AU2008286326A1

AU2008286326A1 - Treatment of Duchenne muscular dystrophy

Info

Publication number: AU2008286326A1
Application number: AU2008286326A
Authority: AU
Inventors: Olivier De Moor; Peter David Johnson; Cristina Lecci; Severine Poignant; Richard Storer; Renate Van Well; Stephen Paul Wren; Graham Michael Wynne
Original assignee: Summit Corp PLC
Current assignee: Biomarin IGA Ltd
Priority date: 2007-08-15
Filing date: 2008-08-14
Publication date: 2009-02-19
Also published as: GB0715939D0; MX2009012203A; WO2009021750A2; TW200914430A; CN102036972A; JP2010535831A; WO2009021750A3; CA2685605A1

Description

WO 2009/021750 PCT/EP2008/006720 TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY RELATED APPLICATION Priority is claimed herein to British application GB0715939.5, filed August 15, 2007, entitled "TREATMENT OF DUCHENNE MUSCULAR DYSTROPHY." The disclosure of 5 the above-referenced application is incorporated by reference herein in its entirety. FIELD Provided is a method of treatment of Duchenne muscular dystrophy. BACKGROUND Duchenne muscular dystrophy (DMD) is a common, genetic neuromuscular disease 10 associated with the progressive deterioration of muscle function, first described over 150 years ago by the French neurologist, Duchenne de Boulogne, after whom the disease is named. DMD has been characterized as an X-linked recessive disorder that affects 1 in 3,500 males caused by mutations in the dystrophin gene. The gene is the largest in the human genome, encompassing 2.6 million base pairs of DNA and containing 79 exons. 15 Approximately 60% of dystrophin mutations are large insertion or deletions that lead to frameshift errors downstream, whereas approximately 40% are point mutations or small frameshift rearrangements. The vast majority of DMD patients lack the dystrophin protein. Becker muscular dystrophy is a much milder form of DMD caused by reduction in the amount, or alteration in the size, of the dystrophin protein. The high incidence of DMD (1 in 20 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so an effective therapy is highly desirable. A number of natural and engineered animal models of DMD exist, and provide a mainstay for preclinical studies (Allamand, V. & Campbell, K. P. Animal models for muscular dystrophy: valuable tools for the development of therapies. Hum. Mol. Genet. 9, 25 2459-2467 (2000). Although the mouse, cat and dog models all have mutations in the DMD gene and exhibit a biochemical dystrophinopathy similar to that seen in humans, they show surprising and considerable variation in terms of their phenotype. Like humans, the canine (Golden retriever muscular dystrophy and German short-haired pointer) models have a severe phenotype; these dogs typically die of cardiac failure. Dogs offer the best phenocopy for 30 human disease, and are considered a high benchmark for preclinical studies. Unfortunately, breeding these animals is expensive and difficult, and the clinical time course can be variable among litters. 1 WO 2009/021750 PCT/EP2008/006720 The mdx mouse is the most widely used model due to availability, short gestation time, time to mature and relatively low cost (Bulfield, G., Siller, W. G., Wight, P. A. & Moore, K. J. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Natl A cad. Sci. USA 81, 1189-1192 (1984)). 5 Since the discovery of the DMD gene about 20 years ago, varying degrees of success in the treatment of DMD have been achieved in preclinical animal studies, some of which are being followed up in humans. Present therapeutic strategies can be broadly divided into three groups: first, gene therapy approaches; second, cell therapy; and last, pharmacological therapy. Gene- and cell-based therapies offer the fundamental advantage of obviating the 10 need to separately correct secondary defects/ pathology (for example, contractures), especially if initiated early in the course of the disease. Unfortunately, these approaches face a number of technical hurdles. Immunological responses against viral vectors, myoblasts and newly synthesized dystrophin have been reported, in addition to toxicity, lack of stable expression and difficulty in delivery. 15 Pharmacological approaches for the treatment of muscular dystrophy differ from gene- and cell-based approaches in not being designed to deliver either the missing gene and/or protein. In general, the pharmacological strategies use drugs/molecules in an attempt to improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment. These strategies 20 offer the advantage that they are easy to deliver systemically and can circumvent many of the immunological and/or toxicity issues that are related to vectors and cell-based therapies. Although investigations with corticosteroids and sodium cromoglycate, to reduce inflammation, dantrolene to maintain calcium homeostasis and clenbuterol to increase muscle strength, have produced promising results none of these potential therapies has yet been 25 shown to be effective in treating DMD. An alternative pharmacological approach is upregulation therapy. Upregulation therapy is based on increasing the expression of alternative genes to replace a defective gene and is particularly beneficial when an immune response is mounted against a previously absent protein. Upregulation of utrophin, an autosomal paralogue of dystrophin has been 30 proposed as a potential therapy for DMD (Perkins & Davies, Neuromuscul Disord, SI: S78 S89 (2002), Khurana & Davies, Nat Rev Drug Discov 2:379-390 (2003)). When utrophin is overexpressed in transgenic mdx mice it localizes to the sarcolemma of muscle cells and restores the components of the dystrophin-associated protein complex (DAPC), which 2 WO 2009/021750 PCT/EP2008/006720 prevents the dystrophic development and in turn leads to functional improvement of skeletal muscle. Adenoviral delivery of utrophin in the dog has been shown to prevent pathology. Commencement of increased utrophin expression shortly after birth in the mouse model can be effective and no toxicity is observed when utrophin is ubiquitously expressed, which is 5 promising for the translation of this therapy to humans. Upregulation of endogenous utrophin to sufficient levels to decrease pathology might be achieved by the delivery of small diffusible compounds. DESCRIPTION Provided are compounds which upregulate endogenous utrophin in predictive screens 10 and, thus, may be useful in the treatment of DMD. In one embodiment, provided is a compound of Formula (1) A1 Y(/ (R9

A

4 (1) 15 wherein

R

9 represents a C 5

-

10 carbocycle which is partially or fully aromatic containing 0-4 hetero atoms and optionally substituted by 1-4 halogen, Ci-C 6 alkyl, OCI-C 6 alkyl or NR 9 o(C=Q)

M-Z-R

93 wherein R 90 represents H or C 1

-

6 alkyl, Q represents 0, S, or NR 9 wherein R 91 represents H or C 1

-

6 alkyl, M represents C 1

-

3 alkyl optionally substituted with halogen, C 1

.

6 20 alkyl, or C 1

-

6 alkoxy, Z represents 0, S or NR 92 wherein R 92 represents H or C 1

-

6 alkyl and

R

93 represents a C 5 10 carbocycle which is partially or fully aromatic containing 0-4 hetero atoms and optionally substituted by 1-4 halogen, C 1

-C

6 alkyl or OC,-C 6 alkyl; three of A, A 2 , A 3 and A 4 represent CH, and one of A, A 2 , A 3 and A 4 represents CR wherein Ri represents: 25 an alkyl group selected from C 2

-C

3 alkyl, n-butyl and sec-butyl, optionally substituted with hydroxyl, halogen, carboxylic acid, piperidin-1-yl, N-morpholino, -NMe 2 or alkoxy (such as

C

1

-

6 alkoxy); hydroxyl, halogen, C0 2

(CI-

6 alkyl), or -O(Ci- 6 alkyl) or Ci alkyl substituted with hydroxyl, halogen, carboxylic acid, piperidin-1-yl, N-morpholino, -NMe 2 or alkoxy (such as 30 C 1

-

6 alkoxy); 3 WO 2009/021750 PCT/EP2008/006720 hydroxyl, halogen, C0 2

(C

1

-

6 alkyl), or -O(C 1

-

6 alkyl); -N-(S)-2-amino-3-hydroxypropionamide; -N-(S)-2-(methylamino)propionamide; -N-(S)-2-aminopropionamide; 5 -N-2-methylaminoacetamide;

-(S=O)R

21 , wherein R 21 represents Ci-C 6 alkyl; -SOnR 22 wherein n = 0, 1 or 2 and R 22 represents CH 3 , CH 2

CD

3 or C 3

-

6 alkyl, optionally substituted with OH or ethyl substituted with hydroxyl; -S0 2

NR

55

R

23 , wherein R 23 and R 55 which may be the same or different each represent H or 10 C 1 -6 alkyl;

-NR

56 SOnR 24 , wherein n = 0, 1 or 2 and R 24 and R 56 which may be the same or different each represent H or CI-C 6 alkyl; -K-SOn-R 28 , wherein K represents CI-C 3 alkyl optionally substituted with Ci-C 6 alkyl, n=0-2 and R 28 represents CI-C 10 alkyl optionally substituted with one or more hydroxy, halogen, 15 alkoxy (such as CI- 6 alkoxy) or amine; -C0 2

R

26 , wherein R 26 represents CI- 6 alkyl; disubstituted phosphinate, wherein each substituent which may be the same or different may represent Ci- 6 alkyl or C 5 .1 0 aryl; an N-linked mono- or bicylic ring substituted by one or more oxo, hydroxyl, halogen, CI- 6 20 alkyl, alkoxy (such as C 1

-

6 alkoxy) or aryl (such as C 5

-

10 aryl) substituent; or

NR

15

C(=W)R

1 7 wherein W represents NH, S or 0;

R

1 7 represents C 2 -alkyl, n-propyl, or C 4 -Cioalkyl; CI-CIO alkyl substituted with one or more halogen, hydroxyl, alkoxy (such as Ci- 6 alkoxy) or amine; a mono or disaccharide unit 25 attached at the anomeric position via a CI-C 4 alkyl group which is optionally substituted with one or more Ci- 6 alkyl group; CH 2 aryl, wherein aryl represents an aromatic hydrocarbon (such as a 5 to 10 membered aromatic hydrocarbon) or a 5 to 10 membered aromatic heterocyle containing 1 to 4 hetero atoms selected from an oxygen atom, a sulphur atom and a nitrogen atom as a ring constituent besides carbon; -CH 2 0CH 3 , -CH 2 0CH 2

CH

2 0CH 3 , 30 CH 2 piperidin-1-yl or CH 2 -N-morpholinoyl;

R

1 5 represents H, C 1

.

6 alkyl or together with R 17 represents -CH 2

CH

2 -, -CH 2

CH

2 -, or CH 2

CH

2

CH

2 -; X is 0 or N; and Y is 0 or N. 4 WO 2009/021750 PCT/EP2008/006720 Compounds of formula I may exist in tautomeric, enantiomeric and diastereomeric forms, all of which are included within the scope of this disclosure. Certain compounds of formula I are novel. Also provided are those compounds of formula I which are novel, together with processes for their preparation, compositions 5 containing them, as well as their use as pharmaceuticals. Some of the compounds falling within the scope of formula I are known, as such, but not as pharmaceuticals. Also provided are compounds known in the art as such, but not previously described for use as pharmaceuticals, as pharmaceuticals. The instant disclosure will now be described with reference to the accompanying 10 drawings in detail: Figure 1 shows a luciferase reporter assay (murine H2K cells). Figure 2 shows a dose dependent luciferase induction. Figure 3 shows an example of TA muscle sections stained with antibody specific for mouse utrophin. 15 Figure 4 shows that mice exposed to CPD-A (V2 and V3) showed increased levels of utrophin expression compared to control. All of the compounds of formula I may be made by conventional methods. Methods of making heteroaromatic ring systems are well known in the art. In particular, methods of synthesis are discussed in Comprehensive Heterocyclic Chemistry, Vol. 1 (Eds.: AR 20 Katritzky, CW Rees), Pergamon Press, Oxford, 1984 and Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982-1995 The Structure, Reactions, Synthesis, and Uses of Heterocyclic Compounds, Alan R. Katritzky (Editor), Charles W. Rees (Editor), E.F.V. Scriven (Editor), Pergamon Pr, June 1996. Other general resources which would aid synthesis of the compounds of interest include March's Advanced Organic Chemistry: 25 Reactions, Mechanisms, and Structure, Wiley-Interscience; 5th edition (January 15, 2001). Of particular relevance are the synthetic methods discussed in WO 2006/044503. Some general methods of synthesis are as follows. Benzoxazoles of formula I or pharmaceutically acceptable salts thereof may be prepared from compounds of formula II. 5 WO 2009/021750 PCT/EP2008/006720 R R R 0 R when R1=CO2H V.I R-cJ iv. N R v H Scheme 1 Reaction conditions: i. R 9

CO

2 H (or R 9 COCl), PPA, heat; or R 9 COCl, dioxane, microwave, then 5 NaOH ii. R 9 COCl, pyridine, rt (= room temperature) iii. TsOH, xylenes iv. R 9

CO

2 H, HATU, pyridine, DMF v. PPA, heat 10 vi. HATU, DMF, 'Pr 2 NEt, alkylNH 2 , rt Formation of the benzoxazole I can be carried out in a variety of ways, as illustrated above. For example, reaction of the compound of formula II with an acyl derivative, such as the acid or the acid chloride, and heating in an appropriate solvent and an appropriate 15 temperature in the presence of an acid catalyst, for example polyphosphoric acid. This is illustrated above as step (i). The reaction may be carried out in an aprotic solvent, in one embodiment a polar, aprotic solvent, for example tetrahydrofuran, and a temperature of from -10*C to +150*C. Generally the reaction may be carried on at the reflux temperature of the solvent at normal 20 pressure. Alternatively, the compound of formula II may first be reacted with an excess of an acyl derivative R 9 COX (where X is for example Cl), such that acylation takes place on both oxygen and nitrogen. This can be brought about by, for example, reaction in pyridine at 6 WO 2009/021750 PCT/EP2008/006720 room temperature (step ii). Ring closure to form the compound of formula II can then occur in a subsequent ring closure step in which, for example, the doubly acylated product is heated in xylenes in the presence of an acid catalyst such as a sulfonic acid (step iii). Another illustrative example of formation of a compound of formula I is shown by 5 steps iv and v. First the amine is coupled to an acid using a peptide coupling reagent. Available coupling reagents are well known to those skilled in the art, and include HBTU, TBTU and HATU. Amide formation in the presence of an appropriate coupling reagent occurs, for example, in DMF in the presence of a nucleophilic catalyst such as pyridine. When R1 = CO 2 H, this acid may be coupled with an amine as shown by step (vi). 10 Suitable coupling conditions include use of HATU in DMF in the presence of 'Pr 2 NEt,

R'

6

NH

2 at room temperature. Compounds in which the six membered ring is substituted with an amide derivative are of particular interest. These may be produced from an intermediate amine derivative III. OH H2N NH2 OI 2 iv. H 2 N III NH R VI OH 0|| Re v. vii --------- - > - R V. 0 2 N NH 2 0 2 N IV V R N - N ) 15 H IX R1 0 H R H Scheme 2 Reaction conditions: i. As for (i); Scheme 1 20 ii. R 7 COC, pyridine (or NEt 3 , DCM); or R 9

CO

2 H, HATU, pyridine, DMF iii. As for (i); Scheme 1 7 WO 2009/021750 PCT/EP2008/006720 iv. SnCl 2 , EtOH, heat; or Pd/C, H 2 , IMS; or Fe, NH 4 Cl, IMS / water, heat v. R 9 NCO, DCM, rt vi. NaBH(OAc) 3 , R' 0 CHO, DCE, rt 5 vii. R14S0 2 C, pyridine, DCM, rt Intermediate amine III may be synthesised either by using the method outlined in scheme 1, step (i) wherein R1 = NH 2 , or alternatively, in a two step process as defined by steps (iii) and (iv) of scheme 2. Nitro substituted benzoxazole derivative V is produced from 10 nitro substituted phenyl derivative IV, also in a method analogous to. that illustrated by scheme 1, step 1, and then the nitro-benzoxazole derivative V is reduced in a subsequent step to give intermediate amine III. The skilled person is well aware of suitable methods to reduce a nitro group to give an amine. Selective methods for reducing NO 2 to NH 2 include Sn/HCl, or H 2 /Pd/C in a suitable solvent, e.g. ethanol at a temperature of from 0* to 80 0 C or 15 heating in the presence of iron, NH 4 C1 in industrial methylated spirits / water. Intermediate amine III can then be coupled or derivatised as required (see scheme 2a for example). 2N 0R 9 1) HCI, NaNo 2 , H 2 0 R220-R mCPBA R

H

2 N N2) R 22 2HN CHO, 3 NaOH, Cu Scheme 2a 20 Amide derivatives of formula VI can be produced by coupling amine III with an acyl derivative. This can be achieved by, for example, reaction of an appropriate acid chloride in either pyridine, or in CH 2 Cl 2 (step ii). Sulfonamide derivatives VII can be produced by reaction of amine III with an appropriate sulfonyl chloride in, for example, CH 2 Cl 2 in the presence of pyridine.at room 25 temperature. Amine derivatives VIII can be produced by use of an appropriate reductive amination strategy. Methods of reductive amination are well known in the art. They include, for example, reaction of the amine with an appropriate aldehyde and sodium triacetoxyborohydride in 1,2-dichloroethane. 8 WO 2009/021750 PCT/EP2008/006720 Urea derivatives of formula IX can be produced, for example, by reaction of amine III with the appropriate isocyanate, for example, at room temperature in CH 2 Cl 2 . Benzothiazoles of formula X or pharmaceutically acceptable salts thereof may be prepared from compounds of formula XI. 0 2 N NH 2 02N NR 0 2 N N H XI .R R iv. H2 R H7 NIII"N R Na H2NC H 5 X Scheme 3 Reaction conditions: i. R 9 COCI, pyridine, rt ii. Na 2 S, S8, IMS, heat 10 iii. Fe, NH 4 Cl, IMS, heat iv.R1 7 COCl, pyridine (or NEt 3 , DCM); or R 7

CO

2 H, HATU, pyridine, DMF The compounds of formula XI can be converted to the corresponding amide by, for 15 example, reaction with the appropriate acid chloride in pyridine (step (i)), or by using an appropriate peptide coupling reagent. Such methods are well known to the person skilled in the art as discussed hereinabove. The amide can then be converted to the nitro-benzothiazole of formula XII in a one pot procedure involving reaction with Na 2 S, S8 at elevated temperature in industrial 20 methylated spirit. Nitro derivative XII can be reduced as discussed previously and the resulting primary amine manipulated in an analogous manner to the primary amine in scheme 2 steps (ii), (v), (vi) and (vii). 9 WO 2009/021750 PCT/EP2008/006720 H HH 01 NJ N -N HIN N a~R ~ N-i

NH

2 NHNN XIII XII X iv N H R v . N H R O2N No 2

O

2 N NO 2 0 2 N NH 0 2 ON N XIV 4 R

R

4 0 N ) H Scheme 4 Reaction conditions: 5 i. R 9

CO

2 H, PPA, heat; or R 9 COCI, pyridine; then PPA, heat ii. SnCl 2 , IMS, heat; or Pd/C, H 2 , IMS iii. R" 7 COCI, pyridine etc (as per Scheme 1) iv. R 4

NH

2 , DMSO, base, heat v. Sodium dithionite, THF / water; also see (ii) 10 Benzimidazoles of formula XII can be produced according to scheme 4. Reaction of a diaminophenyl derivative of formula XIII with an acyl derivative, such as an acid or an acid chloride in an appropriate solvent and at an appropriate temperature in the presence of an acid catalyst, for example polyphosphoric acid, produces a benzimidazole derivative of formula 15 XII. This is illustrated above as step (i). The nitro group may then be reduced and manipulated to produce other functionality as discussed hereinabove. Alternatively, benzimidazoles may be produced by reacting a di-nitro compound of formula XIV, wherein X represents a leaving group, in one embodiment a halogen such as chlorine or fluorine, with an amine, for example, in DMSO at elevated temperature in the 20 presence of a base. Subsequent selective reduction of one nitro group using sodium dithionite in THF/water can then take place to give a diamine of formula XV. Ring closure to form a benzimidazoles, and manipulation of the nitro group can then proceed as illustrated and discussed previously. 10 WO 2009/021750 PCT/EP2008/006720 A I O H A ' O H ii. A- 0 H N R XI 'NO R9 R X NH, X=NO2 2 XX XXI i.XB2 2~ iv. X=Br v. I Vi. O)-R R )>- R' Y=C, X=NO 2 R N XIX XVIII -= S - vii. )-cI H XXII XXIII 2 A' OH ~ 2,A 0O 3 Mw 3 >-R2 A4NH2 A N XVII XVI Scheme 5 Reaction conditions: 5 i. Na 2 S hydrate, MeOH, NH 4 Cl, water; or Na 2

S

2 0 4 / EtOH; or SnCl 2 , EtOH ii. As for (i), Scheme 1; or R 9 COCl, pyridine; then PPA, heat iii. SnCl 2 , EtOH, heat iv. R'B(OH) 2 , Pd(PPh 3

)

4 , K 2 C0 3 , dioxane / water, microwave 10 v. R 7 COC1, pyridine, rt vi. EtOC(S)SK, pyridine, heat vii. SOCl 2 ; or POCl 3 viii. R 3

B(OH)

2 , Pd(PPh 3

)

4 , K 2

CO

3 , solvent ix. PPA, R 2

CO

2 H heat 15 Benzoxazoles of formula XVI can be made by methods analogous to those discussed previously. For example the method illustrated above (ix) involves heating a compound of formula XVII in an appropriate solvent in the presence of acid catalyst and an appropriate acyl derivative eg a carboxylic acid. 20 Benzoxazoles of formula XVIII and XIX can be synthesised from the appropriate nitro compound of formula XX. Reduction of the nitro compound XX gives the 11 WO 2009/021750 PCT/EP2008/006720 corresponding amino alcohol XXI (for example using Sn / HCl, or any of the other appropriate methods well known to the person skilled in the art). Benzoxazole formation via reaction of the amino alcohol with an appropriate acyl derivative can then be achieved using any of the methods disclosed hereinabove. 5 For oxazoles of formula XXIII in which X = Br, a Suzuki coupling reaction can then be used to give further derivatives. An example of appropriate conditions are R'B(OH) 2 , Pd(PPh 3

)

4 , K 2 C0 3 , dioxane / water, ptwave, in which a benzoxazole of formula XIX results. The person skilled in the art is familiar with Suzuki coupling reactions and could easily manipulate the conditions to produce a wide variety of compounds. 10 For oxazoles produced by step (ii) in which X = NO 2 , the nitro group can be reduced to the corresponding amine, using any of the methods well known to the person skilled in the art discussed hereinabove. The amine may then be manipulated using, for example, any of the methods discussed in scheme 2 above, to give, for example, a compound of formula XVll. 15 Alternatively, benzoxazoles of formula XVIII can be made, also from a compound of formula XX, via thiocarbamate XXII, which is produced by heating a compound of formula XX with EtOC(S)SK in pyridine. The compound of formula XXII can be converted to the chloride of formula XXIII for example by use of well known reagents such as SOCl 2 or POCl 3 . A Suzuki coupling using, for example, conditions illustrated by step viii above gives 20 a benzoxazole of formula XVIII. In the above processes it may be necessary for any functional groups, e.g. hydroxy or amino groups, present in the starting materials to be protected, thus it may be necessary to remove one or more protective groups to generate the compound of formula I. Suitable protecting groups and methods for their removal are, for example, those 25 described in "Protective Groups in Organic Synthesis" by T. Greene and P.G.M. Wutts, John Wiley and Sons Inc., 1991. Hydroxy groups may, for example, be protected by arylmethyl groups such as phenylmethyl, diphenylmethyl or triphenylmethyl; acyl groups such as acetyl, trichloroacetyl or trifluoroacetyl; or as tetrahydropyranyl derivatives. Suitable amino protecting groups include arylmethyl groups such as benzyl, (R,S)-a-phenylethyl, 30 diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or trifluoroacety. Conventional methods of deprotection may be used including hydrogenolysis, acid or base hydrolysis, or photolysis. Arylmethyl groups may, for example, be removed by 12 WO 2009/021750 PCT/EP2008/006720 hydrogenolysis in the presence of a metal catalyst e.g. palladium on charcoal. Tetrahydropyranyl groups may be cleaved by hydrolysis under acidic conditions. Acyl groups may be removed by hydrolysis with a base such as sodium hydroxide or potassium carbonate, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and 5 acetic acid. The compounds of formula I, and salts thereof, may be isolated from their reaction mixtures using conventional techniques. Salts of the compounds of formula I may be formed by reacting the free acid, or a salt thereof, or the free base, or a salt or derivative thereof, with one or more equivalents of the 10 appropriate base or acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. ethanol, tetrahydroftiran or diethyl ether, which may be removed in vacuo, or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin. Pharmaceutically acceptable salts of the compounds of formula I include alkali metal 15 salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g. calcium and magnesium salts; salts of the Group III elements, e.g. aluminium salts; and ammonium salts. Salts with suitable organic bases, for example, salts with hydroxylamine; lower alkylamines, e.g. methylamine or ethylamine; with substituted lower alkylamines, e.g. hydroxy substituted alkylamines; or with monocyclic nitrogen heterocyclic compounds, e.g. piperidine or 20 morpholine; and salts with amino acids, e.g. with arginine, lysine etc, or an N-alkyl derivative thereof; or with an aminosugar, e.g. N-methyl-D-glucamine or glucosamine. In one embodiment, non-toxic physiologically acceptable salts are provided, although other salts are also useful, e.g. in isolating or purifying the product. Diastereoisomers may be separated using conventional techniques, e.g. 25 chromatography or fractional crystallisation. The various optical isomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation. 30 Substituents that alkyl may represent include methyl, ethyl, butyl, eg sec butyl. Halogen may represent F, Cl, Br and I, especially Cl. 13 WO 2009/021750 PCT/EP2008/006720 References to particular elements should be construed to include all isotopes of the particular element. In one group of compounds that may be mentioned A, A 2 and A 4 represent CH, and

A

3 represents CRI. 5 In one group of compounds R 9 represents 2-naphthyl. In another group of compounds that can be mentioned R 9 represents 2-naphthyl optionally substituted with halogen or phenyl optionally substituted with halogen; A, A 2 and A 4 represent CH, and A 3 represents CRI wherein R, represents:

NR

15 C(=W)Ri 7 wherein 10 W represents NH, S or 0;

R

17 represents C 2 -alkyl, n-propyl, or C 4 -Cloalkyl; C 1 -Cioalkyl substituted with one or more halogen, hydroxyl, alkoxy (such as Ci- 6 alkoxy) or amine; a mono or disaccharide unit attached at the anomeric position via a C 1

-C

4 alkyl group which is optionally substituted with one or more C 1 .- alkyl group: CHaryl, wherein arvl represents an aromatic hydrocarbon 15 (such as a 5 to 10 membered aromatic hydrocarbon) or a 5 to 10 membered aromatic heterocyle containing 1 to 4 hetero atoms selected from an oxygen atom, a sulphur atom and a nitrogen atom as a ring constituent besides carbon; CH 2 0CH 3 , CH 2 0CH 2

CH

2

OCH

3 ,

CH

2 piperidin-1-yl or CH 2 -N-morpholino; and

R

1 5 represents H, C 1

-

6 alkyl or together with R 17 represents -CH 2

CH

2 -, -CH 2

CH

2 -, or 20 CH 2

CH

2

CH

2 -. In one group of compounds that may be mentioned R 9 represents a C 5

.

1 0 carbocycle which is partially or fully aromatic containing 0-4 hetero atoms substituted by NR 9 0(C=Q)

M-Z-R

93 wherein R 90 represents H or C 1

-

6 alkyl, Q represents 0, S, or NR 91 wherein R 91 25 represents H or C 1

-

6 alkyl, M represents C 1

.

3 alkyl optionally substituted with halogen, C 1

.

6 alkyl, or C 1

.

6 alkoxy, Z represents 0, S or NR 9 2 wherein R 92 represents H or CI- 6 alkyl and

R

93 represents a C 5

.

10 carbocycle which is partially or fully aromatic containing 0-4 hetero atoms and optionally substituted by 1-4 halogen, CI-C 6 alkyl, OCi-C 6 alkyl. 30 In another group of compounds that can be mentioned R 9 represents a 5-10 membered heterocyclic ring containing one or more SOn units, wherein n=0-2 and may be the same or different for each SO, unit. 14 WO 2009/021750 PCT/EP2008/006720 In one group of compounds that may be mentioned, R, represents a N-linked mono or bicyclic ring which is a lactam. In another group of compounds R, represents -K-SO,-R 28 , wherein K represents C 1 5 C 3 alkyl optionally substituted with Ci-C 6 alkyl; n=0-2 and R 28 represents C 1 -Cioalkyl optionally substituted with one or more hydroxy, halogen, alkoxy (such as C 1

-

6 alkoxy) or amine. In one group of compounds Y represents N. 10 In one group of compounds X represents 0. In one group of compounds Y represents N and X represents 0. 15 Also provided is a method for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia in a patient in need thereof, comprising administering to the patient an effective amount of a' compound of formula (I) or a pharmaceutical acceptable salt. 20 Also provided is use of a compound described herein in the manufacture of a medicament for the treatment or prophylaxis of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia. The compounds of formula I for use in the treatment of DMD will generally be 25 administered in the form of a pharmaceutical composition. Thus, according to a further aspect there is provided a pharmaceutical composition including in one embodiment less than 80% w/w, in another embodiment less than 50% w/w, e.g. 0.1 to 20%, of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined above, in admixture with a pharmaceutically acceptable diluent or carrier. 30 Also provided is a process for the production of such a pharmaceutical composition which comprises mixing the ingredients. Examples of pharmaceutical formulations which may be used, and suitable diluents or carriers, are as follows: 15 WO 2009/021750 PCT/EP2008/006720 for intravenous injection or infusion - purified water or saline solution; for inhalation compositions - coarse lactose; for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, 5 sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes. When the compound is to be used in aqueous solution, e.g. for infusion, it may be necessary to incorporate other excipients. In particular there may be mentioned chelating or sequestering agents, antioxidants, tonicity adjusting agents, pH-modifying agents and 10 buffering agents. Solutions containing a compound of formula I may, if desired, be evaporated, e.g. by freeze drying or spray drying, to give a solid composition, which may be reconstituted prior to use. When not in solution, the compound of formula I is, in one embodiment, in a form 15 having a mass median diameter of from 0.01 to l0jm. The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers, e.g. a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, or a water-soluble glycol such as propylene glycol, sweetening and colouring agents and flavourings. Where appropriate, the compositions may be formulated in sustained release form. 20 The content of compound formula I in a pharmaceutical composition is generally about 0.01-about 99.9wt%, in one embodiment about 0.1-about 50wt%, relative to the entire preparation. The dose of the compound of formula I is determined in consideration of age, body weight, general health condition, diet, administration time, administration method, clearance 25 rate, combination of drugs, the level of disease for which the patient is under treatment then, and other factors. While the dose varies depending on the target disease, condition, subject of administration, administration method and the like, for oral administration as a therapeutic agent for the treatment of Duchenne muscular dystrophy in a patient suffering from such a 30 disease is from 0.01 mg - 10 g, in one embodiment 0.1 - 100 mg, is in certain embodiments administered in a single dose or in 2 or 3 portions per day. 16 WO 2009/021750 PCT/EP2008/006720 The potential activity of the compounds of formula I for use in the treatment of DMD may be demonstrated in the following predictive assay and screens. 1. Luciferase reporter assay (murine H2K cells) 5 The cell line used for the screen is an immortalized mdx mouse H2K cell line that has been stably transfected with a plasmid containing ~5kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene (see Figure 1). Under conditions of low temperature and interferon containing media, the cells remain as 10 myoblasts. These are plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase is then determined by cell lysis and reading of the light output from the expressed luciferase gene utilising a plate luminometer. Example of pharmacological dose respo co in the assay is shown in Figure 2. 2. mdx mouse 15 Data obtained from the ADMET data was prioritised and the compounds with the best in vitro luciferase activity and reasonable ADMET data were prioritised for testing in the mdx proof of concept study where the outcome was to identify whether any of the compounds had the ability to increase the levels of utrophin protein in dystrophin deficient muscle when compared to vehicle only dosed control animals. 20 There were two animals injected with 10mg/kg of compound administered ip daily for 28 days plus age matched controls. Muscle samples were taken and processed for sectioning (to identify increases in sarcolemmal staining of utrophin) and Western blotting (to identify overall increases in utrophin levels). Figure 3 shows an example of TA muscle sections stained with antibody specific for mouse 25 utrophin. Comparison to the mdx muscle only injected with vehicle shows an increase in the amount of sarcolemmal bound utrophin. Muscles from the above treated mice were also excised and processed for Western blotting and stained with specific antibodies (see Figure 4). Again using muscle dosed with CPD-A 17 WO 2009/021750 PCT/EP2008/006720 shows a significant increase in the overall levels of utrophin present in both the TA leg muscle and the diaphragm. Both mice exposed to CPD-A (V2 and V3) showed increased levels of utrophin expression compared to control. 5 Positive upregulation data from the first 28 day study were then repeated in a further two mouse 28 day study. A total of three different compounds have shown in duplicate the ability to increase the level of utrophin expression in the mdx mouse when delivered daily by ip for 28 days. This data demonstrates the ability of the compound when delivered ip causes a significant increase in the levels of utrophin found in the mdx muscle and therefore gives us 10 the confidence that this approach will ameliorate the disease as all the published data to date demonstrates that any increase of utrophin levels over three fold has significant functional effects on dystrophin deficient muscle. hI, -2K/mx/U A r erpter el ...l mitenance 15 The H2K/mdx/Utro A reporter cell line was passaged twice a week until 30% confluent The cells were grown at 33 0 C in the presence of 10% Co 2 . To remove the myoblasts for platting, they were incubated with Trypsin / EDTA until the monolayer started to detach. Growth Medium 20 DMEM Gibco 41966 20% FCS 1% Pen/Strep 1% glutamine I Omls Chick embryo extract 25 Interferon(1276 905 Roche) Add fresh 10pl / 50mls medium Luciferase Assay for 96 Well Plates The H2K/mdx/Utro A reporter cell line cells were plated out into 96 well plates (Falcon 353296, white opaque) at a density of approximately 5000 cells/well in 190pil normal growth 30 medium. The plates were then incubated at 33'C in the presence of 10% CO 2 for 24 hrs. 18 WO 2009/021750 PCT/EP2008/006720 Compounds were dosed by adding 10tl of diluted compound to each well giving a final concentration of 10ptM. The plates were then incubated for a further 48hrs. Cells were then lysed in situ following the manufacture's protocols(Promega Steady Glo Luciferase Assay System(E2520), then counted for 10 seconds using a plate luminometer 5 (Victorl420). Compound Storage Compounds for screening were stored at -20 0 C as 10mM stocks in 100% DMSO until required. 10 Injection of mdx mice with compounds ?A.m& frmm a breeUna colonv were selected for testing. Mice were injected daily with either vehicle or 10mg/kg of compound using the intreperitoneal route (ip). Mice were weighed and compounds diluted in 5% DMSO, 0.1% tween in PBS. 15 Mice were sacrificed by cervical dislocation at desired time points, and muscles excised for analysis. Muscle Analysis Immunohistochemistry 20 Tissues for sectioning were dissected, immersed in OCT (Bright Cryo-M-Bed) and frozen on liquid nitrogen cooled isopentane. Unfixed 8tM cryosections were cut on a Bright Cryostat, and stored at -80C In readiness for staining, sections were blocked in 5% fetal calf serum in PBS for 30 mins. The primary antibodies were diluted in blocking reagent and incubated on sections for 1.5 hrs 25 in a humid chamber then washed three times for 5mins in PBS. Secondary antibodies were also diluted in blocking reagent, and incubated for 1 hr in the dark in a humid chamber. Finally sections were washed three times 5mins in PBS and coverslips were mounted with hydromount. Slides were analysed using a Leica fluorescent microscope. 19 WO 2009/021750 PCT/EP2008/006720 Results Biological activity was assessed using the luciferase reporter assay in mnurine H2K cells, and is classified as follows: 5 + Up to 200% relative to control ++ Between 201% and 300% relative to control +++ Between 301% and 400% relative to control .... Above 401% relative to control 10 Table 1: Compounds made by methods described herein Example IChemical Name Atvity 1 i _ 3,4-dichloro-N-(2-isopropylbenzo[d]oxazol-5-yl)beflzamide ... ___ f 2 - 5-eth lsulfonyl-1 ,3-benzoxazol-2-amine +____ 3 N-(4(belzo[d]oxazoI2-yl)phenyl)2-methylbutanamide ++++-___ 4 IN-(4-(6-benzoylbenzo[dloxaoI2-y)phfl)-2-methylbutalamide 1 5 N-(4-(5(ethylsulfonyl)benzo~d]oxazoI2-y)phenyl)isobutyramide 1 6 J5-(ethylsulfonyI)-2-(3-phe9xyphenl)benzo[d]oxazole 7 .2-(enzo[djoxazol-2-yi)-5-chioropheflo 8 I5-ch oro-2-(5-methyl benzo[dloxazol-2-yl) phenll I 9 J5-am i n-2-(5-methylbenzo[doxazol-2-yl) phenol ~ui 10 J5-(ethylsulfonyl)-2-(1 H-indol-5-yl)benzo[d]oxazole 11 + -+ -. 11 N-4(ez~ltizl2y 1ey)2(uioi--~hi c md 12 2-(6-methyl-4-oxo- 1,4-d ihyd ropyri mid in-2-ylth io)-N-(4-(6 I- ___2____I methylbenzo[d]thiazol-2-yI)phefl)acetamide F 13 ylpenl Iaamd 14 IN-(4-(6-methylbenzofdlth iazl-2-yI) phenY L-2-(quinazolin-4-ylthio)acetamide .... ii J2-(5-isopropyl-4H-1 ,2 ,4-triazol-3-ylthio)-N-(4-(6-methylbelzo[dlth iazol-2- .. 15 jyl)phenyl)acetamide 16 ---yI)phenyl)propanamide 17 5 ,-tha(oe-th I)(-(ethydoxlez +t~Z~ is 3-(5-rnethylbenzod]oxazo-2-y)pyridin-2.... 5-(5-ethybenzodox-2-y~pyridn-2-ol

-

2 0 15-(5-frethylbenzod]oxazo-2-yI)pyridifl-2-aminPe ..- Ii~ 21 f5(5methybeflzo~dioxazol.2:ylpyrimidine:24-dioI 2 N-(4-(6-methylbenzo[d]thiazol-2-yl) phenyl)-2-(4-phenyl-4H-1 ,2,4-triazol-3 2 ythio)acetamide____ 23 IN(4-(6-methybenzo~dthiazoI-2-y)phenyI)-2-(phenylthio)acetamide 20 WO 2009/021750 PCT/EP2008/006720 24 jN-(4-(6-methylbenzo[d]oxazol-2-yl)phenyl)-2-(phenylthio)acetamide I____ 26* fN-(4-(6-methylbenzo[d~thiazol-2-yl)phenyl)-2-phenoxyacetamide ... 26_ Imethyl 2-(naphthalen-2-yI)benzo[d]oxazole-6-carboxylate I+ 27 15-ain2(5-(trifluoromethoxy)benzod]oxazoI2-yl)phenoI .. 28 15-am ino-2-(naphtho[ 1,2-d]oxazol1-2-yl) phenol 4'+ -29 - 5-amino.-2-(5-phenylbenzo[dlox azol-2-yl)phenoI .... ___ 12-(4H- 1 24-triazol-3-ylthio)-N-(4-(6-methylbenzo[d]oxazol-2- + F 30 _ _yl)phenyl)acetamide ____ --- 3 1__2-(3,4'-dichlorophenyl)-6-(ethylsulfonyl)-benzoxazole 1 32 12-(4'-chlorophenyl)-6-(ethylsulfonyl)-benzoxazole ____ 33 j(2-(na phthale n-2-yl)benzo[doxazol-6-yI) methanol 34 12-(5-methyl benzo[d]oxazol-2-yI) phen ol N(-23-dichlorophenyl)benzo[dloxazol-5-yl)-3-(beta-D F 36 1galactopyranosyloxy)propanamide____ -37_ N2- (2,3-dich Iorophenyl)benzo[d]oxazol-5-y)-2hydo~yaCetarnide - ____ 38 ~5-(ethylsulfonyl)-2-(isoquinolin-3-yl~benzo~d]oxazole K 39 -(ehl ! ~l - unln--lbez~lp --. 40 -- J5-(ethylsulfonyl)-2-(quinoxai6yl)bezo~d]oxazole 42 1N(22,3dichorophenybenzodoxazo5yI)3hydroxpropanamide ]+++ 44. 2 -(1 H-im idazol- 1 _ _N(2(ahhae-- Ibnodxal-5yactmd 12-(1 H-imidazol-4'-yI)-N-(2'-(naphthael-2'-y)bezo[doxazolk5.. 45 1y)acetamide hydrochloride 46- .methyl ethyl(2-(naphthaten-2-y)benzodoxazoI-5-yI)phosphiflate F-47~~ (S)-N-(2-(2,3-dichlorophenyl)benzo[doxazoI-5-y)-2- .. 4 _ (methylamino)propanamide 49 1galactopyranosyloxy)a"eanide 1 50 13. 3,3-trifluoro-N-(2-(naphthalen-2-yi)benfdldoxao-5yl)propanamide 15 N,(-2naphthalen2-yl)benzo[d]oxazo15-yl)propionimdamide++ .55-ety ulfiny)-(-naphthaen2YI)bez[oxazole .. 56 IN (2-(naphth ale n-2-y)benzo~d]oxazo-5-yI) methalesu Ifolam ide ++ 57. 2-(4,4-difluorocyclohexyl)-5-(ethylsulfonyl)benzod]oxazole + 1 [__9 jethyl 2-(naphthalen-2-yI)benzo[d]oxazo-5-y(phelyl)phOhilt + ____ 21 WO 2009/021750 PCT/EP2008/006720 60 Imethyl 2-(3,4-dichlorophenyI)benzo[dloxazoI-5-yI(ethyl)phosphinate + f 61 methyl_ 2-(2, 3-dichforophenyl) benzo[dloxazo-5-yI(ethyf) phosph inate____ L~2 5-(ethylsulfony)-2-(naphthalen-2-ylmethyI)benzo~dIoxazole +~ 63 i2-(4-chlorophenyl)benzo[doxazo-5yi~ethy)phospilic acid ____ F - 64 - J-- 2-rnorpholino-N-(2-(naphthalen-2-y)benzo~d]oxazoI-5-yI~acetam ide+ F 65 N-m:ethyI2(naphthalen2-yl~enzo[dloxazole-5sulfonamide F- 66 IN-(4-(6methylbenzo~d~thiazol-2-ylphenly)-2-(pyridil-2-yloxy~acetamide +~ 1 68 __5-(rnethylsulfonyl)-2-(naphthalen-2'-y)benzo[doxazole IN-(2-(2 ,3-dichlorophenyl)benzo[d]oxazo-5-yD-3-(beta-D-.. 69 ~glucopyranosyloxy)propanamTide IN-(2-(2, 3-dichlorophenyl)benzo[d]oxazo-5-yI)-2-(beta-D- 1+ 70 Jmannopyranosyloxy)acetamide 71 IN-(2-(2,3dichorophenyl)benzo~d~oxazoI-5-yi)-2-methylamifloacetamide .... ~ 72 _ 5-(2',2',2 trieuteroethysUfoy)-(a~phthael-2-y)belzo[dxazole 1++____ fI(S)-2-amino-3-hydroxy-N-(2-(naphthae-2-y)befdldoxazoI- 5 -.. KIi o~I -- n -;k - -. 1 z lr 75 2-(-nroialmidazo[,2-a]pyridi-2-y)benzo[d]th iazole ... ___ 76 (E)-5-(ethylsulfonyl)-2-styrylbenzod]oxazole -+ ______ 77 ~5-(ethylsu~fonyI):2-( 1,2, 3,4-tetrahydronphthael-2-y)bezo[doxazole .. 78 5-(ethylsulfony)-2-(4-peOYefIbflOdOaO 1 80 2-(4H-1 ,2,4-triazol-3-ylth io)-N-(4-(benzo[d~thiazoI-2-yI)thiazoI-2-yI)acetamide ... 81 11 -(?(naphthalen-2"-yI)benzo[dIoxazoI-'-y)pyrrod127one +1 8 2-(4H-1 ,2,4-triazo-3-ylthio)-N-(5-(belzofd]thiazoI-2-yI)pyrid ine-3- + 83 - 2-(benzo[b]thiophen-1 , 1 -dioxide-6-y)-5-(etysufofl)belzo[d]oxazole 1 14 5-(mroPho-linomthy)72-(ahthael-2-y)bezo[d]oxazole 85 -15-(ethylsulfony~methyl)-2-(naphthael-2-yI)belzo[d]oxazole 86 5-(methy _uIfonyimethy)-2-(naphthael-7yI)efZo[doxazoI9.

87 J5-(methylsulfonyl)-2-(naphthael-2-y)belzo[dthiazole -88 _-(-nptae--lbnodoao--lmtyaioaei acid 89 j5-(ethylsulfonyl)2(naphthaen-2-ylbenzo[dlthiazole [ 90 jNethyl-2(laphthae-2yl)benzodoxazoe5sulfonamide + - + +___ J (S)-2-hydroxy-N ,N, N-trimethyl-4-(2-(naphthalen-2-y)bezo[d]oxazoI-5-+ 91 jylamino)-4-oxobutan-1 -aminium Further active compounds are 2-naphthalen-2-yl- 5-(pyrrolidine-l1-sulfonyl)-benzooxazole, 5 methoxy-2-(naphthalen-2-yl)benzo [d]oxazole, 2-(naphthalen-2-yI)benzo [d]oxazol-5-ol, 5-(2 22 WO 2009/021750 PCT/EP2008/006720 (benzyloxy)ethoxy)-2-(naphthalen-2-yl)benzo[d]oxazole, 2-(2-(naphthalen-2 yl)benzo[djoxazol-5-yloxy)ethanol, (2-phenyl- I H-indol-3-yl)methanol and 2-(2 (naphthalen-2-yl)benzo[d]oxazol-5-ylsulfonyl)ethanol. 5 Other active compounds include 5-methoxy-2-(naphthalen-2-yl)benzo[d]oxazole (++), 2 (naphthalen-2-yl)benzo[d]oxazol-5-ol (++), 5-(2-(benzyloxy)ethoxy)-2-(naphthalen-2 yl)benzo[d]oxazole (+), 2-(2-(naphthalen-2-yl)benzo[d]oxazol-5-ylsulfonyl)ethanol (++), 2 (naphthalen-2-yl)-5-(pyrrolidin-1-ylsulfonyl)benzo[d]oxazole (+), and 2-(2-(naphthalen-2 yl)benzo[d]oxazol-5-yloxy)ethanol (+), where (++) and (+) have the meanings shown for 10 Table 1. Experimental HPLC-UV-MS was performed on a Gilson 321 HPLC with detection performed by a Gilson 170 DAD and a Finnigan AQA mass spectrometer operating in electrospray ionisation mode. The HPLC column used is a Phenomenex Gemini C18 150x4.6mm. Preparative HPLC was 15 performed on a Gilson 321 with detection performed by a Gilson 170 DAD. Fractions were collected using a Gilson 215 fraction collector. The preparative HPLC column used is a Phenomenex Gemini C18 150xOmm and the mobile phase is acetonitrile/water. 'H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR spectra were obtained as CDCl 3 solutions (reported in ppm), using chloroform as the reference 20 standard (7.25 ppm) or DMSO-D 6 (2.50 ppm). When peak multiplicities are reported, the following abbreviations are used s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets). Coupling constants, when given, are reported in Hertz (Hz). Column chromatography was performed either by flash chromatography (40-65pm silica gel) 25 or using an automated purification system (SP1TM Purification System from Biotage*). Reactions in the microwave were done in an Initiator 8TM (Biotage). The abbreviations used are DMSO (dimethylsulfoxide), HATU (0-(7-azabenzotriazol-lyl) N,N,N',N'-tetramethyluronium hexafluorophosphate), HCl (hydrochloric acid), MgSO 4 (magnesium sulfate), NaOH (sodium hydroxide), Na 2

CO

3 (sodium carbonate), NaHCO 3 30 (sodium bicarbonate), STAB (sodium triacetoxyborohydride), THF (tetrahydrofuran). 23 WO 2009/021750 PCT/EP2008/006720 R- + PPA, 110*C-180 0 C, 3-16h oxalyl chloride, DMF, DCM NH2 R 9 X=OH then PTSA, xylenes, reflux 0q Method 1A) (Method 1Ai) X M(Method1AAIM X=OH or Cl Microwa dioxane, 210 0 C, 15min X=CI (Method 1B) O- H PPA, 160 0 C, 30m -7h N ORg (Method 1C) 1: Major product + Ic, Id, le : Minor products pTsOH, xylene reflux, 3-16h 0 R9 ~(Method 1 D jo 0 O O1 >-R, - H R Ic O Rg (with R=NH2)

HO

2 C OCNRN Id (with R=CO 2 H) Br NH le (with R=Br) EXAMPLE 1 (Compounds 1) 3-(5-Methylbenzo[dloxazol-2-yl)pyridin-2-oI To polyphosphoric acid at 110 C were added simultaneously 2-amino-4-methylphenol (123mg, 1.Ommol) and 2-hydroxynicotinic acid (139mg, 1.Ommol). The resulting mixture was then heated to 180'C for 5h. The solution was then poured into water. The resulting precipitate was basified with aqueous NaOH solution and then collected by filtration to afford 70mg (31%) of the title compound (LCMS RT= 5.19min, MH* 227.1) 'H NMR (DMSO): 8.06 (1H, dd, J 7.4 2.3 Hz), 7.89 (1 H, dd, J 5.2 2.3 Hz), 7.54-7.48 (2H, m), 7.10 (1H, dd, J8.3 1.2 Hz), 6.17 (1H, dd, J7.4 5.8 Hz), 2.41 (3H, s) All compounds below were prepared following the same general method and purified either by trituration, recrystallisation or column chromatography. 3-(5-Methylbenzo[d]oxazol-2-yl)pyridin-2-ol 24 WO 2009/021750 PCT/EP2008/006720 LCMS RT= 5.19min, MH* 227.1; 'H NMR (DMSO): 8.06 (1H, dd, J7.4 2.3 Hz), 7.89 (1H, dd, J5.2 2.3 Hz), 7.54-7.48 (2H, m), 7.10 (1 H, dd, J8.3 1.2 Hz), 6.17 (1H, dd, J7.4 5.8 Hz), 2.41 (3H, s) 5-(5-Methylbenzo[d]oxazol-2-yl)pyridin-2-oI LCMS RT= 5.34min, MH* 227.1; 'H NMR (DMSO): 12.25 (1H, br), 8.23 (1H, d, J2.2 Hz), 8.08 (1H, dd, J 9.6 2.6 Hz), 7.58 (1H, d, J 8.5 Hz), 7.52 (1H, s), 7.18 (1H, d, J8.5 Hz), 6.53 (IH, d, J 9.6 Hz), 2.43 (3H, s) 5-(5-Methylbenzo[d]oxazol-2-yl)pyridin-2-amine LCMS RT= 5.82min, MH* 226.1; 'H NMR (DMSO): 8.72 (1H, s), 8.08 (1H, d, J8.6 Hz), 7.57 (1H, d, J8.6 Hz), 7.49 (1H, s), 7.16 (1H, d, J9.3 Hz), 6.92 (2H, br), 6.62 (1H, d, J9.3 Hz), 2.43 (3H, s) 5-(5-Methyibenzo j[a oxazol- 2 -yI)py imidine-2,4-diol LCMS RT= 4.98min, MH* 244.0; 'H NMR (DMSO): 11.74 (1H, br), 11.55 (lH, s), 8.32 (1H, s), 7.58 (1H, d, J8.6 Hz), 7.51 (1H, s), 7.18 (1H, d, J9.3 Hz), 2.43 (3H, s) 5-Amino-2-(5-(trifluoromethoxy)benzoEd]oxazol-2-yl)phenol LCMS RT= 7.14min, MH* 311.1; 'H NMR (DMSO): 10.93 (1H, br), 7.82 (1H, d, J8.8 Hz), 7.76-7.74 (1H, m), 7.67 (1H, d, J 8.8 Hz), 7.35-7.30 (1H, m), 6.29 (1H, dd, J 8.6 2.2 Hz), 6.20-6.16 (3H, m) 5-Amino-2-(naphtho[1,2-dJoxazol-2-yl)phenol LCMS RT= 7.38min, MH* 277.0; 'H NMR (DMSO): 11.21 (1H, s), 8.40 (1H, d, J8.2 Hz), 8.10 (1H, d, J 8.4 Hz), 7.96-7.89 (2H, m), 7.73-7.67 (2H, m), 7.63-7.56 (1H, m), 6.31 (1H, dd, J8.7 2.1 Hz), 6.23 (1H, d, J2.1 Hz), 6.05 (2H, s) 5-Amino-2-(5-phenylbenzo[dloxazol-2-yl)phenol LCMS RT= 7.75min, MH* 303.1; 'H NMR (DMSO): 11.18 (1H, s), 7.95 (1H, d, J 1.8 Hz), 7.78 (1H, d, J8.6 Hz), 7.75-7.71 (2H, m), 7.67 (1H, d, J8.8 Hz), 7.62 (1H, dd, J8.6 1.9 Hz), 7.52-7.45 (2H, m), 7.41-7.35 (1H, m), 6.30 (1H, dd, J 8.6 2.1 Hz), 6.20 (1H, d, J 2.0 Hz), 6.11 (2H, s) 25 WO 2009/021750 PCT/EP2008/006720 5-(Ethylsulfonyl)-2-(isoquinolin-3-yl)benzo[dloxazole LCMS RT= 5,94min, MH 339.2; 'H NMR (DMSO): 9.55 (IH, s), 8.99 (1H, s), 8.38 (1H, dd, J 1.9 0.6 Hz), 8.32-8.27 (2H, m), 8.16 (1H, dd, J8.5 0.5 Hz), 8.01 (1H, dd, J8.6 1.9 Hz), 7.98-7.85 (2H, in), 3.42 (2H, q, J7.4 Hz), 1.15 (3H, t, J7.4 Hz) 5-(Ethylsulfonyl)-2-(quinolin-6-yl)benzo[d]oxazole LCMS RT= 5.78min, MH+ 339.2; 'H NMR (DMSO): 9.05 (1H, dd, J4.3 1.8 Hz), 8.99 (1H, d, J 1.9 Hz), 8.67 (1H, dd, J8.7 1.3 Hz), 8.54 (1H, dd, J8.9 1.9 Hz), 8.37 (1H, d, J 1.6 Hz), 8.25 (1H, d, J9.0 Hz), 8.13 (1H, d, J8.6 Hz), 8.00 (1H, dd, J8.6 1.7 Hz), 7.69 (1H, dd, J8.4 4.2 Hz), 3.42 (2H, q, J 7.4 Hz), 1.14 (3H, t, J 7.4 Hz) 5-(Ethylsulfonyl)-2-(quinoxalin-6-yl)benzo d]oxazole LCMS RT= 5.57min, (MH+MeCN)* 380.9; 'H NMR (DMSO): 9.10 (2H, dd, J5.9 1.9 Hz), 8.89 (1L, A Q z, 8.64 (1,I dd, J8.9 2.0 14), 8.41 (1H, dd.J1.8 0.5 Hz), 8.36 (1H, d,J 0.0.7 ki,1ki, %A, UJ 1* 1 . . - , 8.8 Hz), 8.17 (1H, dd, J8.5 0.5 Hz), 8.02 (1H, dd, J8.5 1.8 Hz), 3.42 (2H, q, J7.4 Hz), 1.14 (3H, t, J7.4 Hz) Modified proceedure 1A: 5-(Ethylsulfonyl)-2-(naphthalen-2-ylmethyl)benzo[dloxazole A mixture of 2-amino-4-(ethylsulfonyl)phenol (300mg, 1.49mmol) and 2-naphthylacetic acid (417mg, 2.24mmol) was heated at 125'C in polyphosphoric acid (PPA) for hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized with NaOH (5M) to ph =7.The reaction mixture was extracted 3 times with EtOAc, the organic phase combined, dried over sodium sulfate and concentrated in vacuo to give a yellow oil. Purification using biotage 30% EtOAc/ 70% petroleum gave 160mg of a yellow solid 30% Yield, 97% UV purity. LCMS RT= 6.50min, MH* 352.0 'H NMR (CDCl 3 ): 8.19ppm (1H, d, J 1.77 Hz), 7.77ppm (5H, m), 7.55ppm (1H, d, J 8.52 Hz), 7.42ppm (3H, in), 4.41ppm (2H , s), 3.06ppm (2H, q, J7.42 Hz), 1.19ppm (3H,t, J7.42 Hz). 5-(Ethylsulfonyl)-2-(1,2,3,4-tetrahydronaphthalen-2-yl)benzo [doxazole 26 WO 2009/021750 PCT/EP2008/006720 A mixture of 2-amino-4-(ethylsulfonyl)phenol (201 mg; 2 mmol) and 1,2,3,4-tetrahydro-2 naphthoic acid (352 mg; 2 mmol) was heated at 180'C in polyphosphoric acid (PPA) for 16hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized with NaOH (5M) to ph =7.The reaction mixture was extracted 3 times with EtOAc, the organic phase combined, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica with 5:1 Petrol ether/Ethyl acetate. The product was then further purified by HPLC to give the title compound as a white solid, 97 % pure by UV LCMS. LCMS RT= 6.77min, MH*= 342.1; 'H NMR (CDC 3 ): 8.19 (1H, d, J 1.8 Hz), 7.83 (1H, dd, J 8.6 and 1.8 Hz), 7.60 (1H, d, J 8.6 Hz), 7.13-7.04 (4H, in), 3.44-3.33 (1H, in), 3.28-3.20 (2H, in), 3.12-3.04 (2H, q, J7.4 Hz), 2.97-2.90 (2H, in), 2.48-2.37 (1H, in), 2.15-1.99 (1H, m) 1.24-1.16 (3H t. J7.5 Hz). The following two compounds were prepared using the same general method: 5-(Ethylsulfonyl)-2-(4-phenoxyphenyl)benzo[d]oxazole LCMS RT= 7.46min, MH* 379.9; 'H NMR (DMSO): 8.28-8.23 (3H, in), 8.06 (1H, d, J 8.6 Hz), 7.93 (1H, dd, J8.6, J 1.8 Hz), 7.52-7.47 (2H, in), 7.30-7.25 (1H, in), 7.21-7.18 (4H, m), 3.40 (2H, q, J7.4 Hz), 1.12 (3H, t, J7.3 Hz). 2-(2,3-Dihydro-1H-inden-5-yl)-5-(ethylsulfonyl)benzo[dloxazole LCMS RT= 7.42min, MH 4 328.0; 'H NMR (DMSO): 8.27 (1H, d, J1.5 Hz), 8.09-8.02 (3H, in), 7.93 (1H, dd, J8.6, J 1.8 Hz), 7.49 (1H, d, J8.0 Hz), 3.38 (2H, q, J7.4 Hz), 2.98 (4H, q, J7.1 Hz), 2.14-2.04 (2H, in), 1.12 (3H, t, J7.3 Hz). Method 1A (Compounds Ic) 5-(Methylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole Preparation of 2-amino-4-(methylsulfonyl)phenoI Boron tribromide (IM in dichloromethane, 39mL, 39.8mmol) was added to a solution of 2 methoxy-5-(methylsulfonyl)aniline (2g, 9.94mmol) in dichloromethane (30mL) and the 27 WO 2009/021750 PCT/EP2008/006720 resultant solution was allowed to stir at room temperature for 10 minutes before being heated at reflux for 5 hours. After this time the reaction mixture was cooled to 0"C and quenched by the cautious addition of water. The organic layer was separated and the aqueous layer was concentrated in vacuo. The crude reaction mixture was suspended in toluene and concentrated in vacuo to give the title compound as a beige powder (4.4g), contaminated with boron salts after drying under vacuum for 24 hours. 'H NMR (d6-DMSO) 11.67 (1H, br s), 7.70-7.76 (2H, in), 7.16-7.19 (1H, in), 3.18 (3H, s). Preparation of 5-(methylsulfonyl)-2-(naphthalen-2'-yl)benzo[dloxazole 2-amino-4-(methylsulfonyl)phenol (approx. 44% by mass, 2g, 4.700mmol) and 2-naphthoic acid (890mg, 5.170mmol) were mixed and added in one portion to a heated flask of polyphosphoric acid (3OmL, heated at 11 0 0 C). The resultant reaction mixture was heated at 120*C for 16 hours before being diluted with water (200mL). The mixture was adjusted to pT t solid potium carbonate and the title compound collected as an off-white solid by filtration (1.157g, 76%) (LCMS RT=6.73min, MH* 324). 'H NMR (300MHz, DMSO) 8.93 (1H, s), 8.41 (1H, d, J 1.4 Hz), 8.32 (1H, dd, J8.6 1.7 Hz), 8.23-8.26 (1H, in), 8.20 (1H, d, J 8.8 Hz), 8.13 (1H, d, J 8.6 Hz), 8.03-8.10 (2H, in), 3.34 (3H, s). Method 1Ai 2-(4,4-Difluorocyclohexyl)-5-(ethylsulfonyl)benzo[d]oxazole A solution of 4,4-difluorocyclohexane carboxylic acid (0.10g, 0.62mmol) and oxalyl chloride (64 pL, 0.74mmol) in DCM (2 mL), containg one drop of DMF, was stirred at room temperature for Ih. The solvents were removed in vacuo and the residue dissolved in xylene (2 mL), 2-amino-4-(ethylsulfonyl)phenol (0.13g, 0.62mmol) was added and the resulting reaction mixture was heated under reflux at 155 C for lh. PTSA (59mg, 0.31mmol) was added and refluxing was continued for a further 2h, after which the reaction mixture was absorbed onto silica gel. Purification by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 3/7 v/v, afforded 117 mg (57%) of the title compound. (LCMS RT= 6.00min, MH* 330.1) 'H NMR (CDCl 3 ): 8.28 (1H, d, J 1.6 z), 7.93 (1H, dd, J 1.8 z, J 8.6 z), 7.68 (1H, d, J 8.6 Hz), 3.17 (2H, q, J7.5 Hz), 2.31-1.90 (8H, in), 1.57 (1H, bs), 1.30 (3H, t, J7.5 Hz). 28 WO 2009/021750 PCT/EP2008/006720 Method 1B (Compounds I) N-Methyl-(2-naphthalen-2-yl)benzo[dJoxazol-5-yl)sulfonamide A mixture of 2-aminophenol-4-sulfomethylamide (252mg, 1.248mmol) and 2-naphthoyl chloride (285mg, 1.497mmol) in 1,4-dioxane (1.7ml) was heated at 200 0 C for 15mins under microwave activation. After cooling, IM aq. sodium hydroxide was added (pH13) and the resultant solid collected by filtration. Drying in vacuo gave the title compound as an off white solid (280mg, 66%). LCMS RT= 6.62min, peak includes [M+MeCN]*; 'H NMR (CDCl 3 ): 8.84 (1H, br s); 8.34 (2H, m); 8.04 (2H, m); 7.95 (2H, m); 7.78 (1H, m); 7.64 (2H, m); 4.36 (1H, m); 2.74 (3H, d, J= 5.4 Hz). (E)-5-(Ethylsulfonyl)-2-styrylbenzo[djoxazole LCMS RT= .4min, 1* 14.1; 1.H NMR (DMSO): 8.23 (1H, dd, J 1.7, J0.5 Hz), 8.01 (IH, dd, J8.5 J 0.5 Hz), 7.93 (1H, d, J 16.4 Hz), 7.92 (1H, dd, J 8.6, J 1.8 Hz), 7.87-7.84 (2H, m), 7.48-7.44 (2H, m), 7.42 (2H, d, J 16.4 Hz), 3.39 (2H, q, J7.4 Hz), 1.12 (3H, t, J7.3 Hz). Modified procedure 5-(Ethylsulfonyl)-2-(furan-2-yl)benzo[dJoxazole To 2-amino-4-(methylsulfonyl)phenol (201mg, 1.00mmol) in dry dioxane (2mL) was added furan-2-carbonyl chloride (98iL, 1.00mmol) at room temperature. The reaction vessel was heated in the microwave at 210*C for 15min. After cooling, the mixture was slowly poured into water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:2 v/v to afford 40mg (14%) of the title compound (LCMS RT= 5.73min, MH* 277.9); 'H NMR (DMSO): 8.20 (1H, d, J 1.9 Hz), 8.08-8.07 (1H, m), 7.98 (1H, dd, J8.6 0.5 Hz), 7.87 (1H, dd, J8.6 1.8 Hz), 7.52 (1H, dd, J3.6 0.7 Hz), 6.80 (1H, dd, J3.6 1.7 Hz), 3.31 (2H, q,J7.4 Hz), 1.05 (3H, t, J7.4 Hz) All compounds below were prepared following the same general method. The acid chloride used was either a commercially available compound or synthesized from the corresponding carboxylic acid using standard conditions. 29 WO 2009/021750 PCT/EP2008/006720 2-(3',4'-Dichlorophenyl)-6-(ethylsulfonyl)-benzoxazole LCMS RT= 7.45min; 'H NMR (DMSO): 8.40 (1H, d, J 2.0 Hz), 8.36 (1H, d, J 1.7 Hz), 8.20 (1H, dd,J 8.4 2.0 Hz), 8.10 (1H, d,J8.5 Hz), 7.97-7.93 (2H, m), 3.40 (2H, q,J7.4 Hz), 1.13 (3H, t,J7.4 Hz) 2-(4'-Chlorophenyl)-6-(ethylsulfonyl)-benzoxazole 'H NMR (CDC1 3 ): 8.25 (2H, d, J8.6 Hz), 8.20-8.19 (1H, m), 7.95-7.94 (2H, m), 7.58 (2H, d, J8.5 Hz), 3.21 (2H, q, J7.3 Hz), 1.33 (3H, t, J7.4 Hz) Method 1C (Compounds I) 5-(Ethylsulfonyl)-2-(naphthalen-2-ylmethyl)benzo[dioxazole A mixture of 2-amino-4-(ethylsulfonyl)phenol (300mg, 1.49mmol) and 2-naphthylacetic acid (417mg, 2.24mmol) was heated at 125"C in polyphosphoric acid (PPA) for hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized with NaOH (5M) to ph =7.The reaction mixture was extracted 3 times with EtOAc, the organic phase combined, dried over sodium sulfate and concentrated in vacuo to give a yellow oil. Purification using biotage 30% EtOAc/ 70% petroleum gave 160mg of a yellow solid 30% Yield, 97% UV purity. LCMS RT= 6.50min, MH* 352.0; 'H NMR (CDCl 3 ): 8.19ppm (1H, d, J 1.77 Hz), 7.77ppm (5H, m), 7.55ppm (I H, d, J8.52 Hz), 7.42ppm (3H, m ), 4.4 1ppm (2H , s), 3.06ppm (2H, q, J 7.42 Hz), 1.l9ppm (3H,t, J7.42 Hz). 5-(Ethylsulfonyl)-2-(1,2,3,4-tetrahydronaphthalen-2-yl)benzo [d] oxazole A mixture of 2-amino-4-(ethylsulfonyl)phenol (201 mg; 2 mmol) and 1,2,3,4-tetrahydro-2 naphthoic acid (352 mg; 2 mmol) was heated at 180"C in polyphosphoric acid (PPA) for 16hours. After cooling to room temperature, the reaction mixture was poured into ice water and neutralized with NaOH (5M) to ph =7.The reaction mixture was extracted 3 times with EtOAc, the organic phase combined, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica with 5:1 Petrol ether/Ethyl acetate. The 30 WO 2009/021750 PCT/EP2008/006720 product was then further purified by HPLC to give the title compound as a white solid, 97 % pure by UV LCMS. LCMS RT= 6.77min, MH*= 342.1; 'H NMR (CDC1 3 ): 8.19 (1H, d, J 1.8 Hz), 7.83 (1H, dd, J 8.6 and 1.8 Hz), 7.60 (IH, d, J8.6 Hz), 7.13-7.04 (4H, m), 3.44-3.33 (IH, m), 3.28-3.20 (2H, in), 3.12-3.04 (2H, q, J7.4 Hz), 2.97-2.90 (2H, in), 2.48-2.37 (1H, in), 2.15-1.99 (1H, in), 1.24-1.16 (3H, t, J7.5 Hz). The following two compounds were prepared using the same general method: 5-(Ethylsulfonyl)-2-(4-phenoxyphenyl)benzo[d]oxazole LCMS RT= 7.46min, MH 379.9; 'H NMR (DMSO): 8.28-8.23 (3H, in), 8.06 (1H, d, J8.6 Hz), 7.93 (1H, dd, J8.6, J 1.8 Hz), 7.52-7.47 (2H, in), 7.30-7.25 (1H, in), 7.21-7.18 (4H, n), 3.40 (2H, q, J7.4 Hz), 1.12 (3H, t, J7.3 Hz). 2-(2,3-Dihydro-1H-inden-5-yI)-5-(ethylsulfonyl)benzold]oxazole LCMS RT= 7.42min, MH*+ 328.0; 'H NMR (DMSO): 8.27 (1H, d, J 1.5 Hz), 8.09-8.02 (3H, in), 7.93 (1H, dd, J 8.6, J 1.8 Hz), 7.49 (1H, d, J 8.0 Hz), 3.38 (2H, q, J 7.4 Hz), 2.98 (4H, q, J7.1 Hz), 2.14-2.04 (2H, in), 1.12 (3H, t, J7.3 Hz). 31 WO 2009/021750 PCT/EP2008/006720 0o(lz 0 (0 zz 0 o x ~ z 0 z C) 0 0 zx *00 Z Z0 00 CC Z 9 0- o, 0 0 z z 320 WO 2009/021750 PCT/EP2008/006720 EXAMPLE 2 (2-(Naphthalen-2-yl)benzo[dJoxazol-6-yl)methanol To a stirred suspension of methyl 2-(naphthalen-2-yl)benzo[d]oxazole-6-carboxylate (152mg, 0.5mmol) in dry tetrahydrofuran was added lithium aluminium hydride (38mg, 1.Ommol). The resulting solution was stirred at room temperature for 16h. The crude mixture was then diluted with ethyl acetate, washed with aqueous IM HCl solution and brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting product was purified by column chromatography eluting with ethyl acetate/hexanes 1:1 v/v to afford 90mg (66%) of the title compound (LCMS RT= 6.40min, MH* 276.1) 'H NMR (DMSO): 8.83 (1H, s), 8.27 (1H, dd, J8.9 1.8 Hz), 8.21-8.17 (1H, m), 8.14 (1H, d, J 8.9 Hz), 8.06-8.02 (1H, m), 7.78 (1H, d, J 8.2 Hz), 7.74 (1H, s), 7.70-7.62 (2H, m), 7.39 (1H, ddJ 8.0 0.8 Hz), 5.40 (1H, t, J 5.9 Hz), 4.67 (2H, d, J5.6 Hz) EXAMPLE 3 (Compounds 11) 2-(Dimethylamino)-N-(2-(naphthalen-2-yl)benzo[dloxazol-5-yl)acetamide To a solution of 2-(naphthalen-2-yl)benzo[dloxazol-5-amine (390mg, 1.50mmol) in dichloromethane (20mL) at room temperature was added diisopropylethylamine (784ptL, 4.50mmol) and a catalytic amount of DMAP, followed immediately after by the addition of 2-(dimethylamino)acetyl chloride (296mg, 1.88mmol). After 4h at room temperature, a further addition of diisopropylethylamine (784ptL, 4.50mmol) and 2-(dimethylamino)acetyl chloride (237mg, 1.50mmol) was made, and the resulting mixture was stirred at room temperature for 16h. Dichloromethane was then removed in vacuo, water was added, and a solid precipitated out. The obtained solid was washed with aqueous potassium carbonate solution to afford 430.2mg (83%) of the title compound (LCMS RT= 7.52min, MH* 346.2) 'H NMR (DMSO): 9.94 (lH, s), 8.83 (IH, s), 8.28-8.11 (4H, m), 8.06-8.01 (lH, m), 7.75 (1H, d, J8.6 Hz), 7.70-7.62 (3H, m), 3.12 (2H, s), 2.31 (6H, s). LCMS RT= 7.52min, MH* 346.2; 'H NMR (DMSO): 9.94 (1H, s), 8.83 (1H, s), 8.28-8.11 (4H, m), 8.06-8.01 (1H, m), 7.75 (lH, d, J8.6 Hz), 7.70-7.62 (3H, m), 3.12 (2H, s), 2.31 (6H, s). 3,3,3-Trifluoro-N-(2-(naphthalen-2-yl)benzo[dloxazol-5-yl)propanamide 33 WO 2009/021750 PCT/EP2008/006720 LCMS RT= 6.98min, MH* 371; 'H NMR (DMSO): 10.52 (1H, s), 8.85 (1H, s), 8.27 (1H, dd, J 8.6 1.7 Hz), 8.21-8.12 (3H, m), 8.07-8.02 (11H, m), 7.81 (1H, d, J 8.6 Hz), 7.69-7.64 (2H,m), 7.53 (1H, dd, J8.7 2.0 Hz), 3.56 (2H, q, J 11.2 Hz). Precursors to the two compounds below were obtained using this general method for the coupling, but the title compounds product were obtained after deprotection using TFA/DCM 3:10 v/v at room temperature for 2h: (S)-N-(2-(2,3-Dichlorophenyl)benzo[d]oxazol-5-yl)-2-(methylamino)propanamide LCMS RT= 6.29min, MH*364.1; 'H NMR (DMSO): 8.26 (1H, d, J 1.5 Hz), 8.10 (1H, dd, J 7.8 1.5 Hz), 7.90 (1H, dd, J 8.1 1.5 Hz), 7.79-7.69 (2H, m), 7.60 (1H, t, J 8.0 Hz), 3.61 (1H, q, J 7.4 Hz), 2.44 (3H, s), 1.40 (3H, d, J 6.9 Hz). (S)-2-Amino-N-(2-(2,3-dichlorophenyl)benzo[dloxazol-5-yl)propanamide LCMS RT= 5.96min, MH+ 350.1; 'H NMR (DMSO): 8.29 (1H, d, J2.0 Hz), 8.11 (1H, dd, J 7.8 1.5 Hz), 7.93 (1H, dd, J 8.1 1.5 Hz), 7.78 (1H, d, J8.8 Hz), 7.67 (1H, dd, J8.8 2.1 Hz), 7.60 (1H, t, J8.0 Hz), 3.50 (1H, q, J6.6 Hz), 1.26 (3H, d, J6.9 Hz). The compounds below were obtained using the same general method for the coupling, and didn't require a deprotection step: 2-(1H-Imidazol-1-yl)-N-(2-(naphthalen-2-yl)benzo[dloxazol-5-yl)acetamide LCMS RT= 5.79min, MH* 369; 'H NMR (DMSO): 10.52 (1H, s), 8.84 (1H, s), 8.26 (1H, dd, J 8.6 1.6 Hz), 8.20-8.11 (3H, m), 8.06-8.02 (1H, m), 7.80 (lH, d, J 8.9 Hz), 7.70-7.61 (3H, m), 7.56 (1H, dd, J8.8 2.0 Hz), 7.20 (1H, s), 6.92 (1H, s), 4.96 (2H, s). 2-(1H-Imidazol-4-yl)-N-(2-(naphthalen-2-yl)benzo[dJoxazol-5-yl)acetamide LCMS RT= 5.66min, MH* 369; 'H NMR (DMSO): 12.00-11.87 (IH, m), 10.31 (IH, s), 8.83 (1H, s), 8.26 (1H, dd, J8.6 1.7 Hz), 8.22-8.11 (3H, m), 8.06-8.01 (1H, m), 7.76 (1H, d, J 9.0 Hz), 7.68-7.63 (2H, m), 7.60-7.54 (2H, m), 3.59 (2H, s). EXAMPLE 4 (Compounds 1) 34 WO 2009/021750 PCT/EP2008/006720 As Method 3A, except instead of diisopropylamine, triethylamine was used as a base. 2-Methoxy-N-(2-(naphthalen-2-yl)benzo[dJoxazol-5-yl)acetamide LCMS RT= 6.69min, MH* 333.2; 'H NMR (CDCl 3 ): 8.80 (1H, s), 8.40 (1H, br), 8.32 (1H, dd, J 8.5 1.8 Hz), 8.09-8.08 (1H, m), 8.03-7.98 (2H, m), 7.94-7.90 (1H, m), 7.63-7.56 (4H, m), 4.09 (2H, s), 3.57 (3H, s). 2-(2-Methoxyethoxy)-N-(2-(naphthalen-2-yl)benzo[dloxazol-5-yl)acetamide LCMS RT= 6.77min, MH* 377.1; 'H NMR (CDCl 3 ): 9.08 (1H, s), 8.80 (1H, s), 8.33 (1H, dd, J 8.9 1.8 Hz), 8.09 (1H, d, J 1.9 Hz), 8.04-7.98 (2H, m), 7.94-7.90 (1H, m), 7.69-7.56 (4H, m), 4.19 (2H, s), 3.85-3.81 (2H, m), 3.70-3.66 (2H, m), 3.54 (3H, s). EXAMPLE 5 2-Bromo-N-(2-(naphthalen-2-yl)benzo dJoxazol-5-yl)acetamide 2-(naphthalen-2-yl)benzo[d]oxazol-5-amine (leq, 2g, 7.7mmol) was added to a stirred solution of dichloromethane (40ml), to this was added triethylamine (1.2eq, 0.934g, 9.2mmol, 1.28ml) and 2-bromoacetyl bromide (1.leq, 1.706g, 8.4mmol, 0.734ml). This was stirred at room temperature for 18 hours. The crude product was extracted in dichloromethane and washed with water. The organic layer was dried over magnesium sulphate and solvent removed in vacuo. Flash column chromatography of the crude product using a gradient (ethyl acetate/hexanes 1:1 run to ethyl acetate/hexanes 1:0) afforded 2.8g (96%) of the title compound. EXAMPLE 6 2-Morpholino-N-(2-(naphthalen-2-yl)benzo[dJoxazol-5-yl)acetamide 2-bromo-N-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)acetamide (leq, 0.5g, 1.3mmol) and potassium carbonate (1.2eq, 0.218g, 1.6mmol) were added in one portion to stirred dimethylformamide, to this was added morpholine (1.leq, 0.126g, 1.4mmol, 0.12ml). The reaction mixture was stirred at room temperature for 18 hours. The crude product was then extracted in dichloro methane and washed with brine. The organic layer was dried over magnesium sulphate and solvent removed in vacuo. Flash column chromatography of the 35 WO 2009/021750 PCT/EP2008/006720 crude product using a gradient (ethyl acetate/hexanes 1:1 run to ethyl acetate/hexanes 9:1) afforded 0.280g (55%) of the title compound. LCMS RT= 9.11min, MH* 386.5; 1H NMR (DMSO): 9.88 (1H, s), 8.83 (1H, bs), 8.26 (1H, dd, J 8.61 1.71), 8.23-8.17 (2H, m), 8.14 (1H, d, J 8.79), 8.06-8.03 (1H, m), 7.77 (1H, d, J 8.70), 7.68-7.62 (3H, m), 3.11 (2H, s), 1.63-1.56 (4H, m), 1.43-1.41 (2H, m). EXAMPLE 7 N-(2-Naphthalen-2-yl)benzo[dJoxazol-5-yl)methanesulfonamide A mixture of N-(2-naphthalen-2-yl)benzo[d]oxazol-5-amine (92mg, 0.353mmol), methanesulfonyl chloride (30tL, 0.388mmol) and pyridine (5mL) was stirred at room temperature for 3.5h. The mixture was partitioned between ethyl acetate and water and the two layers separated. The aqueous layer was extracted further with ethyl acetate and the combined extracts were dried (over anhydrous MgSO 4 ) and concentrated in vacuo. Purification by column chromatography (eluting with 30% ethyl acetate in 60:40 petroleum ether) gave the title compound as a yellow solid. LCMS RT= 6.48min, MH* 339.1 'H NMR (d6-DMSO): 9.81 (1H, br m); 8.84 (1H, m); 8.27 (1H, m); 8.14-8.22 (2H, m); 8.05 (1H, m); 7.81 (IH, m); 7.67 (3H, m); 7.30 (1H, dd, J= 8.7 & 2.1 Hz); 2.99 (3H, s). EXAMPLE 8 N-(2-Naphthalen-2-yl)benzo[dloxazol-5-yl)propionimidamide To a stirred solution of N-(2-naphthalen-2-yl)benzo[d]oxazol-5-anine (298mg, 1.137mmol) in propionitrile (2mL, 28.03mmol) was added trimethylsilyltrifluoromethane sulfonate (236p.L, 1.304mmol) dropwise at room termperature. After stirring for 24h at room temperature, the mixture was partitioned between IN aq. sodium hydroxide and ethyl acetate and the layers separated. The aqueous layer was extracted further with ethyl acetate and the combined extracts were dried (over anhydrous MgSO 4 ) and concentrated in vacuo. Purification by column chromatography (gradient elution using 30%-90% ethyl acetate in 60:40 petroleum ether, then neat ethyl acetate and methanol) gave the title compound as a brown solid (73mg, 20%). LCMS RT= 4.43min, MH* 316.2 'H NMR (d6-DMSO): 8.85 (IH, s); 8.27 (1H, m); 8.13-8.22 (2H, m); 8.05 (1H, m); 7.78 (1H, m); 7.67 (3H, m); 7.40 (1H, br); 7.03 (1H, br); 2.36 (2H, m); 1.23 (3H, br). 36 WO 2009/021750 PCT/EP2008/006720 O BBr OH Ar-COCI 0 NH2 DCM I NH 2 N reflux, 18h P R' 11 O 0 TMSBr R 0, 1) >-Ar OH( >A R-P R-P N 11 It 0 0 EXAMPLE 9 2-Amino-4-iodophenol A 1 M solution of BBr 3 in DCM (40 mL, 40.15mmol) was added slowly to dry DCM (40mL) at room temperature under an atmosphere of dry nitrogen, followed by 5-iodo-2 methoxyaniline (2.50 g, 10.04mmol). The resulting mixture was refluxed for 18 h under nitrogen and quenched with distilled water (50mL). The pink solid precipitated was collected by filtration and washed with water. It was then taken up in a saturated aqueous solution of sodium bicarbonate (200mL) and the aqueous layer was extracted with ethyl acetate (3 x 100mL). The combined organic extracts were washed with water until pH = 7, dried over anhydrous MgSO4 and evaporated to afford 1.37 g (58%) of 2 as a yellow solid. 'H NMR (DMSO): 9.26 (1H, s), 6.87 (1H, d, J 2.2 Hz), 6.66 (1H, dd, J 8.2 2.2 Hz), 6.44 (IH, d, J8.2 Hz), 4.72 (2H, s) 5-Iodo-2-(naphthalen-2-yl)benzo[doxazole To 2-amino-4-iodophenol (250mg, 1.06mmol) in dioxane (3mL) was added 2-naphthoyl chloride (203mg, 1.06mmol) at room temperature. The reaction vessel was heated in the microwave at 197'C for 15min. After cooling, the mixture was partitioned between ethyl acetate (100mL) and water (70mL) and the two layers were separated. The aqueous layer was extracted further with ethyl acetate (2 x 50mL), the combined extracts were dried over anhydrous MgSO 4 end evaporated in vacuo. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl acetate/hexanes 1:9 v/v) to afford 300mg (76%) of the title compound. 'H NMR (DMSO): 8.83 (1H, s), 8.25-8.12 (4H, m), 8.05-8.02 (1H, m), 7.76 (1H, dd, J 8.5 1.7 Hz), 7.69-7.62 (3H, m) 37 WO 2009/021750 PCT/EP2008/006720 The compounds below were prepared following the same general method. 2-(3,4-Dichlorophenyl)-5-iodobenzo[dioxazole LC RT= 11.45min; 'H NMR (DMSO): 8.31 (1H, d, J2.0 Hz), 8.21 (1H, d, J 1.6 Hz), 8.12 (IH, dd, J8.4 2.0 Hz), 7.89 (1H, d, J8.4 Hz), 7.77 (1H, dd, J8.5 1.6 Hz), 7.66 (1H, d, J8.5 Hz) 2-(2,3-Dichlorophenyl)-5-iodobenzo[dioxazole 'H NMR (DMSO): 8.29 (1H, d, J 1.5 Hz), 8.10 (1 H, dd, J 8.0 1.5 Hz), 7.94 (1H, dd, J 8.0 1.5 Hz), 7.81 (1H, dd, J8.5 1.5 Hz), 7.70 (1H, d, J8.5 Hz), 7.60 (1H, t, J8.0 Hz) EXAMPLE 10 Ethyl 2-(naphthalen-2-yl)benzo[dloxazol-5-yl(phenyl)phosphinate Tetrakis(triphenylphosphine)palladium(O) (47mg, 0.04mmol) was added in one portion to a stirred solution of 5-iodo-2-(naphthalen-2-yl)benzo[d]oxazole (147mg, 0.4mmol) and ethyl phenylphosphinate (89pL, 0.6mmol) in toluene (5mL) in the presence of triethylamine (170iL, 1.19mmol) and the resulting mixture was heated in a sealed tube at 100*C for 3 h under an atmosphere of dry nitrogen. After cooling, the mixture was partitioned between ethyl acetate (100mL) and water (70mL) and the two layers were separated. The aqueous layer was extracted further with ethyl acetate (2 x 50mL), the combined extracts were dried over anhydrous MgSO 4 end evaporated in vacuo. The resulting brown oil was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl acetate/hexanes 8:2 v/v) to afford 109mg (66%) of the title compound (LCMS RT= 7.54min, MH* 414.1). 'H NMR (DMSO): 8.86 (1H, s), 8.29-8.14 (4H, in), 8.06-7.97 (2H, in), 7.88-7.81 (3H, in), 7.71-7.51 (5H, m), 4.10-4.00 (2H, in), 1.33 (3H, t, J7.0 Hz) The compounds below were prepared following the same general method. Methyl ethyl(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)phosphinate 38 WO 2009/021750 PCT/EP2008/006720 LCMS RT= 6.41min, 2MH* 703.2; 'H NMR (DMSO): 8.88 (1H, s), 8.29 (1H, dd, J 8.6 1.7), 8.23-8.15 (3H, m), 8.07-8.00 (2H, m), 7.85-7.78 (1H, m), 7.70-7.66 (2H, m), 3.55 (3H, d, J 10.9 Hz), 2.09-1.95 (2H, m), 1.05-0.93 (3H, m) Methyl 2-(3,4-dichlorophenyl)benzo[dloxazol-5-yl(ethyl)phosphinate LCMS RT= 6.65min, MH* 370.0; 'H NMR (DMSO): 8.37 (1H, d, J 2.0 Hz), 8.19-8.15 (2H, m), 8.00 (1H, dd, J8.3 2.3 Hz), 7.92 (1H, d, J8.4 Hz), 7.86-7.79 (1H, m), 3.53 (3H, d, J 11.0 Hz), 2.08-1.95 (2H, m), 1.03-0.92 (3H, m) Methyl 2-(2,3-dichlorophenyl)benzo d]oxazol-5-yl(ethyl)phosphinate LCMS RT= 6.23min, MH* 370.0;'H NMR (DMSO): 8.24 (1H, d, J 11.2 Hz), 8.13 (1H, d, J 7.9 Hz), 8.05-8.02 (1H, m), 7.97 (IH, d, J8.1 Hz), 7.89-7.83 (1H, m), 7.63 (1H, t, J7.9 Hz), 3.53 (3H, d, J 11.0 Hz), 2.09-1.96 (2H, m), 1.03-0.92 (3H, m) (2-(4-Chlorophenyl)benzo[d]oxazol-5-yi(ethyl)phosphinic acid Trimethylsilyl bromide (120 L, 0.88mmol) was added dropwise to a stirred solution of methyl 2-(4-chlorophenyl)benzo[d]oxazol-5-yl(ethyl)phosphinate (161mg, 0.44mmol) in dry dochloromethane (5mL) at 0 0 C. The resulting solution was allowed to reach room temperature over a period of 2 h and stirred for 16 h. The crude was then diluted with dichloromethane (lOOmL) and the organic layer was washed with water (50mL). The aqueous layer was extracted further with dichloromethane (2 x 30mL), the combined extracts were dried over anhydrous MgSO 4 end evaporated in vacuo. The resulting colorless solid was purified by column chromatography eluting using a gradient (ethyl acetate/methanol 1:0 v/v to ethyl acetate/methanol 0:1 v/v) to afford 77mg (50%) of the title compound (LCMS RT=4.44min, (M-H)* 320.1). 'H NMR (MeOH-d 4 ): 8.12 (2H, d, J 8.8), 8.10-8.06 (IH, n), 7.78-7.72 (1H, m), 7.58 (1H, dd, J 8.1, 1.4), 7.50 (2H, d, J 8.8), 4.49 (1H, br-s), 1.65-1.53 (2H, m), 0.95-0.84 (3H, m). 39 WO 2009/021750 PCT/EP2008/006720 S C I Pridin DCM l Lawesson's. Touene S a NH2 c Method 32 NMethod 33 c I H I ehd3H

I

c I XXIX XXX K3Fe(CN) 6 , Ethan ' S mCPBA. DCM Me2S C NaOH 9D*, 3min a ci rt, 3h Method 34 N XXXI XXXII 5 EXAMPLE 11 (Compound XXXI) 2-Naphthoylchloride (1. 13g, 5.9mmol) was added to a solution of 3-methylsulfonyl aniline hydrochloride (1.12g, 5.4mmol) in pyridine (15mL). After stirring for 4h, the 10 reaction mixture was partitioned between water and EtOAc and the organic phase was dried over MgSO 4 and concentrated in vacuo. The crude title compound was used in the next reaction without further purification. LCMS RT= 5.95min, MH* 326; 'H NMR (DMSO): 10.81 (1H, s), 8.63 (1H, s), 8.47 (1H, s), 8.20-8.17 (1H, m), 8.12-7.99 (4H, m), 7.69-7.64 (4H, m), 3.25 (3H, s). 15 N-(3-(Methylsulfonyl)phenyl)naphthalene-2-carbothioamide A stirred solution of N-(3-(methylsulfonyl)phenyl)naphthamide (1.67g, 5. 1mmol), and lawessons reagent (1.25g, 3.1 mmol) in toluene (36mL) was heated under reflux for 16h. After cooling to room temperature the solvent was evaporated under reduced 20 pressure and the residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/0, v/v, to afford 1.5g (85%) of the title compound. LCMS RT= 6.26min, MH* 342.0; 'H NMR (DMSO): 12.20 (lH, s), 8.53 (1H, s), 8.41 (1H, s), 8.26 (1H, d, J7.9 Hz), 8.10-8.06 (1H, m), 7.99 (3H, m), 7.85 (1H, d, J8.1 Hz), 7.75 (1H, t, J 8.0 Hz), 7.67-7.60 (2H, in), 3.26 (3H, s). 25 5-(Methylsulfonyl)-2-(naphthalen-2-yl)benzo[dJthiazole WO 2009/021750 PCT/EP2008/006720 A solution of potassium hexacyanoferrate(III) (5.96g, 18.1mmol) in water (40mL) was heated to 90'C . To it, a solution of N-(3-(methylsulfonyl)phenyl)naphthalene-2 carbothioamide (1.54g, 4.5mmol) and 3M sodium hydroxide (20mL) in IMS (15mL) was added dropwise over 5 minutes. After stirring for 30 minutes, the reaction was 5 cooled to room temperature, filtered over a vacuum and washed with water. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/4, v/v, to afford 137mg (9%) of the title compound. LCMS RT= 7.45min, MH* 340.1; 'H NMR (DMSO): 8.78 (IH, d, J 1.4 Hz), 8.40 (1H, dd, J8.1, J 1.0 Hz), 8.24 (1H, dd, J8.6, J 1.8 Hz), 8.17-8.14 (1H, m), 8.08 (1H, d, 10 J 8.7 Hz), 8.02 (1H, dd, J 7.7, J 1.0 Hz), 8.00-7.97 (1H, m), 7.80 (1H, t, J 8.0 Hz), 7.62-7.58 (2H, m), 3.34 (3H, s). EXAMPLE 12 (Compound XLV) 15 5-(2,2,2-Trideuteroethylsulfonyl)-2-(naphthalen-2-yl)benzo[dloxazole LHMDS (1M in THF, 1.36mL, 1.36mmol) was added to a solution of 5 (methylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (400mg, 1.237mmol) in THF (30mL) at -78"C under N 2 . The resultant solution was allowed to stir at -78'C for 1 hour before the addition of d 3 -methyliodide. The reaction mixture was allowed to 20 warm to room temperature over 16 hours before the addition of saturated aqueous ammonium chloride (25mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (x3). The combined organic layers were dried over MgSO 4 and concentrated in vacuo to furnish the title compound as an off-white solid (106mg, 25%) after column chromatography (4:1 to 2:1 40-60 petrol:ethyl acetate) (LCMS 25 RT=7.00=6min, MH* 341). 'H NMR (d6-DMSO) 8.93 (1H, s), 8.36 (1H, dd,J 1.8 0.5 Hz), 8.32 (1H, dd, J8.7 1.8 Hz), 8.23-8.26 (IH, m), 8.19 (1H, d, J 8.8 Hz), 8.14 (1H, dd, J 8.6 0.5 Hz), 8.07-8.10 (1H, m), 8.00 (1H, dd, J 8.6 1.8 Hz), 3.41 (2H, s). 30 EXAMPLE 13 Benzyl (2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)acetate. A I WO 2009/021750 PCT/EP2008/006720

BF

3 -OEt 2 (0.39mL, 3.1mmol) was added to a solution of 1,2,3,4,6-penta-O-acetyl-beta D-glucopyranose (1g, 2.56mmol) and benzyl glycolate (0.44mL, 3.1mmol) in anhydrous DCM (1 5mL) and the resulting reaction mixture was stirred for 5hr at room temperature. The solution was neutralized with Et 3 N and concentrated under reduced 5 pressure. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/1, v/v, to afford 1g (78%) of the title compound. (LCMS RT= 5.91min, MNH 4 514). IH NMR (CDC 3 ): 7.35 (5H, bs), 5.23 (1H, t, J9.5 Hz), 5.17 (2H, s), 5.07 (1H, t, J9.8 Hz), 5.03 (1H, dd, J 7.9 Hz, J 9.6 Hz), 4.66 (1H, d, J 7.9 Hz), 4.32 (2H, s), 4.23 (1H, 10 dd, J4.7 Hz, J12.4 Hz), 4.11 (1H, dd, J2.4 Hz, J12.4 Hz), 3.68 (1H, m), 2.06 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 1.99 (3H, s). (2,3,4,6-Tetra-O-acetyl-beta-D-glucopyranosyloxy)acetic acid A solution of benzyl (2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosylox)acetate (lg, 2 15 mmol) was degassed, Pd-C (10%, 50mg) was added and the solution was degassed again. After stirring for 2.5h under a hydrogen atmosphere the reaction mixture was filtered over celite and the filtrate concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/0, v/v, to afford 524 mg (65%) of the title compound. (LCMS RT= 4.32min, M 405.1). 20 'H NMR (CDCl 3 ): 9.18 (1H, bs), 5.23 (1H, t, J 9.5 Hz), 5.07 (1H, t, J 9.8 Hz), 5.02 (IH, dd, J 7.9 Hz, J 9.5 Hz), 4.66 (1H, d, J7.9 Hz), 4.32 (2H, s), 4.24 (1H, dd, J 4.7 Hz, J 12.4 Hz), 4.11 (1H, dd, J 2.3 Hz, J 12.4 Hz), 3.71 (1H, m), 2.07 (3H, s), 2.05 (3H, s), 2.01 (3H, s), 1.99 (3H, s). 25 N-(2-(2,3-Dichlorophenyl)benzo[d]oxazol-5-yl)-2-(2',3',4',6'-tetra-O-acetyl-beta D-glucopyranosyloxy)acetamide A solution of 2-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)acetic acid (524mg, 1.3mmol) and 2-(2,3-dichlorophenyl)benzo[d]oxazol-5-amine (362mg, 1.3mmol) in DMF (6mL) was cooled to 0 0 C, HATU (593 mg, 1.56mmol) and DIPEA (0.68mL, 30 3.9mmol) were added and the resulting reaction mixture was slowly warmed to room temperature. After stirring for 16h the reaction mixture was partitioned between EtOAc(200mL) and brine (150mL), the aqueous phase was extracted with EtOAc (2x15OmL) and the combined organic phase was washed with brine (200mL) and dried

A'I

WO 2009/021750 PCT/EP2008/006720 over MgSO 4 . After removal of the solvent under reduced pressure the residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 7/3, v/v, to afford 762 mg (88%) of a pink solid. 'H NMR (CDCl 3 ): 8.23 (1H, bs), 8.06 (d, J 1.6 Hz), 8.03 (1H, dd, J 1.6Hz, J7.9 Hz), 5 7.68-7.58 (3H, m), 7.39 (1H, t, J 7.9), 5.32 (1H, dd, J 9.5 Hz, J 11.9 Hz), 5.19-5.12 (2H, t, J9.8 Hz), 5.02 (1H, dd, J7.9 Hz, J9.5 Hz), 4.64 (1H, d, J7.8 Hz), 4.52 (1H, d, J 15.0 Hz), 4.34 (1H, dd, J4.9 Hz, J12.5 Hz), 4.26 (1H, d, 115.0 Hz), 4.161 (1H, dd, J 2.3 Hz, 112.5 Hz), 3.80 (1H, m), 2.13 (3H, s), 2.10 (3H, s), 2.08 (3H, s), 2.07 (3H, s). 10 N-(2-(2,3-Dichlorophenyl)benzo[dJoxazol-5-yl)-2-(beta-D glucopyranosyloxy)acetamide A solution of N-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-yl)-2-(2',3',4',6'-tetra-O acetyl-beta-D-glucopyranosyloxy)acetamide (0.76 g, 1.14mmol) and ammonia (7N solution in MeOH, 14mL) was stirred for 16h at ambient temperature. The reaction 15 mixture was diluted with MeOH and concentrated under reduced pressure. The residue was triturated with hot MeOH and Et 2 0 to give 527 mg (93%) of the title compound as a white powder. (LCMS RT= 4.98min, MH*500.8). 'H NMR (DMSO): 10.08 (1H, s), 8.24 (d, J 1.6 Hz), 8.13 (1H, dd, J1.5 Hz, J7.9 Hz), 7.93 (1H, dd, J 1.6 Hz, J8.1 Hz), 7.82 (1H, d, J8.9 Hz), 7.70 (1H, dd, J 2.0 Hz, J 8.9 20 Hz), 7.61 (1H, t, J7.9), 6.12 (1H, d, J3.9 Hz), 5.15 (1H, d, 14.7 Hz), 5.01(1H, d, J5.2 Hz), 4.59 (1H, t, J5.9 Hz), 4.41-4.36 (2H, m), 4.264 (1H, d, J16.1 Hz), 3.69 (1H, dd, J 6.3 Hz, J10.2 Hz), 3.51-3.43 (1H, m), 3.21-3.14 (4H, m). N-(2-(2,3-Dichlorophenyl)benzo[dloxazol-5-yl)-2-(beta-D-galactopyranosyl 25 oxy)acetamide The title compound was prepared using the same method for the building block synthesis, coupling and deprotection. (LCMS RT= 5. 10min, MH* 499.0) 'H NMR (DMSO): 10.21 (1H, s), 8.26 (1H, d, J 1.8 Hz), 8.12 (1H, dd, J 7.9 1.4 Hz), 7.93 (1H, dd, J 8.1 1.5 Hz), 7.81 (1H, d, J 9.0 Hz), 7.73 (1H, dd, J 9.0 1.8 Hz), 7.61 30 (1H, t, J7.7 Hz), 6.03 (1H, d, J4.0 Hz), 4.96 (1H, d, J 5.7 Hz), 4.71 (1H, t, J 6.4 Hz), 4.59 (1H, d, J5.2 Hz), 4.41-4.17 (3H, m), 3.70-3.41 (6H, m) 2,3,4,6-Tetra-O-acetyl-alpha-D-mannopyranosyl bromide 43 WO 2009/021750 PCT/EP2008/006720 A solution of 1,2,3,4,6-penta-O-acetyl-alpha-D-mannopyranose (5g, 12.8mmol) in 33%HBr/AcOH (60mL) was stirred at 0*C for 2h. The reaction mixture was poured into ice-water (1OOmL) and extracted with EtOAc (3x 150mL). The combined organic phase was washed with NaHCO 3 (3x 200mL), dried over MgSO 4 and concentrated in 5 vacuo. The crude title compound was used in the next reaction without any further purification. 'H NMR (CDCI): 6.31 (1H, d, J 1.2 Hz), 5.73 (1H, dd, J 3.4 Hz, J 10.1 Hz), 5.47 (1H, dd, J 1.6 Hz, J 3.4 Hz), 5.38 (1H, t, J 10.1 Hz), 4.35 (1H, dd, J 4.87 Hz, J 12.3 Hz), 4.26 )1H, in), 4.15 (1H, dd, J 2.1 Hz, J 12.3 Hz), 2.20 (3H, s), 2.13 (3H,. s), 2.09 10 (314, s), 2.03 (3H, s). Benzyl (2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyloxy)acetate. A solution of AgOTf (3.6g, 14.1mmol) in anhydrous toluene (20mL) was added to a cooled (0*C) solution of 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl bromide (12.8 15 mmol) and benzyl glycolate (1.82mL, 12.8mmol) in anhydrous DCM (50mL). The resulting reaction mixture was stirred for 16hr, then diluted with DCM (200mL), washed with NaHCO 3 (2x lOOmL) and brine (100mL), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/1, v/v, to afford 20 2.03g (32%) of the title compound. 'H NMR (CDC 3 ): 7.30 (5H, bs), 5.34-5.25 (314, m), 5.14 (2H, s), 4.91 (1H, d J 1.4 Hz), 4.27 (1H, d, J 16.4 Hz), 4.20 (1H, dd, J 4.9 Hz, J 12.2 Hz), 4.15 (1H, d, J 16.4 Hz), 4.14-4.08 (1H, in), 3.99 (1H, dd, J 2.2 Hz, J 12.2 Hz), 2.07 (3H, s), 2.04 (3H, s), 2.02 (3H, s), 1.99 (3H, s). 25 (2,3,4,6-Tetra-0-acetyl-beta-D-mannopyranosyloxy)acetic acid The title compound was prepared as described for (2,3,4,6-tetra-O-acetyl-beta-D glucopyranosyloxy)acetic acid, without the column chromatography step. 30 NMR (CDC1 3 ): 9.18 (114, bs), 5.35-5.27 (3H, in), 4.93 (114, bs), 4.32-4.21 (3H, in), 4.14-4.06 (2H, in), 2.13 (3H, s), 2.09 (3H, s), 2.03 (3H, s), 1.97 (3H, s).

WO 2009/021750 PCT/EP2008/006720 N-(2-(2,3-Dichlorophenyl)benzofdjoxazol-5-y)-2-(2',3',4',6'-tetra-O-acetyl-beta D-mannopyranosyloxy)acetamide The title compound was prepared using the same general method for the coupling. (LCMS RT= 6.62 min, MH 667.5) 5 'H NMR (CDC 3 ): 8.36 (1H, bs), 8.17 (d, J 1.4 Hz), 8.01 (1H, dd, J 1.6Hz, J7.9 Hz), 7.62 (1H, dd, J 1.6 Hz, 8.0 Hz), 7.55 (2H, s), 7.35 (1H, t, J 7.9), 5.44-5.29 (3H, m), 4.99 (1H, s), 4.37 (1H, d, J 15.3 Hz), 4.30 (1H, dd, J 5.9 Hz, J 12.5 Hz), 4.18 (1H, d, J 15.3 Hz), 4.16-4.03 (2H, m), 2.17 (3H, s), 2,09 (3H, s), 2.06 (3H, s), 2.04 (3H, s). 10 N-(2-(2,3-Dichlorophenyl)benzo[djoxazol-5-yI)-2-(beta-D mannopyranosyloxy)acetamide The title compound was prepared using the same general method for the deprotection. (LCMS RT= 5.01 min, MH* 501.1) 1H NMR (CDC1 3 ): 10.02 (1H, s), 8.24 (d, J 1.9 Hz), 8.11 (1H, dd, J 1.5 Hz, J7.9 Hz), 15 7.93 (1H, dd, J 1.5 Hz, J 8.1 Hz), 7.80 (1H, d, J 8.9 Hz), 7.65 (1H, dd, J 1.9 Hz, J 8.9 Hz), 7.60 (1H, t, J 8.1), 4.85 (1H, d, J 4.4 Hz), 4.77 (2H, m), 4.61 (1H, d, J 6.1 Hz), 4.52 (1H, t, J5.6 Hz), 3.83 (2H, m), 3.66 (1H, dd, J6.3 Hz, J10.8 Hz), 3.62-3.56 (1H, m), 3.47-3.31 (3H, m). 20 3'-Benzyloxypropyl 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranoside

BF

3 OEt 2 (0.7lmL, 5.6mmol) was added to a solution of 1,2,3,4,6-penta-O-acetyl-beta D-glucopyranose (2g, 5.1mmol) and 3-benzyloxypropanol (0.90mL, 5.6mmol) in anhydrous DCM (25mL) and the resulting reaction mixture was stirred for 16hr at room temperature. The solution was neutralised with Et 3 N and concentrated under reduced 25 pressure. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/1, v/v, to afford 2.1 g (85%) of the title compound. 'H NMR (CDC1 3 ): 7.40-7.33 (5H, m), 5.42 (1H, dd, J 1.1 Hz, J3.4 Hz), 5.24 (1H, dd, J7.9 Hz, J 10.5 Hz), 5.05 (1H, dd, J 3.4 Hz, J 10.5 Hz), 4.54 (2H, m), 4.49 (1H, d, J 7.9 Hz), 4.22-4.14 (2H, m), 4.04-4.00 (1H, m), 3.93 (1H, dt, J 1.1 Hz, J 6.7 Hz), 3.83 30 (1H, t, J5.6 Hz), 3.74-3.69 (1H, in), 3.60-3.55 (1 H, in), 2.19 (3H, s), 2.09 (3H, s), 2.05 (3H, s), 2.03 (3H, s), 1.96-1.90 (2H, m). 3'-Hydroxypropyl 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranoside WO 2009/021750 PCT/EP2008/006720 A solution of 3'-benzyloxypropyl 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranoside (8.6g, l7mmol) was degassed, Pd-C (10%, 500mg) was added and the solution was degassed again. After stirring for 3h under a hydrogen atmosphere the reaction mixture was filtered over celite and the filtrate concentrated in vacuo. The residue was purified 5 by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/0, v/v, to afford 4.9g (70%) of the title compound. 'H NMR (CDCl 3 ): 5.44 (1H, dd, J 1.1 Hz, J 3.4 Hz), 5.25 (1H, dd, J 7.9 Hz, J 10.5 Hz), 5.06 (1H, dd, J3.4 Hz,] 10.5 Hz), 4.53 (1H, d, J7.9 Hz), 4.22-4.14 (2H, m), 4.09 4.04 (1H, m), 3.96 (1H, dt, J 1.1 Hz, J6.6 Hz), 3.80-3.72 (3H, m), 2.20 (3H, s), 2.12 10 (3H, s), 2.10 (3H, s), 2.03 (3H, s), 1.91-1.86 (2H, m). 3'-(2,3,4,6-Tetra-O-acetyl-beta-D-galactopyranosyloxy)propanoic acid A solution of NaCI (sat. aq. 3mL), NaHCO 3 (sat. aq. 1.5 mL) and NaOC (13%, 3mL) was added to a solution of 3'-hydroxypropyl 2,3,4,6-tetra-O-acetyl-beta-D 15 galactopyranoside (0.5g, 1.2mmol), TEMPO (3mg, 0.02mmol), KBr (12mg, 0.098mmol), TBABr (16mg, 0.062mmol) and NaHCO 3 (sat. aq. 3mL) in DCM (1OmL) at 0*C. After stirring for 30 min at 0*C the reaction mixture was neutralized with 1N HCl, extracted with DCM (3 x 10mL) and the combined organic layers dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column 20 chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/0, v/v, to afford 0.45g (88%) of the title compound. 'H NMR (CDCl 3 ): 5.32 (1H, dd, J 0.9 Hz, J 3.4 Hz), 5.10 (1H, dd, J 7.9 Hz, J 10.5 Hz), 4.95 (1H, dd, J3.4 Hz, J10.5 Hz), 4.46 (1H, d, J7.9 Hz), 4.13-4.01 (3H, m), 3.87 3.78 (2H, m), 2.62-2.56 (2H, m), 2.08 (3H, s), 1.99 (3H, s), 1.97 (3H, s), 1.91 (3H, s). 25 N-(2-(2,3-Dichlorophenyl)benzo[dJoxazol-5-yl)-3-(beta-D-galactopyranosyl oxy)propanamide The title compound was prepared using the standard method for the coupling and deprotection. 30 (LCMS RT= 5.09min, MH* 513.0); 'H NMR (DMSO): 10.13 (1H, s), 8.23 (1H, d, J 1.9 Hz), 8.10 (1H, dd, J7.9 1.6 Hz), 7.92 (1H, dd, J8.2 1.4 Hz), 7.76 (1H, d, J 8.8 Hz), 7.63-7.56 (2H, m), 4.87 (IH, d, J4.0 Hz), 4.71 (IH, d, J5.0 Hz), 4.62 (1H, t, J5.7 Hz), A 1 WO 2009/021750 PCT/EP2008/006720 4.38 (lH, d, J 4.7 Hz), 4.16 (1H, d, J 7.5 Hz), 4.10-4.00 (1H, m), 3.87-3.77 (1H, m), 3.63 (1H, br), 3.58-3.45 (2H, m), 2.66 (2H, d, J6.5 Hz) N-(2-(Naphthalen-2-yl)benzo[dloxazol-5-yl)-2-(beta-D-galactopyranosyl 5 oxy)propanamide The title compound was prepared using the standard method for the coupling and deprotection. LCMS RT= 5.05min, MH*495.2; 'H NMR (DMSO): 10.08 (1H, s), 8.83 (1H, s), 8.27 (1H, dd, J8.6 1.7 Hz), 8.21-8.11 (3H, m), 8.06-8.02 (1H, m), 7.76 (1H, d, J 8.7 10 Hz), 7.68-7.63 (2H, m), 7.57 (1H, dd, J8.6 2.0 Hz), 4.88-4.85 (1H, m), 4.72-4.68 (1H, m), 4.64-4.58 (1H, m), 4.38-4.35 (1H, m), 4.16 (1H, d, J 6.7 Hz), 4.10-4.01 (1H, m), 3.87-3.78 (1H, m), 3.66-3.62 (1H, m), 3.56-3.49 (2H, m), 2.69-2.62 (2H, m). 2-(Benzyloxy)-N-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-yl)acetamide 15 The title compound was obtained using the standard method for coupling. (LCMS RT= 7.87 min, MH* 427.2) H NMR (CDCI 3 ): 8.47 (1H, bs), 8.06 (t, J 1.4 Hz), 7.67 (1H, dd, J 1.6Hz, J 8.0 Hz), 7.59 (2H, m), 7.45-7.36 (6H, m), 4.72 (2H, s), 4.18 (2H, s). 20 N-(2-(2,3-Dichlorophenyl)benzo[dloxazol-5-yl)-2-hydroxyacetamide A solution of 2-(benzyloxy)-N-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-yl)acetamide (0.97g, 2.28 mmol) was degassed, Pd-C (10%, 100mg) was added and the solution was degassed again. After stirring for 6h under a hydrogen atmosphere the reaction mixture was filtered over celite and the filtrate concentrated in vacuo. The residue was purified 25 by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/0, v/v. The white solid was triturated with Et 2 0 (2x) to afford 380mg (50%) of the title compound. (LCMS RT= 5.76min, M 336.9). 'H NMR (DMSO): 9.94 (1H, s), 8.31 (1H, s), 8.10 (1H, dd, J 1.5 Hz, J7.9 Hz), 7.92 (1H, dd, J 1.5 Hz, J 8.0 Hz), 7.78 (2H, m), 7.60 (1H, t, J 8.0 Hz ), 5.74 (1H, t, J 6.0 30 Hz), 4.04 (2H, d, J6.0 Hz). The compounds below were made by the same coupling and deprotection as for N (2-(2,3-Dichlorophenyl)benzo[dJoxazol-5-yl)-2-hydroxyacetamide A'7 WO 2009/021750 PCT/EP2008/006720 N-(2-(2,3-Dichlorophenyl)benzo[dloxazol-5-yl)-3-hydroxypropanamide LCMS RT= 5.71min, MH*352.6; 'H NMR (DMSO): 10.13 (1H, s), 8.25 (1H, d, J1.9 Hz), 8.10 (1H, dd, J 7.9 1.7 Hz), 7.92 (1H, dd, J 8.3 1.6 Hz), 7.76 (1H, d, J 8.8 Hz), 5 7.62-7.56 (2H, m), 4.71 (1H, t, J5.3 H), 3.74 (2H, q, J5.6 Hz), 2H (m, obscured). N-(2-(Naphthalen-2-yl)benzo[dloxazol-5-yl)-3-hydroxypropanamide LCMS RT = 8.03 min, MH*333.2; 'H NMR (DMSO): 10.11 (1H, s), 8.82 (1H, s), 8.28-8.12 (4H, m), 8.06-8.02 (1H, m), 7.75 (1H,d, J 8.8 Hz), 7.68-7.64 (2H, m), 7.56 10 (1H, dd, J2.0 Hz, J8.8 Hz), 4.70 (1H, t, J 5.1 Hz), 3.74 (2H, d, J 5.2 Hz), & 2H (m, obscured). 2-Hvdroxy-N-(2-(naphthalen-2-yl)benzo[dJoxazol-5-yl)acetamide The title compound was obtained using the standard method for coupling: no 15 deprotection required. LCMS RT= 5.95min, MH* 319.1; 'H NMR (DMSO): 9.90 (1H, s), 8.83 (1H, s), 8.28 8.24 (2H, m), 8.20-8.11 (2H, m), 8.06-8.01 (1H, m), 7.76-7.74 (2H,m), 7.68-7.63 (2H, m), 5.74 (1H, t, J6.2 Hz), 4.04 (2H, d, J6.0 Hz). 20 OH EtBr, K 2

CO

3 OH HNO 3 , AcOH OH HS / acetone O NO 2 Fe NH 4 CI IMS-H 2 0 70*C S NH2 NapCOCI, xylene, TsOH 0 -S NH 2 heat S mCPBA, DCM -78*C to -50*C 0 II '. ,; N> 0 EXAMPLE 14

AO

WO 2009/021750 PCT/EP2008/006720 5-(Ethylsulfinyl)-2-(naphthalen-2-yl)benzo[doxazole (i) 4-(Ethylthio)phenol 5 4-mercaptophenol (4.2g, 33.3mmol) was dissolved in acetone (35mL). K 2

CO

3 (4.8g, 35mmol) and EtBr (3.6mL, 49.9mmol) were added and the mixture stirred at room temperature for 17h. the mixture was filtered, and the residue washed with Et 2 O (3x3OmL). the combined organics were washed with IM NaOH (2 x 50mL). the aqueous extracts were combined and acidified with 2M HCl. The acidic solution was 10 extracted with Et 2 0 (2 x 50mL). The combined organic layers were washed with brine, dried (Na 2

SO

4 ), filtered and concentrated under reduced pressure to give a brown oil which crystallized on standing. The crude sulfide was purified by column chromatography (10% EtOAc/hexanes) to give the title compound as a pale yellow oil that crystallized on standing (3.9g, 75%). TY ~A A' DD'IN A Q1 (1 P 15 'H NMR (CDC 3 ): 7.31 (2 H, app d, AA 'BB), 6.79 z E, app U, AA ', 4.1 in), 2.85 (2 H, q, J7.3) and 1.26 (3 H, t, J7.3). (ii) 4-(Ethylthio)-2-nitrophenol 4-(Ethylthio)phenol (3.2g, 20.5mmol) was dissolved in AcOH (l0mL) and cooled to 20 0"C. Concentrated HN0 3 (approx. 16M, 1.28mL, 20.5mmol) was added dropwise. On completion of the addition, the mixture was diluted with H 2 0 (20mL) and extracted with CHCl 3 (2 x 25mL). The combined CHCl 3 extracts were washed with H 2 0 (25mL) and brine (25mL) then dried (MgSO 4 ), filtered and concentrated under reduced pressure. The crude mixture was then purified by column chromatography (25% 25 EtOAc/hexanes) to give the title compound as an orange oil (310mg, 8%). 'H NMR (CDCI): 10.54 (1 H, s), 8.09 (1 H, d, J 2.1), 7.59 (1 H, dd, J 8.8 and 2.2), 7.13 (1 H, d, J8.8), 2.92 (2 H, q, J7.3) and 1.31 (3 H, t, J7.4). (iii) 2-Amino-4-(ethy/thio)phenol 30 4-(ethylthio)-2-nitrophenol (200mg, 1.0mmol) was dissolved in IMS/H 2 0 (5:1, 12mL).

NH

4 Cl (107mg, 2.Ommol) was added and the mixture heated to 80'C. Fe powder (280mg, 5.Ommol) was added and the mixture heated at this temperature for lh, by which time TLC analysis (50% EtOAc/hexanes) indicated no starting material remained. The mixture was cooled and filtered through celite, washing with MeOH

AA

WO 2009/021750 PCT/EP2008/006720 until the filtrate ran colourless. The filtrate was concentrated, then redissolved in EtOAc/H 2 0. The solution was extracted with EtOAc (2 x 30mL). The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to afford the title compound as a brown solid (100mg, 59%). 5 IH NMR (CDC1 3 ): 6.83 (1 H, in), 6.74 (1 H, in), 6.67 (1 H, in), 4.03 (3 H, br s), 2.83 (2 H, q, J7.3) and 1.26 (3 H, t, J7.3). (iv) 5-(Ethylthio)-2-(naphthalen-2-yl)benzo[d]oxazole 2-amino-4-(ethylthio)phenol (100mg, 0.59mmol) was dissolved in xylene (5mL) and 2 naphthoyl chloride (113mg, 0.59mmol) was added. The mixture was heated to 160'C 10 for 15 minutes, by which time TLC analysis (50% EtOAc/hexanes) indicated no starting material was present. pTsOH (225mg, 1.18mmol) was added and the mixture heated at reflux for 2h. The mixture was cooled, diluted with EtOAc and absorbed onto silica. Column chromatography (gradient: 100% hexanes - 20% EtOAc/hexanes) afforded the title compound as an off-white solid (130mg, 72%). 15 'H NMR (CDC1 3 ): 8.79 (1 H, s), 8.32 (1 H, dd, J 8.6 and 1.6), 8.03-7.99 (2 H, in), 7.96-7.91 (1 H, m), 7.84 (1 H, br d), 7.64-7.55 (3 H, m), 7.42 (1 H, dd, J8.4 and 1.8), 3.01 (2 H, q, J7.3) and 1.35 (3 H, t, J7.3). (v) 5-(Ethylsulfinyl)-2-(naphthalen-2-yl)benzo[d]oxazole 20 5-(ethylthio)-2-(naphthalen-2-yl)benzo[d]oxazole (64mg, 0.21mmol) was dissolved in dichloromethane (1OmL) and cooled to -78 0 C. mCPBA (77%, 47mg, 0.21mmol) was added and the mixture stirred for 1h, allowing the temperature to rise to -50 0 C. Aqueous Na 2

SO

3 (1mL) was added and the mixture warmed to room temperature. The mixture was washed with IM NaOH (3 x 5mL) and brine (1OmL). The organic layer 25 was dried (MgSO 4 ), filtered and concentrated. The crude product was combined with a second batch of equivalent scale and purified by column chromatography (gradient: 50% EtOAc/hexanes - EtOAc to afford the title compound as a white solid (40mg, 56%). 0226-56-4 LCMS RT= 6.55min, MH* 322.1; 'H NMR (CDC 3 ): 8.82 (1 H, s), 8.33 (1 H, dd, J 30 8.6 and 1.7), 8.07-8.01 (3 H, in), 7.95-7.92 (1 H, in), 7.79 (1 H, d, J8.5), 7.68 (1 H, dd, J8.5 and 1.6), 7.64-7.59 (2 H, in), 3.04-2.80 (2 H, m) and 1.24 (3 H, t, J 7.4). EXAMPLE 15 WO 2009/021750 PCT/EP2008/006720 General synthetic scheme for (2-(4H-1,2,4-triazol-3-ylthio)-N-(4-(benzoIdithiazol 2-yl)thiazol-2-yl)acetamide & 2-(4H-1,2,4-triazol-3-ylthio)-N-(S-(benzo[djthiazol 2-yl)pyridin-3-yl)acetamide 5 HOOC N 0 NH2 NHCH S NH2 C1ik~ I S N NY CI S SH N NN NH2 H S N N H PPA HOOC - NH 2 o N N C NH

NH

2 O HN HN HN S C c0 SNo N H N N NN 4-(Benzo[dlthiazol-2-yl)thiazol-2-amine 10 2-Aminobenzenethiol (1.OOmL, 9.35mmol) and 2-aminothiazole-4-carboxylic acid (1.59g, 11.21mmol) were added simultaneously to PPA at 120 0 C and the resulting mixture was stirred at 210'C for 18h. The hot crude was poured onto ice/water (150mL) and basified with NaOH pellets until pH=14. The aqueous layer was then extracted with ethyl acetate (3x7OmL), the combined extracts were washed with brine 15 until pH=7 and dried over anhydrous magnesium sulfate. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 7:3 v/v to ethyl acetate/hexanes 1:0 v/v then ethyl acetate/methanol 1:0 v/v to ethyl acetate/methanol 98:2 v/v) to afford 407mg (12%) of the title compound. LCMS RT= 5.53min, MH* 234.1; 'H NMR (DMSO): 8.09-8.07 (1H, m), 7.99-7.96 20 (1H, m), 7.54-7.48 (2H, m), 7.44-7.39 (3H, m). The compounds below were prepared following the same general method. 5-(Benzo[d]thiazol-2-yl)pyridin-3-amine WO 2009/021750 PCT/EP2008/006720 LCMS RT= 5.37min, MHW 228.1; 'H NMR (DMSO): 8.41 (1H, d, J 1.95), 8.18-8.15 (1H, in), 8.09-8.05 (2H, m), 7.61-7.45 (3H, in), 5.72 (2H, s). N-(4-(Benzo[dlthiazol-2-yl)thiazol-2-yl)-2-chloroacetamide 5 Chloroacetyl chloride (340ptL, 4.29mmol) was added dropwise to a stirred solution of 4-(benzo[d]thiazol-2-yl)thiazol-2-amine (250mg, 1.07mmol) in dichloromethane/tetrahydrofuran (20mL, 1:1 v/v) in the presence of diisopropylethylamine (1.12mL, 6.43mmol). The resulting mixture was stirred at room temperature for 18h, then the crude was diluted with dichloromethane (1 50mL) and the 10 organic layer was washed with brine (50mL). The aqueous layer was extracted with dichloromethane (2x5OmL) and the combined extracts were dried over anhydrous magnesium sulphate. The resulting oil was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl acetate/hexanes 3:7 v/v) to afford 211mg (64%) of the title compound. 15 LCMS RT= 6.07min, MH* 310.0; 'H NMR (DMSO): 12.94 (1H, bs), 8.13 (1H, d, J 7.50), 8.12 (1H, s), 8.04 (1H, d, J7.50), 7.55 (1H, td, J7.50 1.20), 7.46 (1H, td, J7.50 1.20), 4.45 (2H, s). The compounds below were prepared following the same general method. 20 N-(5-(Benzofdjthiazol-2-yl)pyridin-3-yI)-2-chloroacetamide LCMS RT= 5.83min, MH+ 304.1; 'H NMR (DMSO): 10.81 (1H, bs), 8.99 (1H, d, J 2.10), 8.87 (1H, d, J 2.10), 8.84 (1H, t, J 2.10), 8.21 (1H, d, J 7.30), 8.13 (iH, d, J 7.30), 7.60 (1H, td, J7.30 1.30), 7.52 (1H, td, J7.30 1.30), 4.37 (2H, s). 25 2-(4H-1,2,4-Triazol-3-ylthio)-N-(4-(benzo[dJthiazol-2-yl)thiazol-2-yl)acetamide A mixture of N-(4-(benzo[dlthiazol-2-yl)thiazol-2-yl)-2-chloroacetamide 2 (205mg, 0.66mmol), 1H-1,2,4-triazole-5(4H)-thione (74mg, 0.73mmol) and potassium carbonate (110mg, 0.8mmol) in acetone (20mL) was refluxed for 2h. The solvent was 30 removed in vacuo and the resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl acetate/hexanes 1:0 v/v) to afford 120mg (48%) of the title compound.

WO 2009/021750 PCT/EP2008/006720 LCMS RT= 5.42min, MH* 375.0; 'H NMR (DMSO): 13.53 (1H, bs), 8.50 (1H, bs), 8.14 (1H, d, J7.40), 8.08 (1H, s), 8.04 (1H, d, J7.40), 7.55 (1H, td, J7.50 1.20), 7.46 (1H, td, J7.50 1.20), 4.19 (2H, s). 5 The compounds below were prepared following the same general method. 2-(4H-1,2,4-triazol-3-ylthio)-N-(5-(benzo[dJthiazol-2-yl)pyridin-3-yl)acetamide LCMS RT= 5.17min, MH*+ 369.0; 'H NMR (DMSO): 14.00 (1H, bs), 10.80 (1H, bs), 8.95 (1H, d, J 1.77), 8.86-8.83 (2H, m), 8.48 (1H, s), 8.20 (1H, d, J7.30), 8.13 (1H, d, J 7.30), 7.59 (1H, td, J7.30 1.30), 7.51 (1H, td, J7.30 1.30), 4.14 (2H, s). 10 EXAMPLE 16 1-(2-(Naphthalen-2-yl)benzo[dloxazol-5-yl)pyrrolidin-2-one 4-bromobutyryl chloride (195ptL, 1.69mmol) was added dropwise to a solution of 2 (naphthalen-2-yl)-5-amino-benzo[d]oxazole (400mg, 1.537mmol) in anhydrous pyridine (7.5mL) at 0C and the resultant reaction mixture allowed to warm to room temperature over 16 hours. After this time, the reaction mixture was diluted with ethyl 20 acetate and washed with saturated aqueous copper sulphate solution (x2) then saturated aqueous potassium carbonate solution (x2). The organic layer was dried over MgSO 4 and concentrated in vacuo to furnish 4-chloro-N-(2-(naphthalen-2-yl)benzo[d]oxazol-5 yl)butanamide (115mg, 21%) after column chromatography (2:1 to 1:1 40-60 petrol:ethyl acetate) (LCMS RT=7.42min, MH* 365). 25 'IH NMR (300MHz, DMSO) 10.19 (1H, s), 8.83 (1H, s), 8.26 (1H, dd, J8.6, 1.7 Hz), 8.17-8.20 (2H, m), 8.14 (1H, d, J 8.7 Hz), 8.03-8.06 (IH, m), 7.76 (1H, d, J 8.8 Hz), 7.62-7.70 (2H, m), 7.55 (LH, dd, J 8.8 2.1 Hz), 3.74 (lH, t, J6.5 Hz), 2.54 (obsc.), 2.08 (2H, quintet, J6.9 Hz). 30 1-(2-(Naphthalen-2-yl)benzo[dJoxazol-5-yl)pyrrolidin-2-one Diethylamine (20pL, 0.187mmol) and potassium carbonate (26mg, 0.187mmol) were added to a solution of 4-chloro-N-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)butanamide (62mg, 0.1 70mmol) in anhydrous DMF under nitrogen and the reaction mixture heated to 50*C. for 16 hours. After cooling to room temperature, the reaction mixture was WO 2009/021750 PCT/EP2008/006720 diluted with ethyl acetate and washed with brine (x3). The organic layer was dried over MgSO 4 and concentrated in vacuo to furnish the title compound (28mg, 50%) as a pale yellow powder after column chromatography (2:1 to 1:1 40-60 petrol:ethyl acetate) (LCMS RT=7.02min, MH* 329). 5 'H NMR (300MHz, DMSO) 8.84 (1H, s), 8.27 (1H, dd, J 8.6 1.7 Hz), 8.13-8.21 (2H, m), 8.03-8.08 (2H, m), 7.83 (1H, d, J 8.7 Hz), 7.78 (LH, dd, J 8.9 2.0 Hz), 7.63-7.70 (2H, m), 3.95 (2H, t, J7.0 Hz), 2.54 (obsc.), 2.11 (2H, quintet, J7.5 Hz). EXAMPLE 17 10 2-(Benzo[bithiophen-1,1-dioxide-6-yl)-5-(ethylsulfonyl)benzo[d]oxazole m-chloroperbenzoic acid (0.65g, 3.8mmol) was added to a solution of 2 (benzo[b]thiophen-6-yl)-5-(ethylsulfonyl)benzo[d]oxazole (0.56g, 1.5mmol) in chloroform (15mL). After stirring for 16h, sodium suite solution (170) was added 15 and shaken with the reaction mixture, which was then partitioned. The organic phase was dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 4/1, v/v, then recrystallised using ethanol to afford 88mg (15%) of the title compound. LCMS RT= 5.66min, MH n/a; 'H NMR (DMSO): 8.48 (1H, d, J0.9 Hz), 8.44 (1H, 20 dd, J7.9, J 1.4 Hz), 8.38 (1H, d, J 1.3 Hz), 8.15-8.12 (2H, m), 8.02 (1H, dd, J8.6, J 1.8 Hz), 7.83 (1H, dd, J6.9, J 0.8 Hz), 7.56 (1H, d, J6.9 Hz), 3.38 (2H, q, J7.4 Hz), 1.12 (3H, t, J7.3 Hz). EXAMPLE 18 25 General scheme to synthesise common intermediate A OH 1.' naphth-CHO, 0'oieoie B MeOH, 50 0 c - / benzoleoie B c 2 ' rt chlorobenzene, reflux Br / \ / Step1 Step2 A Step: 30 54 WO 2009/021750 PCT/EP2008/006720 A solution of 2-amino-4-methylphenol (900mg, 7.30mmol, 1 eq) and 2-naphthaldehyde (1.14g, 7.30mmol, leq) in MeOH (30mL) was heated for 30 minutes at 50*C. After concentration in vacuo, the residue was suspended in DCM (40mL) and treated with DDQ (2,3 dichloro,5,6-dicyano-1,4-benzoquinone, 1.74g, 1.05eq, 766mmol). The 5 reaction mixture was stirred at room temperature for 10 minutes and diluted with DCM. The organic phase was washed with brine and NaHC0 3 aq , dried over Na 2

SO

4 , concentrated in vacuo. This reaction gave us the desired compound in a quantitative yield, no further purification needed. LCMS RT= 9.39min, MH*= 260.1, 97% UV 10 'H NMR (CDCl 3 ): 8.69 (1H, s), 8.23 (1H, dd, J3.41Hz), 7.90 (2H, m, J4.35 Hz), 7.82 (1H, m, J4.62Hz), 7.50 (3H, m, J 4.71Hz), 7.42 (11H, d, J8.28Hz), 7.11 (1H, dd, J 4.11 Hz), 2.5 (3H, s). 15 Step 2: To a stirred solution of the methyl compound (1.9g, 7.33mmol, leq) in chlorobenzene (60mL) at 90'C was added NBS (1.3g, 7.33mmol, leq) and benzoylperoxide (catalytic amount) in one portion. The reaction mixture was heated at 90'C for 1 hour and heated 20 at reflux for 4 more hours. After cooling down, the reaction mixture was concentrated in in vacuo, suspended in EtOAc. The residue was filtered and gave 350mg of the desired product. The organic phase was washed with brine, NaHCO3 aq, dried over Na 2

SO

4 , concentrated in vacuo. The solid was triturate in EtOAc and provide 400mg of desired Bromo compound. No further purification was attempted. 25 LCMS RT= 9.00min, MH= 338.1, 96% UV 'H NMR (CDC1 3 ): 8.70 (1H, s), 8.23 (1H, dd, J8.23Hz), 7.91 (2H, m, J4.02 Hz), 7.82 (1H, m, J4.69Hz), 7.75 (1H, d, J 1.50Hz), 7.51 (3H, m, J2.81Hz), 7.36 (1H, dd, J3.37 Hz), 4.59 (3H, s). 30 5-(Morpholinomethyl)-2-(naphthalen-2-yl)benzo[doxazole The Bromo compound A (200mg, 0.592mmol, leq) was dissolved in dry DMF, (V=6mL), potassium carbonate (9 1mg, 0.65 1mmol, 1. leq) and morpholine (0.0057mL, 35 0.651mmol, 1.leq) were added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. Water was added. The aqueous phase was extracted WO 2009/021750 PCT/EP2008/006720 three times with EtOAc, the organic phases were washed with water and brine, dried over Na 2

SO

4 , concentrated in vacuo. Purification by Flash Jones chromatography gave 68mg of the desired compound in 34% yield. 5 LCMS RT= 8.08min, MH*= 345.3, 100% UV 'H NMR (DMSO): 8.89 (1H, s), 8.32 (1H, dd, J3.40Hz), 8.25 (2H, m, J 4.66Hz and J 7.84Hz), 8.09 (1H, dd, J 4.60Hz), 7.82 (2H, d, J 8.44Hz), 7.73( 2H, q, J 4.09Hz), 7.47 (1H, dd, J4.09Hz), 3.65 ( 6H, m), 2.47 (4H, m, J4.23Hz). 10 5-(Ethylsulfonylmethyl)-2-(naphthalen-2-yl)benzo[doxazole & 5-(methylsulfonylmethyl)-2-(naphthalen-2-yl)benzo[dloxazole Step 3: The bromo compound A (300mg, 0.887mml, leg) 'w Asdisslved in dry THF (15mL); 15 a Sodium ethanethiolate (82mg, 0.976mmol, 1.1 eq) or b sodium thiomethoxide (68mg, 0.976mmol, 1.1 eq) was added at room temperature. The reaction mixture was refluxed for 4 hours. After cooling down the mixture was diluted with water, extracted three times with DCM. The organics phases were washed with brine, dried over Na 2

SO

4 , concentrated in vacuo. 20 Bromo starting material and desired product were co-spotting by TLC. In the crude mixture 59% desired compound was present by LCMS (a). No further purification was attempted in both cases. LCMS (a) RT= 9.83min, MH = 320.2, 59% UV a: 5-(ethylsulfonylmethyl)-2-(naphthalen-2-yl)benzo[dJoxazole 'H NMR (CDCl 3 ): 25 8.71 (LH, s), 8.25 (1H, m, J 2.54Hz), 7.87 (3H, m, J 6.44Hz), 7.70 (1H, d, J 7.28Hz), 7.53 ( 3H, m, J 3.44Hz), 7.37, (1H, m), Other impurities present from the starting material bromo compound, 3.80 (2H,s), 2.41 (2H, q, J 10.21Hz) I impurity underneath the peak, 1.18 (3H, t, J7.37Hz). 30 b: 5-(methylsulfonylmethyl)-2-(naphthalen-2-yl)benzoIdioxazole 'H NMR (DMSO): 8.24 (1H,s), 8.33 (1H, dd, J3.44Hz), 8.23 (21-1, m, J4.69Hz), 8.11 (1H, m, J 3.14Hz), 7.85 (2H, dd, J 8.46Hz), 7.73 (2H, q, J2.92Hz), 7.48 (1H, dd, J 3.37 Hz), 3.93 ( 2H,s), 2.05 (3H, s).

WO 2009/021750 PCT/EP2008/006720 Step 4: 5 a (or b) was dissolved in 1OmL of chloroform, 4 eq of MPCBA was added in one portion at 0*C. The reaction mixture was stirred at room temperature overnight. a: The reaction mixture was diluted with DCM, washed twice with NaOH IN and water. The organic phase was dried over Na 2

SO

4 , concentrated in vacuo. Purification by trituration in DCM and ether gave the desired product in 20% yield. 10 b: a solid crashed out, it was filtered and washed with ether to give the desired product in 25% yield. LCMS (a) RT= 6.59min, MH*= 352.2, 93.6% UV LCMS (b) RT= 6.46min, MH*= 338.2, 99.5% UV Ci - liry xT1itsp j'1iurqr o oc (itT -,% 0 -0 (lE-T A A T~ I TT 0 17 f)LT - T C <)T-,% 15 a: II NMRV11 (DMS1O%1F). O.O6 (1H, k ), 8.28 (1H, dU d, J3.43z), 0.1 (2H, , ) 5.62Hz), 8.04 (1H, m, J4.47Hz), 7.87 (2H, d, J8.61Hz), 7.66 (2H, q, J2.98Hz), 7.49 (1H, dd, J 3.35Hz), 4.64 (2H, s), 3.06 (2H, q, J7.42Hz), 1.24 (3H, t, J7.44Hz). b: 'H NMR (DMSO): 8.86 (1H, s), 8.28 (1H, dd, J 3.43Hz), 8.17 (2H, m, J 4.55Hz), 20 8.04 (1H, m, J4.60Hz), 7.88 (2H, m, J 3.97Hz), 7.66 (2H, q, J2.98Hz), 7.50 (1H, dd, J 3.35Hz), 4.66 (2H, s), 2.94(3H, s). EXAMPLE 19 WO 2009/021750 PCT/EP2008/006720 Me O OOH 2Me0 N 0 / HATU, iPr 2 NEt, DMF, rt X' N N " H --- TFA, DCM [X = Boc, 7, 65% O X = H, 8,72% H 2N NN 1 Fmoc' OH 3 OTBDMS OO HATU, iPr 2 NEt, DMF, rt X' N H OR X = Fmoc, R = TBDMS, 4, quantitative piperidine, DMF X = H, R = TBDMS, 5, quantitative TBAF,THF -E X = R = H, 6, 27% [((S)-(9H-Fluoren-9-yl)methyl 3-(tert-butyldimethylsilyloxy)-1-(2-(naphthalen-2 5 yl)benzo[d]oxazol-5-ylamino)-1-oxopropan-2-ylcarbamatel, 4 HATU (1.271g, 3.34mmol) was added in one portion at room temperature to a stirred solution of (S)-N-Boc-0-TBDMS-serine (1.477g, 3.34mmol) in DMF (50mL) in the presence of diisopropylethylamine (1.59mL, 9.12mmol), followed by 2-(naphthalen-2 yl)benzo[d]oxazol-5-amine (791mg, 3.04mmol); the resulting mixture was stirred at 10 room temperature for 18h. The crude was partitioned between ethyl acetate (200mL) and brine (1 50mL) and the two layers were separated. The aqueous layer was extracted further with ethyl acetate (2 x 50mL) and the combined extracts were dried over anhydrous magnesium sulphate. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl 15 acetate/hexanes 1:0 v/v) to afford 2.05g (98%) of the title compound. 'H NMR (DMSO): 10.30 (1H, s), 8.80 (1H, s), 8.25-8.09 (4H, m), 8.02-7.99 (1H, m), 7.92-7.85 (2H, m), 7.76-7.70 (3H, m), 7.64-7.55 (4H, m), 7.41-7.27 (4H, m), 4.39-4.32 (1H, m), 4.28-4.17 (3H, m), 3.86-3.74 (2H, m), 0.78 (9H, s), -0.01 (6H, d, J 8.28). 20 The compounds below were prepared following the same general method. 58 WO 2009/021750 PCT/EP2008/006720 (S)-Tert-butyl methyl(1-(2-(naphthalen-2-yl)benzo d]oxazol-5-ylamino)-1 oxopropan-2-yI)carbamate, 7 LCMS RT= 8.19min, MH* 446.4; 'H NMR (DMSO): 10.12 (0.5H, bs), 10.02 (0.5H, bs), 8.83 (1H, s), 8.26 (1H, dd, J8.61 1.70), 8.20-8.12 (3H, m), 8.05-8.02 (1H, m), 7.77 5 (1H, d, J 8.80), 7.70-7.61 (2H, m), 7.58 (1H, dd, J 8.80 2.04), 4.73 (0.5H, bm), 4.41 (0.5H, bm), 2.89 (3H, s), 1.39 (3H, d, J7.17), 1.34 (9H, s). [(S)-2-Amino-3-(tert-butyldimethylsilyloxy)-N-(2-(naphthalen-2 yl)benzo d]oxazol-5-yl)propanamide], 5 10 Piperidine (4mL, 40.5mmol) was added dropwise at room temperature to a stirred solution of 4 (2.08g, 3.04mmol) in dimethylformamide (16mL) and the resulting mixture was stirred for 18h. The crude was partitioned between ethyl acetate (150mL) and brine (10OmL) and the two layers were separated. The aqueous layer was extracted further with ethyl acetate (2 x 50mL) and the combined extracts were dried over 15 anhydrous magnesium sulfate. The resulting oil was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 3:7 v/v to ethyl acetate/hexanes 1:0 v/v) to afford 1.39 (99%) of the title compound. LCMS RT= 9.59min, MIH462.3; 'H NMR (DMSO): 8.81 (lH, s), 8.26-8.23 (2H, m), 20 8.18-8.15 (1H, m), 8.12 (1H, d, J8.80), 8.04-8.00 (1H, m), 7.94 (1H, s), 7.75 (1H, d, J 8.80), 7.68-7.60 (3H, m), 3.79 (IH, dd, J 9.72 5.10), 3.70 (1H, dd, J 9.72 5.85), 3.47 (1H, t, J5.46), 0.81 (9H, s), 0.00 (6H, s). [(S)-2-Amino-3-hydroxy-N-(2-(naphthalen-2-yl)benzo[dJoxazol-5 25 yl)propanamide], 6 TBAF (1M in THF, 12.16mL, 12.16mmol) was added dropwise at room temperature to a stirred solution of 5 (1.40g, 3.04mmol) in THF (1OmL) and the resulting mixture was stirred for 60h. The crude was evaporated to dryness, dissolved in ethyl acetate (200mL) and washed with IM NaOH in water (1OOmL). The aqueous layer was 30 extracted further with ethyl acetate (2 x 50mL) brine (1 OOmL) and the two layers were separated. The aqueous layer was extracted further with ethyl acetate (2x5OmL) and the combined extracts were washed with brine (2 x 50mL) and dried over anhydrous Cai WO 2009/021750 PCT/EP2008/006720 magnesium sulfate. The resulting solid was precipitated from IMS/methanol to afford 282mg (27%) of the title compound as a colourless solid. LCMS RT= 5.52min, MlHl 348.1; 'H NMR (DMSO): 8.83 (1H, s), 8.28-8.25 (2H, m), 5 8.20-8.12 (2H, m), 8.05-8.02 (1H, m), 7.76 (1H, d, J 8.80), 7.67-7.64 (3H, m), 4.87 (1H, t, J5.18), 3.62-3.57 (2H, m), 3.44-3.40 (1H, m). [(S)-2-(Methylamino)-N-(2-(naphthalen-2-yl)benzo djoxazol-5-yl)propanamidel, 8 TFA (2mL) was added dropwise at room temperature to a stirred solution of 7 (557mg, 10 1.25mmol) in DCM (10mL) and the resulting mixture was stirred for 3h. The reaction was quenched with NaHCO 3 (sat.) (1OmL) and the aqueous layer was extracted with DCM (3 x 50mL). The combined extracts were dried over anhydrous magnesium sulphate and evaporated to dryness. The resulting yellow solid was purified by column chromatography eluting using a gradient (ethyl acetate/methanol 1:0 v/v to ethyl 15 acetate/methanol 7:3 v/v) to afford 310mg (72%) of the title compound. LCMS RT= 6.64min, MH 346.1; 'H NMR (DMSO): 10.04 (1H, s), 8.82 (1H, s), 8.27-8.24 (2H, m), 8.20-8.16 (1H, m), 8.12 (1H, d, J 8.80), 8.05-8.02 (lH, m), 7.76 (1H, d, J 8.80), 7.67-7.63 (3H, m), 3.17 (lH, q, J 6.82), 2.28 (3H, s), 1.24 (3H, d, J 20 6.82). 3-(5-Isobutyramidobenzo[d]oxazol-2-yl)quinoline 1-oxide To a stirred suspension of N-(2-(quinolin-3-yl)benzo[d]oxazol-5-yl)isobutyramide (250mg, 0.75mmol) in dry dichloromethane (15mL) was added a solution of 2,2,2 25 trifluoroacetic anhydride (533pL, 3.77mmol) and hydrogen peroxide (35% wt in H 2 0, 550pVL, 5.66mmol) in dichloromethane (5mL). The resulting solution was refluxed for 16h. After cooling, the crude mixture was diluted with dichloromethane and washed with aqueous NaHCO 3 solution. The aqueous layer was extracted with dichloromethane and the organic layers were washed with water until neutral pH was reached. The 30 combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting product was purified by recrystallisation from dichloromethane to afford 24mg (9%) of the title compound (LCMS RT= 5.15min, (M+MeCN)* 388.9) WO 2009/021750 PCT/EP2008/006720 'H NMR (DMSO): 10.07 (IH, s), 9.10 (1H, d, J 1.3 Hz), 8.79 (1H, s), 8.59 (1H, d, J 8.8 Hz), 8.35 (1H, d, J 7.8 Hz), 8.26 (1H, d, J 2.0 Hz), 7.98-7.92 (1H, m), 7.89-7.83 (1H, m), 7.78 (1H, d, J 8.8 Hz), 7.61 (1H, dd, J 8.8 2.2 Hz), 2.68-2.60 (1H, in), 1.14 (6H, d, J 6.7 Hz). 5 EXAMPLE 20 2-(Dimethylamino)-N-(2-(naphthalen-2-yl)benzo[dioxazol-5-yl)acetamide hydrochloride 10 4M HCI in 1,4-dioxane (4mL) was added to a stirred solution of 2-(dimethylamino)-N (2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)acetamide (50mg, 0.145mmol) in methanol (5mL) and the resultant solution allowed to stir for 10 minutes before being concentrated in vacuo. The crude residue was resuspended in toluene and again concentrated in vacuo to give the crude product as a yellow solid. This was triturated 15 with diethyl ether and the title compound isolated as a yellow powder (42mg, 76%) by filtration under reduced pressure (LCMS RT=6.5 1min, MH* 346). 'H NMR (CDCla) 11.05 (1H, s), 9.99 (1H, br s), 8.86 (1H, s), 8.28 (1H, dd, J 8.6 1.7Hz), 8.15-8.24 (3H, in), 8.05-8.08 (1H, in), 7.86 (1H, d, J 8.8), 7.65-7.73 (2H, in), 7.61 (1H, dd, J8.8 2.1Hz), 4.23 (2H, d, J 4.6Hz), 2.92 (6H, d, J 4.2Hz). 20 2-(1H-Imidazol-4-yi)-N-(2-(naphthalen-2-yl)benzo[dJoxazol-5-yl)acetamide hydrochloride 2-(1 H-imidazol-4-yl)-N-(2-(naphthalen-2-yl)benzo [d]oxazol-5-yl)acetamide (50mg, 0.136mmol) was suspended in 4M HCl in 1,4-dioxane (4mL) and the resultant mixture 25 heated at 150'C for 10minutes in a CEM Discover microwave. After this time the reaction mixture was concentrated in vacuo. The crude residue was resuspended in toluene and again concentrated in vacuo to give the crude product as a yellow solid. This was triturated with diethyl ether and the title compound isolated as a yellow powder (47mg, 85%) by filtration under reduced pressure (LCMS RT=4.60min). 30 'H NMR (CDCl 3 ) 14.48 (IH, br s), 14.27 (lH, br s), 10.72 (1H, s), 9.08 (IH, d, J 1.3Hz), 8.85 (1H, s), 8.28 (1H, dd, J8.6 1.7Hz), 8.14-8.24 (3H, in), 8.05-8.08 (1H, m), 7.82 (IH, d, J 8.8), 7.59-7.72 (4H, in), 3.98 (2H, s).

WO 2009/021750 PCT/EP2008/006720 EXAMPLE 21 0 N + 0HOR HATU, iPr 2 EtN S R I~ / NH 2 + a, DCM -aNN 5 (N-(4-(6-Methylbenzo[dJthiazol-2-yl)phenyl)-2-(pyridin-2-yloxy)acetamide) HATU (442mg, 1.1 6mmol) was added in one portion to a stirred solution of 2-(pyridin 2-yloxy)acetic acid in DCM (30mL) in the presence of diisopropylethylamine (510tL, 2.90mmol), followed by 4-(6-methylbenzo[d]thiazol-2-yl)aniline (233mg, 0.97mmol); the resulting mixture was stirred at room temperature for 18h. The solid formed was 10 filtered off, washed with methanol, collected and dried to afford 143mg (37%) of the title compound. H NMR (DMSO): 10.67 (1H, s), 8.04 (2H, d,J 8.5), 7.91-7.88 (2H, m), 7.77 (2H, d, J 8.5), 7.69-7.67 (1H, bd), 7.50-7.45 (1H, bt), 7.36-7.33 (1H, bd), 6.42-6.39 (1H, bd), 6.29-6.24 (1H, bt), 4.78 (2H, s), 2.45 (3H, s). 15 The compounds below were prepared following the same general method. N-(4-(6-Methylbenzo[d]thiazol-2-yl)phenyl)-2-(phenylthio)acetamide LCMS RT= 7.77min, M* 390.9; 'H NMR (DMSO): 10.52 (1H, s), 8.03 (2H, d, J 20 8.73), 7.91-7.89 (2H, m), 7.76 (2H, d, J 8.73), 7.44-7.41 (2H, m), 7.36-7.31 (3H, m), 7.24-7.19 (IH, m), 3.91 (2H, s), 2.46 (3H, s). N-(4-(6-Methylbenzo[d]oxazol-2-yl)phenyl)-2-(phenylthio)acetamide LCMS RT= 7.29min, M* 374.9; 'H NMR (DMSO): 10.55 (iH, s), 8.12 (2H, d, J 25 8.77), 7.79 (2H, d, J 8.77), 7.63 (1H, d, J 8.10), 7.57 (1H, s), 7.44-7.41 (2H, m), 7.36 7.31 (2H, m), 7.24-7.19 (2H, m), 3.91 (2H, s), 2.46 (3H, s). N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-phenoxyacetamide LCMS RT= 7.77min, M+ 374.9; 'H NMR (DMSO): 10.40 (1H, s), 8.04 (2H, d, J 30 8.79), 7.91-7.89 (2H, m), 7.85 (21-1, d, J 8.79), 7.36-7.30 (3H, m), 7.03-6.96 (3H, m), 7.63 (1H, d, J8.10), 4.75 (2H, s), 2.45 (3H, s).

WO 2009/021750 PCT/EP2008/006720 2-(4H-1,2,4-triazol-3-ylthio)-N-(4-(6-methylbenzo[dioxazol-2-yl)phenyl)acetamide LCMS RT= 7.26min, M+ 366.1; 'H NMR (DMSO): 14.09 (1H, bs), 10.62 (1H, s), 8.49 (1H, bs), 8.12 (2H, d, J8.74), 7.80 (2H, d, J8.74), 7.63 (1H, d, J8.10), 7.57 (1H, 5 s), 7.21 (1H, d, J 8.25), 4.11 (2H, s), 2.46 (3H, s). EXAMPLE 22 10 2-((2-(Naphthalen-2-yl)benzo[djoxazol-5-yl)methylamino)acetic acid Glycine ethyl ester hydrochloride salt (91mg, 1.leq, 0.653mmol) was dissolved in dry DMF (4mL), leq of triethylamine was added and the reaction mixture was stirred at room temperature for 5 minutes. In a separate flask the bromide (300mg, leq, 15 0.59mmol) was dissolved in dry DMF (6mL), potassium carbonate was added to the mixture following by the solution of free based glycine ethyl ester in DMF. The reaction mixture was stirred at room temperature overnight. After 18 hours, some starting material was still present by TLC (50% ethyl acetate, 50% petrol ether), 1.leq of free based glycine ethyl ester was added and the reaction mixture was heated at 70 0 C 20 for 3 hours. After cooling down, the reaction mixture was concentrated in vacuo, diluted with DCM. The organic phase was washed with water, brine, dried over Na 2

SO

4 , concentrated in vacuo. Purification by flash Jones chromatography provided a yellow solid in 42% yield. 'H NMR (CDC1 3 ): 8.25 (1H, s), 8.23 (1H, dd, J 3.44Hz), 7.91 (2H, m, J6.52Hz), 7.82 25 (1H, t, J 4.69Hz), 7.68 (1H, s), 7.50 (3H, m, J 3.47Hz), 7.31 (1H, dd, J 3.32Hz), 4.13 (2H, q, J7.14Hz), 3.89 (2H, s), 3.78 (2H, s), 1.20 (3H, t, J8.5OHz). Thise ester (75mg, 0.208mmol, leq) was dissolved in a mixture of water THF 1/1 30 (V=4mL), 5mL of a I M NaOH solution was added at room temperature. The reaction mixture was stirred at room temperature for 18 hours. A solution of 2N HCl was added .to the mixture until pH=3. A white solid crashed out, it was filtered, washed with ether and dry in the vac oven for 4 hours. It gave the desired product in a 56% yield.

WO 2009/021750 PCT/EP2008/006720 LC: RT= 4.93min, 99.17% UV. H NMR (DMSO): 8.18 (1H, s), 8.28 (1H, dd, J3.44Hz), 8.17 (2H, m, J4.13Hz), 8.04 (2H, m, J3.38Hz), 7.90 (1H, d, J8.37Hz), 7.64 (3H, m), 4.33 (2H, s), 3.86 (2H, s). 5 EXAMPLE 23 C1 0 -/ + cl dioxane R- - /41 R\N'l/O210"C,15 mins ~N I~ 10 The compounds below were prepared following~ thL am1eerlmehd Rr 8.5 (40:60 EtOAc:Pet Ether); 1H NMR (DMSO): 8.82 (1H, s), 8.30-8.04 (6H, in), 15 7.92-7.89 (1H, dd, J), 7.72-7.63 (2H, in), 7.44-7.41 (2H, in), 3.20 (4H, t, J), 1.65 (4H, t, J). N-EthyI-2-(naphthal-2-y)benzolOdlloxazole-5-sulfonamide LC RT= 6.86min, UV ; 'H NMR (DMSO): 8.94 (1H, s), 8.34 (1H, dd, J 8.6, J 1.6 20 Hz), 8.28-8.25 (2H, m), 8.22 (1H, d, J 8.8 Hz), 8.10 (2H, d, J 8.5 Hz), 7.95 (1H, dd, J 8.6, J1.8 Hz), 7.77-7.68 (3H, m), 2.87 (2H, q, J7.2 Hz), 1.03 (3H, t, J7.2 Hz). N-(3-(Ethylsulfonyl)phenyl)naphthalene-2-carbothioamide LHMDS (IM, 0.62mmol) was added to a solution of 5-(methylsulfonyl)-2-(naphthalen 25 2-yl)benzo[d]thiazole (0.19g, 0.56mmol) in dry THF (7mL) cooled to -78'C. After stirring for lh, iodomethane (0.16g, 1.23mmol) was added, and the reaction was warmed to room temperature. After stirring for 16h, ammonium chloride (10mL) was added and the reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over MgSO 4 and concentrated in vacuo. The residue was WO 2009/021750 PCT/EP2008/006720 purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/4, v/v, to afford 102mg (51%) of the title compound. LC RT= 7.74min, UV ; 'H NMR (DMSO): 8.83 (1H, d, J 1.4 Hz), 8.46 (1H, dd, J8.1, J 0.9 Hz), 8.29 (1H, dd, J 8.6, J 1.8 Hz), 8.22-8.19 (1H, m), 8.13 (1H, d, J 8.7 Hz), 5 8.05-8.01 (2H, m), 7.86 (1H, t, J 8.0 Hz), 7.70-7.62 (2H, in), 3.48 (2H, q, J 7.4 Hz), 1.16 (3H, t, J7.3 Hz). EXAMPLE 24 10 (S)-2-Hydroxy-N,N,N-trimethyl-4-(2-(naphtalen-2-yl)benzo[djoxazol-5-ylamino) 4-oxobutan-1-aminium TFA salt HATU (0.22g, 0.57mmol) and DiPEA (0.20mL, 1. 14mmol) were added to a solution of L-Carnitine (89mg, 0.55mmol) and 2-(naphtalen-2-yl)benzo[d]oxazol-5-amine (100mg, 0.38 mmol) in DMF (2mL) at 0*C. After stirring for 16h at ambient temperature the 15 reaction mixture was concentrated and the residue treated with DCM/MeOH. The precipitate was filtered off and purified by HPLC (H 2 0/MeCN, 0.1% TFA) to give 29mg (15%) of the title compound. (LCMS RT= 4.4 1min, MH= 404.2) 'H NMR (DMSO): 10.28 (1H, s), 8.82 (1H, s), 8.27-8.23 (2H, in), 8.20-8.12 (2H, in), 7.78 (1H, d, J8.8 Hz), 7.68-7.64 (2H, in), 7.56 (1H, dd, J2.0 Hz, J8.8 Hz), 5.75 (1H, 20 bs), 4.59 (1H, in), 3.44 (2H, d, J5.7 Hz), 3.17 (9H, s), 2.57 (2H, in). EXAMPLE 25 0 OH Fe, NH4CI OH C 0 NO 2

IMS/H

2 0 0 NH 2 V, 210*C, 15 min O BBr 3 - -

N

0 - / _____ / R DCM, reflux HO O ROK 2

CO

3 RO ON 25 2-Amino-4-methoxyphenol A mixture of 2-nitro-4-methoxyphenol (6.00g, 35.5mmol) and ammonium chloride (9.48g, 177.4mmol) in IMS/H20 (180mL, 2:1) was heated to 70 0 C, then iron (9.91g, WO 2009/021750 PCT/EP2008/006720 177.4mmol) was added and the resulting mixture was refluxed for 18. The crude was cooled down and filtered through a pad of celite. The filter was washed with ethyl acetate and the filtrate evaporated to dryness to afford a brown solid, which was partitioned between ethyl acetate (250mL) and brine (150mL). The two layers were 5 separated, the aqueous layer was extracted further with ethyl acetate (2 x 50mL) and the combined extracts were dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded a brown solid which was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl acetate/hexanes 3:2 v/v) to afford 3.84g (78%) of the title compound. 10 Rf = 0.47 (ethyl acetate/hexanes 1:1 v/v); 'H NMR (DMSO): 8.44 (1H, s), 6.51 (1H, d, J8.46), 6.20 (1H, d, J2.97), 5.94 (1H, dd, J8.46 2.97), 4.72 (2H, s) 5-Methoxy-2-(naphthalen-2-yl)benzo[dloxazole Prepared using previously described standard microwave route. 15 Rf = 0.79 (ethyl acetate/hexanes 1:1 v/v); 'H NMR (DMSO): 8.79 (1H, s), 8.24 (1H, dd, J 8.65 1.71), 8.18-8.15 (1H, m), 8.12 (IH, d, J 8.65), 8.04-8.01 (1H, in), 7.71 (1H, d, J8.88), 7.68-7.61 (2H, m), 7.39 (1H, d, J2.52), 7.03 (1H, dd, J8.88 2.52), 3.85 (3H, s). 20 2-(Naphthalen-2-yl)benzo[dJoxazol-5-ol A 1M solution of BBr 3 in DCM (21.3mL, 21.3mmol) was added slowly to dry DCM (20mL) at room temperature under an atmosphere of dry nitrogen, followed by 5 methoxy-2-(naphthalen-2-yl)benzo[d]oxazole 2 (1.567g, 5.33mmol). The resulting mixture was refluxed for 18 h under nitrogen and quenched with distilled water 25 (20mL). The crude was then partitioned between ethyl acetate (200mL) and water (1OOmL) and the two layers were separated. The aqueous layer was extracted further with ethyl acetate (2 x 50mL) and the combined extracts were dried over anhydrous MgSO 4 . Evaporation of the solvent afforded a yellow solid which was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl 30 acetate/hexanes 1:1 v/v) to afford 848mg (57%) of the title compound. Rr = 0.66 (ethyl acetate/hexanes 1:1 v/v); 'H NMR (DMSO): 9.58 (1H, s), 8.78 (IH, s), 8.22 (1H, dd, J 8.61 1.71), 8.17-8.14 (1H, in), 8.11 (1H, d, J 8.76), 8.03-8.00 (IH, in), 7.68-7.59 (3H, in), 7.14 (1H, d, J2.30), 6.88 (1H, dd, J8.76 2.30).

WO 2009/021750 PCT/EP2008/006720 5-(2-(Benzyloxy)ethoxy)-2-(naphthalen-2-yl)benzo[dloxazole NaH (60% dispersion in oil,34mg, 0.86mmol) was added to a solution of 2 (naphthalen-2-yl)benzo[d]oxazol-5-ol (0.2g, 0.71mmol) in DMF (4mL) at room 5 temperature. After stirring for 0.5h benzyl 2-chloroethyl ether (0.14mL, 0.92mmol) was added and the reaction mixture was stirred at 50*C for 16h and quenched with distilled water (0.5mL). The reaction mixture was partitioned between EtOAc (40mL) and water (30mL) and the organic phase was washed with water (2x 30mL) and brine (30mL), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified 10 by column chromatography eluting using a gradient (ethyl acetate/hexanes 0:1 v/v to ethyl acetate/hexanes 3:7 v/v) to afford 170mg (61%) of the title compound. Rr = 0.70 (ethyl acetate/hexanes 1:1 v/v). IH NMR (DMSO):, 8.79 (1H, s), 8.22 (lH, dd, J 8.6 1.7), 8.18-8.11 (2H, in), 8.04-8.00 (IH, in), 7.71 (1H, d, J 8.9), 7.66-7.629 (2H, m), 7.40 (1H, d, J2.5), 7.36-7.34 (4H, m), 7.30-7.27 (1H, m), 7.05(1H, dd, J8.9 15 2.5), 4.57 (2H, s), 4.22 (2H, in), 3.80 (2H, in). EXAMPLE 26 (2-Phenyl-1H-indol-3-yl)methanoI To a solution of 2-phenylindole-3-carboxaldehyde (500mg, 2.62mmol, leq) in dry 20 MeOH (30mL) was added sodium borohydride (103mg, 1.2eq, 2.71mmol) in one portion at 0 'C. The reaction mixture was stirred at room temperature for 18hours. Water was added to the reaction mixture and the aqueous phase was extracted three times with dichloromethane, dried over Na 2

SO

4 , concentrated in vacuo. Purification by recrystallisation in dichloromethane gave the title compound. 25 LCMS RT= 5.63min, 99.65% UV, Rf =0.46 in 20% Ethylacetate /80% Petrol ether 'H NMR (DMSO): 11.33 (1H, s, OH), 7.79 (2H, dd, J 4.47Hz), 7.66 (1H, d, J 7.71 Hz), 7.52 (2H, t, J7.64Hz), 7.39 (2H, t, J7.05Hz), 7.10 (2H, dt, J4.5OHz), 4.94 (1H, d, J9.66 Hz, NH), 4.68 (2H, d, J4.56Hz). 30 EXAMPLE 27 5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[dlthiazole 1" WO 2009/021750 PCT/EP2008/006720 LHMDS (1 M, 0.62mmol) was added to a solution of 5-(methylsulfonyl)-2-(naphthalen 2-yl)benzo[d]thiazole (0.19g, 0.56mmol) in dry THF (7mL) cooled to -78'C. After stirring for lh, iodomethane (0.16g, 1.23mmol) was added, and the reaction was warmed to room temperature. After stirring for 16h, ammonium chloride (1OmL) was 5 added and the reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over MgSO 4 and concentrated in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 1/4, v/v, to afford 102mg (51%) of the title compound. LCMS RT= 7.74min; 'H NMR (DMSO): 8.83 (1H, d, J 1.4 Hz), 8.46 (1H, dd, J8.1, J 10 0.9 Hz), 8.29 (1H, dd, 1 8.6, J 1.8 Hz), 8.22-8.19 (11H, m), 8.13 (1H, d, J8.7 Hz), 8.05 8.01 (2H, m), 7.86 (1H, t, J 8.0 Hz), 7.70-7.62 (2H, in), 3.48 (2H, q, J 7.4 Hz), 1.16 (3H, t, J 7.3 Hz). EXAMPLE 28 15 2-(2-(Naphthalen-2-yl)benzo[dloxazol-5-ylsulfonyl)ethanol A solution of 2-(naphthalen-2-yl)benzo[d]oxazol-5-amine (0.15g, 0.57mmol) and hydrochloric acid (3mL) was stirred for 30 minutes at 50'C, then cooled to O'C. A 20 solution of sodium nitrite (0.044g, 0.63mmol) in water (0.5mL) was added to the reaction drop-wise and stirred for 45 minutes, before the pH was adjusted to pH 7 with 1M sodium hydroxide. The mixture was added drop-wise to a solution of 2 mercapoethanol (0.08mL) in IM sodium hydroxide (1.2mL) containing a copper suspension (0.036g, 0.58mmol) and heated to 60'C. After stirring for 30 minutes, the 25 reaction mixture was cooled and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude compound was purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 3/7, v/v, to afford 127mg (69%) of 2-(2-(naphthalen-2 yl)benzo[d]oxazol-5-ylthio)ethanol. mCPBA (0.17g, 0.99mmol) was added to a 30 solution of 2-(2-(naphthalen-2-yl)benzo[d]oxazol-5-ylthio)ethanol (0.13g, 0.40mmol) in chloroform (5mL) and stirred for 16 hours. Sodium sulfite solution (10%, 5mL) was added to the reaction mixture. The organic phase was washed with IM sodium hydroxide, dried over MgSO4 and concentrated in vacuo. The crude compound was WO 2009/021750 PCT/EP2008/006720 purified by column chromatography, eluting with ethyl acetate/petroleum ether 0/1 to 6/4, v/v, to afford 22mg (11%) of the title compound. Rf value (Petrol:EtOAc 1:1, v/v): 0.39 1H NMR (DMSO): 8.83 (1H, s), 8.27 (1H, d), 8.21 (1H, dd, J 8.6, J 1.7 Hz), 8.16 5 8.08 (2H, in), 8.03-7.97 (2H, m), 7.91 (IH, dd, J 8.6, J 1.8 Hz), 7.65-7.57 (2H, in), 4.80 (1H, t, J 5.4 Hz), 3.64 (2H, q, J 6.5 Hz), 3.48 (2H, t, 6.1 Hz).

Claims

1. A compound of Formula (1) A x I( Rg A3 A 4 (1) 5 wherein R 9 represents a C 5 - 1 0 carbocycle which is partially or fully aromatic containing 0-4 hetero atoms and optionally substituted by 1-4 halogen, CI-C 6 alkyl, OC-C 6 alkyl or NR 9 o(C=Q)-M-Z-R 9 3 wherein R 90 represents H or C 1 - 6 alkyl, Q represents 0, S, or NR 91 10 wherein R 91 represents H or C 1 - 6 alkyl, M represents C 1 . 3 alkyl optionally substituted with halogen, C 1 - 6 alkyl, or C 1 - 6 alkoxy, Z represents 0, S or NR 92 wherein R 92 represents H or C 1 - 6 alkyl and R 93 represents a C 5 - 1 0 carbocycle which is partially or fully aromatic containing 0-4 hetero atoms and optionally substituted by 1-4 halogen, C 1 -C 6 alkyl or OC-C 6 alkyl; 15 three of A, A 2 , A 3 and A 4 represent CH, and one of A, A 2 , A 3 and A 4 represents CRI wherein R 1 represents: an alkyl group selected from C 2 -C 3 alkyl, n-butyl and sec-butyl, optionally substituted with hydroxyl, halogen, carboxylic acid, piperidin-1-yl, N-morpholino, -NMe 2 or alkoxy; 20 hydroxyl, halogen, C0 2 (C- 6 alkyl), or -O(CI- 6 alkyl) or C 1 alkyl substituted with, halogen, carboxylic acid, piperidin- 1 -yl, N-morpholino, -NMe 2 or alkoxy; hydroxyl, halogen, CO 2 (C- 6 alkyl), or -O(CI- 6 alkyl); -N-(S)-2-amino-3-hydroxypropionamide; -N-(S)-2-(methylamino)propionamide; 25 -N-(S)-2-aminopropionamide; -N-2-methylaminoacetamide; -(S=0)R 21 , wherein R 21 represents C-C 6 alkyl; -SOR 22 wherein n = 0, 1 or 2 and R 22 represents CH 3 , CH 2 CD 3 or C 3 - 6 alkyl, optionally substituted with OH or ethyl substitued with hydroxyl; WO 2009/021750 PCT/EP2008/006720 -S0 2 NR 55 R 23 , wherein R 23 and R 55 which may be the same or different each represent H or C 1 .6 alkyi; -NR 56 SOR 24 , wherein n = 0, 1 or 2 and R 24 and R 56 which may be the same or different each represent H or CI-C 6 alkyl; 5 -K-SO,-R 28 , wherein K represents CI-C 3 alkyl optionally substituted with Ci-C 6 alkyl, n=0-2 and R 2 8 represents CI-C 10 alkyl optionally substituted with one or more hydroxy, halogen, alkoxy or amine; -C0 2 R 26 , wherein R 26 represents C 1 - 6 alkyl; disubstituted phosphinate, wherein each substituent which may be the same or different 10 may represent CI- 6 alkyl or C 5 .io aryl; an N-linked mono- or bicylic ring substituted by one or more oxo, hydroxyl, halogen, CI-C 6 alkyl, alkoxy or aryl substituent; or NR 15 C(=W)Ri 7 wherein W represents NH, S or 0; 15 R 1 7 represents C 2 -alkyl, n-propyl, or C 4 -Cioalkyl; CI-CIo alkyl substituted with one or more halogen, hydroxyl, alkoxy or amine; a mono or disaccharide unit attached at the anomeric position via a Ci-C 4 alkyl group which is optionally substituted with one or more CI- 6 alkyl group; CH 2 aryl, wherein aryl represents an aromatic hydrocarbon or a 5 to 10 membered aromatic heterocyle containing I to 4 hetero atoms selected from an 20 oxygen atom, a sulphur atom and a nitrogen atom as a ring constituent besides carbon; CH 2 OCH 3 , -CH 2 0CH 2 CH 2 OCH 3 , CH 2 piperidin-1-yl or CH 2 -N-morpholinoyl; and R 15 represents H, C 1 - 6 alkyl or together with R 17 represents -CH 2 CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -; X is O or N; and 25 Y is O or N.

2. A compound according to claim 1, wherein A, A 2 and A 4 represent CH, and A 3 represents CRI. 30 3. A compound according to any preceding claim, wherein R 9 represents 2 naphthyl. PF I WO 2009/021750 PCT/EP2008/006720

4. A compound according to claim I wherein R 9 represents 2-naphthyl optionally substituted with halogen or phenyl optionally substituted with halogen; A, A 2 and A 4 represent CH, and A 3 represents CRi wherein R, represents: NRsC(=W)R 17 wherein 5 W represents NH, S or 0; R 17 represents C 2 -alkyl, n-propyl, or C 4 -Cioalkyl; Ci-Cloalkyl substituted with one or more halogen, hydroxyl, alkoxy or amine; a mono or disaccharide unit attached at the anomeric position via a CI-C 4 alkyl group which is optionally substituted with one or more C 1 - 6 alkyl group; CH 2 aryl, wherein aryl represents an aromatic hydrocarbon or a 5 10 to 10 membered aromatic heterocyle containing 1 to 4 hetero atoms selected from an oxygen atom, a sulphur atom and a nitrogen atom as a ring constituent besides carbon; CH 2 OCH 3 , CH 2 0CH 2 CH 2 0CH 3 , CH 2 piperidin-1-yl or CH 2 -N-morpholino; and R 15 represents H, C 1 - 6 alkyl or together with R 17 represents -CH 2 CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. 15

5. A compound according to claim I wherein R 9 represents a 5-10 membered heterocyclic ring containing one or more SOn units, wherein n=0-2 and may be the same or different for each SOn unit. 20 6. A compound according to claim 1, wherein R, represents a N-linked mono- or bi-cylic ring which is a lactam.

7. A compound according to claim 1, wherein R, represents -K-SO,-R 28 , wherein K represents CI-C 3 alkyl optionally substituted with Ci-C 6 alkyl; n=0-2 and R 28 25 represents Ci-Cloalkyl optionally substituted with one or more halogen, alkoxy or amine.

8. A compound according to claim 1, wherein R 9 represents a C 5 . 10 carbocycle which is partially or fully aromatic containing 0-4 hetero atoms substituted by 30 NR 9 o(C=Q)-M-Z-R 93 wherein R 90 represents H or C 1 . 6 alkyl, Q represents 0, S, or NR 9 1 wherein R 91 represents H or CI- 6 alkyl, M represents C,. 3 alkyl optionally substituted with halogen, C,. 6 alkyl, or CI- 6 alkoxy, Z represents 0, S or NR 92 wherein R 92 represents H or C 1 - 6 alkyl and R 93 represents a C 5 . 10 carbocycle which is partially or WO 2009/021750 PCT/EP2008/006720 fully aromatic containing 0-4 hetero atoms and optionally substituted by 1-4 halogen, C 1 -C 6 alkyl, 0C 1 -C 6 alkyl.

9. A compound according to claim 1 wherein Y represents N. 5

10. A compound according to claim 1 wherein X represents 0.

11. A compound according to claim 1 wherein Y represents N and X represents 0. 10 12. A compound selected from the following table: f-- ---- 3,4dichoroN(2isopopybenz dqoxazOI-57-Y~benzamide I 3 'T T)Ibtnmd f6 15(ethy~su~lfonyl)-2-(3-pheloxyphel)belzo[doxazole I ~ I27(benzo[d]oxazoI!2?- )5-chlorophe noI 8 5-chloro-2-(5-methylbeflz[doxa ol-2yl)phenbI 1 5-(ethylsuylfonYl--(1_H-indol5y~ez~~xzl - 11 eamid

12-(6-methyl-4-oxo-1 ,4-d ihydropyrimidin-2-ylthio)-N-(4-( 12 metylbenzoldlhiazol-2-yI)phefl)acetamide - 1,3,J yl)pheny!)butaflamide - --- -14 -(4-(6methyl4H-1 izl2-lpeyl7-9~nzln4-lhopc md 2-(5-isopropyl-4H-1 ,2,4-a--yltio-N-(4- -. hybnz~diazol-2- 15 ____y)phenyl)acetamide 16 y pnlprpnmd f 17 .15-(ethylsulfonyl)-2-(fural-2-y)belzo[dloxazole -1- 18 -13-(5-methylbenzo[d]oxazol-2-yl)Ryri-2-oI FT9 5-(5-metylbenzo~d] azo-2-yI)pyridil-2-oI I 2 I5-(5-methylbenzo[doxazol-2-yI) pyridin-2-amine F-21 ]5-(5-methylbenzodoxazol-2-yI)pyriidifle-2,4dioI -- (6mtybno ~hao--y~hnl -(-hnl4 ,2,4-triazol-3 r 23 lyti~ctmd WO 2009/021750 PCT/EP2008/006720 -24 JN-(4-(6-methylbenzofdloxazol-2-yl)phenyl)-2-(phenylthio)acetamide 25 IP-(4-(6-methylbenzo[d]th iazol-2-yI)phenyl)-2-phenoxyacetamide

36- methyl_2-(na phth alen-2-yI)benzo[d]oxazole-6-ca rboxyl ate 27 15-amino-2-(5-(trifluoromethoxy)benzo[dloxazol-2-yI)phenoI 28 5-amino-2-(naphtho[1 ,2-d]oxazol-2-yl)phenol F 29 7 15-amino-2-(5-phenylbenzo[dloxazol-2-yI)phenoI . 1 2-(4H-1,2,4-triazol-3-ylthio)-N-(4-(6-methylbenzo[d]oxazol-2 31-- -. -(34'dhenloroetami -ethlufnl-ezx 32 j2-('4-chlorophenyl)-6-(ethylsulfonyl)-benzoxazoe - 33 (2-(naphthalen-2-ylbenzo[dloxazol-6-yI)methanoI 34 _.12-(5-m ethyl benzoldloxazol-2-yI)ph en ol I -_-N-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-yI)-2-(beta-D 1 N-(2-(2,3-di hlorophenyl)benzo[djoxazol-5-yl)-3-(beta-D 36 II,Ilctp__noyl ------ naid i 37 .1 !rney!hn rlrv---,- N0h~ 38 __5-(ethyisulfonyl)-27(iso~quinolin-3-yl)benzofdoxazole 1 39 5-(ethylsulfonyl)-2-(quinolin-6-yl)benzo[d]oxazole 40 ~5-(ethylsulfonyI)-2-(quinoxalin-6-yI)benzo~d]oxazole 41 .2-(dimethylamino)-N-(2-(naphthalen-2-y)benzo[d]oxazoI-5-yi)acetamide 43 N-(-((ihoriobhnbenzo[d~oxazo--y)-iif 1oxde pnaid 44 2-(l H-imidazol-1 -7YI):-(2-(naphthalen-2-yl)benzo[dloxazoI-5-yI)acetamide 2-(1 H-imidazoI-4'-yI)-N-(2"-(naphthaen-2"'-yI)benzotd]oxazoI-5" 1. 45 Ilaeaiehydrochlpoe 46 Jmethyl ethyl(2-(naphthalen-2-yl)benzo[d]oxazoI-5-yl)phosphiflat 47 (mtyaio~rpnmd { 48 .2-hydroxy-N-(2-(pt len-2-y)benzo[d~o azl--y~aS eiTiAml 51 N2-(mathan-N2-phhaen-ibezo zodoxlzI-(eta etmi 52 .2-(2methoxyeth-N-(hhl2-phhaen2benod~xzol-d-oxazO--aetamide 52 2(2mehx hx)N-(2-(naphthalen-2-y)benzoldjoxazol-5-yIlprpioimi amide F5 ~5-(etthylsulfinyl)-2-(naphthalen-2-y )benzo[dloxazole 56 N-(2-(nphthaen-2-yl)benzo[doxazo-5-y)methanesulfo-namide [57 12-(4,4-difluorocyclohexyl)-5-(ethylsulfonyl)benzo[d]oxazole 1 5 8 3-hyd roxy-N-(2-(naphthalen-2-yI)benzo[d]oxazol-5-y)propanamide '7A WO 2009/021750 PCT/EP2008/006720 -59 ethyl 2-(naphthalen-2-yl)benzo[dloxazol-5-yl(phenyl)phosphinate 60 methy-(3,4-dchlorophenyl)benzo[d]oxazol-5-yl(ethyl)phosphinate 61 methyl 2-(2,3-d ichlorophenyl)benzo[d]oxazol-5-yl(ethyl)phosphinate 62 15-(ethylsulfonyl)-2-(naphthalen-2-ylmethyl)benzo[d]oxazole 63 j2-(4-chlorophenyl)benzo[d]oxazo-5-y (ethyl)phosphinic acid 64 2-morpholino-N-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)acetamide 65 N-methyl-2-(naphthalen-2-yl)benzo[d]oxazole-5-sulfonamide 66 N-(4-(6-methylbenzo[d]thiazol-2-yl)pheny)-2-(pyridi n-2-yloxy)acetamide 67 N-(2-(naphthalen-2-yl)benzo[d]oxazol-5-y)-2-(piperidin-1-yl)acetamide 68 5-(methylsulfony)-2-(naphthalen-2'-yl)benzo[doxazole 'N-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-yl)-3-(beta-D-

69- Ig ucopyranosyloxy)propanamide IN-(2-(2,3-dichlorophenyl)benzo[dloxazol-5-yI)-2-(beta-D 70 mannopyranosyloxy)acetamide 71 - N-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-yl)-2-methy aminoacetamide 72 .15-(2',2',2'-trdeuteroethylsulfonyl)-2-(naphthalen-2"-yl)benzo~d]oxazole (S)-2-amino-3-hydroxy-N-(2-(naphthalen-2-yl)benzo[d]oxazol-5 73 yl)propanamide S(S)-2-(methylamino)-N-(2-(naphthalen-2-yl)benzo[d]oxazo-5 74 yl)propanamide f 75 -12-(6-nitroimidazo[1 2-apyridin-2-yl)benzo[d]thiazole 76 (E)-5-(ethylsulfonyl)-2-styrylbenzo[d]oxazole 17 5-(ethylsulfonyl)-2-(1 ,2,3,4-tetrahydronaphthalen-2-y)benzo[d]oxazole 78 5-(ethylsulfonyl)-2-(4-phenoxyphel)blenzo[doxazole 79 2-(2,3-dihydro-1 H-inden-5-y)-5-(ethylsufonyl)benzo[d]oxazole 80 2-(4H-1,2,4-triazol-3-ylthio)-N-(4-(benzo[d]thiazol-2-y)thiazol-2-yi)acetamide 81 1l-(2'-(naphthalen-2-yl)benzo[d]oxazo-5'-y)pyrroidin-2-one [2-(4H-1,2,4-triazol-3-ylthio)-N-(5-(benzo[d]thiazol-2-yl)pyridine-3 1--82- ly )acetamide 83 2-(benzo[b]thiophen-1 1-d ioxide-6-yl)-5-(ethylsulfonyl)benzo[d]oxazo e 84 5-(morpholinomethyl)-2-(naphthalen-2-y)benzo[d]oxazole 85 5-~(ethylsu fonYlmethy)2(naphthalen-2-yl)benzo[d]oxazole 86 5-(methylsulfonylmethyl)-2-(naphthalen-2-yl)benzo[d]oxazo e 87 5-(methylsulfony)-2-(naphthalen-2-yl)benzo[d]thiazole 88 2-((2-(naphthalen-2-yl)benzo[d]oxazo-5-yl)methylamino)acetc acid 89 5-(ethyIsuIfony1)-2-(naphtha Ien-2-y)benzo[d]thiazoI e 90 - N-ethyl-2-(naphthalen-2-yl)benzofdloxazole-5-sulfonamide (S)-2-hydroxy-N,N,N-trimethyl-4-(2-(naphthalen-2-yl)benzo[d]oxazol-5 91 lylamino)-4-oxobutan-1-aminium WO 2009/021750 PCT/EP2008/006720 13. A pharmaceutical composition, comprising the compound of any of claims 1-12 and a pharmaceutically acceptable carrier. 14. A method of treatment or prophylaxis of Duchenne muscular dystrophy, Becker 5 muscular dystrophy or cachexia, comprising administering the compound of any of claims 1-12. 76