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USOO900643OB2
(12) United States Patent
Berdini et al.
(10) Patent No.: US 9,006.430 B2
(45) Date of Patent:
Apr. 14, 2015
(54) ORTHO-CONDENSED PYRIDINE AND PYRIMIDINEDERIVATIVES (E.G., PURINES)
AS PROTEIN
(71) Applicants: Astex Therapeutics Limited, Cambridge (GB); The Institute of
Cancer Research: Royal Cancer Hospital, London (GB); Cancer Research Technology Limited, London (GB)
(72) Inventors: Valerio Berdini, Cambridge (GB); Robert George Boyle, Cambridge (GB);
Gordon Saxty, Cambridge (GB); David Winter Walker, Cambridge (GB); Steven John Woodhead, Cambridge (GB); Paul Graham Wyatt, Perth (GB);
Alastair Donald, Oxfordshire (GB); John Caldwell, Sutton (GB); Ian Collins, Sutton (GB); Tatiana Faria Da Fonseca, Sutton (GB)
(73) Assignees: Astex Therapeutics Limited, Cambridge (GB); The Institute of
Cancer Research: Royal Cancer Hospital, London (GB); Cancer Research Technology Limited, London
(GB)
(*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days.
(21) Appl. No.: 14/310,475
(22) Filed: Jun. 20, 2014
(65)
Prior Publication Data
US 2014/O3O3177 A1 Oct. 9, 2014
Related U.S. Application Data
(60) Continuation of application No. 14/017.814, filed on Sep. 4, 2013, now Pat. No. 8,809,336, which is a division of application No. 1 1/577.963, filed as application No. PCT/GB2005/004119 on Oct. 25,
2005, now Pat. No. 8,546,407.
(60) Provisional application No. 60/621,821, filed on Oct. 25, 2004, provisional application No. 60/684,119, filed on May 24, 2005.
(30)
Foreign Application Priority Data
Oct. 25, 2004 (GB) ................................... O423655.O
(51) Int. Cl.
CO7D 487/04 C07D 471/02 CO7D 47L/04 CO7D 473/34 A6 IK3 L/4545 A 6LX3/59 A6 IK3I/52 A6 IK3I/522
(2006.01) (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) (2006.01) (2006.01)
(52) U.S. Cl. CPC ............ C07D 471/04 (2013.01); C07D473/34 (2013.01); C07D 487/04 (2013.01); A61 K 3 1/4545 (2013.01); A61 K3I/519 (2013.01): A6 IK3I/52 (2013.01); A61 K3I/522 (2013.01)
(58) Field of Classification Search
USPC ........................................... 544/280:546/113
See application file for complete search history.
Primary Examiner -- Jeffrey H Murray
Assistant Examiner -- Oluwafemi Masha
(74) Attorney, Agent, or Firm -- Heslin Rothenberg Farley
& Mesiti P.C.
(57)
ABSTRACT
The invention provides a compound for use as a protein kinase B inhibitor, the compound being a compound of the
formula (I) or salts, solvates, tautomers or N-oxides thereof,
wherein T is N or CR: J'-J is N=C(R), (R)C--N, (R) N. C(O), (R),C C(O), N=N or (R7)C=C(R); E is a
monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroa
toms selected from O, NandS; Q is a bondora saturated C.
hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONR or NRCO where R is hydrogen or methyl, or R is a C alkylene chain linked to R or a carbon
atom of Q' to form a cyclic moiety; and wherein the carbon atoms of the linker group Q' may optionally bear one or more substituents selected from fluorine and hydroxy; Q is a bond
or a saturated hydrocarbon linker group containing from 1 to
3 carbonatoms, wherein one of the carbonatoms in the linker group may optionally be replaced by an oxygen or nitrogen
atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluo rine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the G
group; andprovided that when E is arylorheteroaryl, then Q is other than a bond; G is hydrogen, NRR, OH or SH provided that when E is aryl or heteroaryland Q is a bond, then G is hydrogen; R' is hydrogen or an aryl or heteroaryl group, with the proviso that when R' is hydrogen and G is NRR, then Q is a bond; and R. R. R. R. and Rare as
defined in the claims.
(I)
R-QN-o-G
21 N.
1s /
R4 N
H
20 Claims, No Drawings
US 9,006,430 B2
1.
2
ORTHO-CONDENSED PYRONE AND
a metabolic enzyme, regulatory protein, receptor, cytoskel
PYRIMIDINE DERIVATIVES (E.G., PURINES)
AS PROTEIN
CROSS REFERENCE TO RELATED
etal protein, ion channel or pump, or transcription factor.
Uncontrolled signalling due to defective control of protein phosphorylation has been implicated in a number ofdiseases, including, for example, inflammation, cancer, allergy/
APPLICATIONS
asthma, diseases and conditions of the immune system, dis
eases and conditions of the central nervous system, and
This application is a continuation of U.S. application Ser. angiogenesis.
No. 14/017.814, filed on Sep. 4, 2013 (published as U.S. Apoptosis or programmed cell death is an important physi
2014-0107137 A1 on Apr. 17, 2014), which is a divisional of 10 ological process which removes cells no longer required by U.S. application Ser. No. 1 1/577.963 (published as U.S. an organism. The process is important in early embryonic
2009-024.7538 A1 on Oct. 1, 2009), and issued as U.S. Pat. growth and development allowing the non-necrotic con
No. 8,546.407 on Oct. 1, 2013, which was a filing under 35 U.S.C. S371 of PCT International Application No. PCT/ GB2005/004119 filed Oct. 25, 2005 (published in English as
WO 2006/046024 on May 4, 2006, which claimed priority to GB Application No. 0423655.0 filed Oct. 25, 2004, to U.S.
Provisional Application No. 60/621,821 filed Oct. 25, 2004, and to U.S. Provisional Application No. 60/684,119 filed
15
trolled breakdown, removal and recovery of cellular compo nents. The removal of cells by apoptosis is also important in
the maintenance of chromosomal and genomic integrity of growing cell populations. There are several known check points in the cell growth cycle at which DNA damage and genomic integrity are carefully monitored. The response to
May 24, 2005. The entire disclosures of each of the prior the detection of anomalies at Such checkpoints is to arrest the
applications are hereby incorporated herein by reference. growth ofsuch cells and initiate repair processes. Ifthe dam
age oranomalies cannot be repaired then apoptosis is initiated
TECHNICAL FIELD
by the damaged cell in order to prevent the propagation of
faults and errors. Cancerous cells consistently contain numer
This invention relates to purine, purinone and deaZapurine 25 ous mutations, errors or rearrangements in their chromo
and deazapurinone compounds that inhibit or modulate the somal DNA. It is widely believed that this occurs in part
activity of protein kinase B (PKB) and protein kinase A because the majority of tumours have a defect in one or more
(PKA), to the use of the compounds in the treatment or of the processes responsible for initiation of the apoptotic
prophylaxis of disease states or conditions mediated by PKB process. Normal control mechanisms cannot kill the cancer
and PKA, and to novel compounds having PKB and PKA 30 ous cells and the chromosomal or DNA coding errors con
inhibitory or modulating activity. Also provided are pharma tinue to be propagated. As a consequence restoring these
ceutical compositions containing the compounds and novel pro-apoptotic signals or Suppressing unregulated Survival sig
chemical intermediates.
nals is an attractive means of treating cancer.
The signal transduction pathway containing the enzymes
BACKGROUND OF THE INVENTION
35 phosphatidylinositol 3-kinase (PI3K), PDK1 and PKB
amongst others, has long been known to mediate increased
Protein kinases constitute a large family of structurally resistance to apoptosis or Survival responses in many cells.
related enzymes that are responsible for the control of a wide There is a substantial amount of data to indicate that this
variety of signal transduction processes within the cell (Har pathway is an important Survival pathway used by many
die, G. and Hanks, S. (1995) The Protein Kinase Facts Book. 40 growth factors to Suppress apoptosis. The enzymes of the
I and II, Academic Press, San Diego, Calif.). The kinases may PI3K family are activated by a range of growth and survival
be categorized into families by the substrates they phospho factors e.g. EGF, PDGF and through the generation of poly
rylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, phosphatidylinositols, initiates the activation of the down
etc.). Sequence motifs have been identified that generally stream signalling events including the activity of the kinases
correspond to each of these kinase families (e.g., Hanks, S. 45 PDK1 and protein kinase B (PKB) also known as akt. This is
K., Hunter, T., FASEB 1, 9:576-596 (1995); Knighton, et al., also true in host tissues, e.g. Vascular endothelial cells as well
Science, 253:407-414 (1991); Hiles, et al., Cell, 70:419?429 as neoplasias. PKB is a protein ser/thrkinase consisting of a
(1992); Kunz, et al., Cell, 73:585-596 (1993); Garcia-Bustos, kinase domain together with an N-terminal PH domain and
et al., EMBO.J., 13:2352-2361 (1994)).
C-terminal regulatory domain. The enzyme PKB (akt1)
Protein kinases may be characterized by their regulation 50 itself is phosphorylated on Thr308 by PDK1 and on Ser 473
mechanisms. These mechanisms include, for example, auto by a kinase referred to as PDK2, whereas PKB (akt2) is
phosphorylation, transphosphorylation by otherkinases, pro phosphorylated on Thr 309 and on Ser 474, and PKBganana
tein-protein interactions, protein-lipid interactions, and pro (akt3) is phosphorylated on Thr 305 and on Ser 472.
tein-polynucleotide interactions. An individual protein At least 10 kinases have been suggested to function as a Ser
kinase may be regulated by more than one mechanism. 55 473 kinase including mitogen-activated protein (MAP)
Kinases regulate many different cell processes including, kinase-activated protein kinase-2 (MK2), integrin-linked
but not limited to, proliferation, differentiation, apoptosis, kinase (ILK), p38 MAP kinase, protein kinase Calpha (PK
motility, transcription, translation and other signalling pro Calpha), PKCbeta, the NIMA-related kinase-6 (NEK6), the
cesses, by adding phosphate groups to target proteins. These mammalian target of rapamycin (mTOR), the double
phosphorylation events act as molecular on/off Switches that 60 stranded DNA-dependent protein kinase (DNK-PK), and the
can modulate or regulate the target protein biological func ataxiatelangiectasia mutated (ATM) gene product. Available
tion. Phosphorylation of target proteins occurs in response to data Suggest that multiple systems may be used in cells to
a variety of extracellular signals (hormones, neurotransmit regulate the activation of PKB. Full activation of PKB
ters, growth and differentiation factors, etc.), cell cycle requires phosphorylation at both sites whilst association
events, environmental or nutritional stresses, etc. The appro 65 between PIP3 and the PH domain is required for anchoring of
priate protein kinase functions in signalling pathways to acti the enzyme to the cytoplasmic face of the lipid membrane
vate or inactivate (either directly or indirectly), for example, providing optimal access to Substrates.
US 9,006,430 B2
3
4
Activated PKB in turns phosphorylates a range of sub tiple Sclerosis and arthritis. Expansion of lymphocyte
strates contributing to the overall survival response. Whilst populations responding inappropriately to foreign antigens is
we cannot be certain that we understand all of the factors a feature of another set of conditions such as allergic
responsible for mediating the PKB dependent survival responses and asthma. In summary inhibition of PKB could
response, some important actions are believed to be phospho provide a beneficial treatment for immune disorders.
rylation and inactivation of the pro-apoptotic factor BAD and Other examples of inappropriate expansion, growth, pro
caspase 9, phosphorylation of Forkhead transcription factors liferation, hyperplasia and survival of normal cells in which
e.g. FKHR leading to their exclusion from the nucleus, and activation of the NfkappaB pathway by phosphorylation of
upstream kinases in the cascade. In addition to the anti-apoptotic and pro-Survival actions of
the PKB pathway, the enzyme also plays an important role in promoting cell proliferation. This action is again likely to be
mediated via several actions, some of which are thought to be phosphorylation and inactivation of the cyclin dependent
10 15
PKB may play a role include but are not limited to athero Sclerosis, cardiac myopathy and glomerulonephritis.
In addition to the role in cell growth and survival, the PKB pathway functions in the control of glucose metabolism by
insulin. Available evidence from mice deficient in the alpha and beta isoforms of PKB suggests that this action is mediated by the beta isoform primarily. As a consequence, modulators
kinase inhibitor of p21 '''', and phosphorylation and of PKB activity may also find utility in diseases in which there
activation of mTOR, a kinase controlling several aspects of is a dysfunction of glucose metabolism and energy storage
cell size, growth and protein translation.
Such as diabetes, metabolic disease and obesity.
The phosphatase PTEN which dephosphorylates and inac Cyclic AMP-dependent protein kinase (PKA) is a serine/
tivates polyphosphatidyl-inositols is a key tumour Suppressor threonine protein kinase that phosphorylates a wide range of
protein which normally acts to regulate the PI3K/PKB sur Substrates and is involved in the regulation of many cellular
vival pathway. The significance of the PI3K/PKB pathway in processes including cell growth, cell differentiation, ion
tumourigenesis can be judged from the observation that channel conductivity, gene transcription and synaptic release
PTEN is one of the most common targets of mutation in of neurotransmitters. In its inactive form, the PKA holoen
human tumours, with mutations in this phosphatase having 25 Zyme is a tetramer comprising two regulatory subunits and
been found in ~50% or more of melanomas (Guldberg et al two catalytic subunits.
1997, Cancer Research 57, 3660-3663) and advanced pros PKA acts as a link between G-protein mediated signal
tate cancers (Cairns et al 1997 Cancer Research 57, 4997). transduction events and the cellular processes that they regu
These observations and others suggest that a wide range of late. Binding of a hormone ligand Such as glucagon to a
tumour types are dependent on the enhanced PKB activity for 30 transmembrane receptor activates a receptor-coupled G-pro
growth and Survival and would respond therapeutically to tein (GTP-binding and hydrolyzing protein). Upon activa
appropriate inhibitors of PKB.
tion, the alpha subunit of the G protein dissociates and binds
There are 3 closely related isoforms of PKB called alpha, to and activates adenylate cyclase, which in turn converts ATP
beta and gamma, which genetic studies suggest have distinct to cyclic-AMP (cAMP). The cAMP thus produced then binds
but overlapping functions. Evidence Suggests that they can all 35 to the regulatory subunits of PKA leading to dissociation of
independently play a role in cancer. For example PKB beta the associated catalytic Subunits. The catalytic Subunits of
has been found to be over-expressed or activated in 10-40% of PKA, which are inactive when associated with the regulatory
ovarian and pancreatic cancers (Bellacosa et al 1995, Int. J. Sub-units, become active upon dissociation and take part in
Cancer 64,280?285; Cheng etal 1996, PNAS 93,3636-3641: the phosphorylation of other regulatory proteins.
Yuan et al 2000. Oncogene 19, 2324-2330), PKB alpha is 40 For example, the catalytic sub-unit of PKA phosphorylates
amplified in human gastric, prostate and breast cancer (Staal the kinase Phosphorylase Kinase which is involved in the
1987, PNAS 84,5034-5037; Sun et al 2001, Am. J. Pathol. phosphorylation of Phosphorylase, the enzyme responsible
159, 431-437) and increased PKB gamma activity has been for breaking down glycogen to release glucose. PKA is also
observed in steroid independent breast and prostate cell lines involved in the regulation of glucose levels by phosphorylat
(Nakatani et al 1999, J. Biol. Chem. 274, 21528-21532). 45 ing and deactivating glycogen synthase. Thus, modulators of
The PKB pathway also functions in the growth and survival PKA activity (which modulators may increase or decrease
ofnormal tissues and may be regulated during normal physi PKA activity) may be useful in the treatment or management
ology to control cell and tissue function. Thus disorders asso of diseases in which there is a dysfunction of glucose metabo
ciated with undesirable proliferation and survival of normal lism and energy storage such as diabetes, metabolic disease
cells and tissues may also benefit therapeutically from treat 50 and obesity.
ment with a PKB inhibitor. Examples of such disorders are PKA has also been established as an acute inhibitor of T
disorders of immune cells associated with prolonged expan cell activation. Anndahl et al., have investigated the possible
sion and Survival ofcell population leading to a prolonged or role ofPKA type I in HIV-induced T cell dysfunction on the
up regulated immune response. For example, T and B lym basis that T cells from HIV-infected patients have increased
phocyte response to cognate antigens or growth factors such 55 levels of cAMP and are more sensitive to inhibition by cAMP
as interferon gamma activates the PI3K/PKB pathway and is analogues than are normal T cells. From their studies, they
responsible for maintaining the Survival of the antigen spe concluded that increased activation of PKA type I may con
cific lymphocyte clones during the immune response. Under tribute to progressive T cell dysfunction in HIV infection and
conditions in which lymphocytes and other immune cells are that PKA type I may therefore be a potential target for immu
responding to inappropriate self or foreign antigens, or in 60 nomodulating therapy.--Aandahl, E. M., Aukrust, P. Skal
which other abnormalities lead to prolonged activation, the hegg, B.S., M?ller, F. Froland, S.S., Hansson, V., Task?n, K.
PKB pathway contributes an important survival signal pre Protein kinase A type I antagonist restores immune responses
venting the normal mechanisms by which the immune of T cells from HIV-infected patients. FASEB.J. 12, 855-862
response is terminated via apoptosis of the activated cell (1998).
population. There is a considerable amount of evidence dem 65 It has also been recognised that mutations in the regulatory onstrating the expansion oflymphocyte populations respond sub-unit of PKA can lead to hyperactivation in endocrine
ing to self antigens in autoimmune conditions such as mul tissue.
US 9,006,430 B2
5
6
Because of the diversity and importance of PKA as a mes U.S. Pat. No. 6,162,804 (Merck) discloses a class of ben
senger in cell regulation, abnormal responses of cAMP can Zimidazole and aza-benzimidazole compounds that have
lead to a variety of human diseases derived from this, Such as tyrosine kinase inhibitor activity.
irregular cell growth and proliferation (Stratakis, C.A.: Cho
Chung, Y. S.; Protein Kinase A and human diseases. Trends
SUMMARY OF THE INVENTION
Endrocri. Metab. 2002, 13, 50-52). Over-expression of PKA
has been observed in a variety of human cancer cells includ ing those from ovarian, breast and colon patients. Inhibition of PKA would therefore bean approach to treatment of cancer (Li, Q.: Zhu, G-D.: Current Topics in Medicinal Chemistry,
2002, 2,939-971). For a review of the role of PKA in human disease, see for
example, Protein Kinase A and Human Disease, Edited by
10
The invention provides compounds that have protein
kinase B (PKB) and/or protein kinase A (PKA) inhibiting or modulating activity, and which it is envisaged will be useful
in preventing or treating disease states or conditions mediated by PKB and/or PKA.
Accordingly, in one aspect, the invention provides a com pound for use as a protein kinase B inhibitor, the compound being a compound of the formula (I):
Constantine A. Stratakis, Annals of the NewYork Academy of 15
Sciences, Volume 968, 2002, ISBN 1-57331-412-9.
PRIOR ART
(I)
R-Q-o-G
Several classes ofcompounds have been disclosed as hav
ing PKA and PKB inhibitory activity. For example, a class of isoquinolinyl-Sulphonamido-di
amines having PKB inhibitory activity is disclosed in WO
ra R
1s /
01/91754 (Yissum).
H
WO 93/13072 (Ital farmaco) discloses a class of bis-sul 25
phonamido diamines as protein kinase inhibitors.
or salts, solvates, tautomers or N-oxides thereof, wherein
WO 99/65909 (Pfizer) discloses a class of pyrrole 2,3-d T is N or a group CR; pyrimidine compounds having protein tyrosine kinase activ J'-J represents a group selected from N=C(R), (R)
ity and which are of potential use as immunosuppressant
agents.
30
WO 2004/074287 (Astra Zeneca) discloses piperazinyl
pyridyl amides for use in treating autoimmune diseases Such
as arthritis. The piperazine group in the compounds can be
linked to a purine group. WO02/18348 (F. Hoffman La Roche) discloses a class of 35
amino-quinazoline derivatives as alpha-1 adrenergic antago
nists. A method for preparing the amino-quinazoline com
pounds involves the use of a gem-disubstituted cyclic amine
Such as piperidine in which one of the gem Substituents is an 40 aminomethyl group.
WO03/088908 (Bristol Myers Squibb) discloses N-het eroaryl-4,4-disubstituted piperidines as potassium channel
C--N, (R)N C(O), (R)C C(O), N=N and (R7) C?C(R):
E is a monocyclic carbocyclic or heterocyclic group of 5 or
6 ring members wherein the heterocyclic group contains
up to 3 heteroatoms selected from O, N and S;
Q' is a bond or a saturated hydrocarbon linker group con
taining from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom, or an adjacent
pair of carbon atoms may be replaced by CONR or NRCO where R is hydrogen, C alkyl or cyclopro
pyl, or R is a C alkylene chain that links to R' or to another carbon atom of Q' to form a cyclic moiety; and wherein the carbon atoms of the linker group Q' may
optionally bear one or more substituents selected from
inhibitors.
fluorine and hydroxy:
WO01/07050 (Schering) discloses substituted piperidines 45 Q is a bond or a saturated hydrocarbon linker group con
as nociceptin receptor ORL-1 agonists for use in treating cough.
taining from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be
US 2003/0139427 (OSI) discloses pyrrolidine- and piperi
replaced by an oxygen or nitrogenatom; and wherein the
dine-substituted purines and purine analogues having
carbon atoms of the linker group may optionally bear
adenosine receptor binding activity.
50 one or more substituents selected from fluorine and
WO 2004/043380 (Harvard College et al.) discloses tech
hydroxy, provided that the hydroxy group when present
netium and rhenium labelled imaging agents containing dis
is not located at a carbon atom C. with respect to the G
ubstituted piperidine metal ion-chelating ligands.
group;
WO97/38665 (Merck) discloses gem-disubstituted piperi G is selected from hydrogen, NRR, OH and SH with the
dine derivatives having farnesyl transferase inhibitory activ 55 proviso that when E is aryl or heteroaryl and Q is a
ity.
bond, then G is hydrogen;
EP 1568699 (Eisai) discloses 1,3-dihydroimidazole fused R" is hydrogen or an aryl or heteroaryl group, with the
ring compounds having DPPIV-inhibiting activity. The com
proviso that when R' is hydrogen and G is NRR, then
pounds are described as having a range of potential uses
Q is a bond;
including the treatment of cancer.
60 RandR are independently selected from hydrogen; C.
US 2003/0073708 and US 2003/045536 (both in the name
hydrocarbyl and C acyl wherein the hydrocarbyl and
of Castelhano et al), WO 02/057267 (OSI Pharmaceuticals)
acyl groups are optionally Substituted by one or more
and WO99/62518 (Cadus Pharmaceutical Corporation) each
Substituents selected from fluorine, hydroxy, cyano,
disclose a class of 4-aminodeazapurines in which the 4-amino
amino, methylamino, dimethylamino, methoxy and a
group can form part of a cyclic amine Such as aZetidine, 65 monocyclic or bicyclic aryl or heteroaryl group;
pyrrolidine and piperidine, The compounds are described as or RandR together with the nitrogenatom to which they
having adenosine receptor antagonist activity.
are attached form a cyclic group selected from an imi
US 9,006,430 B2
7
8
dazole group and a saturated monocyclic heterocyclic
group having 4-7 ring members and optionally contain
ing a second heteroatom ring member selected from O
and N:
or one of R and R together with the nitrogen atom to
which they are attached and one or more atoms from the
group Q form a saturated monocyclic heterocyclic
group having 4-7 ring members and optionally contain
ing a second heteroatom ring member selected from O
and N:
10
or NR'R' when present and a carbonatom of linker group
Q' to which it is attached together form a cyano group:
and
R. Rand Rareeach independently selected from hydro
gen, halogen, Cs saturated hydrocarbyl, cyano, 15
CONH CONHR, CF, NH, NHCOR and
NHCONHR:
RandR are each independently selected from hydrogen,
halogen, Cs saturated hydrocarbyl, cyano and CF;
Risphenylorbenzyl eachoptionally substitutedby one or
Substituents selected from halogen, hydroxy, trifluo
romethyl, cyano, nitro, carboxy, amino, mono- or
di-Ca hydrocarbylamino; a group R-R wherein R is
a bond, O, CO, X'C(X), C(X)X, XCCX)X', S, SO,
SO, NR, SONR or NRSO; and R is selected from 25
hydrogen, heterocyclic groups having from 3 to 12 ring
members, and a Cls hydrocarbyl group optionally Sub
stituted by one or more substituents selected from
hydroxy, Oxo, halogen, cyano, nitro, carboxy, amino,
mono- or di-Ca hydrocarbylamino, carbocyclic and 30
heterocyclic groups having from 3 to 12 ring members
and wherein one or more carbonatoms of the Chydro
carbyl group may optionally be replaced by O, S, SO,
SO, NR, X'C(X), C(X)X' or XCCX)X';
R is selected from hydrogen and Ca hydrocarbyl, and 35
X' is O, S or NR and X is ?O,-S or -NR.
In a further aspect, the invention provides a compound for
use as a protein kinase B inhibitor, the compound being a
compound of the formula (Ia):
G ipsrosevliescotetdhaftrwomhehnydrEogisena,ryNlRorRh,etOerHoaarynld aSnHdwQithitshae
bond, then G is hydrogen;
R" is hydrogen or an aryl or heteroaryl group, with the proviso that when R' is hydrogen and G is NRR, then
RaQndisRa baornedi;ndependently selected from hydrogen; C.
hydrocarbyl and C acyl wherein the hydrocarbyl and acyl groups are optionally Substituted by one or more Substituents selected from fluorine, hydroxy, amino, methylamino, dimethylamino, methoxy and a monocy clic or bicyclic aryl or heteroaryl group;
or RandR together with the nitrogenatom to which they
are attached form a cyclic group selected from an imi dazole group and a saturated monocyclic heterocyclic group having 4-7 ring members and optionally contain ing a second heteroatom ring member selected from O and N:
or one of R and R together with the nitrogen atom to
which they are attached and one or more atoms from the
group Q form a saturated monocyclic heterocyclic
group having 4-7 ring members and optionally contain ing a second heteroatom ring member selected from O and N:
or NR'R' when present and a carbon atom of linker group Q' to which it is attached together form a cyano group:
and
R. Rand Rare each independently selected from hydro
gen, halogen, Cls Saturated hydrocarbyl, cyano,
CONH CONHR, CF, NH, NHCOR and NHCONHR: RandR are each independently selected from hydrogen,
halogen, Cs saturated hydrocarbyl, cyano and CF;
Risphenylor benzyl each optionally substituted by one or
Substituents selected from halogen, hydroxy, trifluo romethyl, cyano, nitro, carboxy, amino, mono- or
di-C, a hydrocarbylamino; a group R-R wherein R is a bond, O, CO, XCCX), C(X)X, XCCX)X', S, SO, SO, NR, SONR or NRSO, and R is selected from
hydrogen, heterocyclic groups having from 3 to 12 ring
members, and a Cs hydrocarbyl group optionally Sub
40 stituted by one or more substituents selected from
hydroxy, Oxo, halogen, cyano, nitro, carboxy, amino,
R-QS -Q-G
(Ia)
mono- or di-Ca hydrocarbylamino, carbocyclic and
heterocyclic groups having from 3 to 12 ring members
and wherein one or more carbonatoms of the Cs hydro
ra R
1s / H
45 carbyl group may optionally be replaced by O, S, SO,
SO, NR, X'C(X), C(X)X' or X'C(X)X';
R is selected from hydrogen and Ca hydrocarbyl, and X is O, S or NR and X is ?O, -S or -NR. In another aspect, the invention provides a compound for
50 use as a protein kinase B inhibitor, the compound being a
or salts, solvates, tautomers or N-oxides thereof, wherein
T is N or a group CR;
compound of the formula (Ib):
J-J represents a group selected from N=C(R), (R)
C--N, (R)N C(O), (R),C C(O), N=N and (R7)
C?C(R):
E is a monocyclic carbocyclic or heterocyclic group of 5 or
55
R-QS -Q-G
(Ib)
6 ring members wherein the heterocyclic group contains
up to 3 heteroatoms selected from O, N and S;
Q' and Q are the same or different and are each a bond or
a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in 60 the linker group may optionally be replaced by an oxy
ra J.\
1s /
R4 N
H
gen or nitrogen atom; and wherein the carbon atoms of
the or each linker group Q' and Q may optionally bear or salts, solvates, tautomers or N-oxides thereof, wherein one or more substituents selected from fluorine and T is N or a group CR;
hydroxy, provided that the hydroxy group when present 65 J'-J represents a group selected from N=C(R), (R)
is not located at a carbon atom C. with respect to the G
C--N, (R)N C(O), (R)C C(O), N=N and (R7)
group;
C?C(R):
................
................
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