U.S. patent application number 15/171582 was filed with the patent office on 2016-12-08 for casein kinase 1delta (ck 1delta) inhibitors and their use in the treatment of neurodegenerative diseases such as tauopathies.
This patent application is currently assigned to Electrophoretics Limited. The applicant listed for this patent is Electrophoretics Limited. Invention is credited to William D.O. Hamilton, Jonathan R. Heal, Ian Pike, Joseph M. Sheridan.
Application Number | 20160354375 15/171582 |
Document ID | / |
Family ID | 45444638 |
Filed Date | 2016-12-08 |
United States Patent
Application |
20160354375 |
Kind Code |
A1 |
Sheridan; Joseph M. ; et
al. |
December 8, 2016 |
CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE
TREATMENT OF NEURODEGENERATIVE DISEASES SUCH AS TAUOPATHIES
Abstract
The invention relates to pharmaceutical compositions comprising
casein kinase 1 delta (CK1.delta.) and to the use of said
inhibitors in the treatment of neurodegenerative disorders such as
Alzheimer's disease.
Inventors: |
Sheridan; Joseph M.;
(Surrey, GB) ; Heal; Jonathan R.; (Surrey, GB)
; Hamilton; William D.O.; (Surrey, GB) ; Pike;
Ian; (Surrey, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Electrophoretics Limited |
Surrey |
|
GB |
|
|
Assignee: |
Electrophoretics Limited
Surrey
GB
|
Family ID: |
45444638 |
Appl. No.: |
15/171582 |
Filed: |
June 2, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13993288 |
Sep 19, 2013 |
|
|
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PCT/GB2011/052475 |
Dec 14, 2011 |
|
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15171582 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 25/16 20180101;
A61K 31/4439 20130101; A61K 31/444 20130101; A61K 31/517 20130101;
A61P 21/04 20180101; C07D 405/04 20130101; A61K 31/4045 20130101;
A61P 39/02 20180101; C07D 413/06 20130101; C07D 209/42 20130101;
C07D 471/04 20130101; C07D 407/12 20130101; A61K 31/55 20130101;
C07D 405/12 20130101; A61K 31/4192 20130101; C07D 413/14 20130101;
A61P 25/28 20180101; A61P 25/00 20180101; C07D 487/14 20130101;
C07D 495/14 20130101; A61P 21/00 20180101; A61K 31/519 20130101;
A61K 31/437 20130101; C07D 403/06 20130101; C07D 487/04 20130101;
A61P 21/02 20180101; A61P 43/00 20180101; C07D 401/12 20130101;
A61K 31/53 20130101; A61K 31/397 20130101; A61K 31/506 20130101;
C07D 401/04 20130101; C07D 277/68 20130101 |
International
Class: |
A61K 31/517 20060101
A61K031/517; A61K 31/444 20060101 A61K031/444; A61K 31/506 20060101
A61K031/506 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 14, 2010 |
GB |
1021161.3 |
Jun 1, 2011 |
GB |
1109162.6 |
Claims
1-29. (canceled)
30. A method of treating a neurodegenerative disorder in a subject,
comprising administering an effective amount of a casein kinase 1
delta (ck1.delta.) inhibitor compound of formula (IC), or a
pharmaceutically acceptable salt or solvate thereof: ##STR00009##
wherein "Het C" represents pyridinyl, pyrimidinyl or quinazolinyl;
X.sub.c and Y.sub.c independently represent a bond or NH; R.sup.1c
and R.sup.2c independently represent phenyl, benzodioxinyl,
pyridinyl, pyrazol-4-yl, thiophenyl or benzoxazolyl, wherein
R.sup.1c and R.sup.2c may be substituted by one or more R.sup.4c
groups; R.sup.4c represents selected from hydroxyl, methoxy or
--CONH.sub.2; p represents an integer from 0 to 2; R.sup.3c
represents halogen, halo C.sub.1-6 alkyl, C.sub.1-6 alkyl,
hydroxyl, C.sub.1-6 alkoxy, --S--C.sub.1-6 alkyl,
--CH.sub.2--S--C.sub.1-6 S--C.sub.1-6 alkyl, --S--C.sub.2-6
alkynyl, amino, cyano, NO.sub.2, .dbd.O, .dbd.S,
--SO.sub.2--C.sub.1-6 alkyl, --CONH.sub.2, --CO--C.sub.1-6 alkyl,
--COO--C.sub.1-6 alkyl, --NH--C.sub.1-6 alkyl, --NH--CO--C.sub.1-6
alkyl, --NH--CO--CH.dbd.CH--CH.sub.2--N(Me).sub.2, C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --CO--NH--CH(Me)--COOH,
--S--CH.sub.2--CO--N(Et).sub.2, --NH--(CH.sub.2).sub.2--OH,
--NH--(CH.sub.2).sub.3--OH, --NH--CH(Et)--CH.sub.2--OH,
--CO--NH--(CH.sub.2).sub.3--OH, --CH(CH.sub.2OH).sub.2 or
--S--CH.sub.2--CO--NH--CO--NH--C.sub.1-6 alkyl, aryl, C.sub.3-8
cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or
bicyclic heteroaryl ring system, wherein said aryl, heterocyclyl or
heteroaryl groups of R.sup.3c may be optionally substituted by one
or more R.sup.4c groups and wherein said C.sub.1-6 alkyl groups of
R.sup.3c may be optionally substituted by one or more hydroxyl
groups; with the proviso that the compound is other than compound
number 867.
31. The method of claim 30, wherein "Het C" represents
quinazolinyl.
32. The method of claim 30, wherein one of X.sub.c and
Y.sub.crepresents a bond and the other represents NH.
33. The method of claim 30, wherein R.sup.1c and R.sup.2c
independently represent phenyl, pyridinyl, pyrazol-4-yl or
thiophenyl, wherein R.sup.1c and R.sup.2c may be substituted by one
or more R.sup.4c groups selected from hydroxyl, methoxy or
--CONH.sub.2.
34. The method of claim 33, wherein R.sup.1C and R.sup.2c
independently represent unsubstituted phenyl, unsubstituted
pyridinyl or pyrazol-4-yl.
35. The method of claim 30, wherein p is 0.
36. The method of claim 30, wherein R.sup.3c represents .dbd.O,
cyano or pyridinyl.
37. The method of claim 36, wherein p is 1 and R.sup.3c represents
pyridinyl.
38. The method of claim 36, wherein p is 2 and R.sup.3c represents
.dbd.O or cyano.
39. The method of claim 30, wherein the compound of formula (IC) is
selected from the group consisting of:
2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700);
N-(2,3-Dihydro-1,4-benzadioxin-6-yl)-2-phenylquinazolin-4-amine
(Compound 868);
4-{([2-(Thiophen-3-yl)quinazolin-4-yl]amino}benzamide (Compound
870); 2-Phenyl-N-(1H-pyrazol-4-yl)quinazolin-4-amine (Compound
894); 2-[2-Methyl-4-(pyridin-4-yl)pyrimidin-5-yl]-1,3-benzoxazole
(Compound 949);
2-[2-(Pyridin-2-yl)-4-(pyridin-4-yl)pyrimidin-5-yl]-1,3-benzoxazole
(Compound 950);
5-(1,3-Benzoxazol-2-yl)-2-oxo-6-(pyridin-4-yl)-1,2-dihydropyridine-3-carb-
onitrile (Compound 951); 4-[(2-Phenylquinazolin-4-yl)amino]phenol
(Compound 957);
N-(4-Methoxyphenyl)-2-(thiophen-2-yl)quinazolin-4-amine (Compound
973); N-(4-Methoxyphenyl)-2-(pyridin-2-yl)quinazolin-4-amine
(Compound 977);
6-Phenyl-2-(pyridin-2-yl)-N-(pyridin-4-yl)pyrimidin-4-amine
(Compound 986); and 4-[(2-Phenylquinazolin-4-yl)amino]benzamide
(Compound 993); or a pharmaceutically acceptable salt or solvate
thereof.
40. The method of claim 39, wherein the compound of formula (IC) is
2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700) or a
pharmaceutically acceptable salt or solvate thereof.
41. The method of wherein the neurodegenerative disorder is a
tauopathy,
42. The method of claim 41, wherein the tauopathy is selected from
Alzheimer's disease, frontotemporal dementia with Parkinsonism
linked to chromosome 17 (FTDP-17), progressive supranuclear palsy
(PSP), Pick's disease, corticobasal degeneration, multisystem
atrophy (MSA), neuobasal degeneration with iron accumulation, type
1 (Hallervorden-Spatz), argyrophilic grain dementia, Down's
syndrome, diffuse neurofibrillary tangles with calcification,
dementia pugilistica, Gerstmann-Straussler-Scheinker disease,
myotonic dystrophy, Niemann-Pick disease type C, progressive
subcortical gliosis, prion protein cerebral amyloid angiopathy,
tangle only dementia, postencephalitic parkinsonism, subacute
sclerosing panencephalitis, Creutzfeldt-Jakob disease, amyotrophic
lateral sclerosis/parkinsonism-dementia complex, non-Guamanian
motor neuron disease with neurofibrillary tangles/dementia, and
Parkinson's disease.
43. The method of claim 42, wherein the tauopathy comprises
Alzheimer's disease.
Description
CROSS-REFERENCE TO RELATED APPLICATION(S)
[0001] This application is a divisional application that claims
priority to U.S. application Ser. No. 13/993,288 filed on Sep. 19,
2013, which is the U.S. national stage entry of International
Patent Application No. PCT/GB2011/052475 filed on Dec. 14, 2011,
which claims priority to GB Application No. 1109162.6 filed on Jun.
1, 2011 and GB Application No. 1021161.3 filed on Dec. 14, 2010,
the entire contents of each of which is incorporated herein by
reference in their entireties.
FIELD OF THE INVENTION
[0002] The invention relates to pharmaceutical compositions
comprising casein kinase 1 delta (CK1.delta.) inhibitors and to the
use of said inhibitors in the treatment of neurodegenerative
disorders such as Alzheimer's disease.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease (AD; also known as senile dementia of
the Alzheimer type (SDAT), primary degenerative dementia of the
Alzheimer's type (PDDAT), or Alzheimer's) is the most common form
of dementia. Most often, Alzheimer's disease is diagnosed in people
over 65 years of age, although the less-prevalent early-onset
Alzheimer's can occur much earlier. In 2006, there were 26.6
million sufferers worldwide. Alzheimer's is predicted to affect 1
in 85 people globally by 2050.
[0004] Alzheimer's disease is a neurodegenerative disease
characterised by the presence of senile plaques and neurofibrillary
tangles in the brain. The degree of dementia at death correlates
better with neurofibrillary tangle numbers than with senile plaques
counts. The presence of neurofibrillary tangles in neurons results
in the death of those neurons, implying that prevention of tangle
formation is an important therapeutic goal. The principal protein
that forms the neurofibrillary tangle is the microtubule-associated
protein, tau, which assembles into filaments that have the
appearance of twisting about each other in pairs and are referred
to as paired helical filaments (PHF). PHF are present in different
locations in degenerating neurons in the Alzheimer brain and when
many aggregate in the neuronal cell body, they produce the
neurofibrillary tangle (Lee et al, 2001).
[0005] Intraneuronal deposits of tau in the form of typical
neurofibrillary tangles of AD or other morphologically distinct tau
aggregates in a number of other neurodegenerative diseases, is the
basis for grouping these conditions as tauopathies. Thus, in
addition to AD, the main examples of the tauopathies are
frontotemporal dementia with Parkinsonism linked to chromosome 17
(FTDP-17), progressive supranuclear palsy (PSP), Pick's disease,
corticobasal degeneration, and multisystem atrophy (MSA). The
intracellular tau deposits (usually neuronal but can also be glial)
are all filamentous and mostly in a hyperphosphorylated state
compared to the level of phosphorylation of tau from control human
brain. In the case of AD, this hyperphosphorylated tau is often
referred to as PHF-tau because it is derived from the PHF.
[0006] Tau is a phosphoprotein, the function of phosphorylation
remaining to be unequivocally established. However, increased
phosphorylation of tau on multiple serine and threonine residues
reduces the ability of tau to promote microtubule assembly and to
stabilise assembled microtubules, effects that have been
demonstrated both in vitro and in cells. Many studies have shown
that PHF-tau from AD brain is more heavily phosphorylated on serine
and threonine than tau from control brain. This has been
demonstrated partly by protein sequencing and partly by
demonstrating that certain monoclonal antibodies only label either
PHF-tau or non-phosphorylated tau and not PHF-tau; the epitopes for
many of these antibodies have been mapped to particular
phosphorylated residues present in PHF-tau and absent from control
brain tau. The pathological tau from most other cases of other
tauopathies seems to be similarly hyperphosphorylated to
PHF-tau.
[0007] These findings strongly imply that similar abnormalities in
regulating phosphorylation of tau are shared by all the tauopathies
including AD.
[0008] A number of proline-directed and non-proline directed
protein kinases have been suggested to have a role in the
generation of PHF-tau in Alzheimer brain, including casein kinase
1.
[0009] Mammalian casein kinase-1 exists as multiple isoforms
CK1.alpha., CK1.beta., CK1y1, CK1y2, CK1y3, CK1.delta. and
CK1.epsilon.. The role of CK1.delta. as a potential tau kinase is
of particular interest since it has been reported that CK1 O
protein is increased more than 30-fold in the hippocampus of
Alzheimer brain compared to equivalent controls (Ghoshal, N. et al
(1999) Am. J. Pathol 155, 1163-1172) while its mRNA content is
increased 24-fold (Yasojima, K. et al (2000) Brain Res 865,
116-120) and CK1 has also been shown to be tightly associated with
PHF (Kuret, J. et al (1997) J. Neurochem 69, 2506-2515). CK1.delta.
has also been reported to phosphorylate tau at two epitopes
detecting using phospho-specific monoclonal antibodies to tau, and
exogenous expression of CK1.delta. in non-neuronal cells reduces
binding of tau to microtubules (Li, G. et al (2004) J. Biol. Chem.
279, 15938-15945). Of note in the context of Alzheimer's disease is
a report that CK1 activity is stimulated by amyloid beta-peptide
(A(.beta.), a component of the senile neuritic plaques that,
together with tangles, characterise Alzheimer brain (Chauhan, A. et
al (1993) Brain Res. 629, 47-52). Additional evidence for possible
involvement of CK1 in Alzheimer's disease comes from the reported
influence of CK1 in the regulation of A.beta. production in neurons
(Flajolet, M. et al (2007) PNAS USA 104, 4159-4164). Further work
has confirmed that at least 6 newly identified phosphorylation
sites in PHF-tau (all on serine or threonine residues) can be
generated by CK1.delta.. The finding that a number of
phosphorylation sites in PHF-tau for which CK1 is a strong
candidate kinase, including three for which it is the only known
kinase, implies that CK1 may make an important contribution to the
pathogenesis of Alzheimer's disease (Hanger et al (2007) J. Biol.
Chem. 282, 23645-23654).
[0010] There is therefore a need for CK1.delta. inhibitors which
may be of potential therapeutic benefit in the treatment of
neurodegenerative diseases, such as tauopathies including
Alzheimer's disease, frontotemporal dementia with Parkinsonism
linked to chromosome 17 (FTDP-17), progressive supranuclear palsy
(PSP), Pick's disease, corticobasal degeneration, and multisystem
atrophy (MSA).
DETAILED DESCRIPTION
[0011] According to a first aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (IA) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00001##
wherein "Het A" represents a 4 or 5 membered heterocyclic ring
system containing 1 to 3 heteroatoms selected from O, N or S,
wherein said ring system is optionally fused to one or more (e.g.
1-3) further rings to form a polycyclic ring system comprising up
to 4 rings; X and Y independently represent a bond,
--C(R.sup.7a)(R.sup.8a)--,(CH.sub.2).sub.2, --O--, --S--,
--CH.sub.2--O--, --(CH.sub.2).sub.2--O--, NR.sup.6a,
--N(R.sup.6a)--C(R.sup.7a)(R.sup.8a)--,
--N(R.sup.6a)--(CH.sub.2).sub.2--,
--N(R.sup.6a)--(CH.sub.2).sub.3--,
--CH.sub.2--N(R.sup.6a)--(CH.sub.2).sub.2--, --N(R.sup.6a)--CO--,
--CH.sub.2--NH--CO--(CH.sub.2).sub.2--,
--N(R.sup.6a)--CO--CH.sub.2--,
--N(R.sup.6a)--OO--(CH.sub.2).sub.2--,
--CO--N(R.sup.6a)--CH.sub.2--, .dbd.N--, --C(H)(CN)--,
--C(.dbd.N--NH--COC.sub.1-6 alkyl)-, --CH.dbd.C(R.sup.6a)--OO--,
.dbd.CH--, --CH.dbd.CH--, .dbd.CH--CO--, --N.dbd.CH--,
--N.dbd.C(Me)--, --C(R.sup.6a).dbd.CH--, --NH--N.dbd.C(H)--,
--NH--CO--C(.dbd.CH-heteroaryl)-, --C.dbd.C(Me).sub.2--,
--CH.dbd.CH--CO--N(R.sup.6a)--, --CH.dbd.C(R.sup.6a)--NH--CO--,
--CH.dbd.C(R.sup.6a)--C--O--CH.sub.2--, --CS--S--CH.sub.2--,
--NH--CS--NH--, --NH--CS--NH--CH.sub.2--,
--NH--CS--NH--(CH.sub.2).sub.2--,
--CH.sub.2--N(CSNH.sub.2)--CH.sub.2--, --S--CH.sub.2--,
--S--CH.sub.2--, --S--(CH.sub.2).sub.2--O--, SO.sub.2,
--NH--SO.sub.2--, --CH.sub.2--N(R.sup.6a)--SO.sub.2--, CO,
--CH.sub.2--CO--, --(CH.sub.2).sub.2--CO--, --O--CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, COO, --COO--C(R.sup.7a)CO--,
--CH.dbd.C(R.sup.5a)--CONH--CH.sub.2--,
--CO--CH.sub.2--N(R.sup.6a)--CO--,
--CO--CH.sub.2--C(R.sup.6a)--CH.sub.2--CO--,
--CO--CH.sub.2N(R.sup.6a)--CH.sub.2--,
--CO--NH--N.dbd.C(R.sup.7a)--, --S--CH.sub.2--CO--,
--S--CH.sub.2--CO--N(R.sup.6a)--,
--S--CH.sub.2--CO--N(R.sup.6a)--CH.sub.2--,
--SO.sub.2--N(R.sup.6a)--C(R.sup.7a)(R.sup.8a) --CONH--,
--SO.sub.2--N(R.sup.6a)--CH(--CH.sub.2-aryl)-CONH--CH.sub.2--,
--CH(--S--C.sub.1-6 alkyl)--C(Me)(OH)--,
--CH.sub.2--C(R.sup.6a)(OH)--, --C(OH)(CH(Me)(C.sub.3-8
cycloalkyl))-CH.sub.2--, --C(OH)(R.sup.6a)--CH.sub.2--,
--CH(Me)--NH--CO--CH.sub.2--, --CO--N(R.sup.6a)--CH.sub.2--,
--CO--N(R.sup.6a)--CH.sub.2--CH.sub.2--,
--CO--(R.sup.6a)--CH.sub.2--CH.sub.2--CO--NH--CH.sub.2--,
--CO--NH--C(--CONH.sub.2).dbd.CH--,
--CO--NH--CH(--CONH.sub.2)--CH.sub.2--,
--CH.sub.2--C(H)(Me)--CH.sub.2--S--, --O--CH.sub.2--CO--NH--,
--CH.sub.2--N(R.sup.6a)--CO--CH.sub.2--O--,
--N(R.sup.6a)--CO--CH.sub.2--O--, --C(H)(--CH.sub.2-aryl)-,
--C(H)(--CH.sub.2-heteroaryl)-, --C(NH-aryl)=N--N.dbd.CH--,
--C(NH-aryl)=N--N.dbd.CH--, --NH--N.dbd.C(-aryl)-,
--NH--N.dbd.C(-aryl)-CO--, --NH--C(.dbd.N--CO--C.sub.1-6
alkyl)-NH--(CH.sub.2).sub.2--, --C(--NH-aryl)=N--N.dbd.CH--,
--NH--C(--NH-aryl)=N--CONH--, --C(.dbd.CH-aryl)-CONH--CH.sub.2--,
--CH.dbd.C(R.sup.6a)--CONH--, --CH(--CH.sub.2-aryl)-NH--CO-- or
--CH(OH)--, wherein said aryl or heteroaryl groups of X and Y may
be optionally substituted by one or more halogen, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, NO.sub.2 or hydroxyl groups; R.sup.5a represents
hydrogen, C.sub.1-6 alkyl or cyano; R.sup.6a represents hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cyano, C.sub.3-8 cycloalkyl,
--CH.sub.2--C.sub.3-8 cycloalkyl, aryl, heteroaryl, --C.sub.1-6
alkylene-aryl, --CO-aryl, --CO-heteroaryl or
--C(R.sup.7a)(R.sup.8a)-heteroaryl, wherein said aryl groups of
R.sup.6a may be optionally substituted by one or more halogen or
C.sub.1-6 alkoxy groups; R.sup.7a and R.sup.8a independently
represent hydrogen or C.sub.1-6 alkyl; R.sup.1a and R.sup.2a
independently represent aryl, C.sub.3-8 cycloalkyl, monocyclic or
bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring
system, wherein R.sup.1a and R.sup.2a may be substituted by one or
more (e.g. 1, 2 or 3) R.sup.4a groups; R.sup.4a represents halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 alkynyl, C.sub.3-8
cycloalkyl, haloC.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy,
--O--C.sub.1-6 alkenyl, haloC.sub.1-6 alkoxy, --COOH,
--CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl, --CONH.sub.2,
--CH.sub.2--CONH.sub.2, --NH--C.sub.1-6 alkyl,
--NH--C.sub.2-6alkenyl, --NH--CO--C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --O--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl, --S--C.sub.1-6
alkyl, --SO--C.sub.1-6 alkyl, --SO.sub.2--C.sub.1-6 alkyl,
--SO.sub.2--NH--C.sub.1-6 alkyl,
--S--CH.sub.2--CO--C.sub.2-6alkenyl, --SO.sub.2--OH, amino, cyano,
NO.sub.2, .dbd.O, --CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8
cycloalkyl, --CO-heterocyclyl, --CO-aryl, --CO-heteroaryl,
--COO--(CH.sub.2).sub.2-heterocyclyl, --OCH.sub.2-aryl,
--OCH.sub.2-heteroaryl, --CH.sub.2--O--CO-aryl, --O-aryl,
--NH--CO-heteroaryl, --NH--CO--CH.sub.2-aryl, --NH-aryl,
--NH--SO.sub.2-aryl, aryl or heteroaryl groups, wherein said aryl,
heterocyclyl or heteroaryl groups of R.sup.4a may be optionally
substituted by one or more halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, .dbd.S or hydroxyl groups and wherein said C.sub.1-6 alkyl
or C.sub.2-6 alkenyl groups of R.sup.4a may be optionally
substituted by one or more hydroxyl, amino, cyano, C.sub.1-6
alkoxy, CONH.sub.2 or --COO--C.sub.1-6 alkyl groups; n represents
an integer from 0 to 3; R.sup.3a represents halogen, haloC.sub.1-6
alkyl, C.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy, --S--C.sub.1-6
alkyl, --CH.sub.2--S--C.sub.1-6 alkyl, --S--C.sub.2-6 alkynyl,
amino, cyano, NO.sub.2, .dbd.O, .dbd.S, --SO.sub.2--C.sub.1-6alkyl,
--CONH.sub.2, --CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl,
--NH--C.sub.1-6 alkyl, --NH--CO--C.sub.1-6 alkyl,
--NH--CO--CH.dbd.CH--CH.sub.2--N(Me).sub.2, C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --CO--NH--CH(Me)--COOH,
--S--CH.sub.2--CO--N(Et).sub.2, --NH--(CH.sub.2).sub.2--OH,
--NH--(CH.sub.2).sub.3--OH, --NH--CH(Et)--CH.sub.2--OH,
--CO--NH--(CH.sub.2).sub.3--OH, --CH(CH.sub.2OH).sub.2 or
--S--CH.sub.2--CO--NH--CO--NH--Cl.sub.1-6 alkyl, aryl, C.sub.3-8
cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or
bicyclic heteroaryl ring system, wherein said aryl, heterocyclyl or
heteroaryl groups of R.sup.3a may be optionally substituted by one
or more (e.g. 1, 2 or 3) R.sup.4a groups and wherein said C.sub.1-6
alkyl groups of R.sup.3a may be optionally substituted by one or
more hydroxyl groups; with the proviso that the compound is other
than compound number 38, 138, 212, 243, 378, 415, 441, 480, 577,
579, 580, 587-589, 593, 598, 600, 629, 636, 678, 684, 747, 760,
802, 861, 871, 873, 879, 883, 897-899, 904-905, 907, 909, 915,
917-919, 922-923, 925, 929-930, 938-939, 961.
[0012] In one embodiment, the compound of formula (IA) is selected
from any of compounds: 1, 4-17, 19-25, 36-37, 39-40, 42, 44-45, 52,
61, 71-76, 80-83, 86-91, 93-97, 102-107, 110-112, 114, 117-122,
139-143, 149-151, 153, 158-160, 163-170, 174-177, 185-197, 200,
202-203,208-209, 211, 213-221, 223-224, 226, 228-229, 232, 234,
237-240, 256, 261-264, 267-268, 270, 272, 275-283, 296, 304, 313,
319, 321-323, 326-328, 332, 334-335, 342-345, 350, 356, 361-365,
367-369, 372, 377, 379, 383, 393, 398, 403, 406, 412-413, 416-423,
431-432, 434, 436, 438-440, 442-447, 460, 463, 465-466, 468-476,
478, 481, 487-488, 492-494, 499, 501, 506, 508-510, 512-515,
517-518, 521-522, 525, 527-529, 531-532, 534, 551-552, 554-555,
558, 562-563, 569, 573, 576, 578, 581-582, 584, 586, 599, 604-605,
610-614, 617, 619, 623-625, 628, 630, 633-635, 639, 643-644,
650-652, 654, 656, 664-667, 670, 672, 676-677, 679, 683, 695,
697-698, 704, 707-708, 710, 714, 717, 733, 736, 741-743, 750,
761-766, 768, 773, 782, 787, 791, 794, 807, 809-812, 815-816, 820,
841-843, 846, 849-856, 859-860, 862-864, 931, 947-948, 967, 970,
982, 984, 989, 991-992, 1000 and 1002 as described herein or a
pharmaceutically acceptable salt or solvate thereof.
[0013] In a further embodiment, the compound of formula (IA) is
selected from any of compounds: 5-6, 9-11, 16-17, 19-20, 23-25, 37,
39-40, 42, 44-45, 52, 71, 73, 76, 80-83, 86-87, 89, 91, 93-94,
96-97, 102, 104-106, 111-112, 114, 117-122, 139-143, 149-151, 153,
159, 164, 166, 168, 174-177, 185-187, 190, 192, 195-197, 202-203,
208-209, 211, 214-221, 223-224, 226, 228-229, 232, 234, 237-238,
240, 261-264, 267, 270, 275-283, 313, 319, 321-322, 327-328, 332,
334-335, 342-345, 350, 361-365, 367, 369, 372, 377, 379, 383, 393,
398, 403, 406, 412-413, 416-419, 421, 423, 431-432, 440, 442-445,
447, 463, 465-466, 469-472, 474-476, 478, 481, 488, 494, 499, 501,
506, 508-510, 512-513, 515, 518, 521-522, 525, 528, 532, 552,
554-555, 558, 562, 569, 576, 578, 582, 584 and 586 as described
herein or a pharmaceutically acceptable salt or solvate
thereof.
[0014] In a yet further embodiment, the compound of formula (IA) is
selected from any of compounds:
[0015] 10, 25, 45, 223, 240, 281-282, 321, 465, 506, 512, 611-614,
623-624, 633, 654, 656, 670, 676-677, 697, 717, 736, 766, 851 and
856 as described herein or a pharmaceutically acceptable salt or
solvate thereof.
[0016] In a still yet further embodiment, the compound of formula
(IA) is selected from any of compounds: 10, 45, 240, 654, 656, 766
and 856 as described herein or a pharmaceutically acceptable salt
or solvate thereof, such as compounds 10, 654 and 856.
[0017] In one embodiment, the compound of formula (IA) is selected
from any of compounds: 10, 25, 42, 45, 223, 240, 281-282, 321, 439,
465, 506, 512, 611-614, 619, 623-624, 633, 639, 654, 656, 670, 672,
676-677, 683, 697, 717, 736, 761, 765-766, 768, 809-810, 820, 842,
851, 856, 859-860, 863, 931, 947-948, 967, 970, 982, 984, 989,
991-992, 1000 and 1002 as described herein or a pharmaceutically
acceptable salt or solvate thereof. The compounds of this
embodiment were tested in the CK1.delta. inhibition assay as
described herein and exhibited inhibition of greater than 5%.
[0018] In one embodiment, the compound of formula (IA) is selected
from any of compounds:
[0019] 10, 42, 45, 240, 654, 656, 766, 856, 859, 863, 931, 947-948
and 967 as described herein or a pharmaceutically acceptable salt
or solvate thereof. The compounds of this embodiment were tested in
the CK1.delta. inhibition assay as described herein and exhibited
inhibition of greater than 50%.
[0020] In one embodiment, the compound of formula (IA) is selected
from any of compounds: 10, 654, 856, 859, 931 and 947 as described
herein or a pharmaceutically acceptable salt or solvate thereof.
The compounds of this embodiment were tested in the CK1.delta.
inhibition assay as described herein and exhibited inhibition of
greater than 90%.
[0021] According to a second aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (IB) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00002##
wherein "Het B" represents a 5 membered heterocyclic ring system
containing 1 to 3 heteroatoms selected from O, N or S, wherein said
ring system is fused to one or more (e.g. 1-3) further rings to
form a polycyclic ring system comprising up to 4 rings; Z
represents a bond, --C(R.sup.7b)(R.sup.8b)--, (CH.sub.2).sub.2,
--O--, --S--, --CH.sub.2--O--, --(CH.sub.2).sub.2--O--, NR.sup.6b,
--N(R.sup.6bb)--C(R.sup.7b)(R.sup.8b)--,
--N(R.sup.6b)--(CH.sub.2).sub.2--,
--N(R.sup.6b)--(CH.sub.2).sub.3--,
--CH.sub.2--N(R.sup.6b)--(CH.sub.2).sub.2--, --N(R.sup.6b)--OO--,
--CH.sub.2--NH--CO--(CH.sub.2).sub.2--,
--N(R.sup.6b)--CO--CH.sub.2--, .dbd.N--, --C(H)(CN)--,
--C(.dbd.N--NH--COC.sub.1-6alkyl)--, --CH.dbd.C(R.sup.6b)--CO--,
.dbd.CH--, --N.dbd.CH--, --N.dbd.C(Me)--, --C(R.sup.6b).dbd.CH--,
--NH--CO--C(.dbd.CH-heteroaryl)-, --C.dbd.C(Me).sub.2--,
--CH.dbd.CH--CO--N(R.sup.6b)--,
--CH.dbd.C(R.sup.6b)--CO--NH--CH.sub.2--,
--CH.dbd.C(R.sup.6b)--NH--CO--,
--CH.dbd.C(R.sup.6b)--CO--O--CH.sub.2--, --CS--S--CH.sub.2--,
--NH--CS--NH--, --NH--CS--NH--CH.sub.2--,
--NH--CS--NH--(CH.sub.2).sub.2--,
--CH.sub.2--N(CSNH.sub.2)--CH.sub.2--,
--S--C(R.sup.5b)(R.sup.6b)--, --S--(CH.sub.2).sub.2--O--, SO.sub.2,
--NH--SO.sub.2--, --CH.sub.2--NH--SO.sub.2--, CO, --CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, --O--CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, COO, --COO--C(R.sup.7b)CO--,
--CH.dbd.C(R.sup.5b)--CONN--CH.sub.2--,
CO--CH.sub.2--N(R.sup.6b)--CO--,
--CO--CH.sub.2--C(R.sup.6b)--CH.sub.2--CO--,
--CO--CH.sub.2--N(R.sup.6b)--CH.sub.2--,
--CO--NH--N.dbd.C(R.sup.7b)--, --S--CH.sub.2--CO--,
--S--CH.sub.2--CO--N(R.sup.6b)--,
--S--CH.sub.2--CO--N(R.sup.6b)--CH.sub.2--,
--SO.sub.2--N(R.sup.6b)--C(R.sup.7b)(R.sup.8b--CONH--,
--SO.sub.2--N(R.sup.6b)--CH(--CH.sub.2-aryl)-CONH--CH.sub.2--,
--CH(--S--C.sub.1-6 alkyl)-C(Me)(OH)--,
--CH.sub.2--C(R.sup.6b)(OH)--, --C(OH)(CH(Me)(C.sub.3-8
cycloalkyl))-CH.sub.2--, --C(OH)(R.sup.6b)--CH.sub.2--,
CH(Me)--NH--CO--CH.sub.2--, --CO--N(R.sup.6b)--CH.sub.2--,
--C(H)(R.sup.6b)--CO--N(R.sup.5b)--CH.sub.2--,
--CO--N(R.sup.6b)--CH.sub.2--CH.sub.2--,
--CO--N(R.sup.6b)--CH.sub.2--CH.sub.2--CO--NH--CH.sub.2--,
--CO--NH--C(--CONH.sub.2).dbd.CH--,
--CO--NH--CH(--CONH.sub.2)--CH.sub.2--,
--CH.sub.2--C(H)(Me)--CH.sub.2--S--, --O--CH.sub.2--CO--NH--,
--CH.sub.2--N(R.sup.6b)--CO--CH.sub.2--O--,
--N(R.sup.6b)--CO--CH.sub.2--O--, --C(H)(--CH.sub.2-aryl)-,
--C(H)(--CH.sub.2-heteroaryl)-, --C(NH-aryl)=N--N.dbd.CH--,
--C(NH-aryl)=N--N.dbd.CH--, --NH--CO--CH.sub.2--N(R.sup.6b)--,
--NH--N.dbd.C(-aryl)-, --NH--N.dbd.C(-aryl)-CO--,
--NH--C(.dbd.N--CO--C.sub.1-6 alkyl)-NH--(CH.sub.2).sub.2--,
--C(--NH-aryl)=N--N.dbd.CH--, --NH--C(--NH-aryl)=N--CONH--,
--C(.dbd.CH-aryl)-CONH--CH.sub.2--, --CH.dbd.C(R.sup.6b)--CONH--,
--CH(--CH.sub.2-aryl)-NH--CO-- or --CH(OH)--, wherein said aryl or
heteroaryl groups of Z may be optionally substituted by one or more
halogen, C.sub.1-6 alkyl, C.sub.1-6alkoxy, NO.sub.2 or hydroxyl
groups; R.sup.5b represents hydrogen, C.sub.1-6 alkyl or cyano;
R.sup.6b represents hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy,
cyano, COOH, --COOC.sub.1-6alkyl, C.sub.3-8 cycloalkyl,
--CH.sub.2--C.sub.3-8 cycloalkyl, aryl, heteroaryl, --C.sub.1-6
alkylene-aryl, --CO-aryl, --O--CO-heteroaryl, --CO--heteroaryl or
--C(R.sup.7b)(R.sup.8b)-heteroaryl, wherein said aryl groups of
R.sup.6b may be optionally substituted by one or more halogen or
C.sub.1-6 alkoxy groups; R.sup.7b and R.sup.8b independently
represent hydrogen or C.sub.1-6 alkyl; R.sup.1b represents aryl,
C.sub.3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a
monocyclic or bicyclic heteroaryl ring system, wherein R.sup.ib may
be substituted by one or more (e.g. 1, 2 or 3) R.sup.4b groups;
R.sup.4b represents halogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkynyl, C.sub.3-8 cycloalkyl, haloC.sub.1-6 alkyl,
hydroxyl, C.sub.1-6 alkoxy, alkenyl, haloC.sub.1-6alkoxy, --COOH,
--CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl, --CONH.sub.2,
--CH.sub.2--CONH.sub.2, --NH--C.sub.1-6 alkyl, --NH--C.sub.2-6
alkenyl, --NH--CO--C.sub.1-6 alkyl, --CO--NH--C.sub.1-6 alkyl,
--O--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl, --S--C.sub.1-6
alkyl, --SO--C.sub.1-6 alkyl, --SO.sub.2--C.sub.1-6alkyl,
--SO.sub.2--NH--C.sub.1-6 alkyl,
--S--CH.sub.2--CO--C.sub.2-6alkenyl, --SO.sub.2--OH, amino, cyano,
NO.sub.2, .dbd.O, --CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8
cycloalkyl, --CH.sub.2--CO--NH--C.sub.3-8 cycloalkyl,
--CO-heterocyclyl, --CO-heteroaryl,
--COO--(CH.sub.2).sub.2-heterocyclyl, --OCH.sub.2-aryl,
--OCH.sub.2-heteroaryl, --CH.sub.2--O--CO-aryl, --O-aryl,
--NH--CO-aryl, --NH--CO-heteroaryl, --NH--CO--CH.sub.2-aryl,
--NH-aryl, aryl or heteroaryl groups, wherein said aryl,
heterocyclyl or heteroaryl groups of R.sup.4b may be optionally
substituted by one or more halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, .dbd.S or hydroxyl groups and wherein said C.sub.1-6 alkyl
or C.sub.2-6 alkenyl groups of R.sup.4b may be optionally
substituted by one or more hydroxyl, amino, cyano, C1-6 alkoxy,
CONH2 or -COO-C1-6 alkyl groups; m represents an integer from 0 to
3; R.sup.2b represents halogen, haloC.sub.1-6 alkyl, C.sub.1-6
alkyl, hydroxyl, C.sub.1-6 alkoxy, --S--C.sub.1-6 alkyl,
--CH.sub.2--S--C.sub.1-6 alkyl, --S--C.sub.2-6 alkynyl, amino,
cyano, NO.sub.2, .dbd.O, .dbd.S, --SO.sub.2--C.sub.1-6 alkyl,
--CONH.sub.2, --CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl,
--NH--C.sub.1-6 alkyl, --NH--CO--C.sub.1-6 alkyl,
--NH--CO--CH.dbd.CH--CH.sub.2--N(Me).sub.2, C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --CO--NH--CH(Me)--COOH,
--S--CH.sub.2--CO--N(Et).sub.2, --NH--(CH.sub.2).sub.2--OH,
--NH--(CH.sub.2).sub.3--OH, --NH--CH(Et)--CH.sub.2--OH,
--CO--NH--(CH.sub.2).sub.3--OH, --CH(CH.sub.2OH).sub.2 or
--S--CH.sub.2--CO--NH--CO--NH--C.sub.1-6 alkyl, wherein said
C.sub.1-6 alkyl groups of R.sup.2b may be optionally substituted by
one or more hydroxyl groups; with the proviso that the compound is
other than compound number 54, 373, 458, 496, 585, 590, 594,
596-597, 601-602, 649, 703, 778, 877, 891, 910, 912, 926 and
962-963.
[0022] In one embodiment, the compound of formula (IB) is selected
from any of compounds 2-3, 26-28, 30-33, 35, 47-48, 51, 57-60,
63-64, 78, 84, 113, 123, 127-129, 145, 155-157, 171-173, 204,
206-207, 210, 225, 227, 233, 235-236, 241-242, 244, 249, 269, 285,
288, 303, 307-312, 314-316, 320, 324-325, 333, 336, 351, 357-360,
374-375, 384-391, 396, 399-402, 404-405, 407-411, 414, 424-425,
427-428, 437, 448, 456-457, 482, 484-485, 489-491, 495, 497-498,
505, 507, 516, 519, 524, 526, 553, 559-560, 568, 570, 575, 609,
615-616, 618, 626-627, 638, 653, 669, 692-694, 705, 709, 712, 716,
719, 725, 734, 738, 740, 746, 749, 753-754, 756, 758-759, 767, 770,
777, 784-785, 790, 792, 796, 800-801, 804- 805, 808, 819, 821,
827-828, 831, 833, 838, 844, 847, 857-858, 869, 872, 875, 933, 952,
955, 969, 987, 990 and 999 as described herein or a
pharmaceutically acceptable salt or solvate thereof.
[0023] In a further embodiment, the compound of formula (IB) is
selected from any of compounds: 2-3, 26-28, 30, 32-33, 47-48, 51,
59-60, 84, 113, 123, 127, 129, 145, 155, 157, 172-173, 204,
206-207, 210, 225, 233, 235-236, 241, 244, 269, 285, 288, 307-311,
315-316, 320, 324-325, 333, 336, 351, 357-360, 374-375, 385-386,
388-391, 396, 399-402, 404-405, 407-410, 414, 424, 427-428, 437,
457, 482, 490, 495, 497-498, 505, 516, 519, 553, 559- 560 and 568
as described herein or a pharmaceutically acceptable salt or
solvate thereof.
[0024] In a yet further embodiment, the compound of formula (IB) is
selected from any of compounds:
[0025] 30, 314, 324-325, 391, 405, 626, 705, 753-754, 759, 770,
784, 808, 833 and 847 as described herein or a pharmaceutically
acceptable salt or solvate thereof.
[0026] In a still yet further embodiment, the compound of formula
(IB) is selected from any of compounds:
[0027] 324-325, 405, 754 and 847 as described herein or a
pharmaceutically acceptable salt or solvate thereof, such as
compound 324.
[0028] According to a third aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (IC) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00003##
wherein "Het C" represents a 6 membered heterocyclic ring system
containing 1 to 3 heteroatoms selected from O, N or S, wherein said
ring system is optionally fused to one or more (e.g. 1-3) further
rings to form a polycyclic ring system comprising up to 4 rings;
X.sub.c and Y.sub.c independently represent a bond,
--C(R.sup.7c)(R.sup.8c)--, (CH.sub.2).sub.2, --O--, --S--,
--CH.sub.2--O--, --(CH.sub.2).sub.2--O--, NR.sup.6c,
--N(R.sup.6c)--C(R.sup.7c)(R.sup.8c)--,
--N(R.sup.6c)--(CH.sub.2).sub.2--,
--N(R.sup.6c)--(CH.sub.2).sub.3--,
--CH.sub.2--N(R.sup.6c)--(CH.sub.2).sub.2--, --N(R.sup.6c)--CO--,
--CH.sub.2--NH--CO--(CH.sub.2).sub.2--,
--N(R.sup.6c)--CO--CH.sub.2--, --CO--N(R.sup.6c)--CH.sub.2--,
.dbd.N--, --C(H)(CN)--, --C(.dbd.N--NH--COC.sub.1-6 alkyl)-,
--CH.dbd.C(R.sup.6c)--CO--, .dbd.CH--, --N.dbd.CH--,
--N.dbd.C(Me)--, --C(R.sup.6c).dbd.CH--,
--NH--CO--C(.dbd.CH-heteroaryl)-, --C.dbd.C(Me).sub.2--,
--CH.dbd.CH--CO--N(R.sup.6c)--, --CH.dbd.C(R.sup.6c)--NH--CO--,
--CH.dbd.C(R.sup.6c)--CO--O--CH.sub.2--, --CS--S--CH.sub.2--,
--NH--CS--NH--, --NH--CS--NH--CH.sub.2--,
--NH--CS--NH--(CH.sub.2).sub.2--,
--CH.sub.2--N(CSNH.sub.2)--CH.sub.2--, --S--CH.sub.2--,
--S--(CH.sub.2).sub.2--O--, SO.sub.2, --NH--SO.sub.2--,
--CH.sub.2--NH--SO.sub.2--, CO, --CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, --O--CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, COO, --COO--C(R.sup.6c)(1R.sup.7c)CO--,
--CH.dbd.C(R.sup.5c)--CONH--CH.sub.2--,
--CO--CH.sub.2--N(R.sup.6c)--CO--,
--CO--CH.sub.2--C(R.sup.6c)--CH.sub.2--CO--,
--CO--CH.sub.2--N(R.sup.6c)--CH.sub.2--,
--CO--NH--N.dbd.C(R.sup.7c)--, --S--CH.sub.2--CO--,
--S--CH.sub.2--CO--N(R.sup.6c)--,
--S--CH.sub.2--CO--N(R.sup.6c--CH.sub.2--,
--SO.sub.2--N(R.sup.6c)--C(R.sup.7c)(R.sup.8c)--CONH--,
--SO.sub.2--N(R.sup.6c)--CH(--CH.sub.2-aryl)-CONH--CH.sub.2--,
--CH(--S--C.sub.1-6 alkyl)-C(Me)(OH)--,
--CH.sub.2--C(R.sup.6c)(OH)--, --C(OH)(CH(Me)(C.sub.3-8
cycloalkyl))-CH.sub.2--, --C(OH)(R.sup.6c)--CH.sub.2--,
--CH(Me)--NH--CO--CH.sub.2--, --CO--N(R.sup.6c)--CH.sub.2--,
--CO--N(R.sup.6c)--CH.sub.2--CH.sub.2--,
--CO--N(R.sup.6c)--CH.sub.2--CH.sub.2--CO--NH--CH.sub.2--,
--CO--NH--C(--CONH.sub.2).dbd.CH--,
--CO--NH--CH(--CONH.sub.2)--CH.sub.2--,
--CH.sub.2--C(H)(Me)--CH.sub.2--S--, --O--CH.sub.2--CO--NH--,
--CH.sub.2--N(R.sup.6c)--CO--CH.sub.2--O--,
--N(R.sup.6c)--CO--CH.sub.2--O--, --C(H)(--CH.sub.2-aryl)-,
--C(H)(--CH.sub.2-heteroaryl)-, --C(NH--aryl)=N--N.dbd.CH--,
--C(NH-aryl)=N--N.dbd.CH--, --NH--N.dbd.C(-aryl)-,
--NH--N.dbd.C(-aryl)-CO--, --NH--C(.dbd.N--CO--C.sub.1-6
alkyl)-NH--(CH.sub.2).sub.2--, --C(--NH-aryl)=N--N.dbd.CH--,
--NH--C(--NH-aryl)=N--CONH--, --C(.dbd.CH-aryl)-CONH--CH.sub.2--,
--CH.dbd.C(R.sup.6c)--CONH--, --CH(--CH.sub.2-aryl)-NH--CO-- or
--CH(OH)--, wherein said aryl or heteroaryl groups of X.sub.c and
Y.sub.c may be optionally substituted by one or more halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, NO.sub.2 or hydroxyl groups;
R.sup.5c represents hydrogen, C.sub.1-6 alkyl or cyano; R.sup.6c
represents hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cyano,
C.sub.3-8 cycloalkyl, --CH.sub.2--C.sub.3-8 cycloalkyl, aryl,
heteroaryl, --C.sub.1-6 alkylene-aryl, --CO-aryl, --CO-heteroaryl
or --C(R.sup.7c)(R.sup.8c)-heteroaryl, wherein said aryl groups of
R.sup.6c may be optionally substituted by one or more halogen or
C.sub.1-6 alkoxy groups; R.sup.7c and R.sup.8c independently
represent hydrogen or C.sub.1-6 alkyl; R.sup.1c and R.sup.2c
independently represent aryl, C.sub.3-8 cycloalkyl, monocyclic or
bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring
system, wherein R.sup.1c and R.sup.2c may be substituted by one or
more (e.g. 1, 2 or 3) R.sup.4c groups; R.sup.4c represents halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6 alkynyl, C.sub.3-8
cycloalkyl, haloC.sub.1-6 alkyl, hydroxyl, C.sub.1-6 alkoxy,
--O--C.sub.1-6 alkenyl, haloC.sub.1-6 alkoxy, --COOH,
--COO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl, --CONH.sub.2,
--CH.sub.2--CONH.sub.2, --NH--C.sub.1-6 alkyl, --NH--C.sub.2-6
alkenyl, --NH--CO--C.sub.1-6 alkyl, --CO--NH--C.sub.1-6 alkyl,
--O--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl, --S--C.sub.1-6
alkyl, --SO--C.sub.1-6 alkyl, --SO.sub.2--C.sub.1-6 alkyl,
--SO.sub.2--NH--C.sub.1-6 alkyl,
--S--CH.sub.2--CO--C.sub.2-6alkenyl, --SO.sub.2--OH, amino, cyano,
NO.sub.2, .dbd.O, --CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8
cycloalkyl, --CO-heterocyclyl, --CO-heteroaryl,
--COO--(CH.sub.2).sub.2-heterocyclyl, --OCH.sub.2-aryl,
--OCH.sub.2-heteroaryl, --CH.sub.2--O--CO-aryl, --O-aryl,
--NH--CO-heteroaryl, --NH--CO--CH.sub.2-aryl, aryl or heteroaryl
groups, wherein said aryl, heterocyclyl or heteroaryl groups of
R.sup.4c may be optionally substituted by one or more halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, .dbd.S or hydroxyl groups and
wherein said C.sub.1-6 alkyl or C.sub.2-6 alkenyl groups of
R.sup.4c may be optionally substituted by one or more hydroxyl,
amino, cyano, C.sub.1-6 alkoxy, CONH.sub.2 or --COO--C.sub.1-6
alkyl groups; p represents an integer from 0 to 3; R.sup.3c
represents halogen, haloC.sub.1-6 alkyl, C.sub.1-6 alkyl, hydroxyl,
C.sub.1-6 alkoxy, --S--C.sub.1-6 alkyl, --CH.sub.2--S--C.sub.1-6
alkyl, --S--C.sub.2-6 alkynyl, amino, cyano, NO.sub.2, .dbd.O,
.dbd.S, --SO.sub.2--C.sub.1-6 alkyl, --CONH.sub.2, --CO--C.sub.1-6
alkyl, --COO--C.sub.1-6 alkyl, --NH--C.sub.1-6 alkyl,
--NH--CO--C.sub.1-6 alkyl,
--NH--CO--CH.dbd.CH--CH.sub.2--N(Me).sub.2, C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --CO--NH--CH(Me)--COOH,
--S--CH.sub.2--CO--N(Et).sub.2, --NH--(CH.sub.2).sub.2--OH,
--NH--(CH.sub.2).sub.3--OH, --NH--CH(Et)--CH.sub.2--OH,
--CO--NH--(CH.sub.2).sub.3--OH, --CH(CH.sub.2OH).sub.2 or
--S--CH.sub.2--CO--NH--CO--NH--C.sub.1-6 alkyl, aryl, C.sub.3-8
cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or
bicyclic heteroaryl ring system, wherein said aryl, heterocyclyl or
heteroaryl groups of R.sup.3c may be optionally substituted by one
or more (e.g. 1, 2 or 3) R.sup.4c groups and wherein said C.sub.1-6
alkyl groups of R.sup.3c may be optionally substituted by one or
more hydroxyl groups; with the proviso that the compound is other
than compound number 161, 648, 658, 680, 726, 824, 867, 880, 892,
896, 901, 903, 906, 928 and 944.
[0029] In one embodiment, Het C represents a 6 membered
heterocyclic ring system containing 1 to 3 heteroatoms selected
from O, N or S, wherein said ring system is optionally fused to one
further ring to form a bicyclic ring system. In a further
embodiment, Het C represents a 6 membered heterocyclic ring system
containing 1 to 3 heteroatoms selected from O, N or S, wherein said
ring system is optionally fused to a phenyl ring to form a bicyclic
ring system. In a yet further embodiment, Het C represents a 6
membered heterocyclic ring system containing 1 or 2 nitrogen atoms,
wherein said ring system is optionally fused to a phenyl ring to
form a bicyclic ring system. In a yet further embodiment, Het C
represents pyridinyl, pyrimidinyl or quinazolinyl. In a yet further
embodiment, Het C represents quinazolinyl.
[0030] In one embodiment, X.sub.c and Y.sub.c independently
represent a bond or NR.sup.6c. In a further embodiment, X.sub.c and
Y.sub.c independently represent a bond or NH. In a yet further
embodiment, one of X.sub.c and Y.sub.c represents a bond and the
other represents a bond or NH. In a yet further embodiment, one of
X.sub.c and Y.sub.c represents a bond and the other represents
NH.
[0031] In one embodiment, R.sup.1c and R.sup.2c independently
represent aryl, bicyclic heterocyclyl or a monocyclic or bicyclic
heteroaryl ring system, wherein R.sup.1c and R.sup.2c may be
substituted by one or more (e.g. 1, 2 or 3) R.sup.4c groups. In a
further embodiment, R.sup.1c and R.sup.2c independently represent
aryl (e.g. phenyl), bicyclic heterocyclyl (e.g. benzodioxinyl),
monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) or
bicyclic heteroaryl ring system (e.g. benzoxazolyl), wherein
R.sup.1c and R.sup.2c may be substituted by one or more (e.g. 1, 2
or 3) R.sup.4c groups. In a yet further embodiment, R.sup.1c and
R.sup.2c independently represent aryl (e.g. phenyl), bicyclic
heterocyclyl (e.g. benzodioxinyl), monocyclic heteroaryl (e.g.
pyridinyl, pyrazolyl or thiophenyl) or bicyclic heteroaryl ring
system (e.g. benzoxazolyl), wherein R.sup.1c and R.sup.2c may be
substituted by one or more (e.g. 1) R.sup.4c groups selected from
hydroxyl, C1 -6 alkoxy (e.g. methoxy) or --CONH.sub.2.
[0032] In a yet further embodiment, R.sup.1c and R.sup.2c
independently represent aryl (e.g. phenyl) or monocyclic heteroaryl
(e.g. pyridinyl, pyrazolyl or thiophenyl) wherein R.sup.1c and
R.sup.2c may be substituted by one or more (e.g. 1) R.sup.4c groups
selected from hydroxyl, C.sub.1-6 alkoxy (e.g. methoxy) or
--CONH2.
[0033] In a yet further embodiment, R.sup.1c and R.sup.2c
independently represent unsubstituted aryl (e.g. phenyl) or
unsubstituted monocyclic heteroaryl (e.g. pyridinyl or
pyrazolyl).
[0034] In a yet further embodiment, one of R.sup.1c and R.sup.2c
represents unsubstituted aryl (e.g. phenyl) and the other
represents unsubstituted monocyclic heteroaryl (e.g. pyridinyl or
pyrazolyl).
[0035] In one embodiment, p represents an integer from 0 to 2. In
one embodiment, p represents 0. In an alternative embodiment, p
represents 1. In an alternative embodiment, p represents 2.
[0036] In one embodiment, R.sup.3c represents .dbd.O, cyano or a
monocyclic heteroaryl ring system (e.g. pyridinyl).
[0037] In one embodiment, when p represents 1, R.sup.3c represents
a monocyclic heteroaryl ring system (e.g. pyridinyl).
[0038] In one embodiment, when p represents 2, R.sup.3c represents
.dbd.O and cyano.
[0039] In one embodiment, the compound of formula (IC) is selected
from any of compounds:
[0040] 43, 46, 49, 147, 152, 154, 178-181, 183-184, 294-295, 305,
329, 339-341, 366, 370-371, 376, 435, 455, 459, 462, 486, 520,
539-543, 546-549, 556-557, 567, 631-632, 640-642, 645, 657, 661,
668, 671, 674, 681, 700-702, 727, 735, 755, 817-818, 823, 826, 845
or 865-866, 868, 870, 888-890, 894, 946, 949-951, 953, 957, 973,
977, 981, 983, 985-986, 993 and 995 as described herein or a
pharmaceutically acceptable salt or solvate thereof.
[0041] In a further embodiment, the compound of formula (IC) is
selected from any of compounds: 46, 147, 294-295, 329, 341, 435,
486, 520, 539, 542-543, 547-549, 556 and 567 as described herein or
a pharmaceutically acceptable salt or solvate thereof.
[0042] In a yet further embodiment, the compound of formula (IC) is
selected from any of compounds:
[0043] 567, 631, 640, 661 and 700 as described herein or a
pharmaceutically acceptable salt or solvate thereof, such as
compound 700.
[0044] In one embodiment, the compound of formula (IC) is selected
from any of compounds: 567, 631, 640, 661, 668, 700, 727, 823, 868,
870, 888-890, 894, 946, 949-951, 953, 957, 973, 977, 981, 983,
985-986, 993 and 995 as described herein or a pharmaceutically
acceptable salt or solvate thereof. The compounds of this
embodiment were tested in the CK1.delta. inhibition assay as
described herein and exhibited inhibition of greater than 5%.
[0045] In one embodiment, the compound of formula (IC) is selected
from any of compounds: [0046]
2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700); [0047]
N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-2-phenylquinazolin-4-amine
(Compound 868); [0048]
4-{[2-(Thiophen-3-yl)quinazolin-4-yl]amino}benzamide (Compound
870); [0049] 2-Phenyl-N-(1H-pyrazol-4-yl)quinazolin-4-amine
(Compound 894); [0050]
2[2-Methyl-4-(pyridin-4-yl)pyrimidin-5-yl]-1,3-benzoxazole
(Compound 949); [0051]
2-[2-(Pyridin-2-yl)-4-(pyridin-4-yl)pyrimidin-5-yl]-1,3-benzoxazole
(Compound 950); [0052]
5-(1,3-Benzoxazol-2-yl)-2-oxo-6-(pyridin-4-yl)-1,2-dihydropyridine-3-carb-
onitrile (Compound 951); [0053]
4-[(2-Phenylquinazolin-4-yl)amino]phenol (Compound 957); [0054]
N-(4-Methoxyphenyl)-2-(thiophen-2-yl)quinazolin-4-amine (Compound
973); [0055] N-(4-Methoxyphenyl)-2-(pyridin-2-yl)quinazolin-4-amine
(Compound 977); [0056]
6-Phenyl-2-(pyridin-2-yl)-N-(pyridin-4-yl)pyrimidin-4-amine
(Compound 986); and [0057]
4-[(2-Phenylquinazolin-4-yl)amino]benzamide (Compound 993); [0058]
or a pharmaceutically acceptable salt or solvate thereof. The
compounds of this embodiment were tested in the CK1.delta.
inhibition assay as described herein and exhibited inhibition of
greater than 25%.
[0059] In a further embodiment, the compound of formula (IC) is
selected from any of compounds: [0060]
2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700); [0061]
2-Phenyl-N-(1H-pyrazol-4-yl)quinazolin-4-amine (Compound 894);
[0062] 2-[2-Methyl-4-(pyridin-4-yl)pyrimidin-5-yl]-1,3-benzoxazole
(Compound 949); and [0063]
6-Phenyl-2-(pyridin-2-yl)-N-(pyridin-4-yl)pyrimidin-4-amine
(Compound 986); [0064] or a pharmaceutically acceptable salt or
solvate thereof. The compounds of this embodiment were tested in
the CK1.delta. inhibition assay as described herein and exhibited
inhibition of greater than 50%.
[0065] In a yet further embodiment, the compound of formula (IC) is
selected from any of compounds: [0066]
2-Phenyl-N-(pyridin-4-yl)quinazolin-4-amine (Compound 700); and
[0067] 2-Phenyl-N-(1H-pyrazol-4-yl)quinazolin-4-amine (Compound
894); [0068] or a pharmaceutically acceptable salt or solvate
thereof. The compounds of this embodiment were tested in the
CK1.delta. inhibition assay as described herein and exhibited
inhibition of greater than 80%.
[0069] According to a fourth aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (ID) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00004##
wherein "Het D" represents a 6 membered heterocyclic ring system
containing 1 to 3 heteroatoms selected from O, N or S, wherein said
ring system is fused to one or more (e.g. 1-3) further rings to
form a polycyclic ring system comprising up to 4 rings; Z.sub.d
represents a bond, --C(R.sup.7d)(R.sup.8d)--,
--(CH.sub.2)--C(R.sup.7d)(R.sup.8d)--, --O--, --S--,
--CH.sub.2--O--, --(CH.sub.2).sub.2--O--, NR.sup.6d,
--N(R.sup.6d)--C(R.sup.7d)(R.sup.8d)--,
--N(R.sup.6d)--(CH.sub.2).sub.2--,
--N(R.sup.6d)--(CH.sub.2).sub.3--,
--CH.sub.2--N(R.sup.6d)--(CH.sub.2).sub.2--, --N(R.sup.6)--CO--,
--CH.sub.2--NH--CO--(CH.sub.2).sub.2--,
--N(R.sup.6d)--CO--CH.sub.2--, --CO--N(R.sup.6d)--CH.sub.2--,
.dbd.N--, --C(H)(CN)--, --C(.dbd.N--NH--COC.sub.1-6 alkyl)-,
--CH.dbd.C(R.sup.6d)--CO--, .dbd.CH--, --N.dbd.CH--,
--N.dbd.C(Me)--, --C(R.sup.6d).dbd.CH--,
--NH--CO--C(.dbd.CH-heteroaryl)-, --C.dbd.C(Me).sub.2--,
--CH.dbd.CH--CO--N(R.sup.6d)--, --CH.dbd.C(R.sup.6d)--NH--CO--,
--CO--O--CH.sub.2--, --CH.dbd.C(R.sup.6d)--CO--O--CH.sub.2--,
--CS--S--CH.sub.2--, --NH--CO--NH--, --NH--CS--NH--,
--NH--CS--NH--CH.sub.2--, --NH--CS--NH--(CH.sub.2).sub.2--,
--CH.sub.2--N(CSNH.sub.2)--CH.sub.2--, --S--CH.sub.2--,
--S--(CH.sub.2).sub.2--O--, SO.sub.2, --NH--SO.sub.2--,
--CH.sub.2--NH--SO.sub.2--, CO, --CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, --O--CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, COO, --COO--C(R.sup.7d)CO--,
--CH.dbd.C(R.sup.5d)--CONH--CH.sub.2--,
--CO--CH.sub.2--N(R.sup.6d)--CO--,
--CO--CH.sub.2--C(R.sup.6d)--CH.sub.2--CO--,
--CO--CH.sub.2--N(R.sup.6d)--CH.sub.2--,
--CO--NH--N.dbd.C(R.sup.7d)--, --S--CH.sub.2--CO--,
--S--CH.sub.2--CO--N(R.sup.6d)--,
--S--CH.sub.2--CO--N(R.sup.6d)--CH.sub.2--,
--SO.sub.2--N(R.sup.6d)--C(R.sup.7d)(R.sup.8d)--CONH--,
--SO.sub.2--N(R.sup.6d)--CH(--CH.sub.2-aryl)-CONH--CH.sub.2--,
--CH(--S--C.sub.1-6 alkyl)-C(Me)(OH)--,
--CH.sub.2--C(R.sup.6d)(OH)--, --C(OH)(CH(Me)(C.sub.3-8
cycloalkyl))- CH.sub.2--, --C(OH)(R.sup.6d)--CH.sub.2--,
--CH(Me)--NH--CO--CH.sub.2--, --CO--N(R.sup.6d)--CH.sub.2--,
--CO--N(R.sup.6d)--CH.sub.2--CH.sub.2--,
--CO--N(R.sup.6d)--CH.sub.2--CH.sub.2--CO--NH--CH.sub.2--,
--CO--NH--C(--CONH.sub.2).dbd.CH--,
--CO--NH--CH(--CONH.sub.2)--CH.sub.2--,
--CH.sub.2--C(H)(Me)--CH.sub.2--S--, --O--CH.sub.2--CO--NH--,
--CH.sub.2--N(R.sup.6d)--CO--CH.sub.2--O--,
--N(R.sup.6d)--CO--CH.sub.2--O--, --C(H)(--CH.sub.2-aryl)-,
--C(H)(--CH.sub.2-heteroaryl)-, --C(NH-aryl)=N--N.dbd.CH--,
--C(NH-aryl)=N--N.dbd.CH--, --NH--N.dbd.C(-aryl)-,
--NH--N.dbd.C(-aryl)-CO--, --NH--C(.dbd.N--CO--C.sub.1-6
alkyl)-NH--(CH.sub.2).sub.2--, --C(--NH-aryl)=N--N.dbd.CH--,
--NH--C(-NH-aryl)=N--CONH--, --C(.dbd.CH-aryl)-CONH--CH.sub.2--,
--CH.dbd.C(R.sup.6d)--CONH--, --CH(--CH.sub.2-aryl)-NH--CO-- or
--CH(OH)--, wherein said aryl or heteroaryl groups of Z.sub.d may
be optionally substituted by one or more halogen, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, NO.sub.2 or hydroxyl groups; R.sup.5d represents
hydrogen, C.sub.1-6 alkyl or cyano; R.sup.6d represents hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cyano, C.sub.3-8 cycloalkyl,
--CH.sub.2--C.sub.3-8 cycloalkyl, aryl, heteroaryl, --C.sub.1-6
alkylene-aryl, --CO-aryl, --CO-heteroaryl or
--C(R.sup.7d)(R.sup.8d)-heteroaryl, wherein said aryl groups of
R.sup.6d may be optionally substituted by one or more halogen or
C.sub.1-6 alkoxy groups; R.sup.7d and R.sup.8d independently
represent hydrogen or C.sub.1-6 alkyl; R.sup.1d represents aryl,
C.sub.3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a
monocyclic or bicyclic heteroaryl ring system, wherein R.sup.1d may
be substituted by one or more (e.g. 1, 2 or 3) R.sup.4d groups;
R.sup.4d represents halogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkynyl, C.sub.3-8 cycloalkyl, haloC.sub.1-6 alkyl,
hydroxyl, C.sub.1-6 alkoxy alkoxy, --COOH, --CO--C.sub.1-6 alkyl,
--COO--C.sub.1-6 alkyl, --CONH.sub.2, --CH.sub.2--CONH.sub.2,
--NH--C.sub.1-6 alkyl, --NH--C.sub.2-6 alkenyl, --NH--CO--C.sub.1-6
alkyl, --CO--NH--C.sub.1-6 alkyl, --O--CH.sub.2--CO--NH--C.sub.1-6
alkyl, --CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--S--C.sub.1-6 alkyl, --SO--C.sub.1-6 alkyl, --SO.sub.2--C.sub.1-6
alkyl, --SO.sub.2--NH--C.sub.1-6 alkyl,
--S--CH.sub.2--CO--C.sub.2-6alkenyl, --SO.sub.2--OH, amino, cyano,
NO.sub.2, .dbd.O, --CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8
cycloalkyl, --CO-heterocyclyl, --CO-heteroaryl,
--COO--(CH.sub.2).sub.2-heterocyclyl, --OCH.sub.2-aryl,
--OCH.sub.2-heteroaryl, --CH.sub.2--O--CO-aryl, --O-aryl,
--NH--CO-aryl, --NH--CO-heteroaryl, --NH--CO--CH.sub.2-aryl, aryl
or heteroaryl groups, wherein said aryl, heterocyclyl or heteroaryl
groups of R.sup.4d may be optionally substituted by one or more
halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, .dbd.S or hydroxyl
groups and wherein said C.sub.1-6 alkyl or C.sub.2-6 alkenyl groups
of R.sup.4d may be optionally substituted by one or more hydroxyl,
amino, cyano, C.sub.1-6 alkoxy, CONH.sub.2 or --COO--C.sub.1-6
alkyl groups; q represents an integer from 0 to 3; R.sup.2d
represents halogen, haloC.sub.1-6 alkyl, C.sub.1-6 alkyl, hydroxyl,
C.sub.1-6 alkoxy, --S--C.sub.1-6 alkyl, --CH.sub.2--S--C.sub.1-6
alkyl, --S--C.sub.2-6 alkynyl, amino, cyano, NO.sub.2, .dbd.O,
.dbd.S, .dbd.NH, --SO.sub.2--C.sub.1-6 alkyl, --CONH.sub.2,
--CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl, --NH--C.sub.1-6
alkyl, --NH--CO--C.sub.1-6 alkyl,
--NH--CO--CH.dbd.CH--CH.sub.2--N(Me).sub.2, C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --CO--NH--CH(Me)--COOH,
--S--CH.sub.2--CO--N(Et).sub.2, --NH--(CH.sub.2).sub.2--OH,
--NH--(CH.sub.2).sub.3--OH, --NH--CH(Et)--CH.sub.2--OH,
--CO--NH--(CH.sub.2).sub.3--OH, --CH(CH.sub.2OH).sub.2 or
--S--CH.sub.2--CO--NH--CO--NH--C.sub.1-6 alkyl, wherein said
C.sub.1-6 alkyl groups of R.sup.2d may be optionally substituted by
one or more hydroxyl groups; with the proviso that the compound is
other than compound number 273, 286, 467, 533, 544, 571, 591, 662,
783, 795, 806, 884, 887, 895, 902, 908, 921, 932, 934, 942, 959-960
and 1001.
[0070] In one embodiment, the compound of formula (ID) is selected
from any of compounds: 29, 34, 41, 65-70, 92, 109, 116, 126,
130-137, 162, 182, 231, 246, 252-255, 258, 274, 290-293, 297-298,
317-318, 330-331, 347-349, 352, 450-454, 483, 536-538, 545, 550,
564-565, 572, 620, 637, 655, 663, 675, 682, 686, 691, 696, 706,
711, 724, 728-729, 737, 744-745, 748, 752, 774-776, 781, 797-799,
832, 834, 954, 958, 964-965, 971, 974-976, 978-980, 994 and 997-998
as described herein or a pharmaceutically acceptable salt or
solvate thereof.
[0071] In a further embodiment, the compound of formula (ID) is
selected from any of compounds: 34, 41, 65-66, 68-69, 109, 126,
130, 132-137, 162, 182, 231, 246, 252-255, 258, 274, 290, 293,
297-298, 317-318, 348-349, 352, 450-453, 536, 545, 550, 564-565 and
572 as described herein or a pharmaceutically acceptable salt or
solvate thereof.
[0072] In a yet further embodiment, the compound of formula (ID) is
selected from any of compounds:
[0073] 663, 682, 696, 737, 748, 832 and 834 as described herein or
a pharmaceutically acceptable salt or solvate thereof, such as
compound 682.
[0074] In one embodiment, the compound of formula (ID) is selected
from any of compounds: 663, 675, 682, 696, 706, 737, 748, 797, 832,
834, 954, 958, 964-965, 971, 974-976, 978980, 994 and 997-998 as
described herein or a pharmaceutically acceptable salt or solvate
thereof. The compounds of this embodiment were tested in the
CK1.delta. inhibition assay as described herein and exhibited
inhibition of greater than 5%.
[0075] In one embodiment, the compound of formula (ID) is selected
from any of compounds: 682, 954, 964, 978-979 and 997 as described
herein or a pharmaceutically acceptable salt or solvate thereof.
The compounds of this embodiment were tested in the CK1.delta.
inhibition assay as described herein and exhibited inhibition of
greater than 50%.
