WO2004013135A1 - 2-phenylpyridin-4-yl derivatives as alk5 inhibitors - Google Patents

2-phenylpyridin-4-yl derivatives as alk5 inhibitors Download PDF

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WO2004013135A1
WO2004013135A1 PCT/EP2003/008496 EP0308496W WO2004013135A1 WO 2004013135 A1 WO2004013135 A1 WO 2004013135A1 EP 0308496 W EP0308496 W EP 0308496W WO 2004013135 A1 WO2004013135 A1 WO 2004013135A1
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pyridin
alkyl
hydrogen
compounds
formula
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PCT/EP2003/008496
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French (fr)
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Nerina Dodic
Francoise Jeanne Gellibert
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Smithkline Beecham Corporation
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Priority claimed from GB0217751A external-priority patent/GB0217751D0/en
Priority claimed from GB0314698A external-priority patent/GB0314698D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to US10/522,969 priority Critical patent/US20050245520A1/en
Priority to JP2004525405A priority patent/JP2005539000A/en
Priority to AU2003260345A priority patent/AU2003260345A1/en
Priority to EP03766385A priority patent/EP1539748A1/en
Publication of WO2004013135A1 publication Critical patent/WO2004013135A1/en

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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to novel 2-phenylpyridin-4-yl heterocyclyl derivatives which are inhibitors of the transforming growth factor, (“TGF”)- ⁇ signalling pathway, in particular, the phosphorylation of smad2 or smad3 by the TGF- ⁇ type I or activin-like kinase (“ALK”)-5 receptor, methods for their preparation and their use in medicine, specifically in the treatment and prevention of a disease state mediated by this pathway.
  • TGF transforming growth factor
  • ALK activin-like kinase
  • TGF- ⁇ 1 is the prototypic member of a family of cytokines including the TGF- ⁇ s, activins, inhibins, bone morphogenetic proteins and M ⁇ llerian-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 II receptors.
  • ALK activin like kinase
  • the ALK receptors are distinguished from the type II 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 II receptor.
  • the type II receptor phosphorylates the GS domain of the type I receptor for TGF- ⁇ , ALK5, in the presence of TGF- ⁇ .
  • 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.
  • the invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate or derivative thereof:
  • 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 1 is hydrogen, C ⁇ -6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, halo, cyano, perfluoro C -6 alkyl, perfluoroC 1-6 alkoxy, -NR 5 R 6 , -(CH 2 ) n NR 5 R 6 , -O(CH 2 ) n OR 7 , -O(CH 2 ) n -Het, -O(CH 2 ) n NR 5 R 6 , -CONR 5 R 6 , -CO(CH 2 ) n NR 5 R 6 , -SO 2 R 7 , -SO 2 NR 5 R 6 ,
  • R 2 is hydrogen, C 1-6 alkyl, halo, cyano or perfluoroC 1 . 6 alkyl;
  • R 3 is hydrogen or halo;
  • R 4 is hydrogen, halo, phenyl, C 1-6 alkyl or -NR 5 R 6 ;
  • R 5 and R 6 are independently selected from hydrogen; Het; C 3-6 cycloalkyl optionally substituted by C 1-6 alkyl; or by C 1-6 alkyl optionally substituted by Het, alkoxy, cyano or -NR a R b (where R a and R b which may the same or different are hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are attached may form a 4,5 or 6-membered saturated ring); or R 5 and
  • R 6 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, -CF 3 , hydroxy, -OCF 3 , C 1-6 alkyl and C 1-6 alkoxy;
  • halo such as fluoro, chloro, bromo
  • cyano, -CF 3 cyano, -CF 3 , hydroxy, -OCF 3 , C 1-6 alkyl and C 1-6 alkoxy
  • R 7 is selected from hydrogen and C 1-6 alkyl
  • 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 C 1-6 alkyl; 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 1 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo, cyano, perfluoroC 1-6 alkyl or perfluoroC ⁇ alkoxy; R 2 is hydrogen, C 1-6 alkyl, halo, cyano or perfluoroC 1-6 alkyl; and R 3 is hydrogen or halo; then R 4 is not NH 2 ; and b) when X is N, A is pyrazole (where the ring containing X is attached to the pyrazole ring at carbon atom next
  • C 1-6 alkyl 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.
  • 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.
  • alkoxy refers to an alkyl ether radical, wherein the term “alkyl” is defined above.
  • alkoxy groups in particular include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert- butoxy.
  • perfluoroalkyl as used herein includes compounds such as trifluoromethyl.
  • perfluoroalkoxy as used herein includes compounds such as trifluoromethoxy.
  • halo or halogen are used interchangeably herein to mean radicals derived from the elements chlorine, fluorine, iodine and bromine.
  • 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.
  • heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyr
  • 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.
  • A is furan, thiophene, pyrrole, imidazole, pyridine, pyrimidine, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, imidazopyridine, pyrazole or triazole; each of which is optionally substituted by one or more of the substituents R 4 .
  • A is triazole, imidazopyridine, thiazole, imidazole or pyrazole; each of which is optionally substituted by one or more of the substituents R 4 .
  • A is imidazopyridine, thiazole or imidazole; each of which is optionally substituted by one R 4 substitutent.
  • A is imidazole optionally substituted by one R 4 substitutent.
  • X is N.
  • R 1 is C 1-6 alkyF, C 1-6 alkoxy, halo, cyano, perfluoroC 1-6 alkoxy, -NR 5 R 6 , -(CH 2 ) n NR 5 R 6 , -O(CH 2 ) n OR 7 , -O(CH 2 ) n -Het, -O(CH 2 ) n NR 5 R 6 , -CONR 5 R 6 , -SO 2 R 7 , -NR 5 SO 2 R 7 , -NR 5 COR 7 -O(CH 2 ) n CONR 5 R 6 , -NR 5 CO(CH 2 ) n NR 5 R 6 or -C(O)R 7 .
  • R 1 is C 1-6 alkoxy, halo, perfluoroC 1-6 alkoxy, -NR 5 R 6 , -(CH 2 )nNR 5 R 6 , -O(CH 2 ) n OR 7 , -O(CH 2 ) n -Het, -O(CH 2 ) n NR 5 R 6 , -CONR 5 R 6 , -SO 2 R 7 or -O(CH 2 ) n CONR 5 R 6 .
  • R 2 is hydrogen, C 1-6 alkyl or fluoro. More preferably R 2 is hydrogen or methyl. More preferably still, R 2 is methyl. Preferably R 3 is hydrogen.
  • R 2 is methyl. More preferably when X is N and R 2 is methyl, R 3 is hydrogen.
  • R 4 is hydrogen, phenyl, C 1-6 alkyl or halo. More preferably tert-butyl, isopropyl or methyl.
  • R 5 and R 6 are independently selected from hydrogen; Het (preferably tetrahydropyranyl); C 3 ⁇ cycloalkyl optionally substituted by C ⁇ -6 alkyl; or by C 1-6 alkyl optionally substituted by Het (preferably furyl), alkoxy, cyano or-NR a R b (where R a and R b which may the same or different are hydrogen or C 1-6 alkyl, or R a and R b together with the nitrogen atom to which they are attached may form a 4, 5 or 6- membered saturated ring); or R 5 and R 6 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, -CF 3 , hydroxy, -OCF 3 , C 1-4 alkyl or C 1- alkoxy.
  • halo such as fluoro, chloro, brom
  • R 5 and R 6 are independently selected from hydrogen, Het
  • R 5 and R 6 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, -CF 3 , hydroxy, -OCF 3 , C 1-4 alkyl or C 1-4 alkoxy.
  • halo such as fluoro, chloro, bromo
  • A is imidazole;
  • X is N;
  • R 1 is C 1-6 alkyl, C 1-6 alkoxy, halo, cyano, perfluoroC 1-6 alkoxy, -NR 5 R 6 , -(CH 2 ) n NR 5 R 6 ,
  • -(CH 2 ) n OR 7 -O(CH 2 )n-Het (preferably imidazolyl), -O(CH 2 ) n NR 5 R 6 , -CONR 5 R 6 , -SO 2 R 7 , -NR 5 SO 2 R 7 , -R 5 COR 7 , -O(CH 2 ) n CONR 5 R 6 , -NR 5 CO(CH 2 ) n NR 5 R 6 or . -C(O)R 7 ;
  • R 2 is hydrogen, C ⁇ alkyl or fluoro
  • R 3 is hydrogen or halo
  • R 4 is hydrogen, phenyl, C 1-6 alkyl or halo
  • R 5 and R 6 are independently selected from hydrogen, Het (preferably tetrahydropyranyl) or C 1-6 alkyl; or R 5 and R 6 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, -CF 3 , hydroxy, -OCF 3 , C 1-4 alkyl or C 1-4 alkoxy; R 7 is selected from hydrogen and C 1-6 alkyl;
  • 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 C 1-6 alkyl; and n is 1-4.
  • Compounds of formula (I) which are of special interest as agents useful in the treatment or prophylaxis of disorders characterised by the overexpression of TGF- ⁇ 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-tetf-Butyl-5- ⁇ 6-methyl ⁇ -pyridin-2-yl-1H-imidazol-4-yl)-pyridin-2-yl]-phenyl ⁇ - morpholine (Example 86);
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • 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.
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the compound of formula (I), 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 pharmaceutically acceptable salts, solvates or prodrugs.
  • Suitable pharmaceutically 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.
  • organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluen
  • 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.
  • compounds, their pharmaceutically acceptable salts, their solvates and polymorphs, defined in any aspect of the invention 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.
  • 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.
  • Preferred catalysts include tetrakis(triphenlyphosphine) palladium(O), palladium(ll) acetate, dichlorobis(triphenylphosphine) palladium(ll), tris(dibenzylideneacetone) dipalladium(O) and dichlorobis(triphenylphosphine) nickel.
  • Compounds of formula (IVA) may be deprotected under acidic conditions (preferably hydrochloric acid) to give compounds of formula (lAa).
  • Compounds of formula (lAb) 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.
  • 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.
  • Compounds of formula (IVAc), i.e. compounds of formula (IVA) (see reaction scheme 1A) where R 1 is -CH2NR 5 R 6 , may be prepared according to reaction scheme 6A by reacting compounds of formula (IXA) with R 5 R 6 NH in the presence of a reducing agent, preferably sodium triacetoxyborohydride in acetic acid, in a solvent such as dichloroethane at room temperature.
  • a reducing agent preferably sodium triacetoxyborohydride in acetic acid
  • Compounds of formula (IIA) may be prepared according to reaction scheme 7A. Firstly, 2-bromo-4-methy!pyridine 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(trimethyisilyl)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 R 2 is hydrogen.
  • a base such as sodium bis(trimethylsilyl)amide or potassium bis(trimethyisilyl)amide in tetrahydrofuran at a range of temperature from -70°C to 0°C.
  • 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 (IIB) with trimethylsilylazide at elevated temperature in a suitable solvent such as dimethylformamide.
  • 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 (lVB) 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(O), palladium(ll) acetate, dichlorobis(triphenylphosphine) palladium(ll), tris(dibenylideneacetone) dipalladium(O) and dichlorobis(triphenylphosphine) nickel.
  • 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 tetrakisftriphenlyphosphine) palladium(O) and dichlorobis(triphenylphosphine) palladium(ll).
  • Compounds of formula (VIB) may be prepared according to reaction scheme 4B where Y 1 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.
  • Compounds of formula (IIBa), i.e. compounds of formula (IIB) where R 1 is -O(CH 2 ) 2 NR 5 R 6 , 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 (IIBa) in one step.
  • compounds of formula (IIIB) may firstly be reacted with 4-hydroxy-phenyl boronic acid, followed by alkylation with R 5 R 6 N(CH 2 ) 2 CI in the presence of a base such as potassium carbonate or sodium hydride in a solvent such as dimethylformamide.
  • 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(PPh 3 ) 4 ) and a suitable base (preferably sodium carbonate) in an inert solvent (preferably 1 ,2-dimethoxyethane) at elevated temperature.
  • a suitable palladium catalysis preferably Pd(PPh 3 ) 4
  • a suitable base preferably sodium carbonate
  • Compounds of formula (ICa), i.e. compounds of formula (IC) where R 1 is -CH2NR 5 R 6 , may be prepared by reductive amination of compounds of formula (IVC) according to reaction scheme 2C.
  • Preferred reaction conditions comprise reacting (IVC) with HNR 5 R 6 in the presence of NaHB(OAc) 3 , in a suitable solvent (preferably dichloromethane) at room temperature.
  • Compounds of formula (ICb), i.e. compounds of formula (IC) where R 1 is -NR 5 R 6 may be prepared according to reaction scheme 3C by reacting compounds of formula (ICc), i.e. compounds of formula (IC) where R 1 is bromine, with HNR 5 R 6 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.
  • 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.
  • Compounds of formula (ICd), i.e. compounds of formula (IC) where R is -OCH2CH2NR 5 R 6 , 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 HNR 5 R 6 in a suitable solvent such as tetrahydrofuran at elevated temperature gives (ICd).
  • Compounds of formula (ICe), i.e. compounds of general formula (IC) where R 1 is -CONR 5 R 6 , 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 HNR 5 R 6 in the presence of HOBT, EDCI and a suitable base such as triethylamine in a suitable solvent such as dimethylformamide at room temperature.
  • Compounds of formula (ICg), i.e. compounds of general formula (IC) where R 1 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.
  • a base such as triethylamine
  • a suitable solvent such as dichloromethane
  • compounds of formula (IC) may also be prepared by introducing R 1 before formation of the imidazopyridine.
  • compounds of formula (ICi) i.e. compounds of formula (IC) where R 1 is morpholine, X is N and R 3 is H may be prepared according to reaction scheme 7C.
  • Compounds of formula (IIC) may be prepared in two steps according to reaction scheme 8C.
  • Compounds of formula (VI IC) 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.
  • 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).
  • 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.
  • a suitable base such as sodium bis(trimethylsilyl)amide
  • a suitable solvent such as tetrahydrofuran at -78 °C to -30°C.
  • Compounds of formula (ID) may be prepared according to Scheme 1D.
  • Compounds of formula (IID) may be treated with sodium nitrite in HCI to give compounds of formula (MID).
  • Compounds of formula (HID) 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.
  • Suitable bases include sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide.
  • Suitable catalysts include tetrakis(triphenlyphosphine) palladium(O), palladium(ll) acetate, dichlorobis(triphenylphosphine) palladium(ll), tris(dibenylideneacetone) dipalladium(O) and dichlorobis(triphenylphosphine) nickel.
  • Compounds of formula (IDb), i.e. compounds of formula (ID) where X is N, R 1 is - NR 5 R 6 and R 3 is hydrogen, may be prepared according to reaction scheme 3D by reacting compounds of formula (VID) with HNR 5 R 6 in the presence of a catalyst system preferably tris(dibenzylidene acetone)dipalladium(O) and 2,2'- bis(diphenylphosphino)-1,1 '-binaphthyl (Binap) in potassium tert-butoxide in a suitable solvent such as toluene at elevated temperature.
  • a catalyst system preferably tris(dibenzylidene acetone)dipalladium(O) and 2,2'- bis(diphenylphosphino)-1,1 '-binaphthyl (Binap) in potassium tert-butoxide in a suitable solvent such as toluene at elevated temperature.
  • Preferred reaction conditions comprise treating the intermediate carboxylic acid with HNR 5 R 6 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.
  • HBT hydroxybenzotriazole
  • EDCI 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
  • a suitable base such as triethylamine
  • Compounds of formula (lEa), i.e. compounds of general formula (IE) where A is S, B is N and R 4 is NH 2 , may be prepared by reacting compounds of formula (ME) 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).
  • a suitable polymer-supported bromine reagent such as polymer-supported pyridinium perbromide
  • Compounds of formula (HE) 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.
  • compounds of formula (HE) 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-
  • VIE VIE
  • VIIE VIIE
  • HE HE
  • HIE Compounds of formula (HIE) 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.
  • compounds of formula (HIE) 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.
  • a suitable base such as cesium carbonate
  • a suitable solvent such as tetrahydrofuran and isopropanol
  • 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.
  • Compounds of general formula (IE) may also be prepared using solid supported chemistry.
  • Compounds of formula (lEc), i.e. compounds of general formula (I) where A is S, B is N, R is -OR (where R is for example -(CH 2 ) n -Het or -CH 2 CONR 5 R 6 ) and R 4 is NH 2 , may be prepared from solid supported compounds of formula (XllE) 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 (XllE) 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.
  • 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.
  • 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).
  • 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.
  • a compound library comprising at least 2 compounds of the invention.
  • TGF- ⁇ 1 Activation of the TGF- ⁇ 1 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- ⁇ 1 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- ⁇ 1 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.
  • TGF- ⁇ 1 has been implicated in many renal fibrotic disorders. Border W.A., et al, N. Engl. J. Med., 1994; 331(19), 1286-92. TGF- ⁇ 1 is elevated in acute and chronic glomerulonephritis Yoshioka K., et al, Lab.
  • TGF- ⁇ 1 normal glomeruli, mesangial cells and non-renal cells can be induced to produce extracellular-matrix protein and inhibit protease activity by exogenous TGF- ⁇ 1 in vitro.
  • TGF- ⁇ 1 and its receptors are increased in injured blood vessels and are indicated in neointima formation following balloon angioplasty Saltis J., et al, Clin. Exp. Pharmacol. Physiol., 1996; 23(3), 193-200.
  • TGF- ⁇ 1 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 restenos ⁇ s.
  • SMC smooth muscle cell
  • TGF- ⁇ receptor ALK5 correlated with total cholesterol (P ⁇ 0.001) Blann A.D., et al, Atherosclerosis, 1996; 120(1-2), 221-6.
  • SMC derived from human atherosclerotic lesions have an increased ALK5/TGF- ⁇ type II receptor ratio. Because TGF- ⁇ 1 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- ⁇ 1 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- ⁇ -dependent mechanism. Therefore, inhibiting the action of TGF- ⁇ 1 on ALK5 is also indicated in atherosclerosis and restenosis. TGF- ⁇ is also indicated in wound repair. Neutralizing antibodies to TGF- ⁇ 1 have been used in a number of models to illustrate that inhibition of TGF- ⁇ 1 signalling is beneficial in restoring function after injury by limiting excessive scar formation during the healing process.
  • TGF- ⁇ 1 and TGF- ⁇ 2 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.
  • TGF- ⁇ 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.
  • TGF- ⁇ 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- ⁇ 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 mRNA levels for cytokines and integrins in hairless mouse skin- modulation by topical tretinoin", Archives if Dermatological Research, 290(3): 137-144, 1998 Mar.)
  • 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.
  • 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,
  • the disease or condition mediated by ALK-5 inhibition is fibrosis.
  • fibrosis Preferably kidney fibrosis.
  • 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 II receptor antagonists for kidney diseases.
  • other therapeutic agents for example antiviral agents for liver diseases, or in combination with ACE inhibitors or angiotensin II 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.
  • 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.
  • 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.
  • 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 emollients 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.
  • suitable 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.
  • 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
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • 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.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised 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.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • 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.
  • 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.
  • composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent
  • 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
  • HBV hepatitis B virus
  • HCV
  • a combination of a compound of the invention with an ACE inhibitor or an angiotensin II receptor antagonist iv) a combination of a compound of the invention with an ACE inhibitor or an angiotensin II receptor antagonist.
  • 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, benzof ⁇ ran, indole, isoindole, indazole, imidazopyridine, quinazoline, quinoline, isoquinoline and triazole;
  • R 1 is selected from H, C -6 alkyl, C 1-6 alkenyl, C ⁇ alkoxy, halo, cyano, perfluoro C. ⁇ alkyl, perfluoroC 1-6 alkoxy, -NR 5 R 6 , -(CH 2 ) n NR 5 R 6 , -O(CH 2 ) n OR 5 , -O(CH 2 ) n NR 5 R 6 , -CONR 5 R 6 , -CO(CH 2 ) n NR 5 R 6 , -SO 2 R 5 , -SO 2 NR 5 R 6 ,
  • R 2 is selected from H, C ⁇ alkyl, halo, CN or perfluoroC 1-6 alkyl;
  • R 3 is selected from H or halo
  • R 4 is selected from H, halo, C 1-6 alkyl or -NR 5 R 6 ;
  • R 5 and R 6 are independently selected from H or C ⁇ alkyl; or R 5 R 6 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, -CF 3 , - OH, -OCF 3 , C 1-6 alkyl and C 1-6 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 1 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halo,
  • Step 1 Rink Argopore resin (12g, 0.58 mmol/g substitution) was placed into a peptide vessel and washed with CH 2 CI 2 (3x100mL). The resin was then treated for 10min with a solution of piperidine 20% in DMF (3x40mL). After washing with DMF (3x100mL) and CH 2 CI 2 (3x100mL), the resin was treated with a solution of Fmoc- NCS (0.2M) in CH 2 CI 2 (170mL) under argon at room temperature for 1h.
  • 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.
  • 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), CH 2 CI 2 (3x100mL) and dried under a stream of nitrogen overnight.
  • 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 CH 2 CI 2 to give the title compound which was characterised by LC-MS (purity>96%); [APCI MS] m/z 347/ 349/ 350 (MH+).
  • Example 8 4-[3-(6-methylpyridin-2-yl)-1 H-pyrazol-4-yl]-2-f4-(pyrrolidin-1- ylmethvPphenv ⁇ pyridine
  • Step 1 To a solution of intermediate 96 (0.633g, 1mmoI) in toluene (10ml) were added morpholine (0.348g, 4mmol, 4eq), Pd 2 (dba) 3 (0.045g, 0.049mmol, 0.05eq), binap (0.062g, 0.1 mmol, 0.1 eq) 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 Na 2 SO 4 .
  • Step 2 4-(4- ⁇ 4-[3-(6-Methyl-2-pyridinyI)-1-(triphenylmethyl)-1 H-pyrazol-4-yl]-2- pyridinyl ⁇ phenyl)morpholine was treated with a mixture of MeOH/HCI 1N (3 :2, 50ml) under reflux for 2 hours. The reaction mixture was poured into water and extracted with CH 2 CI 2 . The aqueous phase was basified with NaOH (1N) and extracted with CH 2 CI 2 .
  • Example 75 7-methyl-2-(6-methyl-pyridin-2-yl)-3-(2-r4-((1-methyl-imidazol-4- yl)methyloxy)phenyl1-pyridin-4-yl)-imidazoM,2-alpyridine
  • Example 77 7-methyl-2-(6-methyl-pyridin-2-yl)-3-l2- r4(aminocarbonylmethyloxy)phenvn-pyridin-4-yl -imidazo[1,2-alpyridine
  • Example 78 8-methyl-2-(6-methyl-pyridin-2-yl)-3-(2-r4- (aminocarbonylmethylo ⁇ yl)phenvn-pyridin-4-yl)-imidazo[1,2-alpyridine
  • Example 80 7-methyl-2-(6-methyl-pyridin-2-yl)-3-(2-r4-(morpholin-4-yl)phenv ⁇ - ⁇ pyridin-4-yl)-imidazo[1,2-alPyridine
  • intermediate 120 (0,9 ⁇ g, 2. ⁇ 6mmol) in a mixture of DME (30ml) and water (1 ⁇ ml) were added intermediate 33 (0.93g, 2.81 mmol), tetrakis(triphenylphosphine) palladium(O) (0.1g, 0.086mmol) and Na 2 CO 3 (solution 2M, 5ml) and the mixture was heated under reflux overnight and then poured into water. After extraction with CH CI 2 , the organic phase was dried over Na 2 SO 4 , and concentrated under reduced pressure. The residue was recrystallised from EtOAc to afford the title compound as yellow crystals (0.77g, 56.36%); m.p. 174°C ; TOF MS ES + exact mass calculated for C 3 oH 33 N 5 O 2 : 496.2712(MH+). Found : 496.2662 (MH+).
  • Example 106 4-(2-tert-Butyl-5-f6-methyl)-pyridin-2-yl-1H-imidazol-4-vn-2-r4-(1- methyl-1H-imidazol-4-ylmethoxy)-phenyll-pyridine
  • intermediate 126 (0.49g, 1.27mmol) in DMF (20ml) was added portionwise sodium hydride (60% in mineral oil, 0.162g, 3.81 mmol) 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 Na 2 SO 4 and concentrated under reduced pressure.
  • Example 108 4-(2-tert-Butyl- ⁇ -f6-methyl -pyridin-2-yl-1 H-imidazol-4-yl)-2-f4-(2- Pyrrolidin-1-yl-ethoxy)-phenvn-pyridine
  • example 83 (0.26g , 0.67mmol) in CH 2 CI 2 (40ml) was added boron tribromide (2.1ml, 2.1 mmol, 3.2eq, solution 1 in CH 2 CI 2 ). 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 CH 2 CI . The aqueous phase was acidified with HCI (1 N) and extracted with CH 2 CI 2 .
  • Example 110 4- ⁇ 2-Phenyl-5-[6-methvn-pyridin-2-yl-1 H-imidazol-4-yl)-2-(4- methanesulfonyl-phenvD-pyridine
  • Step 1 Intermediate 128 supported on resin (1g) was weighed out into a peptide vessel. Then 4-formylphenylboronic acid (870mg, 5.8mmol, 10eq), Pd(PPh 3 ) (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 (3x1 OmL), water (3x1 OmL), EtOH (3x1 OmL) and CH 2 CI 2 (3x1 OmL).
  • Step 2 The product from step 1 was placed into a peptide vessel with a solution of NHR 5 R 6 ( ⁇ . ⁇ mmol, 10eq) in trimethylorthoformate (5.4mL). Then a solution of sodium cyanoborohydride (0.2M) in THF (5.4mL) with acetic acid (110 ⁇ L) 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 (3x1 OmL), EtOH (3x1 OmL) and CH 2 CI 2 (3x1 OmL). The resin was treated with a solution of 20% TFA in CH 2 CI 2 and the solvent was removed under reduced pressure. Purification of the residue by HPLC chromatography (water/ acetonitrile gradient) gave the products of formula (lEh) shown in Table 22.
  • 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(PPh 3 ) 4 (134 mg, 0.16mmol, 0.2eq), and sodium carbonate (615mg, ⁇ . ⁇ mmol, 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 (3x1 OmL), water (3x1 OmL), EtOH (3x1 OmL) and CH 2 CI 2 (3x10mL).
  • Step 2 The product from step 1 was placed into a peptide vessel with a solution of R-CI ( ⁇ . ⁇ mmol, 10eq) in DMSO (10mL). Then a solution of potassium carbonate (802mg, ⁇ . ⁇ mmol, 10eq) in DMSO ( ⁇ mL) was added. The reaction vessel was purged with argon for ⁇ min and the mixture was stirred at 90°C for 16h. The resin was washed with DMF (3x1 OmL), EtOH (3x1 OmL) and CH 2 Ci 2 (3x1 OmL). The resin was treated with a solution of 20% TFA in CH 2 CI 2 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.
  • Step 1 Intermediate 129 supported on resin (1g) was weighed out into a peptide vessel. Then 4-methoxycarbonylphenylboronic acid (1.05g, ⁇ . ⁇ mmol, 10eq), Pd(PPh 3 ) (0.134 g, 0.16mmol, 0.2eq), and a aqueous solution of sodium carbonate (0.615g, ⁇ . ⁇ mmol, 2M) were added and suspended in toluene/EtOH ( ⁇ :2, 20mL). The reaction vessel was purged with argon for ⁇ min, and the mixture was stirred at 90°C for 16h.
  • the biological activity of the compounds of the invention may be assessed using the following assays: 106
  • the potential for compounds of the invention to inhibit TGF- ⁇ signalling 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- ⁇ 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- ⁇ .
  • cells were transfected with a second luciferase (Renilla) gene which was not driven by a TGF- ⁇ 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 ⁇ l of serum- containing medium. These plates were placed in a cell incubator. 16 to 24 hours later (Day 2), cell-incubation procedure was launched. Cells were incubated with TGF- ⁇ and a candidate compound at concentrations in the range 50 nM to 10 ⁇ M (final concentration of DMSO 1%). The final concentration of TGF- ⁇ (rhTGF ⁇ -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- ⁇ . The final volume of the test reaction was 150 ⁇ l. 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 ⁇ wells in which the cells were incubated in the presence of TGF- ⁇ , without a candidate compound. Column 11 was used to determine the 'reference TGF- ⁇ induced firefly luciferase value' against which values measured in the test wells (to quantify inhibitory activity) were compared. In wells A12 to D12, cells were grown in medium without TGF- ⁇ . 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- ⁇ and 600 ⁇ M CPO (Cyclopentenone, Sigma), a cell toxic compound. The toxicity was revealed by decreased firefly and renilla luciferase activities (around 60 % of those obtained in column 11).
  • 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 ⁇ l 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 ⁇ l of luciferase assay reagent and 60 ⁇ l 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- ⁇ only) was considered to represent 100% and values obtained in wells A12 to D12 (cells in medium alone) gave a basal level (0%).
  • a concentration response curve was constructed from which an IC 50 value was determined graphically.
  • Kinase inhibitor compounds conjugated to fluorophores can be used as fluorescent ligands to monitor ATP competitive binding of other compounds to a given kinase.
  • This protocol details the use of a rhodamine green-labelled ligand for assays using recombinant GST-ALK5 (residues 198-603).
  • Assay buffer components 62.5 mM Hepes pH 7.5 (Sigma H-4034), 1 mM DTT (Sigma D-0632), 12.5 mM MgCI 2 (Sigma M-9272), 1.26 mM CHAPS (Sigma C-3023).
  • 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 ⁇ l was added to each well of the previously prepared assay plates.
  • a control compound (1 ⁇ l) 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 ⁇ l DMSO in column 12, rows A-D) and the low controls (1 ⁇ l of control compound in column 12, rows E-H). An IC 50 value was then calculated for each compound
  • Example 86 4- ⁇ 4-[4-(2-tett-Butyl-5- ⁇ 6-methyl ⁇ -pyridin-2-yl-1H-imidazol-4-yl)-pyridin-2-yl]-phenyl ⁇ - morpholine (Example 86) showed an ALK5 receptor modulator activity of 34 nM and TGF- ⁇ cellular activity of 183 nM.
  • N-(tetrahydropyran-4-yl)-4-(4- ⁇ 2-isopropyl- ⁇ -[6-methyl-pyridin-2-yl]-1 H-imidazol-4-yl ⁇ - pyridin-2-yl)-benzamide (Example 96) showed an ALK ⁇ receptor modulator activity of 26 nM and TGF- ⁇ cellular activity of ⁇ 14 nM.

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Abstract

This invention relates to novel 2-phenylpyridin-4-yl heterocyclyl derivatives which are inhibitors of the transforming growth factor, ('TGF')-ß signalling pathway, in particular, the phosphorylation of smad2 or smad3 by the TGF-β type I or activin-like kinase ('ALK')-5 receptor, methods for their preparation and their use in medicine, specifically in the treatment and prevention of a disease state mediated by this pathway.

Description

2-PHENY PYRIDIN-4-Y DERIVATIVES AS ALK5 INHIBITORS
This invention relates to novel 2-phenylpyridin-4-yl heterocyclyl derivatives which are inhibitors of the transforming growth factor, ("TGF")-β signalling pathway, in particular, the phosphorylation of smad2 or smad3 by the TGF-β type I or activin-like kinase ("ALK")-5 receptor, methods for their preparation and their use in medicine, specifically in the treatment and prevention of a disease state mediated by this pathway.
TGF-β1 is the prototypic member of a family of cytokines including the TGF-βs, activins, inhibins, bone morphogenetic proteins and Mϋllerian-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 II receptors. The ALK receptors are distinguished from the type II 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 II receptor. Several studies have shown that TGF-β signalling requires both the ALK and type II receptors. Specifically, the type II receptor phosphorylates the GS domain of the type I receptor for TGF-β, ALK5, in the presence of TGF-β. 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 pharmaceutically acceptable salt, solvate or derivative thereof:
Figure imgf000003_0001
(I) 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;
R1 is hydrogen, Cι-6alkyl, C1-6alkenyl, C1-6alkoxy, halo, cyano, perfluoro C -6alkyl, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR7, -O(CH2)n-Het, -O(CH2)nNR5R6, -CONR5R6, -CO(CH2)nNR5R6, -SO2R7, -SO2NR5R6,
-NR5SO2R7, -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 C1-6alkyl; 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; R1 is hydrogen, C1-6alkyl, C1-6alkoxy, halo, cyano, perfluoroC1-6alkyl or perfluoroC^alkoxy; 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 pyrazole (where the ring containing X is attached to the pyrazole ring at carbon atom next to a pyrazole 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, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, 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, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, imidazopyridine, pyrazole 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 pyrazole; 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 C1-6alkyF, C1-6alkoxy, halo, cyano, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR7, -O(CH2)n-Het, -O(CH2)nNR5R6, -CONR5R6, -SO2R7, -NR5SO2R7, -NR5COR7 -O(CH2)nCONR5R6, -NR5CO(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, -SO2R7 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, C1-6alkyl or halo. More preferably tert-butyl, isopropyl or methyl.
Preferably R5 and R6 are independently selected from hydrogen; Het (preferably tetrahydropyranyl); C3^cycloalkyl optionally substituted by Cι-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- alkoxy.
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 C1-4alkoxy.
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)R7;
R2 is hydrogen, C^alkyl 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 R5and 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; 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 C1-6alkyl; and n is 1-4.
Compounds of formula (I) which are of special interest as agents useful in the treatment or prophylaxis of disorders characterised by the overexpression of TGF-β 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-tetf-Butyl-5-{6-methyl}-pyridin-2-yl-1H-imidazol-4-yl)-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-lsopropyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-pyridin-2-yl}-benzyl)- dimethyl-amine (Example 105); 4-(4-{4-[2-lsopropyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-pyridin-2-yl}-benzyl)- morpholine (Example 104); N-(tetrahydropyran-4-yl)-4-(4-{2-te/t-Butyl-5-[6-methyl-pyridin-2-yl]-1H-imidazol-4-yl}- pyridin-2-yl)-benzamide (Example 81);
(4-{4-[2-tett-Butyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-pyridin-2-yl}-benzyl)- pyrrolidine (Example 103); 4-(2-te/t-Butyl-5-{6-methyl}-pyridin-2-yl-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-1H-imidazol-4-yl)-pyridin-2-yl]-phenyl}- morpholine (Example 98); and pharmaceutically 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 pharmaceutically acceptable salt, solvate, ester or amide, or salt or solvate of such ester or amide, of the compound of formula (I), 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 pharmaceutically acceptable salts, solvates or prodrugs.
Suitable pharmaceutically 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 R1 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), (III), (IV) etc. Subsets of these general formulae are defined as (la), (lb), (lc) etc .... (IVa), (IVb), (IVc) etc.
Pyrazole Derivatives (IA) Compounds of formula (lAa) may be prepared according to reaction scheme 1 A from compounds of formula (IIA). Compounds of formula (IIA) are reacted with boron- containing compounds of formula (IMA) 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(O), palladium(ll) acetate, dichlorobis(triphenylphosphine) palladium(ll), tris(dibenzylideneacetone) dipalladium(O) 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
Figure imgf000010_0001
Figure imgf000010_0002
(lAa)
Compounds of formula (lAb) 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
Figure imgf000011_0001
(VA) (lAb)
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
Figure imgf000011_0002
(VIA)
Figure imgf000011_0003
Compounds of formula (IVAa), i.e. compounds of formula (IVA) (see reaction scheme 1A) where R1 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
Figure imgf000012_0001
(VIIA) (IVAa)
Compounds of formula (IVAb), i.e. compounds of formula (IVA) (see reaction scheme 1A) where R1 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
Figure imgf000012_0002
Compounds of formula (IVAc), i.e. compounds of formula (IVA) (see reaction scheme 1A) where R1 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
Figure imgf000013_0001
(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-methy!pyridine 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(trimethyisilyl)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
Figure imgf000014_0001
(XA) (XIA)
Figure imgf000014_0002
(XIIA) (IIA)
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 (IIB) with trimethylsilylazide at elevated temperature in a suitable solvent such as dimethylformamide.
Scheme 1B
Figure imgf000014_0003
(IIB) (IB)
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 (lVB) 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(O), palladium(ll) acetate, dichlorobis(triphenylphosphine) palladium(ll), tris(dibenylideneacetone) dipalladium(O) and dichlorobis(triphenylphosphine) nickel.
Scheme 2B
Figure imgf000015_0001
(IIIB) (IVB)
(IIB)
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 tetrakisftriphenlyphosphine) palladium(O) and dichlorobis(triphenylphosphine) palladium(ll). Scheme 3B
Figure imgf000016_0001
(VB) (VIB) (IIIB)
Compounds of formula (VIB) may be prepared according to reaction scheme 4B where Y1 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
Figure imgf000016_0002
(VIIB) (VIIIB) (VIB)
Compounds of formula (IIBa), i.e. compounds of formula (IIB) where R1 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 (IIBa) 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
Figure imgf000017_0001
("IB) (IIBa)
Compounds of formula (IIBb), i.e. compounds of general formula (IIB) where R1 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
Figure imgf000017_0002
(IIIB) (XB) (IIBb) 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
Figure imgf000018_0001
Compounds of formula (ICa), i.e. compounds of formula (IC) where R1 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
Figure imgf000019_0001
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 R1 is -NR5R6, may be prepared according to reaction scheme 3C by reacting compounds of formula (ICc), i.e. compounds of formula (IC) where R1 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
Figure imgf000020_0001
(ICc) (ICb)
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
Figure imgf000020_0002
(VC) (ICd)
Compounds of formula (ICe), i.e. compounds of general formula (IC) where R1 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
Figure imgf000021_0001
(IVC) (ICe)
Compounds of formula (ICg), i.e. compounds of general formula (IC) where R1 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 1. remove acetyl
2. sulfonylation
Figure imgf000022_0002
(ICh) (ICg)
It will be apparent to the skilled person that compounds of formula (IC) may also be prepared by introducing R1 before formation of the imidazopyridine. For instance, compounds of formula (ICi), i.e. compounds of formula (IC) where R1 is morpholine, X is N and R3 is H may be prepared according to reaction scheme 7C.
Scheme 7C
Figure imgf000023_0001
(ICi)
Compounds of formula (IIC) (see Scheme 1C) may be prepared in two steps according to reaction scheme 8C. Compounds of formula (VI IC) 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
Figure imgf000024_0001
(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.
Figure imgf000024_0002
(IXC) (VIIC)
Imidazole Derivatives (ID)
Compounds of formula (ID) may be prepared according to Scheme 1D. Compounds of formula (IID) may be treated with sodium nitrite in HCI to give compounds of formula (MID). Compounds of formula (HID) 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(O), palladium(ll) acetate, dichlorobis(triphenylphosphine) palladium(ll), tris(dibenylideneacetone) dipalladium(O) and dichlorobis(triphenylphosphine) nickel.
Scheme 1D
Figure imgf000025_0001
()ID) (HID)
Figure imgf000025_0002
Compounds of formula (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
Figure imgf000025_0003
(VD) (IDa)
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 HNR5R6 in the presence of a catalyst system preferably tris(dibenzylidene acetone)dipalladium(O) 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
Figure imgf000026_0001
(VID) (IDb)
Compounds of formula (IDc), i.e. compounds of formula (ID) where X is N, R1 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
Figure imgf000026_0002
(VIID) (IDc)
Compounds of formula (IDd), i.e. compounds of formula (ID) where X is N, R1 is -OCH2-Het and R3 is hydrogen, may be prepared according to reaction scheme 5D by reacting compounds of formula (VIHD) 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
Figure imgf000027_0001
(VIIID) (IDd)
Compounds of formula (IDe), i.e. compounds of general formula (ID) where X is N, R1 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
Figure imgf000027_0002
Compounds of formula (ID) where X is N and R1 is -NHSO2CF3 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 7 D
Figure imgf000028_0001
Aminothiazole Deriviatives (IE)
Compounds of formula (lEa), 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 (ME) 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 1E
Figure imgf000028_0002
(ME) (lEa)
Compounds of formula (lEb), 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 (HIE) under analogous conditions to reaction scheme 1 E (see reaction scheme 2E).
Scheme 2E
Figure imgf000029_0001
Compounds of formula (HE) 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
Figure imgf000029_0002
(IVE) (HE)
Alternatively compounds of formula (HE) 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
Figure imgf000030_0001
(VIE) (VIIE) (HE)
Compounds of formula (HIE) 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
Figure imgf000030_0002
(VIIIE) (HIE)
Alternatively compounds of formula (HIE) 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
Figure imgf000031_0001
(IXE) (HIE)
Compounds of formula (VIIIEa), i.e. compounds of general formula (VIIIE) (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
Figure imgf000031_0002
(VIIIEa)
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
Figure imgf000032_0001
(XIE) (IXE)
Compounds of general formula (IE) may also be prepared using solid supported chemistry.
Compounds of formula (lEc), 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 (XllE) 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 (XllE) 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
Figure imgf000032_0002
(XllE) (lEc)
Compounds of formula (lEd), i.e. compounds of general formula (IE) where A is S, B is N, R1 is -CH2NR5R6 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 (lEd).
Scheme 10E
Figure imgf000033_0001
Compounds of formula (lEe), 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 11E. 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 (lEe).
Scheme 11 E
Figure imgf000034_0001
Compounds of formula (XllE), (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
Figure imgf000034_0002
(XVE) (XllE, XIIIE, XIVE)
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
DMF, r.t CH2CI2, r.t
0τ *JHFmoc *- ) 2 - @> fl NHFmoc
Rink resin (0.58 mmol /g)
Figure imgf000035_0001
(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-β1 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-β1 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-β1 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-β 1 has been implicated in many renal fibrotic disorders. Border W.A., et al, N. Engl. J. Med., 1994; 331(19), 1286-92. TGF-β1 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-β1 expression coincide with the production of extracellular matrix. Three lines of evidence suggest a causal relationship between TGF-β1 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-β1 in vitro. Second, neutralizing anti-bodies against TGF-β1 can prevent the accumulation of extracellular matrix in nephritic rats. Third, TGF-β1 transgenic mice or in vivo transfection of the TGF-β1 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-β1 activity is indicated as a therapeutic intervention in chronic renal disease.
TGF-β 1 and its receptors are increased in injured blood vessels and are indicated in neointima formation following balloon angioplasty Saltis J., et al, Clin. Exp. Pharmacol. Physiol., 1996; 23(3), 193-200. In addition TGF-β1 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 restenosϊs. Moreover, in multivariate analysis of the endothelial cell products against total cholesterol, TGF-β 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-β type II receptor ratio. Because TGF-β1 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-β1 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-β-dependent mechanism. Therefore, inhibiting the action of TGF-β1 on ALK5 is also indicated in atherosclerosis and restenosis. TGF-β is also indicated in wound repair. Neutralizing antibodies to TGF-β1 have been used in a number of models to illustrate that inhibition of TGF-β1 signalling is beneficial in restoring function after injury by limiting excessive scar formation during the healing process. For example, neutralizing antibodies to TGF-β1 and TGF-β2 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-β 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-β would be beneficial in many tissues and suggest that any disease with chronic elevation of TGF-β would benefit by inhibiting smad2 and smad3 signalling pathways.
TGF-β 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-β 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 mRNA 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 II 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 emollients 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 glyceride.
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 lyophilised 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 pharmaceutically 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 II 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, benzofύran, indole, isoindole, indazole, imidazopyridine, quinazoline, quinoline, isoquinoline and triazole;
R1 is selected from H, C -6alkyl, C1-6alkenyl, C^alkoxy, halo, cyano, perfluoro C.βalkyl, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR5, -O(CH2)nNR5R6, -CONR5R6, -CO(CH2)nNR5R6, -SO2R5, -SO2NR5R6,
-NR5SO2R5 and -NR5COR6;
R2 is selected from H, C^alkyl, halo, CN or perfluoroC1-6alkyl;
R3 is selected from H or halo;
R4 is selected from H, halo, C1-6alkyl or -NR5R6; R5 and R6 are independently selected from H or C^alkyl; 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, C1-6 alkyl and C1-6 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; R1 is hydrogen, C1-6alkyl, C1-6alkoxy, halo, cyano, perfluoroC1-6alkyl or perfluoroC1-5alkoxy; R2 is hydrogen, C1-6alkyl, halo, cyano or perfluoroCι-6alkyl; and R3 is hydrogen or halo; then R4 is not NH2; and b) when X is N, A is pyrazole (where the ring containing X is attached to the pyrazole ring at carbon atom next to a pyrazole 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
Cul 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
KMnO4 potassium permanganate
LiAIH4 lithium aluminium hydride
MeCN acetonitrile
MeOH methanol
Na2CO3 sodium carbonate
NaH sodium hydride
NaHB(OAc)3 sodium triacetoxyborohydride
NaHCOs 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 Na2SO . The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (eluent : CH2CI2 then CH2CI2/ CH3OH 99 :1) to give the title compound as an orange solid (9.5g, 63%); H NMR (300 MHz, CDCI3) δ ppm: 7.99 (1H, d), 7.68 (1H, s), 7.52 (1H, d); (GC-MS) m/z : 239.
Intermediate 2: 2-Methyl-6-trimethylsilanylethvnyl-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(O) (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, CDCI3) δ 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-Ethvnyl-6-methyl-pyridine
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; 1H NMR (300 MHz, CDCI3) δ ppm: 7.45-7.34 (m, 1H), 7.14 (d, 1H), 6.98 (d, 1H), 2.97 (s, 1H), 2.40 (s, 3H).
Intermediate 4: 6-Methyl-2-r(2-chloro-pyridin-4-vO-ethvnvπ-PVridine
Figure imgf000044_0001
To a solution of intermediate 1 (1.85g, 7.74mmol) in dry THF (40mL) were added under nitrogen TMEDA (20mL) and intermediate 3 (1.1 eq, 1g, 8.51 mmol). The resulting mixture was degassed with nitrogen for ten mins, tetrakis(triphenlyphosphine)palladium(0) (0.537g, 0.464mmol) 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 Na2SO 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%); 1H NMR (300 MHz, CDCI3) δ 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 s: 2-f(2-(4-methylsulfonylphenyl)-pyridin-4-yl)-ethvnyll-6-methyl-pyridine
Figure imgf000045_0001
A solution of intermediate 4 (1g, 4.37mmol), 4-(methylsulfonyl)phenyl boronic acid (1.14g, 5.7 mmol), tetrakis(triphenlyphosphine) palladium(O) (0.118 g, O.lmmol) 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 hydrolysed 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, CDCI3) δ 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 (IIBc) were prepared by methods analogous to that described for intermediate 5 using the appropriate boronic acid derivative (see Table 1).
Figure imgf000046_0001
(IIBc)
Table 1
Figure imgf000046_0003
Intermediate 15: 4-(4-[4-(6-Methyl-pyridin-2-ylethynyl)-pyridin-2-yn-benzyl)- morpholine
Figure imgf000046_0002
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 CH2CI2. 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-dimethyl-2-[(4-(4-(6-methyl-pyridin-2-yl-ethvnyl)-pyridin-2- yltohenvDoxylethanamine
Figure imgf000047_0001
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 1N. 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%); 1H NMR (300 MHz, CDCI3) .5 ppm: 7.84 (m, 2H), 7.22 (m, 1H), 4.37 (q, 2H), 1.38 (t, 3H).
Intermediate 19: 6-methyl-pyridine-2-carboxylic acid ethyl ester 6-MethyI-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%); 1H NMR (300 MHz, CDCI3) δ 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-carboxylic acid To a solution of 2-fluoro-6-methyl-pyridine (2.5g , 22.5 mmol) in water (170 ml) was added portionwise KMnO4 (2g, 12.65 mmol) and the mixture was heated to reflux. Then KMnO4 (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 Na2SO 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-methyl-4-hvdroxymethyl-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 1M 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%); 1H NMR (300 MHz, CDCI3) jδ ppm: 7.25 (s, 1H), 6.7 (s, 1H), 5.25 (m, 1H), 4.4 (s, 2H), 3.45 (s, 3H).
Intermediate 23: 1-methyl-4-chloromethyl-imidazole hvdrochloride To a solution of intermediate 22 (5g, 44.64 mmol) in CH2CI2 (10 ml) at 0°C was added dropwise thionyl chloride (50 ml) 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%); 1H NMR (300 MHz, d6-DMSO) δ ppm: 9.25 (s, 1H), 7.8 (s, 1H), 4.95 (s, 2H), 3.9 (s, 3H).
Intermediate 24: 4-(morpholin-4-yl)-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-ethyl-4-(4-bromophenyl)-piperazine
To a solution of 1-ethyl-4-phenylpiperazine (18g, 95mmol) in ethanol (600ml) cooled in an iced bath, was added dropwise bromine (5.1ml, 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 Na2SO 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-(pyrrolidin-1-yl)-ethoxy)-iodobenzene
Figure imgf000049_0001
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%); 1H NMR (300MHz, CDCI3, ppm) δ: 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-r4-(4.4.5.5-tetramethyl-f1.3.21-dioxaborolan-2-yl)-phenvπ- morpholine
Figure imgf000049_0002
To a solution of intermediate 24 (20g, 82.64 mmol) in dioxane (200ml) was added 4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (13.2 ml, 99.17 mmol), dichloro bis(triphenylphosphine) palladium(ll) (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 CH2CI2l 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)phenyri- piperazine
Figure imgf000050_0001
To a solution of intermediate 25 (3g, 11 mmol) in dioxane (100ml) was added 4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (1.8ml, 12mmol) , dichlorobis(triphenylphosphine)palladium(ll) (0.392g, 0.57mmoi) 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-r2-(pyrrolidin-1-yl)-ethoxy1-4-r4,4.5.5-tetramethyl-1 ,3,2- dioxaborolan-2-vn-benzene
Figure imgf000050_0002
Intermediate 26 (8g, 25.24mmol) and 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (4ml, 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-faminocarbonylmethyloxy1-4-r4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-vn-benzene
Figure imgf000051_0001
To a solution of 4-[4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl]-phenol (5g, 22.7mmol) in acetone (80ml) 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-methyl-imidazol-4-yl)-methyloxy1-4-r4.4.5,5-tetramethyl-1 ,3,2- dioxaborolan-2-vn-benzene
Figure imgf000051_0002
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%); 1H NMR (300MHz, CDCI3, ppm) δ :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-r(morpholin-4-yl)carbonylmethyloxy1-4-r4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-vn-benzene
Figure imgf000051_0003
To a solution of 4-[4,4,5,5-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 Na2SO 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-tetramethyl-H ,3,21dioxaborolan-2-yl)-N-(tetrahvdro-pyran- 4-yl)-benzamide
Figure imgf000052_0001
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, CDCI3, ppm) δ : 7.85 (d, 2H), 7.72 (d, 2H), 5.98 (m, 1H), 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-tetramethyl-[1,3,2ldioxaborolan-2-yl)-phenvn- methanesulfonamide
Figure imgf000052_0002
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline (Aldrich, 5g, 22.8 mmol) in CH2CI2 (20ml) was added NaHCO3 (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 Na2SO , and concentrated under reduced pressure. Crystallisation from diethyl ether gave the title compound as a white powder (2.52g, 37%); 1H NMR (300 MHz, CDCI3, ppm) δ : 7.78 (d, 2H), 7.18 (d, 2H), 6.69 (m, 1 H), 3.02 (s, 3H), 1.33 (s, 12H). Intermediate 35: N-f(4-(4,4,5,5-tetramethyl-π ,3,21dioxaborolan-2-vn- phenvDcarbonyll-morpholine
Figure imgf000053_0001
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 (4.2ml, 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%); 1H NMR (300 MHz, CDCI3, ppm) δ : 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-r(4-(4,4,5,5-tetramethyl-π ,3,21dioxaborolan-2-vn- phenvDcarbonyll-piperazine
Figure imgf000053_0002
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-bromophenv0-4-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%); H NMR (300MHz, CDCI3, ppm) δ 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-yl)phenyl]-4-methyl-pyridine
Figure imgf000054_0001
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 Na2SO , 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%); H NMR (300MHz, CDCI3, ppm) δ: 8.5 (d, 1H), 7.95 (d, 2H), 7.5 (s, 1H), 7 (m, 3H), 3.9 (m, 4H), 3.3 (m, 4H), 2.4 (s, 3H).
Intermediate 39 : 2-f2-bromo-pyridin-4-vn-1-pyridin-2-yl-ethanone
Figure imgf000054_0002
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 1M 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-r2-bromo-pyridin-4-vn-1-(6-methyl-pyridin-2-yl)-ethanone
Figure imgf000055_0001
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 1h, 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)-ethanone
Figure imgf000055_0002
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-yl)-1 -(3,4-difluoro-phenvπ-ethanone
Figure imgf000055_0003
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-pyridin-4-yl)-1-(3-chloro-phenyl)-ethanone
Figure imgf000056_0001
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%); 1H NMR (300 MHz, CDCI3, ppm) δ: 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, 1H), 4.24 (s, 2H).
Intermediate 44 : 2-(2-bromo-pyridin-4-yl)-1-(6-fluoro-pyridin-2-yl)-ethanone
Figure imgf000056_0002
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 : 2-f2-(4-(morpholin-4-yl)phenyl)-pyridin-4-vπ-1-pyridin-2-yl-ethanone
Figure imgf000056_0003
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 1M 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) δ: 8.7 (d, 1H), 8.55 (d, 1H), 8.05 (d, 1H), 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-f2-(4-(methanesulfonyl)phenyl)-pyridin-4-vn-1-(6-methylpyridin-2- vD-ethanone
Figure imgf000057_0001
To a solution of intermediate 40 (2g, 6.87mmol) in DME (80ml) was added 4- (methanesulfonyl)-phenyl boronic acid (2.1g, 10.31 mmol), tetrakis(triphenylphosphine) palladium(O) (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 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). The title compound was obtained as a yellow oil (1.1g, 43.73%); [APCI MS] m/z=367 (MH+).
The following compounds of formula (IIEa) were prepared by methods analogous to that described for intermediate 46 using the appropriate boronic acid derivative (see Table 2).
Figure imgf000058_0001
Figure imgf000058_0004
Intermediate 56: 2-f2-(4-(carboxy)-phenyl)-pyridin-4-vn-1 -(6-methylpyridin-2-yl)- ethanone
Figure imgf000058_0002
To a solution of intermediate 49 (1.2g, 3.47mmo!) in MeOH (100ml) 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 1N (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-vπcarbonyl)-phenyl)-pyridin-4-vn-1-(6- methylpyridin-2-yl)-ethanone
Figure imgf000058_0003
To a solution of intermediate 56 (0.8g, 2.41 mmol) in CH2CI2 (50ml) were added morpholine (0.32ml, 3.61 mmol), 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 CH2Cl2/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-f4-((tetrahvdropyran-4-yl)-aminocarbonyl)-phenyllpyridin-4-yl>- 1-(6-methylpyridin-2-yl)-ethanone
Figure imgf000059_0001
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%); 1H NMR (300MHz, CDCIg, ppm) δ : 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 ( , 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-yl)methyl)-phenyl)-pyridin-4-vn-1-(6- methylpyridin-2-yl)-ethanone
Figure imgf000059_0002
To a solution of intermediate 50 (1g, 3.2mmol) in CH2CI2 (100ml) were added morpholine (0.36g, 4.1 mmol) and sodium triacetoxyborohydride (0.88g, 4.1 mmol) 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: r(2-(4-ethanesulfonylphenyl)-pyridin-4-yl)-(phenylamino)-methyl]- phosphonic acid diphenylester
Figure imgf000060_0001
To a solution of 2-chloro-pyridine-4-carboxaldehyde (1g, 7.06mmol) in DME (50ml) was added 4-(ethanesulfonyl)phenyl boronic acid (1.97g, 9.18 mmol), tetrakis(triphenylphosphine) palladium(O) (0.816g, O mmol) 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 (1.91ml, 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-ethanesulfonylphenyl)-Pyridin-4-vn-2-r6-methyl-pyridin-2-vn- ethanone
Figure imgf000060_0002
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 (0.321 g, 34.02%); [APCI MS] m/z 381 (MH+).
Intermediate 62: 2-bromo-N-methoxy-N-methyl-4-pyridinecarboxamide
Figure imgf000061_0001
To a suspension of 2-bromo-4-pyridinecarboxylic acid (23.5g, 116mmol) in CH2CI2 (600mL) were added under nitrogen HOBT (17.3g, 128mmol), EDCI (24.5g, 128mmol), triethylamine (46.85g, 464mmol) 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 Na2SO , 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-pyridin-4-vπ-2-rpyridin-2-vπ-ethanone
Figure imgf000061_0002
To a solution of 6-methylpyridine (2.79g; 30 mmol) in dry THF (20ml) under nitrogen cooled at -80°C, was added dropwise NaHMDS (solution 1M/THF, 36 ml, 36 mmol). and the mixture was stirred for 1hour at -80°C. A solution of intermediate 62 (7.35g; 30 mmol) in dry THF (1 OmL) 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-pyridin-4-vπ-2-r6-methyl-pyridin-2-yll-ethanone
Figure imgf000062_0001
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 Na2SO , filtered and evaporated under reduced pressure . The residue was purified by chromatography on silica gel 60 (CH2CI2/ 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 (IIIEa) were prepared by methods analogous to that described for intermediate 46 using the starting materials indicated (see Table 3)-
Figure imgf000062_0002
(IIIEa)
Figure imgf000062_0003
Intermediate 77: 2-(6-methylpyridin-2-yl)-1- f2-(4-((morpholin-4-yl)methyl)-phenyl)- pyridin-4-vπ-ethanone
Figure imgf000063_0001
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- r2-(4-((pyrolidin-1-yl)methyl)-phenyl)- pyridin-4-vn-ethanone
Figure imgf000063_0002
Intermediate 76 (0.7g, 2.2 mmol) and pyrolidine (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-methylPyridin-2-yl)-1- r2-(4-((dimethylamino)methyl)-phenyl)- pyridin-4-vn-ethanone
Figure imgf000063_0003
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%); [APCI MS] m/z 346 (MH+).
Intermediate 80: 2-Bromo-4-(3-(6-methyl-pyridin-2-yl)-1 H-pyrazol-4-yl)pyridine
Figure imgf000064_0001
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 ml, 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 (300ml) and extracted with CH2CI2 . The organic phases were combined, dried over Na2SO4 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-f5-methyl-3-(6-methylpyridin-2-yl)-1 H-pyrazol-4- yllpyridine
Figure imgf000064_0002
Intermediate 40 (2 g, 6.9mmol) was reacted with N.N-dimethylacetamide dimethylacetal (1.38g, 10mmol) 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-r3-(6-methylpyridin-2-vπ-1-trityl-1 H-pyrazol-4-
yllpyridine
Figure imgf000064_0003
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 H2O. 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-[5-methyl-3-(6-methylpyridin-2-yl)-1 -trityl-1 H-pyrazol-4- yllpyridine
Figure imgf000065_0001
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-yl)-2-(pyridin-2-yl)-imidazof 1 ,2-alpyridine
Figure imgf000065_0002
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 Na2SO4 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. 227°C. The following intermediates (see Table 4) were prepared by methods analogous to that described for intermediate 84 from the starting materials indicated.
Table 4
Figure imgf000066_0001
Intermediate 93: 4-(4-l3-(6-Methylpyridin-2-vπ-1-trityl-1 H-pyrazol-4-vπpyridin-2-yl>- phenol
Figure imgf000067_0001
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 Na2SO 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-(4-f3-(6-Methylpyridin-2-yl)-1-trityl-1 H-pyrazol-4-vπpyridin-2-yll- benzoic acid
Figure imgf000067_0002
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-{4-r3-(6-methylpyridin-2-yl)-1-trityl-1 H-pyrazol-4-vnpyridin-2- yl benzaldehyde
Figure imgf000067_0003
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-vπ-1 -(triphenylmethyl)- 1 H-pyrazol-4-vπpyridine
Figure imgf000068_0001
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-yl)-1 -(triphenylmethvD-1 H-pyrazol-4-yl]- Pyridin-2-yl)phenyl)amine
Figure imgf000068_0002
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 (1g, 98%) containing the 2-trityl isomer as a minor component; [APCI MS] m/z 570 (MH+).
Intermediate 98: 4-(4-r5-methyl-3-(6-methylPyridin-2-yl)-1-(triphenylmethyl)-1 H-
Pyrazol-4-vn-2-pyridinyl}benzaldehvde
Figure imgf000068_0003
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-yl)- imidazoM ,2-a]pyridine
Figure imgf000069_0001
A solution of intermediate 85 (500mg, 1.37 mmol) in DME (50 mL) was treated with tetrakis (triphenylphosphine)palladium(O) (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%); 1H NMR (300 MHz, CDCI3, ppm) δ: 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,1H); 7.61 (t, 1H); 7.51 (m, 1H); 7.30 ( t, 1H); 7.04 (d, 1H) ; 6.85(t,1H) ; 2.31 (s, 3H).
The following intermediates (see Table 5) were prepared by methods analogous to that described for intermediate 99.
Table 5
Figure imgf000069_0002
Figure imgf000070_0001
Intermediate 113 : 3-{2-[4-(2-bromo-ethoxy)-phenvn-pyridin-4-yl)-2-pyridin-2-yl- imidazoH ,2-alpyridine
Figure imgf000071_0001
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 (CDCI3, 300 MHz) .δ 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, 1H), 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
Figure imgf000071_0002
Figure imgf000072_0003
Intermediate 118: 2-Hvdroximino-2-[2-Bromo-pyridin-4-vπ-1-(6-methyl-pyridin-2-yl)- ethan-1-one
Figure imgf000072_0001
A solution of intermediate 40 (20g, 68.7mmol) in aqueous HC1 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-yl1-1-(pyridin-2-yl)-ethan-1- one
Figure imgf000072_0002
The title compound was obtained from intermediate 39, as described for intermediate 118, as a solid (36g, 98%); m.p. 200°C; [APCI MS] m/z 307 (MH+).
Intermediate 120 : 2-tert-butyl-4-(6-methyl-pyridin-2-yl)-5-(2-bromo-pyridin-4-yl)- imidazole
Figure imgf000073_0001
Intermediate 118 (6g, 18.7mmol) was dissolved in acetic acid (50mL) and treated with ammonium acetate (4.33g, 56.1 mmol) 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; (6.31 g, 87%). 2-tert-Butyl-4-(6-methyl- pyridin-2-yl)-N-1-hydroxy-5-(2-bromo-pyridin-4-yl)-imidazole (6.31g, 16.21 mmol) was dissolved in DMF (60mL), treated with triethyl phosphite ( 2.78mL, 16.21 mmol) 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).
Figure imgf000073_0002
(IVDa)
Table 7
Figure imgf000073_0003
Figure imgf000074_0003
Intermediate 125: 4-f4-l2-tert-Butyl-5-(6-methyl-pyridin-2-yl)-1 H-imidazol-4-yll- pyridin-2-yl)-benza!dhvde
Figure imgf000074_0001
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-f2-tert-Butyl-5-(6-methyl-pyridin-2-vn-1 H-imidazol-4-yll- pyridin-2-yl>-phenol
Figure imgf000074_0002
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; CDCI3, ppm) δ: 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-r2-isoproPyl-5-(6-methyl-PVridin-2-ylV1 H-imidazol-4-yll- pyridin-2-yl)-benzaldhvde
Figure imgf000075_0001
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%); 1H NMR (300 MHz; CDCI3, ppm) δ: 9.90 (1 H,s), 8.54 (1H, d), 8.02 (2H, d), 7.79 (2H, d), 7.47-7.16 (3H, m), 6.87 (1 H, d), 3.12-2.95 (1H, m), 2.39(3H, s), 1.25 (6H, d); [APCI MS] m/z 383 (MH+).
Intermediate 128: Polymer supported 5-(2-bromo-4-pyridinylV4-(2-pyridinyl)-1,3- thiazol-2-amine
Figure imgf000075_0002
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-methyl-2- pyridinyl)-1 ,3-thiazol-2-amine
Figure imgf000076_0001
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+).
Pyrazole Examples
Example 1 :2-(4-f(1 -methyl-1 H-imidazol-4-yl)methoxy]phenyl)-4-f3-(6-methylpyridin-2- yl)-1 H-pyrazol-4-yllpyridine
Figure imgf000076_0002
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 ml) 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 ) 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-r4-(Ethylsulfonyl)phenvπ-4-r3-(6-methylpyridin-2-yl)-1 H-pyrazol-4- yllpyridine
Figure imgf000077_0001
To a solution of intermediate 82 (0.5 g, 0.9 mmol) in a mixture of DME (18 ml) and water (9 ml) was added 4-(ethylsulfonyl)phenyl boronic acid (1.3 eq, 0.25 g, 1.17 mmol), tetrakis (triphenylphosphine)palladium(O) (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 (1N, 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).
Figure imgf000077_0002
(IAb)
Table 9
Figure imgf000078_0002
Example 8: 4-[3-(6-methylpyridin-2-yl)-1 H-pyrazol-4-yl]-2-f4-(pyrrolidin-1- ylmethvPphenvπpyridine
Figure imgf000078_0001
To a solution of intermediate 95 (0.29g, O.δmmol) 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/ HC1 1 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 CH2CI2and 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%) ; 1H NMR (CDCi3) δ 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).
Figure imgf000079_0001
(lAa)
Table 10
Figure imgf000079_0003
Example 13: 4-(4-(4-r3-(6-methylpyridin-2-vπ-1 H-pyrazol-4-vnpyridin-2- yl>benzoyl)morpholine
Figure imgf000079_0002
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 hydrolysed and extracted with CH2CI2. The solvent was removed under reduced pressure. The residue was treated with MeOH/ HC1 1 N (3/2, 30ml) at reflux for 1h. 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 1N 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%); 1H NMR (300MHz, CDCI3) δ 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 C25H23 5O2: 426.1930(MH+) . Found : 426.1931 (MH+) .
Example 14: 4-{4-f3-(6-methylpyridin-2-yl)-1 H-pyrazol-4-vπpyridin-2-yl)-N-(tetrahvdro- 2H-pyran-4-yl)benzamide
Figure imgf000080_0001
Intermediate 94 (0.4g, 0.67mmol) and 4-aminotetrahydropyran (0.081 g, O.δmmol) 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 C26H25N5O2: 440.2086(MH+). Found : 440.2060(MH+).
Example 15: N-(4-(4-[3-(6-methylpyridin-2-yl)-1 H-pyrazol-4-yllpyridin-2-yl}phenyl)-2- morpholin-4-ylacetamide
Figure imgf000080_0002
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%) ; 1H NMR (300MHz, CDCI3) δ 9.10 (1 H, 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 (1H, m); 3.71 (4H, t); 3.08 (3H, s); 2.56 (4H, t); 2.50 (3H, s); TOF MS ES+ exact mass calculated for C26H26N6O2: 455.2195 (MH+). Found : 455.2195 (MH+).
Example 16: 4-(4-{4-[3-(6-methylpyridin-2-yl)-1 H-pyrazol-4-vπpyridin-2- yl)phenyl)morpholine
Figure imgf000081_0001
Step 1: To a solution of intermediate 96 (0.633g, 1mmoI) in toluene (10ml) were added morpholine (0.348g, 4mmol, 4eq), Pd2(dba)3 (0.045g, 0.049mmol, 0.05eq), binap (0.062g, 0.1 mmol, 0.1 eq) 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 Na2SO4. 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)-1H-pyrazol-4-yl]-2-pyridinyl}phenyl)morpholine . Step 2: 4-(4-{4-[3-(6-Methyl-2-pyridinyI)-1-(triphenylmethyl)-1 H-pyrazol-4-yl]-2- pyridinyl}phenyl)morpholine was treated with a mixture of MeOH/HCI 1N (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 (1N) 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 (0.31 g, 78%); TOF MS ES+ exact mass calculated for C24H23N5O: 398.1981 (MH+). Found 398.1961 (MH+).
Example 17: 2-r4-(2-methyl-1 H-imidazol-1-yl)phenyll-4-f3-(6-methylpyridin-2-vn-1 H- pyrazol-4-vnpyridine
Figure imgf000081_0002
Intermediate 96 (0.308g, O.δmmol) and 2-methyl-1 H-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; 1H NMR (300 MHz; CDCI3) δ: 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 (1 H, d), 6.99 (2H, d), 2.52 (3H, s), 2.35 (3H, s).
Example 18: 3-r2-(4-((tetrahvdropyran-4-yl)aminocarbonyl)phenyl)pyridin-4-vn-4-r6- methylpyridin-2-yl]-1 H-pyrazole
Figure imgf000082_0001
To a solution of intermediate 71 (0.6g, 1.44 mmol) in DMF (10ml) 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 C26H25N5O2: 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).
Figure imgf000082_0002
(IAb)
Table 11
Figure imgf000082_0003
Figure imgf000083_0003
Triazole Examples
Example 24 : 2-(4-Methanesulfonylphenyl)-4-(5-(6-methyl)-pyridin-2-yl-3H- f1 ,2,31triazol-4-yl)-pyridine
Figure imgf000083_0001
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 hydrόlysed 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; 1H NMR (300 MHz, CDCI3) δ: 8.70 (1 H, 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 C2oH17N5O2S: 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).
Figure imgf000083_0002
(IBa)
Table 11
Figure imgf000084_0002
Imidazopyridine Examples
Example 34: 3-f2-(4-methoxyphenyl)-pyridin-4-yll-2-pyridin-2-yl-imidazo[1 ,2- alpyridine
Figure imgf000084_0001
A solution of intermediate 84 (500mg,'1.42 mmol) in toluene (10 ml) was treated with tetrakis(tripheny!phosphine)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 Na2SO 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 CH2CI2/pentane to give the title compound as a cream powder (68mg, 13%); m.p. 222°C; TOF MS ES + exact mass calculated for C24H18N4O : 379.1559(MH+). Found: 379.1540 (MH+). The following compounds of formula (ICj) were prepared by methods analogous to that described for Example 34 using the starting materials indicated (see Table 12).
Figure imgf000085_0001
(icj)
Table 12
Figure imgf000085_0002
Figure imgf000086_0003
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).
Figure imgf000086_0001
(ICk Table 13
Figure imgf000086_0004
Example 52: 2-(6-methyl-Pyridin-2-yl)-3-f2-[4-amino-phenyll-Pyridin-4-yl)-imidazof 1.2- alpyridine
Figure imgf000086_0002
A solution of example 43 (2.3g, 5.48 mmol) in MeOH (50 ml) and HCI 1N (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+); 1H NMR (300 MHz, CDCI3) δ ppm: 8.7 (d, 1H), 8.1 (d, 1 H), 7.85 (m, 3H), 7.7 (d, 1H), 7.6 (d, 1 H), 7.45 (t, 1 H), 7.25 (m, 2H), 7 (d, 1H), 6.8 (t, 1 H), 6.7 (d, 2H), 3.85 (m, 2H), 2.4 (s, 3H).
Example 53 : 2-(6-methyl-pyridin-2-yl)-3-{2-[4-(trifluoromethylsulfonylamino)phenvn- pyridin-4-yl)-imidazof1,2-alpyridine
Figure imgf000087_0001
To a solution of example 52 (390mg, 1.03mmol) in CH2CI2 (10ml) 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 C25H18F3N5O2S: 510.1212(MH+). Found: 510.1229(MH+).
Example 54 : 3-f2-(4-(morpholin-4-yl)-phenyl)-pyridin-4-vπ-2-pyridin-2-yl-imidazo[1,2- alpyridine
Figure imgf000087_0002
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. ml) was heated under reflux for 2 hours. After dilution with CH2CI2, 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 CH2CI2/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 C2 H23N5O: 434.1981 (MH+). Found: 434.1993(MH+).
Example 55 : 3-(2-[4-(4-methylpiperazin-1-yl)-phenvn-pyridin-4-yl>-2-pyridin-2-yl- imidazo[1 ,2-a]pyridine
Figure imgf000088_0001
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)phenyl)-pyridin- 4-vπ-imidazoπ ,2-alpyridine
Figure imgf000088_0002
To a solution of intermediate 99 (31 Omg, 0.79mmol) and morpholine (1.5 eq, 0.1 ml, 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 1N, 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).
Figure imgf000089_0001
Table 14
Figure imgf000089_0003
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).
Figure imgf000089_0002
(ICm) Table 15
Figure imgf000090_0003
Example 66 : 2-(6-methyl-pyridin-2-yl)-3-(2-[4-((morpholin-4-yl)carbonyl)phenyll- pyridin-4-yll-imidazo[1,2-alPyridine
Figure imgf000090_0001
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; 1.48mmo!) and the mixture was stirred at room temperature overnight and then diluted with CH2CI2. The organic phase was washed with sodium hydroxide solution 1N, 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-ylV3-f2-r4-((3- methoxypropylamino)carbonyl)phenyl1-Pyridin-4-yl>-imidazo[1,2-alpyridine
Figure imgf000090_0002
Intermediate 106 ( 400mg, 0.98mmol) and 3-methoxypropylamine (0.11ml, 1.18mmoI) were coupled and treated as described for example 66 to afford, after trituration with CH2CI2/pentane, the title compound as a pale yellow solid (21 Omg, 44.69%); m.p. 165°C; [APCI MS] m/z 478 (MH+).
Example 68: 2-(pyridin-2-yl)-3-(2-f4-(2-(pyrrolidin-1-yl)ethoxy)phenvn-pyridin-4-yl>- imidazof 1 ,2-alPyridine
Figure imgf000091_0001
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 CH2CI2/MeOH/TEA (80/20/1%). The title compound was obtained as a brown gum (13 mg, 10%); [APCI MS] m/z 462 (MH+); 1H NMR (300 MHz, CDCI3) δppm: 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 (ICp) were prepared by methods analogous to that described for Example 68 using the starting materials indicated (see Table 16).
Figure imgf000091_0002
Table 16
Figure imgf000091_0003
Figure imgf000092_0002
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).
Figure imgf000092_0001
(ICq)
Table 17
Figure imgf000092_0003
Example 75: 7-methyl-2-(6-methyl-pyridin-2-yl)-3-(2-r4-((1-methyl-imidazol-4- yl)methyloxy)phenyl1-pyridin-4-yl)-imidazoM,2-alpyridine
Figure imgf000093_0001
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 C30H26N6O: 487.2246(MH+). Found: 487.2247(MH+).
Example 76: 2-(6-methyl-pyridin-2-yl)-3-(2-r4-((1 -methyl-imidazol-4- yl)methyloxy)phenvn-pyridin-4-yl)-imidazof1,2-a1pyridine
Figure imgf000093_0002
Intermediate 108 (400mg, LOδmmol) 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-yl)-3-l2- r4(aminocarbonylmethyloxy)phenvn-pyridin-4-yl -imidazo[1,2-alpyridine
Figure imgf000094_0001
To a solution of intermediate 111 (500mg, 1.27mmol) in acetone (25ml) 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 Na2SO and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (95/δ). After trituration with pentane/ethyl acetate, the title compound was obtained as a pale yellow solid (133mg, 23%); m.p. 213°C; [APCI MS] m/z 460 (MH+).
Example 78 : 8-methyl-2-(6-methyl-pyridin-2-yl)-3-(2-r4- (aminocarbonylmethyloχyl)phenvn-pyridin-4-yl)-imidazo[1,2-alpyridine
Figure imgf000094_0002
Intermediate 110 ( δOOmg, 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 460 (MH+).
Example 79: 2-(6-methyl-pyridin-2-yl)-3-f2-r4-(morpholin-4-vnphenvπ-pyridin-4-yl>- imidazoH ,2-alPyridine
Figure imgf000094_0003
To a solution of intermediate 48 (3g, 8.04mmol) in CH2CI2 (80 ml) was added bromine-polymer-supported (δ.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.δ1g, 16.08 mmol) and the resin washed δ 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 CH2Cl2. 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 96 :δ) to give an oil which crystallised by trituration from 0 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 C28H25N5O (MH+): 448.2137. Found: 448.2081
Example 80 : 7-methyl-2-(6-methyl-pyridin-2-yl)-3-(2-r4-(morpholin-4-yl)phenvπ- δ pyridin-4-yl)-imidazo[1,2-alPyridine
Figure imgf000095_0001
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 0 (MH+): 462.2294. Found: 462.2263
Imidazole Examples
Example 81 : N-(tetrahvdropyran-4-yl)-4-(4-f2-tert-Butyl-δ-r6-methyl-pyridin-2-vn-1H- imidazol-4-yl)-pyridin-2-yl)-benzamide
Figure imgf000095_0002
To a solution of intermediate 120 (0,9δg, 2.δ6mmol) in a mixture of DME (30ml) and water (1δml) were added intermediate 33 (0.93g, 2.81 mmol), tetrakis(triphenylphosphine) palladium(O) (0.1g, 0.086mmol) and Na2CO3 (solution 2M, 5ml) and the mixture was heated under reflux overnight and then poured into water. After extraction with CH CI2, 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, 56.36%); m.p. 174°C ; TOF MS ES+ exact mass calculated for C3oH33N5O2: 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).
Figure imgf000096_0001
(IDf)
Table 18
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000098_0002
Example 101 : (4-(4-r2-tert-Butyl-δ-(6-methyl-pyridin-2-yl)-1H-imidazol-4-vn-pyridin-2- vD-benzvD-dimethyl-amine
Figure imgf000098_0001
To a solution of intermediate 126 (0.8g, 2.02mmol) in CH2CI2 (δOml) were added dimethylamine (2M solution in MeOH, 1.1ml, 2.22mmol) and sodium triacetoxyborohydride (0.8δ6g, 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 C27H31N5:426.2657(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).
Figure imgf000099_0001
(IDg) Table 19
Figure imgf000099_0002
Example 106 : 4-(2-tert-Butyl-5-f6-methyl)-pyridin-2-yl-1H-imidazol-4-vn-2-r4-(1- methyl-1H-imidazol-4-ylmethoxy)-phenyll-pyridine
Figure imgf000100_0001
To a solution of intermediate 126 (0.49g, 1.27mmol) in DMF (20ml) was added portionwise sodium hydride (60% in mineral oil, 0.162g, 3.81 mmol) and the mixture was stirred at room temperature for 10 minutes. Intermediate 22 (0.3g, 1.8mmol) was δ 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 (0.30δg, 60%), gummy at 128°C; 1H NMR (300 MHz; CDCI3) δ: 0 8.61 (1 H, d), 7.87 (1H, s), 7.82 (2H, d), 7.40 (1 H, d), 7.40-7.28 (3H, m), 7.22 (1H, d), 6.96 (1H, d), 6.89 (1H, d), 6.86 (1H, s), 4.97 (2H, s), 3.66 (3H, s), 2.36 (3H, s), 1.32 (9H, s); TOF MS ES* exact mass calculated for C29H30N6O : 479.2δδ9(MH+). Found 479.2δ49(MH+).
5 Example 107: 2-(4-r4-(2-tert-Butyl-δ-f6-methyl)-pyridin-2-yl-1 H-imidazol-4-yl)-pyridin- 2-yll-phenoxy>-acetamide
Figure imgf000100_0002
Intermediate 126 (O.δg , 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 (0.347g, 60.46%); m.p. 210°C; TOF MS ES* exact mass calculated for C26H27N5O2 : 442.2243 (MH+). Found: 442.2221 (MH+).
Example 108: 4-(2-tert-Butyl-δ-f6-methyl -pyridin-2-yl-1 H-imidazol-4-yl)-2-f4-(2- Pyrrolidin-1-yl-ethoxy)-phenvn-pyridine
Figure imgf000101_0001
Intermediate 126 (0.4g , 1.04mmo!) and 1-(2-chloroethyl)pyrrolidine hydrochloride (0.3δ4g, 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-δ-pyridin-2-yl-1H-imidazol-4-yl)-2-f4-(1-methyl-1H- imidazol-4-ylmethoxy)-phenyll-pyridine
Figure imgf000101_0002
To a solution of example 83 (0.26g , 0.67mmol) in CH2CI2 (40ml) was added boron tribromide (2.1ml, 2.1 mmol, 3.2eq, solution 1 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 CH2CI . 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-δ-pyridin-2-yl-1H-imidazoi-4-yl}-pyridin-2-yl]-phenol (0.14g, 0.37mmol) in acetone K2CO3 (0.156g, 1.1 mmol) and intermediate 22 (0.094g, O.δδmmol) 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 CH2Cl2. The organic phase was washed with water, dried over Na2SO4 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. 1δ6°C; TOF MS ES* exact mass calculated for C28H28N6O : 466.2403 (MH*). Found: 466.2396 (MH*).
Example 110: 4-{2-Phenyl-5-[6-methvn-pyridin-2-yl-1 H-imidazol-4-yl)-2-(4- methanesulfonyl-phenvD-pyridine
Figure imgf000102_0001
Intermediate 118 (6.5g, 20.3mmol) and benzaldehyde (4.3ml, 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, 1.53mmoI) 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; CDCI3) δ: 8.67 (1H, d), 8.13-8.12 (2H, m), 7.96 (2H, d), 7.92 (1H, s), 7.68-7.26(8H, m), 7.02 (1H, d), 3.02 (3H, s), 2.54 (3H, s); TOF MS ES* exact mass calculated for C27H22N4O2S: 467.1542 (MH*). Found : 467.1513 (MH*).
Aminothiazole Examples
Example 111: 5-(2-f4-(morpholin-4-yl)phenvnpyridin-4-yl>-4-(pyridin-2-yl)-1 ,3-thiazol- 2-amine
Figure imgf000102_0002
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 CH2Cl2. 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).
Figure imgf000103_0001
(lEf)
Table 20
Figure imgf000103_0002
Figure imgf000104_0002
The following compounds of formula (lEg) were prepared by methods analogous to that described for Example 111 using the starting materials indicated (see Table 21).
Figure imgf000104_0001
(lEg)
Table 21
Figure imgf000104_0003
Figure imgf000105_0002
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) (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 (3x1 OmL), water (3x1 OmL), EtOH (3x1 OmL) and CH2CI2 (3x1 OmL). Step 2: The product from step 1 was placed into a peptide vessel with a solution of NHR5R6 (δ.δmmol, 10eq) in trimethylorthoformate (5.4mL). Then a solution of sodium cyanoborohydride (0.2M) in THF (5.4mL) with acetic acid (110μL) 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 (3x1 OmL), EtOH (3x1 OmL) and CH2CI2 (3x1 OmL). 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 (lEh) shown in Table 22.
Figure imgf000105_0001
(lEh)
Table 22
Figure imgf000106_0002
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, δ.δmmol, 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 (3x1 OmL), water (3x1 OmL), EtOH (3x1 OmL) and CH2CI2 (3x10mL).
Step 2: The product from step 1 was placed into a peptide vessel with a solution of R-CI (δ.δmmol, 10eq) in DMSO (10mL). Then a solution of potassium carbonate (802mg, δ.δmmol, 10eq) in DMSO (δmL) was added. The reaction vessel was purged with argon for δ min and the mixture was stirred at 90°C for 16h. The resin was washed with DMF (3x1 OmL), EtOH (3x1 OmL) and CH2Ci2 (3x1 OmL). 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 (lEj) shown in Table 23.
Figure imgf000106_0001
(lEj)
Table 23
Figure imgf000106_0003
Figure imgf000107_0002
Examples 145 to 166
Step 1: Intermediate 129 supported on resin (1g) was weighed out into a peptide vessel. Then 4-methoxycarbonylphenylboronic acid (1.05g, δ.δmmol, 10eq), Pd(PPh3) (0.134 g, 0.16mmol, 0.2eq), and a aqueous solution of sodium carbonate (0.615g, δ.δmmol, 2M) were added and suspended in toluene/EtOH (δ:2, 20mL). The reaction vessel was purged with argon for δ min, and the mixture was stirred at 90°C for 16h. The resin was washed with DMF (3x1 OmL), water (3x1 OmL), EtOH (3x1 OmL) and CH2CI2 (3x1 OmL). 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 (3x1 OmL), EtOH (3x1 OmL) and CH2CI2 (3x1 OmL). Step 2: The product from step 1 was placed into a peptide vessel with a solution of NHR5R6 (δ.δmmol, 10eq) in DMF (δmL). Then a solution of HOBT (1.1 δg, 8.7mmol, 1δeq) and EDCI (1.36mL, 8.7mmol, 1δeq) in DMF (δmL) was added. The reaction vessel was purged with argon for δ min and the mixture was stirred at 70°C for 16h. The resin was washed with DMF (3x1 OmL), EtOH (3x1 OmL), CH2CI2 (3x1 OmL). 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 (lEk) shown in Table 24.
Figure imgf000107_0001
(lEk)
Table 24
Figure imgf000108_0001
Biology
The biological activity of the compounds of the invention may be assessed using the following assays: 106
Assay 1 (Cellular transcriptional assay)
The potential for compounds of the invention to inhibit TGF- β signalling 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-β 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-β. In addition, cells were transfected with a second luciferase (Renilla) gene which was not driven by a TGF-β 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 μl of serum- containing medium. These plates were placed in a cell incubator. 16 to 24 hours later (Day 2), cell-incubation procedure was launched. Cells were incubated with TGF-β and a candidate compound at concentrations in the range 50 nM to 10 μM (final concentration of DMSO 1%). The final concentration of TGF-β (rhTGFβ-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-β. The final volume of the test reaction was 150 μl. 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 δ wells in which the cells were incubated in the presence of TGF-β, without a candidate compound. Column 11 was used to determine the 'reference TGF-β induced firefly luciferase value' against which values measured in the test wells (to quantify inhibitory activity) were compared. In wells A12 to D12, cells were grown in medium without TGF-β. 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-β and 600 μM CPO (Cyclopentenone, Sigma), a cell toxic compound. The toxicity was revealed by decreased firefly and renilla luciferase activities (around 60 % of those obtained in column 11).
12 to 1δ 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 μl 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 μl of luciferase assay reagent and 60 μl 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-βonly) 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 (Alkδ 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 198-603).
Assay buffer components: 62.5 mM Hepes pH 7.5 (Sigma H-4034), 1 mM DTT (Sigma D-0632), 12.5 mM MgCI2 (Sigma M-9272), 1.26 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-welI, 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 Rapidplate™-96 was used to transfer 1 μl 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 μl) was added to each well of the previously prepared assay plates. A control compound (1 μl) 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 μl DMSO in column 12, rows A-D) and the low controls (1 μl 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 show ALKδ receptor modulator activity (having IC50 values in the range of 0.4 to 27δnM) and TGF-β cellular activity (having IC50 values in the range of 0.001 to 10μM).
4-{4-[4-(2-tett-Butyl-5-{6-methyl}-pyridin-2-yl-1H-imidazol-4-yl)-pyridin-2-yl]-phenyl}- morpholine (Example 86) showed an ALK5 receptor modulator activity of 34 nM and TGF-β cellular activity of 183 nM.
N-(tetrahydropyran-4-yl)-4-(4-{2-isopropyl-δ-[6-methyl-pyridin-2-yl]-1 H-imidazol-4-yl}- pyridin-2-yl)-benzamide (Example 96) showed an ALKδ receptor modulator activity of 26 nM and TGF-β cellular activity of <14 nM.

Claims

Claims
1 A compound of formula (I), a pharmaceutically acceptable salt, solvate or derivative thereof:
Figure imgf000112_0001
(I) 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; R1 is hydrogen, C1-6alkyl, C1-6alkenyl, Cι-6alkoxy, halo, cyano, perfluoro
C1-6alkyl, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR7, -O(CH2)n-Het, -O(CH2)nNR5R6, -CONR5R6, -CO(CH2)nNR5R6, -SO2R7, -SO2NR5R6, -NR5SO2R7, -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 4,6 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, d. 6alkyl and C1-6aIkoxy;
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 C1-6alkyl; 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; R1 is hydrogen, C1-6alkyl, C^alkoxy, halo, cyano, perfluoroC1-6alkyl or perfluoroC1-6alkoxy; R2 is hydrogen, Cι„ 6alkyl, halo, cyano or perfluoroCι-6alkyl; and R3 is hydrogen or halo; then R4 is not NH2; and b) when X is N, A is pyrazole (where the ring containing X is attached to the pyrazole ring at carbon atom next to a pyrazole ring nitrogen), R2 is hydrogen then R3 is not hydrogen.
A compound according to any preceding claim wherein A is imidazole optionally substituted by one R4 substitutent.
A compound according to any preceding claim wherein X is N.
A compound according to any preceding claim wherein R is C1-6alkyl,
C1-6alkoxy, halo, cyano, perfluoroC1-6alkoxy, -NR5R6, -(CH2)nNR5R6, -O(CH2)nOR7, -O(CH2)n-Het, -O(CH2)nNR5R6, -CONR5R6, -SO2R7, -NR5SO2R7, -NR5COR7, -O(CH2)nCONR5R6, -NR5CO(CH2)nNR5R6 or -C(O)R7.
A compound according to any preceding claim wherein R2 is hydrogen,
C1-6alkyl or fluoro.
A compound according to any preceding claim wherein R3 is hydrogen.
A compound according to any preceding claim wherein R4 is hydrogen, phenyl, C*,-6alkyl or halo. A compound according to any preceding claim wherein R5 and R6 are independently selected from hydrogen; Het; C3-6cycloaIkyl 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 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
Cι-4alkoxy.
A compound according to claim 1 wherein A is imidazole; X is N;
R1 is C*,.6alkyl, C1-6alkoxy, halo, cyano, perfluoroC1-6alkoxy, -NR5R6,
-(CH2)nNR5R6, -(CH2)nOR7, -O(CH2)n-Het, -O(CH2)nNR5R6, -CONR5R6,
-SO2R7, -NR5SO2R7, -R5COR7, -O(CH2)nCONR5R6,
-NR5CO(CH2)nNR5R6 or -C(O)R7; R2 is hydrogen, C1-6alkyl or fluoro;
R3 is hydrogen or halo;
R4 is hydrogen, phenyl, C1-6alkyl or halo; R5 and R6 are independently selected from hydrogen, Het 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 C^alkoxy;
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
C1-6alkyl; and n is 1-4.
A compound according to claim 1 wherein the compound is selected from the list: 4-{2-te/τ-Butyl-δ-[6-methyI]-pyridin-2-yl-1H-imidazol-4-yl}-2-(4- methanesulfonyl-phenyl)-pyridine (Example δ4); 4-{4-[4-(2-fe/τ-Butyl-5-{6-methyl}-pyridin-2-yl-1H-imidazol-4-yl)-pyridin-2-yl]- phenylj-morpholine (Example δ6); N-(tetrahydropyran-4-yl)-4-(4-{2-isopropyl-δ-[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-yI-1H-imidazol-4-yl)-pyridin-2-yl]- phenyl}-morpholine (Example 97); 4-(4-{4-[2-lsopropyl-5-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-pyridin-2-yl}- benzyl)- dimethyl-amine (Example 106);
4-(4-{4-[2-lsopropyl-δ-(6-methyl-pyridin-2-yl)-1H-imidazol-4-yl]-pyridin-2-yl}- benzyl)-morpholine (Example 104); N-(tetrahydropyran-4-yl)-4-(4-{2-te/τ-Butyl-5-[6-methyl-pyridin-2-yl]-1H- imidazol-4-yl}-pyridin-2-yl)-benzamide (Example 61); (4-{4-[2-te/τ-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-yl-1H-imidazol-4-yl)-2-[4-(2-pyrrolidin-1- yl-ethoxy)-phenyl]-pyridine (Example 103); and 4-{4-[4-(2-methyl-5-{6-methyI}-pyridin-2-yl-1H-imidazol-4-yl)-pyridin-2-yl]- phenylj-morpholine (Example 98); and pharmaceutically acceptable salts, solvates and derivatives thereof.
A pharmaceutical composition comprising a compound defined in any preceding claim and a pharmaceutically acceptable carrier or diluent.
The use of a compound defined in any one of claims 1 to 10 in the manufacture of a medicament for the treatment or prophylaxis of a disorder mediated by the ALKδ receptor in mammals.
The use according to claim 12 wherein the disorder is selected from chronic renal disease, acute renal disease, wound healing, arthritis, osteoporosis, kidney disease, congestive heart failure, 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 lung fibrosis, kidney fibrosis, liver fibrosis [for example, hepatitis B virus (ΗBV), hepatitis C virus (HCV)], alcohol induced hepatitis, retroperitoneal fibrosis, mesenteric fibrosis, haemochromatosis and primary biliary cirrhosis, endometriosis, keloids and restenosis.
The use according to claim 13 wherein the disorder is kidney fibrosis.
A compound defined in any one of claims 1 to 10 for use as a medicament.
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