U.S. patent application number 14/899397 was filed with the patent office on 2016-05-26 for compounds for treating spinal muscular atrophy.
This patent application is currently assigned to F. Hoffmann-La Roche AG. The applicant listed for this patent is HOFFMANN-LA ROCHE INC., PTC THERAPEUTICS INC.. Invention is credited to Amal Dakka, Luke Green, Gary Karp, Jana Narasimhan, Nikolai Naryshkin, Emmanuel Pinard, Hongyan Qi, Hasane Ratni, Nicole Risher, Marla Weetall, Matthew Woll.
Application Number | 20160145270 14/899397 |
Document ID | / |
Family ID | 48669815 |
Filed Date | 2016-05-26 |
United States Patent
Application |
20160145270 |
Kind Code |
A1 |
Dakka; Amal ; et
al. |
May 26, 2016 |
COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY
Abstract
The present invention provides compounds of formula (I) wherein
A, B, X, Y, R1 and R2 are as described herein, as well as
pharmaceutically acceptable salts thereof. Further the present
invention is concerned with the manufacture of the compounds of
formula (I), pharmaceutical compositions comprising them and their
use as medicaments. ##STR00001##
Inventors: |
Dakka; Amal; (Whitehouse
Station, NJ) ; Green; Luke; (Basel, CH) ;
Karp; Gary; (Princeton Junction, NJ) ; Narasimhan;
Jana; (Scotch Plains, NJ) ; Naryshkin; Nikolai;
(East Brunswick, NJ) ; Pinard; Emmanuel;
(Linsdorf, FR) ; Qi; Hongyan; (Plainsboro, NJ)
; Ratni; Hasane; (Habsheim, FR) ; Risher;
Nicole; (Hillsborough, NJ) ; Weetall; Marla;
(Morristown, NJ) ; Woll; Matthew; (Dunellen,
NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HOFFMANN-LA ROCHE INC.
PTC THERAPEUTICS INC. |
Little Falls
South Plainfield |
NJ
NJ |
US
US |
|
|
Assignee: |
F. Hoffmann-La Roche AG
Basel
NJ
PTC Therapeutics Inc.
South Plainfield
|
Family ID: |
48669815 |
Appl. No.: |
14/899397 |
Filed: |
June 23, 2014 |
PCT Filed: |
June 23, 2014 |
PCT NO: |
PCT/US2014/043577 |
371 Date: |
December 17, 2015 |
Current U.S.
Class: |
514/210.21 ;
514/249; 514/253.04; 514/253.1; 514/254.02; 514/300; 544/349;
544/350; 544/362; 544/365; 544/368; 546/121 |
Current CPC
Class: |
A61P 21/00 20180101;
A61P 21/04 20180101; C07D 413/12 20130101; A61P 25/00 20180101;
A61P 25/02 20180101; C07D 487/10 20130101; C07D 471/04 20130101;
C07D 519/00 20130101; C07D 263/56 20130101; A61P 25/28 20180101;
A61P 43/00 20180101; C07D 487/04 20130101 |
International
Class: |
C07D 519/00 20060101
C07D519/00; C07D 263/56 20060101 C07D263/56; C07D 413/12 20060101
C07D413/12; C07D 487/04 20060101 C07D487/04; C07D 471/04 20060101
C07D471/04 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 25, 2013 |
EP |
13173487.3 |
Claims
1. A compound of formula (I): ##STR00136## wherein: X is N or
CR.sup.3; Y is N or CR.sup.4; with the proviso that not both X and
Y are N; A is a bicyclic 9-membered heteroaryl comprising two or
three heteroatoms independently selected from N or O, wherein A can
be optionally substituted with one, two or three R.sup.5; B is a
saturated or partially unsaturated mono- or bicyclic 4 to
9-membered heterocycloalkyl comprising one or two ring nitrogen
atoms, the remaining ring atoms being carbon, wherein B can be
optionally substituted with one, two or three R.sup.6; R.sup.1 is
hydrogen, halo, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl,
C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy; R.sup.2 is hydrogen,
halo, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl, C.sub.1-7-alkoxy or
C.sub.1-7-haloalkoxy; R.sup.3 is hydrogen, halo, C.sub.1-7-alkyl,
C.sub.1-7-haloalkyl, C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy;
R.sup.4 is hydrogen, halo, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl,
C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy; each R.sup.5 is
independently selected from halo, cyano, C.sub.1-7-alkyl,
C.sub.1-7-haloalkyl or C.sub.3-7-cycloalkyl; each R.sup.6 is
independently selected from C.sub.1-7-alkyl, or two R.sup.6
together form a C.sub.2-7-alkylene; or a pharmaceutically
acceptable salt thereof.
2. The compound according to claim 1, wherein A is selected from
the group of imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyridinyl,
and benzo[d]oxazolyl, which can be optionally substituted with one,
two or three R.sup.5.
3. The compound according to claim 1, wherein A is selected from
the group of imidazo[1,2-a]pyrazin-2-yl substituted with two
C.sub.1-7-alkyl, imidazo[1,2-a]pyridin-6-yl substituted with one or
two C.sub.1-7-alkyl, imidazo[1,2-a]pyridin-6-yl substituted with
one C.sub.1-7-alkyl and one halo, imidazo[1,2-a]pyridin-6-yl
substituted with one C.sub.1-7-alkyl and one C.sub.1-7-haloalkyl,
benzo[d]oxazol-6-yl substituted with one C.sub.1-7-alkyl, and
benzo[d]oxazol-6-yl substituted with one C.sub.1-7-alkyl and one
halo.
4. The compound according to claim 1, wherein A is selected from
2-methylbenzo[d]oxazol-6-yl, 4-fluoro-2-methylbenzo[d]oxazol-6-yl,
6,8-dimethylimidazo[1,2-a]pyrazin-2-yl,
2-methylimidazo[1,2-a]pyridin-6-yl,
2,7-dimethylimidazo[1,2-a]pyridin-6-yl,
2,8-dimethylimidazo[1,2-a]pyridin-6-yl,
2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl,
8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl, and
8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl.
5. The compound according to claim 1, wherein each R.sup.5 is
independently selected from halo, C.sub.1-7-alkyl, or
C.sub.1-7-haloalkyl.
6. The compound according to any claim 1, wherein each R.sup.5 is
independently selected from methyl, fluoro, chloro, and
trifluoromethyl.
7. The compound according to claim 1, wherein B as defined herein
is further characterized in that one ring nitrogen atoms is
basic.
8. The compound according to claim 1, wherein B is selected from
1,2,3,6-tetrahydropyridinyl, 2,6-diazaspiro[3.3]heptanyl,
hexahydropyrrolo[3,4-c]pyrrolyl, hexahydropyrrolo[1,2-a]pyrazinyl,
piperazinyl, and piperidinyl, wherein each can be optionally
substituted with one, two or three R.sup.6.
9. The compound according to claim 1, wherein B is selected from
piperazin-1-yl, 3-methyl-piperazin-1-yl, and
3,3-dimethylpiperazin-1-yl.
10. The compound according to claim 1, wherein each R.sup.6 is
C.sub.1-7-alkyl.
11. The compound according to claim 1, wherein each R.sup.6 is
independently selected from methyl, and ethyl.
12. The compound according to claim 1, wherein X is CR.sup.3 and Y
is CR.sup.4, or X is N and Y is CR.sup.4, or X is CR.sup.3 and Y is
N.
13. The compound according to claim 1, wherein X is CR.sup.3 and Y
is CR.sup.4.
14. The compound according to claim 1, wherein X is N and Y is
CR.sup.4.
15. The compound according to claim 1, wherein R.sup.1 is hydrogen,
halo, C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy.
16. The compound according to claim 1, wherein R.sup.1 is hydrogen,
fluoro, methoxy, ethoxy or trifluoroethoxy.
17. The compound according to claim 1, wherein R.sup.1 is
hydrogen.
18. The compound according to claim 1, wherein R.sup.2 is hydrogen,
halo, or C.sub.1-7-alkyl.
19. The compound according to claim 1, wherein R.sup.2 is hydrogen,
fluoro or methyl.
20. The compound according to claim 1, wherein R.sup.2 is
hydrogen.
21. The compound according to claim 1, wherein R.sup.3 is hydrogen
or fluoro.
22. The compound according to claim 1, wherein R.sup.3 is
hydrogen.
23. The compound according to claim 1, wherein R.sup.4 is hydrogen,
halo or C.sub.1-7-alkoxy.
24. The compound according to claim 1, wherein R.sup.4 is hydrogen,
fluoro, methoxy, ethoxy or trifluoroethoxy.
25. The compound according to claim 1, wherein R.sup.4 is hydrogen
or fluoro.
26. The compound according to claim 1, wherein R.sup.4 is hydrogen,
halo or C.sub.1-7-alkoxy.
27. The compound according to claim 1, selected from the group
consisting of:
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamid-
e;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazin-1-y-
l)benzamide;
N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-y-
l)-benzamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin--
1-yl)benzamide;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nico-
tinamide;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpipera-
zin-1-yl)nicotinamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicot-
inamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-
-yl)picolinamide;
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)-
picolinamide;
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide-
;
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nic-
otinamide;
6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-
-6-yl)nicotinamide;
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;
6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a]pyridi-
n-6-yl)nicotinamide;
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)-
nicotinamide;
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)pico-
linamide;
rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide;
N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-
-yl)nicotinamide:
rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methy-
lpiperazin-1-yl)nicotinamide;
(S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluorom-
ethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide;
6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-
-a]pyridin-6-yl)nicotinamide;
6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)ni-
cotinamide;
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicoti-
namide;
(S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1-
,2-a]pyrazin-2(1H)-yl)nicotinamide;
N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;
rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-yl)-ni-
cotinamide;
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;
rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)be-
nzamide;
4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-
-6-yl)benzamide;
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimida-
zo[1,2-a]pyridin-6-yl)benzamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl-
)nicotinamide;
(S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrro-
lo[1,2-a]pyrazin-2-yl-benzamide;
(R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl)benzamide;
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(t-
rifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de;
rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpip-
erazin-1-yl)benzamide;
rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)be-
nzamide;
rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-
-methylpiperazin-1-yl)benzamide;
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-y-
l)benzamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotin-
amide;
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpipe-
razin-1-yl)nicotinamide;
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin--
1-yl)picolinamide;
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de;
rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3--
methylpiperazin-1-yl)benzamide;
rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide;
rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylp-
iperazin-1-yl)nicotinamide;
rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylp-
iperazin-1-yl)picolinamide;
rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide;
(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide;
(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide;
rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide;
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylp-
iperazin-1-yl)nicotinamide;
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylp-
iperazin-1-yl)benzamide;
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide;
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylp-
iperazin-1-yl)picolinamide;
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-met-
hylpiperazin-1-yl)benzamide;
2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benza-
mide;
2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)--
4-(piperazin-1-yl)benzamide;
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyri-
din-4-yl)benzamide;
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide;
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-
picolinamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1--
yl)nicotinamide;
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-y-
l)benzamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-y-
l)nicotinamide;
4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1--
yl)nicotinamide;
4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2-
,2-trifluoroethoxy)nicotinamide;
2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2-
,2-trifluoroethoxy)nicotinamide;
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide;
6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin--
6-yl)-2-methoxynicotinamide;
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide;
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-
nicotinamide;
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotina-
mide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)ni-
cotinamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl-
)nicotinamide;
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-y-
l)benzamide; and
rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-
nicotinamide; or a pharmaceutically acceptable salt thereof.
28. The compound according to claim 1, selected from the group
consisting of:
rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide;
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-y-
l)benzamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotin-
amide;
rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-m-
ethylpiperazin-1-yl)picolinamide;
rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide;
(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide;
(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide;
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylp-
iperazin-1-yl)benzamide;
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylp-
iperazin-1-yl)picolinamide;
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide;
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide;
4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide;
4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide;
2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide;
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; and
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; or a pharmaceutically acceptable salt
thereof.
29. A process for the preparation of a compound according to claim
1, comprising the step of: a) the Buchwald-Hartwig amination
reaction of a compound of formula (II) ##STR00137## with a compound
of formula B--H, in the presence of a catalyst and a ligand and a
base and a solvent, wherein the hydrogen H of the compound of
formula B--H is bound to a ring nitrogen atom of B, V is chloro or
bromo, and A, B, X, Y, R.sup.1, and R.sup.2 are as defined in claim
1; or b) a nucleophilic aromatic substitution reaction between a
compound of formula (II) with a compound of formula B--H by heating
in a solvent, wherein the hydrogen H of the compound of formula
B--H is bound to a ring nitrogen atom of B, V is fluoro if X is
CR.sup.3 or V is chloro if X is N, and A, B, X, Y, R.sup.1, R.sup.2
and R.sup.3 are as defined in claim 1; or c) the Suzuki coupling
reaction of a compound of formula (II) with a compound of formula
PG-B-pinB in the presence of a base and a catalyst, followed by
removal of PG, wherein pinB is pinacolboranyl which is bound to a
ring carbon atom of B, PG is an amino-protecting group, V is fluoro
or chloro, and wherein A, B, X, Y, R.sup.1, and R.sup.2 are as
defined in claim 1; or d) the amidation reaction of a compound of
formula (III) ##STR00138## with a compound of formula A-NH.sub.2 in
the presence of a tertiary amine and a coupling reagent, optionally
followed by the removal of PG, wherein PG is an optional
amino-protecting group, and wherein A, B, X, Y, R.sup.1, and
R.sup.2 are as defined in claim 1.
30. (canceled)
31. A pharmaceutical composition, comprising a therapeutically
effective amount of a compound according to claim 1, or a
pharmaceutically acceptable salt thereof, and one or more
pharmaceutically acceptable excipients.
32-33. (canceled)
34. A method for the treatment or prevention of spinal muscular
atrophy (SMA), comprising the step of administering a
therapeutically effective amount of a compound according to claim
1, or a pharmaceutically acceptable salt thereof, to a subject in
need thereof.
35-37. (canceled)
Description
INTRODUCTION
[0001] The present invention provides compounds which are SMN2 gene
splicing modulators, their manufacture, pharmaceutical compositions
comprising them and their use as medicaments for the treatment of
spinal muscular atrophy (SMA).
[0002] In particular, the present invention relates to compounds of
formula (I)
##STR00002##
wherein A, B, X, Y, R.sup.1 and R.sup.2 are as described herein,
and pharmaceutically acceptable salts thereof.
BACKGROUND
[0003] Spinal muscular atrophy (SMA), in its broadest sense,
describes a collection of inherited and acquired central nervous
system (CNS) diseases characterized by progressive motor neuron
loss in the spinal cord and brainstem causing muscle weakness and
muscle atrophy. The most common form of SMA is caused by mutations
in the Survival Motor Neuron (SMN) gene and manifests over a wide
range of severity affecting infants through adults (Crawford and
Pardo, Neurobiol. Dis., 1996, 3:97).
[0004] Infantile SMA is the most severe form of this
neurodegenerative disorder. Symptoms include muscle weakness, poor
muscle tone, weak cry, limpness or a tendency to flop, difficulty
sucking or swallowing, accumulation of secretions in the lungs or
throat, feeding difficulties, and increased susceptibility to
respiratory tract infections. The legs tend to be weaker than the
arms and developmental milestones, such as lifting the head or
sitting up, cannot be reached. In general, the earlier the symptoms
appear, the shorter the lifespan. As the motor neuron cells
deteriorate, symptoms appear shortly afterward. The severe forms of
the disease are fatal and all forms have no known cure. The course
of SMA is directly related to the rate of motor neuron cell
deterioration and the resulting severity of weakness. Infants with
a severe form of SMA frequently succumb to respiratory disease due
to weakness in the muscles that support breathing. Children with
milder forms of SMA live much longer, although they may need
extensive medical support, especially those at the more severe end
of the spectrum. The clinical spectrum of SMA disorders has been
divided into the following five groups. [0005] (a) Type 0 SMA (In
Utero SMA) is the most severe form of the disease and begins before
birth. Usually, the first symptom of Type 0 SMA is reduced movement
of the fetus that can first be observed between 30 and 36 weeks of
pregnancy. After birth, these newborns have little movement and
have difficulties with swallowing and breathing. [0006] (b) Type 1
SMA (Infantile SMA or Werdnig-Hoffmann disease) presents symptoms
between 0 and 6 months. form of SMA is also very severe. Patients
never achieve the ability to sit, and death usually occurs within
the first 2 years without ventilatory support. [0007] (c) Type 2
SMA (Intermediate SMA) has an age of onset at 7-18 months. Patients
achieve the ability to sit unsupported, but never stand or walk
unaided. Prognosis in this group is largely dependent on the degree
of respiratory involvement. [0008] (d) Type 3 SMA (Juvenile SMA or
Kugelberg-Welander disease) is generally diagnosed after 18 months.
Type 3 SMA individuals are able to walk independently at some point
during their disease course but often become wheelchair-bound
during youth or adulthood. [0009] (e) Type 4 SMA (Adult onset SMA).
Weakness usually begins in late adolescence in the tongue, hands,
or feet, then progresses to other areas of the body. The course of
adult SMA is much slower and has little or no impact on life
expectancy.
[0010] The SMN gene has been mapped by linkage analysis to a
complex region in chromosome 5q. In humans, this region contains an
approximately 500 thousand base pairs (kb) inverted duplication
resulting in two nearly identical copies of the SMN gene. SMA is
caused by an inactivating mutation or deletion of the telomeric
copy of the gene (SMN1) in both chromosomes, resulting in the loss
of SMN1 gene function. However, all patients retain the centromeric
copy of the gene (SMN2), and the copy number of the SMN2 gene in
SMA patients generally correlates inversely with the disease
severity; i.e., patients with less severe SMA have more copies of
SMN2. Nevertheless, SMN2 is unable to compensate completely for the
loss of SMN1 function due to alternative splicing of exon 7 caused
by a translationally silent C to T mutation in exon 7. As a result,
the majority of transcripts produced from SMN2 lack exon 7
(.DELTA.7 SMN2), and encode a truncated SMN protein that has an
impaired function and is rapidly degraded.
[0011] The SMN protein is thought to play a role in RNA processing
and metabolism, having a well characterized function of mediating
the assembly of a specific class of RNA-protein complexes termed
snRNPs. SMN may have other functions in motor neurons, however its
role in preventing the selective degeneration of motor neurons is
not well established.
[0012] In most cases, SMA is diagnosed based on clinical symptoms
and by the presence of at least one copy of the SMN1 gene test.
However, in approximately 5% of cases SMA is caused by mutation in
genes other than the inactivation of SMN 1, some known and others
not yet defined. In some cases, when the SMN 1 gene test is not
feasible or does not show any abnormality, other tests such as an
electromyography (EMG) or muscle biopsy may be indicated.
[0013] Medical care for SMA patients at present is limited to
supportive therapy including respiratory, nutritional and
rehabilitation care; there is no drug known to address the
underlying cause of the disease. Current treatment for SMA consists
of prevention and management of the secondary effects of chronic
motor unit loss. The major management issue in Type 1 SMA is the
prevention and early treatment of pulmonary problems, which are the
cause of death in the majority of the cases. While some infants
afflicted with SMA grow to be adults, those with Type 1 SMA have a
life expectancy of less than two years.
[0014] Several mouse models of SMA have been developed. In
particular, the SMN delta exon 7 (.DELTA.7 SMN) model (Le et al.,
Hum. Mol. Genet., 2005, 14:845) carries both the SMN2 gene and
several copies of the .DELTA.7 SMN2 cDNA and recapitulates many of
the phenotypic features of Type 1 SMA. The .DELTA.7 SMN model can
be used for both SMN2 expression studies as well as the evaluation
of motor function and survival. The C/C-allele mouse model (Jackson
Laboratory strain #008714, The Jackson Laboratory, Bar Harbor, Me.)
provides a less severe SMA disease model, with mice having reduced
levels of both SMN2 full length (FL SMN2) mRNA and SMN protein. The
C/C-allele mouse phenotype has the SMN2 gene and a hybrid
mSMN1-SMN2 gene that undergoes alternative splicing, but does not
have overt muscle weakness. The C/C-allele mouse model is used for
SMN2 expression studies.
[0015] As a result of improved understanding of the genetic basis
and pathophysiology of SMA, several strategies for treatment have
been explored, but none have yet demonstrated success in the
clinic.
[0016] Gene replacement of SMN1, using viral delivery vectors, and
cell replacement, using differentiated SMN1.sup.+/+ stem cells,
have demonstrated efficacy in animal models of SMA. More research
is needed to determine the safety and immune response and to
address the requirement for the initiation of treatment at the
neonatal stage before these approaches can be applied to
humans.
[0017] Correction of alternative splicing of SMN2 in cultured cells
has also been achieved using synthetic nucleic acids as therapeutic
agents: (i) antisense oligonucleotides that target sequence
elements in SMN2 pre-mRNA and shift the outcome of the splicing
reaction toward the generation of full length SMN2 mRNA (Passini et
al., Sci. Transl. Med., 2011, 3:72ra18; and, Hua et al., Nature,
2011, 478:123) and (ii) trans-splicing RNA molecules that provide a
fully functional RNA sequence that replace the mutant fragment
during splicing and generate a full length SMN1 mRNA (Coady and
Lorson, J Neurosci., 2010, 30:126).
[0018] Other approaches under exploration include searching for
drugs that increase SMN levels, enhance residual SMN function, or
compensate for its loss. Aminoglycosides have been shown to enhance
expression of a stabilized SMN protein produced from .DELTA.7 SMN2
mRNA by promoting the translational read-through of the aberrant
stop codon, but have poor central nervous system penetration and
are toxic after repeat dosing. Chemotherapeutic agents, such as
aclarubicin, have been shown to increase SMN protein in cell
culture; however, the toxicity profile of these drugs prohibits
long-term use in SMA patients. Some drugs under clinical
investigation for the treatment of SMA include transcription
activators such as histone deacetylase ("HDAC") inhibitors (e.g.,
butyrates, valproic acid, and hydroxyurea), and mRNA stabilizers
(mRNA decapping inhibitor RG3039 from Repligen), the goal being to
increase the amount of total RNA transcribed from the SMN2 gene.
However, the use of the HDAC inhibitors or mRNA stabilizers does
not address the underlying cause of SMA and may result in a global
increase in transcription and gene expression with potential safety
problems in humans.
[0019] In an alternative approach, neuroprotective agents such as
Olesoxime have been chosen for investigation. Such strategies are
not aimed at SMN for the treatment of SMA, but instead are being
explored to protect the SMN-deficient motor neurons from
neurodegeneration.
[0020] A system designed for identifying compounds that increase
the inclusion of exon 7 of SMN into RNA transcribed from the SMN2
gene and certain benzooxazole and benzoisoxazole compounds
identified thereby have been described in International Patent
Application WO2009/151546A1. A system designed for identifying
compounds that cause ribosomal frameshifting to produce a
stabilized SMN protein from .DELTA.7 SMN2 mRNA and certain
isoindolinone compounds identified thereby have been described in
International Patent Application WO2010/019236A1.
[0021] Despite the progress made in understanding the genetic basis
and pathophysiology of SMA, there remains a need to identify
compounds that alter the course of spinal muscular atrophy, one of
the most devastating childhood neurological diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0022] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the invention,
suitable methods and materials are described below.
[0023] All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference in their
entirety.
[0024] The nomenclature used in this Application is based on IUPAC
systematic nomenclature, unless indicated otherwise.
[0025] Any open valency appearing on a carbon, oxygen, sulfur or
nitrogen atom in the structures herein indicates the presence of a
hydrogen, unless indicated otherwise.
[0026] The definitions described herein apply irrespective of
whether the terms in question appear alone or in combination. It is
contemplated that the definitions described herein can be appended
to form chemically-relevant combinations, such as e.g.
"heterocycloalkylaryl", "haloalkylheteroaryl",
"arylalkylheterocycloalkyl", or "alkoxyalkyl". The last member of
the combination is the radical which is binding to the rest of the
molecule. The other members of the combination are attached to the
binding radical in reversed order in respect of the literal
sequence, e.g. the combination arylalkylheterocycloalkyl refers to
a heterocycloalkyl-radical which is substituted by an alkyl which
is substituted by an aryl.
[0027] The term "moiety" refers to an atom or group of chemically
bonded atoms that is attached to another atom or molecule by one or
more chemical bonds thereby forming part of a molecule. For
example, the variables R.sup.1 and R.sup.2 of formula (I) refer to
moieties that are attached to the core structure of formula I by a
covalent bond.
[0028] When indicating the number of substituents, the term "one or
more" refers to the range from one substituent to the highest
possible number of substitution, i.e. replacement of one hydrogen
up to replacement of all hydrogens by substituents.
[0029] The term "optional" or "optionally" denotes that a
subsequently described event or circumstance can but need not
occur, and that the description includes instances where the event
or circumstance occurs and instances in which it does not.
[0030] The term "substituent" denotes an atom or a group of atoms
replacing a hydrogen atom on the parent molecule.
[0031] The term "substituted" denotes that a specified group bears
one or more substituents. Where any group can carry multiple
substituents and a variety of possible substituents is provided,
the substituents are independently selected and need not to be the
same. The term "unsubstituted" means that the specified group bears
no substituents. The term "optionally substituted" means that the
specified group is unsubstituted or substituted by one or more
substituents, independently chosen from the group of possible
substituents. When indicating the number of substituents, the term
"one or more" means from one substituent to the highest possible
number of substitution, i.e. replacement of one hydrogen up to
replacement of all hydrogens by substituents.
[0032] The term "compound(s) of this invention" and "compound(s) of
the present invention" refers to compounds of formula (I) as
disclosed herein and stereoisomers, tautomers, solvates, and salts
(e.g., pharmaceutically acceptable salts) thereof.
[0033] When the compounds of the invention are solids, it is
understood by those skilled in the art that these compounds, and
their solvates and salts, may exist in different solid forms,
particularly different crystal forms, all of which are intended to
be within the scope of the present invention and specified
formulas.
[0034] The term "pharmaceutically acceptable salts" denotes salts
which are not biologically or otherwise undesirable.
Pharmaceutically acceptable salts include both acid and base
addition salts.
[0035] The term "pharmaceutically acceptable acid addition salt"
denotes those pharmaceutically acceptable salts formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and
organic acids selected from aliphatic, cycloaliphatic, aromatic,
araliphatic, heterocyclic, carboxylic, and sulfonic classes of
organic acids such as formic acid, acetic acid, propionic acid,
glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic
acid, malic acid, maleic acid, maloneic acid, succinic acid,
fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic
acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid,
mandelic acid, embonic acid, phenylacetic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicyclic
acid.
[0036] Particular pharmaceutically acceptable salts of the present
invention are salts formed with hydrochloric acid yielding a
hydrochloride, dihydrochloride, or trihydrochloride salt.
[0037] 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. 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 substituents attached to the chiral center
under consideration are ranked in accordance with the Sequence Rule
of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit.
1966, 5, 385; errata 511). 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 designating that the compound is
levorotatory. A compound prefixed with (+) or D is
dextrorotatory.
[0038] The "basicity" of a compound is expressed herein by the
negative decadic logarithm of the acidity constant of the conjugate
acid (pKa=-log Ka). The larger the pKa of the conjugate acid, the
stronger the base (pKa+pKb=14). In this application, an atom or
functional group is denoted "basic" if it is suitable to accept a
proton and if the calculated pKa of its conjugate acid is at least
7, more particularly if the calculated pKa of its conjugate acid is
at least 7.8, most particularly if the calculated pKa of its
conjugate acid is at least 8. pKa values were calculated in-silico
as described in F. Milletti et al., J. Chem. Inf Model (2007)
47:2172-2181.
[0039] The term "halo", "halogen", and "halide" are used
interchangeably herein and denote fluoro, chloro, bromo, or iodo.
Particular examples of halo are fluoro and chloro, most
particularly fluoro.
[0040] The term "alkyl" denotes a monovalent linear or branched
saturated hydrocarbon group of 1 to 7 carbon atoms. In particular
embodiments, alkyl has 1 to 4 carbon atoms, and in more particular
embodiments 1 to 2 carbon atoms. Examples of alkyl include methyl,
ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, or
tert-butyl. Particular examples of alkyl are methyl and ethyl.
[0041] The term "alkoxy" denotes a group of the formula --O--R',
wherein R' is an alkyl group. Examples of alkoxy moieties include
methoxy, ethoxy, isopropoxy, and tert-butoxy. Particular examples
of alkoxy are methoxy and ethoxy.
[0042] The term "haloalkyl" denotes an alkyl group wherein at least
one of the hydrogen atoms of the alkyl group has been replaced by
same or different halogen atoms, particularly fluoro atoms.
Examples of haloalkyl include monofluoro-, difluoro- or
trifluoro-methyl, -ethyl or -propyl, for example
3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl,
fluoromethyl, or trifluoromethyl. The term "perhaloalkyl" denotes
an alkyl group where all hydrogen atoms of the alkyl group have
been replaced by the same or different halogen atoms. Particular
example of haloalkyl is trifluoromethyl.
[0043] The term "haloalkoxy" denotes an alkoxy group wherein at
least one of the hydrogen atoms of the alkoxy group has been
replaced by same or different halogen atoms, particularly fluoro
atoms. Examples of haloalkoxyl include monofluoro-, difluoro- or
trifluoro-methoxy, -ethoxy or -propoxy, for example
3,3,3-trifluoropropoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy,
fluoromethoxy, or trifluoromethoxy. The term "perhaloalkoxy"
denotes an alkoxy group where all hydrogen atoms of the alkoxy
group have been replaced by the same or different halogen atoms.
Particular example of haloalkoxy is 2,2,2-trifluoroethoxy.
[0044] The term "bicyclic ring system" denotes two rings which are
fused to each other via a common single or double bond (annelated
bicyclic ring system), via a sequence of three or more common atoms
(bridged bicyclic ring system) or via a common single atom (spiro
bicyclic ring system). Bicyclic ring systems can be saturated,
partially unsaturated, unsaturated or aromatic. Bicyclic ring
systems can comprise heteroatoms selected from N, O and S.
[0045] The term "cycloalkyl" denotes a monovalent saturated
monocyclic hydrocarbon group of 3 to 7 ring carbon atoms. Examples
for cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl,
cyclohexyl or cycloheptyl. Particular example for cycloalkyl is
cyclopropyl.
[0046] The term "heterocycloalkyl" denotes a monovalent saturated
or partly unsaturated mono- or bicyclic ring system of 3 to 9 ring
atoms, comprising 1, 2, or 3 ring heteroatoms selected from N, O
and S, the remaining ring atoms being carbon. In particular
embodiments, heterocycloalkyl is a monovalent saturated monocyclic
ring system of 4 to 7 ring atoms, comprising 1, 2, or 3 ring
heteroatoms selected from N, O and S, the remaining ring atoms
being carbon. Examples for monocyclic saturated heterocycloalkyl
are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl,
tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl,
imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl,
piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl,
morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl,
azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for
bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl,
quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,
9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or
3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturated
heterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl,
tetrahydro-pyridinyl, or dihydropyranyl. Particular examples of
heterocycloalkyl are saturated or partially unsaturated mono- or
bicyclic 4 to 9-membered heterocycloalkyl comprising one or two
ring nitrogen atoms, the remaining ring atoms being carbon.
Particular examples for monocyclic saturated heterocycloalkyl are
piperidinyl and piperazinyl. Particular example for monocyclic
partially unsaturated heterocycloalkyl is
1,2,3,6-tetrahydropyridin-4-yl. Particular examples for bicyclic
saturated heterocycloalkyl are hexahydropyrrolo[1,2-a]pyrazin-2-yl,
hexahydropyrrolo[3,4-c]pyrrol-2-yl, and
2,6-diazaspiro[3.3]heptan-2-yl. Most particular examples for
heterocycloalkyl is piperazinyl.
[0047] The term "located opposite of the site of attachment"
denotes the position of an atom in a cyclic ring system. If the
point of attachment of a monocyclic ring to the rest of the
molecular backbone is termed position 1, then "located opposite of
the site of attachment" denotes position 3 for a monocylic
4-membered ring, positions 3 or 4 for a monocyclic 5-membered ring,
position 4 for a monocylic 6-membered ring, and positions 4 or 5
for a monocyclic 7-membered ring. For bicyclic ring systems,
"located opposite of the site of attachment" denotes a ring atom of
the second fused ring (including bridgehead atoms).
[0048] The term "aromatic" denotes the conventional idea of
aromaticity as defined in the literature, in particular in
IUPAC--Compendium of Chemical Terminology, 2nd, A. D. McNaught
& A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford
(1997).
[0049] The term "heteroaryl" denotes a monovalent aromatic
heterocyclic mono- or bicyclic ring system of 5 to 12 ring atoms,
comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the
remaining ring atoms being carbon. Examples of heteroaryl moieties
include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl,
thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl,
pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,
triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl,
isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl,
benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl,
benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl,
benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl,
or quinoxalinyl. Particular examples for heteroaryl are bicyclic
9-membered heteroaryl comprising 2 or 3 heteroatoms selected from N
or O. More particular examples for heteroaryl are
imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-6-yl, and
benzo[d]oxazol-6-yl. Most particular heteroaryl is
imidazo[1,2-a]pyridin-6-yl.
[0050] The term "alkylene" denotes a linear saturated divalent
hydrocarbon group of 2 to 7 carbon atoms or a divalent branched
saturated divalent hydrocarbon group of 3 to 7 carbon atoms.
Examples of alkylene groups include methylene, ethylene, propylene,
2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene.
Particular examples of alkylene are methylene and ethylene.
[0051] The term "protecting group" denotes the group which
selectively blocks a reactive site in a multifunctional compound
such that a chemical reaction can be carried out selectively at
another unprotected reactive site in the meaning conventionally
associated with it in synthetic chemistry. Protecting groups can be
removed at the appropriate point. Exemplary protecting groups are
amino-protecting groups, carboxy-protecting groups or
hydroxy-protecting groups.
[0052] The term "amino-protecting group" denotes groups intended to
protect an amino group and includes benzyl, benzyloxycarbonyl
(carbobenzyloxy, CBZ), Fmoc (9-Fluorenylmethyloxycarbonyl),
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
tert-butoxycarbonyl (BOC), and trifluoroacetyl. Particular
amino-protecting group is tert-butoxycarbonyl (BOC). Further
examples of these groups are found in T. W. Greene and P. G. M.
Wuts, "Protective Groups in Organic Synthesis", 2nd ed., John Wiley
& Sons, Inc., New York, N.Y., 1991, chapter 7; E. Haslam,
"Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed.,
Plenum Press, New York, N.Y., 1973, Chapter 5, and T. W. Greene,
"Protective Groups in Organic Synthesis", John Wiley and Sons, New
York, N.Y., 1981. The term "protected amino group" refers to an
amino group substituted by an amino-protecting groups.
[0053] The term "deprotection" or "deprotecting" denotes the
process by which a protective group is removed after the selective
reaction is completed. Deprotecting reagents include acids, bases
or hydrogen, in particular potassium or sodium carbonates, lithium
hydroxide in alcoholic solutions, zinc in methanol, acetic acid,
trifluoroacetic acid, palladium catalysts, or boron tribromide.
Most particular deprotecting reagent is hydrochloric acid.
[0054] The term "active pharmaceutical ingredient" (or "API")
denotes the compound or molecule in a pharmaceutical composition
that has a particular biological activity.
[0055] The term "pharmaceutical composition" refers to a
preparation which is in such form as to permit the biological
activity of an active ingredient contained therein to be effective,
and which contains no additional components which are unacceptably
toxic to a subject to which the composition would be
administered.
[0056] The term "pharmaceutically acceptable" denotes an attribute
of a material which is useful in preparing a pharmaceutical
composition that is generally safe, non-toxic, and neither
biologically nor otherwise undesirable and is acceptable for
veterinary as well as human pharmaceutical use.
[0057] The term "pharmaceutically acceptable excipient" denotes any
ingredient having no therapeutic activity and being non-toxic such
as disintegrators, binders, fillers, solvents, buffers, tonicity
agents, stabilizers, antioxidants, surfactants or lubricants used
in formulating pharmaceutical products.
[0058] A "pharmaceutically acceptable carrier" refers to an
ingredient in a pharmaceutical composition, other than an active
ingredient, which is nontoxic to a subject. A pharmaceutically
acceptable carrier includes, but is not limited to, a buffer,
excipient, stabilizer, or preservative.
[0059] An "individual" or "subject" is a mammal. Mammals include,
but are not limited to, domesticated animals (e.g., cows, sheep,
cats, dogs, and horses), primates (e.g., humans and non-human
primates such as monkeys), rabbits, and rodents (e.g., mice and
rats). In certain embodiments, the individual or subject is a
human. In a particular embodiment of the invention the subject is a
human with spinal muscular atrophy (SMA). In another specific
embodiment, the subject is a human with SMA caused by an
inactivating mutation or deletion in the SMN1 gene on both
chromosomes, resulting in a loss of SMN1 gene function.
[0060] The term "spinal muscular atrophy" (or SMA) relates to a
disease caused by an inactivating mutation or deletion in the SMN1
gene on both chromosomes, resulting in a loss of SMN1 gene
function.
[0061] Symptoms of SMA include muscle weakness, poor muscle tone,
weak cry, weak cough, limpness or a tendency to flop, difficulty
sucking or swallowing, difficulty breathing, accumulation of
secretions in the lungs or throat, clenched fists with sweaty hand,
flickering/vibrating of the tongue, head often tilted to one side,
even when lying down, legs that tend to be weaker than the arms,
legs frequently assuming a "frog legs" position, feeding
difficulties, increased susceptibility to respiratory tract
infections, bowel/bladder weakness, lower-than-normal weight,
inability to sit without support, failure to walk, failure to
crawl, and hypotonia, areflexia, and multiple congenital
contractures (arthrogryposis) associated with loss of anterior hom
cells.
[0062] The term "treating spinal muscular atrophy (SMA)" or
"treatment of spinal muscular atrophy (SMA)" includes one or more
of the following effects: (i) reduction or amelioration of the
severity of SMA; (ii) delay of the onset of SMA; (iii) inhibition
of the progression of SMA; (iv) reduction of hospitalization of a
subject; (v) reduction of hospitalization length for a subject;
(vi) increase of the survival of a subject; (vii) improvement of
the quality of life of a subject; (viii) reduction of the number of
symptoms associated with SMA; (ix) reduction of or amelioration of
the severity of one or more symptoms associated with SMA; (x)
reduction of the duration of a symptom associated with SMA; (xi)
prevention of the recurrence of a symptom associated with SMA;
(xii) inhibition of the development or onset of a symptom of SMA;
and/or (xiii) inhibition of the progression of a symptom associated
with SMA.
[0063] More particular, "treating SMA" denotes one or more of the
following beneficial effects: (i) a reduction in the loss of muscle
strength; (ii) an increase in muscle strength; (iii) a reduction in
muscle atrophy; (iv) a reduction in the loss of motor function; (v)
an increase in motor neurons; (vii) a reduction in the loss of
motor neurons; (viii) protection of SMN deficient motor neurons
from degeneration; (ix) an increase in motor function; (x) an
increase in pulmonary function; and/or (xi) a reduction in the loss
of pulmonary function.
[0064] In detail, "treating SMA" results in the functional ability
or helps retain the functional ability for a human infant or a
human toddler to sit up unaided or for a human infant, a human
toddler, a human child or a human adult to stand up unaided, to
walk unaided, to run unaided, to breathe unaided, to tum during
sleep unaided, or to swallow unaided.
[0065] An "effective amount" of an agent, e.g., a pharmaceutical
composition, refers to an amount effective, at dosages and for
periods of time necessary, to achieve the desired therapeutic or
prophylactic result.
[0066] The term "preventing" or "prevention" of a disease state
denotes causing the clinical symptoms of the disease state not to
develop in a subject that can be exposed to or predisposed to the
disease state, but does not yet experience or display symptoms of
the disease state.
[0067] The term "EC.sub.1.5.times. concentration for production of
full length SMN2 minigene mRNA" (or "EC.sub.1.5.times. minigene")
is defined as that concentration of test compound that is effective
in increasing the amount of full length SMN2 minigene mRNA to a
level 1.5-fold greater relative to that in vehicle-treated
cells.
[0068] The term "EC.sub.1.5.times. concentration for SMN protein
expression" (or "EC.sub.1.5.times. SMN protein") is defined as that
concentration of test compound that is effective in producing 1.5
times the amount of SMN protein in an SMA patient fibroblast cell
compared to the amount produced from the vehicle control.
