Field of the Invention

The present invention relates to new resorcinol N-aryl amide (NAA) compounds, for use as PDK inhibitors.

Background to the invention Warburg metabolism

Under normal physiological conditions, mammalian cells generate the majority of their chemical energy in the form of ATP from glucose via the oxygen-dependent process of oxidative phosphorylation which occurs in mitochondria. Since the seminal discovery by Otto Warburg in the 1920s, it has been known that tumour cells exhibit both an increase in glucose uptake compared to normal cells as well as a greatly augmented contribution to cellular ATP generation form anaerobic glycolysis, even in the presence of oxygen (Warburg, et al., 1927). This phenomenon has become known as the 'Warburg effect' and is now widely considered to be one of the hallmarks of cancer biology. The Warburg phenotype in cancer cells is thought to be important for cancer growth and survival for a number of reasons. Firstly, although ATP generation via glycolysis is less efficient than oxidative phosphorylation, it is considerably more rapid. This may be more suited to supplying the energetic needs of a rapidly proliferating cell. Similarly, elevated glycolytic activity can enable cancer cells to increase flux through pathways which supply metabolites for anabolic metabolism required for growth and proliferation (such as the pentose phosphate pathway for nucleotide synthesis). Another potential advantage is that the decreased extracellular pH resulting from increased lactate production in cancer cells with a Warburg phenotype may facilitate local invasion as a result of increased activity of matrix degrading enzymes as well as contributing to suppression of the immune system. Greater reliance on oxygen-independent generation of ATP via glycolysis will also favour survival in hypoxic regions of the tumour microenvironment.

In the past decade there has been a resurgence of interest in cancer metabolism as a promising field for the development of novel therapeutic agents. This has resulted in a number of discoveries that have greatly increased our understanding of the altered metabolic state in cancer cells as well as the genetic alterations that drive this process (reviewed in Cairns et al., 2011 ). These findings have led to the belief that the aberrant metabolic programme found in cancer cells is not a secondary consequence resulting from common genetic alterations, but rather a reason that these genetic alterations are actively selected for as a driver of oncogenic transformation. The challenge within the field of cancer metabolism is to identify critical nodes in metabolic pathways which are central to the maintenance of this altered metabolic state as well being characterised by limited cellular capacity for compensation when their activity is inhibited. Naturally, targets which fulfil these characteristics should also demonstrate selectivity for cancer cells such that a reasonable therapeutic window can be achieved. Pyruvate dehydrogenase kinase

Pyruvate dehydrogenase kinase (PDK), a member of the GHKL ATPase/kinase superfamily, is a key regulator of the activity of the pyruvate dehydrogenase complex (PDC). The PDC represents a central control point in cellular energy metabolism in that it links glycolysis with the TCA cycle by catalysing the oxidative decarboxylation of pyruvate to acetyl-CoA in the matrix of the mitochondria. Therefore the PDC controls the degree to which glycolytically- derived Pyruvate is utilised for ATP generation via oxidative phosphorylation or whether it is subjected to alternative metabolic fates such as oxidation to Lactate or transamination to Alanine.

The PDC is a protein complex which comprises three different enzymes: pyruvate dehydrogenase (E1 ), dihydrolipoamide transacetylase (E2) and dihydrolipoamide dehydrogenase (E3) as well as the structural component called E3-binding protein (E3bp). PDK reduces PDC activity by phosphorylating three serine residues on the E1 subunit (an α ₂ β2 heterodimer). The E1 enzyme has 6 phosphorylation sites (3 on each a subunit): Ser 264 (site 1 ), Ser 271 (site 2), and Ser 203 (site 3) (Mann et al, 2000). Of the four PDK isozymes known to exist in mammals (PDK-1 ,2,3 & 4), Ser 264 is phosphorylated equally well by all four isozymes; however, phosphorylation of Ser 271 and Ser 203 are isoenzyme specific, with the latter being phosphorylated by PDK-1 alone (Korotchkina et al, 2001 ). Reactivation of PDH is controlled by the activity of two PDH phosphatase isozymes, PDP-1 and PDP-2, which can dephosphorylate all three of the above phosphoryated serines on E1.

PDK is reversibly regulated by the products and substrates of the pyruvate dehydrogenase reaction (Bowker-Kinley et al., 1998): NADH and Acetyl-CoA are activators of PDK (through reduction and acetylation, respectively, of the E2 lipoyl domains which form the binding site for PDK on the PDC), whereas CoA, pyruvate and NAD ⁺ inhibit PDK activity. In addition, PDK-2 and PDK-4 are negatively regulated through direct binding of Pyruvate (Patel & Korotchkina, 2006). The isozymes of PDK vary with respect to their tissue distribution, kinetic parameters and relative degree of regulation by the above factors. PDK-2 and PDK-4 levels are also selectively increased at the transcriptional level by metabolic disorders such as diabetes, heart disease and long-term starvation (Jeong et a!, 2012).

PDK as a therapeutic target

There is now a considerable body of evidence which points to an important role for PDK in cancer and, in particular, the maintenance of the glycolytic phenotype of cancer cells. Firstly, PDK isozymes have been shown to be over-expressed in clinical cancer specimens compared to normal counterpart tissues and this augmented expression has been correlated with poor prognosis as well as drug resistance (Lu et al, 2011 ; Wigfield et al, 2008; Koukourakis et al, 2005). Furthermore, PDK gene expression has been shown to be up-regulated under conditions relevant to the tumour microenvironment such as hypoxia (PDK-1 & PDK-3) or by inactivating mutations in common tumour suppressor genes such as p53 (PDK-2) and pRB (PDK-4) (Contractor and Harris, 2011 ; Hsieh et al., 2008). Both knock-down and pharmacological approaches have been employed to study the role of PDK in cancer both in vitro and in murine tumour xenograft studies. The latter have mainly employed DCA as a small molecule inhibitor of PDK, albeit a non-specific one. These studies have demonstrated the ability of DCA to depolarise the electrochemical gradient across the inner mitochondrial membrane of cancer cells and induce apoptosis as well as inducing a reversal of the Warburg phenotype as evidenced by a decrease in lactate production and increased glucose oxidation (Bonnet et al., 2007; Wong et al., 2008; Sun et al., 2010). In addition, RNA interference studies have demonstrated that PDK-1 knock-down results in increased cell death under hypoxic conditions in HNSCC and colon cancer cell lines and, similar to the DCA studies above, mitochondrial inner membrane depolarisation and reversal of the Warburg phenotype (Panpandreou et al., 2006; McFate et al., 2008). Furthermore, DCA treatment has also been show to synergise with other anti-cancer agents such as Sorafenib and Ecesclemol (Shen et al., 2012; Kluza et al., 2012). Both DCA treatment and PDK-1 knock-down have also been shown to inhibit the growth of tumours in murine xenograft studies (Bonnet et al, 2007; Sun et al., 2010; Panpandreou et al., 2006; McFate et al., 2008). Another interesting observation is that PDK-1 knock-down has been shown to result in a substantial reduction in HIF-1a expression under both normoxic and hypoxic conditions (McFate et al., 2008). This is an attractive outcome of PDK inhibition as HIF-1 a has been implicated as an important factor in cancer progression in several cancer types based on studies with clinical specimens as well as murine xenografts using cell lines in which HIF-1 a levels have been genetically manipulated (Reviewed in Semenza, 2010).

It should be stressed that, in addition to cancer, PDK has been shown to be a potential therapeutic target for several other indications. For example, DCA has been demonstrated to have a carioprotective effect in animal models of ventricular hypertrophy (Atherton et al, 201 1 ; Kato, T et al, 2010). In addition, the lipoamide site inhibitor, AZD7545, has been shown to improve glucose control in a rodent model of diabetes (Mayers et al., 2003). DCA has also been shown to be effective in preventing and reversing monocrotaline-induced pulmonary arterial hypertension in rats as well as showing efficacy in models of stroke and spinal chord injury (McMurty, M. S. et al., 2004; Marangos, P. J. et al, 1999).

References

Atherton, H.J. et al. (201 1 ). Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study. Circulation. 123(22): 2552-61.

Bonnet, S. et al. (2007). A mitochondrial-K ⁺ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 1 1 : 37-51.

Bowker-Kinley M. et al. (1998). Evidence for the existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J. 329: 191 -96.

Cairns, R.A. et al. (2011 ). Regulation of cancer cell metabolism. Nature Rev cancer. 1 1 : 85-95.

Contractor, T and Harris, C.R. (2012). p53 negatively regulates transcription of the pyruvate dehydrogenase kinase PDK2. Cancer Res. 72(2): 560-67.

Hsieh, M.C. et al. (2008). Regulation of the PDK4 isozyme by the Rb-E2F1 complex. J Biol Chem. 283(41 ): 27401 -7.

Jeong, J.Y. et al. (2002). Transcriptional regulation of pyruvate dehydrogenase. Diabetes Metab J. 36: 328-335.

Kato, T. et al. (2012). Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail. 3(3): 420-30.

Kluza, J. et al. (2012). Inactivation of the HIF-1 a/PDK-3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res. 72(19): 5035-47.

Koukourakis et al. (2005). Pyruvate dehydrogenase and Pyruvate dehydrogenase kinase expression in non-small cell lung cancer and tumour- associated stroma. Neoplasia. 7(1 ): 1-6. Lu, C-W. et al. (2011 ). Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer.

Mann W. et al. (2000). Diverse mechanisms of inhibition of pyruvate dehydrogenase kinase by structurally distinct inhibitors. Biochem Biophys Acta. 1480: 283-92

Marangos, P.J. et al. (2003). Dichloroacetate and cerebral ischemia therapeutics. Expert Opinon Drugs. 8(4): 373-82.

Mayers, R.M. et al. (2003). AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats. Biochem Soc Trans. 31 (pt. 6): 1165-7.

McFate, T. et al. (2008). Pyruvate dehydrogenase complex activity controls metabolic and malignant phenotype in cancer cells. J Biol Chem. 283(33): 22700-8.

McMurty, M.S. et al. (2004). Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circulation Research. 95: 830-840.

Patel, M.S. and Korotchkina, L.G. (2006). Regulation of the pyruvate dehydrogenase complex. Biochem Soc Trans. 34(Pt 2):217-22.

Semenza, G.L. (2010). Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 29(5): 625-34.

Shen, Y-C. et al. (2012). Activating oxidative phosphorylation by a pyruvate dehydrogenase kinase inhibitor overcomes Sorafenib resistance of hepatocellular carcinoma. Br J Cancer. 108(1 ): 72-81.

Sun, R.C. et al. (2010). Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Can Res Treat. 120(1 ): 253-60.

Warburg, O. et al. (1927). The metabolism of tumors in the body. J. Gen. Physiol. 8, 519-530.

Wigfield, S.M. et al. (2008). PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer. Br J Cancer. 98(12): 1975-84.

Wong, J.Y.Y. et al. (2008) Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecologic Oncology. 109: 394-402. The present invention relates to the use of resorcinol N-aryl amide (NAA) compounds, which are suitable for use as PDK inhibitors, for example for inhibition of cancer cell proliferation.

The present invention relates to a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Y is -CONRi- or optionally substituted arylene or optionally substituted heteroarylene;

each R ₄ is independently H, CH ₃ or F;

R ₅ is H or CH _3;

each R ₂ and R ₆ is independently (Alk) _n -R _n -(Alk) _n -R _n -(Alk) _n -X;

each Alk is independently (Ci to Ci ₂ ) alkylene or (C ₂ to Ci ₂ ) alkenylene, each of which may be optionally substituted;

each n is independently 0 or 1 ;

each R is independently optionally substituted arylene, optionally substituted cycloalkylene or optionally substituted heterocyclic, -0-, -S-, -(C=0)-, -(C=S)-, -SC-2-, -C(=0)0- -C(=0)NR ^A -, -C(=S)NR ^A -, -S0 ₂ NR ^A -, -NR ^A C(=0)-, - NR ^A S0 ₂ -, -NR ^B R ^C - or — NR ^A -, wherein R ^A is hydrogen, Ci-C ₆ alkyl, -C C ₆ alkyl(cycloalkyl), Ci-C ₆ alkyl(d-C ₆ alkoxy), Ci-C ₆ alkylenearyl, Ci-C ₆ akyleneheteroaryl or Ci-C ₆ alkoxy, and wherein R ^B and R ^c , when taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclic; and

each X is independently halogen, -H, -OR ^A , S0 ₂ NR ^A R ^A , NR ^A R ^A , NR ^B R ^C , C(=0)OR ^A , -C(=0)NR ^A R ^A , C(=0)NR ^B R ^c , C(=S)NR ^A R ^A , -C(=S)NR ^B R ^C , S0 ₂ NR ^A R ^A , S0 ₂ NR ^B R ^c , -NR ^A C(0=)-OR ^A , NR ^A C(=0)R ^A , optionally substituted aryl or heteroaryl, or optionally substituted cycloalkyi or heterocyclic, CN or C(halogen) _a H _b , wherein a is 1 , 2, or 3, and b is (3-a), and wherein R ^A , R ^B and R ^c are as defined above. Description of the Preferred Embodiments

As used herein, the term "(C _a -C _b )alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

As used herein the term "(C _a -C _b )alkylene" wherein a and b are integers refers to a saturated hydrocarbon chain having from a to b carbon atoms and two unsatisfied valences.

As used herein, the term "(C _a -C _b )alkenyl" wherein a and b are integers refers to a straight or branched chain alkenyl radical having from a to b carbon atoms and containing at least one double bond of E or Z configuration, including for example, ethenyl and allyl.

As used herein the term "(C _a -C _b )alkenylene" wherein a and b are integers refers to a hydrocarbon chain having from a to b carbon atoms, at least one double bond, and two unsatisfied valences. As used herein, the term "(C _a -C _b )alkynyl" wherein a and b are integers refers to a straight or branched chain alkenyl radical having from a to b carbon atoms and containing at least one triple bond, including for example, ethynyl and prop-2- ynyl. As used herein, the term "(C _a -C _b )alkynylene" wherein a and b are integers refers to a straight or branched chain alkynyl radical having from a to b carbon atoms and containing at least one triple bond, and two unsatisfied valencies. It will be apparent that the suffix "-ene" usually indicates that a group is divalent.

As used herein the term "cycloalkyl" refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein the term "cycloalkenyl" refers to a carbocyclic radical having from 3-8 carbon atoms containing at least one double bond, and includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. As used herein the term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.

As used herein the term "heteroaryl" refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl. Preferably, the heteroaryl contains from 3 to 10 atoms in the ring.

As used herein the unqualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl" as defined above, and also includes, and in particular means, a mono-, bi- or tri-cyclic non-aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non- aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups. Preferably, the heterocyclyl group contains from 3 to 10 atoms in the ring.

Any aromatic ring (e.g. aryl or heteroaryl) may be fused with and/or bridged to a non-aromatic cycloalkyl or heterocycloalkyl group.

Each of the groups mentioned above may be optionally substituted.

Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (C C ₆ )alkyl, (d-C ₆ )alkoxy, hydroxy, hydroxy(CrC ₆ )alkyl, mercapto, mercapto(Ci- C ₆ )alkyl, (CrC ₆ )alkylthio, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, phenyl, -COOH, - COOR ^D , -COR ^D , -S0 ₂ R ^D , -SR _A -CONH ₂ , -S0 ₂ NH ₂ , -CONHR ⁰ , -S0 ₂ NHR ^D , - CONR ^D R ^E , -S0 ₂ NR ^D R ^E , -NH ₂ , -NHR ^E , -NR ^D R ^E , -OCONH ₂ , -OCONHR ⁰ ,- OCONR ^D R ^E , -NHCOR ⁰ , -NHCOOR ⁰ , -NR ^E COOR ^D , -NHS0 ₂ OR ^D , -NR ^E S0 ₂ OH, -NR ^E S0 ₂ OR ^D ,-NHCONH ₂ , -NR ^D CONH ₂ , -NHCONHR ^E -NR ^D CONHR ^E ,

NHCONR ^D R ^E _, or -NR ^D CONR ^D R ^E wherein R ^D and R ^E are independently a (C C ₆ )alkyl group. An "optional substituent" may be one of the foregoing substituent groups. Of the above substituents, (Ci-C ₆ )alkyl, halo, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, and phenyl are those most commonly regarded as lipophilic. Other substituents listed which contain alkyl groups may be lipophilic depending on the particular alkyl groups present.

Where applicable, any of the above optional substituents may be divalent, and attached at two different positions of the group to be substituted, to form a bridged structure (e.g. a bridged heteroaryl).

Preferred optional substituents are Ci to C ₆ alkyl and halogen, in particular CF ₃ .

Preferred groups for compounds of the invention will now be discussed. The group R ₅

Preferably, R ₅ is H. The group R ₆

Preferably, R ₆ is thiophenyl, pyridinyl or arylene-(Alk) _n -R _n -(Alk) _n -X. In one embodiment, R ₆ is phenyl. In other embodiments, R ₆ is a heterocyclic group or a cycloalkyl group, which is attached via a methylene linker.

In the most preferred embodiments, R ₆ is a substituted arylene. Preferably R ₆ is -(Alk) _n -NR _A R _A , -(Alk) _n -NR _B R _C , -(Alk) _n -NC(=0)-R _A R _A or -(Alk) _n - NCO-R _B R _C - More preferably, R ₆ is arylene (preferably phenylene) bonded to - (Alk) _n -NR _A R _A , -(Alk)n-NR _B Rc, -(Alk) _n -NC(=0)-R _A R _A or -(Alk) _N -NCO-R _B R _c . Most preferably, R ₆ is -(phenylene)-(Alk) _n -NHC(=0)-X, where X is preferably alkyl optionally substituted by one of more halogens, preferably fluorine. For the avoidance of doubt, the NCO can be orientated as OCN.

The group R ₂

Preferably, R ₂ is halogen. In a particularly preferred arrangement, Y is optionally substituted heteroarylene and R ₂ is halogen, in particular CI or F. It is most preferred that the heteroarylene in this context is pyrimidine. In addition to the halogen, it may be substituted by an alkyl or an alkoxy group.

Preferably, the group Y-R ₂ is:

In other embodiments R ₂ is (Alk) _n -X.

In certain embodiments, it may be preferable to have an enantiomerically pure compound. The compounds of the invention are PDK inhibitors and accordingly, are useful in the treatment of cancer and various other diseases (references provided above). Accordingly, the invention also provides:

(i) a method of treatment of diseases or conditions responsive to inhibition of PDK activity in mammals, particularly humans, which method comprises administering to the mammal an amount of a compound of formula I as defined above, or a salt, hydrate or solvate thereof, effective to inhibit said PDK activity; and

(ii) a compound of formula I as defined above, or a salt hydrate or solvate thereof, for use in human or veterinary medicine, particularly in the treatment of diseases or conditions responsive to inhibition of PDK activity;

(iii) a pharmaceutical composition comprising a compound of formula I as defined and specified above, together with a pharmaceutically acceptable carrier. In particular, the invention includes a solution or suspension of such compound in a sterile, physiologically acceptable carrier, for example aqueous saline.

It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the causative mechanism and severity of the particular disease undergoing therapy. In general, a suitable dose for orally administrable formulations will usually be in the range of 0.1 to 3000 mg once, twice or three times per day, or the equivalent daily amount administered by infusion or other routes. However, optimum dose levels and frequency of dosing will be determined by clinical trials as is conventional in the art. The compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties. The orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. For topical application to the skin, the drug may be made up into a cream, lotion or ointment. Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia. The active ingredient may also be administered parenterally in a sterile medium. Depending on the vehicle and concentration used, the drug can either be suspended or dissolved in the vehicle. Advantageously, adjuvants, such as a local anaesthetic, preservative and buffering agents, can be dissolved in the vehicle. The compounds of the invention may be useful in the treatment of cancer, ventricular hypertrophy, diabetes (type I and/or type II), hypertension, (for example pulmonary arterial hypertension), stroke and spinal cord injury. It is believed that the compounds of the invention will be useful in at least the indications listed above as the compounds of the invention have been shown to be PDK inhibitors, and PDK inhibitor has been associated with these diseases (see references in the background section). Compounds of the invention are also useful in in vitro assays dependent on inhibition of PDK activity, for example in screening for alternative classes of PDK inhibitors wherein the test compound competes with or displaces a compound of this invention. Accordingly, in yet another aspect, the invention includes a method of inhibiting PDK activity, comprising bringing into contact, in vitro, an PDK enzyme and a compound of formula I as defined and specified above.

The following examples illustrate the preparation and activities of specific compounds of the invention and are not intended to be limiting of the full scope of the invention.

General Procedures

All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying. Flash chromatography was performed with pre- packed silica gel cartridges (Strata SI-1 ; 61 A, Phenomenex, Cheshire UK or 1ST Flash II, 54A, Argonaut, Hengoed, UK) or by automated flash chromatography using a Combiflash R _f apparatus (Teledyne Isco Inc.) using RediSep R _f prepacked silica columns (Teledyne Isco Inc) or SilaSep pre-packed columns (Silicycle Inc.). Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F ₂ 5 ₄ silica gel.

The compounds of the present invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) on either an Agilent HP1200 Rapid Resolution Mass detector 6140 multimode source M/z range 150 to 1000 amu or an Agilent HP1 100 Mass detector 1946D ESI source M/z range 150 to 1000 amu. The conditions and methods listed below are identical for both machines.

Column for 7.5min run: GeminiNX, 5pm, C18, 30 x 2.1 mm (Phenomenex) or Zorbax Eclipse Plus, 3.5 m, C18, 30 x 2.1 mm (Agilent).

Temperature: 35 C.

Column for 3.75 min run: GeminiNX, 5pm, C18, 30 x 2.1 mm (Phenomenex) or Zorbax Eclipse Plus, 3.5 m, C18, 30 x 2.1 mm (Agilent). Temperature: 35 C.

Column for 1.9 min run: Kinetex, 2.5 m, C18, 50 x 2.1 mm (Phenomenex) or Accucore, 2.6 m, C18, 50 x 2.1 mm.

Temperature: 55 C.

Mobile Phase: A - H ₂ 0 + 10 mmol / ammonium formate + 0.08% (v/v) formic acid at pH ca 3.5.

B - 95% Acetonitrile + 5% A + 0.08% (v/v) formic acid.

Injection Volume: 1 μL

Method A "Short" method gradient table, either positive (pos) or positive and negative (pos / neg) ionisation

Method B "Super Short" method gradient table, either positive (pos) or positive and negative (pos / neg) ionisation

Method C "Long" method gradient table, either positive (pos) or positive and negative (pos / neg) ionisation

Detection: UV detection at 230, 254 and 270 nm.

Nuclear magnetic resonance (NMR) analysis was performed with a Brucker DPX-400 MHz NMR spectrometer. The spectral reference was the known chemical shift of the solvent. Proton NMR data is reported as follows: chemical shift (δ) in ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, dd = doublet of doublet, br = broad), integration, coupling constant.

Some compounds of the invention were purified by preparative HPLC. Preparative HPLC purifications were performed on a Waters FractionLynx MS Autopurification system with a Gemini ^® 5 μΜ C18(2), 100 mm x 20 mm i.d. column from Phenomenex, running at a flow rate of 20 mL min ^-1 with UV diode array detection (210 - 400 nm) and mass-directed collection. Gradients used for each compound are shown in Table 1.

At pH 4:Solvent A: HPLC grade Water + 10mM ammonium acetate + 0.08% v/v formic acid.

Solvent B: 95% v/v HPLC grade acetonitrile + 5% v/v Solvent A + 0.08% v/v formic acid.

At pH 9:Solvent A: HPLC grade Water + 10 mM ammonium acetate + 0.08% v/v ammonia solution. Solvent B: 95% v/v HPLC grade acetonitrile + 5% v/v Solvent A + 0.08% v/v ammonia solution..

The mass spectrometer was a Waters Micromass ZQ2000 spectrometer operating in positive or negative ion electrospray ionisation modes, with a molecular weight scan range of 150 to 1000. Table 1 Preparative HPLC gradients

lUPAC chemical names were generated using AutoNom Standard.

The compounds of the invention were tested in the one or more of the assays described below and are assigned an activity range A, B, C or D in one or more of these assays according to the following criteria: Activity "A": IC ₅₀ = 10 nM to 99 nM

Activity "B": IC ₅₀ = 100 nM to 999 nM

Activity "C": IC ₅₀ = 1.00 μΜ to 9.99 μΜ

Activity "D": IC ₅₀ = 10 μΜ to 50 μΜ

Assay methods Fluorescence Polarisation Assay

Fluorescence polarization {also known as fluorescence anisotropy} measures the rotation of a fluorescing species in solution, where the larger the molecule the more polarized the fluorescence emission.

The FP probe, VER-00160364, is a fluorescein labeled version of VER- 00050589 which binds to the ATP binding site of PDK resulting in an increase in anisotropy. If a compound is present which competitively binds to the same site as the probe, thereby releasing it, anisotropy decreases due to the increased amount of free probe.

VER-00160364 Compound handling

Compounds are made up in 100 % DMSO.

The assay tolerates a DMSO concentration of 1 %, so compounds are made up at 100 X the required test concentration in DMSO. The compound titrations / daughter plates are prepared in quadruplicate in 96 well plates and finally combined in a 384 well plate to yield four IC ₅₀ values per compound.

A 1 in 3 tripling dilution 10 point concentration curve was performed in DMSO in 96 well Greiner V bottom plates as follows:

1. Transfer 9 μΙ of compound into column 1 & serially dilute 3 μΙ of compound into 6μΙ of DMSO (columns 2 to 10).

2. Include one control titration compound.

Controls are added to columns 1 1 and 12 as follows:-

1. Row A (for FP blanks): dispense 10 μΙ of DMSO & 90 μΙ of PDK buffer (10% DMSO). 2. Rows B, C and D (for total binding): Add 10 μΙ of DMSO and 90 μΙ of PDK buffer (10% DMSO).

3. Rows E,F,G and H (for non-Specific Binding): Add 10 μΙ of 10 mM VER- 00049009 (does not bind to PDK-1 ) & 90 μΙ of PDK buffer (10% DMSO).

4. Aliquot 5 μΙ of the controls to the assay plate Cols 21 to 24.

Transfer 4μΙ aliquots of the compound titrations or 40 μΙ of controls into a second dilution (daughter) plate and add 36 μΙ of PDK buffer to the compound titration wells only (1 :10 dilution) and mix.

Add 5 μΙ aliquots of the buffered dilution to a black 384 well low binding assay plate (Corning 3575) in a Z format. Probe / Protein mix

For a 384-well plate, prepare 18mls of 10 nM probe & 30 nM PDK-1 in assay buffer.

Add 45ul of probe / protein mix to all wells of the assay plate except row A and row B, cols 21 to 24 which will be the FP blanks. To these wells add 45 μΙ of PDK buffer only.

Incubation and plate read

Seal the plates with a foil seal and leave in the dark for 90 minutes at room temperature. Plates were then read on a Biotek Synergy plate reader. Reagents

Buffer: 50 mM MOPS pH7.5; 50 mM K ₂ PO ₄ ;150 mM NaCI; 1 mM DTT; 5 % Glycerol; 0.1 % Octyl-D- -glucopyranoside. pH to 7.5 with 10M NaOH and autoclave to sterilize.

Phospho(Ser ²⁹³ )E1a MSD ELISA Assay This is a sandwich ELISA assay in which the capture antibody (which binds specifically to E1 a with a phosphorylated Serine 293 residue) is coated onto a standard bind Meso Scale Discovery (MSD) plate, followed by loading of a whole cell lysate and subsequent addition of the detection antibody which binds total E1a. Finally, addition of a Sulfo-tag secondary Ab enables quantification of the relative abundance of pSer ²⁹³ E1a in the samples by electrochemi-luminescence.

Day 1 : Cell seeding

Seed PC-3 cells @ 7500 cells / well into the relevant number of 96 well cell culture plates (all wells) in 100 μΙ of RPMI-1640 media + 10 % FCS / well.

Day 2: Compound master plate preparation, compound addition and plate coating

1. Prepare a 10 point 1 :3 dilution series master plate in DMSO as follows.

Add 20 μΙ of a 20 mM stock of each compound to be tested to separate wells in column 1 of a V-bottom polypropylene 96 well plate (including at least one standard compound to assess inter-plate and inter-experiment variability). Add 20 μΙ of DMSO to all of the wells in columns 2 to 1 1 (row 11 is the 100 % signal control). Prepare a separate plate containing a sufficient quantity (3 μΙ per number plates being run) of 20 mM VER- 00236550 (known to achieve complete suppression of pE1 a levels at a concentration of 80 μΜ) in each well of column 12 (0 % signal control plate).

2. Prepare a 1 :3 dilution series from column 1 to column 10 by transferring 10 μΙ from each column to the adjacent column (changing tips between transfers).

3. Prepare an appropriate number of replicate 96 well polypropylene plates containing 147 μΙ of serum free media in all of the wells. Transfer 3 μΙ from each well of the above DMSO master plate to the corresponding well (1 :50 dilution) in the media plate and mix thoroughly. Add 3 μΙ per well to column 12 of the media plate from the 0 % control plate.

4. Remove the media from the 96 well plates of PC-3 cells and replace with 160 ul of serum-free RPMI media. Add 40 μΙ of compound / media from the above master plates to the corresponding wells in the relevant plate of PC-3 cells (final 1 :250 dilution of the original DMSO master plate, yielding a final top concentration of 80 μΜ).

5. Incubate the compound-treated cells @ 37°C for 90 minutes in a CO ₂ incubator, aspirate the media and transfer the plates to a -80°C freezer.

6. MSD plate coating: Add 45 μΙ / well of 2 μg / ml (diluted in PBS) Custom p(Ser293)E1 a pAb (Genescript). Use standard bind MSD plates. Shake plate to ensure complete well coverage. Store the plate at 4°C O/N.

Day 3: Complete MSD assay and read plates

1. Remove MSD plates from the fridge and wash 3 X with 120 μΙ / well TBST. Remove final wash and add 120 μΙ / well of TBST containing 3 % (w/v) MSD blocker A. Seal plates and incubate @ RT for 1 h on a rocking platform. 2. Remove cell plates from the - 80 °C freezer and place on ice. Add 55 μΙ / well MSD lysis buffer and incubate on ice for 45 min.

3. Wash the MSD plates with 3 X with 120 μΙ / well TBST. Add 25 μΙ lysate / well to the corresponding wells on the MSD plates. Seal the plates and incubate @ RT for 2 h on a plate rocker.

4. Wash MSD plates 3 X with 120 μΙ / well TBST. Add 25 ul / well of 2 μg / ml (in TBST with 3 % (w/v) Blocker A) Mitosciences monoclonal E1 a Ab (Cat # MSP03). Seal and incubate plates @ RT for 1 h on a plate rocker.

5. Wash 3 X with 120 μΙ / well TBST and add 25 μΙ / well of 1 μg / ml Goat anti-mouse Sulfotag Ab (in TBST with 3 % (w/v) Blocker A). Seal and incubate plates at RT for 1 h on a plate rocker.

6. Wash 3 X with 120 μΙ / well TBST, add 120 μΙ /well of 2 X Read buffer T and read on the MSD imager. Read plates within 10 minutes of adding the read buffer.

Reagents

Lysis Buffer (for MSD assay): 1 mM EGTA, 1 mM EDTA, 1 mM NaF, Roche (Complete) protease and phosphatase (PhosStop) tablets, 1 % Triton-x100 in TBS.

10 X TBS: 200 mM TRIS Base pH 7.5, 1.37 M NaCI

TBST: 20 mM TRIS-HCI pH 7.5, 137 mM NaCI, 0.05 % Tween-20

Blocking Buffer: 3 g MSD blocker A dissolved in 100 ml TBST

DELFIA Functional Assay

The PDK1 DELFIA immuno-assay measures phosphorylation of E1 by PDK-1 with 5 μΜ ATP. Once the kinase reaction has been quenched, the reaction mixture is loaded onto high-binding plates and levels of plate-bound phosphorylated E1 a are quantitated by immunodetection methodology. Plates are incubated with a custom made rabbit anti-p(Ser293)E1 a primary antibody (Genescript), followed by an anti-rabbit secondary antibody labeled with europium (Eu-N1). Addition of DELFIA enhancement solution causes dissociation of Eu ³⁺ from the antibody complex into homogeneous Eu micellar chelates which are readily detected by time-resolved fluorescence. Compound handling

Compound stocks are provided reconstituted in 100 % DMSO at 20 mM.

Serial dilutions should be carried out in V-bottom plates using 100 % DMSO to produce concentrations 100-fold higher than the desired assay concentrations. Compounds are then diluted 1 :20 in MOPS Buffer before being diluted a further 1 :5 on addition to the kinase assay, producing a final DMSO concentration of 1 %. For example, a 10-point, 3-fold serial dilution with a top concentration of 10 μΜ should be carried out as follows:

1. Pre-dilute 20 mM compounds 1 :20 in 100% DMSO to produce 1 mM solutions. 2. Add 15 μL 1 mM compound to Column 1 of a V-bottom plate.

3. Add 10 μL 100% DMSO to all other columns of plate.

4. Carry out a 10-point, 3-fold serial dilution across the plate, i.e. transfer 5μL from Column 1 to Column 2; Column 2 to Column 3... etc. Remove 5μL ίΓ0ΐτι Column 10 and leave Columns 1 1 and 12 as 100% DMSO. Kinase Reaction

The kinase reaction is carried out with 10 nM PDK-1 , 300 nM E1 , 0.1 mg / mL BSA, 1 mM DTT and 5 μΜ ATP.

1. 17.5 μL / well enzyme mix is added to wells of V-bottom plates.

2. Compounds in 5% DMSO are added to the enzyme mix at 5 μL / well using a Perkin Elmer Evolution P3 Robot.

3. Plates are sealed and pre-incubated on a bench-top shaker for 1 hr.

Following this time period, plates are centrifuged briefly to remove any material that may have condensed on the plate seal. 4. 100 mM ATP is diluted 1 :2000 in MOPS Buffer to produce a 50 μΜ working stock. 2.5 μL / well working stock is then added to Columns 1-1 1 of the kinase assay plates to start the reaction. Column 12 is left as a no ATP negative control.

5. Assay plates are sealed, shaken briefly to mix, and are then incubated at 30°C for 60 min.

6. The reaction is quenched using a Perkin Elmer Evolution P3 Robot to transfer 100 μΙ / well STOP solution, followed by the transfer of 25 μΙ / well to corresponding DELFIA plates.

7. The DELFIA plates are sealed and stored overnight at 4°C. Detection

1. DELFIA plates are washed with 3 X 200 μΙ_ TBST using a BioTek Plate Washer.

2. Blocking buffer is added at 200 μL / well, and plates are left shaking on the bench for 1 -2 hrs.

3. Plates are washed with 2 X 200 μL TBST using the BioTek Plate Washer.

4. Primary antibody (Custom Genescript anti-(pSer293)E1 a) is diluted in blocking buffer to produce a 2 nM solution (1 :2000 dilution). This is then added to plates at 100 μυ νβΙΙ. Plates are incubated with shaking on the bench for 1-2 hrs.

5. Plates are washed 3 X 200μL with TBST using the BioTek Plate Washer.

6. Secondary anti-rabbit lgG-Eu-N1 antibody is made up in assay buffer to produce a 1 nM solution (note that stock concentrations vary according to batch), then added to plates at 100 μL / well. Plates are left shaking on the bench for a further 1 -2 hrs.

7. Plates are washed 4 X 200 μL P.E. wash buffer using the BioTek Plate washer. 8. Enhancement solution is added at 100 μL / well. Plates are left shaking on the bench for 15 min before being read using the relevant protocol on a Perkin Elmer Victor2 plate reader.

Reagents MOPS Buffer: 60 mM MOPS pH 7.2, 15mM Magnesium acetate, 60 mM KCL

STOP Solution: 50 mM Carbonate-Bicarbonate Buffer, pH9.6

10X TBS: 200 mM TRIS Base pH 7.5, 1.37 M NaCI

TBST: 20 mM TRIS-HCI pH 7.5, 137 mM NaCI, 0.05 % Tween-20

Blocking Buffer: protein free T20, Fisher #37571 Assay Buffer: Perkin Elmer # 1244-1 11

P.E. Wash Buffer: Perkin Elmer Wash Concentrate (#1244-114) diluted 1 :25 in dH ₂ O

Enhancement Solution: Perkin Elmer # 4001 -0010

Methods for the Preparation of Compounds of the Formula (I) Some compounds of the invention can be synthesised by the general routes shown below:

Some compounds of the invention can be made (by way of example) by following the route outlined in scheme 1 (PG = protecting group). Experimental Methods, reagents and product isolation methods will be known to those skilled in the art of organic synthesis. It is understood that other methods can also be used.

SCHEME 1

Compounds of the invention such as I (scheme 1) may be prepared by reacting resorcinol acids (II) with N-aryl amines (III) wherein R = an appropriate protecting group, for example (but not limited to) acetate (OAc) or benzyl (Bn). Many methods for the preparation of removal of protecting groups are known to persons skilled in the art.; some are illustrated in Protective Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wutz, John Wiley and Sons, Inc and Protecting Groups, Philip J. Kociehski, Thieme. Numerous methods exist for the formation of amide bonds from acids and amines (step 1 ) are known to those skilled in the art. These include (but are not limited to) a process of pre- activating the carboxylic acid via conversion to the corresponding acid chloride by reaction with oxalyl chloride and a catalytic amount of DMF or reaction of the acid with thionyl chloride and reaction of the acid chloride with an amine in presence of a non-interfering base such as triethylamine. In certain cases the reacting amide may be converted to its sodium salt by reaction with sodium hydride in a non protic solvent such as DMF or THF, prior to reaction with the acid chloride. Amides may also be synthesised by reacting carboxylic acids such as II with amines in presence of an amide coupling agents of the type commonly used in the formation of peptides. Examples of such reagents include 1 ,3-dicyclohexylcarbodiimide (DCC) (sheehan et al, J. Amer. Chem., Soc. 1995, 77, 1067), 1 -ethyl-3-(3'-dimethylaminopropyl)-carbodimide (EDC or EDAC), uranium based coupling agents such as 0-(Benzotriazol-1 -yl)-/V,/V,/V',/V- tetramethyluronium hexafluorophosphate (HBTU) or 0-(7-azabenzotriazol-1-yl)- Λ,Λ ,Λ ',/V-tetramethyluronium hexafluorophosphate (HATU) and phosphonium- base reagents such as 1 -benzotriazolyoxytris-(pyrrolidino)phosphonium hexafluorophosphate, (PyBOP) (Castro et al, Tetrahedron Lett, 1990, 31 , 205). The coupling reaction is typically carried out in a non-aqueous, non protic solvent such as dioxin, dichloromethane (DCM), dimethylformamide (DMF) or acetonitrile (MeCN). The reaction can be carried out at room temperature or where reactants are less reactive, at an appropriate elevated temperature. The reaction is carried out in the presence of a non-interfering base (e.g. triethylamine or diisopropylamine).

The amines may be commercially available or prepared by methods well known to those skilled in the art, see for example, Advanced Organic Chemistry, by Jerry March, 4 ^th Edition, Wiley Interscience, New York; Fiesers' Reagents for Organic Synthesis, Volumes 1 -17, John Wiley, edited by Mary Fieser (ISBN: 0- 471 -58283-2) and Organic Syntheses, Volumes 1-8, John Wley, edited by J. P. Freeman (ISBN: 0-471 -31 192-8).

Compounds of the invention such as X (scheme 2) may be prepared by reacting amine ester V with II as previously described. Hydrolysis of VI (step 4) affords the acid VIII. Amide formation via reaction with R5R6NH (IX) as described and protecting group removal (step 6) affords X.

SCHEME 2.

SCHEME 3.

[Wherein for Ar-X, X = Halogen, for example, Chloro, Bromine or Iodine; Ar = Aryl moiety]

Compounds of the invention such as XV (scheme 3) may be prepared via boronate acid esters such as, for example, the boronate ester XIII (or the corresponding boronic acid). Boronate esters may be made from halogen containing moieties such XII by transition metal catalysed processes or from the organo-lithium or organo-magnesium derivate of XII. Methods and appropriate reagents are known to those skilled in the art. For example, reacting a boronic acid (ArB(OH) ₂ ) or a corresponding boronic acid ester compound of formula XIII by means of a cross-coupling reaction, such as Suzuki coupling (N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457), or other transition metal-catalysed cross- coupling reactions as described in [D. W. Knight, "Coupling Reactions Between sp2 Carbon Centres" in Comprehensive Organic Synthesis, v. 3, pp. 481 -520, Pergamon Press, 1991 , with an Aryl halide (Ar-X), where Ar represents for example phenyl, or related aryl moiety and X = a halogen atom such as Chlorine, bromine or iodine or activated alkoxy derivative such as a trifluoromethane sulfonate moiety (triflate, OTf)) in a suitable solvent such as a mixture of 1 ,4-dioxane and water or tetrahydrofuran and water in the presence of a suitable catalyst such as bis (tri-tert-butylphosphine)palladium(0) or 1 ,1'- jb/s(diphenylphosphino)ferrocene and a suitable base such as sodium hydrogen carbonate or potassium carbonate at a suitable temperature from 60-150 °C (step 9) can prepare compound XIV. Removal of protecting groups "R" affords XV. Many of the halides required for cross coupling reactions are commercially available or can be prepared using methods well known to those skilled in the art. The heating could be performed in a microwave system. Like-wise reaction of boronic acid or boronic acid ester XIII (scheme 4) with a herocyclic or heteroaryl moiety enables formation of XVI and, after protecting group removal, compounds of the invention XVII. It is understood that for intermediate XII in schemes 3, that the bromine may be replaced by chlorine, iodine or triflate or other appropriate cross coupling partner.

X = Halogen such Chloro, Bromine, Iodine; HET = heterocyclo, heteroaryl moiety. SCHEME 4. Some compound of the invention may be made as outlined in scheme 5. Thus the protected boronate ester XIII may be reacted with chloro pyridine substrates XVIII. This transformation may be affected by transition-metal catalysed cross coupling conditions, such as those used in the Suzuki cross coupling protocol. The resulting products XX may be de-protected by appropriate methods to the resorcinol derivatives XXI.

SCHEME 5 Compounds of the invention such as X, XV and XVII may also be prepared by the route outlined in scheme 6, whereby the secondary amides XXII, XXIV and XXV are reacted with suitable R2 containing moiety XXIII wherein Ύ" is a suitable leaving group such as a bromine, chlorine, iodine or activated alkoxy derivative (e.g. a mesylate or tosylate). The reaction is performed in the presence of a base such as sodium hydroxide in a non-protic solvent, for example toluene or sodium hydride in DMF.

SCHEME 6 An alternative route to compounds such as X, XV and XVII is outlined in scheme 7 and involves a change in the order of synthetic steps, whereby the resorcinol amide is formed as the penultimate step from carboxylic acid II and amines that have been constructed using the methods discussed previously.

SCHEME 7

Synthesis of Intermediates:

Synthesis of Intermediates A0001 to A0022 (Schemes 8 and 9).

A0013

SCHEME 8

1) Preparation of compound A0001

To a solution of compound A (300 mg, 1.33 mmol) in DCM (5 mL) was added compound 1 (213 mg, 1.99 mmol) and stirred at r.t. for 1 h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ SO ₄ , concentrated and purified by chromatography on silica gel (hexanes: ethyl acetate=5: 1) to afford compound A0001 as colourless solid (270 mg, 68% yield).

2) Preparation of compound A0002

To a solution of compound A (300 mg, 1.33 mmol) in DCM (5 mL) was added compound 2 (225 mg, 1.99 mmol) and mixture stirred at r.t. for 1 h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ S0 ₄ , concentrated and purified by chromatography on silica gel (eluting with hexanes: ethyl acetate 5:1 ) to afford compound A0002 as white solid (260 mg, 64.7% yield).

3) Preparation of compound A0003

To a solution of compound A (300 mg, 1.33 mmol) in DCM (5 mL) was added compound 3 (176 mg, 1.99 mmol) and stirred at r.t. for 4h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ S0 ₄ , concentrated and purified by chromatography on silica gel (eluting with hexanes: ethyl acetate 5:1 ) to afford compound A0003 as white solid (345 mg, 93% yield).

4) Preparation of compound A0005

a) Preparation of compound A0005-1

To a solution of compound A (400 mg, 1.77 mmol) in DCM (5 mL) was added compound 5 (173 mg, 2.3 mmol) and stirred at r.t. for 4h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ S0 ₄ , concentrated and purified by chromatography on silica gel (hexanes: ethyl acetate 5:1 ) to afford compound A0005-1 as white solid (370 mg, 79% yield). b) Preparation of compound A0005

To A solution of compound A0005-1 (50 mg, 0.19 mmol) and NaHC0 ₃ (16 mg, 0.19 mmol) in DCM (2 mL) was added to DMP (155 mg, 0.38 mmol) and the reaction mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified by chromatography on silica gel (eluting with hexanes: ethyl acetate 5:1 ) to afford compound A0005 as white solid (53 mg, 100% yield).

5) Preparation of compound A0008

To a solution of compound A (300 mg, 1.33 mmol) in DCM (5 mL) was added compound 8 (173 mg, 1.99 mmol) and stirred at r.t. for 4h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ S0 ₄ , concentrated and purified by chromatography on silica gel (eluting with hexanes: ethyl acetate 5:1 ) to afford compound A0008 as a white solid (330 mg, 89% yield).

6) Preparation of compound A0009

To a solution of compound A (300 mg, 1.33 mmol) in THF (5 mL) was added compound 9 (N-Methyl piperazine) (200 mg, 1.99 mmol) and stirred at 45°C for 20h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ S0 ₄ , concentrated and purified by chromatography on silica gel (eluting with hexanes : ethyl acetate 5:1 ) to get compound A0009 as white solid (280 mg, 72% yield).

7) Preparation of compound A0007

To a solution of compound A (300 mg, 1.33 mmol) in DCM (5 mL) was added compound 7 (200 mg, 1.99 mmol) and stirred at r.t. for 4h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ S0 ₄ , concentrated and purified by chromatography on silica gel (hexane : ethyl acetate 5:1 ) to afford compound A0007 as white solid (300 mg, 82% yield).

8) Preparation of compound A0006

a) Preparation of compound A0006-1

To a solution of compound A (400 mg, 1.77 mmol) in DCM (5 mL) was added compound 6 (186 mg, 2.48 mmol) and stirred at r.t. for 4h. The mixture was diluted with DCM and washed with sat. NaHC0 ₃ aqueous, dried over Na ₂ S0 ₄ , concentrated and purified by chromatography on silica gel (hexanes: ethyl acetate 5:1 ) to afford compound A0006-1 as white solid (430 mg, 88% yield).

To a solution of compound A0006-1 (380 mg, 1.44 mmol) in THF (40 mL) was added NaH (174 mg, 4.32 mmol) at ice bath temperature and the mixture stirred for 30 min, iodomethane (613 mg, 4.32 mmol) was added and the mixture was stirred overnight at r.t.. Water was added and the THF was removed in vacuo the residue was extracted with DCM, washed with brine, dried over Na ₂ S0 ₄ filtered and filtrate concentrated. The residue was purified by chromatography on silica gel eluting with (hexane : ethyl acetate= 1 :1 ) to afford A0006 as a white solid (260 mg, yield 69%).

9) Preparation of compound A0004

a) Preparation of compound 4-1

To a solution of compound 4 (4.0 g, 66.6 mmol) in DCM (100 mL ) was added Boc ₂ 0 (3.6g, 16.6 mmol) at r.t. and the mixture was stirred for 1 h. The mixture was washed with sat. NaHC0 ₃ aqueous, brine, dried over Na ₂ S0 ₄ filtered and the filtrate concentrated. The residue was dissolved and purified by flash column chromatography on silica gel (DCM:MeOH=20: 1) to afford compound 4-1 as a colourless oil (1.2 g, yield 45%). b) Preparation of compound A0004-1

A mixture of compound A (50 mg, 0.221 mmol), K ₂ CO ₃ (30.5 mg, 0.221 mmol) and compound 4-1 (53 mg, 0.332 mmol,) in DCM (5 mL ) was stirred at r.t. for 2h. The mixture was concentrated and purified by column chromatography (hexane: ethyl acetate = 1 : 1) to afford A0004-1 as a white solid (56 mg, yield = 73%). c) Preparation of compound A0004 To a solution of compound A0004-1 (50 mg, 0.143 mmol) in methanol (10 mL) was added TFA (1 mL) and stirred at r.t. for 2h. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with sat. NaHC0 ₃ (aqueous), brine, dried over Na ₂ S0 ₄ , filtered and the filtrate concentrated to afford crude product as a white solid (20 mg, yield 56%).

10) Preparation of compound A0010

To a solution of compound 10 (1 15 mg, 1.36 mmol) in THF (4 mL) was added n- BuLi (2.5 M in THF, 0.54 mL, 1.36 mmol) at -78°C and the mixture was stirred at r.t. for 30 min, then the solution was added to a solution of compound A (205 mg, 0.90 mmol) in THF (4 mL) at r.t. and stirring was continued at r.t. for 10 min. NH4CI (aq.) was added and the mixture was extracted with ethyl acetate, washed with brine, dried over Na ₂ S0 ₄ and concentrated to afford crude product as an off-white solid which was purified by flash chromatography eluting with hexane : ethyl acetate (234 mg, yield 95%).

11) Preparation of compound A0011

To a solution of compound A (250 mg, 1.1 mmol) and Et ₃ N (0.3 mL) in DCM (5 mL) was added pyridin-2-ylmethanamine (144 mg, 1.33 mmol) and stirred at r.t. for 2h. The mixture was diluted with DCM, washed with water, dried over Na ₂ S0 ₄ and concentrated to afford crude product. The crude product was purified by column chromatography eluting with hexane : ethyl acetate to afford compound A0011 as white solid (270 mg, yield 82%). 12) Preparation of compound A0012

To a solution of compound A (50 mg, 0.22 mmol) and 3,3-difluoroazetidine hydrochloride (28.6 mg, 0.22 mmol) in DCM (3 mL) was added Et ₃ N (0.1 mL) and stirred at r.t. for 2h. The mixture was diluted with DCM, washed with water, dried over Na ₂ S0 ₄ and concentrated to afford compound A0012 as white solid (62 mg, yield 100%).

13) Preparation of compound A0013

a) Preparation of compound 13-1

To a solution of compound 13 (2.0 g, 10.7 mmol) and Et ₃ N (7.4 mL, 53.5 mmol) in DCM (20 mL) was added acetyl chloride (1.2 mL, 16.1 mmol) and stirred at r.t. for 2h. The mixture was diluted with DCM, washed with water, dried over Na ₂ S0 ₄ , concentrated and purified by column chromatography on silica gel (EtOAc / hexanes) to afford compound 13-1 as yellow solid (1.6 g, yield 65%). b) Preparation of compound 13-2 A mixture of compound 13-1 (1.6 g, 7 mmol) in 3M HCI/methanol (20 mL) was stirred at r.t. for 4h. The mixture was concentrated; ethanol was added and concentrated again in vacuo to afford compound 13-2 as pale yellow solid (1.2 g, yield 100%). a) Preparation of compound A0013

To a solution of compound A (250 mg, 1.1 mmol) and compound 13-2 (273.3 mg, 1.66 mmol) in DCM (5 mL) was added Et ₃ N (0.27 mL) and stirred at r.t. for 3h. The mixture was diluted with DCM, washed with water, dried over Na ₂ S0 ₄ and concentrated to afford crude product. The crude product was purified by column chromatography on silica gel, eluting with hexane : ethyl acetate to afford compound A0013 as white solid (250 mg, yield 71 %).

The intermediates in scheme X were prepared by the methods outlined for A0001 from compound A and the appropriate amine.

SCHEME 9

Synthesis of Intermediates B0001 to E0001

[B0001] 2,4-bis(acetyloxy)benzoic acid

To a stirred suspension of 2,4-dihydrobenzoic acid (40g, 259.5 mmol) in acetic anhydride (85 ml_) was added cone. H ₂ S0 ₄ (20 drops) and then the mixture was warmed to 65°C for 30mins. Analysis by LCMS and TLC indicated formation of the desired product. The reaction mixture was cooled to ambient temperature and then poured onto a mixture of ice and water (1 :1) (1700 ml_) with rapid stirring. Stirring was continued for 30mins. The solid was collected via filtration, washed well with water and then iso-hexane, before drying in vacuo at 40°C overnight to afford the desired product (49.4g, 80%) as a colourless solid.

LC/MS (method B): RT = 0.93 min; m/z = 256 [M+NH ₄ ] ⁺ . Total run time 1.90 mins.

¹ H NMR (d ₆ DMSO): δ 2.24 (s, 3H), 2.29 (s, 3H), 7.09 (d, 1 H, J = 2.3 Hz), 7.18 (dd, 1 H, J = 8.8, 2.3 Hz), 7.98 (d, 1 H, J = 8.6 Hz), 13.17 (brs, 1 H). [B0002] 2,4-bis(acetyloxy)-5-chlorobenzoic acid

To a stirred suspension of 5-chloro-2,4-dihydrobenzoioc acid (2.5g, 5.3mmol) in acetic anhydride (4.4ml_, 4.75g, 46.4mmol) was added cone. H ₂ S0 ₄ (6-7 drops) and then the mixture was warmed (block temp 65°C) for 30mins, then cooled to ambient temperature and poured onto a mixture of ice and water (1 :1 ) (100ml_) with rapid stirring. Stirring was continued for 30 mins and the solids were separated via filtration washed well with water and then iso-hexane before drying in vacuo at 40°C for 1 hr to obtain a salmon pink solid 2.54 g, 70%.

LC/MS (method A): RT = 1.93 min; m/z = 290 [M+NH ₄ ] ⁺ . Total run time 3.75 mins. [B0003] 2,4-bis(benzyloxy)benzoic acid

2,4-dihydroxybenzoic acid (29.3 g, 0.19 mol) was stirred in DMF (500ml_) and potassium carbonate (105 g, 0.76mol) was added. To this stirred mixture was added benzyl bromide (99.2 g, 69 mL, 0.58mol) in DMF (100 mL) drop-wise at RT and the reaction was stirred at ambient temperature overnight. A further 7 mL of benzyl bromide was added and the reaction mixture heated at 50°C for 2 hours to give complete conversion to the tris-benzylated product. When complete an aqueous solution of potassium hydroxide (17 g, 0.3 mol) in water (200 mL) was added followed by methanol (300 mL) and the mixture heated at reflux until complete hydrolysis of the benzyl ester. When complete, the mixture was cooled and poured carefully into 1 N HCI (2000 mL) and was then extracted with ethyl acetate (4 x 500mL). The combined extracts were washed with brine (5 x 800mL), water (800mL), dried (MgS0 ₄ ) and concentrated in vacuo. The resultant solid material was washed with petroleum ether and diethyl ether and dried to yield 2,4-bis(benzyloxy)benzoic acid (63.53 g, 96%).

LC/MS (method A): RT = 2.63 min; m/z = 333 [M-H]\ Total run time 3.75 mins.

[B0004] 2,4-bis(benzyloxy)-5-chlorobenzoic acid

Step 1

Acetic acid (17.5 mL) was added drop-wise to a slurry of 4-chlororesorcinol (42.5g, 0.29 mol) in boron trifluoride diethyl etherate (200 mL) under a nitrogen atmosphere. The mixture was heated at 90°C for 4 hours, and then allowed to cool to ambient temperature with stirring overnight. A light-brown precipitate had formed and the mixture was poured, in portions, in to a 10% (w/v) solution of sodium acetate (700mL) and stirred at room temperature for 3 hours. A brown oily layer initially forms on top of the mixture, and with vigorous stirring a light brown precipitate is slowly evolved as the brown oily layer recedes. The precipitate was filtered and washed with water. The resultant light brown solid mass was triturated with ethyl acetate and hexane mixture to give 1 -(5-chloro- 2,4-dihydroxyphenyl)ethan-1 -one as a cream coloured solid (17.29 g, 31.5%).

LC/MS (method A): RT = 1.99 min; m/z = no ionisation. Total run time 3.75 mins. Step 2

1-[2,4-bis(benzyloxy)-5-chlorophenyl]ethan-1-one

Potassium carbonate (32 g, 0.232 mol) added, to a solution of 1-[2,4- bis(benzyloxy)-5-chlorophenyl]ethan-1 -one (17.29 g, 0.09 mol) in acetonitrile (250 ml_). Benzyl bromide ( 23.1 ml_, 0.19 mol) was added slowly and the m ixture was refluxed under nitrogen for 1 hour. A further 4 ml_ of benzyl bromide was added and heating continued for another hour. The mixture was allowed to cool to ambient temperature and stirred at room temperature overnight. The mixture was filtered and solids washed three times with DCM. Combined organics were then concentrated to give a light yellow solid which was triturated from ethyl acetate and hexane to give a white powder (crop 1). A second crop was isolated from the concentrated mother liquors using the same trituration conditions. Total product isolated was (29.1 g, 86%).

LC/MS (method A): RT = 2.84 min; m/z = 389 [M+Na]+. Total run time 3.75 mins. Step 3

To a stirred mixture of 1 -[2,4-bis(benzyloxy)-5-chlorophenyl]ethan-1-one (5.00 g, 13.63 mmol) in dry 1 ,4-dioxane (50 ml_) in an open flask was added drop wise a solution of aqueous sodium hydroxide (5.452 g, 136.3 mmol, dissolved in 20 ml_ of water). Bromine (2.20 ml_, 42.93 mmol) was then added drop-wise over 30 seconds. The biphasic yellow solution was stirred vigorously at room temperature for 4 hours. A fluffy white solid precipitates out after several hours. The reaction was then reduced in vacuo to yield a pale yellow solid, which was suspended in water and acidified to pH 2 with hydrochloric acid. The reaction went cloudy and after shaking, an off-white solid precipitated. The solid was collected by filtration, washed with water and air-dried overnight to afford 2,4- bis(benzyloxy)-5-chlorobenzoic acid as a pale yellow / off-white powder (4.738 g, 94.3%).

LC/MS (method A): RT = 2.84 min; m/z = 367 [M-H]\ Total run time 3.75 mins.

[B0005] 2,4-bis(benzyloxy)-5-methylbenzoic acid

Step 1

4-methylbenzene-1 ,3-diol

To a solution of 2,4-dihydroxybenzaldehyde (20 g, 145 mmol) and sodium cyanoborohydride (31.2 g, 496 mmol) in THF (600 ml_) was slowly added 1 N HCI (400 ml_) at RT and the mixture stirred at RT for 3h. Water was added and extracted with ether, washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give product as white solid (18 g, 100%).

Step 2 2,4-dihydroxy-5-methylbenzoic acid

A solution of 4-methylbenzene-1 ,3-diol (18 g, 145 mmol) and KHC0 ₃ (100 g, 31.8 mmol) in water (200 mL) was stirred at 85°C for 6 hour. Then the mixture was heated to refluxing whilst C0 ₂ (gas) was bubbled through the mixture overnight. After cooling, the mixture was acidified by cone. HCI addition and then filtered and dried to give 2,4-dihydroxy-5-methylbenzoic acid as a white solid (1 1 g, 99%).

Step 3 benzyl 2,4-bis(benzyloxy)-5-methylbenzoate

To a solution of compound 2,4-dihydroxy-5-methylbenzoic acid (5.13 g, 30.5 mmol) and K ₂ C0 ₃ (21 g, 152 mmol) in acetone (100 mL) was added benzyl bromide (26 g, 152 mmol) at RT and the mixture was stirred at reflux overnight. The mixture was concentrated in vacuo and water was added and mixture extracted with ethyl acetate. The phases were separated and the organic phase washed with brine, dried over Na ₂ S0 ₄ , concentrated in vacuo and purified by flash chromatography on silica gel to give product as a clear oil (1 1 g, 82%).

Step 4

2,4-bis(benzyloxy)-5-methylbenzoic acid

A solution of benzyl 2,4-bis(benzyloxy)-5-methylbenzoate (11.0 g, 25 mmol) and NaOH (4.0 g, 100 mmol) in methanol/THF/water (150mL/50mL/50mL) was stirred at reflux for 2 h. The mixture was concentrated in vacuo and the residue was acidified by addition of 2N HCI and filtered then dried to give product as a white solid (8.7 g, 100%).

[B0006] 2,4-bis(benzyloxy)-5-(trifluoromethyl)benzoic acid

Step 1 benzyl 2,4-bis(benzyloxy)benzoate

2,4-dihydroxybenzoic acid (46 g, 0.298 mol) was stirred in acetonitrile (400ml_) and potassium carbonate (200 g, 1.45 mol) was added. To this stirred mixture was added benzyl bromide (110 ml) drop-wise at RT and the reaction was heated at 85°C overnight. The reaction mixture was allowed to cool to ambient temperature then poured into water (1200 ml_). The resulting solids were filtered and washed with water (2 x 400 mL) then hexane (400 mL) to afford powder which was dried in vacuo at 40°C, affording benzyl jb/s(benzyloxy)benzoate as white powder (125.8 g).

Step 2 benzyl 4-(benzyloxy)-2-hydroxy-5-iodobenzoate

Iodine monochloride solution (1.0M in DCM, 55 mL, 55 mmol) ) was added slowly to a stirred solution of the benzyl 2,4-jb/s(benzyloxy)benzoate (21.50 g, 50.65 mmol) in DCM (400 mL), under a nitrogen atmosphere, to give a pale red solution. The resulting solution was stirred for ca. 90 mins at room temperature. The solution was washed with saturated aqueous sodium hydrogen carbonate solution (2 x 125 mL), then aqueous sodium thiosulphate (125 mL), water (2 x 125 mL) and saturated aqueous sodium chloride solution (125 mL). The solution was dried over anhydrous magnesium sulphate, filtered and the filtrate concentrated in vacuo to a pale-yellow solid.

Step 3 benzyl 2,4-bis(benzyloxy)-5-iodobenzoate

Benzyl bromide (12 mL, 100.9 mmol) was added to a suspension of benzyl 4- (benzyloxy)-2-hydroxy-5-iodobenzoate (24 g, 53.5 mmol) and potassium carbonate (27.6 g) in acetone (100 mL), and the suspension was heated, 75 C for 5 hrs. The resulting suspension was allowed to cool and poured into water (1000 mL). The mixture was extracted with dichloromethane (400 mL) and the extracts were washed with water (2 x 250 mL) and saturated aqueous sodium chloride solution (125 mL).The solution was dried over anhydrous magnesium sulphate filtered and filtrate and concentrated in vacuo to a dark yellow gum. Toluene (100 mL) was added and the solution concentrated, (repeated this process twice), to give a dark yellow gum. Trituration with hexane (100 mL) gave an off-white solid, the suspension was stirred for 30 mins and the solids were removed by filtration and washed with hexane (2 x 100 mL) and dried in vacuo dried (40 ^° C).

LC/MS (method C): RT = 5.34 min; m/z = 424 [M+H] ⁺ . Total run time 7.5 mins. Step 4 benzyl 2,4-bis(benzyloxy)-5-(trifluoromethyl)benzoate

Methyl fluorosulphonyldifluoroacetate (13.0 mL, 102.1 mmol) was added slowly to a suspension of benzyl 2,4-jb/s(benzyloxy)-5-iodobenzoate (1 1.0 g, 19.99 mmol) and copper(l) iodide (19.04 g, 100 mL) in DMF (40 mL) under a nitrogen atmosphere and the suspension heated at 95 C for 5 hrs to give a brown suspension. The suspension was allowed to cool and ethyl acetate (150 mL) added and the mixture was filtered through a pad of celite, and the solids washed with ethyl acetate (150 mL). The combined filtrate was washed with saturated aqueous ammonium chloride solution (125 mL), saturated aqueous sodium hydrogen carbonate solution (2 x 125mL), water (3 x 125 mL) and saturated aqueous sodium chloride solution (125 mL) and organic phase was dried over anhydrous magnesium sulphate and concentrated in vacuo to a red- orange gum (9.10 g). LC/MS (method C): RT = 5.30 min; m/z = 493 [M+H] ⁺ . Total run time 7.5 mins.

Step 5 2,4-bis(benzyloxy)-5-(trifluoromethyl)benzoic acid

Potassium hydroxide (25 g) was added to a mixture of benzyl 2,4- bis(benzyloxy)-5-(trifluoromethyl)benzoate (9.10 g, 18.48 mmol) in a mixture of methanol (25 ml_) and water (75 ml_) and the mixture was heated at 100 C for 3 hrs. The resulting mixture was allowed to cool and water (250 ml_) added. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate (150 ml_). The extracts were washed with water (2 x 100 ml_) and saturated aqueous sodium chloride solution (100ml). The solution was dried over anhydrous magnesium sulphate and concentrated to a pale brown gum. The crude product was purified by flash column chromatography, isolute flash silica (100g), eluting with ethyl acetate/ hexane (1 :2) to give a pale yellow semi-solid. Trituration with hexane (50 ml_) gave a white solid which was stirred in suspension for ca 60mins. Solids was filtered and washed with hexane (75 ml_) to give an off-white powder which was dried in vacuo (50°C) to afford 2,4-bis(benzyloxy)-5- (trifluoromethyl)benzoic acid (7.04 g, 94%).

[B0007] 2,4-bis(benzyloxy)-5-fluorobenzoic acid

This intermediate was prepared by the route and methods used for [B0004] utilizing 4-fluororesorcinol in step 1. [C0001] 4-[N-(thiophen-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benzoi c acid

Step 1 methyl 4-[(thiophen-3-ylmethyl)amino]benzoate

Sodium triacetoxyborohydride (1.523 g, 7.28 mmol) was added to a stirred solution of methyl-4-aminobenzoate (1.0 g, 6.62 mmol) and 3- thiophenecarboxaldehyde (0.74 g, 0.62 mmol) in DCM (20 mL). Acetic acid (0,48 g, 7,94 mmol) was added and the reaction was stirred at RT for ca 3.5 h. Further NaBH(OAc) ₃ (0.5eq, 0.70 g) was added and stirring continued at RT overnight. The reaction was quenched with 2M NaOH (aq) then extracted with DCM. The combined organic extracts were washed with H ₂ 0 followed by brine then dried over (MgS04) and the solvent removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 10 to 20% EtOAc in hexane. This affords methyl 4-[(thiophen-3- ylmethyl)amino]benzoate (1.64 g, 77%).

LC/MS (method B): RT = 1.29 min; m/z = 248 [M+H] ⁺ . Total run time 1.90 mins

Step 2 methyl 4-[N-(thiophen-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benzoa te

Oxalyl chloride solution (2.0M in DCM, 5.12 ml_, 10. 24 mmol) was added drop- wise to a stirred solution of 2,4-bis(acetyloxy)benzoic acid ([B0001], 1.22 g, 5.12 mmol) in DCM (30 ml_). DMF (few drops) were added and the reaction was stirred at RT for ca. 45 min then the solvent was removed in vacuo. The resultant residue was re-dissolved in DCM (30 ml_) then triethylamine (3.56 ml_) followed by methyl 4-[(thiophen-3-ylmethyl)amino]benzoate (1.27 g, 5.12 mmol) were added. The reaction was stirred at RT overnight then diluted with DCM and washed with sat. aq. NaHC0 ₃ solution followed by brine. The organic extract was dried over MgS0 ₄ then the solvent removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 0 to 40% EtOAc in hexane to afford product as a colourless solid (1.73 g, 72%).

LC/MS (method B): RT = 1.31 min; m/z = 468 [M+H] ⁺ . Total run time 1.90 mins Step 3

4-[N-(thiophen-3-ylmethyl)2,4-dihydroxybenzamido]benzoic acid

NaOH (1.0N, 7.41 ml_, 7.41 mmol) was added to a stirred suspension of methyl 4-[N-(thiophen-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benzoa te in EtOH (30 ml_) The reaction was heated to 60 °C, forming a clear solution, where it was maintained for ca 3 h. Further NaOH (5 eq, 2M in H ₂ 0) was added and stirring at ca 60 °C maintained overnight. The reaction was cooled to RT then the EtOH was removed in vacuo. The reaction was acidified with 2M HCI (aq) forming a pale yellow solid which was collected by filtration. The solid was dissolved in diethyl ether, dried over MgS0 ₄ , filtered and the filtrate solvents removed in vacuo to afford 4-[N-(thiophen-3-ylmethyl)2,4-dihydroxybenzamido]benzoic acid as a pale-yellow foam-like solid (1.33 g, 97%).

LC/MS (method B): RT = 1.06 min; m/z = 368 [M-H]\ Total run time 1.90 mins Step 4 4-[N-(thiophen-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benzoi c acid

Sulphuric acid (few drops) was added to a stirred suspension of 4-[N-(thiophen- 3-ylmethyl)2,4-dihydroxybenzamido]benzoic acid (1.33 g, 3.60 mmol) in acetic anhydride (1.7 ml_, 18 mmol) forming a brown solution. The reaction was heated to ca 60 °C, where it was maintained for ca 1 h. The reaction mix was cooled to RT then poured onto ice-water and extracted with DCM once the ice had melted. The organic extract was washed with brine, dried (MgS0 ₄ ), and the solvent removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 0 to 50% EtOAc in hexane to afford product as a colourless foam (0.67 g, 42%).

LC/MS (method B): RT = 1.14 min; m/z = 454 [M+H] ⁺ . Total run time 1.90 mins.

[C0002] 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)benzamido]benzoi c acid

Step 1 methyl 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)benzamido]benzoa te

Oxalyl chloride solution (2.0M in DCM, 5.12 ml_, 10.24 mmol) was added drop- wise to a stirred solution of 2,4-bis(benzyloxy)benzoic acid ([B0003], 0.57 g, 1.72 mmol) in DCM (20 ml_). DMF (few drops) were added and the reaction was stirred at RT for ca. 2 hr then the solvent was removed in vacuo. The resultant residue was re-dissolved in DCM (10 ml_) then triethylamine (1.20 ml_, 8.6 mmol) followed by methyl 4-[(thiophen-3-ylmethyl)amino]benzoate (0.51 g, 2.06 mmol) were added. The reaction was stirred at RT overnight then diluted with DCM and washed with sat. aq. NaHCO ₃ solution, followed by brine. The organic extract was dried over MgSO ₄ then the solvent was removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 20 to 30% EtOAc in hexane to afford product as a yellow gum (0.74 g, 77%).

LC/MS (method B): RT = 1.48 min; m/z = 564 [M+H] ⁺ . Total run time 1.90 mins Step 2 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)benzamido]benzoi c acid

A solution of methyl 4-[N-(thiophen-3-ylmethyl)2,4- bis(benzyloxy)benzamido]benzoate and aqueous NaOH (2.24 ml_. 2.24 mmol) in EtOH (10 ml_) was heated to 60 °C, where it was maintained for ca 4h. The reaction mixture was cooled to RT then the solvent removed in vacuo. The resultant residue was dissolved in EtOAc then washed with water. Some compound remained in the aqueous extract therefore the aqueous extract was acidified to ca pH=2 with 2M HCI (aq) then extracted with EtOAc. The organic extracts were combined, washed with brine then dried (MgSO4) and the solvent removed in vacuo to afford colourless foam (0.676 g, 93%).

LC/MS (method B): RT = 1.42 min; m/z = 550 [M+H] ⁺ . Total run time 1.90 mins

[C0003] 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)-5- methylbenzamido]benzoic acid

This intermediate was prepared by way of the methods outlined for intermediate C0002, utilizing intermediate B0005, 2,4-bis(benzyloxy)-5-methylbenzoic acid in the appropriate step.

[C0004] 4-[N-(pyridin-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benzoic acid

Step 1 benzyl 4-aminobenzoate

To a stirred solution of 4-aminobenzoic acid (10.00 g, 72.9 mmol) in DMF (400 mL) was added potassium carbonate (50.40 g, 364.6 mmol) followed by benzyl bromide (9.53 mL, 80.21 mmol). The reaction mixture was allowed to stir at RT for 2 h, then poured into water (400 mL) and extracted with EtOAc (3 x 300 mL), washed with brine (1 x 300 mL), dried (MgS0 ₄ ) and solvent removed in vacuo to afford benzyl 4-aminobenzoate as a yellow oil.

LC/MS (method A): RT = 2.36 min; m/z = 228 [M+H] ⁺ . Total run time 3.75 mins.

Step 2 benzyl 4-[(pyridin-3-ylmethyl)amino]benzoate

Benzyl 4-aminobenzoate (16.57 g, 72.91 mmol) and pyridine-3-carbaldehyde (7.50 mL, 80.20 mmol) were dissolved in isopropyl acetate (27.3 mL) followed by the addition of TFA (1 1.17 mL, 145.82 mmol). Sodium triacetoxyborohydride, NaBH(OAc) ₃ (18.54 g, 87.49 mmol) was added as a solid in portions over 1 minute and reaction mixture was left to stir at RT for 2 days. Analysis by LCMS and TLC indicated some presence of the desired product along with starting material. Reaction mixture was heated to reflux and NaBH(OAc) ₃ (10.0 g, 47.50 mmol) was added. Reaction mixture was heated at reflux for a further 5 hours. Reaction mixture was allowed to cool to ambient temperature. A solution of 10% aq NaOH was added to the reaction mixture until pH was measured at pH = 8-9. The aqueous phase was washed with EtOAc (4 x 150 ml_), and the combined organic phases were washed with brine (1 x 150 ml_), dried (MgS0 ₄ ) filtered and filtrate solvent removed in vacuo to afford a yellow gum. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 0 to 75% EtOAc in hexane to afford product as a pale-yellow solid (14.7 g, 63%)

LC/MS (method B): RT = 1.23 min; m/z = 319 [M+H] ⁺ . Total run time 1.90 mins. Step 3 benzyl 4-[N-(pyridin-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benzoat e

2,4-bis(acetyloxy)benzoic acid [B0001] (14.26 g, 59.86 mmol) was dissolved in DCM (230 ml_). Oxalyl chloride (34.5 ml_, 69.08 mmol) was added to the reaction mixture followed by DMF (few drops). Reaction mixture was left to stir at rt for 1 h. Solvent was removed in vacuo to afford a yellow gum and the acid chloride was used without further purification. Sodium hydride (60 wt% dispersion in mineral oil, 1.88 g, 78.29 mmol) was dissolved in THF (150 ml_) and benzyl 4-[(pyridin-3-ylmethyl)amino]benzoate (14.66 g, 46.05 mmol) was added. The reaction mixture was stirred at RT for 2 h. Then a solution of the acid chloride dissolved in THF (150 ml_) was added to the solution of benzyl 4- [(pyridin-3-ylmethyl)amino]benzoate and NaH. The reaction mixture was heated at reflux for 18 h. Reaction mixture was cooled, partitioned between sat aq NaHC0 ₃ (300 ml_) and DCM (300 ml), extracted with DCM (3 x 200 ml_). Combined organic extracts were washed with sat aq NaCI solution (1 x 300 ml_), dried (phase separator), filtered and solvent removed in vacuo to afford a brown gum. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 0 to 100% EtOAc in hexane to afford product as a pale yellow gum (20.08 g, 81 %).

LC/MS (method B): RT = 1.32 min; m/z = 539 [M+H] ⁺ . Total run time 1.90 mins.

Step 4

4-[N-(pyridin-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benz oic acid

Benzyl 4-[N-(pyridin-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benzoat e (20.08 g, 37.29 mmol) was dissolved in EtOAc (200 ml_) and transferred into a hydrogenation round bottom flask flushed with nitrogen gas and Pd/C (cat) was added. Reaction flask was flushed with hydrogen gas shaken under an atmosphere of H ₂ at RT overnight. The reaction mixture was filtered through a pad of celite and the celite was washed with EtOAc (150 ml_). The combined filtrate solvent was removed in vacuo to afford a clear gum. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 0 to 10% MeOH in DCM to afford product as a colourless solid (6.48 g, 39%).

LC/MS (method B): RT = 0.95 min; m/z = 449 [M+H] ⁺ . Total run time 1.90 mins. [C0005] 4-[N-benzyl-2,4-bis(acetyloxy)benzamido]benzoic acid

Step 1 benzyl 4-(benzylamino)benzoate

Benzyl 4-aminobenzoate (8.28 g, 36.41 mmol) and benzaldehyde (4.08 mL, 40.13 mmol) were dissolved in isopropyl acetate (97 mL) followed by the addition of TFA (5.59 mL, 72.9 mmol). NaBH(OAc) ₃ (12.37 g, 58.37 mmol) was added as a solid over 1 minute and reaction mixture was left to stir at RT for 2 hours. Reaction mixture was allowed to cool to ambient temperature. A solution of 10% aq NaOH was added to the reaction mixture until pH was measured at pH = 8-9. The aqueous phase was washed with EtOAc (4 x 150 mL), and the combined organic phases were washed with brine (1 x 150 mL), dried (MgS0 ₄ ) filtered and the filtrate solvent removed in vacuo to afford a yellow gum. The crude product was purified by flash column chromatography on silica gel, eluting with gradient of 0 to 25% EtOAc in hexane to afford product as a colourless solid (9.05 g, 78%).

LC/MS (method B): RT = 1.48 min; m/z = 318 [M+H] ⁺ . Total run time 1.90 mins. Step 2 Benzyl 4-[N-benzyl2,4-bis(acetyloxy)benzamido]benzoate

This compound was prepared by the method utilised for intermediate [C0004], step 3. Thus 2,4-bis(acetyloxy)benzoic acid [B0001] (8.83 g, 37.07 mmol) was reacted with oxalyl chloride solution (2.0 M in DCM, 14.3 mL) and the resulting acid chloride reacted with NaH (60 wt% dispersion in mineral oil (1.16 g) and benzyl 4-(benzylamino)benzoate (9.05 g, 28 mmol). The crude product isolated after work up was purified by flash column chromatography on silica gel, eluting with a gradient of 0 to 25% EtOAc in hexane to afford product as a yellow gum (5.26 g, 34%).

Step 3

4-[N-benzyl-2,4-bis(acetyloxy)benzamido]benzoic acid

Benzyl 4-[N-benzyl2,4-bis(acetyloxy)benzamido]benzoate (5.25 g, 9.77 mmol) was dissolved in EtOAc (200 mL) and transferred into a hydrogenation round bottom flask, and purged with nitrogen gas. 10% palladium on charcoal (cat) was added and the reaction flask was flushed with hydrogen gas shaken under an atmosphere of hydrogen at RT overnight. Reaction mixture was filtered through a pad of celite and celite pad washed with EtOAc (150 mL). Combined filtrate solvent was removed in vacuo to afford 4-[N-benzyl-2,4- bis(acetyloxy)benzamido]benzoic acid as a white solid (4.13 g, 95%).

LC/MS (method B): RT = 1.18 min; m/z = 448 [M+H] ⁺ . Total run time 1.90 mins.

[D0001] 2,4-bis(benzyloxy)-N-[4-(tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-N-(thiophen-3-ylmethyl)benzamide

Stepl

4-bromo-N-(thiophen-3-ylmethyl)aniline

To a stirred mixture of 4-bromoaniline (2.500 g, 14.53 mmol) and 3- thiophenecarboxaldehyde (1.27 mL, 14.53 mmol) in dry dichloromethane (75 mL) was added glacial acetic acid (0.68 mL, 11.91 mmol) and sodium triacetoxyborohydride (3.387 g, 15.98 mmol). The reaction was stirred at room temperature for 4 hours and was then quenched with 2.0 M aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and reduced under vacuum to yield a dark orange oil, which was purified by flash chromatography on silica gel eluting with 4% ethyl acetate in hexane to afford a yellow oil (3.827 g, 98%).

LC/MS (method B): RT = 1.46 min; m/z = 267 [M+H] ⁺ . Total run time 1.90 mins

Step 2 2,4-bis(benzyloxy)-N-(4-bromophenyl)-N-(thiophen-3-ylmethyl) benzamide

Oxalyl chloride solution (2.0M in DCM, 9.45 mL, 18.9 mmol) was added drop- wise to a stirred solution of 2,4-bis(benzyloxy)benzoic acid ([B0003], 3.16 g, 9.45 mmol) in DCM (80 mL). DMF (few drops) were added and the reaction was stirred at RT for ca. 1.5 hr then the solvent was removed in vacuo to afford a yellow slurry. To this stirred slurry was added a solution of 4-bromo-N- (thiophen-3-ylmethyl)aniline (3.04g, 11.34 mmol) in DCM (40 mL) then triethylamine (6.57 mL, 47.2 mmol) was added and the reaction was stirred at RT overnight then diluted with DCM and washed with sat. aq. NaHC0 ₃ solution followed by brine. The organic extract was dried over MgS0 ₄ then the solvent removed in vacuo to a red oil. The crude product was purified by flash column chromatography on silica gel, eluting with 10% EtOAc in hexane to afford product as an off-white solid (3.76 g, 68%).

LC/MS (method B): RT = 1.67 min; m/z = 586 [M+H] ⁺ . Total run time 1.90 mins Step 3

2,4-bis(benzyloxy)-N-[4-(tetramethyl-1,3,2-dioxaborolan-2 -yl)phenyl]-N- (thiophen-3-ylmethyl)benzamide

To a stirred solution of 2,4-bis(benzyloxy)-N-(4-bromophenyl)-N-(thiophen-3- ylmethyl)benzamide (1.000 g, 1.71 mmol) in dry dimethylformamide (20 mL) in a microwave vial was added potassium acetate (0.503 g, 5.13 mmol) and jb/s(pinacolato)diboron (0.521 g, 2.05 mmol). The microwave vial was degassed with nitrogen gas, and [1 ,1 '-jb/s(diphenylphosphino)ferrocene]dichloropalladium (II) (0.125 g, 0.171 mmol) was then added and the vial was purged again with nitrogen. The reaction was then heated to 160°C in a microwave synthesiser for 30 minutes. The purple-coloured reaction mixture was then transferred to a large round bottomed flask with methanol and reduced under vacuum. The purple residue obtained was dissolved in dichloromethane and filtered through celite. The filtrate was then washed with water and brine. The organic layers were then dried over magnesium sulphate and reduced under vacuum to yield a purple residue, which purified by flash chromatography on silica gel eluting with 40% ethyl acetate in hexane, to afford a green gum (0.842 g, 78%).

LC/MS (method B): RT = 1.63 min; m/z = 632 [M+H] ⁺ . Total run time 1.90 mins.

[D0002] 2,4-bis(benzyloxy)-5-chloro-N-[4-(tetramethyl-1,3,2-dioxabor olan-2- yl)phenyl]-N-(thiophen-3-ylmethyl)benzamide

This compound was made by way of the methods described for intermediate D0001 , utilizing 2,4-bis(benzyloxy)-5-chlorobenzoic acid [B0004] in step 2. The compound was purified by flash chromatography on silica gel, eluting with 20% EtOAc in hexane to afford a green solid (0.814 mg, 76%). LC/MS (method B): RT = 1.68 min; m/z = 666 [M+H] ⁺ . Total run time 1.90 mins.

[D0003] 2,4-bis(benzyloxy)-5-methyl-N-[4-(tetramethyl-1,3,2-dioxabor olan-2- yl)phenyl]-N-(thiophen-3-ylmethyl)benzamide

This compound was made by way of the methods described for intermediate D0001 , utilizing 2,4-bis(benzyloxy)-5-methylbenzoic acid [B0005] in step 2. The compound was purified by flash chromatography on silica gel, eluting with 20% EtOAc in hexane to afford an off-white solid (0.382 mg, 71 %).

LC/MS (method B): RT = 1.71 min; m/z = 644 [M+H] ⁺ . Total run time 1.90 mins.

[D0004] 3-(acetyloxy)-4-[(pyridin-3-ylmethyl)[4-(tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]carbamoyl]phenyl acetate

Step 1 4-bromo-N-(pyridin-3-ylmethyl)aniline

4-Bromoaniline (38.50 g, 223.8 mmol) was added to a solution of 3- pyridinecarboxadehyde (24.00 g, 224.1 mmol) in methanol (200 mL) and the solution heated, 85 C for ca 3hrs to give a pale yellow solution. The resulting solution was allowed to cool to RT and then cooled further with ice-water bath. Sodium borohydride (18.91 g, 500 mmol) was added portion-wise and the suspension stirred for ca 90 mins at 0 ^° C and for ca 18hrs at room temperature to give a yellow / green solution. The solution was poured into water (60 OmL) to give a pale yellow suspension. The solids were removed by filtration and washed with water (3 x 200ml). The solids were taken up in dichloromethane (500 mL) and the solution washed with water (200 mL) and saturated aqueous sodium chloride solution (200 mL). The solution wad dried over anhydrous magnesium sulphate filtered and the filtrate concentrated in vacuo to afford 4-bromo-N- (pyridin-3-ylmethyl)aniline as a pale-yellow solid (58.89 g, 94.8%).

LC/MS (method B): RT = 1.10 min; m/z = 265 [M+H] ⁺ . Total run time 1.90 mins. Step 2

3-(acetyloxy)-4-[(4-bromophenyl)(pyridin-3-ylmethyl)carba moyl]phenyl acetate

2,4-bis(acetyloxy)benzoic acid ([B0001], 4.98g, 20.90 mmol) was dissolved in dry DCM (100 mL). Oxalyl chloride (2.0M in DCM, 14.25 mL, 28.5 mmol) was added followed by DMF (few drops). The reaction mixture was allowed to stir at RT for 1 hour. The reaction mixture was cooled to 0 ^° C, Et ₃ N (10.57 mL, 76 mmol) was added, followed by 4-bromo-N-(pyridin-3-ylmethyl)aniline (5.0 g, 19 mmol) and reaction mixture was stirred at RT overnight. Reaction mixture was washed with water (1 x 100 mL) and the aqueous layer was extracted with DCM (2 x 70 mL). Organic layers were combined, washed with brine (1 x 100 mL), dried over magnesium sulphate and solvent removed in vacuo to afford a brown gum. The crude product was purified by automated column chromatography on silica gel, eluting with a gradient of 0-100% EtOAc in hexane. Fractions found to contain product were combined and solvent removed in vacuo to afford a pale-yellow solid (6.00 g, 65%).

LC/MS (method A): RT = 2.31 min; m/z = 485 [M+H] ⁺ . Total run time 3.75 mins. Step 3

3-(acetyloxy)-4-[(pyridin-3-ylmethyl)[4-(tetramethyl-1,3, 2-dioxaborolan-2- yl)phenyl]carbamoyl]phenyl acetate

A mixture of 3-(acetyloxy)-4-[(4-bromophenyl)(pyridin-3- ylmethyl)carbamoyl]phenyl acetate (10.12 g 294 mmol), jb/s(pinacolato)diboron (5.8 g, 23 mmol) and potassium acetate ( 3.23 g, 3.35 mmol) in dry 1 ,4 - dioxane (150 mL) was degassed and stirred at RT. Pd ₂ (dba) ₃ (1.72 g 188 mmol) and tricyclohexyl phosphine (645 mg, 2.30 mmol) in dry 1 ,4- dioxane (20 mL) was dissolved and degassed in a separate reaction flask. Reaction mixtures were combined and heated at 85 C for 20 h. The reaction mixture was allowed to cool to ambient temperature and material was filtered through a pad of celite which was washed with EtOAc (100 mL). The combined filtrates were washed with water (2 x 100 mL), brine (1 x 80 mL), dried (MgS0 ₄ ) and solvent removed in vacuo to afford a yellow gum.

Crude material was purified by automated column chromatography on silica gel, eluting with a gradient of 0-100% EtOAc / Hexane Fractions found to contain product were combined and solvent removed in vacuo to afford 3-(acetyloxy)-4- [(pyridin-3-ylmethyl)[4-(tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]carbamoyl]phenyl acetate as a yellow foam (8.16 g, 73%).

LC/MS (method A): RT = 2.47 min; m/z = 531 [M+H] ⁺ . Total run time 3.75 mins.

[D0005] 2,4-bis(benzyloxy)-5-chloro-N-(pyridin-3-ylmethyl)-N-[4- (tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzamide

Step 1

2,4-bis(benzyloxy)-N-(4-bromophenyl)-5-chloro-N-(pyridin- 3- ylmethyl)benzamide

This compound was prepared by way of the methods utilized in the prep of [D0004], using [B0004] 2,4-bis(benzyloxy)-5-chlorobenzoic acid and 4-bromo-N- (pyridin-3-ylmethyl)aniline.

The crude product was purified by automated column chromatography on silica gel, eluting with a gradient of 50-60% EtOAc in hexane to afford product as a cream-coloured solid.

LC/MS (method B): RT = 1.54 min; m/z = 613 [M+H] ⁺ . Total run time 1.90 mins. Step 2

2,4-bis(benzyloxy)-5-chloro-N-(pyridin-3-ylmethyl)-N-[4-( tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]benzamide

Nitrogen gas was bubbled through a solution of 2,4-bis(benzyloxy)-N-(4- bromophenyl)-5-chloro-N-(pyridin-3-ylmethyl)benzamide (0.64 g, 1.04 mmol), jb/s(pinacolato)diboron (0.32 g, 1.25 mmol) and potassium acetate (0.306 g, 3.12 mmol) in DMF (10 ml_) then [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (76 mg, 0.104 mmol) was added and the reaction mixture was heated in a microwave synthesiser at 120°C for 1 h. The solvent was removed in vacuo. And the resultant residue was dissolved in DCM then washed with sat. aqueous NaHC0 ₃ solution, followed by brine. The organic extract was dried (MgS0 ₄ ) then the solvent removed in vacuo. The crude product was purified by flash column chromatography on silica gel using a stepped gradient of 50% EtOAc/hexane, 60% EtOAc/hexane then 70% EtOAc/hexane as the eluent to afford 2,4-bis(benzyloxy)-5-chloro-N- (pyridin-3-ylmethyl)-N-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]benzamide as a cream-colored solid (0.459 g, 66.6%). LC/MS (method B): RT = 1.60 min; m/z = 661 [M+H] ⁺ . Total run time 1.90 mins.

[D0006] 3-(acetyloxy)-4-{benzyl[4-(tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl] carbamoyl}phenyl acetate

Step 1

N-benzyl-4-bromoaniline

4-bromoaniline (2.50 g, 14.53 mMol) and benzaldehyde (1.044 mL, 14.53 mmol) in anhydrous DCM (75 mL) was treated with NaBH(OAc) ₃ (3.39 g, 15.98 mmol) and glacial acetic acid (0.68 mL, 11.91 mMmol). Reaction mixture was stirred at RT overnight. The reaction mixture was quenched with 1 N NaOH, extracted with DCM (3 x 20 mL), and the combined extracts were washed with water (1 x 30 mL), brine (1 x 30 mL), dried (through phase separator) and solvent removed in vacuo to afford a dark grey oil. Crude reaction mixture was purified by automated column chromatography, eluting with EtOAc/ Hexane (0-5 % gradient). Fractions found to contain product were combined and solvent removed in vacuo to afford a yellow oil (2.07 g, 54%).

LC/MS (method B): RT = 1.46 min; m/z = 262 [M+H] ⁺ . Total run time 1.90 mins. Step 2

3-(acetyloxy)-4-[benzyl(4-bromophenyl)carbamoyl]phenyl acetate

This compound was prepared by way of the methods utilized in the prep of [D0004] (step 2), using 2,4-jb/s(acetyloxy)benzoic acid [B0001] (12.36 g) and N- benzyl-4-bromoaniline (13.6 g). The crude product was purified by automated column chromatography on silica gel, eluting with a gradient of 0-32% EtOAc in hexane to afford product as a colourless solid (15.05 g, 60%).

LC/MS (method B): RT = 1.43 min; m/z = 484 [M+H] ⁺ . Total run time 1.90 mins.

Step 3

3-(acetyloxy)-4-{benzyl[4-(tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl] carbamoyl}phenyl acetate

This compound was prepared by way of the methods utilized in the prep of [D0004] (step 3), using 3-(acetyloxy)-4-[benzyl(4-bromophenyl)carbamoyl]phenyl acetate

(25 g) and jb/s(pinacolato)diboron (14.48 g). The crude product was purified by automated column chromatography on silica gel, eluting with a solvent gradient of 0-35% EtOAc in hexane to afford product as a colourless solid (26 g, 94%).

LC/MS (method A): RT = 2.74 min; m/z = 530 [M+H] ⁺ . Total run time 3.75 mins.

[D0007] N-benzyl-2,4-bis(benzyloxy)-5-chloro-N-[4-(tetramethyl-1,3,2 - dioxaborolan-2-yl)phenyl]benzamide

This compound was prepared by way of the methods utilized in the prep of [D0005] using N-benzyl-4-bromoaniline in step 1. The title compound was purified by automated column chromatography on silica gel, eluting with a gradient of 0-30% EtOAc in hexane to afford product as a cream-coloured solid. LC/MS (method B): RT = 1.68 min; m/z = 660 [M+H] ⁺ . Total run time 1.90 mins.

[D0008] 3-(acetyloxy)-4-{[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phe nyl](1,2- thiazol-4-ylmethyl)carbamoyl}phenyl acetate

This compound was prepared by way of the methods outlined for [D0004] using 4-bromo-N-(1 ,2-thiazol-4-ylmethyl)aniline (preparation below) in step 2.

The crude product was adsorbed onto silica gel then purified by flash chromatography (40g silica cartridge), eluting with a gradient of 0 to 60% ethyl acetate in hexane.

LC/MS (method B): RT = 1.42 min; m/z = 537 [M+H] ⁺ . Total run time 1.90 mins. Preparation of 4-bromo-N-(1 ,2-thiazol-4-ylmethyl)aniline

Step 1 methyl 1 ,2-thiazole-4-carboxylate

To a solution of 1 ,2-thiazole-4-carboxylic acid (10.0 g, 77.4 mmol) in methanol (200 mL) was added drop-wise thionyl chloride (8 mL) and the mixture was stirred at reflux for 2h. The mixture was cooled to RT and the solvent was evaporated to give product as brown solid (1 1.0 g, 99%).

Step 2

1,2-thiazol-4-ylmethanol To a solution of methyl 1 ,2-thiazole-4-carboxylate (1 1 g, 77.4 mmol) in THF (150 ml_) was added lithium aluminium hydride (6.8 g, 178 mmol) at -10°C and the mixture was stirred at -10°C for 1 h. The solution was quenched with wet Na ₂ S0 ₄ , which was then filtered off and the filtrate was concentrated in vacuo to give 1 ,2-thiazol-4-ylmethanol as a pale yellow oil (6.36 g, yield 71 %). Step 3

1,2-thiazole-4-carbaldehyde

To a solution of 1 ,2-thiazol-4-ylmethanol (6.36 g, 55.3 mmol) in DCM (150 ml_) was added 1 ,1 ,1 -triacetoxy-1 ,1-dihydro-1 ,2-benziodooxo-3(1 H)-one (Dess- Martin Periodinane; 28 g, 66 mmol) and the mixture was stirred at RT for 0.5 h. The reaction solution was partitioned between H ₂ 0 and DCM, washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate solvent was concentrated to give crude product as yellow oil (6.25 g, crude yield 99%).

Step 4

4-bromo-N-(1,2-thiazol-4-ylmethyl)aniline To a solution of 1 ,2-thiazole-4-carbaldehyde (5.62 g, 49.7 mmol) and 4- bromoaniline (8.55 g, 49.7 mmol) in methanol (80 ml_) was added NaBH(OAc) ₃ (12.64 g, 59.6 mmol) and stirred at RT for 1 h. The solution was partitioned between EtOAc and H ₂ 0, washed with brine, dried over Na ₂ S0 ₄ , filtered and filtrate concentrated to the crude product which was purified by flash column chromatography on silica gel eluting with mix of hexane and EtOAc to give crude product as pale yellow solid (3.58 g, 24%).

[E0001] 3-(acetyloxy)-4-[(4-aminophenyl)(benzyl)carbamoyl]phenyl acetate

Step 1

N-benzyl-4-nitroaniline

Diisopropylamine (9.25 mL) was added to a solution of benzylamine (3.80 g, 0.40 mmol) in acetonitrile (3 mL), followed by addition of 4-nitrofluorobenzene (2.5 g, 0.20 mmol). A further 4 mL of MeCN was added and the mixture was irradiated in microwave at 150°C for 1 hour to afford a bright yellow solution with a large amount of precipitate. The mixture was concentrated in vacuo then partitioned between EtOAc and 1 M HCI (aq). Organic phase was separated, washed with saturated sodium bicarbonate solution, dried (MgSO ₄ ) then concentrated to give a yellow solid, which was triturated from ethyl acetate with hexane to give bright yellow needles which were filtered, washed with hexane and dried to afford N-benzyl-4-nitroaniline (3.5 g. 86%).

LC/MS (method A): RT = 2.51 min; m/z = 229 [M+H] ⁺ . Total run time 3.75 mins Step 2

3-(acetyloxy)-4-[benzyl(4-nitrophenyl)carbamoyl]phenyl acetate

This compound was prepared by way of the method used for intermediate [C0004], step 3.

Step 3 3-(acetyloxy)-4-[(4-aminophenyl)(benzyl)carbamoyl]phenyl acetate

Palladium on carbon catalyst (10%) was added to a solution of 3-(acetyloxy)-4- [benzyl(4-nitrophenyl)carbamoyl]phenyl acetate (1.47 g, 3.28 mmol) in ethyl acetate (40 mL) under a nitrogen atmosphere. The flask was flushed with hydrogen gas and shook under a hydrogen atmosphere overnight. The mixture was filtered through a pad of celite and the filtrates evaporated to give an off- white foam (1.29 g, 94%).

LC/MS (method A): RT = 2.33 min; m/z = 419 [M+H] ⁺ . Total run time 3.75 mins Specific Compounds of the Invention Example 1

2,4-dihydroxy-N-{4-[methyl(quinolin-4-ylmethyl)carbamoyl] phenyl}-N- (thiophen-3-ylmethyl)benzamide

Oxalyl chloride solution (2.0M in DCM, 0.22 mL, 0.44 mmol) was added drop- wise to a stirred solution of 4-[N-(thiophen-3-ylmethyl)2,4- bis(acetyloxy)benzamido]benzoic acid [C0001] (100 mg, 0.22 mmol) in DCM (10 mL). DMF (few drops) were added and the reaction was stirred at RT for ca. 45 min then the solvent was removed in vacuo. The resultant residue was re- dissolved in DCM (5 mL) then triethylamine (0.15 mL) followed by N-methyl-1 - quinolin-2-ylmethanamine (57 mg, 0.33 mmol) were added. The reaction was stirred at RT overnight then 7N ammonia in methanol solution (1 mL) was added and stirring continued at RT for 6 hours. The reaction mix was diluted with DCM and washed with sat. aq. NaHC0 ₃ solution, followed by brine. The organic extract was dried over MgS0 ₄ then the solvent removed in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with 70% EtOAc in iso-hexane then by preparative HPLC at pH = 4 to afford product as an orange solid (35 mg, 30%).

LC/MS (method B): RT = 1.21 min; m/z = 524 [M+H] ⁺ . Total run time 1.90 mins

¹ H NMR (d ₆ DMSO; 353K): 2.96 (s, 3H) 4.78 (brs, 2H), 5.01 (s, 2H), 6.01 (dd, 1 H, J = 8.7, 2.3 Hz), 6.13 (d, 1 H, J = 2.3 Hz), 6.78 (d, 1 H, J = 8.5 Hz), 7.02 (d, 1 H, J = 4.8 Hz), 7.09 (d, 2H, J = 8.1 Hz), 7.24 (s, 1 H), 7.30 (d, 2H, J = 8.4 Hz), 7.36-7.42 (m, 2H), 7.73-7.78 (m, 1 H), 7.73-7.78 (m, 1 H), 7.95 (d, 1 H, J = 7.1 Hz), 7.98 (d, 1 H, J = 8.6 Hz), 8.31 (d, 1 H, J = 8.3 Hz), 9.93 (brs, 2H).

This compound had activity 'B' in the fluorescence polarization assay described above. The following compounds were prepared by the methods outlined in Example 1 using intermediate C0001 and the appropriate commercially available amine.

TABLE 1

2,4-dihydroxy-N-(4-{[(4-methoxyphenyl)methyl](methyl)carb amoyl}ph N-(thiophen-3-ylmethyl)benzamide

Step 1

[(4-methoxyphenyl)methyl](methyl)amine

A solution p-anisaldehyde (2.24 g, 16.44 mmol) and methylamine (2.0 M in THF, 16.44 mL, 32.88 mmol) in THF (10 mL) was cooled to ca 0 °C with ice water bath and then sodium borohydride (0.933 g, 24.66 mmol) was added in portions followed by drop-wise addition MeOH (0.2 mL). The reaction was allowed to gradually warm to RT and then stir overnight. The reaction was cooled to ca 0 °C then slowly acidified to ca pH=2 with 2M aqueous HCI (aq).

The reaction was stirred at ca 0°C for 30 min then adjusted to ca pH=10 with 2M NaOH (aq) solution. The reaction was extracted with EtOAc then the organic extract washed with H ₂ O followed by brine then dried (MgSO ₄ ) and the solvent removed in vacuo. The crude product was purified by flash column chromatography on silica gel using a step gradient of 100% EtOAc, then 5% 7N NHs.MeOH/DCM then 10% 7N NH ₃ MeOH/DCM as the eluent. This afforded the product as a colourless oil (0.403 g, 16%).

LC/MS (method B): RT = 1.50 min; m/z = 150 [M-H]\ Total run time 1.90 mins.

Step 2 N-[(4-methoxyphenyl)methyl]-N-methyl-4-nitrobenzamide

Oxalyl chloride (2.0M in DCM, 3.62 ml_, 7.23 mmol) was added to a stirred solution of 4-nitrobenzoic acid (0.60 g, 3.62 mmol) in DCM (20 ml_). Two drops of DMF were added and the reaction was stirred at RT for ca 45 min then the solvent removed in vacuo. The resultant residue was dissolved in DCM (20 ml_) then Et ₃ N (2.52 ml_, 18.1 mmol) was added followed by [(4- methoxyphenyl)methyl](methyl)amine (0.66 g, 4.34 mmol). The reaction mixture was stirred at RT for ca 2h, then diluted with DCM and washed with sat. aq. NaHC0 ₃ solution followed by brine. The organic extract was dried (MgS04) then the solvent removed in vacuo and the crude product was purified by flash column chromatography on silica using a stepped gradient of 100% hexane, 10% EtOAc/hexane, 20% EtOAc/hexane, 30% EtOAc/hexane then 40% EtOAc/hexane as the eluent to afford the product as a pale yellow oil.

LC/MS (method A): RT = 2.36 min; m/z = 301 [M+H] ⁺ . Total run time 3.75 mins. Step 3

4-amino-N-[(4-methoxyphenyl)methyl]-N-methylbenzamide

A solution of N-[(4-methoxyphenyl)methyl]-N-methyl-4-nitrobenzamide in EtOAc (20 ml_) was added to a flask containing 10% Pd/C under a nitrogen atmosphere. The reaction was placed under a hydrogen atmosphere, where it was shaken overnight. The reaction mixture was filtered through a pad of Celite (pre-washed with EtOAc) then eluted with further EtOAc. The combined filtrate solvents were removed in vacuo to afford a white solid (0.829 g, 90%). LC/MS (method B): RT = 1.05 min; m/z = 271 [M+H] ⁺ . Total run time 1.90 mins. Step 4

N-[(4-methoxyphenyl)methyl]-N-methyl-4-[(thiophen-3- ylmethyl)amino]benzamide

Sodium triacetoxyborohydride (0.172 g, 0.81 mmol) followed by acetic acid ( 0.03 ml_, 0.61 mmol) were added to a stirred solution of 4-amino-N-[(4- methoxyphenyl)methyl]-N-methylbenzamide (0.20 g, 0.74 mmol) and 3- thiophenecarboxaldehyde (0.06 ml_, 0.74 mmol) in DCM (5 ml_). The reaction was stirred at RT overnight. The reaction was quenched with 2M NaOH (aq) then extracted with DCM. The organic extract was washed with H ₂ O followed by brine then dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by flash column chromatography on silica gel using 30% EtOAc/hexane then 40% EtOAc/hexane as the eluent to afford N-[(4- methoxyphenyl)methyl]-N-methyl-4-[(thiophen-3-ylmethyl)amino ]benzamide as an off-white solid (0.22 g, 81 %).

LC/MS (method B): RT = 1.33 min; m/z = 367 [M+H] ⁺ . Total run time 1.90 mins. Step 5

2,4-bis(benzyloxy)-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)-N-(thiophen-3 - ylmethyl)benzamide

Oxalyl chloride (2.0M in DCM, 0.27 ml_, 0.54 mmol) was added to a stirred solution of 2,4-bis(benzyloxy)benzoic acid ([B0003], 90 mg, 0.27 mmol) in DCM (5 ml_). Two drops of DMF were added and the reaction was stirred at RT for ca 45 min then the solvent removed in vacuo. The resultant residue was dissolved in DCM (5 ml_) then Et ₃ N (0.19 ml_, 1.35 mmol) was added followed by N-[(4- methoxyphenyl)methyl]-N-methyl-4-[(thiophen-3-ylmethyl)amino ]benzamide (100 mg, 0.27 mmol). The reaction mixture was stirred at RT for overnight, then diluted with DCM and washed with sat. aq. NaHC0 ₃ solution followed by brine. The organic extract was dried (MgS04) then the solvent removed in vacuo and the crude product was purified by flash column chromatography on silica using a stepped gradient of 20% EtOAc/hexane, 30% EtOAc/hexane then 40% EtOAc/hexane as the eluent to afford the product as a colourless foam 158mg, 85%). LC/MS (method B): RT = 1.50 min; m/z = 683 [M+H] ⁺ . Total run time 1.90 mins. Step 6

2,4-dihydroxy-N-(4-{[(4-methoxyphenyl)methyl](methyl)carb amoyl}phenyl)- N-(thiophen-3-ylmethyl)benzamide

A solution of 2,4-bis(benzyloxy)-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)-N-(thiophen-3 - ylmethyl)benzamide in DCM (5 mL) was cooled to ca 0°C under a nitrogen atmosphere, then BCI ₃ (1.0M in DCM, 1.16 mL, 1.16 mmol) was added slowly. The reaction was allowed to gradually warm to RT, where it was stirred for ca 3h. A further 1.16 mL of 1.0M boron trichloride in DCM solution was added and the reaction mixture stirred overnight. The reaction mixture was quenched by cautious addition of MeOH (5 mL) then the solvents were removed in vacuo. The product was purified by preparative HPLC at pH =4, to afford 2,4-dihydroxy-N-(4- {[(4-methoxyphenyl)methyl](methyl)carbamoyl}phenyl)-N-(thiop hen-3- ylmethyl)benzamide as a colourless solid (29 mg, 25%).

LC/MS (method B): RT = 1.26 min; m/z = 503 [M+H] ⁺ . Total run time 1.90 mins. ¹ H NMR (d ₆ DMSO; 353K): δ 2.78 (s, 3H) 3.76 (s, 3H), 4.43 (brs, 2H), 5.02 (s, 2H), 6.01 (dd, 1 H, J = 8.6, 2.3 Hz), 6.14 (d, 1 H, J = 2.3 Hz), 6.79 (d, 1 H, J = 8.7 Hz), 6.87 -6.92 (m, 2H), 7.04 (dd, 1 H, J = 4.8, 1.3 Hz), 7.07-7.17 (m, 4H), 7.21- 7.26 (m, 3H), 7.40 (dd, 1 H, J = 5.1 , 3.1 Hz), 9.27-9.60 (brs, 1 H), 9.92 (brs, 1 H).

This compound had activity 'B' in the fluorescence polarization assay described above.

Example 11 N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-(thiophen-3-

ylmethyl)benzamide

Step 1

2,4-bis(benzyloxy)-N-[4-(dimethylcarbamoyl)phenyl]-N-(thi ophen-3- lmethyl)benzamide

Oxalyl chloride (2.0M in DCM, 0.27 ml_, 0.54 mmol) was added to a stirred solution of 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)benzamido]benzoi c acid ([C0002], 150 mg, 0.27 mmol) in DCM (10 ml_). Two drops of DMF were added and the reaction was stirred at RT for ca 30 min then the solvent removed in vacuo. The resultant residue was dissolved in DCM (10 ml_) then Et ₃ N (0.19 ml_, 1.35 mmol) was added followed by dimethylamine hydrochloride (30 mg, 0.41 mmol). The reaction mixture was stirred at RT for overnight, then diluted with DCM and washed with sat. aq. NaHCO ₃ solution, followed by brine. The organic extract was dried (MgSO ₄ ) then the solvent removed in vacuo and the crude product was purified by flash column chromatography on silica using a stepped gradient of 20% EtOAc/hexane, 40% EtOAc/hexane then 60% EtOAc/hexane as the eluent to afford the product as a colourless foam (113 mg, 71 %).

LC/MS (method A): RT = 2.71 min; m/z = 577 [M+H] ⁺ . Total run time 3.75 mins. Step 2 N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-N-(thiophen-3- ylmethyl)benzamide

A solution of 2,4-bis(benzyloxy)-N-[4-(dimethylcarbamoyl)phenyl]-N-(thioph en-3- ylmethyl)benzamide (1 10 mg, 0.20 mmol) in DCM (5 mL) was reacted with boron trichloride solution according to the method outlined in example 10 step 6. Purification of the crude product by preparative HPLC at pH = 4 afforded the product as a beige coloured foam (18 mg, 23%).

LC/MS (method B): RT = 1.07 min; m/z = 397 [M+H] ⁺ . Total run time 1.90 mins. ¹ H NMR (d ₆ DMSO): 5 2.78 (s, 3H) 2.91 (s, 3H), 5.01 (s, 2H), 6.03 (dd, 1 H, J = 8.4, 2.4 Hz), 6.10 (d, 1 H, J = 2.2 Hz), 6.84 (d, 1 H, J = 8.5 Hz), 7.05 (dd, 1 H, J = 5.0, 1.2 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.19 (d, 2H, J = 8.5 Hz), 7.30 (d, 1 H, J = 1.7 Hz), 7.46 (dd, 1 H, J = 4.8, 2.8 Hz), OH's not observed.

This compound had activity 'A' in the fluorescence polarization assay described above.

Example 12

2,4-dihydroxy-N-{4-[methyl(naphthalen-1-ylmethyl)carbamoy l]phenyl}-N- (thiophen-3-ylmethyl)benzamide

This example was prepared by way of the method outlined for Example 11 , from 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)benzamido]benzoi c acid [C0002] and 1 -methyl-1 napthylamine, followed by de-protection of benzyl groups with boron trichloride solution. Purification of the crude product by flash chromatography on silica gel, eluting with 2% methanol in DCM, afforded Example 12 as an orange solid (32 mg, 45%).

LC/MS (method A): RT = 2.60 min; m/z = 523 [M+H] ⁺ . Total run time 3.75 mins.

This compound had activity ' in the fluorescence polarization assay described above.

Example 13

2,4-dihydroxy-N-{4-[methyl(naphthalen-2-ylmethyl)carbamoy l]phenyl}-N- (thiophen-3-ylmethyl)benzamide

This example was prepared by way of the method outlined for Example 11 , from

4- [N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)benzamido]benzoic acid [C0002] and methyl(naphthalen-2-ylmethyl)amine followed by de-protection of benzyl groups with boron trichloride solution. Purification of the crude product by flash chromatography on silica gel, eluting with 40% EtOAc in hexane, afforded Example 13 as a brown solid (70 mg, 54%).

LC/MS (method B): RT = 1.36 min; m/z = 523 [M+H] ⁺ . Total run time 1.90 mins.

This compound had activity ' in the fluorescence polarization assay described above. Example 14

5- chloro-2,4-dihydroxy-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)-N-(thiophen-3 - ylmethyl)benzamide

This compound was prepared by way of the methods outlined for Example 10, using intermediate B0004, 2,4-bis(benzyloxy)-5-chlorobenzoic acid and N-[(4- methoxyphenyl)methyl]-N-methyl-4-[(thiophen-3-ylmethyl)amino ]benzamide in step 5.

Compound was purified by preparative HPLC to afford a colourless solid (30 mg, 38%).

LC/MS (method B): RT = 1.31 min; m/z = 537 [M+H] ⁺ . Total run time 1.90 mins.

This compound had activity 'B' in the fluorescence polarization assay described above. Example 15

N-[4-(dimethylcarbamoyl)phenyl]-2,4-dihydroxy-5-methyl-N- (thiophen-3- ylmethyl)benzamide

This compound was prepared by way of the methods outlined for Example 11 , using the intermediate C0003, 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)-5- methylbenzamido] benzoic acid and dimethylamine in the appropriate step. The compound was purified by preparative HPLC pH 9, to give a peach colored solid.

LC/MS (method B): RT = 1.81 min; m/z = 41 1 [M+H] ⁺ . Total run time 1.90 mins. ¹ H NMR (d ₆ DMSO): δ 1.82 (s, 3H), 2.80 (s, 3H) 2.92 (s, 3H), 5.01 (s, 2H), 6.16 (s, 1 H), 6.70 (s, 1 H), 7.05 (d, 1 H, J = 5.0 Hz), 7.08 (d, 2H, J = 8.5 Hz), 7.21 (d, 2H, J = 8.5 Hz), 7.29 (d, 1 H, J = 1.8 Hz), 7.46 (dd, 1 H, J = 4.7, 2.8 Hz), 9.51 - 9.76 (brs, 1 H), 9.87 (brs, 1 H).

This compound had activity 'B' in the Delfia assay described above. Example 16

2,4-dihydroxy-5-methyl-N-{4-[methyl(quinoxalin-6- ylmethyl)carbamoyl]phenyl}-N-(thiophen-3-ylmethyl)benzamide

This compound was prepared by way of the methods outlined for Example 11 , using the intermediate C0003, 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)-5- methylbenzamido] benzoic acid and methyl(quinoxalin-6-ylmethyl)amine in the appropriate step. The compound was purified by flash chromatography on silica gel, eluting with 2% methanol in DCM to afford compound as brown solid (92 mg, 53%).

LC/MS (method B): RT = 1.23 min; m/z = 539 [M+H] ⁺ . Total run time 1.90 mins. This compound had activity 'A' in the Delfia assay described above. Example 17

2,4-dihydroxy-N-(4-{[(4-methoxyphenyl)methyl](methyl)carb amoyl}phenyl)- 5-methyl-N-(thiophen-3-ylmethyl)benzamide

This compound was prepared by way of the methods outlined for Example 11 , using the intermediate C0003, 4-[N-(thiophen-3-ylmethyl)2,4-bis(benzyloxy)-5- methylbenzamido] benzoic acid and 4-methoxy-N-methylbenzylamine in the appropriate step. The compound was purified by flash chromatography on silica gel, eluting with 50% EtOAc in hexane to product as a afford colourless glass. LC/MS (method B): RT = 1.34 min; m/z = 517 [M+H] ⁺ . Total run time 1.90 mins. This compound had activity 'A' in the Delfia assay described above. Example 18

N-{4-[5-(benzylsulfamoyl)-3-methylpyridin-2-yl]phenyl}-2, 4-dihydroxy-N- (thiophen-3-ylmethyl)benzamide

Step 1

2,4-bis(benzyloxy)-N-{4-[5-(benzylsulfamoyl)-3-methylpyri din-2-yl]ph N-(thiophen-3-ylmethyl)benzamide

2,4-bis(benzyloxy)-N-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-N- (thiophen-3-ylmethyl)benzamide (intermediate D0001 , 82 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1 mL) and water (0.1 mL) in a microwave vial. Potassium carbonate (0.054 g, 0.39 mmol) and N-benzyl-6-chloro-5- methylpyridine-3-sulfonamide (intermediate A0001 , 46 mg, 0.16 mmol) were added, and the microwave vial was degassed with nitrogen. [1 , 1'- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.010 g, 0.013 mmol) was then added and the vial was purged again with nitrogen. The reaction was then heated to 120°C in a microwave for 1 hour. The reaction was then diluted with ethyl acetate and washed with water and brine. The organic layer was then dried over magnesium sulphate and reduced in vacuo to yield a black residue, which was purified by flash chromatography eluting with 40% ethyl acetate in hexane to yield a pale orange glass (61 mg, 60.8%).

LC/MS (method B): RT = 1.54 min; m/z = 766 [M+H] ⁺ . Total run time 1.90 mins. Step 2

N-{4-[5-(benzylsulfamoyl)-3-methylpyridin-2-yl]phenyl}-2, 4-dihydroxy-N- (thiophen-3-ylmethyl)benzamide

2,4-bis(benzyloxy)-N-{4-[5-(benzylsulfamoyl)-3-methylpyri din-2-yl]phenyl}-N- (thiophen-3-ylmethyl)benzamide (61 mg, 0.08 mmol) was dissolved in dry dichloromethane (5 ml_) and cooled to 0 ^° C in an ice bath. 1.0 M Boron trichloride solution (1.0M in DCM, 0.40 ml_, 0.40 mmol) was then added, and the reaction was stirred at 0 ^° C for 1 hour, then allowed to warm to room temperature overnight. The reaction was then quenched by cautious addition of methanol and stirred at room temperature for 1 hour. The reaction mixture was then reduced in vacuo to yield a yellow residue which purified by preparative HPLC to afford N-{4-[5-(benzylsulfamoyl)-3-methylpyridin-2-yl]phenyl}-2,4-d ihydroxy-N- (thiophen-3-ylmethyl)benzamide as a white solid (0.010 g, 22.0%).

LC/MS (method B): RT = 1.32 min; m/z = 586 [M+H] ⁺ . Total run time 1.90 mins ¹ H NMR (de DMSO): δ 2.24 (s, 3H) 4.08 (s, 2H), 5.05 (s, 2H), 6.06 (dd, 1H, J = 8.4, 2.5 Hz), 6.13 (d, 1H, J= 2.3 Hz), 6.87 (d, 1H, J= 8.4 Hz), 7.08 (dd, 1H, J = 5.1, 1.3 Hz), 7.15-7.27 (m, 7H), 7.34 (d, 1H, J = 1.8 Hz), 7.38 (d, 2H, J= 8.6 Hz), 7.49 (dd, 1H, J= 4.9, 3.1 Hz), 7.90 (d, 1H, J= 1.4 Hz), 8.38 (brs, 1H), 8.72 (d, 1H, J = 1.7 Hz). OH, s not observed

This compound had activity 'B' in the fluorescence polarization assay described above.

The examples listed in Table 2 were prepared by the methods outlined for Example 18, using intermediates A0001-A0022 and D0001 or D0002 as appropriate.

TABLE 2

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96 /.8Z£0/H0ZaO/13d sztoto/sioz OAV

/.8Z£0/H0ZaO/13d SZtOtO/SlOZ OAV

86 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

X - Activity in Fluorescence polarisation assay described above; Y - Activity Delfia assay described above.

Example 39

N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)-2, 4-dihydroxy-N- (thiophen-3-ylmethyl)benzamide

Step 1 2,4-bis(benzyloxy)-N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin -4-yl}phenyl)- N-(thiophen-3-ylmethyl)benzamide

2,4-bis(benzyloxy)-N-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]-N-

(thiophen-3-ylmethyl)benzamide (intermediate D0001 , 0.150 g, 0.24 mmol) was dissolved in tetrahydrofuran (2 ml_) and water (0.2 ml_) in a microwave vial. Potassium carbonate (0.100 g, 0.72 mmol) and 2,4-dichloro-7H-pyrrolo[2,3- D]pyrimidine (0.054 g, 0.28 mmol) were added, and the microwave vial was degassed with nitrogen. [1 , 1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.018 g, 0.024 mmol) was then added and the vial was purged again with nitrogen. The reaction was then heated to 120°C in a microwave for 2 hours. The reaction was then diluted with ethyl acetate and washed with water and brine. The organic layer was then dried over magnesium sulphate and reduced under vacuum to yield a black residue, which was purified by flash chromatography on silica gel, eluting with 40% ethyl acetate in hexane to afford 2,4-bis(benzyloxy)-N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin -4-yl}phenyl)-N- (thiophen-3-ylmethyl)benzamide as a yellow solid (0.085 g, 54.5%).

LC/MS (method B): RT = 1.54 min; m/z = 657 [M+H] ⁺ . Total run time 1.90 mins. Step 2

N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)-2, 4-dihydroxy-N- (thiophen-3-ylmethyl)benzamide

2,4-bis(benzyloxy)-N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimi din-4-yl}phenyl)-N- (thiophen-3-ylmethyl)benzamide (0.085 g, 0.13 mmol) was dissolved in dry dichloromethane (7 mL) and cooled to 0 ^° C in an ice-water bath. Boron dichloride solution (1 .0M in DCM, 0.65 mL, 0.65 mmol) was then added drop-wise, and the reaction was stirred at 0 ^° C for 1 hour, then left to warm to room temperature overnight. The reaction was then quenched by drop-wise addition of methanol and stirred at room temperature for 1 hour. The reaction was then reduced in vacuo to yield a residue which was purified by preparative HPLC at pH = 4 to yield N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)-2,4-d ihydroxy-N- (thiophen-3-ylmethyl)benzamide as an off-white foam (0.007 g, 10.5%).

LC/MS (method B): RT = 1 .30 min; m/z = All [M+H] ⁺ . Total run time 1 .90 mins.

¹ H NMR (d ₆ DMSO): δ 5.08 (s, 2H), 6.09 (dd, 1 H, J = 8.3, 2.3 Hz), 6.1 1 (d, 1 H, J = 1 .9 Hz), 6.88 (d, 1 H, J = 3.7 Hz), 6.95 (d, 1 H, J = 8.3 Hz), 7.09 (dd, 1 H, J = 5.0, 1.2 Hz), 7.6 (d, 2H, J = 8.8 Hz), 7.38 (d, 2H, J = 8.6 Hz), 7.34 (m, 1 H), 7.48 (dd, 1 H, J = 4.8, 3.1 Hz), 7.67 (d, 1 H, J = 3.7 Hz), 7.99 (d, 2H, J = 8.8 Hz). OH,s, NH not observed.

The examples listed in Table 3 were prepared by the methods outlined for Example 39, using intermediates D0001 , D0002 and D0003 and commercially available halides as appropriate.

TABLE 3

LCMS retention activity activity

EG STRUCTURE Adduct m/z

METHOD time (min) (X) 00

20 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

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90 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/STOZ OAV

90 /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

101 /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

80 /.8Z£0/H0ZaO/I3d SZtOtO/SlOZ OAV

60 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

O /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

X - Activity in Fluorescence polarisation assay described above; Y - Activity in Delfia assay described above.

Example 85 2,4-dihydroxy-N-[4-(3-methylquinolin-2-yl)phenyl]-N-(pyridin -3- ylmethyl)benzamide

3-(acetyloxy)-4-[(pyndin-3-ylmethyl)[4-(tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]carbamoyl]phenyl acetate ([D0004], 100 mg, 0.19 mmol), 2-chloro-3- methylquinoline (36.8 mg, 0.21 mmol), potassium carbonate (105 mg, 0.76 mmol), and [1 ,1 '-jb/s(diphenylphosphino)ferrocene]dichloropalladium (II) (14 mg, 0.019 mmol) were combined, dissolved in THF/H ₂ 0 (4.5 mL : 0.5 mL), and the mixture degassed by bubbling nitrogen gas through for 5 mins. The reaction mixture was heated in a microwave synthesiser at 120°C for 40 mins. Methanolic ammonia solution (7N, 2 mL) was added to the mixture and mixture was stirred at room temperature overnight. The crude material was dissolved in EtOAc (25 mL), and the organic layer was washed in water. The aqueous layer was then washed in EtOAc and the organic layers were combined, washed with brine, dried over MgSO ₄ , filtered, and the filtrate solvent removed under vacuum to afford a brown gum. The crude product was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 5% MeOH in DCM to afford 2,4-dihydroxy-N-[4-(3-methylquinolin-2-yl)phenyl]-N-(pyridin -3- ylmethyl)benzamide as an orange solid.

LC/MS (method A): RT = 2.15 min; m/z= 462 [M+H] ⁺ . Total run time 3.75 mins. ¹ H NMR (d ₆ DMSO): δ 2.34 (s, 3H), 5.15 (s, 2H), 6.09 (dd, 1H, J= 8.5, 2.3 Hz), 6.14 (d, 1H, J= 2.2 Hz), 6.95 (d, 1H, J= 8.4 Hz), 7.18 (d, 2H, J= 8.6 Hz), 7.36 (dd, 1H, J= 7.1, 4.1 Hz), 7.44 (d, 2H, J= 8.6 Hz), 7.53-7.58 (m, 1H), 7.65-7.70 (m, 1H), 7.78 (dt, 1H, J= 8.1, 1.7 Hz), 7.90 (d, 1H, J= 7.4 Hz), 7.97 (d, 1H, J = 8.3 Hz), 8.21 (s, 1H), 8.45 (dd, 1H, J= 4.8, 1.8 Hz), 8.54 (d, 1H, J= 1.5 Hz), 9.51 (brs, 1H), 9.98 (brs, 1H).

This compound had activity 'A' in the fluorescence polarization assay described babove.

Example 86

5-chloro-N-[4-(2-chloro-5-methoxypyrimidin-4-yl)phenyl]-2 ,4-dihydroxy-N- (pyridin-3-ylmethyl)benzamide

Step 1

2,4-bis(benzyloxy)-5-chloro-N-[4-(2-chloro-5-methoxypyrim idin-4- yl)phenyl]-N-(pyridin-3-ylmethyl)benzamide

Nitrogen gas was bubbled through a solution of 2,4-bis(benzyloxy)-5-chloro-N- (pyridin-3-ylmethyl)-N-[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]benzamide ([D0005], 150 mg, 0.23 mmol), 2,4-dichloro-5-methoxypyrimidine (40 mg, 0.23 mmol) and potassium carbonate (95 mg, 0.69 mmol) in THF/H ₂ 0 (2 ml_ / 0.2 ml_) then [1 , 1'-jb/s(diphenylphosphino)ferrocene]dichloropalladium (II) was added and the reaction mixture was heated in a microwave synthesiser at 120 °C for 1 h. The reaction mixture was diluted with EtOAc then washed with sat. aqueous NaHC0 ₃ solution followed by brine. The organic extract was dried (MgS04) then the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel, eluting with a gradient of 50-80% EtOAc in hexane affording 2,4-bis(benzyloxy)-5-chloro-N-[4-(2-chloro-5-methoxypyrimidi n-4- yl)phenyl]-N-(pyridin-3-ylmethyl)benzamide as a brown glass (1 11 mg, 72%).

LC/MS (method B): RT = 1.52 min; m/z = 677 [M+H] ⁺ . Total run time 1.90 mins. Step 2

5-chloro-N-[4-(2-chloro-5-methoxypyrimidin-4-yl)phenyl]-2 ,4-dihydroxy-N- (pyridin-3-ylmethyl)benzamide

2,4-bis(benzyloxy)-5-chloro-N-^

(pyridin-3-ylmethyl)benzamide (0.1 10 g, 0.16 mmol) was dissolved in dry dichloromethane (5 mL) and cooled to 0 ^° C in an ice-water bath. Boron dichloride solution (1 .0M in DCM, 0.49 mL, 0.49 mmol) was then added drop-wise, and the reaction was stirred at 0 ^° C for 1 hour, then left to warm to room temperature overnight. The reaction was then quenched by drop-wise addition of methanol and stirred at room temperature for 1 hour. The reaction was then reduced in vacuo to yield a residue which was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 5% MeOH in DCM to afford 5-chloro-N-[4-(2- chloro-5-methoxypyrimidin-4-yl)phenyl]-2,4-dihydroxy-N-(pyri din-3- ylmethyl)benzamide as a light brown glass (0.072 g, 86%).

LC/MS (method B): RT = 1 .16 min; m/z = 497 [M+H] ⁺ . Total run time 1 .90 mins.

¹ H NMR (d ₆ DMSO): δ 3.96 (s, 3H), 5.24 (s, 2H), 6.31 (s, 1 H), 7.26 (s, 1 H), 7.28 (d, 2H, J = 8.8 Hz), 7.85 (dd, 1 H, J = 7.8, 5.6 Hz), 7.91 (d, 2H, J = 8.8 Hz), 8.32 (d, 1 H, J = 8.4 Hz), 8.63 (s, 1 H), 8.72 (d, 1 H, J = 5.0 Hz), 8.77 (s, 1 H), 9.96 (s, 1 H), 10.34 (s, 1 H).

This compound had activity 'A' in the Delfia assay described above.

The examples listed in Table 4 were prepared by the methods outlined for Example 85 and 86, using intermediates D0004 and D0005 and commercially available halides as appropriate.

TABLE 4

LCMS retention time activity activity

Structure adduct m/z

method (min) (X) 00 87 B 0.97 [M+H]+ 446 A -

OH O

88 A 1 .70 [M+H]+ 412 B -

OH O

89 B 0.85 [M+H]+ 413 B -

OH O

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8 /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

6 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/STOZ OAV 99 B 0.97 [M+H]+ 438 C -

OH 0

100 B 0.97 [M+H]+ 441 A -

OH O

N NH ₂

101 B 0.82 [M+H]+ 414 C -

OH O

2 /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

22 /.8Z£0/H0ZaO/I3d SZtOtO/SlOZ OAV

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92 /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

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8Z /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

62 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/SlOZ OAV

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- V LZV +ΙΗ+ΙΛΙ] 99Ί. V ca¾L„

LSI

o HO

- a LZV +ΙΗ+ΙΛΙ] 69Ί- V

- a 96fr +ΙΗ+ΙΛΙ] OVZ V SCI-

- g 909 +ΙΗ+ΙΛΙ] SZZ V TCI-

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9ε /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

6ε /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

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Example 175 2,4-dihydroxy-N-(4-{3-methyl-5-[(thiophen-2-ylmethyl)sulfamo yl]pyridin-2- yl}phenyl)-N-(pyridin-3-ylmethyl)benzamide

3-(acetyloxy)-4-[(pyridin-3-ylmethyl)[4-(tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]carbamoyl]phenyl acetate (intermediate [D0004], 100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4.5 mL) and water (0.5 mL) in a microwave vial. Potassium carbonate (78 mg, 0.54 mmol) and 6-chloro-5-methyl-N- (thiophen-2-ylmethyl)pyridine-3-sulfonamide (intermediate A0002, 66.6 mg, 0.22 mmol) were added, and the microwave vial was degassed with nitrogen for 5 minutes. [1 , 1'-jb/s(diphenylphosphino)ferrocene]dichloropalladium (II) (0.018 mmol) was then added and the vial was purged again with nitrogen. The reaction was then heated to 120 C in a microwave for 40 minutes. To the cooled reaction mixture was added ammonia in methanol solution (7N, 2.0 ml_) and mixture stirred overnight. Reaction mixture was diluted with EtOAc and washed with H ₂ 0; the organics were dried over MgS0 ₄ and concentrated under reduced pressure. The residual gum was then purified by flash chromatography on silica gel using a solvent gradient of 0 to 5% MeOH in DCM to afford product as an orange foam (40 mg).

LC/MS (method A): RT = 2.16 min; m/z = 587 [M+H] ⁺ . Total run time 3.75 mins.

¹ H NMR (d ₆ DMSO): δ 2.25 (s, 3H) 4.27 (s, 2H), 5.13 (s, 2H), 6.08 (dd, 1 H, J = 8.4, 2.2 Hz), 6.12 (d, 1 H, J = 2.1 Hz), 6.86 (dd, 1 H, J = 5.1 , 3.3 Hz), 6.88-6.91 (m, 1 H), 6.93 (d, 1 H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.6 Hz), 7.33-7.41 (m, 4H), 7.77 (dt, 1 H, J = 8.1 , 1.7 Hz), 7.94 (d, 1 H, J = 1.6 Hz), 8.45 (dd, 1 H, J = 4.9, 1.5 Hz), 8.49 (brs, 1 H), 8.53 (d, 1 H, J = 1.8 Hz), 8.72 (d, 1 H, J = 1.8 Hz), 9.57 (brs, 1 H), 9.92 (s, 1 H).

This compound had activity 'A' in the fluorescence polarization assay described above.

The examples listed in Table 5 were prepared by the methods outlined for Example 175 using intermediates D0004 and the appropriate intermediate from the set [A0001 to A0022] previously described.

TABLE 5

LCMS RETENTION

EG STRUCTURE ADDUCT m/z activity*

METHOD TIME (min)

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9H /.8Z£0/H0ZaO/I3d SZtOtO/SlOZ OAV /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV Example 191

5-chloro-2,4-dihydroxy-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)-N-(pyridin-3- ylmethyl)benzamide

Step 1

2,4-bis(benzyloxy)-5-chloro-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)benzamide

To a stirred solution of 4-amino-N-[(4-methoxyphenyl)methyl]-N- methylbenzamide (Example 10 step 3, 245 mg, 0.91 mmol) in DMF (3 ml_) was added [B0004] 2,4-bis(benzyloxy)-5-chlorobenzoic acid (401 mg, 1.09 mmol) followed by 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 413 mg, 1.09 mmol) and diisopropylethylamine (2 mmol). The reaction was left to stir for 24 h at RT. The crude reaction was partitioned between 1 M HCI (aq) and ethyl acetate, the organic phase was washed with NaHC0 ₃ then brine, dried over MgS0 _4, filtered and solvents evaporated in vacuo to give an off-white foam (625 mg). The residue was purified flash chromatography on silica gel (25g column); gradient eluting with a gradient of EtOAc / Hexane 20 to 80% to afford product as a white foam (308 mg, 54%).

LC/MS (method A): RT = 2.87 min; m/z = 621 [M+H] ⁺ . Total run time 3.75 mins. Step 2

2,4-bis(benzyloxy)-5-chloro-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)-N-(pyridin-3- ylmethyl)benzamide

To a solution of 2,4-bis(benzyloxy)-5-chloro-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)benzamide (100mg) in toluene (2ml_) was added 3-picoyl chloride (41 mg), K ₂ C0 ₃ (25mg), NaOH (50mg) and tetrabutylammonium hydrogen sulphate (4 mg) and the mixture was heated in in a microwave synthesiser at 80°C for 30 min. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate and the combined organics dried over MgS0 ₄ and solvents evaporated in vacuo to give a colourless glass (108mg). LC/MS (method A): RT = 2.69 min; m/z = 712 [M+H] ⁺ . Total run time 3.75 mins.

Step 3

2,4-bis(benzyloxy)-5-chloro-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)benzamide

To a solution of 2,4-bis(benzyloxy)-5-chloro-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)-N-(pyndin-3- ylmethyl)benzamide (108 mg, 0.15 mmol) in DCM (5 ml_) was added boron trichloride solution (1.0M in DCM, 2 ml_) drop wise. Reaction mixture was stirred for 20 min at 0°0 C then allowed to warm to RT and stirred for a further 20 min. The reaction was quenched with MeOH, concentrated in vacuo and partitioned between ethyl acetate and brine. The organic phase was concentrated in vacuo to afford a colourless glass (91 mg) which was purified by preparative HPLC atpH = 4 to afford 2,4-jb/s(benzyloxy)-5-chloro-N-(4-{[(4- methoxyphenyl)methyl](methyl)carbamoyl}phenyl)benzamide as a colourless solid (20 mg, 25%).

LC/MS (method B): RT = 1.08 min; m/z = 532 [M+H] ⁺ . Total run time 1.90 mins.

¹ H NMR (d ₆ DMSO): δ 2.82 and 2.65 (s, 3H), 3.73 (s, 3H), 4.23 (s, 1 H), 4.53 (s, 1 H), 5.08 (s, 1 H), 6.28 (s, 1 H), 6.81-6.98 (m, 3H), 7.05 (s, 1 H), 7.10 (s, 1 H), 7.10-7.37 (m, 6H), 7.72 (d, 1 H, J = 7.4 Hz), 8.34 (s, 1 H), 8.42 (s, 1 H), 8.48 (s, 1 H).

This compound had activity 'A' in the fluorescence polarization assay described above.

Example 192 N-(4-{[(4-chlorophenyl)methyl]carbamoyl}phenyl)-2,4-dihydrox y-N-(pyridin- 3-ylmethyl)benzamide

Step 1

4-[N-(pyridin-3-ylmethyl)2,4-bis(acetyloxy)benzamido]benz oic acid [C0004] (100 mg, 0.22 mmol) was dissolved in dry DCM (4 mL). Oxalyl chloride (0.11 mL, 0.33 mmol) was added followed by DMF (few drops). Reaction mixture was allowed to stir at RT for 45 mins. Solvent was removed in vacuo to afford a yellow gum. The reaction mixture was re-dissolved in dry DCM (4 mL), cooled to 0 ^° C, Et ₃ N (0.14 mL, 0.98 mmol) was added, followed by (4- chlorophenyl)methanamine (47.37 mg, 0.33 mol) and reaction mixture was stirred at RT for 1 h. 7N NH ₃ in MeOH solution (1 mL) was added and the reaction mixture was left stirring at RT overnight. The reaction mixture was washed with water (1 x 30 mL) and the aqueous layer was extracted with DCM (2 x 30 mL). Organic layers were combined, washed with brine (1 x 30 mL), dried (phase separator) and solvent removed in vacuo to afford a yellow gum. Crude product was purified by automated column chromatography, eluting with EtOAc / Hexane (0-100%). Fractions found to contain product were combined and solvent removed in vacuo to afford N-(4-{[(4- chlorophenyl)methyl]carbamoyl}phenyl)-2,4-dihydroxy-N-(pyrid in-3- ylmethyl)benzamide as a white solid (57 mg, 53%). LC/MS (method B): RT = 1.10 min; m/z = 488 [M+H] ⁺ . Total run time 1.90 mins.

¹ H NMR (d ₆ DMSO): δ 4.38 (d, 2H, J = 5.7Hz), 5.1 1 (s, 2H), 6.06-6.09 (m, 2H), 6.94 (dd, 1 H, J = 5.9, 2.7 Hz), 7.15 (d, 2H, J = 8.6 Hz), 7.27 - 7.38 (m, 5H), 7.66 (d, 2H, J = 8.6 Hz), 7.47 (dt, 2H, J = 7.2, 1.7 Hz), 8.42 (dd, 1 H, J = 4.5, 1.4 Hz), 8.48 (d, 1 H, J = 1.78 Hz), 8.98 (t, 1 H, J = 5.9 Hz), 9.59 (brs, 1 H), 9.83 (s, 1 H). This compound had activity 'B' in the fluorescence polarization assay described above. The examples listed in Table 6 were prepared by the methods outlined for Example 191 with intermediate B0004 and the appropriate amide or example 192 using intermediates C0004 and the appropriate amine.

TABLE 6

Z /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

991 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

99 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV 212 B 1 .15 [M+H]+ 518 A

* Activity in the fluorescence polarization assay described above. Example 213

N-benzyl-N-[4-(5-{[2-(dimethylamino)ethyl]sulfamoyl}-3-me thylpyridin-2- yl)phenyl]-2,4-dihydroxybenzamide

Step 1

3-(acetyloxy)-4-{benzyl[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]

carbamoyl}phenyl acetate [D0006], 100 mg, 0.18 mmol) was dissolved in tetrahydrofuran (4.5 mL) and water (0.5 mL) in a microwave vial. Potassium carbonate (78 mg, 0.54 mmol) and 6-chloro-N-[2-(dimethylamino)ethyl]-5- methylpyridine-3-sulfonamide (intermediate A0003, 61 mg, 0.22 mmol) were added, and the microwave vial was degassed with nitrogen for 5 minutes. [1 ,1 '- jb/s(diphenylphosphino)ferrocene]dichloropalladium (II) (0.018 mmol) was then added and the vial was purged again with nitrogen. The reaction was then heated to 120 C in a microwave for 40 minutes. To the cooled reaction mixture was added ammonia in methanol solution (7N, 2.0 mL) and mixture stirred overnight. Reaction mixture was diluted with EtOAc and washed with H ₂ 0; the organics were dried over MgS0 ₄ and concentrated under reduced pressure. The residual gum was then purified by flash chromatography on silica gel using a solvent gradient of 0 to 5% MeOH in DCM to afford product as a yellow foam (71 mg).

LC/MS (method A): RT = 2.00 min; m/z = 561 [M+H] ⁺ . Total run time 3.75 mins.

¹ H NMR (d ₆ DMSO): δ 2.04 (s, 6H), 2.25 (t, 2H, J = 6.8 Hz), 2.30 (s, 3H), 2.89 (t, 2H, J = 6.5 Hz), 3.33 (brs, 2H), 5.1 1 (s, 2H), 6.07 (dd, 1 H, J = 8.3, 2.3 Hz), 6.91 (d, 1 H, J = 8.6 Hz), 7.16 (d, 2H, J = 8.6 Hz), 7.20-7.25 (m, 1 H), 7.29-7.36 (m, 4H), 7.40 (d, 2H, J = 8.6 Hz), 7.69 (brs, 1 H), 8.05 (d, 1 H, J = 1.6 Hz), 8.77 (d, 1 H, J = 1.7 Hz), 9.57 (s, 1 H), 9.95 (s, 1 H).

This compound had activity 'B' in the fluorescence polarization assay described above. The examples listed in Table 7 were prepared by the method outlined for Example 213 using intermediates D0006 and the appropriate intermediate from the set [A0001 to A0022] previously described.

TABLE 7

LCMS RETENTION

STRUCTURE ADDUCT m/z activity*

METHOD TIME (min)

^NH

/

o=s =o

A 1 .23 [M+H]+ 504 B

OH 0

A 2.58 [M+H]+ 580 B

09 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV oύ N

I

=s=o

219 A 2.08 [M+H]+ 573 A

OH 0

220 A 2.52 [M+H]+ 562 B

OH 0

HN

0= =0

221 A 2.25 [M+H]+ 575 A

/.8Z£0/H0ZaO/13d SZtOtO/SlOZ OAV

/.8Z£0/H0ZaO/I3d SZtOtO/SlOZ OAV

* Activity in the fluorescence polarization assay described above. Example 229

5-chloro-N-[(3-cyanophenyl)methyl]-N-[4-(dimethylcarbamoy l)phenyl]-2,4- dihydroxybenzamide

Step 1

N,N-dimethyl-4-nitrobenzamide

4-nitrobenzoic acid (6.50 g, 40 mmol), 2-(1 H-Benzotriazole-1 -yl)-1 , 1 ,3,3- tetramethylaminium tetrafluoroborate (15.62 g), and dimethylamine hydrochloride (15.86 g, 190 mmol) were added to DMF (50 mL). Hunig's base (34 ml_) was added in portions at RT and mixture stirred at rt for 1 hour. The mixture was partitioned between EtOAc and 1 M HCI (aq). Organic phase was washed with saturated sodium bicarbonate solution, water, dried (magnesium sulphate) then concentrated to give a cream solid which was crystallised from ether to give white needles. The aqueous phase was extracted with DCM and then DCM phase separated, washed with saturated sodium bicarbonate solution, water, dried and concentrated to give a light yellow solid. The product was crystallised from ether to afford product as white needles. Combined yield 5.28 g, (70%). LC/MS (method A): RT = 1.60 min; m/z = 195 [M+H] ⁺ . Total run time 3.75 mins. Step 2

4-Amino-N,N-dimethylbenzamide

A solution of N,N-dimethyl-4-nitrobenzamide (2.0 g, 10 mmol) in EtOAc (20 ml_) was added to a flask containing 10% Pd/C under a nitrogen atmosphere. The reaction was placed under a hydrogen atmosphere, where it was shaken overnight. The reaction mixture was diluted with methanol (10 ml_) filtered through a pad of Celite (pre-washed with EtOAc) then eluted with further EtOAc. The combined filtrate solvents were removed in vacuo to afford a light yellow solid (1.69 g, 65%).

LC/MS (method A): RT = 0.41 min; m/z = 165 [M+H] ⁺ . Total run time 3.75 mins.

Step 3

4-{[(3-cyanophenyl)methyl]amino}-N,N-dimethylbenzamide

To a solution of 4-Amino-N,N-dimethylbenzamide (50 mg, 0.30 mmol) in DCM (20 ml_) was added 3-cyanobenzaldehyde (42 mg, 0.32 mmol), followed by tnacetoxyborohydnde (322 mg). Mixture was stirred at rt for 1 hour. A further 25mg of aldehyde was added and stirring continued at RT for a further hour. The mixture was concentrated in vacuo then partitioned between EtOAc and saturated sodium bicarbonate solution. Organic phase was separated and washed with water, dried (magnesium sulphate) then concentrated in vacuo to give a clear oil which was triturated with ethanol/hexane mixture to afford 4-{[(3- cyanophenyl)methyl]amino}-N,N-dimethylbenzamide as a colourless solid (68 mg, 80%).

LC/MS (method A): RT = 2.07 min; m/z = 280 [M+H] ⁺ . Total run time 3.75 mins. Step 4

2,4-bis(benzyloxy)-5-chloro-N-[(3-cyanophenyl)methyl]-N-[ 4- (dimethylcarbamoyl)phenyl]benzamide

Oxalyl chloride solution (2.0M in DCM, 5.12 ml_, 10. 24 mmol) was added drop- wise to a stirred solution of [B0004] 2,4-bis(benzyloxy)-5-chlorobenzoic acid ([B0004], 60 mg, 0.16 mmol) in DCM (5 ml_). DMF (few drops) were added and the reaction was stirred at RT for ca. 5 hours then the solvent was removed in vacuo. The resultant residue was re-dissolved in DCM (5 ml_) then triethylamine (0.14 ml_) followed by 4-{[(3-cyanophenyl)methyl]amino}-N,N- dimethylbenzamide (63 mg, 0.23 mmol) were added. The reaction was stirred at RT overnight then diluted with DCM and washed with sat. aq. NaHC0 ₃ solution followed by brine. The organic extract was dried over MgS0 ₄ then the solvent removed in vacuo. The crude product was triturated with cold EtOAc to afford product as a cream-coloured solid (81 mg). LC/MS (method A): RT = 2.71 min; m/z = 630 [M+H] ⁺ . Total run time 3.75 mins.

Step 5

5-chloro-N-[(3-cyanophenyl)methyl]-N-[4-(dimethylcarbamoy l)phenyl]-2,4- dihydroxybenzamide

To a solution of 2,4-bis(benzyloxy)-5-chloro-N-[(3-cyanophenyl)methyl]-N-[4- (dimethylcarbamoyl)phenyl]benzamide (81 mg) in DCM (5 mL) under a nitrogen atmosphere was added boron trichloride solution (1.0M in DCM, 2.0 mL). The reaction mixture was stirred at RT for 1 hour then quenched by drop-wise addition of methanol (2 mL). The reaction mixture was concentrated in vacuo to afford a solid which was purified by preparative HPLC at pH = 4, to afford 5- chloro-N-[(3-cyanophenyl)methyl]-N-[4-(dimethylcarbamoyl)phe nyl]-2,4- dihydroxybenzamide as a colourless solid (27 mg, 50%).

LC/MS (method A): RT = 2.15 min; m/z = 450 [M+H] ⁺ . Total run time 3.75 mins.

¹ H NMR (d ₆ DMSO): δ 2.76 (s, 3H), 2.90 (s, 3H), 5.10 (s, 2H), 6.29 (s, 1 H), 7.12 (d, 2H, J = 8.7 Hz), 7.13 (s, 1 H), 7.20 (d, 2H, J = 8.5 Hz), 7.53 (dd, 1 H, J = 7.8, 7.8 Hz), 7.68 (d, 1 H, J = 8.4 Hz), 7.71 (d, 1 H, J = 7.5 Hz), 7.83 (s, 1 H), 10.03 (s, 1 H), 10.3 (brs, 1 H).

This compound had activity 'B' in the fluorescence polarization assay described above. Example 230

N-benzyl-2,4-dihydroxy-N-{4-[methyl(quinolin-2- ylmethyl)carbamoyl]phenyl}benzamide

4-[N-benzyl-2,4-bis(acetyloxy)benzamido]benzoic acid [C0005] (100 mg, 0.22 mmol) was dissolved in dry DCM (4 mL). Oxalyl chloride (0.11 mL, 0.33 mmol) was added followed by DMF (few drops). Reaction mixture was allowed to stir at RT for 45 mins. Solvent was removed in vacuo to afford a yellow gum. The reaction mixture was re-dissolved in dry DCM (4 mL), cooled to 0 ^° C, Et ₃ N (0.14 mL, 0.98 mmol) was added, followed by methyl(quinolin-2-ylmethyl)amine (57.6 mg, 0.33 mmol) and reaction mixture was stirred at RT for 1 h. 7N NH ₃ in MeOH solution (1 mL) was added and the reaction mixture was left stirring at RT overnight. The reaction mixture was washed with water (1 x 30 mL) and the aqueous layer was extracted with DCM (2 x 30 mL). Organic layers were combined, washed with brine (1 x 30 mL), dried (phase separator) and solvent removed in vacuo to afford a yellow gum. Crude product was purified by automated column chromatography, eluting with EtOAc / Hexane (0-100 %). Fractions found to contain product were combined and solvent removed in vacuo to afford N-benzyl-2,4-dihydroxy-N-{4-[methyl(quinolin-2- ylmethyl)carbamoyl]phenyl}benzamide as a pale-yellow solid (87 mg, 75%).

LC/MS (method B): RT = 1.29 min; m/z = 518 [M+H] ⁺ . Total run time 1.90 mins. ¹ H NMR (d ₆ DMSO): 5 2.94 (s, 3H), 4.76 (brs, 2H), 5.04 (s, 2H), 6.03 (dd, 1 H, J = 8.2, 2.3 Hz), 6.15 (d, 1 H, J = 2.3 Hz), 6.80 (d, 1 H, J = 8.4 Hz), 7.10 (d, 2H, J = 8.1 Hz), 7.16-7.23 (m, 1 H), 7.24-7.40 (m, 7H), 7.56-7.60 (m, 1 H), 7.72-7.77 (m, 1 H), 7.95 (d, 1 H, J = 7.2 Hz), 7.98 (d, 1 H, J = 8.5 Hz), 8.30 (d, 1 H, J = 8.4 Hz), 9.31 (brs, 1 H), 9.89 (s, 1 H). This compound had activity 'B' in the fluorescence polarization assay described above.

The examples listed in Table 8 were prepared by the methods outlined for Example 229 with the appropriate acid intermediate [B] and the appropriate amide or example 230 using intermediate C0005 and the appropriate amine. TABLE 8

LCMS RETENTION activity activity

STRUCTURE ADDUCT m/z

METHOD TIME (min) (X) 00

B 1 .15 [M+H]+ 425 A

Oil /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

I /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

/.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

9 /.8Z£0/H0ZaO/I3d SZtOtO/STOZ OAV

91 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

II /.8Z£0/H0ZaO/13d SZtOtO/SlOZ OAV

X - Activity in Fluorescence polarisation assay described above; Y - Activity in Delfia assay described above.

Example 241 and 242 were prepared from example 237 by preparative HPLC 5 with a chiral stationary phase.

Example 264

N-benzyl-N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-2, 4- dihydroxybenzamide

3-(acetyloxy)-4-{benzyl[4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]

carbamoyl}phenyl acetate (intermediate [D0006], 100 mg, 0.19 mmol), 2,4- dichloro-5-methylpyrimidine (30.8 mg, 0.19 mmol), potassium carbonate (78.8 mg, 0.57 mmol), and [1 ,1 '-jb/s(diphenylphosphino)ferrocene]dichloropalladium (II) (14.6 mg, 0.019 mmol) were combined, dissolved in THF/H ₂ 0 (4.5 ml_ : 0.5 ml_), and the mixture degassed by bubbling nitrogen gas through for 5 mins. The reaction mixture was then stirred at RT overnight (or in a microwave synthesiser at 120°C for 40 mins). Methanolic ammonia solution (7N, 1 ml_) was added to the mixture and mixture was stirred at room temperature overnight. The crude reaction mixture was dissolved in DCM (25 ml_), and the organic layer was washed in water. The crude product was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 40% EtOAc in hexane to afford N-benzyl- N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-2,4-dihydroxyb enzamide as a colourless solid (36.7 mg, 44%).

LC/MS (method A): RT = 2.51 min; m/z = 446 [M+H] ⁺ . Total run time 3.75 mins. ¹ H NMR (d ₆ DMSO): δ 2.24 (s, 3H), 5.1 1 (s, 2H), 6.07-6.12 (m, 2H), 6.94 (d, 1 H, J = 8.26 Hz), 7.17-7.25 (m, 3H), 7.28-7.36 (m, 4H), 7.51 (d, 2H, J = 8.6 Hz), 8.65 (s, 1 H), 9.59 (s, 1 H), 9.87 (s, 1 H).

This compound had activity 'A' in the fluorescence polarization assay described above.

Example 265

2,4-dihydroxy-N-[4-(3-methylquinolin-2-yl)phenyl]-N-{[3- (trifluoromethyl)phenyl]methyl}benzamide

Step 1

3-methyl-2-(4-nitrophenyl)quinoline

2-chloro-3-methylquinoline (1.00 g, 5.65 mmol), (4-nitrophenyl)boronic acid (1.20 g, 7.22 mmol), and Pd(PPh ₃ ) ₂ CI ₂ catalyst (19.7 mg) was added to DME (16 ml_) in a microwave vial. 2M aqueous potassium carbonate was added (4 ml_) added, vial capped and then mix degassed with nitrogen before being irradiated in the microwave at 120°C for 1 hour. The reaction mixture was partitioned between ethyl acetate and sat. aqueous sodium bicarbonate solution. Organic phase was washed with water, dried (MgSO ₄ ) and concentrated to give a light tan solid, which was purified by flash chromatography on silica gel (40g), eluting with a gradient of 20-50% EtOAc in hexane to give a light-cream solid (1.32 g, 88%).

Step 2

4-(3-methylquinolin-2-yl)aniline

To a solution of 3-methyl-2-(4-nitrophenyl)quinolone (1.25 g, 4.73 mmol) in ethyl acetate (100 mL) under nitrogen atmosphere was added a catalytic amount of 10% palladium on carbon. The flask was purged with hydrogen gas and shaken for 4 hours under Hydrogen atmosphere. The mixture was filtered through sodium sulphate, then evaporated to give an orange crystalline solid (1.1 g, 99%). Used without further purification.

Step 3

2,4-bis(benzyloxy)-N-[4-(3-methylquinolin-2-yl)phenyl]ben zamide

HATU (2.22 g, 5.84 mmol) was added to a solution of 2,4-bis(benzyloxy)benzoic acid ([B0003], 1.30 g, 3.38 mmol) in anhydrous acetonitrile in a microwave vial, followed by diisopropyethylamine (2.0 mL, 1 1.6 mmol). The mixture was stirred for 5 minutes then a solution of 4-(3-methylquinolin-2-yl)aniline (1.09 g, 4.65 mmol) in acetonitrile was added and the mixture was heated at 80°C for 1 hour. The mixture was allowed to cool then evaporated in vacuo and the residue treated with EtOAc and 1 N HCI (aq) solution. The yellow solid was filtered off and washed with water then cold EtOAc, and dried in vacuo to afford product as a yellow solid (1.49, 69%).

LC/MS (method A): RT = 2.70 min; m/z = 551 [M+H] ⁺ . Total run time 3.75 mins. Step 4 2,4-dihydroxy-N-[4-(3-methylquinolin-2-yl)phenyl]-N-{[3- (trifluoromethyl)phenyl]methyl}benzamide

To a solution of 2,4-bis(benzyloxy)-N-[4-(3-methylquinolin-2- yl)phenyl]benzamide (22 mg, 0.04) in toluene (2ml_) was added 1 - (bromomethyl)-3-(trifluoromethyl)benzene (14 mg, 0.06), K ₂ C0 ₃ (27 mg), KOH (22 mg) and tetrabutylammonium hydrogen sulphate (1 mg) and the mixture was heated in in a microwave synthesiser at 120°C for 60 min. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate and the combined organics dried over MgS0 ₄ and solvents evaporated in vacuo to give a crude product that was suspended in anhydrous DCM (2 mL) and then boron trichloride solution was added (1.0M in DCM, 0.12 mL). The mixture was stirred for 30 minutes then quenched by addition of methanol (1 mL), Solvents were evaporated and the crude product purified by prep HPLC to afford product as off-white solid (5 mg). LC/MS (method A): RT = 2.74 min; m/z = 529 [M+H] ⁺ . Total run time 3.75 mins.

The examples listed in Table 9 were prepared by the methods outlined for Example 264 with the appropriate boronic acid ester intermediate [D] and the appropriate halide, or example 265 using the appropriate amide and the appropriate benzylic halide.

TABLE 9

98 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

299 B 1.26 [M-H]- 424.2 B

OH 0

300 B 1.25 [M+Ac]+ 426.2 B

OH 0

301 B 1.20 [M-H]- 410 C

OH O

302 A 2.48 [M+H]+ 450.3 C

OH O

303 B 1.23 [M+H]+ 477.2 D

OH O

6 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/SlOZ OAV

Ζ6 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/SlOZ OAV

86 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/STOZ OAV

66 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

02 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/SlOZ OAV

202 /.8Z£0/H0ZaO/13d s∑;tOtO/ST0∑: OAV 363 A 2.66 [M+H]+ 479 A

OH 0

364 A 2.66 [M+H]+ 479 B

OH 0

365 A 2.70 [M+H]+ 475 A

OH 0

X - Activity in Fluorescence polarisation assay described above; Y - Activity in Delfia assay described above

Example 366

5 N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-({4-[(2,2- difluoroacetamido)methyl]phenyl}methyl)-2,4-dihydroxybenzami de

A mixture of tert-butyl N-[4-(tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]carbamate (Fluorochem, 6.00 g, 18.8 mmol), 2,4-dichloro-5- methylpyrimidine (3.83 g, 23.50 mmol) and potassium carbonate (7.79 g, 56.4 mmol) in THF (90 mL) and water (10 mL) was degassed by bubbling nitrogen gas through the mixture for 5 minutes. [1 ,1 '- jb/s(diphenylphosphino)ferrocene]dichloropalladium (II) (687 mg, 0.94 mmol) was added and the mixture was heated at 60°C overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature and partitioned between EtOAc (200 mL) and water (200 mL). The phases were separated and the organic phase was dried (MgS0 ₄ ), filtered and filtrate solvents removed in vacuo to afford crude product as an oil which was purified by flash column chromatography on silica gel, eluting with a gradient of hexane to 50% hexane in EtOAc to afford tert-butyl N-{[4-(2-chloro-5-methylpyrimidin-4- yl)phenyl]methyl}carbamate as a pale yellow gum (6.63 g).

LC/MS (method A): RT = 2.59 min; m/z = 320 [M+H] ⁺ . Total run time 3.75 mins.

Step 2 4-(2-chloro-5-methylpyrimidin-4-yl)aniline

To a stirred solution of tert-butyl-N-[4-(2-chloro-5-methylpyrimidin-4- yl)phenyl]carbamate (6.01 g, 18.8 mmol) in DCM (100 mL) at room temperature was added trifluoroacetic acid (7.20 mL, 94 mmol). The resulting mixture was left on standing at room temperature for 16 h. The reaction mixture was evaporated below 50 °C and then co-evaporated in vacuo with toluene (3 x 20 mL) to give the [4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]methanamine as the triflouroacetic acid salt (8.3 g). Used without further purification.

LC/MS (method A): RT = 2.04 min; m/z = 220 [M+H] ⁺ . Total run time 3.75 mins. Step 3 tert-butyl-N-{[4-({[4-(2-chloro-5-methylpyrimidin-4- yl)phenyl]amino}methyl)phenyl]methyl}carbamate

tert-butyl N-[(4-formylphenyl)methyl]carbamate (Maybridge UK, 1.00 g, 4.25 mmol) and 4-(2-chloro-5-methylpyrimidin-4-yl)aniline (TFA salt, 1.42 g, 4.25 mmol) were dissolved in DCM (100 mL) and sodium triacetoxyborohydride (0.99 g, 4.68 mmol) was added followed by acetic acid (4.25 mmol). The reaction mixture was stirred at RT for 16 hr. The mixture was then cooled to 0°C and NaOH solution (1.0M, 100 mL) was added and the phases were separated. The aqueous phase was re-extracted with DCM (3 x 20 mL) and the combined organics were washed with sat NaCI (aq), dried over MgS0 ₄ and filtered. The filtrate solvents were solvents removed in vacuo to afford crude product as an oil which was purified by flash column chromatography on silica gel, eluting with a gradient of hexane to 100% hexane in EtOAc to afford tert-butyl-N-{[4-({[4-(2- chloro-5-methylpyrimidin-4-yl)phenyl]amino}methyl)phenyl]met hyl}carbamate as a yellow gum (1.8 g).

LC/MS (method A): RT = 2.71 min; m/z = 383. Total run time 3.75 mins. Step 4 tert-butyl-N-{[4-({1-[2,4-bis(benzyloxy)phenyl]-N-[4-(2-chlo ro-5- methylpyrimidin-4-yl)phenyl]formamido}methyl)phenyl]methyl}c arbamate

Oxalyl chloride (2.0M in DCM, 10.65 mL, 21.3 mmol) was added to a stirred solution of 2,4-bis(benzyloxy)benzoic acid ([B0003], 4.27 g, 12.78 mmol) in DCM (100 mL). Two drops of DMF were added and the reaction was stirred at RT for ca 2 hour min then the solvent removed in vacuo. The resultant residue was dissolved in DCM (100 mL) then triethylamine (21.30 mmol) was added followed by ferf-butyl-N-{[4-({[4-(2-chloro-5-methylpyrimidin-4- yl)phenyl]amino}methyl)phenyl]methyl}carbamate (1.87 g, 4.26 mmol). The reaction mixture was stirred at RT overnight, then diluted with DCM and washed with sat. aq. NaHC0 ₃ solution followed by brine. The organic extract was dried (MgS0 ₄ ) then the solvent removed in vacuo and the crude product was purified by flash column chromatography on silica gel eluting with 0 to 100% EtOAc in hexane to afford product as a yellow foam (2.04 g, 64%).

LC/MS (method A): RT = 1.50 min; m/z = 699 [M-t-Butyl+H] ⁺ . Total run time 3.75 mins. Step 5

N-{[4-(aminomethyl)phenyl]methyl}-2,4-bis(benzyloxy)-N-[4 -(2-chloro-5- methylpyrimidin-4-yl)phenyl]benzamide

Trifluoroacetic acid (0.27 mL) was added drop-wise to a stirred solution of tert- butyl-N-{[4-({1 -[2,4-bis(benzyloxy)phenyl]-N-[4-(2-chloro-5-methylpyrimidin -4-yl) phenyl]formamido}methyl)phenyl]methyl}carbamate (264 mg, 0.35 mmol) in anhydrous DCM (2 mL) under a nitrogen atmosphere. The reaction mixture was evaporated in vacuo and then DCM was added (30 mL). The solution was washed with sat NaHC0 ₃ solution (2 x 30 mL), sat. NaCI (aq) solution (1 x 30 mL), then dried over MgS0 ₄ . The mixture was filtered and the filtrate evaporated to a brown oil which was dried under high vacuum to afford a brown oil (174 mg, 76%). Step 6

2,4-bis(benzyloxy)-N-[4-(2-chloro-5-methylpyrimidin-4-yl) phenyl]-N-({4- [(2,2-difluoroacetamido)methyl]phenyl}methyl)benzamide

N-{[4-(aminomethyl)phenyl]methyl}-2,4-bis(benzyloxy)-N-[4 -(2-chloro-5- methylpyrimidin-4-yl)phenyl]benzamide (90 mg, 0.12 mmol) and HATU (91 mg, 0.12 mmol) were dissolved in acetonitrile (2 mL) in a microwave vial. Difluoroacetic acid (1 1.2 mg, 0.12 mmol) was added followed by diisopropylethylamine (0.08 mL, 0.48 mmol). The mixture was heated in a microwave synthesiser at 80°C for 1 hour then allowed to cool. Solvents were removed in vacuo and the solid was purified by flash column chromatography on silica gel eluting with 0 to 100% EtOAc in hexane to afford product as an off- white gum (46 mg, 56%).

LC/MS (method A): RT = 2.80 min; m/z = 733 [M+H] ⁺ . Total run time 3.75 mins. Step 7

N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-({4-[(2,2 - difluoroacetamido)methyl]phenyl}methyl)-2,4-dihydroxybenzami de

2,4-bis(benzyloxy)-N-[4-(2-chloro-5-methylpyrimidin-4-yl) phenyl]-N-({4-[(2,2- difluoroacetamido)methyl]phenyl}methyl)benzamide (46 mg, 0.06 mmol) was dissolved in anhydrous DCM (10 mL) and the mixture was cooled under a nitrogen atmosphere to -78°C with solid C0 ₂ acetone bath. Boron trichloride solution was added (1.0M in DCM, 0.3 mL, 0.3 mmol) and the mixture stirred for 30 mins at -78°C and then for 4 hours at RT. The mixture was re-cooled to - 78°C and quenched with methanol. The reaction warmed to RT then evaporated in vacuo to give a crude solid which was purified by flash column chromatography on silica gel eluting with 0 to 10% MeOH in DCM to afford product as off-white solid. Further purification by preparative HPLC at pH = 4 afforded N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-({4-[(2,2- difluoroacetamido)methyl]phenyl}methyl)-2,4-dihydroxybenzami de as a colourless solid (6 mg).

LC/MS (method A): RT = 2.33 min; m/z = 553 [M+H] ⁺ . Total run time 3.75 mins. ¹ H NMR (d ₆ DMSO): δ 2.27 (s, 3H), 4.30 (d, 2H, J= 6.1 Hz), 5.10 (s, 2H), 6.09 (dd, 1H, J= 8.3, 2.3 Hz), 6.12 (d, 1H, J= 2.3 Hz), 6.26 (t, 1H, J _H-F = 53.5 Hz), 6.93 (d, 1H, J = 8.3 Hz), 7.19 - 7.23 (m, 4H), 7.31 (d, 2H, J= 8.0 Hz), 7.49 (d, 2H, J= 8.8 Hz), 8.65 (s, 1H), 9.30 (t, 1H, J= 6.0Hz), 9.49-9.79 (brs, 1H), 9.81- 10.02 (brs, 1H).

This compound had activity 'A' in the Delfia assay described above.

The example compounds listed in table 10 were prepared by way of the method outlined for example 366, using the appropriate acid in step 6.

TABLE 10

0 2 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/STOZ OAV

2 /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι SZtOtO/SlOZ OAV /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV /.8Z£0/H0ZaO/13d s∑;tOtO/STO∑: OAV 390 1 .20 [M+H]+ 573

Y - Activity in the Delfia assay described above. Example 391

N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-({4-[(3,3 -difluoropyrrolidin- 1-yl)methyl]phenyl}methyl)-2,4-dihydroxybenzamide

Step 1

4-({[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]amino}meth yl)benzaldehyde

This compound was prepared by way of the method outlined for Example 366 step 3 using benzene-1 ,4-dicarbaldehyde in place of tert-butyl N-[(4- formylphenyl)methyl]carbamate,. The crude product was was purified by flash column chromatography on silica gel, eluting with a gradient of hexane to 70% EtOAc in hexane to afford 4-({[4-(2-chloro-5-methylpyrimidin-4- yl)phenyl]amino}methyl)benzaldehyde as a yellow foam (971 mg, 49 mg).

LC/MS (method A): RT = 2.49 min; m/z = 338 [M+H] ⁺ . Total run time 3.75 mins. Step 2

2,4-bis(benzyloxy)-N-[4-(2-chloro-5-methylpyrimidin-4-yl) phenyl]-N-[(4- formylphenyl)methyl]benzamide

The title compound was prepared by way of the method outlined for Example 366 step 4. The crude product The crude product was was purified by flash column chromatography on silica gel, eluting with a gradient of hexane to 100% in EtOAc in hexane to afford 2,4-bis(benzyloxy)-N-[4-(2-chloro-5- methylpyrimidin-4-yl)phenyl]-N-[(4-formylphenyl)methyl]benza mide as a yellow gum (0.94 g, 50%).

LC/MS (method A): RT = 2.85 min; m/z = 654 [M+H] ⁺ . Total run time 3.75 mins Step 3

2,4-bis(benzyloxy)-N-[4-(2-chloro-5-methylpyrimidin-4-yl) phenyl]-N-({4- [(3,3-difluoropyrrolidin-1-yl)methyl]phenyl}methyl)benzamide

2,4-bis(benzyloxy)-N-[4-(2-chloro-5-methylpynmidin-4-yl)phen yl]-N-[(4- formylphenyl)methyl]benzamide (90 mg, 0.14 mmol) and 3,3-difluoropyrrolidine (20 mg, 4.25 mmol) were dissolved in DCM (100 mL) and sodium triacetoxyborohydride (30 mg, 0.15 mmol) was added followed by acetic acid (0.01 mL). The reaction mixture was stirred at RT for 2 hr. The mixture was then cooled to 0°C and NaOH solution (1.0M, 10 mL) was added and the phases were separated. The aqueous phase was re-extracted with DCM (3 x 10 mL) and the combined organics were washed with sat NaCI (aq), dried over MgS0 ₄ and filtered. The filtrate solvents were solvents removed in vacuo to afford crude product as yellow oil (91 mg).

LC/MS (method A): RT = 2.88 min; m/z = 745 [M+H] ⁺ . Total run time 3.75 mins.

Step 4

N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-({4-[(3,3 -difluoropyrrolidin- 1-yl)methyl]phenyl}methyl)-2,4-dihydroxybenzamide

The title compound was prepared by reaction of the bis benzyl protected compound (91 mg) with boron trichloride solution as previously described for example 366 (step 7). The final product was purified by preparative HPLC to afford N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-N-({4-[(3,3-di fluoropyrrolidin- 1-yl)methyl]phenyl}methyl)-2,4-dihydroxybenzamide as a colourless solid (14 mg).

LC/MS (method A): RT = 2.30 min; m/z = 565 [M+H] ⁺ . Total run time 3.75 mins. This compound had activity 'B' in the Delfia assay described above. Example 392

2,4-dihydroxy-N-[4-(3-methylquinolin-2-yl)phenyl]-N-{[4-( pyrrolidin-1- ylmethyl)phenyl]methyl}benzamide

2,4-bis(benzyloxy)-N-[4-(3-methylquinolin-2-yl)phenyl]-N-{[4 -(pyrrolidin-1 - ylmethyl)phenyl]methyl}benzamide [prepared by methods outlined in Examples 366 and 391 ; using 2-chloro-3-methylquinoline at 366 step 1 and pyrrolidine at 391 step 3] (1 17 mg, 0.16 mmol) was dissolved MeOH (3 mL) and cyclohexadiene (0.25 mL, 2.67 mmol) was added followed by catalytic amount of 10% palladium on carbon. The mixture was heated at reflux for 1 hour then allowed to cool and the mixture filtered through a pad of celite. Filtrate was evaporated in vacuo to afford a solid which was purified by flash column chromatography on silica gel, eluting with a gradient of hexane to 0 to 10% MeOH in DCM to afford 2,4-dihydroxy-N-[4-(3-methylquinolin-2-yl)phenyl]-N-{[4- (pyrrolidin-1 -ylmethyl)phenyl]methyl}benzamide as a colourless solid (33 mg, 37%).

LC/MS (method B): RT = 1.10 min; m/z = 544 [M+H] ⁺ . Total run time 1.90 mins.

This compound had activity 'B' in the Delfia assay described above.

The examples listed in Table 1 1 were prepared by way of the methods utilized in examples 366, 390 and 391. Corresponding 5- substituted resorcinol analogues were prepared by using the appropriate resorcinol acid intermediates [B004 and B005] at the appropriate step.

TABLE 1 1

6 2 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

Delfia assay described above.

Example 412

N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)-2, 4-dihydroxy-N-{[3- (pyrrolidin-1-ylmethyl)phenyl]methyl}benzamide

This compound was made by the route outlined in Scheme 10 below.

SCHEME 10

Step 1 4-bromo-N-{[3-(diethoxymethyl)phenyl]methyl}aniline

Prepared by the method outlined in Example 366 step 3. Step 2

2,4-bis(benzyloxy)-N-(4-bromophenyl)-N-{[3- (diethoxymethyl)phenyl]methyl}benzamide

Prepared by the method outlined in Example 366 step 4.

Step 3

2,4-bis(benzyloxy)-N-(4-bromophenyl)-N-[(3- formylphenyl)methyl]benzamide

2,4-bis(benzyloxy)-N-(4-bromophenyl)-N-{[3-

(diethoxymethyl)phenyl]methyl}benzamide (3.12 g, 4.58 mmol) was dissolved in chloroform (6 ml_), water (1.5 ml_) added followed by TFA (3 ml_). The reaction mixture was stirred overnight at RT. Diluted with DCM and washed with sat. NaHC0 ₃ , dried (MgS0 ₄ ) filtered and filtrate solvent was removed in vacuo to give a white foam 2.62 g (94%).

LC/MS (method A): RT = 2.87 min; m/z = 608 [M+H] ⁺ . Total run time 3.75 mins. Step 4

2,4-bis(benzyloxy)-N-(4-bromophenyl)-N-{[3-(pyrrolidin-1- ylmethyl)phenyl]methyl}benzamide

Prepared by the method outlined in Example 391 step 3.

Step 5

2,4-bis(benzyloxy)-N-{[3-(pyrrolidin-1-ylmethyl)phenyl]me thyl}-N-[4- (tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzamide

Prepared by the method outlined for intermediate [D0001] (Step 3). Step 6 2,4-bis(benzyloxy)-N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin -4-yl}phenyl)- N-{[3-(pyrrolidin-1-ylmethyl)phenyl]methyl}benzamide

Prepared by the method outlined in Example 39 step 1.

Step 7 N-(4-{2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl}phenyl)-2,4-d ihydroxy-N-{[3- (pyrrolidin-1-ylmethyl)phenyl]methyl}benzamide

Prepared by the method outlined in Example 366 step 7.

Crude product was purified by preparative HPLC at pH = 4 to afford the title compound as a colourless solid. LC/MS (method A): RT = 1.91 min; m/z = 554 [M+H] ⁺ . Total run time 3.75 mins.

¹ H NMR (d ₆ DMSO): δ 1.58-1.62 (m, 4H), 2.29-2.35 (m, 4H), 3.51 (s, 2H), 6.08 (dd, 1 H, J = 8.4, 2.3 Hz), 6.14 (d, 1 H, J = 2.0 Hz), 6.85 (d, 2H, J = 8.3 Hz), 7.10- 7.15 (m, 1 H), 7.22-7.26 (m, 4H), 7.65 (d, 1 H, J = 8.5 Hz), OH's not observed.

This compound had activity 'B' in the Delfia assay described above. The Examples listed in TABLE 12 were prepared by the route outlined in the scheme above and the methods used for example 412 using the appropriate amine for step 4 and the appropriate halide for step 6. Corresponding 5-Chloro resorcinol containing analogues use the intermediate [B0004] in step 2.

TABLE 12

LCMS RETENTION activity

EG STRUCTURE ADDUCT m/z

METHOD TIME (min) 00

922 /.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV

LZZ /.8Ζ£0/Η0Ζ3Ο/Ι3<Ι sztoto/sioz OAV

Y - Activity in Delfia assay described above. Example 428

N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-2,4-dihydro xy-N-({3-[2- (pyrrolidin-1-yl)ethoxy]phenyl}methyl)benzamide

SCHEME 1 1

Step 1 3-[2-(pyrrolidin-1 -yl)ethoxy]benzaldehyde

DMF (50 mL) was added to 3-hydroxybenzaldehyde (3.00 g, 24.6 mmol) and cesium carbonate (20.0 g, 61.42 mmol) and to the stirred mixture was added 1 - (2-chloroethyl)pyrrolidine hydrochloride (5.01 g, 29.5 mmol). The mixture was stirred at 50°C for 10 min then filtered through a phase separator and washed through with EtOAc (3 x 20 mL). The filtrate solvent was removed in vacuo and the residue dissolved in EtOAc (50 mL) washed with water (50 mL), dried (MgS0 ₄ ) and filtered, the filtrate solvent was removed in vacuo to give a pale- yellow oil (4.06 g), which was purified by flash chromatography on silica gel eluting with a gradient of 0-5% MeOH in DCM, to afford 3-[2-(pyrrolidin-1 - yl)ethoxy]benzaldehyde as a pale yellow oil 3.16 g (59%).

Step 2

4-bromo-N-({3-[2-(pyrrolidin-1-yl)ethoxy]phenyl}methyl)an iline

Prepared by the method outlined in Example 366 step 3. Step 3

2,4-bis(benzyloxy)-N-(4-bromophenyl)-N-({3-[2-(pyrrolidin -1- yl)ethoxy]phenyl}methyl)benzamide

Prepared by the method outlined in Example 366 step 4.

Step 4

2,4-bis(benzyloxy)-N-({3-[2-(pyrrolidin-1-yl)ethoxy]pheny l}methyl)-N-[4- (tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]benzamide

Prepared by the method outlined for intermediate [D0001] (Step 3).

Step 5

2,4-bis(benzyloxy)-N-[4-(2-chloro-5-methylpyrimidin-4-yl) phenyl]-N-({3-[2- (pyrrolidin-1-yl)ethoxy]phenyl}methyl)benzamide

Prepared by the method outlined in Example 39 step 1.

Step 6

N-[4-(2-chloro-5-methylpyrimidin-4-yl)phenyl]-2,4-dihydro xy-N-({3-[2- (pyrrolidin-1-yl)ethoxy]phenyl}methyl)benzamide

Prepared by the method outlined in Example 366 step 7.

LC/MS (method A): RT = 1.96 min; m/z = 559 [M+H] ⁺ . Total run time 3.75 mins.

¹ H NMR (d _e DMSO): δ 1.65-1.69 (m 4H), 2.25 (s, 3H), 2.51-2.56 (m, 4H), 2.79 (t, 2H, J = 5.8 Hz), 4.02 (t, 2H, J = 5.8 Hz), 5.07 (s, 2H), 6.08-6.13 (m, 2H), 6.77- 6.81 (m, 1 H), 6.89-6.96 (m, 3H), 7.18-7.23 (m, 3H), 7.50 (d, 2H, J = 8.8 Hz), 8.28 (s, 2H), 8.65 (s, 1 H), OH's not observed.

This compound had activity 'B' in the Delfia assay described above.

The Examples listed in TABLE 13 were prepared by the route outlined in the scheme above and the methods used for example 428 using the appropriate amine for step 1.

TABLE 13

Y - Activity in Delfia assay described above. Example 433

N-({4-[2-(diethylamino)ethoxy]phenyl}methyl)-2,4-dihydrox y-N-[4-(3- methylquinolin-2-yl)phenyl]benzamide

Step 1

2,4-bis(benzyloxy)-N-[(4-hydroxyphenyl)methyl]-N-[4-(3-me thylquinolin-2- yl)phenyl]benzamide

2,4-bis(benzyloxy)-N-{[4-(methoxymethoxy)phenyl]methyl}-N -[4-(3- methylquinolin-2-yl)phenyl]benzamide was prepared by the route and method outlined for example 428 utilising 4-(methoxymethoxy)benzaldehyde in place of 3-[2-(pyrrolidin-1 -yl)ethoxy]benzaldehyde for step 2 and 2-chloro-3- methylquinoline in place of 2,4-dichloro-5-methyl pyrimidine for step 5. Of this material, 200 mg (0.29 mmol) was mixed with pyridinium-p-toluenesulfonate (PTSA, 14 mg, 0.06 mmol) in iso-propanol (2 mL) and heated at 85°C for 4 hours. Further PTSA was added (50 mg) and the mixture heated overnight, allowed to cool to RT and reaction mixture partitioned between EtOAc (40 mL) and water (20 mL). Phases were separated and organic dried over magnesium sulphate, filtered and filtrate evaporated to a yellow oil (180 mg, 94%). Step 2

N-({4-[2-(diethylamino)ethoxy]phenyl}methyl)-2,4-dihydrox y-N-[4-(3- methylquinolin-2-yl)phenyl]benzamide

A mixture of 2,4-bis(benzyloxy)-N-[(4-hydroxyphenyl)methyl]-N-[4-(3- methylquinolin-2-yl)phenyl]benzamide (180 mg, 0.27 mmol), (2- bromoethyl)diethylamine hydrobromide (143 mg, 0.55 mmol) and cesium carbonate (537 mg, 1.65 mmol) in acetonitrile (2 mL) was heated at 80°C overnight. The mixture was allowed to cool to RT, partitioned between EtOAc and water, dried over magnesium sulphate and evaporated to an oil which was purified by flash chromatography on silica gel eluting with a gradient of 0 to 10% MeOH in DCM to a afford a brown oil (150 mg). The product of the alkylation was dissolved in MeOH (5 mL) and ammonium formate was added (170 mg, 0.27 mmol) followed by catalytic amount of 10% palladium on charcoal. The mix was heated overnight at reflux then cooled to RT. Solids were filtered and the filtrate evaporated and residue partitioned between EtOAc (40 mL) and water (40 mL) / aq ammonia solution (3 mL). Organic phase was dried (Mg SO ₄ ) filtered and evaporated to afford N-({4-[2-(diethylamino)ethoxy]phenyl}methyl)- 2,4-dihydroxy-N-[4-(3-methylquinolin-2-yl)phenyl]benzamide as a colourless foam (100 mg, 63%). LC/MS (method B): RT = 1.17 min; m/z = 576 [M+H] ⁺ . Total run time 1.90 mins.

This compound had activity ' in the Delfia assay described above.

The Examples listed in TABLE 14 were prepared by the general route outlined in scheme 1 1 above and the methods used for example 428 and 433 using the appropriate halide for cross coupling step, and the appropriate amine for alkylation step.

TABLE 14

LCMS RETENTION activity

EG Structure ADDUCT m/z

METHOD TIME (min) 00

432 B 0.99 [M+H]+ 555 D

433 B 1 .15 [M+H]+ 574 C

434 B 1 .03 [M+H]+ 541 D

435 B 1 .13 [M+H]+ 590 C

Y - Activity in Delfia assay described above Example 436 to 440

The compounds in Table 15 were prepared using the general route shown in schemes 3 and 4 and the intermediate [D0008] using the methods outlined for eg 264. Example 436 uses intermediate [A0002] at the appropriate step, examples 438 to 440 use commercially available chlorides at the appropriate step.

TABLE 15

LCMS RETENTION activity

EG STRUCTURE ADDUCT m/z

METHOD TIME (min) 00

436 B 1 .25 [M+H]+ 593 B

OH O Y A ti it i D lfi d ib d b

Example 441

N-benzyl-N-{4-[(ethylcarbamoyl)amino]phenyl}-2,4-dihydroxybe nzamide

Ethyl isocyanate (13.5 mg, 0.2 mmol) was added to a solution of intermediate [E0001] (40 mg, 0.10 mmol) in DCM (1 ml_) and pyridine (0.1 ml_). The mixture was stirred at RT for 1 hour. The reaction was concentrated in vacuo, and then partitioned between 1 M HCI and ethyl acetate. Organic phase was washed with water, dried over magnesium sulphate then concentrated to give the acetyl protected urea as an oil. This crude product was dissolved in methanol in ammonia solution (7N, 2 ml_) and stirred for 1 hour. The reaction mixture was concentrated then purified by preparative HPLC to afford product as a colourless solid (14 mg).

LC/MS (method B): RT = 1.17 min; m/z = 576 [M+H] ⁺ . Total run time 1.90 mins.

This compound had activity ' in the fluorescence polarization assay described above.

The compounds in Table 16 were prepared from intermediate [E0001] by the methods utilized for example 441.

TABLE 16 LCMS RETENTION activity

EG Structure ADDUCT m/z

METHOD TIME (min) (X)

442 B 1 .24 [M+H]+ 446 D

443 B 1 .04 [M+H]+ 455 C

^lj^l

444 B 1 .25 [M+H]+ 468 C

445 B 0.88 [M+H]+ 461 D

X - Activity in Fluorescence polarisation assay described above.

Example 446

N-(4-benzamidophenyl)-N-benzyl-2,4-dihydroxybenzamide

Step 1

This compound was prepared from intermediate [E0001] using the methods outlined for example 441 using the benzoyl chloride in place of ethyl isocyanate. The crude product was purified by preparative HPLC at pH = 4 to afford a colourless solid.

LC/MS (method B): RT = 1.24 min; m/z = 439 [M+H] ⁺ . Total run time 1.90 mins.

This compound had activity ' in the fluorescence polarization assay described above.

The compounds listed in Table 17 were prepared from intermediate [E0001] using the methods outlined for example 441 using the appropriate acid chloride.

TABLE 17

LCMS RETENTION activity

EG STRUCTURE ADDUCT m/z

METHOD TIME (min) (X)

/.8Z£0/H0ZaO/13d SZtOtO/STOZ OAV X - Activity in Fluorescence polarisation assay described above Example 449

N-benzyl-2,4-dihydroxy-N-(4-methanesulfonamidophenyl)benz amide

Step 1

This compound was prepared from intermediate [E0001] using the methods outlined for example 441 using methane sulphonyl chloride in place of ethyl isocyanate. The crude product was purified by preparative HPLC at pH = 4 to afford a light-pink solid. LC/MS (method B): RT = 1.1 1 min; m/z = 413 [M+H] ⁺ . Total run time 1.90 mins.

This compound had activity ' in the fluorescence polarization assay described above.

Examples 450 to 462.

The compounds in Table 18 were prepared by way of the general route outlined in scheme 6 and by way of the methods utilized for example 191 , using the appropriate halide for step 2.

LCMS RETENTION activity

EG STRUCTURE ADDUCT m/z

METHOD TIME (min) (X) a +ΙΗ+ΙΛΙ] g fr9fr

0

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0

α 63fr +ΙΗ+ΙΛΙ] Ι.6Ί. V 39fr

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0 Z8Z£0/H0ZaO/I3d SZtOtO/SlOZ OAV /.8Z£0/H0ZaO/I3d SZtOtO/SlOZ OAV The following biochemical data illustrate the invention:

MSD ELISA MSD ELISA

EXAMPLE EXAMPLE ASSAY ASSAY

9 C 342 B

22 c 378 B

38 c 380 B

71 c 382 B

80 c 401 B

91 c 405 B

114 c 415 C

177 c 423 C 175 C 430 C

212 C 432 C

225 D 433 c

228 C 433 c

259 C 438 c

263 C 436 c

346 B 459 c

Activity "A": IC ₅₀ = 10 nM to 99 nM

Activity "B": IC ₅₀ = 100 nM to 999 nM Activity "C": IC ₅₀ = 1.00 μΜ to 9.99 μΜ Activity "D": IC ₅₀ = 10 μΜ to 50 μΜ