U.S. patent application number 17/344947 was filed with the patent office on 2021-12-16 for cyclobutyl dihydroquinoline sulfonamide compounds.
This patent application is currently assigned to AMGEN INC.. The applicant listed for this patent is AMGEN INC.. Invention is credited to Alan H CHERNEY, Isaac E MARX, Benjamin C MILGRAM, Haoxuan WANG.
Application Number | 20210387978 17/344947 |
Document ID | / |
Family ID | 1000005680101 |
Filed Date | 2021-12-16 |
United States Patent
Application |
20210387978 |
Kind Code |
A1 |
MILGRAM; Benjamin C ; et
al. |
December 16, 2021 |
CYCLOBUTYL DIHYDROQUINOLINE SULFONAMIDE COMPOUNDS
Abstract
The present invention provides a cyclobutyl dihydroquinoline
sulfonamide compound of Formula (I), ##STR00001## an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, that inhibits
voltage-gated sodium channels, in particular Nav1.7. The compounds
are useful for the treatment of diseases associated with the
activity of sodium channels such as pain disorders, cough, and
itch. Also provided are pharmaceutical compositions containing the
compounds of the present invention. Also further provided is an
atropi-selective preparation of said compounds of Formula (I), and
intermediate thereof.
Inventors: |
MILGRAM; Benjamin C;
(Cambridge, MA) ; MARX; Isaac E; (Arlington,
MA) ; WANG; Haoxuan; (Somerville, MA) ;
CHERNEY; Alan H; (Somerville, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
THOUSAND OAKS |
CA |
US |
|
|
Assignee: |
AMGEN INC.
THOUSAND OAKS
CA
|
Family ID: |
1000005680101 |
Appl. No.: |
17/344947 |
Filed: |
June 11, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
63037001 |
Jun 10, 2020 |
|
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 413/12 20130101;
A61P 25/04 20180101; C07D 401/12 20130101 |
International
Class: |
C07D 413/12 20060101
C07D413/12; A61P 25/04 20060101 A61P025/04; C07D 401/12 20060101
C07D401/12 |
Claims
1. A compound of Formula (I): ##STR00119## an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof; wherein: R.sup.1 is a
saturated or partially-saturated 4-membered monocyclic ring; or a
4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring;
wherein said monocyclic ring or bicyclic ring contains 0, 1, 2 or 3
N atoms and 0, 1, or 2 atoms selected from O and S; and wherein
said monocyclic ring or bicyclic ring is substituted by 0, 1, 2 or
3 R.sup.1a groups selected from hydroxy, halo, C.sub.1-8alk,
C.sub.1-8haloalk, --O--C.sub.1-4alk, --O--C.sub.1-8haloalk,
--C(.dbd.O)C.sub.1-4alk, --O--C(.dbd.O)C.sub.1-4alk, --NH.sub.2,
--NHC.sub.1-4alk, or --N(C.sub.1-4alk)C.sub.1-4alk; R.sup.2 is H,
halo, C.sub.1-6alk, or C.sub.1-6haloalk; R.sup.3 is C.sub.1-6alk,
C.sub.1-6haloalk, --O--C.sub.1-6alk, or --CN; R.sup.4 is a 5- to
6-membered heteroaryl; Each of R.sup.6 and R.sup.7 is hydrogen; and
Each of R.sup.5a; R.sup.5b; R.sup.5c; R.sup.5d; and R.sup.5e is
independently hydrogen or halo.
2. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.1a
group is selected from halo, C.sub.1-8alk, --O--C.sub.1-4alk, or
C.sub.1-8haloalk, wherein said C.sub.1-8haloalk is
C.sub.1-8fluoroalkyl.
3. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.1 is a
cyclobutyl ring; or a 5-, or 6-membered bicyclic ring; wherein said
cyclobutyl ring or bicyclic ring contains 0 N, O, and S atoms; and
wherein said cyclobutyl ring or bicyclic ring is substituted by 1,
2 or 3 R.sup.1a groups selected from F, --CF.sub.3, --O--CF.sub.3,
or --C(CH.sub.3).sub.3.
4. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.1 is a
cyclobutyl ring or bicyclo[1.1.1]pentan-1-yl ring; wherein each
ring is substituted by 1 or 2 F or --CF.sub.3.
5. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.1 is a
cyclobutyl ring substituted by 1 or 2 F or --CF.sub.3.
6. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.1 is a
cyclobutyl ring substituted by 1 or 2 --CF.sub.3.
7. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.1 is a
cyclobutyl ring substituted by 1 or 2 F.
8. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.1 is a
bicyclo[1.1.1]pentan-1-yl ring substituted by 1 or 2 F or
--CF.sub.3.
9. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.2 is
H, fluoro, chloro, methyl, CF.sub.3, CHF.sub.2, or CH.sub.2F.
10. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.2 is
H, fluoro, chloro, or methyl.
11. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.2 is H
or fluoro.
12. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.3 is
methoxy.
13. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.4 is a
5-membered heteroaryl.
14. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.4 is a
6-membered heteroaryl.
15. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.4 is
isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or
pyrimidinyl.
16. The compound according to claim 15, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.4 is
isoxazolyl.
17. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein (a) each of
R.sup.5a; R.sup.5b; R.sup.5c; R.sup.5d; and R.sup.5e is hydrogen;
(b) R.sup.5a is F; and each of R.sup.5b; R.sup.5c; R.sup.5d; and
R.sup.5e is hydrogen; or (c) R.sup.5c is F; and each of R.sup.5a;
R.sup.5b; R.sup.5d; and R.sup.5e is hydrogen.
18. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said R.sup.5a is
F.
19. The compound according to claim 15, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein each of R.sup.5a;
R.sup.5b; R.sup.5c; R.sup.5d; and R.sup.5e is hydrogen.
20. The compound according to claim 15, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein R.sup.5a is F;
and each of R.sup.5b; R.sup.5c; R.sup.5d; and R.sup.5e is
hydrogen.
21. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said compound of
Formula (I) is selected from compounds of Formula (Ia), (Ib), or
(Ic): ##STR00120## wherein each R.sup.1a in said compounds of
Formula (Ia), (Ib), or (Ic) is independently fluoro, chloro,
methyl, --O--CF.sub.3, or CF.sub.3.
22. The compound according to claim 21, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said compound of
Formula (I) is a compound of Formula (Ia); wherein said R.sup.1a is
CF.sub.3; the cyclobutyl ring is a trans isomer; and R.sup.4 is
isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.
23. The compound according to claim 21, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said compound of
Formula (I) is a compound of Formula (Ia); wherein said R.sup.1a is
cis CF.sub.3; the cyclobutyl ring is a cis isomer; R.sup.2 is F;
and R.sup.4 is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or
oxazolyl.
24. The compound according to claim 21, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said compound of
Formula (I) is a compound of Formula (Ib); wherein each R.sup.1a is
fluoro; R.sup.2 is F; and R.sup.4 is isoxazolyl, pyridazinyl,
thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.
25. The compound according to claim 21, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said compound of
Formula (I) is a compound of Formula (Ib); wherein each R.sup.1a is
fluoro; R.sup.5a is F; and R.sup.4 is isoxazolyl, pyridazinyl,
thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.
26. The compound according to claim 21, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said compound of
Formula (I) is a compound of Formula (Ic); wherein each R.sup.1a is
CF.sub.3.
27. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, or a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from: a)
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N--
(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c)
cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)ph-
enyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
d)
trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)-
phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
e)
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; f)
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; g)
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)-
cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; h)
trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-
-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide; i)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide; j)
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobut-
yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
k)
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxa-
zol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; l)
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-
-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; m)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-
-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfon-
amide; n)
trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)c-
yclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de; or o) trans
(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl-
)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
28. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, or a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from: a)
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-
-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; b)
(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxypheny-
l)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; c)
trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methox-
yphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
d)
cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyp-
henyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
e)
cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyp-
henyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
f)
trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methox-
yphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
g)
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(i-
soxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or h)
(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-
-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
29. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, or a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from: a)
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
or b)
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.
30. The compound according to claim 1, an enantiomer,
diastereoisomer, atropisomer thereof, a mixture thereof, or a
pharmaceutically acceptable salt thereof, wherein said atropisomer
is a P atropisomer.
31. A pharmaceutical composition comprising a compound according to
claim 1, an enantiomer, diastereoisomer, atropisomer thereof, a
mixture thereof, or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable excipient.
32. A method of treating pain, cough, or itch, the method
comprising administering to a patient in need thereof a
therapeutically effective amount of a compound according to claim
1, an enantiomer, diastereoisomer, atropisomer thereof, a mixture
thereof, or a pharmaceutically acceptable salt thereof.
33. The method according to claim 32; wherein the pain is selected
from chronic pain, acute pain, neuropathic pain, pain associated
with rheumatoid arthritis, pain associated with osteoarthritis,
pain associated with cancer, peripheral diabetic neuropathy, and
neuropathic low back pain.
34. The method according to claim 32; wherein the cough is selected
from post viral cough, viral cough, or acute viral cough.
35. A method of preparation of a compound of Formula (A):
##STR00121## wherein R is halo; comprising: (1) reacting a trans
olefin compound of Formula (B): ##STR00122## wherein R is halo; and
R.sup.1 is C.sub.1-C.sub.6alkyl; with a UV light or near UV light;
to form a cis olefin compound (C); and (2) reacting said compound
(C) with a chiral acid in an organic solvent to form said compound
of Formula (A).
36. The method of claim 35, wherein said chiral acid is a
phosphorus chiral acid.
37. The method of claim 35 wherein said chiral acid is (S)-TRIP
having the formula: ##STR00123##
38. The method of claim 35, wherein said organic solvent is
dichloromethane.
39. The method of claim 35, wherein said R is bromo.
40. The method of claim 35, wherein said R.sup.1 is ethyl.
41. The method of claim 35, wherein in reaction (2), a P
atropisomer of said compound of Formula (A) is selectively
formed.
42. The method of claim 35, wherein said compound of Formula (A) is
used as an intermediate compound in preparation of a compound of
Formula (I): ##STR00124## or a pharmaceutically acceptable salt
thereof, wherein: R.sup.1 is a saturated or partially-saturated
4-membered monocyclic ring; or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-,
or 12-membered bicyclic ring; wherein said monocyclic ring or
bicyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms
selected from O and S; and wherein said monocyclic ring or bicyclic
ring is substituted by 0, 1, 2 or 3 R.sup.1a groups selected from
hydroxy, halo, C.sub.1-8alk, C.sub.1-8haloalk, --O--C.sub.1-4alk,
--O--C.sub.1-8haloalk, --C(.dbd.O)C.sub.1-4alk,
--O--C(.dbd.O)C.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk; R.sup.2 is H, halo, C.sub.1-6alk, or
C.sub.1-6haloalk; R.sup.3 is C.sub.1-6alk, C.sub.1-6haloalk,
--O--C.sub.1-6alk, or CN; R.sup.4 is a 5- to 6-membered heteroaryl;
Each of R.sup.6 and R.sup.7 is hydrogen; and Each of R.sup.5a;
R.sup.5b; R.sup.5c; R.sup.5d; and R.sup.5e is independently
hydrogen or halo; and Wherein a P atropisomer of said compound of
Formula (I) is selectively formed.
Description
RELATED APPLICATION
[0001] This application claims priority from U.S. Provisional
Application No. 63/037,001, having a filing date of Jun. 10,
2020.
FIELD OF THE INVENTION
[0002] The present invention provides cyclobutyl dihydroquinoline
compounds that are inhibitors of voltage-gated sodium channels
(Nav), in particular Nav 1.7, and are useful for the treatment of
diseases treatable by inhibition of sodium channels such as pain
disorders. Also provided are pharmaceutical compositions containing
compounds of the present invention.
BACKGROUND OF THE INVENTION
[0003] A 2011 report of the institute of medicine estimates that
100 million adults in the US, roughly 30% of the population, suffer
from chronic pain (C & E News, Bethany Halford, "Changing the
Channel", published 3-24). Chronic pain by definition involves
abnormal electrical spiking of neurons in the pain pathways:
peripheral sensory neurons, spinal cord neurons, neurons in the
pain matrix of the brain (e.g., somatosensory cortex, insular
cortex, anterior cingular cortex), and/or neurons in brainstem.
Although firing of these neurons is modulated and governed by many
different receptors, enzymes, and growth factors, in most neurons
the fast upstroke of the electrical spike is produced by entry of
sodium ions through voltage-gated sodium channels (Hille B, Ion
Channels of Excitable Membranes. Sinauer Associates, Inc.:
Sunderland Mass., 3.sup.rd Ed. 2001). There are nine different
isoforms of voltage-gated sodium channel (Nav 1.1-Nav 1.9), and
they have distinct expression patterns in tissues including neurons
and cardiac and skeletal muscle (Goldin, A. L, "Resurgence of
sodium channel research,"Ann Rev Physiol 63:871-894, 2001; Wood, J.
N. and, Boorman, J. "Voltage-gated sodium channel blockers; target
validation and therapeutic potential" Curr. Top Med. Chem.
5:529-537, 2005).
[0004] Nav1.1 and Nav1.2 are highly expressed in the brain
(Raymond, C. K., et al., J. Biol. Chem. (2004) 279 (44):46234-41)
and are vital to normal brain function. Some loss of function due
to Nav 1.1 mutations in humans, have resulted in epilepsy,
presumably as these channels are expressed in inhibitory neurons
(Yu, F. H., et al., Nat. Neuroscience (2006), 9 (9) 1142-1149).
Nav1.1 is also expressed in the peripheral nervous system and
inhibition of Nav1.1 in the periphery may provide relief of pain.
Hence, while inhibiting Nav1.1 may provide use for treating pain,
it may also be undesirable possibly leading to anxiety and over
excitability. Nav1.3 is expressed primarily in the fetal central
nervous system, and expression was found to be upregulated after
nerve injury in rats (Haim, B. D., et al., J. Neuroscience (2030)
23(26):8881-8892). Nav1.4 is expressed primarily in skeletal
muscle. Mutations of the gene and its' product have significant
impact on muscle function, including paralysis (Tamaoka A.,
Internal Medicine (2003), (9):769-770). Nav1.5 is expressed mainly
in cardiac myocytes, including atria, ventricles, the sino-atrial
node, atrioventricular node and cardiac Purkinje fibers. The rapid
upstroke of the cardiac action potential and the rapid impulse
conduction through cardiac tissue is due to the opening of the
Nav1.5 channel Mutations of the Nav1.5 channel have resulted in
arrhythmic syndromes, including QTc prolongation, Brugada syndrome
(BS), sudden unexpected nocturnal death syndrome (SUNDS) and sudden
infant death syndrome (SIDS) (Liu, H., et al., Am. J.
Pharmacogenomics (2003), 3(3):173-179). Nav1.6 is widely
distributed voltage-gated sodium channel expressed throughout the
central and peripheral nervous system. Nav1.8 is expressed
primarily in sensory ganglia of the peripheral nervous system, such
as the dorsal root ganglia. There are no identified Nav1.8
mutations that produce varied pain responses in humans. Nav1.8
differs from most neuronal Nav isotypes in that it is insensitive
to inhibition by tetrodotoxin. Nav1.9, similar to Nav1.8, is also a
tetrodotoxin insensitive sodium channels expressed primarily in
dorsal root ganglia neurons (Dib-Hajj, S. D., et al., Proc. Natl.
Acad. Sci. USA (1998), 95(15):8963-8968).
[0005] Recent evidence from several independent genetic studies has
shown that the tetrodotoxin-sensitive voltage-gated sodium ion
channel Nav 1.7 (SCN9A) is required to sense pain. Rare genetic
forms of severe chronic pain, Primary Erythromelalgia and
Paroxysmal Extreme Pain Disorder, result from mutations that
increase the activity of Nav 1.7 (Fertleman C. R., Baker M. D.,
Parker K. A., Moffatt S., et al., "SCN9A mutations in paroxysmal
extreme pain disorder: allelic variants underlie distinct channel
defects and phenotypes," Neuron 52:767-774, 2006; Yang Y., Wang Y.,
Li S, et al., "Mutations in SCN9A, encoding a sodium channel alpha
subunit, in patients with primary erythermalgia," J. Med. Genet.
41:171-174, 2004; Drenth J. P. H., to Morsche R. H. M., Guillet G.,
Taieb A., et al., "SCN9A mutations define primary erythermalgia as
a neuropathic disorder of voltage gated sodium channels," J Invest
Dermatol 124:1333-1338). Conversely, two separate clinical studies
have determined that the root cause of the genetic disorder
Congenital Indifference to Pain (CIP) is a loss of function of Nav
1.7 via mutations that truncate the protein and destroy function
(Cox J. J., Reimann F, Nicholas A. K., et al. "An SCN9A
channelopathy causes congenital inability to experience pain,"
Nature 444:894-898, 2006; Goldberg Y. P., MacFarlane J., MacDonald
M. L., Thompson J., et al. "Loss-of-function mutations in the
Nav1.7 gene underlie congenital indifference to pain in multiple
human populations," Clin Genet 71:311-319, 2007). The disorder is
inherited in Mendelian recessive manner with 100% penetrance. The
phenotype associated with CIP is extreme: affected individuals are
reported to have experienced painless burns, childbirth,
appendicitis, and bone fractures, as well as to have insensitivity
to clinical measures of pain such as pinprick or tendon pressure.
Yet sensory, motor, autonomic, and other measured functions are
normal, with the only reported abnormality being anosmia (inability
to smell). These studies indicate that among the many possible
targets in the pain pathway, Nav 1.7 governs one or more control
points critical for pain perception.
[0006] Nonselective sodium channel inhibitors such as lidocaine,
mexiletine, and carbamazepine show clinical efficacy in chronic
pain, including neuropathic pain, but they are limited in dose and
in use, likely due to effects on sodium channels outside the pain
pathway. Lidocaine is a local anesthetic doctors use for minor
surgery. Dentists use novocaine. However, these compounds do not
distinguish between the various sodium channel subtypes, making
them unsuitable for use as systemic pain killers. "If you give a
drug that blocks Nav1.7 but also blocks Nav1.5, the patient will
die of heart failure," says Glenn F. King, a professor at
Australia's University of Queensland who studies venoms that block
ion channels. "It will be a completely painless death, but the
patient will die nonetheless." Thus, selectivity for Nav1.7 is
desired, particularly over Nav1.5. Researchers have tailored their
efforts to find a molecule that inhibitors or block the activity of
only Nav1.7. To compound this problem, the identity, every
location, every function and/or the tertiary structures of each
subtype of voltage gated sodium channel proteins are not known or
completely understood.
[0007] Consequently, a number of researchers are attempting to
identify small molecule inhibitors of Nav1.7. For example, Chafeev
et al disclose spiro-oxindole compound for the treatment and/or
prevention of sodium channel-mediated diseases, such as pain, in
U.S. Pat. No. 8,101,647. International Publications WO 2013/134518
and WO 2014/201206 disclose sulfonamide derivatives which are
different from the sulfonamide derivatives of the present
invention. Thus, there is a need to identify Nav1.7 inhibitors
selective over at least Nav1.5 to treat pain. The present invention
provides compounds that are selective inhibitors of Nav 1.7. over
at least Nav1.5.
SUMMARY OF THE INVENTION
[0008] In embodiment 1, the present invention provides a compound
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof,
##STR00002##
[0009] wherein:
[0010] R.sup.1 is a saturated or partially-saturated 4-membered
monocyclic ring; or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring; wherein said monocyclic ring or bicyclic
ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected
from O and S; and wherein said monocyclic ring or bicyclic ring is
substituted by 0, 1, 2 or 3 R.sup.1a groups selected from hydroxy,
halo, C.sub.1-8alk, C.sub.1-8haloalk, --O--C.sub.1-4alk,
--O--C.sub.1-8haloalk, --C(.dbd.O)C.sub.1-4alk,
--O--C(.dbd.O)C.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk;
[0011] R.sup.2 is H, halo, C.sub.1-6alk, or C.sub.1-6haloalk;
[0012] R.sup.3 is C.sub.1-6alk, C.sub.1-6haloalk,
--O--C.sub.1-6alk, or CN;
[0013] R.sup.4 is a 5- to 6-membered heteroaryl;
[0014] Each of R.sup.6 and R.sup.7 is hydrogen; and
[0015] Each of R.sup.5a; R.sup.5b; R.sup.5b; R.sup.5d; and R.sup.5e
is independently hydrogen or halo.
[0016] In sub-embodiment 1a of embodiment 1, the compound of
Formula (I) has a sub-Formula of (Ia):
##STR00003##
wherein R.sub.1a is fluoro, chloro, methyl, --O--CF.sub.3, or
CF.sub.3.
[0017] In a more preferred sub embodiment 1a of embodiment 1,
R.sup.1a is CF.sub.3 or --O--CF.sub.3; R.sup.2 is H, F, or methyl;
and R.sup.4 is isoxazolyl or pyridazinyl.
[0018] In a most preferred sub embodiment 1a of embodiment 1,
R.sup.1a is CF.sub.3; R.sup.2 is F; and R.sup.4 is isoxazolyl.
[0019] In sub-embodiment 1b of embodiment 1, the compound of
Formula (I) has a sub-Formula of (Ib):
##STR00004##
wherein each R.sup.1a is fluoro or CF.sub.3.
[0020] In a more preferred sub embodiment 1b of embodiment 1, each
R.sup.1a is F; R.sup.2 is F or Cl; and R.sup.4 is isoxazolyl.
[0021] In a most preferred sub embodiment 1b of embodiment 1, each
R.sup.1a is F; R.sup.2 is F; and R.sup.4 is isoxazolyl.
[0022] In sub-embodiment 1c of embodiment 1, the compound of
Formula (I) has a sub-Formula of (Ic):
##STR00005##
wherein R.sup.1a is CF.sub.3.
[0023] In a more preferred sub embodiment 1c of embodiment 1,
R.sup.1a is CF.sub.3; R.sup.2 is F; and R.sup.4 is isoxazolyl or
pyrimidyl.
[0024] In a most preferred sub embodiment 1c of embodiment 1,
R.sup.1a is CF.sub.3; R.sup.2 is F; and R.sup.4 is isoxazolyl.
[0025] In embodiment 2, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein the R.sup.1a group is selected from halo,
C.sub.1-8alk, --O--C.sub.1-4alk, or C.sub.1-8haloalk, wherein said
C.sub.1-8haloalk is C.sub.1-8fluoroalkyl.
[0026] In embodiment 3, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is a cyclobutyl ring; or a 5-, or
6-membered bicyclic ring; wherein said cyclobutyl ring or bicyclic
ring contains 0 N, O, and S atoms; and wherein said cyclobutyl ring
or bicyclic ring is substituted by 1, 2 or 3 R.sup.1a groups
selected from F, --CF.sub.3, --O--CF.sub.3, or
--C(CH.sub.3).sub.3.
[0027] In embodiment 4, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is a cyclobutyl ring or
bicyclo[1.1.1]pentan-1-yl ring; wherein each ring is substituted by
1 or 2 F or --CF.sub.3.
[0028] In embodiment 5, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is a cyclobutyl ring substituted by 1 or 2
F or --CF.sub.3.
[0029] In sub-embodiment 5a of embodiment 5, the compound of
Formula (I) has the above sub-Formula of (Ia) and R.sup.1a is
F.
[0030] In sub-embodiment 5b of embodiment 5, the compound of
Formula (I) has the above sub-Formula of (Ib) and R.sup.1a is
--CF.sub.3.
[0031] In sub-embodiment 5c of embodiment 5, R.sup.1 is a
cyclobutyl ring substituted by 1 --CF.sub.3.
[0032] In sub-embodiment 5d of embodiment 5, R.sup.1 is a
cyclobutyl ring substituted by 1 or 2 F.
[0033] In sub-embodiment 5c of embodiment 5, the compound of
Formula (I) has the above sub-Formula of (Ic) and R.sup.1a is
--CF.sub.3.
[0034] In embodiment 6, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is a bicyclo[1.1.1]pentan-1-yl ring
substituted by 1 or 2 F or --CF.sub.3.
[0035] In embodiment 7, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is H, fluoro, chloro, methyl, CF.sub.3,
CHF.sub.2, or CH.sub.2F. In sub embodiment 7a of embodiment 7,
R.sup.2 is fluoro.
[0036] In embodiment 8, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is H, fluoro, chloro, or methyl.
[0037] In embodiment 9, the present invention provides compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or a pharmaceutically acceptable salt
thereof, wherein R.sup.2 is H or fluoro.
[0038] In embodiment 10, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein R.sup.3 is methoxy.
[0039] In embodiment 11, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 is a 5-membered heteroaryl.
[0040] In embodiment 12, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 is a 6-membered heteroaryl.
[0041] In embodiment 13, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 is isoxazolyl, pyridazinyl,
thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.
[0042] In a sub embodiment of embodiment 13a of embodiment 13,
R.sup.4 is isoxazolyl, pyridazinyl, or pyrimidyl.
[0043] In another sub embodiment 13b of embodiment 13, R.sup.4 is
isoxazolyl.
[0044] In embodiment 14a, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein each of R.sup.5a; R.sup.5b; R.sup.5c;
R.sup.5d; and R.sup.5e is hydrogen.
[0045] In embodiment 14b, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein R.sup.5a is F; and each of R.sup.5b;
R.sup.5c; R.sup.5d; and R.sup.5e is hydrogen.
[0046] In embodiment 14c, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein R.sup.5c is F; and each of R.sup.5a;
R.sup.5b; R.sup.5d; and R.sup.5e is hydrogen.
[0047] In embodiment 15, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein said compound of Formula (I) is selected from
compounds of Formula (Ia), (Ib), or (Ic):
##STR00006##
[0048] wherein each R.sup.1a in said compounds of Formula (Ia),
(Ib), or (Ic) is independently fluoro, chloro, methyl,
--O--CF.sub.3, or CF.sub.3.
[0049] In embodiment 16, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein said compound of Formula (I) is a compound of
Formula (Ia); wherein R.sup.1a is CF.sub.3; the cyclobutyl ring is
a trans isomer; and R.sup.4 is isoxazolyl, pyridazinyl, thiazolyl,
thiadiazolyl, or oxazolyl.
[0050] In embodiment 16a, said compound of Formula (I) is a
compound of Formula (Ia); wherein R.sup.1a is cis CF.sub.3; the
cyclobutyl ring is a cis isomer; R.sup.2 is F; and R.sup.4 is
isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.
[0051] In embodiment 16b, said compound of Formula (I) is a
compound of Formula (Ib); wherein each R.sup.1a is fluoro; R.sup.2
is F; and R.sup.4 is isoxazolyl, pyridazinyl, thiazolyl,
thiadiazolyl, oxazolyl, or pyrimidinyl.
[0052] In embodiment 16c, said compound of Formula (I) is a
compound of Formula (Ib); wherein each R.sup.1a is fluoro; R.sup.5a
is F; and R.sup.4 is isoxazolyl, pyridazinyl, thiazolyl,
thiadiazolyl, oxazolyl, or pyrimidinyl.
[0053] In embodiment 16d, said compound of Formula (I) is a
compound of Formula (Ic); wherein each R.sup.1a is CF.sub.3.
[0054] In embodiment 17, the present invention provides compounds
of Formula (I), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein the compound is selected from:
[0055] 1)
(M)-1-(4-(3-(tert-Butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N--
(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0056] 2)
1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(iso-
xazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0057] 3)
(P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N--
(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0058] 4)
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(i-
soxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0059] 5)
(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-met-
hoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0060] 6)
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)p-
henyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0061] 7)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0062] 8)
trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-
-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de;
[0063] 9)
cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-
-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide-
;
[0064] 10)
cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)--
2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamid-
e;
[0065] 11)
trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl-
)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonam-
ide;
[0066] 12) cis-(P)-1-(5-chloro-2-methoxy-4-41 S,3
S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihy-
droquinoline-6-sulfonamide;
[0067] 13) trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3
S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihy-
droquinoline-6-sulfonamide;
[0068] 14)
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-
-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0069] 15)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobuty-
l)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0070] 16)
cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)-
phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0071] 17)
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobuty-
l)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0072] 18)
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidi-
n-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0073] 19)
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobuty-
l)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0074] 20)
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(triflu-
oromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0075] 21)
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-
-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0076] 22)
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-
-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0077] 23)
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazi-
n-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0078] 24)
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-
-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0079] 25)
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,-
2-dihydroquinoline-6-sulfonamide;
[0080] 26)
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1-
,2-dihydroquinoline-6-sulfonamide;
[0081] 27)
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(4-methoxybenzy-
l)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0082] 28)
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidi-
n-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0083] 29)
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2--
dihydroquinoline-6-sulfonamide;
[0084] 30)
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazi-
n-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0085] 31)
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1-
,2-dihydroquinoline-6-sulfonamide;
[0086] 32)
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-
-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0087] 33)
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazi-
n-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0088] 34)
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-
-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0089] 35)
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl-
)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0090] 36)
trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl-
)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0091] 37)
trans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobuty-
l)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0092] 38)
trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-
-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0093] 39)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobuty-
l)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0094] 40)
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethy-
l)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfon-
amide;
[0095] 41)
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-f-
luoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0096] 42)
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]p-
entan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonam-
ide;
[0097] 43)
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phen-
yl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0098] 44)
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0099] 45)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobut-
yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-
e-6-sulfonamide;
[0100] 46)
trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)-
cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonam-
ide;
[0101] 47)
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]p-
entan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfona-
mide;
[0102] 48)
(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(-
isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide; or [0103]
49) trans
(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)-
phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0104] In embodiment 18, the present invention provides a compound
of Formula (I), having sub-Formula of (Ia):
##STR00007##
an enantiomer, diastereoisomer, atropisomer thereof, or a mixture
thereof, or a pharmaceutically acceptable salt thereof, wherein the
compound is selected from:
[0105] 1)
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)p-
henyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0106] 2)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0107] 3)
cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cycl-
obutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0108] 4)
trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cy-
clobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamid-
e;
[0109] 5)
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0110] 6)
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0111] 7)
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluo-
romethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0112] 8)
trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)-
phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0113] 9)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0114] 10)
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethy-
l)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfon-
amide;
[0115] 11)
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phen-
yl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0116] 12)
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0117] 13)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobut-
yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-
e-6-sulfonamide;
[0118] 14)
trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)-
cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonam-
ide; or
[0119] 15) trans
(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)
[0120] 16)
phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamid-
e.
[0121] In sub-embodiment 18a of embodiment 18, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ia), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein the compound is selected from:
[0122] 1)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0123] 2)
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluo-
romethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0124] 3)
trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)-
phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0125] 4)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;
[0126] 5)
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobuty-
l)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-
-6-sulfonamide; or 6)
trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0127] In sub-embodiment 18b of embodiment 18, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ia), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, wherein the compound is
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0128] In sub-embodiment 18c of embodiment 18, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ia), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)-
cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0129] In sub-embodiment 18d of embodiment 18, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ia), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-
-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.
[0130] In sub-embodiment 18e of embodiment 18, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ia), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.
[0131] In sub-embodiment 18f of embodiment 18, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ia), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-
-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfon-
amide.
[0132] In sub-embodiment 18g of embodiment 18, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ia), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0133] In embodiment 19, the present invention provides a compound
of Formula (I), having sub-Formula of (Ib):
##STR00008##
an enantiomer, diastereoisomer, atropisomer thereof, or a mixture
thereof, or a pharmaceutically acceptable salt thereof, which is
selected from:
[0134] 1)
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(i-
soxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0135] 2)
(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-met-
hoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0136] 3)
trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-
-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de;
[0137] 4)
cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-
-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide-
;
[0138] 5)
cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-
-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide-
;
[0139] 6)
trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-
-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de;
[0140] 7)
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fl-
uoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
or
[0141] 8)
(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(i-
soxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0142] In sub-embodiment 19a of embodiment 19 the present invention
provides a compound of Formula (I), having the above sub-Formula of
(Ib), an enantiomer, diastereoisomer, atropisomer thereof, or a
mixture thereof, or a pharmaceutically acceptable salt thereof,
which is selected from:
[0143] 1)
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(i-
soxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
[0144] 2)
trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-
-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de;
[0145] 3)
cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-
-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide-
; or 4)
trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-
-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide-
.
[0146] In sub-embodiment 19b of embodiment 19, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ib), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-
-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0147] In sub-embodiment 19c of embodiment 19, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ib), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methox-
yphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0148] In sub-embodiment 19d of embodiment 19, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ib), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyp-
henyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0149] In sub-embodiment 19e of embodiment 19, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ib), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methox-
yphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0150] In embodiment 20, the present invention provides a compound
of Formula (I) having a sub-Formula of (Ic):
##STR00009##
an enantiomer, diastereoisomer, atropisomer thereof, or a mixture
thereof, or a pharmaceutically acceptable salt thereof, which is
selected from:
[0151]
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]penta-
n-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;
or
[0152]
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]penta-
n-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide-
.
[0153] In sub-embodiment 20a of embodiment 20, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ic), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
[0154] In sub-embodiment 20b of embodiment 20, the present
invention provides a compound of Formula (I), having the above
sub-Formula of (Ic), an enantiomer, diastereoisomer, atropisomer
thereof, or a mixture thereof, or a pharmaceutically acceptable
salt thereof, which is
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.
[0155] In embodiment 21, the present invention provides a P
atropisomer of each individual compound, independently, or a
mixture thereof, or pharmaceutically acceptable salts thereof,
recited in embodiments 18, 19, and 20, or any sub-embodiment
thereof.
[0156] In embodiment 22, the present invention provides an M
atropisomer of each individual compound, independently, or a
mixture thereof, or pharmaceutically acceptable salts thereof,
recited in embodiments 18, 19, and 20, or any sub-embodiment
thereof.
[0157] In embodiment 23, the present invention provides
pharmaceutical compositions comprising a compound, an enantiomer,
diastereoisomer, atropisomer thereof, or a mixture thereof, or
pharmaceutically acceptable salts thereof, in accordance with any
one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, or any sub embodiment thereof, and
a pharmaceutically acceptable excipient.
[0158] In embodiment 24, the present invention provides methods of
treating pain, cough, or itch, the methods comprising administering
to a patient in need thereof a therapeutically effective amount of
a compound, an enantiomer, diastereoisomer, atropisomer thereof, or
a mixture thereof, or pharmaceutically acceptable salts thereof, in
accordance with any one of embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or any sub
embodiment thereof.
[0159] In embodiment 25, the present invention provides methods of
embodiment 24 wherein the pain is selected from chronic pain, acute
pain, neuropathic pain, pain associated with rheumatoid arthritis,
pain associated with osteoarthritis, pain associated with cancer,
peripheral diabetic neuropathy, and neuropathic low back pain.
[0160] In embodiment 26, the present invention provides methods of
embodiment 24 wherein the cough is selected from post viral cough,
viral cough, or acute viral cough. See Dib-Hajj. et. al., "The
Nav1.7 sodium channel; from molecule to man", Nature Reviews
Neuroscience (2013), 14, 49-62.
[0161] In embodiment 27, the present invention provides a method of
preparation of an intermediate compound used in the preparation of
a compound of Formula (I), having the Formula (A):
##STR00010##
wherein R is halo; comprising: [0162] 1) reacting a trans olefin
compound of Formula (B):
##STR00011##
[0162] wherein R is halo; and R.sup.1 is C.sub.1-C.sub.6alkyl; with
a UV light or near UV light; to form a cis olefin compound (C); and
[0163] 2) reacting said compound (C) with a chiral acid in an
organic solvent to form said compound of Formula (A).
[0164] In embodiment 28, the present invention provides a method of
embodiment 27, wherein said chiral acid is a phosphorus chiral
acid.
[0165] In embodiment 29, the present invention provides a method of
embodiment 27, wherein said chiral acid is (S)-TRIP having the
Formula:
##STR00012##
[0166] In embodiment 30, the present invention provides a method of
embodiment 27, wherein said organic solvent is dichloromethane.
[0167] In embodiment 31, the present invention provides a method of
embodiment 27, wherein said R is bromo.
[0168] In embodiment 32, the present invention provides a method of
embodiment 27, wherein said R.sup.1 is ethyl; wherein the compound
of Formula (B) has the formula:
##STR00013##
[0169] In embodiment 33, the present invention provides a method of
embodiment 27, wherein in reaction (2), a P atropisomer of said
compound of Formula (A) is selectively formed.
