 6.49 (d, J = 8.0 Hz, 1H) 392
400 MHz 12.67 (br. s., 1H), 9.31 (d, J = 7.8 Hz, 1H), 8.46 (d, J =
4.5 Hz, d.sub.6-DMSO 1H), 8.34 (s, 1H), 8.25 (br. s., 1H),
7.74-7.83 (m, 2H),
7.70-7.74 (m, 2H), 7.58-7.68 (m, 3H), 7.48 (dt, J = 8.5, 4.4 Hz,
1H), 6.76 (d, J = 7.6 Hz, 1H) 393 400 MHz 12.70 (br. s., 1H), 9.28
(d, J = 7.0 Hz, 1H), 8.58 (d, J = 4.3 Hz, d.sub.6-DMSO 1H),
8.09-8.46 (m, 2H), 7.76-7.92 (m, 2H), 7.49-7.75 (m, 4H), 7.42 (d, J
= 8.6 Hz, 1H), 7.34 (dd, J = 7.1, 5.2 Hz, 1H), 6.52 (d, J = 8.2 Hz,
1H) 394 400 MHz 9.33 (d, J = 7.8 Hz, 1H), 8.46 (d, J = 4.7 Hz, 1H),
8.33 (s, 2H), d.sub.6-DMSO 7.88 (dd, J = 8.6, 1.4 Hz, 1H),
7.70-7.82 (m, 3H), 7.61-7.69 (m, 3H), 7.48 (dt, J = 8.4, 4.4 Hz,
1H), 6.77 (d, J = 7.4 Hz, 1H), 3.87 (s, 3H) 395 400 MHz 9.33 (d, J
= 7.8 Hz, 1H), 8.47 (d, J = 4.7 Hz, 1H), 8.24-8.35 (m, d.sub.6-DMSO
2H), 7.63-7.88 (m, 7H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.82 (d, J
= 7.6 Hz, 1H), 3.90 (s, 3H) 396 400 MHz 9.52 (d, J = 7.8 Hz, 1H),
8.60 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 4.5 Hz, d.sub.6-DMSO 1H),
7.97-8.04 (m, 1H), 7.70-7.91 (m, 4H), 7.62 (d, J = 8.0 Hz, 2H),
7.49 (dt, J = 8.5, 4.4 Hz, 1H), 6.72 (d, J = 7.4 Hz, 1H), 6.58 (d,
J = 9.8 Hz, 1H) 397 400 MHz 12.45 (br. s., 1H), 9.27 (d, J = 7.6
Hz, 1H), 8.43-8.54 (m, 1H), d.sub.6-DMSO 8.11 (s, 1H), 7.71-7.85
(m, 4H), 7.63-7.70 (m, 2H), 7.45-7.54 (m, 2H), 6.78 (d, J = 7.6 Hz,
1H), 2.53 (s, 3H) 398 400 MHz 9.87 (d, J = 7.4 Hz, 1H), 9.21 (dd, J
= 2.0, 0.8 Hz, 1H), d.sub.6-DMSO 8.56-8.63 (m, 1H), 8.52 (dd, J =
8.1, 2.1 Hz, 1H), 8.20 (dd, J = 8.1, 0.7 Hz, 1H), 7.79-7.89 (m,
1H), 7.52-7.63 (m, 3H), 7.37 (d, J = 8.6 Hz, 1H), 6.59 (dd, J =
7.4, 1.4 Hz, 1H), 3.95 (s, 3H) 399 400 MHz 9.46 (d, J = 7.6 Hz,
1H), 8.58 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 4.5 Hz, d.sub.6-DMSO
1H), 7.97-8.06 (m, 1H), 7.88 (s, 0H), 7.72-7.83 (m, 1H), 7.53-7.64
(m, 2H), 7.49 (dt, J = 8.5, 4.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H),
6.68 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 9.8 Hz, 1H) 400 400 MHz 8.51
(d, J = 4.5 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 11.2 Hz, 1H),
d.sub.4-MeOH 7.66 (t, J = 9.1 Hz, 1H), 7.38-7.53 (m, 3H), 7.28-7.37
(m, 1H), 6.68 (s, 1H) 401 400 MHz 8.49 (br. s., 1H), 8.26 (br. s.,
1H), 8.14 (br. s., 1H), 7.64 (t, J = 8.4 Hz, d.sub.4-MeOH 1H),
7.36-7.52 (m, 3H), 7.27-7.35 (m, 1H), 6.67 (br. s., 1H) 402 400 MHz
12.78 (br. s., 1H), 9.36 (d, J = 7.0 Hz, 1H), 8.29-8.53 (m, 3H),
d.sub.6-DMSO 7.77 (t, J = 9.2 Hz, 1H), 7.43-7.64 (m, 3H), 7.33 (d,
J = 8.2 Hz, 1H), 6.68 (d, J = 6.7 Hz, 1H) 403 400 MHz 11.92 (br.
s., 1H), 9.06 (d, J = 7.8 Hz, 1H), 8.44 (d, J = 4.7 Hz,
d.sub.6-DMSO 1H), 8.03 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 1.2 Hz,
1H), 7.76 (ddd, J = 10.0, 8.6, 1.2 Hz, 1H), 7.51-7.63 (m, 2H), 7.48
(dt, J = 8.4, 4.4 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.66 (d, J =
7.6 Hz, 1H), 1.99 (s, 3H) 404 400 MHz 11.09-11.51 (s, 1H), 9.80 (d,
J = 7.2 Hz, 1H), 8.50 (d, J = 4.5 Hz, d.sub.6-DMSO 1H), 7.79-7.88
(m, 1H), 7.44-7.62 (m, 3H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (d, J =
7.2 Hz, 1H), 6.60 (d, J = 6.3 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H),
3.40-3.61 (s, 3H) 405 400 MHz 12.00 (br. s., 1H), 9.15 (d, J = 7.8
Hz, 1H), 8.43 (dt, J = 4.7, 1.4 Hz, d.sub.6-DMSO 1H), 8.16 (d, J =
2.3 Hz, 1H), 7.89 (dd, J = 9.6, 2.7 Hz, 1H), 7.70-7.81 (m, 2H),
7.57 (d, J = 11.9 Hz, 1H), 7.48 (dt, J = 8.5, 4.4 Hz, 1H), 7.42 (d,
J = 8.2 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H)
406 400 MHz 9.88 (d, J = 7.6 Hz, 1H), 9.20 (dd, J = 2.0, 0.8 Hz,
1H), 8.65 (d, d.sub.6-DMSO J = 3.9 Hz, 1H), 8.50 (dd, J = 8.0, 2.2
Hz, 1H), 8.18 (dd, J = 8.0, 0.8 Hz, 1H), 7.85 (td, J = 7.7, 1.9 Hz,
1H), 7.59-7.67 (m, 2H), 7.48-7.58 (m, 1H), 7.32-7.44 (m, 2H), 6.43
(d, J = 7.6 Hz, 1H), 3.93 (s, 3H) 407 400 MHz 9.12 (d, J = 7.6 Hz,
1H), 8.45 (d, J = 2.5 Hz, 2H), 7.98 (dd, J = 9.5, DMSO-d.sub.6 2.4
Hz, 1H), 7.77 (t, J = 9.1 Hz, 1H), 7.51-7.63 (m, 2H), 7.48 (dt, J =
8.5, 4.3 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 6.67 (d, J = 7.6 Hz,
1H), 6.41 (d, J = 9.4 Hz, 1H), 5.63 (s, 1H), 4.03 (s, 2H),
0.67-0.78 (m, 2H), 0.61 (br. s., 2H) 408 400 MHz 9.12 (dd, J =
10.3, 8.1 Hz, 1H), 8.35-8.61 (m, 2H), 7.99 (dd, J = 9.6,
DMSO-d.sub.6 1.4 Hz, 1H), 7.68-7.85 (m, 1H), 7.42-7.65 (m, 3H),
7.33 (d, J = 8.6 Hz, 1H), 6.61-6.82 (m, 2H), 6.46 (d, J = 9.4 Hz,
1H), 4.17-4.51 (m, 2H), 3.58-3.94 (m, 1H) 409 400 MHz 8.95-9.32 (m,
1H), 8.33-8.55 (m, 2H), 7.94-8.09 (m, 1H), DMSO-d.sub.6 7.71-7.84
(m, 1H), 7.52-7.64 (m, 2H), 7.42-7.55 (m, 1H), 7.33 (d, J = 8.4 Hz,
1H), 6.63-6.82 (m, 2H), 6.46 (d, J = 9.6 Hz, 1H), 4.22-4.52 (m,
2H), 3.69-3.87 (m, 1H) 410 400 MHz 12.00 (s, 1H), 9.10 (d, J = 7.6
Hz, 1H), 8.16 (s, 1H), 7.91 (dd, J = 10, DMSO-d.sub.6 2.8 Hz, 1H),
7.71 (d, J = 8.4 Hz, 2H), 7.64-7.56 (m, 3H), 6.30-6.27 (m, 1H),
6.30 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 9.6 Hz, 1H), 2.43 (s, 3H)
411 400 MHz 12.15 (br. s., 1H), 9.0 (d, J = 8.4 Hz, 1H), 8.13 (d, J
= 2.4 Hz, DMSO-d.sub.6 1H), 7.92 (dd, J = 10.0, 2.8 Hz, 1H),
7.47-7.58 (m, 2H), 7.36-7.39 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H),
7.17-7.22 (m, 2H), 6.34-6.38 (m, 2H) 412 400 MHz 12.13 (br. s.,
1H), 9.08 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 2.4 Hz, DMSO-d.sub.6
1H), 7.91 (dd, J = 9.6, 2.4 Hz, 1H), 7.56-7.58 (m, 1H), 7.41-7.52
(m, 2H), 7.16-7.25 (m, 3H), 6.59 (d, J = 7.6 Hz, 1H), 6.36 (d, J =
9.6 Hz, 1H) 413 400 MHz 12.15 (br. s., 1H), 9.05 (d, J = 8.0 Hz,
1H), 8.16 (d, J = 2.4 Hz, DMSO-d.sub.6 1H), 7.93 (dd, J = 9.6, 2.4
Hz, 1H), 7.57-7.61 (m, 1H), 7.47-7.49 (m, 1H), 7.37-7.43 (m, 1H),
7.23-7.34 (m, 2H), 7.13-7.17 (m, 1H), 6.55 (d, J = 8.0 Hz, 1H),
6.37 (d, J = 9.6 Hz, 1H) 414 400 MHz 12.14 (br. s., 1H), 9.04 (d, J
= 7.6 Hz, 1H), 8.17 (d, J = 2.0 Hz, DMSO-d.sub.6 1H), 7.93 (dd, J =
9.6, 2.4 Hz, 1H), 7.58-7.62 (m, 1H), 7.49-7.52 (m, 1H), 7.24-7.33
(m, 4H), 6.56 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 9.6 Hz, 1H) 415 400
MHz 8.52 (br. s., 1H), 8.36 (d, J = 7.8 Hz, 2H), 8.12-8.24 (m, 1H),
d.sub.4-MeOH 7.67 (t, J = 8.9 Hz, 1H), 7.32-7.55 (m, 4H), 6.77 (br.
s., 1H) 416 300 MHz 8.44-8.56 (m, 2H), 7.71 (dd, J = 6.3, 2.2 Hz,
1H), 7.63 (ddd, J = 9.9, d.sub.4-MeOH 8.5, 1.2 Hz, 1H), 7.35-7.49
(m, 5H), 6.66 (d, J = 1.6 Hz, 1H), 6.59 (dd, J = 7.2, 6.4 Hz, 1H)
417 400 MHz 12.15 (br. s., 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.14 (br.
s., 1H), DMSO-d.sub.6 7.91 (d, J = 9.6 Hz, 1H), 7.49-7.59 (m, 3H),
7.12-7.31 (m, 4H), 6.40 (dd, J = 14.4, 10.0 Hz, 2H) 418 400 MHz
12.12 (br. s., 1H), 9.04 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 2.4 Hz,
DMSO-d.sub.6 1H), 7.92 (dd, J = 9.6, 2.4 Hz, 1H), 7.53-7.57 (m,
1H), 7.45-7.49 (m, 2H), 7.12-7.18 (m, 3H), 6.64 (d, J = 7.2 Hz,
1H), 6.34 (d, J = 9.6 Hz, 1H) 419 300 MHz 8.48 (dt, J = 4.7, 1.3
Hz, 1H), 8.14 (dd, J = 2.7, 0.5 Hz, 1H), d.sub.4-MeOH 8.04 (dd, J =
9.6, 2.7 Hz, 1H), 7.63 (ddd, J = 9.8, 8.4, 1.3 Hz, 1H), 7.34-7.51
(m, 3H), 7.25-7.34 (m, 1H), 6.65 (s, 1H), 6.53 (dd, J = 9.6, 0.6
Hz, 1H) 420 400 MHz 12.05 (br. s., 1H), 8.96 (d, J = 8.0 Hz, 1H),
8.14 (br. s., 1H), DMSO-d.sub.6 7.92 (d, J = 11.6 Hz, 1H), 7.70 (t,
J = 8.0 Hz, 1H), 7.61-7.52 (m, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.06
(d, J = 7.2 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.37 (d, J = 9.6 Hz,
1H), 6.29 (d, J = 8.0 Hz, 1H), 3.81 (s, 3H) 421 400 MHz 12.02 (br.
s., 1H), 9.01 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 2.4 Hz,
DMSO-d.sub.6 1H), 8.15 (br. s., 1H), 7.92 (dd, J = 9.6, 2.4 Hz,
1H), 7.51-7.54 (m, 2H), 7.41-7.45 (m, 2H), 7.31 (d, J = 8.4 Hz,
1H), 6.37 (dd, J = 9.2, 5.6 Hz, 2H), 3.81 (s, 3H) 422 400 MHz 12.05
(br. s., 1H), 9.01 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 5.6 Hz,
DMSO-d.sub.6 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.92 (dd, J = 9.6, 2.8
Hz, 1H), 7.50-7.58 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.14 (d, J =
2.4 Hz, 1H), 6.92 (dd, J = 6.0, 2.8 Hz, 1H), 6.36 (dd, J = 8.0, 3.2
Hz, 2H), 3.82 (s, 3H) 423 400 MHz 12.02 (br. s., 1H), 9.03 (d, J =
8.2 Hz, 1H), 8.42 (d, J = 4.9 Hz, DMSO-d.sub.6 1H), 8.17 (d, J =
2.2 Hz, 1H), 7.93 (dd, J = 9.7, 2.6 Hz, 1H), 7.46-7.62 (m, 2H),
7.30-7.44 (m, 2H), 7.17 (d, J = 4.7 Hz, 1H), 6.25-6.44 (m, 2H),
2.34 (s, 3H) 424 400 MHz 12.00 (br. s., 1H), 9.01 (d, J = 8.0 Hz,
1H), 8.33-8.48 (m, 1H), DMSO-d.sub.6 8.15 (d, J = 2.5 Hz, 1H), 7.91
(dd, J = 9.6, 2.8 Hz, 1H), 7.63 (dd, J = 8.0, 1.8 Hz, 1H),
7.46-7.59 (m, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.5 Hz,
1H), 6.36 (dd, J = 8.9, 4.5 Hz, 2H), 2.28 (s, 3H)
Stereochemistry
[0949] Absolute stereochemistry, where noted, was determined by
comparison of either (I) quantum-mechanically predicted optical
rotation values (Stephens, P. J. et. al, J. Phys. Chem. A 2001,
105, 5356) or (II) VCD spectra (Stephens, P. J. et. al, Chirality
2008, 20, 643) to those measured experimentally. A single-crystal
X-ray structure of
(S)-tert-butyl((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)ca-
rbamate (Intermediate 46, Step 5) provided confirmation of the
absolute stereochemistry.
[0950] Computed and observed optical rotation for a subset of
examples in this invention are shown in Table 7. Optical rotations
were measured in CHCl.sub.3 at room temperature using a
Perkin-Elmer digital polarimeter at 589 nm (sodium D line) in a 1.0
dm cell.
TABLE-US-00007 TABLE 7 Computed and Measured Optical Rotation for
Absolute Stereochemistry Assignment Computed Measured Example
Rotation Rotation 41 (S) = + +78.degree. 50 (S) = + +57.degree. 92
(S) = + +16.degree.
[0951] The experimental vibrational circular dichroism (VCD)
spectrum of Example 28 was obtained on a Biotools, Inc. ChiralIR
spectrometer (BaF2 cell, 100 um path length, 48 mg/mL, 4 h
acquisition time in CDCl.sub.3). Comparison of the experimental
spectrum to those computed quantum mechanically for the (S) and (R)
stereoisomers, using the B3LYP hybrid density functional and 6-31G*
basis set, led to the assignment of 28 as the (S)
configuration.
Assays
Luminescence Readout Assay for Measuring Intracellular Calcium.
