U.S. patent application number 16/576569 was filed with the patent office on 2020-04-16 for therapeutic compounds and methods of use thereof.
This patent application is currently assigned to GENENTECH, INC.. The applicant listed for this patent is GENENTECH, INC. XENON PHARMACEUTICALS INC.. Invention is credited to Philippe BERGERON, Ramsay BEVERIDGE, Kwong Wah LAI, Jean-Philippe LECLERC, Alexandre LEMIRE, Steven MCKERRALL, Claudio STURINO, Daniel SUTHERLIN, Michael Scott WILSON, Birong ZHANG, Liang ZHAO.
Application Number | 20200115354 16/576569 |
Document ID | / |
Family ID | 62018232 |
Filed Date | 2020-04-16 |
![](/patent/app/20200115354/US20200115354A1-20200416-C00001.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00002.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00003.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00004.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00005.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00006.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00007.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00008.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00009.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00010.png)
![](/patent/app/20200115354/US20200115354A1-20200416-C00011.png)
View All Diagrams
United States Patent
Application |
20200115354 |
Kind Code |
A1 |
SUTHERLIN; Daniel ; et
al. |
April 16, 2020 |
THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
Abstract
The invention provides a compound of formula I: ##STR00001## or
a pharmaceutically acceptable salt thereof, wherein the variables
X, Y.sup.1--Y.sup.5, R.sup.1, R.sup.2, R.sup.3, R.sup.4, and Het
have the meaning as described herein, and compositions containing
such compounds and methods for using such compounds and
compositions.
Inventors: |
SUTHERLIN; Daniel; (South
San Francisco, CA) ; MCKERRALL; Steven; (South San
Francisco, CA) ; WILSON; Michael Scott; (Burnaby,
CA) ; LAI; Kwong Wah; (Shanghai, CN) ;
BERGERON; Philippe; (South San Francisco, CA) ;
ZHANG; Birong; (South San Francisco, CA) ; BEVERIDGE;
Ramsay; (Montreal, CA) ; LECLERC; Jean-Philippe;
(Montreal, CA) ; LEMIRE; Alexandre; (Montreal,
CA) ; ZHAO; Liang; (Montreal, CA) ; STURINO;
Claudio; (Montreal, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GENENTECH, INC.
XENON PHARMACEUTICALS INC. |
South San Francisco
Burnaby |
CA |
US
CA |
|
|
Assignee: |
GENENTECH, INC.
South San Francisco
CA
XENON PHARMACEUTICALS INC.
Burnaby
|
Family ID: |
62018232 |
Appl. No.: |
16/576569 |
Filed: |
September 19, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15799771 |
Oct 31, 2017 |
10457654 |
|
|
16576569 |
|
|
|
|
PCT/CN2017/103499 |
Sep 26, 2017 |
|
|
|
15799771 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 277/52 20130101;
A61K 31/427 20130101; C07D 403/12 20130101; A61P 19/02 20180101;
A61P 29/00 20180101; A61P 9/00 20180101; C07D 261/16 20130101; C07D
285/08 20130101; C07D 213/76 20130101; C07D 401/12 20130101; A61P
17/04 20180101; A61P 25/00 20180101; C07D 417/12 20130101; C07D
239/69 20130101 |
International
Class: |
C07D 277/52 20060101
C07D277/52; C07D 417/12 20060101 C07D417/12; C07D 403/12 20060101
C07D403/12; C07D 401/12 20060101 C07D401/12; C07D 285/08 20060101
C07D285/08; C07D 261/16 20060101 C07D261/16; C07D 239/69 20060101
C07D239/69; C07D 213/76 20060101 C07D213/76; A61K 31/427 20060101
A61K031/427; A61P 29/00 20060101 A61P029/00; A61P 19/02 20060101
A61P019/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 17, 2016 |
CN |
PCT/CN2016/102263 |
Claims
1-2. (canceled)
3. A compound of formula Ia: ##STR00872## wherein: R.sup.1,
R.sup.2, and R.sup.3 are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, cyano, halo, and C.sub.1-C.sub.6 haloalkyl;
and R.sup.4 and Z together with the benzene ring to which they are
both attached form a 9- or 10-membered heterobicycle; Het is 5- or
6-membered heteroaryl optionally substituted with one to three
substituents each independently selected from C.sub.1-C.sub.6
alkyl, cyano, halo, and C.sub.1-C.sub.6 haloalkyl; X is selected
from --N(R.sup.6).sub.2 and --N(R.sup.7).sub.3.sup.+ -W, and amine
oxides thereof; Y.sup.1 is --C(R.sup.8).sub.2--; and Y.sup.2 is
selected from --(C(R.sup.8).sub.2).sub.n--, --N(R.sup.9)--, --O--,
--C(R.sup.8).sub.2--N(R.sup.9)--, --N(R.sup.9)--C(R.sup.8).sub.2--,
--C(R.sup.8).sub.2--O--, and --O--C(R.sup.8).sub.2--; or Y.sup.1 is
selected from --N(R.sup.9)-- and --O--, and Y.sup.2 is
--(C(R.sup.8).sub.2).sub.n--; n is selected from 0, 1, and 2;
Y.sup.3 and Y.sup.6 are each --C(R.sup.8).sub.2--; Y.sup.4 and
Y.sup.5 are each --C(R.sup.8)--; each R.sup.6 is independently
selected from hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 alkanoyl, 4-7 membered heterocycle, 5-6
membered heteroaryl, and C.sub.6-C.sub.12 aryl, wherein any
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6
alkanoyl, 4-7 membered heterocycle, 5-6 membered heteroaryl, and
C.sub.6-C.sub.12 aryl is optionally substituted with one or more
groups independently selected from deuterium, halo, cyano, hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkanoyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 halocycloalkyl,
--NR.sup.aR.sup.b, --C(.dbd.O)NR.sup.aR.sup.b, R.sup.c, and phenyl,
wherein any C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and
C.sub.1-C.sub.6 alkanoyl is optionally substituted with
C.sub.3-C.sub.6 cycloalkyl; or two R.sup.6 groups together with the
nitrogen to which they are both attached form a 4- to 10-membered
heterocycle that is optionally substituted with one or more groups
independently selected from deuterium, halo, cyano, hydroxy,
C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6 cycloalkyl, which
C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6 cycloalkyl is optionally
substituted with one or more groups independently selected from
hydroxy and halo; each R.sup.7 is independently selected from
C.sub.1-C.sub.6 alkyl; or two R.sup.7 groups together with the
nitrogen to which they are both attached form a 4- to 7-membered
heterocycle; each R.sup.8 is independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl, benzyl, 5-15 membered heteroaryl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy,
hydroxy, halo, cyano, and -L-C6-C.sub.12 aryl; wherein each
C.sub.3-C.sub.6 cycloalkyl, -L-C.sub.6-C.sub.12 aryl, benzyl, 5-15
membered heteroaryl, and C.sub.1-C.sub.6 alkoxy, is optionally
substituted with one to three substituents R.sup.x each
independently selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
cyano, halo, hydroxy, C.sub.3-C.sub.6 cycloalkoxy, C.sub.3-C.sub.6
halocycloalkyl, --S(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl), --S(O).sub.2(C.sub.1-C.sub.6 alkyl),
--NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl or two R.sup.8 that are on adjacent carbons taken
together form a double bond; and R.sup.9 is selected from hydrogen,
C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.12 aryl, which
C.sub.6-C.sub.12 aryl is optionally substituted with one to three
substituents each independently selected from C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, and C.sub.1-C.sub.6
haloalkyl; or one R.sup.8 or R.sup.9 taken together with another
R.sup.8 or R.sup.9 and the atoms to which they are attached form a
3-8 membered fused, bridged or spirocyclic ring, which 3-8 membered
ring is optionally substituted with one to three substituents each
independently selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, cyano, halo, and C.sub.1-C.sub.6 haloalkyl; and L is
selected from a bond, --O--, --S--, --S(O)--, and --S(O).sub.2--;
each R.sup.a and R.sup.b is independently selected from the group
consisting of hydrogen, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6
alkanoyl; each R.sup.c is independently selected from 4-7 membered
heterocycle that is optionally substituted with one or more groups
independently selected from halo, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 haloalkyl; and W.sup.- is a counterion, or a
pharmaceutically acceptable salt thereof.
4. The compound of claim 3, which is a compound of formula Ib:
##STR00873## or a pharmaceutically acceptable salt thereof.
5. The compound of claim 3, which is a compound of formula Ic:
##STR00874## or a pharmaceutically acceptable salt thereof.
6. The compound of claim 3, wherein one of Y.sup.1 and Y.sup.2 is
--CH(R.sup.8)-- and the other of Y.sup.1 and Y.sup.2 is
--CH.sub.2--; R.sup.8 is not H; Y.sup.3 and Y.sup.6 are each
--CH.sub.2--; and Y.sup.4 and Y.sup.5 are each --CH--; or a
pharmaceutically acceptable salt thereof.
7-11. (canceled)
12. The compound of claim 6, wherein R.sup.8 is trifluoromethyl or
phenyl that is optionally substituted with one to three
substituents each independently selected from C.sub.1-C.sub.6
alkyl, cyano, halo, and C.sub.1-C.sub.6 haloalkyl; or a
pharmaceutically acceptable salt thereof.
13. The compound of claim 6, wherein R.sup.8 is trifluoromethyl or
3-trifluoromethylphenyl; or a pharmaceutically acceptable salt
thereof.
14. The compound of claim 6, wherein R.sup.8 is phenyl that is
optionally substituted with one to three substituents R.sup.x each
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, hydroxy, C.sub.3-C.sub.6
cycloalkoxy, C.sub.3-C.sub.6 halocycloalkyl, --S(C.sub.1-C.sub.6
alkyl), --S(O)(C.sub.1-C.sub.6 alkyl), --S(O).sub.2(C.sub.1-C.sub.6
alkyl), --NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl; or a pharmaceutically acceptable salt thereof.
15. The compound of claim 6, wherein R.sup.8 is phenyl that is
optionally substituted with one to three substituents R.sup.x each
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, and C.sub.1-C.sub.6
haloalkyl; or a pharmaceutically acceptable salt thereof.
16. The compound of claim 6, wherein R.sup.8 is phenyl that is
optionally substituted with one to three substituents R.sup.x each
independently selected from the group consisting of F, Cl, CN,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkyl, and C.sub.1-C.sub.6 haloalkoxy;
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 6, wherein R.sup.8 is phenyl that is
optionally substituted with one to three substituents R.sup.x each
independently selected from the group consisting of fluoro, chloro,
trifluoromethyl, propyl, cyclopropyl, and trifluoromethoxy; or a
pharmaceutically acceptable salt thereof.
18-47. (canceled)
48. A pharmaceutical composition comprising a compound of claim 3,
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
49-56. (canceled)
57. The compound of claim 4, wherein one of Y.sup.1 and Y.sup.2 is
--CH(R.sup.8)-- and the other of Y.sup.1 and Y.sup.2 is
--CH.sub.2--; R.sup.8 is not H; Y.sup.3 and Y.sup.6 are each
--CH.sub.2--; and Y.sup.4 and Y.sup.5 are each --CH--; or a
pharmaceutically acceptable salt thereof.
58. The compound of claim 5, wherein one of Y.sup.1 and Y.sup.2 is
--CH(R.sup.8)-- and the other of Y.sup.1 and Y.sup.2 is
--CH.sub.2--; R.sup.8 is not H; Y.sup.3 and Y.sup.6 are each
--CH.sub.2--; and Y.sup.4 and Y.sup.5 are each --CH--; or a
pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/799,771, filed 31 Oct. 2017, which is a
continuation of international patent application number
PCT/CN2017/103499, filed 26 Sep. 2017, the entire contents of the
above referenced applications is hereby incorporated by reference
herein this application also claims priority to international
patent application number PCT/CN2016/102263, filed 17 Oct.
2016.
[0002] The present invention relates to organic compounds useful
for therapy in a mammal, and in particular to inhibitors of sodium
channel (e.g., NaV1.7) that are useful for treating sodium
channel-mediated diseases or conditions, such as pain, as well as
other diseases and conditions associated with the modulation of
sodium channels.
[0003] Voltage-gated sodium channels are transmembrane proteins
that initiate action potentials in nerve, muscle and other
electrically excitable cells, and are a necessary component of
normal sensation, emotions, thoughts and movements (Catterall, W.
A., Nature (2001), Vol. 409, pp. 988-990). These channels consist
of a highly processed alpha subunit that is associated with
auxiliary beta subunits. The pore-forming alpha subunit is
sufficient for channel function, but the kinetics and voltage
dependence of channel gating are in part modified by the beta
subunits (Goldin et al., Neuron (2000), Vol. 28, pp. 365-368).
Electrophysiological recording, biochemical purification, and
molecular cloning have identified ten different sodium channel
alpha subunits and four beta subunits (Yu, F. H., et al., Sci. STKE
(2004), 253; and Yu, F. H., et al., Neurosci. (2003),
20:7577-85).
[0004] The sodium channel family of proteins has been extensively
studied and shown to be involved in a number of vital body
functions. Research in this area has identified variants of the
alpha subunits that result in major changes in channel function and
activities, which can ultimately lead to major pathophysiological
conditions. The members of this family of proteins are denoted
NaV1.1 to NaV1.9.
[0005] NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium
channel encoded by the gene SCN9A. Human NaV1.7 was first cloned
from neuroendocrine cells (Klugbauer, N., et al., 1995 EMBO J., 14
(6): 1084-90.) and rat NaV1.7 was cloned from a pheochromocytoma
PC12 cell line (Toledo-Aral, J. J., et al., Proc. Natl. Acad. Sci.
USA (1997), 94:1527-1532) and from rat dorsal root ganglia
(Sangameswaran, L., et al., (1997), J. Biol. Chem., 272 (23):
14805-9). NaV1.7 is expressed primarily in the peripheral nervous
system, especially nocieptors and olfactory neurons and sympathetic
neurons. The inhibition, or blocking, of NaV1.7 has been shown to
result in analgesic activity. Knockout of NaV1.7 expression in a
subset of sensory neurons that are predominantly nociceptive
results in resistance to inflammatory pain (Nassar, et al., op.
cit.). Likewise, loss of function mutations in humans results in
congenital indifference to pain (CIP), in which the individuals are
resistant to both inflammatory and neuropathic pain (Cox, J. J., et
al., Nature (2006); 444:894-898; Goldberg, Y. P., et al., Clin.
Genet. (2007); 71:311-319). Conversely, gain of function mutations
in NaV1.7 have been established in two human heritable pain
conditions, primary erythromelalgia and familial rectal pain,
(Yang, Y., et al., J. Med. Genet. (2004), 41(3): 171-4). In
addition, a single nucleotide polymorphism (R1150W) that has very
subtle effects on the time- and voltage-dependence of channel
gating has large effects on pain perception (Estacion, M., et al.,
2009. Ann Neurol 66: 862-6; Reimann, F., et al., Proc Natl Acad Sci
USA (2010), 107: 5148-53). About 10% of the patients with a variety
of pain conditions have the allele conferring greater sensitivity
to pain and thus might be more likely to respond to block of
NaV1.7. Because NaV1.7 is expressed in both sensory and sympathetic
neurons, one might expect that enhanced pain perception would be
accompanied by cardiovascular abnormalities such as hypertension,
but no correlation has been reported. Thus, both the CIP mutations
and SNP analysis suggest that human pain responses are more
sensitive to changes in NaV1.7 currents than are perturbations of
autonomic function.
[0006] Sodium channel blockers have been shown to be useful in the
treatment of pain, (see, e.g., Wood, J. N., et al., J. Neurobiol.
(2004), 61(1), 55-71. Genetic and functional studies have provided
evidence to support that activity of NaV1.7 as a major contributor
to pain signalling in mammals. (See Hajj, et al. Nature Reviews
Neuroscience; 2013, vol 14, 49-62; and Lee, et al. Cell; 2014, vol
157; 1-12). Presently, there are a limited number of effective
sodium channel blockers for the treatment of pain with a minimum of
adverse side effects which are currently in the clinic. Thus there
remains a need for selective voltage-gated sodium channel
modulators (e.g., modulators of NaV1.7) that can provide a greater
therapeutic index for treatment.
SUMMARY
[0007] In one aspect the present invention provides novel compounds
having sodium channel blocking activity that are useful for the
treatment of pain.
[0008] In a first embodiment (Embodiment 1; abbreviated as "E1")
the invention provides for a compound of Formula I:
##STR00002##
[0009] or a pharmaceutically acceptable salt thereof, wherein:
[0010] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each
independently selected from hydrogen, C.sub.1-C.sub.6 alkyl, cyano,
C.sub.3-C.sub.6 cycloalkyl, hydroxy, C.sub.1-C.sub.6 alkoxy, nitro,
and halo, wherein any C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6
cycloalkyl is optionally substituted with one or more groups
independently selected from halo, cyano, hydroxy, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkyl, and
phenyl; and Z is selected from --N(R.sup.5)--, --O--, --S--,
--S(O)--, and --S(O).sub.2--; [0011] or [0012] R.sup.1, R.sup.2,
and R.sup.3 are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, cyano, halo, and C.sub.1-C.sub.6 haloalkyl;
and R.sup.4 and Z together with the benzene ring to which they are
both attached form a 9- or 10-membered heterobicycle; [0013] Het is
5- or 6-membered heteroaryl optionally substituted with one to
three substituents each independently selected from C.sub.1-C.sub.6
alkyl, cyano, halo, and C.sub.1-C.sub.6 haloalkyl; X is selected
from --N(R.sup.6).sub.2 and --N(R.sup.T).sub.3.sup.+ -W, and amine
oxides thereof; [0014] Y.sup.1 is --C(R.sup.8).sub.2--; and Y.sup.2
is selected from --(C(R.sup.8).sub.2)--. --N(R.sup.9)--, --O--,
--C(R.sup.8).sub.2--N(R.sup.9)--, --N(R.sup.9)--C(R.sup.8).sub.2--,
--C(R.sup.8).sub.2--O--, and --O--C(R.sup.8).sub.2--; [0015] or
[0016] Y.sup.1 is selected from --N(R.sup.9)-- and --O--; and
Y.sup.2 is --(C(R.sup.8).sub.2).sub.n--; [0017] n is selected from
0, 1, and 2; [0018] Y.sup.3 and Y.sup.6 are each
--C(R.sup.8).sub.2--; [0019] Y.sup.4 and Y.sup.5 are each
--C(R.sup.8)--; [0020] R.sup.5 is selected from hydrogen,
C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6 cycloalkyl; [0021] each
R.sup.6 is independently selected from hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkanoyl, 4-7
membered heterocycle, 5-6 membered heteroaryl, and C.sub.6-C.sub.12
aryl, wherein any C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 alkanoyl, 4-7 membered heterocycle, 5-6
membered heteroaryl, and C.sub.6-C.sub.12 aryl is optionally
substituted with one or more groups independently selected from
deuterium, halo, cyano, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkanoyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkyl,
C.sub.3-C.sub.6 halocycloalkyl, --NR.sup.aR.sup.b,
--C(.dbd.O)NR.sup.aR.sup.b, R.sup.c, and phenyl, wherein any
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and C.sub.1-C.sub.6
alkanoyl is optionally substituted with C.sub.3-C.sub.6 cycloalkyl;
or two R.sup.6 groups together with the nitrogen to which they are
both attached form a 4- to 10-membered heterocycle that is
optionally substituted with one or more groups independently
selected from deuterium, halo, cyano, hydroxy, C.sub.1-C.sub.6
alkyl, and C.sub.3-C.sub.6 cycloalkyl, which C.sub.1-C.sub.6 alkyl,
and C.sub.3-C.sub.6 cycloalkyl is optionally substituted with one
or more groups independently selected from hydroxy and halo; [0022]
each R.sup.7 is independently selected from C.sub.1-C.sub.6 alkyl;
or two R.sup.7 groups together with the nitrogen to which they are
both attached form a 4- to 7-membered heterocycle; [0023] each
R.sup.8 is independently selected from hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl,
benzyl, 5-15 membered heteroaryl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkoxy, hydroxy,
halo, cyano, and -L-C.sub.6-C.sub.12 aryl; wherein each
C.sub.3-C.sub.6 cycloalkyl, -L-C.sub.6-C.sub.12 aryl, benzyl, 5-15
membered heteroaryl, and C.sub.1-C.sub.6 alkoxy, is optionally
substituted with one to three substituents R.sup.X each
independently selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
cyano, halo, hydroxy, C.sub.3-C.sub.6 cycloalkoxy, C.sub.3-C.sub.6
halocycloalkyl, --S(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl), --S(O).sub.2(C.sub.1-C.sub.6 alkyl),
--NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl or two R.sup.8 that are on adjacent carbons taken
together form a double bond; and [0024] R.sup.9 is selected from
hydrogen, C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.12 aryl, which
C.sub.6-C.sub.12 aryl is optionally substituted with one to three
substituents each independently selected from C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, and C.sub.1-C.sub.6
haloalkyl; or one R.sup.8 or R.sup.9 taken together with another
R.sup.8 or R.sup.9 and the atoms to which they are attached form a
3-8 membered fused, bridged or spirocyclic ring, which 3-8 membered
ring is optionally substituted with one to three substituents each
independently selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, cyano, halo, and C.sub.1-C.sub.6 haloalkyl; and L is
selected from a bond, --O--, --S--, --S(O)--, and --S(O).sub.2--;
[0025] each R.sup.a and R.sup.b is independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl, and
C.sub.1-C.sub.6 alkanoyl; [0026] each R.sup.c is independently
selected from 4-7 membered heterocycle that is optionally
substituted with one or more groups independently selected from
halo, C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 haloalkyl; and
[0027] W.sup.- is a counterion.
[0028] E2. The compound of E1 wherein: [0029] R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 are each independently selected from hydrogen,
C.sub.1-C.sub.6 alkyl, cyano, C.sub.3-C.sub.6 cycloalkyl, halo, and
C.sub.1-C.sub.6 haloalkyl; and Z is selected from --N(R.sup.5)--,
--O--, --S--, --S(O)--, and --S(O).sub.2--; [0030] or [0031]
R.sup.1, R.sup.2, and R.sup.3 are each independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, cyano, halo, and C.sub.1-C.sub.6
haloalkyl; and R.sup.4 and Z together with the benzene ring to
which they are both attached form a 9- or 10-membered
heterobicycle; [0032] Het is 5- or 6-membered heteroaryl optionally
substituted with one to three substituents each independently
selected from C.sub.1-C.sub.6 alkyl, cyano, halo, and
C.sub.1-C.sub.6 haloalkyl; [0033] X is selected from
--N(R.sup.6).sub.2 and --N(R.sup.7).sub.3.sup.+ -W; [0034] Y.sup.1
is --C(R.sup.8).sub.2--; and Y.sup.2 is selected from
--(C(R.sup.8).sub.2).sub.n--, --N(R.sup.9)--, --O--,
--C(R.sup.8).sub.2--N(R.sup.9)--, --N(R.sup.9)--C(R.sup.8).sub.2--,
--C(R.sup.8).sub.2--O--, and --O--C(R.sup.8).sub.2--; [0035] or
[0036] Y.sup.1 is selected from --N(R.sup.9)-- and --O--; and
Y.sup.2 is --(C(R.sup.8).sub.2).sub.n--; [0037] n is selected from
0, 1, and 2; [0038] Y.sup.3 and Y.sup.6 are each
--C(R.sup.8).sub.2--; [0039] Y.sup.4 and Y.sup.5 are each
--C(R.sup.8)--; [0040] R.sup.5 is selected from hydrogen,
C.sub.1-C.sub.6 alkyl, and C.sub.3-C.sub.6 cycloalkyl; [0041] each
R.sup.6 is independently selected from hydrogen, C.sub.2-C.sub.6
alkoxyalkyl, C.sub.1-C.sub.6 alkyl, benzyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
hydroxyalkyl, and phenyl; or two R.sup.6 groups together with the
nitrogen to which they are both attached form a 4- to 7-membered
heterocycle; [0042] each R.sup.7 is independently selected from
C.sub.1-C.sub.6 alkyl; or two R.sup.7 groups together with the
nitrogen to which they are both attached form a 4- to 7-membered
heterocycle; [0043] each R.sup.8 is independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 haloalkoxy, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
hydroxyalkyl, hydroxyl, halo, cyano, benzyl and phenyl; wherein
each benzyl or phenyl is optionally substituted with one to three
substituents each independently selected from C.sub.1-C.sub.6
alkyl, cyano, halo, and C.sub.1-C.sub.6 haloalkyl or two R.sup.8
that are on adjacent carbons taken together form a double bond; and
R.sup.9 is selected from hydrogen and C.sub.1-C.sub.6 alkyl; or one
R.sup.8 or R.sup.9 taken together with another R.sup.8 or R.sup.9
and the atoms to which they are attached form a 3-8 membered fused,
bridged or spirocyclic ring; and [0044] W is a counterion; or a
pharmaceutically acceptable salt thereof.
[0045] E3. The compound of E1 or E2, which is a compound of formula
Ia:
##STR00003##
wherein R.sup.4 and Z together with the benzene ring to which they
are both attached form a 9- or 10-membered heterobicycle, or a
pharmaceutically acceptable salt thereof.
[0046] E4. The compound of E1 or E2, which is a compound of formula
Ib:
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0047] E5. The compound of E1 or E2, which is a compound of formula
Ic:
##STR00005##
or a pharmaceutically acceptable salt thereof.
[0048] E6. The compound of E1, E2, E3, E4, or E5, wherein one of
Y.sup.1 and Y.sup.2 is --CH(R.sup.8)-- and the other of Y.sup.1 and
Y.sup.2 is --CH.sub.2--; R.sup.8 is not H; Y.sup.3 and Y.sup.6 are
each --CH.sub.2--; and Y.sup.4 and Y.sup.5 are each --CH--; or a
pharmaceutically acceptable salt thereof.
[0049] E7. The compound of E1 or E2, which is a compound of formula
Id:
##STR00006##
or a pharmaceutically acceptable salt thereof.
[0050] E8. The compound of E1 or E2, which is a compound of formula
Ie:
##STR00007##
or a pharmaceutically acceptable salt thereof.
[0051] E9. The compound of E1 or E2, which is a compound of formula
If:
##STR00008##
or a pharmaceutically acceptable salt thereof.
[0052] E10. The compound of E1 or E2, which is a compound of
formula Ig:
##STR00009##
wherein --- is a single bond or a double bond; or a
pharmaceutically acceptable salt thereof.
[0053] E11. The compound of E1 or E2, which is a compound of
formula Ih:
##STR00010##
or a pharmaceutically acceptable salt thereof.
[0054] E12. The compound of E6, E7, E8, E9, E10, or E11, wherein
R.sup.8 is trifluoromethyl or phenyl that is optionally substituted
with one to three substituents each independently selected from
C.sub.1-C.sub.6 alkyl, cyano, halo, and C.sub.1-C.sub.6 haloalkyl;
or a pharmaceutically acceptable salt thereof.
[0055] E13. The compound of E6, E7, E8, E9, E10, or E11, wherein
R.sup.8 is trifluoromethyl or 3-trifluoromethylphenyl; or a
pharmaceutically acceptable salt thereof.
[0056] E14. The compound of E6, E7, E8, E9, E10, or E11, wherein
R.sup.8 is phenyl that is optionally substituted with one to three
substituents R.sup.X each independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, cyano, halo,
hydroxy, C.sub.3-C.sub.6 cycloalkoxy, C.sub.3-C.sub.6
halocycloalkyl, --S(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6
alkyl), --S(O).sub.2(C.sub.1-C.sub.6 alkyl),
--NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl; or a pharmaceutically acceptable salt thereof.
[0057] E15. The compound of E6, E7, E8, E9, E10, or E11, wherein
R.sup.8 is phenyl that is optionally substituted with one to three
substituents R.sup.X each independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, cyano, halo,
and C.sub.1-C.sub.6 haloalkyl; or a pharmaceutically acceptable
salt thereof.
[0058] E16. The compound of E6, E7, E8, E9, E10, or E11, wherein
R.sup.8 is phenyl that is optionally substituted with one to three
substituents R.sup.X each independently selected from the group
consisting of F, Cl, CN, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, and
C.sub.1-C.sub.6 haloalkoxy; or a pharmaceutically acceptable salt
thereof.
[0059] E17. The compound of E6, E7, E8, E9, E10, or E11, wherein
R.sup.8 is phenyl that is optionally substituted with one to three
substituents R.sup.X each independently selected from the group
consisting of fluoro, chloro, trifluoromethyl, propyl, cyclopropyl,
and trifluoromethoxy; or a pharmaceutically acceptable salt
thereof.
[0060] E18. The compound of E1 or E2, which is a compound of
formula (Ik):
##STR00011##
wherein: [0061] n is 1, 2, or 3; and [0062] each R.sup.X is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, hydroxy, C.sub.3-C.sub.6
cycloalkoxy, C.sub.3-C.sub.6 halocycloalkyl, --S(C.sub.1-C.sub.6
alkyl), --S(O)(C.sub.1-C.sub.6 alkyl), --S(O).sub.2(C.sub.1-C.sub.6
alkyl), --NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl; [0063] or a pharmaceutically acceptable salt
thereof.
[0064] E19. The compound of E1 or E2, which is a compound of
formula (Im):
##STR00012##
wherein: [0065] n is 1, 2, or 3; and [0066] each R.sup.X is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, hydroxy, C.sub.3-C.sub.6
cycloalkoxy, C.sub.3-C.sub.6 halocycloalkyl, --S(C.sub.1-C.sub.6
alkyl), --S(O)(C.sub.1-C.sub.6 alkyl), --S(O).sub.2(C.sub.1-C.sub.6
alkyl), --NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl; [0067] or a pharmaceutically acceptable salt
thereof.
[0068] E20. The compound of E1 or E2, which is a compound of
formula (In):
##STR00013##
wherein: [0069] n is 1, 2, or 3; and [0070] each R.sup.X is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, hydroxy, C.sub.3-C.sub.6
cycloalkoxy, C.sub.3-C.sub.6 halocycloalkyl, --S(C.sub.1-C.sub.6
alkyl), --S(O)(C.sub.1-C.sub.6 alkyl), --S(O).sub.2(C.sub.1-C.sub.6
alkyl), --NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl; or a pharmaceutically acceptable salt thereof.
[0071] E21. The compound of E1 or E2, which is a compound of
formula (Ip):
##STR00014##
wherein: [0072] n is 1, 2, or 3; and [0073] each R.sup.X is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, cyano, halo, hydroxy, C.sub.3-C.sub.6
cycloalkoxy, C.sub.3-C.sub.6 halocycloalkyl, --S(C.sub.1-C.sub.6
alkyl), --S(O)(C.sub.1-C.sub.6 alkyl), --S(O).sub.2(C.sub.1-C.sub.6
alkyl), --NH.sub.2--NH(C.sub.1-C.sub.6 alkyl), --N(C.sub.1-C.sub.6
alkyl).sub.2, 4-6 membered heterocycle, and C.sub.1-C.sub.6
haloalkyl; or a pharmaceutically acceptable salt thereof
[0074] E22. The compound of E1 or E2, which is a compound of
formula (Ir):
##STR00015##
wherein: [0075] R.sup.X is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, cyano, halo, hydroxy,
C.sub.3-C.sub.6 cycloalkoxy, C.sub.3-C.sub.6 halocycloalkyl,
--S(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--S(O).sub.2(C.sub.1-C.sub.6 alkyl), --NH.sub.2--NH(C.sub.1-C.sub.6
alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2, 4-6 membered heterocycle,
and C.sub.1-C.sub.6 haloalkyl; or a pharmaceutically acceptable
salt thereof
[0076] E23. The compound of E1 or E2, which is a compound of
formula (Is):
##STR00016##
wherein: [0077] R.sup.X is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, cyano, halo, hydroxy,
C.sub.3-C.sub.6 cycloalkoxy, C.sub.3-C.sub.6 halocycloalkyl,
--S(C.sub.1-C.sub.6 alkyl), --S(O)(C.sub.1-C.sub.6 alkyl),
--S(O).sub.2(C.sub.1-C.sub.6 alkyl), --NH.sub.2--NH(C.sub.1-C.sub.6
alkyl), --N(C.sub.1-C.sub.6 alkyl).sub.2, 4-6 membered heterocycle,
and C.sub.1-C.sub.6 haloalkyl; or a pharmaceutically acceptable
salt thereof.
[0078] E24. The compound of E18, or E19, E20, E21, E22, or E23,
wherein each R.sup.X is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, cyano, halo,
and C.sub.1-C.sub.6 haloalkyl; or a pharmaceutically acceptable
salt thereof.
[0079] E25. The compound of E18, or E19, E20, E21, E22, or E23,
wherein each R.sup.X is independently selected from the group
consisting of F, Cl, CN, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, and
C.sub.1-C.sub.6 haloalkoxy; or a pharmaceutically acceptable salt
thereof.
[0080] E26. The compound of E18, or E19, E20, E21, E22, or E23,
wherein each R.sup.X is independently selected from the group
consisting of fluoro, chloro, trifluoromethyl, propyl, cyclopropyl,
and trifluoromethoxy; or a pharmaceutically acceptable salt
thereof.
[0081] E27. The compound of E18, or E19, E20, E21, E22, or E23,
wherein each R.sup.X is independently selected from F and CF.sub.3;
or a pharmaceutically acceptable salt thereof.
[0082] E28. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, or E17, wherein X is
--N(R.sup.6).sub.2 and each R.sup.6 is independently selected from
hydrogen, C.sub.2-C.sub.6 alkoxyalkyl, C.sub.1-C.sub.6 alkyl,
benzyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 haloalkyl, and
C.sub.1-C.sub.6 hydroxyalkyl; or a pharmaceutically acceptable salt
thereof.
[0083] E29. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, or E17, wherein X is
--N(R.sup.6).sub.2 and two R.sup.6 groups together with the
nitrogen to which they are both attached form a 4- to 7-membered
heterocycle; or a pharmaceutically acceptable salt thereof.
[0084] E30. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, or E17, wherein X is selected
from the group consisting of: --NH.sub.2, --NHMe, --N(Me).sub.2,
--NHEt, --NMeEt, --N+(Me).sub.3,
##STR00017##
or a pharmaceutically acceptable salt thereof.
[0085] E31. The compound of E1, E3, E4, E5, E6, E7, E8, E9, E10,
E11, E12, E13, E14, E15, E16, or E17, wherein X is selected from
the group consisting of:
##STR00018## ##STR00019## ##STR00020## ##STR00021##
##STR00022##
or a pharmaceutically acceptable salt thereof.
[0086] E32. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, or E31, wherein R is H; or
a pharmaceutically acceptable salt thereof.
[0087] E33. The compound of The compound of E1, E2, E3, E4, E5, E6,
E7, E8, E9, E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20,
E21, E22, E23, E24, E25, E26, E27, E28, E29, E30, E31, or E32,
wherein R.sup.2 is selected from hydrogen and halo; or a
pharmaceutically acceptable salt thereof.
[0088] E34. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, or E32, wherein
R.sup.2 is selected from hydrogen and fluoro; or a pharmaceutically
acceptable salt thereof.
[0089] E35. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, or E34,
wherein R.sup.3 is hydrogen; or a pharmaceutically acceptable salt
thereof.
[0090] E36. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, or E35,
wherein R.sup.4 is selected from fluoro, chloro, bromo,
cyclopropyl, and trifluoromethyl; or a pharmaceutically acceptable
salt thereof.
[0091] E37. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, or E35,
wherein R.sup.4 is selected from hydrogen, fluoro, chloro, bromo,
cyclopropyl, cyclobutyl, hydroxy, methoxy, and trifluoromethyl; or
a pharmaceutically acceptable salt thereof.
[0092] E38. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, or E35,
wherein R.sup.4 is chloro; or a pharmaceutically acceptable salt
thereof.
[0093] E39. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, E35,
E36, E37, or E38, wherein Het is a 5-membered heteroaryl optionally
substituted with one to three substituents each independently
selected from C.sub.1-C.sub.6 alkyl, cyano, halo, and
C.sub.1-C.sub.6 haloalkyl; or a pharmaceutically acceptable salt
thereof.
[0094] E40. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, E35,
E36, E37, or E38, wherein Het is a 6-membered heteroaryl optionally
substituted with one to three substituents each independently
selected from C.sub.1-C.sub.6 alkyl, cyano, halo, and
C.sub.1-C.sub.6 haloalkyl; or a pharmaceutically acceptable salt
thereof.
[0095] E41. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, E35,
E36, E37, or E38, wherein Het is selected from the group consisting
of: thiazole, pyrimidine, oxazole, and thiadiazole, each optionally
substituted with 1, 2, or 3 substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, cyano, halo,
and C.sub.1-C.sub.6 haloalkyl; or a pharmaceutically acceptable
salt thereof.
[0096] E42. The compound of E1, E2, E3, E4, E5, E6, E7, E8, E9,
E10, E11, E12, E13, E14, E15, E16, E17, E18, E19, E20, E21, E22,
E23, E24, E25, E26, E27, E28, E29, E30, E31, E32, E33, E34, E35,
E36, E37, or E38, wherein Het is selected from the group consisting
of: 1,3-thiazol-2-yl, pyrimidin-4-yl, e, 1,2-oxazol-3-yl, and
1,2,4-thiadiazol-5-yl; or a pharmaceutically acceptable salt
thereof.
[0097] E43. The compound of E1 or E2, wherein the group
##STR00023##
is selected from the group consisting of:
##STR00024## ##STR00025##
or a pharmaceutically acceptable salt thereof
[0098] E44. The compound of E1, wherein the group
##STR00026##
is selected from the group consisting of:
##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##
##STR00032## ##STR00033## ##STR00034## ##STR00035## ##STR00036##
##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041##
##STR00042##
or a pharmaceutically acceptable salt thereof.
[0099] E45. The compound of E1, which is selected from the group
consisting of:
##STR00043## ##STR00044## ##STR00045## ##STR00046##
##STR00047##
or a pharmaceutically acceptable salt thereof.
[0100] E46. The compound of E1, which is selected from the group
consisting of:
##STR00048## ##STR00049## ##STR00050## ##STR00051##
or a pharmaceutically acceptable salt thereof.
[0101] E47. The compound of E1, which is selected from the group
consisting of:
##STR00052## ##STR00053## ##STR00054## ##STR00055## ##STR00056##
##STR00057## ##STR00058## ##STR00059## ##STR00060## ##STR00061##
##STR00062## ##STR00063## ##STR00064## ##STR00065## ##STR00066##
##STR00067## ##STR00068## ##STR00069## ##STR00070## ##STR00071##
##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076##
##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081##
##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086##
##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091##
##STR00092## ##STR00093##
or a pharmaceutically acceptable salt thereof.
[0102] E48. A compound of formula (Id') of E1 or E2:
##STR00094##
or a pharmaceutically acceptable salt thereof.
[0103] E49. A compound of formula (Ie') of E1 or E2:
##STR00095##
or a pharmaceutically acceptable salt thereof.
[0104] E50. A compound of formula (If') of E1 or E2:
##STR00096##
or a pharmaceutically acceptable salt thereof.
[0105] E51. A compound of formula (Ig') of E1 or E2:
##STR00097##
wherein --- is a single bond or a double bond; or a
pharmaceutically acceptable salt thereof.
[0106] E52. A compound of formula (Ih') of E1 or E2:
##STR00098##
or a pharmaceutically acceptable salt thereof.
[0107] E53. A compound of formula of E1 or E2 selected from:
##STR00099##
or a pharmaceutically acceptable salt thereof.
[0108] E54. A compound of E1 or E2 selected from:
##STR00100## ##STR00101##
or a pharmaceutically acceptable salt thereof.
[0109] E55. A compound of E1 or E2 selected from:
##STR00102## ##STR00103##
or a pharmaceutically acceptable salt thereof.
[0110] E56. The compound of E1, E2, E3, E4, E5, E28, E29, E30, E31,
E32, E33, E34, E35, E36, E37, E38, E39, E40, E41, or E42, wherein
R.sup.8 or R.sup.9 taken together with another R.sup.8 or R.sup.9
and the atoms to which they are attached form a 3-8 membered fused
ring, which is a benzo ring.
[0111] In another aspect the present invention provides for a
pharmaceutical composition comprising a compound of formula I or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable excipient.
[0112] In another aspect the present invention provides for a
method of treating a disease or condition in a mammal selected from
the group consisting of pain, depression, cardiovascular diseases,
respiratory diseases, and psychiatric diseases, and combinations
thereof, wherein the method comprises administering to the mammal
in need thereof a therapeutically effective amount of a compound of
formula I, or a pharmaceutically acceptable salt thereof. In
another aspect of the present invention said disease or condition
is selected from the group consisting of neuropathic pain,
inflammatory pain, visceral pain, cancer pain, chemotherapy pain,
trauma pain, surgical pain, post-surgical pain, childbirth pain,
labor pain, neurogenic bladder, ulcerative colitis, chronic pain,
persistent pain, peripherally mediated pain, centrally mediated
pain, chronic headache, migraine headache, sinus headache, tension
headache, phantom limb pain, dental pain, peripheral nerve injury
or a combination thereof. In another aspect of the present
invention said disease or condition is selected from the group
consisting of pain associated with HIV, HIV treatment induced
neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia,
heat sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns
disease, pain associated with multiple sclerosis (MS), amyotrophic
lateral sclerosis (ALS), diabetic neuropathy, peripheral
neuropathy, arthritis, rheumatoid arthritis, osteoarthritis,
atherosclerosis, paroxysmal dystonia, myasthenia syndromes,
myotonia, malignant hyperthermia, cystic fibrosis,
pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar
depression, anxiety, schizophrenia, sodium channel toxin related
illnesses, familial erythromelalgia, primary erythromelalgia,
familial rectal pain, cancer, epilepsy, partial and general tonic
seizures, restless leg syndrome, arrhythmias, fibromyalgia,
neuroprotection under ischaemic conditions cause by stroke or
neural trauma, tach-arrhythmias, atrial fibrillation and
ventricular fibrillation.
[0113] In another aspect the present invention provides for a
method of treating pain in a mammal by the inhibition of ion flux
through a voltage-dependent sodium channel in the mammal, wherein
the method comprises administering to the mammal in need thereof a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0114] In another aspect the present invention provides for a
method of decreasing ion flux through a voltage-dependent sodium
channel in a cell in a mammal, wherein the method comprises
contacting the cell with a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0115] In another aspect the present invention provides for a
method of treating pruritus in a mammal, wherein the method
comprises administering to the mammal in need thereof a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0116] In another aspect the present invention provides for a
method of treating cancer in a mammal, wherein the method comprises
administering to the mammal in need thereof a therapeutically
effective amount a compound of formula I, or a pharmaceutically
acceptable salt thereof.
[0117] In another aspect the present invention provides for a
method of treating, but not preventing, pain in a mammal, wherein
the method comprises administering to the mammal in need thereof a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof.
[0118] In another aspect of the present invention the pain is
selected from the group consisting of neuropathic pain,
inflammatory pain, visceral pain, cancer pain, chemotherapy pain,
trauma pain, surgical pain, post-surgical pain, childbirth pain,
labor pain, neurogenic bladder, ulcerative colitis, chronic pain,
persistent pain, peripherally mediated pain, centrally mediated
pain, chronic headache, migraine headache, sinus headache, tension
headache, phantom limb pain, dental pain, peripheral nerve injury
or a combination thereof. In another aspect the present invention
the pain is associated with a disease or condition selected from
the group consisting of HIV, HIV treatment induced neuropathy,
trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat
sensitivity, tosarcoidosis, irritable bowel syndrome, Crohns
disease, pain associated with multiple sclerosis (MS), amyotrophic
lateral sclerosis (ALS), diabetic neuropathy, peripheral
neuropathy, arthritis, rheumatoid arthritis, osteoarthritis,
atherosclerosis, paroxysmal dystonia, myasthenia syndromes,
myotonia, malignant hyperthermia, cystic fibrosis,
pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar
depression, anxiety, schizophrenia, sodium channel toxin related
illnesses, familial erythromelalgia, primary erythromelalgia,
familial rectal pain, cancer, epilepsy, partial and general tonic
seizures, restless leg syndrome, arrhythmias, fibromyalgia,
neuroprotection under ischaemic conditions cause by stroke or
neural trauma, tach-arrhythmias, atrial fibrillation and
ventricular fibrillation.
[0119] In another aspect the present invention provides for a
method for the treatment or prophylaxis of pain, depression,
cardiovascular disease, respiratory disease, or psychiatric
disease, or a combinations thereof, in an animal which method
comprises administering an effective amount of a compound of
formula I, or a pharmaceutically acceptable salt thereof.
[0120] In another aspect the present invention provides for a
compound of formula I, or a pharmaceutically acceptable salt
thereof for the use as a medicament for the treatment of diseases
and disorders selected from the group consisting of pain,
depression, cardiovascular diseases, respiratory diseases, and
psychiatric diseases, or a combination thereof.
[0121] In another aspect the present invention provides for the use
of a compound of formula I, or a pharmaceutically acceptable salt
thereof for the manufacture of a medicament for the treatment of
diseases and disorders selected from the group consisting of pain,
depression, cardiovascular diseases, respiratory diseases, and
psychiatric diseases, or a combination thereof.
[0122] In another aspect the present invention provides for the
invention as described herein.
DETAILED DESCRIPTION
Definitions
[0123] As used herein, the term "alkyl", by itself or as part of
another substituent, means, unless otherwise stated, a straight or
branched chain hydrocarbon radical, having the number of carbon
atoms designated (i.e., C.sub.1-8 means one to eight carbons).
Examples of alkyl groups include methyl, ethyl, n-propyl,
iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl,
n-hexyl, n-heptyl, n-octyl, and the like.
[0124] The terms "alkoxy," "alkylamino" and "alkylthio", are used
in their conventional sense, and refer to those alkyl groups
attached to the remainder of the molecule via an oxygen atom
("oxy"), an amino group ("amino") or thio group. Additionally, for
dialkylamino groups, the alkyl portions can be the same or
different.
[0125] The terms "halo" by itself or as part of another
substituent, mean, unless otherwise stated, a fluorine, chlorine,
bromine, or iodine atom.
[0126] The term "haloalkyl" refers to an alkyl that is substituted
with one or more (e.g. 1, 2, 3, 4, 5, or 6) halo groups. For
example the term includes an alkyl group having 1-6 carbon atoms
that is substituted with one or more halo groups. Non-limiting
examples of the term C.sub.1-C.sub.6 haloalkyl include
fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, and
2,2,2-trifluoroethyl.
[0127] The term "halocycloalkyl" refers to a cycloalkyl that is
substituted with one or more (e.g. 1, 2, 3, 4, 5, or 6) halo
groups. For example the term includes a cycloalkyl group having 3-6
carbon atoms that is substituted with one or more halo groups.
Non-limiting examples of the term C.sub.1-C.sub.6 halocycloalkyl
include 1-fluorocyclopropyl.
[0128] The term "hydroxyalkyl" refers to an alkyl that is
substituted with one or more (e.g. 1, 2, 3, 4, 5, or 6) hydroxy
groups. For example the term includes C.sub.1-C.sub.6 hydroxyalkyl,
which is an alkyl group having 1-6 carbon atoms that is substituted
with one or more hydroxy groups. Non-limiting examples of the term
C.sub.1-C.sub.6 hydroxyalkyl include hydroxymethyl, 2-hydroxyethyl,
and 3-hydroxypropyl.
[0129] The term "alkoxyalkyl" refers to an alkyl that is
substituted with one or more (e.g. 1, 2, 3, 4, 5, or 6) alkoxy
(alkyl-O--) groups. For example the term C.sub.2-C.sub.6
alkoxyalkyl refers to an alkyl that is substituted with one or more
alkoxy groups, wherein the total number of carbons is 2, 3, 4, 5,
or 6. Non-limiting examples of the term C.sub.2-C.sub.6 alkoxyalkyl
include methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl,
3-methoxypropyl, and 3-ethoxypropyl.
[0130] The term "aryl" as used herein refers to a single all carbon
aromatic ring or a multiple condensed all carbon ring system
wherein at least one of the rings is aromatic. For example, in
certain embodiments, an aryl group has 6 to 20 carbon atoms, 6 to
14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl
radical. Aryl also includes multiple condensed ring systems (e.g.,
ring systems comprising 2, 3 or 4 rings) having about 9 to 20
carbon atoms in which at least one ring is aromatic and wherein the
other rings may be aromatic or not aromatic (i.e., carbocycle).
Such multiple condensed ring systems are optionally substituted
with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle
portion of the multiple condensed ring system. The rings of the
multiple condensed ring system can be connected to each other via
fused, spiro and bridged bonds when allowed by valency
requirements. It is to be understood that the point of attachment
of a multiple condensed ring system, as defined above, can be at
any position of the ring system including an aromatic or a
carbocycle portion of the ring. Non-limiting examples of aryl
groups include, but are not limited to, phenyl, indenyl, naphthyl,
1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.
[0131] The term "carbocycle" or "carbocyclyl" refers to a single
saturated (i.e., cycloalkyl) or a single partially unsaturated
(e.g., cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having
3 to 7 carbon atoms (i.e., (C.sub.3-C.sub.7)carbocycle). The term
"carbocycle" or "carbocyclyl" also includes multiple condensed,
saturated and partially unsaturated all carbon ring systems (e.g.,
ring systems comprising 2, 3 or 4 carbocyclic rings). Accordingly,
carbocycle includes multicyclic carbocyles such as a bicyclic
carbocycles (e.g., bicyclic carbocycles having about 6 to 20 or 6
to 12 carbon atoms such as bicyclo[3.1.0]hexane and
bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic
and tetracyclic carbocycles with up to about 20 carbon atoms). The
rings of the multiple condensed ring system can be connected to
each other via fused, spiro and bridged bonds when allowed by
valency requirements. For example, multicyclic carbocyles can be
connected to each other via a single carbon atom to form a spiro
connection (e.g., spiropentane, spiro[4,5]decane, etc), via two
adjacent carbon atoms to form a fused connection (e.g., carbocycles
such as decahydronaphthalene, norsabinane, norcarane) or via two
non-adjacent carbon atoms to form a bridged connection (e.g.,
norbornane, bicyclo[2.2.2]octane, etc). The "carbocycle" or
"carbocyclyl" can also be optionally substituted with one or more
(e.g., 1, 2 or 3) oxo groups. In one embodiment the term carbocycle
includes a C.sub.3-12 carbocycle. In one embodiment the term
carbocycle includes a C.sub.3-8 carbocycle. In one embodiment the
term carbocycle includes a C.sub.3-6 carbocycle. In one embodiment
the term carbocycle includes a C.sub.3-5 carbocycle. Non-limiting
examples of carbocycles include cyclopropyl, cyclobutyl,
cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,
1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,
1-cyclohex-2-enyl, bicyclo[2.2.1]heptane, pinane, adamantane,
norborene, spirocyclic C.sub.5-12 alkane, and 1-cyclohex-3-enyl. In
one embodiment the term "cycloalkyl" refers to a single saturated
all carbon ring having 3 to 8 carbon atoms. Non-limiting examples
of carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl.
[0132] The term "heteroaryl" as used herein refers to a single
aromatic ring that has at least one atom other than carbon in the
ring, wherein the atom is selected from the group consisting of
oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple
condensed ring systems that have at least one such aromatic ring,
which multiple condensed ring systems are further described below.
Thus, "heteroaryl" includes single aromatic rings of from about 1
to 6 carbon atoms and about 1-4 heteroatoms selected from the group
consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen
atoms may also be present in an oxidized form provided the ring is
aromatic. Exemplary heteroaryl ring systems include but are not
limited to pyridyl, pyrimidinyl, oxazolyl or furyl. "Heteroaryl"
also includes multiple condensed ring systems (e.g., ring systems
comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined
above, is condensed with one or more rings selected from
heteroaryls (to form for example a naphthyridinyl such as
1,8-naphthyridinyl), heterocycles, (to form for example a
1,2,3,4-tetrahydronaphthyridinyl such as
1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for
example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example
indazolyl) to form the multiple condensed ring system. Thus, a
heteroaryl (a single aromatic ring or multiple condensed ring
system) has about 1-20 carbon atoms and about 1-6 heteroatoms
within the heteroaryl ring. A heteroaryl (a single aromatic ring or
multiple condensed ring system) can also have about 5 to 20 or
about 5 to 15 or about 5 to 10 members within the heteroaryl ring.
Such multiple condensed ring systems may be optionally substituted
with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle
or heterocycle portions of the condensed ring. The rings of the
multiple condensed ring system can be connected to each other via
fused, spiro and bridged bonds when allowed by valency
requirements. It is to be understood that the individual rings of
the multiple condensed ring system may be connected in any order
relative to one another. It is also to be understood that the point
of attachment of a multiple condensed ring system (as defined above
for a heteroaryl) can be at any position of the multiple condensed
ring system including a heteroaryl, heterocycle, aryl or carbocycle
portion of the multiple condensed ring system. It is also to be
understood that the point of attachment for a heteroaryl or
heteroaryl multiple condensed ring system can be at any suitable
atom of the heteroaryl or heteroaryl multiple condensed ring system
including a carbon atom and a heteroatom (e.g., a nitrogen).
Exemplary heteroaryls include but are not limited to pyridyl,
pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl,
indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl,
oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl,
benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,
5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl,
thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one,
triazolyl, 4,5,6,7-tetrahydro-1H-indazole and
3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.
In one embodiment the term "heteroaryl" refers to a single aromatic
ring containing at least one heteroatom. For example, the term
includes 5-membered and 6-membered monocyclic aromatic rings that
include one or more heteroatoms. Non-limiting examples of
heteroaryl include but are not limited to pyridyl, furyl, thiazole,
pyrimidine, oxazole, and thiadiazole.
[0133] The term "heterocyclyl" or "heterocycle" as used herein
refers to a single saturated or partially unsaturated ring that has
at least one atom other than carbon in the ring, wherein the atom
is selected from the group consisting of oxygen, nitrogen and
sulfur; the term also includes multiple condensed ring systems that
have at least one such saturated or partially unsaturated ring,
which multiple condensed ring systems are further described below.
Thus, the term includes single saturated or partially unsaturated
rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6
carbon atoms and from about 1 to 3 heteroatoms selected from the
group consisting of oxygen, nitrogen and sulfur in the ring. The
ring may be substituted with one or more (e.g., 1, 2 or 3) oxo
groups and the sulfur and nitrogen atoms may also be present in
their oxidized forms. Exemplary heterocycles include but are not
limited to azetidinyl, tetrahydrofuranyl and piperidinyl. The term
"heterocycle" also includes multiple condensed ring systems (e.g.,
ring systems comprising 2, 3 or 4 rings) wherein a single
heterocycle ring (as defined above) can be condensed with one or
more groups selected from heterocycles (to form for example a
1,8-decahydronapthyridinyl), carbocycles (to form for example a
decahydroquinolyl) and aryls to form the multiple condensed ring
system. Thus, a heterocycle (a single saturated or single partially
unsaturated ring or multiple condensed ring system) has about 2-20
carbon atoms and 1-6 heteroatoms within the heterocycle ring. Such
multiple condensed ring systems may be optionally substituted with
one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or
heterocycle portions of the multiple condensed ring. The rings of
the multiple condensed ring system can be connected to each other
via fused, spiro and bridged bonds when allowed by valency
requirements. It is to be understood that the individual rings of
the multiple condensed ring system may be connected in any order
relative to one another. Accordingly, a heterocycle (a single
saturated or single partially unsaturated ring or multiple
condensed ring system) has about 3-20 atoms including about 1-6
heteroatoms within the heterocycle ring system. It is also to be
understood that the point of attachment of a multiple condensed
ring system (as defined above for a heterocycle) can be at any
position of the multiple condensed ring system including a
heterocycle, aryl and carbocycle portion of the ring. It is also to
be understood that the point of attachment for a heterocycle or
heterocycle multiple condensed ring system can be at any suitable
atom of the heterocycle or heterocycle multiple condensed ring
system including a carbon atom and a heteroatom (e.g., a nitrogen).
In one embodiment the term heterocycle includes a C.sub.2-20
heterocycle. In one embodiment the term heterocycle includes a
C.sub.2-7 heterocycle. In one embodiment the term heterocycle
includes a C.sub.2-5 heterocycle. In one embodiment the term
heterocycle includes a C.sub.2-4 heterocycle. Exemplary
heterocycles include, but are not limited to aziridinyl,
azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,
morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl,
dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl,
1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl,
chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl,
1,3-benzodioxolyl, 1,4-benzodioxanyl,
spiro[cyclopropane-1,1'-isoindolinyl]-3'-one, isoindolinyl-1-one,
2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one
N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam,
valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,
1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide,
thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone,
tetrhydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane,
(1R,5S)-3-azabicyclo[3.2.1]octane, (1
s,4s)-2-azabicyclo[2.2.2]octane,
(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one. In
one embodiment the term "heterocycle" refers to a monocyclic,
saturated or partially unsaturated, 3-8 membered ring having at
least one heteroatom. For example, the term includes a monocyclic,
saturated or partially unsaturated, 4, 5, 6, or 7 membered ring
having at least one heteroatom. Non-limiting examples of
heterocycle include aziridine, azetidine, pyrrolidine, piperidine,
piperidine, piperazine, oxirane, morpholine, and thiomorpholine.
The term "9- or 10-membered heterobicycle" as used herein refers to
a partially unsaturated or aromatic fused bicyclic ring system
having at least one heteroatom. For example, the term 9- or
10-membered heterobicycle includes a bicyclic ring system having a
benzo ring fused to a 5-membered or 6-membered saturated, partially
unsaturated, or aromatic ring that contains one or more
heteroatoms.
[0134] As used herein, the term "heteroatom" is meant to include
oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). The nitrogen
and sulfur can be in an oxidized form when feasible.
[0135] As used herein, the term "chiral" refers to molecules which
have the property of non-superimposability of the mirror image
partner, while the term "achiral" refers to molecules which are
superimposable on their mirror image partner.
[0136] As used herein, the term "stereoisomers" refers to compounds
which have identical chemical constitution, but differ with regard
to the arrangement of the atoms or groups in space.
[0137] As used herein a wavy line "" that intersects a bond in a
chemical structure indicates the point of attachment of the bond
that the wavy bond intersects in the chemical structure to the
remainder of a molecule.
[0138] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers can separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0139] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0140] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., New York, 1994. The compounds of the
invention can contain asymmetric or chiral centers, and therefore
exist in different stereoisomeric forms. It is intended that all
stereoisomeric forms of the compounds of the invention, including
but not limited to, diastereomers, enantiomers and atropisomers, as
well as mixtures thereof such as racemic mixtures, form part of the
present invention. Many organic compounds exist in optically active
forms, i.e., they have the ability to rotate the plane of
plane-polarized light. In describing an optically active compound,
the prefixes D and L, or R and S, are used to denote the absolute
configuration of the molecule about its chiral center(s). The
prefixes d and l or (+) and (-) are employed to designate the sign
of rotation of plane-polarized light by the compound, with (-) or l
meaning that the compound is levorotatory. A compound prefixed with
(+) or d is dextrorotatory. For a given chemical structure, these
stereoisomers are identical except that they are mirror images of
one another. A specific stereoisomer can also be referred to as an
enantiomer, and a mixture of such isomers is often called an
enantiomeric mixture.
[0141] A 50:50 mixture of enantiomers is referred to as a racemic
mixture or a racemate, which can occur where there has been no
stereoselection or stereospecificity in a chemical reaction or
process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0142] When a bond in a compound formula herein is drawn in a
non-stereochemical manner (e.g. flat), the atom to which the bond
is attached includes all stereochemical possibilities. When a bond
in a compound formula herein is drawn in a defined stereochemical
manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be
understood that the atom to which the stereochemical bond is
attached is enriched in the absolute stereoisomer depicted unless
otherwise noted. In one embodiment, the compound may be at least
51% the absolute stereoisomer depicted. In another embodiment, the
compound may be at least 80% the absolute stereoisomer depicted. In
another embodiment, the compound may be at least 90% the absolute
stereoisomer depicted. In another embodiment, the compound may be
at least 95% the absolute stereoisomer depicted. In another
embodiment, the compound may be at least 97% the absolute
stereoisomer depicted. In another embodiment, the compound may be
at least 98% the absolute stereoisomer depicted. In another
embodiment, the compound may be at least 99% the absolute
stereoisomer depicted.
[0143] As used herein, the term "tautomer" or "tautomeric form"
refers to structural isomers of different energies which are
interconvertible via a low energy barrier. For example, proton
tautomers (also known as prototropic tautomers) include
interconversions via migration of a proton, such as keto-enol and
imine-enamine isomerizations. Valence tautomers include
interconversions by reorganization of some of the bonding
electrons.
[0144] As used herein, the term "solvate" refers to an association
or complex of one or more solvent molecules and a compound of the
invention. Examples of solvents that form solvates include, but are
not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl
acetate, acetic acid, and ethanolamine. The term "hydrate" refers
to the complex where the solvent molecule is water.
[0145] As used herein, the term "protecting group" refers to a
substituent that is commonly employed to block or protect a
particular functional group on a compound. For example, an
"amino-protecting group" is a substituent attached to an amino
group that blocks or protects the amino functionality in the
compound. Suitable amino-protecting groups include acetyl,
trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)
and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a
"hydroxy-protecting group" refers to a substituent of a hydroxy
group that blocks or protects the hydroxy functionality. Suitable
protecting groups include acetyl and silyl. A "carboxy-protecting
group" refers to a substituent of the carboxy group that blocks or
protects the carboxy functionality. Common carboxy-protecting
groups include phenylsulfonylethyl, cyanoethyl,
2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl,
2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl,
2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general
description of protecting groups and their use, see P. G. M. Wuts
and T. W. Greene, Greene's Protective Groups in Organic Synthesis
4.sup.th edition, Wiley-Interscience, New York, 2006.
[0146] As used herein, the term "mammal" includes, but is not
limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats,
horses, cows, pigs, and sheep.
[0147] As used herein, the term "pharmaceutically acceptable salts"
is meant to include salts of the active compounds which are
prepared with relatively nontoxic acids or bases, depending on the
particular substituents found on the compounds described herein.
When compounds of the present invention contain relatively acidic
functionalities, base addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired base, either neat or in a suitable inert solvent. Examples
of salts derived from pharmaceutically-acceptable inorganic bases
include aluminum, ammonium, calcium, copper, ferric, ferrous,
lithium, magnesium, manganic, manganous, potassium, sodium, zinc
and the like. Salts derived from pharmaceutically-acceptable
organic bases include salts of primary, secondary and tertiary
amines, including substituted amines, cyclic amines,
naturally-occurring amines and the like, such as arginine, betaine,
caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine,
2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lysine,
methylglucamine, morpholine, piperazine, piperidine, polyamine
resins, procaine, purines, theobromine, triethylamine,
trimethylamine, tripropylamine, tromethamine and the like. When
compounds of the present invention contain relatively basic
functionalities, acid addition salts can be obtained by contacting
the neutral form of such compounds with a sufficient amount of the
desired acid, either neat or in a suitable inert solvent. Examples
of pharmaceutically acceptable acid addition salts include those
derived from inorganic acids like hydrochloric, hydrobromic,
nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,
monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
as well as the salts derived from relatively nontoxic organic acids
like acetic, propionic, isobutyric, malonic, benzoic, succinic,
suberic, fumaric, mandelic, phthalic, benzenesulfonic,
p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
Also included are salts of amino acids such as arginate and the
like, and salts of organic acids like glucuronic or galactunoric
acids and the like (see, for example, Berge, S. M., et al.,
"Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977,
66, 1-19). Certain specific compounds of the present invention
contain both basic and acidic functionalities that allow the
compounds to be converted into either base or acid addition
salts.
[0148] The neutral forms of the compounds can be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of the
compound differs from the various salt forms in certain physical
properties, such as solubility in polar solvents, but otherwise the
salts are equivalent to the parent form of the compound for the
purposes of the present invention.
[0149] In one embodiment, W.sup.- is a pharmaceutically acceptable
anion. In another embodiment W.sup.- is chloride, bromide, iodide,
tosylate, methanesulfonate, acetate, citrate, malonate, tartrate,
succinate, fumarate, benzoate, ascorbate, .alpha.-ketoglutarate,
.alpha.-glycerophosphate, benzenesulfonate, lactate, bicarbonate,
malate, maleate, carbonate, methylbromide, chloride, nitrate,
gluconate, salicylate, glutamate, stearate, or sulfate.
[0150] In addition to salt forms, the present invention provides
compounds which are in a prodrug form. As used herein the term
"prodrug" refers to those compounds that readily undergo chemical
changes under physiological conditions to provide the compounds of
the present invention. Additionally, prodrugs can be converted to
the compounds of the present invention by chemical or biochemical
methods in an ex vivo environment. For example, prodrugs can be
slowly converted to the compounds of the present invention when
placed in a transdermal patch reservoir with a suitable enzyme or
chemical reagent.
[0151] Prodrugs of the invention include compounds wherein an amino
acid residue, or a polypeptide chain of two or more (e.g., two,
three or four) amino acid residues, is covalently joined through an
amide or ester bond to a free amino, hydroxy or carboxylic acid
group of a compound of the present invention. The amino acid
residues include but are not limited to the 20 naturally occurring
amino acids commonly designated by three letter symbols and also
includes phosphoserine, phosphothreonine, phosphotyrosine,
4-hydroxyproline, hydroxylysine, demosine, isodemosine,
gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic
acid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,
penicillamine, ornithine, 3-methylhistidine, norvaline,
beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine,
homoserine, methyl-alanine, para-benzoylphenylalanine,
phenylglycine, propargylglycine, sarcosine, methionine sulfone and
tert-butylglycine.
[0152] Additional types of prodrugs are also encompassed. For
instance, a free carboxyl group of a compound of the invention can
be derivatized as an amide or alkyl ester. As another example,
compounds of this invention comprising free hydroxy groups can be
derivatized as prodrugs by converting the hydroxy group into a
group such as, but not limited to, a phosphate ester,
hemisuccinate, dimethylaminoacetate, or
phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D.
et al., (1996) Improved oral drug delivery: solubility limitations
overcome by the use of prodrugs Advanced Drug Delivery Reviews,
19:115. Carbamate prodrugs of hydroxy and amino groups are also
included, as are carbonate prodrugs, sulfonate esters and sulfate
esters of hydroxy groups. Derivatization of hydroxy groups as
(acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group
can be an alkyl ester optionally substituted with groups including,
but not limited to, ether, amine and carboxylic acid
functionalities, or where the acyl group is an amino acid ester as
described above, are also encompassed. Prodrugs of this type are
described in J. Med. Chem., (1996), 39:10. More specific examples
include replacement of the hydrogen atom of the alcohol group with
a group such as (C.sub.1-6)alkanoyloxymethyl,
1-((C.sub.1-6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-6)alkanoyloxy)ethyl,
(C.sub.1-6)alkoxycarbonyloxymethyl,
N--(C.sub.1-6)alkoxycarbonylaminomethyl, succinoyl,
(C.sub.1-6)alkanoyl, alpha-amino(C.sub.1-4)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.1-6)alkyl).sub.2 or glycosyl (the radical resulting
from the removal of a hydroxyl group of the hemiacetal form of a
carbohydrate).
[0153] For additional examples of prodrug derivatives, see, for
example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier,
1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K.
Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design
and Development, edited by Krogsgaard-Larsen and H. Bundgaard,
Chapter 5 "Design and Application of Prodrugs," by H. Bundgaard p.
113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews,
8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical
Sciences, 77:285 (1988); and e) N. Kakeya, et al., Chem. Pharm.
Bull., 32:692 (1984), each of which is specifically incorporated
herein by reference.
[0154] Additionally, the present invention provides for metabolites
of compounds of the invention. As used herein, a "metabolite"
refers to a product produced through metabolism in the body of a
specified compound or salt thereof. Such products can result for
example from the oxidation, reduction, hydrolysis, amidation,
deamidation, esterification, deesterification, enzymatic cleavage,
and the like, of the administered compound.
[0155] Metabolite products typically are identified by preparing a
radiolabelled (e.g., .sup.14C or .sup.3H) isotope of a compound of
the invention, administering it parenterally in a detectable dose
(e.g., greater than about 0.5 mg/kg) to an animal such as rat,
mouse, guinea pig, monkey, or to man, allowing sufficient time for
metabolism to occur (typically about 30 seconds to 30 hours) and
isolating its conversion products from the urine, blood or other
biological samples. These products are easily isolated since they
are labeled (others are isolated by the use of antibodies capable
of binding epitopes surviving in the metabolite). The metabolite
structures are determined in conventional fashion, e.g., by MS,
LC/MS or NMR analysis. In general, analysis of metabolites is done
in the same way as conventional drug metabolism studies well known
to those skilled in the art. The metabolite products, so long as
they are not otherwise found in vivo, are useful in diagnostic
assays for therapeutic dosing of the compounds of the
invention.
Compounds
[0156] In one aspect the present invention provides for compounds
of Formula I and its embodiments as described hereinbove.
[0157] In another embodiment, the compound is selected from
compounds of formula I as described in the Examples herein and
salts thereof.
Synthesis of Compounds
[0158] Compounds of formula (I) may be prepared as illustrated in
Scheme 1 below and as shown in the Examples herein.
##STR00104##
Pharmaceutical Compositions and Administration
[0159] In addition to one or more of the compounds provided above
(or stereoisomers, geometric isomers, tautomers, solvates,
metabolites, isotopes, pharmaceutically acceptable salts, or
prodrugs thereof), the invention also provides for compositions and
medicaments comprising a compound of formula I or and embodiment
thereof and at least one pharmaceutically acceptable carrier,
diluent or excipient. The compositions of the invention can be used
to selectively inhibit NaV1.7 in patients (e.g, humans).
[0160] The term "composition," as used herein, is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts. By "pharmaceutically acceptable" it is meant the
carrier, diluent or excipient must be compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof.
[0161] In one embodiment, the invention provides for pharmaceutical
compositions (or medicaments) comprising a compound of formula I or
an embodiment thereof, and its stereoisomers, geometric isomers,
tautomers, solvates, metabolites, isotopes, pharmaceutically
acceptable salts, or prodrugs thereof) and a pharmaceutically
acceptable carrier, diluent or excipient. In another embodiment,
the invention provides for preparing compositions (or medicaments)
comprising compounds of the invention. In another embodiment, the
invention provides for administering compounds of formula I or its
embodiments and compositions comprising compounds of formula I or
an embodiment thereof to a patient (e.g., a human patient) in need
thereof.
[0162] Compositions are formulated, dosed, and administered in a
fashion consistent with good medical practice. Factors for
consideration in this context include the particular disorder being
treated, the particular mammal being treated, the clinical
condition of the individual patient, the cause of the disorder, the
site of delivery of the agent, the method of administration, the
scheduling of administration, and other factors known to medical
practitioners. The effective amount of the compound to be
administered will be governed by such considerations, and is the
minimum amount necessary to inhibit NaV1.7 activity as required to
prevent or treat the undesired disease or disorder, such as for
example, pain. For example, such amount may be below the amount
that is toxic to normal cells, or the mammal as a whole.
[0163] In one example, the therapeutically effective amount of the
compound of the invention administered parenterally per dose will
be in the range of about 0.01-100 mg/kg, alternatively about e.g.,
0.1 to 20 mg/kg of patient body weight per day, with the typical
initial range of compound used being 0.3 to 15 mg/kg/day. The daily
does is, in certain embodiments, given as a single daily dose or in
divided doses two to six times a day, or in sustained release form.
In the case of a 70 kg adult human, the total daily dose will
generally be from about 7 mg to about 1,400 mg. This dosage regimen
may be adjusted to provide the optimal therapeutic response. The
compounds may be administered on a regimen of 1 to 4 times per day,
preferably once or twice per day.
[0164] The compounds of the present invention may be administered
in any convenient administrative form, e.g., tablets, powders,
capsules, solutions, dispersions, suspensions, syrups, sprays,
suppositories, gels, emulsions, patches, etc. Such compositions may
contain components conventional in pharmaceutical preparations,
e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents,
and further active agents.
[0165] The compounds of the invention may be administered by any
suitable means, including oral, topical (including buccal and
sublingual), rectal, vaginal, transdermal, parenteral,
subcutaneous, intraperitoneal, intrapulmonary, intradermal,
intrathecal and epidural and intranasal, and, if desired for local
treatment, intralesional administration. Parenteral infusions
include intramuscular, intravenous, intraarterial, intraperitoneal,
intracerebral, intraocular, intralesional or subcutaneous
administration.
[0166] The compositions comprising compounds of formula I or an
embodiment thereof are normally formulated in accordance with
standard pharmaceutical practice as a pharmaceutical composition. A
typical formulation is prepared by mixing a compound of the present
invention and a diluent, carrier or excipient. Suitable diluents,
carriers and excipients are well known to those skilled in the art
and are described in detail in, e.g., Ansel, Howard C., et al.,
Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.
Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,
Alfonso R., et al. Remington: The Science and Practice of Pharmacy.
Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,
Raymond C. Handbook of Pharmaceutical Excipients. Chicago,
Pharmaceutical Press, 2005. The formulations may also include one
or more buffers, stabilizing agents, surfactants, wetting agents,
lubricating agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents, diluents
and other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0167] Suitable carriers, diluents and excipients are well known to
those skilled in the art and include materials such as
carbohydrates, waxes, water soluble and/or swellable polymers,
hydrophilic or hydrophobic materials, gelatin, oils, solvents,
water and the like. The particular carrier, diluent or excipient
used will depend upon the means and purpose for which a compound of
the present invention is being applied. Solvents are generally
selected based on solvents recognized by persons skilled in the art
as safe (GRAS) to be administered to a mammal. In general, safe
solvents are non-toxic aqueous solvents such as water and other
non-toxic solvents that are soluble or miscible in water. Suitable
aqueous solvents include water, ethanol, propylene glycol,
polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures
thereof. The formulations can also include one or more buffers,
stabilizing agents, surfactants, wetting agents, lubricating
agents, emulsifiers, suspending agents, preservatives,
antioxidants, opaquing agents, glidants, processing aids,
colorants, sweeteners, perfuming agents, flavoring agents and other
known additives to provide an elegant presentation of the drug
(i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0168] Acceptable diluents, carriers, excipients and stabilizers
are nontoxic to recipients at the dosages and concentrations
employed, and include buffers such as phosphate, citrate and other
organic acids; antioxidants including ascorbic acid and methionine;
preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium
chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as
methyl or propyl paraben; catechol; resorcinol; cyclohexanol;
3-pentanol; and m-cresol); low molecular weight (less than about 10
residues) polypeptides; proteins, such as serum albumin, gelatin,
or immunoglobulins; hydrophilic polymers such as
polyvinylpyrrolidone; amino acids such as glycine, glutamine,
asparagine, histidine, arginine, or lysine; monosaccharides,
disaccharides and other carbohydrates including glucose, mannose,
or dextrins; chelating agents such as EDTA; sugars such as sucrose,
mannitol, trehalose or sorbitol; salt-forming counter-ions such as
sodium; metal complexes (e.g., Zn-protein complexes); and/or
non-ionic surfactants such as TWEEN.TM., PLURONICS.TM. or
polyethylene glycol (PEG). A active pharmaceutical ingredient of
the invention (e.g., compound of formula I or an embodiment
thereof) can also be entrapped in microcapsules prepared, for
example, by coacervation techniques or by interfacial
polymerization, for example, hydroxymethylcellulose or
gelatin-microcapsules and poly-(methylmethacylate) microcapsules,
respectively, in colloidal drug delivery systems (for example,
liposomes, albumin microspheres, microemulsions, nano-particles and
nanocapsules) or in macroemulsions. Such techniques are disclosed
in Remington: The Science and Practice of Pharmacy: Remington the
Science and Practice of Pharmacy (2005) 21.sup.st Edition,
Lippincott Williams & Wilkins, Philidelphia, Pa.
[0169] Sustained-release preparations of a compound of the
invention (e.g., compound of formula I or an embodiment thereof)
can be prepared. Suitable examples of sustained-release
preparations include semipermeable matrices of solid hydrophobic
polymers containing a compound of formula I or an embodiment
thereof, which matrices are in the form of shaped articles, e.g.,
films, or microcapsules. Examples of sustained-release matrices
include polyesters, hydrogels (for example,
poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)),
polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic
acid and gamma-ethyl-L-glutamate (Sidman et al., Biopolymers
22:547, 1983), non-degradable ethylene-vinyl acetate (Langer et
al., J. Biomed. Mater. Res. 15:167, 1981), degradable lactic
acid-glycolic acid copolymers such as the LUPRON DEPOT.TM.
(injectable microspheres composed of lactic acid-glycolic acid
copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric
acid (EP 133,988A). Sustained release compositions also include
liposomally entrapped compounds, which can be prepared by methods
known per se (Epstein et al., Proc. Natl. Acad. Sci. U.S.A.
82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A. 77:4030,
1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).
Ordinarily, the liposomes are of the small (about 200-800
Angstroms) unilamelar type in which the lipid content is greater
than about 30 mol % cholesterol, the selected proportion being
adjusted for the optimal therapy.
[0170] The formulations include those suitable for the
administration routes detailed herein. The formulations can
conveniently be presented in unit dosage form and can be prepared
by any of the methods well known in the art of pharmacy. Techniques
and formulations generally are found in Remington: The Science and
Practice of Pharmacy: Remington the Science and Practice of
Pharmacy (2005) 21.sup.st Edition, Lippincott Williams &
Wilkins, Philidelphia, Pa. Such methods include the step of
bringing into association the active ingredient with the carrier
which constitutes one or more accessory ingredients.
[0171] In general the formulations are prepared by uniformly and
intimately bringing into association the active ingredient with
liquid carriers, diluents or excipients or finely divided solid
carriers, diluents or excipients, or both, and then, if necessary,
shaping the product. A typical formulation is prepared by mixing a
compound of the present invention and a carrier, diluent or
excipient. The formulations can be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., compound of the present invention or stabilized
form of the compound (e.g., complex with a cyclodextrin derivative
or other known complexation agent) is dissolved in a suitable
solvent in the presence of one or more of the excipients described
above. A compound of the present invention is typically formulated
into pharmaceutical dosage forms to provide an easily controllable
dosage of the drug and to enable patient compliance with the
prescribed regimen.
[0172] In one example, compounds of formula I or an embodiment
thereof may be formulated by mixing at ambient temperature at the
appropriate pH, and at the desired degree of purity, with
physiologically acceptable carriers, i.e., carriers that are
non-toxic to recipients at the dosages and concentrations employed
into a galenical administration form. The pH of the formulation
depends mainly on the particular use and the concentration of
compound, but preferably ranges anywhere from about 3 to about 8.
In one example, a compound of formula I (or an embodiment thereof)
is formulated in an acetate buffer, at pH 5. In another embodiment,
the compounds of formula I or an embodiment thereof are sterile.
The compound may be stored, for example, as a solid or amorphous
composition, as a lyophilized formulation or as an aqueous
solution.
[0173] Formulations of a compound of the invention (e.g., compound
of formula I or an embodiment thereof) suitable for oral
administration can be prepared as discrete units such as pills,
capsules, cachets or tablets each containing a predetermined amount
of a compound of the invention.
[0174] Compressed tablets can be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as a powder or granules, optionally mixed with a binder, lubricant,
inert diluent, preservative, surface active or dispersing agent.
Molded tablets can be made by molding in a suitable machine a
mixture of the powdered active ingredient moistened with an inert
liquid diluent. The tablets can optionally be coated or scored and
optionally are formulated so as to provide slow or controlled
release of the active ingredient therefrom.
[0175] Tablets, troches, lozenges, aqueous or oil suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
e.g., gelatin capsules, syrups or elixirs can be prepared for oral
use. Formulations of a compound of the invention (e.g., compound of
formula I or an embodiment thereof) intended for oral use can be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
can contain one or more agents including sweetening agents,
flavoring agents, coloring agents and preserving agents, in order
to provide a palatable preparation. Tablets containing the active
ingredient in admixture with non-toxic pharmaceutically acceptable
excipient which are suitable for manufacture of tablets are
acceptable. These excipients can be, for example, inert diluents,
such as calcium or sodium carbonate, lactose, calcium or sodium
phosphate; granulating and disintegrating agents, such as maize
starch, or alginic acid; binding agents, such as starch, gelatin or
acacia; and lubricating agents, such as magnesium stearate, stearic
acid or talc. Tablets can be uncoated or can be coated by known
techniques including microencapsulation to delay disintegration and
adsorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate alone
or with a wax can be employed.
[0176] An example of a suitable oral administration form is a
tablet containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80
mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of
the invention compounded with about 90-30 mg anhydrous lactose,
about 5-40 mg sodium croscarmellose, about 5-30 mg
polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium
stearate. The powdered ingredients are first mixed together and
then mixed with a solution of the PVP. The resulting composition
can be dried, granulated, mixed with the magnesium stearate and
compressed to tablet form using conventional equipment. An example
of an aerosol formulation can be prepared by dissolving the
compound, for example 5-400 mg, of the invention in a suitable
buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g.
a salt such sodium chloride, if desired. The solution may be
filtered, e.g., using a 0.2 micron filter, to remove impurities and
contaminants.
[0177] For treatment of the eye or other external tissues, e.g.,
mouth and skin, the formulations are preferably applied as a
topical ointment or cream containing the active ingredient(s) in an
amount of, for example, 0.075 to 20% w/w. When formulated in an
ointment, the active ingredient can be employed with either a
paraffinic or a water-miscible ointment base. Alternatively, the
active ingredients can be formulated in a cream with an
oil-in-water cream base. If desired, the aqueous phase of the cream
base can include a polyhydric alcohol, i.e., an alcohol having two
or more hydroxyl groups such as propylene glycol, butane 1,3-diol,
mannitol, sorbitol, glycerol and polyethylene glycol (including PEG
400) and mixtures thereof. The topical formulations can desirably
include a compound which enhances absorption or penetration of the
active ingredient through the skin or other affected areas.
Examples of such dermal penetration enhancers include dimethyl
sulfoxide and related analogs.
[0178] The oily phase of the emulsions of this invention can be
constituted from known ingredients in a known manner. While the
phase can comprise merely an emulsifier, it desirably comprises a
mixture of at least one emulsifier with a fat or an oil or with
both a fat and an oil. Preferably, a hydrophilic emulsifier is
included together with a lipophilic emulsifier which acts as a
stabilizer. It is also preferred to include both an oil and a fat.