[0170] In embodiment 34, the present invention provides a method of
embodiment 27, wherein said compound of Formula (A) is used as an
intermediate compound in preparation of a compound of Formula
(I):
##STR00014##
or a pharmaceutically acceptable salt thereof,
[0171] wherein:
[0172] R.sup.1 is a saturated or partially-saturated 4-membered
monocyclic ring; or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic ring; wherein said monocyclic ring or bicyclic
ring contains 0, 1, 2 or 3 N atoms and 0, 1, or 2 atoms selected
from O and S; and wherein said monocyclic ring or bicyclic ring is
substituted by 0, 1, 2 or 3 R.sup.1a groups selected from hydroxy,
halo, C.sub.1-8alk, C.sub.1-8haloalk, --O--C.sub.1-4alk,
--O--C.sub.1-8haloalk, --C(.dbd.O)C.sub.1-4alk,
--O--C(.dbd.O)C.sub.1-4alk, --NH.sub.2, --NHC.sub.1-4alk, or
--N(C.sub.1-4alk)C.sub.1-4alk;
[0173] R.sup.2 is H, halo, C.sub.1-6alk, or C.sub.1-6haloalk;
[0174] R.sup.3 is C.sub.1-6alk, C.sub.1-6haloalk,
--O--C.sub.1-6alk, or CN;
[0175] R.sup.4 is a 5- to 6-membered heteroaryl;
[0176] Each of R.sup.6 and 127 is hydrogen; and
[0177] Each of R.sup.5a; R.sup.5b; R.sup.5c; R.sup.5d; and R.sup.5e
is independently hydrogen or halo; and
Wherein a P atropisomer of said compound of Formula (I) is
selectively formed.
DETAILED DESCRIPTION OF THE INVENTION
[0178] The present invention provides compounds of Formula (I), as
defined above, an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or pharmaceutically acceptable salts thereof.
The present invention also provides pharmaceutical compositions
comprising a compound of Formula (I), an enantiomer,
diastereoisomer, atropisomer thereof, or a mixture thereof, or
pharmaceutically acceptable salts thereof, and methods of treating
diseases and/or conditions, such as pain, using compounds of
Formula (I), an enantiomer, diastereoisomer, atropisomer thereof,
or a mixture thereof, or pharmaceutically acceptable salts
thereof.
[0179] The term "C.sub..alpha.,.beta.alk" means an alkyl group
comprising a minimum of .alpha. and a maximum of .beta. carbon
atoms in a branched or linear relationship or any combination of
the two, wherein .alpha. and .beta. represent integers. A
designation of C.sub.0alk indicates a direct bond. Examples of
C.sub.1-6alk include, but are not limited to, the following:
##STR00015##
[0180] The term "halo" or "halogen" means a halogen atoms selected
from F, Cl, Br or I.
[0181] The term "C.sub..alpha.-.beta.haloalk" means an alk group,
as defined herein, in which at least one of the hydrogen atoms has
been replaced with a halo atom, as defined herein. Common
C.sub..alpha.-.beta.haloalk groups are C.sub.1-3fluoroalk. An
example of a common C.sub.1-3fluoroalk group is --CF.sub.3.
[0182] The term "heteroatom" as used herein means an oxygen,
nitrogen or sulfur atom.
[0183] The term "monocyclic ring" as used herein means a group that
features one single ring. A monocyclic ring can be carbocyclic (all
of the ring atoms are carbons), or heterocyclic (the rings atoms
include at least 1 heteroatom, for example, 1, 2 or 3 heteroatoms,
such as N, O, or S, in addition to carbon atoms). Examples of
monocyclic rings include, but are not limited to: cyclobutyl,
cyclopentyl, or cyclohexyl.
[0184] The term "bicyclic ring" as used herein means a group that
features two joined rings. A bicyclic ring can be carbocyclic (all
of the ring atoms are carbons), or heterocyclic (the rings atoms
include at least one heteroatom, for example, 1, 2 or 3
heteroatoms, such as N, O, or S, in addition to carbon atoms). The
two rings can both be aliphatic (e.g. decalin and norbornane), or
can be aromatic (e.g. naphthalene), or a combination of aliphatic
and aromatic (e.g. tetralin). Bicyclic rings include (a)
spirocyclic compounds, wherein the two rings share only one single
atom, the Spiro atom, which is usually a quaternary carbon.
Examples of spirocyclic compound include, but are not limited
to:
##STR00016##
[0185] or
(b) fused bicyclic compounds, wherein two rings share two adjacent
atoms, in other words, the rings share one covalent bond. i.e. the
bridgehead atoms are directly connected (e.g. .alpha.-thujene and
decalin). Examples of fused bicyclic rings include, but are not
limited to:
##STR00017##
and (c) bridged bicyclic compounds, wherein the two rings share
three or more atoms, separating the two bridgehead atoms by a
bridge containing at least one atom. For example, norbornane, also
known as bicyclo[2.2.1]heptane, can be thought of as a pair of
cyclopentane rings each sharing three of their five carbon atoms.
Examples of bridged bicyclic rings include, but are not limited
to:
##STR00018##
[0186] The term "aryl" means a cyclic, aromatic hydrocarbon.
Examples of aryl groups include phenyl and naphthyl. Common aryl
groups are six to thirteen membered rings.
[0187] The term "heteroaryl" means a cyclic, aromatic hydrocarbon
in which one or more carbon atoms of an aryl group have been
replaced with a heteroatom. If the heteroaryl group contains more
than one heteroatom, the heteroatoms may be the same or different.
Examples of heteroaryl groups include pyridyl, pyrimidinyl,
imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, indolyl,
triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl,
isoquinolyl, quinolyl, naphthyridinyl, quinoxalinyl, isothiazolyl
and benzo[b]thienyl. Common heteroaryl groups are five to thirteen
membered rings that contain from 1 to 4 heteroatoms. Heteroaryl
groups that are five and six membered rings that contain 1 to 3
heteroatoms are particularly common.
[0188] The term "saturated, partially-saturated or unsaturated"
includes substituents saturated with hydrogens, substituents
completely unsaturated with hydrogens and substituents partially
saturated with hydrogens.
[0189] The term "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. For additional
examples of "pharmacologically acceptable salts," and Berge et al.,
J. Pharm. Sci. 66:1 (1977).
[0190] The term "substituted" means that a hydrogen atom on a
molecule or group is replaced with a group or atom other than
hydrogen. Typical substituents include: halogen, C.sub.1-8alkyl,
hydroxyl, C.sub.1-8alkoxy, NR.sup.xR.sup.x, nitro, cyano, halo or
perhaloC.sub.1-8alkyl, C.sub.2-8alkenyl, C.sub.2-8 alkynyl,
SR.sup.x, --S(.dbd.O).sub.2R.sup.x, C(.dbd.O)OR.sup.x,
C(.dbd.O)R.sup.x, wherein each R.sup.x is independently hydrogen or
C.sub.1-C.sub.8 alkyl. It is noted that when the substituent is
NR.sup.xR.sup.x, the R.sup.x groups may be joined together with the
nitrogen atom to form a ring.
[0191] A group or atom that replaces a hydrogen atom is also called
a substituent.
[0192] Any particular molecule or group can have one or more
substituent depending on the number of hydrogen atoms that can be
replaced.
[0193] The term "unsubstituted" means a hydrogen atom on a molecule
or group.
[0194] The symbol "--" represents a covalent bond and can also be
used in a radical group to indicate the point of attachment to
another group. In chemical structures, the symbol is commonly used
to represent a methyl group in a molecule.
[0195] The term "leaving group" generally refers to groups readily
displaceable by a nucleophile, such as an amine, a thiol or an
alcohol nucleophile, or by metallic agent such as boronic acids or
boronates under transition metal catalyzed coupling conditions.
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.
[0196] The term "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.
[0197] 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 tert-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.
[0198] 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
(Bundgaard 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.
[0199] The term "therapeutically effective amount" means an amount
of a compound that ameliorates, attenuates or eliminates one or
more symptom of a particular disease or condition, or prevents or
delays the onset of one of more symptoms of a particular disease or
condition.
[0200] The term "patient" means animals, such as dogs, cats, cows,
horses, sheep and humans. Particular patients are mammals. The term
patient includes males and females.
[0201] The term "pharmaceutically acceptable" means that the
referenced substance, such as a compound of Formula (I), or a salt
of a compound of Formula (I), or a formulation containing a
compound of Formula (I), or a particular excipient, are suitable
for administration to a patient.
[0202] The terms "treating", "treat" or "treatment" and the like
include preventative (e.g., prophylactic) and palliative
treatment.
[0203] The term "excipient" means any pharmaceutically acceptable
additive, carrier, diluent, adjuvant, or other ingredient, other
than the active pharmaceutical ingredient (API), which is typically
included for formulation and/or administration to a patient.
[0204] The compounds of the present invention are administered to a
patient in a therapeutically effective amount. The compounds can be
administered alone or as part of a pharmaceutically acceptable
composition or formulation. In addition, the compounds or
compositions can be administered all at once, as for example, by a
bolus injection, multiple times, such as by a series of tablets, or
delivered substantially uniformly over a period of time, as for
example, using transdermal delivery. It is also noted that the dose
of the compound can be varied over time.
[0205] In addition, the compounds of the present invention can be
administered alone, in combination with other compounds of the
present invention, or with other pharmaceutically active compounds.
The other pharmaceutically active compounds can be intended to
treat the same disease or condition as the compounds of the present
invention or a different disease or condition. If the patient is to
receive or is receiving multiple pharmaceutically active compounds,
the compounds can be administered simultaneously, or sequentially.
For example, in the case of tablets, the active compounds may be
found in one tablet or in separate tablets, which can be
administered at once or sequentially in any order. In addition, it
should be recognized that the compositions may be different forms.
For example, one or more compound may be delivered by a tablet,
while another is administered by injection or orally as syrup. All
combinations, delivery methods and administration sequences are
contemplated.
[0206] The compounds of the present invention may be used in the
manufacture of a medicament for the treatment of a disease and/or
condition mediated by Nav 1.7, such as pain, chronic cough or
itch.
[0207] Pain is typically divided into primary types: chronic and
acute pain based on the duration of the pain. Typically, chronic
pain lasts for longer than 3 months. Examples of chronic pain
include pain associated with rheumatoid arthritis, osteoarthritis,
lumbosacral radiculopathy or cancer. Chronic pain also includes
idiopathic pain, which is pain that has no identified cause. An
example of idiopathic pain is fibromyalgia.
[0208] Another type of pain is nociceptive pain. Nociceptive pain
is caused by stimulation of peripheral nerve fibers that respond to
highly noxious events such as thermal, mechanical or chemical
stimuli.
[0209] Still another type of pain is neuropathic pain. Neuropathic
pain is pain that is caused by damage or disease affecting a part
of the nervous system. Phantom limb pain is a type of neuropathic
pain. In phantom limb pain, the body detects pain from a part of a
body that no longer exists. For example, a person who has had a leg
amputated may feel leg pain even though the leg no longer
exists.
[0210] In one embodiment of the methods of treatment provided by
the present invention using the compounds of Formula (I), or
pharmaceutically acceptable salts thereof, the disease is chronic
pain. In another aspect, the chronic pain is associated with, but
are not limited to, post-herpetic neuralgia (shingles), rheumatoid
arthritis, osteoarthritis, diabetic neuropathy, complex regional
pain syndrome (CRPS), cancer or chemotherapy-induced pain, chronic
back pain, phantom limb pain, trigeminal neuralgia, HIV-induced
neuropathy, cluster headache disorders, and migraine, primary
erythromelalgia, and paroxysmal extreme pain disorder. Other
indications for Nav 1.7 inhibitors include, but are not limited to,
depression (Morinville et al., J Comp Neurol., 504:680-689 (2007)),
bipolar and other CNS disorders (Ettinger and Argoff,
Neurotherapeutics, 4:75-83 (2007)), epilepsy: ibid., and Gonzalez,
Termin, Wilson, Methods and Principles in Medicinal Chemistry,
29:168-192 (2006)), multiple sclerosis (Waxman, Nature Neurosci.
7:932-941 (2006)), Parkinson's (Do and Bean, Neuron 39:109-120
(2003); Puopolo et al., J. Neurosci. 27:645-656 (2007)), restless
legs syndrome, ataxia, tremor, muscle weakness, dystonia, tetanus
(Hamann M., et. al., Exp. Neurol. 184(2):830-838, 2003), anxiety,
depression: McKinney B. C, et. al., Genes Brain Behav.
7(6):629-638, 2008), learning and memory, cognition (Woodruff-Pak
D. S., et. al., Behav. Neurosci. 120(2):229-240, 2006), cardiac
arrhythmia and fibrillation, contractility, congestive heart
failure, sick sinus syndrome (Haufe V., et. al., J. Mol. Cell
Cardiol. 42(3):469-477, 2007), schizophrenia, neuroprotection after
stroke, drug and alcohol abuse (Johannessen L. C., CNS Drugs
22(1)27-47, 2008), Alzheimer's (Kim D. Y., et. al., Nat. Cell.
Biol. 9(7):755-764, 2007), and cancer (Gillet L., et. al., J. Biol
Chem 2009, Jan. 28 (epub)).
[0211] Another aspect of the invention relates to a method of
treating acute and/or chronic inflammatory and neuropathic pain,
dental pain, general headache, migraine, cluster headache,
mixed-vascular and non-vascular syndromes, tension headache,
general inflammation, arthritis, rheumatic diseases, rheumatoid
arthritis, 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 pain 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 according to the present
invention. A preferred type of pain to be treated is chronic
neuropathic pain. Another preferred type of pain to be treated is
chronic inflammatory pain.
[0212] In another aspect of the invention, the compounds of the
present invention can be used in combination with other compounds
that are used to treat pain. Examples of such other compounds
include, but are not limited to aspirin, celecoxib, hydrocodone,
oxycodone, codeine, fentanyl, ibuprofen, ketoprofen, naproxen,
acetaminophen, gabapentin and pregabalin. Examples of classes of
medicines that contain compounds that can be used in combination
with the compounds of the present invention include non-steroidal
anti-inflammatory compounds (NSAIDS), steroidal compounds,
cyclooxygenase inhibitors and opioid analgesics.
[0213] The compounds of the present invention may also be used to
treat diabetes, obesity and/or to facilitate weight loss.
[0214] The compounds of the present invention may be used in
combination with other pharmaceutically active compounds. It is
noted that the term "pharmaceutically active compounds" can include
biologics, such as proteins, antibodies and peptibodies.
[0215] Since one aspect of the present invention contemplates the
treatment of the disease/conditions with a combination of
pharmaceutically active compounds that may be administered
separately, the invention further relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: a compound of the present
invention, and a second pharmaceutical compound. The kit comprises
a container for containing the separate compositions such as a
divided bottle or a divided foil packet. Additional examples of
containers include syringes, boxes and bags. Typically, the kit
comprises directions for the use of the separate components. The
kit form is particularly advantageous when the separate components
are preferably administered in different dosage forms (e.g., oral
and parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician or veterinarian.
[0216] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed by said opening.
[0217] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, . . . etc. . . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several pills or capsules to be taken
on a given day. Also, a daily dose of a compound of the present
invention can consist of one tablet or capsule, while a daily dose
of the second compound can consist of several tablets or capsules
and vice versa. The memory aid should reflect this and aid in
correct administration of the active agents.
[0218] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. Preferably, the dispenser is
equipped with a memory-aid, so as to further facilitate compliance
with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal
readout, or audible reminder signal which, for example, reads out
the date that the last daily dose has been taken and/or reminds one
when the next dose is to be taken.
[0219] The compounds of the present invention and other
pharmaceutically active compounds, if desired, can be administered
to a patient either orally, rectally, parenterally, (for example,
intravenously, intramuscularly, or subcutaneously)
intracisternally, intravaginally, intraperitoneally,
intravesically, locally (for example, powders, ointments or drops),
or as a buccal or nasal spray. All methods that are used by those
skilled in the art to administer a pharmaceutically active agent
are contemplated.
[0220] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions, or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles include water, ethanol, polyols (propylene
glycol, polyethylene glycol, glycerol, and the like), suitable
mixtures thereof, vegetable oils (such as olive oil) and injectable
organic esters such as ethyl oleate. Proper fluidity can be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0221] These compositions may also contain adjuvants such as
preserving, wetting, emulsifying, and dispersing agents.
Microorganism contamination can be prevented by adding various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example, sugars, sodium
chloride, and the like. Prolonged absorption of injectable
pharmaceutical compositions can be brought about by the use of
agents delaying absorption, for example, aluminum monostearate and
gelatin.
[0222] Solid dosage forms for oral administration include capsules,
tablets, powders, and granules. In such solid dosage forms, the
active compound is admixed with at least one inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, mannitol, and silicic acid; (b) binders, as for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for
example, glycerol; (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates, and sodium carbonate; (a) solution
retarders, as for example, paraffin; (f) absorption accelerators,
as for example, quaternary ammonium compounds; wetting agents, as
for example, cetyl alcohol and glycerol monostearate; (h)
adsorbents, as for example, kaolin and bentonite; and (i)
lubricants, as for example, talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, or
mixtures thereof. In the case of capsules, and tablets, the dosage
forms may also comprise buffering agents.
[0223] Solid compositions of a similar type may also be used as
fillers in soft and hard filled gelatin capsules using such
excipients as lactose or milk sugar, as well as high molecular
weight polyethylene glycols, and the like.
[0224] Solid dosage forms such as tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells, such
as enteric coatings and others well known in the art. They may also
contain opacifying agents and can also be of such composition that
they release the active compound or compounds in a certain part of
the intestinal tract in a delayed manner. Examples of embedding
compositions that can be used are polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0225] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage form may contain inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents and
emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl
alcohol, polyethylene glycols and fatty acid esters of sorbitan, or
mixtures of these substances, and the like.
[0226] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compound, may contain
suspending agents, as for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, or mixtures of these substances, and the like.
[0227] Compositions for rectal administration are preferably
suppositories, which can be prepared by mixing the compounds of the
present invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository
wax, which are solid at ordinary room temperature, but liquid at
body temperature, and therefore, melt in the rectum or vaginal
cavity and release the active component.
[0228] Dosage forms for topical administration of a compound of the
present invention include ointments, powders, sprays and inhalants.
The active compound or fit compounds are admixed under sterile
condition with a physiologically acceptable carrier, and any
preservatives, buffers, or propellants that may be required.
Ophthalmic formulations, eye ointments, powders, and solutions are
also contemplated as being within the scope of this invention.
[0229] The compounds of the present invention can be administered
to a patient at therapeutically effective dosage levels. The
specific dosage and dosage range that can be used depends on a
number of factors, including the requirements of the patient, the
severity of the condition or disease being treated, and the
pharmacological activity of the compound being administered.
[0230] The compounds of the present invention can be administered
as pharmaceutically acceptable salts, co-crystals, esters, amides
or prodrugs. The term "salts" refers to inorganic and organic salts
of compounds of the present invention. The salts can be prepared in
situ during the final isolation and purification of a compound, or
by separately reacting a purified compound in its free base or acid
form with a suitable organic or inorganic base or acid and
isolating the salt thus formed. Representative salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,
oxalate, palmitiate, stearate, laurate, borate, benzoate, lactate,
phosphate, tosylate, citrate, maleate, fumarate, succinate,
tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and
laurylsulphonate salts, and the like. The salts may include cations
based on the alkali and alkaline earth metals, such as sodium,
lithium, potassium, calcium, magnesium, and the like, as well as
non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to, ammonium, tetramethylammonium,
tetraethylammonium, me thylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. See, for example, S. M.
Berge, et al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19
(1977).
[0231] Examples of pharmaceutically acceptable esters of the
compounds of the present invention include C.sub.1-C.sub.8 alkyl
esters. Acceptable esters also include C.sub.5-C.sub.7 cycloalkyl
esters, as well as arylalkyl esters such as benzyl. C.sub.1-C.sub.4
alkyl esters are commonly used. Esters of compounds of the present
invention may be prepared according to methods that are well known
in the art.
[0232] Examples of pharmaceutically acceptable amides of the
compounds of the present invention include amides derived from
ammonia, primary C.sub.1-C.sub.8 alkyl amines, and secondary
C.sub.1-C.sub.8 dialkyl amines. In the case of secondary amines,
the amine may also be in the form of a 5 or 6 membered
heterocycloalkyl group containing at least one nitrogen atom.
Amides derived from ammonia, C.sub.1-C.sub.3 primary alkyl amines
and C.sub.1-C.sub.2 dialkyl secondary amines are commonly used.
Amides of the compounds of the present invention may be prepared
according to methods well known to those skilled in the art.
[0233] The term "prodrug" means compounds that are transformed in
vivo to yield a compound of the present invention. The
transformation may occur by various mechanisms, such as through
hydrolysis in blood. A discussion of the use of prodrugs is
provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery
Systems," Vol. 14 of the A.C.S. Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
[0234] To illustrate, if the compound of the invention contains a
carboxylic acid functional group, a prodrug can comprise an ester
formed by the replacement of the hydrogen atom of the acid group
with a group such as (C.sub.1-C.sub.8 alkyl,
(C.sub.2-C.sub.12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from
5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6
carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon
atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8
carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-3)alkyl.
[0235] Similarly, if a compound of the present invention comprises
an alcohol functional group, a prodrug can be formed by the
replacement of the hydrogen atom of the alcohol group with a group
such as (C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyloxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylacyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl, where each .alpha.-aminoacyl
group is independently selected from the naturally occurring
L-amino acids, --P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from the removal of a hydroxyl group of the hemiacetal
form of a carbohydrate).
[0236] In addition, if a compound of the present invention
comprises a sulfonamide moiety, a prodrug can be formed by
replacement of the sulfonamide N(H) with a group such as
--CH.sub.2P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or
--CH.sub.2OC(O)(C.sub.1-C.sub.6)alkyl.
[0237] The compounds of the present invention also include
tautomeric forms of prodrugs.
[0238] The compounds of the present invention may contain
asymmetric or chiral centers, and therefore, exist in different
stereoisomeric forms. It is contemplated that all stereoisomeric
forms of the compounds as well as mixtures thereof, including
racemic mixtures, form part of the present invention. In addition,
the present invention contemplates all geometric and positional
isomers. For example, if the compound contains a double bond or
disubstituted cycloalkyl group, both the cis and trans isomers,
unless the specific isomer is specified, as well as mixtures, are
contemplated. In disubstituted cycloalkyl containing compounds, the
cis and trans isomers refer to the relative positions of the
substitutions. For example:
##STR00019##
(A) represents trans cyclobutyl isomer because the --CF.sub.3 group
is pointing up while the --CH.sub.3 group is pointing down, while
(B) represents cis cyclobutyl isomer because both the --CF.sub.3
group and the --CH.sub.3 groups are pointing down.
[0239] Mixtures of stereoisomers, such as diastereomeric mixtures,
can be separated into their individual stereochemical components on
the basis of their physical chemical differences by known methods
such as chromatography and/or fractional crystallization.
Enantiomers can also be separated by converting the enantiomeric
mixture into a diasteromeric mixture by reaction with an
appropriate optically active compound (e.g., an alcohol),
separating the diastereomers and converting (e.g., hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers.
[0240] The compounds of general Formula (I) may also exist in the
form of atropisomers. Atropisomers are compounds with identical
structural formulae, but which have a particular spatial
configuration resulting from a restricted rotation around a single
bond, due to steric hindrance on either side of this single bond.
Atropisomerism is independent of the presence of stereogenic
elements, such as an asymmetric carbon. The terms "P atropisomer"
or "M atropisomer" are used herein in order to be able to clearly
name two atropisomers of the same pair. For example, the following
intermediate compound having the structure below can be separated
into the pair of atropisomers P and M via a chiral column
chromatography:
##STR00020##
[0241] The compounds of the present invention may exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water (hydrate), ethanol, and the like.
The present invention contemplates and encompasses both the
solvated and unsolvated forms.
[0242] It is also possible that compounds of the present invention
may exist in different tautomeric forms. All tautomers of compounds
of the present invention are contemplated. For example, all of the
tautomeric forms of the tetrazole moiety are included in this
invention. Also, for example, all keto-enol or imine-enamine forms
of the compounds are included in this invention. Other examples of
tautomerism are as follows:
##STR00021##
[0243] Those skilled in the art will recognize that the compound
names and structures contained herein may be based on a particular
tautomer of a compound. While the name or structure for only a
particular tautomer may be used, it is intended that all tautomers
are encompassed by the present invention, unless stated
otherwise.
[0244] It is also intended that the present invention encompass
compounds that are synthesized in vitro using laboratory
techniques, such as those well known to synthetic chemists; or
synthesized using in vivo techniques, such as through metabolism,
fermentation, digestion, and the like. It is also contemplated that
the compounds of the present invention may be synthesized using a
combination of in vitro and in vivo techniques.
[0245] The present invention also includes isotopically labelled
compounds, which are identical to those recited herein, but for the
fact that one or more atoms are replaced by an atom having an
atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.16O, .sup.17O, .sup.31F, .sup.32F, .sup.35S, .sup.18F, and
.sup.36Cl. In another aspect, the compounds of the present
invention contain one or more deuterium atoms (2H) in place of one
or more hydrogen atoms.
[0246] Compounds of the present invention that contain the
aforementioned isotopes and/or other isotopes of other atoms are
within the scope of this invention. Certain isotopically labelled
compounds of the present invention, for example those into which
radioactive isotopes such as .sup.3H and .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution assays.
Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes
are particularly preferred for their ease of preparation and
detection. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of
this invention can generally be prepared by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
[0247] The compounds of the present invention may exist in various
solid states including crystalline states and as an amorphous
state. The different crystalline states, also called polymorphs,
and the amorphous states of the present compounds are contemplated
as part of this invention.
[0248] All patents and other publications recited herein are hereby
incorporated by reference in their entirety.
[0249] The examples presented below illustrate specific embodiments
of the present invention. These examples are meant to be
representative and are not intended to limit the scope of the
claims in any manner.
[0250] It is noted that when a percent (%) is used with regard to a
liquid, it is a percent by volume with respect to the solution.
When used with a solid, it is the percent with regard to the solid
composition. Materials obtained from commercial suppliers were
typically used without further purification. Reactions involving
air or moisture sensitive reagents were typically performed under a
nitrogen or argon atmosphere. Purity was measured using high
performance liquid chromatography (HPLC) system with UV detection
at 254 nm and 215 nm (System A: HALO C8, 3.0.times.50 mm, 2.7 am, 5
to 95% CH.sub.3CN in H.sub.2O with 0.1% TFA for 2.0 min at 2.0
mL/min) (Agilent Technologies, Santa Clara, Calif.). Silica gel
chromatography was generally performed with prepacked silica gel
cartridges (BIOTAGE.RTM., Uppsala, Sweden or Teledyne-Isco,
Lincoln, Nebr.). .sup.1H NMR spectra were recorded on a Bruker
AV-400 (400 MHz) spectrometer (Bruker Corporation, Madison, Wis.)
or a Varian (Agilent Technologies, Santa Clara, Calif.) 400 MHz
spectrometer at ambient temperature. All observed protons are
reported as parts per million (ppm) downfield from
tetramethylsilane (TMS) or other internal reference in the
appropriate solvent indicated. Data are reported as follows:
chemical shift, multiplicity (s=singlet, d=doublet, t=triplet,
q=quartet, br=broad, m=multiplet), coupling constants, and number
of protons. Low-resolution mass spectral (MS) data were determined
on an Agilent 1100 Series (Agilent Technologies, Santa Clara,
Calif.) LC/MS with UV detection at 254 nm and 215 nm and a low
resonance electrospray mode (ESI).
[0251] The following abbreviations may be used herein: [0252]
2-PrOH Isopropanol [0253] AgOTf silver(I) trifluoromethanesulfonate
[0254] AIBN Azobisisobutyronitrile [0255] aq. Aqueous [0256] Bu
Butyl [0257] ca. Circa [0258] Cm centimeter(s) [0259] CPhos
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'biphenyl [0260]
DAST diethylaminosulfur trifluoride [0261] Dba Dibenzylideneacetone
[0262] DCM Dichloromethane [0263] Deoxy-Fluor
bis(2-methoxyethyl)aminosulfurtrifluoride [0264] DIPEA
N,N-diisopropylethylamine [0265] DMF N,N-dimethylformamide [0266]
DMSO Dimethylsulfoxide [0267] ESI or ES electrospray ionization
[0268] Et Ethyl [0269] Et.sub.2O diethyl ether [0270] EtOAc ethyl
acetate [0271] EtOH Ethanol [0272] G gram(s) [0273] H hour(s)
[0274] HPLC high pressure liquid chromatography [0275] IPA
2-propanol [0276] Kg kilogram(s) [0277] L liter(s) [0278] LCMS
liquid chromatography mass spectroscopy [0279] LHMDS lithium
hexamethyldisilazide [0280] M Molar [0281] m/z mass divided by
charge [0282] Me Methyl [0283] Me OH Methanol [0284] Me-THF Methyl
tetrahydrofuran [0285] Mg milligram(s) [0286] MHz Megahertz [0287]
Min minute(s) [0288] mL or ml milliliter(s) [0289] Mmol
millimole(s) [0290] Mol mole(s) [0291] MTBE methyl tert-butyl ether
[0292] N Normal [0293] NaOMe sodium methoxide [0294] n-Bu n-butyl
[0295] NEt.sub.3 Triethylamine [0296] NMR nuclear magnetic
resonance [0297] OAc Acetate [0298] OTf Trifluoromethanesulfonate
[0299] PFP-OH Perfluorophenol [0300] Ph Phenyl [0301] PhMe Toluene
[0302] PMB 4-methoxy benzyl [0303] Ppm parts per million [0304] Pr
Propyl [0305] rac racemic [0306] rt room temperature [0307] sat.
Saturated [0308] SFC supercritical fluid chromatography [0309] TBAF
tetra-n-butylammonium fluoride [0310] TFA trifluoroacetic acid
[0311] THF Tetrahydrofuran [0312] Ti(OiPr).sub.4 titanium(IV)
isopropoxide [0313] TLC thin-layer chromatography [0314]
TMS-CF.sub.3 (trifluoromethyl)trimethylsilane [0315] wt %
percentage by weight [0316] XantPhos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [0317] XtalFluor-M
difluoro(morpholino)sulfonium tetrafluoroborate
[0318] The following compounds presented herein, as examples of the
present invention, and intermediates thereof as building blocks to
prepare compounds provided by the invention, may be made by the
various methods and synthetic strategies taught herein below. These
compounds, and others provided by the invention, may also be
prepared using methods described in International Publication No.
WO2014/201206, filed Jun. 12, 2014, which specification is
incorporated herein by reference in their entirety.
[0319] In addition, the present inventors have developed a
photochemical atrop-selective ring-closure to form N-aryl
quinolinones compounds. Specifically, the P atropisomer compound 3
is selectively formed in the photochemical reaction of the
invention. A general representation of the photochemistry step of
the present invention is described below:
##STR00022##
[0320] The reaction relies on UV or near-UV light to excite the
olefin 1; wherein R is halo; and R.sup.1 is C.sub.1-C.sub.6alkyl;
and induce a cis-trans isomerization to transiently form 2; wherein
R is halo; and R.sup.1 is C.sub.1-C.sub.6alkyl. Preferably, R.sup.1
is ethyl. Cis olefin 2 can then be activated by chiral acid
(S)-TRIP to asymmetrically form ring-closed quinolinone 3, wherein
R is as defined above. Preferably, R is Br. A screen of chiral
phosphoric acids revealed that (S)-TRIP was the preferred chiral
acid. The preferred organic solvent is dichloromethane. The
photochemical reaction has been scaled to 1 g in a batch reactor
and has also been demonstrated in a small photochemical flow
reactor.
[0321] The present photochemical step can operate well without the
present of a bulky barrier substituent to rotation, such as
tert-butyl group in the starting material. Rather, the present
novel photochemical step has been demonstrated in the presence of a
much smaller methoxy group in the starting material. The mild
reaction conditions further allow for compounds with low barriers
to rotation to be prepared in a stereoselective fashion.
Intermediate A:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihy-
droquinoline-6-Sulfonamide
##STR00023## ##STR00024##
[0322] Step 1: 4-Bromo-2-Iodoaniline
[0323] To a solution of 4-bromo-aniline (500 g, 2.90 mol) in
cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol), and the
mixture was heated at 50.degree. C. After 30 min, the reaction
mixture became homogenous, and 30% aqueous hydrogen peroxide
solution (250 mL) was added to the reaction mixture. The reaction
was heated for 4 h at 50.degree. C. The reaction was cooled to room
temperature, diluted with ethyl acetate (5.0 L) and washed with
aqueous sodium sulphite (2.5 kg in 4.0 L) solution. The organic
layer was washed with water (3.0 L) and brine (3.0 L), dried over
magnesium sulfate, filtered and concentrated under reduced pressure
to obtain the initial product which was purified by column
chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl
acetate and hexanes) to get 4-bromo-2-iodoaniline (650 g, 75%), as
an off white solid. TLC solvent system: 100% hexanes. Product's
R.sub.f: 0.6. MS (ESI, positive ion) m/z: 297.0 (M+1). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.72 (d, J=2.5 Hz, 1H), 7.23 (dd,
J=8.4, 2.1 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 4.09 (s, 2H).
Step 2: Ethyl (E)-3-(2-Amino-5-Bromophenyl)Acrylate
[0324] To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol) in
DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol) and sodium
bicarbonate (680 g, 6.29 mol). The reaction mixture was degassed
with nitrogen for 20 min followed by the addition of palladium
acetate (28.8 g, 128.27 mmol). The reaction mixture was heated at
70.degree. C. for 3 h. The reaction was filtered through
CELITE.RTM. and the CELITE bed was washed with ethyl acetate
(2.times.500 mL). The filtrate was concentrated under reduced
pressure to obtain a residue which was purified by column
chromatography (silica gel; mesh size 60-120, elution 0-20% ethyl
acetate in hexanes) to obtain (E)-ethyl
3-(2-amino-5-bromophenyl)acrylate (620 g, 77%), as yellow solid.
TLC solvent system: 20% ethyl acetate in hexanes. Product's
R.sub.f: 0.4. MS (ESI, positive ion) m/z; 270.2 (M+1). .sup.1H NMR
(400 MHz, DMSO) .delta. 7.75 (d, J=16.1 Hz, 1H), 7.57 (d, J=2.0 Hz,
1H), 7.16 (dd, J=9.1, 2.4 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.43 (d,
J=8.6 Hz, 1H), 5.81 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2
Hz, 3H). Other acrylates can be used in place of ethyl acrylate to
provide different esters. For example methyl acrylate, propyl
acrylate, butyl acrylate, and others may be used instead of ethyl
acrylate.
Step 3: Ethyl (E)-3-(2-Amino-5-(Benzylthio)Phenyl) Acrylate
[0325] To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate
(620 g, 2.29 mol) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L,
8.88 mol, 3.9 equiv, GLR), and the mixture was degassed with
nitrogen for 20 mins. XantPhos (92.9 g, 106 mmol), and
tris(dibenzylideneacetone)dipalladium(0) (84 g, 91.0 mmol) were
added to the reaction mixture. The mixture was purged with nitrogen
and heated to 80.degree. C. for 30 min. The reaction was cooled to
RT, benzyl mercaptan (455.5 g, 3.67 mol) was added, and the
reaction was heated at 80.degree. C. for an additional 4 h. The
reaction was cooled to room temperature and diluted with ethyl
acetate (4.0 L). The mixture was filtered through CELITE and the
CELITE bed was washed with ethyl acetate (2.times.1.0 L). The
filtrate was concentrated under reduced pressure to obtain the
initial product which was purified by chromatography (silica gel;
mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether)
to obtain (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520
g, 72.0%), as yellow solid. TLC solvent system: 30% ethyl acetate
in hexanes. Product's R.sub.f: 0.4. MS (ESI, positive ion) m/z;
314.1 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 7.79 (d, J=16.1
Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J=8.4,
2.1 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.32 (d, J=15.2 Hz, 1H), 5.75
(s, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J=7.2 Hz,
3H).
Step 4: 1-Bromo-2-Fluoro-4-Iodo-S-Methoxybenzene
[0326] To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g,
2.44 mol) in DCM (5.0 L) was added silver trifluoromethanesulfonate
(686.0 g, 2.68 mol) and the reaction mixture was stirred for 20
min. Iodine (678.0 g, 2.68 mol) was added to the reaction and the
mixture was stirred at room temperature for 16 h. The mixture was
diluted with DCM (3.0 L) and filtered through CELITE. The CELITE
bed was washed with DCM (2.times.1.0 L) and the filtrate was washed
with 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous
sodium bicarbonate solution (3.0 L). The organic layer was dried
over sodium sulfate, filtered and concentrated under reduced
pressure to obtain the initial product which was purified by
chromatography (silica gel; mesh size 60-120, elution 0-5% ethyl
acetate and petroleum ether) to get
1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%), as off-white
solid. TLC solvent system: 100% hexanes. Product's R.sub.f: 0.6. MS
(ESI, positive ion) m/z: 331.0 (M+1). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.55 (d, J=7.2 Hz, 1H), 6.95 (d, J=5.6 Hz, 1H),
3.89 (s, 3H).
Step 5: Ethyl
(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)Phenyl)
Acrylate
[0327] To a solution of (E)-ethyl
3-(2-amino-5-(benzylthio)phenyl)acrylate (300 g, 958.1 mmol) and
1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g, 1051.6 mmol) in
toluene (2.5 L) was added Cs.sub.2CO.sub.3 (468 g, 1436.3 mmol).
The resulting mixture was degassed with nitrogen for 20 mins.
Pd.sub.2(dba).sub.3 (35 g, 38.2 mmol) and XantPhos (44.6 g, 76.4
mmol) were added to the reaction mixture and the mixture was heated
at 110.degree. C. for 5 h. The reaction mixture was allowed to cool
to room temperature, diluted with dichloromethane (2.0 L) and
filtered through CELITE. The filtrate was concentrated under
reduced pressure to obtain the initial product which was purified
by stirring with 5% ethyl acetate in hexanes (3.0 L) for 30 min and
filtered to obtain (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acryl-
ate (350 g, 71%) as yellow solid. TLC solvent system: 30% ethyl
acetate in hexanes. Product's R.sub.f: 0.5. MS (ESI, positive ion)
m/z; 516.2 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 7.73-7.61 (m,
3H), 7.34-7.15 (m, 6H), 7.02 (d, J=11.4 Hz, 1H), 6.60 (d, J=21.2
Hz, 1H), 6.33 (d, J=14.1 Hz, 1H), 4.26 (s, 2H), 4.16-4.09 (m, 2H),
3.81 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). Note: NH proton not
observed.
Step 6:
6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)Quinolin-2(1H)--
One
[0328] To a solution of (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acryl-
ate (250.0 g, 484.0 mmol) in methanol (2.5 L) was added
tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8
mmol) and the reaction mixture was heated at 70.degree. C. for 5 h.
The reaction mixture was allowed to cool to rt, and was then
concentrated under reduced pressure to obtain the initial product
which was purified by stirring with 5% ethyl acetate in hexanes
(1.0 mL) and filtered to obtain
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)--
one (201.0 g, 88%) as an off white solid. TLC solvent system: 30%
ethyl acetate in hexanes. Product's R.sub.f: 0.3. MS (ESI, positive
ion) m/z; 470.0 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 7.92 (d,
J=9.1 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.65 (d, J=6.1 Hz, 1H), 7.57
(d, J=8.8 Hz, 1H), 7.40-7.22 (m, 6H), 6.68 (d, J=9.6 Hz, 1H), 6.56
(d, J=8.8 Hz, 1H), 4.24 (s, 2H), 3.69 (s, 3H).
[0329] Alternatively, the P atropisomer title compound of step 6
can be selectively prepared by using a photochemistry route from
ethyl
(E)-3-[5-benzylsulfanyl-2-(4-bromo-5-fluoro-2-methoxy-anilino)phenyl]prop-
-2-enoate starting material as described in the following
procedures:
Photochemistry Preparation Method 1
##STR00025##
[0331] To a flask was added (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenypacryla-
te (4.0 g, 7.6 mmol),
(S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl
hydrogen phosphate ((S)-TRIP) (290 mg, 0.38 mmol) and DCM (40 mL).
The resulting solution was continuously stirred and recirculated
for 2.5 h through narrow-diameter tubing that was exposed to 467 nm
LED light. The reaction solution was concentrated to approximately
8 mL and charged with MeOH (80 mL). The solution was concentrated
to approximately 50 mL and heated to 60.degree. C. The solution was
filtered to remove any precipitate and then allowed to cool to room
temperature overnight. The resulting slurry was cooled to 0.degree.
C. for 2 h and then filtered. The filter cake was rinsed with cold
MeOH to deliver
(P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one
as a tan solid (2.12 g, 89 wt %, 4.0 mmol). .sup.1H NMR (300 MHz,
DMSO-d6) .delta. 7.95 (d, J=9.6 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H),
7.64 (d, J=6.3 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.42-7.16 (m, 6H),
6.67 (d, J=9.5 Hz, 1H), 6.55 (d, J=8.8 Hz, 1H), 4.24 (s, 2H), 3.68
(s, 3H). .sup.19F NMR (282 MHz, DMSO-d6) .delta. -117.08 (dd, 1F,
J=8.7, 6.3 Hz). ee determined by chiral normal phase chromatography
(CHIRALPAK IC-3, 4.6.times.150.times.3), mobile phase of 60%
Heptane/40% (0.2% ethanesulfonic acid in Ethanol) v/v, with flow
rate of 1.5 mL/min.
Photochemistry Preparation Method 2
##STR00026##
[0333] To a flask was added (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenypacryla-
te (50.0 g, 96.8 mmol),
(S)-3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl
hydrogen phosphate ((S)-TRIP) (1.46 g, 1.94 mmol), toluene (750 mL)
and DCM (750 mL). The reaction headspace was purged with N.sub.2.
The reaction solution was warmed to 30.degree. C. and stirred. The
solution was recirculated at a flow rate of 50 g/min via
peristaltic pump for 10 h through 1/8'' FEP tubing (approximately
10 mL internal volume) that was exposed to 457 nm LED light. The
reaction solution was concentrated to a yellow-brown solid and then
slurried in .sup.iPrOAc (250 mL) for 30 min at 30.degree. C. To the
slurry was added heptane (500 mL) over 30 min. The slurry was
cooled to 0.degree. C. over 2 h and then placed in a -20.degree. C.
freezer for 36 h. The slurry was filtered and the filter cake was
rinsed with 10% v/v .sup.iPrOAc/heptane (2.times.150 mL). The
solids were dried in a vacuum oven to provide
(P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one
as a tan solid (34.7 g, 98 wt %, 72.6 mmol, 89% ee).
Steps 7 & 8: Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydro
Quinoline-6-Sulfonate
[0334] To a solution of
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one
(250.0 g, 531.5 mmol) in acetonitrile (2.5 L) were added acetic
acid (200 mL) and water (130 mL). The resulting mixture was cooled
to 0.degree. C. and
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (188.5 g, 956.7
mmol) was added portion-wise over 20 min keeping the internal
temperature below 5.degree. C. The resulting suspension was stirred
at 0-5.degree. C. under nitrogen for 45 min. Then a solution of
pentafluorophenol (127.2 g, 690.95 mmol) in acetonitrile (200 mL)
was added over 5 min followed by NEt.sub.3 (307.7 mL, 2.12 mol)
over 20 min keeping the internal temperature below 5.degree. C. The
mixture was continued to be stirred at 0-5.degree. C. for 30 min.
Water (4.0 L) was added and extracted with ethyl acetate
(2.times.2.0 L). The organic layer was washed with brine (1.0 L),
dried over sodium sulfate, filtered and concentrated under reduced
pressure to obtain the initial product which was purified by
stirring with isopropyl alcohol:hexanes (1:1, 1.0 L) and filtered
to obtain perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (190 g, 60%) as white solid. TLC solvent system: 30% ethyl
acetate in pet ether, Product's R.sub.f: 0.4. MS (ESI, positive
ion) m/z; 594.2 (M+1). .sup.1H-NMR (400 MHz, DMSO) .delta. ppm 8.60
(d, J=2.0 Hz, 1H), 8.26 (d, J=9.8 Hz, 1H), 7.95 (dd, J=2.2, 9.1 Hz,
1H), 7.70 (t, J=8.6 Hz, 2H), 6.95-6.88 (m, 2H), 3.72 (s, 3H).
Step 9: (P)-Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfona-
te
[0335] Racemic perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (76.90 g) was separated via Chiralcel OJ column (40% MeOH/60%
CO.sub.2) to give (P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te and (M)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te as pale yellow flocculent solids. Data for peak 1: m/z (ESI)
594.0 (M+H).sup.+. Data for peak 2: m/z (ESI) 594.0
(M+H).sup.+.
Step 10:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo--
1,2-Dihydroquinoline-6-Sulfonamide
[0336] A THF (200 mL) solution of (P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 mL, 11.11 mmol)
in a 250-mL round-bottom flask was cooled to 0.degree. C., and
lithium bis(trimethylsilyl)amide, (1.0 M solution in THF, 21.20 mL,
21.20 mmol) was added dropwise. After stirring the yellow solution
at 0.degree. C. for 15 min, it was quenched at 0.degree. C. with 1
N HCl and extracted thrice with EtOAc. The organic extracts were
combined, dried over MgSO.sub.4, filtered, and concentrated to a
light tan residue. Et.sub.2O was added, and the slurry was
triturated and sonicated. Filtration afforded an off-white solid,
which was washed twice with Et.sub.2O and dried in vacuo to afford
3.88 g of product as an off-white solid. The filtrate was
concentrated in vacuo and purified via column chromatography (12 g
silica gel, 35% to 100% EtOAc/hept gradient) to afford an
additional 1.36 g of product as a pale yellow flocculent solid. A
total of 5.24 g of
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihy-
droquinoline-6-sulfonamide was afforded. m/z (ESI) 494.1
(M+H).sup.+.
Intermediate A: (3-(Tert-Butyl)Cyclobutyl)Zinc(II) Iodide, 0.2 M in
THF
##STR00027##
[0338] A three-necked oven-dried round-bottom flask equipped with a
magnetic stir bar and a rubber septum was charged with lithium
chloride (96 mg, 2.3 mmol). The vessel was heated with a heat gun
for 10 min under vacuum and backfilled with nitrogen after cooling
to room temperature. Zinc (148 mg, 2.27 mmol) was added. The vessel
was again heated with a heat gun for 10 min under vacuum and
backfilled with nitrogen after cooling to room temperature. THF
(3.4 mL) and 1,2-dibromoethane (4.9 .mu.L, 0.057 mmol) were added
via syringe and the reaction mixture was heated at 60.degree. C.
until bubbling occurred. After cooling to room temperature,
chlorotrimethylsilane (4.4 .mu.L, 0.034 mmol) and a solution of
iodine (2.9 mg, 0.011 mmol) in THF (0.1 mL) were added via syringe.
The reaction mixture was heated at 60.degree. C. for 20 min and
then cooled to room temperature. 1-(tert-Butyl)-3-iodocyclobutane
(270 mg, 1.13 mmol) was added, and the reaction was stirred at
50.degree. C. for 18 h. The reaction mixture was allowed to stand
at room temperature for 1 h. The solution was titrated by adding
dropwise to a cooled (0.degree. C.) solution of iodine (3 mg, 0.012
mmol) in lithium chloride (0.5 M in THF, 2.3 mL, 1.1 mmol) until
the orange color disappeared. 0.06 mL of solution was used,
corresponding to a concentration of 0.2 M.
Intermediate B: 5,8-Dioxaspiro[3.4]Octan-2-Ylzinc(II) Bromide, 0.1
Min THF
##STR00028##
[0340] An oven-dried round-bottom flask equipped with a magnetic
stir bar and a rubber septum was charged with lithium chloride
(0.878 g, 20.72 mmol). The vessel was heated with a heat gun for 10
min under vacuum and backfilled with nitrogen after cooling to room
temperature. Zinc (1.355 g, 20.72 mmol) was added. The vessel was
again heated with a heat gun for 10 min under vacuum and backfilled
with nitrogen after cooling to room temperature. THF (13.8 mL) and
1,2-dibromoethane (0.045 mL, 0.518 mmol) were added via syringe and
the reaction mixture was heated at 60.degree. C. until bubbling
occurred. After cooling to room temperature, chlorotrimethylsilane
(0.040 mL, 0.311 mmol) and a solution of iodine (0.026 g, 0.104
mmol) in THF (0.2 mL) were added via syringe. The reaction mixture
was heated at 60.degree. C. for 20 min and then cooled to room
temperature. 2-Bromo-5,8-dioxaspiro[3.4]octane (1.3 mL, 10 mmol)
was added and the reaction was stirred at 50.degree. C. for 16 h.
The resulting solution was used as is.
Intermediate C: (3-(Trifluoromethyl)Cyclobutyl) Zinc(II) Bromide,
0.15 M in THF
##STR00029##
[0342] This intermediate was synthesized in the same manner and
stoichiometry as Intermediate B using
1-bromo-3-(trifluoromethyl)cyclobutane (2.00 g, 9.85 mmol).
Intermediate D: Perfluorophenyl
(P)-1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate
##STR00030## ##STR00031##
[0343] Step 1: (E)-Ethyl
3-(5-(Benzylthio)-2-((4-Bromo-2-Methoxyphenyl)Amino)Phenyl)Acrylate
[0344] A round-bottom flask was charged with (E)-ethyl
3-(2-amino-5-(benzylthio)phenyl)acrylate (2.39 g, 7.63 mmol),
4-bromo-1-iodo-2-methoxybenzene (2.86 g, 9.15 mmol), XantPhos
(0.221 g, 0.381 mmol), tris(dibenzylideneacetone)dipalladium(0)
(0.175 g, 0.191 mmol), and cesium carbonate (4.97 g, 15.25 mmol)
were added. A reflux condenser was attached and the flask was
lowered into a 110.degree. C. heating bath. After 2 h, an
additional portion of cesium carbonate (1.4 g) was added, and the
bath temperature was raised to 120.degree. C. The mixture was
heated for another 2 h then cooled to room temperature, diluted
with EtOAc, and filtered through CELITE with the aid of EtOAc. The
filtrate was concentrated. The oily residue was taken up in 2-PrOH.
The mixture was concentrated to give a yellow solid with some oily
solid present. The mixture was taken up in 2-PrOH to give a
suspension, and the suspension was stirred for 16 h. The mixture
was filtered, and the filtered solid was washed with 2-PrOH
(3.times.). The collected solid was dried on the filter under a
flow of N.sub.2 for 15 min to give (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)
acrylate (3.136 g, 6.29 mmol, 83% yield) as a bright-yellow solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.72 (d, J=16.0 Hz,
1H), 7.68 (d, J=2.2 Hz, 1H), 7.47 (s, 1H), 7.37-7.19 (m, 6H), 7.13
(d, J=2.2 Hz, 1H), 6.94 (dd, J=2.2, 8.4 Hz, 1H), 6.86 (d, J=8.5 Hz,
1H), 6.55 (s, 1H), 6.52 (d, J=7.7 Hz, 1H), 4.24 (s, 2H), 4.15 (q,
J=7.1 Hz, 2H), 3.82 (s, 3H), 1.23 (t, J=7.1 Hz, 3H). m/z (ESI)
498.0 (M+H).sup.+.
Step 2:
6-(Benzylthio)-1-(4-Bromo-2-Methoxyphenyl)Quinolin-2(1H)-One
[0345] A round-bottom flask was charged with (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenypacrylate
(3.13 g, 6.28 mmol) and MeOH (31.4 mL) to give a yellow suspension.
Sodium methoxide (25 wt % in MeOH, 0.271 mL, 1.256 mmol) was added.
A reflux condenser was attached, and the flask was lowered into a
75.degree. C. heating bath. The bath quickly spiked to ca.
80-85.degree. C., but returned to 70-75.degree. C. after 30 min.
The reaction was stirred for 16 h, and the mixture was diluted with
DCM and concentrated. The residue was purified by chromatography on
silica gel (50-g SNAP Ultra column, 25-g silica gel loading column,
10-60% EtOAc/Heptane) to give
6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (1.95
g, 4.31 mmol, 69% yield) as a yellow solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 7.94 (d, J=9.5 Hz, 1H), 7.78 (d, J=2.2
Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.43-7.16 (m, 8H), 6.66 (d, J=9.6
Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 4.23 (s, 2H), 3.69 (s, 3H). m/z
(ESI) 452.0 (M+H).sup.+.
Step 3: Perfluorophenyl
1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-DIHYDROQUINOLINE-6-SULFONATE
[0346] A round-bottom flask was charged with
6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (1.777
g, 3.93 mmol), acetonitrile (18.49 mL), acetic acid (0.693 mL), and
water (0.462 mL) to give a solution. The flask was cooled in an
ice-water bath for 10 min, then
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813 g, 4.12
mmol) was added in one portion. After 20 min, an additional portion
of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813 g, 4.12
mmol) was added in one portion. After another 20 min,
2,3,4,5,6-pentafluorophenol (1.085 g, 5.89 mmol) was added, and the
mixture was stirred for 5 min. Triethylamine (2.190 mL, 15.71 mmol)
was added dropwise over 30 s then the mixture was stirred for 20
min. The reaction mixture was diluted with water and extracted with
DCM (3.times.). The combined organic extracts were dried over
sodium sulfate, filtered, and concentrated. The residue was
purified by chromatography on silica gel (50-g SNAP Ultra column,
25-g silica gel loading column, 10-60% EtOAc/Heptane).
Perfluorophenyl
1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
(1.644 g, 2.85 mmol, 72.6% yield) was isolated as a white foam.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 8.59 (d, J=2.2 Hz,
1H), 8.24 (d, J=9.6 Hz, 1H), 7.95 (dd, J=2.3, 9.1 Hz, 1H), 7.56 (d,
J=1.9 Hz, 1H), 7.44-7.26 (m, 2H), 6.86 (dd, J=9.4, 13.7 Hz, 2H),
3.72 (s, 3H). m/z (ESI) 575.9 (M+H).sup.+.
Step 4: Perfluorophenyl
(P)-1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate
and Perfluorophenyl
(M)-1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate
[0347] Racemic perfluorophenyl
1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
(3000 g) was separated in 5 600-g batches using a Regis Whelk-O
(S,S), 3.times.15 cm column. The mobile phase was run under
isocratic conditions; supercritical CO.sub.2 with 60% [2:3
isopropanol:dichloromethane]; flow rate: 150 mL/min. The first
eluting peak was assigned perfluorophenyl
(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
(1459.2 g). The second eluting peak was assigned perfluorophenyl
(M)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
(1492.9 g).
Step 5:
(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydr-
oquinoline-6-Sulfonamide
[0348] Racemic
1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline--
6-sulfonamide (400 mg) was purified using a (S,S) Whelk-O,
2.times.15 cm column. The mobile phase was run under isocratic
conditions; supercritical CO.sub.2 with 60% isopropanol; flow rate:
80 mL/min. The first eluting peak was assigned
(M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinol-
ine-6-sulfonamide (150 mg). The second eluting peak was assigned
(P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinol-
ine-6-sulfonamide (154 mg). Data for peak 1: .sup.1H NMR (400 MHz,
ACETONITRILE-d.sub.3) .delta. ppm 8.65-8.94 (m, 1H), 8.37 (d, J=1.9
Hz, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.97 (d, J=9.3 Hz, 1H), 7.78 (dd,
J=8.9, 2.3 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.3, 2.1
Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.70-6.80 (m, 2H), 6.45 (d, J=1.9
Hz, 1H), 3.69 (s, 3H). m/z (ESI, positive ion) 476.0 (M+H).sup.+.
Data for peak 2: .sup.1H NMR (400 MHz, ACETONITRILE-d.sub.3) 6 ppm
8.72-8.87 (m, 1H), 8.37 (d, J=1.7 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H),
7.97 (d, J=9.5 Hz, 1H), 7.78 (dd, J=9.0, 2.2 Hz, 1H), 7.43 (d,
J=2.1 Hz, 1H), 7.34 (dd, J=8.3, 1.9 Hz, 1H), 7.16 (d, J=8.3 Hz,
1H), 6.69-6.80 (m, 2H), 6.45 (d, J=1.9 Hz, 1H), 3.69 (s, 3H). m/z
(ESI, positive ion) 476.0 (M+H).sup.+.
Intermediate E: N-(4-Methoxybenzyl)Isoxazol-3-Amine
##STR00032##
[0350] To a 20-L round-bottom flask was added isoxazol-3-amine (150
g, 1784 mmol) and 4-methoxybenzaldehyde (274 g, 2016 mmol) in
methanol (9000 mL), water (150 mL), and acetic acid (101 mL) and
stirred for 15 min at room temperature. Then molybdenum dichloride
dioxide (17.74 g, 89 mmol) and phenylsilane (193 g, 1784 mmol) were
added. The reaction mixture was stirred at room temperature for 16
h. After completion of the reaction, the reaction mass was
concentrated, diluted with dichloromethane (5000 mL) and washed
with sat. aq. NaHCO.sub.3 (2000 mL). The organic layer was washed
with water (2000 mL) and dried over Na.sub.2SO.sub.4. The solution
was filtered and concentrated in vacuo to give the initial product
as an orange solid. The initial product was absorbed onto a plug of
silica gel and purified by column chromatography (Silica gel,
60-120 mesh) eluting with a gradient of 0% to 30% EtOAc in hexane,
to provide N-(4-methoxybenzyl)isoxazol-3-amine (272 g, 1332 mmol,
75% yield) as an off-white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.36 (d, J=1.8 Hz, 1H), 7.16-7.37 (m,
2H), 6.71-6.97 (m, 2H), 6.56 (t, J=6.0 Hz, 1H), 5.97 (d, J=1.8 Hz,
1H), 4.18 (d, J=6.0 Hz, 2H), 3.73 (s, 3H). m/z (ESI, positive ion)
205.1 (M+H).sup.+.
Intermediate F:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybe-
nzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00033##
[0351] Step 1: 4-Bromo-2-Iodoaniline
[0352] To a solution of 4-bromo-aniline (500 g, 2.90 mol, 2.0
equiv, Saibain Chem) in cyclohexane (2.5 L) was added iodine (368
g, 1.45 mol, 1.0 equiv, Qualigens) and the mixture was heated at
50.degree. C. After 30 min, the reaction mixture became homogenous.
30% aqueous hydrogen peroxide solution (250 mL, Spectrochem) was
added to the reaction mixture. The reaction was heated for 4 h at
50.degree. C. The reaction was cooled to room temperature, diluted
with ethyl acetate (5.0 L) and washed with aqueous sodium-sulphite
(2.5 Kg in 4.0 L) solution. The organic layer was washed with water
(3.0 L) and brine (3.0 L) dried over magnesium sulfate, filtered
and concentrated under reduced pressure to obtain the initial
product which was purified by column chromatography (silica gel;
mesh size 60-120, elution 0-20% ethyl acetate and hexanes) to get
4-bromo-2-iodoaniline (650 g, 75.0%), as off white solid. TLC
solvent system: 100% hexanes. Product's R.sub.f: 0.6. MS (ESI,
positive ion) m/z: 297.0 (M+1). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.72 (d, J=2.5 Hz, 1H), 7.23 (dd, J=8.4, 2.1 Hz, 1H), 6.62
(d, J=8.3 Hz, 1H), 4.09 (s, 2H).
Step 2: Ethyl (E)-3-(2-Amino-5-Bromophenyl)Acrylate
[0353] To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0
equiv) in DMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol,
1.1 equiv, Avra) and sodium bicarbonate (680 g, 6.29 mol, 2.5
equiv). The reaction mixture was degassed with nitrogen for 20 min
followed by the addition of palladium acetate (28.8 g, 128.27 mmol,
0.05 equiv, Hindustan Platinum). The reaction mixture was heated at
70.degree. C. for 3h. The reaction was filtered through CELITE.RTM.
and the CELITE.RTM. bed was washed with ethyl acetate (2.times.500
mL). The filtrate was concentrated under reduced pressure to obtain
the initial product which was purified by column chromatography
(silica gel; mesh size 60-120, elution 0-20% ethyl acetate in
hexanes) to obtain (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620
g, 77.0%), as yellow solid. TLC solvent system: 20% ethyl acetate
in hexanes. Product's R.sub.f: 0.4. MS (ESI, positive ion) m/z;
270.2 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 7.75 (d, J=16.1
Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.16 (dd, J=9.1, 2.4 Hz, 1H), 6.66
(d, J=8.6 Hz, 1H), 6.43 (d, J=8.6 Hz, 1H), 5.81 (s, 2H), 4.20 (q,
J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).
##STR00034##
Step 3: Ethyl (E)-3-(2-Amino-5-(Benzylthio)Phenyl)Acrylate
[0354] To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate
(620 g, 2.29 mol, 1.0 equiv) in 1,4-dioxane (4.0 L) was added DIPEA
(1.26 L, 8.88 mol, 3.9 equiv, GLR) and degassed with nitrogen for
20 mins. XantPhos (92.9 g, 106 mmol, 0.05 equiv, GLR), and
tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv,
Hindustan Platinum) was added to the reaction mixture. The mixture
was purged with nitrogen and heated to 80.degree. C. for 30 mins.
The reaction was cooled to RT and benzyl mercaptan (455.5 g, 3.67
mol, 1.6 equiv, Alfa Aesar) was added and the reaction was heated
at 80.degree. C. for an additional 4 h. The reaction was cooled to
room temperature and diluted with ethyl acetate (4.0 L). The
mixture was filtered through CELITE.RTM. and the CELITE.RTM. bed
was washed with ethyl acetate (2.times.1.0 L). The filtrate was
concentrated under reduced pressure to obtain the initial product
which was purified by chromatography (silica gel; mesh size 60-120,
elution 0-40% ethyl acetate and petroleum ether) to obtain
(E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%),
as yellow solid. TLC solvent system: 30% ethyl acetate in hexanes.
Product's R.sub.f: 0.4. MS (ESI, positive ion) m/z; 314.1 (M+1).
.sup.1H NMR (400 MHz, DMSO) .delta. 7.79 (d, J=16.1 Hz, 1H), 7.37
(d, J=2.0 Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J=8.4, 2.1 Hz, 1H),
6.61 (d, J=8.3 Hz, 1H), 6.32 (d, J=15.2 Hz, 1H), 5.75 (s, 2H), 4.20
(q, J=7.2 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).
##STR00035##
Step 4: 1-Bromo-2-Fluoro-4-Iodo-5-Methoxybenzene
[0355] To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g,
2.44 mol, 1.0 equiv) in DCM (5.0 L) was added silver
trifluoromethane sulfonate (686.0 g, 2.68 mol, 1.1 equiv, Angene)
and the reaction mixture was stirred for 20 mins. Iodine (678.0 g,
2.68 mol, 1.1 equiv) was added to the reaction and the mixture was
stirred at room temperature for 16h. The mixture was diluted with
DCM (3.0 L) and filtered through CELITE.RTM.. The CELITE bed was
washed with DCM (2.times.1.0 L) and the filtrate was washed with
20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodium
bicarbonate solution (3.0 L). The organic layer was dried over
sodium sulfate, filtered and concentrated under reduced pressure to
obtain the initial product which was purified by chromatography
(silica gel; mesh size 60-120, elution 0-5% ethyl acetate and
petroleum ether) to get 1-bromo-2-fluoro-4-iodo-5-methoxybenzene
(720 g, 87%), as off-white solid. TLC solvent system: 100% hexanes.
Product's R.sub.f: 0.6. MS (ESI, positive ion) m/z: 331.0 (M+1).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.55 (d, J=7.2 Hz, 1H),
6.95 (d, J=5.6 Hz, 1H), 3.89 (s, 3H).
Step 5: Ethyl
(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)Phenyl)
Acrylate
[0356] To a solution of (E)-ethyl
3-(2-amino-5-(benzylthio)phenyl)acrylate (300 g, 958.1 mmol, 1.0
equiv) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g,
1051.6 mmol, 1.1 equiv) in toluene (2.5 L) was added
Cs.sub.2CO.sub.3 (468 g, 1436.3 mmol, 1.5 equiv, Spectrochem) and
the mixture was degassed with nitrogen for 20 mins.
Pd.sub.2(dba).sub.3 (35 g, 38.2 mmol, 0.04 equiv, Hindustan
Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 equiv, GLR) were
added to the reaction mixture and the mixture was heated at
110.degree. C. for 5h. The reaction mixture was allowed to cool to
room temperature, diluted with dichloromethane (2.0 L) and filtered
through CELITE.RTM. The filtrate was concentrated under reduced
pressure to obtain the initial product which was purified by
stirring with 5% ethyl acetate in hexanes (3.0 L) for 30 min and
filtered to obtain (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acryl-
ate (350 g, 71%) as yellow solid. TLC solvent system: 30% ethyl
acetate in hexanes. Product's R.sub.f: 0.5. MS (ESI, positive ion)
m/z; 516.2 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 7.73-7.61 (m,
3H), 7.34-7.15 (m, 6H), 7.02 (d, J=11.4 Hz, 1H), 6.60 (d, J=21.2
Hz, 1H), 6.33 (d, J=14.1 Hz, 1H), 4.26 (s, 2H), 4.16-4.09 (m, 2H),
3.81 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). Note: NH proton not
observed.
##STR00036##
Step 6: 6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)
Quinolin-2(1H)-One
[0357] To a solution of (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenypacryla-
te (250.0 g, 484.0 mmol, 1.0 equiv) in methanol (2.5 L) was added
tri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8
mmol, 0.2 equiv, Spectrochem) and the reaction mixture was heated
at 70.degree. C. for 5 h. The reaction mixture was allowed to cool
to rt, concentrated under reduced pressure to obtain the initial
product which was purified by stirring with 5% ethyl acetate in
hexanes (1.0 mL) and filtered to obtain
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)--
one (201.0 g, 88%) as off white solid. TLC solvent system: 30%
ethyl acetate in hexanes. Product's R.sub.f: 0.3. MS (ESI, positive
ion) m/z; 470.0 (M+1). .sup.1H NMR (400 MHz, DMSO) .delta. 7.92 (d,
J=9.1 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.65 (d, J=6.1 Hz, 1H), 7.57
(d, J=8.8 Hz, 1H), 7.40-7.22 (m, 6H), 6.68 (d, J=9.6 Hz, 1H), 6.56
(d, J=8.8 Hz, 1H), 4.24 (s, 2H), 3.69 (s, 3H).
Steps 7+8: Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfona-
te
[0358] To a solution of
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one
(250.0 g, 531.5 mmol, 1.0 equiv) in acetonitrile (2.5 L) were added
acetic acid (200 mL) and water (130 mL). The resulting mixture was
cooled to 0.degree. C. and
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (188.5 g, 956.7
mmol, 1.8 equiv, Aldrich) was added portion-wise over 20 min
keeping the internal temperature below 5.degree. C. The resulting
suspension was stirred at 0-5.degree. C. under nitrogen for 45 min.
Then a solution of pentafluorophenol (127.2 g, 690.95 mmol, 1.3
equiv, Apollo) in acetonitrile (200 mL) was added over 5 min
followed by NEt.sub.3 (307.7 mL, 2.12 mol, 4.0 equiv) over 20 min
keeping the internal temperature below 5.degree. C. The mixture was
continued to be stirred at 0-5.degree. C. for 30 min. Water (4.0 L)
was added and extracted with ethyl acetate (2.times.2.0 L). The
organic layer was washed with brine (1.0 L), dried over sodium
sulfate, filtered and concentrated under reduced pressure to obtain
the initial material which was purified by stirring with isopropyl
alcohol:hexanes (1:1, 1.0 L) and filtered to obtain racemic
perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (190 g, 60%) as white solid. TLC solvent system: 30% ethyl
acetate in pet ether, Product's R.sub.f: 0.4. MS (ESI, positive
ion) m/z; 594.2 (M+1). .sup.1H-NMR (400 MHz, DMSO) .delta. 8.60 (d,
J=2.0 Hz, 1H), 8.26 (d, J=9.8 Hz, 1H), 7.95 (dd, J=2.2, 9.1 Hz,
1H), 7.70 (t, J=8.6 Hz, 2H), 6.95-6.88 (m, 2H), 3.72 (s, 3H).
##STR00037##
Step 9:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo--
1,2-Dihydroquinoline-6-Sulfonamide
[0359] Racemic perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te was separated via Chiralcel OJ column (40% MeOH/60% CO.sub.2) to
give (P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te and (M)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te as pale yellow flocculent solids. Data for peak 1: m/z (ESI)
594.0 (M+H).sup.+. Data for peak 2: m/z (ESI) 594.0
(M+H).sup.+.
##STR00038##
Step 10:
(P)-L-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4--
Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0360] A 250-mL round-bottom flask was charged with
(P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (11.34 g, 19.08 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine
(4.09 g, 20.04 mmol), then purged with nitrogen. Tetrahydrofuran
(191 mL) was introduced, and the resultant brown solution cooled to
0.degree. C. A solution of lithium bis(trimethylsilyl)amide (1.0 M
in THF, 21.0 mL, 21.0 mmol) was added dropwise via syringe to the
stirred reaction mixture over 10 min. After 15 min, 1.0 N HCl (100
mL) was introduced and the resultant reaction mixture was allowed
to warm to rt. The mixture was diluted with and EtOAc (100 mL) and
the layers were separated, and the aqueous layer was further
extracted with EtOAc (2.times.100 mL). The combined organic layers
were then washed with brine (100 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure. The
residue was then purified by flash column chromatography (100-g
BIOTAGE.RTM. column, eluent: gradient, 0 to 100% EtOAc in heptane
with 10% CH.sub.2Cl.sub.2 as an additive) to afford
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (9.54 g, 15.53 mmol,
81% yield) as a white amorphous solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.82 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.3
Hz, 1H), 8.17 (d, J=9.4 Hz, 1H), 7.76 (t, J=5.1 Hz, 1H), 7.68 (d,
J=6.1 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.26 (d, J=7.9 Hz, 2H),
6.91-6.78 (m, 4H), 6.74 (d, J=2.0 Hz, 1H), 4.92 (s, 2H), 3.73-3.69
(m, 6H), 3.32 (s, 1H). m/z (ESI) 615.1 (M+H).sup.+.
Intermediate G: 1-Bromo-2-Chloro-4-Iodo-5-Methoxybenzene
##STR00039##
[0362] To a solution of 2-bromo-1-chloro-4-methoxybenzene (500 g,
2258 mmol) in dichloromethane (7500 mL) was added silver(I)
trifluoromethanesulfonate (638 g, 2483 mmol) at ambient temperature
under nitrogen environment. The reaction mixture was stirred for 20
mins at ambient temperature and iodine (630 g, 2483 mmol) was
added. The reaction mixture was stirred at ambient temperature for
16 h. The mixture was then diluted with DCM (4500 mL) and filtered
through CELITE. The CELITE bed was washed with DCM (2.times.1.0 L).
The filtrate was washed with 20% aqueous sodium thiosulfate (5.0 L)
and saturated aqueous sodium bicarbonate solution (5.0 L). The
organic layer was dried over sodium sulfate, filtered and
concentrated under reduced pressure to obtain the initial product
which was purified by column chromatography (silica gel; mesh size
60-120, elution 0-5% ethyl acetate and petroleum ether) to afford
1-bromo-2-chloro-4-iodo-5-methoxybenzene (610 g, 1756 mmol, 78%
yield) as off-white solid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 7.83 (s, 1H), 7.03 (s, 1H), 3.89 (s, 3H).
Intermediate H: N-(4-Methoxybenzyl)Pyrimidin-2-Amine
##STR00040##
[0364] In a 50-mL microwave vial were successively dissolved in
EtOH (20 mL), 2-chloropyrimidine (1.5 g, 13.10 mmol),
(4-methoxyphenyl)methenamine (2.15 g, 15.72 mmol, 1.2 equiv), and
triethylamine (2.65 g, 26.2 mmol, 2.0 equiv). The reaction tube was
sealed and irradiated in the cavity of a microwave reactor at a
ceiling temperature of 120.degree. C. at 80 W maximum power for 1
h. After the reaction mixture was cooled with an air flow for 15
min, it was diluted with water (100 mL), extracted with
CH.sub.2Cl.sub.2 (2.times.150 mL) and dried over Na.sub.2SO.sub.4.
The reaction mixture was diluted with water (50 mL) and extracted
with ethyl acetate (2.times.50 mL). The organic extract was washed
with sat. aq. NaCl (1.times.50 mL) and dried over Na.sub.2SO.sub.4.
The solution was filtered and concentrated in vacuo to give the
initial product as a yellow oil. The initial product was absorbed
onto a plug of silica gel and purified by chromatography through a
Redi-Sep pre-packed silica gel column (12 g), eluting with a
gradient of 20% to 30% EtOAc in hexane, to provide
N-(4-methoxybenzyl)pyrimidin-2-amine (1.5 g, 6.97 mmol, 53% yield)
as an off white solid. m/z (ESI) 216.2 (M+H).sup.+.
Intermediate I:
(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyr-
imidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00041## ##STR00042##
[0365] Step 1:
(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Chloro-2-Methoxyphenyl)Amino)Phenyl)A-
crylate
[0366] To a solution of ethyl
(E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (175 g, 555.0 mmol)
and 1-bromo-2-chloro-4-iodo-5-methoxybenzene (231.3 g, 666.2, mmol)
in toluene (1.5 L) was added cesium carbonate (357.5 g, 1100 mmol)
and the mixture was degassed with nitrogen for 20 mins.
tris(dibenzylideneacetone)dipalladium(0) (12.5 g, 13.0 mmol) and
XantPhos (15.8 g, 27.2 mmol, 0.05 equiv) were added to the reaction
mixture and the mixture was heated at 110.degree. C. for 5 h. The
reaction mixture was allowed to cool to room temperature, diluted
with dichloromethane (1.0 L) and filtered through CELITE. The
filtrate was concentrated under reduced pressure to obtain the
initial product which was purified by stirring with 5% ethyl
acetate in hexane (1.5 L) for 30 min and filtered to obtain ethyl
(E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenypac-
rylate (290 g, 85% yield) as yellow solid. m/z (ESI) 532.2
(M+H).sup.+.
Step 2:
6-(Benzylthio)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)Quinolin-2(1H)--
One
[0367] To a solution of ethyl
(E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)a-
crylate (300.0 g, 5630.0 mmol) in methanol (3.0 L) was added
tri(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126
mmol) and the reaction mixture was heated at 70.degree. C. for 5 h.
The reaction mixture was allowed to cool to room temperature,
concentrated under reduced pressure to obtain the initial product
which was purified by stirring with 5% ethyl acetate in hexane (1.0
mL) and filtered to obtain
6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)--
one (210.0 g, 76.6%) as an off white solid, m/z (ESI) 486.0
(M+H).sup.+.
Step 3: Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfona-
te
[0368] To a solution of
6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one
(400.0 g, 824.9 mmol) in acetonitrile (2.5 L) and THF (2.5 L) were
added acetic acid (1.0 L) and water (700 mL). The resulting mixture
was cooled to 0.degree. C. and
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (292 g, 1484.8
mmol) was added portionwise over 30 min keeping the internal
temperature below 5.degree. C. The resulting suspension was stirred
at 0.degree. C. under nitrogen for 45 min. Then a solution of
pentafluorophenol (197.4 g, 1072.3 mmol) in acetonitrile (500 mL)
was added over 5 min followed by triethylamine (477 mL, 3299 mmol)
over 30 min keeping the internal temperature below 5.degree. C. The
mixture was continued to be stirred at 0.degree. C. for 50 min.
Water (4.0 L) was added and extracted with ethyl acetate
(3.times.2.0 L). The organic layer was washed with brine (2.0 L),
dried over sodium sulfate, filtered and concentrated under reduced
pressure to obtain the initial product which was purified by
stirring with isopropyl alcohol/hexane (1:1, 2.0 L) and filtered to
obtain perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydro
quinoline-6-sulfonate (360 g, 72%) as a white solid. m/z (ESI)
610.6 (M+H).sup.+.
Step 4: (P)-Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfona-
te & (M)-Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfona-
te
[0369] Perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydro
quinoline-6-sulfonate (156 g, 255 mmol) was purified via chiral SFC
chromatography ((S,S) Whelk-O, 45% isopropanol) to afford
(P)-perfluorophenyl
1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (72.66 g, 93% yield) and (M)-perfluorophenyl
1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (76.13 g, 98% yield) as white solids, m/z (ESI) 610.6
(M+H).sup.+.
Step 5:
(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-
-N-(Pyrimidin-2-YL)-1,2-Dihydroquinoline-6-Sulfonamide
[0370] N-(4-Methoxybenzyl)pyrimidin-2-amine (9.72 g, 45.1 mmol) and
(P)-perfluorophenyl
1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (25.06 g, 41.0 mmol) were added to a 500-mL flask. The flask was
flushed with N.sub.2 stream then tetrahydrofuran (136 mL) was added
and the reaction was cooled to 2.degree. C. under N.sub.2. Sodium
tert-pentoxide (30% solution in THF, 197 mL, 492 mmol) was added
over 30 min via addition funnel maintaining internal temperature
around 5.degree. C., and the pale yellow solution turned orange
upon the addition. The reaction was stirred for 30 min in the ice
bath. The reaction was then quenched with sat. aq. NH.sub.4Cl and
diluted with EtOAc. The layers were separated and the water layer
was extracted twice with EtOAc. The combined organics were dried
with Na.sub.2SO.sub.4, filtered, and evaporated. IPA was added and
a white precipitate crashed out. The solvent was evaporated to
approximately 100 mL then additional IPA was added and the reaction
was stirred for 18 h. The slurry was filtered and the solid was
washed with IPA.
[0371] The solid was taken up in 150 mL of MTBE and heated at
40.degree. C. for 2 hours. The slurry was cooled to ambient
temperature and filtered to obtain a white solid. The impure
material was dissolved in 500 mL of 10% MeOH/DCM and stirred with
500 mL of sat. aq. NaHCO.sub.3 for 30 minutes. The layers were
separated and the water layer was extracted twice with 10%
MeOH/DCM. The combined organics layers were dried and evaporated.
The filtrates from IPA and MTBE titrations were combined and loaded
onto 25 g silica cartridge and purified by column chromatography
(RediSep Rf Gold 120 g column, gradient elution 10% to 50% 3:1
EtOAc:EtOH in heptane with 10% dichloromethane additive). The pure
product of the column and the product from the NaHCO.sub.3
extraction were combined to afford
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-
-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (16.94 g,
26.4 mmol, 64% yield) as a pale yellow foam. .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 8.58 (d, J=4.9 Hz, 2H), 8.39 (d, J=2.1
Hz, 1H), 8.13 (d, J=9.6 Hz, 1H), 7.96 (dd, 2.3 Hz, 1H), 7.76 (s,
1H), 7.73 (s, 1H), 7.29 (d, J=8.8 Hz, 2H), 7.13 (t, J=4.9 Hz, 1H),
6.87 (d, J=8.8 Hz, 2H), 6.78 (d, J=9.6 Hz, 1H), 6.74 (d, J=9.1 Hz,
1H), 5.36 (s, 2H), 3.72 (s, 3H), 3.71 (s, 3H). m/z (ESI, positive
ion) 642.8 (M+H).sup.+.
Intermediate J: N-(4-Methoxybenzyl)Pyridazin-3-Amine
##STR00043##
[0373] To a 25-mL round-bottomed flask was added
4-methoxybenzaldehyde (1.00 g, 7.34 mmol) and pyridazin-3-amine
(0.838 g, 8.81 mmol) in tetrahydrofuran (10 mL). Then, titanium(IV)
isopropoxide (6.46 mL, 22.03 mmol) was added, and the reaction
mixture was stirred at 70.degree. C. for 16 h. Then the reaction
mixture was cooled to 0.degree. C., and sodium borohydride (0.556
g, 14.69 mmol) was added portionwise. The reaction mixture was then
stirred for 2 h at 0.degree. C. The reaction mixture was diluted
with water (20 mL) and filtered. The filtrate was then extracted
with EtOAc (3.times.50 mL). The organic extract was washed with
sat. aq. NaCl (30 mL) and dried over Na.sub.2SO.sub.4. The solution
was filtered and concentrated in vacuo to give the initial product
as a orange oil. The initial product was absorbed onto a plug of
silica gel and purified by chromatography through a Redi-Sep
pre-packed silica gel column (40 g), eluting with 0% to 15% MeOH in
CH.sub.2Cl.sub.2 to provide N-(4-methoxybenzyl)pyridazin-3-amine
(0.680 g, 3.16 mmol, 43.0% yield) as yellow solid. m/z (ESI,
positive ion) 216.2 (M+H).sup.+.
Intermediate K:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyr-
idazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00044##
[0375] A 100-mL recovery flask containing perfluorophenyl
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (5.00 g, 8.41 mmol) and N-(4-methoxybenzyl)pyridazin-3-amine
(1.902 g, 8.83 mmol) was flushed with nitrogen and subsequently
charged with THF (34 mL). The solution was cooled to 0.degree. C.,
and sodium tert-pentoxide (8.4 mL, 11.78 mmol, 1.4 M in THF) was
added slowly. The pale yellow solution was stirred at 0.degree. C.
for 15 min, and then volatiles were removed in vacuo. Water was
added to cause formation of a white precipitate. This precipitate
was isolated, dissolved in dichloromethane, and treated with
heptane to cause formation of
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (4.20 g, 6.71 mmol,
80% yield) as a white precipitate. m/z (ESI, positive ion) 625.0
(M+H).sup.+.
Intermediate L: Perfluorophenyl
(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sul-
fonate
##STR00045## ##STR00046##
[0376] Step 1: (E)-Ethyl
3-(5-(Benzylthio)-2-((4-Bromo-2-Methoxy-5-Methylphenyl)Amino)Phenyl)Acryl-
ate
[0377] A round-bottom flask was charged with (E)-ethyl
3-(2-amino-5-(benzylthio)phenyl)acrylate (4.729 g, 15.09 mmol),
1-bromo-4-iodo-5-methoxy-2-methylbenzene (5.18 g, 15.84 mmol),
XantPhos (0.437 g, 0.754 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.345 g, 0.377 mmol),
cesium carbonate (9.83 g, 30.2 mmol), and toluene (30 mL) were
added. A reflux condenser was attached, and the mixture was heated
to reflux. After 4 h, additional portions of
tris(dibenzylideneacetone)dipalladium(0) (172 mg) and XantPhos (213
mg) were added. After 2 h, additional portions of cesium carbonate
(ca. 2 g) and 1-bromo-4-iodo-5-methoxy-2-methylbenzene (600 mg)
were added. Following an additional 30 min of reflux, the mixture
was cooled and filtered through CELITE. The filter pad was washed
with EtOAc (3.times.). The filtrate was concentrated. The residue
was concentrated from MeOH, and taken up in MeOH. The resulting
suspension was heated to boiling, then sonicated and cooled to RT.
The mixture was filtered, and the collected solid was washed with
MeOH (3.times.) and dried under a stream of N2 for 48 h to give
(E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acryl-
ate (5.21 g, 10.17 mmol, 67.4% yield) as a bright-yellow solid.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 7.75 (d, J=15.9 Hz,
1H), 7.66 (d, J=2.1 Hz, 1H), 7.42 (s, 1H), 7.37-7.20 (m, 6H), 7.14
(s, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.62 (s, 1H), 6.51 (d, J=15.9 Hz,
1H), 4.23 (s, 2H), 4.15 (q, J=7.0 Hz, 2H), 3.78 (s, 3H), 2.14 (s,
2H), 1.23 (t, J=7.1 Hz, 3H). m/z (ESI) 512.2 (M+H).sup.+.
Step 2:
6-(Benzylthio)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)Quinolin-2(1H)--
One
[0378] A round-bottom flask was charged with (E)-ethyl
3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenypacryla-
te (5.12 g, 9.99 mmol) and MeOH (50.0 mL) to give a yellow
suspension. Sodium methoxide (25 wt % in MeOH, 0.432 mL, 1.998
mmol) was added. A reflux condenser was attached, and the flask was
lowered into a 70.degree. C. heating bath. After 1 h, additional
portions of MeOH (25 mL) and sodium methoxide solution (ca. 0.85
mL) were added in sequence. After 7 h, the mixture was cooled and
concentrated under vacuum. The residue was purified by
chromatography on silica gel (80-g Redi-Sep column, 25-g silica gel
loading column, loaded as a solution in MeOH-DCM, then eluted with
25-75% EtOAc/heptane containing 10% DCM). The fractions containing
product were combined and concentrated to give
6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2
(1H)-one (4.233 g, 9.08 mmol, 91% yield) as a tan solid. m/z (ESI)
466.1 (M+H)+.
Step 3: Perfluorophenyl
1-(4-Bromo-2-Methoxy-5-Methylphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfona-
te
[0379] A round-bottom flask was charged with
6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2(1H)-one
(4.23 g, 9.07 mmol), DCM (71.1 mL), acetic acid (2.67 mL), and
water (1.778 mL) to give clear, light-brown solution. The flask was
cooled in an ice-water bath for 10 min, then
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.66 g, 18.59
mmol) was added in one portion. After 40 min, an additional portion
of oxidant (850 mg) was added. The mixture was stirred for another
20 min, then 2,3,4,5,6-pentafluorophenol (2.504 g, 13.60 mmol) and
triethylamine (5.06 mL, 36.3 mmol) were added in sequence. After 20
min, the mixture was diluted with water. The layers were separated,
and the aq. layer was extracted with DCM. The combined organic
extracts were dried over sodium sulfate, filtered, and
concentrated. The residue was purified by chromatography on silica
gel (80-g Redi-Sep Gold column, 25-g silica gel loading column,
10-60% EtOAc/Heptane with 10% DCM) to afford perfluorophenyl
1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (3.37 g, 5.71 mmol, 63% yield). m/z (ESI) 590.0 (M+H).sup.+.
Step 4: Perfluorophenyl
(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sul-
fonate
[0380] Perfluorophenyl
1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
te (22.896 g, 38.79 mmol) was purified using a (S,S) Whelk-O,
5.times.25 cm column. The mobile phase was run under isocratic
conditions; supercritical CO.sub.2 with 50% dichloromethane; flow
rate: 350 mL/min. The first eluting peak was assigned
perfluorophenyl
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (10.425 g). The second eluting peak was assigned
perfluorophenyl
(M)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (10.76 g). Data for peak 1: m/z (ESI) 590.0 (M+H).sup.+.
Data for peak 2: m/z (ESI) 590.0 (M+H).sup.+.
Intermediate M:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyr-
imidin-2-YL)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00047##
[0382] A 250-mL round-bottom flask was sequentially charged with
perfluorophenyl
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (2.00 g, 3.37 mmol), tetrahydrofuran (17 mL), and
N-(4-methoxybenzyl)pyrimidin-2-amine (0.724 g, 3.37 mmol), and the
resulting solution was cooled to 0.degree. C. Lithium
bis(trimethylsilyl)amide (3.70 mL, 3.70 mmol, 1.0 M in THF) was
then added dropwise to the stirred reaction mixture. After 15 min,
aqueous HCl solution (1.0 M, 100 mL) and EtOAc (100 mL) were added
to the reaction mixture, which was subsequently allowed to warm to
ambient temperature. The layers were separated, and the aqueous
layer was extracted with EtOAc (2.times.100 mL). The combined
organic layers were then washed with brine (100 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was then purified by flash column
chromatography (100 g BIOTAGE.RTM. column, gradient elution 0-100%
EtOAc:heptane with 10% dichloromethane as co-eluent) to afford
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (1.10 g, 1.76 mmol,
52% yield) as a white solid. m/z (ESI, positive ion) 625.8
(M+H).sup.+.
Intermediate N:
(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybe-
nzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00048##
[0384] To a 0.degree. C. solution of
N-(4-methoxybenzyl)isoxazol-3-amine (83 mg, 0.407 mmol) and
perfluorophenyl
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (200 mg, 0.339 mmol) in tetrahydrofuran (1.7 mL) was added
sodium tert-pentoxide (30 wt % in THF, 176 .mu.L, 0.440 mmol)
slowly. The reaction was stirred for 30 minutes at 0.degree. C.
After 30 min, the reaction mixture was partitioned between ethyl
acetate and saturated aqueous ammonium chloride. The organic layer
was concentrated, and the residue was triturated with MTBE (2 mL)
to provide
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (191 mg, 0.313 mmol,
92% yield) as a white powder. m/z (ESI, positive ion) 609.8
(M+H).sup.+.
Intermediate O: N-(4-Methoxybenzyl)Oxazol-2-Amine
##STR00049##
[0386] In a 250-mL flask, 1,3-oxazol-2-amine (5.00 g, 59.5 mmol)
and 4-anisaldehyde (10.53 g, 8.85 mL, 77 mmol) were heated in
toluene (119 mL) for 2 hours at 90.degree. C. The reaction was
cooled to ambient temperature, and sodium triacetoxyhydroborate
(18.91 g, 89 mmol) was added portion-wise. The yellow reaction was
stirred for 18 hours. The reaction was then quenched with water,
the layers were separated, and the water layer was extracted twice
with dichloromethane. The combined organics were dried with
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
loaded onto 25 g silica cartridge and purified by column
chromatography (RediSep Rf Gold 120 g column, gradient elution
10-50% EtOAc:heptane) to afford N-(4-methoxybenzyl)oxazol-2-amine
(1.588 g, 7.78 mmol, 13% yield) as a white solid. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 7.55 (br t, J=6.1 Hz, 1H), 7.39 (d,
J=1.0 Hz, 1H), 7.24 (d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 6.73
(d, J=1.0 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H), 3.72 (s, 3H). m/z (ESI,
positive ion) 205.2 (M+H).sup.+.
Intermediate P:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-N-(Oxazol-2--
YL)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00050##
[0388] To a 0.degree. C. solution of
N-(4-methoxybenzyl)oxazol-2-amine (82 mg, 0.404 mmol) and
perfluorophenyl
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (200 mg, 0.337 mmol) in tetrahydrofuran (1.6 mL) was slowly
added sodium tert-pentoxide, (30 wt % in THF, 175 .mu.L, 0.438
mmol). The reaction was stirred for 30 minutes at 0.degree. C. The
reaction mixture was then partitioned between ethyl acetate and
saturated aqueous ammonium chloride. The organic layer was
concentrated. The residue was purified by silica gel column
chromatography (gradient elution 20-80% [3:1 ethyl
acetate/ethanol]:heptane with 10% dichloromethane as a co-eluent)
to provide
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(o-
xazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (180 mg, 0.293
mmol, 87% yield) as a white powder. m/z (ESI, positive ion) 613.8
(M+H).sup.+.
Intermediate Q:
(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(Isoxazol-3-YL)-N-(4-Methoxybenzyl)-2-O-
xo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00051##
[0390] To a 0.degree. C. solution of
N-(4-methoxybenzyl)isoxazol-3-amine (128 mg, 0.625 mmol) and
perfluorophenyl
(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
(300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) was slowly added
sodium tert-pentoxide (30 wt % in THF, 271 .mu.L, 0.677 mmol)
slowly. The reaction was stirred for 30 minutes at 0.degree. C. The
reaction mixture was then partitioned between ethyl acetate and
saturated aqueous ammonium chloride. The organic layer was
concentrated. The residue was triturated with MTBE to provide
1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1-
,2-dihydroquinoline-6-sulfonamide (350 mg, 0.587 mmol, >99%
yield) as an off-white solid. m/z (ESI, positive ion) 595.8
(M+H).sup.+.
Intermediate R:
(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2--
Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00052##
[0392] The title compound was prepared according to the method and
purification protocol of Intermediate R using
N-(4-methoxybenzyl)pyrimidin-2-amine (134 mg, 0.625 mmol). This
afforded
1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)--
1,2-dihydroquinoline-6-sulfonamide (140 mg, 0.230 mmol, 44% yield)
as an off-white solid. m/z (ESI, positive ion) 606.8
(M+H).sup.+.
Intermediate S:
(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyr-
imidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00053##
[0394] The title compound was prepared according to the method and
purification protocol of Intermediate R using perfluorophenyl
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (200 mg, 0.339 mmol). This afforded
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (130 mg, 0.209
mmol, 62% yield) as a white solid. m/z (ESI, positive ion) 620.8
(M+H).sup.+.
Intermediate T: N-(2,4-Dimethoxybenzyl)Oxazol-2-Amine
##STR00054##
[0396] In a 250 mL flask, a mixture of 1,3-oxazol-2-amine (5.00 g,
59.5 mmol) and 2,4-dimethoxybenzaldehyde (10.87 g, 65.4 mmol) were
heated in toluene (100 mL) at 90.degree. C. for 1 h. The reaction
was cooled to rt then treated with sodium triacetoxyborohydride
(18.91 g, 89 mmol). The mixture was stirred at 100.degree. C. for 1
h, then at rt for 60 h. Additional sodium triacetoxyborohydride
(18.91 g, 89 mmol) was added and the reaction stirred at
100.degree. C. for 2 h. The reaction was then cooled and diluted
with ethyl acetate (500 mL) and water (100 mL). The organic layer
was washed with saturated sodium bicarbonate solution (3.times.200
mL) and brine (2.times.100 mL) and dried over magnesium sulfate.
The solvent was removed under reduced pressure to give a viscous
brown oil, which was flushed through a plug of silica gel, washing
with 50% [3:1 ethyl acetate:ethanol]:heptane. The filtrate was
concentrated and then purified by flash chromatography (HP silica
220 g column, gradient elution 0-70% ethyl acetate: [9:1
heptane:DCM]) to afford N-(2,4-dimethoxybenzyl)oxazol-2-amine (1.18
g, 5.04 mmol, 8% yield) as a pale yellow solid. m/z (ESI, positive
ion) 235.2 (M+H).sup.+.
Intermediate U:
(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-YL)-2-
-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00055##
[0398] To a 0.degree. C. solution of
N-(2,4-dimethoxybenzyl)oxazol-2-amine (146 mg, 0.625 mmol) and
perfluorophenyl
(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
(300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) was slowly added
sodium tert-pentoxide (30 wt % in THF, 0.271 mL, 0.677 mmol). The
reaction was stirred for 30 minutes at 0.degree. C. The reaction
mixture was then partitioned between ethyl acetate and saturated
aqueous sodium bicarbonate. The organic layer was concentrated. The
residue was purified by silica gel column chromatography (gradient
elution 40-100% ethyl acetate:heptane with 10% dichloromethane as a
co-eluent) to provide
(P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-
-oxo-1,2-dihydroquinoline-6-sulfonamide (0.200 g, 0.319 mmol, 61.3%
yield) as a colorless oil. m/z (ESI, positive ion) 625.8
(M+H).sup.+.
Intermediate V:
(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyr-
idazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00056##
[0400] To a 0.degree. C. solution of
N-(4-methoxybenzyl)pyridazin-3-amine (0.219 g, 1.02 mmol) and
perfluorophenyl
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (0.5 g, 0.847 mmol) in tetrahydrofuran (4.2 mL) was slowly
added sodium tert-pentoxide (30 wt % solution in THF, 0.41 mL, 1.0
mmol). The reaction was stirred for 30 minutes at 0.degree. C. The
reaction mixture was then partitioned between ethyl acetate and
saturated aqueous ammonium chloride. The organic layer was
concentrated. The residue was purified by silica gel column
chromatography (gradient elution 40-100% ethyl acetate:heptane with
10% dichloromethane as a co-eluent) to provide
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (367 mg, 0.591
mmol, 70% yield) as a white solid. m/z (ESI, positive ion) 620.8
(M+H).sup.+.
Intermediate W:
(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazo-
l-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00057##
[0402] N-(2,4-dimethoxybenzyl)oxazol-2-amine (0.211 g, 0.901 mmol)
and perfluorophenyl
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (0.500 g, 0.819 mmol, Syngene) were added to a 40-mL vial.
The vial was flushed with nitrogen, tetrahydrofuran (2.7 mL) was
added, and then the reaction was cooled to 0.degree. C. Sodium
tert-pentoxide (3.2 M in PhMe, 0.33 mL, 1.1 mmol) was added slowly.
After stirring for 30 min at .degree. C., sat. aq. ammonium
chloride and EtOAc were added to the cold reaction. The phases were
separated, and the water phase was extracted twice with EtOAc. The
combined organic extracts were dried and evaporated. The residue
was purified by column chromatography (two sequential RediSep Rf
Gold 40 g columns, gradient elution 0-40% [3:1 EtOAc:EtOH]:[10:1
heptane:dichloromethane]) to provide
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazo-
l-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.347 g, 0.525
mmol, 64% yield) as a yellow solid. m/z (ESI, positive ion) 681.8
(M+Na).sup.+.
Intermediate X:
(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyridazin-3--
Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00058##
[0404] In a 250-mL flask, perfluorophenyl
(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate
(7.00 g, 12.15 mmol) and N-(4-methoxybenzyl)pyridazin-3-amine (3.14
g, 14.58 mmol) were suspended in tetrahydrofuran (100 mL). The pale
brown suspension was cooled in an ice bath and treated dropwise
with sodium tert-pentoxide (40 wt % in toluene, 7.77 mL, 19.43
mmol). The reaction was stirred at 0.degree. C. for 30 min and
allowed to warm to rt. After 2 h, additional base sodium
tert-pentoxide (40 wt % in toluene, 1 mL) was added, and the
reaction stirred at rt for an additional 15 h. Additional
tert-pentoxide (40 wt % in toluene, 1 mL) was added, and the
reaction stirred at rt for an additional 2 h. The reaction was
cooled in an ice bath and quenched with saturated ammonium chloride
solution (50 mL), and the reaction stirred vigorously for 15 min.
The phases were separated, and the aqueous phase was extracted with
ethyl acetate (3.times.50 mL). The residue was purified via silica
gel column chromatography (gradient elution 0-100% [3:1
EtOAc:EtOH]: [9:1 heptane:dichloromethane]). The product was
further purified by trituration with ethyl acetate:heptane (1:1) to
give
(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3--
yl)-1,2-dihydroquinoline-6-sulfonamide (1.56 g, 2.57 mmol, 21%
yield) as an off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.04 (dd, J=4.5, 1.7 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H),
8.16 (d, J=9.3 Hz, 1H), 7.67-7.77 (m, 2H), 7.64 (dd, J=9.1, 2.3 Hz,
1H), 7.53 (d, J=1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.30-7.34 (m, 1H),
7.15 (d, J=8.8 Hz, 2H), 6.76-6.85 (m, 3H), 6.72 (d, J=9.1 Hz, 1H),
5.03 (s, 2H), 3.72 (s, 3H), 3.66 (s, 3H). m/z (ESI, positive ion)
607.0 (M+H).sup.+.
Intermediate Y:
(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyr-
idazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00059##
[0406] The title compound was prepared according to the method and
purification protocol of Intermediate V using perfluorophenyl
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonate (5.00 g, 8.19 mmol). This afforded
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (2.84 g, 4.42 mmol,
54% yield). m/z (ESI, positive ion) 641.0 (M+H).sup.+.
Intermediate Z:
(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazo-
l-2-YL)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00060##
[0408] The title compound was prepared according to the method of
Intermediate N using N-(2,4-dimethoxybenzyl)oxazol-2-amine (0.236
g, 1.01 mmol). The product was purified via column chromatography
(two sequential RediSep Rf Gold 40 g columns, gradient elution
0-40% [3:1 EtOAc:EtOH]: [9:1 heptane:dichloromethane]) to afford
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazo-
l-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.38 g, 0.59
mmol, 65% yield). .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm
7.92 (d, J=2.1 Hz, 1H), 7.86 (dd, J=9.0, 2.2 Hz, 1H), 7.69 (d,
J=9.6 Hz, 1H), 7.46 (d, J=0.8 Hz, 1H), 7.33 (s, 1H), 7.16 (d, J=8.3
Hz, 1H), 7.08 (s, 1H), 7.01 (d, J=0.8 Hz, 1H), 6.82 (d, J=9.6 Hz,
1H), 6.68 (d, J=9.1 Hz, 1H), 6.37 (dd, J=8.3, 2.3 Hz, 1H), 6.17 (d,
J=2.3 Hz, 1H), 4.94 (s, 2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.44 (s,
3H), 2.40 (s, 3H).
Intermediate AB:
(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Zinc(II) Iodide
##STR00061##
[0410] An oven-dried vial was charged with
1-iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (100 mg, 0.382
mmol), purged with nitrogen, and was added Rieke zinc, 5% in
tetrahydrofuran (27 mg, 0.549 mL, 0.420 mmol). The mixture was
stirred at room temperature for 3 hours. The resulting suspension
was allowed to settle down. The product was used without further
purification.
Intermediate AC: (P)-Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline--
6-Sulfonate
##STR00062## ##STR00063##
[0411] Step 1: 4-Bromo-5-Fluoro-2-Iodoaniline
[0412] N-iodosuccinimide (710 g, 3158 mmol) was added portion-wise
to a solution of 4-bromo-3-fluoroaniline (500 g, 2631 mmol) in
acetic acid (4000 mL) at 10-15.degree. C. The reaction was stirred
at rt for 1 hour. The reaction was then quenched with ice water (7
L) and the precipitated solid was filtered. The solid was washed
with 5% sodium thiosulphate solution (6 L) and water (4 L), and
dried to afford 4-bromo-5-fluoro-2-iodoaniline as brown solid (750
g, 2374 mmol, 90% yield). .sup.1H NMR (400 MHz, DMSO-d6): .delta.
ppm 7.76 (d, J=7.8 Hz, 1H), 6.68 (d, J=11.5 Hz, 1H), 5.68 (s,
2H).
Step 2: Ethyl (E)-3-(2-Amino-5-Bromo-4-Fluorophenyl)Acrylate
[0413] To a stirred solution of 4-bromo-5-fluoro-2-iodoaniline (500
g, 1583 mmol) in isopropanol (2550 mL) was added triethylamine (331
mL, 2374 mmol) at room temperature. The reaction mixture was
degassed with nitrogen for 20 minutes.
Tris(dibenzylideneacetone)dipalladium (0) (36.2 g, 39.6 mmol) was
added, followed by slow addition of ethyl acrylate (162 g, 1614
mmol) under nitrogen atmosphere. Then the reaction mixture was
heated to 70.degree. C. and stirred for 6 hours. After completion,
the reaction mixture was filtered through Celite and washed with
dichloromethane (2 L). The filtrate was concentrated under reduced
pressure to give the initial product. The initial product was
stirred in 3% ethyl acetate in petroleum ether (6 L) and filtered.
The solid obtained was washed with 3% EtOAc in petether (2 L) and
dried to give ethyl (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate
(433 g, 1505 mmol, 95% yield) as a yellow solid. MS (ESI, positive
ion) m/z: 288.0 (M+1). .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm
7.69-7.98 (m, 2H), 6.61 (d, J=11.4 Hz, 1H), 6.45 (d, J=15.6 Hz,
1H), 6.12 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz,
3H).
Step 3: Ethyl
(E)-3-(2-Amino-5-(Benzylthio)-4-Fluorophenyl)Acrylate
[0414] To a solution of ethyl
(E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate (500.0 g, 1735 mmol)
in 1,4-dioxane (2500 mL) was added
N-ethyl-N-isopropylpropan-2-amine (449 g, 3471 mmol) and degassed
with nitrogen for 20 minutes.
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (50.2 g,
87 mmol) and tris(dibenzylideneacetone)dipalladium (0) (39.7 g,
43.4 mmol) were added to the reaction mixture. The mixture was
purged with nitrogen and heated to 80.degree. C. for 10 minutes.
The reaction was cooled to room temperature and phenylmethanethiol
(237 g, 1909 mmol) was added. The reaction was heated at 90.degree.
C. for 12 hours. The reaction was cooled to room temperature and
diluted with ethyl acetate (1000 mL). The mixture was filtered
through Celite and the Celite bed was washed with ethyl acetate
(2500 mL). The filterate was concentrated under reduced pressure to
obtain the initial product. The initial product was purified by
column chromatography (silica gel; mesh size 60-120, gradient
elution 0-15% ethyl acetate and petroleum ether) to obtain ethyl
(E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (300.0 g, 905
mmol, 52% yield) as yellow solid. MS (ESI, positive ion) m/z: 332.1
(M+1). .sup.1H NMR (400 MHz, DMSO-d6): .delta. ppm 7.72 (d, J=15.7
Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.01-7.32 (m, 5H), 6.38-6.55 (m,
1H), 6.24 (d, J=15.7 Hz, 1H), 6.11 (s, 2H), 4.17 (q, J=7.1 Hz, 2H),
3.89-4.07 (m, 2H), 1.26 (t, J=7.1 Hz, 3H).
Step 4: Ethyl
(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)-4-Fluor-
ophenyl)Acrylate
[0415] To a 250 mL 3-neck round-bottomed flask charged with ethyl
(E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (10 g, 30.2
mmol) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (10.48 g, 31.7
mmol) in toluene (100 mL) was added cesium carbonate (39.3 g, 121
mmol). The mixture was degassed with nitrogen for 15 minutes.
Tris(dibenzylideneacetone)dipalladium (0) (1.105 g, 1.207 mmol) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (1.397 g,
2.414 mmol) were added to the reaction mixture and the mixture was
heated at 110.degree. C. for 16 hours. The reaction mixture was
allowed to cool to room temperature, diluted with dichloromethane
(200 mL) and filtered through Celite. The filtrate was concentrated
under reduced pressure to obtain the initial product which was
purified by stirring with methanol (250 mL) for 1 hour and
filtered. The cake was washed with methanol (100 mL) and dried to
obtain ethyl
(E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluor-
ophenyl)acrylate (13.5 g, 25.3 mmol, 84% yield) as yellow solid. MS
(ESI, positive ion) m/z: 534.0 (M+1). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. ppm 7.97 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.66
(d, J=15.9 Hz, 1H), 7.05-7.43 (m, 6H), 6.77 (d, J=11.1 Hz, 1H),
6.63 (d, J=10.2 Hz, 1H), 6.52 (d, J=15.9 Hz, 1H), 4.25 (s, 2H),
4.16 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.23 (t, J=7.1 Hz, 3H).
Step 5:
6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoroquinol-
in-2(1H)-One
[0416] To 500 mL 3-necked round-bottom flask was charged with ethyl
(E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluor-
ophenypacrylate (13.5 g, 25.3 mmol) in methanol (140 mL) was added
tributylphosphane (50% solution in ethylacetate) (3.74 mL, 7.58
mmol). The reaction mixture was heated at 70.degree. C. for 5
hours. The reaction mixture was allowed to cool 15.degree. C.,
filtered and washed with cold methanol (100 mL) and dried to give
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H-
)-one (9.5 g, 19.45 mmol, 77% yield) as yellow solid. MS (ESI,
positive ion) m/z: 488.0 (M+1). .sup.1H NMR (400 MHz, DMSO-d6):
.delta. ppm 7.88-8.02 (m, 2H), 7.64 (d, J=6.3 Hz, 1H), 7.56 (d,
J=8.6 Hz, 1H), 7.20-7.38 (m, 5H), 6.64 (d, J=9.6 Hz, 1H), 6.48 (d,
J=11.3 Hz, 1H), 4.23 (s, 2H), 3.71 (s, 3H).
Step 6 & 7: Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline--
6-Sulfonate
[0417] To a 250 mL 3-necked round-bottom flask charged with
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H-
)-one (9.5 g, 19.45 mmol) in acetonitrile (95 mL) were added acetic
acid (6.4 mL) and water (4.13 mL). The resulting mixture was cooled
to 0-5.degree. C. and
1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (6.13 g, 31.1
mmol) was added portion-wise over 10-20 min keeping the internal
temperature below 5-10.degree. C. The resulting suspension was
stirred at 5-10.degree. C. under nitrogen for 45 minutes. Then a
solution of 2,3,4,5,6-pentafluorophenol (7.16 g, 38.9 mmol) in
acetonitrile (10 mL) was added over 10-15 min, followed by
triethylamine (13.54 mL, 97 mmol) over 20 min keeping the internal
temperature below 5-10.degree. C. The mixture was continued to be
stirred at 5-10.degree. C. for 30 min. Ice water (200 mL) was added
and the precipitated solid was filtered and washed with water (100
mL). The initial product was purified by stirring with methanol (50
mL), filtered, washed with MeOH (50 mL) and dried to obtain
perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (9.5 g, 15.52 mmol, 80% yield) as an off white solid.
MS (ESI, positive ion) m/z; 612.0 (M+1). .sup.1H NMR (400 MHz,
DMSO-d6): .delta. ppm 8.53 (d, J=7.4 Hz, 1H), 8.20 (d, J=9.8 Hz,
1H), 7.67 (dd, J=16.2, 7.4 Hz, 2H), 6.99 (d, J=12.1 Hz, 1H), 6.83
(d, J=9.8 Hz, 1H), 3.74 (s, 3H).
Step 8: (P)-Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline--
6-Sulfonate
[0418] Perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (135 g, 220 mmol) was purified by SFC via an Regis
Whelk-O s,s 5.times.15 cm, 5 .mu.m column; a mobile phase of 50%
dichloromethane using a flowrate of 350 mL/min to generate
(P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (49.2 g, 80.4 mmol, 36% yield). MS (ESI, positive ion)
m/z: 612.7 (M+1).
CHEMICAL EXAMPLES
Examples 1 & 2:
(M)-1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-
-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide and
1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Y-
l)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide, Respectively
##STR00064##
[0419] Step 1:
(M)-1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-
-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0420] A vial was charged with palladium(II) acetate (2.7 mg, 0.012
mmol),
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (10.6 mg, 0.024 mmol), and
(M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihy-
droquinoline-6-sulfonamide (0.100 g, 0.202 mmol).
(3-(tert-butyl)cyclobutyl)zinc(II) iodide (0.2 M in THF, 2.0 mL,
0.41 mmol) was added and the reaction was stirred for two hours at
50.degree. C. The reaction was then diluted with ethyl acetate and
washed twice with 1 N HCl. The organic layer was washed with brine,
dried with sodium sulfate, filtered, and concentrated. The material
was purified via column chromatography (RediSep Gold 40 g column,
gradient elution 0-50% [3:1 EtOAc:EtOH]:heptane) to give
(M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-
-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (50 mg, 0.095 mmol,
47% yield) as a mixture of cis and trans isomers. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 11.65 (s, 1H), 8.73 (d, J=1.9 Hz,
1H), 8.30-8.41 (m, 1H), 8.20 (d, J=10.0 Hz, 1H), 7.72-8.00 (m, 1H),
7.04-7.29 (m, 2H), 6.73-6.85 (m, 2H), 6.44 (d, J=1.5 Hz, 1H),
3.64-3.75 (m, 3H), 3.45-3.63 (m, 1H), 2.18-2.38 (m, 4H), 1.89-2.04
(m, 1H), 0.83-0.97 (m, 9H). m/z (ESI, positive ion) 526.2
(M+H).sup.+.
Step 2:
1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxa-
zol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0421]
(M)-1-(4-(3-(tert-Butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(is-
oxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (44 mg) was
epimerized by heating at 130.degree. C. for 3 h in DMSO. This was
then concentrated and dried to give
1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-y-
l)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 11.66 (s, 1H), 8.74 (d, J=1.7 Hz, 1H),
8.31-8.41 (m, 1H), 8.14-8.30 (m, 1H), 7.75-7.93 (m, 1H), 7.03-7.32
(m, 2H), 6.74-6.84 (m, 2H), 6.45 (d, J=1.5 Hz, 1H), 3.70 (d, J=10.0
Hz, 3H), 3.57-3.64 (m, 1H), 2.19-2.41 (m, 4H), 1.91-2.06 (m, 1H),
0.86-0.96 (m, 9H). m/z (ESI, positive ion) 526.2 (M+H).sup.+.
Example 3:
(P)-1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro)-2-Methoxyphenyl)--
N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydro Quino Line-6-Sulfonamide
##STR00065##
[0423] A vial was charged with palladium(II) acetate (7.3 mg, 0.032
mmol)
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (28 mg, 0.065 mmol), and
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihy-
droquinoline-6-sulfonamide (160 mg, 0.324 mmol).
(3-(tert-Butyl)cyclobutyl)zinc(II) iodide (0.2 M in THF, 3.2 mL,
0.65 mmol) was added, and the reaction was stirred for two hours at
50.degree. C. The reaction was then diluted with ethyl acetate and
washed twice with 1 N HCl. The organic layer was washed with brine,
dried with sodium sulfate, filtered, and concentrated. The material
was purified via column chromatography (RediSep Gold 40 g column,
gradient elution 0-50% [3:1 EtOAc:EtOH]:heptane) to give
(P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-
-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (90 mg, 0.17 mmol,
53% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 11.65
(s, 1H), 8.72 (d, J=1.9 Hz, 1H), 8.29-8.38 (m, 1H), 8.20 (d, J=10.0
Hz, 1H), 7.84 (dt, J=9.0, 1.9 Hz, 1H), 7.03-7.33 (m, 2H), 6.71-6.85
(m, 2H), 6.44 (d, J=1.7 Hz, 1H), 3.69 (d, J=10.2 Hz, 3H), 3.53-3.63
(m, 1H), 2.16-2.37 (m, 4H), 1.91-2.07 (m, 1H), 0.80-0.95 (m, 9H).
m/z (ESI, positive ion) 526.2 (M+H).sup.+.
Example 4: (P)-1-(4-(3,3-Difluoro
Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydro
Quinoline-6-Sulfonamide
##STR00066## ##STR00067##
[0424] Step 1:
(P)-1-(5-Fluoro-2-Methoxy-4-(5,8-Dioxaspiro[3.4]Octan-2-Yl)Phenyl)-N-(Iso-
xazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0425] A vial was charged with
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Intermediate F)
(0.500 g, 0.814 mmol), palladium(II) acetate (10.96 mg, 0.049
mmol), and
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (0.043 g, 0.098 mmol).
5,8-Dioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.1 M in THF, 14 mL,
0.70 mmol) was added and the reaction was stirred at 50.degree. C.
for 16 h. The reaction was then diluted with ethyl acetate and
washed with water. The aqueous layer was extracted with ethyl
acetate, and the combined organic layers were washed with brine,
dried with sodium sulfate, filtered, and concentrated. The material
was purified via column chromatography (RediSep Gold 40 g column,
gradient elution 0-100% EtOAc:heptane) to afford
(P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(iso-
xazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.258 g, 0.398 mmol, 49% yield) as a light yellow solid. m/z (ESI,
positive ion) 648.2 (M+H).sup.+.
Step 2:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-
-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0426]
(P)-1-(5-Fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)--
N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
mide (0.258 g, 0.398 mmol) was dissolved in tetrahydrofuran (4 mL).
Hydrochloric acid (1 N in water, 2.0 mL, 2.0 mmol) was added and
the reaction was stirred at 50.degree. C. for three days. The
reaction was then diluted with ethyl acetate and washed with water.
The aqueous layer was extracted with ethyl acetate, and the
combined organic layers were washed with brine, dried with sodium
sulfate, filtered, and concentrated. The material was purified via
column chromatography (RediSep Gold 40 g column, gradient elution
0-100% EtOAc:heptane) to afford
(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.179
g, 0.297 mmol, 74% yield) as a light yellow solid. m/z (ESI,
positive ion) 604.2 (M+H).sup.+.
Step 3:
(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Iso-
xazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0427] A vial was charged with
(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.169
g, 0.280 mmol) and diethylaminosulfur trifluoride (1.85 mL, 14.0
mmol). The reaction was stirred for one hour at room temperature.
The reaction was then poured into a 250-mL round-bottom flask,
diluted with ethyl acetate, and saturated aqueous sodium
bicarbonate solution was carefully added until bubbling ceased. The
layers were separated, and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed with brine,
dried with sodium sulfate, filtered, and concentrated. The material
was purified via column chromatography (RediSep Gold 12 g column,
gradient elution 0-100% EtOAc:heptane) to afford
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-
-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.142 g, 0.227 mmol, 81% yield) as a white solid. m/z (ESI,
positive ion) 626.2 (M+H).sup.+.
Step 4:
(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Iso-
xazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0428]
(P)-1-(4-(3,3-Difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isox-
azol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.142 g, 0.227 mmol) was dissolved in TFA (1 mL). The solution was
heated to 50.degree. C. and stirred for two hours. The reaction was
concentrated and purified via column chromatography (RediSep Gold
40 g column, gradient elution 0-75% [3:1 EtOAc/EtOH]:heptane) to
afford
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-
-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.109 g, 0.216 mmol,
95% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 11.66 (s, 1H), 8.74 (d, J=1.9 Hz, 1H), 8.37 (d, J=2.3
Hz, 1H), 8.22 (d, J=9.5 Hz, 1H), 7.84 (dd, J=8.9, 2.3 Hz, 1H), 7.36
(d, J=10.2 Hz, 1H), 7.27 (d, J=6.8 Hz, 1H), 6.76-6.84 (m, 2H), 6.45
(d, J=1.7 Hz, 1H), 3.71 (s, 3H), 3.57-3.68 (m, 1H), 2.91-3.13 (m,
4H). m/z (ESI, positive ion) 506.0 (M+H).sup.+.
Example 5:
(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Me-
thoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00068##
[0429] Step 1:
(P)-1-(5-Fluoro-4-(3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphen-
yl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sul-
fonamide
[0430] A round-bottom flask was charged with
(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500
g, 0.828 mmol) and THF (4.1 mL). Trifluoromethyltrimethylsilane
(0.21 mL, 1.4 mmol) and tetra-n-butylammonium fluoride (1.0 M in
THF, 0.083 mL, 0.083 mmol) were added in succession, and the
reaction was stirred for one hour at room temperature. Additional
(trifluoromethyl)trimethylsilane (0.208 ml, 1.408 mmol) and
tetra-n-butylammonium fluoride (1.0 M in THF, 0.5 mL, 0.5 mmol)
were added, and the reaction was stirred for 16 h. HCl (1 N in
water, 5.8 mL, 5.8 mmol) was added, and the reaction was stirred
for one hour. The reaction was then extracted twice with ethyl
acetate. The combined organic layers were washed with brine, dried
with sodium sulfate, filtered, and concentrated. The material was
purified via column chromatography (BIOTAGE.RTM. SNAP 25 g column,
gradient elution 0-100% EtOAc:heptane) to afford
(P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphen-
yl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonamide (0.433 g, 0.643 mmol, 78% yield) as a tan solid. m/z (ESI,
positive ion) 674.0 (M+H).sup.+.
STEP 2:
(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Metho-
xyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-
-6-Sulfonamide
[0431] To a vial charged with
(P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphen-
yl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonamide (0.131 g, 0.194 mmol) was added
bis(2-methoxyethyl)aminosulfur trifluoride (1.0 mL, 5.4 mmol). The
reaction was heated to 50.degree. C. and stirred for 16 h. The
reaction was diluted with ethyl acetate and carefully quenched with
saturated aqueous sodium bicarbonate solution. The aqueous layer
was extracted with ethyl acetate, and the combined organic layers
were washed with brine, dried with sodium sulfate, filtered, and
concentrated. The material was purified via column chromatography
(RediSep Gold 12 g column, gradient elution 0-100% EtOAc:heptane)
and then via reverse phase HPLC using a XBridge Prep Shield RP18
19.times.100 mm column. The mobile was run under a gradient
elution; 50-95% acetonitrile:water with 0.1% formic acid; flow
rate: 40 mL/min. This afforded
(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxypheny-
l)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulf-
onamide (0.027 g, 0.040 mmol, 21% yield) as a white solid. m/z
(ESI, positive ion) 676.0 (M+H).sup.+.
Step 3:
(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Metho-
xyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0432] A vial was charged with
(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxypheny-
l)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulf-
onamide (0.027 g, 0.040 mmol) and TFA (0.2 mL) and stirred
overnight at room temperature. The reaction was then concentrated
and purified via column chromatography (BIOTAGE.RTM. SNAP 10 g
column, gradient elution 0-75% [3:1 EtOAc/EtOH]:heptane) to afford
(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxypheny-
l)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.018 g, 0.032 mmol, 81% yield) as an off-white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 11.67 (s, 1H), 8.73 (d, J=1.7
Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.23 (d, J=9.5 Hz, 1H), 7.85 (dd,
J=8.9, 2.3 Hz, 1H), 7.41-7.53 (m, 2H), 6.81 (d, J=9.7 Hz, 1H), 6.76
(d, J=9.1 Hz, 1H), 6.45 (d, J=1.9 Hz, 1H), 5.95-6.22 (m, 2H), 5.86
(s, 1H), 3.64-3.80 (m, 3H), 3.07-3.21 (m, 1H), 2.81-2.98 (m, 1H).
m/z (ESI, positive ion) 556.0 (M+H).sup.+.
Examples 6 & 7:
Cis-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N--
(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide and
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,
Respectively
##STR00069## ##STR00070##
[0433] Step 1:
(P)--O-(3-(2-Fluoro-4-(6-(N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)Sulfamoyl)-
-2-Oxoquinolin-1(2H)-Yl)-5-Methoxyphenyl)-1-(Trifluoromethyl)Cyclobutyl)
O-Phenyl Carbonothioate
[0434]
(P)-1-(5-Fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-metho-
xyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-
-6-sulfonamide (0.200 g, 0.297 mmol), which was prepared according
to procedures described in Steps 1-2 of Example 4 followed by Step
1 of Example 5, was dissolved in THF (1.5 mL) and cooled to
0.degree. C. Sodium hydride (60% dispersion in mineral oil, 0.018
g, 0.45 mmol) was added and the reaction was allowed to warm to
room temperature over 30 minutes. Phenyl chlorothionoformate (0.103
mL, 0.742 mmol) was added and the reaction was stirred for three
hours. The reaction was then cooled to 0.degree. C. and an
additional portion of sodium hydride (60% dispersion in mineral
oil, 0.018 g, 0.445 mmol) was added. The reaction was warmed to
room temperature and stirred for 30 minutes, then additional phenyl
chlorothionoformate (0.103 mL, 0.742 mmol) was added. The reaction
was stirred at room temperature for 16 h. The reaction was then
diluted with ethyl acetate and washed with saturated aqueous sodium
bicarbonate solution. The aqueous layer was extracted with ethyl
acetate, and the combined organic layers were washed with brine,
dried with sodium sulfate, filtered, and concentrated. The material
was purified via column chromatography (BIOTAGE.RTM. SNAP 25 g
column, gradient elution 0-100% EtOAc:heptane) to afford
(P)--O-(3-(2-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-
-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)
O-phenyl carbonothioate (0.215 g, 0.265 mmol, 89% yield) as a light
yellow solid.
Step 2:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-
-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfon-
amide
[0435]
(P)--O-(3-(2-Fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulf-
amoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobu-
tyl)-O-phenyl carbonothioate (0.119 g, 0.147 mmol) was dissolved in
toluene (1.5 mL). Tri-n-butyl tin hydride (0.39 mL, 1.5 mmol) and
azobisisobutyronitrile (0.024 g, 0.15 mmol) were added, and the
reaction was degassed for 20 minutes with nitrogen, then heated to
50.degree. C. and stirred for two hours. The reaction was also run
twice under the same conditions and reagent stoichiometry using
04342-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoq-
uinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)
0-phenyl carbonothioate (0.025 g, 0.031 mmol). All three reactions
were then combined, loaded onto a silica cartridge, and purified
via column chromatography (BIOTAGE.RTM. SNAP 25 g column, gradient
elution 0-100% EtOAc:heptane) to afford
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(iso-
xazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.101 g, 0.154 mmol, 74% yield) as a light yellow solid. m/z (ESI,
positive ion) 658.0 (M+H).sup.+.
Step 3:
Cis-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phe-
nyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide and
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0436] A vial was charged with
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(iso-
xazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.101 g, 0.154 mmol) and TFA (1.0 mL) and stirred overnight at
room temperature. The reaction was then concentrated and purified
via column chromatography (BIOTAGE.RTM. SNAP 10 g column, gradient
elution 0-75% [3:1 EtOAc/EtOH]:heptane) to afford 81 mg of material
as an off-white solid. This material was further purified using two
sequential Chiralcel OJ-H, 2.times.25 cm columns. The mobile phase
was run under isocratic conditions; supercritical CO.sub.2 with 15%
methanol; flow rate: 80 mL/min. The first eluting peak was assigned
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N--
(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (39 mg).
The second eluting peak was assigned
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (11 mg).
Data for peak 1: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
11.65 (s, 1H), 8.60-8.83 (m, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.20 (d,
J=9.6 Hz, 1H), 7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.31 (d, J=10.1 Hz,
1H), 7.14 (d, J=6.7 Hz, 1H), 6.71-6.89 (m, 2H), 6.44 (d, J=1.8 Hz,
1H), 3.71-3.83 (m, 1H), 3.69 (s, 3H), 3.24-3.31 (m, 1H), 2.56-2.65
(m, 2H), 2.31-2.44 (m, 2H). m/z (ESI, positive ion) 538.0
(M+H).sup.+. Data for peak 2: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 11.65 (s, 1H), 8.73 (d, J=1.8 Hz, 1H), 8.36 (d, J=2.3
Hz, 1H), 8.21 (d, J=9.6 Hz, 1H), 7.84 (dd, J=9.0, 2.2 Hz, 1H),
7.24-7.40 (m, 2H), 6.79 (d, J=9.6 Hz, 2H), 6.44 (d, J=1.6 Hz, 1H),
3.94 (quin, J=8.9 Hz, 1H), 3.71 (s, 3H), 3.25-3.31 (m, 1H),
2.56-2.75 (m, 4H). m/z (ESI, positive ion) 538.0 (M+H).sup.+.
Example 7a:
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00071##
[0437] Step 1:
(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl-
)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfo-
namide
[0438] A 2 L three-neck round-bottom flask equipped with overhead
stirrer, distillation head, thermocouple, addition funnel, and
nitrogen inlet was charged with zinc dust (112 g, 1.72 mol),
lithium chloride (16.0 g, 389 mmol), and anhydrous tetrahydrofuran
(750 mL). Half of the tetrahydrofuran was removed via distillation
at atmospheric pressure. The resultant mixture was cooled to
30.degree. C. and chlorotrimethylsilane (3.0 mL, 23.5 mmol) was
added. The mixture was warmed to 50.degree. C. for 30 minutes, the
temperature was raised, and the reaction volume was reduced by
about 50 mL via distillation. The resultant mixture was cooled to
30.degree. C. before trans-1-bromo-3-(trifluoromethyl)cyclobutane
(75.0 g, 369 mmol, Enamine, LLC) was introduced. The mixture was
then warmed to 40.degree. C. A significant exotherm was observed
and the heating mantle was replaced with an ambient temperature
water bath. Once the exotherm had ceased, the water bath was
removed and the reaction mixture stirred at 50.degree. C. for 1
hour. The mixture was allowed to settle overnight and cool to
ambient temperature. The supernatant was used without further
manipulation. A separate 2 L three-neck round-bottom flask equipped
with overhead stirrer, thermocouple, reflux condenser, and nitrogen
inlet was charged with
1,2,3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferrocene (0.90 g,
1.27 mmol, Strem Chemicals, Inc.),
tris(dibenzylideneacetone)dipalladium (0.60 g, 0.66 mmol, Strem
Chemicals, Inc.), and anhydrous tetrahydrofuran (50 mL). The
resultant mixture was warmed to 45.degree. C. After 15 minutes, the
reaction mixture was allowed to cool to room temperature before
anhydrous tetrahydrofuran (250 mL) and
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (Intermediate F)
(187 g, 304 mmol) were introduced and the mixture was stirred until
all solids dissolved. The resultant reaction mixture was warmed to
40.degree. C. before the supernatant from the previous reaction
containing trans-3-(trifluoromethyl)cyclobutyl)zinc(II) bromide in
THF was added dropwise via cannula. The reaction was mildly
exothermic and the rate of addition was adjusted to keep the
internal temperature between 40-45.degree. C. Once the addition was
complete, the mixture was warmed to 50.degree. C. After 3 hours, an
aqueous solution of citric acid (1M, 400 mL) and water (500 mL)
were introduced and the resultant mixture was extracted with ethyl
acetate (1500 mL). The organic layer was washed with brine (500 mL)
and concentrated under reduced pressure. The resultant solid was
suspended in isopropanol (1 L) and stirred at 40.degree. C. for 20
minutes. The mixture was cooled to ambient temperature and filtered
through a sintered glass fritted filter. The solids were washed
with isopropanol (40 mL) and transferred to a 2 L round-bottomed
flask. Isopropyl acetate (1 L) was added and the mixture stirred at
40.degree. C. for 20 minutes. The suspension was filtered through a
sintered glass fritted filter and the solids were washed with
additional isopropyl acetate (50 mL). The filtrate was transferred
to a 2 L round-bottomed flask and SiliaMetS Thiol metal scavenger
(20 g, Silicycle) and activated carbon (20 g) were added. The
mixture stirred at ambient temperature for 20 minutes. The
suspension was filtered through a pad of Celite and the solids
washed with isopropyl acetate (500 mL). The filtrate was
concentrated under reduced pressure. A mixture of dichloromethane
and methyl tert-butyl ether (1:1 mixture, 1 L) was added to the
solids and the resultant mixture stirred at 40.degree. C. for 20
minutes. The mixture was filtered through a sintered glass fritted
filter and the trace solids were washed with methyl tert-butyl
ether (30 mL). The combined filtrate was concentrated under reduced
pressure to afford
(P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl-
)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfo-
namide (150 g, 228 mmol, 75% yield) as a reddish solid that was
used in the next step without further purification. m/z (ESI) 658.0
(M+H).sup.+.
Step 2:
(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl-
)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0439] A 2 L three-neck round-bottom flask equipped with an
overhead stirrer, a Claisen adapter, addition funnel, a
thermocouple, a reflux condenser, and a nitrogen inlet was charged
with
(P)-1-(5-fluoro-2-methoxy-4-(1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-
-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfon-
amide (150 g, 228 mmol) and triethylsilane (85 mL, 532 mmol).
Trifluoroacetic acid (500 mL) was added dropwise over 60 min at a
rate to prevent the internal temperature of the reaction exceeding
40.degree. C.-50.degree. C. The reaction mixture was warmed to
50.degree. C. for 30 min before it was allowed to cool to room
temperature. Heptane (800 mL) was introduced and the mixture was
concentrated under reduced pressure. The resultant solid was
azeotroped with heptane (2.times.800 mL) then suspended in heptane
(800 mL). The mixture was stirred at ambient temperature for 10
minutes before the heptane was decanted away. The remaining
material was dissolved in dichloromethane (1.5 L) and was washed
with an aqueous solution of tribasic sodium phosphate (0.2 N,
2.times.300 mL). The organic layer was separated and concentrated
under reduced pressure. The residue was suspended in methyl
tert-butyl ether (2 L) and stirred at 40.degree. C. for 20 minutes.
The suspension was filtered through a sintered glass fritted filter
and the solids washed with methyl tert-butyl ether (100 mL). The
filtrate was evaporated to dryness under reduced pressure and the
product was suspended in methanol (500 mL). The resultant
suspension was concentrated under reduced pressure and the residue
was purified via SFC in two steps (Step 1: Waters Torus 2-PIC, 5
.mu.M, 3.times.15 cm column using 25% methanol as an eluent at 180
mL/min flow rate; Step 2: Chiralcel OJ-H, 5 .mu.m, 5.times.40 cm
column using 20% methanol as an eluent at 240 mL/min flow rate) to
afford
(P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl-
)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (63.3
g, 118 mmol, 52% yield). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.:
8.58 (s, 1H), 8.26 (s, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.78 (t, J=9.9
Hz, 2H), 6.92-6.98 (m, 2H), 6.86 (d, J=9.6 Hz, 1H), 6.77 (d, J=9.0
Hz, 1H), 6.59 (s, 1H), 3.98 (quin, J=9.0 Hz, 1H), 3.72-3.80 (m,
3H), 2.99-3.11 (m, 1H), 2.69-2.74 (m, 2H), 2.60-2.65 (m, 2H).
.sup.13C NMR (126 MHz, CDCl.sub.3) .delta.: 161.57, 159.89, 156.85,
154.94 (d, J=241.6 Hz), 151.41 (d, J=2.7 Hz), 143.79, 139.41,
133.89 (d, J=15.4 Hz), 132.62, 128.19, 128.30 (q, J=276.1 Hz),
124.00, 123.34, 120.04, 117.16 (d, J=25.4 Hz), 116.42, 111.73 (d,
J=5.5 Hz), 98.59, 56.39, 34.01 (q, J=30.0 Hz), 31.80, 27.76, 27.50,
27.31. m/z (ESI) 538.0 (M+H).sup.+.
Examples 8 and 9:
Trans-(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methox-
yphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
and
Cis-(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyp-
henyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,
Respectively
##STR00072##
[0441] A vial was charged with
(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxypheny-
l)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulf-
onamide (0.212 g, 0.314 mmol) and TFA (1 mL) and stirred at
50.degree. C. for two hours. The reaction was then concentrated and
purified using two sequential Chiralpak IC, 2.times.15 cm columns.
The mobile phase was run under isocratic conditions; supercritical
CO.sub.2 with 25% methanol; flow rate: 80 mL/min. The first eluting
peak was assigned
trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methox-
yphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(62 mg). The second eluting peak was assigned
cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyp-
henyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(42 mg). Data for peak 1: .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 11.65 (s, 1H), 8.73 (d, J=1.7 Hz, 1H), 8.37 (d, J=2.3
Hz, 1H), 8.22 (d, J=9.5 Hz, 1H), 7.84 (dd, J=8.9, 2.3 Hz, 1H), 7.49
(d, J=10.2 Hz, 1H), 7.44 (d, J=6.2 Hz, 1H), 6.79 (dd, J=9.2, 5.7
Hz, 2H), 6.44 (d, J=1.9 Hz, 1H), 5.95-6.14 (m, 2H), 5.85 (s, 1H),
3.71 (s, 3H), 3.15 (td, J=15.3, 9.8 Hz, 1H), 2.79-2.99 (m, 1H). m/z
(ESI, positive ion) 555.2 (M+H).sup.+. Data for peak 2: .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. ppm 11.65 (s, 1H), 8.73 (d, J=1.7
Hz, 1H), 8.37 (d, J=2.3 Hz, 1H), 8.23 (d, J=9.7 Hz, 1H), 7.84 (dd,
J=8.9, 2.3 Hz, 1H), 7.49 (d, J=10.0 Hz, 1H), 7.44 (d, J=6.2 Hz,
1H), 6.80 (d, J=9.7 Hz, 1H), 6.76 (d, J=9.1 Hz, 1H), 6.45 (d, J=1.7
Hz, 1H), 5.96-6.17 (m, 2H), 5.85 (s, 1H), 3.70 (s, 3H), 3.14 (td,
J=15.5, 9.6 Hz, 1H), 2.79-2.99 (m, 1H). m/z (ESI, positive ion)
555.4 (M+H).sup.+.
Examples 10 and 11:
Cis-(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyp-
henyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
and
Trans-(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methox-
yphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,
Respectively
##STR00073## ##STR00074##
[0442] Step 1:
(P)-1-(5-Chloro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N--
(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0443] A 3-neck 250-mL round-bottom flask equipped with reflux
adapter and internal temp probe was charged with
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (5 g, 7.93 mmol),
palladium(II) acetate (0.107 g, 0.476 mmol), and
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (0.415 g, 0.951 mmol) then evacuated and
backfilled with nitrogen. 5,8-Dioxaspiro[3.4]octan-2-ylzinc(II)
bromide (0.4 M in THF, 30 mL, 12 mmol) was added, and the reaction
was stirred at 50.degree. C. for 20 h. The mixture was then
quenched with 2 N aq. HCl (80 mL). The temperature was elevated to
50.degree. C., and the mixture was stirred for 4 h. The mixture was
then partitioned between water and EtOAc. The layers were
separated. The aqueous extract was extracted with EtAOc
(2.times.100 mL). The combined extracts were washed with brine and
then concentrated to a black residue. The product was purified by
column chromatography, (200 g silica column, gradient elution
0-100% EtOAc:heptane) to afford
(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide as a tan
solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 8.80 (d,
J=1.6 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.15 (d, J=9.9 Hz, 1H), 7.78
(dd, J=9.1, 2.1 Hz, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.25 (d, J=8.8
Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 6.82 (d, J=9.6 Hz, 1H), 6.69-6.76
(m, 2H), 4.91 (s, 2H), 3.97-4.07 (m, 2H), 3.75 (s, 3H), 3.71 (s,
3H), 3.47-3.52 (m, 3H). m/z (ESI, positive ion) 620.0
(M+H).sup.+.
Step 2:
(P)-1-(5-Chloro-4-(3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl)-2-Meth-
oxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinolin-
e-6-Sulfonamide
[0444] A 25-mL round-bottom flask was charged with
(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.806
g, 1.30 mmol) and THF (6.5 mL) and equipped with an internal temp
probe. (Trifluoromethyl)trimethylsilane (0.38 mL, 2.6 mmol) was
introduced and tetrabutylammonium fluoride, 1.0 m solution in
tetrahydrofuran (1.300 ml, 1.300 mmol) was added dropwise to the
reaction mixture ensuring the internal temperature did not exceed
35.degree. C. An exotherm and bubbling was observed. The reaction
was stirred for 3 h and then diluted with sat. aq. NH.sub.4Cl and
extracted twice with ethyl acetate. The combined organic layers
were washed with brine, dried with sodium sulfate, filtered, and
concentrated. The material was purified via column chromatography
(BIOTAGE.RTM. SNAP 100 g column, gradient elution 0-100%
EtOAc:heptane) to afford
(P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphen-
yl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonamide as an off-white solid. m/z (ESI, positive ion) 690.0
(M+H).sup.+.
Step 3:
(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Metho-
xyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-
-6-Sulfonamide
[0445] A 2-neck 50-mL round-bottom flask equipped with a reflux
adapter was purged with nitrogen then charged with triethylamine
trihydrofluoride (1.4 mL, 8.7 mmol), triethylamine (0.61 mL, 4.4
mmol), and dichloromethane (9.7 mL) and cooled to 0.degree. C.
Difluoro(morpholino)sulfonium tetrafluoroborate (1.58 g, 6.52 mmol)
and a solution of
(P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphen-
yl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sul-
fonamide (1.00 g, 1.45 mmol) in dichloromethane (4.8 mL) were added
successively, and the reaction was warmed to 50.degree. C. and
stirred for 16 h. The reaction was then cooled to 0.degree. C. and
quenched carefully with saturated aqueous sodium bicarbonate
solution and then extracted thrice with ethyl acetate. The combined
organic layers were dried with magnesium sulfate, filtered, and
concentrated. The material was purified via column chromatography
(BIOTAGE.RTM. SNAP 50 g column, gradient elution 0-100%
EtOAc:heptane) to afford
(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxypheny-
l)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulf-
onamide (599 mg, 0.866 mmol, 60% yield) as a tan solid. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 8.81 (d, J=1.0 Hz, 1H),
8.32-8.44 (m, 1H), 8.16 (d, J=9.6 Hz, 1H), 7.78 (dd, J=9.1, 2.1 Hz,
1H), 7.67 (d, J=4.2 Hz, 1H), 7.47 (d, J=6.2 Hz, 1H), 7.26 (d, J=8.6
Hz, 2H), 6.80-6.90 (m, 3H), 6.69-6.77 (m, 2H), 5.97-6.16 (m, 2H),
5.88 (s, 1H), 4.92 (s, 2H), 3.76 (d, J=4.7 Hz, 3H), 3.71 (s, 3H),
3.06 (tt, J=15.8, 10.8 Hz, 1H), 2.78-2.96 (m, 1H). m/z (ESI,
positive ion) 692.2 (M+H).sup.+.
STEP 4:
CIS-(P)-1-(5-CHLORO-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-M-
ethoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
and
Trans-(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Me-
thoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0446] A 40-mL vial was charged with
(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxypheny-
l)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulf-
onamide (599 mg, 0.866 mmol) dichloromethane (1.3 mL), and TFA (1.3
mL). The vial was sealed and warmed to 50.degree. C. and stirred
for 16 h. The reaction was then concentrated under reduced pressure
and purified by silica gel column chromatography (50 g column,
gradient elution 0-75% [3:1 EtOAc/EtOH]:heptane). Further
purification was accomplished using a Chiralpak IC, 2.times.25 cm
column. The mobile phase was run under isocratic conditions;
supercritical CO.sub.2 with 30% methanol; flow rate: 80 mL/min. The
first eluting peak was assigned
cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyp-
henyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
The second eluting peak was assigned
trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methox-
yphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.
Data for peak 1: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
11.66 (s, 1H), 8.73 (d, J=1.8 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.22
(d, J=9.9 Hz, 1H), 7.84 (dd, J=8.8, 2.1 Hz, 1H), 7.66 (s, 1H), 7.46
(s, 1H), 6.80 (dd, J=9.2, 4.3 Hz, 2H), 6.44 (d, J=1.6 Hz, 1H),
5.97-6.14 (m, 2H), 5.88 (s, 1H), 3.75 (s, 3H), 3.06 (td, J=15.8,
9.9 Hz, 1H), 2.78-2.94 (m, 1H). m/z (ESI, positive ion) 572.0
(M+H).sup.+. Data for peak 2: .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 11.66 (s, 1H), 8.73 (d, J=1.6 Hz, 1H), 8.38 (d, J=2.1
Hz, 1H), 8.23 (d, J=9.6 Hz, 1H), 7.84 (dd, J=8.8, 2.1 Hz, 1H), 7.66
(s, 1H), 7.45 (s, 1H), 6.80 (d, J=9.9 Hz, 1H), 6.77 (d, J=8.8 Hz,
1H), 6.45 (d, J=1.6 Hz, 1H), 6.00-6.18 (m, 2H), 5.89 (s, 1H), 3.74
(s, 3H), 3.05 (td, J=16.2, 9.5 Hz, 1H), 2.79-2.94 (m, 1H). m/z
(ESI, positive ion) 572.0 (M+H).sup.+.
Examples 12 & 13:
Cis-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N--
(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide and
Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,
Respectively
##STR00075## ##STR00076##
[0447] Step 1:
(P)--O-(3-(2-Chloro-4-(6-(N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)Sulfamoyl)-
-2-Oxoquinolin-1(2H)-Yl)-5-Methoxyphenyl)-1-(Trifluoromethyl)Cyclobutyl)
O-Phenyl Carbonothioate
[0448]
(P)-1-(5-Chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-metho-
xyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-
-6-sulfonamide (1.00 g, 1.45 mmol) was dissolved in THF (7.25 ml)
and cooled to 0.degree. C. Sodium hydride (60% dispersion in
mineral oil. 0.087 g, 2.2 mmol) was added, and the reaction was
allowed to warm to room temperature over 30 minutes. Phenyl
chlorothionoformate (0.50 mL, 3.6 mmol) was added and the reaction
was stirred for 2 hours. Saturated aqueous sodium bicarbonate
solution was then introduced. The mixture was extracted thrice with
ethyl acetate and the combined organic layers were dried with
magnesium sulfate, filtered, and concentrated. The material was
purified via column chromatography (BIOTAGE.RTM. SNAP 50 g column,
gradient elution 0-100% EtOAc:heptane) to afford
(P)--O-(3-(2-chloro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-
-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)
0-phenyl carbonothioate (896 mg, 1.08 mmol, 75% yield) as a light
yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
8.71-8.87 (m, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.15 (d, J=9.6 Hz, 1H),
7.73-7.82 (m, 1H), 7.56 (s, 1H), 7.44-7.55 (m, 2H), 7.29-7.42 (m,
3H), 7.25 (d, J=8.3 Hz, 3H), 6.86 (d, J=8.8 Hz, 2H), 6.82 (d, J=9.9
Hz, 1H), 6.65-6.77 (m, 2H), 4.91 (s, 2H), 3.75-3.80 (m, 3H), 3.71
(s, 3H), 3.67 (br d, J=9.1 Hz, 1H), 3.53-3.62 (m, 1H), 3.33-3.42
(m, 2H), 3.04-3.18 (m, 1H). m/z (ESI, positive ion) 826.1
(M+H).sup.+.
Step 2:
(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-
-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfon-
amide
[0449] A 40-mL vial was charged with
(P)--O-(3-(2-chloro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-
-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)
0-phenyl carbonothioate (896 mg, 1.08 mmol), toluene (11 mL),
tri-n-butyltin hydride (2.87 mL, 10.8 mmol) and
azobisisobutyronitrile (178 mg, 1.08 mmol). The reaction mixture
was degassed with nitrogen for 20 minutes, then sealed and heated
to 50.degree. C. for 1 hour. The reaction was then stirred at rt
for 16 h. During this time, a white solid had formed, which was
isolated and washed with heptane to afford
(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(iso-
xazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(596 mg, 0.884 mmol, 82% yield) as an off-white solid. m/z (ESI,
positive ion) 674.2 (M+H).sup.+.
Step 3:
Cis-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phe-
nyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide and
Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0450] A 20 mL vial was charged with
(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(iso-
xazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(596 mg, 0.884 mmol), dichloromethane (1.4 mL) and TFA (1.4 mL).
The vial was sealed and warmed to 50.degree. C. for 16 h. The
reaction was then cooled to RT and concentrated under reduced
pressure. The residue was purified by column chromatography (50 g
silica gel column, gradient elution 0-75% [3:1
EtOAc/EtOH]:heptane). Further purification was accomplished using
two sequential Chiralcel OJ-H, 2.times.25 cm columns. The mobile
phase was run under isocratic conditions; supercritical CO.sub.2
with 15% methanol; flow rate: 80 mL/min. The first eluting peak was
assigned cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3
S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihy-
droquinoline-6-sulfonamide (305 mg). The second eluting peak was
assigned trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3
S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihy-
droquinoline-6-sulfonamide (72 mg). Data for peak 1: .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 11.65 (s, 1H), 8.73 (d, J=1.8
Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.21 (d, J=9.6 Hz, 1H), 7.83 (dd,
J=9.0, 2.2 Hz, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 6.79 (d, J=9.6 Hz,
2H), 6.44 (d, J=1.8 Hz, 1H), 3.79 (br t, J=9.2 Hz, 1H), 3.73 (s,
3H), 3.27-3.34 (m, 1H), 2.61-2.71 (m, 2H), 2.26-2.43 (m, 2H). m/z
(ESI, positive ion) 554.0 (M+H).sup.+. Data for peak 2: .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 11.65 (br s, 1H), 8.72 (d,
J=1.6 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H), 8.21 (d, J=9.6 Hz, 1H), 7.84
(dd, J=9.1, 2.1 Hz, 1H), 7.51 (s, 1H), 7.37 (s, 1H), 6.78 (dd,
J=9.3, 6.0 Hz, 2H), 6.44 (d, J=1.6 Hz, 1H), 4.00 (quin, J=8.9 Hz,
1H), 3.76 (s, 3H), 3.22-3.28 (m, 1H), 2.93 (br d, J=3.6 Hz, 1H),
2.66-2.75 (m, 1H), 2.59-2.63 (m, 2H). m/z (ESI, positive ion) 554.0
(M+H).sup.+.
Example 14:
(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-
-Dihydroquinoline-6-Sulfonamide
##STR00077##
[0452] To a vial was added
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (146 mg, 0.238
mmol), palladium(II) acetate (2.7 mg, 0.012 mmol),
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (8.3 mg, 0.019 mmol), and cyclobutylzinc
bromide (0.5 M in THF, 0.95 mL, 0.47 mmol). The reaction mixture
was flushed with nitrogen and stirred at 50.degree. C. for 1 h. The
mixture was then purified directly via column chromatography
(gradient elution 0-30% [3:1 EtOAc/EtOH]:heptane). The isolated
product was then taken up in TFA (0.5 mL) and heated to 50.degree.
C. for 16 h. The reaction was then concentrated in vacuo and
purified using a Torus 2-PIC, 30.times.150 cm column. The mobile
phase was run under gradient elution conditions; supercritical
CO.sub.2 with 20-50% methanol; flow rate: 100 mL/min. This afforded
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)--
2-oxo-1,2-dihydroquinoline-6-sulfonamide (101 mg, 0.215 mmol, 90%
yield). .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 11.23-12.01
(m, 1H), 8.70 (d, J=1.5 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.19 (d,
J=9.4 Hz, 1H), 7.83 (dd, J=9.1, 2.2 Hz, 1H), 7.24 (d, J=9.8 Hz,
1H), 7.19 (d, J=6.9 Hz, 1H), 6.77 (d, J=9.4 Hz, 2H), 6.43 (d, J=1.8
Hz, 1H), 3.74-3.83 (m, 1H), 3.69 (s, 3H), 2.32-2.40 (m, 3H),
2.22-2.31 (m, 1H), 2.01-2.13 (m, 1H), 1.84-1.94 (m, 1H). m/z (ESI,
positive ion) 470.0 (M+H).sup.+.
Example 15:
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00078##
[0454] To a vial was added
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (359 mg, 0.573
mmol), palladium(II) acetate (6.4 mg, 0.029 mmol),
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (25 mg, 0.057 mmol),
(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (0.15 M in THF, 5.7
mL, 0.86 mmol) was added. The reaction mixture was flushed with
nitrogen and stirred at 50.degree. C. for 1 h. The mixture was then
purified directly via column chromatography (gradient elution 0-30%
[3:1 EtOAc/EtOH]:heptane). The isolated product was then taken up
in TFA (0.5 mL) and heated to 50.degree. C. for 16 h. The reaction
was then concentrated in vacuo and purified using sequential
Chiralcel OJ-H, 2+15 and 2.times.25 cm columns. The mobile phase
was run under isocratic conditions; supercritical CO.sub.2 with 20%
methanol; flow rate: 80 mL/min. This afforded
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (63
mg). .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 9.60-9.88 (m,
1H), 8.51-8.63 (m, 2H), 8.44 (d, J=2.1 Hz, 1H), 8.06 (dd, J=9.0,
2.2 Hz, 1H), 7.85 (d, J=9.9 Hz, 1H), 6.99 (t, J=4.9 Hz, 1H),
6.91-6.96 (m, 2H), 6.85 (d, J=9.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H),
3.98 (quin, J=8.8 Hz, 1H), 3.73 (s, 3H), 3.04 (dtd, J=14.9, 9.8,
9.8, 4.9 Hz, 1H), 2.67-2.79 (m, 2H), 2.54-2.66 (m, 2H). m/z (ESI,
positive ion) 549.2 (M+H).sup.+.
Examples 16 & 17:
Cis-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2--
Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide and
Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide,
Respectively
##STR00079##
[0456] The title compounds were prepared according to the method of
Example 15 using
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (368 mg, 0.573
mmol). The sample was purified using a Chiralcel OJ-H, 2.times.15
cm column. The mobile phase was run under isocratic conditions;
supercritical CO.sub.2 with 30% methanol; flow rate: 80 mL/min. The
sample was further purified using a Chiralcel OJ-H, 3.times.25 cm
column. The mobile phase was run under isocratic conditions;
supercritical CO.sub.2 with 20% methanol; flow rate: 100 mL/min.
The first eluting peak was assigned
cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2--
oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (21.8
mg). The second eluting peak was assigned
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (142.8
mg). Data for peak 1: .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta.
ppm 9.99-10.35 (m, 1H), 8.59 (d, J=4.7 Hz, 2H), 8.43 (d, J=2.1 Hz,
1H), 8.07 (dd, J=9.0, 2.2 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.19 (s,
1H), 7.02 (s, 1H), 6.99 (t, J=4.9 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H),
6.76 (d, J=9.1 Hz, 1H), 3.82 (quin, J=9.3 Hz, 1H), 3.76 (s, 3H),
2.99-3.11 (m, 1H), 2.66-2.77 (m, 2H), 2.37 (quin, J=10.8 Hz, 2H).
m/z (ESI, positive ion) 564.8 (M+H).sup.+. Data for peak 2: .sup.1H
NMR (500 MHz, CHLOROFORM-d) .delta. ppm 9.09-9.31 (m, 1H), 8.54 (d,
J=4.9 Hz, 2H), 8.44 (d, J=2.1 Hz, 1H), 8.07 (dd, J=9.0, 2.2 Hz,
1H), 7.85 (d, J=9.6 Hz, 1H), 7.21 (s, 1H), 7.05 (s, 1H), 6.98 (t,
J=4.9 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H),
4.04-4.13 (m, 1H), 3.77 (s, 3H), 2.92-3.05 (m, 1H), 2.71-2.84 (m,
2H), 2.47-2.66 (m, 2H). m/z (ESI, positive ion) 564.8
(M+H).sup.+.
Example 18:
(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,-
2-Dihydroquinoline-6-Sulfonamide
##STR00080##
[0458] The title compound was prepared according to the method of
Example 14 using
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-o-
xo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (153 mg,
0.238 mmol). The sample was purified via reverse phase HPLC using a
XBridge Prep Shield RP18 19.times.100 mm column. The mobile was run
under a gradient elution; 25-70% acetonitrile:water with 0.1%
formic acid; flow rate: 40 mL/min. This afforded
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,-
2-dihydroquinoline-6-sulfonamide (18 mg, 0.036 mmol, 15% yield).
.sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 11.20-11.51 (m,
1H), 8.65 (d, J=4.9 Hz, 2H), 8.41 (d, J=2.1 Hz, 1H), 8.04 (dd,
J=9.1, 2.1 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.15 (s, 1H), 7.06 (s,
1H), 7.01 (t, J=5.1 Hz, 1H), 6.85 (d, J=9.9 Hz, 1H), 6.77 (d, J=8.8
Hz, 1H), 3.87 (quin, J=8.8 Hz, 1H), 3.75 (s, 3H), 2.44-2.53 (m,
2H), 2.15-2.30 (m, 2H), 2.03-2.15 (m, 1H), 1.85-1.97 (m, 1H). m/z
(ESI, positive ion) 497.0 (M+H).sup.+.
Example 19:
Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00081##
[0460] The title compound was prepared according to the method of
Example 15 using
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-o-
xo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (368 mg,
0.573 mmol). The sample was purified using a Zorbax Eclipse Plus
C18, 2.1.times.10 cm column. The mobile phase was run under
gradient elution conditions; 41.3-61.3% water:acetonitrile with
0.1% formic acid as co-eluent; flow rate: 40 mL/min. The material
was further purified using a Chiralcel OJ-H, 2.times.15 cm column.
The mobile phase was run under isocratic conditions; supercritical
CO.sub.2 with 25% methanol; flow rate: 80 mL/min. This afforded
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (38.4
mg). .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 12.38-12.76
(m, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.10 (dd, J=3.9, 1.6 Hz, 1H), 7.91
(dd, J=9.1, 2.1 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.33-7.37 (m, 1H),
7.29 (d, J=1.6 Hz, 1H), 7.21 (s, 1H), 7.05 (s, 1H), 6.84 (d, J=9.6
Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 4.08 (quin, J=8.9 Hz, 1H), 3.77
(s, 3H), 2.91-3.06 (m, 1H), 2.69-2.83 (m, 2H), 2.48-2.62 (m, 2H).
m/z (ESI, positive ion) 565.2 (M+H).sup.+.
Example 20:
Trans-(P)--N-(Isoxazol-3-Yl)-1-(2-Methoxy-5-Methyl-4-(3-(Trifluoromethyl)-
Cyclobutyl)Phenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00082##
[0462] The title compound was prepared according to the method of
Example 15 using
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4--
methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (350 mg,
0.573 mmol). The sample was purified using a Zorbax Eclipse Plus
C18, 2.1.times.10 cm column. The mobile phase was run under
gradient elution conditions; 46.4-66.4% acetonitrile:water with
0.1% formic acid as co-eluent; flow rate: 40 mL/min. The material
was further purified using a Chiralcel OJ-H, 2.times.15 cm column.
The mobile phase was run under isocratic conditions; supercritical
CO.sub.2 with 20% methanol; flow rate: 80 mL/min. This afforded
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)-
cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (65.8
mg). .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.25 (d, J=1.8
Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.83-8.04 (m, 1H), 7.76 (d, J=9.6
Hz, 1H), 7.72 (dd, J=9.0, 2.2 Hz, 1H), 7.01 (s, 1H), 6.95 (s, 1H),
6.86 (d, J=9.6 Hz, 1H), 6.76 (d, J=9.1 Hz, 1H), 6.60 (d, J=1.8 Hz,
1H), 3.94 (quin, J=8.8 Hz, 1H), 3.75 (s, 3H), 2.89-3.07 (m, 1H),
2.70 (ddd, J=12.8, 8.8, 4.0 Hz, 2H), 2.46-2.60 (m, 2H), 2.19 (s,
3H). m/z (ESI, positive ion) 534.2 (M+H).sup.+.
Example 21:
(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-
-Dihydroquinoline-6-Sulfonamide
##STR00083##
[0464] The title compound was prepared according to the method of
Example 14 using
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4--
methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (150 mg,
0.238 mmol). The sample was purified via reverse phase HPLC using a
XBridge Prep Shield RP18 19.times.100 mm column. The mobile was run
under a gradient elution; 25-70% acetonitrile:water with 0.1%
formic acid; flow rate: 40 mL/min. This afforded
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-
-dihydroquinoline-6-sulfonamide (92 mg, 80% yield). .sup.1H NMR
(500 MHz, CHLOROFORM-d) .delta. ppm 8.40 (br s, 1H), 8.25 (d, J=1.6
Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.78 (d, J=9.6 Hz, 1H), 7.75 (dd,
J=9.0, 2.2 Hz, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.87 (d, J=9.6 Hz,
1H), 6.77 (d, J=9.1 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 3.80-3.91 (m,
1H), 3.75 (s, 3H), 2.42-2.56 (m, 2H), 2.16-2.27 (m, 2H), 2.04-2.16
(m, 1H), 1.84-1.96 (m, 1H). m/z (ESI, positive ion) 486.0
(M+H).sup.+.
Example 22:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-
-Dihydro Quinoline-6-Sulfonamide
##STR00084##
[0465] Step 1:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-N-(4-Meth-
oxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0466] To a THF (1 mL) solution of
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (191 mg, 0.313 mmol)
was added 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl
(27.3 mg, 0.063 mmol), and palladium(II) acetate (14.05 mg, 0.063
mmol). The reaction mixture was sparged with argon, and then
cyclobutylzinc bromide (0.5 M in THF, 1.9 mL, 0.94 mmol) was added.
The reaction was stirred at 50.degree. C. After 2 h, additional
portions of
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (27.3 mg,
0.063 mmol), palladium(II) acetate (14.1 mg, 0.063 mmol), and
cyclobutylzinc bromide (0.5 M in THF, 1.9 mL, 0.94 mmol) were
added. After stirring for 1 h at 50.degree. C., the reaction was
cooled to room temperature, quenched with saturated aqueous sodium
bicarbonate, and partitioned between water and ethyl acetate. The
organic extract was concentrated and purified by silica gel column
chromatography (gradient elution, 40-100% EtOAc:heptane with 10%
dichloromethane co-eluent) to afford
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-meth-
oxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (123 mg, 0.210
mmol, 67% yield) as a brown solid. m/z (ESI, positive ion) 586.0
(M+H).sup.+.
Step 2:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-2--
Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0467]
(P)-1-(4-Cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(-
4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (123 mg,
0.210 mmol) was dissolved in TFA (2 mL) and stirred at 40.degree.
C. After 2 h, the reaction was concentrated, and the residue was
purified via silica gel column chromatography (gradient elution
20-80% [3:1 EtOAc/EtOH]:heptane with 10% dichloromethane co-eluent)
to afford
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-
-dihydroquinoline-6-sulfonamide (73 mg, 0.157 mmol, 75% yield) as a
light purple solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
11.60 (br s, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H),
8.18 (d, J=9.6 Hz, 1H), 7.82 (dd, 2.2 Hz, 1H), 7.09 (s, 1H), 7.00
(s, 1H), 6.77 (d, J=9.6 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.43 (d,
J=1.8 Hz, 1H), 3.69-3.74 (m, 1H), 3.68 (s, 3H), 2.33-2.43 (m, 2H),
2.26 (quin, J=9.6 Hz, 1H), 2.11-2.19 (m, 4H), 1.98-2.09 (m, 1H),
1.79-1.90 (m, 1H). m/z (ESI, positive ion) 465.8 (M+H).sup.+.
Example 23:
(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,-
2-Dihydroquinoline-6-Sulfonamide
##STR00085##
[0468] Step 1:
(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-
-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
[0469] To a THF (0.8 mL) solution of a
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (150 mg, 0.240
mmol) was added
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (20.9 mg,
0.048 mmol), and palladium(II) acetate (10.8 mg, 0.048 mmol). The
reaction mixture was sparged with argon, and then cyclobutylzinc
bromide (0.5m in THF, 1.4 mL, 0.72 mmol) was added. The reaction
was stirred at 50.degree. C. After 90 min, the reaction mixture was
quenched with saturated aqueous sodium bicarbonate and partitioned
between water and ethyl acetate. The organic layers were
concentrated. The residue was purified by silica gel column
chromatography (gradient elution 40-100% EtOAc:heptane with 10%
dichloromethane co-eluent) to afford
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-
-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (156 mg, 0.260
mmol, >99% yield) as a brown solid. m/z (ESI, positive ion)
601.0 (M+H).sup.+.
Step 2:
(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-
-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
[0470]
(P)-1-(4-Cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-
-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (156 mg,
0.260 mmol) was dissolved in TFA (3.0 mL) and stirred at 40.degree.
C. After 2 h, the reaction was concentrated, and the residue was
purified by silica gel chromatography 20-80% [3:1
EtOAc/EtOH]:heptane with 10% dichloromethane co-eluent) to afford
1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-di-
hydroquinoline-6-sulfonamide (86 mg, 0.179 mmol, 69% yield) as an
off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
14.28-14.68 (m, 1H), 8.23-8.39 (m, 2H), 8.17 (d, J=9.6 Hz, 1H),
7.89-8.00 (m, 1H), 7.79-7.86 (m, 1H), 7.68 (dd, J=9.5, 4.0 Hz, 1H),
7.22 (d, J=9.9 Hz, 1H), 7.19 (d, J=6.7 Hz, 1H), 6.75 (d, J=9.6 Hz,
1H), 6.70 (d, J=8.8 Hz, 1H), 3.78 (quin, J=8.9 Hz, 1H), 3.69 (s,
3H), 2.32-2.38 (m, 3H), 2.23-2.32 (m, 1H), 2.02-2.14 (m, 1H),
1.84-1.95 (m, 1H). m/z (ESI, positive ion) 480.8 (M+H).sup.+.
Example 24:
(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-D-
ihydroquinoline-6-Sulfonamide
##STR00086##
[0472] The title compound was prepared according to the method and
purification protocol of Example 23 using
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2--
yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (180 mg, 0.293 mmol).
This afforded
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2--
oxo-1,2-dihydroquinoline-6-sulfonamide (54 mg, 0.115 mmol, 39%
yield over 2 steps) as a light purple solid. .sup.1H NMR (500 MHz,
CHLOROFORM-d) .delta. ppm 9.65-10.09 (m, 1H), 8.19 (d, J=2.1 Hz,
1H), 7.87 (dd, 2.2 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.08 (d, J=1.8
Hz, 1H), 6.98 (d, J=6.2 Hz, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.86 (d,
J=1.8 Hz, 1H), 6.84 (d, J=9.6 Hz, 1H), 6.76 (d, J=9.1 Hz, 1H), 3.82
(quin, J=8.8 Hz, 1H), 3.72 (s, 3H), 2.39-2.49 (m, 2H), 2.21-2.34
(m, 2H), 2.08-2.18 (m, 1H), 1.88-1.99 (m, 1H). m/z (ESI, positive
ion) 469.8 (M+H).sup.+.
Example 25:
(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroq-
uinoline-6-Sulfonamide
##STR00087##
[0474] The title compound was prepared according to the method and
purification protocol of Example 23 using
(P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-o-
xo-1,2-dihydroquinoline-6-sulfonamide (140 mg, 0.235 mmol). This
afforded
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroq-
uinoline-6-sulfonamide (89 mg, 0.197 mmol, 84% yield over 2 steps)
as an off-white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 11.60 (s, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.3 Hz, 1H),
8.19 (d, J=9.9 Hz, 1H), 7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.18 (d,
J=8.0 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 7.02 (dd, J=7.9, 1.7 Hz,
1H), 6.77 (d, J=9.6 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.44 (d, J=1.8
Hz, 1H), 3.67 (s, 3H), 3.58-3.67 (m, 1H), 2.32-2.42 (m, 2H),
2.16-2.27 (m, 2H), 1.99-2.08 (m, 1H), 1.82-1.92 (m, 1H). m/z (ESI,
positive ion) 452.0 (M+H).sup.+.
Example 26:
(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydro-
quinoline-6-Sulfonamide
##STR00088##
[0476] The title compound was prepared according to the method and
purification protocol of Example 23 using
(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2--
yl)-1,2-dihydroquinoline-6-sulfonamide (140 mg, 0.230 mmol). This
afforded
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydro-
quinoline-6-sulfonamide (50 mg, 0.108 mmol, 47% yield over 2 steps)
as a white solid. .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm
8.57 (d, J=4.9 Hz, 2H), 8.42 (d, J=2.1 Hz, 1H), 8.02 (dd, J=9.1,
2.1 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.07-7.10 (m, 1H), 6.93-7.03
(m, 3H), 6.87 (d, J=9.6 Hz, 1H), 6.78 (d, J=9.1 Hz, 1H), 3.72 (s,
3H), 3.65 (quin, J=9.0 Hz, 1H), 2.34-2.46 (m, 2H), 2.18-2.31 (m,
2H), 2.06-2.14 (m, 1H), 1.85-1.96 (m, 1H). m/z (ESI, positive ion)
463.0 (M+H).sup.+.
Example 27:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,-
2-Dihydro Quinoline-6-Sulfonamide
##STR00089##
[0478] The title compound was prepared according to the method and
purification protocol of Example 22 using
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (130 mg, 0.209
mmol). This afforded
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl-
)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (60
mg, 0.126 mmol, 60% yield over 2 steps) as a white solid. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 11.43-12.18 (m, 1H), 8.50
(d, J=4.9 Hz, 2H), 8.44 (d, J=2.1 Hz, 1H), 8.21 (d, J=9.6 Hz, 1H),
7.95 (dd, J=9.0, 2.2 Hz, 1H), 7.09 (s, 1H), 7.05 (br t, J=4.8 Hz,
1H), 6.99 (s, 1H), 6.75 (d, J=9.9 Hz, 1H), 6.69 (d, J=9.1 Hz, 1H),
3.68-3.75 (m, 1H), 3.67 (s, 3H), 2.32-2.44 (m, 2H), 2.26 (quin,
J=9.7 Hz, 1H), 2.11-2.20 (m, 4H), 1.99-2.07 (m, 1H), 1.80-1.90 (m,
1H). m/z (ESI, positive ion) 477.0 (M+H).sup.+.
Example 28:
(P)-1-(4-CYCLOBUTYL-5-FLUORO-2-METHOXYPHENYL)-2-Oxo-N-(Pyrimidin-2-Yl)-1,-
2-Dihydroquinoline-6-Sulfonamide
##STR00090##
[0480] The title compound was prepared according to the method and
purification protocol of Example 23 using
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (120 mg, 0.192
mmol). This afforded
(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-
-2-yl)-1,2-dihydroquinoline-6-sulfonamide (20 mg, 0.042 mmol, 22%
yield). .sup.1H NMR (500 MHz, CHLOROFORM-d) .delta. ppm 8.59 (d,
J=4.9 Hz, 2H), 8.43 (d, J=2.1 Hz, 1H), 8.06 (dd, J=9.0, 2.2 Hz,
1H), 7.84 (d, J=9.6 Hz, 1H), 6.96-7.02 (m, 2H), 6.87 (d, J=3.6 Hz,
1H), 6.85 (d, J=4.4 Hz, 1H), 6.78 (d, J=9.1 Hz, 1H), 3.82 (quin,
J=9.1 Hz, 1H), 3.72 (s, 3H), 2.37-2.48 (m, 2H), 2.23-2.35 (m, 2H),
2.07-2.18 (m, 1H), 1.88-2.00 (m, 1H). m/z (ESI, positive ion) 481.0
(M+H).sup.+.
Example 29:
(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroqui-
noline-6-Sulfonamide
##STR00091##
[0481] Step 1:
(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2--
Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0482] To a THF (1.2 mL) solution of
(P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-
-oxo-1,2-dihydroquinoline-6-sulfonamide (200 mg, 0.319 mmol) was
added 2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl
(41.8 mg, 0.096 mmol) and palladium(II) acetate (21.50 mg, 0.096
mmol). The reaction mixture was sparged with argon, and then
cyclobutylzinc bromide (0.5 M in THF, 2.55 mL, 1.28 mmol) was
added. The reaction was stirred at 50.degree. C. After 3 h, the
reaction was quenched with saturated aqueous sodium bicarbonate and
partitioned between water and ethyl acetate. The organic layer was
concentrated. The residue were purified by silica gel column
chromatography (gradient elution 40-100% ethyl acetate:heptane with
10% dichloromethane as a co-eluent) to provide
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2--
yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (73 mg, 0.12 mmol, 38%
yield) as a yellow oil. m/z (ESI, positive ion) 602.0
(M+H).sup.+.
Step 2:
(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dih-
ydroquinoline-6-Sulfonamide
[0483]
(P)-1-(4-Cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxa-
zol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (73 mg, 0.12
mmol) was dissolved in TFA (3.0 mL). The reaction mixture was
stirred at 40.degree. C. After 1 h, the reaction was concentrated,
and the residue was purified by silica gel column chromatography
(gradient elution 20-80% [3:1 EtOAc/EtOH]:heptane with 10%
dichloromethane co-eluent) to afford
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroqui-
noline-6-sulfonamide (46 mg, 0.10 mmol, 85% yield) as a white
solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 12.12 (br s,
1H), 8.29 (d, J=2.1 Hz, 1H), 8.15 (d, J=9.6 Hz, 1H), 7.83 (dd,
J=9.0, 2.2 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.26 (d, J=1.6 Hz, 1H),
7.17 (d, J=7.8 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 7.02 (dd, J=8.0,
1.6 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.68
(s, 3H), 3.58-3.67 (m, 1H), 2.31-2.39 (m, 2H), 2.17-2.28 (m, 2H),
1.96-2.10 (m, 1H), 1.82-1.92 (m, 1H). m/z (ESI, positive ion) 451.8
(M+H).sup.+.
Example 30:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,-
2-Dihydroquinoline-6-Sulfonamide
##STR00092##
[0485] The title compound was prepared according to the method and
purification protocol of Example 23 using
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (367 mg, 0.591
mmol). This afforded
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-
-3-yl)-1,2-dihydroquinoline-6-sulfonamide (144 mg, 0.302 mmol, 51%
yield over 2 steps) as a white solid. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 14.35-14.59 (m, 1H), 8.23-8.34 (m, 2H),
8.16 (d, J=9.5 Hz, 1H), 7.88-7.98 (m, 1H), 7.82 (br d, J=8.3 Hz,
1H), 7.59-7.73 (m, 1H), 7.08 (s, 1H), 6.99 (s, 1H), 6.74 (d, J=9.5
Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 3.63-3.76 (m, 4H), 2.31-2.44 (m,
2H), 2.21-2.30 (m, 1H), 2.13-2.20 (m, 4H), 2.00-2.09 (m, 1H),
1.81-1.92 (m, 1H). m/z (ESI, positive ion) 477.0 (M+H).sup.+.
Example 31:
(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydro-
quinoline-6-Sulfonamide
##STR00093##
[0487] The title compound was prepared according to the method of
Example 23 using
(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.494
mmol). The sample was purified via reverse phase HPLC using a
XBridge Prep Shield RP18 19.times.100 mm column. The mobile was run
under a gradient elution; 15-70% acetonitrile:water with 0.1%
formic acid; flow rate: 40 mL/min. This afforded
(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydro-
quinoline-6-sulfonamide (130 mg, 0.281 mmol, 57% yield over 2
steps) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 14.39 (br s, 1H), 8.31 (d, J=2.1 Hz, 2H), 8.16 (d,
J=9.6 Hz, 1H), 7.85-7.93 (m, 1H), 7.82 (dd, J=9.0, 2.2 Hz, 1H),
7.66 (dd, J=9.6, 4.2 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.11 (d,
J=1.6 Hz, 1H), 7.02 (dd, J=8.0, 1.3 Hz, 1H), 6.74 (d, J=9.6 Hz,
1H), 6.64 (d, J=8.8 Hz, 1H), 3.67 (s, 3H), 3.59-3.66 (m, 1H),
2.30-2.41 (m, 2H), 2.16-2.29 (m, 2H), 1.96-2.10 (m, 1H), 1.81-1.93
(m, 1H). m/z (ESI, positive ion) 463.0 (M+H).sup.+.
Example 32:
(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-D-
ihydroquinoline-6-Sulfonamide
##STR00094##
[0489] The title compound was prepared according to the method of
Example 23 using
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-
-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (347 mg,
0.525 mmol). The sample was purified via reverse phase HPLC using a
XBridge Prep Shield RP18 19.times.100 mm column. The mobile was run
under a gradient elution; 15-60% acetonitrile:water with 0.1%
formic acid; flow rate: 40 mL/min. The material was further
purified using a Whelk-O, 2.times.15 cm column. The mobile phase
was run under isocratic conditions; supercritical CO.sub.2 with 60%
isopropanol; flow rate: 70 mL/min. This afforded
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-d-
ihydroquinoline-6-sulfonamide (74 mg, 0.15 mmol, 29% yield over 2
steps) as a white solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.15 (br s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.16 (d,
J=9.6 Hz, 1H), 7.84 (dd, J=9.0, 2.2 Hz, 1H), 7.59 (d, J=1.6 Hz,
1H), 7.43 (s, 1H), 7.23-7.30 (m, 2H), 6.75 (d, J=9.6 Hz, 1H), 6.69
(d, J=8.8 Hz, 1H), 3.82 (quin, J=8.8 Hz, 1H), 3.74 (s, 3H),
2.39-2.44 (m, 2H), 2.29-2.35 (m, 1H), 2.23 (quin, J=9.5 Hz, 1H),
2.00-2.12 (m, 1H), 1.81-1.92 (m, 1H). m/z (ESI, positive ion) 486.0
(M+H).sup.+.
Example 33:
(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,-
2-Dihydroquinoline-6-Sulfonamide
##STR00095##
[0490] Step 1:
(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-
-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
[0491] To a 20-mL scintillation vial was added
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (20.4 mg,
0.047 mmol), palladium(II) acetate (5.3 mg, 0.023 mmol), and
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.467
mmol). The reaction mixture was sparged with nitrogen, and then
cyclobutylzinc bromide (0.5 M in THF, 1.87 mL, 0.935 mmol) was
added. After stirring at 50.degree. C. for 1 h, an additional
portion of cyclobutylzinc bromide (0.5 M in THF, 1.87 mL, 0.935
mmol) was added. After stirring an additional 2 h at 50.degree. C.,
the reaction mixture was quenched with saturated aqueous sodium
bicarbonate and partitioned between water and ethyl acetate. The
organic layer was concentrated. The initial products were purified
by silica gel column chromatography (gradient elution 0-60% [3:1
EtOAc/EtOH]:heptane with 10% dichloromethane co-eluent) to provide
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-
-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (216 mg, 0.350
mmol, 75% yield) as a yellow solid. m/z (ESI, positive ion) 616.8
(M+H).sup.+.
Step 2:
(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-
-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
[0492]
(P)-1-(5-Chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-
-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (216 mg,
0.350 mmol) was taken up in trifluoroacetic acid (2.6 mL) and the
reaction was heated to 40.degree. C. After 2 h, the reaction was
then concentrated and purified via reverse phase HPLC using a
XBridge Prep Shield RP18 19.times.100 mm column. The mobile was run
under a gradient elution; 15-70% acetonitrile:water with 0.1%
formic acid; flow rate: 40 mL/min. This afforded
(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,-
2-dihydroquinoline-6-sulfonamide (83 mg, 0.167 mmol, 48% yield) as
a yellow solid. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm
14.46 (br s, 1H), 8.33 (d, J=2.1 Hz, 2H), 8.17 (d, J=9.6 Hz, 1H),
7.88 (br d, J=3.9 Hz, 1H), 7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.67 (dd,
J=9.6, 4.2 Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.75 (d, J=9.6 Hz,
1H), 6.69 (d, J=8.8 Hz, 1H), 3.82 (quin, J=8.8 Hz, 1H), 3.73 (s,
3H), 2.35-2.47 (m, 2H), 2.28-2.34 (m, 1H), 2.22 (quin, J=9.9 Hz,
1H), 1.97-2.11 (m, 1H), 1.80-1.91 (m, 1H). m/z (ESI, positive ion)
497.0 (M+H).sup.+.
Example 34:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenzyl)-N-(-
Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00096##
[0493] Step 1:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenzyl)-N-(-
Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0494] To a 20-mL scintillation vial was added
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (26 mg,
0.060 mmol), palladium(II) acetate (6.7 mg, 0.030 mmol), and
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazo-
l-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (384 mg, 0.600
mmol). The reaction mixture was sparged with nitrogen, and then
cyclobutylzinc bromide (0.5 M in tetrahydrofuran, 3.60 mL, 1.80
mmol) was added. The reactions were stirred at 50.degree. C. After
1 h, the reaction mixture was quenched with saturated aqueous
sodium bicarbonate and partitioned between water and ethyl acetate.
The organic layer was dried over sodium sulfate and concentrated.
The residue was purified by silica gel column chromatography
(gradient elution 0-30% [3:1 EtOAc/EtOH]:heptane with 10%
dichloromethane co-eluent) to provide
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(-
oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (255 mg,
0.414 mmol, 69% yield) as a white solid. m/z (ESI, positive ion)
616.2 (M+H).sup.+.
Step 2:
(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenz-
yl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0495]
(P)-1-(4-Cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzy-
l)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (255
mg, 0.414 mmol) was taken up in TFA (3 mL) and heated to 50.degree.
C. After stirring for 1 h, the reaction was concentrated and
purified using a Torus 2-PIC, 3.times.15 cm column. The mobile
phase was run under gradient elution conditions; supercritical
CO.sub.2 with 10-40% methanol; flow rate: 100 mL/min. This afforded
(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-d-
ihydroquinoline-6-sulfonamide (71 mg, 0.15 mmol, 25% yield over 2
steps). .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. ppm 12.12 (br
s, 1H), 8.29 (d, J=1.8 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.83 (dd,
J=8.9, 2.0 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.26 (d, J=1.5 Hz, 1H),
7.09 (s, 1H), 6.99 (s, 1H), 6.74 (d, J=9.4 Hz, 1H), 6.65 (d, J=8.7
Hz, 1H), 3.63-3.75 (m, 4H), 2.33-2.44 (m, 2H), 2.27 (quin, J=9.7
Hz, 1H), 2.12-2.21 (m, 4H), 1.97-2.10 (m, 1H), 1.80-1.92 (m, 1H).
m/z (ESI, positive ion) 466.0 (M+H).sup.+.
Example 35:
Trans-(P)--N-(Isoxazol-3-Yl)-1-(2-Methoxy-4-((Trifluoromethyl)Cyclobutyl)-
Phenyl)-2-Oxo-1,2-Dihydro Quinoline-6-Sulfonamide
##STR00097##
[0496] Step 1:
(P)--N-(Isoxazol-3-Yl)-1-(2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phen-
yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0497]
(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzy-
l)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.47 g, 0.788 mmol),
palladium(II) acetate (0.023 g, 0.10 mmol), and
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.076 g,
0.173 mmol) were placed in a vial, and the resulting mixture was
sparged with nitrogen prior to the addition of tetrahydrofuran (3.1
mL). (3-(Trifluoromethyl)cyclobutyl)zinc(II) bromide (0.125 M in
THF, 9.46 mL, 1.182 mmol) was then added dropwise. The reaction
mixture was then warmed to 50.degree. C. and stirred at this
temperature for 1.25 h. After cooling to ambient temperature, the
reaction mixture was quenched with 5 M aqueous ammonium chloride
solution, and the aqueous phase was extracted twice with ethyl
acetate. The combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated under vacuum. The resulting
residue was purified by flash column chromatography (gradient
elution 0-50% [3:1 EtOAc/EtOH]:heptane with 10% dichloromethane
co-eluent) to afford
(P)--N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobut-
yl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.489 g, 0.764 mmol, 97% yield). m/z (ESI, positive ion) 640.2
(M+H).sup.+.
Step 2:
Trans-(P)--N-(Isoxazol-3-Yl)-1-(2-Methoxy-4-((Trifluoromethyl)Cycl-
obutyl)Phenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0498]
(P)--N-(Isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobuty-
l)
phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.489 g, 0.764 mmol) was dissolved in TFA (1.3 mL) and stirred at
40.degree. C. for 2.5 h. After cooling to ambient temperature,
volatiles were removed under vacuum, and the residue was purified
using a ChromegaChiral CC4, 2.times.25 cm column. The mobile phase
was run under isocratic conditions; supercritical CO.sub.2 with 40%
methanol; flow rate: 80 mL/min. This afforded
trans-(P)--N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobuty-
l)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (296 mg, 0.570
mmol, 72% yield over 2 steps). .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 11.60 (s, 1H), 8.71 (d, J=1.6 Hz, 1H), 8.34 (d, J=2.1
Hz, 1H), 8.19 (d, J=9.6 Hz, 1H), 7.83 (dd, J=9.1, 2.3 Hz, 1H),
7.20-7.28 (m, 2H), 7.11 (dd, J=7.9, 1.4 Hz, 1H), 6.78 (d, J=9.6 Hz,
1H), 6.71 (d, J=9.1 Hz, 1H), 6.43 (d, J=1.8 Hz, 1H), 3.80 (quin,
J=8.6 Hz, 1H), 3.69 (s, 3H), 3.22-3.28 (m, 1H), 2.54-2.61 (m, 4H).
m/z (ESI, positive ion) 520.0 (M+H).sup.+.
Example 36:
Trans-(P)-1-(2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(-
Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00098##
[0500] The title compound was prepared according to the method of
Example 23 by using
(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2--
yl)-1,2-dihydroquinoline-6-sulfonamide (479 mg, 0.788 mmol) in
place of
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide. The sample was
purified using a Chiralpak IC, 2.times.15 cm column. The mobile
phase was run under isocratic conditions; supercritical CO.sub.2
with 60% [1:1 methanol:dichloromethane]; flow rate: 80 mL/min. This
afforded
trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-
-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (204 mg,
0.384 mmol, 49% yield over 2 steps). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. ppm 11.57-12.03 (m, 1H), 8.50 (br d, J=4.9
Hz, 2H), 8.45 (d, J=1.8 Hz, 1H), 8.22 (d, J=9.6 Hz, 1H), 7.82-8.03
(m, 1H), 7.18-7.25 (m, 2H), 7.11 (dd, J=8.0, 1.6 Hz, 1H), 7.05 (br
s, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 3.80 (quin,
J=9.0 Hz, 1H), 3.68 (s, 3H), 3.21-3.28 (m, 1H), 2.53-2.63 (m, 4H).
m/z (ESI, positive ion) 531.0 (M+H).sup.+.
Example 37:
Trans-(P)-1-(2-Methoxy-5-Methyl-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00099##
[0502] The title compound was prepared according to the method of
Example 35 by using
(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (470 mg, 0.756
mmol) in place of
(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. The sample was
purified using two sequential Chiralpak OJ-H, 3.times.15 cm
columns. The mobile phase was run under isocratic conditions;
supercritical CO.sub.2 with 20% methanol; flow rate: 80 mL/min. The
sample was further purified via silica gel column chromatography
(gradient elution 0-100% EtOAc:heptane with 10% dichloromethane
co-eluent) to afford
trans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (103
mg, 0.189 mmol, 25% yield over 2 steps) as a light pink solid.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 14.17-14.75 (m,
1H), 8.25-8.35 (m, 2H), 8.16 (d, J=9.9 Hz, 1H), 7.86-7.99 (m, 1H),
7.83 (dd, J=8.7, 1.7 Hz, 1H), 7.67 (br dd, J=8.6, 3.9 Hz, 1H), 7.22
(s, 1H), 7.04 (s, 1H), 6.74 (d, J=9.6 Hz, 1H), 6.65 (d, J=9.1 Hz,
1H), 3.88 (quin, J=8.9 Hz, 1H), 3.71 (s, 3H), 3.18-3.28 (m, 1H),
2.54-2.66 (m, 4H), 2.16 (s, 3H). m/z (ESI, positive ion) 545.0
(M+H).sup.+.
Example 38:
Trans-(P)-1-(2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(-
Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00100##
[0504] The title compound was prepared according to the method of
Example 35 by using
(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3--
yl)-1,2-dihydroquinoline-6-sulfonamide (459 mg, 0.756 mmol) in
place of
(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-o-
xo-1,2-dihydroquinoline-6-sulfonamide. The sample was purified
using a Chiralpak AS-H, 2.times.25 cm column. The mobile phase was
run under isocratic conditions; supercritical CO.sub.2 with 35%
methanol; flow rate: 50 mL/min. The sample was further purified via
silica gel column chromatography (gradient elution 0-100%
EtOAc:heptane with 10% dichloromethane co-eluent) to afford
trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(-
pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (247 mg, 466
mmol, 62% yield over 2 steps) as a light pink solid. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 14.26-14.69 (m, 1H), 8.23-8.35
(m, 2H), 8.16 (d, J=9.6 Hz, 1H), 7.89-7.98 (m, 1H), 7.82 (br d,
J=8.0 Hz, 1H), 7.68 (br dd, J=9.7, 4.0 Hz, 1H), 7.18-7.25 (m, 2H),
7.11 (dd, J=8.0, 1.6 Hz, 1H), 6.75 (d, J=9.6 Hz, 1H), 6.65 (d,
J=9.1 Hz, 1H), 3.80 (quin, J=8.8 Hz, 1H), 3.69 (s, 3H), 3.24-3.28
(m, 1H), 2.54-2.62 (m, 4H). m/z (ESI, positive ion) 531.0
(M+H).sup.+.
Example 39:
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)-
Phenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide
##STR00101##
[0506] The title compound was prepared according to the method of
Example 35, by using
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
idazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (382 mg, 0.756
mmol) in place of
(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide. The sample was
purified using two sequential Chiralcel, 3.times.15 cm columns. The
mobile phase was run under isocratic conditions; supercritical
CO.sub.2 with 20% methanol; flow rate: 80 mL/min. The sample was
further purified via silica gel column chromatography (gradient
elution 0-100% EtOAc:heptane with 10% dichloromethane co-eluent) to
afford
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide (59.5
mg, 0.108 mmol, 14% yield over 2 steps) as a white solid. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 14.23-14.74 (m, 1H),
8.24-8.37 (m, 2H), 8.18 (d, J=9.6 Hz, 1H), 7.88-7.98 (m, 1H),
7.80-7.86 (m, 1H), 7.68 (br dd, J=9.5, 3.8 Hz, 1H), 7.32 (d, J=7.0
Hz, 1H), 7.29 (d, J=9.9 Hz, 1H), 6.75 (d, J=9.6 Hz, 1H), 6.70 (d,
J=9.1 Hz, 1H), 3.95 (quin, J=9.0 Hz, 1H), 3.71 (s, 3H), 3.24-3.28
(m, 1H), 2.56-2.70 (m, 4H). m/z (ESI, positive ion) 549.0
(M+H).sup.+.
Example 40:
(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl-
)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00102## ##STR00103##
[0507] Step 1:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-7-Fluoro-
-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0508] A 250 mL round-bottom flask was charged with
(P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (5.0 g, 8.17 mmol) and
N-(2,4-dimethoxybenzyl)isoxazol-3-amine (2.37 g, 10.1 mmol). The
flask was purged with nitrogen for 5 minutes before tetrahydrofuran
(20 mL) was introduced. The resultant mixture was cooled to
-78.degree. C. in dry ice-acetone bath and sodium tert-pentoxide
(30% solution in THF, 5.0 mL, 12.5 mmol) was added dropwise. The
reaction mixture then stirred for 15 min. An aqueous solution of
ammonium chloride (5 M) was introduced, the resultant mixture was
allowed to warm to ambient temperature, and was then extracted with
EtOAc. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (BIOTAGE.RTM., 100 g Silica
Cartridge, eluent: 0-80% ethyl acetate in heptane with 10%
dichloromethane additive) to afford
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-7-fluoro-
-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (1.92
g, 2.90 mmol, 35.5% yield) as a white solid. m/z (ESI) 662.0 and
664.0 (M+H).sup.+.
Step 2:
(P)--N-(2,4-Dimethoxybenzyl)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-((1R-
,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dih-
ydroquinoline-6-Sulfonamide
[0509] A 100 mL round-bottom flask equipped with a reflux condenser
was charged with magnesium turnings (796 mg, 32.8 mmol) and purged
with nitrogen for 15 minutes. Iodine (151 mg, 0.596 mmol) was
introduced and the flask was warmed with a heat gun until the
iodine visibly sublimated. After cooling to ambient temperature, a
slight vacuum was applied to remove excess of iodine.
Tetrahydrofuran (12.5 mL) was introduced.
Trans-1-bromo-3-(trifluoromethyl)cyclobutane (5.00 g, 24.6 mmol,
Enamine, LLC) was then slowly added to the stirred reaction mixture
via syringe, resulting in a slight exotherm and loss of iodine
color. The reaction vessel was submerged in an ice/water bath as
needed to prevent excessive exotherm. After stirring for 1 h,
tetrahydrofuran (12.5 mL) was added. After an additional 1 h, zinc
chloride solution (1.9 M in 2-methyltetrahydrofuran, 14.0 mL, 26.6
mmol, Sigma-Aldrich Corporation) was added, resulting in the
formation of a white precipitate. The resulting mixture was stirred
at ambient temperature overnight and used without further
manipulation. The organozinc solution was titration with iodine to
provide an estimated concentration of 0.33 M. A separate 100 mL
round-bottom flask was charged with
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.501 g,
1.15 mmol),
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-7-
-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(1.90 g, 2.87 mmol), palladium(II) acetate (129 mg, 0.57 mmol), and
tetrahydrofuran (14.0 mL). The reaction mixture was sparged with
nitrogen for 10 minutes. A portion of the
(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide solution prepared
above (10 mL, 3.30 mmol) was added dropwise via syringe to the
reaction mixture. Following addition, the resultant mixture was
warmed to 50.degree. C. After 1.5 h, water was introduced and the
mixture was extracted with ethyl acetate. The organic layer was
dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (BIOTAGE.RTM., 100 g Silica Cartridge, eluent: 0-50%
ethyl acetate in heptane with 10% DCM additive) to afford
(P)--N-(2,4-dimethoxybenzyl)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3--
(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroqui-
noline-6-sulfonamide (2.0 g, 2.83 mmol, 99% yield). m/z (ESI) 705.8
(M+H).sup.+.
Step 3:
(P)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)C-
yclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonami-
de
[0510] A 50 mL round-bottomed flask was charged with
(P)--N-(2,4-dimethoxybenzyl)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3--
(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroqui-
noline-6-sulfonamide (2.0 g, 2.83 mmol), dichloromethane (12 mL),
and trifluoroacetic acid (2.8 mL). The reaction mixture stirred at
room temperature for 2 hours before the solvent was removed under a
stream of nitrogen. The residue was purified by flash column
chromatography (BIOTAGE.RTM., 25 g Silica Cartridge, eluent: 0-70%
ethyl acetate in heptane with 10% DCM additive). Fractions
containing desired product were combined, the solvent was removed
under reduced pressure, and the residue (1.5 g) was further
purified by SFC using a Chiralpak AD-H column (3.times.25 cm, 5
micron), with a mobile phase of 20% ethanol using a flowrate of 160
mL/min to afford
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobut-
yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(844 mg, 1.52 mmol, 54% yield), .sup.1H NMR (500 MHz,
DMSO-d.sub.6,) .delta.: 11.97 (br s, 1H), 8.72 (d, J=1.8 Hz, 1H),
8.46 (d, J=7.8 Hz, 1H), 8.22 (d, J=9.7 Hz, 1H), 7.23-7.40 (m, 2H),
6.75 (d, J=9.7 Hz, 1H), 6.53 (d, J=11.9 Hz, 1H), 6.39 (d, J=1.8 Hz,
1H), 3.86-4.02 (m, 1H), 3.73 (s, 3H), 3.17-3.30 (m, 1H), 2.53-2.75
(m, 4H). m/z (ESI) 556.0 (M+H).sup.+.
Example 41:
(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-N-(I-
soxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00104## ##STR00105## ##STR00106##
[0511] Step 1: (P)-Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline--
6-Sulfonate and (M)-Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline--
6-Sulfonate
[0512] rac-Perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (see Intermediate AB) (257 g, 420 mmol) was purified by
SFC via an Regis Whelk-O s,s, 5.times.15 cm, 5 .mu.m column; a
mobile phase of 40% isopropanol/dichloromethane (1:1 mix) using a
flowrate of 350 mL/min; to generate (P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate as the first eluting peak (123 g, 201 mmol) and
(M)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate as the second eluting peak (137 g, 224 mmol).
Step 2:
(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-N-(Isoxazol-3-Yl-
)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0513] A 3 L three-neck round-bottom flask equipped with
thermocouple, overhead stirrer, addition funnel, and nitrogen inlet
was charged with (P)-perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (175 g, 286 mmol), N-(4-methoxybenzyl)isoxazol-3-amine
(64.2 g, 314 mmol), and 2-methyltetrahydrofuran (953 mL). The
reaction vessel was then purged with nitrogen. The reaction mixture
was cooled to 0.degree. C. The addition funnel was charged with a
30% solution of sodium tert-pentoxide in THF (149 mL, 372 mmol) and
added dropwise to the stirred reaction mixture over 15 mins. After
10 min, an aqueous solution of HCl (2 N, 200 mL) was added to the
reaction mixture at 0.degree. C. The resultant mixture was allowed
to warm to room temperature and the layers were separated. The
aqueous layer was extracted with and EtOAc (2.times.100 mL). The
combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by SFC via a Regis Whelk-O s,s
5.times.15 cm, 5 .mu.m column; a mobile phase of 40%
methanol/dichloromethane (1:1 mix) using a flowrate of 350 mL/min
to afford
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl-
)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (148
g, 234 mmol, 82% yield). m/z (ESI) 632.0/634.0 (M+H)+.
Step 3:
(P)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-(5,8-Dioxaspiro[3.4]Octan-2-Y-
l)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-
-6-Sulfonamide
[0514] An oven-dried 100 mL three-neck round-bottom flask was
charged with zinc dust (10.3 g, 158 mmol) and lithium chloride
solution in THF (0.5 M, 45.0 mL, Sigma Aldrich). The mixture was
stirred at 50.degree. C. under a stream of nitrogen until the
reaction volume was reduced by half 1,2-Dibromoethane (0.74 g, 0.34
mL, 3.95 mmol) was introduced and the reaction mixture was warmed
to 50.degree. C. Once the internal temperature reached 50.degree.
C., the reaction mixture was held at that temperature for 20 min,
then cooled to room temperature. Chlorotrimethylsilane (0.43 g,
0.50 mL, 3.95 mmol) was added and the reaction mixture was warmed
to 50.degree. C. and held for 20 min, then cooled to room
temperature. A solution of iodine (0.40 g, 1.58 mmol) in THF (1.0
mL) was then added and the reaction mixture was warmed to
50.degree. C. and held for 20 min.
2-Bromo-5,8-dioxaspiro[3.4]octane (15.3 g, 15.3 mL, 79.0 mmol,
Enamine, LLC) was added and the reaction mixture stirred at
50.degree. C. for 48 hours. The reaction mixture was then cooled to
room temperature and the residual zinc dust was allowed to settle
before the supernatant solution was removed via syringe and used
without further purification. A separate oven-dried 100 mL
round-bottom flask was charged with palladium (II) acetate (0.36 g,
1.58 mmol), CPhos (1.38 g, 3.16 mmol), and THF (10 mL). A solution
of
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4--
methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (10.0 g,
15.8 mmol) in THF (10 mL) was then introduced and the resultant
mixture was sparged with nitrogen for 10 min. The previously
prepared solution of organozinc complex was then added to the
reaction mixture via syringe and the resultant mixture stirred at
50.degree. C. After 2 h, methanol (5 mL) and silica gel (about 25
g) were added to the reaction mixture and the volatiles were
removed under reduced pressure. The silica-adsorbed material was
purified by flash column chromatography (ISCO CombiFlash, 330 g
Silica Cartridge, eluent: 0-70% ethyl acetate/ethanol (3:1 mix)
gradient in heptane/DCM (9:1 mix)) to afford
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)pheny-
l)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulf-
onamide (9.56 g, 14.4 mmol, 91% yield). m/z (ESI) 666.2 (M+H)+.
Step 4:
(P)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(I-
soxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0515] A 100 mL round-bottom flask was charged with
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)pheny-
l)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulf-
onamide (9.56 g, 14.4 mmol) and THF (20 mL). An aqueous solution of
HCl (6 M, 10 mL) was introduced, and the resultant reaction mixture
was warmed to 40.degree. C. After 2 h, the reaction mixture was
cooled to room temperature before a saturated sodium bicarbonate
solution (100 mL) and DCM (100 mL) were introduced. The layers were
separated and the aqueous layer was extracted with DCM (2.times.50
mL). The combined organic layers were dried over anhydrous
magnesium sulfate, filtered, concentrated under reduced pressure,
and purified by flash column chromatography (ISCO CombiFlash, 330 g
Silica Cartridge, eluent: 0-70% ethyl acetate/ethanol (3:1 mix)
gradient in heptane/DCM (9:1 mix)) to afford
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-
-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(8.56 g, 13.8 mmol, 87% yield). m/z (ESI) 622.0 (M+H)+.
Step 5:
(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-7-Fluo-
ro-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulf-
onamide
[0516] A 250 mL round-bottom flask was charged with
(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-
-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(5.00 g, 8.04 mmol) and DCM (40.2 mL). The reaction mixture was
cooled to 0.degree. C. in an ice-water bath before DAST (25.9 g,
21.3 mL, 161 mmol) was added slowly via syringe. The ice-water bath
was removed and the reaction mixture was allowed to warm to room
temperature. After 2 h, the reaction mixture was carefully
transferred into a mixture of a saturated aqueous solution of
sodium bicarbonate and ice (about 300 mL, 1:1). The layers were
separated and the aqueous layer was extracted with DCM. The
combined organic layers were washed with brine, dried over
anhydrous magnesium sulfate, filtered, concentrated under reduced
pressure, and purified by flash column chromatography (ISCO
CombiFlash, 100 g Silica Cartridge, eluent: 0-70% ethyl
acetate/ethanol (3:1 mix) gradient in heptane/DCM (9:1 mix) to
afford
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(i-
soxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(4.32 g, 6.71 mmol, 83% yield). m/z (ESI) 644.0 (M+H)+.
Step 6:
(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-7-Fluo-
ro-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0517] A 250 mL round-bottom flask was charged with
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(i-
soxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(9.90 g, 15.4 mmol), triethylsilane (8.94 g, 8.94 mL, 77.0 mmol),
and 1,1,1-trifluoroacetic acid (52.3 g, 35.1 mL, 459 mmol). The
reaction mixture was warmed to 40.degree. C. After 6 hours, the
reaction mixture was concentrated under reduced pressure and
carefully poured into a saturated aqueous solution of sodium
bicarbonate. The mixture was extracted with EtOAc (3.times.) and
the combined organic layers were washed with brine, dried over
anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The product was azeotroped with heptane
(3.times.70 mL) and purified by flash column chromatography
(BIOTAGE.RTM., 100 g Silica Cartridge, eluant: 0-50% EtOAc/heptane)
to afford
(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluo-
ro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (6.85
g, 13.1 mmol, 85% yield). .sup.1H NMR (DMSO-d.sub.6, 500 MHz)
.delta.: 11.8-12.1 (m, 1H), 8.70 (d, 1H, J=1.7 Hz), 8.44 (d, 1H,
J=7.7 Hz), 8.22 (d, 1H, J=9.6 Hz), 7.33 (d, 1H, J=10.0 Hz), 7.24
(d, 1H, J=6.9 Hz), 6.74 (d, 1H, J=9.7 Hz), 6.51 (s, 1H), 6.54 (s,
1H), 6.37 (d, 1H, J=1.7 Hz), 3.72 (s, 3H), 3.62 (br t, 1H, J=8.8
Hz), 2.9-3.1 (m, 4H). m/z (ESI) 524.0 (M+H)+.
Example 42:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl-
)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00107##
[0518] Step 1:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl-
)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydro
Quinoline-6-Sulfonamide
[0519] An oven-dried 40-mL vial was charged with
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (32.9 mg, 0.075 mmol) and palladium(II)
acetate (8.47 mg, 0.038 mmol) and
1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl-
)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (464 mg, 0.755 mmol).
The reaction mixture was sparged with nitrogen for 15 min, and then
(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide
solution (272 mg, 0.83 mmol) was added after filtering through a
0.45 micron PTFE filter. The reactions were stirred at 50.degree.
C. After 2 hours, the reaction mixture was quenched with saturated
aqueous sodium bicarbonate and partitioned between water and ethyl
acetate; the organic layer was dried over sodium sulfate and
concentrated. The initial product was purified via column
chromatography (elution with 0-40% ethyl acetate in heptane with
10% dichloromethane) to provide
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline--
6-sulfonamide (128 mg, 0.191 mmol, 25% yield) as a brown foam. m/z
(ESI, positive ion) 670.0 (M+H).sup.+.
Step 2:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pent-
an-1-Yl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0520]
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]penta-
n-1-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquin-
oline-6-sulfonamide (190 mg, 0.284 mmol) was dissolved in TFA (1.2
mL) and stirred at 40.degree. C. After completion, the reaction was
concentrated, and subjected to reverse phase purification, eluted
with 35 to 80% acetonitrile in water (with 0.1% formic acid) to
provide
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(112 mg, 0.204 mmol, 72% yield) as a white solid after
lyophilization. .sup.1H NMR (500 MHz, CHLOROFORM-d,) 6 ppm 8.28 (d,
J=1.7 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.80 (d, J=9.6 Hz, 1H), 7.76
(dd, J=2.2, 9.0 Hz, 1H), 7.72 (s, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.87
(d, J=9.7 Hz, 1H), 6.8-6.8 (m, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.62
(d, J=1.8 Hz, 1H), 3.73 (s, 3H), 2.43 (s, 6H). m/z (ESI, positive
ion) 550.0 (M+H)+.
Example 43:
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00108##
[0521] Step 1:
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(4-Methoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonami-
de
[0522] A vial was charged with
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2--
yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.494 g, 0.804 mmol),
palladium(ii) acetate (0.023 g, 0.102 mmol), and
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.076 g,
0.173 mmol). The resulting mixture was sealed via septum cap and
sparged with nitrogen for 10 minutes prior to the addition of
tetrahydrofuran (3.09 mL).
trans-(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (9.46 mL,
1.182 mmol) solution was then dropwise via syringe. After complete
addition, the reaction was warmed to 50.degree. C. and stirred at
this temperature for 1.25 hours. After cooling to ambient
temperature, the reaction was quenched with 5 M aqueous ammonium
chloride solution. The mixture was extracted with ethyl acetate
(2X). After removal of solvent, the residue was purified by flash
column chromatography (elution 0-50% 3:1 ethyl acetate:ethanol in
heptane with 10% dichloromethane additive) to afford
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobuty-
l)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-
-sulfonamide (0.384 g, 0.584 mmol, 73% yield). m/z (ESI, positive
ion) 658.0 (M+H)+.
Step 2:
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)P-
henyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0523]
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de (0.384 g, 0.584 mmol) was dissolved in 1,1,1-trifluoroacetic
acid (1.348 g, 1.348 mL, 11.82 mmol) and stirred under a nitrogen
atmosphere at 40.degree. C. for 2.5 hours. After cooling to ambient
temperature, excess TFA was removed under vacuum and the resulting
solid was triturated with diethyl ether and filtered. The initial
product was purified by column chromatography (gradient elution of
0-100% EtOAc in heptane with 10% dichloromethane as additive) to
afford
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxa-
zol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (70.8 mg, 0.132
mmol, 23% yield). .sup.1H NMR (500 MHz, DMSO-d6) .delta. ppm 12.13
(br s, 1H), 8.31 (d, J=2.21 Hz, 1H), 8.17 (d, J=9.60 Hz, 1H), 7.84
(dd, J=8.89 Hz, 2.14 Hz, 1H), 7.59 (d, J=1.56 Hz, 1H), 7.34-7.25
(m, 3H), 6.75 (d, J=9.32 Hz, 1H), 6.70 (d, J=8.76 Hz, 1H), 3.95
(quin, J=8.99 Hz, 1H), 3.72 (s, 3H), 3.29-3.21 (m, 1H), 2.75-2.56
(m, 4H). m/z (ESI, positive ion) 538.0 (M+H)+.
Examples 44 & 45:
1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-
-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide and
1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-
-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00109## ##STR00110##
[0524] Step 1:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N--
(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0525] A vial was charged with
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.850 g, 1.383
mmol), diacetoxypalladium (0.040 g, 0.180 mmol), and
2'-(dicyclohexylphosphaneyl)-N2,N2,N6,N6-tetramethyl-[1,1'-biphenyl]-2,6--
diamine (0.133 g, 0.304 mmol). The resulting mixture was sealed via
septum cap and sparged with nitrogen for 10 minutes prior to the
addition of tetrahydrofuran (6.92 mL).
(5,8-dioxaspiro[3.4]octan-2-yl)zinc(II) bromide solution (1.660
mmol) was then added dropwise via syringe. After complete addition,
the reaction was warmed to 50.degree. C. and stirred for 1.25
hours. After cooling to ambient temperature, the reaction was
quenched with 5 M aqueous ammonium chloride solution and the
product extracted with ethyl acetate (2.times.). The combined
organic phases were dried over MgSO.sub.4, filtered and
concentrated. The residue was purified by flash column
chromatography (elution 0-50% 3:1 ethyl acetate:ethanol in heptane
with 10% dichloromethane as additive) to afford
(P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-
-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfon-
amide (0.896 g, 1.383 mmol, 100% yield). m/z (ESI, positive ion)
648.0 (M+H)+.
[0526]
(P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)--
N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
mide (0.896 g, 1.383 mmol) was dissolved in THF (13.8 ml). Hydrogen
chloride (1 N in water) (6.92 mL, 6.92 mmol) was added and the
reaction was stirred at 50.degree. C. overnight. The reaction was
diluted with ethyl acetate and washed with water. The aqueous layer
was extracted with ethyl acetate, and the combined organic layers
were washed with brine, dried with MgSO.sub.4, filtered, and
concentrated. The
(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.835
g, 1.383 mmol, 100% yield) thus obtained was used as such in the
next step. m/z (ESI, positive ion) 604.0 (M+H)+.
Step 2:
(P)-1-(5-Fluoro-4-(3-Hydroxycyclobutyl)-2-Methoxyphenyl)-N-(Isoxaz-
ol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0527] A vial was charged with
(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.835
g, 1.383 mmol) in methanol (6.92 mL) and THF (6.92 mL) at 0.degree.
C. was added portionwise sodium tetra hydroborate (0.052 g, 1.383
mmol). The reaction mixture was stirred 15 minutes a 0.degree. C.
and then 30 minutes at RT. The reaction mixture was quenched with
water and extracted with DCM (3.times.). The combined organic
phases were concentrated in vacuo. The initial product was purified
by column chromatography (gradient elution 0-40% EtOAc/EtOH (3/1)
in heptanes with 10% dichloromethane as additive) to afford
(P)-1-(5-fluoro-4-(3-hydroxycyclobutyl)-2-methoxyphenyl)-N-(iso-
xazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.454 g, 0.749 mmol, 54% yield). m/z (ESI, positive ion) 606.0
(M+H)+.
Step 3:
Cis-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethoxy)Cyclobutyl)Ph-
enyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-S-
ulfonamide and
Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-
-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfon-
amide
[0528] A vial was charged with silver trifluoromethanesulfonate
(0.513 g, 1.996 mmol), selectfluor (0.354 g, 0.998 mmol), potassium
fluoride (0.155 g, 2.66 mmol) and
(P)-1-(5-fluoro-4-(3-hydroxycyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl-
)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.4029 g, 0.665 mmol) in a nitrogen-filled glovebox. Then
anhydrous ethyl acetate (3.33 mL), 2-fluoropyridine (0.194 g, 0.172
mL, 1.996 mmol) and trimethyl(trifluoromethyl)silane (0.284 g,
0.295 mL, 1.996 mmol) were added successively under nitrogen
atmosphere. The reaction mixture was stirred at room temperature
for 18 hours. The reaction mixture was filtered through a plug of
silica (eluted with ethyl acetate). The filtrate was concentrated,
and the product was purified by column chromatography (gradient
elution 0-40% EtOAc-EtOH (3/1) in heptanes with 10% dichloromethane
as additive) to give
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(is-
oxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(358 mg, 0.531 mmol, 80% yield). m/z (ESI, positive ion) 674.0
(M+H)+.
[0529] The two isomers were separated by SFC via two Chiralpak
AD-H, 5 .mu.m columns (3.times.25 cm+3.times.15 cm) with a mobile
phase of 25% ethanol using a flowrate of 80 mL/min. Peak 1 was
assigned as
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-
-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonam-
ide (28.8 mg) and peak 2 was assigned as
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-
-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfon-
amide (228.4 mg).
Step 4:
1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Ph-
enyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
and
1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-
-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0530]
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)
phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline--
6-sulfonamide (0.0288 g, 0.043 mmol), triethylsilane (0.044 g,
0.061 mL, 0.375 mmol), and trifluoracetic acid (0.370 g, 0.242 mL,
3.25 mmol) were combined under nitrogen. The reaction mixture was
stirred at 50.degree. C. for 5 hours. The mixture was cooled,
diluted with heptane and evaporated to dryness under reduced
pressure. The product was then purified by flash chromatography
(gradient elution 0-40% ethyl acetate/EtOH (3:1) in heptane with
10% dichloromethane as additive) to afford
cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)ph-
enyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(13.3 mg, 0.024 mmol, 56% yield). .sup.1H NMR (500 MHz, DMSO-d6)
.delta. ppm 11.62 (s, 1H), 8.71 (s, 1H), 8.34 (d, J=2.08 Hz, 1H),
8.20 (d, J=9.60 Hz, 1H), 7.83 (dd, J=8.95, 2.21 Hz, 1H), 7.32-7.27
(m, 2H), 6.78 (d, J=9.38 Hz, 2H), 6.43 (d, J=1.43 Hz, 1H), 5.11 (t,
J=5.77 Hz, 1H), 4.00-3.92 (m, 1H), 3.71 (s, 3H), 2.83-2.71 (m, 4H),
2.55-2.52 (m, 1H). m/z (ESI, positive ion) 554.0 (M+H)+.
[0531]
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)
phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline--
6-sulfonamide (0.2284 g, 0.339 mmol), triethylsilane (0.346 g,
0.481 mL, 2.98 mmol), and trifluoracetic acid (2.94 g, 1.920 mL,
25.8 mmol) were combined under nitrogen. The reaction mixture was
stirred at 50.degree. C. for 5 hours. The mixture was cooled,
diluted with heptane and evaporated to dryness under reduced
pressure. The product was then purified by flash chromatography
(gradient elution 0-40% ethyl acetate/EtOH (3:1) in heptane with
10% dichloromethane as additive) to afford
trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)-
phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.1623 g, 0.293 mmol, 86% yield). .sup.1H NMR (500 MHz, DMSO-d6)
.delta. ppm 11.62 (s, 1H), 8.72 (d, J=1.82 Hz, 1H), 8.35 (d, J=2.21
Hz, 1H), 8.20 (d, J=9.60 Hz, 1H), 7.83 (dd, J=9.02, 2.27 Hz, 1H),
7.30 (d, J=9.99 Hz, 1H), 7.23 (d, J=6.62 Hz, 1H), 6.78 (d, J=9.47
Hz, 2H), 6.44 (d, J=1.82 Hz, 1H), 4.92 (quin, J=7.40 Hz, 1H), 3.38
(tt, J=10.46, 7.51 Hz, 1H), 3.32-3.25 (m, 3H), 2.84 (dquin,
J=12.05, 6.07, 6.07, 6.07, 6.07 Hz, 2H), 2.55-2.52 (m, 1H),
2.47-2.41 (m, 1H). m/z (ESI, positive ion) 554.0 (M+H)+.
Example 46:
Trans-(P)-5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl-
)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00111## ##STR00112## ##STR00113##
[0532] Step 1: 4-Bromo-3-Fluoro-2-Iodoaniline
[0533] To a solution of 2-iodo-3-fluoroaniline hydrogen chloride
(6.45 g, 23.59 mmol) and N,N'-diisopropylethylamine (3.05 g, 4.11
mL, 23.59 mmol) in N, N-dimethylformamide (59.0 mL) was added
N-bromosuccinimide (4.20 g, 23.59 mmol). After 20 minutes, the
reaction was quenched with water. The mixture was extracted with
ethyl acetate. The organic layer was separated, dried over
magnesium sulfate, filtered and concentrated under reduced pressure
to obtain the initial product which was purified by column
chromatography (BIOTAGE.RTM. ISOLERA ONE, BIOTAGE SFAR SILICA 50 g,
0-30% ethyl acetate in heptane) to afford
4-bromo-3-fluoro-2-iodoaniline (6.8 g, 21.52 mmol, 91% yield) as a
tan, almost copper-colored solid. m/z (ESI, positive ion) 315.8
(M+H)+.
[0534] Step 2: Ethyl
(E)-3-(6-Amino-3-Bromo-2-Fluorophenyl)Acrylate
[0535] A 100 mL flask was charged with sodium hydrogen carbonate
(4.19 g, 49.9 mmol), ethyl acrylate (2.096 g, 2.355 mL, 20.94
mmol), and palladium (ii) acetate (0.090 g, 0.399 mmol). A solution
of 4-bromo-3-fluoro-2-iodoaniline (6.3 g, 19.94 mmol) in N,
N-dimethylformamide (13.29 mL) was added to the reaction mixture.
The reaction was stirred at 100.degree. C. under nitrogen for 3
hours. The reaction was diluted with ethyl acetate and filtered
through CELITE. The filtrate was concentrated under reduced
pressure to obtain the initial product which was purified by column
chromatography to give ethyl
(E)-3-(6-amino-3-bromo-2-fluorophenyl)acrylate (5.92 g, 20.55 mmol,
103% yield). .sup.1H NMR (400 MHz, DMSO-d6) .delta. ppm 7.50-7.68
(m, 1H), 7.29 (t, J=8.3 Hz, 1H), 6.34-6.60 (m, 2H), 6.07 (s, 1H),
3.98-4.24 (m, 2H), 3.35 (br s, 1H), 1.08-1.36 (m, 3H).
[0536] Step 3: Ethyl
(E)-3-(6-Amino-3-(Benzylthio)-2-Fluorophenyl)Acrylate
[0537] A 250 mL round-bottom flask was charged with ethyl
(E)-3-(6-amino-3-bromo-2-fluorophenyl)acrylate (4.0 g, 13.88 mmol),
1,4-dioxane (34.7 mL) and 1,1'-dimethyltriethylamine (3.59 g, 4.85
mL, 27.8 mmol). The flask was sealed and sparged with nitrogen for
20 minutes. In a separate 20 mL vial,
bis[tris(dibenzylideneacetone)palladium(0)](0.890 g, 0.972 mmol)
and
(5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane
(1.125 g, 1.944 mmol) were added. The vial was sparged with
nitrogen for 5 minutes prior to the addition of 1,4-dioxane (5 mL).
This catalyst solution was transferred via syringe to the
acrylate-containing flask. Then 1-toluenethiol (1.379 g, 1.379 mL,
11.11 mmol) was added in one portion. The mixture was stirred at
80.degree. C. for 16 hours. The reaction was cooled and filtered
over CELITE. The CELITE was washed with ethyl acetate. The solvent
was removed under reduced pressure. The residue was purified by
column chromatography (BIOTAGE.RTM. Isolera One, BIOTAGE.RTM. SNAP
Ultra 100 g, 0-30% ethyl acetate in heptane) to afforded ethyl
(E)-3-(6-amino-3-(benzylthio)-2-fluorophenyl)acrylate (2.78 g, 8.39
mmol, 60% yield) as a yellow orange solid. m/z (ESI, positive ion)
332.2 (M+H)+.
[0538] Step 4: Ethyl
(E)-3-(3-(Benzylthio)-6-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)-2-Fluor-
ophenyl)Acrylate
[0539] A 40 mL vial was charged with ethyl
(E)-3-(6-amino-3-(benzylthio)-2-fluorophenyl)acrylate (0.876 g,
2.64 mmol), 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (1.07 g, 3.23
mmol), and cesium carbonate (2.58 g, 7.93 mmol). Toluene (8.81 mL)
was added to the vial. The mixture was sparged with nitrogen for 20
minutes before tris (dibenzylideneacetone)-dipalladium(0) (0.194 g,
0.194 mL, 0.211 mmol) and
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.245 g, 0.423
mmol) were quickly added. After sparging with nitrogen for an
additional 5 minutes, the reaction was warmed to 110.degree. C.
After stirring for 16 hours, the reaction was cooled to ambient
temperature, diluted with dichloromethane, and filtered over
CELITE. Solvent was removed under reduced pressure. The residue was
purified by column chromatography (BIOTAGE.RTM. ISOLERA ONE,
BIOTAGE SFAR SILICAHC D 25 g, 0-40% ethyl acetate in heptane) to
afforded ethyl
(E)-3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluor-
ophenyl)acrylate (0.600 g, 1.123 mmol, 43% yield) as a yellow
solid. m/z (ESI, positive ion) 535.8 (M+H)+.
Step 5:
6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-5-Fluoroquinol-
in-2(1H)-One
[0540] Ethyl
(E)-3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluor-
ophenyl)acrylate (1.44 g, 2.69 mmol) was dissolved in methanol (33
mL). Sodium methoxide, 25 wt % solution in methanol (0.582 g, 0.616
mL, 2.69 mmol) was added at ambient temperature. The reaction was
warmed to 60.degree. C. and stirred at this temperature for 2
hours. The reaction was cooled to ambient temperature and quenched
by the addition of water. The product was extracted with ethyl
acetate (2.times.). The organic layer was separated and solvent was
removed in vacuo. The residue was purified by column chromatography
(BIOTAGE.RTM. Isolera One, BIOTAGE.RTM. Sfar Silica HC D 50 g,
0-40% Ethyl acetate in heptane with 10% dichloromethane as
additive) to provided
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H-
)-one (0.717 g, 1.468 mmol, 55% yield) as an off white solid. m/z
(ESI, positive ion) 490.0 (M+H)+.
Step 6 & 7: Perfluorophenyl
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-5-Fluoro-2-Oxo-1,2-Dihydroquinoline--
6-Sulfonate
[0541] A 40 mL vial was charged with
6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H-
)-one (0.710 g, 1.454 mmol), acetonitrile (7.04 mL), acetic acid
(0.134 mL), and water (0.095 mL). The reaction was cooled to
0.degree. C. by means of an ice bath before
1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (0.430 g, 2.181
mmol) was added in one portion. After 10 minutes, pentafluorophenol
(0.321 g, 1.745 mmol) and then triethylamine, anhydrous (0.588 g,
0.817 mL, 5.82 mmol) were added. After 1 hour the reaction was
quenched with 2 M aqueous HCl and was extracted with ethyl acetate.
The organic layer was separated and solvent was removed in vacuo.
The residue was purified by column chromatography (BIOTAGE.RTM.
Isolera One, BIOTAGE.RTM. Sfar 25 g silica HC D, 0-40% ethyl
acetate in heptane with 10% dichloromethane as additive) to provide
perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (0.676 g, 1.104 mmol, 76% yield) as a white solid. m/z
(ESI, positive ion) 614.0 (M+H)+.
Steps 8:
1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-5-Fluoro-N-(Isoxazol-3-Yl)-N-
-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0542] A 40 mL vial was charged with perfluorophenyl
1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline--
6-sulfonate (0.676 g, 1.104 mmol) and
N-(4-methoxybenzyl)isoxazol-3-amine (0.271 g, 1.325 mmol). The vial
was purged with nitrogen for 5 minutes prior to the addition of
tetrahydrofuran (2.208 mL). The reaction was then cooled to
-78.degree. C. and sodium tert-pentoxide, 30% solution in thf
(0.574 mL, 1.435 mmol) was slowly added. After 10 minutes the
reaction was warmed to 0.degree. C. prior to quenching the reaction
with 5 M aqueous ammonium chloride solution. The mixture was
extracted with ethyl acetate. The organic layer was separated and
solvent was removed under reduce pressure. The residue was purified
by column chromatography (BIOTAGE.RTM. ISOLERA ONE, BIOTAGE SFAR
SILICA 25 g, 0-50% ethyl acetate in heptane with 10%
dichloromethane as additive) to provides
1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-N-(isoxazol-3-yl)-N-(4-meth-
oxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.302 g, 0.478
mmol, 43% yield) as a white solid. m/z (ESI, positive ion) 634.0
(M+H)+.
Step 9:
5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Ph-
enyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-S-
ulfonamide
[0543] A 40 mL vial was charged with
1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-N-(isoxazol-3-yl)-N-(4-meth-
oxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.320 g, 0.506
mmol), palladium(ii) acetate (0.011 g, 0.051 mmol), and
2'-(dicyclohexylphosphino)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl-[1-
,1'-biphenyl]-2,6-diamine (0.044 g, 0.101 mmol). The vial was
sealed and sparged with nitrogen for 5 minutes. Tetrahydrofuran
(2.53 mL) was then added, followed by the addition of
(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (1.381 mmol). The
reaction was then stirred at 50.degree. C. for 1.5 hours. The
reaction was cooled to ambient temperature, quenched with 5M
aqueous ammonium chloride solution, and extracted with ethyl
acetate. The organic layer was separated and solvent was removed
under reduced pressure. The residue was purified by column
chromatography (BIOTAGE.RTM. ISOLERA ONE, BIOTAGE SFAR SILICAHC D
10 g, 0-40% ethyl acetate in heptane with 10% dichloromethane as
additive) to affords
5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-
-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonam-
ide (0.208 g, 0.308 mmol, 61% yield) as a light pink solid. m/z
(ESI, positive ion) 676.2 (M+H)+.
Step 10:
5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)P-
henyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0544] A 40 mL vial was charged with
5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-
-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonam-
ide (0.208 g, 0.308 mmol), triethylsilane (0.179 g, 0.249 mL, 1.539
mmol) and 1,1,1-trifluoroacetic acid (2.282 g, 2.282 mL, 20.01
mmol). The mixture was stirred at 40.degree. C. for 2 hours.
Solvent was removed in vacuo. The mixture was purified by column
chromatography (BIOTAGE.RTM. ISOLERA ONE, BIOTAGE SFAR SILICA HC D
10 g, 0-100% ethyl acetate in heptane with 10% dichloromethane as
additive) to afforded
5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-
-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.153 g,
0.275 mmol, 89% yield) as an off white solid. m/z (ESI, positive
ion) 556.2 (M+H)+.
Step 11:
Trans-(P)-5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(TRIFLUOROMETHYL)CY-
CLOBUTYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamid-
e
[0545]
5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phe-
nyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.153 g, 0.275 mmol) was purified by SFC via 2 steps. Step 1: a
Regis Whelk-O s,s 2.times.15 cm, 5 .mu.m column; a mobile phase of
35% methanol using a flowrate of 60 mL/min; Step 2: (separation of
Peak1 & Peak2): two Chiralpak AD-H, 5 .mu.m columns(3.times.15
cm+3.times.25 cm); a mobile phase of 30% ethanol using a flowrate
of 80 mL/min. Peak 1 was lyophilized to yield
trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl-
)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.0305 g, 0.055 mmol, 18% yield) as a white solid. .sup.1H NMR
(500 MHz, DMSO-d6) .delta. ppm 12.01 (br s, 1H), 8.72 (d, J=1.8 Hz,
1H), 8.18 (d, J=9.9 Hz, 1H), 7.87 (t, J=8.1 Hz, 1H), 7.34 (s, 1H),
7.33 (d, J=3.4 Hz, 1H), 6.83 (d, J=9.9 Hz, 1H), 6.59 (d, J=9.2 Hz,
1H), 6.37 (d, J=1.8 Hz, 1H), 3.95 (t, J=9.0 Hz, 1H), 3.73 (s, 3H),
3.22-3.28 (m, 1H), 2.55-2.72 (m, 4H). m/z (ESI, positive ion) 556.2
(M+H)+.
Example 47:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl-
)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00114##
[0546] Step 1:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl-
)Phenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-
-6-Sulfonamide
[0547] An oven-dried 40 mL vial was charged with
2'-(dicyclohexylphosphaneyl)-N.sup.2,N.sup.2,N.sup.6,N.sup.6-tetramethyl--
[1,1'-biphenyl]-2,6-diamine (0.046 g, 0.106 mmol), palladium(II)
acetate (0.012 g, 0.053 mmol) and
(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyr-
imidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (0.663 g, 1.060
mmol). The reaction mixture was sparged with nitrogen for 15
minutes, and then
(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide
solution (1.59 mmol) was added after filtering through a 0.45
micron PTFE filter. The reactions were stirred at 50.degree. C. for
3 hours. The reaction mixture was quenched with saturated aqueous
sodium bicarbonate and partitioned between water and ethyl acetate.
The organic layer was dried over sodium sulfate and concentrated.
The initial product was purified by column chromatography (gradient
elution 0-60% ethyl acetate in heptane with 10% dichloromethane as
additive) to afford
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-
-6-sulfonamide (0.241 g, 0.354 mmol, 33% yield) as a light grey
foam. m/z (ESI, positive ion) 681.1 (M+H).sup.+.
STEP 2:
(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pent-
an-1-Yl)Phenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamid-
e
[0548]
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]penta-
n-1-yl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroqui-
noline-6-sulfonamide (241 mg, 0.354 mmol) was dissolved in
trifluoroacetic acid (3.63 g, 2.44 mL, 31.9 mmol) in a 20 mL vial
and the reaction was heated to 40.degree. C. and stirred for 2
hours. The reaction was cooled to RT. The reaction was made basic
using saturated NaHCO.sub.3 solution, extracted with
dichloromethane. The combined organic layer was dried over sodium
sulfate and concentrated. The initial product was subjected to
reverse phase purification (gradient elution 25 to 70% acetonitrile
in water with 0.1% formic acid to afford
(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl-
)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide
(103 mg, 0.184 mmol, 52% yield) as a white solid after
lyophilization. .sup.1H NMR (CHLOROFORM-d, 500 MHz) .delta. ppm
10.27 (br s, 1H), 8.60 (d, J=4.9 Hz, 2H), 8.43 (d, J=2.1 Hz, 1H),
8.07 (dd, J=2.1, 9.0 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.00 (t,
J=4.9 Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H), 6.83
(d, J=6.4 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 3.72 (s, 3H), 2.42 (s,
6H). m/z (ESI, positive ion) 561.0 (M+H)+.
Example 48:
(P)-1-(5-Chloro-4-(3,3-Difluorocyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-
-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00115## ##STR00116##
[0549] Step 1:
(P)-1-(5-Chloro-2-Methoxy-4-(5,8-Dioxaspiro[3.4]Octan-2-Yl)Phenyl)-N-(Iso-
xazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0550] A vial was charged with
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybe-
nzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.500 g, 0.793
mmol), tetrahydrofuran (1.585 mL), palladium(II) acetate (0.018 g,
0.079 mmol), and
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.069 g,
0.159 mmol). 5,8-The vial was purged with nitrogen before
dioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.1 M in THF, 1.110
mmol) was added and the reaction was stirred at 50.degree. C. for 1
hour. The reaction was then diluted with ethyl acetate and
acidified with 1 N hydrochloric acid. The organic layer was
separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were washed with brine, dried with
sodium sulfate, filtered, and concentrated. The material was
purified via column chromatography (gradient elution 0-100%
EtOAc:heptane) to afford
(P)-1-(5-chloro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(iso-
xazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.420 g, 0.632 mmol, 80% yield). m/z (ESI, positive ion) 664.0
(M+H).sup.+.
Step 2:
(P)-1-(5-Chloro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-
-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0551]
(P)-1-(5-chloro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)--
N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfona-
mide (0.420 g, 0.632 mmol) was dissolved in dichloromethane (2 mL).
Hydrochloric acid (2 N in water, 2.0 mL, 4.0 mmol) was added and
the reaction was stirred at 50.degree. C. for three days. The
reaction was then diluted with dichloromethane and washed with
water. The aqueous layer was extracted with dichloromethane. The
combined organic layers were washed with brine, dried with sodium
sulfate, filtered, and concentrated. The resulting
(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.330
g, 0.532 mmol, 67% yield) was used in the next step without further
purification. m/z (ESI, positive ion) 620.0 (M+H).sup.+.
Step 3:
(P)-1-(5-Chloro-4-(3,3-Difluorocyclobutyl)-2-Methoxyphenyl)-N-(Iso-
xazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0552] A vial was charged with
(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N--
(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.330
g, 0.532 mmol), dichloromethane (1.064 mL), and diethylaminosulfur
trifluoride (2.145 g, 1.758 mL, 13.30 mmol). The reaction was
stirred for 3 hours at room temperature. The reaction was then
poured into a round-bottom flask, diluted with dichloromethane, and
saturated aqueous sodium bicarbonate solution was carefully added
until bubbling ceased. The layers were separated, and the aqueous
layer was extracted with dichloromethane. The combined organic
layers were washed with brine, dried with sodium sulfate, filtered,
and concentrated. The material was purified via column
chromatography (gradient elution 0-50% EtOAc:heptane) to afford
(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(is
oxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.350 g, 0.545 mmol, 102% yield).
Step 4:
(P)-1-(5-Chloro-4-(3,3-Difluorocyclobutyl)-2-Methoxyphenyl)-N-(Iso-
xazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0553]
(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isox-
azol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide
(0.350 g, 0.545 mmol) was dissolved in TFA (1 mL) and
dichloromethane (1 mL). The solution was heated to 40.degree. C.
and stirred overnight. Solvents were removed in vacuo and the
residue was washed with aqueous solution of NaHCO.sub.3. The
mixture was extracted with dichloromethane, dried over MgSO.sub.4
and filtered. The initial product was purified via flash column
chromatography (gradient elution 0-50% EtOAc in heptane). The
sample was re-purified by SFC via a Regis Whelk-O s,s 2.times.15
cm, 5 .mu.m column with a mobile phase of 40% methanol using a
flowrate of 70 mL/min to afford
(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-
-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.173 g, 0.331 mmol,
62% yield). .sup.1H NMR (600 MHz, DMSO-d6) .delta. ppm 11.63 (br s,
1H), 8.71 (d, J=1.63 Hz, 1H), 8.35 (d, J=2.18 Hz, 1H), 8.20 (d,
J=9.63 Hz, 1H), 7.83 (dd, J=8.99, 2.27 Hz, 1H), 7.54 (s, 1H), 7.30
(s, 1H), 6.78 (dd, J=9.35, 5.36 Hz, 2H), 6.44 (d, J=1.82 Hz, 1H),
3.74 (s, 3H), 3.67 (quin, J=8.67 Hz, 1H), 3.09 (dtt, J=18.20, 9.04,
9.04, 4.38, 4.38 Hz, 2H), 3.02-2.89 (m, 2H). m/z (ESI, positive
ion) 521.8 (M+H).sup.+.
Example 49:
Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
##STR00117##
[0554] Step 1:
Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)--
N-(4-Methoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonami-
de
[0555] A vial was charged with
(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2--
yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.508 g, 0.804 mmol),
palladium(ii) acetate (0.023 g, 0.102 mmol), and
2-dicyclohexylphosphino-2',6'-dimethylamino-1,1'-biphenyl (0.076 g,
0.173 mmol). The resulting mixture was sealed via septum cap and
sparged with nitrogen for 10 minutes prior to the addition of
tetrahydrofuran (3.09 mL). (3-(trifluoromethyl)cyclobutyl)zinc(II)
bromide (1.182 mmol) solution. After complete addition, the
reaction was warmed to 50.degree. C. and stirred at this
temperature for 1.25 hours. After cooling to ambient temperature,
the reaction was quenched with 5 M aqueous ammonium chloride
solution. The mixture was extracted with ethyl acetate (2.times.).
The organic layer was separated. After removal of solvent, the
residue was purified by flash column chromatography (gradient
elution 0-50% 3:1 ethyl acetate:ethanol in heptane with 10%
dichloromethane as additive) to afford
trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de (0.368 g, 0.546 mmol, 68% yield). m/z (ESI, positive ion) 673.6
(M+H)+.
Step 2:
Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)P-
henyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide
[0556]
(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)--
N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonami-
de (0.368 g, 0.546 mmol) was dissolved in 1,1,1-trifluoroacetic
acid (1.348 g, 1.348 mL, 11.82 mmol). The reaction was stirred
under a nitrogen atmosphere at 40.degree. C. for 2.5 hours. After
cooling to ambient temperature, excess TFA was removed in vacuo and
the resulting solid was triturated with diethyl ether and filtered.
The initial product was purified by column chromatography (gradient
elution 0-100% in heptanes with 10% dichloromethane as additive to
afford trans
(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl-
)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (49.6
mg, 0.092 mmol, 17% yield). .sup.1H NMR (500 MHz, DMSO-d6) .delta.
ppm 12.13 (br s, 1H), 8.31 (d, J=2.08 Hz, 1H), 8.17 (d, J=9.60 Hz,
1H), 7.84 (dd, J=8.95, 2.21 Hz, 1H), 7.59 (d, J=1.56 Hz, 1H), 7.49
(s, 1H), 7.38 (s, 1H), 7.25 (d, J=1.43 Hz, 1H), 6.75 (d, J=9.60 Hz,
1H), 6.69 (d, J=8.95 Hz, 1H), 4.00 (quin, J=8.99 Hz, 1H), 3.77 (s,
3H), 3.27-3.20 (m, 1H), 2.75-2.60 (m, 4H). m/z (ESI, positive ion)
554.0 (M+H)+.
BIOLOGICAL EXAMPLES
[0557] The following assays were used in testing the exemplary
compounds of the invention. Data for those examples tested in
accordance with the procedures described below are presented in
Table 1 below.
Ionaworks Barracuda (DNB) Automated Patch Clamp Assay (Same
Protocol for Both Human and Mouse)
[0558] Human Nav1.7 currents were recorded in population
patch-clamp mode with the IWB automated electrophysiology system
(Molecular Devices, LLC, Sunnyvale, Calif.). Spiking HEK cells
(without Kir2.1 transfection) were cultured and prepared for
recordings as previously described for IonWorks Quattro
testing.sup.1. The external solution consisted of the following (in
mM): NaCl 140, KCl 5, CaCl.sub.2 2, MgCl.sub.2 1, HEPES 10, and
glucose 11, pH 7.4, with N-methyl-D-glucamine at 320 mOsmol. The
internal solution consisted of the following (in mM): KCl 70, KF
70, MgCl.sub.2 0.25, HEDTA 5, and HEPES 10, pH 7.25, with
Nmethyl-D-glucamine, 300 mOsmol. From a holding potential of -110
mV, currents were elicited by a train of 26 depolarizations of 150
ms duration to -20 mV at a frequency of 5 Hz. Cells were then
clamped to -20 mV for a period of 4 minutes in the presence of a
single concentration of test compound. Following this compound
incubation period, cells were clamped to -110 mV for three seconds
to recover unbound channels and put through the same 26 pulse
voltage protocol as above. Peak inward current during the 26th
pulse to -20 mV in the presence of compound was divided by the peak
inward current evoked by the 26th pulse to -20 mV in the absence of
compound to determine percent inhibition. Concentration-response
curves of percent inhibition as a function of concentration were
generated to calculate IC.sub.50 values as described in Kornecook,
T. J.; Yin, R.; Altmann, S.; et al. Pharmacologic Characterization
of AMG8379, a Potent and Selective Small Molecule Sulfonamide
Antagonist of the Voltage-Gated Sodium Channel NaV1. 7. J.
Pharmacol. Exp. Ther. 2017, 362, 146-160.
[0559] Microsomal Intrinsic Clearance Assay
[0560] The purpose of this assay is to determine the intrinsic
clearance of test compound in microsomes from preclinical species
and human by monitoring the disappearance of test article over time
in hepatic microsomes. 20 mg/mL stock, stored at -80.degree. C.
microsome was used. List of chemical used: (1) Test article, 10 mM
stock (DMSO) or powder from sample bank; (2) Verapamil, 10 mM
stock; (3) NADPH, powder (Sigma); (4) Potassium phosphate buffer,
100 mM, pH 7.4; and (5) Tolbutamide (or equivalent). Final
incubation concentrations were 0.25 mg/mL microsomal protein and
0.5 .mu.M test article, and incubations are performed in
triplicate. The typical time points for the assay were 1, 5, 10,
20, 30, and 40. The assay was carried out in 96-well format, and
serially sampled from 400 .mu.L incubation. At the appropriate
timepoints, the incubations were quenched with acetonitrile
containing internal standard (tolbutamide). Tolbutamide was the
default internal standard because it has a signal by positive or
negative ion mass spectrometry. The positive control for microsomal
intrinsic clearance assay was verapamil. Samples were subjected to
LC-MS/MS analysis, and relative amount of compound was calculated
by peak area of compound normalized to peak area of internal
standard (A/IS). Calculations of intrinsic clearance were performed
with Galileo.
[0561] Procedure:
[0562] Microsomes were removed from -80.degree. C. freezer and
thawed at room temperature or in 37.degree. C. water bath. Once
thawed, they were stored on ice. Microsomes were added (0.53 mg/)
to 0.1 M phosphate buffer and 250 .mu.L aliquot was taken per
reaction. 10 mM stock of test article was prepared in DMSO. A 1/100
portion was diluted into acetonitrile:water 50:50 to make 100 .mu.M
stock. About 2.5 .mu.L of the 100 .mu.M test article stock was
added to each reaction to a final concentration of 1.05 .mu.M
substrate. (NB: At this stage, concentrations were about 2.times.
higher than the final incubation conditions, to account for about
1:1 dilution with NADPH).
[0563] 1.9 mM NADPH solution was prepared in 0.1 mM phosphate
buffer. 4.times.250 .mu.L replicate wells of substrate and the
microsomes containing 1.05 .mu.M substrate and 0.53 mg/mL protein
were the prepared. 3 replicate wells containing 210 .mu.L 1.90 mM
NADPH+1 well of buffer (-NADPH) were also prepared. The microsomes,
0.1 M phosphate buffer, and the test article were preincubated for
5 minutes at 37.degree. C. To initiate the reaction, 190 .mu.L of
the substrate was added to the wells containing NADPH, to yield a
final concentration of 0.25 mg/mL microsomes, 0.5 .mu.M test
article, and 1 mM NADPH. 35 .mu.L aliquots were removed at 1, 5,
10, 20, 30, and 40 minutes. The reaction was then quenched at a 1:1
ratio with acetonitrile containing internal standard, placed in a
Vortex mixer and centrifuged. The solution was then transferred for
bioanalysis by LC-MS/MS.
[0564] Open-Field Locomotor Activity in Mice.
[0565] On the day of testing, C57B1/6 male mice were orally
administered either Nav1.7 compound or a vehicle control
formulation at a dose volume of 10 ml/kg. The vehicle used was 2%
HPMC/1% Tween 80 pH 10 with NaOH; DI water at pH 10 w/NaOH; or 2%
HPMC/1% Tween 80 pH 2.2.
[0566] Two to three hours following test article treatment,
depending on the cmax of the each Nav1.7 test compound of the
invention, animals were placed into open-field chamber and the
animal behavior was monitored over a 30-minute period. For the
Thousand Oaks Site Experiments, 16''.times.16'' open-field chamber,
KINDER SCIENTIFIC.RTM., San Diego, Calif., was used. For the
Cambridge Mass. Site Experiments, 16''.times.16'' open-field
chamber, SAN DIEGO INSTRUMENTS.RTM., San Diego, Calif., was used.
Locomotor activity (horizontal movement and rearing activity)
parameters were measured in an automated manner via infrared
photo-beam breaks.
[0567] Human CYP 3A4 Induction Assay
[0568] Cryopreserved human hepatocytes were seeded in 96-well
collagen coated plates at 70,000 cells per well in hepatocyte
plating media (HPM, final concentrations: 1.times. Dulbecco's
Modified Eagle's Medium, 0.1 .mu.M dexamethasone, 10% fetal bovine
serum, 1.times.ITS, 1.times.PSG) followed by incubation at
37.degree. C. under 5% CO2 and 90% relative humidity for 2 days to
allow hepatocytes to form a confluent layer. On Day 3, hepatocytes
were treated with either test compound or rifampin (20 .mu.M,
positive control for CYP3A induction) prepared in hepatocyte
incubation media ((HIM, final concentrations: 1.times. William's
Medium E, 0.1 .mu.M dexamethasone, 1.times.ITS, 1.times.PSG).
Treatment was performed for 72 hours with either 2 concentrations
(2 .mu.M or 10 .mu.M) or a range of concentrations (0.001 .mu.M to
100 .mu.M) of the test compound to obtain full dose-response curve.
Fresh media containing the relevant concentrations of the test
compound was replaced every day until the samples were processed.
After 72 hours of incubation, samples were processed for mRNA
analysis using bDNA technology using manufacturer's instructions
(Affymetrix, Fremont, Calif.). Cell viability was tested at the end
of the experiment using MTT assay kit (Roche Diagnostics, Basel,
Switzerland). Data was analyzed and presented as percent of control
(POC) and E.sub.max and EC.sub.50 obtained when appropriate
according to guidance from Center for Drug Evaluation and Research
(CDER), 2006, Guidance for Industry, Drug Interaction Studies Study
Design, Data Analysis, and Implications for Dosing and
Labeling.
[0569] Cryopreserved human hepatocytes were seeded in 96-well
collagen coated plates at 70,000 cells per well in hepatocyte
plating media (HPM, final concentrations: lx Dulbecco's Modified
Eagle's Medium, 0.1 .mu.M dexamethasone, 10% fetal bovine serum, lx
ITS, lx PSG) followed by incubation at 37.degree. C. under 5% CO2
and 90% relative humidity for 2 days to allow hepatocytes to form a
confluent layer. On Day 3, hepatocytes were treated with either
test compound or rifampin (20 .mu.M, positive control for CYP3A
induction) prepared in hepatocyte incubation media ((HIM, final
concentrations: 1.times. William's Medium E, 0.1 .mu.M
dexamethasone, 1.times.ITS, 1.times.PSG). Treatment was performed
for 72 hours with either 2 concentrations (2 .mu.M or 10 .mu.M) or
a range of concentrations (0.001 .mu.M to 100 .mu.M) of the test
compound to obtain full dose-response curve. Fresh media containing
the relevant concentrations of the test compound was replaced every
day until the samples were processed. After 72 hours of incubation,
samples were processed for mRNA analysis using bDNA technology
using manufacturer's instructions (Affymetrix, Fremont, Calif.).
Cell viability was tested at the end of the experiment using MTT
assay kit (Roche Diagnostics, Basel, Switzerland). Data was
analyzed and presented as percent of control (POC) and E.sub.max
and EC.sub.50 obtained when appropriate, as described in Halladay,
J. et al, 2012, An "all-inclusive" 96-well cytochrome P450
induction method: Measuring enzyme activity, mRNA levels, protein
levels, and cytotoxicity from one well using cryopreserved human
hepatocytes, Pharmacological and Toxicological Methods,
66:270-275.
[0570] The compounds of the present invention may also be tested in
the following in vivo assays.
[0571] Rat Formalin Model of Persistent Pain
[0572] On the test day, animals (Naive, male Sprague Dawley rats)
weighing between 260-300 g at the start of testing can be obtained
from Harlan (Indianapolis, Ind.). All animals may be housed under a
12/12 h light/dark cycle with lights on at 0600. Rodents can be
housed two to a cage on solid bottom cages with corn cob bedding
and can have access to food and water ad libitum. Animals should be
allowed to habituate to the vivarium for at least five days before
testing is begun and should be brought into the testing room at
least 30 minutes prior to dosing. Animals are pretreated with the
appropriate test compound either by oral gavage or intraperitoneal
injection at the desired pretreatment time (typically two hours
before test onset) and then returned to their home cages. After
dosing and at least 30 minutes prior to test onset, animals can be
acclimated to the individual testing chambers. At test time, each
animal can be gently wrapped in a towel with the left hind paw
exposed. A dilute solution of formalin (2.5%) in phosphate buffered
saline can be injected subcutaneously into the dorsal surface of
the left hind paw in a volume to 50 .mu.L with a 30 g needle.
Immediately following injection, a small metal band can be affixed
to the plantar side of the left hind paw with a drop of LOCTITE
(adhesive). Animals may be then placed into the testing chambers
and the number of flinches can be recorded between 10 to 40 minutes
after formalin injection. A flinch is defined as a quick and
spontaneous movement of the injected hind paw not associated with
ambulation. Flinches can be quantified with the aid of the
Automated Nociception Analyzer built by the University of
California, San Diego Department of Anesthesiology. Individual data
can be expressed as a % maximal potential effect (% MPE) calculated
with the following formula: (-(Individual score-Vehicle average
score)/Vehicle average score))*100=% MPE
[0573] Statistical analysis can be performed by analysis of
variance (ANOVA), with post-hoc analysis using Bonferroni compared
to the vehicle group for a significant main effect. Data can be
represented as mean % MPE+/-standard error for each group.
[0574] Rat Open Field Assay
[0575] On the test day, animals (Naive, male Sprague Dawley rats)
weighing between 260-300 g at the start of testing may be obtained
from Harlan (Indianapolis, Ind.). All animals can be housed under a
12/12 h light/dark cycle with lights on at 0600. Rodents can be
housed two to a cage on solid bottom cages with corn cob bedding
and can have access to food and water ad libitum. Animals should be
allowed to habituate to the vivarium for at least five days before
testing is begun and should be brought into the testing room at
least 30 minutes prior to dosing. In a room separate from the
testing room, animals can be pretreated with the appropriate test
compound either by oral gavage or intraperitoneal injection at the
desired pretreatment time (typically two hours before test onset)
and then can be returned to their home cages until the pretreatment
has elapsed. At test time, animal can be transferred to the open
field testing room in their home cages. Each animal may be placed
in a separate testing chamber and the motion tracking system is
started. The house lights in the testing room should be turned off
and the animals can be allowed to explore the novel open field for
30 minutes. An automated motion tracker, made by San Diego
Instruments, San Diego, Calif., can be used to capture animal
exploration with the aid of infrared photo beams to detect animal
movement. These behaviors include basic movement and vertical
rearing, which can be used as the primary endpoints for this assay.
At the end of the test, house lights can be turned on and the
animals should be removed from the testing apparatus. Data can be
expressed as a percent change from the vehicle control using the
following equation.
(1-(Test mean/Vehicle mean))*100=% Change.
[0576] Statistical analysis can be performed by analysis of
variance (ANOVA), with post-hoc analysis using Dunnett to follow up
significant main effects.
[0577] Mouse Formalin Model of Persistent Pain
[0578] Mice (Naive, male C57B1/6) weighing between 22-30 g at the
start of testing were obtained from Harlan (Indianapolis, Ind.).
All animals were housed under a 12/12 h light/dark cycle with
lights on at 0630. Rodents were singly housed on solid bottom cages
with corn cob bedding and had access to food and water ad libitum.
Animals were allowed to habituate to the vivarium for at least five
days before testing was begun and were brought into the testing
room at least 30 minutes prior to dosing. Animals were pretreated
with the appropriate test compound either by oral gavage or
intraperitoneal injection at the desired pretreatment time
(typically two hours before test onset) and then returned to their
home cages. After dosing and at least 5 minutes prior to test
onset, animals were acclimated to the individual testing chambers.
At test time, each animal was gently wrapped in a cloth glove with
the left hind paw exposed. A dilute solution of formalin (2%) in
phosphate buffered saline was injected subcutaneously into the
dorsal surface of the left hind paw in a volume to 20 .mu.L with a
30 g needle. Animals were then placed into the observation chambers
and the behaviors were recorded for 60 minutes following the
formalin injection. A pain-like behavior was defined as licking
and/or non-weight bearing of the injected hind paw not associated
with ambulation.
[0579] Statistical analysis was performed by analysis of variance
(ANOVA), with post-hoc analysis using the Dunnett post-hoc test
compared to the vehicle group for any significant main effect. Data
were represented as mean+/-standard error for each group.
[0580] Table 1 provides data for compounds exemplified in the
present application and priority document thereof, as
representative compounds of the present invention, as follows:
compound name (as named using ChemDraw Ultra version 15.1; specific
stereochemical designations such as P, M, cis, and trans were
added); and biological data including in-vitro human Nav 1.7 IWQ
data (IC.sub.50 in uM) and Human CYP3A4 mRNA Induction at 10 uM
percent of control (POC) (%), where available. Ex. # refers to
Example No. ND means no data was available.
[0581] The potency of the compounds of the present invention were
evaluated on human Na.sub.v1.7 channels using the above described
IonWorks Barracuda automated electrophysiology platform that
evaluates the ability of compounds to block sodium conductance
through Na.sub.v1.7 channels. A voltage-protocol that prosecutes
both state-dependent as well as use-dependent inhibition was used
as these modes of action are thought to be more relevant for the
native state of Na.sub.v1.7 channels in pain sensing neurons in
vivo.
[0582] The cytochrome P450 (CYP) is a well-known superfamily of
enzymes that are responsible for the oxidative and reductive
metabolic transformation of medications used in clinical practice.
In addition, the CYP enzymes are commonly associated with causing
many clinically relevant drug-drug interactions. Of the CYP
enzymes, CYP3A4 is not only the most prevalent CYP enzyme in the
liver and intestine, but is responsible for metabolism and
elimination of approximately 50% of marketed drugs. In addition,
CYP3A4 activity can be induced (or increased) or inhibited
(decreased) in response to administration of certain drugs, thereby
affecting concentrations of their own or certain concomitant drugs
present in the body. Typically, the induction of CYP3A4 is an
undesired property of the drug molecule as it can result in the
reduction of parent drug concentrations that may put patients at
increased risk for lack of efficacy or increased metabolite
formation that can lead to safety risk. The CYP3A4 induction
property was evaluated in an in vitro induction assay where human
hepatocytes were exposed to the test compounds at physiologically
relevant concentrations. Changes in the levels of CYP3A4 were
evaluated at the end of the experiment and compared against the
increased levels upon treatment with rifampin, a well-established
CYP3A4 inducer.
[0583] Representative compounds of the present invention show
either favorable activities against hNav1.7 IWQ or favorable human
CYP3A4 induction data as compared to Compound X, which is named
1-(4-cyclopropyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-di-
hydroquinoline-6-sulfonamide, having the structure below:
##STR00118##
[0584] Compound X was exemplified in International Patent
Publication No. WO2014201206A1, Example No. 1145. Preferred
compounds of the present invention have both favorable activities
against human Nav1.7 IWQ and favorable human CYP3A4 induction data
as compared to Compound X.
TABLE-US-00001 TABLE 1 BIOLOGICAL DATA Hu CYP3A4 hNaV1.7 mRNA IWB-U
Induction Ex.# IC50 (10 uM POC) Compound X 0.048 84.31 1 ND ND 2
0.025 ND 3 0.033 ND 4 0.015 14.71 5 0.002 ND 6 0.011 83.89 7 0.007
16.35 8 0.005 10.51 9 0.002 ND 10 0.008 5.66 11 0.002 7.29 12 0.007
68.98 13 0.006 46.85 14 0.016 18.3 15 0.017 36 16 0.018 130.1 17
0.015 61.91 18 0.022 20.78 19 0.015 60.73 20 0.012 42.22 21 0.012
17.07 22 0.05 24.14 23 0.102 14.37 24 0.013 89.26 25 0.037 18.57 26
0.08 14.58 27 0.104 48.14 28 0.054 60.29 29 0.037 34.63 30 0.137 ND
31 ND ND 32 0.01 88 33 ND ND 34 0.028 69.54 35 0.02 13.33 36 0.014
19.16 37 0.062 49.51 38 0.021 4.43 39 0.011 21.68 40 0.005 74.43 41
0.011 52.8 42 0.006 19.25 43 0.007 68.28 44 0.007 ND 45 0.008
36.685 46 0.008 6.6 47 0.008 19.64 48 0.01 110.2 49 0.01 64.94
[0585] The foregoing invention has been described in some detail by
way of illustration and example, for purposes of clarity and
understanding. Those skilled in the art understand that changes and
modifications may be practiced within the scope of the appended
claims. Therefore, it is to be understood that the above
description is intended to be illustrative and not restrictive. The
scope of the invention should, therefore, be determined not with
reference to the above description, but should instead be
determined with reference to the following appended claims, along
with the full scope of equivalents to which such claims are
entitled.
[0586] All patents, patent applications and publications cited
herein are hereby incorporated by reference in their entirety for
all purposes to the same extent as if each individual patent,
patent application or publication were so individually denoted.
* * * * *