WO2008152387A1

WO2008152387A1 - Quinazoline derivatives as pi3 kinase inhibitors

Info

Publication number: WO2008152387A1
Application number: PCT/GB2008/002009
Authority: WO
Inventors: Stewart J. Baker; Timothy Colin Hancox; Neil Anthony Pegg; Alan John Nadin; Stephen Price
Original assignee: F.Hoffmann-La Roche Ag
Priority date: 2007-06-12
Filing date: 2008-06-12
Publication date: 2008-12-18

Abstract

The invention provides a compound which is a quinazoline of formula (I): and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over other class Ia PI3 kinases and over class Ib kinases. The compounds may 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 function disorders and neurological disorders.

Description

QUINAZOLINE DERIVATIVES AS PI3 KINASE INHIBITORS

Field of the Invention

The present invention relates to indolyl quinazoline compounds and to their use as inhibitors of phosphatidylinositol 3-kinase (PI3K).

Background to the Invention

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

PBK was originally considered to be a single enzyme, but it has now been clarified that a plurality of subtypes are present in PI3K. Each subtype has its own mechanism for regulating activity. Three major classes of PBKs 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 PBKs are PI, PI 4-phosρhate (PI4P) and PI 4,5-biphosphate (PI (4,5)P2). Class I PBKs are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism. Class Ia PBKs include PBK pi 10a, pi lOβ and pi lOδ subtypes, which transmit signals from tyrosine kinase-coupled receptors. Class Ib PBK includes a pi 1 Oγ subtype activated by a G protein-coupled receptor. PI and PI(4)P are known as substrates for class II PBKs. Class II PBKs include PBK C2α, C2β and C2γ subtypes, which are characterized by containing C2 domains at the C terminus. The substrate for class III PBKs is PI only.

In the PI3K subtypes, the class Ia subtype has been most extensively investigated to date. The three subtypes of class Ia 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 PBK activity of the pi 10 catalytic subunit which phosphorylates its lipid substrate. Thus, the class Ia subtypes are considered to be associated with cell proliferation and carcinogenesis, immune disorders and conditions involving inflammation. WO 01/083456 describes a series of condensed heteroaryl derivatives which have activity as inhibitors of PI3 K and which suppress cancer cell growth.

Summary of the Invention It has now been found that a series of novel quinazoline compounds have activity as inhibitors of PI3K. The compounds exhibit selectivity for the pi lOδ subtype of PI3 kinase, over both other class Ia and class Ib PDKs. Accordingly, the present invention provides a compound which is a quinazoline of formula (I):

wherein

R¹ and R² form, together with the N atom to which they are attached, a group of the following formula (Ha):

in which A is selected from:

(a) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O, the ring being unsubstituted or substituted;

(b) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O, the ring being fused to a second ring selected from a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, a 5- to 12-menibered unsaturated heterocyclic ring, a 5- to 7-membered saturated O-containing heterocyclic ring, a 3- to 12- membered saturated carbocyclic ring and an unsaturated 5- to 12- menibered carbocyelic ring to form a heteropolycyclic ring system, the heteropolycyclic ring system being unsubstituted or substituted;

(c) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and which further comprises, linking two constituent atoms of the ring, a bridgehead group selected from -(CR'₂)_n~ and -(CR'₂)_r-O-(CR'₂)_s- wherein each R' is independently H or C₁ - Ce alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the remaining ring positions being unsubstituted or substituted; and

(d) a group of formula (lib) :

(lib)

wherein ring B is a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and ring B' is a 3- to 12- membered saturated carbocyclic ring, a 5- to 7- membered saturated O-containing heterocyclic ring or a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, each of B and B' being unsubstituted or substituted; or one of R¹ and R² is C₁ - C₆ alkyl and the other of R¹ and R² is selected from a 3- to

12- membered saturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated heterocyclic group which is unsubstituted or substituted, a 4- to 12- membered saturated heterocyclic group which is unsubstituted or substituted and a C₁ - C₆ alkyl group which is substituted by a group selected from a 3- to 12- membered saturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated heterocyclic group which is unsubstituted or substituted and a 4- to 12-membered saturated heterocyclic group which is unsubstituted or substituted; m is 0, 1 or 2; R³ is H or C₁-C₆ alkyl;

R^a is selected from R, halo, CN, C(O)NR₂, halo(d-C₆)alkyl, SO₂R, SO₂NR₂, NRSO₂R, NRC(O)R, NRC(O)OR, NRC(O)NR₂, OR and NR₂, wherein each R is independently H or Ci-C₆ alkyl; and R⁴ is an indole group which is unsubstituted or substituted; or a pharmaceutically acceptable salt thereof.

Detailed description of the Invention

As used herein, the term "fused" indicates that two rings are joined together by a common bond between two adjacent ring atoms. The term "spiro-fused" indicates that two rings are linked through a single common carbon atom, The term "bridgehead" denotes a linking group, of one or more atoms in length, which connects two non-adjacent ring atoms. In each of these three cases a polycyclic (typically a bicyclic) structure is the result.

When any group, ring, group, ring, substituent or moiety defined herein is substituted, it is typically substituted by Z or R⁵ as defined below.

A C₁-C₆ alkyl group is linear or branched. A Cj-C₆ alkyl group is typically a C₁-C₄ alkyl group, for example a methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group. A Ci-C₆ alkyl group is unsubstituted or substituted, typically by one or more groups Z or R⁵ as defined below. Typically it is C₁-C₄ alkyl, for example methyl, ethyl, i-propyl, n- propyl, t-butyl, s-butyl or n-butyl.

Z is selected from H, unsubstituted Ci-C₆ alkyl, halo, -OR₅ -SR, -(C(R⁶)₂)_qR, - CH₂OR, -CF₃, -(halo)-Ci-C₆ alkyl, -(C(R⁶)₂)_qO-(halo)-C_rC₆ alkyl, -CO₂R, -(C(R⁶)₂)_qCO₂R, - (C(R⁶)₂)_qCOR, CF₂OH, CH(CF₃)OH₅ C(CF₃)₂OH, -(CH₂)_qOR, -(C(R⁶)₂)_qOR, -(CH₂)_qNR₂, -

-C(O)N(R)₂, -(C(R⁶)₂)_qCONR₂ , -NR₂, -(C(R⁶)₂)_qNR₂, -(C(R⁶)₂)_qNRC(O)R, - (C(R⁶)₂)_qNRC(O)OR, -S(O)_PR, -S(O)_PN(R)₂, -(C(R⁶)₂)_qS(O)_pN(R)₂, -OC(O)R, - (C(R^₂)_C1OC(O)R, -OC(O)N(R)₂, -(C(R⁶)₂)_qOC(O)N(R)₂, -NRS(O)_PR, -(C(R⁶)₂)_qNRS(O)_pR, - NRC(O)N(R)₂, -(C(R⁶)₂)_qNRC(O)N(R)₂, CN, -NO₂, =0, a 3- to 12- membered saturated carbocyclic ring which is unsubstituted or substituted, a 5- to 12-membered unsaturated carbocyclic which is unsubstituted or substituted, a 5- to 12-membered unsaturated heterocyclic group which is unsubstituted or substituted and a 4- to 12-membered saturated heterocyclic group which is substituted or unsubstituted, wherein each R is independently selected from H, C₁-C₆ alkyl, C₃-C_1O cycloalkyl and a 5- to 12-membered aryl or heteroaryl group, the group being unsubstituted or substituted, or when two groups R are attached to an N atom they form, together with the N atom, a 4- to 7-membered saturated N-containing heterocyclic ring; p is 1 or 2 and q is 0, 1 or 2.

R⁵ is selected from C₁-C₆ alkoxy, OR⁶, SR⁶, S(O)_PR⁶, nitro, CN, halogen, -C(O)R⁶, - CO₂R⁶, -C(O)N(R⁶)₂ and -N(R⁶)₂. R⁶, each of which is the same or different when more than one is present in a given substituent, is selected from H, C₁-C₆ alkyl and C₃-C1₀ cycloalkyl, and p is 1 or 2. A halogen or halo group is F, Cl, Br or I. Preferably it is F, Cl or Br. A Ci-C₆ alkyl group substituted by halogen may be denoted by the term "1IaIo-C₁-C₆ alkyl", which means an alkyl group in which one or more hydrogens is replaced by halo. A halo-Ci-C6 alkyl group preferably contains one, two or three halo groups. A preferred example of such a group is trifluoromethyl. A Ci-C ₆ alkoxy group is linear or branched. It is typically a C₁-C₄ alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-propoxy, n-butoxy, sec-butoxy or tert- butoxy group. A C₁-C₆ alkoxy group is unsubstituted or substituted, typically by one or more groups Z or R⁵ as defined above.

