U.S. patent application number 16/768931 was filed with the patent office on 2020-10-29 for 1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors.
The applicant listed for this patent is Oryzon Genomics, S.A.. Invention is credited to Elena CARCELLER GONZ LEZ, Alberto ORTEGA MUNOZ, Jorge SALAS SOLANA.
Application Number | 20200339569 16/768931 |
Document ID | / |
Family ID | 1000005002136 |
Filed Date | 2020-10-29 |
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United States Patent
Application |
20200339569 |
Kind Code |
A1 |
CARCELLER GONZ LEZ; Elena ;
et al. |
October 29, 2020 |
1,2,4-OXADIAZOLE DERIVATIVES AS HISTONE DEACETYLASE 6
INHIBITORS
Abstract
The invention relates to compounds of Formula (I) as described
herein, useful as histone deacetylase 6 (HDAC6) inhibitors. The
invention also relates to pharmaceutical compositions comprising
these compounds and to their use in therapy.
Inventors: |
CARCELLER GONZ LEZ; Elena;
(Sant Cugat del Valles, ES) ; ORTEGA MUNOZ; Alberto;
(Vilassar de Dalt, ES) ; SALAS SOLANA; Jorge;
(Granollers, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Oryzon Genomics, S.A. |
Mdrid |
|
ES |
|
|
Family ID: |
1000005002136 |
Appl. No.: |
16/768931 |
Filed: |
December 5, 2018 |
PCT Filed: |
December 5, 2018 |
PCT NO: |
PCT/EP2018/083655 |
371 Date: |
June 2, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 413/14 20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04; C07D 413/14 20060101 C07D413/14 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 5, 2017 |
EP |
17382835.1 |
Jul 26, 2018 |
EP |
18382562.9 |
Claims
1. A compound of Formula (I) or a salt thereof: ##STR00163##
wherein m is 0, 1 or 2; each R.sup.1 is independently selected from
halo, methyl and trifluoromethyl; A is selected from: i) a 5- or
6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl ring
that is fully aromatic, and ii) a 9- or 10-membered bicyclic
heteroaryl ring consisting of a 5- or 6-membered monocyclic
heteroaryl ring fused to a saturated or partially unsaturated
carbocyclic or heterocyclic ring, wherein the 9- or 10-membered
bicyclic heterocyclic ring is linked to the rest of the molecule
through the 5- or 6-membered monocyclic heteroaryl ring, wherein A
contains one ring N atom at a position adjacent to the ring atom
through which ring A is attached to the rest of the molecule,
wherein A optionally contains from 1 to 3 additional ring
heteroatoms selected independently from N, O and S, and wherein A
is optionally substituted with one or two R.sup.2 and in addition A
is optionally substituted with one R.sup.3; each R.sup.2 is
independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-7 cycloalkyl and --(C.sub.1-6
alkylene)-OR.sup.4; R.sup.3 is selected from -L.sup.1-R.sup.5,
-L.sup.2-OR.sup.6, -L.sup.3-NR.sup.7R.sup.8,
-L.sup.4-CONR.sup.9R.sup.10, -L.sup.5-NR.sup.11COR.sub.12,
--Y-L.sup.6-OR.sup.6 and --Y-L.sup.7- NR.sup.7R.sup.8; L.sup.1,
L.sup.2, L.sup.3, L.sup.4 and L.sup.5 are each independently
selected from a bond and C.sub.1-6 alkylene; L.sup.6 and L.sup.1
are each independently selected from C.sub.2-6 alkylene; each Y is
independently selected from --O--, --NR.sup.13--, --CONR.sup.14--
and --NR.sup.15CO--; each R.sup.4 is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl and C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl; each R.sup.5
is independently selected from carbocyclyl, aryl, heterocyclyl and
heteroaryl, wherein the carbocyclyl, the aryl, the heterocyclyl and
the heteroaryl are each optionally substituted with one or more
R.sup.16; R.sup.6 and R.sup.12 are each independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and
-L.sup.1-R.sup.5; R.sup.7 and R.sup.8 are each independently
selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
--(C.sub.1-6 alkylene)-OR.sup.4 and -L.sup.1-R.sup.5; R.sup.9 and
R.sup.10 are each independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, --(C.sub.1-6 alkylene)-OR.sup.4 and
-L.sup.1-R.sup.5, or R.sup.9 and R.sup.10 taken together with the N
atom to which they are attached form a saturated 4- to 12-membered
heterocyclic ring optionally containing one additional heteroatom
selected from N, O and S, wherein said heterocyclic ring is
optionally substituted with one or more R.sup.16; R.sup.11,
R.sup.13, R.sup.14 and R.sup.15 are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl and --(C.sub.1-6
alkylene)-OR.sup.4; each R.sup.16 is independently selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkoxy,
C.sub.1-6 haloalkoxy, --OH, --NR.sup.17R.sup.18, --COR.sup.19,
--CN, -L.sup.8-carbocyclyl, -L.sup.8-aryl, -L.sup.8-heterocyclyl
and -L.sup.8-heteroaryl, wherein the carbocyclyl in
-L.sup.8-carbocyclyl, the aryl in -L.sup.8-aryl, the heterocyclyl
in -L.sup.8-heterocyclyl and the heteroaryl in -L.sup.8-heteroaryl
are each optionally substituted with one or more R.sup.20; each
L.sup.8 is independently selected from a bond and C.sub.1-6
alkylene; R.sup.17 and R.sup.18 are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl and C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl; R.sup.19 is
selected from hydrogen, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl;
and each R.sup.20 is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
--OH, --NR.sup.17R.sup.18, --COR.sup.19 and --CN.
2. The compound of claim 1, wherein A is selected from: i) a 5- or
6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl ring
that is fully aromatic, and ii) a 9- or 10-membered bicyclic
heteroaryl ring consisting of a 5- or 6-membered monocyclic
heteroaryl ring fused to a saturated or partially unsaturated
carbocyclic or heterocyclic ring, wherein the 9- or 10-membered
bicyclic heterocyclic ring is linked to the rest of the molecule
through the 5- or 6-membered monocyclic heteroaryl ring, wherein A
contains one ring N atom at a position adjacent to the ring atom
through which ring A is attached to the rest of the molecule,
wherein A optionally contains from 1 to 3 additional ring N atoms,
and wherein A is optionally substituted with one or two R.sup.2 and
in addition A is optionally substituted with one R.sup.3.
3. The compound of claim 1, wherein A is a 5- or 6-membered
monocyclic or 9- or 10-membered bicyclic heteroaryl ring that is
fully aromatic, wherein A contains one ring N atom at a position
adjacent to the ring atom through which ring A is attached to the
rest of the molecule, wherein A optionally contains from 1 to 3
additional ring N atoms, and wherein A is optionally substituted
with one or two R.sup.2 and in addition A is optionally substituted
with one R.sup.3.
4. The compound of claim 1, wherein A is selected from the cyclic
groups listed below: ##STR00164## wherein A is optionally
substituted with one or two R.sup.2 and in addition A is optionally
substituted with one R.sup.3.
5. The compound of claim 1, wherein A is selected from the cyclic
groups listed below: ##STR00165## wherein A is optionally
substituted with one or two R.sup.2 and in addition A is optionally
substituted with one R.sup.3.
6. The compound of claim 1, wherein the compound has formula (IIa)
or (IIb), or a salt thereof ##STR00166## wherein one of Z.sup.1,
Z.sup.2 and Z.sup.3 is H and the others are independently selected
from H and R.sup.2.
7. The compound of claim 1, wherein the compound has formula (IIIa)
or (IIIb), or a salt thereof ##STR00167## wherein one of Z.sup.1,
Z.sup.2 and Z.sup.3 is R.sup.3 or H, and the others are
independently selected from H and R.sup.2.
8. The compound of claim 1, wherein the compound has formula (IVa),
or a salt thereof ##STR00168## wherein one of Z.sup.1, Z.sup.2,
Z.sup.3 and Z.sup.4 is selected from R.sup.2, R.sup.3 and H, and
the others are independently selected from H and R.sup.2, with the
proviso that only up to two of Z.sup.1, Z.sup.2, Z.sup.3 and
Z.sup.4 are R.sup.2.
9. The compound of claim 1, wherein the compound has formula (IVb),
or a salt thereof ##STR00169## wherein one of Z.sup.1, Z.sup.2,
Z.sup.3 and Z.sup.4 is selected from R.sup.2, R.sup.3 and H, and
the others are independently selected from H and R.sup.2, with the
proviso that only up to two of Z.sup.1, Z.sup.2, Z.sup.3 and
Z.sup.4 are R.sup.2.
10. The compound of any one of claims 1 to 9, wherein m is 0.
11. The compound of any one of claims 1 to 10, wherein R.sup.3 is
selected from -L.sup.1-R.sup.5, -L.sup.2-OR.sup.6,
-L.sup.3-NR.sup.7R.sup.8, --CONR.sup.9R.sup.10,
--NR.sup.11COR.sup.12 and --Y-L.sup.7-NR.sup.7R.sup.8.
12. The compound of any one of claims 1 to 11, wherein R.sup.3 is
-L.sup.1-R.sup.5.
13. The compound of any one of claims 1 to 11, wherein R.sup.3 is
--CONR.sup.9R.sup.10 or --NR.sup.11COR.sup.12.
14. The compound of any one of claims 1 to 11, wherein R.sup.3 is
--Y-L.sup.7-NR.sup.7R.sup.8, and Y is selected from --O-- and
--NR.sup.13--.
15. The compound of any one of claims 1 to 11, wherein R.sup.3 is
--OR.sup.6, wherein R.sup.6 is -L.sup.1-R.sup.5, or R.sup.3 is
--NR.sup.7R.sup.8, wherein one of R.sup.7 or R.sup.8 is
-L.sup.1-R.sup.5.
16. The compound of any one of claims 1 to 11, wherein R.sup.3 is
-L.sup.2-OR.sup.6 or -L.sup.3-NR.sup.7R.sup.8, wherein L.sup.2 and
L.sup.3 are each independently selected from C.sub.1-6
alkylene.
17. The compound of any one of claims 1 to 16, wherein each R.sup.2
is independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl
and --(C.sub.1-4 alkylene)-OR.sup.4.
18. The compound of claim 1, which is a compound selected from
3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole,
3-(2-(1-Propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluorome-
thyl)-1,2,4-oxadiazole,
1-Butyl-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrid-
in-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
N,N-Diethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyr-
idin]-5-yl)oxy)propan-1-amine,
1-Butyl-N-ethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2--
yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
4-(3-((4'-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5-y-
l)oxy)propyl)morpholine,
3-(5'-(3-(4,4-Difluoropiperidin-1-yl)propoxy)-[2,2'-bipyridin]-4-yl)-5-(t-
rifluoromethyl)-1,2,4-oxadiazole,
3-(2-(3-(Piperidin-1-ylmethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyr-
idin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine,
N-Butyl-3-methoxy-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'--
bipyridin]-5-yl)propanamide,
N-(Cyclopropylmethyl)-N-methyl-4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3--
yl)-[2,2'-bipyridin]-5-amine,
N1,N1-Diethyl-N3-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bip-
yridin]-5-yl)propane-1,3-diamine,
N-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-methyl-4'-(5-(trifluoromethyl)-
-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5-amine,
N,N-Diethyl-3-(2-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-y-
l)pyrimidin-5-yloxy)propan-1-amine,
N1,N1-Diethyl-N3-methyl-N3-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-
-2,2'-bipyridin-5-yl)propane-1,3-diamine,
3-(2-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin--
4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
N-Ethyl-N-phenethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,-
2'-bipyridin]-5-yl)oxy)propan-1-amine,
2-Phenyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin-
]-5-yl)acetamide,
3-(2-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-
pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(4'-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-[2,2'-bipyridin]-4-yl)-5-(tr-
ifluoromethyl)-1,2,4-oxadiazole,
4-(2-((4'-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-4-y-
l)oxy)ethyl)morpholine,
N,N,1-Trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2--
yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin--
4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
1-Butyl-N,N-diethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridi-
n-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(t-
rifluoromethyl)-1,2,4-oxadiazole,
2-(4,4-Difluoropiperidin-1-yl)-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-
-3-yl)-[2,2'-bipyridin]-4-yl)acetamide,
N-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-4'-(5-(trifluoromethyl)-1,2,4-oxa-
diazol-3-yl)-[2,2'-bipyridin]-4 amine,
3-(2-(3-(Piperidin-1-ylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-y-
l)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-6--
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
1-Methyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin-
]-5-yl)piperidine-4-carboxamide,
3-Phenyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin-
]-4-yl)propanamide,
2-Cyclobutyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyr-
idin]-4-yl)acetamide,
N-(Piperidin-3-yl)-4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bi-
pyridine]-4-carboxamide,
3-(5'-(3-(1H-Pyrazol-1-yl)propoxy)-[2,2'-bipyridin]-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole,
(1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-
-pyrrolo[2,3-c]pyridin-3-yl)methanol,
3-(2-(3-(Methoxymethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4--
yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine,
3-(2-(1H-Pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole,
3-(2-(1-(Pyridin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)--
5-(trifluoromethyl)-1,2,4-oxadiazole,
N-((1-Methylpiperidin-4-yl)methyl)-4'-(5-(trifluoromethyl)-1,2,4-oxadiazo-
l-3-yl)-[2,2'-bipyridine]-4-carboxamide,
N-((1-Methylpiperidin-4-yl)methyl)-4'-(5-(trifluoromethyl)-1,2,4-oxadiazo-
l-3-yl)-[2,2'-bipyridine]-5-carboxamide,
3-(2-(1-(1-(2,2,2-Trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-
-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Methyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin--
4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3--
c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
N-Methyl-3-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-2,2'-bipyridin--
5-yloxy) propan-1-amine,
1-(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1-
H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine,
3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole,
N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-4-yl)pi-
peridine-3-carboxamide,
1-(2-Methoxyethyl)-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-
-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
3-(2-(1-(2-Methoxyethyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-y-
l)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluorome-
thyl)-1,2,4-oxadiazole,
3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(t-
rifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(Pyridin-3-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)--
5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(Pyridin-2-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)--
5-(trifluoromethyl)-1,2,4-oxadiazole,
2-(Methyl(3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyrid-
in]-5-yl)oxy)propyl)amino)ethan-1-ol,
3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(-
trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(2-(2-Methoxyethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(-
trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole,
N,N-Dimethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipy-
ridin]-5-yl)oxy)propan-1-amine,
3-(2-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluorom-
ethyl)-1,2,4-oxadiazole,
3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(-
trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluorome-
thyl)-1,2,4-oxadiazole,
3-(2-(1-(2-(1-Methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3--
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and
3-(2-(1-((1-Methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-
pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, or a salt
thereof.
19. A pharmaceutical composition which comprises a compound of any
one of claims 1 to 18 or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
20. A compound of any one of claims 1 to 18, or a pharmaceutically
acceptable salt thereof, for use as a medicament.
21. A compound of any one of claims 1 to 18, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition of claim
19, for use in the treatment of a disease associated with
HDAC6.
22. A compound of any one of claims 1 to 18, or a pharmaceutically
acceptable salt thereof, or a pharmaceutical composition of claim
19, for use in the treatment of a disease selected from cancer, an
autoimmune or inflammatory disease, transplant rejection, a
ciliopathy, a disease of the nervous system, a mental or behavioral
disorder, an infectious disease, a cardiovascular disease, muscle
atrophy and cachexia.
23. A method for treating a disease associated with HDAC6,
comprising administering a therapeutically effective amount of a
compound of any one of claims 1 to 18, or a pharmaceutically
acceptable salt thereof, to a patient in need thereof.
24. A method for treating a disease selected from cancer, an
autoimmune or inflammatory disease, transplant rejection, a
ciliopathy, a disease of the nervous system, a mental or behavioral
disorder, an infectious disease, a cardiovascular disease, muscle
atrophy and cachexia, comprising administering a therapeutically
effective amount of a compound of any one of claims 1 to 18, or a
pharmaceutically acceptable salt thereof, to a patient in need
thereof.
25. Use of a compound of any one of claims 1 to 18, or
pharmaceutically acceptable salt thereof, for the manufacture of a
medicament for the treatment of a disease associated with
HDAC6.
26. Use of a compound of any one of claims 1 to 18, or
pharmaceutically acceptable salt thereof, for the manufacture of a
medicament for the treatment of a disease selected from cancer, an
autoimmune or inflammatory disease, transplant rejection, a
ciliopathy, a disease of the nervous system, a mental or behavioral
disorder, an infectious disease, a cardiovascular disease, muscle
atrophy and cachexia.
27. Use of a compound of any one of claims 1 to 18, or
pharmaceutically acceptable salt thereof, for treating a disease
associated with HDAC6.
28. Use of a compound of any one of claims 1 to 18, or
pharmaceutically acceptable salt thereof, for treating a disease
selected from cancer, an autoimmune or inflammatory disease,
transplant rejection, a ciliopathy, a disease of the nervous
system, a mental or behavioral disorder, an infectious disease, a
cardiovascular disease, muscle atrophy and cachexia.
29. The compound for use according to any one of claims 20 to 22,
or the pharmaceutical composition for use according to claim 21 or
22, or the method of claim 23 or 24, or the use of any one of
claims 25 to 28, wherein the patient to be treated is a human.
30. In vitro method of inhibiting HDAC6, the method comprising
applying a compound of any one of claims 1 to 18, or a
pharmaceutically acceptable salt thereof, to a sample.
31. In vitro use of a compound of any one of claims 1 to 18, or a
pharmaceutically acceptable salt thereof, as an HDAC6 inhibitor.
Description
TECHNICAL FIELD
[0001] The invention relates to 1,2,4-oxadiazole derivatives useful
as histone deacetylase 6 inhibitors. The invention also relates to
pharmaceutical compositions comprising these compounds and to their
use in therapy.
BACKGROUND
[0002] Histone deacetylases (HDACs) are part of a large family of
enzymes that catalyze the removal of acetyl group from histones and
non-histone proteins. HDACs have crucial roles in numerous
biological processes, largely through their repressive influence on
transcription. In humans, there are four classes of HDACs which
include a total of 18 proteins: class I HDACs are HDAC1, HDAC2,
HDAC3 and HDAC8; class II HDACs are HDAC4, HDAC5, HDAC6, HDAC7,
HDAC9 and HDAC10; class III HDACs are Sir2-like proteins SIRT1,
SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7; and class IV HDACs,
which is HDAC11. The class II enzymes are further divided into two
subclasses, class IIa (HDAC4, HDAC5, HDAC7 and HDAC9) and class IIb
(HDAC6 and HDAC10).
[0003] Histone deacetylase 6 (HDAC6) catalyzes primarily the
deacetylation of non-histone substrates such as alpha-tubulin, heat
shock protein (Hsp)90 and cortactin.
[0004] HDAC6 activity has been reported to be involved in several
pathological conditions, including cancer, neurological,
ciliopathic, infectious, cardiovascular, infectious and immune and
inflammatory diseases, as discussed in more detail below. HDAC6
inhibitors have thus emerged as an attractive therapeutic approach
to treat a broad spectrum of diseases.
[0005] Many of the HDAC inhibitors currently in development are
pan-HDAC inhibitors, which are non-selective against different HDAC
isoforms. Pan-HDAC inhibitors are known to exhibit significant side
effects; in particular, toxic side effects have been associated
with inhibition of certain HDAC class I isoforms, particularly
HDAC1 and HDAC2.
[0006] It would be advantageous to identify HDAC inhibitors that
inhibit one or more, but not all HDAC isoforms, and in particular
compounds that inhibit HDAC6 while not inhibiting or inhibiting to
a much lower extent HDAC1 or HDAC2.
SUMMARY OF THE INVENTION
[0007] In one aspect, the present invention provides a compound of
Formula (I) as described below or a salt thereof:
##STR00001##
wherein m is 0, 1 or 2; each R.sup.1 is independently selected from
halo, methyl and trifluoromethyl; A is selected from: [0008] i) a
5- or 6-membered monocyclic or 9- or 10-membered bicyclic
heteroaryl ring that is fully aromatic, and [0009] ii) a 9- or
10-membered bicyclic heteroaryl ring consisting of a 5- or
6-membered monocyclic heteroaryl ring fused to a saturated or
partially unsaturated carbocyclic or heterocyclic ring, wherein the
9- or 10-membered bicyclic heterocyclic ring is linked to the rest
of the molecule through the 5- or 6-membered monocyclic heteroaryl
ring, wherein A contains one ring N atom at a position adjacent to
the ring atom through which ring A is attached to the rest of the
molecule, wherein A optionally contains from 1 to 3 additional ring
heteroatoms selected independently from N, O and S, and wherein A
is optionally substituted with one or two R.sup.2 and in addition A
is optionally substituted with one R.sup.3; each R.sup.2 is
independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-7 cycloalkyl and --(C.sub.1-6
alkylene)-OR.sup.4; R.sup.3 is selected from -L.sup.1-R.sup.5,
-L.sup.2-OR.sup.6, -L.sup.3-NR.sup.7R.sup.8,
-L.sup.4-CONR.sup.9R.sup.10, -L.sup.6-NR.sup.11COR.sup.12,
--Y-L.sup.6-OR.sup.6 and --Y-L.sup.7- NR.sup.7R.sup.8; L.sup.1,
L.sup.2, L.sup.3, L.sup.4 and L.sup.5 are each independently
selected from a bond and C.sub.1-6 alkylene; L.sup.6 and L.sup.7
are each independently selected from C.sub.2-6 alkylene; each Y is
independently selected from --O--, --NR.sup.13--, --CONR.sup.14--
and --NR.sup.15CO--; each R.sup.4 is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl and C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl; each R.sup.5
is independently selected from carbocyclyl, aryl, heterocyclyl and
heteroaryl, wherein the carbocyclyl, the aryl, the heterocyclyl and
the heteroaryl are each optionally substituted with one or more
R.sup.16; R.sup.6 and R.sup.12 are each independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and
-L.sup.1-R.sup.5; R.sup.7 and R.sup.8 are each independently
selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
--(C.sub.1-6 alkylene)-OR.sup.4 and -L.sup.1-R.sup.5; R.sup.9 and
R.sup.10 are each independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, --(C.sub.1-6 alkylene)-OR.sup.4 and
-L.sup.1-R.sup.5, or R.sup.9 and R.sup.10 taken together with the N
atom to which they are attached form a saturated 4- to 12-membered
heterocyclic ring optionally containing one additional heteroatom
selected from N, O and S, wherein said heterocyclic ring is
optionally substituted with one or more R.sup.16; R.sup.11,
R.sup.13, R.sup.14 and R.sup.15 are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl and --(C.sub.1-6
alkylene)-OR.sup.4; each R.sup.16 is independently selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkoxy,
C.sub.1-6 haloalkoxy, --OH, --NR.sup.17R.sup.18, --COR.sup.19,
--CN, -L.sup.8-carbocyclyl, -L.sup.8-aryl, -L.sup.8-heterocyclyl
and -L.sup.8-heteroaryl, wherein the carbocyclyl in
-L.sup.8-carbocyclyl, the aryl in -L.sup.8-aryl, the heterocyclyl
in -L.sup.8-heterocyclyl and the heteroaryl in -L.sup.8-heteroaryl
are each optionally substituted with one or more R.sup.20; each
L.sup.8 is independently selected from a bond and C.sub.1-6
alkylene; R.sup.17 and R.sup.18 are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl and C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl; R.sup.19 is
selected from hydrogen, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl;
and each R.sup.20 is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
--OH, --NR.sup.17R.sup.18, --COR.sup.19 and --CN.
[0010] The compounds of Formula (I) as described herein are
inhibitors of HDACs, particularly HDAC6. These compounds, and
pharmaceutical compositions comprising these compounds, are useful
for the treatment of diseases associated with HDAC6. For example,
the disease is cancer, an autoimmune or inflammatory disease,
transplant rejection, a ciliopathy, a disease of the nervous
system, a mental or behavioral disorder, an infectious disease, a
cardiovascular disease, muscle atrophy or cachexia.
[0011] The present invention further provides a pharmaceutical
composition comprising a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier.
[0012] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use as a
medicament.
[0013] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition comprising said compound and a
pharmaceutically acceptable carrier, for use in the treatment of a
disease associated with HDAC6.
[0014] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of a disease
associated with HDAC6.
[0015] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
treating a disease associated with HDAC6.
[0016] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use as a
HDAC6 inhibitor.
[0017] The present invention further provides a method for treating
a disease associated with HDAC6, comprising administering a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, to a patient in need
thereof.
[0018] The present invention further provides a method of
inhibiting HDAC6 activity, comprising administering to a patient in
need of said treatment an amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, sufficient to inhibit
HDAC6 activity.
[0019] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, or a
pharmaceutical composition comprising said compound and a
pharmaceutically acceptable carrier, for use in the treatment of a
disease selected from cancer, an autoimmune or inflammatory
disease, transplant rejection, a ciliopathy, a disease of the
nervous system, a mental or behavioral disorder, an infectious
disease, a cardiovascular disease, muscle atrophy and cachexia.
[0020] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of a disease
selected from cancer, an autoimmune or inflammatory disease,
transplant rejection, a ciliopathy, a disease of the nervous
system, a mental or behavioral disorder, an infectious disease, a
cardiovascular disease, muscle atrophy and cachexia.
[0021] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
treating a disease selected from cancer, an autoimmune or
inflammatory disease, transplant rejection, a ciliopathy, a disease
of the nervous system, a mental or behavioral disorder, an
infectious disease, a cardiovascular disease, muscle atrophy and
cachexia.
[0022] The present invention further provides a method for treating
a disease selected from cancer, an autoimmune or inflammatory
disease, transplant rejection, a ciliopathy, a disease of the
nervous system, a mental or behavioral disorder, an infectious
disease, a cardiovascular disease, muscle atrophy and cachexia,
comprising administering a therapeutically effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to a patient in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present invention provides a compound of Formula (I) or
a salt thereof:
##STR00002##
wherein m is 0, 1 or 2; each R.sup.1 is independently selected from
halo, methyl and trifluoromethyl; A is selected from: [0024] i) a
5- or 6-membered monocyclic or 9- or 10-membered bicyclic
heteroaryl ring that is fully aromatic, and [0025] ii) a 9- or
10-membered bicyclic heteroaryl ring consisting of a 5- or
6-membered monocyclic heteroaryl ring fused to a saturated or
partially unsaturated carbocyclic or heterocyclic ring, wherein the
9- or 10-membered bicyclic heterocyclic ring is linked to the rest
of the molecule through the 5- or 6-membered monocyclic heteroaryl
ring, wherein A contains one ring N atom at a position adjacent to
the ring atom through which ring A is attached to the rest of the
molecule, wherein A optionally contains from 1 to 3 additional ring
heteroatoms selected independently from N, O and S, and wherein A
is optionally substituted with one or two R.sup.2 and in addition A
is optionally substituted with one R.sup.3; each R.sup.2 is
independently selected from halo, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-7 cycloalkyl and --(C.sub.1-6
alkylene)-OR.sup.4; R.sup.3 is selected from -L.sup.1-R.sup.5,
-L.sup.2-OR.sup.6, -L.sup.3-NR.sup.7R.sup.8,
-L.sup.4-CONR.sup.9R.sup.10, -L.sup.5-NR.sup.11COR.sup.12,
--Y-L.sup.6-OR.sup.6 and --Y-L.sup.7- NR.sup.7R.sup.8; L.sup.1,
L.sup.2, L.sup.3, L.sup.4 and L.sup.5 are each independently
selected from a bond and C.sub.1-6 alkylene; L.sup.6 and L.sup.7
are each independently selected from C.sub.2-6 alkylene; each Y is
independently selected from --O--, --NR.sup.13--, --CONR.sup.14--
and --NR.sup.15CO--; each R.sup.4 is independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, cycloalkyl and
C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl; each R.sup.5 is independently
selected from carbocyclyl, aryl, heterocyclyl and heteroaryl,
wherein the carbocyclyl, the aryl, the heterocyclyl and the
heteroaryl are each optionally substituted with one or more
R.sup.16; R.sup.6 and R.sup.12 are each independently selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl and
-L.sup.1-R.sup.5; R.sup.7 and R.sup.8 are each independently
selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
--(C.sub.1-6 alkylene)-OR.sup.4 and -L.sup.1-R.sup.5; R.sup.9 and
R.sup.10 are each independently selected from hydrogen, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, --(C.sub.1-6 alkylene)-OR.sup.4 and
-L.sup.1-R.sup.5, or R.sup.9 and R.sup.10 taken together with the N
atom to which they are attached form a saturated 4- to 12-membered
heterocyclic ring optionally containing one additional heteroatom
selected from N, O and S, wherein said heterocyclic ring is
optionally substituted with one or more R.sup.16; R.sup.11,
R.sup.13, R.sup.14 and R.sup.15 are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl, C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl and --(C.sub.1-6
alkylene)-OR.sup.4; each R.sup.16 is independently selected from
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkoxy,
C.sub.1-6 haloalkoxy, --OH, --NR.sup.17R.sup.18, --COR.sup.19,
--CN, -L.sup.8-carbocyclyl, -L.sup.8-aryl, -L.sup.8-heterocyclyl
and -L.sup.8-heteroaryl, wherein the carbocyclyl in
-L.sup.8-carbocyclyl, the aryl in -L.sup.8-aryl, the heterocyclyl
in -L.sup.8-heterocyclyl and the heteroaryl in -L.sup.8-heteroaryl
are each optionally substituted with one or more R.sup.20; each
L.sup.8 is independently selected from a bond and C.sub.1-6
alkylene; R.sup.17 and R.sup.18 are each independently selected
from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-7
cycloalkyl and C.sub.3-7 cycloalkyl-C.sub.1-6 alkyl; R.sup.19 is
selected from hydrogen, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl;
and each R.sup.20 is independently selected from C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, halo, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy,
--OH, --NR.sup.17R.sup.18, --COR.sup.19 and --CN.
[0026] Embodiments of the present invention are outlined in the
following paragraphs. Each of the embodiments described below can
be combined with any other embodiment described herein that is not
inconsistent with the embodiment with which it is combined.
[0027] Combinations of substituents and variables envisioned by
this invention are only those that result in the formation of
stable compounds. The term "stable", as used herein, refers to
compounds which possess stability sufficient to allow manufacture
and which maintains the integrity of the compound for a sufficient
period of time to be useful for the purposes detailed herein (e.g.,
therapeutic administration to a subject).
[0028] Furthermore, each of the embodiments described herein
envisions within its scope the salts (for example pharmaceutically
acceptable salts) of the compounds described herein. Accordingly,
the phrase "or a salt thereof" (including also "or a
pharmaceutically acceptable salt thereof") is implicit in the
description of all compounds described herein. The invention also
specifically relates to all compounds described herein in non-salt
form.
[0029] In a compound of Formula (I) each R.sup.1 is independently
selected from halo, methyl and trifluoromethyl, and preferably each
R.sup.1 is fluoro. It will be understood that each substituent
R.sup.1 can be placed at any available ring C atom of the pyridine
ring to which R.sup.1 is attached.
[0030] Preferably, in a compound of Formula (I) m is 0.
[0031] In a compound of Formula (I), A is a cyclic group selected
from: [0032] i) a 5- or 6-membered monocyclic or 9- or 10-membered
bicyclic heteroaryl ring that is fully aromatic, and [0033] ii) a
9- or 10-membered bicyclic heteroaryl ring consisting of a 5- or
6-membered monocyclic heteroaryl ring fused to a saturated or
partially unsaturated carbocyclic or heterocyclic ring, wherein the
9- or 10-membered bicyclic heterocyclic ring is linked to the rest
of the molecule through the 5- or 6-membered monocyclic heteroaryl
ring, wherein A contains one ring N atom at a position adjacent to
the ring atom through which ring A is attached to the rest of the
molecule, wherein A optionally contains from 1 to 3 additional ring
heteroatoms selected independently from N, O and S (and wherein all
remaining ring atoms of A are carbon atoms), and wherein A is
optionally substituted with one or two R.sup.2 and in addition A is
optionally substituted with one R.sup.3. It will be understood that
ring A can be attached to the rest of the molecule via a ring C
atom or a ring N atom of A.
[0034] It will be understood that each substituent R.sup.2 or
R.sup.3 which is attached to ring A can be placed at any available
ring atom. In particular, any substituent R.sup.2 or R.sup.3 (if
present) can be attached to a ring C atom or a ring N atom of A. It
will further be understood that if ring A is a bicyclic ring, the
substituent(s) R.sup.2 and/or R.sup.3 can each be attached to any
available ring atom (e.g., any available ring C atom or any
available ring N atom) of any one of the rings constituting the
bicyclic ring group A. For example, if ring A is a bicyclic ring,
the one or two optional substituents R.sup.2 (if present) and the
optional substituent R.sup.3 (if present) may be attached to the
ring that does not contain the ring atom through which A is
attached to the rest of the molecule, or said optional
substituent(s) may be attached to the ring that contains the ring
atom through which A is attached to the rest of the molecule, or
the respective optional substituents may be attached to both rings
constituting the bicyclic ring group A. Moreover, it will be
understood that the one or two optional substituents R.sup.2 (if
present) and the optional substituent R.sup.3 (if present) are
typically each attached to a different ring atom of A. The
attachment of two of these optional substituents to the same ring
atom of A is possible only if the corresponding ring atom has
enough available attachment sites. For example, if A is a
2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl ring (which is composed
of a pyridine ring fused to a pyrrolidine ring), a ring atom
--CH.sub.2-- of the pyrrolidine moiety of the
2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl ring may be substituted
by two of the aforementioned optional substituents (e.g., by two
substituents R.sup.2, resulting in a ring atom
--C(R.sup.2)(R.sup.2)--, or by one substituent R.sup.2 and one
substituent R.sup.3, resulting in a ring atom
--C(R.sup.2)(R.sup.3)--).
[0035] Non-limiting examples of cyclic groups A include the groups
listed in Table 1 below, and any tautomeric form thereof:
TABLE-US-00001 TABLE 1 ##STR00003## ##STR00004## ##STR00005##
##STR00006## ##STR00007## ##STR00008## ##STR00009## ##STR00010##
##STR00011## ##STR00012## ##STR00013## ##STR00014## ##STR00015##
##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020##
##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025##
##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##
##STR00031## ##STR00032## ##STR00033## ##STR00034## ##STR00035##
##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040##
##STR00041## ##STR00042## ##STR00043## ##STR00044## ##STR00045##
##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##
##STR00051## ##STR00052## ##STR00053##
wherein any of said A groups depicted in Table 1 is optionally
substituted with one or two R.sup.2 and in addition any of said A
is optionally substituted with one R.sup.3.
[0036] In some embodiments, in a compound of Formula (I), A is
selected from the groups listed in Table 1 (including any
tautomeric form thereof), wherein A is optionally substituted with
one or two R.sup.2 and in addition A is optionally substituted with
one R.sup.3.
[0037] Preferably, in a compound of Formula (I), A is selected
from: [0038] i) a 5- or 6-membered monocyclic or 9- or 10-membered
bicyclic heteroaryl ring that is fully aromatic, and [0039] ii) a
9- or 10-membered bicyclic heteroaryl ring consisting of a 5- or
6-membered monocyclic heteroaryl ring fused to a saturated or
partially unsaturated carbocyclic or heterocyclic ring, wherein the
9- or 10-membered bicyclic heterocyclic ring is linked to the rest
of the molecule through the 5- or 6-membered monocyclic heteroaryl
ring, wherein A contains one ring N atom at a position adjacent to
the ring atom through which ring A is attached to the rest of the
molecule, wherein A optionally contains from 1 to 3, preferably 1
or 2, additional ring N atoms (and wherein all remaining ring atoms
of A are carbon atoms), and wherein A is optionally substituted
with one or two R.sup.2 and in addition A is optionally substituted
with one R.sup.3.
[0040] More preferably, in a compound of Formula (I), A is a 5- or
6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl ring
that is fully aromatic, wherein A contains one ring N atom at a
position adjacent to the ring atom through which ring A is attached
to the rest of the molecule, wherein A optionally contains from 1
to 3, preferably 1 or 2, additional ring N atoms (and wherein all
remaining ring atoms of A are carbon atoms), and wherein A is
optionally substituted with one or two, preferably one, R.sup.2 and
in addition A is optionally substituted with one R.sup.3.
[0041] Still more preferably, in a compound of Formula (I), A is
selected from the cyclic groups listed below:
##STR00054##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3.
[0042] It is particularly preferred that in a compound of Formula
(I), A is selected from the cyclic groups listed below:
##STR00055##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3.
[0043] In some embodiments, in a compound of Formula (I) A is
substituted, i.e. at least one of the optional substituents R.sup.2
and/or R.sup.3 is present. Said substitutent(s) can be attached to
any available ring atom of A (including any available ring N atom),
as previously indicated. In some embodiments, in a compound of
Formula (I), A is substituted with one R.sup.3 and in addition is
optionally substituted with one or two (preferably one)
R.sup.2.
[0044] In some other embodiments, in a compound of Formula (I), A
is unsubstituted (i.e. A does not have any optional substituent
R.sup.2 or R.sup.3).
[0045] In some preferred embodiments, in a compound of Formula (I),
A is
##STR00056##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3, wherein it is preferred that A is substituted with one
R.sup.3 and in addition is optionally substituted with one or two,
preferably one, R.sup.2. In certain embodiments, A is substituted
with one R.sup.3 and has no optional substituent(s) R.sup.2.
Preferably, the substituent R.sup.3, if present, is placed at the
ring C atom at position 4 or 5 of the pyridyl ring A, according to
the numbering indicated in the chemical drawing below:
##STR00057##
[0046] In some other preferred embodiments, in a compound of
Formula (I), A is
##STR00058##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3. Preferably, the one or two optional substituent(s) R.sup.2
(if present) and the optional substituent R.sup.3 (if present) are
attached to the pyrrole ring forming part of ring A. In certain
embodiments, A is unsubstituted. More preferably, A is substituted
with one R.sup.3 and in addition is optionally substituted with one
or two, preferably one, R.sup.2, wherein the substituent R.sup.3
and the one or two optional substituents R.sup.2 (if present) are
preferably attached to the pyrrole ring forming part of ring A.
[0047] In some other preferred embodiments, in a compound of
Formula (I), A is
##STR00059##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3. Preferably, the one or two optional substituent(s) R.sup.2
(if present) and the optional substituent R.sup.3 (if present) are
attached to the pyrrole ring forming part of ring A. In certain
preferred embodiments, A is unsubstituted. In certain other
preferred embodiments, A is substituted with one R.sup.3 and in
addition is optionally substituted with one or two, preferably one,
R.sup.2, wherein the substituent R.sup.3 and the one or two
optional substituents R.sup.2 (if present) are preferably attached
to the pyrrole ring forming part of ring A.
[0048] In some other preferred embodiments, in a compound of
Formula (I), A is
##STR00060##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3.
[0049] In some other preferred embodiments, in a compound of
Formula (I), A is
##STR00061##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3.
[0050] In some embodiments, in a compound of Formula (I), each
R.sup.2 is independently selected from halo, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl and --(C.sub.1-4
alkylene)-OR.sup.4.
[0051] Preferably, in a compound of Formula (I), each R.sup.2 is
independently selected from C.sub.1-4 alkyl, C.sub.1-4 haloalkyl
and --(C.sub.1-4 alkylene)-OR.sup.4. In some embodiments, each
R.sup.2 is independently selected from C.sub.1-4 alkyl and
--(C.sub.2-4 alkylene)-OR.sup.4. In some embodiments, one R.sup.2
is selected from methyl, ethyl, propyl and butyl (e.g., n-butyl).
In some embodiments, one R.sup.2 is
--CH.sub.2CH.sub.2--OCH.sub.3.
[0052] In some embodiments, in a compound of Formula (I), R.sup.3
is selected from -L.sup.1-R.sup.5, -L.sup.2-OR.sup.6,
-L.sup.3-NR.sup.7R.sup.8, --CONR.sup.9R.sup.10,
--NR.sup.11COR.sup.12 and --Y-L.sup.7-NR.sup.7R.sup.8, wherein
preferably Y is selected from --O-- and --NR.sup.13--.
[0053] In some preferred embodiments, in a compound of Formula (I),
R.sup.3 is -L.sup.1-R.sup.5, wherein preferably R.sup.5 is selected
from heterocyclyl and heteroaryl, wherein the heterocyclyl and the
heteroaryl are each optionally substituted with one or more
R.sup.16.
[0054] In some preferred embodiments, in a compound of Formula (I),
R.sup.3 is --CONR.sup.9R.sup.10 or --NR.sup.11COR.sup.12.
[0055] In some preferred embodiments, in a compound of Formula (I),
R.sup.3 is --Y-L.sup.7-NR.sup.7R.sup.8, wherein Y is selected from
--O-- and --NR.sup.13--.
[0056] In some preferred embodiments, in a compound of Formula (I),
R.sup.3 is --OR.sup.6, wherein R.sup.6 is -L.sup.1-R.sup.5, wherein
L.sup.1 in said -L.sup.1-R.sup.5 is preferably C.sub.1-6 alkylene,
more preferably C.sub.1-4 alkylene, and R.sup.5 in said
-L.sup.1-R.sup.5 is preferably selected from heterocyclyl and
heteroaryl, wherein the heterocyclyl and the heteroaryl are each
optionally substituted with one or more R.sup.16, or R.sup.3 is
--NR.sup.7R.sup.8, wherein one of R.sup.7 or R.sup.8 is
-L.sup.1-R.sup.5, wherein L.sup.1 in said -L.sup.1-R.sup.5 is
preferably C.sub.1-6 alkylene, more preferably C.sub.1-4 alkylene,
and R.sup.5 in said -L.sup.1-R.sup.5 is preferably selected from
heterocyclyl and heteroaryl, wherein the heterocyclyl and the
heteroaryl are each optionally substituted with one or more
R.sup.16.
[0057] In some preferred embodiments, in a compound of Formula (I),
R.sup.3 is -L.sup.2-OR.sup.6 or -L.sup.3-NR.sup.7R.sup.8, wherein
L.sup.2 and L.sup.3 are each independently selected from C.sub.1-6
alkylene, preferably C.sub.1-4 alkylene.
[0058] In some embodiments, in a compound of Formula (I), R.sup.11,
R.sup.13, R.sup.14 and R.sup.15 are each independently selected
from hydrogen, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl.
[0059] In some embodiments, in a compound of Formula (I), each
R.sup.16 is independently selected from C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, halo, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, --OH,
--NR.sup.17R.sup.18, --COR.sup.19, --CN and C.sub.3-7
cycloalkyl.
[0060] A preferred embodiment relates to a compound of Formula (I),
or a salt thereof, wherein:
A is a cyclic group selected from: [0061] i) a 5- or 6-membered
monocyclic or 9- or 10-membered bicyclic heteroaryl ring that is
fully aromatic, and [0062] ii) a 9- or 10-membered bicyclic
heteroaryl ring consisting of a 5- or 6-membered monocyclic
heteroaryl ring fused to a saturated or partially unsaturated
carbocyclic or heterocyclic ring, wherein the 9- or 10-membered
bicyclic heterocyclic ring is linked to the rest of the molecule
through the 5- or 6-membered monocyclic heteroaryl ring, and
preferably A is a 5- or 6-membered monocyclic or 9- or 10-membered
bicyclic heteroaryl ring that is fully aromatic, wherein A contains
one ring N atom at a position adjacent to the ring atom through
which ring A is attached to the rest of the molecule, wherein A
optionally contains from 1 to 3, preferably 1 or 2, additional ring
N atoms (and wherein all remaining ring atoms of A are carbon
atoms), and wherein A is optionally substituted with one or two
R.sup.2 and in addition A is optionally substituted with one
R.sup.3; R.sup.3, if present, is selected from -L.sup.1-R.sup.5,
-L.sup.2-OR.sup.6, -L.sup.3-NR.sup.7R.sup.8, --CONR.sup.9R.sup.10,
--NR.sup.11COR.sup.12 and --Y-L.sup.7-NR.sup.7R.sup.8, wherein
preferably Y is selected from --O-- and --NR.sup.13--; and wherein
preferably m is 0.
[0063] A more preferred embodiment relates to a compound of Formula
(I), or a salt thereof, wherein:
A is selected from the cyclic groups listed below:
##STR00062##
and preferably A is selected from the cyclic groups listed
below:
##STR00063##
wherein A is optionally substituted with one or two, preferably
one, R.sup.2 and in addition A is optionally substituted with one
R.sup.3; R.sup.3, if present, is selected from -L.sup.1-R.sup.5,
-L.sup.2-OR.sup.6, -L.sup.3-NR.sup.7R.sup.8, --CONR.sup.9R.sup.10,
--NR.sup.11COR.sup.12 and --Y-L.sup.7-NR.sup.7R.sup.8, wherein
preferably Y is selected from --O-- and --NR.sup.13--; and wherein
preferably m is 0.
[0064] In a particularly preferred embodiment, the invention
provides a compound of Formula (I), or a salt thereof, having
formula (IIa) or (IIb):
##STR00064##
wherein one of Z.sup.1, Z.sup.2 and Z.sup.3 is H and the others are
independently selected from H and R.sup.2, and preferably all of
Z.sup.1, Z.sup.2 and Z.sup.3 are H; and wherein preferably R.sup.3
is selected from -L.sup.1-R.sup.5, -L.sup.2-OR.sup.6,
-L.sup.3-NR.sup.7R.sup.8, --CONR.sup.9R.sup.10,
--NR.sup.11COR.sup.12 and --Y-L.sup.7-NR.sup.7R.sup.8, and more
preferably R.sup.3 is selected from --OR.sup.6, --NR.sup.7R.sup.8,
--NR.sup.11COR.sup.12 and --Y-L.sup.7-NR.sup.7R.sup.8, wherein
preferably Y is selected from --O-- and --NR.sup.13--; and wherein
preferably m is 0. In certain preferred embodiments, in a compound
of Formula (IIa) or (IIb) R.sup.3 is --NR.sup.11COR.sup.12. In
certain other preferred embodiments, in a compound of Formula (IIa)
or (IIb) R.sup.3 is --Y-L.sup.7-NR.sup.7R.sup.8 and Y is selected
from --O-- and --NR.sup.13--. In certain other preferred
embodiments, in a compound of Formula (IIa) or (IIb) R.sup.3 is
--OR.sup.6, wherein R.sup.6 is -L.sup.1-R.sup.5, wherein L.sup.1 in
said -L.sup.1-R.sup.5 is preferably C.sub.1-4 alkylene and R.sup.5
in said -L.sup.1-R.sup.5 is preferably selected from heterocyclyl
and heteroaryl, wherein the heterocyclyl and the heteroaryl are
each optionally substituted with one or more R.sup.16, or R.sup.3
is --NR.sup.7R.sup.8, wherein one of R.sup.7 or R.sup.8 is
-L.sup.1-R.sup.5, wherein L.sup.1 in said -L.sup.1-R.sup.5 is
preferably C.sub.1-4 alkylene and R.sup.5 in said -L.sup.1-R.sup.5
is preferably selected from heterocyclyl and heteroaryl, wherein
the heterocyclyl and the heteroaryl are each optionally substituted
with one or more R.sup.16.
[0065] In another particularly preferred embodiment, the invention
relates to a compound of Formula (I), or a salt thereof, having
formula (IIIa) or (IIIb):
##STR00065##
wherein one of Z.sup.1, Z.sup.2 and Z.sup.3 is R.sup.3 or H,
preferably R.sup.3, and the others are independently selected from
H and R.sup.2; wherein preferably R.sup.3, if present, is selected
from -L.sup.1-R.sup.5, -L.sup.2-OR.sup.6, -L.sup.3-NR.sup.7R.sup.8,
--CONR.sup.9R.sup.10, --NR.sup.11COR.sup.12 and
--Y-L.sup.7-NR.sup.7R.sup.8, wherein preferably Y is selected from
--O-- and --NR.sup.13--, and more preferably R.sup.3 is selected
from -L.sup.1-R.sup.5, -L.sup.2-OR.sup.6, -L.sup.3-NR.sup.7R.sup.8
and --CONR.sup.9R.sup.10, wherein preferably L.sup.2 and L.sup.3
are each independently selected from C.sub.1-4 alkylene; and
wherein preferably m is 0. In certain preferred embodiments, the
compound of Formula (I) is a compound of formula (IIIa). In certain
preferred embodiments, the compound of Formula (I) is a compound of
formula (IIIb). In certain preferred embodiments, in a compound of
Formula (IIIa) or (IIIb) one of Z.sup.1, Z.sup.2 and Z.sup.3,
preferably Z.sup.2, is R.sup.3 and the others are independently
selected from H and R.sup.2, and R.sup.3 is --CONR.sup.9R.sup.10.
In certain other preferred embodiments, in a compound of Formula
(IIIa) or (IIIb) one of Z.sup.1, Z.sup.2 and Z.sup.3 is R.sup.3 and
the others are independently selected from H and R.sup.2, and
R.sup.3 is -L.sup.1-R.sup.5, wherein preferably R.sup.5 in said
-L.sup.1-R.sup.5 is selected from heterocyclyl and heteroaryl,
wherein the heterocyclyl and the heteroaryl are each optionally
substituted with one or more R.sup.16. In certain other preferred
embodiments, in a compound of Formula (IIIa) or (IIIb) one of
Z.sup.1, Z.sup.2 and Z.sup.3 is R.sup.3 and the others are
independently selected from H and R.sup.2, and R.sup.3 is
-L.sup.2-OR.sup.6 or -L.sup.3-NR.sup.7R.sup.8 wherein L.sup.2 and
L.sup.3 are each independently selected from C.sub.1-4
alkylene.
[0066] In another particularly preferred embodiment, the invention
relates to a compound of Formula (I), or a salt thereof, having
formula (IVa):
##STR00066##
wherein one of Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 is selected
from R.sup.2, R.sup.3 and H, and the others are independently
selected from H and R.sup.2, with the proviso that only up to two
of Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 are R.sup.2; and wherein
preferably m is 0. In certain preferred embodiments, in a compound
of Formula (IVa) Z.sup.4 is selected from R.sup.2, R.sup.3 and H,
and Z.sup.1, Z.sup.2 and Z.sup.3 are independently selected from H
and R.sup.2 with the proviso that only up to two of Z.sup.1,
Z.sup.2, Z.sup.3 and Z.sup.4 are R.sup.2, and wherein preferably
Z.sup.3 is H. In certain preferred embodiments, in a compound of
Formula (IVa) Z.sup.4 is selected from R.sup.2, R.sup.3 and H, and
Z.sup.1, Z.sup.2 and Z.sup.3 are H.
[0067] In another particularly preferred embodiment, the invention
relates to a compound of Formula (I), or a salt thereof, having
formula (IVa-1):
##STR00067##
wherein one of Z.sup.1, Z.sup.2 and Z.sup.3 is R.sup.3 or H, and
the others are independently selected from H and R.sup.2, and
preferably all of Z.sup.1, Z.sup.2 and Z.sup.3 are H; and wherein
preferably m is 0.
[0068] In another particularly preferred embodiment, the invention
relates to a compound of Formula (I), or a salt thereof, having
formula (IVb):
##STR00068##
wherein one of Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 is selected
from R.sup.2, R.sup.3 and H, and the others are independently
selected from H and R.sup.2, with the proviso that only up to two
of Z.sup.1, Z.sup.2, Z.sup.3 and Z.sup.4 are R.sup.2; and wherein
preferably m is 0.
[0069] In another particularly preferred embodiment, the invention
relates to a compound of Formula (I), or a salt thereof, having
formula (IVb-1):
##STR00069##
wherein one of Z.sup.1, Z.sup.2 and Z.sup.3 is R.sup.3 or H, and
the others are independently selected from H and R.sup.2, and
wherein preferably m is 0.
[0070] In certain embodiments, the invention provides a compound of
Formula (I), or a salt thereof, selected from: [0071]
3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole, [0072]
3-(2-(1-Propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluorome-
thyl)-1,2,4-oxadiazole, [0073]
1-Butyl-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrid-
in-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, [0074]
N,N-Diethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyr-
idin]-5-yl)oxy)propan-1-amine, [0075]
1-Butyl-N-ethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2--
yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, [0076]
4-(3-((4'-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5-y-
l)oxy)propyl)morpholine, [0077]
3-(5'-(3-(4,4-Difluoropiperidin-1-yl)propoxy)-[2,2'-bipyridin]-4-yl)-5-(t-
rifluoromethyl)-1,2,4-oxadiazole, [0078]
3-(2-(3-(Piperidin-1-ylmethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyr-
idin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0079]
4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine, [0080]
N-Butyl-3-methoxy-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'--
bipyridin]-5-yl)propanamide, [0081]
N-(Cyclopropylmethyl)-N-methyl-4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3--
yl)-[2,2'-bipyridin]-5-amine, [0082]
N1,N1-Diethyl-N3-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bip-
yridin]-5-yl)propane-1,3-diamine, [0083]
N-(3-(4,4-Difluoropiperidin-1-yl)propyl)-N-methyl-4'-(5-(trifluoromethyl)-
-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5-amine, [0084]
N,N-Diethyl-3-(2-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-y-
l)pyrimidin-5-yloxy)propan-1-amine, [0085]
N1,N1-Diethyl-N3-methyl-N3-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-
-2,2'-bipyridin-5-yl)propane-1,3-diamine, [0086]
3-(2-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin--
4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0087]
N-Ethyl-N-phenethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,-
2'-bipyridin]-5-yl)oxy)propan-1-amine, [0088]
2-Phenyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin-
]-5-yl)acetamide, [0089]
3-(2-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-
pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0090]
3-(4'-(2-(4,4-Difluoropiperidin-1-yl)ethoxy)-[2,2'-bipyridin]-4-yl)-5-(tr-
ifluoromethyl)-1,2,4-oxadiazole, [0091]
4-(2-((4'-(5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl)[2,2'-bipyridin]-4-yl-
)oxy)ethyl)morpholine, [0092]
N,N,1-Trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2--
yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, [0093]
3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin--
4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0094]
1-Butyl-N,N-diethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridi-
n-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, [0095]
3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(t-
rifluoromethyl)-1,2,4-oxadiazole, [0096]
2-(4,4-Difluoropiperidin-1-yl)-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-
-3-yl)-[2,2'-bipyridin]-4-yl)acetamide, [0097]
N-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-4'-(5-(trifluoromethyl)-1,2,4-oxa-
diazol-3-yl)-[2,2'-bipyridin]-4-amine, [0098]
3-(2-(3-(Piperidin-1-ylmethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-y-
l)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0099]
3-(2-(1-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-6--
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0100]
1-Methyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin-
]-5-yl)piperidine-4-carboxamide, [0101]
3-Phenyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin-
]-4-yl)propanamide, [0102]
2-Cyclobutyl-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyr-
idin]-4-yl)acetamide, [0103]
N-(Piperidin-3-yl)-4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bi-
pyridine]-4-carboxamide, [0104]
3-(5'-(3-(1H-Pyrazol-1-yl)propoxy)-[2,2'-bipyridin]-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole, [0105]
(1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-
-pyrrolo[2,3-c]pyridin-3-yl)methanol,
3-(2-(3-(Methoxymethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4--
yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0106]
4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl)morpholine, [0107]
3-(2-(1H-Pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole, [0108]
3-(2-(1-(Pyridin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)--
5-(trifluoromethyl)-1,2,4-oxadiazole, [0109]
N-((1-Methylpiperidin-4-yl)methyl)-4'-(5-(trifluoromethyl)-1,2,4-oxadiazo-
l-3-yl)-[2,2'-bipyridine]-4-carboxamide, [0110]
N-((1-Methylpiperidin-4-yl)methyl)-4'-(5-(trifluoromethyl)-1,2,4-oxadiazo-
l-3-yl)-[2,2'-bipyridine]-5-carboxamide, [0111]
3-(2-(1-(1-(2,2,2-Trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-
-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0112]
3-(2-(1-Methyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin--
4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0113]
3-(2-(1-Butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3--
c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0114]
N-Methyl-3-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-2,2'-bipyridin--
5-yloxy)propan-1-amine, [0115]
1-(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1-
H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine, [0116]
3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0117]
N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-4-yl)pi-
peridine-3-carboxamide, [0118]
1-(2-Methoxyethyl)-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-
-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, [0119]
3-(2-(1-(2-Methoxyethyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-y-
l)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0120]
3-(2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluorome-
thyl)-1,2,4-oxadiazole, [0121]
3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(t-
rifluoromethyl)-1,2,4-oxadiazole, [0122]
3-(2-(1-(Pyridin-3-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)--
5-(trifluoromethyl)-1,2,4-oxadiazole, [0123]
3-(2-(1-(Pyridin-2-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)--
5-(trifluoromethyl)-1,2,4-oxadiazole, [0124]
2-(Methyl(3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyrid-
in]-5-yl)oxy)propyl)amino)ethan-1-ol, [0125]
3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(-
trifluoromethyl)-1,2,4-oxadiazole, [0126]
3-(2-(2-(2-Methoxyethyl)-2H-pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)-5-(-
trifluoromethyl)-1,2,4-oxadiazole, [0127]
3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0128]
N,N-Dimethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipy-
ridin]-5-yl)oxy)propan-1-amine, [0129]
3-(2-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluorom-
ethyl)-1,2,4-oxadiazole, [0130]
3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(-
trifluoromethyl)-1,2,4-oxadiazole, [0131]
3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluorome-
thyl)-1,2,4-oxadiazole, [0132]
3-(2-(1-(2-(1-Methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3--
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and [0133]
3-(2-(1-((1-Methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-
pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, or a salt
thereof.
[0134] Further examples of compounds of Formula (I) according to
the invention include the compounds shown below and salts
thereof:
##STR00070## ##STR00071## ##STR00072## ##STR00073## ##STR00074##
##STR00075## ##STR00076## ##STR00077##
[0135] In a particularly preferred embodiment, the invention
provides a compound of Formula (I), or a salt thereof, selected
from [0136]
N,N-Diethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyr-
idin]-5-yl)oxy)propan-1-amine, [0137]
1-Butyl-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyrid-
in-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, [0138]
N,N,1-Trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2--
yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, [0139]
3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin--
4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0140]
2-(4,4-Difluoropiperidin-1-yl)-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-
-3-yl)-[2,2'-bipyridin]-4-yl)acetamide, [0141]
3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(-
trifluoromethyl)-1,2,4-oxadiazole, [0142]
3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluorome-
thyl)-1,2,4-oxadiazole, [0143]
3-(2-(1-(2-(1-Methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3--
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, [0144]
3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, and [0145]
3-(2-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluorom-
ethyl)-1,2,4-oxadiazole, or a salt thereof.