[0069] In detail, the present invention relates to compounds of
formula (I)
##STR00003##
[0070] wherein [0071] X is N or CR.sup.3; [0072] Y is N or
CR.sup.4; with the proviso that not both X and Y are N; [0073] A is
a bicyclic 9-membered heteroaryl comprising two or three
heteroatoms independently selected from N or O, wherein A can be
optionally substituted with one, two or three R.sup.5; [0074] B is
a saturated or partially unsaturated mono- or bicyclic 4 to
9-membered heterocycloalkyl comprising one or two ring nitrogen
atoms, the remaining ring atoms being carbon, wherein B can be
optionally substituted with one, two or three R.sup.6; [0075]
R.sup.1 is hydrogen, halo, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl,
C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy; [0076] R.sup.2 is
hydrogen, halo, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl,
C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy; [0077] R.sup.3 is
hydrogen, halo, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl,
C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy; [0078] R.sup.4 is
hydrogen, halo, C.sub.1-7-alkyl, C.sub.1-7-haloalkyl,
C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy; [0079] each R.sup.5 is
independently selected from halo, cyano, C.sub.1-7-alkyl,
C.sub.1-7-haloalkyl or C.sub.3-7-cycloalkyl; [0080] each R.sup.6 is
independently selected from C.sub.1-7-alkyl, or two R.sup.6
together form a C.sub.2-7-alkylene; [0081] and pharmaceutically
acceptable salts thereof.
[0082] Particular embodiments of the present invention are
compounds of formula (I) and pharmaceutically acceptable salts
thereof.
[0083] Further, it is to be understood that every embodiment
relating to a specific A, B, X, Y, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 or R.sup.6 as disclosed herein may be combined
with any other embodiment relating to another A, B, X, Y, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5 or R.sup.6 as disclosed
herein.
[0084] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is selected from the group of
imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyridinyl, and
benzo[d]oxazolyl, which can be optionally substituted with one, two
or three R.sup.5.
[0085] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is selected from the group of
imidazo[1,2-a]pyrazin-2-yl, imidazo[1,2-a]pyridin-6-yl, and
benzo[d]oxazol-6-yl, which can be optionally substituted with one,
two or three R.sup.5.
[0086] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is selected from the group of
imidazo[1,2-a]pyrazin-2-yl substituted with two C.sub.1-7-alkyl,
imidazo[1,2-a]pyridin-6-yl substituted with one or two
C.sub.1-7-alkyl, imidazo[1,2-a]pyridin-6-yl substituted with one
C.sub.1-7-alkyl and one halo, imidazo[1,2-a]pyridin-6-yl
substituted with one C.sub.1-7-alkyl and one C.sub.1-7-haloalkyl,
benzo[d]oxazol-6-yl substituted with one C.sub.1-7-alkyl, and
benzo[d]oxazol-6-yl substituted with one C.sub.1-7-alkyl and one
halo.
[0087] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is imidazo[1,2-a]pyridinyl
which can be optionally substituted with one or two R.sup.5.
[0088] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is imidazo[1,2-a]pyridin-6-yl
substituted with one C.sub.1-7-alkyl and one halo.
[0089] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is selected from
2-methylbenzo[d]oxazol-6-yl, 4-fluoro-2-methylbenzo[d]oxazol-6-yl,
6,8-dimethylimidazo[1,2-a]pyrazin-2-yl,
2-methylimidazo[1,2-a]pyridin-6-yl,
2,7-dimethylimidazo[1,2-a]pyridin-6-yl,
2,8-dimethylimidazo[1,2-a]pyridin-6-yl,
2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl,
8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl, and
8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl.
[0090] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is selected from
8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl and
8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl.
[0091] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.5 is independently
selected from halo, C.sub.1-7-alkyl, or C.sub.1-7-haloalkyl.
[0092] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.5 is independently
selected from methyl, fluoro, chloro, and trifluoromethyl.
[0093] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is substituted by two R.sup.5
wherein one R.sup.5 is methyl and the other R.sup.5 is fluoro or
chloro.
[0094] A particular embodiment of the present invention relates to
compounds of formula (I), wherein A is selected from the group
of
##STR00004##
wherein R.sup.51, R.sup.52 and R.sup.53 are independently selected
from the group of hydrogen, halo, cyano, C.sub.1-7-alkyl,
C.sub.1-7-haloalkyl and C.sub.3-7-cycloalkyl.
[0095] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.51, R.sup.52 and R.sup.53
are independently selected from the group of hydrogen, methyl,
fluoro, chloro, and trifluoromethyl.
[0096] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.51 is selected from
hydrogen and C.sub.1-7-alkyl.
[0097] A more particular embodiment of the present invention
relates to compounds of formula (I), wherein R.sup.51 is selected
from hydrogen and C.sub.1-2-alkyl.
[0098] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.52 is independently
selected from hydrogen, halo, cyano, C.sub.1-7-alkyl,
C.sub.1-7-haloalkyl and C.sub.3-7 cycloalkyl.
[0099] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.52 is independently
selected from hydrogen, halo, cyano, C.sub.1-2-alkyl,
C.sub.1-2-haloalkyl and cyclopropyl.
[0100] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.52 is independently
selected from hydrogen and fluoro.
[0101] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.53 is independently
selected from hydrogen, chloro, C.sub.1-7-alkyl,
C.sub.1-7-haloalkyl and C.sub.3-7 cycloalkyl.
[0102] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.53 is independently
selected from hydrogen, chloro, C.sub.1-2-alkyl,
C.sub.1-2-haloalkyl and cyclopropyl.
[0103] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B as defined herein is further
characterized in that one ring nitrogen atoms is basic.
[0104] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B as defined herein is further
characterized in that its one, two or three optional substituent(s)
R.sup.6 are attached at and/or directly adjacent to the basic ring
nitrogen atoms.
[0105] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B is selected from
1,2,3,6-tetrahydropyridinyl, 2,6-diazaspiro[3.3]heptanyl,
hexahydropyrrolo[3,4-c]pyrrolyl, hexahydropyrrolo[1,2-a]pyrazinyl,
piperazinyl, and piperidinyl, wherein each can be optionally
substituted with one, two or three R.sup.6.
[0106] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B is selected from
1,2,3,6-tetrahydropyridin-4-yl, 2,6-diazaspiro[3.3]heptan-2-yl,
hexahydropyrrolo[3,4-c]pyrrol-2-yl,
hexahydropyrrolo[1,2-a]pyrazin-2-yl, piperazin-1-yl, and
piperidin-4-yl, wherein each can be optionally substituted with
one, two or three R.sup.6.
[0107] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B is selected from
1,2,3,6-tetrahydropyridin-4-yl, and piperazin-1-yl, wherein each
can be optionally substituted with one, two or three R.sup.6.
[0108] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B is piperazin-1-yl optionally
substituted with one, two or three R.sup.6.
[0109] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B is selected from
piperazin-1-yl, 3-methyl-piperazin-1-yl, and
3,3-dimethylpiperazin-1-yl.
[0110] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.6 is C.sub.1-7
alkyl.
[0111] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.6 is independently
selected from methyl, and ethyl.
[0112] A particular embodiment of the present invention relates to
compounds of formula (I), wherein each R.sup.6 is independently
selected from methyl.
[0113] A particular embodiment of the present invention relates to
compounds of formula (I), wherein B is selected from the group
of
##STR00005##
wherein R.sup.61, R.sup.62, R.sup.63 and R.sup.64 are independently
selected from hydrogen or C.sub.1-7-alkyl, or wherein two of
R.sup.61, R.sup.62 and R.sup.63 together are forming a
C.sub.2-7-alkylene.
[0114] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.61, R.sup.62, R.sup.63 and
R.sup.64 are independently selected from hydrogen, methyl, and
ethyl.
[0115] A particular embodiment of the present invention relates to
compounds of formula (I), wherein X is CR.sup.3 and Y is CR.sup.4,
or X is N and Y is CR.sup.4, or X is CR.sup.3 and Y is N.
[0116] A particular embodiment of the present invention relates to
compounds of formula (I), wherein X is CR.sup.3 and Y is
CR.sup.4.
[0117] A particular embodiment of the present invention relates to
compounds of formula (I), wherein X is N and Y is CR.sup.4.
[0118] A particular embodiment of the present invention relates to
compounds of formula (I), wherein X is CR.sup.3 and Y is N.
[0119] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.1 is hydrogen, halo,
C.sub.1-7-alkoxy or C.sub.1-7-haloalkoxy.
[0120] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.1 is hydrogen, fluoro,
methoxy, ethoxy or trifluoroethoxy.
[0121] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.1 is hydrogen.
[0122] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.2 is hydrogen, halo, or
C.sub.1-7-alkyl.
[0123] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.2 is hydrogen, fluoro or
methyl.
[0124] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.2 is hydrogen.
[0125] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.3 is hydrogen or halo.
[0126] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.3 is hydrogen or
fluoro.
[0127] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.3 is hydrogen.
[0128] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.4 is hydrogen, halo or
C.sub.1-7-alkoxy.
[0129] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.4 is hydrogen or halo.
[0130] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.4 is hydrogen, fluoro,
methoxy, ethoxy or trifluoroethoxy.
[0131] A particular embodiment of the present invention relates to
compounds of formula (I), wherein R.sup.4 is hydrogen or
fluoro.
[0132] Particular compounds of formula (I) of the present invention
are those selected from the group consisting of: [0133]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;
[0134]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazi-
n-1-yl)benzamide; [0135]
N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-y-
l)-benzamide; [0136]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin--
1-yl)benzamide; [0137]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide; [0138]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nico-
tinamide; [0139]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)-
nicotinamide; [0140]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicot-
inamide; [0141]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)pico-
linamide; [0142]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)-
picolinamide; [0143]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide-
; [0144]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-
-yl)nicotinamide; [0145]
6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nico-
tinamide; [0146]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;
[0147]
6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a-
]pyridin-6-yl)nicotinamide; [0148]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)-
nicotinamide; [0149]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)pico-
linamide; [0150]
rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0151]
N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-
-yl)nicotinamide: [0152]
rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methy-
lpiperazin-1-yl)nicotinamide; [0153]
(S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluorom-
ethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide; [0154]
6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-
-a]pyridin-6-yl)nicotinamide; [0155]
6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)ni-
cotinamide; [0156]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicoti-
namide; [0157]
(S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)nicotinamide; [0158]
N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;
[0159]
rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-
-yl)-nicotinamide; [0160]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;
[0161]
rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0162]
4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)be-
nzamide; [0163]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimida-
zo[1,2-a]pyridin-6-yl)benzamide; [0164]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl-
)nicotinamide; [0165]
(S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrro-
lo[1,2-a]pyrazin-2-yl-benzamide; [0166]
(R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl)benzamide; [0167]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(t-
rifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide; [0168]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de; [0169]
rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-me-
thylpiperazin-1-yl)benzamide; [0170]
rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)be-
nzamide; [0171]
rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0172]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-y-
l)benzamide; [0173]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotin-
amide; [0174]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide; [0175]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin--
1-yl)picolinamide; [0176]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de; [0177]
rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-
)-4-(3-methylpiperazin-1-yl)benzamide; [0178]
rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide; [0179]
rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylp-
iperazin-1-yl)nicotinamide; [0180]
rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylp-
iperazin-1-yl)picolinamide; [0181]
rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide; [0182]
(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0183]
(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0184]
rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide; [0185]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylp-
iperazin-1-yl)nicotinamide; [0186]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylp-
iperazin-1-yl)benzamide; [0187]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide; [0188]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylp-
iperazin-1-yl)picolinamide; [0189]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-met-
hylpiperazin-1-yl)benzamide; [0190]
2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benza-
mide; [0191]
2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(pi-
perazin-1-yl)benzamide; [0192]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyri-
din-4-yl)benzamide; [0193]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide; [0194]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide; [0195]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-
picolinamide; [0196]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1--
yl)nicotinamide; [0197]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0198]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-y-
l)benzamide; [0199]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-y-
l)nicotinamide; [0200]
4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0201]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1--
yl)nicotinamide; [0202]
4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0203]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2-
,2-trifluoroethoxy)nicotinamide; [0204]
2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0205]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2-
,2-trifluoroethoxy)nicotinamide; [0206]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0207]
6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin--
6-yl)-2-methoxynicotinamide; [0208]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0209]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-
nicotinamide; [0210]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotina-
mide; [0211]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotin-
amide; [0212]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl-
)nicotinamide; [0213]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-y-
l)benzamide; [0214]
rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-
nicotinamide; [0215] and pharmaceutically acceptable salts
thereof.
[0216] Particular compounds of formula (I) of the present invention
are those selected from the group consisting of: [0217]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;
[0218]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazi-
n-1-yl)benzamide; [0219]
N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-y-
l)-benzamide; [0220]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin--
1-yl)benzamide; [0221]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide; [0222]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nico-
tinamide; [0223]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)-
nicotinamide; [0224]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicot-
inamide; [0225]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)pico-
linamide; [0226]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)-
picolinamide; [0227]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide-
; [0228]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-
-yl)nicotinamide; [0229]
6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nico-
tinamide; [0230]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;
[0231]
6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a-
]pyridin-6-yl)nicotinamide hydrochloride; [0232]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)-
nicotinamide hydrochloride: [0233]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)pico-
linamide; [0234]
rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0235]
N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-
-yl)nicotinamide: [0236]
rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methy-
lpiperazin-1-yl)nicotinamide; [0237]
(S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluorom-
ethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide; [0238]
6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-
-a]pyridin-6-yl)nicotinamide; [0239]
6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)ni-
cotinamide; [0240]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicoti-
namide; [0241]
(S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)nicotinamide; [0242]
N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;
[0243]
rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-
-yl)-nicotinamide; [0244]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;
[0245]
rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0246]
4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)be-
nzamide; [0247]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimida-
zo[1,2-a]pyridin-6-yl)benzamide; [0248]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl-
)nicotinamide; [0249]
(S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrro-
lo[1,2-a]pyrazin-2-yl-benzamide; [0250]
(R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl)benzamide; [0251]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(t-
rifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide; [0252]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de hydrochloride; [0253]
rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide dihydrochloride; [0254]
rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)be-
nzamide dihydrochloride; [0255]
rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide dihydrochloride; [0256]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-y-
l)benzamide dihydrochloride; [0257]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotin-
amide dihydrochloride; [0258]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide dihydrochloride; [0259]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin--
1-yl)picolinamide dihydrochloride; [0260]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de hydrochloride; [0261]
rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide hydrochloride; [0262]
rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide hydrochloride; [0263]
rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylp-
iperazin-1-yl)nicotinamide hydrochloride; [0264]
rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylp-
iperazin-1-yl)picolinamide hydrochloride; [0265]
rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide hydrochloride; [0266]
(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide hydrochloride; [0267]
(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide hydrochloride; [0268]
rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide dihydrochloride; [0269]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylp-
iperazin-1-yl)nicotinamide hydrochloride; [0270]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylp-
iperazin-1-yl)benzamide dihydrochloride; [0271]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide dihydrochloride; [0272]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylp-
iperazin-1-yl)picolinamide dihydrochloride; [0273]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-met-
hylpiperazin-1-yl)benzamide trihydrochloride; [0274]
2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benza-
mide; [0275]
2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(pi-
perazin-1-yl)benzamide; [0276]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyri-
din-4-yl)benzamide hydrochloride; [0277]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide hydrochloride; [0278]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide dihydrochloride; [0279]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-
picolinamide dihydrochloride; [0280]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1--
yl)nicotinamide; [0281]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0282]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-y-
l)benzamide; [0283]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-y-
l)nicotinamide; [0284]
4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0285]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1--
yl)nicotinamide; [0286]
4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0287]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2-
,2-trifluoroethoxy)nicotinamide; [0288]
2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0289]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2-
,2-trifluoroethoxy)nicotinamide; [0290]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0291]
6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin--
6-yl)-2-methoxynicotinamide; [0292]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0293]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-
nicotinamide hydrochloride; [0294]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotina-
mide; [0295]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotin-
amide dihydrochloride; [0296]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl-
)nicotinamide; [0297]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-y-
l)benzamide hydrochloride; [0298]
rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-
nicotinamide; [0299] and pharmaceutically acceptable salts
thereof.
[0300] Particular compounds of formula (I) of the present invention
are those selected from the group consisting of: [0301]
rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0302]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-y-
l)benzamide; [0303]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotin-
amide; [0304]
rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylp-
iperazin-1-yl)picolinamide; [0305]
rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide; [0306]
(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0307]
(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0308]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylp-
iperazin-1-yl)benzamide; [0309]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylp-
iperazin-1-yl)picolinamide; [0310]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide; [0311]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide; [0312]
4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0313]
4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0314]
2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0315]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0316]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0317] and pharmaceutically acceptable
salts thereof.
[0318] A particular embodiment of the present invention relates to
compounds of formula (I')
##STR00006##
[0319] wherein A, B, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as
described herein.
[0320] Particular compounds of formula (I') of the present
invention are those selected from the group consisting of: [0321]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;
[0322]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazi-
n-1-yl)benzamide; [0323]
N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-y-
l)-benzamide; [0324]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin--
1-yl)benzamide; [0325]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide; [0326]
rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0327]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;
[0328]
rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0329]
4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)be-
nzamide; [0330]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimida-
zo[1,2-a]pyridin-6-yl)benzamide; [0331]
(S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrro-
lo[1,2-a]pyrazin-2-yl-benzamide; [0332]
(R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl)benzamide; [0333]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(t-
rifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide; [0334]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de; [0335]
rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-me-
thylpiperazin-1-yl)benzamide; [0336]
rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)be-
nzamide; [0337]
rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0338]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-y-
l)benzamide; [0339]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de; [0340]
rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-
)-4-(3-methylpiperazin-1-yl)benzamide; [0341]
rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide; [0342]
rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide; [0343]
(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0344]
(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0345]
rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide; [0346]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylp-
iperazin-1-yl)benzamide; [0347]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-met-
hylpiperazin-1-yl)benzamide; [0348]
2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benza-
mide; [0349]
2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(pi-
perazin-1-yl)benzamide; [0350]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyri-
din-4-yl)benzamide; [0351]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide; [0352]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-y-
l)benzamide; [0353]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-y-
l)benzamide; [0354] and pharmaceutically acceptable salts
thereof.
[0355] A particular embodiment of the present invention relates to
compounds of formula (I'')
##STR00007##
[0356] wherein A, B, R.sup.1, R.sup.2 and R.sup.4 are as described
herein.
[0357] Particular compounds of formula (I'') of the present
invention are those selected from the group consisting of: [0358]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nico-
tinamide; [0359]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)-
nicotinamide; [0360]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicot-
inamide; [0361]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nico-
tinamide; [0362]
6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nico-
tinamide; [0363]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;
[0364]
6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a-
]pyridin-6-yl)nicotinamide; [0365]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)-
nicotinamide; [0366]
N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-
-yl)nicotinamide; [0367]
rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methy-
lpiperazin-1-yl)nicotinamide; [0368]
(S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluorom-
ethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide; [0369]
6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-
-a]pyridin-6-yl)nicotinamide; [0370]
6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)ni-
cotinamide; [0371]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicoti-
namide; [0372]
(S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)nicotinamide; [0373]
N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;
[0374]
rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-
-yl)-nicotinamide; [0375]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl-
)nicotinamide; [0376]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotin-
amide; [0377]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide; [0378]
rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylp-
iperazin-1-yl)nicotinamide; [0379]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylp-
iperazin-1-yl)nicotinamide; [0380]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide; [0381]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide; [0382]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1--
yl)nicotinamide; [0383]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0384]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-y-
l)nicotinamide; [0385]
4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0386]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1--
yl)nicotinamide; [0387]
4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0388]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2-
,2-trifluoroethoxy)nicotinamide; [0389]
2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0390]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2-
,2-trifluoroethoxy)nicotinamide; [0391]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0392]
6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin--
6-yl)-2-methoxynicotinamide; [0393]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0394]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-
nicotinamide; [0395]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotina-
mide; [0396]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotin-
amide; [0397]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl-
)nicotinamide; [0398]
rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-
nicotinamide; [0399] and pharmaceutically acceptable salts
thereof.
[0400] A particular embodiment of the present invention relates to
compounds of formula (I''')
##STR00008##
[0401] wherein A, B, R.sup.1, R.sup.2 and R.sup.3 are as described
herein.
[0402] Particular compounds of formula (I''') of the present
invention are those selected from the group consisting of: [0403]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)pico-
linamide; [0404]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)-
picolinamide; [0405]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide-
; [0406]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-
-yl)picolinamide; [0407]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin--
1-yl)picolinamide; [0408]
rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylp-
iperazin-1-yl)picolinamide; [0409]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylp-
iperazin-1-yl)picolinamide; [0410]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-
picolinamide; [0411] and pharmaceutically acceptable salts
thereof.