[0076] According to a fifth aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (1E) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00005##
wherein "Het E" represents a 6 membered heterocyclic ring system
containing 1 to 3 heteroatoms selected from O, N or S; Z.sub.e
represents a bond, --C(R.sup.7e)(R.sup.8e)--, (CH.sub.2).sub.2,
--O--, --S--, --CH.sub.2--O--, --(CH.sub.2).sub.2--O--, NR.sup.6e,
--N(R.sup.6e)--C(R.sup.7e)(R.sup.8e)--,
--N(R.sup.6e)--(CH.sub.2).sub.2--,
--N(R.sup.6e)--(CH.sub.2).sub.3--,
--CH.sub.2--N(R.sup.6e)--(CH.sub.2).sub.2--, --N(R.sup.6e)--CO--,
--CH.sub.2--NH--CO--(CH.sub.2).sub.2--,
--N(R.sup.6e)--CO--CH.sub.2--, --CO--N(R.sup.6e)--CH.sub.2--,
.dbd.N--, --C(H)(CN)--, --C(.dbd.N--NH--COC.sub.1-6 alkyl)-,
--C(R.sup.6e).dbd.N--NH--CO--, --CH.dbd.C(R.sup.6e)--CO--,
.dbd.CH--, --N.dbd.CH--, --N.dbd.C(Me)--, --C(R.sup.6e).dbd.CH--,
--NH--CO--C(.dbd.CH-heteroaryl)-, --C.dbd.C(Me).sub.2--,
--CH.dbd.CH--CO--N(R.sup.6e)--, --CH.dbd.C(R.sup.6e)--NH--CO--,
--CH.dbd.C(R.sup.6e)--CO--O--CH.sub.2--, --CS--S--CH.sub.2--,
--NH--CS--NH--, --N(R.sup.6e)--CO--N(R.sup.7e)--,
--NH--CS--N(R.sup.6e)--CH(R.sup.7e)--, --CO--NH--CS--N(R.sup.6e)--,
--NH--CS--NH--(CH.sub.2).sub.2--,
--CH.sub.2--N(CSNH.sub.2)--CH.sub.2--, --S--CH.sub.2--,
--S--(CH.sub.2).sub.2--O--, SO.sub.2, --NH--SO.sub.2--,
--CH.sub.2--N(R.sup.6e)--SO.sub.2--, CO, --CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, --O--CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, COO, --COO--C(R.sup.7e)CO--,
--CH.dbd.C(R.sup.5e)--CONH--CH.sub.2--,
--CO--CH.sub.2--N(R.sup.6e)--CO--,
--CO--CH.sub.2--C(R.sup.6e)--CH.sub.2--CO--,
--C(R.sup.6e)--CO--CH.sub.2--,
--CO--CH.sub.2--N(R.sup.6e)--CH.sub.2--,
--CO--NH--N.dbd.C(R.sup.7e)--, --S--CH.sub.2--CO--,
--S--CH.sub.2--CO--N(R.sup.6e)--,
--S--CH.sub.2--CO--N(R.sup.6e)--CH.sub.2--,
--SO.sub.2--N(R.sup.6e)--C(R.sup.7e)(R.sup.8e)--CONH--,
--SO.sub.2--N(R.sup.6e)--CH(--CH.sub.2-aryl)-CONH--CH.sub.2--,
--CH(--S--C.sub.1-6 alkyl)--C(Me)(OH)--,
--CH.sub.2--C(R.sup.6e)(OH)--, --C(OH)(CH(Me)(C.sub.3-8
cycloalkyl))-CH.sub.2--, --C(OH)(R.sup.6e)--CH.sub.2--,
--CH(Me)--NH--CO--CH.sub.2--, --CO--N(R.sup.6e)--CH.sub.2--,
--CO--N(R.sup.6e)--CH.sub.2--CH.sub.2--,
--CO--N(R.sup.6e)--CH.sub.2--CH.sub.2--O--CO--,
--CO--N(R.sup.6e)--CH.sub.2--CH.sub.2--CO--NH--CH.sub.2--,
--CO--NH--C(--CONH.sub.2).dbd.CH--,
--CO--NH--CH(--CONH.sub.2)--CH.sub.2--,
--CH.sub.2--C(H)(Me)--CH.sub.2--S--, --O--CH.sub.2--CO--NH--,
--CH.sub.2--N(R.sup.6e)--CO--CH.sub.2--O--,
--N(R.sup.6e)--CO--CH.sub.2--O--, --C(H)(--CH.sub.2-aryl)-,
--C(H)(--CH.sub.2-heteroaryl)-, --C(NH-aryl)=N--N.dbd.CH--,
--C(NH-aryl)=N--N.dbd.CH--, --NH--N.dbd.C(-aryl)-,
--NH--C(R.sup.6e).dbd.N--SO.sub.2--, --NH--N.dbd.C(-aryl)-CO--,
--NH--C(.dbd.N--CO)(R.sup.6e)--, --NH--C(.dbd.N--CO--C.sub.1-6
alkyl)-NH--(CH.sub.2).sub.2--, --C(--NH-aryl)=N--N.dbd.CH--,
--NH--C(--NH-aryl)=N--CONH--, --C(.dbd.CH-aryl)-CONH--CH.sub.2--,
--CH.dbd.C(R.sup.6e)--CONH--, --CH(--CH.sub.2-aryl)-NH--CO-- or
--CH(OH)--, wherein said aryl or heteroaryl groups of Z.sub.e may
be optionally substituted by one or more halogen, C.sub.1-6 alkyl,
C.sub.1-6alkoxy, NO.sub.2 or hydroxyl groups; R.sup.5e represents
hydrogen, C.sub.1-6 alkyl or cyano; R.sup.6e represents hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamino, cyano,
C.sub.3-8 cycloalkyl, --CH.sub.2-C.sub.3-8 cycloalkyl, aryl,
heteroaryl, --C.sub.1-6 alkylene-aryl, --C.sub.1-6
alkylene-heteroaryl, --NH--CO-aryl, --CO-aryl, --CO-heteroaryl or
--C(R.sup.7e)(R.sup.8e)-heteroaryl, wherein said aryl groups of
R.sup.6e may be optionally substituted by one or more halogen or
C.sub.1-6 alkoxy groups; R.sup.7e and R.sup.8e independently
represent hydrogen or C.sub.1-6 alkyl; R.sup.1e represents aryl,
C.sub.3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a
monocyclic or bicyclic heteroaryl ring system, wherein R.sup.1d may
be substituted by one or more (e.g. 1, 2 or 3) R.sup.4e groups;
R.sup.4e represents halogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkynyl, C.sub.3-8 cycloalkyl, haloC.sub.1-6 alkyl,
hydroxyl, C.sub.1-6 alkoxy, alkenyl, haloC.sub.1-6 alkoxy, --COOH,
--CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl, --CONH.sub.2,
--SO.sub.2NH.sub.2, --CH.sub.2--CONH.sub.2, --NH--C.sub.1-6 alkyl,
--NH--C.sub.2-6 alkenyl, --NH--CO--C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --NH--NH.sub.2,
--O--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl, --S--C.sub.1-6
alkyl, --SO--C.sub.1-6 alkyl, --SO.sub.2--C.sub.1-6 alkyl,
--SO.sub.2--NH--C.sub.1-6 alkyl, --S--CH.sub.2--CO--C.sub.2-6
alkenyl, --SO.sub.2--OH, amino, cyano, NO.sub.2, .dbd.O,
--CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8 cycloalkyl,
--CO-heterocyclyl, --CO-heteroaryl,
--COO--(CH.sub.2).sub.2-heterocyclyl, --OCH.sub.2-aryl,
--OCH.sub.2-heteroaryl, --CH.sub.2--O--CO-aryl, --O-aryl,
--CO--NH-aryl, --NH--SO.sub.2-aryl, --NH--CO-heteroaryl,
--NH--C.sub.1-4 alkylene-heteroaryl, --NH--CO--CH.sub.2-aryl, aryl
or heteroaryl groups, wherein said C.sub.1-6 alkynyl, aryl,
heterocyclyl or heteroaryl groups of R.sup.4e may be optionally
substituted by one or more halogen, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, .dbd.S or hydroxyl groups and wherein said C.sub.1-6 alkyl
or C.sub.2-6 alkenyl groups of R.sup.4e may be optionally
substituted by one or more hydroxyl, amino, cyano, C.sub.1-6
alkoxy, CONH.sub.2 or --COOC.sub.1-6 alkyl groups; r represents an
integer from 0 to 3; R.sup.2e represents halogen, haloC.sub.1-6
alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkynyl, hydroxyl, C.sub.1-6
alkoxy, --S--C.sub.1-6 alkyl, --CH.sub.2--S--C.sub.1-6alkyl,
--S--C.sub.2-6 alkynyl, amino, cyano, NO.sub.2, .dbd.O, .dbd.S,
--SO.sub.2--C.sub.1-6 alkyl, --CONH.sub.2, --CO--C.sub.1-6 alkyl,
--COO--C.sub.1-6 alkyl, --NH--C.sub.1-6 alkyl, --NH--CO--C.sub.1-6
alkyl, --NH--CO--CH.dbd.CH--CH.sub.2--N(Me).sub.2, C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --CO--NH--CH(Me)--COOH,
--S--CH.sub.2--CO--N(Et).sub.2, --NH--(CH.sub.2).sub.2--OH,
--NH--(CH.sub.2).sub.3--OH, --NH--CH(Et)--CH.sub.2--OH,
--CO--NH--(CH.sub.2).sub.3--OH, --CH(CH.sub.2OH).sub.2 or
--S--CH.sub.2--CO--NH--CO--NH--C.sub.1-6alkyl, wherein said
C.sub.1-6 alkyl or C.sub.1-6 alkynyl, groups of R.sup.2e may be
optionally substituted by one or more hydroxyl or alkylamino
groups; with the proviso that the compound is other than compound
number 250, 647, 685, 751, 769, 803, 874, 876, 893, 900, 911,
913-914, 916, 920, 927, 936-937, 940, 943 and 945.
[0077] In one embodiment, the compound of formula (IE) is selected
from any of compounds:
[0078] 18, 50, 55-56, 62, 77, 85, 108, 115, 144, 146, 148, 198-199,
201, 222, 230, 245, 247, 251, 265, 284, 287, 300, 306, 337-338,
346, 381-382, 392, 426, 429-430, 479, 561, 566, 583, 603, 606-608,
621-622, 646, 659-660, 687-688, 690, 699, 715, 718, 720-723,
730732, 739, 771-772, 780, 793, 813-814, 822, 829-830, 835-837,
840, 848, 885-886, 941, 966 and 988 as described herein or a
pharmaceutically acceptable salt or solvate thereof.
[0079] In a further embodiment, the compound of formula (IE) is
selected from any of compounds: 18, 62, 115, 146, 148, 222, 230,
251, 265, 300, 306, 338, 346, 381, 392, 426, 561 and 583 as
described herein or a pharmaceutically acceptable salt or solvate
thereof.
[0080] In a yet further embodiment, the compound of formula (IE) is
selected from any of compounds:
[0081] 583, 660, 822 and 830 as described herein or a
pharmaceutically acceptable salt or solvate thereof.
[0082] In one embodiment, the compound of formula (IE) is selected
from any of compounds: 583, 646, 660, 723, 730, 780, 822, 830,
885-886, 941, 966 and 988 as described herein or a pharmaceutically
acceptable salt or solvate thereof. The compounds of this
embodiment were tested in the CK1.delta. inhibition assay as
described herein and exhibited inhibition of greater than 5%.
[0083] According to a sixth aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (IF) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00006##
wherein "Het F" represents a heterocyclic ring system containing 1
to 3 heteroatoms selected from 0, N or S, wherein said ring system
is fused to one or more (e.g. 1-3) further rings to form a
polycyclic ring system comprising up to 4 rings; R.sup.1f
represents halogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl, C.sub.1-6
alkynyl, C.sub.3-8 cycloalkyl, haloC.sub.1-6 alkyl hydroxyl,
C.sub.1-6 alkoxy, --O--C.sub.1-6 alkenyl, haloC.sub.1-6 alkoxy,
--COOH, --CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl,
--CONH.sub.2, --CH.sub.2--CONH.sub.2, --NH--C.sub.1-6 alkyl,
--NH--C.sub.2-6 alkenyl, --NH--CO--C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --O--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl, --SO--C.sub.1-6
alkyl, --SO.sub.2--C.sub.1-6alkyl, --SO.sub.2--NH--C.sub.1-6 alkyl,
--S--CH.sub.2--CO--C.sub.2-6 alkenyl, --SO.sub.2--OH, amino, cyano,
NO.sub.2, .dbd.O, --CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8
cycloalkyl, wherein said C.sub.1-6 alkyl or C.sub.2-6 alkenyl
groups of R.sup.1f may be optionally substituted by one or more
hydroxyl, amino, cyano, C.sub.1-6 alkoxy, CONH.sub.2 or
--COO--C.sub.1-6 alkyl groups; s represents an integer from 1 to 3;
with the proviso that the compound is other than compound number
592 and 595.
[0084] In one embodiment, the compound of formula (IF) is selected
from any of compounds: 53, 79, 124-125, 205, 289, 299, 301-302,
353-355, 397, 500 and 511 as described herein or a pharmaceutically
acceptable salt or solvate thereof.
[0085] In a further embodiment, the compound of formula (IF) is
selected from any of compounds: 79, 125, 205, 289, 299, 301-302,
353-355, 397, 500 and 511 as described herein or a pharmaceutically
acceptable salt or solvate thereof.
[0086] In one embodiment, the compound of formula (IF) is Compound
205 as described herein or a pharmaceutically acceptable salt or
solvate thereof. The compound of this embodiment was tested in the
CK1.delta. inhibition assay as described herein and exhibited
inhibition of greater than 50%.
[0087] According to a sixth aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (IG) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00007##
wherein Z.sub.g represents a bond, --C(R.sup.7g)(R.sup.8g)--,
(CH.sub.2).sub.2, --O--, --S--, --CH.sub.2--O--,
--(CH.sub.2).sub.2--O--, NR.sup.6g,
--N(R.sup.6g)--C(R.sup.7g)(R.sup.8g)--,
--N(R.sup.6g)--(CH.sub.2).sub.2--,
--N(R.sup.6g)--(CH.sub.2).sub.3--,
--CH.sub.2--N(R.sup.6g)--(CH.sub.2).sub.2--, --N(R.sup.6g)--CO--,
--CH.sub.2--NH--CO--(CH.sub.2).sub.2--,
--N(R.sup.6g)--CO--CH.sub.2--, .dbd.N--, --C(H)(CN)--,
--C(.dbd.N--NH--COC.sub.1-6 alkyl)-, --CH.dbd.C(R.sup.6g)--CO--,
.dbd.CH--, --N.dbd.CH--, --N.dbd.C(Me)--, --C(R.sup.6g).dbd.CH--,
--NH--CO--C(.dbd.CH-heteroaryl)-, --C.dbd.C(Me).sub.2--,
--CH.dbd.CH--CO--N(R.sup.6g)--, --CH.dbd.C(R.sup.6g)--NH--CO--,
--CH.dbd.C(R.sup.6g)--CO--O--CH.sub.2--, --CS--S--CH.sub.2--,
--NH--CS--NH--, --NH--CS--NH--CH.sub.2--,
--NH--CS--NH--(CH.sub.2).sub.2--,
--CH.sub.2--N(CSNH.sub.2)--CH.sub.2--, --S--CH.sub.2--,
--S--(CH.sub.2).sub.2--O--, SO.sub.2, --NH--SO.sub.2--,
--CH.sub.2--NH--SO.sub.2--, CO, --CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, --O--CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, COO, --COO--C(R.sup.7g)CO--,
--CH.dbd.C(R.sup.5g)--CONH--CH.sub.2--,
--CO--CH.sub.2--N(R.sup.6g)--CO--,
--CO--CH.sub.2--C(R.sup.6g)--CH.sub.2--CO--,
--CO--CH.sub.2--N(R.sup.6g)--CH.sub.2--,
--CO--NH--N.dbd.C(R.sup.7g)--, --S--C(R.sup.6g)(R.sup.7g)--CO--,
--S--CH.sub.2--CO--N(R.sup.6g)--,
--S--CH.sub.2--CO--N(R.sup.6g)--CH.sub.2--,
--SO.sub.2--N(R.sup.6g)--C(R.sup.7g)(R.sup.8g)--CONH--,
--SO.sub.2--N(R.sup.6g)--CH(--CH.sub.2-aryl)--CONH--CH.sub.2--,
--CH(--S--C.sub.1-6 alkyl)--C(Me)(OH)--,
--CH.sub.2--C(R.sup.6g)(OH)--, --C(OH)(CH(Me)(C.sub.3-8
cycloalkyl))-CH.sub.2--, --C(OH)(R.sup.6g)--CH.sub.2--,
--CH(Me)--NH--CO--CH.sub.2--, --CO--N(R.sup.6g)--CH.sub.2--,
--CO--N(R.sup.6g)--CH.sub.2--CH.sub.2--,
--CO--N(R.sup.6g)--CH.sub.2--CH.sub.2--CO--NH--CH.sub.2--,
--CO--NH--C(--CONH.sub.2).dbd.CH--,
--CO--NH--CH(--CONH.sub.2)--CH.sub.2--,
--CH.sub.2--C(H)(Me)--CH.sub.2--S--, --O--CH.sub.2--CO--NH--,
--CH.sub.2--N(R.sup.6g)--CO--CH.sub.2--O,
--N(R.sup.6g)--CO--CH.sub.2--O--, --C(H)(--CH.sub.2-aryl)-,
--C(H)(--CH.sub.2-heteroaryl)-, --C(NH-aryl).dbd.N--N.dbd.CH--,
--C(NH-aryl).dbd.N--N.dbd.CH--, --NH--N.dbd.C(-aryl)-,
--NH--N.dbd.C(-aryl)-CO--, --NH--C(.dbd.N--CO--C.sub.1-6
alkyl)-NH--(CH.sub.2).sub.2--, --C(--NH-aryl)=N--N.dbd.CH--,
--NH--C(--NH-aryl)=N--CONH--, --C(.dbd.CH-aryl)-CONH--CH.sub.2--,
--CH.dbd.C(R.sup.6g)--CONH--, --CH(--CH.sub.2-aryl)-NH--CO-- or
--CH(OH)--, wherein said aryl or heteroaryl groups of Z.sub.g may
be optionally substituted by one or more halogen, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, NO.sub.2 or hydroxyl groups; R.sup.5g represents
hydrogen, C.sub.1-6 alkyl or cyano; R.sup.6g represents hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cyano, C.sub.3-8 cycloalkyl,
--CH.sub.2--C.sub.3-8 cycloalkyl, aryl, heteroaryl, --C.sub.1-6
alkylene-aryl, --CO-aryl, --CO-heteroaryl or
--C(R.sup.7g)(R.sup.8g)-heteroaryl, wherein said aryl groups of
R.sup.6g may be optionally substituted by one or more halogen or
C.sub.1-6 alkoxy groups; R.sup.7g and R.sup.8g independently
represent hydrogen or C.sub.1-6 alkyl; R.sup.1g represents aryl,
C.sub.3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a
monocyclic or bicyclic heteroaryl ring system, wherein R.sup.1g may
be substituted by one or more (e.g. 1, 2 or 3) R.sup.4g groups;
R.sup.4g represents halogen, C.sub.1-6 alkyl, C.sub.1-6 alkenyl,
C.sub.1-6 alkynyl, C.sub.3-8 cycloalkyl, haloC.sub.1-6 alkyl,
hydroxyl, C.sub.1-6 alkoxy, haloC.sub.1-6 alkoxy, --COOH,
--CO--C.sub.1-6 alkyl, --COO--C.sub.1-6 alkyl, --CONH.sub.2,
--CH.sub.2--CONH.sub.2, --NH--C.sub.1-6 alkyl, --NH--C.sub.2-6
alkenyl, --NH--CO--C.sub.1-6 alkyl, --CO--NH--C.sub.1-6 alkyl,
--O--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl, --S--C.sub.1-6
alkyl, --SO--C.sub.1-6 alkyl, --SO.sub.2--C.sub.1-6 alkyl,
--SO.sub.2--NH--C.sub.1-6 alkyl, --S--CH.sub.2--CO--C.sub.2-6
alkenyl, --SO.sub.2--OH, amino, cyano, NO.sub.2, .dbd.O,
--CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8 cycloalkyl,
--CO-heterocyclyl, --CO-heteroaryl,
--COO--(CH.sub.2).sub.2-heterocyclyl, --OCH.sub.2-aryl,
--OCH.sub.2-heteroaryl, --CH.sub.2--O--CO-aryl, --O-aryl,
--NH--CO-heteroaryl, --NH--CO--CH.sub.2-aryl, aryl or heteroaryl
groups, wherein said aryl, heterocyclyl or heteroaryl groups of
R.sup.4g may be optionally substituted by one or more halogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, .dbd.S or hydroxyl groups and
wherein said C.sub.1-6 alkyl or C.sub.2-6 alkenyl groups of
R.sup.4g may be optionally substituted by one or more hydroxyl,
amino, cyano, C.sub.1-6 alkoxy, CONH.sub.2 or --COO--C.sub.1-6
alkyl groups; t represents an integer from 0 to 3; R.sup.2g
represents halogen, haloC.sub.1-6 alkyl, C.sub.1-6 alkyl, hydroxyl,
C.sub.1-6 alkoxy, --CH.sub.2--S--C.sub.1-6 alkyl, --S--C.sub.2-6
alkynyl, amino, cyano, NO.sub.2, .dbd.O, .dbd.S,
--SO.sub.2--C.sub.1-6 alkyl, --CONH.sub.2, --CO--C.sub.1-6 alkyl,
--COO--C.sub.1-6 alkyl, --NH--C.sub.1-6 alkyl, --NH--CO--C.sub.1-6
alkyl, --NH--CO--CH.dbd.CH--CH.sub.2--N(Me).sub.2, C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --CO--NH--CH(Me)--COOH,
--S--CH.sub.2--CO--N(Et).sub.2, --NH--(CH.sub.2).sub.2--OH,
--NH--(CH.sub.2).sub.3--OH, --NH--CH(Et)--CH.sub.2--OH,
--CO--NH--(CH.sub.2).sub.3--OH, --CH(CH.sub.2OH).sub.2 or
--S--CH.sub.2--CO--NH--CO--NH--C.sub.1-6 alkyl, wherein said
C.sub.1-6 alkyl groups of R.sup.2g may be optionally substituted by
one or more hydroxyl groups; with the proviso that the compound is
other than compound number 789, 839 and 924.
[0088] In one embodiment, the compound of formula (IG) is selected
from any of compounds: 98-101, 248, 257, 259-260, 266, 271, 380,
394, 449, 461, 464, 477, 502-504, 523, 530, 535, 574, 673, 713,
779, 788, 825, 881-882, 935, 956, 968, 972 and 996 as described
herein or a pharmaceutically acceptable salt or solvate
thereof.
[0089] In a further embodiment, the compound of formula (IG) is
selected from any of compounds:
[0090] 98, 101, 248, 257, 259-260, 266, 271, 380, 394 and 530 as
described herein or a pharmaceutically acceptable salt or solvate
thereof.
[0091] In a yet further embodiment, the compound of formula (IG) is
compound 825 as described herein or a pharmaceutically acceptable
salt or solvate thereof.
[0092] In one embodiment, the compound of formula (IG) is selected
from any of compounds: 825, 881-882, 935, 956, 968, 972 and 996 as
described herein or a pharmaceutically acceptable salt or solvate
thereof. The compounds of this embodiment were tested in the CK1 O
inhibition assay as described herein and exhibited inhibition of
greater than 5%.
[0093] In one embodiment, the compound of formula (IG) is Compound
972 as described herein or a pharmaceutically acceptable salt or
solvate thereof. The compound of this embodiment was tested in the
CK1O inhibition assay as described herein and exhibited inhibition
of greater than 50%.
[0094] According to a seventh aspect of the invention there is
provided a pharmaceutical composition comprising a compound of
formula (IH) or a pharmaceutically acceptable salt or solvate
thereof:
##STR00008##
wherein "Het H1" and "Het H2" independently represent a 5 membered
heterocyclic ring system containing 1 to 3 heteroatoms selected
from O, N or S; Z.sub.h represents a bond,
--C(R.sup.7h)(R.sup.8h)--, (CH.sub.2).sub.2, --O--, --S--,
--CH.sub.2--O--, --(CH.sub.2).sub.2--O--, NR.sup.6h,
--N(R.sup.6h)--C(R.sup.6h)(R.sup.7h)--,
--N(R.sup.6h)--(CH.sub.2).sub.2--,
--N(R.sup.6h)--(CH.sub.2).sub.3--,
--CH.sub.2--N(R.sup.6h)--(CH.sub.2).sub.2--, --N(R.sup.6h)--CO--,
--CH.sub.2--NH--CO--(CH.sub.2).sub.2--,
--N(R.sup.6h)--CO--CH.sub.2--, .dbd.N--, --C(H)(CN)--,
--C(.dbd.N--NH--COC.sub.1-6alkyl)-, --CH.dbd.C(R.sup.6h)--CO--,
.dbd.CH--, --N.dbd.CH--, --N.dbd.C(Me)--, --C(R.sup.6h).dbd.CH--,
--NH--CO--C(.dbd.CH-heteroaryl)-, --C.dbd.C(Me).sub.2--,
--CH.dbd.CH--CO--N(R.sup.6h)--, --CH.dbd.C(R.sup.6h)--NH--CO--,
--CH.dbd.C(R.sup.6h)--CO--O--CH.sub.2--, --CS--S--CH.sub.2--,
--NH--CS--NH--, --NH--CS--NH--CH.sub.2--,
--NH--CS--NH--(CH.sub.2).sub.2--,
--CH.sub.2--N(CSNH.sub.2)--CH.sub.2--, --S--CH.sub.2--,
--S--(CH.sub.2).sub.2--O--, SO.sub.2, --NH--SO.sub.2--,
--CH.sub.2--NH--SO.sub.2--, CO, --CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, --O--CH.sub.2--CO--,
--(CH.sub.2).sub.2--CO--, COO, --COO--C(R.sup.7h)CO--,
--CH.dbd.C(R.sup.5h)--CONH--CH.sub.2--,
--CO--CH.sub.2--N(R.sup.6h)--CO--,
--CO--CH.sub.2--C(R.sup.6h)--CH.sub.2--CO--,
--CO--CH.sub.2--N(R.sup.6h)--CH.sub.2--,
--CO--NH--N.dbd.C(R.sup.7h)--, --S--CH.sub.2--CO--,
--S--CH.sub.2--CO--N(R.sup.6h)--,
--S--CH.sub.2--CO--N(R.sup.6h)--CH.sub.2--,
--SO.sub.2--N(R.sup.6h)--C(R.sup.7h)(R.sup.8h)--CONH--,
--SO.sub.2--N(R.sup.6h)--CH(--CH.sub.2-aryl)--CONH--CH.sub.2--,
--CH(--S--C.sub.1-6 alkyl)-C(Me)(OH)--,
--CH.sub.2--C(R.sup.6h)(OH)--, --C(OH)(CH(Me)(C.sub.3-8
cycloalkyl))-CH.sub.2--, --C(OH)(R.sup.6h)--CH.sub.2--,
--CH(Me)--NH--CO--CH.sub.2--, --CO--N(R.sup.6h)--CH.sub.2--,
--CO--N(R.sup.6h)--CH.sub.2--CH.sub.2--,
--CO--N(R.sup.6h)--CH.sub.2--CH.sub.2--CO--NH--CH.sub.2--,
--CO--NH--C(--CONH.sub.2).dbd.CH--,
--CO--NH--CH(--CONH.sub.2)--CH.sub.2--,
--CH.sub.2--C(H)(Me)--CH.sub.2--S--, --O--CH.sub.2--CO--NH--,
--CH.sub.2--N(R.sup.6h)--CO--CH.sub.2--O--,
--N(R.sup.6h)--CO--CH.sub.2--O--, --C(H)(--CH.sub.2-aryl)-,
--C(H)(--CH.sub.2-heteroaryl)-, --C(NH-aryl).dbd.N--N.dbd.CH--,
--C(NH-aryl).dbd.N--N.dbd.CH--, --NH--N.dbd.C(-aryl)-,
--NH--N.dbd.C(aryl)-CO--, --NH--C(.dbd.N--CO--C.sub.1-6
alkyl)-NH--(CH.sub.2).sub.2--, --C(--NH-aryl)=N--N.dbd.CH--,
--NH--C(--NH-aryl)=N--CONH--, --C(.dbd.CH-aryl)-CONH--CH.sub.2--,
--CH.dbd.C(R.sup.6h)--CONH--, --CH(--CH.sub.2-aryl)-NH--CO-- or
--CH(OH)--, wherein said aryl or heteroaryl groups of Z.sub.h may
be optionally substituted by one or more halogen, C.sub.1-6 alkyl,
C.sub.1-6 alkoxy, NO.sub.2 or hydroxyl groups; R.sup.5h represents
hydrogen, C.sub.1-6 alkyl or cyano; R.sup.6h represents hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, cyano, C.sub.3-8 cycloalkyl,
--CH.sub.2--C.sub.3-8 cycloalkyl, aryl, heteroaryl, --C.sub.1-6
alkylene-aryl, --CO-aryl, --CO-heteroaryl or
--C(R.sup.7h)(R.sup.8h)-heteroaryl, wherein said aryl groups of
R.sup.6h may be optionally substituted by one or more halogen or
C.sub.1-6 alkoxy groups; R.sup.7h and R.sup.8h independently
represent hydrogen or C.sub.1-6 alkyl; R.sup.1h and R.sup.2h
independently represent halogen, C.sub.1-6 alkyl, C.sub.1-6
alkenyl, C.sub.1-6 alkynyl, C.sub.3-8 cycloalkyl, haloC.sub.1-6
alkyl, hydroxyl, C.sub.1-6 alkoxy, --O--C.sub.1-6 alkenyl,
haloC.sub.1-6 alkoxy, --COOH, CO--C.sub.1-6 alkyl, --COO--C.sub.1-6
alkyl, --CONH.sub.2, --CH.sub.2--CONH.sub.2, --NH--C.sub.1-6 alkyl,
--NH--C.sub.2-6 alkenyl, NH--CO--C.sub.1-6 alkyl,
--CO--NH--C.sub.1-6 alkyl, --O--CH.sub.2--CO--NH--C.sub.1-6 alkyl,
--CH.sub.2--CH.sub.2--CO--NH--C.sub.1-6 alkyl, --S--C.sub.1-6
alkyl, --SO--C.sub.1-6 alkyl, --SO.sub.2C.sub.1-6 alkyl,
--SO.sub.2--NH--C.sub.1-6 alkyl, --S--CH.sub.2--CO--C.sub.2-6
alkenyl, --SO.sub.2--OH, amino, cyano, NO.sub.2, .dbd.O,
--CO--NH--(CH.sub.2).sub.2)--OMe, --NH--C.sub.3-8 cycloalkyl,
--CO-heterocyclyl, --CO-heteroaryl,
--COO--(CH.sub.2).sub.2-heterocyclyl, --OCH.sub.2-aryl,
--OCH.sub.2-heteroaryl, --CH.sub.2--O--CO-aryl, --O-aryl,
--NH--CO-heteroaryl, --NH--CO--CH.sub.2-aryl, aryl or heteroaryl
groups, wherein said aryl, heterocyclyl or heteroaryl groups of
R.sup.1h and R.sup.2h may be optionally substituted by one or more
halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, .dbd.S or hydroxyl
groups and wherein said C.sub.1-6 alkyl or C.sub.2-6 alkenyl groups
of R.sup.1h and R.sup.2h may be optionally substituted by one or
more hydroxyl, amino, cyano, C.sub.1-6 alkoxy, CONH.sub.2 or
--COO--C.sub.1-6 alkyl groups; u and v independently represent an
integer from 0 to 3; with the proviso that the compound is other
than compound number 757 and 878.
[0095] In one embodiment, the compound of formula (IH) is selected
from any of compounds:
[0096] 395, 433, 689 and 786 as described herein or a
pharmaceutically acceptable salt or solvate thereof.
[0097] In the present context, the term "pharmaceutically
acceptable salt" is intended to indicate salts which are not
harmful to the patient. Such salts include pharmaceutically
acceptable acid addition salts, pharmaceutically acceptable metal
salts and pharmaceutically acceptable akaline addition salts. Acid
addition salts include salts of inorganic acids as well as organic
acids.
[0098] Representative examples of suitable inorganic acids include
hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric
acids and the like. Representative examples of suitable organic
acids include formic, acetic, trichloroacetic, trifluoroacetic,
propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic,
maleic, malic, malonic, mandelic, oxalic, picric, pyruvic,
salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric,
ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic,
gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic,
p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids
and the like. Further examples of pharmaceutically acceptable
inorganic or organic acid addition salts include the
pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977,
66, 2, which is incorporated herein by reference. Examples of metal
salts include lithium, sodium, potassium, magnesium salts and the
like. Examples of ammonium and alkylated ammonium salts include
ammonium, methylammonium, dimethylammonium, trimethylammonium,
ethylammonium, hydroxyethylammonium, diethylammonium,
butylammonium, tetramethylammonium salts and the like.
[0099] Representative examples of alkaline salts include, for
example, sodium, potassium, lithium, calcium, magnesium or ammonium
or organic bases such as, for example, methylamine, ethylamine,
propylamine, trimethylamine, diethylamine, triethylamine, N,
N-dimethylethanolamine, tris(hydroxymethyl)aminomethane,
ethanolamine, pyridine, piperidine, piperazine, picoline,
dicyclohexylamine, morpholine, benzylamine, procaine, lysine,
arginine, histidine, N-methylglucamine.
[0100] According to the invention, the compounds of formulae
(IA)-(IH) can be in racemic forms, as well as in the form of pure
enantiomers or non racemic (scalemic) mixture of enantiomers,
including when the compounds of formulae (IA)-(IH) have more than
one stereogenic centre.
[0101] In case the compounds of formulae (IA)-(IH) have unsaturated
carbon carbon double bonds, both the cis (Z) and trans (E) isomers
and their mixtures belong to the invention.
[0102] References herein to "halogen" means a fluorine, chlorine,
bromine or iodine atom.
[0103] References herein to "C.sub.1-6 alkyl" means any linear,
branched hydrocarbon groups having 1 to 6 carbon atoms, or cyclic
hydrocarbon groups having 3 to 6 carbon atoms. Representative
examples of such alkyl groups include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl and t-butyl, n-pentyl, isopentyl,
neopentyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
References to "haloC.sub.1-6 alkyl" mean a C.sub.1-6 alkyl group
substituted by one or more halogen atoms as herein defined.
[0104] References herein to "C.sub.1-6 alkylene" means a saturated
divalent hydrocarbon chain having the specified number of member
atoms. For example, C.sub.1-6 alkylene refers to a bond or an
alkylene group having from 1 to 6 member atoms. Alkylene groups may
be straight or branched. Representative branched alkylene groups
have one or two branches. Alkylene includes methylene, ethylene,
propylene (n-propylene and isopropylene) and butylene (n-butylene,
isobutylene, and t-butylene).
[0105] References herein to "C.sub.2-6 alkenyl" means any linear,
branched hydrocarbon groups of 2 to 6 carbon atoms, or cyclic
hydrocarbon group having 3 to 6 carbon atoms having at least one
double bond. Representative examples of such alkenyl groups include
ethenyl, propenyl, butenyl and cyclohexenyl.
[0106] References herein to "C.sub.2-6 alkynyl" means any linear,
or branched hydrocarbon groups of 2 to 6 carbon atoms, having at
least one triple bond. Representative examples of such alkynyl
groups include ethynyl, propargyl and butynyl.
[0107] References herein to `C.sub.1-6 alkoxy` means an
--O--C.sub.1-6 alkyl group wherein C1-6 alkyl is as defined herein.
Examples of such groups include methoxy, ethoxy, propoxy, butoxy,
pentoxy or hexoxy and the like.
[0108] References herein to `C.sub.3-8 cycloalkyl` means a
saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms.
Examples of such groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the
like.
[0109] References herein to `aryl` means a C.sub.6-12 monocyclic or
bicyclic hydrocarbon ring wherein at least one ring is aromatic.
Examples of such groups include phenyl, indyl or naphthyl and the
like.
[0110] References herein to "heteroatom" means a nitrogen, sulphur,
or oxygen atom.
[0111] References herein to "heterocyclyl" means a saturated or
unsaturated non-aromatic ring containing from 1 to 4 heteroatoms as
member atoms in the ring. Heterocyclyl groups containing more than
one heteroatom may contain different heteroatoms. Heterocyclyl
groups may be optionally substituted with one or more substituents
as defined herein. Heterocyclyl groups are monocyclic ring systems
or fused bicyclic or polycyclic ring systems or bicyclic structures
known as heterocyclic "Spiro" ring systems. In certain embodiments,
heterocyclyl is saturated. In other embodiments, heterocyclyl is
unsaturated and non-aromatic. Non-limiting examples of monocyclic
heterocyclyl ring systems include pyrrolidinyl, tetrahydrofuranyl,
dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl,
tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,
piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,
thiamorpholinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,
1,3-oxathiolanyl, 1 ,3-oxathianyl, 1,3-dithianyl, and
azetidinyl.
[0112] References herein to "heteroaryl" means an aromatic ring
containing from 1 to 4 heteroatoms as member atoms in the ring.
Heteroaryl groups containing more than one heteroatom may contain
different heteroatoms. Heteroaryl groups may be optionally
substituted with one or more substituents as defined herein.
Heteroaryl groups are monocyclic ring systems or are fused bicyclic
or polycyclic ring systems. Monocyclic heteroaryl rings have 5 or 6
member atoms. Bicyclic heteroaryl rings have from 7 to 11 member
atoms. Bicyclic heteroaryl rings include those rings wherein phenyl
and a monocyclic heterocyclyl ring are attached forming a fused
bicyclic ring system, and those rings wherein a monocyclic
heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl,
heterocyclyl, or heteroaryl ring are attached forming a fused
bicyclic ring system. Non-limiting examples of heteroaryl includes
pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl,
pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl,
indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl,
isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl,
benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl,
isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and
napthyridinyl.
[0113] References herein to "heterocyclic ring system" mean either
a heterocyclyl ring system or a heteroaryl ring system as
hereinbefore defined.
[0114] Representative compounds of the invention include compounds
1-1002 as set forth below:
TABLE-US-00001 Lengthy table referenced here
US20160354375A1-20161208-T00001 Please refer to the end of the
specification for access instructions.
[0115] According to a further aspect of the invention, there is
provided a compound of any one of formulae (IA)-(1H) for use as a
casein kinase 1 delta (CK1.delta.) inhibitor in the treatment of a
neurodegenerative disorder, such as tauopathies.
[0116] According to a further aspect of the invention, there is
provided a compound of formula 1-37, 39-53, 55-137, 139-160,
162-211, 213-242, 244-249, 251-272, 274-285, 287-372, 374-377,
379-414, 416-440, 442-457, 459-466, 468-479, 481-495, 497-532,
534-543, 545-570, 572-576, 578, 581-584, 586, 588-599, 603-628,
630-635, 637-646, 650-657, 659-661, 663-677, 679, 681-683, 686-702,
704-725, 727-746, 748-750, 752-756, 758-759, 761-768, 770-777,
779-782, 784-788, 780-801, 804-805, 807-823, 825-838, 840-860,
862-866, 868-870, 872, 875, 881-882, 885-886, 888-890, 894-894,
904-905, 931, 933, 935, 941, 946-958, 964-1000 and 1002 or a
pharmaceutically acceptable salt or solvate thereof for use as a
casein kinase 1 delta (CK1.delta.) inhibitor in the treatment of a
neurodegenerative disorder, such as tauopathies.
[0117] Compounds of formula 1-1002 are either commercially
available or may be prepared in accordance with known synthetic
procedures.
[0118] According to a further aspect of the invention there is
provided a pharmaceutical composition comprising any one of the
compounds of formulae (IA)-(IH) for use in the treatment of a
neurodegenerative disorder, such as tauopathies.
[0119] The pharmaceutical compositions of the invention may
comprise, in addition to one of the above substances, a
pharmaceutically acceptable excipient, carrier, buffer, stabiliser
or other materials well known to those of ordinary skill in the
art. Such materials should be non-toxic and should not interfere
with the efficacy of the active ingredient. The precise nature of
the carrier or other material may depend on the route of
administration, e. g., oral, intravenous, cutaneous or
subcutaneous, nasal, intramuscular, intraperitoneal routes.
[0120] Pharmaceutical compositions for oral administration may be
in tablet, capsule, powder or liquid form. A tablet may include a
solid carrier such as gelatin or an adjuvant.
[0121] Liquid pharmaceutical compositions generally include a
liquid carrier such as water, petroleum, animal or vegetable oils,
mineral oil or synthetic oil. Physiological saline solution,
dextrose or other saccharide solution or glycols such as ethylene
glycol, propylene glycol or polyethylene glycol may be
included.
[0122] For intravenous, cutaneous or subcutaneous injection, or
injection at the site of affliction, the active ingredient will be
in the form of a parenterally acceptable aqueous solution which is
pyrogen-free and has suitable pH, isotonicity and stability. Those
of ordinary skill in the art are well able to prepare suitable
solutions using, for example, isotonic vehicles such as Sodium
Chloride Injection, Ringer's Injection, Lactated Ringer's
Injection. Preservatives, stabilisers, buffers, antioxidants and/or
other additives may be included, as required.
[0123] The compounds of formulae (IA)-(IH) are believed to be
casein kinase 1 delta (CK1.delta.) inhibitors. Certain compounds of
formulae (IA)-(IH) have inhibitory activity of greater than 5%, in
particular greater than 10%, more particularly greater than 25%,
yet more particularly greater than 50%, especially greater than
75%, such as greater than 90%. Such compounds may be useful in the
treatment in neurodegenerative disorders such as tauopathies.
Tauopathies are conditions which are characterised by
neurofibrillary tangles or aggregates of the tau protein.
Tauopathies are a recognised class of conditions known to those
skilled in the art and include Alzheimer's disease, frontotemporal
dementia with Parkinsonism linked to chromosome 17 (FTDP-17),
progressive supranuclear palsy (PSP), Pick's disease, corticobasal
degeneration, multisystem atrophy (MSA), neurobasal degeneration
with iron accumulation, type 1 (Hallervorden-Spatz), argyrophilic
grain dementia, Down's syndrome, diffuse neurofibrillary tangles
with calcification, dementia pugilistica,
Gerstmann-Straussler-Scheinker disease, myotonic dystrophy,
Niemann-Pick disease type C, progressive subcortical gliosis, prion
protein cerebral amyloid angiopathy, tangle only dementia,
postencephalitic parkinsonism, subacute sclerosing panencephalitis,
Creutzfeldt-Jakob disease, amyotrophic lateral
sclerosis/parkinsonism-dementia complex, non-Guamanian motor neuron
disease with neurofibrillary tangles/dementia, and Parkinson's
disease. The intracellular tau deposits are usually neuronal or
glial and are filamentous and generally in a hyperphosphorylated
state as compared to the level of phosphorylation in tau from
control human brain. In the case of AD, this hyperphosphorylated
tau is often referred to a paired helical filament tau (PHF) tau
because it is derived from the PHF. In one embodiment, the
tauopathy comprises Alzheimer's disease.
[0124] According to a further aspect of the invention, there is
provided a method of treating a neurodegenerative disorder, such as
tauopathies, which comprises administering a therapeutically
effective amount of a compound of formulae (1A)-(1 H).
Biological Data
[0125] CK1.delta. Inhibition Assay The compounds of the invention
may be tested for inhibition of casein kinase 1 delta (CK1.delta.)
in accordance with the assay protocols described in US
2010/0152157, EP 1,636,375 or Hanger et al (2007) J. Biol. Chem.
282, 23645-23654. In particular, the assay was conducted in
accordance with the following protocol:
Reaction Buffer
[0126] Base Reaction buffer; 20 mM Hepes (pH 7.5), 10 mM MgCl2, 1
mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na3VO4, 2 mM DTT, 1%
DMSO
[0127] It should be noted that required cofactors are added
individually to each kinase reaction.
Reaction Procedure
[0128] 1. Prepare indicated substrate in freshly prepared Base
Reaction Buffer as described above
[0129] 2. Deliver any required cofactors to the substrate
solution
[0130] 3. Deliver indicated kinase into the substrate solution and
gently mix
[0131] 4. Deliver compounds in DMSO into the kinase reaction
mixture
[0132] 5. Deliver .sup.33P-ATP (specific activity 0.01 .mu.Ci/.mu.l
final) into the reaction mixture to initiate the reaction
[0133] 6. Incubate kinase reaction for 120 min. at room
temperature
[0134] 7. Reactions are spotted onto P81 ion exchange paper
(Whatman # 3698-915)
[0135] 8. Wash filters extensively in 0.75% Phosphoric acid
Kinase Information
[0136] CK1d--Genbank Accession # NP_620693
[0137] Recombinant human full-length construct. GST-tagged,
expressed in insect cells.
[0138] Final concentration in assay =4 nM
[0139] Substrate: CKltide
[0140] Substrate sequence: [KRRRAL[pS]VASLPGL]
[0141] Final substrate concentration in assay=20 .mu.M
[0142] It should be noted that no additional cofactors are added to
the reaction mixture.
[0143] Compounds 10, 25, 30, 42, 45, 205, 223, 240, 281-282, 288,
314, 321, 324-325, 336, 374, 391, 405, 439, 465, 506, 512, 567,
583, 611-616, 619, 623-624, 626, 631, 633, 639-640, 646, 654, 656,
660-661, 663, 668, 670, 672, 675-677, 682-683, 696-697, 700,
705-706, 717, 723, 727, 730, 736-737, 740, 748, 753-754, 756, 759,
761, 765-766, 768, 770, 780, 790, 797, 784, 808-810, 819-820,
822-823, 825, 830, 832-834, 842, 844, 847, 851, 856, 859-860, 863,
868-870, 872, 875, 881-882, 885-886, 888-890, 894, 931, 933, 935,
941, 946-958, 964-1000 and 1002 were tested in the CK1.delta.
inhibition assay and exhibited inhibition of greater than 5%.
[0144] In particular, compounds 10, 42, 45, 205, 240, 324-325, 405,
654, 656, 682, 700, 754, 766, 847, 856, 859, 863, 894, 931,
947-949, 951-952, 954, 964, 967, 972, 978-979, 986-987, 990, 997
and 999 exhibited inhibition of greater than 50%.
[0145] Yet more particularly, compounds 10, 324, 654, 856, 859,
931, 947, 952, 987, 990 and 999 exhibited inhibition of greater
than 90%.
TABLE-US-LTS-00001 LENGTHY TABLES The patent application contains a
lengthy table section. A copy of the table is available in
electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20160354375A1).
An electronic copy of the table will also be available from the
USPTO upon request and payment of the fee set forth in 37 CFR
1.19(b)(3).
* * * * *
References