Together, the emulsifier(s) with or without stabilizer(s) make up
the so-called emulsifying wax, and the wax together with the oil
and fat make up the so-called emulsifying ointment base which forms
the oily dispersed phase of the cream formulations. Emulsifiers and
emulsion stabilizers suitable for use in the formulation of the
invention include Tween.RTM. 60, Span.RTM. 80, cetostearyl alcohol,
benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium
lauryl sulfate.
[0179] In one aspect of topical applications, it is desired to
administer an effective amount of a pharmaceutical composition
according to the invention to target area, e.g., skin surfaces,
mucous membranes, and the like, which are adjacent to peripheral
neurons which are to be treated. This amount will generally range
from about 0.0001 mg to about 1 g of a compound of the invention
per application, depending upon the area to be treated, whether the
use is diagnostic, prophylactic or therapeutic, the severity of the
symptoms, and the nature of the topical vehicle employed. A
preferred topical preparation is an ointment, wherein about 0.001
to about 50 mg of active ingredient is used per cc of ointment
base. The pharmaceutical composition can be formulated as
transdermal compositions or transdermal delivery devices
("patches"). Such compositions include, for example, a backing,
active compound reservoir, a control membrane, liner and contact
adhesive. Such transdermal patches may be used to provide
continuous pulsatile, or on demand delivery of the compounds of the
present invention as desired.
[0180] Aqueous suspensions of a compound of the invention (e.g.,
compound of formula I or an embodiment thereof) contain the active
materials in admixture with excipients suitable for the manufacture
of aqueous suspensions. Such excipients include a suspending agent,
such as sodium carboxymethylcellulose, croscarmellose, povidone,
methylcellulose, hydroxypropyl methylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing
or wetting agents such as a naturally occurring phosphatide (e.g.,
lecithin), a condensation product of an alkylene oxide with a fatty
acid (e.g., polyoxyethylene stearate), a condensation product of
ethylene oxide with a long chain aliphatic alcohol (e.g.,
heptadecaethyleneoxycetanol), a condensation product of ethylene
oxide with a partial ester derived from a fatty acid and a hexitol
anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous
suspension can also contain one or more preservatives such as ethyl
or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents and one or more sweetening agents, such as
sucrose or saccharin.
[0181] Formulations of a compound of the invention (e.g., compound
of formula I or an embodiment thereof) can be in the form of a
sterile injectable preparation, such as a sterile injectable
aqueous or oleaginous suspension. This suspension can be formulated
according to the known art using those suitable dispersing or
wetting agents and suspending agents which have been mentioned
above. The sterile injectable preparation can also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, such as a solution in 1,3-butanediol
or prepared as a lyophilized powder.
[0182] Among the acceptable vehicles and solvents that can be
employed are water, Ringer's solution and isotonic sodium chloride
solution. In addition, sterile fixed oils can conventionally be
employed as a solvent or suspending medium. For this purpose any
bland fixed oil can be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid can
likewise be used in the preparation of injectables.
[0183] The amount of active ingredient that can be combined with
the carrier material to produce a single dosage form will vary
depending upon the host treated and the particular mode of
administration. For example, a time-release formulation intended
for oral administration to humans can contain approximately 1 to
1000 mg of active material compounded with an appropriate and
convenient amount of carrier material which can vary from about 5
to about 95% of the total compositions (weight:weight). The
pharmaceutical composition can be prepared to provide easily
measurable amounts for administration. For example, an aqueous
solution intended for intravenous infusion can contain from about 3
to 500 .mu.g of the active ingredient per milliliter of solution in
order that infusion of a suitable volume at a rate of about 30
mL/hr can occur.
[0184] Formulations suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which can
contain anti-oxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended
recipient; and aqueous and non-aqueous sterile suspensions which
can include suspending agents and thickening agents.
[0185] Formulations suitable for topical administration to the eye
also include eye drops wherein the active ingredient is dissolved
or suspended in a suitable carrier, especially an aqueous solvent
for the active ingredient. The active ingredient is preferably
present in such formulations in a concentration of about 0.5 to 20%
w/w, for example about 0.5 to 10% w/w, for example about 1.5%
w/w.
[0186] Formulations suitable for topical administration in the
mouth include lozenges comprising the active ingredient in a
flavored basis, usually sucrose and acacia or tragacanth; pastilles
comprising the active ingredient in an inert basis such as gelatin
and glycerin, or sucrose and acacia; and mouthwashes comprising the
active ingredient in a suitable liquid carrier.
[0187] Formulations for rectal administration can be presented as a
suppository with a suitable base comprising for example cocoa
butter or a salicylate.
[0188] Formulations suitable for intrapulmonary or nasal
administration have a particle size for example in the range of 0.1
to 500 microns (including particle sizes in a range between 0.1 and
500 microns in increments microns such as 0.5, 1, 30 microns, 35
microns, etc.), which is administered by rapid inhalation through
the nasal passage or by inhalation through the mouth so as to reach
the alveolar sacs. Suitable formulations include aqueous or oily
solutions of the active ingredient. Formulations suitable for
aerosol or dry powder administration can be prepared according to
conventional methods and can be delivered with other therapeutic
agents such as compounds heretofore used in the treatment of
disorders as described below.
[0189] The formulations can be packaged in unit-dose or multi-dose
containers, for example sealed ampoules and vials, and can be
stored in a freeze-dried (lyophilized) condition requiring only the
addition of the sterile liquid carrier, for example water, for
injection immediately prior to use. Extemporaneous injection
solutions and suspensions are prepared from sterile powders,
granules and tablets of the kind previously described. Preferred
unit dosage formulations are those containing a daily dose or unit
daily sub-dose, as herein above recited, or an appropriate fraction
thereof, of the active ingredient.
[0190] When the binding target is located in the brain, certain
embodiments of the invention provide for a compound of formula I
(or an embodiment thereof) to traverse the blood-brain barrier.
Certain neurodegenerative diseases are associated with an increase
in permeability of the blood-brain barrier, such that a compound of
formula I (or an embodiment thereof) can be readily introduced to
the brain. When the blood-brain barrier remains intact, several
art-known approaches exist for transporting molecules across it,
including, but not limited to, physical methods, lipid-based
methods, and receptor and channel-based methods.
[0191] Physical methods of transporting a compound of formula I (or
an embodiment thereof) across the blood-brain barrier include, but
are not limited to, circumventing the blood-brain barrier entirely,
or by creating openings in the blood-brain barrier.
[0192] Circumvention methods include, but are not limited to,
direct injection into the brain (see, e.g., Papanastassiou et al.,
Gene Therapy 9:398-406, 2002), interstitial
infusion/convection-enhanced delivery (see, e.g., Bobo et al.,
Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080, 1994), and implanting a
delivery device in the brain (see, e.g., Gill et al., Nature Med.
9:589-595, 2003; and Gliadel Wafers.TM., Guildford Pharmaceutical).
Methods of creating openings in the barrier include, but are not
limited to, ultrasound (see, e.g., U.S. Patent Publication No.
2002/0038086), osmotic pressure (e.g., by administration of
hypertonic mannitol (Neuwelt, E. A., Implication of the Blood-Brain
Barrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y.,
1989)), and permeabilization by, e.g., bradykinin or permeabilizer
A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and
5,686,416).
[0193] Lipid-based methods of transporting a compound of formula I
(or an embodiment thereof) across the blood-brain barrier include,
but are not limited to, encapsulating the a compound of formula I
(or an embodiment thereof) in liposomes that are coupled to
antibody binding fragments that bind to receptors on the vascular
endothelium of the blood-brain barrier (see, e.g., U.S. Patent
Application Publication No. 2002/0025313), and coating a compound
of formula I (or an embodiment thereof) in low-density lipoprotein
particles (see, e.g., U.S. Patent Application Publication No.
2004/0204354) or apolipoprotein E (see, e.g., U.S. Patent
Application Publication No. 2004/0131692).
[0194] Receptor and channel-based methods of transporting a
compound of formula I (or an embodiment thereof) across the
blood-brain barrier include, but are not limited to, using
glucocorticoid blockers to increase permeability of the blood-brain
barrier (see, e.g., U.S. Patent Application Publication Nos.
2002/0065259, 2003/0162695, and 2005/0124533); activating potassium
channels (see, e.g., U.S. Patent Application Publication No.
2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S.
Patent Application Publication No. 2003/0073713); coating a
compound of formula I (or an embodiment thereof) with a transferrin
and modulating activity of the one or more transferrin receptors
(see, e.g., U.S. Patent Application Publication No. 2003/0129186),
and cationizing the antibodies (see, e.g., U.S. Pat. No.
5,004,697).
[0195] For intracerebral use, in certain embodiments, the compounds
can be administered continuously by infusion into the fluid
reservoirs of the CNS, although bolus injection may be acceptable.
The inhibitors can be administered into the ventricles of the brain
or otherwise introduced into the CNS or spinal fluid.
Administration can be performed by use of an indwelling catheter
and a continuous administration means such as a pump, or it can be
administered by implantation, e.g., intracerebral implantation of a
sustained-release vehicle. More specifically, the inhibitors can be
injected through chronically implanted cannulas or chronically
infused with the help of osmotic minipumps. Subcutaneous pumps are
available that deliver proteins through a small tubing to the
cerebral ventricles. Highly sophisticated pumps can be refilled
through the skin and their delivery rate can be set without
surgical intervention. Examples of suitable administration
protocols and delivery systems involving a subcutaneous pump device
or continuous intracerebroventricular infusion through a totally
implanted drug delivery system are those used for the
administration of dopamine, dopamine agonists, and cholinergic
agonists to Alzheimer's disease patients and animal models for
Parkinson's disease, as described by Harbaugh, J. Neural Transm.
Suppl. 24:271, 1987; and DeYebenes et al., Mov. Disord. 2: 143,
1987.
[0196] A compound of formula I (or an embodiment thereof) used in
the invention are formulated, dosed, and administered in a fashion
consistent with good medical practice. Factors for consideration in
this context include the particular disorder being treated, the
particular mammal being treated, the clinical condition of the
individual patient, the cause of the disorder, the site of delivery
of the agent, the method of administration, the scheduling of
administration, and other factors known to medical practitioners. A
compound of formula I (or an embodiment thereof) need not be, but
is optionally formulated with one or more agent currently used to
prevent or treat the disorder in question. The effective amount of
such other agents depends on the amount of a compound of the
invention present in the formulation, the type of disorder or
treatment, and other factors discussed above.
[0197] These are generally used in the same dosages and with
administration routes as described herein, or about from 1 to 99%
of the dosages described herein, or in any dosage and by any route
that is empirically/clinically determined to be appropriate.
[0198] For the prevention or treatment of disease, the appropriate
dosage of a compound of formula I (or an embodiment thereof) (when
used alone or in combination with other agents) will depend on the
type of disease to be treated, the properties of the compound, the
severity and course of the disease, whether the compound is
administered for preventive or therapeutic purposes, previous
therapy, the patient's clinical history and response to the
compound, and the discretion of the attending physician. The
compound is suitably administered to the patient at one time or
over a series of treatments. Depending on the type and severity of
the disease, about 1 .mu.g/kg to 15 mg/kg (e.g., 0.1 mg/kg-10
mg/kg) of compound can be an initial candidate dosage for
administration to the patient, whether, for example, by one or more
separate administrations, or by continuous infusion. One typical
daily dosage might range from about 1 .mu.g kg to 100 mg/kg or
more, depending on the factors mentioned above. For repeated
administrations over several days or longer, depending on the
condition, the treatment would generally be sustained until a
desired suppression of disease symptoms occurs. One exemplary
dosage of a compound of formula I (or an embodiment thereof) would
be in the range from about 0.05 mg/kg to about 10 mg/kg. Thus, one
or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg
(or any combination thereof) may be administered to the patient.
Such doses may be administered intermittently, e.g., every week or
every three weeks (e.g., such that the patient receives from about
two to about twenty, or, e.g., about six doses of the antibody). An
initial higher loading dose, followed by one or more lower doses
may be administered. An exemplary dosing regimen comprises
administering an initial loading dose of about 4 mg/kg, followed by
a weekly maintenance dose of about 2 mg kg of the compound.
However, other dosage regimens may be useful. The progress of this
therapy is easily monitored by conventional techniques and
assays.
[0199] Other typical daily dosages might range from, for example,
about 1 g/kg to up to 100 mg/kg or more (e.g., about 1 .mu.g kg to
1 mg/kg, about 1 .mu.g/kg to about 5 mg/kg, about 1 mg kg to 10
mg/kg, about 5 mg/kg to about 200 mg/kg, about 50 mg/kg to about
150 mg/mg, about 100 mg/kg to about 500 mg/kg, about 100 mg/kg to
about 400 mg/kg, and about 200 mg/kg to about 400 mg/kg), depending
on the factors mentioned above. Typically, the clinician will
administer a compound until a dosage is reached that results in
improvement in or, optimally, elimination of, one or more symptoms
of the treated disease or condition. The progress of this therapy
is easily monitored by conventional assays. One or more agent
provided herein may be administered together or at different times
(e.g., one agent is administered prior to the administration of a
second agent). One or more agent may be administered to a subject
using different techniques (e.g., one agent may be administered
orally, while a second agent is administered via intramuscular
injection or intranasally). One or more agent may be administered
such that the one or more agent has a pharmacologic effect in a
subject at the same time. Alternatively, one or more agent may be
administered, such that the pharmacological activity of the first
administered agent is expired prior the administration of one or
more secondarily administered agents (e.g., 1, 2, 3, or 4
secondarily administered agents).
Indications and Methods of Treatment
[0200] The compounds of the invention modulate, preferably inhibit,
ion flux through a voltage-dependent sodium channel in a mammal,
(e.g, a human). Any such modulation, whether it be partial or
complete inhibition or prevention of ion flux, is sometimes
referred to herein as "blocking" and corresponding compounds as
"blockers" or "inhibitors". In general, the compounds of the
invention modulate the activity of a sodium channel downwards by
inhibiting the voltage-dependent activity of the sodium channel,
and/or reduce or prevent sodium ion flux across a cell membrane by
preventing sodium channel activity such as ion flux.
[0201] Accordingly, the compounds of the invention are sodium
channel blockers and are therefore useful for treating diseases and
conditions in mammals, for example humans, and other organisms,
including all those diseases and conditions which are the result of
aberrant voltage-dependent sodium channel biological activity or
which may be ameliorated by modulation of voltage-dependent sodium
channel biological activity. In particular, the compounds of the
invention, i.e., the compounds of formula (I) and embodiments and
(or stereoisomers, geometric isomers, tautomers, solvates,
metabolites, isotopes, pharmaceutically acceptable salts, or
prodrugs thereof), are useful for treating diseases and conditions
in mammals, for example humans, which are the result of aberrant
voltage-dependent NaV1.7 biological activity or which may be
ameliorated by the modulation, preferably the inhibition, of NaV1.7
biological activity. In certain aspects, the compounds of the
invention selectively inhibit NaV1.7 over NaV1.5.
[0202] As defined herein, a sodium channel-mediated disease or
condition refers to a disease or condition in a mammal, preferably
a human, which is ameliorated upon modulation of the sodium channel
and includes, but is not limited to, pain, central nervous
conditions such as epilepsy, anxiety, depression and bipolar
disease; cardiovascular conditions such as arrhythmias, atrial
fibrillation and ventricular fibrillation; neuromuscular conditions
such as restless leg syndrome and muscle paralysis or tetanus;
neuroprotection against stroke, neural trauma and multiple
sclerosis; and channelopathies such as erythromyalgia and familial
rectal pain syndrome.
[0203] In one aspect, the present invention relates to compounds,
pharmaceutical compositions and methods of using the compounds and
pharmaceutical compositions for the treatment of sodium
channel-mediated diseases in mammals, preferably humans and
preferably diseases and conditions related to pain, central nervous
conditions such as epilepsy, anxiety, depression and bipolar
disease; cardiovascular conditions such as arrhythmias, atrial
fibrillation and ventricular fibrillation; neuromuscular conditions
such as restless leg syndrome and muscle paralysis or tetanus;
neuroprotection against stroke, neural trauma and multiple
sclerosis; and channelopathies such as erythromyalgia and familial
rectal pain syndrome, by administering to a mammal, for example a
human, in need of such treatment an effective amount of a sodium
channel blocker modulating, especially inhibiting, agent.
[0204] A sodium channel-mediated disease or condition also includes
pain associated with HIV, HIV treatment induced neuropathy,
trigeminal neuralgia, glossopharyngeal neuralgia, neuropathy
secondary to metastatic infiltration, adiposis dolorosa, thalamic
lesions, hypertension, autoimmune disease, asthma, drug addiction
(e.g., opiate, benzodiazepine, amphetamine, cocaine, alcohol,
butane inhalation), Alzheimer, dementia, age-related memory
impairment, Korsakoff syndrome, restenosis, urinary dysfunction,
incontinence, Parkinson's disease, cerebrovascular ischemia,
neurosis, gastrointestinal disease, sickle cell anemia, transplant
rejection, heart failure, myocardial infarction, reperfusion
injury, intermittant claudication, angina, convulsion, respiratory
disorders, cerebral or myocardial ischemias, long-QT syndrome,
Catecholeminergic polymorphic ventricular tachycardia, ophthalmic
diseases, spasticity, spastic paraplegia, myopathies, myasthenia
gravis, paramyotonia congentia, hyperkalemic periodic paralysis,
hypokalemic periodic paralysis, alopecia, anxiety disorders,
psychotic disorders, mania, paranoia, seasonal affective disorder,
panic disorder, obsessive compulsive disorder (OCD), phobias,
autism, Aspergers Syndrome, Retts syndrome, disintegrative
disorder, attention deficit disorder, aggressivity, impulse control
disorders, thrombosis, pre clampsia, congestive cardiac failure,
cardiac arrest, Freidrich's ataxia, Spinocerebellear ataxia,
myelopathy, radiculopathy, systemic lupus erythamatosis,
granulomatous disease, olivo-ponto-cerebellar atrophy,
spinocerebellar ataxia, episodic ataxia, myokymia, progressive
pallidal atrophy, progressive supranuclear palsy and spasticity,
traumatic brain injury, cerebral oedema, hydrocephalus injury,
spinal cord injury, anorexia nervosa, bulimia, Prader-Willi
syndrome, obesity, optic neuritis, cataract, retinal haemorrhage,
ischaemic retinopathy, retinitis pigmentosa, acute and chronic
glaucoma, macular degeneration, retinal artery occlusion, Chorea,
Huntington's chorea, cerebral edema, proctitis, post-herpetic
neuralgia, eudynia, heat sensitivity, sarcoidosis, irritable bowel
syndrome, Tourette syndrome, Lesch-Nyhan Syndrome, Brugado
syndrome, Liddle syndrome, Crohns disease, multiple sclerosis and
the pain associated with multiple sclerosis (MS), amyotrophic
lateral sclerosis (ALS), disseminated sclerosis, diabetic
neuropathy, peripheral neuropathy, charcot marie tooth syndrome,
arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,
atherosclerosis, paroxysmal dystonia, myasthenia syndromes,
myotonia, myotonic dystrophy, muscular dystrophy, malignant
hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis,
mental handicap, hypothyroidism, bipolar depression, anxiety,
schizophrenia, sodium channel toxin related illnesses, familial
erythromelalgia, primary erythromelalgia, rectal pain, cancer,
epilepsy, partial and general tonic seizures, febrile seizures,
absence seizures (petit mal), myoclonic seizures, atonic seizures,
clonic seizures, Lennox Gastaut, West Syndome (infantile spasms),
multiresistant seizures, seizure prophylaxis (anti-epileptogenic),
familial Mediterranean fever syndrome, gout, restless leg syndrome,
arrhythmias, fibromyalgia, neuroprotection under ischaemic
conditions caused by stroke or neural trauma, tachy-arrhythmias,
atrial fibrillation and ventricular fibrillation and as a general
or local anaesthetic.
[0205] As used herein, the term "pain" refers to all categories of
pain and is recognized to include, but is not limited to,
neuropathic pain, inflammatory pain, nociceptive pain, idiopathic
pain, neuralgic pain, orofacial pain, burn pain, burning mouth
syndrome, somatic pain, visceral pain, myofacial pain, dental pain,
cancer pain, chemotherapy pain, trauma pain, surgical pain,
post-surgical pain, childbirth pain, labor pain, chronic regional
pain syndrome (CRPS), reflex sympathetic dystrophy, brachial plexus
avulsion, neurogenic bladder, acute pain (e.g., musculoskeletal and
post-operative pain), chronic pain, persistent pain, peripherally
mediated pain, centrally mediated pain, chronic headache, migraine
headache, familial hemiplegic migraine, conditions associated with
cephalic pain, sinus headache, tension headache, phantom limb pain,
peripheral nerve injury, pain following stroke, thalamic lesions,
radiculopathy, HIV pain, post-herpetic pain, non-cardiac chest
pain, irritable bowel syndrome and pain associated with bowel
disorders and dyspepsia, and combinations thereof.
[0206] Furthermore, sodium channel blockers have clinical uses in
addition to pain. The present invention therefore also relates to
compounds, pharmaceutical compositions and methods of using the
compounds and pharmaceutical compositions for the treatment of
diseases or conditions such as cancer and pruritus (itch).
[0207] Pruritus, commonly known as itch, is a common dermatological
condition. While the exact causes of pruritus are complex and
incompletely understood, there has long been evidence that itch
involves sensory neurons, especially C fibers, similar to those
that mediate pain (Schmelz, M., et al., J. Neurosci. (1997), 17:
8003-8). In particular, it is believed that sodium influx through
voltage-gated sodium channels is essential for the propagation of
itch sensation from the skin. Transmission of the itch impulses
results in the unpleasant sensation that elicits the desire or
reflex to scratch.
[0208] Multiple causes and electrical pathways for eliciting itch
are known. In humans, pruritus can be elicited by histamine or
PAR-2 agonists such as mucunain that activate distinct populations
of C fibers (Namer, B., et al., J. Neurophysiol. (2008), 100:
2062-9). A variety of neurotrophic peptides are known to mediate
itch in animal models (Wang, H., and Yosipovitch, G., International
Journal of Dermatology (2010), 49: 1-11). Itch can also be elicited
by opioids, evidence of distinct pharmacology from that of pain
responses.
[0209] There exists a complex interaction between itch and pain
responses that arises in part from the overlapping sensory input
from the skin (Ikoma, A., et al., Arch. Dermatol. (2003), 139:
1475-8) and also from the diverse etiology of both pain and
pruritus. Pain responses can exacerbate itching by enhancing
central sensitization or lead to inhibition of painful scratching.
Particularly severe forms of chronic itch occur when pain responses
are absent, as in the case of post-herpetic itch (Oaklander, A. L.,
et al., Pain (2002), 96: 9-12).
[0210] The compounds of the invention can also be useful for
treating pruritus. The rationale for treating itch with inhibitors
of voltage-gated sodium channels, especially NaV1.7, is as
follows:
[0211] The propagation of electrical activity in the C fibers that
sense pruritinergic stimulants requires sodium entry through
voltage-gated sodium channels.
[0212] NaV1.7 is expressed in the C fibers and kerotinocytes in
human skin (Zhao, P., et al., Pain (2008), 139: 90-105).
[0213] A gain of function mutation of NaV1.7 (L858F) that causes
erythromelalgia also causes chronic itch (Li, Y., et al., Clinical
and Experimental Dermatology (2009), 34: e313-e4).
[0214] Chronic itch can be alleviated with treatment by sodium
channel blockers, such as the local anesthetic lidocaine
(Oaklander, A. L., et al., Pain (2002), 96: 9-12; Villamil, A. G.,
et al., The American Journal of Medicine (2005), 118: 1160-3). In
these reports, lidocaine was effective when administered either
intravenously or topically (a Lidoderm patch). Lidocaine can have
multiple activities at the plasma concentrations achieved when
administered systemically, but when administered topically, the
plasma concentrations are only about 1 .mu.M (Center for Drug
Evaluation and Research NDA 20-612). At these concentrations,
lidocaine is selective for sodium channel block and inhibits
spontaneous electrical activity in C fibers and pain responses in
animal models (Xiao, W. H., and Bennett, G. J. Pain (2008), 137:
218-28). The types of itch or skin irritation, include, but are not
limited to: [0215] psoriatic pruritus, itch due to hemodyalisis,
aguagenic pruritus, and itching caused by skin disorders (e.g.,
contact dermatitis), systemic disorders, neuropathy, psychogenic
factors or a mixture thereof, itch caused by allergic reactions,
insect bites, hypersensitivity (e.g., dry skin, acne, eczema,
psoriasis), inflammatory conditions or injury; [0216] itch
associated with vulvar vestibulitis; and [0217] skin irritation or
inflammatory effect from administration of another therapeutic such
as, for example, antibiotics, antivirals and antihistamines.
[0218] The compounds of the invention are also useful in treating
certain cancers, such as hormone sensitive cancers, such as
prostate cancer (adenocarcinoma), breast cancer, ovarian cancer,
testicular cancer and thyroid neoplasia, in a mammal, preferably a
human. The voltage gated sodium channels have been demonstrated to
be expressed in prostate and breast cancer cells. Up-regulation of
neonatal NaV1.5 occurs as an integral part of the metastatic
process in human breast cancer and could serve both as a novel
marker of the metastatic phenotype and a therapeutic target (Clin.
Cancer Res. (2005), Aug. 1; 11(15): 5381-9). Functional expression
of voltage-gated sodium channel alpha-subunits, specifically
NaV1.7, is associated with strong metastatic potential in prostate
cancer (CaP) in vitro. Voltage-gated sodium channel alpha-subunits
immunostaining, using antibodies specific to the sodium channel
alpha subunit was evident in prostatic tissues and markedly
stronger in CaP vs non-CaP patients (Prostate Cancer Prostatic
Dis., 2005; 8(3):266-73). See also Diss, J. K. J., et al., Mol.
Cell. Neurosci. (2008), 37:537-547 and Kis-Toth, K., et al., The
Journal of Immunology (2011), 187:1273-1280.
[0219] In consideration of the above, in one embodiment, the
present invention provides a method for treating a mammal for, or
protecting a mammal from developing, a sodium channel-mediated
disease, especially pain, comprising administering to the mammal,
especially a human, in need thereof, a therapeutically effective
amount of a compound of the invention or a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention wherein the compound modulates the
activity of one or more voltage-dependent sodium channels.
[0220] In another embodiment of the invention is a method of
treating a disease or a condition in a mammal, preferably a human,
wherein the disease or condition is selected from the group
consisting of pain, depression, cardiovascular diseases,
respiratory diseases, and psychiatric diseases, and combinations
thereof, and wherein the method comprises administering to the
mammal in need thereof a therapeutically effective amount of an
embodiment of a compound of the invention, as set forth above, as a
stereoisomer, enantiomer or tautomer thereof or mixtures thereof,
or a pharmaceutically acceptable salt, solvate or prodrug thereof,
or a pharmaceutical composition comprising a therapeutically
effective amount of a compound of the invention, as set forth
above, as a stereoisomer, enantiomer or tautomer thereof or
mixtures thereof, or a pharmaceutically acceptable salt, solvate or
prodrug thereof, and a pharmaceutically acceptable excipient.
[0221] One embodiment of this embodiment is wherein the disease or
condition is selected from the group consisting of acute pain,
chronic pain, neuropathic pain, inflammatory pain, visceral pain,
cancer pain, chemotherapy pain, trauma pain, surgical pain, post
surgical pain, childbirth pain, labor pain, neurogenic bladder,
ulcerative colitis, persistent pain, peripherally mediated pain,
centrally mediated pain, chronic headache, migraine headache, sinus
headache, tension headache, phantom limb pain, peripheral nerve
injury, and combinations thereof.
[0222] Another embodiment of this embodiment is wherein the disease
or condition is selected from the group consisting of pain
associated with HIV, HIV treatment induced neuropathy, trigeminal
neuralgia, post herpetic neuralgia, eudynia, heat sensitivity,
tosarcoidosis, irritable bowel syndrome, Crohns disease, pain
associated with multiple sclerosis (MS), amyotrophic lateral
sclerosis (ALS), diabetic neuropathy, peripheral neuropathy,
arthritic, rheumatoid arthritis, osteoarthritis, atherosclerosis,
paroxysmal dystonia, myasthenia syndromes, myotonia, malignant
hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis,
hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium
channel toxin related illnesses, familial erythromelalgia, primary
erythromelalgia, familial rectal pain, cancer, epilepsy, partial
and general tonic seizures, restless leg syndrome, arrhythmias,
fibromyalgia, neuroprotection under ischaemic conditions caused by
stroke or neural trauma, tachy arrhythmias, atrial fibrillation and
ventricular fibrillation.
[0223] Another embodiment of the invention is a method of treating,
but not preventing, pain in a mammal, wherein the method comprises
administering to the mammal in need thereof a therapeutically
effective amount of a compound of the invention, as set forth
above, as a stereoisomer, enantiomer or tautomer thereof or
mixtures thereof, or a pharmaceutically acceptable salt, solvate or
prodrug thereof, or a pharmaceutical composition comprising a
therapeutically effective amount of a compound of the invention, as
set forth above, as a stereoisomer, enantiomer or tautomer thereof
or mixtures thereof, or a pharmaceutically acceptable salt, solvate
or prodrug thereof, and a pharmaceutically acceptable
excipient.
[0224] One embodiment of this embodiment is a method wherein the
pain is selected from the group consisting of neuropathic pain,
inflammatory pain, visceral pain, cancer pain, chemotherapy pain,
trauma pain, surgical pain, post surgical pain, childbirth pain,
labor pain, dental pain, chronic pain, persistent pain,
peripherally mediated pain, centrally mediated pain, chronic
headache, migraine headache, sinus headache, tension headache,
phantom limb pain, peripheral nerve injury, trigeminal neuralgia,
post herpetic neuralgia, eudynia, familial erythromelalgia, primary
erythromelalgia, familial rectal pain or fibromyalgia, and
combinations thereof.
[0225] Another embodiment of this embodiment is a method wherein
the pain is associated with a disease or condition selected from
HIV, HIV treatment induced neuropathy, heat sensitivity,
tosarcoidosis, irritable bowel syndrome, Crohns disease, multiple
sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy,
peripheral neuropathy, rheumatoid arthritis, osteoarthritis,
atherosclerosis, paroxysmal dystonia, myasthenia syndromes,
myotonia, malignant hyperthermia, cystic fibrosis,
pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar
depression, anxiety, schizophrenia, sodium channel toxin related
illnesses, neurogenic bladder, ulcerative colitis, cancer,
epilepsy, partial and general tonic seizures, restless leg
syndrome, arrhythmias, ischaemic conditions caused by stroke or
neural trauma, tachy arrhythmias, atrial fibrillation and
ventricular fibrillation.
[0226] Another embodiment of the invention is the method of
treating pain in a mammal, preferably a human, by the inhibition of
ion flux through a voltage dependent sodium channel in the mammal,
wherein the method comprises administering to the mammal in need
thereof a therapeutically effective amount of an embodiment of a
compound of the invention, as set forth above, as a stereoisomer,
enantiomer or tautomer thereof or mixtures thereof, or a
pharmaceutically acceptable salt, solvate or prodrug thereof, or a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of the invention, as set forth above, as a
stereoisomer, enantiomer or tautomer thereof or mixtures thereof,
or a pharmaceutically acceptable salt, solvate or prodrug thereof,
and a pharmaceutically acceptable excipient.
[0227] Another embodiment of the invention is the method of
treating pruritus in a mammal, preferably a human, wherein the
method comprises administering to the mammal in need thereof a
therapeutically effective amount of an embodiment of a compound of
the invention, as set forth above, as a stereoisomer, enantiomer or
tautomer thereof or mixtures thereof, or a pharmaceutically
acceptable salt, solvate or prodrug thereof, or a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention, as set forth above, as a stereoisomer,
enantiomer or tautomer thereof or mixtures thereof, or a
pharmaceutically acceptable salt, solvate or prodrug thereof, and a
pharmaceutically acceptable excipient.
[0228] Another embodiment of the invention is the method of
treating cancer in a mammal, preferably a human, wherein the method
comprises administering to the mammal in need thereof a
therapeutically effective amount of an embodiment of a compound of
the invention, as set forth above, as a stereoisomer, enantiomer or
tautomer thereof or mixtures thereof, or a pharmaceutically
acceptable salt, solvate or prodrug thereof, or a pharmaceutical
composition comprising a therapeutically effective amount of a
compound of the invention, as set forth above, as a stereoisomer,
enantiomer or tautomer thereof or mixtures thereof, or a
pharmaceutically acceptable salt, solvate or prodrug thereof, and a
pharmaceutically acceptable excipient.
[0229] Another embodiment of the invention is the method of
decreasing ion flux through a voltage dependent sodium channel in a
cell in a mammal, wherein the method comprises contacting the cell
with an embodiment of a compound of the invention, as set forth
above, as a stereoisomer, enantiomer or tautomer thereof or
mixtures thereof, or a pharmaceutically acceptable salt, solvate or
prodrug thereof.
[0230] Another embodiment of the invention is the method of
selectively inhibiting a first voltage-gated sodium channel over a
second voltage-gated sodium channel in a mammal, wherein the method
comprises administering to the mammal an inhibitory amount of a
compound of formula (I), or an embodiment of a compound of formula
(I).
[0231] Another embodiment of the invention is the method of
selectively inhibiting NaV1.7 in a mammal or a mammalian cell as
compared to NaV1.5, wherein the method comprises administering to
the mammal in need thereof an inhibitory amount of a compound of
formula (I) or an embodiment of an embodiment thereof.
[0232] For each of the above embodiments described related to
treating diseases and conditions in a mammal, the present invention
also contemplates relatedly a compound of formula I or an
embodiment thereof for the use as a medicament in the treatment of
such diseases and conditions.
[0233] For each of the above embodiments described related to
treating diseases and conditions in a mammal, the present invention
also contemplates relatedly the use of a compound of formula I or
an embodiment thereof for the manufacture of a medicament for the
treatment of such diseases and conditions.
[0234] Another embodiment of the invention is a method of using the
compounds of formula (I) as standards or controls in in vitro or in
vivo assays in determining the efficacy of test compounds in
modulating voltage-dependent sodium channels.
[0235] In another embodiment of the invention, the compounds of
formula (I) are isotopically-labeled by having one or more atoms
therein replaced by an atom having a different atomic mass or mass
number. Such isotopically-labeled (i.e., radiolabelled) compounds
of formula (I) are considered to be within the scope of this
invention. Examples of isotopes that can be incorporated into the
compounds of formula (I) include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and
iodine, such as, but not limited to, .sup.2H, .sup.3H, .sup.11C,
.sup.13C, .sup.14C, .sup.13N, .sup.15N, .sup.15O, .sup.17O,
.sup.18O, .sup.31P, .sup.32P, .sup.35S, .sup.8F, .sup.36Cl,
.sup.123I, and .sup.125I, respectively. These isotopically-labeled
compounds would be useful to help determine or measure the
effectiveness of the compounds, by characterizing, for example, the
site or mode of action on the sodium channels, or binding affinity
to pharmacologically important site of action on the sodium
channels, particularly NaV1.7. Certain isotopically-labeled
compounds of formula (I), for example, those incorporating a
radioactive isotope, are useful in drug and/or substrate tissue
distribution studies. The radioactive isotopes tritium, i.e.
.sup.3H, and carbon-14, i.e., .sup.14C, are particularly useful for
this purpose in view of their ease of incorporation and ready means
of detection.
[0236] Substitution with heavier isotopes such as deuterium, i.e.
.sup.2H, may afford certain therapeutic advantages resulting from
greater metabolic stability, for example, increased in vivo
half-life or reduced dosage requirements, and hence may be
preferred in some circumstances.
[0237] Substitution with positron emitting isotopes, such as
.sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of formula (I)
can generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the Examples as set out below using an appropriate
isotopically-labeled reagent in place of the non-labeled reagent
previously employed.
Testing Compounds
[0238] The assessment of the compounds of the invention in
mediating, especially inhibiting, the sodium channel ion flux can
be determined using the assays described hereinbelow.
Alternatively, the assessment of the compounds in treating
conditions and diseases in humans may be established in industry
standard animal models for demonstrating the efficacy of compounds
in treating pain. Animal models of human neuropathic pain
conditions have been developed that result in reproducible sensory
deficits (allodynia, hyperalgesia, and spontaneous pain) over a
sustained period of time that can be evaluated by sensory testing.
By establishing the degree of mechanical, chemical, and temperature
induced allodynia and hyperalgesia present, several
physiopathological conditions observed in humans can be modeled
allowing the evaluation of pharmacotherapies.
[0239] In rat models of peripheral nerve injury, ectopic activity
in the injured nerve corresponds to the behavioural signs of pain.
In these models, intravenous application of the sodium channel
blocker and local anesthetic lidocaine can suppress the ectopic
activity and reverse the tactile allodynia at concentrations that
do not affect general behaviour and motor function (Mao, J. and
Chen, L. L, Pain (2000), 87:7-17). Allometric scaling of the doses
effective in these rat models, translates into doses similar to
those shown to be efficacious in humans (Tanelian, D. L. and Brose,
W. G., Anesthesiology (1991), 74(5):949-951). Furthermore,
Lidoderm.RTM., lidocaine applied in the form of a dermal patch, is
currently an FDA approved treatment for post-herpetic neuralgia
(Devers, A. and Glaler, B. S., Clin. J. Pain (2000),
16(3):205-8).
[0240] The present invention readily affords many different means
for identification of sodium channel modulating agents that are
useful as therapeutic agents. Identification of modulators of
sodium channel can be assessed using a variety of in vitro and in
vivo assays, e.g., measuring current, measuring membrane potential,
measuring ion flux, (e.g., sodium or guanidinium), measuring sodium
concentration, measuring second messengers and transcription
levels, and using e.g., voltage-sensitive dyes, radioactive
tracers, and patch-clamp electrophysiology.
[0241] One such protocol involves the screening of chemical agents
for ability to modulate the activity of a sodium channel thereby
identifying it as a modulating agent.
[0242] A typical assay described in Bean et al., J. General
Physiology (1983), 83:613-642, and Leuwer, M., et al., Br. J.
Pharmacol (2004), 141(1):47-54, uses patch-clamp techniques to
study the behaviour of channels. Such techniques are known to those
skilled in the art, and may be developed, using current
technologies, into low or medium throughput assays for evaluating
compounds for their ability to modulate sodium channel
behaviour.
[0243] Throughput of test compounds is an important consideration
in the choice of screening assay to be used. In some strategies,
where hundreds of thousands of compounds are to be tested, it is
not desirable to use low throughput means. In other cases, however,
low throughput is satisfactory to identify important differences
between a limited number of compounds. Often it will be necessary
to combine assay types to identify specific sodium channel
modulating compounds.
[0244] Electrophysiological assays using patch clamp techniques is
accepted as a gold standard for detailed characterization of sodium
channel compound interactions, and as described in Bean et al., op.
cit. and Leuwer, M., et al., op. cit. There is a manual
low-throughput screening (LTS) method which can compare 2-10
compounds per day; a recently developed system for automated
medium-throughput screening (MTS) at 20-50 patches (i.e. compounds)
per day; and a technology from Molecular Devices Corporation
(Sunnyvale, Calif.) which permits automated high-throughput
screening (HTS) at 1000-3000 patches (i.e. compounds) per day.
[0245] One automated patch-clamp system utilizes planar electrode
technology to accelerate the rate of drug discovery. Planar
electrodes are capable of achieving high-resistance, cells-attached
seals followed by stable, low-noise whole-cell recordings that are
comparable to conventional recordings. A suitable instrument is the
PatchXpress 7000A (Axon Instruments Inc, Union City, Calif.). A
variety of cell lines and culture techniques, which include
adherent cells as well as cells growing spontaneously in suspension
are ranked for seal success rate and stability. Immortalized cells
(e.g. HEK and CHO) stably expressing high levels of the relevant
sodium ion channel can be adapted into high-density suspension
cultures.
[0246] Other assays can be selected which allow the investigator to
identify compounds which block specific states of the channel, such
as the open state, closed state or the resting state, or which
block transition from open to closed, closed to resting or resting
to open. Those skilled in the art are generally familiar with such
assays.
[0247] Binding assays are also available. Designs include
traditional radioactive filter based binding assays or the confocal
based fluorescent system available from Evotec OAI group of
companies (Hamburg, Germany), both of which are HTS.
[0248] Radioactive flux assays can also be used. In this assay,
channels are stimulated to open with veratridine or aconitine and
held in a stabilized open state with a toxin, and channel blockers
are identified by their ability to prevent ion influx. The assay
can use radioactive 22[Na] and 14[C] guanidinium ions as tracers.
FlashPlate & Cytostar-T plates in living cells avoids
separation steps and are suitable for HTS. Scintillation plate
technology has also advanced this method to HTS suitability.
Because of the functional aspects of the assay, the information
content is reasonably good.
[0249] Yet another format measures the redistribution of membrane
potential using the FLIPR system membrane potential kit (HTS)
available from Molecular Dynamics (a division of Amersham
Biosciences, Piscataway, N.J.). This method is limited to slow
membrane potential changes. Some problems may result from the
fluorescent background of compounds. Test compounds may also
directly influence the fluidity of the cell membrane and lead to an
increase in intracellular dye concentrations. Still, because of the
functional aspects of the assay, the information content is
reasonably good.
[0250] Sodium dyes can be used to measure the rate or amount of
sodium ion influx through a channel. This type of assay provides a
very high information content regarding potential channel blockers.
The assay is functional and would measure Na+ influx directly.
CoroNa Red, SBFI and/or sodium green (Molecular Probes, Inc. Eugene
Oreg.) can be used to measure Na influx; all are Na responsive
dyes. They can be used in combination with the FLIPR instrument.
The use of these dyes in a screen has not been previously described
in the literature. Calcium dyes may also have potential in this
format.
[0251] In another assay, FRET based voltage sensors are used to
measure the ability of a test compound to directly block Na influx.
Commercially available HTS systems include the VIPR.TM. II FRET
system (Life Technologies, or Aurora Biosciences Corporation, San
Diego, Calif., a division of Vertex Pharmaceuticals, Inc.) which
may be used in conjunction with FRET dyes, also available from
Aurora Biosciences. This assay measures sub-second responses to
voltage changes. There is no requirement for a modifier of channel
function. The assay measures depolarization and hyperpolarizations,
and provides ratiometric outputs for quantification. A somewhat
less expensive MTS version of this assay employs the
FLEXstation.TM. (Molecular Devices Corporation) in conjunction with
FRET dyes from Aurora Biosciences. Other methods of testing the
compounds disclosed herein are also readily known and available to
those skilled in the art.
[0252] Modulating agents so identified are then tested in a variety
of in vivo models so as to determine if they alleviate pain,
especially chronic pain or other conditions such as cancer and
pruritus (itch) with minimal adverse events. The assays described
below in the Biological Assays Section are useful in assessing the
biological activity of the instant compounds.
[0253] Typically, the efficacy of a compound of the invention is
expressed by its IC50 value ("Inhibitory Concentration--50%"),
which is the measure of the amount of compound required to achieve
50% inhibition of the activity of the target sodium channel over a
specific time period. For example, representative compounds of the
present invention have demonstrated IC50's ranging from less than
100 nanomolar to less than 10 micromolar in the patch voltage clamp
NaV1.7 electrophysiology assay described herein.
[0254] In another aspect of the invention, the compounds of the
invention can be used in in vitro or in vivo studies as exemplary
agents for comparative purposes to find other compounds also useful
in treatment of, or protection from, the various diseases disclosed
herein.
[0255] Another aspect of the invention relates to inhibiting
NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or
NaV1.9 activity, preferably NaV1.7 activity, in a biological sample
or a mammal, preferably a human, which method comprises
administering to the mammal, preferably a human, or contacting said
biological sample with a compound of formula (I) or a
pharmaceutical composition comprising a compound of formula (I).
The term "biological sample", as used herein, includes, without
limitation, cell cultures or extracts thereof; biopsied material
obtained from a mammal or extracts thereof; and blood, saliva,
urine, feces, semen, tears, or other body fluids or extracts
thereof.
[0256] Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5,
NaV1.6, NaV1.7, NaV1.8, or NaV1.9 activity in a biological sample
is useful for a variety of purposes that are known to one of skill
in the art. Examples of such purposes include, but are not limited
to, the study of sodium ion channels in biological and pathological
phenomena; and the comparative evaluation of new sodium ion channel
inhibitors.
[0257] The compounds of the invention (or stereoisomers, geometric
isomers, tautomers, solvates, metabolites, isotopes,
pharmaceutically acceptable salts, or prodrugs thereof) and/or the
pharmaceutical compositions described herein which comprise a
pharmaceutically acceptable excipient and one or more compounds of
the invention, can be used in the preparation of a medicament for
the treatment of sodium channel-mediated disease or condition in a
mammal.
Combination Therapy
[0258] The compounds of the invention may be usefully combined with
one or more other compounds of the invention or one or more other
therapeutic agent or as any combination thereof, in the treatment
of sodium channel-mediated diseases and conditions. For example, a
compound of the invention may be administered simultaneously,
sequentially or separately in combination with other therapeutic
agents, including, but not limited to: [0259] opiates analgesics,
e.g., morphine, heroin, cocaine, oxymorphine, levorphanol,
levallorphan, oxycodone, codeine, dihydrocodeine, propoxyphene,
nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine,
methadone, nalorphine, naloxone, naltrexone, buprenorphine,
butorphanol, nalbuphine and pentazocine; [0260] non-opiate
analgesics, e.g., acetomeniphen, salicylates (e.g., aspirin);
[0261] nonsteroidal antiinflammatory drugs (NSAIDs), e.g.,
ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac,
diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,
flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,
meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,
nimesulide, nitroflurbiprofen, olsalazine, oxaprozin,
phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and
zomepirac; [0262] anticonvulsants, e.g., carbamazepine,
oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin and
pregabalin; [0263] antidepressants such as tricyclic
antidepressants, e.g., amitriptyline, clomipramine, despramine,
imipramine and nortriptyline; [0264] COX-2 selective inhibitors,
e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib,
etoricoxib, and lumiracoxib; [0265] alpha-adrenergics, e.g.,
doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine,
modafinil, and 4-amino-6,7-dimethoxy-2-(5-methane
sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)
quinazoline; [0266] barbiturate sedatives, e.g., amobarbital,
aprobarbital, butabarbital, butabital, mephobarbital, metharbital,
methohexital, pentobarbital, phenobartital, secobarbital, talbutal,
theamylal and thiopental; [0267] tachykinin (NK) antagonist,
particularly an NK-3, NK-2 or NK-1 antagonist, e.g.,
(.alpha.R,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9--
methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-
-dione (TAK-637),
5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophe-
nyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one
(MK-869), aprepitant, lanepitant, dapitant or
3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine
(2S,3S); [0268] coal-tar analgesics, in particular paracetamol;
[0269] serotonin reuptake inhibitors, e.g., paroxetine, sertraline,
norfluoxetine (fluoxetine desmethyl metabolite), metabolite
demethylsertraline, '3 fluvoxamine, paroxetine, citalopram,
citalopram metabolite desmethylcitalopram, escitalopram,
d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin,
litoxetine, dapoxetine, nefazodone, cericlamine, trazodone and
fluoxetine; [0270] noradrenaline (norepinephrine) reuptake
inhibitors, e.g., maprotiline, lofepramine, mirtazepine,
oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion,
buproprion metabolite hydroxybuproprion, nomifensine and viloxazine
(Vivalan.RTM.)), especially a selective noradrenaline reuptake
inhibitor such as reboxetine, in particular (S,S)-reboxetine, and
venlafaxine duloxetine neuroleptics sedative/anxiolytics; [0271]
dual serotonin-noradrenaline reuptake inhibitors, such as
venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,
clomipramine, clomipramine metabolite desmethylclomipramine,
duloxetine, milnacipran and imipramine; [0272] acetylcholinesterase
inhibitors such as donepezil; [0273] 5-HT3 antagonists such as
ondansetron; [0274] metabotropic glutamate receptor (mGluR)
antagonists; [0275] local anaesthetic such as mexiletine and
lidocaine; [0276] corticosteroid such as dexamethasone; [0277]
antiarrhythimics, e.g., mexiletine and phenytoin; [0278] muscarinic
antagonists, e.g., tolterodine, propiverine, tropsium t chloride,
darifenacin, solifenacin, temiverine and ipratropium; [0279]
cannabinoids; [0280] vanilloid receptor agonists (e.g.,
resinferatoxin) or antagonists (e.g., capsazepine); [0281]
sedatives, e.g., glutethimide, meprobamate, methaqualone, and
dichloralphenazone; [0282] anxiolytics such as benzodiazepines,
[0283] antidepressants such as mirtazapine, [0284] topical agents
(e.g., lidocaine, capsacin and resiniferotoxin); [0285] muscle
relaxants such as benzodiazepines, baclofen, carisoprodol,
chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;
[0286] anti-histamines or H1 antagonists; [0287] NMDA receptor
antagonists; [0288] 5-HT receptor agonists/antagonists; [0289] PDEV
inhibitors; [0290] Tramadol.RTM.; [0291] cholinergic (nicotinc)
analgesics; [0292] alpha-2-delta ligands; [0293] prostaglandin E2
subtype antagonists; [0294] leukotriene B4 antagonists; [0295]
5-lipoxygenase inhibitors; and [0296] 5-HT3 antagonists.
[0297] Sodium channel-mediated diseases and conditions that may be
treated and/or prevented using such combinations include but not
limited to, pain, central and peripherally mediated, acute,
chronic, neuropathic as well as other diseases with associated pain
and other central nervous disorders such as epilepsy, anxiety,
depression and bipolar disease; or cardiovascular disorders such as
arrhythmias, atrial fibrillation and ventricular fibrillation;
neuromuscular disorders such as restless leg syndrome and muscle
paralysis or tetanus; neuroprotection against stroke, neural trauma
and multiple sclerosis; and channelopathies such as erythromyalgia
and familial rectal pain syndrome.
[0298] As used herein "combination" refers to any mixture or
permutation of one or more compounds of the invention and one or
more other compounds of the invention or one or more additional
therapeutic agent. Unless the context makes clear otherwise,
"combination" may include simultaneous or sequentially delivery of
a compound of the invention with one or more therapeutic agents.
Unless the context makes clear otherwise, "combination" may include
dosage forms of a compound of the invention with another
therapeutic agent. Unless the context makes clear otherwise,
"combination" may include routes of administration of a compound of
the invention with another therapeutic agent. Unless the context
makes clear otherwise, "combination" may include formulations of a
compound of the invention with another therapeutic agent. Dosage
forms, routes of administration and pharmaceutical compositions
include, but are not limited to, those described herein.
[0299] The invention will be more fully understood by reference to
the following examples. They should not, however, be construed as
limiting the scope of the invention.
EXAMPLES
[0300] These examples serve to provide guidance to a skilled
artisan to prepare and use the compounds, compositions and methods
of the invention. While a particular embodiment of the present
invention are described, the skilled artisan will appreciate that
various changes and modifications can be made without departing
from the spirit and scope of the inventions.
[0301] The chemical reactions in the examples described can be
readily adapted to prepare a number of other compounds of the
invention, and alternative methods for preparing the compounds of
this invention are deemed to be within the scope of this invention.
For example, the synthesis of non-exemplified compounds according
to the invention can be successfully performed by modifications
apparent to those skilled in the art, for example, by appropriately
protecting interfering groups by utilizing other suitable reagents
known in the art other than those described, and/or by making
routine modifications of reaction conditions.
[0302] In the examples below, unless otherwise indicated all
temperatures are set forth in degrees Celsius. Commercially
available reagents were purchased from suppliers such as Aldrich
Chemical Company, Lancaster, TCI or Maybridge and were used without
further purification unless otherwise indicated. The reactions set
forth below were done under a positive pressure of nitrogen or
argon or with a drying tube (unless otherwise stated) in anhydrous
solvents, and the reaction flasks were typically fitted with rubber
septa for the introduction of substrates and reagents via syringe.
Glassware was oven dried and/or heat dried. .sup.1H NMR spectra
were obtained in deuterated CDCl.sub.3, d.sub.6-DMSO, CH.sub.3OD or
d.sub.6-acetone solvent solutions (reported in ppm) using or
trimethylsilane (TMS) or residual non-deuterated solvent peaks as
the reference standard. When peak multiplicities are reported, the
following abbreviates are used: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), br (broad), dd (doublet of
doublets), dt (doublet of triplets). Coupling constants, when
given, are reported in Hz (Hertz).
[0303] All abbreviations used to describe reagents, reaction
conditions or equipment are intended to be consistent with the
definitions set forth in the "List of standard abbreviates and
acronyms". The chemical names of discrete compounds of the
invention were obtained using the structure naming feature of
ChemDraw naming program.
Abbreviations
[0304] MeCN Acetonitrile [0305] EtOAc Ethyl acetate [0306] DCE
Dichloroethane [0307] DCM Dichloromethane [0308] DIPEA
Diisopropylethylamine [0309] DEA Diethylamine [0310] DMAP
4-dimethylaminopyridine [0311] DMF N,N-Dimethylformamide [0312]
DMSO Dimethyl sulfoxide [0313] FA Formic acid [0314] IPA Isopropyl
alcohol [0315] TFA Trifluoroacetic acid [0316] EDCI
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride [0317]
HCl Hydrochloric acid [0318] HPLC High Pressure Liquid
Chromatography [0319] LCMS Liquid Chromatography Mass Spectrometry
[0320] MeOH Methanol [0321] NMP N-methyl-2-pyrrolidone [0322]
RPHPLC Reverse phase high pressure liquid chromatography [0323] RT
Retention time [0324] SFC Supercritical Fluid Chromatography [0325]
THF Tetrahydrofuran [0326] TEA Triethylamine
Example 1
##STR00105##
[0327]
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-
-yl)benzenesulfonamide
##STR00106##
[0328] Step 1
##STR00107##
[0329]
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benze-
nesulfonamide
[0330] Lithium Bis(trimethylsilyl)amide (1.0 M, 4.8 mL, 4.8 mmol)
was added dropwise to a solution of
N-[(2,4-dimethoxyphenyl)methyl]thiazole-2-amine (1.0 g, 4.0 mmol)
in THF (30 mL) at room temperature. After stirring for 30 minutes,
a solution of 5-chloro-2,4-difluoro-benzenesulfonyl chloride (987
mg, 4.0 mmol) in THF (10 mL) was added. The reaction was stirred at
room temperature for 3 hours, then concentrated. The crude product
was purified by column chromatography (iPrOAc/Heptane) to provide
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (850 mg, 46% yield) as a white solid. LCMS (ESI) m/z: 461.0
[M+H].sup.+. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.92 (dd,
J=7.9, 7.0 Hz, 1H), 7.42 (d, J=3.6 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H),
7.04-6.96 (m, 2H), 6.39-6.33 (m, 2H), 5.18 (s, 2H), 3.76 (s, 3H),
3.72 (s, 3H).
Step 2
##STR00108##
[0331]
tert-butyl((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiaz-
ol-2-yl)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)carbamate
[0332]
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benze-
nesulfonamide (850 mg, 1.8 mmol) was dissolved in DMF (18 mL). TEA
(1.3 mL, 9.2 mmol) and tert-butyl
N-[(1S,2S)-2-aminocyclohexyl]carbamate (395 mg, 1.8 mmol) were
added sequentially. The reaction was stirred at room temperature
for 20 hours, then quenched by the addition of saturated aqueous
NaHCO.sub.3 (50 mL) and DCM (50 mL). The mixture was separated and
the aqueous layer was extracted with DCM (3.times.50 mL). The
combined organic fractions were dried with NaSO.sub.4, filtered,
and concentrated. The crude product was purified by column
chromatography (iPrOAc/Heptane) to provide
tert-butyl((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-y-
l)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)carbamate (900 mg,
75%) as a white solid. LCMS (ESI) m/z: 677.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, Chloroform-d) .delta. 7.70 (d, J=7.2 Hz, 1H), 7.38
(d, J=3.6 Hz, 1H), 7.21 (dt, J=8.5, 0.9 Hz, 1H), 6.95 (d, J=3.6 Hz,
1H), 6.37 (d, J=7.4 Hz, 2H), 6.20 (d, J=12.7 Hz, 1H), 5.92 (d,
J=6.4 Hz, 1H), 4.52 (d, J=8.6 Hz, 1H), 5.19 (s, 2H), 3.75 (s, 3H),
3.75 (s, 3H), 3.63 (d, J=10.4 Hz, 1H), 3.04-2.89 (m, 1H), 2.19-2.02
(m, 2H), 1.80 (t, J=14.4 Hz, 2H), 1.41 (s, 9H), 1.38-1.24 (m,
4H).
[0333] Step 3
##STR00109##
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)be-
nzenesulfonamide
[0334] Trifluoroacetic acid (0.34 mL, 4.59 mmol) was added dropwise
to a solution of
tert-butyl((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-y-
l)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)carbamate (300 mg,
0.46 mmol) in DCM (1.5 mL) at room temperature. After 16 hours, the
reaction was concentrated. The crude product (185 mg) was used
without further purification in the subsequent step. A small
portion was purified by HPLC to give
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide as a white solid. LCMS (ESI) m/z: 405.0
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.80 (s, 1H),
7.57 (d, J=7.3 Hz, 1H), 6.98 (d, J=3.9 Hz, 1H), 6.71 (d, J=12.8 Hz,
1H), 6.50 (d, J=3.8 Hz, 1H), 5.70 (dd, J=9.7, 2.0 Hz, 1H),
3.43-3.32 (m, 1H), 3.31-3.11 (m, 1H), 2.07 (s, 1H), 1.98 (d, J=12.4
Hz, 1H), 1.91-1.83 (m, 1H), 1.70 (d, J=13.0 Hz, 1H), 1.63 (d,
J=12.2 Hz, 1H), 1.44-1.23 (m, 3H), 1.22 (dd, J=14.5, 10.7 Hz,
1H).
Example 2
##STR00110##
[0335]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(thiazol-2-yl)benzenesulfonamide
[0336]
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-
-yl)benzenesulfonamide (185 mg, 0.46 mmol) was suspended in MeCN
(4.5 mL). Formaldehyde (37% w/w in H.sub.2O, 0.2 mL, 2.7 mmol) and
NaBH(OAc).sub.3 (970 mg, 4.5 mmol) were added sequentially at room
temperature. After 4 hours, the reaction was concentrated and
purified by HPLC to give
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(thiaz-
ol-2-yl)benzenesulfonamide (42.1 mg, 21%) as a white solid. LCMS
(ESI) m/z: 433.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.56 (d, J=7.3 Hz, 1H), 7.11-6.94 (m, 1H), 6.62 (d, J=12.6
Hz, 1H), 6.56 (d, J=4.0 Hz, 1H), 6.52 (s, 1H), 5.65 (s, 1H),
3.24-3.18 (m, OH), 2.62-2.53 (m, 1H), 2.17 (s, 7H), 1.88-1.71 (m,
2H), 1.60 (d, J=13.3 Hz, 1H), 1.36 (dd, J=14.6, 11.0 Hz, 1H),
1.30-1.02 (m, 4H).
Example 3
##STR00111##
[0337]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(t-
hiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate
[0338] Sodium hydride (60 mass %) in mineral oil (23.6 mg, 0.59
mmol) was added to a solution of tert-butyl
N-[(1S,2S)-2-[2-chloro-4-[(2,4-dimethoxyphenyl)methyl-thiazol-2-yl-sulfam-
oyl]-5-fluoro-anilino]cyclohexyl]carbamate (387 mg, 0.59 mmol) in
N,N-dimethylformamide (5 mL). The mixture was stirred at room
temperature for 10 min then iodomethane (83.8 mg, 0.59 mmol) was
added. The reaction was stirred at room temperature for 2 h. The
reaction was then quenched by addition of 15 mL of water. The
resulting solid was collected by filtration, washed with water and
dried in vacuo for 12 h. The solid was dissolved in dichloromethane
(3 mL) and trifluoroacetic acid (0.45 mL, 5.9 mmol) was added. The
reaction was stirred at room temperature for 1 h, concentrated and
purified by reverse phase HPLC to afford 22.9 mg (9%) of
5-chloro-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(thia-
zol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate as a white
solid. LCMS (ESI) m/z: 419.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.67 (d, J=7.4 Hz, 1H), 7.11 (dd, J=11.8, 4.4 Hz,
1H), 7.05-6.96 (m, 1H), 6.58-6.51 (m, 1H), 3.29 (s, 3H), 3.13-3.05
(m, 1H), 2.68 (d, J=7.6 Hz, 2H), 2.50 (d, J=13.1 Hz, 3H), 2.18 (d,
J=9.1 Hz, 1H), 1.69 (ddd, J=31.0, 24.2, 10.2 Hz, 2H), 1.58 (s, 1H),
1.51 (d, J=11.0 Hz, 1H), 1.22 (dd, J=13.7, 5.0 Hz, 2H).
Example 4
##STR00112##
[0339]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(t-
hiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate
[0340] Following the procedure described in Example 3 and making
non-critical variations as required to replace iodomethane with
iodoethane,
5-chloro-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(thiazol-
-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate was obtained as a
white solid. LCMS (ESI) m/z: 433.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.58 (d, J=7.3 Hz, 1H), 7.02 (d, J=4.0 Hz,
1H), 6.74 (d, J=12.8 Hz, 1H), 6.55 (d, J=4.0 Hz, 1H), 5.75 (d,
J=9.1 Hz, 1H), 3.28 (d, J=6.6 Hz, 1H), 3.08 (s, 1H), 2.86 (dp,
J=28.0, 6.5 Hz, 1H), 2.09 (d, J=13.0 Hz, 1H), 1.96-1.87 (m, 1H),
1.73 (d, J=12.4 Hz, 1H), 1.62 (d, J=12.3 Hz, 1H), 1.45-1.16 (m,
3H), 1.10 (t, J=7.1 Hz, 3H).
Example 5
##STR00113##
[0341]
4-(((1S,2S)-2-(benzylamino)cyclohexyl)amino)-5-chloro-2-fluoro-N-(t-
hiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate
[0342] Following the procedure described in Example 3 and making
non-critical variations as required to replace iodomethane with
benzyl bromide,
4-(((1S,2S)-2-(benzylamino)cyclohexyl)amino)-5-chloro-2-fluoro-N-
-(thiazol-2-yl)benzenesulfonamide 2,2,2-trifluoroacetate was
obtained as a white solid. LCMS m/z: 495.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 7.58 (d, J=7.3 Hz, 1H), 7.31-7.14 (m,
6H), 6.78-6.69 (m, 2H), 5.74 (d, J=7.2 Hz, 1H), 3.84 (d, J=13.5 Hz,
1H), 3.70 (d, J=13.5 Hz, 1H), 3.41-3.31 (m, 1H), 3.29 (s, 1H), 2.62
(s, 1H), 2.09 (s, 1H), 1.95 (d, J=12.5 Hz, 1H), 1.70 (s, 1H), 1.61
(d, J=13.4 Hz, 1H), 1.35 (t, J=11.9 Hz, 1H), 1.20 (t, J=10.9 Hz,
3H).
Example 6
##STR00114##
[0343]
4-(((1S,2S)-2-(benzyl(ethyl)amino)cyclohexyl)amino)-5-chloro-2-fluo-
ro-N-(thiazol-2-yl)benzenesulfonamide
[0344] Sodium triacetoxyborohydride (78.5 mg 0.37 mmol) was added
to a mixture of
4-[[(1S,2S)-2-aminocyclohexyl]amino]-5-chloro-2-fluoro-N-thiazol-2-yl-ben-
zenesulfonamide (30 mg, 0.07 mmol) and benzaldehyde (9.4 mg, 0.09
mmol) in 1,2-dichloroethane (2 mL) at 70.degree. C. The mixture was
stirred at 70.degree. C. for 16 h. The reaction was then cooled to
room temperature, quenched by addition of 1 mL of methanol,
concentrated and purified by reverse phase HPLC to give 1.4 mg of
4-(((1S,2S)-2-(benzyl(ethyl)amino)cyclohexyl)amino)-5-chloro-2-fluoro-N-(-
thiazol-2-yl)benzenesulfonamide as a white solid. LCMS (ESI) m/z:
523.1 [M+H].sup.+.
Example 7 & Example 8
##STR00115##
[0345]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(t-
hiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide
##STR00116##
[0346] Step 1:
##STR00117##
[0347] Racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)cyclohexyl)-
oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide & racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-2-((2-(dimethylamino)cyclohexyl)-
oxy)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0348] To a solution of racemic
(trans)-2-(dimethylamino)cyclohexanol (1.0 g, 5.93 mmol) in
anhydrous THF (8.5 mL) at 0 HC was added NaH (60%, 0.36 g, 8.9
mmol). The reaction mixture was stirred at 0.degree. C. for 0.5 h.
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (2.87 g, 6.23 mmol) at 0.degree. C. was added portionwise.
The reaction mixture was stirred at room temperature for an
additional 2 h. Sat. aq. NH.sub.4Cl (50 mL) was added and extracted
with EtOAc (200 mL). The organic layer was washed with water (50
mL), brine (80 mL.times.2), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude residue was purified
by silica gel chromatography (DCM/MeOH=20:1) to give a mixture of
title compounds (3 g, rac-3A:rac-3B.about.5:4) as yellow oil. LCMS
(ESI) m/z: 584 [M+H].sup.+.
Step 2
##STR00118##
[0349] Racemic
(trans)-5-chloro-4-((2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide & racemic
(trans)-5-chloro-2-((2-(dimethylamino)cyclohexyl)oxy)-4-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide
[0350] To a solution of racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)cyclohexyl)-
oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide and racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-2-((2-(dimethylamino)cyclohexyl)-
oxy)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide (1.0 g, 1.71 mmol)
in DCM (10 mL) was added trifluoroacetic acid (1.31 mL, 17.12
mmol). The reaction mixture was stirred at room temperature for 2
h. DCM (20 mL) was added and the mixture was basified with
NH.sub.4OH to pH 12. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by reverse phase chromatography (acetonitrile
25-55%/0.05% NH.sub.4OH in water) to give racemic
(trans)-5-chloro-4-((2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N--
(thiazol-2-yl)benzenesulfonamide (100 mg, first peak) as a white
solid and racemic
(trans)-5-chloro-2-((2-(dimethylamino)cyclohexyl)oxy)-4-fluoro-N--
(thiazol-2-yl)benzenesulfonamide (62 mg, second peak) as a white
solid. First peak: LCMS (ESI) m/z: 434 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.75 (d, J=7.2 Hz, 1H), 7.42 (d,
J=12.0 Hz, 1H), 7.22 (d, J=4.4 Hz, 1H), 6.78 (d, J=4.0 Hz, 1H),
4.75-4.61 (m, 1H), 2.88-2.76 (m, 1H), 2.36 (s, 6H), 2.09-1.99 (m,
1H), 1.89-1.77 (m, 1H), 1.75-1.56 (m, 2H), 1.40-1.24 (m, 4H). F NMR
(400 MHz, DMSO-d.sub.6) .delta. -107.48 (s, 1F). Second peak: LCMS
(ESI) m/z: 434 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.78 (d, J=8.8 Hz, 1H), 7.34 (d, J=10.8 Hz, 1H), 7.07 (d,
J=3.6 Hz, 1H), 6.64 (d, J=4.0 Hz, 1H), 4.60-4.51 (m, 1H), 3.61-3.51
(m, 1H), 2.85 (s, 6H), 2.15-2.05 (m, 1H), 1.85-1.71 (m, 2H),
1.49-1.35 (m, 5H). F NMR (400 MHz, DMSO-d.sub.6) .delta. -109.10
(s, 1F).
Step 3:
##STR00119##
[0351]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(t-
hiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide
[0352] Racemic
(trans)-5-chloro-4-((2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide (0.6 g) was separated by using chiral SFC
(Chiralpak C2 (250 mm*30 mm, 10 um), Supercritical
CO.sub.2/EtOH+0.1% NH.sub.4OH=40/40; 60 mL/min) to give
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide (167 mg, first peak) as a white solid and
5-chloro-4-(((1R,2R)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-
-2-yl)benzenesulfonamide (164 mg, second peak) as a white solid.
Absolute configuration was arbitrarily assigned to each enantiomer.
Example 1: LCMS (ESI) m/z: 434 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.74 (d, J=7.6 Hz, 1H), 7.41 (d, J=12.0 Hz,
1H), 7.21 (d, J=4.4 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 4.72-4.59 (m,
1H), 2.85-2.77 (m, 1H), 2.34 (s, 6H), 2.09-1.93 (m, 1H), 1.89-1.77
(m, 1H), 1.75-1.56 (m, 2H), 1.40-1.15 (m, 4H). Example 2: LCMS
(ESI) m/z: 434 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.74 (d, J=7.6 Hz, 1H), 7.40 (d, J=12.0 Hz, 1H), 7.20 (d,
J=4.4 Hz, 1H), 6.76 (d, J=4.4 Hz, 1H), 4.72-4.59 (m, 1H), 2.83-2.73
(m, 1H), 2.34 (s, 6H), 2.07-1.99 (m, 1H), 1.88-1.80 (m, 1H),
1.71-1.57 (m, 2H), 1.42-1.17 (m, 4H).
Example 9 & Example 10
##STR00120##
[0353]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-(-
thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-(thiazo-
l-2-yl)benzenesulfonamide
##STR00121##
[0354] Step 1:
##STR00122##
[0355] Racemic (trans)-2-(dimethylamino)cyclopentanol
[0356] A mixture of 6-oxabicyclo[3.1.0]hexane (1.0 g, 11.89 mmol)
and 33% aqueous solution of dimethylamine (7.3 mL, 47.55 mmol) was
stirred at room temperature for 16 h. Water (15 mL) was added and
extracted with EtOAc (20 mL.times.3). The combined organic layers
were dried over anhydrous MgSO.sub.4, filtered and concentrated in
vacuo to give the title compound (1.13 g, crude) as colorless oil
that required no further purification. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 4.11-4.01 (m, 1H), 2.52-2.42 (m, 1H), 2.28 (s,
6H), 2.00-1.88 (m, 1H), 1.87-1.76 (m, 1H), 1.75-1.40 (m, 4H).
Step 2:
##STR00123##
[0357] Racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)cyclopentyl-
)oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0358] To a solution of racemic
(trans)-2-(dimethylamino)cyclopentanol (0.4 g, 3.1 mmol) in
anhydrous DMF (13 mL) at 0.degree. C. was added NaH (60%, 0.18 g,
4.5 mmol). The reaction mixture was stirred at 0.degree. C. for 0.5
h.
5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (1.3 g, 2.82 mmol) at 0.degree. C. was added portionwise.
The reaction mixture was stirred at room temperature for an
additional 16 h. EtOAc (50 mL) was added and washed with water (15
mL.times.3). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
title compound (1.08 g, crude) as yellow oil that required no
further purification. LCMS (ESI) m/z: 570 [M+H].sup.+.
Step 3:
##STR00124##
[0359] Racemic
(trans)-5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-
-(thiazol-2-yl)benzenesulfonamide
[0360] To a solution of racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)cyclopentyl-
)oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (1.08 g, 1.89
mmol) in DCM (5 mL) was added trifluoroacetic acid (1.41 mL, 18.94
mmol). The reaction mixture was stirred at room temperature for 12
h and concentrated in vacuo. The crude residue was purified by
reverse phase chromatography (acetonitrile 10-40%/0.05% HCl in
water) to give the title compound (240 mg, 30%) as colorless oil.
LCMS (ESI) m/z: 420 [M+H].sup.+.
Step 4:
##STR00125##
[0361]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-(-
thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-(thiazo-
l-2-yl)benzenesulfonamide
[0362] Racemic
(trans)-5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-
-(thiazol-2-yl)benzenesulfonamide (240 mg) was separated by using
chiral SFC (Chiralpak C2 (250 mm*30 mm, 10 um), Supercritical
CO.sub.2/MeOH+0.1% NH.sub.4OH=60/40; 60 mL/min) to give
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-(thiazo-
l-2-yl)benzenesulfonamide (49 mg, first peak) as a yellow solid and
5-chloro-4-(((1R,2R)-2-(dimethylamino)cyclopentyl)oxy)-2-fluoro-N-(thiazo-
l-2-yl)benzenesulfonamide (102 mg, second peak) as a yellow solid.
Absolute configuration was arbitrarily assigned to each enantiomer.
Example 3: LCMS (ESI) m/z: 420 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.75 (d, J=7.6 Hz, 1H), 7.32 (d, J=12.0 Hz,
1H), 7.22 (d, J=4.4 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 4.90-4.83 (m,
1H), 3.10-3.01 (m, 1H), 2.31 (s, 6H), 2.17-2.04 (m, 1H), 2.00-1.89
(m, 1H), 1.75-1.50 (m, 4H). Example 4: LCMS (ESI) m/z: 420
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.75 (d,
J=7.6 Hz, 1H), 7.31 (d, J=12.4 Hz, 1H), 7.22 (d, J=4.0 Hz, 1H),
6.79 (d, J=4.0 Hz, 1H), 4.84-4.77 (m, 1H), 3.02-2.94 (m, 1H), 2.27
(s, 6H), 2.15-2.02 (m, 1H), 1.97-1.87 (m, 1H), 1.72-1.47 (m,
4H).
Example 11
##STR00126##
[0363]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(pyrimidin-4-yl)benzenesulfonamide
##STR00127##
[0364] Step 1:
##STR00128##
[0365]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclo-
hexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0366] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide (130 mg, 0.31 mmol, US201210182, preparation 110) and
K.sub.2CO.sub.3 (127 mg, 0.92 mmol) in DMF (2 mL) was added
(1S,2S)--N.sup.1,N.sup.1-dimethylcyclohexane-1,2-diamine (43 mg,
0.31 mmol). The reaction mixture was stirred at room temperature
for 16 h. The mixture was diluted with EtOAc (30 mL), washed with
water (20 mL), brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
title compound (110 mg, crude) as a yellow solid that required no
further purification. LCMS (ESI) m/z: 578 [M+H].sup.+.
Step 2:
##STR00129##
[0367]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(pyrimidin-4-yl)benzenesulfonamide
[0368] A mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)-
amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (110 mg, 0.19
mmol) and formic acid (8.0 mL) was stirred at room temperature for
6 h. The reaction mixture was concentrated in vacuo. The crude
residue was purified by reverse phase chromatography (acetonitrile
0-30%/0.225% formic acid in water) to give the title compound (30
mg, 37%) as as a white solid. LCMS (ESI) m/z: 428 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.36 (s, 1H), 8.03 (d,
J=6.0 Hz, 1H), 7.63 (d, J=7.2 Hz, 1H), 6.78 (d, J=13.2 Hz, 1H),
6.66 (d, J=6.0 Hz, 1H), 5.83 (d, J=7.6 Hz, 1H), 3.60-3.40 (m, 1H),
3.17-3.03 (m, 1H), 2.44 (s, 6H), 2.06-1.89 (m, 2H), 1.82-1.73 (m,
1H), 1.66-1.56 (m, 1H), 1.43-1.10 (m, 4H).
Example 12
##STR00130##
[0369] Step 1:
##STR00131##
[0370]
4-(((1S,2S)-2-aminocyclopentyl)amino)-5-chloro-N-(2,4-dimethoxybenz-
yl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0371] A mixture of
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-yl-benz-
enesulfonamide (165 mg, 0.36 mmol),
(1S,2S)-cyclopentane-1,2-diamine; dihydrochloride (158 mg, 0.91
mmol) and potassium carbonate (297 mg, 2.15 mmol) in
1-methyl-2-pyrrolidinone (4 mL) was heated in a sealed vial at
60.degree. C. for 18 h. The mixture was The mixture was mixed with
5% aq. citric acid and extracted with ethyl acetate. The organic
extracts were washed with water and then discarded. All aqueous
washings were combined, pH was adjusted to 10 by addition of 1 N aq
NaOH and then extracted with ethyl acetate. The organic extracts
were washed with water, brine, dried over Na2SO4 and concentrated
to afford 154 mg (79.5%) of the title product, which was used in
the next step without further purification. LCMS (ESI) m/z: 541
[M+H].sup.+.
Step 2:
##STR00132##
[0372]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclo-
pentyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0373]
4-[[(1S,2S)-2-aminocyclopentyl]amino]-5-chloro-N-[(2,4-dimethoxyphe-
nyl)methyl]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (154 mg,
0.29 mmol) was dissolved in 4 ml of dichloroethane, 37% aqueous
formaldehyde (0.064 mL, 0.86 mmol) and triethylamine (0.16 mL, 1.1
mmol) were added and the mixture was stirred for 10 min. sodium
triacetoxyborohydride (217 mg, 1.02 mmol) was added in one portion
and the mixture was stirred for 2 hours. The mixture was
concentrated in vacuum, the residue partitioned between water and
ethyl acetate. The organic extracts were washed with brine, dried
over Na2SO4 and concentrated to afford 144 mg (89%) of the title
compound, was used in the next step without further purification.
LCMS (ESI) m/z: 569 [M+H].sup.+.
Step 3:
##STR00133##
[0374]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclopentyl)amino)-2-fluoro-N-
-(thiazol-2-yl)benzenesulfonamide
[0375] 0.5 ml of trifluoroacetic acid was added to a solution of
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamino)cyc-
lopentyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (144 mg,
0.25 mmol) in 2 ml of DCM. The mixture was stirred for 1 hour and
concentrated in vacuum. The residue was triturated with ethyl ether
forming a precipitate. The precipitate was filtered, washed with
ethyl ether and dried on air to afford 99 mg (73%) of a crude title
product as a trifluoroacetate salt. 15 mg of the product was
purified by reverse phase liquid chromatography to afford 6.2 mg of
the title product as a base. LCMS (ESI) m/z: 419 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.59 (d, J=7.3 Hz, 1H), 7.24
(d, J=4.6 Hz, 1H), 6.83-6.78 (m, 2H), 6.51 (s, 1H), 6.09 (br. s,
1H), 3.93-3.79 (m, 1H), 2.42 (s, 6H), 2.14-2.02 (m, 1H), 1.93-1.81
(m, 1H), 1.72-1.56 (m, 4H), 1.45-1.35 (m, 1H).
Example 13
##STR00134##
[0376]
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2,5-difluoro-N-(1,2,-
4-thiadiazol-5-yl)benzenesulfonamide formate
Step 1:
##STR00135##
[0377]
N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)ami-
no)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide
[0378] Following the procedure described in Example 11, step 1 and
making non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenes-
ulfonamide,
N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2,-
5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide was obtained
as an off-white solid. LCMS (ESI) m/z: 568.1 [M+H].sup.+.
.sup.1H-NMR (300 MHz; CDCl.sub.3): .delta. 8.15 (s, 1H), 7.39-7.32
(m, 1H), 7.16-7.13 (m, 1H), 6.36-6.33 (m, 1H), 6.29 (d, J=2.2 Hz,
1H), 6.24-6.17 (m, 1H), 5.73-5.68 (m, 1H), 5.24 (s, 2H), 3.74 (d,
J=2.0 Hz, 6H), 2.98-2.90 (m, 1H), 2.50-2.42 (m, 1H), 2.20-2.19 (m,
6H), 1.95-1.87 (m, 2H), 1.78-1.73 (m, 1H), 1.32-1.13 (m, 5H).
Step 2:
##STR00136##
[0379]
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2,5-difluoro-N-(1,2,-
4-thiadiazol-5-yl)benzenesulfonamide formate
[0380] Following the procedure described in Example 11, step 2,
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2,5-difluoro-N-(1,2,4-thia-
diazol-5-yl)benzenesulfonamide formate was obtained as a white
solid. LCMS (ESI) m/z: 418.1 [M+H].sup.+. 1H-NMR (300 MHz, d6-dmso)
.delta. 10.03-9.13 (br s, 1H), 7.88 (s, 1H), 7.31 (dd, J=6.5, 11.3
Hz, 1H), 6.91 (dd, J=6.9, 12.4 Hz, 1H), 6.13 (d, J=10.1 Hz, 1H),
3.83-3.72 (m, 1H), 3.37-3.23 (m, 1H), 2.72-2.56 (m, 6H), 2.08-1.93
(m, 2H), 1.84-1.79 (m, 1H), 1.65-1.60 (m, 1H), 1.47-1.12 (m,
4H).
Example 14
##STR00137##
[0381]
5-bromo-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl]amino]-2-fluoro-N-t-
hiazol-2-yl-benzenesulfonamide
##STR00138##
[0382] Step 1:
##STR00139##
[0383]
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-yl-
-benzenesulfonamide
[0384] To a solution of
N-[(2,4-dimethoxyphenyl)methyl]thiazol-2-amine (1.0 g, 4.0 mmol) in
THF (10 mL) at -78.degree. C. was added lithium
bis(trimethylsilyl)amide (6.0 mL, 6.0 mmol, 1.0 M) dropwise under a
nitrogen atmosphere. The reaction mixture was stirred at
-78.degree. C. for 0.5 h, then the cooling bath was removed and the
reaction was warmed to room temperature for 0.5 h, then cooled back
to -78.degree. C. A solution of
5-bromo-2,4-difluorobenzenesulfonylchloride (1.8 g, 6.0 mmol) in
THF (2 mL) at -78.degree. C. was added dropwise to the mixture. The
reaction mixture was stirred at room temperature for an additional
1 h. Sat. aq. NH.sub.4Cl (50 mL) was added and extracted with EtOAc
(100 mL). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (petroleum
ether/EtOAc=6:1) to give the title compound (0.6 g, 30%) as a
yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.12-8.02
(m, 1H), 7.43 (d, J=3.2 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.04 (d,
J=3.6 Hz, 1H), 7.02-6.94 (m, 1H), 6.41-6.32 (m, 2H), 5.19 (s, 2H),
3.77 (s, 3H), 3.74 (s, 3H).
Step 2:
##STR00140##
[0385]
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamin-
o)cyclohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide
[0386] To a solution of
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-yl-benze-
nesulfonamide (300 mg, 0.59 mmol) in DMF (3 mL) was added potassium
carbonate (246 mg, 1.78 mmol) and
(1S,2S)--N.sup.1,N.sup.1-dimethylcyclohexane-1,2-diamine (93 mg,
0.65 mmol). The reaction mixture was stirred at room temperature
for 16 h. Water (10 mL) was added and extracted with EtOAc (10
mL.times.2). The combined organic layers were washed with water (10
mL.times.3), brine (15 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo to give the title compound (187
mg, crude) as a yellow solid that required no further purification.
