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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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