WO2012066335A1 - Composés phénol en tant qu'agonistes du récepteur 7 de type toll - Google Patents

Composés phénol en tant qu'agonistes du récepteur 7 de type toll Download PDF

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Publication number
WO2012066335A1
WO2012066335A1 PCT/GB2011/052245 GB2011052245W WO2012066335A1 WO 2012066335 A1 WO2012066335 A1 WO 2012066335A1 GB 2011052245 W GB2011052245 W GB 2011052245W WO 2012066335 A1 WO2012066335 A1 WO 2012066335A1
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Prior art keywords
amino
methyl
formula
compound
methylpyrimidin
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PCT/GB2011/052245
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English (en)
Inventor
Andrew Bailey
Adrian John Highton
Thomas Mcinally
Tobias Mochel
Daisuke Urabe
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Astrazeneca Ab
Dainippon Sumitomo Pharma Co., Ltd.
Astrazeneca Uk Limited
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Publication of WO2012066335A1 publication Critical patent/WO2012066335A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to novel phenol compounds and, more particularly, to novel phenol compounds that act as TLR7 agonists.
  • This invention also relates to methods for the preparation of such compounds and novel intermediates in the preparation thereof, to pharmaceutical compositions containing such compounds, to the use of such compounds in the preparation of medicaments, and to the use of such compounds in the treatment of conditions mediated by TLR7, such as allergic diseases, autoimmune diseases, viral diseases and, in particular, cancer.
  • TLRs Toll-like receptors
  • DCs dendritic cells
  • TLRs recognise molecular motifs on pathogens called pathogen-associated molecular patterns (PAMPs).
  • PAMPs pathogen-associated molecular patterns
  • TLRs recognise different pathogen-derived ligands, for example TLRs 2 (bacterial lipoproteins), 3 (double-stranded RNA/poly (LC)), 4 (lipopolysaccharides), 5 (flagellin), 7 (single- stranded RNA) and 9 (CpG-containing DNA).
  • Ligation of TLRs on antigen-presenting cells, such as DCs leads to production of proinflammatory cytokines, DC maturation and priming of the adaptive immune system.
  • TLR7 and TLR9 are expressed by plasmacytoid dendritic cells (pDCs) and ligand recognition leads to the secretion of interferon-a (INF-a).
  • pDCs plasmacytoid dendritic cells
  • TLR7 agonists include the imidazoquinoline, imiquimod, which has been used to treat a number of dermatological conditions e.g. genital warts, molluscum contagiosum and melanoma.
  • imiquimod which has been used to treat a number of dermatological conditions e.g. genital warts, molluscum contagiosum and melanoma.
  • topically applied imiquimod (AldaraTM, Graceway Pharmaceuticals, Bristol, TN) demonstrated therapeutic responses in cutaneous metastatic melanoma and lentigo maligna and has been approved for the treatment of superficial basal cell carcinoma (BCC).
  • 852A is another imidazoquinoline, which unlike imiquimod, is suitable for systemic administration.
  • 852A is in phase II clinical trials in a number of cancer indications, including melanoma.
  • TLR7 agonists which are more effective in the treatment of disease, for example cancer, by reason of their superior potency and/or advantageous physical properties (for example, higher permeability, and/or lower plasma protein binding) and/or favourable toxicity profiles and/or favourable metabolic profiles in comparison with other known TLR7 agonists, for example 852A.
  • the phenol compounds of the present invention are capable of activating TLR7 in vitro.
  • the phenol compounds of the present invention are expected to have value in the prevention or treatment of human disease, for example cancer, either as a monotherapy or in combination with other chemotherapeutic agents or radiotherapy regimens.
  • TLR7 and TLR8 differ in their cellular expression and as a result stimulation with selective agonists induces different cytokine profiles.
  • TLR8 stimulation results in enhanced levels of pro-inflammatory cytokines including TNFa, IL- ⁇ and IL-6 (Gorden et al (2005) J. Immunol. 174, 1259-1268). Conversely, TLR8 stimulation results in lower levels of IFNa.
  • a TLR7 selective agonist would favour induction of IFNa, which is important in suppression of Th2 cytokines (Huber et al (2010) J. Immunol. 185; 813-817) that are elevated in allergic disease.
  • Th2 cytokines Hauber et al (2010) J. Immunol. 185; 813-817) that are elevated in allergic disease.
  • compounds selective for TLR7 compared to TLR8 the induction of proinflammatory cytokines would be reduced thus avoiding inflammatory responses in man.
  • some compounds of the invention also have a surprisingly advantageous hERG profile.
  • Compounds that have significant activities against the hERG ion channel are relevant to inducing QT prolongation and are disfavored because such activity is implicated in the development of Torsades de Pointes and cardiac death.
  • Q is a direct bond, -0-(C 2 - 4 alkylene)- or -(Ci_ 4 alkylene)-;
  • R 1 is selected from hydrogen, Ci_ 4 alkyl, Ci_ 3 alkoxyC 2 - 4 alkyl, hydroxyC 2 _ 4 alkyl, C 3 _ 5 cycloalkyl, tetrahydropyranyl, benzyl, C-linked pyrrolidinyl, C-linked piperidinyl and (R x )(R Y )N-C 2 - 4 alkyl, wherein R x and R Y each independently represent hydrogen or Ci_ 3 alkyl; and
  • R 2 is selected from hydrogen, Ci_ 4 alkyl and Ci_ 3 alkoxyC 2 - 4 alkyl;
  • R 1 and R 2 together with the nitrogen to which they are attached form a saturated heterocyclyl selected from azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl, morpholin-4-yl, piperazin-l-yl, azepan-l-yl, 1,4-diazepan-l-yl; wherein one or two carbon atoms within said heterocyclyl may be substituted by oxo and wherein the available nitrogen of said piperazin-l-yl and 1,4-diazepan-l-yl is optionally substituted by Ci_ 3 alkyl,
  • 5-membered aromatic heterocyclyl containing a total of 1-3 nitrogen atoms; wherein said 5-membered aromatic heterocyclyl is optionally substituted on a ring carbon atom by Ci_ 3 alkyl;
  • R 3 is selected from hydrogen, hydroxymethyl and 2-hydroxyethyl
  • the "available nitrogen" of a piperazin-l-yl and 1,4- diazepan-l-yl is at the 4-positions of the piperazin-l-yl and the 1,4-diazepan-l-yl.
  • optically active or racemic forms by virtue of one or more asymmetric carbon atoms
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter.
  • Ci_ 4 alkylene is intended to mean divalent group of a saturated carbon chain of 1 to 4 carbon atoms in length which may be straight-chained or branched, preferably straight chained.
  • Ci_ 4 alkylene includes, but is not limited to, methylene, ethylene, trimethylene, tetramethylene.
  • C 2 - 4 alkylene is to be construed accordingly.
  • Ci_ 4 alkyl is intended to mean a saturated carbon chain of 1 to 4 carbon atoms in length which may be straight-chained or branched. However references to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched-chain alkyl groups such as tert-butyl are specific for the branched chain version only.
  • “Ci_ 4 alkyl” includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl.
  • the term “C 2 _ 4 alkyl” and “Ci_ 3 alkyl” are to be construed accordingly.
  • Ci_ 3 alkoxyC 2 - 4 alkyl is intended to mean a saturated carbon chain of 1 to 3 carbon atoms in length, which may be straight-chained or branched, linked via oxygen to another saturated carbon chain of 2 to 4 carbon atoms in length, which may be straight- chained or branched.
  • “Ci_ 3 alkoxyC 2 - 4 alkyl” includes, but is not limited to, methoxyethyl, methoxypropyl, ethoxypropyl, propoxyethyl and methoxypropyl.
  • hydroxyC 2 - 4 alkyl is intended to mean a saturated carbon chain of 2 to 4 carbon atoms in length, which may be straight-chained or branched, wherein one of the hydrogen atoms has been replaced by a hydroxy group.
  • hydroxyC 2 - 4 alkyl includes, but is not limited to, hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- hydroxyisopropyl and 4-hydroxybutyl.
  • (R x )(R Y )N-C 2 - 4 alkyl is intended to mean a saturated carbon chain of 2 to 4 carbon atoms in length, which may be straight-chained or branched, wherein one of the hydrogen atoms has been replaced by a group "(R X )(R Y )N-", wherein R x and R Y each independently represent hydrogen or Ci_ 3 alkyl.
  • the "Ci_ 3 alkyl” is intended to mean a saturated carbon chain of 1 to 3 carbon atoms in length which may be straight-chained or branched, including methyl, ethyl, propyl and isopropyl.
  • R 1 , R 2 , R 3 and Q may take any of the values defined herein R 1 , R 2 , R 3 and Q respectively.
  • variable groups R 1 , R 2 , R 3 and Q may also take the values as indicated below. Such values may be used together with any of the definitions, claims, aspects or embodiments defined herein to provide further embodiments or claims of the invention, and unless the context does not permit, any number of said variable group definitions may be used in any combination with each other to form further embodiments, aspects and claims.
  • Q is -0-(C 2 - 4 alkylene)-.
  • Q is -O-CH2CH2- or -O-CH2CH2CH2-.
  • Q is -(Ci_ 4 alkylene)-.
  • Q is -CH 2 - or -CH 2 CH 2 CH 2 -.
  • Q is -CH 2 CH 2 CH 2 -.
  • Q is -0-(C 2 _ 4 alkylene)- or -(Ci_ 4 alkylene)-.
  • Q is -0-(C 2 _ 4 alkylene)- or -(Ci_ 4 alkylene)- wherein said alkylene is a straight chain alkylene.
  • R 1 is hydrogen
  • R 1 is Ci_ 4 alkyl, Ci_ 3 alkoxyC 2 _ 4 alkyl, hydroxyC 2 _ 4 alkyl, C 3 _ 5 Cycloalkyl,
  • R 1 is Ci_ 4 alkyl, Ci_ 3 alkoxyC 2 _ 4 alkyl or hydroxyC 2 _ 4 alkyl.
  • R 1 is selected from methyl, ethyl, 2-methoxyethyl and 2-hydroxyethyl.
  • R 2 is hydrogen
  • R 2 is Ci_ 4 alkyl or Ci_ 3 alkoxyC 2 _ 4 alkyl.
  • R 2 is Ci_ 4 alkyl.
  • R 2 is methyl or ethyl.
  • R 2 is Ci_ 3 alkoxyC 2 _ 4 alkyl.
  • 1,4-diazepan-l-yl is optionally substituted by Ci_ 3 alkyl, hydroxyCi_ 3 alkyl or
  • 5-membered aromatic heterocyclyl containing a total of 1-3 nitrogen atoms; wherein said 5-membered aromatic heterocyclyl is optionally substituted on a ring carbon atom by Ci_ 3 alkyl.
  • R 1 is Ci_ 4 alkyl, Ci_ 3 alkoxyC 2 - 4 alkyl or hydroxyC 2 - 4 alkyl; and R 2 is Ci_ 4 alkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a pyrrolidine- 1-yl or piperazin-l-yl wherein said piperazin-l-yl is substituted by Ci_ 3 alkyl.
  • R 1 is methyl, ethyl, 2-methoxyethyl or 2-hydroxyethyl; and R 2 is methyl or ethyl; or R 1 and R 2 together with the nitrogen to which they are attached form a pyrrolidine- 1-yl or 4-methylpiperazin-l-yl.
  • R 3 is hydrogen
  • R 3 is hydroxymethyl
  • R 3 is 2-hydroxyethyl.
  • R 3 is hydroxymethyl or 2-hydroxyethyl.
  • Q is -0-(C 2 - 4 alkylene)- or -(Ci_ 4 alkylene)-;
  • R 3 is selected from hydrogen, hydroxymethyl and 2-hydroxyethyl.
  • a suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, an acid-addition salt of a compound of the Formula (I), for example an acid- addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid.
  • an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric or maleic acid.
  • the compounds of the invention may be administered in the form of a pro-drug, that is a compound that is broken down in the human or animal body to release a compound of the invention.
  • a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
  • a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in-vivo cleavable amide derivatives that may be formed at an amino group in a compound of the Formula (I).
  • the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses an amino group is, for example, an in-vivo cleavable amide derivative thereof.
  • Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with Ci_ioalkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl,
  • the in-vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in-vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
  • the compound of Formula (I) may be prepared by reacting a compound of Formula (II), or a salt thereof,
  • R 1 , R 2 and Q may take any of the values for R 1 , R 2 and Q as defined herein, and where R 4 may take any of the values for R 3 as defined herein or R 4 may be a protected hydroxyalkyl group: PG 1 -0-(CH 2 ) n -, wherein n is 1 or 2 and PG 1 is a protecting group.
  • n is 1.
  • n is 2.
  • PG 1 is selected from a benzyl-based protecting group and a silyl-based protecting group.
  • a benzyl-based protecting group may be benzyl.
  • a silyl-based protecting group may be a tri(Ci_ 4 alkyl)silyl group, for example a triemthylsilyl (TMS) or fert-butyldimethylsilyl (TBDMS) protecting group.
  • TMS triemthylsilyl
  • TDMS fert-butyldimethylsilyl
  • a compound of Formula (II), or a salt thereof as defined herein.
  • the preparation of a compound of Formula (I) from a compound of Formula (II) may be carried out with or without any hydroxy group within R 4 being protected. Any protecting group used on a hydroxyl group within R 4 may be removed before or after the reaction with BBr 3 (the chemistry that reveals the phenol functionality).
  • the R 5A group of the compound of Formula (III-A) may be a substituted or unsubstituted hydrocarbyl group.
  • R 5A may be a hydrocarbyl group selected from benzyl and Ci_ 4 alkyl, for example methyl or ethyl.
  • the LG 2A group of the compound of Formula (III-B) may be any convenient leaving group which are well-known to the skilled person, for example a substituted or unsubstituted hydrocarbylsulfonyloxy leaving group, for example a tosylate or mesylate group, or a halo leaving group such as iodo or more conveniently, a bromo or chloro leaving group.
  • Step (i) - Compounds of Formula (IV) may be prepared by a standard alkylation reaction using compounds of Formula (III- A) and Formula (III-B): For example, reaction of a compound of Formula (III-B) with a base, such as NaH, in a suitable solvent, such as THF or DMF, at a suitable temperature, for example 0-20°C, followed by addition of a compound of Formula (III-A). The reaction may be heated, for example at 50-100°C, optionally in the presence of a catalytic amount of an iodide salt, such as KI.
  • a base such as NaH
  • a suitable solvent such as THF or DMF
  • Step (ii) - Compounds of Formula (V) may be prepared by reacting a compound of Formula (IV) with guanidine or guanidine carbonate in a suitable solvent, such as methanol or ethanol, at elevated temperature, for example 50-150°C.
  • a suitable solvent such as methanol or ethanol
  • the compound of Formula (V) may be isolated as a salt.
  • Step (iii) - Compounds of Formula (VI) may be prepared by reacting a compound of Formula (V) with POCI3, at elevated temperature, for example 50-110°C.
  • the compound of Formula (V) may be isolated as a salt.
  • Step (iv) - Compounds of Formula (VII) may be prepared by reacting a compound of Formula (VI) with an excess of butylamine or the appropriate amino alcohol (where the amino alcohol may optionally have its alcohol group protected) in a suitable solvent, such as propionitrile, butanol or 1,4-dioxane, in the presence of trifluoroacetic acid (TFA) at elevated temperature (for example 50-200°C) using conventional or microwave heating.
  • TFA trifluoroacetic acid
  • the R 4 group in the compound of Formula (VII) and the compound of Formula (VIII) is independently selected from same R 4 values described hereinbefore in connection with the compound of Formula (II).
  • the compound of Formula (VII) and/or the compound of Formula (VIII) and/or the compound of Formula (II- A), when R 4 is other than hydrogen, has an (5)-stereocentre at the asymmetric carbon atom where the R 4 group is attached.
  • the optionally used protecting group incorporated into the compound of Formula (VII) and/or Formula (VIII) may be removed at any convenient point in the synthesis using standard deprotection conditions that are well known to the skilled person.
  • the compounds of Formula (VII) and the compound of Formula (VIII) may be isolated as a salt.
  • Step (v) - Compounds of Formula (VIII) may be prepared by reacting a compound of Formula (VII) with Raney nickel in a suitable solvent mixture such as pyridine, acetic acid and water, at a suitable temperature, for example 20-50°C.
  • a suitable solvent mixture such as pyridine, acetic acid and water
  • Step (vi) - Compounds of Formula (II- A) may be prepared by reaction of a compound of (VIII) with the appropriate amine (FINR ⁇ 2 ) under reductive amination conditions, which are well known to the skilled person.
  • the reductive amination may be carried out using a suitable reducing agent such as sodium
  • triacetoxyborohydride in a suitable solvent such as CH 2 CI 2 and acetic acid in the presence of activated molecular sieves, or by using NaBH 4 in a suitable solvent such as methanol.
  • the R group of the compound of Formula (IX) may be a substituted or unsubstituted hydrocarbyl group.
  • R 5B may be a hydrocarbyl group selected from benzyl and Ci_4alkyl, for example methyl or ethyl.
  • the LG 2B group of the compound of Formula (X) may be any convenient leaving group which are well-known to the skilled person, for example a substituted or unsubstituted hydrocarbylsulfonyloxy leaving group, for example a tosylate or mesylate group, or a halo leaving group such as iodo or more conveniently, a bromo or chloro leaving group.
  • R 6 group of the compound of Formula (X) may be a substituted or unsubstituted hydrocarbyl group.
  • R 6 may be a hydrocarbyl group selected from benzyl and Ci_4alkyl, for example methyl or ethyl.
  • Step (i) - Compounds of Formula (XI) may be prepared by a standard alkylation reaction using compounds of Formula (IX) and Formula (X): For example, reaction of a compound of Formula (IX) with a base, such as NaH, in a suitable solvent, such as THF or DMF, at a suitable temperature, for example 0-20°C, followed by addition of a compound of Formula (X). The reaction may be heated, for example at 50-100°C, optionally in the presence of a catalytic amount of an iodide salt, such as KI.
  • a base such as NaH
  • a suitable solvent such as THF or DMF
  • Step (ii) - Compounds of Formula (XII) may be prepared by reacting a compound of Formula (XI) with guanidine or guanidine carbonate in a suitable solvent, such as methanol or ethanol, at elevated temperature, for example 50-150°C.
  • a suitable solvent such as methanol or ethanol
  • the compound of Formula (XII) may be isolated as a salt.
  • R 7 group in the compound of Formula (XIII) may be a substituted or unsubstituted hydrocarbyl group, for example a Ci_ 4 alkyl group or a phenyl group optionally substituted by 1 , 2 or 3 Ci_ 4 alkyl groups, for example R 7 may conveniently be methyl, ethyl, 2,4,6-trimethylphenyl or 2,4,6-triisopropylphenyl.
  • (XIII) may be prepared by reacting a compound of Formula (XII) with a hydrocarbyl sulfonyl chloride: R 7 S0 2 C1, for example trimethylbenzene sulfonyl chloride or
  • reaction may be carried out in a suitable solvent, such THF in the presence of a suitable base, such as, triethylamine or tetramethyl- propylenediamine, at a suitable temperature, for example 0-50°C.
  • a suitable solvent such as THF
  • a suitable base such as, triethylamine or tetramethyl- propylenediamine
  • Step (iv) - Compounds of Formula (XIV) may be prepared by reacting a compound of Formula (XIII) with an excess of butylamine or the appropriate amino alcohol (where the amino alcohol may optionally have its alcohol group protected) in a suitable solvent, such as propionitrile, butanol or 1 ,4-dioxane, in the presence of TFA at elevated temperature (for example 50-200°C) using conventional or microwave heating.
  • a suitable solvent such as propionitrile, butanol or 1 ,4-dioxane
  • the compound of Formula (XIV) has an (iS)-stereocentre at the asymmetric carbon atom in the amino alcohol part of the molecule.
  • the optionally used protecting group incorporated into the compound of Formula (XIV) and/or Formula (XV) may be removed at any convenient point in the synthesis using standard deprotection conditions that are well known to the skilled person.
  • the compound of Formula (XIV) may be isolated as a salt.
  • Step (v) Compounds of Formula (XV) may be prepared by reacting a compound of Formula (XIV) with any standard reducing agent known to be capable of reducing an ester to the corresponding alcohol.
  • any standard reducing agent known to be capable of reducing an ester to the corresponding alcohol.
  • LiBH 4 may be used, in a suitable solvent mixture such as THF and methanol at a suitable temperature, for example 20-60°C.
  • the compound of Formula (XV) may be isolated as a salt.
  • Step (vi) Compounds of Formula (VIII) may be prepared by reacting a compound of Formula (XV) in the presence of a suitable oxidising agent such as Mn0 2 in a suitable solvent mixture such as THF and CH 2 C1 2 at a suitable temperature, for example 20-60°C.
  • a suitable oxidising agent such as Mn0 2
  • a suitable solvent mixture such as THF and CH 2 C1 2
  • the compounds of Formula (XIV- A) and (XV- A) are compounds of Formula (XIV) and (XV) respectively, as hereinbefore defined, wherein R 4 is either hydrogen or PG 1 -0-(CH 2 ) n -, as defined hereinbefore.
  • R 4 is either hydrogen or PG 1 -0-(CH 2 ) n - wherein n is 1 or 2, and wherein PG 1 is a tert-butyldimethylsilyl (TBDMS) protecting group; or a salt thereof.
  • Step (i) Compounds of Formula (XV- A) may be prepared from compounds of Formula (XIV- A) by reacting with a reducing agent that is known to the skilled person for its capability for reducing esters to alcohols, for example LiBH 4 , in a suitable solvent mixture such as THF and methanol, at a suitable temperature, for example 20-60°C
  • a reducing agent that is known to the skilled person for its capability for reducing esters to alcohols, for example LiBH 4
  • a suitable solvent mixture such as THF and methanol
  • LG 3 group in the compound of Formula (XVI) is a leaving group where suitable leaving groups are well known to the skilled person.
  • LG 3 may be chloro or bromo.
  • Compounds of Formula (XVI) may be prepared by reacting a compound of Formula (XV- A) with a hydrocarbyl sulfonyl bromide or chloride in the presence of LiBr or LiCl, for example CH 3 SO 2 CI with LiCl, in a suitable solvent such as THF at a suitable temperature, for example 20°C, followed by treatment with an acid such as HC1 in dioxane, a suitable solvent such as methanol at a suitable temperature, for example 20°C.
  • a suitable solvent such as THF at a suitable temperature, for example 20°C
  • an acid such as HC1 in dioxane
  • a suitable solvent such as methanol
  • Compounds of Formula (XVI) may be converted into a compound of Formula (II- A) by an alkylation reaction using the appropriate amine (FfNR ⁇ R 2 ) using alkylation conditions that are well known to the skilled person.
  • the alkylation may be achieved using a suitable base such as Na 2 C0 3 , in a suitable solvent, such as acetonitrile.
  • the compound of Formula (XVI) may be isolated as a salt.
  • a compound of Formula (XVI), as defined herein, or a salt thereof in one embodiment LG 3 is chloro.
  • the compound of Formula (XVI), when R 4 is other than hydrogen, has an (iS)-stereocentre at the carbon atom to which the R 4 group is attached.
  • the R 7 group in the compound of Formula (XXII) may take any of the values of R 7 described herein.
  • R 7 may be a 2,4,6-trimethylphenyl group.
  • the PG 3 group in the compounds of Formula (XXII) and Formula (XXVII) may be any suitable protecting group for an alcohol, for example a tri(Ci_ 4 alkyl)silyl protecting group, such as TBDMS.
  • TBDMS tri(Ci_ 4 alkyl)silyl protecting group
  • the R 4 group in the compound of Formula (XXVI) is other than hydrogen then the alcohol group within the R 4 group is protected by a benzyl-based protecting group PG 4 , for example with a benzyl group.
  • Step (x): Compounds of Formula (XXVII) may be prepared by reacting a compound of Formula (XXII) with an excess of a compound of Formula (XXVI) in a suitable solvent, such as propionitrile, butanol or 1,4-dioxane, in the presence of TFA at a suitable temperature, for example 50-150°C. Alternatively, the reaction may be performed in a microwave at a suitable temperature, for example 50-200°C.
  • a suitable solvent such as propionitrile, butanol or 1,4-dioxane
  • the reaction may be carried out using an acid such as hydrochloric acid or TFA, in a suitable solvent, such as 1,4-dioxane or MeOH at a suitable temperature, for example 0-50°C.
  • Step (xii): Compounds of Formula (XXIX) may be prepared by reacting a compound of Formula (XXVIII) with a hydrocarbyl sulfonyl chloride: R 7 S0 2 C1, for example mesyl chloride, trimethylbenzene sulfonyl chloride or triisopropylbenzenesulfonyl chloride, in a suitable solvent, such as CH 2 C1 2 or THF in the presence of a suitable base, such as metal carbonate base, or an organic base, such as tertiary amine base, for example, triethylamine, at a suitable temperature, for example 0-50°C.
  • a suitable solvent such as CH 2 C1 2 or THF
  • a suitable base such as metal carbonate base
  • organic base such as tertiary amine base, for example, triethylamine
  • reaction may be performed in a microwave at a suitable temperature, for example 50-200°C.
  • the reaction may be carried out with a catalyst such as Pd/C under H 2 atmosphere (1-20 bar) in a suitable solvent, such as MeOH at a suitable temperature, for example 20-100°C, optionally in the presence of an additive such as hydrochloric acid or acetic acid.
  • the compound of Formula (XXII) may be prepared as shown in Scheme 6.
  • Step (i): Compounds of Formula (XVII) may be prepared using an alkylation reaction, for example by reacting a compound of Formula (XVI) with (3-bromopropoxy)- tert-butyldimethylsilane in the case where PG 3 is TBDMS, in a suitable solvent, such as DMF in the presence of a suitable base, such as K 2 CO 3 at a suitable temperature, for example 0-50°C.
  • a suitable solvent such as DMF
  • a suitable base such as K 2 CO 3
  • Step (ii): Compounds of Formula (XVIII) may be prepared using any reducing agent that is known to be capable of reducing an aldehyde to the corresponding alcohol, for example by reacting a compound of Formula (XVII) with NaBH 4 in a suitable solvent, such as MeOH at a suitable temperature, for example 0°C to 50°C.
  • a suitable solvent such as MeOH
  • Step (iii): Compounds of Formula (XIX) may be prepared by reacting a compound of Formula (XVII) with a hydrocarbylsulfonyl chloride and a salt such as LiCl, in a suitable solvent, such as THF in the presence of a suitable base, such as DIPEA, at a suitable temperature, for example 0-50°C.
  • Step (iv): Compounds of Formula (XX) can be prepared by reaction of a compound of Formula (III-A), for example, methylacetoacetate, with a base, such as NaH, in a suitable solvent, such as THF or DMF, at a suitable temperature, for example 0-20°C, followed by addition of a compound of Formula (XIX). The reaction is then preferably heated, for example at 50-100°C, optionally in the presence of an additive such as KI.
  • a compound of Formula (III-A) for example, methylacetoacetate
  • a suitable solvent such as THF or DMF
  • Step (v): Compounds of Formula (XXI) may be prepared by reacting a compound of Formula (XX) with guanidine or guanidine carbonate in a suitable solvent, such as MeOH or EtOH, and at a suitable temperature, for example 50-150°C.
  • a suitable solvent such as MeOH or EtOH
  • Step (vi): Compounds of Formula (XXII) may be prepared by reacting a compound of Formula (XXI) with a suitable a hydrocarbyl sulfonyl chloride: R 7 S0 2 C1, for example trimethylbenzene sulfonyl chloride or triisopropylbenzenesulfonyl chloride.
  • the reaction may be carried out in a suitable solvent, such THF in the presence of a suitable base, such as, triethylamine or tetramethylpropylenediamine (TMPDA) at a suitable temperature, for example 0-50°C.
  • Step (vii): Compounds of Formula (XXIV) may be prepared by reacting a compound of Formula (XXIII) with di-fert-butyl dicarbonate. The reaction may be carried out in a suitable solvent, such methanol and water in the presence of a suitable base, such as, NaOH at a suitable temperature, for example 0-50°C.
  • a suitable solvent such methanol and water
  • a suitable base such as, NaOH
  • Step (viii): Compounds of Formula (XXV) may be prepared by reacting a compound of Formula (XXIV) with the appropriate benzyl bromide or chloride in a suitable solvent, such as DMF in the presence of a suitable base, such as DIPEA, at a suitable temperature, for example 0-50°C.
  • Step (ix) Compounds of Formula (XXVI) may be prepared by reacting a compound of Formula (XXV) with an acid such as hydrochloric acid or TFA in a suitable solvent, such as 1,4-dioxane or MeOH at a suitable temperature, for example 0-50°C.
  • an acid such as hydrochloric acid or TFA
  • a suitable solvent such as 1,4-dioxane or MeOH
  • Scheme 8 Step (i): Compounds of Formula (XXXIII) can be prepared by reaction of a compound of Formula (XXXII) with a base, such as NaH, in a suitable solvent, such as THF or DMF, at a suitable temperature, for example 0-20°C, followed by addition of a compound of Formula (III- A) wherein LG 4 represents a suitable leaving group, for example bromo or chloro. The reaction is then preferably heated, for example at 50-100°C, optionally in the presence of an additive such as KI.
  • a base such as NaH
  • a suitable solvent such as THF or DMF
  • Step (ii): Compounds of Formula (XXXIV) may be prepared by reacting a compound of Formula (XXXIII) with guanidine or guanidine carbonate in a suitable solvent, such as MeOH or EtOH, and at a suitable temperature, for example 50-150°C.
  • a suitable solvent such as MeOH or EtOH
  • Step (iii): Compounds of Formula (XXXV) may be prepared by reacting a compound of Formula (XXXIV) with a a hydrocarbyl sulfonyl chloride: R 7 S0 2 C1, for example trimethylbenzene sulfonyl chloride or triisopropylbenzenesulfonyl chloride.
  • the reaction may be carried out in a suitable solvent, such THF in the presence of a suitable base, such as, triethylamine or TMPDA or DABCO at a suitable temperature, for example 0-50°C.
  • Step (iv): Compounds of Formula (XXVI) may be prepared by reacting a compound of Formula (XXXV) with a suitable acrylamide such as N,N-dimethyl- acrylamide. The reaction may be carried out in a suitable base such as triethylamine in the presence of palladium (II) acetate and tri-ort/zo-tolylphosphine at a suitable temperature for example 70-80°C.
  • a suitable base such as triethylamine
  • palladium (II) acetate and tri-ort/zo-tolylphosphine at a suitable temperature for example 70-80°C.
  • Step (v): Compounds of Formula (XXXVII) may be prepared by treating a compound of Formula (XXXVI) with H 2 in the presence of palladium on carbon, in a suitable solvent such as ethanol or EtOAc.
  • Step (vi): Compounds of Formula (XXXVIII) may be prepared by reacting a compound of Formula (XXXVII) with an excess of the appropriate amine, in a suitable solvent, such as propionitrile, butanol, butyronitrile or 1,4-dioxane, in the presence of TFA at a suitable temperature, for example 50-150°C. Alternatively, the reaction may be performed in a microwave at a suitable temperature, for example 50-100°C.
  • a suitable solvent such as propionitrile, butanol, butyronitrile or 1,4-dioxane
  • Step (vii): Compound of Formula (VI V) may be prepared by reacting a compound of Formula (XXXVIII) with BH 3 -dimethyl sulphide complex in a suitable solvent such as THF at a suitable temperature, for example 60°C.
  • a suitable solvent such as THF
  • Compounds of Formula (II-B) may also be prepared as shown in Scheme 9.
  • Step (i): Compounds of a Formula (XLIII) may be prepared by reacting compounds of Formula (XLI) and (XLII) in a suitable solvent such as DMF in the presence of Pd-118 (1,1 -bis(di-tert-butylphosphino)-ferrocenepalladium(II) dichloride), tetrabutylammonium chloride, hydrate and N-cyclohexyl-N-methylcyclo-hexanamine at a sutiable temperature, for example 100°C.
  • LG 5 is a leaving group, for example a chloro or bromo.
  • PG 5 is a suitable protecting group, for example a benzyl-based protecting group, for example benzyl.
  • Step (ii): Compounds of Formula (XLIV) may be prepared by reacting a compound of Formula (XLIII) with guanidine or guanidine carbonate, in a suitable solvent, such as MeOH or EtOH, and at a suitable temperature, for example 50-150°C.
  • a suitable solvent such as MeOH or EtOH
  • Step (iii): Compounds of Formula (XLV) may be prepared by reacting a compound of Formula (XLIV) with POCI 3 , at a suitable temperature, for example 50-110°C.
  • Step (iv): Compounds of Formula (XL VI) may be prepared by reacting a compound of Formula (XLV) with an excess of the appropriate amine, in a suitable solvent, such as propionitrile ,butanol or 1,4-dioxane, in the presence of TFA at a suitable temperature, for example 50-150°C.
  • the reaction may be performed in a microwave at a suitable temperature, for example 50-200°C.
  • Step (v): -Compounds of Formula (XL VII) may be prepared by reacting a compound of Formula (XL VI) with a suitable protecting group.
  • PG 6 may be a tri(Ci_ 4 alkyl)silyl group, for example TBDMS or TMS.
  • PG 6 is a silicon based protecting group, it may be added using, for example TBDMSCl, or TMSCl, in the presence of a suitable base, for example imidazole, in a suitable solvent such as DMF.
  • Step (vii): Compounds of Formula (XLIX) may be prepared by reacting a compound of a Formula (XL VIII) with the appropriate amino alcohol, in a suitable solvent such as THF using Mitsunobu conditions, for example using diisopropyl azodicarboxylate and tripheny lphosphine .
  • Step (viii): Compounds of Formula (XXXI) may be prepared by using appropriate deprotection conditions known to be suitable for removing the PG 6 group.
  • deprotection conditions known to be suitable for removing the PG 6 group.
  • PG 6 were a silicon-based protecting group
  • the deprotection could involve reaction of a compound of Formula (XLIX) with a fluoride salt, for example tetra-n-butylammonium fluoride (TBAF), in a suitable solvent such as CH 2 C1 2 .
  • a deproection may be performed using SCX resin with a suitable solvent such as acetonitrile.
  • a pharmaceutical composition which comprises a compound of the Formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically- acceptable diluent or carrier.
  • the pharmaceutical composition may be used in the treatment of cancer.
  • the composition may be in a form suitable for oral administration, for example as a tablet or capsule; for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion; for topical administration as an ointment or cream; or for rectal administration as a
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof could also be administered as an air spray for inhalation.
  • the air spray e.g., spray, aerosol, dry powder preparation, etc.
  • a dry powder preparation may also be used.
  • An aerosol appropriate for inhalation may be either a suspension or solution, and would typically contain the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and any appropriate propellants such as a fluorocarbon or hydrogen-containing chlorofluorocarbon or a mixture thereof.
  • hydrofluoroalkane particularly 1 ,1 , 1 ,2-tetrafluoroethane, heptafluoroalkane (HFA) such as 1 ,1 , 1 ,2,3,3,3-heptafluoro-n-propane, or a mixture thereof.
  • HFA heptafluoroalkane
  • An aerosol may optionally contain an additional preparation excipient well-known to those skilled in the art such as surfactant (e.g., oleic acid or lecithin) and cosolvent (e.g., ethanol), etc.
  • surfactant e.g., oleic acid or lecithin
  • cosolvent e.g., ethanol
  • an aerosol preparation could be delivered using the inhaler known as
  • the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • an adjuvant or a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or
  • suspensions for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compound of Formula (I) will normally be administered to a warm-blooded animal at a unit dose within the range 5-5000 mg/m z body area of the animal, i.e.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • the daily dose will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly the optimum dosage may be determined by the practitioner who is treating any particular patient.
  • treatment is intended to have its normal everyday meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • prophylaxis is intended to have its normal everyday meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • the compounds defined in the present invention are effective activators of TLR7 in vitro. Accordingly, the compounds of the present invention are expected to be potentially useful agents in the treatment of diseases or medical conditions mediated alone or in part by TLR7. For example, the following diseases and conditions listed in paragraphs 1 to 8 below may be treatable with compounds of the present invention.
  • obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;
  • COPD chronic obstructive pulmonary disease
  • lung fibrosis including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus;
  • eyes blepharitis; conjunctivitis, including perennial and vernal allergic
  • nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);
  • allograft rejection acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;
  • thrombocytopaenic purpura eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome and Sazary syndrome;
  • oncology treatment of common cancers including bladder, head and neck, prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and
  • infectious diseases virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, parainfluenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.
  • virus diseases such as genital warts, common warts, plantar wart
  • the compound of Formula (I) will be administered to a mammal, more particularly a human being.
  • the compound of Formula (I) will be administered to a mammal, more particularly a human being.
  • said disease mediated through TLR7 is cancer.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • said disease mediated through TLR7 is asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease mediated through TLR7.
  • said disease mediated through TLR7 is cancer.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • said disease mediated through TLR7 is asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • a method of using a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof, for the treatment of cancer comprises administering to said animal an effective amount of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • a method of treating a human suffering from a disease in which activation of TLR7 is beneficial comprising the steps of administering to a person in need thereof of a therapeutically effective amount of a compound of Formula (I) as defined hereinbefore, or a
  • the disease in which activation of TLR7 is beneficial is cancer.
  • said cancer is selected from bladder cancer, head and neck cancer, prostate cancer, breast cancer, lung cancer, uterus cancer, pancreatic cancer, liver cancer, renal cancer, ovarian cancer, colon cancer, stomach cancer, skin cancer, cerebral tumor, malignant myeloma and lymphoproliferative tumors.
  • the disease in which activation of TLR7 is beneficial is asthma, COPD, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, hepatitis B, hepatitis C, HIV, HPV, bacterial infections or dermatosis.
  • the cancer may be bladder cancer.
  • the cancer may be prostate cancer.
  • the cancer may be breast cancer.
  • the cancer may be lung cancer.
  • the cancer may be uterus cancer.
  • the cancer may be pancreatic cancer.
  • the cancer may be liver cancer.
  • the cancer may be renal cancer.
  • the cancer may be ovarian cancer.
  • the cancer may be colon cancer.
  • the cancer may be stomach cancer. In any aspect or embodiment described herein the cancer may be skin cancer.
  • the cancer may be cerebral tumor.
  • the cancer may be malignant myeloma cancer.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents :-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, miriplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, amrubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkal
  • epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -yl)ethoxy] -5 -tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341), N-(2- chloro-6-methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-l-yl]-2-methylpyrimidin-4- ylamino ⁇ thiazole-5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7- [2-(4-methylpiperazin- 1 -yl)ethoxy] -5 -
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbBl antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, ppl 1-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
  • N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3- morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signal
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3- pyrrolidin-l-ylpropoxy)quinazoline (AZD2171; Example 240 within WO 00/47212), compounds such as those disclosed in International Patent Applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and compounds that work by other
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669,
  • an endothelin receptor antagonist for example zibotentan (ZD4054) or atrasentan;
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
  • (ix) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
  • GDEPT gene-directed enzyme pro-drug therapy
  • (x) immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as inter leukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine -transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies, approaches to decrease the function of immune suppressive cells such as regulatory T cells, myeloid-derived suppressor cells or IDO (indoleamine 2,3,-deoxygenase)-expressing dendritic cells, and approaches using cancer vaccines consisting of proteins or peptides derived from tumour-associated antigens such as NY-ESO-1, MAGE-3, WT1 or Her2/neu.
  • cytokines such as inter leukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
  • a pharmaceutical product comprising a compound of the Formula (I) as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer.
  • a pharmaceutical product comprising a compound of the Formula (I) as defined hereinbefore and an additional anti-tumour substance for the conjoint treatment of cancer.
  • a combination suitable for use in the treatment of cancer comprising a compound of Formula (I) as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and any one of the anti tumour agents listed under (i) - (ix) above.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above, in association with a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above, in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • a compound of the Formula (I), or a pharmaceutically acceptable salt thereof in combination with an anti- tumour agent selected from one listed under (i) - (ix) herein above for use in the treatment of cancer in a warm-blooded animal, such as man.
  • a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above.
  • kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent selected from one listed under (i) - (ix) herein above.
  • a kit comprising:
  • an anti-tumour agent selected from one listed under (i) - (ix) herein above; in a second unit dosage form;
  • kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with an additional anti-tumour agent.
  • a kit comprising:
  • the compounds of Formula (I) may be useful as vaccine adjuvants.
  • the invention still further provides a method of treating, or reducing the risk of, a disease or condition, which method comprises administering to a patient in need thereof a therapeutically effective amount of a vaccine and a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • the invention still further provides a method of increasing the response to a vaccine in a patient, which method comprises administering to a patient in need thereof a therapeutically effective amount of a vaccine and a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein.
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • FCC flash column chromatography using silica
  • TFA TFA
  • DIPEA diisopropylethylamine
  • DMSO dimethylsulfoxide
  • aq aqueous
  • eq. molar equivalents
  • RT room temperature
  • LC-MS liquid chromatography with mass spectrometry
  • m/z measured mass to charge ratio
  • SCX refers to solid phase extraction with a sulfonic acid sorbent
  • M molar.
  • Proton nuclear magnetic resonance data (“ 1 H NMR”) was generally obtained at 300-500 MHz and using deuterated DMSO unless otherwise stated.
  • Example 1A 2-[(2-Amino-4- ⁇ [(3S -l-hvdroxyhexan-3-yllamino ⁇ -6-methylpyrimidin- 5-yl)methyll-5- ⁇ [(2-hvdroxyethyl)(methyl)aminolmethyl ⁇ phenol bis saccharin salt
  • the title compound may be prepared by the steps described below:
  • Butylamine (1.26 g; 5eq) was reacted using the general method described for step (iv) of Example 1, and with heating for 3h. Purification by FCC, eluting with 0-20% CH 3 OH (and 0.7M NH 3 ) in CH 2 C1 2 gave the sub-title compound (0.7 g) as an oil; LC-MS: m/z 326 APCI+.
  • Example 3 2- ⁇ [2- Amino-4-(butylamino)-6-methylpyrimidin-5-yll methyl ⁇ -5- ⁇ (4- methylpiperazin-l-vDmethyllphenol
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • the crude material was dissolved in CH 3 OH (25 mL), acidified with acetic acid (1 mL) and loaded on to a 50g SCX cartridge. The impurities were washed through with CH 3 OH (125 mL) and discarded. The product was eluted with 1M NH 3 /CH 3 OH (250 mL) and concentrated in vacuo. The product was purified by FCC, eluting with 10% CH 3 OH in EtOAc to give the subtitle compound (1 g) as a yellow gum; LC-MS: m/z 370 APCI+.
  • the title compound may be prepared by the steps described below:
  • Example 8 2-[(2-Amino-4- ⁇ [(2S -l-hvdroxypentan-2-yllamino ⁇ -6-methylpyrimidin-5- vDmethyll -5- [(dimethylamino)methyll phenol
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • PBr 3 (0.95 mL) was added drop-wise to a vigorously stirred solution of (4-bromo-2- methoxyphenyl)methanol (4.4 g) in CH 2 CI 2 (100 mL) at 0°C. After 40 mins the mixture was slowly quenched with ice/water and the organic solution was separated and the aqueous phase was extracted with CH 2 CI 2 . The organic solutions were combined, washed with water, dried (MgS0 4 ), and concentrated in vacuo to give the sub-title compound (5.2 g); 1H NMR: 7.19 (d, 1H), 7.07 (dd, 1H), 7.01 (d, 1H), 4.49 (s, 2H), 3.89 (s, 3H).
  • the title compound may be prepared by the steps described below:
  • Example 12 2-[(2-Amino-4- ⁇ [(3S -l-hvdroxyhexan-3-yllamino ⁇ -6-methylpyrimidin- 5-vDmethyll -5- [3-(dimethylamino)propoxyl phenol
  • the title compound may be prepared by the steps described below:
  • Methanesulfonyl chloride (4.02 mL) was added to a mixture of ⁇ 4-[3-(tert- butyldimethylsilyloxy)-propoxy]-2-methoxyphenyl ⁇ methanol (8.47 g), DIPEA (13.4 mL) and LiCl (3.29 g) in THF (105 mL) at RT. The mixture was then stirred for 40 mins and then diluted with water and brine.
  • Example 13 2-[(2-Amino-4- ⁇ [(3S -l-hvdroxyhexan-3-yllamino ⁇ -6-methylpyrimidin- 5-vDmethyll -5- ⁇ r(2-methoxyethyl)(methyl)aminol methyljphenol
  • the title compound may be prepared by the steps described below:
  • the title compound may be prepared by the steps described below:
  • Methyl 2-[4-(benzyloxy)-2-methoxybenzyl]-3-oxobutanoate (870 mg) was dissolved in CH 3 OH (14 mL) and guanidine hemicarbonate (687 mg) was added. The mixture was then heated to 60°C for 5h and allowed to cool to RT. The mixture was then filtered and washed with diethyl ether and water. The filtrate was concentrated in vacuo and more diethyl ether and water added.
  • Imidazole (94 mg) was added to a solution of (35)-3-( ⁇ 2-amino-5-[4-(benzyloxy)-2- methoxybenzyl]-6-methylpyrimidin-4-yl ⁇ amino)-hexan-l-ol (310 mg) and tert-butyl- dimethylsilyl chloride (207 mg) in DMF (2.5 mL) under an atmosphere of N 2 , and the mixture was stirred 24h. Further tert-butyldimethylsilyl chloride (104 mg) and imidazole (47 mg) were then added and the mixture was stirred for a further 3h.
  • Diisopropyl azodicarboxylate (117 ⁇ ) was added to 4-[(2-amino-4- ⁇ [(35)-l- ⁇ [tert- butyl(dimethyl)silyl]oxy ⁇ hexan-3-yl]amino ⁇ -6-methyl-pyrimidin-5-yl)methyl]-3- methoxyphenol (94 mg), 2-(dimethylamino)ethanol (99 ⁇ ) and triphenylphosphine (156 mg) in THF (2 mL) under N 2 at 0°C.
  • Recombinant human TLR7 was stably expressed in a HEK293 cell line already stably expressing the pNiFty2-SEAP reporter plasmid; integration of the reporter gene was maintained by selection with the antibiotic zeocin.
  • the most common variant sequence of human TLR7 (represented by the EMBL sequence AF240467) was cloned into the mammalian cell expression vector pUNO and transfected into this reporter cell-line.
  • Transfectants with stable expression were selected using the antibiotic blasticidin.
  • expression of secreted alkaline phosphatase (SEAP) is controlled by an NFkB/ELAM-1 composite promoter comprising five NFkB sites combined with the proximal ELAM-1 promoter.
  • TLR signaling leads to the translocation of NFkB and activation of the promoter results in expression of the SEAP gene.
  • TLR7-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37°C with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • TLR7 activity for compounds of the present invention was assessed using the human TLR7 assay and the results are shown in Table 1 below wherein the degree of TLR7 activation for each compound is expressed as a pEC 5 o value.
  • HEK293-hTLR8 cells stably transfected with human TLR8 (pUNO expression vector) and pNiFty2-SEAP (Secretory Alkaline Phosphatase) reporter plasmid were maintained in DMEM, FCS 10% (v/v), 2 mM /-glutamine, non-essential amino acids, 10 ⁇ g/mL blasticidin S and 10 ⁇ g/mL zeocin.
  • the human TLR8 sequence used was identical to GenBank sequence AAZ95441.1. Cells were seeded in tissue culture treated clear flat bottom polystyrene 96 well plates at 2> ⁇ 10 4 cells/well.
  • Dose response curves were generated by addition of test compounds and incubated for 20h at 37°C in an atmosphere of 5% C0 2 .
  • the SEAP released was quantified using /?-nitrophenyl phosphate as a substrate and the absorbance at 405 nm was determined by a microplate reader.
  • TLR8/NF-kB/SEAPorterTM HEK 293 Cell Line (Imgenex Corporation) is a stably co- transfected cell line which expresses full-length human TLR8 and the secreted alkaline phosphatase (SEAP) reporter gene under the transcriptional control of an NF- ⁇ response element. TLR8 expression in this cell line has been tested by flow cytometry. Transfectants with stable expression were selected using the antibiotic blasticidin and geneticin. TLR signaling leads to the translocation of NF- ⁇ and activation of the promoter results in expression of the SEAP gene. TLR8-specific activation was assessed by determining the level of SEAP produced following overnight incubation of the cells at 37°C with the standard compound in the presence of 0.1% (v/v) dimethylsulfoxide (DMSO).
  • DMSO dimethylsulfoxide
  • Concentration dependent induction of SEAP production by compounds was expressed as the concentration of compound which produced half of the maximal level of SEAP induction for that compound (EC 50 ).
  • TLR8 activity for compounds of the present invention was assessed using the human TLR8 assay and the results are shown in Table 2 below wherein the degree of TLR8 activation for each compound is expressed as a pEC 5 o value.
  • the hERG potassium current is measured in a hERG-stably-expressing Chinese hamster ovary Kl (CHO) cells.
  • the experiments were performed using an automated planar patch-clamp system QPatch HT (Sophion Bioscience A/S).
  • QPatch HT Sophion Bioscience A/S
  • the application of pressure for forming gigaseals and whole-cell patch clamp configuration were established using the QPatch assay software. Patch-clamp experiments were performed in voltage-clamp mode and whole-cell currents were recorded from individual cells. The following stimulation protocol was applied to investigate the effects of compounds on hERG potassium channel.
  • the membrane potential was held at -80 mV and repetitively (every 15 s) depolarized to +20 mV for 5 s after the pulse to -50 mV for 20 ms served to define the baseline, followed by repolarizing step to -50 mV for 5 s to evaluate of the tail current amplitude.
  • Experiments were conducted at room temperature (22 ⁇ 2°C).
  • the test solution includes:
  • Extracellular solution 2mM of CaCl 2 , lmM of MgCl 2 , lOmM of HEPES, 4mM of KC1, 145 mM of NaCl, and lOmM of glucose; and
  • Intracellular solution 5.4mM of CaCl 2 , 1.8mM of MgCl 2 , lOmM of HEPES, 31mM of KOH, lOmM of EGTA, 120mM of KC1, and 4mM of ATP.
  • the hERG-expressing Chinese hamster ovary Kl (CHO) cells described by (Persson, Carlsson, Duker, & Jacobson, 2005) are grown to semi-confluence at 37°C in a humidified environment (5% C0 2 ) in F-12 Ham medium containing L-glutamine, 10% foetal calf serum (FCS) and 0.6mg/mL hygromycin (all available from Sigma-Aldrich). Prior to use, the monolayer is washed using a pre-warmed (37°C) 3mL aliquot of Versene 1 :5,000 (Invitrogen).
  • CHO-Kvl .5 cells which are used to adjust the voltage offset on Ion WorksTM HT, are maintained and prepared for use in the same way.
  • PatchPlate TM in which a recording is attempted in each well by using suction to position and hold a cell on a small hole separating two isolated fluid chambers. Once sealing has taken place, the solution on the underside of the PatchPlate TM is changed to one containing amphotericin B. This permeablises the patch of cell membrane covering the hole in each well and, in effect, allows a perforated, whole-cell patch clamp recording to be made.
  • a ⁇ -test Ion WorksTM HT from Essen Instrument was used. There is no capability to warm solutions in this device hence it is operated at ⁇ r.t. ( ⁇ 21°C), as follows.
  • the reservoir in the "Buffer” position is loaded with 4 mL of PBS and that in the "Cells” position with the CHO-hERG cell suspension described above.
  • a 96-well plate (V-bottom, Greiner Bio-one) containing the compounds to be tested (at 3 -fold above their final test concentration) is placed in the "Plate 1" position and a PatchPlateTM is clamped into the PatchPlateTM station.
  • Each compound plate is laid-out in 12 columns to enable ten, 8-point
  • concentration-effect curves to be constructed the remaining two columns on the plate are taken up with vehicle (final concentration 0.33% DMSO), to define the assay baseline, and a supra-maximal blocking concentration of cisapride (final concentration 10 ⁇ ) to define the 100% inhibition level.
  • the fluidics-head (F-Head) of IonWorksTM HT then adds 3.5 ⁇ of PBS to each well of the PatchPlateTM and its underside is perfused with "internal" solution that had the following composition (in mM): K-Gluconate (100 parts), KC1 (40 parts), MgCl 2 (3.2 parts), EGTA ( 3 parts) and HEPES (5 parts, pH 7.25-7.30 using 10M KOH).
  • the electronics-head After priming and de-bubbling, the electronics-head (E-head) then moves round the PatchPlateTM performing a hole test (i.e. applying a voltage pulse to determine whether the hole in each well is open).
  • the F-head then dispenses 3.5 ⁇ of the cell suspension described above into each well of the PatchPlateTM and the cells are given 200 seconds to reach and seal to the hole in each well.
  • the E-head moves round the PatchPlateTM to determine the seal resistance obtained in each well.
  • the solution on the underside of the PatchPlateTM is changed to "access" solution that has the following composition (in mM): KC1 (140 parts), EGTA (1 part), MgCl 2 (1 part) and HEPES (20 parts, pH 7.25-7.30 using 10M KOH) plus 100 ⁇ g/mL of amphotericin B (Sigma- Aldrich).
  • KC1 140 parts
  • EGTA 1 part
  • MgCl 2 MgCl 2
  • HEPES 20 parts, pH 7.25-7.30 using 10M KOH
  • 100 ⁇ g/mL of amphotericin B Sigma- Aldrich
  • the E-head moves round the PatchPlateTM 48 wells at a time to obtain pre-compound hERG current measurements.
  • the F-head then adds 3.5 ⁇ of solution from each well of the compound plate to 4 wells on the PatchPlateTM (the final DMSO concentration is 0.33% in every well).
  • the pre- and post-compound hERG current is evoked by a single voltage pulse consisting of a 20 second period holding at -70mV, a 160millisecond step to -60mV (to obtain an estimate of leak), a lOOmillisecond step back to -70mV, a 1 second step to + 40mV, a 2 second step to -30mV and finally a 500 millisecond step to -70mV.
  • a single voltage pulse consisting of a 20 second period holding at -70mV, a 160millisecond step to -60mV (to obtain an estimate of leak), a lOOmillisecond step back to -70mV, a 1 second step to + 40mV, a 2 second step to -30mV and finally a 500 millisecond step to -70mV.
  • Currents are leak- subtracted based on the estimate of current evoked during the +10mV step at the start of the voltage pulse protocol. Any voltage offsets in Ion WorksTM
  • a depolarising voltage ramp is applied to CHO-Kvl .5 cells and the voltage noted at which there was an inflection point in the current trace (i.e. the point at which channel activation is seen with a ramp protocol).
  • the voltage at which this occurred has previously been determined using the same voltage command in conventional electrophysiology and found to be -15mV (data not shown); thus an offset potential could be entered into the Ion WorksTM HT software using this value as a reference point.
  • any offset is adjusted by determining the hERG tail current reversal potential in
  • Ion WorksTM HT comparing it with that found in conventional electrophysiology (-82m V) and then making the necessary offset adjustment in the Ion WorksTM HT software.
  • the current signal is sampled at 2.5kHz.
  • Pre- and post-scan hERG current magnitude was measured automatically from the leak subtracted traces by the Ion WorksTM HT software by taking a 40ms average of the current during the initial holding period at -70 mV (baseline current) and subtracting this from the peak of the tail current response.
  • the acceptance criteria for the currents evoked in each well are: pre-scan seal resistance >60 ⁇ , pre-scan hERG tail current amplitude >150pA; post-scan seal resistance >60 ⁇ .
  • the degree of inhibition of the hERG current can be assessed by dividing the post-scan hERG current by the respective pre-scan hERG current for each well. References: Persson, F. et al, J Cardiovasc.ElectrophysioL, 16, 329-341 (2005), and Schroeder, K., et al, J Biomol Screen., 8, 50-64, (2003).

Abstract

L'invention concerne des composés de Formule (I) : où R1, R2, R3 et Q sont tels que définis dans la description. La présente invention concerne également des procédés de préparation de tels composés, de nouveaux intermédiaires utiles dans la préparation de tels composés, des compositions pharmaceutiques les contenant et leur utilisation en tant qu'agonistes du récepteur 7 de type toll.
PCT/GB2011/052245 2010-11-19 2011-11-17 Composés phénol en tant qu'agonistes du récepteur 7 de type toll WO2012066335A1 (fr)

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