[0412] A particular embodiment of the present invention relates to
compounds of formula (I.sup.a)
##STR00009##
[0413] wherein B, X, Y, R.sup.1, R.sup.2, R.sup.51 and R.sup.52 are
as described herein.
[0414] Particular compounds of formula (I.sup.a) of the present
invention are those selected from the group consisting of: [0415]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide;
[0416]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(3-methylpiperazi-
n-1-yl)benzamide; [0417]
N-(6,8-Dimethyl-imidazo[1,2-a]pyrazin-2-yl)-4-((S)-3-methyl-piperazin-1-y-
l)-benzamide; [0418]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(4-methylpiperazin--
1-yl)benzamide; [0419]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide; [0420]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-methylpiperazin-1-yl)nico-
tinamide; [0421]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(3-methylpiperazin-1-yl)-
nicotinamide; [0422]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-6-(4-ethylpiperazin-1-yl)nicot-
inamide; [0423]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(4-methylpiperazin-1-yl)pico-
linamide; [0424]
rac-N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(3-methylpiperazin-1-yl)-
picolinamide; [0425]
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-5-(piperazin-1-yl)picolinamide-
; [0426] and pharmaceutically acceptable salts thereof.
[0427] A particular embodiment of the present invention relates to
compounds of formula (I.sup.b)
##STR00010##
[0428] wherein B, X, Y, R.sup.1, R.sup.2, R.sup.51, R.sup.52 and
R.sup.53 are as described herein.
[0429] Particular compounds of formula (I.sup.b) of the present
invention are those selected from the group consisting of: [0430]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nico-
tinamide; [0431]
6-(3,3-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nico-
tinamide; [0432]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotinamide;
[0433]
6-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-(2-methylimidazo[1,2-a-
]pyridin-6-yl)nicotinamide; [0434]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(2,6-diazaspiro[3.3]heptan-2-yl)-
nicotinamide; [0435]
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin-1-yl)pico-
linamide; [0436]
rac-2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0437]
N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-
-yl)nicotinamide; [0438]
rac-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-6-(3-methy-
lpiperazin-1-yl)nicotinamide; [0439]
(S)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(trifluorom-
ethyl)imidazo[1,2-a]pyridin-6-yl)nicotinamide; [0440]
6-(3,5-dimethylpiperazin-1-yl)-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-
-a]pyridin-6-yl)nicotinamide; [0441]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimida-
zo[1,2-a]pyridin-6-yl)benzamide; [0442]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(4-methylpiperazin-1-yl-
)nicotinamide; [0443]
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methyl-8-(t-
rifluoromethyl)imidazo[1,2-a]pyridin-6-yl)benzamide; [0444]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de; [0445]
rac-N-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-me-
thylpiperazin-1-yl)benzamide; [0446]
rac-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0447]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-y-
l)benzamide; [0448]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)nicotin-
amide; [0449]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide; [0450]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylpiperazin--
1-yl)picolinamide; [0451]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de; [0452]
rac-2,3-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl-
)-4-(3-methylpiperazin-1-yl)benzamide; [0453]
rac-2,5-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide; [0454]
rac-5-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylp-
iperazin-1-yl)nicotinamide; [0455]
rac-3-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-(3-methylp-
iperazin-1-yl)picolinamide; [0456]
rac-2,6-difluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-met-
hylpiperazin-1-yl)benzamide; [0457]
(S)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0458]
(R)-2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(3-methylp-
iperazin-1-yl)benzamide; [0459]
rac-N-(2,7-dimethylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylpipera-
zin-1-yl)benzamide; [0460]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-fluoro-6-(3-methylp-
iperazin-1-yl)nicotinamide; [0461]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-fluoro-4-(3-methylp-
iperazin-1-yl)benzamide; [0462]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin--
1-yl)nicotinamide; [0463]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-fluoro-5-(3-methylp-
iperazin-1-yl)picolinamide; [0464]
rac-N-(8-chloro-2-methylimidazo[1,2-a]pyridin-6-yl)-2,6-difluoro-4-(3-met-
hylpiperazin-1-yl)benzamide; [0465]
2-fluoro-N-(2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)-4-(pi-
perazin-1-yl)benzamide; [0466]
2-fluoro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetrahydropyri-
din-4-yl)benzamide; [0467]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide; [0468]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide; [0469]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)-
picolinamide; [0470]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1--
yl)nicotinamide; [0471]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0472]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-3-methyl-4-(piperazin-1-y-
l)benzamide; [0473]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-5-methyl-6-(piperazin-1-y-
l)nicotinamide; [0474]
4-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0475]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(piperazin-1--
yl)nicotinamide; [0476]
4-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0477]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-4-(2,2-
,2-trifluoroethoxy)nicotinamide; [0478]
2-ethoxy-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-y-
l)nicotinamide; [0479]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperazin-1-yl)-2-(2,2-
,2-trifluoroethoxy)nicotinamide; [0480]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0481]
6-(3,3-dimethylpiperazin-1-yl)-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin--
6-yl)-2-methoxynicotinamide; [0482]
rac-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-methoxy-6-(3-methyl-
piperazin-1-yl)nicotinamide; [0483]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-
nicotinamide; [0484]
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotina-
mide; [0485]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotin-
amide; [0486]
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl-
)nicotinamide; [0487]
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-y-
l)benzamide; [0488]
rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-
nicotinamide; [0489] and pharmaceutically acceptable salts
thereof.
[0490] A particular embodiment of the present invention relates to
compounds of formula (I.sup.c)
##STR00011##
[0491] wherein B, X, Y, R.sup.1, R.sup.2, R.sup.51, and R.sup.52
are as described herein.
[0492] Particular compounds of formula (I.sup.c) of the present
invention are those selected from the group consisting of: [0493]
6-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)ni-
cotinamide; [0494]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(4-methylpiperazin-1-yl)nicoti-
namide; [0495]
(S)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-6-(hexahydropyrrolo[1,2-a]py-
razin-2(1H)-yl)nicotinamide; [0496]
N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-piperazin-1-yl-nicotinamide;
[0497]
rac-N-(4-Fluoro-2-methyl-benzooxazol-6-yl)-6-(3-methyl-piperazin-1-
-yl)-nicotinamide; [0498]
N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benzamide;
[0499]
rac-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin--
1-yl)benzamide; [0500]
4-(3,5-dimethylpiperazin-1-yl)-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)be-
nzamide; [0501]
(S)-2-Fluoro-N-(4-fluoro-2-methyl-benzooxazol-6-yl)-4-(S)-hexahydro-pyrro-
lo[1,2-a]pyrazin-2-yl-benzamide; [0502]
(R)-2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(hexahydropyrrolo-
[1,2-a]pyrazin-2(1H)-yl)benzamide; [0503]
rac-2-fluoro-N-(2-methylbenzo[d]oxazol-6-yl)-4-(3-methylpiperazin-1-yl)be-
nzamide; [0504]
2-fluoro-N-(4-fluoro-2-methylbenzo[d]oxazol-6-yl)-4-(piperazin-1-yl)benza-
mide; [0505] and pharmaceutically acceptable salts thereof.
[0506] Manufacturing Processes
[0507] Compounds of formula (I) and pharmaceutically acceptable
salts thereof as defined above be prepared following standard
methods known in the art.
[0508] In a particular embodiment, the invention further relates to
a process for the manufacture of compounds of formula (I) and
pharmaceutically acceptable salts thereof as defined above,
comprising: [0509] a) the Buchwald-Hartwig amination reaction of a
compound of formula (II)
[0509] ##STR00012## [0510] with a compound of formula B--H, in the
presence of a catalyst (e.g.
tris(dibenzylidene-acetone)dipalladium(0) (Pd.sub.2(dba).sub.3))
and a ligand (e.g. 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
(BINAP)) and a base (e.g. cesium carbonate) and a solvent (e.g.
toluene), wherein the hydrogen H of the compound of formula B--H is
bound to a ring nitrogen atom of B, V is chloro or bromo, and A, B,
X, Y, R.sup.1, and R.sup.2 are as defined above; or [0511] b) a
nucleophilic aromatic substitution reaction between a compound of
formula (II) with a compound of formula B--H by heating (e.g.
T=120.degree. C.-200.degree. C.) in a solvent (e.g. dimethyl
sulfoxide (DMSO), N-methylpyrrolidone (NMP), or dimethylformamide
(DMF)), wherein the hydrogen H of the compound of formula B--H is
bound to a ring nitrogen atom of B, V is fluoro if X is CR.sup.3 or
V is chloro if X is N, and A, B, X, Y, R.sup.1, R.sup.2 and R.sup.3
are as defined above; or [0512] c) the Suzuki coupling reaction of
a compound of formula (II) with a compound of formula PG-B-pinB in
the presence of a base (e.g. K.sub.2CO.sub.3) and a catalyst (e.g.
PdCl.sub.2), followed by removal of PG, wherein pinB is
pinacolboranyl (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) which
is bound to a ring carbon atom of B, PG is an amino-protecting
group such as tert-butoxycarbonyl (BOC), V is fluoro or chloro, and
wherein A, B, X, Y, R.sup.1, and R.sup.2 are as defined above; or
[0513] d) the amidation reaction of a compound of formula (III)
[0513] ##STR00013## [0514] with a compound of formula A-NH.sub.2 in
the presence of a tertiary amine (e.g. N,N-diisopropylethylamine
(DIPEA) or triethylamine (TEA)) and a coupling reagent (e.g.
2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate methanaminium (HATU) or
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU)), optionally followed by the removal of
PG, wherein PG is an optional amino-protecting group such as
tert-butoxycarbonyl (PG), and wherein A, B, X, Y, R.sup.1, and
R.sup.2 are as defined above.
[0515] Particularly, compounds of formula (I) and pharmaceutically
acceptable salts thereof can be prepared in accordance to the
methods described in the examples herein.
[0516] Pharmaceutical Compositions
[0517] Another embodiment provides pharmaceutical compositions or
medicaments comprising the compounds of the invention and a
therapeutically inert carrier, diluent or pharmaceutically
acceptable excipient, as well as methods of using the compounds of
the invention to prepare such compositions and medicaments.
[0518] 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.
[0519] 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,
or subcutaneous administration.
[0520] 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
comprise components conventional in pharmaceutical preparations,
e.g., diluents, carriers, pH modifiers, preservatives,
solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,
colorants, flavorants, salts for varying the osmotic pressure,
buffers, masking agents, antioxidants, and further active agents.
They can also comprise still other therapeutically valuable
substances.
[0521] A typical formulation is prepared by mixing a compound of
the present invention and a carrier or excipient. Suitable carriers
and excipients are well known to those skilled in the art and are
described in detail in, e.g., Ansel H. C. et al., Ansel's
Pharmaceutical Dosage Forms and Drug Delivery Systems (2004)
Lippincott, Williams & Wilkins, Philadelphia; Gennaro A. R. et
al., Remington: The Science and Practice of Pharmacy (2000)
Lippincott, Williams & Wilkins, Philadelphia; and Rowe R. C,
Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press,
Chicago. 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).
[0522] The dosage at which compounds of the invention can be
administered can vary within wide limits and will, of course, be
fitted to the individual requirements in each particular case. In
general, in the case of oral administration a daily dosage of about
0.01 to 1000 mg per person of a compound of general formula (I)
should be appropriate, although the above upper limit can also be
exceeded when necessary.
[0523] An example of a suitable oral dosage form is a tablet
comprising about 100 mg to 500 mg of the compound of the invention
compounded with about 30 to 90 mg anhydrous lactose, about to 40 mg
sodium croscarmellose, about 5 to 30 mg polyvinylpyrrolidone (PVP)
K30, and about 1 to 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.
[0524] An example of an aerosol formulation can be prepared by
dissolving the compound, for example 10 to 100 mg, of the invention
in a suitable buffer solution, e.g. a phosphate buffer, adding a
tonicifier, e.g. a salt such as sodium chloride, if desired. The
solution may be filtered, e.g., using a 0.2 .mu.m filter, to remove
impurities and contaminants.
Uses
[0525] As described above, the compounds of formula (I) and their
pharmaceutically acceptable salts possess valuable pharmacological
properties and have been found to be enhancing inclusion of exon 7
of SMN1 and/or SMN2 into mRNA transcribed from the SMN1 and/or SMN2
gene, thereby increasing expression of SMN protein in a human
subject in need thereof.
[0526] The compounds of the present invention can be used, either
alone or in combination with other drugs, for the treatment or
prevention of diseases caused by an inactivating mutation or
deletion in the SMN1 gene and/or associated with loss or defect of
SMN1 gene function. These diseases include, but are not limited to
spinal muscular atrophy (SMA).
[0527] A particular embodiment of the present invention relates to
pharmaceutical compositions comprising compounds of formula (I) as
defined above or their pharmaceutically acceptable salts as defined
above and one or more pharmaceutically acceptable excipients.
[0528] A particular embodiment of the present invention relates to
pharmaceutical compositions comprising compounds of formula (I) or
their pharmaceutically acceptable salts as defined above and one or
more pharmaceutically acceptable excipients for the treatment or
prevention of diseases caused by an inactivating mutation or
deletion in the SMN1 gene and/or associated with loss or defect of
SMN1 gene function, particularly for the treatment or prevention of
spinal muscular atrophy (SMA).
[0529] A particular embodiment of the present invention relates to
compounds of formula (I) or their pharmaceutically acceptable salts
as defined above for use as therapeutically active substances,
especially for use as therapeutically active substances for the
treatment or prevention of diseases caused by an inactivating
mutation or deletion in the SMN1 gene and/or associated with loss
or defect of SMN1 gene function, particularly for the treatment or
prevention of spinal muscular atrophy (SMA).
[0530] A particular embodiment of the present invention relates to
compounds of formula (I) or their pharmaceutically acceptable salts
as defined above for the use in the treatment or prevention of
diseases caused by an inactivating mutation or deletion in the SMN1
gene and/or associated with loss or defect of SMN1 gene function,
particularly for use in the treatment or prevention of spinal
muscular atrophy (SMA).
[0531] A particular embodiment of the present invention relates to
a method for the treatment or prevention of diseases caused by an
inactivating mutation or deletion in the SMN1 gene and/or
associated with loss or defect of SMN1 gene function, particularly
for the treatment or prevention of spinal muscular atrophy (SMA),
which method comprises administering compounds of formula (I) or
their pharmaceutically acceptable salts as defined above to a
subject.
[0532] A particular embodiment of the present invention relates to
the use of compounds of formula (I) or their pharmaceutically
acceptable salts as defined above for the treatment or prevention
of diseases caused by an inactivating mutation or deletion in the
SMN1 gene and/or associated with loss or defect of SMN1 gene
function, particularly for the treatment or prevention of spinal
muscular atrophy (SMA).
[0533] A particular embodiment of the present invention relates to
the use of compounds of formula (I) or their pharmaceutically
acceptable salts as defined above for the preparation of
medicaments for the treatment or prevention of diseases caused by
an inactivating mutation or deletion in the SMN1 gene and/or
associated with loss or defect of SMN1 gene function, particularly
for the treatment or prevention of spinal muscular atrophy (SMA).
Such medicaments comprise compounds of formula (I) or their
pharmaceutically acceptable salts as defined above.
EXAMPLES
[0534] The invention will be more fully understood by reference to
the following examples. They should however not be construed as
limiting the scope of the invention.
Preparation of Intermediates
Example A.1
Preparation of
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluorobenzamide
##STR00014##
[0536] To a mixture of 6,8-dimethylimidazo[1,2-a]pyrazin-2-amine
trihydrochloride (Example B.1) (134 mg, 494 .mu.mol) and
N-Ethyldiisopropylamine (320 mg, 420 .mu.l, 2.47 mmol) in dioxane
(2.0 ml) was added dropwise a solution of 4-fluorobenzoyl chloride
(80 mg, 60.3 .mu.l, 494 .mu.mol) in dioxane (0.5 ml) at room
temperature. The mixture was stirred for 1 hour. The solvent was
removed in vacuo. The solid was taken in water and the suspension
was stirred for 15 minutes. The solid was filtered and dried to
provide 125 mg (89%) of the title compound as an off-white solid.
MS (m/e): 285.4 (M+H+)
[0537] In analogy to Example A. 1, Examples A.2 to A.7 of the
following table were prepared from the acylchloride and amine
derivatives:
TABLE-US-00001 Example No. Structure Systematic Name Starting
materials A.2 ##STR00015## N-(6,8- dimethylimidazo[1,2-
a]pyrazin-2-yl)-2,4- difluorobenzamide 6,8-dimethylimidazo[1,2-
a]pyrazin-2-amine trihydrochloride (Example B.1)and 2,4-
difluorobenzoyl chloride (commercial) A.3 ##STR00016##
6-chloro-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2- yl)nicotinamide
6,8-dimethylimidazo[1,2- a]pyrazin-2-amine trihydrochloride
(Example B.1)and 6- chloronicotinoyl chloride (commercial) A.4
##STR00017## N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-5-
fluoropicolinamide 6,8-dimethylimidazo[1,2- a]pyrazin-2-amine
trihydrochloride (Example B.1) and 5-Fluoro- pyridine-2-carbonyl
chloride (717871-83-5) A.5 ##STR00018## 6-chloro-N-(2-
methylimidazo[1,2- a]pyridin-6- yl)nicotinamide
2-methylimidazo[1,2- a]pyridin-6-amine hydrobromide (commercial)
and 6- chloronicotinoyl chloride (commercial) A.6 ##STR00019##
5-fluoro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)picolinamide
2-methylimidazo[1,2- a]pyridin-6-amine hydrobromide (commercial)
and 5- Fluoro-pyridine-2- carbonyl chloride (717871-83-5) A.7
##STR00020## 2,4-difluoro-N-(2- methylimidazo[1,2- a]pyridin-6-
yl)benzamide 2-methylimidazo[1,2- a]pyridin-6-amine hydrobromide
(commercial) and 2,4- difluorobenzoyl chloride (commercial)
Example A.8
Preparation of
6-Chloro-N-(2-methyl-8-trifluoromethyl-imidazo[1,2-a]pyridin-6-yl)-nicoti-
namide
##STR00021##
[0539] To a solution of 6-chloronicotinic acid (332 mg, 2.11 mmol)
in DMF (4 ml) under argon at room temperature, were added HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) (1.2 g, 3.16 mmol) and
N,N-diisopropylethylamine (1.4 ml, 8.42 mmol). After 5 minutes
stirring, 2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-amine
hydrochloride (Example B.2) (530 mg, 2.11 mmol) was added. The
mixture was stirred at room temperature for two days. The solvent
was removed in vacuo. The residue was taken in aqueous bicarbonate.
The aqueous layer was extracted 3 times with ethyl acetate. The
combined extracts were dried over sodium sulfate, filtered and
concentrated in vacuo. The crude mixture was purified with flash
column chromatography on silica eluting with a gradient formed from
dichloromethane and methanol (0 to 5%) to provide the title
compound.
[0540] In analogy to Example A.8, Examples A.9 to A.10 of the
following table were prepared from the acid and amine
derivatives:
TABLE-US-00002 Example No. Structure Systematic Name Starting
materials A.9 ##STR00022## 6-chloro-N-(4-fluoro-2- methylbenzo[d]
oxazol-6- yl)nicotinamide 4-fluoro-2- methylbenzo[d]oxazol- 6-amine
hydrochloride (Example B.3) and 6- chloronicotinic acid
(commercial) A.10 ##STR00023## 4-fluoro-N-(4-fluoro-2-
methylbenzo[d] oxazol-6- yl)benzamide 4-fluoro-2- methylbenzo[d]
oxazol- 6-amine hydrochloride (Example B.3) and 4- fluorobenzoic
acid (commercial)
Example B.1
Preparation of 6,8-dimethylimidazo[1,2-a]pyrazin-2-amine
trihydrochloride
##STR00024##
[0541] a) Step 1
Ethyl 6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylate
hydrobromide
[0542] To a solution of 3,5-dimethylpyrazin-2-amine (200 mg, 1.62
mmol) in DME (6.00 ml) was added ethyl 3-bromo-2-oxopropanoate (380
mg, 245 .mu.l, 1.95 mmol) at 0.degree. C. The mixture was stirred
for 2 hours at room temperature. The suspension was filtered and
washed with dimethoxyethane. The filtrate was taken in ethanol (4
ml) and refluxed for 1.5 hours. The reaction mixture was cooled to
room temperature, filtered and washed with ethanol to provide 323
mg (66.3%) of the title compound as a light yellow solid. MS (m/e):
220.1 (M+H+)
b) Step 2
6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylic acid
hydrochloride
[0543] To a solution of ethyl
6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylate hydrobromide (300
mg, 0.999 mmol) in ethanol (6 ml) and water (3 ml) under nitrogen
at room temperature, was added sodium hydroxide 2M (1.05 ml, 2.1
mmol). The reaction mixture was stirred at 90.degree. C. for 2
hours. The mixture was cooled to room temperature and acidified
with 1 ml HCl solution (2 M). The resulting suspension was cooled
to 0.degree. C., filtered, washed with cold diethyl ether and dried
to provide 128 mg (56.3%) of the title compound as a light brown
solid. MS (m/e): 192.1 (M+H+)
c) Step 3
tert-butyl 6,8-dimethylimidazo[1,2-a]pyrazin-2-ylcarbamate
[0544] To a suspension of
6,8-dimethylimidazo[1,2-a]pyrazine-2-carboxylic acid hydrochloride
(5 g, 22.0 mmol) in tert-butanol (50.9 ml) under nitrogene at room
temperature, was added triethylamine (9.17 ml, 65.9 mmol). After
stirring for 10 minutes, diphenylphosphoryl azide (4.85 ml, 22.0
mmol) was added. The reaction mixture was stirred at 85.degree. C.
overnight.
