GB2431156A - 1-cyclyl-3-substituted- -benzenes and -azines as inhibitors of phosphatidylinositol 3-kinase - Google Patents

Abstract

A compound which is an arylamine of formula (I): <EMI ID=1.1 HE=42 WI=52 LX=457 LY=163 TI=CF> <SL> <LI>wherein R<6> and R<7> form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and <EMI ID=1.2 HE=17 WI=36 LX=538 LY=772 TI=CF> <LI>wherein Y is a C2 - C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from O, N and S, and which is unsubstituted or substituted; R<2> is-LR<21> wherein L is selected from a direct bond, -O-, -CR'R''- and - NR'- wherein R' and R'' are each, independently, H or C1-C6 alkyl and R<21> is selected from: </SL> <SL> <LI>(a') a group of the following formula: <EMI ID=1.3 HE=14 WI=13 LX=799 LY=1297 TI=CF> wherein B is a phenyl ring which is unsubstituted or substituted <LI>(b') a heteroaryl group as defined; and <LI>(c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined X<1> and X<2> are each, independently, N or CH; and either </SL> <SL> <LI>(a'') one of X<3> and X<4> is CR<3> and the other is N or CR<3>, wherein R<3> is H, C1-C6 alkyl or a group of formula (II): <EMI ID=1.4 HE=20 WI=30 LX=708 LY=1883 TI=CF> wherein m is 0 or 1; R<4> and R<5> form, together with the N atom to which they are attached, a ring as defined; or one of R<4> and R<5> is alkyl and the other is a 5- or 6-membered saturated N-containing heterocyclic group as defined or an alkyl group which is substituted by such a heterocyclic group; or <LI>(b'') X<3> and X<4> are each CR<6> wherein the groups R<6> form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring and a 5-or 6-membered group containing 1 or 2 N atoms, which ring is substituted by a group R<3> as defined above; </SL> or a pharmaceutically acceptable salt thereof; with certain provisos] has activity as inhibitors of PI3K and may thus be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation metabolism/endocrine disorders and neurological disorders.

Description

PHARMACEUTICAL COMPOUNDS

Field of the Invention

The present invention relates to arylamines and to their use as inhibitors of phosphati dylinositol 3 -kinase (P13K).

Background to the Invention

Phosphatidylinositol (hereinafter abbreviated as "P1") is one of a number of phospholipids found in cell membranes. In recent years it has become clear that P1 plays an important role in intracellular signal transduction. In the late 1980s, a P13 kinase (P13K) was found to be an enzyme which phosphorylates the 3-position of the inositol ring of phosphatidylinositol (D. Whitman et al, 1988, Nature, 332, 664).

P13K was originally considered to be a single enzyme, but it has now been clarified that a plurality of subtypes are present in P13 K. Each subtype has its own mechanism for regulating activity. Three major classes of PI3Ks have been identified on the basis of their in vitro substrate specificity (B. Vanhaesebroeck,1997, Trend in Biol. Sci, 22, 267). Substrates for class I PI3Ks are P1, P1 4-phosphate (PI4P) and P1 4,5-biphosphate (PT (4,5)P2). Class I PI3Ks are further divided into two groups, class Ta and class Tb, in terms of their activation mechanism. Class Ta PI3Ks include P13K p11 Oa, p1 1 0f3 and pllO subtypes, which transmit signals from tyrosine kinase-coupled receptors. Class lb P13K includes a pilOy subtype activated by a G protein-coupled receptor. PT and PI(4)P are known as substrates for class II PI3Ks. Class TT PI3Ks include P13K C2a, C213 and C2y subtypes, which are characterized by containing C2 domains at the C terminus. The substrate for class III PI3Ks is P1 only.

In the P13K subtypes, the class Ia subtype has been most extensively investigated to date. The three subtypes of class Ta are heterodimers of a catalytic 110 kDa subunit and regulatory subunits of 85 kDa or 55 kDa. The regulatory subunits contain SH2 domains and bind to tyrosine residues phosphorylated by growth factor receptors with a tyrosine kinase activity or oncogene products, thereby inducing the P13K activity of the p110 catalytic subunit which phosphorylates its lipid substrate. Thus, the class Ta subtypes are considered to be associated with cell proliferation and carcinogenesis.

WO 01/083456 and W02004/048365 describe hcteroary] derivatives which have activity as inhibitors of P13 K and which suppress cancer cell growth.

Summary of the Invention

It has now been found that a novel class of arylamine compounds are effective inhibitors of P13 K, with drug-like physicochemical and pharmacokinetic properties. The compounds exhibit selectivity for class Ia PI3Ks over class lb. Accordingly, the present invention provides a compound which is an aryl amine of formula (I): R1 (I) X R2 wherein R' is selected from: (a) R6 - N" R7 wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and (b) CH2 wherein Y is a C2 - C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, I or 2 heteroatoms selected from 0, N and S, and which is unsubstituted or substituted; R2 is -LR2' wherein L is selected from a direct bond, -0-, -CR'R"- and - NR'- wherein R' and R" are each, independently, H or C1-C6 alkyl and R2' is selected from: (a') a group of the following formula: z wherein B is a benzene ring which is unsubstituted or substituted and Z is selected from OR, CH2OR, CO2R, CF2OH, CH(CF3)OH, C(CF3)20F1, (CH2)qOR and (CH2)qNR2 wherein each R is independently H or alkyl and q is 0, 1 or 2; (b') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; X' and X2 are each, independently, N or CH; and either (a") one of X3 and X4 is CR3 and the other is N or CR3, wherein R3 is H, C1-C6 alkyl or a group of formula (11): (II) R4 )J -ECH2--

R (II)

wherein mis 0 or 1; and R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and 0, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N- containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated Ncontaining heterocyclic group as defined above; or (b") X3 and X4 are each CR6 wherein the groups R6 form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring and a 5- or 6-membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above; or a pharmaceutically acceptable salt thereof with the provisos that: (i) when R' is morpholine, X1 is N, X2 is CFI, X3 is CR3 and X4 is N, then R3 is H or C1-C6 alkyl; and (ii) when R1 is morpholine, X1 and X2 are both N and X3 and X4 are both CR6 in which the groups R6 form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring and a 5- or 6- membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above, then R3 is a group of formula (II) as defined above.

Detailed description of the Invention

As specified herein, an alkyl group is a straight or branched chain saturated hydrocarbon radical which is unsubstituted or substituted, for instance by one or more groups Z as defined above or R2 as defined below. Typically it is C1-C20 alkyl, for instance C1-C10 alkyl, such as C1-C6 alkyl or C1-C4 alkyl, for example methyl, ethyl, i-propyl, n-propyl, tbutyl, s-butyl or n-butyl. It may also be pentyl, hexyl, heptyl, octyl and the various branched chain isomers thereof.

R2 is selected from halogen, alkoxy, carbocyclyl, a 5- or 6-membered saturated N-containing heterocyclic group as defined above, OH, SR, CN, nitro, NR2 -COOR, -C(O)R, S(O)1R and -CONR2, wherein each R is H, unsubstituted alkyl or C3-C10 cycloalkyl and m is I or 2. It is, for instance, a haloalkyl group or a group - alk-N(R4)(R5) wherein alk is an alkylene chain and R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and 0, which may be fused to a benzene ring and which is unsubstituted or An alkylene group is unsubstituted or substituted, straight or branched chain saturated divalent hydrocarbon group. Typically it is C1-C8 alkylene, for instance C1-C6 alkylene. Preferably it is C1-C4 alkylene, for example C2-C4 alkylene, such as methylene, ethylene, i-propylene, n-propylene, tbutylene, s-butylene or n-butylene.

It may also be pentylene, hexylene, heptylene, octylene and the various branched chain isomers thereof. When the alkylene group is substituted it is typically substituted by a group Z or R2 as defined above.

An alkenyl group is an unsubstituted or substituted, straight or branched chain hydrocarbon radical having one or more double bonds. Typically it is C2-C8 alkenyl, for instance C2-C6 alkenyl, such as allyl, butenyl, butadienyl, pentenyl or hexenyl. When the alkenyl group is substituted it is typically substituted by a group Z or R2 as defined above.

An alkynyl group is an unsubstituted or substituted, straight or branched chain hydrocarbon radical having one or more triple bonds. Typically it is C2-C8 alkynyl, for instance C2-C6 alkynyl, such as ethynyl, propynyl or butynyl. When the alkynyl group is substituted it is typically substituted by a group Z or R2 as defined above.

A haloalkyl group is an alkyl group as defined above, substituted by one or more halogen atoms. It can be a perhaloalkyl group, for instance trifluoromethyl or perfluorohexyl.

A halogen is chlorine, fluorine, bromine or iodine. It is typically bromine or iodine.

An alkoxy group is typically C1-C6 alkoxy, for instance C1-C4 alkoxy, such as methoxy, ethoxy, i-propoxy, n-propoxy, t-butoxy, n-buloxy or s- butoxy. It is unsubstituted or substituted, for instance by a group Z or R2 as defined above.

Typically it is substituted by carhocyclyl, morpholino, Oil, CN, NR2, COOR or - CONR2, wherein each R is H or unsubstituted alkyl as defined above.

A carbocyclyl group is a non-aromatic saturated or unsaturated monocyclic hydrocarbon ring, typically having from 3 to 10 carbon atoms. It may be a C3-C8 cycloalkyl group, or C5-C10 cycloalkyl group, for instance cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Alternatively it may be a cycloalkenyl group, typically C4-C8 cycloalkenyl, for instance cylcopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclohepadienyl, cyclooctenyl or cyclooctadienyl. A carbocyclyl group may be unsubstituted or substituted, for instance by a group Z or R2 as defined above. Typically it is substituted by alkoxy, morpholino, OH, CN, NR2, -COOR and -CONR2, wherein each R is H or unsubstituted alkyl as defined above.

A 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and 0, which may be fused to a benzene ring and which is unsubstituted or substituted is typically selected from morpholine, piperidine, piperazine, pyrrolidine, thiomorpholine, quinoline, isoquinoline, diazepane, oxazepane and thiazepane.

When a 5- or 6-membered saturated N-containing heterocyclic group as defined above is substituted it may be substituted by a group Z or R2 as defined above. Typically it is substituted by alkyl which is unsubstituted or substituted, hydroxyalkyl, alkoxy which is unsubstituted or substituted, a second 5- or 6- membered saturated N-containing heterocyclic group as defined above, a 5- or 6- membered N-containing heteroaryl group which is unsubstituted or substituted and which may be fused to a benzene ring, -COOR, -CONR2, -CONR, oxo (=0), OH, - NSO2R, -SO2NR2 or -CO(CH2)OR wherein R is H or alkyl, -NR'R" wherein each of R' and R" is independently H, alkyl or alkoxy, and -S02R" wherein R" is alkyl which is unsubstituted or substituted, for instance by NR2 or a 5- or 6-membered saturated N-containing heterocyclic group as defined above.

A 5-, 6- or 7-membered saturated heterocyclic group which contains 1 or 2 heteroatoms selected from N, S and 0 and which is unsubstituted or substituted is typically selected from tetrahydropyran, tetrahydrothiopyran, tetrahydrofuran and tetrahydrothiofuran.

When a 5-, 6- or 7-membered saturated heterocyclic group which contains I or 2 heteroatoms selected from N, S and 0 is substituted it may be substituted by a group Z or R2 as defined above. Typically it is substituted by one or more substituents selected from alkyl as defined above which is unsubstituted or substituted by a group R2 as defined above, haloalkyl as defined above, alkoxy as defined above which is unsubstituted or substituted, halogen, hydroxy, CN, nitro, amino, oxo (=0) , and -NR'R" wherein each of R' and R" is independently H or alkyl.

A heteroaryl group is a heteroaryl group which contains 1, 2 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0, N and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted. It is typically a 5- to I 2-membered ring. Examples of a heteroaryl group include pyrrole, pyrazole, triazole, tetrazole, indazole, thiazole, isothiazole, oxazole, isooxazole, indole, isoindole, 1,3 dihydro-indol-2-one, pyridine-2-one, pyridine, pyridin-3 -ol, imidazole, 1,3 -dihydro-benzimidazolone, benzimidazole, benzothiazole, benzothiadiazole, quinoline, isoquinol in quinoxal in pyrazolopyri dine, aminopyrazolinone, imidazopyridine, pyrimidine, pyridazine, pyrazine and isatin groups. Preferred examples include indazole, indole, pyrazole and tetrazole groups.

These groups may be unsubstituted or substituted, for instance by a group Z or R2 as specified above.

A 5- or 6-membered N-containing heteroaryl group which may be fused to a benzene ring is typically selected from pyrrole, pyrazole, imidazole, triazole, tetrazole, indazole, thiazole, isothiazole, oxazole, isooxazole, indole, isoindole, 1,3- dihydro-indol-2-one, pyri dine-2-one, pyri dine, pyridin-3 -.01, 1,3 - dihydro- benzimjdazolone, benzimjdazoje, benzothiazol e, benzothiadiazoj e, quinoline, i soquinoline, quinoxaline, pyrazol opyridine, aminopyrazolinone, imidazopyridine, pyrimidine, pyridazine and pyrazine. When such a heteroaryl group is substituted it may be substituted by a group Z or R2 as defined above.

A 5- or 6-membered heteroaryl group containing 1 or 2 N atoms is typically selected from pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyridazine, pyrazine, oxazole, isoxazole, thiazole, pyridine- 2-one and pyridine-3-ol. It is unsubstituted or substituted. Typical substituents include a group Z or R2 as defined above.

An aryl group is a 5- to I 2-membered aromatic carbocyclic group. It is monocyclic or bicyclic. Examples include phenyl and naphthyl groups. The group is unsubstituted or substituted, for instance by a group Z or R2 as defined above.

In formula (II) as defined above, m is 0 or I, typically 1. R' and R5 typically form, together with the N atom to which they are attached, a saturated N-containing heterocyclic group selected from morpholine, thiomorpholine, piperidine, piperazine, pyrrolidine, quinoline, isoquinoline, dia.zepane, oxazepane and thiazepane. The heterocylic group formed by R4 and R5 is unsubstituted or substituted, for instance by a group Z or R2 as defined above.

In definition (a) of R1 above, the ring formed by R6 and R7 is typically morpholine which is unsubstituted or substituted, for instance as specified above. It may alternatively be a group selected from tetrahydropyran, tetrahydrothiopyran, tetrahydrofuran and tetrahydrothiofuran, each of which is unsubstituted or substituted, for instance by a group R2 as defined above. When the ring formed by R6 and R7 is substituted it may be substituted on either a ring heteroatom or a ring carbon atom, for instance by a group R2 as defined above.

In definition (b) of R' above, the alkylene chain represented by Y forms, together with the carbon atoms to which it is attached, a saturated 5-, 6or 7- membered heterocyclic ring which contains 1 or 2 heteroatoms selected from 0, N and S and which is unsubstjtuted or substituted. Examples of the heterocyclic ring include tetrahydropyran, tetrahydrofuran, tetrahydrothiopyran, tetrahydrothiofuran and morpholine. When the heterocyclic ring is substituted it is typically substituted by one or more substituents, for instance 1, 2 or 3 substituents, selected from halogen, alkyl, haloalkyl (for instance trifluoromethyl), alkoxy, OH, CN, NR2, oxo (0), -COOR and -CONR2, wherein each R is H or unsubstituted alkyl as defined above.

In the definition (a') for R2 the phenyl ring B is unsubstituted (apart from group Z) or substituted. When it is unsubstituted the group Z is the sole substituent.

When it is substituted it typically comprises, in addition to group Z, one or more substituents selected from halo, alkyl, alkenyl, alkynyl, CN, NO2, OR', SR', NR'2, C(O)R', SOR', SO2 R', SO2NR'2, NC(O)R' and CO2 R', wherein each R' is independently H or C1-C6 alkyl.

Group Z is bonded to any available ring position on the phenyl ring B. Thus it may be situated at the 2-, 3-, 4-, 5- or 6- position of the phenyl ring. Typically it is bonded at position 3 or 4. Z is most typically other than H, such that moiety -BZ is a substituted phenyl ring. A typical example of Z is a group OR as defined above, in particular OH. In this embodiment the OR group, or OH group, is typically bonded at ring position 3 or 4 of phenyl ring B. Typically -BZ is a 3- hydroxyphenyl or 4hydroxyphenyl group, or an isostere thereof.

An isostere as used herein is a functional group which possesses binding properties which are the same as, or similar to, the 3-hydroxyphenyl or 4hydroxyphenyl group in the context of the structure of formula (I). Isosteres of 3- hydroxyphenyl and 4-hydroxyphenyl groups are encompassed within definitions (b') and (c') above for R2' In definition (b') for R2' the heteroaryl group is unsubstituted or substituted.

If it is substituted it may be substituted by one or more substituents selected from a group Z or R2 as defined above, any group specified above as an additionJ substituent on the phenyl ring B, and an oxo group (=O). Typically, if substituted, the heteroaryl group is substituted by OH, NH2 or an oxo group. In one embodiment the heteroaryl group is unsubstituted.

In definition (c') for R2' the benzene ring is unsubstituted or substituted. If it is substituted it may be substituted by a group Z or R2 as defined above or by any of the groups specified above as an additional substituent on the phenyl ring B. The heteroaryl group to which the benzene ring is fused is itself unsubstituted or substituted, for instance by a group Z or R2 as defined above, by any group specified above as an option for an additional substituent on the phenyl ring B, or by an oxo group (=0). In one embodiment both the benzene ring and the heteroaryl Examples of the groups included in definitions (b') and (c') for R2' include pyrrole, pyrazole, triazole, tetrazole, indazole, thiazole, isothiazole, oxazole, isooxazole, indole, isoindole, 1,3 dihydro-indol-2-one, pyridine-2-one, pyridine, pyridin-3 -ol, imidazole, 1,3 -dihydro-benzimidazojone, benzimi dazole, benzothiazole, benzothiadjazole, quinoline, isoquinoline, quinoxaline, pyrazolopyridine, arninopyrazoljnone, imidazopyridine, pyrimidine, pyridazine, pyrazine and isatin groups. Preferred examples include indazole, indole, pyrazole and tetrazole groups. These groups may be unsubstituted or substituted, for instance by a group Z or R2 as specified above. Typically these groups are isosteres.

More specifically, groups included in definitions (b') and (c') for R2' as defined above include the following structures, which are typically isosteres as defined above: W=W

W w W

ii 1 ii

NH

W W w-

liii liv

II

N

NH NH R10

R1 R1 2i 2ii 2iii

N

" N, I \

NH

NH N

NN/ R10 2iv 2v W. _W 61i 6i W w_.. w 6vi 6v wherein each R' is independently selected from H, C1-C6 alkyl C1-C6 alkoxy, C1- C6 acyl, -C(O)NR'R", -S(O)NR'R", aryl, heteroaryl, suiphonyl and halogen, whrein R' and R" are each independently H or C1-C6 alkyl and t is 1 or 2; each R'1 is independently selected from -OR' and -N(R' )2, wherein R' is as defined above; each R'2 is independently H, F or CF3; each W is independently selected from CR' and N, wherein R' is as defined above; and W' is selected from 0, S and NR'2 wherein R'2 is as defined above.

Formula (I) as defined above embraces monocyclic and fused bicyclic compounds.

The linker group X in formula (I) is typically a direct bond, -0-, -CH2-, -CHR13-, -NH- or -NR'3 wherein R'3 is C1-C6 alkyl. Most typically it is a direct bond.

In one embodiment the invention provides a compound which is monocyclic, wherein, in formula (I), R', R2, X and X2 are as defined above; and one of X3 and X4 is CR3 and the other is N or CR3, wherein R3 is as defined above; or a pharmaceutically acceptable salt thereof with the proviso that, when X1 is N, X2 is Cl-I, X3 is CR3 and X4 is N, then R3 is H or C1C6 alkyl.

In a further embodiment the invention provides a compound which is a fused bicyclic arylamine of formula (Ta): R1 (ia) R2 wherein R' is selected from: (a) R6 - N' R7 wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepaneor thiazepane group which is unsubstituted or substituted; and (b) CH2 wherein Y is a C2 - C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from 0, N and S, and which is unsubstituted or substituted; R2 is -LR2' wherein L is selected from a direct bond, -0-, -CR'R"- and - NR'- wherein R' and R" are each, independently, H or Ci-C6 alkyl and R21 is selected from:: (a') a group of the following formula: wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from H, -OR, -SR, CH2OR, -CO2R, CF2OH, CFI(CF3)OH, C(CF3)20H, - (CH2)qOR, (CH2)qNR2 C(O)N(R)2, NR2, -NRC(O)R, S(O)mN(R)2, 0C(O)R, OC(O) N(R)2, -NRS(O) mR, -NRC(O)N(R)2 CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 C10 cycloalkyl and a 5- to 12- membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is I or2andqisO, 1 or2; (b') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; X' and X2 are each, independently, N or CH; R3 is H, Cj-C6 alkyl or a group of formula (II): (I') R4 )J -ECH2--

R (II)

wherein mis 0 or 1; and R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and 0, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N- containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated Ncontaining heterocyclic group as defined above; and Q represents a ring selected from a benzene ring and a 5- or 6-membered heteroaromatic ring containing 1 or 2 N atoms; or a pharmaceutically acceptable salt thereof with the proviso that, when X' and X2 are both N, then R3 is a group of formula (II) as defined above.

In a further aspect of the invention the compounds are subject to the proviso that one of X', X2, X3 and X4 is N and the other three are other than N. Typically one of X', X2 and X4 is N and the other two are other than N, while X3 is also other than N. In yet another aspect of the invention the compounds are subject to the proviso that two of X', X2, X3 and X4 are N and the other two are other than N. Typically X' and X2 are N while X3 and X4 are other than N; or X1 and X4* are N while X2 and X3 are other than N; or X2 and X4 are N while X' and X3 are other than N. In a further embodiment of formula (I) as defined above, R1 is morpholine.

The invention accordingly provides a compound which is an arylmorpholine of formula (Ib): (Ib) wherein R2 is -LR21 wherein L is selected from a direct bond, -0-, -CR'R"- and - NR'- wherein R' and R" are each, independently, H or C1-C6 alkyl and R2' is selected from: (a') a group of the following formula: wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from H, -OR, -SR, CH2OR, -CO2R, CF2OH, CH(CF3)OH, C(CF3)20H, - (CH2)qOR, (CFI2)qNR2 C(O)N(R)2, NR2, NRC(O)R, S(O)mN(R)2, 0C(O)R, OC(O) N(R)2, -NRS(O) 1R, -NRC(O)N(R)2 CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 C10 cycloalkyl and a 5- to 12- membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is 1 or2andqisO, 1 or2; (b') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; X' and X2 are each, independently, N or Cl-I; and either (a") one of X3 and X4 is CR3 and the other is N or CR3, wherein R3 is H, C1-C6 alkyl or a group of formula (II): (TI) R4 )l -ECH2--

R (II)

wherein m is 0 or 1; and R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and 0, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N- containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated Ncontaining heterocyclic group as defined above; or (b") X3 and X4 are each CR6 wherein the groups R6 form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring and a 5- or 6-membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above; or a pharmaceutically acceptable salt thereof, with the provisos that: (i) when X1 is N, X2 is CH, X3 is CR3 and X4 is N, then R3 is H or C1-C6 alkyl; and (ii) when X1 and X2 are both N and X3 and X4 are both CR6 in which the groups R6 form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring and a 5- or 6-membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above, then R3 is a group of formula (II) as defined above.

In a further embodiment the invention provides a compound which is an arylamine of formula (Ic):

R R9NR2

wherein: R' is selected from: (a) R6 - N' R7 wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and (b) CH2 wherein Y is a C2 - C4 alkylene chain which contain', between constituent carbon atoms of the chain andlor at one or both ends of the chain, I or 2 heteroatoms selected from 0, N and S, and which is unsubstituted or substituted; R2 is -LR2' wherein L is selected from a direct bond, -0-. -CR'R"- and - NR'- wherein R' and R" are each, independently, I-I or C-C6 alkyl and R2' is selected from: (a') a group of the following formula: wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from I-I, -OR, -SR, CH2OR, -CO2R, CF2OH, CH(CF3)OH, C(CF3)20H, - (CH)qOR, (CH2)qNR2 -C(O)N(R)2, NR2, -NRC(O)R, S(O)mN(R)2, 0C(O)R, OC(O) N(R)2, NRS(O) mR, -NRC(O)N(R)2 CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 - C10 cycloalkyl and a 5- to 12- membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is I or2andqisO, I or2; (b') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; arid (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; and either (a") one of R8 and R9 is H and the other is Ci C6 alkyl or a group of formula (II) as defined above; or (b") R8 and R9 together form, with the carbon atoms to which they are attached, a ring selected from a benzene ring and an imidazole ring, which ring is substituted by a group R3 as defined above; or a pharmaceutically acceptable salt thereof.

Specific compounds of the invention include: 3 -(6-Morpholin-4-yI-pyrimidin-4-yl)-phenol; 3 -(4-Morpholin-4-yl-pyrimidin-2yI)phenol; 3'-Morpholin-4-yl-biphenyl-3 -01; 3 -(6-Morpholin-4-yl-9H-purin-2-yl)phenol; 3 -(1 -Morpholin-4-yl-isoquinolin-3 -yl)-phenol; 3 -(4-Methyl-6-morpholin-4-ylpyrimidin2..yl)phenoI; 3 -(5-Methyl-4-morphol in-4-yl -pyrimi din-2-yl)-phenol; 3 -(6-Morpholin-4-yI -pyridin-2-yI)-phenol; 3-(4Morpholin-4-yl-pyridin2yl)..pheno1; 3 -[2-(4-Methyl-piperazin- l-yl)-6-morpholin-4-yl-pyrimidin4..yl]..phenol; 3 -(2-Morphol in-4-yl-pyrimidin-4-yl)-phenol; 3-[6-(4-methyl-piperazinlylmethyl)4morpholin4ylquinazoIjn2yI]pheflol; and 2- {4-[2-( iperazin..l-yl} - ethanol; and the pharmaceutically acceptable salts thereof.

The compounds of formula (I) may exist in the form of geometrical isomers or tautomers depending on the kinds of substituent groups, and these isomers in separated forms or mixtures thereof may be used in the present invention. Where the compounds have asymmetric carbon atoms, optical isomer forms may exist based on such carbon atoms. All of the mixtures and the isolated forms of these optical isomers may be used in the present invention.

A suitable synthetic strategy for producing compounds of formula (I) which are monocyclic comprises a palladium-mediated (Suzuki-type) crosscoupling reaction of a chlorinated monocyclic precursor compound. The present invention therefore further provides a process for producing a compound of formula (I) as defined above, which process comprises: treating a compound of formula (III): (IU) x wherein R', X' and X2 are as defined above, one of X3 and X4 is CR3 and the other is N or CR3 wherein R3 is as defined above, with a boronic acid of formula R2B(OH)2 in which R2 is as defined above, in the presence of a Pd catalyst.

The Pd-mediated cross-coupling step take place under conventional conditions, for instance in the presence of a base and a solvent. The base may be, for instance, caesium carbonate or sodium bicarbonate. The solvent may be dioxane or may comprise toluene, ethanol and water. The palladium catalyst may he any that is typically used for Suzuki-type cross-couplings, such as PdCI2(PPh3)2 When R2 is a group -LR21 in which R21 is an isostere of a 3- or 4- hydroxyphenyl group, namely a group as defined under option (b') or (c') for R2' above, the required boronic acid of formula R2B(OH)2 may be prepared by treating the corresponding brominated heterocycle with an alkyllithium base, followed by quenching with a trialkylborate.

A compound of formula (I) in which L is other than a direct bond may be prepared by treating a compound of formula (III) as defined above with a suitable amine or alcohol nucleophile under neutral or basic conditions.

A compound of formula (III) wherein R' is

N R R7

wherein R6 and R7 are as defined above may be produced by treating a compound of formula (lila):

CI (IIIa x

with an amine of formula R6

HN R7

wherein R6 and R7 are as defined above, in the presence of a base in an organic solvent. A suitable base is potassium carbonate. A suitable solvent is acetonitrile.

A suitable synthetic strategy for producing compounds of formula (I) which are bicyclic and in which R3 is a group of formula (II) wherein m is 1 employs the precursor carboxaldehyde of formula (IV): (IV) R1 o wherein Q and R' are as defined above. Starting from this precursor the synthesis comprises performing in either order, a palladium-mediated (Suzuki-type) cross- coupling reaction and a reductive amination. The present invention therefore further provides a process for producing a compound of formula (I) as defined above which are bicyclic and in which R3 is a group of formula (II) wherein m is 1, which process comprises: (a) treating a compound of formula (V) R1 N (V)

H N

wherein Q and R' are as defined above, with a boronic acid of formula R2B(OH)2 in which R2 is as defined above, in the presence of a Pd catalyst; and treating the resulting compound of formula (VI): R1 \ N (VI) R2 wherein Q, R and R2 are as defined above, with an amine of formula NHR4R5 in which R4 and R5 are as defined above, in the presence of a suitable reducing agent; or (b) treating a compound of formula (V) as defined above with an amine of formula NHR4R5 wherein R4 and R5 are as defined above, in the presence of a suitable reducing agent; and treating the resulting compound of formula (VII): R1 R\ (VII) R' N1 wherein Q, R', R4 and R5 are as defined above, with a boronic acid of formula R2B(OH)2 in which R2 is as defined above, in the presence of a Pd catalyst.

Both the amination step and the Pd-mediated cross-coupling step take place under conventional conditions. The palladium catalyst may be any that is typically used for Suzuki-type cross-couplings, such as PdCl2(PPh3)2. The Suzuki cross- coupling may be performed under any suitable conditions, for instance as described above. The reducing agent is typically a borohydride, for instance NaBH(OAc)3, NaBH4 or NaCNBH4, in particular NaBH(OAc)3.

The carboxaldehyde precursor of formula (IV) may be produced by a process which comprises treating a compound of formula (VIII): R1 (VIII) Br N CI wherein Q and R' are as defined above, with a lithiating agent followed by N,N- dimethylformamide (DMF). The reaction is typically conducted by adding a solution of the lithiating agent in a non-polar organic solvent, for instance a hydrocarbon such as hexane, to a suspension of the compound of formula (VIII) in an organic solvent such as tetrahydrofuraji (THF). If THF is used the addition takes place at a low temperature, of about -78 c. The lithiating agent is typically an alkyllithium, for instance nbutyllithium.

The invention further provides a process for producing a compound of formula (I) which is bicyclic and in which R3 is a group of formula (II) wherein m is I and R2 is a 3- or 4-hydroxyphenyl group, which process comprises: (a) treating a compound of formula (IX): R1 wherein OR' is bonded at position 3 or 4 of the phenyl ring to which it is attached, R' is a hydroxy protecting group and Q and R' are as defined above, with an amine of formula NHR4R5 wherein R4 and R5 are as defined above, in the presence of a suitable reducing agent; and (b) removing the hydroxy protecting group.

The reducing agent is typically a borohydride, for instance as specified above.

Examples of hydroxy protecting groups are known in the art, for instance as described in "Protective Groups for Organic Chemistry", Third Edition, T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999. For instance, a hydroxy group can be protected as an acetal, a substituted acetal, an ester, a xanthate, an ether or a silyl ether. The acetal is preferably tetrahydropyran. The silyl ether is preferably trimethylsilyl ether, t-butyl dimethylsilyl ether, triiso-propylsilyl ether or tbutyldiphenyl-silyl ether. These protecting groups are removed by conventional techniques.

A compound of formula (IX) as defined above may be produced by a process which comprises treating a compound of formula (X): R1

OR

wherein Q, R1 and R' are as defined above, with a lithiating agent followed by N,N'- dimethylformamide (DMF). The reaction is typically conducted by adding a solution of the lithiating agent in a non-polar organic solvent, for instance a hydrocarbon solvent such as hexane, to a suspension of the compound of formula (VI) in an organic solvent such as tetrahydrofuran (THF). If THF is used the addition takes place at a low temperatuse, of about -78 C. The lithiating agent is typically an alkyl lithium, for instance n-butyllithium.

A compound of formula (X) as defined above may be produced by a process which comprises treating a compound of fornrnla (XI): R1 (N) Nci wherein Q and R' are as defined above, with a boronic acid for formula (XII): (VIII) (OH)2B wherein R' is as defined above, in the presence of a palladium catalyst. The reaction is conducted under conventional conditions for a Suzuki-type cross-coupling reaction, for instance as described above.

A compound of formula (V) as defined above wherein R' is -NR6R7 may be prepared by a process which comprises treating a compound of formula (XIII): t\ /R

N

(XIII) wherein Q, R6 and R7 are as defined above, with a lithiating agent followed by N,N'- dimethylformamide (DMF). The reaction is typically carried out as described above for the production of a compound of formula (IX).

A compound of formula (XIII) as defined above may be produced by a process which comprises treating a compound of formula (XIV):

CI

(XIV) N with an amine of formula NHR6R7, wherein R6 and R7 are as defined above, in an organic solvent. The solvent is typically an alcohol, such as methanol. The reaction is generally conducted at room temperature.

A compound of formula (XIV) may be prepared by the process described in Reference Example 1 for the preparation of 2,4-dichloro-thieno[3,2-d] pyrjmjdjne, or by analogy with such a process.

A compound of formula (V) as defined above wherein R' is of formula wherein Y is as defined above may be prepared by a process which comprises submitting a compound of formula (XV):

CI (XV)

wherein Q and R2 are as defined above, to palladium-mediated crosscoupling with a compound of formula (XVI): (XVI;

E--CHCH

wherein Y is as defined above and L is H or a group selected from halo, OSO2CF3, - B(OR)2, -Sn(R)3 and -Si(R)3 wherein R is H or alkyl as defined above, followed by reduction, to yield a compound of the following formula (XVII) : (?H2 (XVII wherein Q, R and Y are as defined above.

The compound of formula (XVII) may be converted to the corresponding carboxaldehyde by treatment with a lithiating agent followed by N,N'dimethylformamide (DMF), for instance under the conditions described above for the conversion of a compound of formula (X) to a compound of formula (IX). The lithiating agent is typically as defined above. The resulting carboxaldehyde may then be converted into a desired final compound of formula (I) as defined above, in which m is I, by treatment with an amine of formula NHR4R5 in which R4 and R5 are as defined above, in the presence of a suitable reducing agent, for instance a borohydride as specified above, in particular NaBH(OAc)3 A compound of formula (I) as defined above in which R3 of formula (II) wherein m is 0 may be prepared by a Buchwald-type palladium-mediated nitrogen insertion reaction. Such a process may comprise treating a compound of formula (XVIII): R1 JIII) N"2 wherein Q, R' and R2 are as defined above and V is a halo group selected from Br and I, with an amine of formula NHR4R5 in which R4 and R5 are as defined above, in the presence of a palladium catalyst.

A compound of formula (XVIII) may be produced by treating a compound of formula (XIX): R1 (XDc H R2 wherein Q, R' and R2 are as defined above, with a lithiating agent and a halogen selected from bromine and iodine. The lithiating agent is typically an alkyllithium, for instance butyllithium. The halogen is typically iodine, which gives rise to a compound of formula (XVIII) in which V is I..

A compound of formula (1) as defined above in which R3 is of formula (II) in which m is 0 may also be prepared by an SNAr displacement reaction, for instance under the conditions described by D. Prim and G. Kirsch in Tetrahedron 55 (21), 11-6526, 1999. Such a process comprises treating a compound of formula (XVIII) as defined above in which V is Br with an amine of formula NHR4R5 in which R4 and R5 are as defined above in 1120 under reflux for 12 hours.

A compound of formula (I) as defined above in which R3 is of formula (II) wherein m is 0 may alternatively be prepared by treating a compound of formula (XVIII) as defined above in which V is I with an amine of formula NHR4R5 in which R4 and R5 are as defined above in 1,4-dioxane in the presence of CuT/En and K3P04.

The reaction is conducted at about 110 C for 24 hours. This procedure is described by Kang S-K et al in Synlett, (3), 427-430, 2002.

An arylamine of formula (I) may be converted into a pharmaceutically acceptable salt, and a salts may be converted into the free compound, by conventional methods. Examples of pharmaceutically acceptable salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid and phosphoric acid; and organic acids such as formic acid, acetic acid, trifluoroacetjc acid, propionic acid, oxalie acid, malonic acid, suceinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonjc acid, ethanesulfonjc acid, aspartic acid and glutamic acid. In the case of compounds of the invention bearing a free carboxy substituent, the salts include the salts of alkali and alkaline earth metals and ammonium, for instance the salts of sodium, potassium, magnesium, calcium and ammonium. The latter are prepared by treating the free fused pyrimidine of formula (I), or an acid addition salt thereof, with the corresponding metal base or ammonia.

The compounds of formula (I) and their salts may exist as hydrates or solvates.

Compound of the present invention have been found in biological tests to be inhibitors of P13 kinase. The compounds are typically selective for class Ia P13 kinases over class lb and may exhibit at least a 20-fold selectivity for class Ia over class lb P13 kinases. In particular, the compounds are selective for the p1 lOa isoform over p11 Oy.

A compound of the present invention may thus be used as an inhibitor of P13 kinase, in particular of a class Ia P13 kinase. Accordingly, a compound of the present invention can be used to treat a disease or disorder arising from abnormal cell growth, function or behaviour associated with P13 kinase. Examples of such diseases and disorders are discussed by Drecs et al in Expert Opin. Ther. Patents (2004) 14(5):703 732. These include cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disordcrs. Exampes of metabolism/endocrine disorders include diabetes and obesity.

Examples of cancers which the present compounds can be used to treat include leukaemia, brain tumours, renal cancer, gastric cancer and cancer of the skin, bladder, breast, uterus, lung, colon, prostate, ovary and pancreas.

A human or animal patient suffering from an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, a metabolism/endocrine disorder or a neurological disorders may thus be treated by a method comprising the administration thereto of a compound of the present invention as defined above. The condition of the patient may thereby be improved or ameliorated.

In addition to possessing biochemical potency the compounds of the invention exhibit physicochemical and pharmacokinetic properties which make them particularly well adapted for drug use. This is shown for instance in the results of the biological assays described in Example 3, which follows. In particular the compounds possess high aqueous solubility at physiological pH; many have a solubility of at least 40 tM and a significant number have a solubility of greater than 100 jiM. High solubility at physiological pH is desirable since it promotes bioavailability. The compounds also possess high metabolic stability, as shown in particular by the hepatocyte clearance assay described in Example 3 in which most of the tested compounds were shown to have low hepatocyte clearance. LowS hepatocyte clearance correlates with a low rate of liver metabolism. It can therefore be seen that the compounds of the present invention possess improved physicochemical and pharmacokinetic properties whilst retaining biochemical potency as inhibitors of P13 kinase.

A compound of the present invention can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. The compound may therefore be given by injection or infusion.

The dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Daily dosages can vary within wide limits and will be adjusted to the individual requirements in each particular case. Typically, however, the dosage adopted for each route of administration when a compound is administered alone to adult humans is 0.0001 to mg/kg, most commonly in the range of 0. 00 1 to 10 mg/kg, body weight, for instance 0.01 to 1 mg/kg. Such a dosage may be given, for example, from 1 to 5 times daily. For intravenous injection a suitable daily dose is from 0.000 1 to I mg/kg body weight, preferably from 0.0001 to 0.1 mg/kg body weight. A daily dosage can be administered as a single dosage or according to a divided dose schedule.

A compound is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form. The compound may be administered in any conventional form, for instance as follows: A) Orally, for example, as tablets, coated tablets, dragees, troches, lozenges, aqueous or oily suspensions, liquid solutions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, dextrose, saccharose, cellulose, corn starch, potato starch, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch, alginic acid, alginates or sodium starch glycolate; binding agents, for example starch, gelatin or acacia; lubricating agents, for example silica, magnesium or calcium stearate, stearic acid or talc; effervescing mixtures; dyestuffs, sweeteners, wetting agents such as lecithin, polysorbates or lauryl sulphate. The tablets may he uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Such preparations may be manufactured in a known manner, for example by means of mixing, granulating, tableting, sugar coating or film coating processes.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is present as such, or mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose sodium alginate, polyvinylpyrrolidone guhi tragacanth and gum acacia; dispersing or wetting agents may be naturally-occurring phosphatides, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides for example polyoxyethylene sorbitan mono oleate.

The said aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more colouring agents, such as sucrose or saccharin.

Oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by this addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures of these.

Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally occuring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids an hexitol anhydrides, for example sorbitan mono-oleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavouring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose.

Tn particular a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not nietabolise to glucose or which only metabolise a very small amount to glucose.

Such formulations may also contain a demulcent, a preservative and flavouring and coloring agents; B) Parenterafly, either subcutaneously, or intravenously, or intramuscularly, or intrastemally, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. This suspension may be formulated according to the known art using those suitable dispersing of wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic paternally-acceptable diluent or solvent, for example as a solution in I, 3-butane diol.

Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition fatty acids such as oleic acid find use in the preparation of

injectables;

C) By inhalation, in the form of aerosols or solutions for nebulizers; D) Rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and poly- ethylene glycols; E) Topically, in the form of creams, ointments, jellies, collyriums, solutions or suspensions.

The invention will be further described in the Examples which follow: Example I: - Monocycljc Compounds Compounds were prepared according to the following synthetic scheme: 6 7 6 7 XX1 Step i R Step 2. Method Aor B R

II II I

x2 ci CI X> R2 x Y z Preparation of Intermediates, Y (1) Preparation of 4-(6-Chloro-pyrimidin-4-yl)-morpholine: precursor to (1) A mixture of 4,6-dichloropyrimidine (1.01 g), morpholine (591 p.L) and potassium carbonate (1.03g) was heated to reflux in acetonitrile. After 3 hours at reflux the reaction mixture was cooled, diluted with ethyl acetate, washed with water and the organic phase dried (MgSO4) and the solvent was removed in vacuo to furnish the title compound as a white solid.

The following compounds were prepared in an analogous maimer using the appropriate starting materials.

is (ii) 4-(2-Chloro-pyrimidin-4-yl)-morpholine - precursor to (2) - was prepared from 2,4-dichloropyrimidine using methanol as solvent. 4-(4Chloro- pyrimidin-2-yl)-morpholine was also isolated as a minor product from this reaction.

(iii) 4-(3-Bromo-phenyl)-morpholine - precursor to (3) - was prepared from 1,3-dibromobenzene using the procedure described in.Journal of Organic Chemistry, 2001, 66, 1405.

(iv) 2-Chloro-6-morpholin-4-yI-9H-purine - precursor to (4) - was prepared from 2,6-dichioropurine and morpholine in methanol.

(v) 3-Chloro-l-morpho1in-4y1isoqujnoljne - precursor to (5) - was prepared from 1,3-dichloroisoquinoline.

(vi) 4-(2-Chloro-6-methyl-pyrimidin4yl)morphotjne - precursor to (6) - was prepared from 2,4-dichloro-6-methylpyrjmjdjne using diisopropylethylamine as base in ethanol; (vii) 4-(2-Chloro-5-methyl-pyrjmidin4yl)morphol Inc precursor to (7) - was prepared from 2,4-dichloro-5-methylpyrjrnidine.

(viii) 4-(6-Chloro-pyridin-2-yl)-morpholinc - precursor to (8) - was prepared from 2,6-dichloropyridine using N,N-dimethy]formamide as solvent.

(ix) 4-(2-Chloro-pyridin-4-yl)-morpholine - precursor to (9) - was prepared from 2,4-dichloropyridine.

(x) 4- [6-Chloro-2-(4-methyl-p iperazin-1-yl)-pyrimid in-4-ylJ morpholine - precursor to (10) - was prepared by treatment of 4-(2,6-dichloro- pyrimidin-4-yl)- morpholine with N-methylpiperazine in acetonitrile with potassium carbonate as base. 4-(2,6-Dichloro-pyrimidjn-4-yl)-morpholjne in turn was prepared from 2,4,6- trchloropyrimidine and morpholine in methanol.

Preparation of Target Compounds, Z Compounds Prepared by Method A (i) Preparation of 3-(6-Morpholin-4-yl-pyrimidin-4-yI)-phenol, (1).

A mixture of 4-(6-chloro-pyrimidin-4-yl)-morpholjne (286mg), 3 hydroxybenzene boronic acid (237mg), caesium carbonate (931mg), bis(triphenylphosphine)palladium (II) chloride (50mg), water (2mL) and dioxane (8mL) was purged with argon and then heated to reflux. After 3 hours the reaction mixture was cooled, diluted with chloroform, washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography, followed by recrystallisation to yield the title compound as a white solid.

The following compounds were prepared in a similar manner using the appropriate starting materials: (ii) 3 -(4-Morpholin-4-yl-pyrimidin-2-yl)-phenol, (2) (iii) 3 -Morpholin-4-yl -biphenyl-3 -01, (3) (iv) 3 -(4-Methyl-6-morpho1in4ylpyrimjdjn2yl)pheno1, (6) (v) 3-(6-Morpho1in-4-yl-pyridin2yl)phenol, (8) Compounds Prepared by Method B (i) Preparation of 3-(S-Methyl-4-morpholin-4-yl-pyrimidin-2-yl)-phenol, (7) A mixture of 4-(2-chloro-5-methyl-pyrirnidin-4-yl)-morphol me (73mg), 3- hydroxybenzene boronic acid (95mg), sodium bicarbonate (90mg), bis(triphenylphosphine)palladiurn (H) chloride (14mg), toluenc (2mL), ethanol(lmL) and water (0.5mL) was heated in the microwave at 135 C for 1 hour. The reaction mixture was cooled, diluted with chloroform, washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield the title compound.

The following compounds were prepared in a similar manner using the appropriate starting materials.

(ii) 3 -(1 -Morpholin-4-yl-i soquinol in-3 -yl)-phenol, (5) (iii) 3 -(2-Morpholin-4-yl -pyrimidin-4-yl)-phenol, (11) (iv) 3 -(4-MorphoIin-4-yl-pyridin-2yl)pheno1, (9) (v) 3- [2-(4-Methyl -piperazinI -yl)-6-morpholin-4-yl-pyrimidin-4-yl] - phenol, (10) (vi) Preparation of 3-(6-Morpholin-4-yI-9H-purin...2...yl)...phenol (4) 2-Chloro-6-morpholin-4-yl-9H-purine was treated with 3,4-dihydro-2H-pyran in ethyl acetate with a catalytic amount of pTSA to yield 2-chloro-6morpholin-4-yl-9- (tetrahydro-pyran-2-yI)-9H-purine. Reaction with 3-hydroxybenzene boronic acid using the reaction conditions described in Method A above yielded 3-[6- Morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-2-yl] -phenol. Treatment of this compound with HC1 in THF yielded the desired title compound.

Example 2- Bicyclic Compounds Compounds were prepared according to the following synthetic scheme: 0 0 Cl BrtJJO BrIiNH BrN I: NH2 NO NCI 0 0 0 BrJN _______ Ri NCI R2

D E F

R 1N N R2 NR3

G

Preparation of 6-bromo-1 H-quinazoline-2, 4-dione, B A mixture of methyl2-amino-5-bromobepoa (12.5 g), and urea (18.5 g) was heated in a melt at 180-185 C for 4.5 hours. The mixture was cooled and the white residue treated with 2M sodium hydroxide (400 ml), then acidified with concentrated hydrochloric acid at 0 C to give a white solid which was collected by filtration, washed with water and dried to yield the title compound.

Preparation of 6-bromo-2, 4-dichtoroquinazoline, C A mixture of 6-brorno1H-quinazoline-2, 4-dione (12.5 g) and phosphorus oxychloride (93 ml) was heated at 110 C for 12 hours.The mixture was then cooled and excess phosphorus oxychioride removed in vacuo to give an oily residue which was quenched carefully with water at 0 C and the precipitate collected by filtration, washed with water and dried to give the title compound as a white solid.

Preparation of 6-bromo-2-ch1oro4morpho1ifl_4y1qujnazo1jne, D A mixture of 6-hromo-2, 4-dichloroquinazoline (5.0 g) and morpholine (3.16 ml) was stirred in dry methanol at room temperature for 4.5 hours. The volume of the mixture was then reduced in vacuo to give a precipitate which was collected by filtration, washed with water and dried to give the title compound as a yellow solid Preparation of E To 6-bromo-2chloro4morpholjn4yIquinazoline (4.3 g) stirring in anhydrous tetrahydrofijran at -78 C under a nitrogen atmosphere was added n-butyl lithium (6.3 ml, 2.5 M solution in hexanes) dropwise over 5 minutes. The mixture was stirred for 35 minutes and anliydrous dimethyl formamide (1.52 ml) was added dropwise over 5 minutes and stirred for 1 hour at -78 C, then allowed to warm to room temperature and stirred for a further 2 hours. The mixture was quenched with 50 % ammonium chloride solution and partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified using flash chromatography to yield the title compound as a pale yellow solid.

Preparation of 2-chloro-6- (4-methyl-piperazin-1-yl-methyj) -4-morpholin4-yl- quinazoline, F To a mixture of (150 mg) and 1 -methylpiperazine (71mg) stirring in anhydrous 1, 2-dichioroethane (5 ml) was added glacial acetic acid (33 uI) followed by sodium triacetoxyborohydride (149 mg). The mixture was stirred for 12 hours at room temperature, then diluted with dichioromethane (20 ml) and washed with SO % sodium bicarbonate solution. The organic phase was dried (MgSO4) and the solvent removed in vacuo to give a residue which was purified using flash silica chromatography to yield the title compound as a white solid.

Preparation of 3- [6-(4-methyl-piperazin-l -ylmethyl)-4-morpholin-4-ylquinazolin-2-yll-phenoi, (12), via compound of the generic structure F A mixture of 2-chloro-6- (4-methyl-piperazin-1-yl-methyl) -4-morpholin-4yl- quinazoline (70 mg), sodium bicarbonate (34 mg), 3-(tertbutyldimethylsilyloxy)- phenylboronic acid (61 rng), bis(triphenylphosphine) palladium (11) chloride (7 mg) toluene (2 ml), ethanol (1.0 ml), and water (0.5 ml) was heated in a microwave oven at 130 C for 1 hour. The reaction mixture was cooled, diluted with dichloromethane (20 ml), washed with water, dried (MgSO4) and the solvent removed in vacuo, to give after purification using flash chromatography, 2-[3-(tert-butyl- dimethylsilanyloxy)-phenyl] -6-(4-methyl-piperazine- I -ylmethyl)-4- morpholin-4-yl- quinazoline as a white solid. To this compound in anhydrous tetrahydrofuran (2 ml) was added tetrabutylammonium fluoride (126 l, 1.0 M solution in tetrahydrofuran), and stirred at room temperature for 4 hours. The reaction mixture was quenched by the addition of flash silica (1 g) and purified using flash silica chromatography to yield the title compound as a white solid.

The following compound was made in an analogous manner using the appropriate starting materials.

-

yI}-ethanol., (13), via compound of the generic structure F Aiijytica1 Data (1) HNMR (400MHz, d6-DMSO) 9.55(111, s), 8.55 (IH, s), 7.55-7.50 (2F1, m), 7. 28- 7.22 (2H, m), 6.85 (111, dd), 3.72-3.70 (8H,m). MS (ESf) 258 (MH). (2)

I-INMR (400MHz, CDCI3) 3.71-3.73 (m, 411, 2 x Ci12), 3.8 1-3.83 (m, 4H, 2 x CH2), 5.45 (sbr, H, 01-I), 6.41 (d, H, ArH,), 6.92-6.95 (m, H, ArH), 7.31 (t, H, ArH), 7.87- 7.88 (m, H, ArFI), 7.94 (d, H, ArH), 8.34 (d, H, ArH). Structure confirmed by NOEsy analysis. MS (ESi) 258.05 (MH). (3)

1HNMR (400MHz, CDCI3) 3.2 1-3.23 (m, 41-1, 2 x Cl-I2), 3.87-3.89 (m, 4H, 2 x CH2), 4.75 (s, H, OH), 6.79-6.82 (m, H, ArH), 6.89-6.92 (m, H, ArH), 6.99-7.15 (m, 4H, 4 x ArH), 7.26-7.33 (m, 211, 2 x ArH). MS (ESf) 256.08 (MH). (4)

iINMR (400MFIz, d6-DMSO) 13.0(111, br.), 9.45(IH, br. s), 8.12 (IH, s), 7. 80- 7.78(2H, m), 7.23-7.20 (lI-I, m), 6,80 (111, dd), 4.25-4.20 (4H, br), 3. 80-3.75 (4H,m).

MS (ESF') 298 (MI-f1). (5)

HNMR (400Mhz, CDCI3) 3.52-3.54 (m,4H, 2 x CH2), 4.00-4.02 (m,4H, 2 x 4.87 (br. s, H, OH), 6.86 (d, H, ArT-I), 7.34 (t, H, An-I), 7.48 (t, H, ArH), 7.60 (t, H, ArlI), 7.69-7.7 1 (m, 3H, 3 x ArH), 7.80 (d, H, ArH), 8. 08 (d, I-I, ArH). Structure confirmed by NOEsy analysis. MS (ESI) 307.04 (MH). (6)

1HNMR (400MHz, d6-DMSO) 9.41(1H,s), 7.80-7.75 (2H,m), 7.21-7.19 (1H,m), 6.80 (IH,dd), 6.60 (IH,s), 3.72-3.61 (8H,m), 2.35 (3H,s). Structure confirmed by NOEsy analysis. MS (ESF) 272 (MH4). (7)

HNMR (400MHz, CDCI3) 2.26 (s, 311, CH3), 3.54-3.57 (m, 4H, 2 x CH2), 3.843.86 (m, 4H, 2 x Cl-I2), 5.13 (sbr, H, OH), 6.92 (d, I-I, AFH), 7.32 (t, H, ArH), 7.86 (s, H, ArH), 7.95 (d, H, ArH), 8.24 (s, H, ArH). Structure confirmed by NOEsy analysis.

MS (ES1) 272.19 (MH). (8)

1HNMR (400MHz, CDC13) 7.49 (m, 3H); 7.23 (t, IH, J8.1); 7.05 (d, 111, . 1=7.5); 6.77 (m, 111); 6.52 (d, IH); 4.97 (s, 1H); 3.8 (m, 4H); 3.54 (m, 4H). MS (ESL) 257.18 (MI-It). (9)

IIINMR (400MHz, CDC13) 3.35-3.37 (m, 4H, 2 x CH2), 3.85-3.87 (m, 4H,2 x 6.63-6.65 (m, I-I, ArH), 6.85-6.87 (m, H, ArH), 7.03 (m, H, ArH), 7.25-7. 36 (m, 21-i, 2 x ArH, part under CDCI3), 7.54 (m, H, ArH), 8.36 (d, H, ArH). Structure confirmed by NOEsy analysis. MS (ESF) 257.17 (MIff). (10)

TIINMR (400MHz, CDCI3) 2.37 (s, 3H, CR3), 2.59 (m, 4H, 2 x CH2), 3.61-3. 64 (m, 4H, 2 x Cu2), 3.77-3.80 (rn, 411, 2 x CH2), 3.97 (m, 411, 2 x CH2), 6.29 (s, H, OH), 6.89-6.91 (m, H, ArH), 7.26-7.29 (m, 2H, 2 x An-I part under CDCI3), 7.42 (d, H, ArH), 7.57 (m, H, ArH). Structure confirmed by NOEsy analysis. MS (ESl) 356.23 (MH). (11)

1HNMR (400MHz, CDC13) 3.79-3.81 (m, 4H, 2 x CH2), 3.89-3.91 (m, 4H, 2 x CH2), 4.87 (s, H, OH), 6.92-6.94 (m, 2H, 2 x ArH), 7.33 (t, H, ArH), 7.56-7.58 (rn, 2H, 2 x ArH), 8.37 (d, H, ArH). Structure confirmed by NOEsy analysis. MS (ESL) 258.17 (MH). (12)

HNMR (400MHz, d6-DMSO) 9.49 (IH, s); 7.83 (5H, m); 7.28 (1H, t); 6.87(111, m); 3.84 (4H, m); 3.78 (4H, m); 3.64 (2H, s); 2.38 (8H, br. m); 2.16 (3H, s).

Structure confirmed by NOEsy analysis. MS (ESJ) 420.24 (MH). (13)

I-INMR (400MHz, d6-DMSO) 13.2 (br. s, 1H); 9.01 (s, 1H); 8.33 (d, IH); 7. 98 (d, IH),7.91 (s, 111); 7.79 (d, 1H, J= 8.5 Hz); 7.69 (d, 1H);7.49 (t, IH); 4.35 (br. s, 111); 3.85 (m, C112 x 4); 3.67 (s, 211); 3.48 (m, 211); 2.43 (m, 1011, CH2 x 4, CH2). MS (ESL1) 474.3 (MH).

Example 3 Biological Testing Compounds of the invention, prepared as described in the preceding Examples, were submitted to the following series of biological assays: (i) P13K Biochemical Screening Compound inhibition of P13K was determined in a radiometric assay using purified, recombinant enzyme and ATP at a concentration of luM. All compounds were serially diluted in 100% DMSO. The kinase reaction was incubated for 1 hour at room temperature, and the reaction was terminated by the addition of PBS. IC50 values were subsequently determined using sigmoidal dose-response curve fit (variable slope). All of the compounds tested had an 1C50 against P13K (p1 loa)of 5OuM or less, typically lOuM or less.

(ii) Cellular Proliferation Inhibition Cells were seeded at optimal density in a 96 well plate and incubated for 4 days in the presence of test compound. Alamar B1ueTM was subsequently added to the assay medium, and cells were incubated for 6 hours before reading at 544nm excitation, 590nm emission. EC50 values were calculated using a sigmoidal dose response curve fit. All the compounds tested had an EC50s of 5OuM or less in the range of cell lines utilized.

(iii) Caco-2 Permeability Caco-2 cells were seeded onto Millipore Multiscreen plates at 1 x I 5 cells/cm2, and were cultured for 20 days. Assessment of compound permeability was subsequently conducted. The compounds were applied to the apical surface (A) of cell monolayers and compound permeation into the basolateral (B) compartment was measured. This was performed in the reverse direction (B-A) to investigate active transport. A permeability coefficient value, Papp, for each compound, a measure of the rate of permeation of the compound across the membrane, was calculated.

Compounds were grouped into low (Papp </= 1.0 x 1 O6cm/s) or high (Papp > / 1.0 X 1 O6cm/s) absorption potential based on comparison with control compounds with established human absorption.

For assessment of a compound's ability to undergo active efflux, the ratio of basolateral (B) to apical (A) transport compared with A to B was determined. Values of B-A/A-B >/= 1.0 indicated the occurrence of active cellular efflux. All of the compounds tested through the Caco-2 permeability screen had Papp values >/= 1.0 x 1 O6cmIs.

(iv) Hepatocyte Clearance Suspensions of cryopreserved human hepatocytes were used. Incubations were performed at compound concentration of 1mM or 3tM at a cell density of 0.5 x 106 viable cells/mL. The final DMSO concentration in the incubation was 0. 25%.

Control incubations were also performed in the absence of cells to reveal any non- enzymatic degradation. Duplicate samples (50tL) were removed from the incubation mixture at 0, 5, 10, 20, 40 and 60 minutes (control sample at 60 minutes only) and added to methanol - containing intcrnal standard (100tL) - to terminate the reaction.

Tolbutarnjde, 7-hydroxycoumarin, and testosterone were used as control compounds.

Samples were centrifuged and the supernatants at each time point pooled for analysis by LC-MSMS. From a plot of In peak area ratio (parent compound peak area / internal standard peak area) against time, intrinsic clearance (CL1) was calculated as follows: CL1 (jfl/min/mill ion cells) = V x k, where k is the elimination rate constant, obtained from the gradient of In concentration plotted against time; V is a volume term derived from the incubation volume and is expressed as uL 106 cells'.

Compounds were classified with low (CL</= 4.6jiL/minllO6 cells), medium (CL >7= 4.6; <1= 25.2 pi/minll06 cells) and high (>7= 25.2p1/minllO6 cells) clearance. The majority of the tested compounds of the invention were determined to have low hepatocyte clearance.

(v) Cytochrome P450 Inhibition Compounds of the invention were screened against five CYP45O targets (1A2, 2C9, 2C19, 2D6, 3A4) at 10 concentrations in duplicate, with a top concentration of 1 OOuM being used. Standard inhibitors (furafylline, sulfaphenazole, tranylcypromine, quinidine, ketoconazole) were used as controls. Plates were read using a BMG LabTechnologies PolarSiar in fluorescence mode. The majority of the tested compounds assessed in this assay displayed weak activity (IC50 >/5uM) against all isoforms of CYP45O.

(vi) Cytochrome P450 Induction Freshly isolated human hepatocytes from a single donor were cultured for 48 hours prior to addition of test compound at three concentrations and were incubated for 72 hours. Probe substrates for CYP3A4 and CYP1A2 were added for 30 minutes and 1 hour before the end of the incubation. At 72 hours, cells and media were removed and the extent of metabolism of each probe substrate quantified by LC- MS/MS. The experiment was controlled by using inducers of the individual P450s incubated at one concentration in triplicate. The compounds of the invention assessed in this assay showed negligible effects on induction of cytochrome P450 enzymes.

(vii) Plasma Protein Bindjg Solutions of test compound (5urn, 0.5% final DMSO concentration) were prepared in buffer and 10% plasma (v/v in buffer) . A 96 well HT dialysis plate was assembled so that each well was divided in two by a semi-permeable cellulose membrane. The buffer solution was added to one side of the membrane and the plasma solution to the other side; incubations were then conducted at 37 C over 2 hours in triplicate. The cells were subsequently emptied, and the solutions for each batch of compounds were combined into two groups (plasma-free and plasmacontaining) then analysed by LC-MSMS using two sets of calibration standards for plasma-free (6 points) and plasma-containing solutions (7 points). The fraction unbound value for each compound was calculated: highly protein bound compounds (>/=90% bound) had an Fu </=0. 1. The compounds of the invention assessed in this assay had Fu values >/= 0.1.

(viii) hERG channel blockage Compounds of the invention were evaluated for their ability to modulate rubidium efflux from HEK-294 cells stably expressing IIERG potassium channels using established flux methodology. Cells were prepared in medium containing RbC1 and were plated into 96well plates and grown overnight to form monolayers. The efflux experiment was initiated by aspirating the media and washing each well with 3 x 100tL of pre-incubation buffer (containing low [KJ) at room temperature.

Following the final aspiration, 50.iL of working stock (2x) compound was added to each well and incubated at room temperature for 10 minutes. 501. iL of stimulation buffer (containing high [K+]) was then added to each well giving the final test compound concentrations. Cell plates were then incubated at room temperature for a further 10 minutes. 8OtL of supernatant from each well was then transferred to equivalent wells of a 96-well plate and analysed via atomic emission spectroscopy.

Compounds were screened as 1 Opt duplicate IC50 curves, n=2, from a top concentration of 1OOtM.

Example 4 Tablet composition Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention were manufactured as follows: Composition for 10,000 tablets Active compound (250 g) Lactose (800 g) Corn starch (415g) Talc powder (30 g) Magnesium stearate (5 g) The active compound, lactose and half of the corn starch were mixed. The mixture was then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste was used to granulate the powder. The granulate was dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium was added, carefully mixed and processed into tablets.

Example 5: Injectable Formulation Formulation A Active compound 200 mg Hydrochloric Acid Solution 0.1 M or Sodium Hydroxide Solution 0.1M q.s. to pH 4.0 to 7.0 Sterile water q.s. to 10 ml The compound of the invention was dissolved in most of the water (35 400 C) and the pIT adjusted to between 4.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate. The batch was then made up to volume with water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and scaled with sterile closures and overseals.

Formulation B Active Compound 125 mg Sterile, Pyrogen-free, pH 7 Phosphate Buffer, q.s. to 25 ml Active compound 200 mg Benzyl Alcohol 0. 10 g Glycofurol75 1.45g Water for injection q.s to 3.00 ml The active compound was dissolved in the glycofurol. The benzyl alcohol was then added and dissolved, and water added to 3 ml. The mixture was then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (type 1).

Example 6: Syrup Formulation Active compound 250 mg Sorbitol Solution 1. 50 g Glycerol 2.OOg Sodium benzoate 0.005 g Flavour 0.0125 ml Purified Water q.s. to 5.00 ml The compound of the invention was dissolved in a mixture of the glycerol and most of the purified water. An aqueous solution of the sodium benzoate was then added to the solution, followed by addition of the sorbital solution and finally the flavour. The volume was made up with purified water and mixed well. 5]

Claims (14)

1. A compound which is an arylamine of formula (I): R1 X R2 wherein R' is selected from: (a) R6 - N' R7 wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and (b) CH2 wherein Y is a C2 - C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from 0, N and S, and which is unsubstituted or substituted; R2 is -LR21 wherein L is selected from a direct bond, -0-, -CR'R"- and - NR'- wherein R' and R" are each, independently, H or C1-C6 alkyl and R2' is selected from: (a') a group of the following formula: wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from H, -OR, -SR, CH2OR, -CO2R, CF2OII, CH(CF3)OH, C(CF3)20H, - (CH2)qOR, (CH2)qNR2 C(O)N(R)2, NR2, NRC(O)R, S(O)mN(R)2, 0C(O)R, OC(O)N(R) 2, NRS(O) mR, -NRC(O)N(R)2 CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 - C10 cycloalkyl and a 5- to 12- membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is I or2andqisO, I or2; (b') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; X' and X2 are each, independently, N or CII; and either (a") one of X3 and X4 is CR3 and the other is N or CR3, wherein R3 is H, C1-C6 alkyl or a group of formula (II): (TI) R4 )J -ECH2---

R (II)

wherein in is 0 or 1; R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or I additional heteroatoms selected from N, S and 0, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N- containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated Ncontaining heterocyclic group as defined above; or (b") X3 and X4 are each CR6 wherein the groups R6 form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring aI1d a 5- or 6-membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above; or a pharmaceutically acceptable salt thereof; with the provisos that: (i) when R' is morpholine, X1 is N, X2 is Cii, X3 is CR3 and X4 is N, then R3 is H or C1-C6 alkyl; and (ii) when R' is morpholine, X1 and X2 are both N and X3 and X4 are both CR6 in which the groups R6 form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring and a 5- or 6- membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above, then R3 is a group of formula (II) as defined above.

2. A compound which is a fused bicyclic arylamine of formula (Ia): R1 (Ia)

R

wherein R' is selected from: (a) R6 - N' p7 wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and (b)

CYD CH2

wherein Y is a C2 - C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from 0, N and S, and which is unsubstituted or substituted; R2 is -LR2' wherein L is selected from a direct bond, -0-, -CR'R"- and - NR'- wherein R' and R" are each, independently, H or C1-C6 alkyl and R21 is selected from:: (a') a group of the following formula: z wherein B is a phenyl ring which is unsubstituted or substituted arid Z is selected from H, -OR, -SR, CH2OR, -CO2R, CF2OH, CH(CF3)OH, C(CF3)20H, (CI12)qOR, (CH2)qNR2 C(O)N(R)2, NR2, NRC(O)R, S(O)mN(R)2, 0C(O)R, OC(O) N(R)2, NRS(O) mR, -NRC(O)N(R)2 CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 - C10 cycloalkyl and a 5to 12- membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is 1 or2andqisO, 1 or2; (h') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; X' and X2 are each, independently, N or CH; R3 is H, C1-C6 alkyl or a group of formula (IT): R4 -E CH2--- (II) wherein mis Oor 1; and R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and 0, which may be fused to a benzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N- containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated Ncontaining heterocyclic group as defined above; and Q represents a ring selected from a benzene ring and a 5- or 6-mernbered heteroaromatic ring containing 1 or 2 N atoms; or a pharmaceutically acceptable salt thereof with the proviso that, when X' and X2 are both N, then R3 is a group of formula (II) as defined above.

3. A compound which is an arylmorpholine of formula (Tb): (Ib) wherein R2 is -LR2' wherein L is selected from a direct bond, -0-, -CR'R"- and - NR'wherein R' and R" are each, independently, H or C1-C6 alkyl and R2' is selected from: (a') a group of the following formula: wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from H, -OR, -SR, CI-120R, -CO2R, CF2OH, CH(CF3)OH, C(CF3)20H, - (CH2)qOR, (CH2)qNR2 C(O)N(R)2, NR2, -NRC(O)R, S(O)mN(R)2, 0C(O)R, OC(O) N(R)2, NRS(O) mR, -NRC(O)N(R)2 CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 - C10 cycloalkyl and a 5to 12- membered aryl or heteroaryl group, the group being unsubstituted or substituted, m is 1 or2andqisO, 1 or2; (b') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; X' and X2 arc each, independently, N or Cl-I; and either (a") one of X3 and X4 is CR3 and the other is N or CR3, wherein R3 is H, C1-C6 alkyl or a group of formula (II): (II) R4 )i -ECH2---

R (I')

wherein misOorl;and R4 and R5 form, together with the N atom to which they are attached, a 5- or 6-membered saturated N-containing heterocyclic group which includes 0 or 1 additional heteroatoms selected from N, S and 0, which may be fused to a*henzene ring and which is unsubstituted or substituted; or one of R4 and R5 is alkyl and the other is a 5- or 6-membered saturated N- containing heterocyclic group as defined above or an alkyl group which is substituted by a 5- or 6-membered saturated Ncontaining heterocyclic group as defined above; or (b") X3 and X4 are each CR6 wherein the groups R6 form, together with the carbon atoms to which they are attached, a ring selectcd from a benzene ring and a 5- or 6-membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above; or a pharmaceutically acceptable salt thereof; with the provisos that: (i) when X' is N, X2 is CH, X3 is CR3 and X4 is N, then R3 is H or C1-C6 alkyl; and (ii) when X' and X2 are both N and X3 and X4 are both CR6 in which the groups R6 form, together with the carbon atoms to which they are attached, a ring selected from a benzene ring and a 5- or 6-membered group containing 1 or 2 N atoms, which ring is substituted by a group R3 as defined above, then R3 is a group of formula (II) as defined above.

4. A compound which is an arylamine of formula (Ic): R1 (Ic)

R N R2

wherein: R' is selected from: (a) R6 - N" R7 wherein R6 and R7 form, together with the nitrogen atom to which they are attached, a morpholine, thiomorpholine, piperidine, piperazine, oxazepane or thiazepane group which is unsubstituted or substituted; and (b) CH2 wherein Y is a C2 - C4 alkylene chain which contains, between constituent carbon atoms of the chain and/or at one or both ends of the chain, 1 or 2 heteroatoms selected from 0, N and S, and which is unsubstituted or substituted; R2 is -LR2' wherein L is selected from a direct bond, -0-, -CR'R"- and - NR'- wherein R' and R" are each, independently, H or C1-C6 alkyl and R2' is selected from: (a') a group of the following formula: wherein B is a phenyl ring which is unsubstituted or substituted and Z is selected from H, -OR, -SR, CiI2OR, -CO2R, CF2OH, CH(CF3)OH, C(CF3)20H, - (CH2)qOR, (CH2)qNR2 C(O)N(R)2, NR2, NRC(O)R, S(O)rnN(R)2, 0C(O)R, OC(O) N(R)2, -NRS(O) mR, -NRC(O)N(R)2 CN, halogen and -NO2, wherein each R is independently selected from H, C1-C6 alkyl, C3 - C10 cycloalkyl and a 5- to 12- membered aryl or heteroaryl group, the group being unsubstituted or substituted, m islor2andqisO,lor2; (b') a heteroaryl group which contains 1, 2, 3 or 4 ring nitrogen atoms and 0, 1 or 2 additional heteroatoms selected from 0 and S, which group is monocyclic or bicyclic and which is unsubstituted or substituted; and (c') a group comprising a benzene ring which is unsubstituted or substituted and which is fused to a heteroaryl group as defined above; and either (a") one of R8 and R9 is H and the other is C1 C6 alkyl or a group of formula (II) as defined above; or (b") R8 and R9 together form, with the carbon atoms to which they are attached, a ring selected from a benzene ring and an imidazole ring, which ring is substituted by a group R3 as defined above; or a pharmaceutically acceptable salt thereof.

5. A compound which is selected from: 3 3 -(4-Morpholin-4-yl-pyrimidin2yl)phenol; 3 -Morpholin-4-yl-biphenyl-3 -ol; 3 -(6-Morpholin-4-yl-9H-purin2yl)pbeno1; 3 -( I -Morpholin-4-yl-i soquinolin-3 -yl)-phenol; 3 -(4-Methyl-6-morpholin-4-yl -pyrimidin-2-yl)-phenol; 3 -(5 -Methyl-4-morpholin-4-yl-pyrimidjn2-yl)phenol; 3 -(6-Morpholin-4-yl-pyri din-2-yl)-phenol; 3 -(4-Morpholin-4-yl-pyri din-2-yl)-phenol; 3 -[2-(4-Methyl-piperazin- I -yl)-6-morpho] in-4-yl-pyrimidin-4-yI]- phenol; 3 -(2-Morpholin-4-yl-pyrimidin-4-yl)-phenol; 3- [6-(4-methyl-piperazin- 1 -ylmethyl)-4-morpholin-4-yI -quinazolin-2-yI] -phenol; and 2-{4-[2-(1 H-lndazol-4-yl)-4-morpholin4yl..quinazol in-6-ylmethyl]- piperazin- l-yl}ethanol; and the pharmaceutically acceptable salts thereof

6. A process for producing a compound as defined in claim 1 which is monocyclic, which process comprises: treating a compound of formula (III) : R1 (lit) xxcI wherein R', X' and X2 are as defined in claim 1, with a boronic acid of formula R2B(OH)2 wherein R2 is as defined in claim I, in the presence of a Pd catalyst.

7. A process for producing a compound as defined in claim I which i bicyclic, which process comprises: (a) treating a compound of formula (V): wherein Q and R1 are as defined in claim 2, with a boronic acid of formula R2B(OH)2 in which R2 is as defined in claim 2, in the presence of a Pd catalyst; and treating the resulting compound of formula (VI): R1 O\ I) HN2 wherein Q, R and R2 are as defined above, with an amine of formula NI1R4R5 in which R4 and R5 are as defined in claim 2, in the presence of a suitable reducing agent; or (b) treating a compound of formula (V) as defined above with an amine of formula NHR4R5 wherein R4 and R5 are as defined above, in the presence of a suitable reducing agent; and treating the resulting compound of formula (VII): R1 R\ N (Vii) R1 wherein Q, R', R4 arid R5 are as defined above, with a boronic acid of formula R2B(OH)2 in which R2 is as defined above, in the presence of a Pd catalyst.

8. A process according to claim 6 or 7 which further comprises converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier or diluent and, as an active ingredient, a compound as claimed in any one of claims 1 to 5.

10. A compound as defined in claim I for use in a method of treatment of the human or animal body by therapy.

11. Use of a compound as defined in claim 1 in the manufacture of a medicament for treating a disease or disorder arising from abnormal cell growth, function or behaviour associated with P13 kinase.

12. Use according to claim 11 wherein the disease or disorder is selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, nietabolismlendocrine disorders and neurological disorders.

13. A method of treating a disease or disorder arising from abnormal cell growth, function or behaviour associated with P13 kinase, which method comprises administering to a patient in need thereof a compound as defined in claim 1.

14. A method according to claim 13 wherein the disease or disorder is selected from the group consisting of cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders.