Prodrugs of benzimidazole derivatives of formula (i)

Abstract

The present invention provides compounds according to formula (I) as defined herein, or pharmaceutically acceptable salts or solvates thereof. The invention further provides pharmaceutical compositions comprising the compounds, and the use of the compounds or pharmaceutical compositions as a medicament, particularly for use in the treatment or prophylaxis of a disease or disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections.

Description

[0001] PRODRUGS OF BENZIMIDAZOLE DERIVATIVES OF FORMULA (I)

[0002] FIELD OF INVENTION

[0003] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof and their use for the treatment and / or prophylaxis of diseases such as chronic inflammatory diseases, cancers and parasitic diseases and infections.

[0004] BACKGROUND OF INVENTION

[0005] Benzimidazole drugs are a family of drug compounds containing a benzene ring fused to an imidazole ring. There are many known benzimidazole drugs in this family, including mebendazole, albendazole, fenbendazole, nocodazole, flubendazole, ricobendazole and oxfendazole.

[0006] The structure of mebendazole is as follows:

[0007]

[0008] The structure of albendazole is as follows:

[0009]

[0010] Mebendazole (Vermox®) is an anti-parasitic agent that is clinically used for treatment of various forms of helminthic diseases. Mebendazole has been used extensively for local gut helminthic infections at low dose but also at considerably higher doses. Mebendazole has also been reported to be useful for the treatment of cancer and chronic inflammatory diseases. For example, it has been reported that mebendazole has caused tumour remission in a patient with metastatic colon cancer including nearly complete remission of metastasesin the lungs and lymph nodes and a good partial remission in the liver (Nygen, P., Larsson, R., Acta Oncologica, 2013. Early online: 1-2). WO 2019 / 043108 also reports a protocol for using mebendazole as an anticancer agent. Mebendazole has also been shown to be effective in decreasing the size of sarcoid tissue in a patient suffering from the chronic inflammatory disease sarcoidosis, as well as effective in treating a mouse model of the chronic inflammatory disease systemic lupus erythematosus (WO 2019 / 121996).

[0011] However, the use of mebendazole is limited by its pharmacokinetic properties.

[0012] Mebendazole's poor solubility leads to low oral bioavailability and to low and highly variable levels of systemic exposure in humans. Furthermore, it has been found that higher doses of mebendazole do not always result in increased exposure, and there can be significant variation in the maximum plasma concentration of mebendazole between patients after administration (WO 2019 / 043108).

[0013] Mebendazole prodrugs which aim to increase the systemic exposure of mebendazole have been reported, for example in WO 2019 / 157338 and Zimmerman, S. C., et al, J. Med. Chem.

[0014] 2018, 61, 9, 3918–3929. Those known mebendazole prodrugs are converted into mebendazole in the intestine (Zimmerman, S. C., et al, J. Med. Chem. 2018, 61, 9, 3918–3929). This can limit the systemic exposure of the pharmaceutically active compound, mebendazole, as it is released in the intestine and so is exposed to intestinal metabolism.

[0015] Therefore, there is a need for improved or alternative prodrugs of mebendazole, and other benzimidazole drugs, for example prodrugs of mebendazole, and other benzimidazole drugs, that display beneficial pharmacokinetic properties such as good aqueous solubility and / or oral bioavailability, and / or efficient systemic exposure of the parent benzimidazole drug.SUMMARY OF THE INVENTION

[0016] The present invention provides a compound according to formula (I), or a pharmaceutically acceptable salt or solvate thereof,

[0017]

[0018] wherein,

[0019] X is a linear C2-3alkylene optionally substituted with one, two or three groups independently selected from the group consisting of F; OH; -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; -OC1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -C3-5cycloalkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0020] R1is selected from the group consisting of -C1-4alkyl, -C3-6cycloalkyl, -Ra, and -C1-4alkyl-Ra, wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0021] Rais -C6-10aryl, a 4-, 5- or 6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N, or a 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of N, S and O, wherein said heterocyclyl, aryl or heteroaryl groups are optionally substituted with one, two or threegroups independently selected from the group consisting of halogen, OH, -C1-4alkyl, and -OC1-4alkyl;

[0022] R2is selected from the group consisting of H and -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0023] R3is -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0024] R4is -NHC(O)OC1-4alkyl; and

[0025] R6is H, and R5is selected from the group consisting of -C(O)C6-10aryl, -SC1-4alkyl, -S(O)C1-4alkyl, -S(O)2C1-4alkyl, -C(O)C3-6alkyl, -C(O)C3-6cycloalkyl, -SC6-10aryl, -S(O)C6-10aryl, -S(O)2C6-10aryl, and -C(O)-(5- or 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O), wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of OH, F and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH, and wherein said aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen; OH; -CN; -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0026] or

[0027] R5is H, and R6is selected from the group consisting of -C(O)C6-10aryl, -SC1-4alkyl, S(O)C1-4alkyl, S(O)2C1-4alkyl, -C(O)C3-6alkyl, -C(O)C3-6cycloalkyl, -SC6-10aryl, -S(O)C6-10aryl, -S(O)2C6-10aryl, and -C(O)-(5- or 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O), wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of OH, F and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH, and wherein said aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen; OH; -CN; -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0028] Compounds of the invention are prodrug compounds that are converted within the body (i.e. in vivo) into a benzimidazole drug, i.e. compound of formula (X):

[0029]

[0030] (X)

[0031] wherein R4, R5and R6are as defined above for a compound of formula (I), or an active metabolite or residue thereof. For example, depending on the R4, R5and R6groups present in a compound of the invention, a compound of the invention may be converted within the body into mebendazole, albendazole, fenbendazole, nocodazole, flubendazole, ricobendazole, or oxfendazole. Accordingly, the compounds of formula (I) find use in the treatment or prophylaxis of diseases and disorders know to be treated or prevented by benzimidazole drugs, for example chronic inflammatory diseases, cancers and parasitic diseases and infections.Thus, the present invention further provides a pharmaceutical composition comprising a compound of formula (I), together with a pharmaceutically acceptable carrier.

[0032] The present invention further provides a compound of formula (I), or pharmaceutical composition comprising a compound of formula (I), for use as a medicament, and in particular for use in the treatment or prophylaxis of a disease or disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections, or for use as an antiparasitic agent.

[0033] The present invention further provides a method for treating a patient which comprises administering a pharmaceutically effective amount of a compound of formula (I) or a pharmaceutical composition of a compound of formula (I). The present invention also provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections.

[0034] Preferred but optional features are set out in the dependent claims. Additional aspects and embodiments of the compounds and methods of the present invention will be apparent from the following description, figures and claims.

[0035] DESCRIPTION OF THE DRAWINGS FIG. 1 shows the formation of mebendazole (Mbz) over time (min) from Example Compounds 1 and 2 and Comparative Example A when incubated in vitro with mouse hepatocytes.

[0036] FIG. 2 shows the plasma concentration of mebendazole (Mbz) and mebendazole metabolites (2-amino-5-benzoylbenzimidazole: Mbz-NH2; 5-hydroxymebendazole: Mbz-OH, and 2-amino-5(6)-[a-hydroxybenzyl]benzimidazole: Mbz-NH2-OH) in CD-I mice followingoral administration of A) mebendazole (Mbz), B) Example Compound 2, or C) Example Compound 1.

[0037] FIG. 3 shows the plasma concentration of mebendazole (Mbz) and mebendazole metabolites (Mbz-NH2 and Mbz-OH) in CD-1 mice following oral administration of A) mebendazole or B) Example Compound 9.

[0038] DETAILED DESCRIPTION OF INVENTION

[0039] The present invention provides a compound of formula (I) as defined herein. The compounds of the present invention are prodrugs of benzimidazole drugs. The present inventors have found that the compounds of the present invention have improved pharmacokinetic properties compared to known benzimidazole drugs, such as mebendazole and albendazole.

[0040] A compound which, upon administration to a subject / patient, is capable of being converted into a pharmacologically active compound, 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 gastrointestinal tract (for example, the stomach, small intestine, large intestine), the liver and / or the blood into its active form that has medical effects. As described above, the compounds for use in the embodiments of the present invention function as prodrugs of benzimidazole drugs. More specifically, compounds of formula (I) of the present invention are converted within the body into a benzimidazole drug, and more specially a benzimidazole drug of formula (X):wherein R4, R5and R6are as defined herein for a compound of formula (I), or an active metabolite or residue thereof. For example, depending on the R4, R5and R6groups present in the compound, a compound of the invention may be converted within the body into mebendazole, albendazole, fenbendazole, nocodazole, flubendazole, ricobendazole, or oxfendazole, or an active metabolite or residue thereof.

[0041] The present inventors believe that the compounds of the present invention, when administered orally, are more stable in the stomach, intestine and the intestinal brush border gut membrane, and thus are not fully converted into a pharmacologically active compound until the compounds reach the liver. For example, in vitro pharmacokinetic testing of compounds of the invention have shown that the membrane permeability of compounds of the invention is high, and that the compounds of the invention are more soluble and / or stable than mebendazole or albendazole when exposed in vitro to conditions similar to those of the stomach and intestine. The in vitro pharmacokinetic testing also indicated that the reaction to release the pharmaceutically active compound likely occurs primarily in the liver, thereby preventing the high degree of reductive metabolism of pharmaceutically active compound that can occur in the intestine (see experiments (a) to (d) of Biological Example 1 disclosed in the Examples section herein).

[0042] Without wishing to be bound by theory, the present inventors believe that, once in the liver, the compounds of formula (I) are enzymatically hydrolysed to expose a terminal amine group on the substituent group attached to the nitrogen of the benzimidazole ring (i.e. enzymatic hydrolysis of the -C(O)O-R1group of a compound of formula (I)). The terminal amine group then acts as an internal nucleophile to produce the benzimidazole drug (i.e. a compound of formula (X)), with the elimination of a cyclic urea from the molecule after a spontaneous cyclization-elimination reaction.

[0043] Release of the benzimidazole drug (i.e. a compound of formula (X), for example mebendazole or albendazole) by a compound of formula (I) primarily in the liver is expectedto result in efficient systemic exposure of the benzimidazole drug compared to when release of the benzimidazole drug primarily occurs in the stomach, intestine or intestinal brush border. In this regard, the in vivo mouse studies reported herein show that after oral administration of a mebendazole prodrug compound of the invention, peak plasma mebendazole exposure (Cmax) was fast, and resulted in higher mebendazole levels at Cmax compared to equimolar oral doses of mebendazole itself (see Biological Example 2 disclosed in the Examples section herein.

[0044] The efficiency of the compounds of the invention in releasing a benzimidazole drug refers to the proportion of benzimidazole drug formed from the compound of the invention relative to the proportion of benzimidazole drug-related compounds formed, such as metabolites and other degradation products. Efficient formation of the benzimidazole drug is expected to result in a more controlled exposure of the drug and to reduce the possibility of adverse effects associated with any of the metabolites or other degradation products.

[0045] The present inventors have also found that compounds of the present invention also display good aqueous solubility (see experiments (a) of Biological Example 1 below). Poor aqueous solubility is a major problem encountered with formulation development of new chemical entities for use as medicaments, in particular medicaments that may be administered orally. Many benzimidazole drugs, including mebendazole and albendazole, are known to have poor aqueous solubility, which leads to low oral bioavailability and / or variable levels of systemic exposure when they are administered orally. The aqueous solubility of the compounds of the invention makes them especially suitable for use as medicaments, and in particular medicaments suitable for oral administration.

[0046] The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.As used herein, "linear alkylene", means straight chain saturated aliphatic hydrocarbon groups of the specified number of carbon atoms. For example, "linear C2-3alkylene" denotes alkylene having 2 or 3 carbon atoms, "linear C2alkylene" denotes alkylene having 2 carbon atoms, and "linear C3alkylene" denotes alkylene having 3 carbon atoms. As used herein, the groups linked by an alkylene group are intended to be attached to the first and to the last carbon of the alkylene group. Examples of alkylene according to the present invention include ethylene and propylene.

[0047] As used herein, the term " Ci-xalkyl" means both straight and branched chain saturated hydrocarbon groups having 1 to X carbon atoms in the hydrocarbon chain. X may be, for example 2, 3, 4, 5 or 6. Preferably X is 2, 3 or 4, for example 2 or 3, or 2. Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, pentyl and hexyl groups. Among unbranched alkyl groups, there are preferred methyl, ethyl, propyl, iso-propyl, n-butyl groups. Among branched alkyl groups, there may be mentioned tert-butyl, iso-butyl, 1-ethylpropyl and 1-ethylbutyl groups.

[0048] As used herein, the term " OCi-xalkyl" means an alkoxy group, where " Ci-xalkyl" is used as described above. Examples of OCi-xalkyl groups include O-methyl (OCialkyl, methoxy) and O-ethyl (OC2al kyl, ethoxy) groups. Other examples include O-propyl (OCsalkyl, propoxy) and O-butyl (OC4alkyl, butoxy).

[0049] As used herein, the term " Cs-xcycloalkyl" means a saturated group in a ring system of the specified number of carbon atoms. X may be, for example 4, 5 or 6. For example, " C3-ecycloalkyl" denotes a cycloalkyl group having 3, 4, 5 or 6 carbon atoms. A cycloalkyl group of the present invention having 3, 4, 5 or 6 carbon atoms is monocyclic. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0050] As used herein, the term "saturated heterocyclyl" means a non-aromatic cyclic group of carbon atoms wherein from 1 or 2 of the carbon atoms is / are replaced by one or twoheteroatoms independently selected from nitrogen or oxygen. A 4-, 5-, or 6-membered saturated heterocyclyl of the present invention is monocyclic. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides.

[0051] As used herein, the term " C6-10aryl" means an aromatic cyclic group of carbon atoms of the specified number of carbon atoms. An aryl group of the present invention may be monocylic or bicylic. Preferably the C6-10aryl has 6 or 10 carbon atoms. Thus, preferably, the C6-10aryl is phenyl or naphthyl.

[0052] As used herein, the term "heteroaryl" means an aromatic cyclic group of carbon atoms wherein from 1 to 3 of the carbon atoms is / are replaced by one or more heteroatoms independently selected from nitrogen (N), oxygen (O) or sulfur (S). A 5- or 6-membered heteroaryl group of the present invention is monocyclic. A heteroatom may be S, O or N and is preferably S or N. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides. Examples of 5- or 6-membered heteroaryl groups comprising 1, 2 or 3 heteroatoms include furanyl, pyrrolyl, thiophenyl, pyridinyl, imidazolyl (1,3-diazolyl), pyrazolyl (1,2-diazolyl), 1,3-oxazolyl, isoxazolyl (1,2-oxazolyl), thiazolyl (1,3-thiazolyl), isothiazolyl (1,2-thiazolyl), 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, furazanyl (1,2,5-oxadiazolyl), 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl (1,2-diazinyl), pyrimidinyl (1,3-diazinyl), pyrazinyl (1,4-diazinyl), 1,2,3-triazinyl, 1,2,4-triazinyl, and 1,3,5-triazinyl.

[0053] As noted above, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0054]

[0055] In the compounds of formula (I), X is a linear C2-3alkylene that is optionally substituted. Thus, in the compounds of formula (I), X may be an unsubstituted linear C2-3alkylene (for example -CH2-CH2- or -CH2-CH2-CH2-) or a substituted linear C2-3alkylene. In embodiments where X is a substituted linear C2-3alkylene, X may be substituted with one, two or three groups independently selected from the group consisting of F; OH; -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; -OC1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -C3-5cycloalkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0056] In one embodiment, X is a linear C2-3alkylene optionally substituted with one or two groups (for example one group) independently selected from the group consisting of F; OH; -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; -OC1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -C3-5cycloalkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH. For example, X may be a linear C2-3alkylene optionally substituted with one or two groups (for example one group) independently selected from the group consisting of F; OH; -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-3alkyl optionally substituted with one, two or three groups independently selected from the group consistingof F and OH. Or, for example, X may be a linear C2-3alkylene optionally substituted with one or two groups (for example one group) independently selected from the group consisting of F; OH; methyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -O-methyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0057] In one preferred embodiment, X is a linear C2alkylene optionally substituted with one, two or three groups independently selected from the group consisting of F; OH; -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; -OC1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -C3-5cycloalkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH. For example, X may be a linear C2alkylene optionally substituted with one or two groups (for example one group) independently selected from the group consisting of F; OH; -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OCi-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH. In another embodiment, X is a linear C2alkylene optionally substituted with one or two groups (for example one group) independently selected from the group consisting of F; OH; methyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -O-methyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0058] In another embodiment, X is a linear Csalkylene optionally substituted with one, two or three groups independently selected from the group consisting of F; OH; -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; -OC1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -C3-5cycloalkyl optionally substituted with one, two or three groups independently selected from the group consisting of F andOH. For example, X is a linear Csalkylene optionally substituted with one or two groups (for example one group) independently selected from the group consisting of F; OH; -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH. In another embodiment, X is a linear C3alkylene optionally substituted with one or two groups (for example one group) independently selected from the group consisting of F; OH; methyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and methoxy optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0059] In one preferred embodiment, X is an unsubstituted linear C2-3alkylene, for example an unsubstituted linear C2alkylene (-CH2-CH2-) or an unsubstituted linear C3alkylene (-CH2-CH2-CH2-). For example, X may be an unsubstituted linear C2alkylene (-CH2-CH2-).

[0060] In the compounds of formula (I), R1is selected from the group consisting of -C1-4alkyl, -C3-6cycloalkyl, -Ra, and -C1-4alkyl-Ra, wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and Rais -C6-10aryl, a 4-, 5- or 6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N, or a 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of N, S and O, wherein said heterocycle, aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -Ci-4a Ikyl, and -OCi-4alkyl.

[0061] In one embodiment, R1is selected from the group consisting of -C1-4alkyl, -C3-6cycloalkyl, -Ra, and -C1-2alkyl-Ra, wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and Rais phenyl, naphthyl, a 5- or 6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N, or a 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of N, S and O, wherein said heterocyclyl, phenyl, naphthyl, or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -C1-4alkyl, and -OC1-4alkyl.

[0062] In another embodiment, R1is selected from the group consisting of -C1-4alkyl, -Ra, and -C1-2alkyl-Ra, wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCi-4alkyl optionally substituted with one, two or three F; and Rais phenyl or a 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of N, S and O, wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, -C1-4alkyl, and -OC1-4alkyl (for example, Rais phenyl or pyridine wherein said phenyl or pyridine groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, -C1-4alkyl, and -OC1-4alkyl).

[0063] In another embodiment, R1is selected from the group consisting of -C1-4alkyl, -C3-6cycloalkyl, -Ra, and -C1-4alkyl-Ra; and Rais -C6-10aryl, a 4-, 5- or 6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N, or a 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of N, S and O. For example, R1may be selected from the group consisting of -C1-4alkyl, -C3-6cycloalkyl, -Ra, and -C1-4alkyl-Ra, wherein said alkyl or cycloalkyl groups are substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and Rais -C6-10aryl, a 4-, 5- or 6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting ofO and N, or a 5- or 6-membered heteroaryl comprising 1 or 2 heteroatoms independently selected from the group consisting of N, S and O, wherein said heterocyclyl, aryl or heteroaryl groups are substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -C1-4alkyl, and -OC1-4alkyl.

[0064] In one preferred embodiment, R1is selected from the group consisting of -C1-4alkyl, -Ra, and -C1alkyl-Ra, wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F and -OC1-4alkyl (for example F and -O-methyl) optionally substituted with one, two or three F for example F and methoxy); and Rais phenyl or a 6-membered heteroaryl comprising 1 or 2 nitrogen atoms, wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, methyl, and methoxy.

[0065] In one preferred embodiment, R1is -C1-4alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl) optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-3alkyl (preferably F or -OCH3); phenyl; pyridine; or -CH2phenyl. For example, R1may be -C1-4alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl) optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-3alkyl (preferably F or -OCH3).

[0066] In one especially preferred embodiment, R1is -C1-2alkyl optionally substituted with one, two or three groups (for example, 1 or 2 groups, or 1 group) independently selected from the group consisting of F and -OCH3. For example, R1may be methyl, -CH2F, -CHF2,

[0067] ethyl, -CH2CH2F, -CH2CH2OCH3, -CH2CF3, -CH2CHF2, or CH2CH(OCH3)2; and more preferably R1is methyl or CH2CH2OCH3.

[0068] In the compounds of formula (I), R2is selected from the group consisting of H and -Ci-ealkyl optionally substituted with one, two or three groups independently selected from the groupconsisting of F, OH and -OCi-4alkyl, optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0069] In certain preferred embodiments, R2is -Ci-ea Ikyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-4alkyl. In another embodiment, R2is selected from the group consisting of H and -Ci-4al kyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-4alkyl. For example, R2may be selected from the group consisting of H and -Ci-sal kyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCi-4alkyl (preferably F and -OCH3); or R2may be selected from the group consisting of H and -Ci-3a I ky I optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCH3

[0070] In one preferred embodiment, R2is -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl. For example, R2is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OC1-4alkyl (preferably F and -OCH3). In one very preferred embodiment, R2is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCH3. For example, R2may be -C1-3alkyl (for example -C1-2alkyl) optionally substituted with one F (and preferably R2is methyl, ethyl or -CH2CH2F, for example, methyl or -CH2CH2F); or R2may be -C1-3alkyl optionally substituted with one -OCH3(and preferably R2is -C1-3alkyl substituted with one -OCH3, for example R2is -CH2CH2OCH3). In one especially preferred embodiment, R2is -C1-3alkyl (for example -C1-2alkyl) optionally substituted with one F (and preferably R2is methyl, ethyl or -CH2CH2F, for example, methyl or -CH2CH2F).

[0071] In the compounds of formula (I), R3is -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionallysubstituted with one, two or three groups independently selected from the group consisting of F and OH.

[0072] In one embodiment, R3is -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0073] In one preferred embodiment, R3is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OC1-4alkyl (preferably F and -OCH3), for example R3is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OC1-3alkyl (preferably F and -OCH3). In one very preferred embodiment, R3is -C1-3alkyl (for example, R3may be methyl, ethyl, propyl or isopropyl, preferably R3is methyl or ethyl). In another very preferred embodiment, R3is -C1-3alkyl (for example methyl, ethyl, propyl or isopropyl, and preferably R3is methyl or ethyl) optionally substituted with one -OCH3(and preferably R3is -C1-3alkyl substituted with one -OCH3, for example R3is -CH2CH2OCH3).

[0074] In one especially preferred embodiment, R2is -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl; and R3is -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0075] In one especially preferred embodiment, R2is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OC1-4alkyl (preferably F and -OCH3); and R3is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OC1-4alkyl (preferably F and -OCH3). For example, R2may be -C1-3alkyl optionally substituted with one F (andpreferably R2is methyl or -CH2CH2F), and R3is -C1-3alkyl (and preferably R3is methyl or ethyl); or R2may be -C1-3alkyl optionally substituted with one -OCH3(and preferably R2is -C1-3alkyl substituted with one -OCH3, for example R2is -CH2CH2OCH3), and R3may be -C1-3alkyl optionally substituted with one -OCH3(and preferably R3is -C1-3alkyl substituted with one -OCH3, for example R3is -CH2CH2OCH3).

[0076] In another especially preferred embodiment, R2is -C1-3alkyl optionally substituted with one F (and preferably R2is methyl or -CH2CH2F), and R3is -C1-3alkyl (and preferably R3is methyl or ethyl).

[0077] In the compounds of formula (I), R4is -NHC(O)OCi-4alkyl. For example, R4may be -NHC(O)OC1-3alkyl or -NHC(O)OC1-2alkyl. In one preferred embodiment, R4is -NHC(O)OCH3.

[0078] In the compounds of formula (I) R6is H, and R5is selected from the group consisting of -C(O)C6-10aryl, -SC1-4alkyl, -S(O)C1-4alkyl, -S(O)2C1-4alkyl, -C(O)C3-6alkyl, -C(O)C3-6cycloalkyl, -SC6-10aryl, -S(O)C6-10aryl, -S(O)2C6-10aryl, and -C(O)-(5- or 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O), wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of OH, F and -OCi-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH, and wherein said aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen (for example F, Cl, Br or I); OH; -CN; -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; or

[0079] R5is H, and R6is selected from the group consisting of -C(O)C6-10aryl, -SC1-4alkyl, -S(O)C1-4alkyl, -S(O)2C1-4alkyl, -C(O)C3-6alkyl, -C(O)C3-6cycloalkyl, -SC6-10aryl, -S(O)C6-10aryl, -S(O)2C6-10aryl, and -C(O)-(5- or 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O), wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of OH, F and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH, and wherein said aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen (for example F, Cl, Br or I); OH; -CN; -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

[0080] In one preferred embodiment, R5is H, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4alkyl, -S(O)Ci-4al kyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)C5-6heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O (for example one S), wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and -OC1-4alkyl and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -C1-4alkyl, and -OC1-4alkyl; or

[0081] R6is H, and R5is selected from the group consisting of -C(O)phenyl, -SC1-4alkyl, -S(O)C1-4alkyl, -S(O)2C1-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)C5-6heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O (for example one S), wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and OC1-4alkyl, and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -C1-4alkyl, and -OC1-4alkyl.In another preferred embodiment, R5is H, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4alkyl, -S(O)Ci-4al kyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)Cs-6heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O (for example, one S), wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and -OCi-4alkyl and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -Ci-4al kyl, and -OCi-4alkyl; or

[0082] R6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4alkyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)Cs-6heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O (for example, one S), wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and OCi-4alkyl, and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -Ci-4alkyl, and -OCi-4alkyl.

[0083] In one preferred embodiment, R5is H, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4alkyl, -S(O)Ci-4al kyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, -OCi-4 alkyl and OH (for example, with one, two or three (for example one) F) (for example, R6may be selected from the group consisting of -C(O)phenyl, -C(O)phenyl substituted with one F, -SCH2CH2CH3, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3, -S-phenyl, -S(O)phenyl, -S(O)2phenyl and -C(O)thienyl); or

[0084] R6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4a I kyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl groups are optionally substituted with one, two or three groupsindependently selected from the group consisting of F, -OC1-4 alkyl and OH (for example, with one, two or three (for example one) F) (for example R6may be selected from the group consisting of -C(O)phenyl, -C(O)phenyl substituted with one F, -SCH2CH2CH3, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3, -S-phenyl, -S(O)phenyl, -S(O)2phenyl and -C(O)thienyl).

[0085] In one very preferred embodiment, R5is H, and R6is selected from the group consisting of -C(O)phenyl, -SC2-4alkyl, -S(O)C2-4alkyl, -S(O)2C2-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, -OC1-4 alkyl and OH (for example, with one, two or three (for example one) F) (for example R6is selected from the group consisting of -C(O)phenyl, -C(O)phenyl substituted with one F, -SCH2CH2CH3, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3, -S-phenyl, -S(O)phenyl, -S(O)2phenyl and -C(O)thienyl); or

[0086] R6is hydrogen, and R5is selected from the group consisting of -C(O)phenyl, -SC2-4al kyl, -S(O)C2-4alkyl, -S(O)2C2-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, -OC1-4 alkyl and OH (for example, with one, two or three (for example one) F) (for example R6is selected from the group consisting -C(O)phenyl, -C(O)phenyl substituted with one F, -SCH2CH2CH3, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3, -S-phenyl, -S(O)phenyl, -S(O)2phenyl and -C(O)thienyl).

[0087] In one especially preferred embodiment, R5is H, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4al kyl and -S(O)2Ci-4alkyl (for example, R6may be selected from the group consisting -C(O)phenyl, -SC2-4alkyl, -S(O)C2-4alkyl and -S(O)2C2-4a I kyl, and more especially selected from the group consisting of -C(O)phenyl, -SCH2CH2CH3, -S(O)CH2CH2CH3and -S(O)2CH2CH2CH3); or

[0088] R6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4a Ikyl and -S(O)2Ci-4alkyl (for example, R5may be selected from the group consisting

[0089] of -C(O)phenyl, -SC2-4alkyl, -S(O)C2-4alkyl and -S(O)2C2-4alkyl, and more especially selectedfrom the group consisting of -C(O)phenyl, -SCH2CH2CH3, -S(O)CH2CH2CH3and -S(O)2CH2CH2CH3).

[0090] In one very especially preferred embodiment, R5is H, and R6is selected from the group consisting of -C(O)phenyl, -S(O)Ci-4al kyl, -S(O)2Ci-4alkyl, and -SCi-4al kyl (for example, R6may be selected from the group consisting of -C(O)phenyl, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3and -SCH2CH2CH3; and preferably R6is -C(O)phenyl); or

[0091] R6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)2Ci-4alkyl and -SCi-4a Ikyl (for example, R5may be selected from the group consisting

[0092] of -C(O)phenyl, -SCH2CH2CH3, -S(O)2CH2CH2CH3and -SCH2CH2CH3; and preferably R5is -C(O)phenyl).

[0093] For example, R5is H, and R6is -C(O)phenyl; or R6is H, and R5is -C(O)phenyl. Alternatively, for example, R5is H, and R6is S(O)Ci-4al kyl, -S(O)2Ci-4alkyl or -SCi-4al kyl (for example R6is -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3or -SCH2CH2CH3); or R6is H, and R5is S(O)Ci-4alkyl, -S(O)2Ci-4alkyl or -SCi-4alkyl (for example, R6may be -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3or -SCH2CH2CH3).

[0094] In one especially preferred embodiment, X is a linear C2-3alkylene optionally substituted with one or two groups (for example, one group) independently selected from the group consisting of F; OH; methyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -O-methyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0095] R1is selected from the group consisting of -Ci-4alkyl, -Ra, and -Cialkyl-Ra, wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCi-4alkyl (for example, F and -O-methyl) optionally substituted with one, two or three F, for example, F and methoxy); and Rais phenyl or a 6-membered heteroaryl comprising 1 or 2 nitrogen atoms, wherein said phenylor heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, methyl, and methoxy;

[0096] R2is selected from the group consisting of H and -Ci-4a Ikyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-4alkyl;

[0097] R3is -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0098] R4is -NHC(O)OC1-4alkyl; and

[0099] R5is hydrogen, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4alkyl, -S(O)Ci-4alkyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)Cs-6heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O (for example, one S), wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and -OCi-4alkyl and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -Ci-4a Ikyl, and -OCi-4alkyl; or

[0100] R6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a Ikyl, -S(O)Ci-4a Ikyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)Cs-6heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O (for example, one S), wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and OCi-4alkyl, and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -Ci-4a Ikyl, and -OCi-4alkyl.

[0101] In another especially preferred embodiment, X is an unsubstituted linear C2-3alkylene (for example, an unsubstituted linear C2alkyene (-CH2-CH2-) or an unsubstituted linear Csalkyene (-CH2-CH2-CH2-));R1is -C1-4alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl) optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-3alkyl (preferably, F or -OCH3); phenyl; pyridine; or -CH2phenyl; R2is -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl;

[0102] R3is -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;

[0103] R4is -NHC(O)OC1-4alkyl; and

[0104] R5is H, and R6is selected from the group consisting of -C(O)phenyl, -SC2-4alkyl, -S(O)C2-4alkyl, -S(O)2C2-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, -OC1-4 alkyl and OH (for example, with one, two or three (for example one) F) (for example, R6is selected from the group consisting of -C(O)phenyl, -C(O)phenyl substituted with one F, -SCH2CH2CH3, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3, -S-phenyl, -S(O)phenyl, -S(O)2phenyl and -C(O)thienyl); or R6is H, and R5is selected from the group consisting of -C(O)phenyl, -SC2-4alkyl, -S(O)C2-4alkyl, -S(O)2C2-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, -OC1-4 alkyl and OH (for example, with one, two or three (for example one) F) (for example, R6may be selected from the group consisting of -C(O)phenyl, -C(O)phenyl substituted with one F, -SCH2CH2CH3, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3, -S-phenyl, -S(O)phenyl, -S(O)2phenyl and -C(O)thienyl).

[0105] In a very especially preferred embodiment, X is an unsubstituted linear C2alkyene (-CH2-CH2-);

[0106] R1is -C1-2alkyl optionally substituted with one, two or three groups (for example 1 or 2 groups, or 1 group) independently selected from the group consisting of F and -OCH3R2is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCH3(for example R2is -C1-3alkyl optionally substituted with one F (and preferably R2is methyl or -CH2CH2F));

[0107] R3is -C1-3alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OC1-4alkyl (preferably F and -OCH3) (for example, R3is -C1-3alkyl (and preferably R3is methyl or ethyl);

[0108] R4is -NHC(O)OCH3; and

[0109] R5is H, and R6is selected from the group consisting of -C(O)phenyl, S(O)C1-4alkyl or -S(O)2C1-4alkyl, and -SC1-4alkyl (for example R6is selected from the group consisting

[0110] of -C(O)phenyl, -S(O)CH2CH2CH3, -S(O)2CH2CH2CH3and -SCH2CH2CH3; and more preferably R6-C(O)phenyl); or

[0111] R6is H, and R5is selected from the group consisting of -C(O)phenyl, S(O)C1-4alkyl or -S(O)2C1-4alkyl, and -SC1-4alkyl (for example R6is selected from the group consisting

[0112] of -C(O)phenyl, -SfOjCFhCFhCHs, -SfO CFhCFhCHs and -SCH2CH2CH3; and more preferably R6-C(O)phenyl).

[0113] In certain preferred embodiments, the compound of formula (I) is a compound selected from the group consisting of:

[0114] (IIa)

[0115]

[0116] (IIIa) , (IIIb)

[0117] (Vb)

[0118] (Vlb)

[0119]

[0120] (Via)

[0121] 1(Vila)

[0122] o II

[0123] (Villa)

[0124] (IXb)

[0125]

[0126] (IXa)

[0127] wherein X, R1, R2, Ra, R3and R4are as defined above for a compound for formula (I).

[0128] In certain preferred embodiments, the compound of formula (I) is a compound selected from the group consisting of:

[0129]

[0130] (IId)

[0131] (Illc)

[0132] (IVc)

[0133] (Vd)

[0134]

[0135] (Vic)

[0136] (Vid)

[0137] (VIId)

[0138] (Vllld)

[0139] (IXd)

[0140]

[0141] wherein X, R1, R2, Ra, and R3are as defined above for a compound for formula (I).In one very preferred embodiment, the compound of formula (I) is a compound of formula (IIa) or (IIb), or a mixture thereof:

[0142] o

[0143]

[0144] wherein X, R1, R2, Ra, R3and R4are as defined above for a compound for formula (I). For example, the compound of formula (I) is a compound of formula (IIc) or (IId), or a mixture thereof:

[0145]

[0146] (IIc) wherein X, R1, R2, Ra, and R3are as defined above for a compound for formula (I).

[0147] In another preferred embodiment, the compound of formula (I) is a compound of formula (IIIa), (IIIb), (VIIa), (VIIb), (IXa), or (IXb), or a mixture thereof:

[0148] (IIIa)

[0149]

[0150] (IXb)

[0151]

[0152] wherein X, R1, R2, Ra, R3and R4are as defined above for a compound for formula (I). For example, the compound of formula (I) may be a compound of formula (IIIc), (IIId), (VIIc), (VIId), (IXc), or (IXd), or a mixture thereof:

[0153]

[0154] (IIIc)(VIId)

[0155] (IXd)

[0156]

[0157] wherein X, R1, R2, Raand R3are as defined above for a compound for formula (I).

[0158] In certain preferred embodiments, the compound of formula (I) is a compound of formula (I) described in the Examples section below, or a pharmaceutically acceptable salt of solvate thereof. In particular, the compound of formula (I) may be a compound selected from the group consisting of:

[0159]

[0160] o

[0161]

[0162]

[0163]

[0164] or a pharmaceutically acceptable salt or solvate thereof.

[0165] It will be appreciated by one of skill in the art that the compounds of the invention may exist as regioisomers. The definitions of the R5and R6groups of the compounds of formula (I) cover the two regioisomeric forms (la) and (lb) shown below, i.e. regioisomeric form (la) when R5is H and R6cannot be H, and regioisomeric form (lb) when R6is H and R5cannot be H:

[0166]

[0167] Regioisomeric form (la) Regioisomeric form (lb).

[0168] Regioisomeric form (la) and regioisomeric form (lb) may be referred to as " N-regioisomers". All individual regioisomers of the compounds for formula (I), as well as mixtures thereof, and in particular mixtures of regioisomeric forms (la) and (lb) (i.e. mixtures of the N-regioisomers of compounds of the present invention) are included within the scope of the invention. It is noted that the examples of compounds of formula (I) provided in the present application were obtained as a mixture of regioisomeric forms (la) and (lb) (i.e. as a mixture of the N-regioisomers).

[0169] As such, for the avoidance of doubt, the compound of formula (I) may be a compound that is an individual regioisomer selected from the group consisting of:

[0170]

[0171] 

[0172]

[0173]

[0174]

[0175] Or, for the avoidance of doubt, the compound of formula (I) may be a mixture of

[0176] regioisomers selected from:

[0177]

[0178] 

[0179]

[0180] and

[0181]

[0182]

[0183] Depending upon the substituents present in the compounds of formula (I), the compounds may exist as stereoisomers and / or geometric isomers. All individual stereoisomers and geometric isomers, including regioisomers as well as mixtures thereof, are included within the scope of the invention. Isotopic forms, for example where a hydrogen atom is replaced with deuterium, are also included within the invention. Certain isotopic forms may have beneficial biological properties, for example improved metabolic stability or enhanced therapeutic activity over other isotopic forms; or a specific isotopic form may be useful for biological imaging purposes, for example carbon-11, nitrogen-13, oxygen-15 or fluorine-18 isotopic variants may be used for positron emission tomography.Depending upon the substituents present in the compounds of formula (I), the compounds may form salts. Salts of the compounds of the present invention which are suitable for use in the present invention are those wherein a counterion is pharmaceutically acceptable. Suitable salts 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 (C1-C4)-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, oxalic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine. Other acids, 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.

[0184] Particular salts of the compounds of the invention may include acid addition salts such as those formed from hydrochloric, hydrobromic, acetic, p-toluenesulfonic, tartaric, sulphuric, succinic, phosphoric, oxalic, nitric, methanesulfonic, malic, maleic and citric acid, and in particular hydrochloric acid.

[0185] 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, acomplex with water is known as a "hydrate". The compounds of the present invention may be in the form of a solvate, such as a hydrate.

[0186] The present invention also provides a compound selected from the group consisting of

[0187]

[0188] or a pharmaceutically acceptable salt or solvate thereof.

[0189] Pharmaceutical compositions

[0190] Compounds, compositions and pharmaceutical compositions according to the invention may be used in the treatment and / or prophylaxis of diseases and disorders know to be treated to prevented by a benzimidazole drug, for example chronic inflammatory diseases, cancers and parasitic diseases and infections.

[0191] While it is possible for a compound according to the invention to be administered alone, it is preferable for it to be present in a composition and particularly in a pharmaceutical composition. Thus, the present invention further provides a pharmaceutical composition which comprises a compound of the invention, together with a pharmaceutically suitable carrier. Such compositions may contain the compound of the invention as the sole active ingredient, or they may contain an additional active ingredient, for example, one or more further therapeutic agents.

[0192] For the avoidance of doubt, in embodiments herein, the word "comprising" may be interpreted as requiring the features mentioned, but not limiting the presence of other features. Alternatively, the word "comprising" may also relate to the situation where onlythe components / features listed are intended to be present (e.g. the word "comprising" may be replaced by the phrases "consists of" or "consists essentially of"). It is explicitly contemplated that both the broader and narrower interpretations can be applied to all aspects and embodiments of the present invention. In other words, the word "comprising" and synonyms thereof may be replaced by the phrase "consisting of' or the phrase "consists essentially of' or synonyms thereof and vice versa.

[0193] Pharmaceutical compositions 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 disease or disorder of the subject undergoing the treatment / prophylaxis.

[0194] Preferred pharmaceutical compositions of the present invention are those suitable for oral administration.

[0195] Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of a compound of the invention; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The compounds may also be presented as a bolus, electuary or paste. Various pharmaceutically acceptable carriers and their formulation are described in standard formulation treatises, e.g., Remington's Pharmaceutical Sciences by E. W. Martin. See also Wang, Y. J. and Hanson, M. A., Journal of Parenteral Science and Technology, Technical Report No. 10, Supp. 42:2S, 1988.

[0196] Pharmaceutical compositions of the present invention suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions 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.

[0197] 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.

[0198] Pharmaceutical compositions of the present invention suitable 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.

[0199] Pharmaceutical compositions of the present invention suitable for rectal administration may be presented as a suppository 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.

[0200] Pharmaceutical compositions of the present invention suitable for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising a compound of the invention in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising a compound of the invention in a basis such as gelatin and glycerine or sucroseand acacia. Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0201] Preferred unit dosage compositions are those containing a therapeutic dose, or an appropriate fraction thereof, of a compound of the invention. Pharmaceutical compositions of the present invention suitable for oral administration may be provided as a pharmaceutical composition in the form of tablets or other forms of presentation provided in discrete units containing, for example, about 1 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg or about 1000 mg of a compound of the invention. A medicament comprising a compound of the invention typically contains from about 1 mg to about 1000 mg of compound, preferably from about 1 mg to about 500 mg of compound, for example about 1 mg, about 10 mg, about 50 mg, about 100 mg, about 200 mg, about 400 mg or about 500 mg of compound. Intravenously, the most preferred doses will range from about 0.1 to about 50 mg / kg / minute during a constant rate infusion. The compounds of the invention may be administered in a single daily therapeutic dose, or may be administered in two, three or four or more times daily as split doses to provide the daily therapeutic dose. Preferably, the compounds are administered in two daily split doses to provide the daily therapeutic dose.

[0202] As used herein, the term "about" can allow for a degree of variability in a value or range, for example, within 10%, within 5%, within 1%, within 0.5%, within 0.1 %, within 0.05%, within 0.01%, within 0.005%, or within 0.001% of a stated value or of a stated limit of a range, and includes the exact stated value or range.

[0203] It should be understood that in addition to the ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavouring agents.In one embodiment, a pharmaceutic composition of the invention consists essentially of a compound of the invention and at least one pharmaceutically acceptable excipient.

[0204] Whilst compounds of the invention may be used as the sole active ingredient in the present invention, it is also possible for the compounds to be used in combination with one or more further therapeutic agent(s). Examples of further therapeutic agents that may be present in a composition of the present invention include, but not limited to, therapeutic agents useful in the treatment or prophylaxis of a disease of disorder that may be treated to prevented by a benzimidazole drug, for example therapeutic agents useful in the treatment or prophylaxis of a disease of disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections, or other pharmaceutically active materials. Such agents are known in the art. Examples of further therapeutic agents that may be present in a composition of the present invention include, but not limited to mebendazole, albendazole, fenbendazole, flubendazole, nocodazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, disease-modifying anti-rheumatic drugs (DMARDs), alkylators, antimetabolites, anti-tumor antibiotics, histone deacetylase inhibitors, immunomodulatory drugs, microtubule interactive drugs, protein kinase inhibitors, steroids, topoisomerase inhibitors, cell cycle inhibitors, angiogenesis inhibitors, ivermectin, praziquantel, diethylcarbamazine, niclosamide, piperazine, pyrantel pamoate, metrifonate, oxamniquine, and bithionol.

[0205] As such, the present invention also provides a pharmaceutical composition comprising a compound of the invention, and which further comprises one or more additional therapeutic agent(s), for example one or more additional therapeutic agent(s) useful in the treatment or prophylaxis of a disease of disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections (for example one or more additional therapeutic agent(s) selected from the group consisting ofmebendazole, albendazole, fenbendazole, flubendazole, nocodazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, disease-modifying anti-rheumatic drugs (DMARDs),alkylators, antimetabolites, anti-tumor antibiotics, histone deacetylase inhibitors, immunomodulatory drugs, microtubule interactive drugs, protein kinase inhibitors, steroids, topoisomerase inhibitors, cell cycle inhibitors, angiogenesis inhibitors, ivermectin, praziquantel, diethylcarbamazine, niclosamide, piperazine, pyrantel pamoate, metrifonate, oxamniquine, and bithionol).

[0206] Treatments

[0207] As mentioned above, compounds of the present invention are prodrugs of benzimidazole drugs, for example prodrugs of mebendazole, albendazole, fenbendazole, nocodazole, flubendazole, ricobendazole, or oxfendazole, and especially prodrugs of mebendazole and albendazole, and more especially prodrugs of mebendazole. The compounds of the present invention are converted in the body (i.e. in vivo) into a benzimidazole drug (for example, a compound of formula (X) as described herein, such as mebendazole, albendazole, fenbendazole, nocodazole, flubendazole, ricobendazole, or oxfendazole, and preferably mebendazole or albendazole, and more preferably mebendazole, or an active metabolite or residue thereof). Benzimidazole drugs are known to treat a variety of diseases and disorders, including but not limited to, chronic inflammatory diseases, cancers, and parasitic diseases and infections.

[0208] The invention provides a compound according to the invention, or a composition comprising a compound according to the invention together with a pharmaceutically acceptable carrier, for use as a medicament.

[0209] In particular, compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a disease or disorder selected from chronic inflammatorydiseases, cancers, and parasitic diseases and infections; as well as finding use as antiparasitic agents.

[0210] The invention also provides a method for treating a patient or subject which comprises administering a pharmaceutically effective amount of a compound of the invention or a pharmaceutical composition of a compound of the invention. In particular, the invention also provides a method for the treatment or prophylaxis of a disease or disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections in a subject or patient (for example a subject or patient in need thereof), comprising administering an effective amount of a compound according to the invention, or a composition comprising a compound according to the invention, to the subject or patient (for example a subject or patient in need thereof). The subject is typically a mammal or human; preferably a human. As such, a compound or composition of the invention may be administered to a patent or subject suffering, or at risk of developing, a chronic inflammatory disease, cancer or parasitic disease or infection.

[0211] Compounds of the invention also find use in the manufacture of a medicament. Thus, the invention also provides the use of a compound of the invention for the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections.

[0212] Examples of chronic inflammatory diseases, cancers, and parasitic diseases and infections that the compounds and compositions of the invention find use in treating (and / or the compounds find use for the manufacture of a medicament for the treatment or prophylaxis of; and / or that may be treated by the method of the invention) are described below.

[0213] For the avoidance of doubt, as used herein the terms "therapy", "treatment" and "treating" include both preventative and curative treatment of a disease or disorder. It also includesslowing, interrupting, controlling or stopping the progression of a disease or disorder. It also includes preventing, curing, slowing, interrupting, controlling or stopping the symptoms of a disease or disorder. For the avoidance of doubt, as the compounds of the invention are prodrugs, the terms "therapy", "treatment" and "treating" also include both a compound of the invention directly treating a disease or disorder, or treating the disease of disorder after the compound of the invention is converted within the body into a pharmacologically active compound or more specifically a benzimidazole drug (for example, a compound of formula (X) as described herein, such as mebendazole or albendazole).

[0214] The amount of a compound of the invention which is required to achieve a therapeutic effect will vary with particular route of administration and the characteristics of the subject under treatment, for example the species, age, weight, sex, medical conditions, the particular disease or condition and its severity, and other relevant medical and physical factors. An ordinarily skilled physician can readily determine and administer an effective amount of the compound of the invention required for treatment or prophylaxis of a disease or disorder.

[0215] The terms "subject" or "patient" as used herein are well-recognized in the art, and are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

[0216] The compound of the invention, or salt and / or solvate thereof, may be administered daily (including several times daily), every second or third day, weekly, every second, third or fourth week or even as a high single dose depending on the subject and disease or disorder to be treated.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 form of tablets or other forms of presentation provided in discrete units containing about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg or about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg or about 800 mg of a compound of the invention for the symptomatic adjustment of the dosage to the subject / 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.

[0217] In one preferred embodiment of the invention, the use of a compound or composition of the invention or a method of treatment of the invention comprises administering a therapeutic dose of a compound of the invention to a subject / patient, wherein the therapeutic dose administered is sufficient to achieve a steady state maximum plasma concentration of the pharmaceutically active agent that the compound is prodrug of (i.e. the benzimidazole drug that the compound of the invention is prodrug of) in the subject / patient of 150 – 350 ng / ml (for example, about 150 – about 250, about 200 – about 300, or about 250 – about 350 ng / ml, and preferably about 200 – about 300 ng / ml). Steady state maximum plasma concentration may be measured as described in WO 2019 / 043108, the contents of which are incorporated herein by reference. In one preferred embodiment of the invention, the use of a compound or composition of the invention or a method of treatment of the invention comprises administering a therapeutic dose of a compound of the invention to a subject / patient, wherein the compound is a compound of the invention is a prodrug ofmebendazole (for example, wherein the compound of the invention is a compound of formula (IIa) and / or (IIa), or formula (IIc) and / or (IId)) and wherein the therapeutic dose administered is sufficient to achieve a steady state maximum plasma concentration of mebendazole in the subject / patient of about 150 – about 350 ng / ml (for example, about 150 – about 250, about 200 – about 300, or about 250 – about 350 ng / ml, and preferably about 200 to about 300 ng / ml). In such embodiments, preferably the compound is for use in the treatment of a chronic inflammatory disease or cancer, and especially cancer.

[0218] Whilst a compound of the invention may be used as the sole active ingredient in the present invention, it is also possible for it to be used in combination with one or more further therapeutic agent(s), and the use of such combinations provides one preferred embodiment of the invention. Such further therapeutic agents may be agents useful in the treatment or prophylaxis of chronic inflammatory diseases, cancers, and parasitic diseases and infections, or other pharmaceutically active materials. Such agents are known in the art. Examples of further therapeutic agents suitable for use in the present invention include, but not limited to mebendazole, albendazole, fenbendazole, flubendazole, nocodazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, disease-modifying anti-rheumatic drugs (DMARDs), alkylators, antimetabolites, anti-tumor antibiotics, histone deacetylase inhibitors, immunomodulatory drugs, microtubule interactive drugs, protein kinase inhibitors, steroids, topoisomerase inhibitors, cell cycle inhibitors, angiogenesis inhibitors, ivermectin, praziquantel, diethylcarbamazine, niclosamide, piperazine, pyrantel pamoate, metrifonate, oxamniquine, and bithionol.

[0219] The one or more further therapeutic agent(s) may be used simultaneously, sequentially or separately with / from the administration of a compound of the invention. The individual components of such combinations can be administered separately at different times during therapy or concurrently in divided or single combination forms.When used in a combination, the precise dosage of the further therapeutic agent(s) will vary with the dosing schedule, the oral potency of the particular agent chosen, the age, size, sex and condition of the subject / patient (typically a mammal or human; preferably a human), the nature and severity of the condition, and other relevant medical and physical factors. Thus, a precise pharmaceutically effective amount can be readily determined by the caregiver or clinician. An appropriate amount can be determined by routine experimentation from animal models and human clinical studies. For humans, an effective dose will be known or otherwise able to be determined by one of ordinary skill in the art.

[0220] Chronic inflammatory diseases

[0221] In one preferred embodiment, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease. Particular examples of chronic inflammatory diseases that may be treated or prevented by administering a compound or composition of the invention include, but not limited to, acne, acid reflux / heartburn, age related macular degeneration (AMD), allergy, Alzheimer's disease, amyotrophic lateral sclerosis, anaemia, appendicitis, arteritis, asthma, atherosclerosis, balanitis, blepharitis, bronchiolitisa bullous pemphigoid, burn, bursitis, carditis, celiac disease, cellulitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, chronic obstructive pulmonary disease (COPD), cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), congestive heart failure, conjunctivitis, cyclophosphamideinduced cystitis, cystic fibrosis, cystitis, common cold, Crohn's disease, dacryoadenitis, dementia, dermatitis, dermatomyositis, digestive system disease, eczema, emphysema, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibromyalgia, fibrosis, fibrositis, foreign body granuloma, gastritis, gastroenteritis, gingivitis, glomerulonephritis, glossitis, heart disease, heart valve dysfunction, hepatitis (such as autoimmune hepatitis), hidradenitis suppurativa, Huntington's disease, hyperlipidemic pancreatitis, hypertension, ileitis, infection (e.g. viral, bacterial, fungal), inflammatory bowel disease, inflammatory cardiomegaly, inflammatory neuropathy,inflammatory lung diseases, neuropathy insulin resistance, interstitial cystitis, interstitial nephritis, iritis, ischemia, ischemic heart disease, keratitis, keratoconjunctivitis, laryngitis, systemic lupus erythematosus, lupus nephritis, mastitis, mastoiditis, meningitis, metabolic syndrome (syndrome X), a migraine, multiple sclerosis, myelitis, myocarditis, myositis, neurological disorders, nephritis, non-alcoholic steatohepatitis, obesity, omphalitis, oophoritis, orchitis, osteochondritis, osteopenia, osteomyelitis, osteoporosis, osteitis, otitis, pancreatitis, Parkinson's disease, parotitis, pelvic inflammatory disease, pemphigus vularis, pericarditis, peritonitis, phlebitis, pleuritis, pneumonitis, polycystic nephritis, proctitis, prostatitis, psoriasis, pulpitis, pyelonephritis, pylephlebitis, renal failure, reperfusion injury, retinitis, rheumatic fever, salpingitis, sarcoidosis, sialadenitis, spastic colon, stenosis, stomatitis, stroke, surgical complication, synovitis, tendonitis, tendinosis, tenosynovitis, thrombophlebitis, tonsillitis, trauma, traumatic brain injury, transplant rejection, trigonitis, tuberculosis, tumour, urethritis, ursitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0222] Further examples of chronic inflammatory diseases that may be treated or prevented by administering a compound or composition of the invention include, but not limited to, diabetes type 1, systemic sclerosis (also called scleroderma), Sjogren's syndrome, rheumatoid arthritis, Grave's disease, Addison's disease and end stage renal disease.

[0223] In certain preferred embodiments, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus, sarcoidosis, Alzheimer's disease, cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), Crohn's disease, hepatitis (such as autoimmune hepatitis), Huntington's disease, inflammatory bowel disease, multiple sclerosis, myositis, psoriasis, renal failure (for example end stage renal disease), tuberculosis, diabetes type 1, systemic sclerosis (also called scleroderma), Sjogren's syndrome, rheumatoid arthritis, Grave's disease and Addison's disease.In certain preferred embodiments, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease wherein the chronic inflammatory disease is characterised by granulomatous inflammation.

[0224] In another preferred embodiment, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus, sarcoidosis, Alzheimer's disease, cirrhosis (such as primary biliary cirrhosis), colitis (such as ulcerative colitis), Crohn's disease, hepatitis (such as autoimmune hepatitis), Huntington's disease, inflammatory bowel disease, myositis, renal failure (for example end stage renal disease), and tuberculosis.

[0225] In another preferred embodiment, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease selected from the group consisting of diabetes type 1, systemic sclerosis (also called scleroderma), and Addison's disease.

[0226] In one very preferred embodiments, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus and sarcoidosis.

[0227] In one embodiment of the invention, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease wherein the CID is a disease associated with impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (and more preferably the CID is a disease mediated by impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (e.g. the CID is a disease that may be treated or prevented by increasing ERK activity and / or increasing ERK signalling and / or activation of ERK)); and / or the CID is associated with defective ERK signalling (for example, the CID is brought about by defects in ERK signalling),and / or is associated with increased Type-1 interferon (interferon alpha and / or beta) response from plasmacytoid dendritic cells or other immune cells, and / or is associated with increased p38 MAP kinase signalling. Examples of such CIDs include systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease.

[0228] In one embodiment of the invention, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease wherein the CID is a disease caused by impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (e.g. the CID is a disease that may be treated or prevented by increasing ERK activity and / or increasing ERK signalling and / or activation of ERK); and / or the CID is associated with defective ERK signalling (for example, the CID is brought about by defects in ERK signalling), and / or is associated with increased Type-1 interferon (interferon alpha and / or beta) response from plasmacytoid dendritic cells or other immune cells, and / or is associated with increased p38 MAP kinase signalling.

[0229] Examples of such CIDs include systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease.

[0230] In certain preferred embodiments, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease wherein the CID is a disease associated with impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (and more preferably the CID is a disease mediated byimpaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (e.g. the CID is a disease that may be treated or prevented by increasing ERK activity and / or increasing ERK signalling and / or activation of ERK)); and / or the CID is associated with defective ERK signalling (for example, the CID is brought about by defects in ERK signalling), and / or is associated with increased Type-1 interferon (interferon alpha and / or beta) response from plasmacytoid dendritic cells or other immune cells, and / or is associated with increased p38 MAP kinase signalling, and the CID is selected from the group consisting of:

[0231] systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease; or

[0232] systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjogren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease; or systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease; or

[0233] Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease.In certain preferred embodiments, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease wherein the CID is a disease associated with impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (and more preferably the CID is a disease mediated by impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (e.g. the CID is a disease that may be treated or prevented by increasing ERK activity and / or increasing ERK signalling and / or activation of ERK)); and / or the CID is associated with defective ERK signalling (for example, the CID is brought about by defects in ERK signalling), and / or is associated with increased Type-1 interferon (interferon alpha and beta) response from plasmacytoid dendritic cells or other immune cells and the CID is selected from the group consisting of:

[0234] systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjogren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, and tuberculosis; or

[0235] systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjogren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, and tuberculosis; or systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, and tuberculosis; or

[0236] Huntington's disease, end stage renal disease, sarcoidosis, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, and tuberculosis.In certain preferred embodiments, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of a chronic inflammatory disease wherein the CID is a disease associated with impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (and more preferably the CID is a disease mediated by impaired ERK activity and / or decreased ERK signalling and / or inactivation of ERK (e.g. the CID is a disease that may be treated or prevented by increasing ERK activity and / or increasing ERK signalling and / or activation of ERK)); and / or the CID is associated with defective ERK signalling (for example, the CID is brought about by defects in ERK signalling), and the CID is selected from the group consisting of:

[0237] systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, and sarcoidosis; or

[0238] Huntington's disease, end stage renal disease, and sarcoidosis.

[0239] In embodiments of the invention that find use in the treatment or prophylaxis of a chronic inflammatory disease, it is also possible for it to be used in combination with one or more further therapeutic agent(s), and the use of such combinations provides one preferred embodiment of the invention. Such further therapeutic agents may be agents useful in the treatment or prophylaxis of chronic inflammatory diseases, or other pharmaceutically active materials. In one embodiment, a compound or composition for use in the present invention for treatment or prophylaxis of a chronic inflammatory disease is administered (for example simultaneously, sequentially or separately) with one or more additional therapeutic agent(s) (for example one or more additional therapeutic agent(s) selected from the group consisting of mebendazole, albendazole, fenbendazole, flubendazole, nocodazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, and diseasemodifying anti-rheumatic drugs (DMARDs)).Cancer

[0240] In another preferred embodiment, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of cancer. As used herein, the term "cancer" refers to all types of cancer, neoplasm or malignant tumours found in mammals, including leukaemias, lymphomas, melanomas, neuroendocrine tumours, carcinomas and sarcomas.

[0241] The present invention finds utility in the treatment or prophylaxis of cancer. In particular, it finds utility in the treatment of gastrointestinal cancer (for example esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer (also referred to as colon cancer or bowel cancer), anal cancer, gastrointestinal carcinoid tumor, cholangiocarcinoma, and MALT lymphoma), lung cancer (including non-small cell lung cancer and small cell lung cancer), breast cancer, prostate cancer, leukemias (for example acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML)), lymphomas (including Hodgkin lymphoma and non-Hodgkin lymphoma), melanoma, brain tumors (for example glioma, meningioma, pituitary adenomas, medulloblastoma, primary central nervous system lymphoma), ovarian cancer, bladder cancer, sarcomas (including osteosarcoma for bone sarcomas, and leiom), and cancerous paraganglioma; and / or wherein the cancer is progressive cancer; and / or wherein the cancer is metastatic cancer.

[0242] The present invention finds particular utility in the treatment or prophylaxis of gastrointestinal cancer. Gastrointestinal cancer includes cancer of the gastrointestinal tract (G I tract) and accessory organs of digestion, including the esophagus, stomach, biliary system (e.g. the biliary tree), pancreas, liver, gall bladder, small intestine, large intestine, colon, rectum, anus, and mucosa-associated lymphoid tissue (MALT). Gastrointestinal cancer may be malignant. Gastrointestinal cancers include oesophageal caner, stomach cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer (also referred to as colon cancer or bowel cancer), anal cancer, gastrointestinal carcinoid tumour,cholangiocarcinoma and MALT lymphoma. The present invention also finds particular utility in the treatment or prophylaxis of colorectal cancer.

[0243] Progressive cancer may be any cancer that is progressing or worsening during treatment, having an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The progressive cancer may be gastrointestinal cancer (such as the types of gastrointestinal cancer listed above) or it may be another form of cancer, for example, adrenocortical carcinoma, lung cancer, ovarian cancer, melanoma, glioblastoma, lymphoma, non-small cell lung cancer, or leukemia. Compounds of the present invention are particularly useful in the treatment of cancer of unknown primary having progressive disease. The present invention is also particularly useful in the treatment of cancer in a patient having progressive disease wherein the patient has had at least at least one round of chemotherapy with one or more anti-cancer drug excluding a benzimidazole drug (for example mebendazole), for example, at least two or at least three rounds of chemotherapy with one or more anti-cancer drug excluding a benzimidazole drug (for example mebendazole) and / or at least one round of radiotherapy.

[0244] The present invention also finds utility in the treatment or prophylaxis of cancer that has metastasised (which may also be referred to as metastatic cancer). Metastatic cancer is cancer which has spread from the primary site of origin into one or more different areas of the body. For example the cancer may be metastatic gastrointestinal cancer (i.e. cancer which has spread from the primary gastrointestinal site of origin into one or more different areas of the body, for example one or more other gastrointestinal site, or another site in the body such as the lungs, liver, or bones), or another form of metastatic cancer, such as metastatic adrenocortical carcinoma, metastatic lung cancer, metastatic ovarian cancer, metastatic melanoma, metastatic glioblastoma, metastatic lymphoma, metastatic non-small cell lung cancer, or metastatic leukemia. The compounds are compounds of the presentinvention are particularly effective in the treatment of gastrointestinal metastatic cancer, and more particularly in the treatment of metastatic colorectal cancer.

[0245] The compounds and compositions of the present invention also find utility in the treatment of squamous cell cancer or adenocarcinoma, including primary cancer of the liver, of the gastrointestinal tract or cancer of unknown origin.

[0246] The compounds and compositions of the present invention also find utility in the treatment of patients in which standard treatment has failed or has started to fail (for example one or more standard treatments have failed or have started to fail, in particular two or more standard treatments, and especially three or more standard treatments have failed or have started to fail). " Standard treatment" means the treatment recommendations that are followed in normal clinical practice, and may differ depending on type of malignancy, staging, local or metastasized disease, performance status, etc. in each patient. The standard treatment may be with one or more chemotherapeutic agents, surgery and / or radiotherapy.

[0247] The compounds and compositions of the invention are particularly effective in patients not amenable to standard treatment. For such patients, treatment with a compound of the invention may be added to the existing standard treatment that has failed or has started to fail. In such embodiments, administering a therapeutic dose of the pharmaceutically active agent that the compound is prodrug of (i.e. the benzimidazole drug that the compound of the invention is prodrug of, for example mebendazole) to the patient sufficient to achieve a steady state maximum plasma concentration (Cmax) of the pharmaceutically active agent of 150 - 350 ng / ml (for example 150 - 250, 200 - 300 or 250 - 350 ng / ml, and preferably 200 to 300 ng / ml) may be simultaneous, sequential or separate to administering the existing standard treatment. Alternatively, or additionally, treatment with a compound of the invention according to the present invention may be started once the existing standard treatment has stopped, for example immediately after the existing standard treatment hasstopped; at least 1 day after the existing standard treatment has stopped, at least 7 days after the existing standard treatment has stopped, at least 14 days after the existing standard treatment has stopped, or at least 28 days after the existing standard treatment has stopped (for example 1, day, 7 days, 14 days, 21 says, 28 days or 42 days after the existing standard treatment has stopped)

[0248] In embodiments of the invention that find use in the treatment or prophylaxis of a cancer, it is also possible for it to be used in combination with one or more further therapeutic agent(s), and the use of such combinations provides one preferred embodiment of the invention. Such further therapeutic agents may be agents useful in the treatment or prophylaxis of cancer, or other pharmaceutically active materials. In one embodiment, a compound or composition for use in the present invention for treatment or prophylaxis of a cancer is administered (for example simultaneously, sequentially or separately) with one or more additional therapeutic agent(s) (for example one or more additional therapeutic agent(s) selected from the group consisting of mebendazole, albendazole, fenbendazole, flubendazole, nocodazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole, alkylators, antimetabolites, anti-tumor antibiotics, histone deacetylase inhibitors, immunomodulatory drugs, microtubule interactive drugs, protein kinase inhibitors, steroids, topoisomerase inhibitors, cell cycle inhibitors, and angiogenesis inhibitors.

[0249] In certain preferred embodiments, the one or more further active agents are agents useful in the treatment of cancer, and may be, for example, one or more agent selected from the group consisting of capecitabine (Xeloda), fluorouracil (5-FU, Adrucil) (optionally with folinic acid), irinotecan (Camptosar), oxaliplatin (Eloxatin), trifluridine / tipiracil (TAS-102, Lonsurf), Regorafenib (Stivarga), cetuximab (Erbitux), bevacizumab (Avastin), panitumumab (Vectibix), ziv-aflibercept (Zaltrap) and ramucirumab (Cyramza).Parasitic diseases

[0250] In another preferred embodiment, the compounds and compositions of the present invention find use in the treatment and / or prophylaxis of parasitic diseases.

[0251] The term parasitic diseases refer to diseases caused by parasites, for example, protozoa, helminths and ectoparasites.

[0252] Particular examples of parasitic diseases that may be treated or prevented by administering a compound or composition of the invention include, but not limited to, infections of threadworm (also known as pinworms), roundworm, whipworm, tapeworm, hookworm, giardia, strongyle worm, liver fluke, filarial or nematode; and / or a parasitic diseases selected from ascariasis, trichuriasis, strongyloidiasis, enterobiasis, taeniases (for example taeniases hymenolepiasis), visceral, ocular, neural, and cutaneous larva migrans, anisakiasis, trichinosis, hepatic and intestinal capillariasis, angiostrongyliasis, gnathostomiasis, gongylonemiasis, thelaziasis, dracunculiasis, cerebral and subcutaneous cysticercosis, cystic echinococcosis, lymphatic filariasis, onchocerciasis, loiasis, mansonellosis, dirofilariasis, trichinosis, helminthiasis, fascioliasis, paragonimiasis, cystic echinococcosis, taeniasis, clonorchiasis, opisthorchiasis, and giardiasis.

[0253] In some embodiments, the compounds of the invention find use as anthelminthic agents. In some embodiments, the compounds of the invention find application as ascaricide agents. In some embodiments, the compounds of the invention find application as antinematode agents.

[0254] In embodiments of the invention that find use in the treatment or prophylaxis of a parasitic disease or infection, it is also possible for it to be used in combination with one or more further therapeutic agent(s), and the use of such combinations provides one preferred embodiment of the invention. Such further therapeutic agents may be agents useful in the treatment or prophylaxis of parasitic diseases or infections, or other pharmaceutically activematerials. In one embodiment, a compound or composition for use in the present invention for treatment or prophylaxis of a parasitic disease or infection is administered (for example simultaneously, sequentially or separately) with one or more additional therapeutic agent(s) (for example one or more additional therapeutic agent(s) selected from the group consisting of mebendazole, albendazole, fenbendazole, flubendazole, nocodazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole, ivermectin, praziquantel, diethylcarbamazine, niclosamide, piperazine, pyrantel pamoate, metrifonate, oxamniquine, and bithionol.

[0255] Kits

[0256] The present invention provides a kit comprising a compound of formula (I), one or more pharmaceutically acceptable excipients, and optionally one or more further therapeutic agent(s). Examples of such further therapeutic agents include those described herein as being suitable for use in the present invention, and being optionally present in a pharmaceutical composition of the invention as a further therapeutic agent.

[0257] Kits of the present invention find use in the treatment and / or prophylaxis of chronic inflammatory diseases, cancers, and parasitic diseases and infections.

[0258] In certain embodiments the kit comprises one or more containers and may also include sampling equipment, for example, bottles, bags (such as intravenous fluid bags), vials, syringes, and test tubes. Other components may include needles, diluents, wash reagents and buffers. Usefully, the kit may include at least one container comprising a pharmaceutically acceptable organic solvent or a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and dextrose solution.

[0259] Preferably, the kit of the invention comprises instructions, for example instructions that instruct a user to admix a stated amount of compound or composition of the present invention with a stated amount physiologically acceptable aqueous solvent or diluent,pharmaceutically acceptable organic solvent, and / or optional one or more further therapeutic agents. Such instructions may also provide guidance on the storage conditions and / or administration instructions.

[0260] For the avoidance of doubt, the compound or composition of the present invention, optional physiologically acceptable aqueous solvent or diluent, optional one or more pharmaceutically acceptable organic solvent, and optional one or more further therapeutic agent, are present in a kit according to the present invention in a form and quantity suitable for the preparation of a pharmaceutical preparation according to the invention. The skilled person can readily determine a quantity of a compound or composition of the present invention, physiologically acceptable aqueous solvent or diluent, pharmaceutically acceptable organic solvent, and optional one or more further therapeutic agents, suitable for the use according to the present invention.

[0261] Equivalents

[0262] The invention has been described broadly and generically herein. Those of ordinary skill in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the scope of the presentinvention. Further, each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0263] Incorporation by Reference

[0264] The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The applicant reserves the right physically to incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other physical and electronic documents.

[0265] The listing or discussion of a prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0266] EXAMPLES

[0267] General Experimental Details

[0268] NMR spectra were recorded on Varian or Bruker spectrometers at 400MHz for1H. Chemical shifts (δ) are reported in ppm with the residual solvent peak as internal standard. The1H NMR spectra of all the compounds containing the mebendazole motif indicate the presence of rotamers (common for carbamates). Regioisomers and more specially the N-regioisomers were also formed in the reaction with mebendazole. Therefore, for most of the example compounds, the aromatic signals are reported as one signal and all aliphatic protons in the shift region 2.8-4.2 ppm integrated together, showing the ratio between the rest of the aliphatic protons (if there were other aliphatic signals) and the aromatic protons. Theregioisomeric ratio was determined by HPLC (UV) dependent on elution order of the peaks. It was not determined which peak corresponded to which regioisomer.

[0269] Analytical RPLC-MS was performed using an Agilent / HP 1200 or 1100 system Liquid Chromatograph / Mass Selective Detector (MSD) (Single Quadrupole) equipped with an electrospray interface (positive mode) and a UV diode array detector. Analyses were performed by two methods using either an ACE 3 C8 (3.0 x 50 mm) column with a gradient of acetonitrile in 0.1% aqueous TFA over 3 min and a flow of 1 mL / min, or an XBridge C18 (3.0 x 50 mm) column with a gradient of acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow of 1 mL / min. The ratio between the regioisomers for the various example compounds are given as peak 1:peak 2 (based on elution order of the peaks) when analyzed by liquid chromatography (LC) using the Xbridge column followed by UV-detection with the wavelength varied from 215-395 nM. Purity is expressed as the percentage area of the combined regioisomers using UV-detection at 254 nM. The mass spectra are reported as the detected molecular ion [M + H]+unless otherwise stated.

[0270] Analytical HPLC-MS was performed using an Agilent 1100 series Liquid Chromatograph / Mass Selective Detector (MSD) (Single Quadrupole) equipped with an electrospray interface and a UV diode array detector. Analyses were performed by two methods using either an ACE 3 C8 (3.0 x 50 mm) column with a gradient of acetonitrile in 0.1% aqueous TFA over 3 min and a flow of 1 mL / min, or an Xbridge C18 (3.0 x 50 mm) column with a gradient of acetonitrile in 10 mM ammonium bicarbonate over 3 min and a flow of 1 mL / min. 1H-NMR spectra were recorded on a Bruker 400 MHz instrument at 25 ºC.

[0271] General Synthetic Methodology

[0272] The methods used for the synthesis of the compounds of the invention are illustrated by the schemes below. The starting materials and reagents used in preparing these compounds are available from commercial suppliers or can be prepared by methods routine to those skilled in the art.Numerous synthetic routes to the compounds of the present invention can be devised by any person skilled in the art and the possible synthetic routes described below do not limit the invention. A number of possible synthetic routes are shown schematically below.

[0273] General procedure 1 ('GP1')

[0274] To a solution of tert-butyl-N-methyl-N-[2-(methylamino)ethyl]carbamate (1 eq) in CH2Cl2 (10 ml) was added a carbonochloridate (1.2 eq) followed by triethylamine (2 eq) in a dropwise fashion at 5°C. The reaction mixture was allowed to warm to room temperature and stirred for a further 2 h. The reaction mixture was then diluted with 100 ml of CH2CI2 and washed with 2N aqueous (aq.) NaOH (50 mL x 3), 2N aq. HCI (50 mL), water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to afford the product. The product was taken forward to subsequent steps without further purification.

[0275] General procedure 2 ('GP2')

[0276] The product of the GP1 step (1 eq) was dissolved in CH2Cl2 (10 ml) and trifluoroacetic acid (1 eq) was added at room temperature. The reaction was stirred at room temperature for 1 h. A further 5 eq of trifluoroacetic acid were added and the reaction mixture was stirred for a further 3 h. The reaction mixture was concentrated under reduced pressure and 3 ml of neat trifluoroacetic acid was added. The reaction mixture was allowed to stir overnight. The reaction mixture was again concentrated under reduced pressure. The product was taken forward to subsequent steps without further purification.

[0277] General procedure 3 ('GP3'):

[0278] The product of the GP2 step (1 eq) was dissolved in CH2Cl2 (10 mL) and stirred at room temperature. Bis(4-nitrophenyl)carbonate was added (1 eq) followed by triethylamine (2 eq) with continued stirring. The reaction mixture turned yellow and LCMS indicated completion of the reaction in approximately 10 minutes. The reaction mixture was diluted with 100 mL CH2Cl2 and washed with 2N aq. NaOH (100 mL x 3), 2N aq. HCl (50 mL), water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to afford a colourless oil.General procedure 4 ('GP4')

[0279] Methyl N-(5-benzoyl-1H-benzimidazol-2-yl)carbamate (3 eq) was dissolved in dry DMF (2 ml) under a nitrogen atmosphere and NaH (60%, 2 eq) was added. The turbid reaction mixture became a clear yellow solution after 20 minutes. A DMF solution (2 ml) of the product of the GP3 reaction step (3 eq) was added and the solution was stirred for 20 h at 40°C. The reaction was monitored by LCMS. The reaction mixture was then added dropwise to 100 ml of HCl (1M) under vigorous stirring. After stirring for 10 minutes the aqueous layer was extracted with ethyl acetate. The resulting organic layer was washed with water, and then brine, and dried over Na2SO4. The filtered organic later was then concentrated under reduced pressure to remove volatiles. The crude product was purified by silica column chromatography (12 gm) by combi-flash using 0-100% ethyl acetate in isohexane as a gradient. The product was eluted at approximately 90% ethyl acetate and unreacted starting material eluted at 70%. The obtained product was dissolved in a mixture of acetonitrile (2 ml) and water (2ml) and freeze dried to furnish a white solid.

[0280] Intermediate Compounds

[0281]

[0282] Intermediate Al

[0283]

[0284] 2-methoxyethyl carbonochloridate (422 mg, 3.19 mmol) was reacted according to general procedure GP1 to afford 2-methoxyethyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (771 mg, 100%).

[0285] Intermediate A2

[0286]

[0287] Phenyl carbonochloridate (499 mg, 3.19 mmol) was reacted according to general procedure GP1 to afford phenyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (819 mg, 100%).

[0288] Intermediate Bl: 2-methoxyethyl N-methyl-N-[2-(methylamino)ethyl]carbamate TFA, CH2Cl2

[0289]

[0290] 2-methoxyethyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (771 mg, 2.66 mmol - Intermediate A1) was reacted according to general procedure GP2 to afford 2-methoxyethyl N-methyl-N-[2-(methylamino)ethyl]carbamate (505 mg, 100%).

[0291] Intermediate B2: phenyl N-methyl-N-[2-(methylamino)ethyl]carbamate

[0292] TFA, CH2Cl2

[0293]

[0294] Phenyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (819 mg, 2.66 mol - Intermediate A2) was reacted according to general procedure GP2 to afford phenyl N-methyl-N-[2-(methylamino)ethyl]carbamate (533 mg, 100%).

[0295] Intermediate Cl: (4-Nitrophenyl)-N-[2-[2-methoxyethoxycarbonyl(methyl)amino]ethyl]-N-methylcarbamate

[0296]

[0297] 2-methoxyethyl N-methyl-N-[2-(methylamino)ethyl]carbamate (505 mg, 2.66 mmol - Intermediate B1) was reacted according to general procedure GP3 to afford (4-nitrophenyl)N-[2-[2-methoxyethoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate. The product was further purified by combi-flash chromatography using 25 gm silica column chromatography using a gradient of ethyl acetate (max. 70%) in petroleum ether to afford the product ((4-nitrophenyl)-N-[2-[2-methoxyethoxycarbonyl(methyl)amino]ethyl]-N- methylcarbamate) as a thick colourless oil (700 mg, 74%).

[0298] Intermediate C2: Phenyl N-methyl-N-[2-[methyl-(4-nitrophenoxy)carbonyl- amino]ethyl]carbamate

[0299]

[0300] Phenyl N-methyl-N-[2-(methylamino)ethyl]carbamate (819 mg, 2.66 mmol - Intermediate B2) was reacted according to general procedure GP3 to afford phenyl N-methyl-N-[2- [methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate. The product was further purified by combi-flash chromatography using 25 gm silica column chromatography using a gradient of ethyl acetate (max. 70%) in petroleum ether to afford the product (phenyl N-methyl-N-[2- [methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate) as a thick colourless oil (850 mg, 86%).

[0301] Example Compounds

[0302] Example 1: Synthesis of

[0303] l-2-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l- yl}carbonylamino)ethyl 1-methyl phenylmethanecarbamate (la) and

[0304] l-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l- yl}carbonylamino)ethyl 1-methyl phenylmethanecarbamate (lb)Step (i): (4-nitrophenyl) N-[2-[benzyloxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate

[0305]

[0306] To a DCM (5 mL) solution of benzyl N-methyl-N-[2-(methylamino)ethyl]carbamate (100 mg; 0.45 mmol), was added bis(4-nitrophenyl) carbonate, (151 mg; 0.50 mmol ) at room temperature and the reaction mixture was stirred for 30 min. LCMS shown completion of reaction. Added silica gel to reaction mixture to adsorb the crude product and purified using 45% ethyl acetate in / so-hexane to afford the product ((4-nitrophenyl) N-[2-[benzyloxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate) as a colorless oil 170 mg (97%), which was used directly in the next step. Purity 99% (UV); MS (M+l-BOC-group) 223.

[0307] Step (ii): Synthesis of la and lb

[0308]

[0309] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (65 mg, 0.220 mmol) and NaH (17.6 mg, 0.440 mmol) were added to dry DMF (1 ml). The turbid reaction mass became a clear yellow solution 20 min after the addition of the sodium hydride. (4-Nitrophenyl) N-[2-[benzyloxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (171 mg, 0.440 mmol) was added and the reaction mixture was stirred at 60 °C for 24 h. The reaction mixture was then added dropwise to 50 mL IM HCI (containing a few ice flakes). The mixture was then extracted with ethyl acetate. The organic layer was then washed with water, brine and then dried over Na2SO4. After filtration, solvent was removed under reduced pressure and the product (a mixture of the N-regioisomers Example la and Example lb) was purified by silica gel column (25 g SNAP) using 100% ethyl acetate to yield the Example la and lb mixture as a thick oil (99 mg, 82.7%). MS (M+l) 544. Purity (LC / MS, UV): 98%. Ratio (peakl:peak2); 62:38.

[0310] 1H NMR (400 MHz, CDCl3) δ 12.22-10-03 (m, 1H), 8.13 - 7.24 (m, 13H), 5.09 (m, 2H), 4.31 -2.51 (m, 13H).

[0311] Example 2: Synthesis ofl-2-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl methanecarbamate (2a) and

[0312] l-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl methanecarbamate (2b)

[0313] Step (i): (4-nitrophenyl) N-[2-[methoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate

[0314]

[0315] To a solution of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (400 mg; 2.12 mmol) and triethyl amine (645 mg; 6.37 mmol) in DCM (10 mL) was added methyl chloroformate (402 mg; 4.25 mmol) in DCM (4 mL) at 0 °C and the reaction mixture was stirred for 2 h at room temperature. At this point the reaction mixture was diluted with DCM (50 mL) and washed by aq. bicarbonate, followed by IM HCI, water and brine. The organic phase was dried over sodium sulfate, filtered, concentrated under reduced pressure and the isolated methyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate was used directly in the next step. Purity 99% (UV). MS (M+l-BOC-group) 147. The methyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate was dissolved in DCM (10 mL) and TFA (1 mL; 5 equiv) was added. The reaction mixture was stirred overnight at room temperature. Volatiles were removed under reduced pressure and the to give the TFA salt of methyl N-methyl-N-[2-(methylamino)ethyl]carbamate, which was used directly in the next step.

[0316] The TFA salt of methyl N-methyl-N-[2-(methylamino)ethyl]carbamate was dissolved in DCM (10 mL) and triethyl amine (644 mg; 6.36 mmol) was added at room temperature. Bis(4-nitrophenyl) carbonate (968 mg; 3.18 mmol) was added and the reaction mixture was stirred for 30 min. Silica gel was added to the reaction mixture and the crude product adsorbed on the silica gel under reduced pressure. The product was purified by flashchromatography (SNAP 50 g, eluted with 50% Ethyl acetate in isohexane). The product, (4-nitrophenyl) N-[2-[methoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (555 mg, 84% yield over 3 steps), was isolated as a colourless thick oil. Purity 99.6% (UV). MS (M+l) 312.

[0317] Step (ii): Synthesis of 2a and 2b

[0318]

[0319] 2b

[0320] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (50 mg, 0.169 mmol) and NaH (13.5 mg, 0.339 mmol) were added to dry DMF (1 ml). The turbid reaction mass became a clear yellow solution 20 min after the addition of the sodium hydride. (4-nitrophenyl) N-[2- [methoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (105 mg, 0.339 mmol) was added and the reaction mixture was stirred at 55 °C for 18 h. The reaction mixture was then added dropwise to 50 mL IM HCI (containing a few ice flakes). The mixture was then extracted with ethyl acetate. The organic layer was then washed with water, brine and then dried over Na2SO4. After filtration, solvent was removed under reduced pressure and the mixture was purified by silica gel column (50 g SNAP) using 20-100% ethyl acetate in isohexane (where the desired compound eluted at 100% ethyl acetate) to yield the productas a thick oil (26.0 mg, 32.8%). Freeze drying provided white solid. Purity (LC / MS, UV): 99%. Ratio (peakl:peak2); 55:45

[0321] 1H NMR (400 MHz, CDCl3) δ 11.92 - 10.88 (m, 1H), 8.09 - 7.28 (m, 8H), 4.04 - 2.50 (m, 16H). MS (M+l) 468.

[0322] Example 3: Synthesis of

[0323] 2-2-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-l / - / -l,3-benzimidazol-l-yl}carbonylamino)ethyl 2-methyl 2-methylpropane-2-carbamate (3a) and

[0324] 2-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-l / - / -l,3-benzimidazol-l-yl}carbonylamino)ethyl 2-methyl 2-methylpropane-2-carbamate (3b)

[0325] Step (i): (4-nitrophenyl) N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate

[0326] O

[0327]

[0328] Bis(4-nitrophenyl) carbonate (1197 mg, 3.93 mmol) was dissolved in DCM (25 mL). Tertbutyl N-methyl-N-[2-(methylamino)ethyl]carbamate (700 pL, 3.56 mmol) was added and the reaction mixture was stirred at room temperature for 3 hrs. EtOAc was added. The solution was washed twice with 40 mL IM HCI, one with 50 mL H2O and twice with 50 mL brine. The combined aqueous phases looked "milky", and therefore back-extracted with ca. 50 mL EtOAc. All organic phases were then combined, dried over MgSO4, and the solvents removed under reduced pressure. The crude product was obtained as a yellow oil (1.84 g). The crude product was dissolved in DCM and evaporated onto silica, and then purified by column chromatography on silica gel (Biotage SNAP cartridge KP-sil 50 g. Gradient 10 to 35%EtOAc in hexanes). The product was isolated as a colorless thick oil (1.1 g). MS (M+l-BOC-group) 254.

[0329] 1H NMR (400 MHz, CDCl3) δ 8.30 - 8.18 (m, 2H), 7.36 - 7.26 (m, 2H), 3.67 - 3.40 (m, 4H), 3.20 - 3.03 (m, 3H), 2.91 (m, 3H), 1.44 (m, 9H) (peaks in spectrum split up due to rotamers).

[0330] Step (ii): Synthesis of 3a and 3b

[0331] NaH, DMF - ►

[0332]

[0333] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (mebendazole. 200 mg, 0.677 mmol) and NaH (54.2 mg, 1.35 mmol) were added to dry DMF (2 ml). The turbid reaction mass became a clear yellow solution 20 min after the addition of the sodium hydride. (4-nitrophenyl) N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (105 mg, 0.339 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. LCMS showed around 20% unreacted mebendazole The reaction mixture was then warmed to 40 °C and allowed to stir for a further 24 h. LCMS showed around 10 - 15% unreacted mebendazole. Further NaH (55 mg) was added and stirring was continued for 25 h at 40 °C. The reaction mixture was then added dropwise to 100 mL IM HCI. The mixture was thenextracted with ethyl acetate. The organic layer was then washed with water, brine and then dried over Na2SO4. After filtration, solvent was removed under reduced pressure and the mixture was purified by column chromatography (50 g SNAP 10-90% Ethyl acetate in isohexane). The product eluted at 80-90% ethyl acetate in isohexane. Removal of the solvent under reduced gave the product (a mixture of the N-regioisomers Example 3a and Example 3b) as a thick oil which solidified on standing (267 mg, 77%). The Example 3a and Example 3b mixture was then freeze dried (white solid). Purity (LC / MS, UV): 97%; HPLC (UV, 305 + / - 90 nM) Ratio (peakl:peak2); 47:53. MS (M+l) 510.

[0334] 1H NMR (400 MHz, CDCl3) 6 11.75 - 11.03 (m, 1H), 8.09 - 7.29 (m, 8H), 4.00 - 2.59 (m, 13H), 1.56 - 1.27 (m, 9H) (the product material on which the NMR was performed was further purified for NMR determination by column chromatography (snap 25g, 100% ethyl acetate).

[0335] Example 4: Synthesis of

[0336] 2-2-(N-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 2-methyl pyridine-2-carbamate (4a) and

[0337] 2-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 2-methyl pyridine-2-carbamate (4b)

[0338] Step (i): 2-pyridyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate

[0339] Et3N CH2Cl2

[0340]

[0341] To a CH2CI2 (5.00 mL) solution of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (250 mg, 1.33 mmol), bis(2-pyridyl) carbonate (316 mg, 1.46 mmol) and triethylamine (0.370 mL, 2.66 mmol) were added and the reaction stirred at room temperature for 10 min. The reaction mixture was diluted with 50 mL CH2CI2 and the organic layer was washed with 0.5 N aq. HCI, water, and brine. The organic layer was dried over Na2SC>4, filtered and concentrated. 2-pyridyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate was obtained as a thick colorless oil and taken forward to the next step without further purification.

[0342] Step (ii): 2-pyridyl N-methyl-N-[2-(methylamino)ethyl]carbamate

[0343] TFA CH2Cl2

[0344]

[0345] 2-pyridyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (410 mg, 1.33 mmol) was dissolved in CH2CI2 (2 mL) and TFA (2 mL) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The volatiles were removed under vacuum. 2-pyridyl N-methyl-N-[2-(methylamino)ethyl]carbamate was obtained as a colorless oil and taken forward to the next step without further purification.

[0346] Step (Hi): (2-pyridyl N-methyl- N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino ]ethyl]carbamate

[0347] EtgN CH2Cl2

[0348]

[0349] To a stirred solution of 2-pyridyl N-methyl-N-[2-(methylamino)ethyl]carbamate (277 mg, 1.33 mmol) in CH2CI2 (10.0 mL) triethylamine (268 mg, 2.65 mmol) was added at 0 °C. Bis(4-nitrophenyl) carbonate (484 mg, 1.59 mmol) was added and the reaction continued at room temperature overnight. Volatiles were removed under vacuum, the crude product adsorbed on silica gel and the product was purified by combi-flash using 25 gm silica column by petroleum ether and ethyl acetate as an eluent. The product was eluted at 90% ethyl acetate in petroleum ether to furnish colorless oil (305 mg, 61% yield) and taken forward to the next step without further purification.

[0350] Step (iv): Synthesis of 4a and 4bNaH, DMF

[0351]

[0352] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (25.0 mg, 0.0847 mmol) and NaH (60.0 %, 9.73 mg, 0.254 mmol) were dissolved in dry DMF (2 mL) under nitrogen atmosphere. The turbid reaction mixture became clear yellow solution in 20 min. A DMF (1 mL) solution of 2-pyridyl N-methyl- N-[2-[methyl-(4-nitrophenoxy)carbonyl- amino]ethyl]carbamate (95.1 mg, 0.254 mmol) was added and stirring continued for 48 h at 40 °C. After this time complete consumption of the carbamate was observed. The reaction mixture was added dropwise to 100 mL water under vigorous stirring. After stirring for 10 min, the water was extracted with ethyl acetate, and the organic layer was washed with water, brine, and finally dried over Na2SO4. The organic layer was filtered and concentrated under vacuum to remove volatiles. The obtained crude product was purified by silica column (12 gm) by combi-flash using 0-100% ethyl acetate in petroleum ether as a gradient. Elution of 4-nitrophenol and unreacted mebendazole was observed. The gradient was then changed to 0-100% CH2CI2 in ethyl acetate. No elution was observed. The gradient was then changed to 0-100% methanol in CH2CI2 and the product was eluted at 45% methanol in CH2CI2. The obtained product (a mixture of the N-regioisomers Example 4a and Example 4b) was dissolved in a mixture of acetonitrile (2 mL) and water (2 mL) and freeze dried to furnishthe Example 4a and Example 4b mixture as a white solid (12 mg, 26.7%). Purity was 95% as determined by analytical HPLC. Regioisomer ratio: 47:53

[0353] XH-NMR (400 MHz, CDCl3) δ 11.50-11.10 (m, 1H), 8.36-8.20 (m, 1H) 7.87-7.31 (m, 9H), 7.21-7.00 (m,2H), 4.35-2.72 (m, 13H)

[0354] Example 5: Synthesis of

[0355] l-2-(N-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl 2,2,2-trifluoroethanecarbamate (5a) and

[0356] l-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl 2,2,2-trifluoroethanecarbamate (5b)

[0357] Step (i): 2,2,2-Trifluoroethyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate

[0358] Et3N CH2Cl2

[0359]

[0360] To a CH2CI2 (10 mL) solution of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (250 mg, 1.33 mmol), 2,2,2-trifluoroethyl carbonochloridate (0.200 mL, 1.46 mmol) was added, followed by triethylamine (0.37 mL, 2.6 mmol), in a dropwise fashion at 5 °C. The reaction mixture was left to let it warm to room temperature and stirred for 1 h.

[0361] The reaction mixture was diluted with 50 mL CH2CI2 and washed by 2N aq. NaOH (50 mL), 2N aq. HCI (50 mL), water and brine. Finally organic layer was dried over Na2SO4, filtered and concentrated to furnish thick colorless oil. The obtained product (2,2,2-trifluoroethyl N-[2- [tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate) was taken forward to the next step without further purification.

[0362] Step (ii): 2,2,2-trifluoroethyl N-methyl-N-[2-(methylamino)ethyl]carbamateTFA

[0363] CH2Cl2

[0364]

[0365] 2,2,2-trifluoroethyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (417 mg, 1.33 mmol) was dissolved in CH2CI2 (2 mL) and TFA (2 mL) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The volatiles were removed under vacuum to remove TFA. The product (2,2,2-trifluoroethyl N-methyl-N-[2-(methylamino)ethyl]carbamate) was obtained as a colorless oil, and was taken forward to the next step without further purification.

[0366] Step (Hi): 2,2,2-trifluoroethyl N-methyl-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino ]ethyl]carbamate

[0367]

[0368] 2,2,2-trifluoroethyl N-methyl-N-[2-(methylamino)ethyl]carbamate (284 mg, 1.33 mmol) was dissolved in 10 mL CH2CI2 and stirred at room temperature. Bis(4-nitrophenyl) carbonate (403 mg, 1.33 mmol) was added in one lot followed by triethylamine (268 mg, 2.65 mmol) and stirring continued. The reaction mixture turned yellow. LCMS showed completion of reaction in 10 min. The volatiles were evaporated under vacuum, the crude product adsorbed on to silica gel and the product was purified by combi-flash using 25 gm silica column with ethyl acetate and petroleum ether as eluent. The product was eluted at 60% ethyl acetate in petroleum ether to furnish 2,2,2-trifluoroethyl N-methyl-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate (440 mg) as a colorless thick oil (87% yield over 3 steps).

[0369] Step (iv): Synthesis of 5a and 5bNaH, DMF

[0370]

[0371] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (25.0 mg, 0.0847 mmol) and NaH (60.0%, 9.73 mg, 0.254 mmol) were mixed and then dry DMF (2 mL) under nitrogen atmosphere was added. The turbid reaction mass became clear dark yellow solution in 20 min. A DMF (1 mL) solution of 2,2,2-trifluoroethyl N-methyl-N-[2-[methyl-(4- nitrophenoxy)carbonyl-amino]ethyl]carbamate (96.3 mg, 0.254 mmol) was added. The reaction mixture was stirred for 20 h at 40 °C. LCMS showed unreacted mebendazole and product peak. The reaction was allowed to stir for a further 24 h. The reaction mixture was then added to 100 mL IM aq. HCI, dropwise under vigorous stirring. After stirring for 10 min, the aqueous layer was extracted with ethyl acetate (500 ml), and the organic layer was washed with water, brine, and finally dried over Na2SO4. The organic layer was filtered and concentrated under vacuum to remove volatiles. The obtained crude product was purified by silica column (12 gm) by combi-flash using 0-100% ethyl acetate in pet ether as a gradient where the product gets eluted at 100% ethyl acetate. The obtained product (a mixture of the N-regioisomers Example 5a and Example 5b) was dissolved in a mixture of acetonitrile (4 mL) and water (4 mL) and freeze dried to furnish the Example 5a and Example 5b mixture asa white solid (18 mg, 39.7%). Purity was 96% as determined by analytical HPLC. Regioisomer ratio: 59:41.

[0372] XH-NMR (400 MHz, CDCI3) 6 11.46-11.18 (m, 1H), 7.84-7.65 (m, 4H), 7.64-7.57 (m, 1H), 7.55-7.45 (m, 2H), 7.11-7.01 (m, 1H), 4.68-4.20 (m, 2H), 3.91-3.43 (m, 7H), 3.33-2.91 (m, 6H)

[0373] Example 6: Synthesis of

[0374] l-2-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl 2,2-difluoroethanecarbamate (6a) and

[0375] l-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl 2,2-difluoroethanecarbamate (6b)

[0376] Step (i): 2,2-Difluoroethyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate

[0377] Et3N CH2Cl2

[0378]

[0379] To a CH2CI2 (10 mL) solution of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (500 mg, 2.66 mmol), 2,2-difluoroethyl carbonochloridate was added (0.399 mL, 3.19 mmol), followed dropwise addition of triethylamine (0.740 mL, 5.31 mmol) at 5 °C. The reaction mixture was left to warm to room temperature and stirred for 1 h.

[0380] The reaction mixture was diluted with 100 mL CH2CI2 and washed by 2N aq. NaOH (20 mL x 3), 2N aq. HCI (20 mL x 3), water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to furnish 2,2-difluoroethyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate as a thick colorless oil. The obtained product (860 mg) was taken forward to the next step without further purification.

[0381] Step (ii): 2,2-Difluoroethyl N-methyl-N-[2-(methylamino)ethyl]carbamate

[0382]

[0383] 2,2-difluoroethyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (787 mg, 2.66 mmol) was dissolved in CH2CI2 (3 mL) and TFA (3 mL) was added at room temperature. The reaction mixture was stirred overnight at room temperature. The volatiles were removed under vacuum to remove TFA. The obtained product (2,2-difluoroethyl N-methyl-N-[2-(methylamino)ethyl]carbamate) was a colorless oil and was taken forward to the next step without further purification.

[0384] Step (Hi): (4-nitrophenyl) N-[2-[2,2-difluoroethoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate

[0385] Et3N CH2Cl2

[0386]

[0387] 2,2-difluoroethyl N-methyl-N-[2-(methylamino)ethyl]carbamate (521 mg, 2.66 mmol) was dissolved in 10 mL CH2CI2 and stirred at room temperature. Bis(4-nitrophenyl) carbonate (889 mg, 2.92 mmol) was added followed by triethylamine (537 mg, 5.31 mmol) and continued stirring. The reaction mixture turned yellow. LCMS showed completion of reaction in 10 min. 3 gm silica was added to the reaction mixture and the volatiles were evaporated under vacuum to adsorb the mixture onto the silica gel. The product was purified by combi-flash using 40 gm silica column, 0-80% ethyl acetate in petroleum ether as gradient. The product was eluted at 60% ethyl acetate in petroleum ether to furnish the product (920 mg) as a colorless thick oil (96% yield over 3 steps).

[0388] Step (iv): Synthesis of 6a and 6b

[0389]

[0390] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (50.0 mg, 0.169 mmol) and NaH (60.0%, 19.5 mg, 0.508 mmol) were mixed and then dry DMF (2 mL) was added under nitrogen atmosphere. The turbid reaction mixture became clear dark yellow solution in 20 min. A DMF (2 mL) solution of (4-nitrophenyl) N-[2-[2,2-difluoroethoxycarbonyl(methyl)amino]ethyl]-N-methyl-carbamate (184 mg, 0.508 mmol) was added. The reaction mixture was stirred for 20 h at 40 °C. LCMS showed unreacted mebendazole and product peak. The reaction mixture was added to 100 mL IM aq. HCI, dropwise under vigorous stirring. After stirring for 10 min, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water, brine, and finally dried over Na2SO4. The organic layer was filtered and concentrated under vacuum to remove volatiles. The obtained crude product was purified by silica column (12 gm) by combi-flash using 0-100% ethyl acetate in pet ether as a gradient where the product gets eluted at 100% ethyl acetate. Starting material was eluted at 60% ethyl acetate. The obtained product (a mixture of the N-regioisomers Example 6a and Example 6b) was dissolved in a mixture of acetonitrile (4 mL) and water (4 mL) and freeze dried to furnish the Example 6a and Example6b mixture as a white solid (65 mg, 74%). Purity was 99% as determined by analytical HPLC. Regioisomer ratio: 60:40.

[0391] XH-NMR (400 MHz, CDCI3) 6 11.47-11.18 (m, 1H), 7.85-7.44 (m, 7H), 7.38-7.27 (m, 1H), 6.15-5.73 (m, 1H), 4.46-2.53 (m, 15H).

[0392] Example 7: Synthesis of

[0393] l-3-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)propyl 1-methyl methanecarbamate (7a) and

[0394] l-3-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)propyl 1-methyl methanecarbamate (7b)

[0395] Step (i): Benzyl N-methyl-N-[3-(methylamino)propyl]carbamate

[0396]

[0397] To a CH2CI2 (50 mL) solution of N, N'-dimethylpropane-l,3-diamine (500 mg, 4.89 mmol), was added a CH2CI2 (10 mL) solution of benzyl(2,5-dioxopyrrolidin-l-yl)carbonate (366 mg, 1.47 mmol) at room temperature. The reaction mixture was stirred overnight. A white precipitate formed which was removed by filtration. The filtrate was concentrated and the product (benzyl N-methyl-N-[3-(methylamino)propyl]carbamate) taken forward to the next step without further purification. LCMS showed presence of unreacted starting material, mono and di- benzyloxycarbonyl products even under dilute reaction condition.

[0398] Step (ii): Methyl N-methyl-N-[3-(methylamino)propyl]carbamate

[0399] Methyl chloroformate TEA CH2Cl2

[0400]

[0401] Benzyl N-methyl-N-[3-(methylamino)propyl]carbamate was dissolved in CH2Cl2(10 mL). Triethylamine (2.05 ml, 14.7 mmol) was added and the reaction mixture was cooled to 0 °C. Methyl chloroformate was added (0.379 ml, 4.89 mmol) and the reaction allowed to stir at room temperature overnight. The reaction mixture was then concentrated under reduced pressure. The crude product was dissolved in 50 ml ethyl acetate and washed with 2N aq. HCI (2 x 50 ml), sat. sodium bicarbonate (2 x 50 ml), water, brine and finally dried over Na2SO4. The organic layer was filtered, concentrated and purified by 25 gm silica gel column and the product was eluted at 90% ethyl acetate in petroleum ether as a gradient.

[0402] Purification afforded the product (methyl N-methyl-N-[3-(methylamino)propyl]carbamate) as a colourless oil (623 mg, 43%).

[0403] Step (iii): Methyl N-methyl-N-[3-(methylamino)propyl]carbamate

[0404] H2, Pd-C MeOH

[0405]

[0406] Methyl N-methyl-N-[3-(methylamino)propyl]carbamate (339 mg, 2.11 mmol) was dissolved in 10 ml methanol and the flask was flushed with nitrogen. A catalytic quantity of Pd-C (5%) was added and the flask was again flushed with nitrogen. The reaction mixture was then stirred under hydrogen bladder pressure for 3 h. The reaction mixture was filtered by syringe to remove insolubles and the filtrate was concentrated to dryness. The product (methyl N-methyl-N-[3-(methylamino)propyl]carbamate) was obtained as a colourless oil (425 mg, >100%), and was used in the next step without further purification.

[0407] Step (iv): (4-Nitrophenyl) N-[3-[methoxycarbonyl(methyl)amino]propyl]-N-methyl-carbamate

[0408] TEA CH2Cl2

[0409]

[0410] Methyl N-methyl-N-[3-(methylamino)propyl]carbamate (425 mg, 2.66 mol) was dissolved in 10 ml CH2CI2 and triethylamine (0.740 ml, 5.31 mmol) was added. Bis(4-nitrophenyl) carbonate (808 mg, 2.66 mol) was added and the reaction stirred overnight. Silica gel was added to the reaction mixture and the volatiles were removed under vacuum to adsorb the mixture onto the silica gel. The product was purified using combi-flash chromatography by 12 gm silica column and using 60% ethyl acetate in petroleum ether to afford the product ((4-nitrophenyl) N-[3-[methoxycarbonyl(methyl)amino]propyl]-N-methyl-carbamate) as a thick oil (310 mg, 35.9%).

[0411] Step (v): Synthesis of 7a and 7b

[0412] > o

[0413] /

[0414]

[0415] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (50.0 mg, 0.169 mmol) and NaH (60.0%, 19.5 mg, 0.508 mmol) were dissolved in dry DMF (2 mL) under a nitrogen atmosphere. The turbid reaction mixture became clear dark yellow solution in 20 min. A DMF (2 mL) solution of (4-nitrophenyl) N-[3-[methoxycarbonyl(methyl)amino]propyl]-N- methyl-carbamate (110 mg, 0.339 mmol) was added and stirring was continued for 40 h at 40 °C. LCMS showed unreacted mebendazole and product peak. The reaction mixture was added dropwise to 100 mL IM aq. HCI under vigorous stirring. After stirring for 10 min, theaqueous layer was extracted with ethyl acetate, the organic layer was washed with water, brine, and finally dried Na2SO4. The filtered organic layer was concentrated under vacuum to remove volatiles. The obtained crude product was purified by silica column (12 gm) using combi-flash and 0-100% ethyl acetate in pet ether as a gradient where the product was eluted at 100% ethyl acetate. The intermediate 5D was eluted at 60% ethyl acetate. The obtained product (a mixture of the N-regioisomers Example 7a and 7b) was dissolved in acetonitrile (4 mL) and added water (4 mL) to it and freeze dried to furnish the Example 7a and Example 7b mixture as a white solid (13 mg, 16%). Purity was 95% as determined by analytical HPLC. Regioisomer ratio: 62:38.

[0416] 1H-NMR (400 MHz, CDCl3) δ 11.56-11.08 (m, 1H), 7.90-7.29 (m, 8H), 3.92-2.61 (m, 16H), 2.19-1.87 (m, 2H).

[0417] Example 8: Synthesis of

[0418] l-2-( / V-ethyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl methanecarbamate (8a) and

[0419] l-2-( / V-ethyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl methanecarbamate (8b)

[0420] Step (i): tert-butyl N-[2-(benzyloxycarbonylamino)ethyl]-N-methyl-carbamate

[0421]

[0422] Tert-butyl N-(2-aminoethyl)-N-methyl-carbamate (500 mg, 2.87 mmol) was dissolved in CH2Cl2(10 ml) and benzyl(2,5-dioxopyrrolidin-l-yl)carbonate (787 mg, 3.16 mmol) and triethylamine (0.440 mL, 3.16 mmol) were added. The mixture was allowed to stir overnight at room temperature. The reaction mixture was then diluted with 50 ml CH2CI2, washed with 2N aq. HCI (50 ml) and saturated (sat.) aq. bicarbonate (50 ml), water, brine and finally dried over Na2SO4. The organic layer was filtered and concentrated under vacuum to furnish athick colourless oil (900 mg, 100%). The product was used in next steps without further purification.

[0423] Step (ii): tert-butyl N-[2-[benzyloxycarbonyl(ethyl)amino]ethyl]-N-methyl-carbamate

[0424] C2H5I NaH DMF

[0425]

[0426] To a stirred solution of tert-butyl-N-[2-(benzyloxycarbonylamino)ethyl]-N-methyl-carbamate (885 mg, 2.87mmol) in DMF (7 mL) at 0 °C, NaH (60.0 %, 165 mg, 4.30 mmol) was added. Stirring was continued for further 10 min and then DMF (3 mL) solution of iodoethane (0.344 mL, 4.30 mmol) was added in dropwise fashion. After the addition was complete, the reaction was left to room temperature for 3 h under stirring. Excess iodoethane was then removed under vacuum. The reaction mixture was diluted with water and extracted into ethyl acetate (100 mL), the organic layer washed with water (3 times), brine and finally dried over sodium sulphate. The filtered organic layer was concentrated under reduced pressure to afford tert-butyl N-[2-[benzyloxycarbonyl(ethyl)amino]ethyl]-N-methyl-carbamate (950 mg, 100%) as a colorless oil. The product was used for subsequent steps without further purification.

[0427] Step (iii): Benzyl N-ethyl-N-[2-(methylamino)ethyl]carbamate

[0428]

[0429] To a stirred solution of tert-butyl N-[2-[benzyloxycarbonyl(ethyl)amino]ethyl]-N-methyl-carbamate (950 mg, 2.82mmol) in CH2CI2 (3 mL), TFA (3 mL) was added at room temperature. After 10 min LCMS showed full conversion. Volatiles were removed under vacuum and the product (benzyl N-ethyl-N-[2-(methylamino)ethyl]carbamate) was taken forward to the next step without further purification (660 mg, 98.9%, thick oil).Step (iv): Ethyl N-[2-[benzyloxycarbonyl(ethyl)amino]ethyl]-N-methyl-carbamate

[0430] , TFA

[0431] CH2Cl

[0432]

[0433] 2

[0434] To a CH2CI2 (8.00 mL) solution of benzyl N-ethyl-N-[2-(methylamino)ethyl]carbamate (660 mg, 2.79 mmol), triethylamine (0.779 mL, 5.59 mmol) was added at 0 °C under stirring, followed by dropwise addition of a solution of methyl chloroformate (0.324 mL, 4.19 mmol) in CH2CI2 (2 mL). The reaction was stirred at room temperature for 30 min. Then the reaction mixture was diluted with CH2CI2 (50 mL) and washed by 2N aq. HCI (50 mL) and 2N aq. NaOH (50 mL), water, brine and finally dried over Na2SO4. The organic layer was filtered and concentrated to afford the crude product as a colorless oil. The product was further purified by using a silica gel column on combi-flash using 60% ethyl acetate in petroleum ether as gradient to afford the product (ethyl N-[2-[benzyloxycarbonyl(ethyl)amino]ethyl]-N-methyl-carbamate) (600 mg, 73%) as a thick colorless oil.

[0435] Step (v): Methyl N-[2-(ethylamino)ethyl]-N-methyl-carbamate

[0436] 5% Pd-C, H2gas Methanol

[0437]

[0438] A stirred solution of methyl N-[2-[benzyloxycarbonyl(ethyl)amino]ethyl]-N-methyl-carbamate (600 mg, 2.04 mmol) in methanol (10 mL) was flushed with nitrogen and 5% Pd-C (catalytic) was added. The reaction mixture was stirred under hydrogen bladder pressure for 3 h. The reaction mixture was filtered using a syringe filter and the organic layer concentrated to furnish the product (methyl N-[2-(ethylamino)ethyl]-N-methyl-carbamate) as a thick colorless oil (305 mg). The product was used in step (vi) without further purification.

[0439] Step (vi): (4-nitrophenyl)-N-ethyl-N-[2-[methoxycarbonyl(methyl)amino]ethyl] carbamateEt3N CH2Cl2

[0440] 11

[0441]

[0442] O To a CH2CI2 (10 mL) solution of methyl N-[2-(ethylamino)ethyl]-N-methyl-carbamate (305 mg, 1.90 mmol), bis(4-nitrophenyl) carbonate (579 mg, 1.90 mmol) and triethylamine (0.531 mL, 3.81 mmol) were added at room temperature and stirring continued for 3 hours. Then silica gel was added to the reaction mixture and the volatiles removed under reduced pressure to adsorb the mixture onto the silica gel. Purification was carried out by 25 gm silica column using 60% ethyl acetate in pet ether gradient to afford (4-nitrophenyl)-N-ethyl-N-[2-[methoxycarbonyl(methyl)amino]ethyl]carbamate (550 mg, 1.69 mmol, 88.8 %) as a colourless oil.

[0443] Step (v): Synthesis of 8a and 8b

[0444]

[0445] Methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate (50.0 mg, 0.169 mmol) and NaH (60.0 %, 13.0 mg, 0.339 mmol) were added to dry DMF (2 mL) under a nitrogen atmosphere. The turbid reaction mixture became a clear yellow solution after 20 min. A DMF (1 mL) solution of (4-nitrophenyl)-N-ethyl-N-[2 [methoxycarbonyl(methyl)amino]ethyl]carbamate (110 mg,0.339 mmol) and 4-dimethylaminopyridine (4.14 mg, 0.0339 mmol) was added. The reaction mixture was stirred for 24 h at 65 °C. After this time, 2 equiv. NaH (13 mg) were added and stirring was continued for 4 h. The reaction mixture was then added dropwise to IM aq. HCI (100 mL) with vigorous stirring. The aqueous layer was extracted with ethyl acetate, washed with water then brine, dried over Na2SO4, and then filtered and concentrated. The crude product was purified by 12 gm silica column using ethyl acetate-petroleum ether as an eluent (product eluted at 100% ethyl acetate). Purification was then repeated using 0-10% methanol in CH2CI2. Further purification was carried out using preparative HPLC (ACE 5 C8 100X2.1MM (5pM particle size). Flow 25 mL / min) using 20-60% gradient (0.1% TFA in Water- acetonitrile) on reverse phase where impurity peak of m / z 424 was separated from product. The pure fractions were mixed, concentrated under vacuum and treated with 1.25 M HCI in methanol. The volatiles were removed under vacuum, the product (a mixture of the N-regioisomers Example 8a and Example 8b) was dissolved in a mixture of 2 mL acetonitrile and 2 mL water. The Example 8a and Example 8b mixture was freeze dried to afford white solid (9 mg, 11%). Purity was 94% as determined by analytical HPLC.

[0446] Regioisomer ratio: 51:49.

[0447] 1H-NMR (400 MHz, CDCl3) δ 11.47-11.15 (m, 1H), 7.85-7.27 (m, 8H), 4.07-2.53 (m, 15H), 1.31-1.17 (m, 3 H).

[0448] Example 9: Synthesis of

[0449] l-2-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-2-fluoroethyl methanecarbamate (9a) and

[0450] l-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-2-fluoroethyl methanecarbamate (9b)Step i): Synthesis of methyl N-(2-fluoroethyl)-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate_

[0451]

[0452] F Step ia): tert-Butyl N-[2-(methoxycarbonylamino)ethyl]-N-methyl-carbamate:

[0453] To a solution of butyl N-(2-aminoethyl)-N-methyl-carbamate (10.0 g, 0.0574 mol) and TEA (17.4 g, 0.172 mol) in CH2CI2 (100.00 mL), methyl chloroformate (10.8 g, 0.115 mol) in CH2CI2 (40 mL) was added in dropwise fashion at -78 °C under stirring over 20 min. The reaction was then stirred at -70 °C for 1 hour. The reaction mixture was then diluted with CH2CI2 (500 mL) and washed with 2M aq. HCI (200 mL), sat. aq. sodium bicarbonate (200 mL), water, brine, and finally dried over magnesium sulfate. The organic layer was filtered and concentrated to afford tert-butyl N-[2-(methoxycarbonylamino)ethyl]-N-methyl-carbamate (12.6 g, yield: 94.4%) as a colorless oil (e.g. HPLC purity: ~95%; MS (ESI+) m / z 133 [M-t- Bu+H]+).

[0454] Step ib): Methyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-(2-fluoroethyljcarbam ate:

[0455] To a stirred solution of tert-butyl N-[2-(methoxycarbonylamino)ethyl]-N-methyl-carbamate 2 (12.6 g, 0.0542 mol) in DMF (100 mL) was added sodium hydride (60.0%, 3.12 g, 0.0813 mol) at 0 °C. Stirring was continued for 20 min and then a solution of l-fluoro-2-iodo-ethane (11.6 g, 0.0667 mol) in DMF (20 mL) was added dropwise over 10 min. After completion of the addition, the reaction was left at room temperature overnight with stirring. After thisthe conversion was 70% by LCMS. The reaction mixture was quenched with 200 mL of IM HCI and extracted with ethyl acetate (3 x 300 mL). The organic layer was washed with sat. NaHCO₃, water, brine, and finally dried over magnesium sulfate. The EtOAc solution was passed through a silica pad to remove colored impurities, and then concentrated to give methyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-(2-fluoroethyl)carbamate (13.0 g), which was used in the next step without additional purification. HPLC purity: ~70%; MS (ESI+) m / z 179 [M-t-Bu+H]+ (with starting material impurity).

[0456] Step ic): Methyl N-(2-fluoroethyl)-N-[2-(methylamino)ethyl]carbamate trifluoroacetic acid salt

[0457] To methyl N-[2-[tert-butoxycarbonyl(methyl)amino]ethyl]-N-(2-fluoroethyl)carbamate (13.0 g, 0.0466 mol) was added 20% solution of TFA in CH2CI2 (40 mL) and the reaction mixture stirred at room temperature for 1 hour. Removal of volatiles under vacuum gave methyl N-(2-fluoroethyl)-N-[2-(methylamino)ethyl]carbamate trifluoroacetic acid salt as a colorless oil (13.6 g). The compound was taken forward to the next step without further purification, assuming 100% conversion. HPLC purity: ~70%; MS (ESI+) m / z 179 [M+H]+.

[0458] Step id): Methyl N-(2-fluoroethyl)-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino ]ethyl]carbamate

[0459] To solution of methyl N-(2-fluoroethyl)-N-[2-(methylamino)ethyl]carbamate; 2,2,2-trifluoroacetic acid (13.6 g, 0.0465 mol) in CH2CI2 (300 mL) cooled in an ice bath, was added N, N-diethylethanamine (16.5 g, 0.163 mol), and then bis(4-nitrophenyl) carbonate (14.9 g, O.0489 mol) was added. The reaction mixture was allowed to warm to room temperature, stirring for 1 hour. The reaction mixture was washed with IM HCI (3 x 200mL), water, and brine. The organic phase was concentrated to dryness and redissolved in CH2CI2 to obtain 50 mL of solution which was subjected to flash chromatography on 330 g silica column using 0 to 50% gradient of ethyl acetate in petroleum ether. Fractions containing product were collected and concentrated giving methyl N-(2-fluoroethyl)-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate (11.3 g, 0.0330 mol, yield: 61.0% over 3 steps from) as a colorless oil HPLC purity: 99%; MS (ESI+) m / z 344 [M+H]+.Step ii): Synthesis of 9a and 9b

[0460] NaH, DMF

[0461] - ►

[0462]

[0463] To a solution of mebendazole (methyl N-(5-benzoyl-lH-benzimidazol-2-yl)carbamate, 21.0 g, 0.0711 mol, 2.2 eq.) in DMF (150 mL) was added sodium hydride (60.0%, 3.10 g, 0.0808 mol, 2.5 eq.) portionwise under nitrogen atmosphere, over 10 min. The turbid reaction mixture gradually became a clear yellow solution. A DMF (50 mL) solution of methyl N-(2- fluoroethyl)-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate 5 (11.1 g, 0.0323 mol, 1 eq.) was added and the mixture stirred overnight at 40 °C. After this time, 1 g (0.8 eq.) of NaH was added and stirring continued for 4h at 50 °C, and then an additional 0.5 g (0.4 eq) of NaH was added and stirring continued for 70 more hours to complete the reaction.

[0464] The reaction mixture was then poured into 3000 mL IM aq. HCI under stirring. The aqueous layer was extracted with ethyl acetate (3 x 250 mL), then the organic layers were combined, washed with IM HCI, water, and brine, dried over magnesium sulfate, filtered, and concentrated. The crude product containing ca. 30% of mebendazole starting material was purified by 330 g silica column using first 0-55% ethyl acetate in petroleum ether gradient for 7 column volumes, then isocratic 55% EtOAc for 7 column volumes, then 55-100% ethylacetate in petroleum ether gradient (6 column volumes), then 100% EtOAc (5 column volumes). Elution of the product was at 100% of EtOAc. Fractions containing the product were combined, concentrated, redissolved in a 1:2 mixture of acetonitile / water, and freeze-dried to give the product (a mixture of the N-regioisomers Example 9a and Example 9b) as an off-white powder. Yield 5.00 g, 31.0%. HPLC purity (XBridge, NH4HCO3 / NH3 (pH 10), 10 min gradient, UV detection at 305±90 nm): 98% (sum of isomers). Regioisomer ratio: 52 / 48.1H NMR (400 MHz, CDCl3) δ 11.37(bs, 1H), 8.1-7.66 (broad m, 4H, include a visible pattern of Ph substituent at 7.78 (d)), 7.60 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H) ), 7.42-7.28 (m, 0.5H), 4.73-4.26 (broad m, 2H), 4.00-3.35 (broad m, 12H, include 2 singlets at 3.78 and 3.76), 3.17 (broad s, 3H).

[0465] MS (ESI+) m / z 500.2 [M+H]+. HPLC for isomer ratio (ACE C8, 0.1% TFA, 20 min gradient, UV detection at 305±90 nm) isomer ratio 65 / 35.

[0466] Example 10: Synthesis of

[0467] l-2-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl 2-methoxyethanecarbamate (10a) and

[0468] l-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl 2-methoxyethanecarbamate (10b)

[0469]

[0470] 10b

[0471] (4-nitrophenyl)-N-[2-[2-methoxyethoxycarbonyl(methyl)amino]ethyl]-N-methylcarbamate (181 mg, 0.508 mmol - Intermediate Cl) was reacted according to general procedure GP4 to afford the product (a mixture of the N-regiomers 10a and 10b) (13 mg, 15%) as a white solid. Purity was 99% as determined by analytical HPLC. Regioisomer ratio: 65.7:34.31H-NMR (400 MHz, CDCl3) δ 11.49-11.18 (m, 1H), 7.85-7.46 (m, 7H), 7.40-7.28 (m, 1H), 4.30-4.14 (m, 2H), 3.90-2.92 (m, 18H).

[0472] Example 11: Synthesis of

[0473] l-2-( / V-methyl{5-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl benzenecarbamate (11a) and

[0474] l-2-( / V-methyl{6-benzoyl-2-[methyl(oxycarbonylamino)]-lH-l,3-benzimidazol-l-yl}carbonylamino)ethyl 1-methyl benzenecarbamate (lib)o,

[0475] NaH, DMF

[0476]

[0477] 11b Phenyl N-methyl-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate (190 mg, 0.508 mmol - Intermediate C2) was reacted according to general procedure GP4 to afford the product (a mixture of the N-regiomers 11a and lib) (12 mg, 13.4%) as a white solid. Purity was 98% as determined by analytical HPLC. Regioisomer ratio: 63:37

[0478] 1H-NMR (400 MHz, CDCl3) δ 11.45-11.15 (m, 1H), 7.89-7.65 (m, 4H), 7.65-7.54 (m, 1H), 7.54-7.27 (m, 5H), 7.23-7.00 (m, 3H), 4.06-3.39 (m, 7H), 3.38-2.97 (m, 6H).

[0479] Example 12: Synthesis of Methyl 4-{2-[(2-fluoroethyl)(methyl)(oxycarbonylamino)]ethyl}-4-methyl-2-[5-(propylthio)-lH-l,3-benzimidazol-2-yl]ureaoate (12a) and

[0480] Methyl 4-{2-[(2-fluoroethyl)(methyl)(oxycarbonylamino)]ethyl}-4-methyl-2-[6- (propylthio)-lH-l,3-benzimidazol-2-yl]ureaoate (12b)

[0481]

[0482] To a solution of albendazole (0.0600 g, 0.226 mmol, 4 eq.) in dry DMF (1 mL) sodium hydride (60.0 %, 0.0130 g, 0.339 mmol, 6 eq) was added under nitrogen atmosphere. The turbid reaction mixture became a clear yellow solution in 10 min. Then a solution of methyl N-(2-fluoroethyl)-N-[2-[methyl-(4-nitrophenoxy)carbonyl-amino]ethyl]carbamate (0.0194 g, 0.0565 mmol, 1 eq. - for synthesis details see 9a and 9b, step i)) was added with continued stirring for 30 h at 50 °C. The reaction mixture was poured dropwise into 50 mL IM aq. HCI, under stirring. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by 12 g silica column (SiliaSep Flash Cartridges, Silica, 40 - 63 pm, 60 A, SiliCycle) using 0-100% ethyl acetate in petroleum ether, gradient over 21 column volumes, then 100% EtOAc for 10 column volumes. Fractions containing mixture of product and albendazole were collected and concentrated. The residue after evaporation was subjected to preparative HPLC (ACE 5 C8100X2.1MM (5p particle size). Flow 25 mL / min), 15-50% acetonitrile in 0.1% TFA buffer. Appropriate fractions were collected, combined, sat.

[0483] NaHCO₃ was added and the combined fractions were extracted with EtOAc. The organic layer was dried over MgSO4 and evaporated to give the product (a mixture of the N-regioisomers 12a and 12b) (0.0120 g, yield: 45.2%). The mixture of 12a and 12b was dissolved in acetonitrile: H2O (1:1) mixture and freeze-dried to obtain off-white crystals.HPLC purity (XBridge, NH4HCO3 / NH3 (pH 10), 10 min gradient, UV detection at 305±90 nm): 97%. MS (ESI+) m / z 470 [M+H]+. HPLC for isomer ratio 55 / 45.

[0484] 1H NMR (400 MHz, CDCl3) δ 11.19 (bs, 1H), 7.54 - 6.92 (bm, 3H), 4.80-4.20 (bm, 2H), 3.94 - 3.41 (bm, 12H, including singlet at 3.79), 3.13 (bs, 3H), 2.94 - 2.78 (m, 2H), 1.71 - 1.54 (m, 2H), 1.00 (m, J = 7.3, 3H).

[0485] Comparative Example A: Synthesis of dimethylcarbamoyl analogue of mebendazole

[0486] NaH, DMF

[0487]

[0488] Mebendazole was suspended in dry DMF (5 ml), NaH (82 mg, 60% dispersion in mineral oil) was added and the reaction was stirred at rt for 15 min (a yellow solution was formed). Dimethylcarbamoyl chloride was added dropwise, and the stirring was continued for 1.5 h. The reaction mixture was poured onto saturated NaHCO₃ (aq) and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated. The crude material was dissolved in MeCN, filtered through a 0.45 pm nylon filter and purified by HPLC 10-80% MeCN (water containing 0.1% TFA). C8, 150x30 mm, 5 pm (crude material was split in 4 injections). The fractions were pooled and saturated NaHCOs (aq) was added, MeCN was removed by evaporation and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated. The desired compound was isolated asa colourless foam (as a mixture of N1 and N3 isomers). Purity (LC / MS, UV): 99%, HPLC (UV, 305 + / - 90 nM) Ratio (peakl:peak2); 31:69. MS (M+l) 367.1H NMR (400 MHz, CDCl3) δ 12.29 (br s, 1H, major isomer), 11.49 (br s, 1H, minor isomer), 8.20 - 7.30 (m, 8H), 3.74 (s, 3H, major isomer), 3.72 (s, 3H, minor isomer), 3.17 (s, 6H, minor isomer), 3.15 (s, 6H, major isomer).

[0489] Biological experiments:

[0490] Table 1 below summarizes the structures of the example compounds tested in the biological experiments described herein. The compounds were tested as mixtures of the N-regioisomers, unless stated otherwise. The N-regioisomers of each example compound tested, and Comparative Example A, are shown in Table 1.

[0491] Table 1: Compounds tested

[0492] Example Regioisomer a Regioisomer b Compound

[0493] No.

[0494] N

[0495] ., O T N"

[0496] N=^

[0497] NH

[0498] °=(

[0499] O

[0500] /

[0501] N

[0502] ',0

[0503] \N

[0504] N= /

[0505]

[0506]

[0507]

[0508]

[0509] Biological Example 1: In vitro absorption, distribution, metabolism, and excretion profiling of Example Compounds, mebendazole, and albendazole

[0510] Example compounds of the invention, mebendazole (Mbz), and albendazole (Abz) were tested in various in vitro absorption, distribution, metabolism, and excretion (ADME) assays to investigate properties of the compounds relevant, in particular, for drugs suitable for oral administration.

[0511] Material and Methods

[0512] a) Solubility and stability in simulated gastric / intestinal fluids

[0513] This assay aimed at determining the thermodynamic solubility from solid of the test compound (Example Compounds 1 to 12, Comparative Example A, Mbz or Abz) and stability from DMSO stock solution of test compound in simulated gastric and intestinal fluids:FassGF (fasted state gastric fluid) at pH 1.6, FessIF (fed state intestinal fluid) at pH 5.0 and FassIF (fasted state intestinal fluid) at pH 6.5.

[0514] Each test compound was weighed in a HPLC vial for the solubility study and used to create DMSO stock solutions of each test compound. FassIF, FessIF and FassGF were constructed according to the manufacturer's instructions (Biorelevant, London UK). A set volume was added (200 pL) to produce > 2 mM solutions (Example Compounds 1 to 11, Comparative Example A - Mbz prodrugs), or > 10 mM solutions (Example Compound 12 - Abz prodrug, and Abz), if all the compound was dissolved. Each vial was sealed and shaken (600 rpm) for 22 - 24 h at 37 °C. The suspensions were transferred to conical glass inserts and centrifuged for 30 min at 10000 x g at 37 °C. Mbz was used in its solid form or in 10 mM DMSO stocks in vials having around 1 mg of each compound. The simulated gastric and intestinal fluids: FassIF, FessIF and FassGF were constructed according to manufacturer's instructions. 0.25 ml of these was added to each vial, the vial sealed and shaken (900 rpm) for 48 h at 37 °C. The Mbz solution was transferred to a conical glass insert and centrifuged for 30 min at 10000 x g and at 37 °C.

[0515] The stability study was performed using DMSO stock, 4 pM (Example Compounds 4 to 11 and Mbz) or 10 pM (Example Compound 1-3, 12, Comparative Example A, and Abz) final concentration, in the same fluid used in the solubility study. For Example Compounds 1 to 11 and Comparative Example A, samples were withdrawn at 0 h, 1 h and 24 h, diluted 1 x in acetonitrile containing Warfarin as the internal standard, and stored at -20 / -80 °C prior to LC-MS / MS analysis. For Example Compound 12 and Abz, samples were withdrawn at 0 h, 1 h, 2 h and 22 h, diluted lx in acetonitrile containing Carbutamide and Warfarin as the internal standard, and stored at -20 / -80 °C prior to LC-MS / MS analysis.

[0516] Quantitative analysis of Example Compounds 1-3, Comparative Example A and Mbz was performed using LC-MS / MS and a standard curve constructed in the same matrix as the test compounds. The instrumentation used was a Sciex QTRAP 6500 coupled to a Waters Acquity UPLC. Mobile phases A0.1% formic acid, B 95% methanol and 0.1% formic acid. Separation was achieved using a HSS T3 C18 2x50mm column at 0.5 ml / min. Run time 2.5 min.Gradient: Omin / 10% B - 0.5 min / 10% B, 0.5 min / 10% B - 1.5min / 60% B, 1.5min / 60% B -1.8min / 95% B, 1.8min / 95% B - 2.2min / 95% B, 2.2min / 95% B - 2.4min / 10% B, 2.4min / 10% B - 2.5min / 10% B.

[0517] b) Caco-2 permeability

[0518] A Caco-2 study to measure membrane permeability of test compounds was performed in accordance with published protocols (Hubatsch et al. Nature Protocols, 2007;2(9):2111-9). Caco-2 cell monolayers (passage 94-105) were grown on permeable filter supports and used for transport study on day 21 after seeding. Prior to the experiment, a test compound solution of 1 pM (Example Compounds 4, 6, and 8 to 11) or 10 pM (Example Compounds 1 to 3, Mbz, Abz, Example Compound 12, and Comparative Example A) was prepared and warmed to 37 °C. The Caco-2 filters were washed with prewarmed Hanks' Balanced Salt Solution (HBSS) prior to the experiment, and thereafter the experiment was started by applying the donor solution (containing the test compound) on the apical (A) or basolateral (B) side. The transport experiments were carried out at pH 7.4 in both the apical and basolateral chamber.

[0519] Enalaprilat was used as a membrane integrity control in each filter. The apparent permeability (Papp) of enalaprilat for a tight monolayer has been determined as being < 1 x 10-6cm / s. The experiments were performed at 37 °C and with a stirring rate of 500 rpm. The receiver compartment was sampled at 15, 30 and 60 minutes for Example Compound 1 to 4, 6, 8 to 11, Comparative Example A, and Mbz, and at 30 min for Example Compound 12 and Abz. At the final time point, a sample from the applied donor solution was taken to calculate the mass balance of the test compound. The samples (100 pl) were transferred to a 96-well plate containing 100 pl methanol and Warfarin as internal standard and sealed until LC-MS / MS analysis. The LC-MS / MS analysis for Example Compounds 1-3 was performed on a Sciex QTRAP 6500 MS coupled to an Acquity UPLC system, column BEH C8 50x2mm, H₂O / acetonitrile 0.1% formic acid based mobile phases.

[0520] c) Hepatocyte stabilityCryopreserved hepatocytes from CD-I mice (Example Compound 1 and 2: Sekisui / Xenotech lot# 1810191, viability 67%; Comparative Example A: lot #1710229, viability 73%) were used in experiments. The control experiments indicated good activity of the enzymes (CYP4503A4 and 2D6, for both Example Compound 1 and 2 and Comparative Example A experiments) within the cells. The cellular incubation concentration was approximately 0.32 x 106cells / ml. Incubation medium was Williams medium E with HEPES (20 mM). The test compound incubation concentration was 1 pM, from 10 mM DMSO stocks. For the comparative example A an incubation concentration of 0.38 x 106cells / ml, 10 pM (from 10 mM DMSO stock) and the same medium was used.

[0521] d) Metabolic stability test compounds in subcellular fractions

[0522] The stability and production of drug (Mbz for Example Compound 1 to 11 and Comparative Example A, or Abz for Example Compound 12) of the test compound incubated with S9 fractions of human intestine (HIS9), liver (HLS9), mouse intestine (MIS9) and liver (MLS9) was studied (Nishimuta, H. et al. Drug Metabolism and disposition (2013), 41: 1104-1111). All incubations of test compounds contained 0.2% DMSO final. The final protein concentration in each incubation with the HIS9 / MIS9 and HLS9 / MLS9 fractions was 0.2 mg / ml and 0.4 mg / ml, respectively. Human liver microsome (HLM) and mouse liver microsome (MLM) final concentrations in the respective fractions were 0.5 mg / ml (Xenotech H0610. IS9, H0610. S9, M1000. IS9, M1000. S9). All incubations contained 1 mM NADPH. Reactions were carried out in HPLC vials, at 37 °C and rotation 600 rpm. 100 pL aliquots were transferred at the indicated time points to 100 pL acetonitrile and warfarin as internal standard, on 96-well plates.

[0523] For a) to d) above, unless stated otherwise, all quantitative analysis of example Mbz and Abz was performed using LC-MS / MS and against a standard curve constructed in a blank buffer matrix, devoid of proteins. The instrumentation used was a Waters TqS micro coupled to a Waters Acquity UPLC. Mobile phases A 0.1% formic acid, B acetonitrile and 0.1% formic acid. For Example Compounds 1 to 11, separation on an HSS T3 C18 2x50 mm column at 0.7ml / min. Run time 3 min. For Example Compound 12, Abz and Comparative Example A, separation on a BEH C182x50 mm column at 0.5 ml / min. Run time 3 min.

[0524] Results

[0525] a) Solubility and Stability in simulated gastric / intestinal fluids

[0526] Solubility is a fundamental physicochemical property that influences many processes in drug discovery. The number of drug compounds with severe solubility problems has increased largely attributed to the techniques applied, such as high throughput screening and combinatorial chemistry, which favor lipophilic compounds. The solubility and stability results for Example Compounds 1 to 12, Mbz, Abz and Comparative Example A in simulated gastric / intestinal fluids assay are shown in Table 2 below.

[0527] Table 2: The stability and solubility of the test compounds in simulated gastric / intestinal fluids

[0528] Test Solubilit Solubility, Solubility, Halflife Halflife Halflife Compound y, FassGF FessIF pH: FassIF pH: [FassGF [FessIF [FassIF pH: 1.60 5.00 (pM) 6.50 (pM) pH: 1.60] pH: 5.00] pH: (pM) (hrs) (hrs) 6.50] (hrs)

[0529] 1 17 330 76 >24 >24 >24

[0530] 2 510 1200 980 >24 >24 >24

[0531] 3 Not 520 230 Not >24 >24

[0532] detected detected

[0533] 4 140 480 580 >24 >24 >24

[0534] 5 100 210 190 >24 >24 >24

[0535] 6 70 350 450 >24 >24 >24

[0536] 7 280 820 750 >24 >24 >24

[0537]

[0538] 8 30 830 420 >24 >24 >24 9 960 990 1050 >24 >24 >24 10 3640 2400 3450 >24 >24 >24 11 120 130 170 >24 >24 >24 12 3000 11000 1600 >22 8.1 25 Mbz 190 40 50 >24 >24 >24 Abz 890 25 6 >22 2.2 4.8 Comparative 200 200 240 >24 >24 >24 Example A

[0539]

[0540] Most of the example compounds show high stability in the FassGF (fasted state gastric fluid) at pH 1.6, FessIF (fed state intestinal fluid) at pH 5.0 and FassIF (fasted state intestinal fluid) at pH 6.5. Example Compound 10 showed the highest solubility in FassGF at pH 1.6, FessIF at pH 5.0 and FassIF at pH 6.5, followed by Example Compound 9. Abz showed moderate solubility. In FessIF, containing most lipids, Example Compound 12 showed high solubility and Abz low solubility. The same is seen in FassIF. Both Abz and its prodrug (i.e. Example Compound 12) showed moderate to poor stability in the higher pH solvents FessIF and FassIF. For Abz, spontaneous sulfoxidation (Abz-SO) was detected, for Example Compound 12 this oxidation probably occurs too, but to a lesser extent. Comparative Example A showed moderate solubility in FassGF, FessIF and FassIF.

[0541] b) Caco-2 permeability

[0542] Membrane permeability is an important property of a compound to be used as a drug for oral administration as the extent to which a compound will diffuse through the membrane will influence the absorption from the gastrointestinal tract, the distribution of the compound throughout the body, the metabolism and the excretion pattern. By studying thePapp in a human cell monolayer information regarding these properties can be obtained. Another important value to follow in this context is the efflux ratio describing the likelihood of a compound to be actively transported out of a cell by efflux transporters. Example Compounds 1-4, 6, 8-12, Mbz, Abz and Comparative Example A were tested this this assay, and the Papp and efflux ratio results are shown in Table 3.

[0543] Table 3: Apparent permeability (Papp) in a human cell monolayer of test compounds.

[0544] Test Compound Caco-2: Papp A-B (1E-6 cm / s) Caco-2: Efflux Ratio B-A / A- B

[0545] 1 12 16

[0546] 2 17 11

[0547] 3 13 12

[0548] 4 2.1 91

[0549] 6 9.1 21

[0550] 8 65 2

[0551] 9 43 3.6

[0552] 10 9.2 14

[0553] 11 66 1.9

[0554] 12 204 1.5

[0555] Mbz 230 0.7

[0556] Abz 348 0.9

[0557] Comparative 140 0.9

[0558] Example A

[0559]

[0560] Most of the test compounds showed high cell membrane permeability and several showed low efflux (e.g. Example Compounds 8, 9, 11, 12, and Comparative Example A).

[0561] The efflux values are of less importance since the uptake in the gut is mostly driven by the Papp values (intrinsic permeability) that are in general modest to high for the tested compounds. In systemic circulation, ideally the prodrug liberates the parent drug (Mbz or Abz), which both have very high Papp and a low efflux, so cellular uptake will not be limited. c) Hepatocyte stability

[0562] Table 4 and FIG. 1 show the results of the incubation of Example Compounds 1-2 and Comparative Example A with mouse hepatocytes. The rate of formation is calculated by fitting the apparent linear part of the curve (30 min) to a linear equation and normalized by the cell incubation number.

[0563] Table 4: Metabolic stability of test compounds in the mouse hepatocyte stability assay.

[0564] Test Compound Formation of Mbz (Mbz

[0565] pmol / min / 106hepatocyte cells)

[0566] 1 26

[0567] 2 12

[0568] Comparative Example A No Mbz detected

[0569]

[0570] Despite a 10-fold higher incubation concentration, no liberation of Mbz was detected from Comparative Example A, while both Example Compounds 1 and 2 clearly formed Mbz when incubated with the mouse hepatocytes. This result demonstrates that prodrug design of the present invention is effective at releasing Mbz in the presence of hepatocytes.

[0571] d) Metabolic stability of test compounds in subcellular fractions

[0572] The aim of this experiment was to test the stability and the production of Mbz when an example compound is incubated with S9 fractions of human intestine (HIS9), human liver (HLS9), mouse intestine (MIS9) and mouse liver (MLS9). Table 5 shows the intrinsicclearance of the example compounds and Mbz. Most of the compounds showed a lower intrinsic clearance in the intestinal S9 fractions compared to Mbz, indicating that they are likely to survive the intestinal first passage effect

[0573] Table 5: Intrinsic clearance of selected example compounds and Mbz.

[0574] Test Compound Intrinsic clearance (pl / min / mg

[0575] of protein in S9 fraction)

[0576] HIS9 HLS9 MIS9 MLS9

[0577] Mbz 60 26 26 17

[0578] 1 160 200 82 270

[0579] 2 56 21 8.3 36

[0580] 4 44 13 4.0 13

[0581] 5 52 21 2.8 38

[0582] 6 30 16 13 30

[0583] 7 150 49 4.3 19

[0584] 8 7.5 39 10 44

[0585] 9 19 43 6.6 18

[0586] 10 7 20 0.5 15

[0587] 11 48 51 9.0 38

[0588] Abz 25 12 81 25

[0589] 12 25 31 15 56

[0590]

[0591] Table 6 shows the formation rate of Mbz of selected example compounds when incubated with the S9 factions.Table 6: Formation of Mbz from selected example compounds.

[0592] Test Compound Mbz formation (pmol / min / mg)

[0593] HIS9 HLS9 MIS9 MLS9

[0594] 1 37* 11* 78 90

[0595] 2 5.1* 2.2* 9 26

[0596] 9 1.8 6.4 19 42

[0597] 12 4 4 5 36

[0598]

[0599] *10 pM prodrug was used for the experiment. Values reported were compensated for this (multiplied by 0.1). In the case of non-linearity between 1 pM and 10 pM, the values assumed to be underestimated.

[0600] The formation of Mbz from Example Compounds 2 and 9 in the intestinal S9-fractions (human and mice) is lower than from Example Compound 1. This suggests that Example Compounds 2 and 9 may be metabolized at a slower rate than Example Compound 1.

[0601] The formation of Abz from Example Compound 12 was much higher in the mouse intestinal S9-fractions compared to the human intestinal S9-fractions, and greater overall in the liver than in the intestine S9-fractions. For the Example Compound 12 incubations, a major metabolite, albendazole sulfoxide (Abz-SO) was observed, as well as the secondary dioxidation product albendazole sulfone (Abz-SO₂) at low to very low levels. These findings show clear release and even further metabolism in the S9-fractions of Example Compound 12.

[0602] Biological Example 2: Oral mouse pharmacokinetics of Mbz and Example Compounds 1, 2 and 9

[0603] Mbz, Example Compound 1, 2 or 9 were dosed orally to CD-I mice to investigate the pharmacokinetics (PK) and production of Mbz.Mbz and Mbz metabolite (Mbz-NH2, Mbz-OH, and Mbz-NH2-OH) formation following oral administration of a test compound was measured by LC-MS / MS analysis of plasma samples obtained from the CD-I mice following administration of a test compound.

[0604] Material and Methods

[0605] The test compounds were administered at an equimolar dose to Mbz (30 mg / kg). Table 7 shows the dose administered to the CD-I mice.

[0606] Table 7: Doses used for each test compound

[0607] Test compound Dose (mg / kg)

[0608] Mbz 30.0

[0609] 1 55.2

[0610] 2 47.5

[0611] 9 50

[0612]

[0613] Example Compound 1, 2 or 9, or Mbz were orally administered to CD-I mice as a formulation containing the test compound and diluent comprising ethanol (5% v / v), polysorbate 80 (5% v / v), PEG300 (20% v / v) and H₂O (70% v / v). The example compounds were dissolved in this formulation, while Mbz was a suspension.

[0614] Nine mice were dosed for each dose group and 3 samples per animal. Time points for plasma extraction were: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h and 32 h. Plasma samples (50 pL) were precipitated with 150 pL methanol containing warfarin as an Internal Standard. A standard curve was created in blank CD-I mouse plasma. The samples were centrifuged and analyzed according to the below.

[0615] All quantitative analysis was performed using liquid chromatography coupled to tandem mass spectrometry (LC-MS / MS) and against the standard curve constructed in the same matrix. The instrumentation used was a Sciex QTRAP 6500 coupled to a Waters Acquity UPLC. Mobile phases A: 0.1% formic acid, B: 95% methanol and 0.1% formic acid. Separationon a HSS T3 C18 2x50 mm column at 0.5 ml / min. Run time 2.5 min. Gradient: 0min / 10% B -0.5 min / 10% B, 0.5 min / 10% B - 1.5 min / 60% B, 1.5 min / 60% B - 1.8 min / 95% B, 1.8 min / 95% B - 2.2 min / 95% B, 2.2 min / 95% B - 2.4 min / 10% B, 2.4 min / 10% B - 2.5 min / 10% B.

[0616] Area Under Curve (AUC) and other calculations / plots were generated using GraphPad Prism v8 or an MS Excel based tool.

[0617] Results

[0618] The main purpose of the study was to test Example Compound 1, 2 and 9 for Mbz formation in vivo. In vitro testing of Example Compounds 1, 2 and 9 indicated that cell permeability of these compounds is high and that the reaction to release Mbz likely occurs largely in the liver, thereby possibly reducing or preventing reductive metabolism in the intestine. FIG. 2A-C, FIG. 3A-B and Tables 8 and 9 show results from the study.

[0619] Table 8: Average Cmax (± SD) and Area Under the Curve (AUC) for Mbz, Example Compounds 1, 2 and 9 (prodrug) and all related Mbz compounds following administration of MBz, Example Compound 1, 2 or 9.

[0620] Test Mbz Cmax Prodrug Cmax AUC (0-t) (pM x h AUC (0-t) (pM x h Compound (pM) (pM) of Mbz)+ of all Mbz related compounds)*

[0621] Mbz 2.7 ± 1.0* - 26 ± 8.2* 52*

[0622] 1 9.1 ± 5.6 4.4 ± 2.8 22 ± 2.8 100

[0623] 2 17 ± 6.0 13 ± 4.4 33 ±4.1 97

[0624] 9 30 ± 6.0 13 ± 8.8 58 ± 3.4 111

[0625]

[0626] *Mean value determined from separate experiments; † t = the last quantifiable timepoint of the experiment.

[0627] The peak Mbz exposure (Cmax) after administration was rapid for all tested compounds (see FIG. 2 and 3). Example Compounds 1, 2 and 9 each showed faster and higher levels of Mbzat Cmax in the mouse plasma following administration compared to following administration of Mbz itself. Administration of Example Compound 9 resulted in a notably higher AUC of Mbz compared to administration of Mbz itself, which suggests that administration of Example Compound 9 also results in a higher Mbz exposure over time (see Table 8, fourth column). The level of all Mbz related compound formed following administration of the example compounds was also higher than when Mbz itself was administered (see Table 8, fifth column).

[0628] To assess the efficiency of the Mbz formation for each example compound, the Mbz metabolite (Mbz-OH and Mbz-NH2) exposure following administration of an example compound or Mbz itself was also determined. The ratio of Mbz exposure to Mbz metabolite exposure is shown in Table 9.

[0629] Table 9: Ratio of Mbz and Mbz metabolite exposure in mice relative to exposure to all Mbz related compounds.

[0630] Test AUC (0-t) AUC (0-t) AUC (0-t) Mbz- AUC (0-t) Compound Mbz / AUC (0-t) of Mbz- OH / AUC (0-t) of Mbz-OH / AUC all Mbz related NH2 / AUC (0-t) all Mbz related* (0-t) Mbz- compounds* of all Mbz NH2†

[0631] related*

[0632] Mbz 0.34 0.26 0.36 1.4

[0633] 1 0.22 0.38 0.36 0.9

[0634] 2 0.34 0.30 0.28 0.9

[0635] 9 0.52 0.19 0.19 1

[0636]

[0637] * t = the last quantifiable timepoint of the experiment.

[0638] The " AUC (0-t) Mbz / AUC (0-t) of all Mbz" ratio shown in Table 9 shows that Mbz exposure relative to exposure to all Mbz related compounds (i.e. the total exposure to Mbz,metabolites and any other degradation products) was similar in mice administered Mbz itself, Example Compound 1 or Example Compound 2 (see column 2 of Table 9). For mice administered Example Compound 9, the Mbz exposure relative to exposure to all Mbz related compounds was higher, indicating that Example Compound 9 allows for more efficient formation of Mbz itself in vivo (see column 2 of Table 9). This is also demonstrated by the lower Mbz metabolite (Mbz-NH2and Mbz-OH) exposure relative to exposure to all Mbz related compounds seen for Example Compound 9 (see column 3-5 of Table 9). The Mbz-OH metabolite is believed to be preferentially formed in the intestine after reduction of the keto group of Mbz (Nishimuta, H. et al. Drug Metabolism and disposition (2013), 41: 1104-1111). The exposure to a lower level of Mbz-OH relative to Mbz-NH2 following administration of an example compound compared to following administration of Mbz itself could indicate a lower intestinal metabolism of the example compounds.

Claims

CLAIMS1. A compound according to formula (I), or a pharmaceutically acceptable salt or solvate thereof,wherein,X is a linear C2-3alkylene optionally substituted with one, two or three groups independently selected from the group consisting of F; OH; -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; -OC1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -C3-5cycloalkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;R1is selected from the group consisting of -C1-4alkyl, -C3-6cycloalkyl, -Ra, and -C1-4alkyl-Ra, wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;Rais -Ce-ioaryl, a 4-, 5- or 6-membered saturated heterocyclyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N, or a 5- or 6-membered heteroaryl comprising1 or 2 heteroatoms independently selected from the group consisting of N, S and O, wherein said heterocycle, aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -C1-4alkyl, and -OC1-4alkyl;R2is selected from the group consisting of H and -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;R3is -C1-6alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;R4is -NHC(O)OC1-4alkyl; andR6is H, and R5is selected from the group consisting of -C(O)C6-10aryl, -SC1-4alkyl, -S(O)C1-4alkyl, -S(O)2C1-4alkyl, -C(O)C3-6alkyl, -C(O)C3-6cycloalkyl, -SC6-10aryl, -S(O)C6-10aryl, -S(O)2C6-10aryl, and -C(O)-(5- or 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O), wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of OH, F and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH, and wherein said aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen; OH; -CN; -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH;orR5is H, and R6is selected from the group consisting of -C(O)C6-10aryl, -SC1-4alkyl, S(O)C1-4alkyl, S(O)2C1-4alkyl, -C(O)C3-6alkyl, -C(O)C3-6cycloalkyl, -SC6-10aryl, -S(O)C6-10aryl, -S(O)2C6-10aryl, and -C(O)-(5- or 6-membered heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O), wherein said alkyl or cycloalkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of OH, F and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH, and wherein said aryl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen; OH; -CN; -C1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH; and -OC1-4alkyl optionally substituted with one, two or three groups independently selected from the group consisting of F and OH.

2. The compound as claimed in claim 1, wherein R2is -Ci-ea Ikyl optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-4alkyl.

3. The compound as claimed in claim 1 or 2, wherein X is optionally substituted C2alkylene (for example wherein X is -CH2-CH2-).

4. The compound as claimed in any one of claims 1 to 3, wherein R2is -Ci-3a I kyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCi-4alkyl (preferably F and -OCH3); and R3is -Ci-3al kyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCi-4alkyl (preferably F and -OCH3).

5. The compound as claimed in any one of claims 1 to 4, wherein R2is -Ci-3a I kyl optionally substituted with one F (and preferably R2is methyl or -CH2CH2F), and R3is -Ci-sa Ikyl (and preferably R3is methyl or ethyl); orwherein R2is -Ci-sal kyl optionally substituted with one -OCH3 (and preferably R2is -Ci-sal kyl substituted with one -OCH3, for example R2is -CH2CH2OCH3), and R3is -Ci-sa Ikyl optionally substituted with one -OCH3 (and preferably R3is -Ci-sal kyl substituted with one -OCH3, for example R3is -CH2CH2OCH3).

6. The compound as claimed in any one of claims 1 to 5, wherein R1is -Ci-4a I kyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl) optionally substituted with one, two or three groups independently selected from the group consisting of F, OH and -OCi-3alkyl (preferably F or -OCH3); phenyl; pyridine; or -CH2phenyl.

7. The compound as claimed in any one of claims 1 to 6, wherein R1is -Ci-2a I kyl optionally substituted with one, two or three groups independently selected from the group consisting of F and -OCH3(for example, R1is methyl, -CH2F, -CHF2, ethyl, -CH2CH2F, -CH2CH2OCH3, -CH2CHF2, or CH2CH(OCH3)2; and preferably R1is methyl or CH2CH2OCH3).

8. The compound as claimed in any one of claims 1 to 7, wherein R4is -NHC(O)OCH3.

9. The compound as claimed in any one of claims 1 to 8, whereinR5is H, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4a I kyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)Cs-6heteroaryl comprising one, two or three heteroatoms independently selected from the group consisting of N, S and O, wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and -OCi-4alkyl and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -Ci-4al kyl, and -OCi-4alkyl; orR6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4alkyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)Cs-6heteroaryl comprising one, two or three heteroatoms independently selected from the groupconsisting of N, S and O, wherein said alkyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, OH, and OCi-4alkyl, and wherein said phenyl or heteroaryl groups are optionally substituted with one, two or three groups independently selected from the group consisting of halogen, OH, -CN, -Ci-4alkyl, and -OCi-4alkyl.

10. The compound as claimed in any one of claims 1 to 9, whereinR5is H, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4a I ky I, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl groups are optionally substituted with one, two or three groups independently selected from the group consisting of F, -OC1-4 alkyl and OH; orR6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4alkyl, -S(O)2Ci-4alkyl, -S-phenyl, -S(O)phenyl, -S(O)2phenyl, and -C(O)thienyl, wherein said alkyl, phenyl or thienyl group are optionally substituted with one, two or three groups independently selected from the group consisting of F, -OC1-4 alkyl and OH.

11. The compound as claimed in any one of claims 1 to 10, whereinR5is H, and R6is selected from the group consisting of -C(O)phenyl, -SCi-4a I kyl, -S(O)Ci-4a Ikyl and -S(O)2Ci-4alkyl (for example R6is selected from the group consisting -C(O)phenyl, -SCH2CH2CH3, -S(O)CH2CH2CH3and -S(O)2CH2CH2CH3); orR6is H, and R5is selected from the group consisting of -C(O)phenyl, -SCi-4a Ikyl, -S(O)Ci-4a Ikyl and -S(O)2Ci-4alkyl (for example R5is selected from the groupconsisting -C(O)phenyl, -SCH2CH2CH3, -S(O)CH2CH2CH3and -S(O)2CH2CH2CH3).

12. A compound as claimed in claim 1, wherein the compound is selected from the group consisting of:o ooor a pharmaceutically acceptable salt or solvate thereof.

13. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 12, together with a pharmaceutically acceptable carrier.

14. A pharmaceutical composition as claimed in claim 13, which further comprises one or more additional therapeutic agent(s), for example one or more additional therapeutic agent(s) selected from the group consisting ofmebendazole, albendazole, fenbendazole, nocodazole, flubendazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole,non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, disease-modifying anti-rheumatic drugs (DMARDs),alkylators, antimetabolites, anti-tumor antibiotics, histone deacetylase inhibitors, immunomodulatory drugs, microtubule interactive drugs, protein kinase inhibitors, steroids, topoisomerase inhibitors, cell cycle inhibitors, angiogenesis inhibitors,ivermectin, praziquantel, diethylcarbamazine, niclosamide, piperazine, pyrantel pamoate, metrifonate, oxamniquine, and bithionol.

15. A compound as claimed in any one of claims 1 to 10, or a pharmaceutical composition as claimed in claim 13 or 14, for use as a medicament.

16. A compound as claimed in any one of claims 1 to 12, or a pharmaceutical composition as claimed in claim 13 or 14, for use in the treatment or prophylaxis of a disease or disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections.

17. A compound as claimed in any one of claims 1 to 12, or a pharmaceutical composition as claimed in claim 13 or 14, for use as an antiparasitic agent; and preferably for use as an anthelminthic or ascaricide agent; and more preferably for use as an antinematode agent.

18. A compound or composition for use as claimed in claim 16 or 17, wherein the compound or composition is administered (for example simultaneously, sequentially or separately) with one or more additional therapeutic agent(s) (for example one or more additional therapeutic agent(s) selected from the group consisting of:mebendazole, albendazole, fenbendazole, flubendazole, nocodazole, ricobendazole, oxfendazole, oxibendazole, thiabendazole, triclabendazole, parbendazole, triclabendazole, dribendazole, cyclobendazole, bendazole, carbendazim, methiazole,non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, disease-modifying anti-rheumatic drugs (DMARDs),alkylators, antimetabolites, anti-tumor antibiotics, histone deacetylase inhibitors, immunomodulatory drugs, microtubule interactive drugs, protein kinase inhibitors, steroids, topoisomerase inhibitors, cell cycle inhibitors, angiogenesis inhibitors,ivermectin, praziquantel, diethylcarbamazine, niclosamide, piperazine, pyrantel pamoate, metrifonate, oxamniquine, and bithionol.

19. A method for treating a patient which comprises administering a pharmaceutically effective amount of a compound as claimed in any one of claims 1 to 12 or a pharmaceutical composition as claimed in claim 13 or 14.

20. A method for the treatment or prophylaxis of a chronic inflammatory disease, a cancer, or a parasitic disease or infection, comprising administering an effective amount of acompound as claimed in any one of claims 1 to 12 or a pharmaceutical composition as claimed in claim 13 or 14.

21. Use of a compound as claimed in any one of claims 1 to 12 in the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder selected from the group consisting of chronic inflammatory diseases, cancers, and parasitic diseases and infections.

22. A compound or composition for use as claimed in claim 15 to 18, or the method as claimed in claim 19 or 20, or the use as claimed in claim 21, whereinthe chronic inflammatory disease is an inflammatory diseases, an autoinflammatory diseases and / or an autoimmune disease; and / orwherein the chronic inflammatory disease is selected from the group consisting of sarcoidosis, systemic lupus erythematosus, Huntington's disease, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Crohn's disease, ulcerative colitis, coeliac disease, Addison's disease, Sjögren's syndrome, and rheumatoid arthritis (for example sarcoidosis, systemic lupus erythematosus Huntington's disease, psoriasis, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Crohn's disease, ulcerative colitis, coeliac disease, Addison's disease, and Sjögren's syndrome; and preferably sarcoidosis, systemic lupus erythematosus, Huntington's disease, primary biliary cirrhosis, autoimmune hepatitis, Crohn's disease, ulcerative colitis, coeliac disease, and Addison's disease); and / orwherein the chronic inflammatory disease is selected from the group consisting of systemic lupus erythematosus (SLE), sarcoidosis, Huntington's disease, end stage renal disease, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjögren's syndrome, rheumatoid arthritis, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis,inflammatory bowel disease and Alzheimer's disease (for example systemic lupus erythematosus (SLE), sarcoidosis, Huntington's disease, end stage renal disease, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, multiple sclerosis, Sjögren's syndrome, psoriasis, primary biliary cirrhosis, autoimmune hepatitis, Graves' disease, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease; and preferably sarcoidosis, systemic lupus erythematosus (SLE), Huntington's disease, end stage renal disease, systemic sclerosis (also called scleroderma), myositis, diabetes type 1, primary biliary cirrhosis, autoimmune hepatitis, Addison's disease, tuberculosis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and Alzheimer's disease); and / orwherein the chronic inflammatory disease is characterised by granulomatous inflammation.

23. A compound or composition for use as claimed in claim 15 to 18, or the method as claimed in claim 19 or 20, or the use as claimed in claim 21, wherein the cancer is selected from the group consisting of gastrointestinal cancer (for example esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, gallbladder cancer, colorectal cancer (also referred to as colon cancer or bowel cancer), anal cancer, gastrointestinal carcinoid tumor, cholangiocarcinoma, and MALT lymphoma), lung cancer (including non-small cell lung cancer and small cell lung cancer), breast cancer, prostate cancer, leukemias (for example acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML)), lymphomas (including Hodgkin lymphoma and non-Hodgkin lymphoma), melanoma, brain tumors (for example glioma, meningioma, pituitary adenomas, medulloblastoma, primary central nervous system lymphoma), ovarian cancer, bladder cancer, sarcomas (including osteosarcoma for bone sarcomas, and leiom), and cancerous paraganglioma; and / or wherein the cancer is progressive cancer; and / or wherein the cancer is metastatic cancer.

24. A compound or composition for use as claimed in claim 15 to 18, or the method as claimed in claim 19 or 20, or the use as claimed in claim 21, wherein the parasitic disease or infection is selected from an infection of threadworm (also known as pinworms), roundworm, whipworm, tapeworm, hookworm, giardia, strongyle worm, liver fluke, filarial or nematode; and / or a parasitic diseases selected from ascariasis, trichuriasis, strongyloidiasis, enterobiasis, taeniases (for example taeniases hymenolepiasis), visceral, ocular, neural, and cutaneous larva migrans, anisakiasis, trichinosis, hepatic and intestinal capillariasis, angiostrongyliasis, gnathostomiasis, gongylonemiasis, thelaziasis, dracunculiasis, cerebral and subcutaneous cysticercosis, cystic echinococcosis, lymphatic filariasis, onchocerciasis, loiasis, mansonellosis, dirofilariasis, trichinosis, helminthiasis, fascioliasis, paragonimiasis, cystic echinococcosis, taeniasis, clonorchiasis, opisthorchiasis, and giardiasis.

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