[0545] The solvent was removed in vacuo. The residue was taken in
aqueous bicarbonate. The aqueous layer was extracted 3 times with
ethyl acetate. The combined extracts were dried over sodium
sulfate, filtered and concentrated in vacuo. The crude orange oil
was purified with flash column chromatography on silica eluting
with a gradient formed from n-heptane and ethyl acetate (0 to 60%)
to provide 3.57 g (y: 62.0%) of the title compound as a white foam.
MS(m/e): 263.5 (M+H+)
d) Step 4
6,8-dimethylimidazo[1,2-a]pyrazin-2-amine trihydrochloride
[0546] To a yellow solution of tert-butyl
6,8-dimethylimidazo[1,2-a]pyrazin-2-ylcarbamate (3.57 g, 13.6 mmol)
in methanol (35.7 ml) under nitrogene at room temperature, was
added dropwise hydrogen chloride (34.0 ml, 136 mmol, 4M in
dioxane). The reaction mixture was stirred at room temperature
overnight. The mixture was evaporated to provide 3.66 g (99%) of
the title compound as a yellow solid. MS(m/e): 163.2 (M+H+)
Example B.2
Preparation of
2-Methyl-8-trifluoromethyl-imidazo[1,2-a]pyridin-6-ylamine
hydrochloride
##STR00025##
[0547] a) Step 1
6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine
[0548] In a 30 ml sealed reactor,
5-bromo-3-(trifluoromethyl)pyridin-2-amine (CAS:79456-34-1) (2.5 g,
10.4 mmol) was combined with 1-chloropropan-2-one (1.04 ml, 12.4
mmol) in acetonitrile (25 ml) and heated at 130.degree. C. for 2
days. The reaction mixture was cooled to room temperature, quenched
with 100 ml of a saturated aqueous sodium bicarbonate solution. The
reaction was extracted with ethylacetate and water. The organic
layers were dried over sodium sulfate and concentrated in vacuo.
The crude residue was purified with flash column chromatography on
silica eluting with a gradient formed from n-heptane and ethyl
acetate (0 to 25%) to provide 1.2 g (y: 41.5%) of the title
compound as a pink solid.
b) Step 2
N-(diohenylmethylene)-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6--
amine
[0549] In a 250 mL pear-shaped flask,
6-bromo-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridine (2.79 g,
10.0 mmol), rac 2,2'-bis(diphenylphosphino)-1,1'-binaphtalene (623
mg, 1.00 mmol), palladium (II) acetate (224 mg, 1.00 mmol), cesium
carbonate (8.14 g, 25.0 mmol) and diphenylmethanimine (2.48 g, 2.3
ml, 13.0 mmol) were combined with THF (70 ml) to give a orange
suspension. The reaction mixture was heated to 70.degree. C. and
stirred for 23 h. The reaction was extracted with ethylacetate and
water. The organic layers were dried over sodium sulfate and
concentrated in vacuo. The crude residue purified with flash column
chromatography on silica eluting with a gradient formed from
n-heptane and ethyl acetate (0 to 25%) to provide 2.33 g (y: 61.0%)
of the title compound as a yellow oil. MS(m/e): 380.5 (M+H+).
c) Step 3
2-Methyl-8-trifluoromethyl-imidazo[1,2-a]pyridin-6-ylamine
hydrochloride
[0550] To a solution of
N-(diohenylmethylene)-2-methyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-6-
-amine (2.3 g, 6.06 mmol) in dioxane (20 ml) was added HCl 1N (7.58
ml, 7.58 mmol). The mixture was stirred at room temperature for 30
minutes. The solvent was removes in vacuo. The residue was
triturated in acetonitrile. The white solid was filtered, washed
with acetonitrile and dried to provide 1.08 g (71%) of the expected
compound as a white solid. MS (m/e): 216.5 (M+H+)
Example B.3
Preparation of 4-fluoro-2-methylbenzo[d]oxazol-6-amine
hydrochloride
##STR00026##
[0551] a) Step 1
6-Bromo-4-fluoro-2-methyl-benzooxazole
[0552] To a solution of 4'-bromo-2',6'-difluoroacetanilide (4.0 g,
15.6 mmol, CAS: 658072-14-1) in N-methyl-2-pyrrolidinone (25 ml)
was added cesium carbonate (10.3 g, 31.6 mmol) and the mixture
heated to 150.degree. C. for 1 h. The reaction was then diluted
with water and extracted with ethyl acetate. The organic phase was
washed with brine, dried over sodium sulfate and concentrated in
vacuo. The crude residue was purified with flash column
chromatography on silica eluting with a gradient formed from
n-heptane and ethyl acetate (20% to 50%) to provide 1.5 g (42%) of
the title compound as a light brown solid. MS (m/e): 273.1
(M+H+MeCN).
B) STEP 2
4-fluoro-2-methylbenzo[d]oxazol-6-amine hydrochloride
[0553] In analogy to the procedure described for the synthesis of
example B.2 (steps: 2-3), the title compound was prepared from
6-Bromo-4-fluoro-2-methyl-benzooxazole. MS (m/e): 216.5 (M+H+).
Example B.4
Preparation of 8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylamine
hydrochloride
##STR00027##
[0555] In analogy to the procedure described for the synthesis of
example B.2 (steps: 1-3), the title compound was prepared from
5-bromo-3-fluoro-pyridin-2-ylamine (CAS: 748812-37-5). MS (m/e):
166.2 (M+H+).
Example B.5
Preparation of 8-chloro-2-methylimidazo[1,2-a]pyridin-6-amine
hydrochloride
##STR00028##
[0557] In analogy to the procedure described for the synthesis of
example B.2 (steps: 1-3), the title compound was prepared from
5-bromo-3-chloro-pyridin-2-ylamine (CAS: 38185-55-6). MS (m/e):
182.1 (M+H+).
Example C.1
Preparation of
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic
acid
##STR00029##
[0558] a) Step 1
(S)-methyl
2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoate
[0559] Toluene (1.5 ml) was added to a mixture of methyl
4-bromo-2-fluorobenzoate (200 mg, 832 .mu.mol) and
(S)-octahydropyrrolo[1,2-a]pyrazine (130 mg, 999 .mu.mol). The
mixture was stirred until complete dissolution. Then cesium
carbonate (407 mg, 1.25 mmol) was added. Then Pd.sub.2(dba).sub.3
(22.9 mg, 25.0 .mu.mol) and BINAP (46.7 mg, 74.9 .mu.mol) were
added. The reaction mixture was stirred vigorously for 24 hours at
110.degree. C. The reaction mixture was cooled to room temperature.
Water and ethylacetate were added. The layers were separated. The
aqueous layer was extracted twice with ethylacetate. The combined
organic layers were washed with water, dried over sodium sulfate,
filtered and evaporated. The crude orange oil was purified with
flash column chromatography on silica eluting with a gradient
formed from n-heptane and ethyl acetate (0 to 80%) to provide 121
mg (y: 52.2%) of the title compound as a yellow oil MS (m/e): 279.5
(M+H+)
b) Step 2
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic
acid
[0560] To a solution of (S)-methyl
2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoate (100
mg, 359 .mu.mol) in tetrahydrofuran (513 .mu.l), methanol (256
.mu.l) and water (256 .mu.l) was added lithium hydroxide
monohydrate (45.2 mg, 1.08 mmol). The mixture was stirred at room
temperature for 6 hours. The mixture was evaporated. HCl 2N was
added dropwise to pH 3-4. Dichloromethane was added and the aqueous
layer was extracted 3 times with dichloromethane NaOH 5N was added
to the aqueous phase to reach pH 6. The solution was evaporated.
The residue was suspended in dichloromethane and methanol, filtered
and evaporated to provide 82 mg (86.4%) of the title compound as
colorless oil. MS (m/e): 265.5 (M+H+)
Example C.2
Preparation of
(R)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic
acid
##STR00030##
[0562] In analogy to the procedure described for the synthesis of
example C.1 (steps: 1-2), the title compound was prepared from
4-bromo-2-fluorobenzoate and
(R)-octahydropyrrolo[1,2-a]pyrazine.
Example C.3
Preparation of
rac-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoic
acid
##STR00031##
[0563] a) Step 1
rac-tert-butyl
4-(4-(ethoxycarbonyl)-3-fluorophenyl)-2-methylpiperazine-1-carboxylate
[0564] A solution of ethyl 2,4-difluorobenzoate (200 mg, 1.07 mmol)
and 2-methylpiperazine (538 mg, 5.37 mmol) in DMA (2 ml) was heated
to 100.degree. C. in a microwave reactor for 15 minutes.
[0565] Ethyl acetate and water was added. The layers were separated
and the aqueous layer was extracted twice with ethyl acetate. The
combined organic layers were dried over sodium sulfate, filtered
and evaporated. A solution of this crude material and triethylamine
(131 mg, 180 .mu.l, 1.29 mmol) in dichloromethane (2.00 ml) was
cooled to 0.degree. C. Di-tert-butyl dicarbonate (352 mg, 1.61
mmol) in dichloromethane (0.5 ml) was added dropwise. The mixture
was stirred at room temperature overnight. Water was added. The
layers were separated. The aqueous layer was extracted twice with
dichloromethane. The combined organic layers were dried over
sodiumsulfate, filtered and evaporated. The crude product was
purified with flash column chromatography on silica gel (Eluent:
Heptane/ethyl acetate 0 to 20) to provide 155 mg (34%) of the title
compound as a light yellow oil.
b) Step 2
rac-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoic
acid
[0566] In analogy to the procedure described for the synthesis of
example C.1 (step: 2), the title compound was prepared from
rac-tert-butyl
4-(4-(ethoxycarbonyl)-3-fluorophenyl)-2-methylpiperazine-1-carboxylate
Example C.4
Preparation of rac-4-(6-Carboxy-pyridin-3-yl)-2-methyl-piperazine-1
carboxylic acid tert-butyl ester
##STR00032##
[0568] A solution of 5-fluoropicolinic acid (0.47 g, 3.33 mmol) and
2-methylpiperazine N1 Boc (1.00 g, 5.00 mmol) in DMA (2.00 ml) was
heated to 160.degree. C. in a microwave reactor for 1 hour. The
solvent was evaporated under high vacuum. The residue was taken in
water and acidified to pH 3. The aqueous phase was extracted 3
times with ethyl acetate, dried and concentrated. The crude product
was purified with flash column chromatography on silica gel
(Eluent: Heptane/ethyl acetate 0 to 20) to provide 1.17 g (100%) of
the title compound.
Example C.5
Preparation of
rac-4-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2,3-difluorobenzoi-
c acid
##STR00033##
[0570] In analogy to the procedure described for the synthesis of
example C.3 (steps: 1-2), the title compound was prepared from
2,3,4-trifluoro-benzoic acid ethyl ester and
rac-2-methylpiperazine.
Example C.6
Preparation of
rac-4-(4-Carboxy-2,5-difluoro-phenyl)-2-methyl-piperazine-1-carboxylic
acid tert-butyl ester
##STR00034##
[0572] In analogy to the procedure described for the synthesis of
example C.3 (steps: 1-2), the title compound was prepared from
2,4,5-Trifluoro-benzoic acid methyl ester and
rac-2-methylpiperazine.
Example C.7
Preparation of
rac-6-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-5-fluoronicotinic
acid
##STR00035##
[0574] In analogy to the procedure described for the synthesis of
example C.3 (steps: 1-2), the title compound was prepared from
6-Chloro-5-fluoro-nicotinic acid methyl ester and
rac-2-methylpiperazine.
Example C.8
Preparation of
rac-5-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-3-fluoropicolinic
acid
##STR00036##
[0576] In analogy to the procedure described for the synthesis of
example C.3 (steps: 1-2), the title compound was prepared from
3,5-Difluoro-pyridine-2-carboxylic acid methyl ester and
rac-2-methylpiperazine.
Example C.9
Preparation of
rac-4-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-2,6-difluorobenzoic
acid
##STR00037##
[0578] In analogy to the procedure described for the synthesis of
example C.3 (steps: 1-2), the title compound was prepared from
2,4,6-Trifluoro-benzoic acid methyl ester and
rac-2-methylpiperazine.
Example C.10
Preparation of
(S)-4-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoic
acid
##STR00038##
[0580] In analogy to the procedure described for the synthesis of
example C.1 (steps: 1-2), the title compound was prepared from
methyl 4-bromo-2-fluorobenzoate and (S)-tert-butyl
2-methylpiperazine-1-carboxylate.
Example C.11
Preparation of
(R)-4-(4-(tertbutoxycarbonyl)-3-methylpiperazin-1-yl)-2-fluorobenzoic
acid
##STR00039##
[0582] In analogy to the procedure described for the synthesis of
example C.1 (steps: 1-2), the title compound was prepared from
methyl 4-bromo-2-fluorobenzoate and (R)-tert-butyl
2-methylpiperazine-1-carboxylate.
Example C.12
Preparation of
4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoi-
c acid
##STR00040##
[0583] a) Step 1
tert-butyl
4-(3-fluoro-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H-
)-carboxylate
[0584] To a solution of methyl 4-bromo-2-fluorobenzoate (94 mg, 395
.mu.mol) in Dioxane (2 ml) were added tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (179.3 mg, 580 .mu.mol),
tetrakis-(triphenylphosphine)palladium (22.8 mg, 19.8 .mu.mol, Eq:
0.05) and tripotassium phosphate (170.1 mg, 801 .mu.mol). Under an
inert atmosphere, the mixture was heated at 100.degree. C. for 18
h. The reaction was filtered and the filtrate was concentrated in
vacuo. The resulting brown oil was purified by flash column
chromatography on silica (Eluent: Heptane/ethyl acetate 0 to 20) to
provide 121 mg (91%) of the title compound as a light yellow oil.
MS (m/e): 280.4 (M+H-56)
b) Step 2
4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic
acid
[0585] In analogy to the procedure described for the synthesis of
example C.1 (step: 2), the title compound was prepared from
tert-butyl
4-(3-fluoro-4-(methoxycarbonyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxyl-
ate
Example C.13
Preparation of
6-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)nicotinic
acid
##STR00041##
[0587] To a solution of 6-chloronicotinic acid (200 mg, 1.26 mmol)
in dry DMF (2.5 ml) under nitrogen at room temperature, were added
tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (466 mg, 1.51 mmol), tetrakis(triphenylphosphine)
palladium (0) (147 mg, 126 .mu.mol) and potassium carbonate
anhydrous (521 mg, 3.77 mmol). The reaction mixture was degased
with nitrogen for 10 minutes. The mixture was then stirred at
125.degree. C. in microwave for 45 min. The mixture was diluted
with DMF. Water was added to the suspension and the mixture was
cooled to 0.degree. C. HCl 1N was slowly added, until pH 3-4. The
suspension was filtered and the solid was washed with water and
then ethyl acetate to provide 158 mg (41.3%) of the title compound
as a white solid. MS (m/e): 305.5 (M+H+)
Example C.14
Preparation of
5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinic
acid
##STR00042##
[0588] a) Step 1
methyl
5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinat-
e
[0589] To a solution of methyl 5-bromopicolinate (205 mg, 930
.mu.mol) in DMF (2 ml) under nitrogen at room temperature, was
added tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (300 mg, 970 .mu.mol), followed by sodium carbonate 2M
aq. (650 .mu.l, 1.3 mmol). The reaction mixture was degased with
argon for 10 minutes. Finally,
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloromethane adduct (30.5 mg, 41.7 .mu.mol) was added and the
mixture was then stirred at 60.degree. C. in microwave for 10
minutes, and then 70.degree. C. for 70 minutes. Ethyl acetate and
water were added to the reaction mixture. Both layers were
separated and the aqueous layer was extracted two times with ethyl
acetate. The combined organic layers were dried over sodium
sulfate, filtered and concentrated in vacuo. The crude brown oil
was purified with flash column chromatography on silica (Eluent:
Heptane/ethyl acetate 0 to 20) to provide 202 mg (68%) of the title
compound as a white solid. MS (m/e): 319.5 (M+H-56)
b) Step 2
4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic
acid
[0590] In analogy to the procedure described for the synthesis of
example C.1 (step: 2), the title compound was prepared from methyl
5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)picolinate.
Example C.15
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxynicotinic
acid
##STR00043##
[0591] a) Step 1
tert-butyl
4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carbox-
ylate
[0592] To an ice-cold solution of methyl 2,6-difluoronicotinate
(2.0 g, 11.6 mmol, CAS 11767-02-0) and triethylamine (1.6 ml, 11.6
mmol) in DMF (10 ml) was added dropwise a solution of tert-butyl
piperazine-1-carboxylate (2.2 g, 11.6 mmol) in DMF (5 ml). The
reaction was stirred for 0.5 h at 0.degree. C. after which time it
was diluted with ethyl acetate, washed with water, brine, dried
over sodium sulfate, filtered and concentrated in vacuo. The crude
oil was purified with flash column chromatography on silica
(Eluent: Heptane/ethyl acetate 10 to 20%) to provide 2.7 g (68%) of
the title compound as a white solid. MS (m/e): 340.2 (M+H).
b) Step 2
tert-butyl
4-(6-methoxy-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carbo-
xylate
[0593] To a solution of tert-butyl
4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate
(0.40 g, 1.2 mmol) in methanol (5 ml) was added potassium
tert-butoxide (0.13 g, 1.2 mmol) and the mixture heated to reflux.
After 4 h the reaction was diluted with dichloromethane, washed
with brine, dried over sodium sulfate, filtered and concentrated in
vacuo to provide 0.4 g (92%) of the title compound as a white
solid. MS (m/e): 352.4 (M+H).
c) Step 3
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxynicotinic
acid
[0594] To a solution of tert-butyl
4-(6-methoxy-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate
(0.38 g, 1.1 mmol) in methanol (5 ml) was added 6 N sodium
hydroxide (0.36 ml, 2.2 mmol) and the reaction heated to 80.degree.
C. for 16 h. The reaction was concentrated to dryness, 5% aqueous
citric acid was added and the resulting precipitate isolated by
filtration, affording 0.31 g (86%) of the title compound as a white
solid. MS (m/e): 338.3 (M+H).
Example C.16
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-fluoronicotinic
acid
##STR00044##
[0596] To a suspension of tert-butyl
4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate
(0.1 g, 0.3 mmol)--Example C.15 (step 1) in tert-butanol (2 ml) was
added 6 N sodium hydroxide (0.1 ml, 0.6 mmol) and the mixture
heated to 100.degree. C. for 3 h. The reaction was concentrated to
dryness, 5% aqueous citric acid was added and the resulting
precipitate isolated by filtration, affording 0.08 g (87%) of the
title compound as a white solid. MS (m/e): 326.4 (M+H).
Example C.17
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoronicotinic
acid
##STR00045##
[0597] a) Step 1
tert-butyl 4-(4-fluoropyridin-2-yl)piperazine-1-carboxylate
[0598] In analogy to the procedure described for the synthesis of
example C.1 (step 1), the title compound was prepared from
2-chloro-4-fluoropyridine and (tert-butyl piperazine-1-carboxylate.
MS (m/e): 282.5 (M+H).
b) Step 2
tert-butyl
4-(4-fluoro-5-iodopyridin-2-yl)piperazine-1-carboxylate
[0599] To a solution of tert-butyl
4-(4-fluoropyridin-2-yl)piperazine-1-carboxylate (67 mg, 0.2 mmol)
in DMF (0.5 ml) was added N-iodo-succinamide (82 mg, 0.4 mmol) and
the mixture stirred for 24 h. The reaction was then diluted with
water, extracted with ethyl acetate, the organic phase was washed
with brine, dried over sodium sulfate, filtered and concentrated in
vacuo. The crude oil was purified with flash column chromatography
on silica (Eluent: Heptane/ethyl acetate 0 to 30%) to provide 73 mg
(75%) of the title compound as a light yellow solid. MS (m/e):
408.5 (M+H).
c) Step 3
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-fluoronicotinic
acid
[0600] To an ice-cold suspension of tert-butyl
4-(4-fluoro-5-iodopyridin-2-yl)piperazine-1-carboxylate (63 mg, 0.2
mmol) in tetrahydrofuran (0.2 ml) under argon was added
isopropylmagnesium chloride lithium chloride complex (0.13 ml, 1.3
M in THF, 0.2 mmol). The mixture was allowed to come to ambient
temperature and stirred for 45 minutes before carbon dioxide gas
was bubbled into the reaction. After 1 h the mixture was diluted
with water, extracted with ethyl acetate, the aqueous layer was
then acidified with 5% aqueous citric acid solution and
re-extracted with ethyl acetate. The ethyl acetate was then washed
with brine, dried over sodium sulfate, filtered and concentrated in
vacuo to provide 29 mg (58%) of the title compound as an off-white
foam. MS (m/e): 326.5 (M+H).
Example C.18
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-methoxynicotinic
acid
##STR00046##
[0602] In analogy to the procedure described for the synthesis of
example C.17 (steps: 1-3), the title compound was prepared from
2-chloro-4-methoxypyridine. MS (m/e): 338.6 (M+H).
Example C.19
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-ethoxynicotinic
acid
##STR00047##
[0604] In analogy to the procedure described for the synthesis of
example C.17 (steps: 1-3), the title compound was prepared from
2-chloro-4-ethoxypyridine. MS (m/e): 352.5 (M+H).
Example C.20
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nicoti-
nic acid
##STR00048##
[0605] a) Step 1
2-chloro-4-(2,2,2-trifluoroethoxy)pyridine
[0606] To a solution of 2-chloro-4-nitropyridine (0.5 g, 3.2 mmol)
in tetrahydrofuran (20 ml) was added 2,2,2-trifluoroethanol (0.25
ml, 3.5 mmol) and potassium tert-butoxide (0.4 g, 3.5 mmol). The
reaction mixture was stirred at 60.degree. C. overnight in a sealed
vessel. The reaction was concentrated to dryness, the residue
re-dissolved in ethyl acetate, washed with sodium hydrogen
carbonate, brine, dried over sodium sulfate, filtered and
concentrated in vacuo. The crude oil was purified with flash column
chromatography on silica (Eluent: Heptane/ethyl acetate 0 to 30%)
to provide 0.6 g (91%) of the title compound as a colourless
liquid. MS (m/e): 212.2 (M+H).
b)
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-(2,2,2-trifluoroethoxy)nico-
tinic acid
[0607] In analogy to the procedure described for the synthesis of
example C.17 (steps: 1-3), the title compound was prepared from
2-chloro-4-(2,2,2-trifluoroethoxy)pyridine. MS (m/e): 406.6
(M+H).
Example C.21
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-ethoxynicotinic
acid
##STR00049##
[0609] In analogy to the procedure described for the synthesis of
example C.15 (steps: 1-3), except that ethanol is used in place of
methanol as solvent in step 2, afforded the title compound. MS
(m/e): 352.5 (M+H).
Example C.22
Preparation of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(2,2,2-trifluoroethoxy)nicoti-
nic acid
##STR00050##
[0611] In analogy to the procedure described for the synthesis of
example C.15 (steps: 1-3), except that 2,2,2-trifluoroethanol is
used in place of methanol as solvent in step 2, afforded the title
compound. MS (m/e): 404.7 (M-H).
Example C.23
Preparation of
rac-6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-2-methoxynicotinic
acid
##STR00051##
[0613] In analogy to the procedure described for the synthesis of
example C.15 (steps: 1-3), the title compound was prepared from
rac-tert-butyl 2-methylpiperazine-1-carboxylate and methyl
2,6-difluoronicotinate. MS (m/e): 350.5 (M-H).
Example C.24
Preparation of
6-(4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)-2-methoxynicotinic
acid
##STR00052##
[0615] In analogy to the procedure described for the synthesis of
example C.15 (steps: 1-3), the title compound was prepared from
2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and
methyl 2,6-difluoronicotinate. MS (m/e): 364.5 (M-H).
Example C.25
Preparation of
rac-6-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)-4-methoxynicotinic
acid
##STR00053##
[0617] In analogy to the procedure described for the synthesis of
example C.18, the title compound was prepared from rac-tert-butyl
2-methylpiperazine-1-carboxylate and 2-chloro-4-methoxypyridine. MS
(m/e): 352.5 (M+H).
DESCRIPTION OF EXAMPLES
Example 1
Preparation of
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-(piperazin-1-yl)benzamide
##STR00054##
[0619] To a solution of
N-(6,8-dimethylimidazo[1,2-a]pyrazin-2-yl)-4-fluorobenzamide
(Example A. 1) (20 mg, 70.4 .mu.mol) in N,N-dimethylacetamide (200
.mu.l) under nitrogen at room temperature, was added piperazine
(60.6 mg, 704 .mu.mol). The reaction mixture was microwaved at
160.degree. C. for 90 minutes. The mixture was cooled to room
temperature. The resulting precipitate was filtered, rinsed with
diethyl ether and dried to provide 4 mg (16.2%) of the title as an
off-white solid. MS (m/e): 351.4 (M+H+)
[0620] In analogy to Example 1, compounds 2 to 30 of the following
table were prepared by reacting an halo-substituted amide
derivative with an amino-substituted derivative at the indicated
temperature:
TABLE-US-00003 MW Example found No. Structure Systematic Name
Starting materials T (.degree. C.) (MH.sup.+) 2 ##STR00055##
rac-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 4-(3-
methylpiperazin-1- yl)benzamide N-(6,8- dimethylimidazo[1,2-
a]pyrazin-2-yl)-4- fluorobenzamide (Example A.1) and rac-2-
methylpiperazine (commercial) 160 365.5 3 ##STR00056##
N-(6,8-Dimethyl- imidazo[1,2- a]pyrazin-2-yl)-4- ((S)-3-methyl-
piperazin-1-yl)- benzamide N-(6,8- dimethylimidazo[1,2-
a]pyrazin-2-yl)-4- fluorobenzamide (Example A.1) and (S)-(+)-2-
methylpiperazine (commercial) 200 365.5 4 ##STR00057## N-(6,8-
dimethylimidazo[1,2- a]pyrazin-2-yl)- 2-fluoro-4-(4-
methylpiperazin-1- yl)benzamide N-(6,8- dimethylimidazo[1,2-
a]pyrazin-2-yl)-2,4- difluorobenzamide (Example A2) and 1-
methylpiperazine (commercial) 180 383.5 5 ##STR00058## rac-N-(6,8-
dimethylimidazo[1,2- a]pyrazin-2-yl)- 2-fluoro-4-(3-
methylpiperazin-1- yl)benzamide N-(6,8- dimethylimidazo[1,2-
a]pyrazin-2-yl)-2,4- difluorobenzamide (Example A2) and rac-2-
methylpiperazine (commercial) 180 383.5 6 ##STR00059## N-(6,8-
dimethylimidazo[1,2- a]pyrazin-2-yl)- 6-(4- methylpiperazin-1-
yl)nicotinamide 6-chloro-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-
yl)nicotinamide (Example A3) and 1- methylpiperazine (commercial)
120 366.5 7 ##STR00060## rac-N-(6,8- dimethylimidazo[1,2-
a]pyrazin-2-yl)- 6-(3- methylpiperazin-1- yl)nicotinamide
6-chloro-N-(6,8- dimethylimidazo[1,2- a]pyrazin-2- yl)nicotinamide
(Example A3) and rac-2- methylpiperazine (commercial) 180 366.5 8
##STR00061## N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)- 6-(4-
ethylpiperazin-1- yl)nicotinamide 6-chloro-N-(6,8-
dimethylimidazo[1,2- a]pyrazin-2- yl)nicotinamide (Example A3) and
1- ethylpiperazine (commercial) 130 380.5 9 ##STR00062## N-(6,8-
dimethylimidazo[1,2- a]pyrazin-2-yl)- 5-(4- methylpiperazin-1-
yl)picolinamide N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-5-
fluoropicolinamide (Example A4) and 1- methylpiperazine
(commercial) 160 366.5 10 ##STR00063## rac-N-(6,8-
dimethylimidazo[1,2- a]pyrazin-2-yl)- 5-(3- methylpiperazin-1-
yl)picolinamide N-(6,8- dimethylimidazo[1,2- a]pyrazin-2-yl)-5-
fluoropicolinamide (Example A4) and rac-2- methylpiperazine
(commercial) 160 366.5 11 ##STR00064## N-(6,8- dimethylimidazo[1,2-
a]pyrazin-2-yl)- 5-(piperazin-1- yl)picolinamide N-(6,8-
dimethylimidazo[1,2- a]pyrazin-2-yl)-5- fluoropicolinamide (Example
A4) and piperazine (commercial) 160 352.5 12 ##STR00065## rac-N-(2-
methylimidazo[1,2- a]pyridin-6-yl)-6- (3- methylpiperazin-1-
yl)nicotinamide 6-chloro-N-(2- methylimidazo[1,2- a]pyridin-6-
yl)nicotinamide (Example A5) and rac-2- methylpiperazine
(commercial) 130 351.4 13 ##STR00066## 6-(3,3- dimethylpiperazin-
1-yl)-N-(2- methylimidazo[1,2- a]pyridin-6- yl)nicotinamide
6-chloro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)nicotinamide
(Example A5) and 2,2-Dimethyl- piperazine (commercial) 130 365.5 14
##STR00067## N-(2- methylimidazo[1,2- a]pyridin-6-yl)-6-
(piperazin-1- yl)nicotinamide 6-chloro-N-(2- methylimidazo[1,2-
a]pyridin-6- yl)nicotinamide (Example A5) and piperazine
(commercial) 130 337.5 15 ##STR00068## 6- hexahydropyrrolo
[3,4-c]pyrrol-2(1H)- yl)-N-(2- methylimidazo[1,2- a]pyridin-6-
yl)nicotinamide hydrochloride 6-chloro-N-(2- methylimidazo[1,2-
a]pyridin-6- yl)nicotinamide (Example A5) and hexahydro-
pyrrolo[3,4-c]pyrrole- 2-carboxylic acid tert-
butylester(commercial) followed by treatment with HCl 130 363.5 16
##STR00069## N-(2- methylimidazo[1,2- a]pyridin-6-yl)-6- (2,6-
diazaspiro[3.3] heptan-2- yl)nicotinamide hydrochloride
6-chloro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)nicotinamide
(Example A5) and 2,6-Diaza- spiro[3.3]heptane-2- carboxylic acid
tert- butyl ester (commercial) followed by treatment with HCl 130
349.5 17 ##STR00070## rac-N-(2- methylimidazo[1,2-
a]pyridin-6-yl)-5- (3- methylpiperazin-1- yl)picolinamide 5-
fluoro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)picolinamide
(Example A6) and rac-2- methylpiperazine (commercial) 160 351.5 18
##STR00071## rac-2-fluoro-N-(2- methylimidazo[1,2-
a]pyridin-6-yl)-4- (3- methylpiperazin-1- yl)benzamide
2,4-difluoro-N-(2- methylimidazo[1,2- a]pyridin-6- yl)benzamide
(Example A7) and rac-2- methylpiperazine (commercial) 100 368.5 19
##STR00072## N-(2-methyl-8- (trifluoromethyl) imidazo[1,2-
a]pyridin-6-yl)-6- (piperazin-1- yl)nicotinamide 6-Chloro-N-(2-
methyl-8- tritluoromethyl- imidazo[1,2-a]pyridin-
6-yl)-nicotinamide (Example A8) and piperazine (commercial) 130
405.4 20 ##STR00073## rac-N-(2-methyl-8- (trifluoromethyl)
imidazo[1,2- a]pyridin-6-yl)-6- (3- methylpiperazin-1-
yl)nicotinamide 6-Chloro-N-(2- methyl-8- trifluoromethyl-
imidazo[1,2-a]pyridin- 6-yl)-nicotinamide (Example A8) and rac-2-
methylpiperazine (commercial) 130 419.4 21 ##STR00074## (S)-6-
(hexahydropyrrolo [1,2-a]pyrazin- 2(1H)-yl)-N-(2- methyl-8-
(trifluoromethyl) imidazo[1,2- a]pyridin-6- yl)nicotinamide
6-Chloro-N-(2- methyl-8- trifluoromethyl- imidazo[1,2-a]pyridin-
6-yl)-nicotinamide (Example A8) and (S)- octahydropyrrolo[1,2-
a]pyrazine (commercial) 130 445.7 22 ##STR00075## 6-(3,5-
dimethylpiperazin- 1-yl)-N-(2-methyl- 8- (trifluoromethyl)
imidazo[1,2- a]pyridin-6- yl)nicotinamide 6-Chloro-N-(2- methyl-8-
trifluoromethyl- imidazo[1,2-a]pyridin- 6-yl)-nicotinamide (Example
A8) and 2,6- dimethylpiperazine 130 433.7 23 ##STR00076## 6-(3,5-
dimethylpiperazin- 1-yl)-N-(4-fluoro- 2- methylbenzo[d] oxazol-6-
yl)nicotinamide 6-chloro-N-(4-fluoro- 2- methylbenzo[d]oxazol-
6-yl)nicotinamide (Example A9) and 2,6- dimethylpiperazine 130
384.6 24 ##STR00077## N-(4-fluoro-2- methylbenzo[d]
oxazol-6-yl)-6-(4- methylpiperazin-1- yl)nicotinamide
6-chloro-N-(4-fluoro- 2- methylbenzo[d]oxazol- 6-yl)nicotinamide
(Example A9) and 1- methylpiperazine (commercial) 130 370.6 25
##STR00078## (S)-N-(4-fluoro-2- methylbenzo[d] oxazol-6-yl)-6-
(hexahydropyrrolo [1,2-a]pyrazin- 2(1H)- yl)nicotinamide
6-chloro-N-(4-fluoro- 2-methylbenzo[d] oxazol-6- yl)nicotinamide
(Example A9) and (S)- octahydropyrrolo[1,2- a]pyrazine (commercial)
130 396.6 26 ##STR00079## N-(4-Fluoro-2- methyl- benzooxazol-6-yl)-
6-piperazin-1-yl- nicotinamide 6-chloro-N-(4-fluoro-
2-methylbenzo[d] oxazol-6- yl)nicotinamide (Example A9) and
piperazine (commercial) 130 356.6 27 ##STR00080##
rac-N-(4-Fluoro-2- methyl- benzooxazol-6-yl)- 6-(3-methyl-
piperazin-1-yl)- nicotinamide 6-chloro-N-(4-fluoro- 2-
methylbenzo[d] oxazol-6- yl)nicotinamide (Example A9) and rac-2-
methylpiperazine (commercial) 130 370.6 28 ##STR00081##
N-(4-fluoro-2- methylbenzo[d] oxazol-6-yl)-4- (piperazin-1-
yl)benzamide 4-fluoro-N-(4-fluoro- 2-methylbenzo[d]
oxazol-6-yl)benzamide (Example A10) and piperazine (commercial) 160
355.6 29 ##STR00082## rac-N-(4-fluoro-2- methylbenzo[d]
oxazol-6-yl)-4-(3- methylpiperazin-1- yl)benzamide
4-fluoro-N-(4-fluoro- methylbenzo[d]oxazol- 6-yl)benzamide (Example
A10) and rac-2- methylpiperazine (commercial) 160 369.6 30
##STR00083## 4-(3,5- dimethylpiperazin- 1-yl)-N-(4-fluoro-
2-methylbenzo[d] oxazol-6- yl)benzamide 4-fluoro-N-(4-fluoro- 2-
methylbenzo[d] oxazol-6-yl)benzamide (Example A10) and 2,6-
dimethylpiperazine 160 383.7
Example 31
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-N-(2-methylimidaz-
o[1,2-a]pyridin-6-yl)benzamide
##STR00084##
[0622] To a solution of
(S)-2-fluoro-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)benzoic
acid (Example C.1) (80 mg, 303 .mu.mol) in N,N-dimethylformamide
(800 .mu.l) under nitrogen at room temperature, were added HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) (173 mg, 454 .mu.mol) and
N-ethyldiisopropylamine (156 mg, 206 .mu.l, 1.21 mmol). After 5
minutes stirring at room temperature,
2-methylimidazo[1,2-a]pyridin-6-amine hydrobromide (commercial)
(69.0 mg, 303 .mu.mol) was added. The mixture was shaked at
60.degree. C. for 5.5 hours and then at room temperature for two
days. The solvent was removed in vacuo. The residue was taken in a
saturated aqueous solution of bicarbonate. Ethyl acetate was added.
The resulting precipitate was filtered, rinsed with ethyl acetate
and dried. The solid was stirred in ethyl acetate, filtered, rinsed
with cold ethyl acetate and n-hexane and dried to provide 11 mg
(9%) of the title compound as a light brown solid. MS (m/e): 394.6
(M+H)
[0623] In analogy to Example 31, compounds 32 to 35 of the
following table were prepared from the acid and amine
derivatives:
TABLE-US-00004 MW Expl. found No. Structure Systematic Name
Starting materials (MH.sup.+) 32 ##STR00085## N-(8-fluoro-2-
methylimidazo[1,2- a]pyridin-6-yl)-6-(4- methylpiperazin-1-
yl)nicotinamide 6-(4-Methyl-piperazin-1- yl)-nicotinic acid
(commercial) and 8-Fluoro- 2-methyl-imidazo[1,2-
a]pyridin-6-ylamine hydrochloride (Example B.4) 369.5 33
##STR00086## (S)-2-Fluoro-N-(4- fluoro-2-methyl-
benzooxazol-6-yl)-4- (S)-hexahydro- pyrrolo[1,2-a]pyrazin-
2-yl-benzamide (S)-2-fluoro-4- (hexahydropyrrolo[1,2-
a]pyrazin-2(1H)-yl)benzoic acid (Example C.1) and 4- fluoro-2-
methylbenzo[d]oxazol-6- amine hydrochloride (Example B.3) 413.7 34
##STR00087## (R)-2-fluoro-N-(4- fluoro-2- methylbenzo[d]oxazol-
6-yl)-4- (hexahydropyrrolo[1,2- a]pyrazin-2(1H)- yl)benzamide
(R)-2-fluoro-4- (hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)benzoic
acid (Example C.2) and 4- fluoro-2- methylbenzo[d]oxazol-6- amine
hydrochloride (Example B.3) 413.6 35 ##STR00088## (S)-2-fluoro-4-
(hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)- N-(2-methyl-8-
(trifluoromethyl) imidazo[1,2- a]pyridin-6- yl)benzamide
(S)-2-fluoro-4- (hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)benzoic
acid (Example C.1) and 2- Methyl-8-trifluoromethyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.2)
462.5
Example 36
Preparation of
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperazin-1-yl)benzami-
de hydrochloride
##STR00089##
[0625] To a solution of
4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (commercial)
(109 mg, 357 .mu.mol) in N,N-dimethylformamide (1.00 ml) under
nitrogen at room temperature, were added HATU
(O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate) (204 mg, 536 .mu.mol) and
N-ethyldiisopropylamine (185 mg, 243 .mu.l, 1.43 mmol). After 5
minutes stirring at room temperature,
8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride
(Example B.4) (72 mg, 357 .mu.mol) was added. The mixture was
stirred at room temperature for 21 hours and then at 60.degree. C.
for 2 hours. The solvent was removed in vacuo. The residue was
taken in a saturated aqueous solution of bicarbonate and extracted
three times with ethyl acetate. The combined extracts were dried
over sodium sulfate, filtered and concentrated in vacuo. The crude
oil was purified on silica gel (Eluent: heptane/ethyl acetate 0 to
10%) to provide 78 mg of tert-butyl
4-(4-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)phenyl)piperaz-
ine-1-carboxylate. To a suspension of this compound (40 mg, 88.2
.mu.mol) in methanol (400 .mu.l) was added HCl 4M in dioxane (221
.mu.l, 882 .mu.mol). The light yellow suspension was stirred at
room temperature for 17 hours. The solid was filtered, washed with
ether and hexane and dried to provide 25 mg (72.7%) of the title
compound as a light yellow solid. MS(m/e): 354.5 (M+H).
[0626] In analogy to Example 36, compounds 37 to 63 of the
following table were prepared from the acid and amine derivatives
followed by treatment with HCl or TFA.
TABLE-US-00005 MW Expl. found No. Structure Systematic Name
Starting materials (MH.sup.+) 37 ##STR00090## rac-N-(2,8-
dimethylimidazo[1,2- a]pyridin-6-yl)-2- fluoro-4-(3-
methylpiperazin-1- yl)benzamide dihydrochloride
4-(4-(tert-butoxycarbonyl)- 3-methylpiperazin-1-yl)-2-
fluorobenzoic acid (Example C.3) and 2,8- dimethylimidazo[1,2-
a]pyridin-6-amine hydrochloride (CAS: 1216295-25-8) followed by
treatment with HCl 382.6 38 ##STR00091## rac-2-fluoro-N-(2-
methylbenzo[d]oxazol- 6-yl)-4-(3- methylpiperazin-1- yl)benzamide
dihydrochloride 4-(4-(tert-butoxycarbonyl)-
3-methylpiperazin-1-yl)-2- fluorobenzoic acid (Example C.3) and 2-
Methyl-benzooxazol-6- ylamine (commercial) followed by treatment
with HCl 369.5 39 ##STR00092## rac-2-fluoro-N-(8- fluoro-2-
methylimidazo[1,2- a]pyridin-6-yl)-4-(3- methylpiperazin-1-
yl)benzamide dihydrochloride 4- (4-(tert-butoxycarbonyl)-
3-methylpiperazin-1-yl)-2- fluorobenzoic acid (Example C.3) and 8-
Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride
(Example B.4) followed by treatment with HCl 386.6 40 ##STR00093##
2-fluoro-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-4-
(piperazin-1- yl)benzamide dihydrochloride 4-(4-(tert-
butoxycarbonyl)piperazin-1- yl)-2-fluorobenzoic acid (CAS:
1121596-45-9) and 8-Fluoro-2-methyl- imidazo[1,2-a]pyridin-6-
ylamine hydrochloride (Example B.4) followed by treatment with HCl
372.6 41 ##STR00094## N-(8-fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-6- (piperazin-1- yl)nicotinamide dihydrochloride
4-(5-Carboxy-pyridin-2-yl)- piperazine-1-carboxylic acid tert-butyl
ester (CAS: 201809-22-5) and 8-Fluoro- 2-methyl-imidazo[1,2-
a]pyridin-6-ylamine hydrochloride (Example B.4) followed by
treatment with HCl 355.5 42 ##STR00095## rac-N-(8-fluoro-2-
methylimidazo[1,2- a]pyridin-6-yl)-6-(3- methylpiperazin-1-
yl)nicotinamide dihydrochloride rac-6-(4-(tert- butoxycarbonyl)-3-
methylpiperazin-1- yl)nicotinic acid (CAS: 904817-70-5) and
8-Fluoro- 2-methyl-imidazo[1,2- a]pyridin-6-ylamine hydrochloride
(Example B.4) followed by treatment with HCl 369.6 43 ##STR00096##
rac-N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-5-(3-
methylpiperazin-1- yl)picolinamide dihydrochloride
rac-4-(6-Carboxy-pyridin-3- yl)-2-methyl-piperazine-1- carboxylic
acid tert-butyl ester (Example C.4) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 369.6 44 ##STR00097## 2-fluoro-N-(2-
methylimidazo[1,2- a]pyridin-6-yl)-4- (piperazin-1- yl)benzamide
hydrochloride 4-(4-(tert- butoxycarbonyl)piperazin-1-
yl)-2-fluorobenzoic acid (CAS: 1121596-45-9) and
2-methylimidazo[1,2- a]pyridin-6-amine hydrobromide (commercial)
followed by treatment with HCl 354.6 45 ##STR00098##
rac-2,3-difluoro-N-(8- fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloride
rac-4-(4-(tert- butoxycarbonyl)-3- methylpiperazin-1-yl)-2,3-
difluorobenzoic acid (Example C.5) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 404.6 46 ##STR00099##
rac-2,5-difluoro-N-(8- fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloride
rac-4-(4-Carboxy-2,5- difluoro-phenyl)-2-methyl-
piperazine-1-carboxylic acid tert-butyl ester (Example C.6) and
8-Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride
(Example B.4) followed by treatment with HCl 404.5 47 ##STR00100##
rac-5-fluoro-N-(8- fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-6-(3- methylpiperazin-1- yl)nicotinamide
hydrochloride rac-6-(4- (tertbutoxycarbonyl)-3-
methylpiperazin-1-yl)-5- fluoronicotinic acid (Example C.7) and 8-
Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride
(Example B.4) followed by treatment with HCl 387.5 48 ##STR00101##
rac-3-fluoro-N-(8- fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-5-(3- methylpiperazin-1- yl)picolinamide
hydrochloride rac-5-(4- (tertbutoxycarbonyl)-3-
methylpiperazin-1-yl)-3- fluoropicolinic acid (Example C.8) and 8-
Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride
(Example B.4) followed by treatment with HCl 387.6 49 ##STR00102##
rac-2,6-difluoro-N-(8- fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloride
rac-4-(4- (tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2,6-
difluorobenzoic acid (Example C.9) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 404.6 50 ##STR00103##
(S)-2-fluoro-N-(8- fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloride
(S)-4-(4- (tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2-
fluorobenzoic acid (Example C.10) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 386.6 51 ##STR00104##
(R)-2-fluoro-N-(8- fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-4-(3- methylpiperazin-1- yl)benzamide hydrochloride
(R)-4-(4- (tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2-
fluorobenzoic acid (Example C.11) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 386.6 52 ##STR00105## rac-N-(2,7-
dimethylimidazo[1,2- a]pyridin-6-yl)-2- fluoro-4-(3-
methylpiperazin-1- yl)benzamide dihydrochloride rac-4-(4-(tert-
butoxycarbonyl)-3- methylpiperazin-1-yl)-2- fluorobenzoic acid
(Example C.3) and 2,7- dimethylimidazo[1,2- a]pyridin-6-amine
hydrochloride (CAS: 1216109-27-1) followed by treatment with HCl
382.5 53 ##STR00106## rac-N-(8-chloro-2- methylimidazo[1,2-
a]pyridin-6-yl)-5- fluoro-6-(3- methylpiperazin-1- yl)nicotinamide
hydrochloride rac-6-(4- (tertbutoxycarbonyl)-3-
methylpiperazin-1-yl)-5- fluoronicotinic acid (Example C.7) and 8-
chloro-2- methylimidazo[1,2- a]pyridin-6-amine hydrochloride
(Example B.5) followed by treatment with HCl 403.5 54 ##STR00107##
rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-2-
fluoro-4-(3- methylpiperazin-1- yl)benzamide dihydrochloride
rac-4-(4-(tert- butoxycarbonyl)-3- methylpiperazin-1-yl)-2-
fluorobenzoic acid (Example C.3) and 8- chloro-2-
methylimidazo[1,2- a]pyridin-6-amine hydrochloride (Example B.5)
followed by treatment with HCl 402.5 55 ##STR00108##
rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-6-(3-
methylpiperazin-1- yl)nicotinamide dihydrochloride rac-6-(4-(tert-
butoxycarbonyl)-3- methylpiperazin-1- yl)nicotinic acid (CAS:
904817-70-5) and 8-chloro- 2-methylimidazo[1.2- a]pyridin-6-amine
hydrochloride (Example B.5) followed by treatment with HCl 385.6 56
##STR00109## rac-N-(8-chloro-2- methylimidazo[1,2-
a]pyridin-6-yl)-3- fluoro-5-(3- methylpiperazin-1- yl)picolinamide
dihydrochloride rac-5-(4- (tertbutoxycarbonyl)-3-
methylpiperazin-1-yl)-3- fluoropicolinic acid (Example C.8) and 8-
chloro-2- methylimidazo[1,2- a]pyridin-6-amine hydrochloride
(Example B.5) followed by treatment with HCl 403.5 57 ##STR00110##
rac-N-(8-chloro-2- methylimidazo[1,2- a]pyridin-6-yl)-2,6-
difluoro-4-(3- methylpiperazin-1- yl)benzamide trihydrochloride
rac-4-(4- (tertbutoxycarbonyl)-3- methylpiperazin-1-yl)-2,6-
difluorobenzoic acid (Example C.9) and 8- chloro-2-
methylimidazo[1,2- a]pyridin-6-amine hydrochloride (Example B.5)
followed by treatment with HCl 420.5 58 ##STR00111##
2-fluoro-N-(4-fluoro- 2- methylbenzo[d]oxazol-
6-yl)-4-(piperazin-1- yl)benzamide 4-(4-(tert-
butoxycarbonyl)piperazin-1- yl)-2-fluorobenzoic acid (CAS:
1121596-45-9) and 4-fluoro-2- methylbenzo[d]oxazol-6- amine
hydrochloride (Example B.3) followed by treatment with TFA 373.5 59
##STR00112## 2-fluoro-N-(2-methyl- 8-(trifluoromethyl) imidazo[1,2-
a]pyridin-6-yl)- 4-(piperazin-1- yl)benzamide 4-(4-(tert-
butoxycarbonyl)piperazin-1- yl)-2-fluorobenzoic acid (CAS:
1121596-45-9) and 2-Methyl-8-trifluoromethyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.2)
followed by treatment with TFA 422.5 60 ##STR00113## 2-fluoro-N-(2-
methylimidazo[1,2- a]pyridin-6-yl)-4- (1,2,3,6-
tetrahydropyridin-4- yl)benzamide hydrochloride
4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-
yl)-2-fluorobenzoic acid (Example C.12) and 2- methylimidazo[1,2-
a]pyridin-6-amine hydrobromide (commercial followed by treatment
with HCl 351.5 61 ##STR00114## 2-fluoro-N-(8-fluoro-
2-methylimidazo[1,2- a]pyridin-6-yl)-4- (1,2,3,6-
tetrahydropyridin-4- yl)benzamide hydrochloride
4-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-
yl)-2-fluorobenzoic acid (Example C.12) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 369.5 62 ##STR00115## N-(8-fluoro-2-
methylimidazo[1,2- a]pyridin-6-yl)-6- (1,2,3,6-
tetrahydropyridin-4- yl)nicotinamide dihydrochloride
6-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-
yl)nicotinic acid (Example C.13) and 8-Fluoro-2-
methyl-imidazo[1,2- a]pyridin-6-ylamine hydrochloride (Example B.4)
followed by treatment with HCl 352.5 63 ##STR00116## N-(2-
methylimidazo[1.2- a]pyridin-6-yl)-5- (1,2,3,6-
tetrahydropyridin-4- yl)picolinamide dihydrochloride
5-(1-(tert-butoxycarbonyl)- 1,2,3,6-tetrahydropyridin-4-
yl)picolinic acid (Example C.14) and 2- methylimidazo[1,2-
a]pyridin-6-amine hydrobromide (commercial followed by treatment
with HC1 334.5
Example 64
Preparation of
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-2-methoxy-6-(piperazin-1--
yl)nicotinamide
##STR00117##
[0628] To a solution of
6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-methoxynicotinic acid
(Example C.15) (100 mg, 296 .mu.mol) and
8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-ylamine hydrochloride
(Example B.4) (60 mg, 296 .mu.mol) in N,N-dimethylformamide (1.00
ml) under argon at room temperature, was added
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (114 mg, 536 .mu.mol) and triethylamine (124
.mu.l, 0.89 mmol). The mixture was stirred at 55.degree. C. for 16
hours and then at 90.degree. C. for 3 hours. The reaction was
poured into water and extracted with ethyl acetate. The ethyl
acetate was dried over sodium sulfate, filtered and concentrated in
vacuo. The crude oil was purified on silica gel (Eluent:
heptane/ethyl acetate 50 to 100%) to provide 76 mg of tert-butyl
4-(5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)-6-methoxypyri-
din-2-yl)piperazine-1-carboxylate. This compound was then dissolved
in 4M HCl in dioxane (2 ml) and the mixture stirred for 0.5 h. The
mixture was evaporated to dryness in vacuo, the residue dissolved
in saturated sodium hydrogen carbonate and repeatedly extracted
with dichloromethane. The combined extracts were dried over sodium
sulfate, filtered and concentrated in vacuo. dried to provide 39 mg
(63%) of the title compound as an off-white solid. MS(m/e): 385.4
(M+H).
[0629] In analogy to Example 64, compounds 65 to 76 of the
following table were prepared from the acid and amine derivatives
followed by treatment with HCl
TABLE-US-00006 MW Expl. found No. Structure Systematic Name
Starting materials (MH.sup.+) 65 ##STR00118## 2-fluoro-N-(8-fluoro-
2-methylimidazo[1,2- a]pyridin-6-yl)-6- (piperazin-1-
yl)nicotinamide 6-(4-(tert- butoxycarbonyl)piperazin-1-
yl)-2-fluoronicotinic acid (Example C.16) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 373.3 66 ##STR00119## N-(8-fluoro-2-
methylimidazo[1,2- a]pyridin-6-yl)-3- methyl-4-(piperazin-1-
yl)benzamide 4-(4-(tert- butoxycarbonyl)piperazin-1-
yl)-3-methylbenzoic acid (CAS: 196203-51-7) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 368.6 67 ##STR00120## N-(8-fluoro-2-
methylimidazo[1,2- a]pyridin-6-yl)-5- methyl-6-(piperazin-1-
yl)nicotinamide 6-(4-(tert- butoxycarbonyl)piperazin-1-
yl)-5-methylnicotinic acid (CAS: 1211527-14-8) and
8-Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride
(Example B.4) followed by treatment with HCl LG 68 ##STR00121##
4-fluoro-N-(8-fluoro- 2-methylimidazo[1,2- a]pyridin-6-yl)-6-
(piperazin-1- yl)nicotinamide 6-(4-(tert-
butoxycarbonyl)piperazin-1- yl)-4-fluoronicotinic acid (Example
C.17) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine
hydrochloride (Example B.4) followed by treatment with HCl 373.7 69
##STR00122## N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-4-
methoxy-6-(piperazin- 1-yl)nicotinamide 6-(4-(tert-
butoxycarbonyl)piperazin-1- yl)-4-methoxynicotinic acid (Example
C.18) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine
hydrochloride (Example B.4) followed by treatment with HCl 385.6 70
##STR00123## 4-ethoxy-N-(8-fluoro- 2-methylimidazo[1,2-
a]pyridin-6-yl)-6- (piperazin-1- yl)nicotinamide 6-(4-(tert-
butoxycarbonyl)piperazin-1- yl)-4-ethoxynicotinic acid (Example
C.19) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine
hydrochloride (Example B.4) followed by treatment with HCl 399.6 71
##STR00124## N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6-
(piperazin-1-yl)-4- (2,2,2- trifluoroethoxy) nicotinamide
6-(4-(tert- butoxycarbonyl)piperazin-1- yl)-4-(2,2,2-
trifluoroethoxy)nicotinic acid(Example C.20) and 8-
Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride
(Example B.4) followed by treatment with HCl 453.6 [ 72
##STR00125## 2-ethoxy-N-(8-fluoro- 2-methylimidazo[1,2-
a]pyridin-6-yl)-6- (piperazin-1- yl)nicotinamide 6-(4-(tert-
butoxycarbonyl)piperazin-1- yl)-2-ethoxynicotinic acid (Example
C.21) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine
hydrochloride (Example B.4) followed by treatment with HCl 399.6 73
##STR00126## N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-6-
(piperazin-1-yl)-2- (2,2,2- trifluoroethoxy) nicotinamide
6-(4-(tert- butoxycarbonyl)piperazin-1- yl)-2-(2,2,2-
trifluoroethoxy)nicotinic acid (Example C.22) and 8-
Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine hydrochloride
(Example B.4) followed by treatment with HCl 453.6 74 ##STR00127##
rac-N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-2-
methoxy-6-(3- methylpiperazin-1- yl)nicotinamide rac-6-(4-(tert-
butoxycarbonyl)-3- methylpiperazin-1-yl)-2- methoxynicotinic acid
(Example C.23) and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6-
ylamine hydrochloride (Example B.4) followed by treatment with HCl
399.6 75 ##STR00128## 6-(3,3- dimethylpiperazin-1-
yl)-N-(8-fluoro-2- methylimidazo[1,2- a]pyridin-6-yl)-2-
methoxynicotinamide 6-(4-(tert-butoxycarbonyl)-
3,3-dimethylpiperazin-1-yl)- 2-methoxynicotinic acid (Example C.24)
and 8- Fluoro-2-methyl- imidazo[1,2-a]pyridin-6- ylamine
hydrochloride (Example B.4) followed by treatment with HCl 411.6 76
##STR00129## rac-N-(8-fluoro-2- methylimidazo[1,2-
a]pyridin-6-yl)-4- methoxy-6-(3- methylpiperazin-1- yl)nicotinamide
6-(4-(tert-butoxycarbonyl)- 3-methylpiperazin-1-yl)-4-
methoxynicotinic acid (Example C.25) and 8- Fluoro-2-methyl-
imidazo[1,2-a]pyridin-6- ylamine hydrochloride (Example B.4)
followed by treatment with HCl 399.5
Example 77
Preparation of
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-
nicotinamide hydrochloride
##STR00130##
[0630] a) Step 1
tert-butyl
4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)-
-5,6-dihydropyridine-1 (2H)-carboxylate
[0631] To a solution of
6-chloro-N-(2-methylimidazo[1,2-a]pyridin-6-yl)nicotinamide
(Example A5) (100 mg, 349 .mu.mol) in a mixture of
1,2-dimethoxyethane (1.25 ml), ethanol (625 .mu.l) and water (1.25
ml) under nitrogen at room temperature, were added tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-
-carboxylate (129 mg, 419 .mu.mol), K2CO3 (122 mg, 875 .mu.mol) and
PdCl2(Ph3P)2 (25.2 mg, 35.9 .mu.mol, Eq: 0.103). The reaction
mixture was heated in an oil bath at 100.degree. C. for 40 minutes.
After cooling to room temperature, the solvent was removed under
reduced pressure. The residue was dissolved in dichloromethane and
washed with brine. The aqueous phase was extracted three times with
methylene chloride and the combined organic phase was dried with
Na2SO4, filtered and concentrated to dryness to obtain 285 mg of a
dark brown solid. This solid was suspended in ethyl acetate,
filtered and dried to provide 86 mg (56.9%) of the title compound
as a light brown solid. MS (m/e): 434.5 (M+H+).
b) Step 2
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyridin-4-yl)n-
icotinamide hydrochloride
[0632] To a solution of tert-butyl
4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)-5,6-dihyd-
ropyridine-1(2H)-carboxylate (20 mg, 46.1 .mu.mol) in methanol (200
.mu.l) under nitrogene at room temperature, was added dropwise
hydrogen chloride (4M in dioxane) (115 .mu.l, 461 .mu.mol). The
reaction mixture was stirred at room temperature overnight. The
resulting precipitation was filtered, rinsed with diethyl ether and
dried to provide 12.6 mg (73.8%) of the expected compound as a grey
solid. MS(m/e): 334.5 (M+H+).
Example 78
Preparation of
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotina-
mide
##STR00131##
[0633] a) Step 1
tert-butyl
4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)-
piperidine-1-carboxylate
[0634] To a solution of tert-butyl
4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)-5,6-dihyd-
ropyridine-1(2H)-carboxylate (Example 77, step 1) (123 mg, 284
.mu.mol) in methanol (7 ml) and tetrahydrofurane (3.5 ml) under
nitrogen at room temperature was added palladium on activated
charcoal (54.3 mg, 51.0 .mu.mol). The reaction mixture was stirred
under a hydrogen atmosphere overnight. The reaction mixture was
purged with argon, filtered and the solvent was evaporated. The
crude oil was purified with flash column chromatography on silica
eluting with a gradient formed from n-heptane and ethyl acetate (0
to 100%) and ethyl acetate and methanol (0 to 15%) to provide 86 mg
(69.6%) of the title compound as an off-white solid. MS (m/e):
436.6 (M+H)
b) Step 2
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide
[0635] To a suspension of tert-butyl
4-(5-(2-methylimidazo[1,2-a]pyridin-6-ylcarbamoyl)pyridin-2-yl)piperidine-
-1-carboxylate (17 mg, 39.0 .mu.mol) in methanol (170 .mu.l) was
added HCl 4M in dioxane (97.6 .mu.l, 390 .mu.mol). The light yellow
solution was stirred at room temperature overnight. The solvent was
evaporated to provide 14 mg (87.8%) of the title compound as a grey
solid. MS(m/e): 336.3 (M+H)
c) Step 3
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl)nicotinam-
ide
[0636] To a suspension of
N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotinamide
(25 mg, 74.5 .mu.mol) in 1,2-dichloroethane (250 .mu.l) under
nitrogene at 5-10.degree. C., was added sodium
triacetoxyborohydride (26.3 mg, 112 .mu.mol), followed dropwise
(over 5 minutes) by formaldehyde solution (37% in water) (18.1 mg,
16.6 .mu.l, 224 .mu.mol). The temperature was kept to 5-10.degree.
C. and the reaction mixture was stirred for 40 minutes. The
reaction was quenched with a 2N sodium carbonate aqueous solution.
The resulting precipitation was stirred at room temperature for 30
minutes, filtered, rinsed and dried to provide 17 mg (65.3%) of the
title compound as an off-white solid. MS(m/e): 350.5 (M+H+)
Example 79
Preparation of
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotin-
amide dihydrochloride
##STR00132##
[0638] To a solution of
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1,2,3,6-tetrahydropyri-
din-4-yl)nicotinamide dihydrochloride (Example 62) (30 mg, 70.7
.mu.mol) in methanol (1.7 ml) and tetrahydrofurane (850 .mu.l)
under nitrogen at room temperature, was added palladium on
activated charcoal (20 mg, 18.8 .mu.mol, Eq: 0.266). The reaction
mixture was stirred under a hydrogen atmosphere for 4 hours. The
reaction mixture was purged with argon, filtered and the solvent
was evaporated to provide 28 mg (92.9%) of the title compound as a
yellow solid. MS (m/e): 354.5 (M+H+).
Example 80
Preparation of
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(1-methylpiperidin-4-yl-
)nicotinamide
##STR00133##
[0640] In analogy to the procedure described for the synthesis of
example 78 (steps: 3), the title compound was prepared from
N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-6-(piperidin-4-yl)nicotin-
amide dihydrochloride (Example 79). MS (m/e): 368.5 (M+H+).
Example 81
Preparation of
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(piperidin-4-y-
l)benzamide hydrochloride
##STR00134##
[0642] In analogy to the procedure described for the synthesis of
example 79, the title compound was prepared from
2-fluoro-N-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-4-(1,2,3,6-tetra-
hydropyridin-4-yl)benzamide (Example 61). MS (m/e): 371.5
(M+H+).
Example 82
Preparation of
rac-6-(3,4-dimethylpiperazin-1-yl)-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-
nicotinamide
##STR00135##
[0644] In analogy to the procedure described for the synthesis of
example 78 (step 3), the title compound was prepared from
rac-N-(2-methylimidazo[1,2-a]pyridin-6-yl)-6-(3-methylpiperazin-1-yl)nico-
tinamide (Example 12). MS (m/e): 365.6 (M+H+).
[0645] Biological Assays
[0646] To describe in more detail and assist in understanding the
present description, the following non-limiting biological examples
are offered to more fully illustrate the scope of the description
and are not to be construed as specifically limiting the scope
thereof. Such variations of the present description that may be now
known or later developed, which would be within the purview of one
skilled in the art to ascertain, are considered to fall within the
scope of the present description and as hereinafter claimed. These
examples illustrate the testing of certain compounds described
herein in vitro and/or in vivo and demonstrate the usefulness of
the compounds for treating of SMA by enhancing the inclusion of
exon 7 of SMN2 into mRNA transcribed from the SMN2 gene. Compounds
of formula (I) enhance inclusion of exon 7 of SMN2 into mRNA
transcribed from the SMN2 gene and increase levels of SMN protein
produced from the SMN2 gene, and thus can be used to treat SMA in a
human subject in need thereof. These examples further illustrate
the testing of certain compounds described herein in vitro and/or
in vivo and demonstrate the usefulness of the compounds for
enhancing the inclusion of exon 7 of SMNI into mRNA transcribed
from the SMN1 gene. Accordingly, compounds of formula (I) also
enhance the inclusion of exon 7 of SMN1 into mRNA transcribed from
the SMN1 gene and increase levels of SMN protein produced from the
SMN1 gene.
Example D.1
SMN2 Minigene mRNA Splicing RT-qPCR Assay in Cultured Cells
[0647] The reverse transcription-quantitative PCR-based (RT-qPCR)
assay is used to quantify the level of the full length SMN2
minigene (referred to herein by the term "FL SMN2mini") mRNA
containing SMN2 exon 7 in a HEK293H cell line stably transfected
with said minigene and treated with a test compound.
TABLE-US-00007 Material Source HEK293H cells Life Technologies,
Inc. (formerly Invitrogen) Catalog No. 11631-017 Cells-To-Ct lysis
Life Technologies, Inc. (formerly Applied buffer Biosystems) part
No. 4399002 DMEM Life Technologies, Inc. (formerly Invitrogen)
Catalog No. 11960-044 96-well flat-bottom Becton Dickinson Catalog
No. 353072 plates RT-PCR Enzyme Life Technologies, Inc. (formerly
Applied Mix Biosystems) part No. 4388520 RT-PCR buffer Life
Technologies, Inc. (formerly Applied Biosystems) part No. 4388519
AgPath-ID One- Life Technologies, Inc. (formerly Applied Step
RT-PCR kit Biosystems) part No. 4387391 Thermocycler Life
Technologies, Inc. (formerly Applied Biosystems) 7900HT
[0648] The SMN2-A minigene construct was prepared as described in
International Patent Application WO2009/151546A1 page 145 paragraph
[00400] to page 147 paragraph [00412] (incl. FIG. 1 and FIG. 3
therein).
[0649] HEK293H cells stably transfected with the SMN2-A minigene
construct (10,000 cells/well) are seeded in 200 .mu.L of cell
culture medium (DMEM plus 10% FBS, with 200 g/mL hygromycin) in
96-well flat-bottom plates and the plate is immediately swirled to
ensure proper dispersal of cells and the formation of an even
monolayer of cells. Cells are allowed to attach for 6 hours. Test
compounds are serially diluted 3.16-fold in 100% DMSO to generate a
7-point concentration curve. A solution of test compound (1 .mu.L,
200.times. in DMSO) is added to each cell-containing well and the
plate is incubated for 24 hours in a cell culture incubator
(37.degree. C., 5% C0.sub.2, 100% relative humidity). 2 replicates
are prepared for each test compound concentration. The cells are
then lysed in the Cells-To-Ct lysis buffer and the lysate is stored
at -80.degree. C.
[0650] Full length SMN2-A minigene and GAPDH mRNA are quantified
using the primers and probes referenced in Table 1. Primer SMN
Forward A (SEQ ID NO.1) hybridizes to a nucleotide sequence in exon
7 (nucleotide 22 to nucleotide 40), primer SMN Reverse A (SEQ ID
NO.2) hybridizes to a nucleotide sequence in the coding sequence of
Firefly luciferase, SMN Probe A (SEQ ID NO.3) hybridizes to a
nucleotide sequence in exon 7 (nucleotide 50 to nucleotide 54) and
exon 8 (nucleotide 1 to nucleotide 21). The combination of these
three oligonucleotides detects only SMN1 or SMN2 minigenes
(RT-qPCR) and will not detect endogenous SMN1 or SMN2 genes.
TABLE-US-00008 TABLE 1 Primers/Probes Sequences Source SMN Forward
SEQ ID NO.1: GAAGGAAGGTGCTCA PTC.sup.1 Primer A CATT SMN Reverse
SEQ ID NO.2: TCTTTATGTTTTTGG PTC.sup.1 Primer A CGTCTTC SMN Forward
SEQ ID NO.3: 6FAM-AAGGAGAAAT PTC.sup.1 Probe A
GCTGGCATAGAGCAGC-TAMRA hGAPDH Forward SEQ ID NO.4: VIC-CGCCTGGTCAC
LTI.sup.2 Probe CAGGGCTGCT-TAMRA hGAPDH Forward SEQ ID NO.5:
CAACGGATTTGGTCG LTI.sup.2 Primer TATTGG hGAPDH Reverse SEQ ID NO.6:
TGATGGCAACAATAT LTI.sup.2 Primer CCACTTTACC .sup.1Primers and
probes designed by PTC Therapeutics, Inc.; .sup.2Commercially
available from Life Technologies, Inc. (formerly Invitrogen).
[0651] The SMN forward and reverse primers are used at final
concentrations of 0.4 .mu.M. The SMN probe is used at a final
concentration of 0.15 .mu.M. The GAPDH primers are used at final
concentrations of 0.2 .mu.M and the probe at 0.15 .mu.M.
[0652] The SMN2-minigene GAPDH mix (15 .mu.L total volume) is
prepared by combining 7.5 .mu.L of 2.times.RT-PCR buffer, 0.4 .mu.L
of 25.times.RT-PCR enzyme mix, 0.75 .mu.L of 20.times.GAPDH
primer-probe mix, 4.0075 .mu.L of water, 2 .mu.L of 10-fold diluted
cell lysate, 0.06 .mu.L of 100 .mu.M SMN forward primer, 0.06 .mu.L
of 100 .mu.M SMN reverse primer, and 0.225 .mu.L of 100 .mu.M SMN
probe.
[0653] PCR is carried out at the following temperatures for the
indicated time: Step 1: 48.degree. C. (15 min); Step 2: 95.degree.
C. (10 min); Step 3: 95.degree. C. (15 sec); Step 4: 60.degree. C.
(1 min); then repeat Steps 3 and 4 for a total of 40 cycles.
[0654] Each reaction mixture contains both SMN2-A minigene and
GAPDH primers/probe sets (multiplex design), allowing simultaneous
measurement of the levels of two transcripts.
[0655] The increase in the abundance of the FL SMN2mini mRNA
relative to that in cells treated with vehicle control is
determined from real-time PCR data using a modified
.DELTA..DELTA.Ct method (as described in Livak and Schmittgen,
Methods, 2001, 25:402-8). The amplification efficiency E is
calculated from the slope of the amplification curve for FL
SMN2mini and GAPDH individually. The abundance of FL SMN2mini and
GAPDH mRNA are then calculated as (1+E).sup.-Ct, where Ct is the
threshold value for each amplicon. The abundance of FL SMN2mini
mRNA is normalized to GAPDH mRNA abundance. The normalized FL
SMN2mini mRNA abundance from test compound-treated samples is then
divided by normalized FL SMN2mini mRNA abundance from
vehicle-treated cells to determine the level of FL SMN2mini mRNA
relative to vehicle control.
[0656] Table 2 provides EC.sub.1.5.times. concentrations for
production of full length SMN2 minigene mRNA that was obtained from
the 7-point concentration data generated according to the above
procedure for particular compounds of the present invention.
[0657] Particular compounds of the present invention exhibit an
EC.sub.1.5.times. concentration for production of full length SMN2
minigene mRNA .ltoreq.1 .mu.M.
[0658] More particular compounds of the present invention exhibit
an EC.sub.1.5.times. concentration for production of full length
SMN2 minigene mRNA .ltoreq.0.1 .mu.M.
[0659] Most particular compounds of the present invention exhibit
an EC1.5.times.concentration for production of full length SMN2
minigene mRNA .ltoreq.0.02 .mu.M.
TABLE-US-00009 TABLE 2 EC.sub.1.5x concentrations for production of
full length SMN2 minigene mRNA. Ex. EC.sub.1.5x minigene (.mu.M) 1
0.0316 2 0.1399 3 0.5522 4 0.2323 5 0.0612 6 0.2332 7 0.1423 8
0.201 9 0.794 10 0.6652 11 0.2971 12 0.3122 13 1.0335 14 0.2314 15
0.2539 16 1.0364 17 0.2334 18 0.0523 19 0.2673 20 0.4894 21 0.3856
22 0.2626 23 0.201 24 0.6489 25 0.3823 26 0.0445 27 0.0989 28
0.2524 29 0.2667 30 0.4096 31 0.1195 32 0.0938 33 34 0.328 35
0.2022 36 0.0278 37 0.028 38 0.4717 39 0.0168 40 0.0108 41 42
0.0544 43 0.057 44 0.0648 45 0.0615 46 0.0887 47 0.3964 48 0.0164
49 0.0107 50 0.0068 51 0.0084 52 0.04 53 0.2104 54 0.0128 55 0.1411
56 0.017 57 0.0262 58 0.0398 59 0.1089 60 0.0428 61 0.01 62 0.0136
63 0.1602 64 0.0291 65 0.0762 66 0.5177 67 0.3175 68 0.0285 69
0.0308 70 71 0.077 72 0.015 73 0.062 74 0.0161 75 0.0654 76 0.0187
77 0.0641 78 0.6222 79 0.0559 80 0.1148 81 0.0374 82 0.3714
Example D.2
SMN Protein Assay in Cultured Cells
[0660] The SMN HTRF (homogeneous time resolved fluorescence) assay
is used to quantify the level of SMN protein in SMA patient
fibroblast cells treated with test compounds.
TABLE-US-00010 Material Source SMA Type 1 human GM03813 (Coriell
Institute) cells Protease inhibitor Roche Applied Science Catalog
No. cocktail 11836145001 Anti-SMN d2 Blue cap Cisbio Catalog No.
63IDC002-SMN Anti-SMN kryptate Red cap Cisbio Catalog No.
63IDC002-SMN SMN reconstitution Cisbio Catalog No.
63IDC002-SMN-Buffer buffer DMEM Life Technologies (formerly
Invitrogen) Catalog No. 11960-044 RIPA Lysis Buffer 20 mM Tris-HCl
pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% Thermo Scientific NP-40 Surfact-
Amps Detergent Solution (Fisher Scientific, Pittsburgh/PA), 1%
Sodium deoxycholate Diluent Buffer 20 mM Tris-HCl pH 7.5, 150 mM
NaCl Envision Plate Perkin Elmer Model # 2103 Reader
[0661] Cells are thawed and cultured in DMEM-10% FBS for 72 hours.
Cells are trypsinized, counted and re-suspended to a concentration
of 25,000 cells/mL in DMEM-10% FBS. The cell suspensions are plated
at 5,000 cells per well in a 96 well microtiter plate and incubated
for 3 to hours. Test compounds are serially diluted 3.16-fold in
100% DMSO to generate a 7-point concentration curve. 1 .mu.L of
test compound solution is transferred to cell-containing wells and
cells are incubated for 48 hours in a cell culture incubator
(37.degree. C., 5% C0.sub.2, 100% relative humidity). Triplicate
samples are set up for each test compound concentration. After 48
hours, the supernatant is removed from the wells and 25 .mu.L of
the RIPA lysis buffer, containing protease inhibitors, is added to
the wells and incubated with shaking at room temperature for 1
hour. 25 .mu.L of the diluent is added and then 35 .mu.L of the
resulting lysate is transferred to a 384-well plate, where each
well contains 5 .mu.L of the antibody solution (1:100 dilution of
anti-SMN d2 and anti-SMN kryptate in SMN reconstitution buffer).
The plate is centrifuged for 1 minute to bring the solution to the
bottom of the wells, then incubated overnight at room temperature.
Fluorescence for each well of the plate at 665 nm and 620 nm is
measured on an EnVision multilabel plate reader (Perkin-Elmer).
[0662] The normalized fluorescence signal is calculated for each
sample, Blank and vehicle control well by dividing the signal at
665 nm by the signal at 620 nm. Normalizing the signal accounts for
possible fluorescence quenching due to the matrix effect of the
lysate. The .DELTA.F value (a measurement of SMN protein abundance
as a percent value) for each sample well is calculated by
subtracting the normalized average fluorescence for the Blank
control wells from the normalized fluorescence for each sample
well, then dividing this difference by the normalized average
fluorescence for the Blank control wells and multiplying the
resulting value by 100. The .DELTA.F value for each sample well
represents the SMN protein abundance from test compound-treated
samples. The .DELTA.F value for each sample well is divided by the
.DELTA.F value for the vehicle control wells to calculate the fold
increase in SMN protein abundance relative to the vehicle control.
Table 3 provides EC.sub.1.5.times.concentrations for SMN protein
expression that was obtained from the 7-point concentration data
generated according to the above procedure for particular compounds
of the present invention.
[0663] Particular compounds of the present invention exhibit an
EC.sub.1.5.times. concentration for SMN protein expression
.ltoreq.2 .mu.M.
[0664] More particular compounds of the present invention exhibit
an EC.sub.1.5.times. concentration for SMN protein expression
.ltoreq.0.3 .mu.M.
[0665] Most particular compounds of the present invention exhibit
an EC.sub.1.5.times. concentration for SMN protein expression
.ltoreq.0.1 .mu.M.
[0666] Table 4 provides the maximum fold increase of SMN protein
that was obtained from the 7-point concentration data generated
according to the above procedure for particular compounds of the
present invention
[0667] Particular compounds of the present invention exhibit a
maximum fold increase >1.4.
[0668] More particular compounds of the present invention exhibit a
maximum fold increase >1.7.
[0669] Most particular compounds of the present invention exhibit a
maximum fold increase >1.8.
TABLE-US-00011 TABLE 3 EC.sub.1.5x concentrations for SMN protein
expression. Ex. EC.sub.1.5x SMN protein (.mu.M) 1 0.7747 2 0.2984 3
1.47 4 0.5614 5 0.107 6 0.5305 7 0.2834 8 0.5175 9 1.527 10 0.329
11 0.321 12 0.7037 13 1.7564 14 0.7944 15 0.281 16 1.1992 17 0.5022
18 0.1346 19 1.3818 20 0.8065 21 0.6542 22 0.4468 23 0.5092 24
1.2616 25 0.5694 26 0.2853 27 0.3964 28 0.2868 29 0.4618 30 0.7612
31 0.2746 32 0.2028 33 0.5703 34 0.7793 35 1.2664 36 0.1094 37
0.1196 38 0.6124 39 0.0147 40 0.0276 41 0.0508 42 0.1488 43 0.104
44 0.13 45 0.5147 46 0.3584 47 0.611 48 0.0621 49 0.1733 50 0.0344
51 0.0561 52 0.1518 53 0.7455 54 0.056 55 0.7112 56 0.07 57 1.7363
58 0.1159 59 0.2749 60 0.107 61 62 63 1.0431 64 0.1192 65 0.1135 66
0.6108 67 0.866 68 0.057 69 0.1645 70 0.0187 71 0.4077 72 0.1324 73
0.7589 74 0.1524 75 0.3061 76 0.1629 77 0.2279 78 1.013 79 0.2559
80 0.52 81 0.2723 82 0.7698
TABLE-US-00012 TABLE 4 Maximum fold increase of SMN protein. Ex.
max. fold increase 1 1.6736 2 1.8878 3 1.7558 4 1.769 5 1.7757 6
1.8047 7 1.7936 8 1.7677 9 1.6085 10 1.735 11 1.7143 12 1.6512 13
1.624 14 1.5912 15 1.6859 16 1.6598 17 1.6966 18 1.7677 19 1.664 20
1.7789 21 1.7755 22 1.7566 23 1.6942 24 1.756 25 1.6652 26 1.8316
27 1.6617 28 1.7291 29 1.632 30 1.6734 31 1.7849 32 1.7579 33
1.7541 34 1.6527 35 1.6275 36 1.7018 37 1.7758 38 1.8706 39 1.8791
40 1.7607 41 1.7973 42 1.6988 43 1.7873 44 1.8243 45 1.6445 46
1.5572 47 1.7065 48 1.738 49 1.658 50 1.6607 51 1.7266 52 1.8152 53
1.6563 54 1.8217 55 1.8752 56 1.7299 57 1.578 58 1.7744 59 1.7116
60 1.7375 61 1.7077 62 1.5583 63 1.6807 64 1.7581 65 1.7675 66
1.5438 67 1.6552 68 1.6943 69 1.7612 70 1.933 71 1.4815 72 1.7095
73 1.5775 74 1.709 75 1.7035 76 1.7274 77 1.6649 78 1.7897 79
1.6574 80 1.5928 81 1.6719 82 1.7306
Sequence CWU 1
1
6119DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1gaaggaaggt gctcacatt 19222DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
2tctttatgtt tttggcgtct tc 22326DNAArtificial SequenceDescription of
Artificial Sequence Synthetic probe 3aaggagaaat gctggcatag agcagc
26421DNAArtificial SequenceDescription of Artificial Sequence
Synthetic probe 4cgcctggtca ccagggctgc t 21521DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
5caacggattt ggtcgtattg g 21625DNAArtificial SequenceDescription of
Artificial Sequence Synthetic primer 6tgatggcaac aatatccact ttacc
25
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