LCMS (ESI) m/z: 627 [M+H].sup.+.
Step 3:
##STR00141##
[0387]
5-bromo-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl]amino]-2-fluoro-N-t-
hiazol-2-yl-benzenesulfonamide
[0388] A mixture of
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamino)cycl-
ohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (187 mg,
0.30 mmol) and formic acid (2 mL) was stirred at room temperature
for 2 h. The mixture was concentrated in vacuo. The crude residue
was purified by reverse phase chromatography (acetonitrile
26-56%/0.225% formic acid in water) to give the title compound (91
mg, 64%) as a white solid. LCMS (ESI) m/z: 477 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16 (s, 1H), 7.74 (d, J=7.6
Hz, 1H), 7.19 (d, J=4.4 Hz, 1H), 6.75-6.70 (m, 2H), 5.78-5.73 (m,
1H), 3.42-3.34 (m, 1H), 2.82-2.74 (m, 1H), 2.27 (s, 6H), 2.13-2.05
(m, 1H), 1.93-1.85 (m, 1H), 1.79-1.74 (m, 1H), 1.66-1.57 (m, 1H),
1.44-1.05 (m, 4H).
Example 15
##STR00142##
[0389]
5-cyclopropyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluo-
ro-N-(thiazol-2-yl)benzenesulfonamide
##STR00143##
[0390] Step 1:
##STR00144##
[0391]
5-cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimeth-
ylamino)cyclohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide
[0392] To a solution of
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamino)cycl-
ohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (100 mg,
0.16 mmol) in toluene (2.5 mL) and water (0.5 mL) was added
palladium(II) acetate (7.2 mg, 0.03 mmol), tricyclohexylphosphine
(18 mg, 0.06 mmol), cyclopropylboronic acid (27 mg, 0.32 mmol) and
K.sub.3PO.sub.4 (101 mg, 0.48 mmol). The reaction mixture was
heated to 100.degree. C. for 16 h. After cooling to room
temperature, the mixture was concentrated in vacuo. EtOAc (30 mL)
was added, washed with water (10 mL.times.3), brine (10 mL), dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude residue was purified by silica gel chromatography
(solvent gradient: 0-100% EtOAc in petroleum ether) to give the
title compound (50 mg, 53%) as light yellow oil. LCMS (ESI) m/z:
589 [M+H].sup.+.
Step 2:
##STR00145##
[0393]
5-cyclopropyl-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl]amino]-2-fluo-
ro-N-thiazol-2-yl-benzenesulfonamide
[0394] A mixture of
5-cyclopropyl-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamin-
o)cyclohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (50
mg, 0.08 mmol) and formic acid (1.5 mL) was stirred at room
temperature for 2 h. The mixture was concentrated in vacuo. The
crude residue was purified by reverse phase chromatography
(acetonitrile 18-48%/0.225% formic acid in water) to give the title
compound (10 mg, 27%) as a light yellow solid. LCMS (ESI) m/z: 439
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.17 (s,
1H), 7.31 (d, J=8.0 Hz, 1H), 7.18 (d, J=4.4 Hz, 1H), 6.72 (d, J=4.4
Hz, 1H), 6.46 (d, J=13.2 Hz, 1H), 5.96 (s, 1H), 3.24-3.13 (m, 1H),
2.70-2.60 (m, 1H), 2.23 (s, 6H), 2.22-2.12 (m, 1H), 1.91-1.74 (m,
2H), 1.68-1.48 (m, 2H), 1.45-1.08 (m, 4H), 0.95-0.83 (m, 2H),
0.60-0.50 (m, 1H), 0.32-0.22 (m, 1H).
Example 16
##STR00146##
[0395]
5-chloro-4-[[(1S,2S)-2-(cyclobutylamino)cyclohexyl]amino]-2-fluoro--
N-thiazol-2-yl-benzenesulfonamide
[0396] Following the procedure described in Example 2 and making
non-critical variations as required to replace formaldehyde with
cyclobutanone,
5-chloro-4-[[(1S,2S)-2-(cyclobutylamino)cyclohexyl]amino]-2-fluoro-N-thia-
zol-2-yl-benzenesulfonamide was obtained as a white solid. LCMS
(ESI) m/z: 459.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 8.50 (s, 1H), 7.54 (d, J=7.3 Hz, 1H), 6.92 (d, J=3.8 Hz,
1H), 6.54 (d, J=12.6 Hz, 1H), 6.43 (d, J=3.8 Hz, 1H), 5.50-5.30 (m,
1H), 2.11-2.01 (m, 2H), 1.92 (dd, J=32.5, 12.0 Hz, 3H), 1.77 (s,
3H), 1.58-1.45 (m, 7H), 1.23 (s, 3H), 1.04 (d, J=6.1 Hz, 2H), 0.94
(d, J=6.5 Hz, 2H).
Example 17
##STR00147##
[0397]
5-chloro-4-[[(1S,2S)-2-(diethylamino)cyclohexyl]amino]-2-fluoro-N-t-
hiazol-2-yl-benzenesulfonamide
[0398] Following the procedure described in Example 2 and making
non-critical variations as required to replace formaldehyde with
acetaldehyde,
5-chloro-4-[[(1S,2S)-2-(diethylamino)cyclohexyl]amino]-2-fluoro-N-thiazol-
-2-yl-benzenesulfonamide was obtained as a white solid. LCMS (ESI)
m/z: 461.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.55
(d, J=7.3 Hz, 1H), 6.92 (d, J=3.8 Hz, 1H), 6.51 (d, J=12.3 Hz, 1H),
6.43 (d, J=3.8 Hz, 1H), 6.27 (s, 3H), 5.78 (d, J=2.2 Hz, 1H), 3.06
(t, J=10.3 Hz, 1H), 2.50-2.37 (m, 2H), 2.34-2.19 (m, 2H), 1.85-1.74
(m, 1H), 1.59 (s, 1H), 1.40 (d, J=12.9 Hz, 1H), 1.24 (s, 1H),
1.17-1.05 (m, 1H), 0.98-0.86 (m, 6H).
Example 18
##STR00148##
[0399]
5-chloro-4-(((1S,2S)-2-(ethyl(methyl)amino)cyclohexyl)amino)-2-fluo-
ro-N-(thiazol-2-yl)benzenesulfonamide
[0400] Following the procedure described in Example 2 and making
non-critical variations as required to replace
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)be-
nzenesulfonamide and formaldehyde,
5-chloro-2-fluoro-4-[[(1S,2S)-2-(methylamino)cyclohexyl]amino]-N-thiazol--
2-yl-benzenesulfonamide and acetaldehyde,
5-chloro-4-[[(1S,2S)-2-[ethyl(methyl)amino]cyclohexyl]amino]-2-fluoro-N-t-
hiazol-2-yl-benzenesulfonamide was obtained as a white solid. LCMS
(ESI) m/z: 447.0 [M+H]+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
7.58 (d, J=6.8 Hz, 1H), 7.18 (d, J=4.8 Hz, 1H), 6.75-6.65 (m, 2H),
5.88 (d, J=4.4 Hz, 1H), 2.78-2.68 (m, 1H), 2.43-2.38 (m, 2H), 2.16
(s, 3H), 2.13-2.05 (m, 1H), 1.87-1.70 (m, 2H), 1.66-1.55 (m, 1H),
1.43-1.05 (m, 5H), 0.96 (t, J=7.2 Hz, 3H).
Example 19
##STR00149##
[0401]
5-chloro-4-(((1S,2S)-2-(cyclopropyl(methyl)amino)cyclohexyl)amino)--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0402] Following the procedure described in Example 18 and making
non-critical variations as required to replace acetaldehyde with
(1-ethoxycyclopropoxy)trimethylsilane,
5-chloro-4-[[(1S,2S)-2-[cyclopropyl(methyl)amino]cyclohexyl]amino]-2-fluo-
ro-N-thiazol-2-yl-benzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 459.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.57 (d, J=7.6 Hz, 1H), 7.26 (d, J=4.8 Hz,
1H), 6.81 (d, J=4.8 Hz, 1H), 6.69 (d, J=12.8 Hz, 1H), 5.59 (d,
J=3.6 Hz, 1H), 3.27-3.16 (m, 1H), 2.71-2.62 (m, 1H), 2.19-2.09 (m,
1H), 2.13 (s, 3H), 2.03-1.95 (m, 1H), 1.94-1.85 (m, 1H), 1.83-1.73
(m, 1H), 1.66-1.57 (m, 1H), 1.45-1.06 (m, 4H), 0.48-0.36 (m, 2H),
0.29-0.20 (m, 1H), 0.16-0.08 (m, 1H).
Example 20
##STR00150##
[0403]
5-chloro-2-fluoro-4-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino-
)-N-(thiazol-2-yl)benzenesulfonamide
[0404] Following a procedure similar to that of Example 3,
5-chloro-2-fluoro-4-(methyl((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(t-
hiazol-2-yl)benzenesulfonamide was obtained. LCMS (ESI) m/z: 433.0
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.67 (d, J=7.4
Hz, 1H), 7.11 (dd, J=11.8, 4.4 Hz, 1H), 7.05-6.96 (m, 1H),
6.58-6.51 (m, 1H), 3.29 (s, 3H), 3.13-3.05 (m, 1H), 2.68 (d, J=7.6
Hz, 2H), 2.50 (d, J=13.1 Hz, 3H), 2.18 (d, J=9.1 Hz, 1H), 1.69
(ddd, J=31.0, 24.2, 10.2 Hz, 2H), 1.58 (s, 1H), 1.51 (d, J=11.0 Hz,
1H), 1.22 (dd, J=13.7, 5.0 Hz, 2H).
Example 21
##STR00151##
[0405]
4-(((1S,2S)-2-(azetidin-1-yl)cyclohexyl)amino)-5-chloro-2-fluoro-N--
(thiazol-2-yl)benzenesulfonamide
[0406] Following a procedure similar to that of Example 3,
4-(((1S,2S)-2-(azetidin-1-yl)cyclohexyl)amino)-5-chloro-2-fluoro-N-(thiaz-
ol-2-yl)benzenesulfonamide was obtained. LCMS (ESI) m/z: 445.0
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.57 (d, J=7.3
Hz, 1H), 7.13 (d, J=4.3 Hz, 1H), 6.72 (d, J=13.2 Hz, 1H), 6.68 (d,
J=4.3 Hz, 1H), 5.77 (d, J=9.2 Hz, 1H), 3.61-3.38 (m, 5H), 2.75 (d,
J=11.9 Hz, 1H), 1.98 (p, J=7.2 Hz, 2H), 1.87 (d, J=12.1 Hz, 1H),
1.79-1.63 (m, 2H), 1.59 (d, J=12.0 Hz, 1H), 1.34 (q, J=11.2 Hz,
2H), 1.24-1.02 (m, 2H).
Example 22
##STR00152##
[0407]
5-chloro-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro-N-(py-
rimidin-4-yl)benzenesulfonamide
[0408] Following a procedure similar to Example 3,
5-chloro-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro-N-(pyrimidi-
n-4-yl)benzenesulfonamide was obtained. LCMS (ESI) m/z: 428.1
[M+H].sup.+. H NMR (400 MHz, DMSO-d6) .delta. 8.28 (s, 1H), 7.93
(d, J=6.0 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 6.72 (d, J=12.7 Hz, 1H),
6.56 (d, J=5.9 Hz, 1H), 5.74 (d, J=9.5 Hz, 1H), 3.46 (s, 2H),
3.10-2.83 (m, 2H), 2.18-2.07 (m, 1H), 1.95-1.81 (m, 1H), 1.80-1.70
(m, 1H), 1.68-1.57 (m, 1H), 1.44-1.19 (m, 4H), 1.16 (t, J=7.1 Hz,
3H).
Example 23
##STR00153##
[0409]
5-chloro-4-(((1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex--
3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
##STR00154## ##STR00155##
[0410] Step 1:
##STR00156##
[0411] (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic Acid
[0412] To a solution of (2S)-2-aminopent-4-enoic acid (40.0 g,
347.43 mmol) in 1,4-dioxane (400 mL) at 0.degree. C. was added NaOH
(31.96 g, 799.1 mmol) in water (800 mL) and di-tert-butyl
dicarbonate (91 g, 416.92 mmol) slowly. The reaction mixture was
stirred at room temperature for 16 h. The reaction was concentrated
in vacuo to get rid of dioxane. The aqueous phase was washed with
EtOAc (600 mL.times.3). The aqueous phase was acidified to pH 2
with 2 M aq. H.sub.2SO.sub.4 and extracted with EtOAc (600
mL.times.3). The combined organic layers were washed with brine
(600 mL), dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo to give the title compound (63.6 g, crude) as
colorless oil that required no further purification. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 12.40 (s, 1H), 7.04 (d, J=8.0 Hz,
1H), 5.83-5.68 (m, 1H), 5.14-4.96 (m, 2H), 3.97-3.87 (m, 1H),
2.48-2.23 (m, 2H), 1.37 (s, 9H).
Step 2:
##STR00157##
[0413] (S)-tert-butyl(1-diazo-2-oxohex-5-en-3-yl)carbamate
[0414] To a solution of
(S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (25.0 g, 116.14
mmol) in THF (500 mL) at 0.degree. C. was added triethylamine (32.4
mL, 232.29 mmol) and methanesulfonyl chloride (26.61 g, 232.29
mmol). The mixture was stirred at 0.degree. C. for 2 h and
filtered. The filtrate was added (trimethylsilyl)diazomethane
(174.22 mL, 348.43 mmol, 2 M in hexane) at 0.degree. C. slowly. The
mixture was stirred at 0.degree. C. for an additional 2 h. The
mixture was quenched with water (100 mL) slowly at 0.degree. C. and
extracted with EtOAc (250 mL.times.2). The combined organic layers
were washed with brine (150 mL.times.2), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (petroleum
ether/EtOAc=10:1) to give the title compound (3.9 g, 14%) as light
yellow oil. H NMR (400 MHz, CDCl.sub.3) .delta. 5.79-5.66 (m, 1H),
5.47 (s, 1H), 5.21-5.12 (m, 2H), 5.08 (s, 1H), 4.31-4.18 (m, 1H),
2.59-2.48 (m, 1H), 2.47-2.36 (m, 1H), 1.45 (s, 9H).
Step 3:
##STR00158##
[0415] (S)-3-((tert-butoxycarbonyl)amino)hex-5-enoic Acid
[0416] To a solution of
(S)-tert-butyl(1-diazo-2-oxohex-5-en-3-yl)carbamate (15.3 g, 63.94
mmol) in 1,4-dioxane (180 mL) and water (20 mL) was added silver(I)
oxide (1.48 g, 6.39 mmol). The mixture was sonicated in an
ultrasound bath at room temperature for 1 h. The mixture was
concentrated in vacuo. Water (200 mL) was added and the mixture was
basified with solid NaHCO.sub.3 to pH 8 and then extracted with
EtOAc (100 mL.times.2). The aqueous layer was acidified with 4 M
aq. HCl to pH 2 and extracted with EtOAc (100 mL.times.3). The
combined organic layers were washed with brine (50 mL), dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give the title compound (9.1 g, crude) as light yellow oil that
required no further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 5.85-5.65 (m, 1H), 5.18-5.06 (m, 2H), 5.05-4.86 (m, 1H),
4.09-3.85 (m, 1H), 2.65-2.50 (m, 2H), 2.39-2.28 (m, 2H), 1.45 (s,
9H).
Step 4:
##STR00159##
[0417] (S)-tert-butyl 4-allyl-6-oxo-1,3-oxazinane-3-carboxylate
[0418] To a solution of
(S)-3-((tert-butoxycarbonyl)amino)hex-5-enoic acid (9.1 g, 39.69
mmol) in toluene (80 mL) was added formaldehyde (5.96 g, 198.46
mmol) and (1S)-(+)-10-camphorsulfonic acid (1.84 g, 7.94 mmol) and
4A molecular sieve (13 g). The mixture was heated to 90.degree. C.
for 6 h under nitrogen atmosphere. After cooling to room
temperature, the mixture was filtered and concentrated in vacuo.
EtOAc (100 mL) was added and washed with sat. aq. NaHCO.sub.3 (50
mL) and brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The crude residue was purified
by silica gel chromatography (petroleum ether/EtOAc=5:1) to give
the title compound (6.9 g, 72%) as light yellow oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 5.95-5.65 (m, 2H), 5.24-5.09 (m, 2H),
4.93 (d, J=10.8 Hz, 1H), 4.30-4.08 (m, 1H), 2.83-2.70 (m, 1H),
2.62-2.53 (m, 1H), 2.49-2.34 (m, 2H), 1.50 (s, 9H).
Step 5:
##STR00160##
[0419] (4S,5S)-tert-butyl
4-allyl-6-oxo-5-(2-(trifluoromethyl)allyl)-1,3-oxazinane-3-carboxylate
[0420] To a solution of (S)-tert-butyl
4-allyl-6-oxo-1,3-oxazinane-3-carboxylate (7.3 g, 30.26 mmol) and
2-(trifluoromethyl)allyl 4-methylbenzenesulfonate (9.33 g, 33.28
mmol) in THF (70 mL) -78.degree. C. was added potassium
bis(trimethylsilyl)amide (80 mL, 40 mmol, 0.5 M in toluene) slowly.
The mixture was stirred at -78.degree. C. for 3 h. The reaction was
quenched with sat. aq. NH.sub.4Cl (20 mL) slowly. The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (petroleum ether/EtOAc=10:1) to give the title
compound (4.3 g, 41%) as light yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 5.86 (s, 1H), 5.85-5.71 (m, 2H), 5.67 (s, 1H),
5.25-5.14 (m, 2H), 5.03-4.87 (m, 1H), 4.14-3.81 (m, 1H), 2.93-2.76
(m, 2H), 2.74-2.60 (m, 1H), 2.45-2.28 (m, 2H), 1.49 (s, 9H).
Step 6:
##STR00161##
[0421] (4aS,8aS)-tert-butyl
4-oxo-6-(trifluoromethyl)-2,4,4a,5,8,8a-hexahydro-1H-benzo[d][1,3]oxazine-
-1-carboxylate
[0422] To a solution of (4S,5S)-tert-butyl
4-allyl-6-oxo-5-(2-(trifluoromethyl)allyl)-1,3-oxazinane-3-carboxylate
(4.3 g, 12.31 mmol) in toluene (180 mL) was added Hoveyda-Grubbs
catalyst 2.sup.nd generation (771 mg, 1.23 mmol). The mixture was
heated to 100.degree. C. for 2 h under nitrogen atmosphere. After
cooling to room temperature, the mixture was purified by silica gel
chromatography (petroleum ether/EtOAc=6:1) to give the title
compound (2.8 g, 71%) as a light yellow solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 6.33 (s, 1H), 6.10-5.70 (m, 1H), 5.07 (s,
1H), 4.00-3.70 (m, 1H), 3.05-2.88 (m, 1H), 2.87-2.78 (m, 1H),
2.77-2.66 (m, 1H), 2.61-2.46 (m, 1H), 2.31-2.12 (m, 1H), 1.50 (s,
9H).
Step 7:
##STR00162##
[0423]
(1S,6S)-6-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)cyclohex--
3-enecarboxylic acid
[0424] To a solution of (4aS,8aS)-tert-butyl
4-oxo-6-(trifluoromethyl)-2,4,4a,5,8,8a-hexahydro-1H-benzo[d][1,3]oxazine-
-1-carboxylate (2.8 g, 8.71 mmol) in THF (250 mL) at 0.degree. C.
was added 4 M aq. LiOH (54.47 mL, 217.87 mmol). The mixture was
stirred at room temperature for 16 h and concentrated in vacuo.
Water (20 mL) was added and washed with petroleum ether (15 mL).
The aqueous layer was acidified with 4 M HCl to pH 3 and extracted
with EtOAc (150 mL). The organic layer was washed with brine (10
mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo to give the title compound (2.6 g, crude) as
light yellow oil that required no further purification. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 6.28 (s, 1H), 4.27-3.99 (m, 1H),
3.01-2.80 (m, 1H), 2.77-2.58 (m, 2H), 2.56-2.42 (m, 1H), 2.25-2.10
(m, 1H), 1.45 (s, 9H).
Step 8:
##STR00163##
[0425]
tert-butyl((1S,6S)-6-isocyanato-4-(trifluoromethyl)cyclohex-3-en-1--
yl)carbamate
[0426] To a solution of
(1S,6S)-6-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)cyclohex-3-enec-
arboxylic acid (2.6 g, 8.41 mmol) in toluene (25 mL) was added
triethylamine (2.34 mL, 16.81 mmol) and diphenylphosphoryl azide
(2.71 mL, 12.61 mmol). The mixture was heated to 80.degree. C. for
3 h under nitrogen atmosphere. After cooling to room temperature,
the mixture was purified by silica gel chromatography (petroleum
ether/EtOAc=1:1) to give the title compound (2.0 g, 78%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.39 (s, 1H), 5.51
(s, 1H), 3.68-3.54 (m, 1H), 3.44-3.33 (m, 1H), 3.16-3.01 (m, 1H),
2.71-2.58 (m, 1H), 2.44-2.23 (m, 2H), 1.55 (s, 9H).
Step 9:
##STR00164##
[0427]
tert-butyl((1S,6S)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)ca-
rbamate
[0428] To a solution of
tert-butyl((1S,6S)-6-isocyanato-4-(trifluoromethyl)cyclohex-3-en-1-yl)car-
bamate (2.0 g, 6.53 mmol) in THF (30 mL) was added 4 .mu.M aq. NaOH
(9.79 mL, 39.18 mmol). The mixture was stirred at room temperature
for 16 h. The mixture was concentrated in vacuo. EtOAc (50 mL) was
added and washed with brine (10 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (petroleum
ether/EtOAc=10:1, 0.5% triethylamine) to give the title compound
(0.6 g, 33%) as an off-white solid. LCMS (ESI) m/z: 281.1
[M+H].sup.+. H NMR (400 MHz, CDCl.sub.3) .delta. 6.25 (s, 1H),
4.68-4.52 (m, 1H), 3.60-3.45 (m, 1H), 2.96-2.86 (m, 1H), 2.80-2.65
(m, 1H), 2.63-2.52 (m, 1H), 2.13-1.98 (m, 2H), 1.47 (s, 9H).
Step 10:
##STR00165##
[0429]
tert-butyl((1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex-3--
en-1-yl)carbamate
[0430] To a solution of
tert-butyl((1S,6S)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e (300 mg, 1.07 mmol) in 1,2-dichloroethane (9 mL) was added
paraformaldehyde (161 mg, 5.35 mmol) and sodium
triacetoxyborohydride (1.13 g, 5.35 mmol). The mixture was stirred
at room temperature for 16 h. The reaction was quenched with sat.
aq. NaHCO.sub.3 and extracted with EtOAc (15 mL). The organic layer
was washed with brine (3 mL.times.2), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (petroleum
ether/EtOAc=2:1) to give the title compound (0.15 g, 46%) as light
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.23 (s, 1H),
5.57 (s, 1H), 3.52-3.38 (m, 1H), 3.20-3.06 (m, 1H), 2.78-2.60 (m,
1H), 2.36-2.13 (m, 2H), 2.28 (s, 6H), 2.05-1.93 (m, 1H), 1.47 (s,
9H).
Step 11:
##STR00166##
[0431]
(1S,2S)--N.sup.1,N.sup.1-dimethyl-5-(trifluoromethyl)cyclohex-4-ene-
-1,2-diamine
[0432] To a solution of
tert-butyl((1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex-3-en-1-y-
l)carbamate (40 mg, 0.13 mmol) in DCM (1 mL) was added
trifluoroacetic acid (0.29 mL, 3.89 mmol). The mixture was stirred
at room temperature for 1 h. The mixture was concentrated in vacuo
to give the title compound (27 mg, crude) as light yellow oil that
required no further purification.
Step 12:
##STR00167##
[0433]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,6S)-6-(dimethylamino)-4-(t-
rifluoromethyl)cyclohex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide
[0434] To a solution of
(1S,2S)--N.sup.1,N.sup.1-dimethyl-5-(trifluoromethyl)cyclohex-4-ene-1,2-d-
iamine (27 mg, 0.13 mmol) in DMF (1 mL) was added potassium
carbonate (90 mg, 0.65 mmol) and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (120 mg, 0.26 mmol). The mixture was stirred at room
temperature for 16 h. EtOAc (20 mL) was added and washed with water
(5 mL.times.3), brined (5 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
title compound (150 mg, crude) as light yellow oil that required no
further purification. LCMS (ESI) m/z: 649.2 [M+H].sup.+.
Step 13:
##STR00168##
[0435]
5-chloro-4-[[(1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex--
3-en-1-yl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide
[0436] A mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,6S)-6-(dimethylamino)-4-(trifluo-
romethyl)cyclohex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfona-
mide (150 mg, 0.07 mmol) and formic acid (3 mL) was stirred at room
temperature for 1 h. The mixture was concentrated in vacuo. The
crude residue was purified by reverse phase chromatography
(acetonitrile 12-42%/0.225% formic acid in water) to give the title
compound (17 mg, 15%) as a white solid. LCMS (ESI) m/z: 499.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60 (d,
J=7.2 Hz, 1H), 7.25 (d, J=4.4 Hz, 1H), 6.85 (d, J=12.8 Hz, 1H),
6.80 (d, J=4.4 Hz, 1H), 6.35 (s, 1H), 6.07 (d, J=5.2 Hz, 1H),
3.70-3.60 (m, 1H), 3.15-3.05 (m, 1H), 2.93-2.80 (m, 1H), 2.54-2.50
(m, 1H), 2.32-2.26 (m, 1H), 2.22 (s, 6H), 2.14-2.00 (m, 1H).
Example 24 & Example 25
##STR00169##
[0437]
5-cyclopropyl-4-[(1S,2S)-2-(dimethylamino)cyclohexoxy]-2-fluoro-N-t-
hiazol-2-yl-benzenesulfonamide &
5-cyclopropyl-4-[(1R,2R)-2-(dimethylamino)cyclohexoxy]-2-fluoro-N-thiazol-
-2-yl-benzenesulfonamide
[0438] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamino)cycl-
ohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide with
racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)cyclohexyl)-
oxy)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide and racemic
(trans)-5-chloro-N-(2,4-dimethoxybenzyl)-2-((2-(dimethylamino)cyclohexyl)-
oxy)-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide, racemic
(trans)-5-cyclopropyl-4-((2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(th-
iazol-2-yl)benzenesulfonamide was obtained as a white solid.
Racemic
(trans)-5-cyclopropyl-4-((2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(th-
iazol-2-yl)benzenesulfonamide was separated by using chiral SFC
(Chiralpak C2 (250 mm*30 mm, 10 um), Supercritical
CO.sub.2/EtOH+0.1% NH.sub.4OH=55/55; 80 mL/min) to give
5-cyclopropyl-4-[(1S,2S)-2-(dimethylamino)cyclohexoxy]-2-fluoro-N-thiazol-
-2-yl-benzenesulfonamide (first peak) as a white solid and
5-cyclopropyl-4-[(1R,2R)-2-(dimethylamino)cyclohexoxy]-2-fluoro-N-thiazol-
-2-yl-benzenesulfonamide (second peak) as a white solid. Absolute
configuration was arbitrarily assigned to each enantiomer. Example
24: LCMS (ESI) m/z: 440 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.20 (d, J=4.0 Hz, 1H), 7.19 (s, 1H), 7.10
(d, J=12.8 Hz, 1H), 6.74 (d, J=4.8 Hz, 1H), 4.64-4.52 (m, 1H),
2.77-2.68 (m, 1H), 2.34 (s, 6H), 2.10-1.99 (m, 2H), 1.86-1.78 (m,
1H), 1.72-1.56 (m, 2H), 1.40-1.23 (m, 4H), 0.95-0.87 (m, 2H),
0.62-0.53 (m, 2H). Example 25: LCMS (ESI) m/z: 440 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.20 (d, J=2.8 Hz, 1H),
7.19 (s, 1H), 7.11 (d, J=12.4 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H),
4.64-4.52 (m, 1H), 2.78-2.69 (m, 1H), 2.34 (s, 6H), 2.09-1.99 (m,
2H), 1.88-1.77 (m, 1H), 1.73-1.56 (m, 2H), 1.40-1.23 (m, 4H),
0.94-0.83 (m, 2H), 0.63-0.51 (m, 2H).
Example 26
##STR00170##
[0439]
5-chloro-N-(5-chlorothiazol-2-yl)-4-(((1S,2S)-2-(dimethylamino)cycl-
ohexyl)amino)-2-fluorobenzenesulfonamide
[0440] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-(5-chlorothiazol-2-yl)-N-[(2,4-dimethoxyphenyl)methyl]-2,4-dif-
luoro-benzenesulfonamide,
5-chloro-N-(5-chlorothiazol-2-yl)-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl-
]amino]-2-fluorobenzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 466.9 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.55 (d, J=7.2 Hz, 1H), 6.97-6.88 (m, 2H),
5.89 (d, J=10.0 Hz, 1H), 3.90-3.37 (m, 1H), 3.20-3.10 (m, 1H), 2.62
(s, 6H), 2.08-2.01 (m, 1H), 1.98-1.87 (m, 1H), 1.86-1.76 (m, 1H),
1.66-1.57 (m, 1H), 1.49-1.31 (m, 2H), 1.29-1.16 (m, 2H).
Example 27
##STR00171##
[0441]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(4-methylthiazol-2-yl)benzenesulfonamide Formate
[0442] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-(4-methylthiazol--
2-yl)benzenesulfonamide,
5-chloro-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl]amino]-2-fluoro-N-(4-met-
hylthiazol-2-yl)benzenesulfonamide formate was obtained as a white
solid. LCMS (ESI) m/z: 447.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.15 (s, 1H), 7.57 (d, J=7.2 Hz, 1H), 6.75
(d, J=13.2 Hz, 1H), 6.34 (s, 1H), 5.86 (d, J=6.0 Hz, 1H), 3.36-3.32
(m, 1H), 2.75-2.65 (m, 1H), 2.22 (s, 6H), 2.07 (s, 3H), 1.89-1.83
(m, 1H), 1.81-1.73 (m, 1H), 1.64-1.56 (m, 1H), 1.42-1.31 (m, 1H),
1.27-1.08 (m, 4H).
Example 28
##STR00172##
[0443]
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-3-nitro-N-(thiazol-2-
-yl)benzenesulfonamide
[0444] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
N-(2,4-dimethoxybenzyl)-4-fluoro-3-nitro-N-(thiazol-2-yl)benzenesulfonami-
de, the title compound was obtained as a white solid. LCMS (ESI)
m/z: 426.1 [M+H].sup.+.
Example 29
##STR00173##
[0445]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(propyl)amino)cyclohexyl)ami-
no)-N-(thiazol-2-yl)benzenesulfonamide
##STR00174##
[0446] Step 1:
##STR00175##
[0447]
N-((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)-
sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)-2,2,2-trifluoroacetamide
[0448] A mixture of
4-[[(1S,2S)-2-aminocyclohexyl]amino]-5-chloro-N-[(2,4-dimethoxyphenyl)met-
hyl]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (5.0 g, 9.01 mmol)
and ethyl trifluoroacetate (1.18 mL, 9.91 mmol) in tetrahydrofuran
(20 mL) was stirred at room temperature for 6h. The mixture was
then concentrated and purified by silica chromatography (0 to 70%
EtOAc/Heptane) to give the title compound (3.8 g, 65%) as yellow
oil.
Step 2:
##STR00176##
[0449]
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamin-
o)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0450] Potassium tert-butoxide (390 mg, 3.5 mmol) was added to a
solution of
N-[(1S,2S)-2-[2-chloro-4-[(2,4-dimethoxyphenyl)methyl-thiazol-2-yl-sul-
famoyl]-5-fluoro-anilino]cyclohexyl]-2,2,2-trifluoroacetamide (1.50
g, 2.30 mmol) in N,N-dimethylformamide (5 mL). After the mixture
was stirred for 10 min, iodomethane (0.22 mL, 3.5 mmol) was added.
The mixture was stirred for 1 h then cooled to 5.degree. C. 20%
aqueous NH.sub.4Cl was added. The resulting precipitate was
collected by filtration and washed with water. The solid was
dissolved in methanol (5 mL) and a solution of 10N KOH (3.8 mL) was
added. The mixture was stirred at room temperature for 36h. The
mixture was concentrated to remove methanol and the aqueous phase
was extracted with DCM. The organic phase was dried with
MgSO.sub.4, filtered and concentrated. The crude product was
purified by silica gel chromatography (0 to 10% MeOH/DCM) to give
title compound (1.30 g, 71%) as a yellow solid. LCMS (ESI) m/z:
569.1 [M+H]+.
Step 3:
##STR00177##
[0451]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(propyl)amino)cyclohexyl)ami-
no)-N-(thiazol-2-yl)benzenesulfonamide
[0452] 1-Iodopropane (0.02 mL, 0.20 mmol) was added to a solution
of
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2-fluoro-4-[[(1S,2S)-2-(methylam-
ino)cyclohexyl]amino]-N-thiazol-2-yl-benzenesulfonamide (75 mg,
0.13 mmol) and N,N-diisopropylethylamine (0.046 mL, 0.26 mmol) in
N,N-dimethylformamide (2 mL) and the mixture was stirred at
60.degree. C. for 16h. the reaction was cooled down and water was
added. The resulting precipitate was collected by filtration and
washed with water. The residue was stirred in formic acid (1 mL)
for 30 min and concentrated. The crude residue was purified by
reverse phase chromatography (acetonitrile 26-56%/0.225% formic
acid in water) to give the title compound (23 mg, 29%) as a white
solid.
[0453] LCMS (ESI) m/z: 461.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.41 (s, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.22 (d,
J=4.5 Hz, 1H), 6.80-6.67 (m, 2H), 5.86 (dd, J=4.7, 1.8 Hz, 1H),
3.29 (s, 1H), 2.63 (s, 1H), 2.50-2.28 (m, 2H), 2.12 (s, 3H), 2.07
(s, 1H), 1.79 (d, J=18.2 Hz, 2H), 1.61 (d, J=12.5 Hz, 1H), 1.37
(dtd, J=18.1, 13.7, 6.7 Hz, 3H), 1.32-1.06 (m, 3H), 0.77 (t, J=7.3
Hz, 3H).
Example 30
##STR00178##
[0454]
5-chloro-2-fluoro-4-(((1S,2S)-2-(pyrrolidin-1-yl)cyclohexyl)amino)--
N-(thiazol-2-yl)benzenesulfonamide
##STR00179##
##STR00180##
[0455]
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzy-
l)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0456] A mixture of
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-yl-benz-
enesulfonamide (8.60 g, 18.7 mmol), (1S,2S)-cyclohexane-1,2-diamine
(4.26 g, 37.3 mmol), and triethylamine (13.0 mL, 93.3 mmol) was
stirred in N,N-dimethylformamide (93 mL) at room temperature for
2h. 100 mL of aqueous NaHCO.sub.3 were added and the aqueous phase
was extracted with dichloromethane. The organic phase was dried
with MgSO.sub.4, filtered and concentrated on silica gel.
Purification by silica gel chromatography (0-10% MeOH/DCM gradient)
to afford the title compound (8.70 g, 84%) as a white solid. LCMS
(ESI) m/z: 556.1 [M+H]+. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. 7.72 (d, J=7.1 Hz, 1H), 7.38 (d, J=3.6 Hz, 1H), 7.21 (dt,
J=8.4, 1.0 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H), 6.45 (d, J=12.7 Hz,
1H), 6.36 (d, J=7.4 Hz, 2H), 5.19 (s, 2H), 4.90-4.79 (m, 1H), 3.75
(s, 3H), 3.75 (s, 3H), 3.01-2.92 (m, 1H), 2.75-2.61 (m, 1H),
2.11-1.93 (m, 2H), 1.86-1.67 (m, 2H), 1.39-1.05 (m, 4H).
##STR00181##
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(pyrrolidin-1-yl)-
cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0457] A mixture of
4-[[(1S,2S)-2-aminocyclohexyl]amino]-5-chloro-N-[(2,4-dimethoxyphenyl)met-
hyl]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (250 mg, 0.45
mmol), 1,4-dibromobutane (0.054 mL, 0.45 mmol), and
N,N-diisopropylethylamine (0.16 mL, 0.9 mmol) was stirred in
acetonitrile (1.8 mL) at reflux for 17h. The mixture was cooled
down and diluted with DCM and aqueous NaHCO.sub.3. The phases were
separated and the aqueous phase was extracted with DCM. The
combined organic phases were dried with MgSO.sub.4, filtered and
concentrated. The crude product was purified by silica gel
chromatography to give the title compound (240 mg, 87.4%) as a
white solid. LCMS (ESI) m/z: 609.1 [M+H]+. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. 7.70 (d, J=7.1 Hz, 1H), 7.38 (d, J=3.6 Hz,
1H), 7.21 (dd, J=7.7, 0.9 Hz, 1H), 6.95 (d, J=3.6 Hz, 1H),
6.39-6.33 (m, 2H), 6.29 (d, J=12.7 Hz, 1H), 6.03 (s, 1H), 5.19 (s,
2H), 3.75 (d, J=1.1 Hz, 6H), 3.03 (ddd, J=13.2, 9.4, 3.6 Hz, 1H),
2.75-2.65 (m, 1H), 2.54 (tp, J=5.4, 2.5 Hz, 4H), 2.27 (d, J=12.6
Hz, 1H), 1.96-1.80 (m, 2H), 1.80-1.64 (m, 5H), 1.47-1.13 (m,
4H).
##STR00182##
5-chloro-2-fluoro-4-(((1S,2S)-2-(pyrrolidin-1-yl)cyclohexyl)amino)-N-(thi-
azol-2-yl)benzenesulfonamide
[0458] A mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(pyrrolidin-1-yl)-
cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (240 mg, 0.39
mmol) and formic acid (2 mL) was stirred at room temperature for 2
h. The mixture was concentrated in vacuo. The crude residue was
purified by reverse phase chromatography (acetonitrile
26-56%/0.225% formic acid in water) to give the title compound (22
mg, 12%) as a white solid. LCMS (ESI) m/z: 459.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.59 (d, J=7.3 Hz, 1H), 7.16
(d, J=4.4 Hz, 1H), 6.80-6.66 (m, 2H), 5.86 (d, J=6.4 Hz, 1H), 3.41
(s, 1H), 2.99 (d, J=11.0 Hz, 1H), 2.78 (d, J=8.3 Hz, 2H), 2.69 (d,
J=7.7 Hz, 2H), 2.07 (s, 2H), 1.90 (dd, J=12.6, 3.8 Hz, 1H),
1.81-1.73 (m, 1H), 1.76-1.56 (m, 5H), 1.47-1.14 (m, 4H).
Example 31
##STR00183##
[0459]
5-chloro-4-(((1S,2S)-2-((cyclopropylmethyl)(methyl)amino)cyclohexyl-
)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0460] Following the procedure described in Example 29 and making
non-critical variations as required to replace the iodopropane with
iodomethylcyclopropane, the title compound was obtained. LCMS (ESI)
m/z: 473.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
12.38 (s, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.21 (d, J=4.5 Hz, 1H),
6.79-6.66 (m, 2H), 5.93 (dd, J=4.6, 1.7 Hz, 1H), 2.74 (s, 1H), 2.31
(s, 2H), 2.21 (s, 4H), 2.07 (s, 1H), 1.79 (dd, J=20.7, 7.6 Hz, 2H),
1.61 (d, J=13.2 Hz, 1H), 1.36 (t, J=13.1 Hz, 1H), 1.30-1.06 (m,
3H), 0.82-0.72 (m, 1H), 0.50-0.33 (m, 2H), 0.13-0.03 (m, 1H).
Example 32
##STR00184##
[0461]
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-methoxyethyl)(methyl)amino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate
[0462] Following the procedure described in Example 29 and making
non-critical variations as required to replace the iodopropane with
2-bromoethyl methyl ether, the title compound was obtained as a
white solid. LCMS (ESI) m/z: 477.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.15 (s, 1H), 7.59 (d, J=7.6 Hz, 1H),
7.24 (d, J=4.4 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 6.69 (d, J=12.8 Hz,
1H), 5.92 (d, J=3.6 Hz, 1H), 3.34-3.21 (m, 3H), 3.13 (s, 3H),
2.66-2.57 (m, 2H), 2.52 (d, J=2.0 Hz, 1H), 2.17 (s, 3H), 2.16-2.08
(m, 1H), 1.87-1.71 (m, 2H), 1.64-1.54 (m, 1H), 1.42-1.31 (m, 1H),
1.27-1.21 (m, 2H), 1.17-1.05 (m, 1H).
Example 33
##STR00185##
[0463]
5-chloro-2-fluoro-4-(((1S,2S)-2-(isopropyl(methyl)amino)cyclohexyl)-
amino)-N-(thiazol-2-yl)benzenesulfonamide
[0464] Following the procedure described in Example 18 and making
non-critical variations as required to replace the acetaldehyde
with acetone, the title compound was obtained. LCMS (ESI) m/z:
461.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.58 (d,
J=7.3 Hz, 1H), 7.20 (d, J=4.5 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.68
(d, J=12.7 Hz, 1H), 5.80 (d, J=4.2 Hz, 1H), 3.82-3.71 (m, 1H),
3.44-3.20 (m, 1H), 3.28 (s, 3H), 2.56-2.44 (m, 1H), 2.17 (d, J=6.1
Hz, 1H), 2.12 (s, 4H), 1.78 (dd, J=26.8, 11.8 Hz, 3H), 1.61 (d,
J=12.8 Hz, 1H), 1.37 (d, J=12.5 Hz, 1H), 1.28 (d, J=33.2 Hz, 1H),
1.17 (d, J=12.4 Hz, 1H), 0.99 (d, J=6.3 Hz, 6H).
Example 34
##STR00186##
[0465]
5-chloro-2-fluoro-4-(((1S,2S)-2-(propylamino)cyclohexyl)amino)-N-(t-
hiazol-2-yl)benzenesulfonamide
[0466] Following the procedure described in Example 29, step 2 and
making non-critical variations as required to replace the
iodomethane with 1-iodopropane, the title compound was obtained.
LCMS (ESI) m/z: 447.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 7.57 (d, J=7.4 Hz, 1H), 7.03 (d, J=4.1 Hz, 1H), 6.72 (d,
J=12.8 Hz, 1H), 6.60-6.49 (m, 1H), 5.75 (d, J=9.3 Hz, 1H), 2.99 (d,
J=10.6 Hz, 1H), 2.81-2.62 (m, 2H), 2.12-2.03 (m, 1H), 1.93 (dd,
J=12.7, 3.7 Hz, 1H), 1.72 (d, J=11.7 Hz, 1H), 1.62 (d, J=12.9 Hz,
1H), 1.58-1.29 (m, 3H), 1.22 (dtd, J=16.5, 12.7, 6.4 Hz, 3H), 0.85
(t, J=7.4 Hz, 3H).
Example 35
##STR00187##
[0467]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(6-fluoropyridin-2-yl)benzenesulfonamide
[0468] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine-2-yl)be-
nzenesulfonamide,
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(6-flu-
oropyridin-2-yl)benzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 445.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.71 (dd, J=7.9, 5.7 Hz, 2H), 6.81-6.73 (m,
2H), 6.57-6.50 (m, 1H), 5.95 (d, J=6.4 Hz, 1H), 2.80 (s, 1H), 2.27
(s, 6H), 2.10-1.99 (m, 2H), 1.88 (d, J=9.1 Hz, 1H), 1.77 (d, J=11.0
Hz, 1H), 1.65-1.56 (m, 1H), 1.44-1.23 (m, 1H), 1.24-1.11 (m,
2H).
Example 36 & Example 82
##STR00188##
[0469]
5-chloro-4-(((1R,2R,4R)-2-(dimethylamino)-4-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
##STR00189##
[0470] Step 1
##STR00190##
[0471]
(trans)-tert-butyl(2-amino-4-(trifluoromethyl)cyclohexyl)carbamate
[0472] To a solution of
(trans)-tert-butyl(6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e (300 mg, 1.07 mmol) in EtOAc (8 mL) was added Pd(OH).sub.2 (20%,
451 mg, 0.64 mmol). The mixture was stirred at room temperature for
2 h under hydrogen atmosphere (15 psi). The mixture was filtered
and concentrated in vacuo to give the title compound (0.28 g,
crude) as a light yellow solid that required no further
purification.
Step 2
##STR00191##
[0473]
(trans)-tert-butyl(2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)-
carbamate
[0474] To a solution of
(trans)-tert-butyl(2-amino-4-(trifluoromethyl)cyclohexyl)carbamate
(260 mg, 0.92 mmol) in MeOH (1 mL) was added AcOH (0.11 mL, 1.84
mmol) and paraformaldehyde (138 mg, 4.61 mmol). The mixture was
stirred at room temperature for 10 min and sodium cyanoborohydride
(289 mg, 4.61 mmol) was added. The mixture was stirred at room
temperature for an additional 16 h. The reaction was quenched with
sat. aq. NaHCO.sub.3 (10 mL) and extracted with DCM (20
mL.times.3). The combined organic layer were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (solvent
gradient: 0-100% EtOAc (0.5% TEA) in petroleum ether) to give the
title compound (280 mg, 98%) as a light yellow solid.
Step 3
##STR00192##
[0475]
(trans)-N.sup.1,N.sup.1-dimethyl-5-(trifluoromethyl)cyclohexane-1,2-
-diamine
[0476] To a solution of
(trans)-tert-butyl(2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)carbam-
ate (260 mg, 0.84 mmol) in DCM (3 mL) was added trifluoroacetic
acid (1.24 mL, 16.75 mmol). The mixture was stirred at room
temperature for 2 h and concentrated in vacuo to give the title
compound (176 mg, crude) as light yellow oil that required no
further purification.
Step 4
##STR00193##
[0477] (trans,
cis)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)-4-(trifluorom-
ethyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
& (trans,
trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)-4-(-
trifluoromethyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonam-
ide
[0478] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (1.16 g, 2.51 mmol) and N,N-diisopropylethylamine (0.69 mL,
4.19 mmol) in DMF (5 mL) was added
(trans)-N.sup.1,N.sup.1-dimethyl-5-(trifluoromethyl)cyclohexane-1,2-diami-
ne (176 mg, 0.84 mmol). The reaction mixture was stirred at room
temperature for 16 h and concentrated in vacuo. The crude residue
was purified by silica gel chromatography (solvent gradient:
0-10%-25% EtOAc (1% TEA) in petroleum ether) to give (trans,
cis)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)-4-(trifluorom-
ethyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(160 mg, less polar on TLC) as a light yellow solid and (trans,
trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)-4-(trifluor-
omethyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(70 mg, more polar on TLC) as a light yellow solid. Less polar on
TLC: LCMS (ESI) m/z: 651.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.74 (d, J=7.2 Hz, 1H), 7.40 (d, J=3.6 Hz, 1H),
7.22 (d, J=8.4 Hz, 1H), 6.97 (d, J=3.2 Hz, 1H), 6.41-6.33 (m, 2H),
6.28 (d, J=12.4 Hz, 1H), 5.93 (s, 1H), 5.20 (s, 2H), 3.76 (s, 3H),
3.76 (s, 3H), 3.07-2.96 (m, 1H), 2.65-2.55 (m, 1H), 2.49-2.39 (m,
1H), 2.25 (s, 3H), 2.25 (s, 3H), 2.21-2.11 (m, 2H), 2.05-1.96 (m,
1H), 1.53-1.42 (m, 1H), 1.41-1.31 (m, 1H), 1.28-1.23 (m, 1H). More
polar on TLC: LCMS (ESI) m/z: 651.3 [M+H].sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.74 (d, J=7.2 Hz, 1H), 7.40 (d, J=3.6 Hz,
1H), 7.22 (d, J=8.0 Hz, 1H), 6.97 (d, J=3.6 Hz, 1H), 6.42-6.33 (m,
2H), 6.28 (d, J=12.4 Hz, 1H), 5.48 (s, 1H), 5.20 (s, 2H), 3.76 (s,
3H), 3.76 (s, 3H), 3.48-3.38 (m, 1H), 2.62-2.51 (m, 2H), 2.29 (s,
3H), 2.29 (s, 3H), 2.20-2.10 (m, 1H), 1.92-1.76 (m, 4H), 1.68-1.55
(m, 1H).
Step 5
##STR00194##
[0479] (trans,
cis)-5-chloro-4-((2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)amino)--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide formate
[0480] A mixture of (trans,
cis)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)-4-(trifluorom-
ethyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(160 mg, 0.25 mmol) and formic acid (5.0 mL) was stirred at room
temperature for 1 h. The reaction mixture was concentrated in
vacuo. The crude residue was purified by reverse phase
chromatography (acetonitrile 10-40%/0.225% formic acid in water) to
give the title compound (82 mg, 67%) as a white solid. LCMS (ESI)
m/z: 501.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.14 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H),
6.87-6.74 (m, 2H), 5.81 (d, J=4.8 Hz, 1H), 3.45-3.38 (m, 1H),
2.88-2.77 (m, 1H), 2.45-2.35 (m, 1H), 2.20 (s, 3H), 2.20 (s, 3H),
2.20-2.09 (m, 1H), 2.03-1.94 (m, 1H), 1.84-1.73 (m, 1H), 1.59-1.44
(m, 1H), 1.37-1.18 (m, 2H).
Step 6
##STR00195##
[0481]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R,4R)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0482] (trans,
cis)-5-chloro-4-((2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)amino)--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide formate (82 mg) was
separated by using chiral SFC (Chiralpak OJ (250 mm*30 mm, 5 um),
Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=75/25; 60 mL/min) to
give
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (20 mg, first
peak) as a white solid and
5-chloro-4-(((1R,2R,4R)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (32 mg, second
peak) as a white solid. Absolute configuration was arbitrarily
assigned to each enantiomer. Example 82: LCMS (ESI) m/z: 501.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.58 (d,
J=6.8 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 6.87-6.74 (m, 2H), 5.81 (d,
J=4.8 Hz, 1H), 3.45-3.38 (m, 1H), 2.88-2.77 (m, 1H), 2.45-2.35 (m,
1H), 2.20 (s, 3H), 2.20 (s, 3H), 2.20-2.09 (m, 1H), 2.03-1.94 (m,
1H), 1.84-1.73 (m, 1H), 1.59-1.44 (m, 1H), 1.37-1.18 (m, 2H).
Example 36: LCMS (ESI) m/z: 501.2 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.58 (d, J=6.8 Hz, 1H), 7.23 (d, J=3.6
Hz, 1H), 6.87-6.74 (m, 2H), 5.81 (d, J=4.8 Hz, 1H), 3.45-3.38 (m,
1H), 2.88-2.77 (m, 1H), 2.45-2.35 (m, 1H), 2.20 (s, 3H), 2.20 (s,
3H), 2.20-2.09 (m, 1H), 2.03-1.94 (m, 1H), 1.84-1.73 (m, 1H),
1.59-1.44 (m, 1H), 1.37-1.18 (m, 2H).
Example 77 & Example 81
##STR00196##
[0483]
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Step 1
##STR00197##
[0484] (trans,
trans)-5-chloro-4-((2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0485] Following the procedure described in Example 36, step 5, and
making non-critical variations as required to replace (trans,
cis)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)-4-(trifluorom-
ethyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with (trans,
trans)-5-chloro-N-(2,4-dimethoxybenzyl)-4-((2-(dimethylamino)-4-(-
trifluoromethyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonam-
ide, (trans,
trans)-5-chloro-4-((2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was obtained as a
white solid. LCMS (ESI) m/z: 501.2 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.60 (d, J=7.2 Hz, 1H), 7.24 (d, J=4.4
Hz, 1H), 6.83-6.74 (m, 2H), 5.74 (d, J=6.0 Hz, 1H), 3.66-3.50 (m,
1H), 2.78-2.67 (m, 2H), 2.23 (s, 3H), 2.23 (s, 3H), 2.01-1.90 (m,
1H), 1.90-1.66 (m, 4H), 1.54-1.40 (m, 1H).
Step 2
##STR00198##
[0486]
5-chloro-4-(((1R,2R,4S)-2-(dimethylamino)-4-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0487] (trans,
trans)-5-chloro-4-((2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (45 mg) was separated
by using chiral SFC (Chiralpak AS (250 mm*30 mm, 5 um),
Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=75/25; 60 mL/min) to
give
5-chloro-4-(((1R,2R,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (12 mg, first
peak) as a white solid and
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (8 mg, second
peak) as a white solid. Absolute configuration was arbitrarily
assigned to each enantiomer. Example 81: LCMS (ESI) m/z: 501.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60 (d,
J=7.2 Hz, 1H), 7.24 (d, J=4.4 Hz, 1H), 6.83-6.74 (m, 2H), 5.74 (d,
J=6.0 Hz, 1H), 3.66-3.50 (m, 1H), 2.78-2.67 (m, 2H), 2.23 (s, 3H),
2.23 (s, 3H), 2.01-1.90 (m, 1H), 1.90-1.66 (m, 4H), 1.54-1.40 (m,
1H). Example 77: LCMS (ESI) m/z: 501.2 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.60 (d, J=7.2 Hz, 1H), 7.24 (d,
J=4.4 Hz, 1H), 6.83-6.74 (m, 2H), 5.74 (d, J=6.0 Hz, 1H), 3.66-3.50
(m, 1H), 2.78-2.67 (m, 2H), 2.23 (s, 3H), 2.23 (s, 3H), 2.01-1.90
(m, 1H), 1.90-1.66 (m, 4H), 1.54-1.40 (m, 1H).
Example 37
##STR00199##
[0488]
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-fluoroethyl)(methyl)amino)cyclo-
hexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate
[0489] Following the procedure described in Example 29 and making
non-critical variations as required to replace iodopropane with
1-bromo-2-fluoroethane,
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-fluoroethyl)(methyl)amino)cyclohexyl)-
amino)-N-(thiazol-2-yl)benzenesulfonamide formate was obtained as a
white solid. LCMS (ESI) m/z: 465.0 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.14 (s, 1H), 7.58 (d, J=7.2 Hz, 1H),
7.25 (d, J=4.4 Hz, 1H), 6.81 (d, J=4.8 Hz, 1H), 6.70 (d, J=13.2 Hz,
1H), 5.89 (d, J=3.6 Hz, 1H), 4.47-4.40 (m, 1H), 4.34-4.28 (m, 1H),
3.31-3.23 (m, 2H), 2.72-2.61 (m, 2H), 2.18 (s, 3H), 2.16-2.08 (m,
1H), 1.85-1.69 (m, 2H), 1.65-1.55 (m, 1H), 1.44-1.30 (m, 1H),
1.30-1.19 (m, 2H), 1.19-1.07 (m, 1H).
Example 38
##STR00200##
[0490]
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate
[0491] Following the procedure described in Example 29 and making
non-critical variations as required to replace iodopropane with
2-bromoethanol,
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino)cyclohexyl-
)amino)-N-(thiazol-2-yl)benzenesulfonamide formate was obtained as
a white solid. LCMS (ESI) m/z: 463.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.15 (s, 1H), 7.58 (d, J 7.2 Hz, 1H),
7.23 (d, J=4.4 Hz, 1H), 6.79 (d, J=4.8 Hz, 1H), 6.73 (d, J=13.2 Hz,
1H), 5.97 (d, J=4.8 Hz, 1H), 3.49-3.38 (m, 2H), 3.37-3.29 (m, 1H),
2.80-2.71 (m, 1H), 2.65-2.52 (m, 2H), 2.23 (s, 3H), 2.14-2.06 (m,
1H), 1.90-1.71 (m, 2H), 1.66-1.55 (m, 1H), 1.44-1.31 (m, 1H),
1.30-1.19 (m, 2H), 1.19-1.06 (m, 1H).
Example 39
##STR00201##
[0492]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chlor-
o-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide dihydrochloride
##STR00202##
[0493] Step 1
##STR00203##
[0494] tert-butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)amino)azetidine-1-carboxylate
[0495] To a solution of
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzyl)-2-f-
luoro-N-(thiazol-2-yl)benzenesulfonamide (5.5 g, 9.91 mmol) in DCM
(100 mL) was added AcOH (0.057 mL, 0.99 mmol) and tert-butyl
3-oxoazetidine-1-carboxylate (1.7 g, 9.91 mmol). The mixture was
stirred at room temperature for 1 h and sodium
triacetoxyborohydride (6.3 g, 29.73 mmol) was added. The mixture
was stirred at room temperature for an additional 12 h. The
reaction was quenched with 1N NaOH (35 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude residue was purified by silica gel chromatography
(solvent gradient: 0-40% EtOAc in petroleum ether) to give the
title compound (5.39 g, 77%) as a yellow solid. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.74 (d, J=7.2 Hz, 1H), 7.40 (d, J=3.6 Hz,
1H), 7.22 (d, J=8.0 Hz, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.42 (d,
J=12.4 Hz, 1H), 6.40-6.35 (m, 2H), 5.20 (s, 2H), 4.97-4.88 (m, 1H),
4.14-4.06 (m, 2H), 3.76 (s, 3H), 3.76 (s, 3H), 3.69-3.61 (m, 1H),
3.60-3.53 (m, 2H), 3.09-2.98 (m, 1H), 2.51-2.41 (m, 1H), 2.14-2.07
(m, 1H), 2.04-1.95 (m, 1H), 1.83-1.74 (m, 2H), 1.43 (s, 9H),
1.35-1.27 (m, 2H), 1.23-1.13 (m, 2H).
Step 2
##STR00204##
[0496] tert-butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)(methyl)amino)azetidine-1-carboxylat-
e
[0497] To a solution of tert-butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)amino)azetidine-1-carboxylate
(5.39 g, 7.59 mmol) in MeOH (90 mL) was added paraformaldehyde
(1.14 g, 37.94 mmol). The mixture was stirred at room temperature
for 1 h and sodium cyanoborohydride (0.95 g, 15.18 mmol) was added.
The mixture was stirred at room temperature for an additional 12 h.
The reaction was quenched with water (10 mL) and concentrated in
vacuo. The crude residue was purified by silica gel chromatography
(petroleum ether/EtOAc=3:1) to give the title compound (5.1 g, 93%)
as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.72
(d, J=6.4 Hz, 1H), 7.40 (dd, J=3.6, 1.2 Hz, 1H), 7.21 (d, J=8.0 Hz,
1H), 6.98 (dd, J=3.2, 1.2 Hz, 1H), 6.42-6.34 (m, 2H), 6.29 (d,
J=12.4 Hz, 1H), 5.86 (s, 1H), 5.19 (s, 2H), 4.36 (s, 1H), 3.99-3.89
(m, 2H), 3.86-3.78 (m, 2H), 3.76 (s, 3H), 3.76 (s, 3H), 3.62-3.52
(m, 1H), 3.06-2.94 (m, 1H), 2.54-2.42 (m, 1H), 2.39-2.26 (m, 1H),
2.08 (s, 3H), 1.94-1.71 (m, 3H), 1.45 (s, 9H), 1.37-1.26 (m, 3H),
1.22-1.06 (m, 1H)
Step 3
##STR00205##
[0498]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chlor-
o-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide dihydrochloride
[0499] A mixture of tert-butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)(methyl)amino)azetidine-1-carboxylat-
e (1.1 g, 1.52 mmol) and formic acid (33 mL) was stirred at room
temperature for 4 h. The mixture was concentrated in vacuo. The
crude residue was purified by reverse phase chromatography
(acetonitrile 3-33%/0.05% HCl in water) to give the title compound
(603 mg, 83%) as a white solid. LCMS (ESI) m/z: 474.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.91 (s, 1H),
11.85-9.95 (m, 1H), 9.81 (s, 1H), 9.60-8.96 (m, 1H), 7.63 (d, J=7.2
Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 7.08 (s, 1H), 6.85 (d, J=4.4 Hz,
1H), 6.32 (s, 1H), 4.66-3.86 (m, 5H), 3.68-3.55 (m, 1H), 2.63 (s,
3H), 2.53-2.51 (m, 1H), 2.14-1.69 (m, 3H), 1.67-1.53 (m, 1H),
1.52-1.31 (m, 3H), 1.30-1.15 (m, 1H).
Example 40
##STR00206##
[0500]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(5-methylthiazol-2-yl)benzenesulfonamide formate
[0501] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-methylthiazol-2-yl)ben-
zenesulfonamide,
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(5-met-
hylthiazol-2-yl)benzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 447.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.16 (s, 1H), 7.56 (d, J=7.2 Hz, 1H), 6.93
(s, 1H), 6.76 (d, J=12.8 Hz, 1H), 5.86 (d, J=5.2 Hz, 1H), 3.39-3.35
(m, 1H), 2.76-2.69 (m, 1H), 2.24 (s, 3H), 2.24 (s, 3H), 2.17 (s,
3H), 2.11-2.03 (m, 1H), 1.91-1.83 (m, 1H), 1.81-1.71 (m, 1H),
1.66-1.56 (m, 1H), 1.44-1.30 (m, 1H), 1.28-1.07 (m, 3H).
Example 41
##STR00207##
[0502]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-methylazetidin-3-yl)amino-
)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate
[0503] To a solution of
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chloro-2-fl-
uoro-N-(thiazol-2-yl)benzenesulfonamide (185 mg, 0.39 mmol) in MeOH
(2 mL) was added paraformaldehyde (14 mg, 0.47 mmol). The mixture
was stirred at room temperature for 1 h and sodium cyanoborohydride
(49 mg, 0.78 mmol) was added. The mixture was stirred at room
temperature for an additional 12 h. The reaction was quenched with
water (1 mL) and concentrated in vacuo. The crude residue was
purified by reverse phase chromatography (acetonitrile
26-56%/0.225% formic acid in water) to give the title compound (77
mg, 39%) as a white solid. LCMS (ESI) m/z: 488.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.22 (s, 1H), 7.58 (d,
J=7.2 Hz, 1H), 7.14 (d, J=4.4 Hz, 1H), 6.72-6.66 (m, 2H), 5.72-5.66
(m, 1H), 3.85-3.73 (m, 2H), 3.67-3.57 (m, 1H), 3.47-3.37 (m, 1H),
3.35-3.25 (m, 2H), 2.53 (s, 3H), 2.53-2.52 (m, 1H), 2.03 (s, 3H),
2.08-1.97 (m, 1H), 1.75-1.68 (m, 1H), 1.67-1.54 (m, 2H), 1.40-1.11
(m, 4H).
Example 42 & Example 43
##STR00208##
[0504]
5-chloro-4-(((1S,2S)-2-(ethylamino)cyclohexyl)oxy)-2-fluoro-N-(thia-
zol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R)-2-(ethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-2--
yl)benzenesulfonamide
[0505] Following the procedure described in Examples 7 & 8, and
making non-critical variations as required to replace racemic
(trans)-2-(dimethylamino)cyclohexanol with racemic
(trans)-2-(ethylamino)cyclohexan-1-ol, the title compounds was
obtained as a mixture of enantiomers. The individual isomers were
separated by chiral SFC and the stereochemistry was assigned
arbitrarily.
[0506] Example 42: LCMS (ESI) m/z: 434 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.80 (d, J=7.3 Hz, 1H), 7.50 (d,
J=11.8 Hz, 1H), 7.29 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.5 Hz, 1H),
4.57 (td, J=10.0, 4.3 Hz, 1H), 3.50-3.36 (m, 1H), 3.13 (q, J=7.2
Hz, 2H), 2.16 (br.t, J=8.9, 5.9, 4.2 Hz, 2H), 1.78-1.60 (m, 2H),
1.51-1.25 (m, 4H), 1.20 (t, J=7.2 Hz, 3H)
[0507] Example 43: LCMS (ESI) m/z: 434 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.80 (d, J=7.4 Hz, 1H), 7.51 (d,
J=11.8 Hz, 1H), 7.30 (d, J=4.6 Hz, 1H), 6.88 (d, J=4.5 Hz, 1H),
4.57 (td, J=10.0, 4.4 Hz, 1H), 3.47-3.33 (m, 1H), 3.13 (q, J=7.2
Hz, 2H), 2.16 (br. t, 2H), 1.80-1.60 (m, 2H), 1.52-1.25 (m, 4H),
1.21 (t, J=7.2 Hz, 3H).
##STR00209##
5-chloro-2-fluoro-4-(((1S,2S)-2-(2-methylpyrrolidin-1-yl)cyclohexyl)amino-
)-N-(thiazol-2-yl)benzenesulfonamide
[0508] Following the procedure described in Example 30 and making
non-critical variations as required, the title compound was
obtained as a mixture of diastereomers. LCMS (ESI) m/z: 473.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.83 (s, 1H),
7.58 (d, J=7.3 Hz, 1H), 7.19 (d, J=4.4 Hz, 1H), 6.77-6.69 (m, 2H),
5.96 (dd, J=6.4, 1.8 Hz, 1H), 3.17 (s, 1H), 3.00 (s, 1H), 2.95 (s,
1H), 2.75 (t, J=8.4 Hz, 1H), 2.10-1.99 (m, 1H), 1.88-1.64 (m, 3H),
1.59 (tt, J=8.5, 4.1 Hz, 1H), 1.48-1.33 (m, 1H), 1.32-1.11 (m, 2H),
0.89 (d, J=6.1 Hz, 3H).
Example 45
##STR00210##
[0509]
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxypropyl)(methyl)amino)cyc-
lohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0510] Following the procedure described in Example 29 and making
non-critical variations as required to replace the iodopropane with
1-bromo-2-propanol, the title compound was obtained as a mixture of
diastereomers. LCMS (ESI) m/z: 477.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.57 (d, J=7.3 Hz, 1H), 7.23 (d, J=4.5 Hz,
1H), 6.79 (d, J=4.6 Hz, 1H), 6.71 (d, J=12.9 Hz, 1H), 5.90 (d,
J=10.1 Hz, 1H), 4.25 (s, 1H), 3.64 (s, 1H), 3.43-3.30 (m, 1H), 3.29
(s, 4H), 3.30-3.20 (m, 1H), 2.46 (s, 5H), 2.16 (d, J=13.7 Hz, 3H),
1.82 (s, 1H), 1.76 (s, 1H), 1.60 (d, J=13.5 Hz, 1H), 1.34 (dd,
J=23.7, 11.5 Hz, 1H), 1.25 (d, J=11.1 Hz, 2H), 1.13 (d, J=17.1 Hz,
1H), 1.02 (d, J=6.2 Hz, 1H), 0.90 (d, J=6.1 Hz, 1H).
Example 46
##STR00211##
[0511]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(thiazol-4-yl)benzenesulfonamide
[0512] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
tert-butyl((5-chloro-2,4-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate,
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(thiaz-
ol-4-yl)benzenesulfonamide was obtained as a white solid. LCMS
(ESI) m/z: 433.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.97 (s, 1H), 8.86 (d, J=2.1 Hz, 1H), 7.58 (d, J=7.4 Hz,
1H), 6.97-6.86 (m, 1H), 6.75 (d, J=13.2 Hz, 1H), 6.02-5.84 (m, 1H),
3.17 (d, J=5.0 Hz, 1H), 2.64-2.55 (m, 1H), 2.16 (s, 6H), 2.13-2.03
(m, 1H), 1.90-1.70 (m, 2H), 1.60 (d, J=13.1 Hz, 1H), 1.35 (dd,
J=14.6, 11.0 Hz, 1H), 1.28-1.09 (m, 3H).
Example 47
##STR00212##
[0513]
5-chloro-2-fluoro-4-(((1S,2S)-2-(3-hydroxyazetidin-1-yl)cyclohexyl)-
amino)-N-(thiazol-2-yl)benzenesulfonamide
[0514] Following the procedure described in Example 30 and making
non-critical variations as required, the title compound was
obtained. LCMS (ESI) m/z: 461.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 7.58 (dd, J=9.6, 7.4 Hz, 1H), 7.16 (d, J=4.4 Hz,
1H), 6.74-6.66 (m, 2H), 5.74 (d, J=9.1 Hz, 1H), 5.30 (s, 1H), 4.08
(q, J=6.0 Hz, 1H), 3.55 (s, 1H), 3.44 (s, 1H), 3.12 (s, 1H), 2.93
(s, 1H), 2.54 (s, 1H), 2.47 (s, 2H), 1.82 (d, J=12.5 Hz, 1H), 1.73
(s, 1H), 1.65 (d, J=13.9 Hz, 2H), 1.58 (s, 1H), 1.33 (t, J=9.2 Hz,
2H), 1.24-1.13 (m, 1H), 1.05 (t, J=11.9 Hz, 1H).
Example 48
##STR00213##
[0515]
5-chloro-4-(((1R,6R)-6-(dimethylamino)-3-(trifluoromethyl)cyclohex--
3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
Step 1
##STR00214##
[0516]
4-(((1R,6R)-6-amino-3-(trifluoromethyl)cyclohex-3-en-1-yl)amino)-5--
chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0517] Following the procedure described in Example 1 and making
non-critical variations as required to replace tert-butyl
N-[(1S,2S)-2-aminocyclohexyl]carbamate with
tert-butyl((1R,6R)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e,
4-(((1R,6R)-6-amino-3-(trifluoromethyl)cyclohex-3-en-1-yl)amino)-5-chlo-
ro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was obtained as a
light yellow solid. LCMS (ESI) m/z: 470.8 [M+H].sup.+.
Step 2
##STR00215##
[0518]
5-chloro-4-(((1R,6R)-6-(dimethylamino)-3-(trifluoromethyl)cyclohex--
3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
[0519] Following the procedure described in Example 2 and making
non-critical variations as required to replace
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)be-
nzenesulfonamide with
4-(((1R,6R)-6-amino-3-(trifluoromethyl)cyclohex-3-en-1-yl)amino)-5-chloro-
-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide,
5-chloro-4-(((1R,6R)-6-(dimethylamino)-3-(trifluoromethyl)cyclohex-3-en-1-
-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide formate was
obtained as a white solid. LCMS (ESI) m/z: 499.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13 (s, 1H), 7.62 (d,
J=7.2 Hz, 1H), 7.27 (d, J=4.4 Hz, 1H), 6.94 (d, J=13.2 Hz, 1H),
6.83 (d, J=4.4 Hz, 1H), 6.47 (s, 1H), 6.14 (d, J=6.4 Hz, 1H),
3.97-3.83 (m, 1H), 3.25-3.16 (m, 1H), 2.73-2.67 (m, 1H), 2.46-2.40
(m, 1H), 2.35-2.31 (m, 1H), 2.30 (s, 3H), 2.30 (s, 3H), 2.23-2.12
(m, 1H).
Example 49
##STR00216##
[0520]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N--
(5-fluorothiazol-2-yl)benzenesulfonamide
[0521] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(5-fluorothiazol-2-yl)ben-
zenesulfonamide,
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(5-flu-
orothiazol-2-yl)benzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 451.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.55 (d, J=7.6 Hz, 1H), 6.92 (d, J=12.8 Hz,
1H), 6.71 (s, 1H), 5.86 (d, J=8.4 Hz, 1H), 3.88-3.70 (m, 1H),
3.43-3.35 (m, 1H), 2.60 (s, 3H), 2.60 (s, 3H), 2.10-1.89 (m, 2H),
1.87-1.77 (m, 1H), 1.69-1.58 (m, 1H), 1.47-1.30 (m, 2H), 1.29-1.13
(m, 2H).
Example 50
##STR00217##
[0522]
5-bromo-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(th-
iazol-2-yl)benzenesulfonamide Formate
Step 1:
##STR00218##
[0523]
5-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino-
)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0524] Following the procedure described in Example 29 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-bromo-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulfo-
namide,
5-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamin-
o)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide was obtained
as a white solid. LCMS (ESI) m/z: 613.2 [M+H].sup.+.
Step 2:
##STR00219##
[0525]
5-bromo-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(th-
iazol-2-yl)benzenesulfonamide Formate
[0526] Following the procedure described in Example 11, step 2,
5-bromo-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(thiazol--
2-yl)benzenesulfonamide formate was obtained as a white solid. LCMS
(ESI) m/z: 463.1 [M+H].sup.+. H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.19 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.06 (d, J=4.0 Hz, 1H), 6.75
(d, J=13.2 Hz, 1H), 6.60 (d, J=4.0 Hz, 1H), 5.63 (d, J=9.6 Hz, 1H),
3.64-3.60 (m, 1H), 3.23-3.15 (m, 1H), 2.52 (s, 3H), 2.15-2.06 (m,
1H), 1.92-1.84 (m, 1H), 1.79-1.70 (m, 1H), 1.66-1.58 (m, 1H),
1.44-1.17 (m, 4H).
Example 51
##STR00220##
[0527]
5-cyclopropyl-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-
-N-(thiazol-2-yl)benzenesulfonamide Formate
[0528] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with
5-bromo-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclo-
hexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide,
5-cyclopropyl-2-fluoro-4-(((1S,2S)-2-(methylamino)cyclohexyl)amino)-N-(th-
iazol-2-yl)benzenesulfonamide formate was obtained as a white
solid. LCMS (ESI) m/z: 425.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.26 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.06
(d, J=4.4 Hz, 1H), 6.58 (d, J=4.0 Hz, 1H), 6.48 (d, J=13.6 Hz, 1H),
5.50 (d, J=9.6 Hz, 1H), 3.67-3.58 (m, 1H), 3.20-3.13 (m, 1H), 2.52
(s, 3H), 2.15-2.06 (m, 1H), 1.97-1.89 (m, 1H), 1.81-1.73 (m, 1H),
1.67-1.59 (m, 1H), 1.58-1.34 (m, 3H), 1.30-1.17 (m, 2H), 0.90-0.83
(m, 1H), 0.82-0.74 (m, 1H), 0.57-0.49 (m, 1H), 0.24-0.14 (m,
1H).
Example 52
##STR00221##
[0529]
5-bromo-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro-N-(thi-
azol-2-yl)benzenesulfonamide Formate
[0530] Following the procedure described in Example 50 and making
non-critical variations as required to replace iodomethane with
iodoethane,
5-bromo-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-
-yl)benzenesulfonamide formate was obtained as a white solid. LCMS
(ESI) m/z: 477.0 [M+H].sup.+. H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.18 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.01 (d, J=4.0 Hz, 1H), 6.70
(d, J=12.8 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 5.53 (d, J=8.0 Hz, 1H),
3.10-2.98 (m, 1H), 2.90-2.85 (m, 1H), 2.82-2.76 (m, 1H), 2.13-2.03
(m, 1H), 1.96-1.87 (m, 1H), 1.77-1.68 (m, 1H), 1.66-1.55 (m, 1H),
1.40-1.17 (m, 5H), 1.09 (t, J=7.2 Hz, 3H).
Example 53
##STR00222##
[0531]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chlor-
o-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
Step 1:
##STR00223##
[0532]
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzy-
l)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0533] Following the procedure described in Example 29, step 1 and
making non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxyb-
enzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was obtained
as a yellow solid. LCMS (ESI) m/z: 571.9 [M+Na].sup.+.
Step 2:
##STR00224##
[0534]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chlor-
o-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0535] Following the procedure described in Example 39 and making
non-critical variations as required to replace
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzyl)-2-f-
luoro-N-(thiazol-2-yl)benzenesulfonamide with
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzyl)-2-f-
luoro-N-(pyrimidin-4-yl)benzenesulfonamide,
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chloro-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide was obtained as a white
solid. LCMS (ESI) m/z: 469.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.31 (s, 1H), 7.95 (d, J=4.0 Hz, 1H), 7.58
(d, J=8.0 Hz, 1H), 7.63-6.58 (m, 2H), 5.51 (d, J=4.0 Hz, 1H),
3.95-3.80 (m, 5H), 3.34-3.31 (m, 1H), 2.67-2.58 (m, 1H), 2.14 (s,
3H), 2.00-1.97 (m, 1H), 1.71-1.56 (m, 3H), 1.33-1.12 (m, 4H).
Example 54
##STR00225##
[0536]
4-((1S,2S)-2-(dimethylamino)cyclohexyl)-N-(thiazol-2-yl)-3,4-dihydr-
o-2H-benzo[b][1,4]oxazine-7-sulfonamide
##STR00226## ##STR00227##
[0537] Step 1
##STR00228##
[0538] tert-butyl 2-(4-bromo-2-chlorophenoxy)acetate
[0539] tert-butyl 2-bromoacetate (3.10 mL, 21.0 mmol) was added to
a mixture of 4-bromo-2-chlorophenol (4.15 g, 20.0 mmol) and cesium
carbonate (7.17 g, 22.0 mmol) in N,N-dimethylformamide (10 mL). The
mixture was heated at 80.degree. C. for 18 hours, cooled down and
mixed with water. The product was extracted with ethyl acetate. The
organic extracts were washed with water (.times.2), brine, dried
over Na2SO4 and concentrated to give tert-butyl
2-(4-bromo-2-chlorophenoxy)acetate (6.42 g, 99.8%) as a colorless
oil, which was used without further purification in the next
step.
Step 2
##STR00229##
[0540] 2-(4-bromo-2-chlorophenoxy)acetic Acid
[0541] 10 ml of TFA were added dropwise to a solution of tert-butyl
2-(4-bromo-2-chloro-phenoxy)acetate (6.42 g, 19.96 mmol) in 10 ml
of DCM. The mixture was stirred for 18 hours at room temperature,
then concentrated in vacuum and the residue partitioned between
ethyl acetate and water. The organic extracts were washed with
water (.times.2), brine, dried over MgSO4 and concentrated to give
2-(4-bromo-2-chlorophenoxy)acetic acid (5.13 g, 97%) as a colorless
solid.
Step 3
##STR00230##
[0542]
2-(4-bromo-2-chlorophenoxy)-N-((1S,2S)-2-(dimethylamino)cyclohexyl)-
acetamide
[0543] HATU (4268 mg, 11.22 mmol) was added to a mixture of
2-(4-bromo-2-chlorophenoxy)acetic acid (2655 mg, 10.00 mmol),
(1S,2S)--N.sup.1,N.sup.1-dimethylcyclohexane-1,2-diamine (1494 mg,
10.50 mmol) and triethylamine (3.50 mL, 25.1 mmol) in 30 ml of DMF.
The mixture was stirred for 4 hours, concentrated in vacuum and the
residue partitioned between water and ethyl acetate. The organic
extracts were washed with sat. NaHCO.sub.3, water, brine, dried
over Na2SO4 and concentrated to give
2-(4-bromo-2-chlorophenoxy)-N-((1S,2S)-2-(dimethylamino)cyclohexyl)acetam-
ide (4010 mg, 100%) as a colorless oil, which was used without
further purification in the next step. LCMS (ESI) m/z: 389.1
[M+H].sup.+.
Step 4
##STR00231##
[0544]
7-bromo-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-2H-benzo[b][1,4]oxa-
zin-3(4H)-one
[0545] A mixture of
2-(4-bromo-2-chloro-phenoxy)-N-[(1S,2S)-2-(dimethylamino)cyclohexyl]aceta-
mide (4010 mg, 10.29 mmol) and cesium carbonate (4023 mg, 12.35
mmol) in N,N-dimethylformamide (40 mL) was heated at 130.degree. C.
for 24 hours. The mixture was cooled, diluted with 30 ml of DCM,
filtered and the filtrate concentrated in vacuum. The residue was
dry loaded on a 80 g silica gel column and purified using 0-10%
MeOH gradient in DCM to give
7-bromo-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-2H-benzo[b][1,4]oxazin-3(-
4H)-one (1712 mg, 47%) as a yellowish oil. LCMS (ESI) m/z: 353.1
[M+H].sup.+.
Step 5
##STR00232##
[0546]
7-(benzylthio)-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-2H-benzo[b][-
1,4]oxazin-3(4H)-one
[0547] A degassed mixture of
7-bromo-4-[(1S,2S)-2-(dimethylamino)cyclohexyl]-1,4-benzoxazin-3-one
(810 mg, 2.30 mmol), phenylmethanethiol (0.41 mL, 3.5 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (266 mg, 0.46
mmol), bis(dibenzylideneacetone)palladium (132 mg, 0.23 mmol) and
triethylamine (1.0 mL, 7.1 mmol) in 1,4-dioxane (20 mL) was heated
at 120.degree. C. in a sealed vial for 3 hours. The mixture was
diluted with water and extracted with ethyl acetate. The organic
extracts were washed with water, brine, dried over Na2SO4 and
concentrated. The residue was purified on a 24 g silica gel column
eluting with 0-6% gradient of MeOH in DCM to give
7-(benzylthio)-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-2H-benzo[b][1,4]ox-
azin-3(4H)-one (807 mg, 89%) as a yellowish oil. LCMS (ESI) m/z:
397.2 [M+H].sup.+.
Step 6
##STR00233##
[0548]
4-((1S,2S)-2-(dimethylamino)cyclohexyl)-3-oxo-3,4-dihydro-2H-benzo[-
b][1,4]oxazine-7-sulfonyl Chloride
[0549] Sulfuryl chloride (0.33 mL, 4.1 mmol) was added dropwise to
a mixture of
7-benzylsulfanyl-4-[(1S,2S)-2-(dimethylamino)cyclohexyl]-1,4-benzoxazin-3-
-one (400 mg, 1.00 mmol), acetic acid (0.23 mL, 4.0 mmol) and water
(0.073 mL, 4.1 mmol) in dichloromethane (10 mL) at 0.degree. C. The
mixture was stirred at room temperature for 2 hours, concentrated
in vacuum and the volatile materials were coevaporated with toluene
twice to give
4-((1S,2S)-2-(dimethylamino)cyclohexyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4-
]oxazine-7-sulfonyl chloride (380 mg, 100%) as a yellowish oil.
LCMS (ESI) m/z: 373.1 [M+H]+.
