WO2012095781A1

WO2012095781A1 - Indazole derivatives as sodium channel inhibitors

Info

Publication number: WO2012095781A1
Application number: PCT/IB2012/050102
Authority: WO
Inventors: Andrew Simon Bell; Marcel John De Groot; Russell Andrew Lewthwaite; Ian Roger Marsh; Nunzio Sciammetta; Robert Ian Storer; Nigel Alan Swain
Original assignee: Pfizer Ltd Great Britain
Current assignee: Pfizer Ltd Great Britain
Priority date: 2011-01-13
Filing date: 2012-01-09
Publication date: 2012-07-19
Anticipated expiration: 2013-07-13

Abstract

The invention relates to acyl sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new acyl sulfonamide Nav1.7 inhibitors of formula (I): or a pharmaceutically acceptable salt thereof, wherein U, V, W, X, Y, R° and R¹ are as defined in the description. Nav 1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.

Description

INDAZOLE DERIVATIVES AS SODIUM CHANNEL INHIBITORS

The invention relates to acyl sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.

Voltage-gated sodium channels are found in all excitable cells including myocytes of muscle and neurons of the central and peripheral nervous system. In neuronal cells, sodium channels are primarily responsible for generating the rapid upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signals in the nervous system. Proper and appropriate function of sodium channels is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (see Hubner CA, Jentsch TJ, Hum. Mol. Genet, 11 (20): 2435-45 (2002) for a general review of inherited ion channel disorders) including epilepsy (Yogeeswari et ai, Curr. Drug Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D., Proc. Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)) myotonia (Cannon, SC, Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, JN et ai, J. Neurobiol., 61 (1 ): 55-71 (2004)). There are currently at least nine known members of the family of voltage-gated sodium channel (VGSC) alpha subunits. Names for this family include SCNx, SCNAx, and Na_vx.x. The VGSC family has been phylogenetically divided into two subfamilies Na_v1.x (all but SCN6A) and Na_v2.x (SCN6A). The Navl .x subfamily can be functionally subdivided into two groups, those which are sensitive to blocking by tetrodotoxin (TTX- sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX- resistant or TTX-r).

The Na_v1 .7 (PN 1 , SCN9A) VGSC is sensitive to blocking by tetrodotoxin and is preferentially expressed in peripheral sympathetic and sensory neurons. The SCN9A gene has been cloned from a number of species, including human, rat, and rabbit and shows -90 % amino acid identity between the human and rat genes (Toledo-Aral et ai, Proc. Natl. Acad. Sci. USA, 94(4): 1527-1532 (1997)). An increasing body of evidence suggests that Na_v1 .7 may play a key role in various pain states, including acute, inflammatory and/or neuropathic pain. Deletion of the SCN9A gene in nociceptive neurons of mice led to a reduction in mechanical and thermal pain thresholds and reduction or abolition of inflammatory pain responses (Nassar et al., Proc Natl Acad Sci USA, 101 (34): 12706-1 1 (2004)). In humans, Na_v1 .7 protein has been shown to accumulate in neuromas, particularly painful neuromas (Kretschmer et al., Acta. Neurochir. (Wien), 144(8): 803-10 (2002)). Gain of function mutations of Na_v1 .7, both familial and sporadic, have been linked to primary erythermalgia, a disease characterized by burning pain and inflammation of the extremities (Yang et al., J. Med. Genet, 41 (3): 171 -4 (2004), and paroxysmal extreme pain disorder (Waxman, SG Neurology. 7;69(6): 505-7 (2007)). Congruent with this observation is the report that the non-selective sodium channel blockers lidocaine and mexiletine can provide symptomatic relief in cases of familial erythermalgia (Legroux- Crepel et al., Ann. Dermatol Venereol., 130: 429-433) and carbamazepine is effective in reducing the number and severity of attacks in PEPD (Fertleman et al, Neuron. ;52(5):767-74 (2006). Further evidence of the role of Nav1 .7 in pain is found in the phenotype of loss of function mutations of the SCN9A gene. Cox and colleagues (Nature, 444(7121 ):894-8 (2006)) were the first to report an association between loss- of-function mutations of SNC9A and congenital indifference to pain (CI P), a rare autosomal recessive disorder characterized by a complete indifference or insensitivity to painful stimuli. Subsequent studies have revealed a number of different mutations that result in a loss of function of the SCN9A gene and and the CI P phenotype (Goldberg et al, Clin Genef.;71 (4): 31 1 -9 (2007), Ahmad et al, Hum Mol Genet. 1 ; 16(17): 21 14-21 (2007)).

Nav 1 .7 inhibitors are therefore potentially useful in the treatment of a wide range of disorders, particularly pain, including: acute pain; chronic pain; neuropathic pain; inflammatory pain; visceral pain; nociceptive pain including post-surgical pain; and mixed pain types involving the viscera, gastrointestinal tract, cranial structures, musculoskeletal system, spine, urogenital system, cardiovascular system and CNS, including cancer pain, back and orofacial pain.

Certain inhibitors of voltage gated sodium channels useful in the treatment of pain are known. Thus WO-A-2005/013914 discloses heteroarylamino sulfonylphenyl derivatives, WO-A-2008/1 18758 aryl sulphonamides and WO-A-2009/012242 N-thiazolyl benzenesulfonamides.

There is, however, an ongoing need to provide new Na_v1 .7 inhibitors that are good drug candidates.

Prefererably compounds are selective Nav1 .7 channel inhibitors. In particular, they should show an affinity for the Nav1 .7 channel which is greater than their affinity for Nav1 .5 channels. Advantageously, compounds should show little or no affinity for the Nav1 .5 channel.

Selectivity for the Nav1 .7 channel over Nav1 .5 may potentially lead to one or more improvements in side-effect profile. Without wishing to be bound by theory, such selectivity is thought to reduce any cardiovascular side effects which may be associated with affinity for the Nav1 .5 channel. Preferably compounds demonstrate a selectivity of 10-fold, more preferably 30-fold, most preferably 100-fold, for the Nav 1 .7 channel when compared to their selectivity for the Nav1 .5 channel whilst maintaining good potency for the Nav1 .7 channel. Furthermore, preferred compounds should have one or more of the following properties: be well absorbed from the gastrointestinal tract; be metabolically stable; have a good metabolic profile, in particular with respect to the toxicity or allergenicity of any metabolites formed; or possess favourable pharmacokinetic properties whilst still retaining their activity profile as Nav1 .7 channel inhibitors. They should be non-toxic and demonstrate few side-effects. Ideal drug candidates should exist in a physical form that is stable, non-hygroscopic and easily formulated.

We have now found new acyl sulphonamide Nav1 .7 inhibitors. According to a first aspect of the invention there is provided a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R° and U are independently H or F;

V is (Ci-C₄)alkyl, optionally substituted by one to three F;

W is H, (C C₄)alkyl or (C₃-C₄)cycloalkyl;

X is O or NR² or is absent;

Y is H, F or CI;

R¹ and R² are independently H; (Ci-C8)alkyl optionally substituted by one to three atoms or groups selected from F, (C3-C8)cycloalkyl, (CrC6)alkyloxy, phenyl optionally substituted by F, or Het; Het; or (C3-C8)cycloalkyl; wherein (C3-C8)cycloalkyl may be optionally fused to a phenyl ring or may be substituted by one to three atoms or groups selected from F, (d-C6)alkyl optionally substituted by one to three F, or (CrC6)alkyloxy; or

where both R¹ and R² are attached to the same nitrogen atom they may, together with that nitrogen, form: (i) a saturated, monocyclic, 4 to 7-membered ring which may optionally contain oxygen as an additional ring member or may optionally be fused to a phenyl ring, which 4 to 7-membered ring may also optionally be substituted with one to three atoms or groups selected from halo, (CrC6)alkyl, (CrC₄)alkyloxy(Co-C₄)alkylene or (C3-C8)cycloalkyl; or (ii) a saturated, bridged, 7 to 9-membered ring; and

Het is 'C-linked', 3- to 8-membered, saturated, monoheterocycloalkyi comprising one or two ring members selected from -NH- or -0-.

Described below are a number of embodiments (E) of this first aspect of the invention, where for convenience E1 is identical thereto. E1 A compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

E2 A compound according to E1 wherein X is O.

E3 A compound according to E1 wherein X is NR².

E4 A compound according to E1 wherein X is absent. E5 A compound according to any one of E1 to E4 wherein U is H.

E6 A compound according to any one of E1 to E4 wherein U is F.

E7 A compound according to any one of E1 to E6 wherein V is (C-|-C₄)alkyl, such as methyl.

E8 A compound according to any one of E1 to E7 wherein W is (CrC₄)alkyl, such as methyl. E9 A compound according to any one of E1 to E8 wherein Y is CI.

E10 A compound according to any one of E1 to E9 wherein R° is H.

E1 1 A compound according to any one of E1 to E10 wherein R¹ is (CrC8)alkyl optionally substituted by a (C3-C8)cycloalkyl group; or (C3-C8)cycloalkyl; wherein

(C3-C8)cycloalkyl is optionally substituted by a (d-C6)alkyl group.

E12 A compound according to any one of E1 to E1 1 wherein R¹ is (CrC₄)alkyl optionally substituted by a (C3-C5)cycloalkyl group; or (C3-C5)cycloalkyl; wherein (C3-C5)cycloalkyl is optionally substituted by a (CrC3)alkyl group.

E13 A compound according to E1 selected from the compounds of Examples 1 to E14 A compound according to E1 selected from:

1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide;

1 -(5-Chloro-6-isobutoxypyridin-3-yl)-6-fluoro-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide; and

1 -(5-chloro-6-((1 -methylcyclopropyl)methoxy)pyridin-3-yl)-6-fluoro-3-methyl-N-

(methylsulfonyl)-1 H-indazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof. Alkyl, alkylene, and alkoxy groups, containing the requisite number of carbon atoms, can be unbranched or branched. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1 , 1 -ethylene, 1 , 2-ethylene, 1 , 1 -propylene, 1 , 2-propylene, 1 , 3-propylene and 2, 2-propylene.

Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Halo means fluoro, chloro, bromo or iodo.

The term 'C-linked' used in the definition means that Het is joined via a ring carbon atom. Hereinafter, all references to compounds of the invention include compounds of formula (I) or pharmaceutically acceptable salts, solvates, or multi-component complexes thereof, or pharmaceutically acceptable solvates or multi-component complexes of pharmaceutically acceptable salts of compounds of formula (I), as discussed in more detail below.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. The skilled person will appreciate that the aforementioned salts include ones wherein the counterion is optically active, for example d-lactate or l-lysine, or racemic, for example dl-tartrate or dl-arginine.

For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) using the desired acid or base; or

(iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. The compounds of formula (I) or pharmaceutically acceptable salts thereof may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂0, de- acetone and de-DMSO. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995), incorporated herein by reference. Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.

When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').

Also included within the scope of the invention are multi-component complexes (other than salts and solvates) of compounds of formula (I) or pharmaceutically acceptable salts thereof wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, XT., 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), incorporated herein by reference.

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -COO^"Na⁺, -COO^"K⁺, or -SCVNa*) or non-ionic (such as -N^"N⁺(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshorne and A. Stuart, 4^th Edition (Edward Arnold, 1970), incorporated herein by reference.

The compounds of the invention may be administered as prodrugs. Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).

Prodrugs can, for example, be produced by replacing appropriate functionalities present in a compound of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985).

Examples of prodrugs include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert-butyl) phosphate prodrugs. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.

Also included within the scope of the invention are metabolites of compounds of formula (I), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include, where the compound of formula (I) contains a phenyl (Ph) moiety, a phenol derivative thereof (-Ph > -PhOH);

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Included within the scope of the invention are all stereoisomers of the compounds of the invention and mixtures of one or more thereof.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1 - phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994. The scope of the invention includes all crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomerates) thereof. Stereoisomeric conglomerates may also be separated by the conventional techniques described herein just above. The scope of the invention includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0, ¹⁷0 and ¹⁸0, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵0 and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Also within the scope of the invention are intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I). The invention includes all polymorphs of the aforementioned species and crystal habits thereof.

When preparing a compound of formula (I) in accordance with the invention, a person skilled in the art may routinely select the form of intermediate which provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

The compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either. The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed for the preparation of compounds of formula (I). It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

In addition, the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or desirable to protect amino groups. The protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fourth edition, (John Wiley and Sons, 2006), in particular chapter 7 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.

In the following general methods U, V, W, X, Y, R°, R¹, R² and Het are as previously defined for a compound of formula (I) unless otherwise stated. R is alkyl, such as (Cr Ce)alkyl (e.g. methyl) or, when part of the moiety -B(OR)₂, may also be H or each R, together with the O atom to which it is attached, forms a cyclic boronic ester moiety, such as

Compounds of formula (I) wherein X is O and Y is H or CI may be prepared as shown in Scheme 1 by reaction of an alcohol of formula (V) with a compound of formula (IV). The reaction is typically carried out in an inert solvent (e.g. dimethyl sulphoxide, tetrahydrofuran), in the presence of a base (e.g. sodium hydride, lithium bis(trimethylsilyl)amide, cesium carbonate) and at an elevated temperature for a period of 2 to 72 hours. In a preferred procedure, a mixture of the alcohol of formula (V), compound of formula (IV) and cesium carbonate in dimethyl sulphoxide is heated at 100°C for 16 to 72 hours. Scheme 1

R¹OH (V)

Compounds of formula (IV) may be prepared by reaction of a compound of formula (II) with a boronic acid or ester of formula (III). The reaction is typically carried out in an inert solvent or mixture of inert solvents (e.g. one or more of dimethyl sulphoxide, dimethylformamide, dichloromethane), in the presence of a base (e.g. pyridine, triethylamine), a copper salt (e.g. copper acetate), at a temperature ranging from ambient to elevated and in the presence of air or oxygen. Optionally, molecular sieves may be added to the reaction mixture and the reaction may be accelerated by heating using microwave irradiation. In a preferred procedure, the reaction is carried out open to air in dimethylformamide in the presence of copper acetate and pyridine at 50-80°C.

Alternatively, compounds of formula (I) may be prepared as shown in Scheme 2 by reaction of a compound of formula (II) with a boronic acid or ester of formula (VI) in an analogous manner to that described for the preparation of compounds of formula (IV) in Scheme 1. Scheme 2

Alternatively, compounds of formula (I) wherein X is NR² and Y is H or CI may be prepared as shown in Scheme 3 by reaction of an amine of formula (VIII) and a compound of formula (VII).

Scheme 3

Typically the reaction is carried out neat or in a suitable inert solvent or mixture of solvents (e.g. dimethyl sulphoxide and/or dimethylformamide) in the presence of a base (e.g. potassium carbonate, cesium carbonate, sodium hydride) and at elevated temperature. Optionally, a metal salt (e.g. copper (I) iodide) may be added and/or heating of the reaction mixture may be carried out using microwave irradiation. In a preferred procedure, the reaction is carried out in dimethyl sulphoxide at 150°C.

Compounds of formula (VII) may be prepared in an analagous manner to that used for the preparation of compounds of formula (IV). Alternatively, compounds of formula (I) may be prepared as shown in Scheme 4 by reaction of a compound of formula (IX) with a compound of formula (X). Scheme 4

Typically the reaction is carried out in a suitable inert solvent or mixture of inert solvents (e.g. dichloromethane and/or dimethylformamide), in the presence of a base (e.g. 4-dimethylaminopyridine, Ν,Ν-diisopropylethylamine) and a suitable coupling agent (e.g 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,

0- (7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and at ambient temperature. In a preferred procedure, the reaction is carried out in dichloromethane at room temperature in the presence of 4-dimethylaminopyridine and

1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

Compounds of formula (IX) may be prepared by saponification of a solution of a compound of formula (XI) in a suitable solvent or mixture of solvents (e.g. one or more of tetrahydrofuran, methanol, water, dichloromethane), in the presence of a base (e.g. sodium hydroxide, lithium hydroxide, potassium hydroxide) and at ambient to elevated temperature. In a preferred procedure, the reaction is carried out in a mixture of tetrahydrofuran, methanol and water in the presence of lithium hydroxide at reflux.

Compounds of formula (XI) may be prepared by reaction of a compound of formula (XII) with a boronic acid or ester of formula (VI) in an analogous manner to that described for the preparation of compounds of formula (IV) in Scheme 1. Alternatively, compounds of formula (I) wherein X is O and Y is H or CI may be prepared as shown in Scheme 5 by reaction of a compound of formula (IX) with a compound of formula (X) in an analogous manner to that described for the preparation of compounds of formula (I) in Scheme 4. Compounds of formula (IX) may be prepared from compounds of formula (XI) in a manner also analogous to that described in Scheme 4.

Compounds of formula (XI) may be prepared by reaction of an alcohol of formula (V) with a compound of formula (XIII). The reaction is typically carried out in an inert solvent (e.g. dimethyl sulphoxide, tetrahydrofuran, dimethylformamide), in the presence of a base (e.g. sodium hydride, lithium bis(trimethylsilyl)amide, cesium carbonate, potassium carbonate) and at an elevated temperature for a period of 2 to 72 hours. In a preferred procedure, a mixture of the alcohol of formula (V), compound of formula (XIII) and potassium carbonate in dimethylformamide is heated at 70°C for 16 hours.

Compounds of formula (XIII) may be prepared by reaction of a compound of formula (XII) with a boronic acid or ester of formula (III) in an analogous manner to that described for the preparation of compounds of formula (IV) in Scheme 1. Scheme 5

Alternatively, compounds of formula (I) and Y is H or CI may be prepared as shown in Scheme 6 by reaction of a compound of formula (IX) with a compound of formula (X) in an analogous manner to that described for the preparation of compounds of formula (I) in Scheme 4. Scheme 6

Compounds of formula (IX) may also be prepared in an analogous manner to that described for the preparation of such compounds in Scheme 4.

Compounds of formula (XI) may be prepared by reaction of a compound of formula (XII) with an aryl halide of formula (XIV) in the presence of a copper salt, ligand and base, in a solvent. In a preferred procedure, the reaction is carried out in the presence of copper (I) iodide, potassium phosphate tribasic and trans-N,N'-dimethylcyclohexane-1 ,2- diamine, in toluene, at 1 10°C.

Alternatively, compounds of formula (I) may be prepared as shown in Scheme 7 by reaction of a compound of formula (XVI) with a boronic acid or ester of formula (XVII), wherein W is as defined in formula (I) or is an unsaturated or partially unsaturated precursor thereof. Scheme 7

The reaction is typically carried out in a suitable inert solvent or mixture of inert solvents (e.g. one or more of dimethoxyethane, toluene, dimethylformamide, dioxane, water), in the presence of a base (e.g. cesium carbonate, potassium carbonate, potassium phoshate) and a catalyst (e.g. palladium tetrakis, [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane), and at a temperature ranging from ambient to elevated. In a preferred procedure, the reaction is carried out in a mixture of dioxane/water, in the presence of cesium carbonate and palladium tetrakis, and at 100°C. If in the above-mentioned preparation of compounds of formula (I) substituent W is an unsaturated or partially unsaturated precursor of the desired alkyl moiety, it may be reduced to give the saturated alkyl analogue using an appropriate method. In a preferred method the reduction is carried out in ethanol as solvent by the action of triethyl silane and palladium on carbon as a catalyst.

Compounds of formula (XVI) may be prepared by reaction of a compound of formula (XV) with a compound of formula (X) in an analogous manner to that described for the preparation of compounds of formula (I) in Scheme 4. Compounds of formula (XV) may be prepared by saponification of a compound of formula (XVIII) in an analogous manner to that described for the preparation of compounds of formula (IX) in Scheme 4.

Compounds of formula (XVIII) may be prepared by reaction of a compound of formula (XIX) with a boronic acid or ester of formula (VI) in an analogous manner to that described for the preparation of compounds of formula (IV) in Scheme 1.

Compounds of formulae (II), (III), (VI), (VIII), (X), (XII), (XIV), (XVII) and (XIX) are either commercially available, known from the literature, easily prepared by methods well known to those skilled in the art, or can be made according to preparations described herein.

All new processes for preparing compounds of formula (I), and corresponding new intermediates employed in such processes, form further aspects of the present invention.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term 'excipient' is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

In another aspect the invention provides a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable excipients.

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

Suitable modes of administration include oral, parenteral, topical, inhaled/intranasal, rectal/intravaginal, and ocular/aural administration.

Formulations suitable for the aforementioned modes of administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches..

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, V_ (6). 981-986, by Liang and Chen (2001 ).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage Forms: Tablets", Vol. 1 , by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1 -14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298. The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile nonaqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water. The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents. Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 , 1 ,2-tetrafluoroethane or 1 , 1 , 1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μΙ to 10ΟμΙ. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from ^g to 100mg of the compound of formula (I). The overall daily dose will typically be in the range ^g to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis. The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in I nternational Patent Applications Nos. WO 91/1 1 172, WO 94/02518 and WO 98/55148. For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 1 mg to 10g, such as 10mg to 1 g, for example 25mg to 500mg depending, of course, on the mode of administration and efficacy. For example, oral administration may require a total daily dose of from 50mg to 100mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly. As noted above, the compounds of the invention are useful because they exhibit pharmacological activity in animals, i.e., Nav1 .7 channel inhibition. More particularly, the compounds of the invention are of use in the treatment of disorders for which a Nav1 .7 inhibitor is indicated. Preferably the animal is a mammal, more preferably a human.

In a further aspect of the invention there is provided a compound of the invention for use as a medicament. In a further aspect of the invention there is provided a compound of the invention for the treatment of a disorder for which a Nav1 .7 inhibitor is indicated.

In a further aspect of the invention there is provided use of a compound of the invention for the preparation of a medicament for the treatment of a disorder for which a Nav1 .7 inhibitor is indicated.

In a further aspect of the invention there is provided a method of treating a disorder in an animal (preferably a mammal, more preferably a human) for which a Nav1 .7 inhibitor is indicated, comprising administering to said animal a therapeutically effective amount of a compound of the invention.

Disorders for which a Nav1 .7 inhibitor is indicated include pain, particularly neuropathic, nociceptive and inflammatory pain.

Physiological pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment. The system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol. , 57, 1 -164 for a review). These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The nociceptors are found on nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated. Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate. These effects lead to a hightened sensation of pain. In acute pain these mechanisms can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitivity returns to normal once the injury has healed. However, in many chronic pain states, the hypersensitivity far outlasts the healing process and is often due to nervous system injury. This injury often leads to abnormalities in sensory nerve fibres associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivity feature among the patient's symptoms. Patients tend to be quite heterogeneous and may present with various pain symptoms. Such symptoms include: 1 ) spontaneous pain which may be dull, burning, or stabbing; 2) exaggerated pain responses to noxious stimuli (hyperalgesia); and 3) pain produced by normally innocuous stimuli (allodynia - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients suffering from various forms of acute and chronic pain may have similar symptoms, the underlying mechanisms may be different and may, therefore, require different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain. Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy. Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role. It is often present well after the original cause has dissipated, commonly lasting for years, significantly decreasing a patient's quality of life (Woolf and Mannion, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141 -S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus). The inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most common inflammatory pain. Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estimated that almost 16 million Americans have symptomatic osteoarthritis (OA) or degenerative joint disease, most of whom are over 60 years of age, and this is expected to increase to 40 million as the age of the population increases, making this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook of Pain, 387-395). Most patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant impact on psychosocial and physical function and is known to be the leading cause of disability in later life. Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.

Another type of inflammatory pain is visceral pain which includes pain associated with inflammatory bowel disease (IBD). Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain. Commonly encountered gastrointestinal (Gl) disorders that cause pain include functional bowel disorder (FBD) and inflammatory bowel disease (I BD). These Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (I BS) and functional abdominal pain syndrome (FAPS), and, in respect of I BD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain. Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain. It should be noted that some types of pain have multiple aetiologies and thus can be classified in more than one area, e.g. back pain and cancer pain have both nociceptive and neuropathic components. Other types of pain include:

• pain resulting from musculoskeletal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;

• heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;

• head pain, such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders;

· erythermalgia; and

• orofacial pain, including dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain.

A Nav1.7 inhibitor may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. Such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.

In the combinations that follow the compound of the invention may be administered simultaneously, sequentially or separately in combination with the other therapeutic agent or agents.

A Nav1.7 inhibitor of formula (I), or a pharmaceutically acceptable salt thereof, as defined above, may be administered in combination with one or more agents selected from:

• an alternative Nav1.7 channel modulator, such as another compound of the present invention or a compound disclosed in WO 2009/012242; an alternative sodium channel modulator, such as a Nav1 .3 modulator (e.g. as disclosed in WO2008/1 18758); or a Nav1 .8 modulator (e.g. as disclosed in

WO 2008/135826, more particularly N-[6-Amino-5-(2-chloro-5- methoxyphenyl)pyridin-2-yl]-1 -methyl-1 H-pyrazole-5-carboxamide);

an inhibitor of nerve growth factor signaling, such as: an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagoinsist;

a compound which increases the levels of endocannabinoid, such as a compound with fatty acid amid hydrolase inhibitory (FAAH) activity, in particular those disclosed in WO 2008/047229 (e.g. N-pyridazin-3-yl-4-(3-{[5-(trifluoromethyl)pyridine-2- yl]oxy}benzylidene)piperidene-1 -carboxamide);

an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;

a nonsteroidal antiinflammatory drug (NSAI D), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;

a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;

an Hi antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;

a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;

a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;

an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-{2- [4-(3-fluorophenyl)-4-hydroxy-1 -piperidinyl]-1 -hydroxyethyl-3,4-dihydro-2(1 H)- quinolinone;

• an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido- 1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;

· a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;

• an anticonvulsant, e.g. carbamazepine, lamotrigine, topiratmate or valproate;

• a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g.

(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9, 10, 1 1-tetrahydro-9-methyl-5-(4- methylphenyl)-7H-[1 ,4]diazocino[2,1 -g][1 ,7]-naphthyridine-6-13-dione (TAK-637), 5- [[(2R,3S)-2-[(1 R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4- morpholinyl]-methyl]-1 ,2-dihydro-3H-1 ,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2- phenylpiperidine (2S,3S);

• a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine, tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

• a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

• a coal-tar analgesic, in particular paracetamol;

• a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;

· a vanilloid receptor agonist (e.g. resinferatoxin) or antagonist (e.g. capsazepine);

• a beta-adrenergic such as propranolol;

• a local anaesthetic such as mexiletine;

• a corticosteroid such as dexamethasone; • a 5-HT receptor agonist or antagonist, particularly a 5-HT-I_B/-ID agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;

• a 5-HT_2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

• a 5-HT₃ antagonist, such as ondansetron

• a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

• Tramadol®;

• a PDEV inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1- methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12, 12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)- pyrazino[2',1 ':6, 1]-pyrido[3,4-b]indole-1 ,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1- f][1 ,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl- 3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-c ]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3- pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3- c ]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1 -ylsulphonyl)pyridin-3-yl]-3-ethyl-

2- [2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-4- methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2- ylmethyl)pyrimidine-5-carboxamide, 3-(1 -methyl-7-oxo-3-propyl-6,7-dihydro-1 H- pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4- propoxybenzenesulfonamide;

• an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (1 a,3a,5a)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-

3- aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1 R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6- yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1 ,2,4]oxadiazol-5-one, C-[1- (1 H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1 -aminomethyl-3,4- dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5- dimethyl-octanoic acid;

metabotropic glutamate subtype 1 receptor (mGluRI ) antagonist;

a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;

a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;

an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1 - iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1 -iminoethyl)-amino]ethyl]-4,4-dioxo- L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2- methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1 R,3S)-3-amino-4- hydroxy-1- (5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1 R,3S)-3-amino-4- hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro- 5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,

2-[[(1 R,3S)-3-amino-4-hydroxy-1 -(5-thiazolyl) butyl]thio]-6-(trifluoromethyl)-3 pyridinecarbonitrile, 2-[[(1 R,3S)-3- amino-4-hydroxy- 1 -(5-thiazolyl)butyl]thio]-5- chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2- carboxamidine, or guanidinoethyldisulfide;

an acetylcholinesterase inhibitor such as donepezil;

a prostaglandin E₂ subtype 4 (EP4) antagonist such as /\/-[({2-[4-(2-ethyl-4,6- dimethyl-1 H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4- methylbenzenesulfonamide or 4-[(1 S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl}amino)ethyl]benzoic acid;

a microsomal prostaglandin E synthase type 1 (mPGES-1 ) inhibitor; • a leukotriene B4 antagonist; such as 1 -(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7- yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4- methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-1 1870;

• a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3, 4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1 -methyl-2-quinolone (ZD-2138), or

2,3,5-trimethyl-6-(3-pyridylmethyl), 1 ,4-benzoquinone (CV-6504).

There is also included within the scope the present invention combinations of a compound of the invention together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients. Increasing the exposure in such a manner is known as boosting. This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose. The metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes. Thus, among the agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes. The isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that may be used to inhibit CYP 3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2-{[(4- methoxypyridin-3-yl)amino]sulfonyl}benzamide and N-(1 -(2-(5-(4-fluorobenzyl)-3- (pyridin-4-yl)-1 H-pyrazol-1 -yl)acetyl)piperidin-4-yl)methanesulfonamide.

It is within the scope of the invention that two or more pharmaceutical compositions, at least one of which contains a compound of the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions. Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid. In another aspect the invention provides a pharmaceutical product (such as in the form of a kit) comprising a compound of the invention together with one or more additional therapeutically active agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a disorder for which a Nav1.7 inhibitor is indicated. It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions may be used:

AcOH means acetic acid,

CS2CO3 means caesium carbonate

Cu(acac)2 means copper (II) acetylacetonate

Cul means copper (I) iodide

Cu(OAc)₂ means copper (II) acetate

DAD means diode array detector

DCM means dichloromethane; methylene chloride;

DIPEA means N-ethyldiisopropylamine, N,N-diisopropylethylamine;

DMAP means 4-dimethylaminopyridine;

DMF means N,N-dimethylformamide;

DMSO means dimethyl sulphoxide;

EDTA means ethylenediaminetetraacetic acid

ELSD means evaporative light scattering detection

Et₂0 means diethyl ether

EtOAc means ethyl acetate

EtOH means ethanol

HCI means hydrochloric acid;

I PA means isopropanol

lr₂(OMe)₂COD₂ means bis(1 ,5-cyclooctadiene)di^-methoxydiiridium (I) K2CO3 means potassium carbonate;

KHS0₄ means potassium hydrogen sulphate

KOAc means potassium acetate

KOH means potassium hydroxide;

K₃P0₄ means potassium phosphate tribasic

LiOH means lithium hydroxide

MeOH means methanol

MgS0₄ means magnesium sulphate

NaH means sodium hydride;

NaHCC>3 means sodium hydrogencarbonate

Na₂C0₃ means sodium carbonate;

NaHSC means sodium bisulphite

NaHS0₄ means sodium hydrogensulphate

NaOH means sodium hydroxide;

Na₂S0₄ means sodium sulphate

NH₄CI means ammonium chloride

Pd/C means palladium on carbon

Pd(PPh₃)₄ means palladium tetrakis;

Pd(dppf)₂CI₂ means [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane;

THF means tetrahydrofuran;

THP means tetrahydropyran;

TLC means thin layer chromatography; and

WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

¹H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI3, deuterochloroform; d6-DMSO, deuterodimethylsulphoxide. Mass spectra (m/z) were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). When relevant, and unless stated otherwise, the m/z data provided are for isotopes ¹⁹F, ³⁵CI and ⁷⁹Br. Where compounds were analysed by LCMS and/or purified by HPLC the following methods were used:

Method A1 : Acidic Preparative HPLC

Column: SunFire C18, 5μηι 19x100mm

Temperature: Ambient

Detection: ELSD-MS

Fractionlynx 1

Injection Volume: 1000μΙ_

Flow Rate: 18ml/min

Mobile Phase: A: water + 0.1 % formic acid, B: acetonitrile + 0.1 % formic acid

Gradient (Time/mins,%B) - (0-1 , 5),( 1 -7, 5-98),(7-9, 98),(9-9.1 , 98-5),(9.1 -10, 5)

Method A2: Basic Preparative HPLC

Column: XTerra C18, 5μηι 19x100mm

Temperature: Ambient

Detection: ELSD MS

Fractionlynx 1

Injection Volume: 1000μΙ_

Flow Rate: 18ml/min

Mobile Phase: A: water + 0.1 % diethylamine, B: acetonitrile + 0.1 % diethylamine Gradient (Time/mins,%B) - (0-1 , 5),( 1 -7, 5-98),(7-9, 98),(9-9.1 , 98-5),(9.1 -10, 5)

Method A3: Acidic Analytical LCMS

Column: SunFire C18, 5μηη 4.6x50mm

Temperature: Ambient

Detection: UV 225nm-ELSD-MS

System/Data file: CTC-MUX1

Injection volume: 5μΙ_

Flow rate: 1 .5ml/min Mobile phase: A: water + 0.1 % formic acid, B: acetonitrile + 0.1 % FOA

Gradient (Time/mins, %B) -(0,5),(3,95),(4,95),(4.1 ,5),(5,5)

Method A4: Basic Analytical LCMS

Column: XTerra C18, 5 m 4.6x50mm

Temperature: Ambient

Detection: UV 225nm-ELSD-MS

System/Data file: CTC-MUX1

Injection volume: 5μΙ_

Flow rate: 1 .5ml/min

Mobile phase: A: water + 0.1 % ammonia, B: acetonitrile + 0.1 % ammonia

Gradient (Time/mins, %B) -(0,5),(3,95),(4,95),(4.1 ,5),(5,5)

Method A5: Acidic 2 minute LCMS

Mobile phase A: 0.1 % formic acid in water

Mobile phase B: 0.1 % formic acid in 70% methanol :30% isopropanol

Column: C18 phase Phenomenex 20x4.0mm with 3micron particle size

Gradient: 98-10% A over 1 .5min, 0.3 min hold, 0.2 re-equilbration, 2ml/min flow rate UV: 210nm-450nm DAD

Temperature: 75°C

Or

Mobile phase A: 0.1 % formic acid in water

Mobile phase B: 0.1 % formic acid in acetonitrile

Column: C18 phase Phenomenex 20 x 4.0mm with 3micron particle size

Gradient: 70-2% A over 1 .5min, 0.3 min hold, 0.2 re-equilbration, 1 .8ml/min flow rate UV: 210nm-450nm DAD

Temperature: 75°C

Method A6: Acidic 6 minute LCMS

Mobile phase A: 0.1 % formic acid in water

Mobile phase B: 0.1 % formic acid in acetonitrile

Column: C18 phase Waters Sunfire 50x4.6mm with 5micron particle size

Gradient: 95-5% A over 3min, 1 min hold, 2min re-equilibration, 1 .5ml/min flow rate UV: 210nm-450nm DAD

Temperature: 50°C

Method A7: Basic 6 minute LCMS

Mobile phase A: 0.1 % ammonium hydroxide in water

Mobile phase B: 0.1 % ammonium hydroxide in acetonitrile

Column: C18 phase Fortis 50x4.6mm with 5micron particle size

Gradient: 95-5% A over 3min, 1 min hold, 2min re-equilibration, 1 ml/min flow rate UV: 210nm-450nm DAD

Temperature: 50°C

Method A8: 30 minute LCMS

Mobile phase A: 0.1 % formic acid in water

Mobile phase B: 0.1 % formic acid in acetonitrile

Column: Phenomenex C18 phase Gemini 150x4.6mm with 5micron particle size Gradient: 98-2% A over 18min, 2min hold, 1 ml/min flow rate

UV: 210nm-450nm DAD

Temperature: 50°C Method A9: 30 minute LCMS

Mobile phase A: 10mM ammonium acetate in water

Mobile phase B: 10mM ammonium acetate in methanol

Column: Phenomenex Phenyl Hexyl 150x4.6mm with 5micron particle size

Gradient: 98-2% A over 18min, 2min hold, 1 ml/min flow rate

UV: 210nm-450nm DAD

Temperature: 50°C

Method A10: Preparative HPLC

Column: Phenomenex Synergi C18 250 x 50 mm x 10 μηη. Gradient Mobile Phase elution from from 15% acetonitrile in water (+ 0.225% formic acid) to 40% acetonitrile in water (+ 0.225 % formic acid) using UV detection at 220nm.

Method A1 1 : Analytical LCMS

Column: Welch XB-C18 2.1 x50mm 5μηι, temperature = 50°C Mobile Phase A = 0.0375% trifluoroacetic acid in water, mobile Phase B = 0.01875% trifluoroacetic acid in acetonitrile

Gradient: O.Omin 1 % B, 0.6min 5% B, 4.0min 100% B, 4.3min 1 % B, 4.7min 1 % B Flow rate = 0.8 ml/min, Injection volume = 2μΙ

Agilent 1200 HPLC/1956 MS/SEDEX 75 ELSD

Ionization Mode = API-ES, Polarity = Positive

Method A12: Analytical LCMS

Column: Welch XB-C18 2.1 x50mm 5μηι, temperature = 50°C

Mobile Phase A = 0.0375% trifluoroacetic acid in water, mobile Phase B = 0.01875% trifluoroacetic acid in acetonitrile

Gradient: - O.Omin 10% B, 0.5min 10% B, 4.0min 100% B, 4.3min 10% B, 4.7min 10% B Flow rate = 0.8 ml/min, Injection volume = 2μΙ

Agilent 1200 HPLC/1956 MS/SEDEX 75 ELSD

Ionization Mode = API-ES, Polarity = Positive

Method A13: Analytical LCMS

Column: Welch XB-C18 2.1 x50mm 5μηι, temperature = 50°C

Gradient: O.Omin 40% B, 0.4min 40% B, 2.8min 100% B, 4.0min 100% B, 4.2min 40% B, 4.7min 40% B

Flow rate = 0.8 ml/min, Injection volume = 2μΙ

Agilent 1200 HPLC/1956 MS/SEDEX 75 ELSD

Ionization Mode = API-ES, Polarity = Positive

Method A14: Analytical LCMS

Column: Welch XB-C18 2.1 x50mm 5μηι, temperature = 50°C

Gradient: O.Omin 25% B, 0.5min 25% B, 3.5min 100% B, 4.0min 25% B, 4.7min 25% B Flow rate = 0.8ml/min, Injection volume = 2μΙ

Agilent 1200 HPLC/1956 MS/SEDEX 75 ELSD

Ionization Mode = API-ES, Polarity = Positive Method A15: Analytical LCMS

Column: Welch XB-C18 2.1 x50mm δμηι, temperature = 50°C

Mobile Phase A = 0.05% ammonium hydroxide in water, mobile Phase B = 100% acetonitrile

Gradient: O.Omin 15% B, 0.5min 15% B, 3.4min 100% B, 3.9min 100% B, 3.91 min 15% B, 4.7min 15% B

Flow rate = 0.8ml/min, Injection volume = 2μΙ

Agilent 1200 HPLC/1956 MS/SEDEX 75 ELSD

Ionization Mode = API-ES, Polarity = Positive

Method A16 (Preparative HPLC): Column: Kromasil Eternity-5-C18 150*30mrr^m. Gradient Mobile Phase: Acetonitrile-Water (+0.1 % trifluoroacetic acid). Flow rate = 30ml/min. Detection: UV

Method A17 (Preparative HPLC): Column: Phenomenex Synergi C18 150*30ηΊΓη*4μΓη. Gradient Mobile Phase: Acetonitrile-Water (+0.1 % trifluoroacetic acid). Flow rate = 35ml/min. Detection: MS Method A18 (Preparative HPLC): Column: YMC-pack ODS-AQ 150*30mrr^m. Gradient Mobile Phase: Acetonitrile-Water (+0.1 % trifluoroacetic acid). Flow rate = 35ml/min. Detection: MS

Method A19 (Preparative HPLC): Column: Agella Venusil ASB C18 150*21 .2ηΊΓη*5μΓη. Gradient Mobile Phase: Acetonitrile-Water (+0.1 % trifluoroacetic acid). Flow rate = 28ml/min. Detection: UV

Method A20 (Preparative HPLC): Column: Boston Symmetrix ODS-H 150*30ηΊΓη*5μΓη. Gradient Mobile Phase: Acetonitrile-Water (+0.1 % trifluoroacetic acid). Flow rate = 30ml/min. Detection: UV

Method A21 (Preparative HPLC): Column: Grace Vydac C18 150*20 ΓηΓη*5μΓη . Gradient Mobile Phase: Acetonitrile-Water (+ 0.1 %trifluoroacetic acid). Flow rate = 25ml/min. Detection: UV Method A22 (Preparative HPLC): Column: Phenomenex Gemini C18 150*3θΓηΓη*5μΓη. Gradient Mobile Phase: Acetonitrile-Water (+ ammonium hydroxide pH 10). Flow rate = 25ml/min. Detection: UV

Method A23 (Preparative HPLC): Column: Grace Vydac C18 200*20mm*5 m. Gradient Mobile Phase: Acetonitrile-Water (+0.1 % trifluoroacetic acid). Flow rate = 25ml/min. Detection: MS Method A24 (Preparative HPLC): Column: Phenomenex Luna C18 100*21 .2mm*5 m. Gradient Mobile Phase: Acetonitrile-Water (+0.1 % trifluoroacetic acid). Flow rate = 25ml/min. Detection: UV

Method A25 (Preparative HPLC): Column: Symmetrix ODS-H, 30.0*150mm*5 m. Gradient Mobile Phase: Acetonitrile-Water (+0.225% formic acid). Flow rate = 25ml/min. Detection: UV

Examples prepared according to Scheme 1 Example 1 : 1 -f5-chloro-6-f(1 -methylcvclopropyl)methoxy1pyridin-3-yl}-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

CS2CO3 (380mg, 1 .15mmol) was weighed into a reaction vial and a solution of 1 -(5- chloro-6-fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 7] (300mg, 0.55mmol) in DMSO (4ml) added followed by 1 - methylcyclopropylmethanol (473mg, 5.5mmol). The vial was capped and the mixture heated at 100°C for 16 hours. The mixture was added to an aqueous solution of KHS0₄ (30ml, 0.5M) and the resulting solid was collected by filtration, washed with water and dried by suction. The solid was dissolved in EtOAc (20ml), dried over MgS0₄, filtered and evaporated onto silica. After purification by column chromatography (ISCO Companion, Biotage KP-C18-HS 12g cartridge, 2 injections, mobile phase A: 10mM ammonium acetate in water, mobile phase B: acetonitrile) the product fractions were combined and concentrated in vacuo. The residue was treated with an aqueous solution of KHS0₄ (10ml, 1 M) and extracted with DCM (3x5ml). The extracts were combined, dried over MgS0₄, filtered and concentrated in vacuo to give the title compound which crystallised on treatment with ethanol (61 mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 0.44 - 0.50 (m, 2 H) 0.60 - 0.67 (m, 2 H) 1 .29 (s, 3 H) 2.70 (s, 3 H) 3.51 (s, 3 H) 4.25 (s, 2 H) 7.59 - 7.67 (m, 1 H) 7.94 (dd, J=8.79, 1 .76 Hz, 1 H) 8.01 (d, J=2.34 Hz, 1 H) 8.29 - 8.38 (m, 2 H) 8.95 (br. s., 1 H)

LCMS (method A5): Rt 1 .67min, MS m/z 449[MH]+, 895 [M₂H]+

LCMS (method A8): Rt 18.76min, MS m/z 449 [MH]+ Example 2: 1 -i5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N-imethylsulfonyl)-1 H- indazole-5-carboxamide-dfi

A mixture of CS2CO3 (51 1 mg, 1 .57mmol), 1 -(5-chloro-6-fluoropyridin-3-yl)-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 7] (300mg, 0.78mmol) and d6- isobutanol (628mg, 7.84mmol) in DMSO (4ml) was stirred under nitrogen at 100°C for 18 hours. After cooling, the brown solution was added to an aqueous solution of KHS0₄ (30ml, 0.5M) and the mixture extracted with ethyl acetate (30ml). The organic layer was separated and back-extracted with brine (3x20ml). The organic layer was separated, dried over Na₂S0₄, filtered and concentrated in vacuo to give a foam. The foam was triturated with Et₂0 and a beige solid filtered off. The filtrate was concentrated in vacuo to give a pale solid (270mg) which was dissolved in DCM plus one drop of methanol, then purified by column chromatography (ISCO Companion, 12g silica column) eluting with DCM:formic acid 99.8:0.2 to DCM:MeOH:formic acid 95.8:5:0.2. The appropriate fractions were combined and concentrated in vacuo to give a solid. The solid was dissolved in Et₂0 and concentrated in vacuo (3 times) to give the title compound as a colourless solid (1 10mg).

1 H NMR (400 MHz, CDCI₃) δ ppm 2.16 (t, J=6.5Hz, 1 H) 2.70 (s, 3 H) 3.51 (s, 3 H) 4.23 (d, J=6.5 Hz, 2 H) 7.64 (dd, J=8.88, 0.68 Hz, 1 H) 7.93 (dd, J=8.79, 1.76 Hz, 1 H) 8.01 (d, J=2.54 Hz, 1 H) 8.33 (dd, J=1 .66, 0.68 Hz, 1 H) 8.37 (d, J=2.54 Hz, 1 H) 8.81 (br, 1 H)

LCMS (method A5): Rt 1 .86min, MS m/z 443 [MH]+, 441 [MH]- Mpt: change at 143°C, melt 165-166°C

Example 3: 3-cvclopropyl-1 -( 6-ΓΜ -methylcvclopropyl)methoxy1pyridin-3-yl}-N-

(methylsulfonyl)-1 H-indazole-5-carboxamide

To a reaction vial containing 1 -methylcyclopropylmethanol (33mg, 0.38mmol) and CS2CO3 (124mg, 0.38mmol) was added a solution of 3-cyclopropyl-1 -{6-[(1 - methylcyclopropyl)methoxy]pyridin-3-yl}-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 1 1 ] (75mg, 0.19mmol) in DMSO (1 ml). The vial was flushed with nitrogen, capped, and heated at 100°C for 48 hours. The mixture was cooled to room temperature then an aqueous solution of KHS0₄ (5ml, 1 M) added to facilitate precipitation. The mixture was diluted with water (5ml) and extracted with EtOAc (2x10ml). The extracts were combined, evaporated onto silica and purified by column chromatography (ISCO companion, silica 4g) eluting with a gradient of heptane and 90: 10 EtOAc:AcOH(10-50%) to afford the title compound (32mg).

1 H NMR (400 MHz, CDCI₃) δ ppm 0.41 - 0.49 (m, 2 H) 0.55 - 0.64 (m, 2 H) 1 .10 - 1 .22 (m, 4 H) 1 .26 (s, 3 H) 2.31 (tt, J=8.05, 5.22 Hz, 1 H) 3.51 (s, 3 H) 4.16 (s, 2 H) 6.91 - 7.00 (m, 1 H) 7.54 - 7.64 (m, 1 H) 7.85 (dd, J=8.98, 2.73 Hz, 1 H) 7.88 - 7.93 (m, 1 H) 8.40 (dd, J=2.73, 0.78 Hz, 1 H) 8.42 - 8.45 (m, 1 H) 9.07 (br. s., 1 H) LCMS (method A5): Rt 1 .60min, MS m/z 441 [MH]+, 439 [MH]-

Example 4: 3-cyclopropyl-1 -(6-isobutoxypyridin-3-yl)-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

To a reaction vial containing isobutanol (33mg, 0.38mmol) and CS2CO3 (124mg, 0.38mmol) was added a solution of 3-cyclopropyl-1 -{6-[(1 - methylcyclopropyl)methoxy]pyridin-3-yl}-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 1 1 ] (75mg, 0.19mmol) in DMSO (1 ml). The vial was flushed with nitrogen, capped, and heated at 100°C for 48 hours. The mixture was cooled to room temperature then an aqueous solution of KHS0₄ (5ml, 1 M) added to facilitate precipitation. The mixture was diluted with water (5ml) and extracted with EtOAc (2x10ml). The extracts were combined, evaporated onto silica and purified by column chromatography (ISCO companion, silica 4g) eluting with a gradient of heptane and 90: 10 EtOAc:AcOH(10-50%) to afford the title compound (52mg)

¹ H NMR (400 MHz, CDCI3) δ ppm 0.99 - 1 .09 (m, 6 H) 1 .10 - 1 .23 (m, 4 H) 2.04 - 2.22 (m, 1 H) 2.31 (tt, J=8.10, 5.37 Hz, 1 H) 3.51 (s, 3 H) 4.13 (d, J=6.64 Hz, 2 H) 6.91 (d, J=8.20 Hz, 1 H) 7.58 (dd, J=8.98, 0.78 Hz, 1 H) 7.84 (dd, J=8.98, 2.73 Hz, 1 H) 7.91 (dd, J=8.98, 1 .95 Hz, 1 H) 8.42 (d, J=2.34 Hz, 1 H) 8.43 - 8.45 (m, 1 H) 9.1 1 (br. s., 1 H) LCMS (method A5): Rt 1 .60min, MS m/z 429 [MH]+, 427 [MH]-

In addition to the above examples the following General Procedures were also used to prepare further examples according to Scheme 1 , which are listed in Tables 1 and 2: General Procedure 1 : A solution of 1 -(6-fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)- 1 H-indazole-5-carboxamide [preparation 6] or 1 -(5-chloro-6-fluoropyridin-3-yl)-3-methyl- N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 7] in DMSO was made up to a concentration such that 0.5ml would deliver 20mg (~0.05mmol) of material. To a vial containing the alcohol of formula (V) (0.32mmol) was added CS2CO3 (approx. 35mg, 0.1 1 mmol) and the solution of the N 1 -fluoropyridyl indazole (0.5ml). The vials were flushed with nitrogen, capped and stirred at 100°C for a period of 16-72 hours. Reactions were monitored by LCMS and those containing compounds of formula (I ) were filtered, diluted to 1 ml volume with DMSO and purified using preparative HPLC.

General Procedure 2: A 0.15M solution of 1 -(6-fluoropyridin-3-yl)-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 6] or 1 -(5-chloro-6- fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 7] in DMSO was prepared and 500μΙ (75μηΊθΙ, 1 .0eq) dispensed to 8ml reaction vials. The alcohol of formula (V) was prepared as a 0.45M solution in DMSO and 500μΙ of solution (225μηΊθΙ, 3.0eq) was dispensed into the appropriate vial. CS2CO3 (225μηΊθΙ, 3.0eq) was added to each vial and the vials were capped and shaken at 100°C for 18 hours. The reaction mixtures were filtered and the filtrate evaporated using a vacuum centrifuge and the crude material purified by preparative HPLC to afford the compound of formula (I).

Tables 1 and 2: Examples prepared using, respectively, General Procedures 1 and 2 (wherein: 'P hplc' denotes Preparative HPLC Method, Ά hplc' denotes Analytical HPLC Method and Ά rt' denotes Analytical retention time (min)).

Table 1

P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

5 1 -(5-chloro-6-propoxypyridin-3-yl)-3-methyl- A2 A4 2.29 423 [MH]+

N-(methylsulfonyl)-1 H-indazole-5- 421 [MH]- carboxamide

6 1 -[5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3- A2 A3 3.74 463 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 461 [MH]- 5-carboxamide

7 1 -{6-[(3,3-difluorocyclobutyl)methoxy]pyridin- A2 A3 3.55 451 [MH]+

3-yl}-3-methyl-N-(methylsulfonyl)-1 H- 449 [MH]- indazole-5-carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

8 1-{5-chloro-6-[(3,3- A1 A3 3.72 485 [MH]+ difluorocyclobutyl)methoxy]pyridin-3-yl}-3- 483 [MH]- methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide

9 3-methyl-N-(methylsulfonyl)-1-[6-(2,2,2- A1 A3 3.60 443 [MH]+ trifluoro-1 -methylethoxy)pyridin-3-yl]-1 H- 441 [MH]- indazole-5-carboxamide

10 3-methyl-N-(methylsulfonyl)-1-[6-(4,4,4- A1 A3 3.60 457 [MH]+ trifluorobutoxy)pyridin-3-yl]-1 H-indazole-5- 455 [MH]- carboxamide

1 1 1-{6-[(1 S)-1-(4-fluorophenyl)ethoxy]pyridin-3- A1 A3 3.72 469 [MH]+ yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- 467 [MH]- 5-carboxamide

12 1-[6-(cyclopropylmethoxy)pyridin-3-yl]-3- A1 A3 3.40 401 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole-5- 399 [MH]- carboxamide

13 3-methyl-N-(methylsulfonyl)-1-(6-{[4- A1 A3 3.99 51 1 [MH]+ (trifluoromethyl)cyclohexyl]methoxy}pyridin- 509 [MH]- 3-yl)-1 H-indazole-5-carboxamide

14 1-{6-[(4,4-difluorocyclohexyl)methoxy]pyridin- A1 A3 3.62 479 [MH]+

3-yl}-3-methyl-N-(methylsulfonyl)-1 H- 477 [MH]- indazole-5-carboxamide

15 3-methyl-N-(methylsulfonyl)-1-(6- A1 A3 3.62 389 [MH]+ propoxypyridin-3-yl)-1 H-indazole-5- 387 [MH]- carboxamide

16 1-(6-butoxypyridin-3-yl)-3-methyl-N- A2 A4 2.25 403 [MH]+ (methylsulfonyl)-1 H-indazole-5-carboxamide 401 [MH]-

17 1-[6-(cyclobutyloxy)pyridin-3-yl]-3-methyl-N- A2 A4 2.25 399 [MH]- (methylsulfonyl)-1 H-indazole-5-carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

18 1-[6-(2,2-dimethylpropoxy)pyridin-3-yl]-3- A2 A4 2.35 417 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole- 5- 415 [MH]- carboxamide

19 3-methyl-1-[6-(3-methylbutoxy)pyridin-3-yl]- A1 A4 2.52 417 [MH]+

N-(methylsulfonyl)-1 H-indazole-5- 415 [MH]- carboxamide

20 1-[6-(2-cyclopropylethoxy)pyridin-3-yl]-3- A2 A3 3.79 415 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole- 5- 413 [MH]- carboxamide

21 1-[6-(cyclobutylmethoxy)pyridin-3-yl]-3- A2 A4 2.25 415 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole- 5- 413 [MH]- carboxamide

22 3-methyl-1 -(6-{[(1 S)-1 - A1 A3 3.80 417 [MH]+ methylbutyl]oxy}pyridin-3-yl)-N- 415 [MH]- (methylsulfonyl)-l H-indazole- 5-carboxamide

23 1-[6-(cyclopentylmethoxy)pyridin-3-yl]-3- A1 A4 2.27 429 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole- 5- 427 [MH]- carboxamide

24 3-methyl-1 -{6-[(1- A1 A3 3.95 429 [MH]+ methylcyclobutyl)methoxy]pyridin-3-yl}-N- 427 [MH]- (methylsulfonyl)-l H-indazole- 5-carboxamide

25 1-[6-(3,3-dimethylbutoxy)pyridin-3-yl]-3- A1 A4 2.32 431 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole- 5- 429 [MH]- carboxamide

26 1-(6-{[(1 R)-1 ,3-dimethylbutyl]oxy}pyridin-3- A1 A3 3.99 431 [MH]+ yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole- 429 [MH]- 5-carboxamide

27 1-{6-[(4-fluorobenzyl)oxy]pyridin-3-yl}-3- A1 7.27 477

methyl-N-(methylsulfonyl)-1 H-indazole- 5- * [MNa]+^* carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

28 1 -{6-[( 1 -f I u orocycloh exy I )m eth oxy] pyridin-3- A1 A4 2.29 461 [MH]+ yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- 459 [MH]- 5-carboxamide

29 1 -{6-[(1 R)-1 -(4-f luorophenyl)ethoxy]pyridin-3- A1 A3 3.75 469 [MH]+ yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- 467 [MH]- 5-carboxamide

30 3-methyl-N-(methylsulfonyl)-1-[6-(4,4,4- A1 A3 3.72 471 [MH]+ trifluoro-2-methylbutoxy)pyridin-3-yl]-1 H- 469 [MH]- indazole-5-carboxamide

31 1 -(6-{[(1 S)-1 ,3-dimethylbutyl]oxy}pyridin-3- A1 A3 3.97 431 [MH]+ yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole- 5-carboxamide

32 1-{5-chloro-6-[(4,4- A2 A4 2.50 513 [MH]+ d if I uorocycl oh exyl )m ethoxy] pyrid i n-3-yl}-3- 51 1 [MH]- methyl-N-(methylsulfonyl)-1 H-indazole- 5- carboxamide

33 1-[5-chloro-6-(cyclopropylmethoxy)pyridin-3- A2 A4 2.29 435 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 433 [MH]- 5-carboxamide

34 1-(5-chloro-6-{[4- A2 A4 2.55 545 [MH]+

(trifluoromethyl)cyclohexyl]methoxy}pyridin- 543 [MH]-

3-yl)-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

35 1-[5-chloro-6-(cyclobutyloxy)pyridin-3-yl]-3- A1 A3 3.85 435 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole- 5- 433 [MH]- carboxamide

36 1-[5-chloro-6-(2,2-dimethylpropoxy)pyridin-3- A1 A4 2.54 449 [MH]- yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 5-carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

37 1-(6-sec-butoxy-5-chloropyridin-3-yl)-3- A1 A4 2.29 437 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole-5- 435 [MH]- carboxamide

38 1-[5-chloro-6-(1 ,2-dimethylpropoxy)pyridin-3- A1 A4 2.45 451 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 449 [MH]- 5-carboxamide

39 1-[5-chloro-6-(1-cyclopropylethoxy)pyridin-3- A1 A3 3.94 449 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 5-carboxamide

40 1-[5-chloro-6-(3-methylbutoxy)pyridin-3-yl]-3- A1 A4 2.47 451 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole-5- 449 [MH]- carboxamide

41 1-[5-chloro-6-(2-cyclopropylethoxy)pyridin-3- A1 A4 2.47 447 [MH]- yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 5-carboxamide

42 1-[5-chloro-6-(cyclobutylmethoxy)pyridin-3- A1 A4 2.47 449 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 447 [MH]- 5-carboxamide

43 1-[5-chloro-6-(cyclopentylmethoxy)pyridin-3- A1 A4 2.55 463 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 461 [MH]- 5-carboxamide

44 1-(5-chloro-6-{[(1 S)-1 ,3- A1 A4 2.47 465 [MH]+ dimethylbutyl]oxy}pyridin-3-yl)-3-methyl-N- 463 [MH]-

(methylsulfonyl)-1 H-indazole-5-carboxamide

45 1-{5-chloro-6-[(1- A1 A4 2.48 463 [MH]+ methylcyclobutyl)methoxy]pyridin-3-yl}-3- 461 [MH]- methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide

46 1 -[5-ch loro-6-(2 , 2 ,2-trif lu oro- 1 - A2 A4 2.35 475 [MH]- methylethoxy)pyridin-3-yl]-3-methyl-N-

(methylsulfonyl)-1 H-indazole-5-carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

47 1-[5-chloro-6-(3,3-dimethylbutoxy)pyridin-3- A2 A4 2.48 465 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 463 [MH]- 5-carboxamide

48 1-[5-chloro-6-(4,4,4-trifluorobutoxy)pyridin-3- A1 A4 2.42 491 [MH]+ yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- 489 [MH]- 5-carboxamide

49 1-{5-chloro-6-[(4-fluorobenzyl)oxy]pyridin-3- A1 A4 2.35 489 [MH]+ yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- 487 [MH]- 5-carboxamide

50 1 -[5-ch loro-6-(4 , 4 ,4-trif lu oro-2- A1 A4 2.47 505 [MH]+ methylbutoxy)pyridin-3-yl]-3-methyl-N- 503 [MH]-

(methylsulfonyl)-1 H-indazole-5-carboxamide

51 1-{5-chloro-6-[(1 R)-1 -(4- A1 A4 2.45 503 [MH]+ fluorophenyl)ethoxy]pyridin-3-yl}-3-methyl-N- 501 [MH]-

(methylsulfonyl)-1 H-indazole-5-carboxamide

52 1-{5-chloro-6-[(1 S)-1-(4- A1 A4 2.52 503 [MH]+ fluorophenyl)ethoxy]pyridin-3-yl}-3-methyl-N- 501 [MH]-

(methylsulfonyl)-1 H-indazole-5-carboxamide

^*Retention time in preparative HPLC method A2; [MNa]+ detected

Table 2

P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1-[6-(cyclopentyloxy)pyridin-3-yl]-3-

53 methyl-N-(methylsulfonyl)-1 H-indazole-5- A16 A12 3.34 415 [MH]+ carboxamide

1-[6-(benzyloxy)pyridin-3-yl]-3-methyl-N-

54 (methylsulfonyl)-l H-indazole-5- A18 A12 3.30 437 [MH]+ carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1 -[6-(2,3-dihydro-1 H-inden-2- yloxy)pyridin-3-yl]-3-methyl-N-

55 A18 A14 2.92 463 [MH]+ (methylsulfonyl)-l H-indazole-5- carboxamide

3-methyl-N-(methylsulfonyl)-1 -[6-(2-

56 phenylethoxy)pyridin-3-yl]-1 H-indazole-5- A18 A14 2.83 451 [MH]+ carboxamide

1 -[5-chloro-6-(cyclopentyloxy)pyridin-3-

57 yl]-3-methyl-N-(methylsulfonyl)-1 H- A18 A14 3.18 449 [MH]+ indazole-5-carboxamide

1 -[5-chloro-6-(2,3-dihydro-1 H-inden-2- yloxy)pyridin-3-yl]-3-methyl-N-

58 A18 A14 3.18 497 [MH]+ (methylsulfonyl)-l H-indazole-5- carboxamide

Examples prepared according to Scheme 2

Example 59: 1 -i5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N-imethylsulfonyl)-1 H- indazole-5-carboxamide

To a solution of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 5] (6.4g, 22mmol) and 2-isobutoxy-3-chloropyridine-5-boronic acid (5.07g, 22mmol) in DMF (100ml) was added pyridine (5.36ml, 66mmol) and copper acetate (8.02g, 44mmol). The reaction was warmed to 50°C for 16 hours. The solvent was concentrated in vacuo, the crude mixture slurried with EDTA solution (200ml, 5% aqueous), and the pH adjusted to -3 by addition of an aqueous KHS0₄ solution (~10ml, 1 M). The slurry was stirred for -20 minutes, the solid was collected by filtration and the EDTA slurry repeated once more. The resulting pale green solid was collected by filtration, washed with water (2x50ml) and dried by suction. The solid was suspended in acetone (150ml) and evaporated onto silica then purified by column chromatography (ISCO, 300g column, dry load, heptane: EtOAc+10%AcOH 95:5 to 1 : 1 ) to give a white solid (4.8g, 35%). This material was re-dissolved in hot EtOAc:heptane (80ml, 3:5), filtered whilst hot and the mixture left to crystallise for 16 hours. The resulting white crystals were collected by filtration, washed with 4: 1 heptane:EtOAc (2x5ml) and dried by suction to give product (1 .89g). The mother liquors were concentrated in vacuo and the resulting solid re-dissolved in hot EtOH (8ml) and left to crystallise. The crystals were collected by filtration, washed with EtOH (2ml), and dried by suction to give additional product (562mg). Batches of material made by the above method (3.12g combined) were recrystallised from hot ethanol (40ml) allowing the mixture to cool slowly. The resulting fine needle crystals were collected by filtration, dried by suction and then in vacuo to afford the title compound (2.70g).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .08 (d, J=6.64 Hz, 6 H) 2.1 1 - 2.28 (m, 1 H) 2.70 (s, 3 H) 3.51 (s, 3 H) 4.23 (d, J=7.03 Hz, 2 H) 7.64 (dd, J=8.98, 0.78 Hz, 1 H) 7.94 (dd, J=8.98, 1 .95 Hz, 1 H) 8.00 (d, J=2.34 Hz, 1 H) 8.32 - 8.35 (m, 1 H) 8.37 (d, J=2.73 Hz, 1 H) 8.93 (s, 1 H)

¹³C + DEPT NMR: 1 1 .81 (CH3), 19.15 (CH3), 27.90 (CH), 41 .88 (CH3), 73.63 (CH2), 1 10.13 (CH), 1 19.02 (Cq), 122.75 (CH), 123.82 (Cq), 124.55 (Cq), 126.88 (CH), 130.18 (Cq), 133.47 (CH), 138.06 (CH), 141 .56 (Cq), 146.51 (Cq), 158.17 (Cq), 165.42 (Cq) CHN: Calc %C 52.23, %H 4.84, %N 12.82; Found %C 52.20, %H 4.85, %N 12.75 HRMS (Bruker MICRO-TOF): Meas. m/z=437.1042, calcd m/z=437.1045, err=0.6ppm LCMS (Method A6): Rt 3.24min MS m/z 437 [MH]+, 435 [MH]- LCMS (Method A8): Rt 18.88min, MS m/z 437 [MH]+

LCMS (Method A9): Rt 19.65min, MS m/z 437 [MH]+, 459 [MNa]+

Mpt: 157-158°C Example 60: 3-methyH -{6-Γ(1 -methylcvclopropyl)methoxy1pyridin-3-yl}-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To a flask containing a solution of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide [preparation 5] (250mg, 0.86mmol) and 2-(1 -methyl-cyclopropylmethoxy)- 5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridine [preparation 36] (250mg, 0.86mmol) in DMF (5ml) was added pyridine (0.21 ml, 2.59mmol) and copper acetate (314mg, 1 .73mmol). The reaction was warmed to 50°C for 16 hours. After this time additional 2-(1 -methyl-cyclopropylmethoxy)-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan- 2-yl)-pyridine (190mg) was added and stirred at 50°C for a further 5 hours. The reaction mixture was diluted with EtOAc (25ml) and washed with saturated EDTA solution (2x30ml). The organic phase was separated, dried over MgS0₄, filtered and concentrated in vacuo to give an amber coloured oil. Purification by column chromatography (ISCO, 25g Thomson column, dry load, heptane:EtOAc+10%AcOH 100:0 to 50:50) gave a colourless oil (140mg). Crystallisation from hot ethanol gave the title compound (68mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 0.42 - 0.49 (m, 2 H) 0.56 - 0.65 (m, 2 H) 1 .26 (s, 3 H) 2.70 (s, 3 H) 3.51 (s, 3 H) 4.16 (s, 2 H) 6.92 - 7.01 (m, 1 H) 7.60 (d, J=8.98 Hz, 1 H) 7.83 - 7.89 (m, 1 H) 7.92 (dd, J=8.98, 1 .56 Hz, 1 H) 8.31 - 8.38 (m, 1 H) 8.42 (dd, J=2.73, 0.78 Hz, 1 H) 9.04 (br. s., 1 H)

LCMS (Method A5): Rt 1 .70min, MS m/z 415 [MH]+, 413 [MH]- Example 61 : 1 -(5-chloro-6-methoxypyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

A mixture of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 5] (501 mg, 1 .98mmol), 2-methoxy-3-chloropyridine-5-boronic acid (380mg, 2.03mmol), copper acetate (740mg, 4.07mmol) and pyridine (320μΙ, 4.00mmol) in DMF (10ml) was stirred uncapped at 60°C for 20 hours. The mixture was concentrated in vacuo and an aqueous solution of HCI (50ml, 2M) added and stirred for 1 hour to facilitate precipitation. The resulting solid was collected by filtration, washed with further aqueous HCI solution (10ml, 2M) and dried by suction to afford the crude product (293mg). Recrystallisation from AcOH:water (1 : 1 , 3 times) gave the title compound (1 19mg). ¹ H NMR (499 MHz, d₆-DMSO) δ ppm 2.64 (s, 3 H) 3.41 (s, 3 H) 4.04 (s, 3 H) 7.84 (d, J=8.79 Hz, 1 H) 8.02 (d, J=9.77 Hz, 1 H) 8.31 (d, J=2.44 Hz, 1 H) 8.56 (d, J=2.44 Hz, 1 H) 8.64 (s, 1 H) 12.15 (br. s., 1 H)

LCMS (Method A9) Rt 17.61 min. MS m/z 395 [MH]+, 417 [MNa]+

LCMS (Method A8) Rt 15.91 min. MS m/z 395 [MH]+

Mpt: 218-220°C

Example 62: 1 -f5-chloro-6-fisobutyl(methyl)amino1pyridin-3-yl}-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To an 8ml reaction vial charged with a solution of 3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide [preparation 5] (50mg, 0.17mmol) in DMF (1 ml) was added copper acetate (63mg, 0.35mmol) and pyridine (35μΙ, 0.43mmol). The dark green solution was stirred at room temperature, then a solution of [3-chloro-5-(4, 4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-isobutyl-methylamine [preparation 29] (56mg, 0.17mmol) in DMF (1 ml) was added and the mixture stirred at 60°C for 16 hours open to the air. The mixture was partitioned between EtOAc (8ml) and a 5% aqueous EDTA solution (16ml). The phases were separated and the aqueous layer extracted again with EtOAc (4ml). The organics were combined and evaporated onto silica. The crude product was purified by column chromatography (ISCO, 12g column, dry load; heptane:EtOAc+10%AcOH 90: 10 to 0: 100) to afford the title compound as a white solid (17mg).

1 H NMR (400 MHz, CDCI₃) δ ppm 0.92 (d, J=6.64 Hz, 6 H) 1 .99 - 2.1 1 (m, 1 H) 2.68 (s, 3 H) 3.10 (s, 3 H) 3.35 (d, J=7.42 Hz, 2 H) 3.50 (s, 3 H) 7.63 (d, J=8.59 Hz, 1 H) 7.87 (d, J=2.34 Hz, 1 H) 7.92 (dd, J=8.59, 1 .56 Hz, 1 H) 8.33 (d, J=0.78 Hz, 1 H) 8.44 (d, J=2.34 Hz, 1 H).

LCMS (Method A6): Rt 3.29min. MS m/z 450 [MH]+, 448 [MH]-

Example 63: 1 -r5-chloro-6-(oxetan-3-ylmethoxy)pyridin-3-vn-3-cvclopropyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To a reaction vial containing 3-cyclopropyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide [preparation 10] (0.49mmol) and copper acetate (178mg, 0.98mmol) was added a solution of 3-chloro-2-(oxetan-3-ylmethoxy)-pyridine-5-boronic acid [preparation 34] (0.49mmol) in DMF (5ml) followed by pyridine (120μΙ, 1 .47mmol). The reaction vial was then warmed to 50°C for 16 hours with stirring. The solvent was concentrated in vacuo and the residue partitioned between DCM (20ml) and a mixture of aqueous KHS0₄ solution (10ml, 0.5M) and 5% aqueous EDTA solution (10ml). The phases were separated and the aqueous extracted with DCM (10ml). The organics were combined, evaporated onto silica gel and purified by column chromatography (ISCO Companion, silica 12g) eluting with a gradient of heptane and 90: 10 EtOAc:AcOH (10-50%). Additonal purification by preparative HPLC (Method A2) gave the title compound (7.2mg).

LCMS (Method A3): Rt 2.19min MS m/z 475 [MH]- Example 64: 1 -r5-chloro-6-i2-fluoro-2-methylpropoxy)pyridin-3-vn-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To a stirred solution of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 5] (55mg, 0.19mmol) and 3-chloro-2-(2-fluoro-2-methyl-propoxy)-5-(4, 4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridine [preparation 38] (75mg, 0.23mmol) in DMF (3ml) were added pyridine (38μΙ, 0.48mmol) and copper acetate (35mg, 0.19mmol). The reaction was heated at 60°C for 18 hours then left to stand at room temperature over the weekend. EtOAc and an aqueous solution of NH₄CI were added and the organic phase separated and washed with further NH₄CI solution and brine, dried over MgS0₄ and the solvent removed in vacuo. Crystallisation from I PA gave a solid, which was dried and triturated with MeOH to afford the title compound as a pale brown solid (22mg).

¹ H NMR (400 MHz, d₆-DMSO) δ ppm 1.45 (s, 3 H) 1 .51 (s, 3 H) 2.64 (s, 3 H) 3.40 (s, 3 H) 4.46 (s, 1 H) 4.51 (s, 1 H) 7.84 (d, 1 H) 8.03 (dd, J=8.88, 1 .66 Hz, 1 H) 8.35 (d, J=2.54 Hz, 1 H) 8.55 (d, J=2.54 Hz, 1 H) 8.64 (dd, J=1 .56, 0.78 Hz, 1 H) 12.17 (br s, 1 H)

LCMS: Rt 1 .74; MS m/z 455 [MH]+, 453 [MH]-

In addition to the above examples the following General Procedures were also used to prepare further examples according to Scheme 2, which are listed in Table 3: General Procedure 3: To 8ml reaction vials containing 3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide [preparation 5] (25mg, Ι ΟΟμηηοΙ) was added the appropriate boronic acid or ester of formula (VI) (125μηΊθΙ) followed by copper acetate (39mg, 200μηΊθΙ), pyridine (16μΙ, 200μmol) and DMF (1 ml). The vials were heated uncapped at 60°C for 16 hours. The reactions were quenched by addition of an aqueous solution of HCI (2ml, 2M) and the precipitate collected by filtration, then rinsed with water (1 ml). The precipitate was dissolved in DMSO (1 ml) and purified by preparative HPLC to give the compound of formula (I). General Procedure 4: A 1 .0M solution of N-(ethylsulfonyl)-1 H-indazole-5-carboxamide [preparation 26] in DMF was prepared and 75μΙ of solution (75μηΊθΙ, 1 .0eq) dispensed to 8ml reaction vials containing the boronic acid or ester of formula (VI) (Ι δΟμηηοΙ, 2.0eq) suspended in 0.675ml DCM. Cu(OAc)₂ (13.6mg, 75μηΊθΙ, 1 .0eq), pyridine (15μΙ, 150μηΊθΙ, 2.0eq) and 4 A molecular sieves (10mg) were added to each vial and the vials were capped and shaken at 60°C for 48 hours. The reaction mixtures were filtered and the filtrate concentrated using a vacuum centrifuge. The crude products were purified by preparative HPLC to afford the compounds of formula (I).

General Procedure 5: A 0.1 M solution of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide [preparation 5] in DMF was prepared and 750μΙ of solution (75μηΊθΙ, 1 .0eq) dispensed to 8ml reaction vials containing the boronic acid or ester of formula (VI) (150μηιοΙ, 2.0eq). Cu(OAc)₂ (13.6mg, 75μηιοΙ, 1.0eq), f-BuOK (75μΙ, 75μηιοΙ, 1 .0eq, 1 .0M in THF) and CsF (22.8mg, Ι δΟμηηοΙ, 2.0eq) were added to each vial and the vials were capped and shaken at 30°C for 16 hours. The reaction mixtures were filtered and the filtrate concentrated using a vacuum centrifuge. The crude products were purified by preparative HPLC to afford the compounds of formula (I).

General Procedure 6: A 0.1 M solution of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide [preparation 5] in DMF was prepared and 750μΙ of solution (75μηΊθΙ, 1 .0eq) dispensed to 8ml reaction vials containing the boronic acid or ester of formula (VI) (150μΓΤΐοΙ, 2.0eq). Cu(OAc)₂ (4.1 mg, 22.5μΓηοΙ, 0.3eq), f-BuOK (1 .0M in THF, 75μΙ, 75μηΊθΙ, 1 .Oeq) and CsF (1 1.6mg, 75μηΊθΙ, 1 .Oeq) were added to each vial and the vials were capped and shaken at 30°C for 24 hours. The reaction mixtures were concentrated using a vacuum centrifuge. The crude products were dissolved in DMSO, filtered and purified by preparative HPLC to afford the compounds of formula (I).

Table 3: Examples prepared using General Procedures 3, 4, 5 or 6, as indicated (wherein: 'GP' denotes General Procedure, 'P hplc' denotes Preparative HPLC Method, Ά hplc' denotes Analytical HPLC Method and Ά rt' denotes Analytical retention time (min)).

Table 3

P A

Ex. lUPAC Name GP A rt Ms m/z hplc hplc

1-(6-butoxy-5-chloropyridin-3-yl)-3-

65 methyl-N-(methylsulfonyl)-1 H- 3 A2 A3 4.04 435 [MH]- indazole-5-carboxamide

1-(5-chloro-6-ethoxypyridin-3-yl)-3-

66 methyl-N-(methylsulfonyl)-1 H- 3 A2 A3 3.6 407 [MH]- indazole-5-carboxamide

1-(5-chloro-6-isopropoxypyridin-3-yl)-

423 [MH]+

67 3-methyl-N-(methylsulfonyl)-1 H- 3 A1 A3 3.82

421 [MH]- indazole-5-carboxamide

1-(5-fluoro-6-methoxypyridin-3-yl)-3-

68 methyl-N-(methylsulfonyl)-1 H- 3 A2 A3 3.25 379 [MH]+ indazole-5-carboxamide

69 No example 69

1-[6-(cyclohexylmethoxy)pyridin-3-yl]-

70 N-(ethylsulfonyl)-1 H-indazole-5- 4 A23 A14 2.99 443 [MH]+ carboxamide

1-(6-isobutoxypyridin-3-yl)-3-methyl-

71 N-(methylsulfonyl)-1 H-indazole-5- 5 A24 A14 2.76 403 [MH]+ carboxamide P A

Ex. lUPAC Name GP A rt Ms m/z hplc hplc

3-methyl-N-(methylsulfonyl)-1 -(6-

72 piperidin-1 -ylpyridin-3-yl)-1 H-indazole- 4 A23 A1 1 2.76 414 [MH]+ 5-carboxamide

1 -(6-ethoxypyridin-3-yl)-3-methyl-N-

73 (methylsulfonyl)-l H-indazole-5- 6 A25 A1 1 3.06 375 [MH]+ carboxamide

3-methyl-N-(methylsulfonyl)-1 -(6-

74 morpholin-4-ylpyridin-3-yl)-1 H- 6 A24 A1 1 2.51 416 [MH]+ indazole-5-carboxamide

1 -[6-(cyclohexylmethoxy)pyridin-3-yl]-

75 3-methyl-N-(methylsulfonyl)-1 H- 6 A25 A13 2.49 443 [MH]+ indazole-5-carboxamide

Examples prepared according to Scheme 3

Example 76: 3-methyl-N-(methylsulfonyl)-1 -(6-pyrrolidin-1 -ylpyridin-3-yl)-1 H- indazole-5-carboxamide

To a microwave vial containing 1 -(6-chloropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide [preparation 12] (20mg, 55μηιοΙ) was added pyrrolidine (0.5ml). The vial was flushed with nitrogen, capped and heated at 100°C for 90 minutes. The solvent was concentrated in vacuo and the crude product purified by preparative HPLC (method A1 ) to afford the title compound (12.4mg).

LCMS (method A3): Rt 2.42min, MS m/z 400 [MH]+, 398 [MH]- Example 77: 1 -f5-chloro-6-(isobutylamino)pyridin-3-vn-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To a reaction vial containing 1-(5,6-dichloropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide [preparation 13] (15mg, 38μηιοΙ) in DMF (0.5ml) was added isobuytlamine (19μΙ, 0.19mmol) and potassium carbonate (5mg, 38μmol). The vial as flushed with nitrogen, capped, and stirred at 80°C for 2 hours and then at 60°C for 16 hours. Additional isobutylamine (19μΙ, 0.19mmol) and copper iodide (3.6mg, 19μηιοΙ) were added, the vial flushed with nitrogen and the solution heated at 60°C for a further 24 hours. After this time a small amount of sodium hydride was added and heating continued for 72 hours. The solvent was concentrated in vacuo and the crude product purified by preparative HPLC (method A1 ) to afford the title compound (1 .7mg).

LCMS (method A3): Rt 3.73min, MS m/z 436 [MH]+, 434 [MH]- In addition to the above examples the following General Procedure was also used to prepare further examples according to Scheme 3, which are listed in Table 4:

General Procedure 7: A 0.15M solution of 1 -(6-fluoropyridin-3-yl)-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 6] or 1 -(5-chloro-6- fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 7] in DMSO was prepared and 500μΙ (75μηΊθΙ, 1 .0eq) dispensed to 8ml reaction vials containing the amine of formula (VIII) (1 12.5μηΊθΙ, 1.5 eq). CS2CO3 (Ι δΟμηηοΙ, 2.0eq, 48.8mg) was added to each vial and the vials were capped and shaken at 150°C for 16 hours. The reaction mixtures were filtered and the filtrate purified by preparative HPLC to afford the compound of formula (I).

Table 4: Examples prepared using General Procedure 7 (wherein: 'P hplc' denotes Preparative HPLC Method, Ά hplc' denotes Analytical HPLC Method and Ά rt' denotes Analytical retention time (min)). Table 4

P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

3-methyl-1 -(6-{[(1 R)-1-

78 methylpropyl]amino}pyridin-3-yl)-N- A19 A1 1 2.21 402 [MH]+

(methylsulfonyl)-1 H-indazole-5-carboxamide

1-{6-[(2-methoxyethyl)amino]pyridin-3-yl}-3-

79 methyl-N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.02 404 [MH]+ carboxamide

1-[6-(cyclobutylamino)pyridin-3-yl]-3-methyl-

80 N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.20 400 [MH]+ carboxamide

1-{5-chloro-6-[(2R)-2-methylpyrrolidin-1-

81 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A18 A12 3.53 448 [MH]+ 1 H-indazole-5-carboxamide

3-methyl-1 -[6-(2-methylpiperidin-1-yl)pyridin-

82 3-yl]-N-(methylsulfonyl)-1 H-indazole-5- A19 A12 2.28 428 [MH]+ carboxamide

1-{6-[butyl(methyl)amino]pyridin-3-yl}-3-

83 methyl-N-(methylsulfonyl)-1 H-indazole-5- A19 A12 2.24 416 [MH]+ carboxamide

1-{6-[(cyclobutylmethyl)amino]pyridin-3-yl}-3-

84 methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A12 2.17 414 [MH]+ carboxamide

1-[6-(cyclohexylamino)pyridin-3-yl]-3-methyl-

85 N-(methylsulfonyl)-1 H-indazole-5- A19 A12 2.13 428 [MH]+ carboxamide

1-{6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-

86 yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- A17 A1 1 2.43 444 [MH]+ 5-carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1-{6-[(3R,4R)-3,4-difluoropyrrolidin-1 -

87 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A1 1 2.47 436 [MH]+ 1 H-indazole-5-carboxamide

1-{6-[(4,4-difluorocyclohexyl)amino]pyridin-3-

88 yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- A17 A1 1 2.48 464 [MH]+ 5-carboxamide

1-{6-[(cyclopentylmethyl)amino]pyridin-3-yl}-

89 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A12 2.31 428 [MH]+ carboxamide

3-methyl-1 -{6-[methyl(propyl)amino]pyridin-3-

90 yl}-N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.28 402 [MH]+ carboxamide

1-[6-(isopropylamino)pyridin-3-yl]-3-methyl-

91 N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.28 388 [MH]+ carboxamide

3-methyl-N-(methylsulfonyl)-1-{6-

92 [(tetrahydrofuran-3-ylmethyl)amino]pyridin-3- A17 A1 1 2.13 430 [MH]+ yl}-1 H-indazole-5-carboxamide

1-[6-(diethylamino)pyridin-3-yl]-3-methyl-N-

93 A19 A1 1 2.24 402 [MH]+ (methylsulfonyl)-1 H-indazole-5-carboxamide

3-methyl-1 -{6-[(3S)-3-methylpiperidin-1 -

94 yl]pyridin-3-yl}-N-(methylsulfonyl)-1 H- A17 A12 2.42 428 [MH]+ indazole-5-carboxamide

1-[6-(3-fluoropyrrolidin-1-yl)pyridin-3-yl]-3-

95 methyl-N-(methylsulfonyl)-1 H-indazole-5- A20 A1 1 2.23 418 [MH]+ carboxamide

1-[6-(sec-butylamino)pyridin-3-yl]-3-methyl-

96 N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.20 402 [MH]+ carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1-{6-[cyclopropyl(methyl)amino]pyridin-3-yl}-

97 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A1 1 2.27 400 [MH]+ carboxamide

3-methyl-N-(methylsulfonyl)-1-[6-(tetrahydro-

98 2H-pyran-3-ylamino)pyridin-3-yl]-1 H- A20 A1 1 2.19 430 [MH]+ indazole-5-carboxamide

1-[6-(cyclopentylamino)pyridin-3-yl]-3-methyl-

99 N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.25 414 [MH]+ carboxamide

1-{6-

[(cyclopropylmethyl)(methyl)amino]pyridin-3-

100 A20 A1 1 2.44 414 [MH]+ yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- 5-carboxamide

3-methyl-N-(methylsulfonyl)-1-{6- [(tetrahydro-2H-pyran-2-

101 A20 A1 1 2.36 444 [MH]+ ylmethyl)amino]pyridin-3-yl}-1 H-indazole-5- carboxamide

1-{6-[(3,3-difluorocyclohexyl)amino]pyridin-3-

102 yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- A20 A1 1 2.54 464 [MH]+ 5-carboxamide

3-methyl-N-(methylsulfonyl)-1-[6-(tetrahydro-

103 2H-pyran-4-ylamino)pyridin-3-yl]-1 H- A20 A1 1 2.14 430 [MH]+ indazole-5-carboxamide

1-{6-[(cyclopropylmethyl)amino]pyridin-3-yl}-

104 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.16 400 [MH]+ carboxamide

1-(6-{[(1 S,3S)-3- fluorocyclopentyl]amino}pyridin-3-yl)-3-

105 A18 A1 1 2.38 432 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1-{6-[(3S)-3-methoxypyrrolidin-1-yl]pyridin-3-

106 yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- A20 A1 1 2.19 430 [MH]+ 5-carboxamide

1-{6-[(3,3-difluorocyclopentyl)amino]pyridin-

107 3-yl}-3-methyl-N-(methylsulfonyl)-1 H- A18 A1 1 2.54 450 [MH]+ indazole-5-carboxamide

3-methyl-1 -[6-(2-methylpyrrolidin-1 -yl)pyridin-

108 3-yl]-N-(methylsulfonyl)-1 H-indazole-5- A20 A1 1 2.3 414 [MH]+ carboxamide

3-methyl-N-(methylsulfonyl)-1-{6-[4-

109 (trifluoromethyl)piperidin-1-yl]pyridin-3-yl}- A18 A15 1.86 482 [MH]+ 1 H-indazole-5-carboxamide

3-methyl-N-(methylsulfonyl)-1-{6- [methyl(tetrahydro-2H-pyran-3-

1 10 A18 A1 1 2.5 444 [MH]+ yl)amino]pyridin-3-yl}-1 H-indazole- 5- carboxamide

1-[6-(ethylamino)pyridin-3-yl]-3-methyl-N-

1 1 1 A18 A1 1 2.14 374 [MH]+ (methylsulfonyl)-1 H-indazole-5-carboxamide

3-methyl-N-(methylsulfonyl)-1-{6-[(4,4,4-

1 12 trifluoro-2-methyl butyl )amino]pyridin-3-yl}- A18 A1 1 2.67 470 [MH]+ 1 H-indazole-5-carboxamide

1-{6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-

1 13 yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- A21 A1 1 2.43 444 [MH]+ 5-carboxamide

1-[5-chloro-6-(3-fluoropyrrolidin-1 -yl)pyridin-

1 14 3-yl]-3-methyl-N-(methylsulfonyl)-1 H- A18 A12 3.12 452 [MH]+ indazole-5-carboxamide

1-[5-chloro-6-(ethylamino)pyridin-3-yl]-3-

1 15 methyl-N-(methylsulfonyl)-1 H-indazole- 5- A18 A1 1 3.06 408 [MH]+ carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

3-methyl-N-(methylsulfonyl)-1-(6-{[(2R)-

1 16 4,4,4-trifluoro-2-methylbutyl]amino}pyridin-3- A18 A1 1 2.67 470 [MH]+ yl)-1 H-indazole-5-carboxamide

1-{5-chloro-6-[(3R,4R)-3,4-difluoropyrrolidin-

1 17 1-yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A18 A12 3.16 470 [MH]+ 1 H-indazole-5-carboxamide

1 -[6-(2-cycl opro py I pyrrol i d i n - 1 -y I ) py rid i n-3-

1 18 yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- A18 A12 2.32 440 [MH]+ 5-carboxamide

1-[6-(4-methoxypiperidin-1-yl)pyridin-3-yl]-3-

1 19 methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A1 1 2.49 444 [MH]+ carboxamide

1-[6-(1 ,3-dihydro-2H-isoindol-2-yl)pyridin-3-

120 yl]-3-methyl-N-(methylsulfonyl)-1 H-indazole- A17 A12 2.58 448 [MH]+ 5-carboxamide

1-[6-(4,4-dimethylpiperidin-1 -yl)pyridin-3-yl]-

121 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A18 A12 2.69 442 [MH]+ carboxamide

1-[5-chloro-6-(dimethylamino)pyridin-3-yl]-3-

122 methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A1 1 3.25 408 [MH]+ carboxamide

1-[6-(3-methoxypiperidin-1-yl)pyridin-3-yl]-3-

123 methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A1 1 2.55 444 [MH]+ carboxamide

3-methyl-1 -[6-(4-methylpiperidin-1-yl)pyridin-

124 3-yl]-N-(methylsulfonyl)-1 H-indazole-5- A18 A12 2.55 428 [MH]+ carboxamide

1-[6-(4-isopropylpiperidin-1 -yl)pyridin-3-yl]-3-

125 methyl-N-(methylsulfonyl)-1 H-indazole-5- A22 A12 2.81 456 [MH]+ carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1-{6-[(2S)-2-(methoxymethyl)pyrrolidin-1-

126 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A1 1 2.39 444 [MH]+ 1 H-indazole-5-carboxamide

1-{6-[(3S)-3-fluoropyrrolidin-1 -yl]pyridin-3-yl}-

127 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A1 1 2.31 418 [MH]+ carboxamide

1 -{6-[(1 R,4S)-2-azabicyclo[2.2.1 ]hept-2-

128 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A1 1 2.35 426 [MH]+ 1 H-indazole-5-carboxamide

1-{6-[(2R)-2-(methoxymethyl)pyrrolidin-1-

129 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A1 1 2.39 444 [MH]+ 1 H-indazole-5-carboxamide

1-[6-(dimethylamino)pyridin-3-yl]-3-methyl-N-

130 A17 A1 1 2.15 374 [MH]+ (methylsulfonyl)-1 H-indazole-5-carboxamide

1 -{6-[2-(methoxymethyl)pyrrolidin-1 -

131 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A1 1 2.39 444 [MH]+ 1 H-indazole-5-carboxamide

1 -{5-ch loro-6-[(3S)-3-f luoropyrrol idi n- 1 -

132 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A12 3.12 452 [MH]+ 1 H-indazole-5-carboxamide

1-{6-[(3R)-3-methoxypyrrolidin-1-yl]pyridin-3-

133 yl}-3-methyl-N-(methylsulfonyl)-1 H-indazole- A17 A1 1 2.24 430 [MH]+ 5-carboxamide

1-{5-chloro-6-

[cyclobutyl(methyl)amino]pyridin-3-yl}-3-

134 A17 A12 3.58 448 [MH]+ methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide

1 -{6-[(1 R,5S)-3-azabicyclo[3.3.1 ]non-3-

135 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A22 A12 2.60 454 [MH]+ 1 H-indazole-5-carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1 -{6-[(3R)-3-f luoropyrrolidin-1 -yl]pyridin-3-yl}-

136 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A17 A1 1 2.30 418 [MH]+ carboxamide

1-{5-chloro-6-[(3R)-3-fluoropyrrolidin-1 -

137 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A12 3.12 452 [MH]+ 1 H-indazole-5-carboxamide

1-[6-(cyclopropylamino)pyridin-3-yl]-3-

138 methyl-N-(methylsulfonyl)-1 H-indazole-5- A19 A1 1 2.24 386 [MH]+ carboxamide

1-[5-chloro-6-(propylamino)pyridin-3-yl]-3-

139 methyl-N-(methylsulfonyl)-1 H-indazole-5- A18 A14 2.53 422 [MH]+ carboxamide

1-{6-[cyclobutyl(methyl)amino]pyridin-3-yl}-3-

140 methyl-N-(methylsulfonyl)-1 H-indazole-5- A18 A1 1 2.54 414 [MH]+ carboxamide

3-methyl-N-(methylsulfonyl)-1-[6-

141 (propylamino)pyridin-3-yl]-1 H-indazole-5- A19 A1 1 2.31 388 [MH]+ carboxamide

1-[5-chloro-6-(cyclobutylamino)pyridin-3-yl]-

142 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A18 A14 2.67 434 [MH]+ carboxamide

1 -{6-[(1 S,5R)-6-azabicyclo[3.2.1 ]oct-6-

143 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A12 2.21 440 [MH]+ 1 H-indazole-5-carboxamide

1 -{6-[(1 R,4S)-2-azabicyclo[2.2.1 ]hept-2-yl]-5-

144 chloropyridin-3-yl}-3-methyl-N- A17 A12 3.49 460 [MH]+

(methylsulfonyl)-1 H-indazole-5-carboxamide

1-[5-chloro-6-(3,3-difluoropyrrolidin-1 -

145 yl)pyridin-3-yl]-3-methyl-N-(methylsulfonyl)- A17 A12 3.33 470 [MH]+ 1 H-indazole-5-carboxamide P A

Ex. lUPAC Name A rt Ms m/z hplc hplc

1-[5-chloro-6-(isopropylamino)pyridin-3-yl]-3-

146 methyl-N-(methylsulfonyl)-1 H-indazole-5- A18 A12 3.18 422 [MH]+ carboxamide

1-[6-(3,5-dimethylpiperidin-1 -yl)pyridin-3-yl]-

147 3-methyl-N-(methylsulfonyl)-1 H-indazole-5- A18 A12 2.83 442 [MH]+ carboxamide

1-{5-chloro-6-[(2S)-2-methylpyrrolidin-1-

148 yl]pyridin-3-yl}-3-methyl-N-(methylsulfonyl)- A17 A12 3.37 448 [MH]+ 1 H-indazole-5-carboxamide

Examples prepared according to Schemes 4 to 7

Example 149: 1 -i5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N- trifluoro methyl )sulfonyl1-1 H-indazole-5-carboxamide

To a stirred solution of 1-(5-chloro-6-isobutoxy-pyridin-3-yl)-3-methyl-1 H-indazole-5- carboxylic acid [preparation 16] (150mg, 0.42mmol) in DCM was added WSCDI (160mg, 0.83mmol), DIPEA (254μΙ, 1.46mmol), DMAP (51 mg, 0.42mmol) and trifluoromethanesulfonamide (62mg, 0.42mmol). The reaction was stirred at room temperature for 16 hours. After evaporation of the solvent in vacuo, the crude product was solubilised in DMSO and purified by reverse phase column chromatography to afford the product (150mg). Further purification by column chromatography eluting with EtOAc in heptane 50% to 100% gave the title compound (90mg).

1H NMR (400 MHz, d₆-DMSO) δ ppm 1.00 (m, 6H), 2.10 (m, 1 H), 2.60 (s, 3H), 4.20 (m, 2H), 7.70 (m, 1 H), 8.05 (m, 1 H), 8.30 (m, 1 H), 8.40 (m, 1 H), 8.50 (m, 1 H).

LCMS: Rt 1.92min. MS m/z 491 [MH]+, 489 [MH]- Example 150: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N-r(2.2.2- trifluoroethyl)sulfonyll-1 H-indazole-5-carboxamide

To a stirred solution of 1 -(5-chloro-6-isobutoxy-pyridin-3-yl)-3-methyl-1 H-indazole-5- carboxylic acid [preparation 16] (250mg, 0.70mmol) in DCM was added WSCDI (266mg, 1 .40mmol), DI PEA (424μΙ, 2.43mmol), DMAP (85mg, 0.70mmol) and 2,2,2- trifluoroethanesulfonic acid amide [preparation 39] (136mg, 0.83mmol). The reaction was stirred at room temperature for 16 hours. Silica was added to the reaction mixture and the volatiles concentrated in vacuo. The product was purified by silica gel column chromatography eluting with EtOAc in heptane 50% to 100% to afford product (170mg). Purification by reverse phase chromatography (30g Biotage column; gradient elution with acetonitrile:water + 0.1 % formic acid; 5% acetonitrile for 2 column volumes, 5% - 100% acetonitrile over 10 column volumes, 100% acetonitrile for 2 column volumes) gave the title compound (124mg).

¹ H NMR (400 MHz, d₆-DMSO) δ ppm 1.00 (m, 6H), 2.10 (m, 1 H), 2.60 (s, 3H), 4.20 (m, 2H), 4.80 (m, 2H), 7.80 (m, 1 H), 8.00 (m, 1 H), 8.30 (m, 1 H), 8.45 (m, 1 H), 8.60 (m, 1 H).

Example 151 : 1 -r5-chloro-6-ioxetan-3-ylmethoxy)pyridin-3-vn-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To a solution of 1 -[5-chloro-6-(oxetan-3-ylmethoxy)-pyridin-3-yl]-3-methyl-1 H-indazole- 5-carboxylic acid [preparation 18] (210mg, 0.50mmol) in DCM (10ml) was added methanesulfonamide (96mg, 1 .01 mmol), DMAP (124mg, 1 .01 mmol), and WSCDI (194mg, 1 .01 mmol). The solution was stirred at room temperature for 16 hours under nitrogen. The mixture was washed with an aqueous solution of KHS0₄ (0.5 M) and the organics separated using a phase separation cartridge. The aqueous phase was extracted with DCM (10ml). The extracts were combined and evaporated onto silica. Purification by FC (ISCO Companion, silica 12g, eluting with a gradient of heptane to 90: 10 EtOAc:AcOH (25-75%)) gave a clear oil (139.5mg). Additonal purification by preparative HPLC (method A2, in two batches) gave the title compound (1 1 .6mg).

LCMS (method A3): Rt 3.22min. MS m/z 451 [MH]+, 449 [MH]-

Example 152: 3-methyl-N-(methylsulfonyl)-1 -r6-(2,2,2-trifluoroethoxy)pyridin-3-vn-

1 H-indazole-5-carboxamide

A mixture of methyl 3-methyl-1 -[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]-1 H-indazole-5- carboxylate [preparation 20] (130mg,0.356mmol) and KOH (202mg, 3.56mmol) in DCM/MeOH/water (5ml, 5:5:1 ) was heated to reflux under nitrogen for 16 hours. The mixture was concentrated to near dryness, then partitioned between DCM/MeOH (45ml, 95:5) and an aqueous solution of HCI (40ml, 2M). The aqueous phase was washed with further DCM/MeOH (20ml) then the organics combined, passed through a phase separation cartridge and concentrated in vacuo to give the intermediate acid, which was used without further purification. The intermediate acid was suspended in DCM (3ml) then DMAP (130mg, 1 .07mmol) added followed by WSCDI (205mg, 1 .07mmol). The reaction mixture was stirred under nitrogen at room temperature for 15 minutes, then methanesulphonamide (68mg, 0.712mmol) was added and the reaction mixture stirred under nitrogen at room temperature over the weekend. The mixture was diluted with DCM (10ml), partitioned with an aqueous solution of HCI (10ml) and the organics passed through a phase separation cartridge. The organics were evaporated onto silica and purified on a 5g silica column, eluting with 0-100% EtOAc in heptane followed by 10% MeOH in EtOAc. Analysis of fractions by TLC and LCMS shows that product fractions had co-eluted with a by-product, so product fractions were re-combined and dissolved in minimal DCM then re-purified (ISCO companion, 4g silica column using a gradient of 0-5% MeOH in DCM). The desired fractions were combined and concentrated in vacuo to afford the title compound (54mg).

¹ HNMR (400MHz, d₆-DMSO) δ ppm 2.63 (s, 3H), 3.39 (s, 3H), 5.07 (q, 2H), 7.21 (dd, 1 H), 7.80 (dd, 1 H), 8.01 (dd, 1 H), 8.19 (dd, 1 H), 8.60 (dd, 1 H), 8.63 (dd, 1 H), 12.15 (br, 1 H)

LCMS (Method A6) Rt 2.73min. MS m/z 429 [MH]+, 427 [MH]-

Example 153: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-cvclopropyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To a solution of 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-cyclopropyl-1 H-indazole-5- carboxylic acid [preparation 15] (55mg, 0.14mmol) in DCM (10ml) was added methanesulfonamide (27mg, 0.29mmol), DMAP (35mg, 0.20mmol), and WSCDI (55mg, 0.29mmol). The solution was stirred for 16 hours and then washed with an aqueous solution of KHS0₄ (5ml, 1 M). The organics were separated using a phase separation cartridge and the aqueous phase extracted with additional DCM (5ml). The organics were combined and evaporated onto silica gel. Purification by column chromatography (ISCO Companion, silica, 4g eluting with a gradient of heptane and 90: 10 EtOAc:AcOH(10->50%)) gave the title compound as a white solid (51 .9mg).

1 H NMR (400 MHz, d₆-DMSO) δ ppm 1 .01 (d, 6H), 1 .13-1 .15 (m, 4H), 2.07-2.14 (m, 1 H), 2.40-2.45 (m, 1 H), 3.40 (s, 3H), 4.20 (d, 2H), 7.81 (d, 1 H), 8.00 (dd, 1 H), 8.28 (d, 1 H), 8.51 (d, 1 H), 8.63 (dd, 1 H), 12.24 (br s, 1 H). LCMS (Method A5) Rt 1 .77min, MS m/z 463 [MH]+, 461 [MH]-

Example 154: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-ethyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

(i) A solution of 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-iodo-N-(methylsulfonyl)-1 H- indazole-5-carboxamide [preparation 23] (50mg, 91 μηιοΙ), vinylboronic acid pinacol ester (30μΙ_, 180μηιοΙ) and CS2CO3 (74mg, 227μηιοΙ) in 1 ,4-dioxane (4ml) and water (0.8ml) was degassed by evacuating and flushing with nitrogen 6 times. Pd(PPh₃)₄ (10.4mg, 9μηιοΙ) was added and the mixture heated to 100°C under nitrogen for 6 hours, then allowed to cool. The solvent was concentrated in vacuo and the residue partitioned between DCM and an aqueous 10% KHS0₄ solution, and the organics passed through a phase separation cartridge and concentrated in vacuo. Purification by column chromatography (2g Si column, eluting with 0-50% EtOAc in heptane) gave the intermediate C3-vinyl indazole (26mg).

(ii) The C3-vinyl indazole (26mg) was dissolved in EtOH (3ml) and 10% Pd/C (5mg) added followed by triethylsilane (150μΙ, 0.91 mmol). The mixture was stirred under nitrogen at reflux for 5 hours. The reaction was filtered through arbocel, washed with EtOH, and the filtrate concentrated in vacuo. The residue was partitioned between DCM and an aqueous KHS0₄ solution, and the organics passed through a phase separation cartridge and concentrated in vacuo. The crude product was purified by preparative HPLC (method A2) to afford the title compound (13.8mq).

LCMS (method A4): Rt 2.75min, MS m/z 451 [MH]+, 449 [MH]- Example 155: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-isopropyl-N-(methylsulfonyl)- 1 H-indazole-5-carboxamide

(i) A solution of 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-iodo-N-(methylsulfonyl)-1 H- indazole-5-carboxamide [preparation 23] (50mg, 91 μηιοΙ), isoprenylboronic acid pinacol ester (20μΙ, 109μηιοΙ) and Cs₂C0₃ (74mg, 227μηιοΙ) in 1 ,4-dioxane (4ml) and water (0.8ml) was degassed by evacuating and flushing with nitrogen 6 times. Pd(PPh₃)₄ (10.4mg, 9μηιοΙ) was added and the mixture heated to 100°C under nitrogen for 2 hours and then allowed to cool. The solvent was concentrated in vacuo and the residue partitioned between DCM and an aqueous 10% KHS0₄ solution. The organics passed through a phase separation cartridge and concentrated in vacuo. Purification by column chromatography (2g Si column, eluting with 0-100% EtOAc in heptane) gave the intermediate C3-isoprenyl indazole (33mg).

(ii) The C3-isoprenyl indazole (33mg) was dissolved in EtOH (5ml) and 10% Pd/C (5mg) added followed by triethylsilane (100μΙ, 0.63mmol). The mixture was stirred under nitrogen at reflux for 16 hours. Additional 10% Pd/C (5mg) and triethylsilane (150μΙ, 0.91 mmol) were added and the mixture stirred under nitrogen at reflux for a further 5 hours. The reaction was filtered through arbocel, washed with EtOH, and the filtrate concentrated in vacuo. The crude product was purified by preparative HPLC (method A2) to afford the title compound (16.6mg).

LCMS (method A4): Rt 2.66min, MS m/z 465 [MH]+, 463 [MH]- Example 156: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-N-(methylsulfonyl)-1 H-indazole- 5-carboxamide

To a solution of 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-iodo-N-(methylsulfonyl)-1 H- indazole-5-carboxamide [preparation 23] (50mg, 0.091 mmol) in DMSO (1 .5ml) in a reaction vial was added CS2CO3 (59mg, 0.18mmol), Cu(acac)2 (7.9mg, 0.03mmol) and pentanedione (20μΙ_, 0.195mmol). The vial was capped and heated to 100°C for 16 hours. The mixture was partitioned between EtOAc and saturated aqueous EDTA solution. The organic phase was separated and washed with water (2x10ml), dried over MgS0₄ and concentrated in vacuo. The crude product was purified by preparative HPLC (method A2) to afford the title compound (13mg).

LCMS (method A3): Rt 3.70min, MS m/z 423 [MH]+, 421 [MH]-

Example 157: 1 -f6-(isobutylamino)pyridin-3-yl1-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

To a vial containing isobutylamine (25μΙ, 0.25mmol) was added CS2CO3 (approx 35mg, 0.1 1 mmol) and solution of 1 -(5-chloro-6-fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)- 1 H-indazole-5-carboxamide [preparation 7] (20mg, 0.05mmol) in DMSO (0.5ml). The vial was flushed with nitrogen, capped and stirred at 60°C for a period of 72 hours and then at 100°C for a further 24 hours. The reaction mixture was filtered, diluted to 1 ml volume with DMSO and the crude material purified by preparative HPLC (method A1 ) to give the title compound (9.3mg).

LCMS (method A4): Rt 2.00min, MS m/z 402 [MH]+, 400 [MH]- Example 158: 1 -f6-risobutylimethyl)amino1pyridin-3-yl>-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

To a vial containing a solution of 1-(5-chloro-6-fluoropyridin-3-yl)-3-methyl-N- (methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 7] (25mg, 0.063mmol) in DMSO (0.5ml) was added Cs₂C0₃ (approx 45mg, 0.14mmol) and N- methylisobutylamine (38μΙ, 0.32mmol). The vial was flushed with nitrogen, capped and stirred at 100°C for 24 hours. The reaction mixture was filtered, diluted to 1 ml volume with DMSO and the crude material purified by preparative HPLC (method A2) to give the title compound (15.7mg).

LCMS (method A3): Rt 2.88min, MS m/z = 416 [MH]+, 414 [MH]-

Example 159: 1 -(5-chloro-6-cvclopropylpyridin-3-yl)-3-methyl-N-(methylsulfonyl)- 1 H-indazole-5-carboxamide

To a stirred solution of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide (Preparation 5, 500 mg, 1 .97 mmol) in degassed DMF (2 mL) was added Copper (I I) acetate (717 mg, 3.95 mmol). The reaction was stirred at room temperature for 5 minutes then triethylamine (0.82 mL, 5.92 mmol) added dropwise. The mixture was heated at 70 °C for 15 min then 3-chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine (Preparation 41 , 552 mg, 1 .97 mmol) was added dropwise. The reaction was stirred under air at 70 °C overnight. The reaction was cooled to room temperature and partitioned between DCM (75 mL) and 10% aq. EDTA solution (50 ml_). The two layers were separated and the aqueous layer extracted with DCM (50 ml_). The combined organic extracts were washed with 10% aq. EDTA solution (50 ml.) and brine (50 ml_), dried over MgS0₄, filtered and the solvent removed in vacuo. The crude material was purified by flash column chromatography eluting with DCM:MeOH:AcOH (98:2:0.001 ) followed by trituration with EtOAc to afford the title compound as a white solid (45 mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .08-1 .14 (m, 2H), 1 .16-1 .20 (m, 2H), 2.56-2.60 (m, 1 H), 2.70 (s, 3H), 3.52 (s, 3H), 7.72 (d, 1 H), 7.94 (d, 1 H), 7.98 (s, 1 H), 8.36 (s, 1 H), 8.74 (d, 1 H) and 8.88 (br s, 1 H)

LCMS: Rt 3.39 min, MS m/z 405 [MH]+

Example 160: 1 -i5-chloro-6-cvclopropylpyridin-3-yl)-4-fluoro-3-methyl-N-

(methylsulfonyl)-1 H-indazole-5-carboxamide

To a solution 1 -(5-chloro-6-cyclopropylpyridin-3-yl)-4-fluoro-3-methyl-1 H-indazole-5- carboxylic acid (Preparation 47, 32 mg, 0.09 mmol) in dichloromethane was added WSCDI (27 mg, 0.14 mmol) and DMAP (17 mg, 0.14 mmol). The reaction was allowed to stir at room temperature for 20 minutes, before the addition of methane sulfonamide (17 mg, 0.19 mmol) and DI PEA (0.03 ml_, 0.19 mmol). The reaction was allowed to stir at room temperaute for 18 hours. The solvent was removed in vacuo to leave a yellow solid. The crude material was purified by flash column chromatography (silica), eluting first with ethyl acetate, followed by 9:1 methanohethyl acetate to afford an off white solid. The material was further purified by preparative HPLC to provide the title compound (3.6 mg, 9%). ¹H NMR (400 MHz, MeOD) δ ppm 1.06-1.17 (m, 4H), 2.57-2.65 (m, 1H), 2.74 (s, 3H), 3.35 (s, 3H), 7.57 (d, 1H), 7.78-7.84 (m, 1H), 8.13 (s, 1H), 8.72 (s, 1H)

1⁹F NMR (400 MHz, MeOD) δ ppm -119 (s)

LCMS: Rt 2.73 min, MS m/z 423 [MH]+

Example 161: 1-i5-chloro-6-cvclopropylpyridin-3-yl)-6-fluoro-3-methyl-N-

(methylsulfonyl)- H-indazole-5-carboxamide

/V,/V-Diisopropylethylamine (83 μΙ, 0.47 mmol) was added to a solution of 1-(5-chloro-6- cyclopropylpyridin-3-yl)-6-fluoro-3-methyl-i/-/-indazole-5-carboxylic acid (Preparation 51, 41 mg, 0.12 mmol), methyl sulfonamide (17 mg, 0.18 mmol) and HATU (68 mg, 0.18 mmol) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 18 hours, and then concentrated in vacuo. The crude compound was purified by flash chromatography (silica gel) eluting with ethyl acetate:methanol (gradient from 100:0 to 90:10) to give the title compound as a white solid (12 mg).

¹H NMR (400 MHz, c^-dmso): δ ppm 0.98-1.13 (m, 4H), 2.51-2.55 (m, 1H), 2.60 (s, 3H), 3.33 (s, 3H), 7.82 (d, 1H), 8.21 (d, 1H), 8.28 (d, 1H), 8.81 (d, 1H)

1⁹F NMR (400 MHz, d⁶-dmso): δ ppm -113 (dd)

LCMS Rt = 3.37 minutes, MS m/z 423 [MH]⁺ Example 162: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-6-fluoro-3 -methyl -N-

(methylsulfonyl)-1 H-indazole-5-carboxamide

To a solution 1 -(5-chloro-6-isobutoxypyridin-3-yl)-6-fluoro-3-methyl-1 H-indazole-5- carboxylic acid (Preparation 54, 92 mg, 0.24 mmol) in dichloromethane (5 mL) was added WSCDI (70 mg, 0.36 mmol), DMAP (44 mg, 0.36 mmol), triethylamine (49 mg, 0.48 mmol) and methanesulfonamide (35 mg, 0.36 mmol). The reaction was allowed to stir at room temperature for 18 hours. The mixture was diluted with water (20 mL) and extracted with DCM (3 x 30 mL), washed with 0.1 M aqueous HCI (2 x 10 mL), water (10 mL) and dried over MgS0₄. The solvent was removed in vacuo to leave a yellow residue. The crude material was purified by flash column chromatography on silica, eluting first with cyclohexane, followed by cyclohexane:ethyl acetate 1 : 1 to afford the title compound as an off white solid (62 mg, 56 %).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .06 (d, 6H), 2.18 (m, 1 H), 2.66 (s, 3H), 3.47 (s, 3H), 4.21 (d, 2H), 7.29 (d, 1 H), 7.96 (d, 1 H), 8.31 (d, 1 H), 8.59 (d, 1 H)

1⁹F NMR (400 MHz, CDCI₃) δ ppm -1 13 (dd)

LCMS (acidic, 4.5 min): Rt 3.71 min, MS m/z 455 [MH]+ Example 163: 1 -(5-chloro-6-((1 -methylcvclopropyl)methoxy)pyridin-3-yl)-6-fluoro- 3-methyl-N-imethylsulfonyl)-1 H-indazole-5-carboxamide

To a solution 1 -(5-chloro-6-((1 -methylcyclopropyl)methoxy)pyridin-3-yl)-6-fluoro-3- methyl-1 H-indazole-5-carboxylic acid (Preparation 57, 460 mg, 1 .18 mmol) in dichloromethane was added WSCDI (339 mg, 1 .77 mmol), DMAP (216 mg, 1 .77 mmol), triethylamine (239 mg, 2.36 mmol) and methanesulfonamide (168 mg, 1 .77 mmol). The reaction was allowed to stir at room temperature for 18 hours. The mixture was diluted with water (20 mL) and extracted with DCM (3 x 30 mL), washed with 0.1 M aqueous HCI (2 x 20 mL), water (30 mL) and dried over MgS0₄. The solvent was removed in vacuo to leave a yellow residue. The crude material was purified by flash column chromatography on silica, eluting first with cydohexane, followed by cyclohexane:ethyl acetate 70:30 to afford the title compound as an off white solid (225 mg, 41 %).

1 H NMR (400 MHz, CDCI₃) δ ppm 0.46 (m, 2H), 0.62 (m, 2H), 1 .27 (s, 3H), 2.67 (s, 3H), 3.47 (s, 3H), 4.25 (d, 2H), 7.29 (d, 1 H), 7.96 (d, 1 H), 8.29 (d, 1 H), 8.60 (d, 1 H), 8.85 (br.s, 1 H)

¹⁹F NMR (400 MHz, CDCI₃) δ ppm -1 13 (dd)

LCMS (acidic, 4.5 min): Rt 3.70 min, MS m/z 467 [MH]+ Preparation 1 : methyl 3-iodo-1-(tetrahvdro-2H-pyran-2-yl)-1 H-indazole-5- carboxylate

To a solution of methyl 3-iodo-1 H-indazole-5-carboxylate (45g, 0.15mol) in anhydrous DCM (500ml) was added 3,4-dihydro-2H-pyran (18.77g, 0.22mol) and 4-toluenesulfonic acid (5.13g, 0.03mol) at room temperature. The mixture was stirred at room temperature for 5 hours. The mixture was washed with saturated aqueous NaHCC>3 solution (150ml), brine (100ml) and dried over Na₂S0₄. The solution was filtered and concentrated in vacuo to give the crude product as a solid, which was washed with methanol (2x250ml) to afford the title compound as a light yellow solid (51 .1 g, 89%).

1 H NMR (400MHz CDCI₃): δ 1 .70-1 .81 (m, 3H), 2.08-2.19 (m, 2H), 2.53-2.60 (m, 1 H), 3.73-3.79 (m, 1 H), 3.98 (s, 3H), 4.02-4.06 (m, 1 H), 5.72-5.75 (m, 1 H), 7.60-7.62 (d, 1 H), 8.12-8.15 (d, 1 H), 8.25 (s, 1 H)

MS m/z 408.9 [MNa]+, 386.9 [MH]+

Preparation 2: methyl 3-methyl-1 -(tetrahvdro-2H-pyran-2-yl)-1 H-indazole-5- carboxylate

A solution of methyl 3-methyl-1 H-indazole-5-carboxylate (100g, 0.53mol), 3,4-dihydro- 2H-pyran (88.6g, 1.05mol) and 4-toluenesulfonic acid (10.3g, 0.053mol) in THF (1 .5L) was stirred at 80°C for 5 hours. The reaction mixture was added to water (500ml) and extracted with EtOAc (3x1 L). The organic layer was dried over Na₂S0₄, and concentrated in vacuo to afford the title compound as a white solid (100g, 70%). ¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .61 - 1 .69 (m, 1 H) 1 .71 - 1 .84 (m, 2 H) 2.00 - 2.09 (m, 1 H) 2.10 - 2.19 (m, 1 H) 2.49 - 2.60 (m, 1 H) 2.61 (s, 3 H) 3.70 - 3.80 (m, 1 H) 3.95 (s, 3 H) 4.05 - 4.12 (m, 1 H) 5.65 (dd, 1 H) 7.52 (dd, 1 H) 8.06 (dd, 1 H) 8.43 (dd, 1 H) Preparation 3: 3-methyl-1 -itetrahydro-2H-pyran-2-yl)-1 H-indazole-5-carboxylic acid

A solution of methyl 3-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-5-carboxylate [preparation 2] (100g, 0.363mol) and LiOH (26.2g, 1 .1 mol) in THF (1 L) was stirred at 80°C for 5 hours. The reaction mixture was acidified with NaHS0₄ to pH 3 and washed with Et₂0 (2x200ml) to afford the title compound as a white solid (88g, 93%).

1 H NMR (400 MHz, CDCI₃) δ ppm 1 .61 - 1 .72 (m, 1 H) 1 .74 - 1 .86 (m, 2 H) 2.01 - 2.10 (m, 1 H) 2.1 1 - 2.22 (m, 1 H) 2.49 - 2.61 (m, 1 H) 2.64 (s, 3 H) 3.70 - 3.82 (m, 1 H) 4.05 - 4.15 (m, 1 H) 5.68 (dd, 1 H) 7.57 (dd, 1 H) 8.13 (dd, 1 H) 8.53 (dd, 1 H)

Preparation 4: 3-methyl-N-(methylsulfonyl)-1 -itetrahydro-2H-pyran-2-yl)-1 H- indazole-5-carboxamide

A solution of 3-methyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-5-carboxylic acid [preparation 3] (80g, 0.307mol), methanesulphonamide (58.44g, 0.6mol), WSCDI (1 17g, 0.614mol) and DMAP (75.06g, 0.6mol) in DCM (1 .5L) was stirred at 40°C for 14 hours. The reaction mixture was acidified with an aqueous KHS0₄ solution to pH 5 and extracted with DCM (3x1 L). The organic layer was dried over Na₂S0₄, and concentrated in vacuo to afford the title compound as a white solid (102g, 98%). ¹H NMR (400 MHz, CDCI₃) δ ppm 1.52 - 1.94 (m, 4 H) 1.96 - 2.07 (m, 1 H) 2.1 1 - 2.21 (m, 1 H) 2.47 - 2.58 (m, 1 H) 2.60 (s, 3 H) 3.53 (s, 3 H) 3.73 - 3.87 (m, 1 H) 4.13 - 4.25 (m, 1 H) 5.62 (dd, J=10.15, 2.34 Hz, 1 H) 7.39 - 7.50 (m, 1 H) 7.70 (dd, J=8.79, 1.76 Hz, 1 H) 8.08 - 8.18 (m, 1 H) 9.07 (br. s., 1 H)

Preparation 5: 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide

To a solution of 3-methyl-N-(methylsulfonyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole- 5-carboxamide [preparation 4] (92g, 0.27mol) was added 4M HCI in 1 ,4-dioxane (1 .5L). The mixture was stirred at 40°C for 6 hours. The mixture was filtered and dried in vacuo to give the title compound as an off-white solid (75g, 80%).

LCMS (Method A5) Rt 0.75min, MS m/z 254 [MH]+, 507 [M₂H]+, 252 [MH]-, 505 [M₂H]- ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.54 (s, 3 H) 3.39 (s, 3 H) 7.54 (dd, J=8.59, 0.78 Hz, 1 H) 7.88 (dd, J=8.79, 1.76 Hz, 1 H) 8.54 (dd, J=1.56, 0.78 Hz, 1 H) 12.04 (s, 1 H)

Preparation 6: 1 -(6-fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide

A mixture of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 5] (25g, 0.1 mol), 2-fluoropyridine-5-boronic acid (18g, 0.13 mol), Cu(OAc)₂ (36g, 0.2mol) and pyridine (40ml) in DMF (500ml) was heated to 80°C open to air for 16 hours. The reaction mixture was concentrated to obtain a residue which was purified by preparative HPLC (method A10) to give the title compound as a white solid (10.15g, 25%).

1H NMR (400 MHz, d₆-DMSO) δ ppm 2.69 (s, 3H) 3.44 (s, 3H) 7.46-7.49 (m, 1 H) 7.94- 7.96 (m, 1 H) 8.07-8.09 (m, 1 H) 8.42-8.47 (m, 1 H) 8.69-8.71 (m, 2H) 12.23 (br s, 1 H) MS m/z 349 [MH]+, 371 [MNa]+, 719 [M₂Na]+

Preparation 7: 1 -(5-chloro-6-fluoropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

A mixture of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 5] (30g, 0.12mol), 3-chloro-2-fluoro-5-(4,4_!5_!5-tetramethyl-[1 _!3,2]dioxaborolan-2-yl)- pyridine [preparation 27] (35g, 0.12mol), Cu(OAc)₂ (46g, 0.25mol) and pyridine (40ml) in DMF (800ml) was heated to 80°C open to air for 16 hours. The reaction mixture was concentrated to obtain the crude product. Purification by preparative HPLC was not successsful and 2.0g of the title compound in high purity (99% purity by HPLC) was obtained by crystallisation from MeOH/DMF along with 5.5g of lower purity product (80% purity by HPLC).

¹ H NMR (400 MHz, DMSO-d6) δ ppm 2.64 (s, 3H) 3.39 (s, 3H) 7.97 (d, 1 H) 8.04-8.07 (dd, 1 H) 8.62-8.66 (m, 3H) 12.21 (br s, 1 H)

MS m/z 383 [MH]+, 405 [MNa]+, 787 [M₂Na]+

Preparation 8: methyl 3-cvclopropyl-1-(tetrahvdro-2H-pyran-2-yl)-1 H-indazole-5- carboxylate

A suspension of the 3-iodo-1 -(tetrahydropyran-2-yl)-1 H-indazole-5-carboxylic acid methyl ester [preparation 1 ] (10. Og, 25.9mmol), cyclopropyl boronic acid (3.93g, 38.8mmol) and K₃P0₄ (22.0g, 104.0mmol) in toluene (300ml) and water (20ml) was degassed by evacuating and filling with nitrogen. Pd(PPh₃)₄ (2.99g, 2.59mmol, previously washed with EtOH) was added, the mixture degassed three times. The reaction mixture was heated under nitrogen at reflux for 16 hours. The mixture was washed with water (500ml) then brine (100ml). The aqueous phases were combined and extracted with DCM (100ml). The organics were combined, dried over MgS0₄, filtered and evaporated onto silica. The crude product was purified by column chromatography (ISCO, 240g Thomson column, 85ml/min flow, dry load, heptane:EtOAc 100:0 to 50:50) to give an orange oil which crystallised on final drying in vacuo to afford the title compound (6520mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .04 - 1 .16 (m, 4 H) 1 .62 - 1 .70 (m, 1 H) 1 .71 - 1 .79 (m, 2 H) 1 .97 - 2.08 (m, 1 H) 2.13 (ddd, J=9.27, 4.39, 1 .95 Hz, 1 H) 2.18 - 2.31 (m, 1 H) 2.47 - 2.59 (m, 1 H) 3.68 - 3.80 (m, 1 H) 3.95 (s, 3 H) 3.99 - 4.09 (m, 1 H) 5.63 (dd, J=9.76, 2.73 Hz, 1 H) 7.52 (d, J=8.98 Hz, 1 H) 8.04 (dd, J=8.79, 1 .76 Hz, 1 H) 8.44 - 8.51 (m, 1 H)

LCMS (Method A5): Rt 1 .73min. MS m/z 301 [MH]+, 323 [MNa]+

LCMS (Method A6): Rt 3.09min. MS m/z 301 [MH]+

Preparation 9: methyl 3-cyclopropyl-1 H-indazole-5-carboxylate

To methyl 3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-5-carboxylate [preparation 8] was added HCI in 1 ,4-dioxane (50ml, 4M), and the mixture stirred at room temperature under nitrogen for 16 hours. The solvent was concentrated in vacuo and the residue suspended in f-butylmethyl ether (50ml). The solid was collected by filtration, washed with f-butylmethyl ether (2x20ml) and dried by suction to afford the title compound (1 .62g).

1 H NMR (400 MHz, d₆-DMSO) δ ppm 0.91 - 0.97 (m, 2 H) 0.97 - 1 .05 (m, 2 H) 2.37 (m, 1 H) 3.87 (s, 3 H) 7.52 (dd, J=8.98, 0.78 Hz, 1 H) 7.89 (dd, J=8.59, 1 .56 Hz, 1 H) 8.46 (dd, J=1 .56, 0.78 Hz, 1 H)

LCMS (Method A5): Rt 1 .52min. MS m/z 217 [MH]+, 215 [MH]- LCMS (Method A6): Rt 2.30min. MS m/z 217 [MH]+ Preparation 10: 3-cvclopropyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide

To methyl 3-cyclopropyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole-5-carboxylate [preparation 8] (4.50g, 15.0mmol) in THF (50ml) was added LiOH (1 .79g, 74.9mmol) followed by water and methanol to give a solution (5ml). The mixture was heated to reflux under nitrogen for 2.5 hours. The mixture was cooled to room temperature, concentrated in vacuo then diluted with water (50ml) and acidified with an aqueous solution of KHS0₄ (1 M). The mixture was extracted with DCM (3x 10ml). To the DCM solution containing the acid intermediate was added methanesulfonamide (2.85g, 30.0mmol), DMAP (3.66g, 30.0mmol) and WSCDI (5.74g, 30.0mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then washed with an aqueous solution of KHS0₄ (50ml, 1 M) and the aqueous phase extracted with DCM (3x25ml). The extracts were combined and evaporated onto silica. Purification by column chromatography (ISCO Companion, silica 120g column eluting with a gradient of heptane and 90: 10 EtOAc:AcOH(0-50%)) gave the intermediate N 1 - THP protected acylsulphonamide as a white solid (2.44g). The THP protecting group was cleaved by treatment with 4M HCI in 1 ,4-dioxane (50ml) at room temperature for for 16 hours and then at 50°C for 3 hours. The resulting white precipitate was collected by filtration, washed with Et₂0 (2x20ml) and dried by suction. The solid was crystallised from acetic acid (100ml) and water (15ml) to afford the title compound (1 .26g).

¹ H NMR (400 MHz, d₆-DMSO) δ ppm 0.97 - 1 .09 (m, 4 H) 2.28 - 2.37 (m, 1 H) 3.39 (s, 3 H) 7.52 (d, J=8.59 Hz, 1 H) 7.86 (dd, J=8.79, 1 .76 Hz, 1 H) 8.51 - 8.55 (m, 1 H) 12.08 (s, 1 H) 12.95 (br s, 1 H),

LCMS (2 min acidic) Rt 1 .1 1 min. MS m/z 280 [MH]+, 278 [MH]- Preparation 11 : 3-cyclopropyl-1 -{6-Γ(1 -methyl cvclopropyl)methoxy1pyridin-3-yl}-N- (methylsulfonyl)-1 H-indazole-5-carboxamide

A mixture of 3-cyclopropyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 10] (500mg, 1 .47mmol), 2-fluoropyridine-5-boronic acid (31 1 mg, 2.21 mmol), Cu(OAc)2 (535mg, 2.95mmol) and pyridine (0.357ml, 4.42mmol) in DCM (50ml) was stirred for 72 hours at room temperature. An aqueous solution of KHS0₄ (30ml, 1 M) and EDTA (5% w/v, 30ml) was added and the organic phase separated. The aqueous phase was extracted with DCM (20ml) and the extracts combined and evaporated onto silica. Purification by column chromatography (ISCO Companion, 80g silica column) eluting with heptane and EtOAc:AcOH (9: 1 ) gave a pale orange solid. Recrystallisation from acetonitrile gave the title compound as a white solid (151 mg).

¹ H NMR (400 MHz, d₆-DMSO) δ ppm 1.16-1 .14 (m, 4H), 2.47-2.42 (m, 1 H), 3.41 (s, 3H), 7.42 (dd, 1 H), 7.89 (d, 1 H), 8.03 (dd, 1 H), 8.40-8.36 (m, 1 H), 8.66 (m, 2H), 12.25 (br-s, 1 H)

LCMS (Method A5): Rt 1 .27min. MS m/z 375 [MH]+, 373 [MH]-

Preparation 12: 1 -(6-chloropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole- 5-carboxamide

To a mixture of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 5] (1 .00g, 3.95mmol) and Cu(OAc)₂ (1 .44g, 7.93mmol) in DMF (50ml) was added 2- chloropyridine-5-boronic acid (0.78g, 4.94mmol) followed by pyridine (0.70ml, 8.69mmol). The reaction was stirred at 50°C open to the air. The reaction mixture was evaporated onto silica and purified by column chromatography (ISCO companion, silica 40 g) eluting with a gradient of heptane to 90:10 EtOAc:AcOH. The product fractions were combined and concentrated in vacuo. The pale green solid was redissolved in warm EtOAc (75ml) and washed with aqueous 10% EDTA solution (2x10ml), water (10ml), dried over MgS0₄ and the solvent concentrated in vacuo to give a white solid that was recrystallised from AcOH to afford the title compound (409mg).

1 H NMR (400 MHz, d₆-DMSO) δ ppm 2.66 (s, 3 H) 3.39 (s, 3 H) 7.74 (d, J=8.59 Hz, 1 H) 7.96 - 8.00 (m, 1 H) 8.05 - 8.07 (dd, J=1 .95 Hz, 1 H) 8.30 (dd, J=8.59, 3.12 Hz, 1 H) 8.66 (d, J=1 .56 Hz, 1 H) 8.89 (d, J=2.73 Hz, 1 H) 12.18 (br. s., 1 H)

LCMS (Method A5) Rt 1 .50min, MS m/z 365 [MH]+, 363 [MH]-

Preparation 13: 1 -(5,6-dichloropyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

To a mixture of 3-methyl-N-(methylsulfonyl)-1 H-indazole-5-carboxamide [preparation 5] (1 .31 g, 5.16mmol) and 2,3-dichloropyridine-5-boronic acid (0.99g, 5.16mmol) was added copper acetate (1 .54g, 7.74mmol_), DMF (20ml) and pyridine (0.85ml, 1 1 .0mmol). The mixture was stirred open to the air at 60°C for 16 hours. The solvents were concentrated in vacuo, and the residue treated with an aqueous solution of HCI (50ml, 2M) and stirred for 1 hour. The resulting off-white precipitate was collected by filtration, re-dissolved in EtOAc (100ml) and acetone (15ml) and evaporated onto silica. Purification by column chromatography (ISCO Companion, silica 40g) eluting with a gradient of heptane - 90: 10 EtOAc:AcOH gave the title compound as a white solid (90.4mg)

¹ H NMR (400 MHz, d₆-DMSO) δ ppm 2.66 (s, 3H), 3.40 (s, 3H), 8.04-8.09 (m, 2H), 8.57

(d, 1 H), 8.65 (dd, 1 H), 8.90 (d, 1 H), 12.21 (br s, 1 H).

LCMS (Method A5) Rt 1 .78min, MS m/z 399 [MH]+, 397 [MH]-

Mpt 258-260°C. Preparation 14: methyl 1 -i5-chloro-6-isobutoxypyridin-3-yl)-3-cvclopropyl-1 H- indazole-5-carboxylate

A mixture of methyl 3-cyclopropyl-1 H-indazole-5-carboxylate [preparation 9] (100mg, 0.396mmol), Cul (7.6mg, 0.40mmol), K₃P0₄ (168mg, 0.792mmol), and 5-bromo-3- chloro-2-isobutoxy-pyridine [preparation 30] (105mg, 0.396mmol) was added to a septum sealed reaction vial and degassed. A solution of trans-N, N'- dimethylcyclohexane-1 ,2-diamine in toluene (2ml) was added. The mixture was degassed and filled with nitrogen three times, then stirred at 1 10°C for 4 days. The mixture was allowed to cool and then partitioned between water (5ml) and DCM (5ml). The DCM phase was separated and the aqueous extracted with further DCM (5ml). The extracts were combined and evaporated onto silica. Purification by column chromatography (ISCO Companion, silica 12g, eluted with a gradient of heptane to 40% EtOAc in heptane) gave the title compound as clear oil (100.4mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .07 (d, 6H), 1 .19-1 .12 (m, 4H), 2.18 (septuplet, 1 H), 2.27-2.34 (m, 1 H), 3.97 (s, 3H), 4.21 (d, 2H), 7.55 (dd, 1 H), 7.98 (d, 1 H), 8.09 (dd, 1 H), 8.35 (d, 1 H), 8.58 (dd, 1 H).

LCMS (Method A5) Rt 1 .83 min, MS m/z 400 [MH]+ Preparation 15: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-cvclopropyl-1 H-indazole-5- carboxylic acid

To a solution of 1 -(5-chloro-6-isobutoxy-pyridin-3-yl)-3-cyclopropyl-1 H-indazole-5- carboxylic acid methyl ester [preparation 14] (66mg, 0.16mmol) in THF (5ml) was added LiOH (39.5mg, 1 .65mmol) and water (5ml). The mixture was stirred at room temperature under nitrogen for 72 hours. The solvent was concentrated in vacuo, azeotroping with toluene (2x 5ml). The residue was partitioned between EtOAc (20ml) and water (20ml) and the aqueous phase acidified with an aqueous solution of KHS0₄ (1 M). The organics were separated, washed with water (5ml) and brine (5ml), dried over MgS0₄ and the solvent concentrated in vacuo to afford the title compound as a white solid (55mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 0.93 (d, 6H), 0.99-1 .05 (m, 4H), 1 .99-2.08 (m, 1 H), 2.18-2.22 (m, 1 H), 4.07 (d, 2H), 7.47 (dd, 1 H), 7.86 (d, 1 H), 8.01 (dd, 1 H), 8.24 (d, 1 H), 8.51 (dd, 1 H),

LCMS (Method A5) Rt 1 .73min, MS m/z 386 [MH]+, 384 [MH]-

Preparation 16: 1 -(5-chloro-6-isobutoxy-pyridin-3-yl)-3-methyl-1 H-indazole-5- carboxylic acid

To a 2-necked flask was added copper acetate (9.55g, 52.6mmol) and DMF (150ml) followed by pyridine (7.44ml, 92.0mmol). The mixture was stirred for -15 minutes under argon. 3-Chloro-2-isobutoxy-5-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridine [preparation 32] (9.83g, 31.5mmol) and 3-methyl-1 H-indazole-5-carboxylic acid methyl ester [(5.00g, 26.3mmol) were added and the reaction mixture was heated for 2 hours at 55°C. The reaction mixture was cooled to room temperature, diluted with EtOAc (200ml) and washed with water (3 x 500ml). (NB: the product is in suspension in the organic phase). The organics were concentrated in vacuo and a yellow paste isolated. The product was suspended in THF (100ml) and LiOH (1.26g, 52.6mmol) added as a solution in water. The reaction mixture was heated to 70°C for 5 hours. The reaction mixture was then washed with DCM (100ml) and EtOAc (100ml). The aqueous phase was acidified and extracted with EtOAc: MeOH 9:1 (2x500ml) and after evaporation of the volatiles in vacuo, 4g of a mixture of hydrolysed starting material and desired product was isolated. The desired product was purified by reverse phase column chromatography to afford the title compound (1 .9g).

¹H NMR (400 MHz, d₆-DMSO) δ ppm 1.02 (d, J=6.83 Hz, 6 H) 2.1 1 (dt, J=13.33, 6.71 Hz, 1 H) 2.63 (s, 3 H) 4.20 (d, J=6.64 Hz, 2 H) 7.76 - 7.82 (m, 1 H) 8.02 (dd, J=8.79, 1.56 Hz, 1 H) 8.28 (d, J=2.54 Hz, 1 H) 8.47 (dd, J=1.46, 0.88 Hz, 1 H) 8.51 (d, J=2.54 Hz, 1 H).

LCMS: Rt 3.72min. MS m/z 360 [MH]+, 358 [MH]- Preparation 17: 1 -f5-chloro-6-(oxetan-3-ylmethoxy)-pyridin-3-vn-3-methyl-1 H- indazole-5-carboxylic acid methyl ester

To a solution of 3-methyl-1 H-indazole-5-carboxylic acid methyl ester (270mg, 1.42mmol) and 3-chloro-2-(oxetan-3-ylmethoxy)-pyridine-5-boronic acid [preparation 34] (1.07g, 2.5mmol) in DMF (10ml) was added copper acetate (550mg, 3.03mmol) and pyridine (0.23ml, 2.84mmol). The reaction was warmed to 50°C for 16 hours with stirring. The solvent was concentrated in vacuo and the residue partitioned between DCM (50ml) and a 50 ml mixture of aqueous KHS0₄ solution (0.5M) and 5% aqueous EDTA solution. The organics were separated and the aqueous extracted with further DCM (25ml). The organics were combined, evaporated onto silica and purified by column chromatography (ISCO Companion, silica 40g, eluted with a gradient of EtOAc and heptane (80-50%)) to afford the title compound as a fluffly white solid (209mg) ¹ H NMR (400 MHz, CDCI₃) δ ppm 2.69 (s, 3H), 3.52-3.59 (m, 1 H), 3.99 (s, 3H), 4.65 (t, 2H), 4.70 (d, 2H), 4.91 (dd, 2H), 7.59 (dd, 1 H), 8.04 (d, 1 H), 8.13 (dd, 1 H), 8.40 (d, 1 H), 8.51 (dd, 1 H).

LCMS (Method A5): Rt 1 .50min, MS m/z 388 [MH]+

Preparation 18: 1 -r5-chloro-6-ioxetan-3-ylmethoxy)-pyridin-3-vn-3-methyl-1 H- indazole-5-carboxylic acid

To a solution of 1 -[5-chloro-6-(oxetan-3-ylmethoxy)-pyridin-3-yl]-3-methyl-1 H-indazole- 5-carboxylic acid methyl ester [preparation 17] (194mg, 0.50mmol) in THF (20ml) was added LiOH (49mg, 2.0mmol) followed by enough water and methanol to achieve a solution (1 -5ml). The solution was stirred at 50°C under nitrogen for 24 hours. Additional LiOH was added (~50mg) and the mixture heated at reflux for a further 24 hours. The solvents were concentrated in vacuo and the residue treated with an aqueous solution of KHS0₄ (10ml, 0.5M) and extracted with DCM (2x10ml). The organics were combined, passed through a hydrophobic frit and concentrated in vacuo to afford the title compound which was used without further purification (210mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm (s, 3H), 3.52-3.59 (m, 1 H), 4.66-4.71 (m, 4H), 4.92- 4.96 (m, 2H), 7.60 (dd, 1 H), 8.04 (d, 1 H), 8.17 (dd, 1 H), 8.40 (d, 1 H), 8.58 (dd, 1 H). LCMS (Method A6) Rt 2.78min, MS m/z 374 [MH]+, 372 [MH]- Preparation 19: methyl 1 -(6-fluoropyridin-3-yl)-3-methyl-1 H-indazole-5-carboxylate

To a solution of methyl 3-methyl-1 H-indazole-5-carboxylate (500mg, 2.63mmol) in DMF (6ml) was added Cu(OAc)₂ (955mg, 5.26mmol), pyridine (0.532ml, 6.57mmol), molecular sieves (approx. 500mg) and 2-fluoropyridine-5-boronic acid (445mg, 3.16mmol). The mixture was stirred for 7 hours at 50°C with air bubbled through the mixture. Additional 2-fluoropyridine-5-boronic acid (223mg, 1 .58mmol), Cu(OAc)₂ (477mg, 2.63mmol) and pyridine (0.320ml, 4.33mmol) were added and stirring continued for a further 20 hours. The reaction mixture was diluted with DCM (60ml), washed with a saturated aqueous solution of EDTA (50ml) and the aqueous phase back extracted with DCM/MeOH (9: 1 , 30ml). The organics were combined, washed with a saturated aqueous solution of EDTA (40ml) and evaporated in vacuo. The residue was dissolved in Et₂0 (60ml), washed with water (3x40ml), dried over MgS0₄ and evaporated in vacuo. Purification by column chromatography (ISCO Companion, 12g silica column) eluting with DCM then DCM/EtOAc (99: 1 ) gave the title compound (188mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 2.70 (s, 3 H) 3.99 (s, 3 H) 7.13-7.16 (m, 1 H) 7.64 (dd, 1 H) 8.14-8.19 (m, 2 H) 8.53 (dd, 1 H) 8.62 (m, 1 H), LCMS (Method A5) Rt 1 .59min, MS m/z 286 [MH]+

Preparation 20: methyl 3-methyl-1 -r6-(2.2.2-trifluoroethoxy)pyridin-3-vn-1 H- indazole-5-carboxylate

Trifluoroethanol (96μΙ_, 1 .32mmol) was dissolved in DMF (0.5ml). Potassium carbonate (182mg, 1 .32mmol) was added and the mixture stirred under nitrogen at room temperature for 15 minutes. Methyl 1 -(6-fluoropyridin-3-yl)-3-methyl-1 H-indazole-5- carboxylate [preparation 19] (188mg, 0.66mmol) was added and the reaction mixture stirred under nitrogen at 70°C for 16 hours. The mixture was diluted with DCM (25ml), and washed with water (25ml, then 15ml), then passed through a phase separation cartridge and concentrated in vacuo. The residue was taken up in EtOAc (30ml), washed with water (3x20ml) and the organics dried over MgS0₄ and concentrated in vacuo to afford the title compound (230mg) which was carried though to the subsequent hydrolysis step without purification.

¹ H NMR (400 MHz, CDCI₃) δ ppm 2.69 (s, 3 H) 3.99 (s, 3 H) 4.78 - 4.88 (m, 2 H) 7.06 (dd, J=8.79, 0.59 Hz, 1 H) 7.58 (dd, J=8.88, 0.88 Hz, 1 H) 8.00 (dd, J=8.79, 2.73 Hz, 1 H) 8.1 1 - 8.19 (m, 1 H) 8.49 - 8.55 (m, 2 H)

LCMS (Method A5) Rt 1 .83min, MS m/z 366 [MH]+

Preparation 21 : methyl 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-iodo-1 H-indazole-5- carboxylate

To a solution of methyl 3-iodo-1 H-indazole-5-carboxylate (1 .28g, 3.79mmol) in DMF (10ml) were added molecular sieves (~1 .2g), copper acetate (1 .38g, 7.58mmol) and pyridine (1 .07ml, 13.3mmol). The mixture was stirred for 15 minutes. A solution of 2- isobutoxy-3-chloropyridine-5-boronic acid (445mg, 3.16mmol) in DMF (5ml) was added and the mixture heated for 2 hours at 50°C, with air bubbled through the mixture. The mixture was cooled to room temperature and partitioned between EtOAc (75ml) and aqueous EDTA solution. The organics were separated, washed with further EDTA solution (2 x 30ml), dried over MgS0₄ and concentrated in vacuo to give a yellow- orange solid. The crude product was evaporated onto silica and purfied by column chromatography (ISCO Companion, 25g Si cartridge, eluting with 0-25% EtOAc in heptane) to afford the title compound as a white solid (360mg). A further batch of material (500mg) was isolated from impure fractions as a yellow solid, which was triturated with f-butylmethyl ether and heptane to yield further title compound as an off- white solid (147mg).

¹ H N MR (400 MHz, d₆-DMSO): δ ppm 1 .00 (d, 6H), 2.07-2.17 (m, 1 H), 3.91 (s, 3H), 4.21 (d, 2H), 7.84 (dd, 1 H), 8.06 - 8.10 (m, 1 H), 8.12 - 8.14 (m, 1 H), 8.33 (d, 1 H), 8.51 (d, 1 H).

LCMS (Method A5): Rt 1 .80min, MS m/z 486 [MH]+

Preparation 22: 1 -(5-chloro-6-isobutoxy-pyridin-3-yl)-3-iodo-1 H-indazole-5- carboxylic acid

To a suspension of methyl 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-iodo-1 H-indazole-5- carboxylate [preparation 21 ] (600mg, 1 .24mmol) in MeOH (10ml) was added an aqueous solution of NaOH (2M, 8.2ml, 16.4mmol) and the reaction mixture stirred under nitrogen at 50°C for 3 hours. The mixture was concentrated in vacuo and partitioned between EtOAc (75ml) and water (100ml). The organics were separated and re- partitioned between EtOAc and an aqueous solution of HCI (1 M). The original water phase was neutralised with an aqueous solution of HCI (~8ml, 2M)) and then extracted with EtOAc (2x50ml). The extracts were washed with aqueous NaHC0₃ solution and the NaHC03 wash back-extracted with EtOAc (50ml). The organics were combined, washed with an aqueous solution of HCI (2M), dried over MgS0₄ and concentrated in vacuo to afford the title compound (537mg).

¹ H NMR (400 MHz, d₆-DMSO) δ ppm 1 .00 (d, 6H), 2.05-2.19 (m, 1 H), 4.20 (d, 2H) 7.81 (dd, 1 H), 8.05 - 8.10 (m, 1 H), 8.1 1 (d, 1 H), 8.33 (d, 1 H), 8.51 (d, 1 H).

LCMS (Method A5) Rt 1 .95min, MS m/z 472 [MH]+, 470 [MH]- Preparation 23: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-3-iodo-N-(methylsulfonyl)-1 H- indazole-5-carboxamide

To a suspension of 1-(5-chloro-6-isobutoxy-pyridin-3-yl)-3-iodo-1 H-indazole-5- carboxylic acid [preparation 22] (537mg, 1.14mmol) in DCM (10ml) was added DMAP

(348mg, 2.84mmol) and WSCDI (545mg, 2.84mmol). The mixture was stirred under nitrogen at room temperature for 5 minutes and methanesulphonamide (271 mg,

2.84mmol) added. The reaction mixture was stirred at room temperature for 18 hours.

The mixture was diluted with DCM (50ml) and washed with an aqueous 10% KHS0₄ solution (50ml). The aqueous phase was back-extracted with DCM (30ml) and the organics combined, dried over MgS0₄ and concentrated in vacuo to afford the title compound as a cream coloured solid (590mg).

¹H NMR (400 MHz, d₆-DMSO) δ ppm 1.00 (d, 6H), 2.04 - 2.16 (m, 1 H), 3.40 (s, 3H), 4.20 (d, 2H), 7.84 (d, 1 H), 8.07 (dd, 1 H), 8.32 - 8.36 (m, 2H), 8.51 (d, 1 H), 12.38 (br. s, 1 H).

LCMS (Method A5) Rt 1.84min, MS m/z 549 [MH]+

Preparation 24: 1 -(terf-butoxycarbonyl)-1 H-indazole-5-carboxylic acid

To a suspension of 1 H-indazole-5-carboxylic acid (9g, 0.055mol) in 1 ,4-dioxane (200ml) was added aqueous NaOH (66ml, 1 M, 0.066mol), followed by di-ferf-butyldicarbonate (13.2g, 0.06mol). The mixture was stirred at room temperature under nitrogen for 16 hours and turned from a clear to cloudy mixture. The reaction mixture was concentrated in vacuo, and the pH adjusted to -4 by addition of 10% aqueous citric acid solution, which resulted in formation of a cream coloured solid. The solid was isoalted by filtration, washed with water, then dissolved in acetone, dried over Na₂S0₄, filtered and evaporated to give the crude product (1 Og) as a light yellow solid. Purification by column chromatography (eluting with petroleum ether/EtOAc from 20:1 to 5: 1 ) gave the title compound as an off-white solid (4g, 40%) and recovered 1 H-indazole-5-carboxylic acid (4g, 44%).

1H NMR (400 MHz, CDCI₃) δ ppm 1.74 (s, 9H) 8.28 (d, 2H) 8.30 (s, 1 H) 8.58 (s, 1 H)

Preparation 25: terf-butyl 5-r(ethylsulfonyl)carbamovn-1 H-indazole-1 -carboxylate

A mixture of 1-(ferf-butoxycarbonyl)-1 H-indazole-5-carboxylic acid [preparation 24] (7g, 0.027mol), ethanesulphonamide (7g, 0.064mol), WSCDI (6.1 g, 0.032mol) and DMAP (8.2g, 0.067mol) in DCM (150ml) was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (100ml), washed with aqueous HCI (3x100ml, 1 M), dried over Na₂S0₄, filtered and evaporated to give the title compound as a white foamy solid (9g, 94%).

1H NMR (400 MHz, CDCI₃) δ ppm 1 .48 (t, 3H) 1.75 (s, 9H) 3.66 (q, 2H) 7.99 (d, 1 H) 8.28-8.33 (d, 2H) 8.28-8.33 (s, 1 H) 8.52 (s, 1 H)

Preparation 26: N-(ethylsulfonyl)-1 H-indazole-5-carboxamide

ferf-Butyl 5-[(ethylsulfonyl)carbamoyl]-1 H-indazole-1-carboxylate [preparation 25] (9g, 25mmol) was treated with 4M HCI in 1 ,4-dioxane (100ml) and stirred at room temperature for 16 hours. The reaction mixture was evaporated in vacuo to give the title compound as the hydrochloride salt (5.6g, 86%).

¹H NMR (400 MHz, D₂0) δ ppm 1.41 (t, 3H) 3.66 (q, 2H) 7.68 (d, 1 H) 7.85 (dd, 1 H) 8.29 (m, 1 H) 8.38 (m, 1 H)

MS m/z 254 [MH]+, 276 [MNa]+, 529 [M₂Na]+ Preparation 27: 3-Chloro-2-fluoro-5-(4,4,5,5-tetramethyl-ri ,3,21dioxaborolan-2-yl)- pyridine

A mixture of 5-bromo-3-chloro-2-fluoropyridine (70g, 0.33mol), Pd(dppf)₂C (13g, 0.016mol), KOAc (98g, 0.99 mol) and bis-pinacolatodiboronate (100g, 0.4mol) in DMF (1000ml) was degassed by evacuating and filling with nitrogen three times. The mixture was heated to 80°C for 2 hours. The reaction mixture was concentrated in vacuo to obtain a residue which was purified by column chromatography on silica gel (eluting with petroleum ether) to give the title compound as a white solid (35g, 48%).

1H NMR (400 MHz, CDCI₃) δ ppm 1.35 (s, 12H); 8.17 (dd, 1 H); 8.44 (dd, 1 H)

Preparation 28: i5-Bromo-3-chloro-pyridin-2-yl)-isobutyl-methylamine

To a solution of 5-bromo-2,3-dichloropyridine (1.00g, 4.41 mmol) in DMSO (5ml) was added N-methylisobutylamine (1.05ml, 8.81 mmol) and the mixture heated at 1 10°C for 2 hours, after which time additional N-methylisobutylamine (1.05ml, 8.81 mmol) was added and heating continued for a further 18 hours. The reaction mixture was partitioned between f-butylmethyl ether (40ml) and water (100ml) and the phases separated. The aqueous phase was extracted with further f-butylmethyl ether (20ml) and the organics combined, washed with brine (50ml), dried over Na₂S0₄, filtered and concentrated in vacuo to afford a pale orange oil. The material was purified by column chromatography (ISCO, 40g column, hexane:EtOAc 100:10 to 80:20) to afford the title compound as a colourless oil (908mg).

1H NMR (400 MHz, CDCI₃) δ ppm 0.88 (d, J=6.6Hz, 6H); 1.93-2.03 (m, 1 H); 2.99 (s, 3H); 3.24 (d, J=7.4Hz, 2H); 7.65 (d, J=2Hz, 1 H); 8.14 (d, J=2Hz, 1 H)

LCMS (Method A5): Rt 2.00min. MS m/z 277 [MH]+ Preparation 29: r3-Chloro-5-(4A5,5-tetramethyl-ri ,3,21dioxaborolan-2-yl)-pyridin- 2-yll-isobutyl-methylamine

To a dry vial was added (5-bromo-3-chloro-pyridin-2-yl)-isobutyl-methylamine [preparation 28] (500mg, 1 .80mmol), KOAc (530mg, 5.40mmol), bis- pinacolatodiboronate (572mg, 2.25mmol) and Pd(dppf)2Cl2 (74mg, 0.09mmol) and the reaction system degassed twice by evacuating and filling with nitrogen. DMF (3ml) was added, the mixture degassed twice more and heated with stirring at 80°C under nitrogen for 6 hours, then left to stir at room temperature for 16 hours. The mixture was partitioned between EtOAc (20ml) and water (50ml) and the phases separated. The organic phase was washed with brine, dried over MgS0₄, filtered and evaporated onto silica. Purification by column chromatography (ISCO, 40g Si column, hexane:EtOAc 100:0 to 50:50) gave the title compound as pale green oil (360mg) which contained some residual pinacolato residues but was used without additional purification.

1 H NMR (400 MHz, CDCI₃) δ ppm 0.87 (d, J=6.6Hz, 6H); 1 .27 (s, 5H, residual pinacolatoboronate); 1 .33 (s, 12H); 1 .96-2.06 (m, 1 H); 3.08 (s, 3H); 3.37 (d, J=7.4Hz, 2H); 7.85 (d, J=2Hz, 1 H); 8.43 (d, J=2Hz, 1 H)

LCMS (Method 6): Compound decomposes to show both boronic ester and acid. Rt 2.39min, MS m/z 243 [MH]+, 241 [MH]- (boronic acid). Rt 4.16min, MS m/z 325 [MH]+ (boronic ester)

Preparation 30: 5-Bromo-3-chloro-2-isobutoxy-pyridine

To a solution of 5-bromo-3-chloro-2-fluoropyridine (1 .00g, 4.75mmol) in DMSO (5ml) was added isobutanol (2.19ml, 23.8mmol) followed by caesium carbonate (3.10g, 9.50mmol). The reaction mixture was heated at 100°C for 16 hours. Additional isobutylalcohol (2.19ml, 23.8mmol) was added, and heating continued for an additional for 16 hours period. The reaction mixture was partitioned between water (130ml) and EtOAc (100ml). The organics were washed with brine (40ml), dried over MgS0₄, filtered and concentrated in vacuo to give the crude product which was dissolved in DCM (10ml). MP-Trisamine (3g) was added and the mixture stirred at room temperature for 16 hours. The MP-trisamine was filtered off and the filtrate concentrated in vacuo to afford the title compound as a pale orange oil (824mg)

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .04 (d, J=6.64 Hz, 6 H) 2.07 - 2.19 (m, 1 H) 4.12 (d, J=6.64 Hz, 2 H) 7.75 (d, J=2.34 Hz, 1 H) 8.07 (d, J=2.34 Hz, 1 H)

LCMS (2min run): Rt 2.00min. MS m/z 264 [MH]+

Preparation 31 : 3-Chloro-2-isobutoxy-pyridine

To an oven dried flask was added sodium hydride (60% dispersion in oil, 4.05g, 101 .0mmol). The sodium hydride was washed with heptane (3x 15ml) and suspended in anhydrous TH F (50ml). Isobutanol was added slowly and the mixture stirred under nitrogen until gas evolution subsided. 2,3-Dichloropyridine (10. Og, 67.6mmol) was added as a solution in a minimum amount of THF (~20ml) and the mixture stirred at room temperature for 16 hours and then at reflux for 48 hours. The solvent was concentrated in vacuo and the residue partitioned between EtOAc (100ml) and water (100ml). The organics were separated and washed with water (2x 50ml), brine (25ml), dried over MgS0₄ and the solvent concentrated in vacuo to afford the title compound as a pale yellow oil (12.64g).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .04 (d, 6H), 2.15 (septuplet, 1 H), 4.14 (d, 2H), 6.82 (dd, 1 H, J=7.4, 5 Hz), 7.62 (dd, 1 H, J=7.4, 1 .53 Hz), 8.03 (dd, 1 H, J=5, 1 .53 Hz).

LCMS (2 min acidic) Rt 1 .50min. MS m/z 186 [MH]+ Preparation 32: 3-Chloro-2-isobutoxy-5-(4 A5,5-tetramethyl-H ,3,21dioxaborolan-2- -pyridine

Method (i): To a dry flask was added 5-bromo-3-chloro-2-isobutoxy-pyridine [preparation 30] (825mg, 3.12mmol), KOAc (918mg, 9.35mmol), bis- pinocolatodiboronate (989mg, 3.90mmol) and Pd(dppf)₂CI₂ (127mg, 0.156mmol) followed by DMF (10ml). The mixture was degassed twice by evacuating and filling with nitrogen and heated at 80°C for 6 hours under nitrogen. The reaction mixture was partitioned between EtOAc (30ml) and water (30ml), and the organics washed with brine (20ml), dried over MgS0₄, filtered and concentrated in vacuo. Purification by column chromatography (ISCO Companion, 40g, heptane - 30% EtOAc:heptane) gave the desired product as a colourless oil (227mg).

¹ H NM (400 MHz, CDCI₃) δ ppm 1 .04 (d, J=6.64 Hz, 6 H) 1 .34 (s, 12 H) 2.09 - 2.21 (m, 1 H) 4.18 (d, J=6.64 Hz, 2 H) 7.97 (d, J=1 .56 Hz, 1 H) 8.37 (d, J=1 .56 Hz, 1 H) impurities present

Method (ii): To a stirred solution of 3-chloro-2-isobutoxy-pyridine [preparation 31 ] (27.7g, 149.0mmol) in 1 ,4-dioxane (300ml) was added bis-pinocolatodiboronate (75.8g, 298.0mmol). The reaction mixture was degassed for 30 minutes by bubbling nitrogen through the solution. 4,4-Di-tert-butyl-2,2-dipyridyl (2.40g, 8.95mmol) and lr₂(OMe)₂COD₂ (2.97g, 4.48mmol) were added portion-wise under nitrogen and the reaction mixture left to stir at room temperature for 16 hours. The solvent was removed in vacuo to leave an orange/red oil. Purification twice by column chromatography (silica), eluting with heptane to 20% ethyl acetate/heptane gave the title compound as a pale yellow oil (38.0g).

¹ H N MR (400 MHz, CDCI₃) δ ppm 1 .03-1 .06 (m, 6H), 1 .33 (s, 12H), 2.08-2.20 (m, 1 H), 4.16-4.20 (m, 2H), 7.94 (s, 1 H), 8.37 (s, 1 H).

LCMS: Rt 4.73min, 312 [MH]+ Preparation 33: 5-Bromo-3-chloro-2-(oxetan-3-ylmethoxy)-pyridine

Sodium hydride (60% dispersion in oil, 684mg, 17.1 mmol) was washed with heptane (3x15ml) and suspended in anhydrous THF (20ml). A solution of oxetan-3-yl-methanol (2.01 g, 22.8mmol) in THF (10ml) was then added slowly and allowed to stir under nitrogen until gas evolution subsided. A solution of 5-bromo-3-chloro-2-fluoropyridine (2.40g, 1 1.0mmol) in THF (~20ml) was then added. The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc (50ml), washed with an aqueous solution of NaOH (25ml, 1 M), water (25ml) and brine (10ml). The organics were dried over MgS0₄ and concentrated in vacuo to afford the title compound as a clear oil (3.1 1 g)

¹H NMR (400 MHz, CDCI₃) δ ppm 3.42 - 3.55 (m, 1 H) 4.55 - 4.67 (m, 4 H) 4.78 - 4.90 (m, 2 H) 7.76 (d, J=1.95 Hz, 1 H) 8.07 (d, J=1 .95 Hz, 1 H)

LCMS (Method 5): Rt 1 .40min. MS m/z 278 [MH]+

Preparation 34: 3-Chloro-2-ioxetan-3-ylmethoxy)-pyridine-5-boronic acid

A mixture of 5-bromo-3-chloro-2-(oxetan-3-ylmethoxy)-pyridine [preparation 33] (1.94g, 6.97mmol), KOAc (2.14g, 21 .8mmol), bis-pinacolatodiboronate (2.20g, 8.66mmol) in DMF (20ml) was degassed twice by evacuating and filling with nitrogen. Pd(dppf)₂Cl₂ (313mg, 0.38mmol) was added, the mixture degassed twice more and the red solution heated at 80°C under nitrogen for 16 hours. The solvent was concentrated in vacuo and the residue partitioned between EtOAc (100ml) and an aqueous solution of KHS0₄ (100ml, 1 M). The organic phase was washed with water (25ml), brine (25ml), dried over MgS0₄ and concentrated in vacuo to afford the title compound (3.26g) which was used directly without purification. Preparation 35: 5-lodo-2-(1 -methyl-cvclopropylmethoxy)-pyridine

Sodium hydride (60% dispersion in oil, 807mg,20.2mmol) was washed with heptane (3x10 ml) and suspended in anhydrous THF (20ml). 1-Methylcyclopropylmethanol (3.48g, 40.4mmol) was added slowly and the reaction mixture allowed to stir under nitrogen until gas evolution subsided. A solution of 2-fluoro-5-iodopyridine in THF (10ml) was then added. The mixture was stirred at room temperature for 20 hours, and then at reflux for 2 hours. The mixture was poured into an aqueous solution of KHS0₄ (50ml, 0.5M) and the product extracted with f-butylmethyl ether (50ml). The organic phase was washed with saturated aqueous NaHC0₃ solution (50ml), dried over MgS0₄, filtered and concentrated in vacuo. Further azeotroping with toluene and drying in vacuo to remove residual alcohol, gave the title compound (3.31 g).

¹H NMR (400 MHz, CDCI₃) δ ppm 0.38 - 0.44 (m, 2 H) 0.52 - 0.57 (m, 2 H) 1.21 (s, 3 H) 4.04 (s, 2 H) 6.60 - 6.66 (m, 1 H) 7.73 - 7.82 (m, 1 H) 8.25 - 8.34 (m, 1 H)

LCMS (Method A6): Rt 3.37min. MS m/z 290 [MH]+

Preparation 36: 2-(1 -Methyl -cvclopropylmethoxy)-5-(4,4, 5,5-tetramethyl- ri ,3,21dioxaborolan-2-yl)-pyridine

A mixture of 5-iodo-2-(1-methyl-cyclopropylmethoxy)-pyridine [preparation 35] (1.3g, 5.00mmol), KOAc (1.32g, 13.5mmol) and bis-pinacolatodiboronate (1 .43g, 5.62mmol) in DMF (10ml) was degassed twice by evacuating and filling with nitrogen. Pd(dppf)₂Cl2 (184mg, 0.23mmol) was added and the mixture degassed twice more then heated for 16 hours at 80°C under nitrogen.. The mixture was poured into water (100ml) and the pH adjusted to 4 with an aqueous solution of KHS0₄ (1 M). The mixture was extracted with a mixture of f-butylmethyl ether (50ml) and EtOAc (50ml). The extracts were separated and the organics dried over MgS0₄, filtered and concentrated in vacuo. Purification by column chromatography (ISCO Companion, 80g column) eluting with heptane:EtOAc 100:0 to 2:1 gave the title compound as a pale green oil that crystallised on standing (660mg).

1 H NMR (400 MHz, CDCI₃) δ ppm 0.37 - 0.43 (m, 2 H) 0.53 - 0.59 (m, 2 H) 1.22 (s, 3 H) 1.34 (s, 12 H) 4.12 (s, 2 H) 6.75 (dd, J=8.20, 0.78 Hz, 1 H) 7.89 - 7.95 (m, 1 H) 8.50 (dd, J=1 .95, 0.78 Hz, 1 H)

Preparation 37: 3-Chloro-2-(2-fluoro-2-methyl-propoxy)-pyridine

To a solution of 2-fluoro-2-methyl-propan-1 -ol (344mg, 3.73mmol) in a mixture of THF and Et₂0 (15ml) was added portionwise NaH (60% dispersion in oil, 72mg, 1.80mmol). The mixture was stirred until the effervescence had subsided then 2,3-dichloropyridine (178mg, 1 .20mmol) was added in a single portion. The reaction was heated at reflux for 16 hours. The mixture was allowed to cool, quenched by dropwise addition of water and partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried over MgS0₄ and the solvent removed in vacuo. Purification by silica gel flash column chromatography eluting with EtOAc:heptane, 1 :9 gave a the title compound as a colourless oil (103mg)

¹H NMR (400 MHz, CDCI₃) δ ppm 1.50 (s, 3 H) 1.55 (s, 3 H) 4.41 (s, 1 H) 4.37 (s, 1 H) 6.87 (dd, J=7.71 , 4.98 Hz, 1 H) 7.66 (dd, J=7.62, 1.76 Hz, 1 H) 8.04 (dd, J=4.88, 1.76 Hz, 1 H)

LCMS Rt 2.76 mins. MS m/z 204 [MH]+

Preparation 38: 3-Chloro-2-(2-fluoro-2-methyl-propoxy)-5-(4,4,5,5-tetramethyl- ri .3.21dioxaborolan-2-yl)-pyridine [00703461 -0022]

To a stirred solution of 3-chloro-2-(2-fluoro-2-methyl-propoxy)-pyridine [preparation 37] (103mg, 0.51 mmol) in degassed 1 ,4-dioxane (1 ml) was added bis-pinocolatodiboronate (257mg, 1 .01 mmol), followed by 4,4-di-tert-butyl-2,2-dipyridyl (8.1 mg, 0.03mmol) and lr₂(OMe)₂COD₂ (9.9mg, 0.015mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica eluting with EtOAc:heptane 1 :9 to afford the title compound (75mg).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .34 (s, 12 H) 1 .49 (s, 3 H) 1 .54 (s, 3 H) 4.40 (s, 1 H) 4.45 (s, 1 H) 8.00 (d, J=1 .56 Hz, 1 H) 8.37 (d, J=1 .76 Hz, 1 H)

Preparation 39: 2.2.2-Trifluoroethanesulfonic acid amide

To a 100ml flask charged with ammonia in MeOH (15ml, 7M) at 0°C, was added 2,2,2- trifluoroethanesulfonyl chloride (0.606ml, 5.48mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was concentrated in vacuo to give a white solid. The solid was washed with Et₂0 and the filtrate concentrated in vacuo to afford the title compound (136mg).

1 H NMR (400 MHz, d₆-DMSO) δ ppm 4.20 (m, 2H), 7.45 (m, 2H).

Preparation 40: 3-chloro-2-cvclopropylpyridine

2-bromo-3-chloropyridine (70 g, 363.8 mmol), cycloproyl boronic acid (31 .3 g, 363.8 mmol), and potassium phosphate tribasic (193 g, 909.5 mmol) were suspended in a mixture of toluene (600 mL) and water (120 mL) with rapid stirring. The suspension was heated to 80 °C, and the solvent de-gassed by direct bubbling of N₂ gas through the suspension for 30 mins. The reaction was then heated to 95 °C, and tricyclohexyl phosphine (10.2 g, 36.4 mmol) rapidly followed by palladium acetate (4.10 g, 18.2 mmol) were added. The reaction was left to stir and heated at 95 °C for 18 hours. The reaction was cooled to room temperature, and run through a plug of arbocel, eluting with ethyl acetate. The solvent was removed to leave a dark yellow oil. TBME was added (300 mL), and the organics washed with 2M HCI solution (3 x 200 mL). The organics were discarded. TBME (300 mL) was added to the combined aqueous layers, and solid sodium bicarbonate was added until the aqueous layer reached pH 7. The mixture was transferred to a separating funnel, the organic layer was removed, and the aqueous layer was extracted into TBME (2 x 100 mL). The combined organics were dried over magnesium sulfate, filtered and the solvent removed to leave an orange oil. The material was purified by column chromatography (silica), eluting with 4: 1 heptane:ethyl acetate, affording the title compound as a pale yellow oil (38.6 g).

1 H NMR (400 MHz, CDCI₃) δ ppm 0.95-1 .10 (m, 4H), 2.45-2.57 (m, 1 H), 6.98 (dd, 1 H), 7.39 (d, 1 H), 8.30 (d, 1 H)

LCMS Rt = 2.61 minutes, MS m/z 154 [MH]+

Preparation 41 : 3-chloro-2-cvclopropyl-5-i4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-

2-yl)pyridine

To a solution of dioxane (500 mL) was added 3-chloro-2-cyclopropylpyridine (Preparation 40, 44.5 g, 290.8 mmol) and bis(pinacolato)diboron (66.4 g, 261 .8 mmol). The solution was de-gassed by bubbling of N₂ through the solution for 30 minutes. The solution was heated to 90 °C, and 4,4-di-tert-butyl-2,2-dipyridyl (0.78 g, 2.90 mmol) plus cyclooctadiene(dimethoxy) Iridium (I) dimer (0.96 g, 1 .45 mmol) were added. The flask was de-gassed with N₂ (x3), and left at 90 °C for 18 hours. The reaction was cooled in an ice bath, and quenched by slow addition of methanol (100 mL) before concentrating in vacuo to provide the title compound as a red-brown oil which was used crude (81 g). ¹ H NMR (400 MHz, CDCI₃) δ ppm 0.99 -1 .05 (m, 2H), 1.10-1 .17 (m, 2H), 1 .31 (s, 12H), 2.49-2.58 (m, 1 H), 7.91 (s, 1 H), 8.60 (s, 1 H).

Preparation 42: 1 -(3-bromo-2,6-difluorophenyl)ethanol

To a solution of anhydrous diethyl ether (25 mL) was added 3-bromo-2,6- difluorobenzaldehyde (5.00 g, 22.6 mmol), and the flask cooled to 5 °C (ice bath). To the solution was added methyl magnesium bromide (8.30 mL, 3M) via syringe over 5 minutes. The reaction was maintained at 5 °C for 30 minutes, after which the reaction was quenched by slow addition of water (50 mL). The reaction mixture was extracted into ethyl acetate (3 x 50 mL). The combined organics were dried over MgS04, filtered and the solvent removed to afford the title compound as a colourless oil (5.64 g, 100%). No further purification undertaken.

¹ H N MR (400 MHz, CDCI₃) δ ppm 1 .64 (d, 3H), 2.21 (br-s, 1 H), 5.26 (br-q, 1 H), 6.77 - 6.85 (m, 1 H), 7.37-7.48 (m, 1 H)

¹⁹F NMR (400 MHz, CDCI₃) δ ppm -108 (s), -1 16 (s)

LCMS Rt 2.16 min, MS m/z No mass ion -(3-bromo-2,6-difluorophenyl)ethanone

To a solution of dichloromethane (50 mL) was added 1 -(3-bromo-2,6- difluorophenyl)ethanol (Preparation 42, 5.64 g, 23.8 mmol), followed by pyridinium dichromate (13.4 g, 35.7 mmol). The reaction was allowed to stir at room temperature for 18 hours, after which a further portion of pyridinium dichromate (3 g) was added, and the reaction left to stir at room temperature for a further 24 hours. The resulting suspension was run through a plug of arbocel, eluting with dichloromethane (200 mL). The solvent was removed in vacuo to leave an orange oil. The crude oil was purified by flash column chromatography (silica), eluting with 2: 1 heptane:ethyl acetate, to afford the title compound as a colourless oil (3.42 g, 61 %).

1 H N MR (400 MHz, CDCI₃) δ ppm 2.60 (s, 3H), 6.87 (t, 1 H), 7.55-7.66 (m, 1 H).

1⁹F NMR (400 MHz, CDCI₃) δ ppm -104 (s), -1 13 (s).

LCMS: Rt 2.37 min, MS m/z No mass ion. -bromo-4-fluoro-3-methyl-1H-indazole

To a solution of 1 -(3-bromo-2,6-difluorophenyl)ethanone (Preparation 43, 500 mg, 2.13 mmol) in ethylene glycol (5 ml.) was added hydrazine monohydrate (160 mg, 2.34 mmol) and triethylamine (0.33 ml_, 2.34 mmol), and the reaction heated to 100 °C for 18 hours. To the reaction was added a further 1 equivalent of hydrazine monohydrate, and the reaction heated to 150 °C for a further 4 hours. The reaction was cooled to room temperature, washed with water (100 ml.) and extracted into ethyl acetate (3 x 50 ml_). The combined organics were dried over MgS04, filtered and the solvent removed to leave a brown oil. The crude material was purified by flash column chromatography (silica), eluting with 2: 1 heptane:ethyl acetate to afford the title compound as a white solid (71 mg, 15%).

¹ H N MR (400 MHz, CDCI₃) δ ppm 2.69 (s, 3H), 7.08 (d, 1 H), 7.38-7.48 (m, 1 H)

1⁹F NMR (400 MHz, CDCI₃) δ ppm -1 14 (s)

LCMS Rt 2.31 min, MS m/z 229 [MH]+

Preparation 45: 5-bromo-1 -(5-chloro-6-cvclopropylpyridin-3-yl)-4-fluoro-3-methyl- 1 -indazole

To a solution of 5-bromo-4-fluoro-3-methyl-1 H-indazole (Preparation 44, 71 mg, 0.31 mmol) in anhydrous 1 ,2-dichloroethane (2 mL) was added anhydrous pyridine (0.08 ml_, 0.93 mmol) and 3-chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (Preparation 41 , 172 mg, 0.62 mmol). Finally copper(l l)acetate (1 13 mg, 0.62 mmol) was added and the reaction stirred rapidly at room temperature in air for 4 days. The reaction mixture was diluted with dichloromethane (50 mL), and washed with a saturated aqueous solution of EDTA (100 mL). The reaction mixture was further extracted into dichloromethane (3 x 50 mL). The combined organics were dried over MgS04, filtered and the solvent removed to leave a brown oil. The crude material was purified by flash column chromatography (silica), eluting with 2: 1 heptane:ethyl acetate to afford the title compound as a white solid (65 mg, 55%).

¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .04-1 .18 (m, 4H), 2.52-2.61 (m, 1 H), 2.73 (s, 3H) 7.25 - 7.30 (m, 1 H), 7.46-7.53 (m, 1 H), 7.96 (s, 1 H), 8.66 (m, 1 H)

1⁹F NMR (400 MHz, CDCI₃) δ ppm -1 13 (s)

LCMS: Rt 3.33 min, MS m/z 381 [MH]+

Preparation 46: methyl 1 -(5-chloro-6-cvclopropylpyridin-3-yl)-4-fluoro-3-methyl-

1 -indazole-5-carboxylate

To a pressurized vessel was added 5-bromo-1-(5-chloro-6-cyclopropylpyridin-3-yl)-4- fluoro-3-methyl-1 H-indazole (Prepartion 45, 65 mg, 0.17 mmol), Pd(dppf)CI₂ (25 mg, 0.03 mmol), sodium acetate (42 mg, 0.51 mmol), methanol (1 .5 mL) and dimethylformamide (2 mL). CO gas (60 psi), and the reaction heated to 80 °C for 24 hours. The reaction mixture was cooled to room temperate and the solvent removed in vacuo to leave a brown solid. The crude material was purified by flash column chromatography (silica), eluting with 4: 1 heptane:ethyl acetate to afford the title compound as a white solid (53 mg, 86%).

¹ H N MR (400 MHz, CDCI₃) δ ppm 1 .06 -1 .18 (m, 4H), 2.52-2.61 (m, 1 H), 2.75 (s, 3H), 3.96 (s, 3H), 7.38 (d, 1 H), 7.94-7.99 (m, 2H), 8.70 (s, 1 H)

1⁹F NMR (400 MHz, CDCI₃) δ ppm -1 13 (s) LCMS: Rt 3.14 min, MS m/z 360 [MH]+

Preparation 47: 1 -(5-chloro-6-cvclopropylpyridin-3-yl)-4-fluoro-3-methyl-1 H- indazole-5-carboxylic acid

To a solution methyl 1 -(5-chloro-6-cyclopropylpyridin-3-yl)-4-fluoro-3-methyl-1 H- indazole-5-carboxylate (Preparation 46, 53 mg, 0.15 mmol) in 1 :1 tetrahydrofuran:water (5mL:5ml_) was added lithium hydroxide (18 mg, 0.74 mmol), and the reaction heated to 50 °C for 18 hours. The reaction was cooled to room temperature, washed with a saturated aqueous solution of ammonium chloride (100 ml.) and extracted into ethyl acetate (3 x 50 ml_). The combined organics were dried over MgS0₄, filtered and the solvent removed to afford the title compound as a white solid (43 mg, 84%). No further purification required.

¹ H NMR (400 MHz, MeOD) δ ppm 1.03-1 .12 (m, 4H), 2.52 - 2.62 (m, 1 H), 2.75 (s, 3H), 7.40 (d, 1 H), 7.86 (t, 1 H), 8.07 (s, 1 H)

¹⁹F NMR (400 MHz, MeOD) δ ppm -121 (s)

LCMS: Rt 2.80 min, MS m/z 346 [MH]+

Preparation 48: S-bromo-G-fluoro-S-methyl-iH-indazole

To a solution of 5-bromo-2,4-difluoroacetophenone (5.95 g, 25.3 mmol) in ethylene glycol (30 mL) was added hydrazine monohydrate (2.0 ml_, 30.3 mmol, 50% solution) and the reaction heated to 100 °C for 4 hours then at 150 °C for 18 hours. The reaction was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (6 x 50 mL) and DCM (3 x 50 mL). The combined organics were dried over MgS0₄, filtered and concentrated in vacuo. The crude yellow solid (6.7g) was triturated with DCM and cyclohexane to afford the title compound as an amber solid (4.128g, 85%). ¹ H N MR (400 MHz, CDCI₃) δ ppm 2.54 (s, 3H), 7.17 (d, 1 H), 7.85 (d, 1 H)

1⁹F NMR (400 MHz, CDCI₃) δ ppm -108 (s)

LCMS (acidic, 4.5min): Rt 2.79 min, MS m/z 231 [MH]+

Preparation 49: 5-bromo-1 -i5-chloro-6-cvclopropylpyridin-3-yl)-6-fluoro-3-methyl- iH-indazole

In a microwave tube, 3-chloro-2-cyclopropyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)pyridine (Preparation 41 , 244 mg, 0.88 mmol) was added to a solution of 5-bromo- 6-fluoro-3-methyl-7/-/-indazole (Preparation 48, 100 mg, 0.44 mmol), Cu(OAc)₂ (158 mg, 0.88 mmol) and anhydrous pyridine (106 μΙ, 1 .31 mmol) in anhydrous 1 ,2- dichloroethane (1 ml). The reaction mixture was vigorously stirred under air atmosphere for 3 days then diluted with dichloromethane (3 ml) and a saturated solution of EDTA (5 ml) was added. The reaction mixture was stirred at room temperature for 1 hour. The aqueous layer was extracted with dichloromethane (2 x 5 ml). The combined organic layers were dried (MgS0₄), filtered and concentrated in vacuo. The crude compound was purified by column chromatography (Biotage SP1 , 25 g SNAP cartridge) eluting with heptane:ethyl acetate (gradient from 100:0 to 90:10) to give the title compound as a white solid (66 mg).

¹ H NMR (400 MHz, CDCI₃): δ ppm 1 .01 -1 .04 (m, 2H), 1 .07-1 .10 (m, 2H), 2.46-2.51 (m, 1 H), 2.52 (s, 3H), 7.32 (d, 1 H), 7.83 (d, 1 H), 7.87 (d, 1 H), 8.58 (d, 1 H)

1⁹F NMR (400 MHz, CDCI₃): δ ppm -106

LCMS Rt = 4.25 minutes, MS m/z 380 [MH]⁺ Preparation 50: methyl 1 -i5-chloro-6-cvclopropylpyridin-3-yl)-6-fluoro-3-methyl- -indazole-5-carboxylate

5-Bromo-1 -(5-chloro-6-cyclopropylpyridin-3-yl)-6-fluoro-3-methyl-i/-/-indazole

(Preparation 49, 66 mg, 0.18 mmol), PdCI₂.dppf (27 mg, 0.04 mmol), NaOAc (45 mg, 0.55 mmol), methanol (1 ml) and DMF (1 ml) were charged into a pressure vessel then stirred at 80 °C under CO atmosphere for 24 hours. The reaction mixture was concentrated in vacuo, water (5 ml) was added and the solution was acidified to pH 5 with citric acid (10% aqueous solution). The aqueous solution was extracted with ethyl acetate (3 x 5 ml) and the combined organic layers were dried (MgS0₄), filtered and concentrated in vacuo. The crude was purified by column chromatography (Biotage SP1 , 12 g SNAP cartridge) with heptane:ethyl acetate (gradient from 100:0 to 90:10) to give the title compound as a white solid (47 mg).

1 H NMR (400 MHz, CDCI₃): δ ppm 1 .08-1 .12 (m, 2H), 1 .15-1 .19 (m, 2H), 2.54-2.61 (m, 1 H), 2.65 (s, 3H), 3.98 (s, 3H), 7.33 (d, 1 H), 7.96 (d, 1 H), 8.40 (d, 1 H), 8.67 (d, 1 H) ¹⁹F NMR (400 MHz, CDCI₃): δ ppm -1 10

LCMS Rt = 3.93 minutes, MS m/z 360 [MH]⁺ + NH₃ Preparation 51 : 1 -i5-chloro-6-cvclopropylpyridin-3-yl)-6-fluoro-3-methyl- H-

Sodium hydroxide (1 M, 2 ml) was added to a solution of methyl 1 -(5-chloro-6- cyclopropylpyridin-3-yl)-6-fluoro-3-methyl-iH-indazole-5-carboxylate (Preparation 50, 47 mg, 0.13 mmol) in TH F:MeOH (1 ml : 1 ml). The reaction mixture was stirred at room temperature for 2 days then acidified to pH 2 with HCI (1 M) and extracted with ethyl acetate (3 x 5 ml). The combined organic layers were dried (MgS0₄), filtered and concentrated in vacuo to give the title compound as a colourless solid (45 mg).

1 H NMR (400 MHz, c -dmso): δ ppm 1 .02-1 .1 1 (m, 4H), 2.49-2.56 (m, 1 H), 2.60 (s, 3H), 7.76 (d, 1 H), 8.21 (d, 1 H), 8.41 (d, 1 H), 8.80 (d, 1 H)

1⁹F NMR (400 MHz, d⁶-dmso): δ ppm -1 1 1

LCMS Rt = 3.45 minutes, MS m/z 346 [MH]⁺ Preparation 52: 5-bromo-1 -i5-chloro-6-isobutoxypyridin-3-yl)-6-fluoro-3-methyl-

1 H-indazole

To a solution of 5-bromo-6-fluoro-3-methyl-1 H-indazole (Preparation 48, 387 mg, 1 .69 mmol) in anhydrous 1 ,2-dichloroethane (20 mL) was added anhydrous pyridine (0.41 mL, 5.06 mmol) and 3-chloro-2-isobutoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyridine (Preparation 32, 1 .053 g, 3.37 mmol) followed by copper(l l)acetate (614 mg, 3.37 mmol) and the reaction stirred rapidly at 80 °C in air (condenser and drying tube fitted) for 3 days. The reaction mixture was cooled and poured onto water (50 mL) containing 20% ammonia solution and extracted with DCM (3 x 50 mL), washed with water (2 x 40 mL) and dried over MgS0₄, filtered and concentrated in vacuo. The residue was absorbed onto silica and purified by flash column chromatography on silica eluting with cyclohexane:EtOAc 95:5 to afford the title compound as a white solid (383 mg, 55%).

1 H N MR (400 MHz, CDCI₃) δ ppm 1 .06 (d, 6H), 2.18 (m, 1 H), 2.59 (s, 3H), 4.20 (d, 2H), 7.30 (d, 1 H), 7.90 (d, 1 H), 7.95 (d, 1 H), 8.30 (d, 1 H)

1⁹F NMR (400 MHz, CDCI₃) δ ppm -106 (dd)

LCMS (acidic, 4.5 min): Rt 4.44 min, MS m/z 412 [MH]+ Preparation 53: methyl 1 -(5-chloro-6-cvclopropylpyridin-3-yl)-4-fluoro-3-methyl-

1 H-indazole-5-carboxylate

To a pressurized reaction vessel was added 5-bromo-1 -(5-chloro-6-isobutoxypyridin-3- yl)-6-fluoro-3-methyl-1 H-indazole (Preparation 52, 670 mg, 1 .62 mmol), Pd(dppf)CI₂ (237 mg, 0.32 mmol), sodium acetate (399 mg, 4.87 mmol), anhydrous methanol (4 mL) and dimethylformamide (4 mL). The reaction was heated to 80 °C at 60 psi under an atmosphere of CO for 24 hours. The reaction mixture was cooled to room temperate and the solvent removed in vacuo to leave a brown solid. The crude material was purified by flash column chromatography on silica eluting with cyclohexane:dichloromethane 1 : 1 then dichloromethane to afford the title compound as a white solid (127 mg, 20%). ¹ H NMR (400 MHz, CDCI₃) δ ppm 1 .07 (d, 6H), 2.18 (m, 1 H), 2.65 (s, 3H), 3.97 (s, 3H),

4.21 (d, 2H), 7.24 (d, 1 H), 7.97 (d, 1 H), 8.32 (d, 1 H), 8.40 (d, 1 H)

¹⁹F NMR (400 MHz, CDCI₃) δ ppm -1 10 (dd)

LCMS (acidic, 4.5min): Rt 4.15 min, MS m/z 392 [MH]+

Preparation 54: 1 -(5-chloro-6-isobutoxypyridin-3-yl)-6-fluoro-3-methyl-1 H-

To a solution of methyl 1 -(5-chloro-6-cyclopropylpyridin-3-yl)-4-fluoro-3-methyl-1 H- indazole-5-carboxylate (Preparation 53, 120 mg, 0.31 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added 1 M aqueous sodium hydroxide (3 mL, 3.0 mmol), and the reaction stirred at room temperature for 18 hours. The solvent was partially evaporated in vacuo and diluted with 1 M HCI (3 mL) in water (20 mL), extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with water (20 mL) and dried over MgS0₄, filtered and the solvent removed in vacuo to afford the title compound as a white solid (92 mg, 80%). No further purification required.

1 H NMR (400 MHz, CDCI₃/MeOD) δ ppm 0.90 (d, 6H), 2.48 (s, 3H), 4.04 (d, 2H), 7.09 (d, 1 H), 7.81 (d, 1 H), 8.15 (d, 1 H), 8.28 (d, 1 H)

1⁹F NMR (400 MHz, CDCI₃/MeOD) δ ppm -1 10 (dd)

LCMS (acidic, 4.5min): Rt 3.75 min, MS m/z 378 [MH]+

Preparation 55: Methyl 6-fluoro-3-methyl-1 H-indazole-5-carboxylate

To a pressurized reaction vessel was added 5-bromo-6-fluoro-3-methyl-1 H-indazole (Preparation 48, 1.046 g, 4.57 mmol), Pd(dppf)CI₂ (668 mg, 0.91 mmol), sodium acetate (1 .124 g, 13.7 mmol), anhydrous methanol (10 mL) and dimethylformamide (10 mL). The reaction was heated to 80 °C at 60 psi under an atmosphere of CO for 24 hours. The reaction mixture was cooled to room temperate and the solvent removed in vacuo to leave a brown solid. The crude material was purified by flash column chromatography on silica eluting with heptanes:ethyl acetate 1 : 1 to afford the title compound as a pale yellow solid (478 mg, 50%).

¹ H NMR (400 MHz, CDCI₃) δ ppm 2.60 (s, 3H, CH3), 3.96 (s, 3H, CH3), 7.13 (d, 1 H, Ar), 8.34 (d, 1 H, Ar), 10.85 (br s, 1 H, NH)

1⁹F NMR (400 MHz, CDCI₃) δ ppm -1 12 (dd)

LCMS (system 1 , acidic, 4.5min): Rt 2.37 min, MS m/z 209 [MH]+

Preparation 56: Methyl 1 -i5-chloro-6-ii1 -methylcvclopropyl)methoxy)pyridin-3-yl)- -fluoro-3-methyl-1 H-indazole-5-carboxylate

To a solution of methyl 6-fluoro-3-methyl-1 H-indazole-5-carboxylate (Preparation 55, 470 mg, 2.25 mmol) in anhydrous 1 ,2-dichloroethane (10 mL) was added anhydrous pyridine (0.55 mL, 6.77 mmol) and 3-chloro-2-((1 -methylcyclopropyl)methoxy)-5- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (Preparation 58, 1 .461 g, 4.51 mmol) followed by copper(l l)acetate (820 mg, 4.51 mmol) and the reaction stirred rapidly at 80 °C in air (condenser and drying tube fitted) for 18 hours. The reaction mixture was cooled and poured onto water (50 mL) containing 20% ammonia solution and extracted with DCM (3 x 50 mL), washed with water (2 x 40 mL) and dried over MgS0₄, filtered and concentrated in vacuo. The residue was absorbed onto silica and purified by flash column chromatography on silica eluting with cyclohexane:EtOAc 100:0 to 90: 10 to afford the title compound as a white solid (840 mg, 92 %).

1 H N MR (400 MHz, CDCI₃) δ ppm 0.48 (m, 2H), 0.64 (m, 2H), 1 .30 (s, 3H), 2.67 (s, 3H), 4.00 (s, 3H), 4.27 (s, 2H2HH), 7.29 (d, 1 H), 8.00 (d, 1 H), 8.33 (d, 1 H), 8.42 (d, 1 H) ¹⁹F NMR (400 MHz, CDCI₃) δ ppm -1 10 (dd)

LCMS (acidic, 4.5 min): Rt 4.1 1 min, MS m/z 404 [MH]+

Preparation 57: 1 -(5-chloro-6-(( 1 -methylcvclopropyl)methoxy)pyridin-3-yl)-6-

To a solution methyl 1 -(5-chloro-6-((1 -methylcyclopropyl)methoxy)pyridin-3-yl)-6-fluoro- 3-methyl-1 H-indazole-5-carboxylate (Preparation 56, 582 mg, 1 .44 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide (10 mL, 10.0 mmol), and the reaction stirred at room temperature for 18 hours. The solvent was partially evaporated in vacuo and diluted with 1 M HCI (10 mL) in water (50 mL), extracted with ethyl acetate (3 x 20 mL). The combined organics were washed with water (20 mL) and dried over MgS0₄, filtered and the solvent removed n vacuo to afford the title compound as a white solid (520 mg, 91 %). No further purification required.

1 H NMR (400 MHz, CDCI₃/MeOD) δ ppm 0.31 (m, 2H), 0.48 (m, 2H), 1.13 (s, 3H), 2.51 (s, 3H), 4.10 (d, 2H), 7.25 (d, 1 H), 7.84 (d, 1 H), 8.16 (d, 1 H), 8.31 (d, 1 H)

1⁹F NMR (400 MHz, CDCI₃/MeOD) δ ppm -1 10 (dd)

LCMS (acidic, 4.5min): Rt 3.70 min, MS m/z 390 [MH]+ Preparation 58: 3-chloro-2-r(1 -methylcvclopropyl)methoxy1-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridine

The material was made according to Preparation 41 using 3-chloro-2-[(1- methylcyclopropyl)methoxy]pyridine (Preparation 59, 8.08 g, 40.88 mmol) and purified via column chromatography on silica gel eluting with heptanes to heptanes/ethyl acetate

(4:1 ) to provide the title compound as a colourless oil (1 1.86 g, 89%).

¹H NMR (400MHz, CDCI₃) δ ppm 0.42 (dd, 2H), 0.60 (dd, 2H), 1.34 (s, 3H), 1.24-1.39

(m, 12H), 4.22 (s, 2H), 7.97 (d, 1 H), 8.35 (d, 1 H)

LCMS Rt = 4.51 min. MS m/z 323 [M+H]

Preparation 59: 3-chloro-2-r( 1 -methylcvclopropyDmethoxylpyridine

The material was made according to Preparation 31 using 2,3-dichloropyridine (10. Og, 67.6 mmol) and 1 -methylcyclopropanemethanol (8.80 g, 100 mmol) and purified via column chromatography on silica gel eluting with heptanes to heptanes/ethyl acetate

(19:1 ) to provide the title compound as a colourless oil (8.10 g, 60%).

¹H NMR (400MHz, CDCI₃) δ ppm 0.43 (dd, 2H), 0.60 (dd, 2H), 1.26 (s, 3H), 4.17 (s, 2H),

6.82 (dd, 1 H), 7.63 (dd, 1 H), 8.01 (dd, 1 H)

LCMS Rt = 1 .75 min. MS no mass ion observed

The ability of the compounds of formula (I) to block the Nav1.7 (or SCN9A) channel were measured using the assay described below. Cell line construction and maintenance Human Embryonic Kidney (HEK) cells were transfected with an hSCN9A construct using lipofectamine reagent (Invitrogen), using standard techniques. Cells stably expressing the hSCN9A constructs were identified by their resistance to G-418 (400 μg ml). Clones were screened for expression using the whole-cell voltage-clamp technique.

Cell Culture

HEK cells stably transfected with hSCN9A were maintained in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum and 400 μg ml G-418 in an incubator at 37°C with a humidified atmosphere of 10% C0₂ . For HTS, cells were harvested from flasks by trypsinization and replated in an appropriate multi-well plate (typically 96 or 384 wells/plate) such that confluence would be achieved within 24 hours of plating. For electrophysiological studies, cells were removed from the culture flask by brief trypsinization and re-plated at low density onto glass cover slips. Cells were typically used for electrophysiological experiments within 24 to 72 hours after plating.

Electrophysiological Recording

Cover slips containing HEK cells expressing hSCN9A were placed in a bath on the stage of an inverted microscope and perfused (approximately 1 ml/minutes) with extracellular solution of the following composition: 138 mM NaCI , 2 mM CaCI₂, 5.4 mM KCI , 1 mM MgCI₂, 10 mM glucose, and 10 mM HEPES, pH 7.4, with NaOH. Pipettes were filled with an intracellular solution of the following composition: 135 mM CsF, 5 mM CsCI, 2 mM MgCI₂, 10 mM EGTA, 10 mM HEPES, pH 7.3 with NaOH, and had a resistance of 1 to 2 megaohms. The osmolarity of the extracellular and intracellular solutions was 300 mOsm/kg and 295 mOsm/kg, respectively. All recordings were made at room temperature (22-24°C) using AXOPATCH 200B amplifiers and PCLAMP software (Axon Instruments, Burlingame, CA). hSCN9A currents in H EK cells were measured using the whole-cell configuration of the patch-clamp technique (Hamill et al., 1981 ). Uncompensated series resistance was typically 2 to 5 mega ohms and >85% series resistance compensation was routinely achieved. As a result, voltage errors were negligible and no correction was applied. Current records were acquired at 20 to 50 KHz and filtered at 5 to 10 KHz. HEK cells stably transfected with hSCN9A were viewed under Hoffman contrast optics and placed in front of an array of flow pipes emitting either control or compound- containing extracellular solutions. All compounds were dissolved in dimethyl sulfoxide to make 10 mM stock solutions, which were then diluted into extracellular solution to attain the final concentrations desired. The final concentration of dimethyl sulfoxide (<0.3% dimethyl sulfoxide) was found to have no significant effect on hSCN9A sodium currents. The voltage-dependence of inactivation was determined by applying a series of depolarizing prepulses (8 sec long in 10 mV increments) from a negative holding potential. The voltage was then immediately stepped to 0 mV to assess the magnitude of the sodium current. Currents elicited at 0 mV were plotted as a function of prepulse potential to allow estimation of the voltage at which 50% of the channels were inactivated (midpoint of inactivation or V1/2). Compounds were tested for their ability to inhibit hSCN9A sodium channels by activating the channel with a 20 msec voltage step to 0 mV following an 8 second conditioning prepulse to the empirically determined V1/2. Compound effect (% inhibition) was determined by difference in current amplitude before and after application of test compounds. For ease of comparison, "estimated IC- 50" (EIC50) values were calculated from single point electrophysiology data by the following equation, (tested concentration, uM) X (100-% inhibition/% inhibition). Inhibition values <20% and >80% were excluded from the calculation.

Electrophysiological assays were conducted with PatchXpress 7000 hardware and associated software (Molecular Devices Corp). All assay buffers and solutions were identical to those used in conventional whole-cell voltage clamp experiments described above. hSCN9A cells were grown as above to 50% - 80% confluency and harvested by trypsinization. Trypsinized cells were washed and resuspended in extracellular buffer at a concentration of 1x10⁶ cells/ml. The onboard liquid handling facility of the PatchXpress was used for dispensing cells and application of test compounds. Determination of the voltage midpoint of inactivation was as described for conventional whole-cell recordings. Cells were then voltage-clamped to the empirically determined V1/2 and current was activated by a 20 msec voltage step to 0 mV.

Electrophysiological assays may also be conducted using the lonworks Quattro automated electrophysiological platform (Molecular Devices Corp). Intracellular and extracellular solutions were as described above with the following changes, 100μg/ml amphotericin was added to the intracellular solution to perforate the membrane and allow electrical access to the cells. hSCN9A cells were grown and harvested as for PatchXpress and cells were resuspended in extracellular solution at a concentration of 3-4x10⁶ cells/ml. The onboard liquid handling facility of the lonworks Quattro was used for dispensing cells and application of test compounds. A voltage protocol was then applied that comprised of a voltage step to fully inactivate the sodium channels, followed by a brief hyperpolarized recovery period to allow partial recovery from inactivation for unblocked sodium channels, followed by a test depolarized voltage step to assess magnitude of inhibition by test compound. Compound effect was determined based on current amplitude difference between the pre-compound addition and post- compound addition scans.

Compounds of the Examples were tested in the assay described above using the PatchXpress platform and found to have the Nav1 .7 EIC₅₀ (uM) values specified in the table below.

Ex. EICso Ex. EICso Ex. EICso Ex. EICso Ex. EICso

1 0.008 33 0.090 65 0.028 97 >3 129 10.0

2 ND 34 0.025 66 ND 98 >3 130 >3

3 0.13 35 0.028 67 0.034 99 8.9 131 7.0

4 0.96 36 0.028 68 3.9 100 >0.3 132 0.74

5 0.058 37 0.037

6 0.16 38 ND 70 0.22 102 >3 134 0.10

7 0.38 39 0.071 71 0.1 1 103 >3 135 0.67

8 0.13 40 0.017 72 1 .4 104 >3 136 >1

9 0.34 41 0.048 73 2.3 105 >3 137 1 .5

10 0.39 42 0.063 74 >1 106 >3 138 >3

1 1 0.25 43 0.033 75 0.041 107 >3 139 0.75

12 0.44 44 ND 76 7.0 108 >1 140 0.3

13 0.1 1 45 0.027 77 ND 109 0.62 141 >3

14 0.17 46 0.048 78 >3 1 10 > 1 142 0.47

15 1.6 47 0.026 79 >3 1 1 1 >3 143 1 .9

16 0.28 48 0.015 80 >3 1 12 9.7 144 0.72 17 0.60 49 0.072 81 ND 1 13 >1 145 0.31

18 0.16 50 0.024 82 2.8 1 14 1 .09 146 7.4

19 0.069 51 0.063 83 0.81 1 15 >3 147 >1

20 0.42 52 0.016 84 >3 1 16 8.6 148 0.14

21 0.075 53 0.46 85 4.0 1 17 1 .6 149 0.04

22 ND 54 ND 86 >1 1 18 >1 150 0.049

23 0.070 55 0.092 87 >3 1 19 >3 151 10.01

24 0.13 56 0.17 88 >3 120 0.88 152 0.52

25 0.046 57 0.042 89 6.3 121 0.46 153 0.032

26 ND 58 0.026 90 >0.3 122 1 .3 154 0.037

27 0.13 59 0.022 91 >3 123 >1 155 0.056

28 0.15 60 0.21 92 >3 124 1 .8 156 0.29

29 0.23 61 0.35 93 >1 125 0.14 157 17

30 0.13 62 0.077 94 0.92 126 >3 158 1.2

31 ND 63 0.28 95 >3 127 >1 159 0.400

32 0.025 64 0.14 96 12 128 >1 160 3.346

161 0.165

The ability of compounds of formula (I) to block the Nav1 .5 (or SCN5A) channel can also be measured using an assay analogous to that described above but replacing the SCN9A gene with the SCN5A gene. All other conditions remain the same including the same cell line and conditions for cell growth. The estimated IC50s are determined at the half inactivation for Nav1 .5. These results can be compared to the EIC50 value at the Nav1.7 channel to determine the selectivity of a given compound for Nav1.7 vs Nav1.5.

Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

R° and U are independently H or F;

V is (CrC₄)alkyl, optionally substituted by one to three F;

W is H, (CrC₄)alkyl or (C₃-C₄)cycloalkyl;

X is O or NR² or absent;

Y is H, F or CI;

R¹ and R² are independently H; (Ci-Ce)alkyl optionally substituted by one to three atoms or groups selected from F, (C3-Ce)cycloalkyl, (CrC6)alkyloxy, phenyl optionally substituted by F, or Het; Het; or (C3-Ce)cycloalkyl; wherein (C3-C8)cycloalkyl may be optionally fused to a phenyl ring or may be substituted by one to three atoms or groups selected from F, (Ci-Ce)alkyl optionally substituted by one to three F, or (Ci-Ce)alkyloxy; or

where both R¹ and R² are attached to the same nitrogen atom they may, together with that nitrogen, form: (i) a saturated, monocyclic, 4 to 7-membered ring which may optionally contain oxygen as an additional ring member or may optionally be fused to a phenyl ring, which 4 to 7-membered ring may also optionally be substituted with one to three atoms or groups selected from halo, (Ci-C6)alkyl, (Ci-C₄)alkyloxy(Co-C₄)alkylene or (C3-Ce)cycloalkyl; or (ii) a saturated, bridged, 7 to 9-membered ring; and

Het is 'C-linked', 3- to 8-membered, saturated, monoheterocycloalkyl comprising one or two ring members selected from -NH- or -0-.

2. A compound according to claim 1 wherein X is O.

3. A compound according to claim 1 wherein X is NR².

4. A compound according to claim 1 wherein X is absent.

5. A compound according to any preceding claim wherein U is H.

6. A compound according to any of claims 1 to 4 wherein U is F.

7. A compound according to any preceding claim wherein V is (C-|-C₄)alkyl, such as methyl.

8. A compound according to any preceding claim wherein W is (C-|-C₄)alkyl, such as methyl.

9. A compound according to any preceding claim wherein Y is CI.

10. A compound according to any preceding claim wherein R° is H.

1 1. A compound according to any preceding claim wherein R¹ is (CrC8)alkyl optionally substituted by a (C3-C8)cycloalkyl group; or (C3-C8)cycloalkyl: whein (C3-C8)cycloalkyl is optionally substituted by a (d-C6)alkyl group.

12.. A compound according to any preceding claim wherein R¹ is (Ci-C₄)alkyl optionally substituted by a (C3-C5)cycloalkyl group; or (C3-C5)cycloalkyl; wherein (C3- C5)cycloalkyl is optionally substituted by a (CrC3)alkyl group.

13. A compound of formula (I) selected from:

1-(5-chloro-6-isobutoxypyridin-3-yl)-3-methyl-N-(methylsulfonyl)-1 H-indazole-5- carboxamide;

1-(5-chloro-6-isobutoxypyridin-3-yl)-6-fluoro-3-methyl-N-(methylsulfonyl)-1 H- indazole-5-carboxamide; and 1-(5-chloro-6-((1-methylcyclopropyl)methoxy)pyridin-3-yl)-6-fluoro-3-methyl-N-

(methylsulfonyl)-1 H-indazole-5-carboxamide;

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together, as defined in any of claims 1 to 13, with one or more pharmaceutically acceptable excipients.

15. A pharmaceutical composition according to claim 14 including one or more additional therapeutic agents.

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 13, for use as a medicament.

17. A compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 13, for use in the treatment of a disorder for which a Nav1 .7 inhibitor is indicated.

18. A compound for use according to claim 17 wherein the disorder for which a Nav1.7 inhibitor is indicated is pain, preferably neuropathic, nociceptive or inflammatory pain.

19. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 13, for the preparation of a medicament for the treatment of a disorder for which a Nav1.7 inhibitor is indicated.

20. A method of treating a disorder in a human or animal for which a Nav1.7 inhibitor is indicated, comprising administering to said human or animal a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in any of claims 1 to 13.