WO2009083526A1 - Novel compounds - Google Patents

Abstract

The invention relates to novel benzimidazole compounds of formula (I) wherein R1 to R1 are as defined in the specification, pharmaceutically acceptable salts thereof, to pharmaceutical compositions containing them and their use in medicine. In particular, the invention relates to compounds that are agonists of peroxisome proliferators-activated receptorγ (PPARγ).

Description

NOVEL COMPOUNDS

The present invention relates to novel benzimidazole compounds that are agonists of peroxisome proliferators-activated receptorγ (PPARγ), processes for their preparation, to compositions containing them and to their use in the treatment of diseases treatable by modulation of blood glucose levels (for example diabetes) and to their use in the treatment of mild cognitive impairment, Alzheimer's disease and other dementias.

Alzheimer's disease (AD) was first described in 1907 by the Bavarian psychiatrist Alois Alzheimer. It is a progressive, debilitating disease and is the most common cause of dementia. Typical symptoms include memory impairment, disordered cognitive function, behavioural changes (including paranoia, delusions, loss of inhibitions) and decline in language function. Pathologically, AD has been traditionally characterised by the presence of two distinct types of brain lesion - neuritic plaques (sometimes referred to as senile plaques) and neurofibrillary tangles.

Neuritic plaques are extracellular amyloid β-protein (Aβ) deposits, typically in a filamentous form, which are around 10 to 150 μm in cross-section and are associated with axonal and dendritic injury. Aβ is formed by the cleavage of amyloid precursor protein (APP) by a series of secretases. Aβ₄₀, a forty residue peptide, is the form of Aβ normally produced in greatest abundance by cells, however, much of the Aβ found within neuritic plaques contains 42 amino acids (Aβ₄₂). Aβ₄₂ is significantly more hydrophobic than Aβ₄₀, and is therefore more prone to aggregation, although Aβ₄₀ is also localised with the plaques. Neuritic plaques are believed to develop over a substantial period of time (months to years). Amyloid depositions in the form of plaques are known to occur prior to the appearance of clinical symptoms, though the correlation between the extent of amyloid deposition and cognitive impairment remains a point of contention.

Neurofibrillary tangles are usually found within the perinuclear cytoplasm of neurons from AD sufferers. The tangles are formed from pairs of filaments which are wound into helices. These highly insoluble filaments have been shown to be composed of the microtubule-associated protein tau in an abnormally hyperphosphorylated state. There is some evidence that the formation of tangles is a response by neurons to the gradual accumulation of Aβ.

For further information on AD in general see: Selkoe D., Physiol. Rev., 2001 , 81(2), 741- 766; and Watson G. et al., CNS Drugs, 2003, 17(1), 27-45.

Mild cognitive impairment (MCI) is a condition in which subjects have a slight impairment in cognitive function that is detectable from their pre-morbid baseline, but which also is not sufficiently severe to fulfil diagnostic criteria for AD. As such, MCI may be considered as a transition state between normal cognitive function in a normal aging subject, and the abnormal cognitive function in dementia. MCI can be subdivided into categories based upon the types of cognitive deficits that are detected. A deficit of memory alone typifies amnestic MCI; whereas other types of MCI involve deficits in multiple cognitive domains including memory, or deficits in a single, non-memory domain. The rate of progression from amnestic MCI to AD has been measured in cohort studies to range from 10 - 20% per year (for more information see Petersen et al., Arch Neurol., 2001 , S3, 1985-1992).

Other dementias which similarly give rise to cognitive deficits include vascular dementia, Lewy body dementia, frontotemporal dementia and dementia associated with Parkinson's disease.

Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) is an orphan member of the steroid/thyroid/retinoid receptor superfamily of ligand-activated transcription factors. PPAR-gamma is one of a subfamily of closely related PPARs encoded by independent genes (Dreyer C. et al., Cell, 1992, 68, 879-887; Schmidt A. et al., MoI. Endocrinol., 1992, 6, 1634-1641 ; Zhu et al., J. Biol. Chem., 1993, 268, 26817- 26820; Kliewer et al., Proc. Nat. Acad. Sci. USA, 1994, 91 , 7355-7359). Three mammalian PPARs have been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also known as NUC-1 ). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPREs have been identified as the enhancers of a number of genes encoding proteins that regulate lipid metabolism, suggesting that PPARs play a pivotal role in the adipogenic signalling cascade and lipid homeostasis (Keller H et al., Trends Endocrin. Mef., 1993, 4, 291-296).

European Patent 306228 describes a class of PPAR-gamma agonists which are thiazolidinedione derivatives for use as insulin sensitisers in the treatment of Type Il diabetes mellitus. These compounds have anti-hyperglycaemic activity. One preferred compound described therein is known by the chemical name 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione and has been given the generic name rosiglitazone. Salts of this compound, including the maleate salt, are described in WO94/05659. European Patent Applications, Publication Numbers: 0008203, 0139421 , 0032128, 0428312, 0489663, 0155845, 0257781 , 0208420, 0177353, 0319189, 0332331 , 0332332, 0528734, 0508740; International Patent Applications, Publication Numbers 92/18501 , 93/02079, 93/22445 and United States Patent Numbers 5104888 and 5478852, also disclose certain thiazolidinedione PPAR-gamma agonists. Specific compounds that may be mentioned include 5-[4-[2-(5-ethyl-2- pyridyl)ethoxy]benzyl]thiazolidine-2,4-dione (also known as pioglitazone), 5-[4-[(1- methylcyclohexyl)methoxy]benzyl]thiazolidine-2,4-dione (also known as ciglitazone), 5- [[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2- yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione (also known as troglitazone) and 5-[(2- benzyl-2,3-dihydrobenzopyran)-5-ylmethyl)thiazolidine-2,4-dione (also known as englitazone).

US patent 6,294,580 (the disclosure of which is herein incorporated by reference) describes a series of PPAR gamma agonist compounds not of the thiazolidinedione class but which are instead O- and N- substituted derivatives of tyrosine which nevertheless are effective as insulin sensitisers in the treatment of Type Il diabetes mellitus. One such compound has chemical name N-(2-benzoylphenyl)-O-[2-(5-methyl-

2-phenyl-4-oxazolyl)ethyl]-L-tyrosine (also known as 2(S)-(2-Benzoyl-phenylamino)-3-{4-

[2-5- methyl- 2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid, or by the generic name farglitazar).

It has been found by various researchers that agonists of the nuclear receptor, PPARγ, have ameliorated Alzheimer's Disease-related pathology in animal models (Landreth, G., Current Alzheimers Research, 2007, 4, 159-164, and US 6,191 ,154). There is as yet no consensus as to the mechanism by which PPARγ agonists exert their effect. Postulated mechanisms include insulin sensitization (insulin is known to have significant cognition enhancing effects in humans), inhibition or suppression of inflammation in the brain; neuroprotection (PPARγ agonists have been reported to protect neurons from death in response to various insults); regulation of Aβ homeostasis; and various mitochondrial mechanisms.

It is postulated that PPARγ agonists are effective in utilizing the hypothesized neuroprotective action. Neurons express PPARγ only at modest levels (Cimini, A. et al., Neuroscience, 2005, 130, 325-337). However, there is good evidence that PPARγ can be induced following injury (Sundararajan, S. et al., Neurochem. Int, 2006, 49, 136-144) or following exposure to noradrenaline (Klotz, L. et al., J. Neurochem., 2003, 86, 907- 916). PPARγ agonists have been reported to suppress neuronal iNOS-mediated cell death (Heneka, M. T. et al., J. Neuroimmunol., 1999, 100, 156-168) as well as preventing neuronal death induced either by glutamate or by low potassium in vitro (Uryu, S. et al., Brain Res., 2002, 924, 229-236). A direct neuroprotective effect was demonstrated in studies of hippocampal neurons challenged with neurotoxic beta-amyloid peptides (Inestrosa, N, et al., Exp. Cell Res., 2005, 304, 91-104). The protective effect was correlated with a PPARγ-mediated inhibition of the protein kinase GSK3β and elevation of cellular β-catenin levels, although it is unclear how these effects were elicited.

International patent application WO98/39967 discloses a method for the treatment or prevention of AD by administering an agent which reduces serum insulin levels, such as a thiazolidinedione. International patent application WO99/25346 discloses a method for the treatment or prevention of a disease mediated by apoptosis, such as neurodegenerative disorders including AD and Parkinson's disease by administering an apoptosis inhibitor, for example an insulin sensitising agent such as rosiglitazone. International patent application WO00/32190 discloses a method for the treatment or prevention of AD by administering a PPAR-gamma agonist, such as the thiazolidinediones pioglitazone and rosiglitazone. International patent application WO00/35437 discloses methods of improving mental performance in subjects suffering from reduced mental performance by the administration of insulin sensitising agents, such as the thiazolidinediones pioglitazone and rosiglitazone. International patent application WO02/49626 discloses a method for the promotion of growth and/or repair of neurons in diseases or conditions characterised by neuron degeneration, injury or impaired plasticity which method comprises the administration of an effective, non-toxic and pharmaceutically acceptable amount of a PPAR gamma agonist or a pharmaceutically acceptable derivative thereof.

Whilst there remain uncertainties regarding the precise mechanism of action, compounds that are PPARγ agonists are expected to provide a beneficial effect the treatment and prevention of diseases or conditions characterised by neuron degeneration, injury or impaired plasticity, the treatment and prevention of mild cognitive impairment, the treatment and prevention of Alzheimer's disease, and other dementias, and in the improvement of cognitive function in those diseases.

PPARγ agonists are expected to provide a beneficial effect in the treatment and prevention of other diseases involving cognitive deficits, for example schizophrenia.

Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.

Thiazolidinedione compounds such as those described above (for example rosiglitazone, troglitazone or piaglitazone) have emerged as effective antidiabetic agents that enhance the insulin sensitivity of target tissues (skeletal muscle, liver, adipose) in patients with non-insulin dependent diabetes mellitus (NIDDM). A number of those compounds have been approved for use in the treatment of diabetes. It is generally believed that glitazones exert their effects by binding to the peroxisome proliferator activated receptor (PPAR) family of receptors, controlling certain transcription elements having to do with the biological entities listed above. (See HuNn et ai, Current Pharm. Design, 1996, 2, 85- 102).

The PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (Keller and Wahli, Trends Endocrin. Met, 1993, 4, 291-296). It has also been reported that thiazolidinediones are potent and selective activators of PPAR- gamma and bind directly to the PPAR-gamma receptor (Lehmann et. al., J. Biol. Chem.,

1995, 270, 12953-12956), providing evidence that PPAR-gamma is a target for the therapeutic actions of the thiazolidinediones.

Compounds with PPAR-gamma receptor agonist activity are thus expected to be of use for the treatment and/or prophylaxis of hyperglycaemia, dyslipidemia, and, in particular,

Type Il diabetes. They are further expected to be useful in the treatment of other diseases relating to glucose metabolism, including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic, hyperlipidemia, hypercholesteremia, hypertension and cardiovascular disease, especially atherosclerosis.

We have now discovered a novel group of compounds which bind to and activate the PPAR-gamma receptor.

The present invention provides, in a first aspect, a compound of formula (I)

(I) wherein:

R¹ is selected from hydrogen, C_1-4alkyl optionally substituted with one or more halo groups; C_3-6cycloalkyl optionally substituted with one or more halo groups; and C(O)C_{1- 3}alkyl optionally substituted with one or more halo groups;

R² is selected from hydrogen and C_1-4alkyl optionally substituted with one or more halo groups; R³ is selected from:

- phenyl optionally substituted with one or more groups selected from halo, Ci_-3alkyl optionally substituted with one or more halo groups, Ci_-3alkoxy optionally substituted with one or more halo groups, and C(O)O-Ci_3alkyl optionally substituted with one or more halo groups;

- a five- or six-membered heteroaryl group comprising from one to three heteroatoms independently selected from N, O and S, and optionally substituted with one or more groups selected from halo, Ci_-3alkyl optionally substituted with one or more halo groups, Ci_-3alkoxy optionally substituted with one or more halo groups, and C(O)O-Ci_-3alkyl optionally substituted with one or more halo groups;

- C_3-8cycloalkyl optionally substituted with one or more groups selected from halo and Ci- ₃alkyl optionally substituted with one or more halo groups; or

- a 4- to 7-membered saturated heterocyclic ring containing an oxygen atom in the ring;

R⁴ is selected from a Ci_-4alkyl group optionally substituted with one or more groups selected from halo and hydroxyl;

R⁵ is selected from:

- phenyl optionally substituted with 1 , 2 or 3 groups selected from halo,

optionally substituted with one or more halo groups, and Ci_-4alkoxy optionally substituted with one or more halo groups;

- a five- or six-membered heteroaryl group comprising from one to three heteroatoms independently selected from N, O and S, and optionally substituted with 1 , 2 or 3 groups selected from halo, Ci_-4alkyl optionally substituted with one or more halo groups, and Ci- ₄alkoxy optionally substituted with one or more halo groups;

- Ci_-4alkyl optionally substituted with one or more halo groups;

- C_3-6cycloalkyl optionally substituted with one or more halo groups;

R⁶ is selected from hydrogen and a Ci_-2alkyl group optionally substituted with one or more groups selected from halo and hydroxyl;

R⁷, R⁸ and R⁹ are each independently selected from hydrogen and halo;

or a salt or solvate thereof.

The compounds bind to and activate the PPAR-gamma receptor and thus find use in the treatment of diseases treatable by modulation of blood glucose levels (for example diabetes), in the treatment of diseases or conditions characterised by neuron degeneration, injury or impaired plasticity, and in the treatment of mild cognitive impairment, Alzheimer's disease and other dementias. Certain of the compounds are partial agonists of the PPAR-gamma receptor. In one aspect, R¹ is selected from hydrogen, optionally substituted with one or more halo groups; C_3-6cycloalkyl optionally substituted with one or more halo groups; C(O)Ci_-3alkyl optionally substituted with one or more halo groups. In a further aspect, R¹ is selected from hydrogen, Ci_-3alkyl optionally substituted with one or more halo groups; cyclopropyl optionally substituted with one or more halo groups; C(O)Ci_-2alkyl optionally substituted with one or more halo groups. For example, R¹ may be selected from hydrogen, methyl, ethyl, propyl, iso-propyl, trifluoromethyl and C(O)ethyl. For example R¹ is hydrogen.

In one aspect, R² is selected from methyl and hydrogen. For example R² is hydrogen.

In one aspect, R³ is selected from:

- phenyl optionally substituted with one or more groups selected from halo, Ci_-3alkyl optionally substituted with one or more halo groups, Ci_3alkoxy optionally substituted with one or more halo groups, and C(O)O-Ci_-3alkyl optionally substituted with one or more halo groups; or

- a five- or six-membered heteroaryl group comprising from one to three heteroatoms independently selected from N, O and S, and optionally substituted with one or more groups selected from halo, Ci_-3alkyl optionally substituted with one or more halo groups, Ci_-3alkoxy optionally substituted with one or more halo groups, and C(O)O-Ci_-3alkyl optionally substituted with one or more halo groups.

In a further aspect, R³ is selected from:

- phenyl optionally substituted with one or more groups selected from halo, Ci_-3alkyl optionally substituted with one or more halo groups, Ci_-3alkoxy optionally substituted with one or more halo groups, and C(O)O-Ci_-3alkyl optionally substituted with one or more halo groups; or

- pyridyl optionally substituted with one or more groups selected from halo, Ci_-3alkyl optionally substituted with one or more halo groups, Ci_-3alkoxy optionally substituted with one or more halo groups, and C(O)O-Ci_-3alkyl optionally substituted with one or more halo groups.

In one aspect, R³ is selected from phenyl optionally substituted with one or more halo atoms, in particular fluoro and/or chloro atoms. For example R³ is 2-fluorophenyl.

In one aspect, R³ is selected from pyridyl optionally substituted with one or more halo atoms, for example one or two halo atoms. In one aspect, the pyridyl group is 2-pyridyl.

In a further aspect, the pyridyl group is 2-[3 chloropyridyl], 2-[3,5 difluoro-pyridyl] or 2-

[3,5 dichloro-pyridyl].

In one aspect, R⁴ is selected from unsubstituted Ci_-4alkyl. For example, R⁴ is methyl or ethyl. In one aspect, R⁵ is selected from:

- phenyl optionally substituted with 1 , 2 or 3 groups selected from halo,

optionally substituted with one or more halo groups, and Ci_-4alkoxy optionally substituted with one or more halo groups; and - a five- or six-membered heteroaryl group comprising from one to three heteroatoms independently selected from N, O and S, and optionally substituted with 1 , 2 or 3 groups selected from halo,

optionally substituted with one or more halo groups, and Ci- ₄alkoxy optionally substituted with one or more halo groups.

In one aspect, R⁵ is phenyl optionally substituted with 1 , 2 or 3 groups selected from halo, Ci_-2alkyl optionally substituted with one or more halo groups, and Ci_-2alkoxy optionally substituted with one or more halo groups. In a further aspect, R⁵ is phenyl optionally substituted with 1 , 2 or 3 halo atoms. For example R⁵ is unsubstituted phenyl.

In one aspect, R⁵ is selected from thiophenyl, furanyl, pyridyl and thiazolyl optionally substituted with 1 , 2 or 3 groups selected from halo, Ci_-4alkyl optionally substituted with one or more halo groups, and Ci_-4alkoxy optionally substituted with one or more halo groups. In one aspect, R⁵ is unsubstituted thiophenyl, furanyl, pyridyl or thiazolyl.

In one aspect R⁶ is selected from hydrogen and a

group. For example R⁶ is hydrogen.

In one aspect, R⁷ is selected from hydrogen and fluorine. For example R⁷ is hydrogen.

In one aspect, R⁸ is hydrogen.

In one aspect, R⁹ is hydrogen.

The term alkyl' as used herein refers to a linear or branched saturated hydrocarbon group. Examples of alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl. Examples of Ci_-4 alkyl groups include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, sec-butyl and tert-butyl.

As used herein, the term "cycloalkyl" refers to a cyclic hydrocarbon group. The hydrocarbon group may be saturated; it may be monocyclic or bicyclic, including bridged bicyclic. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In one aspect, the cycloalkyl group has from 5 to 7 carbon atoms.

As used herein, the term "alkoxy" refers to an -O-alkyl group wherein alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy and butoxy. The term 'heteroaryl' as used herein refers to an aromatic ring of the specified ring size containing at least one heteroatom selected from oxygen, nitrogen and sulphur. Preferred heteroaryl groups have 5- or 6-membered rings. In one aspect, "heteroaryl" moieties are selected from furan, thiophene, pyrrole, oxazole, isoxazole, imidazole, thiazole, isothiazole, pyrazole, 1 ,2,3-oxadiazole, furazan, 1 ,2,3-triazole, 1 ,2,4-triazole, 1 ,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. All isomers of the above heteroaryls are within the scope of this invention. Each heteroaryl group may, for example, be attached at a ring carbon.

The term 'saturated heterocyclic ring containing an oxygen atom in the ring' as used herein refers to a ring of the specified ring size containing an oxygen atom. Examples of such groups include oxetane, tetrahydrofuran, tetrahydropyran and oxepane groups.

As used herein, "halogen" or "halo" refer to a fluorine, chlorine, bromine or iodine atom. References to "fluoro", "chloro", "bromo" or "iodo" should be construed accordingly.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and the mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by methods known in the art (e.g. separation by chiral HPLC), or any given isomer may be obtained by stereoselective or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

In particular it may be mentioned that certain compounds of the invention may exist in two enantiomeric forms when R⁴, R⁵ and R⁶ represent three different groups. In one embodiment of compounds in which R⁶ represents hydrogen and R⁵ represents an optionally substituted phenyl, heteroaryl or cycloalkyl group as set out in more detail above, R⁴ is preferably oriented as follows:

Compounds of the invention include those of Examples 1-75 below, and (where appropriate) salts, (where appropriate) different salts, or solvates thereof, namely:

1 -[(3,4-Dichlorophenyl)methyl]-Λ/-[(1 R)- 1 -phenylpropyl]-2-(trif luoromethyl)-1 H- benzimidazole-5-carboxamide (E1 ) 1-[(4-Fluorophenyl)methyl]-2-methyl-/V-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E2)

1-[(3_!5-Difluoro-2-pyridinyl)methyl]-Λ/-[(1R)-1-phenylpropyl]-2_!3-dihydro-1H- benzimidazole-5-carboxamide HCI salt (E3) 1-[(2-Fluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide

(E4)

1-(Phenylmethyl)-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E5)

1-{[2-(Methyloxy)phenyl]methyl}-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E6) 1-[(2,4-Difluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide

(E7)

1-[(2-Chloro-4-fluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E8)

1-[(4-Chloro-2-fluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E9)

1-[(2,4-Dichlorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E10)

N-[(1 R)-1-Phenylpropyl]-1-(2-pyridinylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E11 ) N-[(1 R)-1-Phenylpropyl]-1-(1 ,3-thiazol-2-ylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E12)

1-[(3-Chloro-2-pyridinyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide hydrochloride (E13)

1-[(3,5-Dichloro-2-pyridinyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide hydrochloride (E14)

1-[(5-Chloro-2-pyridinyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide hydrochloride (E15)

N-[(1 R)-1-Phenylpropyl]-1-(3-pyridinylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E16) N-[(1 R)-1-Phenylpropyl]-1-(4-pyridinylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E17)

Methyl 4-{[5-({[(1 R)-1-phenylpropyl]amino}carbonyl)-1 H-benzimidazol-1- yl]methyl}benzoate (E18)

1-[(3,4-Difluorophenyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E19)

1-[(3-Chloro-4-fluorophenyl)methyl]-Λ/-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E20)

1-[(2,6-Dichlorophenyl)methyl]-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E21 ) 1-[(1 R)-1-Phenylethyl]-Λ/-[(1R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E22)

1-[(3,4-Dichlorophenyl)methyl]-Λ/-{(2£)-1-ethyl-2-[(1Z)-1-propen-1-yl]-2,4-pentadien-1-yl}-

2-methyl-1 H-benzimidazole-5-carboxamide (E23) 1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 /?)-1-phenylpropyl]-1 /-/-benzimidazole-5- carboxamide (E24)

1-[(3_!4-Dichlorophenyl)methyl]-2-methyl-/V-[(1 R)-1-phenylethyl]-1 H-benzimidazole-5- carboxamide (E25) 1-[(3_!4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 S)-1-phenylethyl]-1 /-/-benzimidazole-5- carboxamide (E26)

1 -[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-{(1 R)- 1 -[4-(methyloxy)phenyl]ethyl}-1 H- benzimidazole-5-carboxamide (E27)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-(1-methyl-1-phenylethyl)-1 /-/-benzimidazole-5- carboxamide (E28)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-/V-[(1 S)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E29)

2-Cyclopropyl-1-[(3,4-dichlorophenyl)methyl]-/V-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-

5-carboxamide (E30) 2-Cyclopropyl-1-[(3,4-dichlorophenyl)methyl]-/V-[(1 S)-1-phenylpropyl]-1 H-benzimidazole-

5-carboxamide (E31 )

1-[(3,4-Dichlorophenyl)methyl]-2-ethyl-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E32)

1-[(3,4-Dichlorophenyl)methyl]-2-ethyl-/V-[(1 S)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E33)

1-[(3,4-Dichlorophenyl)methyl]-2-(1-methylethyl)-Λ/-[(1R)-1-phenylpropyl]-1 H- benzimidazole-5-carboxamide (E34)

1-[(3,4-Dichlorophenyl)methyl]-2-(1-methylethyl)-Λ/-[(1 S)-1-phenylpropyl]-1 H- benzimidazole-5-carboxamide (E35) Λ/-[(1 R)-1-(3-Chlorophenyl)propyl]-1-[(3,4-dichlorophenyl)methyl]-2-methyl-1 H- benzimidazole-5-carboxamide (E36)

1-[(3,4-Dichlorophenyl)methyl]-/V-[(1 R)-1-(3-fluorophenyl)propyl]-2-methyl-1 H- benzimidazole-5-carboxamide (E37)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-/V-{(1 R)-1-[3-(trifluoromethyl)phenyl]propyl}-1 H- benzimidazole-5-carboxamide (E38)

1-[(4-Chlorophenyl)methyl]-/V-[(1 /?)-1-phenylethyl]-1 H-benzimidazole-5-carboxamide

(E39)

1-[(4-Chlorophenyl)methyl]-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide

(E40) 1 -[(4-Chlorophenyl)methyl]-Λ/-[(1 R)- 1 -(4-fluorophenyl)ethyl]-1 H-benzimidazole-5- carboxamide (E41 )

1 -[(4-Chlorophenyl)methyl]-Λ/-[(1 /?)-1 -(4-fluorophenyl)propyl]-1 H-benzimidazole-5- carboxamide (E42)

1-[(4-Chlorophenyl)methyl]-Λ/-{(1R)-1-[3-(methyloxy)phenyl]ethyl}-1 H-benzimidazole-5- carboxamide (E43)

1-[(4-Chlorophenyl)methyl]-/V-{(1/?)-1-[4-(methyloxy)phenyl]ethyl}-1 H-benzimidazole-5- carboxamide (E44) 1-[(4-Chlorophenyl)methyl]-Λ/-[(1 R)-1-(3-pyridinyl)ethyl]-1H-benzimidazole-5- carboxamide hydrochloride (E45)

1-[(4-Chlorophenyl)methyl]-Λ/-[(1 R)-1-(2-pyridinyl)ethyl]-1 H-benzimidazole-5- carboxamide hydrochloride (E46) 1-[(4-Chlorophenyl)methyl]-Λ/-[(1 R)-1-(2-fluorophenyl)ethyl]-1 H-benzimidazole-5- carboxamide (E47)

1-[(4-Chlorophenyl)methyl]-/V-[(1 /?)-1-(2-fluorophenyl)propyl]-1 H-benzimidazole-5- carboxamide (E48)

1-[(4-Chlorophenyl)methyl]-Λ/-[(1 R)-1-(4-methyl-1 ,3-thiazol-2-yl)ethyl]-1 H-benzimidazole- 5-carboxamide (E49)

1 -[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 S)- 1 -(4-methylphenyl)propyl]-1 H- benzimidazole- 5-carboxamide (E50)

Λ/-[(1 S)-1-(4-Chloro-2-fluorophenyl)propyl]-1-[(3,4-dichlorophenyl)methyl]-2-methyl-1 H- benzimidazole- 5-carboxamide (E51 ) 1-[(3,4-Dichlorophenyl)methyl]-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E52)

1-[(3,4-Dichlorophenyl)methyl]-/V-[(1 /?)-1-phenylpropyl]-2-propanoyl-1 H-benzimidazole-

5-carboxamide (E53)

1-[(2-Chlorophenyl)methyl]-2-methyl-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E54)

1-[(3-Chlorophenyl)methyl]-2-methyl-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E55)

1-[(4-Chlorophenyl)methyl]-2-methyl-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E56) 1-[(3,4-Dichlorophenyl)methyl]-/V-[1-(2-furanyl)propyl]-2-methyl-1 H-benzimidazole-5- carboxamide (E57)

/V-[(1 /?)-1-Phenylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 /-/-benzimidazole-5- carboxamide (E58)

1-(Cyclohexylmethyl)-Λ/-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E59) /V-[(1 /?)-1-Phenylpropyl]-1-(tetrahydro-3-furanylmethyl)-1 H-benzimidazole-5- carboxamide (E60)

1-[(3,5-Dichloro-2-pyridinyl)methyl]-/V-(1-methylethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E61 )

1-[(3,5-Dichloro-2-pyridinyl)methyl]-/V-(1-methylpropyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E62)

1 -[(3, 5-Dichloro-2-pyridinyl)methyl]-Λ/-(1-ethylpropyl)-1 H-benzimidazole- 5-carboxamide hydrochloride (E63)

1-[(3,5-Dichloro-2-pyridinyl)methyl]-/V-(1-methyl-1-phenylethyl)-1 H-benzimidazole-5- carboxamide hydrochloride (E64) 2-Methyl-1-{[3-(methyloxy)phenyl]methyl}-/V-(1-phenylpropyl)-1H-benzimidazole-5- carboxamide (E65)

2-Methyl-Λ/-{1-[4-(methyloxy)phenyl]ethyl}-1-{[3-(methyloxy)phenyl]methyl}-1H- benzimidazole- 5-carboxamide (E66) 1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[1-(2-thienyl)propyl]-1 /-/-benzimidazole-5- carboxamide (E67)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[1-(2-thienyl)pentyl]-1 /-/-benzimidazole-5- carboxamide (E68) 1-[(3_!4-Dichlorophenyl)methyl]-2-methyl-Λ/-[1-(5-methyl-2-thienyl)propyl]-1 H- benzimidazole-5-carboxamide (E69)

1-[(3_!4-Dichlorophenyl)methyl]-2-methyl-Λ/-[1-(4-methyl-3-thienyl)propyl]-1 H- benzimidazole-5-carboxamide (E70)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-/V-[3-methyl-1-(2-thienyl)butyl]-1 H- benzimidazole-5-carboxamide (E71 )

2-Methyl-/V-[(1 /?)-1-phenylpropyl]-1-(2-thienylmethyl)-1 H-benzimidazole-5-carboxamide

(E72)

1-[(5-Methyl-3-isoxazolyl)methyl]-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E73) /V-[(1 /?)-1-Phenylpropyl]-1-(1 ,3-thiazol-4-ylmethyl)-1 H-benzimidazole-5-carboxamide

(E74)

4-Fluoro-1-(phenylmethyl)-/V-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide

(E75)

Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminium, ammonium, bismuth, calcium, copper, ferric, ferrous, lithium, magnesium, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, and cyclic amines. Particular pharmaceutically acceptable organic bases include arginine, caffeine, choline, N, N'- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (TRIS, trometamol) and the like. Salts may also be formed from basic ion exchange resins, for example, polyamine resins. Salts may also be prepared from pharmaceutically acceptable acids including inorganic and organic acids. Such acids include acetic, L-ascorbic acid (vitamin C), L-aspartic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanedisulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, nicotinic, phosphoric, succinic, sulphuric, tartaric, p-toluenesulfonic, perchloric, fluoboric, and the like.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I). The invention also includes within its scope solvates (including hydrates) of the compounds of formula (I) and their pharmaceutically acceptable salts.

Compounds of formula (I) can be prepared as set forth in the following schemes and in the examples wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined for compounds of formula (I) above. The following processes form a further aspect of the present invention. Scheme 1 :

step (iii)

(VIM) step (vii)

(I)

(IX)

Scheme 1 Wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above for compounds of formula (I) and P¹ is a suitable protecting group such as an alkyl group (e.g. methyl or ethyl), or a benzyl group.

Step (i) typically comprises reacting a compound of formula (II) with a suitable reagent such as thionyl chloride or oxalyl chloride and a compound of formula P¹OH, where P¹ is a protecting group as defined above (e.g. P¹ = Me). The compound of formula P¹OH may advantageously be used as a solvent, at an elevated temperature (e.g. reflux).

Step (ii) typically comprises reaction of a compound of formula (III) with a compound of formula (IV) in the presence of a suitable base (e.g. di-isopropylethylamine) in a suitable solvent (e.g. tetrahydrofuran) at an elevated temperature.

Step (iii) typically comprises reaction of a compound (V) with a suitable reducing agent (e.g. tin(ll) chloride dihydrate) in the presence of a suitable solvent (e.g. ethyl acetate) at an elevated temperature.

Step (iv) typically comprises of reaction of a compound of formula (Vl) with a compound of formula R¹(C=O)L¹, where L¹ is a leaving group such as halogen e.g. chlorine, in the presence of a suitable base (e.g. di-isopropylethylamine) and a suitable solvent (e.g. tetrahydrofuran) at an elevated temperature.

Step (v) typically comprises dehydration of a compound of formula (VII) in the presence of a suitable solvent (e.g. acetic acid) at an elevated temperature.

Alternatively, when R¹ is hydrogen, Ci_-4 alkyl or C_3-6 cycloalkyl, compounds of formula (VIII) may be prepared by reaction of compounds of formula (Vl) with a suitable acid R¹CO₂H (e.g. formic acid or acetic acid) at an elevated temperature as shown in Step (vi).

Step (vii) typically comprises hydrolysis of a compound of formula (VIII) using a suitable reagent (e.g. lithium hydroxide) in the presence of a suitable solvent (e.g. 1 :1 tetrahydrofuran : water) at an elevated temperature.

Step (viii) typically comprises reaction of a compound of formula (IX) with a compound of formula (X) in the presence of a suitable coupling reagent (e.g. O-(7-azabenzotriazol-1- yl)Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate or Λ/-(3-dimethylaminopropyl)-Λ/'- ethylcarbodiimide hydrochloride), optionally in the presence of a catalyst such as 1- hydroxybenzotriazole, and a suitable base (e.g. di-isopropylethylamine), in a suitable solvent (e.g. dimethylformamide, dichloromethane and/or tetrahydrofuran). Alternatively, compounds of formula (I) may be prepared from compounds of formula (Xl):

using a synthetic sequence analogous to that described in steps (ii), (iii), (iv), (v) and (vi) of Scheme 1. Compounds of formula (Xl) may be prepared from compounds of formula (II) as defined above and a compound of formula (X) as defined above, using an analogous method to that described for step (viii) of scheme 1.

Alternatively, compounds of formula (I) can be prepared as set forth in Scheme 2 where R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above.

, separation of

regio-isomers

(I) Scheme 2

Step (i) typically comprises reaction of a compound of formula (XII) with a compound of formula (X) in the presence of a suitable coupling reagent (e.g. O-(7-azabenzotriazol-1- yl)Λ/,Λ/,Λ/',Λ/-tetramethyluroniumhexafluorophosphate or Λ/-(3-dimethylaminopropyl)-Λ/'- ethylcarbodiimide hydrochloride), optionally in the presence of a catalyst such as 1- hydroxybenzotriazole and a suitable base (e.g. di-isopropylethylamine), in a suitable solvent (e.g. dimethylformamide).

Step (ii) typically comprises reaction of a compound of formula (XIII) with a compound of formula (XIV) wherein L² is a leaving group such as halogen (e.g. Br) or alkylsulfonyloxy, in the presence of a suitable inorganic base (e.g. sodium hydride) in a suitable solvent (e.g. dimethylformamide) at low temperature (e.g. 0⁰C), followed by separation of the regioisomers (for example using chromatography) to give a compound of formula (I). Compounds of formula (IXa), in which the benzimidazole is substituted at C-4 with a fluorine atom (i.e. R⁷ = F and R⁸ = R⁹ = H), can be prepared as set forth in Scheme 3 and by methods analogous to those described in the examples.

R³

Scheme 3

Step (i) typically comprises reaction of a compound of formula (XV) with a compound of formula (IV) in the presence of a suitable base (e.g. di-isopropylethylamine) in a suitable solvent (e.g. tetrahydrofuran) at an elevated temperature.

Step (ii) typically comprises reaction of a compound of formula (XVI) with a suitable reducing agent (e.g. tin(ll) chloride dihydrate) in the presence of a suitable solvent (e.g. ethyl acetate) at an elevated temperature.

Step (iii) typically comprises of reaction of compounds of formula (XVII) with a suitable acid R¹CO₂H (e.g. formic acid) at an elevated temperature.

Step (iv) typically comprises reaction of compounds of formula (XVIII) with an organometallic reagent such as an alkyl lithium reagent (e.g. n-butyl lithium and s-butyl lithium) followed by reaction of the resulting anion with carbon dioxide, and acidification using a suitable acid (e.g. hydrochloric acid), in a suitable solvent (e.g. tetrahydrofuran) at a low temperature (e.g. -78 ⁰C).

Compounds (II), (IV), (X), (XII) and (XV) are known in the literature or may be prepared by analogous methods to those described in the literature. The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:

(a) interconversions of compounds of formula (I);

(b) formation of a pharmaceutically active salt and/or solvate.

The compounds of the invention find use in the treatment of a disease treatable by modulation of blood glucose levels. Such diseases include hyperglycaemia, dyslipidemia, and, in particular, Type Il diabetes. They further find use in the treatment of other diseases relating to glucose metabolism, including Type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, heart failure, diabetic, hyperlipidemia, hypercholesteremia, hypertension and cardiovascular disease, especially atherosclerosis.

Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease treatable by modulation of blood glucose levels.

The compounds of the invention find use in the treatment of diseases characterised by neuron degeneration, neuron injury or impaired plasticity. Particular diseases or conditions that are characterised by neuron degeneration and thus benefit from the growth and/or repair of neurons include stroke, Alzheimer's disease, fronto-temporal dementias (tauopathies), Parkinson's disease, Amyotrophic lateral sclerosis, dementia with Lewy bodies, traumatic brain or spinal injury, multiple sclerosis, the spinocerebellar degenerations, multiple systems atrophy, inborn errors of metabolism and Huntington's disease; suitably stroke; suitably Alzheimer's disease; suitably frontotemporal dementias (tauopathies); suitably Parkinson's disease; suitably Amyotrophic lateral sclerosis; suitably dementia with Lewy bodies; suitably traumatic brain or spinal injury; suitably multiple sclerosis; suitably the spinocerebellar degenerations; suitably multiple systems atrophy; suitably inborn errors of metabolism; or suitably Huntington's disease. The compounds of the invention find particular use in the treatment of mild cognitive impairment, Alzheimer's disease or another dementia.

Compounds of the invention are also of use in treating other diseases involving cognitive deficits, for example Schizophrenia.

Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance in the treatment or prophylaxis of the above disorders, in particular the treatment of mild cognitive impairment, Alzheimer's disease or another dementia, in particular Alzheimer's disease. The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of the above disorders.

When used in therapy, the compounds of formula (I) are usually formulated in a pharmaceutical composition. Such compositions can be prepared using standard procedures.

Thus, the present invention further provides a pharmaceutical composition for use in the treatment of the above disorders which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition which comprises the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Compounds of formula (I) may be used in combination with other therapeutic agents, for example medicaments claimed to be useful in the treatment of diseases treatable by modulation of blood glucose levels.

Medicaments claimed to be useful in the treatment of diseases treatable by modulation of blood glucose levels that may be used in combination with compounds of the invention include insulin, GLP-1 (glucagon like peptide-1 ) derivatives such as those disclosed in WO 98/08871 , as well as orally active hypoglycaemic agents. Orally active hypoglycaemic agents preferably include sulphonylureas (eg. tolbutamide, glibenclamide, glipizide orglicazide), biguanides (eg metformin), meglitinides (eg. repaglinide or orsenaglinide.), α-glucosidase inhibitors (eg. miglitol or acarbose), glucagon antagonists (for example such as those disclosed in WO99/01423), GLP-1 agonists, potassium channel openers (for example such as those disclosed in WO 97/26265 and WO 99/03861 ), DPP-IV (dipeptidyl peptidase IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenosis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as HMG CoA inhibitors (statins), compounds lowering food intake, RXR agonists and agents acting on the ATP- dependent potassium channel of the β cells (eg. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide). In a further embodiment compounds of formula (I) are administered in combination with anantihyperlipidemic agent or antilipidemic agent, for example cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.

In a further embodiment compounds of formula (I) are administered in combination with more than one of the above-mentioned compounds eg. in combination with a sulphonylurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and asulphonylurea, insulin and metformin, insulin, insulin andlovastatin, etc.

Compounds of formula (I) may be used in combination with other therapeutic agents, for example medicaments claimed to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease. Suitable examples of such other therapeutic agents are M1 muscarinic receptor agonists or allosteric modulators, M2 muscarinic antagonists, acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine), nicotinic receptor agonists or allosteric modulators (such as α7 agonists or allosteric modulators or α4β2 agonists or allosteric modulators), γ secretase inhibitors or modulators, 5-HT₄ receptor partial agonists, histamine H3 antagonists, 5-HT₆ receptor antagonists or 5HT1A receptor antagonists and NMDA receptor antagonists or modulators, and β-secretase inhibitors.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a further therapeutic agent or agents.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.

Examples

Abbreviations

Solid phase extraction (SPE); liquid chromatography/mass spectrometry (LCMS, LC/MS & LC-MS); MDAP (Mass Directed Auto Preparation); NMR (nuclear magnetic resonance); s, d, t, dd, m, b (singlet, doublet, triplet, doublet of doublets, multiplet, broad); Ph, Me, Et, Pr, Bu, Bn (phenyl, methyl, ethyl, propyl, butyl, benzyl), tetrahydrofuran (THF), dichloromethane (DCM), N, N-dimethylformamide (DMF), h (hours), ethylenediaminetetraacetic acid (EDTA), N-(3-dimethylaminopropyl)N'- ethylcarbodiimide hydrochloride (EDC & EDAC), 4-N,N-dimethylaminopyridine (DMAP), di-isopropylethylamine (DIPEA, DIEA), O-(7-Azabenzotriazol-1-yl)-Λ/,Λ/,Λ/',/V- tetramethyluroniumhexafluorophosphate (HATU), dimethylsulfoxide (DMSO), ultraviolet (UV), room temperature (RT), retention time (Rt), minutes (min), EtOAc (ethyl acetate), Et₂O (diethyl ether), MeCN (acetonitrile), EtOH (ethanol), PhCH₃ & PhMe (toluene), t.l.c. (thin layer chromatography), BINAP ((rac)-2,2'-bis(di(phenylphophino)-1 ,1 '-binapthyl), column volumes (CV), high vacuum (HV), di-isopropylethylamine (DIPEA), reverse phase liquid chromatography (RPLC).

Purification of Reaction Products

Conventional techniques may be used herein for work up of reactions and purification of the products of the Examples.

References in the Examples below relating to the drying of organic layers or phases may refer to drying the solution over magnesium sulfate or sodium sulfate and filtering off the drying agent in accordance with conventional techniques. Products may generally be obtained by removing the solvent by evaporation under reduced pressure.

Purification of the Examples may be carried out by conventional methods such as chromatography and/or recrystallisation using suitable solvents. Chromatographic methods are known to the skilled person and include e.g. column chromatography, flash chromatography, HPLC (high performance liquid chromatography), and MDAP (mass directed auto preparation, also referred to as mass directed LCMS purification). MDAP is described in e.g. W. Goetzinger et al, Int. J. Mass Spectrom., 2004, 238, 153-162.

The terms "Biotage^®", "Biotage 75" and "Biotage SP4^®", "Isco CombiFlash XL" when used herein refer to commercially available automated purification systems using prepacked silica gel cartridges.

LCMS

The following LCMS conditions were used during the preparation of the examples.

Method 1

Software

Waters MassLynx version 4.0 SP2

Column

The column used is a Waters Atlantis, the dimensions of which are 4.6mm x 50mm. The stationary phase particle size is 3um.

Solvents

A : Aqueous solvent = Water + 0.05% Formic Acid B : Organic solvent = Acetonitrile + 0.05% Formic Acid

The generic method 1 used has a 5 minute runtime.

The above method has a flow rate of 3ml/min. The injection volume for the generic method is 5ul The column temperature is 30 degrees The UV detection range is from 220 to 330nm

Method 2

Software

Waters MassLynx version 4.1

Column

The column used is a Waters Acquity BEH UPLC C18, the dimensions of which are 2.1 mm x 50mm. The stationary phase particle size is 1.7μ m.

Solvents

A : Aqueous solvent = Water + 0.05% Formic Acid B : Organic solvent = Acetonitrile + 0.05% Formic Acid Weak Wash = 1 :1 Methanol : Water Strong Wash = Water

The generic method 2 has a 2 minute run time

The above method has a flow rate of 1 ml/min. The injection volume for the generic method is 0.5ul

The column temperature is 40 degrees

The UV detection range is from 220 to 330nm

All retention times are measured in minutes.

In the Examples, unless stated otherwise, LCMS Method 1 was used. Data acquired using LCMS Method 2 is indicated by "[LCMS2]"

Mass Directed Auto Preparation

Hardware

D Waters 2525 Binary Gradient Module

D Waters 515 Makeup Pump D Waters Pump Control Module

D Waters 2767 Inject Collect

D Waters Column Fluidics Manager

D Waters 2996 Photodiode Array Detector

D Waters ZQ Mass Spectrometer D Gilson 202 fraction collector

D Gilson Aspec waste collector

Software

Waters MassLynx version 4 SP2

Column

The columns used are Waters Atlantis, the dimensions of which are 19mm x 100mm

(small scale) and 30mm x 100mm (large scale). The stationary phase particle size is

5μm.

Solvents

A : Aqueous solvent = Water + 0.1% Formic Acid

B : Organic solvent = Acetonitrile + 0.1% Formic Acid

Make up solvent = Methanol : Water 80:20 Needle rinse solvent = Methanol

Methods

There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.

Large/Small Scale 1.0-1.5 min = 5-30% B Large/Small Scale 1.5-2.2 min = 15-55% B

Large/Small Scale 2.2-2.9 min = 30-85% B

Large/Small Scale 2.9-3.6 min = 50-99% B

Large/Small Scale 3.6-5.0 min = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)

Flow rate

All of the above methods have a flow rate of either 20mls/min (Small Scale) or 40mls/min (Large Scale).

Mass Directed Auto Preparation - "high pH method"

Hardware

Waters 2525 Binary Gradient Module

Waters 515 Makeup Pump Waters Pump Control Module

Waters 2767 Inject Collect

Waters Column Fluidics Manager

Waters 2996 Photodiode Array Detector

Waters ZQ Mass Spectrometer Waters FC III waste collector

Software

Waters MassLynx version 4 SP2

Column

The column used is Waters X-bridge, the dimensions of which are 30mm x 100mm. The stationary phase particle size is 5μm.

Solvents A : Aqueous solvent = 1 OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.

B : Organic solvent = Acetonitrile.

Make up solvent = Methanol : Water 80:20

Needle rinse solvent = Methanol

Methods There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.

Large/Small Scale 1.0-1.5 = 5-30% B

Large/Small Scale 1.5-2.2 = 15-55% B

Large/Small Scale 2.2-2.9 = 30-85% B

Large/Small Scale 2.9-3.6 = 50-99% B

Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)

Flow rate

All of the above methods have a flow rate of either 20mls/min (Small Scale) or 40mls/min (Large Scale).

In the procedures that follow, after each starting material, reference to a description is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared as described in the description referred to. Certain compounds described below were prepared as salts, for example hydrochloride salts. Except where otherwise stated, the stoichiometry of the salts has not been investigated, so a given salt may have 1 :1 stoichiometry, or it may have some other stoichiometry.

Description 1 (DD

Methyl 4-fluoro-3-nitrobenzoate

4-Fluoro-3-nitrobenzoic acid (Aldrich, 2Og, 108mmol) was dissolved in Methanol (500ml) and treated dropwise with Thionyl Chloride (0.78ml, 10.8mmol). The mixture was heated at reflux overnight, then for a further 8 hours. The reaction was cooled and the solvent evaporated to give the title compound as a cream solid (23g, 1 15mmol). LC/MS: Rt=2.60 min, [MH]⁺ no mass ion

Description 2 (D2)

4-Fluoro-3-nitro-Λ/-r(1 /?)-1 -phenylpropylibenzamide

To a solution of 4-fluoro-3-nitrobenzoic acid (10.6 g, 57.0 mmol) in dry DCM (225 ml) at 0⁰C was added EDAC (13.1 g, 68.4 mmol). The solution was stirred at 0⁰C under an atmosphere of argon for 1.5 hours. After this time, a solution of [(1 R)-I- phenylpropyl]amine (7.79 ml, 54.1 mmol) in dry THF (60 ml) was added dropwise over 2 hours to the reaction mixture. The reaction was then stirred at 0⁰C for 3 hours and then allowed to warm to room temperature overnight. The reaction was monitored by LC-MS. The reaction was concentrated under reduced pressure and the resulting slurry was diluted with EtOAc (500 ml) and washed sequentially with HCI (100 ml, 2M, aq. soln.) to give pH 2, then NaHCO₃ (100 ml, sat. aq soln) to give pH 8-9 and then brine/water (100 ml). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow solid. The residue was chromatographed [SiO₂, DCM:iso-hexane 50-100%] to give a pale yellow solid, 4-fluoro-3-nitro-N-[(1 R)-1- phenylpropyl]benzamide (13.3 g, 81 %). LC/MS Rt = 3.07 min, [MH⁺] 303

¹H NMR (400 MHz, DMSO) δ 9.10 (d, J = 8.33 Hz, 1 H), 8.69, (dd, J = 7.24, 2.19 Hz, 1 H), 8.34 - 8.30 (m, 1 H), 7.40 - 7.38 (m, 2 H), 7.33 (t, J = 7.45 Hz, 2 H), 7.23 (tt, J = 7.23, 1.32 Hz, 2 H), 4.91 (q, J = 7.75 Hz, 1 H), 1.92 - 1.77 (m, 2 H), 0.91 (t, J = 7.45 Hz, 3 H).

Description 3 (D3)

Methyl 4-{r(3,4-dichlorophenyl)methyllamino)-3-nitrobenzoate

Methyl 4-fluoro-3-nitrobenzoate (preparable, for example, as in D1 ) (10.12g, 50.9mmol) was dissolved in THF (400ml) and cooled in an ice bath to O⁰C. 3,4-dichlorobenzylamine (8.1 ml, 61 mmol) was added dropwise and stirred at room temperature. After 5 minutes a yellow precipitate had formed and DIPEA (8.8ml, 50.9mmol) was added. The mixture was stirred for a further 2 hours and left to stand at room temperature overnight. The reaction mixture was filtered, washing well with THF. The filtrate was evaporated to give a yellow solid which was triturated in cold ether. The solid was collected and dried to give the title compound as a yellow solid (16.86g, 47.6mmol, 94% yield).

LC/MS: Rt=3.72 min, [MH]⁺ 354

The following compounds were prepared in a similar manner to Methyl 4-{[(3,4- dichlorophenyl)methyl]amino}-3-nitrobenzoate using the appropriate starting materials

Description 8 (D8)

Methyl 4-{r(2-chlorophenyl)methyl1amino)-3-nitrobenzoate

A solution of methyl 4-fluoro-3-nitrobenzoate (preparable, for example, as in D1 ) (2.00 g, 10.05 mmol) in dry THF (40 ml) was stirred at room temperature under an atmosphere of argon. DIPEA (1.922 ml, 11.05 mmol) was added to the solution. 2-chlorobenzylamine (1.216 ml, 10.05 mmol) was added to the solution and the solution was stirred overnight at room temperature. After this time, the solution was concentrated under reduced pressure to give the crude product as a yellow solid. LC/MS Rt = 3.52 min, [MH]⁺ 321.

The following compound was prepared in a similar manner;

Description 10 (D10)

Methyl- 4-{r(3,5-dichloro-2-pyridinyl)methvnamino)-3-nitrobenzoate

Methyl-4-fluoro-3-nitrobenzoate (preparable, for example, as in D1 ) (2 g, 10.04 mmol) was dissolved in tetrahydrofuran (40 ml) and cooled in an ice bath. [(3,5-dichloro-2- pyridinyl)methyl]amine (2.134 g, 12.05 mmol) was first added to the mixture and then di- isopropylamine (4.27 ml, 25.1 mmol) dropwise. The mixture was allowed to warm to room temperature and was stirred overnight at room temperature. The mixture was filtered and washed with tetrahydrofuran. The filtrate was evaporated to give a yellow solid. (2.93 g) LC/MS Rt = 3.63 min, [MH]⁺ 356, 359.

Description 11 (D11) 4-ff(2-Fluorophenyl)methvπamino)-3-nitro-N-f(1R)-1 -phenyl propylibenzamide

To a solution of 4-fluoro-3-nitro-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (4.00 g, 13.2 mmol) in dry THF (44 ml) was added DIPEA (5.78 ml, 33.1 mmol) and [(2-fluorophenyl)methyl]amine (1.82 ml, 15.9 mmol). The reaction solution was stirred at 60⁰C under an atmosphere of argon for 4 hours. The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure to give 4-{[(2-fluorophenyl)methyl]amino}-3-nitro- N-[(1 R)-1-phenylpropyl]benzamide. LC/MS Rt = 3.48 min, [MH⁺] 408.

¹H NMR (400 MHz, DMSO) δ 8.85 (t, J = 6.14 Hz, 1 H), 8.75 (d, J = 8.33 Hz, 1 H), 8.72 (d, J = 2.19 Hz, 1 H), 7.97 (dd, J = 9.21 , 2.19 Hz, 1 H), 7.37-7.13 (m, 9 H), 6.98 (d, J = 8.99 Hz, 1 H), 4.88 (q, J = 7.75 Hz, 1 H), 4.74 (d, J = 6.14 Hz, 2 H), 1.88 - 1.76 (m, 2 H), 0.88 (t, J = 7.23 Hz, 3 H).

Description 12 (D12) 3-Nitro-4-f(phenylmethyl)amino1-Λ/-f(1/?)-1-phenylpropyπbenzamide

To a solution of 4-fluoro-3-nitro-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (0.250 g, 0.831 mmol) in dry THF (2.8 ml) was added (phenylmethyl)amine (0.108 ml, 0.997 mmol) and DIPEA (0.362 ml, 2.08 mmol). The reaction solution was stirred at 60⁰C under an atmosphere of argon for 17-23 hours (overnight). The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure to give 3-nitro-4- [(phenylmethyl)amino]-N-[(1 R)-1-phenylpropyl]benzamide, LC/MS Rt = 3.37 min, [MH⁺] 390.

The following compounds were prepared in a similar manner to the above procedure:

Description 18 (D18)

Methyl 4-αr2-nitro-4-αr(1 R)-1- phenylpropyl1amino)carbonyl)phenyl1arnino)methyl)benzoate

To a solution of 4-fluoro-3-nitro-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (3.00 g, 9.92 mmol) in dry THF (33.1 ml) was added DIPEA (4.33 ml, 24.8 mmol) followed by methyl 4-(aminomethyl)benzoate (2.40 g, 11.9 mmol). The yellow reaction solution was stirred at 60⁰C under an atmosphere of argon for 21 hours (overnight). The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure to give methyl 4- ({[2-nitro-4-({[(1 R)-1-phenylpropyl]amino}carbonyl)phenyl]amino}methyl)benzoate. LC/MS Rt = 3.34 min, [MH⁺] 448.

Description 19 (D19) 3-Nitro-Λ/-r(1/?)-1-phenylpropyπ-4-r(2-pyridinylmethyl)amino1benzamide

To a solution of 4-fluoro-3-nitro-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (0.500 g, 1.66 mmol) in dry THF (5.5 ml) was added (2- pyridinylmethyl)amine (0.205 ml, 1.99 mmol) and DIPEA (0.721 ml, 4.14 mmol). The reaction solution was stirred at 60⁰C under an atmosphere of argon for 17 hours (overnight). The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure to give 3-nitro-N- [(1 R)-1 -phenylpropyl]-4-[(2-pyridinylmethyl)amino]benzamide. LC/MS Rt = 2.79 min, [MH+] 391.

The following compound was prepared in a similar manner to the above procedure:

^*in this example (1 ,3-thiazol-2-ylmethyl)amine hydrochloride was used as the source of amine.

Description 21 (D21) 4-{r(3-Chloro-2-pyridinyl)methvπamino)-3-nitro-N-r(1R)-1-phenylpropyπbenzamide

To a solution of 4-fluoro-3-nitro-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (0.400 g, 1.32 mmol) in dry THF (4.4 ml) was added 1-(3-chloro-2- pyridinyl)methanamine dihydrochloride (342 mg, 1.59 mmol) and DIPEA (0.576 ml, 3.31 mmol). The reaction solution was stirred at 60⁰C under an atmosphere of argon for 17 hours (overnight). The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure to give 4- {[(3-chloro-2-pyridinyl)methyl]amino}-3-nitro-N-[(1 R)-1-phenylpropyl]benzamide. LC/MS Rt = 3.46 min, [MH⁺] 425, 427.

The following compounds were prepared in a similar manner to the above procedure:

^*in these examples the dihydrochloride salt was used as the source of amine. #in these examples the free base was used as the source of amine.

Description 26 (D26) 4-fr(4-Fluorophenyl)methvπamino)-3-nitro-Λ/-r(1/?)-1-phenylpropyπbenzamide

A solution of 4-fluoro-3-nitro-Λ/-[(1/?)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (0.250 g, 0.83 mmol) in dry THF (3.0 ml) was stirred at room temperature under an atmosphere of argon. DIPEA (0.360 ml, 2.08 mmol) was added to the solution. 4-fluorobenzylamine (0.103 g, 0.83 mmol) was added to the solution and the mixture was stirred at room temperature for 2 ^ΛA hours. The mixture was then heated to 60⁰C for 24 hours. 4-fluoro-benzylamine (0.21 mmol) was added to the reaction mixture and the mixture was stirred at 60⁰C for a further 18 hours under an atmosphere of argon, the reaction mixture was concentrated under reduced pressure. LC/MS Rt = 3.45 min, [MH]⁺ 408, 409

Description 27 (D27)

4-{[(3,5-Difluoro-2-pyridinyl)methyl]amino}-3-nitro-Λ/-[(1/?)-1 - phenylpropyl]benzamide

To a solution of 4-fluoro-3-nitro-Λ/-[(1/?)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (6g, 19.85mmol) in tetrahydrofuran (100ml) was added [(3,5-difluoro-

2-pyridinyl)methyl]amine (4.4Og, 23.82mmol) and DIPEA (8.67ml, 49.6mmol) . The mixture was heated to 6O⁰C for 7 hours. The mixture was evaporated and the residue was chromatographed using the lsco Combiflash XL [SiO₂, Ethyl acetate: Hexane 0-

100%] to give the title compound as a yellow solid on evaporation. Yield: 8.04g (95%) LC/MS Rt=1.20 min [MH]^" 425. [LCMS2]

1 H NMR (CDCI3) δ ppm 0.98 (3H, t), 1.89-2.08 (2H, m), 4.67- 4.75 (2H, m), 5.04 - 5.14 (1 H, m), 6.25 - 6.35 (1 H, m), 7.02-7.09 (1 H, m), 7.24- 7.42 (5H, m), 7.98- 8.07 (1 H, m), 8.42 (1 H, d), 8.59 ( 1 H, d), 9.27 - 9.38 (1 H, bs).

Description 28 (D28)

4-fr(3.4-Difluorophenyl)methvπamino)-3-nitro-Λ/-r(1/?)-1 -phenylpropyπbenzamide

4-Fluoro-3-nitro-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (250 mg, 0.827 mmol) was dissolved in tetrahydrofuran (2 ml) and treated with DIPEA (0.144 ml, 0.827 mmol). [(3,4-difluorophenyl)methyl]amine (0.099 ml, 0.910 mmol) was then added. The reaction was stirred overnight. The reaction was heated at 7O⁰C for 2hours. The mixture was left to stand overnight and solvent evaporated to give the title compound as a yellow oil (345mg, 0.77mmol) LC/MS: Rt=3.45 min [MH]⁺ 426

The following compounds were prepared in a similar manner (varying the reaction times of some examples) to 4-{[(3,4-Difluorophenyl)methyl]amino}-3-nitro-Λ/-[(1/?)-1- phenylpropyl]benzamide using the appropriate starting materials.

^* reaction was carried out at room temperature and then evaporated. The residue was partitioned between DCM and water in a hydrophobic frit. Combined organics were evaporated, the resulting oil was triturated with ether to give a yellow solid that was collected by filtration.

Description 33 (D33) 4-fr(3,4-Dichlorophenyl)methvπamino)-3-nitro-Λ/-r(1/?)-1-phenylpropyπ benzamide

4-fluoro-3-nitro-Λ/-[(1/?)-1-phenylpropyl]benzamide (preparable, for example, as in D2) (2 g, 6.6 mmol) was dissolved in THF (80 ml) and cooled to 0 ⁰C in an ice bath. It was treated dropwise with 3,4-dichlorobenzylamine (0.96 ml, 7.2 mmol) and DIEA (1.15 ml, 6.6 mmol) simultaneously. It was allowed to warm to room temperature, stirred at room temperature for a total of 24 hours, then stood over the weekend. 0.5 equivalents of benzylamine were added and stirring continued for 2 hours. The reaction was filtered, washing with THF, filtrate evaporated to yellow solid.

LC/MS Rt = 1.35 min, [MH]⁺ 458 [LCMS2]

Description 34 (D34) 3-Fluoro-2-nitro-Λ/-(phenylmethyl)aniline

To a solution of 1 ,3-difluoro-2-nitrobenzene (5g, 31.4mmol) in THF (75ml) was added DIPEA (13.72ml, 7mmol) followed by (phenylmethyl) amine (3.78ml, 34.6mmol) at room temperature. The mixture was warmed to 70⁰C for 5 hours. The solvent was removed on a rotary evaporator, the residue was taken up into DCM(150ml) and washed with water (100ml). The DCM layer was dried (MgSO4) and evaporated. The residue was not purified.

Yield:6.8g (88%). LCMS: Rt = 3.81 min, No MH+ seen.

Description 35 (D35)

Methyl 3-amino-4-{r(3,4-dichlorophenyl)methyllamino)benzoate

Methyl 4-{[(3,4-dichlorophenyl)methyl]amino}-3-nitrobenzoate (preparable, for example, as in D3) (20.8g, 58.7mmol) was suspended in ethyl acetate (400ml) and SnCI₂.2H₂O (66.3g, 293.8mmol) was added. It was heated to reflux for 2 hours then cooled to room temperature. The reaction mixture was poured onto ~400ml of cold water and cooled in an ice bath. It was basified with careful addition of saturated NaHCO₃ solution (-2.4L). The precipitate was removed by filtration through celite, washing well with ethyl acetate. The filtrate was transferred to separating funnel and aqueous phase separated and extracted with ethyl acetate (-60OmI). The combined organics were dried over MgSO₄ and evaporated to give the title compound as a pale yellow solid (21.7g, 66.9mmol).

LC/MS: Rt=3.05 min [MH]⁺ 325

The following compounds were prepared in a similar manner to Methyl 3-amino-4-{[(3,4- dichlorophenyl)methyl]amino}benzoate using the appropriate starting materials.

Description 39 (D39) Methyl 3-amino-4-ff(4-chlorophenyl)methvnamino)benzoate

A solution of methyl 4-{[(4-chlorophenyl)methyl]amino}-3-nitrobenzoate (preparable, for example, as in D7) (assume 10.05 mmol) was stirred at room temperature under an atmosphere of argon. SnCI₂.2H₂O (11.37 g, 50.25 mmol) was added to the solution. The mixture was stirred for 2 hours at reflux. After this time, the solution was allowed to cool to room temperature. The mixture was diluted with EtOAc and neutralised with NaHCO₃ (sat. aq. soln.). The organics were dried over MgSO₄, filtered and concentrated under reduced pressure to give a yellow coloured solid.

LC/MS Rt = 2.89 min, [MH]⁺ 291

The following compounds were prepared in a similar manner;

Description 42 (D42)

3-Amino-4-r(phenylmethyl)amino1-N-r(1 R)-1 -phenylpropyπbenzamide

To a solution of 3-nitro-4-[(phenylmethyl)amino]-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D12) (assumed 0.828 mmol) in EtOAc (4.0 ml) was added tin(ll)chloride dihydrate (0.934 g, 4.14 mmol). The suspension was stirred at 80°C under an atmosphere of argon for 17 hours (overnight). The reaction was monitored by LC-MS. The reaction slurry was allowed to cool to room temperature and was diluted with EtOAc (10-20 ml). On addition of NaHCO₃ (10-20 ml, sat. aq soln), a white precipitate formed. The slurry was filtered over a bed of celite and washed with further EtOAc (10 ml). The aqueous layer was re-extracted with EtOAc (10 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-amino-4-[(phenylmethyl)amino]-N-[(1 R)-1-phenylpropyl]benzamide. LC/MS Rt = 2.83 min, [MH⁺] 360.

The following compounds were prepared using a similar procedure:

Description 48 (D48) 3-Amino-4-{r(4-fluorophenyl)methvπamino)-Λ/-r(1/?)-1-phenylpropyπbenzamide

A suspension of 4-{[(4-fluorophenyl)methyl]amino}-3-nitro-Λ/-[(1/?)-1- phenylpropyl]benzamide (preparable, for example, as in D26) (assume 0.83 mmol from previous step) in EtOAc (4 ml) was stirred at room temperature under an atmosphere of argon. SnCI₂.2H₂O (0.939 g, 4.15 mmol) was added to the mixture. The mixture was then heated to reflux and stirred for 5 hours. The mixture was subsequently allowed to cool to room temperature. The mixtures were diluted with EtOAc and washed with NaHCO₃ (sat. aq. soln.). The organics were separated and the aqueous phase was further extracted with EtOAc. The combined organics were dried over MgSO₄, filtered and concentrated under reduced pressure. LCMS Rt = 2.94 min, [MH]⁺ 378, 379

Description 49 (D49) 3-Amino-N-r(1R)-1-phenylpropyπ-4-r(2-pyridinylmethyl)amino1benzamide

To a solution of 3-nitro-N-[(1 R)-1-phenylpropyl]-4-[(2-pyridinylmethyl)amino]benzamide (preparable, for example, as in D19) (assumed 1.66 mmol) in EtOAc (8.3 ml) was added tin(ll)chloride dihydrate (1.87 g, 8.28 mmol). The suspension was stirred at 80°C under an atmosphere of argon for 1.5 hours. The reaction was monitored by LC-MS. The reaction slurry was allowed to cool to room temperature and diluted with EtOAc (100 ml). On addition of NaHCO₃ (50 ml, sat. aq soln), a precipitate formed. The slurry was filtered and washed with further EtOAc (100 ml). The aqueous layer was re-extracted with EtOAc (50 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-amino-N-[(1 R)-1-phenylpropyl]-4-[(2- pyridinylmethyl)amino]benzamide, (397 mg, 66%) LC/MS Rt = 1.85 min [MH]⁺ 361.

The following compound was prepared using a similar procedure:

Description 51 (D51)

3-Amino-4-U(3,5-difluoro-2-pyridinyl)methyl1amino)-Λ/-r(1/?)-1 - phenylpropyllbenzamide

To a solution of 4-{[(3,5-difluoro-2-pyridinyl)methyl]amino}-3-nitro-Λ/-[(1/?)-1- phenylpropyl]benzamide (preparable, for example, as in D27) (8.04g, 18.85mmol) in ethyl acetate (125ml) was added Tin (II) chloride dihydrate (21.27g 94mmol) and the reaction was warmed to 8O⁰C overnight. The mixture was allowed to cool and poured onto ice (50Og), neutralized using aqueous saturate sodium hydrogen carbonate. The resulting suspension was diluted with ethyl acetate (500ml) and filtered to remove the tin residues. The ethyl acetate layer was separated and the aqueous layer was extracted with a further 2 x 500ml of ethyl acetate. The organics were combined, dried (MgSO4) and evaporated. The residue was purified using a Biotage SP4 [SiO2, Ethyl acetate: Hexane 0-100%] to give the title compound as a pale yellow solid. Yield: 6.49g (87%) LC/MS Rt = 0.97 min, [MH]⁺ 397 [LCMS2] 1H NMR (CDCI3) δ ppm 0.96 (3H, t), 1.84-2.03 (2H, m), 3.80-4.40 (3H, br) 4.51 (2H, m), 5.03-5.13 (1 H, m), 6.20- 6.33 (1 H, m) 6.70 (1 H, m), 7.20 - 7.20 (8H, m), 8.32 - 8.37 (1 H, m),

The following compounds were prepared in a similar manner from the appropriate starting materials;

Description 54 (D54) 3-Amino-4-{r(2-fluorophenyl)methvπamino)-N-r(1R)-1-phenylpropyπbenzamide

To a solution of 4-{[(2-fluorophenyl)methyl]amino}-3-nitro-N-[(1 R)-1- phenylpropyl]benzamide (preparable, for example, as in D11 ) (assumed 13.2 mmol) in EtOAc (66 ml) was added tin(ll)chloride dihydrate (14.9 g, 66.2 mmol). The suspension was stirred at 80⁰C under an atmosphere of argon for 17 hours (overnight). The reaction was monitored by LC-MS. The reaction slurry was allowed to cool to room temperature and was diluted with EtOAc (50 ml). On addition of NaHCO₃ (200 ml, sat. aq soln), a white precipitate formed. The slurry was filtered. The aqueous layer was re-extracted with EtOAc (200 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was chromatographed [SiO₂, DCM:iso-hexane 12-50%] to give 3-amino-4-{[(2- fluorophenyl)methyl]amino}-N-[(1 R)-1-phenylpropyl]benzamide (3.83 g, 77%). LC/MS Rt = 2.89 min, [MH]⁺ 378.

¹H NMR (400 MHz, DMSO) δ 8.15 (d, J = 8.55 Hz, 1 H), 7.35 - 7.06 (m, 11 H), 6.33 (d, J = 8.11 Hz, 1 H), 5.59 (t, J = 5.92 Hz, 1 H), 4.84 (q, J = 7.82 Hz, 1 H), 4.71 (s, 2 H), 4.40 (d, J = 5.92 Hz, 2 H), 1.84 - 1.69 (m, 2 H), 0.86 (t, J = 7.23 Hz, 3 H).

Description 55 (D55)

3-Amino-4-f f(3-chloro-2-pyridinyl)methvπamino)-N-f(1 R)-1 - phenyl propylibenzamide

To a solution of 4-{[(3-chloro-2-pyridinyl)methyl]amino}-3-nitro-N-[(1 R)-1- phenylpropyl]benzamide (preparable, for example, as in D21 ) (assumed 1.32 mmol) in EtOAc (6.6 ml) was added tin(ll)chloride dihydrate (1.49 g, 6.62 mmol). The suspension was stirred at 80⁰C under an atmosphere of argon for 17 hours (overnight). The reaction was monitored by LC-MS.

The reaction slurry was allowed to cool to room temperature and was diluted with EtOAc (100 ml). On addition of NaHCO₃ (50 ml, sat. aq soln), a white precipitate formed. The slurry was filtered. The aqueous layer was re-extracted with EtOAc (50 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 3-amino-4-{[(3-chloro-2-pyridinyl)methyl]amino}-N-[(1 R)-1- phenylpropyl]benzamide, Rt = 2.66 min, [MH]⁺ 395, 397.

The following compounds were prepared using a similar procedure:

All compounds above were taken on to next stage without further purification.

^* For these compounds, the reaction slurry was allowed to cool to room temperature and concentrated under reduced pressure to give crude products. The tin impurities were taken on to the next stage of the reaction.

Description 60 (D60) Methyl 4-(f \2 -amino-4-(( FdR)-I- phenylpropyl1amino)carbonyl)phenyl1amino)methyl)benzoate

To a solution of methyl 4-({[2-nitro-4-({[(1 R)-1-phenylpropyl]amino}carbonyl) phenyl]amino}methyl)benzoate (preparable, for example, as in D18) (assumed 9.92 mmol) in EtOAc (49.6 ml) was added tin(ll)chloride dihydrate (11.2 g, 49.6 mmol). The suspension was stirred at 80⁰C under an atmosphere of argon for 17 hours (overnight). The reaction was monitored by LC-MS. The reaction slurry was allowed to cool to room temperature and was diluted with EtOAc (500 ml). On addition of NaHCO₃ (400 ml, sat. aq soln), a white precipitate formed. The slurry was filtered. The aqueous layer was re- extracted with EtOAc (300 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give methyl 4-({[2-amino-4- ({[(1 R)-1-phenylpropyl]amino}carbonyl)phenyl]amino}methyl)benzoate. LC/MS Rt = 2.85 min, [MH]⁺ 418.

Description 61 (D61) 3-Amino-4-fr(3,4-difluorophenyl)methvπamino)-Λ/-r(1/?)-1-phenylpropyπbenzamide

4-{[(3,4-Difluorophenyl)methyl]amino}-3-nitro-N-[(1 R)-1 -phenylpropyl]benzamide (as prepared in D28) (345mg, 0.81 mmol) was dissolved in Ethyl acetate (40 ml). Tin(ll) Chloride Dihydrate (732 mg, 3.24 mmol) was added. The reaction was heated to 8O⁰C and left to reflux overnight. The reaction was allowed to cool, then placed on ice. The reaction was basified using NaHCO3 to pH8. The aqueous layer was extracted with ethyl acetate and brine. The combined organic layers dried over magnesium sulphate and evaporated to give the title compound as a yellow oil (321 mg, 0.81 mmol)

LC/MS: Rt= 2.95 min [MH]⁺ 396

The following compounds were prepared in a similar manner to 3-Amino-4-{[(3,4- difluorophenyl)methyl]amino}-Λ/-[(1 R)-1-phenylpropyl]benzamide using the appropriate starting materials.

^* heated for 2 hours and underwent purification. Water was added and the mixture was neutralised with sat. NaHCO₃. The mixture was filtered through celite and washed with EtOAc. The aqueous layer was re-extracted with EtOAc. The organics were dried over MgSO₄, filtered and evaporated. The residue was chromatographed [SiO₂, 0-100% EtOAc in hexane].

Description 66 (D66) S-Fluoro-Λ/MphenylmethylH ^-benzenediamine

To a solution of 3-fluoro-2-nitro-N-(phenylmethyl) aniline (preparable, for example, as in D34) (2g, 8.12mmol) in ethyl acetate (75ml) was added tin(ll) chloride dihydrate (9.16g, 40.6mmol) and the mixture was heated to reflux for 2 hours. On cooling, the mixture was neutralized using aqueous saturated sodium hydrogen carbonate. The mixture was filtered through Celite, the mixture was extracted with ethyl acetate (3x 100ml), to give the title compound as the major product. No purification was carried out. Yield: 1.88g (107%)

LCMS: Rt 3.29 min, [MH]⁺ 217

Description 67 (D67)

Methyl 3-(acetylamino)-4-(r(3,4-dichlorophenyl)methyllamino)benzoate

Methyl 3-amino-4-{[(3,4-dichlorophenyl)methyl]amino}benzoate (preparable, for example, as in D35) (9g, 27.7mmol) was dissolved in THF (120ml) and cooled in an ice bath. It was treated dropwise with DIPEA (14.5ml, 83.1 mmol) followed by acetyl chloride (2ml, 28.1 mmol). The reaction mixture was allowed to warm to room temperature, under argon over 30 minutes. The solvent was evaporated to give the title compound as a yellow oil (17.8g)

LC/MS: Rt=2.92 min [MH]⁺ 367 The following compounds were prepared in a similar manner to Methyl 3-(acetylamino)- 4-{[(3,4-dichlorophenyl)methyl]amino}benzoate using the appropriate starting materials.

Description 74 (D74)

4-{r(3,4-Dichlorophenyl)methvπamino)-Λ/-r(1/?)-1-phenylpropyπ-3- r(trifluoroacetyl)amino1benzamide

3-Amino-4-{[(3,4-dichlorophenyl)methyl]amino}-Λ/-[(1 /?)-1-phenylpropyl]benzamide (preparable, for example, as in D53) (100mg, 0.22mmol) was dissolved in acetonitrile (2ml) and treated with trifluoroacetic anhydride (0.032ml, 0.22mmol). The mixture was stirred at room temperature in the absence of light for 1 hour. Water was added and the reaction was extracted with ethyl acetate (2x 20ml). The combined organics were dried over MgSO₄ and evaporated to give the title compound as a yellow oil (154mg).

LC/MS: Rt=3.43 min [MH]⁺ 524

Description 75 (D75)

Methyl 4-f r(3,4-dichlorophenyl)methyl1amino)-3-( \(Λ - hydroxycvclopropyDcarbonyliaminolbenzoate

1-Hydroxy-1 -cyclopropane carboxylic acid (1.27g, 12.50mmol) was dissolved in DMF (60ml) and treated with HATU (4.75g, 12.50mmol) and DIPEA (1.63ml, 9.38mmol). Stirred for 30 minutes at room temperature. Methyl 3-amino-4-{[(3,4- dichlorophenyl)methyl]amino}benzoate (preparable, for example, as in D35) (2.02g, 6.25mmol) was then added and stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organics were washed with water (x2) and the aqueous phases re-extracted with ethyl acetate. The combined organics were washed with brine and dried over MgSO₄. The mixture was evaporated to give a dark brown oil which was purified by flash chromatography eluting with 0-5% MeOH in DCM to give the title compound as a brown oil (2.28g)

LC/MS: Rt=2.89 min [MH]⁺ 409

Description 76 (D76)

3-(Acetylamino)-4-f f(4-fluorophenyl)methvπamino)-Λ/-f(1 /?)-1 - phenyl propylibenzamide

A solution of 3-amino-4-{[(4-fluorophenyl)methyl]amino}-Λ/-[(1/?)-1- phenylpropyl]benzamide (preparable, for example, as in D48) (assume 0.83 mmol from previous step) in dry THF (2.77 ml) was stirred at room temperature under an atmosphere of argon. DIPEA (0.432 ml, 2.49 mmol) and acetyl chloride (0.059 ml, 0.84 mmol) were added to the solution. The solution was stirred at room temperature for Vi hour. The solution was concentrated under reduced pressure. LCMS Rt = 2.90 min, [MH]⁺ 420

Description 77 (D77) 3-(Acetylamino)-Λ/-f(1/?)-1 -phenylpropyπ-4-f(2-thienylmethyl)amino1benzamide

To 3-amino-Λ/-[(1 /?)-1-phenylpropyl]-4-[(2-thienylmethyl)amino]benzamide (preparable, for example, as in D65) (45mg, 0.12 mmol) in THF (3ml) with DIPEA (0.064ml, 0.37mmol), was added acetyl chloride (9.96ul, 0.136mmol). The mixture was stirred at room temperature for 30 minutes. Further acetyl chloride (5ul) was added to the reaction in 2 portions to drive the reaction to completion. The mixture was evaporated to a yellow oil and used without further purification (assume ~0.12mmols)

LC/MS: Rt=2.76 min [MH]⁺408.

Description 78 (D78)

Methyl 1 -r(3,4-dichlorophenyl)methyl1-2-methyl-1 H-benzimidazole-5-carboxylate

Methyl 3-(acetylamino)-4-{[(3,4-dichlorophenyl)methyl]amino}benzoate (preparable, for example, as in D67) (27.7mmol) was dissolved in glacial acetic acid (120ml) and heated to 100°C under argon, overnight. The mixture was cooled to room temperature and the solvent evaporated to give an orange solid which was dissolved in ethyl acetate (200ml), washed with water (2x 250ml) and brine (250ml) and dried over MgSO₄. The solvent was evaporated to give an orange oil which crystallised on standing to give the title compound (9g, 25.8mmol, 93% yield)

LC/MS: Rt=2.57 min [MH]⁺ 349, 350

The following compounds were prepared in a similar manner to Methyl 1-[(3,4- dichlorophenyl)methyl]-2-methyl-1 H-benzimidazole-5-carboxylate using the appropriate starting materials

Description 85 (D85)

Methyl 1 -r(4-chlorophenyl)methyl1-1 H-benzimidazole-5-carboxylate

Methyl 3-amino-4-{[(4-chlorophenyl)methyl]amino}benzoate (preparable, for example, as in D39) (500mg, 1.72mmol) was dissolved in formic acid (4.25ml) and heated to 11 O⁰C for 30 minutes. The mixture was cooled to room temperature and then to O⁰C. It was neutralised carefully with saturated sodium bicarbonate solution (~100ml). It was then extracted with ethyl acetate (50ml) which was washed with brine (50ml), and water (3x50ml) then dried over MgSO₄. The mixture was evaporated to give the title compound as a yellow solid (500mg, 1.66mmol, 97% yield).

LC/MS: Rt=2.66 min, [MH]⁺ 301

The following compounds were prepared in a similar manner from the appropriate starting materials;

Description 90 (D90)

4-Fluoro-1 -(phenylmethvD-1 H-benzimidazole

To 3-fluoro-N1-(phenylmethyl)-1 ,2-benzenediamine (preparable, for example, as in D66) (1.88g, 8.69mmol) was added formic acid (10ml) and the mixture was heated at 100⁰C for 1 hour. On cooling the mixture was neutralized using aqueous saturated sodium hydrogen carbonate, and the resulting mixture was extracted with ethyl acetate (3x 100ml). The organics were combined, dried (MgSO4) and evaporated on a rotary evaporator. The residue was purified using an SP4 column eluting with 0-100% ethyl acetate / isohexane to give the title compound with some impurities. Yield: 1.55g (79%) LCMS: ret time = 0.89 minutes, [MH]⁺ = 227 [LCMS2]

Description 91 (D91)

Methyl i-rOΛ-dichlorophenvDmethvπ-Σ-d-hvdroxycvclopropyD-IH-benzimidazole-

5-carboxylate

Methyl 4-{[(3,4-dichlorophenyl)methyl]amino}-3-{[(1-hydroxycyclopropyl)carbonyl]amino} benzoate (preparable, for example, as in D75) (2.28g, 5.6mmol) was dissolved in Glacial acetic acid (100ml) and heated to reflux overnight. The mixture was then cooled to room temperature and the solvent evaporated. The mixture was diluted with ethyl acetate and washed with water (x2). The aqueous fraction was re-extracted with ethyl acetate and the combined fractions were dried over MgSO₄ The mixture was evaporated to give a orange oil which was purified by flash chromatography eluting 0-3% MeOH in DCM to give the title compound as a pale foam (600mg, 1.53mmol, 27% yield).

LC/MS: Rt=3.00 min [MH]⁺ 390

Description 92 (D92) i-fO^-DichlorophenvDmethvπ-Σ-methyl-IH-benzimidazole-δ-carboxylic acid

Methyl 1 -[(3,4-dichlorophenyl)methyl]-2-methyl-1 /-/-benzimidazole-5-carboxylate

(preparable, for example, as in D78) (9g, 25.9mmol) was suspended in 48ml of THF: water, 2:1 and 1 M LiOH solution (257ml). The mixture was heated to reflux overnight then cooled to room temperature. The THF was evaporated and the aqueous solution was cooled in an ice bath and carefully acidified to pH4 with 2M HCI solution. The cream precipitate was filtered and washed with water. The solid was dried in a vacuum oven to give the title compound as a cream solid (6.6g, 19.8mmol, 76% yield)

LC/MS: Rt=2.23 min [MH]⁺ 334, 336

The following compounds were prepared in a similar manner to 1-[(3,4- Dichlorophenyl)methyl]-2-methyl-1 H-benzimidazole-5-carboxylic acid using the appropriate starting materials

Description 101 (D101)

1 -f(2-Chlorophenyl)methvπ-2-methyl-1 H-benzimidazole-5-carboxylic acid

A solution of methyl 1-[(2-chlorophenyl)methyl]-2-methyl-1H-benzimidazole-5- carboxylate (as prepared in D82) (10.05 mmol) in THF (14 ml) and H₂O (7 ml) was stirred at room temperature under argon. LiOH (1.205 g, 50.25 mmol) was added to the solution and the solution was heated to 60⁰C for 19 hours (overnight). After this time, the solution was allowed to cool to room temperature. The solution was then washed with EtOAc (^χ2). The aqueous layer was acidified using 2M HCI and the organics extracted into EtOAc. The combined organics were concentrated under reduced pressure to give an off-white coloured solid. LC/MS Rt = 2.04 min, [MH]⁺ 301 , 303

The following compounds were prepared in a similar manner form the appropriate starting materials.

Description 104 (D104) i-rOΛ-DichlorophenvDmethvπ-IH-benzimidazole-δ-carboxylic acid and 1-r(3,4- dichlorophenvDmethvπ-Σ-propanoyl-IH-benzimidazole-δ-carboxylic acid

Methyl 1-[(3,4-dichlorophenyl)methyl]-2-(1-hydroxycyclopropyl)-1 H-benzimidazole-5- carboxylate (as prepared in D91 ) (600mg, 1.5mmol) was dissolved in THF (3ml) and treated with 1 M LiOH solution (16ml, 15mmol). The mixture was heated to reflux overnight. Then the reaction was cooled and the solvent evaporated and acidified to pH 4 with 2M HCI. The precipitate was filtered, washed with water, collected and dried in a vacuum oven overnight to give the title compounds as a mixture of ratio 2:3.

LC/MS: Rt=2.52 min [MH]⁺ 320 LC/MS: Rt=3.19 min [MH]⁺ 376

Description 105 (D105) 2-Methyl-1-ff3-(methyloxy)phenvπmethyl)-1H-benzimidazole-5-carboxylic acid

Methyl 4-fluoro-3-nitrobenzoate (preparable, for example, as in D1 ) (500 mg, 2.51 1 mmol) was treated with 3-methoxybenzylamine (0.39 ml, 3.013 mmol) in THF (10 ml). After 1.5h at room temperature THF was evaporated in vacuo.

The residue was dissolved in EtOH (100 ml), to this solution was SnCI₂ (3.399 g, 15.065 mmol) was added. After reflux for 16h, analysis by LCMS showed complete consumption of nitro aniline. The mixture was then poured in 250 ml of water, then slowly basified with Na₂CO₃ to pH = 10-11. Extraction with CH₂CI₂. The organics were dried over MgSO₄ and concentrated in vacuo. The residue was treated with acetyl chloride (0.2 ml, 2.536 mmol) in THF (10 ml) in the presence of DIPEA (1.31 ml, 7.533 mmol) in a microwave vial until disappearance of the starting aniline by LC/MS (35 min). The mixture was then concentrated to dryness. Acetic acid (10 ml) was added and the reaction mixture was heated in a microwave oven at 100 ⁰C for 20 min. Control by LC/MS showed complete formation of the benzimidazole ring. The mixture was concentrated to dryness, and lithium hydroxide (609 mg, 25.36 mmol) was added along with a 4 ml of a 2:1 mixture of THF (10 ml) and water. The new reactive mixture was heated at 120 ⁰C for 30 min by microwave. The mixture was then poured into EtOAc, acidified to pH=4, extracted with EtOAc, dried over MgSO₄ and concentrated to dryness in vacuo. (350 mg, 47%)

Description 106 (D106) Λ/-r(1/?)-1-(3-Chlorophenyl)propyl1-2-methyl-2-propanesulfinamide

To a 0.5M solution of Ti(OEt)₄ (1.3ml, 6.2mmol) in THF (12ml) was added 3- Chloropropiophenone (621 mg, 3.7mmol), followed by R-(+)-2-methyl-2-propylsulfinamide (375mg, 3.1 mmol). The mixture was heated at 7O⁰C overnight. It was cooled to room temperature and then to -5O⁰C and treated portionwise with sodium borohydride (470mg,12.4mmol). The reaction was allowed to warm to room temperature slowly over 4 hours. Then the reaction was complete so it was cooled in an ice bath, and 10ml of water was added slowly. On cessation of gas evolution 10ml of DCM was added and the mixture passed down a hydrophobic frit. The DCM layer was separated and the aqueous was washed with 2x 10ml of DCM. Combined DCM extracts were dried over MgSO₄, and then evaporated to an oil. The product was purified by chromatography on silica gel eluting with 0-50% ethyl acetate in hexane over 5CV, followed by 50% ethyl acetate in hexane over 5CV, and then 50-100% ethyl acetate in hexane over 5CV. Fractions were evaporated to give the title compound as a white solid (630mg, 2.3mmol, 74% yield)

The following compounds were prepared in a similar manner to Λ/-[(1/?)-1-(3- chlorophenyl)propyl]-2-methyl-2-propanesulfinamide using the appropriate starting materials.

Description 115 (D115) 2-Methyl-Λ/-r(1E)-(4-methylphenyl)methylidene1-2-propanesulfinamide

4-Methylbenzaldehyde (1g, 8.33mmol), 2-Methyl-2-propylsulfinamide (1g) and Ti(OEt)₄ (3.47ml) in THF (15ml) were sealed in a carousel and heated at reflux under nitrogen overnight. The mixture was cooled to room temperature and the THF was evaporated. Water (20ml) was added. The aqueous layer was washed with DCM (20ml) separating layers through a hydrophobic frit. The mixture was dried over MgSO₄ and evaporated to give the title compound (1.87g)

The following compound was prepared in a similar manner to 2-Methyl-Λ/-[(1£)-(4- methylphenyl)methylidene]-2-propanesulfinamide using the appropriate starting materials

Description 117 (D117)

2-Methyl-Λ/-r(1 SH -(4-methylphenyl)propyl1-2-propanesulfinamide

2-Methyl-Λ/-[(1 £)-(4-methylphenyl)methylidene]-2-propanesulfinamide (preparable, for example, as in D115) (1.874g, 8.4mmol) was dissolved in dry DCM (30ml) and cooled to -7O⁰C under nitrogen. The solution was treated with LiO¹Bu 1 M in cyclohexane (15.12ml, 15.1 mmol) and ethylmagnesium bromide 3M in Et₂O (8.4ml, 25.2mmol). The reaction mixture was stirred at -2O⁰C for 2 hours and then allowed to warm to room temperature, stirring for a further 2 hours. The reaction mixture was quenched by addition of NH₄CI and water at -1O⁰C. The aqueous layer was extracted with 2x 20ml of ethyl acetate which were combined and dried over MgSO₄. The mixture was filtered and evaporated and then purified by flash chromatography twice eluting 0-100% ethyl acetate in cyclohexane to give the title compound.

The following compound was prepared in a similar manner to 2-Methyl-Λ/-[(1 S)-1-(4- methylphenyl)propyl]-2-propanesulfinamide using the appropriate starting materials

Description 119 (D119)

(1/?)-1-(3-Chlorophenyl)-1 -propanamine hydrochloride

Λ/-[(1 /?)-1-(3-Chlorophenyl)propyl]-2-methyl-2-propanesulfinamide (preparable, for example, as in D106) (630mg, 2.3mmol) was dissolved in Methanol (3ml) and treated with 4M HCI in Dioxan (1.15ml, 4.6mmol). The mixture was stirred at room temperature for 30-45 minutes then evaporated and triturated with diethyl ether. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white solid (394mg, 2.02mmol, 88% yield).

The following compounds were prepared in a similar manner to (1R)-1-(3-chlorophenyl)- 1-propanamine hydrochloride using the appropriate starting materials. Description Structure Name CharacterNumber isation

D120 NH₂ (1R)-1-(3-Fluorophenyl)-1- Structure propanamine confirmed hydrochloride by ¹H NMR

D121 (1 /?)-1-[3- Structure

(Trifluoromethyl)phenyl]-1 - confirmed propanamine by ¹H NMR hydrochloride

D122 NH, (1R)-1-(4-Fluorophenyl)-1- Structure propanamine confirmed hydrochloride by ¹H NMR

D123 (1 /?)-1-(3- Structure

Pyridinyl)ethanamine confirmed hydrochloride by ¹H NMR

D124 (1 /?)-1-(2- Structure

Pyridinyl)ethanamine confirmed hydrochloride by ¹H NMR

D125 1 R)-1 -(2- Structure

Fluorophenyl)ethanamine confirmed hydrochloride by ¹H NMR

D126 NH (1R)-1-(2-Fluorophenyl)-1- Structure propanamine confirmed hydrochloride by ¹H NMR

These compounds were prepared using diethyl ether as a solvent instead of methanol, and 3eq of 4M HCI in Dioxan were used, filtering and collecting the precipitate which formed during the reaction.

Description 130 (D130)

Λ/-r(1 /?)-1 -PhenylpropylH H-benzimidazole-5-carboxamide

To a solution of IH-benzimidazole-5-carboxylic acid (2g, 12.33mmol) in DMF (20ml) was added HATU (5.25g, 13.81 mmols) followed by (1 R)-1-phenylpropyl]amine (1.87g,13.81 mmol) and DIPEA (4.78ml, 37mmol). The mixture was stirred at room temperature for 1 hour and 15 minutes. Water was added with stirring, and the resulting pink solid was collected by filtration and washed with water. This was dried under vacuum in an oven to give the title compound (2.58g, 9.24mmol)

LC/MS: Rt=1.76 min [MH]⁺280.

Description 131 (D131) 4-Fluoro-1 -(phenylmethyl)-i H-benzimidazole-5-carboxylic acid

A solution of 4-fluoro-1-(phenylmethyl)-1 H-benzindazole (preparable, for example, as in D90) (0.5g, 2.21 mmol) in THF (10ml) was cooled to -70C and 2.5M n- butyllithium(0.972ml, 2.431 mmol) was added dropwise giving a light brown solution. The mixture was stirred for 30 minutes and TMS-bromide (0.287ml. 2.210mmol) was added dropwise. A pale yellow solution resulted. To this mixture was added 1.4M sec- butyllithium (1.894ml, 2.65mmol) and the mixture was stirred at -70C for a further 30 minutes. This mixture was poured into a flask containing about 10 pieces of cardice in THF (10ml). The mixture was allowed to warm to room temperature, the solvent was removed and water (50ml) was added to the residue. This was extracted with DCM (50ml), the aqueous layer was separated and then acidified using 2M aqueous hydrochloric acid to a pH= 2. The acidic mixture was extracted with DCM (2x 50ml), the organics were combined and evaporated to give a pale yellow oil. This was purified using a SAX (10g) cartridge eluting with 10% hydrochloric acid in methanol, to give the title compound as one of three components in the mixture. The mixture was not purified. Yield: 70mg LCMS: shows a mixture of three components Rt = 2.14, 2.22 and 2.91 min all showing an [MH]⁺ = 271

Example 1 (ED

1 -r(3,4-Dichlorophenyl)methvπ-Λ/-r(1 KH -phenylpropyn-2-(trifluoromethyl)-1 H- benzimidazole-5-carboxamide

4-{[(3,4-Dichlorophenyl)methyl]amino}-Λ/-[(1/?)-1-phenylpropyl]-3- [(trifluoroacetyl)amino]benzamide (preparable, for example, as in D74) (229mg, 0.43mmol) was dissolved in acetic acid (10ml) and heated to 100°C for 3 hours. The mixture was cooled and passed down a 5g SCX cartridge eluting with MeOH, followed by 2M NH₃ in MeOH. LC/MS indicated the product eluted in methanolic fractions, so they were evaporated and dissolved in ethyl acetate. That was washed with water (x2) and the aqueous fractions re-extracted. The combined organics were dried over MgSO₄ and the solvent was evaporated to give a yellow oil. This was purified by flash chromatography eluting 0-5% MeOH in DCM. Fractions showed impurity present so compound was then purified by MDAP to give the title compound as a yellow solid (49mg, O.IOmmol, 22% yield).

LC/MS: Rt=3.69 min [MH]⁺ 506

The following compound was prepared in a similar manner from the appropriate starting materials;

Example 3 (E3)

1 -r(3,5-Difluoro-2-pyridinyl)methvn-Λ/-r(1 /?)-1 -phenylpropyll-2,3-dihvdro-1 H- benzimidazole-5-carboxamide HCI salt

To a solution of 3-amino-4-{[(3,5-difluoro-2-pyridinyl)methyl]amino}-Λ/-[(1/?)-1- phenylpropyl]benzamide (preparable, for example, as in D51 ) (6.49g, 16.37mmol) was added formic acid(40ml) and the mixture was heated to 11 O⁰C for 1 hour. The mixture was allowed to cool and the formic acid was neutralized using aqueous sodium hydrogen carbonate followed by using solid sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (3x250ml). The organics were combined, dried (MgSO₄) and evaporated. The residue was purified using a Biotage SP4 [SiO₂, DCM:Methanol 0- 10%]. Further purification [SiO₂, 100% EtOAc] was required to give 1-[(3,5-difluoro-2- pyridinyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-2,3-dihydro-1 H-benzimidazole-5-carboxamide as a white solid. Yield: 5.54g (82%) Rt = 0.91 min, [MH]⁺ 407.

1-[(3,5-difluoro-2-pyridinyl)methyl]-Λ/-[(1 R)-1-phenylpropyl]-2,3-dihydro-1 H- benzimidazole-5-carboxamide (5.54g) was taken up into methanol (50ml) and 1 M HCI in ether (27.29ml) was added dropwise over 15min. The mixture was stirred at room temperature for 30mins. The mixture was evaporated on a rotary evaporator to give the title compound. Yield:5.97g,

LC/MS Rt= 0.91 min, [MH]⁺ 407 1 H NMR (DMSO) δ ppm 0.92 (3H, t), 1.74-2.02 (2H, m), 4.81-5.00 (1 H, m) 5.90-6.10

(2H, m), 7.15-7.50 (6H, m), 7.84 (1 H, d), 8.01 (1 H, d), 8.11 (1 H, t), 8.38 (2H, d), 8.99

(1 H, d), 9.45 (1 H, bs)

Example 3a (E3a) 1 -r(3.5-Difluoro-2-pyridinyl)methvπ-Λ/-rn fl)-1 -phenylpropyn-2.3-dihvdro-1 H- benzimidazole-5-carboxamide HCI salt - alternative procedure

3-Amino-4-{[(3,5-difluoro-2-pyridinyl)methyl]amino}-Λ/-[(1/?)-1-phenylpropyl]benzamide (preparable, for example, as in D51 ) (524 mg, 1.323 mmol) was stirred in formic acid (3349 μl_, 87 mmol) at 110 ⁰C under an atmopshere of argon for 2 hours. The reaction was monitored by LCMS. The reaction was allowed to cool to room temperature. The reaction was diluted with EtOAc (50 ml) and washed with sodium bicarbonate (sat. aq. soln., 100 ml) to give pH 9. During this addition, vigorous fizzing was observed. The organics were then washed with further water (20 ml) and brine (20 ml). The organics were dried over MgSO₄, filtered and concentrated to give the crude product.

100 mg of crude product was purified using MDAP. The oil obtained was stirred in methanol (2 ml) and 1 M HCI in diethyl ether (excess) for 10 min. This was then concentrated under reduced pressure to give a colourless oil, and triturated with hexane to give the mono-hydrochloride salt as a white coloured solid. (52 mg) LC/MS Rt = 2.55 min [MH⁺] 407.

Example 4 (E4)

1 -r(2-Fluorophenyl)methvn-N-r(1 R)-1 -phenylpropylH H-benzimidazole-5- carboxamide

A solution of 3-amino-4-{[(2-fluorophenyl)methyl]amino}-N-[(1 R)-1-phenylpropyl] benzamide (preparable, for example, as in D54) (3.83 g, 10.15 mmol) in formic acid (26 ml) was stirred at 1 10⁰C under an atmosphere of argon for 30 minutes. The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure. The resulting residue was partitioned between EtOAc (100 ml) and NaHCO₃ (100 ml, sat. aq soln) to give pH 9. The aqueous layer was re-extracted using EtOAc (50 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The resulting residue was chromatographed [SiO₂, EtOAc:iso-hexane 50-100%]. The white solid obtained was then refluxed at 80⁰C in iso-hexane (100 ml). To this was added EtOAc (approx 75 ml) slowly until the white precipitate dissolved. While adding the EtOAc, the temperature was maintained at reflux. When the entire solid had dissolved the solution was allowed to cool slowly to room temperature overnight. On doing so, crystals precipitated out. These were filtered and washed with cold hexane and dried in HV oven at 45°C overnight. The filtrate was concentrated under reduced pressure to reduce the volume by half. This was then left over the weekend at room temperature. On doing so, crystals precipitated out. These were then filtered and washed with cold hexane and dried in HV oven at 45°C overnight. Both batches of the compound were combined to give 1-[(2-fluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole- 5-carboxamide (3.00 g, 76%). LC/MS Rt = 2.67 min, [MH]⁺ 388. ¹H NMR (400 MHz, DMSO) δ 8.71 (d, J = 8.33 Hz, 1 H), 8.45 (s, 1 H), 8.30 (s, 1 H), 7.78 (dd, J = 8.55, 1.53 Hz, 1 H), 7.59 (d, J = 8.55 Hz, 1 H), 7.41 - 7.15 (m, 9 H), 5.61 (s, 2 H), 4.92 (q, J = 7.82 Hz, 1 H), 1.91 - 1.75 (m, 2 H), 0.91 (t, J = 7.35, 3 H).

Example 4a (E4a)

1 -f(2-Fluorophenyl)methvn-N-f(1 R)-1 -phenylpropyli-1 H-benzimidazole-5- carboxamide

3-amino-4-{[(2-fluorophenyl)methyl]amino}-Λ/-[(1/?)-1-phenylpropyl]benzamide (preparable, for example, as in D54) (0.828 mmol) was stirred in HCOOH (2 ml) at 110⁰C under argon for 1 hour. The reaction was monitored by LCMS. The solution was allowed to cool to room temperature. The solution was then partitioned between EtOAc (10 ml) and NaHCO₃ (sat. aq. soln. 10 ml), fizzing was observed. The organics were washed with water (10 ml) and brine (10 ml). The organics were dried over MgSO₄, filtered and concentrated under reduced pressure to give product. The crude product was purified using MDAP. The resulting oil was triturated with ether and filtered to remove white solid. This was repeated a further 2 times to give the title compound as a white solid. (68 mg) LC/MS Rt = 2.71 min, [MH]⁺ 388.

Example 5 (E5)

1 -(PhenylmethvP-N-rd RH -phenylpropyli-1 H-benzimidazole-5-carboxamide

A solution of 3-amino-4-[(phenylmethyl)amino]-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D42) (assumed 0.828 mmol) in formic acid (2 ml) was stirred at 110⁰C under an atmosphere of argon for 1 hour. The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and partitioned between EtOAc (10-20 ml) and NaHCO₃ (10 ml, sat. aq soln). Effervescence was observed. The organics were washed with water (10 ml) and brine (10 ml). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The resulting residue was purified using Mass Directed

Automated Purification to give 1-(phenylmethyl)-N-[(1 R)-1-phenylpropyl]-1 H- benzimidazole-5-carboxamide (37 mg, 12%)

LC/MS Rt = 2.62 min, [MH]⁺ 370

In some cases trituration with iso-hexane (post MDAP) was required to obtain a white solid.

The following compounds were prepared in a similar manner to the above procedure:

Example 11 (E11)

N-[(1 R)-1 -Phenylpropyl]-1 -(2-pyridinylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride

A solution of 3-amino-N-[(1 R)-1-phenylpropyl]-4-[(2-pyridinylmethyl)amino]benzamide (preparable, for example, as in D49) (359 mg, 0.996 mmol) in formic acid (2.5 ml) was stirred at 110⁰C under an atmosphere of argon for 1 hour. The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and then partitioned between EtOAc (20 ml) and NaHCO₃ (100 ml, sat. aq soln) to give pH 8-9. The organics were washed with water (10 ml) and brine (10 ml). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The resulting residue was purified using Mass Directed Automated Purification and the resulting oil was stirred in 1 M HCI in diethylether (excess) and methanol (2 ml) for 10 min. The solution was concentrated under reduced pressure and triturated with ether to give a white solid, N-[(1 R)-1-phenylpropyl]-1-(2-pyridinylmethyl)-1 H- benzimidazole-5-carboxamide hydrochloride (226 mg, 51%) LC/MS Rt = 2.21 min, [MH]⁺ 371.

The following compounds were prepared in a similar manner to the above procedure:

Example 13 (E13)

1 -r(3-Chloro-2-pyridinyl)methvn-N-r(1 R)-1 -phenylpropyli-1 H-benzimidazole-5- carboxamide hydrochloride

A solution of 3-amino-4-{[(3-chloro-2-pyridinyl)methyl]amino}-N-[(1 R)-1- phenylpropyl]benzamide (preparable, for example, as in D55) (assumed 1.32 mmol) in formic acid (3.3 ml) was stirred at 1 10⁰C under an atmosphere of argon for 2 hours. The reaction was monitored by LC-MS.

The reaction solution was allowed to cool to room temperature and partitioned between EtOAc (50 ml) and NaHCO₃ (100 ml, sat. aq soln). Effervescence was observed. The organics were washed with water (20 ml) and brine (20 ml). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The resulting residue was purified using Mass Directed Automated Purification and the resulting oil was stirred in 1 M HCI in diethylether (excess) and methanol (2 ml) for 10 min. The solution was concentrated under reduced pressure and triturated with iso-hexane to give a white solid, 1-[(3-chloro-2-pyridinyl)methyl]-N-[(1 R)-1-phenylpropyl]- 1 H-benzimidazole-5-carboxamide hydrochloride (195 mg, 31 %) LC/MS Rt = 2.51 min, [MH⁺] 405, 407.

The following compounds were prepared using a similar procedure:

^*For these compounds care was taken during work-up - tin impurities were still present from previous reaction. The reaction solution was allowed to cool to room temperature and was diluted with EtOAc (50 ml). On addition of NaHCO₃ (100 ml, sat. aq soln), a white precipitate formed. The slurry was filtered. The organics were then washed with water (20 ml) and brine (20 ml). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The resulting residue was purified using Mass Directed Automated Purification and the resulting oil was stirred in 1 M HCI in diethylether (excess) and methanol (2 ml) for 10 min. The solution was concentrated under reduced pressure and triturated with iso-hexane to give a white solid.

Example 18 (E18)

Methyl 4-f [5-(ITd R)-1 -phenylpropynamino)carbonyl)-1 H-benzimidazol-1 - yllmethvDbenzoate

A solution of methyl 4-({[2-amino-4-({[(1 R)-1-phenylpropyl]amino}carbonyl)phenyl] amino}methyl)benzoate (preparable, for example, as in D60) (assumed 9.92 mmol) in formic acid (27 ml) was stirred at 1 10⁰C under an atmosphere of argon for 1 hour. The reaction was monitored by LC-MS. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure to give a brown oil. The resulting residue was then partitioned between EtOAc (100 ml) and NaHCO₃ (200 ml, sat. aq soln) to give pH 9. The organics were washed with water (50 ml) and brine (50 ml). The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was chromatographed [SiO₂, EtOAc:iso- hexane 75-100%] to give methyl 4-{[5-({[(1 R)-1-phenylpropyl]amino}carbonyl)-1 H- benzimidazol-1-yl]methyl}benzoate (3.47 g, 76%) LC/MS Rt = 2.69 min, [MH]⁺ 428.

Example 19 (E19)

1-r(3,4-Difluorophenyl)methvn-Λ/-r(1/?)-1-phenylpropyn-1H-benzimidazole-5- carboxamide

3-Amino-4-{[(3,4-difluorophenyl)methyl]amino}-N-[(1 R)-1-phenylpropyl]benzamide (preparable, for example, as in D61 ) (335mg, 0.84 mmol) was dissolved in 2.1 ml of formic acid and refluxed at 1 10°C for two hours. The reaction was left to stand overnight. The solution was cooled on ice and basified using NaCO₃. The organic layer was separated, dried over Magnesium Sulphate and the solvent was evaporated. The crude product was purified by MDAP. The pure fractions were combined and the solvent evaporated to give the title compound as a white solid (83mg, 0.21 mmol).

LC/MS: Rt=2.81 min [MH]⁺406

The following compounds were prepared in a similar manner to 1-[(3,4- Difluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide using the appropriate starting materials.

Example Structure Name Data

E20 1-[(3-Chloro-4- LC/MS f Iuorophenyl)methyl]-Λ/-[(1 R)-1 - Rt=2.89 phenylpropyl]-1 H- min benzimidazole-5-carboxamide [MH]⁺422

Example 23 (E23)

1-r(3,4-Dichlorophenyl)methvn-Λ/-f(2E)-1-ethyl-2-r(1Z)-1-propen-1 -vn-2,4-pentadien- 1 -yl)-2-methyl-1 H-benzimidazole-5-carboxamide

Solution of 1-[(3,4-Dichlorophenyl)methyl]-2-methyl-1 H-benzimidazole-5-carboxylic acid (preparable, for example, as in D92) (1.592 g, 4.76 mmol) in dry DMF (23 ml) was stirred at room temperature under an atmosphere of argon. HATU (1.989 g, 5.24 mmol) and DIPEA (1.075 ml, 6.19 mmol) were added to the solution. The solution was stirred for 20 minutes. After this time, α-ethyl benzylamine (0.753 ml, 5.24 mmol) was added to the solution. Stirring was continued for a further 3 hours. The solution was diluted with EtOAc and washed with water (x 3). The organics were dried over MgSO₄, filtered and concentrated under educed pressure to give an orange coloured oil. The residue was chromatographed [Siθ₂, EtOAc]. The resulting residue was then dissolved in a minimum amount of MeOH and passed through an SCX cartridge (previously wetted with MeOH). The cartridge was flushed with MeOH, and then 0.5M NH₃/MeOH. The fractions containing NH₃ contained the desired product. (1.00 g, 47% yield)

LCMS: Rt 2.83 min, [MH]⁺ 452, 455.

¹H NMR (400 MHz, CDCI₃): δ 8.20 (1 H, d); 7.44 (1 H, dd); 7.35-7.41 (5H, m); 7.24-7.26 (1 H,m), 7.20 (1 H, d); 7.14 (1 H, d); 6.83 (1 H, dd), 6.35 (1 H,d), 5.30 (2H, s), 5.10 (1 H, q), 2.58 (3H, s), 1.85-2.10 (2H, m), 1.00 (3H, t).

Example 23a (E23a) 1-r(3,4-Dichlorophenyl)methvn-Λ/-{(2E)-1-ethyl-2-r(1Z)-1-propen-1 -vn-2,4-pentadien- 1 -yl)-2-methyl-1 H-benzimidazole-5-carboxamide

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-1 /-/-benzimidazole-5-carboxylic acid (15 mg, 0.045 mmol) was dispensed in a vial. A solution of HATU (19 mg, 0.049 mmol) and DIEA (6 mg, 0.049 mmol) in DMF (1 ml) was added to the vial. Alpha-ethylbenzylamine (0.053 mmol) was added to the vial. The reaction mixture was mixed at room temperature overnight. The reaction was monitored by LCMS. The compound was purified by RPLC.

Example 24 (E24)

1-r(3,4-Dichlorophenyl)methvn-2-methyl-Λ/-r(1/?)-1 -phenylpropyn-1H- benzimidazole-5-carboxamide

i-KS^-Dichloropheny^methylJ^-methyl-I H-benzimidazole-S-carboxylic acid

(preparable, for example, as in D92) (100mg, 0.30mmol), HATU (125mg, 0.33mmol) and DIPEA (0.068ml, 0.39mmol) dissolved in DMF (2ml) were stirred at room temperature for 20 minutes. R-(+)-alpha-ethylbenzylamine (45mg, 0.33mmol) was added with 1 ml of DMF. The mixture was stirred overnight at room temperature under argon. On completion the reaction mixture was loaded onto a 5g SCX cartridge, washing with MeOH, followed by 2M NH₃/MeOH solution. The basic fractions were evaporated. The mixture was purified by high pH MDAP and fractions evaporated to give the title compound as a white solid (90mg, 0.20mmol, 66% yield).

LC/MS: Rt=2.64 min [MH]⁺ 452

The following compounds were prepared in a similar manner to 1-1(3,4- Dichlorophenyl)methyl]-2-methyl-Λ/-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide using the appropriate starting materials.

These compounds were separated by flash chromatography (after SCX instead of

MDAP) eluting 0-5% MeOH in DCM

# these compounds were treated with HCI in Et₂O to prepare the hydrochloride salts.

The following compounds were prepared in a similar manner to the procedure above in Example 23a,

Example 67 (E67)

1-r(3.4-Dichlorophenyl)methvn-2-methyl-Λ/-ri-(2-thienyl)propyn-1H-benzimidazole-

5-carboxamide

A solution of i-^S^-Dichloropheny^methy^^-methyl-IH-benzimidazole-S-carboxylic acid (preparable, for example, as in D92) (0.100 g, 0.30 mmol) in dry DMF (1.5 ml) was stirred at room temperature under an atmosphere of argon. HATU (0.125 g, 0.33 mmol) and DIPEA (0.068 ml, 0.39 mmol) were added to the solution. The solution was left to stir for 1 hour. After this time, [1-(2-thienyl)propyl]amine hydrochloride (0.059 g, 0.33 mmol) was added to the stirred solution. The solution was stirred for a further 18 hours (overnight). After this time, more DIPEA (0.156 ml, 0.9 mmol) and [1-(2- thienyl)propyl]amine (0.33 mmol) were added to the solution. The solution was then stirred for a further 24 hours. The solution was passed through a 5g SCX cartridge, washing initially with MeOH and then with 1 M NH₃ in MeOH. Fractions obtained from NH₃/Me0H washings were concentrated under reduced pressure. The residue was purified using high pH MDAP, followed by column chromatography [Siθ₂, MeOH/DCM 0-

LCMS Rt = 3.16 min, [MH]⁺ 458, 461.

The following compounds were prepared in a similar manner using the appropriate amine and carboxylic acid.

Example 72 (E72)

2-Methyl-Λ/-r(1/?)-1-phenylpropyn-1 -(2-thienylmethyl)-1H-benzimidazole-5- carboxamide

3-(Acetylamino)-Λ/-[(1 /?)-1-phenylpropyl]-4-[(2-thienylmethyl)amino]benzamide (preparable, for example, as in D77) (~0.12mmol) was dissolved in acetic acid (3ml) and heated to 100⁰C for 1 hour and 20 minutes. The reaction was evaporated to a yellow oil then water was added. The resulting beige solid was collected by filtration and washed with water. This was purified by MDAP and the clean fraction was evaporated to give the title compound as a white solid (18 mg, 0.05mmol).

LC/MS: Rt=2.29 min [MH]⁺ 390.

Example 73 (E73)

1 -r(5-Methyl-3-isoxazolyl)methvn-Λ/-r(1 /?)-1 -phenylpropyli-1 H-benzimidazole-5- carboxamide

To a solution of Λ/-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (preparable, for example, as in D130) (100mg, 0.358mmol) in DMF (4ml) cooled to 0⁰C was added sodium hydride -60%dispersion (15.75mg, 0.394mmols). This was stirred at 0⁰C for 5 minutes, then a solution of 3-(bromomethyl)-5-methylisoxazole (69.3mg, 0.394mmol) in DMF (1 ml) was added. This was stirred at room temperature for 30 minutes, then partitioned between water and ethyl acetate. The organic layer was washed with brine 3 times, dried through a hydrophobic frit and evaporated to a brown oil. This was purified by chromatography on silica eluting with 0-6% methanol in DCM over 12 column volumes. The clean fractions were evaporated to a yellow oil.

The 2 regioisomers were separated using a chiralpak AD column, eluting with heptane : ethanol (80 : 20).

The second eluting isomer was evaporated to give the title compound (54.4mg, 0.14mmol) LC/MS: Rt=2.47 [MH]⁺375.

The first eluting isomer was evaporated to give the other region-isomer compound (1-[(5- methyl-3-isoxazolyl)methyl]-Λ/-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-6-carboxamide) (48.9mg, 0.13mmol) LC/MS: Rt=2.44 [MH]⁺375

The following compound (E74) was prepared in a similar manner to 1-[(5-methyl-3- isoxazolyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide using 4- (chloromethyl)-1 ,3-thiazole. The other regio-isomer obtained in the preparation of E74 was Λ/-[(1/?)-1-phenylpropyl]-1-(1 ,3-thiazol-4-ylmethyl)-1H-benzimidazole-6-carbox- amide.

Example 75 (E75)

4-Fluoro-1-(phenylmethyl)-Λ/-r(1/?)-1-phenylpropyll-1H-benzimidazole-5- carboxamide

To a solution of the three component mixture from the previous reaction (preparable, for example, as in D131 ) (70mg, 0.259mmol) in DCM (5ml) was added [[(1 R)-I- phenylpropyl]amine(1 R)-1-phenyl-1-propanamine (35mg, 0.259mmol) and n(3- dimethylaminopropyl)n-ethyl carbodiimide HCI (72mg, 0.389mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the residue was purified using an SP4 eluting with 0-100% ethyl acetate / isohexane to give the title compound. Yield:30mg

LCMS: ret time 1.09minutes, MH= 388 [LCMS2] It will be appreciated that reference in a synthesis description to a compound of an earlier Example or Description as a starting material does not necessarily mean that the compound that was actually used in the synthesis described was actually synthesised by the method set out in the earlier Example or Description. The reference to the earlier Example or Description merely indicates that the compound can be synthesised by the method of the earlier Example or Description.

Biological Data

Compounds of the invention may be tested for in vitro biological activity in accordance with the following assay. The skilled person will be aware that the same activities of the compounds may be tested using variants of the assay described below.

PPARg Assay

Preparation of cells

Frozen PPARg Luciferase reporter CV-1 cells were produced by taking African green monkey kidney cell line CV-1 cells (ATCC CCL-70) maintained in DMEM (Invitrogen) containing 10% fetal bovine serum (FBS) and 2mM glutamine, and passaging them into Transfection/Assay media (DMEM/F-12 phenol red free medium, supplemented with 5 % Charcoal Stripped dextran-treated FBS (Hyclone), 2mM glutamine) for 3 days.

Cells were harvested using 10%TrypLE Select in HBSS (Invitrogen) and then transfected using FuGENE (Roche, Basel, Switzerland), according to the manufacturer's specifications. 3.95ml FuGENE was added directly into 97ml OptiMEM-1 (Invitrogen) in a 1 litre shake-flask. This was incubated at room temperature while the following plasmids were mixed in a 2ml sterile cryostorage tube (Nunc) containing 1 ml OptiMEM-

1 : pFA_CMV_GAL4_hPPARgammaLBD =20.3ug

UAS-tk-Luc = 403ug pBluescript Il KS+ = 890ug

pFA_CMV_GAL4_hPPARgammaLBD and UAS-tk-Luc plasmids are described in Graham R A. et al., 2006, Toxicological Sciences 92: 356-367.

The plasmid mix was then added to the OptiMEM-1/FuGENE and incubated for 30min at room temperature while the cells were detached using 10% TrypLE in HBSS (Invitrogen) and counted using a ViCeII-XR (Beckman Coulter).

The quantitiy of plasmid mix was for 5.09 x 10e8 cells, therefore the appropriate volume of cell suspension was added to the incubated plasmid/OptiMEM-1/FuGENE mix and then the mixture was diluted to 1200ml with transfection assay media before inoculating into a 10-stack cell factory (Corning) and incubating at 37°C, in an atmosphere of 5%CO₂ in air overnight (18-24hrs).

Following incubation the cells are harvested as follows: The cells were washed with 200ml HBSS (Invitrgen) then detached in 150ml 10%TrypLE in HBSS solution. The cell suspension was diluted with 150ml transfection assay media and a sample taken for counting using the ViCeII-XR. The cells were then spun 895gx10min, the supernatant was discarded and the cells were re-suspended to 24ml in Freezing medium (90% Charcoal Stripped dextran-treated FBS (Hyclone ) + 10% DMSO (Sigma). The suspension was aliquoted into 1 ml lots in 2ml cryostrage vials (NUNC) at an appropriate cell concentration for the assay, typically 2 x 10e7cells/ml and frozen in a controlled rate freezer (Planer Kryosave 750-30). The vials were then transferred to -140⁰C storage for future use.

PPARg agonist assay procedure

To assay for PPAR agonists, aliquots of frozen cells were taken and thawed. The cells were slowly aspirated from the vials with a 2ml pipette into a sterile 50ml centrifuge tube. 5ml of pre-warmed Transfection/Assay Media was added slowly and then made up to approximately 40ml. The cells were centrifuged for 5 minutes at 800rpm. The supernatant was discarded and the cells resuspended in Transfection/Assay medium to give to 3x10e5 cell/ml.

To each well of a tissue culture treated 384 well plate was added 0.1 μl test compound in neat DMSO, and 25μl/well of cell suspension. The mixture was incubated at 37°C, 5% CO₂, humidified incubator for 22 hours. Steadylite (Perkin Elmer) or Steady GIo (Promega) luciferase substrate reagents were equilibrated to room temperature. 10μl substrate reagent was added to each well, and the plates were incubated for a minimum of 10 minutes. The luminescence was then read on a Viewlux (Perkin Elmer) using optimized read times. Data analysis was carried out by standard methods within Activitybase (IDBS).

% activation was calculated for each concentration of each test compound using the equation %activation =(Test - Control 1 )/(Control 2 -Control 1 )^*100

where control 1 =DMSO no inhibition and Control 2 = A compound known to give

100% activation.

% activation was plotted against log concentration using a 4 parameter logistic fit to determine the pEC50 and for each compound.

Results The compounds of the Examples were tested in the PPARgamma assay described above. All compounds exhibited a pEC50 >5 in this assay. Preferred compounds of the invention are agonists or partial agonists as determined using the assay described above.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Claims

1. A compound of formula (I)

(I) wherein:

R¹ is selected from hydrogen, C_1-4alkyl optionally substituted with one or more halo groups; C_3-6cycloalkyl optionally substituted with one or more halo groups; and C(O)C_{1- 3}alkyl optionally substituted with one or more halo groups;

R² is selected from hydrogen and C_1-4alkyl optionally substituted with one or more halo groups;

R³ is selected from:

- phenyl optionally substituted with one or more groups selected from halo, C_1-3alkyl optionally substituted with one or more halo groups, C_1-3alkoxy optionally substituted with one or more halo groups, and C(O)O-C_1-3alkyl optionally substituted with one or more halo groups;

- a five- or six-membered heteroaryl group comprising from one to three heteroatoms independently selected from N, O and S, and optionally substituted with one or more groups selected from halo, C_1-3alkyl optionally substituted with one or more halo groups, C_1-3alkoxy optionally substituted with one or more halo groups, and C(O)O-C_1-3alkyl optionally substituted with one or more halo groups;

- C_3-8cycloalkyl optionally substituted with one or more groups selected from halo and C_{1- 3}alkyl optionally substituted with one or more halo groups; or

- a 4- to 7-membered saturated heterocyclic ring containing an oxygen atom in the ring;

R⁴ is selected from a C_1-4alkyl group optionally substituted with one or more groups selected from halo and hydroxyl;

R is selected from:

- phenyl optionally substituted with 1 , 2 or 3 groups selected from halo, C_1-4alkyl optionally substituted with one or more halo groups, and C_1-4alkoxy optionally substituted with one or more halo groups; - a five- or six-membered heteroaryl group comprising from one to three heteroatoms independently selected from N, O and S, and optionally substituted with 1 , 2 or 3 groups selected from halo, Ci_-4alkyl optionally substituted with one or more halo groups, and Ci- ₄alkoxy optionally substituted with one or more halo groups; - Ci_-4alkyl optionally substituted with one or more halo groups;

- C_3-6cycloalkyl optionally substituted with one or more halo groups;

R⁶ is selected from hydrogen and a

group optionally substituted with one or more groups selected from halo and hydroxyl;

R⁷, R⁸ and R⁹ are each independently selected from hydrogen and halo;

or a salt or solvate thereof.

2. A compound as claimed in claim 1 , wherein R⁵ is selected from:

- phenyl optionally substituted with 1 , 2 or 3 groups selected from halo,

optionally substituted with one or more halo groups, and Ci_-4alkoxy optionally substituted with one or more halo groups; and

- a five- or six-membered heteroaryl group comprising from one to three heteroatoms independently selected from N, O and S, and optionally substituted with 1 , 2 or 3 groups selected from halo,

optionally substituted with one or more halo groups, and Ci- ₄alkoxy optionally substituted with one or more halo groups.

3. A compound as claimed in claim 1 which is the compound of any one of:

1 -[(3,4-Dichlorophenyl)methyl]-Λ/-[(1 R)- 1 -phenylpropyl]-2-(trif luoromethyl)-1 H- benzimidazole-5-carboxamide (E1 )

1-[(4-Fluorophenyl)methyl]-2-methyl-Λ/-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E2) 1-[(3,5-Difluoro-2-pyridinyl)methyl]-Λ/-[(1R)-1-phenylpropyl]-2,3-dihydro-1H- benzimidazole-5-carboxamide HCI salt (E3)

1-[(2-Fluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide

(E4)

1-(Phenylmethyl)-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E5) 1-{[2-(Methyloxy)phenyl]methyl}-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E6)

1-[(2,4-Difluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide

(E7)

1-[(2-Chloro-4-fluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E8)

1-[(4-Chloro-2-fluorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E9) 1-[(2,4-Dichlorophenyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E10)

N-[(1 R)-1-Phenylpropyl]-1-(2-pyridinylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E11 ) N-[(1 R)-1-Phenylpropyl]-1-(1 ,3-thiazol-2-ylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E12)

1-[(3-Chloro-2-pyridinyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide hydrochloride (E13)

^[(S^-Dichloro^-pyridiny^methyO-N-^I R^I-phenylpropyO-I H-benzimidazole-S- carboxamide hydrochloride (E14)

1-[(5-Chloro-2-pyridinyl)methyl]-N-[(1 R)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide hydrochloride (E15)

N-[(1 R)-1-Phenylpropyl]-1-(3-pyridinylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E16) N-[(1 R)-1-Phenylpropyl]-1-(4-pyridinylmethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E17)

Methyl 4-{[5-({[(1 R)-1-phenylpropyl]amino}carbonyl)-1 H-benzimidazol-1- yl]methyl}benzoate (E18)

1-[(3,4-Difluorophenyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E19)

1-[(3-Chloro-4-fluorophenyl)methyl]-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E20)

1-[(2,6-Dichlorophenyl)methyl]-/V-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E21 ) 1-[(1 R)-1-Phenylethyl]-Λ/-[(1R)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E22)

1-[(3,4-Dichlorophenyl)methyl]-Λ/-{(2£)-1-ethyl-2-[(1Z)-1-propen-1-yl]-2,4-pentadien-1-yl}-

2-methyl-1 H-benzimidazole-5-carboxamide (E23)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E24) 1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 R)-1-phenylethyl]-1 H-benzimidazole-5- carboxamide (E25)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 S)-1-phenylethyl]-1 H-benzimidazole-5- carboxamide (E26)

1 -[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-{(1 /?)-1 -[4-(methyloxy)phenyl]ethyl}-1 H- benzimidazole-5-carboxamide (E27)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-(1-methyl-1-phenylethyl)-1 H-benzimidazole-5- carboxamide (E28)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 S)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E29) 2-Cyclopropyl-1 -[(3, 4-dichlorophenyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-1 H-benzimidazole- 5-carboxamide (E30)

2-Cyclopropyl-1 -[(3, 4-dichlorophenyl)methyl]-Λ/-[(1 S)-1-phenylpropyl]-1 H-benzimidazole- 5-carboxamide (E31 ) 1-[(3,4-Dichlorophenyl)methyl]-2-ethyl-/V-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E32)

1-[(3,4-Dichlorophenyl)methyl]-2-ethyl-/V-[(1 S)-1-phenylpropyl]-1H-benzimidazole-5- carboxamide (E33) 1-[(3,4-Dichlorophenyl)methyl]-2-(1-methylethyl)-/V-[(1R)-1-phenylpropyl]-1 H- benzimidazole-5-carboxamide (E34)

1-[(3,4-Dichlorophenyl)methyl]-2-(1-methylethyl)-/V-[(1 S)-1-phenylpropyl]-1H- benzimidazole-5-carboxamide (E35)

^-[(IRJ-I^S-ChlorophenyOpropyll-i-p^-dichlorophenyOmethyl^-methyl-I H- benzimidazole-5-carboxamide (E36)

1-[(3_!4-Dichlorophenyl)methyl]-Λ/-[(1R)-1-(3-fluorophenyl)propyl]-2-methyl-1H- benzimidazole-5-carboxamide (E37)

1-[(3_!4-Dichlorophenyl)methyl]-2-methyl-Λ/-{(1R)-1-[3-(trifluoromethyl)phenyl]propyl}-1H- benzimidazole-5-carboxamide (E38) 1-[(4-Chlorophenyl)methyl]-Λ/-[(1/?)-1-phenylethyl]-1 H-benzimidazole-5-carboxamide

(E39)

1-[(4-Chlorophenyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-1H-benzimidazole-5-carboxamide

(E40)

1-[(4-Chlorophenyl)methyl]-Λ/-[(1/?)-1-(4-fluorophenyl)ethyl]-1H-benzimidazole-5- carboxamide (E41 )

1-[(4-Chlorophenyl)methyl]-Λ/-[(1/?)-1-(4-fluorophenyl)propyl]-1H-benzimidazole-5- carboxamide (E42)

1-[(4-Chlorophenyl)methyl]-Λ/-{(1 R)-1-[3-(methyloxy)phenyl]ethyl}-1H-benzimidazole-5- carboxamide (E43) 1-[(4-Chlorophenyl)methyl]-Λ/-{(1 R)-1-[4-(methyloxy)phenyl]ethyl}-1H-benzimidazole-5- carboxamide (E44)

1-[(4-Chlorophenyl)methyl]-Λ/-[(1R)-1-(3-pyridinyl)ethyl]-1H-benzimidazole-5- carboxamide hydrochloride (E45)

1-[(4-Chlorophenyl)methyl]-Λ/-[(1R)-1-(2-pyridinyl)ethyl]-1H-benzimidazole-5- carboxamide hydrochloride (E46)

1-[(4-Chlorophenyl)methyl]-Λ/-[(1R)-1-(2-fluorophenyl)ethyl]-1H-benzimidazole-5- carboxamide (E47)

1-[(4-Chlorophenyl)methyl]-/V-[(1/?)-1-(2-fluorophenyl)propyl]-1H-benzimidazole-5- carboxamide (E48) 1-[(4-Chlorophenyl)methyl]-Λ/-[(1R)-1-(4-methyl-1 ,3-thiazol-2-yl)ethyl]-1H-benzimidazole-

5-carboxamide (E49)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[(1 S)-1-(4-methylphenyl)propyl]-1 H- benzimidazole-5-carboxamide (E50)

Λ/-[(1 S)-1-(4-Chloro-2-fluorophenyl)propyl]-1-[(3,4-dichlorophenyl)methyl]-2-methyl-1 H- benzimidazole-5-carboxamide (E51 )

1-[(3,4-Dichlorophenyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E52) 1-[(3,4-Dichlorophenyl)methyl]-Λ/-[(1/?)-1-phenylpropyl]-2-propanoyl-1/-/-benzimidazole-

5-carboxamide (E53)

1-[(2-Chlorophenyl)methyl]-2-methyl-Λ/-[(1/?)-1-phenylpropyl]-1 /-/-benzimidazole-5- carboxamide (E54) 1-[(3-Chlorophenyl)methyl]-2-methyl-Λ/-[(1 /?)-1-phenylpropyl]-1 /-/-benzimidazole-5- carboxamide (E55)

1-[(4-Chlorophenyl)methyl]-2-methyl-Λ/-[(1 /?)-1-phenylpropyl]-1 /-/-benzimidazole-5- carboxamide (E56)

1-[(3,4-Dichlorophenyl)methyl]-/V-[1-(2-furanyl)propyl]-2-methyl-1 H-benzimidazole-5- carboxamide (E57)

/V-[(1 /?)-1-Phenylpropyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1 /-/-benzimidazole-5- carboxamide (E58)

1-(Cyclohexylmethyl)-Λ/-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide (E59)

/V-[(1 /?)-1-Phenylpropyl]-1-(tetrahydro-3-furanylmethyl)-1 H-benzimidazole-5- carboxamide (E60)

1-[(3,5-Dichloro-2-pyridinyl)methyl]-/V-(1-methylethyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E61 )

1-[(3,5-Dichloro-2-pyridinyl)methyl]-/V-(1-methylpropyl)-1 H-benzimidazole-5-carboxamide hydrochloride (E62) 1 -[(3, 5-Dichloro-2-pyridinyl)methyl]-Λ/-(1-ethylpropyl)-1 H-benzimidazole- 5-carboxamide hydrochloride (E63)

1-[(3,5-Dichloro-2-pyridinyl)methyl]-/V-(1-methyl-1-phenylethyl)-1 H-benzimidazole-5- carboxamide hydrochloride (E64)

2-Methyl-1-{[3-(methyloxy)phenyl]methyl}-/V-(1-phenylpropyl)-1H-benzimidazole-5- carboxamide (E65)

2-Methyl-Λ/-{1-[4-(methyloxy)phenyl]ethyl}-1-{[3-(methyloxy)phenyl]methyl}-1H- benzimidazole- 5-carboxamide (E66)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-/V-[1-(2-thienyl)propyl]-1H-benzimidazole-5- carboxamide (E67) 1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[1-(2-thienyl)pentyl]-1 H-benzimidazole-5- carboxamide (E68)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[1-(5-methyl-2-thienyl)propyl]-1 H- benzimidazole- 5-carboxamide (E69)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[1-(4-methyl-3-thienyl)propyl]-1 H- benzimidazole- 5-carboxamide (E70)

1-[(3,4-Dichlorophenyl)methyl]-2-methyl-Λ/-[3-methyl-1-(2-thienyl)butyl]-1 H- benzimidazole- 5-carboxamide (E71 )

2-Methyl-/V-[(1 /?)-1-phenylpropyl]-1-(2-thienylmethyl)-1 H-benzimidazole-5-carboxamide

(E72) 1-[(5-Methyl-3-isoxazolyl)methyl]-Λ/-[(1 /?)-1-phenylpropyl]-1 H-benzimidazole-5- carboxamide (E73)

Λ/-[(1 /?)-1-Phenylpropyl]-1-(1 ,3-thiazol-4-ylmethyl)-1 H-benzimidazole- 5-carboxamide

(E74) 4-Fluoro-1-(phenylmethyl)-/V-[(1/?)-1-phenylpropyl]-1 H-benzimidazole-5-carboxamide

(E75) or (where appropriate) a salt, (where appropriate) a different salt, or solvate thereof.

4. A compound as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof for use as a medicament.

5. A compound as claimed in claim 4 for use in the treatment of a disease treatable by modulation of blood glucose levels.

6. A compound as claimed in claim 4 for use in the treatment of a disease or condition characterised by neuron degeneration, injury or impaired plasticity, in the treatment of mild cognitive impairment, Alzheimer's disease or another dementia, or in the treatment of schizophrenia.

7. A pharmaceutical composition which comprises the compound of formula (I) as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

8. Use of a compound as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease treatable by modulation of blood glucose levels.

9. Use of a compound as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or condition characterised by neuron degeneration, injury or impaired plasticity, or the treatment of mild cognitive impairment, Alzheimer's disease or another dementia, or for the treatment of schizophrenia..

10. A method of treatment of a disease treatable by modulation of blood glucose levels which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof.

11. A method of treatment of a disease or condition characterised by neuron degeneration, injury or impaired plasticity, or the treatment of mild cognitive impairment, Alzheimer's disease or another dementia, or the treatment of schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 3 or a pharmaceutically acceptable salt or solvate thereof.