WO2010061180A1

WO2010061180A1 - Quinoline derivatives as p13 kinase inhibitors

Info

Publication number: WO2010061180A1
Application number: PCT/GB2009/002741
Authority: WO
Inventors: Rebekah Elisabeth Beevers; Stephen Robert Mack; Verity Margaret Sabin
Original assignee: Ucb Pharma S.A.
Priority date: 2008-11-27
Filing date: 2009-11-23
Publication date: 2010-06-03
Also published as: GB0821693D0

Abstract

A series of quinoline derivatives, substituted at the 2-position by a heteroaryl group attached via an alkylene chain optionally linked to a heteroatom, and at the 3-position by a carbocyclic or heterocylic ring, being selective inhibitors of PD kinase enzymes, are accordingly of benefit in medicine, for example in the treatment of inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive or ophthalmic conditions.

Description

QUINOLINE DERIVATIVES AS P13 KINASE INHIBITORS

The present invention relates to a class of substituted quinoline derivatives, and to their use in therapy. These compounds are selective inhibitors of phosphoinositide 3- kinase (PDK) enzymes, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

The PBK pathway is implicated in a variety of physiological and pathological functions that are believed to be operative in a range of human diseases. Thus, PDKs provide a critical signal for cell proliferation, cell survival, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization and chemotaxis (cf. S. Ward et al., Chemistry & Biology, 2003, 10, 207- 213; and S.G. Ward & P. Finan, Current Opinion in Pharmacology, 2003, 3, 426-434); and are known to be involved in the pathology of cancer, and metabolic, inflammatory and cardiovascular diseases (cf. M.P. Wymann et al., Trends in Pharmacol. Sci., 2003, 24, 366-376). Aberrant upregulation of the PDK pathway is implicated in a wide variety of human cancers (cf. S. Brader & S. A. Eccles, Tumori, 2004, 90, 2-8).

The compounds in accordance with the present invention, being potent and selective PDK inhibitors, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, asthma, inflammatory bowel disease, psoriasis and transplant rejection; cardiovascular disorders including thrombosis, cardiac hypertrophy, hypertension, and irregular contractility of the heart (e.g. during heart failure); neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma and seizures; metabolic disorders such as obesity and type 2 diabetes; oncological conditions including leukaemia, glioblastoma, lymphoma, melanoma, and human cancers of the liver, bone, skin, brain, pancreas, lung, breast, stomach, colon, rectum, prostate, ovary and cervix; pain and nociceptive disorders; and ophthalmic disorders including age- related macular degeneration (ARMD).

In addition, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of this invention maybe useful as radioligands in assays for detecting compounds capable of binding to human PDK enzymes.

WO 2008/118454, WO 2008/118455 and WO 2008/118468 describe various series of quinoline and quinoxaline derivatives that are structurally related to each other and are stated to be useful to inhibit the biological activity of human PDKδ and to be of use in treating PI3K-mediated conditions or disorders.

Copending international patent application PCT/GB2008/004171, published on 2 July 2009 as WO 2009/081105 (claiming priority from United Kingdom patent applications 0725030.1 and 0815177.1), describes a class of quinoline and quinoxaline derivatives as selective inhibitors of PI3K enzymes that are of benefit in the treatment of adverse inflammatory, autoimmune, cardiovascular, neurodegenerative, metabolic, oncological, nociceptive and ophthalmic conditions.

None of the prior art available to date, however, discloses or suggests the precise structural class of substituted quinoline derivatives as provided by the present invention. The compounds of the present invention are potent and selective PI3K inhibitors having a binding affinity (IC₅₀) for the human PI3Kα and/or PI3Kβ and/or PI3Kγ and/or PDKδ isoform of 50 μlvl or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC₅₀ figure denotes a more active compound). The compounds of the invention may possess at least a 10-fold selective affinity, typically at least a 20-fold selective affinity, suitably at least a 50-fold selective affinity, and ideally at least a 100-fold selective affinity, for the human PDKα and/or PDKβ and/or PDKγ and/or PDKδ isoform relative to other human kinases. The present invention provides a compound of formula (I) or an TV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

(I) wherein

AIk¹ represents an optionally substituted straight or branched C_1-3 alkylene chain;

L¹ represents oxygen, sulfur, NR⁶ or a covalent bond;

Y represents an optionally substituted mono- or bicyclic heteroaryl group containing at least one nitrogen atom;

R¹ represents a group of formula (a):

in which the asterisk (*) represents the point of attachment of the ring A to the remainder of the molecule; A represents a saturated, partially saturated or unsaturated A-, 5-, 6- or 7- membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one O or S atom;

R^la, R^lb and R^lc independently represent hydrogen, halogen, cyano, nitro, oxo, Ci_-6 alkyl, C_3-7 cycloalkyl, aryl, C_3-7 heterocycloalkyl (optionally substituted by Ci_-6 alkyl), heteroaryl, trifluoromethyl, hydroxy, Ci_-6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_-6 alkylthio, Ci_-6 alkylsulfinyl, Ci_-6 alkylsulfonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, Ci_-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylaminocarbonyl, di(Ci_-6)alkylaminocarbonyl, aminosulfonyl, Ci_-6 alkylaminosulfonyl or di(Ci_-6)alkylaminosulfonyl;

R², R³, R⁴ and R⁵ independently represent hydrogen, halogen, cyano, nitro, Ci_-6 alkyl, trifluoromethyl, aryl(Ci_-6)alkyl, hydroxy, Ci_-6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_-6 alkylthio, Ci_-6 alkylsulfinyl, Ci_-6 alkylsulfonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, Ci_-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylaminocarbonyl, di(Ci_-6)alkylaminocarbonyl, aminosulfonyl, Cj_-6 alkylaminosulfonyl or di(Ci_-6)alkylaminosulfonyl; and R⁶ represents hydrogen or Ci_-6 alkyl. Where any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more - A -

substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.

For use in medicine, the salts of the compounds of formula (I) will be, pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.

Suitable alkyl groups which may be present on the compounds of the invention include straight-chained and branched Ci_-6 alkyl groups, for example Ci_-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, zz-propyl, isopropyl, π -butyl, .sec-butyl, isobutyl, tert-bλxty\, 2,2-dimethylpropyl and 3-methylbutyl. Derived expressions such as "Ci_-6 alkoxy", "Ci_-6 alkylthio", "Ci_-6 alkylsulphonyl" and "Ci_-6 alkylamino" are to be construed accordingly.

The expression "Ci_-3 alkylene chain" refers to a divalent straight or branched alkylene chain containing 1 to 3 carbon atoms. Typical examples include methylene, ethylene, methylmethylene, ethylmethylene and dimethylmethylene.

Specific C_3-7 cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.

Suitable aryl(C_1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups, which may comprise benzo-fused analogues thereof, include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, piperidinyl, 1,2,3,4- tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl and thiomorpholinyl.

Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-ό]pyridinyl, pyrrolo[3,2- cjpyridinyl, pyrazolyl, pyrazolo[l,5-α]pyridinyl, indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[ 1 ,2-α]pyridinyl, imidazo[4,5-&]pyridinyl, imidazo[ 1 ,2-α]pyrimidinyl, imidazo[l,2-α]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl, quinoxalinyl and chromenyl groups.

The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.

Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise, hi addition, compounds of formula (I) may exist as tautomers, for example keto (CH2C=O)<→enol (CH=CHOH) tautomers or amide (TSJHC=O)<→hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. It is to be understood that each individual atom present in formula (I), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter, may be present as a ¹H, ²H (deuterium) or ³H (tritium) atom, preferably ¹H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, maybe present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.

Examples of suitable substituents on the alkylene chain represented by AIk¹ include trifiuoromethyl, aryl, oxo, hydroxy, C_1-6 alkoxy, C_2-6 alkoxycarbonyl(C_1-6)alkoxy, aminocarbonyl(C_1-6)alkoxy, trifiuoromethoxy, aminocarbonyl, C_1-6 alkylaminocarbonyl and di(C i _-6)alkylaminocarbonyl.

Examples of particular substituents on the alkylene chain represented by AIk¹ include trifiuoromethyl, phenyl, oxo, hydroxy, ethoxy, ethoxycarbonylmethoxy, aminocarbonylmethoxy, trifiuoromethoxy, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.

Typical values of AIk¹ include methylene (-CH₂-), (methyl)methylene, ethylene (-CH₂CH₂-), (ethyl)methylene, (dimethyl)methylene, (methyl)ethylene and (dimethyl)ethylene, any of which chains may be optionally substituted by one or more substituents. Suitably, such chains are unsubstituted, monosubstituted or disubstituted. Preferably, such chains are unsubstituted or monosubstituted. In one embodiment, such chains are unsubstituted. ha another embodiment, such chains are monosubstituted.

Suitable values of AIk¹ include -CH₂- (methylene), -CH(CH₃)- (methyl- methylene) and -CH(CH₂CH₃)- (ethylmethylene). AIk¹ typically represents methylene.

Suitably, L¹ represents oxygen or sulfur. hi one embodiment, L¹ represents oxygen. In another embodiment, L¹ represents sulfur, hi a further embodiment, L¹ represents NR⁶. hi a still further embodiment, L¹ represents a covalent bond. The expression "mono- or bicyclic heteroaryl group containing at least one nitrogen atom" in relation to the group Y refers in particular to a mono- or bicyclic aromatic ring system containing one, two, three or four heteroatoms selected from oxygen, sulfur and nitrogen atoms, with at least one of the heteroatoms being nitrogen. The ring Y may be linked to the group L¹ through any available carbon or nitrogen atom. Suitable examples include pyrrolyl, pyridinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indazolyl, benzimidazolyl, furopyridinyl, thienopyridinyl, benzoxazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, imidazopyridinyl, pyrazolopyridinyl, purinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, triazolopyrimidinyl, pyridopyrimidinyl, pyridopyrazinyl, pyridopyridazinyl, naphthyridinyl and pteridinyl.

Suitable values of Y include pyrimidinyl and purinyl, either of which groups may be optionally substituted by one or more substituents. Alternative values of Y include pyrrolyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, pyrazolyl, triazolyl, pyridazinyl, pyrazinyl, triazinyl, indazolyl, benzimidazolyl, furopyridinyl, thienopyridinyl, benzoxazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazolopyrimidinyl, pyridopyrimidin-4-yl, pyridopyrazinyl, pyridopyridazinyl, naphthyridinyl and pteridinyl, any of which groups may be optionally substituted by one or more substituents.

Particular values of Y include pyrimidinyl, triazinyl and purinyl, any of which groups may be optionally substituted by one or more substituents. In one embodiment, Y represents optionally substituted pyrimidinyl. hi another embodiment, Y represents optionally substituted triazinyl. In a further embodiment, Y represents optionally substituted purinyl.

Examples of optional substituents which may be present on the group Y include one, two or three substituents independently selected from halogen, cyano, nitro, oxo, Ci_-6 alkyl, trifluoromethyl, hydroxy, Ci_-6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_-6 alkylthio, Ci_-6 alkylsulfmyl, Ci_-6 alkylsulfonyl, amino, Ci_-6 alkylamino, di(Ci_-6)alkyl~ amino, arylamino, C_2-6 alkylcarboiiylamino, Ci_-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, C_3-6 cycloalkylcarbonyl, C_3-6 heterocycloalkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylaminocarbonyl, di(Ci_-6)alkylaminocarbonyl, amiiiosulfonyl, Ci_-6 alkylaminosulfonyl and di(Ci_-6)alkylaminosulfonyl.

Typical examples of optional substituents on the group Y include Ci_-6 alkyl and amino.

Examples of particular substituents on the group Y include fluoro, chloro, bromo, cyano, nitro, oxo, methyl, isopropyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert- butylamino, dimethylamino, phenylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, N- methylazetidinylcarbonyl, pyrrolidinylcarbonyl, N-memylpyrrolidinylcarbonyl, piperidinylcarbonyl, N~methylpiperidinylcarbonyl, piperazinylcarbonyl, N- methylpiperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

Typical examples of particular substituents on the group Y include methyl and amino. Typical values of Y include aminopyrimidinyl (especially 2-aminopyrimidin-4-yl),

(ammo)(metliyl)pyrimidinyl (especially 2-amino-4-methylpyrimidin-6-yl), (amino)- (methyl)triazinyl (especially 2-amino-4-methyltriazin-6-yl) and purinyl (especially purin- 6-yl).

Suitable values for the group -AIk¹ -L¹ -Y include 2-aminopyrimidin-4-yloxy- methyl, 2-amino-4-methylpyrimidin-6-yloxymethyl, 2-amino-4-methyltriazin-6-yl- oxymethyl and purin-6-ylthiomethyl. hα one embodiment, A is a four-membered monocyclic ring. In another embodiment, A is a five-membered monocyclic ring. In a further embodiment, A is a six- membered monocyclic ring, hi an additional embodiment, A is a seven-membered monocyclic ring. hi one embodiment, ring A is fully saturated. In another embodiment, ring A is partially saturated. In a further embodiment, ring A is unsaturated. hi one embodiment, ring A contains no heteroatoms (i.e. it is a carbocyclic ring), hi another embodiment, ring A contains one heteroatom selected from N, O and S. hi a further embodiment, ring A contains two heteroatoms selected from N, O and S, of which not more than one is O or S. hi a still further embodiment, ring A contains three heteroatoms selected from N, O and S, of which not more than one is O or S. hi a yet further embodiment, ring A contains four heteroatoms selected from N, O and S, of which not more than one is O or S. Suitably, ring A represents phenyl.

Typical values of R^la, R^lb and/or R^lc include hydrogen, halogen, Ci_-6 alkyl, trifluoromethyl, Ci_-6 alkoxy, trifluoromethoxy, C_2-6 alkylcarbonylamino and aryl.

Suitably, R^la, R^lb and R^lc independently represent hydrogen, fluoro, chloro, bromo, cyano, nitro, oxo, methyl, ethyl, isopropyl, cyclopropyl, azetidinyl, N- methylazetidiiiyl, tetrahydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, imidazolidinyl, N-methylimidazolidinyl, tetraliydropyranyl, piperidinyl, N-methylpiperidinyl, piperazinyl, N-methylpiperazinyl, morpholinyl, thiomorpholinyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl or dimethylaminosulfonyl.

Typically, R^la represents hydrogen, halogen, C_1-6 alkyl, trifluoromethyl, C_1-6 alkoxy, trifluoromethoxy, C_2-6 alkylcarbonylamino or aryl.

Suitably, R^la represents hydrogen. Typically, R^lb represents hydrogen, halogen or C_1-6 alkyl.

Suitably, R^lb represents hydrogen.

Typically, R^lc represents hydrogen.

In a particular embodiment, R^lb and R^lc both represent hydrogen.

Typical values of R², R³, R⁴ and/or R⁵ include hydrogen, halogen, Ci_-6 alkyl, aryl(Ci_-6)alkyl and Ci_-6 alkoxy.

Suitably, R², R³, R⁴ and R⁵ independently represent hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, benzyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl or dimethylaminosulfonyl.

Typically, R² represents hydrogen, halogen, Ci_-6 alkyl, aryl(Ci_-6)alkyl or Ci_-6 alkoxy. Suitably, R² represents hydrogen or Ci_-6 alkyl, typically methyl. hi one embodiment, R² represents hydrogen, hi another embodiment, R² represents halogen, particularly fluoro or chloro. In one aspect of that embodiment, R² represents fluoro. In another aspect of that embodiment, R² represents chloro. hi a further embodiment, R² represents Ci_-6 alkyl, particularly methyl or ethyl. In one aspect of that embodiment, R² represents methyl, hi another aspect of that embodiment, R² represents ethyl. In a still further embodiment, R² represents aryl(Ci_-6)alkyl, especially benzyl, hi an additional embodiment, R² represents C_1-6 alkoxy, especially methoxy.

Typically, R³ represents hydrogen or halogen. In one embodiment, R³ represents hydrogen. In another embodiment, R³ represents halogen, particularly fluoro or chloro. In one aspect of that embodiment, R³ represents fluoro. In another aspect of that embodiment, R³ represents chloro.

Typically, R represents hydrogen.

In a particular embodiment, R³ and R⁴ both represent hydrogen.

Typically, R⁵ represents hydrogen or C_1-6 alkyl, especially methyl.

In one embodiment, R⁵ represents hydrogen. In another embodiment, R⁵ represents C_1-6 alkyl, particularly methyl.

In one embodiment, R⁶ represents hydrogen. In another embodiment, R⁶ represents Ci_-6 alkyl, especially methyl.

Suitable values of the group R⁶ include hydrogen and methyl.

One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and iV-oxides thereof, and pharmaceutically acceptable salts and solvates thereof:

(HA)

wherein

R »21 represents hydrogen, halogen, Ci_-6 alkyl, aryl(Ci_-6)alkyl or Ci_-6 alkoxy;

R .31 represents hydrogen or halogen;

R , 51 represents hydrogen or C_1-6 alkyl; and AIk¹, L¹, Y and R¹ are as defined above.

In one embodiment, R²¹ represents hydrogen, hi another embodiment, R²¹ represents halogen, particularly fluoro or chloro. In one aspect of that embodiment, R²¹

01 represents fluoro. In another aspect of that embodiment, R represents chloro. hi a further embodiment, R represents Ci_-6 alkyl, particularly methyl or ethyl. In one aspect of that embodiment, R²¹ represents methyl. In another aspect of that embodiment, R²¹ represents ethyl. In a still further embodiment, R²¹ represents aryl(C_1-6)alkyl, especially benzyl, hi an additional embodiment, R²¹ represents C_1-6 alkoxy, especially methoxy. hi one embodiment, R³¹ represents hydrogen, hi another embodiment, R³¹ represents halogen, particularly fluoro or chloro. hi one aspect of that embodiment, R³¹ represents fluoro. hi another aspect of that embodiment, R³¹ represents chloro. hi one embodiment, R⁵¹ represents hydrogen, hi another embodiment, R⁵¹ represents C_1-6 alkyl, particularly methyl.

Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.

The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable earners. Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, macrocrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.

In addition to the formulations described above, the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.

For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoro ethane, carbon dioxide or other suitable gas or mixture of gases.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

For topical administration the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.

For ophthalmic administration the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum.

For rectal administration the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

The quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.

The compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):

CDO)

wherein AIk¹, L¹, Y, R¹, R², R³, R⁴ and R⁵ are as defined above, and LG¹ represents a suitable leaving group.

The leaving group LG is typically a halogen atom, e.g. bromo. The reaction is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. Aζ N-dimethylformamide or acetonitrile. The reaction may be performed in the presence of a suitable base, e.g. an inorganic base such as potassium carbonate, cesium carbonate, sodium hydride or aqueous sodium hydroxide. The intermediates of formula (III) above wherein LG¹ is bromo maybe prepared from a compound of formula (V):

(V)

wherein AIk¹, R¹, R², R³, R⁴ and R⁵ are as defined above; by bromination.

The reaction is conveniently effected by stirring compound (V) with an appropriate brominating agent, e.g. phosphorus tribromide, in a suitable solvent, e.g. a halogenated hydrocarbon such as dichloromethane. In another procedure, the compounds of formula (I) wherein L¹ represents oxygen may be prepared by a process which comprises reacting a compound of formula (V) as defined above with a compound of formula LG²- Y, in which Y is as defined above and

LG represents a suitable leaving group.

The leaving group LG is typically a halogen atom, e.g. chloro. The reaction is conveniently effected by stirring compound (V) with a compound

LG² -Y in a suitable solvent, e.g. N, iV-dimethylformamide, typically under basic conditions, e.g. in the presence of an inorganic base such as sodium hydride.

In another procedure, the compounds of formula (I) wherein L¹ represents sulfur may be prepared by a process which comprises reacting a compound of formula LG² -Y with a compound of formula (VI):

(VI)

wherein AIk¹, Y, R¹, R², R³, R⁴, R⁵ and LG² are as defined above. The reaction is conveniently effected by stirring compound (VI) with a compound LG²-Y in a suitable solvent, e.g. a lower alkanol such as methanol, typically under basic conditions, e.g. in the presence of an alkali metal alkoxide such as sodium methoxide.

The intermediates of formula (VI) may typically be prepared by treating a suitable compound of formula (III) above with thiolacetic acid; followed by treatment of the resulting compound with a base, e.g. an alkali metal alkoxide such as sodium methoxide.

In another procedure, the compounds of formula (I) wherein L¹ represents NR⁶ may be prepared by a process which comprises reacting a compound of formula LG²-Y with a compound of formula (VII):

(vπ)

wherein AIk¹, Y, R¹, R², R³, R⁴, R⁵, R⁶ and LG² are as defined above.

The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. tetrahydrofuran, π-butanol or l-methyl-2-pyrrolidinone (NMP). The reaction may be performed in the presence of a suitable base, e.g. an organic base such as N,N- diisopropylethylamine.

The intermediates of formula (VII) wherein R⁶ represents hydrogen may be prepared by treating a suitable compound of formula (III) above with potassium phthalimide; followed by treatment of the resulting compound with hydrazine.

Alternatively, they may be prepared by treating a suitable compound of formula (III) above with sodium azide; followed by treatment of the resulting compound with triphenylphosphine.

In an additional procedure, the compounds of formula (I) wherein AIk¹ represents methylene and L¹ represents NR⁶ may be prepared by a process which comprises reacting a compound of formula Y-N(H)R⁶ with a compound of formula (VIII):

(VHI)

wherein Y, R¹, R², R³, R , R⁵ and R⁶ are as defined above; under reducing conditions.

The reaction is conveniently effected by stirring compound (VIII) with a compound Y-N(H)R⁶ at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, in the presence of a reducing agent. A suitable reducing agent comprises a mixture of di-«-butyltin dichloride and phenylsilane.

The intermediates of formula (VII) wherein AIk¹ represents methylene and R⁶ represents Ci_-6 alkyl, e.g. methyl, may be prepared by treating a suitable compound of formula (VIII) above with a Ci_-6 alkylamine, e.g. methylamine, in the presence of titanium(rV) n-propoxide and a base, e.g. an organic base such as AζiV-diisopropylamine; followed by treatment of the resulting compound with a reducing agent, e.g. sodium triacetoxyborohydride.

The intermediates of formula (V) wherein AIk¹ represents methylene may be prepared from the corresponding compound of formula (VIII) by treatment with a reducing agent, e.g. sodium borohydride.

Where they are not commercially available, the starting materials of formula (IV) and (VIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. By way of illustration, the group R¹ may be introduced into the molecule by standard techniques, such as Suzuki conditions.

It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of illustration, a compound of formula (I) wherein the moiety Y is substituted by a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein Y is substituted by amino (-NH₂) by treatment with ammonia. Similarly, a compound of formula (I) wherein the moiety Y is substituted by a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein Y is substituted by Ci_-6 alkylamino (e.g. methylamino or tert-butylamino), di(Ci_-6)alkylamino (e.g. dimethylamino) or arylamino (e.g. phenylamino) by treatment with the appropriate Ci_-6 alkylamine (e.g. methylamine or tert- butylamine), di(Ci_-6)alkylamine (e.g. dimethylamine) or arylamine (e.g. aniline) respectively.

Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques, hi particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. aracemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3^rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

The following Examples illustrate the preparation of compounds according to the invention.

The compounds in accordance with this invention potently inhibit the activity of human PBKα and/or PBKβ and/or PBKγ and/or PBKδ.

Enzyme Inhibition Assays Measurement of the ability of compounds to inhibit the lipid kinase activity of the four class 1 PB kinase isoforms (α, β, γ and δ) was performed using a commercially available homogeneous time-resolved fluorescence assay as described by Gray et al., Anal. Biochem., 2003, 313, 234-245, according to the manufacturer's instructions (Upstate). All assays were performed at 2 μM ATP and a concentration of purified class 1 PB kinase known to generate product within the linear range of the assay. Dilutions of inhibitor in DMSO were added to the assay and compared with assays run in the presence of 2% (v/v) DMSO alone (100% activity). The concentration of inhibitor required to inhibit the enzyme activity by 50% is quoted as the IC₅₀.

When tested in the above assay, the compounds of the accompanying Examples were all found to possess IC₅₀ values for inhibition of activity of human PBKα and/or PBKβ and/or PBKγ and/or PBKδ of 50 μM or better.

EXAMPLES

Abbreviations

DCM: dichloromethane DMF: N,N-dimethylformamide

DMSO: dimethylsulphoxide EtOAc: ethyl acetate

MeCN: acetonitrile MeOH: methanol THF: tetrahydrofuran SiO₂: silica br: broad h: hour(s)

M: mass r.t: room temperature RT: retention time ES+: electrospray positive ionisation

HPLC: high performance liquid chromatography

LCMS: liquid chromatography mass spectrometry

Analytical Conditions

All NMRs were obtained either at 300 MHz or 400 MHz.

Compounds were named with the aid of Beilstein Autonom.

All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere using dried solvents and glassware. Degassing was performed by bubbling nitrogen through the reaction mixture.

Compounds that required preparative HPLC were purified using Method 1 or Method 2 below.

Method 1: Phenomenex Luna Cl 8(2) 250 x 21.2 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid. Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient.

Method 2: Phenomenex Luna C18(2) 250 x 21.2 mm, 5 μm column. Mobile phase A: 10 mM ammonium acetate in water. Mobile Phase B: 10 mM ammonium acetate in MeCN. Gradient program (flow rate 25.0 mL/min), column temperature: ambient, variable gradient.

Analytical methods used for LCMS were Method 3 and Method 4 below.

Method 3: Phenomenex Luna C18(2) 100 x 4.6 mm, 5 μm column. Mobile phase A: 99.92% water, 0.08% formic acid. Mobile phase B: 99.92% MeCN, 0.08% formic acid. Gradient program (flow rate 3.0 mL/min, column temperature 35⁰C):

Time A % B %

0.00 95.0 5.0

4.40 5.0 95.0

5.30 5.0 95.0 5.32 95.0 5.0

6.50 95.0 5.0 Method 4: Phenomenex Luna C 18(2) 100 x 4.6 mm, 5 μm column. Mobile phase A: 5 mM NH₄OAc, pH 5.8. Mobile phase B: 95:5 MeCN:100 mM NH₄OAc, pH 5.8. Gradient program (flow rate 3.0 mL/min, column temperature 35°C):

Time A % B % 0.00 95.0 5.0

4.40 5.0 95.0 5.30 5.0 95.0 5.32 95.0 5.0 6.50 95.0 5.0

INTERMEDIATE 1

4-Methyl-3-phenylquinoline-2-carboxylic acid methyl ester

To a solution of 2-chloro-4-methyl-3-phenylqumoline (200 mg, 0.78 mmol) in MeOH (5 mL) was added triethylamine (0.5 mL) and [l,r-bis(diphenylphosphino)- ferrocene]dichloropalladi Um(II), dichloromethane adduct (10 mg). The reaction mixture was heated at 100⁰C under an atmosphere of carbon monoxide in a Parr bomb for 24 h.

The solvent was removed in vacuo and the residue purified by column chromatography

(SiO₂, 0-10% EtOAc in heptane) to give the title compound as an off-white solid (220 mg, quantitative). δ_H (DMSO-d₆) 8.24-8.26 (m, IH), 8.09-8.11 (m, IH), 7.70-7.80 (m, 2H),

7.40-7.50 (m, 3H), 7.23-7.33 (m, 2H), 3.55 (s, 3H), 2.48 (s, 3H). LCMS (ES+) 278.0

(M+H)⁺, RT 3.88 minutes {Method 3).

INTERMEDIATE 2

2-Bromomethyl-4-methyl-3-phenylquinolme

To a suspension of sodium borohydride (180 mg, 4.76 mmol) in dry THF (8 mL) was added Intermediate 1 (220 mg, 0.79 mmol) and the mixture heated at reflux for 15 minutes. The reaction was allowed to cool to r.t., saturated NH₄Cl solution (10 mL) was added and the mixture extracted with EtOAc (40 mL). The organic layer was separated, dried (MgSO₄), filtered and the solvent removed in vacuo. Purification was by column chromatography (SiO₂, 0-10% MeOH in DCM) to give the desired intermediate. To a solution of this intermediate (30 mg, 0.12 mmol) in DCM (0.5 mL) was added phosphorus tribromide (0.022 mL, 0.24 mmol) and the reaction was stirred at r.t. for 2 h. 10% aqueous K₂CO₃ solution (10 mL) was added cautiously to the mixture which was then extracted with DCM (3 x 20 mL). The organic layers were combined, dried (MgSO₄), filtered and the solvent removed in vacuo to give the title compound (40 mg, 16%) as a brown glass. δ_H (CDCl₃) 8.00-8.20 (m, 2H), 7.25-7.75 (m, 7H), 4.50 (s, 2H), 2.40 (s, 3H). LCMS (ES+) 312.1, 314.1 (M+H)⁺, RT 4.29 minutes (Method 3).

INTERMEDIATE 3

(3-Phenylqumolin-2-yl)methanol

To a solution of 3-phenylquinoline-2-carboxylic acid methyl ester (226 mg, 0.86 mmol) in THF (15 mL) under nitrogen was added ethanol (1.5 mL) followed by sodium borohydride (72 mg, 1.89 mmol) and lithium chloride (81 mg, 1.93 mmol). The reaction mixture was stirred at r.t. for 18 h. Water (30 mL) was added and the mixture extracted with DCM (2 x 30 mL). The organic layers were combined, dried (MgSO₄), filtered and the solvent removed in vacuo. Purification of the residue by column chromatography (SiO₂, 2% MeOH in DCM) gave the title compound (147 mg, 73%) as an orange gum. δ_H (DMSO-d₆) 8.27 (s, IH), 8.08 (d, J 8.5 Hz, IH), 8.04 (d, J 7.4 Hz, IH), 7.76-7.84 (m, IH), 7.44-7.68 (m, 6H), 5.26 (t, J5.5 Hz, IH), 4.64 (d, J5.5 Hz, 2H). LCMS (ES+) 236.1 (M+H)⁺, RT 2.35 minutes (Method 3).

INTERMEDIATE 4

2-Bromomethyl-3-phenylquinolme To a solution of Intermediate 3 (224 mg, 0.95 mmol) in DCM (0.5 mL) was added phosphorus tribromide (0.45 mL, 4.75 mmol) and the reaction was stirred at r.t. for 2 h.

The mixture was poured into aqueous K₂CO₃ solution (60 mL) and extracted with DCM

(2 x 50 mL). The organic layers were combined, washed with aqueous K₂CO₃ solution

(100 mL), separated, dried (MgSO₄), filtered and the solvent removed in vacuo to give the title compound (154 mg, 54%) as a beige solid. δ_H (CDCl₃) 8.15 (d, J 8.5 Hz, IH), 8.05

(s, IH), 7.81-7.86 (m, IH), 7.72-7.79 (m, IH), 7.45-7.63 (m, 6H), 4.69 (s, 2H). LCMS

(ES+) 298.1, 300.1 (M+H)⁺, RT 4.19 minutes (Method 3). EXAMPLE 1

4-Methyl-3-phenyl-2-(9/i-purin-6-ylsulfanylmethvDquinoline

To a solution of Intermediate 2 (40 mg, 0.13 mmol) in dry DMF (0.5 niL) under nitrogen at r.t. was added 6-mercaptopurine (21.8 mg, 0.13 mmol). The reaction mixture was stirred at r.t. for 18 h. Purification by preparative HPLC (Method 2) gave the title compound (16 mg, 33%) as an off-white glass. δ_H (CDCl₃) 8.58 (br s, IH), 8.27 (br s, IH), 8.11 (d, J 6 Hz, IH), 8.06 (d, J 6 Hz, IH), 7.72 (t, J 6 Hz, IH), 7.60 (t, J 6 Hz, IH), 7.25-7.45 (m, 5H), 4.70 (br s, 2H), 2.44 (s, 3H). LCMS (ES+) 384.2 (M+H)⁺, RT 3.49 minutes {Method 4).

EXAMPLE 2

4-Mefhyl-6-(4-methyl-3 -phenylquinolin-2-ylmethoxy)p yrimidin-2-ylamine formate salt To a suspension of sodium borohydride (180 mg, 4.76 mmol) in dry THF (8 mL) was added Intermediate 1 (220 mg, 0.79 mmol) and the mixture heated at reflux for 15 minutes. The reaction was allowed to cool to r.t., saturated NH₄Cl solution (10 mL) added and the mixture extracted with EtOAc (40 mL). The organic layer was separated, dried (MgSO₄), filtered and the solvent removed in vacuo. Purification was by column chromatography (SiO₂, 0-10% MeOH in DCM) to give the desired intermediate (30 mg, 15%). The reaction was repeated to provide more material. To a solution of this intermediate (100 mg, 0.4 mmol) in dry DMF (2 mL) was added sodium hydride (15.4 mg, 0.4 mmol, 60% dispersion in mineral oil) followed by 2-amino-4-chloro-6-methyl- pyrimidine (57 mg, 0.4 mmol). The reaction mixture was stirred at r.t. for 18 h. Purification by preparative HPLC (Method 1) gave the title compound (17 mg, 12%) as a pale yellow glass. δ_H (CDCl₃) 8.41 (br s, IH), 8.14 (d, J6 Hz, IH), 8.05 (d, J6 Hz, IH), 7.70-7.77 (m, IH), 7.58-7.64 (m, IH), 7.37-7.46 (m, 3H), 7.21-7.24 (m, 2H), 6.48 (br s, 2H), 5.92 (s, IH), 5.30 (s, 2H), 2.44 (s, 3H), 2.39 (s, 3H). LCMS (ES+) 357.1 (M+H)⁺, RT 2.21 minutes {Method 3). EXAMPLE 3

4-f 4-Methyl-3 -phenylquinolm-2-ylmethoxy)p yrimidin-2-ylamine formate salt

To a suspension of sodium borohydride (180 mg, 4.76 mmol) in dry THF (8 mL) was added Intermediate 1 (220 mg, 0.79 mmol) and the mixture heated at reflux for 15 minutes. The reaction was allowed to cool to r.t, saturated NH₄Cl solution (10 mL) added and the mixture extracted with EtOAc (40 mL). The organic layer was separated, dried (MgSO₄), filtered and the solvent removed in vacuo. Purification was by column chromatography (SiO₂, 0-10% MeOH in DCM) to give the desired intermediate (30 mg, 15%). The reaction was repeated to provide more material. To a solution of this intermediate (100 mg, 0.4 mmol) in dry DMF (2 mL) was added sodium hydride (15.4 mg, 0.4 mmol, 60% dispersion in mineral oil) followed by 2-amino-4-chloropyrimidine (52 mg, 0.4 mmol). The reaction mixture was stirred at r.t. for 18 h. Purification by preparative HPLC (Method 1) gave the title compound as a pale yellow foam (28 mg, 20%). δ_H (CDCl₃) 9.70 (br s, 2H), 8.31 (br s, IH), 8.14 (d, J6 Hz, IH), 8.05 (d, J6 Hz, IH), 7.84 (d, J6 Hz, IH), 7.70-7.77 (m, IH), 7.58-7.64 (m, IH), 7.36-7.45 (m, 3H), 7.22- 7.27 (m, 2H), 6.08 (d, J 6 Hz, IH), 5.32 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H). LCMS (ES+) 343.1 (M+H)⁺, RT 2.17 minutes {Method 3).

EXAMPLE 4

4-Methyl-6-(4-methyl-3-phenylquinolin-2-ylmethoxy)-[^"l,3,5]triazin-2-ylamine

To a solution of Intermediate 2 (125 mg, 0.4 mmol) in MeCN (4 mL) was added 4-amino~6-methyl-[l,3,5]triazin-2-ol (50 mg, 0.4 mmol) and K₂CO₃ (110 mg, 0.8 mmol) and the mixture heated at reflux for 18 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Method 1) to give the title compound (9 mg, 6%) as an off-white solid. δ_H (CDCl₃) 8.12 (d, J6 Hz, IH), 8.03 (d, J6 Hz, IH), 7.68-7.75 (m, IH), 7.57-7.63 (m, IH), 7.35-7.45 (m, 3H), 7.24-7.30 (m, 2H), 5.33 (s, 2H), 5.22 (br s, 2H), 2.43 (s, 3H), 2.33 (s, 3H). LCMS (ES+) 358.1 (M+H)⁺, RT 2.74 minutes {Method 3). EXAMPLE 5

3-Phenyl-2-C9H-purin-6-ylsulfanylmethyl^')qumolme

To a solution of 6-mercaptopurine (78 mg, 0.46 mmol) in dry DMF (1 niL) under nitrogen was added slowly a solution of Intermediate 4 (153 mg, 0.61 mmol) in DMF (2 mL). The reaction mixture was stirred at r.t. for 18 h. Purification by preparative HPLC (Method 1) gave the title compound (49 mg, 26%) as a white solid. δ_H (DMSO-d₆) 8.54 (s, IH), 8.42 (s, IH), 8.28 (s, IH), 8.04 (d, J 7.5 Hz, IH), 7.75-7.84 (m, IH), 7.56-7.60 (m, 3H), 7.40-7.53 (m, IH), 4.95 (s, 2H). LCMS (ES+) 370.1 (M+H)⁺, RT 3.02 minutes {Method 3).

Claims

Claims:

1. A compound of formula (I) or an iV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

(I)

wherein

AIk¹ represents an optionally substituted straight or branched C_1-3 alkylene chain; L¹ represents oxygen, sulfur, NR or a covalent bond;

R¹ represents a group of formula (a):

in which the asterisk (*) represents the point of attachment of the ring A to the remainder of the molecule;

A represents a saturated, partially saturated or unsaturated A-, 5-, 6- or 7- membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one O or S atom; R^la, R^Ib and R^Ic independently represent hydrogen, halogen, cyano, nitro, oxo,

C_{J -6} alkyl, C_3-7 cycloalkyl, aryl, C_3-7 heterocycloalkyl (optionally substituted by Cj_-6 alkyl), heteroaryl, trifluoromethyl, hydroxy, Ci_-6 alkoxy, difluoromethoxy, trifluoromethoxy, C_1-6 alkylthio, Ci_-6 alkylsulfinyl, Ci_-6 alkylsulfonyl, amino, Ci_-6 alkylamino, di(C_1-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, Cj_-6 alkylsulfonylarnino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(C_1-6)alkylaminocarbonyl, aminosulfonyl, Ci_-6 alkylaminosulfonyl or di(Ci_-6)alkylaminosulfonyl;

R², R³, R⁴ and R⁵ independently represent hydrogen, halogen, cyano, nitro, C_1-6 alkyl, trifluoromethyl, aryl(Ci_-6)alkyl, hydroxy, C]_-6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_-6 alkylthio, Ci_-6 alkylsulfϊnyl, Cj_-6 alkylsulfonyl, amino, C_1-6 alkylamino, di(C_1-6)alkylamino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, Ci_-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, Ci_-6 alkylaminocarbonyl, di(Ci_-6)alkylaminocarbonyl, aminosulfonyl, Ci_-6 alkylaminosulfonyl or di(Ci_-6)alkylaminosulfonyl; and

R represents hydrogen or Ci_-6 alkyl.

2. A compound as claimed in claim 1 represented by formula (IIA) or an JV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof:

wherein

R >21 represents hydrogen, halogen, C]_-6 alkyl, aryl(Ci_-6) alkyl or Ci_-6 alkoxy;

R .31 represents hydrogen or halogen;

R , 51 represents hydrogen or Cj_-6 alkyl; and

AIk Λ , τ Li , Y and R are as defined in claim 1.

3. A compound as claimed in claim 1 or claim 2 wherein AIk¹ represents methylene, (methyl)methylene or (ethyl)methylene.

4. A compound as claimed in any one of the preceding claims wherein L¹ represents oxygen or sulfur.

5. A compound as claimed in any one of the preceding claims wherein Y represents pyrimidinyl, triazinyl or purinyl, any of which groups may be optionally substituted by one or more substituents.

6. A compound as claimed in any one of the preceding claims wherein Y is unsubstituted, or substituted by one or more substituents selected from C_1-6 alkyl and amino.

7. A compound as claimed in any one of the preceding claims wherein R¹ represents phenyl.

8. A compound as herein specifically disclosed in any one of the Examples.

9. A compound of formula (I) as defined in claim 1 or an iV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

10. A compound of formula (I) as defined in claim 1 or an JV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and/or prevention of a disorder for which the administration of a selective PI3K inhibitor is indicated.

11. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an JV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in association with a pharmaceutically acceptable carrier.

12. The use of a compound of formula (I) as defined in claim 1 or an iV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prevention of a disorder for which the administration of a selective PDK inhibitor is indicated.

13. A method for the treatment and/or prevention of a disorder for which the administration of a selective PI3K inhibitor is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defmed in claim 1 or an JV-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof.