TGF-p1 is the prototypic member of a family of cytokines including the TGF-ßs, activins, inhibins, bone morphogenetic proteins and Mullerian-inhibiting substance, that signal through a family of single transmembrane serine/threonine kinase receptors. These receptors can be divided into two classes, the type I or activin like kinase (ALK) receptors and type 11 receptors. The ALK receptors are distinguished from the type 11 receptors in that the ALK receptors (a) lack the serine/threonine rich intracellular tail, (b) possess serine/threonine kinase domains that are very homologous between type I receptors, and (c) share a common sequence motif called the GS domain, consisting of a region rich in glycine and serine residues. The GS domain is at the amino terminal end of the intracellular kinase domain and is critical for activation by the type 11 receptor. Several studies have shown that TGF-ß signaling requires both the ALK and type 11 receptors. Specifically, the type 11 receptor phosphorylates the GS domain of the type I receptor for TGF-ß, ALK5, in the presence of TGF-ß. The ALK5, in turn, phosphorylates the cytoplasmic proteins smad2 and smad3 at two carboxy terminal serines. The phosphorylated smad proteins translocate into the nucleus and activate genes that contribute to the production of extracellular matrix. Therefore, preferred compounds of this invention are selective in that they inhibit the type I receptor and thus matrix production.

Surprisingly, it has now been discovered that a class of novel 2-phenylpyridin-4-yl heterocyclyl derivatives function as potent and selective non-peptide inhibitors of ALK5 kinase.

According to a first aspect, the invention provides a compound of formula (I), a pharmaceutical acceptable salt, solvate or derivative thereof:

wherein A is furan, dioxolane, thiophene, pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine, morpholine, piperidine, oxazole, isoxazole, oxazoline, oxazolidine, thiazole, isothiazole, thiadiazole, benzofuran, indole, isoindole, indazole, imidazopyridine, quinazoline, quinoline, isoquinoline, pyrazole or triazole ; X is N or CH; R'is hydrogen, C, alkyl, C1-6alkenyl, C1-6alkoxy, halo, cyano, perfluor C1-6alkyl, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR7, -O(CH2)n-Het, - O (CH2) nNR5R6,-CONR5R6,-CO (CH2) nNR5R6,-SO2R7,-SO2NR5R6, - NR5S02R',-NR5COR7,-O (CH2) nCONR5R6,-NR5CO (CH2) nNR5R6 or-C (O) R7 ; R2 is hydrogen, C1-6alkyl, halo, cyano or perfluoroC1-6alkyl ; R3 is hydrogen or halo ; R4 is hydrogen, halo, phenyl, C1-6alkyl or -NR5R6 ; where R5 and R6 are independently selected from hydrogen; Het; C3 6cycloalkyl optionally substituted by C1 6alkyl ; or by C1 6alkyl optionally substituted by Het, alkoxy, cyano or-NRaRb (where Ra and Rb which may the same or different are hydrogen or C1 6alkyl, or Ra and Rb together with the nitrogen atom to which they are attached may form a 4,5 or 6-membered saturated ring); or R5 and R6 together with the nitrogen atom to which they are attached form a 3,4, 5,6 or 7-membered saturated or unsaturated ring which may contain one or more heteroatoms selected from N, S or O, and wherein the ring may be further substituted by one or more substituents selected from halo (such as fluoro, chloro, bromo), cyano,-CF3, hydroxy,-OCF3, C1-6alkyl and C1-6alkoxy ; R7 is selected from hydrogen and C1 6alkyl ; Het is a 5 or 6-membered C-linked heterocyclyl group which may be saturated, unsaturated or aromatic, which may contain one or more heteroatoms selected from N, S or O and which may be substituted by Chalky) ; and

n is 1-4; with the provisos that: a) when A is thiazole (wherein the thiazole sulfur is on the same side as the 4-pyridyl moiety); X is N; R'is hydrogen, C1-6alkyl, C1-6alkoxy, halo, cyano, perfluoroC1 6alkyl or perfluoroC,. 6alkoxy ; R2 is hydrogen, C1 6alkyl, halo, cyano or perfluoroC1 6alkyl ; and R3 is hydrogen or halo ; then R4 is not NH2 ; and b) when X is N, A is pyrazol (where the ring containing X is attached to the pyrazol ring at carbon atom next to a pyrazol ring nitrogen) and R2 is hydrogen then R3 is not hydrogen.

The term"C1 6alkyl"as used herein, whether on its own or as part of a group, refers to a straight or branched chain saturated aliphatic hydrocarbon radical of 1 to 6 carbon atoms, unless the chain length is limited thereto, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl and hexyl.

The term"alkenyl"as a group or part of a group refers to a straight or branched chain mono-or poly-unsaturated aliphatic hydrocarbon radical containing the specified number (s) of carbon atoms. References to"alkenyl"groups include groups which may be in the E-or Z-form or mixtures thereof.

The term"alkoxy"as a group or part of a group refers to an alkyl ether radical, wherein the term"alkyl"is defined above. Such alkoxy groups in particular include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert- butoxy.

The term"perfluoroalkyl"as used herein includes compounds such as trifluoromethyl.

The term"perfluoroalkoxy"as used herein includes compounds such as trifluoromethoxy.

The terms"halo"or"halogen"are used interchangeably herein to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.

The term"heterocyclyl"as used herein includes cyclic groups containing 5 to 7 ring- atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur,

and may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, inidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, <BR> <BR> <BR> isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, tetrazolyl, triazinyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and thiazolinyl. In addition, the term heterocyclyl includes fused heterocyclyl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl and isoindolyl.

Preferably, A is furan, thiophene, pyrrole, imidazole, pyridine, pyrimidine, oxazol, isoxazole, thiazole, isothiazole, thiadiazole, imidazopyridine, pyrazol or triazole ; each of which is optionally substituted by one or more of the substituents R4.

More preferably, A is triazole, imidazopyridine, thiazole, imidazole or pyrazol ; each of which is optionally substituted by one or more of the substituents R4.

Still more preferably A is imidazopyridine, thiazole or imidazole ; each of which is optionally substituted by one R4 substitutent.

Yet more preferably A is imidazole optionally substituted by one R4 substitutent.

Preferably X is N.

Preferably R1 is C1-6alkyl, C1-6alkoxy, halo, cyano, perfluoroC-6alkoxy,-NR5R6, -(CH2)nNR5R6, -O(CH2)nOR7, -O(CH2)n-HET, -O(CH2)nNR5R6, -CONR5R6, -SO2R7, - NR5SO2R',-NR5COR',-O (CH2) nCONR5R6,-NRSCO (CH2) nNR5R6 or-C (O) R7.

More preferably R1 is C1-6alkoxy, halo, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR7, -O(CH2)n-Het,-O (CH2) nNR5R6,-CONR5R6,-S02R'or -o (CH2) nCoNR5R6 Preferably R2 is hydrogen, C1-6alkyl or fluoro. More preferably R2 is hydrogen or methyl. More preferably still, R2 is methyl.

Preferably R3 is hydrogen.

Preferably, when X is N, R2 is methyl. More preferably when X is N and R2 is methyl, R3 is hydrogen.

Preferably R4 is hydrogen, phenyl, Chalky) or halo. More preferably tert-butyl, isopropyl or methyl.

Preferably R5 and R6 are independently selected from hydrogen; Het (preferably tetrahydropyranyl) ; C3-6cycloalkyl optionally substituted by C1-6alkyl ; or by C1-6alkyl optionally substituted by Het (preferably furyl), alkoxy, cyano or-NRaRb (where Ra and Rb which may the same or different are hydrogen or C1 6alkyl, or Ra and Rb together with the nitrogen atom to which they are attached may form a 4,5 or 6- membered saturated ring); or R5 and R6 together with the atom to which they are attached form a morpholine, piperidine, pyrrolidine or piperazine ring, each of which may be substituted by halo (such as fluoro, chloro, bromo), cyano,-CF3, hydroxy, -OCF3, C1-4alkyl or C1 4alkoxy.

More preferably R5 and R6 are independently selected from hydrogen, Het (preferably tetrahydropyranyl) or C1-6alkyl ; or R5 and R6 together with the atom to which they are attached form a morpholine, piperidine, pyrrolidine or piperazine ring, each of which may be substituted by halo (such as fluoro, chloro, bromo), cyano, -CF3, hydroxy, -OCF3, C1-4alkyl or C1-4alkyoxy.

It will be appreciated that the present invention is intended to include compounds having any combination of the preferred groups listed hereinbefore.

Preferably A is imidazole ; X is N ; R1 is C1-6alkyl, C1-6alkoxy, halo, cyano, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -(CH2)nOR7, -O (CH2) n-Het (preferably imidazolyl),-O (CH2) nNR5R6,-CONR5R6, -SO2R7, -NR5SO2R7, -R5COR7, -O(CH2)nCONR5R6, -NR5CO(CH2)nNR5R6 or -C (O) R ; R2 is hydrogen, Cl-6alkyl or fluoro ;

R3 is hydrogen or halo ; R4 is hydrogen, phenyl, C1-6alkyl or halo ; R5 and R6 are independently selected from hydrogen, Het (preferably tetrahydropyranyl) or C1 6alkyl ; or R5 and R6 together with the atom to which they are attached form a morpholine, piperidine, pyrrolidine or piperazine ring, each of which may be substituted by halo (such as fluoro, chloro, bromo), cyano,-CF3, hydroxy,-OCF3, C1-4alkyl or C1 1alkoxy ; is selected from hydrogen and C1 6alkyl ; Het is a 5 or 6-membered C-linked heterocyclyl group which may be saturated, unsaturated or aromatic, which may contain one or more heteroatoms selected from N, S or O and which may be substituted by C1-6alkyl ; and n is 1-4.

Compounds of formula (l) which are of special interest as agents useful in the treatment or prophylaxis of disorders characterised by the overexpression of TGF-ß are selected from the list : 4-{2-tert-Butyl-5-[6-methyl]-pyridin-2-yl-1H-imidazol-4-yl}- 2-(4-methanesulfonyl- phenyl)-pyridine (Example 84); 4- {4- [4- (2-tert-Butyl-5- {6-methyll-pyridin-2-yl-l H-imidazol-4-yi)-pyridin-2-yl]-phenyl}- morpholine (Example 86); N- (tetrahydropyran-4-yl)-4- (4- {2-isopropyl-5- [6-methyl-pyridin-2-yl]-1H-imidazol-4-yl}- pyridin-2-yl)-benzamide (Example 96); 4-{4-[4-(2-isopropyl-5-{6-methyl}-pyridin-2-yl-1H-imidazol-4 -yl)-pyridin-2-yl]-phenyl}- morpholine (Example 97) ; 4-(4-{4-[2-Isopropyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4 -yl]-pyridin-2-yl}-benzyl)- dimethyl-amine (Example 105); 4- (4- {4- [2-Isopropyl-5- (6-methyl-pyridin-2-yl)-1 H-imidazol-4-yl]-pyridin-2-yl}-benzyl)- morpholine (Example 104); N-(tetrahydropyran-4-yl)-4-(4-{2-tert-Butyl-5-[6-methyl-pyri din-2-yl]-1H-imidazol-4-yl}- pyridin-2-yl)-benzamide (Example 81) ; (4- {4- [2-tert-Butyl-5- (6-methyl-pyridin-2-yl)-1 H-imidazol-4-yl]-pyridin-2-yl}-benzyl)- pyrrolidine (Example 103); 4- (2-tert-Butyl-5- {6-methyl}-pyridin-2-y !-1H-imidazol-4-yl)-2- [4- (2-pyrrolidin-1-yl- ethoxy)-phenyl]-pyridine (Example 108); and 4- {4- [4- (2-methyl-5- {6-methyl}-pyridin-2-yl-1 H-imidazol-4-yl)-pyridin-2-yl]-phenyl}- morpholine (Example 98);

and pharmaceutical acceptable salts, solvates and derivatives thereof.

For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

As used herein the term"pharmaceutically acceptable derivative"means any pharmaceutical acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the compound of formula (1), or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) the a compound of formula (I) or an active metabolite or residue thereof, e. g. , a prodrug.

Preferred pharmaceutically acceptable derivatives according to the invention are any pharmaceutical acceptable salts, solvates or prodrugs.

Suitable pharmaceutical acceptable salts of the compounds of formula (I) include acid salts, for example sodium, potassium, calcium, magnesium and tetraalkylammonium and the like, or mono-or di-basic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like. Some of the compounds of this invention may be crystallised or recrystallised from solvents such as aqueous and organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation.

Hereinafter, compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as"compounds of the invention".

The compounds of the invention may exist in one or more tautomeric forms. All tautomers and mixtures thereof are included in the scope of the present invention.

Compounds of the invention may exist in the form of optical isomers, e. g. diastereoisomers and mixtures of isomers in all ratios, e. g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1 %, more suitably at least 5% and preferably from 10 to 59% of a compound of the invention.

Compounds of the invention may be prepared, in known manner in a variety of ways.

In the following reaction schemes and hereafter, unless otherwise stated R'to R7, X and n are as defined in the first aspect. These processes form further aspects of the invention.

Throughout the specification, general formulae are designated by Roman numerals (I), (II), (111), (IV) etc. Subsets of these general formulae are defined as (la), (lb), (Ic) etc.... (IVa), (IVb), (IVc) etc.

Pyrazol Derivatives (IA) Compounds of formula (lAa) may be prepared according to reaction scheme 1A from compounds of formula (IIA). Compounds of formula (IIA) are reacted with boron- containing compounds of formula (IIIA) using Suzuki coupling conditions (see Miyaura et al. Chem. Rev. 1995,95 : 2457) to give compounds of formula (IVA).

Preferably reaction is carried out in the presence of a suitable base such as sodium carbonate, potassium carbonate, potassium hydroxide or sodium hydroxide, in the presence of a palladium or nickel catalyst, preferably at elevated temperature for a

period of between 30 minutes and 48 hours. Preferred catalysts include tetrakis (triphenlyphosphine) palladium (0), palladium (II) acetate, dichlorobis (triphenylphosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0) and dichlorobis (triphenylphosphine) nickel. Compounds of formula (IVA) may be deprotected under acidic conditions (preferably hydrochloric acid) to give compounds of formula (lAa).

Scheme 1A Trityl Trity ! A'A N-non 1 (IIIA) I Cm zu B N N B N R1 (IVA) H N-N : 0 1 1 HCI, reflux I (laya) \ (laya)

Compounds of formula (IAb) may be prepared according to reaction scheme 2A from compounds of formula (VA), by reacting compounds of formula (VA) with dimethylformamide dimethyl acetal and acetic acid in a solvent such as DMF at room temperature, followed by treatment with hydrazine.

Scheme 2A

Compounds of formula (VA) may be prepared using Suzuki coupling methodology (see reaction scheme 1A) from compounds of formula (VIA) according to reaction scheme 3A. Compounds of formula (VIA) may in turn be prepared in two steps from 2-bromo-4-pyridinecarboxylic acid.

Scheme 3A "CH3 zu O NH (Me) OMe. HCI N 3 HOBT, EDCI, TEA, CI-I3 N3C N CH CNZGl2, ct/ NaHMDSTHF, -40degC->r. t. Br N Br N Br N (VIA) 0 N CH 3 g (Oti) z Pd (PPh3) a, Na2C03, DME, reflux xi R (VA) Compounds of formula (IVAa), i. e. compounds of formula (IVA) (see reaction scheme 1A) where R'is OR (where R is C1-6alkyl, -(CH2)nOR7, -(CH2)nNR5R6 or -(CH2)nHet), may be prepared from compounds of formula (VIIA) according to reaction scheme 4A, by reaction with RX (where X is a leaving group such as halogen) in the presence of base such as potassium carbonate or sodium hydride in a solvent such as dimethylformamide.

Scheme 4A Trityl Trity\ N-N N-N p4 N CH Z4 N CH ru R4 z RX CH3 HO RO (VIIA) (IVAa) Compounds of formula (IVAb), i, e. compounds of formula (IVA) (see reaction scheme 1A) where R'is CONR5R6, may be prepared according to reaction scheme 5A, by reacting compounds of formula (VIIIA) with R5R6NH preferably in the presence of hydroxybenzotriazole and 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride.

Scheme 5A Trityl Trityl N-N N-N JL. - RSR6NH \ R5R6NH IN N/I N HO I R5R6N I HO R5R5Nt ° (IVAb) (IVAb) Compounds of formula (IVAc), i. e. compounds of formula ( VA) (see reaction scheme 1A) where R'is-CH2NR5R6, may be prepared according to reaction scheme 6A by reacting compounds of formula (IXA) with R5R6NH in the presence of a reducing agent, preferably sodium triacetoxyborohydride in acetic acid, in a solvent such as dichloroethane at room temperature.

Scheme 6A Trityl Trityl NN NN N-N N-N R4 \ \ CH3 R4 \ CH3 T l R5R6NH, T l reducing agent HJ R3R4NJ<J H \ R3RQN \ i 0 (IXA) (IVAc)

Compounds of formula (VIIA), (VIIIA) and (IXA) may be prepared by Suzuki coupling of compounds of formula (IIA) and the appropriate boron-containing compound, using conditions analogous to those described for reaction scheme 1A.

The skilled person will appreciate that compounds of formula (IVAa), (IVAb) and (IVAc) may also be prepared directly by Suzuki coupling of compounds of formula (IIA) with the appropriate boron-containing compound.

Compounds of formula (IIA) may be prepared according to reaction scheme 7A.

Firstly, 2-bromo-4-methylpyridine may be coupled to compounds of formula (XA) to give compounds of formula (XIA). Preferred reaction conditions comprise treatment with a base such as sodium bis (trimethylsilyl) amide or potassium bis (trimethylsilyl) amide in tetrahydrofuran at a range of temperature from-70°C to 0°C. Compounds of formula (XIA) may then be reacted with dimethylformamide dimethyl acetal and acetic acid in a solvent such as DMF at room temperature followed by treatment with hydrazine to give compounds of formula (XIIA) where R2 is hydrogen. To prepare compounds of formula (XIIA) where R4 is methyl, N, N- dimethylacetamide acetal is used instead of dimethylformamide dimethyl acetal.

Reaction of compounds of formula (XIIA) with trityl chloride gives compounds of formula (IIA).

Scheme 7A Triazole Derivatives (IB) Compounds of formula (IB) may be prepared from compounds of formula (IIB) by treatment with an azide source according to reaction scheme 1 B. Preferred reaction conditions comprise treating compounds of formula (I ! B) with trimethylsilylazide at elevated temperature in a suitable solvent such as dimethylformamide.

Scheme 1 B Compounds of formula (IIB) may be prepared by reacting compounds of formula (IIIB) (where Y is a leaving group such as halogen preferably chlorine) with boronic

acid derivatives of formula (IVB) according to reaction scheme 2B. Preferred conditions are those developed by Miyaura et al (Chem. Rev. 1995,95 : 2457), typically comprising reaction inert solvent in the presence of a base and a palladium or nickel catalyst at a temperature of between room temperature and 130°C for a period between 30 minutes and 48 hours. Suitable bases include sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide. Suitable catalysts include tetrakis (triphenlyphosphine) palladium (0), palladium (II) acetate, dichlorobis (triphenylphosphine) palladium (lI), tris (dibenylideneacetone) dipalladium (0) and dichlorobis (triphenylphosphine) nickel.

Scheme 2B Compounds of formula (IIIB) may be prepared by Sonagashira coupling of compounds of formula (VB) (where preferably Y is chlorine and Z is iodine) with compounds of formula (VIB) according to reaction scheme 3. Preferred reaction conditions comprise reaction in an inert solvent in the presence of a base and a palladium catalyst at a temperature of between room temperature and 80°C, for a period of between 30 minutes and 48 hours. Suitable bases include TMEDA or triethyl amine. Suitable palladium catalysts include tetrakis (triphenlyphosphine) palladium (0) and dichlorobis (triphenylphosphine) palladium (II).

Scheme 3B

Compounds of formula (VIB) may be prepared according to reaction scheme 4B where Y'in compounds of formula (VIIB) is a leaving group, preferably bromine.

Preferred reaction conditions for the preparation of compounds of formula (VIIIB) comprise treating compounds of formula (VIIB) with trimethylsilylacetylene in the presence of TMEDA and copper iodide under palladium catalysis in an inert solvent such as tetrahydrofuran at elevated temperature. The trimethylsilyl group may be removed by treating compounds of formula (VIIIB) with a base such as potassium carbonate in a protic solvent such as methanol.

Scheme 4B Compounds of formula (IlBa), i. e. compounds of formula (IIB) where R'is - O (CH2) 2NR5R6, may be prepared from compounds of formula (IIIB) (where Y is preferably chlorine) according to reaction scheme 5B. Compounds of formula (IIIB) may be reacted with compounds of formula (IXB) to give compounds of formula (IlBa) in one step. Alternatively compounds of formula (IIIB) may firstly be reacted

with 4-hydroxy-phenyl boronic acid, followed by alkylation with R5R6N (CH2) 2CI in the presence of a base such as potassium carbonate or sodium hydride in a solvent such as dimethylformamide.

Scheme 5B

Compounds of formula (IIBb), i. e. compounds of general formula (IIB) where R'is -CH2NR5R6, may be prepared according to reaction scheme 6B. Compounds of formula (IIIB) (where Y is preferably chlorine) may be reacted with 4-formylphenyl boronic acid using analogous conditions to reaction scheme 2 to give compounds of formula (XB). Compounds of formula (XB) may then be reacted with R5R6NH in the presence of a reducing agent, such as sodium cyanoborohydride in acetic acid at room temperature, to give compounds of formula (IIBb).

Scheme 6B

Imidazopyridine Derivatives (IC) Compounds of formula (IC) may be prepared from compounds of formula (IIC) according to reaction scheme 1C, by reacting compounds of formula (IIC) with compounds of formula (IIIC). Preferred reaction conditions comprise boron coupling of compounds of formula (IIIC) where Y is-B (OH) 2 or 4,4, 5, 5-tetramethyl- [1, 3,2]- dioxaborolan-2-yl cyclic derivative, with a compound of formula (IIC) in the presence of a suitable palladium catalysis (preferably Pd (PPh3) 4) and a suitable base (preferably sodium carbonate) in an inert solvent (preferably 1,2-dimethoxyethane) at elevated temperature.

Scheme 1C Compounds of formula (ICa), i. e. compounds of formula (IC) where R'is -CH2NR5R6, may be prepared by reductive amination of compounds of formula (IVC) according to reaction scheme 2C. Preferred reaction conditions comprise reacting (IVC) with HNR5R6 in the presence of NaHB (OAc) 3, in a suitable solvent (preferably dichloromethane) at room temperature.

Scheme 2C

Compounds of formula (IIIC) are available from commercial sources or may be prepared by methods analogous to those described in the Examples section hereinafter.

Compounds of formula (ICb), i. e. compounds of formula (IC) where R'is-NR5R6, may be prepared according to reaction scheme 3C by reacting compounds of formula (ICc), i. e. compounds of formula (IC) where R'is bromine, with HNR5R6 in the presence of a catalyst system preferably tris (dibenzylideneacetone) dipalladium (0) and 2,2'-bis (diphenylphosphino)-1, 1'- binaphthyl (Binap) in potassium tert-butoxide in a suitable solvent such as toluene at elevated temperature.

Scheme 3C

Compounds of formula (ICd), i. e. compounds of formula (IC) where R'is - OCH2CH2NR5R6, may be prepared according to reaction scheme 4C by reacting compounds of formula (VC) with 1,2-dibromoethane in the presence of a base preferably potassium carbonate in a suitable solvent, such as acetone, at elevated temperature. Treatment with HNR5R6 in a suitable solvent such as tetrahydrofuran at elevated temperature gives (ICd).

Scheme 4C Compounds of formula (ICe), i. e. compounds of general formula (IC) where R'is - CONR5R6, may be prepared according to reaction scheme 5C. Compounds of

formula (VIC) (where R is methyl or ethyl) are firstly saponified by heating with sodium hydroxide in methanol, followed by conversion of the resulting carboxylic acid to amide (ICe). Preferred reaction conditions comprise treating the intermediate carboxylic acid with HNR5R6 in the presence of HOBT, EDCI and a suitable base such as triethylamine in a suitable solvent such as dimethylformamide at room temperature.

Scheme 5C R4 R4 NN N N 1. Saponification X 2 2 HNR5R6// ; N R3 N R3 Rus rus 2 NR5R6 C02R 0 NRSRs (IVC) (ICe)

Compounds of formula (ICg), i. e. compounds of general formula (IC) where R'is -NHSO2CF3, may be prepared in two steps according to reaction scheme 6C.

Firstly the acetyl group is removed from compounds of formula (ICh) by treatment with sodium hydroxide in methanol at elevated temperature. The resulting amine is then treated with CF3SO2CI preferably in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane at room temperature.

Scheme 6C Ra Ruz 1 1 I Ni N N N X 2 1. remove acetyl /\ R 2. sulfonylation y 7 N--N-.. Rs Rs NHC (O) Me \HS (0), CF, NHC (O) Me NHS (0) 2CF3 (ICh) OC9)

It will be apparent to the skilled person that compounds of formula (IC) may also be prepared by introducing R'before formation of the imidazopyridine. For instance, compounds of formula (ICi), i. e. compounds of formula (IC) where R'is morpholine, X is N and R3 is H may be prepared according to reaction scheme 7C.

Scheme 7C 0 0 Nu N R2 NJ :)" N Pd (PPh3) a N, \ Br N Na2CO3 DME, reflux 0 R4 R4 CNH2 CN N NH2 N N 1. Fut CH2CI2, rt 2. EtOH, reflux 0. -o' O (ICi)

Compounds of formula (IIC) (see Scheme 1C) may be prepared in two steps according to reaction scheme 8C. Compounds of formula (VIIC) are firstly reacted with a suitable polymer-supported bromine reagent, such as polymer-supported pyridinium perbromide, in a suitable solvent such as dichloromethane at room temperature. Treatment with a compound of formula (VIIIC) in a suitable solvent such as ethanol at elevated temperature gives compounds of formula (IIC).

Scheme 8C 0 R 4 2 Xt 1. Bromine/resin iaN - 2. HZN N\ X z R Ber ( n ) R3 Br (VIIC) (IIC)

Compounds of formula (VIIC) may be prepared according to reaction scheme 9C by reacting 2-bromo-4-methylpyridine with compounds of formula (IXC) in the presence of a suitable base such as sodium bis (trimethylsilyl) amide in a suitable solvent such as tetrahydrofuran at-78 °C to-30°C.

Scheme 9C Imidazole Derivatives (ID) Compounds of formula (ID) may be prepared according to Scheme 1 D. Compounds of formula (IID) may be treated with sodium nitrite in HCI to give compounds of formula (IIID). Compounds of formula (IIID) may then be condensed with a suitably substituted aldehyde and ammonium acetate followed by treatment with triethylphosphite to give compounds of formula (IVD) according to the method outlined in US Pat. 5,656, 644. Boronic acid coupling gives compounds of formula (ID). Preferred coupling conditions are those developed by Miyaura et al (Chem. Rev.

1995,95 : 2457), typically comprising reaction in an inert solvent in the presence of a base and a palladium or nickel catalyst at temperature between room temperature and 130*C-for a period between 30 minutes and 48hours. Suitable bases include sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide.

Suitable catalysts include tetrakis (triphenlyphosphine) palladium (0), palladium (l!)

acetate, dichlorobis (triphenylphosphine) palladium (II), tris (dibenylideneacetone) dipalladium (0) and dichlorobis (triphenylphosphine) nickel.

Scheme 1D 0 X RUZ 0 t RZ NaNOz, HBI/HzO, R2 O C-r. t R3 BaHM S, T F N ber) ' Br N-10°C Br N (11D) (IIID) Ra Ra 1. NH40Ac, AcOH R 4-R'-PhB (OR) 2 N R4CHO, reflux N, Xs R2 Pd (PPh3) 4, Na2CO3 N 2. P (OEt) 3, DMF, 130°C DME, reflux tzars Br N N Br'N r 1 N (IVD) (ID) Compounds of formual (IDa), i. e. compounds of formula (I) where X is N, R1 is- CH2NR5R6 and R3 is hydrogen, may be prepared in one step according to scheme 2D from compounds of formula (VD).

Scheme 2D Compounds of formula (IDb), i. e. compounds of formula (ID) where X is N, R1 is- NR5R6 and R3 is hydrogen, may be prepared according to reaction scheme 3D by reacting compounds of formula (VID) with NHR5R6 in the presence of a catalyst system preferably tris (dibenzylidene acetone) dipalladium (0) and 2,2'- bis (diphenylphosphino)-1, 1'-binaphthyl (Binap) in potassium tert-butoxide in a suitable solvent such as toluene at elevated temperature.

Scheme 3D 4 HNR5R6 R Pd2 (dba) 3 R4 binap N t-BuOK N toluene N reflux RSRsN , N w N- N/ RZ N,/I \ Rz 5 N) R SID) (IDb)

Compounds of formula (IDc), i. e. compounds of formula (ID) where X is N, R'is - OCH2CH2NR5R6 and R3 is hydrogen, may be prepared according to reaction scheme 4D by reacting compounds of formula (VIID) with 1,2-dibromoethane in the presence of a base preferably potassium carbonate in a suitable solvent, such as acetone, at elevated temperature. Treatment with HNR5R6 in a suitable solvent such as tetrahydrofuran at elevated temperature gives (IDc).

Scheme 4D R4 R5-N"R6 R4 s RwN Ra 1. KZC03, acetone, f N/\ HO _ N BrCH2CH2Br, reflux N- N 2. HNR5R6, THF, reflux N-R 2 N-R2 (VIID) (IDc) Compounds of formula (IDd), i. e. compounds of formula (ID) where X is N, R'is -OCH2-Het and R3 is hydrogen, may be prepared according to reaction scheme 5D by reacting compounds of formula (VIIID) with compounds of formula (IXD) in the presence of a base (preferably sodium hydride) in a suitable solvent, such as DMF, at room temperature.

Scheme 5D

Compounds of formula (IDe), i. e. compounds of general formula (ID) where X is N, R'is-CONR5R6 and R3 is hydrogen, may be prepared according to reaction scheme 6D. Compounds of formula (XD) (where R is methyl or ethyl) are saponified by heating with sodium hydroxide in methanol followed by conversion of the resulting carboxylic acid to amide (IDe). Preferred reaction conditions comprise treating the intermediate carboxylic acid with HNR5R6 in the presence of hydroxybenzotriazole (HOBT), 1- [3- (Dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and a suitable base such as triethylamine in a suitable solvent such as dimethylformamide at room temperature.

Scheme 6D R4 1-R= Et or Me NaOH, MeOH R4 o N % reflux o -N----- o N-N //\ Rz HOBT. EDCI e ,-- - NEt,, DMF, rt 1 N-R (XD) (IDe) Compounds of formula (ID) where X is N and R'is-NHS02CF3 or-NHCOCF3, may be prepared from common intermediate of formula (XID) according to reaction scheme 7D. Firstly the acetyl group is removed from compounds of formula (XID) by treatment with sodium hydroxide in methanol at elevated temperature. The resulting amine is then treated with CF3SO2CI or CF3COCI preferably in the presence of a base such as triethylamine in a suitable solvent such as dichloromethane at room temperature.

Scheme 7D R' Fuzz NaOH, MeOH N reflux han lNJ/ RZ N (XID) NEt3, CHZCI CICO-CF3 R4 W NEt3, CH2Cl2 rt Fe w Rua F9CS_ NN H/ H N w ,-N F3CN , Rz O NJ Rx

Aminothiazole Deriviatives (IE) Compounds of formula (fEa), i. e. compounds of general formula (IE) where A is S, B is N and R4 is NH2, may be prepared by reacting compounds of formula (IIE) with a suitable polymer-supported bromine reagent, such as polymer-supported pyridinium perbromide, followed by treatment with thiourea in a suitable solvent such as ethanol, preferably at elevated temperatures (see reaction scheme 1 E).

Scheme 1 E

Compounds of formula (IEb), i. e. compounds of general formula (IE) where A is N, B is S and R4 is NH2, may be prepared by reacting compounds of formula (IIIE) under analogous conditions to reaction scheme 1 E (see reaction scheme 2E).

Scheme 2E

Compounds of formula (IIE) may be prepared by reacting compounds of formula (IVE) with compounds of formula (VE) where Y is a boron containing moiety such as - B (OH) 2 or 4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl according to reaction scheme 3E. Preferred conditions comprise reaction with a suitable catalyst such as tetrakis (triphenylphosphine) palladium (0), in the presence of a suitable base such as sodium carbonate in a suitable solvent such as DME at elevated temperature.

Scheme 3E

Alternatively compounds of formula (IIE) may be prepared by reacting compounds of formula (VIE) with compounds of formula (VIIE) according to reaction scheme 4E.

Preferred reaction conditions comprise reacting (VIE) with sodium bis- (trimethylsilyl) amide in a suitable solvent such as tetrahydrofuran at low temperature, preferably-78°C.

Scheme 4E

Compounds of formula (IIIE) may be prepared according to reaction scheme 5E by reacting compounds of formula (VIIIE) with compounds of formula (VE) (where Y is as defined for reaction scheme 3E) using analogous reaction conditions to those of reaction scheme 3E.

Scheme 5E

Alternatively compounds of formula (IIIE) may be prepared according to reaction scheme 6E by reacting compounds of formula (IXE) with compounds of formula (XE) in the presence of a suitable base such as cesium carbonate in a suitable solvent such as tetrahydrofuran and isopropanol at room temperature.

Scheme 6E

Compounds of formula (VlilEa), i. e. compounds of genera) formuta (VH) E) (see scheme 5E) where X is N, R2 is methyl and R3 is hydrogen, may be prepared according to reaction scheme 7E. Preferred conditions comprise reacting 2, 6-lutidine with a strong base such as n-butyllithium or sodium bis- (trimethylsilyl) amide at low temperature, followed by addition of 2-bromo-N-methoxy-N-methyl-4- pyridinecarboxamide.

Scheme 7E

Compounds of formula (IXE) may be prepared in two steps according to reaction scheme 8E. Preferred reaction conditions for the first step are analogous to those described for reaction scheme 3E. Preferred reaction conditions for the second step comprise reacting compounds of formula (XIE) with aniline and diphenylphosphite in a suitable solvent such as isopropanol at room temperature.

Scheme 8E OPh 0=P 0 H ßB (OH) 2 =H gNHPh H -/ Ha' R N/diphenytphosphite d, N Ri Ri (XIE) (IXE)

Compounds of general formula (IE) may also be prepared using solid supported chemistry.

Compounds of formula (IEc), i. e. compounds of general formula (I) where A is S, B is N, R'is-OR (where R is for example-(CH2) n-Het or-CH2CONR5R6) and R4 is NH2, may be prepared from solid supported compounds of formula (XIIE) by reaction with RX (where X is a suitable leaving group such as chlorine) followed by cleavage under acidic conditions from the solid support, according to reaction scheme 9E.

Preferred conditions comprise treating (XIIE) with RX under basic conditions such as potassium carbonate in a suitable solvent such as DMSO at elevated temperature.

Preferred cleavage conditions are trifluoroacetic acid in a suitable solvent such as dichloromethane at room temperature.

Scheme 9E Compounds of formula (IEd), i. e. compounds of general formula (IE) where A is S, B is N, R'is-CH2NR5R. and R4 is NH2, may be prepared from solid supported

compounds of formula (XIIIE) according to reaction scheme 10E. Preferred reaction conditions comprise treating (XIIIE) with HNR5R6 in trimethylorthoformate and addition of a reducing agent, such as sodium cyanoborohydride in acetic acid at elevated temperature. Cleavage from the solid support using trifluoroacetic acid in dichloromethane gives compounds of formula (IEd).

Scheme 10E

Compounds of formula (IEe), i. e. compounds of general formula (IE) where A is S, B is N, R1 is -C(O)NR5R6 and R4 is NH2, may be prepared from solid supported compounds of formula (XIVE) according to reaction scheme 11 E. Preferred reaction conditions comprise treating (XIVE) with HNR5R6, hydroxybenzotriazole and diisopropylcarbodiimide. Cleavage from the solid support using trifluoroacetic acid in dichloromethane gives compounds of formula (IEe).

Scheme 11 E

Compounds of formula (XIIE), (XIIIE) and (XIVE) may be prepared according to reaction scheme 12E from compounds of formula (XVE) and the appropriate arylboronic acid (XVIE), where Z is-OH, -CHO or-CO2H respectively.

Scheme 12E

Compounds of formula (XVE) may be prepared from solid-phase synthesis according to reaction scheme 13E. Compounds of formula (XVIE) may be prepared by treating compounds of formula (IVE) (see scheme 3E) with a suitable polymer-supported bromine reagent, such as polymer-supported pyridinium perbromide. Treatment of a resin bound thiourea with a dioxane solution of compounds of formula (XVI) gives the compounds (XV) using general conditions described in the literature (Kearney P. C., J. Org. Chem. , (1998), 63, 196).

Scheme 13E piperidine Fmoc-NCS S DMF, r. t CHaCl2, r. t NHFmoc NHZ--- H NHFmoc Rink resin (0. 58 mmol/g) 0 Br R o R3 H f J !/N piperidine S sr son DMF, r. t it (E} S ' RZ --- N NHZ dioxane, r. t Ber N N (XVE)

Further details for the preparation of compounds of formula (I) are found in the examples section hereinafter.

The compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, and more preferably 10 to 100 compounds. Libraries of compounds of the invention may be prepared by a combinatorial'split and mix'approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect there is provided a compound library comprising at least 2 compounds of the invention.

Activation of the TGF-ß1 axis and expansion of extracellular matrix are early and persistent contributors to the development and progression of chronic renal disease and vascular disease. Border W. A. , et al, N. Engl. J. Med. , 1994; 331 (19), 1286-92.

Further, TGF-ß1 plays a role in the formation of fibronectin and plasminogen activator inhibitor-1, components of sclerotic deposits, through the action of smad3 phosphorylation by the TGF-ß1 receptor ALK5. Zhang Y. , et al, Nature, 1998; 394 (6696), 909-13; Usui T. , et al, Invest. Ophthalmol. Vis. Sci. , 1998; 39 (11), 1981-9 Progressive fibrosis in the kidney and cardiovascular system is a major cause of suffering and death and an important contributor to the cost of health care. TGF-, 81 has been implicated in many renal fibrotic disorders. Border W. A. , et al, N. Engl. J.

Med. , 1994; 331 (19), 1286-92. TGF-ß1 is elevated in acute and chronic glomerulonephritis Yoshioka K. , et al, Lab. Invest., 1993; 68 (2), 154-63, diabetic nephropathy Yamamoto, T. , et al, 1993, PNAS 90,1814-1818., allograft rejection, HIV nephropathy and angiotensin-induced nephropathy Border W. A. , et al, N. Engl.

J. Med. , 1994; 331 (19), 1286-92. In these diseases the levels of TGF-ß1 expression coincide with the production of extracellular matrix. Three lines of evidence suggest a causal relationship between TGF-p1 and the production of matrix. First, normal glomeruli, mesangial cells and non-renal cells can be induced to produce extracellular-matrix protein and inhibit protease activity by exogenous TGF-ß1 in vitro. Second, neutralizing anti-bodies against TGF-p1 can prevent the accumulation of extracellular matrix in nephritic rats. Third, TGF-ß1 transgenic mice or in vivo transfection of the TGF-p1 gene into normal rat kidneys resulted in the rapid development of glomerulosclerosis. Kopp J. B. , et al, Lab. Invest., 1996; 74 (6), 991- 1003. Thus, inhibition of TGF-ß1 activity is indicated as a therapeutic intervention in chronic renal disease.

TGF-p1 and its receptors are increased in injured blood vessels and are indicated in neointima formation following balloon angioplasty Saitis J. , et al, Clin. Exp.

Pharmacol. Physiol., 1996; 23 (3), 193-200. In addition TGF-ß1 is a potent stimulator of smooth muscle cell ("SMC") migration in vitro and migration of SMC in the arterial wall is a contributing factor in the pathogenesis of atherosclerosis and restenosis.

Moreover, in multivariate analysis of the endothelial cell products against total cholesterol, TGF-ß receptor ALK5 correlated with total cholesterol (P < 0.001) Blann A. D., et al, Atherosclerosis, 1996; 120 (1-2), 221-6. Furthermore, SMC derived from human atherosclerotic lesions have an increased ALK5/TGF-ß type 11 receptor ratio.

Because TGF-ß1 is over-expressed in fibroproliferative vascular lesions, receptor- variant cells would be allowed to grow in a slow, but uncontrolled fashion, while overproducing extracellular matrix components McCaffrey T. A. , et al, Jr. , J. Clin.

Invest., 1995; 96 (6), 2667-75. TGF-p1 was immunolocalized to non-foamy macrophages in atherosclerotic lesions where active matrix synthesis occurs, suggesting that non-foamy macrophages may participate in modulating matrix gene expression in atherosclerotic remodelling via a TGF-p-dependent mechanism.

Therefore, inhibiting the action of TGF-R1 on ALK5 is also indicated in atherosclerosis and restenosis.

TGF-, 3 is also indicated in wound repair. Neutralizing antibodies to TGF-ß1 have been used in a number of models to illustrate that inhibition of TGF-, 81 signalling is beneficial in restoring function after injury by limiting excessive scar formation during the healing process. For example, neutralizing antibodies to TGF-ß1 and TGF-ß2 reduced scar formation and improved the cytoarchitecture of the neodermis by reducing the number of monocytes and macrophages as well as decreasing dermal fibronectin and collagen deposition in rats Shah M. , J. Cell. Sci. , 1995,108, 985- 1002. Moreover, TGF-ß antibodies also improve healing of corneal wounds in rabbits Moller-Pedersen T. , Curr. Eye Res., 1998, 17,736-747, and accelerate wound healing of gastric ulcers in the rat, Ernst H. , Gut, 1996, 39, 172-175. These data strongly suggest that limiting the activity of TGF-ß would be beneficial in many tissues and suggest that any disease with chronic elevation of TGF-ß would benefit by inhibiting smad2 and smad3 signaling pathways.

TGF-ß is also implicated in peritoneal adhesions Saed G. M. , et al, Wound Repair Regeneration, 1999 Nov-Dec, 7 (6), 504-510. Therefore, inhibitors of ALK5 would be beneficial in preventing peritoneal and sub-dermal fibrotic adhesions following surgical procedures.

TGF-ß is also implicated in photoaging of the skin (see Fisher GJ. Kang SW. Varani J. Bata-Csorgo Z. Wan YS. Data S. Voorhees JJ. , Mechanisms of photoaging and chronological skin ageing, Archives of Dermatology, 138 (11): 1462-1470,2002 Nov. and Schwartz E. Sapadin AN. Kligman LH."Ultraviolet B radiation increases steady state MARNA levels for cytokines and integrins in hairless mouse skin-modulation by topical tretinoin", Archives if Dermatological Research, 290 (3): 137-144,1998 Mar. ) Therefore according to a further aspect, the invention provides the use of a compound defined in the first aspect in the preparation of a medicament for treating or preventing a disease or condition mediated by ALK-5 inhibition.

Preferably the disease or condition mediated by ALK-5 inhibition is selected from the list : chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers (including diabetic ulcers, chronic ulcers, gastric ulcers, and duodenal ulcers), ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer's disease,

atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is a major component, including, but not limited to kidney fibrosis, lung fibrosis and liver fibrosis, for example, hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol- induced hepatitis, haemochromatosis, primary biliary cirrhosis, restenosis, retroperitoneal fibrosis, mesenteric fibrosis, endometriosis, keloids, cancer, abnormal bone function, inflammatory disorders, scarring and photaging of the skin.

More preferably the disease or condition mediated by ALK-5 inhibition is fibrosis.

Preferably kidney fibrosis.

It will be appreciated that references herein to treatment extend to prophylaxis as well as the treatment of established conditions.

Compounds of the invention may be administered in combination with other therapeutic agents, for example antiviral agents for liver diseases, or in combination with ACE inhibitors or angiotensin 11 receptor antagonists for kidney diseases.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art.

These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.

The compositions may be formulated for administration by any route. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as

preservatives, solvents to assist drug penetration and emollient in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone ; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine ; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica ; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol ; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e. g. cocoa-butter or other glycerid.

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

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry Iyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The compositions may contain from 0. 1 % by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i. e. , the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

No toxicological effects are indicated when a compound of the invention is administered in the above-mentioned dosage range.

All publications, including, but not limited to, patents and patent applications cited in this specification, are herein incorporated by reference as if each individual

publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

It will be appreciated that the invention includes the following further aspects. The preferred embodiments described for the first aspect extend these further aspects: i) a pharmaceutical composition comprising a compound of the invention and a pharmaceutical acceptable carrier or diluent ; ii) a compound of the invention for use as a medicament; iii) a method of treatment or prophylaxis of a disorder selected from chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, ulcers (including diabetic ulcers, chronic ulcers, gastric ulcers, and duodenal ulcers), ocular disorders, corneal wounds, diabetic nephropathy, impaired neurological function, Alzheimer's disease, atherosclerosis, peritoneal and sub-dermal adhesion, any disease wherein fibrosis is a major component, including, but not limited to kidney fibrosis, lung fibrosis and liver fibrosis, for example, hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-induced hepatitis, haemochromatosis, primary biliary cirrhosis, restenosis, retroperitoneal fibrosis, mesenteric fibrosis, endometriosis, keloids, cancer, abnormal bone function, inflammatory disorders, scarring and photoaging of the skin, in mammals, which comprises administration to the mammal in need of such treatment, an effective amount of a compound of the invention; and iv) a combination of a compound of the invention with an ACE inhibitor or an angiotensin 11 receptor antagonist.

According to a further aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate or derivative thereof, wherein X is N or CH; A is selected from the list : furan, dioxolane, thiophene, pyrrole, imidazole, pyrrolidine, pyran, pyridine, pyrimidine, morpholine, piperidine, oxazole, isoxazole, oxazoline, oxazolidine, thiazole, isothiazole, thiadiazole, benzofuran, indole,

isoindol, indazole, imidazopyridine, quinazoline, quinoline, isoquinoline and triazole ; R'is selected from H, C106alkyl, C1-6alkenyl, C1-6alkoxy, halo, cyano, perfluoro C1-6alkyl, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR5, - O (CH2) nNR5R6,-CONR5R6,-CO (CH2) nNR5R6,-SO2R5,-S02NR5R6, -NR5SO2R5 and -NR5COR6 ; R2 is selected from H, C1-6alkyl, halo, CN or perfluoroC1-6alkyl ; R3 is selected from H or halo ; R4 is selected from H, halo, C16alkyl or-NR5R6 ; R5 and R6 are independently selected from H or C16alkyl ; or R5R6 together with the atom to which they are attached form a 3,4, 5,6 or 7-membered saturated or unsaturated ring which may contain one or more heteroatoms selected from N, S or O, and wherein the ring may be further substituted by one or more substituents selected from halo (such as fluoro, chloro, bromo),-CN,-CF3,- OH,-OCF3, Ci. alkyl and C16 alkoxy ; and n is 1-4; with the provisos that: a) when A is thiazole (wherein the thiazole sulfur is on the same side as the 4-pyridyl moiety); X is N; R'is hydrogen, C1-6alkyl, C1-6alkoxy, halo, cyano, perfluoroC16alkyl or perfluoroC, 6alkoxy ; R2 is hydrogen, C1-6alkyl, halo, cyano or perfluoroC16alkyl ; and R3 is hydrogen or halo ; then R4 is not NH2 ; and b) when X is N, A is pyrazol (where the ring containing X is attached to the pyrazol ring at carbon atom next to a pyrazol ring nitrogen), R2 is hydrogen then R3 is not hydrogen.

The following examples illustrate the present invention.

Abbreviations Binap 2,2'-Bis (diphenylphosphino)-1, 1'-binaphthyl CH2CI2 dichloromethane Cut copper (l) iodide DCE dichloroethane DMF dimethylformamide DMF. DMA-dimethylformamide dimethylacetal DME 1,2-Dimethoxyethane DMSO dimethylsulfoxide

EDCI 1- [3- (Dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride EtOAc ethyl acetate Et2O diethyl oxide EtOH ethanol Et3N triethylamine Fmoc-NCS fluoromethylcarbonyl isothiocyanate HOBT hydroxybenzotriazole K2CO3 potassium carbonate KMn04 potassium permanganate LiAIH4 lithium aluminium hydride MeCN acetonitrile MeOH methanol Na2CO3 sodium carbonate NaH sodium hydride NaHB (OAc) 3 sodium triacetoxyborohydride NaHC03 sodium hydrogen carbonate NaHMDS sodium bis (trimethylsilyl) amide NaNO2 sodium nitrite NaOH sodium hydroxide NH4CI ammonium chloride Na2SO4 sodium sulfate Pd2 (dba) 3 tris (dibenzylideneacetone) dipalladium (0) Pd (PPh3) 4 tetrakis (triphenylphosphine) palladium (0) PTS para-toluenesulfonic acid TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMEDA N, N, N', N'- Tetramethylethylenediamine TMS trimethylsilyl TMSN3 trimethylsilyl azide t-BuOK potassium tert-butoxide Intermediate 1: 2-Chloro-4-iodo-pyridine To a solution of 4-amino-2-chloro-pyridine (8.09g, 63 mmol, 1eq) in water (150mL) cooled to 0°C was added concentrated 98% HCI. A solution of sodium nitrite (5.65g, 82mmol, 1.3eq) in water (50mL) was added slowly at-10°C and the mixture was

stirred at this temperature for 40 min. A solution of potassium iodide (12. 55g, 75. 6mmol, 1.2eq) in water (50mL) was added and the resulting mixture was stirred at 0°C overnight. After treatment with NaOH (35%) and extraction with ethyl acetate, the organic phases were combined and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then CH2CI2/CH30H 99: 1) to give the title compound as an orange solid (9.5g, 63%) ; 1H NMR (300 MHz, CD13) 8 ppm: 7.99 (1H, d), 7.68 (1H, s), 7.52 (1H, d); (GC-MS) m/z: 239.

Intermediate 2: 2-Methvl-6-trimethvlsilanvlethvnyl-pyridine To a solution of 2-bromo-4-methyl-pyridine (25g, 0.15 mol) in dry THF (200mL) were added TMEDA (200mL) and TMS-acetylene (100mL, excess) under N2. The resulting mixture was degassed with nitrogen for 10 min and then tetrakis (triphenlyphosphine) palladium (0) (3. 7mmol, 4.3g) and copper iodide (14. 7mmol, 2.8g) were added and the mixture was heated at 60°C for 18h. The reaction mixture was concentrated and the residue partitioned between ethyl acetate/water. The organic phase was dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave a crude product which was purified by chromatography on silica gel (CH2CI2) to give the title compound (18.4g, 65%) as a black oil ; 1H NMR (300 MHz, CDC ! s) 8 ppm: 7.58-7. 49 (m, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 2.56 (s, 3H), 0.28 (s, 9H).

Intermediate 3: 2-Ethenvl-6-methyl-pvridine To a solution of intermediate 2 (18. 4g, 0. 097mol) in MeOH (100 ml) was added potassium carbonate (4eq, 0. 39mol, 53.7g) and the reaction mixture was stirred at rt for 30 min. The solvent was removed and the residue was partitioned between ethyl acetate/water. The organic layer was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure to give the title compound (8.75g, 77%) as a brown oil ;'H NMR (300 MHz, CDCI3) 8 ppm: 7.45-7. 34 (m, 1H), 7.14 (d, 1H), 6.98 (d, 1 H), 2.97 (s, 1H), 2.40 (s, 3H).

-intermediate 4: 6-Methvl-2-f (2-chloro-pyridin-4-vl)-ethynvll-pyridine

To a solution of intermediate 1 (1.85g, 7. 74mmol) in dry THF (40mL) were added under nitrogen TMEDA (20mL) and intermediate 3 (1. 1eq, 1g, 8. 51mmol). The resulting mixture was degassed with nitrogen for ten mins, tetrakis (triphenlyphosphine) palladium (0) (0.537g, 0. 464mol) and copper iodide (0. 177g, 0.928 mmol) were added and the mixture was heated at 60°C for 4hours.

The mixture was poured into a saturated solution of NH4CI and extracted with EtOAc.

The organic phase was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (CH2CI2/EtOAc 90: 10) to afford the title compound as a beige solid (1.54g, 86.4%) ;'H NMR (300 MHz, CDCI3) 8 ppm: 8.29 (d, 1H), 7.52 (t, 1H), 7.39 (s, 1H), 7.34-7. 24 (m, 2H), 7.10 (d, 1H), 2.50 (s, 3H).

Intermediate 5: 2- (2- (4-methvlsulfonylphenvl)-pyridin-4-vIy)-ethynyll-6-methvl-py ridine A solution of intermediate 4 (1g, 4. 37mmol), 4-(methylsulfonyl)phenyl boronic acid (1. 14g, 5.7 mmol), tetrakis (triphenlyphosphine) palladium (0) (0.118 g, 0. 1mmol) and aqueous sodium carbonate 2M (8.6mL, 17. 2mmol) in toluene (30mL) and EtOH (10mL) under nitrogen was stirred under reflux for 6 h. The mixture was hydrolyse with water, extracted with ethyl acetate and the combined organic phases were washed with water and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by chromatography on silica gel (eluent : CH2CI2/CH3OH 98: 2) to give the title compound as a yellow oil (0.7g, 46%) ; 1H NMR (300 MHz, CDCl3) 8 ppm: 8.66 (d, 1H), 8.14 (d, 2H), 7.98 (d, 2H), 7.90 (s, 1H), 7.56 (t, 1H), 7.43-7. 32 (m, 2H), 7.12 (d, 1H), 3.03 (s, 3H), 2.50 (s, 3H) ; [APCI MS] m/z 349 (MH+).

The following compounds of formula (IlBc) were prepared by methods analogous to that described for intermediate 5 using the appropriate boronic acid derivative (see Table 1).

Table 1 Int. R1 From Physical data intermediates : 6 methox 4 APCI MS m/z 301 MH+ 7 tetrahydropyran-4-4,33 APCI MS m/z 398 (MH+) taminocarbon ylaminocarbonyl 8 hydroxy 4 APCI MS m/z 287 (MH+) 9 ethyl 4 APCI MS m/z299 (MH+) 10 chloro 4 APCI MS m/z 306 (MH+) 11 trifluoromethox 4 APCI MS m/z 355 (MH+) 12 2-(pyrrolidino) ethoxy 4, 29 APCI MS m/z 384 (MH+) 13 fluoro 4 APClMS m/z 289 (MH+) 14 formyl 4 APCI MS m/z 299 MH+

Intermediate 15: 4-{4-[4-(4-Methyl-pyridin-2-ylethynyl)-pyridin-2-yl]-benzyl morpholine

To a solution of intermediate 14 (0. 45g, 1. 5mmol) in dichloroethane (40ml) were added morpholine (0.9g, 6mmol), sodium triacetoxyborohydride (1.2g, 6mmol) and acetic acid (0.27g, 4mmol). The mixture was stirred at room temperature for 6 hours and then poured into ice and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (0.55g, quantitative); [APCI MS] m/z 370 (MH+).

Intermediate 16: N, N-dimethvl-2-f (4-f4- (6-methvl-Dvridin-2-yl-ethvnyl)-pyridin-2- yl}phenyl)oxy]ethanamine

To a solution of intermediate 8 (0.572g, 2mmol) in acetone (20ml) were added 2-chloro-N, N-dimethylethanamine hydrochloride (0.374g, 2. 6mmol) and potassium carbonate (0.822g, 6mmol) and the mixture was stirred under reflux overnight. The reaction mixture was filtered and concentrated under reduced pressure. The residue was poured into water and extracted with CH2CI2. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil (0.7g, 98%); [APCI MS] m/z= 358 (MH+).

Intermediate 17: 3-chloro-4-fluoro-benzoic acid ethyl ester To a solution of 3-chloro-4-fluoro-benzoic acid (11.75 g, 67.3 mmol) in EtOH was added PTSA (1.2 g) and the resulting mixture was heated under reflux for 2 days. On cooling the mixture was poured into water and the aqueous phase was basified with a solution of NaOH 1 N. The product was extracted with CH2CI2 and the organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the title compound as an oil (13.08g, 96%); [APCI MS] m/z 203 (MH+).

Intermediate 18: 3, 4-difluoro-benzoic acid ethyl ester 3, 4-Difluoro-benzoic acid (11 g, 69.57 mmol) was reacted as described for intermediate 1 to afford the title compound as an oil (11. 78g, 91%) ;'H NMR (300 MHz, CDC13) 6 ppm: 7.84 (m, 2H), 7.22 (m, 1H), 4.37 (q, 2H), 1.38 (t, 3H).

Intermediate 19: 6-methvl-pyridine-2-carboxvlic acid ethyl ester 6-Methyl-pyridine-2-carboxylic acid (25g, 182.3 mmol) was reacted as described for intermediate 1 to afford the title compound as an oil (22.9g, 76.13%) ;'H NMR (300 MHz, CDCls) 6 ppm: 7.95 (d, 1H), 7.75 (t, 1H), 7.35 (d, 1H), 4.5 (q, 2H), 2.7 (s, 3H), 1.45 (t, 3H).

Intermediate 20: 6-fluoro-pyridine-2-carboxviic acid To a solution of 2-fluoro-6-methyl-pyridine (2.5g, 22.5 mmol) in water (170 ml) was added portionwise KMn04 (2g, 12.65 mmol) and the mixture was heated to reflux.

Then KMn04 (8g, 50.63 mmol) was added portionwise and the mixture was heated

under reflux for 3 hours. On cooling, the precipitate was filtered and the filtrate was acidified with a solution of HCI and then concentrated under reduced pressure. The residue was triturated with hot EtOH, the solid was filtered and the filtrate was concentrated to dryness under reduced pressure. The title compound was obtained as a white solid (1.7g, 53%); m. p. 137°C.

Intermediate 21: 6-fluoro-pyridine-2-carboxylic acid isopropyl ester Intermediate 20 (1g, 7.09 mmol) was added portionwise to thionyl chloride (3 ml) and the mixture was heated under reflux for 3 hours and then concentrated under reduced pressure. Isopropanol (3 ml) was added to the residue and the mixture was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was treated with a saturated solution of NaHCO3, extracted with ethyl acetate, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The title compound was obtained as an cream oil (1.2g, 93%); [APCI MS] m/z: 184 (MH+).

Intermediate 22: 1-methvl-4-hydroxemethel-imidazole To a suspension of 1-methyl-imidazole-4-carboxylic acid (11. 4g, 90 mmol) in THF (500ml) at 0°C was added dropwise LiAIH4 (solution 1 M in THF, 117ml. 117 mmol) and the mixture was stirred at room temperature overnight and then at 50°C for 1 hour. On cooling, water (3 ml) was added followed by Na2SO4, and the resulting precipitate was filtered through a celite pad. The filtrate was concentrated under reduced pressure to afford the title compound as a solid (8g, 78.95%) ; H NMR (300 MHz, CDCl3) â ppm: 7. 25 (s, 1 H), 6.7 (s, 1 H), 5.25 (m, 1 H), 4.4 (s, 2H), 3.45 (s, 3H).

Intermediate 23: 1-methyl-4-chloromethvl-imidazole hydrochloride To a solution of intermediate 22 (5g, 44.64 mmol) in CH2CI2 (10 ml) at 0°C was added dropwise thionyl chloride (50 mi) and then the mixture was stirred at room temperature overnight and then at reflux for 3 hours. The mixture was concentrated under reduced pressure, and diethyl ether added. The resulting precipitate was filtered and dried to give the title product as a brown solid (4g, 53. 81%) ;'H NMR (300 MHz, d6-DMSO) â ppm: 9.25 (s, 1 H), 7.8 (s, 1H), 4. 95 (s, 2H), 3.9 (s, 3H).

Intermediate 24: 4-(morpholin-4-vI)-bromobenzene To a solution of 4-phenylmorpholine (18g, 110.4 mmol) in ethanol (400ml) cooled in an iced bath, was added dropwise bromine (5.95 ml, 115.9 mmol) and the mixture

was stirred at room temperature for 2 hours. The mixture was poured into water and the solution was made basic by addition of a solution of sodium hydroxide (1N). The resulting precipitate was filtered, washed with water and dried. Crystallisation from diisopropyl ether gave the title compound as white crystals (15g, 56.13%) ; m. p. 126- 128°C.

Intermediate 25: 1-ethyvf-4- (4-bromophenyl)-piperazine To a solution of 1-ethyl-4-phenylpiperazine (18g, 95mmol) in ethanol (600moi) cooled in an iced bath, was added dropwise bromine (5.1 ml, 99mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water and made basic by addition of a solution of sodium hydroxide (1 N). After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (9/1). The titled compound was obtained as a solid (21g, 82. 4%) ; [APCI MS] m/z= 270 (MH+).

Intermediate 26: 4-(2-(pvrrolidin-1-vl)-ethoxy)-iodobenzene To a solution of 4-iodophenol (6g, 27. 3mmol) in acetone (200ml) were added caesium carbonate (22.2g, 68.4 mmol) and N- (2-chloroethyl)-pyrrolidine hydrochloride (7g, 41 mmol) and the mixture was heated under reflux for 4 hours. On cooling, the mixture was poured into water, and extracted with CH2CI2. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a red oil (8g, 92.53%) ;'H NMR (300MHz, CDCI3, ppm) 8 : 7.5 (d, 2H), 6.65 (d, 2H), 4 (t, 2H), 2.8 (t, 2H), 2.55 (m, 4H), 1.75 (m, 4H).

Intermediate 27: N-f4- (4, 4, 5, 5-tetramethyl-1, 3, 21-dioxaborolan-2-vl)-phenv l- morpholine To a solution of intermediate 24 (20g, 82.64 mmol) in dioxane (200ml) was added 4,4, 5, 5-tetramethyl- [1, 3, 2]-dioxaboro) ane (13. 2 m), 99. 17 mmol), dichloro bis (triphenylphosphine) palladium (II) (3g, 4.13 mmol) and triethylamine (34.5 ml,

247.93 mmol) and the mixture was heated under reflux during 4 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2) to give the title compound as an orange oil which crystallised (19.98 g, 83.94%) ; [APCI MS] m/z 289.07 (MH+).

Intermediate 28: 1-ethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ph enyl]- piperazine

To a solution of intermediate 25 (3g, 11mmol) in dioxane (100ml) was added 4,4, 5,5- tetramethyl-1, 3, 2-dioxaborolane (1. 8ml, 12mol), dichlorobis (triphenylphosphine) palladium (ll) (0.392g, 0. 57mmol) and triethylamine (4. 65ml, 33mmol) and the mixture was heated under reflux for 12 hours. On cooling, the mixture was poured into water and extracted with CH2CI2. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel eluting with CH2CI2/MeOH (90: 10). The titled compound was obtained as a brown oil which crystallised on standing (2g, 55.48%) ; m. p. 130-134°C.

Intermediate 29: 1-[2-(pyrrolidin-1-yl)-ethoxy]-4-[4,4,5,5-tetramethyl-1,3, 2- dioxaborolan-2-vll-benzene

Intermediate 26 (8g, 25. 24mmol) and 4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (4mi, 27. 6mmol) were reacted as described for intermediate 27 to afford the titled compound as a solid (8g, 99.99%) ; m. p. 160-164°C.

Intermediate 30: 1-[aminocarbonylmethyloxy]-4-[4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yll-benzene

To a solution of 4-[4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl]-phenol (5g, 22. 7mmol) in acetone (80mi) were added cesium carbonate (10.37g, 32 mmol) and bromoacetamide (4.39g, 32 mmol) and the mixture was heated at 70°C for 3 hours.

On cooling, the mixture was concentrated under reduced pressure and the residue was treated with water and extracted with CH2CI2. The organic phase was dried over Na2SO4, and concentrated. After trituration with diisopropyl ether, the title compound was obtained as a solid (4g, 63.54%) ; m. p. 166-168°C.

Intermediate 31 : 1-r (1-methvl-imidazol-4-yl)-methvloxvl-4-f4, 4. 5, 5-tetramethyl-1. 3, 2- dioxaborolan-2-yll-benzene

4- [4, 4,5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl] phenol (1g, 4.54 mmol) and intermediate 22 (1.88g, 11.4 mmol) were reacted as described for intermediate 29, to afford, after chromatography on silica gel (CH2CI2/MeOH, 95/5), the title compound as a pale yellow oil (0. 5g, 35%) ;'H NMR (300MHz, CDCl3, ppm) 8 : 7.6 (d, 2H), 7.3 (s, 1H), 6.8 (m, 3H), 4.9 (s, 2H), 3.5 (s, 3H), 1.2 (s, 12H).

Intermediate 32 : 1-rçmorpholin-4-vl) carbonvlmethvloxv1-4-F4, 4, 5, 5-tetramethyl-1, 3, 2- dioxaborolan-2-vl-benzene

To a solution of 4-[4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-phenol (6.6g, 30mmol) in CH3CN were added potassium carbonate (12.42g, 90 mmol) and N- (chloroacetyl)-morpholine (4.89g, 30 mmol) and the mixture was heated under reflux for 3 hours. On cooling the mixture was concentrated under reduced pressure, and

the residue was treated with water and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated. Trituration from hexane gave the title compound as a grey solid (9.5g, 91%); m. p. 112°C ; [APCI MS] m/z 348 (MH+).

Intermediate 33: 4- (4, 4. 5. 5-tetrameth rLl-f1, 3, 21dioxaborolan-2-vl)-N- (tetrahvdro-pyran- 4-vl)-benzamide

4- (4, 4,5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl)-benzoic acid (70.16g, 0.28 mol) was treated with SOCI2 (2 vol.) and the reaction mixture was stirred to reflux for 2 hours.

After evaporation, the residue was diluted in toluene and poured into a solution at 10°C of tetrahydro-pyran-4-ylamine (34. 34g, 0.339) and triethylamine (79 mL, 0.57 mol) in CH2CI2. The reaction mixture was stirred at room temperature during 2 days and water (490 mL) was added to give a precipitate which was filtered off and washed with EtOAc. After purification by flash chromatography using CH2CI2/MeOH (95: 5). The title compound was obtained as a solid (17. 02g, 18%) ; 1H NMR (400 MHz, CDCl3, ppm) 8 : 7.85 (d, 2H), 7.72 (d, 2H), 5.98 (m, 1H) j 4.20 (s, 1H), 3.99 (m, 2H), 3.35 (t, 2H), 2.01 (d, 2H), 1.57 (m, 2H), 1.35 (s, 12H).

Intermediate 34: N-f4- (4, 4, 5, 5-tetramethvl-1. 3, 21dioxaborolan-2-yl)-phenvll- methanesuifonamide

To a solution of4- (4, 4,5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl)-aniline (Aldrich, 5g, 22.8 mmol) in CH2Cl2 (20moi) was added NaHC03 (2.3g, 27.4 mmol) and methanesulfonyl chloride (13.2 mL, 171 mmol) and the reaction mixture was stirred at room temperature during 6 days. Water was added and the product was extracted with CH2CI2. The organic layer was dried over Na2SO4, and concentrated under reduced pressure. Crystallisation from diethyl ether gave the title compound as a white powder (2.52g, 37%) ; 1H NMR (300 MHz, CDCl3, ppm) # : 7.78 (d, 2H), 7. 18 (d, 2H), 6.69 (m, 1 H), 3.02 (s, 3H), 1. 33 (s, 12H). Intermediate 35: N-[(4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- phenvl) carbonyll-morpholine

To a solution of 4- (4, 4,5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl)-benzoic acid (5g, 20.15 mmol) in CH2CI2/DMF (50ml/5ml) were added morpholine (2. 1ml, 24. 2mmol), HOBT (3.3g, 24. 2mmol), EDCI (4.65g, 24. 2mmol) and triethylamine (4. 2moi, 30. 2mmol) and the reaction mixture was stirred at room temperature during 3 days.

Water was added and the product was extracted with CH2CI2. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Trituration with diisopropyl ether gave the title compound as a white solid (4.21g, 66%) ;'H NMR (300 MHz, CDCl3, ppm) 5 : 7.8 (d, 2H), 7. 4 (d, 2H), 3.7 (m, 4H), 3.55 (m, 2H), 3.35 (m, 2H), 1.3 (s, 12H).

Intermediate 36: 1-ethyl-4-[(4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) - phenvl) carbonyll-piperazine 4- (4, 4,5, 5-Tetramethyl- [1, 3,2] dioxaborolan-2-yl)-benzoic acid (8. 24g, 33.22 mmol) and N-ethylpiperazine (5. 1ml, 39. 87mmol) were reacted as described for intermediate 34 to afford, after chromatography on silica gel (CH2CI2/MeOH, 95/5), the title compound as a pale yellow oil which crystallised (9. 64g, 84%); [APCI MS] m/z 345 (MH+). intermediate 37: 2-(4-bromophenyl)-4-methyl-pyridine 2-Bromo-4-methylpyridine (10 g, 58.14 mmol) was dissolved in toluene (100 ml) and tetrakis (triphenylphosphine) palladium (0) (5 mol%, 3. 36 g) added under N2 and degassed. Aqueous sodium carbonate (2M, 2 eq) was added slowly and stirred for 10min. A solution of 4-bromophenylboronic acid (Lancaster, 14 g, 1.2 eq) in ethanol (20 ml) was added dropwise and the mixture was heated under reflux overnight and

then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (CH2CI2/cyclohexane 6/4 then 8/2 then CH2CI2). After crystallisation from pentane, the titled compound was obtained as white crystals (6.3g, 43.7%) ; 1 H NMR (300MHz, CDCI3, ppm) 8 8.5 (d, 1H), 7.83 (d, 2H), 7.56 (d, 2H), 7.5 (s, 1H), 7.05 (m, 1H), 2.4 (s, 3H).

Intermediate 38: 2-f4- (morpholin-4-vl) phenvll-4-methvl-pyridine To a solution of intermediate 37 (2.66 g, 10.72 mmol) in toluene (50 ml) was added morpholine (1.12 ml, 1.2 eq, 12.9 mmol), Pd2 (dba2) 3 (0.49g, 0.05 eq, 0.53 mmol), binap (1g, 0.15 eq, 1.6 mmol) and potassium tert-butoxide (1.44g, 1.4 eq, 15 mmol) and the mixture was heated under reflux for 2 h and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (CH2CI2/MeOH gradient from 99: 1 to 95: 5). The title compound was obtained as a yellow solid (2.6g, 95.43%) ; 1 H NMR (300MHz, CDCI3, ppm) b : 8.5 (d, 1 H), 7.95 (d, 2H), 7.5 (s, 1 H), 7 (m, 3H), 3.9 (m, 4H), 3.3 (m, 4H), 2.4 (s, 3H).

Intermediate 39: 2-f2-bromo-pvridin-4-vll-1-pvridin-2-yl-ethanone To a solution of 2-bromo-4-methyl-pyridine (27 g, 157 mmol) in dry THF (270 ml) was added ethyl picolinate (28.5 g, 188.7 mmol). The resulting mixture was cooled to -78°C under argon and a solution of sodium bis (trimethylsilyl) amide 1 M in THF (345 ml, 345 mmol) was added dropwise at-78°C. The resulting reaction mixture was allowed to reach room temperature and subsequently stirred overnight. The solvent was evaporated under reduced pressure and the solid residue triturated with diethyl ether, filtered and washed with diethyl ether. The solid was then diluted with saturated NH4CI solution and the aqueous phase extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The resulting orange powder was washed with pentane to give the title compound as a yellow solid (33.97 g); m. p.

111. 2°C.

Intermediate 40: 2-f2-bromo-pyridin-4-vl1-1- (6-methvl-pvridin-2-yl)-ethanone

To a solution of 2-bromo-4-methyl-pyridine (5 g, 29mmol) in dry THF (70 ml), a solution of sodium bis- (trimethylsilyl) amide 2M in THF (32 ml, 64 mmol) was added dropwise at-30°C under nitrogen. The mixture was stirred at-30°C for 1 h, then intermediate 19 (4.82 g, 32. 3mmol, 1. 1eq) was added. The reaction mixture was stirred at room temperature overnight. Diethyl ether was added and the precipitated solid was filtered and washed with diethyl ether. The solid was then diluted with saturated NH4CI solution and the aqueous phase was extracted with ethyl acetate.

The organic layer was dried over Na2SO4 and concentrated. The resulting orange powder was washed with pentane to give the title compound as a yellow solid (5.84 g, 70%). [APCI MS] m/z 292 (MH+).

Intermediate 41: 2-(2-bromo-pyridin-4-yl)-1-(3-chloro-4-fluoro-phenyl)-ethano ne 2-Bromo-4-methyl-pyridine (9.2g, 53.5 mmol) and intermediate 17 (13 g, 64.2 mmol) were reacted as described for intermediate 39 to afford the title compound as an orange solid (17.16 g, 98%) ; [APCI MS] m/z: 330 (MH+).

Intermediate 42: 2-(2-bromo-pyridin-4-vI)-1-(3, 4-difluoro-phenel)-ethanone

2-Bromo-4-methyl-pyridine (9.056g, 52.64 mmol) and intermediate 18 (11.75 g, 63.17 mmol) were reacted as described for intermediate 39 to afford the title compound as an ocre solid (14.54 g, 88.5%) ; [APCI MS] m/z: 314 (MH+).

Intermediate 43: 2- (2-bromo-pvridin-4-vl)-1- 3-chloro-phenyl)-ethanone

2-Bromo-4-methyl-pyridine (7.75g, 45.1 mmol) and methyl-3-chlorobenzoate (10 g, 58.6 mmol) were reacted as described for intermediate 39 to afford the title compound as an orange powder (13.02 g, 93%) ;'H NMR (300 MHz, CDCl3, ppm) S : 8.34 (d, 1H), 7.95 (m, 1H), 7.84 (d, 1H), 7.59 (d, 1H), 7.46 (d, 1H), 7.41 (d, 1H), 7.13 (d, 1 H), 4.24 (s, 2H).

Intermediate 44: 2- (2-bromo-pyridin-4-vl)-1- (6-fluoro-prridin-2-vl)-ethanone

To a solution of 2-bromo-4-methyl-pyridine (2.58g, 15 mmol) in anhydrous THF (50 ml) at-30°C, was added dropwise NaHMDS (solution 2M in THF, 15ml, 30 mmol) and the mixture was stirred at-30°C for 2 hours. A solution of intermediate 20 (2.74g, 15 mmol) in THF (50 ml) was added dropwise and the mixture was stirred at -30°C for 1 hour and then poured into water. After extraction with EtOAc, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2/MeOH, 99: 1). The title compound was obtained as a yellow solid (1.6g, 36%); [APCI MS] m/z=295 (MH+).

Intermediate 45: 2l2- (4- (morpholin-4-vl) phenyl)-pvridin-4-vll-1-pvridin-2-vl-ethanone

To a solution of Intermediate 38 (2.6 g, 10.24 mmol) in dry THF (100 ml) under argon, was added dropwise a solution of sodium bis- (trimethylsilyl) amide 1 M in THF (22.52 ml, 2.2 eq, 22.53 mmol). The solution was stirred room temperature for 0.5h, then a solution of ethyl picolinate (1.66 ml, 1.2 eq, 12.3 mmol) in dry THF (20 ml) was added dropwise and the reaction mixture stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure and the solid precipitated with diisopropyl ether. The brown solid was then taken up in saturated NH4CI solution and the aqueous phase extracted with CH2CI2. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to leave a residue which was purified by chromatography on silica gel (CH2CI2 then CH2CI2/MeOH gradient from 99: 1 to 97: 3). The title compound was obtained as an orange oil (1.42 g, 38. 64%) ; 1H NMR (300MHz, CDCI3, ppm) 8 : 8.7 (d, 1 H), 8.55 (d, 1H), 8. 05 (d, 1 H), 7.9 (d, 2H), 7.8 (m, 1H), 7.5 (m, 1H), 7.15 (m, 1H), 6.95 (m, 3H), 4.55 (s, 2H), 3.85 (m, 4H), 3.2 (m, 4H).

Intermediate 46: 2- (2- (4- (methanesulfonvl) phenyl)-pyridin-4-v'-1- (6-methvlpyridin-2- vl)-ethanone To a solution of intermediate 40 (2g, 6. 87mmol) in DME (80ml) was added 4- (methanesulfonyl)-phenyl boronic acid (2.1g, 10. 31mmol), tetrakis (triphenylphosphine) palladium (0) (0.4g, 0. 35mmol) and Na2CO3 (solution 2M, 22ml) and the mixture was heated under reflux overnight and then poured into water.

After extraction with CH2Cl2, the organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (95: 5). The title compound was obtained as a yellow oil (1. 1g, 43.73%) ; [APCI MS] m/z=367 (MH+).

The following compounds of formula ()) Ea) were prepared by methods analogous to that described for intermediate 46 using the appropriate boronic acid derivative (see Table 2).

Table 2 Int. R'Physical data 47 4-ethylpiperazin-1-yl APCI MS m/z 387 (MH+) 48 morpholin-4-yl APCl MS m/z 374 MH+ 49 methoxycarbonyl APCI MS m/z 347 (MH+) 50 formyl APCI MS m/z 317 (MH+) 51 methoxy APCI MS m/z 319 (MH+) 52 trifluoromethoxy m.p. 76-78°C 53 2-(pyrolidin-1-yl) ethoxy APCI MS m/z 402 (MH+) 54 aminocarbonylmethoxy m. p. 144-146°C 55 (1-methyl-imidazol-4-yl) methoxy APCI MS m/z 399 (MH+)

Intermediate 56: 2-[2-(4-(carboxy)-phenyl)-pyridin-4-yl]-1-(6-methylpyridin-2 -yl ethanone To a solution of intermediate 49 (1.2g, 3. 47mmol) in MeOH (100mi) was added sodium hydroxide (solution 1 N, 5ml, 5. 2mmol) and the mixture was heated under reflux for 48 hours. After cooling, a solution of HCI 1 N (5 ml) was added and the precipitate was filtered and dried. The title compound was obtained as an orange solid (0. 8g, 69.5%) ; [APCI MS] m/z= 333 (MH+).

Intermediate 57: 2-[2-(4-((morpholin-4-yl)carbonyl)-phenyl)-pyridin-4-yl]-1-( 6- methylpyridin-2-yl)-ethanone To a solution of intermediate 56 (0.8g, 2.41 mmol) in CH2Cl2 (50ml) were added morpholine (0. 32ml, 3. 61mol), HOBT (0. 49g, 3.61 mmol), EDCI (0. 63g, 3.61 mmol), triethylamine (0. 84ml. 6 mmol) and the mixture was stirred at room

temperature for 24 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (9: 1). The title compound was obtained as an orange oil (0. 8g, 85.35%) ; [APCI MS] m/z= 390 (MH+).

Intermediate 58: 2-{2-[4-((tetrahydropyran-4-yl)-aminocarbonyl)-phenyl]pyridi n-4-yl] 1- (6-methylpyridin-2-vl)-ethanone

Intermediate 56 (1g, 3mmol) and 4-amino-tetrahydropyran (340mg, 3. 3mmol) were reacted as described for intermediate 56 to afford, after chromatography on silica gel (CH2Cl2/MeOH, 9/1), the title compound as a yellow oil (0.3g, 24%);'H NMR (300MHz, Ceci3, ppm) 8 : 8. 58 (d, 1H), 7.98 (m, 2H), 7.8 (m, 3H), 7.66 (m, 2H), 7.29 (m, 1H), 7.19 (m, 1H), 6.01 (m, 1H), 4.57 (s, 2H), 4. 15 (m, 1H), 3.93 (m, 2H), 3.48 (m, 2H), 2.6 (s, 3H), 1.95 (m, 2H), 1.55 (m, 2H).

Intermediate 59: 2-f2- (4- ( (morpholin-4-vl) methvl)-phenyl)-pvridin-4-vll-1- (6- methylpyridin-2-yl)-ethanone

To a solution of intermediate 50 (1g, 3. 2mmol) in CH2CI2 (100mol) were added morpholine (0.36g, 4. 1mmol) and sodium triacetoxyborohydride (0.88g, 4. 1mmol) and the mixture was stirred at room temperature for 3 hours and then poured into a saturated solution of NaHCO3. After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The titled compound was obtained as a yellow oil (1. 1g, 89.82%) ; [APCI MS] m/z= 388 (MH+). intermediate 60: [ (2- (4-ethanesulfonvlphenvl)-pvridin-4-yi)- (phenvlamino)-methvl phosphonic acid diphenylester

To a solution of 2-chloro-pyridine-4-carboxaldehyde (1g, 7. 06mmol) in DME (50mi) was added 4- (ethanesulfonyl) phenyl boronic acid (1.97g, 9.18 mmol), tetrakis (triphenylphosphine) palladium (0) (0.816g, 0. 7mmol) and Na2CO3 (solution 2M, 7ml) and the mixture was heated under reflux overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CL2/MeOH (99/1) to afford 2- (4-ethanesulfonylphenyl)- pyridine-4-carboxaldehyde as a yellow oil (1.94g, 98%). To a solution of 2- (4- ethanesulfonylphenyl)-pyridine-4-carboxaldehyde (1.94g, 7.06 mmol) in iPrOH were added aniline (0. 772ml. 8.47 mmol) and diphenylphosphite (1. 91 ml, 9.9 mmol) and the mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was treated with water and extracted with CH2CI2, the organic phase was dried over Na2SO4 and concentrated. After chromatography on silica gel (CH2CI2), the title compound was obtained as a yellow oil (1.45g, 35.13%) ; [APCI MS] m/z 585 (MH+).

Intermediate 61: 1-r2- (4-ethanesulfonvlphenvl)-pyridin-4-vll-2-r6-methvl-pyridin-2 -vll- ethanone To a solution of intermediate 60 (1.45g, 2. 48 mmol) in THF/iPrOH were added 6- methyl-pyridine-2-carboxaldehyde (0.251g, 2.07 mmol) and cesium carbonate (1.35g, 4.14 mmol) and the mixture was stirred at room temperature for 18 hours and then neutralised with a solution of NaHCO3. After concentration under reduced pressure, the residue was treated with water and extracted with CH2CI2. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. After

chromatography on silica gel (CH2CI2/MeOH, 99: 1), the title compound was obtained as a yellow oil (0. 321g, 34.02%) ; [APCI MS] m/z 381 (MH+).

Intermediate 62 : 2-bromo-N-methoxv-N-methvl-4-pvridinecarboxamide

To a suspension of 2-bromo-4-pyridinecarboxylic acid (23.5g, 116mmol) in CH2CI2 (600mL) were added under nitrogen HOBT (17.3g, 128mol), EDCI (24. 5g, 128mol), triethylamine (46.85g, 464mol) and N, O-dimethylhydroxylamine hydrochloride (17.02g, 175mmol). The reaction mixture was stirred at room temperature for 3 hours and then partitioned between water and CH2CI2. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure to afford the title compound as a white solid (17g, 59.64 %); [APCI MS] m/z 246 (MH+).

Intermediate 63: 1-r2-bromo-pvridin-4-vll-2-fpvridin-2-vll-ethanone

To a solution of 6-methylpyridine (2.79g ; 30 mmol) in dry THF (20mi) under nitrogen cooled at-80°C, was added dropwise NaHMDS (solution 1M/THF, 36 ml, 36 mmol). and the mixture was stirred for 1 hour at-80°C. A solution of intermediate 62 (7.35g ; 30 mmol) in dry THF (10mL) was added dropwise and the mixture was then stirred at room temperature overnight and then concentrated under reduced pressure. The residue was treated with hexane and the resulting precipitate was filtered. The solid was then diluted with saturated NH4CI solution and the aqueous phase extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. After chromatography on silica gel (CH2CI2/MeOH, 98: 2), the title compound was obtained as a yellow solid (4.1g, 49.34%) ; m. p. 96°C. intermediate 63: 1-r2-bromo-pvridin-4-vil-2-f6-methyl-pyridin-2-vll-ethanone

To a solution of 2, 6-lutidine (4.28g ; 40mmol) was dissolved in dry THF (100mL) under nitrogen and the solution was cooled to-30°C. 2.5M n-Butyllithium in hexanes (16mL ; 40mmol) was added at-30°C, then the mixture was stirred 1.5h at ambient temperature before being cooled to-30 to-40°C. A solution of intermediate 62 (4.9g ; 20mmol) in dry THF (20mL) was added at-40°C and the reaction stirred for 2h.

Saturated aqueous ammonium chloride was added and the mixture was extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel 60 (CH2Cl2/MeOH, 99/1) to give the title compound (3.42g ; 58%) as a yellow solid ; m. p. 126°C ; [MS APCI] m/z: 292 (MH+).

The following compounds of formula (IllEa) were prepared by methods analogous to that described for intermediate 46 using the starting materials indicated (see Table 3).

Table 3 Int. R R From Physical data Int. 65 (tetrahydopyran-4-H 63+33 ACE MS m/z 402 (MH+) yl) aminocarbonyl 66 morpholin-4-yl H 63 + 27 APCl MS m/z 360 (MH+) 67 chloro CH3 64 APCI MS m/z 323 (MH+) 68 trifluoromethoxy CH3 64 APCI MS m/z 373 (MH+) 69 morpholin-4-yl)carbonyl CH3 64 + 35 APCl MS m/z 402 (MH+) 70 4-ethylpiperazin-1-yl)carbonyl CH3 64 + 36 APCl MS m/z 429 (MH+) 71 (tetrahydopyran-4-CH3 64+33 ACE MS m/z 416 (MH+) yl) aminocarbonyl 72 morpholin-4-1 CH3 64 + 27 APCI MS m/z 374 (MH+) 73 2-(pyrolidin-1-yl)ethoxy CH3 64 + 29 APCl MS m/z 402 (MH+) 74 aminocarbonylmethoxy CH3 64+30 APCI MS m/z 362 (MH+) 75 (morpholin-4-CH3. 64+32 APCI MS m/z 432 (MH+) l carbonylmethoxy 76 formyl CH3 64 APCI MS m/z 317 (MH+) Intermediate 77: 2-(6-methvlpvridin-2-vl)-1- [2-(4-((morpholin-4-yl) methvl)-phenyl)- Pvridin-4-vll-ethanone

To a solution of intermediate 76 (0. 984g, 3 mmol) in 1, 2-dichloroethane (40 ml) were added morpholine (0. 34g, 3.9 mmol), sodium triacetoxyborohydride (0. 826g, 3.9 mmol) and acetic acid (0. 216g, 3.6 mmol) and the mixture was stirred at room temperature for 3 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure.

The title compound was obtained as an oil (1. 1g, 91%) ; [APCI MS] m/z 388 (MH+).

Intermediate 78: 2- (6-methylpyridin-2-yl)-1- [2- (4- ( (pyrolidin-1-Yl) methyl)-phenvl)- pyridin-4-yl]-ethanone Intermediate 76 (0.7g, 2.2 mmol) and pyridine (0. 203g, 2.8 mmol) were reacted as described for intermediate 76, to afford after chromatography on silica gel (CH2CI2/MeOH, 9: 1), the title compound as a yellow gum (0. 5g, 60.84%) ; [APCI MS] m/z 372 (MH+).

Intermediate 79: 2-(6-methvlpyridin-2-vl)-1- [2-(4-((dimethylamino) methvl)-Phenvl)- pvridin-4-yll-ethanone Intermediate 76 (0. 7g, 2.2 mmol) and dimethylamine (solution 2M in THF, 1. 4ml, 2.86 mmol) were reacted as described for intermediate 76, to afford after chromatography on silica gel (CH2CI2/MeOH, 9: 1), the title compound as a yellow gum (0. 4g, 52.34%) ; lAPCI MS] m/z 346 (MH+).

Intermediate 80: 2-Bromo-4- (3- (6-methvl-pvridin-2-vl)-1H-pvrazol-4-yl) pvridine

A solution of intermediate 40 (5.84 g, 20 mmol) in dry DMF (20 ml) under nitrogen was treated with glacial acetic acid (2.4eq, 2.76 ml) over 2 min. DMF. DMA (1.5eq., 4 ml) was added dropwise and the mixture stirred at room temperature under nitrogen for 1hour. Hydrazine monohydrate (7.5eq, 91 mi, 1.876 mol) was added dropwise at room temperature and the resulting mixture heated at 50°C for 3 hours. The reaction mixture was poured into water (300moi) and extracted with CH2CI2. The organic phases were combined, dried over Na2S04 and filtered. The solvent was evaporated under reduced pressure to afford a brown oil which after purification by chromatography on silica gel (eluent : CH2CI2/CH3OH 98: 2) gave the title compound as a yellow solid (3.07 g, 49%); [APCI MS] m/z 315 (MH+).

Intermediate 81: 2-bromo-4-r5-methyl-3- (6-methvlpvridin-2-yl)-1 H-pvrazol-4- vllpvridine

Intermediate 40 (2 g, 6. 9mmol) was reacted with N, N-dimethylacetamide dimethylacetal (1.38g, 1 Ommol) as described for intermediate 80 to afford the title compound as a brown solid (0. 9 g, %); [APCI MS] m/z 328 (MH-).

Intermediate 82: 2-bromo-4-f3- (6-methvlpvridin-2-vl)-1-tritvl-1 H-pyrazol-4-

TriM JCN1 Br yllpvridine N

Intermediate 80 (3.07 g, 9.8 mmol) and trityl chloride (1.5 eq, 4.1 g, 14.7 mmol) were reacted with potassium carbonate (3eq, 29. 4mmol) in acetone (100ml). The reaction mixture was subsequently heated to reflux and stirred for 24 hours. The reaction mixture was filtered, the filtrate concentrated and then partitioned between CH2CI2 and H20. The organic phase was dried over Na2SO4 and concentrated. The resulting crude material was purified by flash chromatography on silica gel, eluting with CH2CI2/MeOH (98: 2) to give the title compound as the major isomer of a mixture of the two isomers, as a light yellow solid (4.9 g, 90%); [APCI MS] m/z : 558 (MH+).

Intermediate 83: 2-bromo-4-f5-methvl-3- (6-methYlpyridin-2-vl)-1-trityl-1H-pyrazol-4- vllpvridine

Intermediate 81 (0.9 g, 2. 74mmol) and trityl chloride (0.84 g, 3 mmol) were reacted as described for intermediate 82 to afford the title compound as a mixture of the two isomers, as a white powder (1.5 g, 95.87%) ; [APCI MS] m/z 329 (MH+ loss of trityl).

Intermediate 84: 3- (2-bromo-pyridin-4-vI)-2-fpyridin-2-yl)-imidazof1, 2-alpvridine

To a solution of intermediate 39 (5g, 18. 05mmol) in CH2CI2 (30 ml) was added bromine-polymer-supported (11. 28g, 18.05 mmol) and the suspension was stirred at room temperature for 5 hours. The resin was removed by filtration, with the filtrate being added directly to 2-amino-pyridine (3.4 g, 36.06 mmol) and the resin washed many times with ethanol. The filtrate was heated under reflux for 18 hours, allowed to cool and then concentrated. The residue was treated with water and extracted with CH2CI2. The organic phase was dried over Na2S04 and evaporated under reduced pressure to give a crude solid which was precipitated from diisopropyl ether to afford the title compound as a brown powder (3.05g ; 48%); m. p. 2279C.

The following intermediates (see Table 4) were prepared by methods analogous to that described for intermediate 84 from the starting materials indicated.

Table 4 Int. structures From int. Physical data 85 A 40 1H NMR (300MHz, CDCI3, ppm) 6 : t 4 8. 47 (d, 1H), 8. 12 (d, 1H), 7. 8 (m, 2H), 7. 7 (d, 1 H), 7. 6 (t, 1H), 7. 47 (d, 1H), 7. 29 (t, 1H), r N N 86 fq 41 APCì MS m/z 404 (MH) kN4N N-M N F Br_g ACI + 87 42 ACE MS m/z 386 (MH) Br XF N B F r 88 Cx 40 1H NMR (300MHz, CDCI3, ppm) 6 : t 4 8. 5 (d, 1H), 8. 09 (d, 1H), 7. 82 (s, 2H), 7. 65 N (t, 2H), 7. 45 (d, 1H), 7. 27 (d, 1H), 7. 08 (d, 1 H), 2. 39 (s, 3H) N 89 40'H NMR (300MHz, Ceci3, ppm) 8 : 8. 43 (d, 1H), 8. 00 (d, 1H), 7. 82 (s, 1H), 7. 78 I N N (d, 1 H), 7. 60 (t, 1 H), 7. 44 (m, 2H), 7. 05 (d, 1 H), 6. 70 (d, 1 H), 2. 43 (s, 3H), 2. 40 (s, 3H) N 90 ~ 40 H NMR (300MHz, CDCI3, ppm) 8 : tN4N 8. 55 (d, 1 H), 8 (d, 1 H), 7. 85 (d, 1 H), 7. 8 (s, 1 1H), 7. 65 (t, 1H), 7. 45 (d, 1H), 7. 1 (m, 2H), 6. 8 (t, 1 H), 2. 7 (s, 3H), 2. 4 (s, 3H) N 91 43 ACE MS m/z 384 (MH+) N4N N N 92 44 ACE MS m/z 369 (MH+) - N\ N N Intermediate 93: 4-f4-f3- (6-Methylpvridin-2-vl)-1-tritvl-1 H-pvrazol-4-yllpvridin-2-vl phenol Tritt Tribl HO I N, IN N N v N

To a solution of intermediate 82 (2 g, 3.6 mmol) in a mixture of DME (36 ml) and water (18 ml) were added tetrakis-triphenylphosphine palladium (0.2 g), Na2CO3 (0.99g) and 4-hydroxyphenyl boronic acid, pinacol ester (1.4 eq, 1.15 g, 4.32 mmol) and the resulting mixture was heated under reflux overnight. The cooled mixture was poured into water and extracted with CH2CI2. The organic phase was washed with water, dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave a crude oil which was purified by chromatography on silica gel (CH2CI2/MeOH 95: 5) to give the title compound as a white solid (1.7 g, 83%), which contained the 2-trityl isomer as a minor component; [APCI MS] m/z 571 (MH+).

Intermediate 94: 4-f4-f3- (6-Methvlpvridin-2-vl)-1-trityl-1 H-pyrazol-4-vllpvridin-2-vl- benzoic acid T (its Triwj HOOC N N NJ'

Intermediate 82 (1g, 1. 8mmol) and 4-carboxybenzene boronic acid (0.36g, 2. 52mmol) were coupled and treated as described for intermediate 93 to afford the title compound as a white solid (600mg, 61%) containing the 2-trityl isomer as a minor component; [APCI MS] m/z 599 (MH+).

Intermediate 95: 4-f4-f3- (6-methylpvridin-2-vl)-1-tritvl-1 H-pvrazol-4-yllpvridin-2- vllbenzaldehyde Trityl NON N, N 7 \

Intermediate 82 (1g, 1. 8mmol) and 4-formylphenylboronic acid (0.35g, 2. 3mmol) were coupled and treated as described for intermediate 93 to afford the title compound as a grey solid (1g, 96%) containing the 2-trityl isomer as a minor component; [APCI MS] m/z 583 (MH+). Intermediate 96: 2-(4-bromophenyl)-4-[3-(6-methylpyridin-2-yl)-1-(triphenylme thyl 1 H-pyrazol-4-vllpvridine Trityl N Br/ I , 1 \,/N

Intermediate 82 (2g, 3. 6mmol) and 4-bromophenylboronic acid (0.755g, 3. 78mmol) were coupled and treated as described for intermediate 93 to afford the title compound as a white solid (2.1g, 92%) containing the 2-trityl isomer as a minor component; [APCI MS] m/z 633/635 (MH+).

Intermediate 97: (4-f4-f3- (6-methylpyridin-2-yi)-l- (triphenvimethyl)-l H-pyrazol-4-vil- pyridin-3-yl}phenyl) amine Trityl. N I I N N

Intermediate 82 (1g, 1. 8mmol) and 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2- yl) aniline (0.512g, 2. 3mmol) were coupled and treated as described for intermediate 93 to afford the title compound as a yellow solid (1 g, 98%) containing the 2-trityl isomer as a minor component; [APCI MS] m/z 570 (MH+).

Intermediate 98: 4-{4-[5-methyl-3-(6-methylpyridin-2-yl)-1-(triphenylmethyl)- 1H- pyrazol-4-yl]-2-pyridinyl}benzaldenyde

Trityl NON I N, IN NEZ

Intermediate 83 (1.5g, 2. 62mmol) and 4-formylphenylboronic acid (0. 48g, 3. 2mmol) were coupled and treated as described for intermediate 93 to afford the title compound as a yellow oil (1.6g, quantitative) containing the 2-trityl isomer as a minor component; [APCI MS] m/z 355 (MH+, loss of trityl). Intermediate 99: 3-(2-(4-formyl-phenyl)-pyridin-4-yl)-2-(6-methyl-pyridin-2-y l)- imidazofl, 2-alpyridine

A solution of intermediate 85 (500mg, 1.37 mmol) in DME (50 mL) was treated with tetrakis (triphenylphosphine) palladium (0) (158 mg, 10%mol) and stirred at room temperature for 30 min. Na2CO3 (2M) (4.2 ml) was added to the reaction mixture, followed by 4-formylphenyl boronic acid (267mg, 1.78 mmol). The resulting mixture was heated under reflux overnight. The cooled mixture was poured into ice and extracted with CH2CI2. The organic phase was washed with water, dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave a crude oil which was purified by chromatography on silica gel (CH2CI2/MeOH 95: 5). The title compound was obtained as a cream powder (310 mg, 58%) ;'H NMR (300 MHz, CDCI3, ppm) 8 : 10.08 (s, 1H) ; 8.86 (d, 1H) ; 8.10-8. 20 (m, 4H); 7.98 (d, 1H) ; 7.83 (d, 1H) ; 7.75 (d, 1 H) ; 7.61 (t, 1 H) ; 7.51 (m, 1 H) ; 7.30 (t, 1 H) ; 7.04 (d, 1 H) ; 6. 85 (t, 1 H) ; 2.31 (s, 3H).

The following intermediates (see Table 5) were prepared by methods analogous to that described for intermediate 99.

Table 5 int. structures From int. Physical data 100 84 APCI MS m/z 377 (MH+) p N N H w/N N I 101 o % 86 APCI MS m/z 428 (MH+) p N N 0"NN nazi F 102 87 APCI MS m/z 412 (MH+) 0 N N F H F N Int. structures From int. Physical data 103 o nN 88 APCI MS m/z 425 (MH+) O N wN N zon r 104 89 APCI MS m/z 405 (MH+) I p N N H N N 105 ~ 90 H NMR (300MHz, Ceci3, ppm) 8 : t AN 10. 1 (s, 1H), 8. 9 (d, 1H), 8. 2 (d, 2H), 8. 15 (s, 1 H), 8. 1 (d, 1 H), 8 (d, 2H), 7. 85 (d, 1 H), 7. 6 (m, 2H), N 7. 1 (m, 2H), 6. 8 (t, 1H), 2. 8 (s, 3H), 2. 4 (s, 3H) 106 ¢ l 85 APCI MS m/z 407 (MH+) 0 (N L N HO Ho N N 107 84 APCI MS m/z 365 (MH+) N N HO v N 108 _ 85 APCI MS m/z 379 (MH+) Ho N HO lui 109 91'H NMR (300MHz, CDCI3, ppm) 8 : N 9. 05 (s, 1 H), 8. 55 (d, 1 H), 7. 95 (d, 1H), 7. 6 (m, 3H), 7. 5 (m, 2H), 7. 25 ci (m, 1 H), 7. 1 (m, 4H), 6. 7 (m, 3H) Nus, 110 90 APCI MS m/z 393 (MH+) N N HO N \ N 89 ACE MS m/z 393 (MH+) "NN NON HO N li 112 84 APCI MS m/z 428 (MH+) N-N Br w N/ -/ N Intermediate 113: 3-{2-[4-(2-bromo-ethoxy)-phenyl]-pyridin-4-yl}-2-pyridin-2-y l imidazofl, 2-alpyridine

To a solution of intermediate 107 (0.38 g, 1.04 mmol) in acetone (20 ml) was added cesium carbonate (0.68 g, 2.08 mmol) and 1,2-dibromoethane (0.9 ml, 10.4 mmol) and the mixture was heated under reflux for 2 days. After cooling, the reaction was filtered and the solvent was removed in vacuo. After purification by chromatography on silica gel (CH2CI2/MeOH, 90: 10), the title compound was obtained as a yellow gum (140 mg, 28%) ; 1H NMR (CDCl3, 300 MHz) ppm: 8.78 (d, 1H), 8. 49 (d, 1H), 8.14 (d, 1H), 7.93 (m, 4H), 7.72 (t, 2H), 7.34 (m, 2H), 7.17 (m, 1H), 7.00 (d, 2H), 6.83 (t, 1 H), 4.33 (t, 2H), 3.65 (t, 3H).

The following intermediates (see Table 6) were prepared by methods analogous to that described for intermediate 113.

Table 6 Int. structures From Physical data int. 114 , 108 H NMR (300MHz, CDOg, ppm) 8 : la-8. 75 (d, 1H), 8. 15 (d, 1H), 7. 93 (m, 3H), 7. 71 (t, 2H), 7. 56 (t, 2H), 7. 35 N N SY Rd 6. 82 (t, 1H), 4. 33 (t, 2H), 3. 65 (t, 2H), 2. 37 (s, 3H) 115 B 109 APCI MS m/z 505 (MH+) N N cul \ ci N 116 Ill APCI MS m/z 500 (MH+) Ber N 0 N N N 117"'HoH NMR (300MHz, CDCI3, ppm) 8 : 8. 75 (d, 1 H), 8. 05 (d, 1H), 7. 95. (s, 0 1 H), 7. 9 (d, H), 7. 7 (d, 1 H), 7. 55 (t, -C 1 H), 7. 35 (d, 1 H), 7 (m, 2H), 6. 9 (d, N 2H), 6. 75 (t, 1H), 4. 35 (t, 2H), 3. 65 (t, Int. structures From Physical data int. 2H), 2.75 (s, 3H), 2.35 (s, 3H) Intermediate 118: 2-Hvdroximino-2-f2-Bromo-pyridin-4-yll-1- (6-methvl-pyridin-2-vi)- ethan-1-one

A solution of intermediate 40 (20g, 68. 7mmol) in aqueous HCI 18% (360ml) was cooled to 0°C using a dry ice bath. To this solution was added sodium nitrite (5. 6g, 82. 44mmol), the reaction temperature was maintained at 0°C during this addition.

After addition was complete, the dry ice bath was removed and the reaction allowed to warm and stirred at room temperature for 30min. The reaction mixture was basified with aqueous NaOH 35%. The resulting precipitate was filtered, washed with water and dried to give the title compound (mixture of two isomers) as a pink solid (20. 53g, 93%). This compound was used in the next step without purification; [APCI MS] m/z 321 (MH+).

Intermediate 119: 2-Hvdroximino-2-r2-Bromo-pyridin-4-vl1-1-(pvridin-2-vl)-etha n-1- one The title compound was obtained from intermediate 39, as described for intermediate 118, as a solid (36g, 98%); m. p. 200°C ; [APGI MS] m/z 307 (MH+).

Intermediate 120: 2-tert-butvl-4- (6-methyl-pvridin-2-yl)-5- (2-bromo-pyridin-4-yl)- imidazole

Intermediate 118 (6g, 18. 7mmol) was dissolved in acetic acid (50mL) and treated with ammonium acetate (4.33g, 56. 1mmol) and pivalaldehyde (2. 7g, 37. 4mmol). The resulting mixture was heated at reflux for 1 hour, then allowed to cool at room temperature and was concentrated. The residue was dissolved into water and extracted with CH2CI2. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure to give 2-tert-butyl-4-(6-methyl-pyridin-2-yl)-N-1- hydroxy-5-(2-bromo-pyridin-4-yl)-imidazole ; (6. 31g, 87%). 2-tert-Butyl-4- (6-methyl- pyridin-2-yl)-N-1-hydroxy-5-(2-bromo-pyridin-4-yl)-imidazole (6. 31g, 16. 21mmol) was dissolved in DMF (60mL), treated with triethyl phosphite (2.78mL, 16. 21mmol) and the resulting mixture was heated at 130°C for 5 h. To complete the reaction triethyl phosphite (0.2eq) was added and the mixture was stirred at 130°C for 18h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude oil was precipitated with diisopropyl ether to afford the title compound as a brown solid (3.88g, 65%); m. p. 200°C ; [APCI MS] m/z 372 (MH+).

The following compounds of formula (IVDa) were prepared by methods analogous to that described for intermediate 120 using the starting materials indicated (see Table 7).

Table 7 Int. Rz From lnt. Physical data 121 H t-butyl 119 [APCI MS] m/z 358 (MH+) Int. RZ R4 From Int. Physical data 122 methyl i-propyl 118 [APCI MS] m/z 358 (MH+) 123 H i-propyl 119 [APCI MS] m/z 343/345 (MH+) 124 methyl methyl 118 [APCI MSI m/z 330 (MH+) Intermediate 125: 4- 4-r2-tert-Butvl-5- (6-methyl-pvridin-2-vI)-1 H-imidazol-4-vll- PVridin-2-ylT-benzaldhyde

Intermediate 120 (2g, 5. 4mmol) and 4-formylphenyl boronic acid (1. 13g, 7. 56mmol) were reacted as described for intermediate 99 to afford the title compound as a yellow solid (2. 37g, quantitative); [APCI MS] m/z 397 (MH+).

Intermediate 126: 4-{4-[2-tert-Butyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-y l]- Pvridin-2-yl}-phenol Intermediate 120 (2.5g, 6. 7mmol) and 4-hydroxyphenyl boronic acid (1.3g, 9. 38mmol) were reacted as described for intermediate 99, to afford the title compound as a brown solid (1.57g, 61%); 1H NMR (350 MHz; CDCl3, ppm) 8 : 8.37 (1H, d), 7.70 (1H, s), 7.46 (2H, d), 7.30 (1H, t), 7.20-7. 10 (2H, m), 6.83 (1 H, d), 6.60 (1 H, d), 3. 85-3. 23 (4H, brd), 2.27 (3H, s), 1.27 (9H, s) ; [APCI MS] m/z 385 (MH+).

Intermediate 127: 4-{4-[2-isopropyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl ]- pyridin-2-vl3-benzaldhvde

Intermediate 122 (2.05g, 5. 74mmol) and 4-formylphenyl boronic acid (1.2g, 8. 04mmol) were reacted as described for intermediate 99 to afford the title compound as a pale yellow solid (1.22g, 56%) ;'H NMR (300 MHz; CDCl3, ppm) 8 : 9.90 (1H, s), 8. 54 (1H, d), 8.02 (2H, d), 7.79 (2H, d), 7.47-7. 16 (3H, m), 6.87 (1H, d), 3.12-2. 95 (1H, m), 2.39 (3H, s), 1.25 (6H, d); [APCI MS] m/z 383 (MH+). <BR> <BR> lntermediate 128 : Polvmer supported 5- (2-bromo-4-pyridinvl)-4- (2-pyridin !, 3- thiazol-2-amine Step 1: Rink Argopore resin (12g, 0.58 mmol/g substitution) was placed into a peptide vessel and washed with CH2CI2 (3x100mL). The resin was then treated for 10min with a solution of piperidine 20% in DMF (3x40mL). After washing with DMF (3x100mL) and CH2CI2 (3x100mL), the resin was treated with a solution of Fmoc- NCS (0.2M) in CH2CI2 (170mL) under argon at room temperature for 1h. The resin was washed with DMF (3x100mL), EtOH (3x100mL) and CH2CI2 (3x100mL) and subsequently stirred for 10min with a solution of piperidine 20% in DMF (3x40mL) to give after washing with DMF (3x100mL) and CH2CI2 (3x100mL) the resin bound thiourea.

Step 2: To a solution of intermediate 39 (8.5g, 29mmol) in dioxane (145mL) was added under argon polymer-supported pyridinium perbromide (1. 8mmol/g, 16g). The suspension was shaken under argon at room temperature overnight. The resin was removed by filtration and washed with dioxane (25mL) to give 2-bromo-2- (2-bromo-4- pyridinyl)-1-(2-pyridinyl) ethanone which was used in solution in dioxane without purification in the next step.

Step 3: The product from step 1 was stirred with the product from step 2 (0.18M) in dioxane (175mL) for 4h at room temperature under argon. The resin was washed

with dioxane (3x100mL). A second exposure with the product from step 2 (0.18M in dioxane, 175mL) was performed. The resin was washed with DMF (3x100mL), EtOH (3x100mL), CH2CI2 (3x100mL) and dried under a stream of nitrogen overnight. 2 mg of the obtained resin were cleaved with a solution of TFA 20% in CH2CI2 to give the title compound which was characterised by LC-MS (purity>96%) ; [APCI MS] m/z 333,335, 336 (MH+).

Intermediate 129: Polymer supported 5-(2-bromo-4-pyridinyl)-4-(6-methvl-2- PvridinvI)-1, 3-thiazol-2-amine

Intermediate 129 was prepared in analogous fashion to intermediate 128 starting from intermediate 40. After step 3,2 mg of the obtained resin were cleaved with a solution of TFA 20% in CH2CI2 to give the title compound which was characterised by LC-MS (purity>96%); [APCI MS] m/z 347/349/350 (MH+).

Pyrazol Examples Example 1: 2-{4-[(1-methyl-1H-imidazol-4-yl)methoxy]phenyl}-4-[3-(6-met hylpyridin-2- y1)-1 H-pyrazol-4-vllpvridine

To an ice-cooled solution of intermediate 93 (4 g, 7 mmol) in DMF (80 ml) was added portionwise sodium hydride (0.6g, 3 eq, 21 mmol) and the mixture then stirred at room temperature for 30 mins. Intermediate 22 (1.6 g, 10 mmol) was added and the mixture stirred at room temperature overnight and then poured into water and extracted with CH2CI2. The organic layer was dried over Na2SO4 and filtered.

Evaporation of the solvent in vacuo gave a crude oil which was purified by chromatography on silica gel (CH2CI2/MeOH 97: 3) to give the trityl compound as an oil (3 g). This compound was dissolved in methanol (60 ml) and HCI (1 N, 40 mi) and the solution was heated under reflux for 2 hours and then concentrated in vacuo. The residue was dissolved in water and washed with CH2CI2. The aqueous layer was

basified with NaOH (1 N) and extracted with CH2CI2. The organic extract was washed with water and dried over Na2SO4, filtered and evaporated to give a solid which was crystallised from EtOH to give the title compound as white crystals (1.1 g, 37%); m. p. 191°C ; TOF MS ES+ exact mass calculated for C25H22N6O : 423.1933 (MH+). Found: 423.1928 (MH+).

Example 2: 2-f4- (Ethvlsulfonvl) phenvll-4- [3- (6-methylpvridin-2-yl)-1 H-pvrazol-4- pyridine To a solution of intermediate 82 (0.5 g, 0.9 mmol) in a mixture of DME (18 ml) and water (9 mi) was added 4- (ethylsulfonyl) phenyl boronic acid (1.3 eq, 0.25 g, 1.17 mmol), tetrakis (triphenyiphosphine) palladium(0) (0.05 g) and Na2CO3 (3 eq, 0.28g, 2.69 mmol) and the reaction mixture was heated under reflux overnight. The cooled mixture was poured into ice and extracted with CH2CI2. The organic layer was washed with water, dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave an oil which was dissolved in MeOH (30 ml) and HCI (1 N, 20 ml). The solution was heated under reflux for 3 hours and then concentrated under reduced pressure. The residue was dissolved in water and washed with CH2CI2. The aqueous layer was basified with NaOH (1 N) and extracted with CH2CI2. The organic extract was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. After chromatography on silica gel (CH2CI2/MeOH, 95: 5) and crystallisation from DMF, the title compound was obtained as white crystals (166 mg, 45.7%) ; m. p. 244°C ; [APCI MS] m/z 405 (MH+).

The following compounds of formula (lAb) were prepared by methods analogous to that described for Example 2 using the starting materials indicated (see Table 9).

Table 9 Ex R1 From Int. Physical data 3 cyano 82 TOF MS ES+ exact mass calculated for C21H15N5 (MH+): 338.1406, found: 338.1408 ; m.p. 198°C 4 trifluoromethoxy 82 TOF MS ES+ exact mass calculated for C2iHisF3N40 (MH+): 397.1276, found: 397.1269 ; m. p. 131°C 5 chloro 82 TOF MS ES+ exact mass calculated for C20H15ClN4 (MH+): 347.1063, found : 347.1057 ; m. p. 190°C 6 methoxy 82 TOF MS ES+ exact mass calculated for C2iHisN40 (MH+): 343.1600, found: 343.1600 7 methanesulfonyl 82'H NMR (300MHz, CDCl3, ppm) 5 : 8.84 (d, 1 H), 8.52 (d, 2H), 8.44 (s, 1 H), 8.26 (d, 2H), 8.01 (t, 1H), 7.89-7. 68 (m, 2H), 7.50 (d, 1H), 3.51 (s, 3H), 2.64 (s, 3H); m. p. 232-234°C Example 8: 4-[3-(6-methylpyridin-3-yl)-1H-pyrazol-4-yl]-2-[4-(pyrrolidi n-1- vlmethvl) phenvllpvridine

To a solution of intermediate 95 (0.29g, 0. 5mmol) and pyrrolidine (4 eq, 0.142g) in dry dichloroethane (20mL) was added acetic acid (1.5eq, 0.05g) followed by sodium triacetoxyborohydride (2eq, 0.224g). The mixture was stirred at room temperature overnight, diluted with water, extracted with CH2CI2 and dried over Na2SO4. The solvent was removed under reduced pressure and the resulting product was treated with a mixture of MeOH/HC11 N (3: 2, 50ml) at reflux for 3h. The reaction mixture was concentrated to dryness to give a residue which was dissolved in water and washed with CH2CI2. The aqueous phase was basified with NaOH (1 N), extracted with CH2CI2 and dried over Na2SO4. Concentration to dryness gave a solid which was- precipitated from a mixture CH2CI2/hexane to give the title compound as (0.095g, 48%) ; H NMR (CDC13) 8 8.62 (d, 1H); 7.88 (d, 2H); 7.71 (d, 2H); 7.50-7. 39 (m, 3H); 7.26-7. 20 (m, 2H) ; 7.05 (d, 1H) ; 3.76 (brs, 2H) ; 2.79-2. 56 (m, 4H) ; 2.53 (s, 3H) ; 1.91- 1.75 (m, 4H); TOF MS ES+ exact mass calculated for C25H25N5 : 396.2188 (MH+):.

Found: 396.2174 (MH+).

The following compounds of formula (lAa) were prepared by methods analogous to that described for Example 8 using the starting materials indicated (see Table 10).

Table 10 Ex R1 R4 From Physical data Int. 9 (morpholin-4- H 95 TOF MS ES exact mass calculated for yl) methyl C25H25N50 (MH+): 412.2137, found: 412.2150; 1H NMR (300MHz, CDCI3, ppm) 8 : 8.7 (d, 1H), 7.98 (d, 2H), 7.81 (d, 2H), 7.58- 7.41 (m, 3H), 7.37-7. 3 (m, 2H), 7.14 (d, 1H), 3. 89-3.7 (m, 4H), 3.62 (brs, 2H), 2.62 (s, 3H), 2.6-2. 47 (m, 4H) 10 (N-methyl-2-H 95'H NMR (300MHz, Ceci3, ppm) 8 : 8.59 (d, methoxyethylamino 1 H), 7. 83 (d, 2H), 7.71 (s, 1 H), 7.66 (s, 1 H), ) methyl 7.47-7. 29 (m, 3H), 7. 24-7. 18 (m, 2H), 7.03 (d, 1 H), 3.59-3. 5 (m, 2H), 3.45 (brt, 2H), 3.25 (s, 3H), 2.56 (brt, 3H), 2.60-2. 47 (m, 4H), 2.5 (s, 3H) 11 (4-methoxy-H 95 TOF MS EST exact mass calculated for piperidin-1- C 27H29N5O : 440. 2450 (MH+), found: yl) methyl 440.2438 (MH+) ;'H NMR (300MHz, CDCl3, ppm) 8 : 8.64 (d, 1 H), 7.88 (d, 2H), 7.76 (s, 1H), 7.72 (s, 1H), 7.47, (t, 1H), 7.44-7. 35 (m, 2H), 7.29-7. 23 (m, 2H), 7.09 (d, 1H), 3.61- 3.50 (m, 2H), 3.29 (s, 3H), 3.26-3. 14 (m, 1H), 2.81-2. 66 (m, 2H), 2.56 (s, 3H), 2.30-2. 08 (m, 2H), 2.01-1. 82 (m, 2H), 1.69-1. 52 (m, 2H) 12 (morpholin-4-methyl 98 [APCI MS] m/z 426 (MH+) yl) methyl 1H NMR (300MHz, Ceci3, ppm) 8 : 8.66 (d, 1H), 7.86 (d, 2H), 7.64 (s, 1 H), 7.44-7. 30 (m, 3H), 7.15-7. 11 (m, 1H), 7.03-6. 89 (m, 2H), 3.74-3. 60 (m, 4H), 3.51 (brs, 2H), 2.50 (s, 3H), 2.40-2. 34 (m, 4H), 2.25 (s, 3H) Example 13: 4- (4-4-f3-f6-methvlpyridin-2-vi)-1 H-pyrazol-4-yl1pvridin-2- yl}benzoyl)morpholine

To a solution of intermediate 94 (0.2g, 0. 34mmol, 1eq.) in CH2CI2 (50mL) were added morpholine (0. 035g, 0. 4mmol), HOBT (0.59g, 1.3eq.), EDCI (0.83g, 1.3eq.) and Et3N (0.04g, 2.3eq.) and the reaction mixture was stirred at room temperature overnight.

The reaction was hydrolyse and extracted with CH2CI2. The solvent was removed under reduced pressure. The residue was treated with MeOH/HCI 1 N (3/2, 30ml) at reflux for 1 h. After removal of the solvent under reduced pressure, the residue was dissolved in water and washed with CH2CI2. The aqueous phase was basified with NaOH 1 N and extracted with CH2CI2. The organic phase was dried, filtered, and evaporated to dryness to give a crude solid which was precipitated with a mixture CH2CI2/hexane to give the title compound (0.075g ; 52%) ;'H NMR (300MHz, CDCI3) â 8.63 (1H, d); 7.95 (2H, d); 7.76 (2H, s); 7.52-7. 42 (3H, m); 7.27 (2H, d); 7.12-7. 01 (1 H, m); 3.50-3. 32 (8H, m); 2.51 (3H, brs); TOF MS ES+ exact mass calculated for C25H23N5O2 : 426.1930 (MH+). Found: 426.1931 (MH+).

Example 14: 4-f4- (6-methylpvridin-2-yl)-1 H-pvrazol-4-vllpyridin-2-vl}-N- (tetrahydro- 2H-pyran-4-yl) benzamide Intermediate 94 (0.4g, 0. 67mmol) and 4-aminotetrahydropyran (0. 081g, 0. 8mmol) were reacted as was described for example 13 to give the title compound (0.2g, 68%); m. p. 148°C ; TOF MS ES+ exact mass calculated for C26H25N502 : 440.2086 (MH+). Found: 440.2060 (MH+).

Example 15: N-(4-{4-[3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2- yl}phenyl)-2- morpholin-4-vlacetamide Intermediate 97 (0.38g, 0. 67mmol) and 4-morpholinylacetic acid hydrochloride (0. 156g, 0. 86mmol) were reacted as was described for example 13 to give the title compound as an off-white solid (0. 115g, 38%) ;'H NMR (300MHz, CDCI3) 8 9.10 (1H, s); 8.58 (1 H, d); 7.87 (2H, d); 7.70 (2H, s); 7.59 (2H, d) ; 7. 28-7. 18 (2H, m); 7.10-

6.97 (1 H, m); 3.71 (4H, t); 3.08 (3H, s); 2.56 (4H, t); 2.50 (3H, s); TOF MS ES+ exact mass calculated for C2rH26N602 : 455.2195 (MH+). Found: 455.2195 (MH+).

Example 16: 4-(4-{4-[3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl]pyridin-2- vllphenvl) morpholine Step 1: To a solution of intermediate 96 (0. 633g, 1mmol) in toluene (1 Oml) were added morpholine (0. 348g, 4mmol, 4eq), Pd2 (dba) 3 (0.045g, 0. 049mmol, 0.05eq), binap (0. 062g, 0. 1mmol, 0. 1eq) and t-BuOK (0. 134g, 1. 4mmol, 1.4eq) and the reaction mixture was refluxed for 5 hours. The mixture was then poured into ice and extracted with EtOAc. The organic phase was washed with water and dried over Na2S04. Concentration to dryness gave a crude product that was purified by chromatography on silica gel (CH2CI2/CH3OH 98: 2) to afford 4-(4-{4-[3-(6-methyl-2- pyridinyl)-1-(triphenylmethyl)-1 H-pyrazol-4-yl]-2-pyridinyl} phenyl) morpholine.

Step 2: 4- (4- 4- [3- (6-Methyl-2-pyridinyl)-1- (triphenylmethyl)-1 H-pyrazol-4-yl]-2- pyridinyl} phenyl) morpholine was treated with a mixture of MeOH/HCI 1 N (3: 2, 50ml) under reflux for 2 hours. The reaction mixture was poured into water and extracted with CH2CI2. The aqueous phase was basified with NaOH (1 N) and extracted with CH2CI2. The organic phase was washed with water, dried and evaporated to dryness to give a crude product which was precipitated with a mixture of CH2CI2/hexane to afford the title compound as a yellow solid (0. 31g, 78%) ; TOF MS ES+ exact mass calculated for C24H23N5O : 398.1981 (MH+). Found 398. 1961 (MH+).

Example 17: 2-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-4-[3-(6-methylpyridi n-2-yl)-1H- pyrazol-4-vllpyridine Intermediate 96 (0.308g, 0. 5mmol) and 2-methyl-1H-imidazole (0.82g, 1mmol) were reacted as described for example 16 to give the title compound as a white solid

(0.013g, 6%); m. p. 128°C ;'H NMR (300 MHz; CDCl3) 8 : 8.64 (1H, d), 8.02 (2H, d), 7.75 (2H, d), 7.48 (1H, t), 7.37-7. 20 (4H, m), 7.19 (1H, s), 7.08 (1H, d), 6.99 (2H, d), 2.52 (3H, s), 2.35 (3H, s).

Example 18: 3-[2-(4-((tetrahydropyran-4-yl)aminocarbonyl)phenyl)pyridin- 4-yl]-4-[6- methvlpvridin-2-vll-1 H-pyrazole To a solution of intermediate 71 (0.6g, 1.44 mmol) in DMF (10mi) and acetic acid (0. 2ml, 3.47 mmol) was added DMF. DMA (0.258g, 2.16 mmol) and the mixture was stirred at room temperature for 2 h. Hydrazine hydrate (3ml) was added and the mixture was stirred at room temperature overnight, then was heated at 40°C for 2 h and then poured into water. The aqueous phase was extracted with CH2CI2, the organic phase dried over Na2SO4and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2CI2/MeOH (95/5). After crystallisation from EtOAc, the title compound was obtained as white crystals (0. 2g, 31. 51%) ; m. p. 170°C ; TOF MS ES+ exact mass calculated for C26H25N502 : 440.2086 (MH+). Found 440.2065 (MH+).

The following compounds of formula (lAb) were prepared by methods analogous to that described for Example 18 using the starting materials indicated (see Table 11).

Table 11 Ex From Physical data Int. 19 (4-ethylpiperazin-1-70 TOF MS ES+ exact mass calculated for yl) carbonyl C27H28N6O (MH+): 453.2403, found: 453.2394 m. p. 126°C 20 morpholin-4-yl 72 TOF MS ES exact mass calculated for C24H23N5o (MH+) : 398. 1981, found : 398.1955 m. p. 210°C 21 (morpholin-4-yl) methyt 77 TOF MS ES exact mass calculated for C25H25N5O (MH+) : 412. 2137, found : 412.2120 Ex R'From Physical data Int. m.p. 128°C 22 2- (pyrolidin-1-yl) ethoxy 73 TOF MS ES+ exact mass calculated for C26H27N5O (MH+): 426.2294, found: 426.2254 m. p. 96°C 23 (morpholin-4-75 TOF MS ES+ exact mass calculated for yl) carbonylmethoxy C26H25N503 (MH+) : 456. 2036, found: 456.2012 m. p. 170°C Triazole Examples Example 24: 2-(4-Methanesulfonylphenyl)-4-(5-(6-methyl)-pyridin-2-yl-3H- [1, 2, 3]triazol-4-yl)-pyridine

To a solution of intermediate 5 (700mg, 2 mmol) in dry DMF (13 ml) was added azidotrimethylsilane (8 mmol, 930mg) and the reaction mixture was stirred at 100°C overnight. The reaction mixture was hydrolyse with water and extracted with CH2CI2. The organic phase was washed with water, dried over Na2SO4 and filtered.

Evaporation of the solvent in vacuo gave a crude product which was purified by chromatography on silica gel (toluene/isopropylamine 95: 5). The crude oil was precipitated in a mixture CH2CI2/hexane to give the title compound as a yellow powder (260mg, 33.2%), gummy at 150°C ;'H NMR (300 MHz, CDCl3) 8 : 8.70 (1H, d), 8.28 (1H, s), 8.15 (2H, d), 7.95 (2H, d), 7.70-7. 57 (2H, m), 7.50 (1H, d), 7. 15 (1 H, d), 3.00 (3H, s), 2.50 (3H, s), NH triazole not observed; TOF MS ES+ exact mass calculated for C20H17N5O2S : 392.1181 (MH+). Found: 392.1218 (MH+).

The following compounds of formula (IBa) were prepared by methods analogous to that described for Example 24 using the starting materials indicated (see Table 11).

Table 11 Ex R'From Physical data Int. 25 methoxy 6 TOF MS ES exact mass calculated for C20H17N5O(MH+)/ 344.1511. Found: 344.1506. 26 2- (N, N- 16 TOF MS ES + exact mass calculated for dimethylamino)-C23H24N6O (MH+): 401.2090. Found: 401.2063. ethoxy p. 143°C 27 morpholinomethyl 15 TOF MS ES + exact mass calculated for C24H24N60 (MH+): 413.2090. Found: 413.2110. m.p. 110°C 28 ethyl 9 [APCI MS] m/z 342 (MH+) TOF MS ES + exact mass calculated for C21H19N5 (MH+ : 342.1718. Found: 342.1716. 29 tetrahydropyran-4-7 TOF MS ES + exact mass calculated for laminocarbonyl C25H24N60 (MH+) : 441.2039. Found: 441. 2032. 30 chloro 10 TOF MS ES + exact mass calculated for C19H14ClN5 (MH+): 348.1016 Found: 348.1000 ; m. p. 144°C 31 trifluoromethoxy 11 TOF MS ES + exact mass calculated for C2oHi4F3NsO (MH+): 398.1229. Found: 398.1194 ; m. p. 128°C 32 2-(pyrolidin-1- 12 TOF MS ES + exact mass calculated for l ëthoxy C25H26N6O (MH+ : 427.2246. Found: 427.2277. 33 fiuoro 13 TOF MS ES + exact mass calculated for C19H14FN5 (MH+): 332.1311. Found: 332. 1345.

Imidazopvridine Examples Example 34: 3-[2-(4-methoxyphenyl)-pyridin-4-yl]-2-pyridin-2-yl-imidazo[ 1,2- alpyridine

A solution of intermediate 84 (500mg, 1. 42 mmol) in toluene (10 ml) was treated with tetrakis (triphenylphosphine)palladium(0) (165mg, 10% mol) and stirred at room temperature for 30 min. Na2CO3 (2M) (0.6 ml) was added to the reaction mixture, followed by 4-methoxyphenyl boronic acid (282mg, 1.3eq, 1.85 mmol). The resulting mixture was heated under reflux overnight. The cooled mixture was poured into ice and extracted with toluene. The organic layer was washed with water, dried over Na2SO4 and filtered. Evaporation of the solvent in vacuo gave a crude oil which was purified by chromatography on silica gel (CH2CI2/MeOH, 90/10) and triturated in CH2Cl2/pentane to give the title compound as a cream powder (68mg, 13%); m. p.

222°C ; TOF MS ES + exact mass calculated for C24Hl8N40 : 379.1559 (MH+). Found: 379.1540 (MH+).

The following compounds of formula (lCj) were prepared by methods analogous to that described for Example 34 using the starting materials indicated (see Table 12).

Table 12 Ex R1 R R From Physical data Int. 35 methoxy H methyl 85 [APCI MS] m/z: 393 (MH+) , p. 174°C 36 trifluoromethoxy H methyl 85 [APCI MS] m/z: 447 (MH+) m. p. 120°C 37 cyano H methyl 85 [APCI MS] m/z : 388 (MH+) m. p. 214°C 38 methanesulfonyl H H 84 [APCI MS] m/z: 427 (MH+) m. p. 242-244°C 39 methanesulfonyl H methyl 85 APCl MS] m/z: 441 (MH+) H NMR (300MHz, CDCl3, ppm) 8 : 8.85 (d, 1H), 8.2 (d, 1H), 8.14 (d, 1H), 8.09 (m, 2H), 7.82 (d, 1 H), 7.74 (d, 1 H), 7.58 (m, 2H), 7.53 (m, 1 H), 7.44 (dd, 1 H), 7.3 (t, 1 H), 7.05 (d, 1H), 6.85 (t, 1H), 3.09 (s, 3H), 2.31 (s, 3H) 40 methanesulfonyl 8-methyl 90 TAPCI MS] m/z : 455 (MH+) methyl H NMR (300MHz, Ceci3, ppm) 8 : 8.85 (d, 1H), 8.2 (d, 2H), 8.05 (m, 3H), 7. 85 (d, 1 H), 7.5 (m, 3H), 7.1 (m, 2H), 6.8 (t, 1H), 3.1 (s, 3H), 2. 75 s, 3H), 2.35 (s, 3H) 41 acetyl H H 84 [APCI MS] m/z : 391 (MH+) m. p. 214°C 42 methylcarbonyl H H 84 [APCI MS] m/z : 406 (MH+) amino m.p. 133°C 43 methylcarbonyl H methyl 85 TOF MS ES + exact mass amino calculated for C26H21N5O (MH+): 420.1824. Found: 420.1808. m.p. 257°C 44 (tetrahydropyran-H H 84+33 [APCI MS] m/z : 476 (MH+) 4-yl) amino m. p. 179°C carbonyl Ex R1 R4 R2 From Physical data Int. 45 (tetrahydropyran-H methyl 85+33 [APCI MS] m/z : 490 (MH+) 4-yl) amino m. p. 128°C carbonyl 47 (morpholin-4-8-methyl 90+35 [APCI MS] m/z: 490 (MH+) yl) carbonyl methyl 48 (4-ethylpiperazin-8-methyl 90+36 TOF MS ES exact mass 1-yl) carbonyl methyl calculated for C32H32N60 (MH+) : 517.2715, found: 517.2751 m. p. 212°C 49 (morpholin-4-H fluoro 92+35 TOF MS ES+ exact mass yl) carbonyl calculated for C28H22FN502 (MH+) : 480. 1836, found: 480.1756 m.p. 191°C The following compounds of formula (ICk) were prepared by methods analogous to that described for Example 34 using the starting materials indicated (see Table 13).

Table 13 Ex. R'From Physical data Int. 50 methanesulfonyl 91+34 TOF MS ES exact mass calculated for amino C25H19CIN402S (MH+) : 475.0995, found: 475.0975 ; m. p. 60°C (becomes gummy) 51 (tetrahydropyran-4-91+33'H NMR (300MHz, CDCI3, ppm) 8 : 7.85 (d, yl) amino 2H), 7.75 (d, 2H), 7.65-7. 55 (m, 4H), 7.45- carbonyl 7.35 (m, 6H), 7.2 (m, 1 H), 6 (d, 1 H), 4.2 (m, 1H), 4 (m, 2H), 3.5 (m, 2H), 2, (m, 2H), 1.6 m, 2H) ; m.p. 234°C.

Example 52: 2-(6-methyl-pyridin-2-yl)-3-{2-[4-amino-phenyl]-pyridin-4-yl }-imidazo[1,2- alpyridine

A solution of example 43 (2.3g, 5.48 mmol) in MeOH (50 ml) and HCI 1 N (50 ml) was stirred at room temperature for 18 hours and then basified with a solution of NaOH 1 N. After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The title compound was obtained as a yellow solid (0.79g, 38%); [APCI MS] m/z: 378 (MH+) ;'H NMR (300 MHz, CDCl3 8 ppm : 8.7 (d, 1H), 8.1 (d, 1H), 7.85 (m, 3H), 7.7 (d, 1H), 7.6 (d, 1H), 7.45 (t, 1H), 7.25 (m, 2H), 7 (d, 1 H), 6.8 (t, 1 H), 6.7 (d, 2H), 3.85 (m, 2H), 2.4 (s, 3H).

Example 53: 2-(6-methylk-pyridin-2-yl)-3-{2-[4-(trifluoromethylsulfonyla mino)phenyl]- pyridin-4-vl-imidazof1, 2-alpyridine

To a solution of example 52 (390mg, 1. 03mmol) in CH2CI2 (1 Oml) were added trifluoromethanesulfonic anhydride (0. 2ml, 8. 55mmol) and triethylamine (0.17 ml, 1.24 mmol) and the mixture was stirred at room temperature for 3 days and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2CI2/MeOH (9/1). The title compound was obtained as a yellow foam (178mg, 33.8%) ; m. p. 135°C ; TOF MS ES + exact mass calculated for C25H18F3N502S : 510.1212 (MH+). Found: 510.1229 (MH+).

Example 54: 3-[2-(4-(morpholin-4-yl)-phenyl)-pyridin-4-yl]-2-pyridin-2-y l-imidaz[1, 2- alpyridine

A mixture of intermediate 112 (400 mg, 0. 93 mmol), morpholine (1. 2 eq, 0.1 ml, 1.1 mmol), Pd2 (dba) 3 (0.05 eq, 43 mg, 0.05 mmol), BINAP (0.15 eq, 88 mg, 0.14 mmol) and potassium tert-butoxide (1.4 eq, 126 mg, 1.31 mmol) in toluene (50 mi) was heated under reflux for 2 hours. After dilution with CD2Cl2, the organic phase was

washed with water and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue purified by chromatography on silica gel eluting with CH2CI2/MeOH (98: 2,95 : 5 and then 93: 7). The resulting oil was crystallised from CS2Cl2/pentane to give the title compound as a yellow solid (140 mg, 35%); m. p. 145°C (becomes gummy); TOF MS ES + exact mass calculated for C27H23N5O : 434.1981 (MH+). Found: 434.1993 (MH+).

Example 55: 3-{2-[4-(4-methylpiperazin-1-yl)-phenyl]-pyridin-4-yl}-2-pyr idin-2-yl- imidazo[1,2-a]pyridine Intermediate 112 (400mg, 0. 94mmol) and N-methyl-piperazine (0.125 ml, 1.2eq, 1.13 mmol) were coupled and treated as described for example 54 to afford, after crystallisation in CH2CI2/diisopropyl ether, the title compound as cream crystals (70mg, 17%); m. p. 150°C (become gummy); [APCI MS] m/z 447 (MH+).

Example 56: 2-(6-methyl-pyridin-2-yl)-3-[2-(4-(morpholin-4-ylmethyl)phen yl)-pyridin- 4-vil-imidazof1, 2-alpvridine To a solution of intermediate 99 (310mg, 0. 79mmol) and morpholine (1.5 eq, 0. 1ml, 1. 2mmol) in dry dichloroetharie (30ml) was added sodium triacetoxyborohydride (1.5eq, 253mg, 1.2 mmol} and the mixture was stirred for 3 hours at room temperature. The mixture was basified with NaOH 1 N, the aqueous layer was extracted with CH2CI2 and dried over Na2SO4. The resulting product was recrystallised from ethyl acetate to give the title compound as a white powder (194mg, 53%); m. p. 156°C ; [APCI MS] m/z 462 (MH+).

The following compounds of formula (ICj) were prepared by methods analogous to that described for Example 56 using the starting materials indicated (see Table 14).

Table 14 Ex. R'R4 RZ From Physical data Ont 57 (morpholin-4-yl)-H H 100 [APClMS] m/z 448 (MH+) methyl m. p. 80°C (degradation) 58 (morpholin-4-yl)-6-chloro methyl 103 [APCI MS] m/z 496 (MH+) methyl m. p. 157°C 59 (morpholin-4-yl)-7-methyl methyl 104 TOF MS ES + exact mass calculated methyl for C3oH29N50 (MH+): 476. 2450. Found : 476.2445 ; m.p. 188°C 60 (pyrolidin-1-yl)-6-chloro methyl 103 TOF MS ES + exact mass calculated methyl for C29H26CIN5 (MH+): 480.1955. Found: 480. 1900; m,p. 134°C 61 (morpholin-4-yl)-8-methyl methyl 105 [APCI MS] m/z 476 (MH+) methyl @ p. 122°C 62 (pyrolidin-1-yl)-8-methyl methyl 105 1H NMR (300MHz, DMSO d6, ppm) methyl 8 : 8.95 (d, 1 H), 8.45 (m, 2H), 8.2 (d, 2H), 7.95 (t, 1 H), 7.8 (d, 2H), 7.75 (m, 3H), 7.5 (d, 1 H), 7.25 (t, 1 H), 4.4 (m, 2H), 3.3 (m, 2H), 3.05 (m, 2H), 2.95 (s, 3H), 2.5 (s, 3H), 2.05 (m, 2H), 1.9 (m, 2H) ; m. : 197°C

The following compounds of formula (ICm) were prepared by methods analogous to that described for Example 56 using the starting materials indicated (see Table 15).

Table 15 Ex. R1 R2 Ra From Physical data Int. 63 (morpholin-4-yl)-chloro fluoro 101 [APCI MS] m/z 499 (MH+) methyl m. p. 189°C 64 (pyrolidin-1-yl)-fluoro fluoro 102 TOF MS ES + exact mass calculated methyl for C29H24F2N4 (MH+): 467.2047. Found: 467.2063 m.p. 155°C 65 (morpholin-4-yl)-fluoro fluoro 102 TOF MS ES + exact mass calculated methyl for C29H24F2N40 (MH+): 483.1996. Found: 483.2030 m. p. 205°C Example 66: 2-(6-methyl-pyridin-2-yl)-3-{2-[4-((morpholin-4-yl)carbonyl) phenyl]- pyridin-4-yl}-imidazo[1,2-a]pyridine

To a solution of intermediate 106 (500mg, 1. 23mmol) in DMF (30ml) were added morpholine (0. 13ml, 1. 48mmol), HOBT (200mg, 1. 48mmol), EDCI (283mg, 1. 48mmol) and triethylamine (0. 2ml ; 1. 48mmol) and the mixture was stirred at room temperature overnight and then diluted with CH2CI2. The organic phase was washed with sodium hydroxide solution 1 N, then water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with CH2CI2/MeOH (95: 5). After trituration with diisopropyl ether, the title compound was obtained as a pale yellow solid (147mg, 25.13%) ; m. p. 110°C ; [APCI MS] m/z 476 (MH+).

Example 67: 2-(6-methyl-pyridin-2-yl)-3-{2-[4-((3- methoxvpropylamino) carbonvl) phenyl]-pyridin-4-yl-imidazo[1,2-a]pyridine

intermediate 106 (400mg, 0. 98mmol) and 3-methoxypropylamine (0. 11ml, 1. 18mmol) were coupled and treated as described for example 66 to afford, after trituration with CH2CI2/pentane, the title compound as a pale yellow solid (210mg, 44.69%) ; m. p. 165°C ; [APCI MS] m/z 478 (MH+).

Example 68 : 2-(pyridin-2-yl)-3-{2-[4-(2-(pyrrolidin-1-yl)ethoxyl)phenyl] -pyridin-4-yl}- imidazof 1. 2-alpvridine A solution of intermediate 113 (140 mg, 0. 3mmol) and pyrrolidine (0. 75ml, 9 mmol) in EtOH (5 ml) was heated under reflux for 6 days. After cooling, water was added and the product was extracted with CH2CI2. The organic phase was dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by chromatography on silica gel eluting with CH2Cl2/MeOH/TEA (80/20/1%). The title compound was obtained as a brown gum (13 mg, 10%); [APCI MS] m/z 462 (MH+) ;'H NMR (300 MHz, CDCI3) #ppm : 8.75 (d, 1H), 8.5 (d, 1H), 8.15 (d, 1H), 7.9 (m, 3H), 7.85 (s, 1H), 7.7 (m, 2H), 7.3 (m, 2H), 7.2 (m, 1H), 7 (d, 2H), 6.85 (t, 1H), 4.2 (t, 2H), 3 (t, 2H), 2.75 (m, 4H), 1.85 (m, 4H).

The following compounds of formula (lCp) were prepared by methods analogous to that described for Example 68 using the starting materials indicated (see Table 16).

Table 16 Ex. R5R6N R4 From Physical data Vint. Ex. R5R6N R4 From Physical data Int. 69 dimethyl H 114 [APCI MS] m/z : 450 (MH+) amino 1H NMR (300MHz, CDCl3, ppm) 8 : 8.8 (d, 1H), 8.2 (d, 1 H), 7.95 (m, 3H), 7.75 (m, 2H), 7.6 (t, 1H), 7.4 (d, 1H), 7.3 (m, 1H), 7.05 (m, 3H), 6.9 (t, 1 H), 4.25 (t, 2H), 3 (t, 2H), 2.55 (s, 6H), 2.4 (s, 3H) 70 pyrolidin-1-yl 7-methyl 116 TOF MS ES + exact mass calculated for C31H31N5O (MH+): 490.2607. Found: 490.2600 ; m. p. 163°C 71 morpholin-4-yl 7-methyl 116 TOF MS ES + exact mass calculated for C31H3N502 (MH+) : 506.2556. Found: 506.2534 ;'H NMR (300 MHz, CDCl3, ppm) # : 8.8 (d, 1H), 8.05 (d, 1H), 7.9 (m, 3H), 7.7 (d, 1 H), 7.6 (t, 1 H), 7.5 (s, 1 H), 7.35 (d, 1 H), 7 (m, 3H), 6.7 (d, 1H), 4.2 (t, 2H), 3.8 (m, 4H), 2.85 (t, 2H), 2.6 (m, 4H), 2.45 (s, 3H), 2.4 (s, 3H) 72 pyrolidin-1-yi 8-methyl 117 [APCI MS] m/z: 490 (MH+) ; 1H NMR (300 MHz, CDCl3, ppm) 8 : 8.75 (d, 1 H), 8.05 (d, 1H), 7.9 (m, 3H), 7.7 (d, 1H), 7.55 (t, 1H), 7.3 (d, 1 H), 7.05 (m, 2H), 6.95 (d, 2H), 6.7 (t, 1 H), 4. 25 (t, 2H), 3.05 (t, 2H), 2.9 (m, 4H), 2.7 (s, 3H), 2.4 (s, 3H), 1.95 (m, 4H) The following compounds of formula (ICq) were prepared by methods analogous to that described for Example 68 using the starting materials indicated (see Table 17).

Table 17 Ex. R6R5N From Physical data Int. 73 dimethylamino 115 TOF MS ES + exact mass calculated for C28H25CIN40 (MH+): 469.1795. Found: 469.1723 ;'H NMR (300 MHz, CDCl3, ppm) 8 : 8.8 (d, 1H), 8. 1 (d, 1H), 7.9 (d, 2H), 7.8 (s, 1H), 7.7 (m, 2H), 7.45 (d, 1 H), 7.25 (m, 3H), 7.2 (m, 1H), 7 (d, 2H), 6.85 (t, 1H), 4.35 (t, 2H), 3.25 (t, 2H),2. 7 (s, 6H) 74 pyrolidin-1-yi 115 TOF MS ES + exact mass calculated for C30H27ClN4O (MH+): 495.1952. Found: 495.1957 ; m.p. 298°C Example 75 : 7-methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-((1-methyl-imidaz ol-4- yl)methyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2-a]pyridine

To a solution of intermediate 111 (400mg, 1. 02mmol) in DMF (20ml) was added portionwise sodium hydride (60% in mineral oil, 101mg, 2. 55mmol) and the mixture was stirred at room temperature for 20 minutes. Intermediate 22 (173mg, 1. 32mmol) was then added and the mixture was heated at 60°C for 3 days and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (90: 10). After trituration with diisopropyl oxide, the title compound was obtained as a yellow solid (130mg, 26%); m. p. 217°C ; TOF MS ES + exact mass calculated for C3oH26N6O : 487.2246 (MH+). Found: 487. 2247 (MH+).

Example 76: 2-(6-methyl-pyridin-2-yl)-3-{2-[4-((1-methyl-imidazol-4- yl) methyloxv) phenvll-pvridin-4-vl)-imidazof 1, 2-alpyridine Intermediate 108 (400mg, 1. 06mmol) and intermediate 22 (212mg, 1. 27mmol) were coupled and treated as described for example 75 to afford, after trituration with diisopropyl oxide, the title compound as a white solid (200mg, 40%); m. p. 120°C ; [APCI MS] m/z 473 (MH+).

Example 77: 7-methyl-2- (6-methyl-pyridin-2, vi)-342 [4(aminocarbonylmethyloxy)phenyl]-pyridin-4-yl}-imidazo[1,2- a]pyridine

To a solution of intermediate 111 (500mg, 1. 27mmol) in acetone (25mi) were added cesium carbonate (623mg, 1. 91 mmol) and bromoacetamide (264mg, 1. 91 mmol) and the mixture was heated under reflux for 48 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (95/5). After trituration with pentanelethyl acetate, the title compound was obtained as a pale yellow solid (133mg, 23%); m. p. 213°C ; [APCI MS] m/z 450 (MH+).

Example 78: 8-methyl-2- (6-methyl-pyridin-2-vl)-3-f2-r4- (aminocarbonylmethyloxyl)phenyl]-pyridin-4-yl}-imidazo[1,2-1 ]pyridine Intermediate 110 (500mg, 1. 27mmol) and bromoacetamide (264mg, 1. 91mmol) were coupled and treated as described for example 77 to afford, after trituration with diisopropyl oxide, the title compound as a cream solid (80mg, 14%); m. p. 183°C ; [APCI MS] m/z 450 (MH+).

Example 79 : 2-(6-methyl-pyridin-2-yl)-3-{2-[4-(morpholin-4-yl)phenyl]-py ridin-4-yl}- imidazof 1, 2-alPvridine

To a solution of intermediate 48 (3g, 8. 04mmol) in CH2Ci2 (80 ml) was added bromine-polymer-supported (5.03g, 8.04 mmol) and the suspension was stirred at room temperature for 3 hours. The resin was removed by filtration, with the filtrate being added directly to 2-amino-pyridine (1.51g, 16.08 mmol) and the resin washed many times with ethanol. The filtrate was heated at reflux for 18 hours, allowed to cool and concentrated. The residue was treated with water and extracted with CH2CI2. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2/MeOH, 98/2 then 95: 5) to give an oil which crystallised by trituration from diisopropyl oxide. The title compound was obtained as cream crystals (1.2g ; 33. 38%) ; m. p. 190 °C ; TOF MS ES + exact mass calculated for C28H25N50 (MH+): 448.2137. Found: 448.2081 Example 80 : 7-methyl-2-(6-methyl-pyridin-2-yl)-3-{2-[4-(morpholin-4-yl)p henyl]- pvridin-4-yll-imidazof 1, 2-alpvridine

Intermediate 48 (1.27g, 3.4 mmol) was reacted as described for example 79, to afford after trituration with diisopropyl oxide, the title compound as cream crystals (0. 6g, 38.22%) ; m. p. 208°C ; TOF MS ES'exact mass calculated for C29H27N5O (MH+): 462.2294. Found: 462.2263 Imidazole Examples Example 81: N-(tetrahydronvran-4-yl)-4-(4-82-tert-Butvl-5-[6-methyl-pyri din-2-yll-1 H- imidazol-4-yl}-pyridin-2-yl)-benazmide

To a solution of intermediate 120 (0. 95g, 2. 56mmol) in a mixture of DME (30moi) and water (15ml) were added intermediate 33 (0.93g, 2. 81mmol), tetrakis (triphenylphosphine) palladium (0) (0. 1g, 0. 086mmoi) and Na2CO3 (solution

2M, 5ml) and the mixture was heated under reflux overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was recrystallised from EtOAc to afford the title compound as yellow crystals (0.77g, 55.36%) ; m. p. 174°C ; TOF MS ES+ exact mass calculated for C3oH33N502 : 496. 2712 (MH+). Found: 496.2662 (MH+).

The following compounds of formula (IDf) were prepared by methods analogous to that described for Example 81 using the starting materials indicated (see Table 18).

Table 18 Ex. R1 R4 R2 From Physical data Int. 82 (tetrahydro-t-butyl H 121+33 TOF MS ES+ exact mass calculated pyran-4-yl)-for C29H31N5O2 (MH+): 482. 2556. amino-Found : 482.2577 ; m. p. 182°C carbonyl 83 methoxy t-butyl H 121 TOF MS ES+ exact mass calculated for C24H24N4O (MH+): 385.2028. Found: 385.2026 ; m.p. 143°C 84 methane-t-butyl methyl 120 TOF MS ES+ exact mass calculated sulfonyl for C25H26N4O2S (MH+): 447.1855. Found: 447.1905 ; m.p. 144°C 85 chloro t-butyl methyl 120 TOF MS ES+ exact mass calculated for C24H23CIN4 (MH+) : 403.1689. Found: 403 1637; m. p. 122°C 86 morpholin-4-yl t-butyl methyl 120+27 TOF MS ES exact mass calculated for C28H31N5O (MH+): 454.2607. Found : 454.2576 ; m.p. 238°C 87 trifluoro-t-butyl methyl 120 TOF MS ES+ exact mass calculated methoxy for C25H23F3N40 (MH+): 453.1902. Found: 453 1863 ; m.. 179°C 88 (morpholin-4-t-butyl methyl 120+35 TOF MS ES exact mass calculated yl) carbonyl for C29H31N502 (MH+) : 482. 2556. Found : 482.2517 ; m. p. 180°C Ex. From Physical data Int. 89 (4-ethyl-t-butyl methyl 120+36 TOF MS ES exact mass calculated piperazin-1-for C31H36N6O (MH+): 509. 3029. yl)carbonyl Found: 509.3025 ;'H NMR (300 MHz; CDCl3, ppm) 8 : 8.53 (1 H, d), 7.93-7. 84 (3H, m), 7.40 (1 H, d), 7. 37-7. 27 (3H, m), 7.18 (1H, d), 6.86 (1H, d), 3.85-3. 23 (4H, brd), 2.53- 2.21 (9H, m), 1.31 (9H, s), 0.99 (3H, brs). 90 morpholin-4-yl t-butyl H 121+27 TOF MS ES exact mass calculated for C27H29N5O (MH+): 440.2450. Found: 440.2401 ;'H NMR (300 MHz; CDCi3, ppm) ö : 9.92 (1 H, brs), 8.47 (1H, d), 8.38 (1H, d), 7.81 (2H, d), 7.77 (1H, s), 7.36 (2H, d), 7.27 (1 H, d), 6.95 (1H, dd), 6.80 (2H, d), 3.70 (4H, brt), 3.06 (4H, brt), 1.30 (9H, s). 91 4-ethyl-t-butyl H 121+28 TOF MS ES+ exact mass calculated piperazin-1-yi for C29H34N6 (MH+): 467.2923. Found: 467.2880 ; m. p. 190-192°C 92 2- (pyrolidin-1- t-butyl H 121+29 TOF MS ES+ exact mass calculated yl) ethoxy for C27H33N5O (MH+): 468. 2763. Found: 468.2729 ;'H NMR (300 MHz; CDCl3 ppm) 8 : 10.02 (1H, brs), 8.63 (1H, d), 8. 53 (1H, d), 7.94 (2H, d), 7.91 (1H, s), 7.53-7. 48 (2H, m), 7.43 (1 H, d), 7.12-7. 06 (1H, m), 6.96 (2H, d), 4.18 (2H, brt), 2.95 (2H, brt), 2.68 (4H, brs), ), 1.82 (4H, brs), 1.45 (9H, S). 93 4-ethyl-t-butyl methyl 120+28 TOF MS ES exact mass calculated piperazin-1-yl for C3oH36N6 (MH+) : 481.3080. Found : 481. 3092; m. p. 210°C 94 methanesulfo i-propyl H 123 TOF MS ES+ exact mass calculated nyl for C23H22N402S (MH+): 419. 1542. Found: 419. 1543 ; m. 134 °C 95 methane-i-propyl methyl 122 TOFMSES exact mass calculated sulfonyl for C24H24N402S (MH+): 433.1698. Found: 433.1654 ;'H NMR (300 MHz; CDCl3, ppm) # : 8.62 (1H, d), 8. 14 (2H, d), 8.09 (1H, s), 7.95 (2H, d), 7.52 (1 H, d), 7.45 (1H, t), 7.31 (1H, d), 6.98 (1H, d), 3.16-3. 04 (1H, m), 3.02 (3H, s), 2.41 (3H, s), 1.29 6H, d). 96 (tetrahydropyr i-propyl methyl 122+33 TOF MS ES exact mass calculated an-4-yl)amino- for C29H31N5O2(MH+) : 482.2556. carbonyl Found : 482.2509 ; m.p. 233°C Ex. From Physical data Int. 97 morpholin-4-yl i-propyl methyl 122+27 TOF MS ES+ exact mass calculated for C27H29N50 (MH+): 440.2450. Found: 440.2419 ; m. p. 160°C (becomes gummy) ;'H NMR (300 MHz; CDCl3, ppm) 8 : 10.52 (1 H, brs), 8.58 (1H, d), 7.94 (2H, d), 7.90 (1H, s), 7.45-7. 30 (3H, m), 7.00-6. 87 (3H, m), 6.80 (2H, d), 3.83 (4H, brt), 3.20 (4H, brt), 3.17-3. 06 (1H, m), 2.47 (3H, s), 1.35 (6H, d). 98 morpholin-4-yl methyl methyl 124+27 TOF MS ES+ exact mass calculated for C25H25N5O (MH+): 412.2137. Found : 412.2155 ; 1H NMR (300 MHz; CDCl3, ppm) 6 : 8.65 (1H, d), 8.03 (1H, s), 7.97 (2H, d), 7.55- 7.40 (3H, m), 7.04 (1 H, d), 6.97 (2H, d), 3.89 (4H, brt), 3.26 (4H, brt), 2.59 (3H, s), 2.56 (3H, s), NH imidazole not seen 99 (morpholin-4-methyl methyl 124+35 TOF MS ES+ exact mass calculated yl) carbonyl for C26H25N502 (MH+): 440.2086. Found: 440.2144 ; 1H NMR (300 MHz; CDCI3, ppm) 8 : 8. 72 (1 H, d), 8.14 (1H, s), 8.09 (2H, d), 7.63- 7.41 (5H, m), 7.08 (1 H, d), 3.94-3. 62 (8H, m), 2.62 (3H, s), 2.60 (3H, s), NH imidazole not seen. 100 morpholin-4-yl i-propyl H 123+27 TOF MS ES exact mass calculated for C26H27N5O (M+1) +: 425.2294. Found: 425.2295 ; m. p. 160°C (becomes gummy) ; H NMR (300 MHz; CDCl3, ppm) 8 : 8.57 (1H, d), 8.47 (1 H, d), 7.92 (1 H, s), 7.87 (2H, d), 7.49 (2H, brd), 7.36 (1H, d), 7.15- 7.02 (1H, m), 6.90 (2H, d), 3.80 (4H, brt), 3.16 (4H, brt), 3.14-3. 03 (1H, m), 1.34 (6H, d), NH imidazole not seen. Example 101: (4-{4-[2-tert-Butyl-5-(6-methyl-pyridin-2-yl)-1H-inidazol-4- yl]-pyridin-2- yl}-benzyl)-dimethyl-amine

To a solution of intermediate 125 (G. 8g, 2. 02mmol) in CH2CI2 (50ml) were added dimethylamine (2M solution in MeOH, 1. 1 ml, 2. 22mmol) and sodium triacetoxyborohydride (0.856g, 4. 04mmol) and the mixture was stirred at room

temperature for 3 hours. The reaction mixture was poured into a saturated solution of NaHCO3 and extracted with CH2CI2. The organic phase was dried over Na2SO4, and concentrated under reduced pressure. The title compound was obtained, after chromatography on silica gel (CH2CI2/MeOH 98: 2 then 85: 15) and recrystallisation from EtOAc, as a white solid (0.109g, 12.6%) ; m. p. 187°C ; TOF MS ES+ exact mass calculated for C27H3, N5 : 426.2657 (MH+). Found: 426. 2680 (MH+).

The following compounds of formula (IDg) were prepared by methods analogous to that described for Example 101 using the starting materials indicated (see Table 19).

Table 19 Ex. R'R'From Physical data I Int : 102 morpholin-4-yt t-butyl 125 TOF MS ES+ exact mass calculated for C29H33N5O (MH+): 468.2763. Found: 468.2764 ;'H NMR (300 MHz; CDCl3 ppm) 8 : 8.77 (1H, d), 8.13 (1H, s), 8.05 (2H, d), 7.65-7. 41 (5H, m), 7.09 (1 H, d), 3.88-3. 78 (4H, m), 3.69-3. 62 (2H, m), 2.64 (3H, s), 2.60-2. 54 (4H, m), 1.56 (9H, s), NH imidazole not seen. 103 pyrolidin-1-yl t-butyl 125 TOF MS ES+ exact mass calculated for C29H3sNs (MH+): 452.2814. Found: 452.2814 ; m.p. 148°C 104 morpholin-4-yl i-propyl 127 TOFMSES exact mass calculated for C28H3, N5O (MH+): 454.2607. Found: 454.2574 ; m. p. 141°C 105 dimethylamino i-propyl 127 TOF MS ES exact mass calculated for C26H29N5 (MH+): 412.2501. Found: 412. 2523; m.p. 135°C Example 106: 4-(2-tdert-Butyl-5-{6-methyl}-pyridin-2-yl-1H-imidazol-4-yl) -2-[4-(1- methyl-1 H-imidazol-4-ylmethoxy)-phenyl]-pyridine

To a solution of intermediate 126 (0.49g, 1. 27mmol) in DMF (20ml) was added portionwise sodium hydride (60% in mineral oil, 0.152g, 3. 81mmol) and the mixture was stirred at room temperature for 10 minutes. Intermediate 22 (0.3g, 1. 8mmol) was then added and the mixture was stirred for 18 hours at room temperature and then poured into water. After extraction with EtOAc, the organic phase was washed with a solution of NaOH (1 N) and water, dried over Na2SO4 and concentrated under reduced pressure. After precipitation with pentane, the title compound was obtained as an off-white solid (0.305g, 50%), gummy at 128°C ;'H NMR (300 MHz; CDCl3) 5 : 8.51 (1H, d), 7.87 (1H, s), 7. 82 (2H, d), 7.40 (1H, d), 7.40-7. 28 (3H, m), 7.22 (1H, d), 6.96 (1H, d), 6.89 (1H, d), 6.85 (1H, s), 4.97 (2H, s), 3.56 (3H, s), 2.36 (3H, s), 1.32 (9H, s); TOF MS ES+ exact mass calculated for C29H3oN6O : 479.2559 (MH+). Found 479.2549 (MH+).

Example 107: 2-{4-[4-(2-tert-Butyl-5-{6-methyl}-2-yl-1H-imidazol-4-yl)-py ridin- 2-yll-phenoxr}-acetamide Intermediate 126 (0. 5g, 1. 3mmol) and 2-bromoacetamide (0. 197g, 1. 43mmol) were reacted as described for example 106 to afford the title compound as a white solid (0.347g, 60.45%) ; m. p. 210°C ; TOF MS ES+ exact mass calculated for C26H27N502 : 442.2243 (MH+). Found: 442.2221 (MH+).

Example 108: 4-(2-tert-Butyl-5-{6-methyl}-pyridin-2-yl-1H-imidazol-4-yl)- 2-[4-(2- pyrrolidin-1-vi-ethoxv)-phenvll-pvridine

Intermediate 126 (0. 4g, 1. 04mmol) and 1- (2-chloroethyl) pyrrolidine hydrochloride (0.354g, 2. 08mmol) were reacted as described for example 106 to afford the title compound as an off-white solid (0. 12g, 24%); m. p. 168°C ; TOF MS ES+ exact mass calculated for C3oH35N5O : 482.2920 (MH+). Found: 482.2931 (MH+).

Example 109: 4-(2-tert-Butyl-5-pyridin-2-yl-1H-imidazol-4-yl)-2-[4-(1-met hyl-1H- imidazol-4-vlmethoxy)-phenyllidine To a solution of example 83 (0.26g, 0. 67mmol) in CH2Cl2 (40ml) was added boron tribromide (2. 1 ml, 2. 1 mmol, 3.2eq, solution 1 M in CH2CI2). The mixture was stirred at room temperature overnight. The reaction mixture was evaporated and neutralised with NaOH (1 N), the resulting mixture was warmed up to 60°C and stirred for 1 hour.

After cooling to room temperature, the mixture was extracted with CH2CI2. The aqueous phase was acidified with HCI (1 N) and extracted with CH2CI2. The organic phase was washed with NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to give 4-(4-{2-tert-Butyl-5-pyridin-2-yl-1 H-imidazol-4-yl}-pyridin-2- yl]-phenol which was used without purification in the next step. A solution of 4-(4-{2 tert-Butyl-5-pyridin-2-yl-1 H-imidazol-4-yl}-pyridin-2-yl]-phenol (0. 14g, 0. 37mmol) in acetone K2CO3 (0. 156g, 1. 1 mmol) and intermediate 22 (0.094g, 0. 56mmol) were heated at reflux for 2 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was poured into water and extracted with CH2CI2. The organic phase was washed with water, dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (toluene/isopropylamine 90: 10) to afford the title

compound as a yellow solid (0.04g, 23.3%) ; m. p. 156°C ; TOF MS ES+ exact mass calculated for C28H28N6O : 465.2403 (MH+). Found: 465.2395 (MH+).

Example 110: 4-f2-Phenyl-5-f6-methyll-pyridin-2-yl-1 H-imidazol-4-y l-2-(4- methanesulfonvl-phenyl)-pyridine

Intermediate 118 (6.5g, 20. 3mmol) and benzaldehyde (4. 3moi, 40. 6mmol) were reacted as described for intermediate 119 to afford 2-phenyl-4- (pyridin-2-yl)-5- (2- bromo-pyridin-4-yl)-imidazole (4.5g) which was used in the next step without purification. 2-Phenyl-4-(pyridin-2-yl)-5-(2-bromo-pyridin-4-yl)-imidazole (0.6g, 1. 53mmol) and 4- (methanesulfonyl) phenyl boronic acid (0.338g, 1. 69mmol) were reacted as described for example 81 to afford the title compound as a yellow powder (0. 14g, 19.63%) ; 1H NMR (300 MHz; CDCl3) 8 : 8.67 (1H, d), 8. 13-8. 12 (2H, m), 7.96 (2H, d), 7.92 (1 H, s), 7. 68-7. 26 (8H, m), 7. 02 (1 H, d), 3. 02 (3H, s), 2.54 (3H, s); TOF MS ES+ exact mass calculated for C27H22N402S : 467.1542 (MH+). Found: 467.1513 (MH+).

Aminothiazole Examples Example 111: 5-{2-[4-(morpholin-4-yl)phenyl]pyridin-4-yl}-4-(pyridin-2-yl )-1,3-thiazol- 2-amine

To a solution of intermediate 45 (0.4 g, 1.11 mmol) in CH2CI2 (20 ml) was added polymer-supported pyridinium perbromide (0. 62g, 1eq, 1.11 mmol) and the suspension shaken for 50 min. The resin was removed by filtration, with the filtrate being added directly to thiourea (0.25 g, 3 eq, 3.33 mmol) and the resin washed several times with ethanol. The filtrate was heated at reflux overnight, allowed to cool

and concentrated. The residue was basified with aqueous NaOH and extracted with CH2CI2. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. After chromatography on silica gel (CH2CI2/MeOH, 95: 5 then 90: 10) and crystallisation from ethyl acetate, the title compound was obtained as cream crystals (108 mg, 23.35%) ; m. p. 246°C ; [APCI MS] m/z 416 (MH+).

The following compounds of formula (lEf) were prepared by methods analogous to that described for Example 111 using the starting materials indicated (see Table 20).

Table 20 Ex. R1 From Physical data Int. 112 methanesulfonyl 46 TOF MS ES+ exact mass calculated for C21H18N4O2S2 (MH+): 423. 0949. Found: 423. 0945 ; m.. 236-238°C 113 4-ethylpiperazin-1-yl 47 TOF MS ES+ exact mass calculated for C26H28N6S (MH+): 457.2174. Found: 457. 2213 ; m. p. 230-232°C 114 morpholin-4-yl 48 TOF MS ES+ exact mass calculated for C24H23N50S (MH+): 430.1701. Found : 430.1698 ; m. p. 250-252°C 115 (morpholin-4-yl) carbonyl 57 TOF MS ES+ exact mass calculated for C25H23N5O2S (MH+): 458. 1651. Found: 458. 1602; m. p. 158-160°C 116 (tetrahydropyran-4-yl) amino 58 [APCI MS] m/z: 472 (MH+); m. p. 230- carbonyl 232°C 117 (morpholin-4-yl)methyl 59 TOF MS ES+ exact mass calculated for C25H25N50S (MH+) : 443.1860. Found: 443.1800 ; m. p. 190-192°C 118 methoxy 51 [APCI MS] m/z : 375 (MH+); m. p. 188- 190°C 119 trifluoromethoxy 52 [APCI MS] m/z : 429 (MH+); m. p. 222- 224°C 120 aminocarbonyl 54 [APCI MS] m/z : 418 (MH+); m. p. 152- methoxy 154°C 121 2- (pyrolidin-1-yl) ethoxy 53 [APCI MS] m/z: 458 (MH+); m. p. 176- 178°C Ex. R'From Physical data Int. 122 (1-methylimidazol-4-55 TOF MS ES exact mass calculated for yl) methoxy C25H22N60S (MH+): 455.1654. Found: 455.1600 ; m. p. 226-228°C The following compounds of formula (IEg) were prepared by methods analogous to that described for Example 111 using the starting materials indicated (see Table 21).

Table 21 Ex. R'R From Physical data Int. 123 (tetrahydropyran-4-65 TOF MS ES+ exact mass calculated for yl) amino C25H23N5O2S (MH+): 458.1651. Found: carbonyl 458.1637 ; m.p. 268°C 124 morpholin-4-yl H 66 TOF MS ES+ exact mass calculated for C23H21N5OS (MH+): 416. 1545. Found: 416.1504 ; m.p. 276°C 125 chloro methyl 67 TOF MS ES+ exact mass calculated for C20H15ClN4S (MH+): 379.0784. Found: 379. 0772 ; m.p. 222°C 126 trifluoromethoxy methyl 68 TOF MS ES+ exact mass calculated for C21H15F3N40S (MH+): 429.0997. Found: 429.0958 ; m. p. 232°C 127 ethanesulfonyl methyl 61 TOF MS ES+ exact mass calculated for C22H2oN402S2 (MH+): 437.1106. Found: 437.1096 ; m.p. 219°C 128 (tetrahydropyran-4-methyl 71 TOF MS ES+ exact mass calculated for yl)aminocarbonyl C26H25N5O2S (MH+) : 472.1807. Found: 472.1815 ; m.p. 283°C 129 (morpholin-4-methyl 69 TOF MS ES exact mass calculated for yl) carbonyl C25H23N502S (MH+): 458.1651. Found: 458. 1610; m.p. 246°C 130 (4-ethylpiperazin-1-methyl 70 TOF MS ES+ exact mass calculated for yl) carbonyl C27H28N6OS (MH+): 485.2123. Found: 485.2128; m.p. 224°C 131 (morpholin-4-yl) methyl methyl 77 TOF MS ES+ exact mass calculated for C25H2sN50S (MH+): 444.1858. Found: 444. 1862 ; m.p. 236°C 132 morpholin-4-yl Methyl 72 TOF MS ES+ exact mass calculated for C24H23N5OS (MH+) : 430.1701. Found : 430. 1648 ; m.p. 246°C Ex. From Physical data Int. 133 2- (pyrolidin-1-yl) ethoxy methyl 73 TOF MS ES+ exact mass calculated for C26H27N5OS (MH+): 458.2014. Found: 458.1963 ; m. p. 150°C 134 aminocarbonylmethoxy methyl 74 TOF MS ES+ exact mass calculated for C22H19N502S (MH+): 418.1338. Found: 418. 1289; m.p. 191°C 135 (morpholin-4-methyl 75 TOF MS ES+ exact mass calculated for yl) carbonylmethoxy C26H25N503S (MH+): 488.1756. Found: 488.1700 ; m. p. 172°C 136 (pyrolidin-1-yl) methyl methyl 78 TOF MS ES+ exact mass calculated for C25H25N5S (MH+): 428. 1909. Found: 428.1861 ; m. p. 200°C 137 (dimethylamino) methyl methyl 79 TOF MS ES+ exact mass calculated for C23H23N5S (MH+): 402.1752. Found: 402.1707 ; m. p. 210°C

Examples 138 to 140 Step 1: Intermediate 128 supported on resin (1g) was weighed out into a peptide vessel. Then 4-formylphenylboronic acid (870mg, 5. 8mmol, 10eq), Pd (PPh3) 4 (134 mg, 0. 16mmol, 0.2eq), and sodium carbonate (615mg, 5. 8mmol, 2M) were added and suspended in toluene/EtOH (8: 2,20mL). The reaction vessel was purged with argon for 5 min, and the mixture was stirred at 90°C for 16h. The resin was washed with DMF (3x10mL), water (3x10mL), EtOH (3x10mL) and CH2CI2 (3x10mL).

Step 2: The product from step 1 was placed into a peptide vessel with a solution of NHR5R6 (5. 8mmol, 10eq) in trimethylorthoformate (5.4mL). Then a solution of sodium cyanoborohydride (0.2M) in THF (5.4mL) with acetic acid (110uL) was added. The reaction vessel was purged with argon for 5 min and the mixture was stirred at 60°C for 16h. The resin was washed with DMF (3x10mL), EtOH (3x10mL) and CH2CI2 (3x10mL). The resin was treated with a solution of 20% TFA in CH2CI2 and the solvent was removed under reduced pressure. Purification of the residue by HPLC chromatography (water/acetonitrile gradient) gave the products of formula (IEh) shown in Table 22.

Table 22 Ex R5 R6 Physical data 138 H isopropyl APCl MS] m/z 402 MH+ 139- (CH2) 4- TOF MS ES+ exact mass calculated for C24H23N5S (MH+) : 414.1752. Found: 414.1766. 140 H cyclobutyl TOF MS ES+ exact mass calculated for C24H23N5S (MH+) : 414.1752. Found: 414.1749.

Examples 141 to 144 Step 1 : Intermediate 128 or intermediate 129 supported on resin (1g) were weighed out into a peptide vessel. Then 4-hydroxyphenylboronic acid (800mg, 5. 8mmol, 10eq), Pd (PPh3) 4 (134 mg, 0. 16mmol, 0.2eq), and sodium carbonate (615mg, 5. 8mmol, 2M) were added and suspended in toluene/EtOH (8: 2,20mL). The reaction vessel was purged with argon for 5 min, and the mixture was stirred at 90°C for 16h.

The resin was washed with DMF (3x10mL), water (3x10mL), EtOH (3x10mL) and CH2CI2 (3x10mL).

Step 2: The product from step 1 was placed into a peptide vessel with a solution of R-CI (5. 8mmol, 10eq) in DMSO (10mL). Then a solution of potassium carbonate (802mg, 5. 8mmol, 10eq) in DMSO (5mL) was added. The reaction vessel was purged with argon for 5 min and the mixture was stirred at 90°C for 16h. The resin was washed with DMF (3x10mL), EtOH (3x10mL) and CH2CI2 (3x1 OmL). The resin was treated with a solution of 20% TFA in CH2Cl2 and the solvent was removed under reduced pressure. Purification of the residue by HPLC chromatography (water/ acetonitrile gradient) gave the products of formula (lEj) shown in Table 23.

Table 23 Ex RZ From intermediate Physical data supported on resin 141 ol methyl 55 TOF MS ES exact mass calculated for v C25H21N502S (MH+) : 456. 1494. Found : -- 456. 1457. 142 ° cN H 54 TOF MS ES+ exact mass calculated for H C25H21N502S (MH+) : 456. 1494. Found : 456. 1545. Ex R R From intermediate Physical data supported on resin 143 o methyl 55 TOF MS ES exact mass calculated for fNw C26H25N503S (MH+) : 488. 1756. Found : AJ 488. 1792. 144 54 TOF MS ES+ exact mass calculated for CNJW C25H23N503S (MH+) : 474. 1600. Found : °J 474 1552.

Examples 145 to 156 Step 1: Intermediate 129 supported on resin (1g) was weighed out into a peptide vessel. Then 4-methoxycarbonylphenylboronic acid (1.05g, 5. 8mmol, 10eq), Pd (PPh3) 4 (0.134 g, 0. 16mmol, 0.2eq), and a aqueous solution of sodium carbonate (0. 615g, 5. 8mmol, 2M) were added and suspended in toluene/EtOH (8: 2,20mL). The reaction vessel was purged with argon for 5 min, and the mixture was stirred at 90°C for 16h. The resin was washed with DMF (3x10mL), water (3x1 OmL), EtOH (3x1 OmL) and CH2CI2 (3x10mL). Then resin was added to a sodium hydroxide solution (2M) in dioxane (10mL). The reaction mixture was stirred at 50°C for 16h. The resin was washed with DMF (3x10mL), EtOH (3x10mL) and CH2CI2 (3x10mL).

Step 2: The product from step 1 was placed into a peptide vessel with a solution of NHR5R6 (5. 8mmol, 10eq) in DMF (5mL). Then a solution of HOBT (1.18g, 8. 7mmol, 15eq) and EDCI (1.36mL, 8. 7mmol, 15eq) in DMF (5mL) was added. The reaction vessel was purged with argon for 5 min and the mixture was stirred at 70°C for 16h.

The resin was washed with DMF (3x10mL), EtOH (3x10mL), CH2Cl2 (3x10mL). The resin was treated with a solution of 20% TFA in CH2CI2 and the solvent was removed under reduced pressure. Purification of the residue by HPLC chromatography (water/ acetonitrile gradient) gave the products of formula (IEk) shown in Table 24.

Table 24 Ex R°R NCO-Physical data 145 1° TOF MS ES exact mass calculated for N31 C27H28N6OS (MH+) : 485. 2123. Found nu : 485. 2123. zon 146 o TOF MS ES+ exact mass calculated for H3c,, C27H3DN60S (MH+) : 487. 2280. Found : 4. 2267. i I CH3 CH3 147, 10 TOF MS ES+ exact mass calculated for C28H3oN6S (MH+) : 499. 2280. Found N : 499. 2277. H3cy NJ I CH3 148/o TOF MS ES+ exact mass calculated for < N ß C27H28N6OS (MH+) : 485. 2123. Found N : 485. 2094. H 149 o TOF MSES+ exact mass calculated for H3Cs/H C25H25N502S (MH+) : 460. 1807. Found N : 460. 1810. 150 CH3 TOF MS ES+ exact mass calculated for (11 C27H3ON6oS (MH+) : 487. 2280. Found H3cN/oNA : 487. 2260. H 151 CH3 O TOF MS ES+ exact mass calculated for H3c,, l N< C25H25N502S (MH+) : 460. 1807. Found H : 460. 1799. 152 TOF MS ES+ exact mass calculated for o/ C26H25N52S (MH+) : 472. 1807. Found : 472. 1798. 153 TOFMS ES+ exact mass calculated for Ni C24H23N502S (MH+) : 466. 1651. Found 3 H : 466. 1633. 154 o TOF MS EST exact mass calculated for C25H22NrOS (MH+) : 455. 1654. Found H" : 455. 1626. H 155 o TOF MS ES+ exact mass calculated for I C28H29N5OS (MH+) : 484. 2171. Found N-k : 484. 2133. CL, H3 156 TOF MS ES+ exact mass calculated for C27H27N50S (MH+) : 470. 2014. Found : 470. 1964. Hic Biology The biological activity of the compounds of the invention may be assessed using the following assays:

Assay 1 (Cellular transcriptional assav) The potential for compounds of the invention to inhibit TGF-P signaling may be demonstrated, for example, using the following in vitro assay.

The assay was performed in HepG2 cells stably transfected with the PAI-1 promoter (known to be a strong TGF-ß responsive promoter) linked to a luciferase (firefly) reporter gene. The compounds were selected on their ability to inhibit luciferase activity in cells exposed to TGF-P. In addition, cells were transfected with a second luciferase (Renilla) gene which was not driven by a TGF-ß responsive promoter and was used as a toxicity control.

96 well microplates were seeded, using a multidrop apparatus, with the stably transfected cell line at a concentration of 35000 cells per well in 200 pl of serum- containing medium. These plates were placed in a cell incubator.

18 to 24 hours later (Day 2), cell-incubation procedure was launched. Cells were incubated with TGF-ß and a candidate compound at concentrations in the range 50 nM to 10 uM (final concentration of DMSO 1 %). The final concentration of TGF-P (rhTGFß-1) used in the test was 1 ng/mL. Cells were incubated with a candidate compound 15-30 mins prior to the addition of TGF-ß. The final volume of the test reaction was 150 pI. Each well contained only one candidate compound and its effect on the PAI-1 promoter was monitored.

Columns 11 and 12 were employed as controls. Column 11 contained 8 wells in which the cells were incubated in the presence of TGF-ß, without a candidate compound. Column 11 was used to determine the'reference TGF-ß induced firefly luciferase value'against which values measured in the test wells (to quantify inhibitory activity) were compared. In wells12 to D12, cells were grown in medium without TGF-ß. The firefly luciferase values obtained from these positions are representative of the'basal firefly luciferase activity'. In wells E12 to H12, cells were incubated in the presence of TGF-ß and 500 uM CPO (Cyclopentenone, Sigma), a cell toxic compound. The toxicity was revealed by decreased firefly and renilla luciferase activities (around 50 % of those obtained in column 11).

12 to 18 hours later (day 3), the luciferase quantification procedure was launched.

The following reactions were performed using reagents obtained from a Dual Luciferase Assay Kit (Promega). Cells were washed and lysed with the addition of 10 ul of passive lysis buffer (Promega). Following agitation (15 to 30 mins), luciferase activities of the plates were read in a dual-injector luminometer (BMG lumistar). For

this purpose, 50 p. ! of luciferase assay reagent and 50 gi of'Stop & Glo'buffer were injected sequentially to quantify the activities of both luciferases. Data obtained from the measurements were processed and analysed using suitable software. The mean Luciferase activity value obtained in wells A11 to H11 (Column 11, TGF-ponly) was considered to represent 100% and values obtained in wells A12 to D12 (cells in medium alone) gave a basal level (0%). For each of the compounds tested, a concentration response curve was constructed from which an IC50 value was determined graphically.

Assay 2 (Alk5 Fluorescence Polarization Assay) Kinase inhibitor compounds conjugated to fluorophores, can be used as fluorescent ligands to monitor ATP competitive binding of other compounds to a given kinase.

The increase in depolarization of plane polarized light, caused by release of the bound ligand into solution, is measured as a polarization/anisotropy value. This protocol details the use of a rhodamine green-labelled ligand for assays using recombinant GST-ALK5 (residues 198-503).

Assay buffer components: 62.5 mM Hepes pH 7.5 (Sigma H-4034), 1 mM DTT (Sigma D-0632), 12.5 mM Mec12 (Sigma M-9272), 1.25 mM CHAPS (Sigma C-3023).

Protocol : Solid compound stocks were dissolved in 100% DMSO to a concentration of 1 mM and transferred into column 1, rows A-H of a 96-well, U bottom, polypropylene plate (Costar #3365) to make a compound plate. The compounds were serially diluted (3-fold in 100% DMSO) across the plate to column 11 to yield 11 concentrations for each test compound. Column 12 contained only DMSO. A Rapid plate'rm-96 was used to transfer 1 sul of sample from each well into a 96-well, black, U-bottom, non-treated plate (Costar #3792) to create an assay plate.

ALK5 was added to assay buffer containing the above components and 1 nM of the rhodamine green-labelled ligand so that the final ALK5 concentration was 10 nM based on active site titration of the enzyme. The enzyme/ligand reagent (39 ul) was added to each well of the previously prepared assay plates. A control compound (1 ui) was added to column 12, rows E-H for the low control values. The plates were read immediately on a LJL Acquest fluorescence reader (Molecular Devices, serial number AQ1048) with excitation, emission, and dichroic filters of 485nm, 530 nm, and 505 nm, respectively. The fluorescence polarization for each well was

calculated by the Acquest reader and then imported into curve fitting software for construction of concentration response curves. The normalized response was determined relative to the high controls (1 ul DMSO in column 12, rows A-D) and the low controls (1 pi of control compound in column 12, rows E-H). An IC50 value was then calculated for each compound Using the above assays all Examples of the invention showALK5 receptor modulator activity (having tCgn values in the range of 0.4 to 275nM) and TGF-ß cellular activity (having tCgn values in the range of 0.001 to 10pM). <BR> <BR> <BR> <BR> <BR> <P>4- 4- [4- (2-tert-Butyl-5- {6-methyl}-pyridin-2-yl-1 H-imidazol-4-yl)-pyridin-2-yl]-phenyl}- morpholine (Example 86) showed an ALK5 receptor modulator activity of 34 nM and TGF-ß cellular activity of 183 nM. <BR> <BR> <BR> <BR> <BR> <P>N- (tetrahydropyran-4-yl)-4- (4- {2-isopropyl-5- [6-methyl-pyridin-2-yl]-1H-imidazol-4-yl}- pyridin-2-yl)-benzamide (Example 96) showed an ALK5 receptor modulator activity of 25 nM and TGF-ß cellular activity of <14 nM.