[0952] A stable Chinese hamster ovary cell line expressing human
TRPM8 was generated using tetracycline inducible T-REx.TM.
expression system from Invitrogen, Inc. (Carlsbad, Calif.). In
order to enable a luminescence readout based on intracellular
increase in calcium (Le Poul et al., 2002), the cell line was also
co-transfected with pcDNA3.1 plasmid containing jelly fish aequorin
cDNA. Twenty four hours before the assay, cells were seeded in
96-well plates and TRPM8 expression was induced with 0.5 .mu.g/mL
tetracycline. On the day of the assay, culture media was removed
and cells were incubated with assay buffer (Ham's F12 containing 30
mM HEPES) that contained 15 .mu.M coelenterazine (P.J.K, Germany)
for 2 h. Potential antagonists were added 2.5 min prior to the
addition of agonist, 1 .mu.M icilin, 100 .mu.M L-menthol, or 1 min
prior to the addition of cold buffer (<10.degree. C.). The
luminescence was measured by a CCD camera based FLASH-luminometer
built by Amgen, Inc. A cooling device attached to FLASH luminometer
was used for cold activation. Compound activity was calculated
using either GraphPad Prism 4.01 (GraphPad Software Inc, San Diego,
Calif.) or Genedata Screener.
[0953] The following compounds exhibit IC.sub.50 values of less
than 10 .mu.M in the assay described above with icilin activation.
Results are shown in Table 8.
TABLE-US-00008 TABLE 8 hTRPM8 IC.sub.50's for Examples 1-438
Example IC.sub.50 (.mu.M) 1 0.0098 2 0.0170 3 0.0177 4 0.0440 5
0.0219 6 0.0739 7 0.0758 8 0.0543 9 0.146 10 0.0205 11 0.0785 12
0.0754 13 0.0833 14 0.0749 15 0.117 16 0.0807 17 0.230 18 0.157 19
0.0952 20 0.187 21 0.0918 22 0.418 23 1.06 24 0.318 25 0.0368 26
3.29 27 0.129 28 0.194 29 0.0324 30 0.0149 31 0.162 32 0.143 33
0.125 34 0.0322 35 0.0196 36 0.073 37 0.146 38 0.0777 39 0.0178 40
0.0134 41 0.0063 42 0.0539 43 0.0245 44 0.229 45 0.0635 46 0.0123
47 0.0201 48 0.0215 49 0.127 50 0.0105 51 0.0101 52 0.0401 53
0.0455 54 0.0231 55 0.0304 56 0.0092 57 0.0631 58 0.0639 59 0.0416
60 0.0784 61 0.312 62 0.172 63 0.134 64 0.02 65 0.245 66 0.405 67
0.04 68 0.0142 69 0.0129 70 0.0152 71 0.0092 72 0.167 73 0.017 74
0.0853 75 0.0391 76 0.0045 77 0.053 78 0.0148 79 0.0051 80 0.0231
81 0.0248 82 0.0177 83 0.0392 84 0.0053 85 0.0289 86 0.0102 87
0.0089 88 0.0121 89 0.0103 90 0.0062 91 0.0137 92 0.0103 93 0.0178
94 0.0414 95 0.0572 96 0.0376 97 0.119 98 0.125 99 0.129 100 0.0615
101 0.395 102 0.0081 103 0.0078 104 0.0062 105 0.0108 106 0.0089
107 0.0267 108 0.0241 109 0.0639 110 0.0644 111 0.0559 112 0.0844
113 0.0311 114 0.0506 115 0.0562 116 0.0429 117 0.0700 118 0.0905
119 0.100 120 0.0594 121 0.247 122 0.107 123 0.149 124 0.190 125
0.176 126 0.194 127 0.584 128 0.125 129 0.114 130 0.0247 131 0.0189
132 0.0175 133 0.0200 134 0.0310 135 0.0194 136 0.121 137 0.0949
138 0.0464 139 0.0659 140 0.0527 141 0.160 142 0.144 143 0.0874 144
0.200 145 0.0852 146 0.180 147 0.148 148 0.257 149 0.398 150 0.178
151 0.395 152 0.459 153 0.373 154 2.53 155 1.44 156 0.301 157 0.716
158 1.95 159 2.21 160 3.32 161 3.37 162 4.38 163 3.18 164 0.294 165
0.0051 166 0.0076 167 0.0215 168 0.0384 169 0.0104 170 0.0235 171
0.0173 172 0.0181 173 0.0153 174 0.0229 175 0.0303 176 0.0219 177
0.0208 178 0.0262 179 0.0398 180 0.0297 181 0.0266 182 0.0418 183
0.0396 184 0.0529 185 0.0290 186 0.0492 187 0.0453 188 0.0351 189
0.0806 190 0.0331 191 0.0789 192 0.0790 193 0.0348 194 0.0756 195
0.0506 196 0.0671 197 0.115 198 0.0560 199 0.0776 200 0.0493 201
0.0293 202 0.0352 203 0.135 204 0.104 205 0.140 206 0.0675 207
0.121 208 0.0417 209 0.105 210 0.150 211 0.115 212 0.0815 213
0.0430 214 0.121 215 0.0845 216 0.143 217 0.147 218 0.230 219 0.137
220 0.164 221 0.105 222 0.119 223 0.599 224 1.4 225 0.487 226 2.31
227 0.0414 228 0.0397 229 0.354 230 0.0837 231 0.461 232 0.0159 233
0.0831 234 0.169 235 0.226 236 0.239 237 0.733 238 0.547 239 0.016
240 0.081 241 0.59 242 1.03 243 1.44 244 3.38 245 0.0774
246 0.210 247 0.0427 248 0.0119 249 0.0132 250 0.0192 251 0.0193
252 0.0247 253 0.0114 254 0.0118 255 0.0176 256 0.302 257 0.109 258
0.0407 259 0.128 260 0.311 261 0.375 262 0.114 263 0.133 264 0.253
265 0.0622 266 0.223 267 0.0099 268 0.156 269 0.136 270 0.0191 271
0.0089 272 0.0119 273 0.0161 274 0.198 275 0.0686 276 0.177 277
0.188 278 0.317 279 1.81 280 0.0221 281 0.0101 282 0.0117 283
0.0218 284 0.346 285 2.16 286 1.11 287 2.37 288 0.139 289 1.61 290
0.944 291 0.332 292 0.0524 293 0.0137 294 0.0145 295 0.0180 296
0.0231 297 0.0168 298 0.0361 299 0.0175 300 0.0697 301 0.0417 302
0.0709 303 0.143 304 0.0144 305 0.0296 306 0.389 307 0.0454 308
0.0269 309 0.0308 310 0.0160 311 0.0278 312 0.0252 313 0.0259 314
0.0218 315 0.0363 316 0.0314 317 0.0389 318 0.0297 319 0.132 320
0.132 321 0.164 322 0.202 323 0.0367 324 1.05 325 0.644 326 3.21
327 0.302 328 1.06 329 0.841 330 2.68 331 0.965 332 0.268 333 0.658
334 0.103 335 0.209 336 0.136 337 0.313 338 0.264 339 0.915 340
0.808 341 4.28 342 0.255 343 1.48 344 0.0451 345 0.102 346 0.0111
347 0.0100 348 0.0154 349 0.0156 350 0.0227 351 0.0159 352 0.0188
353 0.0277 354 0.0681 355 0.0385 356 0.0784 357 0.0466 358 0.0141
359 0.0136 360 0.0200 361 0.0058 362 0.0042 363 0.0295 364 0.0158
365 0.0401 366 0.0097 367 0.0683 368 0.0210 369 3.71 370 0.0337 371
0.190 372 0.0894 373 0.0206 374 0.0524 375 0.0303 376 0.0530 377
0.0207 378 0.0503 379 0.270 380 0.245 381 0.0104 382 0.0069 383
0.0079 384 0.0058 385 0.0067 386 0.0105 387 0.279 388 2.98 389
0.0183 390 0.136 391 0.0117 392 0.0076 393 0.0061 394 0.0354 395
0.0066 396 0.0201 397 0.0103 398 0.189 399 0.0165 400 0.0069 401
0.0128 402 0.120 403 0.0178 404 3.55 405 0.0175 406 0.241 407
0.0596 408 0.0781 409 0.0892 410 0.0718 411 0.14 412 0.048 413
0.197 414 0.150 415 0.648 416 0.054 417 0.083 418 0.065 419 2.02
420 0.118 421 0.611 422 0.841 423 0.137 424 0.092 425 0.0105 426
0.0097 427 0.0140 428 1.29 429 2.66 430 0.0124 431 0.0564 432
0.0195 433 0.0079 434 0.0121 435 6.24 436 0.0224 437 0.225 438
0.0114
Icilin Biochemical Challenge Models
Inhibition of Icilin Induced Jumping in Mice
[0954] Example compounds at doses ranging from 0.01 to 10 mg/kg
were administered to male C57BL/6 mice (18-25 g, Taconic,
n=10/treatment) 1 h before icilin to assess the ability to block
the spontaneous jumps induced by icilin (i.p. suspended in 100%
PEG400 at 20 mg/kg, 5 mL/kg). The total number of jumps were
recorded during the 10 min post-icilin administration based on the
number of photocell beam breaks from the vertical array of open
field boxes (Kinder Scientific) while movement of the mice was
restricted within a clear Plexiglas cylinder 9.5 cm
diameter.times.30 cm height.
Inhibition of Icilin Induced Shaking in Rats
[0955] Example compounds at doses ranging from 0.01 to 3 mg/kg
(p.o, suspended in 5% Tween80/Oralplus or suspended in 2% HPMC-1%
Tween-80 pH2.2 with MSA, 5 mL/kg) were administered to male Sprague
Dawley rats (200-300 g, Harlan, n=6-8/treatment) 2 h before icilin
to assess the ability to block the spontaneous wet-dog shake
phenomena induced by icilin (i.p., suspended in 100% PEG400 at 0.5
mg/kg, 1 mL/kg or p.o., suspended in 2% HPMC-1% Tween-80 at 3
mg/kg, 2.5 mL/kg). Spontaneous wet-dog shakes were counted manually
by two blinded observers or using LABORAS automation (Metris) for
30 min post-icilin. Results are shown in Table 9.
TABLE-US-00009 TABLE 9 Inhibition of icilin induced wet dog shakes
in rats by select Examples % Inhibition Dose of Wet-Dog Example #
(mg/kg) Shakes 1 1 100 51 1 99 68 1 100 76 1 100 79 1 99 91 1 100
102 1 99 103 1 97 132 1 95 293 1 96 295 1 77 297 1 78 299 1 56 348
1 51 362 1 98 370 1 50 373 1 64 377 1 94 386 1 97 426 1 53 432 1 60
434 1 91
Cold Pressor Test (CPT) as a Translatable PD Model for TRPM8
[0956] The cold pressor test (CPT) was developed as a method to
measure blood pressure response following exposure to a cold
stimulus and has been used over 70 years in the diagnosis of
hypertension and other cardiac autonomic disorders (Hines and Brown
1936). In healthy human subjects, the CPT is typically performed by
immersing a subject's hand into ice water (0-5.degree. C.) which
triggers, through a vascular sympathetic activation of afferent
pain and temperature neurons, an increase in blood pressure. With
some modifications, this test has also been utilized in rat to
delineate the medullary and spinal pathways mediating the
cardio-vascular responses to cold pressor test and to identify
neurotransmitters in these pathways (Sapru N et al 2008) or to
characterize analgesic compounds (Koltzenburg M et al 2006 and
Player M R et al 2011).
[0957] TRPM8 antagonists were evaluated in rat CPT to determine
whether TRPM8 antagonists would attenuate the increase in blood
pressure resulting from exposure to cold stimulation of the paws
and ventral half of the body. Male Sprague-Dawley rats weighing
350-450 g were instrumented with a unilateral carotid
artery-cannula connected to a transducer for measuring blood
pressure using a Digi-Med Blood Pressure Analyzer, Model 400.
Animals were orally administrated with Vehicle (2% HPMC 1% Tween 80
pH 2.2 with MSA) or test compounds at 120 min prior to cold
challenge and anesthetized with sodium pentobarbital at 60 mg/kg ip
at 100 min prior to cold. Blood pressure was recorded for 5 min for
pre-cold baseline and additional 5 min during immersion of the paws
and ventral half of body in ice water. Percent inhibition
attributed to treatment with test compound was then determined
using the following Formula: [1-(cold evoked change in MBP/cold
evoked change in MBP post-vehicle)].times.100. Plasma was collected
through artery catheter immediately after CPT for pk analysis and
IC50/90 determination.
REFERENCES
[0958] Hines, E A and Brown G E. The cold pressor test for
measuring the reactability of the blood pressure. Am. Heart J.
1936, 11:1-9 [0959] Nakamura T, Kawabe K, and Sapru H N. Cold
pressor test in the rat: medullary and spinal pathways and
neurotransmitters. Am J Physiol Heart Circ Physiol 2008,
295:H1780-H1787 [0960] Koltzenburg M, Pokorny R, Gasser U and
Richarz U. Differential sensitivity of three experimental pain
models in detecting the analgesic effects of transdermal fentanyl
and buprenorphine. Pain 2006, 126:165-174 [0961] Parks D, Parsons
W, Colburn R, Meegala S, Ballentine S, Illig C, Qin N, Liu Y,
Hutchinson T, Lubin M, Stone D, Baker J, Schneider C, Ma J, Damiano
B, Flores C, and Player M. Design and optimization of
benzimidazole-containing transient receptor potentiate melastatin 8
(TRPM8) antagonists. J. Med. Chem. 2011, 54:233-247
CCI Model
[0962] Surgery--A chronic constriction injury (CCl) can be produced
as previously described (Bennett & Xie, 1988). Under gaseous
anesthesia with a mixture of isoflurane (3% for induction and 2%
for maintenance) in O.sub.2, the sciatic nerve can be exposed at
the mid-thigh level proximal to the sciatic trifurcation. Four
chromic gut ligatures (4-0) can be tied loosely around nerve, 1-2
mm apart such that the vascular supply will not be compromised.
Behavioral testing--A behavioral test can be performed to estimate
cold-induced ongoing pain as previously described (Choi et al.,
1994). The rat can be placed under a transparent plastic cover on
an aluminum plate (IITC PE34, Woodland, Calif.) which can be kept
at a cold temperature (5.+-.0.5.degree. C.). After 2 min of
adaptation, the cumulative duration of time that the rat lifts its
foot off the plate for the next 5 min can be measured. Foot lifts
associated with locomotion or grooming are not counted. Seven to 9
days after the CCI surgery, baseline of the cold-induced ongoing
pain can be measured. Any rat showing a cold-induced ongoing pain
less than 100 sec out of 300 sec observation period can be
eliminated from the study. Twenty four hours after the baseline
measurement, test compound, positive control, morphine (2 mg/kg,
Sigma, St. Louis) or a vehicle (saline or 2% HPMC/1% Tween 80) can
be administered orally (test compound) or subcutaneously
(morphine). Two hours (test compound) or 30 mins (morphine) after
the drug administration, the cold-induced ongoing pain can be
measured again.
Chung Model
[0963] Surgery--Spinal nerve ligation surgery can be performed as
previously described (Kim & Chung, 1992). Briefly, under
gaseous anesthesia with a mixture of isoflurane (3% for induction
and 2% for maintenance) in O.sub.2, the spinal nerve injury can be
produced by ligating the left L5 and L6 spinal nerves taking
special care to avoid any possible damage to the L4 spinal nerve or
surrounding area. Additional treatments can be performed to
increase the development of mechanical allodynia. First, L5 spinal
nerve can be cut approximately 1 mm distal to the suture as
described by Li et al. (2000). Second, immediately after ligation
and cut, the L4 spinal nerve can be lightly manipulated by slightly
stretching it with a fine hooked glass rod and gently sliding the
hook back and forth 20 times along the nerve as described by Lee et
al. (2003). The whole surgery procedure from anesthesia to the
clipping of the incised skin can take at most 15 min. Behavioral
testing--Two weeks later, mechanical sensitivity can be measured by
determining the median 50% foot withdrawal threshold for von Frey
filaments using the up-down method (Chaplan et al., 1994). The rats
can be placed under a plastic cover (9.times.9.times.20 cm) on a
metal mesh floor. The area tested consists of the middle glabrous
area between the footpads of the plantar surface of the hind paw.
The plantar area can be touched with a series of 9 von Frey hairs
with approximately exponentially incremental bending forces (von
Frey values: 3.61, 3.8, 4.0, 4.2, 4.41, 4.6, 4.8, 5.0 and 5.2;
equivalent to: 0.41, 0.63, 1.0, 1.58, 2.51, 4.07, 6.31, 10 and 15.8
g). The von Frey hair can be presented perpendicular to the plantar
surface with sufficient force to cause slight bending, and held for
approximately 3-4 sec. Abrupt withdrawal of the foot (paw
flinching, shaking or licking for more than 1 sec) can be recorded
as a response. Any rat showing a mechanical threshold of more than
3.16 g or less than 0.7 g after surgery can be eliminated from the
study. After measuring basal threshold, test compound, positive
control gabapentin (Sigma, St. Louis) or a vehicle (saline or 2%
HPMC/1% Tween 80) can be administered orally (test compound) or
intraperitoneally (gabapentin). The measurement of the tactile
threshold can be reassessed at 1.5 and 2 h after drug
administration. Data--Since the von Frey filament set is calibrated
on a logarithmic scale by the vendor (Stoelting) and our selection
of 9 filaments for the up-down method is also based on near equal
logarithmic intervals (Dixon et al., 1980), data can be treated
using logarithmic values in every aspect (statistical treatment as
well as plotting). However, an equivalent gram value scale is
labeled on the Y-axis of the figures for convenience. Data are
expressed as mean.+-.standard error of the mean (S.E.M.).
[0964] For the treatment of TRPM8-receptor-diseases, such as acute,
inflammatory and neuropathic pain, dental pain, general headache,
migraine, cluster headache, mixed-vascular and non-vascular
syndromes, tension headache, general inflammation, arthritis,
rheumatic diseases, osteoarthritis, inflammatory bowel disorders,
inflammatory eye disorders, inflammatory or unstable bladder
disorders, psoriasis, skin complaints with inflammatory components,
chronic inflammatory conditions, inflammatory pain and associated
hyperalgesia and allodynia, neuropathic pain and associated
hyperalgesia and allodynia, diabetic neuropathy pain, causalgia,
sympathetically maintained pain, deafferentation syndromes, asthma,
epithelial tissue damage or dysfunction, herpes simplex,
disturbances of visceral motility at respiratory, genitourinary,
gastrointestinal or vascular regions, wounds, burns, allergic skin
reactions, pruritus, vitiligo, general gastrointestinal disorders,
gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
induced by necrotising agents, hair growth, vasomotor or allergic
rhinitis, bronchial disorders or bladder disorders, the compounds
of the present invention may be administered orally, parentally, by
inhalation spray, rectally, or topically in dosage unit
formulations containing conventional pharmaceutically acceptable
carriers, adjuvants, and vehicles. The term parenteral as used
herein includes, subcutaneous, intravenous, intramuscular,
intrasternal, infusion techniques or intraperitoneally.
[0965] Treatment of diseases and disorders herein is intended to
also include the prophylactic administration of a compound of the
invention, a pharmaceutical salt thereof, or a pharmaceutical
composition of either to a subject (i.e., an animal, preferably a
mammal, most preferably a human) believed to be in need of
preventative treatment, such as, for example, pain, inflammation
and the like.
[0966] The dosage regimen for treating TRPM8-receptor-mediated
diseases, cancer, and/or hyperglycemia with the compounds of this
invention and/or compositions of this invention is based on a
variety of factors, including the type of disease, the age, weight,
sex, medical condition of the patient, the severity of the
condition, the route of administration, and the particular compound
employed. Thus, the dosage regimen may vary widely, but can be
determined routinely using standard methods. Dosage levels of the
order from about 0.01 mg to 30 mg per kilogram of body weight per
day, preferably from about 0.1 mg to 10 mg/kg, more preferably from
about 0.25 mg to 1 mg/kg are useful for all methods of use
disclosed herein.
[0967] The pharmaceutically active compounds of this invention can
be processed in accordance with conventional methods of pharmacy to
produce medicinal agents for administration to patients, including
humans and other mammals.
[0968] For oral administration, the pharmaceutical composition may
be in the form of, for example, a capsule, a tablet, a suspension,
or liquid. The pharmaceutical composition is preferably made in the
form of a dosage unit containing a given amount of the active
ingredient. For example, these may contain an amount of active
ingredient from about 1 to 2000 mg, preferably from about 1 to 500
mg, more preferably 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.
[0969] 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, preferably from about
0.1 to about 10 mg/kg, and more preferably from about 0.25 mg to 1
mg/kg.
[0970] Injectable preparations, such as sterile injectable aqueous
or oleaginous suspensions, may be formulated according to the known
are using suitable dispersing or wetting agents and suspending
agents. 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.
[0971] Suppositories for rectal administration of the drug can be
prepared by mixing the drug with a suitable non-irritating
excipient such as cocoa butter and polyethylene glycols that are
solid at ordinary temperatures but liquid at the rectal temperature
and will therefore melt in the rectum and release the drug.
[0972] A suitable topical dose of active ingredient of a compound
of the invention is 0.1 mg to 150 mg administered one to four,
preferably one or two times daily. For topical administration, the
active ingredient may comprise from 0.001% to 10% w/w, e.g., from
1% to 2% by weight of the formulation, although it may comprise as
much as 10% w/w, but preferably not more than 5% w/w, and more
preferably from 0.1% to 1% of the formulation.
[0973] Formulations suitable for topical administration include
liquid or semi-liquid preparations suitable for penetration through
the skin (e.g., liniments, lotions, ointments, creams, or pastes)
and drops suitable for administration to the eye, ear, or nose.
[0974] For administration, the compounds of this invention are
ordinarily combined with one or more adjuvants appropriate for the
indicated route of administration. The compounds may be admixed
with lactose, sucrose, starch powder, cellulose esters of alkanoic
acids, stearic acid, talc, magnesium stearate, magnesium oxide,
sodium and calcium salts of phosphoric and sulfuric acids, acacia,
gelatin, sodium alginate, polyvinyl-pyrrolidine, and/or polyvinyl
alcohol, and tableted or encapsulated for conventional
administration. Alternatively, the compounds of this invention may
be dissolved in saline, water, polyethylene glycol, propylene
glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil,
tragacanth gum, and/or various buffers. Other adjuvants and modes
of administration are well known in the pharmaceutical art. The
carrier or diluent may include time delay material, such as
glyceryl monostearate or glyceryl distearate alone or with a wax,
or other materials well known in the art.
[0975] The pharmaceutical compositions may be made up in a solid
form (including granules, powders or suppositories) or in a liquid
form (e.g., solutions, suspensions, or emulsions). 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.
[0976] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, and granules. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose, lactose, or starch.
[0977] Such dosage forms may also comprise, as in normal practice,
additional substances other than inert diluents, e.g., lubricating
agents such as magnesium stearate. In the case of capsules,
tablets, and pills, the dosage forms may also comprise buffering
agents. Tablets and pills can additionally be prepared with enteric
coatings.
[0978] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting, sweetening, flavoring, and perfuming agents.
[0979] Compounds of the present invention can possess 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. 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 active starting
materials. These isomers may be in the form of a free acid, a free
base, an ester or a salt.
[0980] Likewise, the compounds of this invention may exist as
isomers, that is compounds of the same molecular formula but in
which the atoms, relative to one another, are arranged differently.
In particular, the alkylene substituents of the compounds of this
invention, are normally and preferably arranged and inserted into
the molecules as indicated in the definitions for each of these
groups, being read from left to right. However, in certain cases,
one skilled in the art will appreciate that it is possible to
prepare compounds of this invention in which these substituents are
reversed in orientation relative to the other atoms in the
molecule. That is, the substituent to be inserted may be the same
as that noted above except that it is inserted into the molecule in
the reverse orientation. One skilled in the art will appreciate
that these isomeric forms of the compounds of this invention are to
be construed as encompassed within the scope of the present
invention.
[0981] The compounds of the present invention can be used in the
form of salts derived from inorganic or organic acids. The salts
include, but are not limited to, the following: acetate, adipate,
alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,
cyclopentanepropionate, dodecylsulfate, ethanesulfonate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methansulfonate,
nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate,
persulfate, 2-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, mesylate, and
undecanoate. 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.
[0982] Examples of acids that may be employed to from
pharmaceutically acceptable acid addition salts include such
inorganic acids as hydrochloric acid, sulfuric acid and phosphoric
acid and such organic acids as oxalic acid, maleic acid, succinic
acid and citric acid. Other examples include salts with alkali
metals or alkaline earth metals, such as sodium, potassium, calcium
or magnesium or with organic bases.
[0983] Also encompassed in the scope of the present invention are
pharmaceutically acceptable esters of a carboxylic acid or hydroxyl
containing group, including a metabolically labile ester or a
prodrug form of a compound of this invention. A metabolically
labile ester is one which may produce, for example, an increase in
blood levels and prolong the efficacy of the corresponding
non-esterified form of the compound. A prodrug form is one which is
not in an active form of the molecule as administered but which
becomes therapeutically active after some in vivo activity or
biotransformation, such as metabolism, for example, enzymatic or
hydrolytic cleavage. For a general discussion of prodrugs involving
esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988)
and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a
masked carboxylate anion include a variety of esters, such as alkyl
(for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl),
aralkyl (for example, benzyl, p-methoxybenzyl), and
alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have
been masked as arylcarbonyloxymethyl substituted derivatives which
are cleaved by esterases in vivo releasing the free drug and
formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs
containing an acidic NH group, such as imidazole, imide, indole and
the like, have been masked with N-acyloxymethyl groups (Bundgaard
Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been
masked as esters and ethers. EP 039,051 (Sloan and Little, Apr. 11,
1981) discloses Mannich-base hydroxamic acid prodrugs, their
preparation and use. Esters of a compound of this invention, may
include, for example, the methyl, ethyl, propyl, and butyl esters,
as well as other suitable esters formed between an acidic moiety
and a hydroxyl containing moiety. Metabolically labile esters, may
include, for example, methoxymethyl, ethoxymethyl,
iso-propoxymethyl, .alpha.-methoxyethyl, groups such as
.alpha.-((C.sub.1-C.sub.4)alkyloxy)ethyl, for example,
methoxyethyl, ethoxyethyl, propoxyethyl, iso-propoxyethyl, etc.;
2-oxo-1,3-dioxolen-4-ylmethyl groups, such as
5-methyl-2-oxo-1,3,dioxolen-4-ylmethyl, etc.; C.sub.1-C.sub.3
alkylthiomethyl groups, for example, methylthiomethyl,
ethylthiomethyl, isopropylthiomethyl, etc.; acyloxymethyl groups,
for example, pivaloyloxymethyl, .alpha.-acetoxymethyl, etc.;
ethoxycarbonyl-1-methyl; or .alpha.-acyloxy-.alpha.-substituted
methyl groups, for example .alpha.-acetoxyethyl.
[0984] Further, the compounds of the invention may exist as
crystalline solids which can be crystallized from common solvents
such as ethanol, N,N-dimethyl-formamide, water, or the like. Thus,
crystalline forms of the compounds of the invention may exist as
polymorphs, solvates and/or hydrates of the parent compounds or
their pharmaceutically acceptable salts. All of such forms likewise
are to be construed as falling within the scope of the
invention.
[0985] While the compounds of the invention can be administered as
the sole active pharmaceutical agent, they can also be used in
combination with one or more compounds of the invention or other
agents. When administered as a combination, the therapeutic agents
can be formulated as separate compositions that are given at the
same time or different times, or the therapeutic agents can be
given as a single composition.
[0986] The foregoing is merely illustrative of the invention and is
not intended to limit the invention to the disclosed compounds.
Variations and changes which are obvious to one skilled in the art
are intended to be within the scope and nature of the invention
which are defined in the appended claims.
[0987] 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.
* * * * *