Drug combinations for the treatment of Duchenne muscular dystrophy

专利摘要:

公开号:AU2008285289A1
申请号:U2008285289
申请日:2008-08-01
公开日:2009-02-12
发明作者:Olivier De Moor；Colin Richard Dorgan；Peter David Johnson；Gary Nugent；Paul Damien Price；Richard Joseph Pye；Richard Storer；Stephen Paul Wren；Graham Michael Wynne
申请人:Biomarin IGA Ltd；
IPC主号:A61K45-06

专利说明:
WO 2009/019504 PCT/GB2008/050648 1 Drug Combinations for the Treatment of Duchenne Muscular Dystrophy Technical Field This invention relates to combinations comprising (or consisting essentially of) one or more 5 compounds of the formula (1) as defined herein with one or more ancillary agents, to processes for preparing the combinations, and to various therapeutic uses of the combinations. Also provided are pharmaceutical compositions containing the combinations as well as a method of treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia using the combinations. 10 Background of the invention Duchenne muscular dystrophy (DMD) is a common, genetic neuromuscular disease associated with the progressive deterioration of muscle function, first described over 150 15 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. Approximately 60% of dystrophin mutations are large insertion or deletions that lead to 20 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 10,000 sperm or eggs) means that genetic screening will never eliminate the disease, so 25 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. MO. Genet. 9, 2459-2467 (2000).) Although the mouse, cat and dog models all have mutations in the DMD gene and 30 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 human disease, and are considered a high benchmark for preclinical WO 2009/019504 PCT/GB2008/050648 2 studies. Unfortunately, breeding these animals is expensive and difficult, and the clinical time course can be variable among litters. 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. 5 X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc. Nat/ Acad. Sci: USA 81, 1189-1192 (1984)). 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 10 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 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 15 vectors, myoblasts and newly synthesized dystrophin have been reported, in addition to toxicity, lack of stable expression and difficulty in delivery. 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 20 improve the phenotype by means such as decreasing inflammation, improving calcium homeostasis and increasing muscle progenitor proliferation or commitment. These strategies 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 25 cromoglycate, to reduce inflammation, dantrolene to maintain calcium homeostasis and clenbuterol to increase muscle strength, have produced promising results none of these potential therapies alone has yet been 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 30 particularly beneficial when an immune response is mounted against a previously absent protein. Upregulation of utrophin, an autosomal paralogue of dystrophin has been 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 WO 2009/019504 PCT/GB2008/050648 3 restores the components of the dystrophin-associated protein complex (DAPC), which 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 5 mouse model can be effective and no toxicity is observed when utrophin is ubiquitously expressed, which is 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. Ancillary agents 10 A wide variety of ancillary agents find application in the combinations of the invention, as described in detail below. Summary of the Invention 15 We have now found a group of compounds which upregulate endogenous utrophin in predictive screens and, thus, may be useful in the treatment of DMD. According to the invention, we provide a combination comprising (or consisting essentially of) an ancillary agent and a compound of Formula (1)
A
1 Rx A3 20 A 4 (I) in which A, A 2 , As and A 4 which may be the same or different, represent N or CR X is a divalent group selected from 0, S(O)., C=W, NR 4 , NC(=O)R and CR 6
R
7 , 25 W is 0, S, NR 20 , Y is N or CR 8 , one of R 4 , R, R 6 , R 8 , R 9 and NR 20 represents - L -R 3 , in which L is a single bond or a linker group, additionally, R 3 - R 9 , which may be the same or different, independently represent 30 hydrogen or a substituent and R 20 represents hydrogen, hydroxyl, alkyl optionally substituted by aryl, alkoxy optionally substituted by aryl, aryl, CN, optionally substituted WO 2009/019504 PCT/GB2008/050648 4 alkoxy, optionally substituted aryloxy, optionally substitute alkanoyl, optionally substituted aroyl, NO 2 , NR 3 oR 3 1, in which R 3 o and R 31 , which may be the same or different, represent hydrogen, optionally substituted alkyl or optionally substituted aryl; additionally, one of Ro and R 31 may represent optionally substituted alkanoyl or optionally substituted aroyl, 5 n represents an integer from 0 to 2, in addition, when an adjacent pair of A 1 - A 4 each represent CR 1 , then the adjacent carbon atoms, together with their substituents may form a ring B, when X is CR 6
R
7 , Re and R 7 , together with the carbon atom to which they are attached may 10 form a ring C, when one of A 1
-A
4 is CR 1 , and R 1 represents COR 16 , R 1 e is preferably alkoxy or NR 1 0
R
11 , or a pharmaceutically acceptable salt thereof (optionally for the therapeutic and/or prophylactic treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia). 15 Compounds of formula I may exist in tautomeric, enantiomeric and diastereomeric forms, all of which are included within the scope of the invention. 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 Katritzky, CW Rees), Pergamon 20 Press, Oxford, 1984 and Comprehensive Heterocyclic Chemistry ll: 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: Reactions, 25 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 30 from compounds of formula 11.
WO 2009/019504 PCT/GB2008/050648 5 1 N[j OHL R NH R R H 2 R when R 1
=CO
2 H 0 Vi. 0 iv.N R vR R H N IVI 'N 0k H Scheme I Reaction conditions: i. R 9
CO
2 H (or R 9 COCI), PPA, heat; or RCOCI, dioxane, pwave, then 5 NaOH ii. R 9 COCI, pyridine, rt iii. TsOH, xylenes iv. R 9 C0 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 Il with an acyl derivative, such as the acid or the acid chloride, and heating in an appropriate solvent and an appropriate temperature in the presence of an acid catalyst, for example polyphosphoric acid. This is 15 illustrated above as step (i). The reaction may be carried out in an aprotic solvent, preferably 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 pressure. Alternatively, the compound of formula Il may first be reacted with an excess of an acyl 20 derivative R 9 COX (where X is for example CI), such that acylation takes place on both oxygen and nitrogen. This can be brought about by, for example, reaction in pyridine at room temperature (step ii). Ring closure to form the compound of formula II can then occur WO 2009/019504 PCT/GB2008/050648 6 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 sulphonic acid (step iii). Another illustrative example of formation of a compound of formula I is shown by steps iv and v. First the amine is coupled to an acid using a peptide coupling reagent. Available 5 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 R 1 = CO 2 H, this acid may be coupled with an amine as shown by step (vi). Suitable coupling conditions include use of HATU in DMF in the presence of 'Pr 2 NEt, R" 1
NH
2 at 10 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 Ill. OH H2N NH 2 O 0- O R O)R2 iv. H 2 N N R OH vvii. I NH 0 N 1 0 2 N NH 2
O
2 N v. IV O R R /-RS 0- 0 N R 15N H /--N XN R14~: > N H10 H R RSH IX Re Ril0V 15 Scheme 2 Reaction conditions: i. As for (i); Scheme I ii. R 17 COC, pyridine (or NEt 3 , DCM); or R 9 C0 2 H, HATU, 20 pyridine, DMF iii. As for (i); Scheme 1 iv. SnC 2 , EtOH, heat; or Pd/C, H 2 , IMS; or Fe, NH 4 CI, IMS I water, heat WO 2009/019504 PCT/GB2008/050648 7 v. R 9 NCO, DCM, rt vi. NaBH(OAc) 3 , R 10 CHO, DCE, rt vii. R 14
SO
2 CI, pyridine, DCM, rt 5 Intermediate amine Ill may be synthesised either by using the method outlined in scheme 1, step (i) wherein R' = 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 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 10 give intermediate amine IIl. 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/HCI, or H2/Pd/C in a suitable solvent, e.g. ethanol at a temperature of from 0" to 80 0 C or heating in the presence of iron, NH 4 CI in industrial methylated spirits / water. Intermediate amine Ill can then be coupled as required. 15 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
CI
2 (step ii). Sulfonamide derivatives VII can be produced by reaction of amine III with an appropriate sulfonyl chloride in, for example, CH 2
CI
2 in the presence of pyridine at room temperature. 20 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. Urea derivatives of formula IX can be produced, for example, by reaction of amine Ill with 25 the appropriate isocyanate, for example, at room temperature in CH 2
CI
2 . Benzothiazoles of formula X or pharmaceutically acceptable salts thereof may be prepared from compounds of formula X1.
WO 2009/019504 PCT/GB2008/050648 8
-
I I 0 2 N NH 2 0 2 N NR 0 2 N : N H Xi 0 iv. R HH 2 N R N X Scheme 3 Reaction conditions: 5 j. R 9 COCI, pyridine, rt ii. Na 2 S, S 8 , IMS, heat iii. Fe, NH 4 CI, IMS, heat iv.R' 7 COCI, pyridine (or NEt 3 , DCM); or R 17
CO
2 H, HATU, pyridine, DMF 10 The compounds of formula XI can be converted to the corresponding amide by, for 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. 15 The aide can then be converted to the nitro-benzothiazole of formula XII in a one-pot procedure involving reaction with Na 2 S, S 8 at elevated temperature in industrial methylated spirit. Nitro derivative X11 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). 20 WO 2009/019504 PCT/GB2008/050648 9 H H 17H
NNH
2 ON RLN N 02N 02 )-RS H 2 N -R R N-R ANH AN A0N H AN XIII XII 4 R X NHR 4 NHR R NV V. N
O
2 N NO 2 O2N NO 2 O2N NH 2 ON N Xlv Xv 1111 4R4 R IN N 0 NN~ > >R RA N-R
H
2 N AN H Scheme 4 Reaction conditions: 5 i. R 9 C0 2 H, PPA, heat; or RCOCI, pyridine; then PPA, heat ii. SnC 2 , IMS, heat; or Pd/C, H 2 , IMS iii. R 17 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 X11 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 15 formula XlI. 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, preferably a halogen such as chlorine or fluorine, with an amine, for example, in DMSO at elevated temperature in the presence of a 20 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.
WO 2009/019504 PCT/GB2008/050648 10 N I O A IOH . A A0 X NO 2 X NH 2 x NR X=NO 2
H
2 N N XX XXI iv. X=Br V. A0 N 0 v1. O> R Y=C, X=NO 2 R N XIX XVIII I AtIv" 0 Vii. Ac X H XG AN XXII XXII A2A' OH i A 2-A' o AN 2
ANH
2 ANA4 N XVII XVI Scheme 5 Reaction conditions: 5 i. Na 2 S hydrate, MeOH, NH 4 CI, water; or Na 2
S
2
O
4 / EtOH; or SnCl2, EtOH ii. As for (i), Scheme 1; or R 9 COCI, pyridine; then PPA, heat iii. SnCl2, EtOH, heat iv. R'B(OH) 2 , Pd(PPh 3
)
4 , K 2 C0 3 , dioxane I water, pwave 10 v. R 17 COCI, pyridine, rt vi. EtOC(S)SK, pyridine, heat vii. SOC 2 ; or POC 3 viii. R 3
B(OH)
2 , Pd(PPh3) 4 , K 2
CO
3 , solvent ix. PPA, R2CO 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 corresponding amino alcohol XXI (for example using Sn I HCI, or any of the other appropriate methods WO 2009/019504 PCT/GB2008/050648 11 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. For oxazoles of formula XXIII in which X = Br, a Suzuki coupling reaction can then be used 5 to give further derivatives. An example of appropriate conditions are R'B(OH) 2 , Pd(PPh 3
)
4 ,
K
2
CO
3 , dioxane / water, pwave, 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. For oxazoles produced by step (ii) in which X = NO 2 , the nitro group can be reduced to the 10 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 XVIll. Alternatively, benzoxazoles of formula XVIII can be made, also from a compound of 15 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
POC
3 . A Suzuki coupling using, for example, conditions illustrated by step viii above gives a benzoxazole of formula XVIII. 20 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 1. Suitable protecting groups and methods for their removal are, for example, those described in "Protective Groups in Organic Synthesis" by T. Greene and P.G.M. Wutts, John Wiley 25 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, diphenylmethyl or triphenylmethyl, and acyl groups such as acetyl, trichloroacetyl or 30 trifluoroacetyl. Conventional methods of deprotection may be used including hydrogenolysis, acid or base hydrolysis, or photolysis. Arylmethyl groups may, for example, be removed by 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 WO 2009/019504 PCT/GB2008/050648 12 potassium carbonate, or a group such as trichloroacetyl may be removed by reduction with, for example, zinc and acetic acid: The compounds of formula I, and salts thereof, may be isolated from their reaction mixtures using conventional techniques. 5 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 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, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying. The reaction may 10 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 salts, e.g. sodium and potassium salts; alkaline earth metal salts, e.g. calcium and magnesium salts; salts of the Group Ill elements, e.g. aluminium salts; and ammonium salts. Salts with suitable organic bases, for example, salts with hydroxylamine; lower alkylamines, e.g. 15 methylamine or ethylamine; with substituted lower alkylamines, e.g. hydroxy substituted alkylamines; or with monocyclic nitrogen heterocyclic compounds, e.g. piperidine or morpholine; and salts with amino acids, e.g. with arginine, lysine etc, or an N-alkyl derivative thereoft or with an aminosugar, e.g. N-methyl-D-glucamine or glucosamine. The non-toxic physiologically acceptable salts are preferred, although other salts are also 20 useful, e.g. in isolating or purifying the product. Diastereoisomers may be separated using conventional techniques, e.g. 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 25 by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation. Substituents that alkyl may represent include methyl, ethyl, butyl, eg sec butyl. Halogen may represent F, Cl, Br and I, especially Cl. Examples of substituents that R 3 in the compound of formula 1 may represent include alkyl, 30 alkoxy or aryl, each optionally substituted by one or more, preferably one to three substituents, R 2 , which may be the same or different. In addition, when L is single bond, R 3 may represent thioalkyl optionally substituted by alkyl or optionally substituted aryl, thioaryl, in which the aryl is optionally substituted, optionally WO 2009/019504 PCT/GB2008/050648 13 substituted aryl, hydroxyl, NO 2 , CN, NR, 1
R
11 , halogen, S0 2
R
12 , NRj 3 S0 2
R
14 , C(=W)R 16 , OC(=W)NR,oR, NR 15
C(=W)R
7 , P(=O)OR 4 oR 41 , R 10 , R 1 1 , R 1 2 , R 13 , R 14 , R 1 5 , R 1 6 , R 1 7 , R 4 0 and R41, which may be the same or which may be the same or different, represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted 5 aryl, in addition,
NROR
11 together with the nitrogen to which they are attached may form a ring,
R
12 may have the same meaning as NROR 11 , when R 17 represents NRoR 1 , that RIO and R, 1 , which may be the same or different, 10 may represent hydrogen, COalkyl and CO optionally substituted aryl, R1 6 and R 1 7 , which may be the same or different, may each represent alkyl substituted by one or more of halogen, alkoxy optionally substituted aryl or optionally substituted aryl, optionally substituted aryloxy, 15 aryl or NR 1 aRII, and when R 1 8 or R 17 represents NR 0
R
1 , one of Rio and R 11 , may additionally represent CO alkyl optionally substituted or COaryl optionally substituted, and in addition to the definitions shared with R 1 7 , R 8 may represent hydroxy. 20 Examples of substituents that R 1 and R 2 , which may be the same or different, may represent include: alkyl optionally substituted by one or more halogen, alkoxy or optionally substituted aryl, thioaryl or aryloxyalkoxy optionally substituted by optionally by alkyl or optionally substituted aryl,hydroxyl,OC(=W)NRoR 1 , optionally substituted aryl,thioalkyl optionally 25 substituted by alkyl or optionally substituted aryl,thioaryl, in which the aryl is optionally substituted,NO 2 ,CN,NRORP, halogen,SO 2
R
2
,NR
3
SO
2
RI
4
,C(=W)R
6 , NR 1 5
C(=W)R
1 7 , R 1 0 ,
R
1 1 , R 1 2 , R 1 3 , R 1 4 , R 1 5 , R 1 6 and R 1 7 , which may be the same or different, represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted aryl, 30 in addition,
NR
0
R
1 together with the nitrogen to which they are attached may form a ring,
R
12 may have the same meaning as NP 1
R
11 , when R 17 represents NR 0
R
1 ,l that R and R 1 1 , which may be the same of different, may represent hydrogen, COalkyl and CO optionally substituted aryl, 35 R 16 may represent hydroxy, alkoxy, or NRjOR 11
,
WO 2009/019504 PCT/GB2008/050648 14
R
17 may represent alkyl substituted by one or more of halogen, alkoxy, optionally substituted aryl or NR 0
R
1 , and when R 1 7 represents NR 0
R
11 , that NR 0
R
11 may represent hydrogen, COalkyl and CO optionally substituted aryl. 5 When L represents a linker group, examples of linker groups that L may represent include: 0, S, (CO)NR 1 8 , 10 alkylene, alkenylene, alkynylene, each of which may be optionally interrupted by one or more of 0, S, NR 1 8 , or one or more C-C single, double or triple bonds, a -N-N- single or double bond,
R
1 8 represents hydrogen, alkyl, COR 1 6 When L is (CO)NR 1 8 , n may represent 0, 1 or 2, when n is 1 or 2, R 1 8 preferably 15 represents hydrogen. Although the scope for variation of R 4 , R 5 , R 6 , R 7 and R3 is large, preferably R 4 , R 5 , R 6 , R 7 and R 8 , represent hydrogen, alkyl or optionally substituted aryl. 20 Preferably Y represents N and X represents 0, S or NR 4 . That is preferably the compound according to formula I is a benzoxazole, a benzthiazole or a benzimidazole. Although any one of R 4 , R 6 , R 8 or R 9 may represent -L-R 3 -, in preferred compounds R 9 represents -L-R 3 . 25 Alkyl may represent any alkyl chain. Alkyl includes straight and branched, saturated and unsaturated alkyl, as well as cyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. However, preferably, when any of the substituents represents alkyl, alkyl is saturated, linear or branched and has from 1 to 10 carbon atoms, preferably 30 from 1 to 8 carbon atoms and more preferably from 1 to 6 carbon atoms. When any of the substituents represents alkyl, a particularly preferred group is cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Aryl may represent any aromatic system. Preferably, in the compounds of formula I, aryl is 35 an aromatic hydrocarbon or a 5 to 10 membered aromatic heterocycle containing 1 to 4 WO 2009/019504 PCT/GB2008/050648 15 hetero atoms selected from an oxygen atom, a sulphur atom and a nitrogen atom as a ring constituent besides carbon. We prefer heterocycles which contain one or two heteroatoms. Aromatic heterocycles that may be mentioned include furan, thiophene, pyrrole, pyridine. 5 Particularly preferably, when aryl is an aromatic hydrocarbon, aryl represents a 6 to 10 membered monocyclic or bicyclic system, for example phenyl or naphthalene. Saturated and unsaturated heterocycles that may be mentioned include those containing 4 to 7 ring atoms, preferably 5 or 6 ring atoms, preferably containing one to two heteroatoms 10 selected from N, S and 0. Heterocycles that may be mentioned include pyrrolidine, piperidine, tetrahydrofuran, piperazine and morpholine. N-containing heterocycles are particularly preferred, eg when NR 1 0
R
1 forms a heterocyclic ring. As detailed above, when an adjacent pair of A 1 - A 4 each represent CRI, the adjacent 15 carbon atoms, together with their substituents may form a ring ring B. Also, when X is
CR
8 Ry, R 6 and R 7 , together with the carbon to which they are attached may form a ring C. Preferably ring B and/or ring C is a saturated or unsaturated 3 to 10 membered carbocylic or heterocyclic ring. 20 Particularly preferably ring B is benzene ring. Particularly preferably ring C is a 3- 10 membered saturated or unsaturated carbocylic ring. We particularly prefer compounds in which at least one R 1 represents NR 1 5
C(=W)R
7 , more 25 particularly the group NR 15
COR
17 . We also prefer compounds in which at least one R 1 represents CONR 1
R
11 . For one group of particularly preferred compounds at least one R 1 represents an amide 30 group NHCOR 1 7 wherein R 17 is selected from: alkyl C 1 - Cc, alkyl C1 - Ce substituted by phenyl alkyl C1 - C6 substituated by alkoxy C 1 - Cr, haloalkyl C1 - C6, 35 perfluoroalkyl C1 - C 6
,
WO 2009/019504 PCT/GB2008/050648 16 phenyl optionally substituted by one or more of halogen, alkyl C - C3, alkoxy C1 C6, amino, (alkyl C1 - Cs)amino, di(alkyl C1 - C) amino or phenyl, CH:CH phenyl, naphthyl, pyridinyl, thiophenyl and furanyl. 5 We prefer compounds in which one or both of R 1 and R2 are other than -COOH. For another group of particularly preferred compounds at least one R, represents a group
NR
15
CONR
1
R
11 , then in which R 1 0 and R 11 , which may be the same or different, are 10 selected from optionally substituted aryl, alkyl and COaryl optionally substituted. A particularly preferred group which at least one of R 1 may represent is NHCONHR 16 and R 16 is selected from phenyl, alkyl C1 to C and COphenyl optionally substituted by one or more halogen. 15 For another group of particularly preferred compounds at least one R 1 represents alkyl C1 to C6, optionally substituted by phenyl or a 5 or 6- membered saturated or unsaturated heterocycle containing one to two heteroatoms selected from N, S and 0. For another group of particularly preferred compounds at least one R 1 represents COR 16 20 and R 16 is alkoxy C1 - C6, amino, (alkyl C1 - C 6 )amino or di(alkyl C, - Cc) amino. For another group of particularly preferred compounds at least one R 1 represents:
NO
2 , halogen, 25 amino or alkyll C1 - C 6 )amino or di(alkyl C1 - Cc) amino in which the alkyl C, to Ca is optionally substituted by phenyl or a 5 or 6 membered saturated or unsaturated heterocycle,
NHSO
2 alkyl C1 - C6, NHSO 2 phenyl,
SO
2 alkyl C1 - C, 30 phenyl optionally substituted by C1 to C6 alkoxy C1 - C6, a 5 - 10 membered, saturated or unsaturated, mono- or bi-cyclic heterocycle containing from 1 - 3 heteroatoms selected from N, S and 0. There is also wide scope for variation of the group R 3 . Preferably R 3 represents aryl and is 35 optionally substituted by one to three substituents, R 2 , which may be the same or different.
WO 2009/019504 PCT/GB2008/050648 17 Particularly preferably, R 3 is a 5 - 10 membered aromatic mono- or bi-cyclic system, especially a hydrocarbon 5 - 10 membered aromatic mono- or bi-cyclic system, for example benzene or naphthalene. Alternatively, the 5 - 10 membered aromatic mono- or bi-cyclic system, may be a heterocyclic system containing up to three heteroatoms 5 selected from N, 0 and S, for example a thiophene, furan, pyridine or pyrrole. Preferably the substituent(s) R 2 is/are selected from: alkyl C1 - C6, optionally substituted by thiophenyl or phenoxy, each optionally substituted by halogen, 10 afkoxy C 1 - C 6 phenyl, thioalkyl C1 - Ce thiophenyl, optionally substituted by halogen, N02, 15 CN
NR
0
R
11 , in which R 1 0 and R 1 1 , which may be the same or different represent hydrogen, alkyl C1 - C6, or together with the nitrogen to which they are attached form a 5 to 7 membered ring which may contain one or more additional heteroatoms selected from N, 0 and S, 20 halogen S0 2
R
2 , in which R 12 represents a 5 to 7 membered ring which may contain one or more additional heteroatoms selected from N, 0 and S
NHCOR
17 , in which R 1 7 represents alkyl C1 - C6, optionally substituted by: 25 phenyl or halogen, or phenyl optionally substituted by alkoxy C1 - C, carboxy or halogen, or a 5 or 6 membered saturated or unsaturated heterocycle, phenyl or a 5 or 6 membered saturated or unsaturated heterocycle 30 optionally substituted by halogen, alkoxy C1 to C6, carboxy or a group S0 2 NRoR, Particularly preferably when R 2 represents NR 10
R
1 , NR 10
R
1 represents N-pyrrole, N piperidine, N'(C 1 - C6) alkyl N piperazine or N-morpholine. 35 Preferably the linker group L represents: WO 2009/019504 PCT/GB2008/050648 18
-NH.NH
-CH=CH
-NCORI
6 in which R 1 6 represents phenyl or a 5 or 6 membered saturated or unsaturated heterocycle optionally-substituted by halogen, alkoxy C1 to C6, 5 carboxy.
A
1 - A 4 may represent N or CRj. Consequently, the benzoxazole six membered ring may contain 1, 2, 3 or 4 nitrogen atoms. Embodiments of the invention exist in which two of A 1 - A 4 represent nitrogen, one of A 1 - A 4 represents nitrogen and in which all of A 1 - A 4 10 represents CRI. In a particularly preferred group of compounds:
A
1 , A 2 , A 3 and A4 which may be the same or different, represent N or CR 1 , X is a divalent group selected from 0, S(O), C=W, NR4, NC(=0)R and CR 6
R
7 , 15 W is 0, S, NR 2 0 , Y is N or CRE, one of R 4 , R 5 , R 8 , R 8 , R 9 and NR 20 represents - L -R 3 , in which L is a single bond or a linker group, additionally, R 4 - R 9 , which may be the same or different, independently represent 20 hydrogen or a substituent and R 2 0 represents hydrogen, hydroxyl, alkyl optionally substituted by aryl, alkoxy optionally substituted by aryl, aryl, CN, optionally substituted alkoxy, optionally substituted aryloxy, optionally substitute alkanoyl, optionally substituted aroyl, NO 2 , NR 30
R
31 , in which Ro and R 31 , which may be the same or different, represent hydrogen, optionally substituted alkyl or optionally substituted aryl; additionally, one of R 30 25 and R 31 may represent optionally substituted alkanoyl or optionally substituted aroyl,n represents an integer from 0 to 2,
R
3 represents alkyl, alkoxy or aryl, each optionally substituted by one to three subsitutuents, R 2 , which may be the same or different
R
1 and R2, which may be the same or different, represent: 30 alkyl optionally substituted by one or more halogen, alkoxy or optionally substituted aryl, thioaryl or aryloxy, alkoxy optionally substituted by optionally by alkyl or optionally substituted aryl, hydroxyl,
OC(=W)NR
1
R
1 35 optionally substituted aryl, WO 2009/019504 PCT/GB2008/050648 19 thioalkyl optionally substituted by alkyl or optionally substituted aryl, thioaryl, in which the aryl is optionally substituted, N02, CN, 5 NRoR11, halogen, S0 2
R
12 ,
NR
1 3SO 2
R
4 , C(=,,W)R13,, 10 NR 15
C(=W)R
17 ,
R
1 , R 11 , R 1 2 , R 1 3 , R 14 , R 1 5, R 16 and R 17 , which may be the same or different, represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted aryl, in addition, 15 NR 1 0
R
1 1 together with the nitrogen to which they are attached may form a ring,
R
12 may have the same meaning as NR 1 0
R
11 , when R 17 represents NR 1
OR
1 I, that NR 1 oR 11 may represent hydrogen, COalkyl and CO optionally substituted aryl, R1 6 may represent hydroxy, alkoxy, or NR 1 oR 1 1 , 20 R 1 7 may represent alkyl substituted by one or more of halogen, alkoxy, optionally substituted aryl or NR 10
R
1 1 and when R 17 represents NR 10
R
11 , that NR 1 oR 11 may represent hydrogen, COalkyl and CO optionally substituted aryl, and in addition, 25 when an adjacent pair of A 1 - A 4 each represent CR 1 , then the adjacent carbon atoms, together with their substituents may form a ring B, when X is CReR 7 , R 6 and R 7 , together with the carbon atom to which they are attached may form a ring C, or a pharmaceutically acceptable salt thereof, optionally for the therapeutic and/or prophylactic treatment of Duchenne muscular dystrophy, Becker muscular 30 dystrophy or cachexia. We also provide 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 combination of the invention. 35 WO 2009/019504 PCT/GB2008/050648 20 General preferences and definitions The combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds when administered separately. 5 The term "efficacious" includes advantageous effects such as additivity, synergism, reduced side effects, reduced toxicity, increased time to disease progression, increased time of survival, sensitization or resensitization of one agent to another, or improved response rate. Advantageously, an efficacious effect may allow for lower doses of each or either component to be administered to a patient, thereby decreasing the toxicity of 10 chemotherapy, whilst producing and/or maintaining the same therapeutic effect. A "synergistic" effect in the present context refers to a therapeutic effect produced by the combination which is larger than the sum of the therapeutic effects of the components of the combination when presented individually. An "additive" effect in the present context refers to a therapeutic effect produced by the 15 combination which is larger than the therapeutic effect of any of the components of the combination when presented individually. A "pharmaceutical composition" is a solid or liquid composition in a form, concentration and level of purity suitable for administration to a patient (e.g. a human or animal patient) upon which administration it can elicit the desired physiological changes. Pharmaceutical 20 compositions are typically sterile andlor non-pyrogenic. The term non-pyrogenic as applied to the pharmaceutical compositions of the invention defines compositions which do not elicit undesirable inflammatory responses when administered to a patient. As used herein, the terms mobilizing agent and mobilization are terms of art referring to agents and treatments which serve to promote the migration of CD34', stem, progenitor 25 andlor precursor cells from the marrow to the peripheral blood (for a review, see e.g. Cottler-Fox et al. (2003) Stem cell mobilization Hematology: 419-437). Current standard agents for mobilization suitable for use according to the invention include G-CSF (Filgrastim T M , Amgen), GM-CSF (Sargramostim
TM
, Berlex, Richmond, CA) and erythropoietin (which has some mobilizing activity wart, CD34* cells). Alternative agents 30 include stem cell factor (SCF) (which is particularly effective when used in combination with G-CSF) and various derivatives of G-CSF (Pegfilgrastim T M , Amgen) and erythropoietin (Darbopoietin@, Amgen). The latter agents benefit from extended half-lives and so WO 2009/019504 PCT/GB2008/050648 21 increase the temporal window available for collection. AMD3100 (AnorMed
TM
, Vancouver, Canada), which is a reversible inhibitor of the binding of stromal derived factor (SDF-1 a) to its cognate receptor CXCR4, is currently in clinical trials as a mobilizing agent. Other agents include docetaxel (see e.g. Prince et al. (2000) Bone Marrow Transplantation 26: 5 483-487). The term "upregulation of utrophin" as used herein includes elevated expression or over expression of utrophin, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation of 10 utrophin, including activation by mutations. The term "utrophin upregulating agent" is to be interpreted accordingly. Thus, upregulation of utrophin covers increasing utrophin activity at the level of the encoding DNA as well as the transcriptional, translational or post translational level. Preferred compounds of formula (1) are utrophin upregulators (as disclosed herein). 15 As used herein, the term "combination", as applied to two or more compounds and/or agents (also referred to herein as the components), is intended to define material in which the two or more compounds/agents are associated. The terms "combined" and "combining" in this context are to be interpreted accordingly. 20 The association of the two or more compounds/agents in a combination may be physical or non-physical. Examples of physically associated combined compounds/agents include: " compositions (e.g. unitary formulations) comprising the two or more 25 compounds/agents in admixture (for example within the same unit dose); * compositions comprising material in which the two or more compounds/agents are chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety); * compositions comprising material in which the two or more compounds/agents are 30 chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets); " pharmaceutical kits, pharmaceutical packs or patient packs in which the two or more compounds/agents are co-packaged or co-presented (e.g. as part of an array of unit doses); 35 WO 2009/019504 PCT/GB2008/050648 22 Examples of non-physically associated combined compounds/agents include: * material (e.g. a non-unitary formulation) comprising at least one of the two or more compounds/agents together with instructions for the extemporaneous association of 5 the at least one compound/agent to form a physical association of the two or more compounds/agents; * material (e.g: a non-unitary formulation) comprising at least one of the two or more compounds/agents together with instructions for combination therapy with the two or more compounds/agents; 10 * material comprising at least one of the two or more compounds/agents together with instructions for administration to a patient population in which the other(s) of the two or more compounds/agents have been (or are being) administered; e material comprising at least one of the two or more compounds/agents in an amount or in a form which is specifically adapted for use in combination with the 15 other(s) of the two or more compounds/agents. As used herein, the term "combination therapy" is intended to define therapies which comprise the use of a combination of two or more compounds/agents (as defined above). Thus, references to "combination therapy", "combinations" and the use of 20 compounds/agents "in combination" in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen. As such, the posology of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times. It will therefore be appreciated that the compounds/agents of the combination may be administered sequentially (e.g. before or after) or 25 simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately). Simultaneously in the same formulation is as a unitary formulation whereas simultaneously in different pharmaceutical formulations is non-unitary. The posologies of each of the two or more compounds/agents in a combination therapy may also differ with respect to the route of administration. 30 As used herein, the term "pharmaceutical kit" defines an array of one or more unit doses of a pharmaceutical composition together with dosing means (e.g. measuring device) and/or delivery means (e.g. inhaler or syringe), optionally all contained within common outer packaging. In pharmaceutical kits comprising a combination of two or more 35 compounds/agents, the individual compounds/agents may unitary or non-unitary WO 2009/019504 PCT/GB2008/050648 23 formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical kit may optionally further comprise instructions for use. As used herein, the term "pharmaceutical pack" defines an array of one or more unit doses 5 of a pharmaceutical composition, optionally contained within common outer packaging. In pharmaceutical packs comprising a combination of two or more compounds/agents, the individual compounds/agents may unitary or non-unitary formulations. The unit dose(s) may be contained within a blister pack. The pharmaceutical pack may optionally further comprise instructions for use. 10 As used herein, the term "patient pack" defines a package, prescribed to a patient, which contains pharmaceutical compositions for the whole course of treatment. Patient packs usually contain one or more blister pack(s). Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patient's supply of a pharmaceutical 15 from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in patient prescriptions. The inclusion of a package insert has been shown to improve patient compliance with the physician's instructions. The combinations of the invention may produce a therapeutically efficacious effect relative to the therapeutic effect of the individual compounds/agents when administered separately. 20 The term "ancillary agent" as used herein may define a compound/agent which yields an efficacious combination (as herein defined) when combined with a compound of the formula (1) as defined herein. The ancillary agent may therefore act as an adjunct to the compound of the formula (1) as defined herein, or may otherwise contribute to the efficacy of the combination (for example, by producing a synergistic or additive effect or improving 25 the response rate, as herein defined). As used herein, the term "antibody" defines whole antibodies (including polyclonal antibodies and monoclonal antibodies (Mabs)). The term is also used herein to refer to antibody fragments, including F(ab), F(ab'), F(ab')2, Fv, Fc3 andsingle chain antibodies 30 (and combinations thereof), which may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. The term "antibody" is also used herein to cover bispecifc or bifunctional antibodies which are synthetic hybrid antibodies having two different heavy/light chain pairs and two different binding sites. Bispecific antibodies can be produced by a variety of methods including fusion of hybridomas or WO 2009/019504 PCT/GB2008/050648 24 linking of Fab' fragments. Also covered by the term "antibody" are chimaeric antibodies (antibodies having a human constant antibody immunoglobulin domain coupled to one or more non-human variable antibody immunoglobulin domain, or fragments thereof). Such chimaeric antibodies therefore include "humanized" antibodies. Also covered by the term 5 "antibody" are minibodies (see WO 94/09817), single chain Fv-Fc fusions and human antibodies antibodies produced by transgenic animals The term "antibody" also includes multimeric antibodies and higher-order complexes of proteins (e.g. heterodimeric antibodies). 10 Ancillary agents for use according to the invention Any of a wide variety of ancillary agents may be used in the combinations of the invention. Preferably, the ancillary agents for use in the combinations of the invention as described 15 herein are selected from the following classes: 1. Antiinflammatory agents; 2. Protease inhibitors; 3. Myostatin antagonists; 20 4. Cytokines and mobilizing agents; 5. Corticosteroids; 6. Anabolic steroids; 7. TGF-p antagonists; 8. Antioxidants and mitochondrial supporting agents; 25 9. Dystrophin expression enhancing agents; 10. Gene replacement/repair agents; 11. Cell-based compositions; 12. Creatine; 13. anti-osteoporotic agents; 30 14. auxiliary utrophin upregulating agents; 15. cGMP signalling modulators; and 16. a combination of two or more of the foregoing classes. A reference to a particular ancillary agent herein is intended to include ionic, salt, solvate, 35 isomers, tautomers, N-oxides, ester, prodrugs, isotopes and protected forms thereof WO 2009/019504 PCT/GB2008/050648 25 (preferably the salts or tautomers or isomers or N-oxides or solvates thereof, and more preferably, the salts or tautomers or N-oxides or solvates thereof). 1. Antinflammatory agents 5 Muscles affected by DMD show signs of inflammation, including an abundance of macrophages. Thus, a wide ran|e of antiinflammatory agents can be used in the treatment of muscular dystrophies, as discussed below. 10 1.1 Beta2-adrenergic receptor agonists In one embodiment of the invention, the ancillary agent is a beta2-adrenergic receptor agonist (e.g. albuterol). 15 Definitions and technical background The term beta2-adrenergic receptor agonist is used herein to define a class of drugs which act on the p2-adrenergic receptor, thereby causing smooth muscle relaxation resulting in dilation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle and release of insulin. A preferred beta2-adrenergic receptor agonist for use according to the invention is albuterol, an immunosuppressant 20 drug that is widely used in inhalant form for asthmatics. Albuterol is thought to slow disease progression by suppressing the infiltration of macrophages and other immune cells that contribute to inflammatory tissue-loss. Albuterol also appears to have some anabolic effects and promotes the growth of muscle tissue. Albuterol may also suppress protein degradation (possibly via calpain inhibition). 25 1.2 nNOS stimulators The loss of dystrophin leads to breaks in the membrane, and destabilizes neuronal nitric oxide synthase (nNOS), a protein which normally generates nitric oxide (NO). It is thought 30 that at least part of the muscle degeneration observed in DMD patients may result from the reduced production of muscle membrane-associated neuronal nitric oxide synthase. This reduction may lead to impaired regulation of the vasoconstrictor response and eventual muscle damage. 35 1.3 Nuclear Factor Kappa-B inhibitors WO 2009/019504 PCT/GB2008/050648 26 A preferred class of antiinflammatory agent suitable for use in the combinations of the invention are Nuclear Factor Kappa-B (NF-kB) inhibitors. NF-kB is a major transcription factor modulating the cellular immune, inflammatory and proliferative responses. NF-kB 5 functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. The activation of this factor in DMD contributes to diseases pathology. Thus, NF-kB plays an important role in the progression of muscular dystrophy and the IKKINF-B signaling pathway is a potential therapeutic target for the treatment of DMD. Inhibitors of NF-kB (for 10 example, IRFI 042, a vitamin E analogue) ameliorate muscle function, decrease serum CK level and muscle necrosis and enhance muscle regeneration. Furthermore, specific inhibition of NF-kB/lKK-mediated signalling has similar benefits. 1.4 TNF-a antagonists 15 TNFa is one of the key cytokines that triggers and sustains the inflammation response. In one embodiment of the invention, the ancillary agent is a TNF-a antagonist (e.g. infliximab). 20 Preferences and specific embodiments: Preferred TNF-a antagonists for use according to the invention include infliximab (Remicade T M ), a chimeric monoclonal antibody comprising murine VK and VH domains and human constant Fc domains. The drug blocks the action of TNFa by binding to it and preventing it from signaling the receptors for TNFo on the surface of cells. Another preferred TNF-a antagonists for use according to the invention is 25 adalimumab (Humira
TM
). Adalimumab is a fully human monoclonal antibody. Another preferred TNF-a antagonists for use according to the invention is etanercept (Enbrel T M ). Etanercept is a dimeric fusion protein comprising soluble human TNF receptor linked to an Fc portion of an IgG1. It is a large molecule that binds to and so blocks the action of TNFa. Etanercept mimics the inhibitory effects of naturally occurring soluble TNF receptors, but as 30 a fusion protein it has a greatly extended half-life in the bloodstream and therefore a more profound and long-lasting inhibitory effect. Enbrel is marketed as a lyophylized powder in 25mg vials which must be reconstituted with a diluent and then injected subcutaneously, typically by the patient at home.
WO 2009/019504 PCT/GB2008/050648 27 Another preferred TNF-a antagonist for use according to the invention is pentoxifylline (Trental T M ), chemical name 1-(5-oxohexyl)-3, 7-dimethylxanthine. The usual dosage in controlled-release tablet form is one tablet (400 mg) three times a day with meals. 5 Posology: Remicade is administered by intravenous infusion, typically at 2-month intervals. The recommended dose is 3 mg/kg given as an intravenous infusion followed with additional similar doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks. Humira is 10 marketed in both preloaded 0.8 ml syringes and also in preloaded pen devices, both injected subcutaneously, typically by the patient at home. Etanercept can be administered at a dose of 25 mg (twice weekly) or 50 mg (once weekly). 1.5 Ciclosporin 15 In one embodiment of the invention, the antinflammatory agent is ciclosporin. Ciclosporin A, the main form of the drug, is a cyclic nonribosomal peptide of 11 amino acids produced by the fungus Tolypocladium inflatum. Ciclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes (especially T 20 lymphocytes). This complex of ciclosporin and cyclophylin inhibits calcineurin, which under normal circumstances is responsible for activating the transcription of interleukin-2. It also inhibits lymphokine production and interleukin release and therefore leads to a reduced function of effector T-cells. It does not affect cytostatic activity. It has also an effect on mitochondria, preventing the mitochondrial PT pore from opening, thus inhibiting 25 cytochrome c release (a potent apoptotic stimulation factor). Ciclosporin may be administered at a dose of 1-10 mg/kg/day. 2. Protease inhibitors 30 Proteins in skeletal muscle are degraded by at least three different proteolytic pathways: (a) lysosomal proteases (e.g. the cathepsins); (b) non-lysosomal Ca 2 ' -dependent proteases (e.g, calpain); and (c) non-lysosomal ATP-ubiquitin-dependent proteases (e.g. the multicatalytic protease complex or proteasome). Several lines of evidence have suggested that enhanced activation of proteolytic degradation pathways underlies the WO 2009/019504 PCT/GB2008/050648 28 pathogenesis of muscular dystrophy. Thus, protease inhibitors can be used in the treatment of muscular dystrophies, as discussed below. Preferred protease inhibitors for use according to the invention may specifically target one 5 of the three degradtion pathways described above. Particularly preferred are protease inhibitors which target the non-lysosomal Ca 2 * -dependent pathway (calpain inhibitors) or the non-lysosomal ATP-ubiquitin-dependent pathway (proteasome inhibitors), as described below: 10 2.1 Calpain inhibitors In one embodiment of the invention, the ancillary agent is a calpain inhibitor. Definitions and technical background: The term "calpain inhibitor" is used herein to define 15 any agent capable of inhibiting the activity of calpain. Calpain is a ubiquitous calcium dependent cysteine protease which cleaves many cytoskeletal and myelin proteins. Calpains belong to a family of Ca2+ activated intracellular proteases whose activity is accelerated when abnormal amounts of Ca2+ enter the cell by virtue of increased membrane permeability as a result of some traumatic or ischemic event and/or a genetic 20 defect. Calpain is one of a relatively small family of cysteine proteases, which are active in promoting programmed cell death, or apoptosis. It has been implicated in the initiation of both necrotic and apoptotic cell death. When calpain is abnormally up regulated, the accelerated degradation process breaks down cells and tissues faster than they can be restored, resulting in several serious neuromuscular and neurodegenerative diseases. 25 Calpain has been implicated in the accelerated tissue breakdown associated with muscular dystrophies (including DMD). The trigger which activates calpain is Ca 2 + ions leaking into cells, where the levels are generally very low. The dystrophin gene is involved in maintaining membrane integrity, and when it is mutated, the membrane is more permeable to calcium ions. Thus, the inhibition of calpain activity in the muscles of DMD patients can 30 preserve muscle integrity and prfevent or slow muscle deterioration. Preferences and specific embodiments: Calpain inhibitors for use according to the invention preferably comprise a calpain inhibiting moiety linked to (or associated with) a carrier (which acts to facilitate targeting of the calpain inhibiting moiety to muscle tissue). 35 The targeting moiety may be chemically linked to the calpain inhibiting moiety, or may be WO 2009/019504 PCT/GB2008/050648 29 physically associated therewith (a liposome carrier). Preferred targeting moieties include carnitine or aminocarnitine. The calpain inhibiting moiety may be leupeptin. Particularly preferred may be Ceptor's Myodur T M . Other such calpain inhibitors are described in W02005124563 (the contents of which are incorporated herein by reference). Other 5 suitable calpain inhibitors are the a-ketocarbonyl calpain inhibitors disclosed in WO 20041078908 (the contents of which are incorporated herein by reference). Of the calpain inhibitors described in WO 2004/078908, preferred may be those which target both calpain and the proteasome. 10 The calpain inhibitors for use according to the invention may be chimaeric compounds or combinations in which the calpain inhibiting moiety is associated (e.g. combined with, co administered with or covalently linked) to a ROS inhibitor. Such agents combine relief of oxidative stress with a reduction in calpain-mediated muscle tissue breakdown. Suitable dual action calpain/ROS inhibitors are described for example in WOO1/32654, 15 W02007/045761, W02005/056551 and WO 2002/40016 (the contents of which are incorporated herein by reference). Other suitable calpain inhibitors can be identified using commercially available assay kits (e.g. the calpain activity kit based on a fluorogenic substrate from Oncogene Research 20 Products, San Diego, CA). This assay measures the ability of calpain to digest the synthetic substrate Suc-LLVY-AMC: free AMC can be measured fluorometrically at an excitation of 360-380 nm and an emission of 440-460 nm. 2.2 Proteasome inhibitors 25 Definitions and technical background: Another class of adjunctive agents suitable for use in the combinations of the invention are proteasome inhibitors. Proteasomes control the half-life of many short-lived biological processes. At the plasma membrane of skeletal muscle fibers, dystrophin associates with a multimeric protein complex, termed the 30 dystrophin-glycoprotein complex (DGC). Protein members of this complex are normally absent or greatly reduced in dystrophin-deficient skeletal muscle fibers and inhibition of the proteasomal degradation pathway rescues the expression and subcellular localization of dystrophin-associated proteins. Thus, proteasome inhibitors have recently been identified as potential therapeutics for the treatment of DMD (see Bonuccelli et al. (2003) Am J 35 Pathol. October; 163(4): 1663-1675). The term "proteasome inhibitor" as used herein WO 2009/019504 PCT/GB2008/050648 30 refers to compounds which directly or indirectly perturb, disrupt, block, modulate or inhibit the action of proteasomes (large protein complexes that are involved in the turnover of other cellular proteins). The term also embraces the ionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes and protected forms thereof (preferably the 5 salts or tautomers or isomers or N-oxides or solvates thereof, and more preferably, the salts or tautomers or N-oxides or solvates thereof), as described above. Preferences and specific embodiments: There are several classes of proteasome Inhibitors suitable for us ein the combinations of the invention, including peptide aldehydes 10 (such as MG-1 32) and the dipeptidyl boronic acid bortezimib(VelcadeTM; formerly known as PS-341) which is a more specific inhibitor of the proteasome. Thus, preferred proteasome inhibitors for use in accordance with the invention include bortezimib ([(1 R)-3 methyl-1 -[[(2S)-1 -oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]-boronic acid). Bortezimib is commercially available for example from Millennium Pharmaceuticals 15 Inc under the trade name Velcade, or may be prepared for example as described in PCT patent specification No. WO 96/13266, or by processes analogous thereto. Bortezimib specifically interacts with a key amino acid, namely threonine, within the catalytic site of the proteasome. Another preferred proteasome inhibitor for use in the combinations of the invention is the cell-permeable proteasomal inhibitor CBZ-leucyl-leucyl-leucinal (MG-132) 20 (as described in Bonuccelli et aL. (2003) Am J Pathol. October; 163(4): 1663-1675, the content of which relating to this compound is incorporated herein by reference). Other inhibitors include those structurally related to MG-132, including MG-1 15 (CBZ-leucyl leucyl-norvalinal) and ALLN (N-acetyl-leucyl-leucyl-norleucinal) (as also described in Bonuccelli et al. (2003) Am J Pathol. October; 163(4): 1663-1675, the content of which 25 relating to this compound is incorporated herein by reference). Posology: The proteasome inhibitor (such as bortezimib) can be administered in a dosage such as 100 to 200 mg/m 2 , These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 30 days. MG-132 can be administered at a dose of 10 pg/kg/day. 3. Myostatin antagonists Definitions and technical background: Another class of adjunctive agents suitable for use 35 in the combinations of the invention are myostatin antagonists. Myostatin, also known as WO 2009/019504 PCT/GB2008/050648 31 growth/differentiation factor 8 (GDF-8) is a transforming growth factor-B (TGF-B) family member involved in the regulation of skeletal muscle mass. Most members of the TGF-B GDF family are widely expressed and are pleiotropic: however, myostatin is primarily expressed in skeletal muscle tissue where it negatively controls skeletal muscle growth. 5 Myostatin is synthesized as an inactive preproprotein which is activated by proteolyic cleavage. The precurser protein is cleaved to produce an approximately 109 amino acid COOH-terminal protein which, in the form of a homodimer of about 25 kDa, is the mature, active form. The mature dimer appears to circulate in the blood as an inactive latent complex bound to the propeptide. As used herein the term "myostatin antagonist" defines 10 a class of agents which inhibit or block at least one activity of myostatin, or alternatively, blocks or reduces the expression of myostatin or its receptor (for example, by interference with the binding of myostatin to its receptor and/or blocking signal transduction resulting from the binding of myostatin to its receptor). Such agents therefore include agents which bind to myostatin itself or to its receptor. 15 Preferences and specific embodiments: Myostatin antagonists for use according to the invention include antibodies to GDF-8; antibodies to GDF-8 receptors; soluble GDF-8 receptors and fragments thereof (e. g. the ActRllB fusion polypeptides as described in US10/689,677, including soluble ActRIlB receptors in whichActRlIB is joined to the Fc 20 portion of an immunoglobulin); GDF-8 propeptide and modified forms thereof (e. g. as described in WO 02/068650 or US10/071499, including forms in which GDF-8 propeptide is joined to the Fc portion of an immunoglobulin and/or form in which GDF-8 is mutated at an aspartate (asp) residue, e. g. , asp-99 in murine GDF-8 propeptide and asp-100 in human GDF-8 propeptide); a small molecule inhibitor of GDF-8; follistatin (e. g. as 25 described in US6,004, 937) or follistatin-domain-containing proteins (e. g. GASP-1 or other proteins as described in US1O/369, 736 and US10/369, 738); and modulators of metalloprotease activity that affect GDF-8 activation, as described in US10/662,438. Preferred myostatin antagonists include myostatin antibodies which bind to and inhibit or 30 neutralize myostatin (including the myostatin proprotein and/or mature protein, in monomeric or dimeric form). Myostatin antibodies are preferably mammalian or non mammalian derived antibodies, for example an IgNAR antibody derived from sharks, or humanised antibodies (or comprise a functional fragment derived from antibodie. Such antibodies are described, for example, in US 2004/0142383, US 2003/1038422, WO 35 2005/094446 and WO 2006/116269 (the content of which is incorporated herein by WO 2009/019504 PCT/GB2008/050648 32 reference). Myostatin antibodies also include those which bind to the myostatin proprotein and prevent cleavage into the mature active form. A particularly preferred myostatin antibody for use in the combinations of the invention is Wyeth's Stamulumab (MYO-029). MYO-029 is a recombinant human antibody which binds to and inhibits the activity of 5 myostatin. Other preferred antibody antagonists include the antibodies described in US6096506 and US6468535 (incorporated herein by reference). In some embodiments, the GDF-8 inhibitor is a monoclonal antibody or a fragment thereof that blocks GDF-8 binding to its receptor. Other illustrative embodiments include murine monoclonal antibody JA-16 (as described in US2003/0138422 (ATCC Deposit No. PTA-4236); humanized 10 derivatives thereof and fully human monoclonal anti-GDF-8 antibodies (e. g. , Myo-29, Myo-28 and Myo-22, ATCC Deposit Nos. PTA-4741, PTA-4740, and PTA-4739, respectively, or derivatives thereof) as described in US2004/0142382 and incorporated herein by reference. 15 Other preferred myostatin antagonists include soluble receptors which bind to myostatin and inhibit at least one activity thereof. The term "soluble receptor" here includes truncated versions or fragments of the myostatin receptor which specifically bind myostatin thereby blocking or inhibiting myostatin signal transduction. Truncated versions of the myostatin receptor, for example, include the naturally-occurring soluble domains, as well as variations 20 elaborated by proteolysis of the N- or C-termini. The soluble domain includes all or part of the extracellular domain of the receptor, either alone or attached to additional peptides or other moieties. Since myostatin binds activin receptors (including activin type IEB receptor (ActRHB) and activin type HA receptor (ActRHA), activin receptors can form the basis of soluble receptor antagonists. Soluble receptor fusion proteins can also be used, including 25 soluble receptor Fc (see US2004/0223966 and W02006/012627, both of which are incorporated herein by reference). Other preferred myostatin antagonists based on the myostatin receptors are ALK-5 and/or ALK-7 inhibitors (see for example WO2006025988 and WO2005084699, the disclosure of 30 which is incorporated herein by reference). As a TGF-R cytokine, myostatin signals through a family of single transmembrane serine/threonine kinase receptors. These receptors can be divided in two classes, the type I or activin like kinase (ALK) receptors and type || receptors. The ALK receptors are distinguished from the Type 11 receptors in that the ALK receptors (a) lack the serine/threonine rich intracellular tail, (b) possess 35 serine/threonine kinase domains that are very homologous between Type I receptors, and WO 2009/019504 PCT/GB2008/050648 33 (c) share a common sequence motif called the GS domain, consisting of a region rich in glycine and serine residues. The GS domain is at the amino terminal end of the intracellular kinase domain and is believed to be critical for activation by the Type Il receptor. Several studies have shown that TGF-B signaling requires both the ALK (Type 1) 5 and Type Il receptors. Specifically, the Type 11 receptor phosphorylates the GS domain of the Type I receptor for TGF-[beta] ALK5, in the presence of TGF-[beta]. The ALK5, in turn, phosphorylates the cytoplasmic proteins smad2 and smad3 at two carboxy terminal serines. Generally, it is believed that in many species, the Type It receptors regulate cell proliferation and the Type I receptors regulate matrix production. Various ALK5 receptor 10 inhibitors have been described (see, for example, US 6,465,493, US2003/0149277, US2003/0166633, US20040063745, and US2004/0039198, the disclosure of which is incoprorated herein by reference). Thus the myostatin antagonists for use according to the invention may comprise the myostatin binding domain of an ALK5 and/or ALK7 receptor. 15 Other preferred myostatin antagonists include soluble ligand antagonists which compete with myostatin for binding to myostatin receptors. The term "soluble ligand antagonist" here refers to soluble peptides, polypeptides or peptidomimetics capable of non-productively binding the myostatin receptor(s) (e.g. the activin type HB receptor (ActRHA)) and thereby 20 competitively blocking myostatin-receptor signal transduction. Soluble ligand antagonists include variants of myostatin, also referred to as "myostatin analogues" that have homology with but not the activity of myostatin. Such analogues include truncates (such an N- or C-terminal truncations, substitutions, deletions, and other alterations in the amino acid sequence, such as variants having non-amino acid substitutions). 25 Other preferred myostatin antagonists further include polynucleotide antagonists. These antagonists include antisense or sense oligonucleotides comprising a single-stranded polynucleotide sequence (either RNA or DNA) capable of binding to target mRNA (sense) or DNA (antisense) sequences. Antisense or sense oligonucleotides for use according to 30 the invention comprise fragments of the targeted polynucleotide sequence encoding myostatin or its receptor, transcription factors, or other polynucleotides involved in the expression of myostatin or its receptor. Such a fragment generally comprises at least about 14 nucleotides, typically from about 14 to about 30 nucleotides. Antisense or sense oligonucleotides further comprise oligonucleotides having modified sugar- phosphodiester 35 backbones (or other sugar linkages, such as those described in WO 91/06629) and WO 2009/019504 PCT/GB2008/050648 34 wherein such sugar linkages are resistant to endogenous nucleases. Such oligonucleotides with resistant sugar linkages are stable in vivo but retain sequence specificity to be able to bind to target nucleotide sequences. Other examples of sense or antisense oligonucleotides include those oligonucleotides which are covalently linked to organic 5 moieties, such as those described in WO 90110448, and other moieties that increases affinity of the oligonucleotide for a target nucleic acid sequence, such as poly- (L)-lysine and morpholinos. Further still, intercalating agents, such as ellipticine, and alkylating agents or metal complexes may be attached to sense or antisense oligonucleotides to modify binding specificities of the antisense or sense oligonucleotide for the target 10 nucleotide sequence. Thus, RNA interference (RNAi) produced by the introduction of specific small interfering RNA (siRNA), may also be used to inhibit or eliminate the activity of myostatin. Particularly preferred myostatin antagonists include but are not limited to follistatin, the 15 myostatin prodomain, growth and differentiation factor 11 (GDF-1 1) prodomain, prodomain fusion proteins, antagonistic antibodies that bind to myostatin, antagonistic antibodies or antibody fragments that bind to the activin type IEB receptor, soluble activin type IHB receptor, soluble activin type IEB receptor fusion proteins, soluble myostatin analogs (soluble ligands), oligonucleotides, small molecules, peptidomimetics, and myostatin 20 binding agents. disclose anti-myostatin antibodies. Other preferred antagonists include the peptide immunogens described in US6369201 and WO 01/05820 (incorporated herein by reference) and myostatin multimers and immunoconjugates capable of eliciting an immune response and thereby blocking myostatin activity. Other preferred antagonists include the protein inhibitors of myostatin described in WOQ2/085306 (and incorporated herein by 25 reference), which include the truncated Activin type I receptor, the myostatin pro-domain, and follistatin. Other myostatin inhibitors include those released into culture from cells overexpressing myostatin (see WO00/43781), dominant negatives of myostatin (see WO 01/53350) including the Piedmontese allele, and mature myostatin peptides having a C terminal truncation at a position either at or between amino acid positions 335 to 375. The 30 small peptides described in US2004/0181033 (incorporated herein by reference) which comprise the amino acid sequence WMCPP, are also suitable for use in the combinations of the invention. 4. Cytokines and mobilizing agents 35 WO 2009/019504 PCT/GB2008/050648 35 Definitions and technical background: Another class of adjunctive agents suitable for use in the combinations of the invention are cytokines, and in particular anabolic cytokines and insulin-like growth factors (such as IGF-1 or IGF-2). The anabolic effect of IGF-1 on muscle is very well established. In muscular dystrophies, a progressive reduction in the 5 proliferative capacity of satellite cells occures and this loss of proliferative capacity may be ameliorated by treatment with IGF-1. Thus, IGF-1 (and othe remembers of this class of cytokine) may help to slow the progress of the dystrophinopathies by enhancing activation of dormant satellite cells. Insulin-like growth factors (IGFs) are members of the highly diverse insulin gene family that includes insulin, IGF-I, IGF-Ii, relaxin, prothoraciotropic 10 hormone (PTTH), and molluscan insulin-related peptide. The IGFs are circulating, mitogenic. peptide hormones that have an important role in stimulating growth, differentiation, metabolism and regeneration both in vitro and in vivo. Preferences and specific embodiments: Preferred cytokines for use according to the 15 invention include IGF-1 and IGF-2. Approximately 99% of IGF-1 in healthy individuals circulates in the blood stream bound to IGFBP-3 where it forms a large ternary 150kD complex after association with acid-labile subunit protein (ALS). The ternary complex is restricted to the circulation by the capillary endothelium and thus serves as a circulatory reservoir of IGF-1. Thus, for therapeutic applications according to the invention iGF-1 is 20 preferably administered in the form of a complex. For example, a preferred cytokine for use in the combinations of the invention is IPLEXTM (recombinant protein complex of insulin-like growth factor-- (IGF-1) and its most abundant binding protein, insulin-like growth factor binding protein-3 (IGFBP-3)). Another suitable cytokine is G-CSF (or other mobilizing agents as herein defined, e.g. GM-CSF), which can support muscle 25 regeneration by mobilizing stem cells from the marrow. Other preferred cytokines include JGF-1 derivatives (1GF-1 E peptides) as described in W02006056885 (the content of which is incorporated herein by reference) which have the appropriate subsets of the function of the full-length 1GF-1and, in particular, its regenerative capacity. Thus, in a preferred embodiment the combinations of the invention comprise the IGF-I Ea peptide (i.e. the 35 30 amino acid C terminal peptide translated from part of exons 4 and 5 of the IGF-I gene as part of the IGF-I propeptide and which is cleaved off during post-translational processing) and/or the IGF-I Eb peptide (i.e. the 41 amino acid C terminal peptide translated from parts of exons 4, 5 and 6 of the IGF-I gene as part of the IGF-i propeptide and which is cleaved off during post-translational processing). 35 WO 2009/019504 PCT/GB2008/050648 36 Posology: IPLEXTM can be administered via subcutaneous injection at an initial dose of 0.5 mg/kg, to be increased into the therapeutic dose range of 1 to 2 mg/kg, given once daily. IPLEXTM can be given in the morning or in the evening but should be administered at approximately the same time every day. In order to establish tolerability to IPLEX T M , 5 glucose monitoring should be considered at treatment initiation or when a dose has been increased. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. Glucose monitoring is also advised for patients with recent occurrences of asymptomatic or symptomatic hypoglycemia. If evidence of hypoglycemia is present at the time of dosing, the dose should be withheld. 10 Dosage can be titrated up to a maximum of 2 mg/kg daily based on measurement of IGF-1 levels obtained 8-18 hours after the previous dose. Dosage should be adjusted downward in the event of adverse effects (including hypoglycemia) and/or IGF-1 levels that are greater than or equal to 3 standard deviations above the normal reference range for IGF-1. 15 5. Corticosteroids In one embodiment of the invention, the ancillary agent is a corticosteroid. 20 Definition and biological activities: The term "corticosteroid" as used herein refers to any of several steroid hormones secreted by the cortex of the adrenal glands and which are involved in one or more of the following physiological processes: stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism and blood electrolyte levels. The term also includes synthetic analogues which share the 25 aforementioned properties. Corticosteroids include glucocorticoids and mineralocorticoids. Glucocorticoids control carbohydrate, fat and protein metabolism and are anti inflammatory. Mineralocorticoids control electrolyte and water levels, mainly by promoting sodium retention in the kidney. Some corticosteroids have dual glucocorticoid and mineralocorticoid activities. For example, prednisone (see below) and its derivatives have 30 some mineralocorticoid action in addition to a glucocorticoid effect. The precise cellular mechanism(s) by which corticosteroids produce antidystrophic effects are not yet known. A multifactorial mechanism is likely and the effects of corticosteroids probably involve a reduction of inflammation, suppression of the immune system, improvement in calcium homeostasis, upregulation of the expression of compensatory proteins and an increase in 35 myoblast proliferation.
WO 2009/019504 PCT/GB2008/050648 37 Problems: The use of corticosteroids is associated with side effects which vary from person to person and on the dosage of the regime used, but they can be severe. The most common side effects are weight gain and mood changes. Weight gain (and attendant 5 changes in muscle activity and use) can abrogate some of the benefits of treatment . Long-term use may lead to growth suppression, cataracts, osteoporosis and muscle atrophy (affecting the same proximal muscles affected in DMD and BMD). These side effects may limit the long-term effectiveness of corticosteroid therapy. Other side effects include hypertension, diabetes, skin atrophy, poor wound healing and immunosuppression. 10 Deflazacort was evaluated in the hope that it would have fewer side effects than prednisone. Preferences and Specific embodiments: Preferred are glucocorticoids (or corticosteroids having dual glucocorticoid/minerlocorticoid activity). Synthetic corticosteroids are 15 preferred. In one embodiment, the corticosteroid is prednisone (prodrug) or prednisolone (liver metabolite of prednisone and active drug). In another embodiment, the corticosteroid is deflazacort. Deflazacort is an oxazoline analogue of prednisone. Other synthetic corticosteroids suitable for use in the combinations of the invention include one or more corticosteroids selected from: alclometasone, amcinonide, beclomethasone (including 20 beclomethasone dipropionate), betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortivazol, deoxycorticosterone, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, fldnisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene, 25 fluticasone, formocortal, halcinonide, halometasone, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednylidene, rimexolone, tixocortol, triamcinolone and ulobetasol (or combinations and/or derivatives (e.g. pharmaceutically acceptable salts) of one or more of 30 the foregoing). Suitable endogenous corticosteroids for use in the combinations of the invention include include one or more corticosteroids selected from aldosterone, cortisone, hydrocortisone/cortisol and desoxycortone (or combinations and/or derivatives (e.g. pharmaceutically acceptable salts) of one or more of the foregoing).
WO 2009/019504 PCT/GB2008/050648 38 Posology: Prednisone may be administered daily in dosages ranging from 0.3 to 1.5 mg/kg (typically 0.7 mg/kg). Some patienmts respond better to 2.5 mg/kg every other day. Deflazacort has an estimated dosage equivalency of 1:1.3 compared with prednisone, though biological equivalence between deflazacort and prednisone also depends on the 5 specific actions under examination. Corticosterods (including delazacort and prednisone) are usually taken orally but can be delivered by intramuscular injection. 6. Anabolic steroids 10 In one embodiment of the invention, the ancillary agent is an anabolic steroid. Definition and biological activities: The term "anabolic steroid" as used herein refers to any of several steroid hormones related to the male hormone testosterone and synthetic analogues thereof. Such steroids are may also be referred to as "anabolic-androgenic 15 steroids" or "AAS". Anabolic steroids increase protein synthesis within cells, promoting anabolism (especially in muscles). The precise cellular mechanism(s) by which anabolic steroids produce antidystrophic effects are not yet known, but it seems that their anabolic effects in muscles effectively compensates for muscle loss. Oxandrolone has been shown to have anabolic effects on DMD muscle as well as decreasing muscle degeneration and 20 so easing the demands for muscle regeneration. By conserving regenerative capacity, anabolic steroids such as oxandrolone may prolong muscle function. Problems: The use of anabolic steroids is associated with severe side effects. The most common side effects are liver and kidney damage, sterility, stunting of growth and severe 25 mood swings. Anabolic steroids also also tend to be androgenizing and can promote growth of beard and body hair, maturation of genitalia and development of acne. Withdrawal can lead to rapid and severe deterioration in muscle mass and function. Preferences and Specific embodiments: Preferred are synthetic anabolic steroids such as 30 oxandrolone (Anavar), norethandrolone and methandrostenolone (Dianabol). Oxandrolone (an oral synthetic analog of testosterone) may be particularly preferred because in addition to its anabolic properties it also blocks the binding of cortisol to glucocorticoid receptors on muscle, thus preventing muscle breakdown. Other anabolic steroids suitable for use in the 35 combinations of the invention include one or more anabolic steroids selected from: DHEA, WO 2009/019504 PCT/GB2008/050648 39 DHT, methenolone, oxymetholone, quinbolone, stanozolol, ethylestrenol, nandrolone (Deca Durabolin), oxabolone cipionate, boldenone undecylenate (Equipoise), stanozolol (Winstrol), oxymetholone (Anadrol-50), fluoxymesterone (Halotestin), trenbolone (Fina), methenolone enanthate (Primobolan), 4-chlordehydromethyltestosterone (Turinabol), 5 mesterolone (Proviron), mibolerone (Cheque Drops), tetrahydrogestrinone and testosterone (or combinations and/or derivatives (e.g. pharmaceutically acceptable salts) of one or more of the foregoing). Posology: Anabolic steroids may be administered as orally in the form of pills, by injection 10 or via skin patches. Oral administration is most convenient, but since the steroid must be chemically modified so that the liver cannot break it down before it reaches the blood stream these formulations can cause liver damage in high doses. Injectable steroids are typically administered intramuscularly. Transdermal patches can be sued to deliver a steady dose through the skin and into the bloodstream. Oxandrolone may be administered 15 orally at a daily dosage of 0.1 mg/kg. 7. TGF-p antagonists Definitions and technical background: Transforming growth factor beta (TGF- P) promotes 20 fibrosis in response to muscle tissue damage associated with DMD that can contribute to disease pathology. In one embodiment of the invention, the ancillary agent is a TGF-p antagonist. The term TGF-p antagonist is used herein to refer to compounds which directly or indirectly perturb, disrupt, block, modulate or inhibit the action of TGF-p. The term also embraces the 25 ionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes and protected forms thereof (preferably the salts or tautomers or isomers or N-oxides or solvates thereof, and more preferably, the salts or tautomers or N-oxides or solvates thereof). Preferences and specific embodiments: Preferred TGF-p antagonists for use according to 30 the invention include anti- TGF-P antibodies, tamoxifen, losartan and pirfenidone. Pirfenodone is an orally active synthetic antifibrotic agent structurally similar to pyridine 2,4 dicarboxylate. Pirfenidone inhibits fibroblast, epidermal, platelet-derived, and TGF-p -1 growth factors and also inhibits DNA synthesis and the production of mRNA for collagen types I and Ill, resulting in a reduction in radiation-induced fibrosis. Losartan is an 35 angiotensin Il receptor antagonist drug used mainly to treat hypertension currently WO 2009/019504 PCT/GB2008/050648 40 marketed by Merck & Co. under the trade name CozaarTM. However, losartan also downregulates the expression of (TGF-s types I and II receptors. Tamoxifen is an orally active selective estrogen receptor modulator (SERM) which is used in the treatment of breast cancer and is currently the world's largest selling drug for this indication. Tamoxifen 5 is sold under the trade names Nolvadex T M , IstubalTM and ValodexTM. Tamoxifen may be administered at a dose of 10-100 mg per day (e.g. 20-40 mg/day). 8. Antioxidants and mitochondrial supporting agents 10 In Duchenne Muscular Dystrophy (DMD), the cytoskeletal protein dystrophin is absent leading to numerous cellular dysfunctions that culminate in muscle cell necrosis. Subsequently, an inflammatory response develops in the necrotic muscle tissue, resulting in increased oxidative stress, responsible for further tissue damage. In the mdx dystrophic mouse, both 15 inflammation and oxidative stress have been identified as aggravating factors for the course of the disease. GTE and EGCG also display unexpected pro myogenic properties. Primary cultures of skeletal muscle cells were established from both normal and dystrophic mice and treated 20 with GTE and EGCG for 1-7 days. As judged by in situ staining of myosin heavy chains (MyHC), we found that GTE and EGCG concentration-dependently stimulated the rate of formation of myotubes within the first 2-4 days of application. The amount of myotubes reached similar level with both agents compared to control thereafter. Western-blot analysis was performed 25 on myotube cultures treated for 7 days. GTE and EGCG promoted the expression of several muscle-specific proteins, such as dystrophin (in control cultures), sarcomeric alpha actinin, and MyHC, while myogenin was unchanged. By contrast, the expression of desmin was down-regulated and redistributed to Z discs. Our results suggest that green tea polyphenols display pro myogenic properties by acting directly on skeletal muscle cells. 30 These findings suggest a beneficial action for muscle regeneration and strengthening in dystrophic condition. Green tea polyphenols, such as epigallocatechin gallate (EGCG), are known to be powerful antioxidants. Because inflammation is involved in the degradation of muscle tissue in MD, 35 oxidative stress is believed to play a role in this process. Thus, green tea and its active WO 2009/019504 PCT/GB2008/050648 41 constituents (including EGCG and other polyphenols) may improve MD prognosis by reducing this oxidative stress. Feeding studies with mdx mice have shown a protective effect of EGCG against the first massive wave of necrosis. It also stimulated muscle adaptation toward a stronger and more resistant phenotype. The effective dosage 5 corresponds to about seven cups of brewed green tea per day in humans Coenzyme Q10 (CoQ10; also called ubiquitin) is a powerful antioxidant and mitochondrial respiratory chain cofactor. It possesses membrane-stabilizing properties and is capable of penetrating cell membranes and mitochondria. Dosages of 100 mg CoQ 10 daily for three 10 months have been shown to be beneficial in human trials, though higher dosages are likely to yield better results. Idebenone is a synthetic analog of Coenzyme Q10 and is thought to perform the same functions as CoQ10 without the risk of auto-oxidation. Like CoQ10, idebenone can 15 therefore contribute to maintaining correct electron balance, which is necessary for the production of cellular energy. Since muscle cells are particularly energy-demanding , idebenone and CoQ10 can preserve mitochondrial function and protect cells from oxidative stress. 20 Glutamine is an important energy source and acute oral glutamine administration appears to have a protein-sparing effect. Arginine (and other pharmacological activators of the NO pathway) may enhance the production of utrophin in MDX mice. The increase is likely to be mediated by arginine-fueled production of nitric oxide (NO), which plays an important role in blood vessel function and is generally lower in people with MD. Studies with MDX 25 mice have also shown that a combination of arginine and deflazacort may be more beneficial than deflazacort alone. Other antioxidants suitable for use according to the invention are the chimaeric compounds or combinations in which the a ROS inhibitor is associated (e.g. combined with, co 30 administered with or covalently linked) to calpain inhibiting moiety. Such agents combine relief of oxidative stress with a reduction in calpain-mediated muscle tissue breakdown. Suitable dual action calpain/ROS inhibitors are described for example in W001/32654, W02007/045761, W02005/056551 and WO 2002/40016 (the contents of which are incorporated herein by reference). 35 WO 2009/019504 PCT/GB2008/050648 42 9. Dystrophin expression enhancing agents 9.1 Read-through agents 5 A subset of DMD patients (around 15%) have a nonsense mutation that produces a premature stop signal in their RNA, resulting in abnormal truncation of protein translation. In one embodiment of the invention, the ancillary agent is an agent which promotes readthrough of premature stop codons ("read-through agent"), thereby bypassing the premature stop codon and restoring the expression of full-length, functional dystrophin. 10 Suitable read-through agents for use according to the invention are 1,2,4-oxadiazole compounds as described in US6992096 (which is incorporated herein by reference): R N 15 One such compound is 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3- yl] -benzoic acid. A preferred readthrough agent is PTC124. PTC124 is a 284-Dalton 1,2,4-oxadiazole that promotes ribosomal readthrough of premature stop codons in mRNA. Thus, the combinations of the invention may comprise 1,2,4-oxadiazole benzoic acid compounds 20 (including 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid) (see e.g. W02006110483, the content of which is incorporated herein by reference). PTC124, 3-[5-(2- fluoro-phenyl)-[l,2,4]oxadiazol-3-yl]-benzoic acid or a pharmaceutically acceptable salt, solvate or hydrate thereof can be administered in single or divided (e.g., 25 three times daily) doses between 0.1 mg/kg and 500 mg/kg, 1 mg/kg and 250 mg/kg, 1 mg/kg and 150 mg/kg, 1 mg/kg and 100 mg/kg, 1 mg/kg and 50 mg/kg, 1 mg/kg and 25 mg/kg, 1 mg/kg and 10 mg/kg or 2 mg/kg and 10 mg/kg to a patent in need thereof. In a particular embodiment, the 3-[5-(2-fluoro-phenyl)- [l,2,4]oxadiazol-3-yI]-benzoic acid or a pharmaceutically acceptable salt, solvate or hydrate thereof is administered in a dose of WO 2009/019504 PCT/GB2008/050648 43 about 4 mg/kg, about 7 mg/kg, about 8 mg/kg, about 10 mg/kg, about 14 mg/kg or about 20 mg/kg. Other readthrough agents for use according to the invention include aminoglycoside 5 antibiotics, including gentamicin. Particularly preferred may be aminoglycosides that contain a 6' hydroxyl group (e.g. paromomycin), which may be effective at lower doses and may display less toxicity than compounds such as gentamicin. 9.2 Exon skipping 10 Most cases of Duchenne muscular dystrophy (DMD) are caused by dystrophin gene mutations that disrupt the mRNA reading frame. In some cases, forced exclusion (skipping) of a single exon can restore the reading frame, giving rise to a shorter, but still functional dystrophin protein (so called quasi-dystrophin). Antisense oligonucleotides (AONs) 15 designed to cause exon skipping can target a broader range of mutations than can compounds that cause cells to ignore premature stop codons by induce cells to leave out sections of genetic instructions that contain mistakes and join together the surrounding, correct instructions. However, since AONs are not self-renewed, they cannot achieve long term correction. To overcome this limitation, antisense sequences can be introduced into 20 small nuclear RNAs (snRNA) and vectorized in AAV and lentiviral vectors. 10. Gene replacement/repair agents In one embodiment of the invention, the ancillary agent is a nucleic acid construct adapted 25 to replace or repair non-functional endogenous genetic material. Gene therapy may be adeno-associated virus (AAV) vector-mediated gene therapy, preferably using the microdystrophin gene. Highly abbreviated microdystrophin cDNAs have been developed for adeno-associated virus (AAV)-mediated DMD gene therapy. Among these, a C terminal-truncated AR4-R23/AC microgene (AR4/AC) is a very promising therapeutic 30 candidate gene. Targeted correction of mutations in the genome holds great promise for the repair/treatment of disease causing mutations either on their own applied directly to the affected tissue, or in combination with other techniques such as stem cell transplantation. 35 Various DNA or RNA/DNA WO 2009/019504 PCT/GB2008/050648 44 based Corrective Nucleic Acid (CNA) molecules such as chimeraplasts, single stranded oligonucleotides, triplex forming oligonucleotides and SFHR have been used to change specific mutant loci. MyoDys@ is comprised of plasmid DNA encoding the full-length human dystrophin gene. Mirus' Pathway IV TM delivery technology is used to administer the 5 pDNA to a patient's limb skeletal muscles. 11. Cell-based therapies In one embodiment of the invention, the ancillary agent is a myogenic cell or tissue 10 composition. Various types of myogenic cell have been shown to have potential in the treatment of DMD, including stem cells f4rom umbilical cord, mesenchymal stem cells and muscle-derived stem cells. 12. Creatine 15 Definition and biological activities: Creatine is an energy precursor that is naturally produced by the body. Creatine kinase (CK) phosphorylates creatine for later donation to contractile muscle filaments: phosphocreatine enters muscle cells and promotes protein synthesis while reducing protein breakdown. In healthy individuals, creatine has been 20 shown to enhance endurance and increase energy levels by preventing depletion of adenosine triphosphate. Among MD patients, studies have suggested that supplemental creatine can improve muscle performance and strength, decrease fatigue, and slightly improve bone mineral density. 25 Problems: High doses of creatine can cause kidney damage and requires cohydration. Behavioral changes have been recorded. Posology: Creatine can be administered as a powdered nutritional supplement. In recent trials with DMD patients, slight increases in muscle strength on administration of low levels 30 (1 to 10 g/day) of creatine monohydrate have been recorded. Intermittent administration (involving a break of one to several weeks) may mitigate side effects whilst providing the same benefits as constant use. Dosages in the region of 100mg/kg/day are well-tolerated and have been found to decrease bone degradation and increase strength and fat-free mass. Benefits have been reported for the co-administration of creatine with conjugated 35 linoleic acid (alpha-lipoic acid), hydroxyl-beta-methylbutyrate and prednisolone.
WO 2009/019504 PCT/GB2008/050648 45 13. Anti-osteoporotic agents Combined therapy to inhibit bone resorption, prevent osteoporosis, reduce skeletal 5 fracture, enhance the healing of bone fractures, stimulate bone formation and increase bone mineral density can be effectuated by combinations comprising various anti osteoporotic agents. Preferred are bisphosphonates including alendronate, tiludronate, dimethyl-APD, risedronate, etidronate, YM-1 75, clodronate, pamidronate and BM-210995 (ibandronate). Otehrs include oestrogen agonist/antagonists. The term oestrogen 10 agonist/antagonists refers to compounds which bind with the estrogen receptor, inhibit bone turnover and prevent bone loss. in particular, oestrogen agonists are herein defined as chemical compounds capable of binding to the estrogen receptor sites in mammalian tissue, and mimicking the actions of estrogen in one or more tissue. Exemplary oestrogen agonist/antagonists include droloxifene and associated compounds (see US 5047431), 15 tamoxifen and associated compounds (see US4536516), 4-hydroxy tamoxifen (see US4623660), raloxifene and associated compounds (see US4418068 and idoxifene and associated compounds (see US4839155). 14. Auxiliary utrophin upregulating agents 20 In addition to the compounds of formula (I) as defined herein, the combinations of the present invention may include one or more auxiliary utrophin upregulating agents. Such auxiliary utrophin upregulating agents are compounds that upregulate (i.e. increase the expression or activity of utrophin) and which do not conform to the structure of formula (1) 25 as defined herein (or the ionic, salt, solvate, isomers, tautomers, N-oxides, ester, prodrugs, isotopes and protected forms thereof). The auxiliary utrophin upregulating agents for use in the combinations of the invention preferably upregulate utrophin via a mechanism that is different from that of the compounds of formula (1) described herein. 30 15. cGMP signalling modulators It has recently been shown (Khairallah et al. (2008) PNAS 105(19): 7028-7033) that enhancement of cGMP signaling by administration of the phosphodiesterase 5 (PDE5) inhibitor sildenafil prevents deterioration of myocardial contractile peformance in mdx 35 hearts.
WO 2009/019504 PCT/GB2008/050648 46 Thus, cGMP signaling enhancers, including in particular selective PDE5 inhibitors (including for example sildenafil, tadalafil, vardenafil, udenafil and avanafil) may be used in combination with the compounds of the invention to treat DMD or BMD. Such 5 combinations find particular application in the treatment of dystrophic cardiopmyopathies and may be used to prevent or delay the onset of dystrophin-related cardiomyopathies as the clinical course of DMD/BMD progresses. Thus, the invention contemplates combinations of the compounds of the invention with 10 cGMP signaling enhancers, including in particular selective PDE5 inhibitors. Preferred combinations are comprise a compound of the invention and a PDE5 inhibitor selected from sildenafil, tadalafil, vardenafil, udenafil and avanafil. Particularly preferred is a combination comprising a compound of the invention and sildenafil. The compound of the invention for use in the aformentioned combinations is preferably compound number 390 of 15 Table 1 being 5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole. Formulation and posology 20 The compounds of formula I for use in the treatment of DMD will generally be administered in the form of a pharmaceutical composition. Thus, according to a further aspect of the invention there is provided a pharmaceutical composition including preferably less than 80% w/w, more preferably less than 50% w/w, e.g. 0.1 to 20%, of a compound of formula I, or a pharmaceutically acceptable salt thereof, 25 as defined above, in admixture with a pharmaceutically acceptable diluent or carrier. We also provide 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: for intravenous injection or infusion purified water or saline solution; for inhalation compositions - coarse lactose; for tablets, 30 capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, 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 WO 2009/019504 PCT/GB2008/050648 47 or sequestering agents, antioxidants, tonicity adjusting agents, pH-modifying agents and 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. 5 When not in solution, the compound of formula I preferably is in a form having a mass median diameter of from 0.01 to 1 Opm. 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 10 compositions may be formulated in sustained release form. The content of compound formula I in a pharmaceutical composition is generally about 0.01-about 99.9wt%, preferably about 01-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 rate, 15 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 disease is 20 from 0.01 mg - 10 g, preferably 0.1 - 100 mg, is preferably administered in a single dose or in 2 or 3 portions per day. Examples The potential activity of the compounds of formula I for use in the treatment of DMD may 25 be demonstrated in the following predictive assay and screens. 1. Luciferase reporter assay (murine H2K cells) 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 30 including the first untranslated exon linked to a luciferase reporter gene. Under conditions of low temperature and interferon containing media, the cells remain as 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 WO 2009/019504 PCT/GB2008/050648 48 expressed luciferase gene utilising a plate luminometer. Example of pharmacological dose response of compounds in the assay is shown in Figure 1. 2. mdx mouse Data obtained from the ADMET data was prioritised and the compounds with the best in 5 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. There were two animals injected with up to 50mg/kg (e.g. 10mg/kg) of compound 10 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 2 shows an example of TA muscle sections stained with antibody specific for mouse utrophin. Comparison to the mdx muscle only injected with vehicle shows an increase in 15 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 3). Again using muscle dosed with CPD-A 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 20 to control. 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 25 and therefore gives us 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. H2K/mdx/Utro A reporter cell line maintenance The H2K/mdx/Utro A reporter cell line was passaged twice a week until 530% confluent. 30 The cells were grown at 33 0 C in the presence of 10% C02. To remove the myoblasts for platting, they were incubated with Trypsin / EDTA until the monolayer started to detach. Growth Medium WO 2009/019504 PCT/GB2008/050648 49 DMEM Gibco 41966 20% FCS 1% Pen/Strep 1% glutamine 5 10mls Chick embryo extract 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 190pl normal 10 growth medium. The plates were then incubated at 33CC in the presence of 10% CO 2 for 24 hrs. Compounds were dosed by adding 1 OpI of diluted compound to each well giving a final concentration of 10pM. 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 15 (Victor1 420). Compound Storage Compounds for screening were stored at -20'C as 10mM stocks in 100% DMSO until required. Infection of mdx mice with compounds 20 Mdx from a breeding colony 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. Mice were sacrificed by cervical dislocation at desired time points, and muscles excised for analysis 25 Muscle Analysis lmmunohistochemistry Tissues for sectioning were dissected, immersed in OCT (Bright Cryo-M-Bed) and frozen on liquid nitrogen cooled isopentane. Unfixed 8pM cryosections were cut on a Bright Cryostatand stored at -80 0
C
WO 2009/019504 PCT/GB2008/050648 50 In readiness for staining, sections were blocked in 5% foetal calf serum in PBS for 30 mins. The primary antibodies were diluted in blocking reagent and incubated on sections for 1.5 hrs in a humid chamber then washed three times for 5mins in PBS. Secondary antibodies also diluted in blocking reagent, were incubated for 1hr in the dark in a humid chamber. 5 Finally sections were washed three times 5mins in PBS and coverslip Mounted with hydromount. Slides were analysed using a Leica fluorescent microscope. Results 10 Biological activity as assessed using the luciferase reporter assay in murine H2K cells, and is classified as follows: + Up to 200% relative to control ++ Between 201% and 300% relative to control ++ Between 301% and 400% relative to control 15 ++++ Above 401% relative to control Table 1: Compounds made by methods described herein ,Exampie Chemical Name Activity 1 N-(2-(4-(dimethylamino)phenyl)benzo[d]oxazol-5-yl)isonicotinamide + 2 N-(2-(4-fluorophenyl)benzo[djoxazol-5-yl)furan-2-carboxamide + 3 12-((4-chlorophenoxy)methyl)--1-methyl-1 H-benzo[d]imidazole 4 12-((4-methoxyphenoxy)methyl)-1 H-benzo[djimidazole ++ 5 lphenyl(2-phenyl-1H-benzo[dJimidazol-6-yl)methanone + 6 N-(2-phenylbenzofd]oxazol-5-yl)nicotinamide 7 3-phenyl-N-(2-phenylbenzo[d]oxazol-5-yl)propanamide + 8 N-(2-phenylbenzo[dloxazol-5-yl)acetamide + + 9 N-(2-phenylbenzo[d]oxazol-5-yl)propionamide ++ 10 JN-(2-phenylbenzo[d]oxazol-5-yl)butyramide +++ '11 jN-(2-phenylbenzo[d]oxazol-5-yl)pentanamide ++ 12 N-(2-phenylbenzo[d]oxazol-5-yl)isobutyramide ++ 13 N-(2-phenylbenzo[dloxazol-5-yl)furan-2-carboxamide ++ 14 -pheybnodoxaol5-amine ++_____ 15 2-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-5-amine + 16 j2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-amine :17 2-(4-(diethylamino)phenyl)benzofd]oxazol-5-amine 18 2-5-amine WO 2009/019504 PCT/GB2008/050648 51 19 4-chIoro-N-(2-p-tolylbenzod]oxazol-5-yl)benzamide 20 14-methoxy-N-(2-p-tolylbenzo[d]oxazol-5-yl)benzamide 21 2-(5-nitrobenzo[d]oxazoI-2-yl)phenol 32 N-(2-phenylbenzo[d]oxazol-5-yl)isonicotinamide 3 4-ch.oro-N-(2-ph.benzo[dJoxazol-5-ylbenzamide + .. 24 4-methyl-N-(2-phenylbenzo[d]oxazol-5-yI)benzam ide 25 4-methoxy-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide 26 12-methoxy-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide 27 4-(dirmethylamino)-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide !+ 28 '3,4-dichloro-N-(2-phenylbenzo[d]oxazol-5-yl)benzamice + 129 N-(2-phenylbenzo[d]oxazol-5-y)-4-(trifluoromethyl)benzamide + 30 3,5-dichloro-N-(2-phenylbenzo[djoxazol-5-yl)benzamide + 31 4-fIuoro-N-(2-phenyl benzo[d]oxazol-5-yl) benzam ide + 32 N-(2-phenylbenzo[d]oxazol-5-yl)biphenyl-4-carboxamide + 33 2-phenyl-N-(2-phenylbenzo[d]oxazol-5-yl)acetamide + 34 N-(2-phenylbenzo[d oxazol-5-yl)cinnamamide + -35 iN-(2-phenylbenzo[d]oxazol-5-y)-1 -naphthamide 36 N-(2-phenylbenzo[d]oxazol-5-yl)-2-naphthamide + 37 N -(2- phenyl benzo[d]oxazo-5-yl)thiophene-2-carboxamide+ 38 j2-(5-aminobenzo[dloxazol-2-yl)phenol ++ 39 IN-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide + 40 4-chloro-N-(2-(pyridin-3-yl)benzo[djoxazol-5-yf)benzamide 41 4-methyl-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide 4-methoxy-N-(2-(pyridin-3-y)benzo[d]oxazol-5-yl)benzamide + 43 i2-methoxy-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide z 44 j4-(dimethylamino)-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamideY 45 3,4-dichloro-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide 1+ 46 N-(2- (pyridin-3-yl)benzo[d]oxazoI-5-yl)-4-(trifluoromethyl)benzam ide+ 47 ___ 3,5-dichloro-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide 48 4-fluoro-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide + 49 N-(2-(pyridin-3-yl)benzo[dloxazol-5-yl)biphenyl-4-carboxamide i+ 50 2-phenyl-N-(2-(pyridin-3-y)benzo[d]oxazol-5-yl)acetam ide +. 51 3-phenyl-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)propanamide 52 'N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)cinnamamide 53 N-(2-(pyridin-3-yl)benzo[dJoxazol-5-yl)propionamide 54 N-(2-(pyridin-3-yl) benzo[d]oxazol-5-yi) butyramide + N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)pentana mide+ WO 2009/019504 PCT/GB2008/050648 52 56 N-(2-(pyridin-3-yl)benzodioxazol-5-yl)isobutyramide ++ 57 ___ N-(2-(pyridin-3-yl) benzo[d]oxazol-5-yl)furan-2-carboxamide 1+ 58 fN-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)furan-2-carboxamide + 59 N-(2-phenylbenzo[d]oxazol-5-yl)benzamide ++ 60 N-(2-(4-(diethylamino)pheny)benzo[djoxazof-5-y-)nicotinamide ++ 61jN-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)isonicotinamide + 62 __ N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)benzamide +_1i i62 -(-4clr-(2-(4(dhylyamino)phenyl)benzo o xlba mI 1 i4-chloro-N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5 + 63 yl)benzamide N-(2-(4-(diethylamino)phenyl)benzo[dloxazol-5-yl)-4 64 methylbenzamide N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)-4 65 methoxybenzamide 'N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-y)-2 66 methoxybenzamide N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-y)-4 67 (dimethylamino)benzamide {3,4-dichloro-N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5 68 yl)benzamide N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)-4- + ~69 (trifluoromethyl)benzamide 3,5-dichloro-N-(2-(4-(diethylamino)phenyl)benzo[d]oxazo-5 70 yl)benzamide N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)-4 71 jfluorobenzamide N-(2-(4-(diethy Tamino)phenyl)benzo[d]oxazol-5-yl)biphenyl-4 72 carboxamide N-(2-(4-(diethylamno)phenyl)benzo[d]oxazol-5-y)-2 73 iphenylacetamide N-(2-(4-(diethyamino)pheny)benzo[djoxazo-5-yl)-3 74 -phenyipropanamide 75 N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)propionamide f++ 76 N-(2-(4-(diethylamino)phenyl)benzo~djoxazol-5-yl)butyramide + 77 N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)pentanamide 78 N-(2-(4-(diethylamino)phenyl)benzo[doxazol-5-y)isobutyramide + N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)thiophene-2 79 carboxamide 80 - 3-(5-propytbenzo[d]oxazol-2-yt)benzoic acid II 81 N-(2-(pyridin-3-yi)benzold]oxazol-5-yl)nicotinamide + 82 1 5-amino-2-(5-aminobenzo[d]oxazol-2-yi)phenol 83 j4-methoxy-N-(2-(4-methoxyphenyl)benzo[d]oxazol-5-yI)benzamide + 84 5-(ethylsulfonyl)-2-phenylbenzo[d]oxazole + 85 j2,5-diphenylbenzo[d]oxazole WO 2009/019504 PCT/GB2008/050648 53 86 .2-phenyInaphtho[1,2-dJoxazole +++ 87 ~ N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)isonicotinamide + 88 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)benzamide + 94-chiloro-N-(2-(4-chIorophenyl)benzo[doxazol-5-yl)benzam ide + 90 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yI)-4-methylbenzamide + 91 N-(2-(4-chlorophenyl)benzo[djoxazol-5-yl)-4-methoxybenzamide i+ 92 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)-2-methoxybenzamide + jN-(2-(4-chlorophenyl)benzotd]oxazol-5-yI)-4 93 (dimethylamino)benzamide N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)-4 94 ( ifuoromethyl)benzamide 95 3,5-dichloro-N-(2-(4-chlorophenyl)benzo[djoxazol-5-yl)benzamide+ 96 LN-(2-(4-chlorophenyl)benzo[d~oxazol-5-yl)-4-fiuorobenzamide 97 IN-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)-2-phenylacetamide 98 N-(2-(4-chlorophenyl)benzofd]oxazol-5-yI)-3-phenylpropanamide + 99 IN-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)butyramide 100 IN-(2-(4-chlorophenyl)benzo[dloxazol-5-y)pentanamide ++ 101 N-(2-(4-chtoropheny )benzo[d]oxazo-5-yl)isobutyramide 102 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yI)furan-2-carboxam ide + 103 fN-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)thiophene-2-carboxamide 104 5-amino-2-(5,6-dimethyl-1 H-benzo[d]imidazol-2-yl)phenol !++ 105 2-(3-methyl-4-nitrophenyl)-1 H-benzodimidazole++ 106 2-(6-nitro-1 H-benzo[d]imidazol-2-yl)phenol 107 2-phenylbenzo[dloxazole-5-carboxylic acid +++ 108 -2-(4-propylphenyl)benzo[d]oxazole-5-carboxylic acid .a i . ...... --- -- 1,09 j2- (4- pro pylIph enyl)benzo [d] oxazole-6-ca rboxyic acid 110 2-(4-propy phenyl)-2,6'-bibenzo[djoxazoIe-6-carboxy ic acid 111 5-chlo ro-2-phenylbenzo[d]oxazole ++--- _------ 112 6-chloro-2-phenylbenzo[d]oxazole ; 113 N-(2-p-tolybenzo[d]oxazo-5-yl)nicotinamide + 114 N-(2-p-tolylbenzo[d]oxazol-5-yl)isonicotinamide + 115 7N-(2-p-tolylbenzo[dVoxazol-5-yl)propionamide++++ 116 N-(2-p-tolylbenzo[d]oxazol-5-yi)butyramnide ++ 117 N-(2-p-tolylbenzo[d]oxazol-5-yl)pentanamide + 118 N-(2-p-tolylbenzo[d]oxazol-5-yl)sobutyramide ++ :119 JN-(2-p-tolylbenzo[d]oxazol-5-yl)furan-2-carboxamide + 120 N-(2-p-tolylbenzo[d]oxazol-5-yl)thiophene-2-carboxamide J++ 121 N-(2-(4-(trifluoromethyl)phenyl)benzod]oxazol-5-yl)nicotinamide + WO 2009/019504 PCT/GB2008/050648 54 122 N -(2-(4-(trifl uo rometh yl)p h eny1) benzo[d]oxazolI-5-y1) is on icoti na mid e+ 123 N-(2-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)acetamide ++ 124 N-(2-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)propio namide + 125 N-(2-(4-(trifluoromethyl)phenyl)benzo[doxazoi-5-yl)butyramide + 126 _N-(2-(4-(trifluoromethyl)phenyl)benzo[dloxazol-5-yl)pentanamide 127 N(2-(4-(trfluoromethyl)phenyl)benzo[d]oxazol-5-yl)isobutyramide + N-(2-(4-(trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)furan-2 128 carboxamide 12 5-tert-butyl-2-phenylbenzo[d]oxazole 130 6-nitro-2-phenylbenzo[d]oxazole ]++ 131 4-(5-chlorobenzo[d]oxazol-2-yl)-N, N-diethylaniline !+++ 32 4-(6-chlorobenzo[d]oxazol-2-yi)-N, N-diethylaniline 133 1 2-(5-amino-1H-benzo[d]imidazol-2-yl)pheno 134 IN-(2-(4-methoxyphenyl)benzold]oxazol-5-yl)isonicotinamide + 135 fN-(2-(4-rnethox pheny)benzo[d]oxazol-5-yl)acetamide +++ 136 ,N-(2-(4-methoxyphenyl)benzo[d]oxazol-5-yl)propionamide +++ 137 N-(2-(4-methoxyphenyl)benzo[d]oxazol-5-yl)butyramide - ++ 138 jN-(2-(4-methoxyphenyl)benzo[d]oxazol-5-yl)pentanamide + 139 N-(2-(4-methoxyphenyl)benzodoxazol-5-yl)isobutyramide 140 N-(2-(4-methoxyphenyl)benzo[d]oxazol-5y)f uraen -2-ca1rsboxamde N-(2-(4-methoxyphenyl)benzo[d]oxazol-5-yl)thiophene-2- + 141 carboxamide 142 4-(5-tert-butylbenzo[d]oxazol-2-yl)-N, N-diethylaniline ++ 143 4-(benzo[d]oxazol-2-yI)-N,N-diethylaniline ++ 144 NN-diethyl-4-(5-(ethylsuIfonyl)benzo[d]oxazol-2-yl)aniline 145 N,N-diethyl-4-(5-phe nytbe nzo[d]oxazol-2-yl)anle n + I - 146 JN,N-diethyl-4-(naphtho[1 ,2-dJoxazol-2-yl)aniline __~ ~ -_ _ _ -__ -_-_-_-- -i-I-...... 147 ridin-2-yl) benzo[d]oxazole 148 iN-(2-(4-chlorophenyl)-2H-benzo[d][1 2 1 3]triazol-5-yl)propionamide ++++ 149 2-(4-(pyrrolidin-1 -yI)phenyr)benzo[d]oxazol-5-arine 150 2-(4-(piperidin-1 -yI)phenyl)benzo[d]oxazol-5-amine 151 2-(4-(4-methylpiperazn-1 -y )phenyl)benzo[d]oxazol-5-amine ++ 152 2- (4-(diethylamino)phenyl)benzo[djoxazole-5-carboxy ic acid 153 16-nitro-2-phenyloxazolo[5, 4-b]pyrdine 154 1 2-propylbenzo[d]oxazol-5-amine + 155 2-phenylbenzo[d]oxazoI-6-amine +++ T156 N-benzyl-2-phenylbenzo[d]oxazol-5-amine +++ 157 2-p-tolyloxazolo[5,4-b]pyridine
!++
WO 2009/019504 PCT/GB2008/050648 55 158 k~2-p-tolyoxazolo[4,5-b]pyridine + 159 2-(4-morpholinophenyl)benzo[d]oxazol-5-amine + 160 ;3-met hoxy-N-(2-p-tolylbenzo[d]oxazol-5-y])propanamide 161 f5-phenyl-2-p-tolylbenzo[djoxazole +++ 162 2-(4-chlorophenyl)-5-phenylbenzo[d]oxazole 163 2-cyclohexyl-5-nitrobenzofdjoxazole 164 j2-(4-chlorophenyl)-6-nitro-1 H-benzo[d]imidazole.++ 165 N-(2-benzylbenzold]oxazol-5-yI)-2-phenylacetarmide + 166 N-(2-p-tolyl-1 H-benzo[d]imidazol-5-yl)butyramide 167 N-butyl-2-phenylbenzo[d]oxazol-5-amine 168 N-isobutyl-2-phenylbenzo[d]oxazol-5-amine ++++ 169 2-phenyloxazolo5,4-b]pyridin-6-amine T ~ ~ ~ --------- 170 jN-(2-phenyloxazolo[5,4-b]pyridin-6-yl)butyramide 171 5-nitro-2-(pyridin-2-yl)benzo[d]oxazole 172 -5-tert-butyl-2-p-tolylbenzo[d]oxazole ++++ 173 12-p-tolylbenzo[d]oxazole 174 '2-(3-(trifluoromethyl)phenyl)benzo[d]oxazol-5-amine __ 175 N-(2-p-toy-1 H-benzo[d]imidazol-5-yl)isobutyramide + 176 iN-butyl-2-p-tolylbenzo[d]oxazole-5-carboxamde 177 N-propyl-2-p-tolylbenzo[d]oxazole-5-carboxamide ++++ 178 N-(2-(4-chlorophenyl)-1 H-benzo[d]imidazol-5-yl)butyrarnide 1 179 5-(ethylsuffonyl)-2-p-tolylbenzo[d]oxazole ++++ 180 _2-(4-chlorophenyl)-5-(ethylsulfonyl)benzoduoxazole ++++ 181 N-isopropyl-2-p-tolylbenzo[d]oxazole-5-carboxamide + 182 ~f'IN-butyl-2-(4-chlorophenyi)benzo[d]oxazo-5-amine 183 2-(4-chlorophenyl)-N-isobutylbenzo[d]oxazol-5-amine +++ 184 TN-benzyl-2-(4-chlorophenyl)benzo[d]oxazol-5-amine 1+ 1l8 N-butyl-2-p-tolylbenzod]oxazol-5-amine +++ 186 N- sobutyl-2-p-tolylbenzo[doxazol-5-amine +++ 187 JN-benzyl-2-p-tolylbenzo[d]oxazol-5-amine +++ 188 jN-(2-phenyl-1 H-benzo[d]imidazol-5-yl)isobutyramide + 189 4-n tro-2-p-tolyibenzofd]oxazole + 190 6-nitro-2-p-tolylbenzofdloxazole +++ 191 2-(4-chlorophenyl)-6-nitrobenzo[d]oxazole ++ 192 2-p-tolyloxazolo[4,5-c]pyridine+ 193 N-(2-phenylbenzo[d]oxazol-5-yl)propane-1-sulfonamide ++ 4 JN-(2-phenyl-1 H-benzo[dimidazol-5-yl)butyramide WO 2009/019504 PCT/GB2008/050648 56 195 N-(2-(4-chlorophenyl)-lH-benzo[d]imidazol-5-yl)isobutyramide ++ 196 2-m-tolylbenzo[d]oxazol-5-amine _197 2-(3-(dimethylamino)phenyl)benzo[d]oxazol-5-amine |+ 198 i5-bromo-2-p-tolylbenzo[dloxazole +++ 199 5-(4-methoxyphenyl)-2-p-tolylbenzo[d]oxazole + 200 jN-(2-m-tolylbenzo[d]oxazol-5-yl)butyramide 201 N-(2-(3-(dimethylamino)phenyl)benzo[d]oxazol-5-yl)butyramide + 202 N-(2-m-tolylbenzo[d]oxazol-5-yl)isobutyramide ++++ 203 IN-(2-(3-(trifluoromethyl)phenyl)benzo[dloxazol-5-yl)1sobutyramide + 205 2-o-tolylbenzo[doxazol-5-amine i+++ 206 -2-(2-chloropheny)benzo[d]oxazol-5-amine ++ 207 N-(2-(4-chlorophenyl)bezo[d]oxazo l-5-y)propionam ide +++ 208 jN-(2-p-tolylbenzo[d]oxazol-5-yl)pivalamide 209 2,2,2-trifluoro-N-(2-p-tolylbenzo[d]oxazol-5-yl)acetamide ++ 210 -N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)pivala m ide ++ 211 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yI)-2,2,2-trifluoroacetamide I++ 212 6-bromo-2-p-tolyloxazolo[5,4-b]pyridine 213 12-p-tolylbenzo[d]thiazol-5-amine + :214 .2-benzyf-5-nitrobenzo[d]oxazole 215 5,6-dimethyl-2-p-tolylbenzo[d]oxazole .... 216 IN-(2-p-tolylbenzo[d]thiazol-5-yl)butyramide i++ 217 N-(2-p-tolylbenzo[d]thiazol-5-yl)isobutyramide 8 2-p-tolylbenzo[d]oxazole-5-carboxamide +++ 21 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)-N-methylpropionamide +++ 220 N-(2-phenylbenzo[d]oxazol-5-yl)propane-2-sulfonamide + 221 N ( p n enz oxazol-5-yl)benzenesulfonamide+ 222 12-(4-chlorophenyl)-5,6-dimethylbenzo[d]oxazole ++++ 223 6-nitro-2-(pyridin-2-yI)benzo[d]oxazole 224 2-(2,4-dichlorophenyl)-5,6-dimethylbenzo[d]oxazole ++++ '225 N-(2-(3-(trifIuoromethyl)phenyl)benzo[d]oxazo7-5-yl)butyram ide 226 N-(2-o-tolylbenzo[d]oxazol-5-yl)isobutyramide 227 N-(2-benzylbenzo[d]oxazol-5-yl)butyramide + 228 N-(2-benzylbenzo[d]oxazol-5-yl)isobutyramide + 229 N-(2-(2-chlorophenyf)benzo[d]oxazol-5-yl)butyramide +++ 230 ___ N-(2-(2-chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide - +++ 231 N-(2-(3-chlorophenyl)benzo[doxazol-5-yl)sobutyramide 1.++++ WO 2009/019504 PCT/GB2008/050648 57 232 2-(3-fluorophenyl)benzo[djoxazol-5-amine ++++ 233 4,4,4-trifluoro-N-(2-p-tolylbenzo[d]oxazol-5-yl)butanamide + 234 2-p-tolylbenzo[d]oxazol-4-amine ++ 235 N-(2-p-tolylbenzo[d]oxazol-4-yl)butyramide 236 N-(2-p-tolylbenzo[d]oxazol-4-yl)isobutyramide + 237 .2-p-tolylbenzofd]oxazol-6-amine ++++ 238 2-(24-difluorobenzamido)-4,5-dimethylphenyl 2,4-difluorobenzoate + 239 N-(2-(3-chlorophenyl)benzo[d]oxazol-5-yl)butyramide + 240 1-phenyl-3-(2-phenyibenzo[d]oxazol-5-yi)urea +++ 241 1 -isopropyl-3-(2-phenylbenzo[d]oxazol-5-yl)urea 242 N-(2-(2-fluorophenyl)benzo[dJoxazol-5-yl)butyramide + 243 N-(2-(2-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide +++ 244 N-(2-(3-fluorophenyl)benzo[d]oxazol-5-yl)butyramide ++++ 245 N-(2-(3-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide tert-butyl 3-oxo-3-(2-phenylbenzo[d]oxazol-5- + 246 ylamino)propylcarbamate 247 2-(2,4-difIuorophe nyl)-5,6-di methylbenzo[d]oxazole 24 N-(2- cycl o hexylIbenzo [d] oxazolI-5-yl) is obutyra mid e ++++ '249 'N-(2-cyclohexylbenzo[djoxazof-5-yl)butyramide+ 250 2-(5-butylpyridin-2-yl)-5-nitrobenzo[d]oxazole + 251 2 p 2-phenylbenzo[d]thiazol-5-amine .. 252 N-(4-(2-(4-chlorophenyl)benzo[dloxazol-5-yl)phenyl)acetamide 253 N-(2-p-toIylbenzo[dJoxazo1-5-yi)propane-1 -sulfonamide 254 13,3,3-trfuoro-N-2-p-tolylbenzo[d]oxazo-5-yupropanamide 255 N-(2-(4-chlorophenyl)benzo[dloxazol-6-yl)isobutyramide 256 N-(2-(4-choropheny)benzo[d]oxazol-6-yl)butyramide + 257 JN-(2-(24-dihlorophenyl)benzo[djoxazol-5-y)isobutyramide +++ 258 ~-N(2(4fluorophenyeodnxzol-5-yxazobut-yraidebtzake:+ . 259 IN-(2-p-tolylbenzold]oxazol-5-yl)propane-2-suIfonamide + 260 N-(2(4-chorophenyl) benzotd]oxazolb-yI propane- -sulfonamide.+ 261 jN-(2-(4-chlorophenyl)benzo[djoxazol-5-yl)propane-2-sulfonamide + .262 2-(5-butylpyrid in-2-yl)-6-n itrobenzofd]oxazole + 263 '2-(4-chlorophenyl)-N-isopropy benzofd]oxazole-5-carboxamide 264 2-(4-ch orophenyl)benzo[d]oxazole-5-carboxamide +++ 265 IN-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)cyclopropanecarboxamide + 266 N-(2-(4-chlorophenyl)benzo[djoxazoi-5-yI)cyclobuta necarboxamide 267 N-(-hnlez jhaol-5-yI)isobutyramide __ WO 2009/019504 PCT/GB2008/050648 58 1268 N-(2-(3,4-dichIarophenyl)benzo[dJoxazo-5-yI)isobutyramide 269 2-(4-chlorophenyi)-5-(4-(ethylsulfonyl pheny)benzo[d]oxazole + 270 IN-(2-(5-chloropynidin-2-yl)benzo[d]oxazol-5-yl)isobutyramide ++ 271 N-(2-(3,5-dichlorophenyl)benzo[d]oxazol-5-yl)isobutyramide ++ '272 (S)-2-amino-N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)propanamide ++ 273 jN-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-y)isobutyramide 274 12-(4-chlorophenyl)-N-isopropylbenzo[d]oxazole-5-carbothioamide I+ N-(2-(4-chlorophenyl)benzo[doxazol-5-yl)-2 275 methylpropanethioamide 276 j2-(4-chlorophenyf)benzo[dJthiazol-5-amine f 1277 N-(2-(4-chlorophenyl)benzo[d]thiazo1-5-yl)isobutyramide +++ 12-(4-chlorophenyl)-N-isopropyl-N-methylbenzo[d]oxazole-5 278 carboxamide 279 |2-(4-chlorophenyl)-N-methylbenzo[d]oxazole-5-carboxamide 280 2-phenethylbenzo[d]oxazol-5-amine ++++ 281 -2-(4-chforophenyl)-5-(isopropylsulfonyl)benzo[d]oxazole ++++ .282 2-(2-chlrophenyl)benzod]tiazo1-5-amine ++++ 283 12-(3-chlorophenyl)benzo[d]thiazol-5-amine ++++ 284 2-(3,4-dichlorophenyl)benzo[d]thiazol-5-amine i++++ 285 13-morpho ino-N-(2-phenylbenzo[d]oxazol-5-yl)propanam ide '286 2-(benzo[d][1 ,3]dioxol-5-yl)-5-nitrobenzofdloxazole 287 methyl 4-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)benzoate + '288 5-bromo-2-(4-chlorophenyl)benzo[djoxazole ++++ 289 - 4-(5-chlorobenzo[d]oxazo-2-yl)aniline-+ 290 4-(6-chlorobenzo[djoxazol-2-yl)aniline 291 12-(4-chlorophenyl)-5-(4-morpholinophenyl)benzo[d]oxazole ++ 292 2-(4-chlorophenyl)-5-(3-(ethylthio)phenyl)benzo[d]oxazole ++ 293 2-(3-chlorophenyl)-5-(ethylsulfonyl)benzo[dloxazole ++++ 294 'N-(2-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)phenyl)acetamide + 296 N-(2-(3-chlorophenyl)benzo[d]thiazol-5-yl)isobutyramide 297 N-(2-(3,4-dichlorophenyl)benzo[d]thiazol-5-yl)isobutyramide ++++ :298 2-(2-Chlorophenyl)-5-(ethylsulfonylbenzo[d]oxazole 299 _T2-(benzo[d][ 1, 3]dioxol-5-yI)benzo[d]oxazol-5-a mine + 300 N-(2-(benzo[d][ 1,3]dioxol-5-yl)benzo[d]oxazol-5-yl)isobutyramide + 301 12-( 3,4-d1Chlorophenyl)-5-(ethylsulfonyl)benzo[d]oxazole ++ 302 jN-(2-phenethylbenzo[d]oxazol-5-yl)isobutyramide + 303 N-(2-(2,3-dichlorophenyl)benzo[d]thiazol-5-yl)isobutyramide j+++ WO 2009/019504 PCT/GB2008/050648 59 304 2-(2,3-diChlorophenyl)-5-(ethylsulfonyl)benzo[dloxazole + 32-(4-chlorophenyl)-5-(6-methoxypyridin-3-y[)benzo[d]oxazole 306 f2-(4-chlorophenyl)-5-(6-methoxypyridin-3-yl)benzo[doxazole + 307 2-(2,3-dichlorophenyl)benzo[d]thiazol-5-amine +++ 308 2-(1-phenylethyl)benzo[d]oxazol-5-amine 309 tN-(2-(1 -phenylethyl)benzo[d]oxazol-5-yl)isobutyramide .310 2-(4-chlorophenyl)-5,6-methylenedioxybenzoxazole 311 IN-(2-(2,5-dichlorophenyl)benzo[d]oxazol-5-yl)jsobutyramide 312 2-(4-chlorophenyl)benzo[d]oxazole-5-sulfonic acid + 313 :3-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)benzoic acidd + 314 .2-(4-chlorophenyl)-5-(6-chloropyridin-3-yl)benzo[d]oxazole 315 2-(4-chlorophenyl)-5-(6-fluoropyridin-3-yI)benzo[d]oxazole + 316 2-(4-chlorophenyl)-5-(6-morpholinopyidin-3-y)benzo[d]oxazole + 317 N-(4-(5-chlorobenzo[d]oxazol-2-yl)phenyl)acetamide +++ 318 IN-(4-(5-chlorobenzo[d]oxazol-2-yl)phenyl)isobutyramide 319 N-(4-(5-chlorobenzo[d]oxazol-2-yl)phenyl)thiophene-2-carboxamide + 319 - ~ eF---- 320 |N-(2-(4-chlorophenyl)benzo[d]oxazol-5-y)-N-methylisobutyramide ++ 321 5-tert-butyl-2-(4-chlorophenyl)benzold]oxazole ++++ 322 i2-(4-chlorophenyl)-N-isobutyl-N-methylbenzo[dloxazol-5-amine + 323 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)-3-methoxypropanamide 324T 2-(3,4-diclrophenyl)-6-ntrobenzo[d]oxazole...++..
325 2-(4-chloropheny)benzo[dloxazole-5-sufonamide++ 326 5-chloro-2-(4-chforophenyl)-6-nitrobenzo[djoxazole 327 2-(4-chlorophenyl)-5-(6-methoxypyrdin-2-yl)benzo[d]oxazole 328 .3-(2-(4-chlorophenyl)benzo[d]oxazo-5-y1)aniIine ++++ 329 j4-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)aniline 330 -- 5-chloro-2-(pyridin-4-y)benzo[d]oxazole +__ 331 6-chloro-2-(pyridin-4-yl)benzo[d]oxazoie 332 jN-(4-(6-chlorobenzo[d]oxazol-2-yf)phenyl)acetamide ++ 333 ~N-(4-(6-chhorobenzo[d]oxazok-2-yphenylsobutyramide iH 334 N-(4-(6-chlorobenzold]oxazol-2-yl)phenyl)thiophene-2-carboxamide 335 12-(4-chlorophenyl)-N,N-diisobutylbenzo[d]oxazol-5-amine + 336 4-(5-bromobenzo[d]oxazo-2-y)anil ine j+++ 337 4-arnino-N-(4-(5-bromobenzo[d]oxazol-2-yl)phenyl)benzamide + 338 5-(2-(4-chlorophenyl)benzo[dJoxazol-5-yl)pyridin-2-anmine 339 2-(4-chlorophenyl)-5-phenyl-1 H-indole 340 N-(2-(2-chloro-4-fluorophenyl)benzo[d]oxazol-5-y)isobutyramide i++++ WO 2009/019504 PCT/GB2008/050648 60 31 N-(2-(2-chloro-6-fluorophenyl)benzodoxazol-5-y )isobutyramide 341 N-(2-(3-chloro-2-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide ++++ 343 N-(2-(4-chloro-2-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide ++++ 344 N-(2-(2-chloro-5-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide + N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yI)-3,3,3 345 trifluoropropanamide 346 N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)cyclopentanecarboxamide !+ 347 N-(5-chloro-2-(4-chlorophenyl)benzo[d]oxazol-6-yl)isobutyramide ++ 348 5-nitro-2-(4-(trifluoromethoxy)phenyl)benzo[d]oxazole ++ 349 N-(2-(tetrahydro-2H-pyran-4-yl)benzo[d]oxazol-5-yl)isobutyramide + 350 2-(4-(trifluoromethoxy)phenyl)benzo[d]oxazol-5-amine ++ N-(2-(3,4-dichlorophenyl)benzo[djoxazol-5 351 yI)cycfopropanecarboxamide 4 N-(2-(3,4-dichlorophenyl)benzo[d]oxazo-5-yl)-3, 3,3 352 trifluoropropanamide 353 N(2-(4-chlorophenyl)benzo[d]oxazoI-6-yl)cyclopropanecarboxamide :++ 354 IN-(2-(2,3-dichlorophenyl)benzotd]oxazol-6-yl)isobutyramide +++ 355 N-(2-(4-(tnifluoromethoxy)phenyl)benzod]oxazol-5-yl)isobutyramide + 356 4-(5-(4-chloropheny)benzo[d]oxazol-2-y)aniline 357 12-morpholino-5-nitrobenzo[d]oxazole 358 jN-(5-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)pyridin-2-yl)acetamide + 359 N-(4-(5-bromobenzo[d]oxazol-2-yl)phenyl)acetamide 360 j2-morpholinobenzo[d]oxazol-5-amine + 361 j2-(3,4-chlorophenyl)-5,6-methylenedioxybenzoxazole + (S)-N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)pyrrolidine-2 J362 carboxamide N-(2-(2,3-dichlorophenyl)benzo[d]oxazo-5-yl)-3,3,3 363 ItrifIuoropropanamide 364 N-(2-cyclopentylbenzold]oxazol-5-yl)isobutyramide 1+ 365 ;N-(4-(5-acetamidobenzo[d]oxazol-2-yl)phenyl)acetamide + 366 2-(furan-2-yl)-5-nitrobenzo[djoxazole itob---~o az l ------ .+........... 367 N-(4-(2-(4-chlorophenyl)-1 H-indol-5-yl)phenyl)acetamide + N-(2-(2-chloro-3-(trifluoromethyl)phenyl)benzo[d]oxazol-5 368 yl)isobutyramide 369 j2-(3,4-dichlorophenyf)benzo[d]oxazol-6-amine 371 2-(benzo[d][1 ,3]dioxol-5-yl)-5-chloro-6-nitrobenzo[d]oxazole +++ 372 N-(4-(5-(4-chlorophenyl)benzo[d]oxazol-2-yl)phenyl)acetarnide + 373 N-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)acetamide 374 N-(2-(4-acetamidophenyl)benzo[d]oxazol-5-yI)isobutyramide j+ WO 2009/019504 PCT/GB2008/050648 61 375 -(2-phenyl-I H-indol-6-yl)isobutyramide I+ 2 3-dichloro-N-(2-(2,3-dichlorophenyl)benzofdloxazol-5 376 [ _ yIbenzamide i(S)-N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yI)-2 377 i(methyfamino)propanamide 378 N-(1-methyl-I H-indol-6-yl)isobutyramide + 379 2-(4-chlorobenzylthio)-5-nitrobenzo[d]oxazoe+ I2-(4-chlorobenzylthio)benzo[d]oxazol-5-amine + 381 N2 -(4-ch orobenzyl)benzo[d]oxazole-2,5-diamine + 382 2-(4-methylbenzylthio)-5-nitrobenzo[d]oxazole + 383 N-(2-(4-chlorobenzylthio)benzo[d]oxazo -5-yl)isobutyramide + '384 N-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)isobutyramide 385 N-(2-(naphthalen-2-yl)benzo[d]oxazol-5-yl)thiophene-2-carboxamde+ 386 ethyl 2-(4-chl orophenyl)benzo[d]oxazo l-5-ylca rbamate I+ 387 !N-(1 -benzyl-1 H-indol-6-yl)isobutyramide 388 __nto2(hipe -- lbezfjx l !+ 389 }N-(1-methyl-2-phenyl-lH-indol-6-yl)isobutyramide
--------------------------------------------
390 15-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole |+++ 391 2-(-choro2-fuorphenyl)-5-(ethylsulfonyl)benzo[d]oxazole ++
-----------
392 2-cyclohexyl-5-(ethylsulfonyl)benzo[d]oxazole 393 2-(5-chloropyridin-2-yl)-5-(ethylsulfonyl)benzo[d]oxazoIe 394 2-(benzo[d][1,3]dioxol-5-yl)-5-(ethylsulfonyl)benzo[djoxazole ++++ 395 5-chloro-2-(4-(methylsulfonyl)phenyl)benzo[d]oxazole ++ 396 N-(2-phenylbenzofuran-5-yl)isobutyramide 397 j2-(benzo[d][1,3]dioxol-5-yl)-5-chlorobenzo[d]oxazol-6-amine + N-(2-(benzo[d]{1,3]dioxo -5-yl)-5-chlorobenzo[d]oxazo -6 A a e 399 12-(4-chlorophenyl)-6-(methylthio)benzo[d]thiazole++ 400 2-(4-chlorophenyl)-5-(methylsulfonyf)benzo[d]oxazole 401 j2-(biphenyl-4-yl)benzo[d]oxazol-5-amine 402 2-(quinolin-2-yl)benzo[d]oxazol-5-amine 403 2-(quinolin-3-yl)benzofd]oxazol-5-amine +++ 404 2(-2-y++ 404 j2-(6-methoxynaphthalen-2-y)benzo[d]oxazol-5-amine + 405 _ -6boonaphtha len-2-yl) benzofd]oxazol-5-amime +____ 406 2-(4-chlorophenyl)-6-(methylsulfonyl)benzo[d]thiazole ++++ 407 IS-2-(4-chlorophenyl)benzo[d]oxazol-5-yI ethanethioate + 408 2-phenyl-5-(3',3%3'-trifluoropropanamido)benzofuran + 409 2-(4-chlorophenyl)naphtho[1,2-d]oxazole WO 2009/019504 PCT/GB2008/050648 62 410 JN-(2-(raphthalen-1 -yI)benzo[dloxazoi-5-yI)isobutyramide + 411 N-(2-(biphenyl-4-yl)benzo[d]oxazol-5-yl)isobutyramide + 412 N-(2-(6-methoxynap hthalen-2-yI)benzo[d]oxazo-5-y)isobutyramide + 413 N-(2-(6-bromonaphthalen-2-yl)benzo[d]oxazol-5-yl)isobutyramide + 414 12-(4'-chlorophenyl)-5-isobutyramido-benzofuran + 415 N-(2-(quinolin-3-yl)benzo[d]oxazol-5-yi)isobutyramide 416 N-(2-(quinolin-2-yl)benzodoxazol-5-yl)isobutyramide 417 f1-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)propan-1 -one 418 5-(ethylsulfonyl)-2-(5-methylthiophen-2-yl)benzod]oxazole .+ 419 N-(2-(furan-2-yl)benzo[doxazol-5-yl)isobutyramide ++++ 420 1-(2-(4-chloropheny)benzo[d]oxazol-5-yl)ethanone 421 2-(4-cyclohexylphenyl)benzo[d]oxazol-5-amine ++++ 422 j5-(ethylsulfonyl)-2-(quinolin-2-yl)benzo[dloxazole 423 J5-(ethylsulfonyl)-2-(quinolin-3-yl)benzo[d]oxazole ++++ 424 1 2-(6-bromonaphthalen-2-yl)-5-(ethylsulfonyl)benzo[d]oxazole ]+ 425 2-(4-cyclohexylphenyl)-5-(ethylsulfonyl)benzo[d]oxazole + 426 2-(biphenyl-4-yl)-5-(ethylsulfonyl)benzo[d]oxazole + 427 5-(ethylsulfonyl)-2-(naphthalen-1 -yl)benzo[d]oxazole + 428 1 5-am i no-2-(5,6-dichlorobenzo[d]oxazol-2-yl)phenol +++ 429 _5-(ethylsulfonyl)-2-(thiophen-2-yl)benzo[doxazole++ 430 N-(2-(4-cyclohexylphenyl)benzo[d]oxazol-5-yl)isobutyramide 431 15-(ethylsulfonyl)-2-(6-fluoronaphthalen-2-yl)benzold]oxazole + 432 2-(benzo bthiophen-5-yl)-5-(ethylsulfonyl)benzo[d]oxazole 433 N-(4-(5,6-d i methyl benzo[d]oxazol-2-yl)-3-hydroxyphenyl)acetamide I++ 434 2-(3,4-dichlorophenyl)-5-(isopropysulfonyl)benzo[d]oxazole +++ 435 N-(4-(5,6-dimethylbenzotd]oxazol-2-yI)-3-hydroxyphenyl)acetamide 436 5-(ethylsulfonyl)-2-(3-methylthiophen-2-yl)benzo[d]oxazole ++ 437 12-(5-(ethylsulfonyl)benzo[d]oxazol-2-yl)naphthalen-1-ol 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5 438 (ethylsulfonyl)benzo[dloxazole 439 2-(4'-chlorophenyl)-5-(N,N-diethylsulfonamidyl)-benzoxazo e + 440 '4- (5,6-dichlorobenzo[d]oxazol-2-yl)aniline +++ 441 5-(ethylsulfonyl)-2-(5-methyfuran-2-yl)benzo[d]oxazole +++ 442 N-(4-(naphthofl,2-d]oxazol-2-yl)phenyl)isobutyramide +++ 15-(ethylsulfony-2-(4-methylthiophen-2-y+)benzo[d+oxazl 5-(ethylsulfonyl)-2-(5,6,7,8-tetrahydronaphthalen-2 444 yl)benzo[d]oxazole 445 u 2-(benzofuran-5-yI)-5-(ethy+su+fonylbenzo[d]oxazole WO 2009/019504 PCT/GB2008/050648 63 46 2-(4'-chlorophenyl)-5-(1'-hydroxyethyl)-benzoxazole ++++ 447 5-Amino-2-(5-(ethylsulfonyl)benzo[doxazo-2-yl)phenol ++ 2-(Naphthalen-2-yl)-5-(trifluoromethoxy)benzo[d]oxazole 449 2-(NaphthaIen-2-yl)benzold]oxazo e-5-carboxy Ic acid ++++ 450 2-(Naphthalen-2-ylbenzo[d]oxazole ++ 451 5 Butyl-2-(naphthalen-2-yl)benzo[d]oxazole -- ~- ------------- 452 5,6-Difluoro-2-(naphthalen-2-yl)benzo[d]oxazole ++ 41-(2-(3" 4"-Dichlorophenyl)benzo[d]oxazol-5'-yl)ethanone 454 N-(4-(Benzo[d]oxazol-2-yl)phenyl)isobutyramide 4,Methyl 2-(4-ch lorophenyl) be nzo[dJoxazol-5-yl (ethyl)phosphinate +++ 456 2-(3',4'-Dichlorophenyl)-5-(1 '-hydroxyethyl)-benzoxazole +++ 1457 2-(4-Chlorophenyi)-6-methylbenzo[djoxazole 4585-Methyl-2-(naphthalen-2-yl)benzo[dloxazole ++++ Table 2: Compounds made by analogues methods to those described herein, or by literature methods known or adapted by the persons skilled in the art. 459 Chemical Name Activity 460 '2-(4-((4-chlorophenylthio)methyl)phenyl)-1H-benzo[d]imidazole 461 2-((2,4-dichlorophenoxy)methyl)-1 H-benzo[d]imidazole 462 '2,6-dichloro-N-(5-methylbenzo[d]thiazol-2-ylcarbamoyl)benzamide + 463 2-(thiophen-2-yl)-1 H-benzo[d]imidazole 464 N-(3-(1H-benzo[d]imidazol-2-yl)phenyl)benzamide + 1-(2-chlorobenzyl)-2-((2,4-dichlorophenoxy)methyl)-1 H 465 benzo[d]imidazole 466 1 -(2-methylbenzo[d]oxazol-6-yl)-3-phenyl urea 467 1-methyl-3-(2-methylbenzo[d]oxazoI-6-yl)urea 468 2-chloro-N-(2-methylbenzo[d]oxazol-6-ylcarbamoyl)benzamide + 469 12-(4-chlorophenyl)-5-(piperidin-1 -ylmethyi)benzo[d]oxazole + 470 2-(4-methoxyphenyl)-1 H-benzo[d]imidazole ++ 471 j2-(phenoxymethyl)-1 H-benzo[d]imidazole 472 1-methyl-2-(4-nitrophenyl)-1 H-benzo[d]imidazole + 473 2-((4-methoxyphenoxy)methyl)-1 H-benzo[d]imidazole ++ 474 1-methyl-2-(phenoxymethyl)-1 H-benzo[d]imidazole + 475 14-(1H-benzo[d]imidazol-2-yl)aniline
.
WO 2009/019504 PCT/GB2008/050648 64 :476 12,2'-(1 ,4-phenylene)bis(1 H-benzo[djimidazol-6-amine) 477 }2-(4-nitrophenyl)benzo[d]oxazole 478 4-(benzo[d]oxazol-2-yi)aniline ++ 479 5-(benzo[djth iazo]-2-yl)-2-methylanil ine++ 480 2-(3,4-dichlorophenyl)benzo[d]oxazol-5-amine ++ 481 J2-(4-ethylphenyl)benzo[d]oxazol-5-amine 482 2- (3,5-dimethylphenyl)benzo[d]oxazo-5-amine 483 2-(benzo[dlth iazol-2-yl) phenol 484 j5-amino-2-(benzo[d]oxazol-2-yl)phenol + + 485 j4-(5,6-dimethylbenzo[d]oxazol-2-yl)aniline 486 *4-(benzo [d]oxazo-2-yl)-N, N-d imethylani line 487 1 2-(4-aminophenyl)-1 H-benzo[d]imidazol-6-amine 488 j2-(4-chlorophenyl)benzo[d]oxazol-5-amine 489 2-(3-chlorophenyl)benzo[d]oxazol-5-amine 490 2-(4-aminophenyl)-1-methyl-1H-benzo[d]imidazol-5-amine + 491 2-(4-(dimethylamino)phenyl)benzo[d]oxazol-5-amine ++ 492 5-nitro-2-phenylbenzo[dJoxazole ++ 493 JN-(4-(1 H-benzo[d]imidazol-2-yl)phenyl)-2-(thiophen-2-yI)acetamide + 494 N-(4-(1 H-benzo[d]imidazol-2-yl)phenyl)-3,4-dimethoxybenzamide i+ 495 ]2-((4-chlorophenoxy)methyl)-1 H-benzo[d]imidazole + 496 4-(5-aminobenzod]oxazol-2-yl)phenol ++ 497 jN-(4-(1 H-benzo[d]imidazol-2-yl)phenyl)benzamide + 498 f4-(1 H-benzo[d]imidazol-2-yl)-NN-dimethylaniline 499 2-(methoxymethyl)-1 H-benzo[d]imidazole 500 ,N-(2-(1 H-benzo[d]imidazol-2-yl)phenyl)-2,4-dichlorobenzamide + 501 JN-(4-(1 H-benzo[dlimidazol-2-yl)phenyl)-2-phenylacetamide + 502 3-(5-ethylbenzo[d]oxazol-2-yl)aniline ++ 503 N-(3-(1 H-benzo[d]1midazol-2-yl)phenyl)acetamide 504 . N-(3-(1 H-benzo[d]imidazol-2-yl)phenyl)thiophene-2-carboxamide + 505 5-methyl-2-(4-nitrophenyl)benzo[d]oxazole ++ 506 j4-(6-methyl benzo[d]oxazol-2-yl)ani line 507 |2-(2-fluorophenyl)-1 H-benzo[d]imidazole ++ :508 2-(furan-2-yl)-5-nitro-1 H-benzofd]imidazole + 509 JN,N-dimethyl-4-(5-nitro-1 H-benzo[djimidazol-2-yl)anifine ++ :510 J2-(furan-2-yl)-1 H-benzo[d]inidazol-5-amine dihydrochloride + N-(2-(1 H-benzold]imidazol-2-yl)phenyl)-4-(pyrrolidin-1 :511 ylsulfonyl)benzamide WO 2009/019504 PCT/GB2008/050648 65 512 i2-(4-methoxyphenyl)benzo[d]oxazol-5-amine 513 N-(3-(benzo[d]thiazol-2-yl)phenyl)acetam ide 514 12-(3-chlorophenyl)-1 H-benzotdjimidazole 515 2-(3,4-dimethoxyphenyl)benzo[doxazo-5-amine ++ 516 2-(4-(piperidin-1 -ylsulfonyl)phenyl)benzo[d]thiazole ++ 517 N-(2-(2,4-dichlorophenyl)benzo[d]oxazol-5-yl)acetamide + 518 4-(5,7-dichlorobenzo[d]oxazol-2-yl)aniline ++ 519 N-(2-(3-chloro-4-methoxyphenyl)benzo[d]oxazol-5-yl)acetamide ++ 520 12-(3,4-dimethoxyphenyl)-5-nitro-1 H-benzo[d]imidazole + 521 2-(3,4-dimethoxyphenyl)-1 -methyl-1 H-benzo[d]imidazole 522 j2-(2-methoxypheny)benzo[d]thiazole 523 2-(4-chloro-3-nitrophenyl)benzo[d]thiazole + 524 2 -(2-chloro-5-nitrophenyl)benzo[d]thiazole 525 2-(4-fluorophenyl)-5-nitrobenzo[d]oxazole 526 2-(3-chloro-4-methylphenyl)benzo[d]oxazol-5-amine ++ 527 '2-(2-chloro-4-methylphenyl)benzofdjoxazol-5-amine + 28 12-((4-methoxyphenoxy)methyl)-1 -methyl-1 H-benzo[d]imidazole l+ 529 N-(4-(5,7-dimethylbenzold]oxazol-2-yl)phenyl)acetamide ++ 530 2-((1 H-benzo[d]imidazo-2-yl)methylthio)-5-phenyl-1,3,4-oxadiazole + 531 j2-(p-tolyloxymethyl)-i H-benzo[d]imidazole ++ 532 4-(5-methyl-1 H-benzo[d]imidazol-2-yl)aniline 533 5-nitro-2-m-tolylbenzo[d]oxazole ++ 534 N-(2-(furan-2-y)-1 H-benzo[d]im idazol-5-yl)acetamide + 535 j2-(4-methoxyphenyl)-1 H-benzo[d]imidazol-5-amine ++ (2-(furan-2-yl)-i H-benzo[d]imidazol-5-yl)-4 536 methylbenzenesulfonamide 537 2-(3,4-dimethoxyphenyl)-5-nitrobenzo[d]oxazole 538 N-(3-(6-methyl-1 H-benzo[d]imidazol-2-yl)phenyl)furan-2-carboxamide + 539 5-chloro-2-(3-methyl-4-nitrophenyl)benzo[djoxazole IN-(4-(I H-benzo[dJimidazol-2-yl)phenyl)benzo[d][1,3]dioxole-5 jo4 'arboxamide _ _ 1 2-(4-chH-benzofdlimidazole ++ 542 N-(5-(benzo[dlthiazol-2-yl)-2-methoxyphenyl)acetamide 543 2-(4-(methylthio)phenyi)-i H-benzo[d]imidazole ++ 2(4aiohnlbenzo[d]oxazol-6-amime ___ 545 ~2-(4-(6-methylbenzo[d]thiazol-2-yl)phenylcarbamoyl)berizoic acid (Z)-1 -(benzo[d]thiazol-2-yl)-4-(1 -(cyclopropylamino)ethylidene)-3- + 546 methyl-1 H-pyrazol-5(4H)-one WO 2009/019504 PCT/GB2008/050648 66 5 47 (E)-2-styryl-1 H-benzo[d]imidazole +++ 548 2-((2,5-dimethylphenoxy)methyl)-1 H-benzold]imidazole + 549 2-(4-ethoxyphenyl)benzo[d]oxazol-5-amine + 550 4-amino-2-(5-aminobenzo[d]thiazol-2-yl)pheno 551 A-am i no-2-(5-ethyl benzo[d]oxazol-2-yl)phenot 552 12-(2-phenylhydrazinyi)benzo[d]thiazole 553 -(5-ethylbenzod]oxazol-2-yl)aniline ++++ 554 j2-(5-methy-1 H-benzod]imidazol-2-yl)aniline +++ 555 N-(6-ethoxybenzo[d]thiazol-2-yl)benzamide + N-(4-(6-acetam ido-5-chloro-1 H-benzo[d]imidazol-2 556 yl)phenyl)acetamide 557 4-(4-(H-benzo[d]imidazol-2-yl)phenoxy)aniline ++++ 558 2-(biphenyl-4-yI)-1 H-benzo[d]imidazole 559 4-amino-2-(5,6-dimethylbenzo[d]oxazoI-2-y])phenol 560 2-(4-chlorophenyl)-1H-benzo[d]imidazol-5-amine 561 2-(thiophen-2-y9)-1 H-naphtho[2,3-d]imidazole 562 N-(4-(1 H-benzo[d]imidazol-2-yl)phenyl)furan-2-carboxamide 563 j2-(ethylthio)benzold]thiazol-6-amine ++ 564 N-(4-(6-methylbenzo[d]oxazol-2-yl)phenyi)isobutyramide 565 '5-amino-2-(5-isopropylbenzo[d]oxazol-2-yl)phenol +++ 566 13-(5-chlorobenzo[d]oxazol-2-yl)-2-methylaniline + 567 JN-(benzo[d]thiazol-2-yl)-2-chloro-4-methylbenzamide + {N-(5-(1 H-benzo[d]imidazol-2-yI)-2-methylphenyl)-2,2,2 568 trifluoroacetamide 569 2-(2-fluorophenyl)benzo[d]oxazol-5-amine + 570 2-butyl-5-(ethylsulfonyl)benzo[d]oxazole 571 5-(ethylsulfonyf)-2-propylbenzo[d]oxazole 572 2-ethyl-5-(ethylsulfonyl)benzo[d]oxazole 573 5-(ethylsulfonyl)benzofd]oxazole 574 5-(ethylsulfonyl)benzo[d]oxazole-2-thiot 575 N-(3-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)phenyl)acetamide 576 :1-(2-tert-butyl-1 H-indol-5-yl)-3-ethylurea + 577 2-(naphthalen-1 -yl)benzo[d]oxazol-5-amine-+ 578 2-(4-chlorophenyl)-5-(propyisulfonyl)benzo[d]oxazole + 579 2-(4-chloropheny)benzo[dloxazo-6-o+ 580 N-(4-(5-Methyl-1H-benzo[dlimidazol-2-yI)phenyl)furan-2-carboxamide +++ 581 jPhenyl (2-phenyl-IH-benzo[d]imidazol-6-yl)methanone + 582 2-(4-Methoxyphenyl)benzo[d]thiazole WO 2009/019504 PCT/GB2008/050648 67 583 2-(4-Methoxyphenyl)benzo[d]oxazole +++ 584 '2-(4-Methoxyphenyl)-6-nitrobenzo[d]oxazole +++ 585 N-(4-(1 H-Benzofd]imidazol-2-yl)phenyl)thiophene-2-carboxamide ++++ 586 _ 2-(4-Methoxyphenyl)-5-nitro-1 H-benzo[d]imidazole ++ N-(4-(1 H-Benzo[d]imidazol-2-yl)phenyl)tetrahydrofuran-2 ~587 coarboxamide _ 588 1-Methyl-2-p-tolyl-1 H-benzo[d]imidazole ++ 589 N-(4-(Benzo[d]oxazol-2-yl)phenyl)acetamide 590 _4-(4,6-Dimethybenzo[d]oxazoW-2-yl)aniline ++++ 591 N-(4-(1H-Benzo[d]imidazol-2-yl)phenyl)acetamide+ 592 5-(Benzold]thiazol-2-y)-2-chloroaniline ++++ 593 i4-(5-Tert-butylbenzo[dloxazol-2-yl)aniline ++ 594 3-(Benzo[d]thiazol-2-yl)phenol +++ 595 J2-(2,4-Dichlorophenyl)benzo[d]thiazole 596 15-(Benzo[d]thiazol-2-yl)-2-methoxyphenoI +++ _ _ _ _ ~ -.- ~.---~--------------------- _ _ 597 5-(Benzold]thiazol-2-yl)-2-methoxyaniline I+++ 598 '2-(3-Chorophenyl)benzo[d]oxazol-6-amine +++ 599 2-(3-Methyl-4-nitrophenyl)benzo[dlthiazole 600 "2-(3-Methoxyphenyl)-1 H-benzo[d]imidazole 601 4-(Benzo[d]thiazol-2-yl)ani ine +++ 602 13-(Benzofd]thiazol-2-yl)aniline +++ 603 12-(3,4-Dimethylphenyl)benzo[dJoxazol-5-amine :604 -6-Nitro-2-phenyl-1H-benzo[d]imidazole-+++ 605 5-Methyl-2-(4-nItropheny)-1 H-benzofd]imidazole 606 12-(3-Methoxyphenyl)benzo[d]thiazole +++ 607 i2-(3-Methy-4-nitrophenyl)benzo[d]oxazole 608 j2-(Benzo[d][1,3]dioxol-5-yl)benzo[d]thiazole 609 4-(5-Sec-butylbenzo[d]oxazol-2-yl)aniline ++ 610 j5-Amino-2-(5,6-dimethylbenzo[d]oxazol-2-y )phenol+ 611 6-Methyl-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole 612 5-Methyl-2-(thiophen-2-yl)benzo[d]oxazole ++ 613 2-p-TolyI-1 H-benzold]imidazole____ 614 2-(Benzo[d][1 ,3]dioxol-5-yloxy)-N-(benzo[d]thiazol-2-yl)acetamide s-+ 615 1 -ethyl-2-methy-N-phenyl-1 H-benzojd]imidazole-5-carboxamide 616 N-(benzo[d]thiazoi-2-yi)-2-bromobenzamide 617 j2-(benzo[d]thiazo-2-ylthio)-1 -(piperidin-1 -yl)ethanone ++++ N-(benzo[d][1,3]dioxo-5-y)-3-chlorobenzo[b]thiophene-2 618 carboxamide WO 2009/019504 PCT/GB2008/050648 68 619 - 5-(benzo[d]oxazol-2-yl)-2-methoxyaniline 620 5-(1 H-benzo[d]imidazol-2-yI)-2-methylaniline 621 '3-chloro-N-(2-fluorophenyl)benzo[b]thiophene-2-carboxamide + + 622 3-(5-chlorobenzo[djoxazol-2-y)aniline ++++ 623 N-(3-(5,6-dimethylbenzo[d]oxazol-2-yl)phenyl)furan-2-carboxamide +++ 624 N-(4-(H-benzotd]imidazol-2-yi)phenyl)-3-methylbutanamide ++++ 625 5-(5-ethylbenzo[dloxazol-2-yl)-2-methylaniline ++++ 626 jN-(benzo[d]thiazol-2-yl)benzofuran-2-carboxamide ++++ 627 2-chloro-5-(5,7-dimethylbenzo[d]oxazol-2-y)aniline ++++ 3-amino-N-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[e]thieno[2,3 628 b]pyridine-2-carboxamide 629 2-bromo-N-(6-fluorobenzo[d]thiazol-2-yl)benzamide 630 '3-(5-methoxybenzofdJoxazol-2-yl)aniline 631 jN-(4-(l H-benzo[d]imidazol-2-yl)phenyl)-2-methylbutanamide 6-9methy2-(5-methyl-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyidin-3 632 famine 633 12-(phenoxymiethylbenzo[d]thiazole 634 1-ethyl-2-methyl-5-phenyl-1 H-benzo[d]imidazole 635 -2-methyl-5-(6-methybenzo[d]oxazo-2-yl)aniline-+++ 636 2-chloro-5-(5-methylbenzo[d]oxazol-2-yl)aniline 637 1 -(benzo[dJthiazol-2-yl)-3-p-tolylurea +++ 638 _ N-(4-(6-methylbenzo[dlthiazol-2-yl)phenyl)nicotinamide +++ 639 2-(quinolin-2-yl)benzod]thiazole+ 640 2-(4-methoxybenzylthio)-1 H-benzo[d]imidazole 641 12-ch lo ro- N- (4-(oxazolol4 1 b-b] py rid in-2 -y1) phenyl) benzarn id e 642 -(3-(5-ethylbenzo[d]oxazol-2-yl)phenyl)acetamide +++ 643 '4-(6-methylbenzo[d]thiazol-2-yl)phenol +++ 644 JN-(3-(5-methylbenzo[dloxazol-2-yl)phenyl)propionamide +++ 645 2-(3-fluoro-4-methoxybenzylthio)-1 -methyl-1 H-benzo[d]imidazole 646 4-chloro-3-(5,6-dimethylbenzo[doxazol-2-yl)aniline 647 3-(benzo[d]thiazo -2-yi)-N-(pyridion-4-ymethyI)aniline J HN-( -benzoldimidazo-2-yl)-2u-methabenzamide '649 '2-(4-bromo-3-methylphenyl)benzoldloxazoI-5-amine 651 1 N-(4-(benzo[dlthiazol-2-yI)phenyl)isobutyramide ~+ 652 N-(6-rnethyibenzo[djth iazol-2-yl)furan-2-carboxamide ___ 653 5-(1H-benzo[d]imidazol-2-yI)-2-chloroaniline +++ 654 :2-(4H-1,2,4-triazol-3-ylthio)-N-(4-(6-methylbenzo[d]thiazol-2- WO 2009/019504 PCT/GB2008/050648 69 __ Y)phenyl)acetamide 655 4-(4-(1H-benzo[d]jmidazol-2-yl)phenylcarbamoy)pheny acetate ++ 656 3,5,6-trimethyl-N-(pyridin-4-ylmethyl)benzofuran-2-carboxamide +++ 657 2-ethoxy-N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)acetamide 658 N-(6-fluorobenzo[d]thiazol-2-yl)thiophene-2-carboxamide .+ 659 1-(1 H-benzo[d]imidazol-2-yl)-3-methyl-4-phenyl-1 H-pyrazol-5-amine +++ 660 3-ethoxy- N- (4-(6-methylbenzo[d]thiazol-2-yl)phenyl)propanamide +++ 661 IN-(4-(benzo[d]thiazol-2-yl)phenyl)cyclopropanecarboxamide 662 ___ ~N-(4-(5-methylbenzo[d]oxazol-2-yl)phenyl)acetamide +++ 663 :_N-(2-bromo-4-methylphenyl)-2-(1 H-indol-3-yl)-2-oxoacetamfde +++ 664 i4-(6-methylbenzo[d]thiazol-2-yl)aniline ++ 665 JN-phenethylbenzofuran-2-carboxamide ++ 66 4-chloro-N-((l -methyl-1 H-benzofd]imidazol-2-yl)methyl)aniline -++ 667 IN-(4-(benzo[dthiazol-2-yl)phenyl)propionamide ++ 668 N-(2-m-tolylbenzo[d]oxazol-5-yl)propionamide ++ 669 N-(i-methyl-1 H-benzo[d]imidazol-2-yl)benzimidamide ++ 670 -4-methyl-N-(i -methyl-1 H-benzo[d]imidazol-5-yl)benzamide ++ ~671 1 N-(benzo[d]thiazol-2-yl)-5-bromo-2-chiorobenzamide ++ 672 N-(4-(6-methylbenzo[dloxazol-2-y)phenyl)thiophene-2-carboxamide ++ !3-amino-N-(2-fluorophenyl)-6,7-dihydro-5H-cyclopentale]thieno[2,3- ++ 673 b]pyridine-2-carboxamide 674 (3-(benzofuran-2-yl)-1 -phenyl-1 H-pyrazol-4-yl)methanol ++ 675 12-(4-methoxyphenyl)-5-methylbenzo[d]oxazole ++ 676 4-ethoxy-N-((1-methyl-1 H-benzo[d]imidazol-2-yl)methyl)aniline ++ N-(2-chloro-5-(5-methylbenzo[d]oxazol-2-y)phenyl)furan-2 677 carboxamide N-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2 678 yl)benzo[d]oxazol-2-amine 679 N-(1 H-benzo[d]imidazol-2-yl)-3-chlorobenzamide 4++ _680 IN-(4-(benzo[d]thiazol-2-yl)phenyl)tetrahydrofuran-2-carboxamide i++ 681 11-(2-(benzo[d]oxazol-2-ylamino)-46-dimethylpyrimdin-5-yl)ethanone + 682 (N-(4-methylpyrimidin-2-yl)benzo[d]oxazol-2-amine -++ N-(6-(N,N-dimethylsuIfamoyl)benzo[d]thiazol-2-y)th ophene-2 683 carboxamide i '5-bromo-N-(4-hyd roxy-3-(5-methyl benzo[d]oxazo 1-2 684 _ y)pheny)nicotinamide _____ ________ 2-(1 H-1,2,4-triazol-3-ylthio)-N-(4-(benzo[d]thiazol-2 £85 j",,,-,.,,.yl)phenyi)acetarnide _ ____ _______ 686 15-(5-methoxybenzo[dloxazol-2-yl)-2-methylaniline_++ 16871 687 N7-(6-(N-methylsulfamoylobenzo[d~thiazoI-2-yl)thiophene-2- + WO 2009/019504 PCT/GB2008/050648 70 -carboxamide . - 2-chloro-N-(4-(5-methybenzo[d]thazo-2-yl)phenyl)-5-(4H-1 ,2,4 '688 triazol-4-yl)benzamide '689 N-(2-fluorophenyl)-2-(1H-indol-3-yl)-2-oxoacetamide ++ ,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(1 H-i ndol-3-yi)-2 :670 1 oxoacetamide WO 2009/019504 PCT/GB2008/050648 71 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 5 HPLC was 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 150xlmm and the mobile phase is acetonitrile/water. 1 H NMR spectra were recorded on a Bruker instrument operating at 300 MHz. NMR 10 spectra were obtained as CDCl 3 solutions (reported in ppm), using chloroform as the reference 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). 15 Column chromatography was performed either by flash chromatography (40-65pm silica gel) or using an automated purification system (SPI TM 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-1 yl) N,N, N'N-tetramethyluronium hexafluorophosphate), HCI (hydrochloric acid), MgSO 4 20 (magnesium sulfate), NaOH (sodium hydroxide), Na 2
CO
3 (sodium carbonate), NaHCO 3 (sodium bicarbonate), STAB (sodium triacetoxyborohydride), THF (tetrahydrofuran).
WO 2009/019504 72 PCT/GB2008/050648 R + PPA, 1104C-1800C, 3-16h
NH
2 R, X=OH (Method 1 A) X=OH r CI Microwa dioxane, 210*C, 15min (Method I B) ' OH R N H R R O PPA, 160C, 30m -7h N RS (Method IC) - I : Major product + Ic, id, le : Minor products pTsOH, xylene reflux, 3-16h (Method 1D) R HN N NH R H R, O - R, {with R=NH 2 ) ~0
HO
2 CjN N Id (with R=CO 2 H) Br NH I F-&NH 2 le (with R=Br) Method 1A (Compounds I) 2-Phenylbenzo[d]oxazol-5-amine To polyphosphoric acid at 110 C were added simultaneously 2,4-diaminophenol dihydrochloride (7.88g, 40mmol) and benzoic acid (4.88g, 40mmol). The resulting mixture was then heated to 1800C for 3h. The solution was then poured into water. The resulting precipitate was collected by filtration and washed with saturated sodium bicarbonate solution. The crude product was recrystallised from ethanol/water to afford 8.15g (97/o) of the title compound (LCMS RT= 5.17min, MH* 211 1) 'H NMR (DMSO): 8,15-8.12 (2H, m), 7.60-7.56 (3H, m), 7.42 (1H, d, J 8.7 Hz), 6.89 (1H, d, J 2.1 Hz), 6.68 (1H, dd, J 8.6 2.2 Hz), 5.12 (2H, s) All compounds below were prepared following the same general method and purified either by trituration, recrystallisation or column chromatography. 2-(4-(Trifluoromethyl)phenyl)benzo[doxazol-5-amine WO 2009/019504 73 PCT/GB2008/050648 LCMS RT= 8.98min, MH*279.0; "H NMR (DMSO): 8.26 (2H, d, J8.2 Hz), 7.88 (2H, d, J 8.3 Hz), 7.40 (1H, d, J 8.7 Hz), 6.84 (1H, d, J2.1 Hz), 6.66 (1H, dd, J8.8 2.2 Hz), 5.13 (2H, s) 2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-amine LCMS RT= 8.98min, MH* 282.2; "H NMR (DMSO): 7.89 (2H, d, J9.1 Hz), 7.30 (1H, d, J 8.5 Hz), 6.80-6.76 (3H, m), 6.54 (1H, dd, J 8.8 2.2 Hz), 4.99 (2H, s), 3.42 (2H, q, J 7.1 Hz), 1. 14 (3H, q, J 7.1 Hz) 2-(Pyridin-3-yl)benzo[d]oxazol-5-amine LCMS RT= 6.42min, MH*212.2; "H NMR (DMSO): 9.29 (1H, d, J 1.9 Hz), 8.77 (1H, dd, J 4.8 1.4 Hz), 8.48-8.44 (1 H, in), 7.62 (1 H; dd, J 9.0 4.8 Hz), 7.46 (1 H, d, J 8.8 Hz), 6.91 (1H, d, J 2.0 Hz), 6.71 (1H, dd, J 8.7 2.1 Hz), 5.18 (2H, s) 2-(5-Nitrobenzo[d]oxazol-2-yl)phenol LCMS RT= 6.94min; 'H NMR (DMSO): 10.91 (1H, s), 8.74 (1H, d, J 2.3 Hz), 8.37 (1H, dd, J9.0 2.4 Hz), 8.11-8.04 (2H, m), 7.60-7.55 (1H, m), 7.18-7.08 (2H, m) 2-(5-Aminobenzo[d]oxazol-2-yl)phenol LCMS RT= 6.08min, MH* 227.2; "H NMR (DMSO): 11.46 (1H, s), 8.02 (1H, dd, J7.8 1.6 Hz), 7.58-7.53 (2H, m), 7.18-7.10 (2H, m), 6.96 (1H, d, J 2.1 Hz), 6.77 (1H, dd, J 8.7 2.2 Hz), 5.29 (2H, s) 3-(5-Propylbenzo[d]oxazol-2-yl)benzoic acid LCMS RT= 4.58min, MH t 282.1; "H NMR (DMSO): 13.44 (1H, s), 8.78 (1H, s), 8.47 (1H, d, J 8.0 Hz), 8.22 (1H, d, J 8.4 Hz), 7.84-7.74 (2H, m), 7.70 (1H, s), 7.35 (1H, d, J 9.0 Hz), 2.78-2.73 (2H, m), 1.71 (2H, q, J 7.6 Hz), 0.98 (3H, d, J 7.2 Hz) 5-Amino-2-(5-aminobenzo[d]oxazol-2-yl)phenol LCMS RT= 5.24min, MH* 242.2; "H NMR (DMSO): 11.40 (1 H, s), 7.63 (1 H, d, J 8.6 Hz), 7.40 (1H, d, J 8.7 Hz), 6.83 (1H, d, J 2.1 Hz), 6.63 (1H, dd, J 8.6 2.3 Hz), 6.31 (1H, d, J8.4 2.2 Hz), 6.22 (1H, d, J 1.9 Hz), 6.05 (2H, s), 5.15 (2H, s) 5-(Ethylsulfonyl)-2-phenylbenzo[d]oxazole LCMS RT= 5.94min, MH* 288.1; "H NMR (DMSO): 8.32 (1H, d, J 1.3 Hz), 8.26 (2H, dd, J6.4 1.6 Hz), 8.10 (1H, d, J 8.5 Hz), 7.97 (1H, dcd, J 8.5 1.7 Hz), 7.72-7.64 (3H, m), 3.43-3.38 (2H, m), 1.14 (3H, t, J 7.4 Hz) 2,5-Diphenylbenzo[d]oxazole LCMS RT= 9.41min, MH* 271.9; 'H NMR (DMSO): 8.26-8.23 (2H, m), 8.08 (1H, d, J 1.3 Hz), 7.89 (1H, d, J 8.5 Hz), 7.77-7.72 (3H, m), 7.68-7.61 (3H, m), 7.51 (2H, t, J 7.7 Hz), 7.43-7.38 (1H, m) 2-Phenylnaphtho[1,2-d]oxazole LCMS RT= 8.75min, MH* 246.2; "H NMR (DMSO): 8.48 (1H, d, J8.1 Hz), 8.32-8.27 (2H, m), 8.14 (1H, d, J 8.1 Hz), 8.01 (2H, s), 7.78-7.72 (1H, m), 7.68-7.60 (4H, m) WO 2009/019504 74 PCT/GB2008/050648 2-Phenylbenzo[d]oxazole-5-carboxylic acid LCMS RT= 4.41min, MH*240.1; 'H NMR (DMSO): 13.00 (1H, br), 8.33 (1Hdd, J1.6 0.5 Hz), 8.26-8.23 (2H, m), 8.06 (1H, dd, J 8.6 1.7 Hz), 7.91 (1H, dd, J 8.5 0.5 Hz), 7.72-7.62 (3H, m) 2-(4-Propylphenyl)benzo[d]oxazole-5-carboxylic acid 1 H NMR (DMSO): 13.10 (1H, br), 8.30 (1H, dd, J 1.5 0.4 Hz), 8.15 (2H, d, J8.3 Hz), 8.04 (1H, dd, J 8.6 1.7 Hz), 7.88 (1H, d, J 8.5 Hz), 7.47 (2H, d, J 8.4 Hz), 2.68 (2H, t, J 8.0 Hz), 1.70-1.62 (2H, m), 0.93 (3H, t, J 7.5 Hz) 2-(4-Propylphenyl)benzo[d]oxazole-6-carboxylic acid 'H NMR (DMSO): 13.10 (1H, br), 8.27 (1H, dd, J 1.5 0.5 Hz), 8.16 (2H, d, J 8.3 Hz), 8.02 (1 H, dd, J 8.3 1.5 Hz), 7.88 (1 H, dd, J 8.3 0.5 Hz), 7.48 (2H, d, J 8.4 Hz), 2.68 (2H, t, J 8.0 Hz), 1.72-1.58 (2H, m), 0.93 (3H, t, J7.5 Hz) 5-Chloro-2-phenylbenzo[d]oxazole LCMS RT= 8.61min, MH* 230.1; 'H NMR (DMSO): 8.21 (2H, dd, J 7.6 1.4 Hz), 7.94 (1H, d, J 2.1 Hz), 7.86 (1H, d, J 8.7 Hz), 7.72-7.60 (3H, m), 7.49 (1H, dd, J 8.7 2,1 Hz) 6-Chloro-2-phenylbenzo[d]oxazole LCMS RT= 9.00min, MH t 230.1; 'H NMR (DMSO): 8.22-8.18 (2H, m), 8.02 (1H, d, J 1.9 Hz), 7.84 (1H, d, J 8.5 Hz), 7.70-7.60 (3H, m), 7.48 (1H, dd, J 8.5 2.0 Hz) 5-Tert-butyl-2-phenylbenzo[d]oxazole LCMS RT= 9.82min, MH*252.0; 'H NMR (DMSO): 7.72-7.70 (4H, m), 7.59 (2H, dt, J 7.6 1.0 Hz), 7.46-7.40 (2H, m), 1.38 (9H, s) 6-Nitro-2-phenylbenzo[d]oxazole LCMS RT= 7.30min; 'H NMR (DMSO): 8.77-8.76 (1 H, m), 8.34 (1 H, d, J 8.8 Hz), 8.27 (2H, d, J 7.7 Hz), 8.05 (1 H, d, J 8.8 Hz), 7.80-7.65 (3H, m) 4-(5-Chlorobenzo[d]oxazol-2-y)-N,N-diethylaniline LCMS RT= 10.17min, MH*301.1; 1 H NMR (DMSO): 8.03 (2H, d, J 8.9 Hz), 7.82-7.76 (2H, m), 7.40 (1 H, dd, J 8.6 2.0 Hz), 6.89 (2H, d, J 8.9 Hz) 4-(6-Chlorobenzo[d]oxazol-2-y)-N,N-diethylaniline LCMS RT= 10.28min, MH* 301.0; 'H NMR (DMSO): 7.95 (2H, d, J9.1 Hz), 7.87 (1H, d, J 1.7 Hz), 7.67 (1H, d, J 8.4 Hz), 7.38 (1H, dd, J 8.4 2.1 Hz), 6.83 (2H, d, J9.1 Hz), 3.45 (4H, q, J 7.2 Hz), 1.15 (6H, t, J7.1 Hz) 4-(5-Tert-butylbenzo[d]oxazol-2-y)-N,N-diethylaniline LCMS RT= 13.81min, MH*323.2; 1 H NMR (DMSO): 7.94 (2H, d, J9.3 Hz), 7.66 (1H, d, J1.5 Hz), 7.58 (1H, d, J 8.6 Hz), 7.36 (1H, dd, J8.6 1.9 Hz), 6.82 (2H, d, J9.2 Hz), 3.44 (4H, q, J 7.0 Hz), 1.35 (9H, s), 1.15 (6H, t, J 7.1 Hz) WO 2009/019504 75 PCT/GB2008/050648 4-(Benzo[d]oxazol-2-yl)-N,N-diethylaniline LCMS RT= 10.50min, MH 4 267.0; 'H NMR (DMSO): 7.97 (2H, d, J9.1 Hz), 7.71-7.64 (2H, m), 7.36-7.30 (2H, m), 6.82 (2H, d, J9.2 Hz), 3.44 (4H, q, J7.0 Hz), 1.15 (6H, t, J7.1 Hz) N,N-Diethyl-4-(5-(ethylsulfonyl)benzo[d]oxazol-2-yl)aniline LCMS RT= 7.45min, MH* 358.9; 'H NMR (DMSO): 8.13 (1 H, dd, J 1.3 0.4 Hz), 8.00 (2H, d, J 9.1 Hz), 7.95 (1H, dd, J 8.1 0.4 Hz), 7.83 (1H, dd, J 8.4 1.8 Hz), 6.85 (2H, d, J9.2 Hz), 3.50-3.39 (6H, m), 1.23-1.04 (9H, m) N,N-Diethyl-4-(5-phenylbenzo[d]oxazol-2-yl)aniline LCMS RT= 15.22min, MH*343.1; 1 H NMR (DMSO): 7.99 (2H, d, J 8.9 Hz), 7.93 (1H, s), 7.77-7.71 (3H, m), 7.60 (1H, d, J 8.3 Hz), 7.52-7.46 (2H, m), 7.40-7.35 (1H, m), 6.84 (2H, d, J 9.0 Hz), 3.44 (4H, q, J 7.0 Hz), 1.15 (6H, t, J 7.1 Hz) N,N-Diethyl-4-(naphtho[1,2-d]oxazol-2-yl)aniline LCMS RT= 11.21min, MH t 317.1; 'H NMR (DMSO): 8.41 (1H, d, J 8.3 Hz), 8.12-8.02 (3H, m), 7.94-7.86 (2H, m), 7.72-7.66 (1H, m), 7.60-7.55 (1H, m), 6.85 (2H, d, J9.0 Hz), 3.44 (4H, q, J7.0 Hz), 1.15 (6H, t, J 7.1 Hz) 2-(Pyridin-2-yl)benzo[d]oxazole LCMS RT= 5.68min, MH* 197.0; 'H NMR (DMSO): 8.87 (1 H, d, J 4.4 Hz), 8.41 (1 H, d, J8.0 Hz), 8.14 (1H, dt, J7.8 1.5 Hz), 7.93 (2H, t, J7.4 Hz), 7.73-7.69 (1H, m), 7.60-7.50 (2H, m) 2-(4-(Piperidin-1 -yl)phenyl)benzo[d]oxazol-5-amine LCMS RT= 6.95min, MH* 206.1; 'H NMR (DMSO): 7.92 (2H, d, J9.0 Hz), 7.32 (1H, d, J 9.0 Hz), 7.05 (2H, d, J 9.0 Hz), 6.80 (1 H, d, J 2.1 Hz), 6.58 (1 H, dd, J 8.0 2.0 Hz), 5.01 (2H, s), 1.60 (6H, m) 2-(4-(4-Methylpiperazin-1 -yI)phenyl)benzo[d]oxazol-5-amine LCMS RT= 5.34min, MH* 309.1; 'H NMR (DMSO): 7.94 (2H, d, J9.0 Hz), 7.33 (1H, d, J9.0 Hz), 7.08 (2H, d, J9.0 Hz), 6.80 (1H, d, J2.1 Hz), 6.58 (1H, dd, J8.0 2.0 Hz), 5.03 (2H, s), 2.60-2.57 (4H, m), 2.45-2.42 (4H, m), 2.23 (3H, s) 2-(4-(Diethylamino)phenyl)benzo[d]oxazole-5-carboxylic acid 'H NMR (DMSO): 13.00 (1H, br), 8.17 (1H, d, J 1.5 Hz), 7.99 (2H, d, J9.0 Hz), 7.94 (1 H, dd, J 8.5 1.7 Hz), 7.77 (1 H, d, J 8.4 Hz), 6.84 (2H, d, J 9.1 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J7.0 Hz) 2-Propylbenzo[d]oxazol-5-amine LCMS RT= 6.81min, MH* 177.2; 'H NMR (DMSO): 7.26 (1H, d, J 8.6 Hz), 6.76 (1H, d, J 2.2 Hz), 6.57 (1H, dd, J 8.6 2.2 Hz), 4.98 (2H, s), 2.80 (2H, t, J7.3 Hz), 1.81-1.70 (2H, m), 0.96 (3H, t, J7.4 Hz) 2-p-Tolyloxazolo[5,4-b]pyridine WO 2009/019504 76 PCT/GB2008/050648 LCMS RT= 6.72min, MH*211.1; 'H NMR (DMSO): 8.38 (1H, dd, J5.0 1.5 Hz), 8.26 (1H, dd, J 7.9 1.6 Hz), 8.14 (2H, d, J 8.2 Hz), 7.53-7.45 (3H, m), 2.44 (3H, s) 2-p-Tolyloxazolo[4,5-b]pyridine LCMS RT= 6.12min, MH*211.1; 1 H NMR (DMSO): 8.54 (1H, dd, J 4.9 1.4 Hz), 8.23 (1H, dd, J8.2 1.4 Hz), 8.16 (2H, d, J8.2 Hz), 7.59-7.44 (3H, m), 2.44 (3H, s) 2-(4-Morpholinophenyl)benzo[d]oxazol-5-amine LCMS RT= 5.52min, MH* 295.8; 'H NMR (DMSO): 7.97 (2H, d, J 9.0 Hz), 7.33 (1 H, d, J9.0 Hz), 7.09 (2H, d, J9.0 Hz), 6.81 (1H, d, J2.1 Hz), 6.59 (1H, dd, J8.0 2.0 Hz), 5.04 (2H, s), 3.77-3.74 (4H, m), 3.29-3.24 (4H, m) 5-Phenyl-2-p-tolylbenzo[d]oxazole LCMS RT= 10.00min, MH* 286.1; 'H NMR (DMSO): 8.12 (2H, d, J 8.5 Hz), 8.06 (1H, d, J 1.8 Hz), 7.86 (1H, d, J 8.6 Hz), 7.77-7.70 (3H, m), 7.53-7.37 (5H, m), 2.43 (3H, s) 2-(4-Chlorophenyl)-5-phenylbenzo[djoxazole LCMS RT= 10.54min, MH* 306.0; 'H NMR (DMSO): 8.24 (2H, d, J 8.6 Hz), 8.09 (1H, d, J 1.8 Hz), 7.89 (1 H, d, J 8.6 Hz), 7.77-7.70 (5H, m), 7.53-7.34 (3H, m) 2-Cyclohexyl-5-nitrobenzo[d]oxazole LCMS RT= 7.90min, MH*247.3; 'H NMR (CDC 3 ): 8.62 (1H, d, J2.2 Hz), 8.33 (1H, dd, J 8.9 2.3 Hz), 7.63 (1H, d, J 8.9 Hz), 3.11-3.01 (1H, m), 2.27-2.21 (2H, m), 1.98 1.92 (2H, m), 1.84-1.71 (3H, m), 1.57-1.37 (3H, m) 5-Tert-butyl-2-p-tolylbenzo[d]oxazole LCMS RT= 10.53min, MH*266.1; H NMR (DMSO): 8.08 (2H, d, J 8.2 Hz), 7.78 (1H, d, J 1.6 Hz), 7.68 (1H, d, J 8.6 Hz), 7.48 (1 H, dd, J 8.7 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 1.37 (9H, s) 2-p-Tolylbenzo[d]oxazole LCMS RT= 7.82min, MH+210.1; 1 H NMR (DMSO): 8.11 (2H, d, J8.2 Hz), 7.81-7.76 (2H, m), 7.46-7.40 (4H, m), 2.42 (3H, s) 2-(3-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-amine LCMS RT= 6.39min, MH* 279.0; 'H NMR (DMSO): 8.41 (1H, d, J8.0 Hz), 8.37 (1H, s), 7.98 (1H, d, J 8.0 Hz), 7.84 (1H, t, J 8.0 Hz), 7.46 (1H, d, J 8.9 Hz), 6.91 (1H, d, J 1.9 Hz), 6.72 (1H, d, J 8.6 2.0 Hz), 5.18 (2H, s) 5-(Ethylsulfonyl)-2-p-tolylbenzo[d]oxazole LCMS RT= 6.46min, MH* 302.0; 'H NMR (DMSO): 8.28 (1H, d, J 1.6 Hz), 8.14 (2H, d, J 8.2 Hz), 8.06 (1H, d, J 8.6 Hz), 7.94 (1H, dd, J 8.6 1.7 Hz), 7.47 (2H, d, J 8.1 Hz), 3.42-3.34 (2H, m), 2.44 (3H, s), 1.12 (3H, t, J7.3 Hz) 2-(4-Chlorophenyl)-5-(ethylsulfonyl)benzo[d]oxazole WO 2009/019504 77 PCT/GB2008/050648 LCMS RT= 6.63min, MH*322.1; 'H NMR (CDCl 3 ): 8.39 (1H, d, J 1.7 Hz), 8.27 (2H, d, J 8.7 Hz), 8.00 (1H, dd, J 8.5 1.8 Hz), 7.80 (1H, d, J 8.5 Hz), 7.60 (2H, d, J 8.6 Hz), 3.23 (2H, q, J 7.6 Hz), 1.36 (3H, t, J 7.4 Hz) 4-Nitro-2-p-tolylbenzold]oxazole LCMS RT= 6.97min, MH*255.0; "H NMR (DMSO): 8.27 (1H, dd, J 8.1 0.8 Hz), 8.23 (1H, dd, J8.2 0.8 Hz), 8.18 (2H, d, J8.2 Hz), 7.65 (1H, t, J8.2 Hz), 7.49 (2H, d, J8.0 Hz), 2.45 (3H, s) 6-Nitro-2-p-tolylbenzo[d]oxazole LCMS RT= 7.83min, MH* 255.0; "H NMR (DMSO): 8.74 (1H, d, J 2.2 Hz), 8.33 (1H, dd, J 8.7 2.2 Hz), 8.17 (2H, d, J 8.2 Hz), 8.02 (1H, d, J 8.8 Hz), 7.49 (2H, d, J7.9 Hz), 2.45 (3H, s) 2-(4-Chlorophenyl)-6-nitrobenzo[d]oxazole LCMS RT= 7.76min; 'H NMR (DMSO): 8.77 (1H, d, J 2.2 Hz), 8.35 (1 H, dd, J 8.7 2.2 Hz), 8.27 (2H, d, J 8.2 Hz), 8.06 (1 H, d, J 8.8 Hz), 7.76 (2H, d, J 7.9 Hz) 2-p-Tolyloxazolo[4,5-c]pyridine LCMS RT= 6.24min, MH*211.0; "H NMR (DMSO): 9.11 (1H, d, J0.9 Hz), 8.59 (1H, d, J 5.6 Hz), 8.14 (2H, d, J 8.2 Hz), 7.90 (1 H, dd, J 5.6 1.0 Hz), 7.47 (2H, d, J 8.0 Hz), 2.44 (3H, s) 2-m-Tolylbenzo[d]oxazol-5-amine LCMS RT= 6.18min, MH*225.0; 'H NMR (DMSO): 7.97-7.91 (2H, m), 7.50-7.39 (3H, m), 6.87 (1H, d, J 2.0 Hz), 6.67 (1H, dd, J 8.7 2.2 Hz), 5.11 (2H, s), 2.42 (3H, s) 2-(3-(Dimethylamino)phenyl)benzo[d]oxazol-5-amine LCMS RT= 6.12min, MH*254.0; 'H NMR (DMSO): 7.48-7.31 (4H, m), 6.96-6.92 (1H, m), 6.87 (1H, d, J 2.2 Hz), 6.66 (1H, dd, J 8.6 2.2 Hz), 5.09 (2H, s), 3.00 (6H, s) 5-Bromo-2-p-tolylbenzo[d]oxazole LCMS RT= 9.41min, MH* 289.8; 'H NMR (DMSO): 8.10 (2H, d, J 8.2 Hz), 8.04 (1H, d, J 1.9 Hz), 7.78 (1H, d, J 8.6 Hz), 7.58 (1H, dd, J 8.7 2.0 Hz), 7.45 (2H, d, J 8,0 Hz), 2.43 (3H, s) 2-o-Tolylbenzo[d]oxazol-5-amine LCMS RT= 6.16min, MH 225.0; 'H NMR (DMSO): 8.05 (1H, d, J 7.7 Hz), 7.53-7.37 (4H, m), 6.90 (1H, d, J2.2 Hz), 6.68 (1H, dd, J8.7 2.2 Hz), 5.10 (2H, s), 2.71 (3H, s) 2-(2-Chlorophenyl)benzo[d]oxazol-5-amine LCMS RT= 4.31 min, MH* 245.0; 1H NMR (DMSO): 8.10 (1H, d, J 7.3 Hz), 7.75-7.52 (3H, m), 7.45 (1H, d, J 8.6 Hz), 6.92 (1H, d, J 1.6 Hz), 6.73 (1H, dd, J 8.8 2.1 Hz), 5.16 (2H, s) 6-Bromo-2-p-tolyloxazolo[5,4-b]pyridine WO 2009/019504 78 PCT/GB2008/050648 LCMS RT= 8.40min, MH* 288.8; 'H NMR (DMSO): 8.59 (1H, d, J2.1 Hz), 8.50 (1H, d, J 2.2 Hz), 8.13 (2H, d, J 8.2 Hz), 7.48 (2H, d, J 8.0 Hz) 5,6-Dimethyl-2-p-tolylbenzo[d]oxazole LCMS RT= 8.76min, MH* 238.0; 'H NMR (DMSO): 8.06 (2H, d, J 8.2 Hz), 7.56 (2H, s), 7.41 (2H, d, J 8.2 Hz), 2.41 (3H, s), 2.35 (3H, s), 2.33 (3H, s) 2-(4-Chlorophenyl)-5,6-dimethylbenzo[d]oxazole LCMS RT= 9.07min, MH 4 258.0; 1H NMR (DMSO): 8.19 (2H, d, J 8.6 Hz), 7.69 (2H, d, J 8.6 Hz), 7.60 (2H, s), 2.38 (3H, s), 2.36 (3H, s) 2-(2,4-Dichlorophenyl)-5,6-dimethylbenzo[d]oxazole LCMS RT= 9.68min, MH* 291.9; "H NMR (DMSO): 8.16 (1H, d, J8.5 Hz), 7.90 (1H, d, J 2.1 Hz), 7.69-7.61 (3H, m), 2.38 (3H, s), 2.36 (3H, s) 2-(3-Fluorophenyl)benzo[d]oxazol-5-amine LCMS RT= 9.45min, MH* 229.1; "H NMR (DMSO): 7.98 (1H, d, J 8.0 Hz), 7.89-7.84 (1H, m), 7.68-7.60 (1H, m), 7.48-7.42 (2H, m), 6.89 (1H, d, J 2.1 Hz), 6.71 (1H, dd, J 8.7 2.2 Hz), 5.15 (2H, s) 2-(5-Butylpyridin-2-yI)-6-nitrobenzo[d]oxazole LCMS RT= 7.34min, MH* 298.0; 'H NMR (DMSO): 8.81 (1H, d, J2.1 Hz), 8.71 (1H, d, J 1.5 Hz), 8.37-8.32 (2H, m), 8.08 (1H, d, J 8.8 Hz), 7.95 (1H, dd, J 8.1 2.1 Hz), 2.75 (2H, t, J7.6 Hz), 1.70-1.59 (2H, m), 1.41-1.29 (2H, m), 0.93 (3H, t, J7.3 Hz) 2-(4-Chlorophenyl)-5-(isopropylsulfonyl)benzo[d]oxazole LCMS RT= 6.98min; 'H NMR (DMSO): 8.29-8.24 (3H, m), 8.09 (1 H, d, J 8.6 Hz), 7.94 (1H, dd, J 8.6 1.7 Hz), 7.74 (2H, d, J 8.6 Hz), 3.56-3.50 (1H, m), 1.19 (6H, d, J 6.8 Hz) 5-Bromo-2-(4-chlorophenyl)benzo[d]oxazole LCMS RT= 9.09min, MH* 307.9; 1 H NMR (DMSO): 8.21 (2H, d, J 8.7 Hz), 8.08 (1H, d, J 1.9 Hz), 7.80 (1 H, d, J 8.7 Hz), 7.71 (2H, d, J 8.7 Hz), 7.62 (1 H, dd, J 8.7 2.0 Hz) 4-(5-Chlorobenzo[d]oxazol-2-yl)aniline LCMS RT= 6.48min, MH* 244.9; "H NMR (DMSO): 7.86 (2H, d, J8.5 Hz), 7.74 (1H, d, J2.1 Hz), 7.70 (1H, d, J 8.6 Hz), 7.34 (1H, dd, J 8.8 2.1 Hz), 6.70 (2H, d, J 8.7 Hz), 6.06 (2H, s) 4-(6-Chlorobenzo[d]oxazol-2-yl)aniline LCMS RT= 6.57min, MH* 245.0; 'H NMR (DMSO): 7.87-7.82 (3H, m), 7.66 (1H, d, J 8.5 Hz), 7.37 (1H, dd, J8.7 2.0 Hz), 6.70 (2H, d, J8.8 Hz), 6.04 (2H, s) 2-(3-Chlorophenyl)-5-(ethylsulfonyl)benzo[djoxazole WO 2009/019504 79 PCT/GB2008/050648 LCMS RT= 6.78min; 'H NMR (DMSO): 8.34 (1H, d, J 1.3 Hz), 8.23-8.20 (2H, m), 8.10 (1H, d, J 8.6 Hz), 7.99 (1H, dd, J 8.6 1.8 Hz), 7.80-7.76 (1H, m), 7.72-7.67 (1H, m), 3.40 (2H, q, J 7.3 Hz), 1.13 (3H, t, J 7.3 Hz) 2-(2-Chlorophenyl)-5-(ethylsulfonyl)benzo(d]oxazole LCMS RT= 6.37min; 'H NMR (DMSO): 8.39 (1H, d, J 1.6 Hz), 8.20 (1H, dd, J7.6 1.7 Hz), 8.12 (1H, d, J8.6 Hz), 8.01 (1H, dd, J 8.6 1.8 Hz), 7.78-7.60 (3H, m), 1.14 (3H, t, J7.3 Hz) 2-( 3,4-Dichlorophenyl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 7.25min; "H NMR (DMSO): 8.39 (1H, d, J 2.0 Hz), 8.35 (1H, d, J 1.4 Hz), 8.19 (1H, dd, J 8.4 2.0 Hz), 8.10 (1H, d, J 8.6 Hz), 7.99 (1H, dd, J 8.6 1.8 Hz), 7.94 (1H, d, J 8.4 Hz), 3.41 (2H, q, J7.3 Hz), 1.13 (3H, t, JI7.3 Hz) 2-(2,3-Dichlorophenyl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 6.80min; 'H NMR (DMSO): 8.42 (1H, d, J 1.8 0.6 Hz), 8.17-8.13 (2H, m), 8.05-7.96 (2H, m), 7.65 (1H, t, J 8.0 Hz), 3.41 (2H, q, J7.3 Hz), 1.14 (3H, t, J7.3 Hz) 2-(1 -Phenylethyl)benzo[d]oxazol-5-amine LCMS RT= 5.80min, MH 239.0; "H NMR (DMSO): 7.35-7.23 (6H, m), 6.80 (1H, d, J 2.1 Hz), 6.57 (1H, dd, J 8.6 2.2 Hz), 5.02 (2H, s), 4.42 (1H, q, J7.1 Hz), 1.66 (3H, d, J7.2 Hz) 2-(4-Chlorophenyl)benzo[d]oxazole-5-sulfonic acid LCMS RT= 4.44min, MH*309.9; "H NMR (DMSO): 8.28 (2H, d, J 8.7 Hz), 8.03 (1H, s), 7.83-7.73 (4H, m) 5-Chloro-2-(pyridin-4-yl)benzo[d]oxazole LCMS RT= 6.51min, MH*231.0; 'H NMR (DMSO): 8.87 (2H, d, J 8.6 Hz), 8.11 (2H, d, J 6.1 Hz), 8.04 (1H, d, J 1.8 Hz), 7.92 (1H, d, J 8.8 Hz), 7.57 (1H, dd, J 8.7 2.1 Hz) 6-Chloro-2-(pyridin-4-yI)benzo[d]oxazole LCMS RT= 6.49min, MH* 231.0; "H NMR (DMSO): 8.87 (2H, d, J 6.1 Hz), 8.10-8.08 (3H, m), 7.93 (1H, d, J 8.6 Hz), 7.54 (1H, dd, J 8.6 2.0 Hz) 4-(5-Bromobenzo[djoxazol-2-yl)aniline LCMS RT= 6.70min, MH*289.2; 'H NMR (DMSO): 7.88-7.83 (3H, m), 7.66 (1H, d, J 8.6 Hz), 7.46 (1 H, dd, J 8.6 2.1 Hz), 6.69 (2H, d, J 8.8 Hz), 6.09 (2H, s) 2-(4-Chlorophenyl)-5-(methylsulfonyl)benzo[d]oxazole LCMS RT= 6.43min, MH* 308.2; "H NMR (CDC1 3 ): 8.43 (1H, dd, J 1.8 0.3 Hz), 8.28 (2H, d, J 8.7 Hz), 8.05 (1 H, dd, J 8.6 1.9 Hz), 7.81 (1H, dd, J 8.5 0.4 Hz), 7.61 (2H, d, J 8.8 Hz), 3.18 (3H, s) 2-(4-Chlorophenyl)-5-(propylsulfonyl)benzo[d]oxazole WO 2009/019504 80 PCT/GB2008/050648 LCMS RT= 7.O9min, MH*335.9; 'H NMR (CDC 3 ): 8.38 (1 H, dd, J 1.7 0.4 Hz), 8.27 (2H, d, J 8.8 Hz), 8.00 (1H, dd, J 8.5 1.8 Hz), 7.80 (1H, dd, J 8.5 0.4 Hz), 7.60 (2H, d, J 8.8 Hz), 3.21-3.15 (2H, m), 1.89-1.76 (2H, in), 1.05 (3H, t, J7.4 Hz) 2-(Naphthalen-1 -yI)benzo[d]oxazol-5-amine LCMS RT= 6.59min, MH t 261.1; 'H NMR (DMSO): 9.41 (1H, d, J 8.6 Hz), 8.38 (1H, dd, J 7.3 1.0 Hz), 8.19 (1H, d, J 8.2 Hz), 8.09 (1H, dd, J7.8 0.9 Hz), 7.79-7.64 (3H, m), 7.49 (1H, d, J 8.7 Hz), 6.99 (1H, d, J2.1 Hz), 6.74 (1H, d, J 8.7 2.2 Hz), 5.17 (2H, s) 2-(Biphenyl-4-yl)benzo[d]oxazol-5-amine LCMS RT= 6.92min, MH* 287.1; 'H NMR (DMSO): 8.22 (2H, d, J 8.2 Hz), 7.90 (2H, d, J 8.3 Hz), 7.81-7.76 (2H, m), 7.53 (2H, t, J7.8 Hz), 7.47-7.41 (2H, m), 6.90 (1H, d, J 2.2 Hz), 6.69 (1 H, d, J 8.6 2.2 Hz), 5.14 (2H, s) 2-(Quinolin-2-yl)benzo[d]oxazol-5-amine LCMS RT= 5.78min, MH* 262.1; 'H NMR (DMSO): 8.60 (1H, d, J8.7 Hz), 8.39 (1H, d, J 8.6 Hz), 8.19 (1H, dd, J 8.3 0.5 Hz), 8.10 (1H, dd, J 8.4 0.8 Hz), 7.92-7.86 (1H, m), 7.76-7.70 (1H, m), 7.56 (1H, d, J 8.7 Hz), 6.97 (1H, d, J 2.1 Hz), 6.79 (1H, dd, J 8.7 2.2 Hz), 5.22 (2H, s) 2-(Quinolin-3-yl)benzo[d]oxazol-5-amine LCMS RT= 5.76min, MH* 262.1; 'H NMR (DMSO): 9.58 (1H, d, J 2.1 Hz), 8.14 (1H, d, J 2.0 Hz), 8.24 (1H, dd, J7.8 0.8 Hz), 8.13 (1H, d, J 8.3 Hz), 7.93-7.88 (1H, m), 7.74 (1 H, td, J 8.0 0.9 Hz), 7.49 (1H, d, J 8.6 Hz), 6.95 (1H, d, J 2.1 Hz), 6.74 (1H, dd, J 8.7 2.2 Hz), 5.20 (2H, s) 2-(6-Methoxynaphthalen-2-yl)benzo[d]oxazol-5-amine LCMS RT= 6.56min, MH 291.1; 'H NMR (DMSO): 8.67 (1H, d, J 1.3 Hz), 8.16 (1H, dd, J 8.6 1.7 Hz), 8.07 (1H, d, J9.1 Hz), 7.99 (1H, d, J 8.8 Hz), 7.45-7.42 (2H, m), 7.27 (1H, dd, J 8.7 2.5 Hz), 6.90 (1H, d, J 2.0 Hz), 6.68 (1H, dd, J 8.6 2.2 Hz), 5.12 (2H, s), 3.92 (3H, s) 2-(6-Bromonaphthalen-2-yl)benzo[d]oxazol-5-amine LCMS RT= 7.59min, MH 339.3; 'H NMR (DMSO): 8.78 (1H, s), 8.34 (1H, d, J 1.7 Hz), 8.26 (1H, d, J 8.6 1.6 Hz), 8.14 (1H, d, J 8.9 Hz), 8.09 (1H, d, J 8.7 Hz), 7.76 (1 H, dd, J 8.9 2.0 Hz), 7.46 (1 H, d, J 8.7 Hz), 6.92 (1 H, d, J 2.2 Hz), 6.72 (1 H, dd, J 8.6 2.2 Hz), 5.16 (2H, s) 2-(4-Chlorophenyl)naphtho[1,2-d]oxazole LCMS RT= 9.55min, MH 4 280.1; 'H NMR (DMSO): 8.47 (1H, dd, J 8.2 0.6 Hz), 8.29 (2H, d, J 8.7 Hz), 8.17-8.13 (1H, m), 8.02 (2H, s), 7.78-7.70 (3H, m), 7.67-7.61 (1H, m) WO 2009/019504 81 PCT/GB2008/050648 1-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)propan-I -one LCMS RT= 7.92min, MH 4 286.1; "H NMR (DMSO): 8.44 (1H, dd, J1.7 0.4 Hz), 8.24 (2H, d, J 8.7 Hz), 8.09 (1 H, dd, J 8.6 1.7 Hz), 7.93 (1 H, dd, J 8.6 0.4 Hz), 7.73 (2H, d, J 8.8 Hz), 3.17 (2H, q, J7.2 Hz), 1.13 (3H, t, J7.1 Hz) 1-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)ethanone LCMS RT= 7.27min, MH*271.7; "H NMR (DMSO): 8.44 (1H, dd, J 1.7 0.4 Hz), 8.24 (2H, d, J 8.8 Hz), 8.08 (1H, dd, J 8.6 1.7 Hz), 7.93 (1H, dd, J 8.5 0.5 Hz), 7.73 (2H, d, J 8.8 Hz), 2.69 (3H, s) 2-(4-Cyclohexylphenyl)benzo[d] oxazol-5-am ine LCMS RT= 8.15min, MH*293.1; "H NMR (DMSO): 8.05 (2H, d, J 8.4 Hz), 7.45-7.38 (3H, m), 6.86 (1H, d, J 2.0 Hz), 6.65 (1H, dd, J 8.8 2.2 Hz), 5.10 (2H, s), 2.64-2.56 (1H, m), 1.83-1.70 (5H, m), 1.51-1.23 (5H, m) 5-(Ethylsulfonyl)-2-(quinolin-2-yl)benzo[d]oxazole LCMS RT= 6.14min, MH* 339.1; "H NMR (DMSO): 8.69 (1H, dd, J 8.5 2.2 Hz), 8.52 8.43 (2H, m), 8.28-8.21 (2H, m), 8.16 (1H, d, J 8.1 Hz), 8.09-8.04 (1H, m), 7.97-7.90 (1H, m), 7.82-7.76 (1H, m), 3.48-3.38 (2H, m), 1.15 (3H, td, J7.3 1.3 Hz) 5-(Ethylsulfonyl)-2-(quinolin-3-yl)benzo[d]oxazole LCMS RT= 6.05min, MH 4 339.1; "H NMR (DMSO): 9.65 (1H, d, J2.1 Hz), 9.31 (1H, d, J2.1 Hz), 8.40 (1H, d, J 1.8 Hz), 8.31 (1H, d, J8.1 Hz), 8.17 (2H, dd, J8.3 2.2 Hz), 8.02 (1 H, dd, J 8.7 1.8 Hz), 8.00-7.93 (1 H, m), 7.82-7.76 (1 H, m), 3.43 (2H, q, J 7.3 Hz), 1.15 (3H, t, J7.5 Hz) 2-(6-Bromonaphthalen-2-yl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 7.86min, MH 418.0; "H NMR (DMSO): 8.95 (1H, m), 8.39-8.33 (3H, m), 8.21 (1H, d, J9.0 Hz), 8.17 (1H, d, J 8.9 Hz), 8.13 (1H, dd, J 8.5 0.5 Hz), 7.99 (1H, dd, J 8.6 1.8 Hz), 7.81 (1H, dd, J 8.7 1.9 Hz), 3.41 (2H, q, J7.3 Hz), 1.15 (3H, t, J7.5 Hz) 2-(4-Cyclohexylphenyl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 8.56min; "H NMR (DMSO): 8.29 (1H, dd, J 1.8 0.4 Hz), 8.17 (2H, d, J 8.3 Hz), 8.07 (1H, dd, J8.6 0.5 Hz), 7.94 (1H, dd, J8.5 1.8 Hz), 7.51 (2H, d, J 8.4 Hz), 3.39 (2H, q, J7.3 Hz), 2.74-2.60 (1H, m), 1.84-1.71 (5H, m), 1.53-1.24 (5H, m), 1.13 (3H, t, J7.5 Hz) 2-(Biphenyl-4-yl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 7.31min, MH* 364.1; "H NMR (DMSO): 8.36-8.32 (3H, m), 8.11 (1H, dd, J 8.6 0.5 Hz), 8.00-7.95 (3H, m), 7.84-7.79 (2H, m), 7.57-7.43 (3H, m), 3.41 (2H, q, J 7.3 Hz), 1.14 (3H, t, J7.5 Hz) 5-(Ethylsulfonyl)-2-(naphthalen-I -yl)benzo[d]oxazole WO 2009/019504 82 PCT/GB2008/050648 LCMS RT=7.03min, MH 4 338.1; 1 H NMR(DMSO): 9.41 (1H, d, J8.8 Hz), 8.52 (1H, dd, J7.2 1.2 Hz), 8.44 (1H, d, J1.7 Hz), 8.30 (1H, d, J8.3 Hz), 8.17-8.12 (2H, m), 8.02 (1H, dd, J 8.6 1.8 Hz), 7.84-7.68 (3H, m), 3.43 (2H, q, J7.3 Hz), 1.15 (3H, t, J 7.5 Hz) 5-(Ethylsulfonyl)-2-(6-fluoronaphthalen-2-yl)benzo[d]oxazole LCMS RT= 7.29min, MH* 356. 1; 'H NMR (DMSO): 8.97 (1H, m), 8.37-8.32 (3H, m), 8.17 (1H, d, J 8.9 Hz), 8.12 (1H, d, J 8.6 Hz), 7.99 (1H, dd, J 8.6 1.6 Hz), 7.89 (1H, dd, J10.0 2.0 Hz), 7.61 (1H, td, J 8.7 2.0 Hz), 3.41 (2H, q, J7.3 Hz), 1.14 (3H, t, J 7.5 Hz) 2-(Benzo[b]thiophen-5-yl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 6.77min, MH*344.1; 'H NMR (CDC 3 ): 8.70 (1H, d, J 1.2 Hz), 8.27 (1H, dd, J 1.8 0.4 Hz), 8.18 (1H, dd, J8.5 1.5 Hz), 7.99 (1H, d, J8.6 Hz), 7.88 (1H, dd, J 8.5 1.8 Hz), 7.70 (1H, dd, J 8.5 0.4 Hz), 7.52 (1H, d, J5.5 Hz), 7.43 (1H, dd, J 5.5 0.6 Hz), 3.12 (2H, q, J7.4 Hz), 1.25 (3H, t, J7.4 Hz) 5-Amino-2-(5,6-dichlorobenzo[d]oxazol-2-yl)phenol LCMS RT= 7.83min, MH 295.1; 'H NMR (DMSO): 10.88 (1H, s), 8.19 (1H, s), 8.06 (IH, s), 7.69 (1H, d, J 8.7 Hz), 6.35 (1H, dd, J 8.7 2.1 Hz), 6.29 (2H, br), 6.24 (1H, d, J 2.1 Hz) 2-(3,4-Dichlorophenyl)-5-(isopropyisulfonyl)benzo[d]oxazole LCMS RT= 7.68min; 1 H NMR (DMSO): 8.41 (1 H, d, J 2.0 Hz), 8.31 (1 H, dd, J 1.8 0.4 Hz), 8.21 (1H, dd, J 8.4 2.0 Hz), 8.11 (1H, dd, J 8.6 0.5 Hz), 7.98-7.93 (2H, m), 3.59 3.50 (1H, m), 1.19 (6H, d, J 6.8 Hz) N-(4-(5,6-Dimethylbenzo[d]oxazol-2-yl)-3-hydroxyphenyl)acetamide LCMS RT= 6.70min, MH* 263.1; 'H NMR (DMSO): 10.83 (1H, s), 8.02 (1H, dd, J9.9 6.9 Hz), 7.85 (1H, dd, J10.4 7.5 Hz), 7.62 (1H, d, J8.6 Hz), 6.29 (1H, dd, J8.7 2.1 Hz), 6.18 (1H, d, J2.0 Hz), 6.15 (2H, br) 4-(5,6-Dichlorobenzo[d]oxazol-2-y)aniline LCMS RT= 7.27min, MH*279.0; 'H NMR (DMSO): 8.10 (1H, s), 7.97 (1H, s), 7.85 (2H, d, J 8.7 Hz), 6.70 (2H, d, J 8.8 Hz), 6.14 (2H, s) 5-(Ethylsulfonyl)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)benzo[d]oxazole LCMS RT= 7.71min, MH*342.2; 'H NMR (CDCIa): 8.03 (1H, dd, J 1.8 0.5 Hz), 7.93 7.87 (2H, m), 7.85 (1H, dd, J 8.5 1.8 Hz), 7.65 (1H, dd, J 8.5 0.5 Hz), 7.23-7.15 (1H, m), 3.11 (2H, q, J 7.4 Hz), 2.85-2.76 (4H, m), 1.81-1.76 (4H, m), 1.24 (3H, t, J7.3 Hz) 5-Amino-2-(5-(ethylsuIfonyl)benzo[d]oxazol-2-yl)phenol LCMS RT= 5.99min, MH*319.2; 'H NMR (DMSO): 10.88 (1H, s), 8.16 (1H, dd, J 1.8 0.5 Hz), 7.97 (1H, dd, J 8.5 0.5 Hz), 7.84 (1H, dd, J 8.4 1.9 Hz), 7.69 (1H, d, J 8.6 WO 2009/019504 83 PCT/GB2008/050648 Hz), 6.31 (1H, dd, J 8.7 2.1 Hz), 6.24 (2H, s), 6.20 (1H, d, J 2.1 Hz), 3.37 (2H, q, J 7.5 Hz), 1.12 (3H, t, J 7.3 Hz) Method 1A (Compounds Ic) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yl)nicotinamide LCMS RT= 4.64min, MH 4 317.1; 'H NMR (DMSO): 10.67 (1H, s), 9.37 (1H, d, J 1.5 Hz), 9.16 (1 H, d, J 1.6 Hz), 8.84-8.78 (2H, m), 8.56 (1 H, dt, J 8.0 1.7 Hz), 8.36-8.32 (2H, m), 7.86 (1 H, d, J 8.8 Hz), 7.80 (1 H, dd, J 8.9 2.0 Hz), 7.70-7.58 (2H, m) 4-Methoxy-N-(2-(4-methoxyphenyi)benzo[d]oxazol-5-yl)benzamide "H NMR (DMSO): 10.25 (1H, s), 8.23 (1H, s), 8.16 (2H, d, J 8.9 Hz), 8.00 (2H, d, J 8.9 Hz), 7.72 (2H, s), 7.17 (2H, d, J9.0 Hz), 7.09 (2H, d, J 8.8 Hz), 3.88 (3H, s), 3.85 (3H, s) N-(2-benzylbenzo[d]oxazol-5-yI)-2-phenylacetamide LCMS RT= 6.22min, MH* 343.1; "H NMR (CDCI 3 ): 7.70 (1H, s), 7.42 (1H, s), 7.30 7.15 (12H, m), 4.14 (2H, s), 3.63 (2H, s) 2,3-Dichloro-N-(2-(2,3-dichlorophenyl)benzo[d]oxazol-5-yI)benzamide LCMS RT= 8.09min, MH*450.9; 'H NMR (DMSO): 10.84 (1H, s), 8.32 (1H, d, J 1.7 Hz), 8.14 (1H, dd, J 8.9 1.5 Hz), 7.95 (1H, dd, J 8.1 1.6 Hz), 7.85 (1H, d, J 8.8 Hz), 7.81 (1H, dd, J 8.0 1.6 Hz), 7.73 (1H, dd, J 8.8 2.1 Hz), 7.65-7.50 (3H, m) Method 1A (Compounds Id) 2'-(4-Propylphenyl)-2,6'-bibenzo[d]oxazole-6-carboxylic acid 1 H NMR (DMSO): 13.20 (1H, br), 8.58 (1H, dd, J1.5 0.4 Hz), 8.33-8.30 (2H, in), 8.19 (2H, d, J 8.2 Hz), 8.06-.802 (2H, m), 7.93 (1 H, d, J 8.3 Hz), 7.50 (2H, d, J 8.4 Hz), 2.69 (2H, t, J7.8 Hz), 1.73-1.61 (2H, m), 0.94 (3H, t, J7.4 Hz) Method 1A (Compounds le) 4-Amino-N-(4-(5-bromobenzo[d]oxazol-2-yI)phenyl)benzamide LCMS RT= 6.87min, MH 4 408.0; 'H NMR (DMSO): 10.14 (1H, s), 8.16 (2H, d, J 8.9 Hz), 8.07-8.01 (3H, m), 7.79-7.74 (3H, in), 7.57 (1 H, dd, J 8.6 2.0 Hz), 6.62 (2H, d, J 8.7 Hz), 5.86 (2H, s) Method 1B (Compounds 1) 2-Benzyl-5-nitrobenzo[d]oxazole WO 2009/019504 84 PCT/GB2008/050648 To 2-amino-4-nitrophenol (300mg, 1.95mmol) in dioxane (2.5mL) was added 2 phenylacetyl chloride (290pL, 2.15mmol) at room temperature. The reaction vessel was heated in the microwave at 210 0 C for 15min. After cooling, the mixture was slowly poured into 1M aqueous sodium hydroxide (50mL), and the resulting precipitate filtered and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:7 v/v to ethyl acetate/hexanes 1:5 vlv) to afford 165mg (33%) of the title compound (LCMS RT= 6.47min, MH*255.2) 'H NMR (DMSO): 8.60 (1H, d, J2.4 Hz), 8.30 (1H, dd, J9.0 2.4 Hz), 7.95 (1H, d, J 9.0 Hz), 7.43-7.27 (5H, m), 4.44 (2H, s) 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. 2-(Benzo[d][1,3]dioxol-5-yI)-5-nitrobenzo[d]oxazole LCMS RT= 6.74min, MH*284.9; 'H NMR (DMSO): 8.60 (1H, d, J 2.3 Hz), 8.31 (1H, dd, J 8.9 2.3 Hz), 7.99 (1 H, d, J 9.0 Hz), 7.82 (1 H, dd, J 8.2 1.7 Hz), 7.66 (1 H, d, J 1.6 Hz), 7.18 (1H, d, J 8.4 Hz), 6.20 (2H, s) 2-(4-Chlorophenyl)-5,6-methylenedioxybenzoxazole LCMS RT= 7.54min, MH 4 274.0; 'H NMR (DMSO): 8.11 (2H, d, J 8.8 Hz), 7.66 (2H, d, J 8.7 Hz), 7.49 (1H, s), 7.36 (1H, s), 6.13 (2H, s) 5-Tert-butyl-2-(4-chlorophenyl)benzo[d]oxazole LCMS RT= 10.20min, MH* 286.0; 'H NMR (DMSO): 8.20 (2H, d, J 8.6 Hz), 7.80 (1H, d, J 1.9 Hz), 7.72-7.68 (3H, m), 7.52 (1H, dd, J 8.7 2.0 Hz), 1.37 (9H, s) 2-(3,4-Dichlorophenyl)-6-nitrobenzo[d]oxazole LCMS RT= 8.40min; 'H NIVIR (DMSO): 8.77 (1 H, d, J 2.1 Hz), 8.40 (1 H, d, J 2.0 Hz), 8.36 (1H, dd, J 8.8 2.2 Hz), 8.21 (1H, dd, J 8.5 2.1 Hz), 8.07 (1H, d, J 8.8 Hz), 7.96 (1H, d, J8.4 Hz) 2-(4-Chlorophenyl)benzo[d]oxazole-5-sulfonamide LCMS RT= 6.04min; 'H NMR (DMSO): 8.27-8.22 (3H, m), 8.02 (1 H, d, J 8.6 Hz), 7.95-7.91 (1H, m), 7.74-7.71 (2H, m), 7.50 (2H, s) 5-Chloro-2-(4-chlorophenyl)-6-nitrobenzo[d]oxazole LCMS RT= 8.10min; 'H NMR (DMSO): 8.73 (1H, s), 8.31 (1H, s), 8.24 (2H, d, J 8.7 Hz), 7.76 (2H, d, J 8.7 Hz) 5-Nitro-2-(4-(trifluoromethoxy)phenyl)benzo[d]oxazole WO 2009/019504 85 PCT/GB2008/050648 LCMS RT= 7.66min; "H NMR (DMSO): 8.72 (1H, d, J 2.3 Hz), 8.38 (3H, m), 8.09 (1H, d, J 8.8 Hz), 7.66 (2H, d, J 8.2 Hz) 2-(3,4-Dichlorophenyl)benzo[d]oxazole[1,3]dioxole LCMS RT= 8.70min, MH* 307.9; 'H NMR (CDCl): 8.18 (1H, d, J 2.0 Hz), 7.91 (1H, dd, J 8.4 2.0 Hz), 7.50 (1H, d, J 8.4 Hz), 7.09 (1H, s), 6.99 (1H, s), 5.99 (2H, s) 2-(Furan-2-yI)-5-nitrobenzo[d]oxazole LCMS RT= 6.24min; "H NMR (DMSO): 8.66 (1 H, d, J 2.3 Hz), 8.35 (1 H, dd, J9.0 2.4 Hz), 8.18 (1H, d, J1.0 Hz), 8.05 (1H, d, J9.0 Hz), 7.62 (1H, d, J3.5 Hz), 6.90-6.88 (1H, m) 2-(Benzo[d][1,3]dioxol-5-yi)-5-chloro-6-nitrobenzo[d]oxazole LCMS RT= 7.21 min; 'H NMR (DMSO): 8.68 (1H, s), 8.23 (1H, s), 7.83 (1H, dd, J 8.2 1.6 Hz), 7.66 (1H, d, J1.7 Hz), 7.20 (1H, d, J8.4 Hz), 6.22 (2H, s) 5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole LCMS RT= 6.94min, MH* 338.1; 'H NMR (DMSO): 8.90 (1H, br), 8.34 (1H, d, J1.4 Hz), 8.30 (1H, dd, J 8.6 1.7 Hz), 8.24-8.05 (4H, m), 7.99 (1H, dd, J 8.5 1.8 Hz), 7.73 7.64 (2H, m), 3.41 (2H, q, J7.3 Hz), 1.15 (3H, t, J7.3 Hz) 2-(3-Chloro-2-fiuorophenyl)-5-(ethylsulfonyl)benzo[djoxazo le LCMS RT= 6.48min, MH*338.8; "H NMR (DMSO): 8.40 (1H, dd, J1.7 0.5 Hz), 8.27 8.21 (1H, m), 8.14 (1H, dd, J8.6 0.4 Hz), 8.01 (1H, dd, J 8.6 1.8 Hz), 7.97-7.92 (1H, m), 7.51 (1H, td, J8.0 1.0 Hz), 3.41 (2H, q, J7.3 Hz), 1.13 (3H, t, J7.3 Hz) 2-Cyclohexyl-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 6.57min, MH* 293.9; "H NMR (DMSO): 8.20 (1H, d, J 1.5 Hz), 7.97 (1H, dd, J 8.5 Hz), 7.88 (1H, dd, J 8.6 1.8 Hz), 3.35 (2H, q, J7.4 Hz), 3.13-3.04 (1H, m), 2.14-2.09 (2H, m), 1.82-1.58 (5H, m), 1.50-1.18 (3H, m), 1.10 (3H, t, J7.4 Hz) 2-(5-Chloropyridin-2-yl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 5.92min, MH* 323.1; 'H NMR (DMSO): 8.91 (1H, d, J 2.4 Hz), 8.42-8.39 (2H, m), 8.25 (1H, dd, J8.5 2.4 Hz), 8.16 (1H, d, J8.6 Hz), 8.03 (1H, dd, J 8.6 1.8 Hz), 3.41 (2H, q, J7.2 Hz), 1.13 (3H, t, J7.3 Hz) 2-(Benzo[d][1,3]dioxo-5-yI)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 6.09min, MH* 332.0; "H NMR (DMSO): 8.26 (1H, dd, J1.8 0.5 Hz), 8.03 (1H, dd, J 8.5 0.5 Hz), 7.92 (1H, dd, J 8.5 1.8 Hz), 7.83 (1H, dd, J 8.2 1.7 Hz), 7.68 (1H, d, J1.6 Hz), 7.19 (1H, d, J8.2 Hz), 6.20 (2H, s), 3.39 (2H, q, J7.3 Hz), 1.12 (3H, t, J7.3 Hz) 5-Chloro-2-(4-(methylsulfonyl)phenyl)benzo[d]oxazole LCMS RT= 6.43min; "H NMR (DMSO): 8.45 (2H, d, J 8.4 Hz), 8.18 (2H, d, J8.5 Hz), 8.02 (1H, d, J1.9 Hz), 7.92 (1H, d, J8.7 Hz), 7.56 (1H, dd, J 8.7 2.1 Hz) 2-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-5-(ethylsulfonyl)benzo[d]oxazole WO 2009/019504 86 PCT/GB2008/050648 LCMS RT= 6.70min; 'H NMR (DMSO): 8.32 (1H, dd, J 1.8 0.5 Hz), 8.24 (IH, d, J1.6 Hz), 8.16 (1H, dd, J 8.5 1.7 Hz), 8.09 (1H, dd, J 8.6 0.5 Hz), 7.97 (1H, dd, J 8.5 1.8 Hz), 7.71 (1 H, d, J 8.5 Hz), 3.40 (2H, q, J 7.3 Hz), 1.13 (3H, t, J 7.4 Hz) 2-(4-Chlorophenyl)benzo[d]oxazol-6-oI LCMS RT= 6.42min, MH*246.0; 'H NMR (DMSO): 9.94 (1H, s), 8.13 (2H, d, J 8.6 Hz), 7.66 (2H, d, J 8.6 Hz), 7.60 (1H, d, J 8-6 Hz), 7.10 (1H, d, J 2.2 Hz), 6.87 (1H, dd, J 8.7 2.3 Hz) 2-(5-(EthylsuIfonyl)benzo[d]oxazol-2-yl)naphthalenA-1 -ol LCMS RT= 7.77min, MH* 353.9; 'H NMR (DMSO): 12.24 (1H, s), 8.44-8.39 (2H, m), 8.19-7.98 (4-, m), 7.77-7.63 (3H, m), 3.42 (2H, q, J7.3 Hz), 1.15 (3H, t, J7.3 Hz) 2-(Benzofuran-5-yl)-5-(ethylsulfonyl)benzo[d]oxazole LCMS RT= 6.47min, MH 4 328.2; 'H NMR (DMSO): 8.61 (1H, d, J1.7 Hz), 8.31 (1H, d, J 1.7 Hz), 8.22 (1H, dd, J 8.5 1.7 Hz), 8.19 (1H, d, J 2.2 Hz), 8.09 (1H, d, J 8.5 Hz), 7.95 (1H, dd, J 8.5 1.9 Hz), 7.88 (1H, d, J 8.7 Hz), 7.19-7.17 (1H, m), 3.40 (2H, q, J7.4 Hz), 1.15 (3H, t, J 7.3 Hz) 2-(4-Chlorophenyl)-N,N-diethylbenzo[d]oxazole-5-sulfonamide LCMS RT= 7.75min, MH 4 364.9; 'H NMR (DMSO): 8.26-8.21 (3H, m), 8.03 (1H, d, J 8.6 Hz), 7.89 (1H, dd, J 8.6 1.8 Hz), 7.74 (2H, d, J 8.6 Hz), 3.22 (4H, q, J 7.2 Hz), 1.06 (6H, t, J7.2 Hz) 2-(Naphthalen-2-yl)-5-(trifluoromethoxy)benzo[d]oxazole LCMS RT= 9.10min, MH330.1; 'H NMR (DMSO): 8.88 (1H, br), 8.27 (1H, dd, J 8.5 1.7 Hz), 8.23-8.19 (1H, m), 8.16 (1H, d, J 8.7 Hz), 8.08-8.04 (1H, m), 7.97 (1H, d, J 8.9 Hz), 7.95-7.93 (1H, m), 7.73-7.64 (2H, m), 7.52-7.47 (1H, m) 2-(Naphthalen-2-yl)benzo[d]oxazole-5-carboxylic acid LCMS RT= 4.83min, MH* 289.0; 'H NMR (DMSO): 13.20 (1H, br), 8.89 (1H, br), 8.36 (1H, dd, J 1.6 0.5 Hz), 8.30 (1H, dd, J8.6 1.8 Hz), 8.24-8.20 (1H, m), 8.17 (1H, d, J 8.8 Hz), 8.10-8.04 (2H, m), 7.94 (1H, dd, J 8.5 0.5 Hz), 7.73-7.63 (2H, m) 2-(Naphthalen-2-yl)benzo[d]oxazole LCMS RT= 8.19min, MH* 246.1; 'H NMR (DMSO): 8.86 (1H, br), 8.29 (1H, dd, J 8.6 1.8 Hz), 8.22-8.18 (1H, m), 8.15 (1H, d, J 8.7 Hz), 8.07-8.03 (1H, m), 7.88-7.83 (2H, m), 7.71-7.62 (2H, m), 7.51-7.42 (2H, m) 5-tert-Butyl-2-(naphthalen-2-yI)benzo[d]oxazole LCMS RT= 10.50min, MH302.2; 'H NMR (CDCI 3 ): 8.70 (1H, s), 8.25 (1H, dd, J 8.6 1.5 Hz), 7.94-7.89 (2H, m), 7.85-7.81 (1H, m), 7.77 (1H, d, J 1.6 Hz), 7.54-7.45 (3H, m), 7.37 (1H, dd, J8.5 1.8 Hz), 1.35 (9H, s) 5,6-Difluoro-2-(naphthalen-2-yl)benzo[d]oxazole WO 2009/019504 87 PCT/GB2008/050648 LCMS RT= 8.57min, MH* 282.1; "H NMR (DMSO): 8.82 (1H, br), 8.24 (1H, dd, J .6 1.8 Hz), 8,21-8.12 (3H, m), 8.07-8.00 (2H, m), 7.72-7.63 (2H, m) 1-(2'-(3",4"-Dichlorophenyl)benzo[d]oxazol-5'-yl)ethanone LCMS RT= 8.19min, MH 4 305.9; 'H NMR (DMSO): 8.45 (1H, dd, J 1.7 0.5 Hz), 8.38 (1H, d, J 2.0 Hz), 8,18 (1H, dd, J 8.5 2.1 Hz), 8.09 (1H, dd, J 8.6 1.8 Hz), 7.96-7.91 (2H, m), 2.69 (3H, s) 2-(4-Chlorophenyl)-6-methylbenzo[d]oxazole LCMS RT= 8.41min, MH* 244.1; "H NMR (DMSO): 8.18 (2H, d, J 8.7 Hz), 7.72-7.61 (4H, m), 7.27-7.23 (1H, m), 2.48 (3H, s) 5-Methyl-2-(naphthalen-2-yl)benzo[d]oxazole LCMS RT= 8.82min, MH 260.2; "H NMR (DMSO): 8.83 (1H, d, J 1.1 Hz), 8.26 (1H, dd, J 8.6 1.7 Hz), 8.21-8.16 (1H, m), 8.13 (1H, d, J 8.7 Hz), 8.06-8.02 (1H, m), 7.72 7.64 (4H, m), 7.30-7.26 (1H, m), 2.47 (3H, s) Method 1C (Compounds I) 6-Nitro-2-phenyloxazolo[5,4-b]pyridine To polyphosphoric acid at 165C was added N-(5-nitro-2-oxo-1,2-dihydropyridin-3 yl)benzamide (300mg, 1.16mmol). The resulting mixture was then heated to 165 0 C for 30min. The solution was then poured into water. The resulting precipitate was collected by filtration, dissolved in diethyl ether, filtered through alumina and evaporated to afford 9mg (3%) of the title compound. "H NMR (DMSO): 9.31 (1H, d, J 2.5 Hz), 9.12 (1H, d, J 2.5 Hz), 8.32-8.27 (2H, m), 7.79-7.67 (3H, m) All compounds below were prepared following the same general method. 5-Nitro-2-(pyridin-2-yl)benzo[d]oxazole LCMS RT= 5.83min, MH* 241.9; "H NMR (DMSO): 8.87-8.84 (1H, m), 8.78 (1H, d, J 2.3 Hz), 8.44-8.40 (2H, m), 8.16-8.10 (2H, m), 7.74-7.69 (1H, m) 6-Nitro-2-(pyridin-2-yl)benzo[d]oxazole LCMS RT= 5.84min, MH 4 242.0; "H NMR (DMSO): 8.79-8.76 (2H, m), 8.34 (1H, dt, J 7.9 1.0 Hz), 8.29 (1H, dd, J 8.8 2.0 Hz), 8.07-8.02 (2H, m), 7.64 (1H, ddd, J7.7 4.8 1.2 Hz) 2-(5-Butylpyridin-2-yI)-5-nitrobenzo[d]oxazole LCMS RT= 7.32min, MH 298.1; "H NMR (DMSO): 8.68 (1H, dd, J 2.3 0.3 Hz), 8.64 (1H, dd, J 2.1 0.5 Hz), 8.33 (1H, dd, J9.0 2.4 Hz), 8.26 (1H, dd, J 8.0 0.6 Hz), 8.05 WO 2009/019504 8g PCT/GB2008/050648 (1H, dd, J9.0 0.3 Hz), 7.88 (1H, dd, J 8.1 2.1 Hz), 2.70-2.66 (2H, m), 1.62-1.52 (2H, m), 1.34-1.22 (2H, m), 0.86 (3H, t, J7.4 Hz) Method 1D (Compounds 1) 2-(2,4-Difluorophenyl)-5,6.-dimethylbenzo[djoxazole A suspension of 2-(2,4-difluorobenzamido)-4,5-dimethylphenyl 2,4-difluorobenzoate (90mg, 0.22mmol) and 4-methylbenzenesulfonic acid (82mg, 0.43mmol) in xylene (2mL) was heated at reflux for 16h. After cooling, the solution was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution followed by brine. 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 1:15 v/v to afford 36mg (64%) of the title compound (LCMS RT= 7.81 min, MH*260.0) 1H NMR (DMSO): 8.30-8.22 (1H, in), 7.63-7.52 (3H, m), 7.39-7.30 (1 H, m), 2.37 (3H, s), 2.35 (3H, s) WO 2009/0 19504 PCT1GB20081050648 0 U3 0 U 0 c0 z0 Cq cn ZV Z >o C' c0 X00 A 0 2i1 z x XXx 0, c to OLI-a ilf C Z -0 flf -o ,0 of C) 3:M0) cca 0 CO zcct . LLJ' Uco 0)l LL LL z - c ) DC)3r WO 2009/019504 90 PCT/GB2008/050648 Method 2A (Compounds Ib) 2-p-Tolylbenzo[d]oxazol-5-amine To 5-nitro-2-p-tolylbenzo[d]oxazole (4.8g, 18.90mmol) in ethyl acetatelacetic acid (250mL/1mL) was added palladium on carbon (480mg). The reaction vessel was purged three times with nitrogen, followed by hydrogen three times, and then left stirring under hydrogen for 16h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite*, which was washed with ethyl acetate. The organic solution was washed with saturated aqueous Na 2
CO
3 , followed by brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 2.5g (60%) of the title compound. 'H NMR (DMSO): 8.02 (2H, d, J 8.2 Hz), 7.39 (3H, d, J 8.5 Hz), 6.86 (1H, d, J 2.0 Hz), 6.65 (1 H, dd, J 8.7 2.2 Hz), 5.09 (2H, s), 2.40 (3H, s) Method 2B (Compounds Ib) As Method 2A, except ethanol was used instead of ethyl acetate/acetic acid. After evaporation of the solvents, the material was taken up in 2M HCI, the resulting precipitate was discarded, and the solution was basified with 2N NaOH to afford the title compound as a precipitate. 2-Phenylbenzo[d]oxazol-6-amine LCMS RT= 5.93min, MH t 211.1; 'H NMR (DMSO): 8.10-8.07 (2H, m), 7.58-7.54 (3H, m), 7.42 (1 H, d, J 8.4 Hz), 6.83 (1 H, d, J 1.9 Hz), 6.65 (1 H, dd, J 8.5 2.0 Hz), 5.46 (2H, s) Method 2C (Compounds Ib) 2-(4-(Trifluoromethoxy)phenyl)benzo[d]oxazol-5-amine To 5-nitro-2-(4-(trifluoromethoxy)phenyl)benzo[d]oxazole (850mg, 2.62mmol) in ethanol (20mL) was added ammonium formate (827mg, 13.1immol) and palladium on carbon (85mg). The mixture was stirred at room temperature for 20min, then filtrated through a pad of Celite*, and washed with ethyl acetate. The organic solution was washed with water, followed by brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 434mg (56%) of the title compound (LCMS RT= 6.51 min, MH*294.9) WO 2009/019504 g PCT/GB2008/050648 'H NMR (DMSO): 8.25 (2H, d, J 8.9 Hz), 7.62-7.56 (2H, m), 7.44 (1 H, d, J 8.7 Hz), 6.89 (1H, d, J 2.0 Hz), 6.70 (1H, dd, J 8.7 2.3 Hz), 5.16 (2H, s) Method 2D (Compounds Ib) 2-p-Tolylbenzo[d]oxazol-4-amine To 4-nitro-2-p-tolylbenzold]oxazole (330mg, 1.30mmol) in ethanol (20mL) was added tin (11) chloride (1.23g, 6.5mmol). The suspension was stirred at 700C for 16h. After cooling, the solution was poured into ice/water and neutralize with saturated aqueous NaHCO 3 The aqueous layer was then extracted twice with ethyl acetate (500mL). The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 188mg (65%) of the title compound (LCMS RT= 6.76min, MH t 225.1) 'H NMR (DMSO): 8.04 (2H, d, J 8.2 Hz), 7.41 (2H, d, J 8.0 Hz), 7.07 (1H, t, J 8.0 Hz), 6.85 (1H, dd, J 8.0 0.8 Hz), 6.55 (1H, dd, J 8.0 0.8 Hz), 5.67 (2H, s), 2.41 (3H, s) The compound below was prepared following the same general method. 2-Phenyloxazolo[5,4-b]pyridin-6-amine LCMS RT= 5.41 min, MH 4 212.1; 'H NMR (DMSO): 8.19-8.15 (2H, m), 7.73 (1H, d, J 2.4 Hz), 7.63-7.58 (3H, m), 7.32 (1H, d, J 2.4 Hz), 5.38 (2H, s) Method 2E (Compounds Ib) 2-p-Tolylbenzo[d]oxazol-6-amine To 6-nitro-2-p-tolylbenzo[d]oxazole (2. 1g, 8.27mmol) in ethanol:water 2:1 v/v (60mL) at 70'C was added iron powder (2.14g, 38.3mmol) and ammonium chloride (819mg, 15.3 mmol). The suspension was stirred at reflux for 16h. After cooling, the solution was filtered through a pad of Celite* and washed with ethanol. After evaporation of the solvent, the aqueous layer was extracted twice 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 1:3 v/v to afford 70mg (4%) of the title compound (LCMS RT= 6.12min, MH*223.1) 'H NMR (DMSO): 7.97 (2H, d, J 8.1 Hz), 7.40-7.36 (3H, m), 6.82 (1 H, d, J 1.9 Hz), 6.64 (1H, dd, J 8.5 2.0 Hz), 5.41 (2H, s), 2.39 (3H, s) All compounds below were prepared following the same general method.
WO 2009/019504 92 PCT/GB2008/050648 2-Phenethylbenzo[d]oxazol-5-amine LCMS RT= 5.82min, MH*238.9; 'H NMR (DMSO): 7.29-7.16 (6H, m), 6.76 (1H, d, J 1.9 Hz), 6.57 (1H, dd, J 8.6 2.2 Hz), 4.98 (2H, s), 3.19-3.06 (4H, m) 2-(Benzo[d][1,3]dioxol-5-yI)benzo[d]oxazol-5-amine LCMS RT= 5.77min, MH* 254.9; 1 H NMR (DMSO): 7.69 (1 H, dd, J 8.2 1.7 Hz), 7.58 (1H, d, J1.7 Hz), 7.37 (1H, d, J8.6 Hz), 7.11 (1H, d, J 8.2 Hz), 6.84 (1H, d, J2.0 Hz), 6.64 (1H, dd, J8.8 2.2 Hz), 6.16 (2H, s), 5.07 (2H, s) 2-(benzo[d][1,3]dioxoi-5-yl)-5-chlorobenzo[d]oxazol-6-amine LCMS RT= 6.52min, MH t 289.1; 'H NMR (DMSO): 7.72 (1H, dd, J 8.2 1.8 Hz), 7.69 (1H, s), 7.61 (1H, d, J 1.6 Hz), 7.17 (1H, d, J 8.2 Hz), 7.13 (1H, s), 6.21 (2H, s), 5.66 (2H, s) Method 2F (Compounds Ib) As Method 2E, except THF:water (2:1 v/v) was used instead of ethanol:water (2:1 vlv). 2-(3,4-Dichlorophenyl)benzo[d]oxazol-6-amine LCMS RT= 7.12min, MH* 278.1; 1 H NMR (DMSO): 8.22 (1H, d, J 1.8 Hz), 8.03 (1H, dd, J 8.4 2.0 Hz), 7.83 (1H, d, J 8.4 Hz), 7.44 (1H, d, J 8.4 Hz), 6.82 (1H, d, J2.0 Hz), 6.68 (1H, dd, J 8.6 2.0 Hz), 5.57 (2H, s) Method 3A (Compounds lI ) 3-Phenyl-N-(2-phenylbenzo[d]oxazol-5-yl)propanamide To a solution of 2-phenylbenzoldloxazol-5-amine (50mg, 0.24mmol) in dichloromethane (2mL) at room temperature was added 3-phenylpropanoyl chloride (44.1mg, 0.26mmol) followed immediately by diisopropylethylamine (82pL, 0.48mmol). The resulting mixture was stirred at room temperature for 16h. Dichloromethane was added and the organic layer was washed with saturated aqueous Na 2
CO
3 . The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting solid was dissolved in methanol, passed through an acidic scavenger column (silica-based quaternary amine SPE-AX from Biotage*) and then evaporated to afford 61.1mg (75%) of the title compound (LCMS RT= 6.45min, MH* 343.2) WO 2009/019504 93 PCT/GB2008/050648 'H NMR (DMSO): 10.11 (1H, s), 8.22-8.15 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.66-7.59 (3H, in), 7.51 (1H, dd, J 8.9 2.1 Hz), 7.33-7.17 (5H, m), 2.96 (2H, t, J7.2 Hz), 2.67 (2H, t, J7.1 Hz) All compounds below were prepared following the same general method. N-(2-Phenylbenzo[djoxazol-5-yI)acetamide LCMS RT= 5.16min, MH*253.1; H NMR (DMSO): 10.14 (1H, s), 8.21-8.14 (3H, m), 7.71 (1 H, d, J 8.8 Hz), 7.65-7.60 (3H, m), 7.51 (1 H, dd, J 9.0 2.1 Hz), 2.09 (3H, s) N-(2-Phenylbenzo[d]oxazol-5-yl)propionamide LCMS RT= 5.49min, MH* 267.1; 1 H NMR (DMSO): 10.09 (1H, s), 8.21-8.16 (3H, m), 7.71 (1H, d, J8.8 Hz), 7.66-7.61 (3H, m), 7.54 (1H, dd, J 9.0 2.1 Hz), 2.37 (2H, q, J 7.6 Hz), 1.12 (3H, t, J7.6 Hz) N-(2-Phenylbenzo[d]oxazol-5-yl)butyramide LCMS RT= 5.78min, MH* 281.1; 'H NMR (DMSO): 10.09 (1H, s), 8.21-8.16 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.64-7.60 (3H, m), 7.54 (1H, dd, J9.Q 2.1 Hz), 2.33 (2H, q, J 7.6 Hz), 1.69-1.61 (2H, m), 0.94 (3H, t, J7.6 Hz) N-(2-Phenylbenzo[d]oxazol-5-yl)pentanamide LCMS RT= 6.21min, MH* 295.1; 'H NMR (DMSO): 10.09 (1H, s), 8.21-8.16 (3H, m), 7.71 (1H, d, J8.8 Hz), 7.65-7.60 (3H, m), 7.54 (1 H, dd, J9.0 2.1 Hz), 2.35 (2H, q, J 7.6 Hz), 1.66-1.58 (2H, m), 1.39-1.31 (2H, m), 0.92 (3H, t, J 7.6 Hz) N-(2-Phenylbenzo[d]oxazol-5-yl)isobutyramide LCMS RT= 5.79min, MH*281.1; 'H NMR (DMSO): 10.02 (1H, s), 8.22-8.18 (3H, m), 7.71 (1H, d, J 8.8 Hz), 7.66-7.60 (3H, m), 7.55 (1H, dd, J 9.0 2.1 Hz), 2.67-2.58 (1H, m), 1.14 (6H, s) N-(2-Phenylbenzo[d]oxazol-5-yl)furan-2-carboxamide LCMS RT= 5.82min, MH* 305.1; 1 H NMR (DMSO): 10.42 (1H, s), 8.26-8.20 (3H, m), 7.97 (1 H, dd, J 1.7 0.8 Hz), 7.77 (2H, d, J 1.3 Hz), 7.66-7.62 (3H, m), 7.38 (1 H, d, J 3.4 Hz), 6.73 (1H, dd, J3.4 1.7 Hz) 4-Chloro-N-(2-p-tolylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 7.23min, MH 4 363.1; 'H NMR (DMSO): 10.55 (1H, s), 8.32-8.31 (1H, m), 8.17 (2H, d, J 8.1 Hz), 8.08 (2H, d, J 8.6 Hz), 7.84-7.77 (2H, m), 7.70 (2H, d, J 8.6 Hz), 7.50 (2H, d, J 8.1 Hz), 2.49 (3H, s) 4-Methoxy-N-(2-p-tolylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 6.41min, MH*359.1; 'H NMR (DMSO): 10.35 (1H, s), 8.33 (1H, s), 8.17 (2H, d, J 8.1 Hz), 8.07 (2H, d, J 8.7 Hz), 7.81 (2H, s), 7.51 (2H, d, J 8.3 Hz), 7.16 (2H, d, J 8.8 Hz), 3.17 (3H, s), 2.49 (3H, s) WO 2009/019504 PCT/GB2008/050648 94 Method 3B (Compounds 11) As Method 3A, except instead of diisopropylamine, triethylamine was used as a base. N-(2-Phenylbenzo[d]oxazol-5-yi)nicotinamide LCMS RT= 5.48min, MH* 316.1; "H NMR (DMSO): 10.70 (1H, s), 9.21 (1H, d, J2.1 Hz), 8.85 (1H, dd, J4.8 1.6 Hz), 8.40 (1H, dt, J 8.0 2.0 Hz), 8.37 (1H, d, J1.8 Hz), 8.30-8.27 (2H, m), 7.89-7.80 (2H, m), 7.72-7.64 (4H, m) N-(2-Phenylbenzo[d]oxazol-5-yl)isonicotinamide LCMS RT= 5.46min, MH316.1;'H NMR (DMSO): 10.76 (1H, s), 8.88 (2H, d, J5.9 Hz), 8.36 (1H, d, J 1.7 Hz), 8.31-8.27 (2H, m), 7.97 (2H, d, J 6.1 Hz), 7.90-7.80 (2H, m), 7.73-7.68 (3H, m) 4-Chloro-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 7.07min, MH* 349.1; "H NMR (DMSO): 10.57 (1H, s), 8.35-8.34 (1H, m), 8.30-8.27 (2H, m), 8.09 (2H, d, J 8.6 Hz), 7.88-7.80 (2H, m), 7.72-7.67 (5H, m) 4-Methyl-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 6.80min, MH t 329.2; "H NMR (DMSO): 10.41 (1H, s), 8.37-8.35 (1H, m), 8.30-8.26 (2H, m), 7.98 (2H, d, J 8.1 Hz), 7.84 (2H, s), 7.72-7.67 (3H, m), 7.43 (2H, d, J 8.0 Hz), 2.47 (3H, s) 4-Methoxy-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 6.37min, MH 4 345.1; "H NMR (DMSO): 10.33 (1H, s), 8.35 (1H, s), 8.30 8.26 (2H, m), 8.06 (2H, d, J 8.7 Hz), 7.83 (2H, s), 7.71-7.67 (3H, m), 7.14 (2H, d, J 8.8 Hz), 3.92 (3H, s) 2-Methoxy-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 7.06min, MH* 345.1; "H NMR (DMSO): 10.37 (1H, s), 8.38-8.36 (1H, m), 8.30-8.26 (2H, m), 7.84-7.56 (7H, m), 7.27 (1H, d, J 8.4 Hz), 7.14 (1H, t, J7.3 Hz), 3.99 (3H, s) 4-(Dimethylamino)-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 6.63min, MH* 358.2; 'H NMR (DMSO): 10.10 (1H, s), 8.35-8.34 (1H, m), 8.30-8.26 (2H, m), 7.96 (2H, d, J 8.9 Hz), 7.82-7.80 (2H, m), 7.71-7.68 (3H, m), 6.84 (2H, d, J 8.9 Hz), 3.08 (6H, s) 3,4-Dichloro-N-(2-phenylbenzo[d]oxazol-5-yI)benzamide LCMS RT= 7.95min, MH* 382.8; 'H NMR (DMSO): 10.63 (1H, s), 8.37-8.26 (4H, m), 8.04 (1H, dd, J 8.4 2.1 Hz), 7.92-7.78 (3H, m), 7.73-7.65 (3H, m) N-(2-Phenylbenzo[d]oxazol-5-y)-4-(trifluoromethyl)benzamide WO 2009/019504 PCT/GB2008/050648 95 LCMS RT= 7.19min, MH* 383.1; 1 H NMR (DMSO): 10.72 (1H, s), 8.37-8.24 (5H, m), 8.00 (2H, d, J 8.4 Hz), 7.89-7.82 (2H, m), 7,74-7.67 (3H, m) 3,5-Dichloro-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 8.30min, MH* 382.9; 'H NMR (DMSO): 10.67 (1H, s), 8.33-8.26 (3H, m), 8.09 (2H, d, J 2.1 Hz), 7.96 (1H, t, J 2.0 Hz), 7.89-7.78 (2H, m), 7.72-7.67 (3H, m) 4-Fluoro-N-(2-phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 6.53min, MH* 333.2; 'H NMR (DMSO): 10.50 (1H, s), 8.34-8.33 (1H, m), 8.39-8.26 (2H, m), 8.16-8.11 (2H, m), 7.86-7.79 (2H, m), 7.71-7.65 (3H, m), 7.45 (2H, t, J8.8 Hz) N-(2-Phenylbenzo[d]oxazol-5-yl)biphenyl-4-carboxamide LCMS RT= 7.74min, MH* 391.1; 'H NMR (DMSO): 10.55 (1H, s), 8.39-8.38 (1H, m), 8.31-8.27 (2H, m), 8.17 (2H, d, J8.5 Hz), 7.93 (2H, d, J 8.4 Hz), 7.86-7.83 (4H, m), 7.72-7.69 (3H, in), 7.62-7.50 (3H, m) 2-Phenyl-N-(2-phenylbenzo[d]oxazol-5-yl)acetamide LCMS RT= 6.32min, MH* 329.2; 1 H NMR (DMSO): 10.42 (1H, s), 8.27-8.21 (3H, m), 7.78 (1H, d, J 8.9 Hz), 7.71-7.65 (3H, m), 7.61 (1H, dd, J8.9 2.1 Hz), 7.45-7.30 (5H, m), 3.75 (2H, s) N-(2-Phenylbenzo[d]oxazol-5-yl)cinnamamide LCMS RT= 6.86min, MH* 341.1; 'H NMR (DMSO): 10.48 (1H, s), 8.37 (1H, d, J 1.9 Hz), 8.29-8.26 (2H, m), 7.83 (1H, d, J8.9 Hz), 7.73-7.67 (7H, m), 7.56-7.48 (3H, m), 6.93 (1H, d, J 15,6 Hz) N-(2-Phenylbenzo[d]oxazol-5-y)-1 -naphthamide LCMS RT= 7.07min, MH*365.0; 'H NMR (DMSO): 10.82 (1H, s), 8.44 (1H, s), 8.31 8.28 (3H, m), 8.18-8.10 (2H, m), 7.88-7.83 (3H, m), 7.73-7.65 (6H, m) N-(2-Phenylbenzo[d]oxazol-5-yI)-2-naphthamide LCMS RT= 7.37min, MH*365.1; 'H NMR (DMSO): 10.69 (1H, s), 8.69 (1H, s), 8.42 (1H, s), 8.31-8.28 (2H, m), 8.20-8.08 (4H, m), 7.90-7.88 (2H, m), 7.75-7.68 (5H, m) N-(2-Phenylbenzold]oxazol-5-yl)thiophene-2-carboxamide LCMS RT= 6.31min, MH*321.1; 'H NMR (DMSO): 10.47 (1H, s), 8.30-8.26 (3H, m), 8.12 (1H, dd, J 3.8 1.1 Hz), 7.94 (1H, dd, J 5.0 1.1 Hz), 7.85 (1H, d, J 8.8 Hz), 7.77 (1 H, dd, J 8.9 2.0 Hz), 7.73-7.65 (3H, m), 7.33-7.30 (1 H, m) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 5.63min, MH* 315.8; 'H NMR (DMSO): 10.53 (1H, s), 9.45-9.42 (1H, m), 8.88 (1H, dd, J 4.9 1.6 Hz), 8.62 (1H, dt, J 8.0 1.8 Hz), 8.42-8.40 (1H, m), 8.06 (2H, dd, J 6.6 1.2 Hz), 7.88 (2H, s), 7.75-7.59 (4H, m) 4-Chloro-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide WO 2009/019504 PCT/GB2008/050648 96 LCMS RT= 6.12min, MH*349.9; 'H NMR (DMSO): 10.58 (1H, s), 9.43-9.42 (1H, in), 8.89-8.87 (1H, m), 8.64-8.59 (1H, m), 8.40-8.38 (1H, n), 8.09 (2H, d, J 8.5 Hz), 7.91 7.83 (2H, m), 7.76-7.69 (3H, m) 4-Methyl-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 5.91min, MH* 330.2; 'H NMR (DMSO): 10.43 (1H, s), 9.43 (1H, dd, J2.1 0.9 Hz), 8.88 (1H, dd, J4.8 1.6 Hz), 8.61 (1H, dt, J8.0 1.9 Hz), 8.40 (1H, t, J 1.2 Hz), 7.98 (2H, d, J 8.2 Hz), 7.87 (2H, d, J 1.2 Hz), 7.75-7.70 (1 H, m), 7.43 (2H, d, J 8.0 Hz), 2.47 (3H, s) 4-Methoxy-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yi)benzamide LCMS RT= 5.64min, MH* 345.9; 'H NMR (DMSO): 10.37 (1H, s), 9.45 (1H, dd, J 1.6 0.8 Hz), 8.90 (1H, dd, J 4.9 1.7 Hz), 8.63 (1H, dt, J 8.0 1.9 Hz), 8.41 (1H, t, J 1.2 Hz), 8.08 (2H, d, J 8.5 Hz), 7.88 (2H, d, J 1.2 Hz), 7.77-7.72 (1H, m), 7.17 (2H, d, J 8.7 Hz), 3.94 (3H, s) 2-Methoxy-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yI)benzamide LCMS RT= 6.02min, MH*345.9; 'H NMR (DMSO): 10.33 (1H, s), 9.38-9.36 (1H, m), 8.82 (1H, dd, J 4.9 1.7 Hz), 8.55 (1H, dt, J 8.0 1.8 Hz), 8.36-8.34 (1H, m), 7.82-7.73 (2H, m), 7.69-7.65 (2H, m), 7.57-7.50 (1H, m), 7.21 (1H, d, J 8.4 Hz), 7.09 (1H, t, J 7.6 Hz), 3.93 (3H, s) 4-(Dimethylamino)-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 5.82min, MH* 358.9; 'H NMR (DMSO): 10.13 (1H, s), 9.45 (1H, dd, J 2.3 0.9 Hz), 8.88 (1H, dd, J 4.8 1.6 Hz), 8.64-8.59 (1H, m), 8.40-8.39 (1H, m), 7.97 (2H, d, J9.1 Hz), 7.86-7.85 (2H, m), 7.75-7.70 (1H, in), 6.86 (2H, d, J9.1 Hz), 3.08 (6H, s) 3,4-Dichloro-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 6.78min, MH* 383.5; 'H NMR (DMSO): 10.66 (1H, s), 9.43 (1H, d, J2.1 0.6 Hz), 8.88 (1H, dd, J 4.8 1.6 Hz), 8.61 (1H, dt, J 8.0 2.0 Hz), 8.37 (1H, d, J 2.0 Hz), 8.32 (1H, d, J 2.1 Hz), 8.04 (1H, dd, J 8.4 2.1 Hz), 7.92-7.82 (3H, m), 7.75-7.71 (1H, m) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yI)-4-(trifluoromethyl)benzamide LCMS RT= 6.32min, MH* 383.6; 'H NMR (DMSO): 10.68 (1H, s), 9.37 (1H, d, J 2.1 Hz), 8.82 (1H, dd, J4.9 1.5 Hz), 8.56 (1H, dt, J 8.0 2.0 Hz), 8.34 (1H, d, J 1.7 Hz), 8.20 (2H, d, J 8.1 Hz), 7.95 (2H, d, J8.4 Hz), 7.88-7.79 (2H, m), 7.69-7.65 (1H, m) 3,5-Dichloro-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 7.06min, MH* 383.7; "H NMR (DMSO): 10.69 (1H, s), 9.43-9.41 (1H, m), 8.88 (1H, dd, J4.9 1.7 Hz), 8.61 (1H, dt, J 8.0 2.0 Hz), 8.37 (1H, d, J 1.9 Hz), 8.09 (2H, d, J 1.9 Hz), 7.96-7.82 (3H, m), 7.75-7.71 (1H, m) 4-Fluoro-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yI)benzamide WO 2009/019504 PCT/GB2008/050648 97 LCMS RT= 5.70min, MH* 334.0; 'H NMR (DMSO): 1047 (1H, s), 9.38-9.36 (1H, m), 8.82 (1H, dd, J 4.9 1.7 Hz), 8.56 (1H, dt, J 8.0 2.0 Hz), 8.33-8.32 (1H, m), 8.11-8.06 (2H, m), 7.85-7.80 (2H, m), 7.69-7.65 (1H, m), 7.40 (2H, t, J 8.9 Hz) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yl)biphenyi-4-carboxamide LCMS RT= 6.78min, MH391.6; 2-Phenyl-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)acetamide LCMS RT= 5.63min, MH* 329.7; 'H NMR (DMSO): 10.46 (1H, s), 9.41-9.39 (1H, m), 8.87 (1H, dd, J 4.9 1.7 Hz), 8.59 (1H, dt, J 8.0 2.0 Hz), 8.26 (1H, d, J 2.0 Hz), 7.82 (1H, d, J 8.8 Hz), 7.73-7.69 (1H, in), 7.64 (1H, dd, J 8.8 2.0 Hz), 7.44-7.30 (5H, m), 3.75 (2H, s) 3-Phenyl-N-(2-(pyridin-3-yl)benzo[d]oxazol-5-yl)propanamide LCMS RT= 5.84min, MH* 343.8; 'H NMR (DMSO): 10.14 (1H, s), 9.35-9.34 (1H, m), 8.81 (1H, dd, J 4.9 1.7 Hz), 8.53 (1H, dt, J 8.0 2.0 Hz), 8.19 (1H, d, J 2.0 Hz), 7.76 (1H, d, J 8.8 Hz), 7.69-7.63 (1H, m), 7.54 (1H, dd, J 8.8 2.0 Hz), 7.33-7.17 (5H, m), 2.95 (2H, t, J 7.6 Hz), 2.67 (2H, t, J 8.0 Hz) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yI)cinnamamide LCMS RT= 6.03min, MH*342.0; 'H NMR (DMSO): 10.46 (1H, s), 9.37-9.35 (1H, m), 8.82 (1H, dd, J4.9 1.7 Hz), 8.55 (1H, dt, J 8.0 2.0 Hz), 8.35 (1H, d, J 1.9 Hz), 7.82 (1H, d, J 8.9 Hz), 7.69-7.63 (5H, m), 7.49-7.41 (3H, m), 6.87 (1H, d, J 15.8 Hz) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yl)propionamide LCMS RT= 4.97min, MH* 267.9; 'H NMR (DMSO): 10.08 (1 H, s), 9.34 (1 H, dd, J 2.2 0.7 Hz), 8.81 (1H, dd, J 4.9 1.7 Hz), 8.53 (1H, dt, J 8.0 2.0 Hz), 8.21 (1H, d, J 2.0 Hz), 7.76 (1H, d, J 8.9 Hz), 7.68-7.63 (1H, m), 7.57 (1H, dd, J 9.0 2.1 Hz), 2.37 (2H, q, J7.6 Hz), 1.12 (3H, t, J7.6 Hz) N-(2-(Pyridin-3-yI)benzo[d]oxazol-5-yl)butyramide LCMS RT= 5.26min, MH*281.9; 'H NMR (DMSO): 10.17 (1H, s), 9.43 (1H, dd, J 2.2 0.7 Hz), 8.89 (1H, dd, J 4.9 1.7 Hz), 8.62 (1H, dt, J 8.0 2.0 Hz), 8.29 (1H, d, J 2.0 Hz), 7.84 (1H, d, J 8.9 Hz), 7.76-7.72 (1H, m), 7.65 (1H, d d, J 9.0 2.1 Hz), 2.42 (2H, q, J7.6 Hz), 1.80-1.67 (2H, m), 1.03 (3H, t, J 7.6 Hz) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yl)pentanamide LCMS RT= 5.60min, MH*296.0; 'H NMR (DMSO): 10.09 (1H, s), 9.36-9.33 (1H, m), 8.81 (1H, dd, J4.9 1.7 Hz), 8.53 (1H, dt, J 8.0 2.0 Hz), 8.20 (1H, d, J 2.0 Hz), 7.75 (1H, d, J 8.9 Hz), 7.648-7.64 (1H, m), 7.57 (1H, dd, J9.0 2.1 Hz), 2.35 (2H, q, J 7.6 Hz), 1.66-1.56 (2H, m), 1.42-1.29 (2H, m), 0.92 (3H, t, J 7.6 Hz) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 5.22min, MH*282.0; 'H NMR (DMSO): 10.11 (IH, s), 9.41 (1H, dd, J 2.2 0.7 Hz), 8.87 (1H, dd, J4.9 1.7 Hz), 8.60 (1H, dt, J 8.0 2.0 Hz), 8.29 (1H, d, J 2.0 WO 2009/019504 PCT/GB2008/050648 98 Hz), 7.83 (1H, d, J 8.9 Hz), 7.74-7.69 (1H, m), 7.65 (1H, dd, J 9.0 2.1 Hz), 2.70 (1H, t, J 6.8 Hz), 1.20 (6H, d, J 6.8 Hz) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yI)furan-2-carboxamide LCMS RT= 5.23min, MH* 305.7; 'H NMR (DMSO): 10.41 (1H, s), 9.37 (1H, dd, J 2.2 0.8 Hz), 8.82 (1H, dd, J4.9 1.7 Hz), 8.55 (1H, dt, J 8.0 2.0 Hz), 8.30 (1H, t, J1.3 Hz), 7.97 (1H, dd, J 1.7 0.8 Hz), 7.82-7.81 (2H, m), 7.69-7.64 (1H, m), 7.37 (1H, dd, J3.5 0.8 Hz), 6.74 (1H, dd, J3.5 1.7 Hz) N-(2-(Pyridin-3-yl)benzo[d]oxazol-5-yl)thiophene-2-carboxamide LCMS RT= 5.55min, MH*322.0; 1 H NMR (DMSO): 10.44 (1H, s), 9.37 (1H, dd, J 2.2 0.8 Hz), 8.82 (1H, dd, J4.9 1.7 Hz), 8.56 (1H, dt, J 8.0 2.0 Hz), 8.28 (1H, t, J 1.3 Hz), 8.06 (1H, dd, J 1.7 0.8 Hz), 7.89 (1H, dd, J5.0 1.0 Hz), 7.83 (1H, d, J 9.0 Hz), 7.77 7.73 (IH, m), 7.70-7.65 (1H, m), 7.26 (1H, dd, J 5.0 1.2 Hz) N-(2-Phenylbenzo[d]oxazol-5-yl)benzamide LCMS RT= 6.82min, MH* 314.9; 'H NMR (DMSO): 10.43 (1H, s), 8.31-8.30 (1H, m), 8.25-8.20 (2H, m), 8.02-7.98 (2H, m), 7.79 (2H, d, J 1.2 Hz), 7.65-7.53 (6H, m) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)nicotinamide LCMS RT= 6.55min, MH* 386.8; 'H NMR (DMSO): 10.57 (1H, s), 9.14 (1H, d, J 2.1 Hz), 8.78 (1H, dd, J 4.8 1.6 Hz), 8.33 (1H, dt, J8.0 2.0 Hz), 8.14 (1H, d, J 1.8 Hz), 7.96 (2H, d, J 9.0 Hz), 7.70-7.52 (3H, m), 6.82 (2H, d, J 9.1 Hz), 3.50-3.41 (4H, m), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)isonicotinamide LCMS RT= 6.63min, MH* 386.8; 'H NMR (DMSO): 10.69 (1H, s), 8.87 (2H, d, J 6.1 Hz), 8.20 (1 H, d, J 1.5 Hz), 8.04 (2H, d, J 9.1 Hz), 7.96 (2H, d, J 6.0 Hz), 7.77-7.69 (2H, m), 6.89 (2H, d, J 9.1 Hz), 3.50-3.46 (4H, m), 1.21 (6H, t, J 7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 7.84min, MH* 386.1; 'H NMR (DMSO): 10.43 (1H, s), 8.22-8.20 (1H, m), 8.06-8.01 (4H, m), 7.72 (2H, d, J 1.2 Hz), 7.68-7.58 (3H, m), 6.89 (2H, d, J 9.1 Hz), 3.51 (4H, q, J 7.0 Hz), 1.21 (6H, t, J 7.0 Hz) 4-Chloro-N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 8.60min, MH* 419.9; 'H NMR (DMSO): 10.44 (1H, s), 8.13 (1H, s), 8.00 7.95 (4H, m), 7.66-7.62 (4H, m), 6.82 (2H, d, J9.1 Hz), 3.45 (4H, q, J7.0 Hz), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazo-5-yl)-4-methylbenzamide LCMS RT= 8.28min, MH* 400.2;'H NMR (DMSO): 10.28 (1H, s), 8.14 (1H, s), 7.97 (2H, d, J 8.9 Hz), 8.03 (2H, d, J8.1 Hz), 7.65 (2H, d, J1.2 Hz), 7.36 (2H, d, J8.1 Hz), 6.82 (2H, d, J9.1 Hz), 3.44 (4H, q, J7.0 Hz), 2.40 (3H, s), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yI)-4-methoxybenzamide WO 2009/019504 PCT/GB2008/050648 99 LCMS RT= 7.86min, MH*416.2; 'H NMR (DMSO): 10.20 (1H, s), 8.13-8.12 (1H, m), 8.00-7.95 (4H, m), 7.64 (2H, d, J1.3 Hz), 7.07 (2H, d, J8.9 Hz), 6.82 (2H, d, J9.1 Hz), 3.85 (3H, s), 3.44 (4H, q, J7.0 Hz), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yI)-2-methoxybenzamide LCMS RT= 8.69min, MH*416.0; 'H NMR (DMSO): 10.24 (1H, s), 8.15 (1H, d, J 1.5 Hz), 7.96 (2H, d, J8.9 Hz), 7.68-7.49 (4H, m), 7.19 (1H, d, J 8.4 Hz), 7.08 (1H, t, J 7.5 Hz), 6.83 (2H, d, J9.1 Hz), 3.92 (3H, s), 3.44 (4H, q, J7.0 Hz), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yI)-4-(dimethylamino)benzamide LCMS RT= 8.08min, MH 4 429.0; 'H NMR (DMSO): 9.98 (1H, s), 8.13 (1H, s), 7.96 (2H, d, J8.9 Hz), 7.90 (2H, d, J 8.9 Hz), 7.64-7.61 (2H, m), 6.84-6.76 (4H, m), 3.44 (4H, q, J 7.0 Hz), 3.01 (6H, s), 1.15 (6H, t, J7.0 Hz) 3,4-Dichloro-N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 9.66min, MH*453.9; 'H NMR (DMSO): 10.52 (1H, s), 8.25 (1H, d, J 2.0 Hz), 8.12 (1H, d, J1.8 Hz), 7.98-7.94 (3H, m), 7.85 (1H, d, J 8.4 Hz), 7.70-7.60 (2H, m), 6.82 (2H, d, J9.2 Hz), 3.45 (4H, q, J7.0 Hz), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-y1)-4-(trifluoromethyl)benzanide LCMS RT= 8.87min, MH*454.4;'H NMR (DMSO): 10.60 (1H, s), 8.20-8.15 (3H, m), 7.99-7.93 (4H, m), 7.70-7.63 (2H, m), 6.83 (2H, d, J 9.2 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J7.0 Hz) 3,5-Dichloro-N-(2-(4-(diethylamino)phenyl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 10.25min, MH 4 453.8; 'H NMR (DMSO): 10.63 (1H, s), 8.21-8.19 (1H, m), 8.09 (2H, d, J 1.9 Hz), 8.05 (2H, d, J9.1 Hz), 7.97 (1H, t, J 1.9 Hz), 7.78-7.69 (2H, m), 6.91 (2H, d, J 9.1 Hz), 3.50 (4H, q, J 7.0 Hz), 1.23 (6H, t, J 7.0 Hz) N.-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yI)-4-fluorobenzamide LCMS RT= 7.95min, MH*404.1; 'H NMR (DMSO): 10.38 (1H, s), 8.13-8.12 (1H, m), 8.09-8.04 (2H, m), 7.96 (2H, d, J 9.1 Hz), 7.68-7.61 (2H, m), 7.39 (2H, t, J 8.9 Hz), 6.82 (2H, d, J9.2 Hz), 3.45 (4H, q, J7.0 Hz), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)biphenyl-4-carboxamide LCMS RT=.9.67min, MH*461.9; 'H NMR (DMSO): 10.42 (1H, s), 8.18-8.17 (1H, m), 8.09 (2H, d, J 8.5 Hz), 7.98 (2H, d, J 9.0 Hz), 7.87 (2H, d, J 8.6 Hz), 7.78 (2H, d, J 7.1 Hz), 7.71-7.65 (2H, m), 7.45-7.41 (3H, m), 6.82 (2H, d, J9.2 Hz), 3.45 (4H, q, J 7.0 Hz), 1.15 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yI)-2-phenylacetamide WO 2009/019504 PCT/GB2008/050648 100 LCMS RT= 7.70min, MH*400.1;'H NMR (DMSO): 10.29 (1H, s), 8.00 (1H, d, J 1.8 Hz), 7.94 (2H, d, J9.1 Hz), 7.59 (1H, d, J8.7 Hz), 7.45-7.23 (6H, m), 6.81 (2H, d, J 9.2 Hz), 3.67 (2H, s), 3.43 (4H, q, J7.0 Hz), 1.14 (6H, t, J7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yI)-3-phenylpropanamide LCMS RT= 8.10min, MH*413.9; 'H NMR (DMSO): 10.03 (1H, s), 7.99 (1H, d, J 1.9 Hz), 7.94 (2H, d, J 9.1 Hz), 7.58 (1H, d, J 8.7 Hz), 7.40 (1H, dd, J 8.7 2.0 Hz), 7.36 7.17 (5H, m), 6.82 (2H, d, J 9.2 Hz), 3.44 (4H, q, J 7.0 Hz), 2.94 (2H, d, J 8.1 Hz), 2.65 (1H, d, J 8.3 Hz), 1.15 (6H, t, J 7.0 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)propionamide LCMS RT= 6.79min, MH 4 338.2;1H NMR (DMSO): 10.11 (1H, s), 8.07 (1H, d, J1.9 Hz), 7.99 (2H, d, J9.0 Hz), 7.65 (1H, d, J 8.7 Hz), 7.48 (1H, dd, J 8.8 2.0 Hz), 6.87 (2H, d, J9.1 Hz), 3.49 (4H, q, J7.0 Hz), 2.41 (2H, q, J7.5 Hz), 1.24-1.14 (9H, m) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 7.24min, MH*352.2; 'H NMR (DMSO): 9.97 (1H, s), 8.00 (1H, d, J 1.9 Hz), 7.95 (2H, d, J9.0 Hz), 7.58 (1H, d, J 8.7 Hz), 7.43 (1H, dd, J 8.8 2.0 Hz), 6.81 (2H, d, J 9.1 Hz), 3.44 (4H, q, J 7.0 Hz), 2.31 (2H, t, J 7.4 Hz), 1.68-1.58 (2H, m), 1.15 (6H, t, J7.0 Hz), 0.94 (3H, t, J7.4 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)pentanamide LCMS RT= 7.84min, MH* 366.0 1 H NMR (DMSO): 9.98 (1 H, s), 8.00 (1 H, d, J 1.9 Hz), 7.95 (2H, d, J9.0 Hz), 7.58 (1H, d, J 8.7 Hz), 7.42 (1H, dd, J 8.8 2.0 Hz), 6.81 (2H, d, J9.1 Hz), 3.44 (4H, q, J7.0 Hz), 2.33 (2H, t, J7.5 Hz), 1.65-1.55 (2H, m), 1.41-1.28 (2H, m), 1.15 (6H, t, J 7.0 Hz), 0.91 (3H, t, J 7.4 Hz) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.25min, MH* 352.2; 1 H NMR (DMSO): 9.99 (1H, s), 8.08 (1H, d, J 1.9 Hz), 8.01 (2H, d, J 9.0 Hz), 7.65 (1 H, d, J 8.7 Hz), 7.51 (1 H, dd, J 8.8 2.0 Hz), 6.88 (2H, d, J 9.1 Hz), 3.50 (4H, q, J7.0 Hz), 2.70-2.64 (1H, m), 1.24-1.17 (12H, m) N-(2-(4-(Diethylamino)phenyl)benzo[d]oxazol-5-yl)thiophene-2-carboxamide LCMS RT= 7.77min, MH* 392.1; 1 H NMR (DMSO): 10.41 (1H, s), 8.14 (1H, d, J 1.8 Hz), 8.12 (1H, dd, J3.8 1.0 Hz), 8.04 (2H, d, J9.1 Hz), 7.95 (1H, dd, J 4.9 1.0 Hz), 7.73 (1H, d, J 8.6 Hz), 7.66 (1H, dd, J 8.7 1.9 Hz), 7.34-7.30 (1H, m), 6.90 (2H, d, J 9.2 Hz), 3.51 (4H, q, J 7.0 Hz), 1.22 (6H, t, J 7.0 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)isonicotinamide LCMS RT= 6.36min, MH t 350.0; 1 H NMR (DMSO): 10.71 (1H, s), 8.82 (2H, d, J 9.0 Hz), 8.32-8.30 (1 H, m), 8.22 (2H, d, J 8.6 Hz), 7.90 (2H, d, J 6.0 Hz), 7.85-7.79 (2H, m), 7.71 (2H, d, J 8.6 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)benzamide WO 2009/019504 PCT/GB2008/050648 101 LCMS RT= 7.67min, MH* 349.0; 'H NMR (DMSO): 10.46 (1H, s), 8.32 (1H, s), 8.22 (2H, d, J 8.5 Hz), 8.01-7.98 (2H, m), 7.79 (2H, d, J 1.1 Hz), 7.71 (2H, d, J 8.6 Hz), 7.65-7.50 (3H, m) 4-Chloro-N-(2-(4-chlorophenyl)banzo[d]oxazol-5-yl)benzamide LCMS RT= 8.51min, MH*383.2; 1 H NMR (DMSO): 10.52 (1H, s), 8.30 (1H, s), 8.22 (2H, d, J 8.8 Hz), 8.03 (2H, d, J 8.8 Hz), 7.82-7.77 (2H, m), 7.71 (2H, d, J 8.4 Hz), 7.64 (2H, d, J8.4 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)-4-methylbenzamide LCMS RT= 8.21min, MH* 362.8; "H NMR (DMSO): 10.36 (1H, s), 8.31 (1H, s), 8.22 (2H, d, J 8.7 Hz), 7.92 (2H, d, J 8.2 Hz), 7.78 (2H, d, J 1.3 Hz), 7.71 (2H, d, J 8.7 Hz), 7.37 (2H, d, J 8.0 Hz), 2.41 (3H, s) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)-4-methoxybenzamide LCMS RT= 7.62min, MH378.7;'H NMR (DMSO): 10.28 (1H, s), 8.30 (1H, s), 8.22 (2H, d, J 8.9 Hz), 7.99 (2H, d, J 8.9 Hz), 7.77 (2H, s), 7.70 (2H, d, J 8.3 Hz), 7.08 (2H, d, J 8.9 Hz), 3.86 (3H, s) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)-2-methoxybenzamide LCMS RT= 8.55min, MH* 379.0; "H NMR (DMSO): 10.29 (1H, s), 8.29 (1H, d, J 1.5 Hz), 8.18 (2H, d, J 8.6 Hz), 7.77-7.62 (5H, m), 7.52-7.46 (1H, m), 7.17 (1H, d, J 8.3 Hz), 7.05 (1H, t, J 7.5 Hz), 3.89 (3H, s) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)-4-(dimethylamino)benzamide LCMS RT= 7.96min, MH 4 392.3;'H NMR (DMSO): 10.12 (1H, s), 8.36 (1H, s), 8.27 (2H, d, J 8.6 Hz), 7.96 (2H, d, J 8.8 Hz), 7.83-7.81 (2H, m), 7.76 (2H, d, J 8.5 Hz), 6.84 (2H, d, J9.0 Hz), 3.07 (6H, s) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)-4-(trifluoromethyl)benzamide LCMS RT= 8.65min, MH* 416.7; 1 H NMR (DMSO): 10.67 (1H, s), 8.32 (1H, s), 8.24 8.18 (4H, m), 7.95 (2H, d, J 8.6 Hz), 7.84-7.77 (2H, m), 7.71 (2H, d, J 8.6 Hz) 3,5-Dichloro-N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)benzamide LCMS RT= 10.09min, MH*417.1; 'H NMR (DMSO): 10.68 (1H, s), 8.34 (1H, d, J 1.8 Hz), 8.28 (2H, d, J 8.6 Hz), 8.08 (2H, d, JI.9 Hz), 7.96 (1H, t, J1.9 Hz), 7.89-7.78 (2H, m), 7.76 (2H, d, J 8.7 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)-4-fluorobenzamide LCMS RT= 7.78min, MH* 367.3; 'H NMR (DMSO): 10.58 (1H, s), 8.35 (1H, s), 8.28 (2H, d, J 8.9 Hz), 8.16-8.11 (2H, m), 7.90-7.82 (2H, m), 7.77 (2H, d, J 8.4 Hz), 7.52 7.42 (2H, m) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)-2-phenylacetamide LCMS RT= 7.48min, MH*362.8; 'H NMR (DMSO): 10.38 (1H, s), 8.22-8.17 (3H, m), 7.75-7.65 (3H, m), 7.55 (1 H, dd, J 9.0 2.1 Hz), 7.38-7.24 (5H, in), 3.69 (2H, s) WO 2009/019504 PCT/GB2008/050648 102 N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-y)-3-phenylpropanamide LCMS RT= 7.92min, MH*377.3; 'H NMR (DMSO): 10.12 (1H, s), 8.19 (2H, d, J 8.8 Hz), 8.16 (1H, d, J 1.8 Hz), 7.74-7.68 (3H, m), 7.51 (1H, dd, J 8.8 2.0 Hz), 7.33-7.17 (5H, m), 2.95 (2H, t, J 7.3 Hz), 2.67 (2H, t, J 7.3 Hz), N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 7.04min, MH*315.1 'H NMR (DMSO): 10.07 (1H, s), 8.21-8.18 (3H, m), 7.73-7.67 (3H, m), 7.54 (1H, dd, J8.8 1.9 Hz), 2.32 (2H, t, J7.4 Hz), 1.72-1.58 (2H, m), 0.94 (3H, t, J7.4 Hz) N-(2-(4-Chlarophenyl)benzo[d]oxazol-5-yI)pentanamide LCMS RT= 7.66min, MH*329.1; 'H NMR (DMSO): 10.07 (1H, s), 8.22-8.16 (3H, m), 7.73-7.68 (3H, m), 7.56-7.51 (1H, m), 2.34 (2H, t, J 7.5 Hz), 1.66-1.56 (2H, im), 1.42 1.30 (2H, m), 0.92 (3H, t, J 7.2 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)isobutyramide LCMS RT= 7.04min, MH 315.1; 'H NMR (DMSO): 10.03 (1H, s), 8.22-8.18 (3H, m), 7.74-7.67 (3H, m), 7.56 (1H, dd, J 8.9 2.1 Hz), 2.67-2.59 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(4-C hlorophenyl)benzo[d]oxazol-5-yI)furan-2-carboxamide LCMS RT= 7.01min, MH 4 338.9; 'H NMR (DMSO): 10.40 (1H, s), 8.27 (1H, d, J 1.1 Hz), 8.22 (2H, d, J 8.5 Hz), 7.97 (1H, s), 7.78 (2H, s), 7.70 (2H, d, J 8.5 Hz), 7.36 (1H, d, J 3-4 Hz), 6.74-6.73 (1H, m) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)thiophene-2-carboxamide LCMS RT= 7.54min, MH* 355.0; 'H NMR (DMSO): 10.42 (1H, s), 8.25-8.21 (3H, m), 8.06 (1H, dd, J 3.9 1.2 Hz), 7.89 (1H, dd, J 5.0 1.0 Hz), 7.80 (1H, d, J 8.8 Hz), 7.74 7.69 (3H, m), 7.26 (1 H, dd, J 5.0 3.8 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yl)nicotinamide LCMS RT= 6.12min, MH* 330.1; 'H NMR (DMSO): 10.62 (1H, s), 9.15 (1H, dd, J 2.1 0.7 Hz), 8.79 (1H, dd, J4.8 1.7 Hz), 8.34 (1H, dt, J7.9 1.8 Hz), 8.27 (1H, d, J 1.6 Hz), 8.11 (2H, d, J 8.2 Hz), 7.82-7.72 (2H, m), 7.63-7.58 (1H, m), 7.44 (2H, d, J 8.0 Hz), 2.43 (3H, s) N-(2-p-Tolylbenzo[d]oxazol-5-yl)isonicotinamide LCMS RT= 6.17min, MH* 330.1; 'H NMR (DMSO): 10.68 (1H, s), 8.82 (2H, d, J 6.0 Hz), 8.27 (1H, d, J1.5 Hz), 8.22 (2H, d, J 8.2 Hz), 7.90 (2H, d, J 6.0 Hz), 7.81-7.72 (2H, m), 7.45 (2H, d, J 8.0 Hz), 2.43 (3H, s) N-(2-p-Tolylbenzo[d]oxazol-5-yl)propionamide WO 2009/019504 PCT/GB2008/050648 103 LCMS RT= 6.34min, MH*281.0; 1 H NMR (DMSO): 10.03 (1H, s), 8.14 (1H, d, J 1.8 Hz), 8.08 (2H, d, J8.2 Hz), 7.69 (1H, d, J8.8 Hz), 7.51 (1H, dd, J8.8 2.0 Hz), 7.44 (2H, d, J 8.0 Hz), 2.42 (3H, s), 2.36 (2H, q, J7.5 Hz), 1.12 (3H, t, J 7.6 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yl)butyramide LCMS RT=6.73min, MH*295.1; 1 H NMR(DMSO): 10.04 (1H, s), 8.13 (1H, d, J1.8 Hz), 8.08 (2H, d, J 8.2 Hz), 7.69 (1 H, d, J 8.8 Hz), 7.51 (1 H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 2.32 (2H, t, J7.4 Hz), 1.71-1.58 (2H, m), 0.94 (3H, t, J 7.4 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yl)pentanamide LCMS RT= 7.20min, MH* 309.1; 'H NMR (DMSO): 10.04 (1 H, s), 8.13 (1H, d, J 1.8 Hz), 8.08 (2H, d, J 8.2 Hz), 7.68 (1H, d, J 8.8 Hz), 7.51 (1H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 2.34 (2H, t, J7.4 Hz), 1.67-1.56 (2H, m), 1.41-1.29 (2H, m), 0.92 (3H, t, J 7.4 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.74min, MH 4 295.1; 'H NMR (DMSO): 10.00 (1H, s), 8.15 (1H, d, J 1.8 Hz), 8.09 (2H, d, J 8.2 Hz), 7.69 (1 H, d, J 8.8 Hz), 7.53 (1 H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.66-2.60 (1H, m), 2.42 (3H, s), 1.13 (6H, d, J 6.8 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yl)furan-2-carboxamide LCMS RT= 6.71min, MH*319.0;"H NMR (DMSO): 10.37 (1H, s), 8.23 (1H, s), 8.10 (2H, d, J 8.2 Hz), 7.98-7.96 (1 H, m), 7.75 (2H, d, J 1.0 Hz), 7.44 (2H, d, J 8.0 Hz), 7.36.(1H, d, J 3.6 Hz), 6.74-6.72 (1 H, m), 2.43 (3H, s) N-(2-p-Tolylbenzo[d]oxazol-5-yl)thiophene-2-carboxamide LCMS RT= 7.15min, MH* 335.0; 'H NMR (DMSO): 10.40 (1H, s), 8.21 (1H, d, J 1.7 Hz), 8.11 (2H, d, J8.2 Hz), 8.05 (1H, dd, J3.8 1.0 Hz), 7.89 (1H, d, J4.9 1.0 Hz), 7.76 (1H, d, J8.8 Hz), 7.69 (1H, dd, J 8.9 2.0 Hz), 7.44 (2H, d, J 8.0 Hz), 7.26 (1H, dd, J5.0 3.8 Hz), 2.43 (3H, s) N-(2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)nicotinamide LCMS RT= 6.49min, MH 4 383.9; 'H NMR (DMSO): 10.70 (1H, s), 9.20-9.18 (1H, in), 8.82 (1H, dd, J 4.6 1.5 Hz), 8.46 (2H, d, J 8.1 Hz), 8.40-8.36 (2H, m), 8.04 (2H, d, J 8.0 Hz), 7.92-7.82 (2H, m), 7.66-7.61 (1H, m) N-(2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)isonicotinamide LCMS RT= 6.52min; 'H NMR (DMSO): 10.80 (1H, s), 8.90 (2H, d, J 6.0 Hz), 8.51 (2H, d, J 8.2 Hz), 8.44 (1H, d, J1.6 Hz), 8.09 (2H, d, J 8.2 Hz), 8.01-7.93 (3H, m), 7.89 (11H, dd, J 8.9 1.9 Hz) N-(2-(4-(Trifluoromethyl)phenyl)benzo[djoxazol-5-yl)acetamide WO 2009/019504 PCT/GB2008/050648 104 LCMS RT= 6.30min, MH*320.7; 1 H NMR (DMSO): 10.17 (IH, s), 8.40 (2H, d, J 8.7 Hz), 8.22-8.19 (1H, m), 7.99 (2H, d, J 85 Hz), 7.77 (1H, d, J 8.7 Hz), 7.58-7.53 (1H, m), 2.09 (3H, s) N-(2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)propionam ide LCMS RT= 6.73min, MH* 335.0; 'H NMR (DMSO): 10.09 (1H, s), 8.40 (2H, d, J 7.8 Hz), 8.23 (1H, d, J 1.9 Hz), 7.99 (2H, d, J 8.2 Hz), 7.77 (1H, d, J 8.7 Hz), 7.57 (1H, dd, J 8.8 2.0 Hz), 2.37 (2H, q, J7.5 Hz), 1.12 (3H, t, J7.5 Hz) N-(2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 7.18min, MH+348.9; 1H NMR (DMSO): 10.10 (1H, s), 8.40 (2H, d, J7.8 Hz), 8.23 (1H, d, J1.9 Hz), 7.99 (2H, d, J 8.2 Hz), 7.77 (1H, d, J8.7 Hz), 7.58 (1H, dd, J8.8 2.0 Hz), 2.33 (2H, t, J7.3 Hz), 1.69-1.59 (2H, m), 0.94 (3H, t, J7.6 Hz) N-(2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)pentanamide LCMS RT= 7.74min, MH*363.1; 'H NMR (DMSO): 10.10 (1H, s), 8.40 (2H, d, J7.8 Hz), 8.22 (1 H, d, J 1.9 Hz), 7.99 (2H, d, J 8.2 Hz), 7.77 (1 H, d, J 8.7 Hz), 7.57 (1 H, dd, J 8.8 2.0 Hz), 2.36 (2H, t, J 7.3 Hz), 1.66-1.58 (2H, m), 1.42-1.29 (2H, m), 0.92 (3H, t, J7.6 Hz) N-(2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.15min, MH* 349.1; 'H NMR (DMSO): 10.09 (1H, s), 8.43 (2H, d, J7.8 Hz), 8.27 (1 H, d, J 1.9 Hz), 8.02 (2H, d, J 8.2 Hz), 7.80 (1 H, d, J 8.7 Hz), 7.63 (1 H, dd, J 8.8 2.0 Hz), 2.72-2.63 (1H, m), 1.18 (6H, d, J 6.8 Hz) N-(2-(4-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yI)furan-2-carboxamide LCMS RT= 7.15min, MH*373.0; 'H NMR (DMSO): 10.28 (1H, s), 8.27 (2H, d, J 8.0 Hz), 8.18-8.16 (1H, m), 7.86 (2H, d, J 8.2 Hz), 7.84-7.82 (1H, m), 7.69-7.67 (2H, m), 7.23 (1H, dd, J 3.5 0.8 Hz), 6.59 (1H, dd, J3.5 1.7 Hz) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yl)isonicotinamide LCMS RT= 5.76min, MH* 346.0; 'H NMR (DMSO): 10.66 (1H, s), 8.81 (2H, d, J6.1 Hz), 8.24 (1H, d, J1.7 Hz), 8.16 (2H, d, J9.0 Hz), 7.90 (2H, d, J 6.1 Hz), 7.77 (1H, d, J 8.8 Hz), 7.72 (1H, dd, J 8.8 1.9 Hz), 7.18 (2H, d, J 8.9 Hz), 3.88 (3H, s) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yl)acetamide LCMS RT= 5.59min, MH283.0;'H NMR (DMSO): 10.09 (1H, s), 8.13 (2H, d, J 8.9 Hz), 8.08 (1H, d, J1.8 Hz), 7.67 (1H, d, J 8.9 Hz), 7.47 (1H, dd, J 8.8 2.0 Hz), 7.16 (2H, d, J9.0 Hz), 3.87 (3H, s), 2.08 (3H, s) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yI)propionamide LCMS RT= 5.89min, MH*297.1; 1 H NMR (DMSO): 10.02 (1H, s), 8.15-8.10 (3H, m), 7.67 (1H, d, J 8.7 Hz), 7.49 (1H, dd, J 8.8 1.8 Hz), 7.16 (2H, d, J 8.8 Hz), 3.88 (3H, s), 2.36 (2H, q, J 7.7 Hz ), 1.11 (3H, t, J 7.5 Hz ) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yl)butyramide WO 2009/019504 PCT/GB2008/050648 105 LCMS RT= 6.19min, MH*31 1.1; 'H NMK (UMSO): 10.02 (1H, s), 8.13 (2H, d, J 9.0 Hz), 8.10 (1H, d, J 1.9 Hz), 7.66 (1H, d, J8.9 Hz), 7.49 (1H, dd, J8.8 1.8 Hz), 7.16 (2H, d, J 9.0 Hz), 3.87 (3H, s), 2.32 (2H, t, J 7.3 Hz), 1.70-1.58 (2H, m), 0.94 (3H, t, J 7.5 Hz) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yl)pentanamide LCMS RT= 6.59min, MH 4 325.1;'H NMR (DMSO): 10.02 (1H, s), 8.13 (2H, d, J9.0 Hz), 8.10 (1H, d, J1.9 Hz), 7.66 (1H, d, J 8,9 Hz), 7.49 (1H, dd, J 8.8 1.8 Hz), 7.16 (2H, d, J9.0 Hz), 3,87 (3H, s), 2.34 (2H, t, J7.3 Hz ), 1.66-1.56 (2H, m), 1.41-1.29 (2H, m), 0.92 (3H, t, J 7.5 Hz ) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.19min, MH 4 311.1; H NMR (DMSO): 9.98 (1 H, s), 8.15-8.11 (3H, m), 7.66 (1H, d, J 8.9 Hz), 7.51 (1H, dd, J 8.8 1.8 Hz), 7.16 (2H, d, J 9.0 Hz), 3.88 (3H, s), 1.13 (6H, d, J 6.9 Hz) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yl)furan-2-carboxamide LCMS RT= 6.16min, MH*335.1;'H NMR (DMSO): 10.36 (1H, s), 8.20-8.13 (3H, m), 7.96 (1H, dd, J 1.8 0.8 Hz), 7.72 (2H, d, J 1.2 Hz), 7.36 (1H, dd, J3.5 0.8 Hz), 7.17 (2H, d, J9.0 Hz), 6.73 (1H, dd, J3.5 1.7 Hz), 3.88 (3H, s) N-(2-(4-Methoxyphenyl)benzo[d]oxazol-5-yi)thiophene-2-carboxamide LCMS RT= 6.54min, MH 351.0; H NMR (DMSO): 10.38 (1H, s), 8.19-8.14 (3H, m), 8.05 (1H, dd, J 3.7 1.0 Hz), 7.88 (1H, dd, J 4.1 1.0 Hz), 7.74 (1H, d, J 8.8 Hz), 7.67 (1H, dd, J 8.8 2.0 Hz), 7.27-7.23 (1H, m), 7.17 (2H, d, J 8.9 Hz), 3.88 (3H, s) N-(2-m-Tolylbenzo[d]oxazol-5-yl)butyramide LCMS RT= 6.67min, MH295.0; N-(2-(3-(Dimethylamino)phenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 6.62min, MH* 324.1;'H NMR (DMSO): 10.06 (1H, s), 8.13 (1H, d, J 1.8 Hz), 7.70 (1H, d, J 8.8 Hz), 7.53 (1H, dd, J 8.8 2.0 Hz), 7.49-7.37 (3H, m), 7.00-6.96 (1H, m), 3.00 (6H, s), 2.32 (2H, t, J 7.6 Hz), 1.71-1.55 (2H, m), 0.94 (3H, t, J 7.4 Hz) N-(2-m-Tolylbenzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.64min, MH* 295.0; 'H NMR (DMSO): 10.02 (1H, s), 8.17 (1H, d, J 1.9 Hz), 8.03-7.98 (2H, m), 7.71 (1H, d, J 8.8 Hz), 7.56-7.44 (3H, m), 2.60-2.58 (1H, m), 2.44 (3H, s), 1.14 (6H, d, J 6.8 Hz) N-(2-(3-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.88min, MH 4 349.0; 'H NMR (DMSO): 10.06 (1H, s), 8.51-8.43 (2H, m), 8.23 (1H, s), 8.03 (1H, d, J7.4 Hz), 7.91-7.85 (1H, m), 7.77 (1H, d, J 8.5 Hz), 7.62 7.57 (1H, m), 2.63 (1H, t, J 6.8 Hz), 1.14 (6H, d, J 6.8 Hz) N-(2-(3-(Dimethylamino)phenyl)benzo[d]oxazol-5-yl)isobutyramide WO 2009/019504 PCT/GB2008/050648 106 LCMS RT= 6.59min, MH*324.1;IH NMR (DMSO): 10.01 (1H, s), 8.15 (1H, d, J1.8 Hz), 7.70 (1H, d, J 8.8 Hz), 7.55 (1H, dd, J 8.8 2.0 Hz), 7.49-7.37 (3H, m), 7.00-6.96 (1H, m), 3.01 (6H, s), 2.65-2.58 (1H, m), 1.13 (6H, d, J 7.0 Hz) N-(2-(3-(Trifluoromethyl)phenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 6.85min, MH2349.0; "H NMR (DMSO): 10.08 (1H, s), 8.48 (1H, d, J7.8 Hz), 8.43 (1 H, s), 8.21 (1 H, d, J 1.9 Hz), 8.02 (1 H, d, J 8.0 Hz), 7.88 (1 H, d, J 7.7 Hz), 7.76 (1H, d, J 8.8 Hz), 7.58 (1H, dd, J 8.8 2.0 Hz), 2.33 (2H, t, J 7.4 Hz), 1.71 1.59 (2H, m), 0.95 (3H, t, J7.4 Hz) N-(2-o-Tolylbenzo[d]oxazol-5-yI)isobutyramide LCMS RT= 6.62min, MH* 295. 1"H NMR (DMSO): 10.00 (1H, s), 8.19 (1H, d, J 1.9 Hz), 8.12 (1H, dd, J7.4 1.5 Hz), 7.71 (1H, d, J 8.8 Hz), 7.57-7.40 (4H, m), 2.75 (3H, s), 2.65-2.59 (1H, m), 1.14 (6H, d, J 6.7 Hz) N-(2-(2-Chlorophenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 6.42min, MH* 315.0; 1 H NMR (DMSO): 10.08 (1H, s), 8.22 (1H, d, J 1.8 Hz), 8.15 (1H, dd, J7.6 1.8 Hz), 7.76-7.55 (5H, m), 2.34 (2H, t, J7.4 Hz), 1.71-1.59 (2H, m), 0.95 (3H, t, J 7.4 Hz) N-(2-(2-Chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.41min, MH* 315.0; "H NMR (DMSO): 10.03 (1H, s), 8.23 (1H, d, J 1.8 Hz), 8.15 (1H, dd, J7.6 1.7 Hz), 7.71-7.55 (5H, m), 2.68-2.58 (1H, m), 1.14 (6H, d, J 6.7 Hz) N-(2-(3-Chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.89min, MH*315.0;"H NMR (DMSO): 10.05 (1H, s), 8.21-8.15 (3H, m), 7.75-7.63 (3H, m), 7.57 (1H, d, J 8.8 2.0 Hz), 2.62-2.58 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(3-chlorophenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 6.89min, MH*315.1; "H NMR (DMSO): 10.07 (1H, s), 8.19-8.11 (3H, m), 7.75-7.63 (3H, m), 7.56 (1H, d, J 8.8 2.0 Hz), 2.33 (2H, t, J7.4 Hz), 1.71-1.59 (2H, m), 0.94 (3H, t, J7.4 Hz) Method 3C (Compounds 11) As Method 3A, except instead of diisopropylamine in dichloromethane, pyridine was used both as solvent and base. N-(2-Phenyloxazolo[5,4-b]pyridin-6-yl)butyramide WO 2009/019504 107 PCT/GB2008/050648 LCMS RT= 5.95min, MH282.0; 1 H NMR (DMSO): 10.31 (1H, s), 8.54 (1H, d, J2.3 Hz), 8.48 (1H, d, J2.3 Hz), 8.24-8.21 (2H, m), 7.72-7.62 (3H, m), 2.37 (2H, t, J7.3 Hz ), 1.72-1.60 (2H, m), 0.95 (3H, t, J 7.5 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)propionamide LCMS RT= 6.54min, MH*301.0; 'H NMR (DMSO): 10.07 (1H, s), 8.21-8.18 (3H, m), 7.73-7.67 (3H, m), 7.53 (1H, dd, J8.8 2.0 Hz), 2.36 (2H, q, J7.6 Hz), 1.12 -(3H, t, J 7.5 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yl)pivalamide LCMS RT= 6.94min, MH* 309.1; 1 H NMR (DMSO): 9.36 (1H, s), 8.13 (1H, d, J 1.8 Hz), 8.09 (2H, d, J 8.2 Hz), 7.69 (1 H, d, J 8.8 Hz), 7.61 (1 H, dd, J 8.8 2.0 Hz), 7.43 (2H, d, J 8.0 Hz), 2.42 (3H, s), 1.26 (9H, s) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)pivalamide LCMS RT= 7.28min, MH*329.1; "H NMR (DMSO): 9.39 (1H, s), 8.20 (2H, d, J8.6 Hz), 8.17 (1H, d, J 1.7 Hz), 7.74-7.62 (4H, m), 1.26 (9H, s) N-(2-Benzylbenzo[d]oxazol-5-yl)butyramide LCMS RT= 5.98min, MH*295.1;IH NMR (DMSO): 9.97 (1H, s), 8.03 (1H, d, J1.8 Hz), 7.56 (1H, d, J 8.7 Hz), 7.44 (1H, dd, J 8.9 2.1 Hz), 7.38-7.35 (4H, m), 7.33-7.25 (1H, m), 4.31 (2H, s), 2.28 (2H, t, J7.3 Hz ), 1.69-1.53 (2H, m), 0.92 (3H, t, J7.5 Hz) N-(2-Benzylbenzo[d]oxazol-5-yl)isobutyramide LCMS RT= 5.96min, MH*295.1; H NMR (DMSO): 9.93 (1H, s), 8.04 (1H, d, J 2.1 Hz), 7.56 (1H, d, J 8.9 Hz), 7.47 (1H, dd, J9.0 2.0 Hz), 7.38-7.35 (4H, m), 7.33-7.28 (1H, m), 4.31 (2H, s), 2.60-2.58 (1H, m), 1.11 (6H, d, J 6.8 Hz) N-(2-p-Tolylbenzo[d]oxazol-4-yl)butyramide LCMS RT= 7.54min, MH295.1; 'H NMR (DMSO): 10.03 (1H, s), 8.13 (2H, d, J 8.2 Hz), 8.03 (1H, d,- J 8.2 Hz), 7.48-7.44 (3H, m), 7.34 (1H, t, J 8.2 Hz), 2.43 (3H, s), 1.72-1.60 (2H, m), 1.09 (3H, t, J 6.9 Hz) N-(2-p-Tolylbenzo[d]oxazol-4-yl)isobutyramide LCMS RT= 7.51min, MH295.1;'H NMR (DMSO): 9.78 (1H, s), 7.93 (2H, d, J 8.4 Hz), 7.83 (1H, d, J 8.2 Hz), 7.28-7.23 (3H, m), 7.14 (1H, t, J 8.4 Hz), 2.22 (3H, s), 0.94 (6H, d, J 6.8 Hz) N-(2-Cyclohexylbenzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.48min, MH*287.1; 'H NMR (CDCi 3 ): 7.82 (1H, d, J 1.7 Hz), 7.66-7.56 (1H, m), 7.46 (1H, d, J 8.8 Hz), 7.30-7.25 (1H, m), 3.07-2.97 (1H, m), 2.65-2.53 (1H, m), 2.26-2.16 (2H, m), 1.97-1.72 (5H, m), 1.56-1.37 (3H, m), 1.33 (6H, t, J 6.8 Hz) N-(2-Cyclohexylbenzo[d]oxazol-5-yl)butyramide WO 2009/019504 PCT/GB2008/050648 108 LCMS RT= 6.51min, MH*287.2;'H NMR (CDCI 3 ): 7.69 (1H, s), 7.45 (1H, d, J8.8 Hz), 7.33 (1 H, d, J 8.8 Hz), 7.16 (1H, s), 2.93-2.83 (1H, m), 2.29 (2H, t, J7.6 Hz), 2.11-2.06 (2H, m), 1.83-1.57 (6H, m), 1.43-1.18 (4H, m), 0.95 (3H, t, J7.5 Hz) N-(2-(2,4-Dichlorophenyl)benzo[d]oxazol-5-yl)isobutyram ide LCMS RT= 7.17min, MH*348.9; 'H NMR (DMSO): 10. 11 (1H, s), 8.23 (1H, d, J 1.7 Hz), 8.19 (1H, d, J 8.8 Hz), 7.92 (1H, d, J 2.1 Hz), 7.75 (1H, d, J 9.0 Hz), 7.68 (1H, dd, J 8.5 2.1 Hz), 7.60 (1H, dd, J 8.7 2.0 Hz), 2.64 (1H, t, J 6.8 Hz), 1.14 (6H, d, J 6.8 Hz) N-(2-(4-Fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.39min, MH* 299.0; 'H NMR (DMSO): 10.00 (1H, s), 8.27-8.23 (2H, m), 8.18-8.17 (1H, m), 7.70 (1H, d, J 8.6 Hz), 7.55 (1H, dd, J 8.7 2.0 Hz), 7.46 (2H, t, J 8.7 Hz), 2.64-2.59 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(3,4-Dichlorophenyl)benzo[d]oxazol-5-yI)isobutyramide LCMS RT= 7.55min, MH 349.5; 'H NMR (DMSO): 10.03 (1H, s), 8.35 (1H, d, J 1.9 Hz), 8.21 (1 H, d, J 1.9 Hz), 8.15 (1 H, d, J 8.4 2.0 Hz), 7.89 (1 H, d, J 8.4 Hz), 7.74 (1H, d, J 8.9 Hz), 7,58 (1H, dd, J8.9 2.0 Hz), 2.67-2.60 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(5-Chloropyridin-2-yl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 5.95min, MH 316.0; 'H NMR (DMSO): 10.05 (1H, s), 8.86 (1H, d, J 2.1 Hz), 8.35 (1H, d, J 8.5 Hz), 8.25 (1H, d, J 1.7 Hz), 8.19 (1H, dd, J 8.5 2.4 Hz), 7.77 (1H, d, J 8.8 Hz), 7.60 (1H, dd, J8.8 2.0 Hz), 2.65-2.61 (1H, m), 1.14 (6H, d, J 6.7 Hz) N-(2-(3,5-Dichlorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.83min, MH 348.7; 'H NMR (DMSO): 10.05 (1H, s), 8.23 (1H, d, J 1.9 Hz), 8.15 (2H, d, J2.0 Hz), 7.92 (1H, t, J2.0 Hz), 7.75 (1H, d, J8.8 Hz), 7.60 (1H, dd, J 8.9 2.0 Hz), 2.68-2.60 (1 H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(2,3-Dichlorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.80min, MH*348.9,'H NMR (DMSO): 10.04 (1H, s), 8.24 (1H, d, J1.8 Hz), 8.11 (1H, dd, J7.9 1.6 Hz), 7.93 (1H, dd, J8.1 1.6 Hz), 7.76 (1H, d, J 8.8 Hz), 7.63-7.59 (2Hm), 2.70-2.58 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-Phenethylbenzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.22min, MH*309.1;'H NMR (DMSO): 9.92 (1H, s), 8.03 (1H, d, J1.8 Hz), 7.57 (1H, d, J8.8 Hz), 7.46 (1H, dd, J 8.7 2.0 Hz), 7.29-7.27 (4H, m), 7.23-7.16 (1H, m), 3.21-3.10 (4H, m), 1.12 (6H, d, J 6.7 Hz) N-(2-(1 -Phenylethyl)benzo[d]oxazol-5-yl)isobutyramide WO 2009/019504 PCT/GB2008/050648 109 LCMS RT= 6.23min, MH T 309.1; "H NMR (DMSO): 9.93 (1H, s), 8.06 (1H, d, J 1.9 Hz), 7.54 (1H, d, J 8.8 Hz), 7.47 (1H, dd, J 8.8 2.1 Hz), 7.36-7.32 (4H, m), 7.30-7.24 (1H, m), 4.51 (1H, q, J7.1 Hz), 2.65-2.57 (1H, m), 1.71 (3H, d, J7.2 Hz), 1.12 (6H, d, J 6.8 Hz) N-(2-f2,5Dichlorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.10min, MH* 349.0; "H NMR (DMSO): 10.11 (1H, s), 8.31 (1H, d, J 1.8 Hz), 8.25 (1H, dd, J 2.4 0.5 Hz), 7.83 (2H, d, J 8.7 Hz), 7.80 (1H, dd, J 8.7 2.5 Hz), 7.67 (1H, dd, J 8.9 2.0 Hz), 2.74-2.64 (1H, m), 1.20 (6H, d, J 6.8 Hz) N-(2-(2-Chloro-4-fluorophenyl)benzofd]oxazol-5-yl)isobutyramide LCMS RT= 6.59min, MH* 333.0; "H NMR (DMSO): 10.05 (1H, s), 8.30-8.20 (2H, m), 7.77-7.73 (2H, m), 7.59 (1H, dd, J 8.8 2.0 Hz), 7.51-7.45 (1H, m), 2.68-2.57 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(2-Chloro-6-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.29min, MH*333.1; 1 H NMR (DMSO): 10.08 (1H, s), 8.26 (1H, d, J 1.9 Hz), 7.80-7.71 (2H, m), 7.64-7.60 (2H, m), 7.57-7.50 (1H, m), 2.68-2.58 (1H, m), 1.14 (6H, d, J 6.9 Hz) N-(2-(3-Chloro-2-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.65min, MH*333.1;"H NMR (DMSO): 10.06 (1H, s), 8.31-8.16 (2H, m), 7.88 (1H, dt, J 8.4 1.7 Hz), 7.77 (1H, d, J 8.8 Hz), 7.60 (1H, dd, J 8.9 2.0 Hz), 7.47 (IH, dt, J 8.0 1.0 Hz), 2.66-2.60 (1H, m), 1.14 (6H, d, J 6.7 Hz) N-(2-(4-Chloro-2-fluorophenyl)benzo[d]oxazol-5-yI)isobutyramide LCMS RT= 6.69min, MH* 333.1; "H NMR (DMSO): 10.05 (1H, s), 8.28-8.21 (2H, m), 7.79-7.73 (2H, m), 7.60-7.53 (2H, m), 2.67-2.58 (1H, m), 1.14 (6H, d, J 6.7 Hz) N-(2-(2-Chloro-5-fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.54min, MH t 333.1; "H NMR (DMSO): 10.07 (1H, s), 8.25 (1H, d, J 1.9 Hz), 7.99 (1H, dd, J9.2 3.2 Hz), 7.80-7.75 (2H, m), 7.63-7.52 (2H, m), 2.68-2.59 (1H, m), 1.14 (6H, d, J 6.7 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)cyclopentanecarboxamide LCMS RT= 7.52min, MH* 341.0; "H NMR (DMSO): 10.08 (1H, s), 8.20-8.16 (3H, in), 7.73-7.66 (3H, m), 7.55 (1H, dd, J8.8 2.0 Hz), 2.85-2.75 (1H, m), 1.93-1.57 (8H, m) N-(5-Chloro-2-(4-chlorophenyl)benzo[d]oxazol-6-yl)isobutyramide LCMS RT= 8.10min; 'H NMR (DMSO): 9.59 (1H, s), 8.20 (2H, d, J8.8 Hz), 8.12 (1H, s), 8.02 (1H, s), 7.71 (2H, d, J 8.6 Hz), 2.84-2.73 (1H, m), 1.16 (6H, d, J 6.8 Hz) N-(2-(Tetrahydro-2H-pyran-4-y)benzo[d]oxazol-5-yi)isobutyramide LCMS RT= 5.38min, MH 4 289.0; "H NMR (DMSO): 9.95 (1H, s), 8.04 (1H, d, J 1.9 Hz), 7.59 (1H, d, J 8.8 Hz), 7.48 (1H, dd, J 8.8 2.0 Hz), 3.95-3.88 (2H, m), 3.47-3.43 WO 2009/019504 PCT/GB2008/050648 110 (3H, m), 2.64-2.55 (1H, m), 2.06-1.9w ( 1, m), 1.89-1.75 (2H, m), 1.12 (6H, d, J 6.8 Hz) N-(2-(3,4-Dichlorophenyl)benzo[d]oxazol-5-yl)cyclopropanecarboxamide LCMS RT= 6.99min, MH 4 *348.8;'H NMR (DMSO): 10.45 (1H, s), 8.30 (1H, dd, J 2.0 Hz), 8.15 (1H, d, J 1.9 Hz), 8.10 (1H, dd, J 8.4 2.0 Hz), 7.86 (1H, d, J 8.4 Hz), 7.71 (1H, d, J 8.9 Hz), 7.53 (1H, dd, J 8.9 2.0 Hz), 1.81-1.74 (1H, m), 0.82-0.76 (4H, m) N-(2-(4-Chlorophenyl)benzo[d]oxazol-6-y)cyclopropanecarboxamide LCMS RT= 6.93min, MH*312.9; 'H NMR (DMSO): 10.53 (1H, s), 8.27 (1H, dd, J 1.7 Hz), 8.18 (2H, d, J 8.7 Hz), 7.74 (1H, d, J 8.7 Hz), 7.68 (2H, d, J8.7 Hz), 7.44 (1H, dd, J8.7 1.9 Hz), 1.86-1.78 (1H, m), 0.85-0.80 (4H, m) N-(2-(2,3-Dichlorophenyl)benzo[d]oxazol-6-yl)isobutyramide LCMS RT= 7.05min; "H NMR (DMSO): 10.21 (1H, s), 8.34 (1H, d, J 1.8 Hz), 8.11 (1H, dd, J 7.9 1.6 Hz), 7.92 (1H, dd, J 8.1 1.5 Hz), 7.81 (1H, d, J 8.7 Hz), 7.60 (1H, t, J 8.0 Hz), 7.48 (1H, dd, J 8.7 1.9 Hz), 2.67-2.61 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(4-(Trifluoromethoxy)phenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.04min;H NMR (DMSO): 10.05 (1H, s), 8.32 (2H, d, J9.0 Hz), 8.20 (1H, d, J 1.9 Hz), 7.74 (1H, d, J 8.9 Hz), 7.63-7.55 (3H, m), 2.68-2.57 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-Cyclopentylbenzo[d]oxazol-5-yl)isobutyramide LCMS RT= 5.23min, MH* 273.0;'H NMR (DMSO): 9.93 (1H, s), 8.01 (1H, d, J 1.8 Hz), 7.57 (1 H, d, J 8.7 Hz), 7.46 (1 H, dd, J 8.8 1.8 Hz), 3.42-3.39 (1 H, m), 2.61-2.57 (1H, m), 2.15-2.04 (2H, m), 1.95-1.87 (2H, m), 1.78-1.62 (4H, m), 1.12 (6H, d, J 6.8 Hz) N-(4-(5-Acetamidobenzo[d]oxazol-2-yl)phenyl)acetamide LCMS RT= 5.08min, MH*309.9;jH NMR (DMSO): 10.31 (1H, s), 10.11 (1H, s), 8.13 8.08 (3H, m), 7.82 (2H, d, J 8.7 Hz), 7.68 (1 H, d, J 8.7 Hz), 7.48 (1 H, dd, J 8.8 2.0 Hz), 2.11 (3H, s), 2.08 (3H, s) N-(2-(2-Chloro-3-(trifluoromethyl)phenyl)benzo[d]oxazol-5-yI)isobutyramide LCMS RT= 6.78min, MH 383.0;H NMR (DMSO): 10.07 (1H, s), 8.40 (1H, dd, J 8.1 1.3 Hz), 8.27 (1H, d, J 1.8 Hz), 8.14 (1H, dd, J7.9 1.3 Hz), 7.82-7.77 (2H, m), 7.62 (1H, dd, J 8.8 2.1 Hz), 2.66-2.61 (1H, m), 1.14 (6H, d, J 6.8 Hz) N-(2-(3,4-Dichlorophenyl)benzo[d]oxazol-6-yl)isobutyramide LCMS RT= 7.82min, MH*349. 1;'H NMR (DMSO): 10.20 (1H, s), 8.33 (1H, d, J 2.0 Hz), 8.31 (1H, d, J 1.7 Hz), 8.14 (1H, dd, J 8.4 2.0 Hz), 7.88 (1H, d, J 8.5 Hz), 7.75 (IH, d, J 8.8 Hz), 7.48 (1H, dd, J 8.7 1.9 Hz), 2.68-2.60 (1H, m), 1.14 (6H, d, J 6.8 Hz) WO 2009/019504 PCT/GB2008/050648 111 N-(2-(Naphthalen-2-yl)benzpod]oxazoi-6-yl)acetamide LCMS RT= 6.45min, MH*303.1; 'H NMR (OlVISO): 10.15 (1H, s), 8.84 (1H, s), 8.27 (1H, dd, J 8.6 1.7 Hz), 8.20-8.13 (3H, m), 8.06-8.03 (1H, m), 7.76 (1H, d, J 8.6 Hz), 7.71-7.63 (2H, m), 7.54 (1H, dd, J 8.8 2.1 Hz), 2.17 (3H, s) N-(2-(4-Acetamidophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 5.52min, MH338.0; 'H NMR (DMSO): 10.46 (1H, s), 10.31 (1H, s), 8.15 8.11 (3H, m), 7.82 (2H, d, J 8.7 Hz), 7.67 (1H, d, J 8.7 Hz), 7.52 (1H, dd, J 8.8 1.9 Hz), 2.67-2.58 (1H, m), 2.11 (3H, s), 1.13 (6H, d, J 6.9 Hz) N-(2-(Naphthalen-2-yl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.10min, MH* 331.1; 'H NMR (DMSO): 10.04 (1H, s), 8.84 (1H, s), 8.28 8.12 (4H, m), 8.07-8.03 (1H, m), 7.76 (1H, d, J8.9 Hz), 7.77-7.62 (2H, m), 7.58 (1H, dd, J 8.8 2.1 Hz), 2.64 (1H, t, J 7.4 Hz), 1.15 (6H, d, J6.9 Hz) N-(2-(Naphthalen-2-yl)benzo[d]oxazol-5-yI)thiophene-2-carboxamide LCMS RT= 7.47min, MH 370.8; 'H NMR (DMSO): 10.44 (1H, s), 8.86 (1H, s), 8.30 8.14 (4H, m), 8.08-8.04 (2H, m), 7.89 (1H, dd, J5.0 1.0 Hz), 7.83 (1H, d, J8.8 Hz), 7.76-7.64 (3H, m), 7.28-7.25 (1H, m) N-(2-(Naphthalen-1 -yl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.25min, MH* 331.2; "H NMR (DMSO): 10.07 (1H,s), 9.42 (1H, dd, J 8.2 0.7 Hz), 8.45 (1H, dd, J7.4 1.2 Hz), 8.29 (1H, d, J 1.9 Hz), 8.26-8.21 (1H, m), 8.13 8.09 (1H, m), 7.81-7.66 (4H, m), 7.61 (1H, dd, J 8.8 2.1 Hz), 2.70-2.61 (1H, m), 1.16 (6H, d, J 6.8 Hz) N-(2-(Biphenyl-4-yl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.56min, MH 357.3; 'H NMR (DMSO): 10.03 (1H, s), 8.28 (2H, d, J 8.5 Hz), 8.20 (1H, d, J2.0 Hz), 7.94 (2H, d, J 8.6 Hz), 7.82-7.78 (2H, m), 7.74 (1H, d, J 8.8 Hz), 7.58-7.41 (4H, m), 2.68-2.59 (1H, m), 1.15 (6H, d, J 6.8 Hz) N-(2-(6-Methoxynaphthalen-2-yl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.02min, MH 361.2; 'H NMR (DMSO): 10.03 (1H, s), 8.75 (1H, d, J0.8 Hz), 8.21 (2H, dd, J 8.9 1.6 Hz), 8.10 (1H, d, J9.0 Hz), 8.02 (1H, d, J 8.7 Hz), 7.73 (1H, d, J 8.7 Hz), 7.56 (1H, dd, J 8.8 2.0 Hz), 7.46 (1H, d, J 2.3 Hz), 7.29 (1H, dd, J 8.8 2.5 Hz), 3.93 (3H, s), 2.68-2.58 (1H, m), 1.15 (6H, d, J 6.8 Hz) N-(2-(6-Bromonaphthalen-2-yl)benzo[d]oxazoi-5-yl)isobutyramide LCMS RT= 8.13min, MH 411.1; 'H NMR (DMSO): 10.06 (1H, s), 8.86 (1H, s), 8.36 (IH, d, J 1.7 Hz), 8.31 (1H, d, J 8.7 1.7 Hz), 8.23 (1H, d, J 1.9 Hz), 8.18 (1H, d, J 8.9 Hz), 8.13 (1H, d, J 8.7 Hz), 7.80-7.74 (2H, m), 7.58 (1H, dd, J8.9 2.2 Hz), 2.68-2.59 (1H, m), 1.15 (6H, d, J 6.8 Hz) N-(2-(Quinolin-3-yl)benzo[d]oxazol-5-yl)isobutyramide WO 2009/019504 PCT/GB2008/050648 112 LCMS RT= 6.24min, MH 4 332.2; 'H NMR (DMSO): 10.08 (1H, s), 9.62 (1H, d, J 2.1 Hz), 9.22 (1H, d, J 1.9 Hz), 8.29-8.24 (2H, m), 8.15 (1H, d, J 8.6 Hz), 7.95-7.90 (1H, m), 7.80-7.73 (2H, m), 7.61 (1H, dd, J8,8 2.2 Hz), 2.69-2.60 (1H, m), 1.15 (6H, d, J 6.9 Hz) N-(2-(Quinolin-2-yl)benzo[d]oxazol-5-yI)isobutyramide LCMS RT= 6.28min, MH* 332.2; 'H NMR (DMSO): 10.09 (1H, s), 8.64 (1H, d, J 8.4 Hz), 8.45 (1H, d, J8.5 Hz), 8.32 (1H, d, J 1.8 Hz), 8.22 (1H, d, J 8.7 Hz), 8.13 (1H, dd, J 8.5 0.9 Hz), 7.94-7.84 (2H, m), 7.78-7.73 (1H, m), 7.63 (1H, dd, J 8.8 2.0 Hz), 2.69-2.60 (1H, m), 1.15 (6H, d, J 6.8 Hz) N-(2-(4-Cyclohexylphenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 8.87min, MH* 363.3; 'H NMR (DMSO): 10,00 (1H, s), 8.15 (1H, d, J 1.9 Hz), 8.11 (2H, d, J8.4 Hz), 7.69 (1H, d, J 8.7 Hz), 7.53 (1H, dd, J 8.8 2.1 Hz), 7.47 (2H, d, J 8.3 Hz), 2.67-2.58 (2H, m), 1.84-1.71 (5H, m), 1.52-1.23 (5H, m), 1.13 (6H, d, J 6.8 Hz) N-(2-(Benzo[d][1,3]dioxol-5-yI)--chlorobenzo[d]oxazol-6-yl)isobutyramide 'H NMR (DMSO): 9.56 (1H, s), 8.05 (1H, s), 7.94 (1H, s), 7.77 (1H, dd, J 8.1 1.7 Hz), 7.64 (1H, d, J 1.6 Hz), 7.16 (1H, d, J 8.2 Hz), 6.19 (2H, s), 2.83-2.72 (1H, m), 1.15 (6H, d, J6.8 Hz) N-(2-(Furan-2-yl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 5.75min, MH* 271.1; 'H NMR (DMSO): 9.95 (1H, s), 8.08 (1H, d, J 1.8 Hz), 8.01 (1H, dd, J1.7 0.7 Hz), 7.62 (1H, d, J 8.9 Hz), 7.47 (1H, dd, J 8.9 2.0 Hz), 7.39 (1H, dd, J3.5 0.7 Hz), 6.75 (1H, dd, J3.5 1.8 Hz), 2.60-2.50 (1H, m), 1.07 (6H, d, J6.8 Hz) N-(4-(Naphtho[1,2-d]oxazol-2-yl)phenyl)isobutyramide LCMS RT= 7.49min, MH* 331.1; 'H NMR (DMSO): 10.22 (1H, s), 8.45 (1H, d, J 8.1 Hz), 8.22 (2H, d, J 8.7 Hz), 8.13 (1 H, d, J 8.5 Hz), 7.98 (2H, s), 7.89 (2H, d, J 8.9 Hz), 7.77-7.70 (1H, m), 7.65-7.59 (1H, m), 2.69-2.60 (1H, m), 1.14 (6H, d, J 6.7 Hz) N-(4-(Benzo[d]oxazol-2-y)phenyl)isobutyramide LCMS RT= 6.48min, MH*281.1; 'H NMR (DMSO): 10.23 (1H, s), 8.14 (2H, d, J 8.9 Hz), 7.86 (2H, d, J8.8 Hz), 7.79-7.75 (2H, m), 7.42-7.38 (2H, m), 2.70-2.60 (1H, m), 1.13 (6H, d, J 6.8 Hz) Method 3D (Compounds 1l) As Method 3A, except instead of diisopropylethylamine in dichloromethane, pyridine in dichloromethane was used.
WO 2009/019504 PCT/GB2008/050648 113 N-(2-(2-Fluorophenyl)benzo[d]oxazol-5-yl)butyramide LCMS RT= 6.10min, MH 4 299.0; 1 H NMR (DMSO): 10.07 (1H, s), 8.25-8.19 (2H, in), 7.75 (1 H, d, J 8.8 Hz), 7.72-7.66 (1 H, n), 7.58-7.42 (3H, n), 2.33 (2H, t, J 7.5 Hz), 1.71-1.59 (2H, n), 0.94 (3H, t, J7.4 Hz) N-(2-(2-Fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.09min, MH* 299.0; 'H NMR (DMSO): 10.09 (1H, s), 8.31-8.25 (2H, m), 7.81 (1H, d, J 8.8 Hz), 7.78-7.72 (1H, m), 7.64 (1H, d, J 8.7 1.8 Hz), 7.58-7.48 (2H, m), 2.74-2.65 (1H, m), 1.20 (6H, d, J 6.8 Hz) N-(2-(3-Fluorophenyl)benzod]oxazol-5-yl)butyramide LCMS RT= 6.39min, MH* 299.0; 'H NMR (DMSO): 10.12 (1H, s), 8.24 (1H, d, J 1.9 Hz), 8.12-8.08 (1H, n), 8.02-7.97 (1H, n), 7.79 (1H, d, J 8.8 Hz), 7.75-7.70 (1H, m), 7.63-7.53 (2H, m), 2.38 (2H, t, J7.4 Hz), 1.77-1.64 (2H, in), 1.00 (3H, t, J7.4 Hz) N-(2-(3-Fluorophenyl)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 6.37min, MH*299.0; 'H NMR (DMSO): 10.08 (1H, s), 8.26 (1H, d, J1.9 Hz), 8.12-8.08 (1H, in), 8.02-7.97 (1H, n), 7.79 (1H, d, J9.0 Hz), 7.75-7.69 (1H, n), 7.63 (1H, dd, J 8.8 1.9 Hz), 7.59-7.52 (1H, m), 2.73-2.66 (1H, m), 1.19 (6H, d, J 6.9 Hz) N-(2-(Benzo[d][1,3]dioxol-5-yl)benzo[djoxazol-5-yl)isobutyramide LCMS RT= 6.14min, MH* 324.9; 1 H NMR (DMSO): 10.04 (1H, s), 8.18 (1H, d, J 1.8 Hz), 7.82 (1H, dd, J 8.2 1.8 Hz), 7.73-7.69 (2H, in), 7.58 (1H, dd, J 8.7 2.0 Hz), 7.20 (1H, d, J 8.2 Hz), 6.24 (2H, s), 2.72-2.65 (1H, in), 1.19 (6H, d, J 6.9 Hz) Ethyl 2-(4-chlorophenyl)benzo[d]oxazoI-5-ylcarbamate LCMS RT= 7.14min, MH* 317.1; 1 H NMR (DMSO): 9.80 (1H, s), 8.18 (2H, d, J 8.6 Hz), 7.96 (1H, d, J 1.7 Hz), 7.71-7.67 (3H, m), 7.45 (1H, dd, J 8.8 2.0 Hz), 4.16 (2H, q, J 7.2 Hz), 1.27 (3H, t, J 7.1 Hz) Method 3E (Compounds 11) As Method 3C, except a flake of DMAP is added to the reaction N-(2-(4-Chlorophenyl)benzo[d]oxazol-6-yl)isobutyramide LCMS RT= 7.07min, MH*314.9; 1 H NMR (DMSO): 10.15 (1H, s), 8.29 (1H, d, J1.7 Hz), 8.18 (2H, d, J 8.8 Hz), 7.73 (1H, d, J 8.7 Hz), 7.68 (2H, d, J 8.7 Hz), 7.49 (1H, dd, J 8.7 1.9 Hz), 2.64 (1H, t, J 6.8 Hz), 1.14 (6H, d, J 6.8 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-6-yl)butyramide WO 2009/019504 PCT/GB2008/050648 114 LCMS RT= 7.07min, MH*314.9; 1 H NMR (DMSO): 10.20 (11H, s), 8.29 (1H, d, J1.7 Hz), 8.18 (2H, d, J 8.8 Hz), 7.73 (1H, d, J 8.7 Hz), 7.68 (2H, d, J 8.7 Hz), 7.43 (1H, dd, J 8.7 1.9 Hz), 2.34 (2H, t, J 7.3 Hz), 1.71-1.59 (2H, m), 0.94 (3H, t, J 7.4 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)cyclopropanecarboxamide LCMS RT= 6.69min, MH* 313.1; 'H NMR (DMSO): 10.39 (1H, s), 8.20-8.15 (3H, m), 7.74-7.68 (3H, m), 7.54 (1H, d, J 8.9 2.1 Hz), 1.84-1.76 (1H, m), 0.81-0.78 (4H, m) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)cyclobutanecarboxamide LCMS RT= 7.07min, MH* 327.0; 'H NMR (DMSO): 9.91 (1H, s), 8.21-8.17 (3H, m), 7.73-7.67 (3H, m), 7.55 (1 H, d, J 8.9 2.1 Hz), 2.33-1.81 (7H, m) Method 3F (Compounds ll) 4,4,4-Trifluoro-N-(2-p-tolylbenzo[d]oxazol-5-yl)butanamide To 4,4,4-trifluorobutanoic acid (128mg, 0.90mmol) in dry dimethylformamide (5mL) was added HATU (397mg, 1.05mmol) and diisopropylethylamine (496pL, 2.85mmol). The mixture was then stirred at room temperature for 10min. 2-p Tolylbenzo[d]oxazol-5-amine (200mg, 0.95mmol) was then added and the resulting mixture was stirred at room temperature for 16h. Ethyl acetate was added and the organic layer was washed once with saturated aqueous Na2CO 3 , followed by another wash with brine. 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 40:60 v/v to afford 26.7mg (8%) of the title compound (LCMS RT= 6.77min, MH*348.9) 'H NMR (DMSO): 10.28 (1H, s), 8.12 (1H, d, J 1.9 Hz), 8.08 (2H, d, J 8.2 Hz), 7.72 (IH, d, J 8.8 Hz), 7.50 (1H, dd, J 8.8 2.1 Hz), 7.43 (2H, d, J 8.1 Hz), 2.67-2.56 (4H, m), 2.42 (3H, s) All compounds below were prepared following the same general method. 3-Methoxy-N-(2-p-tolylbenzo[d]oxazol-5-yl)propanamide LCMS RT= 6.03min, MH* 311.0;'H NMR (DMSO): 10.13 (1H, s), 8.14 (1H, d, J 2.2 Hz), 8.08 (2H, d, J 8.4 Hz), 7.70 (1H, d, J8.9 Hz), 7.52 (1H, dd, J 8.9 2.0 Hz), 7.43 (2H, d, J 8.3 Hz), 3.65 (2H, t, J 6.2 Hz), 3.26 (3H, s), 2.61-2.56 (2H, m), 2.42 (3H, s) Tert-butyl-3-oxo-3-(2-phenylbenzo[d]oxazol-5-ylamino)propylcarbamate LCMS RT= 6.22min, MH*382.0;'H NMR (CDC 3 ): 8.19-8.14 (2H, m), 7.89 (2H, s), 7.50-7.42 (5H, m), 5.15-5.05 (1H, br), 3.49-3.43 (2H, m), 2.59 (2H, t, J7.6 Hz), 1.38 (9H, s) WO 2009/019504 PCT/GB2008/050648 115 3,3,3-Trifluoro-N-(2-p-tolylbenzo[d]oxazol-5-yl)propanamide LCMS RT= 14.01 min, MH* 335.0; 'H NMR (DMSO): 10.48 (1H, s), 8.11-8.08 (3H, m), 7.75 (1H, d, J9.0 Hz), 7.49 (1H, dd, J8.7 2.1 Hz), 7.44 (2H, d, J 8,0 Hz), 3.55 (2H, q, J 10.9 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-y1)-3-methoxypropanamide LCMS RT= 6.32min, MH*331.1; 'H NMR (DMSO): 10.17 (1H, s), 8.22-8.17 (3H, m), 7.74-7.68 (3H, m), 7.54 (1H, dd, J 8.9 2.1 Hz), 3.65 (2H, t, J 6.1 Hz), 3.26 (3H, s), 2.59 (2H, t, J 6.1 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)-3,3,3-trifluoropropanamide LCMS RT= 6.72min, MH*354.7; 1 H NMR (DMSO): 10.52 (1H, s), 8.21 (2H, d, J 8.7 Hz), 8.14 (1H, d, J2.0 Hz), 7.78 (1H, d, J 8.7 Hz), 7.70 (2H, d, J 8.7 Hz), 7.52 (1H, dd, J 8.8 2.1 Hz), 3.56 (2H, q, J 11.1 Hz) N-(2-(3,4-Dichlorophenyl)benzo[d]oxazol-5-yI)-3,3,3-trifluoropropanamide LCMS RT= 7.41min, MH* 388.8; 1 H NMR (DMSO): 10.54 (1H, s), 8.36 (1H, d, J 2.0 Hz), 8.17-8.14 (2H, m), 7.90 (1H, d, J 8.4 Hz), 7.80 (1H, d, J 8.8 Hz), 7.54 (1H, dd, J 8.9 2.1 Hz), 3.56 (2H, q, J 11.1 Hz) N-(2-(2,3-Dichlorophenyl)benzo[d]oxazol-5-yI)-3,3,3-trifluoropropanamide LCMS RT= 6.76min, MH* 388.9; 1 H NMR (DMSO): 10.55 (1H, s), 8.20 (1H, d, J 1.9 Hz), 8.12 (1H, dd, J 7.9 1.6 Hz), 7.94 (1H, dd, J 8.1 1.6 Hz), 7.83 (1H, d, J 8.8 Hz), 7.64-7.55 (2H, m), 3.58 (2H, q, J 11.1 Hz) The compounds below were obtained by Method 3F, using the appropriate Boc amino acid. Coupling was followed by deprotection of Boc group using 4M HCI in dioxane for 20min at room temperature. (S)-N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)pyrrolidine-2-carboxamide LCMS RT= 4.54min, MH* 342.0; "H NMR (DMSO): 10.15 (1H, s), 8.23 (1H, d, J 1.7 Hz), 8.19 (2H, d, J 8.7 Hz), 7.74-7.63 (4H, m), 3.75-3.69 (1H, m), 2.91 (2H, t, J 6.5 Hz), 2.12-2.00 (1H, m), 1.90-1.60 (3H, m) (S)-N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)-2-(methylamino)propanamide LCMS RT= 4.46min, MH* 330.1; 'H NMR (DMSO): 8,20-8.10 (3H, m), 7.67 (2H, d, J 8.8 Hz), 7.58-7.47 (2H, m), 3.00 (1H, q, J 6.8 Hz), 2.24 (3H, s), 1.16 (3H, d, J 6.8 Hz) The compound below was obtained by Method 3F, using the appropriate Fmoc amino acid. Coupling was followed by deprotection of the Fmoc group using piperidine/DMF 20:80 v/v.
WO 2009/019504 PCT/GB2008/050648 116 (S)-2-Amino-N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)propanamide LCMS RT=4.46min, MH*316.1;2H NMR(CDCI): 9.56 (1H, s), 8.11 (2H, d, J8.7 Hz), 7.98 (1H, d, J 1.9 Hz), 7.55 (1H, dd, J 8.8 2.1 Hz), 7.46-7.41 (3H, m), 3.60 (1H, q, J7.0 Hz), 1.41 (3H, d, J7.0 Hz) Method 3G (Compounds ll) As Method 3C, except instead of the acid chloride, the corresponding anhydride was used 2,2,2-Trifluoro-N-(2-p-tolylbenzo[d]oxazol-5-yl)acetamide LCMS RT= 6.93min, MH* 321.0; 'H NMR (DMSO): 11.46 (1 H, br), 8.22 (2H, d, J 8.6 Hz), 8.15 (1H, d, J 1.9 Hz), 7.85 (1H, d, J 8.8 Hz), 7.73-7.68 (3H, m) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)-2,2,2-trifluoroacetamide LCMS RT= 7.12min, MH*340.8;'H NMR (DMSO): 11.43 (1H, br), 8.12-8.09 (3H, m), 7.82 (1H, d, J 8.8 Hz), 7.67 (1H, dd, J 8.9 2.1 Hz), 7.45 (2H, d, J 8.0 Hz) Method 3H (Compounds lI) 3-Morpholino-N-(2-phenylbenzo[d]oxazol-5-yl)propanamide To 2-phenylbenzo[d]oxazol-5-amine (75mg, 0.36mmol) and methyl 3 morpholinopropanoate (63pL, 0.39mmol) in toluene (2.5mL) was added a 2M solution of trimethylaluminum in toluene (0.22mL, 0.43mmol). The resulting solution was heated twice for 5min at 160'C in the microwave. After cooling, sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with brine and the combined organic layers were dried over anhydrous MgSO 4 . After evaporation, the impurities were removed by filtering through on a plug of silica eluting with ethyl acetate/hexanes 50:50 v/v and the desired product was obtained by elution with methanol to afford 17.5mg (14%) of the title compound (LCMS RT= 5.54min, MH* 352.0) 'H NMR (DMSO): 10.25 (1H, s), 8.22-8.15 (3H, m), 7.73 (1H, d, J 8.8 Hz), 7.65-7.59 (3H, m), 7.52 (1 H, dd, J 8.8 2.0 Hz), 3.60-3.57 (4H, m), 2.68-2.64 (2H, m), 2.44-2.41 (4H, m) Method 4 (Compounds 111) N-(2-Phenylbenzo[d]oxazol-5-yl)propane-1 -sulfonamide WO 2009/019504 PCT/GB2008/050648 117 To a solution of 2-phenylbenzodloxazol-5-amine (100mg, 0.48mmol) in dichloromethane (2mL) at room temperature was added pyridine (83pL, 0.95mmol) followed by propane-1 -sulfonyl chloride (61pL, 0.52mmol). The resulting solution was then stirred at room temperature for 16h. Dichloromethane was added and the organic layer was washed with saturated aqueous copper sulfate solution. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting insoluble solid was washed with saturated aqueous NaHCO 3 to afford 37.2mg (25%) of the title compound (LCMS RT= 6.25min, MH*317.0) 'H NMR (DMSO): 9.89 (1H, br), 8.21-8.18 (2H, m), 7.77 (1H, d, J 8.8 Hz), 7.66-7.59 (4H, m), 7.28 (1H, dd, J8.8 2.1 Hz), 3.10-3.04 (2H, m), 1.77-1.64 (2H, m), 0.94 (3H, t, J7.5 Hz) The compounds below were prepared following the same general method, and purified by column chromatography eluting with ethyl acetate:hexanes 30:70 v/v. N-(2-Phenylbenzo[d]oxazol-5-yl)propane-2-sulfonamide LCMS RT= 6.16min, MH* 317.0; 1 H NMR (DMSO): 9.89 (1H, br), 8.21-8.18 (2H, m), 7.76 (1 H, d, J 8.8 Hz), 7.69-7.59 (4H, m), 7.30 (1 H, dd, J 8.8 2.2 Hz), 1.26 (6H, d, J 6.9 Hz) N-(2-Phenylbenzo[d]oxazol-5-yl)benzenesulfonamide LCMS RT= 6.43min, MH*350.8;'H NMR (DMSO): 10.40 (1H, br), 8.15 (2H, dd, J7.2 1.6 Hz), 7.77-7.74 (2H, m), 7.68-7.51 (7H, m), 7.46 (1H, d, J 2.1 Hz), 7.12 (1H, dd, J 8.8 2.1 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yl)propane-1 -sulfonamide LCMS RT= 6.53min, MH* 331.0; 1 H NMR (DMSO): 9.85 (1 H, br), 8.80 (2H, d, J 7.8 Hz), 7.74 (1H, d, J 9.0 Hz), 7.60 (1H, d, J 2.0 Hz), 7.44 (2H, d, J 8.1 Hz), 7.26 (1H, dd, J8.7 2.2 Hz), 3.09-3.04 (2H, m), 2.42 (3H, s), 1.74-1.64 (2H, m), 0.94 (3H, t, J 7.6 Hz) N-(2-p-Tolylbenzo[d]oxazol-5-yI)propane-2-sulfonamide LCMS RT= 6.58min, MH* 330.9;'H NMR (DMSO): 9.85 (1 H, br), 8.08 (2H, d, J 8.2 Hz), 7.72 (1 H, d, J 8.6 Hz), 7.62 (1 H, d, J 1.8 Hz), 7.43 (2H, d, J 8.2 Hz), 7.28 (1 H, dd, J 8.8 2.2 Hz), 2.60-2.57 (1 H, m), 2.42 (3H, s), 1.26 (6H, d, J 6.8 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)propane-1 -sulfonamide LCMS RT= 6.81 min, MH*350.9; 'H NMR (DMSO): 9.73 (1H, br), 8.20 (2H, d, J 8.7 Hz), 7.77 (1H, d, J8.6 Hz), 7.71 (2H, d, J 8.7 Hz), 7.63 (1H, d, J 1.9 Hz), 7.29 (1H, dd, J8.8 2.2 Hz), 3.10-3.05 (2H, m), 1.77-1.65 (2H, m), 0.94 (3H, t, J7.6 Hz) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)propane-2-sulfonamide WO 2009/019504 PCT/GB2008/050648 118 LCMS RT= 6.68min, MH351.0; 'H NMR (DMSO): 9.88 (1H, br), 8.19 (2H, d, J 8.7 Hz), 7.76 (1H, d, J 8.8 Hz), 7.70 (2H, d, J 8.7 Hz), 7.65 (1H, d, J 2.0 Hz), 7.32 (1H, dd, J8.8 2.2 Hz), 3.24 (1H, t, J6.7 Hz), 1.26 (6H, d, J 6.7 Hz) Method 5 (Compounds IV) N-(Pyridin-4-ylmethyl)-2-p-tolylbenzo[d]oxazol-5-amine To 2-p-tolylbenzo[d]oxazol-5-amine (500mg, 2.32mmol) in 1,2-dichloroethane (20mL) at room temperature was added acetic acid (142 pL, 2.32mmol) and isonicotinaldehyde (222.5pL, 2.29mmol) and the mixture was stirred for 1h. Sodium triacetoxyborohydride (707mg, 3.35mmol) was then added and the mixture was stirred at room temperature for 24h. The mixture was then diluted with dichloromethane and the organic layer was washed with saturated aqueous NaHCO 3 . 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 20:80 to afford 328mg (47%) of the title compound (LCMS RT= 6.27min, MH* 316.1) 'H NMR (DMSO): 8.50 (2H, d, J6.0 Hz), 8.00 (2H, d, J 8.1 Hz), 7.48-7.37 (5H, m), 6.76-6.72 (2H, m), 6.51 (1H, t, J 6.2 Hz), 4.38 (2H, d, J 6.1 Hz), 2.39 (3H, s) All compounds below were prepared following the same general method. N-Benzyl-2-phenylbenzo[d]oxazol-5-amine LCMS RT= 7.90min, MH*301.0; 'H NMR (DMSO): 9.14-8.10 (2H, m), 7.61-7.56 (3H, m), 7.48-7.21 (6H, m), 6.79-6.75 (2H, m), 6.39 (1H, t, J 6.0 Hz), 4.32 (2H, d, J 6.1 Hz) N-Butyl-2-phenylbenzo[d]oxazol-5-amine LCMS RT= 8.25min, MH*267.0; "H NMR (DMSO): 8.16-8.12 (2H, m), 7.61-7.58 (3H, m), 7.47 (1 H, d, J 8.7 Hz), 6.81 (1 H, d, J 2.1 Hz), 6.72 (1 H, dcd, J 8.8 2.3 Hz), 6.64 (1H, t, J5.5 Hz), 3.08-3.00 (2H, m), 1.64-1.51 (2H, m), 1.49-1.35 (2H, m), 0.94 (3H, t, J7.2 Hz) N-isobutyl-2-phenylbenzo[d]oxazol-5-amine LCMS RT= 8.26min, MH* 267.0; 1 H NMR (DMSO): 8.15-8.12 (2H, m), 7.62-7.51 (3H, m), 7.46 (1H, d, J8.8 Hz), 6.81 (1H, d, J2.1 Hz), 6.74 (1H, dd, J8.8 2.3 Hz), 5.73 (1H, t, J 5.6 Hz), 2.87 (2H, t, J 6.1 Hz), 1.95-1.82 (1H, m), 0.97 (6H, d, J 6.6 Hz) N-Butyl-2-(4-chlorophenyl)benzo[d]oxazol-5-amine WO 2009/019504 PCT/GB2008/050648 119 LCMS RT= 9.58min, MH 4 301.1; 'H NMR (DMSO): 8.14 (2H, d, J8.7 Hz), 7.66 (2H, d, J 8.7 Hz), 7.47 (1H, d, J 8.7 Hz), 6.81 (1H, d, J2.1 Hz), 6.73 (1H, dd, J 8.8 2.2 Hz), 6.67 (1H, t, J5.7 Hz), 3.07-3.00 (2H, m), 1.62-1.53 (2H, m), 1.48-1.36 (2H, m), 0.94 (3H, t, J7.2 Hz) 2-(4-Chlorophenyl)-N-isobutylbenzo[d]oxazol-5-amine LCMS RT= 8.85min, MH*301.0; 'H NMR (DMSO): 8.14 (2H, d, J 8.7 Hz), 7.66 (2H, d, J 8.7 Hz), 7.47 (1H, d, J 8.8 Hz), 6.80 (1H, d, J2.0 Hz), 6.75 (1H, dd, J 8.8 2.2 Hz), 5.75 (1H, t, J 5.7 Hz), 2.87 (2H, d, J 6.2 Hz), 1.93-1.82 (1H, m), 0.97 (6H, d, J 6.7 Hz) N-Benzyl-2-(4-chlorophenyl)benzo[d]oxazol-5-amine LCMS RT= 8.39min, MH*335.0;'H NMR (DMSO): 8.11 (2H, d, J 8.8 Hz), 7.65 (2H, d, J 8.7 Hz), 7.47 (1 H, d, J 9.4 Hz), 7.42-7.21 (5H, m), 6.81-6.78 (2H, m), 6.42 (1 H, t, J 5.8 Hz), 4.32 (2H, d, J 6.8 Hz) N-Butyl-2-p-tolylbenzo[d]oxazol-5-amine LCMS RT= 8.44min, MH 281.0; 'H NMR (DMSO): 8.02 (2H, d, J 8.2 Hz), 7.46-7.38 (3H, m), 6.79 (1 H, d, J 2.0 Hz), 6.69 (1 H, dd, J 8.8 2.4 Hz), 5.62 (1 H, t, J 5.7 Hz), 3.06-3.00 (2H, m), 2.40 (3H, s), 1.62-1.53 (2H, m), 1.48-1.36 (2H, m), 0.94 (3H, t, J 7.2 Hz) N-sobutyl-2-p-tolylbenzo[d]oxazol-5-amine LCMS RT= 8.48min, MH* 281.0; 'H NMR (DMSO): 8.03 (2H, d, J 8.1 Hz), 7.45-7.38 (3H, m), 6.79 (1H, d, J 2.1 Hz), 6.71 (1H, dd, J 8.8 2.3 Hz), 5.70 (1 H, t, J 5.7 Hz), 2.86 (2H, t, J 6.3 Hz), 2.40 (3H, s), 1.95-1.81 (1H, n), 0.97 (6H, d, J 6.7 Hz) N-Benzyl-2-p-tolylbenzo[d]oxazol-5-amine LCMS RT= 7.95min, MH* 315.1; 'H NMR (DMSO): 8.00 (2H, d, J 8.1 Hz), 7.46-7.21 (8H, m), 6.77-6.73 (2H, m), 6.37 (1H, t, J 6.4 Hz), 4.32 (2H, d, J 6.0 Hz), 2.40 (3H, s) 2-(4-Chlorophenyl)-N, N-diisobutylbenzo[d]oxazol-5-amine LCMS RT= 17.03min, MH+ 357.1; 'H NMR (DMSO): 8.26 (2H, d, J 8.5 Hz), 7.80 (2H, d, J 8.6 Hz), 7.67 (1H, d, J9.0 Hz), 7.09 (1H, d, J2.3 Hz), 6.96 (1H, dd, J9.1 2.4 Hz), 3.32 (4H, d, J7.2 Hz), 2.20-2.10 (2H, m), 1.02 (12H, d, J 6.6 Hz) Method 6 (Compounds V) 1 -Phenyl-3-(2-phenylbenzo[d]oxazol-5-yl)urea To 2-phenylbenzo[djoxazol-5-amine (75mg, 0.36mmol) in dichloromethane (2mL) at room temperature was added phenyl isocyanate (43pL, 0.39mmol). The solution was stirred at room temperature for 16h. The resulting precipitate was filtered off and WO 2009/019504 PCT/GB2008/050648 120 washed with dichloromethane to afford 99.9mg (85%) of the title compound (LCMS RT= 6.45min, MH* 330.1) 'H NMR (DMSO): 8.85 (1H, s), 8.71 (1H, s), 8.22-8.19 (2H, m), 8.00 (1H, d, J 2.0 Hz), 7.71 (1H, d, J 8.9 Hz), 7.65-7.60 (3H, m), 7.50-7.47 (2H, m), 7.40 (1H, dd, J 8.8 2.1 Hz), 7.30 (2H, t, J 8.4 Hz), 7.02-6.95 (1 H, m) The compound below was prepared following the same general method. 1 -Isopropyl-3-(2-phenylbenzo[d]oxazol-5-yl)urea LCMS RT= 5.94min, MH* 296.0; 'H NMR (DMSO): 8.47 (1H, s), 8.20-8.16 (2H, m), 7.93 (1H, d, J 1.9 Hz), 7.64-7.59 (4H, m), 7.30 (1H, dd, J 8.8 2.1 Hz), 6.03 (1H, d, J 7.5 Hz), 3.85-3.74 (1H, m), 1.12 (6H, d, J 6.5 Hz) Method 7 (Compounds VII N-(2-(4-Chlorophenyl)benzo(d]oxazol-5-yl)-N-methylpropionamide To sodium hydride (15mg, 0.37mmol) under nitrogen at 00C was slowly added a solution of N-(2-(4-chlorophenyl)benzofd]oxazol-5-yl)propionamide (100mg, 0.33mmol) in dimethylformamide (1OmL). After 10min at 00C, methyl iodide (56pL, 0.37mmol) was added, and the solution was left warming up to room temperature for 16h. The mixture was then diluted with ethyl acetate, and then washed three times with water. 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 50:50 v/v to afford 36.4mg (35%) of the title compound (LCMS RT= 7.00min, MH*315.0) 'H NMR (CDCis): 8.13 (2H, d, J 8.6 Hz), 7.55-7.52 (2H, m), 7.46 (2H, d, J 8.6 Hz), 7.13 (1 H, dd, J 8.3 2.0 Hz), 3.26 (3H, s), 2.04 (2H, q, J 7.6 Hz), 1.00 (3H, t, J 7.6 Hz) Method 7 (Compounds Vib) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)-N-methylisobutyramide LCMS RT= 7.44min, MH* 329.1; 'H NMR (DMSO): 8.22 (2H, d, J 8.7 Hz), 7.91-7.87 (2H, m), 7.72 (2H, d, J 8.6 Hz), 7.43 (1H, d, J 8.3 Hz), 3.20 (3H, s), 2.46-2.42 (1H, m), 0.93 (6H, d, J6.6 Hz) 2-(4-Chlorophenyl)-N-isobutyl-N-methylbenzo[d]oxazol-5-amine WO 2009/019504 PCT/GB2008/050648 121 LCMS RT= 10.59min, MH*315.1; 'H NMR (DMSO): 8.15 (2H, d, J 8.6 Hz), 7.67 (2H, d, J 8,6 Hz), 7.56 (1H, d, J9.0 Hz), 6.96 (1H, d, J 2.5 Hz), 6.84 (1H, dd, J 9.1 2.5 Hz), 3.17 (2H, d, J7.3 Hz), 2.97 (3H, s), 2.13-1.97 (1H, m), 0.90 (6H, d, J 6.7 Hz) Method 8 (Compounds Vil) N-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)-2-methylpropanethioamide To N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)isobutyramide (50mg, 0.1 6mmol) in toluene (2mL) at 110 C was added Lawesson's reagent (35mg, 0.09mmol). The resulting solution was heated at 1100C for 7h. After cooling, the solution was diluted with water and extracted with ethyl acetate, The combined organic layers were washed with brine, then dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 13.8mg (26%) of the title compound (LCMS RT= 7.36min, MH* 331.2) 'H NMR (DMSO): 11.59 (1H, s), 8.37 (1H, d, J 2.0 Hz), 8.22 (2H, d, J 8.8 Hz), 7.83 (1H, d, J 8.7 Hz), 7.73-7.65 (3H, m), 3.18-3.09 (1H, m), 1.25 (6H, d, J 6.7 Hz) Method 9 (Compound Vill) 2-(4-Chlorophenyl)benzo[d]oxazole-5-diazonium tetrafluoroboric acid salt To a solution of 2-(4-chlorophenyl)benzo[d]oxazol-5-amine (500mg, 2.04mmol) in water (3mL) and tetrafluoroboric acid (50% in water, 2mL) at 00C was added a solution of sodium nitrite (140mg, 2.04mmol) in water (2mL), dropwise over 5min. The resulting mixture was stirred at 00C for 15min, and then at room temperature for 1 h. The solid was then filtered off, washed with dilute aqueous tetrafluoroboric acid solution and methanol to afford 370mg (53%) of the title compound, which was used directly without characterization. Method 10 (Compound IX) S-2-(4-Chlorophenyl)benzo[d]oxazol-5-yI ethanethioate To a stirred solution of potassium thioacetate (130mg, 1.13mmol) in DMSO (2.8mL) at room temperature was added dropwise a solution of 2-(4 chlorophenyl)benzo[d]oxazole-5-diazonium tetrafluoroboric acid salt (370mg, 1.08mmol) in DMSO (1.4mL). After 15min, the mixture was heated at 700C for 1h. After cooling, the mixture was diluted with water, and then extracted several times WO 2009/019504 PCT/GB2008/050648 122 with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 5:95 v/v to ethyl acetate/hexanes 15:85 v/v) and triturated with diethyl ether/hexanes to afford 11.3mg (3%) of the title compound (LCMS RT= 7.89min, MH* 304.2) 'H NMR (CDC 3 ): 8.24 (2H, d, J 8.7 Hz), 7.88 (1H, dd, J 1.7 0.4 Hz), 7.67 (1H, dd, J 8.7 0.4 Hz), 7.57 (2H, d, J 8.8 Hz), 7.46 (1H, dd, J 8.4 1.7 Hz), 2.51 (3H, s) 1.Ethanol, 700C, 1h 0N 0 OH +O 2. MeCN, Pb(OAC) 4 or Phl(OAo) 2 R--F /R R-iNH 2 R,+ 1000, 5minN (Method 11A or 11B) X Method 1 IA (Compound X) 5-(Ethylsulfonyl)-2-(5-methylthiophen-2-yl)benzo[d]oxazole To a stirred solution of 2-amino-4-(ethylsulfonyl)phenol (452.7mg, 2.25mmol) in ethanol (17mL) was added 5-methyl-2-thiophenecarboxaldehyde (242pL, 2.25mmol). The mixture was heated at 70CC for 70min. After cooling, a small amount of precipitate was formed. After filtration and evaporation of the filtrate, the resulting product was dissolved in acetonitrile (9.8mL) and lead tetraacetate (887mg, 2mmol) was added. The resulting mixture was heated at 100 C for 5min. After cooling, the reaction mixture was filtered off, and the filtrate evaporated in vacuo. The resulting mixture was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v, and then purified by reverse phase HPLC to afford 2.2mg (0.3%) of the title product (LCMS RT= 6.41 min, MH*308.1) "H NMR (DMSO): 8.22 (1H, dd, J 1.8 0.5 Hz), 8.02 (1H, dd, J8.6 0.5 Hz), 7.92-7.88 (2H, m), 7.08 (1H, dd, J3.7 1.0 Hz), 3.37 (2H, q, J7.3 Hz), 2.60 (3H, d, J0.6 Hz), 1.12 (3H, t, J7.4 Hz) Method 11B (Compounds X) As for Method 1 IA, but iodosobenzene diacetate was used instead of lead tetraacetate WO 2009/019504 PCT/GB2008/050648 123 5-(Ethylsulfonyl)-2-(thiophen-2-yl)benzo[d]oxazole LCMS RT= 6.08min, MH*294.1; 'H NMR (DMSO): 8.26 (1H, d, J 1.7 Hz), 8.08-8.04 (3H, m), 7.93 (1H, dd, J 8.5 1.8 Hz), 7.36 (1H, dd, J4.9 3.8 Hz), 3.38 (2H, q, J7.3 Hz), 1.13 (3H, t, J7.4 Hz) 5-(Ethylsulfonyl)-2-(3-methylthiophen-2-yI)benzo[d]oxazole LCMS RT= 6.45min, MH* 308.1; 'NH NMR (DMSO): 8.02 (1H, d, J 1.8 0.5 Hz), 7.81 (1H, dd, J 8.5 0.5 Hz), 7.69-7.66 (2H, m), 6.98 (1H, dd, J5.0 0.4 Hz), 3.15 (2H, q, J 7.3 Hz), 2.47 (3H, s), 0.88 (3H, t, J 7.4 Hz) 5-(Ethylsulfonyl)-2-(5-methylfuran-2-yl)benzo[d]oxazole LCMS RT= 5.53min, MH*292.1; 'H NMR (DMSO): 8.00 (1H, d, J 1.8 0.6 Hz), 7.81 (IH, d, J 6.6 Hz), 7.69 (1H, dd, J 8.6 1.9 Hz), 7.26 (1H, d, J 3.7 Hz), 6.31-6.27 (1H, m), 3.18-3.14 (2H, m), 2.24 (3H, s), 0.90 (3H, t, J7.4 Hz) 5-(Ethylsulfonyl)-2-(4-methylthiophen-2-yl)benzo[d]oxazole LCMS RT= 6.40min, MH t 616.9; 'H NMR (DMSO): 8.24 (1H, d, J 1.8 0.5 Hz), 8.03 (1H, dd, J 8.6 0.5 Hz), 7.94-7.89 (2H, m), 7.65 (1H, t, J 1.2 Hz), 3.42-3.36 (2H, m), 2.32 (3H, d, J 0.6 Hz), 1.12 (3H, t, J7.5 Hz) R,
R
1
NH
2 I HATU, base, DMF HN - 0 / R 9 L H02 r, 16h (Method 12) >-RN (Where R =COOH) Lawesson's reagent Toluene, 110 C, 7h (Method 7) (Method 8) NaH, Mel, DMF, rt, 16h R, R, HN R N 0 S N C N iso-VIl iso-VI Method 12 (Compounds XI) N-Butyl-2-p-tolylbenzo[d]oxazole-5-carboxamide To 2-p-tolylbenzo[d]oxazole-5-carboxylic acid (100mg, 0.39mmol) in dry dimethylformamide (1OmL) was added HATU (165mg, 0.44mmol) and WO 2009/019504 PCT/GB2008/050648 124 diisopropylethylamine (206pL, 1.18mmol). The mixture was then stirred at room temperature for 10min. Butan-1-amine (43pL, 0.44mmol) was then added and the resulting mixture was stirred at room temperature for 16h. Ethyl acetate was added and the organic layer was washed three times with water. 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 40:60 vlv to afford 26mg (11%) of the title compound (LCMS RT= 6.81 min, MH*309.1) 'H NMR (CDCi 3 ): 8.22-8.15 (3H, m), 7.89 (1 H, dd, J 8.1 1.1 Hz); 7.67 (1H, d, J 8.3 Hz), 7.40 (2H, d, J7.5 Hz), 6.17 (1H, br), 3.59-3.52 (2H, m), 2.51 (3H, s), 1.72-1.64 (2H, m), 1.54-1.46 (2H, m), 1.03 (3H, t, J7.3 Hz) All compounds below were prepared following the same general method. N-Propyl-2-p-tolylbenzo[d]oxazole-5-carboxamide LCMS RT= 6.42min, MH*295.1; 'H NMR (CDCI 3 ): 8.08 (2H, d, J 8.2 Hz), 8.04 (1H, d, J 1.4 Hz), 7.77 (1 H, dd, J 8.5 1.7 Hz), 7.54 (1 H, d, J 8.6 Hz), 7.28 (2H, d, J 7.9 Hz), 6.07 (1H, br), 3.44-3.37 (2H, m), 2.39 (3H, s), 1.65-1.55 (2H, m), 0.95 (3H, t, J 7.5 Hz) N-Isopropyl-2-p-tolylbenzo[d]oxazole-5-carboxamide LCMS RT= 6.38min, MH 4 *295.1; 'H NMR (CDC 3 ): 8.20 (2H, d, J 8.2 Hz), 8.15 (1H, d, J 1.4 Hz), 7.87 (1 H, dd, J 8.5 1.8 Hz), 7.65 (1 H, d, J 8.5 Hz), 7.40 (2H, d, J 8.0 Hz), 6.00 (1H, br), 4.43-4.31 (1H, m), 2.51 (3H, s), 1.35 (6H, d, J 6.6 Hz) 2-p-Tolylbenzo[d]oxazole-5-carboxamide LCMS RT= 5.61min, MH*253.0; 'H NMR (DMSO): 8.30 (1H, d, J1.2 Hz), 8.12 (2H, d, J 8.2 Hz), 7.98 (1H, dd, J 8.5 1.7 Hz), 7.81 (1H, d, J 8.5 Hz), 7.45 (2H, d, J 8.0 Hz), 2.44 (3H, s) 2-(4-Chlorophenyl)-N-isopropylbenzo[d]oxazole-5-carboxamide LCMS RT= 6.68min, MH* 315.5;'H NMR (DMSO): 8.36-8.31 (2H, m), 8.23 (2H, d, J 8.7 Hz), 7.98 (1H, dd, J 8.5 1.7 Hz), 7.87 (1H, d, J 8.5 Hz), 7.72 (2H, d, J 8.7 Hz), 4.19-4.08 (1H, m), 1.21 (6H, d, J6.6 Hz) 2-(4-Chlorophenyl)benzo[d]oxazole-5-carboxamide LCMS RT= 5.81min, MH*273.2;'lH NMR (DMSO): 8.11 (1H, s), 8.01 (2H, d, J 8.3 Hz), 7.89 (1 H, br), 7.78 (1 H, d, J 8.6 Hz), 7.64 (1 H, d, J 8.6 Hz), 7.49 (2H, d, J 8.3 Hz), 7.25 (1H, br) Method 8 (Compounds iso-VI) WO 2009/019504 PCT/GB2008/050648 125 2-(4-Chlorophenyl)-N-methylben2iu.iole-5-carboxamide LCMS RT= 6.09min, MH*286.9; "H NMR (DMSO): 8.57 (1H, br), 8.28 (1H, d, J1.2 Hz), 8.23 (2H, d, J 8.7 Hz), 7.96 (1 H, dd, J 8.6 1.7 Hz), 7.87 (1 H, d, J 8.6 Hz), 7.72 (2H, d, J8.6 Hz), 2.83 (3H, d, J4.5 Hz) 2-(4-Chlorophenyl)-N-isopropyl-N-methylbenzo[d]oxazole-5-carboxamide LCMS RT= 6.90min, MH 329.0; "H NMR (DMSO): 8.23 (2H, d, J 8.6 Hz), 7.88-7.81 (2H, m), 7.72 (2H, d, J 8.7 Hz), 7.44 (1H, d, J 8.2 Hz), 2.88-2.78 (3H, m), 1.18-1.12 (6H, m) Method 7 (Compounds iso-VIl) 2-(4-Chlorophenyl)-N-isopropylbenzo[d]oxazole-5-carbothioamide LCMS RT= 7.37min, MH'331.0; "H NMR (DMSO): 10.18 (1H, d, J7.3 Hz), 8.23 (2H, d, J 8.8 Hz), 8.11 (1 H, dd, J 1.7 0.5 Hz), 7.88 (1 H, dd, J 8.6 1.8 Hz), 7.83 (1 H, dd, J 8.8
B(OH)
2 Br- / e R /R, N Microwave, dioxane, water K2C03, N Pd(PPh 3
)
4 , 150'C, 15min (Method 13) R1 I (Where R Br)
R
1
NH
2 )Method 13a R= NHC(O)Me 0 Methyl ethylphosphinate P 'Rg Toluene, NEt 3 , Pd(PPh 3
)
4 , 125"C, 18h (Method 13B) Xllb Method 13 (Compounds X11) 5-(4-Methoxyphenyl)-2-p-tolylbenzo[d]oxazole To a solution of 5-bromo-2-p-tolylbenzo[d]oxazole (146.1mg, 0.50mmol) in dioxane (1.5mL) was added water (0.5mL), 4-methoxyphenylboronic acid (114mg, 0.75mmol), potassium carbonate (138mg, 1.00mmol) and tetrakis(triphenylphosphine)palladium(0) (3mg). The resulting suspension was heated WO 2009/019504 PCT/GB2008/050648 126 in the microwave at 150'C for 15min. After cooling, the reaction was diluted with water and 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 1:99 v/v to afford 60mg (38%) of the title compound (LCMS RT= 9.18min, MH*316.1) 'H NMR (DMSO): 8.12 (2H, d, J8.2 Hz), 7.99 (1H, d, J 1.5 Hz), 7.82 (1H, d, J 8.5 Hz), 7.71-7.64 (3H, m), 7.45 (2H, d, J 8.0 Hz), 7.06 (2H, d, J 8.8 Hz), 3.82 (3H, s), 2.43 (3H, s) All compounds below were prepared following the same general method. N-(4-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yI)phenyl)acetamide LCMS RT= 7.51min, MH*362.8; 'H NMR (DMSO): 10.04 (1H, s), 8.23 (2H, d, J 8.5 Hz), 8.05 (1H, d, J 1.6 Hz), 7.86 (1H, d, J8.5 Hz), 7.73-7.69 (7H, m), 2.09 (3H, s) 2-(4-Chlorophenyl)-5-(4-(ethylsulfonyl)phenyl)benzo[djoxazole LCMS RT= 8.31 min, MH t 397.8; 'H NMR (DMSO): 8.27-8.23 (3H, m), 8.09-7.94 (5H, m), 7.85 (1H, dd, J 8.6 1.8 Hz), 7.73 (2H, d, J 8.7 Hz), 3.39-3.34 (2H, m), 1.16 (3H, t, J7.5 Hz) Methyl 4-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)benzoate LCMS RT= 9.34min, MH 4 363.9; 'H NMR (DMSO): 8.25 (2H, d, J 8.7 Hz), 8.20 (1 H, d, J1.3 Hz), 8.08 (2H, d, J8.6 Hz), 7.95-7.91 (3H, m), 7.83 (1H, dd, J 8.6 1.8 Hz), 7.73 (2H, d, J 8.7 Hz), 3.90 (3H, s) N-(3-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)phenyl)acetamide LCMS RT= 7.40min, MH* 363.0; 'H NMR (DMSO): 10.05 (1H, s), 8.25 (2H, d, J8.7 Hz), 8.00 (1 H, d, J 1.4 Hz), 7.98-7.95 (1 H, m), 7.90 (1 H, d, J 8.5 Hz), 7.72 (2H, d, J 8.8 Hz), 7.67 (1H, dd, J 8.5 1.8 Hz), 7.60-7.57 (1H, m), 7.42-7.40 (2H, m), 2.09 (3H, s) 2-(4-Chlorophenyl)-5-(4-morpholinophenyl)benzo[d]oxazole LCMS RT= 17.49min, MH*391.0; 'H NMR (DMSO): 8.23 (2H, d, J 8.9 Hz), 8.00 (1H, d, J 1.4 Hz), 7.83 (1 H, d, J 8.6 Hz), 7.74-7.67 (3H, m), 7.64 (2H, d, J 8.9 Hz), 7.06 (2H, d, J 8.9 Hz), 3.79-3.75 (4H, m), 3.19-3.15 (4H, m) 2-(4-Chlorophenyl)-5-(3-(ethylthio)phenyl)benzo[d]oxazole LCMS RT= 10.82min, MH*365.7; 'H NMR (DMSO): 8.25 (2H, d, J 8.7 Hz), 8.11 (1H, d, J 1.4 Hz), 7.89 (1H, d, J8.6 Hz), 7.77-7.70 (3H, m), 7.62 (1H, t, J 1.7 Hz), 7.55 (1 H, dt, J 7.6 1.2 Hz), 7.44 (1 H, t, J 7.6 Hz), 7.35-7.32 (1 H, m), 3.09 (2H, q, J 7.3 Hz), 1.29 (3H, t, J7.4 Hz) N-(2-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)phenyl)acetamide WO 2009/019504 127 PCT/GB2008/050648 LCMS RT= 6.84min, MH* 363.0; 'H NMR (DMSO): 9.29 (1H, s), 8.24 (2H, d, J 8.6 Hz), 7.86 (1H, d, J 8.4 Hz), 7.78-7.76 (1H, m), 7.72 (2H, d, J 8,5 Hz), 7.53-7.29 (5H, m), 1.87 (3H, s) 2-(4-Chlorophenyl)-5-(4-methoxypyridin-3-yl)benzo[d]oxazole LCMS RT= 7.46min, MH*337.0; "H NMR (DMSO): 8.49 (1H, d, J 5.8 Hz), 8.45 (1H, s), 8.24 (2H, d, J 8.9 Hz), 7.95 (1H, d, J 1.7 0.5 Hz), 7.87 (1H, dd, J 8.5 0.6 Hz), 7.72 (2H, d, J8.8 Hz), 7.58 (1H, dd, J8.5 1.7 Hz), 7.21 (1H, d, J5.8 Hz), 3.89 (3H, s) 2-(4-Chlorophenyl)-5-(6-methoxypyridin-3-yl)benzo[d]oxazole LCMS RT= 8.83min, MH 337.0; "H NMR (DMSO): 8.57 (1 H, dd, J 2.6 0.6 Hz), 8.24 (2H, d, J 8.8 Hz), 8.13-8.10 (2H, m), 7.89 (1H, dd, J8.6 0.5 Hz), 7.75-7.70 (3H, m), 6.95 (1H, dd, J 8.6 0.6 Hz), 3.92 (3H, s) 3-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)benzoic acid LCMS RT= 4.62min, MH* 350.1; "H NMR (DMSO): 8.27-8.23 (3H, m), 8.12 (1H, d, J 1.4 Hz), 8.03-7.95 (2H, m), 7.91 (1H, d, J 8.7 Hz), 7.78 (1H, dd, J 8.5 1.8 Hz), 7.72 (2H, d, J 8.8 Hz), 7.64 (1H, t, J 7.7 Hz) 2-(4-Chlorophenyl)-5-(6-chloropyridin-3-yl)benzo[d]oxazole LCMS RT= 8.59min, MH* 340.9; 1H NMR (DMSO): 8.33 (1H, d, J 2.2 Hz), 8.28-8.23 (4H, m), 7.95 (1 H, d, J 8.6 Hz), 7.83 (1 H, dd, J 8.5 1.8 Hz), 7.73 (2H, d, J 8.7 Hz), 7.65 (1H, d, J 8.4 Hz) 2-(4-Chlorophenyl)-5-(6-fluoropyridin-3-yI)benzo[d]oxazole LCMS RT= 8.05min, MH325.0; "H NMR (DMSO): 8.65 (1 H, d, J 2.7 Hz), 8.39 (1 H, td, J 8.2 2.7 Hz), 8.25 (2H, d, J 8.7 Hz), 8.20 (1 H, dd, J 1.8 0.5 Hz), 7.94 (1 H, dd, J 8.6 0.6 Hz), 7.80 (1 H, dd, J 8.6 1.9 Hz), 7.73 (2H, d, J 8.7 Hz), 7.33 (1 H, dd, J 8.6 3.0 Hz) 2-(4-Chlorophenyl)-5-(6-morpholinopyridin-3-yl)benzo[d]oxazole LCMS RT= 8.46min, MH* 391.8; "H NMR (DMSO): 8.55 (1H, d, J2.4 Hz), 8.23 (2H, d, J 8.7 Hz), 8.06 (1H, d, J 1.4 Hz), 7.98 (1H, dd, J 8.9 2.6 Hz), 7.86 (1H, d, J 8.8 Hz), 7.73-7.69 (3H, m), 6.96 (1 H, d, J 8.9 Hz), 3.75-3.71 (4H, m), 3.53-3.49 (4H, m) 2-(4-Chlorophenyl)-5-(6-methoxypyridin-2-yl)benzo[d]oxazole LCMS RT= 9.84min, MH*337.1; "H NMR (DMSO): 8.54 (1H, d, J 1.6 Hz), 8.26-8.23 (3H, m), 7.91 (1H, d, J 8.7 Hz), 7.82 (1H, t, J 7.9 Hz), 7.74-7.68 (3H, m), 6.81 (1H, d, J 8.1 Hz), 4.00 (3H, s) 3-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)aniline LCMS RT= 7.78min, MH*321.1; "H NMR (DMSO): 8.24 (2H, d, J 8.7 Hz), 7.73 (1H, dd, J 1.8 0.4 Hz), 7.85 (1 H, d, J 8.5 Hz), 7.72 (2H, d, J 8.8 Hz), 7.63 (1 H, dd, J 8.6 1.8 Hz), 7.13 (1H, t, J 7.8 Hz), 6.90 (1H, t, J 1.9 Hz), 6.87-6.82 (1H, m), 6.62-6.57 (IH, m), 5.19 (2H, s) WO 2009/019504 PCT/GB2008/050648 128 4-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)aniline LCMS RT= 7.77min, MH*321.1; 1 H NMR (DMSO): 8.22 (2H, d, J8.7 Hz), 7.91 (1H, d, J 1.5 Hz), 7.78 (1H, d, J 8.6 Hz), 7.71 (2H, d, J 8.6 Hz), 7.61 (1H, dd, J 8.6 1.8 Hz), 7.43 (2H, d, J 8.6 Hz), 6.67 (2H, d, J 8.6 Hz), 5.26 (2H, s) 5-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)pyridin-2-amine LCMS RT= 7.12min, MH* 322.1; 'H NMR (DMSO): 8.32 (1H, d, J 2.2 Hz), 8.23 (2H, d, J 8.7 Hz), 7.98 (1H, d, J1.4 Hz), 7.84-7.77 (2K, m), 7.72 (2H, d, J 8.7 Hz), 7.64 (1H, dd, J 8.5 1.8 Hz), 6.56 (1H, d, J 8.6 Hz), 6.09 (2H, s) 4-(5-(4-Chlorophenyl)benzo[d]oxazol-2-yl)aniline LCMS RT= 7.73min, MH* 320.9; 'H NMR (DMSO): 7.94 (1H, d, J 1.5 Hz), 7.89 (2H, d, J8.6 Hz), 7.78-7.74 (3H, m), 7.60 (1H, dd, J 8.6 1.8 Hz), 7.53 (2H, d, J 8.6 Hz), 6.71 (2H, d, J 8.7 Hz), 6.04 (2H, s) Method 13a (Compound X1ia) N-(5-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)pyridin-2-yl)acetamide To 5-(2-(4-chlorophenyl)benzo[dloxazol-5-yl)pyridin-2-amine (96.5mg, 0.30mmol) in dry pyridine (3mL) at room temperature was added acetyl chloride (26pL, 0.36mmol), and stirred at 800C for 40h. After cooling, the mixture was poured into water to give a precipitate, which was filtered off. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 20:80 v/v to afford 45mg (41 %) of the title compound. 'H NMR (DMSO): 10.61 (1H, s), 8.73-8.71 (1H, m), 8.24 (2H, d, J 8,6 Hz), 8.18-8.16 (3H, m), 7.91 (1H, d, J8.5 Hz), 7.79 (1H, dd, J 8.6 1.8 Hz), 7.73 (2H, d, J8.6 Hz), 2.13 (3H, s) Method 13b (Compound XlIb) Methyl ethylphosphinate In accordance with well known procedures (see Xu, Y. et al., Synthesis, 1984, 778 780.), a solution of methanol (2.70mL, 66.75mmol) and triethylamine (4.23mL, 30.35mmol) in diethyl ether (1 5mL) was added dropwise at 0*C to a solution of ethyl dichlorophosphine (3.15mL, 30.35mmol) in diethyl ether (30mL). After the addition was complete, the resulting slurry was refluxed for 1h. After cooling at 02C, the precipitated solid was filtered off and washed with diethyl ether. The filtrate was then WO 2009/019504 129 PCT/GB2008/050648 concentrated to afford a colourless oii, wrni was used without any purification in the next step. Methyl 2-(4-chlorophenyl)benzo[d]oxazol-5-yl(ethyl)phosphinate To 5-bromo-2-p-tolylbenzo[d]oxazole (519.7mg, 1.68mmol) and methyl ethylphosphinate (276.9mg, 2.02mmol) in anhydrous toluene (1 0mL) was added tetrakis(triphenylphosphine)palladium(0) (101.6mg) and triethylamine (7.5mL, 5.4mmol). The resulting suspension was refluxed under nitrogen for 18h. After cooling, ethyl acetate was added, and the organic layer was washed with water. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (starting with hexanes to ethyl acetate and then methanol/ethyl acetate 5:95 v/v) and then purified by reverse phase HPLC to afford 10.4mg (2%) of the title product (L CMS RT= 6.32min, MH t 336.1) 'H NMR (DMSO): 8.24 (2H, d, J 8.7 Hz), 8.18-8.13 (1H, m), 8.00 (1H, ddd, J 8.5 2.4 0.6 Hz), 7.81 (1H, ddd, J 10.9 8.2 1.4 Hz), 7.73 (2H, d, J 8.7 Hz), 3.54 (3H, d, J 10.9 Hz), 2.09-1.94 (2H, m), 1.04-0.91 (3H, m) 0
NH
2 0 R N Pyridine, 16h, r R-J O R (Method 14) N XII1 Method 14 (Compounds XIII) N-(4-(5-Chlorobenzo[d]oxazol-2-yl)phenyl)acetamide To a solution of 4-(5-chlorobenzo[d]oxazol-2-yl)aniline (122.3mg, 0.50mmol) in pyridine (3mL) at room temperature was added acetyl chloride (39 pL, 0.55mmol). The resulting mixture was stirred at room temperature for 16h. The solution was then poured into water, and the resulting precipitate collected by filtration. The solid was washed with diluted hydrochloric acid solution, followed by diluted sodium hydroxide solution, and then by water to afford 120mg (84%) of the title compound (LCMS RT= 6.38min, MH*287.0) 'H NMR (DMSO): 10.33 (1H, s), 8.14 (2H, d, J 8.7 Hz), 7.88-7.80 (4H, m), 7.45 (1H, dd, J 8.7 2.1 Hz), 2.11 (3H, s) WO 2009/019504 PCT/GB2008/050648 130 All compounds below were prepared following the same general method. N-(4-(5-Chlorobenzo[d]oxazol-2-yl)phenyl)isobutyramide LCMS RT= 7.03min, MH*315.1; 'H NMR (DMSO): 10.22 (1H, s), 8.14 (2H, d, J 8.7 Hz), 7.88-7.79 (4H, m), 7.45 (1H, dd, J 8.7 2.1 Hz), 2.70-2.61 (1H, m), 1.13 (6H, d, J 6.8 Hz) N-(4-(5-Chlorobenzo[d]oxazol-2-yl)phenyl)thiophene-2-carboxamide LCMS RT= 7.44min, MH355.0; 'H NMR (DMSO): 10.57 (1H, s), 8.21 (2H, d, J 8.9 Hz), 8.09 (1H, dd, J3.8 1.1 Hz), 8.02 (2H, d, J8.9 Hz), 7.93-7.90 (2H, m), 7.82 (1H, d, J 8.6 Hz), 7.46 (1H, dd, J 8.6 2.1 Hz), 7.27 (1H, dd, J4.9 3.8 Hz) N-(4-(6-Chlorobenzo[d]oxazol-2-yl)phenyl)acetamide LCMS RT= 6.37min, MH* 287.0; 'H NMR (DMSO): 10.32 (1H, s), 8.13 (2H, d, J 8.8 Hz), 7.96 (1 H, d, J 1.8 Hz), 7.84-7.77 (3H, m), 7.45 (1 H, dd, J 8.4 1.9 Hz), 2.11 (3H, s) N-(4-(6-Chlorobenzo[d]oxazol-2-yi)phenyi)isobutyramide LCMS RT= 7.18min, MH 4 *315.1; 'H NMR (DMSO): 10.22 (1H, s), 8.12 (2H, d, J 8.8 Hz), 7.96 (1H, d, J 1.8 Hz), 7.86 (2H, d, J8.9 Hz), 7.79 (1H, d, J 8.5 Hz), 7.45 (1H, dd, J 8.5 2.0 Hz), 2.70-2.61 (1H, m), 1.13 (6H, d, J 6.9 Hz) N-(4-(6-Chlorobenzo[d]oxazol-2-yI)phenyl)thiophene-2-carboxamide LCMS RT= 7.61min, MH*354.9; 'H NMR (DMSO): 10.57 (1H, s), 8.19 (2H, d, J8.9 Hz), 8.09 (1 H, dd, J 3.7 1.0 Hz), 8.01 (2H, d, J 8.9 Hz), 7.98 (1 H, d, J 1.8 Hz), 7.92 (1 H, dd, J 5.0 1.0 Hz), 7.81 (1 H, d, J 8.5 Hz), 7.46 (1 H, dd, J 8.5 2.0 Hz), 7.26 (1 H, dd, J 5.0 3.8 Hz) N-(4-(5-Bromobenzo[d]oxazol-2-yl)phenyl)acetamide 'H NMR (DMSO): 10.35 (1H, s), 8.14 (2H, d, J 8.8 Hz), 8.01 (1H, d, J 1.8 Hz), 7.83 (2H, d, J 8.7 Hz), 7.76 (1H, d, J8.6 Hz), 7.57 (1H, dd, J 8.6 2.0 Hz), 2.11 (3H, s) N-(4-(5-(4-Chlorophenyl)benzo[d]oxazol-2-yl)phenyl)acetamide LCMS RT= 7.53min, MH* 363.0; 'H NMR (DMSO): 10.34 (1H, s), 8.17 (2H, d, J 8.7 Hz), 8.06-8.04 (1H, m), 7.87-7.82 (3H, m), 7.78 (2H, d, J 8.5 Hz), 7.72-7.67 (1H, m), 7.55 (2H, d, J 8.6 Hz), 2.12 (3H, s) N-(4-(5,6-Dimethylbenzojd]oxazol-2-yl)-3-hydroxyphenyl)acetamide LCMS RT= 7.22min, MH* 297.2; 'H NMR (DMSO): 11.24 (1H, br), 10.24 (1H, s), 7.91 (1 H, d, J 8.6 Hz), 7.59 (2H, d, J 6.4 Hz), 7.51 (1H, d, J 1.9 Hz), 7.22 (1H, dd, J 8.7 2.0 Hz), 2.37 (3H, s), 2.34 (3H, s), 2.09 (3H, s) WO 2009/019504 PCT/GB2008/050648 131 0 NaBH 4 , THF H 0 /ZR> rtl16h HO0 N (Method 15) (Where R = COCH 3 ) XIV Method 15 (Compounds XIV) 1-(2-(4-Chlorophenyl)benzo[d]oxazol-5-yl)ethanol To a solution of 1-(2-(4-chlorophenyl)benzold]oxazol-5-yl)ethanone (150mg, 055mmol) in tetrahydrofuran at 0 0 C was added sodium borohydride (52mg, 1.38mmo). The resulting mixture was stirred at room temperature for 16h. The reaction was then quenched at 0 C with IM hydrochloric acid solution and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes 1:2 vlv) to afford 81.7mg (54%) of the title compound. (LCMS RT= 6.47min, MH*274.0) 'H NMR (DMSO): 8.20 (2H, d, J 8.7 Hz), 7.76-7.68 (4H, m), 7.44 (1H, dd, J 8.6 1.6 Hz), 5.31 (1H, d, J4.3 Hz), 4.92-4.83 (1H, m), 1.38 (3H, d, J6.4 Hz) 2-(3',4'-Dichlorophenyl)-5-(1'-hydroxyethyl)-benzoxazole LCMS RT= 7.18min, MH t 308.1; 1 H NMR (DMSO): 8.36 (1H, d, J 2.0 Hz), 8.16 (1H, dd, J 8.5 2.0 Hz), 7.90 (1H, d, J 8.4 Hz), 7.78-7.77 (1H, m), 7.74 (1H, d, J 8.4 Hz), 7.47 (1H, dd, J 8.6 1.7 Hz), 5.32 (1H, d, J 4.3 Hz), 4.93-4.84 (1H, m), 1.39 (3H, d, J 6.4 Hz) WO 2009/019504 PCT/GB2008/050648 132 N x x 0Z C5 E N CN E 0 0 x x 2 z zz z Ox cC2 00 0 e or .szz Z ClC, zO 0 z C o C 0 OX, co z
N,
WO 2009/019504 PCT/GB2008/050648 133 5-Nitrobenzo[d]oxazole-2(3H)-thione In accordance with well known procedures, (see Batista-Parra, A. et aL Heterocycles, 2003, 60, 1367), a suspension of 2-amino-4-nitrophenol (1.54g, 10mmol) and potassium O-ethyl carbonodithioate (1.68g, 10.5mmol) in dry pyridine (10mL) was stirred at 120'C for 6h, and then at room temperature for 16h. The solution was poured into water and aqueous hydrochloric acid was added. The resulting precipitate was collected by filtration, washed with dilute aqueous hydrochloric acid, followed by water and then dried in the vacuum oven to afford 3.3g (84%) of the title compound. 'H NMR (DMSO): 8.18 (1H, dd, J 8.9 2.4 Hz), 7.94 (1H, dd, J 2.4 0.4 Hz), 7.73 (1H, dd, J 8.9 0.4 Hz) Method 16 (Compound XV) 2-Morpholino-5-nitrobenzo[djoxazole 5-nitrobenzo[d]oxazole-2(3H)-thione (98.1mg, 0.5mmol) and morpholine (66pL, 0.75mmol) in tetrahydrofuran (3mL) were heated at 150'C for 15min in the microwave. After cooling, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO 4 and absorbed on silica. Purification by column chromatography, eluting with ethyl acetate/hexanes 25:75 v/v affords 115mg (92%) of the title compound. 'H NMR (DMSO): 8.10 (1 H, d, J 2.3 Hz), 8.00 (1 H, dd, J 8.8 2.4 Hz), 7.66 (1 H, d, J 8.8 Hz), 3.76-3.72 (4H, m), 3.67-3.64 (4H, m) Method 17a (Compound XVII 2-Morpholinobenzo[d]oxazol-5-amine A solution of 2-morpholino-5-nitrobenzo[d]oxazole (130mg, 0.52mmol) in ethanol/water 1:1 v/v (1OmL) was treated with sodium dithionite (1 82mg, 1.04mmol) at room temperature and then refluxed for 16h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO 4 and evaporated to afford 35mg (30%) of the title compound. 'H NMR (DMSO): 7.03 (1H, d, J 8.5 Hz), 6.50 (1H, d, J 2.1 Hz), 6.25 (1H, dd, J 8.4 2.2 Hz), 4.80 (2H, s), 3.71-3.68 (4H, m), 3.53-3.50 (4H, m) Method 17b (Compound XVI) WO 2009/019504 PCT/GB2008/050648 134 N-2-(4-Chlorobenzyl)benzo[d]oxazole-2,5-diamine To a suspension of N-(4-chlorobenzyl)-5-nitrobenzo[d]oxazo-2-amine (150mg, 0.50mmol) in ethanol/water 1:1 v/v (1OmL) at 900C was added ammonium chloride (53mg, 1.0mmol), followed by iron powder (140mg, 2.5mmol). The resulting mixture was stirred for 4h at 90'C. After cooling; ethyl acetate was added and the solution was passed through a pad of Celite*. The organic layer was then washed with brine, dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetatelhexanes 50:50 v/v to afford 60mg (44%) of the title compound (LCMS RT= 5.60min, MH t 274.0) 'H NMR (DMSO): 8.20 (1 H, t, J 6.2 Hz), 7.42-7.36 (4H, m), 6.97 (1 H, d, J 8.4 Hz), 6.45 (1H, d, J 2.1 Hz), 6.20 (1H, dd, J8.4 2.2 Hz), 4.72 (2H, s), 4.46 (2H, d, J 6.2 Hz) Method 18 (Compound XVII) 2-(4-Chlorobenzylthio)-5-nitrobenzo[d]oxazole To a suspension of 5-nitrobenzo[d]oxazole-2(3H)-thione (196.2mg, 1.0mmol) in chloroform (1OmL) was added triethylamine (278pL, 2mmol) followed by 1 (bromomethyl)-4-chlorobenzene (226mg, 1.1mmol). The reaction was stirred at 600C for 2h. After cooling, the reaction was diluted with ethyl acetate, washed with dilute aqueous hydrochloric solution and brine. 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 1:10 v/v to afford 250mg (78%) of the title compound (LCMS RT= 7.64min) 'H NMR (DMSO): 8.52 (1H, d, J2.3 Hz), 8.27 (1H, dd, J8.9 2.3 Hz), 7.92 (1H, d, J 9.0 Hz), 7.58 (2H, d, J 8.5 Hz), 7.42 (2H, d, J 8.5 Hz), 4.67 (2H, s) Method 19 (Compound XVIII) 2-(4-Chlorobenzylthio)benzo[d]oxazol-5-amine To a suspension of 2-(4-chlorobenzylthio)-5-nitrobenzo[d]oxazole (220mg, 0.70mmol) in ethanol/water (5mL/5mL) at 900C was added ammonium chloride (75mg, 1.4mmol), followed by iron powder (192mg, 3.44mmol). The resulting mixture was stirred for 4h at 900C. After cooling, ethyl acetate was added and the solution was passed through a pad of Celite*. The organic layer was then washed with brine, dried over anhydrous MgSO 4 and evaporated to afford 190mg (94%) of the title compound (LCMS RT= 6.54min, MH*290.9) WO 2009/019504 PCT/GB2008/050648 135 'H NMR (DMSO): 7.52 (2H, d, J 8.7 Hz), 7.40 (2H, d, J 8.5 Hz), 7.26 (1 H, d, J 8.7 Hz), 6.74 (1H, d, J 1.9 Hz), 6.54 (1H, dd, J8.7 2.2 Hz), 5.06 (2H, s), 4.55 (2H, s) Method 20 (Compounds XIX) N-(2-(4-Chlorobenzylthio)benzo[d]oxazol-5-yl)acetamide To a solution of 2-(4-chlorobenzylthio)benzo[d]oxazol-5-amine (87mg, 0.30mmol) in dry pyridine (3mL) at room temperature was added acetyl chloride (21 pL, 0.30mmol). The resulting solution was stirred at room temperature for 16h. Water was then added, the precipitate was collected by filtration, washed with diluted aqueous hydrochloric acid and then with water. Trituration with diethyl ether afforded 40mg (40%) of the title compound (LCMS RT= 6.40min, MH*333.1) 'H NMR (DMSO): 10.08 (1H, s), 8.01 (1H, d, J 1.8 Hz), 7.58-7.52 (3H, m), 7.43-7.35 (3H, m), 4.60 (2H, s), 2.06 (3H, s) The compound below was prepared following the same general method. N-(2-(4-Chlorobenzylthio)benzo[d]oxazol-5-yl)isobutyramide LCMS RT= 7.00min, MH 361.1; 1 H NMR (DMSO): 9.96 (1H, s), 8.04 (1H, d, J 1.8 Hz), 7.58-7.52 (3H, m), 7.43-7.39 (3H, m), 4.60 (2H, s), 2.65-2.60 (1H, m), 1.12 (6H, d, J 6.8 Hz) Method 21 (Compound XX) 2-Chloro-5-nitrobenzofd]oxazole To a solution of 5-nitrobenzo[d]oxazole-2(3H)-thione (2.52g, 12.86mmol) in phosphorous oxychloride (21mL) was added phosphorous pentachloride (2.68g, 12.86mmol) in one portion. The mixture was then heated to 100 C for 2.5h. After cooling, the excess of phosphorous oxychloride was removed in vacuo and the resulting mixture was used crude without characterisation. Method 22 (Compound XXII 5-Nitro-2-(thiophen-2-yl)benzo[d]oxazole A mixture of 2-chloro-5-nitrobenzo[d]oxazole (404mg, 2.04mmol), 2-(tributylstannyl) thiophene (648pL, 2.04mmol) and tetrakis(triphenylphosphine)palladium (0) (40.8mg) in dioxane (12.2mL) was heated at 100 C for 16h under nitrogen. Ethyl acetate was WO 2009/019504 PCT/GB2008/050648 136 added, the organic layer was washed with water, dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetatelhexanes 10:90 v/v, and then purified by reverse phase HPLC to afford 3mg (2%) of the title product (LCMS RT= 6.95min) 'H NMR (DMSO): 8.54 (1H, d, J 2.2 Hz), 8.27 (1H, dd, J9.0 2.3 Hz), 8.04 (1H, dd, J 5.4 1.2 Hz), 7.93 (1H, d, J9.0 Hz), 7.69 (1H, dd, J3.7 1.2 Hz), 7.29 (1H, dd, J 5.4 3.7 Hz) H R_ +NH PPA, 1301C, 16h (Method 23) R N 2 + R R I~ ,-R N NH R9 N OH XXII XXIla R=N0 2 XXIIb R=NH 2 ) (Method 24)
R
1 COCI, pyridine, rt, 16h (Method 25) H HN- NjR N N R1 XXI Method 23 (Compounds XXIl) 5-Amino-2-(5,6-dimethyl-1 H-benzo[d]imidazol-2-yI)phenol To polyphosphoric acid at 130'C were added 4,5-dimethylbenzene-1,2-diamine (500mg, 3.67mmol) and 4-amino-2-hydroxybenzoic acid (562mg, 3.67mmol), and the resulting mixture was then heated to 1300C for 16h. The solution was then poured into water and the resulting precipitate was dissolved in ethyl acetate and washed with Na 2
CO
3 . The aqueous layer was separated and extracted twice 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 WO 2009/019504 PCT/GB2008/050648 137 ethyl acetate/hexanes 50:50 v/v to afford rumg (28%) of the title compound (LCMS RT= 6.14min, MH*254.1) 'H NMR (DMSO): 13.07 (1H, s), 12.40 (1H, s), 7.61 (1H, d, J 8.3 Hz), 7.35 (1H, s), 7.24 (1H, s), 6.19 (1H, dd, J 8.5 2.2 Hz), 6.12 (1H, d, J 2.1 Hz), 5.59 (2H, s), 2.32 (3H, s), 2.30 (3H, s) All compounds below were prepared following the same general method. 2-(3-Methyl-4-nitrophenyl)-1 H-benzo[d]imidazole LCMS RT= 5.87min, MH t 254.1; 'H NMR (DMSO): 13.20 (1H, br), 9.31 (1H, s), 8.21 8.19 (2H, m), 7.67-7.64 (2H, m), 7.28-7.25 (2H, m), 2.65 (3H, s) 2-(6-Nitro-1 H-benzo[d]imidazol-2-yl)phenol LCMS RT= 6.48min, MH* 256.0; 'H NMR (DMSO): 13.50 (1H, br), 12.40 (1H, br), 8.56 (1H, s), 8.20-8.14 (2H, m), 7.84 (1H, d, J 8.8 Hz), 7.48-7.43 (1H, m), 7.12-7.04 (2H, m) 2-(4-Chlorophenyl)-6-nitro-1 H-benzo[d]imidazole LCMS RT= 6.24min, MH* 273.9; 'H NMR (DMSO): 13.80 (1H, br), 8.54 (1H, d, J 2.1 Hz), 8.29 (2H, d, J 8.6 Hz), 8.21 (1 H, dd, J 8.9 2.2 Hz), 7.84 (1 H, d, J 8.9 Hz), 7.75 (2H, d, J 8.5 Hz) Method 24 (Compound XXIlb) 2-(5-Amino-1 H-benzo[d]imidazol-2-yl)phenol To 2-(5-nitro-1 H-benzo[d]imidazol-2-yl)phenol (90mg, 0.35mmol) in ethyl acetate/water/acetic acid 1:1:0.01 v/v/v (1 OmL) was added palladium on carbon (15mg). The reaction vessel was purged three times with nitrogen, followed by three times with hydrogen, and then left stirring under hydrogen for 2h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite*, which was washed with ethyl acetate. The organic layer was washed with saturated aqueous NaHCO 3 . 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 2:1 v/v to afford 60mg (76%) of the title compound (LCMS RT= 5.39min, MH t 226.1) 'H NMR (DMSO): 13.28 (1H, br), 12.63 (1H, br), 7.72 (1H, d, J 8.4 Hz), 7.33-7.28 (2H, m), 6.99-6.94 (2H, m), 6.71-6.58 (2H, m), 5.12 (2H, s) Method 25 (Compounds XXIII) WO 2009/019504 PCT/GB2008/050648 138 N-(2-p-Tolyl-1 H-benzo[d]imidazol-5-yl)butyramide To a solution of 2-p-tolyl-1 H-benzo[d]imidazol-5-amine (150mg, 0.67mmol) in pyridine (1OmL) at room temperature was added butyryl chloride (77pL, 0.74mmol). The resulting mixture was stirred at room temperature for 16h. Ethyl acetate was added and the organic layer was washed twice with saturated aqueous copper sulfate, followed by sodium bicarbonate and brine. 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 50:50 v/v to afford 56mg (28%) of the title compound (LCMS RT= 6.96min, MH*294.0) "H NMR (DMSO): 12.68 (1H, br), 9.87 (1H, s), 8.08-8.00 (3H, m), 7.52-7.20 (4H, m), 2.38 (3H, s), 2.31 (2H, t, J7.3 Hz), 1.70-1.58 (2H, m), 0.94 (3H, t, J 7.4 Hz) All compounds below were prepared following the same general method. N-(2-p-Tolyl-1 H-benzo[d]imidazol-5-yl)isobutyramide LCMS RT= 5.43min, MH* 294.1; 'H NMR (DMSO): 12.67 (1H, br), 9.91 (1H, s), 8.08 8.01 (3H, m), 7.50-7.28 (4H, m), 4.03 (1H, q, J7.2 Hz), 2.38 (311, s), 1.13 (6H, d, J 6.8 Hz) N-(2-(4-Chlorophenyl)-1 H-benzo[d]imidazol-5-yl)butyramide LCMS RT= 5.54min, MH* 314.0; 'H NMR (DMSO): 12.85 (1H, br), 9.90 (1H, s), 8.14 (311, d, J 8.6 Hz), 7.62 (211, d, J 8.7 Hz), 7.53 (1H, br), 7.25 (1H, br), 2.32 (2H, t, J7.1 Hz), 1.71-1.58 (211, m), 0.94 (3H, t, J7.5 Hz) N-(2-Phenyl-1 H-benzo[d]imidazol-5-yl)isobutyramide LCMS RT= 5.32min, MH 4 280.0; 'H NMR (DMSO): 12.80 (1H, br), 9.85 (1H, s), 8.16 8.09 (3H, m), 7.58-7.47 (4H, m), 7.28 (11H, d, J 8.1 Hz), 2.68-2.60 (1 H, m), 1.13 (611, d, J 6.9 Hz) N-(2-Phenyl-1 H-benzo[d]imidazol-5-yl)butyramide LCMS RT= 5.32min, MH*280.0; 'H NMR (DMSO): 12.77 (1H, br), 9.90 (1H, s), 8.15 8.12 (311, m), 7.58-7.45 (411, m), 7.26 (1H, br), 2.31 (2H, t, J 7.1 Hz), 1.71-1.58 (2H, m), 0.94 (311, t, J 7.5 Hz) N-(2-(4-Chlorophenyl)-1 H-benzo[d]imidazol-5-yl)isobutyramide LCMS RT= 5.71min, MH*314.0; 'H NMR (DMSO): 12.89 (1H, br), 9.86 (1H, s), 8.18 8.10 (3H, m), 7.62 (2H, d, J8.8 Hz), 7.52 (1H, d, J8.8 Hz), 7.29 (1H, d, J8.3 Hz), 2.66-2.60 (1H, m), 1.13 (6H, d, J 6.9 Hz) WO 2009/0 19504 PCT1GB20081050648 139 0 CO 'Z X CIO z cc WO 2009/019504 PCT/GB2008/050648 140 Method 26 (Compound XXIV) 2-Amino-4-nitrobenzenethiol 2-Fluoro-5-nitroaniline (1g, 6.41mmol), sodium sulfide nonahydrate (1.7g, 7.05mmol), sodium bicarbonate (600mg, 7.05mmol) and water (1 5mL) were combined and heated in the microwave at 1250C for 5min. After cooling, dichloromethane was added, and the organic layer was washed with 2M aqueous hydrochloric acid and then brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 1.1 g (33%) of the title compound. 'H NMR (DMSO): 7.61-7.55 (2H, m), 7.47 (1H, d, J 8.2 Hz), 7.31 (3H, s) Method 27 (Compound XXV) 2-(2-Chlorophenyl)-5-nitrobenzo[d]thiazole 2-Amino-4-nitrobenzenethiol (315mg, 1,85mmol), 2-chlorobenzoic acid (290mg, 1.85mmol) and Eaton's reagent (5mL) were combined and heated in the microwave at 1300C for 1 0min. After cooling, the mixture was poured into water and basified with 5M aqueous sodium hydroxide to give a precipitate, which was filtered off and dried to afford 530mg (98%) of the title compound. 'H NMR (DMSO): 8.93 (1H, d, J 2.2 Hz), 8.53 (1H, d, J 8.9 Hz), 8.37 (1H, dd, J 8.9 2.2 Hz), 8.29 (1H, dd, J7.4 1.9 Hz), 7,78-7.75 (1H, m), 7.70-7.60 (2H, m) Method 28 (Compound XXVI) N-(2-Chloro-5-nitrophenyl)-4-methylbenzamide To 2-chloro-5-nitroaniline (2g, 11.59mmol) in pyridine (5mL) at room temperature was added 4-methylbenzoyl chloride (1.6mL, 12.17mmol), followed by pyridine (5mL). The mixture was then stirred at room temperature for 16h. Ethyl acetate was then added to the solution to give a precipitate, which was filtered off and washed twice with ethyl acetate, and then hexanes. The resulting solid was then washed with aqueous sodium bicarbonate, 1 M aqueous sodium hydroxide, water and hexanes to afford (1.4g, 42%) of the title compound. 'H NMR (DMSO): 10.26 (1H, s), 8.58 (1H, d, J2.8 Hz), 8.11 (1H, dd, J 8.9 2.8 Hz), 7.93 (2H, d, J 8.2 Hz), 7.87 (1 H, d, J 8.9 Hz), 7.38 (2H, d, J 8.0 Hz), 2.41 (3H, s) Method 29 (Compound XXV) WO 2009/019504 PCT/GB2008/050648 141 5-Nitro-2-p-tolylbenzo[d]thiazole Sodium sulfide nonahydrate (875mg, 3.78mmol) and sulfur (120mg, 3.78mmol) were heated until molten. The water was driven off with nitrogen to give a solid. The obtained solid was added in portions to N-(2-chloro-5-nitrophenyl)-4 methylbenzamide (1g, 3.44mmol) in ethanol (20mL) at 850C. The solution was stirred at 85 0 C for 3h. After cooling, 2M aqueous HCl was added, and the solution was extracted three times 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 10:90 v/v to afford 400mg (43%) of the title compound. "H NMR (DMSO): 8.81 (1H, d, J 2.2 Hz), 8.45 (1H, d, J 8.8 Hz), 8.29 (1H, dd, J 8.8 2.3 Hz), 8.06 (2H, d, J 8.2 Hz), 7.44 (2H, d, J 8.0 Hz), 2.42 (3H, s) Method 30 (Compounds XXVII) 2-p-Tolylbenzo[d]thiazol-5-amine 5-Nitro-2-p-tolylbenzold]thiazole (400mg, 1.48mmol) was suspended in ethanol/water (8mL/4mL) and heated at 800C. Ammonium chloride (160mg, 2.96mmol) and iron powder (414mg, 7.40mmol) were added to the suspension, and the mixture was left stirring at 80'C for 75min. After cooling, the solution was filtrated through a pad of Celite* and the pad washed with ethanol. Water was added to the filtrate, ethanol was evaporated and the remaining aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 220mg (62%) of the title compound (LCMS RT= 6.51 min, MH*241.0) 'H NMR (DMSO): 7.91 (2H, d, J8.1 Hz), 7.68 (1H, d, J 8.6 Hz), 7.35 (2H, d, J 8.0 Hz), 7.15 (1H, d, J2.0 Hz), 6.77 (1H, dd, J8.6 2.0 Hz), 5.32 (2H, s), 2.39 (3H, s) All compounds below were prepared following the same general method. 2-Phenylbenzo[d]thiazol-5-amine LCMS RT= 6.11min, MH* 227.1; 1 H NMR (DMSO): 8.04-8.01 (2H, m), 7.71 (1H, d, J 8.5 Hz), 7.56-7.53 (3H, m), 7.18 (1H, d, J 2.1 Hz), 6.79 (1H, dd, J 8.6 2.3 Hz), 5.33 (2H, s) 2-(4-Chlorophenyl)benzo[d]thiazol-5-amine LCMS RT= 6.72min, MH*260.7; "H NMR (DMSO): 8.04 (2H, d, J 8.7 Hz), 7.72 (1H, d, J 8.6 Hz), 7.61 (2H, d, J 8.7 Hz), 7.17 (1H, d, J2.0 Hz), 6.80 (1H, dd, J 8.6 2.2 Hz), 5.35 (2H, s) WO 2009/019504 PCT/GB2008/050648 142 2-(2-Chlorophenyl)benzo[d]thiazol-5-amine LCMS RT= 6.49min, MH*260.8; 'H NMR (DMSO): 8.19-8.16 (1H, m), 7.76 (1H, d, J 8.6 Hz), 7.69-7.66 (1H, m), 7.56-7.52 (2H, m), 7.22 (1H, d, J2.0 Hz), 6.85 (1H, dd, J 8.6 2.1 Hz), 5.37 (2H, s) 2-(3-Chlorophenyl)benzo[d]thiazol-5-amine LCMS RT= 6.79min, MH*260.8; 'H NMR (DMSO): 8.05-8.04 (1H, m), 7.96 (1H, dt, J 7.0 1.7 Hz), 7.74 (1H, d, J 8.6 Hz), 7.64-7.55 (2H, m), 7.19 (1H, d, J 1.7 Hz), 6.82 (IH, dd, J 8.6 2.2 Hz), 5.37 (2H, s) 2-(3,4-Dichlorophenyl)benzo[d]thiazol-5-amine LCMS RT= 7.49min, MH*294.9; 'H NMR (DMSO): 8.24 (1H, d, J 2.1 Hz), 8.00 (1H, dd, J 8.4 2.1 Hz), 7.82 (1H, d, J 8.4 Hz), 7.76 (1H, d, J 8.6 Hz), 7.20 (1H, d, J 1.9 Hz), 6.84 (1H, dd, J 8.6 2.2 Hz), 5.41 (2H, s) 2-(2,3-Dichlorophenyl)benzo[d]thiazol-5-amine LCMS RT= 7.00min, MH* 294.9; 'H NMR (DMSO): 8.08 (1H, dd, J7.9 1.6 Hz), 7.84 (IH, dd, J 8.0 1.6 Hz), 7.78 (1H, d, J 8.6 Hz), 7.55 (1H, t, J 8.0 Hz), 7.22 (1H, d, J 2.0 Hz), 6.87 (1 H, dd, J 8.6 2.2 Hz), 5.38 (2H, s) Method 31 (Compounds XXVIII) N-(2-p-Tolylbenzo[d]thiazol-5-yI)butyramide To a solution of 2-p-tolylbenzo[d]thiazol-5-amine (110mg, 0.46mmol) in pyridine (3mL) at room temperature was added butyryl chloride (53pL, 0.50mmol). The resulting mixture was stirred at room temperature for 2 days. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate, followed by aqueous sodium bicarbonate and finally with brine. 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 50:50 v/v to afford 25mg (18%) of the title compound (LCMS RT= 7.10min, MH*311.0) 'H NMR (DMSO): 10.12 (1H, s), 8.43 (1 H, d, J 1.8 Hz), 8.02-7.96 (3H, m), 7.58 (1H, dd, J 8.6 2.0 Hz), 7.38 (2H, d, J 8.0 Hz), 2.40 (3H, s), 2.35 (2H, t, J 7.5 Hz), 1.72-1.60 (2H, m), 0.95 (3H, t, J 7.4 Hz) All compounds below were prepared following the same general method. N-(2-p-Tolylbenzo[d]thiazol-5-yl)isobutyramide WO 2009/019504 143 PCT/GB2008/050648 LCMS RT= 7.06min, MH*311.0; 'H Nivir tumiviu): 10.08 (1H, s), 8.44 (1H, d, J 1.3 Hz), 8.03-7.96 (3H, m), 7.60 (1H, dd, J 8.7 1.6 Hz), 7.38 (2H, d, J 8.0 Hz), 2.69-2.60 (1H, n), 2.40 (3H, s), 1.15 (6H, d, J 6.8 Hz) N-(2-Phenylbenzo[d]thiazol-5-yl)isobutyramide LCMS RT= 6.56min, MH* 297.0; 'H NMR (DMSO): 10.07 (1H, s), 8.47 (1H, d, J 1.8 Hz), 8.11-8.07 (2H, m), 8.04 (1 H, d, J 8.6 Hz), 7.64-7.56 (4H, m), 2.70-2.61 (1 H, m), 1.15 (6H, d, J 6.8 Hz) N-(2-(4-Chlorophenyl)benzo[d]thiazol-5-yl)isobutyramide LCMS RT= 7.42min, MH* 331.0; 'H NMR (DMSO): 10.08 (1H, s), 8.47 (1H, d, J 1.9 Hz), 8.10 (2H, d, J8.6 Hz), 8.05 (1H, d, J 8.7 Hz), 7.67-7.61 (3H, m), 2.70-2.60 (1H, m), 1.15 (6H, d, J6.8 Hz) N-(2-(2-Chlorophenyl)benzo[d]thiazol-5-yl)isobutyramide LCMS RT= 6.99min, MH- 330.9; 'H NMR (DMSO): 10.12 (1H, s), 8.55 (1H, d, J 1.9 Hz), 8.25-8.22 (1H, m), 8.10 (1H, d, J 8.8 Hz), 7.74-7.55 (4H, m), 2.72-2.63 (1H, m), 1.17 (6H, d, J6.8 Hz) N-(2-(3-Chlorophenyl)benzo[d]thiazol-5-yl)isobutyramide LCMS RT= 7.34min, MH 330.9; 'H NMR (DMSO): 10.11 (1H, s), 8.50 (1H, d, J 1.7 Hz), 8.13-8.03 (3H, m), 7.69-7.60 (3H, m), 2.71-2.62 (1H, m), 1.17 (6H, d, J 6.8 Hz) N-(2-(3,4-Dichlorophenyl)benzo[d]thiazol-5-yl)isobutyramide LCMS RT= 8.21min, MH*364.7; 'H NMR (DMSO): 10.11 (1H, s), 8.52-8.50 (1H, m), 8.30 (1H, d, J 2.1 Hz), 8.10-8.04 (2H, m), 7.85 (1H, d, J 8.4 Hz), 7.69-7.64 (1H, m), 2.71-2.64 (1H, m), 1.17 (6H, d, J 6.8 Hz) N-(2-(2,3-Dichlorophenyl)benzo[d]thiazol-5-yl)isobutyramide LCMS RT= 7.62min, MH* 364.9; 'H NMR (DMSO): 10.12 (1H, s), 8.55 (1H, d, J 1.7 Hz), 8.14-8.10 (2H, m), 7.88 (1H, dd, J 8.0 1.4 Hz), 7.67 (1H, dd, J8.8 2.0 Hz), 7.58 (1H, t, J 8.0 Hz), 2.70-2.61 (1H, n), 1.15 (6H, d, J 6.8 Hz) 0 t r90min I' gs00 , Nou N. NH 2 Method 32 N Method 33 H I l XXIX XXX
K
3 Fe(0N)c, Ethnol C hPSA DCM MeO 2 S CI $ OH,901XX30mX MethodX35 Method 34 N XXXI
XXXII
WO 2009/019504 PCT/GB2008/050648 144 Method 32 (Compound XXIX) 4-Chloro-N-(4-(methylthio)phenyl)benzamide To 4-(methylthio)aniline (1mL, 8.19mmol) in dichloromethane (20mL) was added pyridine (2mL, 24.6mmol). The resulting solution was cooled to 10-15 0 C and 4 chlorobenzoyl chloride (1.14mL, 9.00mmol) was added over 5min.The mixture was stirred at room temperature for 90min. The precipitate was filtered off, washed with dichloromethane, 1M aqueous sodium hydroxide solution and 1M aqueous hydrochloric acic solution to afford 2.12g (93%) of the title compound. 'H NMR (DMSO): 10.31 (1H, s), 7.98 (2H, d, J 8.7 Hz), 7.73 (2H, d, J 8.8 Hz), 7.61 (2H, d, J 8.8 Hz), 7.28 (2H, d, J 8.8 Hz), 2.47 (3H, s) Method 33 (Compound XXX) 4-Chloro-N-(4-(methylthio)phenyl)benzothioamide A suspension of 4-chloro-N-(4-(methylthio)phenyl)benzamide (1g, 3.60mmol) and Lawesson's reagent (875mg, 2.16mmol) in toluene (25mL) was heated to 1 10 0 C for 16h. After cooling, toluene was removed in vacuo and the resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 30:70 v/v) to afford 503mg (48%) of the title compound. LCMS RT= 6.98min, MH-294.1; 'H NMR (DMSO): 11.80 (1H, s), 7.85 (2H, d, J 8.6 Hz), 7.78 (2H, d, J 8.7 Hz), 7.54 (2H, d, J 8.6 Hz), 7.33 (2H, d, J 8.7 Hz) Method 34 (Compound XXXI) 2-(4-Chlorophenyl)-6-(methylthio)benzo[d]thiazole To a solution of potassium hexacyanoferrate(ll) (670mg, 2.04mmol) in water (5mL) at 90'C was added dropwise over 5 minutes a solution of 4-chloro-N-(4 (methylthio)phenyl)benzothioamide (150mg, 0.51mmol) in ethanol (2mL) and 3M aqueous sodium hydroxide solution (1.4mL, 4.08mmol). The resulting mixture was heated at 900C for 30minutes. After cooling, the precipitate formed was filtered off and washed with water to give a yellow solid. The yellow solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 5:95 v/v) to afford 100mg (67%) of the title compound (LCMS RT= 9.37min, MH*292.2) 'H NMR (DMSO): 8.11-8.06 (3H, m), 7.98 (1H, d, J 8.6 Hz), 7.65 (2H, d, J 8.7 Hz), 7.45 (1H, dd, J 8.6 1.9 Hz), 2.58 (3H, s) WO 2009/019504 PCT/GB2008/050648 145 Method 35 (Compound XXXII) 2-(4-Chlorophenyl)-6-(methylsulfonyl)benzo[d]thiazole To a solution of 2-(4-chlorophenyl)-6-(methylthio)benzo[d]thiazole (240mg, 0.82mmol) in dichloromethane (20mL) was added 3-chloroperoxybenzoic acid (77% in water, 71 0mg, 4.11mmol) over 5min. The resulting mixture was stirred at room temperature for 3h. 1 M aqueous sodium hydroxide solution was added carefully, and the mixture was then stirred for 5min. The organic layer was then washed with 1 M aqueous sodium hydroxide solution, dried over anhydrous MgSO 4 and evaporated. The resulting solid was recrystallised from hot ethyl acetate to afford 125mg (47%) of the title compound (LCMS RT= 6.81 min, MH* 324.0) 'H NMR (CDCI 3 ): 8.61 (1H, dd, J 1.8 0.4 Hz), 8.26 (1H, dd, J 8.6 0.5 Hz), 8.14-8.09 (3H, m), 7.57 (2H, d, J8.6 Hz), 3.19 (3H, s)
Y
Br ___ B(OH) 2 CI Pd(PPh 3
)
4 , dioxarie/water Y N MW 160 0 C, 15min H Method 36 Ci H XXXIll Method 36 (Compounds XXXIII) 2-(4-Chloropheny)-5-phenyl-1 H-indole To a suspension of 5-bromo-2-(4-chlorophenyl)-1 H-indole (200mg, 0.65mmol) in dioxane/water 4:1 v/v (5mL) was added phenylboronic acid (87mg, 0.72mmol) and a few milligrams of tetrakis(triphenylphosphine)palladium(0). The resulting suspension was heated in the microwave at 1600C for 15min. After cooling, the reaction was poured into water to give a precipitate, which was filtered off and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetatelhexanes 30:70 v/v), followed by a recrystallisation from hot ethyl acetate to afford 21mg (11%) of the title compound (LCMS RT= 8.54min, MH* 304.1) WO 2009/019504 146 PCT/GB2008/050648 'H NMR (DMSO): 11.68 (1H, s), 7.91 (2H, d, J 8.6 Hz), 7.81 (1H, d, J 1,1 Hz), 7.70 7.66 (2H, m), 7.55 (2H, d, J 8.6 Hz), 7.50-7.41 (4H, m), 7.33-7.28 (1H, m), 7.01 (1H, d, J 1.2 Hz) The compound below was prepared following the same general method. N-(4-(2-(4-Chlorophenyl)-1 H-indol-5-yl)phenyl)acetamide LCMS RT= 6.69min, MH* 361.0; 'H NMR (DMSO): 11.64 (1H, s), 9.98 (1H, s), 7.91 (2H, d, J 8.6 Hz), 7.77 (1H, d, J 1.0 Hz), 7.68-7.60 (4H, m), 7.54 (2H, d, J 8.6 Hz), 7.46 (1H, d, J 8.3 Hz), 7.41 (1H, dd, J 8.5 1.6 Hz), 6.99 (1H, d, J1.5 Hz), 2.07 (3H, s) KOtBu, RX, 18-Crown-6 THF, rt, 30min 0 2 N N Method 37 R H R Iron,
NH
4 CI, XXXIV R 1 = NO 2 Ethanol/Water, XXXV R 1 = NH 2 70C, 2h Method 38
R
1 COCI Pyridine, rt, 16h Method 39 0 N N H R XXXVI Method 37 (Compound XXXIV) 1 -Methyl-6-nitro-I H-indole To a solution of 6-nitro-1H-indole (100mg, 0.62mmol) and 18-Crown-6 (180mg, 0.68mmol) in anhydrous tetrahydrofuran (2mL) at room temperature was slowly added potassium tert-butoxide (76mg, 0.68mmol) followed by methyl iodide (42pL, 0.68mmol). The solution was stirred at room temperature for 30min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSQ 4 and evaporated to afford 91 mg (84%) of the title compound. 'H NMR (CDC 3 ): 8.16 (1H, d, J 1.8 Hz), 7.85 (1H, dd, J 8.7 1.9 Hz), 7.49 (1H, d, J 8.7 Hz), 7.19 (1H, d, J 3.1 Hz), 6.43 (1H, dd, J 3.1 0.9 Hz), 3.74 (3H, s) Method 38 (Compound XXXV) WO 2009/019504 PCT/GB2008/050648 147 1-Methyl-1 H-indol-6-amine 1-methyl-6-nitro-1H-indole (90mg, 0.51 mmol), ammonium chloride (55mg, 1.02mmol) and iron powder (143mg, 2.55mmol) were suspended in ethanol/water (2mL/1mL) and heated at 700C for 2h. After cooling, the solution was filtrated through a pad of Celite*, which was washed with ethanol. Ethyl acetate was added to the filtrate and the organic layer was washed with water twice. The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 30mg (37%) of the title compound 'H NMR (DMSO): 7.17 (1H, d, J 8.4 Hz), 6.93 (1H, d, J 3.1 Hz), 6.51-6.49 (1H, m), 6.41 (1H, dd, J8.3 1.9 Hz), 6.16 (1H, d, J3.1 Hz), 4.76 (2H, s), 3.60 (3H, s) Method 39 (Compounds XXXVI) N-(1 -Methyl-1 H-indol-6-yl)isobutyramide To a solution of 1-methyl-IH-indol-6-amine (45mg, 0.31mmol) in pyridine (2mL) at room temperature was added isobutyryl chloride (35pL, 0.34mmol). The resulting mixture was stirred at room temperature for 16h. Ethyl acetate was added and the organic layer was washed three times with brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 24.3mg (36%) of the title compound (LCMS RT= 5.73min, MH*217.2) 'H NMR (DMSO): 9.78 (1 H, s), 7.96 (1 H, m), 7.44 (1 H, d, J 8.4 Hz), 7.24 (1 H, d, J 3.1 Hz), 7.08 (1H, dd, J8.4 1.7 Hz), 6.35 (1H, dd, J3.0 0.7 Hz), 3.73 (3H, s), 2.68 2.61 (1H, m), 1.13 (6H, d, J 6.9 Hz) The compound below was prepared following the same general method. N-(1 -Benzyl-1 H-indol-6-yI)isobutyramide LCMS RT= 6.36min, MH* 293.2; 'H NMR (DMSO): 9.73 (1H, s), 7.90 (1H, m), 7.45 (1H, d, J 8.5 Hz), 7.41 (1H, d, J 3.1 Hz), 7.34-7.24 (3H, m), 7.14-7.10 (3H, m), 6.42 (1 H, d, J 3.2 Hz), 5.35 (2H, s), 1.08 (6H, d, J 6.8 Hz) WO 2009/0 19504 PCT1GB20081050648 148 0 0CD LC It 11x) 7q irl x 00 C-) CD 0 j- 0 0 Si- C Zco> xC xa xoC zt 0 0= 0 2 -0(2 WaC) C 0 Z rw a) cu a) LLC dLJ WO 2009/019504 PCT/GB2008/050648 149 Method 40 (Compound XXXVII) N-(2-Hydroxy-5-nitrophenyl)butyramide To a solution of 2-amino-4-nitrophenol (10g, 64.9mmol) in dichloromethane (250mL) 5 under nitrogen at 00C was added pyridine (10.5mL, 129.9mmol) followed by butyryl chloride (7.05mL, 68.2mmol) over a period of 5min. After 30min at 0CC, the solution was left warming up to room temperature for 2 days. The organic layer was washed with aqueous copper sulfate solution and brine. Insoluble material from the aqueous layer was filtered off and washed with water to afford 4.95g (34%) of the title 10 compound. 'H NMR (DMSO): 11.64 (1H, br), 9.37 (1H, s), 8.95 (1H, d, J2.8 Hz), 7.89 (1H, dd, J 8.9 2.8 Hz), 7.02 (1H, d, J 8.9 Hz), 2.43 (2H, t, J7.4 Hz), 1.67-1.55 (2H, m), 0.92 (3H, t, J7.5 Hz) 15 Method 41 (Compound XXXVIII) 2-Butyramido-4-nitrophenyl trifluoromethanesulfonate To a solution of sodium hydride (220mg, 5.58mmol) in dry acetonitrile (40mL) at 00C under nitrogen was added a solution of N-(2-hydroxy-5-nitrophenyl)butyramide (1g, 20 4.46mmol) in dry acetonitrile (90mL). The solution was then stirred at 00C for 30min. Trifluoromethanesulfonic anhydride (825pL, 4.90mmol) was added dropwise at 000 over a period of 10min. After 3h at Q'C, the solution was stirred at room temperature for 3h. Water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was then washed with dilute aqueous hydrochloric acid, aqueous sodium 25 bicarbonate and brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting oil was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate/hexanes 25:75 v/v) to afford 860mg (54%) of the title compound. 'H NMR (CDCI 3 ): 9.37 (1H, d, J 2.8 Hz), 8.09 (1H, dd, J 9.1 2.8 Hz), 7.53 (2H, d, J9.1 30 Hz), 2.50 (2H, t, J 7.6 Hz), 1.91-1.78 (2H, m), 1.09 (3H, t, J 7.5 Hz) Method 42 (Compound XXXIX) N-(5-Nitro-2-(phenylethynyl)phenyl)butyramide 35 To a solution of 2-butyramido-4-nitrophenyl trifluoromethanesulfonate (860mg, 2.42mmol) in dry acetonitrile (30mL) under nitrogen was added tetrabutylammonium WO 2009/019504 PCT/GB2008/050648 150 iodide (1.34g, 3.62mmol), tetrakis(triphenylphosphine)palladium(0) (280mg, 0.24mmol) and copper iodide (140mg, 0.72mmol). Triethylamine (6mL) was then added, followed by phenyl acetylene (530pL, 4.83mmol). The resulting solution was stirred at room temperature for 2h. Ammonium chloride was then added to quench the reaction, and 5 the aqueous layer was extracted. with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate) to afford 580mg (78%) of the title compound. 'H NMR (DMSO): 9.81 (1 H, s), 8.74 (1 H, d, J 2.3 Hz), 8.01 (1 H, dd, J 8.6 2.4 Hz), 7.83 10 (1H, d,.J 8.6 Hz), 7.70-7.67 (2H, m), 7.52-7.49 (3H, n), 1.73-1.61 (2H, m), 0.96 (3H, t, J7.5 Hz) Method 43 (Compound XLa) 15 6-Nitro-2-phenyl-1 H-indole To a solution of N-(5-nitro-2-(phenylethynyl)phenyl)butyramide (580mg, 1.88mmol) in 1-Methyl-2-pyrrolidinone (20mL) under nitrogen was added potassium tert-butoxide (243mg, 2.16mmol). The resulting solution was heated at 700C for 6h, and then left at 20 room temperature for 16h. Water was added and the aqueous layer was extracted several times with ethyl acetate. The combined organic layers were washed 10 times with water, 3 times with brine, dried over anhydrous MgSO 4 and evaporated. The resulting material was purified by column chromatography eluting with ethyl acetate/hexanes 15:85 v/v to afford 175mg (39%) of the title compound. 25 'H NMR (DMSO): 12.35 (1H, s), 8.30 (1H, d, J 2.1 Hz), 7.97-7.90 (3H, m), 7.73 (1H, d, J 8.9 Hz), 7.57-7.52 (2H, m), 7.47-7.42 (1H, m), 7.17 (1H, dd, J 2.0 0.8 Hz) Method 44 (Compound XLb) 30 I -Methyl-6-nitro-2-phenyl-1 H-indole To a solution of 6-nitro-2-phenyl-1 H-indole (1 06mg, 0.44mmol) and 18-Crown-6 (130mg, 0.49mmol) in anhydrous tetrahydrofuran (2mL) at room temperature was added potassium tert-butoxide (55mg, 0.49mmol) followed by methyl iodide (31pL, 35 0.49mmol). The solution was stirred at room temperature for 30min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed WO 2009/019504 PCT/GB2008/050648 151 with water and then brine. The combined organic layers were dried over anhydrous MgSO 4 and evaporated to afford 110mg (98%) of the title compound. 'H NMR (DMSO): 8.60 (1H, d, J 2.1 Hz), 8.03 (1H, dd, J 8.8 2.1 Hz), 7.82 (1H, d, J 8.7 Hz), 7.74-7.71 (2H, m), 7.67-7.57 (3H, m), 6.87 (1H, d, J 0.8 Hz), 3.95 (3H, s) 5 Method 45 (Compound XLI) 2-Phenyl-1 H-indol-6-amine 6-Nitro-2-phenyl-1H-indole (1 75mg, 0.73mmol), ammonium chloride (80mg, 10 1.47mmol) and iron powder (205mg, 3.68mmol) were suspended in ethanol/water (4mL/2mL) and heated at 700C for 2h. After cooling, the solution was filtrated through a pad of Celite*, which was washed with ethanol. The organic layer was evaporated into vacuo to obtain a solid, which was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 10:90 v/v to ethyl acetate/hexanes 50:50 v/v) 15 to afford 54mg (35%) of the title compound. 'H NMR (DMSO): 10.88 (1H, s), 7.76-7.72 (2H, m), 7.39 (2H, t, J 7.9 Hz), 7.23-7.16 (2H, m), 6.67 (1H, dd, J2.0 0.7 Hz), 6.59-6.57 (1H, m), 6.39 (1H, dd, J 8.4 2.0 Hz), 4.82 (2H, s) 20 Method 46 (Compounds XLII) N-(2-Phenyl-1 H-indol-6-yl)isobutyramide To a solution of 2-phenyl-1 H-indol-6-amine (54mg, 0.26mmol) in pyridine (2mL) at room temperature was added isobutyryl chloride (30pL, 0.29mmol). The resulting 25 mixture was stirred at room temperature for 2 days. When water was added, a precipitate was formed. This solid was recrystallised from hot ethyl acetate to afford 15mg (21%) of the title compound (LCMS RT= 6.27min, MH*279.0) 'H NMR (DMSO): 11.40 (1H, s), 9.74 (1H, s), 8.02 (1H, s), 7.82 (2H, d, J7.5 Hz), 7.47-7.40 (3H, m), 7.28 (1H, t, J7.3 Hz), 7.07 (1H, dd, J 8.5 1.6 Hz), 6.83 (1H, d, J 1.1 30 Hz), 2.67-2.60 (1H, m), 1.13 (6H, d, J 6.7 Hz) The compound below was prepared following the same general method. N-(1 -Methyl-2-phenyl-1 H-indol-6-yl)isobutyramide WO 2009/019504 PCT/GB2008/050648 152 LCMS RT= 6.66mir, MH* 293.2; "H NMR (DMSO): 9.83 (1H, s), 8.02 (1H, s), 7.61 7.39 (6H, m), 7.13 (1H, dd, J8.5 1.7 Hz), 6.50 (1H, d, J0.5 Hz), 3.69 (3H, s), 2.69 2.60 (1H, m), 1.13 (6H, d, J 6.8 Hz) OH 0 2 N I 0 r Pd/C Cul, PPh 3 /2N/ R Water, 80"C, 3h 0 2 NJD _ Method 47 XLIla R=N0 2 Fe, NH 4 CI, EtOH/Water 2:1 v/v, 80'C, 4h XLIIIb R=NH 2 Method 48
R
1 COCJ, pyridine, R 1 C0 2 H, DIPEA, DCM, HATU rt, 16h rt,48h Method 49 Method 50 0 N 0 R H 5 XLIV Method 47 (Compound XLilla) 5-N itro-2-phenyl benzofu ran 10 A solution of 2-iodo-4-nitrophenol (500mg, 1.89mmol), prolinol (573mg, 5.66mmol), palladium on carbon (60mg, 0.06mmol), triphenylphosphine (59.4mg, 0.226mmol) and copper iodide (22mg, 0.11 3mmol) in water (6mL) was stirred for 1 h at room temperature. Ethynylbenzene (482mg, 4.72mmol) was slowly added, and the resulting mixture was heated at 800C for 3h. After cooling, ethyl acetate was added, and the 15 mixture was passed through a pad of Celite*. The filtrate was washed with water; the combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting material was purified by column chromatography eluting with ethyl acetate/hexanes 1:40 v/v to afford 134mg (30%) of the title compound. "H NMR (DMSO): 8.62 (1H, d, J2.4 Hz), 8.23 (1H, dd, J9.1 2.5 Hz), 8.00-7.96 (2H, 20 m), 7.89 (1H, d, J9.0 Hz), 7.66 (1H, d, J0.4 Hz), 7.60-7.46 (3H, m) Method 48 (Compound XLIIlb) 2-Phenylbenzofuran-5-amine 25 To 5-Nitro-2-phenylbenzofuran (250mg, 1.04mmol) in ethanol/water 2:1 v/v (12mL) at 800C was added ammonium chloride (112mg, 2.09mmol) and iron powder (292mg, WO 2009/019504 PCT/GB2008/050648 153 5.23mmol). The resulting mixture was heated at 800C for'4h. After cooling, the solution was filtrated through a pad of Celite*, which was washed with ethanol. The organic layer was evaporated into vacuo to obtain a solid, which was then taken up in ethyl acetate and washed with water. The combined organic layers were dried over 5 anhydrous MgSO 4 and evaporated to afford 211mg (96%) of the title compound. 'H NMR (DMSO): 7.87-7.83 (2H, m), 7.50-7.44 (2H, m), 7.40-7.34 (1H, m), 7.28 (1H, d, J8.7 Hz), 7.20 (1H, d, J 0.7 Hz), 6.74 (1H, d, J2.2 Hz), 6.60 (1H, dd, J8.7 2.3 Hz), 4.88 (2H, s) 10 Method 49 (Compounds XLIV) N-(2-Phenylbenzofuran-5-yl)isobutyramide To a solution of 2-phenylbenzofuran-5-amine (210mg, 1.00mmol) in pyridine (5mL) at room temperature was added isobutyryl chloride (120pL, 1.10mmol). The resulting 15 mixture was stirred at room temperature for 16h. Ethyl acetate was added and the organic layer was washed with saturated aqueous copper sulfate solution followed by saturated aqueous potassium carbonate solution. The combined organic layers were dried over anhydrous MgSO 4 and evaporated. The resulting material was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 vlv to 20 ethyl acetate/hexanes 1:2 vlv) to afford 134mg (48%) of the title compound (LCMS RT= 6.81min, MH t 280.1) 'H NMR (DMSO): 9.87 (1H, s), 8.05 (1H, s), 7.91 (2H, d, J7.4 Hz), 7.58-7.48 (3H, m), 7.45-7.38 (3H, m), 2.66-2.54 (1H, m), 1.13 (6H, d, J 6.8 Hz) 25 The compound below was prepared following the same general method. 2-(4'-Chlorophenyl)-5-isobutyramido-benzofuran LCMS RT= 7.41min, MH 314.2; 1 H NMR (DMSO): 9.88 (1H, s), 8.06 (1H, d, J 1.9 Hz), 7.92 (2H, d, J8.7 Hz), 7.59-7.53 (3H, m), 7.49 (1H, d, J0.8 Hz), 7.43 (1H, dd, J9.0 30 2.2 Hz), 2.66-2.56 (1H, m), 1.13 (6H, d, J 6.8 Hz) Method 50 (Compound XLIV) 2-Phenyl-5-(3',3',3'-trifluoropropanamido)benzofuran 35 To 3,3,3-trifluoropropanoic acid (136mg, 1.06mmol) in dry dichloromethane (1 OmL) was added HATU (468mg, 1.23mmol) and diisopropylethylamine (580pL, 3.35mmol).
WO 2009/019504 PCT/GB2008/050648 154 The mixture was then stirred at room temperature for 10min. 2-phenylbenzofuran-5 amine (234mg, 1.12mmol) was then added and the resulting mixture was stirred at room temperature for 48h. Ethyl acetate was added and the organic layer was washed once with saturated aqueous water. The combined organic layers were dried over 5 anhydrous MgSO 4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:3 v/v to ethyl acetate/hexanes I1 v/v) followed by trituration in ethyl acetate to afford 99.3mg (28%) of the title compound (LCMS RT= 6.62min) 1H NMR (DMSO): 10.37 (IH, s), 8.01 (1H, d, J 2.0 Hz), 7.92 (2H, dd, J 7.5 1.5 Hz), 10 7.61 (1H, d, J 8.8 Hz), 7.55-7.41 (4H, m), 7.38 (1H, dd, J 8.9 2.2 Hz), 3.53 (2H, q, J 11.2 Hz) The compounds listed in Table 2, can be prepared by analogues methods to those described above, or by literature methods known or adapted by the persons skilled in 15 the art. Synergistic effect of combinations with prednisone The effect of combinations of a compound of formula (1) with a corticosteroid 20 (prednisolone) was examined by measuring fatigue induced by a forced exercise regime in mdx mice. Four to five week-old male mdx mice were forced to exercise (30 min running on horizontal treadmill at 12 m/min twice a week on the same day and at the same time) 25 over a five week treatment course. Each treatment group included 6 mice. At the end of the treatment course, exhaustion was induced by running on a horizontal treadmill at 5 m/min for 5 min, with incremental speed increases of 1 m/min each minute until exhaustion. The total distance run was then measured. 30 Treatment included dosing (ip) with 50mg/kg 5-(ethylsulfonyl)-2-(naphthalen-2 yl)benzofd]oxazole daily for 5 weeks, alone and in combination with prednisolone. Sedentary and vehicle only groups acted as negative controls.
WO 2009/019504 PCT/GB2008/050648 155 The results are shown in Figure 4. They show that prednisolone (PDN) and 5 (ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (CMPD1) can act in synergy to reduce exercise-induced fatigue in the mdx mouse. 5 Equivalents The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It 10 will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

权利要求:
Claims (53)
[1] 1. A combination comprising (or consisting essentially of) an ancillary agent and a compound of Formula (1): 5 A A 3 A 4 (1) in which A 1 , A 2 , A 3 and A 4 , which may be the same or different, represent N or CR 1 , 10 X is a divalent group selected from 0, S(O),, C=W, NR 4 , NC(=0)R 5 and CR 6 R 7 , W is O, S, NR 20 , Y is N or CR 8 , one of R 4 , R 5 , R6, R 8 , RE and NR 20 represents - L -R 3 , in which L is a single bond or a linker group, 15 additionally, R 1 , R 3 - Rs, which may be the same or different, independently represent hydrogen or a substituent and R 20 represents hydrogen, hydroxyl, alkyl optionally substituted by aryl, alkoxy optionally substituted by aryl, aryl, CN, optionally substituted alkoxy, optionally substituted aryloxy, optionally substitute alkanoyl, optionally substituted aroyl, NO 2 , 20 NR 3 oR 3 1, in which R 30 and R 31 , which may be the same or different, represent hydrogen, optionally substituted alkyl or optionally substituted aryl; additionally, one of Ro and R 31 may represent optionally substituted alkanoyl or optionally substituted aroyl, n represents an integer from 0 to 2, 25 in addition, when an adjacent pair of A 1 - A 4 each represent CR 1 , then the adjacent carbon atoms, together with their substituents may form a ring B, when X is CR 6 R 7 , R and R 7 , together with the carbon atom to which they are attached may form a ring C, 30 or a pharmaceutically acceptable salt thereof, optionally for the therapeutic and/or prophylactic treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia. WO 2009/019504 PCT/GB2008/050648 157
[2] 2. The combination according to claim 1, wherein R 3 in the compound of formula 1 represents alkyl, alkoxy or aryl, each optionally substituted by one to three subsitutuents, R 2 , which may be the same or different. 5
[3] 3. The combination according to claim 1, wherein L is single bond and R 3 represents: thioalkyl optionally substituted by alkyl or optionally substituted aryl, thioaryl, in which the aryl is optionally substituted, optionally substituted aryl, hydroxyl, 10 NO 2 , CN, NR 10 R 11 , halogen, SO2R 1 2 , 15 NR 13 S0 2 R 14 , C(=W)R 16 , OC(=W)NR 10 R NR 15 C(=W)R 17 , Rio, Rj 1 , R 1 2 , R 1 3 , R 1 4 , R 1 5 , R 1 6 and R 1 7, which may be the same or different, 20 represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted aryl, in addition, NRI 0 R 11 together with the nitrogen to which they are attached may form a ring, R 1 2 may have the same meaning as NRI 0 R 11 , 25 when R 1 7 represents NR 1 3 FR 1 1 , that NR 1 R 11 may represent hydrogen, COalkyl and CO optionally substituted aryl, R 16 and R 1 7 , which may be the same or different, may each represent alkyl substituted by one or more of halogen, alkoxy optionally substituted aryl or optionally substituted aryl, 30 optionally substituted aryloxy, aryl or NR 10 FR 11 and when R 16 or R1 7 represents NRj 0 R-,, one of RIo and R 1 , may additionally represent CO alkyl optionally substituted or COaryl optionally substituted, and in addition to the definitions shared with R 1 7 , R-, may represent hydroxy. 35 WO 2009/019504 PCT/GB2008/050648 158
[4] 4. The combination according to claim 2, in which R 1 and R2, which may be the same or different, may represent include: alkyl optionally substituted by one or more halogen, alkoxy or optionally substituted aryl, thioaryl or aryloxy, 5 alkoxy optionally substituted by optionally by alkyl or optionally substituted aryl, hydroxyl, OC(=W)NR 10 R 1 aryl, thioalkyl optionally substituted by alkyl or optionally substituted aryl, 10 thioaryl, in which the aryl is optionally substituted, NO 2 , CN, NRioRii, halogen, 15 S0 2 R 1 2 , NR 13 SO 2 R 1 4 , C(=W)Rla, NR15C(=W)R 17 , P(=O)OR 4 R 41 , 20 Rio, R 11 , R 1 2 , R1 3 , R 1 4 , R 1 5 , R 1 6 , R 1 7 , R 40 and R4 1 which may be the same or different, represent hydrogen, alkyl optionally substituted by optionally substituted aryl, optionally substituted aryl, in addition, NR 10 R 1 together with the nitrogen to which they are attached may form a ring, 25 R 12 may have the same meaning as NR 1 oR 1 , when R 1 7 represents NR 1 oR 1 , that NR 10 R 1 may represent hydrogen, COalkyl and CO optionally substituted aryl, R1 6 may represent hydroxy, alkoxy, or NR 1 oR, R 17 may represent alkyl substituted by one or more of halogen, alkoxy, 30 optionally substituted aryl or NR 1 OR 1 , and when R 17 represents NR 10 Rll, that NR 10 R 11 may represent hydrogen, COalkyl and CO optionally substituted aryl.
[5] 5. The combination of according to claim 1, in which L represents a linker group which 35 is: 0, S, (CO)rNR 1 3, WO 2009/019504 PCT/GB2008/050648 159 n represents an interger form 0 to 2 alkylene, alkenylene, alkynylene, each of which may be optionally interrupted by one or more of 0, S, NR 1 8 , or one or more C-C single, double or triple bonds, a -N-N- single or double bond, 5 R1 8 represents hydrogen, alkyl, COR 8 .
[6] 6. The combination according to claim 1, in which R 4 , R 5 , R6, R and R3, represent hydrogen, alkyl or optionally substituted aryl. 10
[7] 7. The combination according to claim 1, in which Y represents N and X represents 0, S or NR 4 .
[8] 8. The combination according to claim 1, in which R 9 represents -L-R 3 . 15
[9] 9. The combination according to claim 1 in which when any of the substituents represents alkyl, alkyl is saturated and has from 1 to 10 carbon atoms.
[10] 10. The combination according to claim 1, in which aryl is an aromatic hydrocarbon or a 5 to 10 membered aromatic heterocyle containing 1 to 4 hetero atoms selected from 20 an oxygen atom, a sulphur atom and a nitrogen atom as a ring constituent besides carbon.
[11] 11. The combination according to claim 1, in which aryl is phenyl or naphthalene. 25
[12] 12. The combination according to claim 1, in which aryl is furan, thiophene, pyrrole or pyridine.
[13] 13. The combination according to claim 1, in which ring B or ring C is a saturated or unsaturated 3 to 10 membered carbocylic or heterocyclic ring. 30
[14] 14. The combination according to claim 1, in which ring B is benzene ring.
[15] 15. The combination according to claim 1, in which ring C is a 3- 10 membered saturated or unsaturated carbocylic ring. 35 WO 2009/019504 PCT/GB2008/050648 160
[16] 16. The combination according to claim 1, in which at least one R 1 represents NR 1 5C(=W)R 1 7,
[17] 17. The combination according to claim 1, in which at least one R 1 represents 5 NR 1 5 C(=O)Rl 7 .
[18] 18. The combination according to claim 1, in which at least one R, represents C0NR 10 R 1 . 10
[19] 19. The combination according to claim 1, in which at least one R 1 represents NHCOR 1 7 , wherein R 1 7 is selected from: alkyl C- C6, alkyl C1 - C6 substituted by phenyl, alkyl C 1 - C, substituated by alkoxy C1 - CE, 15 haloalkyl C1 - C 6 , perflouroalkyl C1 - C6, phenyl optionally substituted by one or more of halogen, alkyl C 1 - C6, alkoxy C1 - C6, amino, (alkyl C1 - C)amino, di(alkyl C1 - Cc) amino or phenyl, CH:CH phenyl, 20 naphthyl, pyridinyl, thiophenyl and furanyl.
[20] 20. The combination according to claim 1 in which one or both of R, and R 2 is other than -COOH. 25
[21] 21. The combination according to claim 1, in which at least one of R 1 represents NR 1 6 CONR 1 R 1 , wherein R 10 and R 11 , which may be the same or different, are selected from optionally substituted aryl, alkyl and COaryl optionally substituted.
[22] 22. The combination according to claim 1, in which at least one of R 1 represents 30 NHCONHR 1 5 and R 15 is selected from phenyl, alkyl C1 to C 6 and COphenyl optionally substituted by one or more halogen.
[23] 23. The combination according to claim 1, in which at least one of R 1 represents alkyl C, to Cc, optionally substituted by phenyl or a 4 to 7- membered, preferably 5 or 6 35 membered saturated or unsaturated heterocycle preferably containing one to two heteroatoms selected from N, S and 0. WO 2009/019504 PCT/GB2008/050648 161
[24] 24. The combination according to claim 1 in which at least one of R 1 represents COR 1 6 and R 16 is alkoxy C1 - C, amino, (alkyl C1 - C 6 )amino or di(alkyl C1 - C,) amino. 5
[25] 25. The combination according to claim 1, in which at least one of R, represents: N02, halogen, amino or (alkyl C1 - C)amino or di(alkyl C1 - C) amino in which the alkyl C1 to 10 C is optionally substituted by phenyl or a 5 or 6 membered saturated or unsaturated heterocycle, NHSO 2 alkyl C1 - Ca, NHSO 2 phenyl, SO 2 alkyl C1 - C6, phenyl optionally substituted by C1 to C6 alkoxy C1 - C6, 15 a 5 - 10 membered, saturated or unsaturated, mono- or bi-cyclic heterocycle containing from 1 - 3 heteroatoms selected from N, S and 0.
[26] 26. The combination according to claim 1, in which R 3 represent aryl and is optionally substituted by one to three substituents, R2, which may be the same or different. 20
[27] 27. The combination according to claim 25 in which R3 is a 5 - 10 membered aromatic mono- or bi-cyclic system.
[28] 28. The combination according to claim 26, in which the aromatic system is a 25 hydrocarbon.
[29] 29. The combination according to claim 27, in which the aromatic hydrocarbon is benzene or naphthalene.
[30] 30 30. The combination according to claim 26, in which the aromatic system is a heterocyclic system containing up to three heteroatoms selected from N, 0 and S.
[31] 31. The combination according to claim 30, in which the heterocyclic system is thiophene, furan, pyridine or pyrrole. 35 WO 2009/019504 PCT/GB2008/050648 162
[32] 32. The combination according to claim 2, in which the substituent(s) R2 is/are selected from is: alkyl C1 - Cr, optionally substituted by thiophenyl or phenoxy, each optionally substituted by halogen, 5 alkoxy C, - C6, phenyl, thioalkyl C1 - Ca, thiophenyl, optionally substituted by halogen, NO 2 , 10 CN NR1 0 R 11 , in which R 10 and R 11 , which may be the same or different represent hydrogen, alkyl C1 - Cs, or together with the nitrogen to which they are attached form a 5 to 7 membered ring which may contain one or more additional heteroatoms selected from N, 0 and S, 15 halogen, S0 2 R 12 , in which R 12 represents a 5 to 7 membered ring which may contain one or more additional heteroatoms selected from N, 0 and S, NHCOR1 7 , in which R17 represents alkyl C, - C6, optionally substituted by: 20 phenyl or halogen, or phenyl optionally substituted by alkoxy C, - C6, carboxy, or halogen, or a 5 or 6 membered saturated or unsaturated heterocycle, phenyl or a 5 or 6 membered saturated or unsaturated heterocycle 25 optionally substituted by halogen, alkoxy C, to Ce, carboxy or a group SO 2 NR1 0 R11,
[33] 33. The combination according to claim 32 in which NR, R. represents N-pyrrole, N piperidine, N'(C1 - C6) alkyl N piperazine or N-morpholine. 30
[34] 34. The combination according to claim 5 in which the L represents: -NH.NH-, -CH=CH, -NCOR1 6 in which R, 6 represents phenyl or a 5 or 6 membered saturated or unsaturated heterocycle optionally substituted by halogen, alkoxy 35 C1 to C6, carboxy. WO 2009/019504 PCT/GB2008/050648 163
[35] 35. The combination according to claim I in which two of A 1 - A 4 represent nitrogen.
[36] 36. The combination according to claim 1 in which one of A 1 - A 4 represents nitrogen. 5
[37] 37. The combination according to claim 1 in which all of A 1 - A4 represents CR 1 .
[38] 38. The combination of claim 1 wherein the compound of formula (1) is as listed in table 1. 10
[39] 39. The combination of any one of claims 1 to 38 wherein the ancillary agent and compound of formula (1) are physically associated.
[40] 40. The combination of claim 39 wherein the ancillary agent and compound of formula (1) are: (a) in admixture (for example within the same unit dose); (b) 15 chemically/physicochemically linked (for example by crosslinking, molecular agglomeration or binding to a common vehicle moiety); (c) chemically/physicochemically co-packaged (for example, disposed on or within lipid vesicles, particles (e.g. micro- or nanoparticles) or emulsion droplets); (d) unmixed but co-packaged or co-presented (e.g. as part of an array of unit doses). 20
[41] 41. The combination of any one of claims 1 to 39 wherein the ancillary agent and compound of formula (1) are non-physically associated.
[42] 42. The combination of claim 41 wherein the combination comprises: (a) at least one 25 of the two or more compounds together with instructions for the extemporaneous association of the at least one compound to form a physical association of the two or more compounds; or (b) at least one of the two or more compounds together with instructions for combination therapy with the two or more compounds; (c) at least one of the two or more compounds together with instructions for administration to a patient 30 population in which the other(s) of the two or more compounds have been (or are being) administered; (d) at least one of the two or more compounds in an amount or in a form which is specifically adapted for use in combination with the other(s) of the two or more compounds. 35
[43] 43 A pharmaceutical pack, kit or patient pack comprising a combination as defined in any one of claims I to 42. WO 2009/019504 PCT/GB2008/050648 164
[44] 44. A ancillary agent for use in combination therapy with a compound of formula (1) as defined in any one of claims 1 to 39. 5
[45] 45. A compound of formula (1) as defined in any one of claims I to 39 for use in combination therapy with a ancillary agent.
[46] 46. The ancillary agent of claim 44 or compound of claim 45 wherein the combination therapy comprises prophylaxis treatment or a method as defined herein, for example 10 the therapeutic and/or prophylactic treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia.
[47] 47. Use of a ancillary agent for the manufacture of a medicament for use in the. treatment or prophylaxis (e.g. the therapeutic and/or prophylactic treatment of 15 Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia) in a patient undergoing treatment with a compound of formula (1) as defined in any one of claims I to 39.
[48] 48. Use of a compound of formula (1) as defined in any one of claims 1 to 39 for the 20 manufacture of a medicament for use in the treatment or prophylaxis (e.g. the therapeutic and/or prophylactic treatment of Duchenne muscular dystrophy, Becker muscular dystrophy or cachexia) in a patient undergoing treatment with a ancillary agent. 25
[49] 49. The combination of any one of the preceding claims wherein the ancillary agent is selected from: (a) an antiinflammatory agent; (b) a protease inhibitor; (c) a myostatin antagonist; (d) a cytokine or mobilizing agent; (e) a corticosteroid; (f) an anabolic steroid; (g) a TGF-p antagonist; (h) an antioxidant or mitochondrial supporting agent; (1) a dystrophin expression enhancing agent; () a gene replacement/repair agent; (k) 30 a cell-based composition; (1) creatine; (m) an anti-osteoporotic agent; (n) an auxiliary utrophin upregulating agent; (o) a cGMP signalling modulator; and (p) a combination of two or more of the foregoing classes (a) to (o).
[50] 50. The invention of any one of the preceding claims wherein the compound of 35 formula (1) is compound number 390 of Table 1 being 5-(ethylsulfonyl)-2-(naphthalen 2-yl)benzo[d]oxazole. WO 2009/019504 PCT/GB2008/050648 165
[51] 51. The invention of claim 50 wherein the ancillary agent is a corticosteroid.
[52] 52. The invention of claim 51 wherein the corticosteroid is selected from prednisone, 5 prednisolone or deflazacort.
[53] 53. A process for producing a combination as defined in any one of the preceding claims comprising the step of combining a compound of formula (1) as defined in any one of the preceding claims with one or more ancillary agent(s) (as herein defined). 10

类似技术:

---

公开号 | 公开日 | 专利标题

---

CA2685540C|2018-10-16|Drug combinations for the treatment of duchenne muscular dystrophy

---

EP1986633B1|2014-07-30|Treatment of duchenne muscular dystrophy

---

CA2685740A1|2009-02-12|Drug combinations for the treatment of duchenne muscular dystrophy

---

DK2935248T3|2018-04-23|RELATIONS AND PROCEDURE FOR CHINESE MODULATION AND INDICATIONS THEREOF

---

JP5833644B2|2015-12-16|Substituted triazolopyridine

---

JP6672288B2|2020-03-25|1-Cyclohexyl-2-phenylaminobenzimidazole as midh1 inhibitor for treatment of tumors

---

EA027130B1|2017-06-30|Imidazopyrrolidinone compounds

---

CN103443098B|2016-03-16|As the compound of the antagonist of lpa receptor, composition and application thereof

---

AU2007213452A1|2007-08-16|Treatment of Duchenne muscular dystrophy

---

TWI680760B|2020-01-01|A pharmaceutical combination for the treatment of melanoma

---

EP3668880B1|2021-10-06|Inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase

---

JP2018500344A|2018-01-11|6-hydroxybenzofuranyl-substituted and 6-alkoxybenzofuranyl-substituted imidazopyridazines

---

EP2397481B1|2014-03-12|Inhibitor of casein kinase 1deltaand casein kinase 1epsilon

---

JP2021100972A|2021-07-08|COMBINATIONS OF TGFβ INHIBITORS AND CDK INHIBITORS FOR THE TREATMENT OF CANCER

---

AU2014202249A1|2014-05-22|Pharmaceutical combination comprising a Hsp 90 inhibitor and a mTOR inhibitor

同族专利:

---

公开号 | 公开日

---

EP3251694A1|2017-12-06|

---

JP2010535708A|2010-11-25|

---

LT2170396T|2017-03-10|

---

PE20090510A1|2009-05-22|

---

BRPI0811317A2|2015-01-27|

---

EP2170396A1|2010-04-07|

---

US20110195932A1|2011-08-11|

---

TW200911237A|2009-03-16|

---

US8501713B2|2013-08-06|

---

DK2170396T3|2017-03-13|

---

ES2617957T3|2017-06-20|

---

AR068332A1|2009-11-11|

---

PT2170396T|2017-03-31|

---

PL2170396T3|2017-07-31|

---

EP2170396B1|2016-12-21|

---

CN101678107A|2010-03-24|

---

CY1118700T1|2017-07-12|

---

CL2008002279A1|2009-11-27|

---

WO2009019504A1|2009-02-12|

---

US20140011782A1|2014-01-09|

---

RS55735B1|2017-07-31|

---

MX2009012558A|2010-04-21|

---

HUE033195T2|2017-11-28|

---

HRP20170313T1|2017-04-21|

---

SI2170396T1|2017-04-26|

---

CA2685540C|2018-10-16|

---

CA2685540A1|2009-02-12|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

BE628695A|1962-02-21||||

---

BE637389A|1962-09-13||||

---

US3993659A|1971-08-10|1976-11-23|Ciba-Geigy Corporation|Bis-benzoxazolyl-naphthalenes as optical brighteners|

---

CH561242A5|1971-08-10|1975-04-30|Ciba Geigy Ag||

---

CH617809A|1975-10-10|1980-06-30|||

---

US4110246A|1976-05-13|1978-08-29|Hoechst Aktiengesellschaft|Mixture of benzoxazole derivatives|

---

CH616544A|1976-08-26|1980-04-15||Use of 1,4-bisnaphthalenes as optical brighteners|

---

EP0002097B1|1977-08-22|1981-08-05|Imperial Chemical Industries Plc|Triphenylalkene derivatives, process for their preparation and pharmaceutical compositions containing them|

---

DE3027479A1|1980-07-19|1982-03-04|Hoechst Ag, 6000 Frankfurt|MIXTURES OF OPTICAL BRIGHTENERS AND THEIR USE|

---

DE3046719C2|1980-12-11|1983-02-17|Klinge Pharma GmbH, 8000 München|1,1,2-Triphenyl-but-1-ene derivatives, processes for their preparation and pharmaceuticals|

---

US4418068A|1981-04-03|1983-11-29|Eli Lilly And Company|Antiestrogenic and antiandrugenic benzothiophenes|

---

JPH0477747B2|1984-06-15|1992-12-09|Fuji Photo Film Co Ltd||

---

DE3617451A1|1986-05-23|1987-11-26|Hoechst Ag|SULFONATE OR SULFONAMIDE GROUPS CONTAINING BIS-BENZOXAZOLYLNAPHTHALINE, METHOD FOR THE PRODUCTION AND USE THEREOF|

---

EP0260066B1|1986-09-11|1990-05-09|National Research Development Corporation|Tamoxifen derivatives|

---

JP2615805B2|1988-04-15|1997-06-04|ミノルタ株式会社|Photoconductor|

---

DE3819051A1|1988-06-04|1989-12-07|Agfa Gevaert Ag|COLOR PHOTOGRAPHIC RECORDING MATERIAL|

---

JPH04503957A|1989-03-07|1992-07-16|||

---

JPH0369292A|1989-08-08|1991-03-25|Sharp Corp|Pitching correcting device for slow reproduction|

---

AU653504B2|1989-10-24|1994-10-06|Isis Pharmaceuticals, Inc.|Oligonucleotide analogs with novel linkages|

---

ES2092080T3|1991-08-08|1996-11-16|Ciba Geigy Ag|DYES, PROCEDURE FOR THEIR OBTAINING AND USE.|

---

CA2126967A1|1992-11-04|1994-05-11|Anna M. Wu|Novel antibody construct|

---

US5827733A|1993-03-19|1998-10-27|The Johns Hopkins University School Of Medicine|Growth differentiation factor-8 and polynucleotides encoding same|

---

EP0669323B2|1994-02-24|2004-04-07|Haarmann & Reimer Gmbh|Cosmetic and dermatological preparations, containing phenylene-1,4-bisbenzimidazole sulfonic acids|

---

US6004719A|1994-04-25|1999-12-21|Polaroid Corporation|Imaging medium and process for producing an image|

---

US5977101A|1995-06-29|1999-11-02|Smithkline Beecham Corporation|Benzimidazoles/Imidazoles Linked to a Fibrinogen Receptor Antagonist Template Having Vitronectin Receptor Antagonist Activity|

---

AU3002495A|1994-06-30|1996-01-25|Minnesota Mining And Manufacturing Company|Cure-indicating molding and coating composition|

---

WO1996000560A2|1994-06-30|1996-01-11|Minnesota Mining And Manufacturing Company|Dental impression material with cure-indicating dye|

---

JPH0815917A|1994-07-01|1996-01-19|Mitsubishi Chem Corp|Electrostatic charge controlling agent for development of electrostatic charge image|

---

US6083903A|1994-10-28|2000-07-04|Leukosite, Inc.|Boronic ester and acid compounds, synthesis and uses|

---

JPH08175992A|1994-12-21|1996-07-09|Sagami Chem Res Center|Agent for promoting production of nerve growth factor and condensed ring type oxazole compound|

---

JP3216458B2|1994-12-28|2001-10-09|富士レビオ株式会社|Amide derivatives|

---

US6222044B1|1995-03-20|2001-04-24|The Dow Chemical Company|Process for making 2-aryl benz azoles and 2-aminoaryl aminobenz azoles|

---

US5567843A|1995-03-20|1996-10-22|The Dow Chemical Company|Process for making 2-aryl benz azoles and 2-aminoaryl aminobenzazoles|

---

JP3069292B2|1996-06-13|2000-07-24|株式会社分子バイオホトニクス研究所|Immobilized reagent for fluorescence detection of catechol compound and vanillyl compound and detection method|

---

US5645948A|1996-08-20|1997-07-08|Eastman Kodak Company|Blue organic electroluminescent devices|

---

US6110638A|1996-11-27|2000-08-29|Polaroid Corporation|Process and composition for generation of acid|

---

US5914213A|1996-11-27|1999-06-22|Polaroid Corporation|Process and composition for generation of acid|

---

FR2757389B1|1996-12-24|1999-02-05|Oreal|FILTERING COSMETIC COMPOSITION|

---

US5994618A|1997-02-05|1999-11-30|Johns Hopkins University School Of Medicine|Growth differentiation factor-8 transgenic mice|

---

US6891082B2|1997-08-01|2005-05-10|The Johns Hopkins University School Of Medicine|Transgenic non-human animals expressing a truncated activintype II receptor|

---

US6177572B1|1997-08-20|2001-01-23|Sepracor, Inc.|Solid and liquid-phase synthesis of benzoxazoles and benzothiazoles and their use|

---

WO1999016761A1|1997-09-30|1999-04-08|Mitsubishi Chemical Corporation|Oxygenic heterocyclic derivatives|

---

JPH11171881A|1997-09-30|1999-06-29|Mitsubishi Chemical Corp|Oxygen-containing heterocyclic derivative|

---

US6369201B1|1998-02-19|2002-04-09|Metamorphix International, Inc.|Myostatin multimers|

---

US6004937A|1998-03-09|1999-12-21|Genetics Institute, Inc.|Use of follistatin to modulate growth and differentiation factor 8 [GDF-8] and bone morphogenic protein 11 [BMP-11]|

---

US6312822B1|1998-05-28|2001-11-06|Eastman Chem Co|Dispersion aids for optical brighteners in polyolefins|

---

GB9815880D0|1998-07-21|1998-09-16|Pfizer Ltd|Heterocycles|

---

US6436558B1|1998-08-07|2002-08-20|Fuji Photo Film Co., Ltd.|Organic electroluminescence element|

---

SE9804465D0|1998-12-22|1998-12-22|Amersham Pharm Biotech Ab|A method for the removal / purification of serum albumins and means for use in the method|

---

FR2789582B1|1999-02-12|2001-05-04|Oreal|PHOTOPROTECTIVE COMPOSITIONS CONTAINING A BIS-RESORCINYL TRIAZINE DERIVATIVE AND A COMPOUND HAVING BENZOAZOLYL OR BENZODIAZOLYL GROUPINGS|

---

FR2789581B1|1999-02-12|2001-05-04|Oreal|PHOTOPROTECTIVE COMPOSITIONS CONTAINING A BENZOTRIAZOLE DERIVATIVE, A BIS-RESORCINYL TRIAZINE DERIVATIVE, AND A BENZOAZOLYL OR BENZODIAZOLYL GROUP COMPOUND|

---

US6465493B1|1999-04-09|2002-10-15|Smithkline Beecham Corporation|Triarylimidazoles|

---

CA2373293A1|1999-05-07|2000-11-16|Basf Aktiengesellschaft|4- pyrazoles as herbicidal agents|

---

JP2002544201A|1999-05-07|2002-12-24|ビーエーエスエフアクチェンゲゼルシャフト|Benzoheterocyclylcyclohexenone|

---

FR2794645B1|1999-06-08|2001-08-10|Oreal|PHOTOPROTECTIVE COMPOSITIONS CONTAINING A BIS-HYDROXYPHENYLBENZOTRIAZOLE HYDROCARBON COMPOUND AND A BENZOAZOLYL OR BENZODIAZOLYL GROUP COMPOUND|

---

EE200200025A|1999-07-20|2003-04-15|Pharmexa A/S|A method for down-regulating GDF-8 activity, a method for increasing the muscle mass of an animal, a GDF-8 analog, an immunogenic composition, a nucleic acid fragment, a vector, a transformed cell and a method of making it, a composition of anti-GDF-8 antibodies.|

---

JP2001039034A|1999-08-03|2001-02-13|Mitsui Chemicals Inc|Optical recording medium|

---

GB2353038A|1999-08-12|2001-02-14|Eastman Chem Co|Polyolefin composition comprising non-migrating optical brightener|

---

AU7320100A|1999-09-24|2001-04-24|Ono Pharmaceutical Co. Ltd.|Hydroxamic acid derivatives, process for the production thereof and drugs containing the same as the active ingredient|

---

ES2259617T3|1999-11-05|2006-10-16|Societe De Conseils De Recherches Et D'applications Scientifiques |HETEROCICLICAL COMPOUNDS AND ITS APPLICATION AS MEDICINES.|

---

US6565987B2|1999-11-12|2003-05-20|Eastman Chemical Company|Non-exuding optically brightened polyolefin blends|

---

WO2001053350A1|2000-01-18|2001-07-26|Agresearch Limited|Myostatin and mimetics thereof|

---

GB0003256D0|2000-02-11|2000-04-05|Darwin Discovery Ltd|Heterocyclic compounds and their therapeutic use|

---

AR029803A1|2000-02-21|2003-07-16|Smithkline Beecham Plc|IMIDAZOLS REPLACED WITH PIRIDILE AND PHARMACEUTICAL COMPOSITIONS THAT UNDERSTAND THEM|

---

JP2001261664A|2000-03-15|2001-09-26|Konica Corp|Silver halide photosensitive material, method for forming image, compound and method for synthesizing the same compound|

---

GB0007405D0|2000-03-27|2000-05-17|Smithkline Beecham Corp|Compounds|

---

JP2002047278A|2000-08-02|2002-02-12|Fuji Photo Film Co Ltd|Method for producing thioether compound|

---

EP2264018B1|2000-08-24|2015-02-11|University of Pittsburgh - Of the Commonwealth System of Higher Education|Thioflavin derivatives for use in the diagnosis of Alzheimer's disease|

---

US6716413B1|2000-10-16|2004-04-06|Mallinckrodt, Inc.|Indole compounds as tissue-specific exogenous optical agents|

---

FR2816509B1|2000-11-15|2004-02-06|Sod Conseils Rech Applic|ASSOCIATION OF CALPAIN INHIBITORS AND OXYGEN REACTIVE TRAPS|

---

JP2004517068A|2000-11-16|2004-06-10|スミスクライン・ビーチャム・コーポレイション|Compound|

---

JP4343528B2|2000-11-30|2009-10-14|キヤノン株式会社|Light emitting element and display device|

---

FR2818142B1|2000-12-18|2003-12-26|Oreal|ANTISOLAR COMPOSITIONS BASED ON A SYNERGETIC MIXTURE OF FILTERS AND USES THEREOF|

---

GB0102668D0|2001-02-02|2001-03-21|Glaxo Group Ltd|Compounds|

---

TWI329129B|2001-02-08|2010-08-21|Wyeth Corp|Modified and stabilized gdf propeptides and uses thereof|

---

DE10123711A1|2001-05-15|2003-02-27|Wolfgang Altmeyer|Procedure for determining the origin of biological materials|

---

JP2003005356A|2001-06-20|2003-01-08|Fuji Photo Film Co Ltd|Negative type resist composition for electron beam or x-ray|

---

US6702667B2|2001-08-23|2004-03-09|Igt|Apparatus for heating and/or cooling a beverage on a gaming apparatus|

---

US7320789B2|2001-09-26|2008-01-22|Wyeth|Antibody inhibitors of GDF-8 and uses thereof|

---

KR100438706B1|2001-12-10|2004-07-05|삼성전자주식회사|Apparatus and method for supplying power with saving the power|

---

US20050113283A1|2002-01-18|2005-05-26|David Solow-Cordero|Methods of treating conditions associated with an EDG-4 receptor|

---

US20050261298A1|2002-01-18|2005-11-24|David Solow-Cordero|Methods of treating conditions associated with an Edg-7 receptor|

---

AU2003214873A1|2002-01-18|2003-09-02|Ceretek Llc|Methods of treating conditions associated with an edg receptor|

---

WO2003075921A2|2002-03-05|2003-09-18|Transtech Pharma, Inc.|Mono- and bicyclic azole derivatives that inhibit the interaction of ligands with rage|

---

JP4294917B2|2002-07-02|2009-07-15|三井化学株式会社|Optical recording medium and oxazole compound|

---

WO2004035522A1|2002-08-30|2004-04-29|Bf Research Institute, Inc.|Diagnostic probes and remedies for diseases with accumulation of prion protein, and stains for prion protein|

---

US7261893B2|2002-10-22|2007-08-28|Wyeth|Neutralizing antibodies against GDF-8 and uses therefor|

---

US20040223966A1|2002-10-25|2004-11-11|Wolfman Neil M.|ActRIIB fusion polypeptides and uses therefor|

---

AU2003286757B2|2002-11-01|2009-06-04|Merck Sharp & Dohme Corp.|Carbonylamino-benzimidazole derivatives as androgen receptor modulators|

---

EP1581649B1|2002-12-20|2011-01-26|Amgen, Inc|Binding agents which inhibit myostatin|

---

WO2004069394A2|2003-02-03|2004-08-19|The Trustees Of Columbia University In The City Of New York|Synthetic method for direct arylation of heterocyclic arenes|

---

JP2004250411A|2003-02-21|2004-09-09|Bf Kenkyusho:Kk|DIAGNOSTIC PROBE FOR AMYLOID beta-ACCUMULATIVE DISEASE AND THERAPEUTIC COMPOUND|

---

EP1454627A1|2003-03-06|2004-09-08|MyoContract Ltd.|Alpha-Keto carbonyl calpain inhibitors|

---

DK3549936T3|2003-04-11|2021-07-12|Ptc Therapeutics Inc|1,2,4-OXADIAZOLE-BENZOIC ACID COMPOUND AND ITS USE FOR NONSENSE SUPPRESSION AND TREATMENT OF DISEASE|

---

EP1620413A2|2003-04-30|2006-02-01|Cytokinetics, Inc.|Compounds, compositions, and methods|

---

WO2004110357A2|2003-05-16|2004-12-23|Ambit Biosciences Corporation|Heterocyclic compounds and uses thereof|

---

MXPA05012350A|2003-05-20|2006-05-25|Transtech Pharma Inc|Rage antagonists as agents to reverse amyloidosis and diseases associated therewith.|

---

AU2004270733B2|2003-09-11|2011-05-19|Itherx Pharma, Inc.|Cytokine inhibitors|

---

CN1882879B|2003-09-22|2010-08-11|爱克发印艺公司|Photopolymerizable composition|

---

FR2863268B1|2003-12-09|2006-02-24|Sod Conseils Rech Applic|NOVEL DERIVATIVES OF 2-HYDROXYTETRAHYDROFURAN AND THEIR APPLICATION AS MEDICAMENTS|

---

US7097888B2|2003-12-15|2006-08-29|Eastman Kodak Company|Aligned liquid crystal layer containing azolium salts and process for increasing the tilt|

---

US7592373B2|2003-12-23|2009-09-22|Boehringer Ingelheim International Gmbh|Amide compounds with MCH antagonistic activity and medicaments comprising these compounds|

---

WO2005074375A2|2004-02-06|2005-08-18|Insight Biopharmaceuticals Ltd|Heparanase inhibitors and uses thereof|

---

JP2007526337A|2004-03-02|2007-09-13|アクセルロンファーマインコーポレーテッド|ALK7 and myostatin inhibitors and uses thereof|

---

WO2005094446A2|2004-03-23|2005-10-13|Eli Lilly And Company|Anti-myostatin antibodies|

---

WO2005124563A2|2004-06-12|2005-12-29|Ceptor Corporation|Compounds and kits for treating muscle disorders and methods of use thereof|

---

MY144903A|2004-06-17|2011-11-30|Novartis Ag|Pyrrolopyridine derivatives and their use as crth2 antagonists|

---

EP2332977B1|2004-07-23|2015-11-25|Acceleron Pharma Inc.|ActRII receptor polypeptides|

---

AR050187A1|2004-07-29|2006-10-04|Schering Plough Ltd|USE OF ALK 5 INHIBITORS TO MODULATE OR INHIBIT THE ACTIVITY OF MIOSTATINE, TO ACHIEVE GREATER ACCUMULATION OF MAGRO FABRIC IN ANIMALS|

---

US20070258912A1|2004-08-09|2007-11-08|Werner Holzl|Use of Fluorescent Whitening Agents as Antimicrobials|

---

WO2006019270A1|2004-08-19|2006-02-23|Lg Chem. Ltd.|Organic light-emitting device comprising buffer layer and method for fabricating the same|

---

EP2301536B1|2004-10-13|2014-04-09|PTC Therapeutics, Inc.|Compounds and their use for treating nonsense-related diseases|

---

BRPI0406040B1|2004-10-21|2018-09-11|Fundacao Univ De Brasilia|compounds capable of absorbing ultraviolet radiation, compositions containing them and processes for their preparation|

---

WO2006051410A1|2004-11-15|2006-05-18|Pfizer Inc.|Azabenzoxazoles for the treatment of cns disorders|

---

GB0426154D0|2004-11-29|2004-12-29|European Molecular Biology Lab Embl|IGF-1 novel peptides|

---

US20070060589A1|2004-12-21|2007-03-15|Purandare Ashok V|Inhibitors of protein arginine methyl transferases|

---

US7723340B2|2005-01-13|2010-05-25|Signal Pharmaceuticals, Llc|Haloaryl substituted aminopurines, compositions thereof, and methods of treatment therewith|

---

WO2006091862A2|2005-02-24|2006-08-31|Kemia, Inc.|Cytokine inhibitors and their use in therapy|

---

CA2599989A1|2005-03-03|2006-09-08|Sirtris Pharmaceuticals, Inc.|N-phenyl benzamide derivatives as sirtuin modulators|

---

US7998974B2|2005-03-03|2011-08-16|Sirtris Pharmaceuticals, Inc.|Fused heterocyclic compounds and their use as sirtuin modulators|

---

ZA200707896B|2005-03-14|2009-07-29|High Point Pharma Llc|Benzazole derivatives, compositions, and methods of use as B-secretase inhibitors|

---

WO2006110483A1|2005-04-08|2006-10-19|Ptc Therapeutics, Inc.|Compositions of an orally active 1,2,4-oxadiazole for nonsense mutation suppression therapy|

---

CA2605723A1|2005-04-25|2006-11-02|Pfizer Inc.|Antibodies to myostatin|

---

WO2006124780A2|2005-05-12|2006-11-23|Kalypsys, Inc.|Ih-benzo [d] imidazole compounds as inhibitors of b-raf kinase|

---

ES2431050T3|2005-08-04|2013-11-22|Sirtris Pharmaceuticals, Inc.|Benzothiazoles and thiazolopyridines as modulators of sirtuin|

---

FR2889700B1|2005-08-11|2012-11-23|Synthinnove Lab|MARKERS, METHOD FOR PRODUCING THE SAME, AND APPLICATIONS THEREOF|

---

JP2007086165A|2005-09-20|2007-04-05|Fujifilm Corp|Photosensitive composition, lithographic printing plate precursor and image-recording method using the same|

---

DK1954288T3|2005-10-21|2012-09-24|Ipsen Pharma|Amidine derivatives and their use as a drug|

---

KR100890862B1|2005-11-07|2009-03-27|주식회사 엘지화학|Organic electroluminescent device and method for preparing the same|

---

WO2007058990A2|2005-11-14|2007-05-24|Kemia, Inc.|Therapy using cytokine inhibitors|

---

CA2630806C|2005-12-02|2015-01-06|Sachem, Inc.|Anion-exchange displacement chromatography process and anionic organic compounds for use as displacer compounds in anion-exchange displacement chromatography process|

---

KR101213485B1|2006-01-27|2012-12-18|삼성디스플레이 주식회사|Organometallic complexes and organic electroluminescence device using the same|

---

KR101213486B1|2006-02-02|2012-12-20|삼성디스플레이 주식회사|Organometallic complexes and organic electroluminescence device using the same|

---

EP1986633B1|2006-02-10|2014-07-30|Summit Corporation Plc|Treatment of duchenne muscular dystrophy|

---

AU2007217529A1|2006-02-21|2007-08-30|Trigen Limited|Heterocyclic compounds and their use in the treatment of cardiovascular disease|

---

JP4649645B2|2006-03-10|2011-03-16|独立行政法人科学技術振興機構|Process for producing optically active alcohol compounds|

---

KR101325062B1|2006-05-19|2013-11-05|삼성디스플레이 주식회사|Luminescent heteronuclear copper-iridium complex and organic electroluminescence device using the same|

---

WO2007146712A2|2006-06-09|2007-12-21|Kemia, Inc.|Therapy using cytokine inhibitors|

---

US20070287344A1|2006-06-12|2007-12-13|Hiroshi Ohara|Fabric Construction Specifically For Damper|

---

PL2170396T3|2007-08-03|2017-07-31|Summit Limited|Drug combinations for the treatment of duchenne muscular dystrophy|EP2332977B1|2004-07-23|2015-11-25|Acceleron Pharma Inc.|ActRII receptor polypeptides|

---

US8128933B2|2005-11-23|2012-03-06|Acceleron Pharma, Inc.|Method of promoting bone growth by an anti-activin B antibody|

---

EA201692543A1|2005-11-23|2017-08-31|Акселерон Фарма Инк.|ACTIVIN-ACTRIIA ANTAGONISTS AND THEIR APPLICATION FOR STIMULATING BONE GROWTH|

---

US9108948B2|2006-06-23|2015-08-18|Abbvie Inc.|Cyclopropyl amine derivatives|

---

CN101472887A|2006-06-23|2009-07-01|艾博特公司|Cyclopropyl amine derivatives|

---

PL2468290T3|2006-12-18|2015-08-31|Acceleron Pharma Inc|Activin-ActRII Antagonists for use in treating anemia|

---

US8895016B2|2006-12-18|2014-11-25|Acceleron Pharma, Inc.|Antagonists of activin-actriia and uses for increasing red blood cell levels|

---

TR200906131T1|2007-02-01|2009-11-23|Acceleron Pharma Inc.|Activin-actrIIa antagonists and treatment of breast cancer|

---

TW201627320A|2007-02-02|2016-08-01|艾瑟勒朗法瑪公司|Variants derived from ActRIIB and uses therefor|

---

CN104189889A|2007-02-09|2014-12-10|阿塞勒隆制药公司|Activin-actriia antagonists and uses for promoting bone growth in cancer patients|

---

PL2170396T3|2007-08-03|2017-07-31|SummitLimited|Drug combinations for the treatment of duchenne muscular dystrophy|

---

CN103877564A|2007-09-18|2014-06-25|阿塞勒隆制药公司|Activin-actriia antagonists and uses for decreasing or inhibiting fsh secretion|

---

US8216997B2|2008-08-14|2012-07-10|Acceleron Pharma, Inc.|Methods for increasing red blood cell levels and treating anemia using a combination of GDF traps and erythropoietin receptor activators|

---

EP2340031B1|2008-08-14|2019-04-24|Acceleron Pharma Inc.|Gdf traps for use to treat anemia|

---

US8394969B2|2008-09-26|2013-03-12|Merck Sharp & Dohme Corp.|Cyclic benzimidazole derivatives useful as anti-diabetic agents|

---

AU2009307884B2|2008-10-22|2014-07-31|Merck Sharp & Dohme Corp.|Novel cyclic benzimidazole derivatives useful anti-diabetic agents|

---

WO2010051176A1|2008-10-29|2010-05-06|Merck Sharp & Dohme Corp.|Novel cyclic benzimidazole derivatives useful anti-diabetic agents|

---

CA2741672A1|2008-10-31|2010-05-06|Merck Sharp & Dohme Corp.|Novel cyclic benzimidazole derivatives useful anti-diabetic agents|

---

US8138142B2|2009-01-13|2012-03-20|Acceleron Pharma Inc.|Methods for increasing adiponectin in a patient in need thereof|

---

EP2408753A4|2009-03-20|2012-11-07|Univ Brandeis|Compounds and methods for treating mammalian gastrointestinal microbial infections|

---

GB0905667D0|2009-04-02|2009-05-20|Summit Corp Plc|Compounds for treatment of duchenne muscular dystrophy|

---

US9186353B2|2009-04-27|2015-11-17|Abbvie Inc.|Treatment of osteoarthritis pain|

---

CA2764890A1|2009-06-08|2010-12-16|Acceleron Pharma Inc.|Methods for increasing thermogenic adipocytes|

---

WO2010151426A1|2009-06-12|2010-12-29|Acceleron Pharma Inc.|Truncated actriib-fc fusion proteins|

---

JP5540640B2|2009-10-07|2014-07-02|住友化学株式会社|Heterocyclic compounds and their use for controlling harmful arthropods|

---

KR101194995B1|2009-10-14|2012-10-29|주식회사 이큐스앤자루|Novel 4-phenyl-benzimidazole or 4-phenyl-benzoxazole derivates or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical compositions for antivirus containing the same as an active gredient|

---

EP3332796A1|2009-11-17|2018-06-13|Acceleron Pharma Inc.|Actriib proteins and variants and uses therefore relating to utrophin induction for muscular dystrophy therapy|

---

KR20120123509A|2010-02-03|2012-11-08|도꾜 다이가꾸|Read through inducer, and therapeutic agent for nonsense-mutation-type genetic diseases|

---

WO2011099832A2|2010-02-12|2011-08-18|Crystalgenomics, Inc.|Novel benzimidazole compound, preparation method thereof and pharmaceutical composition comprising the same|

---

EP2538784B1|2010-02-25|2015-09-09|Merck Sharp & Dohme Corp.|Benzimidazole derivatives useful anti-diabetic agents|

---

JP5544940B2|2010-03-10|2014-07-09|Ｊｎｃ株式会社|Compound having indole ring, liquid crystal composition, and liquid crystal display device|

---

WO2011133687A2|2010-04-20|2011-10-27|President And Fellows Of Harvard College|Methods and compositions for inhibition of beta2-adrenergic receptor degradation|

---

US8686048B2|2010-05-06|2014-04-01|Rhizen Pharmaceuticals Sa|Immunomodulator and anti-inflammatory compounds|

---

WO2011162364A1|2010-06-23|2011-12-29|住友化学株式会社|Noxious arthropod control composition, and heterocyclic compound|

---

CN106994124A|2010-06-28|2017-08-01|萩原正敏|Prevention/improver of genetic disease|

---

WO2012037258A1|2010-09-16|2012-03-22|Abbott Laboratories|Processes for preparing 1,2-substituted cyclopropyl derivatives|

---

KR20130132824A|2010-11-08|2013-12-05|악셀레론 파마 인코포레이티드|Actriia binding agents and uses thereof|

---

WO2012102937A2|2011-01-25|2012-08-02|Irm Llc|Compounds that expand hematopoietic stem cells|

---

CN102617478B|2011-01-31|2015-07-15|华东理工大学|Synthesis of benzimidazole, oxazole and thiazole derivatives and application thereof|

---

CN103748085A|2011-06-09|2014-04-23|诺华股份有限公司|Heterocyclic sulfonamide derivatives|

---

US20140080896A1|2011-08-30|2014-03-20|The Regents Of The University Of California|Identification of small molecules that facilitate therapeutic exon skipping|

---

JO3192B1|2011-09-06|2018-03-08|Novartis Ag|Benzothiazolone compound|

---

EP2748172B1|2011-09-30|2017-12-06|Kineta, Inc.|Anti-viral compounds|

---

WO2013120040A1|2012-02-10|2013-08-15|Children's Medical Center Corporation|Targeted pathway inhibition to improve muscle structure, function and activity in muscular dystrophy|

---

EP2636673A1|2012-03-06|2013-09-11|Compound Handling B.V.|Aminomethylene pyrazolones with therapeutic activity|

---

CA2864954C|2012-03-06|2020-10-13|Compound Handling B.V.|Aminomethylene pyrazolones with therapeutic activity.|

---

GB201208178D0|2012-05-10|2012-06-20|Summit Corp Plc|Pharmaceutical composition for the treatment of duchenne muscular dystrophy|

---

CA2888369A1|2012-10-17|2014-04-24|F. Hoffmann-La Roche Ag|6-aminoindole derivatives as trp channel antagonists|

---

MX366336B|2012-11-02|2019-07-05|Celgene Corp|Activin-actrii antagonists and uses for treating bone and other disorders.|

---

WO2014144458A1|2013-03-15|2014-09-18|Abbott Laboratories|Methods of maintaining and improving muscle function|

---

WO2015050581A1|2013-04-19|2015-04-09|Cedars-Sinai Medical Center|Phosphodiesterase 5a inhibitors for the treatment of muscular dystrophy|

---

WO2014190250A1|2013-05-23|2014-11-27|The Johns Hopkins University|Activators of soluable guanylate cyclase and their use in treatment of duchenne muscular dystrophy and related disease|

---

CN105636951B|2014-04-14|2018-05-15|上海恒瑞医药有限公司|Amide derivatives and its officinal salt, its preparation method and its application in medicine|

---

EP3154566A4|2014-06-13|2018-01-24|Acceleron Pharma Inc.|Methods and compositions for treating ulcers|

---

GB201412010D0|2014-07-04|2014-08-20|Summit Corp Plc|Treatment of hypertransaminasemia|

---

US9353093B2|2014-10-07|2016-05-31|Allergan, Inc.|Indole-1-carboxamides as kinase inhibitors|

---

US9403803B2|2014-10-08|2016-08-02|Allergan, Inc.|Indole-3-carboxamides as kinase inhibitors|

---

US9371314B2|2014-10-09|2016-06-21|Allergan, Inc.|Pyridyl benzothiophenes as kinase inhibitors|

---

US10399966B2|2016-01-21|2019-09-03|University Of Washington|Compounds for treatment of trypanosomes and neurological pathogens and uses thereof|

---

CN105712950B|2016-01-27|2019-05-21|中国科学院化学研究所|Amides compound and its preparation method and application based on benzothiazole|

---

KR20170108887A|2016-03-17|2017-09-27|연세대학교 산학협력단|Novel compound for inhibiting NamPT and composition comprising the same|

---

CN109803641A|2016-03-30|2019-05-24|萨米特有限公司|For treating the composition of Du's Xing Shi muscular dystrophy|

---

CN109400536A|2018-12-21|2019-03-01|东华大学|A kind of N substituted benzimidazole diamines and preparation method thereof|

---

KR20200080952A|2018-12-27|2020-07-07|제이투에이치바이오텍 |Compounds for treating or preventing muscular dystrophy and medical uses thereof|

---

US11084825B2|2018-12-31|2021-08-10|Biomea Fusion, Llc|Substituted pyridines as irreversible inhibitors of menin-MLL interaction|

---

TW202043205A|2018-12-31|2020-12-01|美商拜歐米富士恩有限公司|Inhibitors of menin-mll interaction|

---

CN109912424B|2019-03-01|2020-08-07|浙江大学|Method for hydrolyzing nitroaniline substances into phenol|

---

AU2020290049A1|2019-06-12|2022-02-03|Tmem16A Limited|Compounds for treating respiratory disease|

---

WO2021119808A1|2019-12-16|2021-06-24|The University Of British Columbia|Antiviral compounds, compositions and methods of use|

法律状态:
2010-01-28| DA3| Amendments made section 104|Free format text: THE NATURE OF THE AMENDMENT IS: AMEND THE APPLICANT NAME FROM SUMMIT CORPORATION PLC TO BIOMARIN IGA LIMITED |

---

2013-01-31| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|

优先权:

---

申请号 | 申请日 | 专利标题

---

GB0715088.1||2007-08-03||

---

GB0715088A|GB0715088D0|2007-08-03|2007-08-03|Drug combinations for the treatment of duchenne muscular dystrophy|

---

GB0807216A|GB0807216D0|2008-04-21|2008-04-21|Drug combination for the treatment of duchenne muscular dystrophy|

---

GB0807216.7||2008-04-21||

---

PCT/GB2008/050648|WO2009019504A1|2007-08-03|2008-08-01|Drug combinations for the treatment of duchenne muscular dystrophy|

---