Step 7
##STR00234##
[0550]
N-(2,4-dimethoxybenzyl)-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-3-o-
xo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide
[0551] Lithium bis(trimethylsilyl)amide in THF (3.0 mL, 3.0 mmol, 1
mol/L) was added dropwise to a solution of
N-[(2,4-dimethoxyphenyl)methyl]thiazol-2-amine (505 mg, 2.0 mmol)
in THF (20 mL) at -78.degree. C. The mixture was allowed to warm to
00C. After stirring for 30 minutes, the mixture was cooled down to
-78.degree. C. and a solution of
4-[(1S,2S)-2-(dimethylamino)cyclohexyl]-3-oxo-1,4-benzoxazine-7-sulfonyl
chloride (G, 376 mg, 1.008 mmol) in THF (5 ml) The reaction was
stirred at -78.degree. C. for 30 min and at 0.degree. C. for 2
hours, quenched with saturated aqueous ammonium chloride and
extracted with ethyl acetate. The organic extracts were washed with
water, brine, dried over sodium sulfate and concentrated. The crude
product was purified by column chromatography (0-10% gradient of
MeOH in DCM) to provide
N-(2,4-dimethoxybenzyl)-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-3-oxo-N-(-
thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide
(208 mg, 35% yield) as a yellowish solid.
[0552] LCMS (ESI) m/z: 587.1 [M+H].sup.+.
Step 8
##STR00235##
[0553]
N-(2,4-dimethoxybenzyl)-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-N-(-
thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide
[0554] 9-borabicyclo[3.3.1]nonane in THF (0.5 mol/L, 5.0 mL, 2.5
mmol) was added to a solution of
N-(2,4-dimethoxybenzyl)-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-3-oxo-N-(-
thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide
(120 mg, 0.21 mmol) in 2 ml of THF. The mixture was heated in a
sealed vial at 65.degree. C. for 12 hours. The mixture was quenched
by stirring with 1 ml of water for 1 hour, concentrated and the
residue purified on a 12 g silica gel column eluting with 0-8% MeOH
gradient in DCM to give
N-(2,4-dimethoxybenzyl)-4-((1S,2S)-2-(dimethylamino)cyclohexyl)-N-(thiazo-
l-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (64 mg,
55%) as an off-white solid.
[0555] LCMS (ESI) m/z: 573.1 [M+H].sup.+.
Step 9
##STR00236##
[0556]
4-((1S,2S)-2-(dimethylamino)cyclohexyl)-N-(thiazol-2-yl)-3,4-dihydr-
o-2H-benzo[b][1,4]oxazine-7-sulfonamide
[0557] Trifluoroacetic acid (1 ml) was added dropwise to a solution
of
N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamino)cyclohexyl]a-
mino]-3-nitro-N-thiazol-2-yl-benzenesulfonamide (64 mg, 0.11 mmol)
in 1 ml of DCM. The mixture was stirred for 2 hours, concentrated
and the residue triturated with ethyl ether to form a precipitate.
The precipitate was filtered, washed with ethyl ether and dried on
air. The solid was dissolved in 10% aqueous acetonitrile, filtered
and lyophilized to give
4-((1S,2S)-2-(dimethylamino)cyclohexyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-b-
enzo[b][1,4]oxazine-7-sulfonamide (29 mg, 61%) as a yellow light
powder. LCMS (ESI) m/z: 423.1 [M+H].sup.+. 1H NMR (400 MHz,
DMSO-d6) .delta. 7.20-7.14 (m, 2H), 6.98 (d, J=2.2 Hz, 1H), 6.89
(d, J=8.8 Hz, 1H), 6.71 (d, J=4.5 Hz, 1H), 4.21-4.08 (m, 3H),
3.80-3.68 (m, 1H), 3.41-3.35 (m, 1H), 3.40-3.21 (m, 2H), 2.69 (d,
J=6.3 Hz, 1H), 2.15 (s, 6H), 1.86 (d, J=11.1 Hz, 1H), 1.75 (d,
J=11.2 Hz, 1H), 1.66 (d, J=10.4 Hz, 2H), 1.39 (q, J=13.9, 13.2 Hz,
2H), 1.29-1.11 (m, 2H).
Example 55
##STR00237##
[0558]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chlor-
o-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide
[0559] Following the procedure described in Example 39 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-I-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine-2-yl)be-
nzenesulfonamide,
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chloro-2-fl-
uoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide was obtained as a
white solid. LCMS (ESI) m/z: 486.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.18 (dd, J=2.6, 1.4 Hz, 1H), 7.62 (d,
J=7.3 Hz, 1H), 7.54-7.36 (m, 1H), 6.72-6.51 (m, 2H), 6.29-6.09 (m,
1H), 5.67-5.47 (m, 1H), 3.98-3.71 (m, 5H), 2.67-2.54 (m, 1H), 2.13
(s, 3H), 2.03-1.95 (m, 1H), 1.77-1.53 (m, 3H), 1.40-1.07 (m,
5H).
Example 56
##STR00238##
[0560]
5-cyclopropyl-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino-
)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
hydrochloride
[0561] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)-
(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide,
5-cyclopropyl-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino)cyclo-
hexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide hydrochloride was
obtained as a white solid. LCMS (ESI) m/z: 469.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.66 (s, 1H),
9.00-8.21 (m, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.23 (d, J=4.8 Hz, 1H),
6.86-6.71 (m, 2H), 5.94-5.75 (m, 1H), 5.55-5.31 (m, 1H), 4.04-3.88
(m, 1H), 3.86-3.56 (m, 3H), 3.18-2.97 (m, 1H), 2.86-2.70 (m, 3H),
2.53-2.52 (m, 1H), 2.25-2.06 (m, 1H), 2.02-1.88 (m, 1H), 1.88-1.71
(m, 2H), 1.69-1.58 (m, 1H), 1.56-1.42 (m, 1H), 1.42-1.18 (m, 3H),
1.06-0.86 (m, 2H), 0.68-0.56 (m, 1H), 0.38-0.24 (m, 1H).
Example 57
##STR00239##
[0562]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-cyclo-
propyl-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
dihydrochloride
[0563] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with tert-butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)(methyl)amino)azetidine-1-carboxylat-
e,
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-cycloprop-
yl-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide dihydrochloride was
obtained as a white solid. LCMS (ESI) m/z: 480.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.69 (s, 1H),
11.87-10.00 (m, 1H), 9.76 (s, 1H), 9.41-8.87 (m, 1H), 7.30 (d,
J=8.0 Hz, 1H), 7.23 (d, J=4.4 Hz, 1H), 6.83-6.72 (m, 2H), 6.08-5.79
(m, 1H), 4.73-4.37 (m, 3H), 4.36-4.12 (m, 1H), 4.10-3.95 (m, 1H),
3.94-3.80 (m, 1H), 2.71-2.56 (m, 3H), 2.54-2.52 (m, 1H), 2.12-1.84
(m, 3H), 1.83-1.70 (m, 1H), 1.69-1.55 (m, 1H), 1.54-1.40 (m, 1H),
1.39-1.20 (m, 3H), 1.09-0.88 (m, 2H), 0.83-0.17 (m, 2H).
Example 58
##STR00240##
[0564]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(2-(methylamino)ethyl)amino)-
cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate
##STR00241##
[0565] Step 1
##STR00242##
[0566]
tert-butyl(2-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(t-
hiazol-2-yl)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)(methyl)amino)ethyl-
)(methyl)carbamate
[0567] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (298 mg, 0.52
mmol) in DCM (10 mL) was added AcOH (0.16 mL, 4.19 mmol),
tert-butyl N-methyl-N-(2-oxoethyl)carbamate (91 mg, 0.52 mmol) and
sodium triacetoxyborohydride (578 mg, 2.73 mmol). The mixture was
stirred at room temperature for 1 h and washed with water (10
mL.times.3). The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
title compound (400 mg, crude) as light yellow oil that required no
further purification. LCMS (ESI) m/z: 726.2 [M+H].sup.+. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (d, J=7.2 Hz, 1H), 7.38 (d,
J=3.6 Hz, 1H), 7.20 (d, J=9.2 Hz, 1H), 6.96 (d, J=3.6 Hz, 1H),
6.38-6.35 (m, 2H), 6.23-6.04 (m, 1H), 5.18 (s, 2H), 3.74 (s, 3H),
3.74 (s, 3H), 3.58-3.51 (m, 1H), 3.44-3.35 (m, 2H), 3.42-3.22 (m,
1H), 2.82 (s, 3H), 2.54-2.45 (m, 2H), 2.41-2.15 (m, 2H), 2.07 (s,
3H), 1.96-1.76 (m, 2H), 1.42 (s, 9H), 1.40-1.30 (m, 4H).
Step 2
##STR00243##
[0568]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(2-(methylamino)ethyl)amino)-
cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide Formate
[0569] A mixture of
tert-butyl(2-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-
-2-yl)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)(methyl)amino)ethyl)(meth-
yl)carbamate (200 mg, 0.28 mmol) and formic acid (3 mL) was stirred
at room temperature for 2 h. The mixture was concentrated in vacuo.
The crude residue was purified by reverse phase chromatography
(acetonitrile 13-43%/0.225% formic acid in water) to give the title
compound (54 mg, 41%) as a white solid. LCMS (ESI) m/z: 476.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.22 (s,
1H), 7.56 (d, J=7.2 Hz, 1H), 7.07 (d, J=4.4 Hz, 1H), 6.66 (d,
J=13.2 Hz, 1H), 6.60 (d, J=4.4 Hz, 1H), 5.68 (d, J=6.0 Hz, 1H),
3.40-3.28 (m, 1H), 2.97-2.82 (m, 2H), 2.69-2.65 (m, 2H), 2.49 (s,
3H), 2.10 (s, 3H), 2.07-2.01 (m, 1H), 1.81-1.69 (m, 2H), 1.65-1.54
(m, 1H), 1.35-1.10 (m, 4H).
Example 59
##STR00244##
[0570]
5-chloro-4-(((3S,4S)-4-(dimethylamino)-3'-(trifluoromethyl)-2,3,4,5-
-tetrahydro-[1,1'-biphenyl]-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesu-
lfonamide
Step 1
##STR00245##
[0571]
tert-butyl((3S,4S)-3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro--
[1,1'-biphenyl]-4-yl)carbamate
[0572] Following the procedure described in Example 23 and making
non-critical variations as required to replace
2-(trifluoromethyl)allyl 4-methylbenzenesulfonate with
1-(3-iodoprop-1-en-2-yl)-3-(trifluoromethyl)benzene,
tert-butyl((3S,4S)-3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'--
biphenyl]-4-yl)carbamate was obtained as a light yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.62 (s, 1H), 7.57-7.49
(m, 2H), 7.48-7.41 (m, 1H), 6.10-6.07 (m, 1H), 4.71-4.60 (m, 1H),
3.65-3.59 (m, 1H), 3.05-2.95 (m, 1H), 2.87-2.71 (m, 2H), 2.45-2.36
(m, 1H), 2.26-2.07 (m, 1H), 1.48 (s, 9H).
Step 2
##STR00246##
[0573]
5-chloro-4-(((3S,4S)-4-(dimethylamino)-3'-(trifluoromethyl)-2,3,4,5-
-tetrahydro-[1,1'-biphenyl]-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesu-
lfonamide
[0574] Following the procedure described in Example 48 and making
non-critical variations as required to replace
tert-butyl((1R,6R)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e with tert-butyl
((3S,4S)-3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'-biphenyl]--
4-yl)carbamate,
5-chloro-4-(((3S,4S)-4-(dimethylamino)-3'-(trifluoromethyl)-2,3,4,5-tetra-
hydro-[1,1'-biphenyl]-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonam-
ide was obtained as a light yellow solid. LCMS (ESI) m/z: 475.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.76-7.71
(m, 2H), 7.63-7.51 (m, 3H), 7.22 (d, J=4.4 Hz, 1H), 6.94 (d, J=12.4
Hz, 1H), 6.78 (d, J=4.4 Hz, 1H), 6.35-6.32 (m, 1H), 6.16-6.12 (m,
1H), 3.75-3.72 (m, 1H), 3.15-3.05 (m, 2H), 2.48-2.35 (m, 3H), 2.25
(s, 3H), 2.25 (s, 3H).
Example 60
##STR00247##
[0575]
5-chloro-2-fluoro-N-(pyrimidin-4-yl)-4-(((1S,2S)-2-(pyrrolidin-1-yl-
)cyclohexyl)amino)benzenesulfonamide
[0576] Following the procedure described in Example 30 and making
non-critical variations as required to replace
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-yl-benz-
enesulfonamide with
4-[[(1S,2S)-2-aminocyclohexyl]amino]-5-chloro-N-[(2,4-dimethoxyphenyl)met-
hyl]-2-fluoro-N-pyrimidin-4-yl-benzenesulfonamide, the title
compound was obtained as a white solid. LCMS (ESI) m/z: 454.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.37 (s,
1H), 8.04 (d, J=6.1 Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 6.78 (d,
J=12.8 Hz, 1H), 6.67 (d, J=6.0 Hz, 1H), 5.99-5.74 (m, 1H),
3.77-3.50 (m, 1H), 3.18-2.80 (m, 4H), 2.04-1.88 (m, 2H), 1.85-1.67
(m, 5H), 1.67-1.55 (m, 1H), 1.49-1.11 (m, 5H).
Example 61
##STR00248##
[0577]
5-chloro-2-fluoro-4-(((1S,2S)-2-(3-hydroxypyrrolidin-1-yl)cyclohexy-
l)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
[0578] Following the procedure described in Example 30 and making
non-critical variations as required to replace
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-yl-benz-
enesulfonamide with
4-[[(1S,2S)-2-aminocyclohexyl]amino]-5-chloro-N-[(2,4-dimethoxyphenyl)met-
hyl]-2-fluoro-N-pyrimidin-4-yl-benzenesulfonamide and
1,4-dibromobutane with 1,4-dibromobutan-2-ol, the title compound
was obtained as a mixture of diastereomers. LCMS (ESI) m/z: 470.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.38 (s, 1H),
8.06 (d, J=6.1 Hz, 1H), 7.65 (d, J=7.4 Hz, 1H), 6.79-6.66 (m, 2H),
6.51 (s, 1H), 5.83 (d, J=7.6 Hz, 1H), 4.98 (s, 1H), 4.23 (s, 1H),
2.54 (s, 1H), 1.96 (s, 3H), 1.90 (dq, J=20.9, 7.3, 6.5 Hz, 1H),
1.78 (d, J=12.1 Hz, 1H), 1.63 (s, 2H), 1.60 (d, J=13.6 Hz, 1H),
1.42-1.36 (m, 1H), 1.40-1.16 (m, 4H).
Example 62
##STR00249##
[0579]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(3-hydroxy-
pyrrolidin-1-yl)cyclohexyl)amino)benzenesulfonamide
[0580] Following the procedure described in Example 30 and making
non-critical variations as required to replace
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-yl-benz-
enesulfonamide with
5-chloro-I-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine-2-yl)be-
nzenesulfonamide and 1,4-dibromobutane with 1,4-dibromobutan-2-ol,
the title compound was obtained as a mixture of diastereomers. LCMS
(ESI) m/z: 487.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 11.14 (s, 1H), 7.70 (d, J=7.4 Hz, 2H), 6.74 (dd, J=14.8,
10.3 Hz, 2H), 6.51 (s, 1H), 5.94 (d, J=5.9 Hz, 1H), 4.70 (s, 1H),
4.11 (d, J=20.6 Hz, 1H), 2.79 (s, 4H), 2.50-2.40 (m, 1H), 2.07 (s,
2H), 1.81 (ddt, J=35.8, 14.0, 6.1 Hz, 4H), 1.65-1.55 (m, 1H), 1.52
(d, J=9.0 Hz, 1H), 1.36 (ddd, J=15.5, 7.7, 3.1 Hz, 1H), 1.30 (s,
2H), 1.31-1.12 (m, 2H).
Example 63
##STR00250##
[0581]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(methyl(1--
methylazetidin-3-yl)amino)cyclohexyl)amino)benzenesulfonamide
[0582] The mixture of
4-[[(1S,2S)-2-[azetidin-3-yl(methyl)amino]cyclohexyl]amino]-5-chloro-2-fl-
uoro-N-(6-fluoro-2-pyridyl)benzenesulfonamide (Example 55, 100 mg,
0.206 mmol) and formaldehyde (9.27 mg, 0.309 mmol) in MeOH (1 mL)
was stirred at room temperature for 30 min. Then NaCNBH.sub.3 (26
mg, 0.412 mmol) was added and the mixture was stirred for 18 h. The
reaction was quenched with water (1 mL), and concentrated. The
residue was purified by HPLC to give
5-chloro-2-fluoro-N-(6-fluoro-2-pyridyl)-4-[[(1S,2S)-2-[methyl-(1-me-
thylazetidin-3-yl)amino]cyclohexyl]amino]benzenesulfonamide (31 mg,
29%) as a white solid. LCMS (ESI) m/z: 500.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.67 (d, J=7.4 Hz, 1H), 7.61
(q, J=8.3 Hz, 1H), 6.76-6.61 (m, 2H), 6.39 (dd, J=7.8, 2.7 Hz, 1H),
5.81-5.67 (m, 1H), 3.75-3.58 (m, 2H), 3.55-3.44 (m, 1H), 3.17-2.99
(m, 2H), 2.41 (s, 3H), 2.11-2.02 (m, 1H), 2.00 (s, 3H), 1.78-1.53
(m, 4H), 1.42-1.07 (m, 5H).
Example 64
##STR00251##
[0583]
5-cyclopropyl-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro--
N-(thiazol-2-yl)benzenesulfonamide Formate
[0584] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amin-
o)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide,
5-cyclopropyl-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro-N-(thi-
azol-2-yl)benzenesulfonamide formate was obtained as a white solid.
LCMS (ESI) m/z: 439.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.22 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.09
(d, J=4.0 Hz, 1H), 6.63 (d, J=4.4 Hz, 1H), 6.54 (d, J=13.2 Hz, 1H),
5.57 (d, J=8.8 Hz, 1H), 3.30-3.25 (m, 1H), 3.20-3.10 (m, 1H),
3.01-2.77 (m, 2H), 2.20-2.15 (m, 1H), 2.0-1.9 (m, 1H), 1.8-1.7 (m,
1H), 1.67-1.53 (m, 2H), 1.47-1.32 (m, 2H), 1.30-1.19 (m, 2H), 1.14
(t, J=7.2 Hz, 3H), 0.99-0.78 (m, 2H), 0.60-0.40 (m, 1H), 0.35-0.25
(m, 1H).
Example 65
##STR00252##
[0585]
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(thiazol--
2-yl)-5-(trifluoromethyl)benzenesulfonamide
##STR00253## ##STR00254##
[0586] Step 1
##STR00255##
[0587] benzyl(2,4-difluoro-5-(trifluoromethyl)phenyl)sulfane
[0588] To a solution of
1-bromo-2,4-difluoro-5-(trifluoromethyl)benzene (0.55 g, 1.81 mmol)
in anhydrous 1,4-dioxane (5 mL) was added N,N-diisopropylethylamine
(0.63 mL, 3.83 mmol), benzyl mercaptan (0.25 mL, 2.11 mmol),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.11 g, 0.19 mmol)
and tris(dibenzylideneacetone)dipalladium(0) (0.09 g, 0.10 mmol).
The reaction mixture was heated to 120.degree. C. for 2 h under a
nitrogen atmosphere. After cooling to room temperature, the mixture
was concentrated in vacuo. The crude residue was purified by silica
gel chromatography (petroleum ether) to give the title compound
(0.55 g, 94%) as colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.51-7.43 (m, 1H), 7.32-7.18 (m, 5H), 6.99-6.92 (m, 1H),
4.07 (s, 2H).
Step 2
##STR00256##
[0589] 2,4-difluoro-5-(trifluoromethyl)benzene-1-sulfonyl
chloride
[0590] To a solution of
benzyl(2,4-difluoro-5-(trifluoromethyl)phenyl)sulfane (250 mg, 0.82
mmol) in THF (4 mL), AcOH (0.1 mL) and water (0.2 mL) was added
1,3-dichloro-5,5-dimethylhydantoin (486 mg, 2.46 mmol) slowly. The
mixture was stirred at 0.degree. C. for 3 h. EtOAc (50 mL) was
added and washed with sat. aq. NaHCO.sub.3 (20 mL), brine (15 mL),
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude residue was purified by silica gel chromatography
(petroleum ether) to give the title compound (250 mg, 76%) as light
yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.34-8.29 (m,
1H), 7.33-7.24 (m, 1H).
Step 3
##STR00257##
[0591]
N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)-5-(trifluorom-
ethyl)benzenesulfonamide
[0592] To a solution of
N-[(2,4-dimethoxyphenyl)methyl]pyrimidin-4-amine (0.16 g, 0.62
mmol) and 2,4-difluoro-5-(trifluoromethyl)benzene-1-sulfonyl
chloride (0.25 g, 0.62 mmol) in THF (3 mL) at -78.degree. C. was
added lithium bis(trimethylsilyl)amide (0.69 mL, 0.69 mmol, 1.0 M
in THF) dropwise under a nitrogen atmosphere. The reaction mixture
was stirred at -78.degree. C. for 2 h. Sat. aq. NH.sub.4Cl (2 mL)
was added and extracted with EtOAc (10 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude residue was purified by silica gel chromatography
(solvent gradient: 0-20% EtOAc in petroleum ether) to give the
title compound (100 mg, 32.4%) as a light yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.16-8.10 (m, 1H), 7.44 (d, J=3.6 Hz,
1H), 7.20 (d, J=8.4 Hz, 1H), 7.10-7.01 (m, 2H), 6.41-6.31 (m, 2H),
5.19 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H).
Step 4
##STR00258##
[0593]
N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)ami-
no)-2-fluoro-N-(thiazol-2-yl)-5-(trifluoromethyl)benzenesulfonamide
[0594] To a solution of
N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)-5-(trifluoromethyl)-
benzenesulfonamide (100 mg, 0.20 mmol) and
N,N-diisopropylethylamine (0.17 mL, 1.01 mmol) in DMF (5 mL) was
added (1S,2S)--N.sup.1,N.sup.1-dimethylcyclohexane-1,2-diamine (58
mg, 0.40 mmol). The reaction mixture was stirred at room
temperature for 16 h. The mixture was diluted with EtOAc (30 mL),
washed with water (20 mL), brine (20 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
title compound (100 mg, crude) as a light yellow solid that
required no further purification. LCMS (ESI) m/z: 617.3
[M+H].sup.+.
Step 5
##STR00259##
[0595]
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(thiazol--
2-yl)-5-(trifluoromethyl)benzenesulfonamide
[0596] A mixture of
N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2--
fluoro-N-(thiazol-2-yl)-5-(trifluoromethyl)benzenesulfonamide (100
mg, 0.16 mmol) and formic acid (2.0 mL) was stirred at room
temperature for 1 h. The reaction mixture was concentrated in
vacuo. The crude residue was purified by reverse phase
chromatography (acetonitrile 10-40%/0.225% formic acid in water) to
give the title compound (17 mg, 22%) as a white solid. LCMS (ESI)
m/z: 467.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.80 (d, J=7.6 Hz, 1H), 7.22 (d, J=4.4 Hz, 1H), 6.84 (d, J=13.2 Hz,
1H), 6.77 (d, J=4.4 Hz, 1H), 6.01 (s, 1H), 3.33-3.28 (m, 1H),
2.65-2.58 (m, 1H), 2.21 (s, 3H), 2.21 (s, 3H), 2.18-2.11 (m, 1H),
1.88-1.74 (m, 2H), 1.66-1.56 (m, 1H), 1.45-1.30 (m, 1H), 1.28-1.18
(m, 2H), 1.17-1.05 (m, 1H).
Example 66
##STR00260##
[0597]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)oxy)-5-chloro--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
##STR00261##
[0598] Step 1
##STR00262##
[0599] tert-butyl
3-(((1S,2S)-2-hydroxycyclohexyl)amino)azetidine-1-carboxylate
[0600] To a solution of (1S,2S)-2-aminocyclohexanol (5.0 g, 43.41
mmol) in DCM (120 mL) was added AcOH (0.25 mL, 4.34 mmol) and
tert-butyl 3-oxoazetidine-1-carboxylate (7.43 g, 43.41 mmol) and
sodium triacetoxyborohydride (2.76 g, 130.24 mmol). The mixture was
stirred at room temperature for 16 h and concentrated in vacuo.
EtOAc (200 mL) was added and washed with water (100 mL.times.2),
brine (50 mL). The organic layer was dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The crude residue
was purified by silica gel chromatography (DCM/MeOH=20:1) to give
the title compound (7.0 g, 60%) as colorless oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 3.96-3.86 (m, 2H), 3.85-3.76 (m, 2H), 3.65
(s, 1H), 3.61-3.52 (m, 1H), 3.40-3.30 (m, 1H), 2.15-2.10 (m, 1H),
1.82-1.58 (m, 4H), 1.43 (s, 9H), 1.31-1.08 (m, 4H).
Step 2
##STR00263##
[0601] tert-butyl
3-(((1S,2S)-2-hydroxycyclohexyl)(methyl)amino)azetidine-1-carboxylate
[0602] To a solution of tert-butyl
3-(((1S,2S)-2-hydroxycyclohexyl)amino)azetidine-1-carboxylate (6.0
g, 22.19 mmol) in MeOH (100 mL) was added paraformaldehyde (9.99 g,
110.96 mmol), AcOH (1.26 mL, 22.19 mmol) and sodium
cyanoborohydride (2.8 g, 44.38 mmol). The mixture was stirred at
room temperature for 16 h and concentrated in vacuo. EtOAc (100 mL)
was added and washed with water (50 mL.times.2), brine (30 mL). The
organic layer was dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (DCM/MeOH=20:1) to give the title compound (4.5 g,
71%) as a white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
3.96-3.86 (m, 2H), 3.85-3.77 (m, 2H), 3.64 (s, 1H), 3.60-3.52 (m,
1H), 3.43-3.32 (m, 1H), 2.22-2.08 (m, 5H), 1.80-1.59 (m, 4H), 1.44
(s, 9H), 1.26-1.06 (m, 4H).
Step 3
##STR00264##
[0603] tert-butyl
3-(((1S,2S)-2-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfam-
oyl)-5-fluorophenoxy)cyclohexyl)(methyl)amino)azetidine-1-carboxylate
[0604] To a solution of tert-butyl
3-(((1S,2S)-2-hydroxycyclohexyl)(methyl)amino)azetidine-1-carboxylate
(1.11 g, 3.91 mmol) in THF (30 mL) at 0.degree. C. was added sodium
hydride (60%, 195 mg, 4.88 mmol). The mixture was stirred at
0.degree. C. for 0.5 h and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (1.5 g, 3.25 mmol) was added. The mixture was stirred at
room temperature for an additional 16 h. EtOAc (100 mL) was added
and washed with water (50 mL.times.2), brine (50 mL). The organic
layer was dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The crude residue was purified by reverse
phase chromatography (acetonitrile 20-65%/0.225% formic acid in
water) to give the title compound (200 mg, 9%) as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.86 (d, J=7.2 Hz, 1H),
7.42 (d, J=3.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.01 (d, J=3.6 Hz,
1H), 6.66 (d, J=11.6 Hz, 1H), 6.42-6.32 (m, 2H), 5.21 (s, 2H),
4.27-4.14 (m, 1H), 3.96-3.89 (m, 1H), 3.87-3.81 (m, 1H), 3.78-3.71
(m, 9H), 2.74-2.63 (m, 1H), 2.19-2.08 (m, 1H), 2.12 (s, 3H),
1.85-1.75 (m, 3H), 1.44 (s, 9H), 1.40-1.19 (m, 4H).
Step 4
##STR00265##
[0605]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)oxy)-5-chloro--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0606] A mixture of tert-butyl
3-(((1S,2S)-2-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfam-
oyl)-5-fluorophenoxy)cyclohexyl)(methyl)amino)azetidine-1-carboxylate
(100 mg, 0.14 mmol) and formic acid (2 mL) was stirred at room
temperature for 1 h. The mixture was concentrated in vacuo. The
crude residue was purified by reverse phase chromatography
(acetonitrile 33-63%/0.225% formic acid in water) to give the title
compound (32 mg, 46%) as a white solid. LCMS (ESI) m/z: 475.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.20 (s,
1H), 7.71 (d, J=7.6 Hz, 1H), 7.30 (d, J=11.6 Hz, 1H), 7.02 (d,
J=4.0 Hz, 1H), 6.58 (d, J=4.0 Hz, 1H), 4.60-4.50 (m, 1H), 4.03-3.91
(m, 1H), 3.85-3.72 (m, 4H), 2.70-2.58 (m, 1H), 2.20 (s, 3H),
2.10-2.00 (m, 1H), 1.71-1.56 (m, 3H), 1.42-1.14 (m, 4H).
Example 67
##STR00266##
[0607]
5-chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-hydroxypyrrolidin-1-yl)cyclo-
hexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0608] Following the procedure described in Example 30 and making
non-critical variations as required to replace 1,4-dibromobutane
with 1,4-dibromobutan-2-ol, the title compound was obtained as a
mixture of diastereomers. Separation of the mixture by chiral SFC
afforded the title compound as a single diastereomer. The
stereochemistry of the hydroxyl stereocenter was assigned
arbitratrily. LCMS (ESI) m/z: 475.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.96 (s, 1H), 7.58 (d, J=7.3 Hz, 1H), 7.18
(d, J=4.4 Hz, 1H), 6.77-6.69 (m, 2H), 5.85 (dd, J=6.2, 1.8 Hz, 1H),
4.73 (s, 1H), 4.16 (dq, J=6.7, 3.3 Hz, 1H), 3.00 (dd, J=9.9, 5.8
Hz, 1H), 2.87 (s, 1H), 2.81 (s, 1H), 2.62 (d, J=10.0 Hz, 1H), 2.05
(d, J=16.7 Hz, 1H), 1.85 (ddd, J=20.2, 10.0, 4.8 Hz, 2H), 1.78 (q,
J=11.0, 8.1 Hz, 2H), 1.64-1.50 (m, 2H), 1.46-1.24 (m, 2H),
1.28-1.12 (m, 2H).
Example 68
##STR00267##
[0609]
5-chloro-2-fluoro-4-(((1S,2S)-2-((R)-3-hydroxypyrrolidin-1-yl)cyclo-
hexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0610] Following the procedure described in Example 30 and making
non-critical variations as required to replace 1,4-dibromobutane
with 1,4-dibromobutan-2-ol, the title compound was obtained as a
mixture of diastereomers. Separation of the mixture by chiral SFC
afforded the title compound as a single diastereomer. The
stereochemistry of the hydroxyl stereocenter was assigned
arbitrarily. LCMS (ESI) m/z: 475.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 7.59 (d, J=7.3 Hz, 1H), 7.19 (d, J=4.4 Hz,
1H), 6.77-6.69 (m, 2H), 5.89-5.82 (m, 1H), 4.74 (s, 1H), 4.11 (d,
J=6.6 Hz, 1H), 2.79 (ddd, J=19.4, 15.7, 7.6 Hz, 4H), 2.55 (s, 1H),
2.07 (s, 2H), 1.87 (dd, J=12.9, 6.8 Hz, 2H), 1.77 (d, J=12.2 Hz,
1H), 1.60 (d, J=13.1 Hz, 1H), 1.61-1.48 (m, 1H), 1.34 (s, 1H),
1.43-1.21 (m, 3H), 1.25-1.12 (m, 1H).
Example 69
##STR00268##
[0611]
5-cyclopropyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluo-
ro-N-(pyrimidin-4-yl)benzenesulfonamide Formate
[0612] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)-
amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide,
5-cyclopropyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(-
pyrimidin-4-yl)benzenesulfonamide formate was obtained as a white
solid. LCMS (ESI) m/z: 434.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.49 (s, 1H), 8.20 (d, J=6.4 Hz, 1H), 8.15
(s, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.84 (d, J=5.6 Hz, 1H), 6.52 (d,
J=13.6 Hz, 1H), 5.90 (s, 1H), 3.44-3.30 (m, 1H), 2.95-2.82 (m, 1H),
2.35 (s, 3H), 2.35 (s, 3H), 2.15-2.05 (m, 1H), 1.96-1.86 (m, 1H),
1.84-1.74 (m, 1H), 1.68-1.51 (m, 2H), 1.45-1.09 (m, 4H), 0.95-0.80
(m, 2H), 0.54-0.33 (m, 2H).
Example 70
##STR00269##
[0613]
5-chloro-2-fluoro-4-(((1S,2S)-2-(piperidin-1-yl)cyclohexyl)amino)-N-
-(thiazol-2-yl)benzenesulfonamide formate
##STR00270## ##STR00271##
[0614] Step 1
##STR00272##
[0615] tert-butyl((1S,2R)-2-hydroxycyclohexyl)carbamate
[0616] To a solution of (1R,2S)-2-aminocyclohexanol hydrochloride
(4.0 g, 26.38 mmol) and sodium hydroxide (2.11 g, 52.76 mmol) in
dioxane (100 mL) and water (10 mL) at 0.degree. C. was added
di-tert-butyl dicarbonate (6.91 g, 31.66 mmol). The mixture was
stirred at room temperature for 16 h and concentrated in vacuo.
EtOAc (100 mL) was added and washed with water (50 mL.times.2),
brine (30 mL). The organic layer was dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The crude residue
was purified by silica gel chromatography (petroleum
ether/EtOAc=4:1) to give the title compound (3.3 g, 58%) as
colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.60-4.51
(m, 1H), 3.36-3.24 (m, 3H), 2.10-1.93 (m, 2H), 1.73-1.66 (m, 2H),
1.46 (s, 9H), 1.37-1.08 (m, 4H).
Step 2
##STR00273##
[0617] (1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl
methanesulfonate
[0618] To a solution of
tert-butyl((1S,2R)-2-hydroxycyclohexyl)carbamate (3.3 g, 15.33
mmol) in DCM (100 mL) at 0.degree. C. was added triethylamine (3.19
mL, 22.99 mmol) and methanesulfonyl chloride (3.8 g, 33.17 mmol).
The mixture was stirred at room temperature for 16 h. The reaction
mixture was washed with water (50 mL), 1N KHSO.sub.4 (50 mL), sat.
aq. NaHCO.sub.3 (40 mL) and brine (40 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo to give the title compound (3.5 g, 78%) as a white solid that
required no further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 4.98 (s, 1H), 4.81-4.72 (m, 1H), 3.75-3.60 (min, 1H), 3.03
(s, 3H), 2.21-2.12 (m, 1H), 1.83-1.69 (m, 2H), 1.63-1.49 (m, 4H),
1.48-1.30 (m, 10H).
Step 3
##STR00274##
[0619]
tert-butyl((1S,2S)-2-(piperidin-1-yl)cyclohexyl)carbamate
[0620] A mixture of
(1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate
(1.0 g, 3.41 mmol) and piperidine (7 mL) was heated to 60.degree.
C. for 24 h. After cooling to room temperature, the mixture was
concentrated in vacuo. EtOAc (100 mL) was added and washed with
water (50 mL.times.2), brine (50 mL). The organic layer was dried
over anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
crude residue was purified by silica gel chromatography
(DCM/MeOH=20:1) to give the title compound (0.5 g, 52%) as a white
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.67-5.22 (m, 1H),
3.35-3.15 (m, 1H), 2.77-2.51 (m, 2H), 2.49-2.09 (m, 4H), 1.95-1.71
(m, 3H), 1.70-1.62 (m, 2H), 1.58-1.50 (m, 3H), 1.46 (s, 9H),
1.43-1.38 (m, 1H), 1.34-1.01 (m, 4H).
Step 4
##STR00275##
[0621] (1S,2S)-2-(piperidin-1-yl)cyclohexanamine
2,2,2-trifluoroacetate
[0622] To a solution of
tert-butyl((1S,2S)-2-(piperidin-1-yl)cyclohexyl)carbamate (0.7 g,
2.48 mmol) in DCM (20 mL) was added trifluoroacetic acid (0.3 mL,
24.79 mmol). The mixture was stirred at room temperature for 16 h
and concentrated in vacuo to give the title compound (0.8 g, crude)
as light yellow oil that required no further purification.
Step 5
##STR00276##
[0623]
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(piperidin--
1-yl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0624] To a solution of (1S,2S)-2-(piperidin-1-yl)cyclohexanamine
2,2,2-trifluoroacetate (489 mg, 1.65 mmol) and
N,N-diisopropylethylamine (1.36 mL, 8.23 mmol) in DMF (15 mL) was
added
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (1.52 g, 3.29 mmol). The reaction mixture was stirred at
room temperature for 16 h. The mixture was diluted with EtOAc (100
mL), washed with water (50 mL.times.2), brine (50 mL). The organic
layer was dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (petroleum ether/EtOAc=3:2) to give the title
compound (0.25 g, 24%) as a white solid. LCMS (ESI) m/z: 623.1
[M+H].sup.+.
Step 6:
##STR00277##
[0625]
5-chloro-2-fluoro-4-(((1S,2S)-2-(piperidin-1-yl)cyclohexyl)amino)-N-
-(thiazol-2-yl)benzenesulfonamide Formate
[0626] A mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(piperidin-1-yl)c-
yclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (150 mg, 0.24
mmol) and formic acid (3.0 mL) was stirred at room temperature for
1 h. The reaction mixture was concentrated in vacuo. The crude
residue was purified by reverse phase chromatography (acetonitrile
8-38%/0.225% formic acid in water) to give the title compound (101
mg, 87%) as a white solid. LCMS (ESI) m/z: 473.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (s, 1H), 7.61 (d,
J=7.2 Hz, 1H), 7.26 (d, J=4.4 Hz, 1H), 6.82 (d, J=4.4 Hz, 1H), 6.76
(d, J=12.8 Hz, 1H), 6.04 (s, 1H), 3.37-3.33 (m, 1H), 2.75-2.65 (m,
1H), 2.64-2.55 (m, 2H), 2.48-2.42 (m, 2H), 2.20-2.05 (m, 1H),
1.95-1.85 (m, 1H), 1.80-1.73 (m, 1H), 1.67-1.57 (m, 1H), 1.53-1.45
(m, 2H), 1.40-1.34 (m, 4H), 1.31-1.11 (m, 4H).
Example 71
##STR00278##
[0627]
5-chloro-4-(((1S,2S)-2-(ethyl(methyl)amino)cyclohexyl)amino)-2-fluo-
ro-N-(6-fluoropyridin-2-yl)benzenesulfonamide
[0628] Following the procedure described in Example 18 and making
non-critical variations as required to replace
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)be-
nzenesulfonamide with
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzyl)-2-f-
luoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide,
5-chloro-4-(((1S,2S)-2-(ethyl(methyl)amino)cyclohexyl)amino)-2-fluoro-N-(-
6-fluoropyridin-2-yl)benzenesulfonamide was obtained as a white
solid. LCMS (ESI) m/z: 459.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.80 (q, J=8.2 Hz, 1H), 7.74 (d, J=7.4 Hz,
1H), 6.93-6.74 (m, 1H), 6.72-6.57 (m, 1H), 6.10 (s, 1H), 2.30-2.11
(m, 2H), 2.11-1.98 (m, 1H), 1.95-1.81 (m, 1H), 1.81-1.70 (m, 1H),
1.68-1.52 (m, 1H), 1.46-1.11 (m, 4H), 1.09-0.86 (m, 3H).
Example 72
##STR00279##
[0629]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-((2-hydrox-
yethyl)(methyl)amino)cyclohexyl)amino)benzenesulfonamide
[0630] Following the procedure described in Example 38 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine-2-yl)be-
nzenesulfonamide, the title compound was obtained as a white solid.
LCMS (ESI) m/z: 475.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d)
.delta. 11.30 (s, 1H), 7.79 (q, J=8.2 Hz, 1H), 7.71 (d, J=7.4 Hz,
1H), 6.91-6.79 (m, 1H), 6.73 (d, J=13.3 Hz, 1H), 6.64 (d, J=7.9 Hz,
1H), 6.10 (d, J=5.3 Hz, 1H), 4.32 (s, 1H), 3.51-3.35 (m, 3H),
2.60-2.52 (m, 2H), 2.17 (s, 3H), 2.13-2.03 (m, 1H), 1.90-1.68 (m,
2H), 1.65-1.54 (m, 1H), 1.45-1.04 (m, 4H).
Example 73
##STR00280##
[0631]
5-chloro-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro-N-(6--
fluoropyridin-2-yl)benzenesulfonamide
[0632] Following the procedure described in Example 29, step 2 and
making non-critical variations as required to replace the
iodomethane with 1-iodoethane and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine-2-yl)be-
nzenesulfonamide, the title compound was obtained. LCMS (ESI) m/z:
445.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.63 (d,
J=7.4 Hz, 1H), 7.44 (d, J=8.3 Hz, 1H), 6.70 (d, J=12.9 Hz, 1H),
6.55 (d, J=7.9 Hz, 1H), 6.16 (s, 1H), 5.78 (s, 1H), 3.31 (d, J=8.5
Hz, 1H), 3.14 (s, 1H), 2.94 (s, 1H), 2.85 (s, 1H), 2.15-2.05 (m,
1H), 1.95-1.86 (m, 1H), 1.74 (d, J=12.5 Hz, 1H), 1.62 (d, J=12.8
Hz, 1H), 1.41-1.16 (m, 2H), 1.12 (t, J=7.2 Hz, 3H).
Example 74
##STR00281##
[0633]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(methylami-
no)cyclohexyl)amino)benzenesulfonamide
[0634] Following the procedure described in Example 29, step 2 and
making non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine-2-yl)be-
nzenesulfonamide, the title compound was obtained. LCMS (ESI) m/z:
431.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 7.52-7.38
(m, 2H), 6.59 (dt, J=8.3, 4.2 Hz, 2H), 6.20-6.12 (m, 1H), 5.75 (d,
J=9.6 Hz, 1H), 3.68 (s, 1H), 3.41 (d, J=11.0 Hz, 4H), 2.55 (s, 3H),
2.17-2.05 (m, 1H), 1.90 (d, J=12.1 Hz, 1H), 1.77 (d, J=13.0 Hz,
1H), 1.62 (d, J=13.1 Hz, 1H), 1.46 (s, 1H), 1.29-1.12 (m, 2H).
Example 75 & Example 83
##STR00282##
[0635]
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R,5R)-2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Step 1
##STR00283##
[0636] (trans,
trans)-5-chloro-4-((2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide & (trans,
cis)-5-chloro-4-((2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)amino)--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0637] Following the procedure described in Example 48 and making
non-critical variations as required to replace
tert-butyl((1R,6R)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e with
(trans)-tert-butyl(2-amino-4-(trifluoromethyl)cyclohexyl)carbamate,
(trans,
trans)-5-chloro-4-((2-(dimethylamino)-5-(trifluoromethyl)cyclohex-
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (first peak
on HPLC) and (trans,
cis)-5-chloro-4-((2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)amino)--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (second peak on HPLC)
were obtained both as white solid. First peak: LCMS (ESI) m/z:
501.1 [M+H].sup.+. H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.62 (d,
J=7.2 Hz, 1H), 7.25 (d, J=4.4 Hz, 1H), 6.81 (d, J=4.4 Hz, 1H), 6.57
(d, J=12.8 Hz, 1H), 5.72 (d, J=6.4 Hz, 1H), 3.79-3.69 (m, 1H),
2.75-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.26 (s, 3H), 2.26 (s, 3H),
2.10-1.99 (m, 1H), 1.83-1.56 (m, 5H). Second peak: LCMS (ESI) m/z:
501.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14
(s, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.23 (d, J=4.4 Hz, 1H), 6.89 (d,
J=12.8 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H), 5.88 (d, J=6.0 Hz, 1H),
3.65-3.53 (m, 1H), 2.86-2.77 (m, 1H), 2.63-2.55 (m, 1H), 2.22 (s,
3H), 2.22 (s, 3H), 2.16-2.08 (m, 1H), 2.00-1.88 (m, 2H), 1.41-1.22
(m, 3H).
Step 2:
##STR00284##
[0638]
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R,5R)-2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0639] (trans,
cis)-5-chloro-4-((2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)amino)--
2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (93 mg) was separated
by using chiral SFC (Chiralpak C2 (250 mm*30 mm, 10 um),
Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=55/45; 40 mL/min) to
give
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (53 mg, first
peak) as a white solid and
5-chloro-4-(((1R,2R,5R)-2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (4 mg, second
peak) as a white solid. Absolute configuration was arbitrarily
assigned to each enantiomer. Example 75: LCMS (ESI) m/z: 501.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.59 (d,
J=7.2 Hz, 1H), 7.22 (d, J=4.4 Hz, 1H), 6.88 (d, J=13.2 Hz, 1H),
6.77 (d, J=4.4 Hz, 1H), 5.85 (d, J=6.0 Hz, 1H), 3.62-3.51 (m, 1H),
2.82-2.73 (m, 1H), 2.65-2.53 (m, 1H), 2.20 (s, 3H), 2.20 (s, 3H),
2.17-2.09 (m, 1H), 1.99-1.88 (m, 2H), 1.40-1.22 (m, 3H). Example
83: LCMS (ESI) m/z: 501.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.15 (s, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.22
(d, J=4.4 Hz, 1H), 6.88 (d, J=13.2 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H),
5.85 (d, J=6.0 Hz, 1H), 3.62-3.51 (m, 1H), 2.82-2.73 (m, 1H),
2.65-2.53 (m, 1H), 2.20 (s, 3H), 2.20 (s, 3H), 2.17-2.09 (m, 1H),
1.99-1.88 (m, 2H), 1.40-1.22 (m, 3H).
Example 76 & Example 84
##STR00285##
[0640]
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1R,2R,5S)-2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0641] (trans,
trans)-5-chloro-4-((2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (51 mg) was separated
by using chiral SFC (Chiralpak AS (250 mm*30 mm, 5 um),
Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=75/25; 50 mL/min) to
give
5-chloro-4-(((1R,2R,5S)-2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (2 mg, first
peak) as a white solid and
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (28 mg, second
peak) as a white solid. Absolute configuration was arbitrarily
assigned to each enantiomer. Example 84: LCMS (ESI) m/z: 501.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (s,
1H), 7.62 (d, J=7.2 Hz, 1H), 7.23 (d, J=4.4 Hz, 1H), 6.79 (d, J=4.4
Hz, 1H), 6.55 (d, J=12.8 Hz, 1H), 5.68 (d, J=6.4 Hz, 1H), 3.78-3.68
(m, 1H), 2.76-2.66 (m, 1H), 2.47-2.41 (m, 1H), 2.23 (s, 3H), 2.23
(s, 3H), 2.10-2.00 (m, 1H), 1.82-1.57 (m, 5H). Example 76: LCMS
(ESI) m/z: 501.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.14 (s, 1H), 7.62 (d, J=7.2 Hz, 1H), 7.23 (d, J=4.4 Hz,
1H), 6.79 (d, J=4.4 Hz, 1H), 6.55 (d, J=12.8 Hz, 1H), 5.68 (d,
J=6.4 Hz, 1H), 3.78-3.68 (m, 1H), 2.76-2.66 (m, 1H), 2.47-2.41 (m,
1H), 2.23 (s, 3H), 2.23 (s, 3H), 2.10-2.00 (m, 1H), 1.82-1.57 (m,
5H).
Example 78
##STR00286##
[0642]
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-2--
yl)-5-(trifluoromethyl)benzenesulfonamide Formate
[0643] Following the procedure described in Example 66 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide and tert-butyl
3-(((1S,2S)-2-hydroxycyclohexyl)(methyl)amino)azetidine-1-carboxylate
with
N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)-5-(trifluorome-
thyl)benzenesulfonamide and (1S,2S)-2-(dimethylamino)cyclohexanol,
4-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-N-(thiazol-2-yl)-5--
(trifluoromethyl)benzenesulfonamide formate was obtained as a white
solid. LCMS (ESI) m/z: 468.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.14 (s, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.54
(d, J=12.0 Hz, 1H), 7.21 (d, J=4.4 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H),
4.84-4.74 (m, 1H), 2.67-2.57 (m, 1H), 2.26 (s, 3H), 2.26 (s, 3H),
2.05-1.95 (m, 1H), 1.85-1.75 (m, 1H), 1.71-1.55 (m, 2H), 1.41-1.17
(m, 4H).
Example 79
##STR00287##
[0644]
2-(((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phen-
yl)amino)cyclohexyl)(methyl)amino)acetamide Formate
[0645] Following the procedure described in Example 29 and making
non-critical variations as required to replace iodopropane with
2-chloroacetamide,
2-(((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl)ami-
no)cyclohexyl)(methyl)amino)acetamide formate was obtained as a
white solid. LCMS (ESI) m/z: 476.0 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.15 (s, 1H), 7.56 (d, J=7.6 Hz, 1H),
7.24 (d, J=4.4 Hz, 1H), 7.11 (d, J=3.2 Hz, 1H), 6.95 (s, 1H), 6.79
(d, J=4.8 Hz, 1H), 6.71 (d, J=13.2 Hz, 1H), 6.17 (d, J=6.4 Hz, 1H),
3.45-3.31 (m, 1H), 3.06-2.97 (m, 1H), 2.95-2.87 (m, 1H), 2.72-2.63
(m, 1H), 2.14 (s, 3H), 2.05-1.97 (m, 1H), 1.85-1.75 (m, 1H),
1.73-1.67 (m, 1H), 1.63-1.53 (m, 1H), 1.38-1.09 (m, 4H).
Example 80
##STR00288##
[0646]
2-(((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phen-
yl)amino)cyclohexyl)(methyl)amino)-N-methylacetamide Formate
[0647] Following the procedure described in Example 29 and making
non-critical variations as required to replace iodopropane with
2-chloro-N-methylacetamide,
2-(((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl)ami-
no)cyclohexyl)(methyl)amino)-N-methylacetamide formate was obtained
as a white solid. LCMS (ESI) m/z: 490.0 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.15 (s, 1H), 7.58 (d, J=7.6 Hz,
1H), 7.28 (d, J=4.4 Hz, 1H), 7.23 (d, J=4.8 Hz, 1H), 6.79 (d, J=4.8
Hz, 1H), 6.72 (d, J=13.2 Hz, 1H), 6.07 (d, J=6.8 Hz, 1H), 3.44-3.37
(m, 1H), 3.06 (d, J=16.0 Hz, 1H), 2.86 (d, J=16.0 Hz, 1H),
2.73-2.62 (m, 1H), 2.44 (d, J=5.2 Hz, 3H), 2.14 (s, 3H), 2.01-1.94
(m, 1H), 1.87-1.79 (m, 1H), 1.78-1.68 (m, 1H), 1.63-1.55 (m, 1H),
1.40-1.13 (m, 4H).
Example 85
##STR00289##
[0648]
5-chloro-N-(6-chloropyridin-2-yl)-4-(((1S,2S)-2-(dimethylamino)cycl-
ohexyl)amino)-2-fluorobenzenesulfonamide
[0649] Following the procedure described in Example 11 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-(6-chloropyridin-2-yl)-N-(2,4-dimethoxybenzyl)-2,4-difluoroben-
zenesulfonamide,
5-chloro-N-(6-chloropyridin-2-yl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl-
)amino)-2-fluorobenzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 461.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.85-7.73 (m, 1H), 7.68-7.53 (m, 1H),
7.11-6.73 (m, 3H), 6.26-5.92 (m, 1H), 3.43-3.39 (m, 1H), 3.32-3.26
(m, 1H), 2.47-2.29 (m, 6H), 2.00-1.85 (m, 2H), 1.87-1.69 (m, 1H),
1.67-1.51 (m, 1H), 1.28 (ddd, J=51.9, 15.9, 9.4 Hz, 4H).
Example 86
##STR00290##
[0650]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-((2-hydrox-
ypropyl)(methyl)amino)cyclohexyl)amino)benzenesulfonamide
[0651] Following the procedure described in Example 29 and making
non-critical variations as required to replace the iodopropane with
1-bromo-2-propanol and
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-2-fluoro-N-(thiazol-2-yl)be-
nzenesulfonamide with
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzyl)-2-f-
luoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide, the title
compound was obtained. LCMS (ESI) m/z: 489.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 11.47 (s, 1H), 7.81 (s, 1H), 7.71
(d, J=7.4 Hz, 1H), 6.84 (s, 1H), 6.75 (d, J=13.2 Hz, 1H), 6.67 (s,
1H), 6.06 (s, 1H), 4.24 (s, 1H), 3.62 (s, 1H), 3.49-3.24 (m, 2H),
3.35 (s, 1H), 2.54 (s, 2H), 2.40 (s, 1H), 2.27 (s, 1H), 2.15 (s,
2H), 2.08 (s, 3H), 1.81 (s, 1H), 1.74 (d, J=10.1 Hz, 1H), 1.58 (d,
J=12.9 Hz, 1H), 1.33 (t, J=12.7 Hz, 1H), 1.22 (t, J=10.7 Hz, 1H),
1.14 (s, 2H), 1.00 (d, J=6.1 Hz, 1H), 0.84 (d, J=5.9 Hz, 2H).
Example 88 & Example 103
##STR00291##
[0652]
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
&
5-chloro-4-(((1R,2R,5S)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Step 1
##STR00292##
[0653]
(trans)-tert-butyl(2-amino-4-(3-(trifluoromethyl)phenyl)cyclohexyl)-
carbamate
[0654] Following the procedure described in Example 36, step 1 and
making non-critical variations as required to replace
(trans)-tert-butyl(6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e with
(trans)-tert-butyl(3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro--
[1,1'-biphenyl]-4-yl)carbamate,
(trans)-tert-butyl(2-amino-4-(3-(trifluoromethyl)phenyl)cyclohexyl)carbam-
ate was obtained as a light yellow solid. LCMS (ESI) m/z: 359.1
[M+H].sup.+.
Step 2
##STR00293##
[0655] (trans,
trans)-5-chloro-4-((2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
(trans,
cis)-5-chloro-4-((2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cyclohex-
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0656] Following the procedure described in Example 48 and making
non-critical variations as required to replace
tert-butyl((1R,6R)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e with (trans)-tert-butyl
(2-amino-4-(3-(trifluoromethyl)phenyl)cyclohexyl)carbamate, (trans,
trans)-5-chloro-4-((2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (first peak
on HPLC) and (trans,
cis)-5-chloro-4-((2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cyclohex-
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (second peak
on HPLC) were obtained both as white solid.
Step 3
##STR00294##
[0657]
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
&
5-chloro-4-(((1R,2R,5S)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0658] (trans,
trans)-5-chloro-4-((2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cycloh-
exyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (65 mg) was
separated by using chiral SFC (Chiralpak AS (250 mm*30 mm, 5 um),
Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=60/40; 50 mL/min) to
give
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (7 mg,
first peak) as a white solid and
5-chloro-4-(((1R,2R,5S)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (35 mg,
second peak) as a white solid. Absolute configuration was
arbitrarily assigned to each enantiomer.
[0659] Example 88: LCMS (ESI) m/z: 577.3 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.70-7.66 (m, 2H), 7.62 (d, J=7.2
Hz, 1H), 7.60-7.57 (m, 2H), 7.21 (d, J=4.4 Hz, 1H), 6.77 (d, J=4.8
Hz, 1H), 6.41 (d, J=12.4 Hz, 1H), 5.68 (d, J=6.0 Hz, 1H), 3.63-3.57
(m, 1H), 3.17-3.12 (m, 1H), 2.47-2.41 (m, 1H), 2.35-2.30 (m, 1H),
2.25 (s, 3H), 2.25 (s, 3H), 2.10-1.97 (m, 1H), 1.82-1.65 (m, 4H).
Example 103: LCMS (ESI) m/z: 577.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.70-7.66 (m, 2H), 7.62 (d, J=7.2 Hz,
1H), 7.60-7.57 (m, 2H), 7.21 (d, J=4.4 Hz, 1H), 6.77 (d, J=4.8 Hz,
1H), 6.41 (d, J=12.4 Hz, 1H), 5.68 (d, J=6.0 Hz, 1H), 3.63-3.57 (m,
1H), 3.17-3.12 (m, 1H), 2.47-2.41 (m, 1H), 2.35-2.30 (m, 1H), 2.25
(s, 3H), 2.25 (s, 3H), 2.10-1.97 (m, 1H), 1.82-1.65 (m, 4H).
Example 87 & Example 93
##STR00295##
[0660]
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
&
5-chloro-4-(((1R,2R,5R)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0661] (trans,
cis)-5-chloro-4-((2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cyclohex-
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (30 mg) was
separated by using chiral SFC (Chiralpak OJ (250 mm*30 mm, 5 um),
Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=80/20; 60 mL/min) to
give
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (9 mg,
first peak) as a white solid and
5-chloro-4-(((1R,2R,5R)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (2 mg,
second peak) as a white solid. Absolute configuration was
arbitrarily assigned to each enantiomer.
[0662] Example 87: LCMS (ESI) m/z: 577.2 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.60-7.51 (m, 5H), 7.19 (d, J=4.8
Hz, 1H), 6.88 (d, J=13.2 Hz, 1H), 6.74 (d, J=4.4 Hz, 1H), 5.87 (d,
J=5.2 Hz, 1H), 3.65-3.58 (m, 1H), 3.00-2.85 (m, 2H), 2.29 (s, 3H),
2.29 (s, 3H), 2.23-2.15 (m, 1H), 2.01-1.90 (m, 2H), 1.58-1.43 (m,
3H). Example 93: LCMS (ESI) m/z: 577.3 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.60-7.51 (m, 5H), 7.17 (d, J=4.8
Hz, 1H), 6.86 (d, J=13.2 Hz, 1H), 6.71 (d, J=4.4 Hz, 1H), 5.84 (d,
J=4.4 Hz, 1H), 3.65-3.58 (m, 1H), 3.00-2.85 (m, 2H), 2.27 (s, 3H),
2.27 (s, 3H), 2.23-2.15 (m, 1H), 2.01-1.90 (m, 2H), 1.58-1.43 (m,
3H).
Example 89
##STR00296##
[0663]
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino)cycl-
ohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide Formate
[0664] Following the procedure described in Example 38 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino)-
cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide formate was
obtained as a white solid. LCMS (ESI) m/z: 458.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.46 (s, 1H), 8.18-8.12
(m, 2H), 7.66 (d, J=7.2 Hz, 1H), 6.79 (d, J=6.0 Hz, 1H), 6.71 (d,
J=12.8 Hz, 1H), 5.93 (d, J=5.2 Hz, 1H), 3.50-3.40 (m, 4H),
2.86-2.83 (m, 1H), 2.69-2.56 (m, 2H), 2.28 (s, 3H), 2.07-2.08 (m,
1H), 1.86-1.89 (m, 1H), 1.76-1.78 (m, 1H), 1.58-1.61 (m, 1H),
1.38-1.10 (m, 4H).
Example 90
##STR00297##
[0665]
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)oxy)-5-cyclopr-
opyl-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0666] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with tert-butyl
3-(((1S,2S)-2-(2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfam-
oyl)-5-fluorophenoxy)cyclohexyl)(methyl)amino)azetidine-1-carboxylate,
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)oxy)-5-cyclopropyl-2-
-fluoro-N-(thiazol-2-yl)benzenesulfonamide formate was obtained as
a white solid. LCMS (ESI) m/z: 481.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.26 (s, 1H), 7.19 (d, J=8.0 Hz, 1H),
7.13-6.95 (m, 2H), 6.61 (s, 1H), 4.50-4.40 (m, 1H), 4.06-4.03 (m,
1H), 3.71-3.62 (m, 4H), 2.70-2.60 (m, 1H), 2.27 (s, 3H), 2.09-1.97
(m, 2H), 1.74-1.55 (m, 3H), 1.46-1.09 (m, 4H), 0.97-0.83 (m, 2H),
0.60-0.42 (m, 2H).
Example 91
##STR00298##
[0667]
5-cyclobutyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluor-
o-N-(thiazol-2-yl)benzenesulfonamide
##STR00299##
[0668] Step 1
##STR00300##
[0669]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclo-
hexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0670] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (1.04 g, 2.25 mmol) and K.sub.2CO.sub.3 (0.93 g, 6.75 mmol)
in DMF (25 mL) was added
(1S,2S)--N.sup.1,N.sup.1-dimethylcyclohexane-1,2-diamine (0.32 g,
2.25 mmol). The reaction mixture was stirred at room temperature
for 16 h. The mixture was diluted with EtOAc (100 mL), washed with
water (100 mL.times.3), brine (100 mL), dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo to give the
title compound (1.2 g, crude) as a brown solid that required no
further purification. LCMS (ESI) m/z: 583.1 [M+H].sup.+.
Step 2
##STR00301##
[0671]
5-cyclobutyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)c-
yclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0672] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)-
amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (500 mg, 0.86
mmol) in toluene (5 mL) and water (1 mL) was added
chloro[(di(1-adamantyl)-n-butylphosphine)-2-(2-aminobiphenyl)]palladium(I-
I) (115 mg, 0.17 mmol), potassium cyclobutyltrifluoroboranuide (280
mg, 1.71 mmol) and Cs.sub.2CO.sub.3 (839 mg, 2.57 mmol). The
reaction mixture was heated to 100.degree. C. for 16 h. After
cooling to room temperature, the mixture was concentrated in vacuo.
EtOAc (50 mL) was added, washed with water (50 mL.times.2), brine
(50 mL), dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The crude residue was purified by silica gel
chromatography (petroleum ether/EtOAc=2:1)) to give the title
compound (30 mg, 6%) as a white solid. LCMS (ESI) m/z: 603.3
[M+H].sup.+.
Step 3
##STR00302##
[0673]
5-cyclobutyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluor-
o-N-(thiazol-2-yl)benzenesulfonamide
[0674] A mixture of
5-cyclobutyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohe-
xyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (25 mg, 0.04
mmol) and formic acid (1.0 mL) was stirred at room temperature for
1 h. The reaction mixture was concentrated in vacuo. The crude
residue was purified by reverse phase chromatography (acetonitrile
12-42%/0.225% formic acid in water) to give the title compound (7
mg, 36%) as a white solid. LCMS (ESI) m/z: 453.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.36 (d, J=8.0 Hz, 1H),
7.19 (d, J=4.4 Hz, 1H), 6.74 (d, J=4.4 Hz, 1H), 6.45 (d, J=13.2 Hz,
1H), 5.25 (s, 1H), 3.24-3.21 (m, 2H), 2.70-2.60 (m, 1H), 2.40-2.28
(m, 2H), 2.22 (s, 3H), 2.22 (s, 3H), 2.17-1.94 (m, 3H), 1.91-1.74
(m, 4H), 1.65-1.70 (m 1H), 1.40-1.30 (m, 1H), 1.25-1.19 (m, 2H),
1.14-0.97 (m, 1H).
Example 92
##STR00303##
[0675]
5-chloro-2-fluoro-N-(4-methylthiazol-2-yl)-4-(((1S,2S)-2-(pyrrolidi-
n-1-yl)cyclohexyl)amino)benzenesulfonamide Formate
[0676] Following the procedure described in Example 30 and
non-critical variations required to substitute
4-[[(1S,2S)-2-aminocyclohexyl]amino]-5-chloro-N-[(2,4-dimethoxyphenyl)met-
hyl]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide with
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzyl)-2-f-
luoro-N-(4-methylthiazol-2-yl)benzenesulfonamide, the title
compound was obtained as a white solid. LCMS (ESI) m/z: 473.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.16 (s,
1H), 7.57 (d, J=7.2 Hz, 1H), 6.76 (d, J=13.2 Hz, 1H), 6.33 (d,
J=1.2 Hz, 1H), 5.92 (d, J=6.0 Hz, 1H), 3.45-3.34 (m, 2H), 3.01-2.90
(m, 1H), 2.76-2.64 (m, 4H), 2.07 (s, 3H), 2.06-2.02 (m, 1H),
1.92-1.86 (m, 1H), 1.79-1.73 (m, 1H), 1.66-1.62 (m, 4H), 1.39-1.32
(m, 2H), 1.29-1.18 (m, 2H).
Example 94
##STR00304##
[0677]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl((S)-3,3,3-trifluoro-2-hydro-
xypropyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0678] Following the procedure described in Example 29 and making
non-critical variations as required to replace the iodopropane with
3-bromo-1,1,1-trifluoro-2-propanol the title compound was obtained
as a mixture of diastereomers. Separation of isomers by HPLC
(acetonitrile 26-56%/0.225% formic acid in water) provided the
title compound. The stereochemistry of alcohol stereocenter was
assigned arbitrarily. LCMS (ESI) m/z: 531.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 12.73 (s, 1H), 7.57 (d, J=7.3 Hz,
1H), 7.24 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.6 Hz, 1H), 6.69 (d,
J=13.1 Hz, 1H), 5.98-5.88 (m, 2H), 3.94 (s, 1H), 2.69 (td, J=14.9,
14.2, 5.3 Hz, 2H), 2.60-2.51 (m, 1H), 2.15 (s, 3H), 2.13-2.06 (m,
1H), 1.77 (t, J=14.4 Hz, 2H), 1.59 (d, J=13.2 Hz, 1H), 1.26 (s,
2H), 1.42-1.04 (m, 2H).
Example 95
##STR00305##
[0679]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl((R)-3,3,3-trifluoro-2-hydro-
xypropyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0680] Following the procedure described in Example 29 and making
non-critical variations as required to replace the iodopropane with
3-bromo-1,1,1-trifluoro-2-propanol the title compound was obtained
as a mixture of diastereomers. Separation of isomers by HPLC
(acetonitrile 26-56%/0.225% formic acid in water) provided the
title compound. The stereochemistry of alcohol stereocenter was
assigned arbitrarily. LCMS (ESI) m/z: 531.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d6) .delta. 12.73 (s, 1H), 7.57 (d, J=7.3 Hz,
1H), 7.24 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.70 (d,
J=13.0 Hz, 1H), 5.94 (s, 1H), 5.89-5.82 (m, 1H), 4.00 (s, 1H),
2.76-2.57 (m, 3H), 2.16 (s, 3H), 2.09 (d, J=12.7 Hz, 1H), 1.77 (dd,
J=22.0, 10.6 Hz, 2H), 1.59 (d, J=13.1 Hz, 1H), 1.41-1.22 (m, 2H),
1.18-1.04 (m, 1H).
Example 96
##STR00306##
[0681]
5-cyclopropyl-4-(((1S,2S)-2-(ethylamino)cyclohexyl)oxy)-2-fluoro-N--
(pyrimidin-4-yl)benzenesulfonamide
##STR00307## ##STR00308##
[0682] Step 1
##STR00309##
[0683]
5-cyclopropyl-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-y-
l)benzenesulfonamide
[0684] Following the procedure described in Example 15, step 1 and
making non-critical variations as required to replace
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamino)cycl-
ohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
5-cyclopropyl-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-
-4-yl)benzenesulfonamide was obtained as a pale yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.81-8.73 (m, 1H), 8.45
(d, J=6.0 Hz, 1H), 7.65-7.58 (m, 1H), 7.22-7.14 (m, 2H), 6.86-6.79
(m, 1H), 6.46-6.39 (m, 2H), 5.24 (s, 2H), 3.80 (s, 3H), 3.78 (s,
3H), 2.11-2.00 (m, 1H), 1.11-1.04 (m, 2H), 0.81-0.74 (m, 2H).
Step 2
##STR00310##
[0685] (1S,2S)-2-(benzylamino)cyclohexanol
[0686] To a solution of (1S,2S)-2-aminocyclohexanol (5.0 g, 43.41
mmol) in DCM (20 mL) was added benzaldehyde (4.61 g, 43.41 mmol).
The mixture was stirred at room temperature for 0.5 h and magnesium
sulfate (7.84 g, 65.12 mmol) was added portionwise. The mixture was
stirred at room temperature for an additional 2.5 h. The reaction
was filtered and sodium borohydride (3.72 g, 98.39 mmol) at
0.degree. C. was added portionwise. The mixture was stirred at
0.degree. C. for 3 h. The reaction was quenched with sat. aq.
NH.sub.4Cl (20 mL) slowly. The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo to
give the title compound (5 g, crude) as colorless oil that required
no further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.38-7.32 (m, 4H), 7.30-7.25 (m, 1H), 4.00-3.97 (m, 1H), 3.74-3.70
(m, 1H), 3.28-3.22 (m, 1H), 2.37-2.31 (m, 1H), 2.20-2.16 (m, 1H),
2.05-2.03 (m, 1H), 1.76-1.72 (m, 2H), 1.35-1.18 (m, 3H), 1.11-1.02
(m, 1H).
Step 3
##STR00311##
[0687] (1S,2S)-2-(benzyl(ethyl)amino)cyclohexanol
[0688] To a solution of (1S,2S)-2-(benzylamino)cyclohexanol (5.0 g,
24.35 mmol) in EtOH (50 mL) was added acetaldehyde (5.42 g, 121.77
mmol). The mixture was stirred at room temperature for 0.5 h and
sodium cyanoborohydride (3.06 g, 48.71 mmol) was added. The mixture
was stirred at room temperature for an additional 12 h. The
reaction was quenched with sat. aq. NH.sub.4Cl (20 mL) and
extracted with EtOAc (50 mL). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
crude residue was purified by silica gel chromatography (solvent
gradient: 0-10% EtOAc in petroleum ether) to give the title
compound (1.0 g, 17%) as yellow oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.35-7.25 (m, 5H), 4.05-3.91 (m, 1H), 3.86 (d,
J=13.6 Hz, 1H), 3.47-3.37 (m, 1H), 3.36 (d, J=13.6 Hz, 1H),
2.70-2.59 (m, 1H), 2.49-2.35 (m, 2H), 2.13-2.12 (m, 1H), 1.90-1.85
(m, 1H), 1.81-1.79 (m, 1H), 1.72-1.70 (m, 1H), 1.29-1.16 (m, 4H),
1.06 (t, J=7.2 Hz, 3H).
Step 4
##STR00312##
[0689] (1S,2S)-2-(ethylamino)cyclohexanol
[0690] To a solution of (1S,2S)-2-(benzyl(ethyl)amino)cyclohexanol
(1.0 g, 4.29 mmol) in EtOH (10 mL) and AcOH (0.1 mL) was added Pd/C
(10%) (0.2 g, 0.19 mmol). The mixture was heated to 40.degree. C.
for 16 h under hydrogen atmosphere (50 psi). The mixture was
filtered and concentrated in vacuo. The crude residue was purified
by silica gel chromatography (solvent gradient: 0-10% EtOAc in
petroleum ether) to give the title compound (0.5 g, 82%) as yellow
oil.
Step 5
##STR00313##
[0691] tert-butyl ethyl((1S,2S)-2-hydroxycyclohexyl)carbamate
[0692] To a solution of (1S,2S)-2-(ethylamino)cyclohexanol (0.5 g,
3.49 mmol) in DCM (15 mL) was added sodium bicarbonate (1.47 g,
17.45 mmol) in water (5 mL) and di-tert-butyl dicarbonate (914 mg,
4.19 mmol) slowly. The reaction mixture was stirred at room
temperature for 12 h. The organic layer was concentrated in vacuo.
The crude residue was purified by silica gel chromatography
(solvent gradient: 0-10% EtOAc in petroleum ether) to give the
title compound (0.3 g, 35%) as yellow oil.
Step 6
##STR00314##
[0693]
tert-butyl((1S,2S)-2-(2-cyclopropyl-4-(N-(2,4-dimethoxybenzyl)-N-(p-
yrimidin-4-yl)sulfamoyl)-5-fluorophenoxy)cyclohexyl)(ethyl)carbamate
[0694] To a solution of tert-butyl
ethyl((1S,2S)-2-hydroxycyclohexyl)carbamate (255 mg, 1.05 mmol) in
THF (5 mL) at 0.degree. C. was added sodium hydride (60%, 57 mg,
1.43 mmol). The mixture was stirred at 0.degree. C. for 0.5 h and
5-cyclopropyl-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benz-
enesulfonamide (0.44 g, 0.95 mmol) was added. The mixture was
stirred at room temperature for an additional 1 h. The mixture was
quenched with sat. aq. NH.sub.4Cl (3 mL) slowly at 0.degree. C. and
extracted with EtOAc (10 mL.times.2). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (petroleum ether/EtOAc=20:1) to give the title
compound (0.2 g, 31%) as colorless oil. LCMS (ESI) m/z: 685.1
[M+H].sup.+.
Step 7
##STR00315##
[0695]
5-cyclopropyl-4-(((1S,2S)-2-(ethylamino)cyclohexyl)oxy)-2-fluoro-N--
(pyrimidin-4-yl)benzenesulfonamide
[0696] A mixture of
tert-butyl((1S,2S)-2-(2-cyclopropyl-4-(N-(2,4-dimethoxybenzyl)-N-(pyrimid-
in-4-yl)sulfamoyl)-5-fluorophenoxy)cyclohexyl)(ethyl)carbamate (200
mg, 0.29 mmol) and formic acid (3 mL) was stirred at room
temperature for 1 h. The mixture was concentrated in vacuo. The
crude residue was purified by reverse phase chromatography
(acetonitrile 10-20%/0.225% formic acid in water) to give the title
compound (15 mg, 11%) as a white solid. LCMS (ESI) m/z: 435.3
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.25 (s,
1H), 7.91 (d, J=6.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.98 (d,
J=12.0 Hz, 1H), 6.54 (d, J=6.4 Hz, 1H), 4.51-4.37 (m, 1H),
3.24-3.23 (m, 3H), 3.03-3.01 (m, 1H), 2.13-2.01 (m, 3H), 1.73-1.61
(m, 2H), 1.40-1.21 (m, 4H), 1.16 (t, J=6.8 Hz, 3H), 0.90-0.80 (m,
2H), 0.55-0.45 (m, 2H).
Example 97
##STR00316##
[0697]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(oxetan-3-yl)amino)cyclohexy-
l)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0698] Following the procedure described in Example 39 and making
non-critical variations as required to replace tert-butyl
3-oxoazetidine-1-carboxylate with oxetan-3-one,
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(oxetan-3-yl)amino)cyclohexyl)amin-
o)-N-(thiazol-2-yl)benzenesulfonamide was obtained as a white
solid. LCMS (ESI) m/z: 475.1 [M+H].sup.+. H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.77 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.27
(d, J=4.8 Hz, 1H), 6.83 (d, J=4.8 Hz, 1H), 6.76 (d, J=12.8 Hz, 1H),
5.83 (d, J=5.2 Hz, 1H), 4.50-4.38 (m, 3H), 4.35-4.32 (m, 1H),
4.05-3.94 (m, 1H), 3.36-3.35 (m, 1H), 2.54-2.53 (m, 1H), 2.06 (s,
3H), 2.04-1.97 (m, 1H), 1.75-1.54 (m, 3H), 1.36-1.26 (m, 1H),
1.26-1.12 (m, 3H).
Example 98 & Example 99
##STR00317##
[0699]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1R,2R)-2-(pyrrolidi-
n-1-yl)cyclohexyl)amino)benzenesulfonamide &
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(pyrrolidin-1-yl-
)cyclohexyl)amino)benzenesulfonamide
##STR00318##
[0700] Step 1
##STR00319##
[0701] Racemic trans-2-(pyrrolidin-1-yl)cyclohexan-1-amine
[0702] The mixture of 7-azabicyclo[4.1.0]heptane (80 mg, 0.823
mmol), pyrrolidine (117 mg, 1.65 mmol) and NH.sub.4Cl (4.4 mg,
0.0823 mmol) in water (0.5 mL) in a sealed microwave tube was
heated at 105.degree. C. for 17 h. The mixture was cooled,
extracted with DCM (2.times.). The combined organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated to give crude racemic
trans-2-pyrrolidin-1-ylcyclohexanamine (100 mg, 72.2%) as a brown
oil.
[0703] This residue was dissolved in MeOH (2 mL), Boc.sub.2O (156
mg, 0.713 mmol) was then added. The mixture was stirred at room
temperature for 4 h, and then concentrated. The residue was
partitioned between EtOAc and 10% citric acid. The aq layer was
extracted with 10% citric acid one more time. The combined aq
layers were basified with sat. Na.sub.2CO.sub.3, extracted with
EtOAc (3.times.). The combined organics were dried
(Na.sub.2SO.sub.4), filtered and concentrated to a brown oil. LCMS
(ESI) m/z: 269 [M+H+]. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
5.21 (d, J=6.2 Hz, 1H), 3.38-3.22 (m, 1H), 2.71-2.46 (m, 4H),
2.45-2.26 (m, 2H), 1.82-1.53 (m, 7H), 1.49-1.41 (m, 9H), 1.37-0.99
(m, 4H).
[0704] This oil was dissolved in THF (3 mL). HCl (4 mol/L) in
1,4-dioxane (2.6 mL) was added. The mixture was stirred at room
temperature for 20 h, then concentrated and dried in high vacuum to
give a brown oil which was used in the next step without
purification.
Step 2
##STR00320##
[0705]
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(3-fluorophenyl)-4-(((1-
R,2R)-2-(pyrrolidin-1-yl)cyclohexyl)amino)benzenesulfonamide &
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(3-fluorophenyl)-4-(((1S,2S)--
2-(pyrrolidin-1-yl)cyclohexyl)amino)benzenesulfonamide
[0706] The mixture of
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-(6-fluoro-2-pyrid-
yl)benzenesulfonamide (180 mg, 0.381 mmol), racemic
trans-2-(pyrrolidin-1-yl)cyclohexan-1-amine, and K.sub.2CO.sub.3
(292 mg, 2.115 mmol) in DMF (2 mL) was stirred at room temperature
for 17 h. The mixture was partitioned between iPrOAc and water. The
aq layer was extracted with iPrOAc (2.times.). The combined
organics were dried (Na.sub.2SO.sub.4), filtered and concentrated.
The crude product was purified by chiral SFC to give
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(3-fluorophenyl)-4-(((1R,2R)--
2-(pyrrolidin-1-yl)cyclohexyl)amino)benzenesulfonamide (first peak,
57 mg, 23.9%) &
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(3-fluorophenyl)-4-(-
((1S,2S)-2-(pyrrolidin-1-yl)cyclohexyl)amino)benzenesulfonamide
(second peak, 81 mg, 34.3%) as white solids. Absolute configuration
was arbitrarily assigned to each enantiomer. LCMS (ESI) m/z: 621.2
[M+H].sup.+.
Step 3
##STR00321##
[0707]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1R,2R)-2-(pyrrolidi-
n-1-yl)cyclohexyl)amino)benzenesulfonamide
[0708] Following the procedure described in Example 1, Step 3 and
making non-critical variations as required to replace
tert-butyl((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-y-
l)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)carbamate with
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(3-fluorophenyl)-4-(((1R,2R)--
2-(pyrrolidin-1-yl)cyclohexyl)amino)benzenesulfonamide,
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1R,2R)-2-(pyrrolidin-1-yl-
)cyclohexyl)amino)benzenesulfonamide was obtained as a white solid.
Example 98: LCMS (ESI) m/z: 471.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.52 (s, 1H), 9.03 (s, 1H), 7.86 (q, J=8.2
Hz, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.03 (d, J=13.6 Hz, 1H), 6.89 (dd,
J=7.9, 2.0 Hz, 1H), 6.73 (dd, J=8.0, 2.4 Hz, 1H), 6.50-6.33 (m,
1H), 3.97-3.77 (m, 1H), 3.62 (t, J=11.1 Hz, 1H), 3.12-2.94 (m, 1H),
2.10 (s, 6H), 1.91-1.73 (m, 6H), 1.68-1.55 (m, 1H), 1.49-1.12 (m,
5H).
##STR00322##
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(pyrrolidin-1-yl-
)cyclohexyl)amino)benzenesulfonamide
[0709] Following the procedure described in Example 1, Step 3 and
making non-critical variations as required to replace
tert-butyl((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-y-
l)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)carbamate with
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(3-fluorophenyl)-4-(((1S,2S)--
2-(pyrrolidin-1-yl)cyclohexyl)amino)benzenesulfonamide,
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(pyrrolidin-1-yl-
)cyclohexyl)amino)benzenesulfonamide was obtained as a white solid.
Example 99: LCMS (ESI) m/z: 471.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 11.52 (s, 1H), 7.86 (q, J=8.2 Hz, 1H), 7.78
(d, J=7.5 Hz, 1H), 7.03 (d, J=13.6 Hz, 1H), 6.89 (dd, J=8.0, 2.1
Hz, 1H), 6.73 (dd, J=8.0, 2.4 Hz, 1H), 6.41 (d, J=10.0 Hz, 1H),
3.95-3.79 (m, 1H), 3.70-3.56 (m, 1H), 3.16-2.94 (m, 1H), 1.94-1.77
(m, 7H), 1.68-1.56 (m, 1H), 1.51-1.15 (m, 4H).
Example 100
##STR00323##
[0710]
5-cyclopropyl-4-(((1S,2S)-2-(ethylamino)cyclohexyl)amino)-2-fluoro--
N-(pyrimidin-4-yl)benzenesulfonamide
[0711] Following the procedure described in Example 29 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide and iodomethane with
5-cyclopropyl-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benz-
enesulfonamide and iodoethane, the title compound was obtained as a
white solid. LCMS (ESI) m/z: 434.2 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.31 (s, 1H), 7.94 (d, J=6.0 Hz, 1H),
7.29 (d, J=8.4 Hz, 1H), 6.62 (d, J=5.6 Hz, 1H), 6.48 (d, J=13.6 Hz,
1H), 5.43 (d, J=9.2 Hz, 1H), 3.23-3.20 (m, 1H), 3.06-2.85 (m, 2H),
2.64-2.57 (m, 1H), 2.19-2.09 (m, 1H), 2.00-1.90 (m, 1H), 1.80-1.70
(m, 1H), 1.67-1.55 (m, 2H), 1.45-1.32 (m, 2H), 1.30-1.21 (m, 2H),
1.15 (t, J=7.2 Hz, 3H), 0.94-0.78 (m, 2H), 0.59-0.45 (m, 1H),
0.37-0.23 (m, 1H).
Example 101
##STR00324##
[0712]
5-chloro-2-fluoro-4-(((1S,2S)-2-morpholinocyclohexyl)amino)-N-(thia-
zol-2-yl)benzenesulfonamide
[0713] Following the procedure described in Example 70 and making
non-critical variations as required to replace piperidine with
morpholine,
5-chloro-2-fluoro-4-(((1S,2S)-2-morpholinocyclohexyl)amino)-N-(thiazol-2--
yl)benzenesulfonamide was obtained as a white solid. LCMS (ESI)
m/z: 475.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.60 (d, J=7.2 Hz, 1H), 7.23 (d, J=4.4 Hz, 1H), 6.79 (d, J=4.4 Hz,
1H), 6.70 (d, J=12.8 Hz, 1H), 5.95 (s, 1H), 3.45-3.40 (m, 4H),
3.28-3.27 (m, 1H), 2.62-2.57 (m, 1H), 2.45-2.27 (m, 4H), 2.20-2.10
(m, 1H), 1.90-1.85 (m, 1H), 1.80-1.70 (m, 1H), 1.65-1.55 (m, 1H),
1.40-1.30 (m, 1H), 1.28-1.09 (m, 3H).
Example 102
##STR00325##
[0714]
5-chloro-4-(((1S,2S)-2-(ethyl(methyl)amino)cyclohexyl)amino)-2-fluo-
ro-N-(4-methylthiazol-2-yl)benzenesulfonamide formate
Step 1
##STR00326##
[0715]
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamin-
o)cyclohexyl)amino)-N-(4-methylthiazol-2-yl)benzenesulfonamide
[0716] Following the procedure described in Example 29 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(4-methylthiazol-2-yl)ben-
zenesulfonamide,
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cycl-
ohexyl)amino)-N-(4-methylthiazol-2-yl)benzenesulfonamide was
obtained as a white solid.
Step 2
##STR00327##
[0717]
5-chloro-4-(((1S,2S)-2-(ethyl(methyl)amino)cyclohexyl)amino)-2-fluo-
ro-N-(4-methylthiazol-2-yl)benzenesulfonamide Formate
[0718] Following the procedure described in Example 58 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide and tert-butyl
N-methyl-N-(2-oxoethyl)carbamate with
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cycl-
ohexyl)amino)-N-(4-methylthiazol-2-yl)benzenesulfonamide and
acetaldehyde,
5-chloro-4-(((1S,2S)-2-(ethyl(methyl)amino)cyclohexyl)amino)-2-fluoro-N-(-
4-methylthiazol-2-yl)benzenesulfonamide formate was obtained as a
white solid. LCMS (ESI) m/z: 461.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.15 (s, 1H), 7.58 (d, J=7.2 Hz, 1H),
6.72 (d, J=13.2 Hz, 1H), 6.35 (d, J=0.8 Hz, 1H), 5.92 (d, J=3.6 Hz,
1H), 3.28-3.27 (m, 1H), 2.69-2.64 (m, 1H), 2.45-2.41 (m, 2H), 2.14
(s, 3H), 2.08 (s, 3H), 1.87-1.72 (m, 2H), 1.65-1.56 (m, 1H),
1.43-1.33 (m, 1H), 1.29-1.08 (m, 4H), 0.96 (t, J=7.2 Hz, 3H).
Example 104
##STR00328##
[0719]
5-chloro-2-fluoro-4-(((1S,2S)-2-(3-fluoropyrrolidin-1-yl)cyclohexyl-
)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0720] Following the procedure described in Example 70 and making
non-critical variations as required to replace piperidine with
3-fluoropyrrolidine,
5-chloro-2-fluoro-4-(((1S,2S)-2-(3-fluoropyrrolidin-1-yl)cyclohexyl)amino-
)-N-(thiazol-2-yl)benzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 477.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.57 (d, J=6.8 Hz, 1H), 7.24 (d, J=4.0 Hz,
1H), 6.79 (d, J=4.0 Hz, 1H), 6.72 (d, J=12.8 Hz, 1H), 5.84 (s, 1H),
5.24-4.92 (m, 1H), 3.28-3.27 (m, 1H), 2.95-2.85 (m, 1H), 2.82-2.68
(m, 4H), 2.13-2.05 (m, 1H), 1.80-1.40 (m, 4H), 1.65-1.55 (m, 1H),
1.45-1.35 (m, 1H), 1.31-1.14 (m, 3H).
Example 105 & Example 106
##STR00329##
[0721]
4-(((1S,2S)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-ch-
loro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide &
4-(((1R,2R)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-chloro-2-
-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide
[0722] Following the procedure described in Example 98 &
Example 99 and making non-critical variations as required to
replace pyrrolidine with 3-azabicyclo[3.1.0]hexane, the title
compounds were obtained as a white solid. The stereochemistry was
assigned arbitrarily to each enantiomer. Example 105: LCMS (ESI)
m/z: 483.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.40 (s, 1H), 7.83 (q, J=8.2 Hz, 1H), 7.73 (d, J=7.4 Hz, 1H), 6.88
(dd, J=7.9, 2.1 Hz, 1H), 6.78-6.63 (m, 2H), 5.86 (d, J=5.3 Hz, 1H),
3.28-3.05 (m, 1H), 2.89-2.62 (m, 3H), 2.42-2.29 (m, 1H), 1.88-1.66
(m, 1H), 1.67-1.53 (m, 1H), 1.51-0.99 (m, 6H), 0.37 (q, J=3.8 Hz,
1H), 0.24-0.10 (m, 1H). Example 106: LCMS (ESI) m/z: 483.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.40 (s, 1H),
7.83 (q, J=8.2 Hz, 1H), 7.73 (d, J=7.4 Hz, 1H), 6.88 (dd, J=7.9,
2.1 Hz, 1H), 6.78-6.63 (m, 2H), 5.86 (d, J=5.3 Hz, 1H), 3.28-3.05
(m, 1H), 2.89-2.62 (m, 3H), 2.42-2.29 (m, 1H), 1.88-1.66 (m, 1H),
1.67-1.53 (m, 1H), 1.51-0.99 (m, 6H), 0.37 (q, J=3.8 Hz, 1H),
0.24-0.10 (m, 1H).
Example 107
##STR00330##
[0723]
5-cyclopropyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluo-
ro-N-(6-fluoropyridin-2-yl)benzenesulfonamide Formate
[0724] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S)-2-(dimethylamino)cycl-
ohexyl]amino]-2-fluoro-N-thiazol-2-yl-benzenesulfonamide with
5-chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(6-flu-
oropyridin-2-yl)-N-(methoxymethyl)benzenesulfonamide,
5-cyclopropyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)amino)-2-fluoro-N-(-
6-fluoropyridin-2-yl)benzenesulfonamide formate was obtained as a
white solid. LCMS (ESI) m/z: 451.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.17 (s, 1H), 7.80-7.72 (m, 1H), 7.42
(d, J=8.4 Hz, 1H), 6.84-6.77 (m, 1H), 6.63-6.59 (m, 1H), 6.47 (d,
J=14.0 Hz, 1H), 6.09 (s, 1H), 3.25-3.14 (m, 1H), 2.69-2.57 (m, 1H),
2.20 (s, 3H), 2.20 (s, 3H), 2.18-2.12 (m, 1H), 1.88-1.73 (m, 2H),
1.67-1.50 (m, 2H), 1.45-1.31 (m, 1H), 1.27-1.06 (m, 3H), 0.95-0.86
(m, 2H), 0.65-0.56 (m, 1H), 0.32-0.23 (m, 1H).
Example 108
##STR00331##
[0725]
5-chloro-2-fluoro-4-(((1S,2S)-2-(piperidin-1-yl)cyclohexyl)amino)-N-
-(pyrimidin-4-yl)benzenesulfonamide
[0726] Following the procedure described in Example 70 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
5-chloro-2-fluoro-4-(((1S,2S)-2-(piperidin-1-yl)cyclohexyl)amin-
o)-N-(pyrimidin-4-yl)benzenesulfonamide was obtained as a white
solid. LCMS (ESI) m/z: 468.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.53 (s, 1H), 8.24 (s, 1H), 7.71 (d, J=6.8
Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 6.75 (d, J=12.8 Hz, 1H), 6.04 (s,
1H), 3.38-3.35 (m, 1H), 2.74-2.66 (m, 1H), 2.64-2.55 (m, 2H),
2.47-2.44 (m, 2H), 2.15-2.05 (m, 1H), 1.95-1.85 (m, 1H), 1.80-1.70
(m, 1H), 1.65-1.55 (m, 1H), 1.52-1.14 (m, 10H).
Example 109
##STR00332##
[0727]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(methyl(1--
methylpiperidin-4-yl)amino)cyclohexyl)amino)benzenesulfonamide
[0728] Following the procedure described in Example 55 and making
non-critical variations as required to replace tert-butyl
3-oxoazetidine-1-carboxylate with 1-methylpiperidin-4-one,
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(methyl(1-methyl-
piperidin-4-yl)amino)cyclohexyl)amino)benzenesulfonamide was
obtained as a white solid. LCMS (ESI) m/z: 528.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.76-7.54 (m, 2H), 6.71
(dd, J=8.0, 2.3 Hz, 1H), 6.64 (d, J=13.1 Hz, 1H), 6.43 (d, J=7.9
Hz, 1H), 5.75 (d, J=4.8 Hz, 1H), 2.99-2.80 (m, 2H), 2.73-2.63 (m,
1H), 2.47-2.36 (m, 1H), 2.35-2.31 (m, 1H), 2.30 (s, 3H), 2.25-2.09
(m, 3H), 2.07 (s, 3H), 1.81-1.67 (m, 3H), 1.66-1.12 (m, 7H).
Example 110
##STR00333##
[0729]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(methyl(pi-
peridin-4-yl)amino)cyclohexyl)amino)benzenesulfonamide
[0730] Following the procedure described in Example 55 and making
non-critical variations as required to replace tert-butyl
3-oxoazetidine-1-carboxylate with tert-butyl
4-oxopiperidine-1-carboxylate,
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(methyl(piperidi-
n-4-yl)amino)cyclohexyl)amino)benzenesulfonamide was obtained as a
white solid. LCMS (ESI) m/z: 528.1 [M+H].sup.+. H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.61 (d, J=7.2 Hz, 1H), 7.39 (q, J=8.4 Hz,
1H), 6.61-6.46 (m, 2H), 6.09 (dd, J=7.8, 3.0 Hz, 1H), 5.51 (d,
J=4.1 Hz, 1H), 3.25-3.13 (m, 3H), 2.91-2.74 (m, 2H), 2.74-2.58 (m,
2H), 2.24-2.13 (m, 1H), 2.08 (s, 3H), 1.91-1.81 (m, 1H), 1.79-1.53
(m, 6H), 1.46-1.05 (m, 4H).
Example 111
##STR00334##
[0731]
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino)cycl-
ohexyl)amino)-N-(4-methylthiazol-2-yl)benzenesulfonamide
[0732] Following the procedure described in Example 29 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide and iodopropane with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(4-methylthiazol-2-yl)ben-
zenesulfonamide and 2-bromoethanol,
5-chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxyethyl)(methyl)amino)cyclohexyl-
)amino)-N-(4-methylthiazol-2-yl)benzenesulfonamide was obtained as
a white solid. LCMS (ESI) m/z: 477.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.57 (d, J=7.2 Hz, 1H), 6.70 (d, J=12.8
Hz, 1H), 6.36 (s, 1H), 5.96 (d, J=4.0 Hz, 1H), 4.35-4.25 (m, 1H),
3.28-3.19 (m, 3H), 2.59-2.54 (m, 2H), 2.45-2.37 (m, 2H), 2.17 (s,
3H), 2.08 (s, 3H), 1.83-1.74 (m, 2H), 1.64-1.56 (m, 1H), 1.41-1.34
(m, 1H), 1.28-1.21 (m, 2H), 1.17-1.05 (m, 1H).
Example 112
##STR00335##
[0733]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00336##
[0734] Step 1
##STR00337##
[0735]
tert-butyl((1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex-3--
en-1-yl)carbamate
[0736] To a solution of
tert-butyl((1S,6S)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e (500 mg, 1.78 mmol) in MeOH (10 mL) was added AcOH (0.2 mL, 3.57
mmol) and paraformaldehyde (268 mg, 8.92 mmol). The mixture was
stirred at room temperature for 10 min and sodium cyanoborohydride
(560 mg, 8.92 mmol) was added. The mixture was stirred at room
temperature for an additional 16 h. The reaction was quenched with
sat. aq. NaHCO.sub.3 (10 mL) and extracted with DCM (20
mL.times.3). The combined organic layer were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (solvent
gradient: 0-100% EtOAc (0.5% TEA) in petroleum ether) to give the
title compound (230 mg, 42%) as a light yellow solid.
Step 2
##STR00338##
[0737]
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohex-
yl)carbamate
[0738] To a solution of
tert-butyl((1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex-3-en-1-y-
l)carbamate (230 mg, 0.75 mmol) in EtOAc (20 mL) was added
Pd(OH).sub.2 (20%, 524 mg, 0.75 mmol). The mixture was stirred at
room temperature for 2 h under hydrogen atmosphere (15 psi). The
mixture was filtered and concentrated in vacuo. The crude residue
was purified by Prep-TLC (petroleum ether/EtOAc=3:1) to give the
title compound (200 mg, 86%) as colorless oil. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 5.31 (s, 1H), 4.28-3.14 (m, 1H), 2.69-2.56
(m, 1H), 2.37-2.30 (m, 1H), 2.25 (s, 3H), 2.25 (s, 3H), 2.05-2.00
(m, 1H), 1.94-1.87 (m, 1H), 1.49-1.40 (m, 1H), 1.46 (s, 9H),
1.40-1.34 (m, 1H), 1.29-1.22 (m, 1H), 1.18-1.06 (m, 1H).
Step 3
##STR00339##
[0739]
(1S,2S,5S)--N.sup.1,N.sup.1-dimethyl-5-(trifluoromethyl)cyclohexane-
-1,2-diamine
[0740] To a solution of
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)car-
bamate (100 mg, 0.32 mmol) in DCM (1 mL) was added trifluoroacetic
acid (0.48 mL, 6.44 mmol). The mixture was stirred at room
temperature for 2 h and concentrated in vacuo to give the title
compound (67 mg, crude) as light yellow oil that required no
further purification.
Step 4
##STR00340##
[0741]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-
-(trifluoromethyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulf-
onamide
[0742] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide (436 mg, 0.96 mmol) and N,N-diisopropylethylamine (0.53
mL, 3.19 mmol) in DMF (5 mL) was added
(1S,2S,5S)--N.sup.1,N.sup.1-dimethyl-5-(trifluoromethyl)cyclohexane-1,2-d-
iamine (67 mg, 0.32 mmol). The reaction mixture was stirred at room
temperature for 16 h and concentrated in vacuo. The crude residue
was purified by silica gel chromatography (solvent gradient:
0-10%-25% EtOAc (1% TEA) in petroleum ether) to give the title
compound (120 mg, 58%) as a light yellow solid. LCMS (ESI) m/z:
646.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.80
(s, 1H), 8.45 (d, J=6.0 Hz, 1H), 7.88 (d, J=7.2 Hz, 1H), 7.31 (d,
J=6.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 6.44-6.36 (m, 2H), 6.25 (d,
J=12.4 Hz, 1H), 5.97 (s, 1H), 5.27 (s, 2H), 3.81 (s, 3H), 3.77 (s,
3H), 3.05-2.98 (m, 1H), 2.65-2.55 (m, 1H), 2.46-2.35 (m, 1H),
2.30-2.10 (m, 4H), 2.25 (s, 3H), 2.05-1.95 (m, 1H), 1.52-1.41 (m,
1H), 1.38-1.28 (m, 1H), 1.25-1.16 (m, 1H).
Step 5
##STR00341##
[0743]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluromethyl)cyclohe-
xyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0744] A mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trif-
luoromethyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamid-
e (120 mg, 0.19 mmol) and formic acid (5.0 mL) was stirred at room
temperature for 1 h. The reaction mixture was concentrated in
vacuo. The crude residue was purified by reverse phase
chromatography (acetonitrile 5-35%/0.225% formic acid in water) to
give the title compound (50 mg, 54%) as a white solid. LCMS (ESI)
m/z: 496.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.51 (s, 1H), 8.20 (d, J=6.0 Hz, 1H), 7.68 (d, J=7.2 Hz, 1H),
6.92-6.76 (m, 2H), 5.95 (d, J=6.4 Hz, 1H), 3.67-3.53 (m, 1H),
3.15-3.00 (m, 1H), 2.45-2.39 (m, 1H), 2.34 (s, 3H), 2.34 (s, 3H),
2.15-2.02 (m, 2H), 1.85-1.73 (m, 1H), 1.59-1.45 (m, 1H), 1.43-1.20
(m, 2H).
Example 113
##STR00342##
[0745]
5-chloro-2-fluoro-4-(((1S,2S)-2-(4-fluoropiperidin-1-yl)cyclohexyl)-
amino)-N-(thiazol-2-yl)benzenesulfonamide
[0746] Following the procedure described in Example 70 and making
non-critical variations as required to replace piperidine with
4-fluoropiperidine,
5-chloro-2-fluoro-4-(((1S,2S)-2-(4-fluoropiperidin-1-yl)cyclohexyl)amino)-
-N-(thiazol-2-yl)benzenesulfonamide was obtained as a white solid.
LCMS (ESI) m/z: 490.9 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.56 (d, J=7.2 Hz, 1H), 7.15 (s, 1H),
6.77-6.57 (m, 2H), 5.87 (d, J=3.2 Hz, 1H), 4.61-4.47 (m, 1H),
3.11-3.03 (m, 1H), 2.67-2.50 (m, 3H), 2.44-2.34 (m, 2H), 2.27-2.18
(m, 1H), 2.15-2.08 (m, 1H), 1.80-1.68 (m, 2H), 1.63-1.52 (m, 3H),
1.50-1.41 (m, 1H), 1.39-1.27 (m, 1H), 1.20-1.10 (m, 3H).
Example 114
##STR00343##
[0747]
5-Cyclopropyl-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)oxy)-2-fluoro-
-N-(6-fluoropyridin-2-yl)benzenesulfonamide Formate
[0748] Following the procedure described in Example 66 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide and tert-butyl
3-(((1S,2S)-2-hydroxycyclohexyl)(methyl)amino)azetidine-1-carboxylate
with
N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)-5-(cyclopropyl-
)benzenesulfonamide and (1S,2S)-2-(dimethylamino)cyclohexanol, the
title compound was obtained as a white solid. LCMS (ESI) m/z: 452.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
11.94-10.89 (m, 1H), 8.14 (s, 1H), 7.72 (s, 1H), 7.30 (d, J=8.4 Hz,
1H), 7.13 (d, J=12.6 Hz, 1H), 6.80-6.70 (m, 1H), 6.62-6.46 (m, 1H),
4.70-4.48 (m, 1H), 2.38-2.19 (m, 7H), 2.18-1.94 (m, 2H), 1.89-1.74
(m, 1H), 1.73-1.52 (m, 2H), 1.45-1.14 (m, 4H), 1.00-0.80 (m, 2H),
0.71-0.51 (m, 2H).
Example 115
##STR00344##
[0749]
5-Chloro-4-(((1S,2S)-2-(cyclobutyl(methyl)amino)cyclohexyl)amino)-2-
-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0750] Following the procedure described in Example 18 and making
non-critical variations as required to replace acetaldehyde with
cyclobutanone, the title compound was obtained as a white solid.
LCMS (ESI) m/z: 473.0, 474.9 [M+H].sup.+. .sup.1H NMR (400 MHz,
dmso) .delta. 12.89-12.18 (m, 2H), 8.14 (s, 1H), 7.59 (d, J=7.3 Hz,
1H), 7.20 (d, J=4.0 Hz, 1H), 6.74 (d, J=3.8 Hz, 1H), 6.69 (d,
J=12.8 Hz, 1H), 5.82 (d, J=3.5 Hz, 1H), 3.25-3.09 (m, 2H), 2.17 (d,
J=10.4 Hz, 1H), 2.00-1.87 (m, 5H), 1.80-1.65 (m, 4H), 1.65-1.48 (m,
4H), 1.44-1.30 (m, 1H), 1.29-1.17 (m, 2H), 1.17-1.05 (m, 1H).
Example 116
##STR00345##
[0751]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-methylpropyl)(methyl)-
amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
formate
##STR00346##
[0752] Step 1
##STR00347##
[0753]
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-
-2-methylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesul-
fonamide
[0754] To a mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (150 mg, 0.26
mmol) and lithium perchlorate (280 mg, 2.64 mmol), in THF (1 mL),
was added a solution of 1,2-Epoxy-2-methylpropane (28 mg, 0.40
mmol), in Et.sub.2O (0.5 mL). After 16 h at rt, a further portion
of 1,2-Epoxy-2-methylpropane (28 mg, 0.40 mmol) was added and after
40 h at rt the mixture was diluted with EtOAc (50 mL) and washed
with H.sub.2O (10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The crude material was purified by flash
chromatrography through Si gel (0-100% EtOAc/CH.sub.2Cl.sub.2) to
provide
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-met-
hylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonami-
de (68 mg, 41%). LCMS (ESI) m/z: 641.1 (M+H).sup.+.
Step 2
##STR00348##
[0755]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-methylpropyl)(methyl)-
amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
Formate
[0756]
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-
-2-methylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesul-
fonamide (68 mg, 0.11 mmol) was treated with 95% formic acid (2
mL), sonicated for 1 min and stirred 1 h at rt. The volatiles were
evaporated in vacuo and the residue was purified by C18 reverse
phase flash chromatography (0-40% MeCN/10 mM aqueous
NH.sub.4CO.sub.2H, pH=3.8). Appropriate fractions were combined and
lyophilized to provide
5-Chloro-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-methylpropyl)(methyl)amino)-
cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate (23
mg, 39%). LCMS (ESI) m/z: 490.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
d6-dmso) .delta. 12.74 (s, 1H), 8.14 (s, 1H), 7.56 (d, J=7.3 Hz,
1H), 7.21 (d, J=4.4 Hz, 1H), 6.76 (d, J=4.3 Hz, 1H), 6.65 (d,
J=13.0 Hz, 1H), 6.12 (d, J=2.3 Hz, 1H), 4.15 (s, 1H), 3.27-3.15 (m,
1H), 2.62 (t, J=11.5 Hz, 1H), 2.40 (d, J=13.7 Hz, 1H), 2.22 (d,
J=13.7 Hz, 1H), 2.16 (s, 3H), 2.15-2.11 (m, 1H), 1.76 (t, J=10.5
Hz, 2H), 1.58 (d, J=13.0 Hz, 1H), 1.46-1.11 (m, 4H), 1.05 (s, 3H),
1.03 (s, 3H).
Example 117 & Example 123
##STR00349##
[0757]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1R,2R)-2-(piperidin-
-1-yl)cyclohexyl)amino)benzenesulfonamide &
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-(piperidin-1-yl)-
cyclohexyl)amino)benzenesulfonamide
[0758] Following the procedure described in Example 98 &
Example 99 and making non-critical variations as required to
replace pyrrolidine with piperidine, the title compounds were
obtained as a white solid. Example 117: LCMS (ESI) m/z: 485.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.37 (s,
1H), 7.80 (q, J=8.2 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 6.85 (dd,
J=7.9, 2.2 Hz, 1H), 6.73 (d, J=13.3 Hz, 1H), 6.66 (d, J=8.1 Hz,
1H), 6.10 (d, J=4.5 Hz, 1H), 3.39-3.32 (m, 1H), 3.29-3.21 (m, 1H),
2.47-2.39 (m, 1H), 2.37-2.24 (m, 2H), 2.19-2.08 (m, 1H), 1.88-1.68
(m, 2H), 1.66-1.55 (m, 1H), 1.45-1.09 (m, 10H). Example 123: LCMS
(ESI) m/z: 485.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 11.37 (s, 1H), 7.81 (q, J=8.2 Hz, 1H), 7.74 (d, J=7.4 Hz,
1H), 6.86 (dd, J=8.0, 2.1 Hz, 1H), 6.70 (dd, J=25.2, 10.6 Hz, 2H),
6.10 (d, J=4.9 Hz, 1H), 3.29-3.18 (m, 1H), 2.40-2.18 (m, 1H),
2.19-2.05 (m, 1H), 1.91-1.67 (m, 2H), 1.68-1.55 (m, 1H), 1.47-1.08
(m, 11H).
Example 118
##STR00350##
[0759]
5-Chloro-2-fluoro-4-(((1S,2S)-2-(((S)-3-fluoro-2-hydroxypropyl)(met-
hyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0760] Following the procedure described in Example 116 and making
non-critical variations required to replace
1,2-Epoxy-2-methylpropane with epifluorohydrin, the title compound
was obtained as a mixture of disatereomers. Separation of isomers
by HPLC provided the title compound. The stereochemistry of the
alcohol stereocenter was assigned arbitrarily. LCMS (ESI) m/z:
495.0 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 12.69 (s,
1H), 7.58 (d, J=7.3 Hz, 1H), 7.27 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6
Hz, 1H), 6.75 (d, J=13.1 Hz, 1H), 5.88 (d, J=5.3 Hz, 1H), 4.99 (s,
1H), 4.41 (ddd, J=26.3, 9.5, 4.2 Hz, 1H), 4.29 (ddd, J=26.4, 9.5,
4.3 Hz, 1H), 3.87-3.67 (m, 1H), 2.86-2.53 (m, 3H), 2.17 (s, 3H),
2.08 (d, J=12.5 Hz, 1H), 1.77 (dd, J=17.5, 10.9 Hz, 2H), 1.59 (d,
J=13.0 Hz, 1H), 1.46-1.04 (m, 5H).
Example 119
##STR00351##
[0761]
5-Chloro-2-fluoro-4-(((1S,2S)-2-(((R)-3-fluoro-2-hydroxypropyl)(met-
hyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0762] Following the procedure described in Example 116 and making
non-critical variations required to replace
1,2-Epoxy-2-methylpropane with epifluorohydrin, the title compound
was obtained as a mixture of disatereomers. Separation of isomers
by HPLC provided the title compound. The stereochemistry of the
alcohol stereocenter was assigned arbitrarily. LCMS (ESI) m/z:
495.0 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 12.69 (s,
1H), 7.57 (d, J=7.3 Hz, 1H), 7.22 (d, J=4.5 Hz, 1H), 6.77 (d, J=4.5
Hz, 1H), 6.69 (d, J=13.0 Hz, 1H), 5.78 (d, J=4.9 Hz, 1H), 4.85 (s,
1H), 4.30 (ddd, J=48.0, 9.4, 2.7 Hz, 1H), 4.09 (ddd, J=48.2, 9.5,
5.5 Hz, 1H), 3.65-3.55 (m, 1H), 2.59 (t, J=9.2 Hz, 1H), 2.41 (dd,
J=12.9, 7.9 Hz, 1H), 2.34 (dd, J=10.1, 2.5 Hz, 1H), 2.17 (s, 3H),
2.08 (dd, J=11.5, 5.7 Hz, 1H), 1.81 (d, J=9.7 Hz, 1H), 1.74 (d,
J=9.8 Hz, 1H), 1.59 (d, J=12.1 Hz, 1H), 1.43-1.05 (m, 5H).
Example 120 & Example 121
##STR00352##
[0763]
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
&
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0764] Following the procedure described in Example 88 and making
non-critical variations as required to replace
(trans)-tert-butyl(3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'--
biphenyl]-4-yl)carbamate and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
tert-butyl((3S,4S)-3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'--
biphenyl]-4-yl)carbamate and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(3-(trifluoromethyl-
)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
(first peak on HPLC) and
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
(second peak on HPLC) were obtained both as white solid. Example
120: LCMS (ESI) m/z: 572.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.40 (s, 1H), 8.13 (s, 1H), 8.09 (d, J=5.6
Hz, 1H), 7.70-7.66 (m, 3H), 7.60-7.58 (m, 2H), 6.72 (d, J=5.6 Hz,
1H), 6.38 (d, J=12.0 Hz, 1H), 5.69 (d, J=6.8 Hz, 1H), 3.60-3.58 (m,
1H), 3.17-3.16 (m, 1H), 2.73-2.71 (m, 1H), 2.35-2.34 (m, 1H), 2.34
(s, 3H), 2.34 (s, 3H), 2.09-2.06 (m, 1H), 1.81-1.68 (m, 4H).
Example 119: LCMS (ESI) m/z: 572.3 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.40 (s, 1H), 8.14 (s, 1H), 8.07 (d,
J=6.0 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.54-7.53 (m, 4H), 6.88 (d,
J=12.8 Hz, 1H), 6.72 (d, J=6.0 Hz, 1H), 5.90 (d, J=7.2 Hz, 1H),
3.76-3.73 (m, 1H), 2.95-2.94 (m, 1H), 2.44 (s, 3H), 2.44 (s, 3H),
2.39-2.28 (m, 1H), 2.17-2.13 (m, 1H), 2.05-2.04 (m, 1H), 2.00-1.98
(m, 1H), 1.58-1.50 (m, 3H).
Example 122
##STR00353##
[0765]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-((3-hydrox-
ypropyl)(methyl)amino)cyclohexyl)amino)benzenesulfonamide
[0766] Following the procedure described in Example 72 and making
non-critical variations as required to replace 2-bromoethanol with
3-iodopropanol,
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-((3-hydroxypropy-
l)(methyl)amino)cyclohexyl)amino)benzenesulfonamide was obtained as
a white solid. LCMS (ESI) m/z: 489.1 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 7.84-7.74 (m, 1H), 7.72 (d, J=7.4 Hz,
1H), 6.83 (d, J=7.9 Hz, 1H), 6.74 (d, J=13.2 Hz, 1H), 6.69-6.54 (m,
1H), 6.00 (s, 1H), 3.48-3.33 (m, 4H), 3.29-3.22 (m, 1H), 2.20-2.08
(m, 4H), 1.89-1.69 (m, 2H), 1.67-1.44 (m, 3H), 1.44-1.06 (m,
4H).
Example 124
##STR00354##
[0767]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-((3-hydrox-
y-3-methylbutyl)(methyl)amino)cyclohexyl)amino)benzenesulfonamide
[0768] Following the procedure described in Example 72 and making
non-critical variations as required to replace 2-bromoethanol with
4-iodo-2-methylbutan-2-ol,
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-((3-hydroxy-3-me-
thylbutyl)(methyl)amino)cyclohexyl)-amino)benzenesulfonamide was
obtained as a white solid. LCMS (ESI) m/z: 517.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.67 (t, J=6.9 Hz, 2H),
6.78-6.63 (m, 2H), 6.61-6.39 (m, 3H), 5.90 (s, 1H), 2.74-2.69 (m,
1H), 2.48-2.41 (m, 2H), 2.15 (s, 3H), 2.11-2.02 (m, 1H), 1.90-1.69
(m, 2H), 1.67-1.47 (m, 2H), 1.45-1.09 (m, 6H), 0.97 (s, 6H).
Example 125
##STR00355##
[0769]
5-Chloro-4-(((1S,2S)-2-((2-cyanoethyl)(methyl)amino)cyclohexyl)amin-
o)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0770] Following the procedure described in Example 29 and making
non-critical variations as required to replace the iodopropane with
acrylonitrile, the title compound was obtained as a white solid.
LCMS (ESI) m/z: 471.9 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO)
.delta. 12.61 (s, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.24 (d, J=4.6 Hz,
1H), 6.79 (d, J=4.6 Hz, 1H), 6.70 (d, J=13.1 Hz, 1H), 5.82 (d,
J=4.2 Hz, 1H), 3.32-3.28 (m, 1H), 2.73-2.59 (m, 3H), 2.59-2.51 (m,
2H), 2.09 (s, 3H), 2.09-2.04 (m, J=2.9 Hz, 1H), 1.79-1.67 (m, 2H),
1.58 (d, J=12.8 Hz, 1H), 1.40-1.04 (m, 4H).
Example 126
##STR00356##
[0771]
5-Chloro-4-(((1S,2S)-2-(((S)-3,3-difluoro-2-hydroxypropyl)(methyl)a-
mino)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0772] Following the procedure described in Example 116 and making
non-critical variations required to replace
1,2-Epoxy-2-methylpropane with 2-(difluoromethyl)oxirane, the title
compound was obtained as a mixture of disatereomers. Separation of
isomers by HPLC provided the title compound. The stereochemistry of
the alcohol stereocenter was assigned arbitrarily. LCMS (ESI) m/z:
513.1 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 12.52 (br
s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.23 (d, J=4.4 Hz, 1H), 6.78 (d,
J=4.4 Hz, 1H), 6.70 (d, J=13.0 Hz, 1H), 6.01-5.64 (m, 2H),
3.76-3.61 (m, 1H), 2.68-2.58 (m, 1H), 2.58-2.53 (m, 2H), 2.14 (s,
3H), 2.09 (d, J=11.4 Hz, 1H), 1.76 (t, J=11.6 Hz, 2H), 1.59 (d,
J=12.3 Hz, 1H), 1.43-1.00 (m, 4H). 2 H not visible (under the HOD
signal).
Example 127
##STR00357##
[0773]
5-Chloro-4-(((1S,2S)-2-(((R)-3,3-difluoro-2-hydroxypropyl)(methyl)a-
mino)-cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0774] Following the procedure described in Example 116 and making
non-critical variations required to replace
1,2-Epoxy-2-methylpropane with 2-(difluoromethyl)oxirane, the title
compound was obtained as a mixture of disatereomers. Separation of
isomers by HPLC provided the title compound. The stereochemistry of
the alcohol stereocenter was assigned arbitrarily. LCMS (ESI) m/z:
513.2 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 12.69 (br
s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.24 (d, J=4.5 Hz, 1H), 6.79 (d,
J=4.5 Hz, 1H), 6.70 (d, J=13.1 Hz, 1H), 5.86 (d, J=4.6 Hz, 1H),
5.75 (td, J=55.6, 2.5 Hz, 1H), 5.31 (br s, 1H), 3.77-3.64 (m, 1H),
2.63 (td, J=10.8, 2.9 Hz, 1H), 2.55 (dd, J=13.1, 6.5 Hz, 1H), 2.45
(dd, J=13.0, 6.8 Hz, 1H), 2.16 (s, 3H), 2.07 (d, J=10.7 Hz, 1H),
1.80 (d, J=10.6 Hz, 1H), 1.74 (d, J=9.2 Hz, 1H), 1.59 (d, J=12.8
Hz, 1H), 1.40-1.29 (m, 1H), 1.28-1.19 (m, 2H), 1.18-1.06 (m, 1H). 1
H under HOD signal.
Example 128
##STR00358##
[0775]
5-Cyclopropyl-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S)-2-((2-h-
ydroxyethyl)(methyl)amino)cyclohexyl)amino)benzenesulfonamide
Formate
[0776] Following the procedure described in Example 72 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine-2-yl)be-
nzenesulfonamide with
5-(cyclopropyl)-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridine--
2-yl)benzenesulfonamide, the title compound was obtained as a white
solid. LCMS (ESI) m/z: 481.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) .delta. 11.27 (br. s, 1H), 8.14 (s, 1H), 7.97-7.61 (m,
1H), 7.40 (d, J=8.3 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.70-6.57 (m,
1H), 6.43 (d, J=13.7 Hz, 1H), 6.13 (s, 1H), 4.46-4.27 (m, 1H),
3.48-3.39 (m, 3H), 3.22-3.10 (m, 1H), 2.19 (dd, J=21.2, 11.1 Hz,
1H), 2.10 (s, 3H), 1.87-1.71 (m, 2H), 1.67-1.48 (m, 3H), 1.47-1.15
(m, 4H), 1.08 (dd, J=23.3, 10.3 Hz, 1H), 0.99-0.82 (m, 2H),
0.67-0.52 (m, 1H), 0.38-0.23 (m, 1H).
Example 129
##STR00359##
[0777]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
formate
Step 1
##STR00360##
[0778]
tert-butyl((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)pheny-
l)cyclohexyl)carbamate &
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cycl-
ohexyl)carbamate
[0779] Following the procedure described in Example 112 and making
non-critical variations as required to replace
tert-butyl((1S,6S)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e with
tert-butyl((3S,4S)-3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro--
[1,1'-biphenyl]-4-yl)carbamate,
tert-butyl((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cycl-
ohexyl)carbamate (20 mg, less polar on TLC) as a light yellow solid
and
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cycl-
ohexyl)carbamate (80 mg, more polar on TLC) as a light yellow
solid. Less polar on TLC: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.50-7.27 (m, 4H), 5.56-5.45 (m, 1H), 3.43-3.41 (m, 1H), 2.72-2.64
(m, 2H), 2.58-2.57 (m, 1H), 2.36 (s, 3H), 2.36 (s, 3H), 2.06-2.01
(m, 1H), 1.93-1.89 (m, 1H), 1.47 (s, 9H). More polar on TLC:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.62-7.58 (m, 2H),
7.54-7.48 (m, 2H), 6.39-6.35 (m, 1H), 3.40-3.37 (m, 1H), 2.67-2.63
(m, 1H), 2.19 (s, 3H), 2.19 (s, 3H), 2.03-2.01 (m, 1H), 1.85-1.81
(m, 1H), 1.68-1.63 (m, 1H), 1.53-1.42 (m, 2H), 1.38 (s, 9H).
Step 2
##STR00361##
[0780]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
[0781] Following the procedure described in Example 112 and making
non-critical variations as required to replace
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)-ca-
rbamate and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cycl-
ohexyl)carbamate and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide,
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)p-
henyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
formate was obtained as a light yellow solid. LCMS (ESI) m/z: 577.0
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (s,
1H), 7.65-7.54 (m, 5H), 7.22 (d, J=4.4 Hz, 1H), 6.82 (d, J=13.2 Hz,
1H), 6.77 (d, J=4.4 Hz, 1H), 5.99 (s, 1H), 3.61-3.57 (m, 1H),
3.08-3.07 (m, 1H), 2.85-2.81 (m, 1H), 2.32 (s, 3H), 2.32 (s, 3H),
2.17-2.13 (m, 1H), 2.05-2.01 (m, 1H), 1.78-1.73 (m, 2H), 1.64-1.56
(m, 1H), 1.39-1.37 (m, 1H).
Example 130
##STR00362##
[0782]
5-chloro-4-(((1S,6S)-6-(dimethylamino)-3-(trifluoromethyl)cyclohex--
3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0783] Following the procedure described in Example 48 and making
non-critical variations as required to replace
tert-butyl((1R,6R)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e with
tert-butyl((1S,6S)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)ca-
rbamate,
4-(((1S,6S)-6-amino-3-(trifluoromethyl)cyclohex-3-en-1-yl)amino)--
5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was obtained
as a white solid. LCMS (ESI) m/z: 499.0 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 7.58 (d, J=7.2 Hz, 1H), 7.24 (d,
J=4.4 Hz, 1H), 6.89 (d, J=12.8 Hz, 1H), 6.79 (d, J=4.4 Hz, 1H),
6.44 (s, 1H), 6.09 (d, J=6.0 Hz, 1H), 3.88-3.77 (m, 1H), 3.17-3.09
(m, 1H), 2.71-2.61 (m, 2H), 2.31-2.27 (m, 1H), 2.23 (s, 3H), 2.23
(s, 3H), 2.17-2.06 (m, 1H).
Example 131
##STR00363##
[0784]
5-chloro-2-fluoro-4-(((1S,2S)-2-(4-hydroxypiperidin-1-yl)cyclohexyl-
)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0785] Following the procedure described in Example 70 and making
non-critical variations as required to replace piperidine with
4-hydroxypiperidine, the title compound was obtained as a white
solid. LCMS (ESI) m/z: 489.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d6) .delta. 12.66 (s, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.24 (d,
J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H), 6.68 (d, J=12.7 Hz, 1H),
6.03 (dd, J=3.7, 1.7 Hz, 1H), 4.49 (s, 1H), 3.42-3.21 (m, 1H),
2.64-2.50 (m, 3H), 2.47-2.37 (m, 1H), 2.23-2.05 (m, 2H), 1.83 (d,
J=8.0 Hz, 1H), 1.75 (s, 1H), 1.62 (d, J=13.2 Hz, 3H), 1.37 (t,
J=10.5 Hz, 2H), 1.27-1.07 (m, 4H).
Example 132
##STR00364##
[0786]
4-((1S,2S)-2-(dimethylamino)cyclohexyl)-6-fluoro-N-(thiazol-2-yl)-3-
,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide
[0787] Following the procedure described in Example 54 and making
non-critical variations as required to replace tert-butyl
2-(4-bromo-2-chlorophenoxy)acetate with
2-(4-bromo-2,5-difluorophenoxy)acetic acid the title compound was
obtained as a white solid. LCMS (ESI) m/z: 441.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.30 (s, 1H), 7.26 (d,
J=4.6 Hz, 1H), 7.18 (d, J=13.3 Hz, 1H), 7.07 (d, J=7.1 Hz, 1H),
6.82 (d, J=4.6 Hz, 1H), 4.42-4.33 (m, 1H), 4.22-4.13 (m, 1H),
4.11-4.04 (m, 1H), 3.56 (d, J=11.8 Hz, 1H), 3.27-3.18 (m, 2H), 2.79
(s, 3H), 2.66 (s, 3H), 2.10 (d, J=11.8 Hz, 1H), 1.82 (d, J=13.0 Hz,
1H), 1.68 (t, J=12.0 Hz, 2H), 1.61-1.35 (m, 3H), 1.32-1.18 (m,
1H).
Example 133
##STR00365##
[0788]
5-chloro-2-fluoro-4-(((1S,2S)-2-((R)-2-(hydroxymethyl)pyrrolidin-1--
yl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0789] Following the procedure described in Example 70 and making
non-critical variations as required to replace the piperidine with
(R)-pyrrolidin-2-ylmethanol, the title compound was obtained. LCMS
(ESI) m/z: 489.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6)
.delta. 12.63 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.23 (d, J=4.5 Hz,
1H), 6.79 (d, J=4.5 Hz, 1H), 6.67 (d, J=12.9 Hz, 1H), 6.07-6.00 (m,
1H), 4.50 (s, 1H), 3.40 (dd, J=10.3, 5.3 Hz, 1H), 3.32-3.18 (m,
1H), 3.17 (s, 1H), 2.93-2.85 (m, 2H), 2.58 (d, J=8.6 Hz, 1H), 2.44
(s, 1H), 2.16 (d, J=12.4 Hz, 1H), 1.84-1.30 (m, 6H), 1.31-1.05 (m,
2H).
Example 134
##STR00366##
[0790]
5-chloro-2-fluoro-4-(((1S,2S)-2-((S)-2-(hydroxymethyl)pyrrolidin-1--
yl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0791] Following the procedure described in Example 70 and making
non-critical variations as required to replace the piperidine with
(S)-pyrrolidin-2-ylmethanol, the title compound was obtained. LCMS
(ESI) m/z: 489.1 [M+H].sup.+. H NMR (400 MHz, DMSO-d6) .delta. 7.59
(d, J=7.3 Hz, 1H), 7.21 (d, J=4.5 Hz, 1H), 6.80-6.67 (m, 2H), 5.92
(d, J=6.0 Hz, 1H), 4.41 (s, 1H), 3.29 (s, 2H), 3.13 (s, 1H),
3.07-2.91 (m, 2H), 2.92 (s, 2H), 2.73-2.66 (m, 1H), 2.06 (d, J=9.4
Hz, 1H), 1.83 (d, J=12.4 Hz, 1H), 1.75 (d, J=12.5 Hz, 1H),
1.65-1.50 (m, 5H), 1.47-1.29 (m, 2H), 1.25 (ddd, J=12.6, 9.5, 2.7
Hz, 1H), 1.13 (dt, J=12.6, 9.2 Hz, 1H).
Example 135
##STR00367##
[0792]
5-chloro-2-fluoro-4-(((1S,2S)-2-((3-fluoropropyl)(methyl)amino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0793] Following the procedure described in Example 72 and making
non-critical variations as required to replace
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2-fluoro-N-(6-fluoro-2-pyridyl)--
4-[[(1S,2S)-2-[2-hydroxyethyl(methyl)amino]cyclohexyl]amino]benzenesulfona-
mide and 2-bromoethanol, with
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide and
1-fluoro-3-iodopropane,
5-chloro-2-fluoro-4-(((1S,2S)-2-((3-fluoropropyl)(methyl)amino)cyclohexyl-
)amino)-N-(thiazol-2-yl)benzenesulfonamide was obtained as a white
solid. LCMS (ESI) m/z: 479.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.59 (s, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.24
(d, J=4.6 Hz, 1H), 6.80 (d, J=4.6 Hz, 1H), 6.71 (d, J=12.9 Hz, 1H),
5.81 (dd, J=5.1, 1.7 Hz, 1H), 4.67-4.25 (m, 2H), 2.72-2.58 (m, 1H),
2.48-2.36 (m, 1H), 2.14-2.09 (m, 5H), 1.88-1.65 (m, 4H), 1.65-1.55
(m, 1H), 1.46-1.07 (m, 4H).
Example 136
##STR00368##
[0794]
5-chloro-2-fluoro-4-(((1S,2S)-2-(((1-fluorocyclopropyl)methyl)(meth-
yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0795] Following the procedure described in Example 18 and making
non-critical variations as required to replace acetaldehyde with
1-fluorocyclopropane carbaldehyde,
5-chloro-2-fluoro-4-(((1S,2S)-2-(((1-fluorocyclopropyl)methyl)(methyl)ami-
no)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide was
obtained as a white solid. LCMS (ESI) m/z: 491.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.76 (s, 1H), 7.59 (d,
J=7.3 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 6.71
(d, J=12.8 Hz, 1H), 5.93 (s, 1H), 2.96-2.64 (m, 2H), 2.24 (s, 3H),
2.20-2.08 (m, 2H), 1.94-1.71 (m, 2H), 1.69-1.57 (m, 1H), 1.48-1.04
(m, 4H), 1.01-0.81 (m, 2H), 0.75-0.43 (m, 2H).
Example 137
##STR00369##
[0796]
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0797] Following the procedure described in Example 129 and making
non-critical variations as required to replace
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cycl-
ohexyl)carbamate with
tert-butyl((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cycl-
ohexyl)carbamate,
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was
obtained as a light yellow solid. LCMS (ESI) m/z: 577.3
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.73 (d,
J=7.2 Hz, 1H), 7.70-7.66 (m, 2H), 7.60-7.53 (m, 2H), 7.11 (d, J=4.4
Hz, 1H), 6.88 (d, J=12.8 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 4.63 (s,
1H), 3.92-3.88 (m, 1H), 3.42-3.98 (m, 1H), 3.11-2.99 (m, 1H), 2.60
(s, 3H), 2.60 (s, 3H), 2.57-2.50 (m, 1H), 2.32-2.24 (m, 1H),
2.11-1.98 (m, 3H), 1.58-1.47 (m, 1H).
Example 138
##STR00370##
[0798]
5-chloro-2-fluoro-4-(((1S,2S,4S)-2-((2-hydroxyethyl)(methyl)amino)--
4-(trifluoromethyl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
##STR00371##
[0799] Step 1
##STR00372##
[0800]
tert-butyl((1S,6S)-6-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-
-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamate
[0801] To a solution of
tert-butyl((1S,6S)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e (200 mg, 0.71 mmol) in MeOH (5 mL) was added AcOH (0.08 mL, 1.43
mmol) and (tert-butyldimethylsilyloxy)acetaldehyde (187 mg, 1.07
mmol). The mixture was stirred at room temperature for 10 min and
sodium cyanoborohydride (135 mg, 2.14 mmol) was added. The mixture
was heated to 40.degree. C. for an additional 2 h. After cooling to
room temperature, the reaction was quenched with sat. aq.
NaHCO.sub.3 (50 mL). The mixture was extracted with DCM (50
mL.times.3). The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The crude
residue was purified by silica gel chromatography (solvent
gradient: 0-25% EtOAc (0.5% TEA) in petroleum ether) to give the
title compound (150 mg, 48%) as a light yellow solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 6.24 (s, 1H), 5.08-4.72 (m, 1H),
3.78-3.60 (m, 3H), 2.99-2.74 (m, 3H), 2.71-2.63 (m, 1H), 2.62-2.50
(m, 1H), 2.12-1.97 (m, 2H), 1.46 (s, 9H), 0.90 (s, 9H), 0.07 (s,
6H).
Step 2
##STR00373##
[0802]
tert-butyl((1S,6S)-6-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methy-
l)amino)-4-(trifluoromethyl) cyclohex-3-en-1-yl)carbamate
[0803] To a solution of
tert-butyl((1S,6S)-6-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-4-(tr-
ifluoromethyl)cyclohex-3-en-1-yl)carbamate (150 mg, 0.34 mmol) in
MeOH (5 mL) was added AcOH (0.04 mL, 0.68 mmol) and
paraformaldehyde (51 mg, 1.71 mmol). The mixture was stirred at
room temperature for 10 min and sodium cyanoborohydride (107 mg,
1.71 mmol) was added. The mixture was heated to 40.degree. C. for
an additional 4 h. After cooling to room temperature, TEA (0.2 mL)
was added and concentrated in vacuo. Water (20 mL) was added and
extracted with DCM (50 mL.times.3). The combined organic layers
were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (solvent gradient: 0-5% EtOAc in petroleum ether) to
give the title compound (150 mg, 97%) as a light yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.21 (s, 1H), 5.68 (s,
1H), 3.76-3.63 (m, 2H), 3.54-3.37 (m, 1H), 3.23-3.09 (m, 1H),
2.84-2.73 (m, 1H), 2.66-2.52 (m, 2H), 2.35-2.15 (m, 1H), 2.27 (s,
3H), 2.05-1.90 (m, 1H), 1.65-1.54 (m, 1H), 1.46 (s, 9H), 0.90 (s,
9H), 0.08 (s, 6H).
Step 3
##STR00374##
[0804]
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohex-
yl)carbamate
[0805] To a solution of
tert-butyl((1S,6S)-6-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amin-
o)-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamate (150 mg, 0.33
mmol) in EtOAc (10 mL) was added Pd(OH).sub.2 (20%, 233 mg, 0.33
mmol). The mixture was stirred at room temperature for 16 h under
hydrogen atmosphere (15 psi). The mixture was filtered and
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (solvent gradient: 0-10% EtOAc in petroleum ether)
to give the title compound (60 mg, 40%) as colorless oil. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 5.39 (s, 1H), 3.74-3.60 (m, 2H),
3.24-3.12 (m, 1H), 2.70-2.57 (m, 2H), 2.56-2.47 (m, 1H), 2.44-2.35
(m, 1H), 2.24 (s, 3H), 2.11-1.97 (m, 2H), 1.94-1.84 (m, 1H), 1.45
(s, 9H), 1.45-1.40 (m, 1H), 1.38-1.25 (m, 2H), 1.16-1.03 (m, 1H),
0.91 (s, 9H), 0.08 (s, 6H).
Step 4
##STR00375##
[0806]
2-(((1S,2S,5S)-2-amino-5-(trifluoromethyl)cyclohexyl)(methyl)amino)-
ethanol
[0807] To a solution of
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)car-
bamate (60 mg, 0.13 mmol) in DCM (0.5 mL) was added trifluoroacetic
acid (0.2 mL, 2.64 mmol). The mixture was stirred at room
temperature for 2 h and concentrated in vacuo to give the title
compound (31 mg, crude) as light yellow oil that required no
further purification.
Step 5
##STR00376##
[0808]
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S,4S)-2-((2-hydr-
oxyethyl)(methyl)amino)-4-(trifluoromethyl)cyclohexyl)amino)-N-(thiazol-2--
yl)benzenesulfonamide
[0809] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (0.18 g, 0.39 mmol) and N,N-diisopropylethylamine (0.21 mL,
1.29 mmol) in DMF (5 mL) was added
2-(((1S,2S,5S)-2-amino-5-(trifluoromethyl)cyclohexyl)(methyl)amino)ethano-
l (31 mg, 0.13 mmol). The mixture was heated to 70.degree. C. for
16 h. After cooling to room temperature, the reaction was
concentrated in vacuo. The crude residue was purified by silica gel
chromatography (solvent gradient: 0-10%-25% EtOAc (1% TEA) in
petroleum ether) to give the title compound (100 mg, 68%) as a
light yellow solid. LCMS (ESI) m/z: 681.3 [M+H].sup.+. H NMR (400
MHz, CDCl.sub.3) .delta. 7.74 (d, J=7.2 Hz, 1H), 7.40 (d, J=3.6 Hz,
1H), 7.22 (d, J=8.0 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H), 6.42-6.33 (m,
2H), 6.29 (d, J=12.4 Hz, 1H), 5.58 (s, 1H), 5.20 (s, 2H), 3.76 (s,
3H), 3.75 (s, 3H), 3.63 (t, J=5.2 Hz, 2H), 3.20-3.10 (m, 1H),
2.72-2.54 (m, 3H), 2.45-2.35 (m, 1H), 2.23 (s, 3H), 2.18-2.10 (m,
1H), 2.06-1.98 (m, 1H), 1.53-1.39 (m, 2H), 1.31-1.18 (m, 2H).
Step 6
##STR00377##
[0810]
5-chloro-2-fluoro-4-(((1S,2S,4S)-2-((2-hydroxyethyl)(methyl)amino)--
4-(trifluoromethyl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0811] A mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S,4S)-2-((2-hydroxyeth-
yl)(methyl)amino)-4-(trifluoromethyl)cyclohexyl)amino)-N-(thiazol-2-yl)ben-
zenesulfonamide (100 mg, 0.09 mmol) and formic acid (3.0 mL) was
stirred at room temperature for 1 h. The reaction mixture was
concentrated in vacuo. The crude residue was purified by reverse
phase chromatography (acetonitrile 22-52%/0.225% formic acid in
water) to give the title compound (19 mg, 41%) as a white solid.
LCMS (ESI) m/z: 531.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.58 (d, J=7.2 Hz, 1H), 7.26 (d, J=4.4 Hz,
1H), 6.86-6.72 (m, 2H), 5.93 (d, J=4.4 Hz, 1H), 3.46-3.38 (m, 3H),
2.83 (t, J=9.6 Hz, 1H), 2.61-2.53 (m, 2H), 2.45-2.36 (m, 1H), 2.17
(s, 3H), 2.20-2.10 (m, 1H), 2.02-1.94 (m, 1H), 1.48-1.78 (m, 1H),
1.59-1.44 (m, 1H), 1.40-1.15 (m, 2H).
Example 139
##STR00378##
[0812]
5-Chloro-4-(((1S,2S)-2-(((S)-2-cyclopropyl-2-hydroxyethyl)(methyl)a-
mino)
cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
##STR00379## ##STR00380##
[0813] Step 1
##STR00381##
[0814]
5-Chloro-4-(((1S,2S)-2-((2-cyclopropyl-2-oxoethyl)(methyl)amino)cyc-
lohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesul-
fonamide
[0815] To
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methyla-
mino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (250 mg,
0.44 mmol) in DMF (2 mL) was added triethylamine (0.09 mL, 0.66
mmol) followed by a solution of 2-bromo-1-cyclopropyl-ethanone (72
mg, 0.44 mmol) in DMF (1 mL). The mixture was then stirred at room
temperature for 3 days. The reaction was diluted with EtOAc (50
mL), washed with saturated aqueous NaHCO.sub.3 solution (10 mL),
then with 50% aqueous NaCl solution (4.times.10 mL), then dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. The
crude product was purified by flash chromatography through Si gel
(0-100% EtOAc/Hexanes) to provide
5-chloro-4-(((1S,2S)-2-((2-cyclopropyl-2-oxoethyl)(methyl)amino)cyclohexy-
l)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonami-
de (144 mg, 50% yield) as a yellow wax. LCMS (ESI) m/z: 651.0
[M+H].sup.+.
Step 2
##STR00382##
[0816]
5-Chloro-4-(((1S,2S)-2-(((S)-2-cyclopropyl-2-hydroxyethyl)(methyl)a-
mino)cyclohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)be-
nzenesulfonamide &
5-chloro-4-(((1S,2S)-2-(((R)-2-cyclopropyl-2-hydroxyethyl)(methyl)amino)c-
yclohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide
[0817]
5-Chloro-4-(((1S,2S)-2-((2-cyclopropyl-2-oxoethyl)(methyl)amino)cyc-
lohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesul-
fonamide (144 mg, 0.22 mmol) was dissolved in a mixture of iPrOH (3
mL) and THF (0.5 mL). This solution was cooled to 0.degree. C. and
to this was added sodium borohydride (25 mg, 0.66 mmol). After 90
min, the mixture was removed from the cooling bath and a further
portion of sodium borohydride (25 mg, 0.66 mmol) was added and
stirred at room temperature. After 1 h, a further portion of sodium
borohydride (75 mg, 1.98 mmol) was added and stirred for 16 h. MeOH
(5 mL) was added and concentrated in vacuo (repeated 3 times). The
crude residue was diluted with EtOAc (50 mL) and saturated aqueous
solution of NaHCO.sub.3 (15 mL) and the phases were separated. The
organic extract was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to provide
5-chloro-4-(((1S,2S)-2-((2-cyclopropyl-2-hydroxyethyl)(methyl)amino)cyclo-
hexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfo-
namide (111 mg, 77%) as a white waxy semi-solid as a mixture of
alcohol diastereomers. The mixture of
5-chloro-4-(((1S,2S)-2-((2-cyclopropyl-2-hydroxyethyl)(methyl)amino)cyclo-
hexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfo-
namide alcohol diastereomers prepared above (111 mg, 0.17 mmol) was
separated using chiral HPLC (ChiralPak IA, 250 mm.times.20 mm ID, 5
.mu.m), 5:5:90 MeOH:DCM:Hexanes, 22 min) to afford
5-chloro-4-(((1S,2S)-2-(((S)-2-cyclopropyl-2-hydroxyethyl)(methyl)amino)c-
yclohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (first peak, 65 mg, 59%) and
5-chloro-4-(((1S,2S)-2-(((R)-2-cyclopropyl-2-hydroxyethyl)(methyl)amino)c-
yclohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (second peak, 39 mg, 35%). Absolute alcohol
configuration was arbitrarily assigned to each isomer. LCMS (ESI)
m/z: 653.1 [M+H].sup.+.
Step 3
##STR00383##
[0818]
5-Chloro-4-(((1S,2S)-2-(((S)-2-cyclopropyl-2-hydroxyethyl)(methyl)a-
mino)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0819] Following the procedure described in Example 115 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-met-
hylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonami-
de with
5-chloro-4-(((1S,2S)-2-(((S)-2-cyclopropyl-2-hydroxyethyl)(methyl)-
amino)cyclohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)b-
enzenesulfonamide (65 mg, 0.10 mmol),
5-chloro-4-(((1S,2S)-2-(((S)-2-cyclopropyl-2-hydroxyethyl)(methyl)amino)c-
yclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (21
mg, 42%) was obtained. LCMS (ESI) m/z: 503.1 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 12.73-11.82 (m, 1H), 7.56 (d,
J=7.3 Hz, 1H), 7.23 (d, J=4.5 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.72
(d, J=13.0 Hz, 1H), 5.96 (d, J=4.0 Hz, 1H), 4.69-3.67 (m, 1H), 3.04
(dd, J=11.4, 5.9 Hz, 1H), 2.75-2.65 (m, 1H), 2.44-2.36 (m, 1H),
2.19 (s, 3H), 2.14 (d, J=23.8 Hz, 1H), 2.08 (s, 2H), 1.79 (dd,
J=28.7, 10.6 Hz, 2H), 1.59 (d, J=12.3 Hz, 1H), 1.46-1.04 (m, 4H),
0.77-0.66 (m, 1H), 0.28-0.17 (m, 1H), 0.17-0.02 (m, 3H).
Example 140
##STR00384##
[0820]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-methyl-1H-pyrazol-4-yl)am-
ino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
##STR00385##
[0821] Step 1
##STR00386##
[0822]
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-((1,3-dioxopropan-2--
yl)(methyl)amino)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfona-
mide
[0823] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methylamino)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (180 mg, 0.32
mmol) and 2-chloromalonaldehyde (34 mg, 0.32 mmol) in MeCN (3 mL)
and DMF (1 mL) was added triethylamine (48 mg, 0.066 mL, 0.47 mmol)
and the mixture stirred at rt overnight. After 16 h, a further
portion of triethylamine (48 mg, 0.066 mL, 0.47 mmol) was added and
the mixture placed in a 65.degree. C. oil bath sealed. After 3
days, the crude mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-((1,3-dioxopropan-2-yl)(me-
thyl)amino)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
was used directly in the next step as is. LCMS (ESI) m/z: 656.9
[M+NH.sub.4]+.
Step 2
##STR00387##
[0824]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-methyl-1H-pyrazol-4-yl)am-
ino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0825]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-((1,3-dioxopropan-2--
yl)(methyl)amino)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfona-
mide (1.33 mL of the crude solution prepared above in step 1, 65
mg, 0.10 mmol) was added to a solution of methylhydrazine sulfate
(44 mg, 0.31 mmol) in MeOH (0.5 mL). To this mixture was then added
4N HCl in dioxanes (0.05 mL, 0.20 mmol) and the flask placed in a
65.degree. C. oil bath sealed. After 2 h, volatiles were removed
under an air stream and the crude residue purified by C18 reverse
phase flash chromatography (0-100% MeCN/10 mM aqueous
NH.sub.4CO.sub.2H, pH=3.8). Appropriate fractions were combined and
lyophilized to provide
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-methyl-1H-pyrazol-4-yl)amino)cy-
clohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (8 mg, 16%) as a
tan powder. LCMS (ESI) m/z: 499.0 [M+H].sup.+. .sup.1H NMR (400
MHz, d6-DMSO) .delta. 12.77 (s, 1H), 7.55 (d, J=7.3 Hz, 1H), 7.20
(d, J=1.7 Hz, 1H), 7.14 (d, J=3.4 Hz, 1H), 6.77 (d, J=13.1 Hz, 1H),
6.68 (d, J=2.9 Hz, 1H), 5.78 (d, J=1.7 Hz, 1H), 5.66 (d, J=7.4 Hz,
1H), 3.70-3.56 (m, 1H), 3.54 (s, 3H), 3.01 (td, J=11.8, 3.3 Hz,
1H), 2.48 (s, 3H), 1.97-1.82 (m, 2H), 1.76-1.68 (m, 1H), 1.63-1.53
(m, 2H), 1.40-1.31 (m, 2H), 1.26-1.18 (m, 1H).
Example 141
##STR00388##
[0826]
5-Chloro-4-(((1S,6S)-6-(dimethylamino)cyclohex-3-en-1-yl)amino)-2-f-
luoro-N-(thiazol-2-yl)benzenesulfonamide Formate
##STR00389## ##STR00390##
[0827] Step 1
##STR00391##
[0828]
Rac-4-(((1,6-trans)-6-aminocyclohex-3-en-1-yl)amino)-5-chloro-N-(2,-
4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0829] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (2.29 g, 4.96 mmol) in DMF (10 mL) was added triethylamine
(2.51 g, 3.46 mL, 24.8 mmol) followed by addition of
rac-trans-cyclohex-4-ene-1,2-diamine dihydrochloride (1.01 g, 5.46
mmol) and the mixture stirred at rt overnight. After 16 h, the
mixture was diluted with EtOAc (100 mL), washed with saturated
NaHCO.sub.3(aq) (25 mL), then with 50% saturated NaCl(aq)
(4.times.10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Purification by flash column chromatography
through Si gel (0-100% EtOAc/hexanes) provided
rac-4-(((1,6-trans)-6-aminocyclohex-3-en-1-yl)amino)-5-chloro-N--
(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(1.33 g, 48%) as a waxy semi-solid. LCMS (ESI) m/z: 553.1
[M+H].sup.+.
Step 2
##STR00392##
[0830]
Rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1,6-trans)-6-(dimethylami-
no)cyclohex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0831] To a solution of
rac-4-(((1,6-trans)-6-aminocyclohex-3-en-1-yl)amino)-5-chloro-N-(2,4-dime-
thoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (1.33 g,
2.40 mmol) in MeOH (20 mL) was added 37% w/w aqueous formaldehyde
(1.95 g, 1.79 mL, 24.0 mmol) followed by addition of sodium
cyanoborohydride (446 mg, 7.21 mmol) and the mixture was stirred at
rt. After 3 days, a further portion of 37% w/w aqueous formaldehyde
(975 mg, 0.90 mL, 12.0 mmol) was added followed by addition of a
further portion of sodium cyanoborohydride (446 mg, 7.21 mmol) and
continued stirring at rt. After 3 h, volatiles were removed in
vacuo and the crude residue partitioned between EtOAc (50 mL) and
saturated NaHCO.sub.3(aq) (10 mL). The phases were separated and
the organic extract dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Purification by flash column chromatography
through Si gel (0-100% EtOAc/CH.sub.2Cl.sub.2) provided
rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1,6-trans)-6-(dimethylamino)cyc-
lohex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(971 mg, 69%) as a clear waxy gum. LCMS (ESI) m/z: 581.1
[M+H].sup.+.
Step 3
##STR00393##
[0832]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,6S)-6-(dimethylamino)cyclo-
hex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
&
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1R,6R)-6-(dimethylamino)cyclohex-3--
en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0833]
Rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1,6-trans)-6-(dimethylami-
no)cyclohex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(837 mg, 1.44 mmol) was separated by using chiral HPLC (Chiralpak
IB (250 mm*20 mm, 5 um), MeOH:DCM:hexane 1:4:95 containing 0.1% of
diethylamine, 15 ml/min) to afford
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,6S)-6-(dimethylamino)cyclohex-3--
en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (first
peak, 367 mg, 43%) as a white solid. LCMS (ESI) m/z: 581.1
[M+H].sup.+. Also afforded afford
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1R,6R)-6-(dimethylamino)cyclohex-3--
en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (second
peak, 366 mg, 43%) as a white solid. LCMS (ESI) m/z: 581.1
[M+H].sup.+.
Step 4
##STR00394##
[0834]
5-Chloro-4-(((1S,6S)-6-(dimethylamino)cyclohex-3-en-1-yl)amino)-2-f-
luoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0835] Following the procedure described in Example 115 and making
non-critical variations to substitute
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-met-
hylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonami-
de with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,6S)-6-(dimethylamino)cycl-
ohex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide,
5-chloro-4-(((1S,6S)-6-(dimethylamino)cyclohex-3-en-1-yl)amino)-2-fluoro--
N-(thiazol-2-yl)benzenesulfonamide formate (41 mg, 99%) was
obtained as a white solid. LCMS (ESI) m/z: 430.9 [M+H].sup.+.
.sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.16 (s, 1H), 7.59 (d, J=7.3
Hz, 1H), 7.18 (d, J=4.3 Hz, 1H), 6.78-6.70 (m, 2H), 6.09 (d, J=3.9
Hz, 1H), 5.72-5.64 (m, 1H), 5.62-5.52 (m, 1H), 3.52 (ddd, J=15.1,
10.0, 5.0 Hz, 1H), 3.00 (td, J=10.5, 5.4 Hz, 1H), 2.70 (dt, J=16.4,
4.5 Hz, 1H), 2.21 (s, 6H), 2.19-2.05 (m, 2H), 1.97-1.85 (m, 1H).
Sulfonamide N--H and formic acid O--H not visible in the NMR.
Example 142
##STR00395##
[0836]
5-Chloro-4-(((1R,6R)-6-(dimethylamino)cyclohex-3-en-1-yl)amino)-2-f-
luoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0837] Following the procedure described in Example 115 and making
non-critical variations to substitute
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-met-
hylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonami-
de with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((R,6R)-6-(dimethylamino)cyclo-
hex-3-en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide,
5-chloro-4-(((1R,6R)-6-(dimethylamino)cyclohex-3-en-1-yl)amino)-2-fluoro--
N-(thiazol-2-yl)benzenesulfonamide formate (41 mg, 99%) was
obtained as a white solid. LCMS (ESI) m/z: 431.90 [M+H].sup.+.
.sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.15 (s, 1H), 7.59 (d, J=7.3
Hz, 1H), 7.20 (d, J=4.4 Hz, 1H), 6.80-6.69 (m, 2H), 6.10 (d, J=3.9
Hz, 1H), 5.75-5.64 (m, 1H), 5.63-5.51 (m, 1H), 3.56-3.49 (m, 1H),
3.01 (td, J=10.5, 5.4 Hz, 1H), 2.70 (dt, J=9.7, 4.2 Hz, 1H), 2.22
(s, 6H), 2.20-2.05 (m, 2H), 1.97-1.87 (m, 1H). Sulfonamide N--H and
formic acid O--H not visible.
Example 143
##STR00396##
[0838]
5-Chloro-4-(((1S,2S)-2-(((R)-2-cyclopropyl-2-hydroxyethyl)(methyl)a-
mino)cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0839] Following the procedure described in Example 115 and making
non-critical variations to substitute
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-met-
hylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonami-
de with
5-chloro-4-(((1S,2S)-2-(((R)-2-cyclopropyl-2-hydroxyethyl)(methyl)-
amino)cyclohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)b-
enzenesulfonamide (39 mg, 0.06 mmol),
5-chloro-4-(((1S,2S)-2-(((R)-2-cyclopropyl-2-hydroxyethyl)(methyl)amino)c-
yclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (16
mg, 52%) was obtained as a white solid. LCMS (ESI) m/z: 502.9
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.38 (bs,
1H), 7.56 (d, J=7.3 Hz, 1H), 7.22 (d, J=4.5 Hz, 1H), 6.77 (d, J=4.5
Hz, 1H), 6.71 (d, J=13.1 Hz, 1H), 5.95 (d, J=4.7 Hz, 1H), 3.06-2.95
(m, 1H), 2.77-2.62 (m, 1H), 2.22 (s, 3H), 2.14-2.04 (m, 1H),
1.93-1.67 (m, 2H), 1.59 (d, J=12.4 Hz, 1H), 1.49-0.99 (m, 4H),
0.89-0.68 (m, 1H), 0.27 (dd, J=8.3, 2.6 Hz, 2H), 0.26-0.09 (m,
2H).
Example 144
##STR00397##
[0840]
5-chloro-4-(((1S,2S)-2-(dimethylamino)cycloheptyl)amino)-2-fluoro-N-
-(thiazol-2-yl)benzenesulfonamide Formate
[0841] Following the procedure described in Example 141 and making
non-critical variations to substitute
rac-trans-cyclohex-4-ene-1,2-diamine with
rac-trans-cycloheptane-1,2-diamine the title compound was obtained.
The absolute stereochemistry was assigned arbitrarily. LCMS (ESI)
m/z: 447.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.22 (s, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.05 (s, 1H), 6.58 (s, 1H),
6.45 (d, J=12.6 Hz, 1H), 5.93 (s, 1H), 3.36-3.29 (m, 1H), 2.74 (t,
J=8.1 Hz, 1H), 2.16 (s, 6H), 1.81-1.69 (m, 3H), 1.59-1.31 (m, 7H)
[acidic N--H and O--H not observed].
Example 145
##STR00398##
[0842]
5-chloro-4-(((1R,2R)-2-(dimethylamino)cycloheptyl)amino)-2-fluoro-N-
-(thiazol-2-yl)benzenesulfonamide Formate
[0843] Following the procedure described in Example 141 and making
non-critical variations to substitute
rac-trans-cyclohex-4-ene-1,2-diamine with
rac-trans-cycloheptane-1,2-diamine the title compound was obtained.
The absolute stereochemistry was assigned arbitrarily. LCMS (ESI)
m/z: 447.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.18 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.08 (d, J=4.1 Hz, 1H), 6.61
(d, J=4.1 Hz, 1H), 6.48 (d, J=12.7 Hz, 1H), 5.96 (d, J=3.8 Hz, 1H),
3.35 (s, 1H), 2.78 (t, J=7.7 Hz, 1H), 2.17 (s, 6H), 1.84-1.65 (m,
3H), 1.64-1.28 (m, 7H) [acidic N--H and O--H not observed].
Example 146
##STR00399##
[0844]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((1-isobutyrylazetidin-3-yl)(methyl-
)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0845] To a solution of
4-(((1S,2S)-2-(azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chloro-2-fl-
uoro-N-(thiazol-2-yl)benzenesulfonamide hydrochloride (80 mg, 0.16
mmol) in a mixture of CH.sub.2Cl.sub.2 (1 mL) and pyridine (0.38
mL, 4.7 mmol) was added isobutyryl chloride (20 uL, 0.19 mmol). The
reaction mixture was stirred at room temperature for 16 hours then
concentrated to dryness. The crude was directly purified by C18
reverse phase flash chromatography (5-70% MeCN/10 mM aqueous
ammonium bicarbonate, pH=10). Appropriate fractions combined and
lyophilized to provide
5-chloro-2-fluoro-4-(((1S,2S)-2-((1-isobutyrylazetidin-3-yl)(methyl)amino-
)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (26 mg, 30%).
LCMS (ESI) m/z: 544.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.68 (br.s, 1H), 7.56 (dd, J=7.3, 2.2 Hz,
1H), 7.26 (d, J=4.7 Hz, 1H), 6.79 (dd, J=23.4, 8.8 Hz, 2H), 5.80
(s, 1H), 4.16-4.02 (m, 1H), 4.00-3.89 (m, 1H), 3.85-3.58 (m, 3H),
2.64-2.53 (m, 1H), 2.45-2.35 (m, 1H), 2.04 (s, 4H), 1.82-1.52 (m,
3H), 1.42-1.09 (m, 5H), 1.00-0.85 (m, 7H).
Example 147
##STR00400##
[0846]
5-Chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-(3-methylbutanoyl)azetidi-
n-3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0847] Following the procedure described in Example 146 and making
non-critical variations as required to replace isobutyryl chloride
with isovaleryl chloride,
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-(3-methylbutanoyl)azetidin-3-yl-
)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide was
obtained as a white solid. LCMS (ESI) m/z: 558.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.75 (bs, 1H), 7.56
(dd, J=7.3, 2.1 Hz, 1H), 7.23 (d, J=4.5 Hz, 1H), 6.76 (dd, J=16.5,
8.8 Hz, 2H), 5.76 (d, J=5.9 Hz, 1H), 4.04 (dd, J=18.3, 8.1 Hz, 1H),
3.98-3.88 (m, 1H), 3.86-3.73 (m, 2H), 3.72-3.56 (m, 2H), 2.12-1.97
(m, 5H), 1.99-1.79 (m, 4H), 1.79-1.51 (m, 3H), 1.25 (dt, J=25.8,
11.9 Hz, 4H), 0.94-0.77 (m, 7H).
Example 148
##STR00401##
[0848]
4-(((1S,2S)-2-((1-Acetylazetidin-3-yl)(methyl)amino)cyclohexyl)amin-
o)-5-chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0849] Following the procedure described in Example 146 and making
non-critical variations as required to replace isobutyryl chloride
with acetyl bromide,
4-(((1S,2S)-2-((1-acetylazetidin-3-yl)(methyl)amino)cyclohexyl)amino)-5-c-
hloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was obtained as a
white solid. LCMS (ESI) m/z: 515.8 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 12.74 (s, 1H), 7.57 (d, J=7.2 Hz, 1H),
7.20 (s, 1H), 6.82-6.59 (m, 2H), 5.75 (s, 1H), 4.09-3.97 (m, 1H),
3.97-3.89 (m, 1H), 3.85-3.71 (m, 2H), 3.71-3.59 (m, 2H), 3.57-3.48
(m, 1H), 3.44-3.37 (m, 1H), 2.64-2.56 (m, 1H), 2.04 (d, J=2.6 Hz,
3H), 2.02-1.99 (m, 1H), 1.71 (d, J=8.6 Hz, 3H), 1.66-1.56 (m, 1H),
1.42-1.15 (m, 4H).
Example 149
##STR00402##
[0850]
5-Chloro-4-(((1S,2S)-2-(4-cyanopiperidin-1-yl)cyclohexyl)amino)-2-f-
luoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0851] Following the procedure described in Example 70 and making
non-critical variations as required to replace piperidine with
4-cyanopiperidine,
5-Chloro-4-(((1S,2S)-2-(4-cyanopiperidin-1-yl)cyclohexyl)amino)-2-fluoro--
N-(thiazol-2-yl)benzenesulfonamide formate (100 mg, 84%) was
obtained. LCMS (ESI) m/z: 498.1 (M+H).sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) .delta. 8.19 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.13 (d,
J=4.2 Hz, 1H), 6.74-6.55 (m, 2H), 5.85-5.75 (m, 1H), 3.27-3.12 (m,
1H), 2.87-2.72 (m, 1H), 2.65-2.52 (m, 2H), 2.48-2.39 (m, 2H),
2.36-2.24 (m, 1H), 2.16 (d, J=10.9 Hz, 1H), 1.84-1.69 (m, 3H),
1.68-1.53 (m, 3H), 1.53-1.31 (m, 2H), 1.29-1.07 (m, 3H).
Example 150
##STR00403##
[0852]
5-chloro-2-fluoro-4-(((1S,2S)-2-(4-hydroxy-4-methylpiperidin-1-yl)c-
yclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide Formate
[0853] Following the procedure described in Example 70 and making
non-critical variations as required to replace piperidine with
4-methylpiperidin-4-ol,
5-chloro-2-fluoro-4-(((1S,2S)-2-(4-hydroxy-4-methylpiperidin-1-yl)cyclohe-
xyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate was obtained.
LCMS (ESI) m/z: 503.1 (M+H).sup.+. .sup.1H NMR (400 MHz, d6-DMSO)
.delta. 8.12 (s, 1H), 7.55 (d, J=7.3 Hz, 1H), 7.16 (d, J=4.4 Hz,
1H), 6.71 (d, J=4.4 Hz, 1H), 6.62 (d, J=12.7 Hz, 1H), 6.06-5.95 (m,
1H), 3.23-3.08 (m, 1H), 2.75-2.60 (m, 1H), 2.48-2.44 (m, 4H), 2.39
(t, J=9.5 Hz, 1H), 2.32-2.19 (m, 2H), 2.15 (d, J=11.1 Hz, 1H),
1.88-1.78 (m, 1H), 1.76-1.66 (m, 1H), 1.58 (d, J=11.7 Hz, 1H),
1.43-1.27 (m, 3H), 1.27-1.03 (m, 3H), 0.98 (s, 3H).
Example 151 & Example 152
##STR00404##
[0854]
4-(((1S,2S)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-ch-
loro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide &
4-(((1R,2R)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-chloro-2-
-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0855] Following the procedure described in Example 105 &
Example 106 and making non-critical variations as required to
replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)ben-
zenesulfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
4-(((1S,2S)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)--
5-chloro-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was obtained
as a white solid. Example 150: LCMS (ESI) m/z: 466.1 [M+H].sup.+. H
NMR (400 MHz, DMSO-d6) .delta. 8.89 (s, 1H), 8.61 (s, 1H), 8.32 (s,
1H), 7.82-7.67 (m, 1H), 7.13-6.86 (m, 2H), 6.38-6.17 (m, 1H),
3.91-3.69 (m, 3H), 3.39-3.18 (m, 3H), 3.06-2.94 (m, 1H), 2.26-2.12
(m, 1H), 1.86-1.71 (m, 5H), 1.66-1.54 (m, 1H), 1.51-1.11 (m, 5H),
0.72 (q, J=7.6 Hz, 1H), 0.53 (q, J=4.7 Hz, 1H).
4-(((1R,2R)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-chloro-2-
-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was obtained as a
white solid. Example 151: LCMS (ESI) m/z: 466.1 [M+H].sup.+. H NMR
(400 MHz, DMSO-d6) .delta. 8.89 (s, 1H), 8.61 (s, 1H), 8.32 (s,
1H), 7.83-7.65 (m, 1H), 7.13-6.79 (m, 2H), 6.36-6.16 (m, 1H),
3.87-3.70 (m, 5H), 3.40-3.13 (m, 2H), 3.10-2.91 (m, 1H), 2.25-2.13
(m, 1H), 1.89-1.68 (m, 4H), 1.66-1.52 (m, 1H), 1.49-1.25 (m, 2H),
1.24 (s, 3H), 0.72 (td, J=8.0, 5.6 Hz, 1H), 0.53 (q, J=4.7 Hz,
1H).
Example 153
##STR00405##
[0856]
5-chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-hydroxypiperidin-1-yl)cycloh-
exyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0857] Following the procedure described in Example 70 and making
non-critical variations as required to replace the piperidine with
(S)-piperidin-3-ol, the title compound was obtained. LCMS (ESI)
m/z: 489.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
12.69 (s, 1H), 7.60 (d, J=7.3 Hz, 1H), 7.25 (d, J=4.5 Hz, 1H), 6.81
(d, J=4.6 Hz, 1H), 6.71 (d, J=12.8 Hz, 1H), 6.03 (dd, J=3.7, 1.6
Hz, 1H), 4.51 (d, J=4.6 Hz, 1H), 3.43-3.15 (m, 5H), 2.64-2.50 (m,
2H), 2.50-2.33 (m, 1H), 2.20 (d, J=12.1 Hz, 1H), 1.83 (t, J=8.2 Hz,
1H), 1.75 (s, 1H), 1.60 (t, J=8.2 Hz, 2H), 1.40 (d, J=11.2 Hz, 2H),
1.25-0.93 (m, 4H).
Example 154
##STR00406##
[0858]
4-(((1S,2S)-2-(6-Azaspiro[2.5]octan-6-yl)cyclohexyl)amino)-5-chloro-
-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0859] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
6-azaspiro[2.5]octane,
4-(((1S,2S)-2-(6-Azaspiro[2.5]octan-6-yl)cyclohexyl)amino)-5-chloro-2-flu-
oro-N-(thiazol-2-yl)benzenesulfonamide formate was obtained. LCMS
(ESI) m/z: 499.0 (M+H).sup.+. .sup.1H NMR (400 MHz, cdcl3) .delta.
7.85 (d, J=7.3 Hz, 1H), 7.15 (d, J=4.6 Hz, 1H), 6.50 (d, J=4.6 Hz,
1H), 6.35 (s, 1H), 6.31 (d, J=12.6 Hz, 1H), 3.07-2.98 (m, 1H),
2.82-2.70 (m, 1H), 2.64-2.56 (m, 2H), 2.54-2.42 (m, 2H), 2.30 (d,
J=13.1 Hz, 1H), 2.06-1.96 (m, 1H), 1.93-1.83 (m, 1H), 1.79-1.70 (m,
1H), 1.50-1.10 (m, 8H), 0.25 (s, 4H).
Example 155
##STR00407##
[0860]
5-Chloro-4-(((1S,2S)-2-((1-(cyclopropanecarbonyl)azetidin-3-yl)(met-
hyl)amino)-cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0861] Following the procedure described in Example 146 and making
non-critical variations as required to replace isobutyryl chloride
with cyclopropanecarbonyl chloride,
5-chloro-4-(((1S,2S)-2-((1-(cyclopropanecarbonyl)azetidin-3-yl)(methyl)am-
ino)-cyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
was obtained as an off-white solid. LCMS (ESI) m/z: 542.1
[M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.15 (s, 1H),
7.56 (d, J=7.0 Hz, 1H), 7.15 (d, J=3.9 Hz, 1H), 6.75-6.64 (m,
J=13.1 Hz, 2H), 5.76-5.61 (m, 1H), 4.18 (dt, J=15.1, 7.6 Hz, 1H),
4.09-3.86 (m, 1H), 3.83-3.74 (m, 1H), 3.74-3.64 (m, J=5.4 Hz, 2H),
3.60-3.52 (m, 1H), 2.59 (t, J=9.5 Hz, 1H), 2.05 (s, 4H), 1.76-1.64
(m, 2H), 1.60 (d, J=11.5 Hz, 1H), 1.55-1.40 (m, 1H), 1.40-1.04 (m,
4H), 0.76-0.55 (m, 4H).
Example 156
##STR00408##
[0862]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((cis-3-hydroxycyclobutyl)(methyl)a-
mino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
Formate
[0863] Following the procedure described in Example 18 and making
non-critical variations as required to replace acetaldehyde with
3-hydroxycyclobutane, the title compound was obtains as a mixture
of diastereomers. Separation of isomers by HPLC gave
5-Chloro-2-fluoro-4-(((1S,2S)-2-((cis-3-hydroxycyclobutyl)(methyl)amino)c-
yclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate as a
white solid. LCMS (ESI) m/z: 489.1 [M+H].sup.+. .sup.1H NMR (400
MHz, d6-DMSO) .delta. 12.61 (s, 1H), 8.14 (s, 1H), 7.59 (d, J=7.3
Hz, 1H), 7.23 (d, J=4.5 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.72 (d,
J=12.9 Hz, 1H), 5.82 (d, J=3.5 Hz, 1H), 4.92 (s, 1H), 4.13 (tt,
J=7.2, 3.8 Hz, 1H), 3.29-3.16 (m, 2H), 2.65-2.55 (m, 1H), 2.20-2.12
(m, 1H), 2.10-2.05 (m, 1H), 2.02-1.92 (m, 4H), 1.91-1.80 (m, 2H),
1.78-1.67 (m, 2H), 1.64-1.56 (m, 1H), 1.42-1.29 (m, 1H), 1.29-1.09
(m, 3H).
Example 157
##STR00409##
[0864]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((trans-3-hydroxycyclobutyl)(methyl-
)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
Formate
[0865] Following the procedure described in Example 18 and making
non-critical variations as required to replace acetaldehyde with
3-hydroxycyclobutane, the title compound was obtains as a mixture
of diastereomers. Separation of isomers by HPLC gave
5-Chloro-2-fluoro-4-(((1S,2S)-2-((trans-3-hydroxycyclobutyl)(methyl)amino-
)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate as a
white solid. LCMS (ESI) m/z: 489.1 [M+H].sup.+. .sup.1H NMR (400
MHz, d6-DMSO) .delta. 12.78 (s, 1H), 8.14 (s, 1H), 7.60 (d, J=7.3
Hz, 1H), 7.21 (d, J=4.2 Hz, 1H), 6.76 (d, J=4.0 Hz, 1H), 6.69 (d,
J=12.8 Hz, 1H), 5.84 (s, 1H), 4.99 (d, J=5.5 Hz, 1H), 3.72 (dd,
J=14.1, 7.4 Hz, 1H), 3.24-3.12 (m, 1H), 2.64-2.56 (m, 1H),
2.38-2.26 (m, 3H), 2.17 (d, J=11.3 Hz, 1H), 1.94 (s, 3H), 1.78-1.65
(m, 2H), 1.65-1.45 (m, 3H), 1.42-1.29 (m, 1H), 1.27-1.04 (m,
3H).
Example 158
##STR00410##
[0866]
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S,4S)-2-((2-hyd-
roxyethyl)(methyl)amino)-4-(trifluoromethyl)cyclohexyl)amino)benzenesulfon-
amide Formate
[0867] Following the procedure described in Example 138 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-2,4-difluoro-N-(6-fluoropyridin-2-yl)-N-(methoxymethyl)benzenesu-
lfonamide,
5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-4-(((1S,2S,4S)-2-((2-
-hydroxyethyl)(methyl)amino)-4-(trifluoromethyl)cyclohexyl)amino)benzenesu-
lfonamide formate was obtained as a white solid. LCMS (ESI) m/z:
543.3 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13
(s, 1H), 7.90-7.80 (m, 1H), 7.73 (d, J=7.6 Hz, 1H), 6.92-6.81 (m,
2H), 6.71 (dd, J=8.0, 2.4 Hz, 1H), 6.16 (d, J=5.2 Hz, 1H),
3.57-3.40 (m, 3H), 3.05-2.86 (m, 1H), 2.65-2.55 (m, 2H), 2.48-2.35
(m, 1H), 2.22 (s, 3H), 2.16-2.07 (m, 1H), 2.06-1.95 (m, 1H),
1.84-1.72 (m, 1H), 1.58-1.43 (m, 1H), 1.42-1.19 (m, 2H).
Example 159 & Example 160
##STR00411##
[0868]
4-(((1R,2R)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-ch-
loro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
4-(((1S,2S)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-chloro-2-
-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0869] Following the procedure described in Example 105 &
Example 106 and making non-critical variations as required to
replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)ben-
zenesulfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide,
4-(((1S,2S)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5--
chloro-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide was obtained as
a white solid. Example 158: LCMS (ESI) m/z: 471.1 [M+H].sup.+. H
NMR (400 MHz, DMSO-d6) .delta. 12.73 (s, 1H), 7.59 (d, J=7.3 Hz,
1H), 7.24 (d, J=4.5 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.67 (d,
J=12.9 Hz, 1H), 5.68 (dd, J=4.7, 1.8 Hz, 1H), 3.20-3.04 (m, 1H),
2.86-2.59 (m, 3H), 2.40-2.27 (m, 1H), 2.16-2.06 (m, 2H), 1.84-1.68
(m, 2H), 1.67-1.54 (m, 1H), 1.48-1.02 (m, 7H), 0.49-0.38 (m, 1H),
0.28-0.13 (m, 1H).
4-(((1R,2R)-2-(3-azabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-5-chloro-2-
-fluoro-N-(thiazol-2-yl)benzenesulfonamide was obtained as a white
solid. Example 159: LCMS (ESI) m/z: 471.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d6) .delta. 12.72 (s, 1H), 7.59 (d, J=7.3 Hz, 1H),
7.24 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.5 Hz, 1H), 6.67 (d, J=12.9 Hz,
1H), 5.69 (dd, J=4.8, 1.9 Hz, 1H), 3.20-3.09 (m, 1H), 2.83-2.63 (m,
3H), 2.36 (d, J=8.2 Hz, 1H), 2.16-2.08 (m, 1H), 1.84-1.67 (m, 2H),
1.66-1.55 (m, 1H), 1.45-1.03 (m, 7H), 0.51-0.37 (m, 1H), 0.27-0.14
(m, 1H).
Example 161
##STR00412##
[0870]
5-Chloro-4-(((1S,2S)-2-((R)-3-cyanopyrrolidin-1-yl)cyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0871] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
(R)-pyrrolidine-3-carbonitrile,
5-chloro-4-(((1S,2S)-2-((R)-3-cyanopyrrolidin-1-yl)cyclohexyl)amino)-2-fl-
uoro-N-(thiazol-2-yl)benzenesulfonamide formate was obtained. LCMS
(ESI) m/z: 483.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.78 (bs, 1H), 8.15 (s, 1H), 7.56 (dd, J=7.1, 5.0 Hz, 1H),
7.14 (s, 1H), 6.67 (d, J=12.4 Hz, 2H), 5.71 (d, J=15.3 Hz, 1H),
3.17-3.02 (m, 1H), 2.93-2.76 (m, 2H), 2.78-2.58 (m, 2H), 2.60-2.51
(m, 1H), 2.20-1.93 (m, 2H), 1.92-1.66 (m, 3H), 1.60 (d, J=13.9 Hz,
1H), 1.48-1.06 (m, 4H).
Example 162
##STR00413##
[0872]
5-Chloro-4-(((1S,2S)-2-((S)-3-cyanopyrrolidin-1-yl)cyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0873] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
(S)-pyrrolidine-3-carbonitrile,
5-chloro-4-(((1S,2S)-2-((S)-3-cyanopyrrolidin-1-yl)cyclohexyl)amino)-2-fl-
uoro-N-(thiazol-2-yl)benzenesulfonamide formate was obtained. LCMS
(ESI) m/z: 484.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.74 (br.s, 1H), 7.57 (dd, J=7.3, 5.4 Hz, 1H), 7.23 (d,
J=4.5 Hz, 1H), 6.78 (d, J=4.5 Hz, 1H), 6.72 (d, J=12.9 Hz, 1H),
5.80 (dd, J=16.3, 4.8 Hz, 1H), 3.18-3.03 (m, 1H), 2.92-2.77 (m,
3H), 2.77-2.58 (m, 2H), 2.59-2.52 (m, 1H), 1.91-1.68 (m, 3H), 1.60
(d, J=13.2 Hz, 1H), 1.48-1.09 (m, 4H).
Example 163
##STR00414##
[0874]
5-Chloro-2-fluoro-4-(((1S,2S)-2-(4-methylpiperazin-1-yl)cyclohexyl)-
amino)-N-(thiazol-2-yl)benzenesulfonamide
[0875] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
1-methylpiperazine,
5-Chloro-2-fluoro-4-(((1S,2S)-2-(4-methylpiperazin-1-yl)cyclohexyl)amino)-
-N-(thiazol-2-yl)benzenesulfonamide was obtained. LCMS (ESI) m/z:
488.0 (M+H).sup.+. .sup.1H NMR (400 MHz, d6-dmso) .delta. 7.59 (d,
J=7.3 Hz, 1H), 7.20 (d, J=4.4 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.68
(d, J=12.9 Hz, 1H), 5.91 (d, J=3.3 Hz, 1H), 3.27-3.17 (m, 1H),
2.63-2.22 (m, 9H), 2.16 (s, 3H), 2.16-2.09 (m, 1H), 1.86-1.70 (m,
2H), 1.66-1.55 (m, 1H), 1.45-1.07 (m, 4H).
Example 164
##STR00415##
[0876]
5-Chloro-4-(((2R,3R)-3-(dimethylamino)-1,2,3,4-tetrahydronaphthalen-
-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
##STR00416##
[0877] Step 1
##STR00417##
[0878] Rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diol
[0879] To a mixture of formic acid (8.84 g, 192 mmol) and hydrogen
peroxide (30% w/w in H.sub.2O) (1.04 g, 9.22 mmol) was added
1,4-dihydronaphthalene (1.0 g, 7.68 mmol). The immiscible layers
are stirred vigorously and the suspension becomes homogeneous after
10 min. The reaction was heated at 60.degree. C. and it is held for
1 hour. Most of the formic acid is removed by distillation and the
residue is heated for 45 min at 60.degree. C. with 5 mL NaOH (20%
in water). After cooling, the yellow solution is neutralized with
HCl (6 M) until pH=1 and extracted with EtOAc (20 mL). The organic
extract was dried over MgSO.sub.4, filtered and concentrated in
vacuo to give crude trans-1,2,3,4-tetrahydronaphthalene-2,3-diol
(1.26 g), which was used directly in the next step without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.16-7.07
(m, 4H), 3.95-3.86 (m, 2H), 3.24-3.16 (m, 2H), 2.89-2.79 (m,
2H).
##STR00418##
Rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diyl
dimethanesulfonate
[0880] Methanesulfonyl chloride (1.19 mL, 15 mmol) was added at
0.degree. C. to a solution of
rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diol (0.63 g, 3.84
mmol) in pyridine (4 mL). The reaction was warmed to rt and stirred
for 1 hour until completion. The reaction mixture was diluted with
cold water (10 mL) and extracted with EtOAc (3.times.10 mL). The
combined organic layers were washed with HCl (0.5N), followed by
brine (10 mL). The organic phase was dried over Na.sub.2SO.sub.4
and the solvent was removed in vacuo to give
rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diyl dimethanesulfonate
(1.23 g, 3.8 mmol, 99% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.23-7.16 (m, 2H), 7.15-7.04 (m, 2H), 5.07 (ddt, J=9.5,
8.3, 4.2 Hz, 2H), 3.53-3.43 (m, 2H), 3.18 (ddd, J=10.4, 5.5, 3.0
Hz, 2H).
Step 3
##STR00419##
[0881] Rac-trans-2,3-diazido-1,2,3,4-tetrahydronaphthalene
[0882] Sodium azide (4.0 g, 62.4 mmol) was added at 120.degree. C.
to a solution of rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diyl
dimethanesulfonate (2.0 g, 6.24 mmol) in DMF (3 mL, anhydrous). The
reaction was stirred for 2 hour until completion. The reaction
mixture was diluted with cold water (30 mL) and extracted with
EtOAc (3.times.30 mL). The combined organic layers were washed with
HCl (0.5 N) then with brine (10 mL). The organic phase was dried
over Na.sub.2SO.sub.4 and the solvent was removed in vacuo to give
rac-trans-2,3-diazido-1,2,3,4-tetrahydronaphthalene (1.2 g, 90%
yield). The crude mixture was used without purification to the next
step. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.20-7.15 (m, 2H),
7.13-7.08 (m, 2H), 3.80-3.69 (m, 2H), 3.26-3.19 (m, 2H).
Step 4
##STR00420##
[0883] Rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diamine
[0884] Rac-trans-2,3-diazido-1,2,3,4-tetrahydronaphthalene (1.3 g,
2.43 mmol) was dissolved in ethanol (1 mL) and to the solution was
added Pd/C (0.5 g, 10% on carbon). The mixture was stirred under
H.sub.2 (1 atm) overnight until completion. The mixture was
filtered through Celite and concentrated in vacuo to give crude
rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diamine (0.82 g, 83%
yield) which was used without further purification. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.10 (ddd, J=16.7, 7.5, 4.3 Hz, 4H),
3.11-3.03 (m, 4H), 2.67 (dd, J=15.9, 10.0 Hz, 2H).
Step 5
##STR00421##
[0885]
Rac-4-((trans-3-amino-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-5-ch-
loro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0886]
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-thiazol-2-y-
l-benzenesulfonamide (200 mg, 0.43 mmol) was dissolved in DMF (2
mL) and to the solution was added
rac-trans-1,2,3,4-tetrahydronaphthalene-2,3-diamine (352 mg, 0.87
mmol) followed by triethylamine (0.18 mL, 1.3 mmol). The reaction
mixture was stirred at rt for 4 days until complete. Diluted the
reaction with EtOAc (30 mL) and washed with water (10 mL) then
brine (2.times.10 mL). The organic layer was separated and dried
over MgSO.sub.4, filtered and removed the solvent in vacuo to
provide the crude
4-((trans-3-amino-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-5-chloro-N-(2,-
4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (220
mg), which was used directly in the next step without further
purification.
Step 6
##STR00422##
[0887]
Rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-((trans-3-(dimethylamino)-1,-
2,3,4-tetrahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesul-
fonamide
[0888] To solution of
rac-4-((trans-3-amino-1,2,3,4-tetrahydronaphthalen-2-yl)amino)-5-chloro-N-
-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(190 mg, 0.32 mmol) in methanol (2 mL) was added formaldehyde (37%
w/w in H.sub.2O) (0.23 mL, 3.15 mmol) followed by sodium
cyanoborohydride (78 mg, 1.26 mmol). The mixture was stirred at rt
overnight. After 16 h, the mixture was concentrated, poured in
CH.sub.2Cl.sub.2 (20 mL) and NaHCO.sub.3 (20 mL, saturated). The
phases were separated and the CH.sub.2Cl.sub.2 phases were dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification by flash chromatography through Si gel (20-100%
EtOAc/hexanes+1% Et.sub.3N) provided
rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-((trans-3-(dimethylamino)-1,2,34-t-
etrahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamid-
e as a mixture of trans enantiomers (123 mg, 62% yield). LCMS (ESI)
m/z: 631.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.75 (d, J=7.1 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.23-7.08 (m, 5H),
6.96 (d, J=3.6 Hz, 1H), 6.38 (dt, J=12.9, 7.5 Hz, 4H), 5.21 (d,
J=2.0 Hz, 2H), 3.75 (s, 6H), 3.49-3.39 (m, 2H), 2.96 (dd, J=45.0,
22.1 Hz, 3H), 2.71 (s, 1H), 2.31 (s, 6H).
Step 7
##STR00423##
[0889]
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((2S,3S)-3-(dimethylamino)-1,2,-
3,4-tetrahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfo-
namide &
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((2R,3R)-3-(dimethylamino)-1,-
2,3,4-tetrahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesul-
fonamide
[0890] Racemic
5-chloro-N-(2,4-dimethoxybenzyl)-4-((trans-3-(dimethylamino)-1,2,3,4-tetr-
ahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(120 mg, 0.190 mmol) was separated by using chiral HPLC (Chiralpak
IB (250 mm.times.20 mm, 5 um), MeOH:DCM:hexane 5:15:85 containing
0.1% of diethylamine, 15 ml/min) to give
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((2R,3R)-3-(dimethylamino)-1,2,3,4-te-
trahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(1st peak, 42 mg, 35% yield) as white solid. LCMS (ESI) m/z: 631.2
[M+H].sup.+. Also afforded was
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((2S,3S)-3-(dimethylamino)-1,2,3,4-te-
trahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(2nd peak, 43 mg, 36% yield). LCMS (ESI) m/z: 631.2 [M+H].sup.+.
Absolute configuration was arbitrarily assigned to each isomer.
Step 8
##STR00424##
[0891]
5-Chloro-4-(((2R,3R)-3-(dimethylamino)-1,2,3,4-tetrahydronaphthalen-
-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0892]
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((2R,3R)-3-(dimethylamino)-1,2,-
3,4-tetrahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfo-
namide (42 mg, 0.07 mmol) was dissolved in 1,4-dioxane (0.50 mL)
and to the solution was added formic acid (0.42 mL, 6.65 mmol). The
reaction was stirred at rt for 2 h then directly purified by C18
reverse phase flash chromatography (MeCN/10 mM aqueous ammonium
bicarbonate, pH=10) to afford
5-chloro-4-(((2R,3R)-3-(dimethylamino)-1,2,3,4-tetrahydronaphthalen-2-yl)-
amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (31 mg, 97%
yield). LCMS (ESI) m/z: 481.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) .delta. 7.60 (d, J=7.3 Hz, 1H), 7.22 (d, J=4.5 Hz, 1H),
7.18-7.06 (m, 5H), 6.87 (d, J=12.9 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H),
6.14 (d, J=4.7 Hz, 1H), 3.76 (d, J=8.3 Hz, 2H), 3.19 (s, 1H), 2.87
(dt, J=27.0, 13.4 Hz, 2H), 2.64 (d, J=15.5 Hz, 1H), 2.28 (s,
6H).
Example 165
##STR00425##
[0893]
5-Chloro-4-(((2S,3S)-3-(dimethylamino)-1,2,3,4-tetrahydronaphthalen-
-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0894]
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((2S,3S)-3-(dimethylamino)-1,2,-
3,4-tetrahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfo-
namide (43 mg, 0.07 mmol) dissolved in 1,4-dioxane (0.50 mL) and to
the solution was added formic acid (0.42 mL, 6.65 mmol). The
reaction was stirred at rt for 2 h, then directly purified by C18
reverse phase flash chromatography (MeCN/10 mM aqueous ammonium
bicarbonate, pH=10) to afford
5-chloro-4-(((2S,3S)-3-(dimethylamino)-1,2,3,4-tetrahydronaphthalen-2-yl)-
amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (31 mg, 95%
yield). LCMS (ESI) m/z: 481.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) .delta. 7.60 (d, J=7.3 Hz, 1H), 7.22 (d, J=4.5 Hz, 1H),
7.18-7.06 (m, 5H), 6.87 (d, J=12.9 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H),
6.14 (d, J=4.7 Hz, 1H), 3.76 (d, J=8.3 Hz, 2H), 3.19 (s, 1H), 2.87
(dt, J=27.0, 13.4 Hz, 2H), 2.64 (d, J=15.5 Hz, 1H), 2.28 (s,
6H).
Example 166
##STR00426##
[0895]
N-((1S,2S)-2-((2-Chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)pheny-
l)amino)cyclohexyl)-N-methylacetamide
##STR00427##
[0896] Step 1
##STR00428##
[0897]
N-((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)-
sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)-N-methylacetamide
[0898]
5-Chloro-N-[(2,4-dimethoxyphenyl)methyl]-2-fluoro-4-[[(1S,2S)-2-(me-
thylamino)cyclohexyl]amino]-N-thiazol-2-yl-benzenesulfonamide (80
mg, 0.14 mmol) was dissolved in CH.sub.2Cl.sub.2 (1 mL) and to the
solution was added pyridine (0.11 mL, 1.41 mmol) followed by acetic
anhydride (26 uL, 0.28 mmol). The reaction is stirred at rt for 20
min then directly purified by flash chromatography through Si gel
(EtOAc/hexanes) to provide
N-((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-y-
l)sulfamoyl)-5-fluorophenyl)amino)cyclohexyl)-N-methylacetamide (81
mg, 94% yield). LCMS (ESI) m/z: 611.1 [M+H].sup.+.
Step 2
##STR00429##
[0899]
N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)pheny-
l)amino)cyclohexyl)-N-methylacetamide
[0900] Following the procedure in Example 165 and making
non-critical modifications to substitute
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((2S,3S)-3-(dimethylamino)-1,2,3,4-te-
trahydronaphthalen-2-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
N-((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)s-
ulfamoyl)-5-fluorophenyl)amino)cyclohexyl)-N-methylacetamide (81
mg, 0.13 mmol),
N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phen-
yl)amino)cyclohexyl)-N-methyl-acetamide (53 mg, 88% yield) was
obtained. LCMS (ESI) m/z: 461.0 [M+H].sup.+. H NMR (400 MHz,
d6-DMSO) .delta. 12.74 (s, 1H), 7.52 (t, J=7.3 Hz, 1H), 7.24 (dd,
J=4.6, 0.9 Hz, 1H), 6.79 (qd, J=23.0, 13.3 Hz, 2H), 3.66 (d, J=50.7
Hz, 1H), 2.52 (s, 3H), 2.05 (s, 1H), 2.00 (d, J=11.3 Hz, 1H), 1.87
(s, 2H), 1.82 (s, 1H), 1.67 (dd, J=31.8, 19.8 Hz, 3H), 1.43-1.15
(m, 3H).
Example 167
##STR00430##
[0901]
N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)pheny-
l)amino)cyclohexyl)-2-(dimethylamino)-N-methylacetamide
[0902] Following the synthetic sequence described in Example 166
and making non-critical modifications to substitute acetic
anhydride with 2-(dimethylamino)acetyl chloride,
N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl)amin-
o)cyclohexyl)-2-(dimethylamino)-N-methylacetamide was obtained.
LCMS (ESI) m/z: 504.0 [M+H].sup.+. .sup.1H NMR (400 MHz, d6DMSO)
.delta. 8.13 (s, 1H), 7.51 (dd, J=7.4, 4.1 Hz, 1H), 7.16 (dd,
J=4.4, 2.1 Hz, 1H), 6.86-6.68 (m, 2H), 5.91-5.28 (m, 1H), 3.73 (t,
J=13.4 Hz, 2H), 3.44 (dd, J=61.1, 14.0 Hz, 1H), 3.26-3.10 (m, 1H),
2.68 (d, J=82.7 Hz, 3H), 2.33 (s, 3H), 2.18 (s, 3H), 1.94 (s, 1H),
1.74-1.53 (m, 4H), 1.31 (s, 3H).
Example 168
##STR00431##
[0903]
5-chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-(hydroxymethyl)piperidin-1-y-
l)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide Formate
[0904] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
(S)-piperidin-3-ylmethanol,
5-chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-(hydroxymethyl)piperidin-1-yl)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate was
obtained. LCMS (ESI) m/z: 503.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-dmso) .delta. 8.14 (s, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.22 (d,
J=4.5 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.68 (d, J=12.8 Hz, 1H),
6.04 (s, 1H), 3.24-3.12 (m, 3H), 2.66-2.58 (m, 1H), 2.55-2.51 (m,
2H), 2.47-2.36 (m, 1H), 2.28-2.16 (m, 1H), 1.94-1.71 (m, 3H),
1.66-1.49 (m, 3H), 1.47-1.30 (m, 3H), 1.27-1.17 (m, 2H), 1.15-1.02
(m, 1H), 0.99-0.84 (m, 1H).
Example 169
##STR00432##
[0905]
5-chloro-2-fluoro-4-(((1S,2S)-2-((R)-3-(hydroxymethyl)piperidin-1-y-
l)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide Formate
[0906] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
(R)-piperidin-3-ylmethanol,
5-chloro-2-fluoro-4-(((1S,2S)-2-((R)-3-(hydroxymethyl)piperidin-1-yl)cycl-
ohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide formate was
obtained. LCMS (ESI) m/z: 503.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-dmso) .delta. 8.14 (s, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.22 (d,
J=4.5 Hz, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.67 (d, J=12.8 Hz, 1H),
6.00 (s, 1H), 4.38 (s, 1H), 3.27 (dd, J=10.6, 5.6 Hz, 1H),
3.24-3.17 (m, 1H), 3.14 (dd, J=10.6, 7.2 Hz, 1H), 2.75-2.69 (m,
1H), 2.57-2.52 (m, 1H), 2.47-2.42 (m, 1H), 2.25-2.10 (m, 2H), 1.99
(t, J=10.5 Hz, 1H), 1.87-1.72 (m, 2H), 1.67-1.30 (m, 5H), 1.29-1.04
(m, 4H), 0.91-0.76 (m, 1H).
Example 170
##STR00433##
[0907]
4-(((1S,2S,4S)-2-(azetidin-3-yl(methyl)amino)-4-(trifluoromethyl)cy-
clohexyl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonami-
de
Step 1
##STR00434##
[0908] benzyl
3-(((1S,6S)-6-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)cyclohex-3--
en-1-yl)(methyl)amino)azetidine-1-carboxylate
[0909] Following the procedure described in Example 138, step 1,
step 2 and making non-critical variations as required to replace
(tert-butyldimethylsilyloxy)acetaldehyde with benzyl
3-oxoazetidine-1-carboxylate, benzyl
3-(((1S,6S)-6-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)cyclohex-3--
en-1-yl)(methyl)amino)azetidine-1-carboxylate was obtained as a
light yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.50-7.31 (m, 5H), 6.22 (s, 1H), 5.24 (s, 1H), 5.11 (s, 2H),
4.05-4.00 (m, 2H), 3.99-3.91 (m, 2H), 3.69-3.65 (m, 1H), 3.64-3.45
(m, 1H), 3.15-3.01 (m, 1H), 2.71-2.66 (m, 1H), 2.31-2.10 (m, 2H),
2.19 (s, 3H), 2.01-1.98 (m, 1H), 1.45 (s, 9H).
Step 2
##STR00435##
[0910] benzyl
3-(((1S,6S)-6-((2-chloro-5-fluoro-4-(N-(6-fluoropyridin-2-yl)-N-(methoxym-
ethyl)sulfamoyl)phenyl)amino)-3-(trifluoromethyl)cyclohex-3-en-1-yl)(methy-
l)amino)azetidine-1-carboxylate
[0911] Following the procedure described in Example 138, step 4,
step 5 and making non-critical variations as required to replace
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)car-
bamate and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)b-
enzenesulfonamide with benzyl
3-(((1S,6S)-6-((tert-butoxycarbonyl)amino)-3-(trifluoromethyl)cyclohex-3--
en-1-yl)(methyl)amino)azetidine-1-carboxylate and
5-chloro-2,4-difluoro-N-(6-fluoropyridin-2-yl)-N-(methoxymethyl)benzenesu-
lfonamide, benzyl
3-(((1S,6S)-6-((2-chloro-5-fluoro-4-(N-(6-fluoropyridin-2-yl)-N-(methoxym-
ethyl)sulfamoyl)phenyl)amino)-3-(trifluoromethyl)cyclohex-3-en-1-yl)(methy-
l)amino)azetidine-1-carboxylate was obtained as a light yellow
solid. LCMS (ESI) m/z: 752.0 [M+Na].sup.+.
Step 3
##STR00436##
[0912]
4-(((1S,6S)-6-(azetidin-3-yl(methyl)amino)-4-(trifluoromethyl)cyclo-
hex-3-en-1-yl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-N-(methoxy-
methyl)benzenesulfonamide
[0913] Following the procedure described in Example 138, step 3 and
making non-critical variations as required to replace
tert-butyl((1S,6S)-6-((2-((tert-butyldimethylsilyl)oxy)ethyl)(methyl)amin-
o)-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamate with benzyl
3-(((1S,6S)-6-((2-chloro-5-fluoro-4-(N-(6-fluoropyridin-2-yl)-N-(methoxym-
ethyl)sulfamoyl)phenyl)amino)-3-(trifluoromethyl)cyclohex-3-en-1-yl)(methy-
l)amino)azetidine-1-carboxylate,
4-(((1S,6S)-6-(azetidin-3-yl(methyl)amino)-4-(trifluoromethyl)cyclohex-3--
en-1-yl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-N-(methoxymethyl-
)benzenesulfonamide was obtained as a yellow solid. LCMS (ESI) m/z:
598.1 [M+H].sup.+.
Step 4
##STR00437##
[0914]
4-(((1S,2S,4S)-2-(azetidin-3-yl(methyl)amino)-4-(trifluoromethyl)cy-
clohexyl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonami-
de
[0915] Following the procedure described in Example 138, step 6 and
making non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S,4S)-2-((2-hydroxyeth-
yl)(methyl)amino)-4-(trifluoromethyl)cyclohexyl)amino)-N-(thiazol-2-yl)ben-
zenesulfonamide with
4-(((1S,6S)-6-(azetidin-3-yl(methyl)amino)-4-(trifluoromethyl)cyclohex-3--
en-1-yl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)-N-(methoxymethyl-
)benzenesulfonamide,
4-(((1S,2S,4S)-2-(azetidin-3-yl(methyl)amino)-4-(trifluoromethyl)cyclohex-
yl)amino)-5-chloro-2-fluoro-N-(6-fluoropyridin-2-yl)benzenesulfonamide
was obtained as a light yellow solid. LCMS (ESI) m/z: 554.2
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.21 (s,
1H), 7.20 (d, J=7.2 Hz, 1H), 7.49-7.42 (m, 1H), 6.71 (d, J=13.2 Hz,
1H), 6.59-6.53 (m, 1H), 6.19-6.16 (m, 1H), 5.60 (d, J=7.6 Hz, 1H),
3.95-3.91 (m, 1H), 3.86-3.78 (m, 4H), 2.83-2.76 (m, 1H), 2.29-2.23
(m, 1H), 2.14 (s, 3H), 2.04-2.01 (m, 1H), 1.81-1.75 (m, 2H),
1.39-1.23 (m, 4H).
Example 171
##STR00438##
[0916]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(4-methylthiazol-2-yl)benzenesulfonamide
Formate
[0917] Following the procedure described in Example 112 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(4-methylthiazol-2-yl)ben-
zenesulfonamide,
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclohexyl)a-
mino)-2-fluoro-N-(4-methylthiazol-2-yl)benzenesulfonamide formate
was obtained as a white solid. LCMS (ESI) m/z: 515.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (s, 1H), 7.57 (d,
J=7.2 Hz, 1H), 6.82 (d, J=13.2 Hz, 1H), 6.37 (d, J=1.2 Hz, 1H),
5.82 (d, J=5.2 Hz, 1H), 3.52-3.48 (m, 1H), 2.86-2.75 (m, 1H),
2.45-2.34 (m, 1H), 2.19 (s, 3H), 2.19 (s, 3H), 2.18-2.11 (m, 1H),
2.08 (s, 3H), 2.03-1.95 (m, 1H), 1.84-1.73 (m, 1H), 1.59-1.44 (m,
1H), 1.35-1.19 (m, 2H).
Example 172
##STR00439##
[0918]
5-Chloro-N-(5-chloro-4-methylthiazol-2-yl)-4-(((1S,2S)-2-(dimethyla-
mino)cyclohexyl)amino)-2-fluorobenzenesulfonamide
##STR00440##
[0919] Step 1
##STR00441##
[0920]
5-Chloro-N-(5-chloro-4-methylthiazol-2-yl)-2,4-difluorobenzenesulfo-
namide
[0921] To a solution of
5-chloro-2,4-difluorobenzenesulfonylchloride (150 mg, 0.61 mmol) in
CH.sub.2Cl.sub.2 (2 mL) and pyridine (1 mL) was added
5-chloro-4-methyl-thiazol-2-amine (108 mg, 0.73 mmol) and the
mixture stirred at rt overnight. After 16 h, the reaction mixture
was diluted with CH.sub.2Cl.sub.2 (50 mL), washed with saturated
aqueous NaHCO.sub.3 (10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to remove pyridine. The crude residue was
purified by flash chromatography through Si gel (0-100%
EA/CH.sub.2Cl.sub.2) to provide
5-chloro-N-(5-chloro-4-methyl-thiazol-2-yl)-2,4-difluoro-benzenesulfonami-
de (86 mg, 39%) as a yellow oil. LCMS (ESI) m/z: 358.9, 360.9
[M+H].sup.+.
Step 2
##STR00442##
[0922]
5-Chloro-N-(5-chloro-4-methylthiazol-2-yl)-N-(ethoxymethyl)-2,4-dif-
luorobenzenesulfonamide
[0923] To a solution of
5-chloro-N-(5-chloro-4-methyl-thiazol-2-yl)-2,4-difluoro-benzenesulfonami-
de (80 mg, 0.22 mmol) in CH.sub.2Cl.sub.2 (0.89 mL) was added
chloromethyl ethyl ether (0.02 mL, 0.27 mmol), followed by DIPEA
(0.06 mL, 0.33 mmol). The reaction mixture was stirred at
25.degree. C. for 16 h. The reaction was diluted CH.sub.2Cl.sub.2
(5 mL) and saturated aqueous NaHCO.sub.3 (10 mL) and the phases
were separated. Organic extract was dried with Na.sub.2SO.sub.4 and
evaporated. The residue was purified by flash chromatography
through Si gel (100% CH.sub.2Cl.sub.2) to provide
5-chloro-N-(5-chloro-4-methyl-thiazol-2-yl)-N-(ethoxymethyl)-2,4-difluoro-
-benzenesulfonamide (33 mg, 36% yield). LCMS (ESI) m/z: 416.9,
418.9 [M+H].sup.+.
Step 3
##STR00443##
[0924]
5-Chloro-N-(5-chloro-4-methylthiazol-2-yl)-4-(((1S,2S)-2-(dimethyla-
mino)cyclohexyl)amino)-N-(ethoxymethyl)-2-fluorobenzenesulfonamide
[0925] Following the procedure described in Example 141 step 1 and
making non-critical variations,
(1S,2S)--N1,N1-dimethylcyclohexane-1,2-diamine was used to afford
5-chloro-N-(5-chloro-4-methylthiazol-2-yl)-4-(((1S,2S)-2-(dimethylamino)c-
yclohexyl)amino)-N-(ethoxymethyl)-2-fluorobenzenesulfonamide (30
mg, 73%). LCMS (ESI) m/z: 539.0, 541.0, 543.0 [M+H].sup.+.
Step 4
##STR00444##
[0926]
5-Chloro-N-(5-chloro-4-methylthiazol-2-yl)-4-(((1S,2S)-2-(dimethyla-
mino)cyclohexyl)amino)-2-fluorobenzenesulfonamide
[0927] Following the procedure described in Example 115 step 2 and
making non-critical variations using
(1S,2S)--N1,N1-dimethylcyclohexane-1,2-diamine and substituting TFA
for formic acid,
5-chloro-N-(5-chloro-4-methylthiazol-2-yl)-4-(((1S,2S)-2-(dimethylamino)c-
yclohexyl)amino)-N-(ethoxymethyl)-2-fluorobenzenesulfonamide,
5-chloro-N-(5-chloro-4-methylthiazol-2-yl)-4-(((1S,2S)-2-(dimethylamino)c-
yclohexyl)amino)-2-fluorobenzenesulfonamide was obtained. LCMS
(ESI) m/z: 481.0 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO)
.delta. 7.52 (d, J=7.2 Hz, 1H), 6.78 (s, 1H), 5.75 (s, 1H),
2.51-2.32 (m, 4H), 2.08 (s, J=42.2 Hz, 7H), 1.80 (d, J=10.4 Hz,
1H), 1.62 (d, J=12.2 Hz, 1H), 1.46-1.12 (m, 6H).
Example 173 & Example 174
##STR00445##
[0928]
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(2-fluorophenyl)cyclohe-
xyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(2-fluorophenyl)cyclohexyl)am-
ino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Step 1
##STR00446##
[0929]
tert-butyl((3S,4S)-3-amino-2'-fluoro-2,3,4,5-tetrahydro-[1,1'-biphe-
nyl]-4-yl)carbamate
[0930] Following the procedure described in Example 23 and making
non-critical variations as required to replace
2-(trifluoromethyl)allyl 4-methylbenzenesulfonate with
1-fluoro-2-(3-iodoprop-1-en-2-yl)benzene,
tert-butyl((3S,4S)-3-amino-2'-fluoro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-
-yl)carbamate was obtained as a white solid.
Step 2
##STR00447##
[0931]
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(2-fluorophenyl)cyclohe-
xyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(2-fluorophenyl)cyclohexyl)am-
ino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0932] Following the procedure described in Example 88 and making
non-critical variations as required to replace
(trans)-tert-butyl(3-amino-3'-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,1'--
biphenyl]-4-yl)carbamate with
tert-butyl((3S,4S)-3-amino-2'-fluoro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-
-yl)carbamate,
5-chloro-4-(((1S,2S,5R)-2-(dimethylamino)-5-(2-fluorophenyl)cyclohexyl)am-
ino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (first peak on
HPLC) and
5-chloro-4-(((1S,2S,5S)-2-(dimethylamino)-5-(2-fluorophenyl)cyclohexyl)am-
ino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (second peak on
HPLC) were obtained both as white solid. Example 173: LCMS (ESI)
m/z: 527.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
7.57 (d, J=7.2 Hz, 1H), 7.30-7.26 (m, 1H), 7.24-7.20 (m, 1H), 7.17
(d, J=4.4 Hz 1H), 7.15-7.10 (m, 2H), 6.83 (d, J=13.2 Hz, 1H), 6.73
(d, J=4.4 Hz, 1H), 5.87 (d, J=6.0 Hz, 1H), 3.73-3.65 (m, 1H),
3.17-3.06 (m, 1H), 2.96-2.88 (m, 1H), 2.30 (s, 3H), 2.30 (s, 3H),
2.14-2.11 (m, 1H), 2.00-1.90 (m, 2H), 1.61-1.55 (m, 1H), 1.53-1.45
(m, 2H). Example 174: LCMS (ESI) m/z: 527.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.62 (d, J=7.2 Hz, 1H),
7.43-7.39 (m, 1H), 7.29-7.24 (m, 1H), 7.22-7.20 (m, 1H), 7.18-7.16
(m, 1H), 7.14-7.11 (m, 1H), 6.76 (d, J=4.4 Hz, 1H), 6.54 (d, J=12.8
Hz, 1H), 5.56 (d, J=6.4 Hz, 1H), 3.85-3.83 (m, 1H), 3.24-3.22 (m,
1H), 2.45-2.43 (m, 1H), 2.30 (s, 3H), 2.30 (s, 3H), 2.24-2.18 (m,
1H), 1.89-1.80 (m, 3H), 1.73-1.64 (m, 2H).
Example 175
##STR00448##
[0933]
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-(2,2,2-trifluoroethyl)aze-
tidin-3-yl)amino)cyclohexyl)-amino)-N-(thiazol-2-yl)benzenesulfonamide
Step 1
##STR00449##
[0934]
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methyl(1-(-
2,2,2-trifluoroethyl)azetidin-3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl-
)benzenesulfonamide
[0935]
4-(((1S,2S)-2-(Azetidin-3-yl(methyl)amino)cyclohexyl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(60 mg, 0.10 mmol) was dissolved in DMF (0.50 mL) and THF (0.50
mL). To the solution was added DIPEA (49.6 mg, 0.38 mmol) followed
by 2,2,2-trifluoroethyl trifluoromethanesulfonate (33 mg, 0.14
mmol). The reaction is stirred at r.t. for 2 hours till completion.
Dilute the reaction with EtOAc (30 mL) and wash it with brine
(3.times.10 mL). The organic layer was dried over Na.sub.2SO.sub.4
and the solvent was removed in vacuo. The crude mixture was
purified by flash column chromatography (silica, EtOAc and hexanes
as eluent) to 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((S,
2S)-2-(methyl(1-(2,2,2-trifluoroethyl)azetidin-3-yl)amino)cyclohexyl)amin-
o)-N-(thiazol-2-yl)benzenesulfonamide (15 mg, 22% yield). LCMS
(ESI) m/z: 706.2 [M+H].sup.+.
Step 2
##STR00450##
[0936]
5-Chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-(2,2,2-trifluoroethyl)aze-
tidin-3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0937] Dissolve
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-(methyl(1-(2,2,2--
trifluoroethyl)azetidin-3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benze-
nesulfonamide (15 mg, 0.02 mmol) in 1,4-dioxane (0.5 mL) and to the
solution was added formic acid (0.50 mL). The reaction was stirred
at rt for 2 hours until completion. The reaction was concentrated
to dryness and purified by reverse phase flash column
chromatography on a C18 column (MeCN/10 mM aqueous ammonium
formate) to afford
5-chloro-2-fluoro-4-(((1S,2S)-2-(methyl(1-(2,2,2-trifluoroethyl)azetidin--
3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (7
mg, 60% yield). LCMS (ESI) m/z: 556.0 [M+H].sup.+. .sup.1H NMR (400
MHz, d6-DMSO) .delta. 8.12 (s, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.15
(d, J=4.3 Hz, 1H), 6.68 (t, J=9.1 Hz, 2H), 5.68 (d, J=4.9 Hz, 1H),
3.43 (dd, J=17.6, 13.2 Hz, 3H), 3.07 (q, J=10.2 Hz, 2H), 2.94 (t,
J=6.5 Hz, 1H), 2.81 (t, J=6.1 Hz, 1H), 2.41 (d, J=10.5 Hz, 1H),
2.05 (s, 1H), 1.61 (dd, J=34.4, 12.9 Hz, 3H), 1.19 (dd, J=39.9,
30.8 Hz, 4H).
Example 176
##STR00451##
[0938]
5-Chloro-4-(((1S,2S)-2-((R)-3-cyanopiperidin-1-yl)cyclohexyl)amino)-
-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0939] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
rac-piperidine-3-carbonitrile, the title compound was obtained as a
mixture of diastereomers. Separation of the isomers by HPLC gave
5-Chloro-4-(((1S,2S)-2-((R)-3-cyanopiperidin-1-yl)cyclohexyl)amino)-2-flu-
oro-N-(thiazol-2-yl)benzenesulfonamide as a white solid. The
stereochemistry of the nitrile group was arbitrarily assigned. LCMS
(ESI) m/z: 497.9 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.40 (br s, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.13 (d, J=4.3
Hz, 1H), 6.67 (d, J=4.3 Hz, 1H), 6.62 (d, J=12.8 Hz, 1H), 5.71 (d,
J=3.2 Hz, 1H), 2.82-2.73 (m, 1H), 2.64 (d, J=4.7 Hz, 2H), 2.59 (t,
J=10.1 Hz, 1H), 2.44-2.38 (m, 1H), 2.38-2.29 (m, 1H), 2.11 (d,
J=11.1 Hz, 1H), 1.79 (d, J=7.2 Hz, 1H), 1.72 (d, J=5.0 Hz, 1H),
1.68-1.45 (m, 4H), 1.41-1.14 (m, 5H), 1.08 (q, J=11.7 Hz, 1H).
Example 177
##STR00452##
[0940]
5-chloro-4-(((1S,2S)-2-((S)-3-cyanopiperidin-1-yl)cyclohexyl)amino)-
-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0941] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
rac-piperidine-3-carbonitrile, the title compound was obtained as a
mixture of diastereomers. Separation of the isomers by HPLC gave
5-Chloro-4-(((1S,2S)-2-((S)-3-cyanopiperidin-1-yl)cyclohexyl)amino)-2-flu-
oro-N-(thiazol-2-yl)benzenesulfonamide as a white solid. The
stereochemistry of the nitrile group was arbitrarily assigned. LCMS
(ESI) m/z: 498.0 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.76 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.24 (d, J=4.6 Hz,
1H), 6.79 (d, J=4.6 Hz, 1H), 6.69 (d, J=13.0 Hz, 1H), 5.92 (d,
J=3.4 Hz, 1H), 2.79 (s, 1H), 2.73-2.55 (m, 3H), 2.21 (t, J=8.0 Hz,
1H), 2.14 (d, J=11.3 Hz, 1H), 1.82-1.67 (m, 2H), 1.67-1.48 (m, 3H),
1.48-1.27 (m, 3H), 1.27-1.05 (m, 3H). 2 CH under the solvent or HOD
signal.
Example 178
##STR00453##
[0942]
5-cyclopropyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)c-
yclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0943] Following the procedure described in Example 15 and making
non-critical variations as required to replace
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)a-
mino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trif-
luoromethyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamid-
e,
5-cyclopropyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cyclo-
hexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was
obtained as a white solid. LCMS (ESI) m/z: 502.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H), 8.29 (d,
J=4.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 6.92 (d, J=5.6 Hz, 1H), 6.56
(d, J=13.2 Hz, 1H), 5.99 (s, 1H), 3.43-3.42 (m, 1H), 2.90-2.80 (m,
1H), 2.24 (s, 3H), 2.24 (s, 3H), 2.20-2.15 (m, 1H), 2.09-1.97 (m,
1H), 1.85-1.76 (m, 1H), 1.63-1.44 (m, 2H), 1.43-1.15 (m, 3H),
0.95-0.80 (m, 2H), 0.65-0.55 (m, 1H), 0.35-0.25 (m, 1H).
Example 179
##STR00454##
[0944]
N-((1S,2S)-2-((2-Chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)pheny-
l)amino)cyclohexyl)-N,1-dimethylazetidine-3-carboxamide
[0945] Following the synthetic sequence described in Example 166
and making non-critical modifications to substitute acetic
anhydride with 1-methylazetidine-3-carboxylic acid and add HATU,
N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl)amin-
o)-cyclohexyl)-2-(dimethylamino)-N-methylacetamide was obtained.
LCMS (ESI) m/z: 516.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.87 (d, J=7.4 Hz, 1H), 6.99 (d, J=4.4 Hz, 1H),
6.48 (d, J=4.4 Hz, 1H), 6.25 (d, J=12.4 Hz, 1H), 5.01 (br s, 1H),
4.64-4.45 (m, 1H), 3.91 (t, J=8.2 Hz, 2H), 3.74-3.46 (m, 2H),
3.39-3.18 (m, 1H), 2.78-2.56 (m, 1H), 2.67 (s, 3H), 2.47 (s, 3H),
2.25-2.14 (m, 1H), 1.93-1.66 (m, 3H), 1.49-1.21 (m, 4H).
Example 180
##STR00455##
[0946]
5-chloro-4-(((1S,2S,4S)-2-(cyclobutyl(methyl)amino)-4-(trifluoromet-
hyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0947] Following the procedure described in Example 138 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide and (tert-butyldimethylsilyloxy)acetaldehyde with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide and cyclobutanone,
5-chloro-4-(((1S,2S,4S)-2-(cyclobutyl(methyl)amino)-4-(trifluoromethyl)cy-
clohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was
obtained as a white solid. LCMS (ESI) m/z: 536.1 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.56 (s, 1H), 8.27 (d,
J=6.0 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 6.92 (d, J=6.0 Hz, 1H), 6.81
(d, J=13.2 Hz, 1H), 5.86 (d, J=4.8 Hz, 1H), 3.42-3.39 (m, 1H),
3.25-3.14 (m, 1H), 2.83-2.73 (m, 1H), 2.43-2.35 (m, 1H), 2.20-2.11
(m, 1H), 1.99 (s, 3H), 1.94-1.84 (m, 2H), 1.82-1.62 (m, 3H),
1.60-1.41 (m, 3H), 1.39-1.21 (m, 2H).
Example 181
##STR00456##
[0948]
5-chloro-4-[[(1S,2S,4S)-2-(dimethylamino)-4-[3-(trifluoromethyl)phe-
nyl]cyclohexyl]amino]-2-fluoro-N-pyrimidin-4-yl-benzenesulfonamide
[0949] Following the procedure described in Example 224 and making
non-critical variations as required to replace
1-(4-(trifluoromethyl)phenyl)ethanone with
1-(3-(trifluoromethyl)phenyl)ethanone,
5-chloro-4-[[(1S,2S,4S)-2-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]cy-
clohexyl]amino]-2-fluoro-N-pyrimidin-4-yl-benzenesulfonamide was
obtained. LCMS (ESI) m/z: 572.0 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.37 (s, 1H), 8.15 (s, 1H), 8.03 (d, J=6.0
Hz, 1H), 7.68-7.60 (m, 3H), 7.58-7.55 (m, 2H), 6.75 (d, J=12.8 Hz,
1H), 6.66 (d, J=6.0 Hz, 1H), 5.88 (d, J=6.4 Hz, 1H), 3.65-3.63 (m,
1H), 3.20-3.15 (m, 1H), 2.85-2.80 (m, 1H), 2.39 (s, 3H), 2.39 (s,
3H), 2.16-2.11 (m, 1H), 2.10-2.01 (m, 1H), 1.78-1.73 (m, 2H),
1.69-1.58 (m, 1H), 1.41-1.37 (m, 1H).
Example 182 & Example 183
##STR00457##
[0950]
5-chloro-4-(((1R,2R)-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-
cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
&
5-chloro-4-(((1S,2S)-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cycloh-
exyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[0951] Following the procedure described in Example 98 &
Example 99 and making non-critical variations as required to
replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)ben-
zenesulfonamide and pyrrolidine, with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide and 6,6-difluoro-3-azabicyclo[3.1.0]hexane, racemic
(trans)-5-chloro-4-((2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cycloh-
exyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was
obtained as a white solid. Racemic
(trans)-5-chloro-4-((2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cycloh-
exyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was
separated by chiral SFC ((Amylose-1 (150 mm*21.2 mm, 10 um),
Supercritical CO.sub.2/MeOH+0.1% NH.sub.4OH=60/40; 70 mL/min) to
give
5-chloro-4-(((1R,2R)-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cycloh-
exyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (first
peak) and
5-chloro-4-(((1S,2S)-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cycloh-
exyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (second
peak) as white solids. Absolute configuration was arbitrarily
assigned to each enantiomer. Example 182: LCMS (ESI) m/z: 502.1
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.60 (s, 1H),
8.32 (s, 1H), 7.70 (d, J=7.3 Hz, 1H), 6.99 (d, J=6.3 Hz, 1H), 6.70
(d, J=13.2 Hz, 1H), 5.79 (d, J=5.1 Hz, 1H), 3.28-3.17 (m, 1H),
3.10-2.97 (m, 2H), 2.94-2.83 (m, 1H), 2.82-2.68 (m, 2H), 2.29-2.13
(m, 2H), 2.14-1.98 (m, 1H), 1.86-1.69 (m, 2H), 1.66-1.51 (m, 1H),
1.42-1.18 (m, 3H), 1.15-1.03 (m, 1H). Example 183: LCMS (ESI) m/z:
502.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.60 (s,
1H), 8.32 (s, 1H), 7.70 (d, J=7.3 Hz, 1H), 6.99 (d, J=6.2 Hz, 1H),
6.70 (d, J=13.2 Hz, 1H), 5.79 (s, 1H), 3.27-3.23 (m, 1H), 3.11-2.97
(m, 2H), 2.93-2.84 (m, 1H), 2.81-2.69 (m, 2H), 2.28-2.14 (m, 2H),
2.15-1.99 (m, 1H), 1.84-1.68 (m, 2H), 1.66-1.52 (m, 1H), 1.45-1.17
(m, 3H), 1.16-1.02 (m, 1H).
Example 184 & Example 185
##STR00458##
[0952]
5-chloro-2-fluoro-4-(((1R,2R)-2-((1R,5S,6R)-6-(hydroxymethyl)-3-aza-
bicyclo-[3.1.0]hexan-3-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfo-
namide &
5-chloro-2-fluoro-4-(((1S,2S)-2-((1R,5S,6R)-6-(hydroxymethyl)-3-a-
zabicyclo[3.1.0]hexan-3-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulf-
onamide
[0953] Following the procedure described in Example 98 &
Example 99 and making non-critical variations as required to
replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(6-fluoropyridin-2-yl)ben-
zenesulfonamide and pyrrolidine, with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide and ((1R,5S,6R)-3-azabicyclo[3.1.0]hexan-6-yl)methanol,
racemic
(trans)-5-chloro-2-fluoro-4-((2-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicycl-
o[3.1.0]hexan-3-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
was obtained as a white solid. Racemic
(trans)-5-chloro-2-fluoro-4-((2-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicycl-
o[3.1.0]hexan-3-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
was separated by chiral SFC ((Chiralpak IC (150 mm*21.2 mm, 10 um),
Supercritical CO.sub.2/MeOH=55/45; 70 mL/min) to give
5-chloro-2-fluoro-4-(((1R,2R)-2-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicycl-
o[3.1.0]hexan-3-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
(first peak) and
5-chloro-2-fluoro-4-(((1S,2S)-2-((1R,5S,6R)-6-(hydroxymethyl)-3-azabicycl-
o[3.1.0]hexan-3-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
(second peak) as white solids. Absolute configuration was
arbitrarily assigned to each enantiomer. Example 184: LCMS (ESI)
m/z: 513.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta.
11.42 (s, 1H), 7.83 (q, J=8.2 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 6.88
(dd, J=8.0, 2.1 Hz, 1H), 6.77-6.59 (m, 2H), 5.90 (d, J=4.0 Hz, 1H),
4.33 (t, J=5.5 Hz, 1H), 3.24-3.06 (m, 3H), 2.79 (s, 2H), 2.74-2.60
(m, 1H), 2.44-2.36 (m, 1H), 2.20-2.01 (m, 1H), 1.87-1.66 (m, 2H),
1.66-1.51 (m, 1H), 1.48-0.99 (m, 7H). Example 185: LCMS (ESI) m/z:
513.1 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.42 (s,
1H), 7.83 (q, J=8.1 Hz, 1H), 7.74 (d, J=7.3 Hz, 1H), 6.88 (d, J=7.9
Hz, 1H), 6.71 (d, J=13.4 Hz, 2H), 5.90 (s, 1H), 4.33 (t, J=5.5 Hz,
1H), 3.24-3.06 (m, 3H), 2.78 (s, 2H), 2.74-2.61 (m, 2H), 2.44-2.34
(m, 1H), 2.18-2.01 (m, 1H), 1.85-1.67 (m, 2H), 1.64-1.51 (m, 1H),
1.46-1.01 (m, 7H).
Example 186
##STR00459##
[0954]
5-Chloro-N-(4-chlorothiazol-2-yl)-4-(((1S,2S)-2-(dimethylamino)cycl-
ohexyl)amino)-2-fluorobenzenesulfonamide
[0955] Following the procedure described in Example 172 and making
non-critical variations substituting
5-chloro-4-methyl-thiazol-2-amine with tert-butyl
N-(4-chlorothiazol-2-yl)carbamate the title compound was obtained
as a white solid. LCMS (ESI) m/z: 466.9, 468.9 [M+H].sup.+. .sup.1H
NMR (400 MHz, d6-DMSO) .delta. 8.57 (s, 1H), 7.57 (d, J=7.1 Hz,
1H), 6.96 (d, J=11.6 Hz, 1H), 6.35 (s, 1H), 5.87 (d, J=9.9 Hz, 1H),
3.89 (d, J=7.5 Hz, 1H), 3.49 (t, J=8.6 Hz, 1H), 2.74 (s, 3H), 2.60
(s, 3H), 2.16-2.00 (m, 1H), 1.95-1.87 (m, 1H), 1.83 (d, J=12.1 Hz,
1H), 1.63 (d, J=11.5 Hz, 1H), 1.48-1.24 (m, 4H).
Example 187
##STR00460##
[0956]
5-chloro-4-(((1S,2S)-2-(dimethylamino)-4,4-difluorocyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
##STR00461## ##STR00462##
[0957] Step 1
##STR00463##
[0958]
Rac-di-tert-butyl(1,2-trans)-cyclohex-4-ene-1,2-diyldicarbamate
[0959] To a suspension of rac-trans-cyclohex-4-ene-1,2-diamine
dihydrochloride (500 mg, 2.7 mmol) in CH.sub.2Cl.sub.2 (10 mL) was
added triethylamine (1.37 g, 1.88 mL, 13.5 mmol) followed by
addition of di-tert-butyl dicarbonate (1.47 g, 6.75 mmol) and the
mixture stirred at rt overnight. After 20 h, the mixture was
diluted with EtOAc (50 mL) and washed with saturated
NaHCO.sub.3(aq) (10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. The crude residue thus obtained was purified
by flash chromatography through Si gel (0-100%
EtOAc/CH.sub.2Cl.sub.2) to provide
rac-di-tert-butyl(1,2-trans)-cyclohex-4-ene-1,2-diyldicarbamate
(726 mg, 86%) as a white solid. LCMS (ESI) m/z: 313.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.65-5.48 (m, 2H), 4.87
(s, 2H), 3.73-3.52 (m, 2H), 2.48 (d, J=16.7 Hz, 2H), 2.05-1.90 (m,
2H), 1.43 (s, 18H).
Step 2
##STR00464##
[0960]
Rac-di-tert-butyl((1,2-trans)-4-oxocyclohexane-1,2-diyl)dicarbamate
[0961] A flask containing
rac-di-tert-butyl(1,2-trans)-cyclohex-4-ene-1,2-diyldicarbamate
(716 mg, 2.29 mmol) was capped and purged with N.sub.2 for 5 min.
The flask was then charged with THF (5 mL) and cooled to 0.degree.
C. before addition of 1M BH.sub.3.THF (3.44 mL, 3.44 mmol) and the
mixture was stirred overnight in the bath allowing to warm to rt.
After 16 h, 1N NaOH (3.44 mL, 3.44 mmol) was cautiously added
followed immediately by addition of 33 wt % H.sub.2O.sub.2(aq) (0.8
mL, 26 mmol) and the resulting mixture stirred at rt. After 1 h,
the mixture was diluted with 50% saturated
Na.sub.2S.sub.2O.sub.3(aq) (30 mL) and extracted with EtOAc (75
mL). Organic extract was dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo to provide
rac-di-tert-butyl((1,2-trans)-4-hydroxycyclohexane-1,2-diyl)dicarbamate
(753 mg, 99%) as a mixture of alcohol isomers as a white solid.
Used directly in the next step without further purification. LCMS
(ESI) m/z: 331.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 5.27-4.94 (m, 2H), 3.80-3.54 (m, 1H), 3.44-3.19 (m, 2H),
2.83 (br.s, 1H), 2.32-2.06 (m, 1H), 1.99-1.88 (m, 4H), 1.86-1.63
(m, 1H), 1.39 (s, 18H).
The crude mixture of
rac-di-tert-butyl((1,2-trans)-4-hydroxycyclohexane-1,2-diyl)dicarbamate
alcohol isomers prepared above (753 mg, 2.28 mmol) was dissolved in
CH.sub.2Cl.sub.2 (10 mL) and to this was then added Dess-Martin
Periodinane (1.16 g, 2.73 mmol) and the mixture stirred at rt
overnight. After 16 h, the mixture was diluted with
CH.sub.2Cl.sub.2 (50 mL), washed with saturated NaHCO.sub.3(aq)
(2.times.10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Purification by flash chromatography through
Si gel (0-100% EtOAc/hexanes) provided
rac-di-tert-butyl((1,2-trans)-4-oxocyclohexane-1,2-diyl)dicarbamate
(392 mg, 52%) as a tan solid. LCMS (ESI) m/z: 329.4 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.08 (d, J=7.5 Hz, 1H),
5.04 (d, J=8.0 Hz, 1H), 3.84-3.62 (m, 2H), 2.71 (dd, J=14.3, 3.5
Hz, 1H), 2.39 (dd, J=10.5, 4.8 Hz, 2H), 2.36-2.26 (m, 1H),
2.26-2.16 (m, 1H), 1.60-1.48 (m, 1H), 1.45-1.36 (m, 18H).
Step 3
##STR00465##
[0962]
Rac-di-tert-butyl((1,2-trans)-4,4-difluorocyclohexane-1,2-diyl)dica-
rbamate
[0963]
Rac-di-tert-butyl((1,2-trans)-4-oxocyclohexane-1,2-diyl)dicarbamate
(392 mg, 1.19 mmol) dissolved in CH.sub.2Cl.sub.2 (5 mL) in a
N.sub.2 flushed flask and cooled to 0.degree. C. Diethylaminosulfur
trifluoride (1.91 mL of a 1M sol'n in CH.sub.2Cl.sub.2, 1.91 mmol)
was then added and the mixture stirred allowing to warm slowly to
rt. After 3 days, the mixture was diluted with CH.sub.2Cl.sub.2 (50
mL), washed with H.sub.2O (10 mL), then with saturated
NaHCO.sub.3(aq) (2.times.10 mL), dried (Na.sub.2SO.sub.4), filtered
and concentrated in vacuo. Purification by flash column
chromatography through Si gel (0-50% EtOAc/hexanes) provided
rac-di-tert-butyl((1,2-trans)-4,4-difluorocyclohexane-1,2-diyl)dicarbamat-
e (215 mg, 51%) as a white solid. LCMS (ESI) m/z: 351.4
[M+H].sup.+. H NMR (400 MHz, CDCl.sub.3) .delta. 5.18-4.99 (m, 1H),
4.94 (d, J=7.8 Hz, 1H), 3.72-3.58 (m, 1H), 3.53-3.35 (m, 1H), 2.45
(dt, J=29.0, 12.2 Hz, 1H), 2.17-1.94 (m, 2H), 1.88-1.61 (m, 1H),
1.54-1.32 (m, 20H).
Step 4
##STR00466##
[0964] Rac-(1,2-trans)-4,4-difluorocyclohexane-1,2-diamine
Dihydrochloride
[0965] To a solution of
rac-di-tert-butyl((1,2-trans)-4,4-difluorocyclohexane-1,2-diyl)dicarbamat-
e (215 mg, 0.61 mmol) in EtOAc (3 mL) was added 4N HCl in dioxanes
(1 mL, 4 mmol) and the mixture stirred at rt. After 18 h, the
mixture was concentrated in vacuo to provide
rac-(1,2-trans)-4,4-difluorocyclohexane-1,2-diamine dihydrochloride
(145 mg, 106%) as a yellow solid which was used directly in the
next step without further purification. LCMS (ESI) m/z: 151.5
[M+H].sup.+.
Step 5
##STR00467##
[0966]
Rac-4-(((1,2-trans)-2-amino-4,4-difluorocyclohexyl)amino)-5-chloro--
N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0967] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (449 mg, 0.97 mmol) in DMF (10 mL) was added triethylamine
(329 mg, 0.45 mL, 3.25 mmol) followed by addition of
rac-(1,2-trans)-4,4-difluorocyclohexane-1,2-diamine dihydrochloride
(145 mg, 0.65 mmol) and the mixture stirred at rt. After 16 h, the
mixture was placed in a 65.degree. C. oil bath sealed. After 2 h,
the mixture was diluted with EtOAc (75 mL), washed with saturated
NaHCO.sub.3(aq) (10 mL), then with 50% saturated NaCl(aq)
(4.times.10 mL), dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Purification by flash column chromatography
through Si gel (0-100% EtOAc/CH.sub.2Cl.sub.2) provided
rac-4-(((1,2-trans)-2-amino-4,4-difluorocyclohexyl)amino)-5-chloro-N-(2,4-
-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (138
mg, 36%) as a yellow oil. LCMS (ESI) m/z: 590.9 [M+H].sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.74 (d, J=7.0 Hz, 1H),
7.38 (d, J=3.6 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.96 (d, J=3.6 Hz,
1H), 6.47 (d, J=12.4 Hz, 1H), 6.42-6.22 (m, 2H), 5.19 (s, 2H), 4.84
(d, J=7.5 Hz, 1H), 3.84-3.68 (m, 6H), 3.20-2.93 (m, 2H), 2.50-2.34
(m, 1H), 2.26-2.13 (m, 1H), 2.13-2.03 (m, 1H), 1.98-1.69 (m, 2H),
1.63-1.44 (m, 3H).
Step 6
##STR00468##
[0968]
Rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1,2-trans)-2-(dimethylami-
no)-4,4-difluorocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonam-
ide
[0969] To a solution of
rac-4-(((1,2-trans)-2-amino-4,4-difluorocyclohexyl)amino)-5-chloro-N-(2,4-
-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (138
mg, 0.23 mmol) in MeOH (5 mL) was added 37% w/w aqueous
formaldehyde (189 mg, 0.17 mL, 2.33 mmol) followed by addition of
sodium cyanoborohydride (43 mg, 0.70 mmol) and the mixture was
stirred at rt overnight. After 16 h, volatiles were removed in
vacuo and the crude residue partitioned between EtOAc (50 mL) and
saturated NaHCO.sub.3(aq) (10 mL). The phases were separated and
the organic extract dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Purification by flash column chromatography
through Si gel (0-100% EtOAc/CH.sub.2Cl.sub.2) provided
rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1,2-trans)-2-(dimethylamino)-4,-
4-difluorocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(64 mg, 440%) as a clear waxy gum. LCMS (ESI) m/z: 619.0
[M+H].sup.+.
Step 7
##STR00469##
[0970]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4--
difluorocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
&
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1R,2R)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0971]
Rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1,2-trans)-2-(dimethylami-
no)-4,4-difluorocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonam-
ide (63 mg, 0.10 mmol) was separated by using chiral HPLC
(Chiralpak IB (250 mm*20 mm, 5 um), MeOH:DCM:hexane 2:5:93
containing 0.1% of diethylamine, 15 ml/min) to afford
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(first peak, 21 mg, 33%) as a white solid. LCMS (ESI) m/z: 619.0
[M+H].sup.+. Also afforded afford
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1R,2R)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(second peak, 21 mg, 33%) as a white solid. LCMS (ESI) m/z: 618.9
[M+H].sup.+. Absolute configuration was arbitrarily assigned to
each enantiomer.
Step 8
##STR00470##
[0972]
5-chloro-4-(((1S,2S)-2-(dimethylamino)-4,4-difluorocyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0973]
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4--
difluorocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(21 mg, 0.03 mmol) was treated with 95% formic acid (2 mL) and the
mixture stirred at rt. After 30 min, volatiles were removed in
vacuo and the crude residue purified by C18 reverse phase flash
chromatography (0-100% MeCN/10 mM aqueous NH.sub.4CO.sub.2H,
pH=3.8). Appropriate fractions were combined and lyophilized to
provide
5-chloro-4-(((1S,2S)-2-(dimethylamino)-4,4-difluorocyclohexyl)amino)-2-fl-
uoro-N-(thiazol-2-yl)benzenesulfonamide formate (14 mg, 805%) as a
white solid. LCMS (ESI) m/z: 469.0 [M+H].sup.+. .sup.1H NMR (400
MHz, d6-DMSO) .delta. 12.64 (s, 1H), 8.14 (s, 1H), 7.58 (d, J=7.3
Hz, 1H), 7.24 (d, J=2.6 Hz, 1H), 6.96-6.64 (m, 2H), 5.87 (s, 1H),
3.68-3.47 (m, 1H), 2.94 (t, J=10.3 Hz, 1H), 2.16 (s, 7H), 2.12-1.95
(m, 3H), 1.94-1.73 (m, 1H), 1.44-1.27 (m, 1H).
Example 188
##STR00471##
[0974]
5-chloro-4-(((1R,2R)-2-(dimethylamino)-4,4-difluorocyclohexyl)amino-
)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0975] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1R,2R)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (21
mg, 0.03 mmol),
5-chloro-4-(((1R,2R)-2-(dimethylamino)-4,4-difluorocyclohexyl)amino)-2-fl-
uoro-N-(thiazol-2-yl)benzenesulfonamide formate was obtained (14
mg, 80%) as a white solid. LCMS (ESI) m/z: 469.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, d6-DMSO) .delta. 12.64 (s, 1H), 8.14 (s, 1H),
7.58 (d, J=7.3 Hz, 1H), 7.23 (d, J=4.4 Hz, 1H), 6.93-6.67 (m, 2H),
5.87 (d, J=5.7 Hz, 1H), 3.67-3.46 (m, 1H), 2.94 (t, J=10.0 Hz, 1H),
2.16 (s, 7H), 2.09-1.95 (m, 3H), 1.94-1.74 (m, 1H), 1.46-1.27 (m,
1H).
Example 189
##STR00472##
[0976]
4-((trans)-2-(ethyl(methyl)amino)cyclohexyl)-6-fluoro-N-(thiazol-2--
yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide
[0977] Starting with racemic mixture of
(trans)-N1-ethyl-N1-methylcyclohexane-1,2-diamine and following the
procedures described in Example 54 and making non-critical
variations the title compound was obtained as a colorless solid and
a mixture of enantiomers. LCMS (ESI) m/z: 455.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.96 (s, 1H), 7.25 (d,
J=4.6 Hz, 1H), 7.17 (dd, J=13.3, 9.5 Hz, 1H), 7.06 (dd, J=7.3, 3.9
Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 6.51 (s, 2H), 4.39 (dd, J=10.8,
5.6 Hz, 1H), 4.21 (dt, J=10.8, 6.2 Hz, 1H), 4.04 (dt, J=10.8, 3.8
Hz, 1H), 3.64 (t, J=12.0 Hz, 1H), 3.26 (s, 3H), 3.07-3.01 (m, 1H),
2.67 (d, J=4.8 Hz. 3H), 2.23-1.99 (m, 1H), 1.84-1.31 (mn, 8H), 1.23
(t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 1H).
Example 190
##STR00473##
[0978]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((1-methylazetidin-3-yl)(2,2,2-trif-
luoroethyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
##STR00474##
[0979] Step 1
##STR00475##
[0980] tert-Butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)amino)azetidine-1-carboxylate
[0981]
4-(((1S,2S)-2-Aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzy-
l)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (412 mg, 0.74 mmol)
and 1-Boc-3-azetidinone (228 mg, 1.34 mmol) were combined in DCM (3
mL) and to this was added sodium triacetoxyborohydride (779 mg,
3.71 mmol) and the mixture was stirred at room temperature. After
16 hours, the mixture was diluted with MeOH (5 mL) and concentrated
in vacuo (repeated 3 times). The crude residue was diluted with
EtOAc (50 mL) and saturated aqueous NaHCO.sub.3 solution (10 mL)
and the phases were separated. The organic phase was dried
(Na.sub.2SO.sub.4), filtered and concentrated. The crude product
was purified by flash column chromatography through Si gel
(EtOAc/DCM) to provide tert-butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)amino)azetidine-1-carboxylate
(498 mg, 94% yield). LCMS (ESI) m/z: 710.2 [M+H].sup.+.
Step 2
##STR00476##
[0982]
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((1-methyla-
zetidin-3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0983] To a solution of tert-butyl
3-(((1S,2S)-2-((2-chloro-4-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfa-
moyl)-5-fluorophenyl)amino)cyclohexyl)amino)azetidine-1-carboxylate
(498 mg, 0.70 mmol) in THF (3.5 mL) was added 2 M lithium aluminum
hydride solution in THF (701 uL, 1.4 mmol). The mixture was stirred
at 60.degree. C. for 70 minutes. The reaction was then cooled to
0.degree. C. and aqueous sodium sulfate decahydrate was added
slowly until no more bubbling occurred then stirred at room
temperature for 15 minutes. The mixture was filtered, rinsed with
DCM and EtOAc and concentrated to provide
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((1-methy-
lazetidin-3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
(441 mg, 100%) which was used without further purification in the
subsequent step. LCMS (ESI) m/z: 624.1 [M+H].sup.+.
Step 3
##STR00477##
[0984]
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2s)-2-((1-methyla-
zetidin-3-yl)(2,2,2-trifluoroethyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl-
)benzenesulfonamide
[0985]
5-Chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((1-methyla-
zetidin-3-yl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
(90 mg, 0.14 mmol) was dissolved in DMF (0.7 mL) and THF (0.7 mL).
To this solution was added DIPEA (100 uL, 0.58 mol) followed by
2,2,2-trifluoroethyl trifluoromethanesulfonate (47 mg, 0.2 mmol).
The reaction was stirred at room temperature for 18 hours then
poured into EtOAc (50 mL) and washed with saturated aqueous brine
solution (3.times.20 mL). The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated. The crude product was purified
by flash column chromatography through Si gel (EtOAc/DCM) to
provide
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((1-methylazetidi-
n-3-yl)(2,2,2-trifluoroethyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benze-
nesulfonamide (39 mg, 38%). LCMS (ESI) m/z: 706.2 [M+H].sup.+.
Step 4
##STR00478##
[0986]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((1-methylazetidin-3-yl)(2,2,2-trif-
luoroethyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[0987] Following the procedure described in Example 115 and making
non-critical variations to substitute
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2S)-2-((2-hydroxy-2-met-
hylpropyl)(methyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonami-
de with
5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-(((1S,2s)-2-((1-methyl-
azetidin-3-yl)(2,2,2-trifluoroethyl)amino)cyclohexyl)amino)-N-(thiazol-2-y-
l)benzenesulfonamide (39 mg, 0.05 mmol),
5-chloro-2-fluoro-4-(((1S,2S)-2-((1-methylazetidin-3-yl)(2,2,2-trifluoroe-
thyl)amino)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide (14
mg, 53%) was obtained. LCMS (ESI) m/z: 556.2 [M+H].sup.+. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.77 (d, J=7.0 Hz, 1H), 7.35
(d, J=10.8 Hz, 1H), 7.19 (d, J=3.9 Hz, 1H), 6.75 (d, J=4.1 Hz, 1H),
3.27-3.06 (m, 5H), 2.80-2.57 (m, 2H), 2.38 (s, 3H), 2.29-2.15 (m,
1H), 1.85-1.72 (m, 1H), 1.72-1.46 (m, 3H), 1.42-1.19 (m, 3H),
0.93-0.72 (m, 1H).
Example
##STR00479##
[0988]
5-chloro-4-(((1S,2S)-2-(dimethylamino)-5-fluorocyclohexyl)amino)-2--
fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
##STR00480##
[0989] Step 1
##STR00481##
[0990]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-5-fl-
uorocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
&
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-fluor-
ocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
&
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4R)-2-(dimethylamino)-4-fluor-
ocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[0991] Iron(III) oxalate hexahydrate (416 mg, 0.86 mmol) was
suspended in H.sub.2O (20 mL) and placed in a 90.degree. C. oil
bath for 10 min to provide a homogeneous yellow solution. This
solution was then cooled to 0.degree. C. and sparged with N.sub.2
for 5 min before addition of a solution of Selectfluor (305 mg,
0.86 mmol) in MeCN (10 mL) followed by addition of a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,6S)-6-(dimethylamino)cyclohex-3--
en-1-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide prepared
in Example 141 (250 mg, 0.43 mmol) in MeCN (10 mL). Sodium
Borohydride (50 mg, 1.38 mmol) was then added and after 2 min a
further portion of Sodium Borohydride (50 mg, 1.38 mmol) was added
and the mixture stirred at rt. After 1 h, the mixture was diluted
with concentrated aqueous NH.sub.4OH (10 mL) and organics extracted
with a solution of 10% MeOH in CH.sub.2Cl.sub.2 (2.times.50 mL).
The organic extracts were combined, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. Purification by flash column
chromatography through Si gel (0-100% EtOAc/CH.sub.2Cl.sub.2)
provided
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-5-fluorocy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (16 mg,
6%) as a clear waxy gum. LCMS (ESI) m/z: 601.3 [M+H].sup.+. Also
isolated was
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-fluor-
ocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide and
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4R)-2-(dimethylamino)-4-fluor-
ocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide as
an inseparable mixture of two fluorine isomers (16 mg, 6%). LCMS
(ESI) m/z: 601.2 [M+H].sup.+. Fluorine regiochemistry and
stereochemistry arbitrarily assigned to all isomers obtained.
Step 5
##STR00482##
[0992]
5-Chloro-4-(((1S,2S)-2-(dimethylamino)-5-fluorocyclohexyl)amino)-2--
fluoro-N-(thiazol-2-yl)benzenesulfonamide Formate
[0993] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-5-fluorocy-
clohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (16 mg,
0.03 mmol),
5-chloro-4-(((1S,2S)-2-(dimethylamino)-5-fluorocyclohexyl)amino)-2-
-fluoro-N-(thiazol-2-yl)benzenesulfonamide formate was obtained (14
mg, 94%) as a white solid. LCMS (ESI) m/z: 451.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.29 (s, 1H), 8.16 (s, 1H),
7.56 (t, J=7.3 Hz, 1H), 7.17-6.90 (m, 1H), 6.80-6.41 (m, 2H),
5.87-5.55 (m, 1H), 5.04 (d, J=48.8 Hz, 1H), 3.02-2.82 (m, 1H),
2.21-2.12 (m, 6H), 2.12-2.02 (m, 1H), 2.01-1.92 (m, 1H), 1.91-1.77
(m, 1H), 1.62 (dt, J=39.7, 13.2 Hz, 1H), 1.44 (ddd, J=27.7, 13.7
Hz, 1H). [aminothiazole NH not observed and one C--H hidden under
H.sub.2O peak].
Example 192 & Example 193
##STR00483##
[0994]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-fluorocyclohexyl)amino)-
-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide &
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-fluorocyclohexyl)amino)-2-flu-
oro-N-(thiazol-2-yl)benzenesulfonamide
[0995] The mixture of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-fluor-
ocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide and
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4R)-2-(dimethylamino)-4-fluor-
ocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (16
mg, 0.03 mmol) fluorine isomers obtained in Example 191 was treated
with 95% formic acid (2 mL) and stirred at rt. After 30 min,
volatiles were removed in vacuo and the crude material purified by
reverse phase prep-HPLC (20-40% MeCN/10 mM aqueous
NH.sub.4CO.sub.2H, pH: 3.8 gradient over 10 min, XBridge BEH C18
OBD Prep Column, 130 .ANG., 5 .mu.m, 30 mm.times.50 mm).
Appropriate fractions combined and lyophilized to provide:
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-fluorocyclohexyl)ami-
no)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide (3 mg, 25%) as a
white solid, LCMS (ESI) m/z: 451.1 [M+H].sup.+, .sup.1H NMR (400
MHz, d6-DMSO) .delta. 8.28 (s, 2H), 7.56 (d, J=7.2 Hz, 1H), 6.95
(d, J=3.7 Hz, 1H), 6.47 (d, J=3.7 Hz, 1H), 6.35 (d, J=12.3 Hz, 1H),
5.59 (d, J=3.7 Hz, 1H), 4.93 (d, J=47.9 Hz, 1H), 2.75-2.63 (m, 2H),
2.16 (s, 6H), 2.09-1.96 (m, 1H), 1.76-1.67 (m, 1H), 1.65-1.35 (m,
3H); and
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-fluorocyclohexyl)amino)-2-flu-
oro-N-(thiazol-2-yl)benzenesulfonamide (7 mg, 58%) as a white
solid, LCMS (ESI) m/z: 451.0 [M+H].sup.+, .sup.1H NMR (400 MHz,
d6-DMSO) .delta. 8.20 (s, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.03 (d,
J=3.9 Hz, 1H), 6.76 (d, J=12.7 Hz, 1H), 6.56 (d, J=3.9 Hz, 1H),
5.59 (d, J=5.0 Hz, 1H), 4.73 (dtd, J=15.1, 10.5, 5.2 Hz, 1H),
2.97-2.86 (m, 1H), 2.70-2.57 (m, 1H), 2.45-2.30 (m, 2H), 2.14 (s,
6H), 1.86-1.74 (m, 1H), 1.44 (dd, J=20.7, 9.9 Hz, 2H), 1.26 (dd,
J=25.2, 9.4 Hz, 1H). Fluorine regiochemistry and stereochemistry
arbitrarily assigned to each isomer.
Example 194
##STR00484##
[0996]
5-Chloro-4-(((1S,3S,4S,6R)-7,7-dichloro-4-(dimethylamino)bicyclo
14.1.01
heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
##STR00485## ##STR00486##
[0997] Step 1
##STR00487##
[0998]
Rac-di-tert-butyl((3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-
-diyl)dicarbamate
[0999] To a solution of
rac-di-tert-butyl(1,2-trans)-cyclohex-4-ene-1,2-diyldicarbamate
(500 mg, 1.6 mmol) and tetrabutylammonium bromide (52 mg, 0.16
mmol) in CHCl.sub.3 (2 mL) was added 50% w/w aqueous NaOH (1.65 mL,
32 mmol) and the mixture stirred at rt over the weekend. After 3
days, the reaction mixture which had become a solid mass was
partitioned between H.sub.2O (25 mL) and CH.sub.2Cl.sub.2 (50 mL)
and the phases were separated. The organic extract was dried
(Na.sub.2SO.sub.4), filtered and concentrated in vacuo.
Purification by flash chromatography through Si gel (0-100%
EtOAc/CH.sub.2Cl.sub.2) provided
rac-di-tert-butyl((3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diyl)-
dicarbamate (155 mg, 24%) as a white solid contaminated with
.about.20%
rac-di-tert-butyl(1,2-trans)-cyclohex-4-ene-1,2-diyldicarbamate
starting material. Used as is without further purification. LCMS
(ESI) m/z: 395.1, 397.1 [M+H].sup.+.
Step 2
##STR00488##
[1000]
Rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride
[1001] To a solution of
rac-di-tert-butyl((3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diyl)-
dicarbamate (287 mg, 0.73 mmol) in EtOAc (5 mL) was added 4N HCl in
dioxanes (2 mL, 8 mmol) and stirred at rt. After 16 h, the mixture
was concentrated in vacuo to provide crude
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride (210 mg, 108%) as a yellow solid which was used
directly in the next step. LCMS (ESI) m/z: 195.2, 197.3
[M+H].sup.+.
Step 3
##STR00489##
[1002] Rac-4-((1,3-trans), (4,6-cis),
(3,4-trans))-4-amino-7,7-dichlorobicyclo[4.1.0]heptan-3-yl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
& Rac-4-((1,3-cis), (4,6-trans),
(3,4-trans))-4-amino-7,7-dichlorobicyclo[4.1.0]heptan-3-yl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1003] To a solution of
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide (536 mg, 1.16 mmol) and
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride (208 mg, 0.78 mmol) in DMF (10 mL) was added
triethylamine (471 mg, 0.65 mL, 4.66 mmol) and the mixture stirred
at rt overnight. After 16 h, the mixture was diluted with EtOAc (50
mL), washed with saturated NaHCO.sub.3(aq) (10 mL), then with 50%
saturated NaCl(aq) (4.times.10 mL), dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo. Purification by flash column
chromatography through Si gel (0-100% EtOAc/CH.sub.2Cl.sub.2
followed by 0-20% MeOH/CH.sub.2Cl.sub.2) provided two cyclopropane
diastereomers: rac-4-((1,3-trans), (4,6-cis),
(3,4-trans))-4-amino-7,7-dichlorobicyclo[4.1.0]heptan-3-yl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(65 mg, 13%) as a yellow oil, LCMS (ESI) m/z: 636.7 [M+H].sup.+;
and rac-4-((1,3-cis), (4,6-trans),
(3,4-trans))-4-amino-7,7-dichlorobicyclo[4.1.0]heptan-3-yl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(88 mg, 18%) as a yellow oil, LCMS (ESI) m/z: 637.1 [M+H].sup.+.
Relative cyclopropane stereochemistry arbitrarily assigned to each
isomer.
Step 4
##STR00490##
[1004] Rac-5-chloro-4-((1,3-trans), (4,6-cis),
(3,4-trans))-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]heptan-3-yl)amin-
o)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
& rac-5-chloro-4-((1,3-cis), (4,6-trans),
(3,4-trans))-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]heptan-3-yl)amin-
o)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1005] To a solution of rac-4-((1,3-trans), (4,6-cis),
(3,4-trans))-4-amino-7,7-dichlorobicyclo[4.1.0]heptan-3-yl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(66 mg, 0.10 mmol) in MeOH (5 mL) was added 37% w/w aqueous
formaldehyde (84 mg, 0.077 mL, 1.04 mmol) followed by addition of
sodium cyanoborohydride (19 mg, 0.31 mmol) and the mixture was
stirred at rt. After 16 h, volatiles were removed in vacuo and the
crude residue partitioned between EtOAc (50 mL) and saturated
NaHCO.sub.3(aq) (10 mL). The phases were separated and the organic
extract dried (Na.sub.2SO.sub.4), filtered and concentrated in
vacuo. Purification by flash column chromatography through Si gel
(0-100% EtOAc/CH.sub.2Cl.sub.2) provided
rac-5-chloro-4-((1,3-trans), (4,6-cis),
(3,4-trans))-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]heptan-3-yl)amin-
o)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(24 mg, 35%) as a clear oil. LCMS (ESI) m/z: 663.1, 665.4
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.73 (d,
J=7.1 Hz, 1H), 7.39 (d, J=3.6 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.97
(d, J=3.6 Hz, 1H), 6.41-6.34 (m, 2H), 6.30 (d, J=12.4 Hz, 1H), 6.09
(s, 1H), 5.20 (s, 2H), 3.75 (s, 6H), 2.93-2.66 (m, 3H), 2.22-2.12
(m, 7H), 2.00-1.83 (m, 3H), 1.36 (t, J=13.0 Hz, 1H).
[1006] Following the procedure described above and making
non-critical variations to replace rac-4-((1,3-trans), (4,6-cis),
(3,4-trans))-4-amino-7,7-dichlorobicyclo[4.1.0]heptan-3-yl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with rac-4-((1,3-cis), (4,6-trans),
(3,4-trans))-4-amino-7,7-dichlorobicyclo[4.1.0]heptan-3-yl)amino)-5-chlor-
o-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(88 mg, 0.14 mmol), rac-5-chloro-4-((1,3-cis), (4,6-trans),
(3,4-trans))-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]heptan-3-yl)amin-
o)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(43 mg, 47%) was obtained as a clear oil. LCMS (ESI) m/z: 663.0,
664.9 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71
(d, J=6.9 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H),
6.96 (d, J=3.5 Hz, 1H), 6.41-6.33 (m, 2H), 6.25 (d, J=12.4 Hz, 1H),
6.12 (s, 1H), 5.19 (s, 2H), 3.75 (s, 6H), 3.21-3.10 (m, 1H), 2.77
(dd, J=14.0, 5.6 Hz, 1H), 2.51 (td, J=12.2, 4.0 Hz, 1H), 2.37 (ddd,
J=14.4, 10.5, 4.1 Hz, 1H), 2.19 (s, 6H), 1.94 (td, J=10.4, 4.0 Hz,
1H), 1.84-1.70 (m, 2H), 1.63-1.47 (m, 1H).
Step 5
##STR00491##
[1007]
5-Chloro-4-(((1S,3S,4S,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.-
1.]heptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)ben-
zenesulfonamide &
5-chloro-4-(((1S,3R,4R,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide &
5-chloro-4-(((1R,3S,4S,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide &
5-chloro-4-(((1R,3R,4R,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide
[1008] Rac-5-chloro-4-((1,3-trans), (4,6-cis),
(3,4-trans))-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]heptan-3-yl)amin-
o)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(23 mg, 0.03 mmol) was separated using chiral HPLC (Chiralpak IB
(250 mm*20 mm, 5 um), MeOH:DCM:hexane 2:8:90 containing 0.1% of
diethylamine, 15 ml/min) to afford:
5-chloro-4-(((1S,3S,4S,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (peak 1, 6 mg, 26%), as a white solid, LCMS (ESI) m/z:
662.9, 664.9 [M+H].sup.+; and
5-chloro-4-(((1S,3R,4R,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (peak 2, 7 mg, 30%) as a white solid, LCMS (ESI) m/z:
663.0, 664.8 [M+H].sup.+.
[1009] In addition, rac-5-chloro-4-((1,3-cis), (4,6-trans),
(3,4-trans))-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]heptan-3-yl)amin-
o)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
(43 mg, 0.06 mmol) was separated using chiral HPLC (Chiralpak IB
(250 mm*20 mm, 5 um), MeOH:DCM:hexane 2:8:90 containing 0.1% of
diethylamine, 15 ml/min) to afford:
5-chloro-4-(((1R,3S,4S,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (peak 1, 11 mg, 26%), as a white solid, LCMS (ESI) m/z:
663.0, 665.0 [M+H]; and
5-chloro-4-(((1R,3R,4R,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (peak 2, 13 mg, 30%) as a white solid, LCMS (ESI) m/z:
662.9, 664.9 [M+H].sup.+. Cyclopropane relative stereochemistry and
absolute stereochemistry arbitrarily assigned.
Step 6
##STR00492##
[1010]
5-Chloro-4-(((1S,3S,4S,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
[1011] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-chloro-4-(((1S,3S,4S,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (6 mg, 0.01 mmol),
5-chloro-4-(((1S,3S,4S,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
formate was obtained (4 mg, 79%) as a white solid. LCMS (ESI) m/z:
512.9, 514.9 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) [thiazole
N--H signal not observed] .delta. 8.18 (s, 1H), 7.57 (d, J=6.9 Hz,
1H), 7.07 (d, J=3.1 Hz, 1H), 6.77 (d, J=12.3 Hz, 1H), 6.61 (d,
J=3.4 Hz, 1H), 5.80 (s, 1H), 3.12-3.01 (m, 1H), 2.78-2.61 (m, 2H),
2.10 (s, 6H), 2.01-1.92 (m, 3H), 1.33-1.03 (m, 2H). Cyclopropane
relative stereochemistry and absolute stereochemistry arbitrarily
assigned.
Example 195
##STR00493##
[1012]
5-Chloro-4-(((1S,3R,4R,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
[1013] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-chloro-4-(((1S,3R,4R,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (7 mg, 0.01 mmol),
5-chloro-4-(((1S,3R,4R,6R)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
formate was obtained (4 mg, 68%) as a white solid. Absolute
stereochemistry and relative cyclopropane stereochemistry was
arbitrarily assigned LCMS (ESI) m/z: 512.9 [M+H].sup.+. .sup.1H NMR
(400 MHz, d6-DMSO) [thiazole N--H signal not observed] .delta. 8.16
(s, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.09 (d, J=3.8 Hz, 1H), 6.78 (d,
J=12.6 Hz, 1H), 6.63 (d, J=3.7 Hz, 1H), 6.56 (s, 1H), 5.82 (s, 1H),
3.14-3.03 (m, 1H), 2.77-2.62 (m, 2H), 2.10 (s, 6H), 2.01-1.91 (m,
3H), 1.30-1.06 (m, 2H).
Example 196
##STR00494##
[1014]
5-Chloro-4-(((1R,3S,4S,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
[1015] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-chloro-4-(((1R,3S,4S,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (11 mg, 0.02 mmol),
5-chloro-4-(((1R,3S,4S,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
formate was obtained (7 mg, 75%) as a white solid. Absolute
stereochemistry and relative cyclopropane stereochemistry was
arbitrarily assigned. LCMS (ESI) m/z: 513.0, 515.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, d6-DMSO) [thiazole N--H signal not observed]
.delta. 8.14 (s, 1H), 7.59 (d, J=7.1 Hz, 1H), 7.18 (d, J=3.7 Hz,
1H), 6.72 (d, J=3.6 Hz, 1H), 6.54 (s, 1H), 6.39 (d, J=12.4 Hz, 1H),
5.95 (s, 1H), 3.23-3.17 (m, 1H), 2.13 (s, 6H), 2.08-1.98 (m, 2H),
1.93-1.77 (m, 3H), 1.43-1.17 (m, 2H).
Example 197
##STR00495##
[1016]
5-Chloro-4-(((1R,3R,4R,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Formate
[1017] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-chloro-4-(((1R,3R,4R,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(thiazol-2-yl)benzenes-
ulfonamide (13 mg, 0.02 mmol),
5-chloro-4-(((1R,3R,4R,6S)-7,7-dichloro-4-(dimethylamino)bicyclo[4.1.0]he-
ptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
formate was obtained (8 mg, 73%) as a white solid. Absolute
stereochemistry and relative cyclopropane stereochemistry was
arbitrarily assigned. LCMS (ESI) m/z: 513.0, 515.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, d6-DMSO) [thiazole N--H signal not observed]
.delta. 8.15 (s, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.14 (d, J=4.2 Hz,
1H), 6.68 (d, J=4.2 Hz, 1H), 6.55 (s, 1H), 6.37 (d, J=12.4 Hz, 1H),
5.92 (d, J=3.7 Hz, 1H), 3.22-3.17 (m, 1H), 2.17-2.08 (m, 7H),
2.08-1.91 (m, 2H), 1.92-1.77 (m, 2H), 1.45-1.06 (m, 2H).
Example 198
##STR00496##
[1018]
N-((1S,2S)-2-((2-Chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)pheny-
l)amino)-cyclohexyl)-2-(dimethylamino)-N,2-dimethylpropanamide
[1019] Following the procedure described in Example 179 and making
non-critical variations as required to replace
1-methylazetidine-3-carboxylic acid with
2-(dimethylamino)-2-methyl-propanoic acid,
N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl)amin-
o)-cyclohexyl)-2-(dimethylamino)-N,2-dimethylpropanamide was
obtained. LCMS (ESI) m/z: 532.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) .delta. 7.50 (d, J=7.3 Hz, 1H), 7.24 (d, J=4.5 Hz, 1H),
6.79 (d, J=4.5 Hz, 2H), 5.67 (s, 1H), 4.51 (s, 1H), 3.66 (s, 1H),
3.17 (s, 3H), 1.96 (s, 8H), 1.66 (d, J=55.5 Hz, 4H), 1.31 (s, 4H),
1.10 (s, 3H), 0.99 (s, 3H).
Example 199
##STR00497##
[1020]
(S)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)-
phenyl)amino)cyclohexyl)-N,1-dimethylpyrrolidine-3-carboxamide
[1021] Following the procedure described in Example 179 and making
non-critical variations as required to replace
1-methylazetidine-3-carboxylic acid with
(3S)-1-methylpyrrolidine-3-carboxylic acid,
(S)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl-
)amino)cyclohexyl)-N,1-dimethylpyrrolidine-3-carboxamide was
obtained. LCMS (ESI) m/z: 530.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.20 (s, 1H), 7.52 (t, J=6.5 Hz, 1H), 7.15
(dd, J=6.5, 4.4 Hz, 1H), 6.88-6.63 (m, 2H), 5.69-5.29 (m, 1H), 4.45
(s, 1H), 3.87-3.53 (m, 2H), 3.32-3.01 (m, 1H), 3.01-2.79 (m, 2H),
2.77 (s, 2H), 2.60 (s, 1H), 2.45 (s, J=16.8 Hz, 1H), 2.37 (s,
J=12.2 Hz, 2H), 2.18-1.80 (m, 3H), 1.80-1.47 (m, 5H), 1.45-1.19 (m,
3H).
Example 200
##STR00498##
[1022]
(R)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)-
phenyl)amino)cyclohexyl)-N,1-dimethylpyrrolidine-3-carboxamide
[1023] Following the procedure described in Example 179 and making
non-critical variations as required to replace
1-methylazetidine-3-carboxylic acid with
(3R)-1-methylpyrrolidine-3-carboxylic acid,
(R)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl-
)amino)cyclohexyl)-N,1-dimethylpyrrolidine-3-carboxamide was
obtained. LCMS (ESI) m/z: 530.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.20 (s, 1H), 7.52 (dd, J=7.3, 5.0 Hz, 1H),
7.15 (dd, J=7.0, 4.3 Hz, 1H), 6.87-6.64 (m, 2H), 5.71-5.26 (m, 1H),
4.45 (s, 1H), 3.89-3.52 (m, 2H), 3.27 (bs, 1H), 2.97 (dt, J=34.8,
12.2 Hz, 3H), 2.77 (s, J=16.7 Hz, 3H), 2.72-2.61 (m, 1H), 2.59 (s,
1H), 2.54 (s, 1H), 2.23-1.81 (m, 3H), 1.81-1.44 (m, 6H), 1.32 (d,
J=8.8 Hz, 3H).
Example 201
##STR00499##
[1024]
(S)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)-
phenyl)amino)cyclohexyl)-N,1-dimethylpyrrolidine-2-carboxamide
[1025] Following the procedure described in Example 179 and making
non-critical variations as required to replace
1-methylazetidine-3-carboxylic acid with
(2S)-1-methylpyrrolidine-2-carboxylic acid,
(S)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl-
)amino)-cyclohexyl)-N,1-dimethylpyrrolidine-2-carboxamide was
obtained. LCMS (ESI) m/z: 530.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) [.about.1:1 mixture of rotomers by NMR] .delta. 11.18 (br,
s, 1H), 7.55 (d, J=7.3 Hz, 1H), 7.26 (d, J=4.6 Hz, 1H), 6.96-6.83
(m, 1H), 6.81 (d, J=4.6 Hz, 1H), 5.98 (d, J=9.7 Hz, 0.5H), 5.49 (s,
0.5H), 4.90 (t, J=8.4 Hz, 0.5H), 4.47 (s, 0.5H), 4.28 (t, J=6.7 Hz,
0.5H), 3.88 (dd, J=10.2, 3.7 Hz, 0.5H), 3.75 (s, 0.5H), 3.55 (dd,
J=9.3, 5.9 Hz, 1H), 3.51-3.44 (m, 0.5H), 3.02 (dd, J=19.7, 8.7 Hz,
0.5H), 2.98-2.90 (m, 0.5H), 2.76 (s, 1.5H), 2.72 (s, 1.5H), 2.65
(s, 3H), 2.44-2.34 (m, J=12.3, 6.2 Hz, 0.5H), 2.24 (td, J=17.4, 8.8
Hz, 0.5H), 2.16-2.04 (m, J=8.3, 4.2 Hz, 0.5H), 2.03-1.86 (m, J=9.0,
5.8 Hz, 2H), 1.86-1.73 (m, 2H), 1.73-1.62 (m, 3H), 1.53-1.18 (m,
3.5H).
Example 202
##STR00500##
[1026]
(S)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)-
phenyl)amino)cyclohexyl)-N,1-dimethylazetidine-2-carboxamide
[1027] Following the procedure described in Example 179 and making
non-critical variations as required to replace
1-methylazetidine-3-carboxylic acid with
(2S)-1-methylazetidine-2-carboxylic acid,
(S)--N-((1S,2S)-2-((2-chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl-
)amino)-cyclohexyl)-N,1-dimethylazetidine-2-carboxamide was
obtained. LCMS (ESI) m/z: 516.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) [.about.1:1 mixture of rotomers by NMR] .delta. 7.54 (t,
J=7.4 Hz, 1H), 7.18 (dd, J=8.0, 4.4 Hz, 1H), 6.86 (d, J=13.3 Hz,
0.5H), 6.83-6.66 (m, 1.5H), 5.93 (d, J=9.9 Hz, 0.5H), 5.36 (s,
0.5H), 4.94 (s, 0.5H), 4.44 (s, 1H), 3.85-3.43 (m, 3.5H), 2.61 (s,
1.5H), 2.60 (s, 1.5H), 2.51 (s, 1.5H), 2.45 (s, 1.5H), 2.25 (dd,
J=18.5, 9.7 Hz, 1H), 1.98 (d, J=8.0 Hz, 0.5H), 1.89 (d, J=13.0 Hz,
0.5H), 1.74 (d, J=10.3 Hz, 1H), 1.69-1.52 (m, 4H), 1.52-1.18 (m,
4H).
Example 203
##STR00501##
[1028]
5-cyclobutyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cy-
clohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1029] Following the procedure described in Example 91 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)cyclohexyl)-
amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trif-
luoromethyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamid-
e,
5-cyclobutyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(trifluoromethyl)cycloh-
exyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was
obtained as a white solid. LCMS (ESI) m/z: 516.3 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.55 (s, 1H), 8.30 (d,
J=6.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 6.48
(d, J=14.4 Hz, 1H), 5.21 (s, 1H), 3.39-3.37 (m, 1H), 3.28-3.23 (m,
1H), 2.73-2.67 (m, 1H), 2.60-2.55 (m, 1H), 2.45-2.40 (m, 2H),
2.37-2.31 (m, 2H), 2.19 (s, 3H), 2.19 (s, 3H), 2.04-2.02 (m, 2H),
1.89-1.80 (m, 3H), 1.57-1.51 (m, 1H), 1.36-1.27 (m, 1H), 1.20-1.19
(m, 1H).
Example 204
##STR00502##
[1030]
(R)--N-((1S,2S)-2-((2-Chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)-
phenyl)amino)cyclohexyl)-N,1-dimethylpyrrolidine-2-carboxamide
[1031] Following the procedure described in Example 179 and making
non-critical variations as required to replace
1-methylazetidine-3-carboxylic acid with
(2R)-1-methylpyrrolidine-2-carboxylic acid,
(R)--N-((1S,2S)-2-((2-Chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl-
)amino)cyclohexyl)-N,1-dimethylpyrrolidine-2-carboxamide was
obtained. LCMS (ESI) m/z: 530.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.79 (d, J=7.3 Hz, 1H), 7.14 (d, J=4.6 Hz, 1H),
6.49 (d, J=4.6 Hz, 1H), 6.26 (d, J=12.5 Hz, 1H), 5.37 (br s, 1H),
4.68 (br s, 1H), 3.34-3.19 (m, 3H), 2.88 (s, 3H), 2.45-2.36 (m,
1H), 2.33 (s, 3H), 2.26-2.08 (m, 2H), 2.04-1.89 (m, 1H), 1.88-1.72
(m, 5H), 1.65-1.37 (m, 2H), 1.36-1.20 (m, 2H).
Example 205
##STR00503##
[1032]
(R)--N-((1S,2S)-2-((2-Chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)-
phenyl)amino)cyclohexyl)-N,1-dimethylazetidine-2-carboxamide
[1033] Following the procedure described in Example 179 and making
non-critical variations as required to replace
1-methylazetidine-3-carboxylic acid with
(2R)-1-methylazetidine-2-carboxylic acid,
(R)--N-((1S,2S)-2-((2-Chloro-5-fluoro-4-(N-(thiazol-2-yl)sulfamoyl)phenyl-
)amino)-cyclohexyl)-N,1-dimethylazetidine-2-carboxamide was
obtained. LCMS (ESI) m/z: 516.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.79 (d, J=7.3 Hz, 1H), 7.15 (d, J=4.6 Hz, 1H),
6.50 (d, J=4.6 Hz, 1H), 6.24 (d, J=12.5 Hz, 1H), 5.37 (br s, 1H),
4.63 (br s, 1H), 3.70 (t, J=8.3 Hz, 1H), 3.55-3.46 (m, 1H), 3.21
(br s, 1H), 2.99-2.89 (m, 1H), 2.67 (s, 3H), 2.39 (s, 3H),
2.34-2.11 (m, 3H), 1.91-1.73 (m, 3H), 1.68-1.37 (m, 2H), 1.37-1.19
(m, 2H).
Example 206
##STR00504##
[1034]
5-chloro-2-fluoro-4-(((1S,2S,4S)-2-(piperidin-1-yl)-4-(trifluoromet-
hyl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
Step 1
##STR00505##
[1035]
tert-butyl((1S,6S)-6-(piperidin-1-yl)-4-(trifluoromethyl)cyclohex-3-
-en-1-yl)carbamate
[1036] To a solution of
tert-butyl((1S,6S)-6-amino-4-(trifluoromethyl)cyclohex-3-en-1-yl)carbamat-
e (100 mg, 0.36 mmol) in MeCN (2 mL) was added 1,5-dibromopentane
(82 mg, 0.36 mmol) and N,N-diisopropylethylamine (0.12 mL, 0.71
mmol). The reaction mixture was irradiated in a microwave at
90.degree. C. for 3 h. After cooling to room temperature, the
mixture was concentrated in vacuo. DCM (30 mL) was added and washed
with water (20 mL.times.2), brine (20 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The crude residue was purified by silica gel chromatography
(solvent gradient: 0-10% EtOAc in petroleum ether) to give the
title compound (42 mg, 34%) as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.21 (s, 1H), 5.67 (s, 1H), 3.53-3.38 (m, 1H),
3.17-3.06 (m, 1H), 2.70-2.53 (m, 3H), 2.40-2.28 (m, 3H), 2.26-2.15
(m, 1H), 2.03-1.93 (m, 1H), 1.73-1.38 (m, 6H), 1.46 (s, 9H).
Step 2
##STR00506##
[1037]
5-chloro-2-fluoro-4-(((1S,2S,4S)-2-(piperidin-1-yl)-4-(trifluoromet-
hyl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
[1038] Following the procedure described in Example 112 and making
non-critical variations as required to replace
tert-butyl((1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex-3-en-1-y-
l)carbamate with
tert-butyl((1S,6S)-6-(piperidin-1-yl)-4-(trifluoromethyl)cyclohex-3-en-1--
yl)carbamate,
5-chloro-2-fluoro-4-(((1S,2S,4S)-2-(piperidin-1-yl)-4-(trifluoromethyl)cy-
clohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide was obtained
as a white solid. LCMS (ESI) m/z: 536.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 8.58 (s, 1H), 8.30 (d, J=4.4 Hz,
1H), 7.73 (d, J=7.6 Hz, 1H), 6.96 (d, J=6.4 Hz, 1H), 6.80 (d,
J=13.2 Hz, 1H), 5.99 (d, J=4.4 Hz, 1H), 3.47-3.36 (m, 1H),
2.78-2.69 (m, 1H), 2.52-2.51 (m, 2H), 2.43-2.34 (m, 2H), 2.22-2.14
(m, 1H), 2.05-1.95 (m, 1H), 1.83-1.75 (m, 1H), 1.54-1.44 (m, 1H),
1.42-1.20 (m, 9H).
Example 207
##STR00507##
[1039]
5-Chloro-4-(((1S,3S,4S,6R)-4-(dimethylamino)-7,7-difluorobicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Step 1
##STR00508##
[1040] Rac-(3,4-trans)-Diethyl
7,7-difluorobicyclo[4.1.0]heptane-3,4-dicarboxylate
[1041] In a test tube was added (1S,2S)-diethyl
cyclohex-4-ene-1,2-dicarboxylate (1.5 g, 6.63 mmol), methyl
benzoate (825 uL, 6.63 mmol) and then sodium fluoride (10 mg, 0.23
mmol). The vial was heated at 110.degree. C. and trimethylsilyl
2,2-difluoro-2-(fluorosulfonyl)acetate (3.9 mL, 19.89 mmol) was
added over 45 minutes using a syringe pump. The mixture was cooled
to room temperature, EtOAc (25 mL) and saturated sodium bicarbonate
solution (10 mL) were added and the phases were separated. The
organic phase was washed with brine (10 ml), dried over sodium
sulfate, filtered and concentrated. The crude product was purified
by flash column chromatography through Si gel (EtOAc/Hexanes) to
provide rac-(3,4-trans)-diethyl
7,7-difluorobicyclo[4.1.0]heptane-3,4-dicarboxylate (Ig, 55%) as a
colorless oil. LCMS (ESI) m/z: 276.9 [M+H].sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 4.19-4.03 (m, 4H), 2.59 (tdd, J=11.4, 5.4,
2.2 Hz, 1H), 2.44 (tdd, J=11.0, 5.0, 1.9 Hz, 1H), 2.34 (ddd,
J=14.4, 9.3, 4.4 Hz, 1H), 2.28-2.18 (m, 1H), 1.88-1.75 (m, 1H),
1.75-1.55 (m, 3H), 1.28-1.19 (m, 6H).
Step 2
##STR00509##
[1042]
Rac-(3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-dicarboxylic
Acid
[1043] In a flask containing rac-(3,4-trans)-diethyl
7,7-difluorobicyclo[4.1.0]heptane-3,4-dicarboxylate was added
lithium hydroxide monohydrate (1.0 g, 24 mmol), water (5 mL),
1,4-Dioxane (3 mL) and Methanol (0.5 mL). The mixture stirred at
25.degree. C. for 72 hours then 6M HCl (10 mL) and EtOAc (50 mL)
were added. The phases were separated and the aqueous phase was
extracted with EtOAc (50 mL). The combined organic extracts were
dried over sodium sulfate, filtered and concentrated to afford
crude
rac-((3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-dicarboxylic
acid (0.76 g, 95%) as an off-white solid which was used directly in
the next step without further purification. LCMS (ESI) m/z: 219.0
[M-H].sup.-. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.52-2.33
(m, 3H), 2.28-2.18 (m, 1H), 1.89-1.68 (m, 3H), 1.61-1.46 (m,
1H).
Step 3
##STR00510##
[1044]
Rac-(3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-diamine
Dihydrochloride
[1045] In a flask containing
rac-((3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-dicarboxylic
acid (750 mg, 3.4 mmol) was added DMF (10 uL, 0.13 mmol) followed
by oxalyl chloride (4 mL, 46.6 mmol). The suspension was stirred at
room temperature for 30 minutes. The mixture was then concentrated
to dryness, dissolved in 1,4-Dioxane (5 mL) and trimethylsilyl
azide (1.3 mL, 9.8 mmol) was added. After 30 minutes, the mixture
was heated to 90.degree. C. for 1 hour. Concentrated HCl (1 mL, 12
mmol) was added and the oil bath was cooled to 45.degree. C. and
the mixture was stirred for 16 h. The mixture was concentrated to
dryness, solubilized in 1,4-dioxane and after stirring for 2 h a
precipitate appeared. The solids were filtered and washed with
diethyl ether, and dried under vacuum to afford
rac-(3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride (170 mg, 21%) as a white solid. LCMS (ESI) m/z:
162.8 [M+H].sup.+. .sup.1H NMR (400 MHz, methanol-d.sub.4) .delta.
3.51-3.34 (m, 2H), 2.49 (ddd, J=17.8, 8.6, 4.7 Hz, 1H), 2.26-2.06
(m, 2H), 2.03-1.83 (m, 2H), 1.67-1.52 (m, 1H).
Step 4
##STR00511##
[1046]
5-Chloro-4-(((1S,3S,4S,6R)-4-(dimethylamino)-7,7-difluorobicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1047] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride the title compound was obtained as a white solid.
Absolute stereochemistry and relative cyclopropane stereochemistry
was arbitrarily assigned. LCMS (ESI) m/z: 481.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.43 (br s, 1H), 7.60
(d, J=7.3 Hz, 1H), 7.23 (d, J=4.5 Hz, 1H), 6.79 (d, J=4.5 Hz, 1H),
6.49 (d, J=12.6 Hz, 1H), 6.09 (d, J=3.7 Hz, 1H), 3.08 (s, 1H),
2.73-2.62 (m, J=11.9 Hz, 1H), 2.46 (d, J=10.9 Hz, 1H), 2.23-2.10
(m, 7H), 1.89 (ddd, J=14.5, 12.9, 4.2 Hz, 1H), 1.83-1.63 (m, 2H),
1.40 (td, J=13.3, 4.1 Hz, 1H).
Example 208
##STR00512##
[1048]
5-Chloro-4-(((1R,3R,4R,6S)-4-(dimethylamino)-7,7-difluorobicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1049] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride the title compound was obtained as a white solid.
Absolute stereochemistry and relative cyclopropane stereochemistry
was arbitrarily assigned. LCMS (ESI) m/z: 481.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.60 (d, J=7.3 Hz, 1H),
7.21 (d, J=4.4 Hz, 1H), 6.76 (d, J=4.4 Hz, 1H), 6.47 (d, J=12.5 Hz,
1H), 6.07 (d, J=3.5 Hz, 1H), 3.07 (s, 1H), 2.67 (td, J=11.0, 3.7
Hz, 1H), 2.48-2.41 (m, 1H), 2.18 (dd, J=8.5, 5.1 Hz, 1H), 2.13 (s,
6H), 1.95-1.83 (m, 1H), 1.82-1.63 (m, 2H), 1.40 (td, J=13.4, 4.0
Hz, 1H).
Example 209
##STR00513##
[1050]
5-Chloro-4-(((1R,3S,4S,6S)-4-(dimethylamino)-7,7-difluorobicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1051] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride the title compound was obtained as a white solid.
Absolute stereochemistry and relative cyclopropane stereochemistry
was arbitrarily assigned. LCMS (ESI) m/z: 481.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.56 (d, J=7.3 Hz, 1H),
7.19 (d, J=4.5 Hz, 1H), 6.81 (d, J=12.8 Hz, 1H), 6.74 (d, J=4.5 Hz,
1H), 5.98 (d, J=3.8 Hz, 1H), 3.16-3.09 (m, 2H), 2.66-2.55 (m, 1H),
2.11 (s, 6H), 1.94 (dd, J=12.4, 4.1 Hz, 1H), 1.90-1.74 (m, 3H),
1.18 (td, J=12.7, 3.6 Hz, 1H).
Example 210
##STR00514##
[1052]
5-Chloro-4-(((1S,3R,4R,6R)-4-(dimethylamino)-7,7-difluorobicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1053] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3,4-trans)-7,7-difluorobicyclo[4.1.0]heptane-3,4-diamine
dihydrochloride the title compound was obtained as a white solid.
Absolute stereochemistry and relative cyclopropane stereochemistry
was arbitrarily assigned. LCMS (ESI) m/z: 481.0 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.59 (d, J=7.3 Hz, 1H),
7.23 (d, J=4.5 Hz, 1H), 6.84 (d, J=12.9 Hz, 1H), 6.78 (d, J=4.5 Hz,
1H), 6.02 (d, J=3.9 Hz, 1H), 3.21-3.12 (m, 2H), 2.68-2.58 (m, 1H),
2.14 (s, 6H), 2.01-1.92 (m, 1H), 1.92-1.76 (m, 3H), 1.24 (td,
J=12.1, 3.9 Hz, 1H).
Example 211
##STR00515##
[1054]
5-Chloro-4-(((1S,2S)-2-(dimethylamino)cyclohexy)amino)-2-fluoro-N-(-
5-fluoro-4-methylthiazol-2-yl)benzenesulfonamide Formate
[1055] Following the procedure described in Example 172 and making
non-critical variations as required to replace
5-chloro-4-methyl-thiazol-2-amine with
5-fluoro-4-methylthiazol-2-amine the title compound was obtained as
a white solid. LCMS (ESI) m/z: 465.1, 467.0 [M+H].sup.+. .sup.1H
NMR (400 MHz, d6-DMSO) .delta. 7.51 (d, J=7.3 Hz, 1H), 6.67 (d,
J=12.6 Hz, 1H), 5.65 (d, J=5.4 Hz, 1H), 2.75 (s, 1H), 2.27 (s,
J=26.3 Hz, 7H), 2.14-1.82 (m, 5H), 1.69 (dd, J=65.9, 11.6 Hz, 2H),
1.42-1.06 (m, 4H).
Example 212
##STR00516##
[1056]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((R)-3-fluoro-3-(hydroxymethyl)pipe-
ridin-1-yl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[1057] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
rac-(3-fluoro-3-piperidyl)methanol, the title compound was obtained
as a mixture of diastereomers. Separation of the isomers by HPLC
gave
5-Chloro-2-fluoro-4-(((1S,2S)-2-((R)-3-fluoro-3-(hydroxymethyl)piperidin--
1-yl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide as a
white solid. The stereochemistry of the hydroxymethyl group was
arbitrarily assigned. LCMS (ESI) m/z: 520.9 [M+H].sup.+. .sup.1H
NMR (400 MHz, d6-dmso) .delta. 12.75 (s, 1H), 7.59 (d, J=7.3 Hz,
1H), 7.25 (d, J=4.6 Hz, 1H), 6.80 (d, J=4.6 Hz, 1H), 6.67 (d,
J=12.8 Hz, 1H), 5.94 (s, 1H), 4.80-4.71 (m, 1H), 3.47 (ddd, J=23.7,
12.2 Hz, 4.2 Hz, 1H), 3.29-3.14 (m, 2H), 2.69-2.41 (m, 4H),
2.36-2.23 (m, 1H), 2.23-2.10 (m, 1H), 1.86-1.71 (m, 2H), 1.68-1.55
(m, 2H), 1.52-1.34 (m, 4H), 1.28-1.02 (m, 3H).
Example 213
##STR00517##
[1058]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-fluoro-3-(hydroxymethyl)pipe-
ridin-1-yl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide
[1059] Following the synthetic sequence described in Example 70 and
making non-critical variations to substitute piperidine with
rac-(3-fluoro-3-piperidyl)methanol, the title compound was obtained
as a mixture of diastereomers. Separation of the isomers by HPLC
gave
5-Chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-fluoro-3-(hydroxymethyl)piperidin--
1-yl)cyclohexyl)amino)-N-(thiazol-2-yl)benzenesulfonamide as a
white solid. The stereochemistry of the hydroxymethyl group was
arbitrarily assigned. LCMS (ESI) m/z: 520.9 [M+H].sup.+. .sup.1H
NMR (400 MHz, d6-dmso) .delta. 12.75 (s, 1H), 7.58 (d, J=7.3 Hz,
1H), 7.26 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 6.69 (d,
J=12.9 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 4.80 (t, J=6.0 Hz, 1H),
3.47 (td, J=24.1 Hz, 5.7 Hz, 2H), 3.29-3.19 (m, 1H), 2.65-2.42 (m,
4H), 2.29-2.21 (m, 1H), 2.17 (d, 1H), 1.89-1.50 (m, 5H), 1.49-1.31
(m, 2H), 1.31-1.08 (m, 4H).
Example 214
##STR00518##
[1060]
5-Chloro-4-(((1S,3S,4S,6R)-4-(dimethylamino)bicyclo[4.1.0]heptan-3--
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
Step 1
##STR00519##
[1061] Rac-(3S,4S)-diethyl
bicyclo[4.1.0]heptane-3,4-dicarboxylate
[1062] In a dry flask under nitrogen was added diethylzinc solution
(1M in hexane, 25.6 mL, 25.6 mmol), then DCM (100 mL) and the
solution was cooled to 0.degree. C. Trifluoroacetic acid (1.97 ml,
25.6 mmol) was added dropwise, then diiodomethane (2.06 ml, 25.6
mmol) was added. After 15 minutes, a solution of racemic
diethyl(1S,2S)-diethyl cyclohex-4-ene-1,2-dicarboxylate (1.45 g,
6.41 mmol) in DCM (33 mL) was added. The mixture was warmed to room
temperature slowly and after stirring for 16 h, methanol (2 mL) was
added, followed by addition of saturated aqueous sodium bicarbonate
(25 mL). The phases were separated. The organic phase was washed
with brine (10 mL), dried over sodium sulfate, filtered and
concentrated. To facilitate separation of the remaining starting
alkene, it was converted to the diol via dihydroxylation. The crude
product containing residual alkene starting material was diluted
with DCM (10 mL), and 4-methylmorpholine N-oxide (751 mg, 6.41
mmol) and osmium tetroxide (4% wt in water, 0.5 ml, 0.080 mmol)
were added and the mixture was stirred for 16 h. EtOAc (50 mL) and
a solution of 50% saturated aqueous sodium thiosulfate 50% (25 mL)
were added. The phases were separated and the organic phase was
dried over sodium sulfate, filtered and concentrated. The crude was
purified by flash column chromatography through Si gel
(EtOAc/hexanes) to provide rac-(3S,4S)-diethyl
bicyclo[4.1.0]heptane-3,4-dicarboxylate (1.34 g, 87%) as a
colorless oil. LCMS (ESI) m/z: 241.1 [M+H].sup.+. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 4.18-3.99 (m, 4H), 2.54-2.37 (m, 2H),
2.36-2.28 (m, 1H), 2.20 (ddd, J=13.3, 4.5, 1.1 Hz, 1H), 1.82 (td,
J=12.9, 5.1 Hz, 1H), 1.51-1.38 (m, 1H), 1.21 (td, J=7.1, 3.0 Hz,
6H), 0.97 (qdd, J=14.1, 10.2, 6.7 Hz, 2H), 0.64 (td, J=8.8, 4.9 Hz,
1H), 0.03 (q, J=5.2 Hz, 1H).
Step 2
##STR00520##
[1063] Rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-dicarboxylic Acid
[1064] In a flask containing rac-(3S,4S)-diethyl
bicyclo[4.1.0]heptane-3,4-dicarboxylate (1.24 g, 5.16 mmol) was
added lithium hydroxide monohydrate (1.27 g, 30.3 mmol), water (5
mL), 1,4-dioxane (3 mL) and methanol (0.5 mL). The mixture was
stirred at 60.degree. C. for 1 hour and then cooled to room
temperature. 6M HCl (10 mL) and EtOAc (50 mL) were added. The
phases were separated and the aqueous phase was extracted with
EtOAc (50 mL). The combined organic extracts were dried over sodium
sulfate, filtered and concentrated to afford crude
rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-dicarboxylic acid (0.93 g,
98%) as a white solid. LCMS (ESI) m/z: 183.1 [M-H].sup.-. .sup.1H
NMR (400 MHz, methanol-d.sub.4) .delta. 2.50-2.35 (m, 2H),
2.34-2.17 (m, 2H), 1.84 (td, J=12.6, 5.1 Hz, 1H), 1.45 (t, J=12.6
Hz, 1H), 1.14-0.97 (m, 2H), 0.69 (td, J=8.8, 4.9 Hz, 1H), 0.07 (q,
J=5.2 Hz, 1H). 2 HO signals exchanged with the solvent and are not
observed.
Step 3
##STR00521##
[1065] Rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-diamine
Dihydrochloride
[1066] In a flask containing
rac-((3S,4S)-bicyclo[4.1.0]heptane-3,4-dicarboxylic acid (500 mg,
2.71 mmol) was added DMF (25 uL, 0.32 mmol) followed by oxalyl
chloride (5 mL, 58 mmol). The suspension was stirred at room
temperature for 30 minutes. The mixture was concentrated to
dryness, dissolved in 1,4-dioxane (5 mL) and trimethylsilyl azide
(0.90 ml, 6.8 mmol) was added. After 30 minutes, the mixture was
heated to 90.degree. C. for 1 hour. Concentrated hydrochloric acid
(2.5 ml, 30 mmol) was then added and the oil bath was cooled to
45.degree. C. and the mixture was stirred for 16 h. The mixture was
concentrated to dryness, diluted with 1,4-dioxane and after
stirring for 15 minutes a precipitate appeared. The suspension was
stirred for 1 hour, the solids were filtered and washed with
diethyl ether, and dried under vacuum to afford
rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-diamine dihydrochloride (190
mg, 35%) as an off-white solid. LCMS (ESI) m/z: 126.9 [M+H].sup.+.
.sup.1H NMR (400 MHz, methanol-d.sub.4) .delta. 3.42-3.33 (m, 2H),
2.65-2.46 (m, 1H), 2.24-2.12 (m, 1H), 2.03 (dt, J=8.9, 4.2 Hz, 1H),
1.49-1.33 (m, 1H), 1.09 (qd, J=9.1, 4.7 Hz, 2H), 0.86 (td, J=8.5,
5.1 Hz, 1H), 0.23 (q, J=5.0 Hz, 1H). 6 N--H exchanged with the
solvent and were not observed.
Step 4
##STR00522##
[1067]
5-Chloro-4-(((1S,3S,4S,6R)-4-(dimethylamino)bicyclo[4.1.0]heptan-3--
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1068] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-diamine the title compound
was obtained as a white solid. Absolute stereochemistry and
relative cyclopropane stereochemistry was arbitrarily assigned.
LCMS (ESI) m/z: 445.1 [M+H].sup.+. H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.29 (br s, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.18 (s, 1H),
6.84-6.64 (m, 2H), 5.97 (s, 1H), 3.14 (s, 1H), 2.73-2.61 (m, 1H),
2.54 (s, 1H), 2.15 (s, 6H), 2.01 (dd, J=12.6, 3.0 Hz, 1H), 1.80
(td, J=12.2, 5.1 Hz, 1H), 1.17 (t, J=12.3 Hz, 1H), 1.10-1.01 (m,
1H), 0.96-0.85 (m, 1H), 0.59 (td, J=8.7, 4.3 Hz, 1H), 0.12 (dd,
J=9.5, 4.7 Hz, 1H).
Example 215
##STR00523##
[1069]
5-Chloro-4-(((1R,3R,4R,6S)-4-(dimethylamino)bicyclo[4.1.0]heptan-3--
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1070] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-diamine the title compound
was obtained as a white solid. Absolute stereochemistry and
relative cyclopropane stereochemistry was arbitrarily assigned.
LCMS (ESI) m/z: 445.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.77-11.45 (br s, 1H), 7.58 (d, J=7.2 Hz,
1H), 7.21 (d, J=4.4 Hz, 1H), 6.88-6.61 (m, 2H), 5.99 (d, J=3.9 Hz,
1H), 3.19 (s, 1H), 2.72-2.62 (m, 1H), 2.62-2.54 (m, 1H), 2.17 (s,
6H), 2.02 (dd, J=12.7, 3.7 Hz, 1H), 1.81 (td, J=12.2, 5.3 Hz, 1H),
1.18 (t, J=11.7 Hz, 1H), 1.12-1.02 (m, 1H), 0.92 (dt, J=8.3, 5.0
Hz, 1H), 0.60 (td, J=8.8, 4.4 Hz, 1H), 0.12 (dd, J=9.7, 4.6 Hz,
1H).
Example 216
##STR00524##
[1071]
5-Chloro-4-(((1R,3S,4S,6S)-4-(dimethylamino)-7,7-difluorobicyclo[4.-
1.0]heptan-3-yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1072] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-diamine the title compound
was obtained as a white solid. Absolute stereochemistry and
relative cyclopropane stereochemistry was arbitrarily assigned.
LCMS (ESI) m/z: 445.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.04 (br s, 1H), 7.58 (d, J=7.3 Hz, 1H),
7.21 (d, J=4.4 Hz, 1H), 6.75 (d, J=4.4 Hz, 1H), 6.71 (d, J=12.9 Hz,
1H), 5.93 (d, J=4.9 Hz, 1H), 3.25-3.16 (m, 1H), 2.85-2.72 (m, 1H),
2.37 (dd, J=13.0, 4.1 Hz, 1H), 2.26-2.21 (m, 1H), 2.19 (s, 6H),
1.71-1.57 (m, 1H), 1.46 (t, J=13.2 Hz, 1H), 1.00-0.85 (m, 2H), 0.56
(td, J=8.9, 4.5 Hz, 1H), 0.41 (q, J=5.0 Hz, 1H).
Example 217
##STR00525##
[1073]
5-Chloro-4-(((1S,3R,4R,6R)-4-(dimethylamino)bicyclo[4.1.0]heptan-3--
yl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
[1074] Following the procedure described in Example 194 and making
non-critical variations as required to replace
rac-(3,4-trans)-7,7-dichlorobicyclo[4.1.0]heptane-3,4-diamine with
rac-(3S,4S)-bicyclo[4.1.0]heptane-3,4-diamine the title compound
was obtained as a white solid. Absolute stereochemistry and
relative cyclopropane stereochemistry was arbitrarily assigned.
LCMS (ESI) m/z: 445.1 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 7.58 (d, J=7.3 Hz, 1H), 7.20 (d, J=4.4 Hz,
1H), 6.75 (d, J=4.4 Hz, 1H), 6.71 (d, J=12.8 Hz, 1H), 5.93 (d,
J=4.7 Hz, 1H), 3.24-3.17 (m, 1H), 2.78 (td, J=11.2, 5.4 Hz, 1H),
2.38 (dd, J=13.2, 4.3 Hz, 1H), 2.22 (d, J=9.2 Hz, 1H), 2.18 (s,
6H), 1.71-1.58 (m, 1H), 1.46 (t, J=13.3 Hz, 1H), 0.91 (d, J=4.7 Hz,
2H), 0.56 (td, J=8.8, 4.4 Hz, 1H), 0.41 (q, J=5.0 Hz, 1H). Acidic
NH not visible.
Example 218
##STR00526##
[1075]
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)-cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00527##
[1076] Step 1
##STR00528##
[1077]
tert-Butyl((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)pheny-
l)cyclohexyl)-carbamate
[1078] To 20% Pd(OH).sub.2 on charcol (700 mg, 46 mmol) was added
tert-butyl
N-[(1S,6S)-6-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]cyclohex-3-en-1-
-yl]carbamate (2300 mg, 5.98 mmol) prepared in Example 181 in ethyl
acetate (30 mL). The reaction is stirred at rt for 2 hours under
H.sub.2 resulting in a mixture of diastereomers. Pd(OH).sub.2 was
filtered through a pad of Celite and the filtrate was concentrated.
The diastereomers were separated by flash column chromatography
through Si gel (0-60% MTBE/hexanes) to provide
tert-butyl((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cycl-
ohexyl)-carbamate (450 mg, 20% yield) as the minor diastereomer.
LCMS (ESI) m/z: 387.2 [M+H].sup.+.
Step 2
##STR00529##
[1079]
(1S,2S,5R)--N.sup.1,N.sup.1-Dimethyl-5-(3-(trifluoromethyl)phenyl)c-
yclohexane-1,2-diamine
[1080]
tert-Butyl((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)pheny-
l)cyclohexyl)-carbamate (200 mg, 0.52 mmol) was dissolved in
1,4-dioxane (1 mL) and to the mixture was added 4M HCl in dioxane
(2 mL, 8.0 mmol). The reaction is stirred at rt for 1 h then
diluted with MTBE (30 mL) and quenched with saturated aqueous
Na.sub.2CO.sub.3 (15 mL). The organic layer was separated and dried
over Na.sub.2SO.sub.4. The solvent was removed in vacuo to provide
crude
(1S,2S,5R)--N,N-dimethyl-5-(3-(trifluoromethyl)phenyl)cyclohexane-1,2-dia-
mine (140 mg, 95% yield) which was used without any further
purification. LCMS (ESI) m/z: 287.1 [M+H].sup.+.
Step 3
##STR00530##
[1081]
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4R)-2-(dimethylamino)-4-
-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)b-
enzenesulfonamide
[1082] In a flask containing
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-pyrimidin-4-yl-be-
nzenesulfonamide (60 mg, 0.13 mmol) was added DMF (0.50 mL), DIPEA
(0.05 mL, 0.26 mmol) and
(1S,2S,5R)--N.sup.1,N.sup.1-dimethyl-5-(3-(trifluoromethyl)phenyl)cyclohe-
xane-1,2-diamine (25 mg, 0.09 mmol). After overnight stirring at
65.degree. C., the reaction was quenched with water (10 mL). The
product was extracted with EtOAc (30 mL), the organic layer was
separated and washed three times with water followed by brine (5
mL). The organic layer was dried over Na.sub.2SO.sub.4, flittered
and concentrated in vacuo. The residue was purified by flash column
chromatography through Si gel (EtOAc/hexanes) to give
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(t-
rifluoromethyl)phenyl)-cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzen-
esulfonamide (53 mg, 84% yield). LCMS (ESI) m/z: 722.3
[M+H].sup.+.
Step 4
##STR00531##
[1083]
5-Chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)-cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1084] In a flask containing
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(t-
rifluoromethyl)phenyl)-cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzen-
esulfonamide (53 mg, 0.07 mmol) was added formic acid (0.47 mL,
7.34 mmol) and the reaction is stirred at 25.degree. C. for 3
hours. The reaction was concentrated and the product was purified
directly by C18 reverse phase flash column chromatography (0-100%
MeCN/10 mM aqueous ammonium formate, pH=3.8). Appropriate fractions
combined and lyophilized to provide
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)p-
henyl)-cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
(23 mg, 55% yield). LCMS (ESI) m/z: 572.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, d6-DMSO) .delta. 8.44 (s, 1H), 8.14 (s, 1H), 7.82-7.42
(m, 6H), 6.83 (d, J=12.9 Hz, 1H), 6.77 (d, J=3.6 Hz, 1H), 5.83 (d,
J=3.8 Hz, 1H), 3.94-3.74 (m, 2H), 3.14-2.77 (m, 2H), 2.43 (s, 6H),
2.23-2.08 (m, 1H), 2.01-1.81 (m, 3H), 1.45-1.28 (m, 1H).
Example 219
##STR00532##
[1085]
5-chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cy-
clohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00533## ##STR00534##
[1086] Step 1
##STR00535##
[1087]
tert-Butyl((3S,4S)-3'-bromo-3-(dimethylamino)-2,3,4,5-tetrahydro-[1-
,1'-biphenyl]-4-yl)carbamate
[1088] Following the procedure as described in Example 224 and
making non-critical variations as required to replace
1-(4-(trifluoromethyl)phenyl)ethanone with
1-(3-bromophenyl)ethanone,
tert-butyl((3S,4S)-3'-bromo-3-(dimethylamino)-2,3,4,5-tetrahydro-[1,1'-bi-
phenyl]-4-yl)carbamate was obtained. LCMS (ESI) m/z: 395.1
[M+H].sup.+.
Step 2
##STR00536##
[1089]
tert-Butyl((3S,4S)-3'-cyclopropyl-3-(dimethylamino)-2,3,4,5-tetrahy-
dro-[1,1'-biphenyl]-4-yl)carbamate
[1090] In a seal tube containing
tert-butyl((3S,4S)-3'-bromo-3-(dimethylamino)-2,3,4,5-tetrahydro-[1,1'-bi-
phenyl]-4-yl)carbamate (440 mg, 1.11 mmol) in degassed toluene (22
mL) and degassed water (10.9 mL) was added cesium carbonate (1.09
g, 3.34 mmol) and potassium cyclopropyltrifluoroborate (659 mg,
4.45 mmol). The tube was bubbled with nitrogen for 1 minute then
palladium acetate (38 mg, 0.17 mmol) and
Butyldi-1-adamantylphosphine (120 mg, 0.33 mmol) were added. The
tube was bubbled for 2 min with nitrogen then sealed and heated at
110.degree. C. for 18 hours. The reaction mixture was cooled down
then filtered trough celite, rinsed with EtOAc and the filtrate
washed with saturated aqueous brine solution, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The crude product was
purified by flash column chromatography through Si gel (0-20%
MeOH/DCM) to provide
tert-butyl((3S,4S)-3'-cyclopropyl-3-(dimethylamino)-2,3,4,5-tetrahydro-[1-
,1'-biphenyl]-4-yl)carbamate (370 mg, 93%). LCMS (ESI) m/z: 357.2
[M+H].sup.+.
Step 3
##STR00537##
[1091]
tert-Butyl((1S,2S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohe-
xyl)carbamate &
tert-butyl((1S,2S)-2-(dimethylamino)-4-(3-propylphenyl)cyclohexyl)carbama-
te
[1092] To
tert-butyl((3S,4S)-3'-cyclopropyl-3-(dimethylamino)-2,3,4,5-tetr-
ahydro-[1,1'-biphenyl]-4-yl)carbamate (330 mg, 0.93 mmol) in ethyl
acetate (3 mL) was added palladium hydroxide 20% on charcol (130
mg). The reaction was submitted to 3 cycles of hydrogen/vacuum
purged and then was stirred at room temperature for 4 hours under
hydrogen atmosphere. The reaction was submitted to 3 cycles of
nitrogen/vacuum purged, filtered through celite, rinsed with EtOAc
and concentrated to provide a mixture of
tert-butyl((1S,2S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohexyl-
)carbamate and
tert-butyl((1S,2S)-2-(dimethylamino)-4-(3-propylphenyl)cyclohexyl)carbama-
te (280 mg, 85%). LCMS (ESI) m/z: 359.3 [M+H].sup.+. The mixture
was used without further purification in the subsequent step.
Step 4
##STR00538##
[1093]
(1S,2S,5S)-5-(3-Cyclopropylphenyl)-N1,N1-dimethylcyclohexane-1,2-di-
amine &
(1S,2S,5S)--N1,N1-dimethyl-5-(3-propylphenyl)cyclohexane-1,2-diami-
ne
[1094] To the mixture of
tert-butyl((1S,2S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohexyl)ca-
rbamate and
tert-butyl((1S,2S)-2-(dimethylamino)-4-(3-propylphenyl)cyclohexyl)carbama-
te (280 mg, 0.78 mmol) in DCM (4 mL) was added HCl 4 N in dioxane
(6 mL, 23 mmol). The reaction was stirred at room temperature for
60 minutes, concentrated and purified directly by C18 reverse phase
flash chromatography (0-40% MeCN/10 mM aqueous ammonium formate,
pH=3.8). Appropriate fractions combined and lyophilized to provide
a mixture of
(1S,2S,5S)-5-(3-cyclopropylphenyl)-N1,N1-dimethylcyclohexane-1,2-diamine
and
(1S,2S,5S)--N1,N1-dimethyl-5-(3-propylphenyl)cyclohexane-1,2-diamine
(51 mg, 22%).
Step 5
##STR00539##
[1095]
5-Chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cy-
clohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzene-
sulfonamide &
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-pr-
opylphenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1096] To the mixture of
(1S,2S,5S)-5-(3-cyclopropylphenyl)-N1,N1-dimethylcyclohexane-1,2-diamine
and
(1S,2S,5S)--N1,N1-dimethyl-5-(3-propylphenyl)cyclohexane-1,2-diamine
(51 mg, 0.2 mmol) in DMF (1 mL) was added DIPEA (0.14 mL, 0.79
mmol) and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide (108 mg, 0.24 mmol). The reaction mixture was stirred at
65.degree. C. for 18 hours and then quenched with water (10 mL).
The product was extracted with EtOAc (50 mL), the organic layer was
separated, washed with water, saturated aqueous brine solution
dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude
product was purified by flash column chromatography through Si gel
(0-20% MeOH/DCM) to provide a mixture of
5-chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohex-
yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfon-
amide and
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino-
)-4-(3-propylphenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide (105 mg, 77%). LCMS (ESI) m/z: 694.3 [M+H]
Step 6
##STR00540##
[1097]
5-Chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cy-
clohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1098] To the mixture of
5-chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohex-
yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfon-
amide and
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino-
)-4-(3-propylphenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide (105 mg, 0.15 mmol) was added formic acid (1 mL, 26.5
mmol). The reaction was stirred at room temperature for 3 hours
then concentrated. The crude was dissolved in a mixture of DMF and
DMSO, filtered and purified by prep-HPLC (CSH C18 col, 5 m,
30.times.75 mm at 40.degree. C.; 45 mL/min, 25-45% MeCN/10 mM
aqueous ammonium formate, pH=3.8). Appropriate fractions combined
and lyophilized to provide
5-chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohex-
yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (48 mg,
58%). LCMS (ESI) m/z: 544.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.34 (s, 1H), 8.15 (s, 1H), 8.01 (d, J=5.0
Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.12-6.97
(m, 2H), 6.88 (d, J=7.7 Hz, 1H), 6.74 (d, J=12.8 Hz, 1H), 6.63 (d,
J=5.1 Hz, 1H), 5.81 (d, J=5.9 Hz, 1H), 2.67-2.55 (m, 1H), 2.35 (s,
6H), 2.14 (dd, J=12.8, 3.1 Hz, 1H), 1.99 (d, J=12.2 Hz, 1H),
1.94-1.82 (m, 1H), 1.69 (dt, J=10.3, 5.1 Hz, 2H), 1.56 (q, J=12.3
Hz, 1H), 1.46-1.27 (m, 1H), 0.99-0.88 (m, 2H), 0.71-0.59 (m, 2H).
Exchangeable NH hydrogens not observed.
Example 220
##STR00541##
[1099]
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00542##
[1100] Step 1
##STR00543##
[1101]
N-(2,4-Dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide
[1102] A solution of
N-[(2,4-dimethoxyphenyl)methyl]pyrimidin-4-amine (1.0 g, 4.1 mmol)
and 2,4,5-trifluorobenzenesulfonyl chloride (1.41 g, 6.12 mmol) and
1,4-diazabicyclo[2.2.2]octane (0.69 g, 6.12 mmol) in MeCN (20 mL)
was stirred at rt for 5 h. The reaction was filtered to remove the
white solid, then concentrated, and purified by flash column
chromatography through Si gel (EtOAc/hexanes) to provide
N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonam-
ide (1.2 g, 67% yield) as a pale yellow solid. LCMS (ESI) m/z:
440.1 [M+H].sup.+.
Step 2
##STR00544##
[1103]
N-(2,4-Dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trif-
luoromethyl)phenyl)cyclohexyl)amino)-2,5-difluoro-N-(pyrimidin-4-yl)benzen-
esulfonamide
[1104] In a flask containing
N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(pyrimidin-4-yl)benzenesulfonam-
ide (184 mg, 0.42 mmol) was added DMF (2 mL), DIPEA (0.15 mL, 0.84
mmol) and
(1S,2S,4S)--N.sup.1,N.sup.1-dimethyl-4-[3-(trifluoromethyl)phenyl]cyc-
lohexane-1,2-diamine (80 mg, 0.28 mmol). After overnight stirring
at 65.degree. C., the reaction was quenched with water (10 mL). The
product was extracted with EtOAc (30 mL), the organic layer was
separated and washed with three times with water and followed by
brine (5 mL). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography through Si gel (EtOAc/hexanes) to
provide N-(2,4-dimethoxybenzyl)-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2,5--
difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (140 mg, 71% yield).
LCMS (ESI) m/z: 706.4 [M+H].sup.+.
Step 3
##STR00545##
[1105]
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1106] Following the procedure described in Example 115 and making
non-critical variations as required using
N-(2,4-dimethoxybenzyl)-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2,5--
difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (185 mg, 0.26 mmol),
4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2,5--
difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (73 mg, 50% yield)
was obtained. LCMS (ESI) m/z: 556.3 [M+H].sup.+. .sup.1H NMR (400
MHz, d6-DMSO) .delta. 8.37 (s, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.59
(dd, J=26.9, 12.1 Hz, 4H), 7.38 (dd, J=11.1, 6.6 Hz, 1H), 6.74 (dd,
J=12.3, 6.9 Hz, 1H), 6.68 (d, J=5.8 Hz, 1H), 6.10 (s, 1H), 3.69 (m,
1H), 3.22-3.20 (m, 1H), 2.80 (m, 1H), 2.45 (s, 6H), 2.08 (m, 2H),
1.66 (m, 3H), 1.36 (s, 1H). Acidic NH not observed
Example 221
##STR00546##
[1107]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((R)-3-fluoro-3-(hydroxymethyl)pipe-
ridin-1-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
[1108] Following the procedure described in Example 212 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
5-Chloro-2-fluoro-4-(((1S,2S)-2-((R)-3-fluoro-3-(hydroxymethyl)-
piperidin-1-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
was obtained. LCMS (ESI) m/z: 516.2 [(M+H]. .sup.1H NMR (400 MHz,
d6-dmso) .delta. 12.54 (s, 1H), 8.55 (s, 1H), 8.26 (d, J=6.0 Hz,
1H), 7.69 (d, J=7.4 Hz, 1H), 6.91 (d, J=6.1 Hz, 1H), 6.67 (d,
J=13.1 Hz, 1H), 5.98 (s, 1H), 4.77 (s, 1H), 3.47 (dd, J=23.9, 12.3
Hz, 2H), 3.28-3.14 (m, 3H), 2.63-2.55 (m, 1H), 2.46-2.41 (m, 1H),
2.32-2.22 (m, 1H), 2.15 (d, J=11.2 Hz, 1H), 1.81 (d, J=7.5 Hz, 1H),
1.78-1.71 (m, 1H), 1.69-1.54 (m, 2H), 1.52-1.43 (m, 2H), 1.43-1.30
(m, 2H), 1.29-1.16 (m, 2H), 1.11 (q, J=10.0 Hz, 1H).
Example 222
##STR00547##
[1109]
5-Chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-fluoro-3-(hydroxymethyl)pipe-
ridin-1-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
[1110] Following the procedure described in Example 212 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(thiazol-2-yl)benzenesulf-
onamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide,
5-Chloro-2-fluoro-4-(((1S,2S)-2-((S)-3-fluoro-3-(hydroxymethyl)-
piperidin-1-yl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
was obtained. LCMS (ESI) m/z: 516.2 [M+H].sup.+. .sup.1H NMR (400
MHz, d6-dmso) .delta. 12.56 (s, 1H), 8.57 (s, 1H), 8.29 (d, J=5.9
Hz, 1H), 7.69 (d, J=7.4 Hz, 1H), 6.94 (d, J=6.1 Hz, 1H), 6.69 (d,
J=13.2 Hz, 1H), 6.00 (s, 1H), 4.81 (s, 1H), 3.46 (dd, J=24.1, 5.5
Hz, 2H), 3.30-3.20 (m, 2H), 2.59 (t, J=11.8 Hz, 2H), 2.45 (d,
J=10.6 Hz, 1H), 2.22 (t, J=8.4 Hz, 1H), 2.13 (d, J=10.8 Hz, 1H),
1.82 (d, J=8.2 Hz, 1H), 1.78-1.71 (m, 1H), 1.71-1.56 (m, 2H),
1.56-1.45 (m, 1H), 1.45-1.29 (m, 2H), 1.29-1.05 (m, 4H).
Example 223
##STR00548##
[1111]
5-Chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-propylphenyl)cyclohe-
xyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1112] Following the procedure described in Example 219 step 6,
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-propylphenyl)cyclohexyl)am-
ino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was obtained.
LCMS (ESI) m/z: 546.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.22 (s, 1H), 7.88 (s, J=52.6 Hz, 1H), 7.57
(d, J=7.3 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 7.11 (d, J=6.0 Hz, 2H),
6.99 (d, J=7.4 Hz, 1H), 6.57 (d, J=12.5 Hz, 1H), 6.48 (d, J=5.3 Hz,
1H), 5.32 (d, J=5.0 Hz, 1H), 2.58-2.49 (m, 2H), 2.41 (t, J=9.0 Hz,
1H), 2.21 (s, 7H), 2.17 (s, 1H), 2.14-1.86 (m, 4H), 1.86-1.68 (m,
2H), 1.63-1.48 (m, 2H), 1.48-1.28 (m, 1H), 0.87 (t, J=7.3 Hz,
3H).
Example 224
##STR00549##
[1113]
5-Chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(4-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00550## ##STR00551##
[1114] Step 1
##STR00552##
[1115] 1-(Prop-1-en-2-yl)-4-(trifluoromethyl)benzene
[1116] To methyltriphenylphosphonium bromide (14.2 g, 39.9 mmol)
was added THF (44 mL). The suspension was cooled to 0.degree. C.
and potassium tert-butoxide (4.47 g, 39.9 mmol) was added. The
resulting yellow suspension was stirred at 0.degree. C. for 45
minutes. To the suspension was added a solution of
1-(4-(trifluoromethyl)phenyl)ethanone (5.0 g, 26.6 mmol) in THF (22
mL) dropwise. The resulting mixture was then brought up to room
temperature slowly and stirred for 16 hours. Reaction mixture was
diluted with hexanes (150 mL) and stirred for 20 min. The resulting
precipitate was filtered, rinsed with hexane and the filtrate was
concentrate. More hexanes (200 mL) was added to the residue and
stirred for 20 min. The resulting precipitate was filtered through
celite and the filtrate was concentrated to provide
1-(prop-1-en-2-yl)-4-(trifluoromethyl)benzene (3.98 g, 80%) .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.61-7.53 (m, 4H), 5.44 (s, 1H),
5.22-5.17 (m, 1H), 2.17 (dd, J=1.3, 0.7 Hz, 3H).
##STR00553##
1-(3-Iodoprop-1-en-2-yl)-4-(trifluoromethyl)benzene
[1117] To iodine (33.9 g, 133.6 mmol) in DMA (180 mL) was added
1-(prop-1-en-2-yl)-4-(trifluoromethyl)benzene (4.98 g, 26.8 mmol)
in DMA (5 mL). The reaction was stirred at room temperature for 20
minutes. A freshly made aqueous solution of saturated aqueous
sodium thiosulfate was added as well as EtOAc (250 mL). The
resulting solution was stirred for 10 minutes, water phase was
removed and organic phase washed with water (2.times.50 mL) and
with saturated aqueous brine solution (100 mL, then 50 mL) dried
over MgSO.sub.4, filtered and concentrated. The crude product was
purified by flash column chromatography through Si gel (100%
Hexanes) to provide
1-(3-iodoprop-1-en-2-yl)-4-(trifluoromethyl)benzene (2.58 g, 31%).
H NMR (400 MHz, CDCl.sub.3) .delta. 7.64 (d, J=8.3 Hz, 2H), 7.56
(d, J=8.2 Hz, 2H), 5.63 (s, 1H), 5.53 (s, 1H), 4.32 (s, 2H).
Step 3
##STR00554##
[1118] (4S,5S)-tert-Butyl
4-allyl-6-oxo-5-(2-(4-(trifluoromethyl)phenyl)allyl)-1,3-oxazinane-3-carb-
oxylate
[1119] A solution of (S)-tert-butyl
4-allyl-6-oxo-1,3-oxazinane-3-carboxylate (2.0 g, 8.3 mmol) in THF
(80 mL) was cooled to -78.degree. C. under nitrogen. KHMDS (0.5 M
in Toluene) (16.6 mL, 8.3 mmol) was then added dropwise and the
solution was left to stir at -78.degree. C. for 30 minutes.
1-(3-iodoprop-1-en-2-yl)-4-(trifluoromethyl)benzene (2.07 g, 6.63
mmol) as a solution in THF (5 mL) was then added at once quickly
and stirring was continued for 4.5 hours at -78.degree. C. The
reaction was quenched with saturated aqueous NH.sub.4Cl solution
(40 mL) at -78.degree. C. and then water (40 mL) and EtOAc (200 mL)
were added. The organic layer was separated and washed with brine
(2.times.40 mL) and then dried over Na.sub.2SO.sub.4 filtered and
concentrated. The crude product was purified by flash column
chromatography through Si gel (EtOAc/Hexanes) to provide
(4S,5S)-tert-butyl
4-allyl-6-oxo-5-(2-(4-(trifluoromethyl)phenyl)allyl)-1,3-oxazinane-3-carb-
oxylate (1.29 g, 37%) as a clear oil. LCMS (ESI) m/z: 326.1
[M-Boc+H].sup.+
Step 4
##STR00555##
[1120] (4aS,8aS)-tert-Butyl
4-oxo-6-(4-(trifluoromethyl)phenyl)-2,4,4a,5,8,8a-hexahydro-1H-benzo[d][1-
,3]oxazine-1-carboxylate
[1121] (4S,5S)-tert-Butyl
4-allyl-6-oxo-5-(2-(4-(trifluoromethyl)phenyl)allyl)-1,3-oxazinane-3-carb-
oxylate (1.1 g, 2.57 mmol) was dissolved in toluene (50 mL) and to
this solution was added Grubbs metal second generation (328 mg,
0.39 mmol). The reaction mixture was stirred at 65.degree. C. for 6
hours. The reaction was cooled down to rt and purified directly by
flash column chromatography through Si gel (EtOAc/Hexanes) to
provide (4aS,8aS)-tert-butyl
4-oxo-6-(4-(trifluoromethyl)phenyl)-2,4,4a,5,8,8a-hexahydro-1H-benzo[d][1-
,3]oxazine-1-carboxylate (926 mg, 90%). LCMS (ESI) m/z: 298.1
[M-Boc+H]
Step 5
##STR00556##
[1122]
(3S,4S)-4-((tert-Butoxycarbonyl)amino)-4'-(trifluoromethyl)-2,3,4,5-
-tetrahydro-[1,1'-biphenyl]-3-carboxylic Acid
[1123] (4aS,8aS)-tert-Butyl
4-oxo-6-(4-(trifluoromethyl)phenyl)-2,4,4a,5,8,8a-hexahydro-1H-benzo[d][1-
,3]oxazine-1-carboxylate (920 mg, 2.32 mmol) was dissolved in THF
(12 mL) and to the mixture was added a solution of lithium
hydroxide (1.7 g, 69.4 mmol) in water (12.3 mL). The mixture was
stirred at room temperature for 18 hours then acidified carefully
with a 6 M aqueous solution of HCl to pH.about.3. The product was
extracted by EtOAc (200 mL) and the organic layer was washed with
saturated aqueous brine solution and dried over Na.sub.2SO.sub.4.
The solvent was removed in vacuo to afford
(3S,4S)-4-((tert-butoxycarbonyl)amino)-4'-(trifluoromethyl)-2,3,4,5-tetra-
hydro-[1,1'-biphenyl]-3-carboxylic acid (845 mg, 95%) and was used
without further purification in the subsequent step. LCMS (ESI)
m/z: 384.1 [M-H].sup.-.
Step 6
##STR00557##
[1124]
tert-Butyl((3S,4S)-3-isocyanato-4'-(trifluoromethyl)-2,3,4,5-tetrah-
ydro-[1,1'-biphenyl]-4-yl)carbamate
[1125] To
(3S,4S)-4-((tert-butoxycarbonyl)amino)-4'-(trifluoromethyl)-2,3,-
4,5-tetrahydro-[1,1'-biphenyl]-3-carboxylic acid (845 mg, 2.19
mmol) in toluene (6.2 mL) was added triethylamine (0.43 mL, 3.06
mmol) and diphenylphosphoryl azide (0.52 mL, 2.41 mmol). The
mixture was heated to 100.degree. C. for 35 minutes then cooled
down to room temperature and purified directly by flash column
chromatography through Si gel (EtOAc/Hexanes) to provide
tert-butyl((3S,4S)-3-isocyanato-4'-(trifluoromethyl)-2,3,4,5-tetrahydro-[-
1,1'-biphenyl]-4-yl)carbamate (616 mg, 73%).
Step 7
##STR00558##
[1126]
tert-Butyl((3S,4S)-3-amino-4'-(trifluoromethyl)-2,3,4,5-tetrahydro--
[1,1'-biphenyl]-4-yl)carbamate
[1127] To
tert-butyl((3S,4S)-3-isocyanato-4'-(trifluoromethyl)-2,3,4,5-tet-
rahydro-[1,1'-biphenyl]-4-yl)carbamate (615 mg, 1.60 mmol) in THF
(3 mL) was added a solution of potassium trimethylsilanolate (248
mg, 1.93 mmol) in THF (1 mL). The mixture was stirred at room
temperature for 18 hours then quenched by addition of saturated
aqueous NaHCO.sub.3 (20 mL) and the product was extracted with
EtOAc (100 mL). The organic layer was separated, dried over
Na.sub.2SO.sub.4, filtered and concentrated to provide
tert-butyl((3S,4S)-3-amino-4'-(trifluoromethyl)-2,3,4,5-tetrahydr-
o-[1,1'-biphenyl]-4-yl)carbamate (507 mg, 88% yield) and was used
without further purification in the subsequent step. LCMS (ESI)
m/z: 357.1 [M+H].sup.+.
Step 8
##STR00559##
[1128]
tert-Butyl((3S,4S)-3-(dimethylamino)-4'-(trifluoromethyl)-2,3,4,5-t-
etrahydro-[1,1'-biphenyl]-4-yl)carbamate
[1129] To
tert-butyl((3S,4S)-3-amino-4'-(trifluoromethyl)-2,3,4,5-tetrahyd-
ro-[1,1'-biphenyl]-4-yl)carbamate (505 mg, 1.42 mmol) in methanol
(4.7 mL) at 0.degree. C. was added formaldehyde (37% w/w in
H.sub.2O) (1.06 mL, 14.2 mmol) followed by sodium cyanoborohydride
(214 mg, 5.7 mmol). The reaction mixture was stirred for 1 hour at
room temperature and then diluted with saturated aqueous
NaHCO.sub.3 (50 mL) and EtOAc (200 mL) and the phases were
separated. The organic layer was washed with saturated aqueous
brine solution, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The crude product was purified by flash column
chromatography through Si gel (MeOH/DCM) to provide
tert-butyl((3S,4S)-3-(dimethylamino)-4'-(trifluoromethyl)-2,3,4,5-tetrahy-
dro-[1,1'-biphenyl]-4-yl)carbamate (422 mg, 77%). LCMS (ESI) m/z:
385.2 [M+H].sup.+.
Step 9
##STR00560##
[1130]
tert-Butyl((1S,2S,4S)-2-(dimethylamino)-4-(4-(trifluoromethyl)pheny-
l)cyclohexyl)carbamate
[1131] To
tert-butyl((3S,4S)-3-(dimethylamino)-4'-(trifluoromethyl)-2,3,4,-
5-tetrahydro-[1,1'-biphenyl]-4-yl)carbamate (420 mg, 1.09 mmol) in
ethyl acetate (5.5 mL) was added palladium hydroxide 20% on charcol
(130 mg). The reaction was submitted to 3 cycles of hydrogen/vacuum
purged and then was stirred at room temperature for 4 hours under
hydrogen atmosphere. The reaction was submitted to 3 cycles of
nitrogen/vacuum purged, filtered through celite, rinsed with EtOAc
and concentrated to provide
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(4-(trifluoromethyl)phenyl)cycl-
ohexyl)carbamate as a mixture of diastereoisomeres (323 mg, 77%).
LCMS (ESI) m/z: 387.2 [M+H].sup.+. The mixture was used without
further purification in the subsequent step.
Step 10
##STR00561##
[1132]
(1S,2S,5S)--N1,N1-Dimethyl-5-(4-(trifluoromethyl)phenyl)cyclohexane-
-1,2-diamine
[1133] To
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-(4-(trifluoromethyl)ph-
enyl)cyclohexyl)carbamate (300 mg, 0.78 mmol) in DCM (2.6 mL) was
added 4 N HCl in dioxane (1 mL, 4 mmol). The reaction was stirred
at room temperature for 2 h then concentrated and purified by C18
reverse phase flash chromatography (5-35% MeCN/10 mM aqueous
ammonium formate, pH=3.8). Appropriate fractions combined and
lyophilized to provide
(1S,2S,5S)--N1,N1-dimethyl-5-(4-(trifluoromethyl)phenyl)cyclohexane-1,2-d-
iamine (93 mg, 42%).
Step 11
##STR00562##
[1134]
5-Chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-
-(4-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)b-
enzenesulfonamide
[1135] To
(1S,2S,5S)--N1,N1-dimethyl-5-(4-(trifluoromethyl)phenyl)cyclohex-
ane-1,2-diamine (100 mg, 0.35 mmol) in DMF (1.7 mL) were added
DIPEA (0.19 mL, 1.05 mmol) and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide (239 mg, 0.52 mmol). The reaction mixture was stirred at
65.degree. C. for 18 hours and then quenched with water (10 mL).
The product was extracted with EtOAc (50 mL), the organic layer was
separated, washed with water, saturated aqueous brine solution
dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude
product was purified by flash column chromatography through Si gel
(0-20% MeOH/DCM) to provide
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(4-(t-
rifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzene-
sulfonamide (250 mg, 99%). LCMS (ESI) m/z: 722.3, 724.3
[M+H].sup.+.
Step 12
##STR00563##
[1136]
5-Chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(4-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1137] Following the procedure described in Example 115 step 2 and
making non-critical variations using
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(4-(t-
rifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzene-
sulfonamide (250 mg, 99%),
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(4-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (91
mg, 46%) was obtained. LCMS (ESI) m/z: 572.2, 574.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.42 (s, 1H), 8.10 (d, J=5.4
Hz, 1H), 7.69 (t, J=7.5 Hz, 4H), 7.53 (d, J=8.2 Hz, 2H), 6.82 (d,
J=12.9 Hz, 1H), 6.74 (d, J=5.9 Hz, 1H), 5.96 (d, J=7.1 Hz, 1H),
3.70 (s, 1H), 2.79 (t, J=11.6 Hz, 1H), 2.41 (s, 7H), 2.16-2.00 (m,
2H), 1.83-1.57 (m, 3H), 1.48-1.33 (m, 1H).
Example 225
##STR00564##
[1138]
5-Chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethoxy)ph-
enyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1139] Following the procedure described in Example 224 and making
non-critical variations as required to replace
1-(4-(trifluoromethyl)phenyl)ethanone with
1-(3-(trifluoromethoxy)phenyl)ethanone,
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethoxy)phenyl)c-
yclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide was
obtained. LCMS (ESI) m/z: 588.4, 590.3 [M+H].sup.+. .sup.1H NMR
(400 MHz, d6-DMSO) .delta. 8.40 (s, 1H), 8.08 (d, J=5.5 Hz, 1H),
7.65 (d, J=7.4 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 7.33 (d, J=7.9 Hz,
1H), 7.28 (s, 1H), 7.23-7.17 (m, 1H), 6.79 (d, J=13.0 Hz, 1H), 6.71
(d, J=5.7 Hz, 1H), 5.94 (d, J=7.1 Hz, 1H), 3.69 (s, 1H), 2.74 (t,
J=12.0 Hz, 1H), 2.41 (s, 7H), 2.07 (s, 2H), 1.79-1.54 (m, 3H),
1.46-1.27 (m, 1H). Acidic NH not observed.
Example 226
##STR00565##
[1140]
5-Chloro-2-fluoro-4-(((1S,2S,4S)-2-(methylamino)-4-(3-(trifluoromet-
hyl)phenyl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00566##
[1141] Step 1
##STR00567##
[1142]
5-Chloro-2-fluoro-4-(((1S,2S,4S)-2-(methylamino)-4-(3-(trifluoromet-
hyl)phenyl)cyclohexyl)amino)-N-(pyrimidin-4-yl)benzenesulfonamide
[1143] To a stirred solution of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide (60 mg, 0.10 mmol) in a
mixture of chloroform (0.5 mL) and IPA (0.2 mL) was added
3-chloroperbenzoic acid (mCPBA) (40 mg, 0.18 mmol). The reaction
was stirred for 15 min before addition of concentrated HCl (50 uL,
0.10 mmol) and ferrocene (31 mg, 0.16 mmol). The mixture was then
stirred at 50.degree. C. overnight. The mixture was diluted in DMSO
(5 mL) and passed through a C18 reverse phase column to remove the
catalyst. The filtrate was concentrated and purified by prep-HPLC
(CSH column, MeCN and 10 mM AmBicarbonate in water as eluent, from
20% MeCN to 40% MeCN) to provide 5-chloro-2-fluoro-4-(((1S,2S,
4S)-2-(methylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-N-(pyr-
imidin-4-yl)benzenesulfonamide (8 mg, 14% yield). LCMS (ESI) m/z:
558.4 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.25 (s,
1H), 7.89 (d, J=5.3 Hz, 1H), 7.67-7.49 (m, 5H), 6.67 (d, J=12.2 Hz,
1H), 6.51 (d, J=5.7 Hz, 1H), 5.76 (s, 1H), 2.79 (m, 1H), 2.41 (s,
3H), 2.18 (m, 1H), 1.99 (m, 1H), 1.76 (m, 2H), 1.55 (m, 1H), 1.43
(m, 1H), 1.22 (m, 1H). Exchangeable NH hydrogens not observed.
Example 227
##STR00568##
[1144]
5-Bromo-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phen-
yl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00569##
[1145] Step 1
##STR00570##
[1146]
5-Bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4--
(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)be-
nzenesulfonamide
[1147] Following the procedure described in Example 220 and making
non-critical variations as necessary to replace
2,4,5-trifluorobenzenesulfonyl chloride with
5-bromo-2,4-difluorobenzene-1-sulfonyl chloride,
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide was obtained. LCMS (ESI)
m/z: 768.3 [M+H].sup.+.
Step 2
##STR00571##
[1148]
5-Bromo-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phen-
yl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1149] Following the procedure described in Example 115 and making
non-critical variations as required using
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(tr-
ifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenes-
ulfonamide, 5-bromo-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide was obtained. LCMS (ESI)
m/z: 616.3 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.40
(s, 1H), 8.07 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.65-7.54 (m, 4H),
6.73 (m, 2H), 5.77 (d, J=6.7 Hz, 1H), 3.62 (m, 1H), 2.81 (m, 1H),
2.36 (s, 6H), 2.09 (dd, J=37.6, 11.8 Hz, 2H), 1.74 (m, 2H),
1.68-1.55 (m, 1H), 1.35 (m, 1H). Exchangeable NH hydrogens not
observed.
Example 228 & Example 229
##STR00572##
[1150]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide
&
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide
Step 1
##STR00573##
[1151]
5-chloro-4-(((1S,2S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl-
)cyclohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide
[1152] Following the procedure described in Example 181 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide with
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(isoxazol-3-yl)benzenesul-
fonamide,
5-chloro-4-(((1S,2S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide
was obtained as a white solid. LCMS (ESI) m/z: 561.2
[M+H].sup.+.
Step 2
##STR00574##
[1153]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide
&
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide
[1154]
5-chloro-4-(((1S,2S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl-
)cyclohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide (90
mg) was separated by using chiral SFC (Chiralpak IC (250 mm*30 mm,
10 um), Supercritical CO.sub.2/EtOH+0.1% NH.sub.4OH=65/35; 60
mL/min) to give
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide (27
mg, first peak) as a white solid and
5-chloro-4-(((1S,2S,4R)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cy-
clohexyl)amino)-2-fluoro-N-(isoxazol-3-yl)benzenesulfonamide (11
mg, second peak) as a white solid. Example 228: LCMS (ESI) m/z:
561.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.35
(s, 1H), 7.65 (s, 1H), 7.64-7.61 (m, 1H), 7.60-7.55 (m, 3H), 6.76
(d, J=12.4 Hz, 1H), 6.16 (s, 1H), 5.86-5.81 (m, 1H), 3.65-3.51 (m,
1H), 3.21-3.15 (m, 1H), 2.87-2.76 (m, 1H), 2.38 (s, 3H), 2.38 (s,
3H), 2.16-2.03 (m, 2H), 1.79-1.71 (m, 2H), 1.69-1.56 (m, 1H),
1.45-1.35 (m, 1H). Acidic NH hydrogen not observed. Example 229:
LCMS (ESI) m/z: 561.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.62 (s, 1H), 7.73-7.72 (m, 1H), 7.67-7.60
(m, 3H), 7.45-7.26 (m, 1H), 7.03 (d, J=12.4 Hz, 1H), 6.31 (s, 1H),
6.26-6.18 (m, 1H), 4.06-3.94 (m, 1H), 3.55-3.45 (m, 1H), 2.61 (s,
3H), 2.61 (s, 3H), 2.26-2.22 (m, 1H), 1.94-1.88 (m, 2H), 1.55-1.43
(m, 2H), 1.38-1.32 (m, 2H). Acidic NH hydrogen not observed.
Example 230
##STR00575##
[1155]
5-Cyclopropyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethy-
l)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
formate
##STR00576##
[1156] Step 1
##STR00577##
[1157]
5-cyclopropyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylami-
no)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-
-yl)benzenesulfonamide
[1158] To a solution of
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(tr-
ifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenes-
ulfonamide prepared in Example 227 (130 mg, 0.17 mmol) in a mixture
of N.sub.2 degassed toluene (2.3 mL) and H.sub.2O (1.15 mL) was
added Cesium carbonate (167 mg, 0.51 mmol), Potassium
cyclopropyltrifluoroborate (100 mg, 0.68 mmol), Pd(OAc).sub.2 (5.7
mg, 0.03 mmol), and butyl di-1-adamantylphosphine (18 mg, 0.05
mmol) in that order. The vessel was capped and N.sub.2 purged 2 min
before being placed in a 110.degree. C. oil bath overnight. After
16 h, the mixture was diluted with EtOAc and H.sub.2O and the
phases were separated. The organic extract was washed with
saturated aqueous NaCl, dried (Na.sub.2SO.sub.4), filtered and
concentrated in vacuo. Purification by flash chromatography through
Si gel (0-60% EtOAc/CH.sub.2Cl.sub.2) provided
5-cyclopropyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4--
(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)be-
nzenesulfonamide (122 mg, 85%). LCMS (ESI) m/z: 728.4
[M+H].sup.+.
Step 2
##STR00578##
[1159]
5-cyclopropyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethy-
l)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
formate
[1160] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-cyclopropyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4--
(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)be-
nzenesulfonamide (122 mg, 0.17 mmol),
5-cyclopropyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phen-
yl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
formate was obtained (64 mg, 61%) as a white solid. LCMS (ESI) m/z:
578.4 [M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) [missing thiazole
N--H signal] .delta. 8.50 (s, 1H), 8.21 (s, 1H), 8.14 (s, 1H),
7.73-7.51 (m, 4H), 7.39 (d, J=8.3 Hz, 1H), 6.84 (d, J=6.6 Hz, 1H),
6.53 (d, J=13.5 Hz, 1H), 6.01 (s, 1H), 3.08-2.91 (m, 2H), 2.91-2.76
(m, 1H), 2.42-2.17 (m, 7H), 2.01 (d, J=13.4 Hz, 1H), 1.84-1.70 (m,
2H), 1.61 (q, J=11.1 Hz, 2H), 1.50-1.17 (m, 1H), 0.92 (d, J=7.4 Hz,
2H), 0.47 (d, J=79.5 Hz, 1H). Acidic NH hydrogen not observed.
Example 231
##STR00579##
[1161]
5-Chloro-4-(((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohe-
xyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
formate
##STR00580## ##STR00581##
[1162] Step 1
##STR00582##
[1163]
tert-Butyl((3S,4S)-3'-chloro-3-(dimethylamino)-2,3,4,5-tetrahydro-[-
1,1'-biphenyl]-4-yl)carbamate
[1164] To
tert-butyl((3S,4S)-3'-bromo-3-(dimethylamino)-2,3,4,5-tetrahydro-
-[1,1'-biphenyl]-4-yl)carbamate (230 mg, 0.58 mmol) in Ethanol (8.3
mL) was added tetrabutyl ammonium chloride (1.72 g, 5.82 mmol),
L-Proline (402 mg, 3.49 mmol) and copper (I) oxide (250 mg, 1.75
mmol) under nitrogen purged. The vial was sealed and heated at
105.degree. C. for 18 hours. The reaction was cooled to room
temperature, poured in EtOAc, washed with aqueous NH.sub.4OH
solution, water and brine, dried over Na.sub.2SO.sub.4, filtered
and concentrated. The crude product was purified by flash column
chromatography through Si gel (0-20% MeOH/DCM) to provide
tert-butyl((3S,4S)-3'-chloro-3-(dimethylamino)-2,3,4,5-tetrahydro-[1,1'-b-
iphenyl]-4-yl)carbamate (111 mg, 54%). LCMS (ESI) m/z: 351.1
[M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.33 (s,
1H), 7.25-7.17 (m, 3H), 6.03-5.94 (m, 1H), 5.59 (s, 1H), 3.54 (bs,
1H), 3.13 (d, J=18.3 Hz, 1H), 2.83-2.71 (m, 1H), 2.51-2.40 (m, 2H),
2.31 (s, 6H), 2.14-1.99 (m, 1H), 1.47 (s, 9H).
Step 2
##STR00583##
[1165]
tert-Butyl((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohexy-
l)carbamate &
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-phenylcyclohexyl)carbamate
[1166] To
tert-butyl((3S,4S)-3'-chloro-3-(dimethylamino)-2,3,4,5-tetrahydr-
o-[1,1'-biphenyl]-4-yl)carbamate (116 mg, 0.33 mmol) in Ethyl
acetate (3.3 mL) was added Pd/C (44 mg). The reaction was submitted
to 3 cycle of hydrogen/vacuum purged and then was stirred at room
temperature for 20 hours under H.sub.2. The reaction was submitted
to 3 cycle of nitrogen/vacuum purging, filtered through celite,
rinsed with EtOAc and concentrated to provide a mixture of
tert-butyl((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohexyl)carb-
amate and
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-phenylcyclohexyl)carba-
mate (110 mg, 94%) which was used without further purification in
the subsequent step.
tert-Butyl((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohexyl)carb-
amate is the major species. LCMS (ESI) m/z: 353.2 [M+H].sup.+.
Step 3
##STR00584##
[1167]
(1S,2S,5S)-5-(3-chlorophenyl)-N1,N1-dimethylcyclohexane-1,2-diamine
hydrochloride &
(1S,2S,5S)--N1,N1-dimethyl-5-phenylcyclohexane-1,2-diamine
hydrochloride
[1168] To a mixture of
tert-butyl((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohexyl)carb-
amate and
tert-butyl((1S,2S,4S)-2-(dimethylamino)-4-phenylcyclohexyl)carba-
mate (160 mg, 0.45 mmol) was added 4 N HCl in dioxane (2 mL, 8
mmol) and the solution was stirred at room temperature for 30
minutes then concentrated to dryness to provide a mixture of
(1S,2S,5S)-5-(3-chlorophenyl)-N1,N1-dimethylcyclohexane-1,2-diamine
hydrochloride and
(1S,2S,5S)--N1,N1-dimethyl-5-phenylcyclohexane-1,2-diamine
hydrochloride (130 mg, quant.) which was used directly in the next
step without further purification.
Step 4
##STR00585##
[1169]
5-Chloro-4-(((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohe-
xyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfo-
namide &
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-
-4-phenylcyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1170] To a flask containing a mixture of
(1S,2S,5S)-5-(3-chlorophenyl)-N1,N1-dimethylcyclohexane-1,2-diamine
hydrochloride and
(1S,2S,5S)--N1,N1-dimethyl-5-phenylcyclohexane-1,2-diamine
hydrochloride (130 mg, 0.45 mmol), was added DMF (2.5 mL) followed
by DIPEA (403 uL, 2.27 mmol) and
5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-4-yl)benzenesu-
lfonamide (227 mg, 0.50 mmol). The reaction was stirred at
65.degree. C. overnight then the reaction was stopped by quenching
with water. The product was extracted with EtOAc, the organic layer
was separated and washed with water and brine. The organic layer
was dried over Na.sub.2SO.sub.4, filtered and concentrated. The
crude product was purified by flash column chromatography through
Si gel (EtOAc/DCM) to provide a mixture of
5-Chloro-4-(((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohexyl)am-
ino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
and
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-p-
henylcyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
(217 mg, 69%).
5-Chloro-4-(((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyc-
lohexyl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenes-
ulfonamide is the major species. LCMS (ESI) m/z: 654.3
[M+H].sup.+.
Step 5
##STR00586##
[1171]
5-Chloro-4-(((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohe-
xyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
[1172] To a mixture of
5-Chloro-4-(((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohexyl)am-
ino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
and
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-p-
henylcyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
(217 mg, 0.32 mmol) was added formic acid (1 mL, 26.5 mmol). The
reaction was stirred at room temperature for 3 hours then
concentrated. The crude was dissolved in a mixture of DMF and DMSO,
filtered and purified by prep-HPLC (CSH C18 column, 5 m,
30.times.75 mm at 40.degree. C.; 45 mL/min, 25-45% MeCN/10 mM
aqueous ammonium bicarbonate, pH=10). Appropriate fractions were
combined and lyophilized. To the solid obtained was added MeCN
(0.30 mL), water (0.60 mL) and formic acid (25 uL). The flask was
frozen and lyophilized to give
5-chloro-4-(((1S,2S,4S)-4-(3-chlorophenyl)-2-(dimethylamino)cyclohexyl)am-
ino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide formate (21 mg,
14% yield). LCMS (ESI) m/z: 538.3 [M+H].sup.+. .sup.1H NMR (400
MHz, DMSO-d6) .delta. 8.37 (s, 1H), 8.14 (s, 1H), 8.04 (d, J=5.1
Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.34 (d,
J=7.7 Hz, 1H), 7.31-7.23 (m, 2H), 6.74 (d, J=12.8 Hz, 1H), 6.66 (d,
J=5.7 Hz, 1H), 5.85 (s, 1H), 3.60 (bs, 1H), 3.13 (bs, 1H),
2.78-2.62 (m, 1H), 2.37 (s, J=15.0 Hz, 6H), 2.20-1.94 (m, 2H),
1.79-1.50 (m, 3H), 1.47-1.27 (m, 1H).
Example 232
##STR00587##
[1173]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-phenylcyclohexyl)amino)-
-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide Formate
[1174] Following the procedure described in Example 231 step 5,
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-phenylcyclohexyl)amino)-2-flu-
oro-N-(pyrimidin-4-yl)benzenesulfonamide formate (43 mg) was
obtained. LCMS (ESI) m/z: 504.3 [M+H].sup.+. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.38 (s, 1H), 8.14 (s, 1H), 8.05 (d, J=5.8
Hz, 1H), 7.65 (d, J=7.3 Hz, 1H), 7.39-7.27 (m, 4H), 7.21 (t, J=6.6
Hz, 1H), 6.79 (d, J=12.9 Hz, 1H), 6.68 (d, J=5.9 Hz, 1H), 5.89 (d,
J=6.8 Hz, 1H), 3.66 (bs, 1H), 3.29-3.03 (m, 1H), 2.76-2.58 (m, 1H),
2.41 (s, 6H), 2.19-1.99 (m, 2H), 1.84-1.54 (m, 3H), 1.49-1.28 (m,
1H).
Example 233
##STR00588##
[1175]
5-Chloro-4-(((3S,4S)-3-(dimethylamino)-1-(3-(trifluoromethyl)phenyl-
)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00589## ##STR00590##
[1176] Step 1
##STR00591##
[1177] Rac-(3S,4S)-methyl
4-((tert-butoxycarbonyl)amino)-1-(3-(trifluoromethyl)phenyl)piperidine-3--
carboxylate
[1178] 1-Bromo-3-(trifluoromethyl)benzene (0.25 ml, 1.81 mmol),
racemic (3S,4S)-methyl
4-((tert-butoxycarbonyl)amino)piperidine-3-carboxylate, cesium
carbonate (742 mg, 2.26 mmol), rac-BINAP (141 mg, 0.23 mmol) and
tris(dibenzylideneacetone)-dipalladium(0) (138 mg, 0.15 mmol) were
charged to a screw-cap reaction vial, which was flushed with
nitrogen for 5 min. N.sub.2 degassed toluene (4 mL) was added and
the mixture was bubbled with nitrogen for 5 minutes. The vial was
capped and stirred at 110.degree. C. for 16 hours. The reaction
mixture was cooled to room temperature and purified directly by
flash column chromatography through Si gel (EtOAc/hexanes) to
provide rac-(3S,4S)-methyl
4-((tert-butoxycarbonyl)amino)-1-(3-(trifluoromethyl)phenyl)piperidine-3--
carboxylate (320 mg, 53%) as a pale yellow solid. LCMS (ESI) m/z:
403.3 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.33
(t, J=7.9 Hz, 1H), 7.18-7.00 (m, 3H), 4.58 (s, 1H), 4.02-3.82 (m,
1H), 3.76 (ddd, J=12.9, 3.8, 2.1 Hz, 1H), 3.72 (s, 3H), 3.65 (ddd,
J=12.7, 6.0, 4.0 Hz, 1H), 3.17 (dd, J=12.9, 10.4 Hz, 1H), 2.97
(ddd, J=12.8, 11.6, 2.9 Hz, 1H), 2.60 (td, J=10.2, 3.8 Hz, 1H),
2.26-2.07 (m, 1H), 1.62-1.54 (m, 1H), 1.43 (s, 9H).
Step 2
##STR00592##
[1179]
Rac-(3S,4S)-4-((tert-butoxycarbonyl)amino)-1-(3-(trifluoromethyl)ph-
enyl)piperidine-3-carboxylic Acid
[1180] Following the procedure described in Example 219 and making
non-critical variations as required to replace (4aS,8aS)-tert-butyl
6-(3-bromophenyl)-4-oxo-2,4,4a,5,8,8a-hexahydro-1H-benzo[d][1,3]oxazine-1-
-carboxylate with rac-(3S,4S)-methyl
4-((tert-butoxycarbonyl)amino)-1-(3-(trifluoromethyl)phenyl)piperidine-3--
carboxylate,
rac-(3S,4S)-4-((tert-butoxycarbonyl)amino)-1-(3-(trifluoromethyl)phenyl)p-
iperidine-3-carboxylic acid (310 mg, 100%) was obtained as an
off-white solid. LCMS (ESI) m/z: 387.4 [M-H].sup.-. .sup.1H NMR
(400 MHz, CDCl.sub.3 and methanol-d.sub.4 (9:1 v/v ratio)) .delta.
7.29 (t, J=8.0 Hz, 1H), 7.10-6.95 (m, 3H), 3.83 (s, 1H), 3.75 (dq,
J=12.1, 1.3 Hz, 1H), 3.59 (d, J=12.9 Hz, 1H), 3.09 (dd, J=12.6,
10.6 Hz, 1H), 2.91 (td, J=12.8, 2.7 Hz, 1H), 2.52 (td, J=10.0, 3.3
Hz, 1H), 2.07 (d, J=9.9 Hz, 1H), 1.54 (q, J=9.3 Hz, 1H), 1.37 (s,
9H). 2 H exchanged with the solvent and are not observed.
Step 3
##STR00593##
[1181]
Rac-tert-butyl((3S,4S)-3-isocyanato-1-(3-(trifluoromethyl)phenyl)pi-
peridin-4-yl)carbamate
[1182] Following the procedure described in Example 219 and making
non-critical variations as required to replace
(3S,4S)-3'-bromo-4-((tert-butoxycarbonyl)amino)-2,3,4,5-tetrahydro-[1,1'--
biphenyl]-3-carboxylic acid with
rac-(3S,4S)-4-((tert-butoxycarbonyl)amino)-1-(3-(trifluoromethyl)phenyl)p-
iperidine-3-carboxylic acid,
rac-tert-butyl((3S,4S)-3-isocyanato-1-(3-(trifluoromethyl)phenyl)piperidi-
n-4-yl)carbamate (290 mg, 58%) was obtained as a colorless oil.
LCMS (ESI) m/z: 408.3 [M+Na].sup.+.
Step 4
##STR00594##
[1183]
Rac-tert-butyl((3S,4S)-3-amino-1-(3-(trifluoromethyl)phenyl)piperid-
in-4-yl)carbamate
[1184] Following the procedure described in Example 219 and making
non-critical variations as required to replace
tert-butyl((3S,4S)-3'-bromo-3-isocyanato-2,3,4,5-tetrahydro-[1,1'-bipheny-
l]-4-yl)carbamate with
rac-tert-butyl((3S,4S)-3-isocyanato-1-(3-(trifluoromethyl)phenyl)piperidi-
n-4-yl)carbamate,
rac-tert-butyl((3S,4S)-3-amino-1-(3-(trifluoromethyl)phenyl)piperidin-4-y-
l)carbamate (250 mg, 92%) was obtained as a colorless oil. LCMS
(ESI) m/z: 304.2 [M+H-tBu].sup.+.
Step 5
##STR00595##
[1185]
Rac-tert-butyl((3S,4S)-3-(dimethylamino)-1-(3-(trifluoromethyl)phen-
yl)piperidin-4-yl)carbamate
[1186] Following the procedure described in Example 219 and making
non-critical variations as required to replace
tert-butyl((3S,4S)-3-amino-3'-bromo-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4--
yl)carbamate with
rac-tert-butyl((3S,4S)-3-amino-1-(3-(trifluoromethyl)phenyl)piperidin-4-y-
l)carbamate, crude
rac-tert-butyl((3S,4S)-3-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)pip-
eridin-4-yl)carbamate (282 mg, 100%) was obtained as a pale yellow
oil. LCMS (ESI) m/z: 388.3 [M+H].sup.+.
Step 6
##STR00596##
[1187]
Rac-(3S,4S)--N.sup.3,N.sup.3-dimethyl-1-(3-(trifluoromethyl)phenyl)-
piperidine-3,4-diamine hydrochloride
[1188] Following the procedure described in Example 219 and making
non-critical variations as required to replace
tert-butyl((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohexyl-
)carbamate with crude
rac-tert-butyl((3S,4S)-3-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)pip-
eridin-4-yl)carbamate,
rac-(3S,4S)--N.sup.3,N.sup.3-dimethyl-1-(3-(trifluoromethyl)phenyl)piperi-
dine-3,4-diamine hydrochloride (307 mg, 100%) was obtained as an
off-white solid. LCMS (ESI) m/z: 288.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, methanol-d.sub.4) .delta. 7.50 (t, J=7.8 Hz, 1H), 7.35
(d, J=8.0 Hz, 2H), 7.22 (d, J=7.5 Hz, 1H), 4.08-4.03 (m, 1H),
4.02-3.97 (m, 1H), 3.75 (td, J=8.2, 3.7 Hz, 1H), 3.63 (dd, J=11.4,
5.7 Hz, 1H), 3.47 (dd, J=13.4, 8.3 Hz, 1H), 3.23 (ddd, J=13.1, 9.8,
3.6 Hz, 1H), 3.06 (br s, 6H), 2.39 (ddd, J=13.8, 8.8, 5.0 Hz, 1H),
2.10-1.98 (m, 1H).
Step 7
##STR00597##
[1189]
Rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3S,4S)-3-(dimethylamino)--
1-(3-(trifluoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-
-yl)benzenesulfonamide
[1190] Following the procedure described in Example 219 and making
non-critical variations as required to replace
(1S,2S,5S)-5-(3-cyclopropylphenyl)-N,N-dimethylcyclohexane-1,2-diamine
with crude
rac-(3S,4S)--N.sup.3,N.sup.3-dimethyl-1-(3-(trifluoromethyl)phenyl)piperi-
dine-3,4-diamine hydrochloride,
rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3S,4S)-3-(dimethylamino)-1-(3-(-
trifluoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)be-
nzenesulfonamide (351 mg, 62%) was obtained as a pale yellow oil.
LCMS (ESI) m/z: 723.5 [M+H].sup.+. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.80 (d, J=0.8 Hz, 1H), 8.45 (d, J=5.9 Hz, 1H),
7.89 (d, J=7.2 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.31 (dd, J=6.0,
1.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 7.16-7.02 (m, 3H), 6.45-6.36
(m, 2H), 6.31 (d, J=12.5 Hz, 1H), 5.75 (d, J=2.5 Hz, 1H), 5.27 (s,
2H), 3.87 (d, J=10.2 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H), 3.72 (d,
J=13.1 Hz, 1H), 3.26 (tt, J=10.1, 3.3 Hz, 1H), 2.93-2.76 (m, 3H),
2.45-2.32 (m, 7H), 1.59 (qd, J=13.0, 4.1 Hz, 1H).
Step 8
##STR00598##
[1191]
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3S,4S)-3-(dimethylamino)-1-(3-
-(trifluoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)-
benzenesulfonamide &
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3R,4R)-3-(dimethylamino)-1-(3-(trif-
luoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzen-
esulfonamide
[1192]
Rac-5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3S,4S)-3-(dimethylamino)--
1-(3-(trifluoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-
-yl)benzenesulfonamide was separated using chiral HPLC (Chiralpak
IB, 250 mm.times.20 mm ID, 5 .mu.m), 7:7:86 MeOH:DCM:hexane
containing 0.1% of diethylamine, 15 ml/min) to afford:
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3S,4S)-3-(dimethylamino)-1-(3-(trif-
luoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzen-
esulfonamide (peak 1, 145 mg, 37%) as a white solid, LCMS (ESI)
m/z: 723.5 [M+H].sup.+; and
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3R,4R)-3-(dimethylamino)-1-(3-(trif-
luoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzen-
esulfonamide (peak 2, 150 mg, 38%) as a white solid, LCMS (ESI)
m/z: 723.5 [M+H].sup.+. Absolute configuration was arbitrarily
assigned to each isomer.
Step 9
##STR00599##
[1193]
5-Chloro-4-(((3S,4S)-3-(dimethylamino)-1-(3-(trifluoromethyl)phenyl-
)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1194] Following the procedure described in Example 219 and making
non-critical variations as required to replace
5-chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohex-
yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfon-
amide with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3S,4S)-3-(dimethylamino)--
1-(3-(trifluoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-
-yl)benzenesulfonamide,
5-chloro-4-(((3S,4S)-3-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)piper-
idin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (84
mg, 73%) was obtained as a white solid. LCMS (ESI) m/z: 573.1
[M+H].sup.+. .sup.1H NMR (400 MHz, dmso-d.sub.6) .delta. 8.53 (s,
1H), 8.27-8.20 (m, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.42 (t, J=8.0 Hz,
1H), 7.29-7.22 (m, 1H), 7.18 (s, 1H), 7.04 (d, J=7.6 Hz, 1H),
6.93-6.85 (m, 2H), 6.08-6.01 (m, 1H), 4.02-3.92 (m, 1H), 3.87-3.74
(m, 2H), 3.12-3.00 (m, 1H), 2.95 (t, J=11.9 Hz, 1H), 2.86 (t,
J=11.9 Hz, 1H), 2.39 (s, 6H), 2.05-1.95 (m, 1H), 1.60-1.45 (m, 1H).
Acidic NH hydrogen not observed. Absolute configuration was
arbitrarily assigned.
Example 234
##STR00600##
[1195]
5-Chloro-4-(((3R,4R)-3-(dimethylamino)-1-(3-(trifluoromethyl)phenyl-
)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
[1196] Following the procedure described in Example 219 and making
non-critical variations as required to replace
5-chloro-4-(((1S,2S,4S)-4-(3-cyclopropylphenyl)-2-(dimethylamino)cyclohex-
yl)amino)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfon-
amide with
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((3R,4R)-3-(dimethylamino)--
1-(3-(trifluoromethyl)phenyl)piperidin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-
-yl)benzenesulfonamide,
5-chloro-4-(((3R,4R)-3-(dimethylamino)-1-(3-(trifluoromethyl)phenyl)piper-
idin-4-yl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
formate (98 mg, 76%) was obtained as a white solid. LCMS (ESI) m/z:
573.0 [M+H].sup.+. .sup.1H NMR (400 MHz, dmso-d.sub.6) .delta. 8.48
(s, 1H), 8.17 (d, J=5.7 Hz, 1H), 8.14 (s, 1H), 7.66 (d, J=7.4 Hz,
1H), 7.42 (t, J=8.0 Hz, 1H), 7.28-7.22 (m, 1H), 7.17 (s, 1H), 7.03
(d, J=7.6 Hz, 1H), 6.84 (d, J=13.2 Hz, 1H), 6.81 (d, J=6.3 Hz, 1H),
5.95 (d, J=5.9 Hz, 1H), 3.97-3.89 (m, 1H), 3.85-3.71 (m, 2H),
3.02-2.90 (m, 2H), 2.84 (t, J=11.8 Hz, 1H), 2.36 (s, 6H), 2.06-1.96
(m, 1H), 1.57-1.44 (m, 1H). Acidic NH hydrogen not observed.
Absolute configuration was arbitrarily assigned.
Example 235
##STR00601##
[1197]
(1S,2S,5S)-2-((2-Chloro-5-fluoro-4-(N-(pyrimidin-4-yl)sulfamoyl)phe-
nyl)amino)-N,N-dimethyl-5-(3-(trifluoromethyl)phenyl)cyclohexanamine
Oxide
##STR00602##
[1198] Step 1
##STR00603##
[1199]
(1S,2S,5S)-2-((2-Chloro-5-fluoro-4-(N-(pyrimidin-4-yl)sulfamoyl)phe-
nyl)amino)-N,N-dimethyl-5-(3-(trifluoromethyl)phenyl)cyclohexanamine
Oxide
[1200] To a stirred solution of
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide (29 mg, 0.05 mmol) in a
mixture of chloroform (0.50 mL) and IPA (0.50 mL) was added
3-chloroperbenzoic acid (mCPBA) (12.5 mg, 0.06 mmol). The mixture
was then stirred at 25.degree. C. for 15 min then the solvent was
removed in vacuo and formic acid (1.0 mL) was added. The mixture
was stirred at rt for 3 hours then the solvent was removed in vacuo
and purified directly by C18 reverse phase flash chromatography
(MeCN/10 mM aqueous ammonium bicarbonate, pH=10). Appropriate
fractions combined and lyophilized to provide
(1S,2S,5S)-2-((2-chloro-5-fluoro-4-(N-(pyrimidin-4-yl)sulfamoyl)phenyl)am-
ino)-NN-dimethyl-5-(3-(trifluoromethyl)phenyl)cyclohexanamine oxide
(19 mg, 64% yield). LCMS (ESI) m/z: 588.1 [M+H].sup.+. .sup.1H NMR
(400 MHz, d6-DMSO) .delta. 8.44 (s, 1H), 8.12 (s, 2H), 7.72-7.55
(m, 5H), 6.77 (d, J=5.8 Hz, 1H), 6.67 (d, J=13.1 Hz, 1H), 3.85 (d,
J=30.4 Hz, 2H), 3.16 (s, 3H), 3.12 (s, 3H), 2.92 (m 1H), 2.31 (m,
1H), 2.15 (m, 1H), 1.90-1.70 (m, 3H), 1.45 (s, 1H). Acidic NH
hydrogen not observed.
Example 236
##STR00604##
[1201]
5-cyclobutyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl-
)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00605##
[1202] Step 1
##STR00606##
[1203]
5-cyclobutyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamin-
o)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4--
yl)benzenesulfonamide
[1204] To a (.about.20 mL) borosilicate glass vial equipped with a
Teflon-coated magnetic stir bar was added nickel glyme (2.87 mg,
0.010 mmol) and 4,4-Di-tert-butyl-2,2-dipyridyl (3.5 mg, 0.010
mmol) and THF (1 mL). The vial was capped and the resulting
suspension was heated briefly with a heat gun until the nickel and
ligand were fully solubilized yielding a pale green solution. The
solvent was then removed under vacuum to give a fine coating of the
ligated nickel complex (pale evergreen in color). Once dry,
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(tr-
ifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenes-
ulfonamide prepared in Example 227 (100 mg, 0.13 mmol), Potassium
cyclobutyltrifluoroborate (32 mg, 0.20 mmol),
[Ir{dF(CF3)ppy}2(dtbpy)]PF6 (15 mg, 0.010 mmol) and Cesium
carbonate (64 mg, 0.20 mmol) were added in that order. The vial was
then capped and 1,4-Dioxane (5 mL) was introduced. The reaction was
purged with N.sub.2 for 3 min and stirred .about.4 cm away from LED
blue light. A fan was blown across the reaction setup to maintain
an ambient temperature .about.24.degree. C. The reaction was
monitored by LCMS and stopped at 80 min. The reaction was then
passed through a pad of silica, washed with 20% MeOH in
CH.sub.2Cl.sub.2 and the filtrate was concentrated and dissolved in
DMSO and purified by reverse phase prep-HPLC (75-100% MeCN/100 mM
aqueous NH.sub.4CO.sub.3H, pH: 10 gradient over 10 min, XBridge BEH
C18 OBD Prep Column, 130 .ANG., 5 .mu.m, 30 mm.times.50 mm).
Appropriate fractions combined and lyophilized to provide
5-cyclobutyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(-
3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)ben-
zenesulfonamide (31 mg, 32%). LCMS (ESI) m/z: 742.4
[M+H].sup.+.
Step 2
##STR00607##
[1205]
5-cyclobutyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl-
)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1206] Following the procedure described in Example 187 and making
non-critical variations as required to replace
5-chloro-N-(2,4-dimethoxybenzyl)-4-(((1S,2S)-2-(dimethylamino)-4,4-difluo-
rocyclohexyl)amino)-2-fluoro-N-(thiazol-2-yl)benzenesulfonamide
with
5-cyclobutyl-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(-
3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)ben-
zenesulfonamide (31 mg, 0.04 mmol),
5-cyclobutyl-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)pheny-
l)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
was obtained (21 mg, 85%) as a white solid. LCMS (ESI) m/z: 592.3
[M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.51 (s, 1H),
8.23 (s, 1H), 7.68-7.50 (m, 5H), 7.44 (d, J=8.3 Hz, 1H), 6.87 (d,
J=5.8 Hz, 1H), 6.50 (d, J=13.7 Hz, 1H), 5.33 (s, 1H), 2.93 (m, 1H),
2.77 (m, 1H), 2.34 m, 3H), 2.27 (s, 6H), 2.17 (m, 1H), 1.99 m, 3H),
1.91-1.69 (m, 5H), 1.59 (m, 1H), 1.27 (m, 1H).
Example 237
##STR00608##
[1207]
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
##STR00609##
[1208] Step 1
##STR00610##
[1209]
N-(2,4-Dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trif-
luoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesul-
fonamide
[1210] To a solution of
5-bromo-N-(2,4-dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(tr-
ifluoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenes-
ulfonamide (20 mg, 0.03 mmol) and potassium
cyclobutyl(trifluoro)boron (5.5 mg, 0.03 mmol), palladium(II)
acetate (1.2 mg, 0.01 mmol) and cesium carbonate (26.0 mg, 0.08
mmol) in toluene (0.50 mL) and water (0.05 mL) was added
n-butyl-di-1-adamantylphosphine (1.9 mg, 0.01 mmol) and the
reaction was degasssed with N.sub.2 for 10 min. The reaction was
heated to 100.degree. C. overnight. The reaction was diluted with
water (3 mL) and EtOAc (5 mL). The organic layer was separated,
dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification by prep-HPLC (CSH column, 60-80% MeCN/10 mM aqueous
ammonium bicarbonate pH=10) provided
N-(2,4-dimethoxybenzyl)-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide (9 mg, 50% yield). LCMS
(ESI) m/z: 688.3 [M+H].sup.+.
Step 2
##STR00611##
[1211]
4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
[1212] Following the procedure described in Example 115 and making
non-critical variations as required using
N-(2,4-dimethoxybenzyl)-4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide (8 mg, 0.01 mmol),
4-(((1S,2S,
4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)-2-fl-
uoro-N-(pyrimidin-4-yl)benzenesulfonamide (5 mg, 80% yield) was
obtained. LCMS (ESI) m/z: 538.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
d6-DMSO) .delta. 8.49 (s, 1H), 8.19 (s, 1H), 8.14 (s, 1H),
7.69-7.49 (m, 6H), 6.83 (s, 1H), 6.53-6.37 (m, 3H), 3.61-3.48 (m,
1H), 2.84-2.75 (m, 2H), 2.30 (s, 6H), 2.11 (dd, J=12.1, 2.4 Hz,
1H), 1.99 (d, J=10.8 Hz, 1H), 1.80-1.68 (m, 2H), 1.66-1.52 (m, 1H),
1.33-1.19 (m, 1H).
Example 238
##STR00612##
[1213]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)oxy)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
##STR00613##
[1214] Step 1:
##STR00614##
[1215]
(1S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclohexan-1-amine
[1216] Tert-butyldimethylchlorosilane (1.0 g, 6.56 mmol) was added
to a solution of (1S,2S)-2-aminocyclohexanol (630 mg, 5.47 mmol)
and triethylamine (0.91 mL, 6.56 mmol) in dichloromethane (10 mL)
and the mixture was stirred at room temperature for 4h. Water was
added and the phases were separated. The aqueous phase was
extracted with dichloromethane. The organic phase was dried with
MgSO.sub.4, filtered and concentrated to give the title compound
(875 mg, 70%) as a yellow oil which was used for next step without
purification.
Step 2:
##STR00615##
[1217]
(1S,2S,4S)-2-amino-4-(3-(trifluoromethyl)phenyl)cyclohexan-1-ol
[1218] 2-hydroxynicotinaldehyde (27 mg, 0.22 mmol), palladium(II)
acetate (24 mg, 0.11 mmol), 3-iodotrifluorotoluene (0.31 mL, 2.2
mmol), silver trifluoroacetate (481 mg, 2.2 mmol), water (0.20 mL),
1,1,1,3,3,3-hexafluoro-2-propanol (5.2 mL), acetic acid (0.27 mL)
were combined in a sealable high pressure vial.
(1R,2R)-2-[tert-butyl(dimethyl)silyl]oxycyclohexanamine (250 mg,
1.09 mmol) was added and the mixture was sealed and heated at
120.degree. C. for 16h. The mixture was cooled down and filtered
through celite. The filtrate was concentrated. The residue was
dissolved in THF (5 mL) and 1N HCl (2 mL) was added. The mixture
was stirred at room temperature for 1 h. The mixture was
concentrated to remove THF and the organic phase was extracted with
DCM. The aqueous phase was then basified by addition of 10N KOH.
The aqueous phase was extracted with DCM. The organic phase was
dried with MgSO.sub.4, filtered and concentrated to give the title
compound (35 mg, 12.4%) as a yellow solid which was used for next
step without purification.
Step 3:
##STR00616##
[1219]
(1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexa-
n-1-ol
[1220] Sodium triacetoxyborohydride (286.1 mg, 1.35 mmol) was added
to a solution of
(1S,2S,4S)-2-amino-4-[3-(trifluoromethyl)phenyl]cyclohexanol (35
mg, 0.13 mmol) and formaldehyde (37% in water) (0.06 mL, 0.81 mmol)
in acetonitrile (3 mL) and the reaction was stirred at room
temperature for 1h. The reaction was quenched by addition of
aqueous NH.sub.4Cl. The mixture was concentrated to remove
acetonitrile and the residue was extracted with DCM. The organic
phase was dried with MgSO.sub.4, filtered and concentrated to give
the title compound (21 mg, 54%) as a yellow solid which was used
for next step without purification.
Step 4:
##STR00617##
[1221]
5-chloro-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)oxy)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
[1222] Sodium hydride (60 mass %) in mineral oil (8.8 mg, 0.22
mmol) was added to a solution of
(1S,2S,4S)-2-(dimethylamino)-4-[3-(trifluoromethyl)phenyl]cyclohexanol
(21 mg, 0.07 mmol) in N,N-dimethylformamide (0.5 mL). The reaction
was stirred for 10 min then
5-chloro-N-[(2,4-dimethoxyphenyl)methyl]-2,4-difluoro-N-pyrimidin-4-yl-be-
nzenesulfonamide (33.32 mg, 0.07 mmol) was added and the mixture
was stirred at room temperature for 3h. The reaction was quenched
by slow addition of water (1 mL). The resulting precipitate was
collected by filtration and washed with water. The crude solid was
purified by silica gel chromatography (0 to 100% EtOAc/Hep). The
purified product was then stirred in formic acid (1 mL) for 1 h.
The mixture was then concentrated and dried under vacuum for 16h to
give the title compound (3.9 mg, 13%) as a white solid. LCMS (ESI)
m/z: 573.2 [M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 8.33
(s, 1H), 8.14 (s, 2H), 8.00 (d, J=6.1 Hz, 1H), 7.79 (d, J=7.4 Hz,
1H), 7.59 (d, J=13.3 Hz, 3H), 7.29 (d, J=11.7 Hz, 1H), 6.62 (d,
J=6.1 Hz, 1H), 6.53 (d, J=15.5 Hz, 1H), 4.77 (td, J=10.2, 4.4 Hz,
1H), 2.41 (s, 6H), 2.24-2.07 (m, 1H), 2.03-1.94 (m, 1H), 1.79-1.61
(m, 2H), 1.31-1.12 (m, 2H), 0.91-0.83 (m, 1H).
Example 239
##STR00618##
[1223]
5-chloro-4-(((1S,2S,4S)-4-(3,5-dichlorophenyl)-2-(dimethylamino)cyc-
lohexyl)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
[1224] Following the sequence described in Example 224 and making
non-critical variations as required to replace
1-(4-(trifluoromethyl)phenyl)ethanone with
1-(3,5-dichlorophenyl)ethanone,
5-chloro-4-(((1S,2S,4S)-4-(3,5-dichlorophenyl)-2-(dimethylamino)cyclohexy-
l)amino)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide formate was
obtained as a white solid. LCMS (ESI) m/z: 572.1, 574.1
[M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.27 (s, 1H),
8.15 (s, 1H), 7.93 (d, J=3.9 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H),
7.51-7.29 (m, 2H), 6.68-6.46 (m, 3H), 5.67 (s, 1H), 2.88-2.68 (m,
3H), 2.21 (s, 6H), 1.94 (d, J=11.8 Hz, 1H), 1.78-1.66 (m, 2H), 1.53
(q, J=11.8 Hz, 1H), 1.38-1.16 (m, 2H). Acidic NH hydrogen not
observed.
Example 240
##STR00619##
[1225]
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2-fluoro-5-hydroxy-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
##STR00620##
[1226] Step 1
##STR00621##
[1227]
N-(2,4-Dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trif-
luoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-5-hydroxy-N-(pyrimidin-4-yl)-
benzenesulfonamide
[1228] To an oven-dried 10 mL screw-cap test tube equipped with a
Teflon-coated magnetic stir bar was charged
2-(di-t-butylphosphino)-3,6-dimethoxy-2',4',6'-tri-i-propyl-1,1'-biphenyl-
, t-butylBrettPhos (25 mg, 0.05 mmol) and
5-bromo-N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S,4S)-2-(dimethylamino)--
4-[3-(trifluoromethyl)phenyl]cyclohexyl]amino]-2-fluoro-N-pyrimidin-4-ylbe-
nzenesulfonamide (200 mg, 0.26 mmol). A solution of CsOH (117 mg,
0.78 mmol) in water (47 mg, 2.61 mmol) was then added followed by
addition of 1,4-dioxane (0.2 mL). The reaction vessel was evacuated
and backfilled with N.sub.2 (this process was repeated a total of
three times). To this was then added a solution of t-BuBrettPhos Pd
G3 (44.6 mg, 0.05 mmol) in 1,4-Dioxane (1 mL) via syringe and the
mixture stirred at rt for 3 h. The mixture was then diluted with
EtOAc (25 mL) and then washed with saturated aqueous NH.sub.4Cl (10
mL). The organic layer was separated and washed with brine, dried
over Na.sub.2SO.sub.4, filtered and concentrated in vacuo.
Purification by flash column chromatography through Si gel (0-20%
MeOH/DCM) afforded
N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S,4S)-2-(dimethylamino)-4-[3-(tr-
ifluoromethyl)phenyl]cyclohexyl]amino]-2-fluoro-5-hydroxy-N-pyrimidin-4-yl-
-benzenesulfonamide (193 mg, 105%). LCMS (ESI) m/z: 704.3
[M+H].sup.+.
Step 2
##STR00622##
[1229]
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2-fluoro-5-hydroxy-N-(pyrimidin-4-yl)benzenesulfonamide
formate
[1230] Following the procedure described in Example 115 step 2 and
making non-critical variations as required using
N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S,4S)-2-(dimethylamino)-4-[3-(tr-
ifluoromethyl)phenyl]cyclohexyl]amino]-2-fluoro-5-hydroxy-N-pyrimidin-4-yl-
-benzenesulfonamide (193 mg, 0.26 mmol),
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)-
amino)-2-fluoro-5-hydroxy-N-(pyrimidin-4-yl)benzenesulfonamide
formate (66 mg, 84%) was obtained. LCMS (ESI) m/z: 554.2
[M+H].sup.+. .sup.1H NMR (400 MHz, d6-DMSO) .delta. 8.45 (s, 1H),
8.13 (s, 1H), 7.64-7.53 (m, 4H), 7.11 (d, J=7.0 Hz, 1H), 6.78 (d,
J=5.9 Hz, 1H), 6.46 (d, J=12.8 Hz, 1H), 5.51 (s, 1H), 2.97 (m, 1H),
2.78 (m, 1H), 2.29 (s, 6H), 2.16 (m, 1H), 2.00 (m, 1H), 1.72 (m,
2H), 1.58 (m, 1H), 1.27 (m, 1H).
Example 241
##STR00623##
[1231]
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2-fluoro-5-methoxy-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
##STR00624##
[1232] Step 1
##STR00625##
[1233]
N-(2,4-Dimethoxybenzyl)-4-(((1S,2S,4S)-2-(dimethylamino)-4-(3-(trif-
luoromethyl)phenyl)cyclohexyl)amino)-2-fluoro-5-methoxy-N-(pyrimidin-4-yl)-
benzenesulfonamide
[1234] A reaction flask was charged with THF (0.40 mL),
triphenylphosphine (63 mg, 0.24 mmol) and diisopropyl
azodicarboxylate (0.05 mL, 0.24 mmol) in that order. The mixture
was stirred at rt for 5 min before addition of a 5% solution of
MeOH in THF (0.17 mL, 0.24 mmol). This mixture was stirred for
another 5 min at rt before addition of
N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S,4S)-2-(dimethylamino)-4-[3-(tr-
ifluoromethyl)phenyl]cyclohexyl]amino]-2-fluoro-5-hydroxy-N-pyrimidin-4-yl-
-benzenesulfonamide (100 mg, 0.14 mmol). The reaction was stirred
at rt for 1 h, concentrated and dissolved in DMSO (3 mL) and
purified directly by Prep-HPLC (CSH column, 65-85% MeCN/10 mM
aqueous ammonium bicarbonate, pH=10). Appropriate fractions
combined and lyophilized to provide
N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S,4S)-2-(dimethylamino)-4-[3-(tr-
ifluoromethyl)phenyl]cyclohexyl]amino]-2-fluoro-5-methoxy-N-pyrimidin-4-yl-
-benzene sulfonamide (37 mg, 36%). LCMS (ESI) m/z: 718.3
[M+H].sup.+.
Step 2
##STR00626##
[1235]
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclo-
hexyl)amino)-2-fluoro-5-methoxy-N-(pyrimidin-4-yl)benzenesulfonamide
Formate
[1236] Following the procedure described in Example 115 step 2 and
making non-critical variations as required using
N-[(2,4-dimethoxyphenyl)methyl]-4-[[(1S,2S,4S)-2-(dimethylamino)-4-[3-(tr-
ifluoromethyl)phenyl]cyclohexyl]amino]-2-fluoro-5-methoxy-N-pyrimidin-4-yl-
-benzenesulfonamide (37 mg, 0.052 mmol),
4-(((1S,2S,4S)-2-(Dimethylamino)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)-
amino)-2-fluoro-5-methoxy-N-(pyrimidin-4-yl)benzenesulfonamide
formate (27 mg, 92%). LCMS (ESI) m/z: 568.2 [M+H].sup.+. H NMR (400
MHz, d6-DMSO) .delta. 8.46 (s, 1H), 8.18-8.09 (m, 2H), 7.71-7.49
(m, 5H), 7.15 (d, J=6.5 Hz, 1H), 6.81 (d, J=5.8 Hz, 1H), 6.54 (d,
J=12.6 Hz, 1H), 5.72 (d, J=6.8 Hz, 1H), 3.78 (s, 3H), 3.59-3.49 (m,
1H), 3.12-2.99 (m, 1H), 2.86-2.73 (m, 1H), 2.34 (s, 6H), 2.15 (dd,
J=12.3, 4.1 Hz, 1H), 2.03 (d, J=12.2 Hz, 1H), 1.79-1.70 (m, 2H),
1.62 (q, J=12.2 Hz, 1H), 1.38-1.24 (m, 1H).
Example 242
##STR00627##
[1237]
5-chloro-2-fluoro-N-(pyrimidin-4-yl)-4-(((1S,2S,4S)-2-(pyrrolidin-1-
-yl)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)benzenesulfonamide
Step 1
##STR00628##
[1238]
tert-butyl((1S,2S,4S)-2-(pyrrolidin-1-yl)-4-(3-(trifluoromethyl)phe-
nyl)cyclohexyl)carbamate
[1239] Following the procedure described in Example 92, step 2 and
making non-critical variations as required to replace
4-(((1S,2S)-2-aminocyclohexyl)amino)-5-chloro-N-(2,4-dimethoxybenzyl)-2-f-
luoro-N-(4-methylthiazol-2-yl)benzenesulfonamide with
tert-butyl((1S,2S,4S)-2-amino-4-(3-(trifluoromethyl)phenyl)cyclohexyl)car-
bamate,
tert-butyl((1S,2S,4S)-2-(pyrrolidin-1-yl)-4-(3-(trifluoromethyl)ph-
enyl)cyclohexyl)carbamate was obtained as a yellow solid. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.48-7.35 (m, 4H), 5.41-5.35 (m,
1H), 3.38-3.25 (m, 1H), 2.73-2.52 (m, 7H), 2.18-2.01 (m, 1H),
1.75-1.72 (m, 1H), 1.69-1.57 (m, 4H), 1.56-1.51 (m, 2H), 1.47 (s,
9H), 1.48-1.26 (m, 1H).
Step 2
##STR00629##
[1240]
5-chloro-2-fluoro-N-(pyrimidin-4-yl)-4-(((1S,2S,4S)-2-(pyrrolidin-1-
-yl)-4-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)benzenesulfonamide
[1241] Following the procedure described in Example 23 and making
non-critical variations as required to replace
tert-butyl((1S,6S)-6-(dimethylamino)-4-(trifluoromethyl)cyclohex-3-en-1-y-
l)carbamate with
tert-butyl((1S,2S,4S)-2-(pyrrolidin-1-yl)-4-(3-(trifluoromethyl)phenyl)cy-
clohexyl)carbamate,
5-chloro-2-fluoro-N-(pyrimidin-4-yl)-4-(((1S,2S,4S)-2-(pyrrolidin-1-yl)-4-
-(3-(trifluoromethyl)phenyl)cyclohexyl)amino)benzene-sulfonamide
was obtained as a white solid. LCMS (ESI) m/z: 598.2 [M+H].sup.+.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.35 (s, 1H), 8.06-8.01
(m, 1H), 7.67-7.57 (m, 3H), 7.56-7.54 (m, 2H), 6.80-6.71 (m, 1H),
6.66 (d, J=6.0 Hz, 1H), 5.97 (d, J=8.0 Hz, 1H), 3.98-3.46 (m, 1H),
3.15-3.10 (m, 3H), 2.98-2.89 (m, 2H), 2.84-2.80 (m, 1H), 2.16-2.04
(m, 2H), 1.91-1.69 (m, 7H), 1.49-1.41 (m, 1H). Exchangable NH
hydrogens not observed.
[1242] Although the preparation of the free-base or a specific salt
form may be illustrated in the Examples above, it is understood
that the free-base and its acid or base salt forms can be
interconverted using standard techniques
Example 243A. Tritiated Compound Binding to Membranes Isolated from
Cells that Heterologously Express hNav1.7 and the .beta.1
Subunit
[1243] Preparation of membranes containing recombinantly expressed
sodium channels: Frozen recombinant cell pellets were thawed on ice
and diluted to 4 times the cell pellet weight with ice cold 50 mM
Tris HCl, pH 7.4 buffer. The cell suspensions were homogenized on
ice using a motorized glass dounce homogeniser. Homogenates were
further diluted 8.4 times with ice cold 50 mM Tris HCl, pH 7.4
buffer and then centrifuged at 200.times.g at 4.degree. C. for 15
min. The supernatants were collected and centrifuged at
10000.times.g at 4.degree. C. for 50 min. The pellets were then
re-suspended in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer
containing 1% v/v protease inhibitors (Calbiochem) and
re-homogenized on ice. The homogenized membranes were then
processed through a syringe equipped with a 26 gauge needle.
Protein concentrations were determined by Bradford Assay and the
membranes were stored at -80.degree. C.
[1244] Radioligand Binding Studies:
[1245] Saturation experiments. A competitive NaV1.7 inhibitor
having a methyl group was tritiated. Three tritiums were
incorporated in place of methyl hydrogens to generate
[.sup.3H]compound. Binding of this radioligand was performed in 5
mL borosilicate glass test tubes at room temperature. Binding was
initiated by adding membranes to increasing concentrations of
[.sup.3H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer
containing 0.01% w/v bovine serum albumin (BSA) for 18h.
Non-specific binding was determined in the presence of 1 .mu.M
unlabeled compound. After 18h, the reactants were filtered through
GF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine.
Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris
HCl, pH7.4 buffer containing 0.25% BSA to separate bound from free
ligand. [.sup.3H]compound bound to filters was quantified by liquid
scintillation counting.
[1246] Competitive Binding Experiments:
[1247] Binding reactions were performed in 96-well polypropylene
plates at room temperature for 18h. In 360 .mu.L, membranes were
incubated with 100 pM [.sup.3H]compound and increasing
concentrations of Test Compound. Non-specific binding was defined
in the presence of 1 .mu.M unlabeled compound. Reactions were
transferred and filtered through 96-well glass fiber/C filter
plates presoaked with 0.5% polyethylene imine. The filtered
reactions were washed 5 times with 200 .mu.L ice cold buffer
containing 0.25% BSA. Bound radioactivity was determined by liquid
scintillation counting.
Data Analysis: For saturation experiments, non-specific binding was
subtracted from total binding to provide specific binding and these
values were recalculated in terms of pmol ligand bound per mg
protein. Saturation curves were constructed and dissociation
constants were calculated using the single site ligand binding
model: Beq=(Bmax*X)/(X+Kd), where Beq is the amount of ligand bound
at equilibrium, Bmax is the maximum receptor density, Kd is the
dissociation constant for the ligand, and X is the free ligand
concentration. For competition studies percent inhibition was
determined and IC.sub.50 values were calculated using a 4 parameter
logistic model (% inhibition=(A+((B-A)/(1+((x/C){circumflex over (
)}D)))) using XLfit, where A and B are the maximal and minimum
inhibition respectively, C is the IC.sub.50 concentration and D is
the (Hill) slope.
Example 243B. Tritiated Compound Binding to Membranes Isolated from
Cells that Heterologous Express hNav1.7 and the .beta.1 Subunit
Preparation of Membranes Containing Recombinantly Expressed Sodium
Channels:
[1248] Following the procedure described in Example 243A, and
making modifications as required to: centrifuge supernatants at
100000.times.g instead of 10000.times. g; re-suspend pellets in a
buffer containing 0.01% BSA in addition to 100 mM NaCl, 20 mM Tris
HCl, pH 7.4 buffer, and 1% v/v proteasome inhibitors; and storing
membranes at -80.degree. C. in single use aliquots instead of
pooled.
Radioligand Binding Studies: Saturation Experiments:
[1249] Following the procedure described in Example 243A, and
making modifications as required to incubate [3H]compound for 3
hours instead of 18 hours.
Competitive Binding Experiments:
[1250] Following the procedure described in Example 243A, and
making modifications as required to: perform binding experiments at
room temperature for 3 hours instead of 18 hours; use 240 uL of
solution and 300 pM of [3H]compound instead of 360 uL and 100 pM of
[3H]compound; and wash filtered reactions 2 times instead of 5
times.
[1251] Data Analysis:
[1252] Following the procedure described in Example 243A.
Example 243C. Electrophysiological Assay (EP) (In Vitro Assay)
[1253] Patch voltage clamp electrophysiology allows for the direct
measurement and quantification of block of voltage-gated sodium
channels (NaV's), and allows the determination of the time- and
voltage-dependence of block which has been interpreted as
differential binding to the resting, open, and inactivated states
of the sodium channel (Hille, B., Journal of General Physiology
(1977), 69: 497-515).
[1254] The following voltage clamp electrophysiology studies were
performed on representative compounds using cells heterologously
expressing Nav1.7 or Nav1.5 channels. cDNAs for Nav1.7 (NM_002977)
and Nav1.5 (AC137587) were stably expressed in Chinese Hamstr Ovary
(CHO) cells and CHL (Chinese Hamster Lung) cells respectively.
Sodium currents were measured in the whole-cell configuration using
Syncropatch 384PE (Nanlon Technologies, Germany). 1NPC.RTM.-384
chips with custom medium resistance and single hole mode are used.
Internal solution consists of (in mM): 110 CsCl, 10 CsCl, 20 EGTA,
and 10 Hepes (pH adjusted to 7.2); and external solution contains
(in mM): 60 NMDG, 80 NaCl, 4 KCl, 1 MgCl.sub.2, 2 CaCl.sub.2, 2
D-Glucose monohydrate, 10 Hepes (pH adjusted to 7.4 with NaOH).
[1255] After system flushing, testing compounds are dissolved in
external solution containing 0.1% Pluronic F-127. The chip is moved
into the measuring head and the instrument primes the chip with
external and internal solutions. 10l cells are added to the chip
from a cell hotel, and a negative pressure of -50 mBar is applied
to form a seal. Following treatment with seal enhancer solution and
wash-off with external solution, negative pressure of -250 mbar is
applied for 1 second to achieve the whole-cell configuration,
followed by three washing steps in external solution. 20 .mu.l of
compounds is added to 40 .mu.l in each well (1:3 dilution of
compounds), and after mixing, 20 .mu.l is removed so the volume is
retained at 40 ul. After approximately 13 minutes recordings, 20
.mu.l/well of 2 uM TTX, or 333 uM Tetracaine (for Nav1.5) is added
to achieve full block.
[1256] For voltage protocol, an holding potential of -50 mV is
applied during the whole experiment. A depolarizing step is applied
to -10 mV for 10 ms, followed by a hyperpolarization step to -150
mV for 20 ms to allow channel recovery from inactivation. A second
depolarizing step is applied from -150 mV to -10 mV for 10 ms,
where currents were measured to derive blocking effects of
compounds. Inhibition is determined based on 7.5 min of compound
incubation.
[1257] Data for representative compounds is provided in Table 1 and
Table 2.
TABLE-US-00001 TABLE 1 Nav1.7 (LBA) Ex- (Ex. am- 243A) ple
Structure (.mu.M) 1 ##STR00630## 0.197 2 ##STR00631## 0.0382 3
##STR00632## 0.016 4 ##STR00633## 0.00415 5 ##STR00634## 0.426 6
##STR00635## 0.994 7 ##STR00636## 0.0899 8 ##STR00637## 3.00 9
##STR00638## 3.00 10 ##STR00639## 0.553 11 ##STR00640## 0.126 12
##STR00641## 0.165 13 ##STR00642## 0.357 14 ##STR00643## 0.0219 15
##STR00644## 0.0269 16 ##STR00645## 0.325 17 ##STR00646## 0.237 18
##STR00647## 0.0168 19 ##STR00648## 0.0451 20 ##STR00649## 0.211 21
##STR00650## 0.214 22 ##STR00651## 0.0951 23 ##STR00652## 0.0084 24
##STR00653## 0.0499 25 ##STR00654## 7.42 26 ##STR00655## 0.0415 27
##STR00656## 0.149
TABLE-US-00002 TABLE 2 Nav1.7 Nav1.7 EP_SP LBA LBA hNav1.7 (Ex.
243A) (Ex. 243B) (Ex. 243B) Example Structure IC.sub.50 (uM)
IC.sub.50 (uM) IC50 (uM) 28 ##STR00657## 0.199 29 ##STR00658##
0.0601 30 ##STR00659## 0.00973 0.00977 31 ##STR00660## 0.163 32
##STR00661## 0.0382 0.0246 33 ##STR00662## 0.0824 34 ##STR00663##
0.0352 35 ##STR00664## 0.0655 0.313 0.0599 36 ##STR00665## 0.0936
37 ##STR00666## 0.00276 38 ##STR00667## 0.00505 0.0349 0.00306 39
##STR00668## 0.00188 0.0128 0.0014 40 ##STR00669## 0.88 41
##STR00670## 0.00451 0.0034 42 ##STR00671## 0.0272 43 ##STR00672##
1.13 44 ##STR00673## 0.0744 45 ##STR00674## 0.0127 46 ##STR00675##
0.77 47 ##STR00676## 0.529 48 ##STR00677## 0.127 49 ##STR00678##
0.0421 50 ##STR00679## 0.0584 51 ##STR00680## 0.0756 52
##STR00681## 0.00848 53 ##STR00682## 0.0305 0.00569 54 ##STR00683##
0.0979 55 ##STR00684## 0.00738 56 ##STR00685## 0.00346 57
##STR00686## 0.00242 58 ##STR00687## 0.00342 59 ##STR00688##
0.00194 60 ##STR00689## 0.198 61 ##STR00690## 0.558 62 ##STR00691##
0.0578 63 ##STR00692## 0.00981 0.00535 64 ##STR00693## 0.0116 65
##STR00694## 0.0293 66 ##STR00695## 0.00207 0.00774 0.00291 67
##STR00696## 0.0173 68 ##STR00697## 0.0166 69 ##STR00698## 0.296 70
##STR00699## 0.00346 71 ##STR00700## 0.0413 72 ##STR00701## 0.0148
73 ##STR00702## 0.0197 74 ##STR00703## 0.0917 75 ##STR00704##
0.0379 76 ##STR00705## 0.116 77 ##STR00706## 0.0432 78 ##STR00707##
0.0956 79 ##STR00708## 0.00928 80 ##STR00709## 0.122 81
##STR00710## 1.74 82 ##STR00711## 0.00335 83 ##STR00712## 0.379 84
##STR00713## 3.0 85 ##STR00714## 0.252 86 ##STR00715## 0.0381 87
##STR00716## 0.000539 88 ##STR00717## 0.201 89 ##STR00718## 0.0599
90 ##STR00719## 0.00264 91 ##STR00720## 0.013 92 ##STR00721## 0.118
93 ##STR00722## 0.0647 94 ##STR00723## 0.0313 95 ##STR00724##
0.0243 96 ##STR00725## 0.63 97 ##STR00726## 0.0364 98 ##STR00727##
3.0 99 ##STR00728## 0.0655 100 ##STR00729## 0.127 101 ##STR00730##
0.0255 102 ##STR00731## 0.424 0.0665 103 ##STR00732## 0.0322 104
##STR00733## 0.0356 105 ##STR00734## 0.0313 0.0045 106 ##STR00735##
0.67 0.0749 107 ##STR00736## 0.137 0.018 108 ##STR00737## 0.166
0.0226 109 ##STR00738## 0.0507 0.00868 110 ##STR00739## 0.0194
0.00371 111 ##STR00740## 0.678 0.0234 112 ##STR00741## 0.229 0.0151
113 ##STR00742## 0.185 0.0117 114 ##STR00743## 0.264 0.0331 115
##STR00744## 0.018 0.00329 116 ##STR00745## 0.307 0.0182 117
##STR00746## 2.22 0.97 118 ##STR00747## 0.242 0.00851 119
##STR00748## 0.184 0.0107 120 ##STR00749## 0.0263 0.0041 121
##STR00750## 1.17 0.121 122 ##STR00751## 0.205 0.0336 123
##STR00752## 0.0175 0.00454 124 ##STR00753## 1.23 0.107 125
##STR00754## 0.204 0.00753 126 ##STR00755## 0.0876 0.00925 127
##STR00756## 0.0615 0.00658 128 ##STR00757## 0.0228 0.00956 129
##STR00758## 0.000255 0.000372 130 ##STR00759## 0.0759 0.00992 131
##STR00760## 0.201 0.00595 132 ##STR00761## 0.306 0.014 133
##STR00762## 0.0208 0.0032 134 ##STR00763## 0.279 0.0186 135
##STR00764## 0.313 0.0328 136 ##STR00765## 0.493 0.0301 137
##STR00766## 0.00357 0.00124 138 ##STR00767## 0.00943 0.00321 139
##STR00768## 0.291 0.0456 140 ##STR00769## 0.17 0.0132 141
##STR00770## 0.275 0.0127 142 ##STR00771## 2.0 1.12 143
##STR00772## 0.418 0.0193 144 ##STR00773## 0.374 0.0258 145
##STR00774## 2.0 0.395 146 ##STR00775## 0.154 0.0154 147
##STR00776## 0.275 0.0272 148 ##STR00777## 0.305 0.0253 149
##STR00778## 0.52 0.0125
150 ##STR00779## 1.41 0.103 151 ##STR00780## 0.181 0.0201 152
##STR00781## 2.0 1.68 153 ##STR00782## 0.0171 0.00407 154
##STR00783## 1.2 0.101 155 ##STR00784## 0.13 0.0123 156
##STR00785## 0.316 0.0189 157 ##STR00786## 0.337 0.0241 158
##STR00787## 0.00596 0.00271 159 ##STR00788## 1.79 0.202 160
##STR00789## 0.0203 0.00227 161 ##STR00790## 0.187 0.00303 162
##STR00791## 0.248 0.00855 163 ##STR00792## 0.201 0.0181 164
##STR00793## 0.0534 0.00743 165 ##STR00794## 2.0 0.511 166
##STR00795## 0.341 0.0139 167 ##STR00796## 0.0917 0.0187 168
##STR00797## 0.04 0.00516 169 ##STR00798## 0.00756 0.00334 170
##STR00799## 0.00292 0.00368 171 ##STR00800## 0.255 0.0122 172
##STR00801## 0.0382 0.0123 173 ##STR00802## 0.0177 0.0026 174
##STR00803## 0.357 0.0502 175 ##STR00804## 0.316 0.0217 176
##STR00805## 0.491 0.00872 177 ##STR00806## 0.0609 0.00291 178
##STR00807## 0.205 0.0191 179 ##STR00808## 0.27 0.00683 180
##STR00809## 0.666 0.0495 181 ##STR00810## 0.00131 0.000783 182
##STR00811## 2.0 1.52 183 ##STR00812## 0.277 0.012 184 ##STR00813##
2.0 4.96 185 ##STR00814## 0.771 0.0362 186 ##STR00815## 0.0314
0.00408 187 ##STR00816## 0.776 0.00765 188 ##STR00817## 2.0 0.684
189 ##STR00818## 0.304 0.0234 190 ##STR00819## 0.478 0.0415 191
##STR00820## 0.777 0.0394 192 ##STR00821## 0.324 0.0255 193
##STR00822## 0.911 0.0394 194 ##STR00823## 2.0 0.4 195 ##STR00824##
0.00811 0.0014 196 ##STR00825## 0.664 0.12 197 ##STR00826## 0.038
0.00385 198 ##STR00827## 0.817 0.0658 199 ##STR00828## 0.131 0.0187
200 ##STR00829## 0.15 0.0167 201 ##STR00830## 0.308 0.0296 202
##STR00831## 0.245 0.0344 203 ##STR00832## 0.0806 0.0116 204
##STR00833## 0.308 0.0205 205 ##STR00834## 0.556 0.0327 206
##STR00835## 0.0411 0.00865 207 ##STR00836## 1.6 0.203 208
##STR00837## 0.0467 0.00612 209 ##STR00838## 0.16 0.00925 210
##STR00839## 2.0 0.415 211 ##STR00840## 1.43 0.12 212 ##STR00841##
0.11 0.00659 213 ##STR00842## 0.218 0.0139 214 ##STR00843## 0.0531
0.00209 215 ##STR00844## 2.0 0.286 216 ##STR00845## 0.0721 0.00477
217 ##STR00846## 1.19 0.112 218 ##STR00847## 0.0209 0.0016 219
##STR00848## 0.00171 0.000942 220 ##STR00849## 0.000418 221
##STR00850## 0.298 0.0629 222 ##STR00851## 0.464 0.124 223
##STR00852## 0.00973 0.00145 224 ##STR00853## 0.00833 0.00236 225
##STR00854## 0.000643 0.0006514 226 ##STR00855## 0.00145 0.00104
227 ##STR00856## 0.00069 0.00119 228 ##STR00857## 0.00578 0.000846
229 ##STR00858## 0.055 0.00838 230 ##STR00859## 0.000627 0.00152
231 ##STR00860## 0.00222 0.000933 232 ##STR00861## 0.0478 0.0105
233 ##STR00862## 0.00982 0.00171 234 ##STR00863## 2.0 0.131 235
##STR00864## 0.0118 0.00814 236 ##STR00865## 0.000593 0.0016 237
##STR00866## 0.00243 0.00107 238 ##STR00867## 0.00554 0.00117 239
##STR00868## 0.00293 0.0015 240 ##STR00869## 0.015 0.0029 241
##STR00870## 0.00373 0.00148 242 ##STR00871## 0.000428 0.000182
Example 244
Analgesia Induced by Sodium Channel Blockers
Heat Induced Tail Flick Latency Test
[1258] In this test, the analgesia effect produced by administering
a compound of the invention can be observed through heat-induced
tail-flick in mice. The test includes a heat source consisting of a
projector lamp with a light beam focused and directed to a point on
the tail of a mouse being tested. The tail-flick latencies, which
are assessed prior to drug treatment, and in response to a noxious
heat stimulus, i.e., the response time from applying radiant heat
on the dorsal surface of the tail to the occurrence of tail flick,
are measured and recorded at 40, 80, 120, and 160 minutes.
[1259] For the first part of this study, 65 animals undergo
assessment of baseline tail flick latency once a day over two
consecutive days. These animals are then randomly assigned to one
of the 11 different treatment groups including a vehicle control, a
morphine control, and 9 compounds at 30 mg/Kg are administered
intramuscularly. Following dose administration, the animals are
closely monitored for signs of toxicity including tremor or
seizure, hyperactivity, shallow, rapid or depressed breathing and
failure to groom. The optimal incubation time for each compound is
determined via regression analysis. The analgesic activity of the
test compounds is expressed as a percentage of the maximum possible
effect (% MPE) and is calculated using the following formula:
% MPE Postdrug latency - Predrug latency Cut - off time ( 10 s ) -
Predrug latency .times. 100 % ##EQU00001##
where:
[1260] Postdrug latency=the latency time for each individual animal
taken before the tail is removed (flicked) from the heat source
after receiving drug.
[1261] Predrug latency=the latency time for each individual animal
taken before the tail is flicked from the heat source prior to
receiving drug.
[1262] Cut-off time (10 s)=is the maximum exposure to the heat
source.
[1263] Acute Pain (Formalin Test)
[1264] The formalin test is used as an animal model of acute pain.
In the formalin test, animals are briefly habituated to the
plexiglass test chamber on the day prior to experimental day for 20
minutes. On the test day, animals are randomly injected with the
test articles. At 30 minutes after drug administration, 50 .mu.L of
10% formalin is injected subcutaneously into the plantar surface of
the left hind paw of the rats. Video data acquisition begins
immediately after formalin administration, for duration of 90
minutes.
[1265] The images are captured using the Actimetrix Limelight
software which stores files under the *.llii extension, and then
converts it into the MPEG-4 coding. The videos are then analyzed
using behaviour analysis software "The Observer 5.1", (Version 5.0,
Noldus Information Technology, Wageningen, The Netherlands). The
video analysis is conducted by watching the animal behaviour and
scoring each according to type, and defining the length of the
behaviour (Dubuisson and Dennis, 1977). Scored behaviours include:
(1) normal behaviour, (2) putting no weight on the paw, (3) raising
the paw, (4) licking/biting or scratching the paw. Elevation,
favoring, or excessive licking, biting and scratching of the
injected paw indicate a pain response. Analgesic response or
protection from compounds is indicated if both paws are resting on
the floor with no obvious favoring, excessive licking, biting or
scratching of the injected paw.
[1266] Analysis of the formalin test data is done according to two
factors: (1) Percent Maximal Potential Inhibitory Effect (% MPIE)
and (2) pain score. The % MPIEs is calculated by a series of steps,
where the first is to sum the length of non-normal behaviours
(behaviours 1, 2, 3) of each animal. A single value for the vehicle
group is obtained by averaging all scores within the vehicle
treatment group. The following calculation yields the MPIE value
for each animal:
MPIE (%)=100-[(treatment sum/average vehicle value).times.100%]
[1267] The pain score is calculated from a weighted scale as
described above. The duration of the behaviour is multiplied by the
weight (rating of the severity of the response), and divided by the
total length of observation to determine a pain rating for each
animal. The calculation is represented by the following
formula:
Pain rating=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)
CFA Induced Chronic Inflammatory Pain
[1268] In this test, tactile allodynia is assessed with calibrated
von Frey filaments. Following a full week of acclimatization to the
vivarium facility, 150 .mu.L of the "Complete Freund's Adjuvant"
(CFA) emulsion (CFA suspended in an oil/saline (1:1) emulsion at a
concentration of 0.5 mg/mL) is injected subcutaneously into the
plantar surface of the left hind paw of rats under light isoflurane
anaesthesia. Animals are allowed to recover from the anaesthesia
and the baseline thermal and mechanical nociceptive thresholds of
all animals are assessed one week after the administration of CFA.
All animals are habituated to the experimental equipment for 20
minutes on the day prior to the start of the experiment. The test
and control articles are administrated to the animals, and the
nociceptive thresholds measured at defined time points after drug
administration to determine the analgesic responses to each of the
six available treatments. The time points used are previously
determined to show the highest analgesic effect for each test
compound.
[1269] Thermal nociceptive thresholds of the animals are assessed
using the Hargreaves test. Animals are placed in a Plexiglas
enclosure set on top of an elevated glass platform with heating
units. The glass platform is thermostatically controlled at a
temperature of approximately 30.degree. C. for all test trials.
Animals are allowed to accommodate for 20 minutes following
placement into the enclosure until all exploration behaviour
ceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter
(IITC, Woodland Hills, Calif.) is used to apply a radiant heat beam
from underneath the glass platform to the plantar surface of the
hind paws. During all test trials, the idle intensity and active
intensity of the heat source are set at 1 and 45 respectively, and
a cut off time of 20 seconds is employed to prevent tissue
damage.
[1270] The response thresholds of animals to tactile stimuli are
measured using the Model 2290 Electrovonfrey anesthesiometer (IITC
Life Science, Woodland Hills, Calif.) following the Hargreaves
test. Animals are placed in an elevated Plexiglas enclosure set on
a mire mesh surface. After 10 minutes of accommodation,
pre-calibrated Von Frey hairs are applied perpendicularly to the
plantar surface of both paws of the animals in an ascending order
starting from the 0.1 g hair, with sufficient force to cause slight
buckling of the hair against the paw. Testing continues until the
hair with the lowest force to induce a rapid flicking of the paw is
determined or when the cut off force of approximately 20 g is
reached. This cut off force is used because it represent
approximately 10% of the animals' body weight and it serves to
prevent raising of the entire limb due to the use of stiffer hairs,
which would change the nature of the stimulus.
Postoperative Models of Nociception
[1271] In this model, the hypealgesia caused by an intra-planar
incision in the paw is measured by applying increased tactile
stimuli to the paw until the animal withdraws its paw from the
applied stimuli. While animals are anaesthetized under 3.5%
isofluorane, which is delivered via a nose cone, a 1 cm
longitudinal incision is made using a number 10 scalpel blade in
the plantar aspect of the left hind paw through the skin and
fascia, starting 0.5 cm from the proximal edge of the heel and
extending towards the toes. Following the incision, the skin is
apposed using 2, 3-0 sterilized silk sutures. The injured site is
covered with Polysporin and Betadine. Animals are returned to their
home cage for overnight recovery.
[1272] The withdrawal thresholds of animals to tactile stimuli for
both operated (ipsilateral) and unoperated (contralateral) paws can
be measured using the Model 2290 Electrovonfrey anesthesiometer
(IITC Life Science, Woodland Hills, Calif.). Animals are placed in
an elevated Plexiglas enclosure set on a mire mesh surface. After
at least 10 minutes of acclimatization, pre-calibrated Von Frey
hairs are applied perpendicularly to the plantar surface of both
paws of the animals in an ascending order starting from the 10 g
hair, with sufficient force to cause slight buckling of the hair
against the paw. Testing continues until the hair with the lowest
force to induce a rapid flicking of the paw is determined or when
the cut off force of approximately 20 g is reached. This cut off
force is used because it represent approximately 10% of the
animals' body weight and it serves to prevent raising of the entire
limb due to the use of stiffer hairs, which would change the nature
of the stimulus.
Neuropathic Pain Model; Chronic Constriction Injury
[1273] Briefly, an approximately 3 cm incision is made through the
skin and the fascia at the mid thigh level of the animals' left
hind leg using a no. 10 scalpel blade. The left sciatic nerve is
exposed via blunt dissection through the biceps femoris with care
to minimize haemorrhagia. Four loose ligatures are tied along the
sciatic nerve using 4-0 non-degradable sterilized silk sutures at
intervals of 1 to 2 mm apart. The tension of the loose ligatures is
tight enough to induce slight constriction of the sciatic nerve
when viewed under a dissection microscope at a magnification of 4
fold. In the sham-operated animal, the left sciatic nerve is
exposed without further manipulation. Antibacterial ointment is
applied directly into the wound, and the muscle is closed using
sterilized sutures. Betadine is applied onto the muscle and its
surroundings, followed by skin closure with surgical clips.
[1274] The response thresholds of animals to tactile stimuli are
measured using the Model 2290 Electrovonfrey anesthesiometer (IITC
Life Science, Woodland Hills, Calif.). Animals are placed in an
elevated Plexiglas enclosure set on a mire mesh surface. After 10
minutes of accommodation, pre-calibrated Von Frey hairs are applied
perpendicularly to the plantar surface of both paws of the animals
in an ascending order starting from the 0.1 g hair, with sufficient
force to cause slight buckling of the hair against the paw. Testing
continues until the hair with the lowest force to induce a rapid
flicking of the paw is determined or when the cut off force of
approximately 20 g is reached. This cut off force is used because
it represents approximately 10% of the animals' body weight and it
serves to prevent raising of the entire limb due to the use of
stiffer hairs, which would change the nature of the stimulus.
[1275] Thermal nociceptive thresholds of the animals are assessed
using the Hargreaves test. Following the measurement of tactile
thresholds, animals are placed in a Plexiglass enclosure set on top
of an elevated glass platform with heating units. The glass
platform is thermostatically controlled at a temperature of
approximately 24 to 26.degree. C. for all test trials. Animals are
allowed to accommodate for 10 minutes following placement into the
enclosure until all exploration behaviour ceases. The Model 226
Plantar/Tail Stimulator Analgesia Meter (IITC, Woodland Hills,
Calif.) is used to apply a radiant heat beam from underneath the
glass platform to the plantar surface of the hind paws. During all
test trials, the idle intensity and active intensity of the heat
source are set at 1 and 55 respectively, and a cut off time of 20
seconds is used to prevent tissue damage.
Neuropathic Pain Model: Spinal Nerve Ligation
[1276] The spinal nerve ligation (SNL) neuropathic pain model is
used as an animal (i.e. rat) model of neuropathic pain. In the SNL
test, the lumbar roots of spinal nerves L5 and L6 are tightly
ligated to cause nerve injury, which results in the development of
mechanical hyperalgesia, mechanical allodynia and thermal
hypersensitivity. The surgery is performed two weeks before the
test day in order for the pain state to fully develop in the
animals. Several spinal nerve ligation variations are used to
characterize the analgesic properties of a compound of the
invention.
[1277] Ligation of the L5 spinal nerve;
[1278] Ligation of the L5 and L6 spinal nerves;
[1279] Ligation and transection of the L5 spinal nerve;
[1280] Ligation and transection of the L5 and L6 spinal nerves;
or
[1281] Mild irritation of the L4 spinal nerve in combination with
any one of the above (1)-(4).
[1282] While the animals are anaesthetized under 3.5% isofluorane
delivered via a nose cone, an approximately 2.5 cm longitudinal
incision is made using a number 10 scalpel blade in the skin just
lateral to the dorsal midline, using the level of the posterior
iliac crests as the midpoint of the incision. Following the
incision, the isoflourane is readjusted to maintenance levels
(1.5%-2.5%). At mid-sacral region, an incision is made with the
scalpel blade, sliding the blade along the side of the vertebral
column (in the saggital plane) until the blade hits the sacrum.
Scissors tips are introduced through the incision and the muscle
and ligaments are removed from the spine to expose 2-3 cm of the
vertebral column. The muscle and fascia are cleared from the spinal
vertebra in order to locate the point where the nerve exits from
the vertebra. A small glass hook is placed medial to the spinal
nerves and the spinal nerves are gently elevated from the
surrounding tissues. Once the spinal nerves have been isolated, a
small length of non-degradable 6-0 sterilized silk thread is wound
twice around the ball at the tip of the glass hook and passed back
under the nerve. The spinal nerves are then firmly ligated by tying
a knot, ensuring that the nerve bulges on both sides of the
ligature. The procedure may be repeated as needed. In some animals,
the L4 spinal nerve may be lightly rubbed (up to 20 times) with the
small glass hook to maximize the development of neuropathic pain.
Antibacterial ointment is applied directly into the incision, and
the muscle is closed using sterilized sutures. Betadine is applied
onto the muscle and its surroundings, followed by skin closure with
surgical staples or sterile non-absorable monofilament 5-0 nylon
sutures.
[1283] The analgesic effect produced by topical administration of a
compound of the invention to the animals can then be observed by
measuring the paw withdrawal threshold of animals to mechanical
tactile stimuli. These may be measured using either the mechanical
allodynia procedure or the mechanical hyperalgesia procedure as
described below. After establishment of the appropriate baseline
measurements by either method, topical formulation of a compound of
the invention is applied on the ipsilateral ankle and foot. The
animals are then placed in plastic tunnels for 15 minutes to
prevent them from licking the treated area and removing the
compound. Animals are placed in the acrylic enclosure for 15
minutes before testing the ipsilateral paw by either of the methods
described below, and the responses are recorded at 0.5, 1.0 and 2.0
hour post treatment.
Mechanical Allodynia Method
[1284] The pain threshold of animals to mechanical alloydnia for
both operated and control animals can be measured approximately 14
days post-surgery using manual calibrated von Frey filaments as
follows. Animals are placed in an elevated plexiglass enclosure set
on a mire mesh surface. Animals are allowed to acclimate for 20-30
minutes. Pre-calibrated Von Frey hairs are applied perpendicularly
to the plantar surface of the ipsilateral paw of the animals
starting from the 2.0 g hair, with sufficient force to cause slight
buckling of the hair against the paw to establish the baseline
measurements. Stimuli are presented in a consecutive manner, either
in an ascending or descending order until the first change in
response is noted, after which four additional responses are
recorded for a total of six responses. The six responses measured
in grams are entered into a formula as described by Chaplan, S. R.
et al., J. Neurosci. Methods, 1994 July; 53(1):55-63, and a 50%
withdrawal threshold is calculated. This constitutes the mechanical
allodynia value.
Mechanical Hyperalgesia Method
[1285] The response thresholds of animals to tactile stimuli are
measured using the Model 2290 Electrovonfrey anesthesiometer (IITC
Life Science, Woodland Hills, Calif.). Animals are placed in an
elevated Plexiglas enclosure set on a wire mesh surface. After 15
minutes of accommodation in this enclosure, a von Frey hair is
applied perpendicularly to the plantar surface of the ipsilateral
hind paws of the animals, with sufficient force, measured in grams,
to elicit a crisp response of the paw. A response indicates a
withdrawal from the painful stimulus and constitutes the efficacy
endpoint. The data are expressed as percent change from baseline
threshold measured in grams.
Example 245 In Vivo Assay for Treatment of Pruritus
[1286] The compounds of the invention can be evaluated for their
activity as antipruritic agents by in vivo test using rodent
models. One established model for peripherally elicited pruritus is
through the injection of serotonin into the rostral back area
(neck) in hairless rats. Prior to serotonin injections (e.g., 2
mg/mL, 50 .mu.L), a dose of a compound of the present invention can
be applied systemically through oral, intravenous or
intraperitoneal routes or topically to a circular area fixed
diameter (e.g. 18 mm). Following dosing, the serotonin injections
are given in the area of the topical dosing. After serotonin
injection the animal behaviour is monitored by video recording for
20 min-1.5 h, and the number of scratches in this time compared to
vehicle treated animals. Thus, application of a compound of the
current invention could suppress serotonin-induced scratching in
rats.
[1287] All of the U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non patent publications referred to in this
specification are incorporated herein by reference in their
entireties.
[1288] Although the foregoing invention has been described in some
detail to facilitate understanding, it will be apparent that
certain changes and modifications may be practiced within the scope
of the appended claims. Accordingly, the described embodiments are
to be considered as illustrative and not restrictive, and the
invention is not to be limited to the details given herein, but may
be modified within the scope and equivalents of the appended
claims.
* * * * *