[0146] The invention also relates to any individual compound or any
subgroup of the compounds recited in the lists above, and their
salts.
[0147] Moreover, the present invention also relates to a compound
of Formula (I), or a salt thereof, as described and defined herein
(including any of the preferred definitions/embodiments described
herein above), wherein it is preferred that the following compounds
are excluded from Formula (I): [0148]
3-(2-(thiazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0149]
3-(2-(2-methylthiazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-
-oxadiazole, [0150]
N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
thiazole-2-carboxamide, [0151]
3-(2-(oxazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0152]
3-(2-(2-methyloxazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4--
oxadiazole, [0153]
N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
oxazole-2-carboxamide, [0154]
3-(2-(1H-imidazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole-
, [0155]
3-(2-(1,2-dimethyl-1H-imidazol-4-yl)pyridin-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole, [0156]
N,N,1-trimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2--
yl)-1H-imidazole-2-carboxamide, [0157]
3-(2-(1H-pyrrol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0158]
3-(2-(5-methyl-1H-pyrrol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0159]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-pyrrole-2-carboxamide, [0160]
3-(2-(1,2,4-thiadiazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadi-
azole, [0161]
3-(2-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0162]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1,2,4-thiadiazole-3-carboxamide, [0163]
3-(2-(1,2,4-oxadiazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadia-
zole, [0164]
3-methyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1,2-
,4-oxadiazole, [0165]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1,2,4-oxadiazole-3-carboxamide, [0166]
3-(2-(1H-1,2,4-triazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadi-
azole, [0167]
3-(2-(3-methyl-1H-1,2,4-triazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0168]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-1,2,4-triazole-3-carboxamide, [0169]
3-(2-(1H-pyrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0170]
3-(2-(3-methyl-1H-pyrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1-
,2,4-oxadiazole, [0171]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-pyrazole-3-carboxamide, [0172]
3-(2-(1H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadi-
azole, [0173]
3-(2-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0174]
N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1H-1,2,3-triazole-1-carboxamide, [0175]
3-(2-(4H-1,2,4-triazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadi-
azole, [0176]
3-(2-(5-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0177]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-4H-1,2,4-triazole-3-carboxamide, [0178]
3-(2-(1,3,4-oxadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadia-
zole, [0179]
3-(2-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole, [0180]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1,3,4-oxadiazole-2-carboxamide, [0181]
3-(2-(1,3,4-thiadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadi-
azole, [0182]
3-(2-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0183]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1,3,4-thiadiazole-2-carboxamide, [0184]
3-(2-(2H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadi-
azole, [0185]
3-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,-
2,4-oxadiazole, [0186]
N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-2H-1,2,3-triazole-2-carboxamide, [0187]
3-(2-(2H-tetrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole-
, [0188]
3-(2-(2-methyl-2H-tetrazol-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-
-1,2,4-oxadiazole, [0189]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-2H-tetrazole-2-carboxamide, [0190]
3-(2-(1,3,5-triazin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazo-
le, [0191]
3-(2-(4-methyl-1,3,5-triazin-2-yl)pyridin-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole, [0192]
N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
-1,3,5-triazine-2-carboxamide, [0193]
3-(2-(pyridazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0194]
3-(2-(6-methylpyridazin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole, [0195]
N,N-dimethyl-6-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
pyridazine-3-carboxamide, [0196]
3-(2-(pyrimidin-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0197]
3-(2-(2-methylpyrimidin-4-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole, [0198]
N,N-dimethyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
pyrimidine-2-carboxamide, [0199]
3-(2-(pyrazin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0200]
3-(2-(5-methylpyrazin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-
-oxadiazole, [0201]
N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-
pyrazine-2-carboxamide, [0202]
3-(2-(indolizin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
[0203]
3-(2-(1H-indol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadia-
zole, [0204]
3-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-
-1,2,4-oxadiazole, [0205]
3-(2-(1-methyl-1H-indazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-ox-
adiazole, [0206]
3-(2-(benzo[d]isothiazol-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxa-
diazole, [0207]
3-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)benzo[d]isoxa-
zole, [0208]
3-(2-(isoquinolin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole-
, [0209]
3-(2-(1,8-naphthyridin-2-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole, and [0210]
3-(2-(phthalazin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole.
[0211] Accordingly, it is preferred that the compounds mentioned in
the preceding sentence as well as salts and tautomers thereof are
excluded.
[0212] Definitions of specific terms as used in the specification
and claims are provided below. All other technical and scientific
terms used herein and not defined below shall have the same meaning
as commonly understood by one of ordinary skill in the art to which
this invention pertains. In the case of conflict, the present
specification, including definitions, will control.
[0213] In the case of conflict between the chemical structures and
names of the compounds disclosed herein, the chemical structures
will control.
[0214] At various places in the present specification, substituents
of compounds of the invention are disclosed in groups or in ranges.
It is specifically intended that the invention include each and
every individual subcombination of the members of such groups and
ranges.
[0215] At various places in the present specification various aryl,
heteroaryl, carbocyclyl and heterocyclyl groups are described.
Unless otherwise specified, these rings can be attached to the rest
of the molecule at any ring member as permitted by valency. For
example, the term "pyridyl" (or pyridinyl) may refer to a
pyridin-2-yl, pyridin-3-yl or pyridin-4-yl ring, and the term
"piperidinyl" may refer to a piperidin-1-yl, piperidin-2-yl,
piperidin-3-yl or piperidin-4-yl ring.
[0216] The term "n-membered" where n is an integer describes the
number of ring-forming atoms in a ring system where the number of
ring-forming atoms is n. For example, phenyl is an example of a
6-membered aryl, cyclopropyl is an example of a 3-membered
carbocyclyl, pyrazolyl is an example of a 5-membered heteroaryl,
quinolinyl is an example of a 10-membered heteroaryl, piperidinyl
is an example of a 6-membered heterocyclyl, and decahydroquinolinyl
is an example of a 10-membered heterocyclyl.
[0217] The term "C.sub.y-z", where y and z are integers, used in
combination with a chemical group, designates a range of the number
of carbon atoms in the chemical group, with y and z being the
endpoints, which are included. Examples include C.sub.1-6,
C.sub.2-6, C.sub.3-7 and the like.
[0218] The term "C.sub.y-z alkyl" refers to a saturated straight or
branched acyclic hydrocarbon group having y to z carbon atoms.
Thus, a C.sub.1-6 alkyl is an alkyl having from one to six carbon
atoms. Examples of C.sub.1-6 alkyl include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, or
sec-hexyl.
[0219] The term "C.sub.y-z alkoxy" refers to an C.sub.y-z alkyl
group (as defined above) covalently linked to an oxygen atom, i.e.
a group of formula --O-alkyl where the alkyl group has y to z
carbon atoms. The term C.sub.1-6 alkoxy thus refers to an alkoxy
group wherein the alkyl moiety has from 1 to 6 carbon atoms.
Examples of C.sub.1-6 alkoxy include, but are not limited to,
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy,
sec-butoxy, tert-butoxy, n-pentoxy or n-hexyloxy.
[0220] The term "C.sub.y-z alkylene" refers to a saturated straight
or branched divalent acyclic hydrocarbon group having from y to z
carbon atoms. Thus, for example, a C.sub.1-6 alkylene is an
alkylene having from one to six carbon atoms. Preferably, said
akylene groups are polymethylene groups, i.e. (CH.sub.2).sub.x,
where x indicates the number of CH.sub.2 units in the respective
alkylene group, like from 1 to 6. Examples of a C.sub.1-6 alkylene
include, but are not limited to, methylene, ethylene, propylene,
n-butylene, n-pentylene or n-hexylene.
[0221] The term "aryl", unless otherwise specified, refers to a 6-
to 18-membered hydrocarbon ring system which contains only hydrogen
and carbon atoms and which is monocyclic or multicyclic (e.g.
fused, bridged or spiro rings), wherein at least one of the rings
in the ring system is aromatic. Aryl as used herein thus covers
fully aromatic hydrocarbon ring systems, i.e. where all the ring(s)
in the system are aromatic, like phenyl, naphthyl or anthracyl, as
well as ring systems in which an aromatic hydrocarbon ring (e.g.
phenyl) is fused to one or more non-aromatic (i.e. saturated or
partially unsaturated) hydrocarbon rings, like indanyl, indenyl,
1-oxo-2,3-dihydro-1H-indenyl, tetrahydronaphthyl, fluorenyl and the
like. In some embodiments, the point of attachment is on the
aromatic hydrocarbon ring. In some embodiments, the aryl group has
from 6 to 10 carbon atoms. In some embodiments, the aryl group is a
fully aromatic hydrocarbon ring system. Preferably, the aryl group
is phenyl. Aryl groups can be optionally substituted, as indicated
elsewhere in the specification, and the substituent(s) may be
placed at any available position in the ring system.
[0222] The term "bond" refers to a single bond, unless specifically
indicated otherwise.
[0223] The term "carbocyclyl", unless otherwise specified, refers
to a 3- to 18-membered non-aromatic hydrocarbon ring system which
contains only hydrogen and carbon atoms and which is monocyclic or
multicyclic (e.g. fused, bridged or spiro rings). Each of the rings
in the ring system is fully saturated or partially unsaturated,
i.e. none of the rings is aromatic. One or more ring carbon atoms
of a carbocyclyl group can each be optionally oxidized to form a CO
group. In some embodiments, carbocyclyl contains from 3 to 10
carbon atoms. In some embodiments, carbocyclyl is a fully saturated
hydrocarbon ring system, i.e. it does not contain any unsaturation;
a fully saturated carbocyclyl is also referred herein as
"cycloalkyl". Examples of carbocyclyl include, but are not limited
to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,
cyclooctenyl, adamantyl, bicyclo[2.2.1]heptanyl,
bicyclo[2.2.2]octanyl, decalinyl, and the like. Preferably,
carbocyclyl is C.sub.3-7 cycloalkyl. Carbocyclyl groups can be
optionally substituted, as indicated elsewhere in the
specification, and the substituent(s) may be placed at any
available position in the ring system.
[0224] The term "C.sub.3-7 cycloalkyl" refers to a monocyclic
cycloalkyl having from 3 to 7 ring-forming carbon atoms, and
includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl. Cycloalkyl groups can be optionally substituted, as
indicated elsewhere in the specification, and the substituent(s)
may be placed at any available position in the ring system.
[0225] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo.
Preferably, halo is fluoro.
[0226] The term "C.sub.y-z haloalkyl" refers to an alkyl group
having from y to z carbon atoms as defined herein which is
substituted one or more times with one or more halo, which can be
the same or different. Accordingly, a C.sub.1-6 haloalkyl is a
C.sub.1-6 alkyl which is substituted one or more times with one or
more halo. Haloalkyl groups include perhaloalkyl groups, i.e. alkyl
groups where all hydrogen atoms are replaced by halo. Examples of
haloalkyl groups include, but are not limited to, fluoromethyl,
difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl,
1-fluoro-2-fluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl,
heptafluoropropyl, 4,4,4-trifluorobutyl chloromethyl,
dichloromethyl, trichloromethyl difluorochloromethyl,
dichlorofluoromethyl, 1,2-dichloroethyl, 3,3-dichloropropyl and the
like. In some embodiments, the haloalkyl is a fluoroalkyl, i.e. an
alkyl group which is substituted one or more times with one or more
fluoro.
[0227] The term "C.sub.y-z haloalkoxy" refers to an haloalkyl group
having y to z carbon atoms as defined herein covalently linked to
an oxygen atom, i.e. a group of formula --O--C.sub.y-z haloalkyl. A
C.sub.1-6 haloalkoxy group thus refers to a haloalkoxy group
wherein the haloalkyl moiety has from 1 to 6 C atoms. Examples of
haloalkoxy groups include, but are not limited to,
trifluoromethoxy, 2-fluoroethoxy, pentafluoroethoxy,
3-chloropropoxy, 3-fluoropropoxy, heptafluoropropoxy, and the
like.
[0228] The term "heteroaryl", unless otherwise specified, refers to
a 5- to 18-membered heterocyclic ring system which is monocyclic or
multicyclic (e.g. fused, bridged or spiro rings) and which
comprises, in addition to C atoms, from 1 to 6 heteroatoms
independently selected from N, O and S, wherein at least one of the
rings in the ring system is aromatic and contains at least one of
the heteroatoms. Heteroaryl as used herein thus covers fully
aromatic ring systems, i.e. where all the ring(s) in the system are
aromatic, like imidazolyl, pyridyl, quinolyl,
pyrido[2,3-d]pyrimidinyl and the like, and groups in which an
heteroaromatic ring(s) is fused to one or more non-aromatic (i.e.
saturated or partially unsaturated) carbocyclic or heterocyclic
rings, such as 5,6,7,8-tetrahydroquinoline,
1,2,3,4-tetrahydro-1,8-naphthyridine and the like. The
heteroatom(s) can be optionally oxidized. Likewise, when the
heteroaryl comprises a heteroaromatic ring fused to one or more
non-aromatic carbocyclic or heterocyclic rings, one or more ring
carbon atoms in the non-aromatic carbocyclic or heterocyclic ring
can each be optionally oxidized to form a CO group. The heteroaryl
group can be attached to the rest of the molecule through any C or
N atom that results in a stable structure. In some embodiments, the
point of attachment is on the heteroaromatic ring. In some
embodiments, the heteroaryl group has from 1 to 4 heteroatoms. In
some embodiments, the heteroaryl group has from 1 to 3 heteroatoms.
In some embodiments, the heteroaryl is 5- to 6-membered monocyclic
or 9- to 10-membered bicyclic. In some embodiments, the heteroaryl
is 5- to 6-membered monocyclic. In some embodiments, the heteroaryl
group is fully aromatic. Nonlimiting examples of heteroaryl groups
include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl,
thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,
isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,
tetrazolyl, triazine, quinolinyl, isoquinolinyl, quinazolinyl,
quinoxalinyl, naphthyridinyl, phthalazinyl, indolyl,
benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl,
benzoxazolyl, cinnolinyl, indazolyl, indolizinyl, isoindolyl,
pteridinyl, purinyl, furopyridinyl, acridinyl, phenazinyl,
5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydro-1,8-naphthyridine
and the like. Heteroaryl groups can be optionally substituted, as
indicated elsewhere in the specification, and the substituent(s)
may be placed at any available position in the ring system.
[0229] The term "heterocyclyl", unless otherwise specified, refers
to a 3- to 18-membered partially unsaturated or fully saturated
heterocyclic ring system which is monocyclic or multicyclic (e.g.
fused, bridged or spiro rings) which comprises, in addition to C
atoms, from 1 to 6 heteroatoms independently selected from N, O and
S. Nitrogen or sulfur atoms may be optionally oxidized (e.g.,
--N.dbd.O, --S(.dbd.O)--, or --S(.dbd.O).sub.2--) and additionally
one or more of the ring carbon atoms of the heterocyclyl may each
be optionally oxidized to form a CO group. "Heterocyclyl" as used
herein also includes groups in which a partially unsaturated or
fully saturated heterocyclic ring is fused to one or more phenyl
rings, as in 1,2,3,4-tetrahydroquinolinyl, benzodioxolyl,
carbazolyl or phthalimidyl. The heterocycyl can be attached to the
rest of the molecule through any ring C or N atom that results in a
stable structure. In some embodiments, the heterocyclyl is 3- to
7-membered monocyclic. Examples of heterocyclyl groups include, but
are not limited to, pyrrolidinyl, 2-oxo-pyrrolidinyl,
tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,
dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, homopiperazinyl, azetidinyl,
oxetanyl, homopiperidinyl, oxepanyl, thiepanyl, 2H-pyranyl,
4H-pyranyl, dioxanyl, 1,3-dioxolanyl, dithianyl, dithiolanyl,
dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrrolinyl,
pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,
oxazolidinyl, indolinyl, 1-oxoisoindolinyl, decahydroquinolinyl,
1,2,3,4-tetrahydroquinolinyl, 6-azabicyclo[3.3.1]heptanyl,
8-azabicyclo[3.2.1]octanyl, 3-azaspiro[5.5]undecanyl,
7-azaspiro[3.5]nonanyl, carbazolyl, phthalimidyl,
tetrahydrothiopyranyl 1,1-dioxide, 2-azaspiro[4.5]decanyl,
2,3-dihydrospiro[indene-1,4'-piperidinyl], and the like.
Heterocyclyl groups can be optionally substituted, as indicated
elsewhere in the specification, and the substituent(s) may be
placed at any available position in the ring system.
[0230] The term "optionally substituted" means unsubstituted or
substituted. As used herein, the term "substituted" means that a
hydrogen atom is removed and replaced by a monovalent substitutent.
It is to be understood that substitution at a given atom is limited
by valency. Unless defined otherwise (or limited by valency), a
group that is optionally substituted with "one or more"
substituents may be unsubstituted or may, for example, carry one,
two or three (particularly one or two) substituents.
[0231] The term "CO" as used herein refers to a carbonyl group.
[0232] The term "partially unsaturated" as used herein in relation
to a ring refers to a ring that includes at least one double bond
between ring atoms but is not fully unsaturated (i.e.
aromatic).
[0233] The term "saturated" is used interchangeably with "fully
saturated" and as used herein in relation to a ring it refers to a
ring that does not contain any unsaturation.
[0234] The term "fully aromatic" is used interchangeably with
"aromatic" and as used herein in relation to a ring it refers to a
ring that is fully unsaturated.
[0235] A wavy line in chemical drawings indicates the point of
attachment to the rest of the molecule.
[0236] For compounds of the invention in which a variable appears
more than once, each variable can be a different moiety
independently selected from the group defining the variable. For
example, where a structure is described having two R groups that
are simultaneously present on the same compound, the two R groups
can represent different moieties independently selected from the
group defined for said R.
[0237] The compounds of the invention may contain one or more
asymmetric centers and may thus give rise to stereoisomers. All
stereoisomers, such as enantiomers, diastereoisomers and mixtures
thereof, are intended unless otherwise indicated. Compounds of the
present invention that contain asymmetrically substituted carbon
atoms can be isolated in optically active form or racemic mixtures.
Methods on how to prepare optically active forms from optically
inactive starting materials are known in the art, and include for
example by resolution of racemic mixtures or by stereoselective
synthesis.
[0238] The compounds presented herein may, in certain embodiments,
exist as tautomers. It should be understood that when compounds
have tautomeric forms, all tautomeric forms are intended to be
included in the scope of the present invention. A "tautomer" refers
to a molecule wherein a proton shift from one atom to another atom
of the same molecule is possible. Examples include ketone-enol
pairs and annular forms where a proton can occupy two or more
positions of a heterocyclic system as for example in 1H- and
3H-imidazole. Tautomeric forms can be in equilibrium or sterically
locked into one form by appropriate substitution.
[0239] Compounds of the invention include unlabeled forms of the
compounds of Formula (I) as well as isotopically labeled forms
thereof. Isotopically labeled forms of the compounds are compounds
that differ only in the replacement of one or more atoms by a
corresponding isotopically enriched atom. Examples of isotopes that
can be incorporated into compounds of the invention include for
example isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine,
chlorine, and iodine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.35S, .sup.18F,
.sup.36Cl, and .sup.125I. Such isotopically labelled compounds are
useful for example as probes in biological assays, as analytical
tools, or as therapeutic agents.
[0240] "Polymorphs" or "crystal forms" refers to crystal structures
in which a compound (or a salt or solvate thereof) can crystallize
in different crystal packing arrangements, all of which have the
same elemental composition. Different crystal forms usually have
different X-ray diffraction patterns, infrared spectra, Raman
spectra, melting points, differential scanning calorimetry (DSC)
spectra, crystal shape, solubility and/or stability, among others.
When compounds of the invention exist in different solid forms, all
forms thereof, including amorphous forms and crystal forms, are
intended to be included in the scope of the present invention.
[0241] The terms "compound of the invention", "compound as
described herein" and the like are meant to include a compound of
Formula (I) (including each and every subgenus of a compound of
Formula (I) as described herein and in the claims as well as the
compounds described in the Examples), including all stereoisomers,
tautomers, isotopically labeled forms and polymorphs thereof.
[0242] The present invention also includes salts of the compounds
of the invention. Preferably, said salts are pharmaceutically
acceptable salts. As used herein, a "pharmaceutically acceptable
salt" is intended to mean a salt that retains the biological
effectiveness and properties of the parent compound (i.e. the free
acid or free base, as applicable) and that is not biologically or
otherwise undesirable. Pharmaceutically acceptable salts include
salts formed with inorganic or organic bases, and salts formed with
inorganic and organic acids. Pharmaceutically acceptable salts are
well known in the art. Exemplary pharmaceutically acceptable salts
include those salts prepared by reaction of the compounds of the
present invention with a mineral or organic acid, such as
hydrochlorides, hydrobromides, sulfates, pyrosulfates, bisulfates,
sulfites, bisulfites, phosphates, monohydrophosphates,
dihydrophosphates, metaphosphates, pyrophosphates, chlorides,
bromides, iodides, nitrates, acetates, haloacetates (e.g.
trifluoroacetates), propionates, decanoates, caprylates, acrylates,
formates, isobutyrates, caproates, heptanoates, propiolates,
oxalates, malonates, succinates, suberates, sebacates, fumarates,
maleates, butyne-1,4 dioates, hexyne-1,6-dioates, benzoates,
chlorobenzoates, methylbenzoates, dinitrobenzoates,
hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
xylenesulfonates, phenylacetates, phenylpropionates,
phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,
glycollates, tartrates, methane-sulfonates, ethane-sulfonates,
propanesulfonates, benzenesulfonates, toluenesulfonates,
trifluoromethansulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, mandelates, pyruvates, stearates,
ascorbates, or salicylates. When the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g. sodium or potassium
salts; alkaline earth metal salts, e.g. calcium or magnesium salts;
and salts formed with suitable organic ligands such as ammonia,
alkylamines, hydroxyalkylamines, lysine, arginine,
N-methylglucamine, procaine and the like. The pharmaceutically
acceptable salts of the present invention can be prepared from the
parent compound which contains a basic or acidic moiety by
conventional chemical methods. For example, such salts can be
prepared by reacting the free acid or base forms of these compounds
with a stoichiometric amount of the appropriate base or acid in a
suitable solvent.
[0243] Additionally, compounds of the present invention, or salts
thereof, may exist in hydrated or unhydrated (anhydrous) form or as
solvates with other solvent molecules. "Solvate" as used herein
means solvent addition forms that contain either stoichometric or
non-stoichometric amounts of solvent. Some compounds have a
tendency to trap a fixed molar ratio of solvent molecules in the
crystalline solid state, thus forming a solvate. If the solvent is
water, the solvate formed is a hydrate. Non-limiting examples of
solvates include hydrates and solvates with alcohols (also named
alcoholates) such as ethanol (ethanolates). When compounds of the
invention (or salts thereof) exist as solvates, all solvates
thereof are intended to be included in the scope of the present
invention, particularly pharmaceutically acceptable solvates. As
used herein a "pharmaceutically acceptable solvate" is a solvate
formed with a pharmaceutically acceptable solvent. Pharmaceutically
acceptable solvents are well known in the art and include solvents
such as water and ethanol.
[0244] Compounds of the invention, including salts thereof, can be
prepared using a number of synthetic routes, including the general
synthetic routes described below, starting from commercially
available starting materials, compounds known in the literature, or
from readily prepared intermediates, by employing standard
synthetic methods and procedures. Standard synthetic methods and
procedures for the preparation of organic compounds and functional
group transformations and manipulations are known in the art and
can be found in standard textbooks such as Smith M. B., "March's
Advanced Organic Chemistry: Reactions, Mechanisms, and Structure",
7.sup.th Edition, Wiley, 2013; Greene T W and Wuts P G M "Greene's
Protective Groups in Organic Synthesis", 4.sup.th edition, Wiley,
2006)
[0245] The reaction schemes described below are only meant as
illustrative of methods to obtain the compounds of the invention.
Other routes known by the ordinary skilled artisan, as well as
other reactants and intermediates, can also be used to arrive at
the compounds of Formula (I).
[0246] In some of the processes described below it may be necessary
or advisable to protect reactive or labile groups with conventional
protecting groups. Both the nature of these protecting groups and
the procedures for their introduction and removal are well known in
the art (see for example Greene T W and Wuts P G M, cited supra).
Whenever a protecting group is present, a subsequent deprotection
step will be required, which can be performed under standard
conditions well known in the art, such as those described in the
above reference.
[0247] Unless otherwise stated, in the methods described below the
meanings of the different substituents in each synthetic
intermediate and in each compound of Formula (I) are the meanings
described above.
[0248] In general, the compounds of Formula (I) can be obtained
following the procedure shown in Scheme 1 below.
##STR00078##
wherein R.sup.1, m and ring A have the same meaning described for
compound of Formula (I), and M, T and X have the meaning defined
below.
[0249] Ring A can be attached to the rest of the molecule via a
ring C atom or a ring N atom of A. When ring A is attached via a
ring C atom, compound of Formula (XI) is obtained via a
cross-coupling reaction of a organometallic species (V) or (VIII)
with a halide (VI) or (VII).
[0250] Several cross-coupling reactions can be used for the
coupling of a compound of Formula (V) with a compound of Formula
(VI) or a compound of Formula (VII) with a compound of Formula
(VIII), including: a Suzuki cross coupling where M is a boronic
acid or boron derivative and X is Cl, Br or I; a Stille reaction
where M is trialkylstannanyl group and X is Cl, Br or I; a Negishi
coupling where M is a zinc halide and X is triflate, Cl, Br or I;
and a Hiyama coupling where M is a trialkylsilyl group and X is Cl,
Br or I.
[0251] When compounds of Formula (XI) are prepared through a Suzuki
cross coupling with the intermediates indicated in Scheme 1, the
reaction can be performed using a suitable Pd/ligand combination
such as XPhos and Pd.sub.2(dba).sub.3 or Pd(PPh.sub.3).sub.4, in
the presence of a suitable Cu salt such as Cu(OAc).sub.2 or CuI, in
a suitable solvent such as tetrahydrofuran or dimethylformamide,
using a suitable base such as potassium carbonate. The temperature
of the reaction typically can go from room temperature to
120.degree. C. and the time of reaction typically from 1 h to 48 h.
Examples of boronic derivatives include among others diethyl,
dimethyl, N-methyliminodiacetic acid (MIDA) derivative and
2,2'-(phenylazanediyl)bis(ethan-1-ol) derivative.
[0252] When compounds of Formula (XI) are prepared through a Stille
cross coupling with the intermediates indicated in Scheme 1, the
reaction can be performed using a suitable Pd/ligand combination
such as Pd(PPh.sub.3).sub.4, Pd(PPh.sub.3)Cl.sub.2 or
Pd(dppb)Cl.sub.2 in the presence of a suitable Cu salt such as CuI
or CuO, in the presence or absence of CsF, in a suitable solvent
such as tetrahydrofuran, dioxane or dimethylformamide. The
temperature of the reaction can typically go from room temperature
to 120.degree. C. and the time of reaction typically from 1 h to 48
h. The organotin employed can be trimethylstannyl derivative. An
intermolecular Stifle Kelly reaction can also be used, in which
both reagents are halo derivatives and are treated with
(Bu.sub.3Sn).sub.2, Et.sub.4NI, and a Pd/ligand combination.
[0253] When compounds of Formula (XI) are prepared through a
Negishi cross coupling with the intermediates indicated in Scheme
1, the reaction can be performed using a suitable Pd/ligand
combination such as PPh.sub.3 and Pd.sub.2(dba).sub.3, XPhos and
Pd.sub.2(dba).sub.3, RuPhos and Pd.sub.2(dba).sub.3 or
Pd(PPh.sub.3).sub.4, in a suitable solvent such as tetrahydrofuran,
dioxane or dimethylformamide. The temperature of the reaction can
typically go from room temperature to 120.degree. C. and the time
of reaction typically from 1 h to 48 h.
[0254] When compounds of Formula (XI) are prepared through a Hiyama
cross coupling with the intermediates indicated in Scheme 1, the
reaction can be performed using a suitable Pd/ligand combination
such as PdCl.sub.2(PPh.sub.3).sub.2 and PPh.sub.3 or Pd(OAc).sub.2
and di(1-adamantyl)-n-butylphosphine in the presence of a suitable
Cu salt such as CuI or CuBr, in the presence or absence of
tetrabutylammonium fluoride in a suitable solvent such as
tetrahydrofuran, dioxane or dimethylformamide. The temperature of
the reaction can typically go from room temperature to 120.degree.
C. and the time of reaction typically from 1 h to 48 h. When ring A
is attached via a ring N atom, compound of Formula (XI) is obtained
by reaction of a compound of Formula (IX) and a compound of Formula
(X) (wherein the ring N atom in A that will form the bond to the
rest of the molecule is in NH form) through a cross coupling
reaction or alternatively, between a compound of Formula (VII) and
a compound of Formula (X) through a displacement reaction. In the
case of a cross-coupling reaction, the Chan-Lam reaction can be
used for the coupling of a compound of Formula (IX) with a compound
of Formula (X). This reaction allows carbon-heteroatom bond
formation via an oxidative coupling of boronic acids, stannanes or
siloxanes with N--H containing compounds in the presence of air. T
in compounds of Formula (IX) is a boron, tin or silicon derivative.
The reaction is induced by a stoichiometric or catalytic amount of
copper salt such as Cu(OAc).sub.2 or CuI, in the presence or
absence of a base such as NEt.sub.3, pyridine or DMAP in a suitable
solvent such as CH.sub.2Cl.sub.2, pyridine or DMSO in the presence
of air. The temperature of the reaction can typically go from room
temperature to 120.degree. C. and the time of reaction typically
from 1 h to 48 h. Alternatively, a compound of formula (XI) can be
obtained by displacement reaction between a compound of Formula
(VII) and a compound of Formula (X), which can be carried out in
the presence of a base such as CsCO.sub.3, tBuOK, K.sub.2CO.sub.3
NaH or pyridine and in the presence or absence of copper derivative
such as Cu.sub.2O or CuI in a suitable solvent such as DMF, DMSO or
THF. The temperature of the reaction can typically go from room
temperature to 120.degree. C. and the time of reaction typically
from 1 h to 48 h.
[0255] Compounds of Formula (I) are obtained in two steps from a
cyano derivative of Formula (XI). In a first step, the cyano
derivative of Formula (XI) is transformed into the
N'-hydroxyimidamide of Formula (XII) by reaction with
hydroxylamine, which is then followed by condensation of (XII) with
trifluoroacetic anhydride to give a compound of Formula (I).
Addition of hydroxylamine to cyano derivatives (XI) is carried out
in a suitable solvent such as EtOH or MeOH, and in the presence of
base in the case hydroxylamine chlorhydrate is used. The
temperature of the reaction can typically go from room temperature
to 60.degree. C. and the time of reaction typically from 1 h to 48
h. The condensation of N'-hydroxyimidamides (XII) with
trifluoroacetic anhydride in a suitable solvent such as
CH.sub.2Cl.sub.2 or THF gives the corresponding
N'-trifluoroacethyloxyimidamide that in the same reaction medium or
after the addition of trilfuoroacetic acid yield 1,2,4-oxadiazoles
of Formula (I).
[0256] Alternatively, compounds of Formula (I) can also be prepared
in three steps building the 1,2,4-oxadiazole from cyano derivative
(VII) before the cross-coupling or displacement reaction with
appropriate ring A derivatives. Reaction of cyano derivative (VII)
with hydroxylamine gives intermediate (XIII) that is then condensed
with trifluoroacetic anhydride to give a compound of formula (XIV),
which is then subjected to cross coupling or displacement reactions
with an appropriate ring A derivative to give a compound of Formula
(I), as outlined in Scheme 2. When a cross-coupling reaction is
used to convert a compound (XIV) to a compound of Formula (I),
organometallic species can be generated either from a
haloderivative of formula (XIV) or from appropriate ring A
derivatives, as in Scheme 1. The reactions outlined in Scheme 2 can
be performed under the same reaction conditions described above for
Scheme 1.
##STR00079##
wherein R.sup.1, m and ring A have the same meaning described for
compound of Formula (I), and X has the meaning defined above.
[0257] The compounds of Formula (V), (VI), (VII), (VIII), (IX), and
(X) are commercial or can be obtained following standard procedures
well known to those skilled in the art of organic chemistry.
[0258] Organometallic derivatives of Formula (V), (VIII), (IX) and
those derived from compounds of Formula (XIV) can be obtained from
compounds of Formula (VII) and (XIV) by transmetallation following
standard procedures in the preparation of reagents for Suzuki,
Stille Hiyama, Negishi and Chan-Lam couplings, well known to those
skilled in the art of organic chemistry. For example,
N-methyliminodiacetic acid boronate derivatives can be prepared by
reaction of compounds of Formula (VII) and (XIV) with nBuLi in the
presence of B(OiPr).sub.3 at -78.degree. C. followed by the
addition of N-methyliminodiacetic acid; trimethyltin derivatives
can be prepared by reaction of compounds of Formula (VII) and (XIV)
with hexamethylditin and Pd (PPh.sub.3).sub.4 in toluene at
110.degree. C. for 16 h; organozinc derivatives can be prepared
from compounds of Formula (VII) and (XIV) by treatment with Zn in
THF at room temperature for 1 to 6 h; and trimetilsilyl derivatives
can be prepared by reaction of compounds of Formula (VII) and (XIV)
with nBuLi in the presence of trimethylsylchloride at -78.degree.
C. in THF.
[0259] Introduction of substituents R.sup.2 and R.sup.3 onto ring A
as well as transformations in R.sup.2 and R.sup.3 substituents of
ring A can be done following standard procedures well known to
those skilled in the art of organic chemistry. Said standard
procedures include, for example: the substitution of a primary or
secondary amines by treatment with an alkylating agent under
standard conditions; or by reductive amination, i.e. by treatment
with an aldehyde or a ketone in the presence of a reducing agent
such as sodium cyanoborohydride or sodium triacetoxyborohydride;
the conversion of an amine into an amide by means of activating
agents such us dicyclohexyl carbodiimide (DCC),
1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu),
1-ethyl-3-(3'-dimethylamino)carbodiimide (EDC) in the presence of a
base, such as, disopropylethylamine, pyridine, thriethylamine, or
N-methylmorpholine, in a solvent, such as dimethoxyethane,
N,N-dimethylformamide, tetrahydrofuran, dichloromethane or dioxane
or alternatively, by reaction with acid chlorides in the presence
of a suitable base; the alkylation of an amide by treatment with an
alkylating agent under basic conditions; the conversion of an
alcohol into an ether under standard conditions; the partial or
total oxidation of an alcohol to give a ketone under standard
oxidizing conditions; the reduction of a ketone by treatment with a
reducing agent such as sodium borohydride; the conversion of an
alcohol into a halogen by reaction with SOCl.sub.2, PBr.sub.3,
tetrabutylammonium bromide in the presence of P.sub.2O.sub.5, or
PCl.sub.3; the conversion of halogen into an amine by reaction with
an amine, optionally in the presence of a suitable solvent, and
preferably heating; and the conversion of a primary amide into a
--CN group under standard conditions.
[0260] Likewise, any of the aromatic rings of the compounds of the
present invention can undergo electrophilic aromatic substitution
reactions or nucleophilic aromatic substitution reactions, widely
described in the literature.
[0261] Some of these interconversion reactions are explained in
greater detail in the examples. As it will be obvious to those
skilled in the art, these interconversion reactions can be carried
out upon a compound of Formula (I), thus generating further
compounds of Formula (I), as well as upon any suitable synthesis
intermediate thereof.
[0262] The salts of a compound of Formula (I) can be obtained
during the final isolation and purification of the compounds of the
invention or can be prepared by treating a compound of Formula (I)
with a sufficient amount of the desired acid (or base) to give the
salt in a conventional manner.
[0263] Where the processes for the preparation of the compounds of
the invention give rise to mixtures of stereoisomers, individual
stereoisomers of a compound of Formula (I) can be obtained for
example by resolution, starting from a compound of formula (I)
obtained as a mixture of stereoisomers, using well known methods
such as formation of diastereomeric pairs by salt formation with an
optically active acid followed by fractional crystallization and
regeneration of the free base, or by chiral preparative
chromatography. Alternatively, it is possible to obtain optically
pure or enantiomerically enriched synthetic intermediates, which
can then be used as such in subsequent steps, at various stages of
the synthetic procedures described above, using any known method
for chiral resolution. Alternatively, it is possible to obtain
optically pure or enantiomerically enriched final compounds (or
synthetic intermediates) by using chiral chromatography.
[0264] The compounds of the invention inhibit the activity of
histone deacetylases. In particular, the compounds of the invention
have been found to be potent inhibitors of HDAC6. The activity of
the compounds of the invention as HDAC6 inhibitors can be
determined using for example the in vitro assays described in the
Examples section. In particular, Example 8 describes a method to
determine HDAC6 inhibitory activity. The compounds of the invention
have been found to be potent HDAC6 inhibitors using the assay
described in Example 8. Compounds of the invention have also been
shown to inhibit HDAC6 activity in cells, as shown by the results
described in Example 9. Selectivity towards HDAC6 compared to other
HDAC isoforms can be assayed using methods well known in the art,
for example in vitro assays similar to the one described in Example
8 using the corresponding HDAC isoform of interest. Compounds of
the invention have been found to exhibit selectivity towards HDAC6
vs HDAC2, as shown by the results in Example 8 against HDAC2 using
representative compounds of the invention.
[0265] HDAC6 is a class IIb HDAC that can deacetylate substrates,
such as tubulin, heat shock protein (Hsp)90 and cortactin. HDAC6
localizes in the cytosol and possesses two catalytic domains and a
C-terminal zinc finger domain that can bind free ubiquitin as well
mono- and polyubiquitinated proteins (Li et al, FEBS J. 2013
February; 280(3):775-93). The ubiquitin-binding domain in HDAC6
associates with several proteins involved in the control of the
ubiquitin, proteasome system, aggresome formation and autophagy.
Additionally, the ability of HDAC6 to deacetylate alpha-tubulin
affects microtubule-mediated processes such as cell migration,
immune synapse formation, viral infection, the degradation of
misfolded proteins and of stress granule. HDAC6 has also been shown
to deacetylate Hsp90 and modulate its chaperone activity, thus
modulating various Hsp90-associated cell signaling pathways such as
the control of stress-related response.
[0266] Many studies have reported the role of HDAC6 in cancer. For
example, inhibition of HDAC6 was shown to reduce growth of multiple
myeloma in preclinical models and to enhance the effect of
proteasome inhibitors and thalidomide-based Immunomodulatory drugs
used as standards of care (Santo et al, Blood. 2012 Mar. 15;
119(11):2579-89; North et al, PLoS One. 2017 Mar. 6;
12(3):e0173507). Inhibition of HDAC6 was also shown to increase the
effect of other standard of care drugs such as paclitaxel in
ovarian, pancreatic and breast cancer cells (Huang et al,
Oncotarget 2017 Jan. 10; 8(2):2694-2707). The antiproliferative
activity of HDAC6 inhibitors has also been observed in prostate
cancer and melanoma cells (Li et al, Eur J Med Chem. 2015 Jul. 15;
100:270-6; Seidel et al, Biochem Pharmacol. 2016 Jan. 1; 99:31-52).
In addition, in vivo efficacy of HDAC6 inhibitors has been reported
in colorectal, inflammatory breast cancer, leukemia, lymphoma and
ARID1A mutant ovarian xenograft models (Yang et al, J Med Chem.
2016 Feb. 25; 59(4):1455-70; Putcha et al, Breast Cancer Res, 2015
Dec. 8; 17(1):149; Bitler et al, Nat Cell Biol. 2017 August;
19(8):962-973). Similarly, HDAC6 knock down reduces uterine
leiomyoma and gastric cancer cell proliferation, while HDAC6
overexpression promotes proliferation and promotes drug-resistance
of non-small cell lung cancer cells and glioblastoma cells (Wei et
al, Reprod Sci. 2011 August; 18(8):755-62; Park et al, Cancer Lett.
2014 Nov. 1; 354(1):97-106; Wang et al, Oncol Rep. 2016 July;
36(1):589-97; Wang et al, Cancer Lett. 2016 Aug. 28;
379(1):134-42). Furthermore, HDAC6 inhibitors were shown to have
anticancer activity by stimulating the immune-response against the
tumors in models of melanoma and non-small cell lung cancer when
used alone or in combination with immune-checkpoints inhibitors or
epigenetic modulators (Knox et al, Abstract 4055, AACR Annual
Meeting 2017; Apr. 1-5, 2017; Washington, D.C.; Woan et al, Mol
Oncol. 2015 August; 9(7):1447-1457; Tavares et al, ACS Med Chem
Lett. 2017 Sep. 5; 8(10):1031-1036; Adeegbe et al, Cancer Discov.
2017 August; 7(8):852-867).
[0267] HDAC6 has also been widely reported to play a role in
inflammatory and autoimmune diseases. Knock out mice for HDAC6 have
an increased number of circulating regulatory T cells (Tregs),
which are key to the maintenance of immune homeostasis. Likewise,
HDAC6 specific inhibitors promote Treg suppressive activity in
models of inflammatory bowel disease and graft versus host disease
(de Zoeten et al, Mol Cell Biol. 2011 May; 31(10):2066-78). HDAC6
inhibitors were shown to have disease modifying activity in models
of inflammation, rheumatoid arthritis and systemic lupus
erythematosus (Vishwakarma et al, Int Immunopharmacol. 2013 May;
16(1):72-8; Regna et al, Clin Immunol. 2016 January; 162:58-73).
Mice lacking HDAC6 display reduction of autophagy, which
ameliorates chronic obstructive pulmonary disease (COPD)-associated
cilia dysfunction (Lam et al, J Clin Invest. 2013 December;
123(12):5212-30).
[0268] HDAC6 inhibitors have also been reported to be effective to
treat ciliopathies. Ciliopathies are genetic diseases associated
with defects in ciliary structure or function, and include, among
others, polycystic kidney disease, polycystic liver disease,
Bardet-Biedl syndrome and retinal degeneration. In a model of
polycystic kidney disease, HDAC6 inhibitors prevented cyst
formation and improved renal function (Cebotaru et al, Kidney Int.
2016 July; 90(1):90-9). Similarly, in a model of polycystic liver
disease, pharmacological inhibition of HDAC6 decreased
proliferation of cystic cholangiocytes, and diminished liver cyst
development and fibrosis (Gradilone et al, Am J Pathol. 2014 March;
184(3):600-8).
[0269] HDAC6 has also been shown to have an important role in
diseases of the nervous system. In particular, HDAC6 inhibitors
showed efficacy in models of peripheral neuropathies such as
Charcot-Marie-Tooth disease and chemotherapy-induced peripheral
neuropathy (Benoy et al, Neurotherapeutics. 2017 April;
14(2):417-428; Krukowski et at, Pain. 2017 June; 158(6):1126-1137).
In addition, in neuronal culture derived from patients with
amyotrophic lateral sclerosis, treatment with HDAC6 inhibitors
rescued their defective phenotype (Guo et al, Nat Commun. 2017 Oct.
11; 8(1):861).
[0270] HDAC6 inhibitors have also been reported to be effective to
treat several other diseases of the nervous system. For example,
reduction or inhibition of HDAC6 has been shown to rescue memory
and improve cognition in mouse models of Alzheimer's disease
(Govindarajan et al, EMBO Mol Med. 2013 January; 5(1):52-63) Loss
or inhibition of HDAC6 suppresses neuritic tau accumulation, thus
HDAC6 inhibition could be useful to treat not only Alzheimer's
disease but also other human 4-repeat tauopathies such as
corticobasal degeneration and progressive supranuclear palsy (Tseng
et al, Cell Rep. 2017 Aug. 29; 20(9):2169-2183). Furthermore, in a
model of Huntington's disease, HDAC6 inhibition reduces the
vulnerability of neurons to mutant huntingtin, thus suggesting a
neuroprotective effect of HDAC6 inhibitors in HD (Guedes-Dias et
al, Biochim Biophys Acta. 2015 November; 1852(11):2484-93).
[0271] HDAC6 has also been reported to play a role in mental and
behavioural disorders such as depression. For example, HDAC6
inhibitors stimulated the mouse exploratory behaviors and had a
positive effect in anxiolytic and social interaction tests (Jochems
et al, Neuropsychopharmacology. 2014 January; 39(2):389-400).
[0272] Moreover, several publications underline the important role
of HDAC6 in infectious diseases. The use of HDAC6 inhibitors
reduced the replication of viruses such as Japanese Encephalitis
Virus (JEV), hepatitis C virus (HCV) and Rabies Virus (Lu et al,
Int J Mol Sci. 2017 May 1; 18(5); Zan et al, Front Cell Infect
Microbial. 2017 Apr. 26; 7:146; Ai et al, J Med Chem. 2015 Jan. 22;
58(2):785-800). HDAC6 was also shown to facilitate cell entry of
influenza A viruses and to control the viral lytic-latency switch
of other viruses (Banerjee et al, Science 2014 Oct. 24;
346(6208):473-7). For example, HDAC6 was reported to be involved in
the maintenance of HIV latency, thus inhibition of HDAC6 could
promote the body clearance of the virus (Huo et al, J Biol Chem.
2011 Mar. 18; 286(11):9280-6). Furthermore, selective HDAC6
inhibitors improved survival and bacterial clearance in models of
sepsis (Zhao et al, J Trauma Acute Care Surg. 2016 January;
80(1):34-40).
[0273] Several publications have also reported a role of HDAC6 in
cardiovascular diseases. Knockout mice for HDAC6 display improved
heart condition in mouse models of heart failure. Moreover, HDAC6
null mice are resistant to skeletal muscle wasting considered a
life threatening complication in congestive heart failure
(Demos-Davies et al, Am J Physiol Heart Circ Physiol. 2014 Jul. 15;
307(2):H252-8). Pharmacological inhibition of HDAC6 was shown to
protect against atrial remodeling in connection to atrial
fibrillation (Zhang et al, Circulation. 2014 Jan. 21;
129(3):346-58). HDAC6 activity was consistently increased in
stressed myocardium, thus suggesting a role for HDAC6 inhibitors in
myocardiopathies (Lemon et al, J Mol Cell Cardiol. 2011 July;
51(1):41-50). Selective inhibition of HDAC6 has also been reported
to improve survival in a rodent model of hemorrhagic shock (Chang
et al, J Trauma Acute Care Surg. 2015 December; 79(6):905-10).
Furthermore, inhibition of HDAC6 improved established pulmonary
artery hypertension in experimental models and exerts a
neuroprotective effect in models of brain ischemia (Boucherat et
al, Sci Rep. 2017 Jul. 3; 7(1):4546; Liesz et al, J Neurosci. 2013
Oct. 30; 33(44):17350-62).
[0274] The compounds of the invention are thus expected to be
useful for treating diseases associated with HDACs, in particular
HDAC6. Examples of diseases associated with HDAC6 include, without
limitation, the diseases listed below:
[0275] Cancers, such as: lung cancer, colon cancer, breast cancer,
prostate cancer, liver cancer, brain cancer and others CNS
neoplasms, kidney cancer, ovarian cancer, stomach cancer, skin
cancer, bone cancer, gastric cancer, pancreatic cancer, cardiac
cancer, glioma, glioblastoma, esophageal cancer, hepatocellular
carcinoma, bone and joint cancer, papillary renal carcinoma, head
and neck squamous cell carcinoma, sarcomas, mesothelioma,
leukemias, lymphomas, and myelomas;
[0276] Autoimmune or inflammatory diseases, such as: rheumatoid
arthritis, osteoarthritis, rheumatoid spondylitis, psoriatic
arthritis, infectious arthritis, progressive chronic arthritis,
deforming arthritis, traumatic arthritis, gouty arthritis, Reiter's
syndrome, polychondritis, acute synovitis and spondylitis,
psoriasis, post ischemic perfusion injury, inflammatory bowel
disease (e.g. ulcerative colitis or Crohn's disease), eczema,
ischemia/reperfusion injury, glomerulonephritis, hemolytic anemia,
aplastic anemia, idiopathic thrombocytopenia, neutropenia, chronic
thyroiditis, Graves' disease, diabetes type I, schleroderma,
diabetes, hepatitis, primary binary cirrhosis, systemic
inflammatory response syndrome, postoperative or posttraumatic
inflammation, myasthenia gravis, pemphigus, alcoholic liver
disease, cystic fibrosis, multiple sclerosis (MS), Addison's
disease, Castleman's disease, polyarteritis nodosa, systemic lupus
erythematosus, atopic dermatitis, contact dermatitis, chronic renal
insufficiency, Stevens-Johnson syndrome, idiopathic sprue,
sarcoidosis, Guillain-Barre syndrome, uveitis, conjunctivitis,
keratoconjunctivitis, otitis media, periodontal disease, pulmonary
interstitial fibrosis, acute respiratory distress syndrome, asthma,
bronchitis, rhinitis, sinusitis, pancreatitis, inflammatory bone
disease, meningitis, cystitis, pharyngolaryngitis, pneumoconiosis,
pulmonary insufficiency syndrome, pulmonary emphysema, chronic
obstructive pulmonary disease (COPD), pulmonary fibrosis,
silicosis, chronic inflammatory pulmonary disease, or peritoneal
fibrosis;
[0277] Transplant rejection, including host versus graft disease,
graft versus host disease and allograft rejection. Infectious
diseases, including influenza, viral encephalitis, HIV, hepatitis
of viral origin, pneumonia and sepsis. Ciliopathies, such as
polycystic kidney disease, polycystic kidney disease, Alstrom
syndrome, Bardet-Biedl syndrome, some forms of retinal
degeneration, Joubert syndrome, Meckel-Gruber syndrome,
nephronophthisis, orofaciodigital syndrome 1, Senior-Loken
syndrome, primary ciliary dyskinesia (Kartagener Syndrome),
orasphyxiating thoracic dysplasia (Jeune), Marden-Walker syndrome,
or isomerism;
[0278] Diseases of the nervous system, such as Wilson's disease,
prion disease, Parkinson's disease, Huntington's disease,
amyotrophic lateral sclerosis, amyloidosis, Alzheimer's disease,
Alexander's disease, Pick's Disease, spinal muscular dystrophy,
Lewy body dementia, chemotherapy-induced cognitive dysfunction,
mitochondrial encephalomyopathies and gut dysmotility syndromes,
motor neurogenesis disease (MND), ataxia syndromes including
Friedreich's ataxia and spinocerebellar ataxia (SCA), spinal cord
injury, olivopontocerebellar atrophy, multiple system atrophy,
progressive supranuclear palsy, synucleinopathies, Down Syndrome,
corticodentatonigral degeneration, progressive familial myoclonic
epilepsy, strionigral degeneration, torsion dystonia, familial
tremor, Gilles de la Tourette syndrome, Shy-Drager syndrome and
Hallervorden-Spatz disease, as well as peripheral neuropathies such
as Charcot-Marie Tooth Disease, peripheral neuropathy induced by
chemotherapeutic agents (e.g. platinum-based chemoterapeutic,
taxane, vincristine, bortezomib, etc.) and the like;
[0279] Mental and behavioral disorders, including psychotic
disorders and schizophrenia spectrum disorders such as schizotypal
(personality) disorder, delusional disorder, brief psychotic
disorder, schizophreniform disorder, schizophrenia, schizoaffective
disorder, substance/medication-induced psychotic disorder, and
psychotic disorder due to another medical condition; bipolar
disorders such as bipolar I disorder, bipolar II disorder,
cyclothymic disorder, substance/medication-induced bipolar and
related disorder; depressive disorders, such as disruptive mood
dysregulation disorder, major depressive disorder, single and
recurrent episodes, persistent depressive disorder (dysthymia),
premenstrual dysphoric disorder, substance/medication-induced
depressive disorder, and depressive disorder due to another medical
condition; anxiety disorders, such as separation anxiety disorder,
selective mutism, specific phobia, social anxiety disorder (social
phobia), panic disorder, agoraphobia, generalized anxiety disorder
and the like;
[0280] Cardiovascular diseases such as heart failure,
myocardiopathy, atrial fibrillation, pulmonary artery hypertension,
hemorrhagic shock, stroke, ischemic heart disease, myocarditis and
valvular disease; Muscle Atrophy; and Cachexia.
[0281] For the uses and methods of treatment described herein, any
of the compounds of the invention, including any of the embodiments
thereof, may be used.
[0282] Accordingly, the invention further provides a compound of
Formula (I), or pharmaceutically acceptable salt thereof, for use
as a medicament.
[0283] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of a disease associated with HDAC6.
[0284] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of a disease
associated with HDAC6.
[0285] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
treating a disease associated with HDAC6.
[0286] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use as a
HDAC6 inhibitor.
[0287] The present invention further provides a method for treating
a disease associated with HDAC6, comprising administering a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, to a patient in need
thereof.
[0288] The present invention further provides a method of
inhibiting HDAC6 activity, comprising administering to a patient in
need of said treatment an amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, sufficient to inhibit
HDAC6 activity.
[0289] The present invention further provides a compound of Formula
(I), or a pharmaceutically acceptable salt thereof, for use in the
treatment of a disease selected from cancer, an autoimmune or
inflammatory disease, transplant rejection, a ciliopathy, a disease
of the nervous system, a mental or behavioral disorder, an
infectious disease, a cardiovascular disease, muscle atrophy and
cachexia.
[0290] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
the manufacture of a medicament for the treatment of a disease
selected from cancer, an autoimmune or inflammatory disease,
transplant rejection, a ciliopathy, a disease of the nervous
system, a mental or behavioral disorder, an infectious disease, a
cardiovascular disease, muscle atrophy and cachexia.
[0291] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, for
treating a disease selected from cancer, an autoimmune or
inflammatory disease, transplant rejection, a ciliopathy, a disease
of the nervous system, a mental or behavioral disorder, an
infectious disease, a cardiovascular disease, muscle atrophy and
cachexia.
[0292] The present invention further provides a method for treating
a disease selected from cancer, an autoimmune or inflammatory
disease, transplant rejection, a ciliopathy, a disease of the
nervous system, a mental or behavioral disorder, an infectious
disease, a cardiovascular disease, muscle atrophy and cachexia,
comprising administering a therapeutically effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, to a patient in need thereof.
[0293] The present invention further provides a method of
inhibiting HDAC6 activity in a sample (e.g. a biological sample),
comprising contacting said sample (e.g. said biological sample)
with a compound of Formula (I), or pharmaceutically acceptable salt
thereof.
[0294] The present invention further provides the use of a compound
of Formula (I), or a pharmaceutically acceptable salt thereof, as a
HDAC6 inhibitor in research, particularly as a research tool
compound for inhibiting HDAC6. Accordingly, the invention relates
to the in vitro use of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, as a HDAC6 inhibitor and,
in particular, to the in vitro use of a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, as a research tool
compound acting as a HDAC6 inhibitor. The invention likewise
relates to a method, particularly an in vitro method, of inhibiting
HDAC6, the method comprising applying a compound of Formula (I), or
a pharmaceutically acceptable salt thereof, to a sample (e.g., a
biological sample). It is to be understood that the term "in vitro"
is used in this specific context in the sense of "outside a living
human or animal body", which includes, in particular, experiments
performed with cells, cellular or subcellular extracts, and/or
biological molecules in an artificial environment such as an
aqueous solution or a culture medium which may be provided, e.g.,
in a flask, a test tube, a Petri dish, a microtiter plate, etc.
[0295] Unless otherwise stated, any description of a method of
treatment includes use of the compounds to provide such treatment
as is described herein, as well as use of the compounds to prepare
a medicament to treat such condition.
[0296] Any reference to a compound of Formula (I) herein includes a
reference to any of the compounds of Formula (IIa), (IIb), (IIIa),
(IIIb), (IVa), (IVa-1), (IVb) and (IVb-1), and to any embodiments
thereof as described herein.
[0297] The term "disease associated HDAC6" and the like refer to
any disease or condition in which HDAC6 plays a role, and/or where
the disease or condition is associated with expression or activity
of a HDAC6, and/or diseases or conditions the course of which can
be influenced by modulating HDAC6. Diseases associated with HDAC6
include, without limitation, the diseases and conditions as
described herein. Preferably, the disease associated with HDAC is a
disease selected from cancer, an autoimmune or inflammatory
disease, transplant rejection, a ciliopathy, a disease of the
nervous system, a mental or behavioral disorder, an infectious
disease, a cardiovascular disease, muscle atrophy and cachexia.
[0298] As used herein, the term "subject" or "patient" or
"individual" refers to any animals, including mammals, preferably
mice, rats, other rodents, rabbits, dogs, cats, swine, cattle,
sheep, horses, or primates, and most preferably humans (e.g., a
male human or a female human).
[0299] As used herein, the term "biological sample" includes,
without limitation, a cell, cell cultures or extracts thereof;
biopsied material obtained from an animal, e.g. a human, or
extracts thereof; and blood, saliva, urine, feces, or any other
body fluids or extracts thereof.
[0300] As used herein, the term "therapeutically effective amount"
refers to the amount of active compound that elicits the biological
or medicinal response that is being sought in subject (preferably a
human). Accordingly, a therapeutically effective amount of a
compound may be an amount which is sufficient to treat a disease or
disorder, delay the onset or progression of a disease or disorder,
and/or alleviate one or more symptoms of the disease or disorder,
when administered to a subject suffering from said disease or
disorder. The precise effective amount for a subject will depend
upon a variety of factors such as the subject's body weight, size
and health, the nature and extent of the condition to be treated,
and the therapeutic or combination of therapeutics selected for
administration. Therapeutically effective amounts for a given
situation can be determined by routine experimentation that is
within the skill and judgement of the clinician.
[0301] For any compound, the therapeutically effective amount can
be estimated initially either in in vitro assays, e.g. cell culture
assays, or in animal models, e.g. mice, rats or dogs. The animal
model may also be used to determine the appropriate concentration
range and route of administration. Such information can then be
used to determine useful doses and routes for administration in
humans. Therapeutic efficacy and toxicity may be determined by
standard procedures in cell cultures or experimental animals, e.g.
ED50 and LD50 values can be determined and the ratio between toxic
and therapeutic effects, also known as therapeutic index, may be
calculated and used to determine suitable doses for use in
humans.
[0302] As used herein, unless otherwise stated, the term "treating"
and "treatment" in relation to a disease, disorder or condition
refers to the management and care of a patient for the purpose of
combating a disease, disorder or condition, such as to reverse,
alleviate, inhibit the process of, or prevent the disease, disorder
or condition to which such term applies, or one or more symptoms of
such disease, disorder or condition, and includes the
administration of a compound of the invention (or a
pharmaceutically acceptable salt thereof) to prevent the onset of
the symptoms or the complications, or alleviating the symptoms or
complications, or eliminating the disease, condition or disorder.
