WO2008152394A1 - Pharmaceutical compounds - Google Patents

Abstract

Furanopyrimidines of formula (I): wherein W represents a furan ring; R1 and R2 form, together with the N atom to which they are attached, a group of the following formula (IIa): 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 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; (b) 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 - 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 (c) a group of formula (IIb): 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; m is 0, 1 or 2; R3 is H or C1-C6 alkyl; R4 is an indole group which is unsubstituted or substituted; and Ra is selected from R, halo, CN, C(O)NR2, halo(C1-C6)alkyl, SO2R, SO2NR2, NRSO2R, NRC(O)R, NRC(O)OR and NRC(O)NR2 wherein each R is independently H or C1-C6 alkyl; 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 both other class Ia and 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

PHARMACEUTICAL COMPOUNDS

Field of the Invention

The present invention relates to indolyl furanopyrimidine 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 PD kinase (PI3K) 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).

PI3K 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 PDKs are PI, PI 4-phosphate (PI4P) and PI 4,5-biphosphate (PI (4,5)P2). Class I PDKs are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism. Class Ia PDKs include PDK pi 10a, pi lOβ and pi lOδ subtypes, which transmit signals from tyrosine kinase-coupled receptors. Class Ib PDK includes a pi lOγ subtype activated by a G protein-coupled receptor. PI and PI(4)P are known as substrates for class II PDKs. Class II PDKs include PDK C2α, C2β and C2γ subtypes, which are characterized by containing C2 domains at the C terminus. The substrate for class III PDKs is PI only.

In the PDK 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 PDK 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 furanopyrimidine 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 PBKs. Accordingly, the present invention provides a compound which is a furanopyrimidine of formula (I):

wherein

W represents a furan ring;

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 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 heteropoly cyclic ring system, the heteropolycyclic ring system 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 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 - 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 (c) 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; m is 0, 1 or 2; R³ is H or Ci-C₆ alkyl; R⁴ is an indole group which is unsubstituted or substituted; and

R^a is selected from R, halo, CN, C(O)NR₂, halo(d-C₆)alkyl, SO₂R, SO₂NR₂, NRSO₂R, NRC(O)R, NRC(O)OR and NRC(O)NR₂ wherein each R is independently H or C₁-C₆ alkyl; and 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.

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

Z is selected from H, unsubstituted C₁-C₆ alkyl, halo, -OR, -SR, -(C(R⁶)₂)_qR, - CH₂OR, -CF₃, -(1IaIo)-C₁-C₆ alkyl, -(C(R⁶)₂)_qO-(halo)-C₁-C₆ alkyl, -CO₂R, -(C(R⁶)₂)_qCO₂R, - (C(R⁶)₂)_qCOR, CF₂OH, CH(CF₃)OH, C(CF₃)₂OH, -(CH₂)_qOR, -(C(R⁶)₂)_qOR, -(CH₂)_qNR₂, - (C(R⁶)₂)_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)₁-JR, -S(O)_PN(R)₂, -(C(R⁶)₂)_qS(O)_pN(R)₂, -OC(O)R, - (C(R⁶)₂)_qOC(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 5- to 12-membered aryl or heteroaryl group, which group is unsubstituted or substituted and a 4- to 7-membered saturated N-containing heterocyclic ring, wherein each R is independently selected from H, Ci-C₆ alkyl, C₃-Ci₀ 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 O, 1 or 2.

R⁵ is selected from C₁-C₆ alkoxy, OR⁶, SR⁶, S(O)₁₅R⁶, 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 C₁-C₆ alkyl group substituted by halogen may be denoted by the term "halo-d-Cδ alkyl", which means an alkyl group in which one or more hydrogens is replaced by halo. A ImIo-C₁-C₆ alkyl group preferably contains one, two or three halo groups. A preferred example of such a group is trifluoromethyl. A C₁-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 Ci-C₆ alkoxy group is unsubstituted or substituted, typically by one or more groups Z or R⁵ as defined above.

A C₃-C₁₀ 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- C]₀ cycloalkyl group is unsubstituted or substituted, typically by one or more groups Z or R as defined above.

A saturated 4- to 7-membered 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 C₁-C₆ alkyl group which is unsubstituted or substituted by a group Z or R⁵ as defined above. A 5- to 7-membered saturated O-containing heterocyclic ring contains at least one O atom and 0, 1 or 2 additional heteroatoms selected from O, N and S. It is, for instance, tetrahydrofuran, tetrahydropyran or morpholine.

A 3- to 12- membered saturated carbocyclic ring 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.

An unsaturated 5- to 12-membered 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 a 5- to 12- membered aryl group. Examples 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. In definition (a) for A in formula (Ha) above, the unsaturated 5- to 12- membered carbocyclic ring is typically other than benzene.

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.

An unsaturated 5- to 12-membered 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. The group may be, 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, isoquinoline, furanopyrimidine, quinoxaline, tetrahydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline, 5,6,7,8-tetrahydro-imidazo[ 1 ,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.

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.

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' ₂)_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. l]heptane, 3,9-diaza-bicyclo[4.2. ljnonane and 3-oxa-7,9- diazabicyclo[3.3.1 ]nonane.

Specific examples of this group include the following structures:

(a')

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]undecane, 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:

(i) (ϋ')

(V) (Vi')

(vii') (viii') (K')

(X')

R⁴ is an indolyl group which is unsubstituted or substituted. The indolyl group may be linked to the furanopyrimidine 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-position, more typically at the 5- or 6-position. An indol-5-yl group is typically substituted at the 4-, 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. In a typical embodiment the indolyl group is substituted by a group selected from R, -OR, -SR, -S(O)_pR, CH₂OR, -C(O)R, -CO₂R, CF₃, CF₂OH, CH(CF₃)OH, C(CF₃)₂OH, -(CH₂)_qOR, -(CH₂)_qNR₂, -C(O)N(R)₂, -NR₂, -N(R)C(O)R, -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 S, 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, CN, halo, -C(O)NR₂, halo(C₁-C₆)alkyl such as CF₃, NO₂ , OR, SR, NR₂, C(O)R, SOR, SO₂ R, SO₂NR₂ , NRC(O)R, CO₂ R and a 5- membered heteroaryl group as defined above. In another more typical embodiment the indolyl group is substituted by a group selected from CN, halo, -C(O)NR₂, IwIo(C₁ -C₆)alkyl such as CF₃, -SO₂R, -SO₂NR₂, and a 5-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms selected from O, N and S. In the above embodiments R is typically H or C₁-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.

In 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, -SO₂Me, - 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 O, 1 or 2. Typically m is 1 or 2. More typically m is 1.

The furan ring W in formula (I) adopts either of the two available regiochemical orientations. The compounds of the invention may thus be furano[3,2-d]pyrimidines or furano[2,3-d]pyrimidines. Thus, in one embodiment the furanopyrimidine is a furano[3,2- djpyrimidine of the following formula (Ia):

wherein R > 1 , t R>2 , r R> 3 , τR>4 , τ R>a^a and m are as defined above for formula (I). In a second embodiment the furanopyrimidine is a furano[2,3-d]pyrimidine of the following formula (Ib):

wherein R¹, R², R³, R⁴, R^a and m are as defined above for formula (I).

In a third embodiment the furanopyrimidine is a furano[2,3-d]pyrimidine of the following formula (Ic):

wherein R¹, R², R³, R⁴, R^a and and m are as defined above for formula (I).

In a fourth embodiment the furanopyrimidine is a furano[3,2-d]pyrimidine of the following formula (Id):

wherein R¹, R², R³, R⁴, R^aand and m are as defined above for formula (I).

Specific examples of compounds of the invention include the compound listed in the following Table 1 : Table 1

and the pharmaceutically acceptable salts thereof.

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

wherein W and R^a are as defined above. Starting from this precursor the synthesis comprises performing, in either order, a reductive amination 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):

wherein W and R^a are as defined above, with an amine of formula NHR^laR^2a in which R^la and R^2a are as defined above for R¹ and R² or Rl ^a 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 (FV):

wherein W, R^a, R^la and R^2a are as defined above, with a boronic acid or ester thereof of formula R⁴ B(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; 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):

wherein W and R^a 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 treating the resulting compound of formula (V):

wherein W, R^a and R⁴ are 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 , for instance as discussed further below and as shown in scheme 5 which follows. In that case the indole protecting group is removed in a subsequent step. Both the reductive 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 reducing agent in the amination step is typically a borohydride, for instance NaBH(OAc)₃, NaBH₄ or NaCNBH₃, in particular NaBH(OAc)₃. A compound of formula (III) as defined above may be produced by a process which comprises treating a compound of formula (VI):

wherein W and R^a are as defined above with a deprotonating agent and then with dimethylformamide at -78⁰C rising to room temperature. A suitable deprotonating agent is a lithiating agent, for instance an alkyllithium such as n-butyllithium in the presence of trimethylethylenediamine in THF at -78⁰C.

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

wherein W and R^a are as defined above with a chlorinating agent followed by morpholine in a suitable solvent, for instance methanol at room temperature.. A suitable chlorinating agent is POCl₃ in PhNMe₂. This reation is suitably conducted at about 10O⁰C.

A compound of formula (VII) may be prepared by known methodologies or by analogy with known methodologies, for instance as shown in scheme 1 which follows. .

Furanopyrimidines 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 furanopyrimidine 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 lOδ isoform over both the pi 1 Oa isoform and the pi lOβ isoform. In particular they are selective for pi lOδ over pi lOβ. The compounds are also selective for the pi lOδ isoform over pi lOγ, 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 lOδ 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 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. 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 is referred to in the Reference Examples and Examples which follow:

Scheme 1

Conditions: (i) (PhO)₂P(O)N₃, Et₃N, ¹BuOH. (ii) n-BuLi, TMEDA, -78 ⁰C, dimethylcarbonate. (iii) TFA, CH₂Cl₂. (iv) ClSO₂NCO, CH₂Cl₂, -78 ⁰C. (v) AcOH - H₂O, 100 ⁰C 2 h. (vi) ¹BuOH, ¹BuOK, 70 ⁰C. (vii) POCl₃, PhNMe₂, 100 ⁰C, 2h. (viii) morpholine, RT. (ix) n-BuLi, TMEDA, THF, -78 ⁰C (x) DMF, -78 °C→RT. (xi) R1R2NH, DCE, Na(AcO)₃BH, AcOH. (xii) Dioxane - water, Cs₂CO₃. Pd (PPh₃)₄, 120 ⁰C, microwave.

Scheme 2

Conditions: (i) H₂SO₄, 21 h. (ii) Dioxane, DMF-DMA, 80 ⁰C 24 h, 90 ° 16 h. (iii) MeOH-THF Raney® Nickel, NH₂NH₂-H₂O, RT, 40 min. (iv) DMSO, KOAc, Pd(dppf)₂Cl₂₎ 80 ⁰C.

Scheme 3

(i) - («i) (iv) - (vi) (vii)

Conditions: (i) DMF, TFAA, 0 ⁰C. (ii) 10% aq NaOH, 100 ⁰C, Ih. (iii) MeOH, H₂SO₄, 65°C, 18 h. (iv)

T1(OCOCF₃)₃, 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.

Scheme 4

Conditions: (i) DCM-pyridine, 0 ⁰C, TFAA, 2 h, RT. (ii) benzoyl peroxide, CCl₄, 80 ⁰C, irradiation, Br₂, 16 h. (iii) Toluene, PPh₃, 60 ⁰C, 2 h then DMF, 16 h, reflux.

Scheme 5

Conditions: (i) NaCN, acetone-H₂0, 48 h, RT. (ii) DMSO, K₂CO₃, H₂O₂, 40 ⁰C. (iii) HCl Et₂O.

Scheme 6

Conditions: (i) DCE, azetidine, Na(OAc)₃BH, 18 h, RT. (ii) TFA-CH₂Cl₂. 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 C18-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.

Microwave Reactions: Microwave experiments were carried out using either a Personal Chemistry Smith Synthesiser or a Biotage Initiator™, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250⁰C can be achieved and pressures of up to 20bar can be reached.

AU solvents and commercial reagents were used as received. Non-commercially available reagents/reactants were prepared according to procedures described in the literature.

Abbreviations used in the experimental section:

aq. = aqueous

BOC = t-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 = (^-(T-Azabenzotriazol-l-y^-ΛyV_r/V_^/V-tetramethyluronium hexafluorophosphate

HCl = hydrochloric acid

H₂O = water

HPLC = high pressure liquid chromatography IMS = industrial methylated spirit iPrOH = isopropanol

K₂CO₃ = potassium carbonate

LCMS = liquid chromatography mass spectrometry ^

M = molar m = multiplet (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

TBAF = tetrabutylammonium fluoride

TBS = tert-butyldimethylsilyl

Reference Example 1 : Formation of boronate ester The boronate ester product of the final step of scheme 1 was prepared as follows. To a solution of halide (1 eq.) and bis(pinacolato)diboron (1.3 eq.) in DMSO were added KOAc (3 eq.) and [l,r-bis(diphenylphosphine)ferrocene]-dichloropalladium (0.05 eq.). The mixture was heated at 90°C until completion of the reaction. The reaction mixture was partioned between EtOAc and H₂O. The organic layer was washed successively with H₂O and brine, dried over Na₂SO₄ and evaporated to dryness. The resultant residue was then purified by column chromatography. Reference Example 2: Suzuki coupling

W=H, or protecting group, e.g. TBS

The following general methods were used for the Suzuki coupling reaction depicted above:

Method A

A mixture of the appropriate 2-chlorofuropyrimidine (1 eq.), Cs₂CO₃ (1.5 eq.), the appropriate indole boronate ester (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) in dioxane/water (3:1) was heated at 125 °C, for 10 - 60 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO₄), filtered and concentrated then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Method B

A mixture of the appropriate 2-chlorofuropyrimidine (1 eq.), Cs₂CO₃ (1.5 eq.), the appropriate indole boronic acid (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) in dioxane/water (3:1) was heated at 125 ⁰C, for 10 - 60 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO₄), filtered and concentrated then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Method C ^

A mixture of the appropriate 2-chlorofuropyrimidine (1 eq.), Cs₂CO₃ (1.5 eq.), the appropriate indole boronate ester (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) in acetonitrile/water (3:1) was heated at 125 °C, for 10 - 60 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO₄), filtered and concentrated then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Method D

A mixture of the appropriate 2-chlorofuropyrimidine (1 eq.), Cs₂CO₃ (1.5 eq.), the appropriate indole boronic acid (1.2 eq.) and tetrakis(triphenylphosphine)palladium (0.05 eq.) in acetonitrile/water (3:1) was heated at 125 °C, for 10 - 60 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO₄), filtered and concentrated then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Method E

A mixture of the appropriate 2-chlorofuropyrimidine (1 eq.), Na₂CO₃ (2 eq.), the appropriate indole boronic acid (1.5 eq.) and tetrakis(triphenylphosphine)palladium (0.1 eq.) in acetonitrile/water (2:1) was heated at 140 °C, for 10 - 60 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO₄), filtered and concentrated then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product. Method F

A mixture of the appropriate 2-chlorofuropyrimidine (1 eq.), Na₂CO₃ (2 eq.), the appropriate indole boronate ester (1.3 eq.) and tetrakis(triphenylphosphine)palladium (0.1 eq.) in acetonitrile/water (2:1) was heated at 140 °C, for 10 - 60 min in a microwave reactor. The resulting mixture was diluted with water then extracted with ethyl acetate. The combined organic extracts were dried (MgSO₄), filtered and concentrated then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Reference Example 3 t-Butoxycarbonyl deprotection

To a solution of the relevant BOC-protected furopyrimidine in DCM was added TFA and the resulting solution was stirred at RT for 30-180 min. The resulting mixture was diluted with water, neutralised with saturated aqueous solution OfNaHCO₃ then extracted with DCM. The combined organic extracts were dried (MgSO₄ or Na₂SO₄), filtered and concentrated in vacuo, then purified by either preparative HPLC or column chromatography to give the desired product. Alternatively, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resulting residue was then purified by either preparative HPLC or column chromatography to give the desired product.

Reference Example 4 TBS-deprotection

To a solution of the relevant TBS-protected 7H-indol-4-ylfuropyrimidine in TΗF was added TBAF and the resulting solution was stirred at RT for 30 min, then concentrated in vacuo. Alternatively, the resulting mixture was diluted with brine then extracted with DCM.

The combined organic extracts were dried (MgSO₄ or Na₂SO₄), filtered and concentrated in vacuo. In either case, the resultant residue was purified by either preparative ΗPLC or column chromatography to give the desired product.

Reference Example 5 Furan-3-yl-carbamic acid tert-butyl ester ^

To a solution of 3-furoic acid (5.0 g, 44.61 mmol) in f-butanol (178 mL) were added diphenylphosphoryl azide (10.7 mL, 49.65 mmol) and triethylamine (8.9 mL, 63.85 mmol) and the mixture heated at reflux for 17 h. The resulting dark solution was cooled to RT, concentrated in vacuo to ~ 50 mL, then poured into an aqueous sat. solution OfNaHCO₃ at 0 °C and stirred for 2 h. The resulting precipitate was collected by filtration, washed with a little water, then air dried. The resultant tan solid was purified by column chromatography to give the title compound as a white solid (4.4 g, 54 %). [M + H]⁺ 184.0

Reference Example 6 3-tert-ButoxycarbonvIamino-furan-2-carboxylic acid methyl ester

To a solution of furan-3-yl-carbamic acid tert-butyl ester (4.2 g, 22.93 mmol) in anhydrous THF (160 mL) was added NJfJT JV-tetramethylethylenediamine (4.3 mL, 28.49 mmol) and the resulting orange solution was cooled to -30 °C. n-Butyl lithium (2.5 M in hexanes, 20.0 mL, 50.0 mmol) was added dropwise and the resulting suspension allowed to warm to 0 ⁰C over 1 h. The reaction mixture was cooled to -30 °C and treated with dimethyl carbonate (5.75 mL, 68.24 mmol), then allowed to warm to 0 °C over 45 min. An aqueous solution of HCl (2 M) was added and the mixture was extracted with EtOAc. The organic layer was isolated, dried (MgSO₄) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a pale yellow solid (4.60 g, 83 %).

¹H NMR (300 MHz, CDCl₃): δ 1.54 (s, 9 H), 3.92 (s, 3 H), 7.22 (bs, 1 H), 7.38 (s, 1 H) and 8.18 (bs, I H).

Reference Example 7 3-Amino-furan-2-carboxylic acid methyl ester

To a solution of 3-tert-butoxycarbonylamino-furan-2-carboxylic acid methyl ester (8.05 g, 33.38 mmol) in DCM (5 mL) was added TFA (5 mL) and the mixture stirred at RT for 5 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH to give the title compound as a brown solid (4.07 g, 86 %).

¹H NMR (400 MHz, CDCl₃): δ 3.87 (s, 3 H), 4.58 (bs, 2 H), 6.12 (d, J = 2 Hz, 1 H) and 7.25 (d, J = 2 Hz, 1 H).

Reference Example 8 3-Ureido-furan-2-carboxylic acid methyl ester

To a solution of 3-amino-furan-2-carboxylic acid methyl ester (20.0 g, 0.142 mol) in anhydrous DCM (250 mL) was added chlorosulfonyl isocyanate (13.6 mL, 0.156 mol) at 0

⁰C. The reaction mixture was stirred at 0 °C for 30 min, then concentrated in vacuo. The resulting gum was suspended in glacial acetic acid (11.6 mL), cooled to 0 °C and carefully treated with H₂O (6.4 mL). The mixture was stirred at RT for 1 h, then concentrated in vacuo.

The resultant solid was partitioned between EtOAc and H₂O, then basified with a aqueous sat. solution OfK₂CO₃. The organic layer was isolated, dried (Na₂SO₄) and concentrated in vacuo.

The resultant solid was triturated with IMS to give the title compound as a yellow solid (11.6 g, 44 %).

¹H NMR (400 MHz, DMSO-(I₆): δ 3.81 (s, 3 H), 6.67 (s, 2 H), 7.26 (d, J = 2 Hz, 1 H), 7.72 (d,

J = 2 Hz, 1 H) and 8.45 (bs, 1 H).

Reference Example 9 1//-Furo f 3,2-</1 pyrimidine-2,4-dione

To a solution of 3-ureido-furan-2-carboxylic acid methyl ester (50 mg, 0.272 mmol) in anhydrous THF (1 mL) was added potassium f-butoxide (45 mg, 0.401 mmol) and the resulting mixture stirred at RT for 1 h, then concentrated in vacuo. The resulting residue was partitioned between EtOAc and H₂O. The organic layer was isolated, dried (MgSO₄) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a cream solid (33 mg, 80 %).

¹H NMR (400 MHz, DMSO-de): δ 6.54 (d, J = 2 Hz, 1 H), 8.03 (d, J = 2 Hz, 1 H), 11.06 (s, 1 H) and 11.20 (s, I H).

Reference Example 10 2,4-DichIoro-furof3,2-</|pyrimidine

To a mixture of lH-furo[3,2-d]pyrimidine-2,4-dione (3.0 g, 0.020 mol) in NJf- dimethylaniline (2.0 mL, 0.016 mol) was added phosphorous oxychloride (18.0 mL, 0.193 mol) and the resulting mixture heated at 130 °C for 2 h. The resulting black solution was cooled to RT, then carefully quenched with crushed ice and H₂O, then extracted with EtOAc.

The organic layer was isolated, dried (MgSO₄) and concentrated in vacuo to give the title compound as a tan solid (3.26 g, 87 %). 1H NMR (400 MHz, CDCl₃): δ 7.02 (d, J = 2.2 Hz, 1 H) and 8.08 (d, J = 2.2 Hz, 1 H).

Reference Example 11 2-Chloro-4-morpholin-4-yl-furo[3,2-</lpyrimidine

To a solution of 2,4-dichloro-furo[3,2-d]pyrimidine (173 mg, 0.915 mmol) in MeOH

(10 mL) was added morpholine (173 μL, 1.978 mmol) and the mixture was stirred at RT for 90 min, then concentrated in vacuo. The resultant solid was purified by column chromatography to give the title compound as a tan solid (197 mg, 90 %). [M + H]⁺ 240.0 ^

Reference Example 12 2-Chloro-4-morpholin-4-yl-furo \ 3,2-<fl pyrimidine-6- carbaldehyde

To a solution of 2-chloro-4-morpholin-4-yl-furo[3,2-d]pyrimidine (50 mg, 0.209 mmol) in anhydrous THF (2.5 mL) were added iV^V^/^-tetramethylethylenediamine (36 μL, 0.239 mmol) and /i-butyl lithium (2.5 M in hexanes, 100 μL, 0.250 mmol) at -78 °C. The reaction mixture was allowed to warm to -30 °C over 90 min, then cooled to -78 ⁰C and anhydrous DMF (38 μL, 0.490 mmol) was added dropwise. The reaction mixture was stirred at -78 ⁰C for 30 min, then allowed to warm to RT over 30 min. An aqueous solution of HCl (0.1 M) was added and the mixture extracted with DCM. The organic layer- was isolated, dried (MgSO₄) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (20 mg, 36 %). [M + H]⁺ 268.0

Reference Example 13 5-(2-Chloro-4-morphoIin-4-yl-furo \3,2-d\ pyrimidin-6- ylmethvD-hexahvdro-pyrrolofS^-clpyrroIe-l-carboxylic acid tert-butyl ester

To a solution of 2-chloro-4-morpholin-4-yl-furo[3,2-d]pyrimidine-6-carbaldehyde (20 mg, 0.075 mmol) in 1,2-dichloroethane (2 mL) was added hexahydro-pyrrolo[3,4-c]pyrrole-2- carboxylic acid tert-butyl ester (19 mg, 0.090 mmol). The mixture was stirred at RT for 5 min before adding sodium triacetoxyborohydride (24 mg, 0.113 mmol). The resulting solution was stirred at RT for 17 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resultant gum was purified by column chromatography to give the title compound as a colourless glass (30 mg, 87 %). [M + H]⁺ 464.3

Reference Example 14 5-Fluoro-4-(4.4.5.5-tetramethvHl,3,21dioxaborolan-2-yl)- ΪH-indole

Step 1

A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 mL) was treated at 0 °C with trifluoroacetic anhydride (6.1 mL, 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 cooled to RT, washed with DCM and acidified with aqueous HCl. The resulting white precipitate was collected by filtration, washed with water, taken up in DCM, 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 concentrated in vacuo to give 5-fluoro-lH- indole-3-carboxylic acid methyl ester as a peach-coloured solid (4.5 g, 83 %).

Step 2

A solution of thallium tris(trifluoroacetate) (8.45 g, 15.6 mmol) in TFA (35 mL) was added to a solution of 5-fluoro-lH-indole-3-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 to RT and extracted with DCM/MeOH (ratio 95:5). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide 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).

Step 3

A solution of 5-fluoro-4-iodo-lH-indole (1.28, 4.90 mmol) in dioxane (5 mL) was treated with triethylamine (1.0 mL, 7.18 mmol), palladium acetate (22.0 mg, 0.098 mmol) and bis(cyclohexyl)phosphino-2-biphenyl (137 mg, 0.40 mmol) then heated to 80 °C. A solution of pinacolborane (1 M in TΗF, 13.0 mL, 13.0 mmol) was added via syringe. After 30 min, the reaction mixture was cooled to RT, then diluted with water (50 mL) and DCM (50 mL). The resulting mixture was passed through a phase separation cartridge, and the organic layer was concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a tan solid (1.06 g, 83 %). [M + H]⁺ 262.1

Reference Example 15 l-Bromo-5-fluoro-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 iV-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 EtOAc and the organic layer washed with brine, dried (MgSO₄) and concentrated in vacuo to give the title compound as a pale oil which crystallised out on standing (11.76 g, 77 %).

NMR δ_H (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 16 4-Bromo-6-fluoro-lJg-indole

To a solution of l-bromo-5-fluoro-2-methyl-3-nitro-benzene (7.49 g, 31.8 mmol) in dioxane (40 mL) were added DMF-DMA (21.0 mL, 158 mmol) and pyrrolidine (2.6 mL, 31.1 mmol). The reaction mixture was heated at 100 ⁰C for 3 h. The mixture was cooled to RT and concetrated in vacuo to give l-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-l -methyl vinyl]- pyrrolidine as a dark red residue. To a suspension of the pyrrolidine (10.0 g, 31.7 mmol) and Raney®-Nickel (suspension in H₂O, 15 mL) in MeOHrTHF (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 concentrated in vacuo and the resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a 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 17 6-Fluoro-4-(4,4,5,5-tetramethyl-[l,3..21dioxaborolan-2-vI)- lH-indole

To a solution of 4-bromo-6-fluoro-lH-indole (6.0 g, 25.53 mmol) and bis(pinacolato)diboron (9.7 g, 38.19 mmol) in anhydrous DMSO (120 mL) were added KOAc (7.5 g, 76.41 mmol) and [l,r-bis(diphenylphosphine)ferrocene]-dichloropalladium (1.0 g, 1.22 mmol). The mixture was heated at 80 °C for 18 h. The reaction mixture was cooled to RT and partioned between EtOAc and H₂O. The organic layer was isolated, washed successively with H₂O and brine, dried (Na₂SO₄) and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel, pentane:EtOAc 75:25) to provide the title compound as a white solid (4.6 g, 61 %). ^

NMR δ_H (300 MHz, CDCl₃) 1.39 (s, 12H), 7.02 (m, IH), 7.14-7.19 (m, IH), 7.20-7.26 (m, IH), 7.38 (dd, J = 2.4, 9.9, IH) and 8.16 (s, IH).

Reference Example 18 2-(2-ChIoro-4-morpholin-4-yl-furo [3,2-</l pyrimidin-6- ylmethyI)-2,7-diaza-spirof3.51nonane-7-carboxyIic acid tert- butyl ester

Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-

4-yl-furo[3 ,2- J]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3 ,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (110 mg, 82 %). [M]⁺ 478.4

Reference Example 19 3-(2-Chloro-4-morphoIin-4-yI-furo f 3,2-</l pyrimidin-6- vImethyl)-3,8-diaza-bicvclof3.2.1]octane-8-carboxylic acid tert-butyl ester

Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin- 4-yl-furo[3,2-J]pyrimidin-6-ylrnethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (127 mg, 98 %). [M + H]⁺ 464.3

Reference Example 20 2-Chloro-6-f(S)-l-(hexahvdro-pyrroIoH,2-α1pyrazin-2- yl)methyll-4-morpholin-4-yl-furo[3,2-</lpyrimidine

Prepare according to the method used in the preparation of 5-(2-chloro-4-morpholin- 4-yl-furo[3,2-J]pyrimidin-6-ylmethyl)-hexahydro-pyπOlo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using (iS)-octahydro-pyrrolo[l,2-α]pyrazine in place of hexahydro-pyrrolo[3,4- c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (94 mg, 89 %). [M + H]⁺ 378.2

Reference Example 21 8-(2-Chloro-4-morpholin-4-yl-furo f 3,2-rfl pyrimidin-6- ylmethvD-2,8-diaza-spiro[4.51decane-2-carboxyIic acid tert- butyl ester

Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin- 4-yl-furo[3,2-J]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a colourless oil (98 mg, 71 %). [M]⁺ 492.4

Reference Example 22 (lS,4S)-5-(2-ChIoro-4-morpholin-4-yl-furo[3,2-./lpyrimidin- 6-vImethyl)-2,5-diaza-bicyclof2.2.11heptane-2-carboxyIic acid tert-butyl ester

To a solution of 2-chloro-4-morpholin-4-yl-furo[3,2-d]pyrimidine-6-carbaldehyde (89 mg, 0.333 mmol) in 1,2-dichloroethane (6 mL) was added (15^r,45)-2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (80 mg, 0.40 mmol). The mixture was stirred at RT for 5 min before adding sodium triacetoxyborohydride (107 mg, 0.500 mmol). The resulting solution was stirred at RT for 17 h, then partitioned between DCM and H₂O. The organic layer was isolated, dried (Na₂SO₄) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (0.11 g, 73 %). [M + H]⁺ 450.3

Reference Example 23 4-Bromo-2-trifluoromethyl-l/y-indoIe

A solution of 2-methyl-3-bromo-aniline (6.05 g, 37 mmol) in pyridine (8 mL) and

DCM (150 mL) was cooled to O⁰C and treated drop- wise with trifluoroacetic anhydride (11.5 mL, 81.4 mmol). The reaction mixture was stirred at RT for 2 h, then quenched with an aqueous solution of ammonium chloride. The organic layer was dried over MgSO₄, and evaporated to dryness to give N-(3-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide as an off-white solid, which was used without further purification (10 g).

NMR δ_H (400 MHz, CDCl₃) 2.38 (s, 3H), 7.14 (apparent t, J = 8.0, IH), 7.53 (d, J = 8.0, IH), 7.66 (d, J = 8.0, IH) and 7.75 (bs, IH).

A solution of iV-(3-bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (2.1 g, 7.4 mmol) and benzoyl peroxide (100 mg) in carbon tetrachloride (50 mL) was heated to reflux under irradiation (150W tungsten lamp). A solution of bromine (0.55 mL, 10.4 mmol) in carbon tetrachloride (3 mL) was then added drop- wise to the refluxing solution, and heating was pursued for 16 h. The reaction mixture was left to cool to RT and diluted with DCM. The organic layer was washed with sodium thiosulfate, and evaporated to dryness to give N-(3- bromo-2-bromomethyl-phenyl)-2,2,2-trifluoro-acetamide as a brown residue which was used without further purification (2.9 g). NMR δ_H (400 MHz, CDCl₃) 4.71 (s, 2H), 7.30 (apparent t, J = 8.0, IH), 7.55 (d, J = 8.0, IH), 7.82 (d, J = 8.0, IH) and 8.79 (bs, IH).

A solution of N-(3-bromo-2-bromomethyl-phenyl)-2,2,2-trifluoro-acetamide (2.9 g) in toluene (40 mL) was treated with triphenylphosphine (2.3 g, 8.7 mmol). The solution was stirred at 6O⁰C for 2 h, then cooled to O⁰C. The beige solid that precipitated was collected by filtration, washed with diethyl ether, then dissolved in DMF (60 mL), and heated to reflux under nitrogen for 16 h. The reaction mixture was evaporated to dryness, then partitioned between EtOAc and a sat. sodium carbonate solution. The organic layer was isolated, dried (MgSO₄), and purified by column chromatography to give the title compound as a yellow solid (1.55 g, 84 %). NMR δ_H (400 MHz₅ CDCl₃) 7.00 (s, IH), 7.19 (apparent t, J = 7.9, IH), 7.36-7.41 (m, 2H) and 8.53 (bs, IH).

Reference Example 24 4-(4.4.5.5-Tetramethyl-[l,3,21dioxaboroIan-2-yl)-2- trifluoromethvl-l/_^r-indole

Prepared by using the method described in J. Org. Chem 1995, 60, 7508-7510. The title compound was obtained as a white solid (1.5 g, 55 %).

NMR δ_H (400 MHz, CDCl₃) 1.40 (s, 12H), 7.33 (dd, J = 7.0, 8.3, IH), 7.42 (s, IH), 7.53 (d, J = 8.3, IH), 7.70 (d, J = 7.0, IH) and 8. 37 (bs, IH).

Reference Example 25 l-(tert-ButvIdimethylsilanyl)-5-fluoro-l-H-indole

To a solution of 5-fluoro-lH-indole (30.0 g, 0.222 mol) in anhydrous THF (250 mL) was added sodium hydride (60 % suspension in mineral oil, 10.22 g, 0.255 mol) portionwise and maintaining the solution at 0 °C. The reaction mixture was stirred at 0 °C for 20 min, then a solution of tert-butylchlorodimethylsilane (40.15 g, 0.266 mol) in anhydrous THF (20 mL) was added and the solution stirred at RT for 25 h. The reaction mixture was poured into H₂O and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO₄), then concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, cyclohexane:DCM 100 % to 50:50) to provide the title compound as a colourless oil (41.2 g, 74 %).

¹H NMR (400 MHz, CDCl₃): δ 0.60 (s, 6 H), 0.94 (s, 9 H), 6.58 (dd, J = 3.2, 1.0 Hz, 1 H), 6.87-6.93 (m, 1 H), 7.23 (d, J = 3.2 Hz, 1 H), 7.24-7.29 (m, 1 H) and 7.41 (m, 1 H).

Reference Example 26 ri-(tert-Butyldimethylsilanvn-5-fluoro-lff-indol-4- yllboronic acid

To a solution of l-(tert-butyldimethylsilanyl)-5-fluoro-lH-indole (30.0 g, 0.12 mol) in anhydrous TΗF (1000 mL) were added N/^^-tetramethylethylenediamine (36.6 mL,

0.241 mol) and a solution of s-butyl lithium (1.4 M in cyclohexane, 172 mL, 0.241 mmol) at - 78 ⁰C. The resulting mixture was stirred at -78 °C for 2 h, then triisopropyl borate (37.5 mL, ^

162.7 mmol) was added dropwise. The resulting solution was stirred at -78 °C for 40 min, then allowed to warm to -20 ⁰C. An aqueous solution of HCl (2.4 M, 250 mL) was added and the resulting mixture was poured into H₂O. The layers were separated and the aqueous layer extracted with EtOAc. The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The resultant yellow solid was then crystallised from DCM and cyclohexane to give the title compound as a white solid (25.0 g, 71 %).

¹H NMR (400 MHz, CD₃OD): δ 0.62 (s, 6 H), 0.92 (s, 9 H), 6.51 (d, J = 3.2 Hz, 1 H), 6.79- 6.90 (m, 1 H), 7.30-7.36 (m, 1 H) and 7.54 (dd, J = 9.0, 4.6 Hz, 1 H).

Reference Example 27 4-(3,3-DifIuoroazetidin-l-yl)piperidine

^

F

To a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.0 g, 5.0 mmol) in DCE (50 mL) was added 3,3-difluoroazetidine hydrochloride (712 mg, 5.5 mmol). The mixture was stirred at RT for 15 min, then sodium triacetoxyborohydride (1.59 g, 7.5 mmol) was added and stirring was continued for 17 h. The reaction mixture was diluted with brine and extracted with DCM. The organic layer was separated, dried (Na₂SO₄) and concentrated in vacuo. The resultant residue was purified by column chromatography to give 4-(3,3- difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester as a pale yellow solid (1.2 g, 88 %). To a solution of 4-(3,3-difluoroazetidin-l-yl)piperidine-l-carboxylic acid tert-butyl ester (552 mg, 2.0 mmol) in DCM (4 mL) was added TFA (2 mL) and the resulting mixture was stirred at RT for 45 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH to give the title compound as a pale yellow solid (271 mg, 77 %). ₆

¹H NMR (400 MHz, CDCl₃): 5 1.16-1.27 (m, 2 H), 1.63-1.72 (m, 2 H), 2.14-2.23 (m, 1 H), 2.54-2.62 (m, 2 H), 3.09 (dt, J = 12.7, 3.9 Hz, 2 H) and 3.46-3.57 (m, 4 H).

Reference Example 28 2-Chloro-6-KS)-l-(hexahvdro-pyrroloH,2- αlpyrazin-2-yl)methvn-4-morpholin-4- ylfuro[3,2-</lpyrimidine

To a solution of 2-chloro-4-moφholin-4-ylfuro[3,2-rf]pyrimidine-6-carbaldehyde (75 mg, 0.288 mmol) in 1,2-dichloroethane (7 mL) was added (5)-octahydro-pyrrolo[l,2- α]pyrazine (42 mg, 0.333 mmol). The mixture was stirred at RT for 5 min before adding sodium triacetoxyborohydride (90 mg, 0.425 mmol). The resulting solution was stirred at RT for 2 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (94 mg, 89 %). [M + H]⁺ 378.1 1H NMR (400 MHz, CDCl₃): δ 1.32-1.43 (m, 1 H), 1.64-1.89 (m, 3 H), 1.96-2.20 (m, 3 H), 2.29 (m, 1 H), 2.35-2.45 (m, 1 H), 2.83-2.89 (m, 1 H), 2.96-3.10 (m, 3 H), 3.67-3.79 (m, 2 H), 3.82 (t, J = 4.8 Hz, 4 H), 3.99 (t, J = 4.8 Hz, 4 H) and 6.60 (s, 1 H).

Reference Example 29 2-Chloro-6-(2,7-diazaspiro \ 3.51 non-2-ylmethvD-4- morpholin-4-ylfuro[3,2-./lpyrimidme

To a solution of 2-chloro-4-morpholin-4-ylfuro[3,2-£f|pyrimidine-6-carbaldehyde (175 mg, 0.654 mmol) in 1,2-dichloroethane (17 mL) was added 2,7-diazaspiro[3.5]nonane-7- carboxylic acid tert-butyl ester (205 mg, 0.906 mmol). The mixture was stirred at RT for 10 min before adding sodium triacetoxyborohydride (210 mg, 0.991 mmol). The resulting solution was stirred at RT for 18 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then, eluted with 2 M NH₃ in MeOH. The resultant residue was purified by column chromatography to give 2-(2-chloro-4-moφholin-4- ylfuro[3,2-J]pyrimidin-6-ylmethyl)-2,7-diazaspiro[3.5]nonane-7-carboxylic acid tert-butyl ^

ester as a white solid. Subsequent BOC-deprotection afforded the title compound as a white solid (186 mg, 76 %).

¹H NMR (400 MHz, CDCl₃): δ 1.71 (m, 4 H), 1.90 (bs, 1 H), 2.68-2.79 (m, 4 H), 3.12 (s, 4 H), 3.73 (s, 2 H), 3.79-3.84 (m, 4 H), 3.93-4.03 (m, 4 H) and 6.54 (s, 1 H).

Reference Example 30 1 - f 2-(2-Chloro-4-morpholin-4-ylfuro f 3,2-</l p yrimidin-6- yImethyl)-2,7-diazaspiro [3.51 non-7-yll ethanone

To a solution of 2-chloro-6-(2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4- ylfuro[3,2-rf]pyrimidine (72 mg, 0.191 mmol) in DCM (1.5 mL) were added triethylamine (27 μL, 0.194 mmol) and acetyl chloride (14 μL, 0.197 mmol). The reaction mixture was stirred at RT for 1 h, then partitioned between water and DCM. The organic layer was separated, then dried (MgSO₄) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a white solid (40 mg, 50 %). [M + H]⁺ 420.4

Reference Example 31 7-Methyl-2,7-diazaspirof3.51nonane

To a solution of 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester hydrochloride (100 mg, 0.381 mmol) in DCE (10 mL) was added an aqueous solution of formaldehyde (37 % w/w, 40 μL, 0.537 mmol). The mixture was stirred at RT for 10 min, then sodium triacetoxyborohydride (121 mg, 0.571 mmol) was added and stirring was continued for 1 h. The reaction mixture was added water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH to give 7-methyl-2,7- diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. To a solution of 7-methyl-2,7- ^

diazaspiro[3.5]nonane-2-carboxylic acid fert-butyl ester in DCM (5 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH₃ in MeOH to give the title compound as a colourless oil (45 mg, 84 %). 1H NMR (400 MHz, CDCl₃): δ 1.81 (m, 4 H), 2.22 (s, 3 H), 2.28 (m, 2 H), 3.22 (bs, 4 H) and 3.38 (bs, 2 H).

Reference Example 32 2-Chloro-6-(7-methyl-2,7-diazaspiro[3.51non-2-ylmethyr)-4- morpholin-4-yIf uro |3,2-<fl pyrimidine

Prepared according to the method used in the preparation of 2-chloro-6-[(5)-l- (hexahydro-pyrrolo[ 1 ,2-α]pyrazin-2-yl)methyl]-4-moφholin-4-ylfuro[3,2-rf]pyrimidine using 7-methyl-2,7-diaza-spiro[3.5]nonane in place of (5)-octahydro-pyrrolo[l,2-α]pyrazine. The title compound was obtained as a white solid (66 mg, 66 %). ' [M + H]⁺ 392.2

Reference Example 33 4-(2-ChIoro-4-morpholiii-4-ylfuro [3,2-</l pyrimidin-6- ylmethyl)-2,2-dimethvIpiperazine-l-carboxyIic acid tert- butyl ester

Prepared according to the method used in the preparation of 2-chloro-6-[(5)-l- (hexahydro-pyrrolo[ 1 ,2-α]pyrazin-2-yl)methyl]-4-morpholin-4-ylfuro[3 ,2- J]pyrimidine using 2,2-dimethylpiperazine in place of (S)-octahyclro-pyrrolo[l,2-a]pyrazine. The title compound was obtained as a yellow solid (139 mg, 80 %). [M + H]⁺ 466.3

Reference Example 34 [l-(2-ChIoro-4-morphoIin-4-ylfuro[3,2-</lpyrimidin-6- yImethvI)piperidin-4-vndimethvIamine

Prepared according to the method used in the preparation of 2-chloro-6-[(5)-l- (hexahydro-pyrrolo[ 1 ,2-α]pyrazin-2-yl)methyl]-4-morpholin-4-ylfuro[3 ,2-cT]pyrimidine using dimethylpiperidin-4-ylamine in place of (5)-octahydro-pyrrolo[l,2-α]pyrazine. The title compound was obtained as a orange solid (200 mg, 84 %). [M + H]⁺ 380.4

Reference Example 35 4-Azetidin-l-yl-piperidine

To a solution of 4-oxo-piperidine-l-carboxylic acid tert-butyl ester (1.75 g, 8.88 mmol) in dichloroethane (80 mL) was added azetidine (0.6 g, 10.53 mmol) and the mixture was stirred at RT for 30 min. Sodium triacetoxyborohydride (3.9 g, 18.44 mmol) was added and the resulting solution was stirred at RT for 18 h. The reaction mixture was partitioned between water and DCM and the layers separated. The organic layer was extracted further with DCM and the combined aqueous layers were concentrated in vacuo. The resultant white semi-solid was suspended in DCM and a saturated aqueous solution OfNaHCO₃ was added. The layers were thoroughly mixed, the organic layer isolated and the aqueous layer further extracted with DCM. The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated in vacuo to give 4-azetidin-l-yl-piperidine-l-carboxylic acid tert-butyl ester as a white solid (2.0 g, 95 %). BOC-deprotection of 4-azetidin-l-yl-piperidine-l-carboxylic acid tert-butyl ester (400 mg, 1.67 mmol) using TFA:DCM (1:4) gave the title compound as a yellow oil (185 mg, 79 %) NMR δ_H (400 MHz, CDCl₃) 1.04-1.16 (m, 2 H), 1.68 (d, J = 12.8 Hz, 2 H), 1.98-2.08 (m, 3 H), 2.55 (td, J = 12.1, 2.6 Hz, 2 H), 3.06 (dt, J = 12.8, 3.6 Hz, 2 H) and 3.15 (t, J = 6.9 Hz, 4 H).

Reference Example 36 6-(4-Azetidin-l-ylpiperidin-l-ylmethyl)-2-chloro-4- morphoIin-4-ylfuro[3,2-</lpyrimidine

Prepared according to the method used in the preparation of 2-chloro-6-[(iS)-l- (hexahydro-pyrrolo[l,2-α]pyrazin-2-yl)methyl]-4-morpholin-4-ylfuro[3,2-i/]pyrimidine using 4-azetidin- 1 -ylpiperidine in place of (,S)-octahydro-pyrrolo[ 1 ,2-α]pyrazine. The title compound was obtained as a pale yellow solid (90 mg, 77 %). [M + H]⁺ 392.3

Reference Example 37 2-Chloro-6-[4-(3,3-difluoroazetidin-l-yI)piperidin-l- yImethyll-4-morpholin-4-ylfuro[3,2-</1pyrimidine

^

Prepared according to the method used in the preparation of 2-chloro-6-[(5)-l- (hexahydro-pyrrolo[l,2-fl]pyrazin-2-yl)methyl]-4-moφholin-4-ylruro[3,2-<i]pyrimidine using 4-(3,3-difluoroazetidin-l-yl)piperidine in place of (S)-octahydro-pyrrolo[l,2-α]pyrazine. The title compound was obtained as a white solid (120 mg, 70 %). [M + H]⁺ 428.4

Reference Example 38 2-Chloro-6-(4-cvclopropyImethylpiperazin-l-vImethyl)-4- morpholin-4-ylfurof3,2-</lpyrimidine

To a solution of 2-chloro-4-morpholin-4-ylfuro[3 ,2-J]pyrimidine-6-carbaldehyde ( 100 mg, 0.0.37 mmol) in 1,2-dichloroethane (10 mL) was added 1-cyclopropylmethylpiperazine (61 μL, 0.41 mmol). The mixture was stirred at RT for 1 h before adding sodium triacetoxyborohydride (119 mg, 0.56 mmol). The resulting solution was stirred at RT for 1 h, and then partitioned between brine and DCM. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (84 mg, 59%). [M + H]⁺ 392.2

Reference Example 39 2-ChIoro-4-morpholin-4-yl-6-(4-morpholin-4-ylpiperidiii-l- vlmethvl)-furo[3,2-<f|pyrimidine

^

Prepared according to the method used in the preparation of 2-chloro-6-(4- cyclopropylmethylpiperazin- 1 -ylmethyl)-4-morpholin-4-ylfuro[3 ,2- d]pyrimidine using 4- piperidin-4-ylmorpholine in place of 1-cyclopropylmethylpiperazine. The title compound was obtained as a cream solid (109 mg, 70 %). [M + H]⁺ 422.2

Reference Example 40 4-(2-Chloro-4-morphoIin-4-ylfuro [3,2-</l pyrimidin-6- ylmethvO-piperazine-1-carboxylic acid tert-butyl ester

Prepared according to the method used in the preparation of 2-chloro-6-(4- cyclopropylmethylpiperazin- 1 -ylmethyl)-4-morpholin-4-ylfuro[3 ,2-rf]pyrimidine using piperazine-1-carboxylic acid tert-butyl ester in place of 1-cyclopropylmethylpiperazine. The title compound was obtained as a yellow solid (115 mg, 71 %). [M + H]⁺ 438.2

Reference Example 41 2-[4-(2-Chloro-4-morpholin-4-ylfurof3,2-</lpyrimidin-6- ylmethvD-piperazin-l-yllisobutyramide

To a solution of tert-butyl- 1-piperazinecarboxylate (15.0 g) in dichloromethane (150 mL) and methanol (150 mL) at 0 °C was added hydrogen chloride (40 mL; 2M solution in diethyl ether). The mixture was stirred at room temperature for 1.5 hours and reduced in vacuo to yield tert-butyl-l-piperazinecarboxylate hydrochloride (17.9 g). To a solution of tert-butyl-1-piperazinecarboxylate hydrochloride (17.9 g) in water (200 mL) at room temperature was added sodium cyanide (3.94 g). A solution of acetone (5.9 mL) in water (20 mL) was then added dropwise and stirred at room temperature for 48 hours. The mixture was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, separated, dried (MgSO₄) and reduced in vacuo to yield 4-(cyano- dimethyl-methyl)-piperazine-l-carboxylic acid tert-butyl ester (17.5 g).

To a solution of 4-(cyano-dimethyl-methyl)-piperazine-l-carboxylic acid tert-butyl ester (960 mg) in methyl sulfoxide (20 mL) at 0 "C was added potassium carbonate (104 mg). Hydrogen peroxide (2.0 mL; 27.5 wt % solution in water) was then added dropwise. The resulting mixture was heated to 40 °C overnight. To the cooled mixture was added water and the precipitated solid filtered and dried yielding 4-(l-carbamoyl-2-methyl-ethyI)-piperazine- 1-carboxylic acid tert-butyl ester (677 mg). The BOC-group was removed using HCl in ether under standard conditions to give 2-piperazine-l-yl-isobutyramide di-hydrochloride (600 mg). The title compound was prepared according to the method used in the preparation of

2-chloro-6-(4-cyclopropylmethylpiperazin-l-ylmethyl)-4-morpholin-4-ylfuro[3,2- J]pyrimidine using 2-piperazin-l-ylisobutyramide in place of 1-cyclopropylmethylpiperazine. The title compound was obtained as a yellow solid (50 mg, 16 %). [M + H]⁺ 423.2

Example 1 2-(6-FIuoro-l/y-indoI-4-yl)-6-(hexahvdro-pyrrolo[3,4-clpyrrol-2- vImethyl)-4-morpholin-4-vI-furoF3,2-.flpvrimidine

The compound was produced by using the general coupling method A described in

Reference Example 2 above, followed by BOC-deprotection using TFA:DCM (1:5). The title compound was obtained as a white glass (10 mg, 46 %).

[M + H]⁺ 463.3 ¹H NMR (400 MHz, CHCl₃-d): δ 2.52 (d, J = 6 Hz, 2 H), 2.68-2.74 (m, 4 H), 2.79 (d, J = 11.5 Hz, 3 H), 2.96 (dd, J = 11.0, 4.9 Hz, 2 H), 3.75 (s, 2 H), 3.90 (t, J = 4.8 Hz, 4 H), 4.12 (t, J = 4.8 Hz, 4 H), 6.74 (s, 1 H), 7.15 (ddd, J = 8.9, 2.4, 1 Hz, 1 H), 7.28 (dd, J = 3.2, 2.2 Hz, 1 H), 7.47 (m, 1 H), 7.89 (dd, J = 11.2, 2.4 Hz, 1 H) and 8.28 (bs, 1 H).

Example 2 6-(2,7-Diaza-spiro[3.51non-2-ylmethyl)-2-(6-fluoro-l.H-indol-4-yl)-4- morpholin-4-yl-furof3,2-</lpyrimidine

Prepared by using the general coupling method A described in Reference Example 2 above, followed by BOC-deprotection using TFA:DCM (1:5). The title compound was obtained as a tan solid (10 mg, 10 %).

[M + H]⁺ 477.3

¹H NMR (400 MHz CD₃OD): δ 1.79 (t, J = 5.3 Hz, 4 H), 2.81 (t, J = 5.3 Hz, 4 H), 3.24 (s, 4

H), 3.81-3.88 (m, 6 H), 4.12 (m, 4 H), 6.73-6.79 (m, 1 H), 7.15-7.20 (m, 2 H), 7.30 (d, J = 3.2 Hz, 1 H) and 7.63 (dd, J = 11.2, 2.4 Hz, 1 H).

Example 3 morpholin-4-yl-furo \3,2-d\ pyrimidine

Prepared by using the general coupling method A described in Reference Example 2 above, followed by BOC-deprotection using TFA:DCM (1:5). The title compound was obtained as a white solid (60 mg, 67 %). [M + H]⁺ 463.2 1H NMR (400 MHz, CDCl₃): δ 1.69-1.75 (m, 2 H), 1.87-1.93 (m, 2 H), 2.36 (d, J = 10.4 Hz, 2 ^

H), 2.71-2.77 (m, 2 H), 3.44 (bs, 2 H), 3.67 (s, 2 H), 3.85 (t, J = 4.7 Hz, 4 H), 4.08 (t, J = 4.7 Hz, 4 H), 6.74 (s, 1 H), 6.86 (bs, 1 H), 7.03 (dd, J = 10.9, 8.8 Hz, 1 H), 7.24 (m, 1 H), 7.33 (dd, J = 8.8, 3.9 Hz, 1 H) and 8.29 (bs, 1 H).

Example 4 2-(6-Fluoro-l.H-indol-4-vπ-6-[(S)-l-(hexahvdro-pyrroIo[l,2-d1pyrazin-2- yl)methyll-4-morpholin-4-vI-furof3,2-</1pvrimidine

Prepared by using the general coupling method A described in Reference Example 2 above. The title compound was obtained as a white solid (21 mg, 19 %). [M + H]⁺ 477.4

¹R NMR (400 MHz, CD₃OD): δ 1.34-1.46 (m, 1 H), 1.75-1.90 (m, 3 H), 2.09 (t, J = 10.6 Hz, 1 H), 2.15-2.25 (m, 2 H), 2.34-2.47 (m, 2 H), 2.93 (d, J = 10.6 Hz, 1 H) 3.00-3.10 (m, 3 H), 3.83-3.88 (m, 6 H), 4.13 (t, J = 4.8 Hz, 4 H), 6.83 (s, 1 H), 7.15-7.20 (m, 2 H), 7.30 (d, J = 3.2 Hz, 1 H) and 7.63 (dd, J = 11.2, 2.3 Hz, 1 H).

Example 5 6-(2,8-Diaza-spirof4.51dec-8-ylmethvI)-2-(6-fluoro-lg-indoI-4-yl)-4- morphoIin-4-yl-furo[3,2-</]pyrimidine

Prepared by using the general coupling method A described in Reference Example 2 above, followed by BOC-deprotection using TFA:DCM (1:5). The title compound was obtained as a colourless glass (13.5 mg, 14 %). [M + H]⁺ 491.4 1H NMR (400 MHz, CD₃OD): δ 1.60-1.69 (m, 6 H), 2.58 (bs, 4 H), 2.73 (s, 2 H), 2.98 (t, J = 7.2 Hz, 2 H), 3.79 (s , 2 H), 3.87 (t, J = 4.7 Hz, 4 H), 4.14 (t, J = 4.7 Hz, 4 H), 6.82 (s, 1 H), 7.16-7.22 (m, 2 H), 7.30 (m, 1 H) and 7.63 (dd, J = 11.2, 2.3 Hz, 1 H).

Example 6 β-UlSA^-l-d.S-Diaza-bicycloM.lΛMieOt-l-yDmethyn-l-ζβ-nuoro-lH- indoI-4-vI)-4-morpholin-4-yl-furo[3,2-</Ipyrimidine

Prepared by using the general coupling method A described in Reference Example 2 above, followed by BOC-deprotection using TFA:DCM (1:5). The title compound was obtained as a tan solid (14 mg, 28 %). [M + H]⁺ 449.2

¹H NMR (400 MHz, CDCl₃): δ 1.29 (bs, 1 H), 1.66 (d, J = 10.2 Hz, 1 H), 1.91 (d, J = 10.5 Hz, 1 H), 2.68 (d, J = 10.2 Hz, 1 H), 2.84 (d, J = 10.5 Hz, 1 H), 2.97-3.02 (m, 1 H), 3.22 (d, J = 10.5 Hz, 1 H), 3.54 (m, 2 H), 3.63 (bs, 1 H), 3.87 (t, J = 4.6 Hz, 4 H), 3.92 (d, J = 14.8 Hz, 1 H), 3.99 (d, J = 14.8 Hz, 1 H), 4.14 (t, J = 4.6 Hz, 4 H), 6.81 (s, 1 H), 7.17-7.22 (m, 2 H), 7.32 (d, J = 3.2 Hz, 1 H) and 7.64 (dd, J = 11.2, 2.4 Hz, 1 H).

Example 7 β-rαS^S^-l-fl.S-Diaza-bicvclori.I.πhept^-vnmethyll^-dg-indoM-yl)- 4-morpholin-4-yl-furo[3,2-</1pyrimidine

Prepared by using the general coupling method A described in Reference Example 2 above, followed by BOC-deprotection using TFA:DCM (1:5). The title compound was obtained as a white solid (35 mg, 74 %). [M + H]⁺ 431.2 ¹H NMR (400 MHz, DMSOd₆): δ 1.46 (d, J = 9.3 Hz, 1 H), 1.70 (d, J = 9.3 Hz, 1 H), 2.49 (m, 1 H), 2.66-2.73 (m, 1 H), 2.91 (dd, J = 9.8, 2.4 Hz₅ 1 H), 3.06 (d, J = 9.8 Hz, 1 H), 3.44 (bs, 2 H), 3.79-3.95 (m, 6 H), 4.03 (m, 4 H), 6.84 (s, 1 H), 7.18 (apparent t, J = 7.8 Hz, 1 H), 7.38 (t, J = 2.6 Hz, 1 H), 7.43 (t, J = 2.6 Hz, 1 H), 7.50 (dd, J = 7.8, 1.0 Hz, 1 H), 8.05 (dd, J = 7.8, 1.0 Hz, 1 H) and 11.19 (bs, 1 H).

Example 8 6-f(S)-l-(Hexahvdro-pyrroIoH,2-αlpyrazin-2-vI)methyll-2-rig-indoI-4-yl)- 4-morpholin-4-vIfuro[3,2-</lpyrimidine

Prepared by using Suzuki coupling method A of Reference Example 2. The title compound was obtained as a cream solid (187 mg, 83 %).

[M + H]⁺ 459.3

¹H NMR (400 MHz, CDCl₃): δ 1.36-1.44 (m, 1 H), 1.67-1.88 (m, 3 H), 2.01-2.20 (m, 3 H),

2.34 (td, J = 11.0, 2.8 Hz, 1 H), 2.45 (td, J = 11.0, 2.89 Hz, 1 H), 2.93 (d, J = 11.0 Hz, 1 H), 3.00-3.10 (m, 3 H), 3.76-3.85 (m, 2 H), 3.90 (t, J = 4.7 Hz, 4 H), 4.13 (t, J = 4.7 Hz, 4 H),

6.78 (s, 1 H), 7.27-7.33 (m, 2 H), 7.45-7.48 (m, 2 H), 8.11 (dd, J = 7.5, 0.9 Hz, 1 H) and 8.30

(bs, 1 H).

Example 9 2-(5-FIuoro-l_Jg-indol-4-yl)-6-r(5)-l-(hexahvdro-pyrroloH.2-αlpyrazin-2- yl)methyll-4-morpholin-4-ylfuro[3.,2-</]pyrimidine

Prepared by using Suzuki coupling method B of Reference Example 2, followed by TBS-deprotection. The title compound was obtained as a cream solid (120 mg, 51 %). [M + H]⁺ 477.2 ¹H NMR (400 MHz, DMSOd₆): δ 1.19-1.32 (m, 1 H), 1.60-1.78 (m, 3 H), 1.89-2.06 (m, 3 H), 2.13-2.31 (m, 2 H), 2.82 (d, J = 10.6 Hz, 1 H), 2.87-3.01 (m, 3 H), 3.77 (t, J = 4.6 Hz, 4 H), 3.80 (s, 2 H), 3.96 (t, J = 4.6 Hz, 4 H), 6.62 (m, 1 H), 6.88 (s, 1 H), 6.98 (dd, J = 11.0, 8.7 Hz, 1 H), 7.40-7.45 (m, 2 H); and 11.21 (bs, 1 H).

Example 10 6-K5)-l-(Hexahvdro-pyrroIoH_<2-αlpyrazin-2-yl)methyIl-4-morpholin-4-yl- 2-(2-trifluoromethyl-liy-indoI-4-v0furo[3,2-<f|pyrimidine

Prepared by using Suzuki coupling method A of Reference Example 2. The title compound was obtained as a cream solid (56 mg, 40 %). [M + H]⁺ 527.2

¹H NMR (400 MHz, CDCl₃): δ 1.40 (s, 1 H), 1.70-1.90 (m, 3 H), 2.12 (m, 3 H), 2.35 (m, 1 H), 2.45 (m, 1 H), 2.92 (d, J = 10.7 Hz, 1 H), 2.99-3.11 (m, 3 H), 3.75-3.84 (m, 2 H), 3.89 (t, J = 4.7 Hz, 4 H), 4.11 (t, J = 4.7 Hz, 4 H), 6.79 (s, 1 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.48 (dt, J = 8.2, 1.0 Hz, 1 H), 7.92 (m, 1 H), 8.17 (dd, J = 7.7, 1.0 Hz, 1 H) and 8.51 (bs, 1 H).

Example 11 l-{2-[2-(5-Fluoro-l.g-indol-4-yl)-4-inorpholin-4-ylfuro[3,2-<fipyrimidin-6- vImethvπ-2,7-diazaspiro[3.51non-7-vUethanone

Prepared by using Suzuki coupling method B of Reference Example 2. The title compound was obtained as a cream solid (23 mg, 46 %). [M + H]⁺ 519.2 ¹H NMR (400 MHz, CD₃OD): δ 1.73 (t, J = 5.5 Hz, 2 H), 1.82 (t, J = 5.5 Hz, 2 H), 2.07 (s, 3 H), 3.25 (s, 4 H), 3.47 (m, 4 H), 3.83 (t, J = 4.7 Hz, 4 H), 3.90 (s, 2 H), 4.04-4.12 (m, 4 H), 6.56 (dd, J = 3.1, 0.8 Hz, 1 H), 6.77 (s, 1 H), 6.95 (dd, J = 10.8, 8.8 Hz, 1 H), 7.30 (d, J = 3.1 Hz, 1 H) and 7.41 (dd, J = 8.8, 4.0 Hz, 1 H).

Example 12 2-(5-Fluoro-l.H-indol-4-vI)-6-(7-methvI-2,7-diazaspirof3.51non-2- vImethyl)-4-morpholin-4-ylfuro \3,2-d\ pyrimidine

Prepared by using Suzuki coupling method B of Reference Example 2. The title compound was obtained as a tan solid (32 mg, 39 %).

[M + H]⁺ 491.2

¹H NMR (400 MHz, CDCl₃): δ 1.82 (bs, 4 H), 2.26 (s, 3 H), 2.35 (m, 4 H), 3.14 (s, 4 H), 3.78

(s, 2 H), 3.84 (t, J = 4.7 Hz, 4 H), 4.07 (t, J = 4.7 Hz, 4 H), 6.71 (s, 1 H), 6.85 (t, J = 2.5 Hz, 1 H), 7.03 (dd, J = 10.9, 8.7 Hz, 1 H), 7.26 (m, 1 H), 7.31-7.36 (m, 1 H) and 8.23 (bs, 1 H).

Example 13 6-(3,3-Dimethylpiperazin-l-ylmethvI)-2-(5-fluoro-l/-^r-indol-4-yl)-4- morphoIin-4-ylf uro [3,2-tfl p yrimidine

Prepared by using Suzuki coupling method B of Reference Example 2, followed by

TBS- and BOC-deprotections. The title compound was obtained as a pale yellow solid (82 mg, 61 %). [M + H]⁺ 465.2 ¹H NMR (400 MHz, CD₃OD): δ 1.17 (s, 6 H), 2.32 (bs, 2 H), 2.53 (bs, 2 H), 2.92 (m, 2 H), 3.75 (s, 2 H), 3.82 (t, J = 4.7 Hz, 4 H), 4.08 (t, J = 4.7 Hz, 4 H), 6.57 (dd, J = 3.1, 0.9 Hz, 1 H), 6.75 (s, 1 H), 6.95 (dd, J = 10.8, 8.7 Hz, 1 H), 7.30 (d, J = 3.1 Hz, 1 H) and 7.38-7.43 (m, I H).

Example 14 {l-f2-(5-Fluoro-l-H-indoI-4-yl)-4-morpholin-4-ylfuro[3.,2-</lpyriinidin-6- ylmeth yll -piperidin-4-yl} dimeth ylamine

Prepared by using Suzuki coupling method D of Reference Example 2. The title compound was obtained as a cream solid (75 mg, 60 %). [M + H]⁺ 479.1

¹H NMR (400 MHz, CDCl₃): δ 1.51-1.64 (m, 2 H), 1.84 (d, J - 12.5 Hz, 2 H), 2.15 (m, 3 H), 2.29 (s, 6 H), 3.02 (d, J = 11.1 Hz, 2 H), 3.73 (s, 2 H), 3.85 (t, J = 4.7 Hz, 4 H), 4.07 (t, J = 4.7 Hz, 4 H), 6.74 (s, 1 H), 6.84-6.86 (m, 1 H), 6.97-7.06 (m, 1 H), 7.26 (m, 1 H), 7.31-7.36 (m, 1 H) and 8.27 (bs, 1 H). c/

Example 15 (l-[2-(lfl-IndoI-4-yl)-4-morpholin-4-ylfuror3,2-<i1pyriinidin-6-ylmethvI]- piperidin-4-vU dimethylamine

Prepared by using Suzuki coupling method C of Reference Exmaple 2. The title compound was obtained as a tan solid (60 mg, 49 %). [M + H]⁺ 461.1 ¹H NMR (400 MHz, CDCl₃): δ 1.63 (m, 2 H), 1.89 (m, 2 H), 2.16 (t, J = 11.6 Hz, 2 H), 2.37 (m, 7 H), 3.04 (d, J = 11.6 Hz, 2 H), 3.72 (s, 2 H), 3.89 (t, J = 4.7 Hz, 4 H), 4.12 (t, J = 4.7 Hz, 4 H), 6.75 (s, 1 H), 7.26-7.32 (m, 2 H), 7.45-7.48 (m, 2 H), 8.10 (dd, J = 7.5, 1.0 Hz, 1 H) and 8.28 (bs, 1 H).

Example 16 6-(4-CvcIopropylmethylpiperazin-l-ylmethyl)-2-(5-fluoro-l_JH-indol-4-yl)- 4-morpholin-4-ylfuro[3,2-</lpyrimidine

Prepared by using Suzuki coupling method B of Reference Example 2, followed by TBS-deprotection. The title compound was obtained as its formate salt as a white solid (5 mg,

5 %).

[M + H]⁺ 491.2

¹H NMR (400 MHz, CDCl₃): δ 0.14 (m, 2 H), 0.51-0.57 (m, 2 H), 0.85-0.94 (m, 1 H), 2.00

(m, 4 H), 2.37 (d, J = 6.6 Hz, 2 H), 2.70 (m, 4 H), 3.75 (s, 2 H), 3.85 (t, J = 4.7 Hz, 4 H), 4.07 (t, J = 4.7 Hz, 4 H), 6.77 (s, 1 H), 6.84 (t, J = 2.5 Hz, 1 H), 6.98-7.06 (m, 1 H), 7.26 (m, 1 H),

7.31-7.36 (m, 1 H) and 8.25 (bs, 1 H).

Example 17 2-(5-Fluoro-lg-indoI-4-yl)-4-morpholin-4-yI-6-(4-morpholin-4- ylpiperidin-l-ylmethyl)-furof3,2-</|pyrimidine

Prepared by using Suzuki coupling method B of Reference Example 2, followed by TBS-deprotection. The title compound was obtained as a white solid (101 mg, 75 %). [M + H]⁺ 521.2

¹H NMR (400 MHz, CDCl₃): δ 1.52-1.67 (m, 2 H), 1.85 (d, J = 12.3 Hz, 2 H), 2.10-2.23 (m, 3 H), 2.55 (t, J = 4.4 Hz, 4 H), 3.04 (d, J = 11.0 Hz, 2 H), 3.68-3.75 (m, 6 H), 3.85 (t, J = 4.7 Hz, 4 H), 4.08 (t, J = 4.7 Hz, 4 H), 6.75 (s, 1 H), 6.86 (t, J = 2.5 Hz, 1 H), 6.98-7.05 (m, 1 H), 7.28 (m, 1 H), 7.34 (m, 1 H) and 8.35 (bs, 1 H).

Example 18 2-(5-Fluoro-lfy-indoI-4-yQ-4-morpholin-4-yl-6-piperazin-l- ylmethylfuro \3,2-d\ pyrimidme

Prepared by using Suzuki coupling method B of Reference Example 2, followed by

TBS- and BOC-deprotection. The title compound was obtained as its formate salt as a white solid (14 mg, 18 %). [M + H]⁺ 437.1 1H NMR (400 MHz, CDCl₃): δ 2.58-2.66 (m, 4 H), 3.01 (m, 4 H), 3.73 (s, 2 H), 3.85 (t, J = 4.7 Hz, 4 H), 4.07 (t, J = 4.7 Hz, 4 H), 6.78 (m, 1 H), 6.84 (m, 1 H), 7.03 (dd, J = 10.9, 8.8 Hz, 1 H), 7.26 (m, 1 H), 7.34 (ddd, J = 8.8, 3.9, 0.9 Hz, 1 H) and 8.23 (bs, 1 H).

Example 19 2-{4- f2-(5-Fluoro-lH-indol-4-yl)-4-morpholin-4-ylfuro [3,2-<fl pyrimidin-6- ylmethyll-piperazin-l-vUisobutyramide

Prepared by using Suzuki coupling method B of Reference Example 2, followed by TBS-deprotection. The title compound was obtained as a white solid (12 mg, 19 %). ^

[M + H]⁺ 522.2

¹H NMR (400 MHz, CDCl₃): δ 1.22 (s, 6 H), 1.61 (bs, 4 H), 2.60 (bs, 4 H), 3.75 (s, 2 H), 3.85 (t, J = 4.7 Hz, 4 H), 4.07 (t, J = 4.7 Hz, 4 H), 5.21 (bs, 1 H), 6.75 (s, 1 H), 6.85 (t, J = 2.5 Hz, 1 H), 6.96-7.05 (m, 2 H), 7.25 (m, 1 H), 7.33 (dd, J = 8.8, 3.8 Hz, 1 H) and 8.30 (bs, 1 H).

Example 20 6-(4-Azetidin-l-ylpiperidin-l-ylmethyl)-2-(5-fluoro-l.g-indoI-4-vI)-4- morpholin-4-ylfurof3.,2-</lpvrimidine

Prepared by using Suzuki coupling method E of Reference Example 2. The title compound was obtained as a white solid (73 mg, 68 %).

[M + H]⁺ 491.2

¹H NMR (400 MHz, CDCl₃): δ 1.30-1.42 (m, 2 H), 1.70 (d, J = 12.7 Hz, 2 H), 1.93-2.13 (m, 3

H), 2.12-2.25 (m, 2 H), 2.85-2.94 (m, 2 H), 3.18 (t, J = 6.9 Hz, 4 H), 3.73 (s, 2 H), 3.85 (t, J = 4.7 Hz, 4 H), 4.08 (t, J = 4.7 Hz, 4 H), 6.74 (s, 1 H), 6.85-6.87 (m, 1 H), 6.97-7.06 (m, 1 H),

7.25 (m, 1 H), 7.33 (ddd, J = 8.9, 4.0, 0.8 Hz, 1 H) and 8.37 (bs, 1 H).

Example 21 6-[4-(3,3-Difluoroazetidin-l-yl)piperidin-l-ylmethyll-2-(l/-^r-indol-4-vI)-4- morpholin-4-yIfurof3,2-</]pyriinidine

Prepared by using Suzuki coupling method F of Reference Example 2. The title compound was obtained as a cream solid (54 mg, 76 %). [M + H]⁺ 509.3

¹H NMR (400 MHz, CDCl₃): δ 1.41-1.52 (m, 2 H), 1.72 (m, 2 H), 2.11-2.28 (m, 3 H), 2.88- 2.95 (m, 2 H), 3.55 (t, J = 11.9 Hz, 4 H), 3.75 (s, 2 H), 3.91 (t, J = 4.8 Hz, 4 H), 4.14 (t, J = 4.8 Hz, 4 H), 6.76 (s, 1 H), 7.28-7.34 (m, 2 H), 7.48 (m, 2 H), 8.12 (dd, J = 7.7, 0.9 Hz, 1 H) and 8.32 (bs, 1 H).

Example 22 6-f4-(3,3-Difluoroazetidin-l-vI)piperidin-l-ylinethvIl-2-(5-fluoro-l-H-indol- 4-vI)-4-morpholin-4-ylfuro[3,2-</|pyrimidine

Prepared by using Suzuki coupling method E of Reference Example 2. The title compound was obtained as a white solid (35 mg, 48 %). [M + H]⁺ 527.3

¹H NMR (400 MHz, CDCl₃): δ 1.38-1.49 (m, 2 H), 1.65-1.74 (m, 2 H)₅ 2.10-2.26 (m, 3 H), 2.85-2.92 (m, 2 H), 3.53 (t, J = 11.9 Hz, 4 H), 3.72 (s, 2 H), 3.84 (t, J = 4.8 Hz, 4 H), 4.07 (t, J = 4.8 Hz, 4 H), 6.73 (s, 1 H), 6.85 (m, 1 H), 6.97-7.05 (m, 1 H), 7.26 (m, 1 H), 7.33 (ddd, J = 8.9, 3.9, 0.9 Hz, 1 H) and 8.31 (bs, 1 H).

Example 23 Biological Testing

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

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. IC₅₀ values were subsequently determined using sigmoidal dose-response curve fit (variable slope). All of the compounds tested had an IC₅₀ against PBK of 50μM or less. Typically the IC₅₀ against the pl lOδ isoform of PBK was less than 50OnM.

Example 24 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 (415g) 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 25 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 26 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 27 Syrup Formulation

Compound of invention 250 mg

Sorbitol Solution 1.50 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 furanopyrimidine of formula (I):

wherein

W represents a furan ring;

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 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;

(b) 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

(C) 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; m is 0, 1 or 2;

R³ is H or C₁-C₆ alkyl;

R⁴ is an indole group which is unsubstituted or substituted; and

R^a is selected from R, halo, CN, C(O)NR₂, halo(CrC₆)alkyl, SO₂R, SO₂NR₂,

NRSO₂R, NRC(O)R, NRC(O)OR and NRC(O)NR₂ wherein each R is independently

H or C₁-C₆ alkyl; and or a pharmaceutically acceptable salt thereof.

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

wherein R > 1 , τ Ri2 , r R«3 , τ R>4 , r R»a^a and m are as defined in claim 1.

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

wherein R k l , , R τ>3 , R τ>4 , R τ*^aa 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(C_!-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-(6-Fluoro- lH-indol-4-yl)-6-(hexahydro-pyrrolo[3 ,4-c]pyrrol-2-ylmethyl)-4-morpholin-4-yl- furo[3 ,2- Jjpyrimidine;

6-(2,7-Diaza-spiro[3.5]non-2-ylmethyl)-2-(6-fluoro-lH-indol-4-yl)-4-moφholin-4-yl- furo[3,2-fiT]pyrimidine;

6-(3,8-Diaza-bicyclo[3.2.1]oct-3-ylmethyl)-2-(5-fluoro-lH-indol-4-yl)-4-morpholin-4-yl- furo[3,2-J]pyrimidine;

2-(6-Fluoro- lH-indol-4-yl)-6-[(S)- 1 -(hexahydro-pyrrolo[ 1 ,2-α]pyrazin-2-yl)methyl]-4- morpholin-4-yl-furo[3,2-J]pyrimidine;

6-(2,8-Diaza-spiro[4.5]dec-8-ylmethyl)-2-(6-fluoro-lH-indol-4-yl)-4-morpholin-4-yl- furo[3 ,2- d]pyrimidine; 6-[(15,45)-l-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)methyl]-2-(6-fluoro-lH-indol-4-yl)-4- morpholin-4-yl-furo[3,2-cf]pyrimidine; _?Q

6-[(l_lS,4₁S)-l-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)methyl]-2-(lH-indol-4-yl)-4-morpholin-4-yl- fiiro[3,2-cT|pyrimidine;

6-[(S)- 1 -(Ηexahydro-pyrrolo[ 1 ,2-α]pyrazin-2-yl)methyl]-2-( lH-indol-4-yl)-4- moφholin-4-ylfuro[3,2-d]pyrimidine; 2-(5-Fluoro-lH-indol-4-yl)-6-[(iS)-l-(hexahydro-pyrrolo[l,2-α]pyrazin-2-yl)methyl]-

4-moφholin-4-ylfuro[3,2-cT|pyrimidine;

6-[(S)- 1 -(Ηexahydro-pyrrolo[ 1 ,2-α]pyrazin-2-yl)methyl]-4-moφholin-4-yl-2-(2- trifluoromethyl-lH-indol-4-yl)furo[3,2-cr|pyrimidine;

1 - {2-[2-(5-Fluoro- lH-indol-4-yl)-4-morpholin-4-ylfuro[3,2-i/]pyrimidin-6-ylmethyl]- 2,7-diazaspiro[3.5]non-7-yl} ethanone;

2-(5-Fluoro- lH-indol-4-yl)-6-(7-methyl-2,7-diazaspiro[3.5]non-2-ylmethyl)-4- morpholin-4-ylfuro[3 ,2- JJpyrimidine;

6-(3,3-Dimethylpiperazin-l-ylmethyl)-2-(5-fluoro-lH-indol-4-yl)-4-morpholin-4- ylfuro[3,2-rf]pyrimidine; {l-[2-(5-Fluoro-lH-indol-4-yl)-4-morpholin-4-ylfuro[3,2-<i]pyrimidin-6-ylmethyl]- piperidin-4-yl } dimethylamine;

{l-[2-(lH-Indol-4-yl)-4-morpholin-4-ylfuro[3,2-rf]pyrimidin-6-ylmethyl]-piperidin-4- yl } dimethylamine;

6-(4-Cyclopropylmethylpiperazin- 1 -ylmethyl)-2-(5-fluoro- lH-indol-4-yl)-4- moφholin-4-ylfiαro[3,2-J]pyrimidine;

2-(5-Fluoro- lH-indol-4-yl)-4-moφholin-4-yl-6-(4-moφholin-4-ylpiperidin- 1 - ylmethyl)-furo[3,2-J]pyrimidine;

2-(5-Fluoro-lH-indol-4-yl)-4-moφholin-4-yl-6-piperazin-l-ylmethylfiiro[3,2-

J]pyrimidine; 2-{4-[2-(5-Fluoro-lH-indol-4-yl)-4-moφholin-4-ylfuro[3,2-cT|pyrimidin-6-ylmethyl]- piperazin- 1 -yl } isobutyramide;

6-(4- Azetidin- 1 -ylpiperidin- 1 -ylmethyl)-2-(5-fluoro- lH-indol-4-yl)-4-moφholin-4- ylfuro[3,2-rf]pyrimidine;

6-[4-(3 ,3 -Difluoroazetidin- 1 -yl)piperidin- 1 -ylmethyl]-2-( lH-indol-4-yl)-4-moφholin-4- ylfuro[3,2-d]pyrimidine; and

6-[4-(3,3-Difluoroazetidin- 1 -yl)piperidin- 1 -ylmethyl]-2-(5-fluoro- lH-indol-4-yl)-4- moφholin-4-ylfuro[3 ,2-c?]pyrimidine; 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 PB 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 PB 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