Field of Invention

This invention relates to compounds for formula (I), (IIA), (IIB), (IIC), (IID), (HE), (IIF), (III) and (IV), which are N-myristoyl transferase inhibitors, and to uses of such compounds as medicaments, in particular in the treatment of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect. Such diseases include microbial infections, including viral and fungal infections, and hyperproliferative disorders, neurological diseases/disorders, ischemia, osteoporosis and diabetes. Certain compounds of the invention find particular use in the treatment of protozoan infections, for example malaria, leishmaniasis and sleeping sickness.

Background to the Invention

N-myristoyltransferase (ΝΜΤ) is a monomelic enzyme, which is ubiquitous in eukaryotes. ΝΜΤ catalyses an irreversible co-translational transfer of myristic acid (a saturated 14-carbon fatty acid) from myristoyl-Coenzyme A (myr-CoA) to a protein substrate containing an N-terminal glycine with formation of an amide bond (Farazi, T. A., Waksman, G., Gordon, J. I., J. Biol. Chem., 2001. 276(43): p. 39501-39504). N-myristoylation by ΝΜΤ follows an ordered Bi-Bi mechanism. Myr-CoA binds to ΝΜΤ in the first ΝΜΤ binding pocket prior to the binding of a protein substrate (Rudnick, D. A., McWherter C. A., Rocque, W. J., et al, J. Biol. Chem., 1991. 266(15): p. 9732-9739). The bound myr-CoA facilitates the opening of a second binding pocket where the protein substrate binds.

Following binding of the protein substrate, transfer of myristate to the protein substrate takes place via a nucleophilic addition-elimination reaction, finally with the release of CoA and the myristoylated protein.

ΝΜΤ plays a key role in protein trafficking, mediation of protein-protein interactions, stabilization of protein structures and signal transduction in living systems. Inhibition of the ΝΜΤ enzyme has the potential to disrupt multi-protein pathways, which is an attractive characteristic to reduce the risk of the development of resistance in, for example, treatment or prophylaxis of microbial infections and hyperproliferative disorders.

Biochemical analysis has shown high conservation of myr-CoA binding sites, but divergent peptide binding specificities between human and fungal and parasitic NMTs (Johnson, D. R., Bhatnagar, R. S., Gordon, J. I., et al., Annu. Rev. Biochem., 1994. 63: p. 869-914). As a consequence, NMT can be viewed as a target with the potential for the development of selective non-peptidic inhibitors.

NMT fungal and mammalian enzymes from various sources have been well characterized, see for example the following references: Saccharomyces cerevisiae (Duronio, R. J., Towler, D. A., Heuckeroth, R. O., et al., Science, 1989. 243(4892): p. 796-800), Candida albicans (Wiegand, R. C, Carr, C, Minnerly, J.C., et al, J. Biol. Chem., 1992. 267(12): p. 8591-8598) and Cryptococcus neoformans (Lodge, J. K., Johnson, R. L., Weinberg, R. A., et al., J. Biol. Chem., 1994. 269(4): p. 2996-3009), human NMT1 (Mcllhinney, R. A. J. and McGlone, K., Exp. Cell Res., 1996. 223: p. 348- 356) and human NMT2 (Giang, D.K. and Cravatt, B. F., J. Biol. Chem., 1998. 273: p. 6595-6598).

NMT has also been characterised in protozoan parasites. See for example the following references: Plasmodium falciparum (Pf) (Gunaratne, R. S., Sajid, M., Ling, I. T., et al., Biochem. J., 2000. 348: p. 459-463), Plasmodium vivax (Pv), Leishmania major (Lm) (Price, H. P., Menon, M. R.,

Panethymitaki, C, et al., J. Biol. Chem., 2003. 278(9): p. 7206-7214), Leishmania donovani (Ld) (Branningan, J. A., Smith, B. A., Yu, Z., et al, J. Mol. Biol, 2010. 396: p. 985-999) and Trypanosoma brucei (Tb) {idem ).

Several myristoylated proteins have been observed in protozoans and their functions have been determined. These proteins and the processes in which they are involved suggest that N- myristoylation may play a role in multiple pathways in the biology of parasites. Inhibition of myristoylation could thus disrupt multiple pathways. The potential for the development of resistance should thus be smaller than for some other targets. To date, only a single isoform of ΝΜΤ has been found in each protozona organism investigated. If it is correct that there is only a single isoform, then that will also assist in reducing the potential for the development of resistance.

As described above, there are two binding pockets in ΝΜΤ. One is the myr-CoA binding pocket and the other is the peptide binding pocket. Most ΝΜΤ inhibitors reported to date target the peptide binding pocket. Most ΝΜΤ inhibitors developed to date have been targeted to fungal NMTs.

WO00/37464 (Roche) discloses certain benzofuran compounds which inhibit NMT and show antifungal activity. In Sheng et al. (Sheng et al, Eur. J. Med. Chem., 2010. 45(9): p. 3531-3540), there are described various benzoxazole and indole derivatives that were shown to inhibit NMT and have antifungal activity. WO2010/026365 (University of Dundee) discloses N-heterocyclic sulphonamide compounds and their use as NMT inhibitors. US2004/0014764 (Smith, C. D., and French, K. J.) discloses cyclohexyl- or methyl- octahydro-pyrolo[l,2-a]pyrazine groups which inhibit human NMT for the treatment of hyperproliferative disorders and viral infections.

Bowyer et al. (Bowyer et al , Biochem. J., 2007. 408: p. 173-180) described that certain benzothiazole derivatives were inhibitors of Plasmodium falciparum NMT. The properties of compounds disclosed in WO00/37464 are described in further detail in Masubuchi et al. (Masubuchi et al, Bioorg. &Med. Chem. Lett., 2001. 11: p. 1833-1837 ). The optimization of the substituents on the furan core lead to the identification of the compound RO-09-4609 as a lead compound with strong inhibitory activity of Candida albicans NMT and high selectivity over human

NMT:

RO-09-4609

It has been found by the current inventors that compounds claimed in WO00/37464, such as RO-09- 4609 are only weak inhibitors of protozoan NMTs (specifically Plasmodium falciparum and Leishmania donovani NMTs).

There remains a need in the art for further compounds that inhibit NMT with high potency, high selectivity and/or without negative side effects. In particular, there remains a need for compounds that are selective inhibitors of protozoan NMTs.

Summary of the Invention

In a first aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect

(I) wherein:

A is either an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle, or a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle; X and Q are either attached to adjacent ring atoms or are attached to ring atoms which are separated by one intervening ring atom, and where A is an 8- to 10-membered aromatic carbocycle or heterocycle, X and Q are attached to the same ring;

either X is -0-, -S-, -NH-, -CH ₂ 0-, -CH ₂ S-, -CH ₂ NH-, -0-Ci_ ₆ alkylene,

-0-C ₂ - ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ - ₇ cycloalkylene,-S-Ci_ ₆ alkylene,

-S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene,

-NH-C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene,

C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is a 3 - to 7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one or two R ¹ groups;

or X is -0-Ci_ ₆ alkylene, -0-C ₂ _ ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ _ ₇ cycloalkylene,

-S-Ci_ ₆ alkylene, -S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene, -NH- C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene or

C ₂ _ ₆ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR ² R ³ ;

each R ¹ is independently selected from Ci_ ₆ alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R' wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

R ² is hydrogen, Ci_ ₆ alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ ₂ alkyl-, or 3- to 10-membered heterocycle-Ci_ ₂ alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

R ³ is hydrogen, Ci_ ₆ alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-Ci_ ₂ alkyl,

C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R' wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

p is an integer of from 0 to 3;

each R ⁴ is independently selected from R ^B groups and cyano;

Q is - Q ¹ - Q ² -, wherein:

Q ¹ is -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0- C(O)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-, -C(0)-N(R ^D )-C(NH)-, -NH-N(R ^D )-C(0)-, -C(O)- NH-C(O)-, or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R ^B groups and Q ² -B;

Q ² is bond, Ci_ ₄ alkylene, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene, wherein said Ci_ ₄ alkylene, C ₂ - ₄ alkenylene or C ₂ - ₄ alkynylene may optionally be substituted with one or two substituents selected from R ^A groups and B, and wherein up to two methylene groups of said

Ci_ ₄ alkylene, C ₂ - ₄ alkenylene or C ₂ - ₄ alkynylene may each independently be replaced by -0-,

-S- or -N(R ^D )-;

B is C ₂ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl-CN, -C(0)-C ₁ _ ₆ alkyl-CN, C(0)NH-C ₁ _ ₆ alkyl-CN and phenyl;

each R ^A is independently selected from OR ^c , N(R ^D ) ₂ and halogen;

each R ^B is independently selected from Ci_ ₄ alkyl, C ₂ _ ₄ alkenyl, C ₂ _ ₄ alkynyl, trihaloCi_ ₄ alkyl,

-C(0)d_ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , C ₃ _ ₆ cycloalkyl, halogen, OR ^c , oxo, N(R ^D ) ₂ and SR ^C ;

each R ^c is independently selected from hydrogen, Ci_ ₄ alkyl, C ₂ _ ₄ alkenyl; C ₂ _ ₄ alkynyl, trihaloCi_ ₄ alkyl and -C(0)Ci_ ₄ alkyl;

each R ^D is independently selected from hydrogen, Ci_ ₄ alkyl, C ₂ _ ₄ alkenyl; C ₂ _ ₄ alkynyl, trihaloCi_ ₄ alkyl,

OH, -C(0)Ci_ ₄ alkyl, -C(0)CF ₃ and cyano; and

each R' is independently selected from hydrogen and Ci_ ₆ alkyl.

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof

(I)

wherein:

A is an 8- to 10-membered bicyclic aromatic heterocycle or carbocycle;

X and Q are attached to the same ring, and are either attached to adjacent ring atoms or are attached to ring atoms which are separated by one intervening ring atom;

either X is -0-, -S-, -NH-, -CH ₂ 0-, -CH ₂ S-, -CH ₂ NH-, -0-Ci_ ₆ alkylene,

-0-C ₂ _ ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ - ₇ cycloalkylene,-S-Ci_ ₆ alkylene,

-S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene,

-NH-C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is a 3 - to 7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one or two R ¹ groups;

or X is -0-Ci_ ₆ alkylene, -0-C ₂ - ₆ alkenylene, -0-C ₂ - ₆ alkynylene, -0-C ₃ _ ₇ cycloalkylene,

-S-Ci_ ₆ alkylene, -S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene, -NH- C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene or

C ₂ _ ₆ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR ² R ³ ;

each R ¹ is independently selected from Ci_ ₆ alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R'; wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

R ² is hydrogen, Ci_ ₆ alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ ₂ alkyl-, or 3- to 10-membered heterocycle-Ci_ ₂ alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

R ³ is hydrogen, Ci_ ₆ alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R', wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

p is an integer of from 0 to 3;

each R ⁴ is independently selected from R ^B groups and cyano;

Q is - Q ¹ - Q ² -, wherein:

Q ¹ is a 5- to 6-membered aromatic heterocycle or carbocycle, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R ^B groups and Q ² -B, or Q ¹ is -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, - CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-, -C(0)-N(R ^D )-C(NH)-, -NH-N(R ^D )-C(0)-, - C(0)-NH-C(0)-;

Q ² is Ci_ ₄ alkylene, bond, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene, wherein said Ci_ ₄ alkylene,

C ₂ _ alkenylene or C ₂ _ alkynylene may optionally be substituted with one or two substituents selected from R ^A groups and B, and wherein up to two methylene groups of said

Ci_ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene may each independently be replaced by -0-,

-S- or -N(R ^D )-;

B is a 5 - to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ Ci_ ₆ alkyl, -S(O) ₀ - ₂ Ci_ ₆ alkyl-CN, -C(0)-Ci_ ₆ alkyl-CN, C(0)NH-Ci_ ₆ alkyl-CN and phenyl, or B is C ₂ _ ₆ alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl, wherein said C ₂ _ ₆ alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups;

each R ^A is independently selected from OR ^c , N(R ^D ) ₂ and halogen;

each R ^B is independently selected from Ci_ ₄ alkyl, C ₂ _ ₄ alkenyl, C ₂ _ ₄ alkynyl, trihaloCi_ ₄ alkyl,

-C(0)d_ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , C ₃ _ ₆ cycloalkyl, halogen, OR ^c , oxo, N(R ^D ) ₂ and SR ^C ;

each R ^c is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;

each R ^D is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl,

OH, -C(0)Ci_ alkyl, -C(0)CF ₃ and cyano; and

each R' is independently selected from hydrogen and Ci_ ₆ alkyl;

with the proviso that the com ound is not:

The invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof

(I)

wherein:

A is a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle;

X and Q are either attached to adjacent ring atoms or are attached to ring atoms which are separated by one intervening ring atom;

either X is -0-, -S-, -NH-, -CH ₂ 0-, -CH ₂ S-, -CH ₂ NH-, -0-Ci_ ₆ alkylene,

-0-C ₂ - ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ - ₇ cycloalkylene,-S-Ci_ ₆ alkylene,

-S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene,

-NH-C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene,

C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is a 3 - to 7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one or two R ¹ groups;

or X is -0-Ci_ ₆ alkylene, -0-C ₂ _ ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ _ ₇ cycloalkylene,

-S-Ci_ ₆ alkylene, -S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene, -NH- C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene or

C ₂ _ ₆ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR ² R ³ ;

each R ¹ is independently selected from Ci_ ₆ alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-Ci_ ₂ alkyl,

C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R';wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

R ² is hydrogen, Ci_ ₆ alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ ₂ alkyl-, or 3- to 10-membered heterocycle-Ci_ ₂ alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

R ³ is hydrogen, Ci_ ₆ alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R'; wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups;

p is an integer of from 0 to 3;

each R ⁴ is independently selected from R ^B groups and cyano; Q is - Q ¹ - Q ² -, wherein:

Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle or -C(0)-N(R ^D )-C(NH)-, -NH-N(R ^D )- C(O)-, -C(0)-NH-C(0)-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R ^B groups and Q ² - B;

Q ² is bond, Ci_ ₄ alkylene, C ₂ - ₄ alkenylene or C ₂ - ₄ alkynylene, wherein said Ci_ ₄ alkylene,

C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene may optionally be substituted with one or two substituents selected from R ^A groups and B, and wherein up to two methylene groups of said

Ci_ ₄ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene may each independently be replaced by -0-,

-S- or -N(R ^D )-;

B is C ₂ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl-CN, -C(0)-C ₁ _ ₆ alkyl-CN, C(0)NH-C ₁ _ ₆ alkyl-CN and phenyl;

each R ^A is independently selected from OR ^c , N(R ^D ) ₂ and halogen;

each R ^B is independently selected from Ci_ alkyl, C ₂ _ alkenyl, C ₂ _ alkynyl, trihaloCi_ alkyl,

-C(0)d_ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , C ₃ _ ₆ cycloalkyl, halogen, OR ^c , oxo, N(R ^D ) ₂ and SR ^C ;

each R ^c is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;

each R ^D is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl,

OH, -C(0)Ci_ alkyl, -C(0)CF ₃ and cyano; and

each R' is independently selected from hydrogen and Ci_ ₆ alkyl;

with the proviso that the compound is not:

The above-defined compounds of formula (I) have surprisingly been found to be NMT inhibitors, and accordingly have use in the treatment or prophylaxis of diseases or disorders in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect.

The invention also provides a compound of formula (ΠΑ), (IIB), (IIC), (IID),(IIE) or (IIF), or a pharmaceutically acceptable salt thereof:

(IIA) (IIB) (IIC)

(IID) (HE) (IIF)

wherein:

either X is -0-, -S-, -CH ₂ -, -0-CH ₂ - or -S-CH ₂ -; and V is a 3-7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one R ¹ group which is Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R';

or X is -0-C ₂ _ ₄ alkylene, -0-C ₂ _ ₄ alkenylene, -0-C ₂ _ ₄ alkynylene, -0-C ₃ _ ₆ cycloalkylene,

-S-C ₂ _ ₄ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene,

-NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene, -NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ - ₄ alkylene, C ₂ - ₄ alkenylene or C ₂ - ₄ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; and V is NR ² R ³ ;

R ² is hydrogen or d_ ₂ alkyl;

R ³ is hydrogen, methyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ C(0)-R' or C(0)-0-

R';

p is an integer of from 0 to 3;

each R ⁴ is independently selected from R ^B groups and cyano;

R ⁵ is hydrogen or Ci_ ₄ alkyl;

Q is - Q ¹ - Q ² -, wherein:

Q ¹ is -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0- C(O)-, -N(R ^D )-,

-CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-, -C(0)-N(R ^D )-C(NH)-, -NH-N(R ^D )-C(0)-, -C(0)-NH-C(0)-, or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R ^B groups and Q ² - B; wherein said R ^D group may in the case of formula (ΠΑ) optionally form, together with the R ⁵ group, the nitrogen atom of the Q ¹ group, and the intervening two ring carbon atoms a 5- or 6- membered ring;

Q ² is bond, Ci_ ₄ alkylene, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene, wherein said Ci_ alkylene,

C ₂ _ alkenylene or C ₂ _ alkynylene may optionally be substituted with one or two substituents selected from R ^A groups and B, and wherein up to two methylene groups of said

Ci_ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene may each independently be replaced by -0-,

-S- or -N(R ^D )-;

B is C ₂ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl-CN, -C(0)-C ₁ _ ₆ alkyl-CN, C(0)NH-C ₁ _ ₆ alkyl-CN and phenyl;

each R ^A is independently selected from OR ^c , N(R ^D ) ₂ and halogen;

each R ^B is independently selected from Ci_ alkyl, C ₂ _ alkenyl, C ₂ _ alkynyl, trihaloCi_ alkyl,

-C(0)C _! _ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , C ₃ _ ₆ cycloalkyl, halogen, OR ^c , oxo, N(R ^D ) ₂ and SR ^C ;

each R ^c is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;

each R ^D is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl, OH, -C(0)Ci_ alkyl, -C(0)CF ₃ and cyano; and each R' is independently selected from hydrogen and Ci_ ₆ alkyl.

The invention also provides a compound of formula (III), or a pharmaceutically acceptable solvate or salt thereof:

(III)

wherein:

X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -;

V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R ¹ group which is Ci _-2 alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ ,C(0)-R' or C(0)-0-R';

p is an integer of from 0 to 3;

R ⁴ is R ^B groups or cyano;

R ⁵ is hydrogen or Ci_ ₄ alkyl;

Q is - Q ¹ - Q ² -, wherein:

Q ¹ is -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0- C(O)-, -N(R ^D )-,

-CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-, -C(0)-N(R ^D )-C(NH)-, -NH-N(R ^D )-C(0)-, -C(0)-NH-C(0)-, or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R ^B groups and Q ² -

B; wherein said R ^D group may optionally form, together with the R ⁵ group, the nitrogen atom of the

Q ¹ group, and the intervening two ring carbon atoms, a 5- or 6- membered ring;

Q ² is bond, Ci_ ₄ alkylene, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene, wherein said Ci_ alkylene,

C ₂ _ alkenylene or C ₂ _ alkynylene may optionally be substituted with one or two substituents selected from R ^A groups and B, and wherein up to two methylene groups of said

Ci_ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene may each independently be replaced by -0-,

-S- or -N(R ^D )-;

B is C ₂ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl-CN, -C(0)-C ₁ _ ₆ alkyl-CN, C(0)NH-C ₁ _ ₆ alkyl-CN and phenyl;

each R ^A is independently selected from OR ^c , N(R ^D ) ₂ and halogen;

each R ^B is independently selected from Ci_ ₄ alkyl, C ₂ - ₄ alkenyl, C ₂ _ ₄ alkynyl, trihaloCi_ ₄ alkyl,

-C(0)d_ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , C ₃ _ ₆ cycloalkyl, halogen, OR ^c , oxo, N(R ^D ) ₂ and SR ^C ;

each R ^c is independently selected from hydrogen, Ci_ ₄ alkyl, C ₂ _ ₄ alkenyl; C ₂ _ ₄ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;

each R ^D is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl, OH, -C(0)Ci_ alkyl, -C(0)CF ₃ and cyano; and

each R' is independently selected from hydrogen and Ci_ ₆ alkyl;with the proviso that the compound of formula (III) is not 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester or 3- methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester.

The invention also provides 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester or 3-methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester, or a

pharmaceutically acceptable salt thereof, for use as a medicament.

The invention also provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection

(IV)

wherein:

X is -0-C ₂ _ alkylene, -0-C ₂ _ alkenylene, -0-C ₂ _ alkynylene, -0-C ₃ _ ₆ cycloalkylene,

-S-C ₂ _ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene,

-NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene, -NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene,

C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; and V is NR ² R ³ ;

R ² is hydrogen or Ci_ ₂ alkyl; R ³ is hydrogen, methyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-

R';

p is an integer of from 0 to 3;

each R ⁴ is independently selected from R ^B groups and cyano;

R ⁵ is hydrogen or Ci_ ₄ alkyl;

Q is - Q ¹ - Q ² -, wherein:

Q ¹ is -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0- C(O)-, -N(R ^D )-,

-CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-, -C(0)-N(R ^D )-C(NH)-, -NH-N(R ^D )-C(0)-, -C(0)-NH-C(0)-, or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R ^B groups and Q ² - B;

Q ² is bond, Ci_ ₄ alkylene, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene, wherein said Ci_ alkylene,

C ₂ _ alkenylene or C ₂ _ alkynylene may optionally be substituted with one or two substituents selected from R ^A groups and B, and wherein up to two methylene groups of said

Ci_ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene may each independently be replaced by -0-,

-S- or -N(R ^D )-;

B is C ₂ _ ₆ alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ ₆ alkyl, C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl-CN, -C(0)-C ₁ _ ₆ alkyl-CN, C(0)NH-C ₁ _ ₆ alkyl-CN and phenyl;

each R ^A is independently selected from OR ^c , N(R ^D ) ₂ and halogen;

each R ^B is independently selected from Ci_ alkyl, C ₂ _ alkenyl, C ₂ _ alkynyl, trihaloCi_ alkyl,

-C(0)d_ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , C ₃ _ ₆ cycloalkyl, halogen, OR ^c , oxo, N(R ^D ) ₂ and SR ^C ;

each R ^c is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;

each R ^D is independently selected from hydrogen, Ci_ alkyl, C ₂ _ alkenyl; C ₂ _ alkynyl, trihaloCi_ alkyl,

OH, -C(0)Ci_ alkyl, -C(0)CF ₃ and cyano; and

each R' is independently selected from hydrogen and Ci_ ₆ alkyl.

Also provided herein is a compound of the invention for use as a medicament. The compounds of the invention are useful in the treatment or prophylaxis of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect. Compounds of the invention wherein:

either X is -0-, -S-, -CH ₂ -, -0-CH ₂ - or -S-CH ₂ -; and V is a 3-7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one R ¹ group which is Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ ;

or X is -0-C ₂ _ ₄ alkylene, -0-C ₂ _ ₄ alkenylene, -0-C ₂ _ ₄ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ ₄ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene,

-NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene, -NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene,

C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; and V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and

R ³ is hydrogen, methyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , (i.e. certain compounds of formula (I), and compounds of formula (IIA), (IIB), (IIC), (IID), (HE), (IIF), (III), (IV), 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester, and 3-methyl-4-(piperidin- 3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester) have surprisingly been found to be inhibitors of protozoan NMT, and are accordingly useful in the treatment or prophylaxis of a disease or disorder which is a protozoan infection.

Also provided herein is a composition comprising a compound of the invention together with a pharmaceutically acceptable carrier.

Detailed Description of Invention

The present invention provides compounds that are NMT inhibitors. The term "NMT inhibitor" as used herein is intended to cover any moiety which binds to NMT and inhibits its activity. The inhibitors may act as competitive inhibitors, or partial competitive inhibitors. The inhibitor may bind to NMT at the myr-CoA binding pocket or at the peptide binding pocket (or inhibit NMT through another mechanism). Compounds of the present invention preferably bind and inhibit NMT through the peptide binding pocket.

Definitions

The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

As used herein, the term "alkyi" means both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl and hexyl groups. Among unbranched alkyl groups, there are preferred methyl, ethyl, n-propyl, iso-propyl, n-butyl groups. Among branched alkyl groups, there may be mentioned t-butyl, i-butyl, 1-ethylpropyl and 1-ethylbutyl groups. As used herein, the term " alkylene" means both straight and branched chain divalent hydrocarbon radical. Examples of alkyl groups include methyene, ethyene, n-propylene, iso-propylene, n-butylen, t-butylen, i-butylen, sec-butylene, pentylen and hexylene groups. Among unbranched alkyl groups, there are preferred methylene, ethylene, n-propylene, iso-propylene, n-butylene groups. Among branched alkyl groups, there may be mentioned t-butylene, i-butylene, 1-ethylpropylene and 1 - ethylbutylene groups

As used herein, the term "alkenyl" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl. Preferred alkenyl groups include ethenyl, 1-propenyl, 2- propenyl and but-2-enyl.

As used herein, the term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical with at least one carbon carbon double bond. Examples of alkenylenes groups include ethenylene, 1-propenylene, 2-propenylene and but-2-enylene.

As used herein, the term "alkynyi" means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond. Examples of alkynyi groups include ethynyl, propynyl, butynyl, pentynyl and hexynyl. Preferred alkynyi groups include ethynyl, 1-propynyl and 2-propynyl.

As used herein, the term "alkynylene" means both straight and branched chain divalent hydrocarbon radical with at least one carbon carbon triple bond. Examples of alkynylene groups include ethynylene, l-propynylene, 2-propynylene, hutynyiene, pentynylene and hexynylene.

As used herein, "carbocycle" is intended to mean any 3- to 13-membered carbon ring system, which may be saturated, partially unsaturated, or aromatic. The carbon ring system may be monocyclic or contain more than one ring (e.g. the ring system may be bicyclic). Examples of monocyclic saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyeloheptyl, cyclooctyl.

Examples of bicyclic saturated carbocycles include bicyclooctane, bicyclononane, bicyclodecane (decalin) and bicyclooctane. A further example of a saturated carbocycle is adamantane. Examples of monocyclic non- saturated carbocycles include cyclobutene, cyclopentene, cyclopentadiene, cyclohexene. Examples of aromatic carbocycles include phenyl and naphthyl. Further examples of carbocycles include tetrahydronaphthyl (tetralin) and indane . As used herein, the term "eycloalkyl" means a saturated group in a ring system. A cycloalkyl group can be monocyclic or bicyclic. A bicyclic group may, for example, be fused or bridged. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl. Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycioheptyl and cyclooctyl. Examples of bicyclic cycloalkyl groups include bicycle [2. 2. 1 |hept-2-vl. Preferably, the cycloalkyl group is monocyclic.

As used herein, the term "cycloalkylene" means a 3 - to 7-membered non-aromatic alicyclic divalent hydrocarbon radical, Examples of cycloalkyl ene include cyclopropyl ene, cyc!obutyl ene and cyclopentylene. Other examples of monocyclic cycloalkyl groups are cyclohexyl ene and

cycloheptylene. Preferably, the cycloalkylene group is monocyclic.

As used herein, the term "halogen" or "halo" means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred.

As used herein, the term "haloalkyl" means an alky 1 group having a halogen substituent, the terms "alkyl" and "halogen" being understood to have the meanings outlined above. Similarly, the term "dihaloalky l" means an alkyl group having two halogen substituents and the term "trihaloalkyl" means an alkyl group having three halogen substituents. Examples of haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, fluoromethyl, fluoropropyl and fluorobutyl groups; examples of dihaloalkyl groups include difluoromethyl and difluoroethvl groups: examples of tnihaloalkyl groups include tri fluoromethyl and trifluoroethyl groups.

As used herein, the term "heterocyclyl" (or heterocycle) means an aromatic or a non-aromatic cyclic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. A heterocyclyl (or heterocycle) group may, for example, be monocyclic or bicyclic. In a bicyclic heterocyclyl (or heterocycle) group there may be one or more heteroatoms in each ring, or only in one of the rings. A heteroatom may be S, O or N, and is preferably O or . Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides.

Examples of monocyclic non-aromatic heterocyclyl (or heterocycle) include aziridinyl, azetidinyl, pyrrolidinvl. imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl,

tetrahydropyranyl, morpholinyl, thiomorpholinyl and azepanyl.

Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranvl, indanvl. indolinyl, isoindolinyl, tetrahydroisoquinoiinvl, tetraliydroquinolvl and benzoazepanyl. Examples of monocyclic aromatic heterocyclyl (or heterocycle) groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, tetrazolyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pvrazolvl and pyrimidinyl .

Examples of bicyclic aromatic heterocyclyl groups (or heterocycle) include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, qiiinolin l. benzofuranyl, indolyl, benzothiazolyl, oxazoiyl[4,5-b]pyridiyl, pyridopyrimidinyl.

isoquinolinyl and benzodroxazole.

The compounds of the invention may contain chiral (asymmetric) centers or the molecule as a whole may be chiral. The individual stereoisomers (enaiitiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.

For the avoidance of doubt, an embodiment or preferred aspect of any one feature of the compounds of the invention may be combined with any embodiment or preferred aspect of another feature of the compounds of the invention to create a further embodiment.

In an embodiment, X and Q are attached to adjacent ring atoms of the A group.

In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments of the compound of formula (I), A is an 8- to 10-membered bicyclic aromatic carbocycle (e.g. napthalenyl) or, preferably, a heterocycle (e.g. quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl, benzothiazolyl, pyridopyridyl, pyrrolopyridyl, furanopyridyl, thienopyridyl). Where A is an 8- to 10-membered bicyclic heterocycle, the heterocyclic ring typically comprises from one to three heteroatoms each independently selected from nitrogen, oxygen and sulfur. In preferred embodiments, the compound of formula (I) has the formula (IA) or (IB)

(IA) (IB)

wherein:

E is -C(R ^E )=C(R ^E )-, -C(R ^E )=N-, -N=C(R ^E )-, -0-, -S- or -N(R ^E )-; G is -C(R ^E )- or -N-; p is 0 or 1; R ⁵ is hydrog en or and each R ^E is independently selected from hydrogen, Ci- ₄ alkyl, C2- ₄ alkenyl, C ₂ - ₄ alkynyl, trihaloCi_ ₄ alkyl, OR ^c , -C(0)Ci_ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ and C ₃ _ ₆ cycloalkyl. More preferably, the compound of formula (I) has the formula (IE), (IF), (IEE), (IG), (IH) or (IEF)

(IG) (IH) (IEF)

wherein p is 0 or 1; still more preferably the compound of formula (I) has the formula (IF) or (IEE), p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; yet more preferably the compound of formula (I) has the formula (IF), p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; most preferably the compound of formula (I) has the formula (IFa), (IFb) or (IFc):

(IFa) (IFb) (IFc),

and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl.

Compounds in which A is an 8- to 10-membered bicyclic aromatic carbocycle (e.g. napthalenyl) or, preferably, a heterocycle (e.g. quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl, benzothiazolyl, pyridopyridyl, pyrrolopyridyl, furanopyridyl, thienopyridyl) are particularly active against NMT of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), and in particular Plasmodium falciparum (Pf).

In other embodiments of the compound of formula (I), A is a 5- to 6-membered monocyclic aromatic carbocycle (e.g. phenyl) or heterocycle (e.g. pyridyl, pyrrolyl, thiophenyl, furanyl). Where A is a 5- to 6-membered monocyclic heterocycle, the heterocyclic ring typically comprises one or two heteroatoms each independently selected from nitrogen, oxygen and sulfur. In preferred

embodiments, the comp

(IC) (ID) wherein:

G is -C(R ^E )- or -N-;

E is -C(R ^E )=C(R ^E )-, -C(R ^E )=N-, -N=C(R ^E )-, -0-, -S- or -N(R ^E )-;

p is 0 or 1; and

each R ^E is independently selected from hydrogen, Ci_ ₄ alkyl, C ₂ - ₄ alkenyl, C ₂ - ₄ alkynyl, trihaloCi_ ₄ alkyl, OR ^c , -C(0)Ci_ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ and C ₃ _ ₆ cycloalkyl. More preferably, the compound of formula (I) h

(IJ) (IK) (IL)

wherein p is 0 or 1 ; still more preferably the compound of formula (I) has the formula (IJ) or (IK), p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; yet more preferably the compound of formula (I) has the formula (IK), p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl. In particularly preferred embodiments where A is a 5- to 6- membered monocyclic aromatic carbocycle or heterocycle, the compound of formula (I) has the formula (IM), (IN), (10), (IP) or (IQ):

(IM) (IN) (10)

and, where present, each R ⁴ is independently selected from the group consisting of Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; more preferably the compound has the formula (IM), (IN), (10), (IP) or (IQ), and where present each R ⁴ is independently selected from the group consisting of halogen or methoxy. In certain preferred embodiments, the compound of formula (I) has the formula (IPP)

(IPP),

wherein R ⁴ is halogen.

Compounds in which A is a 5 - to 6-membered, and especially 6-membered, monocyclic aromatic carbocycle (e.g. phenyl) or heterocycle (e.g. pyridyl, pyrrolyl, thiophenyl, furanyl) are particularly active against NMT of Plasmodium falciparum (Pf), Plasmodium vivax (Pv), and Leishmania donovani (Ld), and in particular Plasmodium falciparum (Pf) and Leishmania donovani (Ld).

Compounds in which A is a 5 - to 6-membered, and especially 6-membered, monocyclic aromatic carbocycle (e.g. phenyl) or heterocycle (e.g. pyridyl, pyrrolyl, thiophenyl, furanyl) substituted with one or more methoxy groups are at least are particularly active against NMT of Plasmodium falciparum (Pf).

In one embodiment X and Q are attached to adjacent ring atoms. In another embodiment, X and Q are attached to ring atoms which are separated by one intervening ring atom.

In some embodiments of compounds of formula (I), X is -0-, -S-, -NH-, -CH ₂ 0-, -CH ₂ S-, -CH ₂ NH-, - 0-Ci_ ₆ alkylene, -0-C ₂ _ ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ - ₇ cycloalkylene,-S-Ci_ ₆ alkylene, -S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene, -NH-C ₂ - ₆ alkenylene, -NH-C ₂ - ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene,

C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; V is a 3- to 7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one or two R ¹ groups; and each R ¹ is independently selected from Ci_ ₆ alkyl, 3- to 10- membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-C^alkyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups. Preferably X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; more preferably X is -0-, -S- or -0-CH ₂ -, most preferably X is -0-. Preferably, V is a 3- to 7-membered nitrogen-containing heterocycle which may be optionally substituted with one R ¹ group; more preferably V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3 -piperidyl or 4-piperidyl; most preferably V is 4- piperidyl. R ¹ where present is preferably Ci_ ₆ alkyl, phenyl-Ci_ ₂ alkyl, 5- or 6-membered heterocycle- d_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R'; wherein said phenyl or heterocycle may optionally be substituted with one or two R ^A groups. In some preferred embodiments R ¹ is phenyl-Ci_ ₂ alkyl or 5- or 6-membered heterocycle-Ci_ ₂ alkyl, wherein said phenyl or heterocycle may optionally be substituted with one or two R ^A groups. Alternatively, R ¹ is preferably absent or is d_ ₃ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR'), C(0)-R' or C(0)-0-R'; more preferably R ¹ is absent or is d_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ - 0-P(0)(OR'), C(0)-R' or C(0)-0-R'; more preferably Ri is absent or is Ci_ ₂ alkyl. In one preferred embodiment Ri is absent. In another preferred embodiment Ri is methyl. In one preferred embodiment, X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen- containing heterocycle which may be optionally substituted with one R ¹ group which is Ci_ ₂ alkyl. More preferably X is -0-, -S- or -0-CH ₂ -; and V is piperidyl. Most preferably, X is -0-; and V is 4- piperidyl. In certain preferred embodiments, X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered non-aromatic nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a pyrrolidine or piperidine ring. In certain referred embodiments, X is -O- and V is 4-

piperidyl or pyrrolidinyl (e.g. X-V may be or

In other embodiments, X is -0-Ci_ ₆ alkylene, -0-C ₂ _ ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ _ vcycloalkylene, -S-Ci_ ₆ alkylene, -S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene,

6alkylene, -NH-C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene, C ₆ alkenylene or C ₂ _ ₆ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; V is NR ² R ³ ; R ² is hydrogen, Ci_ ₆ alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ ₂ alkyl-, or 3- to 10-membered heterocycle-Ci_ ₂ alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups; and R ³ is hydrogen, Ci_ ₆ alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ ₂ alkyl-, 3- to 10-membered heterocycle-Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R ^A groups. Preferably X is -0-C ₂ _ ₄ alkylene, -0-C ₂ _ ₄ alkenylene, -O- C ₂ _ ₄ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ ₄ alkylene, -S-C ₂ _ alkenylene,

-S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene,

-NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; more preferably X is -0-C ₂ _ alkylene or -S-C ₂ _ alkynylene; still more preferably X is X is -0-C ₃ alkylene. Preferably R ² is hydrogen, Ci_ ₆ alkyl, phenyl-Ci_ ₂ alkyl or 5- or 6-membered heterocycle-Ci_ ₂ alkyl, wherein said phenyl or heterocycle may optionally be substituted with one or two R ^A groups. In some preferred embodiments R ² is phenyl-Ci_ ₂ alkyl or 5- or 6-membered heterocycle-Ci_ ₂ alkyl, wherein said phenyl or heterocycle may optionally be substituted with one or two R ^A groups. Alternatively, R ² is preferably hydrog en or Ci_ ₂ alkyl. In one preferred embodiment R ² is hydrogen. In another preferred embodiment R ² is methyl. Preferably R ³ is hydrogen, d_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R'; more preferably R ³ is hydrogen or methyl. In one preferred embodiment R ³ is hydrogen. In another preferred embodiment R ³ is methyl. In certain preferred embodiments, X is -0-C ₂ _ alkylene, -0-C ₂ _ alkenylene, -0-C ₂ _ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ alkylene, -S-C ₂ _ alkenylene,

-S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene,

-NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and R ³ is hydrogen or methyl. In certain preferred embodiments, X is -0-C ₃ _ ₇ cycloalkylene and V is NR ² R ³ , wherein R ² and R ³ are each independently selected from the group consisting of hydrogen and Ci_ ₆ alkyl. In certain referred embodiments, X is -0-C c cloalkylene and V is NR ² R ³ (e.g. X-V may be

or are each

independently selected from the group consisting of hydrogen and Ci_ ₂ alkyl. It is considered that compounds in which R ¹ or R ³ is C(0)-0-C(R') ₂ -0-C(0)R', C(0)-0-C(R') ₂ -0- P(0)(OR') ₂ , C(0)-R' or C(0)-0-R' act as prodrug compounds. In the body, the C(0)-0-C(R') ₂ -0- C(0)R', C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ , C(0)-R' or C(0)-0-R' group is cleaved from the nitrogen atom in the V group leaving an NH group behind to exert its therapeutic effect.

Preferably, p is an integer of from 0 to 2; more preferably p is 0 or 1 ; most preferably p is 0.

Preferably R ⁴ is d_ ₄ alkyl, trihaloC ₁ _ ₄ alkyl, -C(0)C ₁ _ ₄ alkyl, -C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, OR ^c , N(R ^D ) ₂ and SR ^C ; more preferably R ⁴ is halogen, Ci_ ₄ alkyl or -OCi_ ₃ alkyl; still more preferably R ⁴ is Ci_ ₄ alkyl or -OCi_ ₃ alkyl.

Where A is an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle, Q ¹ is preferably - C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; more preferably Q ¹ is -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0-C 0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,

wherein R ^G is selected from hydrogen, Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, halogen and -OCi_ ₃ alkyl. In some preferred embodiments, Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carboc cle or heterocycle may optionally be substituted with one group; more preferably Q is

wherein R ^G is selected from hydrogen, Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, halogen and -OCi_ ₃ alkyl; most

preferably Q ¹ is

Where A is a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle, Q ¹ is preferably a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionall be substituted with one group; more preferably Q is

wherein R ^G is selected from hydrogen, Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, halogen and -OCi_ ₃ alkyl; most

preferably Q ¹ is Q ² is preferably bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may be optionally substituted with one R ^A groups, and wherein one methylene group of said Ci_ ₄ alkylene may optionally be replaced by - 0-, -S- or N(R ^D ); more preferably Q ² is bond, -CH ₂ -, -CH ₂ -CH ₂ - -CH ₂ -CH ₂ -CH _2> -0-CH ₂ -,

-0-CH ₂ -CH ₂ -, -CH ₂ -0-, -CH ₂ -CH ₂ -0-, -S-CH ₂ -, -S-CH ₂ -CH ₂ -, -CH ₂ -S-, -CH ₂ -CH ₂ -S- or -CH ₂ -0- CH ₂ -; most preferably Q ² is -CH ₂ - or -CH ₂ -CH ₂ -

B is preferably C ₂ _ ₄ alkyl, C ₅ _i ₀ cycloalkyl or a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _i ₀ cycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ ₃ alkyl,-N(R ^D ) ₂ , -C(0)d_ ₃ alkyl, -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SC^alkyl; more preferably B is a 5- to 10-membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ ₃ alkyl,-N(R ^D ) ₂ , - C(0)Ci_ ₃ alkyl, -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SCi_ ₃ alkyl; still more preferably B is phenyl or a 5- or 6-membered aromatic heterocycle, wherein said phenyl or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCwalkyl, -OH, -OC^alkyl^NCR ⁰ ),, -C^C^alkyl, -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SCi_ ₃ alkyl. In certain preferred embodiments, B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen; more preferably B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen; still more preferably B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain preferred embodiments Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group, R ^B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH ₂ and hydroxy, Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group, and R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl. More preferably, Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle and Q ² is bond or Ci_

₄ alkylene. Still more preferably, Q is or

, and Q ² is -CH ₂ - or -CH ₂ -CH ₂ -.

Preferably each R ^A is independently selected from OH, OCi_ ₃ alkyl, -NH ₂ , -NH(Ci_ ₃ alkyl), -N(Ci_ ₃ alkyl) ₂ , NHC(0)Ci_ ₄ alkyl and halogen.

In some preferred embodiments, Q is -C(0)0-, C(0)OCH ₂ -, -C(0)0-CH ₂ -CH ₂ -, -C(0)0-CH ₂ -CH ₂ - CH ₂ -, -C(0)0-CH ₂ -CH ₂ -0-, CH ₂ -C(0)0-, CH ₂ -OC(0)-, -C(O)-, -C(0)CH=CH-, -CH ₂ -0, -CH ₂ -0- CH ₂ -, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -, C(0)N-CH ₂ -; and B is ethyl, cyclohexyl, napthalenyl, 3,4-methylenedioxyphenyl, or phenyl, wherein said phenyl may optionally be substituted by one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₃ alkyl, halogen, OH and trihaloCi- ₄ alkyl.

In other preferred embodiments, Q is -C(0)0-CH ₂ -CH ₂ -, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ alkyl.

In certain preferred embodiments Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group, R ^B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH ₂ and hydroxy, Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one group, R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl, and B is a 5- 10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen. More preferably, Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, Q ² is bond or Ci_ alkylene, and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen. Still more preferably, Q ¹ is , Q ² is -CH ₂ - or -CH ₂ - CH ₂ - and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen.

Preferably, each R ^B is independently selected from Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, -C(0)Ci_ alkyl, - C(0)CF ₃ , -C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, OR ^c , N(R ^D ) ₂ and SR ^C .

Preferably, each R ^c is independently selected from hydrogen, Ci_ alkyl and trihaloCi_ alkyl. Preferably, each R ^D is independently selected from hydrogen, Ci_ alkyl and trihaloCi_ alkyl. Preferably, each R' is independently selected from hydrogen and Ci_ ₃ alkyl.

Where A is an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle (e.g. in a compound of formula (IA) or (IB)), preferably Q ¹ is C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, - CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,or a 5- to 6- membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R ^D ); and B is C ₂ _ alkyl, C ₅ _i ₀ cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _i ₀ cycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SCi_ ₃ alkyl. More preferably, either X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -, and V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R ¹ group which is Ci_ ₂ alkyl; or X is -0-C ₂ _ alkylene, -0-C ₂ _ alkenylene, -0-C ₂ _ alkynylene, -O- C ₃ _ ₆ cycloalkylene, -S-C ₂ _ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH- C ₂ _ alkylene, -NH-C ₂ _ alkenylene, -NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and R ³ is hydrogen or methyl; p is 0 or 1 ; R ⁴ is Ci_ alkyl or -OCi_ ₃ alkyl; Q ¹ is C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, - N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R ^D ); and B is C ₂ - ₄ alkyl, C ₅ _i ₀ cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _i ₀ cycloalkyl may optionally be substituted with one or two Ci_ ₄ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, -OH, -OCi_ ₃ alkyl,-N(R ^D ) ₂ , - C(0)d_ ₃ alkyl, -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SC^alkyl.

Where Q ¹ is -C(0)0- and Q ² is bond, preferably B is C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ Ci_ ₆ alkyl, -S(O) ₀ - ₂ Ci_ ₆ alkyl-CN, -C(0)-Ci_ ₆ alkyl-CN, C(0)NH-Ci_ ₆ alkyl-CN and phenyl. More preferably, B is 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -O-C^alkyl-CN, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl-CN, -C C -C^alkyl-CN, C(0)NH-d_ ₆ alkyl-CN and phenyl.

Where A is an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle (e.g. in a compound of formula (IA) or (IB)), preferably B is C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said C ₂ _ ₆ alkenyl or C ₂ _ ₆ alkynyl may optionally be substituted with 1 or 2 R ^A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R ^B , -0-Ci_ ₆ alkyl-CN, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl, -S(O) ₀ - ₂ C ₁ _ ₆ alkyl-CN, -C(0)-C ₁ _ ₆ alkyl-CN, C(0)NH-C ₁ _ ₆ alkyl-CN and phenyl; more preferably B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ alkyl and halogen; still more preferably B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen; yet more preferably B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

Where A is an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle (e.g. in a compound of formula (IA) or (IB)), preferably Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; R ^B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group; R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5- 10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen. More preferably, Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle; Q ² is bond or Ci_ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen. Still more preferably, Q ¹

is ; Q is -CH ₂ - or -CH ₂ -

CH ₂ -; and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In one preferred embodiment, the compound of formula I has the formula (IE), (IF) or (IEE), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is -0-; V is 4- piperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, oxadiazolyl-CH ₂ - or oxadiazolyl-CH ₂ -CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ ₃ alkyl, halogen and trihaloCi_ alkyl.

In certain embodiments of the compound of formula (I) in which A is an 8- to 10-membered bicyclic aromatic heterocycle or carbocycle, A is not naphthalene. In certain embodiments of the compound of formula (I) in which A is an 8- to 10-membered bicyclic aromatic heterocycle or carbocycle, Q ¹ is not pyrimidine. In certain embodiments of the compound of formula (I) in which A is an 8- to 10- membered bicyclic aromatic heterocycle or carbocycle, A is not indole. In certain embodiments of the compound of formula (I) in which A is an 8- to 10-membered bicyclic aromatic heterocycle or carbocycle and V is a 3- to 7-membered nitrogen-containing heterocycle, V is not aromatic.

In certain preferred embodiments the compound has the formula:

(IF)

wherein p is 0 or 1; R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl;

either X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen-containing heterocycle,

or X is -0-C ₃ _ ₇ cycloalkylene; and V is NR ² R ³ ; R ² and R ³ are each independently selected from the group consisting of hydrogen and Ci_ ₆ alkyl; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; R ^B where present is selected from the group consisting of Ci_ ₄ alkyl, 0-Ci_ ₄ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group; R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; V is a 3- to 7- membered nitrogen-containing heterocycle; Q ¹ is a 5- to 6- membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; R ^B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group; R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is -0-; V is a 4-7 membered non-aromatic nitrogen-containing heterocycle; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle; Q ² is bond or Ci_ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is -0-; V is a piperidine or a pyrrolidine ring (e.g. X-V may be ); Q ¹ is

; and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is -0-C ₃ _ vcycloalkylene; V is NR ² R ³ ; R ² and R ³ are each independently selected from the group consisting of hydrogen and Ci_ ₆ alkyl; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; R ^B where present is selected from the group consisting of Ci_ ₄ alkyl, 0-Ci_ ₄ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group; R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is -O- C cycloalkylene; V is NR ² R ³ ; R ² and R ³ are each independently selected from the group consisting of hydrogen and Ci_ ₂ alkyl; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle; Q ² is bond or Ci_ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is

0-C ₄ cycloalkylene; V is NR ² R ³ (e.g. X-V may be

he group consisting of

ydrogen and Ci_ ₂ alkyl; Q ¹ is , or

; Q ² is -CH ₂ - or -CH ₂ -CH ₂ -; and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen.

In another aspect, the invention provides a compound of formula (IF)

(IFa) (IFb) (IFc), or a pharmaceutically acceptable salt thereof,

wherein:

R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S- CH ₂ -; V is a 3- to 7- membered nitrogen-containing heterocycle (e.g. piperidine or pyrrolidine) which is substituted with 1 or 2 fluorine atoms; Q is Q ^: -Q ² ; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R group

present is selected from the group consisting of Ci_ ₄ alkyl, 0-Ci_ ₄ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one group (e.g. Q ² may be -CH ₂ - or -CH ₂ -CH ₂ -); R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

Where A is a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle, preferably Q ¹ is a 5- or 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may be optionally substituted with one R ^A groups, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R ^D ); and B is C ₂ _ alkyl, C ₅ _i ₀ cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _ _l ocycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , - CH ₂ OR ^c , halogen, -SH and -SCi_ ₃ alkyl. More preferably, either X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S- CH ₂ -, and V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R ¹ group which is Ci_ ₂ alkyl; or X is -0-C ₂ _ alkylene, -0-C ₂ _ alkenylene, -O- C ₂ _ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene, -NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; V is NR R ; R is hydrogen or Ci_ ₂ alkyl; and R is hydrogen or methyl; p is 0 or 1; R is Ci_ alkyl or - OCi_ ₃ alkyl; Q ¹ is a 5- or 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; Q ² is bond or Ci_ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R ^D ); and B is C ₂ _ alkyl, C ₅ _i ₀ cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _iocycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ ₃ alkyl,-N(R ^D ) ₂ , -C(0)Ci_ ₃ alkyl, - C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SCi_ ₃ alkyl. In certain preferred embodiments, X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered non-aromatic heterocycle. In certain referred embodiments, X is -O- and V is a pyrrolidine or piperidine ring (e.g. X-V may be

Where A is a phenyl ring, it is preferred that X is -0-, -S-, -NH-, -CH ₂ 0-, -CH ₂ S-, -CH ₂ NH-, -0-Ci_ ₆ alkylene, -0-C ₂ _ ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ - ₇ cycloalkylene,-S-Ci_ ₆ alkylene, -S-C ₂ _ ₆ alkenylene, -S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene,

-NH-C ₂ _ ₆ alkenylene, -NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene,

C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is a 3 - to 7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one or two R ¹ groups. In certain preferred embodiments, where A is a phenyl ring, X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered non-aromatic nitrogen- containin heterocycle. In certain preferred embodiments, X is -O- and V is pyrrolidine or piperidine

In a further embodiment, where A is a phenyl ring, it is preferred that:

either X is -0-, -NH-, -CH ₂ 0-, -CH ₂ S-, -CH ₂ NH-, -0-Ci_ ₆ alkylene, -0-C ₂ _ ₆ alkenylene,

-0-C ₂ _ ₆ alkynylene, -0-C ₃ _ ₇ cycloaikylene,-S-Ci_ ₆ alkylene, -S-C ₂ _ ₆ alkenylene,

-S-C ₂ _ ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene, -NH-C ₂ _ ₆ alkenylene,

-NH-C ₂ _ ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene, C ₂ _ ₆ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is a 3- to 7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one or two R ¹ groups;

or X is -0-Ci_ ₆ alkylene, -0-C ₂ _ ₆ alkenylene, -0-C ₂ _ ₆ alkynylene, -0-C ₃ _ ₇ cycloalkylene, -S-Ci_ ₆ alkylene, -S-C ₂ - ₆ alkenylene, -S-C ₂ - ₆ alkynylene, -S-C ₃ _ ₇ cycloalkylene, -NH-Ci_ ₆ alkylene, -NH- C ₂ _ ₆ alkenylene, -NH-C ₂ - ₆ alkynylene, -NH-C ₃ _ ₇ cycloalkylene, Ci_ ₆ alkylene, C ₂ _ ₆ alkenylene or

C ₂ _ ₆ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR ² R ³ .

In one preferred embodiment, the compound of formula I has the formula (IJ) or (IK), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-; V is 4- piperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ ₄ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ ₄ alkyl.

In certain embodiments of the compound of formula (I) in which A is a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle, X and Q are attached to adjacent ring atoms.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IM), (IN), (10), (IP) or (IQ); where present each R ⁴ is independently selected from the group consisting of Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; V is a 3- to 7- membered nitrogen-containing heterocycle; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; R ^B where present is selected from the group consisting of Ci_ ₄ alkyl, 0-Ci_ ₄ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group; R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula (IM), (IN), (10), (IP) or (IQ); where present each R ⁴ is independently selected from the group consisting of Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-; V is a 4-7 membered non-aromatic nitrogen-containing heterocycle; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle; Q ² is bond or Ci_ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In certain particularly preferred embodiments, the compound of formula (I) has the formula ((IM), (IN), (10), (IP) or (IQ); where present each R ⁴ is independently selected from the group consisting of halogen and methoxy; X is -0-; V is a pyrrolidine or piperidine ring (e.g. X-V may be ; Q is -CH ₂ - or -CH ₂ -CH ₂ -; and B is phenyl or a 5-

6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen.

In another aspect, there is rovided a compound of formula (IM), (IN), 10), (IP) or (IQ)

(IP) (IQ), or a pharmaceutically acceptable salt thereof , wherein: where present each R ⁴ is independently selected from the group consisting of Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; V is a 3- to 7- membered nitrogen- containing heterocycle (e.g. piperidine or pyrrolidine) which is substituted with 1 or 2 fluorine atoms; Q is Q ^: -Q ² ; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group (e.g. Q ¹ may

be ); R where present is selected from the group consisting of Ci_ ₄ alkyl, 0-Ci_ ₄ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group (e.g. Q ² may be -CH ₂ - or -CH ₂ -CH ₂ -); R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen.

In another aspect of the invention, there is provided a compound of formula (ΠΑ), (IIB), (IIC), (IID), (HE) or (IIF) or a pharmaceutically acceptable salt thereof. The preferences for p, R ⁴ , Q ² , B, R R ^B ,

R ^c , R ^D and R' are the same as for the compound of formula (I) above.

In certain preferred embodiments, the compound has the formula ( II A). (IIB), (IIC), (IID) or (HE).

In some embodiments X is -0-, -S-, -CH ₂ -, -0-CH ₂ - or -S-CH ₂ -; and V is a 3-7-membered nitrogen- containing heterocycle, wherein said heterocycle may optionally be substituted with one R ¹ group which is d_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ .

Preferably X is -0-, -S- or -0-CH ₂ -, most preferably X is -0-. Preferably V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3-piperidyl or 4-piperidyl; most preferably V is 4-piperidyl. R ¹ is preferably absent or is Ci_ ₂ alkyl. In one preferred embodiment Ri is absent. In another preferred embodiment Ri is methyl. In one preferred embodiment, X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen- containing heterocycle which may be optionally substituted with one R ¹ group which is Ci_ ₂ alkyl. More preferably, X is -0-, -S- or -0-CH ₂ -; and V is piperidyl.

In certain preferred embodiments, X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered non-aromatic nitrogen-containing heterocycle. In certain referred embodiments, X is -O-

and V is a pyrrolidine or piperidine ring (e.g. X-V may be or

In other embodiments X is -0-C ₂ _ ₄ alkylene, -0-C ₂ _ alkenylene, -0-C ₂ _ alkynylene, -0-C ₃ _

6cycloalkylene, -S-C ₂ _ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH-C ₂ - ₄ alkylene, -NH-C ₂ - ₄ alkenylene, -NH-C ₂ - ₄ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ - ₄ alkylene, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; and V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and R ³ is hydrogen, methyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ . Preferably, X is -0-C ₂ _ ₄ alkylene or -S-C ₂ _ ₄ alkynylene; still more preferably X is -0-C ₃ alkylene. Preferably R ² is hydrogen. In another preferred embodiment R ² is methyl. Preferably R ³ is hydrogen or methyl. In one preferred embodiment R ³ is hydrogen. In another preferred embodiment R ³ is methyl. In one preferred embodiment, X is -0-C ₂ _ ₄ alkylene, -O- C ₂ _ ₄ alkenylene, -0-C ₂ _ ₄ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ ₄ alkylene, -S-C ₂ _ ₄ alkenylene, -S-C ₂ _ ₄ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH-C ₂ _ ₄ alkylene, -NH-C ₂ _ ₄ alkenylene,

-NH-C ₂ _ ₄ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ _ ₄ alkylene, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and R ³ is hydrogen or methyl. In certain preferred embodiments, X is -0-C ₃ _ ₇ cycloalkylene and V is NR ² R ³ , wherein R ² and R ³ are each independently selected from the group consisting of hydrogen and Ci_ ₆ alkyl. In certain referred embodiments X is -0-C ₄ c cloalkylene and V is NR ² R ³ (e.g. X-V may be

are each

independently selected from the group consisting of hydrogen and Ci_ ₂ alkyl. R ⁵ is preferably Ci_ ₃ alkyl, more preferably methyl.

Q ¹ is preferably -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; more preferably Q ¹ is -C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, - CH ₂ -C 0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,

wherein R ^G is selected from hydrogen, Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, halogen and -OCi_ ₃ alkyl. In some preferred embodiments, Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carboc cle or heterocycle may optionally be substituted with one group; more preferably Q is

wherein R ^G is selected from hydrogen, Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, halogen and -OCi_ ₃ alkyl; most

preferably Q ¹ is

In certain preferred embodiments of the compound of formula (IIA), (IIB), (II C), (IID), (HE) or (IIF), Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one group, R ^B where present is selected from the group consisting of Ci_ ₄ alkyl, 0-Ci_ ₄ alkyl, halogen, NH ₂ and hydroxy, Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group, R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl, and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen. More preferably, Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, Q ² is bond or Ci_ alkylene, and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and

halogen. Still more preferably, Q ¹ is , or

, Q ² is -CH ₂ - or -CH ₂ -CH ₂ - and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen. In one preferred embodiment of the compound of formula (ΠΑ), (IIB), (IIC), (IID), (HE) or (IIF), either X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R ¹ group which is Ci_ ₂ alkyl; or X is -0-C ₂ _ ₄ alkylene, -0-C ₂ _ ₄ alkenylene, -0-C ₂ _ ₄ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ ₄ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene, -NH- C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene, C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and R ³ is hydrogen or methyl; p is 0 or 1 ; R ⁴ is C^alkyl or -OC^alkyl; Q ¹ is C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R ^D ); and

B is C ₂ _ alkyl, C ₅ _i ₀ cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _i ₀ cycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ ₃ alkyl,-N(R ^D ) ₂ , - C(0)d_ ₃ alkyl, -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SC^alkyl.

In one preferred embodiment of the compound of formula (ΠΑ), (IIB), (IIC), (IID) or (HE), p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-; V is 4-piperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ alkyl.

In certain particularly preferred embodiments, the compound has the formula (IIF); p is 0; X is -0-, - S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; V is a 3- to 7- membered nitrogen-containing heterocycle; R ⁵ is Ci_ ₃ alkyl; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; R ^B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group; R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen. In certain particularly preferred embodiments, the compound has the formula (IIF); p is 0; X is -0-; V is a 4-7 membered non-aromatic nitrogen-containing heterocycle; R ⁵ is methyl; Q ¹ is a 5- to 6- membered aromatic carbocycle or heterocycle; Q ² is bond or Ci_ ₄ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen.

In certain particularly preferred embodiments, the com ound has the formula (IIF); p is 0; X is -0-; V

is a pyrrolidine or piperidine ring (e.g. X-V may be

is methyl; Q ¹ is ; Q ² is

CH ₂ - or -CH ₂ -CH ₂ -; and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ alkyl and halogen.

In another aspect, the invention provides a compound of formula (ΠΑ), (IIB), (IIC), (IID), (HE) or (IIF)

(IID) (HE) (IIF), or a pharmaceutically acceptable salt thereof, wherein: p is 0 or 1; R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl, X is -0-, -S-, CH ₂ , -O- CH ₂ - or -S-CH ₂ -; V is a 3- to 7- membered nitrogen-containing heterocycle (e.g. piperidine or pyrrolidine) which is substituted with 1 or 2 fluorines; R ⁵ where present is Ci_ ₃ alkyl; Q is Q ^: -Q ² ; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group (e.g. Q ¹ may be

selected from the group consisting of Ci_ ₄ alkyl, 0-Ci_ ₄ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or wherein said may optionally be substituted with one R ^A group (e.g. Q ² may be -CH ₂ - or -CH ₂ -CH ₂ -); R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen. More preferably, the compound has the formula (IIF); p is 0; R ⁵ is Ci_ ₃ alkyl.

In another aspect of the invention, there is provided a compound of formula (III), or a

pharmaceutically acceptable salt thereof. The preferences for p, R ⁴ , R\ Q ¹ , Q ² , B, R \ R ^B , R ^c , R° and R' are the same as for the compounds of formula (II A). (IIB), (IIC), (11D). (HE) or (IIF) above.

Preferably the compound of formula (III) has the formula (Ilia), (Illb)

(Ilia) (Illb) (IIIc)

wherein, where present, R ⁴ is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; and R ⁵ is Ci_ ₃ alkyl. More preferably, the compound of formula (III) has the formula (Ilia), (Illb) or (IIIc); R ⁴ where present is halogen; and R ⁵ is methyl.

Preferably X is -0-, -S- or -0-CH ₂ -, most preferably X is -0-. Preferably V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3-piperidyl or 4-piperidyl; most preferably V is 4-piperidyl. R ¹ is preferably absent or is Ci_ ₂ alkyl. In one preferred embodiment Ri is absent. In another preferred embodiment Ri is methyl. Preferably, X is -0-, -S- or -O-CH ₂ -; and V is piperidyl. More preferably, X is -0-, -S- or -0-CH ₂ -; and V is 3-piperidyl or 4- piperidyl. In certain preferred embodiments, X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; and V is a 3- to 7- membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered non-aromatic nitrogen-containing heterocycle. In certain referred embodiments, X is

-O- and V is a pyrrolidine or piperidine ring (e.g. X-V may be

In one preferred embodiment of the compound of formula (III), X is -0-, -S- or -0-CH ₂ -;

V is piperidyl; p is 0 or 1; R ⁴ is d_ ₄ alkyl or -OCi_ ₃ alkyl; R ⁵ is Ci_ ₄ alkyl; Q ¹ is C(0)0-,-C(0)N(R ^D )-, - 0C(0)-, -N(R ^D )C(0)-, -C(0)-, -0-, -CH ₂ -0-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, - CH ₂ -, -CH=CH-,or a 5 - to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R ^D ); and

B is C ₂ _ alkyl, C ₅ _i ₀ cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _i ₀ cycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ ₃ alkyl,-N(R ^D ) ₂ , - C C Cwalkyl, -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -SC^alkyl.

In a compound of formula (III), preferably Q ¹ is -C(0)0-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ - 0-, -CH ₂ -C(0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-, -C(0)-N(R ^D )-C(NH)-, - NH-N(R ^D )-C(0)-, -C(0)-NH-C(0)-, or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R ^B groups and Q ² -B; wherein said R ^D group may optionally form, together with the R ⁵ group, the nitrogen atom of the Q ¹ group, and the intervening two ring carbon atoms, a 5- or 6- membered ring.

In certain preferred embodiments Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group, R ^B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH ₂ and hydroxy, Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group, R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl, and B is a 5- 10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen. More preferably, Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, Q ² is bond or Ci_ ₄ alkylene, and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ alkyl and halogen. Still more preferably, Q ¹ is

CH ₂ - and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

In a compound of formula (III), in which Q ¹ is -C(0)N(R ^D )-, it is preferred for Q ² to be

Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R ^D ).

In one preferred embodiment of the compound of formula (III) p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-; V is 4-piperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ alkyl.

In certain particularly preferred embodiments, the compound has the formula (Ilia), (Illb) or (IIIc); where present R ⁴ is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; R ⁵ is Ci_ ₃ alkyl; X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; V is a 3- to 7- membered nitrogen-containing heterocycle; R ⁵ is Ci_ ₃ alkyl; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; R ^B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R ^A group; R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen. In certain particularly preferred embodiments, the compound has the formula (Ilia), (Illb) or (IIIc); R ⁴ where present is halogen; R ⁵ is methyl; X is -0-; V is a 4-7 membered non-aromatic nitrogen- containing heterocycle; R ⁵ is methyl; Q ¹ is a 5- to 6-membered aromatic carbocycle or heterocycle; Q ² is bond or Ci_ ₄ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ ₄ alkyl and halogen.

In certain particularly preferred embodiments, the compound has the formula (Ilia), (Illb) or (IIIc); R ⁴ where resent is halogen; R ⁵ is methyl; X is -0-; V is a pyrrolidine or piperidine ring (e.g. X-V may

be or ); R ⁵ is methyl; Q ¹ is

CH ₂ -; and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, OCi_ alkyl and halogen.

In another aspect, the invention provides a compound of formula (Ilia), (Illb) or (IIIc)

(Ilia) (Illb) (IIIc), or a pharmaceutically acceptable salt thereof, wherein:

where present R ⁴ is Ci_ ₂ alkyl, trihalomethyl, halogen or OCi_ ₂ alkyl; R ⁵ is Ci_ ₃ alkyl; X is -0-, -S-, CH ₂ , -0-CH ₂ - or -S-CH ₂ -; V is a 3- to 7- membered nitrogen-containing heterocycle (e.g. piperidine or pyrrolidine) which is substituted with 1 or 2 fluorines; R ⁵ is Ci_ ₃ alkyl; Q is Q ^: -Q ² ; Q ¹ is a 5- to 6- membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally

be substituted with one R ^B group (e.g. Q ¹ may be or

); R where present is selected from the group consisting of Ci_ ₄ alkyl, O-C 1- ₄ alkyl, halogen, NH ₂ and hydroxy; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one group (e.g. Q ² may be -CH ₂ - or -CH ₂ -CH ₂ -); R ^A where present is selected from the group consisting of halogen, OH and OCi_ ₃ alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.

As m entioned above, the compounds of the invention have activity as N-myristoyl transferase inhibitors. Compounds of the invention which are defined as having activity as N-myristoyl transferase inhibitors have an IC ₅₀ of less than or equal to ΙΟΟμΜ, preferably less than or equal to 20μΜ, and more preferably less than or equal to 5μΜ. The compounds of the invention may be competitive inhibitors or partial competitive inhibitors of the NMT enzyme. The compounds of the invention may thus be used in the treatment of diseases or disorders associated with NMT activity or may be used in the treatment of a diseases or disorders by targeting NMT activity (for example in microbial infections, hyperproliferative diseases of disorders). Accordingly, there is provided a compound of the invention for use as a medicament. There is also provided a compound of the invention for use in the treatment or prophylaxis of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect.

The invention also provides a method for the treatment or prophylaxis of a disease or disorder in a subject in which inhibition of N -i \ ri sto I trail s fc rase provides a therapeutic or prophylactic effect, which comprises administering to the mammal a therapeutically effective amount of a compound according to the invention.

The invention also provides the use of a compound according to the invention, for the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect. Clinical conditions (i.e. diseases/disorders) in which inhibition of N-myristoyltransferase provides a therapeutic effect include, but are not limited to, microbial infections including fungi and viruses, hypcrprolifcrativc disorders, neurological diseases/disorders, ischemia, osteoporosis and diabetes.

The compounds of the invention find particular application in the treatment or prophylaxis of the following: microbial infections including fungi and viruses (for example HIV), hyperproliferative disorders (for example cancers such as human colorectal cancer, gallbladder carcinoma and brain tumors) and diabetes.

Compounds of the invention which are selective for a particular NMT enzyme may be particularly useful. For example, use of selective compound may result in reduced side effects compared with use of a less selective compound. Preferably compounds of the invention are selective over Human NMTl and/or Human NMT2. Compounds of the invention which are considered selective have a ratio of IC ₅₀ values of greater than 10, preferably greater than 100, more preferably greater than 1000, and most preferably greater than 10,000.

As mentioned above, it has surprisingly been found that compounds of the invention wherein:

either X is -0-, -S-, -CH ₂ -, -0-CH ₂ - or -S-CH ₂ -; and V is a 3-7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one R ¹ group which is Ci_ ₂ alkyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂ ;

or X is -0-C ₂ _ ₄ alkylene, -0-C ₂ _ ₄ alkenylene, -0-C ₂ _ ₄ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ ₄ alkylene, -S-C ₂ _ alkenylene, -S-C ₂ _ alkynylene, -S-C ₃ _ ₆ cycloalkylene,

-NH-C ₂ _ alkylene, -NH-C ₂ _ alkenylene, -NH-C ₂ _ alkynylene, -NH-C ₃ _ ₆ cycloalkylene,

C ₂ _ alkylene, C ₂ _ alkenylene or C ₂ _ alkynylene; wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; and V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and

R ³ is hydrogen, methyl, C(0)-0-C(R') ₂ -0-C(0)R' or C(0)-0-C(R') ₂ -0-P(0)(OR') ₂

are inhibitors of parasitic/protozoan NMT. Those compounds of the invention include compounds of formula (I) having X,V, R ¹ , R ² and/or R ³ groups as indicated above, as well as compounds of formula (IIA), (IIB), (IIC), (IID), (HE), (IIF) and (III). Accordingly, those compounds find use in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection.

It has also been found that compounds of formula (IV) have surprisingly been found to be inhibitors of parasitic/protozoan NMT, and accordingly those compounds also find use in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection. The preferences for p, R ⁴ , Q ¹ , Q ^: . B, R \ R ^B , R ^c , R ^D . and R' in the compounds of formula (IV) are the same as for the compounds of formula ( I I A). (IIB), (IIC), (IID), ( H E) or (IIF) above

In the compound of formula (IV), X is preferably -0-C ₂ - ₄ alkylene or -S-C ₂ - ₄ alkynylene; still more preferably X is X is -0-C ₃ alkylene. In one preferred embodiment R ² is hydrogen. In another preferred embodiment R ² is methyl. Preferably R ³ is hydrogen or methyl. In one preferred embodiment R ³ is hydrogen. In another preferred embodiment R ³ is methyl.

In one preferred embodiment of the compound of formula (IV), X is -0-C ₂ - ₄ alkylene, -0-C ₂ _ ₄ alkenylene, -0-C ₂ _ ₄ alkynylene, -0-C ₃ _ ₆ cycloalkylene, -S-C ₂ _ ₄ alkylene, -S-C ₂ _ ₄ alkenylene, -S- C ₂ _ ₄ alkynylene, -S-C ₃ _ ₆ cycloalkylene, -NH-C ₂ _ ₄ alkylene, -NH-C ₂ _ ₄ alkenylene, -NH-C ₂ _ ₄ alkynylene, - NH-C ₃ _ ₆ cycloalkylene, C ₂ _ ₄ alkylene, C ₂ _ ₄ alkenylene or C ₂ _ ₄ alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; V is NR ² R ³ ; R ² is hydrogen or Ci_ ₂ alkyl; and R ³ is hydrogen or methyl; p is 0 or 1; R ⁴ is Ci_ ₄ alkyl or -OCi_ ₃ alkyl;

R ⁵ is d_ ₄ alkyl; Q ¹ is C(0)0-,-C(0)N(R ^D )-, -OC(O)-, -N(R ^D )C(0)-, -C(O)-, -0-, -CH ₂ -0-, -CH ₂ - C(0)0-, -CH ₂ -0-C(0)-, -N(R ^D )-, -CH ₂ -N(R ^D )-, -CH ₂ -, -CH=CH-,or a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R ^B group; Q ² is bond or Ci_ ₄ alkylene, wherein said Ci_ ₄ alkylene may optionally be substituted with one R ^A group, and wherein one methylene group of said Ci_ ₄ alkylene may optionally be replaced by -0-, -S- or N(R ^D ); and B is C ₂ _ ₄ alkyl, C ₅ _i ₀ cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C ₅ _i ₀ cycloalkyl may optionally be substituted with one or two Ci_ ₄ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ ₄ alkyl, trihaloCi_ ₄ alkyl, -OH, -OC^alkyl^N R ⁰ ),, -C(0)Ci _-3 alkyl ₅ -C(0)CF ₃ ,-C(0)N(R ^D ) ₂ , -CH ₂ OR ^c , halogen, -SH and -Sd_ ₃ alkyl

Preferred compounds of the invention having activity as inhibitors of parasitic/protozoan NMT include those in which X is -0-, -S- or -0-CH ₂ -; more preferably X is -O-.; and in which V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3-piperidyl or 4-piperidyl; most preferably V is 4-piperidyl. Preferably Ri is absent or is Ci_ ₂ alkyl. In one preferred embodiment Ri is absent. In another preferred embodiment Ri is methyl. In one preferred embodiment, X is -0-, -S- or -0-CH ₂ -; and V is piperidyl. In other preferred embodiments, X is -0-, -S- or -0-CH ₂ -; and V is 4-piperidyl or 3-piperidyl.

Additional preferred compounds of the invention having activity as inhibitors of parasitic/protozoan NMT are those in which X is -0-C ₂ _ ₄ alkylene or -S-C ₂ _ ₄ alkynylene; N is R ² R ³ ; R ² is hydrogen or methyl; and R ³ is preferably hydrogen or methyl. More preferably, X is -0-C ₃ alkylene; R ² is hydrogen or methyl; and R ³ is hydrogen.

In a preferred embodiment, the compound has the formula (IEE), (IEF), (IJ), (IK), (IF) or, (III), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -O- or -S-; V is 4-piperidyl or 4-dimethylpiperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, -C(0)0-CH ₂ , C(0)0-CH ₂ - CH ₂ -0-, -C(0)0-CH=CH-, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -; and B is ethyl, naphthyl, 4- methylenedioxyphenyl or phenyl, wherein said phenyl may optionally be substituted by one to three groups each independently selected from Ci_ ₄ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ ₄ alkyl. In another preferred embodiment, the compound has the formula (IJ), (IF) or, (III), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-; V is 4-piperidyl; Q is - C(0)0-CH ₂ -CH ₂ -, -C(0)0-CH ₂ -, oxadiazolyl-CH ₂ - or oxadiazolyl-CH ₂ -CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from d_ ₃ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ ₄ alkyl. These embodiments may have particular activity as inhibitors of

Plasmodium falciparum (Pf) N-myristoyl transferase.

In a preferred embodiment, the compound has the formula (IF), (IE), (IEE), (IEF), (IJ), (IK) or, (III), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -O- or -S-; V is 4-piperidyl or 4-methylpiperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, -C(0)0-CH ₂ -, -C(0)0-CH ₂ - CH ₂ -CH ₂ -, C(0)0-CH ₂ -CH ₂ -0-, -C(0)N-CH ₂ -CH ₂ -, -C(0)N-CH ₂ -, -C(0)N-CH ₂ -CH ₂ -CH ₂ -, C(0)N- CH ₂ -CH ₂ -0-, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -; and B is ethyl, 4-methylenedioxyphenyl or phenyl, wherein said phenyl may optionally be substituted by one to three groups each independently selected from Ci_ ₄ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ alkyl. In another preferred embodiment the compound has the formula (IF) or (IJ), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-; V is 4-piperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, -C(0)0- CH ₂ -, oxadiazolyl-CH ₂ - or oxadiazolyl-CH ₂ -CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from 0-Ci_ ₃ alkyl, halogen, trihaloCi_ alkyl. These embodiments may have particular activity as inhibitors of Plasmodium vivax (Pv) N-myristoyl transferase.

In a preferred embodiment, the compound has the formula (IJ), (IK), (IL), (IE), (IF) or, (III), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-, -S- or - OCH ₂ -; V is 4-piperidyl or 3- azetidyl; Q is -C(0)0-CH ₂ -CH ₂ -, -C(0)0-CH ₂ -, -C(0)0-CH ₂ -CH ₂ - CH ₂ -, -CH ₂ -0-CH ₂ , -CH ₂ -0-, -CH ₂ -0-C(0)-, CH ₂ -C(0)0-, -C(0)N-CH ₂ -, oxadiazolyl-CH ₂ -, oxadiazolyl-CH ₂ -CH ₂ -; and B is ethyl, naphthyl or phenyl, wherein said phenyl may optionally be substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi- alkyl. In another preferred embodiment, the compound has the formula (IJ), (IK), (IF) or, (III), wherein p is 0 or 1, and R ⁴ where present is Ci_ ₂ alkyl, trihalomethyl, halogen and OCi_ ₂ alkyl; X is -0-; V is 4-piperidyl; Q is -C(0)0-CH ₂ -CH ₂ -, -C(0)0-CH ₂ -, oxadiazolyl-CH ₂ - or oxadiazolyl-CH ₂ - CH ₂ -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ ₄ alkyl, 0-Ci_ ₃ alkyl, halogen, trihaloCi_ ₄ alkyl. These embodiments may have particular activity as inhibitors of Leishmania donovani (Ld) N-myristoyl transferase.

3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester and 3-methyl-4-(piperidin-3- ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester are disclosed as synthetic intermediates in WO00/37464. It has now been found that such compounds have activity as inhibitors of

parasitic/protozoan NMT. Accordingly, those compounds find use as a medicament, particularly in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and in particular those diseases or disorders which are a protozoan infection.

Accordingly, the invention also provides a method for the treatment or prophylaxis of a disease or disorder in a subject in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection, which comprises administering to the mammal a therapeutically effective amount of a compound according to the invention.

The invention also provides the use of a compound according to the invention, for the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection.

Preferably, the disease or disorder is a protozoan infection caused by a species of Plasmodium, Leishmania or Trypanosoma (for example Plasmodium falciparum, Plasmodium, vivax, Leishmania donovani, Trypanosoma brucei).

Diseases or disorders in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect include malaria, leishmaniasis and sleeping sickness (also known as human African trypanosomiasis).

Depending upon the substituents present in compounds of the invention, the compounds may form esters, amides, carbamates and/or salts. Salts of compounds of the invention which are suitable for use in medicine are those wherein a counter-ion is pharmaceutically acceptable. However, salts having non-pharmaceutically acceptable counter-ions are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable salts, and physiologically functional derivatives. By the term "physiologically functional derivative" is meant a chemical derivative of a compound of the invention having the same physiological function as the free compound of the invention, for example, by being convertible in the body thereto. Esters, amides and carbamates are examples of physiologically functional derivatives.

Suitable salts according to the invention include those formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C ₁ -C ₄ )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethane sulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts.

Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed.

Compounds of the invention may have an appropriate group converted to an ester, an amide or a carbamate. Thus typical ester and amide groups formed from an acid group in the compound of the formula I include -C(0)OC ₁ _ ₆ alkyl, -C(0)N(C ₁ _ ₆ alkyl) ₂ , -S(0) ₂ OC ₁ _ ₆ alkyl, or ) ₂ , while typical ester and amide and carbamate groups formed from a hydroxyl or amine group in the compound of the formula I include -OC(0)Ci_ ₆ alkyl, -NHC(0)Ci_ ₆ alkyl, -NHC(0)OCi_ ₆ alkyl - OS(0) ₂ C ₁ _ ₆ alkyl, and -NHS(0) ₂ C ₁ _ ₆ alkyl.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates, such as hydrates, exist when the drug substance incorporates solvent, such as water, in the crystal lattice in either stoichiometric or non-stoichiometric amounts. Drug substances are routinely screened for the existence of hydrates since these may be encountered at any stage of the drug manufacturing process or upon storage of the drug substance or dosage form. Solvates are described in S. Byrn et al , Pharmaceutical Research, 1995. 12(7): p. 954-954, and Water-Insoluble Drug Formulation, 2 ^nd ed. R. Liu, CRC Press, page 553, which are incorporated herein by reference. Accordingly, it will be understood by the skilled person that the compounds of the invention, as well as esters, amides, carbamates and/or salts thereof may therefore be present in the form of solvates. Solvates of compounds of the invention which are suitable for use in medicine are those wherein the associated solvent is pharmaceutically acceptable. For example, a hydrate is an example of a pharmaceutically acceptable solvate. However, solvates having non-pharmaceutically acceptable associated solvents may find use as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable esters, amides, carbamates and/or salts thereof.

A compound which, upon administration to the recipient, is capable of being converted into a compound of the invention as described above, or an active metabolite or residue thereof, is known as a "prodrug". A prodrug may, for example, be converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

The amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated, as well as its severity. An ordinarily skilled phy sician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day, for adult humans. For oral administration, the compositions are preferably provided in the fonn of tablets or other forms of presentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion . Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

While it is possible for the active ingredient to be administered alone, it is preferable for it to be present in a pharmaceutical formulation or composition . Accordingly, the invention provides a pharmaceutical formulation or composition comprising a compound according to the invention, and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier" materials). Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below.

The pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols), nebulizers or insufflators, rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the ait of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid earners or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory- ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomal!}'.

Exemplar compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the ait. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate,

carboxymethylcellulose, polyethylene glycol, waxes and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like. The compounds of formula (I) can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplars forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. For oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.

The compounds of the present invention can also be administered in the form of liposome deliver}' systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanol amine (cephaline) , or phosphatidylcholine (lecithin).

Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

Exemplary compositions for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.

Formulations for rectal administration may be presented as a suppositor with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

Formulations for topical administration in the mouth, for example buccal!} or sublingual!} . include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia. Exemplaiy compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene). Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

Whilst a compound of the invention may be used as the sole active ingredient in a medicament, it is also possible for the compound to be used in combination with one or more further active agents. Accordingly there is provided a compound of the invention, together with a further active ingredient for simulataneous, sequential or separate administration.

Such further active agents may be further compounds according to the invention, or they may be different therapeutic agents, for example agents useful for treatment of malaria, leishmaniasis, sleeping sickness, anti-fungal agents, anti-viral agents (including anti-HIV agents), chemotherapeutic agents, antidepressants, anxiolytic, anti-psychotic, osteoporosis, ischemia and/or diabetes,or other pharmaceutically active material.

In one preferred embodiment, the compounds of the invention may be effectively administered in combination with an effective amount of an anti-protozoan/anti -parasitic agent. One or more anti- protozoan parasite agents may be used in combination with a compound of the invention.

The compounds of the present invention can be used in combination with other agents useful for the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect. The individual components of such combinations can be adm inistered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly. It will be understood that the scope of combinations of the compounds of this invention with other agents useful for treating or prophylaxis of a disease or disorder in which inhibition of N- myristoyl transferase provides a therapeutic or prophylactic effect includes in principle any combination w ith any pharmaceutical composition useful for treating or prophylaxis of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect. The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians' Desk Reference ( PDR) or as otherwise determined by one of ordinary skill in the art.

Where the compounds of the invention are utilized in combination with one or more other therapeutic agent(s), either concurrently or sequentially, the following combination ratios and dosage ranges are preferred:

When combined with a second of further therapeutic agent, the compounds of formula (I) may be employed in a weight ratio to the additional agent within the range from about 10: 1 to about 1 : 10.

The compounds of the invention as described above also find use, optionally in labelled form, as a diagnostic agent for the diagnosis of a disease or disorder in which inhibition of NMT provides a therapeutic or prophylactic effect. For example, such a compound may be radioactively labelled.

The compounds of the invention as described above, optionally in labelled form, also find use as a reference compound in methods of discovering other inhibitors of NMT. Thus, the invention provides a method of discovering a inhibitor of NMT which comprises use of a compound of the invention or a compound of the invention in labelled form, as a reference compound. For example, such a method may involve a competitive binding experiment in which binding of a compound of the invention to the NMT enzyme is reduced by the presence of a further compound which has NMT-binding characteristics, for example stronger NMT-binding characteristics than the compound of the invention in question.

Numerous synthetic routes to the compounds of the present invention can be devised by any person skilled in the art and the exemplified synthetic routes described below do not limit the invention. Many methods exist in the literature for the synthesis of nitrogen -containing heterocycles, for example: Heterocyclic Chemistry, Joule, J. A.; Mills, K. 2000. A number of possible synthetic routes are exemplified below. Where appropriate, any initially produced compound according to the invention can be converted into another compound according to the invention by known methods.

Compounds of the invention include, but are not limited to, the compounds specifically named in the Examples herein.

Examples General Experimental Details

Unless stated otherwise, all reagents/solvents were purchased from commercial sources (Sigma- Aldrich, VWR and Fisher) and used without further purification.

LC-MS

Compounds were purified and analysed on an LC-MS system equipped with both an XBridge prep C18 5 μιη, 19 ^χ 100 mm OBD column and an XBridge C18 5 μιη, 4.6 ^χ 100 mm column. Unless specified otherwise, all compounds were separated over a gradient of methanol in water (5-98% over 12 minutes then 98% methanol for 3 minutes), both containing 0.1% formic acid.

HPLC

Compounds were purified on a prep-HPLC system equipped with a Hichrom ACE 5 CI 8

250 x 21.2 mm semi-preparative column. Unless specified otherwise, all compounds were separated over a gradient of methanol in water (50-98% over 25 minutes then 98% methanol for 5 minutes), both containing 0.1% formic acid.

Flash Column Chromatography

Compounds were purified using an automated system using pre-packed silica cartridges and a gradient of ethyl acetate in «-hexane (typically 5-30% over 20 minutes) with UV detection.

General Procedures

Mitsunobu Reaction (Method A)

Under nitrogen, aromatic alcohol (1.0 eq.), aliphatic alcohol (1.5 eq.) and triphenyl phosphine (PPh ₃ , 2.0 eq.) were dissolved in dry tetrahydrofuran (THF, 10 mL mmoi ^-1 ). A solution of diisopropyl azodicarboxylate (DIAD, 2.0 eq.) in dry THF (2.5 mL mrnol ^-1 ) was added and the reaction mixture stirred for 18 hours at room temperature. All volatiles were removed under reduced pressure and the crude product purified by flash column chromatography.

Mitsunobu Reaction (Method B)

Under nitrogen, aromatic alcohol (1.0 eq.), aliphatic alcohol (1.0 eq.) and triphenyl phosphine (PPh ₃ , 1.3 eq.) were dissolved in dry tetrahydrofuran (THF, 8 mL mrnol ^-1 ). A solution of diisopropyl azodicarboxylate (DIAD, 1.3 eq.) in dry THF (1.5 mL mmol ^-1 ) was added and the reaction mixture stirred for 18 hours at room temperature. All volatiles were removed under reduced pressure and the crude product purified by flash column chromatography.

Mitsunobu Reaction (Method C) Under nitrogen, aromatic alcohol ( 1.0 eq.), aliphatic alcohol (2.5 eq.) and triphenyl phosphine (PPh ₃ , 2.5 eq.) were dissolved in dry tetrahydrofuran (THF, 3 mL mmoi ^-1 ). A solution of diisopropyl azodicarboxylate (DIAD, 2.5 eq.) in dry THF (3 mL mrnol ^-1 ) at 0 °C was added and the reaction mixture was gradually warmed to room temperature for 4 hours. All volatiles were removed under reduced pressure and the crude product purified by flash column chromatography.

Esterification (DCC method)

To a stirring solution of carboxylic acid ( 1.1 eq.) in dry DCM (10 mL mrnol ^-1 ) was added a solution of dicyclohexyl carbodiimide (DCC, 1.0 eq.) in dry DCM ( 1.5 mL mmoi ^-1 ) and the mixture stirred for 10 min. During this time a second vessel was charged with a solution of N,N-dimethylaminopyridine (DMAP, 10 mol%) in dry DCM (25 mL mmol ^-1 ) to which was added alcohol (1.1 eq.) and the reaction mixture allowed to stand for 10 min. After this time the alcohol-DMAP mixture was added to the activated acid-DCC mixture and the reaction allowed to stir at room temperature for 18 hours. During this time a white precipitate was observed (dicyclohexyl urea, DCU) which was removed by filtration. The DCM solution was washed with water (2 x 2 mL), acetic acid _(aq.) (5%, 2 x 2 mL) and water again (2 x 2 mL), before drying the DCM layer over MgS0 ₄ . After filtration all volatiles were removed by exposure to a stream of nitrogen gas. The product was isolated by flash column chromatography .

Esterification (EDC method)

To a stirring solution of carboxylic acid ( 1.1 eq.) in dry acetonitrile (10 mL mmol ^-1 ) was added 3- (ethyliminomethylene amino)-N,N-dimethyl-propan-l -amine (EDC, 1.1 eq.) and

hydroxybenzotriazole (HOBt, 1.3 eq.) and the mixture stirred for 30 min. After that, the mixture was treated with N,N-Diisopropylethylamine (DIPEA, 2.0 eq.) and alcohol (1.1 eq.). The resulting mixture was further stirred at room temperature for another 12 hours. After that, the solution was evaporated to dryness in vacuo. The residue was re-dissolved in ethyl acetate (20 mL mmol ^-1 ) and washed with 5% NaHC0 ₃ , water and brine (each 20 mL mmol ^-1 ). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The product was isolated by flash column

chromatography .

Amide Formation

To a stirring solution of carboxylic acid ( 1.0 eq.) in DCM (20 mL mmol ^-1 ) was added N,N- diisopropylethylamine (1.1 eq.) followed by benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 1.1 eq.). After 30 min stirring at room temperature amine (1.1 eq.) was added and the reaction mixture left stirring for 18 hours. The reaction mixture was diluted with water and extracted with DCM (3 ^χ ) and the combined organic layers dried over MgS0 ₄ . After filtration all volatiles were removed under reduced pressure and the crude produce purified by flash column chromatography .

LiAlH ₄ Reduction

To a stirring solution of ester (1.0 eq.) in anhydrous THF (4 mL mmol ^-1 ) at 0 °C was added L1AIH ₄ (1.5 eq.). The resulting mixture was gradually warmed up to room temperature for 2 hours. Water (10 eq.) was then added to the reaction mixture, followed by the filtration through a celite pad. The filtrate was concentrated in vacuo, to give the desired alcohol without further purification.

Reductive Amination

To a stirring solution of aldehyde/ketone (1.0 eq.) in anhydrous THF (4 mL mmol ^-1 ) was added amine (1.1 eq.) and acetic acid (6.0 eq.) and the mixture was stirred at room temperature for 2 hours. After that, the resulting mixture was added sodium triacetoxyborohydride (5.0 eq.) and further stirred for 12 hours. Then the reaction mixture was diluted with ethyl acetate (20 mL mmol ^-1 ) and sequentially washed with 5% NaHC0 ₃ , water and brine (each 15 mL mmol ^-1 ). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The product was isolated by either flash column chromatography or semi-preparative HPLC.

Amidoxime Formation

To a solution of nitrile (1 eq.) in EtOH (12 mL mmol ^-1 ) was added hydroxylamine (50% v/v in H ₂ 0, 4 mL mmol ^-1 ) and the reaction mixture heated under reflux for 5 hours. After removal of all volatiles under reduced pressure the crude produce was used without further purification.

1,2, 4-Oxadiazole Formation (Method A)

Carboxylic acid (1 eq.), 1-hydroxybenzotriazole (1 eq.) and 3-(ethyliminomethylene amino)-N,N- dimethyl-propan-1 -amine (EDC, 1 eq.) were taken up in DMF (25 mL mmol ^-1 ) and stirred at room temperature for 30 min. To the activated acid was added amidoxime (1 eq.) and the reaction mixture transferred to an oil bath and heated under reflux for 18 hours. All volatiles were removed under reduced pressure and the resultant residues partitioned between EtOAc and water. The organic phase was washed with 0.5 M HCl _(aq.) , saturated aqueous NaHC0 ₃ and brine before drying over MgS0 ₄ . After removal of all volatiles under reduced pressure the product was isolated by flash column chromatography .

1,2, 4-Oxadiazole Formation (Method B)

Carboxylic acid (1 eq.), 1-hydroxybenzotriazole (1 eq.) and 3-(ethyliminomethylene amino)-N,N- dimethyl-propan-1 -amine (EDC, 1 eq.) were taken up in anhydrous acetonitrile (20 mL mmol ^-1 ) and stirred at room temperature for 30 min, followed by the addition of amidoxime (1 eq.) and DIPEA (2.0 eq.). The resulting mixture was further stirred at room temperature for 12 hours. After that, the solution was evaporated to dryness in vacuo. The residue was re-dissolved in ethyl acetate (20 mL mmol ^-1 ) and washed with brine, 5% NaHC0 ₃ and water (each 20 mL mmol ^-1 ). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was then dissolved in dry toluene over 4 A molecular sieve and the resulting mixture was stirred at 110 °C for 4 hours. After that, the reaction mixture was filtered off and the filtration was concentrated in vacuo, to give the 1,2,4-oxadiazole without further purification.

Boc Deprotection

The Boc-protected product was taken up in a solution of trifluoroacetic acid (TFA, 5%) in DCM (30 mL mmol ^-1 ). After stirring at room temperature for 2 hours all volatiles were removed by exposure to a stream of nitrogen gas. The crude product was purified by LC-MS or HPLC.

Trityl Deprotection

The trityl-protected product was taken up in a solution of trifluoroacetic acid (TFA, 0.1%) and water (0.2%) in DCM (10 mL mmol ^-1 ). After stirring at room temperature for 2 hours all volatiles were removed by exposure to a stream of nitrogen gas. The crude product was purified by semi-preparative HPLC, with no formic acid in the mobile phases.

Ester Hydrolysis

To a solution of the ester (1.0 eq.) in methanol (1.4 mL mmol ^"1 ) was added hydrazine monohydrate (1.5 eq.) and the reaction stirred at room temperature for 3 h. Reaction mixture was concentrated under reduced pressure, yielding carboxylic acid without further purification.

Mixed Hydrazide Formation A

To a solution of mono-acylated hydrazide (such as Intermediate 28) (1.0 eq.) and

N,N-diisopropylethylamine (1.2 eq.) in dichloromethane (9 mL mmol ^"1 ) was added acid chloride (e.g. phenylacetyl chloride, 1.2 eq.) and the reaction mixture was stirred at room temperature for 15 mins. The reaction mixture was then diluted with a further dichloromethane (27 mL mmol ^"1 ), washed with water (36 mL mmol ^"1 ) and brine (36 mL mmol ^"1 ), dried over magnesium sulfate and concentrated under reduced pressure yielding desired mixed hydrazide without further purification.

Mixed Hydrazide Formation B

To a solution of mono-acylated hydrazide (such as Intermediate 28, 1.0 eq.) in tetrahydrofuran:N,N- dimethylformamide (4: 1 v/v, 5 mL mmol ^"1 ) was added hydroxybenzotriazole (0.5 eq.), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (1.3 eq.) and carboxylic acid (e.g. 2-hydroxy-2- phenylacetic acid, 1.3 eq.). Reaction mixture stirred at room temperature for 18 h, then diluted with 1.0 M NaOH(aq) (33 mL mmol ^"1 ) and mixed hydrazide was extracted with EtOAc (2 x 42 mL mmol ^l ). Combined organic layers were washed with brine (42 mL mmol ^"1 ), dried over sodium sulfate and concentrated under reduced pressure yielding desired mixed hydrazide without further purification.

1, 3, 4-Oxadiazole Formation

To a solution of mixed hydrazide (1.0 eq.) and 1,2,2,6,6-pentamethylpiperidine (2.1 eq.) in dichloromethane (6 mL mmol ^"1 ) was added ra-toluenesulfonyl chloride (1.05 eq.) and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then purified by flash column chromatography and concentrated under reduced pressure yielding desired 1,3,4-oxadiazole.

Intermediate 1: 4-({l-[(teri-Butoxy)carbonyl]piperidin-4-yl}oxy)-3-methyl-l- benzofuran-2- carboxylic acid

A solution of 2,6-dihydroxyacetophenone (5 g, 32.9 mmol) in 60 mL of acetone was added potassium carbonate (11.3 g, 82 mmol) and ethyl bromoacetate (3.82 mL, 34.5 mmol). The reaction mixture was stirred at 60 °C for 2 hours. The solid was filtered off and the filtrate was concentrated to obtain ethyl

2- (2-acetyl-3-hydroxyphenoxy) acetate as a light-yellow solid (6.95 g, yield: 89%).

To a sodium ethoxide solution, prepared by dissolving sodium (225 mg, 9.8 mmol) in 20 mL anhydrous ethanol under a nitrogen atmosphere and cooled down to around -18 °C, ethyl 2-(2-acetyl-

3- hydroxyphenoxy)acetate (1.55 g, 6.5 mmol) was added. The solution was stirred for 18 hours while the temperature was slowly warmed to room temperature. The mixture was quenched by 20 mL water and extracted by 20 mL EtOAc immediately. The aqueous layer was further extracted by 2 χ 15 mL EtOAc. The above organic layers were combined and dried over sodium sulphate, concentrated and purified by column chromatography on silica gel, to give ethyl 4-hydroxy-3-methylbenzofuran-2- carboxylate as a light-yellow solid (670 mg, yield: 46%).

According to the general Mitsunobu reaction procedure (Method C), prepared from ethyl 4-hydroxy- 3-methylbenzofuran-2-carboxylate (2 g, 9.1 mmol) and /-Butyl 4-hydroxypiperidine-l-carboxylate (4.56 g, 22.7 mmol), /-Butyl 4-{[2-(ethoxycarbonyl)-3-methyl-l-benzofuran-4-yl]oxy} piperidine-1- carboxylate was obtained as colourless oil (3.52 g, yield: 96%).

To a solution of /-Butyl 4-{[2-(ethoxycarbonyl)-3-methyl-l-benzofuran-4-yl]oxy} piperidine-1- carboxylate (1.85 g, 4.6 mmol) in THF-MeOH (40 mL, 1 : 1) was added LiOH H ₂ 0 (1.16 g, 27.5 mmol). The reaction mixture was stirred for 24 hr at room temperature. Volatile components were evaporated in vacuo to give the residue which was dissolved in H ₂ 0 (30 mL), followed by the addition of 3 mL concentrated HCl while stirring. Precipitation occurred in the resulting solution and title compound was collected as a white solid (1.51 g, yield: 88%). Vppm (400 MHz, CD ₃ OD): 7.40 (1H), 7.12 (1H), 6.65 (1H), 4.74-4.69 (1H), 3.69-3.62 (2H), 3.56-3.50 (2H), 2.76 (3H), 2.06-1.99 (2H), 1.94-1.86 (2H), 1.50 (9H).

Intermediate 2: i-Butyl 4-[(2-formyl-3 an-4-yl)oxy]piperidine-l-carboxylate

According to general LiAlH ₄ reduction procedure, prepared from /-Butyl 4-{[2-(ethoxycarbonyl)-3- methyl-l-benzofuran-4-yl]oxy} piperidine-l-carboxylate (1.81 g, 4.5 mmol) (as prepared in step 3 of Intermediate 1 protocol), /-butyl 4-((2-(hydroxymethyl)-3-methylbenzofuran-4-yl)oxy)piperidine -l- carboxylate was obtained as a light-yellow solid without further purification (1.10 g, 68% yield). To a solution of /-butyl 4-((2-(hydroxymethyl)-3-methylbenzofuran-4-yl)oxy)piperidine -l- carboxylate (50 mg, 0.13 mmol) in anhydrous DCM was added activated manganese dioxide (560 mg, 6.5 mmol) at room temperature, and the resulting mixture was stirred at the same temperature for 24 hours. After that, the reaction mixture was filtered over a celite pad and the filtrate was concentrated in vacuo, to afford the title compound as yellow oil (37 mg, yield: 77%). <Vpprn (400 MHz, CD ₃ OD): 9.96 (1H), 7.38 (1H), 7.11 (1H), 6.66 (1H), 4.74-4.69 (1H), 3.69-3.62 (2H), 3.56-3.50 (2H), 2.76 (3H), 2.06-1.99 (2H), 1.94-1.86 (2H), 1.50 (9H).

Intermediate 3a: l-(triphenylmethyl)

4-Hydroxypiperidine (0.30 g, 3.0 mmol) and triphenylmethyl chloride (0.84 g, 3.0 mmol) were dissolved in dichloromethane (5 mL). Triethylamine (0.84 mL, 6.0 mmol) was added dropwise and the resulting mixture was stirred for 24 hours at room temperature. After that, the reaction was diluted with CHC1 ₃ (20 mL) and partitioned with 5% NaHC0 ₃ solution (30 mL). The aqueous layer was then extracted with CHC1 ₃ (2 x 15 mL). The combined organic layers were washed with brine and dried over sodium sulphate, concentrated in vacuo, to give the title compound as a white solid (1.05 g, quantitative yield). ¾-NMR (CDC1 ₃ , 400 MHz): δ 7.49 (brs, 5H), 7.34-7.26 (m, 7H), 7.20-7.16 (m, 3H), 2.91 (brs, IH), 2.03-1.85 (m, 2H), 1.71-1.60 (m, 2H), 1.60-1.24 (m, 4H).

Intermediate 3b: (3-Methyl-4-{[l-(triphenylmethyl)piperidin-4-yl]oxy}-l-benzo furan-2-yl) methanol

According to general Mitsunobu reaction procedure (Method C), prepared from ethyl 4-hydroxy-3- methylbenzofuran-2-carboxylate (100 mg, 0.45 mmol) and l-(triphenylmethyl)piperidin-4-ol

(386 mg, 1.1 mmol) (Intermediate 3a), ethyl 3-methyl-4-{[l-(triphenylmethyl)piperidin-4-yl]oxy}-l- benzofuran-2-carboxylate was obtained as a white solid (160 mg, yield: 65%).

According to general LiAlH ₄ reduction procedure, prepared from ethyl 3-methyl-4-{[l-

(triphenylmethyl)piperidin-4-yl]oxy}-l-benzofuran-2-carbo xylate (160 mg, 0.29 mmol), the title compound was obtained as colourless oil without further purification (150 mg, quantitative yield).

Vppm (400 MHz, CD ₃ OD): 7.68-7.41 (5H), 7.38-7.30 (6H), 7.25-7.14 (4H), 7.10 (IH), 6.98 (IH), 6.54 (IH), 4.70 (2H), 4.06-3.94 (IH), 2.24-2.11 (2H), 2.12-1.97 (4H), 1.91-1.83 (2H).

Intermediate 4: Ethyl-2-(2-ethoxy-2-oxoethoxy)benzoate

To a solution of ethyl-2-hydroxybenzoate (884 μί, 6.02 mmol) in acetone (11 mL) was added potassium carbonate (2.50 g, 18.1 mmol) and ethyl bromoacetate (667 μί, 6.02 mmol). The reaction mixture was stirred at 60 °C for 3 h. The white solid was removed by filtration and the filtrate concentrated under reduced pressure, yielding the desired product as an orange oil (1.46 g, yield:

96%). Vppm (400 MHz, CDC1 ₃ ) 7.83 (IH), 7.45 (IH), 7.06 (IH), 6.90 (IH), 4.71 (2H), 4.38 (2H), 4.28 (2H), 1.40 (3H), 1.30 (3H).

Intermediate 5: Ethyl-3-hydroxybenzofuran-2-carboxylate

To a suspension of potassium fert-butoxide (1.80 g, 16.0 mmol) in tetrahydrofuran (60 mL) was added starting material (2.02 g, 8.01 mmol) in tetrahydrofuran (40 mL) slowly over 2 min. The reaction mixture was stirred at room temperature for 15 min, then quenched with saturated aqueous ammonium chloride solution (100 mL). The product was immediately extracted with 3 ^χ 100 mL portions of ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give desired product as a yellow solid (1.56 g, 94%). <Vppm (400 MHz, CDC1 ₃ ) 8.15 ( IH), 7.75 (IH), 7.49 (2H), 7.31 (IH), 4.50 (2H), 1.47 (3H).

Intermediate 6: Ethyl-3-hydroxybenzo[6]thiophene-2-carboxylate

To a solution of methyl-2-mercaptobenzoate (1.63 mL, 1 1.9 mmol) and ethyl bromoacetate (1.32 mL, 1 1.9 mmol) in dry tetrahydrofuran (130 mL) at 0 °C was added potassium fert-butoxide (5.14 g, 71.3 mmol) gradually over 2 min. The reaction mixture was stirred and allowed to warm to room temperature over 15 min, quenched with 2 M hydrochloric acid to pH 2 and diluted with 75 mL water. The product was immediately extracted with 3 ^χ 75 mL portions of ethyl acetate. The organic layers were combined, washed with 75 mL brine, dried over magnesium sulfate and concentrated under reduced pressure to give desired product as a yellow solid (2.32 g, 88%). <Vppm (400 MHz, CDC1 ₃ ) 10.21 (IH, s), 7.94 (IH), 7.74 (IH), 7.50 (IH), 7.41 (IH), 4.43 (2H), 1.43 (3H).

Intermediate 7: 3-((l-(teri-Butoxycarbonyl)piperidin-4-yl)oxy)benzo[6]thioph ene-2-carboxylic acid

Starting from Intermediate 6, according to the preparation of Intermediate 1, the title compound was obtained as an off-white solid. Vppm (400 MHz, CDC1 ₃ ) 7.87 ( IH), 7.81 (IH), 7.53 (IH), 7.44 (IH), 4.82-4.73 (IH), 4.06-3.93 (2H), 3.15-3.03 (2H), 2.1 1-2.00 (2H), 1.94-1.80 (2H), 1.49 (9H). Intermediate 8: 3-Methoxybenzyl-2-bromoacetate

To a solution of (3-methoxyphenyl)methanol (900 μΐ _^ , 7.24 mmol) and 2-bromoacetic acid ( 1.00 g,

7.20 mmol) in dichloromethane (30 mL) was added N,N'-dicyclohexylcarbodiimide (1.48 g,

7.19 mmol) and 4-dimethylaminopyridine (88 mg, 0.72 mmol) and reaction mixture stirred for 18 h at room temperature. Reaction mixture filtered through celite and washed with ethyl acetate (5 ^χ

20 mL), yielding the product as a yellow oil (1.80 g, yield: 97%) which was used without further purification. Vppm (400 MHz, CDC1 ₃ ) 7.30 (IH), 6.99-6.87 (3H), 5.19 (2H), 3.89 (2H), 3.83 (3H).

Intermediate 9: 3-Methoxyben -carboxylate

was prepared as in Intermediate 6 replacing ethyl bromoacetate with Intermediate 8 (1.80 g, 6.98 mmol) and purified by flash chromatography yielding the product as a yellow oil (1.1 1 g, yield: 51%). Vppm (400 MHz, CDC1 ₃ ) 10.12 ( IH), 7.95 (IH), 7.74 (IH), 7.52 ( IH), 7.42 (IH), 7.33 (IH), 7.04 (IH), 7.01-6.99 ( IH), 6.90 (IH), 5.39 (2H), 3.84 (3H).

Intermediate 10: l-teri-Butyl-3-met oxylate

To a solution of l-(fert-butoxycarbonyl)azetidine-3-carboxylic acid (200 mg, 0.99 mmol) in dichloromethane (2 mL) was added N,N'-dicyclohexylcarbodiimide (246 mg, 1.19 mmol), 4- dimethylaminopyridine (12 mg, 0.12 mmol) and methanol (50 μί, 1.23 mmol) and reaction mixture was stirred at room temperature for 18 h. Urea by-product was removed by filtration then filtrate was concentrated under reduced pressure, yielding the product as a colourless oil (170 mg, yield: 80%). Vppm (400 MHz, CDC1 ₃ ) 4.10 (4H), 3.75 (3H), 3.35 (IH), 1.44 (9H).

Intermediate 11 : teri-Butyl-3-(hydroxymethyl)azetidine-l-carboxylate

To a suspension of lithium aluminium hydride (35 mg, 0.91 mmol) in anhydrous tetrahydrofuran cooled to 0 °C was added Intermediate 10 (130 mg, 0.60 mmol) and reaction mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. Reaction was then quenched with water (100 mL) and 4 M sodium hydroxide solution (25 mL). The slurry formed was filtered through celite and the product extracted with ethyl acetate (3 ^χ 100 mL). Combined organic layers were washed with brine

(100 mL), dried over magnesium sulphate and concentrated under reduced pressure, yielding the product as a white solid (1 10 mg, yield: 97%). Vppm (400 MHz, CDC1 ₃ ) 3.92 (2H), 3.71-3.60 (4H), 2.70-2.59 (IH), 1.38 (9H).

Intermediate 12: teri-Butyl-4-((2-(m n-3-yl)oxy)piperidine-l-carboxylate

Prepared following the general procedure for Mitsunobu reaction: method A, replacing the aromatic alcohol with methyl-3-hydroxythiophene-2-carboxylate (500 mg, 3.16 mmol). Purification by flash column chromatography to furnish the product as a pale yellow oil (1.02 g, yield: 94%). <Vppm (400 MHz, CDC1 ₃ ) 7.41 (IH), 6.83 (IH), 4.59-4.52 (IH), 3.85 (3H), 3.69-3.60 (2H), 3.54-3.44 (2H), 1.92-1.83 (4H), 1.47 (9H).

Intermediate 13: 3-((l-(teri-Butoxyca l)oxy)thiophene-2-carboxylic acid

To a solution of Intermediate 12 (500 mg, 1.46 mmol) in methanol :tetrahydrofuran 1 : 1 (10 mL) was added lithium hydroxide monohydrate (369 mg, 8.79 mmol) and reaction mixture stirred at room temperature for 40 h. Reaction mixture was concentrated under reduced pressure, diluted with water (10 mL) then acidifed to pH 2 with 2 M hydrochloric acid. Precipiate collected by filtration and washed with 5 x 3 mL water, then dried overnight in a vacuum desiccator yielding theproduct as an off-white solid (430 mg, yield: 90%). Vppm (400 MHz, MeOD) 7.64 (1H), 7.06 (1H), 4.74-4.66 (1H), 3.77-3.63 (2H), 3.53-3.41 (2H), 1.98-1.87 (2H), 1.86-1.76 (2H), 1.50 (9H).

Intermediate 14: 2-(3,5-Dimethoxyphenyl)ethanol

To a solution of 2-(3,5-dimethoxyphenyl)acetic acid (300 mg, 1.53 mmol) in anhydrous

tetrahydrofuran (12 mL) cooled to 0 °C was added 1.0 M lithium aluminium hydride solution in tetrahydroiuran (3.1 mL, 3.1 mmol). The reaction mixture was allowed to warm to room temperature over 15 min whilst stirring under a nitrogen atmosphere, then reaction mixture was heated to reflux for a further 90 min. The reaction mixture was allowed to cool to room temperature, quenched with water (15 mL) and filtered through celite. The combined solid was washed with ethyl acetate (3 ^χ 20 mL), saturated ammonium chloride solution (50 mL) and the product was extracted using additional ethyl acetate (50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure, yielding the product as a yellow oil (245 mg, yield: 88%). Vppm (400 MHz, CDC1 ₃ ) 6.42 (2H), 6.38 (1H), 3.89 (2H), 3.82 (6H), 2.84

(2H).

Intermediate 15: c s-4-((teri-Butoxyca hexyl 4-nitrobenzoate

To a solution of fr «5-teri-butyl-(4-hydroxycyclohexyl)carbamate (250 mg, 1.16 mmol) in anhydrous tetrahydrofuran (4 mL) was added triphenylphosphine (761 mg, 2.90 mmol) and 4-nitrobenzoic acid (485 mg, 2.90 mmol). The reaction mixture was stirred at room temperature under nitrogen for 15 min, and then diisopropyl azodicarboxylate (580 μί, 2.90 mmol) in tetrahydrofuran (1 mL) was added dropwise over 2 min. The reaction mixture was stirred at room temperature for 18 h, then concentrated under vacuum and crude product purified by flash chromatography to give the product as a yellow solid (255 mg, yield: 60%). Vppm (400 MHz, CDC1 ₃ ) 8.35-8.29 (2H), 8.26-8.19 (2H), 5.29-5.22 (1H), 4.64-4.51 (1H), 3.70-3.56 (1H), 2.07-1.98 (2H), 1.98-1.88 (2H), 1.86-1.75 (2H), 1.67-1.60 (2H), 1.51-1.44 (9H). Intermediate 16: cis-tertS ty\ (4-hydroxycyclohexyl)carbamate

To a solution of Intermediate 15 (150 mg, 0.41 mmol) in tetrahydrofuran (7.5 mL) was added 2 M sodium hydroxide solution (3 mL) and reaction mixture stirred at 85 °C for 18 h. Reaction mixture was then diluted with water (7.5 mL) and the product was extracted with ethyl acetate (3 ^χ 10 mL). The combined organic layers were washed with brine (7 mL), dried over magnesium sulphate and concentrated under reduced pressure, yielding the product as a yellow solid (50 mg, yield: 56%). Vppm (400 MHz, CDC1 ₃ ) 4.59-4.46 (IH), 3.94-3.87 (IH), 3.61-3.49 (IH), 1.74-1.59 (8H), 1.46 (9H).

Intermediate 17: Methyl 3-((teri-butyl benzoate

To a solution of methyl 3-hydroxybenzoate (114 mg, 0.75 mmol) in N,N-dimethylformamide (1 mL) was added imidazole (82 mg, 1.2 mmol) and fert-butyldimethylsilyl chloride (158 mg, 1.05 mmol) and reaction mixture stirred at room temperature for 4 h. Reaction mixture was then diluted with water (10 mL) and the product was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulphate and concentrated under reduced pressure, yielding the product as a colourless oil (185 mg, yield: 93%). <Vpprn (400 MHz, CDC1 ₃ ) 7.67-7.61 (IH), 7.52-7.48 (IH), 7.30 (IH), 7.04 (IH), 3.91 (3H), 1.00 (9H), 0.22 (6H).

Intermediate 18: (3-((teri-Butyldimethyl l)methanol

Lithium aluminium hydride (53 mg, 1.4 mmol) was added gradually to an ice-cooled solution of Intermediate 17 (185 mg, 0.65 mmol) in anhydrous tetrahydrofuran (1.5 mL) over 5 min. Reaction mixture stirred at 0°C for 10 min, warmed to room temperature over 10 min then stirred at room temperature for 2 h. Reaction mixture was then diluted with saturated ammonium chloride (1.2 mL) and resulting slurry was filtered through a plug of celite which was washed with ethyl acetate (6 ^χ 5 mL). The filtrate was washed with brine (10 mL), dried over magnesium sulphate and concentrated under reduced pressure, yielding the product as a yellow oil (50 mg, yield: 33%). <Vpprn (400 MHz, CDC1 ₃ ) 7.22 (1H), 6.95 (1H), 6.89-6.84 (1H), 6.77 (1H), 4.64 (2H), 1.00 (9H), 0.21 (6H).

Intermediate 19: tert-Butyi 4-((2-(((3-((teri-butyldimethylsilyl)oxy)benzyl)oxy)carbonyl ) benzo[6]thiophen-3-yl)oxy)piperid

Starting from Intermediate 7 (79 mg, 0.21 mmol) and Intermediate 18 (50 mg, 0.21 mmol), according to the EDC method, the title product was obtained as a yellow oil (24 mg, yield: 23%). 5 _H /ppm (400 MHz, CDC1 ₃ ) 7.89-7.83 (1H), 7.77-7.72 (1H), 7.52-7.45 (1H), 7.43-7.36 (1H), 7.28- 7.23 (1H), 7.06-7.02 (1H), 6.97-6.93 (1H), 6.86-6.80 (1H), 5.34-5.29 (2H), 4.73-4.66 (1H), 3.97- 3.84 (2H), 3.08-2.97 (2H), 1.98-1.88 (2H), 1.85-1.73 (2H), 1.51-1.46 (9H), 1.02-0.97 (9H), 0.24- 0.19 (6H).

Intermediate 20: tert-Butyi 4-(hydro e-l-carboxylate

To a stirring solution of 4-piperidinemethanol (5.0 g, 50 mmol) and triethylamine (21 mL, 150 mmol) in DCM (20 mL) cooled to 0 °C in an ice bath, was added boc anhydride (12 g, 55 mmol) portionwise. The reaction mixture was allowed to warm to room temperature and stir for 18 hours. All volatiles were removed under reduced pressure and the crude residues purified by flash column chromatography (R 0.31, 30% EtOAc in «-hexane) to give fert-butyl 4-(hydroxymethyl)piperidine-l- carboxylate as a white amorphous solid (9.51 g, yield: 95%). Vppm (400 MHz, CDC1 ₃ ): 4.15 (2H), 3.53 (2H), 2.73 (2H), 1.72 (2H), 1.49 (9H), 1.44 ( 1H), 1.17 (2H).

Intermediate 21: Benzyl 3-hydroxy benzoate 3 -Hydroxy benzoic acid (2.40 g, 17.4 mmol) was dissolved in DMF (17 mL). Potassium carbonate was added (2.89 g, 20.9 mmol) followed by benzyl bromide (2.1 mL, 17.4 mmol) and the reaction stirred at room temperature for 15 min after which time TLC analysis (10% ethyl acetate in «-hexane) revealed the complete consumption of starting material (R/0.00), a single major product (R/0.18) and excess benzyl bromide (R/0.80). The reaction mixture was diluted with ethyl acetate (100 mL) and the organic phase washed with 100 mL citric acid solution (1 M), then with NaHC0 ₃ (sat. aq), 2 x 100 mL and finally with brine (2 ^χ 100 mL). The organic phase was dried (Na ₂ S0 ₄ ) and the solvents removed under reduced pressure to afford a runny pale yellow oil. The crude was re- dissolved in DCM, preadsorbed on silica and purified using a 50G SNAP column to afford benzyl 3- hydroxy benzoate as a white solid (2.73 g, yield: 69%). Vppm (400 MHz, CDC1 ₃ ): 7.67-7.65 (1H), 7.56 (1H), 7.46-7.30 (6H), 7.06 (1H), 5.36 (2H), 5.21 (1H).

Intermediate 22: (2-Hydroxy-pheny -acetic acid benzyl ester

Prepared according to the method described for benzyl 3 -hydroxy benzoate. The product was isolated as a white solid (1.24 g, yield: 65%). Vppm (400 MHz, CDC1 ₃ ): 7.40-7.35 (5H), 7.32 (1H), 7.23- 7.19 (1H), 7.10 (1H), 6.96-6.87 (2H), 5.17 (2H), 3.73 (2H).

Intermediate 23: Benzyl 4-methyl salicylate

Prepared according to the method described for benzyl 3 -hydroxy benzoate, but starting from 2- hydroxy-4-methylbenzoic acid. The product was isolated as a runny colourless oil (1.05 g, yield: 54%). Vppm (400 MHz, CDC1 ₃ ): 10.71 (1H), 10.76 (1H), 7.46-7.28 (5H), 6.80 (1H), 6.70-6.67 (1H), 5.36 (2H), 2.36 (3H).

Intermediate 24: Benzyl 2-hydroxy-4-methoxybenzoate

Prepared according to the procedure for benzyl 3 -hydroxy benzoate but starting from 2-hydroxy-4- methoxybenzoic acid. The product was isolated as a clear colourless oil (1.24 g, yield: 60%). Vppm (400 MHz, CDC1 ₃ ): 11.01 (1H), 7.82 (1H), 7.43 (5H), 6.47 (2H), 5.39 (2H), 3.86 (3H). Intermediate 25: 2- [(4-A'-Boc-piperi

Methyl thiosalicylate (168 mg, 1.00 mmol) was dissolved in DMSO (1 mL) and 50% NaOH _(aq) (0.5 mL). l-Boc-4-bromopiperidine (264 mg, 1.00 mmol) was added and the mixture stirred at room temperature for 90 min after which time TLC analysis (ethyl acetate) revealed partial consumption of starting material (R/0.89) and a major product (R/0.41). The reaction mixture was diluted with ethyl acetate (30 mL) and the organic phase washed with 2 x 30 mL HC1 solution (2 M) then with brine (30 mL). The organic phase was dried (Na ₂ S0 ₄ ) and the solvents removed under reduced pressure to afford a runny pale yellow oil. The crude was re-dissolved in DCM and purified using a 24G GraceResolv column (using 1% AcOH in the column solvents) to afford 2-[(4- piperidinyl)thio] salicylic acid as a white solid (99 mg, yield: 29%). Vppm (400 MHz, CDC1 ₃ ): 8.12 (1H), 7.51-7.42 (2H), 7.34-7.26 (1H), 4.10-3.97 (2H), 3.39 (1H), 2.97 (2H), 2.04-1.99 (2H), 1.62 (2H), 1.44 (9H).

Intermediate 26: Benzyl 3-hydroxy- -methylbenzoate

Prepared according to the procedure for benzyl 3 -hydroxy benzoate but starting from 3-hydroxy-2- methylbenzoic acid. The product was isolated as a white solid (268 mg, yield: 63%). <Vpprn (400 MHz, CDC1 ₃ ): 7.42 (6H), 7.13 (1H), 6.97 (1H), 5.38 (2H), 5.13 (1H), 2.50 (3H).

Intermediate 27: 2-((l-(teri-Butoxyc oxy)benzoic acid

To a solution of fert-butyl 4-(2-((benzyloxy)carbonyl)phenoxy)piperidine-l-carboxylate (3.0 g, 7.3 mmol) (Intermediate 20) in methanol (30 mL) under a nitrogen atmosphere, was added 10% Pd/C (0.6 g). To this stirring mixture was added triethylsilane (11.6 mL, 72.9 mL) cautiously dropwise. By TLC the reaction was found to be complete by the end of the addition (-10 min), and the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to a clear colourless oil, which crystallised upon standing to a white waxy solid, 2-{{\-{tert- butoxycarbonyl)piperidin-4-yl)oxy)benzoic acid (2.34 g, >99%). Vppm (400 MHz, CDC1 ₃ ): 10.92 (IH), 8.24 (IH), 7.59 (IH), 7.18 (IH), 7.10 (IH), 4.79 (IH), 3.87 (2H), 3.30 (2H), 2.13 (2H), 1.88 (2H), 1.50 (9H); mlz = 406 ([M+H] ⁺ ).

Example 1 : 7V-benzyl-3-methyl-4 -2-carboxamide

According to the general amide formation procedure, prepared from Intermediate 1 (30 mg, 0.08 mmol) and benzylamine (9.6 μί, 0.088 mmol), N-Boc precursor was obtained.

The title compound was obtained via the Boc deprotection method as a white solid (12.5 mg, 33% overall yield). Vppm (400 MHz, CD ₃ OD): 7.40-7.32 (5H), 7.26 (IH), 7.14 (IH), 6.85 (IH), 4.92- 4.87 (IH), 4.58 (2H), 3.45-3.39 (2H), 3.32-3.28 (2H), 2.80 (3H), 2.34-2.24 (2H), 2.20-2.12 (2H). mlz (ESI), found 365.1875 (C ₂ 2H ₂₅ N ₂ 0 ₃ , [M+H] ⁺ , requires 365.1865).

Examples 2 to 4 were prepared in analogous fashion to Example 1.

Example 2: 3-Methyl-7V-(naphthalen-l-ylmethyl)-4-(piperidin-4-yloxy)-be nzofuran-2- carboxamide

White solid (49% overall yield). Vppm (400 MHz, CD ₃ OD): 8.18 (IH), 7.90 (IH), 7.82 (IH), 7.58- 7.44 (4H), 7.33 (IH), 7.10 (IH), 6.80 (IH), 5.05 (2H), 4.89-4.84 (IH), 3.43-3.37 (2H), 3.32-3.26 (2H), 2.80 (3H), 2.28-2.21 (2H), 2.18-2.10 (2H). mlz (ESI), found 415.2020 (C ₂ 6H27N ₂ 0 ₃ , [M+H] ⁺ , requires 415.2022).

Example 3: (3,4-Dihydroisoquinolin-2(lH)-yl)(3-methyl-4-(piperidin-4-yl oxy)-benzofuran-2- yl)methanone

White solid (44% overall yield). Vppm (400 MHz, CD ₃ OD): 7.37 (IH), 7.22 (4H), 7.17 (IH), 6.89 (IH), 4.97-4.92 (IH), 4.85 (2H), 4.00-3.80 (2H), 3.46-3.40 (2H), 3.33-3.28 (2H), 3.02 (2H), 2.61 (3H), 2.32-2.25 (2H), 2.21-2.13 (2H). mlz (ESI), found 391.2029 (C24H27N2O3, [M+H] ⁺ , requires 391.2022).

Example 4: 3-Methyl-7V-(2-ph enzofuran-2-carboxamide

White solid (41% overall yield). Vppm (400 MHz, CD ₃ OD): 7.36 (IH), 7.34-7.32 (4H), 7.23-7.19 (IH), 7.12 (IH), 6.85 (IH), 4.93-4.89 (IH), 3.60 (2H), 3.46-3.39 (2H), 3.31-3.28 (2H), 2.93 (2H), 2.79 (3H), 2.32-2.24 (2H), 2.20-2.12 (2H). mlz (ESI), found 379.2022 (C ₂₃ H ₂₇ N ₂ 0 ₃ , [M+H] ⁺ , requires 379.2022).

Example 5: Benzyl 3-methyl-4-(pip an-2-carboxylate

According to the general EDC ester formation procedure, prepared from Intermediate 1 (15 mg, 0.04 mmol) and benzyl alcohol (4.5 μί, 0.044 mmol), N-Boc precursor was obtained.

The title compound was obtained via the Boc deprotection procedure as a white solid (8.5 mg, 44% overall yield). Vppm (400 MHz, CD ₃ OD): 7.50 (2H), 7.44-7.35 (4H), 7.14 (IH), 6.86 (IH), 5.40 (2H), 4.95-4.91 (IH), 3.45-3.39 (2H), 3.31-3.27 (2H), 2.78 (3H), 2.33-2.23 (2H), 2.15-2.10 (2H). mlz (ESI), found 366.1708 (C ₂₂ H ₂₄ NO ₄ , [M+H] ⁺ , requires 366.1705).

Examples 6 to 14 were prepared in analogous fashion to Example 5. Example 6: Naphthalen-l-ylmethyl 3-methyl-4-(piperidin-4-yloxy)-l-benzo-furan-2- carboxylate

White solid (20% overall yield). Vppm (400 MHz, CD ₃ OD): 8.19 (IH), 7.96 (2H), 7.69 (IH), 7.63- 7.51 (3H), 7.38 (IH), 7.12 (IH), 6.83 (IH), 4.92-4.86 (IH), 3.42-3.35 (2H), 3.31-3.25 (2H), 2.71 (3H), 2.30-2.21 (2H), 2.17-2.10 (2H). mlz (ESI), found 416.1854 (C ₂₆ H ₂₆ N0 ₄ , [M+H] ⁺ , requires 416.1862).

Example 7: (4-Methylphenyl) methyl 3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2- carboxylate

White solid (21% overall yield). Vppm (400 MHz, CD ₃ OD): 7.43-7.37 (3H), 7.24 (2H), 7.15 (IH), 6.87 (IH), 5.36 (2H), 4.96-4.94 (IH), 3.46-3.39 (2H), 3.31-3.28 (2H), 2.78 (3H), 2.38 (3H), 2.32- 2.24 (2H), 2.22-2.13 (2H). mlz (ESI), found 380.1857 (Cz^eNC , [M+H] ⁺ , requires 380.1862).

Example 8: (3-Chlorophenyl) methyl 3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2- carboxylate

Yellow solid (42% overall yield). Vppm (400 MHz, CD ₃ OD): 7.51 (IH), 7.43-7.35 (4H), 7.11 (IH), 6.82 (IH), 5.36 (2H), 4.91-4.88 (IH), 3.45-3.39 (2H), 3.32-3.28 (2H), 2.75 (3H), 2.32-2.24 (2H), 2.20-2.12 (2H). mlz (ESI), found 400.1319 (C ₂ 2H2 ₃ N0 ₄ C1, [M+H] ⁺ , requires 400.1316).

Example 9: (2-Chlorophenyl) methyl 3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2- carboxylate

White solid (45% overall yield). Vppm (400 MHz, CD ₃ OD): 7.62-7.59 (IH), 7.50-7.48 (IH), 7.41- 7.36 (3H), 7.13 (IH), 6.84 (IH), 5.49 (2H), 4.96-4.91 (IH), 3.46-3.40 (2H), 3.33-3.28 (2H), 2.76 (3H), 2.33-2.25 (2H), 2.21-2.13 (2H). mlz (ESI), found 400.1317 ^^NC Cl, [M+H] ⁺ , requires 400.1316).

Example 10: (3-Methylphenyl) methyl 3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2- carboxylate

Off-white solid (35% overall yield). Vppm (400 MHz, CD ₃ OD): 7.40 (IH), 7.33-7.28 (3H), 7.22- 7.17 (2H), 7.14 (IH), 6.86 (IH), 5.36 (2H), 4.96-4.91 (IH), 3.46-3.40 (2H), 3.33-3.28 (2H), 2.78 (3H), 2.39 (3H), 2.33-2.25 (2H), 2.21-2.13 (2H). mlz (ESI), found 380.1858 (Cz^eNC , [M+H] ⁺ , requires 380.1862).

Example 11: (2-Methylphenyl) methyl 3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2- carboxylate

Off-white solid (31% overall yield). Vppm (400 MHz, CD ₃ OD): 7.44 (IH), 7.40 (IH), 7.31-7.21 (3H), 7.14 (IH), 6.85 (IH), 5.44 (2H), 4.97-4.91 (IH), 3.46-3.39 (2H), 3.31-3.28 (2H), 2.77 (3H), 2.45 (3H), 2.32-2.24 (2H), 2.20-2.12 (2H). mlz (ESI), found 380.1855 (C ₂₃ H ₂ 6N04, [M+H] ⁺ , requires 380.1862).

Example 12: (3-Methoxyphenyl) methyl 3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2- carboxylate

Off-white solid (10.9 mg, yield: 39%). Vppm (400 MHz, CD ₃ OD): 7.40 (IH), 7.33 (IH), 7.13 (IH), 7.07-7.05 (2H), 6.95-6.92 (IH), 6.85 (IH), 5.37 (2H), 4.94-4.91 (IH), 3.83 (3H), 3.46-3.40 (2H), 3.33-3.28 (2H), 2.78 (3H), 2.32-2.25 (2H), 2.20-2.13 (2H). mlz (ESI), found 396.1798 (C ₂₃ H ₂₆ N0 ₅ , [M+H] ⁺ , requires 396.1811).

Example 13: 2-Phenylethyl-3- ofuran-2-carboxylate

White solid (9% overall yield). Vppm (400 MHz, CD ₃ OD): 7.41 (IH), 7.34-7.30 (4H), 7.27-7.22 (IH), 7.14 (IH), 6.87 (IH), 5.02-4.92 (IH), 4.59 (2H), 3.49-3.40 (2H), 3.32-3.25 (2H), 3.11 (2H), 2.71 (3H), 2.35-2.26 (2H), 2.23-2.10 (2H). mlz (ESI), found 380.1856 (C ₂₃ H ₂₆ N0 ₄ , [M+H] ⁺ , requires 380.1862).

Example 14: Cyclohexylmethyl 3- )-l-benzofuran-2-carboxylate

White solid (10% overall yield). Vppm (400 MHz, CD ₃ OD): 7.42 (IH), 7.16 (IH), 6.88 (IH), 5.00- 4.94 (IH), 4.19 (2H), 3.50-3.41 (2H), 3.32-3.27 (2H), 2.81 (3H), 2.35-2.26 (2H), 2.24-2.12 (2H), 1.93-1.69 (6H), 1.42-1.25 (3H), 1.21-1.07 (2H). mlz (ESI), found 372.2167 (C ₂₂ H ₃₀ NO ₄ , [M+H] ⁺ , requires 372.2175).

Example 15: Benzyl 3-methyl-4-{[l-(propan-2-yl) piperidin-4-yl]oxy}-l-benzofuran-2- carboxylate

According to the general reductive-amination procedure, prepared from Example 5 (20 mg,

0.042 mmol) and acetone (10 μί, 0.13 mmol) and purified by semi-preparative reverse phase HPLC, the title compound was obtained as colourless oil (11 mg, yield: 64%). <Vpprn (400 MHz, CD ₃ OD): 7.50 (2H), 7.44-7.35 (3H), 7.31 (IH), 7.10 (IH), 6.64 (IH), 5.44 (2H), 4.60-4.51 (IH), 2.84-2.74 (3H), 2.78 (3H), 2.50 (2H), 2.14-2.04 (2H), 2.01-1.90 (2H), 1.09 (6H). mlz (ESI), found 408.2168 (C ₂₅ H ₃ oN0 ₄ , [M+H] ⁺ , requires 408.2175).

Example 16: (3-Methyl-4-(piperidin- -yloxy)benzofuran-2-yl)(phenyl) methanone

A mixture of 2,6-dihydroxy acetophenone (50 mg, 0.33 mmol), 2-bromo-l-phenylethan-l-one (69 mg, 0.34 mmol) and potassium carbonate (136 mg, 1.0 mmol) in acetonitrile (3 mL) was stirred at reflux temperature for 24 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. The residue was purified by column chromatography over silica gel, eluting with hexane:ethyl acetate, 91 :9, 84: 16, to afford 2-benzoyl-3 -methyl- l-benzofuran-4-ol as a light yellow solid (34 mg, yield: 41%).

According to the general Mitsunobu reaction procedure C, prepared from 2 -benzoyl-3 -methyl- 1- benzofuran-4-ol (17 mg, 0.068 mmol), /-butyl 4-hydroxypiperidine-l-carboxylate (34 mg,

0.17 mmol), the N-Boc precursor was obtained. The title compound was obtained via the Boc deprotection procedure as an off-white solid (17.3 mg, overall yield: 84%). <Vpprn (400 MHz,

CD ₃ OD): 8.01 (2H), 7.66 (IH), 7.56 (2H), 7.46 (IH), 7.18 (IH), 6.91 (IH), 5.02-4.95 (IH), 3.51-3.42 (2H), 3.38-3.30 (2H), 2.84 (3H), 2.38-2.28 (2H), 2.25-2.14 (2H). mlz (ESI), found 336.1603 (C ₂ iH ₂₂ N0 ₃ , [M+H] ⁺ , requires 336.1600).

Example 17: Benzyl({[3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2-yl]me thyl})-amine

According to the general reductive-amination procedure, prepared from Intermediate 2 (18 mg, 0.05 mmol) and benzylamine (6.2 μί, 0.055 mmol), N-Boc precursor was obtained.

The title compound was obtained via the Boc deprotection procedure as a yellow solid (5.5 mg, overall yield: 24%). Vppm (400 MHz, CD ₃ OD): 7.54-7.46 (5H), 7.31 (IH), 7.14 (IH), 6.87 (IH), 4.92-4.86 (IH), 4.44 (2H), 4.31 (2H), 3.47-3.40 (2H), 3.32-3.28 (2H), 2.47 (3H), 2.33-2.25 (2H), 2.19-2.11 (2H). mlz (ESI), found 351.2061 (C ₂₂ H ₂₇ N ₂ O ₂ , [M+H] ⁺ , requires 351.2073).

Example 18 was prepared in analogous fashion to Example

Example 18: {[3-Methyl-4-(piperidin-4-yloxy)-l-benzofuran-2-yl] methyl}-(naphthalen-l- ylmethyl)amine

White solid (overall yield: 56%). Vppm (400 MHz, CD ₃ OD): 8.02-7.97 (3H), 7.69 (IH), 7.62-7.54 (3H), 7.33 (IH), 7.16 (IH), 6.89 (IH), 4.91-4.85 (IH), 4.78 (2H), 4.57 (2H), 3.46-3.40 (2H), 3.32- 3.28 (2H), 2.48 (3H), 2.33-2.26 (2H), 2.19-2.11 (2H). mlz (ESI), found 401.2221 (C ₂₆ H ₂₉ N ₂ O ₄ , [M+H] ⁺ , requires 401.2229).

Example 19: 4-{[3-Methyl-2-(ph l]oxy} piperidine

According to the general Mitsunobu reaction procedure (Method C), prepared from Intermediate 3b (30 mg, 0.06 mmol) and phenol (14.1 mg, 0.15 mmol), the N-trityl precursor was obtained.

The title compound was obtained via the trityl deprotection procedure as colourless oil (0.4 mg, overall yield: 2%). Vppm (400 MHz, CD ₃ OD): 7.32-7.28 (2H), 7.24 (IH), 7.09 (IH), 7.04 (2H), 6.98 (IH), 6.81 (IH), 5.15 (2H), 4.96-4.89 (IH), 3.43-3.38 (2H), 3.30-3.26 (2H), 2.48 (3H), 2.30- 2.22 (2H), 2.20-2.11 (2H). mlz (ESI), found 338.1772 (C ₂ iH ₂₄ N0 ₃ , [M+H] ⁺ , requires 338.1756).

Example 20: 4-({2-[(Benzyloxy) -yl}oxy) -piperidine

A solution of Intermediate 3b (30 mg, 0.06 mmol) and sodium hydride (60% w/w, 7.2 mg, 0.18 mmol) in anhydrous DMF was stirred at room temperature for 30 minutes, then treated with benzyl bromide (10.7 μί, 0.09 mmol). The resulting mixture was stirred at room temperature for 12 hours. After that, the reaction mixture was quenched with 100 of cold water, diluted with EtOAc (20 inL) and sequentially washed with water and brine (20 mL each). The organic layer was concentrated in vacuo to give N-trityl precursor without further purification.

The title compound was obtained via the trityl deprotection procedure as colourless oil (2 mg, overall yield: 10%). Vppm (400 MHz, CD ₃ OD): 7.40-7.28 (5H), 7.23 (IH), 7.09 (IH), 6.81 (IH), 4.91-4.85 (IH), 4.64 (2H), 4.60 (2H), 3.46-3.39 (2H), 3.30-3.27 (2H), 2.43 (3H), 2.30-2.22 (2H), 2.20-2.12 (2H). mlz (ESI), found 352.1909 (C ₂₂ H ₂₆ N0 ₃ , [M+H] ⁺ , requires 352.1913).

Example 21: [3-Methyl-4-(pipe methyl benzoate

According to general EDC ester formation procedure, prepared from Intermediate 3b (30 mg, 0.06 mmol) and benzoic acid (7.3 mg, 0.06 mmol), N-trityl precursor was obtained.

The title compound was obtained via the trityl deprotection procedure as colourless oil (2.3 mg, 11% overall yield). Vppm (400 MHz, CD ₃ OD): 8.05 (2H), 7.63 (IH), 7.50 (2H), 7.26 (IH), 7.10 (IH), 6.82 (IH), 5.48 (2H), 4.96-4.86 (IH), 3.46-3.40 (2H), 3.32-3.28 (2H), 2.56 (3H), 2.30-2.23 (2H), 2.21-2.13 (2H). mlz (ESI), found 366.1707 (C ₂₂ H ₂₄ N0 ₄ , [M+H] ⁺ , requires 366.1705).

Example 22: (2£)-l-[3-Methyl-4-(piperidin-4-yloxy)-l-benzofuran-2-yl]-3 -phenylprop-2-en-l- one

A mixture of 2, 6-dihydroxy acetophenone (2 g, 13.1 mmol), l-chloropropan-2-one (1.05 mL, 13.1 mmol) and potassium carbonate (5.4 g, 39.4 mmol) in acetonitrile (30 mL) was stirred at reflux temperature for 24 hours. The reaction mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to afford l-(4-hydroxy-3- methyl-l-benzofuran-2-yl)ethan-l-one as an off-white solid (420 mg, yield: 17%).

According to general Mitsunobu reaction procedure (Method C), prepared from l-(4-hydroxy-3- methyl-l-benzofuran-2-yl)ethan-l-one (190 mg, 1.0 mmol)and /-Butyl 4-hydroxypiperidine-l- carboxylate (500 mg, 2.5 mmol), /-Butyl 4-[(2-acetyl-3 -methyl- l-benzofuran-4-yl)oxy]piperidine-l- carboxylate was obtained as a light yellow solid (318 mg, yield: 84%).

To a mixture of compound /-butyl 4-[(2-acetyl-3-methyl-l-benzofuran-4-yl)oxy]piperidine-l- carboxylate (50 mg, 0.13 mmol) and benzaldehyde (15 μί, 0.15 mmol) in ethanol (1 mL) was added 0.25M NaOH solution (1 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with 20 mL EtOAc, followed by the wash with water and brine (20 mL each). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. And the residue was purified by column chromatography over silica gel, eluting with hexane:ethyl acetate, 6: 1, to give the N-Boc precursor.

The title compound was obtained via the Boc deprotection procedure as a yellow solid (14.7 mg, overall yield: 24%). Vppm (400 MHz, CD ₃ OD): 7.86-7.75 (4H), 7.51-7.45 (4H), 7.24 (1H), 6.89 (1H), 5.02-4.93 (1H), 3.50-3.39 (2H), 3.33-3.27 (2H), 2.88 (3H), 2.36-2.24 (2H), 2.24-2.12 (2H). mlz (ESI), found 362.1750 (C ₂₃ H ₂₄ N0 ₃ , [M+H] ⁺ , requires 362.1756).

Example 23: 4-{[2-(3-Benzyl-l, -oxadiazol-5-yl)-3-methyl-l-benzofuran-4-yl]oxy}piperidine

According to general 1,2,4-oxadiazole formation procedure (Method B), prepared from Intermediate 1 (30 mg, 0.08 mmol) and N'-hydroxybenzyl carboximidamide (13.2 mg, 0.088 mmol), the N-Boc precursor was obtained.

The title compound was obtained via the Boc deprotection procedure as a white solid (11.6 mg, overall yield: 29%). Vppm (400 MHz, CD ₃ OD): 7.46-7.24 (6H), 7.18 (1H), 6.86 (1H), 4.99-4.90 (IH), 4.17 (2H), 3.49-3.38 (2H), 3.33-3.26 (2H), 2.83 (3H), 2.36-2.26 (2H), 2.19-2.09 (2H). mlz (ESI), found 390.1819 (C ₂₃ H ₂₄ N ₃ 0 ₃ , [M+H] ⁺ , requires 390.1818).

Example 24: Ethyl 3-(piperidin-4-yl oxylate

Prepared from Intermediate 5 according to Mitsunobu method A and Boc deprotection. The product was purified by HPLC (R _t 8.5 min) and isolated as a pale yellow solid (36 mg, yield: 25%). <Vpprn (400 MHz, CDC1 ₃ ) 7.65 (IH,), 7.52 (2H), 7.32 (IH), 5.08 (IH), 4.46 (2H), 3.62 (2H), 3.31 (2H), 2.24 (4H), 1.44 (3H); mlz (ESI), found 290.1399 (Ci ₆ H ₂ oN0 ₄ , [M+H] ⁺ , requires 290.1392).

Example 25: Ethyl-3-(piperidin-4-yl 2-carboxylate

Prepared according to Mitsunobu method C and Boc deprotection. The product was purified by HPLC (Pv 15.6 min) and isolated as a colourless oil (29 mg, yield: 75%). Vppm (400 MHz, CDC1 ₃ ) 7.83- 7.75 (2H), 7.52 (IH), 7.44 (IH), 5.00-4.94 (IH), 4.38 (2H), 3.77-3.65 (2H), 3.39-3.24 (2H), 2.36- 2.17 (4H), 1.42 (3H); mlz (ESI), found 306.1173 (Ci ₆ H ₂₀ NO ₃ S, [M+H] ⁺ , requires 306.1164).

Example 26: Ethyl-3-((l-methylpipe ]thiophene-2-carboxylate

Prepared according to the general reductive animation method. The product was purified by HPLC (R _t 14.8 min) yielding the product as a white solid (14 mg, yield: 44%). Vppm (400 MHz, CDC1 ₃ ) 7.87 (IH), 7.75 (IH), 7.48 (IH), 7.40 (IH), 4.69-4.58 (IH), 4.39 (2H), 2.96-2.84 (2H), 2.37 (2H), 2.35- 2.23 (2H), 2.14-1.95 (5H), 1.42 (3H); mlz (ESI), found 320.1322 (Ci ₇ H ₂₂ N0 ₃ S, [M+H] ⁺ , requires 320.1320). Example 27: 7V-Benzyl-3-(piperidi -4-yloxy)benzo [6]thiophene-2-carboxamide

Prepared according to the general methods for amide formation and Boc deprotection. The product was purified by HPLC (R _t 11 -2 min) and isolated as a colourless oil (12 mg, yield: 30%). <Vpprn (400 MHz, CDC1 ₃ ) 7.82 (IH), 7.69 (IH), 7.50-7.28 (8H), 4.68 (2H), 4.56-4.48 (IH), 3.38-3.27 (2H), 2.89-2.79 (2H), 2.16-1.99 (4H); mlz (ESI), found 367.1477 (C ₂ iH ₂₃ N ₂ 0 ₂ S, [M+H] ⁺ , requires 367.1480).

Example 28: 7V-(3-Methoxybenzyl -3-(piperidin-4-yloxy)benzo[6]thiophene-2-carboxamide

Prepared according to the general methods for amide formation and Boc deprotection. The product was purified by HPLC (R _t 9.6 min) and isolated as a colourless oil (25 mg, yield: 81%). <Vpprn (400 MHz, CDC1 ₃ ) 7.81 (IH), 7.74-7.65 (IH), 7.51-7.38 (2H), 7.35-7.26 (2H), 6.98 (IH), 6.96-6.91 (IH), 6.84 (IH), 4.65 (2H), 4.58-4.47 (IH), 3.80 (3H), 3.46-3.29 (2H), 2.98-2.78 (2H), 2.21-2.02 (4H); mlz (ESI), found 397.1581 (C ₂ 2H ₂₅ N ₂ 0 ₃ S, [M+H] ⁺ , requires 397.1586).

Example 29: 7V-(3-Phenylpropyl -3-(piperidin-4-yloxy)benzo[6]thiophene-2-carboxamide

Prepared according to the general methods for amide formation and Boc deprotection. The product was purified by HPLC (R _t 5.5 min) and isolated as a colourless oil (14 mg, yield: 27%). <Vpprn (400 MHz, CDC1 ₃ ) 7.81 (IH), 7.71 (IH), 7.50-7.37 (2H), 7.33-7.25 (3H), 7.24-7.13 (3H), 4.67-4.57 (IH), 3.52 (2H), 3.39 (2H), 2.88 (2H), 2.72 (2H), 2.25 (2H), 2.11 (2H), 2.04-1.92 (2H); mlz (ESI), found 395.1783 (C ₂₃ H ₂₇ N ₂ 0 ₂ S, [M+H] ⁺ , requires 395.1793). Example 30: 7V-(2-Phenoxyethy -3-(piperidin-4-yloxy)benzo [6]thiophene-2-carboxamide

Prepared according to the general methods for amide formation and Boc deprotection. The product was purified by HPLC (R _t 5.3 min) and isolated as a white solid (48 mg, yield: 91%). <Vpprn (400 MHz, CDC1 ₃ ) 7.80 (IH), 7.71 (2H), 7.49-7.37 (2H), 7.30 (2H), 7.03-6.90 (3H), 4.64-4.53 (IH), 4.23-4.16 (2H), 3.97-3.90 (2H), 3.30-3.19 (2H), 2.82-2.69 (2H), 2.23-2.14 (2H), 2.07-1.95 (2H); mlz (ESI), found 397.1576 (C ₂ 2H ₂₅ N ₂ 0 ₃ S, [M+H] ⁺ , requires 397.1586).

Example 31 : 3-Phenylpropyl-3- hene-2-carboxylate

Prepared according to the EDC method for ester formation and Boc deprotection. The product was purified by LC-MS (R _t 6.1 min) and isolated as a white solid (22 mg, yield: 43%). <Vpprn (400 MHz, CDC1 ₃ ) 7.83 (IH), 7.76 (IH), 7.50 (IH), 7.43 (IH), 7.35-7.27 (2H), 7.26-7.18 (3H), 4.94-4.83 (IH), 4.31 (2H), 3.60-3.47 (2H), 3.20-3.07 (2H), 2.79 (2H), 2.30-2.16 (4H), 2.09 (2H); mlz (ESI), found 396.1629 (C ₂₃ H ₂₆ N0 ₃ S, [M+H] ⁺ , requires 396.1633).

Example 32: 3-Metho enzo[b]thiophene-2-carboxylate

Prepared according to the EDC method for ester formation and Boc deprotection. The product was purified by LC-MS (R _t 5.0 min) and isolated as a white solid (18 mg, yield: 35%). <Vpprn (400 MHz, CDC1 ₃ ) 7.81 (IH), 7.77 (IH), 7.51 (IH), 7.43 (IH), 7.29-7.22 (IH), 6.89 (IH), 6.85 (IH), 6.80 (IH), 4.87-4.78 (IH), 4.53 (2H), 3.80 (3H), 3.60-3.48 (2H), 3.21-3.10 (2H), 3.05 (2H), 2.20 (4H); mlz (ESI), found 412.1576 (C ₂₃ H ₂₆ N0 ₄ S, [M+H] ⁺ , requires 412.1583). Example 33: Phenethyl 3-(pipe 2-carboxylate

Prepared according to the EDC method for ester formation and Boc deprotection. The product was purified by LC-MS (R _t 5.0 min) and isolated as a white solid (13 mg, yield: 27%). <Vpprn (400 MHz, CDC1 ₃ ) 7.81 (IH), 7.77 (IH), 7.51 (IH), 7.43 (IH), 7.37-7.23 (5H), 4.89-4.76 (IH), 4.53 (2H), 3.62- 3.44 (2H), 3.21-3.10 (2H), 3.08 (2H), 2.29-2.09 (4H); mlz (ESI), found 382.1460 (C ₂₂ H ₂₄ N0 ₃ S, [M+H] ⁺ , requires 382.1477).

Example 34: 2-Phenoxyethyl 3- hene-2-carboxylate

Prepared according to the EDC method for ester formation and Boc deprotection. The product was purified by LC-MS (R ₍ 5.1 min) and isolated as a white solid (20 mg, yield: 39%). <Vpprn (400 MHz, CDC1 ₃ ) 7.87-7.79 (IH), 7.79-7.71 (IH), 7.53-7.45 (IH), 7.45-7.38 (IH), 7.35-7.28 (2H), 7.02-6.91 (3H), 4.90-4.80 (IH), 4.71-4.61 (2H), 4.35-4.24 (2H), 3.55-3.42 (2H), 3.14-3.02 (2H), 2.28-2.10 (4H); mlz (ESI), found 398.1416 (C ₂₂ H ₂₄ N0 ₄ S, [M+H] ⁺ , requires 398.1426).

Example 35: 3-Methoxybenzyl 3- hiophene-2-carboxylate

Prepared according to the EDC method for ester formation and Boc deprotection. The product was purified by LC-MS (R _t 12.3 min) and isolated as a colourless oil (5 mg, yield: 11%). <Vpprn

(400 MHz, CDC1 ₃ ) 7.82 (IH), 7.76 (IH), 7.56-7.48 (IH), 7.47-7.40 (IH), 7.33 (IH), 7.04 (IH), 7.01- 6.98 (IH), 6.91 (IH), 5.34 (2H), 4.88-4.81 (IH), 3.84 (3H), 3.54-3.44 (2H), 3.11-3.01 (2H), 2.22- 2.11 (4H); mlz (ESI), found 398.1425 (C ₂₂ H ₂₄ N0 ₄ S, [M+H] ⁺ , requires 398.1426).

Example 36: Benzyl 3-(piperidin-4-yloxy)benzo[6]thiophene-2-carboxylate

Prepared according to the EDC method for ester formation and Boc deprotection. The product was purified by LC-MS (R _t 10.4 min) and isolated as a colourless oil (15 mg, yield: 32%). Vppm (400 MHz, CDC1 ₃ ) 7.81 (IH), 7.76 (IH), 7.54-7.34 (7H), 5.36 (2H), 4.90-4.82 (IH), 3.58-3.48 (2H), 3.10 (2H), 2.18 (4H); mlz (ESI), found 368.1308 (C ₂ iH ₂₂ N0 ₃ S, [M+H] ⁺ , requires 368.1320).

Example 37: 3-Benzyl-5-(3-(pip -2-yl)-l,2,4-oxadiazole

Prepared according to the general method for 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was purified by LC-MS (R _t 4.2 min) and isolated as a white solid (12 mg, yield: 29%). Vppm (400 MHz, CDC1 ₃ ) 7.82 (2H), 7.52 (IH), 7.46 (IH), 7.40-7.28 (5H), 4.80-4.72 (IH), 4.16 (2H), 3.56-3.45 (2H), 3.04-2.95 (2H), 2.22-2.15 (4H); mlz (ESI), found 392.1425 (C ₂₂ H ₂₂ N ₃ 0 ₂ S, [M+H] ⁺ , requires 392.1433).

Example 38: 3-(3-Methoxybenzyl)-5-(3-(piperidin-4-yloxy)benzo[6]thiophen -2-yl)-l,2,4- oxadiazole

Prepared according to the general methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was purified by LC-MS (R _t 4.4 min) and isolated as a white solid (35 mg, yield: 17%). Vppm (400 MHz, CDC1 ₃ ) 7.83 (IH), 7.82 (IH), 7.53 (IH), 7.47 (IH), 7.28 (IH), 6.96 (IH), 6.94-6.92 (IH), 6.84 (IH), 4.84-4.77 (IH), 4.13 (2H), 3.82 (3H), 3.57- 3.48 (2H), 3.05-2.97 (2H), 2.23-2.16 (4H); mlz (ESI), found 422.1518 (C ₂₃ H ₂₄ N ₃ 0 ₃ S, [M+H] ⁺ , requires 422.1538). Example 39: 3-(3-Chlorobenzyl)-5-(3-(piperidin-4-yloxy)benzo[6]thiophen- 2-yl)-l,2,4- oxadiazole

Prepared according to the general methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was purified by LC-MS (R ₍ 3.1 min) and isolated as an off-white solid (40 mg, yield: 31%). Vppm (400 MHz, CDC1 ₃ ) 7.86-7.81 (2H), 7.53 (IH), 7.48 (IH), 7.39 (IH), 7.33-7.25 (3H), 4.85-4.76 (IH), 4.14 (2H), 3.61-3.50 (2H), 3.11-3.01 (2H), 2.28- 2.17 (4H); mlz (ESI), found 426.1047 (C ₂ 2H ₂₁ C1N ₃ 0 ₂ S, [M+H] ⁺ , requires 426.1043).

Example 40: 3-Phenethyl-5-(3- hen-2-yl)-l,2,4-oxadiazole

Prepared according to the general methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was purified by LC-MS (R _t 4.7 min) and isolated as a white solid (8 mg, yield: 13%). Vppm (400 MHz, CDC1 ₃ ) 7.84 (2H), 7.57-7.44 (2H), 7.36-7.19 (5H), 4.83 (IH), 3.65-3.52 (2H), 3.20-3.10 (6H), 2.33-2.21 (4H); mlz (ESI), found 406.1586 (C ₂₃ H ₂ 4N ₃ 0 ₂ S, [M+H] ⁺ , requires 406.1589).

Example 41 : 3-Methoxybenzyl-3-(azetidin-3-ylmethoxy)benzo [6]thiophene-2-carboxylate

Prepared according to the general procedure for Mitsunobu reaction and Boc deprotection. The product was purified by LC-MS (R _t 4.2 min) and isolated as a brown oil (50 mg, yield: 69%). Vppm (400 MHz, CDC1 ₃ ) 7.87 (IH), 7.77 (IH), 7.50 (IH), 7.40 (IH), 7.31 (IH), 7.01 (IH), 6.97 (IH), 6.89 (IH), 5.30 (2H), 4.52 (2H), 4.40-4.36 (2H), 4.25-4.18 (2H), 3.83 (3H), 3.30 (IH); mlz (ESI), found 384.1279 (C ₂ iH ₂₂ N0 ₄ S, [M+H] ⁺ , requires 384.1270). Example 42: 3-Methoxybenzyl-c s-3-((4-aminocyclohexyl)oxy)benzo[b]thiophene-2-carboxylate

Prepared according to the general procedure for Mitsunobu reaction and Boc deprotection. The product was purified by LC-MS (R _t 4.8 min) and isolated as a brown solid (13 mg, yield: 20%). Vppm (400 MHz, CDC1 ₃ ) 7.94 (IH), 7.67 (IH), 7.38 (IH), 7.34-7.28 (2H), 7.04-6.95 (2H), 6.88 (IH), 5.31 (2H), 4.90 (IH), 3.81 (3H), 3.23 (IH), 2.24-2.06 (4H), 1.99-1.87 (2H), 1.65-1.51 (2H); mlz (ESI), found 412.1598 (C ₂₃ H ₂₆ N0 ₄ S, [M+H] ⁺ , requires 412.1583).

Example 43: 3-Methoxybenzyl-3-(piperidin-4-yloxy)thiophene-2-carboxylate

Prepared according to the EDC method for ester formation and Boc deprotection. The product was purified by HPLC (R _t 11.05 min;), and isolated as a colourless oil (5 mg, yield: 9% over two steps). Vppm (400 MHz, CDC1 ₃ ) 7.46 (IH), 7.31 (IH), 7.02 (IH), 6.99-6.96 (IH), 6.88 (IH), 6.82 (IH), 5.28 (2H), 4.72-4.66 (IH), 3.82 (3H), 3.43-3.32 (2H), 3.21-3.13 (2H), 2.26-2.14 (2H), 2.14-2.04 (2H); mlz (ESI), found 348.1268 (Ci ₈ H ₂₂ N0 ₄ S, [M+H] ⁺ , requires 348.1270).

Example 44: 3,5-Dimethoxypheneth benzo[b]thiophene-2-carboxylate

Prepared according to the EDC method for esterification and Boc deprotection. The product was purified by LC-MS (R _t 6.7 min) and isolated as a white solid (23 mg, yield: 40%). Vppm (400 MHz, CDC1 ₃ ) 7.81 (IH), 7.76 (IH), 7.51 (IH), 7.43 (IH), 6.45 (2H), 6.36 (IH), 4.90-4.79 (IH), 4.52 (2H), 3.78 (6H), 3.59-3.47 (2H), 3.19-3.09 (2H), 3.02 (2H), 2.29-2.11 (4H); mlz (ESI), found 442.1671 (C ₂₄ H ₂₈ N0 ₅ S, [M+H] ⁺ , requires 442.1688).

Example 45: 3,5-Dimethoxybenzyl-3-(piperidin-4-yloxy)benzo[b]thiophene-2 -carboxylate

Prepared according to the EDC method for esterification and Boc deprotection. The product was purified by LC-MS (R _t 16.1 min) and isolated as a white solid (24 mg, yield: 43%). Vppm

(400 MHz, CDC1 ₃ ) 7.82 (IH), 7.76 (IH), 7.51 (IH), 7.43 (IH), 6.59 (2H), 6.45 (IH), 5.29 (2H), 4.90- 4.83 (IH), 3.82 (6H), 3.57-3.47 (2H), 3.15-3.06 (2H), 2.24-2.15 (4H); mlz (ESI), found 428.1515 (C ₂₃ H ₂₆ N0 ₅ S, [M+H] ⁺ , requires 428.1532).

Example 46: 3-Methoxybenzyl-ira«s-3-((4-aminocyclohexyl)oxy)benzo[b]thi ophene-2- carboxylate

Prepared according to the general procedure for Mitsunobu reaction and Boc deprotection. The product was purified by LC-MS (R _t 4.9 min) and isolated as a white solid (49 mg, yield: 63%).

Vppm (400 MHz, CDC1 ₃ ) 7.80 (IH), 7.73 (IH), 7.47 (IH), 7.38 (IH), 7.30 (IH), 7.02 (IH), 6.99 (IH), 6.88 (IH), 5.32 (2H), 4.48-4.38 (IH), 3.82 (3H), 3.11-3.01 (IH), 2.23-2.14 (2H), 2.12-2.02 (2H), 1.72-1.58 (2H), 1.48-1.34 (2H); mlz (ESI), found 412.1593 (C ₂₃ H ₂₆ N0 ₄ S, [M+H] ⁺ , requires 412.1583).

Example 47: 3-Hydroxybenzyl 3-( thiophene-2-carboxylate

To a solution of Intermediate 19 (24 mg, 0.04 mmol) in chloroform (5 mL) was added trifluoroacetic acid (0.55 mL) and the solution was stirred at room temperature for 2 h then concentrated under reduced pressure. To the concentrated mixture was added tetrahydrofuran (0.8 mL) and

tetrabutylammonium fluoride (0.18 mL of 1.0 M solution in tetrahydrofuran, 0.18 mmol) and yellow solution stirred at room temperature for 10 min. Reaction mixture was concentrated under reduced pressure then purified by HPLC (R, 12.1 min) yielding the product as a pale yellow oil (14 mg, yield: 91%). Vppm (400 MHz, CDC1 ₃ ) 7.78 (2H), 7.55-7.45 (IH), 7.45-7.36 (IH), 7.26 (IH), 7.19-7.12 (1H), 6.99 (1H), 6.91 (1H), 5.32 (2H), 4.87-4.75 (1H), 3.56-3.44 (2H), 3.11-2.97 (2H), 2.18-2.02 (4H); mlz (ESI), found 384.1289 (C ₂ iH ₂₂ N0 ₄ S, [M+H] ⁺ , requires 384.1270).

Example 48: Benzoic acid 2-(4-pip

Prepared according to the general methods of Mitsunobu reaction (Method A) and Boc deprotection above with final purification by HPLC (R _t 7.4 min). The product was isolated as a colourless oil (10 mg, yield: 6%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.84-7.82 (1H), 7.58-7.51 (3H), 7.46-7.35 (3H), 7.30-7.28 (1H), 7.10-7.06 (1H), 5.41 (2H, s, PhCH ₂ ), 5.00-4.96 (1H), 2.52-2.45 (2H), 3.35-3.29 (2H), 2.35-2.27 (2H), 2.15-2.11 (2H); mlz (ESI), found 312.1589 (Ci ₉ H ₂₂ N0 ₃ , [M+H] ⁺ requires 312.1600).

Example 49: 7V-Benzyl-3-(piper

Prepared according to the method of benzoic acid 2-(4-piperidinyloxy) benzyl ester (Example 48) above. Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.67 (1H), 7.60 (1H), 7.52 (2H), 7.42 (4H), 7.26 (1H), 5.40 (2H), 4.03 (2H), 3.75 (2H), 3.15 (2H), 2.25 (1H), 2.09 (2H), 1.80 (2H).

Example 50: Benzoic acid 3-(4-piperidinyloxy) benzyl ester

Prepared according to the procedures for Mitsunobu reaction (Method A) and Boc deprotection with final purification by HPLC (R _t 12.5 min). The product was isolated as a colourless oil (74 mg, yield: 49%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.68-7.66 (2H), 7.52-7.33 (7H), 5.38 (2H), 4.91 (1H), 3.58- 3.51 (2H), 3.41-3.35 (2H), 2.38-2.31 (2H), 2.15-2.09 (2H); mlz (ESI), found 312.1570 (Ci ₅ H ₁₈ N ₇ 0, [M+H] ⁺ requires 312.1573).

Example 51: (2-Hydroxy-phenyl)-2-(4-piperidinyloxy)-acetic acid benzyl ester

Prepared according to the methods for Mitsunobu reaction (Method C) and Boc deprotection with final purification by HPLC (R _t 10.5 min). The product was isolated as a colourless oil (5 mg, yield: 8%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.36-7.24 (7H), 7.06 (IH), 6.92 (IH), 5.16 (2H), 4.85-4.81 (IH), 3.73 (2H), 3.46-3.40 (2H), 3.35-3.29 (2H), 2.30-2.20 (2H), 2.08-2.06 (2H); mlz (ESI), found 326.1738 (C ₂ oH ₂₄ N0 ₃ , [M+H] ⁺ requires 326.1756).

Example 52: Benzoic acid 4-methyl- -(4-piperidinyloxy) benzyl ester

Prepared according to the methods for Mitsunobu reaction (Method A) and Boc deprotection with final purification by HPLC (R _t 15.8 min). The product was isolated as a colourless oil (67 mg, yield: quant.). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.72 (IH), 7.54-7.49 (2H). 7.42-7.32 (3H), 7.11 (IH). 6.87 (IH), 5.35 (2H), 4.92 (IH), 3.47-3.41 (2H), 3.27-3.22 (2H), 2.36 (3H), 2.29-2.21 (2H), 2.09-2.08 (2H); mlz (ESI), found 326.1745 (C ₂ oH ₂₄ N0 ₃ , [M+H] ⁺ requires 326.1756).

Example 53: Benzyl 4-methoxy-2-( e

Prepared according to the methods for Mitsunobu reaction (Method A) and Boc deprotection with final purification by HPLC (R _t 16.0 min). The product was isolated as a colourless oil (54 mg, 93%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.89 (IH), 7.53 (2H), 7.43 (2H), 7.36 (IH), 6.80 (IH), 6.66 (IH), 5.36 (2H), 3.89 (3H), 3.47 (2H), 3.24 (IH), 2.27 (2H), 1.29 (4H).

Example 54: Benzyl 2- [(4-piperidin

2-sulfanylbenzoic acid (1 eq) was dissolved in DMF. Potassium carbonate was added (2eq), followed by benzyl bromide (1.1 eq) and the reaction stirred at room temperature for 1 h.The reaction mixture was diluted with ethyl acetate and the organic phase washed with 50 mL citric acid solution (1 M), then with 2 x 50 mL NaHC0 ₃ (sat. aq.), and finally with brine (50 mL). The organic phase was dried (Na ₂ S0 ₄ ) and the solvents removed under reduced pressure to afford benzyl 2-sulfanylbenzoate as a pale yellow oil. The compound was reacted with tert-butyl 4-hydroxypiperidine-l-carboxylate, according to the General Mitsunobu reaction (method C), to afford the Boc-precursor of the title compound.Boc deprotection following the general method and purification by HPLC provided the product as a colourless oil. Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.86 (IH), 7.61 (IH), 7.52-7.48 (3H), 7.40-7.26 (4H), 5.33 (2H), 3.70 (IH), 3.48 (2H), 3.22-3.15 (2H), 2.26-2.22 (2H), 1.93-1.83 (2H); mlz (ESI), found 328.1367 (Ci ₉ H ₂₂ N0 ₂ S, [M+H] ⁺ requires 328.1371).

Example 55: Benzyl 2-methyl-3-

Prepared according to the methods for Mitsunobu reaction (Method A) and Boc deprotection with final purification by HPLC (R _t 12.0 min). The product was isolated as a colourless oil (56 mg, 15%). Vppm (400 MHz, CD ₃ OD): 7.40 (6H), 7.24 (2H), 5.35 (2H), 4.75 (IH), 3.40 (2H), 3.25 (2H), 2.44 (3H), 2.19 (2H), 2.07 (2H).

Example 56: (S)-Benzyl 2-(piperidin-3-yloxy)benzoate

Prepared according to the methods for Mitsunobu reaction (Method A) and Boc deprotection with final purification by HPLC (R _t 12.4 min). The product was isolated as a colourless oil (29 mg, 29%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.86 (IH), 7.62-7.54 (3H), 7.47-7.36 (4H), 7.14 (IH), 5.40 (2H), 5.04 (IH), 3.45 (IH), 3.36-3.18 (3H), 2.11 (4H).

Example 57: Benzoic acid 3-(3-piperidinyloxy) benzyl ester, formic acid salt

Prepared according to the methods for Mitsunobu reaction (Method A) and Boc deprotection with final purification by HPLC (R _t 14.3 min). The product was isolated as a colourless oil (19 mg, 19%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.67-7.62 (2H), 7.51-7.31 (7H), 5.37 (2H), 4.86-4.81 (IH), 3.43 (IH), 3.21 (IH), 3.14 (2H), 2.08 (2H), 1.95-1.88 (1H),1.79-1.72 (IH); mlz (ESI), found 312.1587 (Ci ₉ H ₂₂ N0 ₃ , [M+H] ⁺ requires 312.1600).

Example 58: Benzoic acid 2-[(4-piperidinyl)thio]-3,5-dimethoxy benzyl ester, formic acid salt H

Prepared according to the general methods for esterification and Boc deprotection, with purification of the final compound by LC-MS (R _t 8.5 min). The product was isolated as a colourless oil (2.4 mg, yield: 3%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.91 (IH), 7.67 (IH), 7.54 (IH), 7.33 (IH), 6.67 (2H), 6.57 (IH), 5.29 (2H), 3.80 (6H), 3.76-3.74 (IH), 3.57 (IH), 3.54 (IH), 3.29-3.27 (2H), 2.33-2.27 (2H), 1.97-1.93 (2H); mlz (ESI), found 388.1583 (C ₂₁ H ₂₆ NO ₄ S, [M+H] ⁺ requires 388.1575).

Example 59: 3-Methoxybenzyl 3-(piperidin-4-yloxy)benzoate

Prepared according to the general methods for esterification and Boc deprotection, with purification of the final compound by LC-MS. The product was isolated as a white solid (19 mg, yield: 31%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.71-7.68 (2H), 7.48 (IH), 7.38-7.33 (2H), 7.09-7.07 (2H), 6.95 (IH), 5.37 (2H), 4.93 (IH), 3.84 (3H), 3.56 (2H), 3.39 (2H), 2.36 (2H), 2.15 (2H).

Example 60: 3,5-Dimethoxybenzyl 3-(piperidin-4-yloxy)benzoate

Prepared according to the general methods for esterification and Boc deprotection, with purification of the final compound by LC-MS. The product was isolated as a white solid (24 mg, yield: 55%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.70-7.67 (2H), 7.48 (IH), 7.37-7.34 (IH), 6.68 (2H), 6.50 (IH), 5.32 (2H), 4.92 (IH), 3.82 (6H), 3.55 (2H), 3.38 (2H), 2.35 (2H), 2.13 (2H).

Example 61: 3-Chlorobenzyl 3-(piperidin-4-yloxy)benzoate

Prepared according to the general methods for esterification and Boc deprotection, with purification of the final compound by LC-MS. The product was isolated as a white solid (18 mg, yield: 39%). Vppm (400 MHz, (CD ₃ ) ₂ CO): 7.71-7.67 (2H), 7.58 (IH), 7.51-7.36 (5H), 5.41 (2H), 4.94 (IH), 3.58 (2H), 3.42 (2H), 2.36 (2H), 2.15 (2H). Example 62: Benzoic acid 3-(4-piperidinyloxy)-3-methoxy benzyl amide, formic acid salt

Prepared according to the general method for amide formation followed by Boc deprotection and purification by LC-MS. The produce was isolated as a white solid (20.2 mg, yield: 10%). <Vpprn (400 MHz, (CD ₃ ) ₂ CO): 7.60-7.54 (2H), 7.39 (IH), 7.24-7.18 (2H), 6.94-6.92 (2H), 6.82-6.97 (IH), 4.86 (IH), 4.56 (2H), 3.76 (3H), 3.55-3.49 (2H), 3.38-3.32 (2H), 2.34-2.28 (2H), 2.13-2.08 (2H); mlz (ESI), found 341.1844 (C ₂ oH ₂₅ N ₂ 0 ₃ , [M+H] ⁺ requires 341.1865).

Example 63: 7V-benzyl-2-(piperidin-

Prepared according to the general method for amide formation followed by Boc deprotection and purification by LC-MS. The produce was isolated as a white solid (33 mg, yield: 63%). <Vpprn (400 MHz, (CD ₃ ) ₂ CO): 7.39 (IH), 7.50-7.43 (2H), 7.37 (2H), 7.29-7.25 (2H), 7.10 (IH), 4.96 (IH), 4.66 (2H), 3.47 (2H), 3.30 (2H), 2.34 (2H), 2.19 (2H).

Example 64: 3-Methoxybenzyl 2-(piperidin-4-yloxy)benzoate

Prepared according to the general methods for esterification and Boc deprotection above. The crude product was purified by LC-MS to provide 3-methoxybenzyl 2-(piperidin-4-yloxy)benzoate as an amorphous off-white solid (8.0 mg, yield: 15%). Vppm (400 MHz, CDC1 ₃ ): 7.91 (IH), 7.49 (IH), 7.33 (IH), 6.98 (5H), 5.35 (2H), 4.80 (IH), 3.84 (3H), 3.42 (2H), 3.18 (2H), 2.16 (4H); mlz (ESI), 342 ([M + H] ⁺ ).

Example 65: 3,5-Dimethoxybenzy ate

Prepared according to the general methods for esterification and Boc deprotection above. The product was isolated as an amorphous off-white solid (3.5 mg, yield: 6%). <Vpprn (400 MHz, CDC1 ₃ ): 7.91 (1H), 7.49 (1H), 7.00 (2H), 6.62 (2H), 6.46 (1H), 5.30 (2H), 4.82 (1H), 3.83 (6H), 3.46 (2H), 3.21 (2H), 2.17 (4H); mlz (ESI), 372 ([M + H] ⁺ ).

Example 66: 3-Chlorobenzyl 2-(p

Prepared according to the general methods for esterification and Boc deprotection above. The product was isolated as an amorphous off-white solid (10.4 mg, yield: 19%). <Vpprn (400 MHz, CDC1 ₃ ): 7.90 (1H), 7.49 (2H), 7.35 (3H), 7.07 (1H), 6.99 (1H), 5.35 (2H), 4.82 (1H), 3.44 (2H), 3.21 (2H), 2.20 (4H); mlz (ESI), 346 ([M + H] ⁺ ).

Example 67: 3-Methylbenzyl 2-(pi

Prepared according to the general methods for esterification and Boc deprotection above. The product was isolated as an amorphous off-white solid (4.0 mg, yield: 8%). <Vpprn (400 MHz, CDC1 ₃ ): 7.88 (1H), 7.44 (5H), 7.05 (1H), 6.99 (1H), 5.34 (2H), 4.82 (1H), 3.43 (2H), 3.19 (2H), 2.20 (4H); mlz (ESI), 326 ([M + H] ⁺ ).

Example 68: Naphthalen-2-ylm oate

Prepared according to the general methods for esterification and Boc deprotection above. The product was isolated as an amorphous off-white solid (22.7 mg, yield: 39%). <Vpprn (400 MHz, CDC1 ₃ ): 7.89 (5H), 7.51 (4H), 7.05 (1H), 6.92 (1H), 5.53 (2H), 4.88 (1H), 4.73 (2H), 3.37 (2H), 3.07 (2H), 2.12 (4H); mlz (ESI), 362 ([M + H] ⁺ ).

Example 69: Phenethyl 2-(piperidin-4-yloxy)benzoate

Prepared according to the general methods for esterification and Boc deprotection above. The product was isolated as an amorphous off-white solid (18.5 mg, yield: 36%). <Vpprn (400 MHz, CDC1 ₃ ): 7.80 (1H), 7.48 (1H), 7.30 (5H), 7.04 (1H), 6.96 (1H), 4.79 (1H), 4.56 (2H), 3.46 (2H), 3.19 (2H), 3.09 (2H), 2.18 (6H); mlz (ESI), 326 ([M + H] ⁺ ).

Example 70: 3-Phenylpropyl 2-

Prepared according to the general methods for esterification and Boc deprotection above. The product was isolated as an amorphous off-white solid (21.1 mg, yield: 39%). <Vpprn (400 MHz, CDC1 ₃ ): 7.82 (1H), 7.49 (1H), 7.27 (5H), 7.06 (1H), 6.99 (1H), 4.82 (1H), 4.35 (2H), 3.54 (2H), 3.25 (2H), 2.80 (2H), 2.20 (6H); mlz (ESI), 340 ([M + H] ⁺ ).

Example 71: 3-Methoxyphen

Prepared according to the general methods for esterification and Boc deprotection above. The product was isolated as an amorphous off-white solid (24.5 mg, yield: 43%). <Vpprn (400 MHz, CDC1 ₃ ): 7.82 (1H), 7.48 (1H), 7.25 (1H), 7.04 (1H), 6.89 (4H), 4.79 (1H), 4.55 (2H), 3.80 (3H), 3.47 (2H), 3.20 (2H), 3.07 (2H), 2.16 (4H); mlz (ESI), 356 ([M + H] ⁺ ).

Example 72: 3-Benzyl-5-(2-(piperi oxadiazole

Prepared according to the general method A for 1,2,4-oxadiazole formation and Boc deprotection. The product was isolated as an off white solid (16.4 mg, yield: 29%). <Vpprn (400 MHz, CDC1 ₃ ): 8.10 (1H), 7.55 (1H), 7.38 (5H), 7.14 (1H), 7.04 (1H), 4.89 (1H), 4.21 (2H), 3.47 (2H), 3.17 (2H), 2.20 (4H); mlz (ESI), found 336.1697 (C ₂ oH ₂₂ N ₃ 0 ₂ ([M + H] ⁺ ) requires 336.1712).

Example 73: 3-(3-Methoxybenz )-l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was isolated as an off white amorphous solid (41.1 mg, yield: 28%). Vppm (400 MHz, CDC1 ₃ ): 8.09 (1H), 7.55 (1H), 7.29 (1H), 7.14 (1H), 7.01 (3H), 6.84 (1H), 4.91 (1H), 4.16 (2H), 3.82 (3H), 3.53 (2H), 3.21 (2H), 2.17 (4H); mlz (ESI), found 366.1801

(C ₂ iH ₂₄ N ₃ 0 ₃ ([M + H] ⁺ ) requires 366.1818).

Example 74: 3-(3-Chlorobenzyl)- l)-l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was isolated as an off white amorphous solid (42.9 mg, yield: 29%). Vppm (400 MHz, CDC1 ₃ ): 8.10 (1H), 7.56 (1H), 7.43 (1H), 7.29 (3H), 7.15 (1H), 7.05 (1H), 4.93 (1H), 4.19 (2H), 3.56 (2H), 3.23 (2H), 2.24 (4H); mlz (ESI), found 370.1314 (C ₂₀ H ₂₁ ClN ₃ O ₂ ([M + H] ⁺ ) requires 370.1322).

Example 75: 3-(3-Fluorobenzyl)- -(2-(piperidin-4-yloxy)phenyl)-l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was isolated as an off white amorphous solid (39.8 mg, yield: 28%). Vppm (400 MHz, CDC1 ₃ ): 8.10 (1H), 7.56 (1H), 7.31 (2H), 7.17 (2H), 7.05 (1H), 6.98 (1H), 4.92 (1H), 4.21 (2H), 3.57 (2H), 3.22 (2H), 2.24 (4H); mlz (ESI), found 354.1604 (C ₂₀ H ₂₁ FN ₃ O ₂ ([M + H] ⁺ ) requires 354.1618). Example 76: 3-Phenethyl-5-(2-( oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was isolated as an off white amorphous solid (53.5 mg, yield: 38%). Vppm (400 MHz, CDC1 ₃ ): 8.13 (1H), 7.57 (1H), 7.28 (5H), 7.16 (1H), 7.06 (1H), 4.93 (1H), 3.58 (2H), 3.29 (2H), 3.18 (2H), 2.24 (4H); mlz (ESI), found 350.1859 (C ₂ iH ₂₄ N ₃ 0 ₂ ([M + H] ⁺ ) requires 350.1869).

Example 77: 3-Benzyl-5-(3-(pip iazole

Prepared according to the methods for 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (49.1 mg, yield: 37%). <Vpprn (400 MHz, CDC1 ₃ ): 7.77 (1H), 7.64 (1H), 7.47 (1H), 7.35 (5H), 7.15 (1H), 4.78 (1H), 4.17 (2H), 3.39 (2H), 3.25 (2H), 2.21 (4H); mlz (ESI), found 336.1701 (C ₂ oH ₂₂ N ₃ 0 ₂ ([M + H] ⁺ ) requires 336.1712).

Example 78: 3-(3-Methoxybe -l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (41.1 mg, yield: 28%). Vppm (400 MHz, CDC1 ₃ ): 7.77 (1H), 7.65 (1H), 7.47 (1H), 7.29 (1H), 7.15 (1H), 6.99 (1H), 6.95 (1H), 6.84 (1H), 4.78 (1H), 4.14 (2H), 3.83 (3H), 3.39 (2H), 3.26 (2H), 2.21 (4H); mlz (ESI), found 366.1803 (C ₂ iH ₂₄ N ₃ 0 ₃ ([M + H] ⁺ ) requires 366.1818).

Example 79: 3-(3-Chlorobenzyl)-5-(3-(piperidin-4-yloxy)phenyl)-l,2,4-oxa diazole Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (40.0 mg, yield: 27%). Vppm (400 MHz, CDC1 ₃ ): 7.77 (1H), 7.65 (1H), 7.48 (1H), 7.40 (1H), 7.29 (3H), 7.16 (1H), 4.79 (1H), 4.14 (2H), 3.40 (2H), 3.26 (2H), 2.20 (4H); mlz (ESI), found 370.1313 (C ₂ oH ₂ iClN ₃ 0 ₂ ([M + H] ⁺ ) requires 370.1322).

Example 80: 3-(3-Fluorobenz l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (29.3 mg, yield: 21%). Vppm (400 MHz, CDC1 ₃ ): 7.77 (1H), 7.65 (1H), 7.48 (1H), 7.33 (1H), 7.14 (3H), 7.00 (1H), 4.79 (1H), 4.16 (2H), 3.40 (2H), 3.26 (2H), 2.20 (4H); mlz (ESI), found 354.1615 (C ₂ oH ₂ iFN ₃ 0 ₂ ([M + H] ⁺ ) requires 354.1618).

Example 81: 3-Phenethyl-5- -(piperidin-4-yloxy)phenyl)-l,2,4- oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (57.3 mg, yield: 41%). Vppm (400 MHz, CDC1 ₃ ): 7.77 (1H), 7.68 (1H), 7.50 (1H), 7.29 (5H), 7.17 (1H), 4.81 (1H), 3.42 (2H), 3.28 (2H), 3.16 (4H), 2.24 (4H); mlz (ESI), found 350.1851 (C ₂ iH ₂₄ N ₃ 0 ₂ ([M + H] ⁺ ) requires 350.1869).

Example 82: 3-(3,5-Dimethoxyb phenyl)-l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (9.4 mg, yield: 6%). Vppm (400 MHz, CDC1 ₃ ): 8.10 (1H), 7.55 (1H), 7.09 (2H), 6.57 (2H), 6.39 (1H), 4.92 (1H), 4.13 (2H), 3.80 (6H), 3.54 (2H), 3.23 (2H), 2.20 (4H). Example 83: 3-(3,4-Dimethoxyb phenyl)-l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (5.8 mg, yield: 4%). Vppm (400 MHz, CDC1 ₃ ): 8.10 (1H), 7.56 (1H), 7.16-6.68 (5H), 4.92 (1H), 4.14 (2H), 3.89 (6H), 3.54 (2H), 3.23 (2H), 2.20 (4H).

Example 84: 3-(3,4,5-Trimeth phenyl)-l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (2.9 mg, yield: 2%). Vppm (400 MHz, CDC1 ₃ ): 8.12 (1H), 7.56 (1H), 7.14 (1H), 7.05 (1H), 6.64 (2H), 4.92 (1H), 4.13 (2H), 3.88 (9H), 3.57 (2H), 3.23 (2H), 2.20 (4H).

Example 85: 3-(4-Methoxybenzyl)- enyl)-l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (7.0 mg, yield: 5%). Vppm (400 MHz, CDC1 ₃ ): 8.09 (1H), 7.54 (1H), 7.33 (2H), 7.13 (1H), 7.04 (1H), 6.89 (2H), 4.90 (1H), 4.13 (2H), 3.80 (3H), 3.53 (2H), 3.22 (2H), 2.20 (4H).

Example 86: 3-(3-Trifluoromethylbenzyl)-5-(2-(piperidin-4-yloxy)phenyl)- l,2,4-oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (2.6 mg, yield: 2%). Vppm (400 MHz, CDC1 ₃ ): 8.10 (1H), 7.71 (1H), 7.62-7.46 (4H), 7.14 (1H), 7.05 (1H), 4.92 (1H), 4.28 (2H), 3.55 (2H), 3.19 (2H), 2.19 (4H).

Example 87: 3-(4-Chlorobenzyl)-5-( enyl)-l,2,4-oxadiazole

i

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (13.9 mg, yield: 9%). Vppm (400 MHz, CDC1 ₃ ): 8.09 (1H), 7.56 (1H), 7.37-7.31 (4H), 7.13 (1H), 7.05 (1H), 4.91 (1H), 4.17 (2H), 3.51 (2H), 3.20 (2H), 2.21 (4H).

Example 88: 3-(Benzo[d] [l,3]dioxol-5-ylmethyl)-5-(2-(piperidin-4-yloxy)phenyl)-l,2, 4- oxadiazole

Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (19.0 mg, yield: 13%). Vppm (400 MHz, CDC1 ₃ ): 8.09 (1H), 7.55 (1H), 7.13 (1H), 7.04 (1H), 6.88 (2H), 6.79 (1H), 5.94 (2H), 4.89 (1H), 4.17 (2H), 3.51 (2H), 3.20 (2H), 2.21 (4H).

Example 89: 4-[2-(3-Benzyl-l,2,4-oxa phenoxy]piperidine

To a stirring solution of 4-methyl salicyclic acid (152 mg, 1 mmol) in DMF (3 inL) was added benzyl bromide (120 μί, 1 mmol) and potassium carbonate (138 mg, 1 mmol). The resulting mixture was stirred at room temperature for 2 hours. After that, the reaction mixture was diluted with water (20 inL) and extracted by EtOAc (2 χ 20 mL). The combined organic layers were washed by brine (30 mL) and dried over anhydrous sodium sulphate. After removal of EtOAc, benzyl 2-hydroxy-4- methylbenzoate was obtained as a light yellow liquid without further purification (207 mg, yield:

86%).

According to the general Mitsunobu reaction procedure (Procedure A), prepared from benzyl 2- hydroxy-4-methylbenzoate (207 mg, 0.86 mmol) and fert-butyl 4-hydroxypiperidine-l-carboxylate (428 mg, 2.1 mmol), fert-butyl 4-(2-((benzyloxy)carbonyl)-5-methylphenoxy)piperidine-l- carboxylate was obtained as colourless oil (325 mg, yield: 89%).

To a solution of fert-butyl 4-(2-((benzyloxy)carbonyl)-5-methylphenoxy)piperidine-l-carb oxylate (325 mg, 0.76 mmol) in Me OH (5 mL) was added 380 of 4 N NaOH solution. The resulting mixture was stirred at 65 °C for 6 hours. Volatile components were removed in vacuo and the residue was partitioned between NaOH _{(aq j} (20 mL, 0.5 N) and EtOAc (20 mL). The pH of the aqueous layer was adjusted to 2 by addition of concentrated HC1, followed by extraction with EtOAc (30 mL). The organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulphate. After removal of EtOAc under reduced pressure, 2-((l-(tert-butoxycarbonyl)piperidin-4-yl)oxy)-4- methylbenzoic acid was obtained as a white solid (215 mg, 84% yield).

According to Method B for 1,2,4-oxadiazole formation and Boc-deprotection procedure, prepared from 2-((l-(teri-butoxycarbonyl)piperidin-4-yl)oxy)-4-methylbenzo ic acid (40 mg, 0.12 mmol), the title compound was obtained as an off-white solid (yield: 45%). <Vppm (400 MHz, CDC1 ₃ ): 7.96 (IH), 7.43-7.31 (4H), 7.25 (IH), 6.93 (IH), 6.82 (IH), 4.84 (IH), 4.17 (2H), 3.53-3.38 (2H), 3.22- 3.12 (2H), 2.42 (3H), 2.29-2.19 (2H), 2.13-2.06 (2H). mlz (ESI), found 350.1874 (C ₂ iH ₂₄ N ₃ 0 ₂ , [M+H] ⁺ , requires 350.1869).

Examples 90 to 105 were prepared in analogous fashion to Example 89.

Example 90: 4-{5-Methyl-2-[3-(2-p ol-5-yl]phenoxy}piperidine

Off-white solid; Vppm (400 MHz, CDC1 ₃ ): 8.00 (IH), 7.34-7.20 (5H), 6.95 (IH), 6.85 (IH), 4.86 (IH), 3.56-3.44 (2H), 3.26-3.12 (2H), 3.16 (4H), 2.44 (3H), 2.32-2.19 (2H), 2.19-2.08 (2H). mlz (ESI), found 364.2014 (C ₂₂ H ₂₆ N ₃ 0 ₂ , [M+H] ⁺ , requires 364.2025).

Example 91: 4-(2-{3-[(3-Methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl}-5- methylphenoxy)piperidine

Yellow oil; Vppm (400 MHz, CDC1 ₃ ): 7.96 (IH), 7.27 (IH), 6.99-6.90 (3H), 6.83-6.79 (2H), 4.85 (IH), 4.14 (2H), 3.81 (3H), 3.52-3.41 (2H), 3.22-3.11 (2H), 2.42 (3H), 2.29-2.17 (2H), 2.17-2.05 (2H). mlz (ESI), found 380.1968 (C ₂₂ H ₂₆ N ₃ 0 ₃ , [M+H] ⁺ , requires 380.1974).

Example 92: 4-[2-(3-Benzyl-l,2,4-oxa xyphenoxy]piperidine

Yellow oil; Vppm (400 MHz, CDC1 ₃ ): 8.05 (IH), 7.41-7.34 (4H), 7.29-7.24 (IH), 6.65 (IH), 6.52 (IH), 4.81 (IH), 4.17 (2H), 3.89 (3H), 3.51-3.40 (2H), 3.25-3.12 (2H), 2.30-2.20 (2H), 2.15-2.07 (2H). mlz (ESI), found 366.1803 (C ₂ iH ₂₄ N ₃ 0 ₃ , [M+H] ⁺ , requires 366.1818).

Example 93: 4-{5-Methoxy-2-[3-(2-p iazol-5-yl]phenoxy}piperidine

Light yellow oil; Vppm (400 MHz, CDC1 ₃ ): 8.09 (IH), 7.35-7.20 (5H), 6.68 (IH), 6.55 (IH), 4.86 (IH), 3.90 (3H), 3.58-3.51 (2H), 3.30-3.21 (2H), 3.15 (4H), 2.33-2.20 (2H), 2.20-2.13 (2H). mlz (ESI), found 380.1963 (C ₂₂ H ₂₆ N ₃ 0 ₃ , [M+H] ⁺ , requires 380.1974).

Example 94: 4-(5-Methoxy-2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol- 5- yl}phenoxy)piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.02 (IH), 7.26 (IH), 6.91-6.79 (5H), 5.00 (IH), 4.11 (2H), 3.90 (3H), 3.80 (3H), 3.54-3.44 (2H), 3.27-3.19 (2H), 2.20-2.08 (4H). mlz (ESI), found 396.1919 (C ₂₂ H ₂₆ N ₃ 0 ₄ , [M+H] ⁺ , requires 396.1923). Example 95: 4-[2-(3-Benzyl-l,2,4-ox henoxy]piperidine

Yellow oil; Vppm (400 MHz, CDC1 ₃ ): 8.03 (IH), 7.43-7.33 (4H), 7.26 (IH), 7.11 (IH), 7.02 (IH), 4.84 (IH), 4.17 (2H), 3.49-3.42 (2H), 3.25-3.14 (2H), 2.32-2.20 (2H), 2.17-2.06 (2H). mlz (ESI), found 370.1326 (C ₂ oH ₂₁ N ₃ 0 ₂ Cl, [M+H] ⁺ , requires 370.1322).

Example 96: 4-{5-Chloro-2-[3-(2-ph ol-5-yl]phenoxy}piperidine

Off-white solid; Vppm (400 MHz, CDC1 ₃ ): 8.06 (IH), 7.33-7.26 (4H), 7.24-7.20 (IH), 7.14 (IH), 7.04 (IH), 4.86 (IH), 3.54-3.43 (2H), 3.29-3.20 (2H), 3.15 (3H), 2.35-2.21 (2H), 2.21-2.09 (2H). mlz (ESI), found 384.1474 (C ₂ iH ₂₃ N ₃ 0 ₂ Cl, [M+H] ⁺ , requires 384.1479).

Example 97: 4-[2-(3-Benzyl-l,2,4-oxa henoxy]piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.57 (IH), 7.39-7.24 (7H), 4.45 (IH), 4.17 (2H), 3.92 (3H), 3.45-3.38 (2H), 3.08-3.02 (2H), 2.09-2.00 (2H), 1.98-1.88 (2H). mlz (ESI), found 366.1803 (C ₂ iH ₂₄ N ₃ 0 ₃ , [M+H] ⁺ , requires 366.1818).

Example 98: 4-(2-Methoxy-6-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol- 5- yl}phenoxy)piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.54 (IH), 7.31 (IH), 7.26-7.22 (2H), 6.90 (2H), 6.83 (IH), 4.45 (IH), 4.11 (2H), 3.89 (3H), 3.77 (3H), 3.44-3.37 (2H), 3.10-2.98 (2H), 2.08-1.98 (2H), 1.96- 1.86 (2H). mlz (ESI), found 396.1906 (C ₂₂ H ₂₆ N ₃ 0 ₄ , [M+H] ⁺ , requires 396.1923). Example 99: 4-[2-(3-Benzyl-l,2,4-oxa phenoxy]piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.83 (IH), 7.53 (IH), 7.42-7.34 (4H), 7.29 (IH), 7.24 (IH), 4.71 (2H), 4.02 (IH), 3.31-3.25 (2H), 2.86-2.79 (2H), 2.38 (3H), 2.03-1.93 (2H), 1.91-1.77 (2H). mlz (ESI), found 350.1867 (C ₂ iH ₂₄ N ₃ 0 ₂ , [M+H] ⁺ , requires 350.1869).

Example 100: 4-[2-(3-Benzyl-l,2,4-oxa phenoxy]piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.82 (IH), 7.40 (IH), 7.36-7.28 (4H), 7.24 (IH), 7.14 (IH), 4.90 (IH), 4.13 (2H), 3.46-3.37 (2H), 3.22-3.12 (2H), 2.32 (3H), 2.13-2.03 (4H). mlz (ESI), found 350.1855 (C ₂ iH ₂₄ N ₃ 0 ₂ , [M+H] ⁺ , requires 350.1869).

Example 101: 4-[2-(3-Benzyl-l,2,4-oxa rophenoxy]piperidine

Off-white solid; Vppm (400 MHz, CD ₃ OD): 8.04 (IH), 7.60 (IH), 7.42-7.25 (6H), 5.02-4.96 (IH), 4.18 (2H), 3.50-3.39 (2H), 3.28-3.17 (2H), 2.20-2.08 (4H). mlz (ESI), found 370.1311

(C ₂ oH ₂₁ N ₃ 0 ₂ Cl, [M+H] ⁺ , requires 370.1322).

Example 102: 4-{4-Chloro-2-[3-(2-phenylethyl)-l,2,4-oxadiazol-5-yl]phenox y}piperidine

Light yellow oil; Vppm (400 MHz, CD ₃ OD): 8.07 (IH), 7.63 (IH), 7.34 (IH), 7.32-7.25 (4H), 7.21 (IH), 5.04 (IH), 3.54-3.47 (2H), 3.32-3.27 (2H), 3.15 (4H), 2.22-2.13 (4H). mlz (ESI), found 384.1491 (C ₂ iH ₂₃ N ₃ 0 ₂ Cl, [M+H] ⁺ , requires 384.1479).

Example 103: 4-{[2-(3-Benzyl-l,2,4-o alen-l-yl]oxy}piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.35 (IH), 8.07 (IH), 7.99 (IH), 7.85 (IH), 7.74-7.64 (2H), 7.45-7.37 (4H), 7.32 (IH), 4.29 (IH), 4.23 (2H), 3.31-3.26 (2H), 2.82-2.75 (2H), 2.13-1.91 (4H). mlz (ESI), found 386.1863 (C ₂ 4H ₂₄ N ₃ 0 ₂ , [M+H] ⁺ , requires 386.1869).

Example 104: 4-({2-[3-(2-Phenylet aphthalen-l-yl}oxy)piperidine

Yellow oil; Vppm (400 MHz, CDC1 ₃ ): 8.32 (IH), 8.08 (IH), 7.91 (IH), 7.76 (IH), 7.68-7.61 (2H), 7.35-7.22 (5H), 4.27 (IH), 3.48-3.37 (2H), 3.20 (4H), 2.95-2.83 (2H), 2.24-2.10 (4H). mlz (ESI), found 400.2018 (C ₂₅ H ₂₆ N ₃ 0 ₂ , [M+H] ⁺ , requires 400.2025).

Example 105: 4-[(2-{3-[(3-Methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl}naph thalen-l- yl)oxy] piperidine

Off-white solid; Vppm (400 MHz, CDC1 ₃ ): 8.32 (IH), 8.06 (IH), 7.89 (IH), 7.74 (IH), 7.67-7.58 (2H), 7.31 (IH), 7.00 (IH), 6.96 (IH), 6.86 (IH), 4.18 (2H), 4.17 (IH), 3.84 (3H), 3.37-3.23 (2H), 2.75-2.60 (2H), 2.17-1.95 (4H). mlz (ESI), found 416.1968 (C ₂₅ H ₂₆ N ₃ 0 ₃ , [M+H] ⁺ , requires

416.1974).

Example 106: Benzyl l-(piperidin-4-yloxy)naphthalene-2-carboxylate

According to the ester formation (EDC protocol) and Boc-deprotection procedure, prepared from 1- ((l-(fert-butoxycarbonyl)piperidin-4-yl)oxy)-2 -naphthoic acid (50 mg, 0.135 mmol), the title compound was obtained as colourless oil (yield: 68%). Vppm (400 MHz, CD ₃ OD): 8.29 (1H), 7.92 (1H), 7.88 (1H), 7.71 (1H), 7.66-7.59 (2H), 7.54 (2H), 7.46-7.37 (3H), 5.43 (2H), 4.31 (2H), 3.42- 3.36 (2H), 2.91-2.85 (2H), 2.05-1.95 (4H). mlz (ESI), found 362.1746 (C ₂₃ H ₂₄ N0 ₃ , [M+H] ⁺ , requires 362.1756).

Example 107 was prepared in analogous fashion to Example 106.

Example 107: 2-Phenylethyl l-(pi e-2-carboxylate

Light yellow oil (yield: 30%); Vppm (400 MHz, CD ₃ OD): 8.29 (1H), 7.93 (1H), 7.78 (1H), 7.69 (1H), 7.67-7.59 (2H), 7.36-7.28 (4H), 7.25 (1H), 4.60 (2H), 4.37 (1H), 3.45 (2H), 3.13 (2H), 3.06- 2.97 (2H), 2.17-1.97 (4H). mlz (ESI), found 376.1909 (C ₂₄ H ₂₆ N0 ₃ , [M+H] ⁺ , requires 376.1913).

Example 108: Benzyl 4-(piperidin-4-yl -carboxylate

To a stirring solution of benzaldehyde (500 mg, 4.7 mmol) and dimethyl succinate (732 mg, 4.7 mmol) in DMF (4 mL) was added potassium fert-butoxide (369 mg, 4.7 mmol) and the mixture was stirred at room temperature for 2 hours. After that, the reaction mixture was diluted with water (30 mL) and extracted by EtOAc (2 x 30 mL). The combined organic layers were washed by brine (50 mL) and dried over anhydrous sodium sulphate. After removal of EtOAc, (E)-3- (methoxycarbonyl)-4-phenylbut-3-enoic acid was obtained as yellow oil without further purification (1.0 g, yield: 97%).

A mixture of (£)-3-(methoxycarbonyl)-4-phenylbut-3-enoic acid (1.0 g, 4.6 mmol), acetic acid (1.6 mL, 27.5 mmol), acetic anhydride (2.6 mL, 27.5 mmol) and sodium acetate (2.3 g, 27.5 mmol) was stirred for 2 hours under refluxing temperature. After that, the reaction mixture was diluted with water (30 inL) and extracted by EtOAc (2 x 30 mL). The combined organic layers were washed by brine (50 mL) and dried over anhydrous sodium sulphate. After removal of EtOAc, the residue was purified by flash column chromatography and methyl 4-acetoxy-2-naphthoate was obtained as yellow oil (170 mg, yield: 15%).

To a solution of methyl 4-acetoxy-2-naphthoate (170 mg, 0.70 mmol) in MeOH (5 mL) was added NaOH _{(aq )} (90 μί, 4 N) and the mixture was stirred at room temperature for 15 hours. After that, all volatiles were removed in vacuo and the residue re-dissolved by 15 mL of water, followed by acidification to pH 2 by concentrated HCl. The precipitate, methyl 4-hydroxy-2-naphthoate, an orange solid, was thus collected, washed with water and diethyl ether and dried in vacuo (120 mg, yield: 84%).

According to the general Mitsunobu reaction procedure (Method C), prepared from methyl 4- hydroxy-2-naphthoate (120 mg, 0.59 mmol), fert-butyl 4-((3-(methoxycarbonyl)naphthalen-l- yl)oxy)piperidine-l-carboxylate was obtained as colourless oil (140 mg, yield: 62%).

To a solution of fert-butyl 4-((3-(methoxycarbonyl)naphthalen-l-yl)oxy)piperidine-l-carb oxylate (140 mg, 0.36 mmol) in MeOH (3 mL) was added 180 of 4N NaOH solution. The resulting mixture was stirred at 65 ^° C for 6 hours. Volatile components were then removed in vacuo and the residue was partitioned between NaOH _{(aq j} (20 mL, 0.5 N) and EtOAc (20 mL) of. The pH of the aqueous layer was adjusted to 2 by addition of concentrated HCl, followed by the extraction with EtOAc (30 mL). The above organic layer was washed by brine (30 mL) and dried over anhydrous sodium sulphate. After removal of EtOAc in vacuo, 4-((l-(fert-butoxycarbonyl)piperidin-4-yl)oxy)-2- naphthoic acid was obtained as a yellow solid (93 mg, yield: 70%).

According to the ester formation (EDC protocol) and Boc-deprotection procedure, prepared from 4- ((l-(fert-butoxycarbonyl)piperidin-4-yl)oxy)-2 -naphthoic acid (40 mg, 0.11 mmol), the title compound was obtained as colourless oil (yield: 40%). Vppm (400 MHz, CD ₃ OD): 8.32 (1H), 8.28 (1H), 7.98 (1H), 7.67-7.58 (2H), 7.52 (1H), 7.51 (2H), 7.44-7.34 (3H), 5.43 (2H), 5.03 (1H), 3.53- 3.46 (2H), 3.34-3.28 (2H), 2.35-2.27 (2H), 2.25-2.17 (2H). mlz (ESI), found 362.1758 (C ₂₃ H ₂₄ N0 ₃ , [M+H] ⁺ , requires 362.1756).

Examples 109 to 111 were prepared in analogous fashion to Example 108.

Example 109: 2-Phenylethyl 4-(piperidin-4-yloxy)naphthalene-2-carboxylate

Light yellow oil; Vppm (400 MHz, CD ₃ OD): 8.31(1H), 8.20 (IH), 7.97 (IH), 7.67-7.60 (2H), 7.43 (IH), 7.37-7.31 (4H), 7.25 (IH), 5.00 (IH), 4.59 (2H), 3.54-3.46 (2H), 3.34-3.28 (2H), 3.13 (2H), 2.37-2.27 (2H), 2.24-2.15 (2H). mlz (ESI), found 376.1909 (Cz^NC^, [M+H] ⁺ , requires 376.1913).

Example 110: 4-{[3-(3-benzyl-l,2,4-ox alen-l-yl]oxy}piperidine

According to the ester formation (EDC protocol) and Boc-deprotection procedure, prepared from 4- ((l-(fert-butoxycarbonyl)piperidin-4-yl)oxy)-2 -naphthoic acid (40 mg, 0.11 mmol), the title compound was obtained as yellow oil (yield: 30%). Vppm (400 MHz, CD ₃ OD): 8.33 (IH), 8.32 (IH), 8.01 (IH), 7.69-7.62 (2H), 7.57 (IH), 7.41-7.34 (4H), 7.29 (IH), 5.04 (IH), 4.19 (2H), 3.52- 3.43 (2H), 3.29-3.23 (2H), 2.38-2.26 (2H), 2.24-2.11 (2H). mlz (ESI), found 386.1862 (C24H24N3O2, [M+H] ⁺ , requires 386.1869).

Example 111: 4-({3-[3-(2-phenylethyl -l,2,4-oxadiazol-5-yl]naphthalen-l-yl}oxy)piperidine

Off-white solid; Vppm (400 MHz, CD ₃ OD): 8.37 (IH), 8.35 (IH), 8.05 (IH), 7.71-7.65 (2H), 7.62 (IH), 7.33-7.26 (4H), 7.21 (IH), 5.11 (IH), 3.58-3.50 (2H), 3.36-3.30 (2H), 3.15 (4H), 2.43-2.31 (2H), 2.31-2.20 (2H). mlz (ESI), found 400.2028 (C ₂₅ H ₂₆ N ₃ 0 ₂ , [M+H] ⁺ , requires 400.2025).

Intermediate 28: teri-Butyl 4-((2-(hydrazinecarbonyl)benzo[6]thiophen-3-yl)oxy)piperidin e-l- carboxylate

To a solution of fert-butyl 4-((2-(ethoxycarbonyl)benzo[6]thiophen-3-yl)oxy)piperidine-l -carboxylate (boc-protected Example 25, 300 mg, 0.74 mmol) in ethanol (1 mL) was added hydrazine monohydrate (145 μί, 2.96 mmol). The reaction mixture was heated under refluxing conditions for 24 h, then concentrated under reduced pressure yielding Intermediate 28 as a yellow oil (217 mg, 75%). Vppm (400 MHz, CDC1 ₃ ) 7.79 (1H), 7.74 (1H), 7.48 - 7.37 (2H), 4.58 (1H), 4.13 - 4.04 (2H), 2.95 - 2.82 (2H), 2.14 - 2.05 (2H), 1.92 - 1.78 (2H), 1.48 (9H).

Intermediate 29: tert-Butyl 4-((2-(2-(2-phenylacetyl)hydrazinecarbonyl)benzo[6]thiophen- 3- yl)oxy)piperidine-l-carboxylate

According to the general mixed hydrazide procedure A, prepared from Intermediate 28 (215 mg, 0.55 mmol) and phenacetyl chloride (commercially available), Intermediate 29 was obtained as an orange oil (256 mg, 91%). Vppm (400 MHz, CDC1 ₃ ) 10.16 (1H), 9.45 (1H), 7.82 - 7.76 (2H), 7.49 - 7.28 (7H), 4.69 (1H), 4.18 - 4.08 (2H), 3.76 (2H), 2.91 - 2.75 (2H), 2.15 - 2.07 (2H), 2.02 - 1.88 (2H), 1.47 (9H).

Intermediate 30: tert-Butyi 4-((2-(2-(2-hydroxy-2- phenylacetyl)hydrazinecarbonyl)benzo[6]thiophen-3-yl)oxy)pip eridine-l-carboxylate

According to the general mixed hydrazide procedure B, prepared from Intermediate 28 (48 mg, 0.12 mmol) and 2-hydroxy-2-phenylacetic acid (commercially available), Intermediate 30 was obtained as a white solid (64 mg, 99%). Vppm (400 MHz, CDC1 ₃ ) 7.87 - 7.75 (2H), 7.59 - 7.34 (7H), 5.38 (1H), 4.68 (1H), 4.22 - 4.02 (2H), 2.85 - 2.81 (2H), 2.16 - 2.06 (2H), 1.99 - 1.83 (2H),

1.47 (9H).

Intermediate 31: tert-Butyi 4-((2-(5-benzyl-l,3,4-oxadiazol-2-yl)benzo[6]thiophen-3- yl)oxy)piperidine-l-carboxylate

According to the general 1,3,4-oxadiazole procedure, prepared from Intermediate 29 (130 mg,

0.26 mmol), Intermediate 31 was obtained as a yellow oil (81 mg, 65%). <Vpprn (400 MHz, CDC1 ₃ ) 7.83 - 7.75 (2H), 7.49 - 7.30 (7H), 4.43 (1H), 4.31 (2H), 3.87 (2H), 2.85 (2H), 1.85 (2H), 1.67 (2H), 1.49 (9H).

Intermediate 32: tert- utyi 4-((2-(2-(2-(3- methoxyphenyl)acetyl)hydrazinecarbonyl)benzo[6]thiophen-3-yl )oxy)piperidine-l-carboxylate

Intermediate 32 was prepared according to the general method for mixed hydrazide formation A prepared from Intermediate 28 (215 mg, 0.55 mmol) and 3-methoxyphenacetyl chloride

(commercially available), yielding Intermediate 32 as a yellow oil (164 mg, 76%). <Vpprn

(400 MHz, CDC1 ₃ ) 10.19 (1H), 9.79 (1H), 7.81 - 7.76 (2H), 7.48 - 7.38 (2H), 7.24 (1H), 6.97 (1H), 6.95 (1H), 6.82 (1H), 4.69 (1H), 4.17 - 4.08 (2H), 3.78 (3H), 3.75 (2H), 2.88 - 2.77 (2H), 2.15 - 2.07 (2H), 2.01 - 1.89 (2H), 1.47 (9H).

Intermediate 33: tert-Butyi 4-((2-(5-(3-methoxybenzyl)-l,3,4-oxadiazol-2-yl)benzo[6]thio phen-3- yl)oxy)piperidine-l-carboxylate

Intermediate 33 was prepared according to the general method for 1,3,4-oxadiazole formation, yielding Intermediate 33 as a colourless oil (23 mg, 48%). Vppm (400 MHz, CDC1 ₃ ) 7.81 (1H), 7.78 (1H), 7.49 - 7.44 (1H), 7.44 - 7.39 (1H), 7.30 (1H), 6.94 (1H), 6.90 (1H), 6.86 (1H), 4.44 (1H), 4.27 (2H), 3.88 (2H), 3.82 (3H), 2.87 (2H), 1.92 - 1.84 (2H), 1.69 (2H), 1.49 (9H). Intermediate 34: Ethyl 3-acetyl-4-oxopentanoate

To a solution of sodium hydride (576 mg, 24.0 mmol) in anhydrous tetrahydrofuran (30 mL) cooled to 0 °C was added pentane-2,4-dione (2.05 mL, 20.0 mmol) in anhydrous tetrahydrofuran (40 mL) and reaction stirred for 1 h. Ethyl bromoacetate (2.66 mL, 24.0 mmol) in anhydrous tetrahydrofuran (30 mL) was then added and the reaction mixture was stirred for 18 h. The reaction mixture was then washed with saturated NH ₄ Cl _(aq) (100 mL) and aqueous layer was extracted with EtOAc (100 mL). Combined organic layers were washed with brine (100 mL), dried over magnesium sulfate and concentrated under reduced pressure, yielding Intermediate 34 as a yellow oil (2.90 g, 78%). Mixture of diketone:enol tautomers 2: 1; Diketone Vppm (400 MHz, CDC1 ₃ );. 4.20 - 4.12 (3H), 2.90 (2H), 2.29 (6H), 1.31 - 1.25 (3H); Enol Vppm (400 MHz, CDC1 ₃ ); 4.22 - 4.08 (2H), 3.25 (2H), 2.17 (6H), 1.32 - 1.23 (3H).

Intermediate 35: Ethyl 2-(3,5-dimethyl-lH-pyrazol-4-yl)acetate

To a solution of Intermediate 34 (400 mg, 2.15 mmol) in methanol (3 mL) was added hydrazine monohydrate (157 μί, 3.23 mmol) and reaction stirred at room temperature for 3 h. Reaction mixture was concentrated under reduced pressure, yielding Intermediate 35 as a colourless oil (349 mg, 83%). Vppm (400 MHz, CDC1 ₃ ); 7.38 (1H), 4.13 (2H), 3.36 (2H), 2.25 (6H), 1.25 (3H).

Intermediate 36: 2-(3,5-Dimethyl-lH-pyrazol-4-yl)acetic acid

Intermediate 36 was prepared as in general method for ester hydrolysis, yielding Intermediate 36 as a white solid (23 mg, 12%). Vppm (400 MHz, CDC1 ₃ ); 3.40 (2H), 2.31 (3H), 2.18 (3H). Intermediate 37: tert- utyi 4-((2-(2-(2-(3,5-dimethyl-lH-pyrazol-4- yl)acetyl)hydrazinecarbonyl)be ine-l-carboxylate

Intermediate 37 was prepared according to the general method for hydrazide formation B from

Intermediates 28 and 36, yielding Intermediate 37 as a yellow solid (30 mg, 48%). <Vpprn

(400 MHz, CDC1 ₃ ); 7.86 - 7.72 (2H), 7.51 - 7.37 (2H), 4.80 - 4.65 (1H), 4.16 - 4.04 (2H), 3.48 (2H), 2.89 - 2.81 (2H), 2.29 (3H), 2.15 - 2.09 (2H), 2.06 (3H), 1.92 - 1.83 (2H), 1.48 (9H).

Intermediate 38: Ethyl 2-(3,5-dimethylisoxazol-4-yl)acetate

To a solution of Intermediate 34 (400 mg, 2.15 mmol) in ethanol (3 mL) was added hydroxylamine hydrochloride (225 mg, 3.23 mmol) and potassium carbonate (595 mg, 4.30 mmol) and reaction stirred at 78 °C for 3 h. Reaction mixture was purified by flash chromatography, yielding

Intermediate 38 as a colourless oil (49 mg, 12%). Vppm (400 MHz, CDC1 ₃ ); 4.16 (2H), 3.30 (2H), 2.35 (3H), 2.24 (3H), 1.27 (3H).

Intermediate 39: 2-(3,5-Dimethylisoxazol-4-yl)acetic acid

Intermediate 39 was prepared as in general method for ester hydrolysis, yielding Intermediate 39 as a white solid (19 mg, 51%). Vppm (400 MHz, CDC1 ₃ ); 3.35 (2H), 2.35 (3H), 2.25 (3H).

Intermediate 40: tert-Butyi 4-((2-(2-(2-(3,5-dimethylisoxazol-4- yl)acetyl)hydrazinecarbonyl)benzo[6]thiophen-3-yl)oxy)piperi dine-l-carboxylate

Intermediate 40 was prepared according to the general method for mixed hydrazide formation B from Intermediates 28 and 39, yielding Intermediate 40 as a yellow solid (34 mg, 55%). <Vpprn (400 MHz, CDC1 ₃ ); 9.94 (1H), 8.99 (1H), 7.88 - 7.74 (2H), 7.54 - 7.38 (2H), 4.72 (1H), 4.22 - 4.04 (2H), 3.46 (2H), 2.92 - 2.76 (2H), 2.43 (3H), 2.31 (3H), 2.18 - 2.05 (2H), 1.99 - 1.87 (2H), 1.47 (9H).

Intermediate 41: Ethyl 2-(l,3,5-trim ethyl- lH-pyrazol-4-yl)acetate

To a solution of Intermediate 34 (400 mg, 2.15 mmol) in acetic acid (3 mL) was added methyl hydrazine (125 μί, 2.37 mmol) dropwise and reaction stirred at room temperature for 3 h. Reaction mixture was concentrated under reduced pressure, yielding Intermediate 41 as a colourless oil (349 mg, 73%). Vppm (400 MHz, CDC1 ₃ ); 4.15 (2H), 3.74 (3H), 3.35 (2H), 2.22 (6H), 1.28 (3H).

Intermediate 42: 2-(l,3,5-Trimethyl-lH-pyrazol-4-yl)acetic acid

To a solution of Intermediate 42 (300 mg, 1.53 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (642 mg, 15.3 mmol) and reaction stirred at room temperature for 18 h. Reaction mixture was diluted with water (20 mL) and acidifed with 2.0M HCl _(aq) to pH 4, then Intermediate 42 was extracted with EtOAc (3 x 20 mL). Combined organic layers were then dried over sodium sulphate and concentrated under reduced pressure, yielding Intermediate 42 as a pink crystalline solid (130 mg, 51%). Vppm (400 MHz, CDC1 ₃ ); 3.80 (3H), 3.41 (2H), 2.24 (3H), 2.23 (3H).

Intermediate 43: tert- utyi 4-((2-(2-(2-(l,3,5-trimethyl-lH-pyrazol-4- yl)acetyl)hydrazinecarbonyl)benzo[6]thiophen-3-yl)oxy)piperi dine-l-carboxylate

Intermediate 43 was prepared according to the general method for mixed hydrazide formation B from Intermediates 28 and 42, yielding Intermediate 43 as an orange oil (43 mg, 66%). <Vpprn (400 MHz, CDC1 ₃ ); 9.75 (1H), 7.89 - 7.72 (3H), 7.53 - 7.37 (2H), 4.75 - 4.65 (1H), 4.12 - 4.06 (2H), 3.76 (3H), 3.46 (2H), 2.86 - 2.82 (2H), 2.26 (6H), 2.14 - 2.09 (2H), 1.99 - 1.87 (2H), 1.48 (9H).

Example 112: 2-Benzyl-5-(3-(piperidin-4-yloxy)benzo[6]thiophen-2-yl)-l,3, 4-oxadiazole

Example 112 was prepared according to the general method for Boc deprotection and purified by HPLC yielding Example 112 as a white solid (7.8 mg, 98%). R, = 10.7 min; Vppm (400 MHz, CDC1 ₃ ) 7.83 - 7.76 (2H), 7.54 - 7.42 (2H), 7.42 - 7.29 (5H), 4.73 (1H), 4.32 (2H), 3.50 (2H), 3.02 (2H), 2.23 - 2.09 (4H); ESI HRMS, found 392.1435 (C ₂ 2H ₂₂ N ₃ 0 ₂ S, [M + H] ⁺ , requires 392.1433).

Example 113: Phenyl(5-(3-(piperidin-4-yloxy)benzo[6]thiophen-2-yl)-l,3,4- oxadiazol-2- yl)methanol

Example 113 was prepared according to the general method for 1,3,4-oxadiazole formation and Boc deprotection using Intermediate 30 and purified by LC-MS yielding Example 113 as a white solid (2.2 mg, 4%). R, = 6.5 min; Vppm (400 MHz, CD ₃ OD) 7.95 - 7.87 (2H), 7.59 - 7.35 (7H), 6.15 (1H), 4.71 - 4.65 (1H), 3.45 (2H), 3.04 - 2.90 (2H), 2.20 - 1.99 (4H); ESI HRMS, found 392.1435 (C ₂₂ H ₂₂ N ₃ 0 ₂ S, [M + H] ⁺ , requires 392.1433).

Example 114: 2-(3-Methoxybenzyl)-5-(3-(piperidin-4-yloxy)benzo[6]thiophen -2-yl)-l,3,4- oxadiazole

Example 114 was prepared according to the general method for Boc deprotection and purified by

HPLC yielding Example 114 as a white solid (11 mg, 55%). R, = 10.7 min; Vppm (400 MHz, CDC1 ₃ ); 7.85 - 7.77 (2H), 7.55 - 7.43 (2H), 7.31 (1H), 6.96 (1H), 6.91 (1H), 6.87 (1H), 4.79 - 4.70 (1H), 4.30 (2H), 3.82 (3H), 3.59 - 3.47 (2H), 3.11 - 2.99 (2H), 2.24 - 2.14 (4H); ESI HRMS, found 422.1535 (C ₂₃ H ₂₄ N ₃ 0 ₃ S, [M + H] ⁺ , requires 422.1538).

Example 115: 4-((2-(3-Benzyl-lH-l,2,4-triazol-5-yl)benzo[6]thiophen-3-yl) oxy)piperidine

A solution of Intermediate 29 (210 mg, 0.41 mmol) in POCl ₃ (3.5 mL) was stirred at 100 °C for 1 h. Reaction was then allowed to cool to room temperature and concentrated under vacuum. Crude residue was then dissolved in acetic acid (1.5 mL) and ammonium acetate (600mg, 7.78 mmol) was added. Reaction mixture was stirred at 140 °C for a further 1.5 h. The reaction mixture was then diluted with EtOAc (20 mL) and washed with 10% NaOH _(aq) (20 mL). The aqueous washings were then back-extracted with EtOAc (20 mL) and combined organic layers were dried over sodium sulfate. Reaction was purified by LC-MS yielding Example 115 as a white solid (10 mg, 6%). R, = 7.2 min; Vppm (400 MHz, CD ₃ OD); 7.88 - 7.74 (2H), 7.50 - 7.39 (2H), 7.39 - 7.18 (5H), 4.66 (1H), 4.20 (2H), 3.79 - 3.62 (1H, m), 3.48 (2H), 3.00 (2H), 2.14 - 1.98 (4H); ESI HRMS, found 391.1577 (C ₂ 2H ₂₃ N ₄ OS, [M + H] ⁺ , requires 391.1593).

Example 116: 2-((3,5-Dimethyl-lH-pyrazol-4-yl)methyl)-5-(3-(piperidin-4- yloxy)benzo[6]thiophen-2-yl)-l,3,4-oxadiazole

Example 116 was prepared according to the general method for 1,3,4-oxadiazole formation and Boc deprotection and purified by LC-MS yielding Example 116 as a yellow solid (4 mg, 8%). R, = 7.7 min; <¾/ppm (400 MHz, CDC1 ₃ ); 7.96 - 7.88 (2H), 7.59 - 7.46 (2H), 4.77 (1H), 4.13 (2H), 3.53 (2H), 3.13 - 3.03 (2H), 2.27 (6H), 2.21 - 2.01 (4H); ESI HRMS, found 410.1653 (C ₂ iH ₂₄ N ₅ 0 ₂ S, [M + H] ⁺ , requires 410.1651).

Example 117: 2-((3,5-Dimethylisoxazol-4-yl)methyl)-5-(3-(piperidin-4-ylox y)benzo [6]thiophen- 2-yl)-l,3,4-oxadiazole

Example 117 was prepared according to the general method for 1,3,4-oxadiazole formation and Boc deprotection and purified by LC-MS yielding Example 117 as a yellow solid (13 mg, 26%). R, = 7.1 min; <¾/ppm (400 MHz, CD ₃ OD); 7.98 - 7.87 (2H), 7.57 - 7.47 (2H), 4.84 (1H), 4.16 (2H), 3.57 (2H), 3.13 (2H), 2.45 (3H), 2.28 (3H), 2.25 - 2.08 (4H); ESI HRMS, found 411.1502 (C ₂ iH ₂₃ N ₄ 0 ₃ S, [M + H] ⁺ , requires 411.1491).

Example 118: 2-(3-(Piperidin-4-yloxy)benzo[6]thiophen-2-yl)-5-((l,3,5-tri methyl-lH-pyrazol-4- yl)methyl)-l,3,4-oxadiazole

Example 118 was prepared according to the general method for 1,3,4-oxadiazole formation and Boc deprotection and purified by LC-MS yielding Example 118 as a yellow solid (9 mg, 17%). R, = 7.1 min; <¾/ppm (400 MHz, CD ₃ OD); 8.47 (1H), 7.99 - 7.88 (2H), 7.61 - 7.45 (2H), 4.81 (1H), 4.12 (2H), 3.72 (3H), 3.56 (2H), 3.11 (2H), 2.29 (3H), 2.22 (3H), 2.21 - 2.04 (4H); ESI HRMS, found 424.1801 (C ₂₂ H ₂₆ N ₅ 0 ₂ S, [M + H] ⁺ , requires 424.1807).

Examples 119 to 137 were prepared in analogous fashion to Example 89.

Example 119: 4-(2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl}-6- methylphenoxy)piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.83 (IH), 7.53 (IH), 7.28 (IH), 7.25 (IH), 6.99-6.93 (2H), 6.87 (IH), 4.14 (2H), 4.01 (IH), 3.81 (3H), 3.31-3.24 (2H), 2.86-2.80 (2H), 2.39 (3H), 2.05-1.94 (2H), 1.91-1.79 (2H). mlz (ESI), found 380.1971 (C ₂₂ H ₂₆ N ₃ 0 ₃ , [M+H] ⁺ , requires 380.1974).

Example 120: 4-(2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl}-4- methylphenoxy)piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.87 (IH), 7.44 (IH), 7.27 (IH), 7.19 (IH), 6.99-6.92 (2H), 6.86 (IH), 4.97 (IH), 4.14 (2H), 3.81 (3H), 3.52-3.44 (2H), 3.26-3.17 (2H), 2.37 (3H), 2.17-2.10 (4H). mlz (ESI), found 380.1961 (C ₂₂ H ₂₆ N ₃ 0 ₃ , [M+H] ⁺ , requires 380.1974).

Example 121: 4-(4-chloro-2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5 - yl}phenoxy)piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.02 (IH), 7.58 (IH), 7.29-7.24 (2H), 6.98-6.89 (2H), 6.85 (IH), 4.97 (IH), 4.14 (2H), 3.79 (3H), 3.51-3.40 (2H), 3.28-3.16 (2H), 2.20-2.06 (4H). mlz (ESI), found 400.1418 (C ₂ iH ₂₃ N ₃ 0 ₃ Cl, [M+H] ⁺ , requires 400.1428).

Example 122: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-4-methoxyphenoxy]piperi dine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.54 (IH), 7.38-7.16 (7H), 4.79 (IH), 4.15 (2H), 3.81 (3H), 3.48-3.38 (2H). 3.22-3.11 (2H), 3.14-2.00 (4H). mlz (ESI), found 366.1802 [M+H] ⁺ , requires 366.1818).

Example 123: 4-(4-methoxy-2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol- 5- yl}phenoxy)piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.56 (IH), 7.26 (IH), 7.24-7.17 (2H), 6.98-6.89 (2H), 6.85 (IH), 4.80 ( IH), 4.14 (2H), 3.83 (3H), 3.80 (3H). 3.51-3.40 (2H), 3.24-3.13 (2H), 2.17-2.04 (4H). mlz (ESI), found 396.1914 (C ₂₂ H ₂₆ N O ₄ , [M+H] ⁺ , requires 396.1923).

Example 124: 3-(3-benzyl-l,2,4-oxadiazol-5-yl)-2-(piperidin-4-yloxy)pyrid ine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.46 (IH), 8.41 (IH), 7.40-7.24 (5H), 7.19 (IH). 5.66 (IH), 4.18 (2H), 3.52-3.42 (2H), 3.32-3.24 (2H), 2.34-2.14 (4H). mlz (ESI), found 337.1665 (C ₁₉ H ₂₁ N ₄ 0 ₂ , [M+H] ⁺ , requires 337.1658). Example 125: 3-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl}-2-(pipe ridin-4- yloxy)pyridine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.46 (IH), 8.41 (IH), 7.26 (IH), 7.19 (IH), 6.98-6.90 (2H), 6.85 (IH), 5.66 ( IH). 4.14 (2H), 3.80 (3H). 3.53-3.42 (2H), 3.31-3.24 (2H), 2.26-2.12 (4H). mlz (ESI), found 367.1770 (C ₂ oH ₂₃ N ₄ 0 ₃ , [M+H] ⁺ , requires 367.1770).

Example 126: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-5-fluorophenoxy]piperid ine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.10 (IH), 7.39-7.31 (4H). 7.27 (IH), 7.17 (IH). 6.93 (IH), 5.01 (IH), 4.16 (2H), 3.51-3.40 (2H), 3.27-3.18 (2H), 2.20-2.09 (4H). mlz (ESI), found 354.1612 (C ₂ oH ₂₁ N ₃ 0 ₂ F, [M+H] ⁺ , requires 354.1618).

Example 127: 4-(5-fluoro-2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5 - yl}phenoxy)piperidine

Yellow solid; Vppm (400 MHz, CD ₃ OD): 8.11 (IH), 7.26 (IH), 7.16 (IH), 6.97-6.89 (3H), 6.85 (IH), 5.00 (IH), 4.13 (2H), 3.79 (2H), 3.53-3.42 (2H), 3.29-3.19 (2H), 3.33-2.09 (4H). mlz (ESI), found 384.1723 (C ₂₁ H ₂₃ N ₃ 0 ₃ F, [M+H] ⁺ , requires 384.1723). Example 128: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-5-bromophenoxy]piperidi ne

Light yellow solid; <¾/ppm (400 MHz, CD ₃ OD): 7.96 (IH), 7.53 (IH), 7.39-7.31 (5H), 7.26 (IH), 5.02 (IH), 4.17 (2H), 3.49-3.39 (2H), 3.28-3.17 (2H), 2.18-2.07 (4H). mlz (ESI), found 414.0825 (C ₂ oH ₂₁ N ₃ 0 ₂ Br, [M+H] ⁺ , requires 414.0825).

Example 129: 4-(5-bromo-2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5- yl}phenoxy)piperidine

Light yellow oil; <¾/ppm (400 MHz, CD ₃ OD): 7.96 (IH), 7.53 (IH), 7.34 (IH), 7.25 (IH), 6.97-6.88 (2H), 6.84 (IH), 5.02 (IH), 4.13 (2H), 3.79 (3H), 3.52-3.41 (2H), 3.28-3.19 (2H), 2.20-2.09 (4H). mlz (ESI), found 444.0919 (C ₂ iH ₂₃ N ₃ 0 ₃ Br, [M+H] ⁺ , requires 444.0923).

Example 130: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-6-fluorophenoxy]piperid ine

Light yellow oil; <¾/ppm (400 MHz, CD ₃ OD): 7.87 (IH), 7.50 (IH), 7.41-7.24 (6H), 4.58-4.50 (IH), 4.19 (2H), 3.48-3.38 (2H), 3.13-3.02 (2H), 2.14-1.97 (4H). mlz (ESI), found 354.1603 (C ₂₀ H ₂₁ N ₃ O ₂ F, [M+H] ⁺ , requires 354.1618).

Example 131: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-4-bromophenoxy]piperidi ne

Light yellow oil; <¾/ppm (400 MHz, CD ₃ OD): 8.16 (IH), 7.72 (IH), 7.42-7.32 (4H), 7.31-7.23 (2H), 4.99 (IH), 4.17 (2H), 3.49-3.38 (2H), 3.27-3.16 (2H), 2.19-2.07 (4H). mlz (ESI), found 414.0829 (C ₂ oH ₂₁ N ₃ 0 ₂ Br, [M+H] ⁺ , requires 414.0817).

Example 132: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-5-nitrophenoxy]piperidi ne

Light yellow oil; <¾/ppm (400 MHz, CD ₃ OD): 8.27 (IH), 8.06 (IH), 7.96 (IH), 7.39-7.28 (4H), 7.25 (IH), 5.14 (IH), 4.18 (2H), 3.47-3.37 (2H), 3.27-3.17 (2H), 2.22-2.09 (4H). mlz (ESI), found 381.1564 (C ₂₀ H ₂₁ N ₄ O ₄ , [M+H] ⁺ , requires 381.1563).

Example 133: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-5-(trifluoromethyl)phen oxy]piperidine

Light yellow oil; <¾/ppm (400 MHz, CD ₃ OD): 8.23 (IH), 7.57 (IH), 7.45 (IH), 7.38-7.29 (4H), 7.25 (IH), 5.08 (IH), 4.17 (2H), 3.48-3.37 (2H), 3.26-3.16 (2H), 2.18-2.06 (4H). mlz (ESI), found 404.1589 (C ₂ iH ₂₁ N ₃ 0 ₂ F ₃ , [M+H] ⁺ , requires 404.1586).

Example 134: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-4-fluorophenoxy]piperid ine

Light yellow oil; Vppm (400 MHz, CD ₃ OD): 7.78 (IH), 7.43-7.23 (7H), 4.91-4.74 (IH), 4.18 (2H), 3.51-3.39 (2H), 3.27-3.15 (2H), 2.19-2.05 (4H). mlz (ESI), found 354.1613 (C ₂ oH ₂ iN ₃ 0 ₂ F, [M+H] ⁺ , requires 354.1618).

Example 135: 4-[2-(3-benzyl-l,2,4-oxadiazol-5-yl)-3-fluorophenoxy]piperid ine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.62 (IH), 7.40-7.31 (4H), 7.27 (IH), 7.10 (IH), 6.97 (IH), 4.60 (IH), 4.20 (2H), 3.25-3.16 (2H), 3.13-3.05 (2H), 2.13-1.95 (4H). mlz (ESI), found 354.1622 (C ₂ oH ₂₁ N ₃ 0 ₂ F, [M+H] ⁺ , requires 354.1618).

Example 136: 2-(3-benzyl-l,2,4-oxadiazol-5-yl)-3-(piperidin-4-yloxy)pyrid ine

Light yellow solid; Vppm (400 MHz, CD ₃ OD): 8.38 (IH), 7.84 (IH), 7.66 (IH), 7.42-7.32 (4H), 7.28 (IH), 5.05 (IH), 4.23 (2H), 3.49-3.38 (2H), 3.26-3.15 (2H), 2.19-2.07 (4H). mlz (ESI), found 337.1659 (Ci ₉ H ₂₁ N ₄ 0 ₂ , [M+H] ⁺ , requires 337.1665).

Example 137: 4-(5-chloro-2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5 - yl}phenoxy)piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.04 (IH), 7.39 (IH), 7.26 (IH), 7.18 (IH), 6.97-6.88 (2H), 6.84 (IH), 5.01 (IH), 4.13 (2H), 3.79 (3H), 3.51-3.41 (2H), 3.28-3.18 (2H), 2.20-2.08 (4H). mlz (ESI), found 400.1428 (C ₂ iH ₂₃ N ₃ 0 ₃ Cl, [M+H] ⁺ , requires 400.1428).

Examples 138 to 139 were prepared in analogous fashion to Example 23.

Example 138: 4-[(2-{3-[(3-methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl}-3-m ethyl-l-benzofuran- 4-yl)oxy] piperidine

Yellow oil; Vppm (400 MHz, CD ₃ OD): 7.34 (IH), 7.23 (IH), 7.13 (IH), 6.93-6.91 (2H), 6.82-6.78 (2H), 4.88 (IH), 4.10 (2H), 3.77 (3H), 3.46-3.40 (2H), 3.29-3.21 (2H), 2.78 (3H), 2.30-2.18 (2H), 2.18-2.06 (2H). mlz (ESI), found 420.1919 (C ₂₄ H ₂₆ N ₃ O ₄ , [M+H] ⁺ , requires 420.1923).

Example 139: 3-({5-[3-methyl-4-(piperidin-4-yloxy)-l-benzofuran-2-yl]-l,2 ,4-oxadiazol-3- yl}methyl)pyridine

Light yellow oil; Vppm (400 MHz, CD ₃ OD): 8.61 (IH), 8.46 (IH), 7.90 (IH), 7.44 (IH), 7.40 (IH), 7.18 (IH), 6.89 (IH), 4.96 (IH), 4.25 (2H), 3.47-3.36 (2H), 3.30-3.21 (2H), 2.84 (3H), 2.33-2.22 (2H), 2.22-2.08 (2H).m/z (ESI), found 391.1775 ^Hz^C , [M+H] ⁺ , requires 391.1770).

Intermediate 44: 4-({l-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}oxy)-3-methyl-l -benzofuran-2- carboxylic acid

Starting from 4-hydroxy-3 -methyl- l-benzofuran-2-carboxylic acid and tert-butyl 3- hydroxypyrrolidine-l-carboxylate, according to the preparation of Intermediate 1, the title compound was obtained as an off-white solid. Vppm (400 MHz, CD ₃ OD): 7.37 (IH), 7.15 (IH), 6.70 (IH), 5.29 (IH), 3.60-3.42 (2H), 2.76 (3H), 2.50-2.30 (2H), 1.50 (9H).

Example 140: 3-({5-[3-methyl-4-(pyrrolidin-3-yloxy)-l-benzofuran-2-yl]-l, 2,4-oxadiazol-3- yl}methyl)pyridine

Example 140 was prepared in analogous fashion to Example 23, using the starting material

Intermediate 44. Yellow oil; Vppm (400 MHz, CD ₃ OD): 8.58 (IH), 8.43 (IH), 7.87 (IH), 7.41 (IH), 7.38 (IH), 7.18 (IH), 6.79 (IH), 5.32 (IH), 4.22 (2H), 3.68 (2H), 3.59-3.44 (2H), 2.76 (3H), 2.49-2.32 (2H). mlz (ESI), found 376.1539 (C ₂ iH ₂ oN ₄ 0 ₃ , [M+H] ⁺ , requires 376.1535).

Details of biological assays, and data

(a) The IC ₅₀ values for Plasmodium vivax (Pv) NMT, Human NMT1 and Human NMT2 were measured using a sensitive fluorescence-based assay based on detection of CoA by 7-diethylamino-3- (4-maleimido-phenyl)-4-methylcoumarin, as described in Goncalves, V., et al, Analytical

Biochemistry, 2012, 421, 342-344 and Goncalves, V., et al. , J. Med. Chem, 2012, 55, 3578. An adapted version of the assay was used to measure the IC ₅₀ values of Plasmodium falciparum (Pf) NMT, and Leishmania donovani (Ld) NMT for certain compounds of the invention. For PfNMT and LdNMT the final enzyme concentration and peptide substrates are modified, see below:

- PfNMT Final Concentration: 400 ng/mL

- LdNMT Final Concentration: 400 ng/mL

- PfNMT and LdNMT Peptide Substrate: Homo sapiens p60 ^src (2-16) Amino Acids, final concentration 4.0 μΜ, Sequence: GSNKSKPKDASQRRR-NH ₂ [SEQ ID NO: 1], as in

PvNMT. (b) IC ₅₀ values for Human NMT1 (Hsl), Human NMT2 (Hs2), Plasmodium falciparum (Pf) NMT, Plasmodium vivax (Pv) NMT and Leishmania donovani (Ld) NMT were measured for certain compounds of the invention using a scintillation proximity assay (SPA) assay (Y u, Z., et al, J. Med. Chem. , 2012, 55, 8879-8890).

(c) EC ₅₀ values for Plasmodium falciparum (Pf) NMT were measured for certain compounds of the invention using an assay utilising fluorescence-activated cell sorting (Y u, Z., et al, J. Med. Chem., 2012, 55, 8879-8890).

(d) EC ₅₀ values for Plasmodium falciparum (Pf) NMT were measured for certain compounds of the invention using an assay utilising SYBRGreen dye. The assay was carried out as follows:

Synchronous Plasmodium falciparum 3D7 late stage trophozoites at 33 - 36 h were used. Final parasitemia and haematocrit were between 0.1 - 0.2% and 2% respectively. Red blood cells used for the assay were centrifuged to remove the buffy coat and washed twice in Roswell Park Memorial Institute (RPMI) Media 1640 so that no white blood cells were present. The culture medium contained RPMI 1640 with 5 g/L Albumax, 0.025 g/L gentamycin and 0.292 g/L L-glutamine.

Sterile 96 well black tissue culture plates (Costar) were used routinely for every assay. Drugs were diluted in culture medium and used in duplicate wells for each dilution ranging from 10.000, 3.333, 1.111, 0.370, 0.123, 0.041 and 0.014 μΜ respectively in a final volume of 100 per well.

Chloroquine was used as a standard with ten times reduced concentrations range as above. Two sets of control were used in duplicate wells, one set with no added drugs (positive control) and one with uninfected red blood cells (negative control).

The plates were incubated at 37 °C for 48 h in a gas chamber flushed with 5% C02, 5% 02 and 90% N ₂ . After 48 h supematants were taken out from each well and replaced with fresh drug and incubated for a further 48 h in the same manner. At the end of the 96 h incubation, 25 of SYBR Green I dye (SYBR Green I nucleic acid gel stain lOOOOx, in DMSO from Invitrogen) in lysis buffer (1 dye to 1 mL lysis buffer) was added to each well and stored overnight at -20 °C. The lysis buffer contained Tris (20 mM, pH 8.0), EDTA (2 mM), Saponin (0.16%) and Triton X-100 (1.6% v/v).

Plates were warmed to room temperature and fluorescence intensity was measured with a FLUOstar Omega Microplate fluorescence reader (BMG Labtech). Values were expressed in relative fluorescence units. Binding of SYBR Green is specific for parasite DNA as mature erythrocytes lack DNA and RNA. Fluorescence intensity unit was converted to percentage (%) of growth as follows:

% growth = (culture under drug) - (uninfected RBC) / (culture with no drug) - (uninfected RBC) x 100 and the EC ₅₀ value was determined.

The compounds of Examples 1-140 exhibit one or more of the following:

(i) inhibition of Plasmodium falciparum (Pf) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 99.9 μΜ in assay (a);

(ii) inhibition of Plasmodium vivax (Pv) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 99.9 μΜ in assay (a);

(iii) inhibition of Leishmania donovani (Ld) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 99.9 μΜ in assay (a);

(iv) inhibition of Plasmodium falciparum (Pf) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 99.9 μΜ in assay (b);

(v) inhibition of Plasmodium vivax (Pv) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 99.9 μΜ in assay (b);

(vi) inhibition of Leishmania donovani (Ld) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 99.9 μΜ in assay (b);

(vii) inhibition of Plasmodium falciparum (Pf) N-myristoyl transferase in the range of EC ₅₀ 0.001 to 99.9 μΜ in assay (c);

(viii) inhibition of Plasmodium falciparum (Pf) N-myristoyl transferase in the range of EC ₅₀ 0.001 to 99.9 μΜ in assay (d);

Certain compounds of Examples 1-140 also exhibit inhibitory activity for Human N-myristoyl transferase 1 (Hsl) and/or Human N-myristoyl transferase 2 (Hs2). Preferably compounds of the invention have IC ₅₀ values for Plasmodium falciparum and/or Plasmodium vivax and/or Leishmania donovani which are less than the IC ₅₀ values for Human NMT1 and/or Human NMT2 by a factor of 10 times, more preferably 100 times, still more preferably 1000 times.

Certain compounds of Examples 1-140 also exhibit inhibitory activity at the level of inhibition of fungal N-myristoyl transferase in the range of IC ₅₀ 0.001 to 99.9 μΜ;

Preferred Example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the IC ₅₀ range shown above. For example, the compounds of examples 223, 25, 32, 33, 34, 35, 37, 38, 39, 40, 44, 45, 58, 72, 73, 74, 75, 77, 78, 79, 82, 83, 84, 86, 88, 89, 91, 92, 94, 95, 96, 101, 103, 105, 110, 111, 112, 113, 114, 115, 116, 117, 118, 121, 122,123, 124, 125, 126, 127, 128, 129, 129, 131, 134, 137, 138, 139 and 140 exhibit IC ₅₀ at Plasmodium falciparum (Pf) N- myristoyl transferase in the range of IC ₅₀ 0.001 to 5 μΜ in assay (a). Preferred Example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the IC ₅₀ range shown above. For example, the compounds of Examples 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 ,42, 44, 45, 47, 52, 53, 54, 58, 59, 60, 64, 65, 71, 72, 73, 74, 75, 76, 77, 78, 80, 82, 83, 84, 85, 86, 87, 88 ,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 107, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 137, 138, 139 and 140 exhibit IC ₅₀ at Plasmodium vivax (Pv) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 5 μΜ in assay (a).

Preferred Example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the IC ₅₀ range shown above. For example, the compounds of Examples 23, 24, 27, 32, 33, 37, 38, 41, 43, 44, 48, 49, 50, 51, 54, 55, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 94, 98, 100, 101, 102, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 134, 135, 136, 138, 139 and 140 exhibit IC ₅₀ at Leishmania donovani (Ld) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 5 μΜ in assay (a).

Preferred Example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the IC ₅₀ range shown above. For example, the compounds of Examples 2, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 22 and 23 exhibit IC ₅₀ at Plasmodium falciparum (Pf) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 5 μΜ in assay (b).

Preferred Example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the IC ₅₀ range shown above. For example, the compounds of Examples 5 and 23 exhibit IC ₅₀ at Plasmodium vivax (Pv) N-myristoyl transferase range in the of IC ₅₀ 0.001 to 5 μΜ in assay (b).

Preferred Example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the IC ₅₀ range shown above. For example, the compounds of Examples 5, 6, 8, 10, 12, 19, 20, and 21 exhibit IC ₅₀ at Leishmania donovani (Ld) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 5 μΜ in assay (b).

The example compounds of the invention for which EC ₅₀ values for Plasmodium falciparum (Pf) were measured using assay (c) all showed EC ₅₀ for Plasmodium falciparum (Pf) in the range of EC ₅₀ 0.001 to 99.9 μΜ. Some of those examples exhibited inhibitory activity at lower concentrations within the EC ₅₀ range shown above. Preferred example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the EC ₅₀ range shown above. For example, the examples 2, 5, 7, 14, 15, 20, 22, 23, 32, 35, 36, 37, 38, 39, 40, 44, 91, 92, 94, 95, 100, 101, 103, 119, 120, 121, 125, 126, 128, 131 andl37 exhibit EC ₅₀ at Plasmodium falciparum (Pf) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 5 μΜ in assay (c).

The example compounds of the invention for which EC ₅₀ values for Plasmodium falciparum (Pf) were measured using assay (d) all showed EC ₅ o for Plasmodium falciparum (Pf) in the range of EC ₅₀ 0.001 to 99.9 μΜ. Some of those examples exhibited inhibitory activity at lower concentrations within the EC ₅₀ range shown above. Preferred example compounds of the invention are those which exhibit inhibitory activity at lower concentrations within the EC ₅₀ range shown above. For example, the examples 116, 118 and 125 exhibit EC ₅₀ at Plasmodium falciparum (Pf) N-myristoyl transferase in the range of IC ₅₀ 0.001 to 5 μΜ in assay (d).

IC ₅₀ values for compounds of the invention tested in assays (a) and/or (b), and EC ₅₀ values for compounds of the invention tested in assays (c) and/or (d) are provided in the table below:

0.12 (Pv)

139 0.73 (Pf)

0.01 (Ld)

0.63 (Pf)

0.26 (Pv

140

0.07 (Ld)

2.6 (Hsl)

Toxicity Experiment

MTS Toxicity Assay

The MTS Toxicity assay is used for determining the number of viable HepG2 cells after treatment with NMT inhibitors. This can be used to establish the median lethal dose (lethal dose, 50% or LD ₅₀ ) of NMT inhibitors. The technique relies on the bioreduction by mitochondrial reductases of 3-(4,5- dimethylthiazol-2-yl)-5 -(3 -carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS), by viable cells, to a formazan product that absorbs at 490 nm. In addition to MTS, phenazine methosulfate (PMS) is used as an electron coupling reagent.

HepG2, are a human liver hepatocellular carcinoma cell line. The cells are cultured in Dulbecco's modified Eagle's medium (DMEM), plus 10% foetal bovine serum (FBS), plus 1%

penicillin/streptomycin, incubated at 37 °C in humidified atmosphere with 5% C0 ₂ .

The assay comprises 3 parts (part 1 : 'Plating Out', part 2: 'Dosing' and part 3: 'Analysis') and takes 5 days to complete.

The Protocol

1. Specific Equipment

96-Well Plates: Purchased from VWR (BD Falcon™ multiwell cell culture plates), Cat. No.

734-0025.

Multi-Channel Reagent Reservoirs: Purchased from VWR (Reservoir Reagent, 12 Channel, sterile),

Cat. No. 613-0100.

Pipette tips: Require autoclaving.

2. Reagents

DMEM: Dulbecco's Modified Eagle's Medium - low glucose. Purchased from Sigma-Aldrich, Cat. No. D6046. Modified with 10% FBS and 1% P/S.

Foetal Bovine Serum (FBS)

Penicillin/Streptomycin (P/S)

Phosphate buffered saline (PBS): Purchased from Sigma-Aldrich (Dulbecco's Phosphate Buffered Saline), Cat. No. D8537.

Versen: 700 of 0.5 M EDTA, in 500 mL PBS, pH 8

Trypsin: 0.4 mL of trypsin stock (from freezer) in 20 mL versene. MTS: Purchased from Promega Corporation (CellTiter 96 " AQ _ueous MTS Reagent Powder), Cat. No. Gl 1 12. Kept in refrigerator (warm to room temperature before opening). Stock made by dissolving 21 mg MTS powder in 10.5 mL. Store at -20 °C away from light.

PMS: Purchased from Sigma-Aldrich (phenazine methosulfate), Cat. No. P9625. Stock made as 0.92 mg mL ^-1 in PBS. Store at -20 °C away from light.

3. Protocol Details

Part 1: 'Plating Out'

All stages carried out under sterile conditions in tissue culture room/laminar flow cabinet. Remove media and trypsin from refrigerator and warm prior to starting.

1. Remove the media from the cells in culture (100 mm dish) using a Pasteur pipette

2. Add 2 mL versene gently to the cells and swirl to cover, then remove

3. Add 0.5 mL trypsin and tip/swirl to cover cells

4. Incubate the cells for 6 minutes

5. Add 5 mL media and wash the cells from the bottom of the dish: This is the 'cell stock'

6. Transfer the cell stock to a small sample bottle and pass through a 1000 pipette tip 20-30 times to break up clumps of cells

7. Pipette 5 of the media into the haemocytometer and count the cells

squares and take the average (= x)

c. Add y of cell stock to 10000 - y media

d. This will give -5000 cells per 50 μΐ _^ per well

8. Transfer the cells to a 100 mm dish and, using the 8-channel pipette, add 50 μί to each of the inner wells of a 96-well plate (repeat for as many plates as desired)

9. Ad 150 μί media to the outer wells

10. Place the plate(s) into the incubator

1 1. Add 9 mL media to a fresh 100 mm tissue culture dish

12. Mix the remaining original cell stock thoroughly through a 1000 μί pipette tip and add 1000 μΐ _^ to the 100 mm dish and swirl to mix

13. Place the dish in the incubator

Part 2: 'Dosing'

All stages carried out under sterile conditions in tissue culture room/laminar flow cabinet. Remove media from refrigerator and warm prior to starting. Thaw puromycin stock before required.

1. Prepare 0.2% DMSO in media (40 μΐ, DMSO in 20 mL media) and mix thoroughly

2. Prepare puromycin control (3 μΐ _^ puromycin stock in 1497 μΐ _^ media) and mix thoroughly 3. For each drug dilution, add 400 0.2% DMSO/media to wells 2-7 of a 12-well reservoir

4. Add 598 μΐ. media (no DMSO) to well 1

5. Add 1.8 μΐ. of drug stock (50 mM in DMSO) to well 1

6. Mix well 1 very thoroughly with a 1000 pipette

7. Transfer 200 μί to well 2 and mix very thoroughly

8. Repeat 200 μί transfers until well 7

9. Using a single channel reservoir and the 8-channel pipette, add 100 μΐ _^ of 0.2% DMSO/media to wells B2-G2 and Bl 1-Gl 1 (positive control wells)

10. Using a single channel reservoir and the 8-channel pipette, add 100 μΐ _^ of puromycin/media to wells B3-G3 (negative control wells)

11. For the first drug, using the 12-well reservoir and the 8-channel pipette, add the 7 drug

dilutions to wells B4-B 10, C4-C10 and D4-D10

12. For the second drug, using the 12-well reservoir and the 8-channel pipette, add the 7 drug dilutions to wells E4-E10, F4-F10 and G4-G10

13. Return the plate(s) to the incubator and inspect cell growth/morphology after 24, 48 and 72 hours. Noteworthy: reduced proliferation, floating cells/debris, rounding up etc.

Part 3: 'Analysis'

First stages carried out under sterile conditions in tissue culture room/laminar flow cabinet. Thaw MTS/PMS stocks before required.

1. Add 150 μί PMS solution to 3 mL MTS solution and mix thoroughly (for 2 plates)

2. Add 20 μΐ _^ to each assay well

3. Return plates to the incubator

4. Check for appearance of colour and read between 1 and 4 hours after addition

5. Read at 490 nm

6. Use Excel template to generate graphs Results:

Example 116 has an average LD ₅₀ of 12.250 μΜ (based on six replicates). Therefore, for Example 116, there is a 40-fold toxicity window compared to the parasite potency.