Preferably, treatment is curative or ameliorating.
[0303] While it is possible that a compound of the invention may be
administered for use in therapy directly as such, it is typically
administered in the form of a pharmaceutical composition. These
compositions comprise a compound of the invention (or a
pharmaceutically acceptable salt thereof) as active pharmaceutical
ingredient together with one or more pharmaceutically acceptable
carriers. For the purposes of the invention, a carrier is suitable
for use in the pharmaceutical compositions described herein if it
is compatible with the other ingredients of the composition and not
deleterious to the recipient of the composition. A
"pharmaceutically acceptable carrier" includes non-API (API refers
to Active Pharmaceutical Ingredient) substances, such as
disintegrators, binders, fillers, lubricants and the like, used in
formulating pharmaceutical products and regarded as safe for
administering to subjects (particularly humans) according to
established governmental standards, including those promulgated by
the United States Food and Drug Administration and the European
Medical Agency. Pharmaceutically acceptable carriers are well known
to those skilled in the art and are selected on the basis of the
chosen type of formulation and route of administration, according
to standard pharmaceutical practice as described for example in
Remington: The Science and Practice of Pharmacy 22nd edition,
edited by Loyd V Allen Jr, Pharmaceutical Press, Philadelphia,
2012).
[0304] Accordingly, provided herein is a pharmaceutical composition
comprising a compound of Formula (I) (including any of its subgenus
of Formula (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVa-1), (IVb) and
(IVb-1), and any embodiments thereof as described herein), or a
pharmaceutically acceptable salt thereof, and one or more
pharmaceutical acceptable carriers.
[0305] Pharmaceutical compositions can be prepared in a manner well
known in the pharmaceutical art, and can be administered by a
variety of routes, for example via oral, parenteral, pulmonary or
topical route. Parenteral administration includes intravenous,
intraarterial, subcutaneous, intraperitoneal or intramuscular.
Parenteral administration can be in the form of a single bolus
dose, or may be, for example, by a continuous perfusion pump.
Pulmonary administration includes e.g. by inhalation or
insufflation of powders or aerosols, including by nebulizer.
Topical administration includes transdermal, epidermal, ophthalmic
and to mucous membranes including intranasal, vaginal and rectal
delivery.
[0306] The compositions can be formulated as to provide quick
(immediate), sustained or delayed release of the active ingredient
after administration to the patient by using methods known in the
art.
[0307] Examples of pharmaceutically acceptable excipients include
lactose, dextrose, sucrose, sorbitol, mannitol, staches, gum
acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium
silicate, microcrystalline cellulose, polyvinylpyrrolidone,
cellulose, water, and methyl cellulose. The pharmaceutical
compositions can additionally include further pharmaceutically
acceptable excipients including: lubricating agents such as talc,
magnesium stearate and mineral oil; wetting agents; emusifying and
suspending agents; preserving agents such as methyl- and
propylhydroxybenzoates; sweetening agents; flavouring agents; and
colouring agents.
[0308] Suitable oral dosage forms include, for examples, tablets,
pills, sachets or capsules of hard or soft gelatin or any other
suitable material. For example, the active compound can be
incorporated into a formulation that includes pharmaceutically
acceptable carriers such as binders (e.g., gelatin, cellulose, gum
tragacanth), excipients (e.g., starch, lactose), lubricants (e.g.,
magnesium stearate, silicon dioxide), disintegrating agents (e.g.,
alginate, Primogel, corn starch), and sweetening or flavoring
agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and
peppermint). They can then be compressed into tablets or enclosed
in capsules using conventional techniques. The capsules and tablets
can also be coated with various coatings known in the art to modify
the flavors, tastes, colors, and shapes of the capsules and
tablets. In addition, liquid carriers such as fatty oil can also be
included in capsules. Oral formulations can also be in the form of
suspensions, solutions, syrups and the like. If desired,
conventional agents for modifying flavors, tastes, color and the
like can be added.
[0309] Pharmaceutical compositions suitable for parenteral
administration include sterile aqueous solutions or suspensions, or
can be alternatively prepared in lyophilized form for
extemporaneous preparation of a solution or suspension using a
sterile aqueous carrier prior to use. In such formulations,
diluents or pharmaceutically acceptable carriers such as sterile
water and physiological saline buffer can be used. Other
conventional solvents, pH buffers, stabilizers, anti-bacterial
agents, surfactants, and antioxidants can all be included. For
example, useful components include sodium chloride, acetates,
citrates or phosphates buffers, glycerin, dextrose, fixed oils,
methyl parabens, polyethylene glycol, propylene glycol, sodium
bisulfate, benzyl alcohol, ascorbic acid, and the like. The
parenteral formulations can be stored in any conventional
containers such as vials and ampoules.
[0310] Compositions for administration by inhalation or
insufflation include solutions and suspensions in pharmaceutically
acceptable aqueous or organic solvents, or mixtures thereof, and
powders. The liquid or solid compositions may include suitable
pharmaceutically acceptable excipients as described above. Such
compositions may be administered by the oral or nasal respiratory
route for local or systemic effect. Compositions can be nebulized
by use of a suitable gas. Nebulized solutions may be breathed
directly from the nebulizing device or the nebulizing device may be
attached to a face mask or the breathing chamber. Solutions,
suspensions and powder compositions can be administered orally or
nasally from devices which deliver the formulation in an
appropriate manner.
[0311] Pharmaceutical compositions for topical administration may
include transdermal patches, ointments, lotions, creams, gels,
drops, suppositories, sprays, liquids and powders. Topical
formulations can contain one or more conventional carriers. For
example, ointments can contain water and one or more hydrophobic
carriers selected from liquid paraffin, polyoxyethylene alkyl
ether, propylene glycol, white vaseline and the like. Carrier
compositions of creams can be based on water in combination with
glycerol and one or more other components such as cetylstearyl
alcohol, glycerin monostearate and the like. Gels can be formulated
using isopropyl alcohol and water, suitably in combination with
other excipients such as glycerol, hydroxyethyl cellulose and the
like.
[0312] The pharmaceutical compositions, like oral and parenteral
compositions, can be formulated in unit dosage forms for ease of
administration and uniformity of dosage. As used herein, "unit
dosage forms" refers to physically discrete units suitable as
unitary dosages for administration to subjects, each unit
containing a predetermined quantity of active ingredient calculated
to produce the desired therapeutic effect, in association with one
or more suitable pharmaceutical carriers.
[0313] In therapeutic applications, pharmaceutical compositions are
to be administered in a manner appropriate to the disease to be
treated, as determined by a person skilled in the medical arts. An
appropriate dose and suitable duration and frequency of
administration will be determined by such factors as the condition
of the patient, the type and severity of the disease, the
particular form of the active ingredient, the method of
administration, among others. In general, an appropriate dose and
administration regimen provides the pharmaceutical composition in
an amount sufficient to provide therapeutic benefit, for example an
improved clinical outcome, such as more frequent complete or
partial remissions, or longer disease-free and/or overall survival,
or lessening of symptoms severity, or any other objectively
identifiable improvement as noted by the clinical. Effective doses
may generally be assessed or extrapolated using experimental models
like dose-response curves derived from in vitro or animal model
test systems.
[0314] The pharmaceutical compositions of the invention can be
included in a container, pack or dispenser together with
instructions for administration.
[0315] The compounds of the invention can be administered as a
single active agent or may also be used or administered in
combination with one or more additional therapeutically active
agents, e.g. drugs useful in the treatment of a disease selected
from cancers, autoimmune or inflammatory diseases, transplant
rejection, ciliopathies, diseases of the nervous system, mental or
behavioral disorders, infectious diseases, cardiovascular diseases,
muscle atrophy and cachexia. Combination therapy includes
administration of a single pharmaceutical dosage formulation which
contains a compound of the invention and one or more additional
therapeutically active agents, as well as administration of the
compound of the invention and each additional therapeutically
active agent in its own separate pharmaceutical dosage formulation
for separate administration. If administered separately, the
administration can be simultaneous, sequential or separate, and the
compound of the invention and the additional therapeutic agent(s)
can be administered via the same administration route or using
different administration routes, for example one compound can be
administered orally and the other intravenously. Moreover, as
explained above, the compounds of the invention can also be used in
monotherapy, particularly in the monotherapeutic treatment of a
disease selected from cancer, an autoimmune or inflammatory
disease, transplant rejection, a ciliopathy, a disease of the
nervous system, a mental or behavioral disorder, an infectious
disease, a cardiovascular disease, muscle atrophy, and
cachexia.
EXAMPLES
[0316] The following abbreviations have been used in the
examples:
AcN: acetonitrile AcOH: acetic acid aq: aqueous, Boc:
tert-butyloxycarbonyl n-BuOH: n-butanol
DCM: Dichloromethane
[0317] DIAD: Diisopropyl azodicarboxylate
DIPEA: N,N-Diisopropylethylamine,
DMF: N,N-dimethylformamide
[0318] EtOAc: ethyl acetate EtOH: ethanol FA: Formic acid HPLC:
high performance liquid chromatography LC-MS: liquid
chromatography-mass spectroscopy
MeI: Iodomethane
[0319] MeOH: methanol PPh.sub.3: triphenylphosphine
Pd(PPh.sub.3).sub.4: tetrakis(triphenylphosphine) palladium (0)
Pd(PPh.sub.3).sub.2Cl.sub.2: Bis(triphenylphosphine)palladium
chloride Pet ether: petroleum ether, pTSA: p-Toluenesulfonic acid
monohydrate rt (or RT): room temperature Rt: retention time, TBAB:
Tetrabutylammonium bromide TEA: triethylamine TFA: Trifluoroacetic
acid THF: tetrahydrofurane THP: tetrahydropyran T.sub.3P:
Propylphosphonic anhydride solution .gtoreq.50 wt. % in ethyl
acetate
[0320] One of the following methods was used for the determination
by LC-MS:
Method 1: Column: KINETEX-1.7 u XB-C18 100A (50 mm.times.2.1 mm,
1.7 .mu.m); Mobile Phase: A: 0.05% Formic Acid in Water B: 0.05%
Formic Acid in Acetonitrile; Gradient: Time/% A: 0/97, 0.3/97,
3.2/2, 4.8/2, 5/97, 5.10/97 Column Temp: 35.degree. C.; Flow Rate:
0.6 mL/min Method 2: Column: Aquity UPLC BEH C18 (50 mm.times.2.1
mm, 1.7 .mu.m); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1%
Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97,
3.2/2, 4/2, 4.01/97; Column Temp: 35.degree. C.; Flow Rate: 0.6
mL/min; Method 3: Column: Aquity UPLC BEH C18 (50 mm.times.2.1 mm,
1.7 .mu.m); Mobile Phase: B: 0.1% Formic Acid in Water, A: 0.1%
Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97,
3.0/2, 4.5/2, 4.51/97; Column Temp: 35.degree. C.; Flow Rate: 0.6
mL/min. Method 4: Column: Aquity UPLC BEH C18 (50 mm.times.2.1 mm,
1.7 .mu.m); Mobile Phase: B: 0.1% Formic Acid in Water A: 0.1%
Formic Acid in Acetonitrile; Gradient: Time/% B: 0/97, 0.3/97,
2.2/2, 3.30/2, 4.5/2, 4.51/97; Column Temp: 35.degree. C.; Flow
Rate: 0.6 mL/min; Method 5: Column--AQUITY UPLC BEH C18 (50
mm.times.2.1 mm, 1.7 .mu.m); Mobile Phase-A: 0.1% FA in Water, B:
0.1% FA in Acetonitrile: T % A of: 0/90, 1/10, 2.20/10, 2.30/90,
2.60./90 Flow-0.8 mL/min, Temp: 50.degree. C. Method 6:
Column--AQUITY UPLC BEH C18 (50 mm.times.2.1 mm, 1.7 .mu.m); Mobile
phase-A: 0.1% FA in Water, B: 0.1% FA in Acetonitrile T % A of:
0/95, 0.3/95, 2.0/5, 3.5/5, 3.6/95, 4.2/95 Flow-0.6 mL/min, Temp:
40.degree. C. Method 7: Column: Aquity UPLC BEH C18 (50
mm.times.2.1 mm, 1.7 .mu.m); Mobile Phase: A: 0.05% Formic Acid in
Acetonitrile, B: 0.05% Formic Acid in Water; Gradient: Time/% B:
0/97, 0.3/97, 3.2/2, 3.8/2, 4.3/97, 4.5/97; Column Temp: 35.degree.
C.; Flow Rate: 0.6 mL/min Method 8: Column: Aquity UPLC BEH C18 (50
mm.times.2.1 mm, 1.7 .mu.m); Mobile Phase: A; 0.1% Formic Acid in
water, B: 0.1% Formic Acid in Acetonitrile; Gradient: Time/% B:
0/97, 0.3/97, 2.7/2, 3.5/2, 3.51/97, Column Temp: 35.degree. C.;
Flow Rate: 0.6 mL/min; Method 9: Column--AQUITY UPLC BEH C18 (50
mm.times.2.1 mm, 1.7 .mu.m); Mobile phase-A: 0.1% FA in Water, B:
0.1% FA in Acetonitrile; T % A of: 0/97, 0.3/97, 3.0/2, 4.0/2,
4.2/97, 4.50/97 Flow-0.6 mL/min, Temp: 35.degree. C. Method 10:
Column: Aquity UPLC BEH C18 (50 mm.times.2.1 mm, 1.7 .mu.m); Mobile
Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in
Acetonitrile; Gradient: Time/% A: 0/97, 0.3/97, 3.0/2, 4.0/2,
4.3/97, 4.50/97; Column Temp: 35.degree. C.; Flow Rate: 0.6 mL/min
Method 11: Column: Aquity UPLC BEH C18 (50 mm.times.2.1 mm, 1.7
.mu.m); Mobile Phase: A: 0.1% Formic Acid in Water, B: 0.1% Formic
Acid in Acetonitrile; Gradient: Time/% B: 0/5, 0.3/95, 2.0/95,
3.7/95, 4.2/5, 5.7/5; Column Temp: 40.degree. C.; Flow Rate: 0.5
mL/min Method 12: Column--AQUITY UPLC BEH C18 (50 mm.times.2.1 mm,
1.7 .mu.m); Mobile phase-A: 0.1% FA in Water, B: 0.1% FA in
Acetonitrile; T % A of: 0/98, 0.2/98, 1.8/2, 2.4/2, 2.60/98,
3.0/98. Flow-0.8 mL/min, Temp: 50.degree. Method 13: Column: YMC
TRAIT C18; Mobile Phase: A: Acetonitrile, B: 0.01 M Ammonium
Bicarbonate in Aq; Gradient: A=40%, B=60%. Flow Rate: 25.0 mL/min.
Method 14: Column: XBridge BEH C18 (50 mm.times.2.1 mm, 2.5 .mu.m);
Mobile Phase: A: 0.01 M Ammonium Formate in water; B: AcN;
Gradient: Time/% B: 0/5, 3/100, 3.5/100, 3.8/5, 4.3/5; Flow Rate:
0.7 mL/min. Temp: 40.degree. C. Method 15: Column: XBridge BEH C18
(50 mm.times.3.0 mm, 2.5 .mu.m); Mobile Phase: A: 0.01 M Ammonium
Formate in water:AcN (95:5), B: 0.01 M Ammonium Formate in
water:AcN (5:95); Gradient: Time/% B: 0/2, 4/98, 4.5/98, 5/2,
5.5/2, 6.5/2; Flow Rate: 1.0 mL/min Method 16: Column: XBridge BEH
C18 (50 mm.times.3.0 mm, 2.5 .mu.m); Mobile Phase: A: 0.01 M
Ammonium Formate in water:AcN (95:5), B: 0.01 M Ammonium Formate in
water:AcN (5:95); Gradient: Time/% B: 0/2, 2/2, 7/98, 7.5/98,
8.5/2, 10/2; Flow Rate: 1.0 mL/min; Method 17: Column: Aquity UPLC
BEH C18 (50 mm.times.2.1 mm, 1.7 .mu.m); Mobile Phase: A: 0.01 M
Ammonium Bicarbonate in Water, B: Acetonitrile; Gradient: Time/% B:
0/3; 1.0/3; 7.0/100; 7.5/100; 9.0/3; 10.0/3. Column Temp:
35.degree. C.; Flow Rate: 0.5 mL/min; Method 18: Column: XBridge
BEH C18 (50 mm.times.2.10 mm, 2.5 .mu.m); Mobile Phase: A: 0.01 M
Ammonium Formate in water:AcN (95:5), B: Acetonitrile; Gradient:
Time/% B: 0/5; 1.0/5; 7/100; 7.5/100; 9/5, 10/5. Column Temp:
40.degree. C.; Flow Rate: 0.7 mL/min; Method 19: Column: XBridge
BEH C18 (50 mm.times.3.0 mm, 2.5 .mu.m); Mobile Phase A: 0.01 M
Ammonium Formate in water:AcN (95:5), B: 0.01 M Ammonium Formate in
water:AcN (5:95); Gradient: Time/% B: 0/2, 1/2, 4/98, 4.5/98,
5.5/2, 6.5/2; Flow Rate: 1.0 mL/min; Method 20: Column: Aquity UPLC
BEH C18 (50 mm.times.2.1 mm, 1.7 .mu.m); Mobile Phase: A: 0.1%
Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile;
Gradient: Time/% A: 0/97, 1.0/97, 7.0/0, 7.5/0, 9.0/97; Column
Temp: 35.degree. C.; Flow Rate: 0.5 mL/min Method 21: Column:
Aquity UPLC BEH C18 (50 mm.times.2.1 mm, 1.7 .mu.m); Mobile Phase:
A: 0.1% Formic Acid in Water, B: 0.1% Formic Acid in Acetonitrile;
Gradient: Time/% A: 0/5, 0.1/5, 2.7/100, 3.5/100, 3.8/5; 4.3/5
Column Temp: 40.degree. C.; Flow Rate: 0.7 mL/min Method 22:
Column: XBridge BEH C18 (50 mm.times.2.1 mm, 2.5 .mu.m); Mobile
Phase A: 0.01 M Ammonium Formate in water:AcN (95:5), B: 0.01 M
Ammonium Formate in water:AcN (5:95); Gradient: Time/% B: 0/2, 1/2,
7/100, 7.5/100, 9/2, 10/2; Flow Rate: 0.7 mL/min; Method 23:
Column: Aquity UPLC BEH C18 (50 mm.times.2.1 mm, 2.5 .mu.m); Mobile
Phase A: 0.01 M Ammonium Acetate in water; B: AcN; Gradient: Time/%
B: 0/5, 0.2/5, 7/100, 8/100, 8.5/5, 11/5; Column Temp: 40.degree.
C.; Flow Rate: 0.5 mL/min; Method 24: Column: Luna Omega 3 .mu.m PS
C18 100A; Mobile Phase A: 0.01 M Ammonium Formate in water:AcN
(95:5); B: 0.01 M Ammonium Formate in water:AcN (5:95); Gradient:
Time/% B: 0/2, 1/2, 4/98, 4.5/98, 5.5/2, 6.5/2; Flow Rate: 1.0
mL/min; Method 25: Column--AQUITY UPLC BEH C18 (50 mm.times.2.1 mm,
1.7 .mu.m); Mobile phase-A: 0.1% FA in Water, B: 0.1% FA in
Acetonitrile T % A of: 0/95, 0.3/95, 2.0/5, 3.5/5, 3.6/95, 4.4/95
Flow-0.6 mL/min, Temp: 40.degree. C. Method 26: Column: Aquity UPLC
BEH C18 (50 mm.times.2.1 mm, 1.7 .mu.m); Mobile Phase A: 0.01 M
Ammonium Acetate in water; B: AcN; Gradient: Time/% A: 0/5, 0.1/5,
2.4/100, 3.8/100, 4.0/5; 4.5/5 Column Temp: 50.degree. C.; Flow
Rate: 0.5 mL/min Method 27: Column: Luna Omega 3 .mu.m PS C18
100A); Mobile Phase A: 0.01 M Ammonium Formate in water: AcN
(95:5), B: 0.01 M Ammonium Formate in water:AcN (5:95); Gradient:
Time/% B: 0/2, 1/2, 7/100, 7.5/100, 9/2, 10/2; Flow Rate: 1.0
mL/min.
Reference Example 1
2-(Trimethylstannyl)isonicotinonitrile
[0321] To a stirred solution of 2-bromoisoniconitrile (2 g, 10.92
mmol) in toluene (20 mL), hexamethylditin (4.6 g, 14.20 mmol), and
Pd(PPh.sub.3)4 (1.2 g, 1.09 mmol) were added at rt. The resulting
solution was degassed with nitrogen for 10 min and heated to
110.degree. C. for 16 h. The reaction mixture was evaporated under
reduced pressure and the crude compound was purified by flash
column chromatography on neutral alumina using 50% EtOAc in
petroleum ether to afford the title compound (1.5 g, 51.7%).
[0322] LC-MS (method 1): R.sub.t=1.93 min; m/z=269.08
(M+H.sup.+)
Reference Example 2
5-Bromo-1-butyl-1H-pyrrolo[2,3-c]pyridine
[0323] To a stirred suspension of 60% NaH (0.146 g, 6.091 mmol) in
DMF (20 mL), 5-bromo-1H-pyrrolo[2,3-c]pyridine (0.8 g, 4.06 mmol)
was added at 0.degree. C. and stirred for 15 min. Then, 1-bromo
butane (0.66 g, 4.873 mmol) was added to the reaction mixture at
0.degree. C. The resulting mixture was allowed to warm to rt and
stirred for 16 h. The reaction mixture was quenched with water and
extracted EtOAc and the organic layer was dried over anhydrous
Na.sub.2SO.sub.4, and it was concentrated under reduced pressure.
The crude compound was purified by flash column chromatography
using 10% EtOAc in pet ether as an eluent to afford the title
compound (0.78 g, 67%).
[0324] LC-MS (method 2): R.sub.t=2.27 min; m/z=253.17
(M+H.sup.+).
[0325] Following a similar procedure to that described in reference
example 2, but using in each case the corresponding starting
materials, the following compounds were obtained:
TABLE-US-00002 Reference Starting HPLC R.sub.t example Compound
name material method (min) m/z 2a 5-Bromo-1-propyl- 1- 3 2.23
239.06 1H-pyrrolo lodopropane (M+H.sup.+) [2,3-c]pyridine 2b
5-Bromo-1-(2- 1-Bromo-2- 15 3.30 255.21 methoxyethyl)-1H- methoxy
(M+H.sup.+) pyrrolo[2,3-c] ethane pyridine (*) (*) 0.02 eq of Nal
were added.
Reference Example 3
5-Bromo-1-butyl-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
Step a.
5-Bromo-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxamide
[0326] To a stirred solution of
5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (500 mg, 2.07
mmol) in DMF, dimethyl amine hydrochloride (168 mg, 2.07 mmol), TEA
(1.49 g, 10.37 mmol) and T.sub.3P (1.97 g, 6.21 mmol) were added at
0.degree. C. The resulting mixture was allowed to stir at rt for 16
h. The reaction mixture was diluted with water and extracted with
EtOAc. The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude compound was purified by silica gel column chromatography
and eluted at 5% MeOH in DCM to afford the title compound (450 mg,
78%).
[0327] LC-MS (method 4): R.sub.t=1.75 min; m/z=270.15
(M+H.sup.++2).
Step b.
5-Bromo-1-butyl-N,N-dimethyl-1H-pyrrolo[2,3-c]pyridine-2-carboxami-
de
[0328] To a stirred solution of the compound obtained in the
previous section, step a (1.4 g, 5.24 mmol) in DMF, 60% NaH (1.04
g, 26.21 mmol) was added at 0.degree. C. The reaction mixture was
stirred for 15 minutes at the same temperature and then butyl
iodide (1.92 g, 10.48 mmol) was added. The suspension was stirred
at rt for 16 h. The reaction mixture was cooled at 0.degree. C.,
quenched with water and extracted with EtOAc. The separated organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure. The crude compound was
purified by silica gel column chromatography and eluted at 5% MeOH
in DCM to afford the title compound (1.0 g, 59.8%)
[0329] LC-MS (method 5): R.sub.t=1.10 min; m/z=325.36
(M+H.sup.+).
[0330] Following a similar procedure to that described in reference
example 3, but using in each case the corresponding starting
material, the following compounds were obtained:
TABLE-US-00003 Reference Starting HPLC R.sub.t example Compound
name material method (min) m/z 3a 5-Bromo-N,N,1- Dimethyl amine 6
1.62 282.10 trimethyl- hydrochloride (M+H.sup.+) 1H-pyrrolo[2,3-c]
(step a) and pyridine-2- iodomethane carboxamide (step b) 3b
5-Bromo-1-butyl- Ethyl amine 6 2.12 322.21 N-ethyl-1H-pyrrolo
hydrochloride (M-H.sup.+) [2,3-c]pyridine- (step a) and
2-carboxamide butyl iodide 3c 5-Bromo-1-butyl- Diethyl amine 6 2.26
352.28 N,N-diethyl- hydrochloride (M+H.sup.+) 1H-pyrrolo[2,3-c]
(step a) and pyridine-2- butyl iodide carboxamide (step b)
Reference Example 4
3-((6-Bromopyridin-3-yl)oxy)-N,N-diethylpropan-1-amine
[0331] To a stirred solution of 6-bromopyridin-3-ol (5.0 g, 28.73
mmol) in THF (50 mL), PPh.sub.3 (15.0 g, 57.47 mmol), DIAD (8.7 g,
43.10 mmol) and 3-(diethylamino)propan-1-ol (5.64 g, 43.10 mmol)
were added at 0.degree. C. The reaction mixture was allowed to stir
at rt for 16 h. The reaction mixture was diluted with water (100
mL) and extracted with EtOAc (2.times.100 mL). The combined organic
layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and the
filtrate was concentrated. The crude compound was purified by flash
column chromatography using 100-200 silica gel and eluted with 40%
EtOAc/pet ether to afford the title compound (3.1 g, 38%) as a
gummy liquid. LC-MS (method 7): R.sub.t=1.50 min; m/z=287.18
(M+H.sup.+).
Reference Example 5
1-(5-Bromo-1-butyl-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine
[0332] To a stirred solution of reference example 2 (500 mg, 1.97
mmol) in n-BuOH (20 mL), 37% formaldehyde aqueous solution (37%)
(0.78 mL, 9.88 mmol), and dimethyl amine hydrochloride (805 mg,
9.88 mmol) were added. The reaction mixture was stirred at
120.degree. C. for 16 h and then it was cooled to rt. The organic
solvent was evaporated under reduced pressure to get a residue that
was diluted with 1N NaOH aqueous solution and extracted with 10%
MeOH/DCM (2.times.50 mL). The crude residue was evaporated to get a
crude compound that was purified by column chromatography on
230-400 silica with 85% EtOAc/pet ether along with 0.5 mL of TEA to
afford 400 mg (65%) of the title compound as a gummy solid.
[0333] LC-MS (method 5): R.sub.t=0.77 min; m/z=312.12
(M+H.sup.++2).
[0334] Following a similar procedure to that described in reference
example 5, but using in each case the corresponding starting
materials, the following compounds were obtained:
TABLE-US-00004 Reference Starting HPLC R.sub.t example Compound
name material method (min) m/z 5a 5-Bromo-3-(piperidin- Piperidine
6 1.46 336.24 1-ylmethyl)-1- and (M+H.sup.+) propyl-1H-pyrrolo
reference [2,3-c]pyridine example 2a 5b 4-((5-Bromo-1- Morpholine 6
1.35 338.21 propyl-1H-pyrrolo and (M+H.sup.+) [2,3-c]pyridin-3-yl)
reference methyl)morpholine example 2a 5c 1-(5-Bromo-1-propyl-
Dimethyl 6 1.33 296.20 1H-pyrrolo[2,3-c] amine (M+H.sup.+)
pyridin-3-yl)-N,N- hydrochloride dimethylmethanamine and reference
example 2a
Reference Example 6
2-Bromo-5-(3-(4,4-difluoropiperidin-1-yl)propoxy)pyridine
Step a. 2-Bromo-5-(3-chloropropoxy)pyridine
[0335] To a stirred solution of 6-bromopyridin-3-ol (3 g, 17.2
mmol) in DMF (50 mL), K.sub.2CO.sub.3 (7.1 g, 51.6 mmol) was added
and stirred at rt for 15 minutes. It was cooled to 0.degree. C. and
1-bromo-3-chloropropane (4 g, 25.8 mmol) was added. The resulting
mixture was stirred at rt for 16 h. The reaction mixture was
diluted with ice cold water and extracted with EtOAc (3.times.100
mL), washed with water (2.times.80 mL) and then brine (50 mL). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to afford the title
compound (2.8 g, 64%) as a yellow gummy liquid.
[0336] LC-MS (method 6): R.sub.t=2.04 min; m/z=250.01
(M+H.sup.+).
Step b.
2-Bromo-5-(3-(4,4-difluoropiperidin-1-yl)propoxy)pyridine
[0337] To a solution of the compound obtained in the previous
section, step a (2 g, 7.98 mmol) in acetonitrile,
4,4-difluoropiperidine hydrochloride (1.88 g, 11.97 mmol),
K.sub.2CO.sub.3 (3.3 g, 23.95 mmol), and NaI (1.19 g, 7.98 mmol)
were added at rt. The resulting mixture was stirred at 70.degree.
C. for 24 h and then it was cooled to rt. The reaction mixture was
poured into ice water (30 mL) and extracted with EtOAc (2.times.80
mL): The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The crude residue
was washed with n-pentane and dried to afford 1.5 g (56%) of the
title compound as a gummy liquid.
[0338] LC-MS (method 5): R.sub.t=0.66 min; m/z=335.15
(M+H.sup.+).
[0339] Following a similar procedure to that described in reference
example 6, but using the corresponding starting material, the
following compound was obtained:
TABLE-US-00005 Refer- ence exam- Starting HPLC R.sub.t ple Compound
name material method (min) m/z 6a 4-(3-((6- Morpholine 6 1.17
301.11 Bromopyridin-3-yl) (M+H.sup.+) oxy)propyl)morpholine 6b
3-(6-Bromopyridin- Demethyl 15 1.77 259.34 3-yloxy)-N,N- amine
(M+H.sup.+) dimethylpropan- hydrochloride 1-amine 6c 2-((3-((6- 2-
14 1.43 289.0 Bromopyridin-3-yl) (Methylamino) (M+H.sup.+)
oxy)propyl)(methyl) ethanol amino)ethan-1-ol
Reference Example 7
N-(6-Bromopyridin-3-yl)-N-butyl-3-methoxypropanamide
Step a. 6-Bromo-N-butylpyridin-3-amine (2) (C2134-130)
[0340] To a stirred solution of 6-bromopyridin-3-amine (10 g, 57
mmol) in MeOH (100 mL), butyraldehyde (4.9 g, 69.36 mmol) was added
and stirred for 16 h at rt. It was cooled to 0.degree. C. and
NaBH.sub.3CN (7.2 g, 115.6 mmol) was added. The resulting mixture
was stirred at rt for 16 h. The reaction mixture was poured into
cold water (100 mL), extracted with EtOAc (2.times.200 mL) and
washed with brine solution (150 mL). The organic layers were dried
over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under
reduced pressure to get a crude compound that was purified by
column chromatography with 13% EtOAc/pet-ether to afford 7 g (52%)
of the title compound.
[0341] LC-MS (method 4): R.sub.t=2.31 min; m/z=229.16
(M+H.sup.+).
Step b. N-(6-Bromopyridin-3-yl)-N-butyl-3-methoxypropanamide
[0342] To a stirred solution of the compound obtained in the
previous section, step a (1500 mg, 6.54 mmol, 1.0 equiv) in DCM,
3-methoxypropanoic acid (1020 mg, 9.84 mmol), TEA (3.30 g, 32.75
mmolv) and T.sub.3P (8.3 g, 26.18 mmol) were added at 0.degree. C.
The reaction mixture was allowed to stir at rt for 16 h. The
reaction mixture was diluted with water and extracted with EtOAc.
The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude compound was purified by silica gel column chromatography
and eluted at 30% EtOAc in pet ether to afford (1450 mg, 70%) of
the title compound. LC-MS (method 10): R.sub.t=2.40 min; m/z=315.12
(M+H.sup.+).
Reference Example 8
6-Bromo-N-(cyclopropylmethyl)-N-methylpyridin-3-amine
[0343] To a stirred solution of 6-bromo-N-methylpyridin-3-amine
(1200 mg, 6.44 mmol) in DMF, 60% NaH (1030 mg, 25.76 mmol) was
added at 0.degree. C. and stirred at rt for 15 minutes. It was
cooled at 0.degree. C., and (bromomethyl)cyclopropane (1738 mg,
12.88 mmol) was added. It was allowed to stir at rt for 1 h. The
reaction mixture was cooled to 0.degree. C., quenched with water
and extracted with EtOAc. The separated organic layer was washed
with water and brine solution and dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude compound was purified by column chromatography and eluted
at 15% EtOAc in pet ether to afford the title compound (1.0 g,
64.2%) as a yellow gummy; LC-MS (method 5): R.sub.t=1.20 min;
m/z=240.97 (M+H.sup.+).
Reference Example 9
Tert-butyl
(6-bromopyridin-3-yl)(3-(diethylamino)propyl)carbamate
Step a. 3-Chloro-N,N-diethylpropan-1-amine hydrochloride
[0344] To a stirred solution 3-(diethylamino)propan-1-ol (1 g, 7.63
mmol) in DCM (10 mL) was added SOCl.sub.2 (1.1 mL, 15.26 mmol) at
0.degree. C. and the resulting mixture was stirred at rt for 3 h.
The reaction was concentrated under reduced pressure to afford the
title compound (1 g, 88%).
Step b. Tert-butyl
(6-bromopyridin-3-yl)(3-(diethylamino)propyl)carbamate
[0345] To a stirred suspension of 60% NaH (0.15 g, 6.598 mmol) in
DMF (50 mL), a solution of tert-butyl
(6-bromopyridin-3-yl)carbamate (1.2 g, 4.399 mmol) in DMF (10 mL)
at 0.degree. C. was added. The resulting mixture was stirred for 15
min, and then the compound obtained in the previous section, step
a, was added (0.785 g, 5.274 mmol) to the reaction mixture at
0.degree. C. The resulting mixture was stirred at rt for 16 h. The
reaction mixture was quenched with ice cold water and extracted
with EtOAc. The organic layer was concentrated under reduced
pressure and the obtained crude compound was purified by flash
column chromatography using 100% EtOAc as an eluent to obtain the
title compound (0.9 g, 53) LC-MS (method 13): R.sub.t=1.55 min;
m/z=388.09 (M+H.sup.++2).
Reference Example 10
6-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)-N-methylpyridin-3-amine
Step a. Tert-butyl
(6-bromopyridin-3-yl)(3-chloropropyl)carbamate
[0346] To a stirred solution of tert-butyl
6-bromopyridin-3-ylcarbamate (2.0 g, 7.352 mmol) in DMF (20 mL),
60% NaH (0.529 g, 22.05 mmol) was added at 0.degree. C. and stirred
at rt for 15 minutes. Then, 1-bromo-3-chloropropane (2.308 g,
14.705 mmol) was added and the resulting mixture was allowed to
stir at rt for 16 h. The reaction mixture was cooled to 0.degree.
C., quenched with ice-water and extracted with EtOAc. The organic
layers were washed with water and brine solution, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The crude compound was purified by silica gel column
chromatography and eluted at 8% EtOAc in pet ether to afford the
title compound (2.0 g, LCMS-75%) as a brown colour gummy; LC-MS
(method 5): R.sub.t=1.31 min; m/z=349.20 (M+H.sup.+).
Step b Tert-butyl
(6-bromopyridin-3-yl)(3-(4,4-difluoropiperidin-1-yl)propyl)carbamate
[0347] To a stirred solution of 4,4-difluoropiperidine
hydrochloride (1.815 g, 11.49 mmol) in AcN (30 mL), NaI (1.027 g,
6.896 mmol) and K.sub.2CO.sub.3 (2.379 g, 17.24 mmol) were added.
The reaction mixture was stirred for 10 minutes, the compound
obtained in the previous section, step a (2.0 g, 5.747 mmol) was
added and heated to 90.degree. C. for 16 h. The reaction mixture
was filtered through a celite pad and it was washed with 10% MeOH
in DCM. The filtrated solution was concentrated under reduced
pressure and the crude compound was purified by silica gel column
chromatography using 25% EtOAc in pet ether as eluent to afford the
title compound (1.1 g, 44%) as an off-white solid;
[0348] LC-MS (method 5): R.sub.t=0.86 min; m/z=434.35
(M+H.sup.+).
Step c.
6-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)pyridin-3-amine
[0349] To a stirred solution of the compound obtained in the
previous section, step b (1.4 g, 3.22 mmol) in DCM (10 mL), TFA
(3.0 ml) was added at 0.degree. C. and it was allowed to stir at rt
for 3 h. The reaction mixture was concentrated under reduced
pressure. The crude residue was diluted with water, basified to
pH-8 using saturated NaHCO.sub.3 aqueous solution and extracted
with EtOAc. The organic layers were washed with water and brine
solution. The organic layers were dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure
to afford the title compound (1.01 g, 94%) as an off white
solid;
[0350] LC-MS (method 6): R.sub.t=1.40 min; m/z=334.11
(M+H.sup.+).
Step d.
6-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)propyl)-N-methylpyridin-3-
-amine
[0351] To a stirred solution of the compound obtained in the
previous section, step c, (3.0 g, 9.0 mmol) in formic acid (40 mL),
paraformaldehyde (2.70 g, 90.09 mmol) was added and heated at
100.degree. C. for 16 h. The reaction mixture was concentrated
under reduced pressure: The crude residue was dissolved in water
and basified to pH.about.8 using saturated NaHCO.sub.3 aqueous
solution and extracted with EtOAc (3.times.50 mL). The separated
organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure The crude compound was
purified by silica gel column chromatography and eluted at 20%
EtOAc in pet ether to afford the title compound (2.5 g, 79%) as an
off-white solid.
[0352] LC-MS (method 6): R.sub.t=1.55 min; m/z=348.13
(M+H.sup.+).
Reference Example 11
3-(2-Bromopyrimidin-5-yloxy)-N,N-diethylpropan-1-amine
Step a. 2-Bromopyrimidin-5-ol
[0353] To a stirred solution of 2-chloropyrimidin-5-ol (2 g, 15.3
mmol) in AcOH (6 mL), HBr (47% aqueous solution) (6 mL) was added
at 0.degree. C. and it was stirred at rt for 15 minutes. The
resulting mixture was stirred at 100.degree. C. for 24 h. The
solvents were evaporated under vacuum and then poured into ice cold
water and extracted with EtOAc (2.times.100 mL). The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated under reduced pressure to get a crude residue that was
purified by column chromatography on 100-200 silica with 30% of
EtOAc/pet ether to afford the title compound (1.5 g, 55%) as an off
white solid.
[0354] LC-MS (method 6): R.sub.t=0.94 min; m/z=175.03
(M+H.sup.+).
Step b. 2-Bromo-5-(3-chloropropoxy)pyrimidine
[0355] To a stirred solution of the compound obtained in the
previous section, step a (1.5 g, 8.6 mmol) in DMF, K.sub.2CO.sub.3
(3.5 g, 25.8 mmol) and 1-bromo-3-chloropropane (2) (2 g, 12.9 mmol)
were added. The resulting mixture was stirred at rt overnight. The
reaction mixture was diluted with water, extracted with EtOAc
(2.times.100 mL). The organic layer was dried over
Na.sub.2SO.sub.4, and evaporated under reduced pressure to afford
1.8 g (83%) of a crude compound that was used for the next step
without any further purification.
[0356] LC-MS (method 6): R.sub.t=1.89 min; m/z=251.08
(M+H.sup.+).
Step c. 3-(2-Bromopyrimidin-5-yloxy)-N,N-diethylpropan-1-amine
[0357] To a stirred solution of the compound obtained in the
previous section, step b (1.8 g, 7.2 mmol) in AcN, K.sub.2CO.sub.3
(2.9 g, 21.6 mmol) and NaI (1.07 g, 7.2 mmol) were added. The
resulting mixture was stirred at rt for 15 minutes and diethyl
amine hydrochloride (2.6 g, 36 mmol) was added at rt. It was
stirred at 70.degree. C. for 16 h. The reaction mixture was diluted
with ice cold water and extracted with EtOAc (3.times.100 mL). The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated under reduced pressure to afford the title
compound (1.2 g, 58%) as a brown gummy liquid.
[0358] LC-MS (method 6): R.sub.t=1.08 min; m/z=288.18
(M+H.sup.+).
Reference Example 12
N.sup.1-(6-Bromopyridin-3-yl)-N.sup.3,N.sup.3-diethyl-N.sup.1-methylpropan-
e-1,3-diamine
Step a.
N.sup.1-(6-Bromopyridin-3-yl)-N.sup.3,N.sup.3-diethylpropane-1,3-d-
iamine
[0359] To a stirred solution of reference example 9 (1.2 g, 3.1
mmol) in DCM (20 ml), TFA (3.5 ml) was added and allowed to stir at
rt for 8 h. The reaction mixture was concentrated to dryness to get
a crude residue that was purified by column chromatography and
eluted at 10% MeOH/DCM to afford 0.9 g (100%) of the title
compound.
[0360] LC-MS (method 6): R.sub.t=1.27 min; m/z=286.13
(M+H.sup.+).
Step b.
N.sup.1-(6-Bromopyridin-3-yl)-N.sup.3,N.sup.3-diethyl-N.sup.1-meth-
ylpropane-1,3-diamine
[0361] To a stirred solution of the compound obtained in the
previous section, step a (800 mg, 2.795 mmol) in formic acid (10
mL), paraformaldehyde (839 mg, 27.95 mmol) at 0.degree. C. was
added slowly and allowed to stir at 95.degree. C. for 16 h. The
reaction mixture was concentrated under reduced pressure and the
residue was dissolved in water. The aqueous layer was basified
using saturated NaOH aqueous solution, and concentrated under
reduced pressure. The obtained crude residue was purified by column
chromatography and eluted at 10% MeOH/DCM to afford the title
compound (700 mg, 67.3%).
[0362] LC-MS (method 6): R.sub.t=1.37 min; m/z=300.16
(M+H.sup.+).
REFERENCE 13
3-(6-Bromopyridin-3-yloxy)-N-methylpropan-1-amine
[0363] In a sealed tube, to a stirred solution of the compound
obtained in reference example 6, step a (1 g, 4 mmol) in AcN,
K.sub.2CO.sub.3 (1.6 g, 12 mmol) and NaI (300 mg, 2 mmol) were
added at 0.degree. C. and stirred at rt for 15 minutes. Then, a
solution of 33% methylamine in EtOH, (0.6 mL, 6 mmol) was added at
0.degree. C. The resulting mixture was stirred at 60.degree. C. for
16 h. It was was diluted with ice cold water and extracted with
EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to get a crude
residue that was purified by column chromatography on 230-400
silica with 2% MeOH/DCM as eluent to afford the title compound (750
mg, 76%) as a gummy liquid.
[0364] LC-MS (method 14): R.sub.t=1.07 min; m/z=245.01
(M+H.sup.+).
REFERENCE 14
6-Bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridine
[0365] To a stirred solution of 6-bromo-1H-pyrrolo[3,2-c]pyridine
(1 g, 3.36 mmol) in DMF (20 mL), tetrahydro-2H-pyran-4-yl
methanesulfonate (1.51 g, 8.38 mmol), and Cs.sub.2CO.sub.3 (5.46 g,
16.8 mmol) were added at 0.degree. C. The resulting mixture was
stirred at 100.degree. C. for 16 h. The reaction mixture was
diluted with EtOAc and washed with water. The the organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrate
under reduced pressure. The crude residue was purified by column
chromatography and eluted at 10% MeOH in DCM to afford the title
compound (0.33 g, 35%) as an off white solid.
[0366] LC-MS (method 6): R.sub.t=1.73 min; m/z=281.07
(M+H.sup.+).
[0367] Following a similar procedure to that described in reference
example 14, but using in the corresponding starting material, the
following compound was obtained:
TABLE-US-00006 Reference Compound Starting HPLC R.sub.t example
name material method (min) m/z 14a 6-Bromo-1- (Tetrahydro-2H- 14
2.05 295.0 ((tetrahydro- pyran-4-yl) 2H-pyran-4-yl) methyl (M+H+)
methyl)- methanesulfonate 1H-pyrrolo [3,2-c]pyridine
Reference Example 15
3-((6-Bromopyridin-3-yl)oxy)-N-ethyl-N-phenethylpropan-1-amine
Step a. 3-((6-Bromopyridin-3-yl)oxy)propan-1-ol
[0368] To a stirred suspension of 6-bromopyridin-3-ol (5.0, 28.73
mmol) in DMF (40 mL), K.sub.2CO.sub.3 (11.90 g, 86.20 mmol) and
3-bromopropanol (4.39 g, 31.60 mmol) were added at rt and stirred
for 16 h. The reaction mixture was quenched with ice cold water
(150 mL) and extracted with ethyl acetate (2.times.60 mL). The
combined organic layers were washed with water (100 mL) followed by
brine solution (100 mL) and dried over anhydrous Na.sub.2SO.sub.4
and filtered. The solution filtrated was concentrated under reduced
pressure and the resulting crude compound was purified by flash
column chromatography using 30% of ethyl acetate in pet ether as
the eluent to afford the title compound (3.50 g, 53%) as color less
liquid.
[0369] LC-MS (method 5): R.sub.t=0.82 min; m/z=232.05
(M+H.sup.+).
Step b. 2-Bromo-5-(3-bromopropoxy)pyridine
[0370] To a solution of the compound obtained in the previous
section, step a, (3.50 g, 15.08 mmol) in DCM (50 mL), PPh.sub.3
(11.0 g, 30.17 mmol) and CBr.sub.4 (9.98 g, 30.17 mmol) were added
at 0.degree. C. The resulting mixture was stirred at room
temperature for 6 h. The solvent was removed under reduced pressure
and the crude residue was purified by silica gel column using 10%
EtOAc in pet ether as an eluent to afford the title compound (2.50
g, 56%) as color less liquid.
[0371] LC-MS (method 5): R.sub.t=1.19 min; m/z=293.99
(M+H.sup.+).
Step c. 3-((6-Bromopyridin-3-yl)oxy)-N-phenethylpropan-1-amine
[0372] To a solution of the compound obtained in the previous
section, step b, (2.50 g, 8.47 mmol) and 2-phenylethanamine (1.54
g, 12.71 mmol) in AcN (50 mL), NaI (1.27 g, 8.47 mmol) and
K.sub.2CO.sub.3 (3.50 g, 25.42 mmol) were added. The resulting
mixture was heated at 60.degree. C. for 16 h. The reaction mixture
was tempered, filtered and the filtrate was concentrated under
reduced pressure: The crude residue was purified by grace reverse
phase column chromatography using 35% AcN in 0.1% aq formic acid as
eluent to afford the title compound (1.50 g, 53%) as color less
liquid.
[0373] LC-MS (method 5): R.sub.t=0.81 min; m/z=335.20
(M+H.sup.+).
Step d.
3-((6-Bromopyridin-3-yl)oxy)-N-ethyl-N-phenethylpropan-1-amine
[0374] To a solution of the compound obtained in the previous
section, step c, (1.50 g, 4.47 mmol) in DMF (20 mL),
K.sub.2CO.sub.3 (1.85 g, 13.43 mmol) and ethyl iodide (1.04 g, 6.71
mmol) were added and stirred at room temperature for 16 h. The
reaction mixture was quenched with ice cold water (150 mL) and
extracted with ethyl acetate (2.times.60 mL). The combined organic
layers were washed with water (100 mL) followed by brine solution
(100 mL) and dried over anhydrous Na.sub.2SO.sub.4 and filtered.
The solution filtrated was concentrated under reduced pressure and
the resulting crude compound was purified by grace reverse phase
column using 40% of Acetonirile in 0.1% aq. Formic acid an eluent
to afford the title compound (1.10 g, 68%) as color less liquid.
LC-MS (method 6): R.sub.t=1.62 min; m/z=363.29 (M+H.sup.+).
Reference Example 16
N-(6-Bromopyridin-3-yl)-2-phenylacetamide
[0375] To a stirred solution of 6-bromopyridin-3-amine (2.0 g,
11.56 mmol) in DCM (50 mL), 2-phenylacetic acid (2.04 g, 15.02
mmol), and TEA (4.60 g, 46.24 mmol) were added, followed by the
addition of T.sub.3P (9.19 g, 28.90 mmol) at 0.degree. C. The
resulting mixture was stirred at rt for 16 h. The reaction mixture
was washed with saturated NaHCO.sub.3 aqueous solution (100 mL).
The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
filtered. The filtered solution was concentrated under reduced
pressure and the resulting crude compound was purified by flash
column chromatography using 25% ethyl acetate in pet ether as
eluent to afford the title compound (2.30 g, 68%) as an off-white
solid.
[0376] LC-MS (method 1): R.sub.t=2.46 min; m/z=291.08
(M+H.sup.+).
[0377] Following a similar procedure to that described in reference
example 16, but using in each case the corresponding starting
material, the following compound were obtained:
TABLE-US-00007 Reference HPLC R.sub.t example Compound name
Starting material method (min) m/z 16a N-(6-Bromopyridin-3-yl)
1-Methylpiperidine-4- 2 1.04 300.15 -1-methylpiperidine- carboxylic
(M+H+) 4-carboxamide acid and 6-bromopyridin- 3-amine 16b
N-(2-Bromopyridin- 2-Cyclobutylacetic 6 1.99 269.10 4-yl)-2- acid
and 6- (M+H+) cyclobutylacetamide bromopyridin4- amine 16c
Tert-butyl 3-(2- 2-Bromoisonicotinic 6 2.18 384.29
bromoisonicotinamido) acid and tert-butyl (M+H+) piperidi
3-aminopiperidine- ne-1-carboxylate (*) 1-carboxylate 16d
2-Bromo-N-((1- 2-Bromoisonicotinic 6 1.28 312.25 methylpiperidin4-
acid I and (1- (M+H+) yl)methyl) methylpiperidin-4- isonicotinamide
yl)methanamine 16e 6-Bromo-N-((1- 6-Bromonicotinic 19 1.89 312.33
methylpiperidin-4- acid and (1- yl)methyl) methylpiperidin-4-
nicotinamide (**) yl)methanamine (*) using THF instead of DCM. (**)
using DMF instead of DCM
Reference Example 17
2-Bromo-4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)pyridine
Step a. 2-((2-Bromopyridin-4-yl)oxy)ethan-1-ol
[0378] To a stirred solution of 2-bromopyridin-4-ol (2.0 g, 11.5
mmol) in DMF, K.sub.2CO.sub.3 (3.96 g, 28.75 mmol) was added at rt.
2-Bromoethanol (2.15 g, 17.25 mmol) was added slowly at 0.degree.
C. Then it was stirred at 70.degree. C. for 12 h. The reaction
mixture was quenched with ice cold water and extracted with DCM.
The organic layer was washed with saturated NaHCO.sub.3 aqueous
solution, followed by brine solution and dried over anhydrous
Na.sub.2SO.sub.4 and filtered. The filtered solution was
concentrated under reduced pressure and the resulting crude
compound was purified by flash column chromatography (100-200)
silica gel using 20% EtOAc/Pet ether as a eluent to afford the
title compound (1.2 g, 47.8%) as a pale yellow liquid.
[0379] LC-MS (method 14): R.sub.t=1.26 min; m/z=220.0
(M+H.sup.++2).
Step b. 2-Bromo-4-(2-bromoethoxy)pyridine
[0380] To a stirred solution of the compound obtained in the
previous section, step a (1.1 g, 5.0 mmol) in DCM, PPh.sub.3 (1.57
g, 1.2 eq) and CBr.sub.4 (3.31 g, 10 mmol) were added at 0.degree.
C. It was stirred at rt for 12 h. The reaction mixture was quenched
with ice cold water and extracted with DCM. The organic layer was
washed with saturated NaHCO.sub.3 aqueous solution, followed by
brine solution and dried over anhydrous Na.sub.2SO.sub.4 and
filtered. The solution filtrated was concentrated under reduced
pressure and the resulting crude compound was purified by flash
column chromatography (230-400) silica gel using 10% EtOAc/Pet
ether as a eluent to afford the title compound (0.9 g, 64%) as a
pale yellow liquid.
[0381] LC-MS (method 14): R.sub.t=2.18 min; m/z=281.9
(M+H.sup.+).
Step c.
2-Bromo-4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)pyridine
[0382] To a stirred solution of the compound obtained in the
previous section, step b (400 mg, 1.42 mmol) in AcN,
K.sub.2CO.sub.3 (0.58 g, 4.26 mmol), NaI (0.1 g, 0.71 mmol) and
difluoropiperidine hydrochloride (0.25 g, 2.13 mmol) were added at
rt and then heated at 80.degree. C. for 12 h. Organic solvents were
evaporated to dryness. The obtained crude residue was dissolved in
water and DCM. The combined organic layers were washed with water
followed by brine solution and dried over anhydrous
Na.sub.2SO.sub.4 and filtered. The filtered solution was
concentrated under reduced pressure and the resulting crude
compound was purified by flash column chromatography (230-400)
silica gel using 50% EtOAc/Pet ether as a eluent to afford the
title compound (0.350 g, 76.7%) as a pale yellow liquid.
[0383] LC-MS (method 15): R.sub.t=2.91 min; m/z=321.30
(M+H.sup.+).
[0384] Following a similar procedure to that described in reference
example 17, but using the corresponding starting material, the
following compound was obtained:
TABLE-US-00008 Reference Compound Starting HPLC R.sub.t example
name material method (min) m/z 17a 4-(2-((2- Morpholine 14 1.45
r289.0 Bromopyridin- (M+H.sup.++2) 4yl)oxy)ethyl) morpholine
Reference Example 18
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)etho-
xy)methyl)-1H-pyrazole
[0385] To a stirred solution of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g,
10.3 mmol) in DMF (30 mL), (2-(chloromethoxy)ethyl)trimethylsilane
(2 g, 12.3 mmol), and Cs.sub.2CO.sub.3 (10 g, 30.9 mmol) were
added. The resulting mixture was stirred at rt for 3 h. Solvents
were evaporated and the crude residue was diluted with ice cold
water and extracted with EtOAc. The combined organic layers were
dried over anhydrous Na.sub.2SO.sub.4 and filtered. The filtered
solution was concentrated under reduced pressure and the resulting
crude compound was purified by flash column chromatography using
20-30% EtOAc/Pet ether to get the title compound (1.5 g, 44%) as
pale yellow gummy.
[0386] LC-MS (method 14): R.sub.t=3.08 min; m/z=325.2
(M+H.sup.+).
Reference Example 19
5-Bromo-1-propyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)--
1H-pyrrolo[2,3-c]pyridine
Step a. 5-Bromo-3-iodo-1H-pyrrolo[2,3-c]pyridine
[0387] To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine
(1 g, 5.1 mmol) in DMF, KOH (0.86 g, 15.3 mmol) was added. It was
stirred at rt for 20 minutes and then, iodine (1.54 g, 6.12 mmol)
was added. The resulting mixture was stirred at rt for 16 h. The
reaction mixture was evaporated under vacuum to get a crude
residue. Crushed ice was added to the obtained crude residue and
the precipitated solid was filtered, dried, and washed with
diethylether to get 1 g (60%) of a crude compound that was used for
the next step without any further purification.
[0388] LC-MS (method 6): R.sub.t=1.94 min; m/z=323.01
(M+H.sup.+).
Step b. 5-Bromo-3-iodo-1-propyl-1H-pyrrolo[2,3-c]pyridine
[0389] To a stirred solution of the compound obtained in the
previous section, step a (1 g, 3.1 mmol) in DMF, NaH (60%) (0.371
g, 9.2 mmol) was added at 0.degree. C. After 15 minutes,
bromopropane (0.45 g, 3.72 mmol) was added slowly and stirred at rt
for 3 h. To the reaction mixture, crushed ice was added, and the
precipitated solid was filtered, dried, and washed with diethyl
ether and n-pentane to get 900 mg (79%) of a crude compound that
was used for the next step without any further purification.
[0390] LC-MS (method 6): R.sub.t=2.28 min; m/z=365.01
(M+H.sup.+).
Step c.
5-Bromo-1-propyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazo-
l-4-yl)-1H-pyrrolo[2,3-c]pyridine
[0391] To a stirred solution of the compound obtained in the
previous section, step b (500 mg, 1.4 mmol) in) in a DMF/water 1:1
mixture, reference example 18 (0.545 g, 1.7 mmol), and
Cs.sub.2CO.sub.3 (1.36 g, 4.2 mmol) were added. The resulting
solution was degassed with nitrogen for 15 minutes, then PdCl.sub.2
dppf (0.1 g, 0.14 mmol) was added and stirred at 90.degree. C. for
16 h. The reaction mixture was evaporated under vacuum to get a
crude residue that was diluted with cold water and extracted with
EtOAc. The combined organic layers were dried over anhydrous
Na.sub.2SO.sub.4 and filtered. The filtered solution was
concentrated under reduced pressure and the resulting crude
compound was purified by flash column chromatography using 20-30%
EtOAc/Pet ether to get the title compound (380 mg, 63%) as pale
brown gummy.
[0392] LC-MS (method 6): R.sub.t=2.39 min; m/z=435.34
(M+H.sup.+).
[0393] Following a similar procedure to that described in reference
example 19, but using the corresponding starting material, the
following compound was obtained:
TABLE-US-00009 Refer- ence exam- Compound Starting HPLC R.sub.t ple
name material method (min) m/z 19a 5-Bromo-1- Iodomethane 6 2.25
407.32 methyl-3-(1-((2- (M+H.sup.+). (trimethylsilyl) ethoxy)
methyl)-1H- pyrazol-4-yl)- 1H-pyrrolo [2,3-c]pyridine 19b
5-Bromo-1-(2- 1-Bromo-2- 6 2.27 451.31 methoxyethyl)- methoxyethane
(M+H.sup.+). 3-(1-((2- (trimethylsilyl) ethoxy)methyl)-
1H-pyrazol-4- yl)-1H-pyrrolo [2,3-c]pyridine
Reference Example 20
N-(2-Bromopyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)acetamide
Step a. N-(2-Bromopyridin-4-yl)-2-chloroacetamide
[0394] To a stirred solution of 2-bromopyridin-4-amine (2 g, 11.5
mmol) in DCM (40 mL), DIPEA (4 mL, 23 mmol) and chloroacetyl
chloride (1.85 mL, 23 mmol) were added at 0.degree. C. It was
stirred at it for 3 h. The reaction mixture was diluted with EtOAc
and washed with water. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The crude compound was purified by column chromatography and eluted
at 20% EtOAc in pet ether to afford the title compound (2.2 g,
76.5%) as an off yellow solid.
[0395] LC-MS (method 6): R.sub.t=1.70 min; m/z=249.02
(M+H.sup.+).
Step b.
N-(2-Bromopyridin-4-yl)-2-(4,4-difluoropiperidin-1-yl)acetamide
[0396] To a stirred solution of the compound obtained in the
previous section, step a (2.1 g, 8.4 mmol) in AcN (50 mL),
K.sub.2CO.sub.3 (3.5 g, 25.2 mmol), NaI (1.62 g, 10.9 mmol), and 4,
4-difluoropiperidine hydrochloride (1.52 g, 12.6 mmol) were added
at 0.degree. C. It was stirred at rt for 16 h. The reaction mixture
was filtered through a celite pad and washed with EtOAc (50 mL).
The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure to afford a crude
compound that was used for the next step without any further
purification (1.5 g, 53.4%)
[0397] LC-MS (method 6): R.sub.t=1.42 min; m/z=336.16 (M+H.sup.+30
2).
Reference Example 21
2-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)ethyl)pyridin-4-amine
[0398] To a stirred solution of reference example 20 (1.0 g, 2.97
mmol) in THF (40 mL), LiAlH.sub.4 (0.135 g, 3.56 mmol) was added at
0.degree. C. It was stirred at rt for 3 h. The reaction mixture was
poured into crushed ice water and diluted with EtOAc. The resulting
mixture was filtered through a celite pad and concentrated under
reduced pressure to afford a crude compound that was used for the
next step without any further purification (0.5 g, 52.6%) LC-MS
(method 19): R.sub.t=3.44 min; m/z=320.31 (M+H.sup.+).
Reference Example 22
5-Bromo-3-(piperidin-1-ylmethyl)-1H-pyrazolo[3,4-c]pyridine
[0399] Following a similar procedure to that described in reference
example 5, but using 5-bromo-1H-pyrazolo[3,4-c]pyridine instead of
reference example 2, the desired compound was obtained.
[0400] LC-MS (method 6): R.sub.t=1.12 min; m/z=295.18
(M+H.sup.+).
Reference Example 23
6-Bromo-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridine
Step a. 6-Bromo-1-(2-bromoethyl)-1H-pyrrolo[3,2-c]pyridine
[0401] To a stirred 40% NaOH aqueous solution (15 mL),
6-bromo-1H-pyrrolo[3,2-c]pyridine (1 g, 5.07 mmol), TBAB (163 mg,
0.50 mmol) and 1,2-dibromoethane (15 mL) were added. The resulting
mixture was stirred at 80.degree. C. for 12 h. The reaction mixture
was quenched with water and extracted EtOAc. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, concentrated under reduced
pressure to get a crude compound that was used for the next step
without any further purification (1.8 g).
[0402] LC-MS (method 6): R.sub.t=1.77 min; m/z=304.80
(M+H.sup.+).
Step b.
6-Bromo-1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]p-
yridine
[0403] To a stirred solution of the compound obtained in the
previous section, step a (1 g, 3.2 mmol) in AcN (50 mL) was added
4,4-difluoropiperidine hydrochloride (780 mg, 5 mmol),
K.sub.2CO.sub.3 (1.3 g, 9.6 mmol). The resulting suspension was
stirred at 70.degree. C. for 16 h. The reaction mixture was poured
into cold water and extracted with EtOAc (2.times.80 mL). The
organic layer was dried and concentrated to get a crude compound
that was purified by flash column chromatography in 230-400 silica
gel 28% EtOAc/pet ether as an eluent to afford the title compound
(650 mg, 59%) as an off white solid.
[0404] LC-MS (method 6): R.sub.t=1.26 min; m/z=344.26
(M+H.sup.+).
Reference Example 24
N-(2-Bromopyridin-4-yl)-3-phenylpropanamide
[0405] To a stirred solution of 2-bromopyridin-4-amine (500 mg, 2.9
mmol) in THF (20 mL), 3-phenylpropanoyl chloride (585 mg, 3.5 mmol)
and DIPEA (1.5 mL, 8.7 mmol) were added and it was stirred at rt
for 16 h. The reaction mixture was poured to into ice water (50 ml)
and extracted with EtOAc (2.times.100 mL). The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered to obtain a crude
residue that was triturated in n-pentane and dried to afford the
title compound (880, 36%) as a gummy solid.
[0406] LC-MS (method 14): R.sub.t=2.27 min; m/z=305.0
(M+H.sup.+).
Reference Example 25
6-Bromo-1-(pyridin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridine
[0407] To a stirred solution of 6-bromo-1H-pyrrolo[3,2-c]pyridine
(1 g, 5.07 mmol) in DMF (25 mL), Cs.sub.2CO.sub.3 (4.95 g, 15.21
mmol) and 4-(bromomethyl)pyridine hydrobromide (1.92 g, 7.60 mmol)
were added. The resulting suspension was allowed to stir at rt, and
then heated to 50.degree. C. for 16 h. The reaction mixture was
poured into ice water and extracted with EtOAc (2.times.120 mL).
The organic layer was washed with water and brine solution, dried
over anhydrous Na.sub.2SO.sub.4, and filtered. The resulting
solution was concentrated under reduced pressure to get a crude
residue that was purified by flash column chromatography in 230-400
silica gel 70% EtOAc/pet ether as an eluent to afford the title
compound (800 mg, 57.7%) of the title compound as a light brown
solid. LC-MS (method 15): R.sub.t=2.33 min; m/z=288.27
(M+H.sup.+).
[0408] Following a similar procedure to that described in reference
example 25, but using in each case the corresponding starting
materials, the following compounds were obtained:
TABLE-US-00010 Refer- ence exam- Compound Starting HPLC R.sub.t ple
name material method (min) m/z 25a 6-Bromo-1-(2- 6-Bromo-1H- 6 1.50
255.0 methoxyethyl)- pyrrolo[3,2-c] (M+H.sup.+) 1H-pyrrolo pyridine
[3,2-c]pyridine and 1-bromo-2- methoxyethane 25b 6-Bromo-
6-Bromo-1H- 21 1.26 288.0 1-(pyridin- pyrrolo[3,2-c] (M+H.sup.+)
3-ylmethyl)- pyridine 1H-pyrrolo and 3- [3,2-c]pyridine
(bromomethyl) pyridine 25c 6-Bromo-1- 6-Bromo-1H- 6 1.56 287.9
(pyridin-2- pyrrolo[3,2-c] (M+H.sup.+) ylmethyl)- pyridine and 2-
1H-pyrrolo (bromomethyl) [3,2-c]pyridine pyridine hydrobromide 25d
5-Bromo-1-(2- 5-Bromo-1H- 19 3.28 256.2 methoxyethyl)-
pyrazolo[3,4- (M+H.sup.+) 1H-pyrazolo c]pyridine and 1- bromo-2-
[3,4-c]pyridine methoxyethane 25e 5-Bromo-2-(2- 5-Bromo-1H- 19 3.08
256.2 methoxyethyl)- pyrazolo[3,4- (M+H.sup.+) 2H-pyrazolo
c]pyridine and 1- [3,4-c]pyridine bromo-2- methoxyethane 25f
6-Bromo-1-((1- 6-Bromo-1H- 6 1.51 291.10 methyl-1H- pyrrolo[3,2-c]
(M+H.sup.+) pyrazol-4-yl) pyridine and methyl)-1H-
4-(chloromethyl)- pyrrolo[3,2-c] 1-methyl- pyridine 1H-pyrazole
Reference Example 26
3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridine
[0409] To a stirred solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine
(200 mg, 1.01 mmol) in DMF (5 mL), 3,4-dihydro-2H-pyran (127 mg,
1.51 mmol) and a catalytic amount of pTSA were added at rt. The
resulting solution was stirred at 85.degree. C. for 24 h. The
reaction was cooled to rt, diluted with water and extracted with
EtOAc. The organic layer was washed with water and brine solution,
dried over anhydrous Na.sub.2SO.sub.4, and filtered. The resulting
solution was concentrated under reduced pressure to get crude a
residue that was purified by flash columnchromatography to afford
the title compound (150 mg, 52.8%).
[0410] LC-MS (method 1): R.sub.t=2.24 min; m/z=282.30
(M+H.sup.+).
Reference Example 27
5-(3-(1H-Pyrazol-1-yl)propoxy)-2-bromopyridine
[0411] To a stirred solution of 1H-pyrazole (378 mg, 5.55 mmol) in)
in DMF (10 mL), 60% NaH (666 mg, 16.6 mmol) was added at 0.degree.
C. and it was stirred at rt for 15 min. Then, the compound obtained
in reference example 6, section a, (1.25 g, 6.1 mmol) was added
(slowly). It was stirred at rt for 3 h. It was purified by silica
gel column chromatography using using 30-80% EtOAc/Pet ether to
afford the title compound (1.2 g, 70%) as off-white solid.
[0412] LC-MS (method 14): R.sub.t=2.09 min; m/z=282.0
(M+H.sup.+).
Reference Example 28
6-Bromo-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridi-
ne
Step a. Tert-butyl
4-(6-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate
[0413] To a stirred solution of tert-butyl
4-(methylsulfonyloxy)piperidine-1-carboxylate in DMF (30 mL),
Cs.sub.2CO.sub.3 (3.08 g. 9.5 mmol) and
6-bromo-1H-pyrrolo[3,2-c]pyridine (372 mg, 1.9 mmol) were added at
rt. The reaction mixture was stirred at 90.degree. C. for 12 h. The
reaction mixture was quenched with ice water and extracted with
DCM. The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
and it was concentrated under reduced pressure. The crude compound
was purified by flash column chromatography using 20% EtOAc in pet
ether as an eluent to afford the title compound (0.60 g, 44%).
[0414] LC-MS (method 14): R.sub.t=2.65 min; m/z=380.0
(M+H.sup.+).
Step b. 6-Bromo-1-(piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridine
hydrochloride
[0415] To a stirred solution the compound obtained in the previous
section, step a, (0.6 g, 1.6 mmol) in dioxane (25 mL), 4M HCl in
dioxane (0.2 mL) was added. The resulting mixture was stirred at rt
for 3 h. Organic solvents were removed under vaccum, and the crude
residue was triturated with dietjyl ether. It was filtered under
reduced pressure to afford 400 mg (89%) of the title compound
[0416] LC-MS (method 14): R.sub.t=1.23 min; m/z=280.0
(M+H.sup.+).
Step c.
6-Bromo-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2--
c]pyridine
[0417] To a stirred solution the compound obtained in the previous
section, step b, (200 mg, 0.7 mmol) in acetone (15 ml),
K.sub.2CO.sub.3 (0.483 mg, 3.5 mmol) and
2,2,2-trifluoroethyltrifluoromethanesulfonate (450 mg, 1.4 mmol)
were added at rt. It was stirred at 55.degree. C. overnight.
Organic solvents were removed under vacuum. The crude residue was
extracted with DCM/water. Then combined organic layer was
concentrated under reduced pressure to afford the title compound
(150 mg. 58%) as an off white solid.
[0418] LC-MS (method 6): R.sub.t=2.07 min; m/z=362.24
(M+H.sup.+).
Reference Example 29
5-Bromo-1-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-
-c]pyridine
Step a.
5-Bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-
-c]pyridine
[0419] To a stirred solution of 5-bromo-1H-pyrrolo[2,3-c]pyridine
(1.0 g, 5.07 mmol) in MeOH (20 mL), powder KOH (1.13 g, 20.28 mmol)
was added. The resulting mixture was stirred at rt for 10 minutes.
Then, 1-methylpiperidin-4-one (1.14 g, 10.14 mmol) was added and it
was refluxed for 16 h. The reaction mixture was quenched with water
and extracted with 10% MeOH in DMC. The separated organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated
under reduced pressure to afford 800 mg (54%) of the title
compound.
[0420] LC-MS (method 6): R.sub.t=0.95 min; m/z=290.20
(M-H.sup.+).
Step b.
5-Bromo-1-butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyr-
rolo[2,3-c]pyridine
[0421] To a stirred solution the compound obtained in the previous
section, step a (800 mg, 2.74 mmol) in DMF (10 mL), NaH (60%) (325
mg, 8.22 mmol) were added at 0.degree. C. and it was stirred for 15
min. Then, idobutane (1.0 g, 5.48 mmol) was added and reaction
mixture was stirred at rt for 16 h. The reaction mixture was
quenched with water and extracted with EtOAc and the organic layer
was dried over anhydrous Na.sub.2SO.sub.4, and it was concentrated
under reduced pressure. The crude compound was purified by flash
column chromatography using 25-30% EtOAc in pet ether as an eluent
to afford the title compound (400 mg, 42%).
[0422] LC-MS (method 6): R.sub.t=1.66 min; m/z=348.29
(M+H.sup.+).
Reference Example 30
N,N-Dimethyl-3-(6-(trimethylstannyl)pyridin-3-yloxy)propan-1-amine)
[0423] To a stirred solution of reference example 6b (500 mg, 1.92
mmol) in toluene (20 mL), hexamethylditin (695 mg, 2.12 mmol), and
Pd(PPh.sub.3).sub.4 (223 mg, 0.192 mmol) were added at rt. The
resulting solution was degassed with nitrogen for 10 min and heated
to 110.degree. C. for 16 h. The reaction mixture was evaporated
under reduced pressure and the crude compound was purified by flash
column chromatography on neutral alumina using 10% EtOAc in
petroleum ether to afford the title compound (390 mg, 58%).
[0424] LC-MS (method 21): R.sub.t=2.02 min; m/z=345.0
(M+H.sup.+)
Reference Example 31
3-(2-Bromopyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole
Step a. 2-Bromo-N-hydroxyisonicotinimidamide
[0425] To a stirred solution of 2-bromoisonicotinonitrile (3 g,
16.4 mmol) in EtOH/MeOH (1:1) (50 mL), a 50% solution of
NH.sub.2OH.HCl (2.2 g, 32.8 mmol) in NaHCO.sub.3 (2.7 g, 32.8 mmol)
was added. The resulting solution was heated to 60.degree. C., for
3 h. The reaction mixture was evaporated under reduced pressure and
poured into ice water (20 mL) and extracted with EtOAc (2.times.150
mL). The organic layer was dried over anhydrous Na.sub.2SO.sub.4,
and filtered. to afford a crude compound that was used for the next
step without any further purification.
[0426] LC-MS (method 21): R.sub.t=0.97 min; m/z=214.90
(M+H.sup.+)
Step b.
3-(2-Bromopyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole
[0427] To a stirred solution the compound obtained in the previous
section, step a (3.4 mg, 15.7 mmol) in THF (20 mL), trifluroacetic
anhydride (4.94 g, 23.5 mmol) was added. The resulting solution was
heated at 50.degree. C. for 2 h. The reaction mixture was
evaporated under vacuum, poured into ice water (30 mL) and
extracted with EtOAc (2.times.50 mL). The organic layer was dried
over anhydrous Na.sub.2SO.sub.4, filtered and the filtrated
solution was concentrated to get a crude residue that was purified
by flash column chromatography on silica using 25% EtOAc in
petroleum ether to afford the title compound (3.2 g, 69%) as of
white solid. LC-MS (method 15): R.sub.t=4.15 min; m/z=293.51
(M+H.sup.+).
Reference Example 32
3-Bromo-1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridine
[0428] To a stirred solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine
(500 mg, 2.52 mmol) in DMF, NaH (60%) (201 mg, 5.04 mmol) was added
at 0.degree. C. and it was stirred for 15 min. Then,
1-bromo-2-methoxyethane (420 mg, 3.02 mmol) was added and the
reaction mixture was stirred at rt for 2 h. The reaction mixture
was quenched with water and extracted with EtOAc. The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, and it was concentrated
under reduced pressure. The crude compound was purified by flash
column chromatography on 230-400 silica using 45% EtOAc in pet
ether as an eluent to afford the title compound (430 mg, 66%) as a
gummy solid.
[0429] LC-MS (method 24): R.sub.t=2.63 min; m/z=258.01 (M+2H+).
[0430] Following a similar procedure to that described in reference
example 32, but using in each case the corresponding starting
materials, the following compounds were obtained:
TABLE-US-00011 Refer- ence exam- Starting HPLC R.sub.t ple Compound
name material method (min) m/z 32a 3-Bromo-1-ethyl- 3-Bromo-1H- 25
1.70 226.04 1H-pyrazolo[4,3- pyrazolo]4,3- (M+H.sup.+) b]pyridine
pyrazolo[4,3- b]pyridine and ethyl iodide 32b 3-Bromo-1-
3-Bromo-1H- 6 1.54 212.05 methyl- pyrazolo[4,3- (M+H.sup.+)
1H-pyrazolo b[pyridine [4,3-b]pyridine and methyl iodide
Reference Example 33
3-Bromo-1-(2-(1-methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridine
[0431] To a stirred solution of 3-bromo-1H-pyrazolo[4,3-b]pyridine
(800 mg, 4.03 mmol), in acetonitrile (10 mL) Cs.sub.2CO.sub.3 (3940
mg, 12.09 mmol), 2-(2-chloroethyl)-1-methyl-1H-imidazole (640 mg,
4.43 mmol) and NaI (303 mg, 2.02 mmol), were added at RT. The
reaction mixture was heated at 90.degree. C. overnight. The crude
reaction was filtered through a celite pad, washed with EtOAc (50
mL), and the solution was evaporated to dryness. The crude compound
was purified twice by column chromatography reverse phase with 10
mM Ammonium acetate/Acetonitrile to afford to afford the title
compound (430 mg, 35%) as a gummy solid.
[0432] LC-MS (method 26): R.sub.t=1.99 min; m/z=306.0
(M+H.sup.+).
Reference Example 34
1-Methyl-3-(trimethylstannyl)-1H-pyrazolo[4,3-b]pyridine
[0433] Following a similar procedure to that described in reference
example 30, but using reference example 32b, instead of reference
example 6b, the desired compound was obtained.
Example 1
3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluorometh-
yl)-1,2,4-oxadiazole
##STR00080##
[0434] Step a.
2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile
##STR00081##
[0436] To a stirred solution of reference example 2 (800 mg, 3.16
mmol) in 1, 4-dioxane (5 mL), reference example 1 (928 mg, 3.47
mmol), CsF (948 mg, 6.32 mmol) and CuI (119 mg, 0.63 mmol) were
added. The resulting solution was degassed with nitrogen for 5
minutes, and then Pd (PPh.sub.3).sub.4 (358 mg, 0.31 equiv) was
added. The reaction mixture was again degassed for another 5 min,
and then heated at 110.degree. C., for 16 h. The crude reaction was
filtered through celite pad, washed with EtOAc (50 mL), and the
filtrated solution was evaporated to dryness. The crude compound
was purified by flash column chromatography in 230-400 silica gel
20% of EtOAc/pet-ether to afford the title compound (500 mg, 57%)
as a light yellow solid.
[0437] LC-MS (method 6): R.sub.t=1.66 min; m/z=277.54
(M+H.sup.+).
Step b.
2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-N-hydroxyisonicotinimida-
mide
##STR00082##
[0439] To a stirred solution the compound obtained in the previous
section, step a (300 mg, 1.08 mmol) in EtOH/MeOH (1:1) (10 mL), 50%
NH.sub.2OH.HCl aqueous solution (300 mg, 2.16 mmol) was added. The
resulting solution was heated to 60.degree. C. for 5 h. The
reaction mixture was evaporated under vacuum, poured into ice water
(20 mL) and extracted with EtOAc (2.times.80 mL). The organic layer
was dried over anhydrous Na.sub.2SO.sub.4, filtered and the
filtrated solution was concentrated to get the title compound (320
mg, 95%), as a gummy solid. LC-MS (method 6): R.sub.t=1.47 min;
m/z=310.27 (M+H.sup.+).
Step c.
3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifl-
uoromethyl)-1,2,4-oxadiazole
##STR00083##
[0441] To a stirred solution the compound obtained in the previous
section, step b (300 mg, 0.97 mmol) in THF (10 mL), trifluroacetic
anhydride (243 mg, 1.16 mmol) was added. The resulting solution was
heated at 50.degree. C. for 4 h. The reaction mixture was
evaporated under vacuum, poured into ice water (20 mL) and
extracted with EtOAc (2.times.80 mL). The organic layer was dried
over anhydrous Na.sub.2SO.sub.4, filtered and the filtrated
solution was concentrated to get a crude residue that was purified
by prep HPLC to afford the title compound (70 mg, 18.6%) as an off
white solid.
[0442] LC-MS (method 6): R.sub.t=2.00 min; m/z=388.28
(M+H.sup.+).
[0443] Preparative HPLC Conditions: Column/dimensions: PRONTOSIL
C18 (20.times.250 mm), 10.0 .mu.m, Mobile phase: 0.1% FA in
water:Acetonitrile (A:B); Gradient (Time/% B): 0/20, 1/20, 10/80,
10.1/98, 14/98, 14.1/20, 17/20, Flow rate: 20 ml/min
[0444] Following a similar procedure to that described in example
1, but using in each case the corresponding starting materials, the
following compounds were obtained:
TABLE-US-00012 Starting HPLC R.sub.t Example Compound name material
method (min) m/z 1a 3-(2-(1-Propyl-1H-pyrrolo[2,3-c]pyridin-
Reference 15 4.25 374.29 5-yl)pyridin-4-yl)-5-(trifluoromethyl)
example 2a (M + H.sup.+) 1,2,4-oxadiazole ##STR00084## 1b
1-Butyl-N,N-dimethyl-5-(4-(5- Reference 15 3.96 459.38
(trifluoromethyl)-1,2,4-oxadiazol-3- example 3 (M + H.sup.+)
yl)pyridin-2-yl)-1H-pyrrolo[2,3- c]pyridine-2-carboxamide
##STR00085## 1c N,N-Diethyl-3-((4'-(5-(trifluoromethyl)- Reference
6 1.84 422.41 1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5- example 4
(M + H.sup.+) yl)oxy)propan-1-amine (obtained as hemiformate salt)
##STR00086## 1d 1-Butyl-N-ethyl-5-(4-(5-(trifluoromethyl)-
Reference 16 6.74 459.41 1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-
example 3b (M + H.sup.+) pyrrolo[2,3-c]pyridine-2-carboxamide
##STR00087## 1e 4-(3-((4'-(5-(Trifluoromethyl)- Reference 15 3.35
436.19 1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5- example 6a (M +
H.sup.+) yl)oxy)propyl)morpholine (obtained as hemitrifluoroacetate
salt) ##STR00088## 1f 3-(5'-(3-(4,4-Difluoropiperidin-1- Reference
16 6.82 470.26 yl)propoxy)-[2,2'-bipyridin]-4-yl)-5- example 6 (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole (obtained as diformate
salt) ##STR00089## 1g 3-(2-(3-(Piperidin-1-ylmethyl)-1-propyl-
Reference 14 2.48 471.1 1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-
example 5a (M + H.sup.+) yl)-5-(trifluoromethyl)-1,2,4-oxadiazole
(obtained as trifluoroacetate salt) ##STR00090## 1h
4-((1-Propyl-5-(4-(5-(trifluoromethyl)- Reference 14 2.79 473.2
1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H- example 5b (M + H.sup.+)
pyrrolo[2,3-c]pyridin-3- yl)methyl)morpholine ##STR00091## 1i
N-Butyl-3-methoxy-N-(4'-(5- Reference 16 6.63 450.37
(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 7 (M + H.sup.+)
[2,2'-bipyridin]-5-yl)propanamide ##STR00092## 1j
N-(Cyclopropylmethyl)-N-methyl-4'-(5- Reference 16 7.05 376.33
(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 8 (M + H.sup.+)
[2,2'-bipyridin]-5-amine ##STR00093## 1k
N.sup.1,N.sup.1-Diethyl-N.sup.3-(4'-(5-(trifluoromethyl)- Reference
6 1.69 421.39 1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5- example 9
(M + H.sup.+) yl)propane-1,3-diamine (**) ##STR00094## 1l
N-(3-(4,4-Difluoropiperidin-1-yl)propyl)- Reference 16 6.88 483.42
N-methyl-4'-(5-(trifluoromethyl)-1,2,4- example 10 (M + H.sup.+)
oxadiazol-3-yl)-[2,2'-bipyridin]-5-amine ##STR00095## 1m
N,N-Diethyl-3-(2-(4-(5-(trifluoromethyl)- Reference 15 2.53 423.22
1,2,4-oxadiazol-3-yl)pyridin-2- example 11 (M + H.sup.+)
yl)pyrimidin-5-yloxy)propan-1-amine (obtained as hemiformate salt)
##STR00096## 1n
N.sup.1,N.sup.1-Diethyl-N.sup.3-methyl-N.sup.3-(4'-(5- Reference 6
2.08 435.40 (trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 12 (M
+ H.sup.+) 2,2'-bipyridin-5-yl)propane-1,3-diamine (obtained as
formate salt) ##STR00097## 1o
3-(2-(1-(Tetrahydro-2H-pyran-4-yl)-1H- Reference 6 1.76 416.33
pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 14 (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00098## 1p
N-Ethyl-N-phenethyl-3-((4'-(5- Reference 6 2.12 498.48
(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 15 (M + H.sup.+)
[2,2'-bipyridin]-5-yl)oxy)propan-1-amine ##STR00099## 1q
2-Phenyl-N-(4'-(5-(trifluoromethyl)- Reference 16 6.38 426.35
1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5- example 16 (M + H.sup.+)
yl)acetamide ##STR00100## 1r 3-(2-(1-((Tetrahydro-2H-pyran-4-
Reference 16 6.33 430.38 yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-
example 14a (M + H.sup.+)
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole ##STR00101##
1s 3-(4'-(2-(4,4-Difluoropiperidin-1- Reference 16 5.56 456.16
yl)ethoxy)-[2,2'-bipyridin]-4-yl)-5- example 17 (M + H.sup.+)
(trifluoromethyl)-1,2,4-oxadiazole ##STR00102## 1t
4-(2-((4'-(5-(Trifluoromethyl)-1,2,4- Reference 16 5.71 422.14
oxadiazol-3-yl)-[2,2'-bipyridin]-4- example 17a (M + H.sup.+)
yl)oxy)ethyl)morpholine ##STR00103## 1u N,N,1-Trimethyl-5-(4-(5-
Reference 16 5.84 417.37 (trifluoromethyl)-1,2,4-oxadiazol-3-
example 3a (M + H.sup.+) yl)pyridin-2-yl)-1H-pyrrolo[2,3-
c]pyridine-2-carboxamide (obtained as ditrifluoroacetate salt)
##STR00104## 1v 3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H- Reference 15
3.69 440.32 pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 19
(M + H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00105## 1w
1-Butyl-N,N-diethyl-5-(4-(5- Reference 18 6.15 487.2
(trifluoromethyl)-1,2,4-oxadiazol-3- example 3c (M + H.sup.+)
yl)pyridin-2-yl)-1H-pyrrolo[2,3- c]pyridine-2-carboxamide
##STR00106## 1x 3-(2-(1-(2-Methoxyethyl)-1H- Reference 16 6.30
390.32 pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 2b (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00107## 1y
2-(4,4-Difluoropiperidin-1-yl)-N-(4'-(5- Reference 18 5.39 469.1
(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 20 (M + H.sup.+)
[2,2'-bipyridin]-4-yl)acetamide ##STR00108## 1z
N-(2-(4,4-Difluoropiperidin-1-yl)ethyl)- Reference 16 5.90 455.39
4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3- example 21 (M + H.sup.+)
yl)-[2,2'-bipyridin]-4-amine (obtained as pentatrifluoroacetate
salt) ##STR00109## 1aa 3-(2-(3-(Piperidin-1-ylmethyl)-1H- Reference
18 4.32 430.1 pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)- example 22
(M + H.sup.+) 5-(trifluoromethyl)-1,2,4-oxadiazole (obtained as
sesquitrifluoroacetate salt) ##STR00110## 1ab
3-(2-(1-(2-(4,4-Difluoropiperidin-1- Reference 16 6.77 479.42
yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-6- example 23 (M + H.sup.+)
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole ##STR00111##
1ac 1-Methyl-N-(4'-(5-(trifluoromethyl)- Reference 6 1.75 433.40
1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5- example 16a (M + H.sup.+)
yl)piperidine-4-carboxamide (obtained as hemiformate salt)
##STR00112## 1ad 3-Phenyl-N-(4'-(5-(trifluoromethyl)- Reference 18
5.60 440.1 1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-4- example 24 (M
+ H.sup.+) yl)propanamide ##STR00113## 1ae
2-Cyclobutyl-N-(4'-(5-(trifluoromethyl)- Reference 18 5.49 404.01
1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-4- example 16b (M + H.sup.+)
yl)acetamide (obtained as hemitrifluoroacetate salt) ##STR00114##
1af N-(Piperidin-3-yl)-4'-(5-(trifluoromethyl)- Reference 18 3.90
419.1 1,2,4-oxadiazol-3-yl)-[2,2'-bipyridine]-4- example 16c (M +
H.sup.+) carboxamide (*) ##STR00115## 1ag
3-(5'-(3-(1H-Pyrazol-1-yl)propoxy)-[2,2'- Reference 16 6.34 417.20
bipyridin]-4-yl)-5-(trifluoromethyl)-1,2,4- example 27 (M +
H.sup.+) oxadiazole ##STR00116## 1ah
(l-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4- Reference 6 1.73 404.36
oxadiazol-3-yl)pyridin-2-yl)-1H- example 5c (M + H.sup.+)
pyrrolo[2,3-c]pyridin-3-yl)methanol (obtained as
sesquitrifluoroacetate salt) ##STR00117## 1ai
3-(2-(3-(Methoxymethyl)-1-propyl-1H- Reference 15 4.10 418.34
pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 5c (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00118## 1aj
(1-butyl-5-(4-(5-(trifluoromethyl)-1,2,4- Referece 6 1.80 418.27
oxadiazol-3-yl)pyridin-2-yl)-1H- example 5 (M + H.sup.+)
pyrrolo[2,3-c]pyridin-3-yl)methanol ##STR00119## 1ak
3-(2-(1H-Pyrrolo[3,2-c]pyridin-6- Referece 16 5.80 332.24
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- example 25 (M +
H.sup.+) oxadiazole (obtained as hemiformate salt) ##STR00120## 1al
3-(2-(1-(Pyridin-4-ylmethyl)-1H- Referece 6 1.57 423.33
pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25 (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole
(obtained as tritrifluoroacetate salt) ##STR00121## 1am
N-((1-Methylpiperidin-4-yl)methyl)-4'-(5- Referece 16 5.10 447.39
(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 16d (M + H.sup.+)
[2,2'-bipyridine]-4-carboxamide (obtained as
hemipentatrifluoroacetate salt) ##STR00122## 1an
N-((1-Methylpiperidin-4-yl)methyl)-4'-(5- Referece 18 4.32 447.1
(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- example 16e (M + H.sup.+)
[2,2'-bipyridine]-5-carboxamide (obtained as hemipentacetate salt)
##STR00123## 1ao 3-(2-(1-(1-(2,2,2- Referece 6 1.97 497.34
Trifluoroethyl)piperidin-4-yl)-1H- example 28 (M + H.sup.+)
pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-
(trifluoromethyl)-1,2,4-oxadiazole ##STR00124## 1ap
3-(2-(1-Methyl-3-(1H-pyrazol-4-yl)-1H- Referece 18 3.96 412.1
pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5- example 19a (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00125## 1aq
3-(2-(1-Butyl-3-(1-methyl-1,2,3,6- Referece 16 6.42 483.41
tetrahydropyridin-4-yl)-1H-pyrrolo[2,3- example 29 (M + H.sup.+)
c]pyridin-5-yl)pyridin-4-yl)-5- (trifluoromethyl)-1,2,4-oxadiazole
##STR00126## 1ar 1-(2-Methoxyethyl)-N,N-dimethyl-5-(4- Referece 20
4.17 461.28 (5-(trifluoromethyl)-1,2,4-oxadiazol-3- example 3d (M +
H.sup.+) yl)pyridin-2-yl)-1H-pyrrolo[2,3- c]pyridine-2-carboxamide
##STR00127## 1as 3-(2-(1-(2-Methoxyethyl)-3-(1H-pyrazol- Referece
18 4.27 456.1 4-yl)-1H-pyrrolo[2,3-c]pyridin-5- example 19b (M +
H.sup.+) yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole
(obtained as hemiformate salt) ##STR00128## 1at
3-(2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin- 5-Bromo-1- 20 3.87 346.1
5-yl)pyridin-4-yl)-5-(trifluoromethyl)- methyl-1H- (M + H.sup.+)
1,2,4-oxadiazole (obtained as pyrrolo[2,3- hemiformate
hemitrifluoroacetate salt) c]pyridine ##STR00129## 1au
3-(2-(1-(2-Methoxyethyl)-1H- Referece 20 3.96 390.26
pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25a (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00130## 1av
3-(2-(1-(Pyridin-3-ylmethyl)-1H- Referece 18 3.78 423.1
pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25b (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00131## 1aw
3-(2-(1-(Pyridin-2-ylmethyl)-1H- Referece 18 3.75 423.1
pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5- example 25c (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00132## 1ax
2-(Methyl(3-((4'-(5-(trifluoromethyl)- Referece 22 4.38 424.38
1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-5- example 6c
yl)oxy)propyl)amino)ethan-1-ol (obtained as formate salt)
##STR00133## 1ay 3-(2-(1-(2-Methoxyethyl)-1H- Referece 23 5.39
390.9 pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)- example 25d (M +
H.sup.+) 5-(trifluoromethyl)-1,2,4-oxadiazole ##STR00134## 1az
3-(2-(2-(2-Methoxyethyl)-2H- Referece 20 4.50 391.18
pyrazolo[3,4-c]pyridin-5-yl)pyridin-4-yl)- example 25e (M +
H.sup.+) 5-(trifluoromethyl)-1,2,4-oxadiazole ##STR00135## 1aaa
3-(2-(1-(2-Methoxyethyl)-1H- Referece 27 4.65 391.27
pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)- example 32 (M + H.sup.+)
5-(trifluoromethyl)-1,2,4-oxadiazole ##STR00136## 1aab
3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin- Referece 27 4.83 361.24
3-yl)pyridin-4-yl)-5-(trifluoromethyl)- example 32a (M + H.sup.+)
1,2,4-oxadiazole ##STR00137## 1aac
3-(2-(1-(2-(1-Methyl-1H-imidazol-2- Referece 27 4.27 441.25
yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3- example 33 (M + H.sup.+)
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole ##STR00138##
1aad 3-(2-(1-((1-Methyl-1H-pyrazol-4- Referece 6 1.74 426.31
yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6- example 25f (M + H.sup.+)
yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4- oxadiazole ##STR00139##
(*) TFA was added for complete Boc deprotection (**) obtained with
0.7 equiv of TFA and 0.3 equiv of formic acid
Example 2
N-Methyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin-
]-5-yl)oxy)propan-1-amine (as Formate Salt)
##STR00140##
[0445] Step a.
5'-(3-(Methylamino)propoxy)-[2,2'-bipyridine]-4-carbonitrile
##STR00141##
[0447] To a stirred solution of reference example 13 (250 mg, 1.01
mmol) in 1, 4-dioxane (20 mL), reference example 1 (16) (299 mg,
1.12 mmol), CsF (308 mg, 2.03 mmol) and CuI (38 mg, 0.20 mmol) wee
added. The resulting solution was degassed with nitrogen for 15
minutes, then Pd(PPh.sub.3).sub.4 (117 mg, 0.1 mmol) was added and
heated at 110.degree. C. for 16 h. The reaction was filtered
through celite pad, washed with EtOAc (50 mL). The filtrated
solution was evaporated to dryness. The crude residue was purified
by column chromatography on 230-400 silica with 90% EtOAc/pet ether
as eluent to afford the title compound (180 mg, 65%) as a gummy
solid. LC-MS (method 14): R.sub.t=1.45 min; m/z=269.1
(M+H.sup.+).
Step b. Tert-butyl
(3-((4'-cyano-[2,2'-bipyridin]-5-yl)oxy)propyl)(methyl)
carbamate
##STR00142##
[0449] To a stirred solution of the compound obtained in the
previous section, step a (180 mg, 0.67 mmol) in acetonitrile (10
mL), Boc anhydride (219 mg, 1.0 mmol), and TEA (0.27 mL, 2.01
mmol), were added. The resulting mixture was stirred rt for 16 h.
The reaction mixture was evaporated under vacuum to afford a crude
compound that was used for the next step without any further
purification (200 mg, 80%)
[0450] LC-MS (method 15): R.sub.t=3.75 min; m/z=369.08
(M+H.sup.+).
Step c. Tert-butyl
(3-((4'-(N-hydroxycarbamimidoyl)-[2,2'-bipyridin]-5-yl)oxy)propyl)(methyl-
) carbamate
##STR00143##
[0452] To a stirred solution of the compound obtained in the
previous section, step b (200 mg, 0.54 mmol) in EtOH/MeOH (4:1),
50% NH.sub.2OH.HCl aqueous solution (75 mg, 1.08 mmol) and
NaHCO.sub.3 (91 mg, 1.08 mmol) were added. The resulting mixture
was stirred at 50.degree. C. for 3 h. The reaction mixture was
concentrated to get a crude residue that was diluted with EtOH and
filtered thorough a Buckner funnel. The filtered solution was
concentrated to dryness to afford the title compound (170 mg (78%)
as a light brown gummy solid that was used in the next step without
purification.
[0453] LC-MS (method 15): R.sub.t=2.89 min; m/z=402.21
(M+H.sup.+).
Step d.
N-Methyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-b-
ipyridin]-5-yl)oxy) propan-1-amine Formate
##STR00144##
[0455] To a stirred solution of the compound obtained in the
previous section, step c (150 mg, 0.37 mmol) in THF trifluroacetic
anhydride (0.1 mL, 0.56 mmol) was added. The resulting mixture was
heated at 70.degree. C. and TFA (0.5 mL, 0.64 mmol) was added. It
was stirred at 50.degree. C. for 2 h. The solvents were evaporated
under vacuum and the crude residue was poured in to ice water and
extracted with EtOAc. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated. The crude compound was
purified by prep HPLC to afford the title compound (65 mg, 45%) as
a pink solid.
[0456] LC-MS (method 15): R.sub.t=2.79 min; m/z=380.15
(M+H.sup.+).
[0457] Prep.HPLC conditions: Column/dimensions: SYNERGY POLAR
C18(21.2.times.250 mm), 5 .mu.m Mobile phase: 0.1% FA: Acetonitrile
(A:B) Gradient (Time/% B): 0/20, 1/20, 7/50, 10/50, 10.1/98, 13/98,
13.120, 16/20. Flow rate: 20 ml/min.
Example 3
1-(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-
-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine
##STR00145##
[0459] To a stirred solution of example 1 (400 mg, 1 mmol) in
n-butanol, HCHO (300 mg, 10 mmol) and dimethyl amine HCl salt (815
mg 10 mmol) were added. The resulting mixture was stirred at
120.degree. C. for 16 h. The reaction mixture concentrated to get a
crude compound that was purified by prep-HPLC to afford the title
compound (38 mg, 8.6%) as a pink sticky solid.
[0460] LC-MS (method 15): R.sub.1=3.37 min; m/z=445.39
(M+H.sup.+).
[0461] Preparative HPLC Conditions: Column/dimensions: XSELECT C18
(19*250*5 .mu.m) Mobile phase A: 0.1% FA in water (aq) Mobile phase
B: Acetonitrile (org) Gradient (Time/% B) 0/10, 1/10, 5/30, 9/30,
9.1/100, 11/100, 11.1/10, 13/10. Flow rate: 18 ml/min Solubility:
Methanol+ THF.
Example 4
3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole
##STR00146##
[0462] Step a.
2-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-b]pyridin-3-yl)isonicotin-
onitrile
##STR00147##
[0464] To a stirred solution of reference example 26 (900 mg, 3.19
mmol) in toluene (25 mL), reference example 1 (1100 mg, 4.15 mmol)
was added and degassed for 10 min with nitrogen gas. Then,
PdCl.sub.2(PPh.sub.3).sub.2 (112 mg, 0.16 mmol) was added and the
resulting solution was degassed for another 5 min and heated at
100.degree. C. for 16 h. The reaction mixture was concentrated
under reduced pressure to afford a crude residue that was purified
by column chromatography to afford the title compound (800 mg,
82.2%).
[0465] LC-MS (method 1): R.sub.t=2.44 min; m/z=306.24
(M+H.sup.+).
Step b. 2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)isonicotinonitrile
##STR00148##
[0467] To a stirred solution of the compound obtained in the
previous section, step a (800 mg, 2.62 mmol) in DCM (15 mL), TFA
(10 mL) was added and it was stirred at rt for 48 h. The reaction
mixture was concentrated under reduced pressure to afford a crude
residue that was purified by column chromatography to afford the
title compound (400 mg, 69.0%).
[0468] LC-MS (method 1): R.sub.t=1.85 min; m/z=222.13
(M+H.sup.+).
Step c.
N-hydroxy-2-(1H-pyrazolo[4,3-b]pyridin-3-yl)isonicotinimidamide
##STR00149##
[0470] Following a similar procedure to that described in example
1, section b, but using the compound obtained in the previous
section, step b, instead of
2-(1-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)isonicotinonitrile, the
desired compound was obtained.
[0471] LC-MS (method 14): R.sub.t=1.25 min; m/z=255.1
(M+H.sup.+).
Step d.
3-(2-(1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole
##STR00150##
[0473] Following a similar procedure to that described in example
1, section c, but using the compound obtained in the previous
section, step c, instead of
2-(1-butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-N-hydroxyisonicotinimidamide,
the desired compound was obtained.
[0474] LC-MS (method 6): R.sub.t=1.98 min; m/z=333.20
(M+H.sup.+).
Example 5
N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]-4-yl)pip-
eridine-3-carboxamide (as Hemiformate Salt)
##STR00151##
[0475] Step a. tert-butyl
3-((4'-cyano-[2,2'-bipyridin]-4-yl)carbamoyl)piperidine-1-carboxylate
##STR00152##
[0477] To a stirred solution of reference example 16c (3 g, 7.81
mmol) in toluene (30 mL), 2-bromoisonicotinonitrile (2.14 g, 11.71
mmol), and hexamethylditin (2.8 mL, 13.67 mmol) were added. The
resulting solution was degassed with argon for 10 minutes, then
Pd(PPh.sub.3).sub.4 (902 mg, 0.781 mmol) was added. The resulting
mixture was degassed for 5 minutes and heated at 110.degree. C. for
16 h. The reaction mixture was diluted with water and extracted
with EtOAc (2.times.20 mL). The organic layer was dried over
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure
to get a crude residue that was purified by column chromatography
using 10% EtOAc in petroleum ether to afford the title compound
(800 mg, 25.1%)
[0478] LC-MS (method 1): R.sub.t=2.62 min; m/z=408.31
(M+H.sup.+).
Step b. N-(4'-cyano-[2,2'-bipyridin]-4-yl)piperidine-3-carboxamide
hydrochloride
##STR00153##
[0480] To a stirred solution of the compound obtained in the
previous section, step a, (200 mg, 0.486 mmol) in DCM (2 mL), 2M
HCl solution in diethylether (3 mL) was added at 0.degree. C. The
reaction mixture was allowed to stir at rt for 2 h. The resulting
mixture was concentrated and the crude residue was triturated with
n-pentane and diethyl ether. It was filtered under reduced pressure
to afford 800 mg (54%) of the title compound
[0481] LC-MS (method 1): R.sub.t=1.54 min; m/z=308.29
(M+H.sup.+).
Step c.
N-(4'-(N-hydroxycarbamimidoyl)-[2,2'-bipyridin]-4-yl)piperidine-3--
carboxamide hydrochloride
##STR00154##
[0483] To a stirred solution of the compound obtained in the
previous section, step b, (50 mg, 0.16 mmol) in EtOH (6 mL),
hydroxylamine hydrochloride (22 mg, 0.32 mmol), and NaHCO.sub.3 (27
mg, 0.32 mmol) in water (2 mL) were added. The reaction mixture was
stirred at 70.degree. C. for 6 h. The resulting solution was
concentrated to dryness and the crude residue was diluted with EtOH
and filtered thorough a Buckner funnel to remove the NaHCO.sub.3.
The filtered solution was concentrated to afford the title compound
(45 mg, 82%) that was used in next step without further
purification.
[0484] LC-MS (method 14): R.sub.t=1.26 min; m/z=341.1
(M+H.sup.+).
Step d.
1-(2,2,2-trifluoroacetyl)-N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiaz-
ol-3-yl)-[2,2'-bipyridin]-4-yl)piperidine-3-carboxamide
##STR00155##
[0486] To a stirred solution of the compound obtained in the
previous section, step c, (40 mg, 0.11 mmol) in THF (5 mL),
trifluroacetic anhydride (0.1 mL) was added. The resulting mixture
was stirred at 70.degree. C. for 3 h. The reaction mixture was
concentrated under reduced pressure to get a crude residue that was
purified by Prep HPLC to afford the title compound (16 mg, 28%) as
an off white solid.
[0487] LC-MS (method 14): R.sub.t=2.82 min; m/z=515.1
(M+H.sup.+).
[0488] Preparative HPLC Conditions: Column/dimensions Prontosil C18
(20.times.250 mm), 10 .mu.m Mobile phase: 0.1% Ammonium Acetate in
water:Acetonitrile (A:B) Gradient (Time/% B): 0/20, 1/20, 5/70,
15/700, 15.1/100 Flow rate: 20 ml/miN Solubility: ACN+THF+WATER
Step e.
N-(4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,2'-bipyridin]--
4-yl)piperidine-3-carboxamide Hemiformate
##STR00156##
[0490] To a stirred solution of the compound obtained in the
previous section, step c, (16 mg, 0.03 mmol) in MeOH (5 ML),
K.sub.2CO.sub.3 (4.7 mg, 0.034 mmol) were added. The resulting
mixture was stirred at rt for 16 h. The reaction mixture was
concentrated under reduced to get a crude residue that was purified
by Prep HPLC to afford the title compound (6 mg, 46%) as an off
white solid.
[0491] LC-MS (method 6): R.sub.t=1.84 min; m/z=419.34
(M+H.sup.+).
[0492] Preparative HPLC Conditions: Column/dimensions: SUN FIRE C18
(19*150 mm, 5 um) Mobile phase A: 0.1% FA in water (aq) Mobile
phase B: Acetonitrile (org) Gradient (Time/% B): 0/10, 1/10, 5/25,
8/25, 8.1/98, 10/98, 10.1/10, 12/10. Flow rate: 18 ml/min
Solubility: Acetonitrile+ THF
Example 6
3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2-
,4-oxadiazole
##STR00157##
[0493] Step a.
2-(1H-pyrazolo[3,4-b]pyridin-1-yl)isonicotinonitrile
##STR00158##
[0495] To a stirred solution of 2-bromoisonicotinonitrile (500 mg,
2.7 mmol) in toluene (25 mL), 1H-pyrazolo[3,4-b]pyridine (0.6432 g,
5.4 mmol), and K.sub.2CO.sub.3 (1.86 g, 13.5 mmol) were added
followed by CuI (0.256 g, 1.35 mmol). The resulting solution was
degassed with nitrogen for 15 minutes, and trans
N,N-dimethylcyclohexane-1,2-diamine (0.192 g, 1.35 mmol) was added.
The resulting reaction was heated at 110.degree. C. for 16 h. The
reaction mixture was evaporated under vacuum to get a crude residue
that was purified by prep HPLC to afford the title compound (300
mg, 29.3%)
[0496] LC-MS (method 6): R.sub.t=1.626 min; m/z=222.01
(M+H.sup.+).
Step b.
N-hydroxy-2-(1H-pyrazolo[3,4-b]pyridin-1-yl)isonicotinimidamide
##STR00159##
[0498] To a stirred solution the compound obtained in the previous
section, step a (300 mg, 1.0 mmol) in EtOH (5 mL), 50%
NH.sub.2OH.HCl aqueous solution (179 mg, 2.1 mmol) and
Na.sub.2CO.sub.3 (296 mg, 2.8 mmol) in H.sub.2O (5 mL) were added.
The resulting solution was stirred at rt for 18 h. The reaction
mixture was evaporated under vacuum, to get a crude compound that
was used for the next step without any further purification.
[0499] LC-MS (method 6): R.sub.t=1.16 min; m/z=255.12
(M+H.sup.+).
Step c.
3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromet-
hyl)-1,2,4-oxadiazole
##STR00160##
[0501] To a stirred solution the compound obtained in the previous
section, step b (300 mg, 1.2 mmol) in THF (10 mL), trifluroacetic
anhydride (252 mg, 1.2 mmol) was added. The resulting solution was
heated at 70.degree. C. for 3 h. The reaction mixture was
evaporated under vacuum to get a crude residue that was purified by
prep HPLC to afford the title compound (115 mg, 29.3%) as an off
white solid.
[0502] LC-MS (method 20): R.sub.t=4.79 min; m/z=333.11
(M+H.sup.+).
Example 7
N,N-Dimethyl-3-((4'-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)-[2,7-bipyri-
din]-5-yl)oxy)propan-1-amine
##STR00161##
[0504] To a stirred solution of reference example 31 (300 mg, 1.0
mmol) in toluene (3 mL), reference example 30 (928 mg, 3.47 mmolv)
was added. The resulting solution was degassed with nitrogen for 15
minutes, and then Pd (PPh.sub.3).sub.4 (115 mg, 0.1 mmol) was
added. The reaction mixture was again degassed for another 5 min,
and then heated at 110.degree. C., for 16 h. The crude reaction was
filtered through a celite pad, washed with EtOAc (50 mL), and the
filtrated solution was evaporated to dryness. The crude compound
was purified by prep HPLC to afford the title compound (65 mg, 16%)
as a light pink solid.
[0505] LC-MS (method 16): R.sub.t=4.49 min; m/z=394.29
(M+H.sup.+).
[0506] Following a similar procedure to that described in example
7, but using the corresponding starting material, the following
compound was obtained:
TABLE-US-00013 Starting HPLC R.sub.t Example Compound name material
method (min) m/z 7a 3-(2-(1-Methyl-1H-pyrazolo[4,3- Reference 27
4.60 347.30 b]pyridin-3-yl)pyridin-4-yl)-5- example 34 (M +
H.sup.+) (trifluoromethyl)-1,2,4-oxadiazole ##STR00162##
Example 8
HDAC6 and HDAC2 Enzyme Inhibition Assay
[0507] Method:
[0508] A fluorimetric assay was used for testing the activity of
compounds of the invention against HDAC6 and HDAC2. Recombinant
proteins reference and amounts used in each assay are listed in the
Table below.
TABLE-US-00014 ng/ Assay Reference reaction HDAC2 BPS Bioscience
7.5 Inc. #50002 (full length with C- terminal His tag) HDAC6 BPS
Bioscience 20 Inc. #50006 (full length with N- terminal GST
tag)
[0509] The compounds were dissolved in DMSO. Serial dilutions were
prepared in DMSO and then diluted 1:10 in HDAC assay buffer
(Tris-buffered solution, BPS Bioscience Inc. #50031). 5 .mu.l of
the compound dilution was added to a 50 .mu.l reaction so that the
final concentration of DMSO was 1%.
[0510] The compounds were pre-incubated in duplicate at RT for 3
hours in a mixture containing HDAC assay buffer, 5 .mu.g BSA and
recombinant HDAC enzyme (see table above). The enzymatic reactions
were initiated by the addition of a fluorogenic, acetylated peptide
substrate based on a histone protein (BPS Bioscience Inc. #50037)
to a final concentration of 10 .mu.M. The enzymatic reaction
proceeded for 30 minutes at 37.degree. C. Then, 50 .mu.l of
2.times.HDAC Developer, which contains peptidase activity and
Trichostatin A (BPS Bioscience Inc. #50030) was added and the plate
was incubated at RT for an additional 15 minutes. Fluorescence
intensity was measured at an excitation of 360 nm and an emission
of 460 nm using a Tecan Infinite M1000 microplate reader.
[0511] Trichostatin A (TSA, Selleckchem # S1045) was used as
reference inhibitor.
[0512] The fluorescent intensity data were analyzed using the
computer software Graphpad Prism (GraphPad Software, San Diego,
Calif.). 100% activity was defined as the fluorescent intensity
(Ft) in the absence of the compound. 0% activity was defined as the
fluorescent intensity (Fb) in the absence of the enzyme. The
percent activity in the presence of each compound was calculated
according to the following equation: % activity=(F--Fb)/(Ft--Fb),
where F=the fluorescent intensity in the presence of the
compound.
[0513] Results:
[0514] The results obtained in the above assays with compounds of
the invention are shown in the table below:
TABLE-US-00015 Exam- HDAC6 HDAC2 ple % inh @ % inh @ # 1 .mu.M 1
.mu.M 1 79 NT 1a NT NT 1b 84 NT 1c 89 3 1d 78 NT 1e 84 9 1f 71 16
1g 96 38 1h 96 NT 1i NT NT 1j 69 10 1k 95 27 1m 81 NT 1n NT NT 1o
97 23 1p NT NT 1q 73 11 1r 92 NT 1s NT NT 1t 88 NT 1u 98 19 1v 66 3
1w 86 6 1x 95 16 1y 92 27 1z 97 46 1aa 92 NT 1ab 93 38 1ac 78 18
1ad NT NT 1ae 85 5 1af NT NT 1ag NT NT 1ah 96 35 1ai NT NT 1aj NT
NT 1ak 90 14 1al 92 31 1am NT NT 1an NT NT 1ao NT NT 1ap 86 6 1aq
89 2 1ar NT NT 1as NT NT 1at NT NT 1au 85 19 1av NT NT 1aw 81 15
1ax NT NT 1ay NT NT 1az NT NT 2 NT NT 3 90 30 4 96 25 5 95 29 6 NT
NT 7 NT NT NT: Not tested
Example 9
In Vitro Cell-Based Assay
[0515] Method:
[0516] In order to determine the cellular activity of HDAC6 upon
treatment with HDAC6 inhibitors, acetylation levels of
Alpha-Tubulin (a HDAC6-specific substrate) were measured by Western
Blot. For this, MOLP8 cells were seeded in 6-well plates at a cell
density of 500.000 cells/well and treated with the selected
compounds at 5 and 1 .mu.M for 18 h at 37.degree. C. and 5%
CO.sub.2 in a humidified tissue culture incubator. Consecutively,
cell pellets were collected and whole protein extracts prepared
using RIPA buffer (SIGMA) supplemented with 1.times. protease
inhibitors (cOmplete mini, Roche). Protein concentration was
determined with Bradford's reagent (Bio-Rad) as per manufacturer's
instructions, and 7 .mu.g of total protein were loaded into
pre-cast 10% NuPAGE Novex gels (Life Technologies). Gels were run
in MOPS-SDS buffer (Life Technologies) and proteins were
transferred using the iBlot 2 Dry Blotting System (Life
Technologies). Blots were subsequently rinsed in distilled water
and stained with Ponceau S solution (SIGMA). Blots were then washed
in distilled water to remove Ponceau excess and scanned with the
Epson Perfection V600 Photo professional Scanner. After this, blots
were de-stained and blocked in 5% milk/PBS-Tween 0.1% for 1 h at
room temperature followed by incubation with anti-Acetyl-alpha
Tubulin (SIGMA cat. # T7451, 1:10.000 dilution) and anti-Beta-actin
(SIGMA, cat. # A5316, 1:2.000 dilution) primary antibodies in 5%
milk/PBS-T 0.1%, overnight at 4.degree. C. on a shaking platform.
After incubation, blots were washed 3 times for 5 minutes each in
PBS-Tween 0.5% and incubated with anti-mouse HRP-conjugated
secondary antibody (Jackson Immuno Research, cat. #115-035-068) at
1:8.000 in 5% milk/PBS-Tween 0.1%, 1 h at room temperature on a
shaking platform. After 3 washes of 5 minutes each with PBS-Tween
0.5% and 1 wash in PBS 1.times., blots were developed with ECL Plus
(GE Healthcare) and the chemiluminescent reaction imaged with the
G:Box Chemi XRQ (Syngene) imaging system. WB and Ponceau images
were analysed with ImageJ software, WB band intensities normalized
by either total protein or Beta-actin content and made relative to
ACY-1215 1 .mu.M (equivalent to 100%). ACY-1215 is a HDAC6
inhibitor, and is also known as ricolinostat, with chemical name
2-(diphenylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-5-pyrimidinecarboxamid-
e. Percentage of band intensities was classified as follows:
TABLE-US-00016 Relative band intensity (%) Classification <50 -
50-150 + 150-300 ++ >300 +++
[0517] Results:
[0518] The results obtained in this assay with compounds of the
invention are shown in the table below:
TABLE-US-00017 Cellular Cellular activity activity Example @ 1
.mu.M @ 5 .mu.M 1 - + 1a - ++ 1b + ++ 1c + ++ 1d + ++ 1e + ++ 1f -
++ 1g + +++ 1h + ++ 1i - + 1j - ++ 1k + + 1l - + 1m - + 1n - + 1o
++ +++ 1p - ++ 1q + ++ 1r ++ ++ 1s - + 1t - + 1u +++ +++ 1v + +++
1w + ++ 1x ++ +++ 1y + ++ 1z + ++ 1aa + + 1ab ++ ++ 1ac + ++ 1ad +
+ 1ae + + 1af + + 1ag - + 1ah + ++ 1ai - + 1aj + + 1ak + ++ 1al ++
++ 1am + + 1an + + 1ao + ++ 1ap + ++ 1aq ++ ++ 1ar + + 1as + + 1at
- + 1au + ++ 1av + ++ 1aw + ++ 1ax + + 1ay - + 1az - + 1aaa + +
1aab + + 1aac + ++ 1aad + ++ 2 - + 3 + +++ 4 ++ +++ 5 ++ ++ 6 + + 7
- + 7a + ++
[0519] The data provided in Examples 8 and 9 show that compounds of
Formula (I) exhibit potent HDAC6 inhibitory activity, including in
cells. Furthermore, compounds of the invention show selectivity
towards HDAC6 vs HDAC2, based on the data obtained for
representative compounds of the invention against HDAC2, as shown
in example 8.
* * * * *