A C₃-Ci_O cycloalkyl group may be, for instance, C₃-C₈ cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Typically it is C₃-C₆ cycloalkyl. A C₃- Cio cycloalkyl group is unsubstituted or substituted, typically by one or more groups Z or R^f as defined above.

A 4- to 7-membered saturated N-containing heterocyclic ring typically contains one nitrogen atom and either an additional N atom or an O or S atom, or no additional heteroatoms. It may be, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine or homopiperazine.

A 4- to 7-membered saturated N-containing heterocyclic ring as defined above is unsubstituted or substituted on one or more ring carbon atoms and/or on any additional N atom present in the ring. Examples of suitable substituents include one or more groups Z or R⁵ as defined above, and a Ci-C₆ alkyl group which is unsubstituted or substituted by a group Z or R⁵ as defined above.

Specific examples of a 4- to 7-membered saturated N-containing heterocyclic ring which is substituted as defined above include the following structures:

(i) (ϋ)

(iii) (iv)

(V) (vi)

(vii) (viii)

A 5- to 7-membered saturated O-containing heterocyclic ring contains at least one O atom and 0, 1 or 2, typically 0 or 1, additional heteroatoms selected from O, N and S. It is, for instance, tetrahydrofuran, tetrahydropyran, oxetane or morpholine. A 3- to 12- membered saturated carbocyclic group is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10, 11- or 12-membered carbocyclic ring containing only saturated bonds. It is a monocyclic or fused bicyclic ring system. It is, for instance, a 3- to 7-membered saturated carbocyclic ring. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, and bicyclic ring systems in which two such rings are fused together. Specific examples of a 3- to 12- membered saturated carbocyclic group include the following structures:

A 5- to 12-membered unsaturated carbocyclic group is a 5-, 6-, 7-, 8-, 9-, 10, 11- or 12-membered carbocyclic ring containing at least one unsaturated bond. It is a monocyclic or fused bicyclic ring system. The group is non-aromatic or aromatic, for instance aryl. Thus, in one embodiment, a 5- to 12-membered unsaturated carbocyclic group is a 5- to 12-membered aryl group. Examples of a 5- to 12-membered unsaturated carbocyclic group include benzene, naphthalene, indane, indene and tetrahydronaphthalene rings, or phenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl groups. The group is unsubstituted or substituted, typically by one or more groups Z or R⁵ as defined above. Specific examples of a 5- to 12- membered unsaturated carbocyclic group include the following structure:

An aryl group is a 5- to 12-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 R⁵ as defined above. Specific examples of an aryl group include the following structures:

A 5- to 12-membered unsaturated heterocyclic group is a 5-, 6-, 7-, 8-, 9-, 10, 11- or 12- membered heterocyclic ring containing at least one unsaturated bond and at least one heteroatom selected from O, N and S. It is a monocyclic or fused bicyclic ring system. The group is non-aromatic or aromatic, for instance heteroaryl. Thus, in one embodiment a 5- to 12- membered unsaturated heterocyclic group is a 5- to 12-membered heteroaryl group. The 5- to 12-membered unsaturated heterocyclic group maybe, for example, furan, thiophene, pyrrole, pyrrolopyrazine, pyrrolopyrimidine, pyrrolopyridine, pyrrolopyridazine, indole, isoindole, pyrazole, pyrazolopyrazine, pyrazolopyrimidine, pyrazolopyridine, pyrazolopyridazine, imidazole, imidazopyrazine, imidazopyrimidine, imidazopyridine, imidazopyridazine, benzimidazole, benzodioxole, benzodioxine, benzoxazole, benzothiophene, benzothiazole, benzofuran, indolizinyl, isoxazole, oxazole, oxadiazole, thiazole, isothiazole, thiadiazole, dihydroimidazole, dihydrobenzofuran, dihydrodioxinopyridine, dihydropyrrolopyridine, dihydrofuranopyridine, dioxolopyridine, pyridine, quinoline, jsoquinoline, purine, quinoxaline, tetrahydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline, 5,6,7,8-tetrahydro-imidazo[l ,5-a]pyrazine, 5,6,7,8-tetrahydro-imidazo[l,2-a]pyrazine, thienopyrazine, pyrimidine, pyridazine, pyrazine, triazine, triazole or tetrazole. The group is unsubstituted or substituted, typically by one or more groups Z or R⁵ as defined above. Specific examples of a 5- to 12- membered unsaturated heterocyclic group include the following structures:

Heteroaryl is a 5- to 12- membered aromatic heterocyclic group which contains 1, 2, 3, or 4 heteroatoms selected from O, N and S. It is monocyclic or bicyclic. Typically it contains one N atom and 0, 1, 2 or 3 additional heteroatoms selected from O, S and N. It may be, for example, a 5- to 7-membered heteroaryl group. Typically it is selected from the heteroaryl groups included in the above list of options for a 5 to 12- membered unsaturated heterocyclic group. A 4- to 12- membered saturated heterocyclic group is a A-, 5-, 6-, 7-, 8-, 9-, 10, 11- or

12- membered heterocyclic ring which contains 1, 2, 3, or 4 heteroatoms selected from O, N and S. It is a monocyclic or fused bicyclic ring system. Examples of such heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, dithianyl, dithiolanyl, imidazolidinyl, 3- azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Spiro moieties are also included within the scope of this definition. In one embodiment the saturated 4- to 12-membered saturated heterocyclic group is a 4- to 7-membered saturated N- containing heterocyclic ring as defined above, which is unsubstituted or substituted. The saturated 4- to 12-membered heterocyclic group is unsubstituted or substituted, typically by one or more groups Z or R⁵ as defined above. Further specific examples of a 4- to 12- membered saturated heterocyclic group (in which the heteroatom is O) include the following structures:

Examples of a 4- to 7-membered saturated N-containing heterocyclic ring which is fused to a second ring as defined above to form a heteropolycyclic ring system include a group selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and homopiperazine, said group being fused to a second ring as defined above. The second ring is typically a 4- to 7-membered saturated N-containing heterocyclic ring as defined above or a 5- to 12-membered unsaturated heterocyclic group. More typically the second ring is a 5-, 6- or 7-membered saturated N-containing heterocyclic ring or a 5- to 7-membered unsaturated heterocyclic ring. Typical examples of the second ring include azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyrrole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrahydrofuran and tetrahydropyran. Examples of the resulting heteropolycyclic system include octahydro- pyrrolo[l,2-a]pyrazine and octahydro-pyrrolo[3,4-c]pyrrole. Specific examples of the heteropolycyclic system include the following structures:

Examples of a 4- to 7-membered saturated N-containing heterocyclic group as defined above which includes a bridgehead group -(CR^)_n- or-(CR'2)r-O-(CR'2)s- as defined above include 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 8-aza- bicyclo[3.2.1]octane, 2-aza-bicyclo[2.2.1]heptane, 3,6-diaza-bicyclo[3.1.1]heptane, 6-aza- bicyclo[3.1.1]heptane, 3,9-diaza-bicyclo[4.2.1]nonane and 3-oxa-7,9- diazabicyclo[3.3. l]nonane.

Specific examples of this group include the following structures:

Examples of a group of formula (lib) as defined above include groups derived from a 4- to 7-membered saturated N-containing heterocyclic group as defined above which is spiro- fused at any available ring carbon atom to a 3 to 12- membered saturated carbocyclic ring, typically to a 3- to 6-membered saturated carbocyclic ring, or to a 4- to 7-membered saturated N-containing heterocyclic group. Examples include a group selected from azetidine, pyrrolidine, piperidine and piperazine which is spiro-fused at a ring carbon atom to a group selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, azetidine, pyrrolidine, piperidine, piperazine and tetrahydropyran.

The group of formula (lib) may, for instance, be a group derived from 3,9- diazaspiro[5.5]undecane₅ 2,7-diazaspiro[3.5]nonane, 2,8-diazaspiro[4.5]decane or 2,7- diazaspiro[4.4]nonane. Specific examples of a group of formula (lib) include the following structures:

(Ui') (iv")

(vii') (viii') (ix')

(X') R⁴ is an indolyl group which is unsubstituted or substituted. The indolyl group may be linked to the quinazoline core via any available ring position. It may, for instance, be an indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl group. Typically it is indol-4-yl or indol-6-yl, more typically an indol-4-yl group. When substituted, the indolyl may be substituted at one or more available ring positions. Typically it bears a substituent on the benzene moiety of the indole group. For instance, an indol-4-yl group is typically substituted at the 5- , 6- or 7-ρosition, more typically at the 5- or 6-position. An indol-5-yl group is typically substituted at the A-, 6- or 7- position, more typically at the 4- or 6-position. An indol-6-yl group is typically substituted at the 4-, 5- or 7-position, more typically at the 4- or 5- position. An indol-7-yl group is typically substituted at the 4-, 5- or 6-position, more typically at the 5- or 6-position.

