WO2012045729A1

WO2012045729A1 - Imidazo [1, 2 -a] pyridine and pyrazolo [1, 5 -a] pyridine derivatives as trpv1 antagonists

Info

Publication number: WO2012045729A1
Application number: PCT/EP2011/067293
Authority: WO
Inventors: Keith Biggadike; Veronique Birault; Aurelie Cecile Champigny; Diane Mary Coe; Owen Rhys Hughes; Deborah Needham; Daniel Terence Tape
Original assignee: Glaxo Group Limited
Priority date: 2010-10-05
Filing date: 2011-10-04
Publication date: 2012-04-12

Abstract

A compound of formula of formula (I) wherein A represents a single bond, a CH₂ group or a CH (Me) group; X¹ represents a hydrogen atom, a fluorine atom or a methyl group; X² represents a hydrogen atom, a fluorine atom, a methyl group or a CH₂OH group; X³ represents a hydrogen atom, a fluorine atom or a CH₂OH group, and at least two of X¹, X² and X³ are hydrogen; Y represents a C atom and Z represents a N atom or Y represents an N atom and Z represents a C atom. R¹ represents a halogen atom, a C_1-4 alkyl group, a trifluoromethyl group or a trifluoromethoxy group, and R² and R³ are each independently selected from a hydrogen atom, a halogen atom, a C_1-4 alkyl group, a trifluoromethyl group or a trifluoromethoxy group. or a pharmaceutically acceptable salt or solvate thereof. salt or solvate thereof.

Description

TITLE OF THE INVENTION

IMIDAZO [1 , 2 -A] PYRIDINE AND PYRAZOLO [1 , 5 -A] PYRIDINE DERIVATIVES AS TRPV1 ANTAGONISTS

FIELD OF THE INVENTION

The present invention relates to novel compounds, being TRPV1 antagonists having pharmacological activity, to pharmaceutical compositions comprising the compounds and to the use of the compounds in medicine, especially in the treatment of rhinitis or the treatment of asthma.

BACKGROUND OF THE INVENTION

Vanilloids are a class of natural and synthetic compounds that are characterised by the presence of a vanillyl (4-hydroxy 3-methoxybenzyl) group or a functionally equivalent group. A wide variety of Vanilloid compounds of different structures are known in the art, for example those disclosed in European Patent Application Numbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB 2226313 and International Patent Application, Publication Number WO 92/09285. Particularly notable examples of vanilloid compounds or vanilloid receptor modulators are capsaicin or trans 8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepper plant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or - N- (4-hydroxy-3-methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).

Vanilloid Receptor (VR-1) has now been renamed as TRPV1 (Transient Receptor Potential Vanilloid subfamily member 1). TRPV1 is a calcium-permeable, ligand gated ion channel which is highly expressed in sensory neurones (Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD and Julius D (1997) Nature 389, 816-824) whose function is modulated by such Vanilloid compounds. TRPV1 has been studied and is extensively reviewed by Szallasi and Blumberg (The American Society for Pharmacology and Experimental Therapeutics, 1999, Vol. 51 , No. 2.). TRPV1 plays a key role in peripheral neuronal signalling where it mediates depolarising, excitatory responses to noxious stimuli such as heat, acid and capsaicin, the pungent component in chilli peppers (Szallasi et al, Nature Reviews Drug Discovery, 6, 357-372 (2007). TRPV1 acts as a polymodal receptor, responding in an integrative manner to an extensive array of activators including products of inflammation such as histamine, prostaglandins and bradykinin (which activate indirectly via protein kinase A and protein kinase C) as well as eicosanoid derivatives such as HPETEs, anandamide and environmental irritants. Upon activation, the channel pore opens and allows influx of cations which depolarises the nerve membrane and triggers neuronal axonal firing and/or local release of neurotransmitters such as Substance P and CGRP. Activation may be caused by a single trigger, such as pH, but may be caused by integration of different triggers acting in concert on the channel. The role of TRPV1 in disease has been studied extensively in pain models where a role in both thermal and post-inflammatory hyperalgesia is well established (Chizh et al, Jara-Oseguera et al, 2008). TRPV1 has also been implicated in other diseases where symptoms are potentially driven wholly or in part by neuronal hypersensitivity or hyperactivity, because of its role in sensory signalling in peripheral nerves. Such diseases include asthma, rhinitis, overactive bladder, reflux oesophagitis, irritable bowel syndrome and migraine. TRPV1 has been implicated in inflammatory responses occurring in dry eye syndrome (Pan, Wang, Yang, Zhang & Reinach (2010), TRPV1 Activation is Required for Hypertonicity Stimulated Inflammatory Cytokine Release in Human Corneal Epithelial Cells, Manuscript IOVS, 10-5801). TRPV1 is also implicated to play a role in metabolic diseases such as diabetes and obesity (Motter AL & Ahern GP (2008) FEBS Letters 582, 2257-2262; Suri & Szallasi A (2007), The emerging role of TRPV1 in diabetes and obesity, Trends in Pharm Sci; Rasavi et al (2006) Cell 127, 1123-1135.)

TRPV1 expression is not limited only to peripheral sensory nerves, but is also expressed in spinal cord and in various regions of the central nervous system. TRPV1 is also found in non- neuronal cells and tissues including various types of epithelial cell and immune cells such as mast cells and dendritic cells (Khairatkar-Joshi N & Szallasi A (2008) Trends in Molecular Medicine.)

International Patent Applications, Publication Numbers WO 02/08221 , WO 02/16317, WO 02/16318 and WO 02/16319 each disclose certain TRPV1 antagonists and their use in the treatment of diseases associated with the activity of TRPV1.

Patent Application Number WO 03/022809 discloses urea derivatives including Λ/-(2- Bromophenyl)-/V'-[((f?)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea and A/-(3-methyl-5- isoquinolinyl))-/V'-[(3f?)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea or pharmaceutically acceptable salts or solvates thereof and their use in the treatment of diseases associated with the activity of TRPV1.

Patent Application Number WO 10/026129 discloses A/-(2-Bromophenyl)-/V-[((ft)-1-(5- trifluoromethyl-2-pyridyl) pyrrolidin-3-yl)] urea for use in the treatment of rhinitis. Patent Application Number WO 10/026128 discloses A/-(3-methyl-5-isoquinolinyl))-/V-[(3ft)-1-(5- trifluoromethyl-2-pyridyl) pyrrolidin-3-yl)] urea for use in the treatment of rhinitis.

It is an object of the invention to provide further TRPV1 antagonists.

BRIEF SUMMARY OF THE INVENTION

In a first aspect of the invention there is provided a compound of formula (I)

(I)

wherein

A represents a single bond, a CH₂ group or a CH(Me) group;

X¹ represents a hydrogen atom, a fluorine atom or a methyl group;

X² represents a hydrogen atom, a fluorine atom, a methyl group or a CH₂OH group;

X³ represents a hydrogen atom, a fluorine atom or a CH₂OH group

and at least two of X¹ , X² and X³ are hydrogen

Y represents a C atom and Z represents a N atom or

Y represents a N atom and Z represents a C atom;

R¹ represents a halogen atom, a d_₄ alkyl group, a trifluoromethyl group or a trifluoromethoxy group, and R² and R³ are each independently selected from a hydrogen atom, a halogen atom, a d_₄ alkyl group, a trifluoromethyl group or a trifluoromethoxy group. or a pharmaceutically acceptable salt or solvate thereof.

Compounds of formula (I) and their pharmaceutically acceptable salts have TRPV1 antagonist activity and are believed to be of potential use for the treatment or prophylaxis of certain disorders, or treatment of the pain associated with them.

Accordingly, in another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect for use in medicine.

According to another aspect of the invention there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition for which a TRPV1 antagonist is indicated, in particular in the treatment and/or prophylaxis of rhinitis or of asthma.

The invention further provides a method for the treatment or prophylaxis of disorders in which antagonism of TRPV1 is beneficial, in a human, which comprises administering a human in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In particular, the invention provides a method for the treatment of rhinitis which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention also provides a method for the treatment of asthma which comprises administering to a human in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The invention provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions in which an antagonist of TRPV1 is indicated, particularly rhinitis or asthma.

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

pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of rhinitis.

Where used herein the term rhinitis is to be understood to include both allergic and non allergic rhinitis. Examples of non-allergic rhinitis include vasomotor rhinitis, irritant rhinitis, occupational rhinitis and NARES (non allergic rhinitis with eosinophils). In one embodiment the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in the treatment of non allergic rhinitis.

A compound of formula (I) may be prepared by methods described herein.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the invention there is provided a compound of formula (I)

wherein

A represents a single bond, a CH₂ group or a CH(Me) group;

X¹ represents a hydrogen atom, a fluorine atom or a methyl group;

X³ represents a hydrogen atom, a fluorine atom or a CH₂OH group

and at least two of X¹ , X² and X³ are hydrogen

Y represents a C atom and Z represents a N atom or

Y represents a N atom and Z represents a C atom;

R¹ represents a halogen atom, a C₁_₄ alkyl group, a trifluoromethyl group or a trifluoromethoxy group, and R² and R³ are each independently selected from a hydrogen atom, a halogen atom, a Ci_₄ alkyl group, a trifluoromethyl group or a trifluoromethoxy group. or a pharmaceutically acceptable salt or solvate thereof.

It will be appreciated that the present invention covers compounds of formula (I) as the free base and as salts thereof, for example as a pharmaceutically acceptable salt thereof. In one embodiment the invention relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof.

Because of their potential use in medicine, salts of the compounds of formula (I) are desirably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid addition salts. For a review on suitable salts see Berge et al., J. Pharm. Sci., 66: 1-19, (1977). Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The resultant salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulphuric, nitric, phosphoric, succinic, maleic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamaic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic, or hexanoic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallisation and filtration. A pharmaceutically acceptable acid addition salt of a compound of formula (I) can comprise or be for example a hydrobromide, hydrochloride, sulphate, nitrate, phosphate, succinate, maleate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p- toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulphonate, naphthalenesulfonate (e.g. 2-naphthalenesulfonate) or hexanoate salt.

Other non-pharmaceutically acceptable salts, e.g. formates, oxalates or trifluoroacetates, may be used, for example in the isolation of the compounds of formula (I), and are included within the scope of this invention.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).

It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvents with high boiling points and/or capable of forming hydrogen bonds such as water, xylene, /V-methyl pyrrolidinone, methanol and ethanol may be used to form solvates. Methods for identification of solvates include, but are not limited to, NMR and microanalysis. Solvates of the compounds of formula (I) are within the scope of the invention.

The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the solvates of the compounds of formula (I).

The compounds of formula (I) may be in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds of formula (I) may exist as polymorphs, which are included within the scope of the present invention. Polymorphic forms of compounds of formula (I) may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC),

thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (SSNMR). Certain of the compounds described herein contain one chiral centre so that optical isomers, i.e. enantiomers may be formed. Accordingly, the present invention encompasses all isomers of the compounds of formula (I) whether as individual isomers isolated such as to be substantially free of the other isomer (i.e. pure) or as mixtures (i.e. racemates and racemic mixtures). An individual isomer isolated such as to be substantially free of the other isomer (i.e. pure) may be isolated such that less than 10%, particularly less than about 1 %, for example less than about 0.1 % of the other isomer is present.

Separation of isomers may be achieved by conventional techniques known to those skilled in the art, e.g. by fractional crystallisation, chromatography or HPLC.

Certain compounds of formula (I) may exist in one of several tautomeric forms. It will be understood that the present invention encompasses all tautomers of the compounds of formula (I) whether as individual tautomers or as mixtures thereof. It will be appreciated from the foregoing that included within the scope of the invention are solvates, isomers and polymorphic forms of the compounds of formula (I) and salts thereof.

In one embodiment, A represents a single bond In one embodiment, X¹ represents a hydrogen atom In one embodiment, X² represents a hydrogen atom

In one embodiment, X³ represents a hydrogen atom or a CH₂OH group In one embodiment Y represents C and Z represents N In another embodiment, Y represents N and Z represents C

In one embodiment, R¹ represents a 1 , 1-dimethylethyl group and R² and R³ independently represent a fluorine atom or a hydrogen atom.

In one embodiment, R¹ represents a 1 , 1-dimethylethyl group at the para position relative to the ether group, R² represents a fluorine atom at a meta position relative to the ether group, and R³ represents a fluorine or a hydrogen atom at the other meta position.

In one embodiment, R¹ represents a 1 , 1-dimethylethyl group at the para position relative to the ether group and both R² and R³ each represent a fluorine atom at the meta positions relative to the ether group. In one embodiment the compound of formula (I) is selected from:

A/-(2-{[4-(1 , 1-Dimethylethyl)phenyl]oxy}ethyl)pyrazolo[1 ,5-a]pyridine-3-carboxamide; A/-(2-{[4-(1 , 1-Dimethylethyl)phenyl]oxy}ethyl)imidazo[1 ,2-a]pyridine-3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)phenyl]oxy}ethyl)-4-methylpyrazolo[1 ,5-a]pyridine-3- carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3-fluorophenyl]oxy}ethyl)pyrazolo[1 ,5-a]pyridine-3- carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)phenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo[1 ,5- a]pyridine-3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)pyrazolo[1 ,5-a]pyridine-3- carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylacetamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylpropanamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)imidazo[1 ,2-a]pyridine-3- carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo [1 ,5-a]pyridine-3-carboxamide; A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-imidazo[1 ,2-a]pyri ylacetamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-8-(hydroxymethyl)im

[1 , 2-a]pyridine-3-carboxamide; or

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-8-fluoroimidazo[1 ,2- a]pyridine-3-carboxamide; or a pharmaceutically acceptable salt thereof In one embodiment the compound of formula (I) is selected from:

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)pyrazolo[1 ,5-a]pyridine- carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo [1 , 5-a]pyridine-3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-imidazo[1 ,2-a]pyridin-3- ylacetamide; or

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-8-(hydroxymethyl)imidazo

[1 , 2-a]pyridine-3-carboxamide;

or a pharmaceutically acceptable salt thereof

In a further aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention for use in therapy

Compounds of formula (I) and their pharmaceutically acceptable salts have TRPV1 antagonist activity and are believed to be of potential use for the treatment or prophylaxis of certain disorders, or treatment of the pain associated with them, such as: respiratory diseases, asthma, cough, COPD, bronchoconstriction, rhinitis, inflammatory disorders, pain, such as acute pain, chronic pain, neuropathic pain, postoperative pain, postrheumatoid arthritic pain, osteoarthritic pain, back pain, visceral pain, cancer pain, algesia, neuralgia, dental pain, headache, migraine, neuropathies, carpal tunnel syndrome, diabetic neuropathy, HlV-related neuropathy, post-herpetic neuralgia, fibromyalgia, neuritis, sciatica, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, multiple sclerosis, oesophagitis, heart burn, Barrett's metaplasia, dysphagia, gastroeosophageal reflux disorder (GERD), stomach and duodenal ulcers, functional dyspepsia, irritable bowel syndrome, inflammatory bowel disease, colitis, Crohn's disease, pelvic hypersensitivity, pelvic pain, menstrual pain, renal colic, urinary incontinence, cystitis, burns, itch, psoriasis, pruritis andemesis, ocular disorders, dry eye disease.

Disorders of particular interest are respiratory diseases, asthma, cough, COPD,

bronchoconstriction and inflammatory disorders.

In a further aspect the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, for use in the treatment of a condition for which a TRPV1 antagonist is indicated for example, rhinitis or asthma In a further aspect the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of a condition for which a TRPV1 antagonist is indicated, for example, rhinitis or asthma. In a further aspect the invention provides a method for the treatment of rhinitis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention. In a further aspect the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the invention in the manufacture of a medicament for the treatment of a condition for which a TRPV1 antagonist is indicated. Also disclosed is a process for the preparation of compounds of formula (I) comprising coupling of a carboxylic acid of formula (II):

(N)

Wherein A, X¹ , X², X³, Y, and Z are as defined above for compounds of formula (I), with amine of formula (III)

(I II) wherein R¹ , R² and R³ are as defined above for compounds of formula (I). This coupling may be conducted, for example, using HATU (0-(7-azabenzotriazol-1-yl)-/V, N, N', Λ/'-tetramethyluronium hexafluorophosphate) in the presence of a suitable base such as triethylamine or DI PEA (N, /V-diisopropylethylamine) in a suitable solvent such as DMF. The coupling may also be conducted using alternative, conventional conditions for amide bond formation known in the art.

Compounds of formula (I I) are either commercially available or may be derived from compounds that are commercially available and/or may be prepared using methodology described in the literature.

For example compounds of formula (I I) may be prepared by hydrolysis of the corresponding esters (IV):

(IV) wherein A, X¹ , X², X³, Y and Z are as defined above for compounds of formula (I) and R is an alkyl group for example methyl or ethyl.

The hydrolysis may be conducted, for example, using aqueous sodium hydroxide in THF.

Compounds of formula (IV) wherein Y is carbon, Z is nitrogen may be prepared by a cycloaddition reaction of an N-amino pyridine of formula (V) with an alkyl propiolate.

(V)

The cycloaddition reaction may be performed, for example, by reacting a compound of formula (V) with methyl or ethyl propiolate in the presence of a suitable base such as potassium hydroxide or potassium carbonate in a suitable solvent such as DMF or DMSO. Where the substituent X¹ or X² in compound (V) are not hydrogen the cycloaddition may give a mixture of regioisomeric cycloaddition products which may be separated for example by chromatography.

Compounds of formula (V) are either commercially available or may be prepared by reaction of the corresponding pyridines (VI) with O-(mesitylsulphonyl) hydroxylamine (VII) in a suitable solvent, for example, DME. Compound of formula (VII) may be generated by reaction of 1 , 1- dimethylethyl {[(2, 4, 6-trimethylphenyl) sulfonyl] oxy} carbamate (VIII) with TFA.

The particular compound of formula (II) where A is a bond, Y is N, Z is C and X³ is a CH₂OH group may be prepared by hydrolysis of the commercially available benzyl ether (IX),

with, for example, concentrated hydrochloric acid. Compounds of formula (II) where A is CH₂ may be prepared by hydrolysis of a corresponding nitrile of formula (X),

wherein X¹ , X², X³, Y and Z are as defined above for compounds of formula (I) with, for example, aqueous sodium hydroxide at 100°C

Compounds of formula (II) where A is CH(Me) may also be prepared from a nitrile of formula (X) by alkylation using, for example, methyl iodide in THF in the presence of a suitable base such as sodium hexamethylsilazide at -70°C to give α-methyl nitriles of formula (XI)

wherein X¹ , X², X³, Y and Z are as defined above for compounds of formula (I)

Hydrolysis of compounds of formula (XI), using, for example, aqueous potassium hydroxide at 100°C may then provide compounds of formula (II) where A is CH(Me) Compounds of formula (III) may be prepared by reaction of phenols of formula (XII),

(XII) wherein R¹ , R² and R³ are as defined above for compounds of formula (I) with an ethanolamine derivative of formula (XIII),

wherein P is a suitable protecting group such as a BOC (tert-butyloxycarbonyl) group followed by removal of the protecting group. Examples of other protecting groups that may be employed in the synthetic routes described herein and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis', 4th Edition, J. Wiley and Sons, 2006, incorporated herein by reference as it relates to such procedures. This ether formation may be conducted for example using Mitsunobu conditions by reacting the phenol (XII) with the protected ethanolamine (XIII) in the presence of diisopropylazodicarboxylate and triphenylphosphine in a suitable solvent such as THF. Where the protecting group is a BOC group this can then be removed under acidic conditions, for example, using hydrochloric acid in dioxane, or TFA in dichloromethane to give compounds of formula (III).

Alternatively, compounds of formula (III) may be prepared by reaction of phenols of formula (XII) with a protected alkyl bromide of formula (XIV) followed by removal of the protecting group.

(XIV)

This alkylation reaction may be conducted by reacting the phenol (XII) with the bromide (XIV) in the presence of a base for example caesium carbonate or potassium carbonate in a suitable solvent such as DMF at a suitable temperature for example 90°C.

Compounds of formulae (VI), (VIII), (X), (XII), (XI II) and (XIV) are either commercially available, for example from Sigma-Aldrich UK, or may be prepared using methodology reported in the literature, or may be prepared by analogy with known procedures, for example those disclosed in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 6th Edition (2007), WileyBlackwell, or Comprehensive Organic Synthesis (Trost B.M. and Fleming I., (Eds.), Pergamon Press, 1991), each incorporated herein by reference as it relates to such procedures. For any of the hereinbefore described reactions or processes, conventional methods of heating and cooling may be employed, for example temperature-regulated oil-baths or temperature-regulated hot-blocks, and ice/salt baths or dry ice/acetone baths respectively. Conventional methods of isolation, for example extraction from or into aqueous or nonaqueous solvents may be used. Conventional methods of drying organic solvents, solutions, or extracts, such as shaking with magnesium sulphate, or sodium sulphate, or passing through a hydrophobic frit, may be employed. Conventional methods of purification, for example crystallisation and chromatography, for example silica chromatography or reverse- phase chromatography, may be used as required. Crystallisation may be performed using conventional solvents such as methanol, ethanol, or butanol, or aqueous mixtures thereof. It will be appreciated that specific reaction times temperatures may typically be determined by reaction-monitoring techniques, for example thin-layer chromatography and LC-MS. Where appropriate individual isomeric forms of the compounds of the invention may be prepared as individual isomers using conventional procedures such as the fractional crystallisation of diastereoisomeric derivatives or chiral high performance liquid chromatography (chiral HPLC). The absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.

Compounds of formula (I) may be in crystalline or non-crystalline form. A compound of formula (I) can form pharmaceutically acceptable salts. Suitable

pharmaceutically acceptable salts are those used conventionally in the art and include those described in Berge, J. Pharm. Sci., 1977, 66, 1-19.

Suitable pharmaceutically acceptable salts include acid addition salts. Suitable

pharmaceutically acceptable acid addition salts include salts with inorganic acids such, for example, as hydrochloric acid, hydrobromic acid, orthophosphoric acid or sulphuric acid, or with organic acids such, for example as methanesulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.

In one embodiment the compound of formula (I) is in the form of a free base.

It will be appreciated that crystalline forms may be optionally hydrated or solvated. This invention includes within the scope of compounds of formula (I) stoichiometric hydrates as well as compounds of formula (I) containing variable amounts of water. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, Solvates include

stoichiometric solvates and non-stoichiometric solvates.

For use in this invention a compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated with one or more pharmaceutically acceptable excipients to provide a pharmaceutical composition.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, inhaled, intranasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such compositions may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). In one embodiment, the invention provides a formulation for intranasal administration comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention, there is provided an aqueous pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular a composition adapted for intranasal administration.

The aqueous pharmaceutical composition of the invention may be in the form of an aqueous suspension or an aqueous solution. In one embodiment, the aqueous pharmaceutical composition of the invention is in the form of an aqueous suspension.

The aqueous component is preferably a high grade quality of water, in particular purified water.

For use in this invention a compound of formula (I) or a pharmaceutically acceptable salt thereof would typically be in a particle-size-reduced form, which may be prepared by conventional techniques, for example, microfluidisation, micronisation and milling e.g. wet bead milling. Generally, the size-reduced (e.g. micronised) compound of formula (I) or a pharmaceutically acceptable salt thereof can be defined by a D₅₀ value of about 0.1 to 10 microns such as about 0.5 to 10 microns, more particularly about 2 to 4 microns (for example as measured using laser diffraction). The proportion of a compound of formula (I) or a pharmaceutically acceptable salt thereof will depend on the precise type of composition to be prepared, but will generally be within the range of from about 0.01 to 20% (w/w), based on the total weight of the composition.

Generally, however for most types of preparations the proportion used will be within the range of from about 0.05 to 10% (w/w), such as about 0.1 to 5% (w/w).

The dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof will vary in the usual way with the seriousness of the disease to be treated and other factors such as the weight of the sufferer. As a general guide suitable unit doses may be about between 0.005 and 1 mg for example between 0.005 and 0.5mg per dose. Such unit doses may be administered once a day, or more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.

The compounds of the invention may be employed alone or in combination with other therapeutic agents. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of at least one other pharmaceutically active agent. Preferably, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one other pharmaceutically active agent. The compound(s) of the invention and the other pharmaceutically active agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of the invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Thus in a further aspect, there is provided a combination comprising a compound of the invention and at least one other pharmaceutically active agent.

Where the composition is an aqueous pharmaceutical composition, optionally a further active ingredient may be incorporated into the aqueous pharmaceutical composition, particularly one used in the treatment of rhinitis and suitable for intranasal administration such as an antihistamine or a corticosteroid.

For use in combination, suitable examples of anti-histamines include azelastine, olopatadine, bepotastine or a compound selected from: A/-[2-((2 )-2-{[4-[(4-chlorophenyl) methyl]-1-oxo-2(1 /-/)-phthalazinyl] methyl}-1 -pyrrolidinyl) ethyl]-4-(methyloxy) butanamide (as disclosed in patent application WO2008/74803);

4-[(4-chlorophenyl) methyl]-2-({(2f?)-1-[4-(4-{[3-(hexahydro-1 /-/-azepin-1-yl)propyl]oxy} phenyl) butyl]-2-pyrrolidinyl}methyl)-1 (2/-/)-phthalazinone (as disclosed in patent application WO2007/122156); or

A/-(4-{4-[(6-butyl-8-quinolinyl)oxy]-1-piperidinyl}butyl)ethanesulfonamide (as disclosed in patent application PCT/EP2008/060622, published as WO2009/021965).

For use in combination, suitable examples of corticosteroids include fluticasone propionate (which is marketed as an intranasal formulation under the trade name Flixonase®), beclomethasone dipropionate (which is marketed as an intranasal formulation under the trade name Beconase®) or fluticasone furoate (which is marketed under the trade name

Veramyst®). In one embodiment the present invention provides for an aqueous

pharmaceutical composition comprising a compound of formula (I). or a pharmaceutically acceptable salt thereof and fluticasone furoate.

When present the proportion of the further active ingredient will generally be in the range from about 0.05 to 10% (w/w), such as about 0.1 to 5% (w/w). Aqueous pharmaceutical compositions of the invention, such as intranasal compositions, may include one or more pharmaceutically acceptable excipients selected from the group consisting of suspending agents, thickening agents, preservatives, wetting agents and isotonicity adjusting agents. Accordingly in one embodiment, there is provided an aqueous pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suspending agent.

The suspending agent, if included, will typically be present in an amount of between about 0.1 and 5% (w/w), such as between about 1.5% and 2.5% (w/w), based on the total weight of the composition. Examples of suspending agents include Avicel®, carboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose and polyethylene glycols, e.g. microcrystalline cellulose or carboxy methylcellulose sodium. In one embodiment, there is provided an aqueous pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a preservative. For stability purposes, the compositions of the invention may be protected from microbial or fungal contamination and growth by inclusion of a preservative. Examples of pharmaceutically acceptable anti-microbial agents or preservatives may include quaternary ammonium compounds (e.g. benzalkonium chloride, benzethonium chloride, cetrimide and

cetylpyridinium chloride), mercurial agents (e.g. phenylmercuric nitrate, phenylmercuric acetate and thimerosal), alcoholic agents (e.g. chlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterial esters (e.g. esters of para-hydroxybenzoic acid), chelating agents such as disodium ethylenediaminetetraacetate (EDTA) and other anti-microbial agents such as chlorhexidine, chlorocresol, sorbic acid and its salts (such as potassium sorbate) and polymyxin. Examples of pharmaceutically acceptable anti-fungal agents or preservatives may include sodium benzoate. The preservative, if included, may be present in an amount of between about 0.001 and 1 % (w/w), such as about 0.015% (w/w), based on the total weight of the composition.

In another embodiment, there is provided an aqueous pharmaceutical composition which is preservative free.

In one embodiment, there is provided an aqueous pharmaceutical composition comprising .a compound of formula (I) or a pharmaceutically acceptable salt thereof and a wetting agent.

Compositions which contain a suspended medicament may include a pharmaceutically acceptable wetting agent which functions to wet the particles of medicament to facilitate dispersion thereof in the aqueous phase of the composition. Typically, the amount of wetting agent used will not cause foaming of the dispersion during mixing. Examples of wetting agents include fatty alcohols, esters and ethers, such as polyoxyethylene (20) sorbitan monooleate (Polysorbate 80). The wetting agent may be present in an amount of between about 0.001 and 1.0% (w/w), such as between about 0.001 and 0.05% (w/w), for example about 0.025% (w/w), based on the total weight of the composition.

In one embodiment, there is provided an aqueous pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and an isotonicity adjusting agent. An isotonicity adjusting agent may be included to achieve isotonicity with body fluids e.g. fluids of the nasal cavity, resulting in reduced levels of irritancy. Examples of isotonicity adjusting agents include sodium chloride, dextrose, xylitol and calcium chloride. An isotonicity adjusting agent may be included in an amount of between about 0.1 and 10% (w/w), such as about 5.0% (w/w), based on the total weight of the composition. Further, the aqueous pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be buffered by the addition of suitable buffering agents such as sodium citrate, citric acid, phosphates such as disodium phosphate (for example the dodecahydrate, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof.

Compositions of the invention e.g. those suitable for intranasal administration may also optionally contain other excipients, such as antioxidants (for example sodium metabisulphite), taste-masking agents (such as menthol) and sweetening agents (for example dextrose, glycerol, saccharin and/or sorbitol).

In one embodiment there is provided an aqueous pharmaceutical composition which comprises:

(i) an aqueous suspension of a compound of formula (I) or a pharmaceutically acceptable salt thereof;

(ii) one or more suspending agents;

(iii) one or more preservatives;

(iv) one or more wetting agents; and

(v) one or more isotonicity adjusting agents. Aqueous pharmaceutical compositions according to the invention can be prepared using standard procedures that are familiar to the person skilled in the art e.g. by admixture of the various components, suitably at ambient temperature and atmospheric pressure.

In one embodiment, the aqueous pharmaceutical compositions of the invention are suitable for intranasal administration.

Intranasal compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may permit the compound(s) to be delivered to all areas of the nasal cavities (the target tissue) and further, may permit the compound(s) to remain in contact with the target tissue for longer periods of time. A suitable dosing regimen for intranasal compositions would be for the patient to inhale slowly through the nose subsequent to the nasal cavity being cleared. During inhalation the composition would be administered to one nostril (for example, as a spray or drops) while the other is manually compressed. This procedure would then be repeated for the other nostril. Typically, one or two sprays per nostril would be administered by the above procedure up to two or three times each day, ideally once daily.

The compositions of the invention are provided in a suitable container. Aqueous

pharmaceutical compositions which are non-pressurized and adapted to be administered topically to the nasal cavity are of particular interest. Aqueous compositions may also be administered to the nose by nebulisation.

Accordingly, there is provided a container comprising an aqueous pharmaceutical

composition comprising a compound of formula (I) suitable for delivering said composition to the nasal cavities.

Typically the composition of the present invention will be packaged into a suitable container being a fluid dispenser e.g. a multi-dose container with a nasal applicator, wherein the dose is capable of being metered by volume. Such a fluid dispenser may typically have a dispensing nozzle or dispensing orifice through which a metered dose of the fluid composition is dispensed upon the application of a user- applied force to a pump mechanism of the fluid dispenser. Such fluid dispensers are generally provided with a reservoir of multiple metered doses of the fluid composition, the doses being dispensable upon sequential pump actuations. The dispensing nozzle or orifice may be configured for insertion into the nostrils of the user for spray dispensing of the fluid composition into the nasal cavity. A fluid dispenser of the aforementioned type is described and illustrated in WO05/044354 the entire content of which is hereby incorporated herein by reference. The dispenser has a housing which houses a fluid discharge device having a compression pump mounted on a container for containing a fluid composition. The housing has at least one finger-operable side lever which is movable inwardly with respect to the housing to cam the container upwardly in the housing to cause the pump to compress and pump a metered dose of the composition out of a pump stem through a nasal nozzle of the housing. In one embodiment, the fluid dispenser is of the general type illustrated in Figures 30 - 40 of WO05/044354.

Abbreviations The following list provides definitions of certain abbreviations as used herein. It will be appreciated that the list is not exhaustive, but the meaning of those abbreviations not herein below defined will be readily apparent to those skilled in the art.

DCM Dichloromethane

DMF N, /V-Dimethylformamide

DMSO Dimethylsulphoxide

DME 1 , 2-Dimethoxyethane

THF Tetrahydrofuran

EtOAc Ethyl acetate

MeOH Methanol

EtOH Ethanol

MeCN Acetonitrile

HCI Hydrochloric acid

HPLC High performance liquid chromatography

MDAP Mass Directed Autopreparative HPLC

SPE Solid phase extraction

MeOH Methanol

TFA Trifluoroacetic acid

DIPEA N, /V-Diisopropylethylamine

HATU 0-(7-Azabenzotriazol-1-yl)-/V, N, N', Λ/'-tetramethyluronium hexafluorophosphate

Experimental Details

NMR

¹ H NMR spectra were recorded in either CDCI₃ or DMSO-d₆ on either a Bruker DPX 400 or Bruker Avance DRX or Varian Unity 400 spectrometer all working at 400 MHz. The internal standard used was either tetramethylsilane or the residual protonated solvent at 7.25 ppm for CDCI₃ or 2.50 ppm for DMSO-d₆.

LCMS

System A

Column: 50mm x 2.1 mm ID, 1.7μΐ ι Acquity UPLC BEH C₁₈

Flow Rate: 1 mL/min.

Temp: 40°C

UV detection range: 210 to 350nm Mass spectrum: Recorded on a mass spectrometer using alternative-scan positive and negative mode electrospray ionisation

Solvents: A: 0.1 % v/v formic acid in water

B: 0.1 % v/v formic acid acetonitrile

Gradient: Time (min.) A% B%

0 97 3

1.5 0 100

1.9 0 100

2.0 97 3

System B Column: 30mm x 4.6mm ID, 3.5μηη Sunfire Ci₈ column

Flow Rate: 3mL/min.

Temp: 30°C

UV detection range: 210 to 350nm

Mass spectrum: Recorded on a mass spectrometer using alternative-scan positive and negative mode electrospray ionisation

Solvents: A: 0.1 % v/v solution of formic acid in water

B: 0.1 % v/v solution of formic acid in acetonitrile Gradient: Time (min.) A% B%

0 97 3

0.1 97 3

4.2 0 100

4.8 0 100

4.9 97 3

5.0 97 3

System C Column: 50mm x 4.6mm ID, 3.5μηι XBridge Ci₈ column

Flow Rate: 3mL/min. Temp: 30°C

UV detection range: 210 to 350nm

Solvents: A: 10mM ammonium bicarbonate in water adjusted to pH10 with ammonia solution

B: acetonitrile Gradient: Time (min.) A% B%

0 99 1

0.1 99 1

4.0 3 97

5.0 3 97

Mass Directed Autopreparative HPLC (MDAP)

Mass directed autopreparative HPLC was undertaken under the conditions given below. The UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.

Method A

Method B was conducted on a Sunfire Ci₈ column (typically 150mm x 30mm i.d. 5μηι packing diameter) at ambient temperature. The solvents employed were:

A = 0.1 % v/v solution of formic acid in water

B = 0.1 % v/v solution of formic acid in acetonitrile. Method B

Method A was conducted on an XBridge C₁₈ column (typically 150mm x 19mm i.d. 5μηι packing diameter) at ambient temperature. The solvents employed were:

A = 10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammonia solution.

B = acetonitrile.

Method C Method C was conducted on a Sunfire C₁₈ column (typically 150mm x 30mm i.d. 5μηι packing diameter) at ambient temperature. The solvents employed were:

A = 0.1 % v/v solution of trifluoroacetic acid in water

B = 0.1 % v/v solution of trifluoroacetic acid in acetonitrile.

The invention is illustrated by reference to, but is in no way limited by the following examples.

Intermediate 1 : Ethyl 6-methylpyrazolo[1 ,5-alpyridine-3-carboxylate

To a solution of 1-amino-3-methylpyridinium (7.998g, 33.9mmol) in DMF (65ml_) stirred at ambient temperature was added ethyl propiolate (14.98ml_, 147mmol) and anhydrous potassium carbonate (15.19g, 110mmol) in one charge. The reaction mixture was stirred at ambient temperature for 20 hours and was then evaporated in vacuo. The residue was partitioned between ethyl acetate (500ml_) and water (500ml_) and the organic layer was washed with water (500ml_), dried over magnesium sulphate for 15 min, filtered through a hydrophobic frit and evaporated in vacuo. The crude product (9.581 g) was dissolved in DCM and the desired product was separated from its 4-methyl isomer by repeated silica gel column chromatography (0-25% ethyl acetate-cyclohexane gradient over 60 min) to provide the title compound in three batches (395, 275 and 184mg).

LCMS (System A): t_RET = 0.94 min; MH⁺ 205 Intermediate 2: 6-Methylpyrazolori ,5-alpyridine-3-carboxylic acid

To a solution of ethyl 6-methylpyrazolo[1 ,5-a]pyridine-3-carboxylate (783mg, 3.83mmol) in THF (8ml_) and methanol (2ml_) stirred at ambient temperature was added 2M sodium hydroxide (10ml_, 20.00mmol) in one charge and the mixture stirred at 50°C for 65 hours. 2M HCI (10m L) was then added and the resulting precipitate was collected to give the title compound as a yellow solid (535mg).

LCMS (System A): t_RET = 0.62 min; MH⁺ 177 Intermediate 3: (2-(r4-(1 , 1-Dimethylethyl)-3-fluorophenyll oxy) ethvDamine hydrochloride

To a stirred suspension of zirconium tetrachloride (3.12g, 13.38mmol) in anhydrous DCM (40ml_) at 0°C was added anhydrous methyl-tert-butyl ether (1.6ml_, 13.43mmol) and the mixture stirred at 0°C under a nitrogen atmosphere for 30 min. A solution of 3-fluorophenol (1.2ml_, 13.38mmol) in anhydrous DCM (10ml_) was then added drop wise over 5 min and the mixture was heated at 60°C for 16 hours. Quenching with saturated aqueous sodium bicarbonate (50ml_) resulted in significant gas evolution and water (20ml_) and dichloromethane (20ml_) were then added. The organic phase was separated, dried using a hydrophobic frit and concentrated in vacuo to give a pink oil which rapidly darkened to purple/brown. This material was subjected to two sequential purifications on silica gel (100g cartridge) using a 0-25% ethyl acetate-cyclohexane gradient over 60 min to give crude 4-(1 , 1-dimethylethyl)-3-fluorophenol (198mg, purity ca 80%) as and an off-white solid. This material (190mg) was dissolved in anhydrous THF (7m L) and 1 , 1-dimethylethyl (2- hydroxyethyl)carbamate (273mg, 1.694mmol), di-isopropylazodicarboxylate (0.44ml_, 2.263mmol) and triphenylphosphine (593mg, 2.259mmol) were added and the mixture stirred at ambient temperature under an atmosphere of nitrogen for 20 hours.

The reaction was concentrated in vacuo and the residue was dissolved in DCM (10m L) and washed successively with 2M aqueous sodium hydroxide (10ml_), water (10ml_) and dried (hydrophobic frit) and concentrated in vacuo to give yellow oil. This material was dissolved in DCM and purified on a silica cartridge (20g) using a 0-25% ethyl acetate-cyclohexane gradient over 40 min to give impure 1 , 1-dimethylethyl (2-{[4-(1 , 1-dimethylethyl)-3- fluorophenyl]oxy}ethyl)carbamate as a colourless oil (95mg). This material (90mg, 0.289mmol) was dissolved in anhydrous 1 ,4-dioxane (2ml_) at ambient temperature and 4M HCI in 1 ,4 dioxane (1 ml_, 4.0mmol) was added in one charge and the mixture stirred at ambient temperature for 16 hours. Diethyl ether (10ml_) was added and the mixture stirred vigorously. The resultant precipitate was collected by filtration and dried in vacuo to give the title compound as a white solid (30 mg).

LCMS (System A): t_RET = 0.78 min; MH⁺ 212 Intermediate 4: Ethyl 6-fluoropyrazoloH ,5-alpyridine-3-carboxylate and Intermediate 5: Ethyl

4-fluoropyrazoloH ,5-alpyridine-3-carboxylate

Trifluoroacetic acid (10m L, 130mmol) was added to 1 , 1-dimethylethyl {[(2,4,6- trimethylphenyl)sulfonyl]oxy}carbamate (4.138g, 13.12mmol) under nitrogen and the mixture stirred at ambient temperature for 2 hours and then poured onto ice water (100ml_). The mixture was stirred until the ice had melted when the resulting precipitate was collected by filtration and washed with water. This solid was dissolved in 1 ,2-dimethoxyethane (DME) (20ml_) and was dried over molecular sieves for 90 min and then filtered though a Celite cartridge washing through with more DME (2 x 10ml_). To the filtrate was added 3- fluoropyridine (1.338g, 13.78mmol) and the mixture stirred at ambient temperature for 65 hours and then evaporated in vacuo. The residue was triturated with diethyl ether (20m L) and the resulting solid collected by filtration, rinsed with diethyl ether, and dried to give 1- amino-3-fluoropyridinium 2, 4, 6-trimethylbenzenesulfonate as off-white solid (1.249g) which was used directly. This material (1.244g, 3.98mmol) was stirred with ethyl propiolate (0.509ml_, 4.98mmol) in DMSO (6ml_) under nitrogen at ambient temperature. A solution of potassium hydroxide (0.145g, 2.59mmol) and potassium carbonate (0.413g, 2.99mmol) in DMSO (6m L) was added in one charge and the mixture was stirred at ambient temperature for 4 hours and then washed with water (2 x 25ml_). The combined aqueous layers were re- extracted with ethyl acetate (2 x 25ml_) and the combined organic extracts were washed with brine (25ml_) and dried over sodium sulphate, filtered and evaporated to leave brown oil (809mg). This crude material was dissolved in dichloromethane and purified on a silica gel cartridge (50g) using a 0-25% ethyl acetate-cyclohexane gradient over 60 min. The appropriate fractions were combined and evaporated in vacuo to give the 6-fluoro isomer Intermediate 4 as an orange solid (125 mg) and 4-fluoro isomer Intermediate 5 as a brown oil (79 mg).

Intermediate 4: LCMS (System B): t_RET = 2.28 min; MH⁺ 209

Intermediate 5: LCMS (System A): t_RET = 2.14 min; MH⁺ 209

Intermediate 6: 6-Fluoropyrazolori ,5-alpyridine-3-carboxylic acid

To a solution of ethyl 6-fluoropyrazolo[1 ,5-a]pyridine-3-carboxylate (125mg, 0.6mmol) in THF (2ml_) stirred at 50°C was added 2M sodium hydroxide (3ml_, 6mmol) and the mixture stirred at 50°C for 22 hours. The reaction mixture was partitioned between DCM (5m L) and water (5ml_). 2M Hydrochloric acid (5ml_) and DCM (5ml_) was added, which resulted in the formation of a precipitate and unclear separation of the organic and aqueous layers. More DCM (100ml_) and water (100ml_) was added and the mixture was filtered to give the title compound as a white solid (8 mg).

LCMS (System A): t_RET = 0.59 min; MH⁺ 181

Evaporation of the organic layer afforded a further quantity of the title compound (25mg). LCMS (System A): t_RET = 0.58 min; MH⁺ 181 Intermediate 7: 4-Fluoropyrazolori ,5-alpyridine-3-carboxylic acid

To a solution of ethyl 4-fluoropyrazolo[1 ,5-a]pyridine-3-carboxylate (79mg, 0.379mmol) in THF (2ml_) stirred at ambient temperature was added 2M sodium hydroxide (1.897ml_, 3.79mmol) in one charge. The reaction mixture was stirred at 50°C for 20 hours and then partitioned between DCM (5ml_) and water (5ml_). 2M HCI (5ml_) was added and the aqueous layer was extracted with ethyl acetate (5ml_). The organic extract was dried using a hydrophobic frit and evaporated in vacuo to give the title compound as a yellow solid (34 mg).

LCMS (System A): t_RET = 0.51 min; MH⁺ 181

Intermediate 8: Methyl 7-(hvdroxymethyl) pyrazolo[1 ,5-alpyridine-3-carboxylate

A solution of potassium hydroxylamine-O-sulfonate (prepared by neutralising hydroxylaminesulfonic acid (3.33g, 0.03mol) in water (16ml_) with a solution of potassium hydroxide (1.68g, 0.3mol) in water (8mL) at 0°C) was added drop wise to a solution of 2- pyridinylmethanol (3.27g, 0.03mol) in water (12ml_) at 60°C over a period of 10 min. The reaction mixture was heated at 70°C for 4 hours then concentrated at 50°C to give a brown solid (10g). The material was dissolved in DMF (50ml) and potassium carbonate (4.17g, 0.045mol) and methyl 2-propynoate (3.78g, 0.045mol) were added. The reaction mixture was stirred overnight at room temperature then added to water (10ml_) and extracted with ethyl acetate (3x50ml_). The organic phases were washed with brine (3x10ml_), dried (Na₂S0₄) and concentrated. The residue was purified by chromatography on silica eluting with petroleum ether / ethyl acetate (4: 1) to give the title compound as a yellow solid (0.92g).

LCMS (Sunfire C₁₈ column, 50x4.6mm, 3.5μηι, mobile phase A= 0.01 % TFA in water, B= 0.01 % TFA in acetontrile, gradient B=5% to 95% in 1.2min, flow rate 2.0 ml/min): t_RET = 1.13 min; MH⁺ 207

Intermediate 9: 7-(Hvdroxymethyl) pyrazolo[1 ,5-alpyridine-3-carboxylic acid

To a solution of methyl 7-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (5.4g, 26.2mmol) in methanol (150ml_) was added aqueous potassium hydroxide (50m L, 10%). The reaction mixture was stirred at 50°C for 14 hours. The reaction mixture was concentrated and acidified to pH 2-3 with 2M hydrochloric acid. The precipitate was collected and washed with water (20ml_) and dried in vacuo to give the title compound as a yellow solid (3.78g).

LCMS (System A): t_RET = 0.44 min; MH⁺ 193

Intermediate 10: 1 , 1-Dimethylethyl [2-({4-[(trifluoromethyl)oxylphenyl)oxy)ethyl1 carbamate

To a stirred solution of 4-(trifluoromethoxy) phenol (500mg, 2.81 mmol) in anhydrous DMF (7ml_) at room temperature was added portion wise over 5 min caesium carbonate (1 189mg, 3.65mmol). To the resulting yellow suspension was added 2-(Boc-amino)ethyl bromide (818mg, 3.65mmol) and the reaction stirred at 90°C under nitrogen for 120 min and then cooled. Methanol (10ml_) and water (10ml_) were added and the mixture left for 30 min and then evaporated in-vacuo. The yellow residue was partitioned between DCM and saturated aqueous citric acid solution. The organic layer was passed through a hydrophobic frit and evaporated in-vacuo to yield the title compound as pale yellow oil (902mg).

LCMS (System C): t_RET = 3.31 min; MH⁺ 322

Intermediate 11 : [2-({4-[(Trifluoromethyl)oxylphenyl)oxy)ethyl1 amine

To a solution of 1 , 1-dimethylethyl [2-({4-[(trifluoromethyl)oxy]phenyl}oxy)ethyl]carbamate (902mg, 2.81 mmol) in anhydrous DCM (10ml) was added, at room temperature, trifluoroacetic acid (2ml_, 26.9mmol). The reaction was stirred at room temperature under nitrogen for 1 hour and then basified to pH9 with saturated aqueous sodium carbonate solution and extracted with DCM (40ml_). The organic layer was passed through a hydrophobic frit and evaporated in-vacuo to yield yellow oil (559mg) which was applied to a methanol pre-conditioned SCX-2 cartridge (50g). The cartridge was washed with methanol and then eluted using 2M ammonia in methanol solution. The 2M ammonia in methanol fractions was combined and evaporated in-vacuo to yield the title compound as yellow oil (430mg).

LCMS (System C): t_RET = 2.44 min; MH⁺ 222

Intermediate 12: 1 , 1-Dimethylethyl(2-{[2-bromo-4-(1 , 1-dimethylethyl)phenyl1oxy)ethyl) carbamate

To a stirred suspension of 1 , 1-dimethylethyl(2-bromoethyl)carbamate (4.37g, 19.5mmol) and caesium carbonate (7.62g, 23.40mmol) in anhydrous DMF (50ml_) at ambient temperature was added 2-bromo-4-(1 , 1-dimethylethyl)phenol (4.91g, 21.45mmol) in one charge and the reaction was then heated to 90°C for 16 hours. The reaction was diluted with DCM (150ml_) and the solid removed by filtration and the filter cake washed with DCM (50ml_). The combined filtrates were dried (hydrophobic frit) and concentrated in vacuo to give brown oil (8.14g). This material was loaded onto a silica cartridge (100g) and eluted with a 0-25% ethyl acetate-cyclohexane gradient over 60 min. The pure product containing fractions were combined and concentrated in vacuo to give a white solid (2.76g) whilst mixed fractions were evaporated to give a colourless oil (4.21g). This impure material was re-chromatographed on silica (100g) using a 0-100% DCM-cyclohexane gradient over 40 min. Product containing fractions were combined and evaporated in vacuo to give a white solid (1.94g) which was combined with the earlier batch (2.76g) in ethyl acetate and evaporated to give the title compound as a white solid (4.6g).

LCMS (System A): t_RET = 1.42 min; MH⁺ 372, 374

Intermediate 13: (2-{[2-Bromo-4-(1 -dimethylethyl)phenyl1oxy)ethyl)amine hydrochloride

To a stirred solution of 1 , 1-dimethylethyl(2-{[2-bromo-4-(1 , 1- dimethylethyl)phenyl]oxy}ethyl)carbamate (4.60g, 12.36mmol) in 1 ,4-dioxane (50ml_) was added 4M hydrochloric acid in 1 ,4-dioxane (50ml_, 200mmol) in one charge. The reaction vessel was sealed and the reaction stirred at ambient temperature for 16 hours. The reaction mixture was then poured into diethyl ether (400ml_) and stirred for 5 min. The resultant white precipitate was collected by filtration and dried in vacuo to give the title compound as a white fluffy solid (3.321 g).

LCMS (System A): t_RET = 0.82 min; MH⁺ 272, 274

Intermediate 14: Ethyl 6-(hydroxymethyl) pyrazoloH ,5-alpyridine-3-carboxylate

Trifluoroacetic acid (20ml_, 260mmol) was added to solid 1 , 1-dimethylethyl{[(2,4,6- trimethylphenyl)sulfonyl]oxy}carbamate (7.851 g, 24.89mmol) and the mixture stirred at room temperature under nitrogen for 2 hours and then poured onto a water/ice mixture (200ml_) and stirred until the ice had melted. The precipitate was collected by filtration under nitrogen and dissolved in anhydrous DCM (25ml_) and dried using a hydrophobic frit. To the filtrate was added more DCM (50ml_) and 3-pyridinylmethanol (2.6ml_, 26.8mmol) and the mixture stirred under nitrogen at ambient temperature for 22 hours. The mixture was then diluted with diethyl ether (150ml_) and the solid collected to give 1-amino-3-(hydroxymethyl)pyridinium 2, 4,6-trimethylbenzenesulfonate (5.4g) which was used directly. This material was dissolved in DMSO (50ml_) and ethyl 2-propynoate (0.316ml_, 3.12mmol), potassium hydroxide (0.091 g, 1.623mmol) and potassium carbonate (0.259g, 1.873mmol) were then added and the mixture stirred under nitrogen at room temperature for 18 hours. The mixture was then diluted with ethyl acetate (200ml_) and washed with water (3 x 200ml_), 0.1 M hydrochloric acid (200ml_) and brine (200ml_), dried over magnesium sulphate, filtered and the solvent evaporated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100g) using a 0- 25% ethyl acetate-DCM gradient over 100 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (1 16mg).

LCMS (System A): t_RET = 0.67 min; MH⁺ 221

The isomeric ethyl 4-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (174mg) was also isolated from this reaction.

LCMS (System A): t_RET = 0.71 min; MH⁺ 221 Intermediate 15: (2-(r4-(1 , 1-Dimethylethyl)-2-methylphenylloxy)ethyl)amine hydrochloride

To a solution of 4-(1 , 1-dimethylethyl)-2-methylphenol (500mg, 3.04mmol) and 1 , 1- dimethylethyl (2-bromoethyl)carbamate (819mg, 3.65mmol) in DMF (10ml_) stirred under nitrogen at ambient temperature was added solid caesium carbonate (1 190mg, 3.65mmol) in one charge. The reaction mixture was stirred at 90°C for 2 hours 30 min and then allowed to stir at ambient temperature for a further 16 hours. LCMS indicated the reaction was incomplete and the mixture was heated to 90°C and stirred for 4 hours at 90°C, after which time LCMS still indicated the presence of unreacted starting material. The reaction mixture was diluted with water (100mL) and extracted with diethyl ether (100mL). The organic layer was washed with aqueous saturated sodium chloride solution (100mL) and concentrated in vacuo to give a colourless oil which solidified (0.629g). This material sample was loaded in DCM onto a silica cartridge (50g) and eluted with a 0-25% ethyl acetate-cyclohexane gradient over 40 min. The product containing fractions were combined and evaporated to give impure appropriate fractions were combined and evaporated in vacuo to give a 2: 1 mixture of 1 , 1- dimethylethyl (2-{[4-(1 , 1-dimethylethyl)-2-methylphenyl]oxy}ethyl)carbamate and unreacted 4- (1 , 1-dimethylethyl)-2-methylphenol. This material (501 mg, 1.630mmol) was dissolved in 1 , 4- dioxane (2ml_) and 4M HCI in dioxane (6.11 ml_, 24.44mmol) was added in one charge. The reaction mixture was stirred at ambient temperature for 84 hours and then evaporated. The residue was triturated with diethyl ether (20ml_) and the resulting solid was collected by filtration, washed with diethyl ether (5ml_) to give the title compound as a white solid (235mg). LCMS (System A): t_RET = 0.78 min; MH⁺ 208 Intermediate 16: (2-{[4-(1 , 1-Dimethylethyl)-2-fluorophenyl1oxy)ethyl)amine hydrochloride

To a solution of 4-(1 , 1-dimethylethyl)-2-fluorophenol (2.0g, 11.9mmol) in DMF (20ml_) at room temperature was added 1 , 1-dimethylethyl(2-bromoethyl)carbamate (5.86g, 26.18mmol) and caesium carbonate (7.73g, 23.8mmol). The reaction mixture was stirred at 95°C for 16 hours and then cooled to room temperature, quenched with ice water and extracted with ethyl acetate (2 x 100ml_). The combined organic extracts were dried over sodium sulphate and evaporated and the residue purified by silica gel chromatography eluting with ethyl acetate: hexane 4:96 to give 1 , 1-dimethylethyl (2-{[4-(1 , 1-dimethylethyl)-2-fluorophenyl] oxy} ethyl) carbamate as a white solid (2.8g). A mixture of this material (2.7g) and 4M hydrochloric acid in 1 , 4-dioxane (13ml_) was stirred at room temperature overnight. The precipitated product was collected and washed with diethyl ether (50ml) to give the title compound as a white solid (1.8g).

LCMS (System A): t_RET = 0.66 min; MH⁺ 212

Intermediate 17: 4-(1 , 1-Dimethylethyl)-3, 5-difluorophenol

Zirconium (IV) chloride (13.44g, 57.69mmol) was added to a stirred mixture of 3, 5- difluorophenol (15g, 115.38mmol) in dry te/f-butyl methyl ether (9.82g, 115.38mmol) under argon and the mixture stirred at room temperature overnight. The mixture was then quenched with saturated ammonium chloride and 2M HCI and extracted with DCM (250m L). The organic extract was washed with 2M sodium hydroxide solution and the aqueous layer then acidified with 2M HCI and extracted with DCM (2 x 250ml_) and the DCM extract dried over sodium sulphate and evaporated. The residue was purified by silica gel chromatography using DCM: hexane 2:98 as eluant to afford the title compound as a white solid (5.6g).

LCMS (System A): t_RET = 1.13 min; MH⁺ 187

Intermediate 18: 1 , 1-Dimethylethyl(2-{[4-(1 , 1-dimethylethyl)-3,5-difluorophenyl1oxy)ethyl) carbamate

To a solution of 1 , 1-dimethylethyl (2-bromoethyl)carbamate (1.8g, 8.03mmol) in DMF (25ml_) was added 4-(1 , 1-dimethylethyl)-3,5-difluorophenol (1g, 5.37mmol) and caesium carbonate (2.6g, 7.98mmol) and the reaction mixture stirred under nitrogen at 90°C for 21.5 hours. The mixture was diluted with DCM (30ml_), filtered and the filtrate evaporated in vacuo. The residue was dissolved in DCM and purified on a silica cartridge (100g) using a 0-50% ethyl acetate-DCM gradient over 40 min. The product containing fractions were combined and evaporated in vacuo to give the title compound as yellow oil (1.68g).

LCMS (System C): t_RET = 3.76 min; MH⁺ 330

Intermediate 19: (2-(r4-(1 , 1-Dimethylethyl)-3,5-difluorophenylloxy)ethyl)amine hydrochloride salt

To a stirred solution of 1 , 1-dimethylethyl(2-{[4-(1 , 1-dimethylethyl)-3,5- difluorophenyl]oxy}ethyl)carbamate (3.2g, 9.72mmol) in 1 ,4-dioxane (5ml_) was added 4M hydrochloric acid in 1 ,4 dioxane (25ml_, 100mmol) in one charge. The reaction was sealed and stirred at ambient temperature for 1 hour. To the reaction was added 1 , 4 dioxane (30ml_) in order to mobilise the solid precipitate and the reaction was stirred at ambient temperature for a further 16 hours. Diethyl ether (100ml_) was then added and the precipitate was collected by filtration and dried in vacuo to give the title compound (2.276g).

LCMS (System A): t_RET = 0.76 min; MH⁺ 230 Intermediate 20: 1 , 1-Dimethylethyl(2-{r2-bromo-4-(trifluoromethyl)phenylloxy)ethyl) carbamate

Prepared similarly to Intermediate 18 from 2-bromo-4-(trifluoromethyl)phenol and 1 , 1- dimethylethyl(2-bromoethyl)carbamate.

LCMS (System A): t_RET = 1.32 min; MH⁺ 384, 386 Intermediate 21 : (2-{[2-Bromo-4-(trifluoromethyl) phenyl1oxy)ethyl)amine hydrochloride

Prepared similarly to Intermediate 19 from 1 , 1-dimethylethyl(2-{[2-bromo-4-(trifluoromethyl) phenyl]oxy}ethyl)carbamate.

LCMS (System A): t_RET = 0.68 min; MH⁺ 284, 286

Intermediate 22: PyrazoloH ,5-alpyridin-3-ylacetic acid

A mixture of pyrazolo[1 ,5-a]pyridin-3-ylacetonitrile (10.8g, 68.7mmol) and sodium hydroxide (40g, 1 mol) in water (160mL) was heated at 100°C for 4 hours and then cooled and the pH adjusted to 5 with 6M HCI. The product was collected by filtration and dried under high vacuum to give the title compound as a yellow solid (7.2g).

LCMS (System A): t_RET =0.51 min; MH⁺ 177

Intermediate 23: 2-PyrazoloH ,5-alpyridin-3-ylpropanenitrile

A solution of pyrazolo[1 ,5-a]pyridin-3-ylacetonitrile (10.8g, 68.7mmol) in THF (200ml_) was cooled to -70°C under nitrogen. A 2M solution of sodium hexamethyldisilazide in THF (36.1 ml_, 72.2mmol) was added over 30min at -70°C and stirring continued at -70°C for a further 40min. lodomethane (10.24g, 72.2mmol) was added quickly and the mixture allowed to warm to room temperature and stirred for a further 30min and then diluted with water (300ml_) and extracted with ethyl acetate (300ml_). The organic extract was dried over anhydrous sodium sulphate and evaporated and the residue purified by silica gel chromatography using hexane: ethyl acetate (8:1) as eluant. Evaporation of the product containing fractions gave the title compound (5g).

LCMS: t_RET =1.20 min; MH⁺ 172

Intermediate 24: 2-Pyrazolori ,5-alpyridin-3-ylpropanoic acid

A mixture of 2-pyrazolo[1 ,5-a]pyridin-3-ylpropanenitrile (5g, 29.2mmol) and potassium hydroxide (36g, 643mmol) in water (100ml_) was heated at 100°C for 3 hours and then cooled and the pH adjusted to 4-5. The product was collected by filtration and dried under high vacuum to give the title compound as a white solid (5.14g).

LCMS (System A): t_RET =0.60 min; MH⁺ 191

Intermediate 25: 1 , 1-Dimethylethyl(2-r(3, 5-difluorophenyl)oxylethyl)carbamate

Prepared similarly to Intermediate 18 from 1 , 1-dimethylethyl(2-bromoethyl)carbamate and 3, 5-difluorophenol but with purification on silica using a 0-25% ethyl acetate-cyclohexane gradient.

LCMS (System A): t_RET = 1.14 min; MH⁺ 274

Intermediate 26: {2-r(3,5-Difluorophenyl)oxylethyl)amine hydrochloride

Prepared similarly to Intermediate 19 from 1 , 1-dimethylethyl{2-[(3,5-difluorophenyl)oxy] ethyl}carbamate and 4M hydrochloric acid in 1 , 4-dioxane but reacted for 15 hours.

LCMS (System A): t_RET = 0.40 min; MH⁺ 174

Intermediate 27: 1 , 1-dimethylethyl(2-r(3-fluoro-2-methylphenyl)oxylethyl)carbamate

Prepared similarly to Intermediate 29 from 1 , 1-dimethylethyl(2-bromoethyl)carbamate and 3- methyl-2-fluorophenol.

LCMS (System A): t_RET = 1.19 min; MH⁺ 270

Intermediate 28: (2-r(3-fluoro-2-methylphenyl)oxylethyl)amine hydrochloride

Prepared similarly to Intermediate 22 from 1 , 1-dimethylethyl{2-[(3-fluoro-2-methylphenyl) oxy]ethyl}carbamate and 4M hydrochloric acid in 1 , 4-dioxane but reacted for 2 hours.

LCMS (System B): t_RET = 0.93 min; MH⁺ 170 Intermediate 29: 1 , 1-Dimethylethyl(2-r(2, 3-dichlorophenyl)oxylethyl)carbamate

Prepared similarly to Intermediate 18 from 1 , 1-dimethylethyl(2-bromoethyl)carbamate and 2,3-dichlorophenol but reacting for 16 hours and with purification on silica using a 0-25% ethyl acetate-cyclohexane gradient.

LCMS (System A): t_RET = 1.23 min; MH⁺ 306, 308, 310

Intermediate 30: (2-r(2,3-dichlorophenyl)oxylethyl)amine hydrochloride

Prepared similarly to Intermediate 19 from 1 , 1-dimethylethyl{2-[(2,3- dichlorophenyl)oxy]ethyl}carbamate and 4M hydrochloric acid in 1 , 4-dioxane but reacted for 4 hours.

LCMS (System A): t_RET = 0.58 min; MH⁺ 206, 208, 210

Intermediate 31 : 8-(Hvdroxymethyl)imidazo[1 ,2-alpyridine-3-carboxylic acid

To a 500m L round bottomed flask fitted with a stirrer bar was added 8-{[(phenylmethyl)oxy] methyl}imidazo[1 ,2-a]pyridine-3-carboxylic acid (Ellanova) (8.0g, 0.028mol) followed by concentrated hydrochloric acid (180ml_). The mixture was heated with a heat gun to dissolve the starting material and then stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residual HCI azeotroped with toluene. Ether was added to the residue, the solid filtered and washed with additional ether to give the title compound as a cream solid (5.5g).

¹ H NMR (400 MHz, DMSO-d₆) δ ppm 7.49 - 7.58 (m, 2 H) 7.86 - 7.95 (m, 2 H) 8.71 (s, 2 H) 9.35 (d, J=6.5 Hz, 2 H) Example V. A/-(2-{r4-(1 , 1-Dimethylethyl)phenylloxy)ethyl)pyrazolori ,5-alpyridine-3- carboxamide

DIPEA (0.105ml_, 0.6mmol) and a solution of pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (32.4mg, 0.2mmol) in DMF (1 mL) were added to HATU (76mg, 0.2mmol) in a microwave vial (2ml_) and the resulting solution stirred for 15 min. A solution of (2-{[4-(1 , 1-dimethylethyl) phenyl] oxy} ethyl) amine (38.7mg, 0.2mmol) in DMF (0.5ml_) was added and the resulting mixture was heated to 100°C for 30 min with microwave irradiation. The mixture was cooled and passed through an aminopropyl cartridge (5g, preconditioned with methanol). The cartridge was eluted with methanol and the product containing fractions were combined and concentrated in vacuo to give an orange residue which was dissolved in a mixture of DMSO (0.5ml_) and methanol (0.5ml_) and purified by MDAP (Method B). Product containing fractions were combined and evaporated to give the title compound as a pale residue (46mg). LCMS (System C): t_RET = 3.00 min; MH⁺ 338

Example 2: /V-(2-{[2-(1-Methylethyl)phenyl1oxy)ethyl)pyrazolo[1 , 5-alpyridine-3-carboxamide

Pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (0.486g, 3mmol) was dissolved in DMF (6ml_) and added to HATU (1.141g, 3mmol) in DMF (6ml_). DIPEA (1.56ml, 9mmol) was then added and solution left to stand for 5min. An aliquot (0.45ml_) of this mixture (containing O. l mmol of pyrazolo[1 , 5-a]pyridine-3-carboxylic acid) was added to (2-{[2-(1-methylethyl) phenyl]oxy}ethyl)amine (O. l mmol) and the solution left at 22°C for 18 hours. The mixture was purified by MDAP (Method C) and the product containing fractions were evaporated using a vacuum centrifuge to give the title compound (3.69mg).

LCMS (System A): t_RET = 1.10 min; MH⁺ 324

Example 3; /V-(2-{[4-(1 , 1-Dimethylethyl)phenyl1oxy)ethyl)imidazo[1 ,2-alpyridine-3- carboxamide

Prepared similarly to Example 2 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and (2-{[4-(1 , 1- dimethylethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 0.94 min; MH⁺ 338

Example 4: A/-(2-{[4-(1 , 1-Dimethylethyl) phenyl] oxy) ethyl)-4-methylpyrazolo[1 ,5-alpyridine-3- carboxamide

Triethylamine (0.158ml_, 1.135mmol) was added to a solution of 4-methylpyrazolo[1 ,5- a]pyridine-3-carboxylic acid (100mg, 0.568mmol) and HATU (216mg, 0.568mmol) in DMF (5 ml_) under nitrogen at room temperature. The mixture was stirred for 15 min and (2-{[4-(1 , 1- dimethylethyl) phenyl] oxy} ethyl) amine (1 10mg, 0.479mmol_) was then added and the mixture stirred for a further 6 hours and then evaporated in vacuo and the residue was partitioned between water (10ml_) and ethyl acetate (10ml_). The organic layer was washed successively with 2M hydrochloric acid (10ml_) and saturated aqueous sodium bicarbonate solution (10ml_), dried using a hydrophobic frit and evaporated. The residue was dissolved in 1 : 1 MeOH: DMSO (2ml_) and purified by MDAP (Method A). Product containing fractions were dried under a stream of nitrogen to give the title compound as a white solid (3.56mg).

LCMS (System A): t_RET = 1.17 min; MH⁺ 352

Example 5: /V-(2-{r4-(1 , 1-Dimethylethyl)phenyl1oxy)ethyl)-6-methylpyrazolori ,5-a]pyridine-3- carboxamide

Prepared similarly to Example 2 from 6-methylpyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4-(1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine with purification using MDAP (Method A).

LCMS (System A): t_RET = 1.19 min; MH⁺ 352

Example 6: A/-{2-r(4-Chlorophenyl)oxylethyl) pyrazoloH ,5-alpyridine-3-carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and {2-[(4- chlorophenyl)oxy]ethyl}amine.

LCMS (System A): t_RET = 0.95 min; MH⁺ 316, 318

Example 7: /V-(2-{r3-(Trifluoromethyl)phenylloxy)ethyl)pyrazolon ,5-alpyridine-3-carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and

(2-{[3-(trifluoromethyl) phenyl] oxy} ethyl) amine hydrochloride.

LCMS (System A): t_RET = 1.00 min; MH⁺ 350

Example 8: A/-(2-{[2-(1 , 1-Dimethylethyl)phenyl1oxy)ethyl)pyrazolo[1 ,5-alpyridine-3- carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[2- (1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 1.12 min; MH⁺ 338

Example 9: A/-(2-{[4-(1-Methylethyl)phenvHoxy)ethyl)pyrazolo[1 ,5-alpyridine-3-carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4-(1- methylethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 1.06 min; MH⁺ 324

Example 10: A/-{2-r(4-Chlorophenyl)oxylethyl)imidazori ,2-alpyridine-3-carboxamide

Prepared similarly to Example 2 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and {2-[(4- chlorophenyl)oxy]ethyl}amine.

LCMS (System A): t_RET = 0.76 min; MH⁺ 316, 318

Example VV. A/-(2-{r2-(1 , 1-Dimethylethyl)phenylloxy)ethyl)imidazori ,2-alpyridine-3- carboxamide

Prepared similarly to Example 2 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and (2-{[2-(1 , 1- dimethylethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 1.77 min; MH⁺ 338

Example 12: Λ/-(2-{[4-(1 , 1-Dimethylethyl)-3-fluorophenyl1oxy)ethyl)pyrazolo[1 ,5-a]pyridine-3- carboxamide

To a stirred solution of pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (13.09mg, 0.081 mmol), (2- {[4-(1 , 1-dimethylethyl)-3-fluorophenyl]oxy}ethyl)amine hydrochloride (20mg, 0.081 mmol) and HATU (30.7mg, 0.081 mmol) in anhydrous DMF (1 ml_) was added triethylamine (0.04ml_, 0.287mmol). The reaction was allowed to stir at room temperature for 3 hours and then concentrated in vacuo. The residue was dissolved in 1 : 1 MeOH: DMSO (1 ml_) and purified by MDAP (Method A). Product containing fractions were dried under a stream of nitrogen to give the title compound (17mg).

LCMS (System A): t_RET = 1.17 min; MH⁺ 356

Example 13: A/-(2-{[4-(Trifluoromethyl)phenyl1oxy)ethyl)pyrazolo[1 ,5-alpyridine-3- carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4- (trifluoromethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 1.10 min; MH⁺ 350

Example 14: /V-{2-r(4-Fluorophenyl)oxylethyl)pyrazoloH ,5-alpyridine-3-carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and {2-[(4- fluorophenyl)oxy]ethyl}amine.

LCMS (System A): t_RET = 0.87 min; MH⁺ 300

Example 15: A/-(2-{[2-(Trifluoromethyl)phenyl1oxy)ethyl)pyrazolo[1 ,5-alpyridine-3- carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[2- (trifluoromethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 0.98 min; MH⁺ 350

Example 16: /V-(2-{r3-(1 , 1-Dimethylethyl)phenylloxy)ethyl)pyrazolon ,5-alpyridine-3- carboxamide

Prepared similarly to Example 2 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[3-

(1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 1.12 min; MH⁺ 338 Example 17: A/-(2-{r4-(Trifluoromethyl)phenylloxy)ethyl)imidazori ,2-alpyridine-3-carboxamide

Prepared similarly to Example 2 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and (2-{[4- (trifluoromethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 0.83 min; MH⁺ 350 Example 18: A/-{2-r(4-Fluorophenyl)oxylethyl)imidazori ,2-alpyridine-3-carboxamide

Prepared similarly to Example 2 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and {2-[(4- fluorophenyl)oxy]ethyl}amine.

LCMS (System A): t_RET = 0.67 min; MH⁺ 300

Example 19: /V-(2-{[2-(Trifluoromethyl)phenyl1oxy)ethyl)imidazo[1 ,2-alpyridine-3-carboxamide

Prepared similarly to Example 2 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and (2-{[2- (trifluoromethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 0.78 min; MH⁺ 350

Example 20: A/-(2-{r3-(1 ,1-Dimethylethyl)phenylloxy)ethyl)imidazori ,2-alpyridine-3- carboxamide

Prepared similarly to Example 2 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and (2-{[3-(1 ,1- dimethylethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 0.92 min; MH⁺ 338 Example 21 : A/-(2-(r4-(1 , 1-Dimethylethyl)phenyll oxy)ethyl)-6-fluoropyrazoloH ,5-alpyridine-3- carboxamide

To a stirred solution of 6-fluoropyrazolo[1 ,5-a]pyridine-3-carboxylic acid (20mg, 0.1 11 mmol), (2-{[4-(1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine (25.5mg, 0.1 11 mmol) and HATU (42.2mg, 0.111 mmol) in DMF (1 ml_) at room temperature was added triethylamine (0.039ml_, 0.278mmol) and the mixture stirred for 90 hours. LCMS indicated incomplete reaction and more (2-{[4-(1 , 1-dimethylethyl) phenyl] oxy} ethyl) amine (1.3mg, 0.006mmol), HATU (2.1 mg, 0.006mmol) and triethylamine (0.007ml_, 0.055mmol) were added and stirring continued for a further 8 hours. LCMS showed no change and the reaction was warmed to about 50°C and was allowed to stir for 20 hours but the reaction was still incomplete by LCMS. More (2-{[4- (1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine (25.5mg, 0.11 1 mmol), HATU (42.7mg, 0.1 11 mmol) and triethylamine (0.016mL, 0.11 1 mmol) were then added and the mixture stirred at 50°C for 3 hours when LCMS indicated the reaction to be complete. The mixture was partitioned between water (5mL) and ethyl acetate (5mL). The organic layer was washed successively with 2M hydrochloric acid (5mL) and saturated aqueous sodium bicarbonate solution (5mL), dried using a hydrophobic frit and evaporated in vacuo. The residue (89mg) was dissolved in 1 : 1 MeOH: DMSO (1 mL) and purified by MDAP (Method A). Product containing fractions were combined and evaporated under a stream of nitrogen to give the title compound as a yellow solid (12mg).

LCMS (System A): t_RET = 1.18 min; MH⁺ 356 Example 22: /V-(2-{r4-(1 , 1-Dimethylethyl)phenylloxy)ethyl)-4-fluoropyrazolon ,5-alpyridine-3- carboxamide

Prepared similarly to Example 21 from 4-fluoropyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4-(1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine.

LCMS (System A): t_RET = 1.14 min; MH⁺ 356

Example 23: A/-(2-{r4-(1 , 1-Dimethylethyl)phenylloxy)ethyl)-7-(hvdroxymethyl)pyrazolori ,5- al pyri d i n e- 3- carboxa m i de

Prepared similarly to Example 12 from 7-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4-(1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine but with a 20 hour reaction time. LCMS (System A): t_RET = 1.07 min; MH⁺ 368

Example 24: A/-r2-({4-r(Trifluoromethyl)oxylphenyl)oxy)ethyllimidazori ,2-alpyridine-3- carboxamide

To a solution of HATU (285mg, 0.463mmol) in anhydrous DMF (2m L) was added at room temperature imidazo[1 ,2-a]pyridine-3-carboxylic acid (50mg, 0.308mmol) followed by DIPEA (0.107ml, 0.617mmol). The reaction was stirred at room temperature for 10 min and then a solution of [2-({4-[(trifluoromethyl)oxy]phenyl}oxy)ethyl]amine (75mg, 0.339mmol) in anhydrous DMF (1 ml_) was added and the mixture stirred at room temperature for 1 hour and then partitioned between water and ethyl acetate. The organic layer was separated, washed with brine:water (1 : 1), passed through a hydrophobic frit and evaporated in-vacuo to yield a yellow oil. This material was dissolved in DMSO (2x1 mL) and purified by MDAP (Method B). Product containing fractions were combined and evaporated in-vacuo to give the title compound as a white solid (50mg).

LCMS (System C): t_RET = 2.78 min; MH⁺ 366 Example 25: A/-r2-({4-r(Trifluoromethyl)oxylphenyl)oxy)ethyllpyrazoloH ,5-alpyridine-3- carboxamide

Prepared similarly to Example 24 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and [2-({4- [(trifluoromethyl)oxy]phenyl}oxy)ethyl]amine.

LCMS (System A): t_RET = 1.04 min; MH⁺ 366 Example 26: Λ/-(2-(Γ2-ΒΙΌΓΤ)Ο-4-(1 , 1-dimethylethyl)phenylloxy)ethyl)pyrazolori ,5-alpyridine-3- carboxamide

To a stirred solution of pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (1.66g, 10.24mmol) and HATU (4.09g, 10.75mmol) in anhydrous DMF (50ml_) was added neat triethylamine (4.28mL, 30.7mmol) and the mixture stirred at ambient temperature for 30 min. A solution of (2-{[2- bromo-4-(1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine hydrochloride (3.32g, 10.75mmol) in DMF (50ml_) was then added drop wise over 10 min and the mixture stirred at ambient temperature for a further 2.5 hours. The majority of the solvent was then removed in vacuo and the residual oil was partitioned between water (250ml_) and ethyl acetate (250ml_). The organic layer was separated and washed successively with saturated aqueous sodium bicarbonate (250ml_), saturated aqueous citric acid (250ml_), water (250ml_) and brine (250ml_) and then dried (MgS0₄) and concentrated in vacuo to give a pale yellow solid. This material was triturated with diethyl ether (100ml_) and the resultant solid collected by filtration and dried in vacuo to give the title compound as a beige solid (1.997g).

LCMS (System A): t_RET = 1.20 min; MH⁺ 416, 418 Example 27: Λ/-(2-(Γ4-(1 , 1-Dimethylethyl)phenylloxy)ethyl)-6-(hvdroxymethyl)pyrazolori ,5-al pyridine-3-carboxamide

A mixture of ethyl 6-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylate (37.5mg, 0.17mmol), (2-{[4-(1 , 1-dimethylethyl)phenyl]oxy}ethyl)amine (39.1 mg, 0.17mmol) and lithium hexamethyldisilazide (1 M solution in THF, 0.341 mL, 0.341 mmol) was stirred at 80°C for 2.5 hours. LCMS indicated incomplete reaction and more lithium hexamethyldisilazide (1 M solution in THF, 0.17mL, 0.17mmol) was added and the mixture stirred at 80°C for 1 hour. Purification by MDAP (Method B) gave the title compound (11.7mg).

LCMS (System A): t_RET = 1.02 min; MH⁺ 368

Example 28: /V-(2-{r4-(1 , 1-Dimethylethyl)-2-methylphenylloxy)ethyl)pyrazolon ,5-alpyridine-3- carboxamide

Prepared similarly to Example 12 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4- (1 , 1-dimethylethyl)-2-methylphenyl]oxy}ethyl)amine hydrochloride.

LCMS (System A): t_RET = 1.21 min; MH⁺ 352

Example 29: A/-(2-{r4-(1 , 1-Dimethylethyl)-2-fluorophenylloxy)ethyl) pyrazolon ,5-al pyridine-3- carboxamide

Prepared similarly to Example 12 from pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4- (1 , 1-dimethylethyl)-2-fluorophenyl]oxy}ethyl)amine hydrochloride.

LCMS (System A): t_RET = 1.14 min; MH⁺ 356

Example 30: Λ/-(2-(Γ4-(1 , 1-Dimethylethyl)-3,5-difluorophenylloxy)ethyl)pyrazolori ,5-al pyridine-3-carboxamide

To a solution of pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (15mg, 0.093mmol) and HATU (36mg, 0.095mmol) in DMF (1 ml_) was added triethylamine (0.039ml_, 0.278mmol) and the mixture stirred at room temperature for 15 min. (2-{[4-(1 , 1-Dimethylethyl)-3,5- difluorophenyl]oxy}ethyl)amine hydrochloride (25mg, 0.094mmol) was added and the mixture stirred at room temperature for 1 hour and then concentrated in vacuo. The residue dissolved in 1 : 1 MeOH:DMSO (1 ml_) and purified by MDAP (Method A). Product containing fractions were combined and dried under a stream of nitrogen to give the title compound as a white solid (18mg).

LCMS (System A): t_RET = 1.22 min; MH⁺ 374

1 H NMR (400 MHz, METHANOL-d₄) δ ppm 1.11 (d, J=6.0 Hz, 1 H) 1.39 (t, J=2.1 Hz, 9 H)

3.74 (t, J=5.5 Hz, 2 H) 4.14 (t, J=5.6 Hz, 2 H) 6.46 - 6.56 (m, 2 H) 7.04 (d, J=1.3 Hz, 1 H) 7.42 - 7.50 (m, 1 H) 8.23 (d, J=8.8 Hz, 1 H) 8.40 (s, 1 H) 8.60 (d, J=7.0 Hz, 1 H)

Example 31 : A/-{2-[(2-Bromo-4-chlorophenyl)oxy1ethyl)pyrazolo[1 ,5-a]pyridine-3-carboxamide

To a stirred solution of pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (4.5g, 27.8mmol) and HATU (1 1.1g, 29.2mmol) in anhydrous DMF (200ml_) was added triethylamine (12ml_, 86mmol). The reaction was stirred at room temperature for 30 min when a solution of {2-[(2-bromo-4- chlorophenyl) oxy] ethyl} amine hydrochloride (8g, 27.9mmol) in DMF (150ml_) was added drop wise over 10 min and the mixture stirred at room temperature for 16 hours. The majority of the solvent was removed in vacuo and the residual oil was partitioned between water (500m L) and ethyl acetate (500m L). The organic was separated and washed successively with saturated aqueous sodium bicarbonate (500ml_), 0.1 M HCI (500ml_), water (500ml_) and brine (500ml_). The organic phase was then dried (MgS0₄) and concentrated in vacuo to give an off white solid (10.32g) which was triturated with diethyl ether (ca. 500ml_), filtered and dried in vacuo to the title compound as a white solid (8.626g).

LCMS (System A): t_RET = 1.06 min; MH⁺ 394, 396, 398

Example 32: /V-(2-{[2-Bromo-4-(trifluoromethyl)phenyl1oxy)ethyl)pyrazolo[1 ,5-alpyridine-3- carboxamide

To a solution of pyrazolo[1 ,5-a]pyridine-3-carboxylic acid (4.75g, 29.3mmol) and HATU (13.00g, 34.2mmol) in DMF (200ml_) stirred under nitrogen at ambient temperature was added triethylamine (12ml_, 86mmol) in one charge. The mixture was stirred at room temperature for 15 min and (2-{[2-bromo-4-(trifluoromethyl) phenyl] oxy} ethyl) amine hydrochloride (9.76g, 30.4mmol) was then added. The reaction was allowed to stir under nitrogen at room temperature for 65 hours and the concentrated in vacuo. The residue (46.02g) was partitioned between water (500ml_) and ethyl acetate (500ml_). The organic layer was washed successively with aqueous sodium bicarbonate solution (500ml_), 0.1 M HCI (500ml_), water (500ml_) and brine (500ml_), dried over magnesium sulphate and concentrated in vacuo. The residue (34.757g) was dissolved in ethyl acetate (500ml_), washed with water (2 x 500ml_), brine (500ml_), dried over magnesium sulphate and concentrated in vacuo. The residue (16.35g) was triturated with diethyl ether (500ml_) and the resulting solid was collected by filtration, washed with diethyl ether (150ml_), and dried to give impure product (7g). This material was dissolved in DCM and purified by chromatography on silica (330g) using a 0-50% ethyl acetate - DCM gradient over 10 column volumes. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (8.71g).

LCMS (System A): t_RET = 1.10 min; MH⁺ 428, 430

Example 33: A/-(2-{r4-(1 , 1-Dimethylethyl)-3,5-difluorophenylloxy)ethyl)-2-pyrazolori ,5-al pyridin-3-ylacetamide

Prepared similarly to Example 12 from pyrazolo[1 ,5-a]pyridin-3-ylacetic acid

and (3-{[4-(1 , 1-dimethylethyl)-3,5-difluorophenyl]oxy}propyl)amine hydrochloride but with a

19 hour reaction time.

LCMS (System B): t_RET = 3.01 min; MH⁺ 388

Example 34: A/-(2-{r4-(1 , 1-Dimethylethyl)-3,5-difluorophenylloxy)ethyl)imidazori ,2-al pyridine-

3-carboxamide

Prepared similarly to Example 12 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and (2-{[4- (1 , 1-dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)amine hydrochloride but with a 4 hour reaction time.

LCMS (System B): t_RET = 2.57 min; MH⁺ 374

Example 35: Λ/-(2-(Γ4-( 1 , 1-Dimethylethyl)-3,5-difluorophenylloxy)ethyl)-2-pyrazolori ,5-al pyridin-3-ylpropanamide

To a solution of 2-pyrazolo[1 ,5-a]pyridin-3-ylpropanoic acid (50mg, 0.263mmol) in DMF (2mL) was added HATU (100mg, 0.263mmol) and triethylamine (0.092ml_, 0.657mmol) and the mixture stirred at room temperature for 5 min. (2-{[4-(1 , 1-Dimethylethyl)-3,5- difluorophenyl]oxy}ethyl)amine hydrochloride (69.9mg, 0.263mmol) was then added and stirring continued at room temperature for 4 hours. DCM (20ml_) was added and the solution was washed with water (20m L) and dried using a hydrophobic frit, and the solvent evaporated in vacuo. The residue was dissolved in 1 : 1 MeOH: DMSO (1 ml_) and purified by MDAP (Method A). Product containing fractions were combined and evaporated under a stream of nitrogen to give the title compound (35.5mg).

LCMS (System A): t_RET = 1.22 min; MH⁺ 402

This racemic material was resolved by preparative chiral HPLC on a Chiralpak IA column (25cm x 2cm) eluted at room temperature with 20% ethanol in heptane at a flow rate of 15mL/min to provide Example 35 - enantiomer 1 (9.9mg) and Example 35 - enantiomer 2 (9.6mg).

Enantiomer 1 : Analytical chiral HPLC: 25cm Chiralpak IA column eluted with 20% ethanol in heptane, flow rate 1 ml_/min: t_RET = 7.87 min.

LCMS (System A): t_RET = 1.21 min; MH⁺ 402

Enantiomer 2: Analytical chiral HPLC: 25cm Chiralpak IA column eluted with 20% ethanol in hep tane, flow rate 1 ml_/min: t_RET = 11.02 min.

LCMS (System A): t_RET = 1.21 min; MH⁺ 402

Example 36: A/-{2-r(4-chlorophenyl)oxylethyl)-7-(hvdroxymethyl)pyrazolori ,5-alpyridine-3- carboxamide

DIPEA (0.052mL, 0.3mmole) was added to 7-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3- carboxylic acid (38mg, 0.2mmole) and HATU (76mg, 0.2mmole) in DMF (0.35mL) and the mixture shaken for 10 min. The mixture was then added to {2-[(4- chlorophenyl)oxy]ethyl}amine hydrochloride in DMF (0.3mL) and the mixture shaken for 10 min and left overnight at room temperature. The mixture was purified by MDAP (Method A). Product containing fractions were combined and evaporated under a stream of nitrogen to give the title compound (4.7mg). LCMS (System A): t_RET = 0.92 min; MH⁺ 346, 348

Example 37: A/-{2-r(4-Chlorophenyl) oxylethyl)-2-pyrazolori ,5-alpyridin-3-ylacetamide

Prepared similarly to Example 36 from pyrazolo[1 ,5-a]pyridin-3-ylacetic acid and {2-[(4- chlorophenyl)oxy]ethyl}amine hydrochloride.

LCMS (System A): t_RET = 0.92 min; MH⁺ 330, 332

Example 38: Λ/-(2-Γ(3, 5-Difluorophenyl)oxylethyl)imidazori ,2-alpyridine-3-carboxamide

Prepared similarly to Example 36 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and {2-[(3,5- difluorophenyl)oxy]ethyl}amine hydrochloride.

LCMS (System A): t_RET = 0.77 min; MH⁺ 318

Example 39: /V-{2-[(3,5-Difluorophenyl)oxy1ethyl)-7-(hvdroxymethyl)pyrazolo[1 ,5-alpyridine-3- carboxamide

Prepared similarly to Example 36 from 7-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and {2-[(3,5-difluorophenyl)oxy]ethyl}amine hydrochloride.

LCMS (System A): t_RET = 0.89 min; MH⁺ 348

Example 40: A/-{2-[(3-Fluoro-2-methylphenyl)oxy1ethyl)imidazo[1 ,2-alpyridine-3-carboxamide

Prepared similarly to Example 36 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and {2-[(3- fluoro-2-methylphenyl)oxy]ethyl}amine hydrochloride.

LCMS (System A): t_RET = 0.82 min; MH⁺ 314

Example 41 : A/-{2-[(3-Fluoro-2-methylphenyl)oxy1ethyl)pyrazolo[1 ,5-alpyridine-3-carboxamide

Prepared similarly to Example 36 from pyrazolo[1 ,5-a/pyridine-3-carboxylic acid and {2-[(3- fluoro-2-methylphenyl)oxy]ethyl}amine hydrochloride.

LCMS (System A): t_RET = 0.99 min; MH⁺ 314

Example 42: A/-{2-r(3-Fluoro-2-methylphenyl)oxylethyl)-7-(hvdroxymethyl)pyrazolori ,5-al pyridine-3-carboxamide

Prepared similarly to Example 36 from 7-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and {2-[(3-fluoro-2-methylphenyl)oxy]ethyl}amine hydrochloride.

LCMS (System A): t_RET = 0.92 min; MH⁺ 344

Example 43: /V-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl1oxy)ethyl)-7-(hvdroxymethyl) pyrazolo [1 ,5-al pyridine-3-carboxamide

Prepared similarly to Example 36 from 7-(hydroxymethyl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid and (2-{[4-(1 , 1-dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)amine hydrochloride.

LCMS (System A): t_RET = 1.16 min; MH⁺ 404 Example 44: N-(2-H4-C\ , 1-Dimethylethyl)-3.5-difluorophenyl1oxy ethyl)-2-imidazori .2-a1 pyridin-3-ylacetamide

Prepared similarly to Example 36 from imidazo[1 ,2-a]pyridin-3-ylacetic acid and (2-{[4-(1 , 1- dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)amine hydrochloride.

LCMS (System A): t_RET = 0.87 min; MH⁺ 388 Example 45: A/-{2-r(2,3-Dichlorophenyl)oxylethyl) pyrazolon ,5-alpyridine-3-carboxamide

HATU (47mg, 0.124mmol) and triethylamine (0.043mL, 0.308mmol) were added to a solution of pyrazolo [1 ,5-a] pyridine-3-carboxylic acid (20mg, 0.123mmol) in DMF (1 ml_) and the mixture stirred for 5 min. {2-[(2,3-dichlorophenyl)oxy]ethyl}amine hydrochloride (30mg, 0.124mmol) was added and the mixture stirred in a sealed vessel for 18 hours and then concentrated in vacuo. The residue was dissolved in 1 : 1 MeOH: DMSO (1 ml_) and purified by MDAP (Method A). Product containing fractions were combined and evaporated under a stream of nitrogen and the residue triturated with methanol to give the title compound as a white solid (25.8mg).

LCMS (System A): t_RET = 1.01 min; MH⁺ 350, 352, 354

Example 46: A/-{2-r(2,3-Dichlorophenyl)oxylethyl)imidazoH ,2-alpyridine-3-carboxamide

Prepared similarly to Example 45 from imidazo[1 ,2-a]pyridine-3-carboxylic acid and {2-[(2,3- dichlorophenyl)oxy]ethyl}amine hydrochloride.

LCMS (System A): t_RET = 0.82 min; MH⁺ 350, 352, 354

Example 47: A/-(2-{r4-(1 , 1-Dimethylethyl)-3,5-difluorophenylloxy)ethyl)-8-(hvdroxymethyl) imidazori ,2-alpyridine-3-carboxamide

To a solution of 8-(hydroxymethyl)imidazo[1 ,2-a]pyridine-3-carboxylic acid (20mg, 0.104mmol) in DMF (1 ml_) was added HATU (39.6mg, 0.104mmol) and triethylamine (0.036mL, 0.260mmol) and the mixture stirred for 5 min. (2-{[4-(1 , 1-Dimethylethyl)-3,5- difluorophenyl]oxy}ethyl)amine hydrochloride (27.7mg, 0.104mmole) was added and the reaction mixture stirred in a sealed vessel for 65 hours and then concentrated in vacuo. The residue was dissolved in 1 : 1 MeOH: DMSO (1 ml_) and purified by MDAP (Method A). Product containing fractions were combined and evaporated under a stream of nitrogen to give impure product which was dissolved in 1 : 1 MeOH: DMSO (1 ml_) and re-purified by a second MDAP purification (Method B). Product containing fractions were combined and evaporated under a stream of nitrogen to give the title compound (20.9mg).

LCMS (System A): t_RET = 1.01 min; MH⁺ 404

Example 48: Λ/-(2-(Γ4-( 1 , 1-Dimethylethyl)-3,5-difluorophenylloxy)ethyl)-8-fluoroimidazori ,2- al pyri d i n e- 3- carboxa m i de

To a stirred suspension of 8-fluoroimidazo[1 ,2-a]pyridine-3-carboxylic acid (160mg, 0.888mmol) in DMF (10ml_) was added triethylamine (0.31 ml_, 2.221 mmol) and HATU (340mg, 0.894mmol) and the reaction mixture stirred at room temperature for 5 min. (2-{[4- (1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)amine hydrochloride (240mg, 0.903mmol) was then added and the reaction mixture stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in dichloromethane (100ml_) and washed with water (100ml_). The organic layer was then dried using a hydrophobic frit and concentrated in vacuo and the residue was dissolved in dichloromethane and purified on a silica cartridge (100g) using a 0-25% ethyl acetate-cyclohexane gradient over 60 min followed by 0-25% methanol-dichloromethane over 20 minutes. The appropriate fractions were combined and evaporated in vacuo to give crude product as an orange oil. Recrystallisation from ethyl acetate (ca.5 ml_) gave the title compound as white crystals (70 mg). LCMS (System A): t_RET = 1.24 min; MH⁺ 392

Compounds of formulae (?), are either known in the literature or are commercially, available for example, from Sigma-Aldrich, UK, or may be prepared by analogy with known procedures, for example those disclosed in standard reference texts of synthetic methodology such as J. March, Advanced Organic Chemistry, 6th Edition (2007), WileyBlackwell, or Comprehensive Organic Synthesis (Trost B.M. and Fleming I., (Eds.), Pergamon Press, 1991), each incorporated herein by reference as it relates to such procedures. Examples of other protecting groups that may be employed in the synthetic routes described herein and the means for their removal can be found in T. W. Greene Protective Groups in Organic Synthesis', 4th Edition, J. Wiley and Sons, 2006, incorporated herein by reference as it relates to such procedures. For any of the hereinbefore described reactions or processes, conventional methods of heating and cooling may be employed, for example temperature-regulated oil-baths or temperature-regulated hot-blocks, and ice/salt baths or dry ice/acetone baths respectively. Conventional methods of isolation, for example extraction from or into aqueous or nonaqueous solvents may be used. Conventional methods of drying organic solvents, solutions, or extracts, such as shaking with magnesium sulphate, or sodium sulphate, or passing through a hydrophobic frit, may be employed. Conventional methods of purification, for example crystallisation and chromatography, for example silica chromatography or reverse- phase chromatography, may be used as required. Crystallisation may be performed using conventional solvents such as methanol, ethanol, or butanol, or aqueous mixtures thereof. It will be appreciated that specific reaction times temperatures may typically be determined by reaction-monitoring techniques, for example thin-layer chromatography and LC-MS.

Where appropriate individual isomeric forms of the compounds of the invention may be prepared as individual isomers using conventional procedures such as the fractional crystallisation of diastereoisomeric derivatives or chiral high performance liquid chromatography (chiral HPLC).

The absolute stereochemistry of compounds may be determined using conventional methods, such as X-ray crystallography.

Biological Assay Assay for the functional inhibition of TRPV1 Ion Channel by test compound using Capsaicin or Acid Stimulus challenge.

Compound Preparation

Compounds were dissolved in DMSO to 1 mM. An 11 point 4 fold serial dilution was prepared and 0.5ul dispensed into Greiner black clear bottom 384 well plates.

Preparation of recombinant HEK-293 cells expressing TRPV1 for assay

HEK-293 cells stably expressing mitochondrial targeted Aequorin were transfected with TRPV1 receptor bacmam at scale for cryopreservation in 1 ml vial aliquots. Cells can be stored at -140°C for up to 18 months.

18-20 hours before assay, cells were rapidly thawed in a water bath at 37°C and transferred to a 50ml Falcon tube. Cells were resuspended in 9mls of M1 'generic' media (DMEM/F12 with 10% dialysed FBS -Invitrogen 041-95750V) for every 1 ml cells and then centrifuged for 5min at lOOOrpm. The cell pellet was resuspended in ~10mls loading buffer (Tyrodes Base Buffer* + 0.1 % Pluronic Acid F68 solution + 0.1 % BSA) and the pH was adjusted to 7.4 for Capsaicin stimulus assay or 6.7 for Acid stimulus assay. Cell density was calculated using the Trypan Blue stain method and adjusted to 2.5 x 10e6 cells /ml using loading buffer. Coelentrazine (DiscoverX Cat. No 0-0084L - 500uM stock made in 100% ethanol) was added to a final concentration of 5uM and the falcon tube was covered in foil (to protect from light) and placed on a windmill rotator at room temperature for approximately 20 hours.

*Base Buffer = Sigma kit T2145 was dissolved in deionised water, 20ml_ HEPES solution (Sigma H0887) and 13.4ml_ of NaHC03 (Sigma S8761) and made up to 1 L.

After loading, a cell count was taken and cell density adjusted accordingly depending on assay stimulus. Capsaicin Assay for TRPV1 receptor Antagonism

For Capsaicin stimulus assay cells were diluted to 1.25x10e5 cells/ml using dilution buffer (Tyrodes Base Buffer + 0.1 % Pluronic Acid F68 solution) at pH 7.4

To the compound plates, the following additions were made:

20ul dilution buffer at pH 7.4 followed by 20ul cells were added to the test compound plate and any agonist activity measured as luminescence AUC counts. The compound/cell mix was incubated for 15 minutes and then challenged with 20ul of a 4xEC50 concentration of Capsaicin (calculated on the day of assay), with concomitant luminescence detection.

AUC data was exported from the reader and data analysis was performed using 4 parameter logistic model, with data normalised to nominal high and low controls within plate.

Each of Examples 1 to 48 had a plC50 of greater than 5.2 in this assay.

Each of Examples 1 , 3, 4, 12, 23, 30, 33, 34, 35, 43, 44, 47 and 48, namely

Λ/-(2-{[4-(1 , 1-Dimethylethyl)phenyl]oxy}ethyl)pyrazolo[1 ,5-a] pyridine-3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl) phenyl]oxy}ethyl)imidazo[1 ,2-a] pyridine-3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)phenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo[1 ,5-a] pyridine-3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo [1 ,5-a]pyridine-3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-imidazo[1 ,2-a]pyridin-3- ylacetamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-8-(hydroxymethyl)imidazo [1 , 2-a]pyridine-3-carboxamide; or

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-8-fluoroimidazo[1 ,2- a]pyridine-3-carboxamide; had a plC50 of greater than 6.8 in the Capsaicin assay.

Each of Examples 30, 33, 34, 43, 44 and 47, namely

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylacetamide; Λ/-(2-{[4-(1 -Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-pyrazolo[1 ,5-a]pyridin-3- ylpropanamide;

Λ/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo [1 , 5-a]pyridine-3-carboxamide;

Λ/-(2-{[4-(1 , 1-Dimethylethyl)-3, 5-difluorophenyl]oxy}ethyl)-2-imidazo[1 , 2-a]pyridin-3- ylacetamide; or

Λ/-(2-{[4-(1 , 1-Dimethylethyl)-3, 5-difluorophenyl]oxy}ethyl)-8-(hydroxymethyl)imidazo [1 , 2-a]pyridine-3-carboxamide; had a plC₅₀ of greater than 7.8 in the Capsaicin assay

Example 30, Λ/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)pyrazolo[1 ,5-a] pyridine-3-carboxamide, had a plC₅₀ of 7.9 in the Capsaicin assay

Acid Stimulus Assay for TRPV1 receptor Antagonism

For Acid stimulus assay, cells were diluted to 2.5x10e5 cells/ml using dilution buffer at pH 6.7. The cells and the compound plates were added to the Lumilux™ reader (Perkin Elmer) with on-board liquid handling.

To the compound plates, the following additions were made:

20ul dilution buffer at pH 6.7 followed by 20ul cells were added to the test compound plate. The compound/cell mix was incubated for 15 minutes and then challenged with 20ul of Acid Stimulus Buffer (NaCI 145mM 8.48g/L, KCL 2.5mM 0.18g/L, CaCI2 2mM 0.294g/L, MgCI2 1 mM 0.203g/L, Glucose 10mM 1.81 g/L, Sucrose 10mM 8.76g/L) + 30ul 1 M HCL for every 10ml Acid Stimulus Buffer (3mM), with concomitant luminescence detection.

AUC data was exported from the reader and data analysis was performed using 4 parameter logistic model, with data normalised to nominal high and low controls within plate

Each of Examples 1 to 47 had a plC₅₀of greater than 4.6 in this acid stimulus assay.

Example 30 had a plC₅₀ of 8.1 in this acid stimulus assay.

Preparation of an aqueous pharmaceutical composition

The following illustrates the preparation of the aqueous pharmaceutical compositions and use thereof in accordance with this invention and is to be considered illustrating and not limiting the scope of the disclosure in any way.

The aqueous pharmaceutical compositions of the invention may be prepared according to the following general method. The isotonicity adjusting agent(s) is charged into a suitable mixing vessel containing purified water and dissolved with stirring. Preservative(s) is pre-dissolved in purified water in a separate vessel, optionally with heating, for example to 50 - 60 °C depending on the preservative chosen, to aid dissolution, and then added to the isotonicity adjusting agent(s) with continuous stirring. The suspending agent(s) is then charged into the mixing vessel and dispersed throughout the solution. The resulting suspending vehicle is allowed to hydrate for an appropriate period of time to ensure cross-linkage and gelation, which may take 60 minutes or longer. In a separate mixing vessel, the wetting agent(s) is mixed with purified water which optionally may be heated, for example to about 50 - 60 °C as appropriate depending on the wetting agent(s) chosen, and stirred to dissolve. A slurry of the compound or a pharmaceutically acceptable salt thereof (alone or in combination with a further active ingredient) is then prepared by adding the resultant wetting agent(s) solution to the active compound(s), which may be particle size reduced for example micronised, and mixed prior to homogenising/refining. Additionally, in a separate mixing vessel, additional preservative(s), if needed, may be diluted with purified water and stirred to mix.

Following the dispersion and gelation the slurry of active compound(s) is added to the mixing vessel containing the suspending agent and dispersed with stirring. Following the addition of the slurry of active compound(s), any additional preservative may be added to the bulk suspension and dispersed with continuous stirring. Finally, the suspension is made to its final mass by adding water and stirred.

Claims

1. A compound of formula of formula (I)

(I)

Wherein;

A represents a single bond, a CH₂ group or a CH (Me) group;

X¹ represents a hydrogen atom, a fluorine atom or a methyl group;

X³ represents a hydrogen atom, a fluorine atom, or a CH₂OH group,

and at least two of X¹ , X² and X³ are hydrogen;

Y represents a C atom and Z represents a N atom or

Y represents an N atom and Z represents a C atom;

R¹ represents a halogen atom, a d_₄ alkyl group, a trifluoromethyl group or a trifluoromethoxy group, and R² and R³ are each independently selected from a hydrogen atom, a halogen atom, a d_₄ alkyl group, a trifluoromethyl group or a trifluoromethoxy group or a pharmaceutically acceptable salt or solvate thereof.

2 A compound according to claim 1 or a salt thereof wherein A represents a single bond.

3 A compound according to claim 1 or claim 2 or a salt thereof wherein X¹ represents a hydrogen atom.

4 A compound according to claim 1 claim 2 or claim 3 or a salt thereof wherein X²

represents a hydrogen atom.

5 A compound according to any one of claims 1 to 4 or a salt thereof wherein X³

represents a hydrogen atom or a CH₂OH group. A compound according to any one of claims 1 to 5 or a salt thereof wherein Y represents C and Z represents N.

A compound according to any one of claims 1 to 5 or a salt thereof wherein Y represents N and Z represents C.

A compound according to any one of claims 1 to 7 or a salt thereof wherein R¹ represents a 1 , 1-dimethylethyl group and R² and R³ independently represent a fluorine atom or a hydrogen atom.

A compound according to claim 8 or a salt thereof wherein R¹ represents a dimethylethyl group at the para position relative to the ether group, R² represents a fluorine atom at a meta position to the ether group, and R³ represents a fluorine or a hydrogen atom at the other meta position to the ether group. A compound according to claim 9 or a salt thereof wherein both R² and R³ each represent a fluorine atom at the meta positions to the ether group. A compound according to any one of claims 1 to 10 which is:

A/-(2-{[4-(1 , 1-Dimethylethyl)phenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo[1 ,5-a] pyridine -3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-7-(hydroxymethyl)pyrazolo [1 ,5-a]pyridine- 3-carboxamide;

A/-(2-{[4-(1 , 1-Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-2-imidazo[1 ,2-a]pyridin-3- ylacetamide; Λ/-(2-{[4-(1 -Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-8-(hydroxymethyl)imidazo [1 ,2-a]pyridine-3-carboxamide; or

Λ/-(2-{[4-(1 -Dimethylethyl)-3,5-difluorophenyl]oxy}ethyl)-8-fluoroimidazo[1 ,2- a]pyridine-3-carboxamide; or a salt thereof A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 1 1 and one or more pharmaceutically acceptable carriers or excipients. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for use in medicine. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11 for use in the treatment of a condition for which a TRPV1 antagonist is indicated. A method for the treatment or prophylaxis of disorders in which antagonism of TRPV1 is beneficial in a human comprising administering to the human in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 1 1.