When the indolyl group is substituted it may be substituted by a group Z or R⁵ as defined above, hi a typical embodiment the indolyl group is substituted by a group selected from R, -OR₅ -SR, -S(O)_PR, CH₂OR, -C(O)R, -CO₂R, CF₃, CF₂OH₅ CH(CF₃)OH, C(CF₃)₂OH, -(CH₂)_qOR, -(CH₂)_qNR₂ , -C(O)N(R)₂, -NR₂, -N(R)C(O)R₅ -S(O)_PN(R)₂, -OC(O)R,

OC(O)N(R)₂, -N(R)S(O)_PR , -NRC(O)N(R)₂, CN, halo, -NO₂ and a 5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S₅ wherein R, p and q are as defined above in the definition of Z. In another typical embodiment the indolyl group is substituted by a group selected from C₁ - C₆ alkyl, CN₅ halo, -C(O)NR₂, halo(Ci-C₆)alkyl such as CF_3, NO₂ , OR₅ SR, NR₂, C(O)R, SOR, SO₂ R, SO₂NR₂ , NRC(O)R₅ CO₂ R and a 5- membered heteroaryl group as defined above, hi another more typical embodiment the indolyl group is substituted by a group selected from CN, halo, -C(O)NR₂, halo(Ci-C₆)alkyl such as CF₃, -SO₂R, -SO₂NR₂, and a 5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O₅ N and S. hi the above embodiments R is typically H or Ci-C₆ alkyl.

Typically the substituent on the indolyl group is an electron-withdrawing group. When the substituent is a 5-membered heteroaryl group it may be, for example, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, or thiadiazole.. hi one embodiment a substituted indolyl group is an indol-4-yl group substituted at the

5- or 6-position, in particular the 6-position, by CN, halo, -C(O)NH₂, -CF₃, -SO₂Me₅ - SO₂NMe₂ or a 5-membered heteroaryl group as defined above. Typically the indol-4-yl group is substituted at the 5- or 6-position by halo, in particular by F. More typically the indol-4-yl group is substituted at the 6-position by halo, in particular by F.

The parameter m in formula (I) is 0, 1 or 2. Typically m is 1 or 2. More typically m is 1. In formula (I)₅ a 4- to 12- membered saturated heterocyclic group in the definitions of

R¹ and R² may be a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O. A 5- to 12- membered unsaturated heterocyclic group in the definitions of R¹ and R² may be a 5- to 12- membered heteroaryl group. A 5- to 12- membered unsaturated carbocyclic group in the definitions of R¹ and R² may be a 5- to 12- membered aryl group.

In one aspect the invention provides a compound which is a quinazoline of formula

(I):

wherein

in which A is selected from:

(b) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O, the ring being fused to a second ring selected from a 4- to 7-membered saturated N- containing heterocyclic ring as defined above, a 5- to 12-membered unsaturated heterocyclic ring, a 5- to 7-membered saturated O-containing heterocyclic ring, a 3- to 12- membered saturated carbocyclic ring and an unsaturated 5- to 12-membered carbocyclic ring to form a heteropolycyclic ring system, the heteropolycyclic ring system being unsubstituted or substituted; (c) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N₅ S and O and which further comprises, linking two constituent atoms of the ring, a bridgehead group selected from -(CR^)_n- and -(CR'₂)_r-O-(CR'₂)_s- wherein each R' is independently H or C₁ - C₆ alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1 , the remaining ring positions being unsubstituted or substituted; and (d) a group of formula (lib):

(lib)

wherein ring B is a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and ring B' is a 3- to 12- membered saturated carbocyclic ring, a 5- to 7- membered saturated O-containing heterocyclic ring or a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, each of B and B' being unsubstituted or substituted; or one of R¹ and R² is C₁ - C₆ alkyl and the other is a 4- to 7-membered saturated N- containing heterocyclic ring as defined above or a Ci - C₆ alkyl group which is substituted by a 4- to 7-membered saturated N-containing heterocyclic ring group as defined above; m is 0, 1 or 2;

R³ is H or Ci-C₆ alkyl;

R^a is selected from R, halo, CN, C(O)NR₂, halo(C_rC₆)alkyl, SO₂R, SO₂NR₂, NRSO₂R, NRC(O)R, NRC(O)OR, NRC(O)NR₂, OR and NR₂, wherein each R is independently H or Ci-C₆ alkyl; and

R⁴ is an indole group which is unsubstituted or substituted; or a pharmaceutically acceptable salt thereof.

In one embodiment the quinazoline is of formula (Ia):

wherein R¹, R², R³, R⁴, R^a and m are as defined above for formula (I), hi a second embodiment the quinazoline is of formula (Ib):

wherein R¹, R², R³, R⁴, R^b and m are as defined above for formula (I). Specific examples of compounds of the invention include those listed in the following Table 1 : Table 1

and the pharmaceutically acceptable salts thereof.

A suitable synthetic strategy for producing a quinazoline of formula (I) employs the precursor carboxaldehyde of formula (HI):

Starting from this precursor the synthesis comprises performing, in either order, a reductive animation and a palladium-mediated (Suzuki-type) cross-coupling reaction.

A compound of the invention may thus be produced by a process which comprises treating a compound of formula (III):

with an amine of formula NHR¹³R²³ in which R^la and R^2a are as defined above for R¹ and R² or R^la and R^2a are as defined above for R¹ and R² wherein an N atom is present and is protected by an amine protecting group, in the presence of a suitable reducing agent; and treating the resulting compound of formula (IV):

wherein R^la and R^2a are as defined above, with a boronic acid or ester thereof of formula R⁴B(OR¹⁵)₂ in which R⁴ is as defined above and each R¹⁵ is H or C₁-C₆ alkyl or the two groups OR¹⁵ form, together with the boron atom to which they are attached, a pinacolato boronate ester group, in the presence of a Pd catalyst; and, if R^la and/or R^2a includes an amine protecting group, removing the protecting group. Any suitable amine protecting groups may be used in R^la and/or R^2a, for instance a butoxycarbonyl (BOC) group.

A compound of formula (I) may also be produced by treating a compound of formula (III):

with a boronic acid or ester thereof of formula R⁴B(OR¹⁵)₂ in which R⁴ is as defined above and each R¹⁵ is H or Ci-C₆ alkyl, or the two groups OR¹⁵ form, together with the boron atom to which they are attached, a pinacolato boronate ester group, in the presence of a Pd catalyst; treating the resulting compound of formula (V) :

wherein R⁴ is as defined above, with an amine of formula NHR^laR^2a in which R^la and R^2a are as defined above, in the presence of a suitable reducing agent; and, if R^la and/or R^2a includes an amine protecting group, removing the protecting group. In this embodiment of the process the N atom of the indole group R⁴ may, if necessary, be protected before the compound of formula (V) is treated with the amine of formula NHR^laR^2a.

Both the reductive animation 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 reducing agent in the amination step is typically a borohydride, for instance NaBH(OAc)₃, NaBH₄ or NaCNBH₃, in particular NaBH(OAc)₃.

Intermediate compounds of formula (III) are known compounds or may be made by routine synthetic chemical techniques, for instance according to the scheme shown in the Examples which follow or by analogy with such a scheme.

Quinazo lines of formula (I) may be converted into pharmaceutically acceptable salts, and salts may be converted into the free compound, by conventional methods. Pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, and salts of organic acids such as acetic acid, oxalic acid, malic acid, methanesulfonic acid, trifluoroacetic acid, benzoic acid, citric acid and tartaric acid. In the case of compounds of the invention bearing a free carboxy substituent, the salts include both the above-mentioned acid addition salts and the salts of sodium, potassium, calcium and ammonium. The latter are prepared by treating the free quinazoline of formula (I), or an acid addition salt thereof, with the corresponding metal base or ammonia. Compounds of the present invention have been found in biological tests to be inhibitors of PB kinase. The compounds are selective for the pi lOδ isoform, which is a class Ia PB kinase, over other class Ia PB kinases. They are thus selective for the pi 10δ isoform over both the pi 1 Oa isoform and the pllOβ isoform. hi particular they are selective forpllOδ over pi lOβ. The compounds are also selective for the pi lOδ isoform over pi 10γ, which is a class Ib kinase.

The selectivity exhibited by compounds of the invention for pi lOδ over other isoforms of PB kinase is at least 2-fold. Typically the selectivity is 5-fold, or 10-fold, or 20- fold, or 50-fold, rising to 100-fold or higher in many cases. Thus the compounds may be 2- fold, 5-fold, 10-fold, 20-fold, 50-fold or 100-fold selective for pi lOδ over pi lOβ. They may also be 2-fold, 5-fold, 10-fold, 20-fold, 50-fold or 100-fold selective for p 11 Oδ over p 11 Oa or over pl lOγ .

A compound of the present invention may be used as an inhibitor of PB kinase, in particular of a class Ia PB 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 PB kinase, in particular the pi lOδ isoform of PB kinase. Examples of such diseases and disorders are discussed by Drees et al in Expert Opin. Ther. Patents (2004) 14(5):703 - 732. These include proliferative disorders such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders. Examples 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 compound of the present invention may be used as an inhibitor of PB kinase. A human or animal patient suffering from a disease or disorder arising from abnormal cell growth, function or behaviour associated with PB kinase, in particular with the pi 1 Oδ isoform of PB kinase such as an immune disorder, cardiovascular disease, viral infection, inflammation, a metabolism/endocrine disorder or a neurological disorder, may thus be treated by a method comprising the administration thereto of a compound of the present invention as defined above. A human or animal patient suffering from cancer may also 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.

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 50 mg/kg, most commonly in the range of 0.001 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 0.0001 to 1 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 of the invention 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 be 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, hydroxypropylmethyl- cellulose, sodium alginate, polyvinylpyrrolidone gum 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 monooleate.

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 polyoxy ethylene 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. In particular a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise 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) Parenterally, either subcutaneously, or intravenously, or intramuscularly, or intrasternally, 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 1,3-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 suspesions.

The invention will be further described in the Examples which follow:

EXAMPLES

General Synthetic Procedure

The following general scheme depicts the synthetic approach referred to in the Reference Examples and Examples which follow:

Scheme 1

Conditions: (i) Urea, 185⁰C, 5 hours, (ii) POCI₃, 115^CC, 12 - 48 hours. (Hi) Morpholine, MeOH, room temperature, (iv) nBuLi, THF, -78°C. (v) DMF, -78°C to room temp, (vi Reductive amination. (vii) Suzuki coupling under microwave hearing. Scheme 2

(i) - (iϋ) (iv) - (vi) (vii)

Conditions: (i) DMF, TFAA, 0 ⁰C. (ii) 10% aq NaOH, 100 ⁰C, Ih. (iii) MeOH, H₂SO₄, 65⁰C, 18 h. (iv) Tl(OCOCF₃)_3s TFA, RT, 2 h. (v) H₂O, KI, RT. (vi) MeOH, 40% aq NaOH, 65 ⁰C, 2 h. (vii) pinacol borane, Et₃N, Dioxane, Pd(OAc)₂, bis(cyclohexyl)phosphino-2-biphenyl, 80°C, 30 min.

General Experimental Details:

NMR spectroscopy

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5 mm inverse detection triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 5 mm inverse detection triple resonance TXI probe operating at 400 MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300 MHz. Shifts are given in ppm relative to tetramethylsilane.

Purification by column chromatography

Compounds purified by column chromatography were purified using silica gel or Isolute® cartridge or Redisep® cartridge, eluting with gradients from 100-0 to 0-100 % of cyclohexane/EtOAc, or from 100-0 to 0-100 % pentane/EtOAc or from 100-0 to 70-30 % DCM/MeOH (with or without the addition OfNH₃ 0.1 %). 'Silica gel' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution. Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using plates, typically 3 x 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm), (e.g. Fluka 60778).

Purification by preparative HPLC: Compounds purified by preparative HPLC were purified using a C 18-reverse-phase column (100 x 22.5 mm i.d Genesis column with 7 μm particle size, UV detection at 230 or 254 nm, flow 5-15 mL/min), or a Phenyl-Hexyl column (250 x 21.2 mm i.d. Gemini column with 5 μm particle size, UV detection at 230 or 254 nm, flow 5-20 mL/min), eluting with gradients from 100-0 % to 0-100 % water/acetonitrile or water/MeOH containing 0.1 % TFA or water/acetonitrile containing 0.1 % formic acid. The free base was liberated by partitioning between EtOAc and a sat. solution of sodium bicarbonate. The organic layer was dried (MgSO₄) and concentrated in vacuo. Alternatively, the free base was liberated by passing through an Isolute® SCX-2 cartridge, eluting with NH₃ in methanol.

Abbreviations used in the experimental section: aq. = aqueous

BOC = ϊ-Butoxycarbonyl bs = broad singlet (NMR)

Cs₂CO₃ = cesium carbonate d = doublet (NMR)

DCM = dichloromethane

DIPEA = diisopropylethylamine

DMA = dimethylacetamide

DMAP = dimethylaminopyridine DMF = dimethylformamide

DMSO = dimethylsulfoxide eq. = equivalents

EtOAc = ethyl acetate

EtOH = ethanol h = hour(s)

HATU = ^-(y-Azabenzotriazol-l-y^-ΛζN_^/VJV-tetramethyluronium hexafluorophosphate

HCl = hydrochloric acid

Jj₂O = water

HPLC = high pressure liquid chromatography IMS = industrial methylated spirit

/PrOH = isopropanol

LCMS = liquid chromatography mass spectrometry

M = molar m = multiple! (NMR)

MeOH = methanol mg = milligram

MgSO₄ = magnesium sulphate min = minute(s) mL = millilitre

Na₂CO₃ = sodium carbonate

NaHCO₃ = sodium hydrogen carbonate

NaOH = sodium hydroxide Na₂SO₄ = sodium sulfate

NMR = nuclear magnetic resonance q = quartet (NMR)

Rt = retention time

RT = room temperature sat = saturated t = triplet (NMR)

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

Reference Example 1 : Preparation of 6-bromo-lH-quinazoline-2, 4-dione

A mixture of methyl-2-amino-5-bromobenzoate (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 solid residue treated with 2M sodium hydroxide (400 ml) for 6hours at room temperature, then acidified with concentrated hydrochloric acid at 0⁰C to give a white solid which was collected by filtration, washed with water and dried to give the title compound (12.5 g), as a white solid. δ_H (400 MHz, DMSO) 7.06 (d, IH)₅ 7.68 (dd, IH), 7.88 (s, IH). Reference Example 2 Preparation of 6-bromo-2, 4-dichloroαuinazoline

A mixture of 6-bromo-lH-qumazoline-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 oxychloride removed in vacuo to give an oily residue which was quenched carefully with ice/water at 0⁰C and the precipitate collected by filtration, washed with water and dried to give the title compound (10.2 g), as a white solid. δ_H(400 MHz, DMSO) 7.98 (d, IH), 8.28 (dd, IH), 8.45 (s, IH).

Reference Example 3: Preparation of 6-bromo-2-chloro-4-morphoIin-4-yl- quinazoline

A mixture of 6-bromo-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 (5.3 g), as a yellow solid δ_H (400 MHz, DMSO) 3.74 (m, 4H), 3.86 (m, 4H), 7.65 (d, IH), 7.95 (dd, IH), 8.15 (s, IH)

Reference Example 4: Preparation of 2-chloro-4-morpholin-4-yl-quinazoline-6- carb aldehyde

To 6-bromo-2-chloro-4-moφholin-4-yl-quinazoline (4.3 g) stirring in anhydrous tetrahydrofuran at -78⁰C 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 anhydrous dimethyl formamide (1.52 ml) was added dropwise over 5 minutes and stirred for 1 hour at -78⁰C , 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 (MgS 04) and the solvent removed in vacuo to give a residue which was purified using flash chromatography to yield the title compound (2.66 g), as a pale yellow solid. δ_H (400 MHz, DMSO) 3.78 (m, 4H), 3.98 (m, 4H), 7.78 (d, IH), 8.16 (dd, IH)₅ 8.60 (s, IH), 10.15 (s, IH).

Reference Example 5: Preparation of 2-chIoro-6- ( 4-methvI-piperazin-l-γI- methyl ) -4-morphoIin-4-yI-quinazoline

To a mixture of 2-chloro-4-morpholin-4-yl-quinazoline-6-carbaldehyde (176 mg) and 1-methylρiperazine (92μl) stirring in anhydrous 1, 2-dichloroethane (8 ml) was added glacial acetic acid (38 μl) followed by sodium triacetoxyborohydride (184 mg). The mixture was stirred for 12 hours at room temperature, then diluted with dichloromethane (20 ml) and washed with 50 % 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(108 mg) as a white solid. δ_H (400 MHz, CDCl₃) 2.31 (s, 3H), 2.52 (m, 8H), 3.63 (s, 2H), 3.88 (m, 8H), 7.72-7.79 (m,

3H).

Reference Example 6 5-FIuoro-4-(4,4-5,5-tetramethyl-ri,3.21dioxaborolaii-2-yl)- lff-indole

A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 mL) was treated at 0 °C with trifluoroacetic anhydride (6.1 mL₅ 42.6 mmol). After 30 min, the reaction was poured into water and the resulting precipitate collected by filtration, washed with water, then dried in vacuo. The solid was then dissolved in 10% aqueous NaOH (200 mL) and heated at reflux for 1 h. The reaction mixture was then cooled, washed with dichloromethane and acidified with aqueous HCl. The resulting white precipitate was collected by filtration, washed with water, taken up in dichloromethane, washed with water, dried (MgSO₄) and evaporated in vacuo. The resulting material (5 g, 75%) was dissolved in methanol (80 mL) and treated with concentrated sulfuric acid (2 mL) then heated at reflux overnight. The reaction was cooled and the resulting precipitate collected, washed with water and evaporated in vacuo to give 5- fluoro-lH-indole-3-carboxylic acid methyl ester as a peach-coloured solid (4.5 g, 83 %).

A solution of thallium tris(trifluoroacetate) (8.45 g, 15.6 mmol) in TFA (35 mL) was added to a solution of S-fluoro-lH-indole-S-carboxylic acid methyl ester (2 g, 10.4 mmol) in TFA (10 mL) at room temperature and stirred for 2 h. The reaction mixture was evaporated in vacuo and the resulting residue suspended in water (25 mL) before being treated with a solution of potassium iodide (5.2 g, 31.3 mmol) in water (50 mL). The reaction mixture was treated with dichloromethane (100 mL) and methanol (5 mL) and the resulting precipitate removed by filtration through celite.

The organic layer was separated, washed successively with sodium thiosulfate solution and brine, then dried (MgSO₄) and evaporated in vacuo. The resultant material was dissolved in methanol (60 mL) and treated with 40% aqueous NaOH solution (60 mL) then refluxed for 2 h. The reaction mixture was cooled and extracted with DCM/MeOΗ (ratio 95:5), dried (MgSO₄), filtered and evaporated in vacuo to give a crude solid. Purification by column chromatography gave 5-fluoro-4-iodo-lH-indole as a pale brown solid (1.05 g, 39 %). NMR δ_Η (300 MHz, CDCl₃) 6.49-6.52 (m, IH), 6.95 (apparent dt, J = 0.4, 8.6, IH), 7.26-7.33 (m, 2H) and 8.35 (s, IH). A solution of 5-fluoro-4-iodo-lH-indole (261 mg, 1.0 mmol) in dioxane (1 mL) was treated with triethylamine (0.2 mL, 1.4 mmol), palladium acetate (4.5 mg, 0.02 mmol) and bis(cyclohexyl)phosphino-2-biphenyl (28 mg, 0.08 mmol) then heated to 80 ⁰C. A solution of pinacolborane (1 M in TΗF, 2.66 mL, 2.66 mmol) was added via syringe. After 30 min, the reaction mixture was cooled, then diluted with water (10 mL) and DCM (10 mL). The resulting mixture was passed through a phase separation cartridge, and the dichloromethane layer was evaporated in vacuo to obtain the title compound which was used without further purification.

l-Bromo-5-flnoro-2-methyl-3-nitro-benzene

To a solution of 4-fluoro-2-nitrotoluene (10.0 g, 64.4 mmol) in trifluoroacetic acid (40 mL) was added concentrated sulfuric acid (12.5 mL) followed by N-bromosuccinimide (17.2 g, 96.6 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was then poured onto ice and water and stirred for 15 min. The product was then extracted into ethyl acetate and the organic layer washed with brine, dried over MgSO₄ and evaporated to dryness to give the title compound as a pale oil which crystallised out on standing (11.76 g,

77 %).

ΝMR δ_Η (300 MHz, CDCl₃) 2.59 (s, 3H), 7.50 (dd, J = 2.8, 7.6, IH) and 7.58 (dd, J = 2.9, 7.4,

IH).

Reference Example 8 4-Bromo-6-fluoro-l/7-indole

To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) was added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mniol). The reaction mixture was heated at 100 ⁰C. The mixture was cooled to RT and evaporated to dryness to give l-[2-(2-bromo-4-fluoro-6-mtro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue (10.0 g, theoretical yield). To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney®-Nickel (suspension in H₂0, 15 mL) in MeOH:THF (1:1, 150 mL) was added hydrazine monohydrate (2.3 mL, 47.4 mmol) at 0 ⁰C and the mixture stirred at RT for 5 hours. The reaction mixture was then filtered through Celite and the filter cake washed with EtOAc. The filtrate was evaporated to dryness and the resulting residue to give the title compound as pale oil (2.57 g, 37 %). NMR δ_H (300 MHz, CDCl₃) 6.57 (apparent t, J = 2.7, IH), 7.04 (dd, J = 2.1, 9.1, IH), 7.12 (dd, J = 2.1, 9.1, IH), 7.20-7.25 (m, IH) and 8.25 (s, IH).

Reference Example 9 6-FIuoro-4-f4.4,5.5-tetramethvI-[l,3-21dioxaboroIan-2-vL)- lH-indoIe

To a stirring mixture of 4-bromo-6-fluoro-lH-indole (6.76 g, 31.5 mmol), bis(pinacolato)diboron (12.8 g, 94.7 mmol) and potassium acetate (9.3 g, 94.7 mmol) in methyl sulfoxide (100 mL) was added l,r-bis(diphenylphosphine)ferrocene- dichloropalladium (1.29 g, 5 mol %). The reaction mixture was flushed out with nitrogen and heated to 100 ⁰C for 16 hours. The mixture was partitioned between ethyl acetate and water and the organic layer washed with brine, dried over MgSO₄ and evaporated down. The crude product was purified by column chromatography followed by triturating to yield the title compound (7.87 g). δ_H(400MHz, CDCl₃) 1.41 (s, 12H)₅ 7.04 (m, IH), 7.16 (dd, IH), 7.26 (t, IH)₅ 7.40 (dd, IH)₅ 8.14 (br S₅ IH).

Reference Example 10 2-Chloro-4-morphoIine-4-yl~Quinazolin-6-ylmethyI-methvI-

(l-methvl-piperidin-4-vD-amine

A mixture of 2-chloro-4-morpholin-4-yl-quinazoline-6-carbaldehyde (150 mg), methyl-(l-methyl-piperidin-4-yl)-amine (123 μl), glacial acetic acid (33 μl) and sodium triacetoxyborohydride (172 mg) was stirred in anhydrous 1,2-dichloroethane (6 ml) for 12 hours at room temperature, then diluted with dichloromethane (20 ml) and washed with 50 % sodium bicarbonate solution. The organic phase was dried (MgSO₄) and the solvents removed in vacuo to give a residue which was purified using flash silica chromatography to yield the title compound (109 mg) as a white solid. δ_H(400 MHz, CDCl₃) 1.74 (m, 2H); 1.81 (m, 2H); 1.97 (m, 2H); 2.23 (s, 3H); 2.29 (s, 3H); 2.47 (m, IH); 2.94 (m, 2H); 3.69 (s, 2H); 3.89 (m, 8H); 7.75 (m, 3H).

Reference Example 11 2-ChIoro-4-morphoIin-4-yl-6-(4-morpholin-4-vI-piperidin-l- ylmethvD-quinazoIine

Prepared using the method described for 2-chloro-4-morpholine-4-yl-quinazolin-6- ylmethyl-methyl-( 1 -methyl-piperidin-4-yl)-amine using 2-chloro-4-rnorpholin-4-yl- quinazoline-6-carbaldehyde and 4-piperidin-4-yl-morpholine to give a white solid (108 mg). δ_H(400 MHz, CDCl₃) 1.52 (m, 2H); 1.84 (m, 2H); 2.06 (m, 2H); 2.21 (m, IH); 2.57 (m, 4H); 2.93 (m, 2H); 3.62 (s, 2H); 3.79 (m, 4H); 3.90 (m, 8H); 7.74 (m, IH); 7.80 (m, 2H).

Reference Example 12 2-Chloro-6-KSVl-(hexahvdro-pyrrolo[1.2-alpyrazin-2- yl)methvI]-4-morphoIin-4-yl-αiiinazoline

Prepared using the method described for 2-chloro-4-morpholine-4-yl-quinazolin-6- ylmethyl-methyl-(l -methyl-piperidin-4-yl)-amine using 2-chloro-4-morpholin-4-yl- quinazoline-6-carbaldehyde and (S)-octahydro-pyrrolo[l,2-a]pyrazine to give a white solid (118 mg). δ_H(400 MHz, CDCl₃) 1.19-2.24 (m, 8H); 2.78 (m, 2H); 2.95 (m, 2H); 3.00 (m, IH); 3.62 (m, 2H); 3.81 (bs, 8H); 7.67 (m, 3H).

Reference Example 13 2~f2-ChIoro-4-morpholin-4-yl-qttinazolin-6-ylmethyr)-2,7- diaza-spiro[3.51nonane-7-carboxylic acid tert-butyl ester.

Prepared using the method described for 2-chloro-4-morpholine-4-yl-quinazolin-6- ylmethyl-methyl-(l -methyl-piperidin-4-yl)-amine using 2-chloro-4-morpholin-4-yl- quinazoline-6-carbaldehyde and 2,7-diaza-spiro [3.5] nonane-7-carboxylic acid tert-butyl ester to give a yellow solid (98 mg). δ_H(400 MHz₅ CDCl₃) 1.47 (s, 9H); 1.74 (m, 6H); 3.08 (s, 2H); 3.36 (m, 4H); 3.50 (s, 2H); 3.83 (s, 2H); 3.91 (m, 8H); 7.89-7.66 (m, 3H).

Reference Example 14 5-(2-Chloro-4-morphoIin-4-yl-qnmazoIin-6-vImethvD- hexahvdro-pyrroloβ.^-clpyrrole^-carboxylic acid tert- butyl ester

Prepared using the method described for 2-chloro-4-morpholine~4-yl-quinazolin-6~ ylmethyl-methyl-(l -methyl-piperidin-4-yl)-amine using 2-chloro-4-morpholin-4-yl- quinazoline-6-carbaldehyde and hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-bvάyl ester to give 5-(2-chloro-4-morpholin-4-yl-quinazolin-6-yhnethyl)-hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid tert-butyl ester (124 mg) as a yellow gum. δ_H(400 MHz, CDCl₃) 1.40 (s, 9H); 2.40 (m, 2H); 2.55 (m, 2H); 2.74 (m, 2H); 3.15 (m, 2H); 3.49 (m, 2H); 3.63 (s, 2H); 3.80 (m, 8H); 7.70 (m, 3H).

Reference Example 15 (l&4S)-5-(2-Chloro-4-morphoIin-4-yl-quinazolin-6- vImethvI)-2,5-diaza-bicyclof2.2.πheptane-2-carboxylic acid tert-bxityl ester

Prepared using the method described for 2-chloro-4-morpholine-4-yl-quinazolin-6- ylmethyl-methyl-(l -methyl-piperidm-4-yl)-arnme using 2-chloro-4-morpholm-4-yl- quinazoline-6-carbaldehyde and (IS, 45)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-bntyl ester to give the title compound as a yellow solid (61 mg). δ_H(400 MHz, CDCl₃) 1.51 (s, 9H); 1.76 (m, IH); 1.91 (m, IH); 2.73 (m, IH); 2.93 (d, IH); 3.21 (d, IH); 3.51 (m_s 2H); 3.64 (m, IH); 3.89 (bs, 10H); 7.79 (m, 3H).

Reference Example 16 2-ChIoro-6-f(3i?,55^-3,5-dimethyl-piperazin-l-ylmethyl]-4- morpholm-4-yϊ-qttinazoIine

Prepared using the method described for 2-chloro-4-morpholine-4-yl-quinazolin-6- ylmethyl-methyl-(l -methyl-piperidin-4-yl)-amine using 2-chloro-4-morpholin-4-yl- quinazoline-6-carbaldehyde and (2R, 6S)-2, 6-dimethyl-piperazine to give the title compound as a white solid (84 mg). δ_H(400 MHz, CDCl₃) 1.44 (m, 6H); 2.36 (m, 2H); 2.83 (m, 2H); 3.28 (m, 2H); 3.69 (s, 2H); 3.91 (s, 8H); 7.74 (m, 2H); 7.84 (d, IH).

Reference Example 17 3-(2-Chloro-4-morpholin-4-yl-quinazolin-6-ylmethyl)-3,8- diaza-bicycIof3.2.11octane-8-carboxylic acid tert-butyl ester

Prepared using the method described for 2-chloro-4-morpholine-4-yl-quinazolin-6- ylmethyl-methyl-(l -methyl-piperidin-4-yl)-amine using 2-chloro-4-morpholin-4-yl- quinazoline-6-carbaldehyde and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester to give the title compound as a yellow gum (146 mg). δ_H(400 MHz, CDCl₃) 1.49 (s, 9H); 1.90 (bs, 4H); 2.36 (bs, 2H); 2.62 (m₅2H); 3.52 (m, IH); 3.61 (s, 2H); 3.65 (m, IH); 3.90 (m, 8H); 7.28 (s, IH); 7.78 (m, 2H). [M + H]⁺ 474.2

Example 1 : Preparation of 2-(lH-Indol-4-vD-6-(4-methyl-piperazin-l-γImethyl>4- morphoIin-4-yI-quinazoline.

A mixture of 2-chloro-6- ( 4-methyl-piperazin-l-yl-methyl ) -4-morpholin-4-yl- quinazoline (107 mg), sodium carbonate (96 mg), 4-(4,4,5,5-tetramethyl~[l,3,2]dioxaborolan- 2-yl)-lH-indole (144 mg), bis(triphenylphosphine) palladium chloride (llmg) , toluene (2 ml), ethanol (1.0 ml), and water (0.5 ml) was heated in a microwave reactor at 130⁰C for 1 hour. The reaction mixture was cooled, diluted with dichloromethane (20 ml), washed with water, dried (MgS 04) and the solvent removed in vacuo, to give after purification using flash chromatography, the title compound (72 mg) as an off-white solid. δ_H (400 MHz, CDCl₃) 2.33 (s, 3H), 2.56 (m, 8H), 3.68 (s, 2H), 3.85 (m, 4H), 3.99 (m, 4H), 7.31 (m, 2H), 7.52 (d, IH), 7.75 (m, 2H), 7.83 (s, IH), 8.00 (d, IH), 8.29 (bs, IH), 8.35 (d, IH).

[M + H]⁺ 443.3

Example 2: Preparation of 2-{4-f2-(lH-Indol-4-yl)-4-mQrpholin-4-yI-quinazoIin-6- ylmethyli-piperazin-l-vU-ethanol.

The above compound was made in an analogous manner to the compound of Example 1, using the appropriate starting materials. δ_H (400 MHz, CDCl₃) 2.59 (bs, 10H), 3.63 (m, 2H), 3.68 (s, 2H), 3.85 (m, 4H), 3.99 (m, 4H), 7.34 (m, 2H), 7.52 (d, IH), 7.75 (m, 2H), 7.83 (s, IH), 8.01 (d, IH), 8.28 (bs, IH), 8.35 (d, IH).

[M + H]⁺ 473.2

Example 3 f 2-(l H-Indol-4- yI)-4-morpholin-4-yI-q u inazolin-ό-ylmethyli -methyl-d - methyI-piperidin-4-yl)-amine

A mixture of 2- chloro-4-morpholine-4-yl-quinazolin-6-ylmethyl-methyl-(l-methyl- piperidin-4-yl)-amine (52 mg), indole-4-boronic acid (39 mg), bis(triphenylphosphine)palladium chloride (5 mg) and sodium carbonate (43 mg) in water (0.41 ml) and acetonitrile (3.0 ml) was heated in a microwave reactor at 140⁰C for 1 hour. The reaction mixture was cooled, diluted with dichloromethane (20 ml), washed with water, dried (MgSO₄) and the solvents removed in vacuo, to give after purification using flash silica chromatography, the title compound (33 mg) as a white solid. δ_H(400 MHz, CDCl₃) 1.88-1.75 (m, 4H); 2.00 (m, 2H); 2.28 (s, 3H); 2.31 (s, 3H); 2.52 (m, IH); 2.95 (m, 2H); 3.76 (s, 2H); 3.88 (m, 4H); 4.01 (m, 4H); 7.36 (m, 2H); 7.52 (d, IH); 7.76 (m, 2H); 7.84 (s, IH); 8.02 (d, IH); 8.36 (m, IH); 8.39 (bs, IH). [M + H]⁺ 471.3

Example 4 f2-(6-FIuoro-lH-indol-4-yl)-4-morpholin-4-yl-quinazolin-6-ylmethvn- methyI-(l-methyl-piperidm-4-yl)-amine

Prepared using the method described for [2-(lH-indol-4-yl)-4-morphoIin-4-yl- qumazolin-6-ylrnethyl]-methyl-( 1 -methyl-ρiperidin-4-yl)-amine from 2-chloro-4-morpholine- 4-yl-quinazolin-6-yhnethyl-methyl-(l-methyl-piperidin-4-yl)-amine and 6-fluoro-4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indole to give the title compound (11 mg) as a white solid. δ_H(400 MHz, CDCl₃) 1.63 (m, 2H); 1.70 (m, 2H); 1.82 (m, 2H); 2.11 (s, 3H); 2.15 (s, 3H);

2.35 (m, IH); 2.80 (m, 2H); 3.60 (s, 2H); 3.71 (m, 4H); 3.85 (m₅ 4H); 7.06 (dd, IH); 7.20 (t, IH); 7.61 (m, 2H); 7.69 (s, IH); 7.86 (d, IH); 7.98 (dd, IH); 8.16 (bs, IH).

[M + H]⁺ 489.3. Example 5 2-riH-Indol-4-yl)-4-morphoIiii-4-yl-6-(4-morpholin-4-vI-piperidm-l- ylmethvD-qiiinazoline

Prepared using the method described for [2-(lH-mdol-4-yl)-4-morpholin-4-yl- qumazolin-6-ylmethyl]-meihyl-(l-methyl-piperidin-4-yl)-aniine using 2-chloro-4-moφholin- 4-yl-6-(4-moφholin-4-yl-piperidin-l-ylmethyl)-quinazoline and indole-4-boronic acid to yield the title compound (28 mg) as a white solid. δ_H(400 MHz, CDCl₃) 1.57 (m, 2H); 1.85 (m, 2H); 2.07 (m, 2H); 2.24 (m, IH); 2.59 (m, 4H); 3.00 (m, 2H); 3.51 (s, 2H); 3.75 (m, 4H); 3.87 (m, 4H); 4.01 (m, 4H); 7.30 (m, 2H); 7.55 (d, IH); 7.76 (m, 2H); 7.85 (s, IH); 8.02 (d, IH); 8.36 (bs, IH); 8.37 (d, IH). [M +H]⁺ 513.5.

Example 6 2-(6-Flttoro-lH-indoI-4-yl)-4-morpholin-4-vI-6-(4-morpholiii-4-yI- piperidin-l-ylmethvD-quiiiazolme

Prepared using the method described for [2-(lH-indol-4-yl)-4-morpholin-4-yl- quinazolin-6-ylmethyl]-methyl-( 1 -methyl-piperidin-4-yl)~amine from 2-chloro-4-morpholin- 4-yl-6-(4-morpholin-4-yl-piperidin-l-ylmethyl)-quinazoline and 6-fluoro-4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indole. To give the title compound (22 mg) as a white solid.

6H(400 MHz, CDCl₃) 1.61 (m, 2H); 1.86 (m, 2H); 2.08 (m, 2H); 2.22 (m, IH); 2.58 (m, 4H);

2.99 (m, 2H); 3.68 (s, 2H); 3.75 (m, 4H); 3.87 (m, 4H); 4.01 (m, 4H); 7.21 (dd, IH); 7.36 (m, IH); 7.76 (m, 2H); 7.85 (s, IH); 8.02 (d, IH); 8.15 (dd, IH); 8.33 (bs, IH).

[M + H]⁺ 531.4 Example 7 6f(ι5^>)-l-fHexahvdro-pyrrolori,2-a1pyrazin-2-yl)methvn-2-(lH-indol-4-yl)- 4-morpholin-4-yI-quinazoIme

Prepared using the method described for [2-(lH-indol-4-yl)-4-moφholin-4-yl- quinazolin-6-ylmethyl]-methyl-(l-methyl-piperidin-4-yl)-amine from 2-chloro-6-[(iS)-l- (hexahydro-pyrrolo[l ,2-a]pyrazin-2-yl)me&yl]-4-morpholin-4-yl-qumazoline and indole-4- boronic acid to yield the title compound (58 mg). δ_H(400 MHz, CDCl₃) 1.44-2.37 (m, 9H); 2.88 (m, IH); 3.02 (m, 2H); 3.12 (m, IH); 3.74 (m, 2H); 3.87 (m, 4H); 4.02 (m, 4H); 7.37 (m, 2H); 7.54 (d, IH); 7.67 (m, 2H); 7.86 (s, IH); 8.03 (d, IH); 8.36 (bs, IH); 8.38 (d, IH). [M + H]⁺ 469.3

Example 8 6-(2,7-Diaza-spiro[3.51non-2-ylmethvI)-2-flH-indoI-4-yI)-4-morphoIin-4- yl-quinazoline

Prepared using the method described for [2-(lH-indol-4-yl)-4-morpholin-4-yl- quinazolin-6-ylmethyl]-methyl-( 1 -methyl-piρeridin-4-yl)-amine using 2-(2-chloro-4- morpholin-4-yl-quinazolin-6-yhnethyl)-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert- butyl ester and indole-4-boronic acid to give 2-[2-(lH-indol-4-yl)-4-morpholin-4-yl- quinazolin-6-yhnethyl]2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-bxAyl ester (65 mg) as an off-white solid. The compound was deprotected with trifluoroacetic acid in dichloromethane, and the title compound obtained by cation exchange chromatography, to give the title compound (33 mg), as an off-white solid. δ_H(400 MHz, CDCl₃) 1.77 (m, 4H); 2.78 (m, 4H); 3.09 (s, 4H); 3.82 (s, 2H); 3.87 (m, 4H); 4.02 (m, 4H); 7.38 (m, 2H); 7.54 (d, IH); 7.70 (dd, IH); 7.75 (d, IH); 7.83 (s, IH); 8.02 (d, IH); 8.33 (bs, IH); 8.36 (d, IH). [ M + H]⁺ 469.3.

Example 9 6-(Hexahvdro-pyrroIof3,4-c1pyrrol-2-ylmethyl)-2-(lH-ϊndol-4-ylV4- morpholm-4-yI-quiiiazoline

Prepared using the method described for [2-(lH-indol-4-yl)-4-morpholin-4-yl- quinazolin-6-ylmethyl]-methyl-(l -methyl-piperidin-4-yl)-amine using 5-(2-chloro-4- morpholm-4-yl-quinazolin-6-ylrαethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-huϊyl ester and indole-4-boronic acid to give 5-[2-(lH-indol-4-yl)-4-morpholin-4-yl- quinazolin-6-yknethyl]-hexahydro-pyrrolo[3_:4-c]pyrrole-2-carboxylic acid tert-butyl ester (109 mg) as a grey solid. The title compound (48 mg) was obtained as a beige solid by the deprotection method described in example 8. δ_H(400 MHz, CDCl₃) 2.36-2.54 (m, 6H); 2.69 (m, 2H); 2.88 (m, 2H); 3.62 (s, 2H); 3.77 (m, 4H); 3.92 (m, 4H); 7.28 (m, 2H); 7.44 (d, IH); 7.66 (m, 2H); 7.73 (s, IH); 7.93 (d, IH); 8.27 (d, IH); 8.32 (bs, IH). [M + H]⁺ 455.3.

Example 10 e-rdS^^-l-fl^-Diaza-bicvclori^.πhept^-vnmethyll-Z-fS-fluoro-lH- indol-4-yl)-4-morpho.m-4-vI-quinazolme

Prepared using the method described for [2-(lH-indol-4-yl)-4-moφholin-4-yl- quinazolin-6-yhnethyl]-methyl-(l-methyl-piperidin-4-yl)-amine using (IS, 4«S}-5-(2-chloro-4- morpholin-4-yl-quinazolin-6-ylmethyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester and 5-fluoro-4-(4₅4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-indole to give 5-[2-(5-fluoro-lΗ-indol-4-yl)-4-morpholin-4-yl-quinazolin-6-ylmethyl]-2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (35 mg) as a buff-solid.

[M + H]⁺ 559.3 Deprotection using a polymer bound sulfonic acid resin, gave the title compound (15 mg) as a white solid. δ_H(400 MHz, DMSO) 1.61 (m, 2H); 1.90 (m, 2H); 2.37 (m, IH); 2.58 (m, IH); 3.67 (s, 2H);

3.88 (m, 4H); 4.01 (m, 4H); 6.79 (t, IH); 7.00 (m, 2H); 7.49 (m, 2H); 7.86 (m, 2H); 7.95 (s,

IH); 11.25 (bs, IH). [M + H]⁺ 459.2

Example 11 6-rf3Jg.55)-3,5-Dimethyl-piperaziii-l-vImethyll-2-riH-indoI-4-yl)-4- morpholm-4-yl-q uinazoline

Prepared using the method described for [2-(lH-indol-4-yl)-4-moφholin-4-yl- quinazolin-6-ylmethyl]-methyl-(l-methyl-piperidin-4-yl)-amine using 2-chloro-6-[(3i?,5^)- 3,5-dimethyl-piperazin-l-ylmethyl]-4-morpholin-4-yl-quinazoline and indole-4-boronic acid to give the title compound (26 mg) as an off-white solid. δ_H(400 MHz, CDCl₃) 1.19 (d, 6H); 1.74 (m, 2H); 2.84 (m, 2H); 3.00 (m, 2H); 3.67 (s, 2H); 3.87 (m, 4H); 4.01 (m, 4H); 7.35 (m, 2H); 7.54 (d, IH); 7.77 (m, 2H); 7.85 (s, IH); 8.03 (d, IH); 8.32 (bs, IH); 8.38 (d, IH). [M + H]⁺ 457.3.

Example 12 e-fS.S-Piaza-bicvcIofSJ.πoct-S-vIinethvD^-dH-indol^-vD^-morphQlin- 4-vl-quinazoIine

Prepared using the method described for [2-(lH-indol-4-yl)-4-moφholin-4-yl- qumazolin-6-ylmethyl]-methyl-(l-methyl-piperidin-4-yl)-amine using 3-(2-chloro-4- moφholin-4-yl-quinazolin-6-ylmethyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid ?ert- butyl ester and indole-4-boronic acid to give 3-[2-(lH-indol-4-yl)-4-moφholin-4-yl- quinazolin-6-ylmethyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, (85 mg) as an orange residue.

Deprotection as for example 10, gave the title compound (15 mg) as a beige solid. δ_H(400 MHz, CDCl₃) 1.55 (m, 2H); 1.97 (m, 2H); 2.29 (d, 2H); 2.72 (m, 2H); 3.47 (s, 2H); 3.64 (s, 2H); 3.86 (m, 4H); 4.03 (m, 4H); 7.39 (m, 2H); 7.54 (d, IH); 7.76 (m, 2H); 7.88 (s, IH); 8.02 (d, IH); 8.34 (bs, IH); 8.37 (d, IH). [M + H]⁺ 455.3

Example 13 Biological Testing

Compounds of the invention, prepared as described in the preceding Examples, were submitted to the following biological assay:

(i) PI3K Biochemical Screening Compound inhibition of PI3K was determined in a radiometric assay using purified, recombinant enzyme and ATP at a concentration of IuM. 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. ICs₀ values were subsequently determined using sigmoidal dose-response curve fit (variable slope). All of the compounds tested had an IC₅₀ against PDK of 50μM or less. Typically the ICs₀ against the pi lOδ isoform of PI3K was less than 50OnM.

Example 14 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

Compound of the invention (250 g) Lactose (800 g)

Corn starch (415 g)

Talc powder (30 g)

Magnesium stearate (5 g)

The compound of the invention, 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 15 Injectable Formulation

Compound of the invention 200mg

Hydrochloric Acid Solution 0.1M or Sodium Hydroxide Solution 0. IM 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°-40°C) and the pH 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 sealed with sterile closures and overseals.

Example 16 Intramuscular Injection

Compound of the invention 200 mg

Benzyl Alcohol 0.10 g

Glycofurol 75 1.45 g Water for injection q.s to 3.00 ml

The compound of the invention 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 17 Syrup Formulation

Compound of invention 250 mg

Sorbitol Solution 1.5O g Glycerol 2.00 g

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.

Claims

1. A compound which is a quinazoline of formula (I):

wherein

in which A is selected from:

(b) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O, the ring being fused to a second ring selected from a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, a 5- to 12-membered unsaturated heterocyclic ring, a 5- to 7-membered saturated O-containing heterocyclic ring, a 3- to 12- membered saturated carbocyclic ring and an unsaturated 5- to 12- membered carbocyclic ring to form a heteropolycyclic ring system, the heteropolycyclic ring system being unsubstituted or substituted;

(c) a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and which further comprises, linking two constituent atoms of the ring, a bridgehead group selected from -(CR'₂)_n- and -<CR'₂)_r-O-(CR'2)_s- wherein each R' is independently H or Ci - C₆ alkyl, n is 1, 2 or 3, r is 0 or 1 and s is 0 or 1, the remaining ring positions being unsubstituted or substituted; and (d) a group of formula (lib) :

(lib)

wherein ring B is a 4- to 7-membered saturated N-containing heterocyclic ring which includes 0 or 1 additional heteroatoms selected from N, S and O and ring B' is a 3- to 12- membered saturated carbocyclic ring, a 5- to 7- membered saturated 0-containing heterocyclic ring or a 4- to 7-membered saturated N-containing heterocyclic ring as defined above, each of B and B' being unsubstituted or substituted; or one of R¹ and R² is Ci - Cβ alkyl and the other of R¹ and R² is selected from a 3- to 12- membered saturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated heterocyclic group which is unsubstituted or substituted, a 4- to 12- membered saturated heterocyclic group which is unsubstituted or substituted and a C₁ - C₆ alkyl group which is substituted by a group selected from a 3- to 12- membered saturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated carbocyclic group which is unsubstituted or substituted, a 5- to 12- membered unsaturated heterocyclic group which is unsubstituted or substituted and a 4- to 12-membered saturated heterocyclic group which is unsubstituted or substituted; m is 0, 1 or 2;

R³ is H or C₁-C₆ alkyl;

R^a is selected from R, halo, CN, C(O)NR₂, halo(C]-C₆)alkyl, SO₂R₅ SO₂NR₂, NRSO₂R₃ NRC(O)R, NRC(O)OR, NRC(O)NR₂, OR and NR₂, wherein each R is independently H or Ci-C₆ alkyl; and R⁴ is an indole group which is unsubstituted or substituted; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein the quinazoline is of formula (Ia):

wherein R ₁ R ₁ R , R and m are as defined in claim 1.

3. A compound according to claim 1 wherein the quinazoline is of formula (Ib):

wherein R¹ , R² , R³ , R⁴ and m are as defined in claim 1.

4. A compound according to any one of the preceding claims wherein R⁴ is an indole group which is unsubstituted or substituted by a group selected from CN, halo, -C(O)NR₂, halo(d-C6)alkyl, -SO₂R, -SO₂NR₂, and a 5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S, wherein R is H or C₁-C₆ alkyl.

5. A compound which is selected from:

2-(lH-Indol-4-yl)-6-(4-methyl-piperazin-l-ylmethyl)-4-morpholin-4-yl-quinazoline; 2-{4-[2-(lH-Indol-4-yl)-4-moφholin-4-yl-qumazolin-6-ylmethyl]-piperazin-l-yl}-ethaiiol; [2-( 1 H-Indol-4-yl)-4-morpholin-4-yl-quinazolm-6-ylmethyl] -methyl-( 1 -methyl-piperidin-4- yl)-amine;

[2-(6-Fluoro-lH-indol-4-yl)-4-morpholin-4-yl-quinazolin-6-yhnethyl]-methyl-(l-methyl- piperidin-4-yl)-amine;

2-( 1 H-Indol-4-yl)-4-morpholin-4-yl-6-(4-morpholin-4-yl-piperidin- 1 -ylmethyl)-quinazoline;

2-(6-Fluoro-lH-indol-4-yl)-4-moφholin-4-yl-6-(4-morpholin-4-yl-piperidin-l-yhnethyl)- quinazoline;

6 [(S)- 1 -(Hexahydro-pyrrolo [ 1 ,2-a]pyrazin-2-yl)methyl] -2-( 1 H-indol-4-yl)-4-morpholin-4-yl- quinazoline;

6-(2, 7-Diaza-spiro [3.5 ]non-2-yknethyl)-2-( 1 H-indol-4-yl)-4-morpholin-4-yl-quinazoline;

6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yhnethyl)-2-(lH-indol-4-yl)-4-morpholm-4-yl- quinazoline;

6-[(15,45)-l-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)methyl]-2-(5-fluoro-lH-indol-4-yl)-4- morpholin-4-yl-quinazoline;

6-[(3R,5S)-3,5-Dimethyl-piperazin-l-ylmethyl]-2-(lH-indol-4-yl)-4-moφholin-4-yl- quinazoline; and 6-(3,8-Diaza-bicyclo[3.2.1]oct-3-yhnethyl)-2-(lH-indol-4-yl)-4-moφholin-4-yl-quinazoline; and the pharmaceutically acceptable salts thereof.

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

7. A compound as defined in any one of claims 1 to 5 for use in a method of medical treatment of the human or animal body by therapy.

8. A compound as defined in any one of claims 1 to 5 for treating a disease or disorder arising from abnormal cell growth, function or behaviour associated with PD kinase.

9. Use of a compound as defined in any one of claims 1 to 5 in the manufacture of a medicament for treating a disease or disorder arising from abnormal cell growth, function or behaviour associated with PD kinase.

10. Use according to claim 9 wherein the medicament is for treating cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.

11. A method of treating a disease or disorder arising from abnormal cell growth, function or behaviour associated with PB kinase, which method comprises administering to a patient in need thereof a compound as defined in any one of claims 1 to 5.

12. A method according to claim 11 wherein the disease or disorder is selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders